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Biology of myocardial recovery in advanced heart failure with long-term mechanical support

https://doi.org/10.1016/j.healun.2022.07.007Get rights and content

Cardiac remodeling is an adaptive, compensatory biological process following an initial insult to the myocardium that gradually becomes maladaptive and causes clinical deterioration and chronic heart failure (HF). This biological process involves several pathophysiological adaptations at the genetic, molecular, cellular, and tissue levels. A growing body of clinical and translational investigations demonstrated that cardiac remodeling and chronic HF does not invariably result in a static, end-stage phenotype but can be at least partially reversed. One of the paradigms which shed some additional light on the breadth and limits of myocardial elasticity and plasticity is long term mechanical circulatory support (MCS) in advanced HF pediatric and adult patients. MCS by providing (a) ventricular mechanical unloading and (b) effective hemodynamic support to the periphery results in functional, structural, cellular and molecular changes, known as cardiac reverse remodeling. Herein, we analyze and synthesize the advances in our understanding of the biology of MCS-mediated reverse remodeling and myocardial recovery. The MCS investigational setting offers access to human tissue, providing an unparalleled opportunity in cardiovascular medicine to perform in-depth characterizations of myocardial biology and the associated molecular, cellular, and structural recovery signatures. These human tissue findings have triggered and effectively fueled a “bedside to bench and back” approach through a variety of knockout, inhibition or overexpression mechanistic investigations in vitro and in vivo using small animal models. These follow-up translational and basic science studies leveraging human tissue findings have unveiled mechanistic myocardial recovery pathways which are currently undergoing further testing for potential therapeutic drug development. Essentially, the field is advancing by extending the lessons learned from the MCS cardiac recovery investigational setting to develop therapies applicable to the greater, not end-stage, HF population. This review article focuses on the biological aspects of the MCS-mediated myocardial recovery and together with its companion review article, focused on the clinical aspects, they aim to provide a useful framework for clinicians and investigators.

Section snippets

Adverse remodeling, reverse remodeling and myocardial recovery at the organ level

Heart failure with reduced ejection fraction (HFrEF) most commonly results from an initial insult that either decreases the number of active cardiomyocytes (e.g., myocardial infarction) or decreases the intrinsic strength of cardiomyocytes (e.g., inherited forms of cardiomyopathies, toxins, viral infections). In either case, changes in the volume and biology of the cardiac myocytes and of the surrounding extracellular matrix underlie remodeling of the ventricular chamber.1 Remodeling results in

Hypertrophy regression

Cardiomyocyte hypertrophy is an adaptive mechanism that the heart uses to reduce increasing wall stress in heart failure state.4 LVAD mediated unloading has been shown to induce regression of hypertrophy,5 (Table 1). On the other hand, mechanical unloading of nonfailing and nonhypertrophic myocardium by means of LVAD6,7 and heterotopic transplantation7 suggested that prolonged unloading may lead to disuse myocardial atrophy. This notion triggered clinical studies with the β2-adrenoceptor

Fibrosis and extracellular matrix

The role of the extracellular matrix (ECM) and myocardial fibrosis is of critical importance in HF in general and also in myocardial recovery/remission following LVAD support in particular. The ECM regulates signal transduction within and between myocytes and also provides mechanical support for transmitting force generation and preventing LV over-stretch at high filling pressures. Yet, excessive fibrosis may encase myocytes and inhibits force production. Features of the ECM differ in dilated

Endothelium and microvasculature: Coronary and peripheral

Both structure and function of coronary microcirculation are impaired in patients with end stage HF.119 Improvement in myocardial flow with impaired coronary flow reserve has been described post LVAD support.120 Using whole field, endocardium-to-epicardium digital microscopy, a study showed ultrastructural and immunohistochemical evidence of post-LVAD endothelial cell activation with decrease of the microvascular luminal area.10 The vascular changes were accompanied by increased fibrosis and

Current status of the field and future directions

Cardiovascular disease and in particular HF poses an enormous medical burden worldwide and is exponentially evolving over the last decade. The dogma that the failing human heart cannot recover after a significant injury has been repeatedly challenged by the current guideline-directed medical therapy. Furthermore, clinical experience in both adult and pediatric populations indicates that chronic ventricular mechanical unloading with LVADs can favorably influence the complex process of adverse

Acknowledgments and disclosures

Stavros Drakos has received consulting fee from Abbott and Arena Pharmaceuticals and grant support from Merck, Novartis and NIH (RO1HL135121, RO1HL156667, RO1HL151924-01, 1K23HL150322-01A1 and T32HL007576). The rest authors have no relevant disclosures.

Funding

None of the authors received any funding for this manuscript.

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