Reverse remodeling in heart failure—mechanisms and therapeutic opportunities

Abstract

Heart failure (HF) involves changes in cardiac structure, myocardial composition, myocyte deformation, and multiple biochemical and molecular alterations that impact heart function and reserve capacity. Collectively, these changes have been referred to as 'cardiac remodeling'. Understanding the components of this process with the goal of stopping or reversing its progression has become a major objective. This concept is often termed 'reverse remodeling', and is successfully achieved by inhibitors of the renin-angiotensin-aldosterone system, β-blockers, and device therapies such as cardiac resynchronization or ventricular assist devices. Not every method of reverse remodeling has long-lasting clinical efficacy. However, thus far, every successful clinical treatment with long-term benefits on the morbidity and mortality of patients with HF reverses remodeling. Reverse remodeling is defined by lower chamber volumes (particularly end-systolic volume) and is often accompanied by improved β-adrenergic and heart-rate responsiveness. At the cellular level, reverse remodeling impacts on myocyte size, function, excitation-contraction coupling, bioenergetics, and a host of molecular pathways that regulate contraction, cell survival, mitochondrial function, oxidative stress, and other features. Here, we review the current evidence for reverse remodeling by existing therapies, and discuss novel approaches that are rapidly moving from preclinical to clinical trials.

Insulin receptor substrate signaling controls cardiac energy metabolism and heart failure

“…Reprogramming of fetal gene expression was found in adverse cardiac remodeling and biomechanical stresses in failing or aging hearts (Marber et al 2010, Koitabashi & Kass 2012. The transcriptional reprogramming in the cardiac remodeling may relate to a diminished cardiac insulin action followed by Foxo1 activation, as insulin resistance develops upon aging processes.…”

“…Currently, the first line of clinical treatment for the patients with heart failure is the blocker for the renin-angiotensin system or the β-adrenergic receptors (Koitabashi & Kass 2012). Insulin protects the heart and reduces blood pressure (Anderson et al 1991).…”

Angiotensin‐Converting Enzyme 3 (ACE3) Protects Against Pressure Overload‐Induced Cardiac Hypertrophy

“…Cardiac hypertrophy is usually characterized by the enlargement of cardiomyocytes, an increase in protein synthesis, the reorganization of sarcomeres and the reactivation of the fetal gene program. Although the initial hypertrophic phase is indeed compensatory to maintain cardiac output, the beneficial effects are contravened by sustained pathological hypertrophy, which eventually results in malignant arrhythmia, heart failure, and sudden death 2, 3, 4. Numerous signal transduction pathways have been studied in the hypertrophic process, such as the PI3K/AKT/GSK3β pathway, the calcineurin/nuclear factor of activated T cells (NFAT) pathway, and the mitogen‐activated protein kinase (MAPK) pathway 5, 6, 7.…”

Why Cardiac Resynchronization Therapy (CRT) is Usually Prescribed along with Automatic Implantable Defibrillation (AID)? Is it a Sensible Decision? Historical Perspective

“…Reverse remodeling is defined by lower chamber volumes (particularly end-systolic volume) and is often accompanied by improved β-adrenergic and heart-rate responsiveness. At the cellular level, reverse remodeling impacts on myocyte size, function, excitation-contraction coupling, bioenergetics and a host of molecular pathways that regulate contraction, cell survival, mitochondrial function, oxidative stress and other features [34]. How much the remodeling or reversal remodeling processes influence the risk of tachyarrhythmias?…”