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Abstract 184: Cardioprotective Effects of Brain-derived Neurotrophic Factor rs6265 Polymorphism in Duchenne Cardiomyopathy

We previously identified brain-derived neurotrophic factor (BDNF) as a putative cardiac-specific biomarker for preserved cardiac function in Duchenne Muscular Dystrophy (DMD). BDNF has cardioprotective qualities that may attenuate dilated cardiomyopathy, and a common, functional BDNF single nucleotide polymorphism rs6265 (Val66-Met) may be correlated with increased risk of cardiovascular events. We hypothesized that BDNF is protective in the setting of DMD and that BDNF’s beneficial effects are diminished in rs6265 allelic carriers. We compared circulating BDNF levels with cardiovascular and skeletal muscle functional parameters in DMD patients stratified by carrier status. Positive association of circulating BDNF with left ventricular ejection fraction in DMD patients was restricted to non-carriers of the rs6265 allele, whereas carriers exhibited worse cardiac function with increased BDNF, more fibrosis and worse skeletal muscle function. To more directly assess association of rs6265 with cardiac function, we used mice with knock-in of BDNF polymorphic Val66Met allele. RNASeq showed higher expression of extracellular matrix genes in Val66Met hearts, and there was a negative correlation of cardiac BDNF protein levels with fibrosis. Additionally, there were baseline echocardiographic and ECG differences, and isolated cardiomyocytes had decreased contractility. This overall cardiac phenotype was substantially enhanced when Val66Met mice were crossed with muscular dystrophy mice. Considered together, our results indicate that BDNF plays a protective role in the dystrophic heart and may represent a novel therapeutic candidate for DMD cardiomyopathy.
 
 
