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      Untangling the pathophysiologic link between coronary microvascular dysfunction and heart failure with preserved ejection fraction

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          Abstract

          Coronary microvascular disease (CMD), characterized by impaired coronary flow reserve (CFR), is a common finding in patients with stable angina. Impaired CFR, in the absence of obstructive coronary artery disease, is also present in up to 75% of patients with heart failure with preserved ejection fraction (HFpEF). Heart failure with preserved ejection fraction is a heterogeneous syndrome comprising distinct endotypes and it has been hypothesized that CMD lies at the centre of the pathogenesis of one such entity: the CMD–HFpEF endotype. This article provides a contemporary review of the pathophysiology underlying CMD, with a focus on the mechanistic link between CMD and HFpEF. We discuss the central role played by subendocardial ischaemia and impaired lusitropy in the development of CMD–HFpEF, as well as the clinical and research implications of the CMD–HFpEF mechanistic link. Future prospective follow-up studies detailing outcomes in patients with CMD and HFpEF are much needed to enhance our understanding of the pathological processes driving these conditions, which may lead to the development of physiology-stratified therapy to improve the quality of life and prognosis in these patients.

          Graphical Abstract

          The mechanistic link between coronary microvascular disease and heart failure with preserved ejection fraction.

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          Sex differences in immune responses

          Sabra L. Klein, Katie Flanagan (2016)
          Males and females differ in their immunological responses to foreign and self-antigens and show distinctions in innate and adaptive immune responses. Certain immunological sex differences are present throughout life, whereas others are only apparent after puberty and before reproductive senescence, suggesting that both genes and hormones are involved. Furthermore, early environmental exposures influence the microbiome and have sex-dependent effects on immune function. Importantly, these sex-based immunological differences contribute to variations in the incidence of autoimmune diseases and malignancies, susceptibility to infectious diseases and responses to vaccines in males and females. Here, we discuss these differences and emphasize that sex is a biological variable that should be considered in immunological studies.
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            A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation.

            Walter Paulus, Carsten Tschöpe (2013)
            Over the past decade, myocardial structure, cardiomyocyte function, and intramyocardial signaling were shown to be specifically altered in heart failure with preserved ejection fraction (HFPEF). A new paradigm for HFPEF development is therefore proposed, which identifies a systemic proinflammatory state induced by comorbidities as the cause of myocardial structural and functional alterations. The new paradigm presumes the following sequence of events in HFPEF: 1) a high prevalence of comorbidities such as overweight/obesity, diabetes mellitus, chronic obstructive pulmonary disease, and salt-sensitive hypertension induce a systemic proinflammatory state; 2) a systemic proinflammatory state causes coronary microvascular endothelial inflammation; 3) coronary microvascular endothelial inflammation reduces nitric oxide bioavailability, cyclic guanosine monophosphate content, and protein kinase G (PKG) activity in adjacent cardiomyocytes; 4) low PKG activity favors hypertrophy development and increases resting tension because of hypophosphorylation of titin; and 5) both stiff cardiomyocytes and interstitial fibrosis contribute to high diastolic left ventricular (LV) stiffness and heart failure development. The new HFPEF paradigm shifts emphasis from LV afterload excess to coronary microvascular inflammation. This shift is supported by a favorable Laplace relationship in concentric LV hypertrophy and by all cardiac chambers showing similar remodeling and dysfunction. Myocardial remodeling in HFPEF differs from heart failure with reduced ejection fraction, in which remodeling is driven by loss of cardiomyocytes. The new HFPEF paradigm proposes comorbidities, plasma markers of inflammation, or vascular hyperemic responses to be included in diagnostic algorithms and aims at restoring myocardial PKG activity. Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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              Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial.

