Preface
The very essence of cardiovascular medicine is the recognition of early heart failure.
Sir Thomas Lewis 1933
Heart failure (HF) is emerging as an important public health problem in India. With
the dual burden of traditional diseases like rheumatic heart diseases and the rising
burden of new-age diseases like coronary artery disease, the burden of HF in India,
is likely to be enormous. Also the varying geographic and ethnic diversity poses a
great challenge to the management of HF in our country.
Since our resources are limited and the vast majority of the population spend out-of-pocket
for treatment, it is an important responsibility of the cardiologists and all concerned
stakeholders to provide the best available therapeutic options in an affordable manner,
based on the latest available medical knowledge and practice.
It is in this context that Cardiological Society of India (CSI) decided to bring together
a group of experts in HF in India, to develop and publish the ‘Position Statement
on management of HF in India’. The purpose of this statement is to provide a single
document for the whole country which provides the latest available data both from
India and the rest of the world. We also have tried to gather data on conditions specific
and relevant to the Indian context like rheumatic heart disease, aortoarteritis and
endomyocardial fibrosis.
This position statement is recommendatory in nature and carries no statutory status.
1
Preamble, epidemiology and evaluation
1.1
Preamble
Heart failure (HF) affects about 26 million people worldwide
1
and its management poses significant strain on healthcare resources of a country.
Ageing population, increasing prevalence of cardiac risk factors and improved survival
of patients with acute cardiovascular diseases have resulted in HF becoming a major
public health problem, across the world. Improving awareness about the condition,
lifestyle modification, early detection, treatment and monitoring are necessary to
keep this public health menace in check. A number of guidelines, mostly Western, are
available for management of patients with this condition but their uniform implementation
may be difficult across all countries because of differences in infrastructure and
local practices. Therefore, there is a need for region specific and country-specific
guidelines which could more appropriately address such issues.
1.1.1
Magnitude of the problem
There is paucity of data on heart failure burden in India because of the absence of
disease surveillance systems in India. HF is not an exception. We have indicators
to assume that the incidence and prevalence rates of heart failure are rising due
to epidemiological and health transitions. Huffman and Prabhakar in their projections,
based on disease-specific estimates projected that a conservative estimate of the
prevalence of heart failure in India due to coronary heart disease, hypertension,
obesity, diabetes and rheumatic heart disease is in the range from 1.3 to 4.6 million,
with an annual incidence of 0.4–1.8 million.
2
Patients with heart failure are younger than in the high income countries, with a
mean average age of around 60 years at presentation. They also have a high in-hospital
mortality and one year mortality, which are significantly higher than that in the
high income countries.
3
1.1.2
Challenges of management of heart failure in India
The challenge is to make quality healthcare services accessible and affordable to
a socioeconomically and linguistically diverse population of more than 1.3 billion
4
spread over 3.287 million km2, with inadequate infrastructure to deliver services
and lack of strict quality control measures. At the 2001 census, 72% of the population
lives in villages which are poorly accessible by roads, making delivery of healthcare
difficult. Only basic health care facilities are available at most of the primary
health centres, which are often understaffed and their services overstretched. Most
of the tertiary healthcare resources are concentrated in the large cities and that
too mostly in the big Metropolis. This inequality in healthcare distribution is a
major impediment for implementation of universal health care in India.
Government of India has cleared the National Health Policy 2017, which promises to
increase public health spending to 2.5% of GDP.
5
This is still lower than the government spending in countries such as UK (7.9%), US
(8.2%) and Japan (9.6%).
6
Private health care runs parallel with government funded health service, but is expensive
and therefore affordability is an issue. As high as 86% of rural population and 82%
of urban population are not covered under any insurance scheme whether public or private,
to support health expenditure.
7
A study on microeconomics of cardiovascular disease (CVD) in India showed that 79%
people have to resort to “distress financing” forcing them to borrow or sell assets
when faced with an acute episode of acute coronary syndrome (ACS) or stroke.
8
In such circumstances, healthcare rationing becomes inevitable. In the private sector,
where services come at a premium, it is solely based on the affordability of the patient
while in the public sector, which is meant for the masses, it depends on the budgetary
allocation for health. We realize that there is a need to move from the ‘ability to
pay’ based rationing to ‘need based rationing’. Therefore, whilst issuing a position
statement, recommendations for the more expensive treatments need to be judged against
the strength of their indications.
One of the striking features of India’s health care sector is the variation in range
of quality in available services. Apart from infrastructural constraints, low level
of provider’s knowledge, large gaps between providers’ knowledge and the care provided,
and poor governance in the healthcare system could be the reasons for poor quality
of services.
9
Efforts to improve the quality of care are particularly challenged by the lack of
reliable data on quality and by technical difficulties in measuring quality.
10
Moreover, the low overall literacy level (72%) limits awareness and resists adoption
of changes.
11
1.1.3
The need for a position statement
There are many reasons why region specific guidelines in the management of heart failure
are necessary. Most of the western guidelines that we follow have been validated for
Caucasians. Unfortunately we do not have the wealth of data to confirm the applicability
of these guidelines to Indians. Where the strength of evidence is high, the class
of indication is unlikely to vary to suit the economic constraints. On the other hand,
where the evidence is relatively weak, the cost-effectiveness need to be considered
in resource constrained settings. Device therapy in heart failure in the Indian context
is a perfect example.
1.1.4
Objective
An expert committee was constituted by Cardiological Society of India (CSI) for formulating
the position statement on heart failure. The objective was to provide a consensus
statement on heart failure management that could be applied across the country and
offer practical suggestions to the problems specific to the country.
1.1.5
Limitations
Lack of adequate data on heart failure in India, remains the main limitation of developing
specific guidelines. Moreover, the purpose of this position statement is recommendatory
in nature and carries no statutory status.
1.2
Epidemiology of heart failure (HF)
Heart Failure (HF) is one of the leading cause of hospitalization in the High Income
Countries (HIC), representing 1% to 2% of the total hospital admissions.
1
HF is a disease associated with significant mortality, which is higher than many common
cancers like breast or colon. It is also associated with high morbidity, and accounts
for a significant share in the healthcare expenditures in the developed world.
11
Though we have good data on the epidemiology of HF from the HIC, data from the low
and middle income countries (LMIC) is very limited and most of them are projections
based on western data or based on risk factor levels.2, 12, 13
The 2017 Heart Disease and Stroke update
14
reports that 6.1 million Americans ≥20 years of age have HF based on the NHANES data.
15
Projected figures estimate that the prevalence of HF in US will increase by 46% from
2012 to 2030 and the estimated medical costs related to HF will increase almost by
127% to $69.7 billion in 2030.
15
Some hospital based data on HF has recently emerged from India,3, 16, but there is
no significant data on the HF burden in the community. A preliminary estimate on the
community-level prevalence of HF in the adult population in India is about 1%.
12
We have certain projections and estimates on HF from India and South Asia.2, 17 Based
on these estimates (where US prevalence data is extrapolated to Indian population),
the prevalence of HF in India is estimated to be 22.7 million.
17
When we try to project the burden of HF in India, we have to give consideration to
the presence of risk factors of HF. Prevalence of HF is likely to be proportionate
to the risk factor levels in the society. India is said to be having the “double burden”.
On one side there is rise in prevalence of conditions like hypertension, diabetes,
and coronary artery disease and on the other side, there is persistence of “traditional
” like rheumatic heart disease.
17
There are also specific conditions which are unique to India, like aortoarterits,
endomyocardial fibrosis, untreated congenital heart disease, high prevalence of chronic
obstructive pulmonary disease (COPD) due to high biomass fuel use which can contribute
to the burden of HF.
1.2.1
HF burden − how India is different?
The age at presentation with HF is dependent upon the level of epidemiological transition
of that country. In the Trivandrum Heart Failure Registry (THFR) from India,
16
the patients with HF were 10 years younger (mean age 61 years) compared to their western
counterparts. In the INTER-CHF study, the mean age among Indians were 56 years, while
the patients from sub-Saharan Africa were even younger at 53 years.
18
By contrast, the mean age at presentation was 72 years in USA
19
and the European data – the mean age was 70 years.
20
The Kerala ACS registry also showed the presentation of ACS was at a younger age in
India.
21
The age distribution of the patients presenting with HF is also different. (Fig. 1)
This data indicates that the burden of HF is in the younger population at productive
ages in India. The gender ratio is also different in India compared to US and Africa.
Male to female ratio is almost equal proportions in US and Africa, while in India
this ratio is 70:30.
16
Fig. 1
Difference in the age distribution of patients with HF from India versus United States3,
19.
Fig. 1
The etiology of HF in India is also different from the west. The INTERCHF data shows
that CAD is the most common etiology of HF in Asia (48%), while in the Trivandrum
Registry IHD accounted for 71%. Table 1 shows the various etiologies in patients from
the Trivandrum registry and the INTER-CHF registry.
18
RHD accounts for 8–10% of the burden in India, but it is not a significant problem
in the west.
19
Table 1
Differences in etiology of Heart failure among large studies form Asia (INTERCHF)
and India (Trivandrum HF registry).
Table 1
ASIA(INTERCHF)
18
Trivandrum Registry
16
ISCHEMIC
48
71
HYPERTENSIVE
14.1
2
DCM
11
15
Rheumatic HD
10
8
ENDOCRINE/METABOLIC
5
VALVULAR −NONRHEUMATIC
3
2.5
Idiopathic/hypertrophic
2
CHD
1
1.3
Peripartum Cardiomyopathy
0.25
Right heart failure
1.5
Notes: DCM- dilated cardiomyopathy, RHD- rheumatic heart disease, CHD- Congenital
heart disease.
The risk factor prevalence in patients with HF is also different from the west. Type
2 Diabetes(T2DM) is much more prevalent among Indians than westerners as per the Trivandrum
Registry.
3
The prognosis of HF in Indians is worse than the Western population. The in-hospital
mortality of 8.4% in THFR is much higher than 4% in the ADHERE registry of USA. But
the thirty-day mortality is similar at 30% in both US and Indian populations. The
Inter CHF study shows that the one year mortality of in-patients with HF is much higher
in India and Africa, about 37% and 60% respectively.
22
Coming to the management of HF, an important issue is the level of evidence based
care. In the Trivandrum registry, it was found that only 25% of the population received
guideline directed medical therapy – GDMT (i.e. a combination of BB + ACEI + Aldosterone
blockers in HF r EF), and those who did not receive GDMT had higher mortality. This
points towards need for quality improvement programs. Fig. 2 summarizes the salient
features of HF epidemiology in India.
Fig. 2
Heart failure Epidemiology – How India is different?.
Fig. 2
1.3
Heart failure − definition and types
Heart failure (HF) is a term easily understood, but is difficult to define. Numerous
definitions of HF are proposed with only a few definitions having widespread acceptance.
23
One of the classical definitions says “HF is a pathophysiological state in which an
abnormality of cardiac function is responsible for the failure of the heart to pump
blood at a rate commensurate with the requirements of the metabolizing tissues or
does so only at elevated filling pressures”.
24
The American College of Cardiology (ACC)/American Heart Association (AHA) guidelines
25
define “HF as a complex clinical syndrome that results from any structural or functional
impairment of ventricular filling or ejection of blood”. The ESC guidelines
26
define HF as “a clinical syndrome characterized by typical symptoms (e.g. breathlessness,
ankle swelling and fatigue) that may be accompanied by signs (e.g. elevated jugular
venous pressure, pulmonary crackles and peripheral oedema) caused by a structural
and/or functional cardiac abnormality, resulting in a reduced cardiac output and/or
elevated intra cardiac pressures at rest or during stress”. A more detailed analysis
of various definitions of HF may be found elsewhere.
23
1.3.1
Stages of HF
All the current definitions of HF are restricted to manifest stages with apparent
clinical symptoms and signs. However, vast majority of patients have asymptomatic
structural or functional cardiac abnormalities like left ventricular (LV) hypertrophy,
LV systolic or diastolic dysfunction, and valve diseases which are well known precursors
of HF. It is important to recognize and treat them as established HF has poor prognosis.
So, control of these HF precursor conditions may prevent or delay progression to overt
HF. In recognition of the importance of the predisposing conditions in the causation
of HF, the ACC/AHA
25
recognizes 4 stages of HF (Table 2). Stage C & D are the clinically recognizable forms,
while stage A & B are the pre-HF forms. HF may be further classified by underlying
etiology, ejection fraction, time course and severity.
Table 2
ACC/AHA Stages of HF.
Table 2
Stages
Definitions
Examples
Stage A
At high risk for HF but without structural heart disease or symptoms of HF
Risk factors for HF like hypertension
Stage B
Structural heart disease but without signs or symptoms of HF
LV dysfunction, LV hypertrophy
Stage C
Structural heart disease with prior or current symptoms of HF
Most forms of chronic HF
Stage D
Refractory HF requiring specialized interventions
Advanced/end stage HF
1.3.2
Types of heart failure
1.3.2.1
Underlying etiology
A critical component of HF diagnosis is defining the aetiology for HF. Most commonly,
LV systolic and/or diastolic dysfunction is the frequent cause of HF across the world.
In India, RHD remain one of the common causes of HF.
27
Additionally, pericardial, endocardial, heart rhythm and conduction abnormalities,
structural heart defects, and metabolic and systemic conditions may also cause HF.
More than one aetiology may contribute to the development and progression of HF in
some cases.
1.3.2.2
Heart failure with preserved,mid-range and reduced ejection fraction (Table 3)
LVEF remains central to the characterization of HF, despite the shortcomings. Traditionally,
HF is classified as HF with reduced EF (HFrEF) and HF with preserved EF (HFpEF). HFrEF
is typically defined as LVEF <40% and HFpEF typically considered as LVEF ≥50%. This
distinction is very important as both these forms have different underlying etiologies,
risk profiles, demographics, and co-morbidities .
Table 3
Definitions for Heart failure with preserved, mid-range and reduced EF.
26
Table 3
HFrEF (HF with reduced EF)
LVEF ≤ 40%
HFpEF (HF with preserved EF)
LVEF ≥ 50%
HFmrEF (HF with mid-range EF)
LVEF 41–49%
The recent ESC guidelines
26
realize that patients of HF with LVEF in the range of 40–49% represent a ‘grey area’,
and have introduced a new term ‘HF with midrange EF (HFmrEF)’. Patients with HFmrEF
are likely to have mild systolic dysfunction with variable amount diastolic dysfunction.
In some of the HFrEF patients, the LVEF may improve with treatment or spontaneously
and may be in HFmrEF or HFpEF. However, their prognosis and outcomes may be different.
Hence, ACC guidelines categories these patients into HFrEF ‘improved’.
HFrEF is easier to diagnose and manage with evidence based guidelines as compared
to HFpEF. Most often patients with HFpEF have normal sized LV with EF > 50%, but with
an increased LV wall thickness and/or increased left atrial (LA) size on echocardiography
along with an evidence of impaired LV filling, hence was referred as diastolic HF.
Earlier classification of HF as systolic HF and diastolic HF was simple, but was realised
to be less accurate. Most patients with systolic HF also have measurable abnormalities
of diastolic function and most patients with diastolic HF also have subtle abnormalities
of systolic function using advanced methods of LV systolic function assessment. Moreover,
not all patients of HFpEF have measurable abnormalities of diastolic function on echocardiography.
Hence, the terms HFrEF and HFpEF are preferred over systolic and diastolic HF.
1.3.2.3
Terminology related to the time course of heart failure
Chronic HF and acute decompensated HF (ADHF) are the two most well recognized forms
of HF with distinctly varying mortality, morbidity and outcomes. Most of the patients
have chronic HF with an insidious onset of symptoms/signs. Acute decompensated HF
is the preferred term for patients presenting acutely with HF, which can be defined
as ‘the sudden or gradual onset of the signs or symptoms of heart failure requiring
unplanned office visits, emergency room visits, or hospitalization’.
28
It may be due to a de novo acute onset HF or due to decompensation in a patient with
chronic stable HF.
A de novo ADHF may present with an acute or subacute onset. Some conditions like myocardial
infarction, myocarditis and acute infective endocarditis are associated with an acute
HF with onset within minutes to hours. Dilated cardiomyopathy, infective endocarditis
and acute rheumatic fever are classical examples of HF with subacute onset within
days to a few weeks. Some of these conditions may resolve completely with or without
specific therapy. However, a significant proportion of patients end up having chronic
forms of HF. Any worsening of HF in a patient with chronic stable HF also leads to
ADHF. Such decompensation of chronic HF is the most common cause of ADHF leading to
hospitalization and increased mortality.
28
Most of the current guidelines25, 26, 29 describe an asymptomatic patient with reduced
LVEF who never exhibited typical signs and symptoms of HF as having ‘asymptomatic
LV systolic dysfunction’. However, such patients are at increased risk of mortality
and future morbidity and some deaths may occur even before the patient exhibits first
signs or symptom of HF. Some of these asymptomatic LV dysfunction patients may have
raised biomarkers. It may be prudent to include a category of ‘asymptomatic HF’ (Stage C,
NYHA class I). This identity is also important in a transiently symptomatic patient
who became asymptomatic on treatment. Then, HF term may no longer be restricted to
patients with manifest signs and symptoms.
1.3.2.4
Terminology related to the symptomatic severity of heart failure
New York Heart Association (NYHA) functional classification (Table 4) remains the
most widely used to assess symptomatic severity and exercise tolerance in HF.
30
However, NYHA classification has several limitations. The symptom stages are clearly
related survival, yet they correlate poorly with measures of LV function. Moreover,
mildly symptomatic patients may also have an increased risk of hospitalization and
death.
Table 4
NYHA classification and definitions.
30
Table 4
Class
Description
I
No limitation of physical activity. Ordinary physical activity does not cause symptoms
of HF.
II
Slight limitation of physical activity. Comfortable at rest, but ordinary physical
activity results in symptoms of HF.
III
Marked limitation of physical activity. Comfortable at rest, but less than ordinary
activity causes symptoms of HF.
IV
Unable to carry on any physical activity without symptoms of HF, or symptoms of HF
at rest.
Patients having a severe form of cardiac dysfunction presenting with severe symptoms
and recurrent decompensation is referred as having ‘advanced HF’. Patients with ‘end-stage
HF’ characteristically have advanced structural heart disease with symptoms of heart
failure at rest or upon minimal physical exertion, despite maximal evidence-based
treatment. Patients who are continually symptomatic despite maximum tolerated medical
therapy are also referred as having ‘refractory HF’.
1.3.2.5
Other commonly used classification terms in HF
Some of the commonly used terms in HF like stable HF, compensated HF, and congestive
HF needs further elaboration. Many or all of these previously defined terms may be
accurately applied to the same patient with HF at different times, depending upon
their stage of illness. ESC defines stable/compensated HF as “a treated patient with
symptoms and signs that have remained generally unchanged for at least 1 month”. Congestive
HF is a term used for patients of acute or chronic HF presenting with evidence of
volume overload. Congestive HF (CHF) or congestive cardiac failure (CCF) are common
terms used in India for chronic HF presenting with clinical signs, but are not specific
and are better avoided.
All the components essential for making a complete diagnosis HF are summarized in
Fig. 3.
Fig. 3
Components of chronic HF Diagnosis.
Fig. 3
1.4
Pathophysiology of heart failure
Heart failure results due to loss of functional myocardial cells (ischemia, myocarditis,
cardio myopathies) and also due to extra-myocardial diseases (valvular heart diseases,
pericardial diseases, systemic hypertension). On a long run, the extra-myocardial
disease processes can also affect the myocardial function by posing pressure and volume
overload.
Heart failure due to any etiology is characterised by changes in vascular function,
fluid volume and neuro-hormonal status, which serve initially to restore the balance,
but are considered to be detrimental over a long term.
1.4.1
Hemodynamic alterations in HF
1.4.1.1
Acute decompensated heart failure
Decrease in cardiac output hikes up the sympathetic nervous tone and inhibit parasympathetic
system which attempt to maintain perfusion by increasing peripheral vascular resistance
and stimulating the contractile reserve of the remaining myocardium. Vasoconstriction
helps to increase the preload and filling pressures. The sarcomere overlap progressively
decreases with distension of the chambers and beyond the point of optimal stretch,
the volume of blood ejected declines, further worsening the stroke volume and increasing
the filling pressures. Salt and fluid retention by kidneys sets in and attempts to
increase the preload and tissue perfusion.
1.4.1.2
Chronic heart failure
The variable recovery of the myocardium along with elevated filling pressures enables
gradual improvement in cardiac output, thus stabilising the patient. The elevated
chamber volume attempts to improve the forward output, but increases the wall stress
by the law of Laplace. This stimulates hypertrophy by laying down of sarcomeres in
series with lengthening of the myofibres, thereby acting as a counter-measure to decrease
the wall stress. Progressive volume overload and/or loss of contractile elements as
in myocardial diseases result in gradual loss of efficacy, increased myocardial oxygen
demand, sub endocardial ischemia and worsening heart failure.
1.4.2
Basis of compensatory mechanisms in heart failure
A series of systemic compensatory mechanisms are initiated once cardiac injury occurs
(Fig. 4). These mechanisms attempt to maintain the cardiac output by affecting the
myocardium and vasculature. The adaptive changes in myocardium are collectively termed
ventricular remodelling. While the compensatory mechanisms in patients with heart
failure with reduced ejection fraction have been documented well, the understanding
of pathophysiological processes involved in patients suffering from heart failure
with preserved ejection fraction is in an evolving stage.
Fig. 4
Various compensatory mechanisms initiated in Heart failure.
ANS – autonomic nervous system; ACE – angiotensin converting enzyme; ADH – antidiuretic
hormone, CO – cardiac output; ET – endothelin; NE – norepinephrine; NFκB – nuclear
factor kappa beta; NO – nitric oxide; RAAS – renin angiotensin aldosterone system;
ROS – reactive oxygen species; SNS – sympathetic nervous system; VC – vasoconstriction
Fig. 4
1.4.3
Ventricular remodelling (Fig. 5)
The term ventricular remodelling encompasses the complex alterations in the ventricle
in response to various mechanical, neurohormonal, and immunological stressors on the
heart, resulting in alterations in volume, wall thickness and/or shape (). Though
initially considered to be protective, adaptive hypertrophic changes over a long term
have adverse consequences. Consequent to identification of adaptive mechanisms at
molecular and biochemical level, the process has been redefined as “genomic expression
resulting in molecular, cellular and interstitial changes that are manifested clinically
as changes in size, shape and function of the heart after cardiac injury.”
31
Fig. 5
Molecular and pathological changes seen during ventricular remodelling.
GPCR – G protein coupled receptor; MHC – myosin heavy chain; MMP – matrix metalloproteinase;
SERCA – Sarcoplasmic Reticulum Calcium – Adenosine triphosphatase
Fig. 5
1.4.4
Pathophysiology of HFPEF
In normal hearts, LV pressure rapidly decreases after systole, facilitating rapid
filling in diastole with low filling pressures. This is aided by active suctioning
effect of left ventricle generated by intraventricular gradients, longitudinal motion
of mitral annulus, untwisting of LV during early diastole and elastic recoil of the
ventricle after the end of the systole. These are impaired in patients with HFPEF
resulting in decreased rate of pressure decay in LV during isovolumic relaxation phase,
progressive.
Initially these may be manifest during exercise only. There is progressive increase
in the reliance on atrial systole for ventricular filling, with worsening left atrial
hypertension and its consequences, pulmonary venous congestion, pulmonary arterial
hypertension and right heart failure. Contractile dysfunction often coexists, not
severe enough to depress ejection fraction in resting state. This may become more
apparent during exercise.
1.5
Clinical evaluation of heart failure patients
Clinical evaluation is one of the most vital parts of management of patients with
heart failure. The purpose of clinical evaluation is to diagnose heart failure, derive
etiological clues, and assess the severity of the condition while taking care to exclude
other causes of dyspnea or edema. Clinical evaluation also assesses response of these
patients to therapy.
1.5.1
History
Clinical evaluation should start with a good history which will give insights into
the etiology of heart failure, the precipitating factors, and the disease severity.
Most common symptoms of HF are dyspnea, symptoms related to fluid retention, palpitation
and fatigue (Table 5). Dyspnea initially may be exertional, but can worsen to present
as paroxysmal nocturnal dyspnea (PND) or orthopnea or dyspnea at rest. Palpitations
can be due to tachycardia, dilated heart or can be due to arrhythmias like atrial
fibrillation or ventricular arrhythmias.
Table 5
Typical symptoms and signs of Heart Failure.
Table 5
Symptoms
Signs
Dyspnea
Elevated jugular venous pressure
PND
Hepatojugular reflux
Orthopnea
Third heart sound
Fatigue
Laterally shifted cardiac apical impulse
Palpitations
Dependent edema
Dependent edema
Basal crepitations
Cachexia
Tender hepatomegaly
Fatigue is due to low cardiac output. Low cardiac output can also manifest as reduced
urine output and also lethargy and mental slowing.
Fluid retention commonly manifest as dependent edema, ascites or pleural effusion.
Gastrointestinal symptoms such as anorexia, early satiety and weight loss are common
in patients with HF and are due to visceral congestion. Cardiac cachexia is associated
with adverse prognosis. Change in body weight is also very important. Rapid weight
gain and development of peripheral edema or ascites suggests volume overload while
weight loss during treatment indicates a good therapeutic response and is helpful
in establishing the diagnosis of heart failure
One should also elicit history which will give clues to the etiology of HF. History
of rheumatic fever in the past, history of myocardial infarction (MI), presence of
risk factors like hypertension or diabetes mellitus, history of a recent viral infection,
pregnancy, history of habituation to alcohol intake, history of cancer chemotherapy,
all can give clues to the etiology.
Recent or frequent prior hospitalizations for HF is associated with adverse prognosis.
It is necessary to assess the compliance to life style, dietary restrictions and physical
activity. It is also very important to assess the compliance to drug therapy as it
is known to affect the prognosis in HF.
At the same time, one should enquire also about medications that may exacerbate HF
(eg NSAIDs) since discontinuation of such medications may represent a therapeutic
opportunity.
1.5.2
Physical examination (Table 5)
Physical examination compliments the history and will give clues to the etiology of
heart failure. It can confirm the diagnosis of HF and also assess the severity of
HF.
General examination can give clues to the etiology, for example evidence of chronic
alcohol intake can point towards alcoholic cardiomyopathy. Presence of mucosal pallor
indicating anemia, can point towards a precipitating factor.
Height, weight and body mass Index (BMI) should be recorded. Periodic weight monitoring
is vital in the management of HF.
Blood pressure (supine and upright) should always be recorded. We should always look
for postural changes in blood pressure and heart rate. These will give clues to volume
depletion or excess vasodilation from medications. Sinus tachycardia, low blood pressure
and reduced pulse pressure indicates a low cardiac output. A pulsus alternans may
indicate depressed cardiac function.
One should look for signs of fluid overload in the form of peripheral edema or ascites
or pleural effusion. Recent weight gain is a clue.
JVP at rest and following abdominal compression (hepatojugular reflux) is extremely
useful part of physical examination to identify systemic congestion.
The most important and specific sign of HF is cardiac enlargement. Size and location
of point of maximal impulse should be looked for and documented. Presence of right
ventricular heave suggests significant right ventricular dysfunction and/or pulmonary
hypertension
Presence of third heart sound (S3) indicates adverse prognosis in HFrEF and is sometimes
the only distinct finding in asymptomatic heart failure patients. Pansystolic murmur
of mitral regurgitation may be audible and should be carefully looked for. Other murmurs
due to valvular heart disease will give clues to the etiology.
Respiratory rate, rales and presence of pleural effusion should be assessed. It is
important to remember that in advanced chronic HF, rales are often absent despite
major pulmonary congestion and hence their absence should not eliminate the possibility
of heart failure.
Hepatomegaly may be looked for carefully. It indicates venous congestion and can be
used to serially monitor the patients. Presence of ascites indicates advanced right
heart failure.
1.5.3
Electrocardiogram
ECG is one of the most crucial diagnostic tools in evaluation of patients with HF.
A 12 lead ECG is recommended in all patients who are suspected of having HF. Occasionally
we may need right sided leads or leads V7 or V8. ECG. Though the ECG may be abnormal
in most of the patients, a normal ECG will not rule out HF.
Pre-existing or development of bundle branch block (BBB) is a poor prognostic factor
in patients with heart failure. Left bundle branch block (LBBB) prevalence is as high
as 25% in patients with chronic heart failure. LBBB causes deterioration of the mechanical
function of the left ventricle secondary to asynchronous myocardial activation, which
sequentially trigger ventricular remodelling and bad prognosis. Right bundle branch
block (RBBB) has been shown in studies to be associated with worse prognosis in patients
with chronic heart failure compared to patients with no BBB.
Non-sustained ventricular tachycardia (NSVT) is common among patients with dilated
cardiomyopathy with reported prevalence of 30–80%. Though common, the prognostic significance
of NSVT as an independent risk factor in heart failure is questionable. Signal averaged
ECG and heart rate variability studies have conflicting evidence as a predictor of
mortality in dilated cardiomyopathy.
Utility of ECG in HF
1.
CAD – Presence of Q waves or loss of R waves or ST segment shift indicates presence
of CAD.
2.
Arrhythmias can give clues to the etiology – eg. Atrial Fibrillation, bradycardia.
3.
ECG can give clues towards electrolyte imbalance
4.
ECG – can provide Prognostic information – Eg. Presence of ventricular arrhythmias.
5.
It can give clues to chamber enlargement – LVH, RVH, LAE
What to assess in ECG in patients with HF?
Heart rate, PR interval, QRS duration, QT interval, pathological Q waves, evidence
of left atrial/right atrial overload, left ventricular/right ventricular hypertrophy,
bundle branch block, atrial and ventricular arrhythmias.
CHEST X Ray
As part of the initial assessment of patients with HF Chest X-ray (CXR) stills remains
an important diagnostic tool. CXR gives two important clues to HF, presence of cardiomegaly
and presence pulmonary congestion, both are very specific to the diagnosis of HF.
What to look for in CXR in HF:
1.
Cardio-thoracic ratio
2.
Pulmonary congestion
3.
Specific cardiac chamber enlargement
4.
Pleural effusion
5.
Other abnormalities – Lung parenchymal abnormalities, Calcification eg. Pericardial
1.6
Echocardiography
1.6.1
Echocardiography
Echocardiography is the critical diagnostic tool in patients with suspected heart
failure, where it provides functional and structural information. With the wide availability
of echocardiography, it has emerged as the most important tool in the diagnosis, assessment
of prognosis and in follow up of patients with HF.
1.6.2
Assessment of structural heart disease
A basic Echocardiographic examination of M-mode, two-dimensional echocardiography,
colour Doppler, pulse Doppler and continuous wave Doppler should be performed in all
patients with suspected heart failure.
Echocardiography gives the diagnosis, confirms the etiology and assesses the severity,
which helps in deciding the type of treatment required.25, 26, 32, 33, 34
Echocardiography provides insights into all stages (A,B,C and D) of heart failure.32,
33, 35
1.6.3
Assessment of systolic and diastolic function
Two-dimensional echocardiography is the mainstay for the assessment of LV systolic
function which includes LV imaging in parasternal long axis view, parasternal short
axis views and apical views.
35
LV measurements should be done from two-dimensional echocardiography, and the assessment
of LV volume by modified biplane Simpson’s method is the most widely accepted method.
Area–length method may be used when biplane Simpson method is technically not feasible.
Care should be taken to get the correct apical views with visualization of the LV
apex and clear identification of the endocardium. In patients with poor image quality,
contrast opacification of LV will help to better delineate the endocardium.
M-mode echocardiography should not be used for LV quantification and it should be
done from two-dimensional echocardiography. Cube method and Quinones method should
not be used for measurement of LV volumes and ejection fraction. Three-dimensional
echocardiography when available should be used for measuring LV volume and ejection
fraction. LV myocardium is divided into 16 or 17 segments and visualized in parasternal
long axis, parasternal short axis and apical views according to the coronary blood
supply. Wall motion abnormalities should be described using this nomenclature with
wall motion scoring index.
Assessment of LV diastolic function is an equally important requirement of echocardiography.
37
Diastolic dysfunction can be identified by doing a left atrial outflow Doppler sampling
between the tips of anterior and posterior mitral leaflets, tissue Doppler from septal
and lateral mitral annulus, pulmonary vein velocity, left atrial volume measurement
and identification of presence or absence of pulmonary hypertension. Left atrial volume
provides incremental information about the severity and chronicity of diastolic dysfunction
and is an important prognostic indicator in various groups of heart diseases. Right
atrial volume measurement and RV diastolic dysfunction has limited value and not recommended
in routine echo.
The LV diastolic dysfunction can be graded into type I abnormal relaxation pattern,
type II pseudo normal pattern and type III restrictive pattern and Type IV irreversible
restrictive pattern (Table 6).
Table 6
Echocardiographic criteria for assessing grades of Left ventricular diastolic dysfunction.
37
Table 6
Diastolic Dysfunction
Normal
Grade I
Grade II
Grade III
Mitral E/A
≥0.8
≤0.8
>0.8 to <2
>2
Average E/e ’ ratio
<10
<10
10–14
>14
Peak TR velocity (m/s)
<2.8
<2.8
>2.8
>2.8
LA volume index
<34 ml/m2
Normal or increased
>34 ml/m2
>34 ml/m2
1.6.4
Assessment of right ventricular function and pulmonary hypertension
The importance of RV function and RV haemodynamics is being increasingly recognized
in the management of HF. Assessment of RV function and hemodynamics is very important
to decide about the management of patients, which includes both medical and surgical
methods of treatment.32, 33 This information can be obtained from two-dimensional
and Doppler echocardiography which is considered now as the non-invasive Swan-Ganz
catheter. Pulmonary artery systolic pressure, diastolic pressure and mean pressure
can be calculated from tricuspid and pulmonary regurgitation. Right atrial pressure
is mainly assessed by using the inferior vena cava dimension and its changes with
respiration. RV function can be assessed by surrogate parameters like, TAPSE (Tricuspid
annular plane systolic excursion), Tricuspid annular tissue Doppler velocity, RV fractional
area change and RV myocardial performance index (Table 7). RV volumes and ejection
fraction can be obtained by three-dimensional echocardiography, but it has not come
into routine clinical practice yet. Cardiac magnetic resonance imaging (CMRI) is still
the gold standard for measuring the RV volumes and ejection fraction.
Table 7
Echocardiographic criteria for assessing severity of right ventricular function.
Table 7
RV Function
Normal
Mildly abnormal
Moderately abnormal
severely abnormal
RV Diastolic Area (cm2)
11–28
29–32
33–37
≥38
RV Fractional Area change (%)
32–60
25–31
18–24
≤17
TAPSE
1.5–2.0
1.3–1.5
1.0–1.2
<1.0
1.6.5
Tissue d Doppler imaging
Tissue Doppler imaging (TDI) gives information about regional and global function.
32
Tissue Doppler of LV is sampled from mitral annulus and from basal and mid-ventricular
myocardial segments. Its use is limited since it’s a Doppler based technique and can
only be used in apical views. TDI is mainly useful for diastolic function assessment
and in the measurement of LV filling pressures (E/e’). It is also useful in assessing
LV and RV function by calculation of myocardial performance index since the parameters
can be measured in the same heartbeat. Conventional echocardiography plays an important
role post CRT for assessing LV function, severity of mitral regurgitation (MR) and
adjusting the atrio-ventricular and inter-ventricular delays after CRT.
1.6.6
Speckle tracking echocardiography
TDI and speckle tracking echocardiography (STE) has helped us to understand LV myocardial
mechanics32, 33, 35 Peak global longitudinal strain (GLS) of LV by STE has come into
clinical use, the normal value being −18% to −22%. GLS value of above −16% indicates
LV systolic dysfunction (Table 8). Regional peak longitudinal strain pattern of LV
myocardial segments can be shown as a Bull’s eye diagram with colour coding and numerical
values. This may be useful to identify affected segments in various disease conditions.
It has also been shown to be useful in identification of areas of fibrosis in patients
with dilated and hypertrophic cardiomyopathy. In amyloidosis, it gives a typical pattern
of apical sparing with marked decrease of strain in basal and mid myocardial LV segments,
the typical “cherry on top of ice cream” appearance.
Table 8
Definition of abnormal global longitudinal strain &clinical situations for it’s use.
Table 8
Global Longitudinal Strain
Abnormal if more than −16% (Normal Range −15.9% to −22.1%)
It is being used to monitor specific clinical conditions to detect sub clinical LV
dysfunction
-Cancer induced chemotherapy
-Aortic stenosis
-May have a role in cardiac amyloid & Hypertrophic cardiomyopathy
In patients with HFpEF, even though LV ejection fraction is in the normal range, strain
is decreased indicating subclinical LV systolic dysfunction. Strain can also be used
to identify sub clinical LV dysfunction after cancer chemotherapy. 25% decrease in
GLS compared to the basal values identifies myocardial systolic dysfunction. GLS can
also be used to predict early LV systolic dysfunction before ejection fraction decreases
in patients with mitral and aortic regurgitation, aortic stenosis, left ventricular
hypertrophy due to systemic hypertension, hypertrophic and restrictive cardiomyopathy.
