Silent disease progression in clinically stable heart failure

Abstract

Heart failure with reduced ejection fraction (HFrEF) is a progressive disorder whereby cardiac structure and function continue to deteriorate, often despite the absence of clinically apparent signs and symptoms of a worsening disease state. This silent yet progressive nature of HFrEF can contribute to the increased risk of death-even in patients who are 'clinically stable', or who are asymptomatic or only mildly symptomatic-because it often goes undetected and/or undertreated. Current therapies are aimed at improving clinical symptoms, and several agents more directly target the underlying causes of disease; however, new therapies are needed that can more fully address factors responsible for underlying progressive cardiac dysfunction. In this review, mechanisms that drive HFrEF, including ongoing cardiomyocyte loss, mitochondrial abnormalities, impaired calcium cycling, elevated LV wall stress, reactive interstitial fibrosis, and cardiomyocyte hypertrophy, are discussed. Additionally, limitations of current HF therapies are reviewed, with a focus on how these therapies are designed to counteract the deleterious effects of compensatory neurohumoral activation but do not fully prevent disease progression. Finally, new investigational therapies that may improve the underlying molecular, cellular, and structural abnormalities associated with HF progression are reviewed.

Keywords: Heart failure; Mechanism; Progressive deterioration; Stable heart failure; Treatment.

Figure 1

Mechanism of action for sacubitril/valsartan.93 Reprinted from Langenickel TH, Dole WP. Angiotensin receptor–neprilysin inhibition with LCZ696: a novel approach for the treatment of heart failure. Drug Discov Today Ther Strateg 2013; 9:e131–e139. ANG, angiotensin; AT₁, angiotensin‐II type 1; cGMP, cyclic guanosine monophosphate; GTP, guanosine‐5'‐triphosphate; NP, natriuretic peptide (e.g. atrial natriuretic peptide, BNP); NPR‐A, NP receptor‐A; RAAS, renin–angiotensin–aldosterone system. *In vitro evidence.

Figure 2

Treatment effect of a partial adenosine A1‐receptor agonist on LV function.90 Left: change Δ (treatment effect) between pre‐treatment and 12 weeks post‐treatment of LV end‐diastolic volume (EDV), end‐systolic volume (ESV), EF, and stroke volume (SV) in untreated control dogs and dogs treated for 3 months with capadenoson. Right: change Δ (treatment effect) between pre‐treatment and 12 weeks post‐treatment in plasma levels of NT‐proBNP. Data are shown as mean ± SEM. Probability values are comparisons between untreated control and capadenoson. Reprinted from Sabbah HN et al. Chronic therapy with a partial adenosine A1‐receptor agonist improves left ventricular function and remodelling in dogs with advanced heart failure. Circ Heart Fail 2013;6:563–571.

Figure 3

Mitochondrial function in cardiomyocytes of LV myocardium of normal dogs, untreated heart failure control dogs (HF‐CON), and dogs with heart failure treated with elamipretide (HF + ELA).92 Top left: mitochondrial state 3 and 4 respiration. Top right: mitochondrial membrane potential. Bottom left: mitochondrial permeability transition pore (mPTP). Bottom right: maximum rate of adenosine triphosphate (ATP) synthesis and ratio of ATP to adenosine diphosphate (ADP). Probability values are comparisons between normal dogs, HF‐CON, and HF + ELA dogs. Statistical significance based on one‐way analysis of variance (ANOVA) followed by the Student–Newman–Keuls test. All bar graphs are depicted as the mean ± SEM. Reprinted from Sabbah HN et al. Chronic therapy with elamipretide (MTP‐131), a novel mitochondria‐targeting peptide, improves left ventricular and mitochondrial function in dogs with advanced heart failure. Circ Heart Fail 2016;9:e002206.