Mutation-specific pathology and treatment of hypertrophic cardiomyopathy in patients, mouse models and human engineered heart tissue

• Published in: Biochimica et biophysica acta. Molecular basis of disease 2020-08, Vol.1866 (8), p.165774-165774, Article 165774
• Main Authors: Wijnker, Paul J.M., van der Velden, Jolanda
• Format: Article
• Language: English
• Subjects: Animals; Calcium - metabolism; Cardiac Myosins - genetics; Cardiac Myosins - metabolism; Cardiomyopathy, Hypertrophic - genetics; Cardiomyopathy, Hypertrophic - metabolism; Cardiomyopathy, Hypertrophic - pathology; Cardiomyopathy, Hypertrophic - therapy; Cardiotonic Agents - therapeutic use; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell- and Tissue-Based Therapy - methods; Death, Sudden, Cardiac - pathology; Death, Sudden, Cardiac - prevention & control; Disease Models, Animal; Genetic Predisposition to Disease; Humans; Hypertrophic cardiomyopathy; Hypertrophy, Left Ventricular - genetics; Hypertrophy, Left Ventricular - metabolism; Hypertrophy, Left Ventricular - pathology; Hypertrophy, Left Ventricular - therapy; Mice; Mutation; Mutation-specific pathology; Mutation-specific treatment; Myocardial Contraction - drug effects; Myosin Heavy Chains - genetics; Myosin Heavy Chains - metabolism; Pathophysiological mechanism; Precision medicine; Sarcomere gene mutation; Sarcomeres - drug effects; Sarcomeres - genetics; Sarcomeres - metabolism; Tropomyosin - genetics; Tropomyosin - metabolism; Troponin I - genetics; Troponin I - metabolism
• ISSN: 0925-4439; 1879-260X
• DOI: 10.1016/j.bbadis.2020.165774

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy and is characterized by asymmetric left ventricular hypertrophy and diastolic dysfunction, and a frequent cause of sudden cardiac death at young age. Pharmacological treatment to prevent or reverse HCM is lacking. This may be partly explained by the variety of underlying disease causes. Over 1500 mutations have been associated with HCM, of which the majority reside in genes encoding sarcomere proteins, the cardiac contractile building blocks. Several mutation-mediated disease mechanisms have been identified, with proof for gene- and mutation-specific cellular perturbations. In line with mutation-specific changes in cellular pathology, the response to treatment may depend on the underlying sarcomere gene mutation. In this review, we will discuss evidence for mutation-specific pathology and treatment responses in HCM patients, mouse models and engineered heart tissue. The pros and cons of these experimental models for studying mutation-specific HCM pathology and therapies will be outlined. •Genotype-specific pathology and treatment responses in HCM patients•Mutation-specific pathology and responses to treatment in HCM mouse models•The advantages of human engineered heart tissue to define direct effects of mutations.•The possible benefit of a precision medicine treatment approach for HCM patients•Pros and cons of different experimental models to study mutation-specific pathology