Molecular Mechanisms and Therapeutic Implications of Endothelial Dysfunction in Patients with Heart Failure

Abstract

Heart failure is a complex medical syndrome that is attributed to a number of risk factors; nevertheless, its clinical presentation is quite similar among the different etiologies. Heart failure displays a rapidly increasing prevalence due to the aging of the population and the success of medical treatment and devices. The pathophysiology of heart failure comprises several mechanisms, such as activation of neurohormonal systems, oxidative stress, dysfunctional calcium handling, impaired energy utilization, mitochondrial dysfunction, and inflammation, which are also implicated in the development of endothelial dysfunction. Heart failure with reduced ejection fraction is usually the result of myocardial loss, which progressively ends in myocardial remodeling. On the other hand, heart failure with preserved ejection fraction is common in patients with comorbidities such as diabetes mellitus, obesity, and hypertension, which trigger the creation of a micro-environment of chronic, ongoing inflammation. Interestingly, endothelial dysfunction of both peripheral vessels and coronary epicardial vessels and microcirculation is a common characteristic of both categories of heart failure and has been associated with worse cardiovascular outcomes. Indeed, exercise training and several heart failure drug categories display favorable effects against endothelial dysfunction apart from their established direct myocardial benefit.

Endothelial dysfunction is associated with reduced myocardial mechano-energetic efficiency in drug-naïve hypertensive individuals with a broad spectrum of glucose tolerance

“…These data may help to shed light into the mechanism underlying the link between reduced myocardial mechano-energetic e ciency per unit of myocardial mass and incident heart failure (12,40). Prior studies have shown that endothelial dysfunction can exert an important role in the pathogenesis of heart failure (21)(22)(23)(24)(25) by reducing nitric oxide production, which ultimately results in vasoconstriction, pro-in ammatory and pro-oxidant state, LV systolic and diastolic dysfunction, myocardial brosis, and hypertrophy (41). The present ndings of an independent association between endothelium-mediated vasodilation and myocardial MEEi coupled with previous studies showing the pathogenic role of impaired myocardial energetics in the development of heart failure led us to hypothesize that endothelial dysfunction may precede and induce a reduction in myocardial MEE, which, in turn, contributes to the increased risk of heart failure (12).…”

“…Pathophysiological mechanisms that may contribute to both impaired endothelium-mediated vasodilation and decreased myocardial MEEi comprise, among the others, abnormalities in body weight, glucose homeostasis, in ammation, insulin resistance, and oxidative stress (41)(42)(43). Notably, our nding that endothelium-mediated vasodilation remained associated with myocardial MEEi even after adjustment for BMI, glucose tolerance status, hsCRP, and HOMA-IR index of insulin resistance argues against the possibility that these cardiovascular risk factors might have contributed to the observed association.…”

Endothelial cell dysfunction in cardiac disease: driver or consequence?

“…While the most prominent clinical approaches to amelioration of ECD in heart disease are discussed above, extensive discussion of small-cohort and currently ongoing clinical trials and their outcomes have been recently summarized elsewhere ( Tsigkou et al, 2023 ). The underwhelming results of most current therapeutic strategies directly targeting the endothelium for heart disease reflect the need for better preclinical models of ECD and CMD.…”

Non-Alcoholic Fatty Liver Disease and Echocardiographic Parameters of Left Ventricular Diastolic Function: A Systematic Review and Meta-Analysis

“…Moreover, both NAFLD and HFpEF may share a common pathophysiologic background. Endothelial dysfunction, systemic inflammation, and inflammatory cytokines are found elevated in both entities [ 10 , 11 , 12 , 13 ]. Moreover, alteration of glycose and fatty acid metabolism under NAFLD impairs glucose metabolism by the myocardium, leading to energy deficiency and the potentiation of HFpEF [ 14 , 15 ].…”