Abstract: Series 104, Lecture 4
The Harvey Lectures Series 104 (2008—2009)
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Lecture #4: Thursday, February 19, 2009 — Time and Location
Cardiac Hypertrophy: From Mutation to Mechanism
Christine Seidman, MD
Thomas W Smith Professor of Medicine and Genetics, Harvard Medical School
Director, Cardiovascular Genetics Center, Brigham and Women's Hospital
Investigator, Howard Hughes Medical Institute
Howard Hughes Medical Institute, Brigham and Women's Hospital, Harvard Medical School
Boston, Massachusetts
Approximately 4% of the population has cardiac hypertrophy, an important risk factor for heart failure, stroke and premature mortality. Cardiac hypertrophy can also be familial and due to a monogenic disorder, hypertrophic cardiomyopathy (HCM) that is caused by mutation in sarcomere protein genes. Inherited forms of cardiac hypertrophy also arise from mutation in the gamma-2 subunit of AMP kinase (PRKAG2) or in the X-linked lysosomal associated membrane protein-2 (LAMP2). With the availability of high-throughput DNA sequencing, one can now test whether genetic variation in genes involved in familial cardiomyopathies contribute to cardiac remodeling that occurs in the general population. This talk will discuss genetic analyses of two cohorts, comprised of either adults or children that demonstrates important roles for variations in these same genes in more prevalent forms of cardiac hypertrophy. High throughput DNA sequencing has also allowed a new strategy to discover the mechanisms by which gene mutations remodel the heart. Use of deep transcriptional profiling approaches to reveal cell and molecular signals triggered by mutations the key molecules involved in hypertrophic growth are being defined, as are potential therapeutic targets that may ultimately abrogate remodeling and improve prognosis in cardiac hypertrophy.