Both TDI and STE have shown some utility in assessing patients after cardiac transplant,
especially patients who are likely to develop rejection
1.6.7
Three-dimensional echocardiography
Trans-thoracic real time three-dimensional echocardiography (RT3DE)
38
provides accurate LV volume and ejection fraction because the volume is measured by
counting the number of voxels present in the LV cast. It is superior since, there
is no geometrical assumption and hence no mathematical formula is involved, provided
the LV is not foreshortened and LV apex is always included. RT3DE LV volume correlates
well with the gold standard of LV volume by CMR imaging.
1.6.8
Contrast echocardiography
Contrast echocardiography using commercially available contrast agents is useful for
LV opacification. Contrast delineates LV endocardium and facilitates more accurate
estimation of LV volume and ejection fraction. Contrast echocardiography can be combined
with stress echocardiography for identification of wall motion abnormalities with
treadmill stress and dobutamine stress echocardiography. It is also useful for identification
of thrombus, aneurysm, non-compaction, viable myocardium and apical hypertrophic cardiomyopathy.
1.6.9
Stress echocardiography
Stress Echocardiography may be combined with physical exercise like treadmill test
or pharmacological stress like dobutamine stress echocardiography (DSE). Stress echocardiography
can be used to identify wall motion abnormalities developing after myocardial ischemia.
DSE is useful to identify the biphasic response which indicates viability of myocardium.
Stress echocardiography can also be used in patients with asymptomatic and low flow
low gradient aortic stenosis. It is also useful in patients with mitral and aortic
regurgitation. Stress echocardiography is not recommended for the diagnosis of pulmonary
hypertension. In patients with significant dyspnoea with normal resting LV diastolic
pressure, diastolic stress test may identify patients with abnormal diastolic dysfunction
where an increase in LV end diastolic pressure produces dyspnoea.
1.7
Biomarkers in heart failure
1.7.1
Introduction
Although heart failure (HF) remains a fundamentally clinical diagnosis, substantial
advances in the understanding of the underlying biology and pathophysiology of this
syndrome has led to a greater interest in objective means to quantify its presence,
severity, and potential future progression. Among the most intensively studied tools
to achieve these goals are circulating biomarkers.
Various remodelling and neurohormonal activation pathways exist whose activity may
be leveraged for biological monitoring. (Table 9)
Table 9
Biomarkers of HF.
Table 9
Myocardial Injury
Neurohormonal Activation
Remodelling
Myocyte Stretch
NT-proBNP, BNP, MR-proANP
Arginine Vasopressin System
Arginine vasopressin
Hypertrophy/Fibrosis
Matrix metalloproteinases, collagen propeptides, galectin 3, soluble ST2
Oxidative Stress
Myeloperoxidase, oxidized low-density lipoproteins, MR-proADM
Renin Angiotensin System
Renin, angiotensin II, aldosterone
Apoptosis
GDF-15
Myocardial Injury
Troponin T, troponin I
Sympathetic Nervous System
Norepinephrine, Chromogranin A
Inflammation
C-reactive protein, tumor necrosis factor α, Fas, interleukins, osteoprotegerin, adiponectin
Among the biomarkers, plasma concentration of natriuretic peptides (NPs) is the most
commonly used initial diagnostic test in India. It may be used, when and where feasible,
particularly when echocardiography is not immediately available Patients with normal
plasma NP concentrations are very less likely to have HF. The upper limits of normal
levels of NPs in the acute and non-acute settings are discussed below.
So, the use of assay of BNP and NT pro-BNP, is recommended to rule-out HF. However,
other biomarkers discussed here, may be used in tertiary care and specialized HF clinic
for select group of patients.
1.7.2
Natriuretic peptides
The natriuretic peptides represent the gold standard for biomarkers in HF. The signs
and symptoms of HF are non-specific, and many patients who are suspected to have HF
referred for echocardiography, finally turned to have no significant cardiac abnormality.
In the developing world, like India, where the availability of echocardiography is
limited, an alternative approach to diagnosis is to measure the blood concentration
of NPs in HF.
36
Many major studies have examined the threshold levels that can be used as a cut-off
to exclude the diagnosis of HF for the two most commonly used natriuretic peptides,
B-type natriuretic peptide (BNP) and N-terminal pro B-type natriuretic peptide (NT-proBNP).39,
40, 41 Different cut-off values have been proposed for patients presenting with acute
decompensated heart failure (ADHF) and those patients presenting with a more gradual
onset of symptoms.
For patients presenting with acute decompensated HF, the ideal exclusion cut-off point
is proposed to be 300 pg/mL for NT-proBNP and 100 pg/mL for BNP.
42
For patients presenting with chronic heart failure, the optimum exclusion cut-off
point is 125 pg/mL for NT-proBNP and 35 pg/mL for BNP. The sensitivity and specificity
of BNP and NT-proBNP for the diagnosis of HF are lower in non-acute settings.39, 40,
41
The blood levels of these biomarkers, BNP and NT-proBNP come down with treatment of
chronic HF, and it correlates with improved clinical outcomes. Thus, the strategy
of using BNP or NT-proBNP “guided” therapy versus standard care without natriuretic
peptide measurement was compared to find out whether guided therapy renders superior
achievement of guideline-directed medical therapy (GDMT) in patients with HF. However,
such RCTs have yielded inconsistent results as we discuss below.
These trials comparing the two strategies, which gave mixed results differ primarily
in their study populations, with successful trials enrolling relatively younger patients
and only those having HFrEF. In addition, the positive “guided trials” aimed at a
lower natriuretic peptide goal and/or a substantial reduction in natriuretic peptides
during treatment.
43
Although most trials examining the strategy of biomarker “guided” management of patients
with HF were small and underpowered, two comprehensive meta-analyses have concluded
that BNP guided therapy reduces all-cause mortality in patients with chronic HF as
compared to usual clinical care44, 45 especially in patients <75 years of age. The
increase in survival could be attributed to the increased achievement of GDMT. In
some cases, as we occasionally encounter in our clinical practice, BNP or NT-proBNP
levels may not be easily modifiable. If the BNP or NT-proBNP value does not fall after
aggressive HF care, we know that the risk for death or re-hospitalization for HF is
significantly higher. On the contrary, some patients with advanced HF have normal
NP levels or have falsely low NP levels because of obesity or they have HFpEF.
There are many cardiac and non-cardiac causes which can elevate NP levels that may
weaken the diagnostic utility in HF. Atrial fibrillation, age and renal failure are
the most important factors which can affect the interpretation of NP measurements.
On the other hand, plasma NP levels may be disproportionally low in obese patients,
which have to be considered when we interpret NP values.
Treatment with ARNI and monitoring with Natriuretic peptides- Sacubitril/valsartan
(ARNI) increases levels of circulating BNP, so BNP is not useful for monitoring the
prognosis of these patients who are on ARNI. NT-proBNP is still useful as changes
in the levels of this biomarker reflect the reduced pre-proBNP secretion as a result
of reduction in the ventricular wall stress in response to HF treatment.
1.7.3
Biomarkers of myocardial injury: cardiac troponin T or I
Higher levels of circulating cardiac troponin are found in patients with HF, without
any evidence of myocardial ischemia and frequently in those without underlying CAD.
This suggests the presence of ongoing myocyte injury or necrosis in these patients
with HF. In chronic HF, elevation of cardiac troponin levels is associated with impaired
hemodynamics, progressive LV dysfunction, and increased mortality rates. The data
is similar in patients with acute decompensated HF also, where elevated cardiac troponin
levels are associated with higher clinical adverse events and mortality. Data also
shows that decrease in troponin levels over time while on treatment is associated
with a better prognosis than persistent elevation in patients with chronic or ADHF.
In India CAD contributes to the majority of HF burden hence, the measurement of troponin
I or T should be routine in patients presenting with acutely decompensated HF syndromes.
Inflammatory CMP should be considered if troponins are elevated.
The other biomarkers which are being evaluated in HF and their pathophysiological
mechanism is given in Table 10. None of these biomarkers have consistently shown usefulness
like BNPs.
Table 10
Novel Biomarkers.
Table 10
Biomarker
Pathophysiological pathway
1
Mid-regional pro adrenomedullin (MR-pro ADM)
Sympathetic nervous system activation
2
Copeptin
Arginine-vasopressin system activation
3
Soluble ST-2 (Soluble suppression of Tumorigenicity −2)
Cardiac Fibrosis – Considered as a marker of long term prognosis.
4
Galectin-3 (Gal −3)
Cardiac Fibrosis
5
Kidney Injury Molecule-1
Indicates renal involvement in HF
1.8
Non-Invasive imaging other than echocardiography
Echocardiography remains the cornerstone of HF evaluation, however, other non-invasive
imaging techniques magnetic resonance imaging, FDG PET as well as nuclear imaging
plays an important role in specific situations.
An overview of the potential role of these imaging techniques are discussed below.
1.8.1
Ischemic heart disease
1.8.1.1
Viability assessment
Patients with severe left lentricular dysfunction are known to improve after revascularization,
suggesting the presence of viable myocardium.
46
Viability assessment can be done by many imaging techniques such as 18F-FDG PET-CT,
Cardiac MRI, SPECT-CT imaging, and dobutamine stress echocardiography. Thallium201
(Tl-201) imaging is an established procedure for the detection of viable myocardium
and various protocols like stress-redistribution, rest-delayed, rest-reinjection are
used for this purpose.
For the last several years many studies have come up which tested for viability with
Technetium (Tc) agents. Tc agents have the advantage of superior imaging characteristics
of 99mTc and hence this allows more doses to be given, along with reduced tissue attenuation
of Tc-agents.
47
Though initial studies have revealed that Tc labelled tracers are less accurate than
Tl-201 for detection of viable myocardium,
48
recent studies have shown that using nitroglycerin and 99mTc-myocardial agents, it
is possible to achieve comparable sensitivity and specificity for myocardial viability
detection as with the use of Tl-201.49, 50
F-18 Fluorodeoxyglucose (FDG) Positron Emission Tomography-Computed Tomography scan
(PET-CT) is also one of the commonly used investigation for accurate assessment of
viable myocardium.
FDG PET requires proper patient preparation. Depending on blood glucose level, glucose
load or intravenous insulin as per sliding scale has to be administered according
to standard protocol. If the patient’s blood glucose level is more than 140 mg/mL,
they have to rescheduled after control of blood glucose levels.
1.8.1.2
Inflammatory myocardial disease
Sarcoidosis is a multisystem granulomatous disease of unknown etiology. The current
diagnostic criteria for cardiac sarcoidosis includes gadolinium-enhanced MRI which
was added as a minor criterion for the clinical diagnosis.
Imaging using 18F-FDG PET, in conjunction with perfusion imaging to assess fibro granulomatous
replacement of the myocardium in sarcoidosis is found to have high sensitivity and
specificity.
In general, PET/CT imaging for cardiac sarcoid disease should be considered in patients
having second or third-degree atrioventricular block of unknown etiology in patients
<55 years of age and when non-ischemic, monomorphic ventricular tachycardia manifests.
In particular, an early identification of cardiac sarcoid involvement with PET/CT
imaging may be crucial to install immunosuppressive therapy and thereby prevent the
development of severe cardiomyopathy and heart failure symptoms.
51
1.8.1.3
Radionuclide ventriculography
With the advent and routine use of gated myocardial perfusion studies (MPS) and highly
improved cardiac computed tomography and magnetic resonance imaging, a number of previous
applications of radionuclide ventriculography using MUGA(Multigated acquisition) or
ERNA(equilibrium radionuclide angiography) have almost gone into oblivion or add little
to the practical management of cardiac patients at present.52, 53
1.8.2
Role of cardiac magnetic resonance imaging (CMR) in evaluation of patients with heart
failure
Over the last two decades Cardiac Magnetic Resonance (CMR) imaging has established
itself as the imaging of choice especially in patients with limited echo windows or
right ventricular pathology.
CMR is excellent in providing accurate anatomical and functional data without exposure
to ionising radiation. It is also recognised as the gold standard modality in assessment
of left ventricular ejection fraction (LVEF).
55
CMR is unique in its ability to characterise myocardial morphology using T1/T2/T2*(star)
mapping wherein relaxation times of different myocardial pathologies can be used to
establish a diagnosis without the use of contrast. Delayed enhancement (DE) imaging
is also unique for CMR wherein imaging is performed 10–15 min after giving contrast.
Abnormal tissue enhances more than normal myocardium and is depicted as bright region
in the background of normal dark myocardium. CMR can characterize underlying cause
of heart failure based on the pattern and location of enhancement/scar/interstitial
fibrosis with DE imaging.
1.8.3
Ischemic heart disease
CMR can help in making important decisions with regards to revascularisation and guiding
further therapy by selecting patients who would benefit from surgical or interventional
revascularisation. CMR can assess myocardial viability and potential to recover by
using various markers- wall motion abnormality, myocardial thinning, delayed enhancement
imaging for transmurality of infarction and by assessing contractile reserve.
Myocardial segments with wall motion abnormalities and no/mild (<25%) scar have good
likelihood of functional recovery following revascularisation. Segments with more
than 75% hyper enhancement have been shown to have little or no potential for functional
recovery following revascularisation.
54
Transmurality of scar is the second most important predictor of functional recovery.
Scar volume by CMR, also predicts survival and all-cause mortality independent of
the left ventricle ejection fraction.55, 56, 57 Viability and potential recovery of
myocardium post revascularisation can also be assessed with the use of low dose Dobutamine
stress by establishing myocardial contractile reserve. Flow reserve can also be determined
with CMR using vasodilator stress and establishing the functional significance of
indeterminate coronary artery stenosis.
CMR clearly depicts the transition zone and represents the gold standard for patient
selection for aneurysmectomy.
58
1.8.4
Non-Ischemic myocardial disease
1.8.4.1
Dilated cardiomyopathy (DCM)
Presence of mid-myocardial delayed gadolinium enhancement suggests fibrosis and is
associated with higher incidence of arrhythmia, adverse events, hospitalisation and
mortality.
59
CMR also provided accurate assessment of LV and RV volumes, mass and systolic function.
It is also very useful in ruling out common other mimics of DCM, especially ischemic
cardiomyopathy in older patients.
1.8.4.2
Myocarditis
Presence of global/regional dysfunction, myocardial oedema and contrast enhancement
in mid myocardial/subepicardial distribution are commonly seen imaging findings in
myocarditis. Parvovirus B19 myocarditis produces lateral wall enhancement and recovery
within a few months, but herpesvirus-6 myocarditis produces septal enhancement and
rapid progression to cardiac failure.
60
1.8.4.3
Granulomatous cardiomyopathy
Two most common causes of granulomatous cardiomyopathy are sarcoidosis and tuberculosis.
CMR can accurately demonstrate myocardial edema and/or fibrosis along with evidence
of extra cardiac involvement of sarcoidosis. Noncaseating granulomas in cardiac sarcoidosis
may involve the LV free wall, basal ventricular septum, right ventricle, papillary
muscles, right and left atria. The clinical manifestations depend on the site and
extent of these granulomas. Also, LGE imaging can act as a guide to decide the site
of endomyocardial biopsy. In spite of extensive myocardial involvement, pericardial
involvement is uncommon and asymptomatic. Presence of mediastinal adenopathy may be
seen and provides an accessible site for biopsy for histopathological confirmation.61,
62
Myocardial tuberculosis is considered an uncommon clinical entity and is only infrequently
diagnosed ante-mortem. Pathologically, there are three patterns of involvement:
•
Miliary tuberculosis, with the heart being just one of the many organs involved
•
Diffuse infiltrating interstitial disease.
•
Caseating nodular disease (tuberculoma).
The miliary form is by far the commonest; tuberculomas are much rarer. The lesions
may involve the atria, the ventricles, or the interventricular septum and may lead
to heart block. It may also present as intracavitory mass lesion, commonly within
the atria. Mediastinal adenopathy and pericardial involvement with pericardial effusion
and pericarditis are common imaging findings.63, 64
1.8.5
Non-ischemic myocardial disease
1.8.5.1
Hypertrophic cardiomyopathy: HCM
CMR will accurately depict various phenotypes of HCM- symmetrical, asymmetrical, apical,
mid cavity etc. The apical variety and RV involvement is often difficult to diagnose
on echocardiography due to poor echo window and CMR is useful. Typical pattern of
LGE in HCM is midwall patchy or punctate hyper enhancement in a thickened myocardium
in a noncoronary distribution.
65
Two common types of HCM progression to the burned-out phase are seen at imaging: a
dilated form where the LV is most commonly affected and a restrictive pattern where
atrial dilatation is the most prominent morphologic finding. Both patterns of progression
lead to heart failure, which is commonly unresponsive to available therapies and ultimately
necessitates cardiac transplant.
CMR allows effective assessment of septal thickness, quantification of ejection fraction
and identification of fibrosis. Cardiac MR imaging can also demonstrate morphologic
abnormalities of the mitral valve apparatus and papillary muscles, which are important
contributors to development of sub aortic gradients and LVOT obstruction. CMR also
can accurately quantify the amount of mitral regurgitation, which can help in deciding
surgical management. Since the most devastating complication of HCM is SCD, cardiac
MR imaging allows prediction of which patients require ICD implantation.
66
1.8.5.2
Iron overload cardiomyopathy
Heart failure due to iron overload is the most common cause of death in patients with
thalassaemia major worldwide.
Iron assessment by T2* relies on the measurement of T2* relaxation from gradient echo
(GRE) sequences. T2* values in the mid-septum have been calibrated to myocardial tissue
iron levels in [Fe] milligrams per gram dry weight and indicate a strong inverse linear
relationship.
67
T2* monitoring is now internationally recommended in the annual monitoring of transfusion-dependent
patients at risk of developing myocardial iron loading. In this way, T2* imaging of
cardiac iron loading has progressed from a research technique to a clinically validated
tool and has transformed clinical outcomes in β-thalassaemia major.
68
1.8.5.3
Arrhythmogenic right ventricular cardiomyopathy (ARVC)
ARVC is characterised by fibro fatty infiltration of the right or both ventricles.
Recently published international task force guidelines emphasise assessment of regional
wall motion abnormality and RV volumes and ejection fraction.
69
CMR can contribute to one major or one minor criteria towards the diagnosis of ARVC
according to the Task Force. LV involvement can also be accurately demonstrated by
CMR.
1.8.5.4
Cardiac amyloidosis
Cardiac amyloidosis is characterized by thickened myocardium, atria, and interatrial
septum, with diminished systolic function and biatrial enlargement. Delayed enhancement
is typically global subendocardial progressing to transmural, but can also occasionally
be patchy.
70
A unique feature of cardiac amyloidosis is the alteration of T1 kinetics of gadolinium
distribution, with nulling of the myocardium before the blood pool due to diffuse
amyloid infiltration, resulting in higher gadolinium uptake and T1 shortening
1.8.5.5
Left ventricular non-compaction
This is characterised by prominent trabeculations in the LV cavity with deep inter-trabecular
recesses. Patients present with heart failure, arrhythmias or embolic events. There
is lack of consensus in diagnostic criteria for LV non-compaction especially due to
overlap with DCM and apical HCM. Both CMR and echo can depict hypertrabeculated myocardium
but CMR can depict biventricular anatomy/function, can exclude other anomalies and
also demonstrate fibrosis.
71
1.9
Invasive evaluation of heart failure
Vast majority of patients with HF can be evaluated using non-invasive modalities like
echocardiography and CMR. But we have to resort to invasive techniques occasionally
as we discuss below.
1.9.1
Indications for invasive testing in heart failure
a)
To resolve diagnostic uncertainties in patients with inconclusive clinical findings.
b)
For evaluation of pulmonary vascular disease.
c)
To look for coronary anatomy when ischemia is suspected as a cause of heart failure
d)
To assess for suitability for advanced therapies in chronic heart failure like work-up
for cardiac transplant
1.9.2
Modalities for invasive assessment of heart failure
Invasive evaluation of heart failure (HF) can be discussed under the following headings-
Right heart catheterization (RHC), Coronary arteriography, Endomyocardial biopsy and
Implantable hemodynamic monitoring devices.
A. Role of RHC in heart failure −
There is no role of routine RHC in management of heart failure
72
as most therapies in treatment of HF are based on either symptomatic improvement or
survival benefit rather than their effect on hemodynamic variables. Routine use of
pulmonary artery catheter insertion to manage heart failure was not found to improve
morbidity and mortality in landmark ESCAPE trial.
72
Thus, it is no longer recommended to use right heart catheterization routinely in
every patient.26, 27 Hemodynamic monitoring can be considered in patients with clinically
indeterminate volume status and those refractory to initial therapy.
The Subset of patients, which might get benefit from RHC include −
1.
Patients with persistent severe symptoms despite optimum medical therapy.
2.
Dependence on intravenous inotropic infusion after initial clinical improvement.
3.
Patients with cardiogenic shock requiring vasopressor therapy and being considered
for mechanical circulatory support.
4.
Patients being evaluated for heart transplantation
B. Role of Coronary arteriography
Those with previous history of angina and CAD and who are considered suitable for
potential coronary revascularization should preferably have an invasive coronary angiogram
in order to establish the diagnosis of CAD and its severity. In view of the high prevalence
of CAD in young population in India, it is better to err on the side of doing a CAG
rather than not doing it.
Patients with malignant arrhythmia and survivors of sudden cardiac death are candidates
for coronary angiogram. Those who have recent worsening of symptoms of CAD also earn
a coronary angiogram even if prior angiograms are unremarkable.
1.10
C. Endomyocardial biopsy -
Given the limited diagnostic yield, routine use of Endomyocardial biopsy (EMB) is
not indicated. It should be considered only when a specific diagnosis is being suspected,
that is likely to impact the therapy. Endomyocardial biopsy should not be performed
in the routine evaluation of HF.
Adult and pediatric patients who present with the sudden onset of severe left ventricular
failure within 2 weeks of a distinct viral illness and who have typical lymphocytic
myocarditis on EMB have an excellent prognosis. Therapy with combinations of immunosuppressive
agents has been associated with improved outcome in giant cell myocarditis and necrotizing
eosinophilic myocarditis. EMB can be helpful in identifying those patients. (Cooper
et al. European Heart Journal (2007) 28, 3076–3093).
EMB is useful for
1.
Rapidly progressive heart failure that worsens despite optimum medical therapy:
a
Unexplained new-onset heart failure (HF) of less than two weeks.
b
Unexplained new-onset HF of two weeks with a dilated left ventricle and new ventricular
arrhythmias or heart block.
2.
Suspected cardiac rejection after heart transplantation
3.
Suspected myocardial infiltrative disorder
Important considerations while planning EMB -
1.
Anticipated yield of the procedure as well as the risk of sampling error and procedure
related complications.
2.
The availability of effective therapy for the diagnosis that is obtained.
3.
EMB is recommended in when the unique prognostic and diagnostic value of the information
gained is likely to outweigh the procedural risk.
4.
Facilities and personal who can interpret the biopsy specimens.
1.10.1
Role of implantable hemodynamic monitoring devices in heart failure
Newer devices permit the measurement of ambulatory hemodynamics with implantable monitors.
These devices include RV leads that measure intrathoracic impedance and pressure,
wireless pulmonary artery pressure monitors, and left atrial pressure sensors. These
devices are based on the principle that rise in LV filling pressure commonly occurs
days before symptoms, changes in weight, or hospitalization. However currently there
is no established role of these devices in heart failure management. The commonly
available devices are the Chronicle device (Medtronic, Inc., Minneapolis), and CardioMEMS™
device.
1.11
Diagnostic evaluation: evaluation protocol for heart failure suited to India −
1.11.1
Introduction
The patients of heart failure require a detailed evaluation for etiology, prognostication,
and assessment of treatable co-morbidities that can improve outcomes in these patients.
1.11.2
Evaluation in patients with HF
After a detailed clinical evaluation, all patients suspected of having HF should have
an ECG, Chest X-Ray and an echocardiogram as discussed. We will be able to diagnose
and prognosticate most of the patients with these three investigations. But we need
further evaluation in a sub-group of patients, one group where we could not reach
a diagnosis and the other group where we need to further quantify or qualify the disease
or the associated co-morbidities.
Some of the patients need advanced imaging modalities like CMR, cardiac CT or invasive
cardiac catheterization. Few patients need to be referred to other sub-specialties
for evaluation. Examples include thyroid dysfunction related cardiomyopathy, hemochromatosis,
sarcoidosis and amyloidosis. Holter monitoring may be required in patients suspected
of having tachycardiomyopathy. Obstructive sleep apnea is a common co-morbidity encountered
with HF and that needs evaluation and prompt treatment.
A proposed algorithm for the work-up of patients and follow-up is given below.
HEARTFAILURE–PROPOSED INVESTIGATION PROTOCOL
FIRST LEVEL–FOR ALL PATIENTS
1.
Height and Weight – at each visit
2.
Heart rate, Supine and standing BP(at each visit)
3.
Chest X Ray and ECG(Initial visit and to be reviewed periodically)
4.
Echocardiogram-(Initial visit and to be reviewed periodically)
5.
Holter – (If atrial fibrillaion or ventricular arrhythmias are suspected or suspected
tachycardiomyopathy)
6.
Complete blood count
7.
ESR
8.
Serum BNP or NT Pro-BNP(to be repeated as and when required)
9.
LFT (Liver function tests) – S bilirubin, SGPT
10.
RFT (Renal function test) – Creatinine with serum electrolytes to be repeated as required
11.
Virology- HIV/HBsAg/AntiHCV antibody
12.
Thyroid profile – Screening with TSH levels.
13.
6 min walk test(ambulant patients)
SECOND LEVEL INVESTIGATIONS- IN SELECTED CASES
1.
Cardiac Cath[Right atrial mean pressure, Pulmonary Capillary Wedge, pulmonary artery
-PA(systolic/diastolic /mean), Left ventricular end-diastolic pressure (LVEDP), pulmonary
vascular resistance (PVR), Coronary angiogram, Coronary venogram, left and right ventricular
(LV and RV) angiogram as required
2.
Cardiac MRI(with hepatic screening for hemochromatosis)
SECOND LEVEL WORKUP- AS PER PHENOTYPE ON Echocardiography.
Expansion of Short forms. HRCT – High Resolution computed Tomography, S.ACE – Serum
Angiotensin converting enzyme, S.Ca – Serum calcium, S.Ph – Serum Phosphorus, ASO
Titer – Antistreptolysin O Titer, S.Ca – Serum calcium.
DCM
HCM
RCM
Family screening
Family screening
S Ferritin
S. Ferritin
Echo–dyssynchrony
Viral Titres (Coxsackie/Enterovirus)
If conduction abnormality/VT: Sarcoidosis to be ruled out-S.Ca /S.Ph /HRCT Chest /
S.ACE
If conduction abn/VT: Sarcoid-S.Ca/S.P/HRCTchest/S.ACE
If ECG/Echo suggestive: Amyloid workup- Abdominal Fat pad Biopsy
If ECG/Echo suggestive: Amyloidworkup-Abdominal Fat pad Biopsy
Pediatric age: ASO titre
2
Management of heart failure
2.1
Non-pharmacological management
Nonpharmacological management occupies an important place in heart failure therapy.
However, most of the recommendations are based on consensus expert opinion or are
derived from limited trial data.
2.1.1
Sodium restriction
Increased salt consumption is one of the most important causes of worsening of heart
failure.73, 74 Dietary sodium restriction results in reduction in dose of diuretic
which helps in reducing plasma renin activity and improves overall outcome.
75
Observational data suggest an association between dietary sodium intake with fluid
retention and risk of hospitalization.76, 77 Other studies have reported worsening
neurohormonal profile with sodium restriction in heart failure.
78
Majority of the studies have been performed in patients with HFrEF except one which
has been performed on HFpEF.
79
These data have been mostly obtained from a predominantly white population and hence
may not be fully extrapolated to the Indian context. The scenario has been further
complicated by the results shown by 2 randomized control trials that lower sodium
intake is associated with worse outcome in patients with HFrEF.80, 81
American Heart Association and the United States Department of Agriculture (USDA)
recommend sodium intake of 2.3 gm (equivalent to 5.7 gm of common salt) per day for
the general population, and 1.5 gm for those with hypertension, blacks and middle-aged
and older people.
82
In India it is reasonable to limit daily sodium intake to 2–3 gm. In severe cases
of heart failure sodium intake may be restricted to 500 mg/day
83
2.1.2
Obesity
Obesity has generally been defined as body mass index (BMI) ≥30 kg/m2. For Asian Indians
25 kg/m2 is accepted as the upper level of normal BMI. However, HF patients with BMI
between 30-35 kg/m2 have lower mortality and hospitalization rates as compared to
those with BMI in normal range.
84
It has been shown that overweight (25–29.9 kg/m2) and obese patient with heart failure
have better survival than patients with ideal body weight (BMI 18.5 to 24.9 kg/m2).85,
86 Low BMI (<18.5 kg/m2) subjects with HF appear to have the highest mortality. Reasons
for this “obesity paradox” remain unexplained. Until further data are available, caloric
restriction as part of the treatment of the severely obese patient with HF and weight
stabilization or reduction in overweight and mildly obese patients seem reasonable.
2.1.3
Fluid intake
Fluid restriction is indicated in setting of symptomatic hyponatraemia whether or
not it is caused by pharmacological therapy. In the outpatient setting, fluid restriction
generally is indicated for advanced HF refractory to high doses of oral diuretic agents.
Most HF management programs monitor patient volume status reliably and effectively
by measuring daily morning weight. Non-adherence with dietary sodium restriction or
pharmacological therapy for HF, use of non-steroidal anti-inflammatory agents and
glitazones and excessive high fluid intake (>6 l per day) are the usual causes of
diuretic refractoriness.
2.1.4
Nutritional management
Cardiac cachexia is associated with stimulation of cytokines, tumor necrotic factor-α
and chronic low cardiac output state. Special nutritional recommendations have been
made regarding frequency and size of meal to ensure high energy diet. There is no
evidence for use of anabolic steroids.
Multivitamin and mineral supplementation, especially thiamine, may be recommended
as all patients, who are on diuretic therapy, are usually deficient of essential vitamins
and minerals.87, 88
Naturoceutical products including ma huang, ephedrine metabolites, hawthorne or imported
Chinese herbs are contraindicated in HF.
89
2.1.5
Lifestyle modification
The diagnosis of HF and its prognosis usually provoke anxiety. Relaxation techniques
like meditation and yoga may improve patient daily functioning.
90
Standard heart failure therapy may worsen sexual dysfunction leading to discontinuation
of HF therapy and deterioration of HF symptoms. Phsophodiesterase – 5 inhibitors can
be safely used in compensated HF patient but not with nitrates.
The reversal of ventricular remodelling and normalization of left ventricular ejection
fraction after cessation of alcohol consumption are established facts.91, 92
2.1.6
Exercise rehabilitation
Several studies have reported that physical conditioning by exercise training improves
functional aerobic capacity, health related quality of life and hospitalization rate
in patients with HF. One large randomized controlled trial has reported a modest but
non-significant reduction in primary composite outcome of all – cause mortality or
all – cause hospitalization.93, 94 In a recent Cochrane review on exercise training
which included 33 trials with 4740 patients with HF (majority HFrEF), it was reported
that there was trend of reduction in mortality.
94
Regular aerobic exercise and inspiratory muscle training programs are recommended.
2.1.7
Other therapies
2.1.7.1
Continuous positive airway pressure
Sleep disorders are highly prevalent in HF patients. It is therefore recommended that
formal sleep evaluation should be undertaken in patients who remain symptomatic despite
optimal HF therapy. It has been shown that use of continuous positive airway pressure
(CPAP) reduces edema, daytime muscle sympathetic nerve activity, systolic blood pressure,
frequency of ventricular premature beats during sleep and improves LV function.95,
96, 97 A Canadian trial found that patients randomized to CPAP had increased LVEF,
improved nocturnal oxygenation and improved 6 min walk distance but no survival benefit
was reported.
98
However, CPAP may be harmful in presence of central sleep apnoea.
2.1.7.2
Supplemental O2
Oxygen supplementation is a useful adjunct in hospitalized HF patients during acute
decompensation. Resting or exertional hypoxemia due to pulmonary congestion requires
increased dose of diuretic agent rather than supplemental O2 therapy.
2.1.7.3
Vaccination
Polysaccharide and conjugated pneumococcal vaccine every 5 years and influenza vaccination
every year are recommended in all HF patients who do not have any known contradictions.
573
2.2
Pharmacological management of acute HF
2.2.1
Aims of management
•
Identification of the hemodynamic profile of patient (by assessing the volume status
and adequacy of systemic perfusion),
•
Identification of the precipitating factor,
•
Relieving symptoms,
•
Directly improving short- and long-term outcomes,
•
Initiation and optimization of long-term therapies.
The central hemodynamic components of decompensated heart failure are the elevation
of filling pressures and the reduction of cardiac output. The assessment of these
hemodynamic profiles helps to direct the pharmacotherapy.
99
Profile B, “warm and wet,” with congestion and adequate perfusion is the most common
type. (Fig. 6, Fig. 7)
Fig. 6
Evaluation of heart failure profiles
99
.
Fig. 6
Fig. 7
Treatment outline for heart failure profiles
99
.
Fig. 7
2.2.2
Optimizing volume status
The rate of diuresis should achieve desirable volume status without causing a rapid
reduction in intravascular volume, which may result in symptomatic hypotension or
renal dysfunction. Diuretics are the mainstay of therapy in acute decompensated heart
failure to decrease volume overload. To date, diuretics have not improved survival
in HF patients. Current guidelines recommend intravenously administered diuretics
as first line therapy for volume overload.
100
Loop diuretics are initial diuretics of choice. DOSE Trial randomized diuretic administered
as continuous infusion or twice daily intravenous bolus. The co primary endpoints,
patient global assessment of symptoms and mean change in serum creatinine at 72 h,
were not significantly different between treatment groups. High dose bolus injection
may cause vestibular toxicity. For secondary endpoints, higher doses were associated
with significantly improved net urine output, weight loss, and dyspnea balanced by
worsening renal function.
101
(Table 11, Table 12)
Table 11
Use of Diuretics for correction fluid overload.
101
Table 11
Diuretic naïve: Furosemide 20–40 mg iv bolus.Previously taking diuretic: Furosemide
2.5 x previous dose (max 180 mg) (1–2 x previous dose if declining renal function,
low albumin or SBP <90 mm Hg).If inadequate diuresis consider:
•
Increasing iv dose or
•
Switching to continuous iv infusion or
•
Add diuretic with different mechanism (e.g. metolazone, hydrochlorthiazide, chlorthalidone)
Table 12
Comparison of commonly used Diuretics available for management of HF.
Table 12
Furosemide
Bumetanide
Torsemide
Metolazone
Chlorothiazide
Mechanism of action
Loop Diuretic
Loop Diuretic
Loop Diuretic
Thiazide-like diuretic
Thiazide diuretic
Bioavailability
40%–70%
80%–95%
80%–90%
65%
N/A
Dose Equivalents
PO: 40 mg. IV:20 mg
1 mg
20 mg
N/A
N/A
Usual oral dosing
40–80 mg once or twice daily, max 600 mg/d
1–2 mg once or twice daily, max 10 mg/d
20–40 mg once or twice daily, max200 mg/d
2.5–5 mg once daily, max 10 mg/d
N/A
Usual intravenous bolus dosing
Diuretic naïve: 40–80 mg q8–24 h
Diuretic naïve:0.5–1 mg q8–24 h
Diuretic naïve: 10–20 mg q8–24 h
N/A
250mg–500 mg q12–24 h,max 2 gm/day
Diuretic PTA:
Diuretic PTA:
Diuretic PTA:
1–2.5 x PO dose PTA*.
1-2.5 x PO dose PTA*
1-2.5 x PO dose PTA*
May repeat in 2–3 h. Max 600 mg/d
May repeat in 2–3 h. Max 10 mg/d
May repeat in 2–3 h. Max 200 mg/d
Usual intravenous continuous infusion dosing
40–80 mg IVB load, then 5–10 mg/h.max 40 mg/hr
1–2 mg IVB load,then 0.5–2 mg/h.max 2 mg/hr
20–40 mg IVB load,then 5–20 mg/h.max 20 mg/hour
N/A
N/A
Duration of action
4–6 h
6–8 h
12–16 h
12–24 h
6–12 h
IVB = intravenous bolus, PO = oral,PTA = prior to admission.
