PII-084 - PHARMACOGENOMICS OF DILATED CARDIOMYOPATHY: A GENETIC DETERMINANT OF MYOCARDIAL RECOVERY

M. Wang¹, D. Liu², L. Wang^2,3, V. Murthy², D. McNamara⁴, M. Skime², A. Batzler², G. Jenkins², M. Merlo⁵, S. Pileggi⁶, L. Mestroni⁷, F. Pinet⁸, R. Weinshilboum², N. Pereira²; ¹Mayo Clinic, Rochester, MN, USA, ²Mayo Clinic, ³Tianjin first central hospital, Tianjin, China, ⁴University of Pittsburgh, ⁵University of Trieste, ⁶Istituto di Ricerche Farmacologiche Mario Negri, ⁷University of Colorado, ⁸University Lille.

Background: The response to standard pharmacotherapy, with drugs such as beta-blockers, ACE inhibitors and angiotensin 2 receptor blockers, for dilated cardiomyopathy (DCM), a surrogate marker of morbidity and mortality in heart failure (HF), is highly variable, with some patients having little or no response. Pharmacogenomic approaches might provide insight into novel biology of DCM pharmacotherapy.

Methods: A genome-wide association study (GWAS) was performed in 686 patients with recent onset DCM who received standard HF therapy with changes in left ventricular ejection fraction (LVEF) measured by echocardiography as GWAS phenotype. Cultured human cardiac fibroblasts (HCFs) were used as a cellular model to functionally validate GWAS signals that might potentially contribute to myocardial recovery and response to DCM pharmacotherapy.

Results: A single-nucleotide polymorphism (SNP), rs11105445 (G>A), mapping to the neuron navigator 3 (NAV3) gene (p=2.37E-07) was identified by GWAS. The variant SNP allele was associated with improved LVEF and, in independent experiments, was associated with decreased NAV3 transcription in left ventricle tissue (p=0.03). Because the GWAS p value, although suggestive, was not statistically significant, we performed validation functional studies. NAV3 is highly expressed in HCFs rather than in cardiomyocytes, cells which are important pathophysiological contributors to cardiac fibrosis, an independent predictor for myocardial recovery in DCM. We demonstrated that knock-down (KD) of NAV3 in cultured HCFs significantly repressed TGF-beta 1 mediated myofibroblast transdifferentiation, a key step in cardiac fibrosis. In addition, transcriptomic profiling after NAV3 KD suggested that NAV3 mediates HCF differentiation by regulating cell cycle pathways.

Conclusion: NAV3, a GWAS-identified biomarker for response to DCM pharmacotherapy, may negatively affect myocardial recovery, likely due to its roles in regulating HCF transdifferentiation and cardiac fibrosis.