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

Significance Defective prelamin A processing causes cardiovascular alterations and premature death in Hutchinson–Gilford progeria syndrome (HGPS) patients and also occurs during physiological aging. We found overt repolarization abnormalities in HGPS patients at advanced disease stages. Similar alterations were present in progeroid Zmpste24 −/− mice, which had cardiomyocytes that exhibited prolonged calcium transient duration and reduced sarcoplasmic reticulum calcium loading capacity and release, consistent with absence of isoproterenol-induced ventricular arrhythmias. Zmpste24 −/− mice developed age-dependent bradycardia and PQ interval/QRS complex prolongation, likely contributing to premature death. These defects correlated with mislocalization of connexin43, which was also noted in heart tissue from HGPS patients. These results reveal molecular alterations that might cause cardiac rhythm alterations and premature death in HGPS.