In patients who are refractory to high dose loop diuretics, combining a loop diuretic
with a distal tubule acting agent such as oral metolazone or intravenous chlorthiazide
produces a synergistic diuretic effect. Inotropic therapy should generally be reserved
for patients with evidence of low cardiac output. Administration of low dose dopamine
to enhance diuresis has been abandoned. Results from the DAD II suggested no difference
between high-dose furosemide, low-dose furosemide, and low-dose furosemide plus dopamine,
on mortality or readmission for ADHF.
102
The EVEREST Trial randomized 4133 patients with ADHF (LVEF ≤40%) to tolvaptan or placebo.
103
The primary outcome was significantly improved with tolvaptan; however, this benefit
was driven primarily by reduction in weight loss.
Ultrafiltration reduces pulmonary artery pressure and increases diuresis. Complications
of ultrafiltration include those associated with central venous access and intravascular
depletion. Beneficial effect on weight loss as compared to diuretics is not full proof.
Plasma creatinine increases more than with diuretics.104, 105
At present the role of ultrafiltration is restricted to diuretic resistant cases and
dyselectrolytemia.
2.2.3
Vasodilators
Intravenous vasodilators often provide rapid symptom resolution, especially in patients
with acute pulmonary edema or severe hypertension. Vasodilators should be avoided
in patients with reduced filling pressures or symptomatic hypotension. But there is
little evidence for improved outcome. Nitroglycerin exhibits primarily venodilation
at low doses and mild arterial vasodilation at higher doses; thus, it is the preferred
agent for preload reduction.
106
Nitroprusside is a balanced arterial and venous vasodilator which results in augmentation
of cardiac output and reduction in filling pressure with greater reduction in pulmonary
artery pressure, systemic vascular resistance, and blood pressure. It is used primarily
in patients with high systemic vascular resistance and often requires invasive hemodynamic
monitoring. The primary disadvantages of nitroprusside are hypotension, tachyphylaxis
and risk of cyanide and thiocyanate accumulation. In patients with substantial hepatic
or renal impairment, this agent should be avoided or dose and duration of therapy
should be minimized.
Nesiritide or human B-type natriuretic peptide produces dose-dependent venous and
arterial vasodilation with increase in cardiac output and natriuresis. This agent
should be used for selected patients (Table 13).107, 108, 109
Table 13
Vasodilators for management of acute heart failure.
Table 13
Nitroglycerin
Nitroprusside
Nesiritide
Mechanism
Increase NO synthesis and cGMP
Increase NO synthesis and cGMP
Activate guanylate cyclase-linked NP receptor A to increase cGMP
Clinical effects
Vasodilator(venous arterial)
Vasodilator(venous = arterial)
Vasodilator(venous = arterial)
Indication
Warm & wet.Cold & Wet.HTN Crises.ACS
Warm & wet.Cold & Wet.HTN Crises
Warm & wet.Cold & Wet
Usual dosing
10-30mcg/min and titrate by 10–20 mcg/min every 10–20 min to max 200 mcg/kg/min
0.1-0.2mcg/kg/min and titrate by 0.1-0.2 mcg/kg/min every 10–20 min to max 2 mcg/kg/min
0.1mcg/kg/min and titrate by 0.005 mcg/kg/min every 3 h. to max 0.03 mcg/kg/min
Onset.Half-life
1–5 min1–4 min
1 min10 min
15–30 min20 min
Elimination
Inactive metabolites in urine(no renal/hepatic adjustment)
Cyanide (hepatic). Thiocynate (renal)
NP receptor C(no renal/hepatic adjustment)
ACS = acute coronary syndrome.cGMP = cyclic guanosine monophosphate.HTN = hypertensive.NO = nitric
oxide.NP = natriuretic peptide.
2.2.4
Inotropic agents
Dobutamine stimulates β-adrenergic receptors with little effect on α-adrenergic receptors,
so that contractility is increased with peripheral and pulmonary vasodilation. It
is started at a high dose and de-escalated to the lowest dosage to maintain the desired
effect. Patients receiving chronic maintenance infusions generally exhibit tachyphylaxis
and require increasing dosages over time.
Dopamine stimulates β-receptors, α-receptors and dopaminergic receptors that cause
vasodilation in renal and peripheral vasculature. At dosages of 3 μg/kg/min or less,
dopamine is predominantly vasodilatory. Alpha-adrenergic stimulation dominates when
dopamine doses reach 5 μg/kg/min, or when other vasopressors are given. When blood
pressure support is the initial need, dopamine should be started at a dosage of at
least 4 μg/kg/min. Similarly, when patients are weaned from the use of dopamine as
a pressor agent, it may be necessary to discontinue it once a dosage of 3 μg/kg/min
is reached.
Milrinone is a phosphodiesterase-III inhibitor that blocks degradation of cAMP. Milrinone
is the drug of choice in patients receiving chronic beta-blocker therapy because its
inotropic effects don’t involve stimulation of beta-receptors. In patients with cardiogenic
shock on beta blockers, initial noradrenaline followed by milrinone is recommended.110,
111, 112, 113
Epinephrine and Norepinephrine provide significant additional inotropic and blood
pressure support for short-term life-saving intervention. Both norepinephrine and
epinephrine stimulate type 1β-adrenergic receptors and α-adrenergic receptors, increasing
contractility, heart rate, and peripheral vascular resistance, while promoting cardiac
arrhythmias and ischemia. These should not be administered except in true emergency
situations.
Vasopressin is used increasingly to potentiate the effects of catecholamines in patients
who remain severely hypotensive despite high-dose pressor support.114, 115 Vasopressin
has been used for days, in doses of 0.05 to over 0.1 U/min. Although vasopressin is
considered an antidiuretic hormone, its use in critical settings is sometimes associated
with profound water diuresis that reverses after discontinuation of the drug. (Table
14)
Table 14
Hemodynamic effects of ionotropic agents.
Table 14
CO
PCWP
SVR
MAP
HR
Dobutamine
↑↑↑
↓/⟵→
↓
↓/⟵→
↑/⟵→
Dopamine- moderate
↑↑
↑/⟵→
↑/⟵→
↑↑
↑
Dopamine- high
↑
↑
↑↑↑
↑↑
↑↑
Milrinone
↑↑
↓
↓↓
↓/⟵→
↑/⟵→
Levosimendan
↑↑↑
↓↓
↓↓
↓
↑
Levosimendan sensitises troponin C to calcium thereby improving myocardial contractility
and haemodynamics. Levosimendan also has vasodilatory and anti-ischaemic properties.116,
117, 118 Levosimendan is currently used in cardiogenic shock in combination with other
vasopressors and over dobutamine only if reversal of beta-blockers is needed to improve
the hypo perfusion.
2.2.5
Ventilatory support
Supplemental oxygen and assisted ventilation should be reserved for patients with
hypoxaemia. In the very few studies that have systematically examined effects of increasing
FiO2, oxygen supplementation causes a fall in cardiac output and increases in SVR
and cardiac filling pressures. In a study by Gray et al., 1069 patients with AHF admitted
with cardiogenic pulmonary oedema and arterial pH of less than 7.35 were randomised
to standard oxygen therapy, continuous positive airway pressure (CPAP), or non-invasive
intermittent positive pressure ventilation (NIPPV). Compared to standard oxygen therapy,
non-invasive ventilation (CPAP or NIPPV) did not alter 7- and 30-day mortality, but
did lead to greater reduction in dyspnoea, heart rate, and hypercapnia
118
. A subsequent meta-analyses on the use of non-invasive positive pressure ventilation
(NIPPV) showed a reduction in hospital mortality compared to standard treatment.
119
This is not suitable for mentally obtunded patients.
Apart from above measures the guideline directed therapies being taken by patient
for heart failure before decompensation also needs to be titrated according to need.
(Table 15)
Table 15
Optimizing therapies for chronic heart failure during acute decompensation.
Table 15
Medication
Transition in Hospital
Monitoring
Diuretics
Continue or augment(if indicated).unless signs/symptoms of dehydration
Daily weight (standing)Strict intake and outputVital signs(BP,HR,RR,O2 saturation)
including orthostatic BP,HRBUN. Serum creatinine Serum potassium and magnesium
Beta blockers and ARBs
Continue unless decompensation due to recent addition or dose increase (in which case
reduce dose) Discontinue if significant hypotension,bradycardia, or overt cardiogenic
shock
BP and HR including orthostatic BP, HR
ACE inhibitors and ARBs
Continue. unless hypotension or acutely worsening renal function
BP and HR including orthostatic BP,HRStrict intake and outputBUN. Serum creatinineSerum
potassium
MRAs
Continue unless K >5.5 CrCI <30 ml/min
BP and HR including orthostatic BP,HRStrict intake and outputBUN. Serum creatinineSerum
potassium
Digoxin
Continue unless acutely worsening renal function. Significant bradycardia (HR <45bpm),
Or signs/symptoms of toxicityNote:half-life = 36 h if normal renal function (minimum
of 5–7 days to reach steady state post initiation or dose change)
HRSerum CreatinineSerum potassium, magnesium, and calciumSerum digoxin concentration
(at least 6 h post dose) if not recently obtained, change in renal function, or addition/removal
of interacting medication
Hydralazine + Isosorbide dinitrate
Continue unless significant hypotension
BP and HR including orthostatic BP. HR
ACE = angiotensin converting enzyme, ARBs = angiotensin receptor blockers, BP = blood
pressure, BUN = blood urea nitrogen, CrCI = creatinine clearance, HR = heart rate,
K+ = potassium, MRAs = mineralocorticoid receptor antagonists, O2 = oxygen,RR = respiratory
rate.
2.3
Pharmacotherapy of heart failure with reduced ejection fraction (HFREF)
The major goals of treatment in patients with HFrEF are to improve symptomatic status
and functional capacity, prevent recurrent hospitalizations and reduce mortality.
This section discusses the pharmacotherapy of HFrEF, Stage C with special focus on:
A. Renin-Angiotensin System (RAS) inhibition
A1. ACE Inhibitors (ACEI)
A2. Angiotensin receptor blockers (ARB’s)
A3. Is a combination of ACEI/ARB recommended for HFrEF?
B. Angiotensin receptor-Neprilysin inhibitors (ARNI)
C. Beta-blockers
a. What first: ACEI or beta-blocker or simultaneous initiation of both?
D. Mineralocorticoid receptor antagonists (MRA’s)
E. Diuretics
F. Ivabradine
G. Digoxin
H. Hydralazine and Isosorbide di nitrate
I. Diuretics
J. Pharmaco-economic aspects of HF in India
K. Summary
A 1 RAS Inhibition (RAS) with ACEI
•
Therapy with ACEI leads to symptomatic improvement, reduced hospitalization and significantly
reduces adverse outcomes in patients with HFrEF. Various randomized controlled trials
(RCTs) have established the role of ACE inhibition in patients across the spectrum
of HF (mild, moderate and severe HF) in those with and without coronary artery disease.120,
121, 122, 123, 124, 125 Meta-analysis of previous ACEI trials have reported lower
all-cause mortality (odds ratio [OR], 0.77 P < 0.001) as well as lower mortality and
HF hospitalization (OR, 0.65 P < .001) in those receiving ACEI.
126
All ACEI’s are reported to reduce the combined end point of mortality and hospitalization
for HF, suggesting a “class effect” with no significant differences among the available
ACEI in their effects on symptoms.
•
Clinical Use:
○
ACEI should be started at low doses (listed in Table 16) and titrated upward (as tolerated)
to doses shown to reduce the risk of cardiovascular events in clinical trials. Dose
adjustments may be made at 1–2 weekly intervals. In case maximal doses are not tolerated,
the immediate lower doses should be tried.
Table 16
Commonly Used drugs in HFrEF and their dose schedules.
Table 16
ACE inhibitors
Initiating dose
Maximum dose
Captopril
6.25 mg 3 times
50 mg 3 times
Enalapril
2.5 mg twice
10 to 20 mg twice
Lisinopril
2.5 to 5 mg once
20 to 40 mg once
Perindopril
2 mg once
8 to 16 mg once
Ramipril
1.25 to 2.5 mg once
10 mg once
ARBs
Losartan
25 to 50 mg once
50 to 150 mg once
Valsartan
20 to 40 mg twice
160 mg twice
ARNI: Sacubitril/valsartan
49/51 mg sacubitril/valsartan bd OR lower dose 24/26 mg BID)
97/103 mg BID (sacubitril/valsartan)
Beta blockers
Bisoprolol
1.25 mg once
10 mg once
Carvedilol
3.125 mg twice
50 mg twice
Carvedilol CR
10 mg once
80 mg once
Metoprolol succinate extended release
12.5 to 25 mg once
200 mg once
Aldosterone antagonists
Spironolactone
12.5 to 25.0 mg once
25 mg once or twice
Eplerenone
25 mg once
50 mg once
Ivabradine
5 mg bd
7.5 mg bd
Loop diuretics
Bumetanide
0.5 to 1.0 mg od/bd
10 mg
Furosemide
20 to 40 mg od/bd
600 mg
Torsemide
10 to 20 mg od
200 mg
Thiazide diuretics
Chlorothiazide
250 to 500 mg od/bd
1000 mg
Chlorthalidone
12.5 to 25.0 mg od
100 mg
Hydrochlorothiazide
25 mg od/bd
200 mg
Indapamide
2.5 mg od
5 mg
Metolazone
2.5 mg od
20 mg
Potassium-sparing diuretics
Spironolactone
12.5 to 25.0 mg od
50–100 mg
Eplerenone
25 mg od
50 mg od
Triamterene
50 to 75 mg bd
200 mg
Amiloride
5 mg od
20 mg
Hydralazine/isosorbide dinitrate
Fixed-dose combination
37.5 mg hydralazine/20 mgisosorbide dinitrate tid
75 mg hydralazine/40 mg isosorbidedinitrate 3 times daily
Digoxin
0.125 mg
0.25 mg (serum level < 1.0 ng/mL)
○
Caution should be exercised in patients with low systemic blood pressure, renal insufficiency
(serum creatinine SCr > 2.5 mg/dl), and elevated serum potassium (>5.0 mEq/L). Careful
monitoring of serum potassium and S Cr is imperative; renal function and electrolytes
should be measured at initiation and with each dose adjustment. Although a slight
increase in SCr often occurs after initiation of ACEI, an exact threshold for discontinuing
therapy has not been established. Up to 50% increase in SCr and increase in potassium
not >5.5 mEq/L is generally considered acceptable.
○
Important side effects in patients with HF relate to hypotension and azotemia. However
both are well tolerated and asymptomatic hypotension does not usually require lowering
the dose or drug discontinuation. The azotemia is frequently due to the relative volume-depletion
accentuated by concomitant diuretics and is therefore often improved by reduction
in diuretic dose. Other side effects include cough in 15–30% (a higher incidence has
been reported amongst Indians as compared to Western cohort)
127
and angioedema (which may occur in <1% of patients) the latter often necessitating
drug withdrawal. It is important to distinguish the ACEI induced cough from that due
to pulmonary congestion from worsening HF or cough due to bronchospasm induced by
concomitant beta blocker use. In occasional cases, if the cough significantly impacts
the patient’s quality of life, a change to an ARB, is needed.
○
ACEI should not be administered to pregnant patients or those planning to become pregnant.
○
An abrupt withdrawal of ACEI can often precipitate clinical deterioration and should
be avoided.
•
Recommendations: All patients with prior or current symptoms of HFrEF regardless of
etiology, should be started on an ACEI, unless there is a contraindication.
A 2 RAS Inhibition with ARB’s
•
Angiotensin-receptor blockers offer an alternative approach to the inhibition of the
RAS. and are known to produce favourable hemodynamic, neurohormonal, and clinical
effects as substantiated in different RCT’s.128, 129, 130, 131, 132
•
Analysis of trials in which ARBs were compared with placebo without background ACEI
therapy, confirmed a benefit of ARBs in reducing mortality and hospitalization although
this was only a non-significant trend.
133
Direct comparison with ACEI did not however reveal any superiority of ARB’s in reducing
either mortality or hospitalization
135
•
In patients of chronic HF on ACEI and also receiving beta-blockers, no significant
effect of ARB’s on mortality or combined endpoint of mortality and morbidity was reported.
134
•
In one of the more recent meta-analysis of ACE/ARB’s in HF by Tai et al. (n = 47,662
patients), ACEI reduced all-cause mortality by 11% and cardiovascular mortality by
14%. In contrast, ARBs had no beneficial effect on reducing all-cause or cardiovascular
mortality.
135
•
Hence, based on current evidence, ACEI/beta-blockers should be considered as first-line
therapy to limit morbidity and mortality outcomes in patients with HF and there is
no additional benefit of adding ARB’s in patients taking both ACEI and beta-blockers,
and tolerating them well.
•
Clinical Use:
○
ARBs also need to be started at low doses and gradually titrated upward (see Table
1), and all attempts should be made to use doses that have been shown to reduce cardiovascular
events in RCT’s. Titration is generally achieved by doubling the doses every few days;
it is important to monitor renal function at initiation and with any dose titration.
○
Similar to the recommendations for ACEI, ARBs should be given with caution to patients
with low blood pressure, azotemia or elevated serum potassium. Unlike ACEI, ARBs do
not inhibit kininase and are hence associated with a lower incidence of cough.
○
Although ARBs are a good alternative for patients with ACEI-induced angioedema, patients
may also develop angioedema with ARBs and hence these drugs are best avoided in patients
with ACEI induced angioedema.
•
Recommendations: Patients with prior or current symptoms of chronic HFrEF who are
intolerant to ACEI (due to cough) are candidates for ARB’s.
A3 Combination of ACEI and ARB:
•
Combination therapy with ARBs and ACEI has no added total mortality benefit in chronic
HFrEF. Rather, this increases the side effects and should be avoided.
B RAS Inhibition with ARNI’s: A deeper understanding of the role of natriuretic peptides
in HF led to the development of the combination drug ARNI containing an ARB (valsartan)
and a neprilysin inhibitor (sacubitril). The PARADIGM-HF trial demonstrated that sacubitril/valsartan
(200 mg twice daily, with the ARB component equivalent to valsartan 160 mg) was superior
to ACEI (viz. enalapril target dose 10 mg bd) in patients with HFrEF.
136
•
Clinical Use: In patients already on ACEI, it is important to discontinue these 48 h
prior to initiating sacubitril/valsartan to avoid the risk of angioedema.
○
The usual starting dose is 49 mg/51 mg bd with attempt to double to target dose of
97 mg/103 mg bd at 2–4 weeks as tolerated by the patient. In ACEI/ARB naïve patients,
the starting dose is lower (24/26 mg bd with a slower titration schedule; double every
3–4 weeks).
○
Although the PARADIGM-HF trial enrolled patients with high baseline BNP/NT-proBNP,
it is not mandatory to estimate these biomarkers prior to initiation of ARNI. It is
however important to remember that since BNP levels are elevated in patients receiving
sacubitril/valsartan (due to neprilysin inhibition), NT-proBNP should be used if biomarker
estimation is contemplated for monitoring treatment and assessing HF severity.
○
Do not initiate therapy with ARNI if baseline serum potassium level is >5.4 mmol/L,
SBP <100 mmHg or there is past history of angioedema.
○
In patients with mild renal impairment (eGFR 60–90 ml/min/1.73 m2), no dose adjustment
is required. In patients with moderate (eGFR 30–60) and severe renal impairment (eGFR
<30), caution should be exercised and consider starting dose of 24 mg/26 mg bd, with
subsequent slow titration, assuming there is no deterioration in renal function. The
drug should be avoided in patients with end stage renal disease.
○
In patients with mild hepatic impairment, no dose adjustment is required. In patients
with moderate hepatic impairment, a lower starting dose (as above) should be used.
The drug should not be used in patients with severe hepatic impairment, cirrhosis
or cholestasis.
○
Potential adverse effects include cough, dizziness, angioedema, hypotension, renal
impairment and hyperkalaemia. If after initiating sacubitril valsartan, there is symptomatic
hypotension, SBP <95 mm Hg, hyperkalaemia or renal dysfunction, adjust other medications
(eg diuretics) or temporarily down-titrate or discontinue sacubitril/valsartan.
•
Recommendations: In all patients with chronic symptomatic HFrEF, ACEI (or ARB) and
beta-blockers remain the first line agents. In patients who remain symptomatic despite
optimal therapy with an ACEI, beta blocker and MRA, consider replacement of ACEI with
ARNI. In patients who are tolerating ACEI (or ARB) well, replacement by ARNI may be
considered on an individualized basis.
B Beta-blockers: Adding beta-blockers to standard treatment in patients with HF has
demonstrated significant risk reduction of up to 30–40% in cardiovascular death, sudden
death, hospitalization for worsening HF.137, 138, 139 Based on these data, beta-blockers
are now accepted as a standard pharmacological treatment along with ACEI in the management
of chronic HFrEF. Three types of beta-blockers (bisoprolol and metoprolol succinate
extended release which selectively block beta-1–receptors; and carvedilol, which blocks
alpha-1–, beta-1–, and beta-2–receptors) are recommended for use in patients with
HFrEF.
•
Clinical Use:
○
Initiation of beta-blockers should only be done once the patient is stable and euvolemic
(i.e., no pulmonary congestion and no more than minimal edema). In patients with fluid
retention, beta-blockers should not be prescribed without diuretics, since exacerbation
of volume overload can occur following initiation of beta-blocker therapy. Worsening
HF symptoms with a beta-blocker should not be a reason to avoid them permanently.
○
Beta blockers can be safely started pre-discharge even in patients hospitalized for
HF, provided patients do not require intravenous inotropic therapy for HF. Even when
symptoms are mild or have improved with other therapies, beta-blockers are imperative
and their initiation should not be delayed.
○
Beta-blockers should be introduced in lowest possible doses and titrated gradually
with periodic assessment of heart rate, blood pressure, and clinical status. The usual
recommended schedule is doubling of the dose at 2-week intervals in ambulatory patients
until the target dose is reached or the maximally tolerated dose is achieved. Patients
should be counselled to monitor weight and report weight gain or worsening signs/symptoms
of HF following initiation or up-titration of therapy. If patients are unable to tolerate
target doses, lower doses should still be given, in view of the mortality benefit
across all dose ranges.
○
Common adverse effects of beta-blockers include fluid retention, bradycardia, hypotension,
conduction disturbances and fatigue. Exacerbation of fluid retention or worsening
HF usually responds to intensification of conventional therapy (eg. diuretics) and
does not necessitate permanent drug withdrawal. Effects of beta-blockers on heart
rate and conduction when asymptomatic require no treatment, while in symptomatic cases
reduction in dose or stoppage may be needed. It is important to remember that abrupt
discontinuation should be avoided due to increased mortality risk.
○
The risk of hypotension can be minimized by administering the beta blocker and ACEI
at different times. Most patients with chronic obstructive pulmonary disease tolerate
beta-blockers well, although they should not be initiated in those with active bronchospasm.
These patients tolerate beta-1 selective agents (metoprolol and bisoprolol) better
than carvedilol, which is non-selective. However, beta receptor selectivity is often
lost at higher doses which are used in patients with HF.
•
Recommendations: Use of any one of the three mentioned beta-blockers is recommended
for all patients with current or prior symptoms of HFrEF in absence of contraindications.
C1 What first: ACEI or beta-blocker? There is uniform agreement that beta-blockers
and ACEIs are complementary, and can be initiated together as soon as the diagnosis
of HFrEF is made. When initiating ACEIs (or ARBs) and beta-blockers, clinical judgment
should be exercised as to which drug to start first, although they can be started
concurrently, unless there is a contra-indication to do so. For example, beta-blockers
may be preferable in HF patients with angina or underlying arrhythmias while ACEI
may be useful in those with diabetes or chronic kidney disease. In stable patients,
it is reasonable to add beta-blockers before full target doses of either ACEI or ARBs
are reached. In patients with relevant concerns (eg: hypotension), it is recommended
that the patient should receive a lower dose of a combination of an ACEI (or ARB)
and beta-blocker, rather than either drug as monotherapy, highlighting the importance
of a synergistic effect among these drugs.
C Mineralocorticoid receptor antagonists (MRA’s): Additive RAS blockade in HF patients
by adding a MRA (spironolactone, eplerenone) has demonstrated ∼ 20-25% reduction in
cardiovascular mortality in patients taking a background of standard therapy (ACEI/ARB’s
and/or beta-blocker).140, 141, 142 A recent meta-analysis (14 trials, n = 1575 patients)
reported a mean improvement in LVEF of 3.2% and significant improvement in NYHA class
following treatment with MRA’s in patients with HFrEF.
143
The difference between eplerenone and spironolactone is not the effectiveness of anti-mineralocorticoid
activity but the selectivity of aldosterone receptor antagonism (spironolactone is
a non-selective blocker while eplerenone is a selective blocker).
•
Clinical Use:
○
Baseline SCr should be <2.5 mg/dL (males) and <2.0 mg/dL (females), eGFR >30 mL/min/1.73 m2),
and potassium should be less than 5.0 mEq/L, prior to drug initiation. It is important
to measure renal function and electrolytes at initiation, after 2–3 days, 1 week later
and at regular intervals thereafter (eg. at least monthly for the first 3 months and
every 3 months thereafter). For those with concerns of renal dysfunction or hyperkalemia,
an initial regimen of every-other-day dosing is advised.
○
Patients on MRA’s should avoid potassium supplementation, NSAID’s and foods rich in
potassium. The major risk associated with use of MRA’s is hyperkalemia (reported incidence
2–5%). Appx 10% of male patients may develop breast tenderness or gynaecomastia with
spironolactone and in these patients eplerenone is a useful alternative.
•
Recommendations: Patients of HFrEF (NYHA II–IV, LVEF <35%) who remain symptomatic
on optimal tolerated doses of an ACEI (or ARB) and beta-blocker should be offered
addition of either spironolactone or eplerenone. MRA’s may also be used following
an acute MI in patients who have LVEF <40% who develop symptoms of HF or who have
a history of diabetes mellitus. Triple combination of an ACEI, ARB and MRA’s should
be avoided.
D Diuretics: While diuretics improve fluid retention, symptoms and exercise tolerance,
no significant mortality reduction is reported in patients with HFrEF. Loop diuretics
which act at the loop of Henle (eg. bumetanide, furosemide, and torsemide) are the
preferred agents for most patients with HFrEF due to their potency and rapidity of
action. In those with gut edema, torsemide is preferred over furosemide. The usual
dosing schedule is twice daily with the second dose being administered in the late
afternoon to minimize nocturnal dieresis. Thiazide diuretics (hydrochlorothiazide,
chlorothiazide, metolazone) and potassium-sparing agents (eg, spironolactone) act
at the distal portion of the tubule. Thiazides are weaker diuretics when used alone,
and are often considered for patients with milder degree of fluid retention, especially
in those with underlying hypertension. Except for metolazone, thiazide-like diuretics
are less effective when creatinine clearance (CrCl) is <30 ml/min.
•
Clinical use:
○
In an out-patient setting, diuretic therapy should be initiated at low doses, with
incremental dosing till urine output increases and there is a weight reduction (usually
in the range of 0.5–1.0 kg/day). Further dose adjustments (along with dietary sodium
restriction) may subsequently be needed to maintain target weight and sustained dieresis,
with a final aim to eliminate clinical evidence of fluid retention.
○
The aim of maintenance diuretic therapy is to achieve and maintain euvolemia with
the lowest possible dose and stable patients may be trained to self-adjust their diuretic
dose based on monitoring of signs/symptoms of congestion and weight charting. Patients
who exhibit resistance (poor diuresis despite high doses of oral diuretics), often
respond to intravenous administration (including the use of continuous infusions)
or combination of different classes of diuretics (eg, metolazone or a MRA with a loop
diuretic).
○
Usual side effects of therapy include fluid and electrolyte depletion, hypotension
and azotemia. These effects are exaggerated when diuretics are used in high doses
or in combinations.
•
Recommendations: Diuretics should be used in patients with HFrEF who have evidence
of fluid retention. They are usually combined with an ACEI (or ARB’s), beta blocker,
and MRA’s.
E Ivabradine: This is a selective inhibitor of the If current in the sinoatrial node,
and provides heart rate reduction with neutral effects on BP and cardiac conduction.
Studies have demonstrated the efficacy of ivabradine in reducing the endpoint of cardiovascular
death or HF hospitalization in patients with HFrEF, primarily driven by a reduction
in HF hospitalization.144, 145
•
Clinical Use:
○
Usual initiating and maintenance doses are listed in Table 1. Dose adjustments can
be made every 5–7 days or over 2 weeks to a maximum dose of 7.5 mg bd (according to
heart rate response, to a target rate of < 60 bpm). If resting heart rate is < 50
bpm or patients develop symptoms related to bradycardia, the dose may be reduced to
2·5 mg bd. Side effects include bradycardia, development of AF and rarely torsade’s.
Visual symptoms (phosphenes) are by far the most common side effect, especially in
those on 7.5 mg bd.
•
Recommendations: Ivabradine should be considered in symptomatic HF patients who are
in sinus rhythm and have a resting heart rate ≥70 bpm despite treatment with maximally
tolerated doses of beta-blocker, ACE-I (or ARB), and an MRA. It should also be considered
for patients unable to tolerate a beta-blocker or those who have contra-indications
for a beta-blocker. It should not be used as substitute for beta-blockers.
F Digoxin: Digoxin reduces hospitalization due to HF but does not improve survival
in patients with HFrEF.146, 147, 148 Benefits are reported irrespective of rhythm
(sinus rhythm or AF), etiology of HF (ischemic or non-ischemic) or with/without ACEI.
•
Clinical Use:
○
Typical initiation doses are 0.125 to 0.25 mg daily; lower doses should be used in
elderly (>70 years), females, renal dysfunction and those with lean body mass. In
most cases of HF, there is no need to use loading doses of digoxin to initiate therapy.
Maintenance dose is 125–250 mcg per day with one or two days of drug holiday each
week; in patients with renal impairment, digoxin is given as half doses or alternate
daily.
○
Usual adverse effects include arrhythmias (especially ectopic and re-entrant tachycardias
with AV block), gastrointestinal symptoms (eg, anorexia, nausea, and vomiting), and
neurological complaints (eg, visual disturbances, disorientation, and confusion).
○
Concomitant use of propafenone, verapamil, quinidine and amiodarone can increase serum
digoxin levels and increase the likelihood of digoxin toxicity.
•
Recommendations: Digoxin is beneficial in patients with HFrEF to reduce HF hospitalizations.
Digoxin is generally used as add-on therapy in persistently symptomatic patients,
despite optimal medical therapy. In patients of HFrEF and AF, beta blockers (rather
than digoxin) are usually more effective for rate control, especially during exercise.
G Hydralazine and isosorbide di nitrate: The rationale of this combination is that
both preload and afterload are reduced while hydralazine also prevents nitrate tolerance
obviating the need for a nitrate-free interval. Although previous trials have demonstrated
benefit of this vasodilator combination better efficacy is reported in African American
patients.149, 150, 151, 152
•
Clinical Use:
○
Therapy should be started at low doses (12.5–25 mg hydralazine and 10–20 mg isosorbide
di nitrate tid) and titrated every 1–2 weeks (or every 1–2 days in hospitalized patients
according to tolerability). The target dose is 225 mg of hydralazine hydrochloride
and 120 mg of isosorbide di nitrate daily.
○
Side effects include headache, dizziness, and non-specific gastrointestinal complaints;
patient compliance is also an issue because of the large number of tablets required
and thrice a day dosing.
•
Recommendations: Although recommended for African Americans patients, it remains to
be investigated whether this benefit is evident in patients of other racial or ethnic
origins. It may be used in patients with HF who remain symptomatic despite optimal
therapy with ACEI and beta blockers or those who are not candidates for ACEI (or ARB’s).
H Pharmaco-economic aspects of HF in India
•
Economics of HF care: The impact of HF has resulted in huge economic burden on health
care across the world. The overall global economic cost of HF in 2012 was estimated
at $108 billion per annum.
153
Costs incurred in HF care include:
○
Direct costs: expenditure on hospital and physician services, drugs, follow-up etc.
○
Indirect costs: due to lost productivity, sickness benefit and welfare support.
While in high-income countries, direct costs are 2 times more predominant than the
indirect costs, in middle and low-income countries like India, indirect costs outweigh
direct costs by nearly 9 times. Pharmacotherapy of HF is very resource consuming and
the developed world spends a substantial part of its health budget to manage these
patients. In terms of overall contribution to global HF spending, USA ranks at the
top, accounting for 28.4% of global costs while South Asia accounts for 1.1%, ranking
below Europe (6.83%), Oceania (2.65%) and Latin America (1.46%). This is due to different
epidemiological and etiological landscape of HF and variations in health infrastructure
across the world. India with an overall GDP of 1,841,717 \(million (of which 3.9%
is spent on health) had an estimated HF cost of ∼1186 \) million (direct costs: 80
\(million, indirect cost 1105 \) million) in 2012.
153
•
Gross under-usage of guideline-directed medical therapy (GDMT) in India: There is
only scant data on use of GDMT in patients with HFrEF in India. In-hospital data from
the Trivandrum Heart Failure Registry reported use of GDMT in only 19% and 25% of
in-patients with HF (n = 1205) during hospital admission and at hospital discharge,
respectively.
3
The Practice Innovation and Clinical Excellence (PINNACLE) India Quality Improvement
Program (PIQIP) is a registry for cardiovascular quality improvement in India supported
by the ACC Foundation. Amongst 15,870 out-patients with HF, this registry observed
use of ACEIs/ARBs, beta-blockers, and both in only 33.5%, 34.9%, and 29.6% respectively.
154
Hence despite a huge clinical burden of HF, prescription and use of GDMT is poor in
India. Large patient numbers, sub-optimal doctor-patient ratios, poor accessibility
to health care and affordability of the population are important reasons for this.
In developing economies like India with limited healthcare provision and social welfare,
where majority of the people meet medical expenses on their own (OOP: out-of-pocket
health spending), HF has wide reaching economic implications at the individual, societal
and national levels. The following measures can be useful in providing cost-effective
HF care to Indian patients:
Dedicated HF services with defined national protocols to diagnose, investigate and
mange patients with HF.
Structured telephonic support programs run by trained nurses to advise patients about
simple measures like weight monitoring and adjusting fluid intake have been found
to be useful in reducing recurrent hospital admissions and limiting health care costs.
Focus on early identification of non-responders to reduce morbidity and mortality
of HF.
Closer networking with the industry and government to facilitate availability of quality-controlled
generic medicines for HF in order to bring down the cost of therapy is necessary.
Similar to the lines for treating coronary artery disease, further research needs
to be done in developing “Polypills” for patients with chronic HF incorporating various
low cost generic ingredients.
Summary of pharmacotherapy for HFrEF: vide Fig. 8
Fig. 8
Flow Chart of Pharmacotherapy for HFrEF.
Fig. 8
Other drugs
a.
Oral anticoagulants should be prescribed in patients with chronic HF with permanent/persistent/paroxysmal
AF, additional risk factors for stroke or those with intracardiac thrombus. The choice
of the agent (vitamin K antagonist or newer oral anticoagulants) should be individualized.
b.
There is no role of adjunctive statin therapy in HF in the absence of other indications
for their use
c.
Long-term intravenous infusion of positive inotropic drugs is potentially harmful
for patients with HFrEF, except as palliative therapy for those with end-stage HF
who cannot be stabilized with standard medical treatment.
d.
Amongst calcium channel blockers, verapamil and diltiazem are contraindicated in patients
with HFrEF because of their negative inotropic effects. Newer generation agents (felodipine
and amlodipine) may be used safely in patients with HFrEF and associated refractory
angina or hypertension not responding to guideline recommended HF therapies.
e.
With the exception of amiodarone and dofetilide, most Class I and Class III antiarrhythmic
drugs should be avoided in patients with HFrEF.
2.4
Management of heart failure with preserved ejection fraction
The Trivandrum HF Registry (THER) reported a prevalence of 26% for HFpEF in a patient
population whose mean age was 61.2 years.
155
In another study from AIIMS comprising of rural population in Northern India, overall
prevalence of heart failure was 1.2/1000 and two-thirds had HFpEF and all of them
had uncontrolled hypertension.
12
Non-cardiac comorbidities such as chronic kidney disease, anaemia, malignancy and
thyroid dysfunction are common in HFpEF; chronic kidney disease in particular may
play a dual role in that it contributes to extracardiac volume overload and the development
of the cardiorenal syndrome.156, 157 Obesity is a predictor for HFpEF but not for
HFrEF.158, 159
Diagnostic Criteria for HFPEF(Fig. 9)
•
Presence of symptoms and signs typical of heart failure
•
A preserved ejection fraction (LVEF ≥ 50%)
•
Elevated levels of natriuretic peptides
Fig. 9
An approach to Diagnosis Heart Failure with Preserved Ejection Fraction
165
.
