Microvascular endothelial dysfunction in heart failure with preserved ejection fraction
Abstract
A new paradigm has emerged in our understanding of the pathophysiology of heart failure (HF) with preserved ejection fraction (HFpEF) versus HF with reduced ejection fraction (HFrEF). Comorbidity-driven cardiac endothelial dysfunction plays a primary role in HFpEF, leading to cardiomyocyte dysfunction, left ventricular (LV) concentric remodelling and predominantly diastolic dysfunction1 (figure 1). Conversely in HFrEF, direct cardiomyocyte injury is the key trigger for systemic neuroendocrine activation, LV eccentric remodelling and predominantly systolic dysfunction.1 Whereas neuroendocrine activation exists as a common defining domain of the HF syndrome in both HFrEF and HFpEF, in HFrEF it plays a dominant role in adverse remodelling and outcomes; thus antagonists of the renin-angiotensin-aldosterone and adrenergic systems have been effective in improving survival in HFrEF. Similarly, whereas cardiovascular endothelial dysfunction exists in both HFpEF and HFrEF, by the new paradigm, it is postulated to play a dominant role in the pathophysiology and outcomes of HFpEF. This distinction is critical since targeting endothelial dysfunction may be a winning strategy in HFpEF—a condition now recognised as one of the largest unmet needs in cardiovascular medicine, responsible for half the HF epidemic and without proven therapies to improve survival.2 Figure 1 Heart failure with preserved ejection fraction (HFpEF) paradigm. In HFpEF, comorbidities (such as hypertension, overweight, diabetes, chronic kidney disease, chronic obstructive pulmonary disease, anaemia and iron deficiency) lead to microvascular inflammation and endothelial activation. This adversely affects the adjacent cardiomyocyte through decreased nitric oxide (NO) bioavailability, reduced cyclic guanosine monophosphate (cGMP) availability, and altered phosphorylation of titin; microvascular ischaemia, concentric left ventricular (LV) remodelling and fibrosis from endothelial-mesenchymal transition (EndMT) contributes further to LV diastolic dysfunction. In contrast, in …
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Inhibition of systemic metabolic inflammation with glucose-lowering drugs is thought to enhance endothelial and cardiomyocyte function.
“Inhibition of systemic metabolic inflammation with glucose-lowering drugs is thought to enhance endothelial and cardiomyocyte function”
From The cardioprotective effects of semaglutide exceed those of dietary weight loss in mice with HFpEF (2023) · cites this paper as [71]
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The cardioprotective effects of semaglutide exceed those of dietary weight loss in mice with HFpEF
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Self-citation
- Authors
- Lam, C. S. P., & Lund, L. H.
- Affiliations
- National University of Singapore (SG)
- Karolinska University Hospital (SE)
- Corresponding author
- Lam, Carolyn S P
- Venue
- Heart
- Publisher
- BMJ
- Published
- 2016-01-27
- Volume
- 102
- Issue
- 4
- Pages
- 257-259
- ISSN
- 1355-6037 (ISSN-L)
- 1468-201X
- OpenAlex
- W2292856586
- Cited by
- 81
- References
- 20
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 10 · 2023: 6 · 2022: 7 · 2021: 5 · 2020: 14 · 2019: 10 · 2018: 13 · 2017: 6 · 2016: 3
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Heart (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Keywords
- heart failure with preserved ejection fraction, endothelial dysfunction, microvascular dysfunction, diastolic dysfunction, left ventricular remodeling, endothelial-to-mesenchymal transition, nitric oxide bioavailability, microvascular inflammation, comorbidities, cardiomyocyte dysfunction, neuroendocrine activation, heart failure with reduced ejection fraction
- MeSH terms
- Heart Failure, Humans, Stroke Volume, Vascular Diseases, Ventricular Dysfunction, Left
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