1. Genetics and pathophysiology of ARVD
ARVD Heart: This heart was removed at the time of cardiac
transplantation. Note the massive enlargement of the right
ventricle, near absence of RV lateral wall myocytes, and subtle
fibrofatty scar beginning to develop in the left ventricle.
Arrhythmogenic Right Ventricular Dysplasia (ARVD) is an inherited form of right ventricular cardiomyopathy characterized by fibrofatty scar formation in the heart. It is one of the most common causes of sudden cardiac death, particularly in athletes. It is typically caused by desmosome mutations. The process by which desmosome gene mutations lead to this right ventricular form of cardiomyopathy is not well understood. My laboratory is investigating both known and novel genes for mutations that cause ARVD, correlating it closely with phenotypic data in the large Johns Hopkins ARVD program, and pursuing additional genetic and environmental factors that lead to this and other more common forms of cardiac arrhythmia. We are developing a murine model of ARVD to investigate the pathophysiology of this condition, as well as therapeutic strategies to prevent or improve this condition.
2. Mitral Valve Disease: From Genetic Mechanisms to Improved Repair
Mitral valves with Fbn1 mutation: Valves with 2 Fbn1 mutations (-/-) are longer
and thicker than those with 1 mutation (+/-) and compared to wild type (+/+)
Mitral valve disease, including myxomatous thickening, prolapse, and insufficiency, is present in approximately 2% of the US population. Rare cases are associated with specific disorders, such as Marfan syndrome or X-linked MVP, though the genetic factors contributing to the majority of cases remain unknown. As part of an international collaboration, we are investigating mitral valve disease associated with mutations in fibrillin-1, developing valve-specific expression of modulating factors, and investigating the valve phenotype in hypertrophic cardiomyopathy.
3. Additional investigation of inherited cardiomyopathies
Nuclei with LMNA mutation: Blue (DAPI) signifies nuclei and green
(FITC) corresponds to lamin A.
Mutations in LMNA, encoding the nuclear envelope isoforms lamin A/C, result in a wide range of phenotypes including isolated dilated cardiomyopathy, muscular dystrophy, and features of premature aging. We have developed an allelic series of cultured dermal fibroblast cell lines from patients with LMNA mutations in order to investigate the causes and possible treatments of laminopathies. In addition, we are pursuing novel treatments for familial transthyretin amyloidosis, a systemic disorder with prominent cardiac features.