SUMMARY The heart either hypertrophies or dilates in response to familial mutations in genes encoding sarcomeric proteins, which are responsible for contraction and pumping. These mutations typically alter calcium-dependent tension generation within the sarcomeres, but how this translates into the spectrum of hypertrophic versus dilated cardiomyopathy is unknown. By generating a series of cardiac-specific mouse models that permit the systematic tuning of sarcomeric tension generation and calcium fluxing, we identify a significant relationship between the magnitude of tension developed over time and heart growth. When formulated into a computational model the integral of myofilament tension development predicts hypertrophic and dilated cardiomyopathies in mice associated with essentially any sarcomeric gene mutations, but also accurately predicts human cardiac phenotypes from data generated in induced-pluripotent stem cell-derived myocytes from familial cardiomyopathy patients. This tension-based model also has the potential to inform pharmacologic treatment options in cardiomyopathy patients.

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Hypertrophic cardiomyopathy (HCM) is a complex disease characterized by thickening of the cardiac muscle. Common symptoms include chest pain, shortness of breath, palpitations, fatigue and syncope (fainting), which are often confused for other conditions. Clinical treatment focuses on the relief of symptoms with medical therapies, which provide adequate to more variable symptomatic relief. Patients may experience more severe complications that require surgical intervention, such as implantable cardioverter-defibrillator therapy or septal myectomy. Despite the potential impact on quality of life, the humanistic burden of HCM is not well established. Here, we present four patient testimonials that highlight challenges faced by patients and clinicians in diagnosing HCM and managing symptoms. These testimonials provide valuable information on the spectrum and expression of HCM across generations. Such testimonials can better inform disease diagnosis and monitoring, maximizing quality of life and improving disease outcome.

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