1
Introduction
In an aging society with persistent high prevalence of cardiovascular disease (CVD)
in the elderly population, the health care system is facing an increasing challenge
to effectively care for these patients. However, due to the under-representation of
CVD patients over 75 years of age in clinical trials, assessing safety and efficacy
of diagnostic and therapeutic approaches, the evidence for managing elderly CVD patients
is especially limited. Physiological changes of aging intertwined with pathophysiology
of CVD, and comorbid conditions often complicate clinical management. With the rapid
adoption in older patients of invasive cardiovascular procedures, such as percutaneous
coronary intervention and trans-catheter aortic valve replacement, the magnitude of
this challenge is increasing. Understanding key aspects of cardiovascular physiology
in older adults can serve as a foundation to guide interpretations of clinical presentation,
diagnostic responses, formulating therapeutic strategies, and monitoring clinical
efficacy in elderly patients with CVD.
Advanced age is an important risk factor for cardiovascular disease, and a powerful
independent predictor of cardiovascular morbidity, mortality and disability. As a
result of decades of complex molecular and cellular aging processes, cardiovascular
physiology in the older adult is characterized by: (1) endothelial dysfunction, (2)
increased arterial stiffness, (3) increased left ventricular (LV) stiffness, (4) altered
coupling of LV and arterial stiffness and function, (5) attenuated baroreflex and
autonomic reflexes, and (6) degenerative changes of the conduction system. These changes
produce a cardiovascular system that has reduced maximal function compared to younger
people and less reserve capacity, and can fail to meet needs when stressed. The purpose
of this paper is to highlight the changes in the vasculature and heart that impact
on the basal and stressed physiology of the older patient with cardiovascular disease.
2
Endothelial dysfunction
2.1
Physiology and age-related changes
The endothelium plays an active role in maintaining vascular homeostasis by balancing
vasodilation and vasoconstriction, growth inhibition and promotion, anti- and pro-thrombosis,
anti- and pro-inflammation, and anti- and pro-oxidation. Endothelial cells secrete
various vasoactive molecules such as the vasodilators, nitric oxide (NO), prostacyclin,
and endothelium-derived hyperpolarizing factor, and vasoconstrictors, such as endothelin-1,
angiotensin II and thromboxane A2. The most frequently used tool to investigate age-related
changes in endothelial function is NO mediated vasodilatation. Age-related decreases
in NO-mediated vasodilatory responses are well documented at every level of the vasculature
from the coronary micro-circulation to larger epicardial coronary arteries and the
peripheral circulation.[1] Endothelial-dependent forearm vasodilation decreases progressively
with advancing age in men, and notably occurs about ten years later in women.[2] The
underlying mechanisms include: (1) increased oxidative stress with increased production
of reactive oxygen species (ROS), which directly reduce NO production by inhibiting
eNOS expression and inducing eNOS uncoupling; (2) increased level and activity of
arginase, which directly limits the availability of eNOS substrate availability and
decreases NO production; (3) increased production of vasoconstrictors, such as thromboxane,
endoperoxide and endothelin-1; and also (4) reduced capacity of endothelial regeneration
due to endothelial cell senescence and decreased availability of endothelial progenitor
cells.
2.2
Clinical implications
The clinical impact of age-related endothelial dysfunction is to reduce the regulatory
capacity of blood flow and promote atherosclerosis and thrombosis. Testing of endothelial
function in the elderly is not usually performed clinically but is a useful clinical
research tool. Importantly, age-related endothelial dysfunction is at least partially
reversible by dynamic physical activity.[3] The older artery remains responsive to
the effects of NO; direct NO donors, such as nitrates, do not rely on endothelial-mediated
activity to stimulate NO and can ameliorate the impact of age-related changes in endothelial
function. These and other vasodilatory agents, such as alpha-blockers, must be used
with care in the elderly due to the potential for excessive vasodilatation and orthostatic
hypotension. Statins, selective beta blockers, angiotensin converting enzyme inhibitors,
and angiotensin receptor blockers also can improve endothelial dysfunction associated
with systemic conditions such as hypertension, diabetes mellitus, inflammatory diseases
etc, but efficacy on age-related changes has not been tested.
3
Increased arterial stiffness
3.1
Physiology and age related changes
Age-related changes occur throughout the arterial wall. The arterial tree is a visco-elastic
tube. In younger individuals, the central arteries are more elastic and less stiff
than the peripheral arteries. Compared to vessels from healthy younger individuals,
arteries from older individuals are characterized by increased reactive oxygen species
(ROS) content, inflammatory changes, decreased NO availability, and endothelial dysfunction.
