The CureHeart project is co-led by Professor Christine Seidman.
My lab employs genetic and genomic strategies to define the molecular pathogenesis of human heart disorders, focusing on hypertrophic and dilated cardiomyopathies, and congenital heart disease. We perform detailed clinical phenotyping, and exome/genome sequence analyses to identify pathogenic variants and model these in cardiomyocytes to define mechanisms for heart disease. These efforts capitalize on the laboratory’s expertise in cardiovascular genetics and genomics, computational and transcriptional biology, and genetic manipulations and functional characterization of mouse models and cardiomyocytes derived from human induced pluripotent stem cells.
These studies have defined critical pathways for heart development, molecular processes that enable life-long efficient contraction and relaxation, and the downstream consequences when these fundamental properties are disturbed. Clinical translation of these insights has propelled clinical adoption of gene-based diagnosis in cardiomyopathies, which has fostered both an understanding of early preclinical phenotypes and the identification of patients at high risks for adverse outcomes. Our mechanistic insights into hypertrophic cardiomyopathy have contributed to the development of a directed therapy for patients with obstructive disease.
I am committed to continuing these efforts, with the ultimate belief that molecular understanding of heart muscle diseases will enable not only therapies but also strategies to prevent disease development.
Professor Seidman has published 388 peer-reviewed manuscripts: find out more about her work.
Discovery of Genetic Causes for Hypertrophic Cardiomyopathy (HCM) and Cardiac Hypertrophy
We discovered the molecular basis for hypertrophic cardiomyopathy (HCM), the most common cause of sudden death, identifying dominant mutations in a number of genes which defined this as a disease of the sarcomere (summarized in Cell, 2001). These pathogenic gene variants account for the majority of HCM cases. We also identified other variatnts that do not cause HCM, but other, related heart diseases that can mimic HCM. Understanding these distinct pathogenetic mechanisms for cardiac hypertrophy has improved the clinical utility and prognostic information of gene-based diagnostics and advanced the development of appropriate therapies.
- Thierfelder L, Watkins H, MacRae C, Lamas R, McKenna W, Vosberg H-P, Seidman JG*, Seidman CE*. α- tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: A disease of the sarcomere. Cell. 1994;77:1-20. doi: 10.1016/0092-8674(94)90054-x.
- Watkins H, Conner D, Thierfelder L, Jarcho JA, MacRae C, McKenna WJ, Maron BJ, Seidman JG*, Seidman CE*. Mutations in the cardiac myosin binding protein-C gene on chromosome 11 cause familial hypertrophic cardiomyopathy. Nat Genet. 1995;11:434-437. doi: 10.1038/ng1295-434.
- Arad M, Benson W, McKenna WH, Perez-Atayde AR, Sparks EA, Kanter RJ, Seidman JG*, Seidman CE*. Constitutively active AMP kinase mutations cause ventricular pre-excitation, atrioventricular block and glyocgen storage disease mimicking hypertrophic cardiomyopathy. J Clin Invest. 2002;109(3):357-362. doi: 10.1172/JCI14571.
- Morita H, Rehm HL, Menesses A, McDonough B, Roberts AE, Kucherlapati R, Towbin JA, Seidman JG*, Seidman CE*. Shared genetic causes of cardiac hypertrophy in children and adults. N Engl J Med. 2008;358(18):1899-908. doi: 10.1056/NEJMoa075463.
Genetic Causes of Dilated Cardiomyopathy (DCM)
We discovered the major genetic causes for non-ischemic DCM including titin (TTN) and other genes. Mutations that truncate titin are the single most common cause of DCM, occurring in approximately 20% of familial and severe cases, more than all other DCM genes combined. Most recently we found that titin mutations are enriched in patients with cancer-therapy induced cardiomyopathy, providing the first evidence for a strong genetic component of this disorder.
- Fatkin D, MacRae C, Sasaki T, Wolff MR, Porcu M, Frenneaux M, Atherton J, Vidaillet HJ, Spudich S, DeGirolami U, Muntoni F, Johnson W, McDonough B, Seidman JG*, Seidman CE*. Missense mutations in the lamin A/C rod cause dilated cardiomyopathy and conduction system disease. New Eng J Med. 1999; 341(23):1715-1724. doi: 10.1056/NEJM199912023412302.
