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.

November 2018 at a glance: from prediction of heart failure in asymptomatic subjects to advanced chronic heart failure

“…Partial adenosine A1‐receptor agonists can improve left ventricular function and remodelling. These effects have been shown in experimental models and small patient groups . Further data are expected from the two phase 2b clinical trials PANTHEON and PANACHE .…”

Dynamic Loading of Human Engineered Heart Tissue Enhances Contractile Function and Drives Desmosome-linked Disease Phenotype

“…The dyn-EHT platform builds off of previous work from our laboratory and other investigators that have used primary, hESC and hiPSC derived cardiomyocytes to engineer functional cardiac tissues in vitro. Indeed, it is critical to acknowledge the important contributions to the field made by researchers using EHTs to model development and disease, and implementing more physiologic-like electromechanical conditioning to drive maturation (14,(16)(17)20,23,(25)(26)28,40,(61)(62)(63)(64). However, these 2D and 3D EHTs are generally isometrically constrained, which means they are unable to undergo significant fractional shortening or be stretched by preload.…”

“…The dyn-EHT model can also be used to investigate temporal changes in contractility, which is important in order to understand the rate of disease progression. For example, studies have reported an increase in heart muscle contractility when initially exposed to pathological wall stresses (63)(64)(65), which is likely due to an overcompensation by remaining heart muscle cells responding to an increase in stretch. Interestingly, we observed a similar finding with DSPmut 8x constrained EHT showing an increase in tissue twitch stress immediately after being removed from the PDMS well ( Fig.…”

Mildly symptomatic heart failure with reduced ejection fraction: diagnostic and therapeutic considerations

“…3 Therefore, the progressive nature of HFrEF, silent at times, renders clinical stability elusive, especially if disease progression is unrecognized. 4 In this review, we (i) highlight the challenges in the definition of clinical stability and the notion of mild symptomatic status of patients with HFrEF; (ii) outline the clinical characteristics of the mildly symptomatic patient with HFrEF; (iii) summarize the available diagnostic tools (and the associated caveats) for early symptom detection and clinical worsening assessment; and (iv) discuss evidence (and gaps thereof) in the current guidelines for the management of these patients. Finally, we summarize the challenges and directions for future research in this group of patients.…”