These changes produce a stiffness gradient along the arterial tree that is reversed,
i.e., greater central artery stiffness than peripheral arteries. In general, arteries
in older adults become longer, wider, thicker and stiffer. Decreased distensibility
or increased stiffness of the large central arteries is a hallmark of vascular aging.[4],[5]
The processes involve complex molecular and cellular mechanisms as summarized in Figure
1, which include (1) migration and proliferation of vascular smooth muscle cells in
the sub-endothelial space; (2) accumulation of collagen and proteoglycan in the intima,
and decrease of hydrolytic turnover and elasticity of collagen due to increased cross-linking;
(3) decreased production and accelerated degradation of elastin, and (4) increased
calcification. Various pathways including inflammatory cytokines and cells, adhesion
molecules, matrix metalloproteinases (MMPs) and transforming growth factor-β are also
affected. These changes coupled with the endothelial changes, result in large artery
stiffening, decreased compliance and recoil, and a diminished capacity to absorb the
pulsatile wavefront produced by the ejecting heart.[6]
As a result of increased arterial stiffness, there is increased LV afterload, contraction
and oxygen requirement. In older adults, LV afterload is increased due to (1) an enlarged
aortic diameter creating more inertance (the pressure gradient in a fluid required
to cause a change in flow-rate with time); (2) decreased aortic compliance requiring
increased LV pressure to maintain cardiac output; (3) the premature reflection of
the arterial pulse wave from the periphery; and (4) an increased in systemic vascular
resistance. Decreased coronary blood flow results from both decreased aortic diastolic
blood pressure and increased LV end diastolic pressure from ventricular stiffness,
left ventricular hypertrophy and increased LV afterload.
Figure 1.
Summary of molecular mechanisms leading to increased arterial stiffness in the older
adult and its' hemodynamic consequences.
AGEs: advanced glycation end products; LV: left ventricular; MMPs: matrix metalloproteases.
3.2
Clinical implications
Regional and local arterial stiffness can be quantified invasively or by non-invasive
measurement. The measurement of pulse wave velocity (PWV) is generally accepted as
the most simple, non-invasive, robust and reproducible method to determine arterial
stiffness. However, because PWV is conventionally measured when the artery is distended
at diastolic pressure, it may underestimate the real stiffness increase with age.
Carotid-femoral PWV is a strong predictor of cardiovascular mortality and morbidity.[7]
In patients with hypertension, aortic stiffness measured by carotid-femoral PWV adds
independent predictive value in addition to other CVD risk factors, such as those
included in the Framingham risk score.[8] Longitudinal epidemiological studies have
demonstrated the independent predictive value of arterial stiffness for cardiovascular
events (all cause and cardiovascular mortalities, fatal and non-fatal coronary events,
and fatal strokes) in patients with uncomplicated essential hypertension, type 2 diabetes,
end stage renal disease, elderly subjects, and the general population.
The increased arterial stiffness and decreased distensibility in the elderly lead
to the age-associated increase in systolic blood pressure, decrease in diastolic blood
pressure (DBP) and widening of pulse pressure (PP). These changes can complicate the
treatment of systolic hypertension in the elderly due to excessive DBP lowering and/or
postural hypotension (in combination with reflex changes discussed below), and coronary
hypoperfusion. Decreased central arterial compliance (increased arterial stiffness)
also creates a system in which small shifts in intravascular volume create large changes
in blood pressure.[9],[10] Furthermore, an increased pulsatility (widened PP) is also
harmful to end organs and increases the risk for renal disease, dementia, myocardial
infarction, stroke, heart failure, arial fibrillation and mortality.
Antihypertensive medications (diuretics, angiotensin converting enzyme-inhibitors,
angiotensin receptor blockers, calcium-channel blockers, and certain beta-blockers)
have been shown to reduce arterial stiffness in investigational studies. Non-pharmacological
interventions, including weight loss, low-sodium diet, and moderate alcohol consumption
can reduce age-related arterial stiffness. Most importantly, regular moderate to vigorous
intensity physical activities (brisk walking, jogging, aerobics, and other sports)
attenuate arterial stiffening during aging. More recently, it has been demonstrated
that light physical activity for longer durations can also reduce arterial stiffening,
especially in older people who have not previously exercised regularly. Thus, all
levels of exercise should be encouraged in older patients, as more vigorous physical
activities are not feasible for some older individuals. Light physical activities
to replace sedentary behavior may be a more practical and achievable preventive strategy
for many elderly.[11]
4
Reduced LV compliance and cardiac reserve
4.1
Physiology and age-related changes
LV function is determined by myocardial contractility, preload, and afterload. It
is also dependent on the “functional” coupling of the LV with the arterial system
(ventricular-vascular coupling), represented by the ratio between arterial effective
elastance (EA) to end-systolic left ventricular elastance (ELV). Primary changes in
cardiomyocytes in older adults include an increase in size (progressive hypertrophy)
and a decrease in the number (progressive loss of myocytes) with an alteration of
myocyte to fibroblast ratio. While resting LV contractility is usually preserved in
the absence of disease, LV stiffness increases and LV volume decreases during aging
with the transition occurring between youth and middle-age, and becoming clinically
manifest between the ages of 50 years to 64 years. Several other factors also lead
to age-associated decreased LV compliance and alterations in contraction-relaxation,
such as increased collagen accumulation and advanced glycation end products -mediated
cross-links, fibrosis and infiltration of inflammatory cells and proteins. In addition,
alterations in calcium signaling in the sarcoplasmic reticulum (SR) of cardiomyocytes
also impair active LV relaxation. Hearts of healthy older adults have less cardiac
SR calcium ATPase (the calcium pump), have lower SR calcium content, and are more
dependent on trans-sarcolemmal calcium fluxes, including those through the L-type
calcium channels and the sodium-calcium exchanger. This increased dependency on calcium
entry through the L-type calcium channels may explain the increased sensitivity of
older people to drugs that block these channels.
