Heart failure: when form fails to follow function

Abstract

Cardiac performance is normally determined by architectural, cellular, and molecular structures that determine the heart's form, and by physiological and biochemical mechanisms that regulate the function of these structures. Impaired adaptation of form to function in failing hearts contributes to two syndromes initially called systolic heart failure (SHF) and diastolic heart failure (DHF). In SHF, characterized by high end-diastolic volume (EDV), the left ventricle (LV) cannot eject a normal stroke volume (SV); in DHF, with normal or low EDV, the LV cannot accept a normal venous return. These syndromes are now generally defined in terms of ejection fraction (EF): SHF became 'heart failure with reduced ejection fraction' (HFrEF) while DHF became 'heart failure with normal or preserved ejection fraction' (HFnEF or HFpEF). However, EF is a chimeric index because it is the ratio between SV--which measures function, and EDV--which measures form. In SHF the LV dilates when sarcomere addition in series increases cardiac myocyte length, whereas sarcomere addition in parallel can cause concentric hypertrophy in DHF by increasing myocyte thickness. Although dilatation in SHF allows the LV to accept a greater venous return, it increases the energy cost of ejection and initiates a vicious cycle that contributes to progressive dilatation. In contrast, concentric hypertrophy in DHF facilitates ejection but impairs filling and can cause heart muscle to deteriorate. Differences in the molecular signals that initiate dilatation and concentric hypertrophy can explain why many drugs that improve prognosis in SHF have little if any benefit in DHF.

Biodegradable Polymeric Nanocapsules Prevent Cardiotoxicity of Anti-Trypanosomal Lychnopholide

“…The heart was able to eject a normal stroke volume but unable to accept a normal venous return, consistent with early concentric LV hypertrophy commonly seen in HF with preserved ejection fraction. This hypertrophic adaptation helps to maintain or enhance blood ejection but, at the same time, compromises chamber filling due to LV stiffness and, thereby, leads to a progressive deterioration of myocardial function until end-stage failure262728. The ballooned apex of the heart was reminiscent of broken heart syndrome or drug-induced Tako-tsubo cardiomyopathy1314.…”

Cardiac aging and heart disease in humans

“…This hypertrophy affects the LV in an asymmetrical way, mostly affecting the interventricular septum and leading to a redistribution of cardiac muscle, explaining the lack of effect on total cardiac mass. As reviewed by Katz and Rolett (2016), concentric hypertrophy and a decreased LV cavity volume are hallmarks of HFpEF. In this disease, further evolution of concentric hypertrophy may eventually contribute to the development of fibrosis, arrhythmias, progressive myocardial deterioration, and end-stage heart failure (Rockey et al 2015).…”

Myocardial reverse remodeling: how far can we rewind?

“…Experimental studies have suggested a potential role for cMyBP-C in diastolic function. For instance, the cMyBP-C null mouse model (116) and cMyBP-C homozygous and heterozygous knockin mouse exhibited diastolic dysfunction with elevated E/E' (120). Moreover, mutations in this protein were observed in patients with hypertrophic cardiomyopathy, among whom a significant percentage presented diastolic dysfunction, demonstrated by slowed cardiac relaxation (225).…”