Hypertrophic Cardiomyopathy: New Clinical and Therapeutic Perspectives of an "Old" Genetic Myocardial Disease

Abstract

Since its first pathological description over 65 years ago, hypertrophic cardiomyopathy (HCM), with a worldwide prevalence of 1:500, has emerged as the most common genetically determined cardiac disease. Diagnostic work-up has dramatically improved over the last decades, from clinical suspicion and abnormal electrocardiographic findings to hemodynamic studies, echocardiography, contrast-enhanced cardiac magnetic resonance, and genetic testing. The implementation of screening programs and the use of implantable cardioverter defibrillators (ICDs) for high-risk individuals have notably reduced arrhythmic sudden deaths, altering the disease's mortality profile. Therapeutic breakthroughs, including surgical myectomy, alcohol septal ablation, and the novel introduction of "myosin inhibitors", have revolutionized symptom management and reduced progression to advanced heart failure (HF) and death. Despite this progress, refractory HF-both with preserved and reduced systolic function-has become the predominant cause of HCM-related mortality. While most patients with HCM experience a favorable clinical course with low morbidity and mortality, timely identification and targeted treatment of high-risk subgroups progressing toward progressive HF remain a pressing challenge, even for expert clinicians.

Keywords: genetics; heart failure; hypertrophic cardiomyopathy; new drugs; sudden cardiac death; surgery; transplantation; treatment.

Figure 1

Main prognostic pathways in HCM.

Figure 2

Sudden death in obstructive HCM. Features of a young HCM patient who died suddenly. Echocardiography short-axis view shows severe asymmetric left ventricular hypertrophy (A) and pathological postmortem examination reveals macroscopic fibrosis, subaortic septal bulging, endocardial fibrous plaque, and a thickened anterior mitral valve (B,C). Histological section highlights myocardial disarray with interstitial and replacement fibrosis (Heidenhain’s Trichrome stain) (D).

Figure 3

“End-stage” evolution of HCM with dilated LV and systolic dysfunction. Heart of a male HCM patient removed at transplantation. Gross examination reveals thinning of the basal and midventricular septum with respect to apical portion (A); a large septal scar is highlighted by arrows (B). Histological section of the septum (C) demonstrates extensive replacement fibrosis with abnormal intramural arterioles (Trichrome stain).

Figure 4

Heart failure in HCM secondary to restrictive physiology and atrial fibrillation. Echocardiographic 4-chamber view (A) and gross pathology findings (B,C) from a male patient with sarcomeric hypertrophic cardiomyopathy (β-myosin heavy chain mutation). Severe dilation of the right (RA) and left atria (LA), normal-sized left (LV) and right ventricles (RV), and mild asymmetric hypertrophy of the ventricular septum (VS) compared to the left ventricular free wall (LVFW) are observed. A thrombus within the LA appendage is indicated by an arrow.

Figure 5

Comparison between HCM, RCM phenotypes, and phenocopies. LVMWT: left ventricular maximal wall thickness. With permission from Vio et al. [29].

Figure 6

Therapeutic flow-chart according to the most recent guidelines for obstructive HCM (modified from [16]).

Figure 7

Therapeutic flow-chart according to the most recent guidelines for non-obstructive HCM with systolic dysfunction (modified from [16]). CRT indicates cardiac resynchronization therapy; EF, ejection fraction; GDMT, guideline-directed management and therapy; HTx, heart transplant; ICD, implantable cardioverter defibrillator; LBBB, left bundle branch block; NYHA, New York Heart Association.