With advanced age, there is prolongation of LV isovolumic relaxation time, reduction
in early diastolic filling, and augmentation of late diastolic filling. The percent
filling of the LV during the early phase of diastole can diminish from 70% to 30%,
and as the LV end diastolic volume (LVEDV) does not change with age, LA volumes increase.
Thus, the older heart is more dependent on active filling in late diastole from the
atrial contraction, can contribute up to 70% of the LVEDV.
4.2
Clinical implications
LV compliance (stiffness) can be determined by the slope of LV diastolic pressure-volume
curve derived from invasive left heart catheterization but is rarely done today, as
noninvasive echocardiographic assessment of LV diastolic function has become the gold
standard. Doppler measurement of mitral inflow velocity and tissue Doppler imaging
assessment of mitral annular velocity are routinely done during transthoracic echocardiography
to assess LV compliance and diastolic function.
Increased LV stiffness in the older adult contributes to the clinical presentations
of heart failure with preserved ejection fraction. It also contributes to the dependence
of LV filling from atrial systole, and explains the relative clinical intolerance
of atrial fibrillation in an older adult compared with a younger patient. The older
patient has a lower threshold for developing dyspnea and/or pulmonary edema, especially
with acute onset episodes of atrial fibrillation or flutter and rapid ventricular
responses. Early LV diastolic filling can also be compromised during any tachycardia.
However, load-dependent BP lability and augmented LV wall stress can occur in response
to relatively minor perturbations in heart rate, BP, intravascular volume, or cardiac
dysfunction. Multiple factors can impact the supply and demand aspects of CV performance
in older patients, tipping the balance to one dependent on cardiac reserve. In clinical
practice, identifying and rectifying the factors that might have altered this balance
can often stabilize an older patient and avoid a higher-risk intervention. Pharmacologic
agents, such as ACE inhibitors and ARB, are effective in dilating vasculature and
reducing after load, and potentially affecting myocardial relaxation and compliance
by reducing interstitial collagen deposition and fibrosis. Calcium channel blockers
improve LV compliance by decreasing cytoplasmic calcium concentration and increasing
myocardial relaxation. These agents often improve exercise capacity and quality of
life for the elderly, in particular, those who experience hypertensive response to
exercise.
5
Impaired beta-adrenergic and parasympathetic function
5.1
Physiology and age-related changes
Physiological responses to autonomic input are keys to maintaining blood pressure
when standing or during volume loss, and increasing cardiac output during exercise
or stress. Decreased responses to beta adrenergic and parasympathetic stimulation
and reflex responses are hallmarks of aging. Chronotropic, inotropic, and lusitropic
responsiveness to beta-adrenergic agonists are decreased with advancing age. During
aging, the heart rate response to atropine is decreased due to an elevated parasympathetic
vagal tone and a reduced sympathetic responsiveness. In response to the administration
of similar doses of isoproterenol, heart rate increased 25 beats/min in young healthy
males, but only 10 beats/min in older healthy males. These changes are the results
of suppressed cAMP generation, decreased beta-receptor numbers and function, and increased
inhibitory G protein activity in the elderly. In contrast, the production and release
of circulating catecholamine and exercise-stimulated levels of epinephrine and norepinephrine
are higher in older adults in comparison to younger healthy adults. These changes
in both limbs of the autonomic nervous system, contribute to the blunted reflex and
baroreflex responses in the elderly, which in turn, diminish the potential for the
body to respond to stressors.
5.2
Clinical implications
Normal responses to sudden lowering of pressure include increases in heart rate, peripheral
vasoconstriction and venous return. The age-related reduction of responsiveness and
blunted reflexes often diminish the normal response and can result in orthostatic
hypotension and syncope.[12] Age-related changes in autonomic responses also contribute
to the lack of CV reserve that can result in cardiac decompensation in older people
faced with sudden or marked increases in cardiac workload, hypovolemia, fever, infection,
or other stressors.
