Abstract 12702: A Novel Human S10F-Hsp20 Mutation Induces Lethal Peripartum Cardiomyopathy (Best of Basic Science Abstract)

Abstract

Background: Heat shock protein 20 (Hsp20) has emerged as a novel cardioprotector against stress-induced injury. In this study, we investigated the functional significance of a novel human Hsp20 mutation (S10F) in peri-partum cardiomyopathy. Methods and Results: We identified a human S10F-Hsp20 mutant with a frequency of 2.8% in dilated cardiomyopathy patients (470 screened), while we did not find any normal subjects carrying this mutation (282 screened). To determine the functional significance of S10F-Hsp20, transgenic mice with cardiac-specific overexpression of this mutant were generated. We observed that female TGs were fertile, and delivered normal litter sizes, but they invariably died after 2, 3 or 4 pregnancies (Fig. 1a). However, overexpression of WT-Hsp20 to similar levels as S10F was not associated with any deaths following multiple pregnancies. Further histological examination of S10F females revealed significantly dilated hearts and increased heart weight/tibia length after the third delivery, compared to WT (non transgenic) mice. (Fig. 1b,c). Echocardiography assessment showed that this dilation (Fig. 1d) is associated with increased left ventricular end-systolic volume (Fig. 1e), increased left ventricular end-diastolic volume, depressed ejection fraction (Fig. 1f) and decreased fractional shortening. Further studies revealed that cardiomyocyte apoptosis was increased by 4 fold in S10F hearts after the third delivery(Fig. 1g,h). The mechanisms associated with the detrimental remodelling in S10F females included decreased Akt (Fig. 1i) and ERK phosphorylation under both baseline and pregnancy conditions. As a result, the activities of Akt and ERK were reduced, contributing to increased cell death in the S10F hearts of pregnant females. Conclusion: The human S10F mutation may compromise the heart’s coping with pregnancy induced stress conditions mainly through increased apoptosis by reduction of Akt and ERK activities.