Systematic review and meta-analysis of nitrates/nitrites in patients with heart failure or pulmonary hypertension

Heart failure (HF) and pulmonary hypertension (PH) are prevalent cardiovascular diseases that often coexist and share common pathophysiological mechanisms, particularly dysregulation of nitric oxide metabolism, yet their clinical efficacy has been inconsistent.

We systematically searched databases including PubMed, Web of Science, Embase, and the Cochrane Library for studies published over the past 15 years assessing nitrate/nitrite effects on cardiac function, hemodynamics, and exercise capacity in HF or PH patients. Data were analyzed using a random-effects model, with results as mean differences (MD) and 95% confidence intervals (CI). PROSPERO registration: CRD42024614911.

14 trials (n = 469) involving HF, PH, or pulmonary hypertension due to left heart disease (PH-LHD) were included. During exercise, nitrates significantly improved cardiac function in HF/PH-LHD patients, increasing stroke volume by 0.86 mL (95% CI 0.35 to 1.36; P < 0.05) and cardiac output by 0.57 L/min (95% CI 0.12 to 1.02; P < 0.05). At rest, nitrates reduced hemodynamic parameters in HF/PH patients: systolic blood pressure  ,SBP (- 0.36 mmHg; 95% CI - 0.53 to - 0.18; P < 0.05), diastolic blood pressure, DBP (- 0.19 mmHg; 95% CI - 0.37 to - 0.01; P < 0.05), and right atrial pressure, RAP (- 0.70 mmHg; 95% CI - 1.35 to - 0.05; P < 0.05). These effects were attenuated during exercise. Neither administration methods, exercise intensity, nor ejection fraction significantly influenced hemodynamic improvements. Nitrates did not significantly improve oxygen consumption at rest (- 0.17 mL/min; 95% CI - 0.56 to 0.21; P = 0.65) or during exercise (0.25 mL/kg/min; 95% CI - 0.04 to 0.54; P = 0.10).

Nitrate/nitrite therapy improves cardiopulmonary hemodynamics at rest and enhances cardiac function during exercise in HF and PH patients, though the drug-related benefits appear more limited. These hemodynamic improvements occur consistently regardless of exercise intensity or baseline ejection fraction. The dissociation between hemodynamic and functional measures suggests nitrate medications may be particularly valuable for addressing resting hemodynamic overload in this population.