The future of pleiotropic therapy in heart failure. Lessons from the benefits of exercise training on endothelial function

Abstract

A novel generation of drugs is introduced in the treatment of heart failure (HF). These drugs, including phosphodiesterase-5 inhibitors, guanylate cyclase stimulators and activators, share the feature that their action is either endothelial-mediated or substitutes for endothelial pathways, in particular the nitric oxide-cyclic guanosine monophosphate pathway, thereby influencing homeostatic balances in virtually each organ system in a pleiotropic fashion. Unfortunately, recent clinical trials with some of these drugs have shown disappointing results, at least in the setting of HF with a preserved ejection fraction. This suggests that their clinical use may require approaches that diverge from traditional pharmacological approaches, the latter often titrated on the effects of drugs on haemodynamic parameters or single biomarkers. In this paper we preconize that HF drugs with an endothelial profile should be applied conform to principles of endothelial physiology and systems pharmacology. This type of drug therapy should be viewed as a systems physio-pharmacological intervention and its clinical use accustomed to systems pharmacological principles, comparable to the systemic endothelial-mediated benefits induced by exercise training in HF. We will review the actions of these drugs and define criteria to which trials with these drugs should comply in order to increase chances of success.

Targeting Endothelial Function to Treat Heart Failure with Preserved Ejection Fraction: The Promise of Exercise Training

“…Sadly, none of these approaches alone has thus far been successful in decreasing HFpEF-related morbidity or mortality. Exercise training integrates all three mechanisms, forming a promising systemically oriented therapy [7]. …”

“…Beta blockers and renin-angiotensin-aldosterone axis antagonists, drugs that mainly target the heart and have reduced mortality in HFrEF, had disappointing results in HFpEF trials [3–5]. As such, a “whole-systems” approach has been proposed, moving therapeutic focus in HFpEF away from the cardiomyocyte [6, 7]. …”

An integrative translational approach to study heart failure with preserved ejection fraction: a position paper from the Working Group on Myocardial Function of the European Society of Cardiology

“…A detailed overview of these RCTs is out of the scope of the current work and can be found elsewhere . Interestingly, changes in lifestyle such as exercise training and caloric restriction have shown the most promising results in short‐term trials, raising the possibility that pleiotropic effects will be needed to change the course of HFpEF . Lack of progress in pharmacological patient management warrants not only for better designed trials with well defined enrolment criteria and end‐points, but also for a clearer understanding of pathophysiology .…”

August 2019 at a glance: arrhythmogenic cardiomyopathy, biomarkers of inflammation, insulin treatment, initiation of sacubitril/valsartan, and pharmacy‐based intervention to increase medication adherence

“…Microvascular function is a major determinant of cardiac function and HF progression . Dynamic retinal vessel analysis is a novel, non‐invasive, method to assess microvascular function.…”

“…Microvascular function is a major determinant of cardiac function and HF progression. 11 Dynamic retinal vessel analysis is a novel, non-invasive, method to assess microvascular function. Barthelmes et al 12 compared retinal microcirculation, assessed as flicker-induced arterial dilatation (FIDa), in healthy controls and patients with coronary artery disease (CAD) without and with HF.…”