Location: Exhibit/Poster Hall A-B - Pennsylvania Convention Center
Poster Board Number: E57
Kashyap Koul (LSU Health Science Center-New Orleans ), Kyle LaPenna (LSU Health Science Center-New Orleans ), Zhen Li (LSU Health Science Center-New Orleans ), Jake Doiron (LSU Health Science Center-New Orleans ), John Wang (LSU Health Science Center-New Orleans ), Thomas Sharp III (LSU Health Science Center-New Orleans ), David Lefer (LSU Health Science Center-New Orleans )
Presenting Author LSU Health Science Center-New Orleans
Introduction: Nitric oxide (NO) based therapeutics have proven to exert cardioprotective actions in the setting of heart failure with reduced ejection fraction (HFrEF). However, NO therapy has failed to exert beneficial effects in clinical studies of heart failure with preserved ejection fraction (HFpEF).
We investigated (1) the effects of the NO donor, sodium nitrite, as a monotherapy, (2) hydralazine monotherapy, a known vasodilator and antioxidant, and (3) combination therapy with both drugs in a murine model of HFpEF. We assessed left ventricular (LV) function, oxidative/nitrosative stress, exercise tolerance, and cardiac fibrosis.
Materials and
Methods: Male, C57/BL6N (n=15 per group) were placed on a Western high fat diet (60% kCal from fat) and treated with L-NG-Nitro arginine methyl ester (L-NAME, 0.5 g/L/day) in the drinking water beginning at 10 weeks of age. At 15 weeks of age, mice were randomly assigned to four separate groups for five additional weeks: HFpEF control, sodium nitrite in drinking water (75 mg/L), hydralazine (2 mg/kg/day, i.p., b.i.d.), or the combination of sodium nitrite and hydralazine.
Plasma was collected to measure circulating 8-isoprostane and 3-nitrotyrosine levels, biomarkers of oxidative and nitrosative stress respectively. In addition, cardiac tissue was harvested at 20 weeks for Masson’s Trichrome staining and to measure cardiac nitrite levels. Echocardiography and exercise tolerance testing was performed at 10, 15, and 20 weeks of age.
Results: There was a significant increase in circulating nitrite levels (p lt; 0.05) in the sodium nitrite + hydralazine group compared to the control and either monotherapy groups. There was no significant difference in the cardiac tissue nitrite levels between the combination therapy and the control group. Plasma 8-isoprostane and 3-nitrotyrosine levels were significantly (p lt; 0.05) reduced in the sodium nitrite + hydralazine group compared to the HFpEF control group, indicating a reduction in oxidative and nitrosative stress. Although there was no significant difference in the extent of interstitial cardiac fibrosis between groups, there was a significant decrease (p lt; 0.05) in myocardial perivascular fibrosis in the sodium nitrite + hydralazine group compared to control. Left ventricular end-diastolic pressure (LVEDP) was significantly reduced in all treatment groups, and LVEDP was reduced to the greatest extent in the nitrite + hydralazine group vs. HFpEF control. Furthermore, we observed a significant (p lt; 0.01) improvement in LV diastolic function (i.e., E/e’) in the sodium nitrite and hydralazine group that was superior to either of the treatments alone. There was no significant difference in the exercise distance or duration among the various groups.
Conclusion: These data demonstrate that the combination of a powerful antioxidant with NO donor therapy significantly enhances the beneficial effects NO therapy in the setting of severe HFpEF.
