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Shared Genetic Predisposition in Peripartum and Dilated Cardiomyopathies
James S Ware1, Jian Li, Erica Mazaika
1From the Department of Genetics, Harvard Medical School (J.S.W., E.M., C.M.Y., C.E.S., J.G.S.), the Howard Hughes Medical Institute (C.E.S.), and the Cardiovascular Division, Brigham and Women's Hospital (J.S.W., E.M., C.E.S., J.G.S.) - all in Boston; the Cardiovascular Institute and the Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (J.L., T.D., T.P.C., Z.A.), the Heart and Vascular Institute, University of Pittsburgh Medical Center, Pittsburgh (I.H., J.P., K.H.-Y., J.G., D.M.M.), and Penn State Hershey Medical Center, Hershey (J.B.) - all in Pennsylvania; the National Institute for Health Research Royal Brompton Cardiovascular Biomedical Research Unit (J.S.W., F.M., S.K.P.) and the National Heart and Lung Institute (J.S.W., F.M., S.A.C., S.K.P.), Imperial College London, London; the Division of Cardiology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York (E.J.T.), and the University of Rochester, Rochester (J.A.) - both in New York; the Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany (D.H.-K.); the Department of Perinatology and Gynecology, the National Cerebral and Cardiovascular Center, Osaka, Japan (C.A.K.); the National Heart Center and Duke-National University of Singapore, Singapore (S.A.C.); the Intermountain Medical Center, Murray, Utah (R.A.); Vanderbilt University, Nashville (J.D.); Cleveland Clinic, Cleveland (E.H.); University of Southern California, Los Angeles (U.E.); McGill University and Jewish General Hospital, Montreal (R.S.), University of Calgary, Calgary, AB (A.K.), and University of Toronto, Toronto (P.L.) - all in Canada; University of Maryland, College Park (G.R.), and Johns Hopkins Hospital, Baltimore (I.S.W.) - both in Maryland; Morristown Hospital, Morristown (J.S.), and Newark Beth Israel Medical Center, Newark (M.J.Z.) - both in New Jersey; Truman Medical Center, University of Missouri, Kansas City (D.F.P.); and Wa
Genetic variants in TTN (titin) are common in peripartum cardiomyopathy, similar to dilated cardiomyopathy. These titin variants are linked to reduced heart function in affected women.
Area of Science:
- Cardiology
- Genetics
- Molecular Biology
Background:
- Peripartum cardiomyopathy (PPCM) shares clinical similarities with idiopathic dilated cardiomyopathy (DCM).
- DCM is associated with mutations in over 40 genes, notably TTN, which encodes the sarcomere protein titin.
- Understanding genetic predispositions in PPCM is crucial for diagnosis and treatment.
Purpose of the Study:
- To investigate the prevalence and types of genetic variants in PPCM.
- To compare the genetic landscape of PPCM with DCM and population controls.
- To identify specific genes and variants associated with PPCM, particularly TTN.
Main Methods:
- Sequencing of 43 genes associated with DCM in 172 women with PPCM.
- Comparison of rare truncating variant prevalence in PPCM, DCM cohorts, and a large reference population.
- Correlation analysis between TTN variants and cardiac function (ejection fraction) in a subset of PPCM patients.
Main Results:
- 26 distinct rare truncating variants in 8 genes were identified in women with PPCM (15% prevalence).
- TTN variants accounted for two-thirds of identified truncating variants in PPCM (10% prevalence), significantly higher than controls (1.4%).
- TTN truncating variants were associated with lower ejection fraction at 1-year follow-up in PPCM patients.
Conclusions:
- The genetic variant distribution in PPCM closely mirrors that of idiopathic DCM.
- TTN truncating variants represent the most common genetic predisposition in both PPCM and DCM.
- Genetic analysis of TTN may aid in understanding and managing PPCM.
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