Abstract P432: Alpha-actinin 2 Missense Variant And Its Role In Cardiac Muscle Force Production And Diastolic Dysfunction

ACTN2 gene encodes for the alpha-actinin 2 protein, which has an actin-binding role. In cardiac muscle, alpha-actinin 2 is located in the Z-disc of the sarcomere, where it anchors myofibrillar actin filaments. A 48-years old female patient presented with ventricular fibrillation arrest was successfully resuscitated. Coronary angiography exhibited normal coronary arteries. Cardiac MRI did not show myocardial scar tissue or arrhythmogenic right ventricular dysplasia (ARVD). Echocardiogram showed normal left ventricular ejection fraction, stage II diastolic dysfunction and elevated right ventricular systolic pressure. Genetic testing identified a missense variant of unknown significance in ACTN2 (a gene previously associated with dilated cardiomyopathy/ARVD), and in SCNB2 (encodes sodium voltage-gated channel beta subunit 2, a gene previously associated with long QT syndrome). We investigated the effects of the ACTN2 variant on cardiac muscle contraction, providing an inside view of the importance of ACTN2 in sarcomere function. Left ventricular free wall samples were obtained from the patient’s explanted heart at the time of cardiac transplantation. Mechanics of contraction were measured in permeabilized cardiac muscle preparations (CMPs) in the presence of 3% dextran T-500 (to restore the myofilament lattice to physiological dimensions) at 30°C. The experiments were performed at sarcomere lengths 2.1 μm and 2.3 μm achieved by HeNe laser diffraction. CMPs containing ACTN2 mutant protein displayed increased myofilament Ca 2+ sensitivity of isometric force and lower maximal isometric force compared to human donor samples (control). Sinusoidal stiffness was decreased at all levels of Ca 2+ activation and isometric force in ACTN2 variant CMPs. The rate of tension redevelopment was faster at all levels of Ca 2+ activation and isometric force. Alpha-actinin 2 is an important sarcomeric protein that regulates the kinetics of cardiac muscle contraction. This work establishes the importance of alpha-actinin 2 in the Z-disc mechanotransduction to thin and thick filament interactions.