Fig. 9
✓BNP level ≥35 pg/mL
✓NT-proBNP level ≥125 pg/mL
•
Objective evidence of other cardiac structural or functional alteration
✓either left ventricular hypertrophy (increased left ventricular mass index) or
left atrial enlargement
✓diastolic dysfunction on echo (increased E/e’ or decreased e’) or cardiac catheterization
(increased LVEFP or PCWP, particularly with exercise)
2.4.1
Treatment
Principles of Management in Patients with HFPEF
A.
. Avoid tachycardia:
Use digoxin or beta-blockers in patients with atrial fibrillation
B.
Control Blood Pressure:
ACE inhibitors, angiotensin receptor blockers and mineralocorticoid receptor antagonists
may be of greatest benefit due to the physiological benefits seen in HFREF; further
studies are required
C.
Treat comorbid conditions:
Optimise cardiac and non-cardiac conditions (commonly atrial fibrillation, pulmonary
disease, anaemia and obesity)
D.
Relieve congestion with diuretics Judicious use of loop diuretic with careful monitoring
of renal function
E.
Encourage Exercise Training:
Improves exercise capacity and physical function
2.4.2
Fluid retention
Diuretics are necessary to overcome Total blood volume (TBV) expansion and congestion
in both forms of HF. Torsemide, in contrast to furosemide, may have additional positive
effects on collagen metabolism by inhibition of procollagen type I (PIP).
161
The vasopressin antagonist tolvaptan can be effective in severe cases accompanied
by hyponatraemia.
162
2.4.3
Atrial contraction
Patients with HFpEF tolerate atrial fibrillation poorly, especially when ventricular
heart rate is high.
163
Restoration of sinus rhythm may improve clinical symptoms. If this is not possible,
ventricular rate should be lowered using beta-blockers or heart rate lowering calcium
antagonists.
164
2.4.4
RAAS blockade
One study of perindopril in HFpEF has shown benefits on HF hospitalisation within
the first year, but did not achieve its primary endpoint.
165
Two large trials have examined the role of angiotensin receptor blockade in patients
with HFpEF. I-PRESERVE showed no impact of irbesartan on death, hospitalisation or
quality of life.
166
CHARM-Preserved demonstrated a modest impact of candesartan on hospitalization in
HFpEF, but it included patients with an ejection fraction down to 40%.
167
Spironolactone was neutral regarding mortality and hospitalization.
168
Angiotensin receptor neprilysin inhibition is under investigation in patients with
HFpEF in the ongoing PARAGON trial.136, 169
2.4.5
Heart rate modification
Diastole is shortened during tachycardia, and a reduction in heart rate would be presumed
to improve symptoms in patients with HFpEF. Trials of beta blockers have been negative
in this regard.170, 171 Trials of heart rate modification with ivabradine have shown
early positive results, but not consistently across all studies.172, 173
2.4.6
Device therapy
To offset left atrial pressure, an inter atrial shunt can be inserted percutaneously,
with recent trial results suggesting significant improvements in quality of life and
functional capacity.
174
Early trials targeted to offset chronotropic incompetence and improve dyssynchrony
with atrial pacing, with larger trials yet to be completed.
175
2.5
Device therapy in the management of heart failure patients in India
2.5.1
Introduction
Unlike western countries where heart failure is predominantly a disease of the elderly,
in India it affects a younger age group. The actual burden of the problem is unknown
but as per projections there are at least 8–10 million patients with HF in India with
a prevalence of about 1% adult population with a high in-hospital mortality rate of
30.8% and with high post-discharge 6 month re-hospitalization and mortality rates
of 40% and 26%, respectively.2, 3 Many patients remain symptomatic despite guideline-directed
medical therapy (GDMT).
Device therapy in heart failure includes the implantable cardioverter defibrillator
(ICD) and cardiac resynchronization therapy (CRT). Beyond improving the quality of
life and reducing the morbidity, CRT has also shown mortality benefit in selected
patients. However, the cost burden it imparts to a developing economy remains its
Achilles heel. Also many patients who currently fall within the guidelines were not
represented in the clinical trials. The morbidity associated with ICD implant is also
overlooked and the cost-benefit analyses are exaggerated in favour of ICD implant.
The optimal use of this therapy will require better risk stratification methods or
lowering of initial device cost. Hence we need to develop our own guidelines for device
based therapy in HF in a resource limited setting taking into account ethnic, socio-economic
and geological factors.
2.5.2
Device therapy in HF- does it save more lives and is it cost effective?
Randomized trials have demonstrated the efficacy of ICD therapy in the reduction of
subsequent death among patients who have been resuscitated from a cardiac arrest.176,
177, 178 Meta-analyses of secondary prevention trials for ICD showed that the relative
risk reduction of death with the ICD was 28% which was secondary to reduction in arrhythmic
death to around 50%. Though this sounds impressive, relative reductions can be misleading;
dissection of the results showed extension of life by a mean of only 4·4 months by
the ICD over a follow-up period of 6 years.
179
The absolute mortality reduction of 7.9% (number needed to treat = 13) by prophylactic
ICDs should be compared with a 6.1% reduction afforded by ACE inhibitors, 4.4% by
beta-blockers, 2.3% by aldosterone antagonists in patients with LV systolic dysfunction
at intermediate-term follow-up.
DINAMIT and CABG Patch trials clearly showed no mortality advantage of ICD therapy
in primary prevention in HF patients with severe LV dysfunction.180, 181 But other
primary prevention ICD trials, most notably MADIT II and SCD-HeFT, have shown that
prophylactic implantation of an ICD significantly reduced overall mortality.182, 183
Interestingly MADIT II trial was prematurely terminated after 20 months follow up
because prophylactic ICD reduced all-cause mortality (14.2% vs. 19.8%; P = 0.016;
NNT = 18). A post-hoc analysis demonstrated that the mortality reduction appeared
to be entirely attributed to a reduction in SCD (3.8% vs. 10.0%; P < 0.01). A major
limitation of two major primary prevention trials, MUSTT and MADIT studies is that
many subjects did not receive what is now considered standard medical therapy. In
particular, only 8% of patients in the control group in the MADIT trial received beta
blockers compared to 26% of patients in the ICD group at the one-month follow-up.
Similarly, in the MUSTT trial, only 29% of the EPS guided therapy group was prescribed
beta-blockers.
184
In the primary prevention setting ICD implantation has a cost-effectiveness ratio
@ $100,000 (@ Rs 70 lakhs!) per QALY gained.
185
CRT-P therapy in class III/IV HF patients with EF<0.35 and wide QRS>150 ms has been
shown to reduce mortality by 10% (absolute risk reduction) in comparison to only medical
therapy in CARE-HF trial therapy.
186
CRT-D implantation in such patients has shown to have mortality benefit over and above
CRT-P therapy by 6%.
187
In spite of its substantial benefits, CRT is underutilised even in developed countries
like US and Europe. The number of CRT implants increased from 13,000 to 55,000 per
year from 2002 to 2005 in the USA; after 2005 the number of implants did not increase.
188
Hence even the developed nation citizens are finding it difficult to adopt such a
promising but costly therapy. The situation is obviously worse in developing countries
like India.
2.5.3
The actual Indian scenario
In a major survey of cardiac implantable electronic devices (CIED) in India,
189
ICDs and CRT-P/D accounted for 10% each out of the total devices implanted. Surprisingly
the indication for ICD implantation was almost equal for primary and secondary prevention
and single chamber ICD was most commonly implanted (65%). Coronary artery disease
was the etiology in 59% of patients with ICD implants. CRT pacemakers were implanted
mostly in patients with NYHA III/IV (82%), left ventricular ejection fraction <0.35
(88%) with CRT-P being most commonly used (57%). In another Indian study on pacemaker
and complex CIED,
190
among the total patients who underwent implants, CRT and ICD accounted for 14%.
Hence, when this is projected to the HF population in India with prevalence around
8 million, device therapy in HF is still in its infancy in terms of its usage. The
main hindrances for optimal use of CIED in HF patients include cost, understanding
of the disease from patient and physician perspective, risk involved with implantation
procedure, availability of experienced implanters in many areas and the need for long
term follow up and management.
2.5.4
Ethnicity- does it matter?
Even within Asian population considerable ethnic differences prevail which was illustrated
in a HF outcome study in Singapore,
191
with Indians and Malays incurring a worse prognosis than ethnic Chinese. The greater
burden of diabetes and atherosclerotic vascular disease in Indians may explain their
worse outcome. When the MADIT-II criteria were applied to a Japanese cohort, patients
who were eligible but did not undergo ICD implantation showed significantly lower
risk of SCD and even better overall survival than the historical Western MADIT-II
population.
192
In contrast, when applied to a Chinese cohort, those satisfying the MADIT-II criteria
were found to be at similar risk of SCD compared with the original Western MADIT-II
population.
193
Thus, previous Asian studies have been criticized for their small sample sizes, possible
selection bias, and retrospective nature. However, they clearly demonstrate the ambiguity
regarding the risk of SCD among Asian patients. Hence these data clearly explains
that CIED for primary prevention may not be that encouraging in our setting especially
in the background of a strained health care economy.
2.5.5
Proposed Indian consensus recommendation
2.5.5.1
ICD therapy for heart failure
i)
Secondary prevention:
ICD implantation is strongly recommended in patients with a history of hemodynamically
significant sustained ventricular arrhythmia or resuscitated sudden cardiac arrest
survivor in the absence of a reversible medical cause and a minimum life expectancy
of more than 2 years. This is in cohesion with the western guidelines and where the
benefit of ICD is expected to be the most. Hence appropriate patients falling under
this category should undergo ICD therapy. In the case of financial constraints refurbished
devices may be strongly considered which have shown equal efficacy and safety rates
as compared to the newer devices.190, 194 Patients in terminal HF with multiple co-morbidities
or stage IV HF without enrolment in any heart transplantation programs should be refrained
from ICD implantation.
ii)
Primary prevention:
ICD therapy is suggested for primary prevention of sudden cardiac death to reduce
total mortality in selected patients with:
•
Non-ischemic dilated cardiomyopathy or ischemic heart disease at least 40 days post-MI,
with LVEF of <0.35 and NYHA Class II or III symptoms, or <0.3 with NYHA Class I.
•
With one additional risk factor such as: Frequent ventricular premature complexes
or non-sustained ventricular tachycardia on Holter monitoring.
These are recommendations for primary prevention in Western guidelines
195
but for a country like India, these should be individualized and financial resources
of the patient and the government reimbursement also needs to be factored in. In clinical
practice, not all patients in this subset are getting ICD implants. We think for Indian
patients, ICD for primary prevention should be individualized. This needs one-to-one
discussion with patient and relatives before undergoing ICD for primary prevention.
On the other hand, we feel that it is also not mandatory to implant ICD if the finance
of the patient is constrained. This is especially valid when the cardiologist or the
electrophysiologist feels the risk of SCD is not considerable.
In borderline cases, ICD implantation should not be based only on scientific trial
data. This typically includes
1. Patients with CAD and LV dysfunction with EF 0.35 to 0.40:
Aggressive anti-ischemic therapy including revascularization is recommended whenever
necessary. Holter monitoring is advised to check for complex ventricular ectopy and
an electrophysiological study (EPS) may be indicated in case of presence of other
risk markers
2. Patients with CAD, LVEF <0.35 with NSVT or complex ventricular ectopy:
EP study to determine inducibility of VT can be strongly considered before embarking
on to ICD therapy in such patients. If sustained VT is inducible, the patient should
receive an ICD. Before implantation of the ICD, it should be ensured that the patient
has not had a recent MI (within 1 month) or revascularization procedure within 3 months
•
Patients with CAD, LVEF <0.30 and no ambient ventricular ectopy should not be advised
an ICD indiscriminately. Further risk stratification in this group should be based
on clinical (NYHA class, QRS width and morphology) and electrophysiological risk markers
on EP study, non-invasive risk markers such as heart rate variability, micro T wave
alternans, signal averaged ECG changes etc.
We recommend an ICD not be prophylactically implanted in
1.
NYHA Class IV HF patients who are not expected to improve with any further therapy
and who are not candidates for cardiac transplant or mechanical circulatory support
2.
Patients with CAD, poor LV function and recurrent hospitalizations for heart failure
should probably not receive an ICD in the absence of a heart failure program/cardiac
resynchronization therapy. Survival in these patients is poor due to competing risk
of pump failure death and significant longevity will not be achieved by addressing
arrhythmic risk alone.
3.
HF patients with EF 0.35 to 0.40 and in some patients even with EF <0.35 without any
high-risk features for SCD.
2.5.6
ICD − single chamber or dual chamber
Unless there is a definite current or future risk of bradycardia needing pacing, a
single chamber ICD should be preferred for prevention of sudden cardiac death. This
is relevant for Indian population as dual chamber ICDs are significantly more expensive,
with less battery life and hence lower warranty period.
2.5.7
Current recommendation for CRT therapy- an Indian perspective
2.5.7.1
Proposed consensus statement
Though the present ACC/AHA guidelines
195
recommend CRT even for class I patients with all appropriate criteria, in the Indian
scenario that might be overenthusiastic. We would rather advise to plan mostly for
Class III/ambulatory class IV patients, though no bar on Class II patients as per
present guidelines, if feasible.
Indications for Cardiac Resynchronization Therapy
•
CRT is indicated for patients who have LVEF of <0.35, in sinus rhythm, LBBB with a
QRS duration of 150 ms or greater, and NYHA Class III, or select ambulatory IV patients
after exhausted or failed maximal guideline directed medical therapy (GDMT) and without
extensive scar burden.
•
CRT can be considered for patients who have LVEF of <0.35, in sinus rhythm, LBBB with
a QRS duration of 120–150 ms with echocardiographic evidence of dyssynchrony and NYHA
Class III, or select ambulatory IV patients after exhausted or failed maximal GDMT
and without extensive scar burden.
•
CRT can be considered for patients who have LVEF of <0.35, in sinus rhythm, a non-LBBB
pattern with a QRS duration of 150 ms or greater, NYHA class II symptoms on GDMT and
echocardiographic evidence of dyssynchrony.
•
CRT can be considered in patients with AF and LVEF of <0.35 if the patient requires
ventricular pacing or otherwise meets CRT criteria. Cardioversion of AF should be
attempted aggressively in these patients before or after CRT.
•
CRT can be considered for patients who have LVEF of <0.35 and are undergoing placement
of a new or replacement pacemaker implantation with anticipated requirement for significant
(>50%) ventricular pacing
CRT is not indicated for patients
1.
Whose co-morbidities limit expected survival to <1 year
2.
HF patients with non-LBBB Pattern with a QRS duration of <150 ms
3.
HF patients with QRS duration <120 ms and only echo evidence of dyssynchrony
When CRT is implanted in younger patients, without co-morbid illnesses, the risk of
ventricular arrhythmias should be carefully assessed and CRT-D should be considered
in patients at high-risk.
2.5.8
Long term follow up of device therapy in HF
Following up HF patients with device implantation incur additional expenditure in
the case of device explantation, lead extractions and pulse generator replacement.
A recent study has demonstrated when ICD patients are followed up, almost 26% of the
patients no longer met guideline-driven indications for an ICD at the time of generator
replacement and an additional 34% had not received any appropriate ICD therapies.
Patients with an initial LVEF of 0.30-0.35 were less likely to meet indications for
ICD therapy at the time of replacement. Patients without ICD indications subsequently
received appropriate ICD therapies at a significantly lower rate than patients with
indications (2.8% vs. 10.7% annually, p < 0.001). If ICD were not replaced in these
patients without ICD indications in the first place, the cost savings would be $1.6
million.
196
2.5.9
Myocardial scar and response to CRT therapy
Myocardial scar burden in patients with ischemic cardiomyopathy is an important determinant
of response to CRT. A large myocardial scar burden assessed by either single-photon
emission computed tomography imaging or magnetic resonance imaging (MRI) is associated
with a poor response to CRT and a poor prognosis. The association between higher scar
burden and poor CRT response may partially explain why patients with non-ischemic
cardiomyopathy tend to respond better to CRT than those with ischemic cardiomyopathy.
The location of scarring in reference to the LV lead has been shown to be an important
factor for the success of CRT. A lead with its tip placed in a scar region is unlikely
to pace the left ventricle effectively, if at all
2.5.10
Summary and conclusions
Device therapy is a boon for HF patients as it has got absolute mortality benefit
in addition to reduction in HF admissions and improving the quality of life. It should
be considered only after exhausting aggressive GDMT. ICD in HF patients is appropriate
in secondary prevention of SCD. The role of ICD for prophylactic reduction of arrhythmic
deaths in all HF patients with EF < 0.35 is debatable especially in our setting inspite
of established western data in the same regard.
CRT therapy is beneficial in i) HF patients with EF <0.35 and in class III, ambulatory
class IV and selected class II patients, sinus rhythm, LBBB >150 ms or ii) LBBB of
120–150 ms with echocardiographic evidence of dyssynchrony and with expected survival
to be at least 2 years.
End stage decompensated HF patients may be refrained from device therapy due to poor
prognosis. But when such patients are enrolled into a heart transplant program which
is becoming a reality in India then device therapy can be considered after stabilisation
in selected patients. In the needy poor HF patients with appropriate indications for
device therapy, refurbished devices can be considered which has shown good efficacy
and safety profile compared to new device implants in Indian population. For cost
consideration we often only think about the first implantation; the cost of delayed
complications and generator replacement should also be considered.
2.6
Device therapy in heart failure: ventricular assist devices and other circulatory
support systems
Both the incidence and prevalence of end-stage heart failure is increasing alarmingly
in India.
197
Optimum medical management and interventional therapy has rapidly improved in the
last decade. However, there still are about 1–5% of patients in end stage heart failure
who need higher support. Prognosis for advanced heart failure is poor worldwide
197
and especially so in India; the life expectancy for majority of patients being 6 months
to 1 year. The availability of donor organ hearts and the current surgical infrastructure
in our country is woefully short to tackle the current need for heart transplantation.
The modality of mechanical circulatory support was introduced in India about 20 years
back; but has gained popularity only in last 5 years. Availability of this improving
technology is a significant advance that improves survival and quality of life significantly
in patients with advanced heart failure.
198
The following review briefly outlines the current status of assist device therapy
specially keeping the Indian scenario in context.
2.6.1
Lvads − basic definition, working and when to use
Ventricular assist devices are pump-flow devices that can temporarily or permanently
support a patient’s circulatory system to bolster the function of an end-stage/failing
heart. The goal is to divert blood away from the failing ventricle, give rest to the
ventricle and maintain adequate cardiac output meanwhile.
199
Main components − The LVADs have an inflow connection to the left ventricle, a pump
that produces continuous (current generation devices) blood flow bypassing the ventricle
and an outflow tube graft that is connected to the aorta. All these 3 components rest
inside the pericardial cavity. There is an electrical driveline that exits from the
iliac fossa and connects the pump to an external rechargeable battery. The computerized
settings of the pump can be altered with a controller unit and a monitor to optimize
pump output with minimal power consumption.
There are well-defined subsets of clinical situations where LVADs are currently used.
200
1.
As Bridge to transplant (BTT) – For ESHF patients who are wait-listed for heart transplant.
2.
As Destination therapy (DT) – For patients who cannot be given the option of heart
transplantation because of currently listed contraindication. Increasing number of
LVAD implantations are DT implants in current clinical practice.
3.
As Bridge to decision (BTD)/Bridge to candidacy – Some patients are too sick at the
time of admission to hospital and their candidacy for heart transplantation is not
established. For them, a period of support with LVAD triages the best course of action
to be followed for them. This forms a small group of implants.
4.
Bridge to recovery (BTR) – In patients with severe acute myocarditis but with possibility
of myocardial recovery, VADs help to tide over the crisis period with significant
unloading of the supported ventricle. Rarely used in our country.
2.6.2
Commonly used devices in India
Heartmate II, Heart mate III and the Heart ware VADs are in current use.
2.6.3
Indications and contraindications
Broad philosophy of LVAD implantation (Based on European Society of Cardiology and
American Heart Association guidelines) for patients in ESHF201, 202 –
Group 1 patients (BTT indication) – Patient suitable for heart transplant; waiting
for donor heart. These patients are on transplant waiting list, have met all institutional
criteria for heart transplantation and are significantly symptomatic (Stage D or NYHA
Class IV). These patients have low peak VO2 (<14 ml/kg/min), are inotrope dependent,
may have starting end-organ damage due to chronic low cardiac output, may be CRT non-responders,
need increasing diuretics or have intolerance to dilator medicines). In these patients,
LVAD is to be implanted (Class I indication) to
–
Improve symptoms
–
Reduce PVRI
–
Reduce episodes of heart failure hospitalizations
–
Reduce risk of death in waiting period before transplant
Group 2 patients, (DT indications) – LVAD implantation is an option in patients deemed
NOT SUITABLE for heart transplant due to
•
Above cutoff age limit
•
Diabetes
•
Significant pulmonary hypertension
•
Established renal dysfunction
•
Recent malignancy
This subset constitutes the destination therapy group of indications.
Patients having ESHF and being considered for device implantation should undergo complete
multidisciplinary team evaluation to determine their ejection fraction, reversibility
of medical condition, presence of other life-limiting comorbidities and latest heart
failure status (NYHA Class). This evaluation should be done by a multidisciplinary
team of cardiac surgeon, cardiologists, nephrologist, hepatologist, physiotherapists,
psychiatry personnel, nurse care providers social worker, rehabilitation physician
among others.
203
Patients should also be classified into one of the established INTERMACS profiles
(Table 17, Ref. [206]); because different levels of INTERMACS profile merit different
treatment strategies based on available worldwide clinical practice evidence.
204
Table 17
Classification, Clinical Profile and Management strategies of patients based on INTERMACS
study.
206
Table 17
S.No
INTERMACS Profile
Clinical picture and description
Treatment strategy advised
1.
Profile I
Crash and burn. Patient with acute severe hypotension, cardiovascular crash, on very
heavy inotropic support. Prognosis poor
Short term circulatory/ECMO support. Long term VAD not advisable because patient prognosis
unclear
2
Profile 2
Progressive decline; sliding fast inspite of significant dose of inotropes
Similar strategy as in INTERMACS
3
Profile 3
Stable but dependent on continuous intravenous inotropes (dependent stability)
Most suitable candidate for LVAD
4
Profile 4
Resting symptoms of congestion at rest or during daily activities on oral therapy
at home
LVAD is a good option
5
Profile 5
Patient comfortable at rest and in activities of daily living; but dyspneic on any
other activity (exertion intolerant)
VAD is an option to be carefully considered. May be watched closely
6
Profile 6
Exertion limited − Patient gets fatigued AFTER the first few minutes of any meaningful
activity (exertion intolerant)
Optimize medical therapy, ICD
7
Profile 7
Patient Advanced NYHA Class III. Patient lives comfortably with self-imposed restriction
on meaningful activity (placeholder)
Medicines, ICD for the time being. LVAD Use is controversial.
2.6.4
CONTRAINDICATIONS TO VADs
In Indian set up, the following group of patients should NOT be considered for VAD
implantation
198
1.
Patients with irreversible renal or hepatic disease
2.
Established severe RV dysfunction
3.
History of/possible future noncompliance to prescribed medicines
4.
Debilitating neurological disease with deficits
5.
Poor self-motivation, inadequate family support, poor English-reading ability
6.
Inadequate understanding of basic concepts of alarms, charging and hygiene
7.
Poor geographical access to a well-equipped tertiary health care center
8.
Patient from remote areas where availability of electricity 24 × 7 is suspect
9.
Surgical situations – (relative contraindication) Congenital heart anomalies, small
ventricles, multiple reoperations, morbid obesity
2.6.5
Cost implications in India
The high cost is essentially due to the cost of the device.
Heartmate II INR 40–60lakhs
Heartware INR 60–80 lakhs
Heartmate III INR 90–100 lakhs
2.6.6
Preoperative evaluation
Suitability of a patient for LVAD implantation is to be decided after thorough investigations.
198
These include −
Routine blood investigations (Hemogram, liver and kidney profile, HbA1C)
Cultures − Blood, Axilla, groin, nasal swab
Pulmonary function assessment
Neurological assessment
Psychological assessment
Nutritional assessment
Chest CT scan (Ascending aorta calcification, redo surgery, Congenital anomalies)
Echo assessment for RV function, aortic regurgitation, mitral and Tricuspid valves,
ASD Assessment for cardiac arrhythmias and peripheral vascular disease
Exclude undetected malignancy
2.6.7
Technique of implantation and early postoperative management
203
Appropriate cannulas (large intravenous, peripheral arterial and pulmonary arterial
lines) are placed for complete hemodynamic monitoring. Broad spectrum antibiotic is
given covering gram – positive and gram-negative bacteria. Midline sternotomy incision
is given. Pericardium is opened. Aorta and Right atrium are cannulated and cardiopulmonary
bypass is instituted. VAD sewing ring is sewn on the LV apex. LV apex is incised and
the pump is connected to the outflow graft securely. The outflow graft is sutured
to the ascending aorta. The driveline is tunneled out through the right iliac fossa.
TEE guidance is used to check inflow lie (parallel to IVS) and adequacy of de airing.
The desired pump flow at shifting is 2800 rpms and acceptable cardiac index is 2.2 l/min/m2
or more.
If moderate or more TR is present, tricuspid annuloplasty is to be added. If a PFO
is present, that must be closed. Only severe mitral regurgitation needs to be corrected.
More than mild aortic regurgitation should be addressed usually by performing bioprosthetic
aortic valve replacement.
203
Aspirin therapy is initiated in first 24 h. Warfarin is started after 24 h; heparin
cover is removed after 48–72 h.
During the convalescence period, patient and family members are educated about alarms,
wound precautions, device complications and safety measures including travel advisory.
203
2.6.8
Outcomes, common complications and management (indianperspective)
Compared to optimum medical management alone for ESHF IV (12–15% survival), the survival
with LVADs has improved to 65–85%.
205
In addition, there is a significant and perceptible increase in the quality of life
in these patients, their activity levels, feeling of wellbeing and psychological makeup
all improve. Some patients who initially were ineligible become transplant eligible
after a significant rest to the LV and consequent reduction in PVRI.
206
Good data on common post implant problems is available even for the latest continuous
flow devices based on detailed follow-up
205
of more than 18000 VADs worldwide. With rapidly enhancing technology, the efficiency
of VAD pumps is increasing and device sizes are decreasing. However, VAD implants
are still associated with significant morbidity. In India, the total number of VADs
implanted till date is less than 100. However, the follow up indicates a similar set
of problems as seen worldwide.
2.6.9
VAD thrombosis
It is a usually insidious but a devastating complication and is life threatening.
Most patient deaths after VAD implants (especially previous generation VADs) are due
to this. Blood clot develops usually within the pump or in inflow/outflow conduits.
Reports have indicated approximately 8% thrombosis rate with Heartmate II model.
207
The newer models are supposedly less thrombosis prone; however, mid – long term follow-up
is awaited.
VAD thrombosis may present in various ways including increase in watts consumed, lower
flow rates, vague discomfort and anorexia, giddiness or even sudden fatal cardiogenic
shock. Routine antiplatelet and anticoagulation are mandatory after VAD implant and
here patient compliance with medicines becomes of utmost importance. INR ratio is
to be maintained as per the device implanted; usual desirable INR ratio is 2.0–3.0.
203
Diagnosis includes assay of lactate dehydrogenase (LDH), indirect bilirubin levels
and plasma free hemoglobin levels, assessment of monitor parameters including previous
log files.
Management – Immediate admission in critical care, start with intravenous heparin
and thrombolytic therapy (if no contraindication) with tirofiban or r-TPA. If thrombolysis
is not successful after a reasonable trial, pump replacement is the preferred option.
203
2.6.10
Right ventricular failure
This occurs very frequently, in almost 20-50% patients
203
following LVAD implantation; either immediately post-op or after variable periods
of upto 2 years (patients present as recurrent heart failure). It may cause significantly
reduced cardiac output (cardiogenic shock) because the output of the LVAD pump is
preload (RV output) dependent. Milrinone, Dobutamine, Sildenafil, optimal preload
and RVAD insertion are the management options. Inotrope weaning is to be attempted
with daily echocardiography and strict VAD parameter – monitoring.
203
2.6.11
Gastrointestinal bleeding
Incidence is 20–30% and both upper and lower GI bleeds are common.
203
The causative factor is development of arteriovenous malformations and gastric stress
ulcers. Other important factors responsible are consumption of von Willebrand factor
and platelet dysfunction due to high shear stress to blood elements in the pump.
Management involves identification of site of bleeding, alteration of antiplatelet
and anticoagulation regimes and supportive measures.
Infection
Driveline infections at the site of exit in iliac fossa are common (15-20%). These
cause morbidity and even death (20% deaths). Common organisms cultured are Staphylococcus/Pseudomonas
or fungi.
203
Common presentation is fever, lethargy and wound discharge. Management consists of
hospitalization, daily dressings, sensitivity specific antibiotics and management
of septic complications.
2.6.12
Neurological deficits
Strokes may present acutely within 30 days of device implant or over long term.
208
Ischemic, hemorrhagic strokes or TIAs are all possible. Newer generation devices show
similar rates of TIAs and strokes. Clot emboli, atherosclerotic debris from aorta
or infective vegetations from outflow conduits are possible causes of stroke.
Neurologist’s examination OINR estimation and CT evaluation are first line of management.
Optimization of anticoagulation status, radiologic intervention for thrombotic strokes
and controlling recurrent emboli from potential source are the principles in management.
2.6.13
Outpatient management guidelines for lvad patients
Management of VAD patients, especially of DT group over long term (5–15 years even)
involves multidisciplinary vigilant approach and is challenging. At least weekly follow
up is advised and all-important parameters are assessed at each visit. (Pump flow
parameters, Blood investigations, INR, Hemolysis markers, cardiologist and cardiac
surgeon’s assessment, psychological and nutritional assessment etc.). CT scans may
be needed to determine problems like outflow graft kinking or obstruction at aortic
anastomosis. Role of allied medical staff like physiotherapists, counsellors, heart
failure nurses is crucial. After 2 months of discharge, longer intervals between follow
up visits are acceptable.
Before discharge, a physician/VAD coordinator nurse should inspect the living quarters
of the patient and ensure that the premises are device friendly and safe. During OPD
visits, the patient should be accompanied by a constant family member/associate so
that he/she may be explained all nuances of registering alterations in VAD parameters
and patient behavior; thus, building up his fluency with device management. Even the
primary care physician of the patient should be trained to detect device parameter
alterations and pump malfunction. There should be a 24 h open communication line between
the patient and atleast 3 members of the VAD implantation team to rapidly advise (trouble
shooting device malfunction) in case of any sudden deterioration.
2.6.14
Temporary support systems
Critical cardiogenic shock in patients with acute or chronic heart failure does not
merit DT LVAD in all cases. These situations (INTERMACS profiles 1 and 2) are good
indications for use of temporary mechanical support systems like portable ECMO (example
Centrimag/Cardiohelp/Hemovent) or Impella devices. This allows partial recovery of
critical end-organs, efficient stabilization of hemodynamics and neurological assessment.
They may also be used to provide RV support (cardiogenic shock due to acute RV failure)
The duration of support accorded may vary from 6 h to 30 days.
209
Some clinical situations for their use include-
•
Acute RV failure following LVAD implant,
•
Failure to wean off CPB following heart transplant operation,
•
Cardiogenic shock following cardiotomy operation,
•
Transferring patients from one centre by surface or air,
•
Bridge to decision (whether a patient is a candidate for heart transplant)
2.6.15
Summary
For increasing number of patients with ESHF stage IV, mechanical circulatory support
devices are the best option. The number of VAD implants all over the world are constantly
increasing. Follow up data convincingly show remarkably good quality of life, reversal
of end-organ damage and increased survival.
210
Constant vigilance, robust followup and awareness about possible device complications
is essential for successful VAD programs. The low numbers of device implants in India
are related to lack of health insurance and steep costs of the available devices.
Other factors like proximity to a tertiary care centre and education level of patients
also limit candidacy of patients for VAD implantation in India.
2.7
Management of heart failure: role of surgical revascularisation and other surgeries
Despite enormous strides made in pharmacotherapy, a large number of patients reach
end stage HF and 30–40% dies, refractory to any form of medical therapy, especially
if associated with structural heart disease. Fortunately a variety of surgical procedures
(Fig. 10) are now available to address these advanced HF patients.
211
Fig. 10
Surgical Strategies in Heart Failure
213
.
Fig. 10
2.7.1
CABG in heart failure
There is a great paucity of data of myocardial revascularization in LV dysfunction
with land mark studies like the European Surgical Study, VA Cooperative Study, CASS
Study, MASS II, Courage, and ISCHAEMIA all excluding patients with severe LV dysfunction.
Even SYNTAX Trial had LVEF <30% in 2% of patients and in FREEDOM Trial, barely 2.5%
of patients had LVEF <30%.
The landmark STICH I failed to demonstrate any benefit of CABG over medical therapy
in five year primary end points, there were some benefits in five years secondary
end points, of cardiovascular mortality (28% vs 33%, p-0.05), composite of cardiovascular
hospitalization plus mortality (58% vs 68%, p < 0.001) and composite of repeat revascularization
plus mortality (39 Vs 55%, p < 0.001). However, the ten year follow up showed unequivocal
superiority of CABG. The STICH Extension (STICHES) trial showed improvement even in
primary end point of all-cause mortality with number needed to treat (NNT) to save
one life of 14, which was highly significant. These improved results of CABG were
magnified with increasing severity of CAD (better results in triple vessel CAD) and
were attenuated with increasing age.
212
With judicious use of Intra-Aortic Balloon Pump (IABP) and careful patient selection,
as also with improvement in intra and post-operative care, results of CABG in this
subset of patients have been gratifying. Salutary results of Off Pump-CABG in patients
with significant LV dysfunction and HF in Indian context were demonstrated.213, 214,
215
Though presence of hibernating or stunned myocardium contributing to viability improves
long term survival,
216
the STICH Trial has conclusively shown that if the distal targets are suitable for
bypass, then viability demonstration is not a pre-requisite for myocardial revascularization.
217
However, both European and ACC/AHA guidelines
218
give Class IIa recommendation to viability testing in moderate to severe ischaemic
LV systolic dysfunction.
Besides direct myocardial viability assessment using Dobutamine Stress Echocardiography
(DSE), PET, Magnetic Resonance Imaging (MRI) or Single Photon Emission Computed Tomography
(SPECT), such other parameters like ventricular wall thickness >8 mm
219
and good sized distal coronary targets are reliable indicators of short and long term
survival. Insertion of IABP, incomplete revascularization, wall motion scores on DSE
and post operative low cardiac output syndrome are significant predictors of adverse
outcomes after CABG in patients with impaired LV systolic function.
220
Recently, Global longitudinal strain, systolic dys-synchrony index and septal-lateral
delay have been validated as echocardiographic predictors of early adverse outcomes
of CABG in patients with severe LV dysfunction as also biomarkers.29, 221
2.7.2
Ischaemic mitral regurgitation
Various pathogenetic mechanisms leading to MR in ischaemic cardiomyopathy may be annular
dilatation, tethering of posterior mitral leaflet due to apical and lateral displacement
of the papillary muscle and LV dys-synchrony.
The debate of repair/replacement in ischaemic MR has not been sorted out, with Acker
et al
222
finding repair not durable and therefore recommending replacement for ischemic MR.
211
Probably percutaneous therapies like mitra clip may be the way forward and are being
investigated in the RESHAPE-HF trial in Europe and COAPT Trial in USA.
2.7.3
LV aneurysm
Over 5000 patients in small trials and registries demonstrated that reduction of LV
volume through SVR improved LVEF and ventricular function.223, 224, 225, 226, 227
Even neuro-hormonal responses to LV reconstruction were salutary with a 34% fall in
Norepinephrine levels, 64.7% fall in plasma Renin activity, 68.3% in Angiotensin2
and 46.3% reduction in BNP levels.
228
However, Society of Thoracic Surgeons national database propounded a contrarian view
point with 30 days mortality of 9.3% and no benefit of SVR in these patients.
STICH 2 Trial
229
too failed in terms of primary outcomes and though there was reduction in mean LV
end systolic volume index (LVESVI) of 19% in CABG + SVR versus only 6% in CABG (p-0.001),
there was no improvement in angina class, HF class, six minute walk test or all cause
death and hospitalization from cardiac causes.
Various postulations as to why STICH failed are wrong patient selection, SVR induced
reduced diastolic distensibility, short axis remodelling in non viable segments after
SVR, no pre-operative core lab analysis,
230
inadequate reduction in the LV size,
231
inadequate experience of the surgeons and the centres.
However, in a retrospective subgroup analysis of core lab measures, Oh et al
232
found that SVR results were good if LVESVI was <60 ml/m2 and LVEF was >33%.
The basic principles of LV aneurysm surgery include
233
:
1.
Relief of ischaemia by concomitant CABG
2.
