Cardiac electrical defects in progeroid mice and Hutchinson–Gilford progeria syndrome patients with nuclear lamina alterations

Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disease caused by defective prelamin A processing, leading to nu- clear lamina alterations, severe cardiovascular pathology, and pre- mature death. Prelamin A alterations also occur in physiological aging. It remains unknown how defective prelamin A processing affects the cardiac rhythm. We show age-dependent cardiac repo- larization abnormalities in HGPS patients that are also present in the Zmpste24−/− mouse model of HGPS. Challenge of Zmpste24−/− mice with the β-adrenergic agonist isoproterenol did not trigger ventricular arrhythmia but caused bradycardia-related premature ventricular complexes and slow-rate polymorphic ventricular rhythms during recovery. Patch-clamping in Zmpste24−/− cardiomyocytes revealed prolonged calcium-transient duration and reduced sarco- plasmic reticulum calcium loading and release, consistent with the absence of isoproterenol-induced ventricular arrhythmia. Zmpste24−/− progeroidmice also developed severe fibrosis-unrelated bradycardia and PQ interval and QRS complex prolongation. These conduction defectswere accompanied by overtmislocalization of the gap junction protein connexin43 (Cx43). Remarkably, Cx43 mislocali- zation was also evident in autopsied left ventricle tissue from HGPS patients, suggesting intercellular connectivity alterations at late stages of the disease. The similarities between HGPS patients and progeroid mice reported here strongly suggest that defective cardiac repolarization and cardiomyocyte connectivity are important abnor- malities in the HGPS pathogenesis that increase the risk of arrhythmia and premature death.