In a collaboration between groups in Kiel, Münster, Heidelberg, Göttingen, Essen, and Cologne, we were able to analyze a unique, very large (and another small) German family with atrial septal defect type II (ASD-II) and identified a novel non-synonymous cardiac alpha-actin (ACTC1) gene mutation as the cause (p. G247D). Of note, these patients developed severe heart failure due to a dilated cardiomyopathy after complaint-free decades and ASD closure. Immunohistology from an explanted mutation carrier’s heart as well as further in-depth molecular and cellular studies revealed sarcomeric disarray, and increased apoptosis as underlying molecular mechanisms due to actin polymerization and turnover defects. These pathological changes are most likely responsible for the detrimental effects on contractile function of the cardiomyocytes.
Thus, this study adds comprehensive mechanistic data to the pathogenesis of a cardiac α-actin mutation associated with a complex, combined phenotype. From a translational perspective, we believe that our findings emphasize the need for more personalized monitoring for the development of late-onset heart failure in ASD patients (independent of ASD closure). Moreover, it is tempting to speculate, whether late-onset DCM might contribute to the development of heart failure after late ASD closure.
October 2019