Reduction of LV volume
3.
Restoration of ventricular geometry
4.
MV intervention to reduce LV volume overload
2.7.4
Stem cells and gene based therapies
These therapies failed to keep the initial promise. Even patient-derived bio-artificial
myocardium, through bioengineering of human myocardium on native extra cellular matrix,
may provide functional support to a failing LV.
234
Thymosin Beta 4, a protein, has been tried to reactivate the myocardial cells’ embryonic
developmental potential and for vascular regeneration
235
with the aim of stimulating angiogenesis and myogenesis. Some studies demonstrated
them to be safe and effective.
2.8
Status of cardiac transplantation in India
Heart Transplantation in India as a planned procedure started in 1994 once the National
Organ Transplant act was passed by Parliament. Computerized Transplant registries
like TRANSTAN (Tamil Nadu), KNOS (Kerala) and jeevandhan (Andhra Pradesh), started
functioning regularly from 2008 onwards.
236
2.8.1
Intermacs grading –
Interagency Registry for mechanical assisted circulatory support (INTERMACS) is a
very Sophisticated Grading used to assess prognosis and sickness level of patients
with advanced Heart failure. This is also widely used to select patients who need
Mechanical assist before Heart Transplants or Implantable VAD’s.
237
If Patient is in INTERMACS grade 3 or less, he is in cardiogenic shock or advanced
Heart failure and may need Mechanical assist (Temporary) or permanent LV Assist device
as a Bridge to eventual Heart Transplantation. INTERMACS grades more than 3 can be
stabilized on Drugs before taking up for Heart Transplantation.
2.8.2
High risk factors for heart transplant
PVR more than 6 Wood units (Prior to vasodilator Challenge)
Creatinine Clearance less than 40 ml/min
Hepatitis C seropositivity
Age less than 1 year
Panel reactive Antibodies (PRA) more than 40%
Diagnosis of congenital heart disease
Interfaces score of 2 and less
Multiple previous operations.
2.8.3
Classical indications of heart transplant
•
Impaired Left or Right Ventricular Systolic Function (LVEF less than 30%) with significant
Breathlessness (NYHA Class 3–4) after Optimal combined medical therapy or CRT device
•
Evidence of Poor prognosis like Vo2 max less than 14 ml/kg/m2 or NT pro BNP more than
1000 units’ pg/ml
•
Recurrent Heart failure episodes more than 2 per 6 months
•
Intractable Ventricular arrhythmias related to Ventricular dysfunction
•
Survival Chances less than 80% at one year by Established Gradings Like Seattle Heart
Survival scores and Ventricular dysfunction
•
Late Stage Congenital heart disease with Ventricular dysfunction or Failed Congenital
Heart Surgery like Failed Fontans operation
•
Late stage Hypertrophic cardiomyopathy or restrictive Cardiomyopathy
•
Severe Pulmonary Hypertension with RV dysfunction
•
Altered Renal or hepatic function secondary to ventricular dysfunction.
•
Age less than 70 years
2.8.4
Absolute contraindications
•
Age More than 75, Biologically unfit or Frail
•
Advanced malignancies
•
HIV/AIDS
•
Severe Renal dysfunction (candidate for Combined heart Kidney transplant)
•
Moderate Liver Cirrhosis
•
HIGH RISK CRITERIA FOR DONORS:
•
Donor Age more than 50 years
•
On multiple Inotropes
•
History of Cardiac arrest
•
Presence of significant degree of ventricular dysfunction not improving with optimization
of Metabolic factors and Inotropes
•
female Donors to male recipients
•
Donor Body weight lower than 20% of recipient weight
•
Donor weight more than twice recipients weight, especially in paediatric transplants
2.8.5
Distinctive clinical features in indian patients
Indian Patients typically present quite late for heart Transplant especially in INTERMACS
grades 3 or less, higher creatinine levels more than 2.5, jaundice and other parameters
of altered Liver dysfunction, with Increased Frailty Index and poorer Nutritional
Status Compared to their western counterparts. Also the Pulmonary vascular resistance
(PVR) tends to be higher in Indian patients with end stage Heart failure, Needing
special vasodilator drug testing protocols and Special pre and perioperative Drugs
regimens to Combat higher Pulmonary vascular resistance (PVR) after HTx.238, 239
2.8.6
Common infections detected in indian patients
In a series of 164 patients from Chennai − 5 patients had significant CMV Infection
from a period of 4 weeks to 1 year after transplant, 3 patients had overwhelming sepsis
in the ICU in the first few days after transplant, 2 had pneumonia 3–5 months after
transplant, one had severe form of lymph node and GI tuberculosis, 2 had mild candida
infection of GI tract. Rest were infection free after they were strictly counselled
to follow an infection avoidance life style and periodic monitoring for life threatening
infections like CMV.
2.8.7
Surveillance endomyocardial biopsies
Surveillance Endomyocardial (EM) biopsies are routinely advocated every month in the
first year after heart Transplant in the Unites States. Since Cost of EM biopsies
is prohibitively high and recalling patients from far flung areas is difficult, it
is prudent to limit the EM Biopsies to two in the first Year – one at one month and
another at one year after Heart Transplant. This policy does not see to impact survival
or rejection rates. In a series of 164 cases clinical and biopsy proved rejection
rates have remained very low(only 8 clinical or biopsy proved rejection in 164 in
a 3 year period).240, 241
Extra care is taken during The EM biopsy to make the procedure Low risk by adopting
all precautions like using a 6 F Mullins Sheath to introduce the 5 F bioptome and
using ECHO guidance to place the Sheath oriented towards the septum. In the 130 EM
Biopsy procedures done there were no cases of pericardial tamponade and only 2 cases
of increased or new tricuspid regurgitation. The EM Biopsy samples are sent for both
cell mediate rejection (CMR) analysis and antibody mediated rejection (AMR) analysis.
2.8.8
Immunological matching before heart transplant
The Immunological Matching prior to Heart Transplant Involves the Following process:
1.
ABO Blood group Match
2.
To Check Quantitative Anti- HLA Pre-Formed Antibodies (PRA)
3.
Complement dependent Cytotoxic assay (CDC assay) between Donor Serum and recipient
Lymphocytes.
4.
So no HLA Typing or HLA cross March is done as a routine.
2.8.9
Preservation and transport of donor organ
The present standard of care for preservation and transport of the donor organ involves
cross clamp and introduction of crystalloid long duration cardioplegia using solutions
like htk – custodial solution.
Then the Donor Heart is transported in ice cold saline at temperatures of 1–4 ° centigrade.
This cold ischemic non-beating heart survives of anaerobic energy generation but at
low levels of metabolism. Since there is loss of tissue ATP levels along with cold
injury during transportation. The maximum tolerated cold ischemic time is 4 h – from
donor body to removal of cross clamp in recipient.
242
2.8.10
Organ care systems (OCS) and normothermic donor organ transport
Transmedics Inc has now introduced a Normothermic, Beating heart, Ex-Vivo Organ care
system for Donor Heart Transport – which can extend the Ex Vivo Warm ischemic time
upto 8–9 h after explanting the Organ.
243
2.8.11
Non-biopsy markers for rejection surveillance
1.
Single Antigen Anti HLA Class 1 or 2 Antibody – Useful in Diagnosis of Antibody mediated
rejection – Available in India (SRL Labs Gurgaon)
2.
Donor Derived Cell Free DNA – Extremely useful one point blood test for early diagnosis
of rejection – Available In USA, Under development in India
3.
Cylex (Immuknow) test – Activated ATP levels in Lymphocytes – levels less than
4.
120 unit Suggest over immunesuppression. More than 180 – Under immune suppression
5.
ALLOMAP – gene Expression Analysis 15/19 gene panel for rejection surveillance– Available
in USA (CAREDx labs).
2.8.12
F. Future directions
In a Large but developing country like India with total Population of 1310 Million
and Area of 3.2 million Square kms and limited resources, The Logistics of Creating
a Nationwide Cadaveric Organ procurement and Sharing network is Extremely Challenging
and daunting by any Criteria.
Hence given the fact that total heart transplants in the country, going by the availability
of cadaveric organs will be in the range of only maximum 150–200 per year for the
next 2 years, there is bound to be a huge gap between demand from dying patients with
heart failure (approximately 2.5 million end stage heart failure patients per year)
ands upply of cadaveric organs (Only 150–200 per year).
Also to facilitate Inter Hospital learning Huge Collaborative efforts need to be put
in Place between Advanced Heart Transplant centers and Preliminary Heart Transplant
programs. Such efforts need to Assisted By National cardiac bodies like Cardiological
society of India (CSI), Indian association of cardiac surgeons (IACTS), Heart failure
societies and the Newly Planned Indian Society for heart Lung Transplantation.
International Collaboration for improving various special areas of heart transplant
is the need of the hour. Such collaborations with International Experts can be in
the Form of visiting fellowships, Travel Grants and Annual Conferences or workshops
The other area where more government help is urgently required is for long distance
organ transport for the harvested cadaveric organ. Because interstate transport of
vital organ like heart with cold ischemic time of 4 h is extremely difficult and expensive
(air charter costs above 5 lakh INR), regular Heart Transplants from distances over
200 Kms will need State aid for unaffordable patients. Also the introduction of the
new Normothermic Organ transport systems (Transmedics, OCS system) would ensure safe
long distance transport of hearts in South Asia.
2.8.13
Conclusion
Heart Transplantation as a standard of care Therapy for end stage Heart Failure has
become established in India. The international guidelines for heart transplantation
are also now widely known and now being implemented in various Indian centres. Safe
Immune suppression and anti-infective measures have also allowed long term survival
of Indian patients. But an Indian Heart Transplant registry and long-term data on
survival of heart transplants are need of the hour for the country.
3
HF situations specific to India
3.1
Acute rheumatic fever
Acute rheumatic fever (ARF) is the result of an autoimmune response to pharyngitis
caused by infection with the beta haemolytic group A Streptococcus (GAS), Streptococcus
pyogenes. The carditis of ARF results in valvular regurgitation with the potential
for secondary HF failure. ARF still occurs at a relatively younger age in India, affecting
children as young as 3 years. The incidence of carditis is also higher during an episode
of ARF.
3.1.1
Mechanism of heart failure in acute rheumatic fever
Heart failure had earlier been thought to be due to rheumatic myocarditis as a part
of pancarditis of ARF. However, echocardiography has always shown severe valvular
regurgitation with almost normal ventricular function in a vast majority of patients
presenting with HF
244
and HF gets ameliorated with successful valve surgery.245, 246 Absence of myocarditis
is further supported by normal levels of MB fraction of creatinine kinase (CK-MB),
troponin I and T and myoglobin.247, 248 Radionuclide studies and myocardial biopsy
have also failed to confirm the presence of myocarditis.249, 250 Hence, congestive
HF in ARF is due to an acute mitral and/or aortic regurgitation but not due to myocarditis
per se.
3.1.2
Management of heart failure in acute rheumatic fever
The diagnosis of ARF is made using clinical criteria (the Jones Criteria).
251
Echocardiography is recommended in all patients and subclinical carditis is taken
as a major criterion. It shows presence of variable degree of mitral and/or aortic
regurgitation and a near normal LV function. Focal nodular changes at the tips and
bodies of the leaflets, mainly in the mitral valve, and with associated annular dilation
has been described for the first time from India. The common echocardiographic changes
in ARF is summarized in Table 18.
Table 18
Echocardiographic changes in acute Rheumatic Fever.
252
Table 18
Valvular regurgitation (WHO/WHF suggested)
Regurgitant jet >1 cm in length
Regurgitant jet seen in at least two planes
Mosaic color jet with a peak velocity > 2.5 m/s
Jet persists throughout systole (mitral valve) and diastole (aortic valve)
Valve stenosis − pre-existing with recurrence of ARF
Leaflet Prolapse
Coaptation defect
Thickening
Focal or irregular
Diffuse thickening of AML
Age specific cut offs; >3 mm
Reduced mobility
Excess leaflet motion
Nodules
Annular dilatation
Chordal elongation/rupture
Increased echogenicity of subvalvular apparatus
Pericardial effusion
Ventricular dilatation and dysfunction (almost always with significant regurgitation)
The mainstay of treatment includes diuretics and vasodilators. Intravenous (IV) furosemide
may be required initially. ACEi such as captopril, enalapril, Ramipril should be used
with diuretics in relatively stable patients with significant valvular regurgitation
and/or left ventricular dysfunction.
253
Patients presenting in NYHA class III or IV with severe valvular regurgitation and
HF, intravenous infusion of vasodilators is preferred over ACEi. Other measures to
control HF include treatment of arrhythmias, if present, bed rest and fluid restriction.
Role of digoxin and betablockers is not clear and are best avoided.
Anti-inflammatory drugs, either corticosteroids or salicylates, are the mainstay of
therapy and are effective in suppressing the acute signs of inflammation. Corticosteroids
have shown a prompter action than salicylates, and can be lifesaving in severe presentations
of carditis. Corticosteroids have been widely used in moderate to severe carditis
including those in HF as these drugs dramatically reduce inflammatory markers of ARF.
Though fever and acute phase reactants show rapid decline but there is no evidence
that the anti-inflammatory therapy affects the frequency or severity of the valvar
lesions, or prevents the cardiac sequels in the chronic phase.254, 255
When comparing salicylates and corticosteroids, no treatment has been shown definitely
to be superior. Despite this, corticosteroids are frequently used to treat severe
carditis around the world.
256
The initial dose of prednisone is given for 2 to 3 weeks depending on the severity
of the carditis. After this period, a gradual tapering is required. The drug should
be slowly withdrawn, decreasing by one-fifth each week, which means a total duration
of the treatment of about 8 to 12 weeks, coinciding with the duration of the acute
episode. Rebounds are sometimes associated with rapid withdrawal of corticosteroids.
Some authors have recommended an overlapping therapy with the aim to prevent rebounds,
with the introduction of salicylates as the dose of corticosteroids is reduced. The
advantage of the use of high doses of methylprednisolone as an alternative treatment
remains controversial. It has most frequently been administered as a lifesaving therapy
for those with severe carditis. Likewise use of intravenous gamma globulin has not
shown superiority over other anti-inflammatory agents in patients with carditis.257,
258
Table 19 summarizes the doses of various drugs used for carditis and other major manifestations
of ARF.
Table 19
Management of Acute Rheumatic Fever.
Table 19
Drug/Situation
Dose
HF
Frusemide
IV 1 mg/kg/dose, 2–4 times a day. Then, oral1–3 mg/kg/day in 2 divided doses.
ACE inhibitors
Enalapril − 0.1-0.5 mg/kg/dose twice a day, start at a smaller dose.
Nitroglycerine
0.5mcg/kg/min IV, up-titrated, maximum of 10mcg/kg/min.
Nitroprusside
0.5mcg/kg/min IV infusion. Gradually titrated to a maximum of 10mcg/kg/min.
Anti-inflammatory
Severe carditis
Prednisone 2 mg/kg/day once daily, maximum dose 80 mg/day
Moderate carditis
Prednisone 1–2 mg/kg/day once dailyorAspirin 75–100 mg/day divided into 4 doses
Eradication of streptococcal infection
Penicillin V (oral)
Children: 250 mg TID for 10 daysAdults: 500 mg BD for 10 days
Benzathine penicillin G (deep IM injection) Given after sensitivity test
For those >27 kg: 12 lakh unitsFor those <27 kg: 6 lakh units
Erythromycin ethyl succinate (oral)
Children: 20 mg/kg/dose(max: 800 mg) BD for 10 daysAdults: 800 mg BD for 10 days
3.1.2.1
Eradication of the Group A streptococcal infection
The most reliable drug is intramuscular benzathine penicillin (BPG) as a single dose
or a full 10 days course of oral penicillin or amoxicillin. Cefadroxyl (oral), and
Cephalexin are also useful.
In all patients, eradication should be followed by long term secondary prophylaxis
to prevent recurrences.
3.1.3
Role of valve interventions for control of HF
Most patients can be stabilized with HF failure treatment. Wherever possible, cardiac
surgery is best delayed until the active inflammation has settled, since the valve
repair during active carditis is associated with higher failure rates and less durability.
259
Valve surgery during ARF may be required in select cases. Even in such cases valve
repair is to be preferred over valve replacement, especially in younger patients.
260
Those with a flail leaflet due to chordae tendinae rupture may present with acute
pulmonary edema due to a rapid rise in left atrial pressure. Emergency surgery in
such cases is life saving.
261
Even balloon mitral valvotomy may be done in selected patients with Indian studies
reporting a similar acute success rate as compared to that reported in a large series
in children.262, 263 Thus, valve interventions/surgery during active carditis should
also be considered in cases with gross valvular lesions where HF is not improving
despite best medical treatment.
The salient features of ARF in our country are detailed in Table 20.
Table 20
Salient features of Acute Rheumatic Fever.
Table 20
RF and RHD continue to be an undesirable burden in India
RF occurs at a young age resulting in significant morbidity as well as mortality in
adolescents and young adults
HF in ARF occurs due to significant valvular regurgitation, with normal or near normal
ventricular function
Early recognition and treatment is of paramount importance as patients may improve
or even completely recovery
Treatment consists of HF therapy, eradication of streptococcal infection and anti-inflammatory
therapy
Urgent valve surgery should be considered in active phase for those who do not stabilize
on medical therapy
All patients should be put on secondary prophylaxis to prevent recurrence of ARF.
3.2
Rheumatic heart disease
Rheumatic heart disease (RHD) is the most common acquired heart disease in children
and young adults in many developing countries including India. At least 33 million
people are estimated to be currently affected by RHD
264
with a significant number of them requiring repeated hospitalization for HF. Surgery
is often required to repair or replace heart valves, the cost of which is very high
and a drain on the limited health resources of poor countries.
3.2.1
Epidemiology of RHD
The burden of RHD remains high in India with 1.3 crore cases of RHD estimated in 2015,
which is nearly one third of all cases of RHD in the globally. India also accounts
for the highest number of RHD-related deaths (1.2 lakh deaths in 2015).
265
These despite a seemingly significant fall in the point prevalence of cases of RHD
reported from school surveys in the same region over different time periods.
266
Recently, one of the largest echocardiographic school survey from 4 states reported
a prevalence of 7.7/1000 children,
267
which is also lower than the prevalence previously reported from other echocardiographic
surveys from India.268, 269 One of the reasons for the high burden of RHD with reducing
prevalence rate in India could be the increase in the population at risk of RHD.
27
3.2.2
RHD & HF
RHD remains one of common causes of HF in India. The proportion of RHD among HF is
higher in lesser developed states and government hospitals. For instance, a study
from secondary care hospital in central India reported RHD to be responsible for more
than half of all admissions for ADHF. However, the proportion of RHD among HF patients
was only 8–10% in the other major registries {AFAR &TVMN Registries}. For this publication,
the hospital admissions of RHD a 3 months period were analyzed at a major tertiary
care hospital. Among the 515, RHD patients admitted, 212 patients were admitted to
ICU. Most common indication for admission was HF (78%) and 7.2% expired despite the
best treatment {personal communication Dr Vijayalakshmi}.
Two large hospital-based echocardiographic studies from India have shown the contemporary
distribution of valve lesions in RHD.270, 271 Mitral valve is the most common valve
involved. Most common lesion in patients aged <18 years is mitral regurgitation (MR)
and in patients above 18 years is mitral stenosis (MS).270, 272 Multivalvular involvement
was seen in a third of all cases. Among the combination lesions, MS and MR was the
commonest followed by MS and AR.
271
Females seem to have severe disease and needing more interventions.
272
3.2.3
Diagnosis
Diagnosis of HF in RHD can be at times challenging. Traditionally, the term HF is
used in a patient with RHD with the presence of congestive symptoms. However, any
patient with dyspnea with severe valve involvement may be construed to have HF. Heart
failure in RHD and in other primary valve diseases may not easily fit in the scheme
of HFrEF and HFpEF. Even though biomarkers are shown to be elevated in patients with
RHD,
273
they are rarely used in routine practice.
Chest radiograph may show chamber enlargement, pulmonary venous hypertension and pulmonary
arterial hypertension. ECG may show evidence of chamber enlargement and abnormalities
of rhythm. Echocardiogram is the mainstay in diagnosis and planning therapy. Echocardiogram
is a useful tool to assess the ventricular function and underlying structural abnormality.
It is a valuable tool in measuring LV volumes, assessment of severity of regurgitation
and stenosis, understand hemodynamics and estimate pulmonary artery pressures.
3.2.4
Management of HF in RHD (Table 21)
Management is to improve symptoms and enhance survival. Diuretics are important in
relieving symptoms. The therapy for RHD related HF is summarized in Table below. The
pharmacotherapy of HF related to RHD is different than those recommended for HFrEF.
The principles of treatment for valve disease in RHD are similar to those recommended
for other valve diseases.274, 275
3.2.5
Infective endocarditis
India has a dual burden of infective endocarditis (IE); modern IE like dialysis and
medical care related IE is being increasing recognized yet, the traditional Oslerian
IE involving previous RHD is still widely prevalent.
277
The major studies of IE from India are compared to a Western series in the Table 22
below.
Table 21
Management of HF in RHD.
Table 21
Common Measures
•
Diuretics − all patients with dyspnea and clinical HF
•
Atrial Fibrillation
○
Rate control
○
Digoxin (if HF present)
○
Beta blockers (reduces both resting/exercise heart rates)
○
CCB − Verapamil/Diltiazem
○
Amiodarone in selected cases
○
Oral anticoagulation − Vitamin K antagonists preferred to NOACS
•
Secondary prevention
•
Recommended in all patients aged <40 years
•
Benzathine penicillin
○
1.2 MU every 21 days (if patient weighs >27 kg)
○
0.6 MU every 14 days (if patient weighs <27 kg)
•
Penicillin V 250 mg BD (in states where injectable Penicillin not used)
•
Erythromycin 250 mg BD (if penicillin allergy is present)
Specific Therapies for Valve Lesions
•
Mitral stenosis
○
Increase filling time − Betablokcer/Ivabradine
276
○
Balloon mitral valvoplasty
○
OMC/MVR (if not suitable for BMV)
•
Valve Regurgitation
•
ACE Inhibitors (ARB if ACEi not tolerated)
•
Valve repair in MR if possible
•
Valve replacement
•
Tricuspid valve disease
•
TV repair
HF − Heart failure, CCB − Calcium channel blockers, NOACS − Novel oral anticoagulants,
MU − million units, BMV − balloon mitral valvoplasty, OMC − open mitral commissurotomy,
MVR − mitral valve regurgitation, ACE − Angiotensin converting enzyme, ARB − Angiotensin
receptor blocker, MR − mitral regurgitation, TV − Tricuspid valve.
Table 22
Major studies of Infective endocarditis from India;* Native valve disease (not RHD).
Table 22
Chandigarh 1981–1991
278
Lucknow 1992–2001
279
New Delhi 2004–2006
280
Vellore 2005–2015
281
Ahmedabad 2011–13
282
Western Series 2000–06
283
N
186
198
104
172
75
2781
Mean age (years)
25.0
27.6
23.5
41.8
27.5
57.9
% Male
71.5
73.4
71.1
78.4
69.3
68.0
RHD related (%)
42%
46.9%
29.8%*
40.6%
41.3%
3%
Culture positive (%)
47%
67.7%
41%
83.7%
40%
90%
Surgery (%)
1%
23.1%
15%
15.7%
16%
48.4%
In hospital mortality (%)
25%
21%
26%
24%
29%
18%
Infective endocarditis in India has several unique features and are summarized in
Table 23 below.
Table 23
Salient features of IE in India.
Table 23
•
IE occurs among younger patients in India
•
RHD is the most common predisposing heart lesion
•
Culture positivity rate is lower
•
Streptococcus species still the dominant organism
•
Surgery is less often performed
•
Outcomes are suboptimal
It is recommended to make special efforts to increase culture positivity, adhere to
guidelines of IE in choosing pharmacotherapy and perform early surgery when indicated.
Current guidelines recommend IE prophylaxis for a limited group of patients with heart
disease.
284
In India, it is also recommended to extend IE prophylaxis to all patients with severe
valve disease as the outcome of IE in India is also suboptimal.
3.2.6
Ischemic cardiomyopathy
Ischemic cardiomyopathy is defined as onset of LV Systolic dysfunction which results
from significant CAD.
285
The incidence of HF, after an ischemic insult steadily increases with time after an
index event ranging from around 10% after 2 years to more than 40% after 6.5 years.
286
Ischemic cardiomyopathy results from loss of cardiac myocytes leading to adverse remodelling
of heart secondary to ischemic insult resulting in LV systolic dysfunction.
287
3.2.7
Indian data
A prospective study on ADHF in Indian patients
288
from a tertiary care center revealed that ischemic cardiomyopathy was the leading
cause for HF (53.9%) and the mean age of presentation was 53 years. “CREATEECLA study
289
” which enrolled 8060 Indian patients out of a total of 20,201 participants, reported
a prevalence of HF at 30 days of 17%. Late and suboptimal reperfusion therapy in STEMI
in India may lead to more patients ending up with HF. IA cross-sectional study involving
120 patients with STEMI reported a prevalence of HF at 30 days of 11%.
290
Thus, the data from various studies from India suggest that ischemic cardiomyopathy
occurs more commonly and at an earlier age compared to western population. Additionally,
the burden of this problem is quite high.
3.2.8
Diagnostic approach to ischemic cardiomyopathy
Coronary angiogram is the gold standard investigation in establishing diagnosis of
significant CAD in a patient presenting with HFrEF. Coronary angiogram should always
be done in patients with previous MI or >40 years of age for establishing the diagnosis
of CAD. Stress echocardiography/nuclear studies with exercise or dobutamine will assess
stress-induced ischemia and will give vital information regarding need for future
revascularization. Positron emission tomography (PET) is regarded as the gold standard
test for assessment of myocardial metabolism and viability. CMRI helps in assessing
viable myocardium and differentiating it from scared myocardium.291, 292 Among the
biomarkers, hs-troponin and BNP are good predicators for diagnosing and guiding therapy
in ischemic cardiomyopathy. High sensitive troponin levels are directly proportional
to the amount of myocardium under jeopardy. The various non-invasive methods for evaluating
HF are discussed in previous sections.
3.2.9
Management
Patients with ischemic cardiomyopathy should be treated with optimal medication sticking
to guidelines of HF. The pharmacological therapy, devices including ICD, CRT have
the same indications in ischemic cardiomyopathy as eluded to in previous sections.
Patients with ischemic heart disease also need additional anti platelet drugs and
Statins in appropriate doses.
3.2.10
Coronary artery revascularization
Revascularization of dysfunctional but viable myocardium may lead to reverse LV remodelling
and confer prognostic benefits in patients with post ischemic HF. About 20 to 50 percent
or more of chronic ischemic LV dysfunction patients have significant viable myocardium
to improve LV function following revascularisation.216, 293, 294 Several studies have
shown that LVEF improved significantly (i.e. >5%) after revascularization in more
than 60% of patients (range, 38–88%).295, 296, 297, 298, 299, 300, 301, 302, 303,
304, 305, 306 However, in the substudy of STITCH trial, presence of myocardial viability
was associated with reduced mortality but did not predict a benefit from revascularization,
which raises the question of whether viability assessment is needed prior to surgical
revascularization. The merits and demerits of coronary revascularization with CABG
are discussed in detail in previous sections.
Data are limited on the relative efficacy of PCI in patients with ischemic cardiomyopathy.
An on-going trial, estimated to be completed in 2019, is comparing the effects of
PCI with medical therapy alone in patients with HF.
307
The best available observational data comparing PCI with CABG in HF comes from the
New York State registries among 2126 propensity score matched patients.
294
At a median follow-up of 2.9 years, there was no significant difference in death between
contemporary PCI and CABG. PCI was associated with a greater risk of MI and need for
repeat revascularization, but a significantly lower risk of stroke as compared with
CABG. Patients with ischemic cardiomyopathy, as well as patients with an LVEF <35
percent in the nonrandomized AWESOME registry, there was no difference in mortality
with CABG or PCI.
307
Despite lack of randomized controlled trials, PCI may be performed in selected patients
with CAD and HFrEF (in the absence of angina) with a coronary anatomy suitable for
PCI, if the benefits of PCI are likely to outweigh the risks as assessed by a heart
team.
3.3
Dilated cardiomyopathy in Indian patients
Dilated Cardiomyopathy (DCM) is a genetic disorder and is characterized by ventricular
dilatation, impaired systolic function, reduced myocardial contractility with LVEF
less than 40% that is not caused by ischemic or valvular heart disease. DCM is next
to ischemia among the causes of HFrEF from the reported studies in India. DCM was
seen in 13% of study population in a series of chronic HF and 19% in a series of ADHF
patients.
3
Some studies indicate that 30–35% of idiopathic DCM may have a positive family history.
308
Most of the familial DCMs have an autosomal dominant inheritance, but autosomal recessive,
X-linked and mitochondrial inheritance are also noted in some cases.
309
Diagnosis: A through clinical history, general physical and cardiovascular examination,
relevant investigations and imaging modalities are cornerstone for diagnosis of DCM.
A thorough evaluation for reversible causes is needed (table below). These conditions
are extremely rare, yet a positive diagnosis and treatment may result in complete
recovery of LV function (Table 24).
Table 24
Curable causes of DCM like echocardiographic picture.
Table 24
•
Obstructions
○
Low gradient AS
○
Coarctation of aorta
○
Aortoarteritis − Aorta/renal artery narrowing
•
Electrophysiological
•
Tachycardiomyopathy
•
Dyssynchrony − WPW syndrome
•
Complete heart block
•
Metabolic/Endocrine
•
Hypocalcemia
•
Vitamin D deficiency
•
Hyperthyroidism
•
Hypopituitarism
•
Deficiency of Carnitine/thiamine/magnesium or Selenium (Keshan disease)
•
Coronary artery abnormalities
•
ALCAPA/ARCAPA
•
Kawasaki disease
•
Inflammatory diseases
•
Myocarditis
•
Cardiac Sarcoidosis
•
Others
•
Peripartum CMP
•
Drug/toxin induced
•
Alcoholic CMP
Treatment: There is no specific therapy for DCM. All the proven Non-pharmacological
& pharmacological therapies of HFrEF are indicated in all patients with DCM. Indication
for devices are the same as in HFrEF. However, for primary prevention of SCD in DCM,
this position statement recommends ICD in only those DCM patients with LVEF <30% with
family history of SCD (as discussed in earlier sections).
3.4
Non-specific aorto arteritis
Non-Specific Aorto Arteritis (NSAA) commonly known as Takayasu arteritis (TA) is a
chronic inflammatory panarteritis affecting large vessels, predominantly the aorta
and its main branches. Vessel inflammation leads to wall thickening, fibrosis, stenosis,
dilatation, aneurysm formation and thrombus formation.310, 311, 312 Women are affected
in 80 to 90 percent of cases, with an age of onset between 10 and 40 years.
313
The onset may be earlier in childhood but rare in infancy.314, 315
There appears to be a wide variation in the prevalence of TA in different geographical
regions of the world. Takayasu arteritis is most commonly seen in Japan, South East
Asia, India, and Mexico.316, 317, 318, 319
The female: male ratio has lot of variation ranging from 9: 1 in Japan to 1.3: 1 in
India.320, 321 It is the commonest cause of renovascular hypertension in Asian children.
315
Its long term prognosis is studies in few series and the mortality ranges from 3 to
15%.322, 323, 324
Clinical manifestations range from asymptomatic disease found as a result of diminished
or impalpable pulses or bruits, to more serious neurological or cardiac emergencies.
The common symptoms are constitutional symptoms, carotidynia, arthralgias, absent
or weak peripheral pulses, limb claudication, gastrointestinal symptoms, skin lesions,
symptoms because of involvement of pulmonary arteries or coronary arteries and neurological
symptoms. Sometimes patient present as hypertension, angina, heart failure, cerebrovascular
events, retinopathy, glomerulonephritis, renal failure, cardiomyopathy, aortic regurgitation,
pulmonary artery hypertension or aneurysm rupture.
Angiographic manifestations is very heterogeneous in different geographical areas
with predilection for stenotic versus dilative and thoracic versus abdominal aortic
involvement in different geographic locations.325, 326, 327, 328, 329, 330
In Indian series, most common clinical presentation was claudication (74%) followed
by musculoskeletal symptoms (48%), fatigue (46%), weight loss (22%), headache (22%),
visual disturbances (16%), syncope (10%). Dyspnea was present in (20%) of the cases.
Absent or diminished pulses were present in 80–82%, hypertension in 61 − 75%, congestive
cardiac failure in 8–38% and claudication in 13–74% of the cases.329, 330, 331, 332
3.4.1
Diagnosis of TA
No well-defined criteria for the clinical diagnosis of TA were available till Ishikawa
proposed his criteria in 1988.
333
The American College of Rheumatology (ACR) classification criteria were basically
developed to distinguish one form of vasculitis from another.
334
Sharma et al., 1995 proposed Modified diagnostic criteria for Takayasu arteritis.
335
Classification according to angiographic findings of TA was also proposed. This classification
was on the basis of the distribution of lesions detected by angiography.
332
Heart failure (HF) in TA
This is not a very uncommon presentation in India, especially in children. Up to 60%
children can present with heart failure.
314
Common Causes of heart failure in TA are
•
Hypertension,
•
Renal Artery Stenosis,
•
Myocarditis,
•
Aortic Regurgitation,
•
Mitral Regurgitation,
•
Pulmonary Artery Involvement,
•
Coronary Artery Involvement,
•
Aortic Stenosis (Thoracic, Abdominal).
TA can rarely present as postpartum cardiomyopathy,
336
Acute Myocardial Infarction with Left Ventricular Failure,
337
Ruptured Right Sinus of Valsalva Aneurysms.
338
3.4.2
Treatment
The primary objectives of treatment include the control of disease activity by drug
therapy, pharmacologic control of blood pressure (BP), supportive management and revascularization
(surgical or endovascular) of the symptomatic ischemic territory.
The disease activity can be assessed by clinical, biochemical, or radiological markers.
339
Presence of new vascular signs and symptoms like bruits, absent pulses, blood pressure
differences in limbs. Raised ESR and CRP levels, Increased IMT in USG, moving bright
spots and linear flow of microbubbles within the vascular lesions with carotid contrast
enhanced ultrasonography, Enhancement of the thickened aortic wall in CT Angiography,
vessel wall thickness, oedema, and contrast enhancement in MRA, 18-F-FDG-PET uptake
in wall of large vessels, PET might be able to distinguish vessel thickening that
is due to active inflammation from that due to scar formation.
Treatment should aim to control disease activity, preserve vascular competence with
minimal long-term side effects.
Beside standard treatment of HF these patients may benefit from immunosuppressive
therapy which has shown promise in short term and long term in patient with myocarditis.340,
341
Steroids are the mainstay of treatment for TA. Approximately half of the patients
respond to steroids. The dose should be adjusted according to the age and constitution
of the patient. As soon as clinical and laboratory findings showed continue improvement
for 2 weeks, the dose should be tapered gradually. The typical maintenance dose is
5 to 10 mg/day. Regular assessment of disease activity and progression should be performed.
Complete glucocorticoid therapy withdrawal should be attempted as soon as possible.
The patient who does not show satisfactory response to steroid or resistant or having
adverse drug reaction with steroid can be treated with cytotoxic drugs like cyclophosphamide,
azathioprine, mycophenolate mofetil and methotrexate.342, 343, 344
Tocilizumab (IL-6 receptor inhibitor),345, 346 Etanercept (Anti-tumor necrosis factor)
347
and Rituximab (a chimeric IgG1 antibody that binds to CD20 expressed on the surface
of B cells)
348
has shown promising results.
Surgical treatment is challenging due to the diffuse nature of the disease and involvement
of adjacent aortic walls. It has a high incidence of anastomotic aneurysm formation
(12 to 14%) and graft failure (20 to 40%) over time.349, 350, 351 In case of focal
stenotic lesions percutaneous procedure can be performed with good long term results,
however stenting all lesions is debatable if good result can be achieved by plane
balloon angioplasty.352, 353, 354, 355
Any intervention in acute setting and in patients with severe signs and symptoms should
be performed after a sedimentation rate of <30 mm/h and CRP of <1.0 mg/dL have been
achieved with treatment, until it is an emergency and patient cannot be stabilized
on medication. If aortic regurgitation is severe and need aortic valve replacement
both mechanical and bio prosthesis valve can be given. Need for Aortic root replacement
depend on the size of aorta but in some cases when inflammation cannot be controlled,
affected vessels should be replaced with a valve conduit (Bentall surgery) even with
our root dilatation.356, 357
Some patient who has severe pulmonary artery hypertension due pulmonary artery stenosis
pericardial patch angioplasty or reconstruction with vascular prostheses should be
performed. When angina pain and Significant coronary stenosis are present, coronary
revascularization can be performed with good long term results.358, 359
Heart failure because of renal artery stenosis (RAS), respond very well with either
percutaneous intervention or surgical treatment. However vascular surgery is associated
with high prevalence of graft occlusion.360, 361 The favored treatment for RAS in
TA, particularly for inactive lesions, is percutaneous transluminal angioplasty (PTA).
