Abstract 13269: Combination Therapy With Sodium Nitrite and Hydralazine Ameliorates the Severity of Heart Failure With Preserved Ejection Fraction

Background: Recent studies suggest that nitrosative stress resulting from an imbalance in nitric oxide (NO) is the primary driver of heart failure with preserved ejection fraction (HFpEF); however, many of the comorbidities present in HFpEF patients are driven by oxidative stress. Due to the failure of nitric oxide (NO) based therapeutics in HFpEF clinical trials and the role of oxidative stress in each of the different HFpEF comorbidities, we sought to investigate the effects of sodium nitrite (NaNO2) therapy alone or in combination with the antioxidant and peroxynitrite scavenger, hydralazine, in a novel, “two-hit” murine model of HFpEF. Methods: HFpEF was induced in nine-week-old C57/BL6N mice (n = 13-15 per group) by high fat diet and L-NAME (0.5 g/L/day) via drinking water for 10 weeks. At 5 weeks, mice were treated with vehicle, sodium nitrite(75 mg/L) via drinking water, hydralazine (2 mg/kg/day B.I.D., I.P, or a combination of sodium nitrite + hydralazine. Cardiac structure and function via echocardiography and exercise capacity were measured at baseline, week 5 (prior to treatment), and week 10 (final endpoint). At week 10, invasive hemodynamic and in-vitro vascular reactivity studies were performed. Results: Sodium nitrite and hydralazine combination therapy resulted in significant (p < 0.01) improvement inE/E’ that was superior to either therapy alone. Hydralazine as a monotherapy and in combination with NaNO2lowered the E/A ratio compared to NaNO2 monotherapy (p <0.05). Aortic vasorelaxation maximal responses to acetylcholine were significantly improved in all study groups with the greatest improvement observed withNaNO2 + hydralazine. Left ventricular end-diastolic pressure (LVEDP) was significantly (p < 0.01) reduced with either therapy alone, but our data indicate that combination therapy was superior to either drug alone. Conclusion: Our data suggest that antioxidant therapy is required in combination with NO based therapeutics in HFpEF.