The age-related changes in heart rate are most evident for maximal and exercise-induced
heart rates with negligible changes in resting heart rate. While vagal withdrawal
may be responsible for increases in heart rate during the first minute of exercise
in younger people, the reductions in maximal heat rate and reduced maximal cardiac
output in the elderly are largely due to the blunted responsiveness to beta-adrenergic
stimulation. In the setting of chronotropic incompetence, exercise-induced increases
in cardiac output may depend substantially on augmented cardiac filling (preload).
In addition to heart rate changes, the maximal increase in LV ejection fraction during
exercise (i.e., EF reserve) is smaller in the older adult than in younger people.
In addition, for a given increase in cardiac output in response to exercise, the concomitant
rise in the systemic and pulmonary arterial pressures is also much greater. Many of
the age-related changes described above and some of the autonomic age-related changes
can be attenuated by exercise.
Table 1.
Physiological changes of other organ systems and potential impacts on caring for CVD
in the older adult.
Organ systems
Physiological changes in the older adult
Potential impact on caring for CVD in theolder adult
Kidney
↓ GFR
- Labile volume status in treating HTN and HF
↓ Numbers of glomeruli
- ↑ Assess risk of contrast-induced nephropathy
↑ Interstitial fibrosis
- Assess secondary cause of HTN and HF
↑ Glomerulosclerosis
Lung
↓ Alveoli
- Monitoring and treatment of hypoxia and hypercapneic respiratory distress
↓ Elastic recoil
- Oxygen therapy if indicated
↓ Gas exchange
↓ Maximal respiratory effort
↓ Tidal volume and minute ventilation
↑ V/Q mismatch
↓ Sensitivity of chemoreceptors to reduced O2 and increased CO2
Endocrine
↓Estrogen (female)
- Assess general wellness (nutrition, bone density, etc)
↓Testosterone (male)
- Risk stratification for CAD
↓Growth hormone
- Assess vascular related vs. endocrinology related erectile dysfunction of male
↓Insulin-like growth factor 1
- Assess secondary causes of CVDs
↓Thyroid hormone
↑Total daily cortisol with disruption of circardian rhythm of cortisol
Gastrointestinal
↑Large bowel transit time susceptible for constipation
- Assess medical absorption- Assess GI bleeding risk while giving antiplatelet or
anti-coagulation therapies
Neurological
↓ Brain size and weight
- Assess medication adherence
↓ Neuronal connectivity and size with unchanged numbers of neurons
- Address communication barriers
↓ Cognitive function
- Give instructions in direct and simple ways
↓ Memory
- Assess increased fall risk while giving anticoagulation or antiplatelet therapies
↓ Pyramidal tract function
- Anticipate atypical presentation of CVDs
↓ Postural sensation and control
- Assess exercise capacity and provide assistance
↓ Special senses (hearing, vision, etc)
↓ Pain sensation
↓ Temperature regulation
Musculoskeletal
↓ Bone density
- Assess fall risk while giving anticoagulation or anti-platelet therapies
↓ Muscle mass and strength
- Assess exercise capacity and provide assistance
↓ Ability to extract oxygen
CVD: cardiovascular disease; GFR: glomerular filtration rate; HF: heart failure; HTN:
Hypertension.
Aging is a systemic process involving all organ systems. Age-associated changes in
other organ systems also greatly impact CV performance, endurance, and response to
stress. Recognition of physiological changes of other organs associated with advanced
age is critical in caring for CVD of the older adult (see Table 1).
6
Opportunities for future research and clinical pearls
The future research needs are: (1) defining exercise prescription for older patients;
(2) establishing prediction schema based on data from older patients that incorporate
measures of age-related changes; (3) discovering treatments that can ameliorate, antagonize,
or prevent the cellular changes in cardiac myocytes with aging; (4) treatments that
can restore endothelial function; (5) treatments that can selectively and directly
reduce central arterial stiffening; and (6) physiological phenotyping and evidence-based
management strategies for heart failure with preserved ejection fraction.
The clinical pearls are: (1) the only tool we currently have to attenuate age-related
CV changes is exercise prescribe it! (2) direct vasodilators (nitrates and alpha-blockers),
may precipitate excessive vasodilatation leading to orthostatic hypotension; (3) widened
pulse pressure with significantly low diastolic pressure without the presence of aortic
regurgitation or heart failure in an elderly person, is suggestive of marked decrease
of vascular compliance, associated with worse cardiovascular outcome; (4) decreased
chronotropic, inotropic and lusitropic myocardial responses, as well as blunted baroreflexes
explain why neurally-mediated and orthostatic types of syncope are the most common
in older adults; and (5) heart rate control of atrial arrhythmias such as atrial fibrillation
are critically important in the elderly, as these can significantly impair effective
cardiac output and coronary perfusion.