362
Percutaneous intervention of aorta in TA is associated with some technical problem
but has good short and long term results (Table 25).362, 363, 364, 365, 366
Table 25
Salient features of takayasu arteritis in India.
Table 25
•
Takayasu arteritis is rare, affects mainly women, and is most commonly seen in Japan,
South East Asia, India, and Mexico, where it usually presents in the 2nd or 3rd decade
of life.
•
Its clinical Manifestations range from asymptomatic disease, to catastrophic complications.
•
Disease symptoms, signs varies between different populations.
•
Hart failure is common in Indian patients especially in children.
•
Hypertension remain the commonest cause of heart failure.
•
Treatment should aim to control heart failure with standard therapy for heart failure
and also to control disease activity and preserve vascular competence, with minimal
long term side effects.
•
Inactive disease carries a good prognosis and these patients should not be put at
risk by treatment that is more harmful than the disease itself
•
Majority of the patients treated with steroids will respond, but steroid unresponsive
patients respond to methotrexate; mycophenolate mofetil or aziothiprim.
•
Surgical intervention and percutaneous intervention in selected patient should be
performed whenever it is needed and can be very useful.
3.5
Peripartum cardiomyopathy
Initially recognized in the 19th century by Virchow, heart failure following pregnancy
was formally described by Hull and Hafkesbring in the 1930s.The term “peripartum cardiomyopathy”
(PPCM) was coined by Demakis et al. in the seminal publication of 1971. PPCM presents
as unexplained left ventricular systolic dysfunction towards the end of pregnancy
or early postpartum period in previously healthy women.
3.5.1
Etiology and pathogenesis
The etiology and pathogenesis of the illness still remain unclear. Since it is a diagnosis
of exclusion, clinical heterogeneity is inherent to any patient population of this
disease. The most common risk factors are summarized in Table 26. In view of the similar
clinical, echocardiographic and nonspecific histological features, considerable interest
revolves around a common basis for dilated cardiomyopathy (DCM) and PPCM. The prevalence
of PPCM in familial DCM is about 6% and a family history of DCM is elicited in 10%
of PPCM patients.
Table 26
Common Risk factors for development of Peri partum cardiomyopathy.
Table 26
Twin pregnancy
Preeclampsia
Advanced maternal age
Multiparity
Long term oral tocolytic therapy with β-agonists
PPCM in previous pregnancy
3.5.2
Diagnosis
The current clinical definition of PPCM includes 4 criteria Table 27.
367
Table 27
Clinical criteria used for definition of PPCM.a
Table 27
Development of HF in the last month of pregnancy or within 5 months after delivery
LV systolic dysfunction (LV EF <45% by echocardiography)
No identifiable cause for HF
No recognized heart disease before the last month of pregnancy
a
All four criteria must be fulfilled to diagnose PPCM thus preventing overdiagnosis
as well as excluding cases of preexisting DCM.
The commonest symptom of heart failure, dyspnea, is predominantly physiological in
pregnancy (60%) with PPCM accounting for only 0.23% of cases presenting with dyspnea.
Antepartum presentation of PPCM is seen in only 10%.Cardiomegaly may not be present
as PPCM can occur without LV dilatation.96% of the patients have an abnormal ECG.
A risk score of ≥2, developed by scoring 1 for each of the three ECG disturbances
(tachycardia, ST–T-wave abnormalities and QRS duration), had a sensitivity of 85.2%,
specificity of 64.9%, negative predictive value of 86.2% for potentially predicting
PPCM.
3.5.3
Prognosis
A mortality rate of 5–10% is found in PPCM and about 4% of cardiac transplantations
in the US are performed for PPCM.A Danish study found a MACE of 14.8% with 3.3% mortality,
8.2% mechanical circulatory support requirement and/or heart transplantation and 4.9%
persistent severe heart failure. The concept of PPCM as a unique entity distinct from
DCM is strengthened by a significantly worse prognosis for DCM compared to PPCM both
at 1 and 3 year follow up. After 1 year, the HF readmission rate did not significantly
differ between the two diseases, suggesting that HF medications should be aggressively
instituted in patients with PPCM.
3.5.4
Indian data
Various Indian series published are summarized in Table 28
Table 28
Summary of major studies of Peripartum cardiomyopathy from India.
Table 28
Study
Follow up (yrs)
Mean Age (years)
Presenting Features
Outcomes
Elkayam et al
368
(n = 123)
NA
31 ± 6
Mean LVEF − 29 ± 11%
•
Complete Recovery of EF in 54%
•
Mortality in 9%
TK Mishra et al
369
(n = 56)
6.1
31± 5
Mean LVEF −31% ± 7.2
•
LVEF improved to 43% ± 8%
•
16% reconceived out of which 55% died during pregnancy and 23% during follow up
Patil et al
370
(n = 65)
7.5
27.5
Mean LVEF- 21%Mean PA pressure = 37 mmHg
•
Breathlessness, palpitation and cough at presentation in all.
•
50% complained of hemoptysis. 50% had pedal edema and 25% gave history of syncope.
PGIMER study
371
(n-38)
NA
NA
Mean gestational age − 35 weeks
•
Maternal mortality was 16%, all of whom presented with NYHA class IV symptoms.
•
Poor obstetric outcome manifested as 8 stillbirths, 40% prematurity and a mean birth
weight of 2 kg
M. Tergestina et al
372
(n = 8760)
6 months
23.8
Mean LVEF −31.4%
•
80% of patients had significantly improved LVEF (mean 50.5% at 6 months).
•
Low EF <30% at baseline significantly correlated with poor recovery
Sion Hospital
373
(n = 22)
6 weeks
26.8
Mean LVEF −25.3%
1 patient (4.8%) showed an improvement in LVEF to >60% and 1 died.
Hubli Study
374
(n = 24)
6 months
29
Mean Parity- 2.187% presented in post partum preiod
•
25% succumbed in the first week after diagnosis.
•
83% of the survivors recovered completely and the rest had residual LV dysfunction
after 6 months.
Gujrat Study
375
4 years
NA
55% − NYHA class III/IV50% − LVEF < 30%.
•
80% required ICU admission
•
Maternal mortality was impressively low (5.5%).
•
Preterm delivery occurred in 50% and stillborn in a substantial 17%
Nagpur study
376
(n = 11)
81% multipara
•
18% developed persistent cardiomyopathy
•
Clinical recovery occurred in 37% but LVEF improved in 27%.
•
Maternal mortality was a substantial 27%.
•
6 out of 11 babies had IUGR. 2 intrauterine and 1 neonatal death was reported
3.5.5
Management of ppcm
The non-pharmacological management of stable patients of PPCM includes salt and fluid
restriction and restricted physical activity. ACEI and ARBs are contraindicated in
pregnancy and are substituted by a combination of hydralazine and nitrates. Benazepril,
captopril and Enalapril are safe in lactating women. In spite of an increased risk
of fetal growth restriction, β blockers are recommended in all stable patients for
at least 6 months following diagnosis with Metoprolol Succinate the preferred agent.
Diuretics in the form of thiazides or frusemide are indicated in patients with pulmonary
congestion but they may lead to placental hypoperfusion. Spironolactone should be
avoided in pregnancy. Digoxin is an add-on drug in patients with low EF and persistent
symptoms. Both pregnancy as well as PPCM are prothrombotic conditions.
Bromocriptine, a dopamine antagonist, inhibits prolactin secretion and has been tried
in addition to conventional therapy.
377
In the retrospective non-randomized German PPCM Registry, treatment with beta-blockers,
ACE inhibitors, and Bromocriptine (2.5 mg twice daily for 2 weeks followed by 2.5 mg
per day for 6 weeks) was associated with favorable outcomes. The effectiveness of
this drug is greater in patients whose symptoms onset occurred before delivery or
in the first month postpartum. The suppression of lactation by bromocriptine is of
crucial importance to the newborn especially in developing countries where there may
be no practically feasible alternative. Bromocriptine may be considered in patient
of PPCM over and above conventional therapy.
Delivery should be conducted in a specialized care setting under multidisciplinary
supervision. Mode of delivery is dictated by hemodynamic status as well as obstetric
indications. In patients with stable hemodynamics, vaginal delivery is preferred due
to less blood loss, less thromboembolism and faster recovery. Moreover, regional anesthesia
is not associated with depression of LV function. With unstable hemodynamics, Cesarian
section is recommended preferably under spinal anesthesia.
3.5.6
Subsequent pregnancy
There is a substantial risk of relapse of PPCM in subsequent pregnancies with its
attendant risks. A multi-centric study of 34 patients found a relapse rate of 56%
with 12% mortality. A reduced LVEF before next pregnancy is associated with higher
mortality and lower rate of full recovery on follow-up. Addition of Bromocriptine
to standard HF therapy after delivery resulted in better outcome in subsequent pregnancy.
Counseling regarding contraception is imperative and as exemplified by the fact that
1 in 4 PPCM patients are sexually active and not using contraception.
3.6
Diabetic cardiomyopathy
Diabetes is rapidly emerging as an epidemic in the modern era, affecting about 300
million people worldwide, and the number is likely to cross 450 million by 2030.
378
India, sometimes referred to as “the diabetic capital” was estimated to have about
69.2 million people living with diabetes in 2015, overall prevalence being 8.7%.
379
Diabetes may affect the heart in three different ways:
378
coronary artery disease due to accelerated atherosclerosis;
379
cardiac autonomic neuropathy and
380
diabetic cardiomyopathy, a relatively newly recognized entity.
Diabetic cardiomyopathy is defined as “a distinct entity characterized by the presence
of abnormal myocardial performance or structure in the absence of epicardial coronary
artery disease, hypertension, and significant valvular disease”.
381
Hence, diabetic cardiomyopathy affects the myocyte at the cellular levels, culminating
in structural and functional abnormalities in the heart.
3.6.1
Prevalence
Exact prevalence is not known, as a diagnostic criterion for this entity does not
exist. Studies have shown that after adjusting for other conventional cardiovascular
risk factors, heart failure is 2–3 times more common among diabetics.
382
According to a study by Bertoni et al., the prevalence of diabetic cardiomyopathy
was 12% and reached 22% in people aged greater than 64 years.
383
Prevalence of diastolic dysfunction, thought to be an early marker of diabetic cardiomyopathy,
was about 30% in some studies, and up to 60% in others.384, 385
Indian studies till date, have focused on prevalence of diastolic dysfunction in diabetes.
The estimated prevalence ranges from 30 to more than 70% of all diabetic patients.
3.6.2
Risk factors
Diabetic cardiomyopathy can occur in both type 1 and type 2 diabetes. Studies have
shown female sex, poor glycemic control, High BMI, advanced age, use of insulin, proteinuria,
coexistence of retinopathy and nephropathy to be risk factors associated with development
of heart failure/cardiomyopathy in diabetic patients.386, 387
However, none of the above is a well-established risk factor for the condition.
3.6.3
Management:-
Standard therapy for HF is applicable to Diabetic Cardiomyopathy however a good glycemic
control and choice of Oral Hypoglycemic Agents also have a bearing on the progression
and outcomes of HF
•
Lifestyle modification: Smoking cessation, exercise, healthy food habits and weight
reduction can be helpful.
•
Glycemic control: Adequate glycemic control might be helpful to retard the progression
of diabetic cardiomyopathy in early stages. Metformin has been found to be particularly
helpful, as it provides mortality benefit, and also can up regulate cardiomyocyte
autophagy, which contributes to prevention of diabetic cardiomyopathy in animal models.
388
(Fig. 11,
371
) Incretin-based therapies (DPP4 inhibitors and GLP 1 agonists) are newer drugs which
may offer cardio-protection and may also improve systolic function.389, 390 Some non-randomized
studies indicate a harmful effect of insulin, though it was not demonstrated in subsequent
studies.
391
Fig. 11
Choice of Antidiabetic agent in patient with Heart failure.
Fig. 11
•
ACE inhibitors, ARBs and aldosterone antagonists: Myocardial fibrosis and hypertrophy
may be prevented by this class of drugs.
•
Beta blockers: Might prove to be beneficial, but randomized trials in diabetic cardiomyopathy
patients is missing.
•
Statins: Independent of their lipid lowering effect, atorvastatin and fluvastatin
have been found to reduce intra-myocardial inflammation, myocardial fibrosis, and
cardiac dysfunction.392, 393
3.6.4
G. diabetic cardiomyopathy: Indian perspective
Large population-based studies focused on diabetic cardiomyopathy are lacking in the
Indian scientific literature. Extensive search revealed a handful of studies, most
of which assessed diastolic dysfunction among diabetic people of different ethnicities.
The following table summarizes the findings from various Indian studies (Table 29
& Fig. 12).
Fig. 12
Key findings of Indian studies on Diabetic Cardiomyopathy.
Fig. 12
Table 29
Summary of major studies on Diabetic cardiomyopathy from India.
Table 29
Authors (Year)
Place of study
Sample size
Key findings
Rothangpui et al. (2011)
394
Manipur
100 type 2DM patients
Prevalence of Diabetic CM was 40%No relation with duration of diabetes and glycemic
controlMajority (67%) had diastolic dysfunctionLV mass was more in females with cardiomyopathyCardiomyopathy
patients had higher LDL, TG and lower HDL
Patil VC et al. (2011)
395
Satara, Maharashtra
127 type 2 DM patients
54.33% had diastolic dysfunctionCorrelation with disease duration, obesity, glycemic
control and microangiopathies was noted
Chaudhary et al (2015)
396
Meerut (UP)
100 newly diagnosed normotensive diabetics
41% had LVDDCorrelated with HbA1c and age
Senthil N et al (2015)
397
Chennai
100 young normotensive (<40 yrs.) diabetics
Overall prevalence of DD was 30%Distinct female preponderanceNo relation with disease
duration, type of diabetes or glycemic control
Dikshit NM et al (2013)
398
Surat
50 normotensive diabetics, 50 matched controls
Prevalence of DD was 66%LV mass and wall thickness was more in diabetics compared
to controls
Patil MB et al (2010)
399
Mysore
50 normotensive diabetics
64% had DDMore in females and increasing agePositive correlation with HbA1c, disease
duration and treatment with both OHA and insulin.
Sridevi et al (2015)
400
Pune
100 patients, 50 non-diabetic controls
79% prevalence of DDCorrelation with coexistent CAD and hypertension
Shekhda et al (2017)
401
Western India
100 normotensive asymptomatic diabetics
Prevalence of DD was 64%Strong association with disease duration and glycemic controlNo
relation to age, gender, lipid parameters and type of treatment
3.7
Right sided heart failure
Right heart failure (RHF) is a complex clinical syndrome that can result from any
structural or functional cardiovascular disorder that impairs the ability of the RV
to fill or to eject blood. Causes of RHF are listed below in Fig. 13.
Fig. 13
Common causes of right sided heart failure.
Fig. 13
The cardinal clinical manifestations are because of fluid retention; decreased systolic
reserve or low cardiac output &atrial or ventricular arrhythmias. RHF due to pressure-overload
may report dyspnea, light headedness, and syncope. In both RV infarction and PE, chest
discomfort, tachycardia and elevated jugular venous pressure are important features.
Patients with acute-on-chronic RVF have hepatic congestion, and lower-extremity swelling.
Physical examination may show parasternal heave, an RV third-heart sound, and tricuspid
regurgitation. Other findings of coexisting LV failure or valvular lesions may be
present.402, 403
The Right Ventricle adapts better to volume-overload than to pressure-overload. In
atrial septal defect (ASD) and tricuspid regurgitation (TR), the RV may tolerate volume-overload
for a long time. In contrast, pH in the adult often leads to RV dilatation and failure.
In acute pressure-overload states such as pulmonary embolism (PE), a previously normal
RV is incapable of acutely generating a mean pulmonary artery pressure (mPAP) >40 mm
Hg, and RV failure occurs early.
Atrial flutter and atrial fibrillation are the most common arrhythmias in severe RV
dysfunction, often lead to hemodynamic instability and are associated with an increased
risk of morbidity or mortality.404, 405, 406, 407, 408
RHF may progress from RV dysfunction to symptomatic RV failure to refractory RV failure.
Decreased exercise tolerance represents most important prognostic factors for death
or hospitalization.409, 410, 411
The clinical syndrome of RVMI characterized by the triad of hypotension, elevated
jugular veins, and clear lung fields in a patient with minimal LV involvement. Hemodynamically
significant RVMI with hypotension occurs in less than10% of IWMI patients.
404
3.7.1
Management
The evidence that guides the management of isolated RV failure is not nearly as well
established as the evidence that guides the management of chronic HF resulting from
LV systolic dysfunction. Most recommendations are based on either retrospective or
small randomized studies.
3.7.2
General measures
Moderate sodium restriction (<2 g/d), daily measurements of weight, and judicious
use of diuretics are recommended. Moderate exercise training may significantly improve
functional capacity and quality of life. Isometric activities may be associated with
syncope and should be avoided. Pregnancy in patients with severe RV failure is associated
with high maternal and fetal mortality rate.412, 413
3.7.3
Preload optimization
In conditions where RV output is impaired due to contractile dysfunction but the afterload
is normal, a higher preload is needed to maintain forward flow. It is generally agreed
that maintaining a moderately high RV diastolic filling pressure of 8–12 mmHg is optimal
in RHF.
414
3.7.4
Afterload reduction
General measures include lung protective ventilation, avoiding hypoxaemia and hypercarbia.
Pulmonary vasodilators are currently not approved for use in critically ill patients
with RV failure not due to PAH. However, inhaled nitric oxide (iNO) with its rapid
onset of action and short half-life is the pulmonary vasodilator of choice in the
critically ill and improves pulmonary haemodynamics in RHF. Inhaled prostacyclin analogues
have been shown to be safe and effective in cardiothoracic surgical patients with
pulmonary hypertension, refractory hypoxaemia. Phosphodiesterase 5(PDE5) inhibitors
decrease PAP and increase cardiac output in both acute and chronic pulmonary hypertension.412,
413, 414, 415, 416, 417, 418
3.7.5
Improving contractility
General measures targets maintaining RV perfusion by reducing wall tension and increasing
coronary artery diastolic pressure and maintaining acellular milieu conducive to myocyte
contractility. The general principles of inotrope use for LVF are applicable for RVF
also.
3.7.6
Rhythm management and resynchronization
Maintenance of sinus rhythm and heart rate control are important in RV failure. Sequential
AV pacing and cardioversion of unstable tachyarrhythmias should be considered promptly
when appropriate.
The study of RV resynchronization is at its initial stages.419, 420
3.7.7
Anticoagulation
The risk of thromboembolic events in patients with RV failure has not been well established.
Although anticoagulation is usually recommended in patients with evidence of intracardiac
thrombus, documented thromboembolic events, paroxysmal or persistent atrial flutter
or fibrillation in the presence of PAH and significant RV dysfunction.407, 412
3.7.8
Neurohormonal modulation of RV failure
ACE inhibitors have been shown to increase RVEF and to reduce RV end-diastolic volume
and filling pressures. Small studies also have demonstrated that β blockade with carvedilol
or bisoprolol improves RV systolic function.
3.7.9
Supplemental oxygen therapy and ventilation
Hypoxemia may lead to pulmonary vasoconstriction and contribute to PH. Supplemental
oxygen is recommended in patients with evidence of resting or exercise-induced hypoxemia.
Patients with hypoxemia associated with pulmonary-to-systemic shunting usually do
not benefit from supplemental oxygen therapy.
415
3.7.10
Atrial septostomy
The observation of improved survival of patients with pulmonary hypertension (PH)
and patent foramen ovale has led to the hypothesis that atrial septostomy, which “decompresses”
the RV and increases right-to-left shunting, may be helpful in severe RV failure.
At this time, atrial septostomy should be considered palliative.
421
3.7.11
Transplantation
Originally, it was believed that patients with advanced RV failure secondary to PH
could be candidates only for heart-lung transplantation. However, lung transplantation
has been tried and has been successful in many patients.
412
3.7.12
RV assist device
In acute RV failure refractory to medical treatment, mechanical support with an RV
assist device maybe used as a bridge to transplantation or to recovery.
422
3.8
Constrictive pericarditis
Chronic Constrictive pericarditis (CCP) represents the end stage of various pericardial
inflammatory processes causing thickening and fibrosis of pericardium which limits
diastolic ventricular filling. This is described more than 300 years ago but in spite
of socioeconomic development, surprisingly the burden of constrictive pericarditis
has not declined.
423
In the majority of cases of CCP the etiology remains unclear. In India majority of
the patients with CCP are suspected to have tuberculosis in past. The common causes
of constrictive pericarditis include infectious diseases like tuberculosis, neoplasms,
cardiac surgery, and irradiation. Less important causes are idiopathic pericarditis,
sarcoidosis, uremia, autoimmune (connective tissue) disorders and trauma.424, 425
In developing countries, tuberculosis is still the leading cause of CCP with a reported
incidence of 38%–89%.426, 427, 428, 429, 430 however developed world has seen rapid
decline in the cases resulting from tuberculosis (only 0%–1%)431, 432 and relative
rise in the incidence of post-operative constrictive pericarditis.433, 434, 435
The risk of progression is especially related to the etiology: low (<1%) in viral
and idiopathic pericarditis, intermediate (2–5%) in immune-mediated pericarditis and
neoplastic pericardial diseases and high (20–30%) in bacterial pericarditis, especially
purulent pericarditis.
436
In hospital series from India constrictive pericarditis used to account for 0.24%
to 0.41% of all medical admissions and 0.77% to 3.0% of all cardiac cases admitted.437,
438, 439
The disease is most prevalent from the second to fourth decades of life and is seldom
seen at the extremes of age.
426
It has been found to be more common in men than women in India as compare to western
world.426, [440], 441 The duration of symptoms before the diagnosis is ranges from
1 to 15 years (mean 6 years) due to late diagnosis of the disease.426, 442 The pathophysiological
hallmark of pericardial constriction is equalization of the end diastolic pressure
in all 4 cardiac chambers which is because of restricted ventricular filling due to
loss of pericardial compliance.
443
The most striking presenting clinical features were ascites, exertional dyspnea and
easy fatigability across all series. Exertional dyspnea and ascites are seen in three
fourths of patients. Pedal edema is seen in nearly half while fatigue is the presenting
symptom in one fourth of patients. Less commonly, gastrointestinal symptoms like anorexia,
abdominal fullness, or abdominal pain may develop secondary to ascites.
A mechanical constriction around the heart produces gross signs of right heart failure
without severe dyspnea. The jugular venous pressure is elevated with a deep, steep
y descent. Positive Kussmaul sign and a pericardial knock favor the diagnosis of constrictive
pericarditis. Pulsus paradoxus is uncommon in constrictive pericarditis.
ECG usually shows nonspecific ST segment and T wave changes. Atrial fibrillation (AF)
has been reported in 25%-30% of patients with CCP.
444
X Ray evidence of pericardial calcification is less in Indian patients (15%) compared
to the reported figures of 30%-50% in the western literature.
442
Echocardiography is usually the choice of imaging in patients with suspected constrictive
pericarditis.
424
CT is useful in diagnosing constrictive pericarditis and can demonstrate increased
pericardial thickness (>4 mm) and calcification.
445
If diagnosis is in doubt then invasive hemodynamic study can be useful.
446
3.8.1
Management
Although the mainstay of treatment of chronic permanent cases is surgery, medical
therapy may have a role in some conditions. Medical therapy of specific etiologies
(i.e. tuberculous) is useful to prevent the progression to constriction. Antituberculosis
antibiotics may significantly reduce the risk of constriction from >80% to <10%.447,
448 Medical therapy (generally based on anti-inflammatory drugs) may solve the transient
constriction occurring in 10–20% of cases within a few months, generally as a temporary
phenomenon during the resolution of pericarditis. Medical therapy is supportive and
aimed at controlling symptoms of congestion in advanced cases and when surgery is
contraindicated or delayed.
Pericardiectomy is the definitive treatment for constrictive pericarditis.
430
There is an improvement in mortality rates in series published after 1985. The actuarial
survival was ∼84% in patients undergoing total pericardiectomy compared to ∼74% in
patients undergoing partial pericardiectomy at a mean follow-up of 18 years.
426
In the western studies, the operative mortality is about 6%.431, 449 Survival at 5-
and 10-years is reported to be 78 ± 5% and 57 ± 8%, respectively, which is inferior
to that reported from India. This has been proposed to be due to older age group of
patients and the higher incidence of post irradiation constrictive pericarditis which
leads to myocardial dysfunction as well. Predictors of late events include 3 baseline
variables: age, NYHA class, and a radiation cause for constrictive pericarditis.
431
Idiopathic CP had the best prognosis (7-year Kaplan-Meier survival: 88%, followed
by postsurgical (66%) and post radiation CP (27%).
449
3.9
Restrictive cardiomyopathy
Restrictive cardiomyopathy (RCM) is the least common type of cardiomyopathy. RCM is
characterised by diastolic dysfunction that results in impaired ventricular filling,
normal or decreased diastolic volume of either or both ventricles, and increased left
ventricular wall thickness.
450
Unlike DCM and HCM, where the definition is morphological, the definition of restrictive
cardiomyopathy requires hemodynamic distinctions. Myocardial relaxation abnormality
with interstitial fibrosis and calcifications compose the fundamental abnormalities
of restrictive cardiomyopathies. RCM constitutes 10–15% of all cases of HFpEF.
451
Etiology (Table 30) −
Table 30
Causes of Restrictive cardiomyopathy.
Table 30
Primary
Familial CardiomyopathyEndomyocardial fibrosisLoeffler endocarditisIdiopathic cardiomyopathy
Secondary
Infiltrative
AmyloidosisSarcoidosis
Non-infiltrative
Myocardial
Scleroderma Diabetic cardiomyopathy Pseudoxanthoma elasticum
Endomyocardial
Carcinoid heart disease Metastatic cancers Radiation Toxic effects of anthracycline Drugs
causing fibrous endocarditis (Serotonin, methysergide, ergotamine, mercurial agents
and busulfan)
Storage disorders
Fabry’s disease Gaucher’s disease Haemochromatosis Hurler’s disease Fatty infiltration Storage
diseases Glycogen storage disease
3.9.1
Idiopathic (Primary) RCM
Idiopathic RCM is a rare condition that may present in both children and adults.452,
453 Both familial and sporadic cases have been described.454, 455 Familial cases are
usually characterized by autosomal dominant inheritance with incomplete penetrance.
The condition warrants earliest recognition as development of pulmonary hypertension
precludes heart transplantation.
456
3.9.2
Amyloidosis
Cardiac amyloidosis is an infiltrative disorder caused by deposition of insoluble
fibrillar protein in the interstitial space.
457
It typically presents as a systemic disorder, with multi organ infiltration. Primary
or systemic amyloid light-chain (AL) amyloidosis is the most common form of amyloidosis
and is associated with blood dyscrasias, such as multiple myeloma. Cardiac involvement
is associated with a poor prognosis, with a median survival from diagnosis of 1 year.
458
The diagnosis of AL amyloidosis should be suspected in any patient with nondiabetic
nephrotic syndrome; nonischemic cardiomyopathy with “hypertrophy” on echocardiography.
459
A detailed description of other conditions causing RCM is beyond the scope of this
document and details can be found elsewhere.
3.9.3
Diagnosis of RCM
The ECG often shows low voltage, nonspecific ST-T wave changes, various arrhythmias
and conduction blocks. Most patients have normal or near-normal cardiac size on examination
and chest x-ray. In advanced cases there is cardiomegaly. Echocardiographic findings
in RCM include biatrial dilatation, hypertrophied ventricles with decreased compliance,
initially small cavities of the left ventricle, and normal-to-depressed systolic function
(Table 31).
460
Table 31
Distinguishing Echocardiographic features in different causes of RCM.
Table 31
Disease
Echocardiographic features
EMF
Cavity obliteration and right ventricular outflow tract dilatation with varying degrees
of atrioventricular valve regurgitation
Cardiac Amyloidosis
Increased thickening of the ventricular wall, mitral and tricuspid leaflets, and interatrial
septum. decreased global longitudinal strain
Friedrich’s ataxia
Hypertrophic cardiomyopathy, including symmetric LV hypertrophy, abnormal myocardial
relaxation, and LV outflow obstruction
Drug induced
Valvular thickening
Other classical features of RCM can be studied using Tissue Doppler,&Strain rate imaging
and Myocardial contraction function
Cardiac magnetic resonance (CMR) is a versatile technique providing anatomical, morphological
and functional information in suspected RCM. In recent years, it has been shown to
provide important information regarding disease mechanisms, and also been found useful
to guide treatment, assess its outcome and predict patient prognosis.
461
It confirms the existence of thrombi or calcifications, allows an exact delineation
of hypoperfused areas that correspond to fibrosis, and provides hemodynamic information.
462
Myocardial suppression scans, acquired after injection of gadolinium, allow exact
appreciation of the disease extension of fibrosis by delayed hyperenhancement of the
pathologic areas.
463
Cardiac catheterization is rarely used for the diagnosis of RCM, since complete noninvasive
assessment is possible in most patients. Endomyocardial biopsy is rarely used in India
to diagnose RCM. It may be done when specific treatable etiologies are suspected.
3.9.4
Outcomes
The course of RCM varies depending on the pathology, and the treatment is often unsatisfactory.
The prognosis for children with IRCM is especially poor. In adult presentation, patients
often have extensive disease; therefore, survival after diagnosis is relatively brief,
averaging approximately two years after symptom onset.
464
Gupta and colleagues,
465
showed a 10 year survival of only 37% in patients of EMF.
3.9.5
Treatment
Unlike the overwhelming evidence for guideline based treatment for dilated and hypertrophic
cardiomyopathy, there has been less direction on the best treatment of RCM. The goal
of treatment in RCM is to reduce symptoms by lowering elevated filling pressures without
significantly reducing cardiac output.
The general principles are summarized below-
•
Principles of Non-pharmacological management are similar to that applied in HF of
other etiologies
•
Diuretics (aldosterone antagonists and loop diuretics) – are the mainstay
•
Midodrine* may be helpful when symptomatic hypotension (*Not available in India)
•
Beta blockers and ACEI:
○
Reasonable if the patient has hypertension
○
Often advanced RCM have low baseline blood pressures
○
Prudent to titrate these drug classes with extreme caution.
•
Calcium Channel blockers:
•
Verapamil/diltiazem useful in RCM
○
Increased LV filling time and improving LV relaxation
○
Relatively contraindicated in amyloidosis – high sensitivity to high-degree heart
block and profound negative inotropic effects.
466
•
Digoxin:
•
Amyloidosis – highly sensitive to digoxin may cause sudden death467, 468
•
Should be avoided.
3.9.5.1
Management of atrial fibrillation
Patients with restrictive physiology rely more heavily on atria’s contribution to
stroke volume. Hence, AF needs to be treated with amiodarone and beta blockers promptly.
Patients with AF warrant standard anticoagulation therapy.
3.9.6
Specific management
RCM has no specific treatment. However, therapies directed at individual causes of
RCM have been proven to be effective (Table 32).
Table 32
Treatment of the Restrictive Cardiomyopathies
Table 32
Treatment
Idiopathic RCM
Heart transplant
EMF
Endocardiectomy, Heart transplant
Amyloidosis
•
Primary (AL)
Bortezomib-based chemotherapy, stem cell transplant, ICD
•
Secondary (AA)
Treat the underlying condition
•
Hereditary (m-TTR)
Heart and/or liver transplant, ICD
Hemochromatosis
Phlebotomy, iron-chelating agents
Anderson-Fabry
Phlebotomy, iron-chelating agents
AA = amyloid A; AL = amyloid light-chain; ICD = implantable cardioverter-defibrillator;
m-TTR = mutant transthyretin; wt-TTR = wild-type transthyretin; other
Cardiac transplantation or mechanicals support therapy can be considered in select
patients of RCM with refractory symptoms who have idiopathic RCM, amyloidosis or EMF.
Cardiac transplantation may be effective in patients with m-TTR amyloid if there is
limited hepatic and nerve involvement. Liver and combined liver–cardiac transplantation
may improve survival in these patients when there is significant liver involvement.
3.10
Endomyocardial fibrosis
EMF is a disease of the tropics and widely prevalent and was then reported from India,
Uganda, Nigeria, Ivory Coast and Brazil.
EMF in India
As per hospital statistics, incidence and prevalence of EMF peaked during 1960–1990
in Kerala and subsequently there has been a marked decrease in newly diagnosed cases
of EMF. In the registry of over 400 cases of EMF during 1978–1990,469, 470 RVEMF was
seen in 30%, LVEMF in 20% and biventricular EMF (BVEMF) in 50%. Mortality at 2 years
in those presenting with NYHA class 3–4 was 50% on optimal medical therapy. During
a five year period from 1998 to 2003, there were only 50 new cases of EMF with mostly
older patients. The patients were less symptomatic; most of the cases were diagnosed
consequent to evaluation of abnormal electrocardiograms and non-specific symptoms.
The mortality of the patients who presented in this period was less than 10 percent
at two years after diagnosis.
3.10.1
Anatomical/structural involvement in EMF
As the name suggests, and as clinically recognized, endomyocardial fibrosis is primarily
a fibrotic disease process involving predominantly the endocardium of either or both
ventricles and conspicuous by sparing the atria of clinically important involvement.
There is a predilection for the pathologic process to involve the apices of the ventricles
and spare the outflows of the right and left ventricles though an occasional case
of RV outflow involvement with the fibrotic process has been described. The endocardial
fibrotic process extends to adjacent myocardium to variable degree and can rarely
cause in addition, systolic ventricular dysfunction. Superimposed thrombus on the
fibrotic endocardial surface can lead to systemic as well as pulmonary thromboembolism
and organized clots are postulated to be an additional reason for ventricular cavity
obliteration. The fibrotic process can involve the papillary muscles of either of
the ventricle and this leads to loss of function of the chordo-papillary structure
often leading to fixity and plastering of the leaflets with reduced mobility and inadequate
coaptation causing atrio-ventricular (AV) valve regurgitation, though primary involvement
of the valve leaflets is not described.
3.10.2
Clinical presentation:
The extent of obliterative endocardial involvement and AV valve incompetence affecting
either or both ventricles will determine the clinical symptomatology. Isolated RVEMF
with obliterative changes and no tricuspid incompetence, are mildly symptomatic and
the only abnormal clinical finding may be prominent ‘a’ wave in JVP. At the other
extreme, patients with isolated RVEMF with severe TR present with features of chronic
right HF with markedly elevated JVP and expansile large ‘v’ waves, pulsatile liver,
hepatomegaly, ascites precox, edema, cyanosis, cachexia, and malnutrition. They may
also have pericardial effusion, marked cardiomegaly, RV third heart sound, and inconspicuous
systolic murmur of TR. The severity of TR rather than the presence of RV diastolic
dysfunction is the determining factor for the outcome of patients with RVEMF.
Isolated LVEMF, in the absence of AV valve incompetence, is often minimally symptomatic.
Hemodynamic study may reveal a prominent ‘a’ wave in the pulmonary artery wedge pressure
and LV end diastolic pressure may be elevated. Patients with LVEMF usually have features
of mitral incompetence with grade 1 to 3/6 intensity systolic murmur. A systolic thrill
is rare, so also is a fourth heart sound. LV third heart sound is common. Patients
with LVEMF and significant mitral incompetence, present similar to patients with valvular
incompetence from rheumatic heart disease. Left atrial and pulmonary venous hypertension
is followed by pulmonary arterial hypertension and RV failure. Features of PAH will
depend on the presence of pulmonary venous hypertension resulting from mitral incompetence
as well as diastolic LV dysfunction. Symptomatic patients with LVEMF usually have
significant AV valve incompetence and symptoms correlate well with severity of mitral
incompetence, suggesting that mitral incompetence is the dominant factor in determining
the clinical disease progression.
Biventricular involvement is seen in at least 50% of patients and clinical presentation
depends upon the severity of mitral incompetence, tricuspid incompetence and diastolic
dysfunction due to obliterative changes in both the ventricles. These patients are
hemodynamically more compromised and deteriorate rapidly and have a poor prognosis.
Though large RA thrombi are occasionally seen, it is rare to see massive pulmonary
embolism and pulmonary infarcts are rarely recognized clinically or at autopsy. Large
pericardial effusion with isolated severe RV EMF rarely contribute to hemodynamic
deterioration and is an indicator of severe disease, re-accumulates rapidly and is
not drained as a routine.
