Idiopathic Dilated Cardiomyopathy: Molecular Basis and Distilling Complexity to Advance

Abstract

Cardiomyopathies are heterogeneous diseases of the myocardium associated with abnormal findings of chamber size, wall thickness, and/or functional contractility. In particular, dilated cardiomyopathy (DCM) is mainly characterized by ventricular chamber enlargement with systolic dysfunction and normal left ventricular (LV) wall thickness. Although DCM is thought to be induced mainly by genetic or environmental factors, in the majority of cases, the cause is unknown. With an estimated prevalence of 1:2500 and an incidence of 1:18,000 per year in adults, DCM is the most frequent indication for heart transplantation, which represents an enormous cost burden on healthcare systems. These figures warrant greater accuracy in patient diagnosis and prognosis and further insight into the underlying basis of DCM. Here, we discuss past and recent findings on the molecular mechanisms involved in DCM. Dilated cardiomyopathy has been linked to the overactivation of extracellular signal-regulated kinase (ERK1/2), which in turn is related to activation of low-density lipoprotein receptorrelated protein-1 (LRP-1). Moreover, a redistribution of LRP-1 into cholesterol-enriched plasma membrane domains (lipid rafts) and alterations in cardiac DNA methylation have been reported in failing hearts. In conclusion, more comprehensive analyses of myocardial lipid rafts and epigenetic mechanisms may advance our understanding of DCM causes and progression. In turn, this understanding may promote the development of innovative treatments.

Class I and II Histone Deacetylase Inhibitors as Therapeutic Modulators of Dilated Cardiac Tissue-Derived Mesenchymal Stem/Stromal Cells

“…Individuals diagnosed with dilated cardiomyopathy (DCM) exhibit a reduced thickness of the heart wall structure, an increased diameter of the left ventricle chamber, and systolic dysfunction [ 2 ]. The etiology of DCM is often complex, involving various factors such as a toxic environment, inflammation, autoimmune or viral diseases, and other elements that impair blood supply and heart function, ultimately leading to heart failure and the need for transplantation [ 3 ]. At the tissue level, dilated hearts manifest multiple abnormalities associated with altered biological and physiological heart parameters, including reduced ejection fraction and impaired structural (sarcomere) and cellular functioning properties [ 4 , 5 ].…”

Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid Improves Energetic Status and Cardiomyogenic Differentiation of Human Dilated Myocardium-Derived Primary Mesenchymal Cells

“…Patients suffering from dilated cardiomyopathy display reduced thickness of heart wall, increased size of left ventricle chamber, and systolic dysfunction [ 3 ]. There are multiple causative factors of DCM, including toxic environmental effects, inflammation, autoimmune disease, viral infections, and others that, in one way or another, affect ventricle blood pumping [ 4 ]. Abnormalities in dilated heart are associated with changed physiological parameters, such as ejection fraction, as well as with impaired structural (sarcomere) and metabolic cell functions [ 5 , 6 ].…”

“…Sirtuins (1)(2)(3)(4)(5)(6)(7), III group of histones deacetylases, are structurally and mechanistically distinct from other classes of histone deacetylases (classes I, IIA, IIB, and IV), which have a different protein fold and use zinc (Zn 2+ ) as a cofactor. Therefore, sirtuins were not investigated in this study.…”