Natural muscles provide billions of work cycles involving tension development or movement and convert the chemical energy to mechanical energy with an exceptional high efficiency. The contractile material of the cardiomyocyte may be primarily affected by gene mutations, with detrimental mechanical and energetic consequences. Faster cross-bridge detachment and increased tension cost, for instance, are hallmarks of hypertrophic cardiomyopathy, identified in human myocardial samples and recapitulated by in vitro models. In selected contexts of HCM, cellular mechanisms leading to enhanced excitability may be as, or more, important than reentry macro-substrates in predicting clinical manifestations.