Safety of inhaled sodium nitrite. Ten patients with PH-HFpEF, 20 patients with Group 1 PAH, and 6 patients with Group 3 PH were studied (Figure 1). Clinical characteristics are presented in Table 1, baseline echocardiographic data in Table 2, and baseline hemodynamics in Table 3 and Supplemental Table 1. The safety stopping criteria consisted of the following: decrease in systemic systolic blood pressure greater than 40 mmHg, decrease in peripheral oxygen saturation greater than 10%, methemoglobin level greater than 5%, and severe bronchospasm or dyspnea. Drug administration appeared to be well tolerated in all patients, even in Group 1 patients on extensive background vasodilator therapy (Table 1). One patient (PH-HFpEF) did not receive the second dose of 90 mg due to an asymptomatic transient decrease in systemic systolic blood pressure that met the prospectively defined stopping criteria but returned to baseline within 5 minutes without intervention. A second patient with Group 2 PH-HFpEF did not receive the second dose of 90 mg due to musculoskeletal back pain during the case and was unable to continue through to the end of the protocol. There were no significant decreases in peripheral oxygen saturation nor increases in methemoglobin levels above the stopping criteria of 5%. The only side effect reported during drug administration was an occasional, self-limited cough that required no intervention.

Figure 1 Screening and enrollment flow chart. PH, pulmonary hypertension; PH-HFpEF, pulmonary hypertension associated with heart failure with preserved ejection fraction; PAH, pulmonary arterial hypertension.

Table 1 Clinical characteristics of the cohorts

Table 2 Baseline echocardiographic data of the cohorts

Table 3 Baseline hemodynamics of the cohorts

Hemodynamic effects on inhaled nitrite in patients with PH-HFpEF. In the 10 patients enrolled with PH-HFpEF, acute administration of inhaled sodium nitrite resulted in significant overall decreases in right atrial pressure, pulmonary capillary wedge pressure, right ventricular systolic and diastolic, and pulmonary artery systolic, diastolic, and mean pressures (Figure 2, and Supplemental Table 2. Of note, by the primary mixed-effect model analysis, pulmonary capillary wedge pressure and mean pulmonary artery pressure markedly decreased by 7.5 mmHg (95% CI –9.0 to –6.0) and 7.9 mmHg (95% CI –9.4 to –6.3), respectively (baseline median values 18 and 34 mmHg, respectively). With significant lowering of all pressures, there was no significant change in transpulmonary gradient and a modest but significant increase in pulmonary vascular resistance (PVR). Cardiac index decreased slightly but significantly (–0.2 l/min/m2, 95% CI –0.3 to –0.07, P = 0.003) as did mean arterial pressure (–5.4 mmHg, 95% CI –9.6 to –1.1, P = 0.013), although there was no significant increase in heart rate; systemic vascular resistance very modestly increased (+0.10 mmHg/l/min, 95% CI +0.03 to +0.18; P = 0.008), probably related to the decrease in cardiac output, and there was no change in systemic arterial compliance. Pulmonary artery compliance (Cpa) increased by 35% (+0.97 ml/mmHg, 95% CI +0.25 to +1.68; P = 0.008).

Figure 2 Effect of inhaled nitric oxide and aerosolized sodium nitrite on PH-HFpEF patients. mPAP, mean pulmonary artery pressure; PA, pulmonary artery; PCWP, pulmonary capillary wedge pressure; PH-HFpEF, pulmonary hypertension associated with heart failure with preserved ejection fraction; PVR, pulmonary vascular resistance. *P < 0.05 for effect of inhaled NO (iNO) or nitrite compared to baseline (mixed-effects model); ‡P < 0.05 for effect of nitrite compared to effect of inhaled NO (Hausman specification test).

