Pathophysiology of cardiac hypertrophy and heart failure: signaling pathways and novel therapeutic targets

Abstract

The onset of heart failure is typically preceded by cardiac hypertrophy, a response of the heart to increased workload, a cardiac insult such as a heart attack or genetic mutation. Cardiac hypertrophy is usually characterized by an increase in cardiomyocyte size and thickening of ventricular walls. Initially, such growth is an adaptive response to maintain cardiac function; however, in settings of sustained stress and as time progresses, these changes become maladaptive and the heart ultimately fails. In this review, we discuss the key features of pathological cardiac hypertrophy and the numerous mediators that have been found to be involved in the pathogenesis of cardiac hypertrophy affecting gene transcription, calcium handling, protein synthesis, metabolism, autophagy, oxidative stress and inflammation. We also discuss new mediators including signaling proteins, microRNAs, long noncoding RNAs and new findings related to the role of calcineurin and calcium-/calmodulin-dependent protein kinases. We also highlight mediators and processes which contribute to the transition from adaptive cardiac remodeling to maladaptive remodeling and heart failure. Treatment strategies for heart failure commonly include diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers and β-blockers; however, mortality rates remain high. Here, we discuss new therapeutic approaches (e.g., RNA-based therapies, dietary supplementation, small molecules) either entering clinical trials or in preclinical development. Finally, we address the challenges that remain in translating these discoveries to new and approved therapies for heart failure.

Baicalin Attenuates Cardiac Dysfunction and Myocardial Remodeling in a Chronic Pressure-Overload Mice Model

“…Pressure overload is associated with numerous cardiac changes and responses including cardiac myocyte hypertrophy, fibrosis, apoptosis and metabolic abnormality [3, 32]. These features lead to cardiac dysfunction and pathological heart dilatation which progresses to heart failure.…”

Stachydrine Protects Against Pressure Overload-Induced Cardiac Hypertrophy by Suppressing Autophagy

“…However, sustained or excessive hypertrophic responses may lead to a transition from compensated hypertrophy to heart failure [1]. Cardiac remodeling involves alterations in the balance between protein synthesis and protein degradation.…”

Carboxyl‐Terminal Modulator Protein Ameliorates Pathological Cardiac Hypertrophy by Suppressing the Protein Kinase B Signaling Pathway

“…Thus, pathological cardiac hypertrophy is a crucial predisposing factor for cardiovascular events and is the leading cause of cardiac morbidity and mortality globally 3, 4. Multiple signaling pathways, including the mitogen‐activated protein kinase (MAPK) pathway, the phosphatidylinositol 3‐kinase/protein kinase B (AKT) pathway, and the protein kinase C pathway, have been identified in the initiation and development of pathological cardiac hypertrophy 5, 6, 7. Nevertheless, the molecular mechanisms that mediate these pathways remain incompletely understood.…”