Hypertrophic Cardiomyopathy Mechanisms and Management

Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disorder marked by asymmetric left ventricular hypertrophy in the absence of loading conditions sufficient to explain wall thickening. Pathogenic variants in sarcomeric protein genes perturb myosin–actin cross-bridge cycling, leading to hypercontractility, impaired relaxation and increased myocardial energy consumption. Recent structural studies have revealed the three-dimensional organisation of myosin, titin and myosin-binding protein C within the thick filament and have elucidated conformational shifts of thin filament components in response to calcium. These insights explain how destabilisation of energy-conserving super relaxed states of myosin accelerates pathological remodelling, arrhythmic risk and heart failure. Management strategies integrate detailed imaging for risk stratification, pharmacological modulation of sarcomere function with novel allosteric inhibitors, and invasive septal reduction when obstruction is significant. Emerging genetic therapies, including precise base editing and allele-specific silencing, have demonstrated preclinical efficacy in preventing phenotype development. Family screening and refined variant interpretation frameworks permit early detection of at-risk individuals and guide personalised surveillance, while lifestyle modification and standard heart failure therapies remain fundamental. Multi-disciplinary care, coupling advances in molecular biology with clinical practice, offers the prospect of disease-modifying treatment and improved long-term outcomes.

Research from Nature Portfolio

High-resolution cryo-electron tomography of native cardiac sarcomeres has defined the spatial arrangement of myosin heads, titin isoforms and myosin-binding protein C, revealing how filament geometry governs force production and strain sensitivity. These structural data underpin our understanding of region-specific susceptibility to pathogenic variants. Separately, in vivo delivery of an adenine base editor via dual adeno-associated viral vectors achieved efficient correction of a dominant myosin heavy chain mutation in murine cardiomyocytes, restoring normal ventricular morphology and function with a single treatment. A complementary genetic approach using RNA-guided nuclease silencing demonstrated allele-specific inactivation of the mutant allele, highlighting a narrow therapeutic window to balance efficacy and off-target toxicity. Together, these studies showcase precise genome-editing methodologies as promising avenues for preventive intervention in HCM.

Hypertrophic Cardiomyopathy Mechanisms and Management publication trend

The graph below shows the total number of articles in hypertrophic cardiomyopathy mechanisms and management across all publications each year (not limited to Nature Index journals).

Technical terms

Sarcomere: The fundamental contractile unit of cardiac muscle, comprising organised arrays of actin and myosin filaments.

Hypercontractility: An increase in force generation by cardiomyocytes, often driven by sarcomeric gene mutations.

Penetrance: The proportion of individuals with a pathogenic variant who manifest the clinical phenotype.

Super relaxed state (SRX): A low-energy myosin conformation that minimises ATP turnover and preserves myocardial efficiency.

Cryo-electron tomography: A technique that images macromolecular complexes in near-native states by rapid freezing and electron microscopy.

Adenine base editor: A genome-editing tool that converts specific adenine bases to guanine without generating double-strand breaks.

References

1. Structure of the native myosin filament in the relaxed cardiac sarcomere. Nature (2023).
2. Cardiac muscle thin filament structures reveal calcium regulatory mechanism. Nature Communications (2020).
3. Efficient in vivo genome editing prevents hypertrophic cardiomyopathy in mice. Nature Medicine (2023).
4. Meta-Analysis of Penetrance and Systematic Review on Transition to Disease in Genetic Hypertrophic Cardiomyopathy. Circulation (2023).
5. Myosin Sequestration Regulates Sarcomere Function, Cardiomyocyte Energetics, and Metabolism, Informing the Pathogenesis of Hypertrophic Cardiomyopathy. Circulation (2020).
6. A small-molecule modulator of cardiac myosin acts on multiple stages of the myosin chemomechanical cycle. Journal of Biological Chemistry (2017).
7. Clinical Utility of Cardiovascular Magnetic Resonance in Hypertrophic Cardiomyopathy. Journal of Cardiovascular Magnetic Resonance (2012).
8. Adaptation and validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: recommendations by ClinGen’s Inherited Cardiomyopathy Expert Panel. Genetics in Medicine (2018).