Further analysis of the dose effect of nitrite (45 mg vs. 90 mg dose) found that most hemodynamics were affected in a dose-dependent manner, with the exception of Cpa. There was a significant dose effect of inhaled sodium nitrite on right atrial pressure (–6.1 and –8.1 mmHg with 45 and 90 mg doses, respectively, P < 0.001), mean pulmonary artery pressure (–7.6 and 8.2 mmHg with 45 and 90 mg doses, respectively, P < 0.001), and pulmonary capillary wedge pressure (–6.9 and –8.4 mmHg with 45 and 90 mg doses, respectively, P < 0.001; Supplemental Table 3). Cardiac index decreased in a dose-dependent manner (–0.2 and –0.3 l/min/m2 with 45 and 90 mg doses, respectively, P < 0.001). The increase in Cpa was not dose related. Inhaled sodium nitrite did have a dose-dependent effect on mean arterial pressure (–3.8 and –7.6 mmHg with 45 and 90 mg doses, respectively, P < 0.001)

Hemodynamic effects on inhaled nitrite in patients with Group 1 PAH. Inhaled sodium nitrite had an overall significant effect in lowering right atrial pressure, pulmonary capillary wedge pressure, right ventricular diastolic, and pulmonary arterial systolic pressures (Figure 3; detailed in Supplemental Table 2). There was no significant effect on the transpulmonary gradient, cardiac index, heart rate, or systemic vascular resistance. There was a modest but significant increase in the PVR, secondary to symmetric decreases in both the mean pulmonary artery pressure and pulmonary capillary wedge pressure, with no change in cardiac output. There was no significant change in Cpa or peripheral oxygen saturation. A decrease in systemic blood pressures (–5.1 mmHg mean arterial pressure, 95% CI –7.6 to –2.6, P < 0.001) was observed.

Figure 3 Effect of inhaled nitric oxide (iNO) and aerosolized sodium nitrite on Group 1 PAH patients. mPAP, mean pulmonary artery pressure; PA, pulmonary artery; PAH, pulmonary arterial hypertension; PCWP, pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance. *P < 0.05 for effect of iNO or nitrite compared with baseline (mixed-effects model); ‡P < 0.05 for effect of nitrite compared to effect of inhaled NO (Hausman specification test).

Analysis of the dose effect of nitrite (45 mg vs. 90 mg) revealed a significant dose-related decrease in right atrial pressure (–1.9 and –2.5 mmHg with 45 and 90 mg doses, respectively, P < 0.001) and pulmonary capillary wedge pressure (–2.0 and –2.9 mmHg with 45 and 90 mg doses, respectively, P < 0.001, Supplemental Table 3). There was a modest but significant dose-related increase in transpulmonary gradient (+1.3 and +2.3 mmHg with 45 and 90 mg doses, respectively, P = 0.008) and PVR (+0.09 and +0.1 Woods units with 45 and 90 mg doses, respectively, P = 0.002), as well as dose-related decrease in mean arterial pressure (–4.6 and –5.6 mmHg with 45 and 90 mg doses, respectively, P < 0.001).

Hemodynamic effects on inhaled nitrite in patients with Group 3 PH. In 6 patients enrolled with Group 3 PH (PH due to lung disease and/or hypoxia), inhaled nitrite caused an acute decrease in right atrial pressure, pulmonary capillary wedge pressure, right ventricular systolic, pulmonary artery systolic, diastolic, and mean pressures (Figure 4 and Supplemental Table 2). There was a modest but significant decrease in PVR. There was no overall change in cardiac index. Cpa significantly increased (+0.39 ml/mmHg, 95% CI +0.11 to +0.67; P = 0.006). There was a significant decrease in mean arterial pressure (–7.5 mmHg in mean arterial pressure, 95% CI –11.0 to –4.0; P < 0.001) and systemic vascular resistance, with an increase in systemic arterial compliance (+0.35 ml/mmHg, 95% CI +0.13 to +0.58; P = 0.002) but no change in heart rate or peripheral oxygen saturation.

Figure 4 Effect of inhaled nitric oxide (iNO) and aerosolized sodium nitrite on Group 3 PH patients. mPAP, mean pulmonary artery pressure; PA, pulmonary artery; PH, pulmonary hypertension; PCWP, pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance. *P < 0.05 for effect of iNO or nitrite compared with baseline (mixed-effects model); ‡P < 0.05 for effect of nitrite compared to effect of inhaled NO (Hausman specification test).