- Herman DS, Lam L, Taylor MR, Wang L, Teekakirikul P, Christodoulou D, Conner L, DePalma SR, McDonough B, Sparks E, Teodorescu DL, Cirino AL, Banner NR, Pennell DJ, Graw S, Merlo M, Di Lenarda A, Sinagra G, Bos JM, Ackerman MJ, Mitchell RN, Murry CE, Lakdawala NK, Ho CY, Barton PJ, Cook SA, Mestroni L, Seidman JG*, Seidman CE*. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012;366(7):619-28. doi: 10.1056/NEJMoa1110186.
- Garcia-Pavia P, Kim, Y, Restrepo-Cirdoba A, Lunde IG, Wakimoto H, Smith AM, Toepfer CN, Getz K, Gorham J, Patel P, Ito K, Willcox JA, Arany Z, Li J, Owens AT, Govind R, Nunez B, Mazaika E, Bayes-Genis A, Walsh R, Finkelman B, Lupon J, Whiffin N, Serrano I, Midwinter W, Wilk A, Bardaji A, Ingold N, Tayal U, Pascual-Figal DA, de Marvao A, Ahmad M, Garcia-Pinilla JM, Pantazis A, Dominguez F, Baski J, O’Reagan DP, Rosen SD, Prasad S, Lara-Pezzi E, Provencio M, Lyon A, Alonso-Pulpon L, Cook SA, DePalma SR, Barton P, Aplenc R, Seidman JG, Ky B, Ware JS, Seidman CE. Gene Variants Associated with Cancer Therapy-Induced Cardiomyopathy. Circulation. 2019;140(1):31-41. doi: 10.1161/CIRCULATIONAHA.118.037934.
Studies of the Molecular Pathogenesis of Cardiomyopathy Variants
To understand the impact of human mutations on sarcomere biology, we have modeled pathogenic variants in mice and cells. Our studies demonstrated have demonstration how hypertrophic cardiomyopathy (HCM) gene variants change the functioning of sarcomeres to cause hyper-contraction, poor relaxation, and excessive energy consumption. We have also shown that switching of causal human HCM gene variants in mice stops the development of HCM in mice, and insufficient titin results in a very different pathobiology: by limiting sarcomere formation in response to cardiac stress, these gene varints reduce the force of contraction and cause dilated cardiomyopathy (DCM). Both HCM and DCM abnormalities promote distinct changes in cardiomyocyte transcription that promote shifts in cardiac metabolism and enhance profibrotic gene expression, processes that propel the development of heart failure. With advance methods to directly study transcriptional responses, we are interrogating these processes in the human hearts obtained from normal donors and from patients with HCM and DCM.
- Jiang J*, Wakimoto H*, Seidman JG, Seidman CE. Allele-specific silencing of mutant Myh6 transcripts supresses hypertrophic cardiomyopathy. Science. 2013 Oct 4;342(6154):111-4. PMCID:PMC4100553 doi: 10.1126/science.1236921.
- Hinson JT, Copra A, Nafissi N, Polacheck WJ, Benson CC, Swiat S, Gorham J, Yang L, Schafer S, Sheng CC, Haghighi A, Homsy J, Hubner N, Church G, Cook SA, Linke WA, Chen CS, Seidman JG*, Seidman CE*. Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyopathy. Science. 2015;349(6251):982-6. doi: 10.1126/science.aaa5458.
- Toepfer CN, Garfinkel AC, Venturini G, Wakimoto H, Repetti G, Alamo L, Sharma A, Agarwal R, Ewoldt J, Cloonan P, Letendre J, Lun M, Olivotto I, Colan S, Ashley E, Jacoby D, Michels M, Redwood CS, Watkins HC, Daly SM, Staples JF, Padron R, Chopra A, Ho CY, Chen CS, Pereira AC, Seidman JG, Seidman CE. Myosin sequestration regulates sarcomere function, cardiomyocyte energetics, and metabolism, informing the pathogenesis of hypertrophic cardiomyopathy. Circulation. 2020;141(10):828-842. doi: 10.1161/CIRCULATIONAHA.119.042339.
- Litviňuková M, Talavera-López C, Maatz H, Reichart D, Polanski K, Fasouli ES, Worth CL, Samari S, Roberts K, Tuck L, Lindberg E, Kanda M, DeLaughter D, Wakimoto H, Nadleman E, Mahbubani K, Saeb-Parsy K, Patone G, Boyle J, Zhang H, Zhang H, Viveiros A, Oudit G, Bayraktar O, Seidman JG*, Seidman CE*, Noseda M*, Hübner N,* Teichmann SA*. Cells and gene expression programs in the adult human heart. Nature. 2020;588(7838):466-472. doi: 10.1038/s41586-020-2797-4