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