Functional Genetics of Peripartum Cardiomyopathy
Abstract
Peripartum cardiomyopathy (PPCM) is marked by loss of cardiac contractile function in women late in pregnancy or soon after delivery. PPCM affects approximately 1:1000 births worldwide, and frequently leads to chronic heart failure, cardiac transplantation, or death. Our proposal was focused on understanding how mutations in TTN predispose to PPCM. Aim 1: Human genetics: we collated a cohort of greater than 600 clinically annotated women with PPCM, and performed deep sequencing of the TTN gene, followed by detailed phenotype/genotype correlations, including evaluation of correlation between TTN mutations and severity of disease on presentation, and recovery from PPCM. This work was published in Circulation in May of 2021. We also analyzed the UPenn and Geisinger Biobank data sets of greater than 70,000 exomes for TTN truncating variants, and concluded that surprisingly large number of people carry these variants without having PPCM or other dilated cardiomyopathy. This work was published in Circulation in April of 2019. Aim 2: Mouse genetics: we generated mice genetically modified to encode mutations in ttn that precisely match those found in three women with PPCM. Baseline phenotyping revealed little baseline dysfunction. Data with cardiotoxic stressors such as chemotoxic agents, transverse aortic banding, and adrenergic infusions, has revealed surprisingly little effect, compared to control animals. On the other hand, data indicated that repeated pregnancies (n=five) do worsen function in these animals, compared to controls. Works to test the impact of various pregnancy hormones on cardiac function in these ttn knock-in mice has not identified causal hormones. Aim 3: Cellular studies: we generated iPSCs bearing the same TTN mutations as in mice above.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2022
- Accession Number
- AD1205001
Entities
People
- Zoltan Arany
Organizations
- University of Pennsylvania