Treating heart failure with preserved ejection fraction: learning from pulmonary fibrosis

Abstract

Heart failure with preserved ejection fraction (HFpEF) has a poor prognosis, and an effective treatment is currently lacking. Increasing evidence suggests a prevailing pathogenic role of cardiac fibrosis in HFpEF, which generates the possibility of a mechanistic overlap with pulmonary fibrosis. Indeed, cardiac and pulmonary fibrosis share some characteristics and molecular pathways, such as that of transforming growth factor-β. If pulmonary and cardiac fibrosis share common pathways, we can hypothesize a beneficial effect of anti-fibrotic drugs used in idiopathic pulmonary fibrosis on cardiac outcomes. Of note, pirfenidone has been tested in animal models of cardiac fibrosis and was found to be effective in reducing ventricular remodelling. Yet, no results are hitherto available for humans. In this review article, we discuss the potential benefit of anti-fibrotic treatment in HFpEF. In particular, we propose to reappraise safety data collected in placebo-controlled trials of anti-fibrotic drugs in idiopathic pulmonary fibrosis, to explore the hypothesis that these might reduce cardiac fibrosis.

Therapeutic approaches in heart failure with preserved ejection fraction: past, present, and future

“…Pirfenidone represents an anti-fibrotic drug which targets the TGF-β signaling pathway and is mainly used in idiopathic pulmonary fibrosis [112]. By activation of myofibroblasts, TGF-β can promote the production of fibronectin, proteoglycans and type I-III collagen.…”

Sympathetic nervous system activation and heart failure: Current state of evidence and the pathophysiology in the light of novel biomarkers

“…Furthermore, hypophosphorylation of constitutive myofilament proteins and increased calcium sensitivity of sarcomeres causes increased LV stiffness and abnormal relaxation contributing to HFpEF onset while these derangements are not present in normal myocardium[ 48 ]. Graziani et al[ 49 ] also proposed that microvascular dysfunction is the common pathophysiological pathway contributing to both microvascular angina and HFpEF[ 49 ]. Of note, endothelial dysfunction represents a pathological vascular phenotype of all systemic arteries that encompasses damaging effects of vasoconstrictive, prothrombotic and proinflammatory substances and mediators on the endothelial vascular lining and diminished repairability of endothelium thus further acting as an independent pathobiological driver of atherosclerosis and overt cardiovascular disease[ 50 - 52 ].…”

Forensic interrogation of diabetic endothelitis in cardiovascular diseases and clinical translation in heart failure

“…There is an undeniable link between systemic inflammation and primary metabolic comorbidities including diabetes, obesity, obstructive sleep apnoea and secondary associations including aging, hypertension, lifestyle. These are all associated with endothelitis and the resulting vascular dysfunction is a “common soil” for atherogenesis and cardiac failure[ 39 , 40 ]. The cellular mechanism for inflammation in the subendothelial space that leads to atherogenesis and the inflammatory changes in the failing heart begins with (1) Dysfunctional endothelial changes that facilitate the recruitment of inflammatory cells; (2) Furthermore, increased barrier permeability, reduced thromboresistance, and altered paracrine signalling associated with endothelitis contributes to and compounds adverse vascular and cardiac remodelling in diabetes; and (3) In so far as, endothelitis is a driving force of progressive cardiac dysfunction in diabetes, then targeting microvascular dysfunction should provide benefits for patients with diabetes.…”