The most prevalent hereditary heart illness is familial hypertrophic cardiomyopathy (HCM), which is caused by abnormalities in genes encoding sarcomeric proteins that govern ventricular contractility. Left ventricular hypertrophy and heart failure, arrhythmias, and sudden cardiac death are all symptoms of HCM. However, how dysregulated sarcomeric force generation is perceived and leads to pathological remodeling in HCM is still unknown, impeding the efficient development of novel therapies.

The discovery was based on insights from a severe HCM phenotype and a second genetic change in a sarcomeric mechanosensing protein. To study human cardiac mechanobiology at both the cellular and tissue levels, researchers derived cardiomyocytes from patient-specific induced pluripotent stem cells and created robust engineered heart tissues by seeding induced pluripotent stem cell-derived cardiomyocytes into a laser-cut scaffold with native cardiac fiber alignment. They identified a new mechanotransduction pathway in HCM, which was shown to be essential in modulating the phenotypic expression of HCM in 5 families with distinct sarcomeric mutations when combined with computational modeling for muscle contraction and rescue of disease phenotype by gene editing and pharmacological interventions.

Increased force production was generated by sarcomeric mutations in cardiac myosin heavy chain (MYH7), which, when combined with slower twitch relaxation destabilized the MLP (muscle LIM protein) stretch-sensing complex at the Z-disc. Following that, a decrease in the sarcomeric muscle LIM protein level resulted in calcineurin–nuclear factor of activated T-cells signaling, which encouraged cardiac hypertrophy. They showed that the common muscle LIM protein–W4R variation is a key modulator, aggravating the phenotypic manifestation of HCM. Still, it is not a disease-causing mutation in and of itself. They eased stress at the Z-disc by moderating heightened actomyosin cross-bridge generation by genetic or pharmacological approaches, avoiding the development of hypertrophy associated with sarcomeric mutations.

The research revealed a unique biomechanical mechanism that detects dysregulated sarcomeric force output and causes pathogenic signaling, remodeling, and hypertrophic responses. The findings laid the groundwork for the development of novel mechanism-based therapies for HCM that stabilize the Z-disc. Mechanosensory complex MLP.