Clinical Insights Into Heritable Cardiomyopathies

Abstract

Cardiomyopathies (CMs) encompass a heterogeneous group of structural and functional abnormalities of the myocardium. The phenotypic characteristics of these myocardial diseases range from silent to symptomatic heart failure, to sudden cardiac death due to malignant tachycardias. These diseases represent a leading cause of cardiovascular morbidity, cardiac transplantation, and death. Since the discovery of the first locus associated with hypertrophic cardiomyopathy 30 years ago, multiple loci and molecular mechanisms have been associated with these cardiomyopathy phenotypes. Conversely, the disparity between the ever-growing landscape of cardiovascular genetics and the lack of awareness in this field noticeably demonstrates the necessity to update training curricula and educational pathways. This review summarizes the current understanding of heritable CMs, including the most common pathogenic gene variants associated with the morpho-functional types of cardiomyopathies: dilated, hypertrophic, arrhythmogenic, non-compaction, and restrictive. Increased understanding of the genetic/phenotypic associations of these heritable diseases would facilitate risk stratification to leveraging appropriate surveillance and management, and it would additionally provide identification of family members at risk of avoidable cardiovascular morbidity and mortality.

Keywords: cardiac phenotypes; genetic expression; genetic testing; heritable cardiomyopathies; myocardial disease.

FIGURE 1

Two-dimensional, apical 4-chamber echocardiographic image depicting an enlarged ventricle with spherical geometry and bilateral atrial enlargement in a patient harboring dilated cardiomyopathy secondary to a pathogenic gene variant in the TTN gene.

FIGURE 2

Two dimensional images of HCM in the parasternal short axis (A) exhibiting significant concentric hypertrophy and corroborated by the parasternal long axis view (B).

FIGURE 3

Distinct phenotypes of non-compaction cardiomyopathy. (A) Echocardiographic 4-chamber view displays the isolated type of LVNC illustrated by the cardinal feature of left ventricular trabeculations (arrow) with normal anatomy and function; (B) from a cardiac magnetic resonance imaging (CMRi), a 4-chamber view displays the dilated sun-type of LVNC, denoting the enlargement of the LV and the presence of inferolateral trabeculations (arrow); (C) echocardiographic 4-chamber view shows the hypertrophic type of LVNC represented by asymmetric hypertrophy of the interventricular septum and the presence of lateral LV trabeculations (arrow); (D) display of the restrictive type of LVNC, significant bilateral atrial enlargement (arrows) and the presence of left ventricular trabeculations; (E) biventricular hypertrabeculations (arrows); (F) cMRI in a short axis view displays a mixed LVNC phenotype represented by dilated and dysfunctional ventricles in a patient with ventricular arrhythmias and biventricular trabeculations secondary to a pathogenic variant in the PRDM16 gene (arrows).

FIGURE 4

Two-dimensional, apical 4-chamber echocardiographic image depicting small, restrictive ventricles and significant biatrial enlargement in a patient with restrictive cardiomyopathy.