Endothelial Dysfunction in Heart Failure

Endothelial cells form a dynamic interface between the bloodstream and the vessel wall, regulating vascular tone, haemostasis, inflammation and permeability. In heart failure, whether with reduced or preserved ejection fraction, perturbations in endothelial function emerge as both contributors to disease progression and potential therapeutic targets. Reduced bioavailability of nitric oxide and increased production of reactive oxygen species foster a pro‐inflammatory, pro‐thrombotic milieu. In the coronary microcirculation, these alterations promote rarefaction, impaired vasodilatation and diminished coronary flow reserve, culminating in myocardial hypoxia, fibrosis and diastolic impairment. Systemic endothelial dysfunction further exacerbates peripheral vascular resistance, impairs skeletal muscle perfusion and drives neurohormonal activation. Recognition of endothelial dysfunction as a unifying mechanism has prompted exploration of novel interventions aimed at restoring endothelial homeostasis, including modulation of nitric oxide signalling, anti‐oxidative strategies and anti‐inflammatory approaches. The global burden of heart failure, its rising prevalence in ageing populations and the paucity of effective therapies for heart failure with preserved ejection fraction underscore the urgency of translating endothelial research into clinical practice.

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Research from all publishers

Recent clinical work has highlighted the predictive value of peripheral microvascular assessments. In a cohort of women with type 2 diabetes, impaired skin microvascular responses to insulin and acetylcholine correlated with markers of diastolic dysfunction and elevated risk scores for heart failure with preserved ejection fraction, suggesting that non‐invasive measures of systemic microvascular dysfunction may serve as early warning signals.

In experimental models, accelerated cardiac ageing in transgenic mice has been linked to pronounced perivascular fibrosis and coronary microvascular dysfunction. Transcriptomic analysis revealed persistent upregulation of ageing‐associated genes governing extracellular matrix remodelling, indicating that interventions targeting fibrotic pathways may preserve microvascular integrity and delay heart failure progression.

Molecular investigations have delineated overlapping mechanisms of endothelial impairment in both heart failure phenotypes. Chronic neurohormonal activation, oxidative stress and inflammatory cytokines converge to reduce nitric oxide bioavailability, disrupt calcium handling and impair mitochondrial function. Importantly, established heart failure therapies—including ACE inhibitors, β‐blockers and exercise training—exhibit ancillary benefits on endothelial function, bolstering the rationale for combined strategies that address both myocardial and vascular pathology.

Endothelial Dysfunction in Heart Failure publication trend

The graph below shows the total number of articles in endothelial dysfunction in heart failure across all publications each year (not limited to Nature Index journals).

Technical terms

Endothelium: The monolayer of cells lining blood vessels, responsible for vascular homeostasis.

Endothelial dysfunction: A state in which endothelial cells lose their regulatory capacity, leading to vasoconstriction, inflammation and thrombosis.

Nitric oxide (NO): A gaseous signalling molecule produced by endothelial cells that induces vasodilatation and inhibits platelet aggregation.

Reactive oxygen species (ROS): Chemically reactive molecules derived from oxygen that can damage cellular structures and reduce NO bioavailability.

Coronary microvascular dysfunction (CMD): Impaired regulation of blood flow in the small vessels of the heart, often manifesting as reduced coronary flow reserve.

Coronary flow reserve (CFR): The ratio of myocardial blood flow during stress to that at rest, reflecting the capacity of coronary circulation to meet increased demand.

Heart failure with preserved ejection fraction (HFpEF): A form of heart failure in which left ventricular ejection fraction is normal but diastolic filling is impaired.

Microvascular rarefaction: A reduction in capillary density, leading to impaired tissue perfusion and oxygen delivery.

References

1. Microvascular endothelial dysfunction in skin is associated with higher risk of heart failure with preserved ejection fraction in women with type 2 diabetes: the Hoorn Diabetes Care System Cohort. Cardiovascular Diabetology (2023).
2. Accelerated ageing and coronary microvascular dysfunction in chronic heart failure in Tgαq*44 mice. GeroScience (2023).
3. Molecular Mechanisms and Therapeutic Implications of Endothelial Dysfunction in Patients with Heart Failure. International Journal of Molecular Sciences (2023).