Advanced Evolution of Pathogenesis Concepts in Cardiomyopathies

Abstract

Cardiomyopathy is a group of heterogeneous cardiac diseases that impair systolic and diastolic function, and can induce chronic heart failure and sudden cardiac death. Cardiomyopathy is prevalent in the general population, with high morbidity and mortality rates, and contributes to nearly 20% of sudden cardiac deaths in younger individuals. Genetic mutations associated with cardiomyopathy play a key role in disease formation, especially the mutation of sarcomere encoding genes and ATP kinase genes, such as titin, lamin A/C, myosin heavy chain 7, and troponin T1. Pathogenesis of cardiomyopathy occurs by multiple complex steps involving several pathways, including the Ras-Raf-mitogen-activated protein kinase-extracellular signal-activated kinase pathway, G-protein signaling, mechanotransduction pathway, and protein kinase B/phosphoinositide 3-kinase signaling. Excess biomechanical stress induces apoptosis signaling in cardiomyocytes, leading to cell loss, which can induce myocardial fibrosis and remodeling. The clinical features and pathophysiology of cardiomyopathy are discussed. Although several basic and clinical studies have investigated the mechanism of cardiomyopathy, the detailed pathophysiology remains unclear. This review summarizes current concepts and focuses on the molecular mechanisms of cardiomyopathy, especially in the signaling from mutation to clinical phenotype, with the aim of informing the development of therapeutic interventions.

Keywords: apoptosis; cardiac remodeling; cardiomyopathy; fibrosis; genetic mutations.

Figure 1

Risk factors of the four major types of cardiomyopathy.

Figure 2

Schematic drawing of the details of the signaling pathways of five major cardiomyopathies. Several pathways, including genetic mutation, Ras/Raf/MEK/ERK signaling pathway, G-protein signaling, Wnt/β-catenin signaling pathway, AKT/PI3K Pathway, TGF-β signaling, JNK/p38 pathway, and apoptosis pathway, are involved in cardiomyopathy to promote angiogenesis, cell growth, apoptosis and fibrosis, leading to ventricular dilation, hypertrophy, or restriction. FGF: Fibroblast growth factor; IGF: Insulin like growth factor; PDGF: Platelet derived growth factor; TGF: transforming growth factor; PKA: Protein kinase A; PIP2: Phosphatidylinositol 4,5-bisphosphate; PKC: Protein kinase C; MEK: Mitogen-activated protein kinase kinase; ERK: Extracellular-signal-regulated kinase; AKT: Protein kinase B; IL: Interleukin; PTEN: Phosphatase and tensin homolog, PI3K: Phosphoinositide 3-kinases; JAK: Janus kinase; MEKK: Mitogen-activated protein kinase kinase kinase; JNK: c-Jun N-terminal kinase; STAT: Signal transducer and activator of transcription; APC, TNF: Tumor necrosis factor receptor type 1; Fas: Fas cell surface death receptor.