3.10.3
Investigations:
Electrocardiogram and Chest skiagram are useful to assess chamber enlargement, pulmonary
venous hypertension, and pericardial effusion. LA enlargement is common finding. RVEMF
is often characterized by qR pattern in V1 with a diminutive ‘R’ and hypothesized
as due to RA enlargement displacing a diminutive RV (Fig. 13, Fig. 14)
Fig. 14
ECG of a patient with LVEMF, showing LVH with strain pattern.
Fig. 14
Echocardiography with Doppler study, and hemodynamic study with ventricular angiography
are essential tools for assessment of the morphological and hemodynamic derangement
in EMF to decide on need for therapeutic interventions (Fig. 15, Fig. 16, Fig. 17,
Fig. 18).460, 471
Fig. 15
Fluoroscopy showing, the presence of LV apical calcium.
Fig. 15
Fig. 16
LV angiogram in a patient with LVEMF, showing the obliteration of the LV apex, transverse
diameter more than the longitudinal diameter and no MR (Primary diastolic HF).
Fig. 16
Fig. 17
RV angiogram in a patient with RVEMF, showing obliteration of the RV apex and body,
RVOF dilatation and significant TR.
Fig. 17
Fig. 18
Echocardiogram, Apical 4 chamber view, showing the presence of calcium at the LV apex.
Fig. 18
Cardiac MRI has the potential to be the choice imaging mode for better delineation
of ventricular morphology, shape, function as well as endocardial thickening, thrombosis,
myocardial characterization for fibrosis and AV valve incompetence. (Fig. 19)
Fig. 19
Perfusion MRI, 4 chamber view in diastole showing fibrosis and obliteration of RV
apex (white arrow) [RV – right ventricle, RA – Right atrium, LA – left atrium].
Fig. 19
3.10.4
Management of HF in EMF
For clinical simplicity, 3 scenarios of EMF which will encompass the majority of clinical
spectrum of EMF are summarized in Table below
1.
Isolated RVEMF:
•
Medical management is as for isolated right HF with diuretics for preload reduction
•
Chronic low pressure TR has a better prognosis with patients often surviving many
years, though the majority may succumb to HF and inter-current illness due to malnutrition
•
Surgical options: TV replacement, TV replacement with Glenn shunt (one and half ventricle
repair) and Fontan type surgery
2.
Isolated LVEMF:
•
Mildly symptomatic patients – small dose diuretics as needed and rhythm management
and anticoagulation when indicated for AF.
•
Ventricular arrhythmias are infrequent and prophylactic ICD/CRT not indicated in view
of preserved LVEF in the vast majority.
•
Severely symptomatic patients – surgery with mitral valve replacement and LV endocardiectomy
•
The short term, intermediate and long term outcome is excellent, though underlying
myocardial dysfunction, extend of restoration of LV cavity and LV compliance at surgery
are confounding factors.
3.
BVEMF with hemodynamically significant biventricular involvement:
•
Most difficult subset of patients to manage medically as well as surgically
•
Medical therapy is supportive with optimal diuretic use, ventricular rate control
and anticoagulation for AF
•
Decision on feasibility of surgery is largely dependent on the extent of RV involvement
and adequacy of RV to support the entire cardiac output by its structure and function.
A hypertensive RV (RV pressure more than 50 mmHg is a useful yardstick) indicates
adequate systolic function to support the systemic circulation and these patients
can undergo MV replacement with LV endocardectomy and TV repair ensuring adequacy
of RV cavity volume and systolic RV function. These patients cannot have Glenn/one
and half ventricle repair/Fontan type surgery along with MV surgery. In the absence
of significant obliterative and contracted volume deficient RV, these patients have
a fair long term surgical outcome.
Severe LV involvement with severe RV involvement characterized by severe TR and severe
RV cavity obliteration are not offered surgical options in view of high surgical risk
and uncertain long term outcome. They are managed as chronic HF and can be listed
for cardiac transplant as there is little risk of recurrence of EMF.
Eosinophilic systemic disease with EMF: Hypereosinophilic syndrome with tissue infiltration
and endo myocardial involvement (Loeffler’s syndrome) can closely mimic tropical EF.
Experience at the Sree Chitra Tirunal Institute for Medical Sciences and Technology
showed 54% survival among 210 medically followed up patients. However those in class
3–4 had 50% mortality at 2 years. 89 patients underwent various surgical procedures
from 1980- 1990.
471
Operative mortality at one month was 30% and additional late mortality of 12%. Late
mortality and morbidity were related to prosthetic valve dysfunction more so in the
tricuspid position with bioprosthesis degeneration and mechanical prosthesis thrombosis.
27 patients with isolated RVEMF had TV replacement with RV endocardectomy with early
mortality 30%. 13 patients with LVEMF had LV endocardectomy and MV replacement including
2 TV annuloplasty, with early mortality 23%. 49 patients with significant BVEMF, had
MVR + TVR+ BV endocardectomy in 12, MVR + LVE+ TVA in 15, MVR+ LV endocardectomy in
11 and TVR + RV endocardectomy in13 (patients with hemodynamically insignificant LV
involvement)with early mortality 30%. Mortality in patients less than 15 years was
58% compared to 22% in those above 15 years. 3 patients showed recurrent fibrosis
of endocardium at follow up of which, one had significant cavity obliteration. In
view of the unsatisfactory surgical outcome, only 7 patients out of 11 patients presenting
in 1990–2000 period were offered surgery and none was offered TV replacement. 3 had
LV endocardectomy with MVR, one LV endocardectomy alone, 1 biventricular endocardectomy,
2 bidirectional Glenn shunt. There was no early or intermediate term mortality, essentially
because of case selection, avoiding patients with severe biventricular disease and
resorting to RV bypass avoiding TV replacement (Table 33).
Table 33
Salient features of EMF in India.
Table 33
•
Endomyocardial fibrosis is presently reported sporadically from many parts of India
•
There is a remarkable reduction in newly diagnosed cases
•
3 Phases − Thrombotic (acute) phase, sub acute phase and chronic fibrotic phase
•
Management − predominantly addressing pulmonary and systemic venous congestion with
diuretics, arrhythmia management and anticoagulation
•
Various surgical interventions have been attempted, and MV replacement and or LV endocardectomy
for isolated LV EMF have similar results to MV replacement in rheumatic valvular heart
disease. Surgical outcome for primary RV involvement is less satisfactory with high
surgical mortality and early prosthetic valve thrombosis.
3.11
Nutritional and metabolic causes of HF
Metabolic derangements are rare but important cause of HF. In developing countries
like India, this becomes even more important due to higher prevalence of malnutrition
and poor general health care leading to delayed diagnosis and ineffective management
of potentially reversible causes of HF.
Metabolic derangements leading to HF can be divided into Nutritional causes and Hormonal
causes (Table 34).
26
Table 34
Metabolic causes of heart failure.
Table 34
Nutritional Causes
Hormonal causes
Deficiency of micronutrients
Thyroid diseases
Thiamine
Parathyroid disease
L-carnitine
Acromegaly
Selenium
GH deficiency
Coenzyme Q10
Hypercortisolemia
Iron
Primary hyperaldosteronism
Phosphates
Addison’s Disease
Calcium
Diabetes mellitus
Complex malnutrition
Metabolic Syndrome
Malignancy
Pheochromocytoma
AIDS
Related to pregnancy and peripartum
Anorexia nervosa
Obesity
3.11.1
Nutritional causes
3.11.1.1
Thiamine deficiency (Beriberi)
Asians have higher incidence of beriberi because the diet consists of a high intake
of polished rice which is deficient in thiamine. Thiamine is required as a cofactor
for energy production via the Krebs cycle at two steps: oxidative decarboxylation
of pyruvate to acetyl coenzyme A and of alpha ketoglutarate to succinyl coenzyme A.
Thiamine deficiency initially presents as a high-output state secondary to vasodilation
and an increase in blood volume this is followed by eventual depression of myocardial
function and the development of a low output state. Direct impairment of myocardial
energy production has been proposed as one possible mechanism of the heart failure
seen in beriberi. Exact mechanism responsible for vasodilation is not clearly understood.472,
473, 474, 475
Classically, beriberi has been divided into two major types: a “dry” form, in which
features of peripheral neuropathy predominate, and a “wet” form, in which signs and
symptoms of right-sided heart failure with normal or high cardiac output are the presenting
features. Rarely, a fulminant or “pernicious” variant, termed Shoshinberiberi, may
occur with severe biventricular failure, metabolic acidosis, and variable cardiac
output with vascular collapse, peripheral cyanosis and death. Laboratory diagnosis
of thiamine deficiency can be made on the basis of an increase in thiamine pyrophosphate
effect (TPPE), decrease in blood thiamine concentration, or a decrease in red cell
transketolase activity.
Thiamine supplementation may be initiated depending on the severity of HF. In mild
deficiency states including lactating women at risk of inadequate thiamine intake,
a daily oral dose of 10 mg thiamine should be given during the first week, followed
by 3–5 mg for at least six weeks. In critically ill child if severe heart failure,
convulsions or coma occur, 25–50 mg of thiamine should be given very slowly intravenously,
followed by a daily intramuscular dose of 10 mg for about a week. This should then
be followed by 3–5 mg of thiamine per day orally for at least 6 weeks. In adults with
severe heart failure 50–100 mg thiamine should be administered very slowly intravenously,
followed by the same oral doses as for children. With appropriate treatment, the cardiac
index and heart rate are reduced and there is an increase in systemic vascular resistance.
Magnesium may have to be co-administered with thiamine, particularly in magnesium-depleted
patients as magnesium depletion alone leads to a blunted response to thiamine supplementation
and loss of thiamine from tissues. Beneficial effects of thiamine have been demonstrated
in Indian population in some small studies.476, 477
3.11.2
L- carnitine deficiency
Carnitine is a naturally occurring hydrophilic amino acid derivative, produced endogenously
in the kidneys and liver and derived from meat and dairy products in the diet. It
plays an essential role in the transfer of long-chain fatty acids into the mitochondria
for beta-oxidation.
The three areas of involvement include
26
the cardiac muscle, which is affected by progressive cardiomyopathy (by far, the most
common form of presentation),
472
the central nervous system, which is affected by encephalopathy caused by hypoketotic
hypoglycemia, and
473
the skeletal muscle, which is affected by myopathy. Cardiomyopathy (affecting older
children) may occur with rapidly progressive heart failure. Pericardial effusion has
also been observed in association with primary carnitine deficiency. In patients with
carnitine deficiency, the carnitine level in plasma is usually less than 5% of normal.
Medical therapy with oral carnitine in primary carnitine deficiency improves fasting
ketogenesis, cardiac function, growth, and cognitive performance. The usual dose of
oral L-carnitine in children is 100 mg/kg per day in four divided doses. The dose
of L-carnitine in adults is 2 to 6 g daily. For life-threatening events, intravenous
therapy of 100 to 400 mg/kg per day should be used.
478
3.11.3
Selenium deficiency
Selenium (Se) is a trace mineral with a role in multiple biologic functions. Seafood,
kidney and liver, and meat are good sources of selenium. Drinking water usually contains
very little selenium.479, 480 The selenium content of grains and seeds is variable
and depends on the selenium content of the soil and the form in which selenium is
present
Severe selenium deficiency is associated with skeletal muscle dysfunction and cardiomyopathy
and may also cause mood disorders and impaired immune function macrocytosis, and whitened
nailbeds. Keshan disease, an endemic cardiomyopathy that affects children and women
of childbearing age in areas of China, has been linked to selenium deficiency.
481
Several cases of selenium deficiency in chronic total parenteral nutrition users have
been reported with cardiomyopathy and skeletal muscle dysfunction.
482
The Recommended dietary allowance for selenium is 20 mcg daily for young children,
rising to 55 mcg daily for adults.
3.11.4
Coenzyme Q10 deficiency
Coenzyme Q10 (CoQ10) is a natural antioxidant synthesized and diet-supplied lipid-soluble
cofactor that acts in the mitochondrial membrane. Coenzyme Q10 (CoQ10) or ubiquinone
can potentially enhance cardiac function through a variety of mechanisms.
483
Coenzyme Q10 deficiency is associated with HF. In patients with HF, the reduced intake
of CoQ10 is correlated with New York Heart Association (NYHA) functional class, lower
left ventricular ejection fraction (LVEF) and increased NT-proBNP levels.
484
Measurement of total CoQ10 represents the sum of the reduced form (Ubiquinol-10) and
the oxidized form (Ubiqinone-10).
Two meta-analyses485, 486 that have examined pooled data from 13 trials demonstrated
an improvement in LVEF of 3.67% (95% CI, 1.6%–5.74%) in those receiving CoQ10 versus
placebo. The majority of benefit of LVEF improvement was in trials published before
1993 (7/13). Lack of contemporary cardiovascular drugs and devices, and use of more
subjective outcomes (such as hospitalizations and symptoms) limit the strength of
these findings. Recent Q-SYMBIO trial completed in 2014 which enrolled 420 patients
demonstrated that compared with placebo, CoQ10 at 100 mg orally thrice a day reduced
the primary two year end point of cardiovascular death, hospital stays for HF, or
mechanical support or cardiac transplant (30 versus 57, P = 0.005).
487
Cochrane Database review no conclusions can be drawn on the benefits or harms of coenzyme
Q10 in heart failure at this time as trials published to date lack information on
clinically relevant endpoints. Furthermore, the existing data are derived from small,
heterogeneous trials that concentrate on physiological measures: their results are
inconclusive. Until further evidence emerges to support the use of coenzyme Q10 in
heart failure, there might be a need to re-evaluate whether further trials testing
coenzyme Q10 in heart failure are desirable.
3.11.5
Iron deficiency
Iron deficiency contributes to cardiac and peripheral dysfunction and is associated
with increased risk of death, independent of the hemoglobin level.
488
Iron deficiency affects nearly 40% of HF patients.
489
Jankowska et al. demonstrated that iron deficiency is a strong and independent predictor
of prognosis in HF, with a 1.58 increased risk of death or heart transplant.
490
In recent INDIC study, iron deficiency was seen in 67.5% patients with systolic heart
failure and was associated with advanced NYHA class.
491
In HF patients, iron deficiency can be defined as ferritin <100 mg/L (absolute iron
deficiency, related to depletion of iron stores), or 100–300 mg/L with transferrin
saturation <20%. CONFIRM-HF trial demonstrated a 61% relative decrease in HF hospitalization
for worsening HF and an improvement in functional capacity, symptoms, and quality
of life in patients receiving intravenous ferric carboxymaltose.
492
A meta-analysis of five randomized clinical trials suggested that intravenous iron
supplementation reduces cardiovascular hospitalization (OR 0.44), cardiovascular death
or hospitalization for worsening HF (OR 0.39), while improving quality of life, functional
capacity and other symptoms.23Recent ESC guidelines recommend Intravenous ferric carboxymaltose
in symptomatic patients with Heart failure with reduced ejection fraction and iron
deficiency (serum ferritin <100 μg/L, or ferritin between 100 and 299 μg/L and transferrin
saturation <20%) in order to alleviate HF symptoms, and improve exercise capacity
and quality of life.
26
Advantages of IV iron therapy include the small number of injections required, rapid
improvement in iron parameters and the cost-effectiveness. Preparation of iv iron
like ferric carboxymaltose (FCM), ferric hydroxide sucrose, ferric gluconate, and
ferric hydroxide dextran are available. The recommended dose for FCM (750 mg) is higher
than that for ferric sucrose (100–400 mg) or ferric gluconate (125 mg), so fewer injections
of FCM are needed to replenish iron stores.
3.11.6
Hormonal causes
3.11.6.1
Thyroid dysfunction
Thyroid hormone regulates cardiac performance by acting on the heart and vascular
system. Several important cardiac structural and functional proteins are transcriptionally
regulated by T3, namely, sarcoplasmic reticulum calcium ATPase (SERCA2), α-myosin
heavy chain (αMHC), β1 adrenergic receptors, sodium/potassium ATPase, voltage-gated
potassium channels, malic enzyme and atrial and brain natriuretic hormone.
493
Short-term hyperthyroidism is characterized by a high cardiac output state with a
remarkable increase in heart rate and cardiac preload and a reduction in peripheral
vascular resistance, resulting in a hyperdynamic circulation. T3 promotes relaxation
of the peripheral vasculature and decreases systemic vascular resistance indirectly
by affecting tissue thermogenesis and directly by acting on vascular smooth muscle
cells and endothelial nitric oxide production. Patients with overt and subclinical
hyperthyroidism are at increased risk of cardiac death. The increased risk of cardiac
mortality might be a consequence of the increased risk of atrial arrhythmias and of
the risk of HF in these individuals. The development of high-output HF in thyrotoxicosis
may be due to ‘tachycardia-mediated cardiomyopathy’.
494
The symptoms and signs of HF occur in the setting of an increased cardiac output with
normal systolic function and low systemic vascular resistance, whereas blood volume
is increased due to the chronic activation of the RAS and, consequently, cardiac preload
is enhanced. Impaired exercise tolerance can be interpreted as the first symptom of
HF in hyperthyroid patients subsequently patient may complain breathlessness at rest,
fatigue and fluid retention with peripheral oedema, pleural effusion, hepatic congestion
and increased pulmonary arterial hypertension. Several case reports suggest that treatment
with β-blockers and diuretics may improve the congestive circulatory symptoms in these
patients.
492
Euthyroidism results in a rapid clinical improvement of cardiac function and symptoms
of congestive HF. However, HF may become irreversible in some cases. Approximately,
one-third of patients may develop hyperthyroid cardiomyopathy.
495
Hypothyroidism causes cardiac atrophy due to decreased αMHC expression and increased
βMHC expression. Moreover, hypothyroidism leads to chamber dilatation and impaired
myocardial blood flow. Even patients with subclinical hypothyroidism are increased
risk of heart failure. The Health Aging and Body Composition population-based study
showed that patients (aged 70–79 years) with TSH level 7 mU/l or greater, who were
monitored for 4 years, had a higher risk of HF events than euthyroid patients.
496
Thyroid function should be evaluated in patients with HF and non-ischaemic dilated
cardiomyopathy to determine whether hypothyroidism and low T3 syndrome caused the
cardiac disease. The American College of Cardiology guidelines for HF recommend screening
of serum thyrotrophin levels for all cases of newly diagnosed HF.
100
The administration of replacement doses of L-T4 reduces myocyte apoptosis and improves
cardiovascular performance and ventricular remodeling. Diastolic dysfunction due to
slowed myocardial relaxation and impaired ventricular filling is reversible after
replacement therapy. Patients with TSH >10 mU/l had an increased risk of HF during
the periods of L-T4 withdrawal than during its use
497
and replacement doses of L-T4 should be considered in patients with Subclinical Hypothyroidism
and TSH > 10 mU/l to prevent the risk of HF events.
Other less common hormonal causes of heart failure are summarized in Table 35.
Table 35
Other hormonal disorders causing heart failure.
Table 35
Disorder
Characteristics
Treatment
Parathyroid diseases
•
Autonomous adenoma or secondary hyperparathyroidism secondary to chronic renal disease
or vitamin D deficiency
•
hypertension, obesity, glucose intolerance, and insulin resistance
•
myocyte hypertrophy, diastolic dysfunction, calcification of aortic valve, mitral
valve and myocardium
•
Surgical removal of adenoma
Acromegaly
•
Benign adenoma in >98% cases,
•
Hypertension, systolic and diastolic dysfunction, increased myocardial mass, interstitial
fibrosis, ventricular cavity dilatation, and increased systemic vascular resistance,
atrial and ventricular arrhythmias,
•
Surgical resection of adenoma, somatostatin analogies
•
May reverse hypertrophy, improve diastolic filling and systolic performance
GH deficiency
•
Atherosclerosis, decreases in LV mass index, impaired LV performance at peak exercise,
and exercise intolerance
•
GH replacement therapy improves cardiac performance and increases LV mass, LV end
diastolic volume, and stroke volume
Cushing’s Syndrome
•
Due to pituitary adenoma or ectopic ACTH syndrome
•
Increased septal and free wall thickness, diastolic dysfunction, subclinical systolic
dysfunction
•
Transphenoidal surgery or bilateral adrenalectomy, radiotherapy
•
Reversible with normalisation
Primary hyperaldosteronism
•
Unilateral adrenal adenoma or bilateral adrenal hyperplasia
•
Hypertension, potassium depletion,
•
Maladaptive cardiac remodelling, diastolic dysfunction
•
Laparoscopic adrenalectomy for unilateral adenoma,
•
MRAs for bilateral hyperplasia
Pheochromocytoma
•
Catecholamine-producing tumours that originate from chromaffin cells of the adrenal
medulla and the sympathetic ganglia
•
Hypertension (episodic or sustained) and paroxysmal symptoms such as dizziness, headache,
flushing, diaphoresis, and palpitations may lead to dilated cardiomyopathy or hypertrophic
cardiomyopathy.
•
Surgical resection, with preoperative medical optimization to obtain adequate blood
pressure control and volume expansion
•
reversal of cardiomyopathy in early stages after surgery
GH − Growth Hormone, MRAs − Mineralocorticoid Receptor Antagonists.
3.12
HIV cardiomyopathy
With the advent of anti-retroviral therapy and better opportunistic infection control,
chronic complications of Human Immunodeficiency Virus (HIV) infection, like HIV cardiomyopathy
is gaining prominence. The cause is multi-factorial, including myocarditis secondary
to HIV itself or other infectious agents, nutritional deficiencies (selenium, carnitine,
and vitamins B1 and B12), autonomic insufficiency, and autoimmune factors (cytokine
imbalances), effects of anti-retroviral drugs etc. Patients living with HIV/AIDS should
be carefully evaluated and screened for presence of HIV cardiomyopathy. Indian data
regarding the prevalence of this condition is inadequate.
In the pre highly active antiretroviral therapy (HAART) era, the heart failure in
HIV-infected individuals was mainly due to myocarditis, related to direct effects
of HIV, opportunistic infections, autoimmunity, nutritional deficiencies, or severe
immune deficiency.
498
After HAART introduction, it has been proposed that incidence of coronary artery disease
is more in HIV affected individuals, probably due to metabolic derangements caused
by protease inhibitors.
Pre-HAART era: HIV-associated cardiomyopathy was broadly defined as a decreased left
ventricular (LV) ejection fraction or dilated LV by imaging studies, with or without
symptoms of heart failure and mainly prevalent in the developing countries.
After introduction of HAART, definition of HIV-associated cardiomyopathy now includes
diastolic dysfunction.499, 500, 501, 502
3.12.1
Pathological features of HIV-associated cardiomyopathy
Gross examination reveals endocardial fibrosis and mural thrombus. Histologically,
there is evidence of myocyte hypertrophy and degeneration, with increased interstitial
and endocardial fibrillar collagen often associated with evidence of previous myocarditis.
3.12.2
Treatment503, 504, 505, 506, 507, 508, 509, 510, 511, 512
No randomized trials of heart failure medications have been performed in HIV cardiomyopathy,
and therapy is based on consensus statements and standard guideline directed medical
treatment for non-HIV heart failure.
3.12.3
The Indian perspective
Studies on cardiovascular manifestations of HIV are sparse in India, as the clinical
picture is still dominated by opportunistic infections, and cardiological symptoms
in these patients are frequently ascribed to non-cardiac causes by the treating physicians
due to lack of awareness. However, after initiation of HAART and better infection
control, there has been a prolongation of life span of HIV patients, and more and
more patients are being diagnosed with cardiomyopathy. According to some case reports,
HAART may prolong life expectancy in HIV cardiomyopathy.
513
Echocardiography remains the mainstay of diagnosis in India, and its use in HIV patients
needs to be encouraged. The ensuing table summarizes the findings of various authors
who have studied HIV related cardiovascular manifestations in the Indian subcontinent
(Table 36).
Table 36
Major studies on HIV associated cardiomyopathy from India.
Table 36
Author
Year of publication
Summary of findings
B P Chattopadhyay, et al
514
2009
150 patients, Male Female ratio 3:1; Mean age 29.2 years; 50 patients had echo abnormalities.Pericardial
effusion in 22.6%, DCM in 11.3%, PAH in 8.6%, diastolic dysfunction in 3.3%, QT prolongation
in 11.3%. Significant relation with CD4 count.
Santanu Guha et al
515
2010
45 asymptomatic HIV ART naive patients; diastolic dysfunction (18%), pericardial effusion
(13%) and systolic dysfunction (7%). Low CD4 count was significantly associated with
pericardial effusion
Sakthi Vadivel, V. et al
516
2014
150 patients; 16 had abnormal echo. Pericardial effusion (56.25%), dilated cardiomyopathy
(31.25%), interventricular septal hypokinesia (6.25%) and infective endocarditis (6.25%)
Joshi et al
517
1998
74 patients; DCM in 10.6%, pericardial effusion 8.5%, vegetation 4.2%, constrictive
pericarditis 2.1% and 10.6% hadincidental valvular HD, LVH, IHD
Mishra et al (AIIMS)
518
2003
36.7% had diastolic dysfunction and 23.3% had systolic dysfunction
P Kannan et al
519
2003
200 patients, LV dysfunction in 28 patients, pericardial effusion in 20, PAH in 6
patients, DCM 1 patient
R. B. Sudagar Singh et al
520
2015
100 patients; 30 moderate risk category and 8 high risk category for Framingham 10 year
absolute risk. Echocardiographic abnormalities in 24 patients. Pulmonary hypertension
(12%), Pericardial effusion (7%), LV systolic dysfunction (6%), Diastolic dysfunction
(23%), RV dysfunction (1%) and Chamber dilatation in 14%
3.13
Management of heart failure in specific situations: alcohol induced cardiomyopathy
Alcohol consumption is common modifiable risk factor for development of Cardiac dysfunction
and symptomatic HF. The diagnosis of Alcohol induced Cardiomyopathy (ACM) is usually
one of exclusion in a patient with DCM with no identified cause and a long history
of heavy alcohol abuse.
Alcohol consumption is very common in the developed world due to easy availability
and low cost In India the prevalence of alcohol consumption is increasing and has
shown 100% rise from 1970 to 1995 and 38% rise from 2003 to 2006
3.13.1
Mechanisms of alcohol toxicity
There are various possible/proposed ways Alcohol can have deleterious effects on cardiac
structure and function and exact pathogenesis is not fully understood. The cardiac
adverse effects could be due to direct toxicity of ethanol or its metabolites,toxicity
of additives (Arsenic, Cobalt), dietary deficiencies (Thiamine, Selenium), electrolyte
imbalance and associated malnutrition. Increased prevalence of various co morbid conditions,
RAAS activation and due to genetic factors may also be responsible.
3.13.2
Treatment
There are no separate guidelines or recommendations for ACM so these patients are
to be treated as chronic heart failure patients. ACM patients should be managed with
guidelines based therapies as other patients with HFrEF. Replacement of nutritional
deficiencies such as B12 and folate, correction of malnutrition and treatment of electrolyte
imbalance is very important. Non pharmacologic measures such as reduced salt and water
intake, regular exercise, vaccinations and treatment of co morbidities should be followed
as per the guidelines.
The most important part of the treatment of ACM is total and sustained abstinence
from alcohol intake and that should be strictly enforced.
3.14
Heart failure in the elderly
3.14.1
Introduction
Heart Failure (HF) in the elderly is a complex outcome of the interactions between
age related physiologic changes, prolonged exposure to the cardiovascular risk factors
and co existent comorbidities. India is witnessing an epidemiological transition wherein
we are increasingly confronted with degenerative diseases in the older population.
3.14.2
Epidemiology
The definition of the age of the elderly and a chronological age above 65 years are
defined as ‘elderly’ by the World Health Organization. Patients aged >65 years are
disproportionately affected and more than 80% of HF patients are 65 years of age or
older.
521
The prevalence of HF doubles for every decade after 40 years and is <1% for age <40
years, and >10% for age >80 years.
522
The prevalence of systolic and solitary diastolic dysfunction in this group is 5.5%
and 36%, respectively.
523
The mortality and the average length of hospitalisation for acute heart failure increases
by 2–4 days in this group. The diagnosis of HF portends a prognosis worse than most
cancers.
524
3.14.3
The pathobiology of aging and heart failure
Aging is associated with a myriad of changes in cellular composition and function
in the organ systems of the body. These changes enhance the susceptibility, alter
the clinical profile, influence management and prognosis of HF in the elderly. The
alterations with a significant impact with respect aging and HF affect the cardio-vascular
system, the body composition, pro-inflammatory state and co-morbid conditions.
3.14.4
The treatment of HF in the elderly
HF in the elderly is a distinctive syndrome and on account of the age associated decline
in organ functions, psycho-social issues, subtle presentations and comorbidities is
a challenge warrants a multidisciplinary, specialty intensive and prompts approach.
The recommendations for the treatment of HF emanate from trials which often excluded
the elderly as a consequence of age, associated comorbidities and limited life expectancy.525,
526
The cornerstone of management of HF is drug therapy and this in the elderly is less
predictable on account of the changes in body composition and slow metabolism. There
is increase in body fat, a reduction in the muscle mass and body water which results
in lower volume of distribution. The levels of hydrophilic drugs increase whereas
the levels of lipophilic drugs decrease.
527
This coupled with the decline the renal and hepatic function alters the pharmacokinetics,
bioavailability and drug interactions.528, 529, 530
3.14.5
Recommendations
The treatment of HF in the elderly is a growing concern on account of the increasing
age of the population and a challenge (Fig. 20). The multitude of issues range from
lack of data on optimal therapy, atypical presentations, coexistent comorbidities,
poly-pharmacy, poorer prognosis, psychosocial isolation and penetration of health
care. There is an urgent need to have multi-disciplinary and joint effort at all levels
to address the preventive aspects, increase awareness, increase the reach of health
care delivery, adopt a cohesive evidence based management, an increasing representation
in research and a need to develop dedicated program at all levels of healthcare.
Fig. 20
HF in Elderly.
Fig. 20
3.15
Management of heart failure in pulmonary hypertension
Management of patients with pulmonary hypertension developing right ventricular failure
is a common challenge encountered in the daily practice. A combination of a low central
venous O2 saturation (≤60%) with increasing levels of lactate and low or absent urine
production in patients with pulmonary hypertension are indicator of imminent right
heart failure.
531
Both right ventricular dysfunction and pulmonary hypertension portend a poor prognosis
and are associated with significant morbidity and mortality.
3.15.1
Pathophysiology of Right Ventricular Failure
In pulmonary hypertension, the compensatory RV hypertrophy results in supply-demand
mismatch. Patients with advanced pH can develop acute RV failure as a result of disease
progression despite appropriate therapy but more commonly it develops following an
triggering event such as medication non- compliance, systemic infection, upper respiratory
infection, anemia, arrhythmias, pulmonary embolism, or changes in overall volume status.
532
3.15.2
Principles of management: (Table 37)
Treatment of triggering factors: In patients presenting with decompensated right ventricular
failure and hemodynamic compromise, infection and anemia must be actively searched
and adequately treated.
533
In patients with Eisenmenger syndrome and cor pulmonale, hyperviscocity and erythrocytosis
be watched and managed accordingly.
534
Pulmonary embolism should be ruled out as it precipitates RV failure. Digoxin, amiodarone,
or diltiazem should be used to control heart in atrial arrhythmias.
535
Beta blockers and calcium channel blockers should be avoided in acute RV failure as
they impair ventricular contraction. Amiodarone, electrical cardioversion and radiofrequency
ablation is often required for rhythm control .
536
Table 37
General Principles of Management.
Table 37
Treatment of triggering factors
Reduction of RV afterload
Maintenance of systemic blood pressure with vasopressors.
Improvement of cardiac output
Ventilatory Support and Tissue Oxygenation
Mechanical RV support
Balloon atrial septostomy (BAS)
Heart lung or Lung-Lung Transplantation
Optimization of fluid balance: Volume loading is useful only in patients with underfilled
right ventricles with low central venous pressures.
537
In patients with fluid overload state, loop diuretics with or without thiazide diuretics
targeting a CVP of 6–12 mmHg is often sufficient.
538
Reduction of RV afterload: Pulmonary vasodilators should be used only after optimization
of RV perfusion and cardiac output. Caution however in needed to avoid systemic hypotension
and pulmonary oedema.
539
Inhaled NO has proven beneficial in improving RV performance in varied scenarios and
should be considered upfront.
540
Prostacyclins, including epoprostenol, treprostinil, and iloprost can improve RV performance
by reducing pulmonary vascular resistance. Because of a global reduction in systemic
vascular resistance and consequent worsening of hypoxia secondary to ventilatory-perfusion
mismatch, intravenous prostacyclins are not preferred. Once stabilized, consideration
must be given for a switch to oral therapy. Though limited, data on their use in acute
setting, has shown promise in facilitating NO weaning and minimizing rebound pulmonary
hypertension following discontinuation of inhaled agents.
Improvement of cardiac output and maintenance of systemic blood pressure with vasopressors:
Dobutamine is preferred inotrope for management of RV failure but should be avoided
in hypotension. Limitation of catecholamine vasopressors (eg: noradrenaline) is that
they tend to increase pulmonary vascular resistance at higher doses. Other vasopressors
like Milrinone, vasopressin and Phenylephrine can be used.
Mechanical RV support: Mechanical support can be utilized as a bridge to recovery
or bridge to transplant. Centrifugal pumps can be surgically implanted (CentriMag,
Thoratec Corporation, Pleasanton, CA) or percutaneously inserted (TandemHeart, Cardiac
Assist, Pittsburg, PA) in selected patients with pH and RV failure. The Impella RP
(Abiomed Inc, Danvers, MA) is another novel percutaneous, axial flow pump offering
support with a single vascular access. Veno-arterial extracorporeal membrane oxygenation
(ECMO) is preferred approach because of additional benefit of unloading the RV.
Ventilatory Support and Tissue Oxygenation: Supplemental oxygen should be given to
maintain near-normal systemic oxygen saturations and adequate hemoglobin level should
be maintained to prevent tissue hypoxia. Endotracheal intubation can cause systemic
hypoperfusion and hemodynamic collapse secondary to the sedatives administered during
intubation. Induction agents that maintain vascular tone and contractility such as
etomidate are often preferred.
Balloon atrial septostomy (BAS): It is currently reserved for patients who are in
WHO-FC IV with right heart failure refractory to medical therapy or with severe syncopal
symptoms and in patients awaiting lung transplantation.
Transplantation: Both heart–lung and double-lung transplantation have been performed
for PAH, although the threshold for unrecoverable RV systolic dysfunction and/or LV
diastolic dysfunction is unknown.
3.16
HF in GUCH (Grown up congenital heart disease )
3.16.1
Introduction
Prior to the advent of specialized cardiac surgery and interventional catheterization
techniques, less than one fifth of children born with congenital heart disease (CHD)
reached adulthood.
541
Most patients who did survive were those who had mild lesions and only a minority
of those with complex lesions survived to adulthood. With earlier diagnosis and better
management facilities being available (especially in the West), the adult survival
rates have increased from ∼10-15% in the 1960s to >85–90% in the current era.542,
543 The term “
grownups with congenital heart disease
” (GUCH) is now often used as a standard terminology for these patients as it best
describes the transition of the pediatric patient through adolescence to adulthood.
Unlike Western countries, unoperated surviving patients still form a significant proportion
of patients with GUCH in India.
With more and more patients with CHD now reaching adulthood, most deaths from CHD
now occur in adults.
544
Frequent reasons for hospital admissions in operated patients with GUCH include management
of atrial and ventricular arrhythmias, infective endocarditis, diagnostic or interventional
cardiac catheterization procedures and HF (HF), with the latter accounting for ∼20%
of hospital admissions in these patients.
545
Presently advanced HF, is the leading cause of death in patients with GUCH.
India specific GUCH data: Of all neonates born with CHD in India, 30–50% have critical
disease that requiring early interventions.
Since only a minority of these receive requisite therapy, the number GUCH patients
in India is also steadily increasing
. Prevalence estimates of GUCH in India are reported to be 2.4/1000, which compares
with 2.2/1000 in the UK, 3.2/1000 in the Netherlands and 4.09/1000 in Canada.546,
547, 548
Composition of patients presenting to GUCH clinics: The type of underlying CHD in
patients with GUCH is significantly different from that presenting to a specialist
pediatric cardiology unit.
The GUCH clinic is likely to include the following three kinds of patients
:
•
Those with complex CHD which was either not diagnosed or not treated, representing
the more severe end of the CHD spectrum.
•
Some patients may have had a palliative surgery in childhood (a situation especially
likely in developing countries like India) or may be survivors of “definitive surgery”
for complex defects.
•
Some patients on the other hand are
“natural survivors”
who often reach adulthood without having had or needed surgery. These include
○
Those with minor abnormalities (small ASD, VSD or PDA)
○
Those with complex CHD with a balanced physiology (eg. univentricular heart without
PS)
○
Those with established pulmonary vascular disease.