A significant dose effect of nitrite (45 mg vs. 90 mg) was noted for right atrial pressure (–1.3 and –2.7 mmHg with 45 and 90 mg doses, respectively, P < 0.001), pulmonary capillary wedge pressure (–3.1 and –5.7 mmHg with 45 and 90 mg doses, respectively, P < 0.001), right ventricular (–1.9 and –4.8 mmHg with 45 and 90 mg doses, respectively, P = 0.003) and pulmonary artery diastolic (–3.8 and –5.1 mmHg with 45 and 90 mg doses, respectively, P < 0.001) and mean pressures (–4.4 and –5.3 mmHg with 45 and 90 mg doses, respectively, P < 0.001, Supplemental Table 3). There was a dose-related increase in cardiac index (+0.1 and +0.4 l/min/m2 with 45 and 90 mg doses, respectively, P = 0.002), but no dose-related effect on PVR. Cpa increased in a dose-dependent manner (+0.36 and +0.43 ml/mmHg, with 45 and 90 mg doses, respectively, P = 0.006). The decrease in mean arterial pressure was also dose related (–7.2 and –7.9 ml/mmHg, with 45 and 90 mg doses, respectively, P = 0.002), as was the increase in methemoglobin levels.

Comparison of effects of inhaled sodium nitrite between different PH groups. The greatest decrease in pulmonary capillary wedge pressure was in PH-HFpEF. Right atrial pressure, pulmonary capillary wedge pressure, right ventricular, and pulmonary artery pressures all decreased more in PH-HFpEF (Supplemental Table 2) as compared with Group 1 PAH patients. There was also a greater effect on pulmonary artery diastolic and mean pressures observed in Group 3 versus Group 1. PH-HFpEF and Group 3 PH had similar decreases in right atrial pressure and pulmonary artery systolic, diastolic, and mean pressures. Cardiac index decreased slightly (<10% of baseline values) in PH-HFpEF and Group 1 PAH patients but not in Group 3. PVR only decreased in Group 3. Cpa increased in PH-HFpEF and Group 3 PH but not Group 1 PAH. Changes in systemic blood pressures were similar across all groups; there were no significant changes in peripheral oxygen saturation.

Comparison of effects of inhaled sodium nitrite with inhaled NO. The effects of nitrite were significantly greater than the effects of inhaled NO (iNO) for lowering right atrial pressure (–8.1 vs. –0.4 mmHg, nitrite and iNO, respectively, P < 0.001) and pulmonary capillary wedge pressure (–7.5 vs. –0.6 mmHg, nitrite and iNO, respectively, P < 0.001), mostly notable for PH-HFpEF (Supplemental Table 4). Mean pulmonary artery pressure was lowered more in PH-HFpEF by inhaled nitrite than iNO (–7.9 vs. –4.3 mmHg, nitrite and iNO, respectively, P < 0.001), while iNO had a greater effect on mean pulmonary artery pressure in Group 1 PAH (–0.9 vs. –5.2 mmHg, nitrite and iNO, respectively, P < 0.001). Transpulmonary gradient was lowered more by iNO in all patients. PVR was decreased more by iNO in PH-HFpEF and Group 1, but lowered similarly to the effect of nitrite in Group 3 patients. Cpa was increased more by nitrite in PH-HFpEF, while iNO increased Cpa more in Group 1, with an equivalent effect in Group 3. Figures 2–4 illustrate the effect of iNO as compared with nitrite in PH-HFpEF, Groups 1 and 3, respectively.

Resistance-compliance relationship. Administration of inhaled nitrite induced a preferential change in Cpa as compared with PVR, most notable in PH-HFpEF and Group 3 PH, but not Group 1 PAH. The change in compliance and not resistance is illustrated by the resistance-compliance curves (Figure 5), in which the data were fit to an inverse hyperbolic curve. There was no difference in the baseline resistance-compliance relationship between patient groups (P = 0.98). There was a trend towards shifting of the resistance-compliance curve up and to the right with administration of inhaled nitrite to patients with PH-HFpEF (Figure 5, P = 0.14).