Myocardial overexpression of ANKRD1 affects developmental cardiac remodeling and leads to adult diastolic dysfunction

Aims: Increased Ankrd1 levels linked to genetic mutations have been correlated to congenital heart disease onset and adult cardiomyopathy occurrence in humans. The link between increased ANKRD1 level and cardiac structural and functional disease onset is not understood. To get insight into this problem, we have generated a ANKRD1 mouse model by overexpressing ANKRD1 in the myocardium. Methods and Results: We show that ANKRD1 delineates discrete sub-compartments in the developing mouse heart. ANKRD1 transgenic mice present impaired cardiac remodeling, which strongly affects the developing sinoatrial region and leads to sinus venosus defects. Transgenic mice survive to adulthood but develop left atrial enlargement accompanied by severe diastolic dysfunction. Embryonic and neonatal transgenic cardiomyocytes present irregular shape and sarcomeric disorganization, which progresses into sarcomeric loss and mitochondrial damage in adult ventricular but not atrial cardiomyocytes. While isolated embryonic transgenic myofibrils show the same mechanical properties of wild type samples, neonatal transgenic myofibrils present higher passive tension and maximal force compared to wild type. This indicates the presence in ANKRD1 transgenic mice of a faster functional shift towards stiffer and hyper-contractile cardiomyocytes, triggered by the increase in workload at birth. At the molecular level, these changes are accompanied by dynamic alterations in titin isoforms ratio. Interestingly, adult wild type and transgenic myofibrils show the same passive tension as transgenic neonatal myofibrils, with adult transgenic myofibrils showing a higher maximal force accompanied at this stage by a marked slowing down of the relaxation phase compatible with the overt diastolic disfunction of adult ANKRD1 transgenic mice. Conclusions: Our data indicate that genetic mutations leading to increased ANKRD1 levels can lead both to congenital heart disease and adult cardiomyopathy via a common cellular mechanism, with ANKRD1 playing the role of a critical strain sensor-signaling molecule finely modulating cardiomyocyte function during development and postnatal life.