Moving Beyond the Sarcomere to Explain Heterogeneity in Hypertrophic Cardiomyopathy: JACC Review Topic of the Week

Abstract

Hypertrophic cardiomyopathy (HCM) has been considered a heterogeneous cardiac disease ascribed solely to single sarcomere gene mutations. However, limitations of this hypothesis suggest that sarcomere mutations alone do not adequately explain all HCM clinical and pathobiological features. Disease-causing sarcomere mutations are absent in ∼70% of patients with established disease, and sarcomere gene carriers can live to advanced ages without developing HCM. Some features of HCM are also inconsistent with the single sarcomere gene hypothesis, such as regional left ventricular hypertrophy and myocardial fibrosis, as well as structurally abnormal elongated mitral valve leaflets and remodeled intramural coronary arterioles, which involve tissue types that do not express cardiomyocyte sarcomere proteins. It is timely to expand the HCM research focus beyond a single molecular event toward more inclusive models to explain this disease in its entirety. The authors chart paths forward addressing this knowledge gap using novel analytical approaches, particularly network medicine, to unravel the pathobiological complexity of HCM.

Keywords: genetics; hypertrophic cardiomyopathy; network medicine.

Figure 1.. Classical model used to describe clinical disorders based on genetics.

(A) A loss- or gain-of-function gene mutation corresponds to an allele, or abnormal trait, which collectively describe a disease-predisposing genotype. A pathogenic gene variant, in turn, results in the development of an endophenotype, which serves as the fundamental basis for a clinical disorder. This classical model provides a direct link between genotype and clinical disease, and has been proposed to explain many diseases associated with rare genetic variants. (B) For example, in cystic fibrosis a deletion of three nucleotides spanning positions 507 and 508 of the transmembrane conductance regulator (CFTR) gene results in a loss of phenylalanine. In >90% of patients, this functions as the molecular event that generates exocrine gland dysfunction (endophenotype), which, in turn, is responsible for the totality of clinical findings in affected patients. However, truly monogenic diseases are exceedingly rare, since most disease, particularly HCM, involve a combination of endophenotypes that converge to produce the clinical phenotype. Images reproduced with permission from: fibrosis, Creative Commons License ShareAll at https://www.neurologyadvisor.com/epilepsy/cardiac-pathology-in-sudep-compared-with-sudden-arrhythmic-or-traumatic-deaths/article/781382/; hypertrophy, Creative Commons License ShareAlike at https://en.wikipedia.org/wiki/Left_ventricular_hypertrophy; thrombosis, Yale Medical Studies Library at http://medcell.med.yale.edu/histology/blood_vessels_lab/coronary_thrombosis.php; calcification, Sage Publications through Rightslink from Morsy, Y., et al. Int J of Artif Organs, 2004; 27:445-451.; Gland dysfunction, Massachusetts Medical Society from Stoltz, D.A., et al. Origins of Cystic Fibrosis Lung Disease. N Engl J Med 372(4): 1574-1575.

Figure 2.. The single sarcomere gene mutation hypothesis suggests HCM is a disease of divergent endophenotypes.

The conventional approach to explaining HCM pathobiology relies on a single cardiomyocyte sarcomere gene mutation to account for multiple endophenotypes. However, many of the HCM endophenotypes involve cell types that do not express cardiomyocyte sarcomeres. Additionally, the single sarcomere gene hypothesis and model corresponds to a collection of divergent endophenotypes, even though multiple endophenotypes are observed within the same patient commonly. LVH, left ventricular hypertrophy; MV, mitral valve. Images reproduced with permission from: long mitral valve, Maron MS, et al. Circulation 2011;124:40.; LV aneurysm, Maron MS, et al. Circulation 2008;118:1541-9.; Anomolous papilary muscle insertion, Rowin EJ, et al. Am J Cardiol. 2013;111:1677-9.; Posterior septum, Rowin EJ, et al. Circulation Cardiovasc Imaging 2017;10(7).

Central Illustration:. Contemporizing the approach to understanding HCM pathobiology.

Left panel: The classical model of hypertrophic cardiomyopathy (HCM). In this monogenic approach, a single molecular event involving a mutant sarcomere gene promotes abnormalities in different cardiac structures. Center panel: However, limitations to this paradigm raise the speculation that parallel or alternative mechanisms to a single sarcomere gene mutation may be important for understanding HCM. (Right panel) We propose a path forward that focuses initially on the totality of HCM endophenotypes, explores acquired (non-genetic) determinants of disease expression, and leverages novel analytical methods, particularly network medicine, in reconsidering the pathobiological basis of HCM. This provides a flexible and integrative framework in which each HCM endophenotype is regulated by a unique network focusing on the functional or physical relationship between biological components (e.g., protein-protein interactions. In this figure a circle represents each protein, or network node, and each functional or physical relationship between proteins is represented by a line, or network edge). Protein-protein interactions (two or more connected circles in this figure) may be influenced by genetic variants or environmental cues among other acquired determinants, and may cross-talk between endophenotype networks. Ultimately, this results in a flexible model emphasizing endophenotype convergence for understanding the heterogeneity of HCM encountered in clinical practice. LV, left ventricle; LVH, left ventricular hypertrophy; PM, papillary muscle.