Cardiac Specific Gene Delivery of the Natriuretic Peptide Receptor Improves Diastolic Function in a Canine Model of HFpEF

• Published in: Journal of cardiac failure Vol. 24; no. 8; pp. S35 - S36
• Main Authors: Gladden, James, Guenzel, Adam, Behfar, Atta, Moulay, Gilles, Fayyaz, Ahmed, Chaanine, Antoine, Russell, Stephen, Redfield, Margaret
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.08.2018
• ISSN: 1071-9164; 1532-8414
• DOI: 10.1016/j.cardfail.2018.07.104

Natriuretic peptides stimulate guanylyl cyclase-A (GCA) to produce cGMP. Deficient myocardial cGMP signaling has been implicated in the pathogenesis of diastolic dysfunction and heart failure (HF) with preserved ejection fraction (HFpEF). We hypothesized that cardiac specific over-expression of GCA via gene-delivery with an adeno-associated virus-9 (AAV9-GCA) vector will enhance response to endogenous natriuretic peptides and improve diastolic dysfunction in experimental HFpEF. The HFpEF model included unilateral renal wrapping (RW) to induce hypertension plus DOCA-salt exposure in aged beagles. Trans-catheter (C-cath®) endocardial injections (≈ 14 per dog) of AAV9-GCA or placebo were performed 2 weeks prior to RW. HFpEF+Placebo (n=8) and HFpEF+AAV9-GCA (n=8) underwent echo and invasive pressure-volume analysis at 11 weeks post-RW. Aged Control (n=6) dogs (no RW) were also studied. In HFpEF dogs, systemic blood pressure (BP) was monitored weekly with an implanted CardioMEMS sensor. All dogs underwent a bio-assay to exclude anti-AAV9 antibodies prior to treatment. At end study, as compared to Control dogs, HFpEF+Placebo dogs had higher EF (67% vs 63%, p=0.03), relative wall thickness (RWT; 0.55 vs 0.47, p<0.01) and diastolic stiffness constant (0.17 vs 0.06, p<0.01). In HFpEF dogs, systolic and diastolic BP elevations over the course of the study were similar in AAV9-GCA and placebo treated dogs. Western blot analysis confirmed myocardial expression of GCA in all AAV9-GCA treated animals whereas myocardial GCA expression was not detectable by Western blot in Control or HFpEF+Placebo. At end study, as compared to HFpEF+placebo, AAV9-GCA treated HFpEF dogs had similar EF (67% vs 67%, p=0.76) and RWT (0.48 vs 0.55, p=0.19) but lower diastolic stiffness constant (0.10 vs 0.17, p=0.04). Catheter based, cardiac specific gene delivery of GCA in experimental HFpEF was feasible, resulted in persistent GCA over-expression at 13 weeks post-delivery and was associated with improved LV diastolic stiffness.