Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) affects 1 in 500 people, or an estimated 600,000 people with HCM in the United States alone. HCM is characterized by left ventricular outflow tract obstruction, diastolic dysfunction, myocardial ischemia and arrhythmias. Strikingly, sudden death among athletes is predominantly associated with HCM. Mutations in sarcomeric genes cause HCM, and mutations in MYBPC3, encoding cardiac myosin binding protein C (cMyBP-C), are responsible for one-third of all HCM cases. However, the pathogenic mechanism of the mutation, whether poison polypeptide or haploinsufficiency, is completely unknown. Recently, studies from the PI’s lab have shown that asymptomatic heterozygous MYBPC3 carriers suffer impairments at the myofilament subset levels and that these impairments may presage the onset of HCM, indicating that haploinsufficiency plays a major role in HCM development, aggressive heart failure, and sudden cardiac death.

The PI and his collaborators previously reported a polymorphic HCM-causing mutation, a 25 base pair (bp) deletion, leading to changes in the C’ region (cMyBP-CC10mut). This specific mutation has been estimated to occur in 55 million people and is associated with the development of HCM and an increased risk of heart failure. Since this mutant gene is present in 4% of South Asian people with a high incidence of heart disease, it may represent a genetic marker providing an early warning for potential heart disease in South Asians. South Asians are individuals who derive their ethnic origins from the Indian Subcontinent, which comprises such countries as India, Pakistan, Bangladesh, Sri Lanka, Nepal and Bhutan, collectively speaking some 150 languages and practicing a variety of spiritual traditions. Often overlooked, South Asians have a high risk of heart attack. This increased risk results from a variety of factors that range from genetics to lifestyle choices. In fact, South Asians have a risk for heart disease 4 times greater than the general population. More specifically, South Asian men and women have a 25- 30% increased risk of heart disease when compared to Caucasians and a 325% increased risk when compared to Chinese. A dominant negative effect of cMyBP-CC10mut on the regulation of contraction is suspected. However, the mechanism by which cMyBP-CC10mut causes cardiomyopathy is unclear. The central hypothesis of this study holds that cMyBP-CC10mut causes contractile dysfunction and leads to the development of HCM.

References:

• Kuster DW, Govindan S, Springer TI, Martin JL, Finley NL, Sadayappan S. A hypertrophic cardiomyopathy-associated MYBPC3 mutation common in populations of South Asian descent causes contractile dysfunction. J Biol Chem. 2015 Jan 12. pii: jbc.M114.607911. [Epub ahead of print]

• Barefield D, Kumar M, Gorham J, Seidman JG, Seidman CE, de Tombe PP, Sadayappan S. Haploinsufficiency of MYBPC3 exacerbates the development of hypertrophic cardiomyopathy in heterozygous mice. J Mol Cell Cardiol. 2015 Feb;79:234-43 (*Accompanied with an editorial article).

• Barefield D, Kumar M, de Tombe PP, Sadayappan S. Contractile dysfunction in a mouse model expressing a heterozygous MYBPC3 mutation associated with hypertrophic cardiomyopathy. Am J Physiol Heart Circ Physiol. 2014 Mar;306(6):H807-15.