Recent studies have reported that although patients with simple defects still predominate
in GUCH clinics, there has been an appx. 6–7 fold increase in the number of patients
with moderate or complex CHD highlighting the fact that more number of these patients
are surviving to adulthood.
549
3.16.2
Pathophysiology of HF in the GUCH population
Causes of HF failure in GUCH patients can be divided into the following groups:
•
Systolic dysfunction of either ventricle (systemic or sub-pulmonary)
○
Systolic dysfunction of the morphological systemic left or sub-pulmonary right ventricle
or morphological systemic right ventricle or systemic single ventricle
•
Acquired heart disease due to
coronary artery disease,hypertension, dyslipidaemia, diabetes mellitus, smoking),
Congenital coronary artery abnormalities (anomalous origin and/or course, extrinsic
compression by a dilated pulmonary artery, coronary kinking after re-implantation
of coronary arteries), include the following mechanisms
•
Altered genetic mechanism
s
3.16.3
Principles of management of GUCH-HF
As the pathophysiology of cardiorespiratory function in GUCH with HF is different
from that of non-GUCH patients, extrapolation of published data to GUCH patients may
be difficult. The current guidelines for HF suggest that diuretics, renin–angiotensin–aldosterone
system (RAAS) blockers, b-blockers, and mineralocorticoid receptor antagonists can
be safely used in the CHD/GUCH population. Hence, clinicians taking care of GUCH patients
in general, should follow current treatment recommendations for HF.
Cardiac resynchronization therapy (CRT) in GUCH-HF: Unlike data for CRT in standard
HF population which is based on multiple randomized clinical trials, evidence for
CRT in GUCH-HF is limited to small studies or anecdotal reports. In general, patients
with NYHA class II–IV symptoms, impaired
systemic
ventricular EF and prolonged QRS duration are candidates for CRT.
Studies have shown that presence of a systemic LV predicted a better CRT response
than a systemic RV and those with single ventricle morphology can achieve further
benefit from optimized pacing sites.550, 551
Implantable cardioverter defibrillator (ICD) in GUCH-HF: Although the overall incidence
of sudden cardiac death (SCD) in patients with CHD is low (<0.1% per year), SCD accounts
for nearly 20–25% of late deaths in GUCH patients. An ICD is recommended for
secondary prevention of SCD
in survivors of SCD due to ventricular fibrillation (VF) or hemodynamically unstable
ventricular tachycardia (VT) without any apparent reversible cause, patients with
spontaneous sustained VT not amenable to ablation or surgery, syncope with inducible
sustained VT/VF at EP study electrophysiology.
•
Ventricular assist devices (VADs) and Cardiac Transplantation: In acute decompensated
HF patients, if despite maximal medical treatment haemodynamics remain unstable, consideration
should be given to extra-corporal membrane oxygenation (ECMO) and/or ventricular assist
device (VAD) or cardiac transplantation. Adult CHD accounts for only 5–10% of all
CT indications in patients aged 18–30 years, according to the 2014 International Society
for Heart Transplantation (ISHLT) Registry and the Scientific Registry of Transplant
Recipients.552, 553
4
Heart failure situations important in Indian settings – II, prevention and future
perspectives
4.1
Role of the heart failure programs
Management of heart failure is complex and evolving. It has been established that
a dedicated heart failure management programs can improve the delivery of care to
the patients and result in better outcomes. Running of a good heart failure program
depends upon the availability of resources in different centres in our country.
Over the last 2 decades many important drug and device clinical trials have been completed
in heart failure population. These have formed the basis of various guidelines that
have been published and regularly updated.26, 29 The appropriate application of these
guidelines however, continues to be inadequate in general practice, resulting in worse
outcomes than those reported in clinical trials.
554
This is where the role of specialised Heart Failure clinic comes. A recent review
of 29 randomised control trial of organised versus usual care showed that heart failure
hospitalization reduced by 26% and mortality reduced by 25% in organised care setting.555,
556, 557 Heart failure setup is an organized way to assess, educate, treat and monitor
patients with heart failure. The program can be developed in any clinical setting
however there are essential components, which have to be considered while planning
such a facility.
While conceptualizing a heart failure management program the following areas need
focus.
1.
Goals and Objectives
2.
Infrastructure required
3.
Personnel Needed
4.
Activities and processes
5.
Audits and feedbacks
Goal and Objective of a heart failure setup is primarily to provide state of the art
care to patients diagnosed to have heart failure in order to minimise the mortality
and morbidity. The program should be flexible and be able to accommodate increasing
number of patients. Infrastructure required to create a good heart failure setup depends
upon the availability of hospital resources. Provision of adequate manpower to conduct
the heart failure service is of paramount importance for the success of the setup.
The heart failure program has to be tailor-made in our country keeping in mind the
paucity of resources. A hub and spoke model appears to be suitable for country, where
the peripheral centres should be able to provide at least a guideline mandated pharmacological
treatment and suggestions for lifestyle modification to the patients. The medium level
centres, where at least echocardiography is available, can function in further refinement
of the diagnosis. Several hubs can be established at district level hospitals, which
would further establish the etiology and long term management strategies for these
patients with heart failure. The higher centres could also take the responsibility
of training the peripheral centres through workshops and symposia regarding the latest
guidelines and the “Do’s and Don’ts in a patient with heart failure.
Such centres would serve as centres for referral of patients from primary or secondary
care physicians. These centres should have availability of biomarker estimation, detailed
echocardiography, cardiac catheterization, electrophysiology service and cardiac surgery.
The role of cardiac MRI in diagnosis and management of heart failure is being increasingly
realised, thus the availability of cardiac MRI along with a trained radiologist in
such centres is the need of the hour.
Personnel for heart failure setup include medical and paramedical staff trained in
the nuances of heart failure along with technical staff required to provide audits
and generate periodic reports.
Medical staff: Studies have demonstrated better outcomes for heart failure patients
once they are admitted under Heart failure cardiologists.557, 558, 559 During this
crucial period the diagnosis must be clarified or revisited, reversible factors looked
for and therapies reviewed. Co-morbidities should be treated appropriately and post
discharged management should be planned. Especially important is up-titration of therapies
or initiation of therapies which could not be started earlier for some reasons even
if a patient was asymptomatic. The cardiologist needs to be aware of newer drugs and
devices which can further improve outcomes and use them judiciously keeping the cost
issues in mind.
Nursing Staff: The value of a heart failure specialist nurse in reducing subsequent
hospitalisation and improving outcomes has been shown in a number of studies.560,
561, 562 The calibre and training of these nurses determines the impact on outcomes.
The role of a heart failure nurse is primarily to spend time in educating the patient,
answer their queries in detail, act as a bridge between the patient and the cardiologist
and follow up with the patient after their discharge from the hospital via a telephone
call or an email. A regular enquiry about pulse rate, blood pressure and weight change,
presence of swelling over legs, breathlessness and unusual weakness can help the nurse
to ascertain if the patient is doing well or otherwise. The training to carry out
these activities can easily be conducted even in a primary care facility.
Multi-disciplinary team: Heart failure management is essentially a multidisciplinary
management and its appropriate application has been slow. This is so because heart
failure in itself is a syndrome, which besides impacting various system organs due
to altered circulatory dynamics, has a significant bearing on social and physical
being of the patient. Inclusion of a nutritionist and physiotherapist in the heart
failure management team is important as many of the patients are malnourished and
do not have adequate counselling regarding DO’s and Don’ts in their diet. Both these
strategies have been shown to be beneficial for the wellbeing of the patients. As
the knowledge of guarded prognosis seeps in depression is a common result in heart
failure patients. Appropriate psychological assessment and counselling is needed for
these patients. Psychologist’s role is even more important in centres where there
is a program for LVAD or heart transplant, where assessment has to be made for capability
of a patient to accept these procedures and their capacity to deal with the problems
that may arise out of them.
Activities and Processes: There are various activities to be conducted in a heart
failure setup, which include running of a specialized outpatient clinic for heart
failure, diagnostic services, educating patients and monitoring of their progress,
conducting training and teaching sessions, establishing institutional guidelines of
heart failure management besides conducting and learning from periodic data audits.
Outpatient clinic: The primary physician should refer the patient to a heart failure
specialist early in the course of management. The responsibility of the specialist
is to confirm the diagnosis, establish the etiology, carry out appropriate investigations,
look of reversible causes and aggravating factors and ensure that appropriate pharmacologic
therapy has been instituted. The referral back to the GP should include instruction
regarding up titrating the drugs and particular precautions relevant to that patient.
A multidisciplinary approach to HF may reduce costs,
563
decrease length of stay564, 565 curtail readmissions,566, 567 improve compliance,
and reduce mortality. The facility should advise on appropriate use of advanced heart
failure therapies such as cardiac resynchronization therapy, ICD, heart transplant
or Ventricular assist devices and other newer medical and surgical therapies about
which the primary or secondary care physician may still be in the dark. Periodic small
group CME’s conducted by the heart failure specialists for primary and secondary care
physicians of their region are very useful for establishing a rapport between the
teams and updating knowledge. These clinics also provide an access to patients who
may have worsening of their clinical status, which may or may not require hospitalisation.
Who needs to attend heart failure Clinic: Since heart failure management programs
were aimed at reducing morbidity and mortality the focus generally has been on sicker
patients. An important set of patients are those who have recently been discharged
from the hospital following an episode of acute heart failure. They have a high incidence
of rehospitalisation in first 6–8 weeks and a high mortality in the first month and
one year. Telemonitoring in many of these patients is useful in identifying patients
at higher risk of sudden cardiac death.
Appropriate application of guidelines in heart failure clinics has been shown to reduce
rehospitalisation, mortality and improve the quality of life in patients with advanced
heart failure.
Formulate and adhere to guidelines: There are well established guidelines for heart
failure from various international societies. These include European society of cardiology,
American heart association and American college of cardiology etc. These guidelines
thus need to be modified and optimised for our country and region.
Diagnostic services: At various levels various diagnostic services may be required.
Primary centre level: Apart from a good history and clinical examination, ECG, Chest
X-Ray, routine haematology and biochemistry should be available.
Secondary Centre level: Apart from the above facilities these centres should have
Echocardiography, NT Pro BNP and CCU with basic hospitalisation facility.
Tertiary care centre level: If possible they should have state of art Echo, Cardiac
catheterization facilities, nuclear cardiology, facilities of Cardiac biopsy and Cardio-Pulmonary
excise testing. They should also have facility for cardiac surgery, Electrophysiology
lab for CRT/D implantation and advanced intensive care unit. A few selected centres
should have transplantation and LV Asset device available.
Periodic Audits: For improvement of services a periodic audit is necessary. This can
help identify gaps in care which may be missed knowingly or unknowingly. Evaluation
of the program should focus on the organisational as well as patient perspective.
4.1.1
Conclusion
Heart Failure clinics in our country are few. Keeping specific problems of resources
and personnel in India in mind it is suggested that a three layer program to be made
available. At a very basic level an MD Physician with interest in heart failure should
be identified and his knowledge upgraded to enable him/her to read ECG’s, Chest X-Ray
an institute guideline mandated, basic investigation and pharmacological treatment.
This should be supplemented by a nurse or a paramedic. The second level centres should
have facilities for good Echocardiography, biomarkers, cardiac catheterisation laboratories
and ICU facilities. They may have cardiac surgery backup. The tertiary care centre
should have in addition advanced therapies including device based therapy, heart transplant
cardiac biopsy and advanced surgical set up with state of the art ICU’s. This three
layered approach will ensure a good basic care for heart failure patients even at
the primary levels and incremental investigative and therapeutic facilities at central
level.
4.2
Stem cell and gene therapy for heart failure
Stem cell therapy and gene therapy has been studied in heart failure.
568
•
In the REPAIR-AMI trial, the combined end point of death, myocardial infarction, need
for revascularisation was reduced in the bone marrow stem cell group.
•
In the BALANCE study, at five years follow up, there was a reduction in mortality.
•
Studies from India have also found modest benefits in patients with chronic ischemic
heart disease, dilated cardiomyopathy, and myocardial infarction.
569
•
A Cochrane review included 38 randomised controlled trials involving almost
570
2000 patients. Stem Cell therapy reduced long-term mortality. It was also associated
with a long-term reduction in the incidence of non-fatal myocardial infarction. The
authors found no evidence of reduction in risk of rehospitalisation for heart failure
or composite incidence of mortality or left ventricular ejection fraction. The Cochrane
review concluded that treatment with bone marrow-derived stem/progenitor cells reduced
mortality and improved left ventricular ejection fraction and could reduce the incidence
of non-fatal myocardial infarction and improve New York Heart Association (NYHA) Functional
Classification in people with heart failure. The authors specified that event rates
were generally low, leading to a lack of precision.
•
Gene therapy using various virus vectors have been tried in clinical trials but as
yet have not been found to be useful.
Stem cell therapy guidelines for India are based on the ICMR guidelines and stem cell
therapy has been to be given under Research Protocols with ICMR approval and with
ethics approval. They cannot be used for commercial purposes. The following are the
current patient groups who are likely to benefit and where trials are going on worldwide:
1.
Cell therapy patients: Ischemic HF/dilated cardiomyopathy. Myocardial infarction may
not be an optimal target, as benefit has not been seen.
2.
Attempts to improve cell therapy results are ongoing with more specific cell types
(i.e., mesenchymal stem cells, cardiac progenitor cells) or ex vivo modified cells.
3.
No gene therapy trials are ongoing in India.
4.3
Prevention of heart failure
Preventing or delaying the onset of HF is a feasible task and a priority for our country
because of the cost effectiveness. HF prevention can be achieved either by targeting
those at high risk (Stage A & B) or by promoting healthy lifestyle for the entire
population.
4.3.1
Population strategy
The measures that need to be taken at population level, to prevent HF and heart diseases
as a whole include. Healthy eating and safe cooking: Calorie restriction, Eating in
time without skipping a meal, Choosing whole grains & legumes and variety of vegetable
oils but not exceeding 5 tsp/day, Consuming 4–6 cups of fruits & vegetables, Limiting
red meat, Avoiding processed meat and transfat and using low fat dairy and 1 tblp
of nuts. Avoiding tobacco, recreational drugs, sugary drinks and excessive salt. Limiting
alcohol (Not to exceed 1 drink for women & 2 drinks for men. Maintaining ideal BMI
(∼23 kg/m2). Exercising at least 150 m/week. Minimizing exposure to indoor and atmospheric
air pollution & Coping up with psychosocial stress.
4.3.2
Targeting stage a
(Above heading - Targeting Stage A) Stage A denotes high risk for HF but without structural
heart disease and it includes those with known risk factors for HF. Major Clinical
risk factors for HF include age, male gender, hypertension, left ventricular hypertrophy
(LVH), myocardial infarction, valvular heart diseases, obesity, increased heart rate,
arrhythmias (SVT, AF, VPDs) and toxic factors like alcohol, chemotherapeutic agents,
cocaine, glitazones and NSAIDs. Minor Clinical risk factors are sleep disordered breathing,
CKD including albuminuria, anemia, sedentary lifestyle and low socioeconomic status.
Morphological risk factors consist of LVH, asymptomatic LV dilatation/dysfunction
and LV diastolic dysfunction. Polymorphisms of alpha 2 adrenergic receptors, beta
1 adrenergic receptors, ACE and AT1 Receptors constitute Genetic risk factors.
Hypertension is widely prevalent affecting nearly 30% of adults and it increases the
risk of HF by 2–3 fold, either directly or by acting as a CAD risk factor. LVH or
albuminuria add to the risk requiring aggressive management. In a systematic review,
575
every 10 mm Hg reduction in systolic blood pressure yielded 28% risk reduction of
HF. Calcium blockers were inferior, diuretics were superior and ACEI/ARBs are neutral
for HF prevention. Intensive BP lowering resulted in 38% relative risk reduction (RRR)
in HF in SPRINT trial, but In a meta-analysis
571
only a modest effect was achieved (15% RRR). Early diagnosis, ensuring drug adherence
and achieving the goal value (<130/80) are more important than the choice of the drug.
Atherosclerotic Coronary Artery Disease is the commonest cause of heart failure. Nearly
60% of HFrEF is due to CAD, occurring mostly after MI and rarely due to hibernation
caused by chronic myocardial ischemia. STEMI increases the risk of HF by 2–3 fold
due to adverse LV remodeling. Reducing the time delay in achieving rapid, effective
and sustained reperfusion is important to salvage the ischemic myocardium. Adequate
post reperfusion pharmacotherapy that includes early administration of optimal doses
of beta blockers, ACEI, Mineralocorticoid receptor antagonists and statins are equally
important. In our country, where the resources are limited, the spoke and hub model
with the hub hospitals providing the 'round the clock' primary PCI and spoke hospitals
providing rapid thrombolysis followed by timely transfer to the nearest hub hospitals
for the timely angiography and PCI yield better outcomes.
576
Data from STEMI INDIA programme suggests non inferiority of pharmaco invasive approach
when compared to primary PCI. Actually heart failure (6.1 vs 7.6%) and cardiogenic
shock (4.4 vs 5.9%) occurred to a lesser extent in them. Similarly optimal usage of
Beta blockers, ACEIs, Statins and Antiplatelets could help in preventing HF in stable
IHD patients. Pooled data from HOPE, EUROPA and PEACE trials confirmed the benefit
of ACEI in reducing HF admissions by 23% even in those with normal LV function. Hence
ACEI should be given for all those atherosclerotic CVD. Aspirin or any other antiplatelet
drug has not been proved to decrease HF, though effective in reducing death and nonfatal
MI.
Dyslipidemia is associated with increased risk of HF but it is not known whether this
association is independent of its predisposition to atherosclerosis and MI. Among
the dyslipidemic drugs, statins remain the cornerstone of therapy because of robust
data. Statin use for more than 4 years offered a modest benefit (10% RRR) on HF hospitalizations
but without benefit on HF related mortality. Moreover, intensive statin therapy (atorvastatin
80 mg) significantly reduced the rate of HF hospitalization by 45% when compared to
moderate dose. However, in those with manifest HF, statins did not improve outcomes
as confirmed by trials like GISSI HF and CORONA. Moreover there is a theoretical risk
of adverse effect of statins in heart failure in the form of inhibition of CoQ synthesis
and interference with lipoprotein mediated inhibition of bacterial lipopolysaccharide
endotoxins. Thus, unless indicated for CAD protection (ischemic HF, those with multiple
CVD risk factors), routine use of statins in HF or asymptomatic LV dysfunction is
not justified.
Diabetes mellitus is associated with 2–5 fold increase in risk of HF. For every 1%
increase in HbA1C there is an 8–16% increase in the risk of hospitalization for HF
and for every 1 mmol increase in fasting blood glucose levels, there is a 5% increase
in the risk of HF admissions. Apart from being a major risk factor for CAD, diabetes
may cause cardiomyopathy as a result of micro vessel disease and metabolic insult
to myocardium. Diabetes is also risk factor for HFpEF, as LVH and diastolic dysfunction
are quite prevalent among them. In a meta-analysis
572
of Turnbull in which the data from ACCORD, UKPDS, ADVANCE and VADT trials have been
pooled, there was 15% RRR for MI with intensive glucose lowering but no protection
against death or HF hospitalization (HR 1.0). In the RENALL study, losartan reduced
the occurrence of HF in diabetics manifesting LVH. In HOPE study, Ramipril given for
diabetics with an additional risk factor, heart failure occurrence was reduced by
20% though hospitalization for heart failure did not reduce significantly. Both the
studies underscore the importance of administering ACEI or ARB in those with diabetes
and additional risk factor particularly those with hypertension, LVH or albuminuria,
to reduce incident HF.
With respect to the drugs used in managing diabetes, glitazones have been found to
increase the occurrence of HF and are contraindicated in class II & IV HF. In a meta-analysis
of 14 trials (95502 patients, median follow up for 4.3 years), the risk of incident
HF increased by 42% with glitazones, 25% with Gliptins and neutral with Insulin Glargine.
577
It looked as if the weight gain with therapies play a role − for every 1 kg weight
gain, there was a 7.1% relative increase in the risk of HF. In TECOS trial, Sitagliptin
was not found to increase heart failure (HR 1.00) while other Gliptin trials have
shown mixed results. SGL2 inhibitor, namely Empaglifozin was found to significantly
reduce HF (HR 0.65). Liraglutide, a GLP-1 analogue reduces HF by 13%. Early detection,
optimal control of dysglycemia, concomitant management of clustering risk factors
and appropriate choice of diabetic drugs are the measures found to be useful to prevent
HF in diabetics.
Chronic Kidney Disease (CKD) is a strong predictor of HF with Diabetes and Hypertension
being the commonest causes of CKD. Incidence of HF is 3 fold in those with eGFR of
< 60 ml/min/m2. 1/3 of dialyzed patients have HF. Though supportive data are not available,
optimal control of BP & DM, early use of beta blockers, ACEI/ARB, correction of Ca-P
metabolism and Vit D3 deficiency, optimization of diuretic/dialytic therapy and correction
of anemia could prevent or delay HF in CKD patients.
Obesity is an important risk factor for heart failure. For every 1 kg/m2 increment
in BMI, the HF risk increases by 5% in men and 7% in women. But prognosis appears
to be better in obese patients with HF and limited data suggest that weight loss predict
worse prognosis in heart failure. In spite of such contradictory findings, prevention
and treatment of obesity can reduce the HF burden and heart disease in general. Sleep
disordered breathing may be a risk factor for HF. An apnea-hypopnea index of > 11,
increases HF by 2.4 fold. Despite lack of data, promoting weight loss and nocturnal
CPAP therapy may prevent HF.
Valvular heart diseases (VHD) contribute to nearly 20% of heart failure in our country.
Effective primary and secondary prophylaxis for rheumatic fever is the most cost effective
method of reducing heart failure due to RHD. Among those with chronic VHD of various
causes, HF can be prevented by prompt surgical or transcatheter management, once the
symptoms manifest or when any of the following high risk features is encountered in
asymptomatic individuals – LV dysfunction in all VHD, rapid progression or dense calcification
in aortic stenosis; pulmonary hypertension, atrial fibrillation or LVESD >40 mm in
mitral regurgitation, LVEDD >65 mm or LVESD >50 mm in aortic regurgitation. It is
reasonable to offer surgery to asymptomatic VHD patients if biomarkers (BNP) are high
or when long axis function of LV declines. Prevention or aggressive treatment of infective
endocarditis could also reduce HF. Though optimal treatment of co-existing hypertension
is definitely indicated, routine vasodilator therapy in chronic regurgitant lesions
is not justified.
Alcohol consumption has a J or U shaped relationship to heart failure as it has with
hypertension, diabetes and MI.
578
Epidemiologic data suggest that consuming less than 14 drinks per week lowers the
risk of HF by 34 to 59% when compared to abstainers. In contrast, heavy drinking increases
the risk of HF by 1.7 fold. Among individuals with ischemic LV dysfunction, moderate
consumption was associated with 23% lower risk of mortality compared with abstainers.
However, because of lack of adequate data, it is prudent to advise abstinence for
those with LV dysfunction. Obviously abstinence is strongly indicated in alcoholic
cardiomyopathy and clinically manifest HF.
Apart from being a major risk factor for CAD including MI and death related to it,
Cigarette smoking is also a strong predictor for the development of HF, sudden death
in patients with HF and of mortality in idiopathic dilated cardiomyopathy. Nonsmokers
have 30% lower mortality, which underscores the importance of achieving abstinence
in smokers.
Physical inactivity is risk factor for HF and there is an inverse dose response relationship
between physical activity and the HF risk. In a pooled analysis of 12 prospective
cohort studies with a median follow up of 13 years,
574
guideline recommended minimum activity (500 MET-min/week) was found to have a modest
reduction of HF risk (10%). Higher levels of activity resulted in much better outcomes
– hazard ratio for 1000 MET-min/week was 0.81 and 0.65 for 2000 MET-min/week. Apart
from favorably modifying the conventional risk factors, exercise may have direct beneficial
action on LV compliance, skeletal muscle performance, peripheral vasculature, heart
rate and lung function all of which could be responsible for reduction of HF risk.
Drugs like NSAIDs, anti-arrhythmic drugs and tricyclic antidepressants may cause or
exacerbate HF. Appetite suppressants, ergot alkaloids and dopaminergic agonists used
for Parkinsonism (cabergoline, pergolide) may cause valve diseases which are preventable
by surveillance. Cancer chemotherapeutic agents, particularly anthracyclines (doxorubicin,
daunorubicin, epirubicin, idarubicin) and Transtuzumab may cause cardiomyopathy and
heart failure.
579
Anthracycline mediated LV dysfunction is either irreversible or partially reversible
and dose related (Type I) while transtuzumab causes reversible LV dysfunction and
not cumulative dose related (Type II). Prevention of heart failure may be achieved
by avoiding their use and choosing an alternative agent in those with baseline LVEF
<50%, Limiting the cumulative dose of doxorubicin to <450 mg/m2, administration by
infusion rather than bolus, by using liposomal formulation, reducing or stopping the
drug if EF falls by >10% or decrease in global longitudinal strain by >15% or if troponin
gets elevated. Baseline echo should be done for all those who receive potentially
cardiotoxic drugs and it should be repeated after completion and 3–6 months later.
For type I agents, echo should be repeated when the dose exceeds 240 mg/m2 and before
each subsequent dose of 50 mg/m2. Limited data suggest that beta blockers particularly
Carvedilol, ACEI/ARB and statins when given prophylactically, could minimize the decline
in LVEF and occurrence of HF. Dexrazoxane, a cytoprotective agent has also been approved
for this purpose.
Incessant tachycardias particularly ectopic atrial tachycardia, permanent form of
junctional reciprocating tachycardia, atrial flutter/fibrillation, ventricular tachycardia
etc. may lead to a reversible form of cardiomyopathy and HF. Prompt restoration of
sinus rhythm or control of ventricular rate either by drugs or catheter ablation is
an effective method of preventing HF in such individuals. Emerging data indicate that
frequent ventricular premature beats (>10% of overall beats) could also lead to LV
dysfunction and HF.
580
Apart from frequency, broader QRS and epicardial origin may imply an increased risk
of LV dysfunction. Despite lack of randomized studies, it is worthwhile to consider
catheter ablation in such patients to prevent HF.
Since as many as 20–50% of dilated cardiomyopathies are familial, first degree relatives
should be screened to identify those with asymptomatic LV dysfunction, who will benefit
from early therapy with neurohormonal agents. Moreover the inheritance pattern and
genetic testing may help the clinician to provide genetic counseling. By avoiding
late pregnancy and multiple pregnancies and prompt treatment of hypertension/pre-eclampsia,
incidence of peripartum cardiomyopathy can be reduced. Prevention of recurrence is
possible by appropriate advice on subsequent pregnancies based on recovery of LV function
after the index pregnancy.
4.3.3
Targeting stage B
Stage B includes those who have structural heart disease but no current or prior symptoms
of HF. The patients with asymptomatic LV dysfunction (ALVD – systolic & diastolic,
ischemic or non-ischemic) form the majority of such patients and the other structural
changes that precede HF include LVH, Post MI remodeling and asymptomatic VHD. As much
as 3–6% of adults in the community have asymptomatic LVSD and outnumber symptomatic
HF by fourfold. 13–30% of such individuals develop HF sooner and 5–7% die suddenly.
In a meta-analysis of 11 studies of ALVD
581
(25369 patients followed up for 7.9 years), the absolute risk of progression to HF
was 8.4 per 100 person years in those with systolic dysfunction, 2.8 person years
in those with diastolic dysfunction and 1.04 person years in those without any dysfunction.
The relative risk of HF per 1 standard deviation of lower EF was 1.4. Multiple RCTs
including SOLVD, SAVE and TRACE have shown benefit of ACEIs and ARBs in these subset
of patient. Beta blockers provide additional benefit in lowering mortality, slowing
progression to Heart failure along with better reverse remodeling.
4.4
FUTURE DIRECTIONS IN HEART FAILURE – INDIAN PRESPECTIVE
Heart failure is reaching epidemic proportions and is a public health challenge in
India. Since it affects Indians a decade earlier, it Impacts on the productivity and
Disability adjusted life years lost (DALYs). The limited Indian data shows that we
have a higher mortality, which lead to huge social and economic costs.
We also know that the therapy of HF is resource intensive. Since 80–90% of Indians
spend out-of-pocket for their health, the available therapies are unaffordable to
the vast majority of the population. Considering the vastness of the country and the
concentration of healthcare facilities in the cities, there are issues of accessibility
and availability.
So there is an urgent need to intervene at every stage of the disease right from understanding
the disease burden to early identification to better management.
4.4.1
Need for generation of data
Country-wide data on HF is sparse and hence the difficulty to quantify the real burden
which might be much higher than the projections estimated currently in various studies,
mostly based on western figures. This data is critical for planning strategies focused
on relevant parameters, which enable managing this burden more effectively with proper
allocation of funds and resources. Hence, the need of the hour is a national HF registry
which is a mammoth task considering the population and the clinical burden on doctors.
With the Indian governments’ decision to introduce a standard based system for creation
and maintenance of electronic health records (EHRs) by healthcare providers, data
collection may become easier.
582
4.4.2
Primary prevention of HF
We know that the therapy to manage HF, once the disease has already set in, is unaffordable
to the vast majority of Indian. Governments cannot prioritize treatment of such end
stage diseases over strategies like immunization in children and maternal health.
So primary and primordial prevention assumes prime importance. This is of paramount
importance as damage to the heart can only be controlled and not reversed. Identifying
risk factors early enough and appropriate modification strategies to reduce the same
can go a long way in reducing the HF burden. Various stakeholders (government, health
care professionals, patients, general public) will need to be involved, educated and
supported to implement preventive strategies.
Salt restriction and tobacco control are cost effective strategies to initiate. Increasing
taxation on tobacco (cigarettes and bidis) has been used to help reduce consumption.
Increasing education of the optimum salt intake and highlighting the salt content
in various foods, especially processed foods is important. Packaged foods should have
labels indicating the salt and trans-fat content to help people make the right choices.
The importance of regular physical activity and the benefits of vegetable and fruit
intake should be emphasised.
Implementing regular screening program scan identify important HF risk factors like
hypertension, diabetes, coronary artery disease and rheumatic heart disease. These
programs can be implemented in high-risk individuals which can be a more effective
targeted approach to identify patients likely to develop HF and thereby intervene
at an early stage. We have data from the west which emphasizes that HF can be prevented
and that the progression of HF can be interrupted.
The Western guidelines recommend focusing on stage A patients, those without symptoms
or detectable LV dysfunction. Hypertension was considered as the most powerful risk
factor, and their recommendation was to think of hypertension as pre-heart failure
situation. Increasing education and awareness regarding the importance of regular
screening tests and regular follow-up to ensure control of risk factors can improve
detection and control. Enforcing a mandatory annual HF risk factor screening program
in the corporate sector, Industrial workers and government employees could be a strategy
to increase detection and improve awareness of this condition.
Increasing awareness amongst the entire community is also an important lever. Media
campaigns can help increase disease awareness about HF amongst the general population.
Social media is also an important tool. Technology can be an effective way to reach
our youth and to access remote areas.
Healthcare professionals (HCP) across all clinical disciplines should be educated
to identify patients with risk factors for HF and intervene appropriately to screen,
refer or treat as needed. Often the general practitioner is the first point of contact
followed by general physicians. Patients present earlier in the course of disease
to these physicians providing an opportunity to prevent disease progression. So increasing
the awareness about HF among primary care physicians is very important.
4.4.3
Impacting HF diagnosis
Clinical approach is the mainstay of heart failure diagnosis and a detailed clinical
examination should be a priority over laboratory and imaging modalities of diagnosis.
The primary care physicians and the general medical specialists should be given adequate
training to detect cases of HF.
ECHO is an extremely important tool to diagnose heart failure and should be ideally
done in all patients. In India, it is an easily available tool and not too expensive.
Biomarkers like NT-proBNP help differentiate HF from chronic obstructive pulmonary
disease (COPD) and should be done wherever feasible. With the availability of point-of-care
devices, which are cost-effective, authorities can make this equipment available in
all PHCs. The Awareness regarding the usefulness of biomarkers needs to be increased
to help improve to diagnosis when somebody is in doubt after clinical examination.
4.4.4
Encouraging guidelines recommended therapy
However, the challenge is that despite clear recommendations and proven mortality
benefits, evidence based guideline recommended therapies are not implemented in majority
of the patients as seen in the Trivandrum registry. The lack of GDMT increases mortality.
Various factors impact this ranging from lack of education to an incorrect prescription
to poor compliance due to various factors, an important one being cost of therapy.
Training programs (planned and conducted by national societies) focusing on clinical
quality for general physicians/consulting physicians is a clear mandate to make them
understand the need for guideline directed therapy and its impact in mortality reduction.
They also should understand the need for appropriate and timely referrals to cardiologists
or heart failure clinics when the need arises for more specialized interventions.
Timely referral is critical in ensuring best treatment for the patients’ condition.
Quality improvement programs are very important in Indian settings. The ACS = QUIK
initiative in Kerala which improved the compliance to therapy is such an initiative.
It should be mandatory for physicians managing HF patients to participate in quality
improvement programs like PIQIP.
154
The cost of various devices and therapies is a limiting factor in implementation of
guideline-based therapy in the Indian healthcare system as these therapies are beyond
the reach of many patients. To overcome this barrier there is a need for the government,
insurance sector and industry to develop programs to address this affordability challenge
and help more patients to get guideline-based therapies. Government mandated price
controls as done for coronary stents recently, may allow a greater application of
device use in HF in India.
Affordability to drugs is a very important problem in management of HF as these patients
require lifelong therapy. Generic drugs can solve the issue to some extent. Authorities
should ensure quality of generics and should ensure availability in PHCs.
4.4.5
Role of physician associations
The role physician associations in increasing the awareness and decimation of HF problems
and good practice management in the care of these patients is very important. Now
we have CME programs dedicated to heart failure which is attracting a large number
of delegates thereby increasing the quality of HF management in our country. These
associations should get affiliated with various world HF bodies allowing our physicians
to interact with world authorities on HF. It is likely that in the near future, HF
will emerge as a separate sub specialty in cardiology in India and this will further
enhance the management this growing problem.
4.4.6
Heart failure clinics
The role of dedicated HF clinics is very important in the specialized management of
HF. WE have already described this in a previous section (Vide Supra)
Vision for reducing HF mortality.
1.
Treatment of HF once the disease has set in, is non-affordable to the patients and
the already constrained Indian health system. So primary prevention is the key, which
is focussing on the control of risk factors. – Concentrating on stage A of HF will
prevent progression and probably lead to far greater reductions in mortality than
more sophisticated and expensive therapies applied at a much later stage.
2.
To emphasize that heart failure can be prevented – To focus on risk factors that lead
to HF and concentrate on aggressive management of these factors even when the patient
feels and looks good.
3.
To get the most out of known effective interventions within the limitations of available
resources – Within the constraints of limited health care budgets and infrastructure,
we need to focus on proven effective interventions suited to our population rather
than all the recommended interventions by global societies.
4.
To ensure HF healthcare access for all patients – Overcoming the challenge of affordability
with better insurance programs can help patients access guideline based therapy thereby
improving their quality of life and reducing mortality.
List of contributors
A K Pancholia, Aditya Kapoor, Ajay Sinha, Ajay U Mahajan, Akshaya Pradhan, R Alagesan,
Amal K Banerjee, Ambuj Roy, Amit Vora, Anita Saxena, Arup Dasbiswas , B C Srinivas,
B P Chattopadhyay, B P Singh, Balachandar J, Balakrishnan K R, Brian Pinto, C N Manjunath,
C Narasimhan, Charan P Lanjewar, Dharmendra Jain , Dipak Sarma, G Justin Paul, Geevar
A Zachariah, H K Chopra, Harikrishnan S, I B Vijayalakshmi, J A Tharakan, J J Dalal,
J P S Sawhney, Jayanta Saha, Johann Christopher, K C Goswami, K K Talwar, K Sarat
Chandra, K Venugopal, Kajal Ganguly, M S Hiremath, Milind Hote, Mrinal Kanti Das,
Neil Bardoloi , Niteen V Deshpande, O P Yadava, P G Kerkar, P K Deb, P P Mohanan,
Prashant Bhardwaj, Pravesh Vishwakarma, Rajeeve Kumar Rajput, Rakesh Gupta, Rakesh
Yadav, Ramakrishnan S, Rishi Sethi, S Shanmugasundaram, S Somasundaram, S N Routray,
S S Iyengar, Sandeep Seth, Sanjay G, Santanu Guha, Satyendra Tewari, Saumitra Ray,
Sengottuvelu G, Soumitra Kumar, Soura Mookerjee, Sundeep Mishra, Suvro Banerjee, Tiny
Nair, Trinath Mishra, U C Samal, U Kaul, V K Bahl, V K Chopra, V S Narain, Vimal Raj,
Yash Lokhandwala.