Functional Genetics of Peripartum Cardiomyopathy
Abstract
Approximately one in a thousand otherwise healthy pregnant women develop profound heart failure around the time of delivery, a disease call Peripartum Cardiomyopathy (PPCM). These women as frequently as not fail to recover, often leading to cardiac transplantation or death. The consequences for healthy young women, in the midst of starting new families after for example returning from duty in the US Armed Forces, are thus devastating. PPCM spares no socioeconomic or racial subgroups, but we have found that it is more common, and more severe, in women of African descent, a group that is overrepresented in the US Armed Forces. Moreover, the highest risk factor for developing PPCM is co-occurrence of preeclampsia, a common disease of pregnancy, and a Fiscal Year 2017 (FY17) Peer Reviewed Medical Research Program (PRMRP) Area of Encouragement. Most recently, we have found that a large fraction of women who develop PPCM bear mutations in a very large gene, named TTN (also known as “titin”). This gene encodes for a key component of the molecular machinery that allows cells in the heart (and muscle) to contract. This seminal discovery has led to a number of key questions, two of which we propose to address here: (1) Does the subset of women with mutations in TTN have a different long-term outcome than women without such mutations? In other words, would genetic testing (which already exists for TTN) be useful in the clinic? (2) How is it that specifically pregnancy triggers heart failure in women with mutations in TTN (in contrast to, for example, exercise, which is equally demanding on the heart)? We will use a range of approaches, including human genetics, studies in model organisms, and studies with induced pluripotent stem cells, to address these questions, and study in depth why this seemingly random and devastating event occurs. The studies will provide important insights into the causes of heart failure and may lead to novel therapeutic approaches for these unfortunate women and their families. The proposed work is thus squarely within the goals of the FY17 PRMRP Topic Area of Women’s Heart Disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810503
Entities
People
- Zoltan Arany
Organizations
- United States Army
- University of Pennsylvania