Evolving molecular diagnostics for familial cardiomyopathies: at the heart of it all

Abstract

Cardiomyopathies are an important and heterogeneous group of common cardiac diseases. An increasing number of cardiomyopathies are now recognized to have familial forms, which result from single-gene mutations that render a Mendelian inheritance pattern, including hypertrophic cardiomyopathy, dilated cardiomyopathy, restrictive cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy and left ventricular noncompaction cardiomyopathy. Recently, clinical genetic tests for familial cardiomyopathies have become available for clinicians evaluating and treating patients with these diseases, making it necessary to understand the current progress and challenges in cardiomyopathy genetics and diagnostics. In this review, we summarize the genetic basis of selected cardiomyopathies, describe the clinical utility of genetic testing for cardiomyopathies and outline the current challenges and emerging developments.

Figure 1. Arrhythmogenic right ventricular cardiomyopathy

(A) Cardiac MRI reveals fibrofatty infiltration of the right ventricular free wall, with some involvement of the left ventricle. (B) Electrocardiogram in normal sinus rhythm exhibiting a repolarization abnormality characteristic of arrhythmogenic right ventricular cardiomyopathy, known as the ‘epsilon wave’ (indicated by arrows). (C) Electrocardiogram demonstrating ventricular tachycardia originating from the RV. RV: Right ventricle; VT: Ventricular tachycardia.

Figure 2. Selected proteins involved in the pathogenesis of cardiomyopathies shown in the context of their respective cellular structures

Cardiomyopathies are a genetically heterogeneous group of diseases that result from dysfunction in a multitude of diverse biological processes, including contractile force generation and transmission, mechanical stretch sensing, nuclear structure and function, and ion channel function.

Figure 3. Hypertrophic cardiomyopathy (HCM)

(A) Transthoracic echocardiogram in the apical four-chamber view demonstrates pronounced thickening of the distal interventricular septum and lateral wall of the left ventricle, consistent with the apical variant of HCM. (B) 12-lead electrocardiogram with evidence of left ventricular hypertrophy and deep T-wave inversions throughout the precordium, characteristic of apical variant HCM. (C) Transthoracic echocardiogram in the apical long-axis view demonstrates left ventricular hypertrophy, most pronounced in the interventricular septum, consistent with HCM. (D) Transthoracic echocardiogram using Doppler signal in the left ventricular outflow tract reveals a resting pressure gradient of 85 mmHg between the cavity of the left ventricle and the aortic root. (E) This pressure gradient augments to 213 mmHg with Valsalva maneuver, characteristic of the dynamic left ventricular outflow tract gradient of obstructive HCM.

Figure 4. Dilated cardiomyopathy

(A) Transthoracic echocardiogram in the parasternal long-axis view demonstrates dilation of the left ventricle. (B) M-mode echocardiography from the same view reveals markedly diminished systolic thickening of the myocardium.

Figure 5. Left ventricular noncompaction cardiomyopathy

(A)Transthoracic echocardiogram in the parasternal short-axis view reveals prominent myocardial noncompaction involving all segments of the left ventricle other than the interventricular septum. (B) Use of injectable echocardiographic contrast in the same view further defines the structural abnormalities.