172. B-Type Natriuretic Peptide Gene Therapy as a Novel Early Treatment for Familial Hypertrophic Cardiomyopathy

Abstract

Hypertrophic cardiomyopathy (HCM) is the most common familial cardiomyopathy, with the prevalence between 0.2 to 0.5%. HCM presents as an increase in left ventricular mass with thickening of the interventricular septum (IVS), myocellular disarray, interstitial fibrosis, heart rhythm abnormalities, and sudden death, necessitating therapeutic intervention. HCM is commonly caused by mutations in genes MYH7, MYBPC3, TNNT2, and TNNI3.The cardiac hormone, B-type natriuretic peptide (BNP) is a guanylyl cyclase A (GC-A) agonist. Physiological effects of BNP include natriuresis, vasodilation and blood pressure-lowering action. Additionally, BNP shows direct cardioprotective properties including anti-hypertrophic and anti-fibrotic effects, independently of its anti-hypertensive effects. We have recently found that genetic BNP ablation results in progressive cardiac hypertrophy with upregulation in HCM-associated genes in rats. In the current study, we tested the hypothesis that sustained BNP treatment with novel gene delivery of BNP may preserve cardiac function and structure in HCM in a mouse model of HCM.We used transgenic HCM mice expressing a mutated α-myosin heavy chain. Adeno-associated virus serotype 9 (AAV9) vectors were utilized to exploit their natural myocardial tropism. Three groups of mice were treated via tail-vein injections at four weeks of age (week one of study); Group 1, No HCM control (C57bl/6, no transgenic α-myosin heavy chain, n=6); Group 2, Untreated HCM mice with transgenic α-myosin heavy chain (PBS treated, n=10); Group 3, AAV9-BNP vector-treated HCM mice (n=6). To observe therapeutic benefit we assayed non-invasive blood pressure, myocardial architecture and remodeling (echocardiography), exercise capacity (treadmills), and any cardiorenal interplay through renal parameters. At 6, 9, 12, 15 and 25 weeks after AAV vector administration, left ventricular mass by echo was significantly higher in the untreated HCM group than the AAV-BNP-treated HCM and wildtype C57bl/6 mice. Significant increases in IVS and posterior wall thickness were also observed in control HCM group. At 11, 19, and 25 weeks after AAV vector administration, exercise capacity, monitored by treadmill tolerance, was significantly lower in the control HCM group than the AAV-BNP-treated HCM mice. No significant changes were seen in urine outputs. HCMAAV9-BNP treated mice showed a trend towards a lower blood pressure than both C57bl/6 and HCM mice.Our data demonstrate that AAV9-mediated BNP over-expression blocks progressive left ventricular enlargement and improves exercise capacity in a mouse model of HCM. The present study supports the BNP/GC-A/cGMP axis as a novel therapeutic target for the treatment of HCM.