              Margaret M. Redfield, Horng Chen, Barry Borlaug … (2013)
              Studies in experimental and human heart failure suggest that phosphodiesterase-5 inhibitors may enhance cardiovascular function and thus exercise capacity in heart failure with preserved ejection fraction (HFPEF). To determine the effect of the phosphodiesterase-5 inhibitor sildenafil compared with placebo on exercise capacity and clinical status in HFPEF. Multicenter, double-blind, placebo-controlled, parallel-group, randomized clinical trial of 216 stable outpatients with HF, ejection fraction ≥50%, elevated N-terminal brain-type natriuretic peptide or elevated invasively measured filling pressures, and reduced exercise capacity. Participants were randomized from October 2008 through February 2012 at 26 centers in North America. Follow-up was through August 30, 2012. Sildenafil (n = 113) or placebo (n = 103) administered orally at 20 mg, 3 times daily for 12 weeks, followed by 60 mg, 3 times daily for 12 weeks. Primary end point was change in peak oxygen consumption after 24 weeks of therapy. Secondary end points included change in 6-minute walk distance and a hierarchical composite clinical status score (range, 1-n, a higher value indicates better status; expected value with no treatment effect, 95) based on time to death, time to cardiovascular or cardiorenal hospitalization, and change in quality of life for participants without cardiovascular or cardiorenal hospitalization at 24 weeks. Median age was 69 years, and 48% of patients were women. At baseline, median peak oxygen consumption (11.7 mL/kg/min) and 6-minute walk distance (308 m) were reduced. The median E/e' (16), left atrial volume index (44 mL/m2), and pulmonary artery systolic pressure (41 mm Hg) were consistent with chronically elevated left ventricular filling pressures. At 24 weeks, median (IQR) changes in peak oxygen consumption (mL/kg/min) in patients who received placebo (-0.20 [IQR, -0.70 to 1.00]) or sildenafil (-0.20 [IQR, -1.70 to 1.11]) were not significantly different (P = .90) in analyses in which patients with missing week-24 data were excluded, and in sensitivity analysis based on intention to treat with multiple imputation for missing values (mean between-group difference, 0.01 mL/kg/min, [95% CI, -0.60 to 0.61]). The mean clinical status rank score was not significantly different at 24 weeks between placebo (95.8) and sildenafil (94.2) (P = .85). Changes in 6-minute walk distance at 24 weeks in patients who received placebo (15.0 m [IQR, -26.0 to 45.0]) or sildenafil (5.0 m [IQR, -37.0 to 55.0]; P = .92) were also not significantly different. Adverse events occurred in 78 placebo patients (76%) and 90 sildenafil patients (80%). Serious adverse events occurred in 16 placebo patients (16%) and 25 sildenafil patients (22%). Among patients with HFPEF, phosphodiesterase-5 inhibition with administration of sildenafil for 24 weeks, compared with placebo, did not result in significant improvement in exercise capacity or clinical status. clinicaltrials.gov Identifier: NCT00763867.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Eur Heart J
                Journal ID (iso-abbrev): Eur Heart J
                Journal ID (publisher-id): eurheartj
                Title: European Heart Journal
                Publisher: Oxford University Press
                ISSN (Print): 0195-668X
                ISSN (Electronic): 1522-9645
                Publication date Collection: 14 November 2021
                Publication date (Electronic): 16 September 2021
                Publication date PMC-release: 16 September 2021
                Volume: 42
                Issue: 43 , Focus Issue on Heart Failure and Cardiomyopathies
                Pages: 4431-4441
                Affiliations
                British Heart Foundation Centre of Excellence and National Institute for Health Research Biomedical Research Centre at the School of Cardiovascular Medicine and Sciences, King’s College London , St. Thomas' Hospital, Westminster bridge road, London SE1 7EH, UK
                Author notes
                Corresponding author. Tel: +44 20 71881048, Fax: +44 20 71880970, Email: divaka.perera@ 123456kcl.ac.uk
                Author information
                https://orcid.org/0000-0001-5407-4943
                https://orcid.org/0000-0003-1369-5553
                https://orcid.org/0000-0002-8109-1877
                https://orcid.org/0000-0002-6547-0631
                https://orcid.org/0000-0001-6362-1291
                Article
                Publisher ID: ehab653
                DOI: 10.1093/eurheartj/ehab653
                PMC ID: 8599060
                PubMed ID: 34529791
                SO-VID: 51cd4540-626e-4adf-b028-717a38aee2c8
                Copyright © © The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License ( https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                Date received : 09 April 2021
                Date revision received : 10 June 2021
                Date accepted : 03 September 2021
                Date: 19 August 2021
                Date: 12 November 2021
                Page count
                Pages: 11
                Funding
                Funded by: Medical Research Council, DOI 10.13039/501100000265;
                Award ID: MR/T029390/1
                Funded by: British Heart Foundation, DOI 10.13039/501100000274;
                Award ID: FS/16/49/32320
                Award ID: CH/1999001/11735
                Award ID: RE/18/2/34213
                Funded by: UK National Institute for Health Research;
                Funded by: Fondation Leducq, DOI 10.13039/501100001674;
                Categories
                Subject: State of the Art Review
                Subject: Heart Failure and Cardiomyopathies
                Subject: AcademicSubjects/MED00200

                ScienceOpen disciplines: Cardiovascular Medicine
                Keywords: coronary microvascular disease,coronary flow reserve,subendocardial ischaemia,lusitropy,heart failure with preserved ejection fraction
                Data availability:
                ScienceOpen disciplines: Cardiovascular Medicine
                Keywords: coronary microvascular disease, coronary flow reserve, subendocardial ischaemia, lusitropy, heart failure with preserved ejection fraction

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