Lipid overload - a culprit for hypertrophic cardiomyopathy?

Abstract

Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy in the absence of loading conditions such as hypertension or valvular diseases. It is the most common cause of inherited cardiac diseases, with a prevalence of 1 in 500 worldwide [1] . It is also the most common cause of sudden death in the young [2] . While etiology is heterogenous, at least half of the HCMs with a molecular diagnosis were due to pathogenic or likely pathogenic variants in sarcomere protein encoding genes, predominantly MYH7 (encoding beta-myosin heavy chain) and MYBPC3 (encoding cardiac myosin binding protein C) [2] . While the pathophysiology of HCM has been heavily debated, the most recent studies converge on the hypercontractility hypothesis [3] . Contractile protein mutations that cause either increased contractility or impaired relaxation can result in HCM. The main mechanisms that have been proposed are associated with increased calcium sensitivity, increased myosin head ATPase activity, or reduced myosin super-relaxed state among others. This hypothesis has been well supported by studies utilizing the disease-modeling murine models carrying human pathogenic variants or the patient-derived human induced pluripotent stem cell differentiated cardiomyocytes models [4] . The concentric hypertrophy associated with HCM has been attributed to increased calcium induced calcineurin signaling and activation of mitogen-activated protein kinase kinase 1-extracellular signal-regulated kinase 1/2 (MEK1-ERK1/2) signaling pathways [5