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STAT

An MUSC blog
Date: Aug 28, 2015

Genetic Origin of Mitral Valve ProlapseAs part of a multi-center investigation recently reported in the journals Nature1 and Nature Genetics,2 researchers at the Medical University of South Carolina (MUSC) and Harvard/Massachusetts General Hospital as well as other international institutes have discovered genetic and biological causes for MVP. The investigators identify that MVP can be a result of heritable genetic errors that occur during embryonic cardiac development and progress over the lifespan of affected individuals.

Mitral valve prolapse (MVP) affects 1 in 40 individuals making it one of the most prevalent human diseases. Many individuals with MVP develop potentially life-threatening cardiac arrhythmia and heart failure.

In MVP, one or both flaps of the mitral valve bulge backward into the left atrium causing it to close improperly upon termination of atrial systole. Mitral valve prolapse is often detected as a heart murmur and is usually asymptomatic, but in roughly 10% of cases mitral valve regurgitation intensifies to a clinically severe stage. In severe cases, arrhythmic heartbeats develop, which increases the risk of stroke, heart failure and sudden cardiac death. In fact, the risks are high enough in MVP to make it the leading indication for mitral valve surgery.

In the Nature article,1 investigators used linkage analyses and capture sequencing technology to examine protein-coding genes on chromosome 11 in four members of a large family segregating non-syndromic MVP. They discovered a missense mutation in the DCHS1 gene, which codes for the protein dachsous homolog 1, a member of the calcium-dependent cell-cell adhesion family of cadherins. Another DCHS1 mutation was found in additional families segregating deleterious MVP. Both mutations reduce DCHS1 protein stability in mitral valve interstitial cells (MVICs), a finding corroborated with the discovery of the original mutation in MVICs in a human patient with MVP that underwent mitral valve repair surgery. Dchs1 mutant mice displayed similar pathology, along with scattered migration of MVICs during growth, suggesting that protein stability is essential to maintaining cues for cell polarity during mitral valve development.

In a subsequent manuscript published in Nature Genetics,2 the investigators performed a genome-wide association study (GWAS) to identify genetic variants in a population of  more than 10,000 subjects.  Single nucleotide variants (SNPs) with genome-wide significance were identified in the patient cohorts and genes surrounding these SNPs were functionally evaluated in multiple in vivo models. 

The results from both studies highlight a potential unifying biological cause for MVP in the population.

“We have found a genetic and biological reason for one of the most common diseases affecting the human population," says MUSC researcher Russell A. (Chip) Norris, Ph.D., who was a co-senior author on the studies. "This is a critical initial step as we transform this discovery into new remedial therapies to treat the disease.”  Roger R. Markwald, Ph.D.,  and Andy Wessels, Ph.D. both of the Department of Regenerative Medicine and Cell Biology at MUSC, were also co-authors.

If you are interested in supporting medical research, visit donorscure.org, an MUSC-affiliated 501(c)(3) nonprofit organization that allows you to fund biomedical research projects led by researchers across the United States.

References

1 Durst, et al. Mutations in DCHS1 cause mitral valve prolapse. Nature. 2015 Aug 10 [Epub ahead of print]. Available at http://dx.doi.org/10.1038/nature14670

2 Dina C, et al. Genetic association analyses highlight biological pathways underlying mitral valve prolapse.
Nat Genet. 2015 Aug 24.  [Epub ahead of print] Available at http://dx.doi.org/10.1038/ng.3383.

Photo of veteranA study among military veterans needing psychotherapy for depression has demonstrated that such therapy delivered via telemedicine in patients’ homes achieves outcomes that are not significantly inferior to those of traditional in-person clinical encounters.1 In their editorial in the August 2015 The Lancet Psychiatry, Hoge and Rye describe this study as the kind of rigorous clinical trial that is necessary to establish acceptable standards of care, calling it “a vanguard of demonstration of safety and efficacy of in-home telemental health.”  All research team members were affiliated with the Medical University of South Carolina (MUSC) or the Ralph H. Johnson Veterans Affairs Medical Center in Charleston, SC. The Principal Investigator was Leonard E. Egede, M.D., Professor of Medicine at MUSC, Director of the MUSC Center for Health Disparities Research, and the Director of the Charleston VA HSR&D Health Equity and Rural Outreach Innovation Center. In the 2007 - 2011 study (NCT00324701), 204 veterans aged 58 years and older were treated via either telemedicine or same-room treatment. Their response to the treatments did not differ significantly. The researchers’ interpretation of this data, which is in the same issue of The Lancet Psychiatry2, is that evidence-based psychotherapy delivered to patients in their homes is not only not inferior, it is advantageous because it overcomes distance, attendance, and stigma barriers faced by some veterans. "This is the first study in the elderly that shows that in-home telemedicine works as well as face-to-face sessions for the treatment of depression,” says Egede. “It provides strong evidence for using in-home telemedicine to treat depression and possibly other mental health conditions in those with stigma or mobility challenges, the home-bound, or those who are geographically isolated and cannot get to care easily. In addition, there were no adverse events, which have always been a concern for mental health treatment delivery via telemedicine.”

1 Egede LE, Acierno R, Knapp RG, et al. Psychotherapy for depression in older veterans via telemedicine: a randomized, controlled, open-label, non-inferiority trial. The Lancet Psychiatry 2015; 2(8): 693-701.

2 Hoge, CW, Rye, CB. Efficacy and challenges of in-home telepsychotherapy. The Lancet Psychiatry 2015; 2(8): 668-669.

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