Acute hemodynamic effects of inhaled sodium nitrite in pulmonary hypertension associated with heart failure with preserved ejection fraction

Abstract

Background: Pulmonary hypertension (PH) is associated with poor outcomes, yet specific treatments only exist for a small subset of patients. The most common form of PH is that associated with left heart disease (Group 2), for which there is no approved therapy. Nitrite has shown efficacy in preclinical animal models of Group 1 and 2 PH, as well as in patients with left heart failure with preserved ejection fraction (HFpEF). We evaluated the safety and efficacy of a potentially novel inhaled formulation of nitrite in PH-HFpEF patients as compared with Group 1 and 3 PH.

Methods: Cardiopulmonary hemodynamics were recorded after acute administration of inhaled nitrite at 2 doses, 45 and 90 mg. Safety endpoints included change in systemic blood pressure and methemoglobin levels. Responses were also compared with those administered inhaled nitric oxide.

Results: Thirty-six patients were enrolled (10 PH-HFpEF, 20 Group 1 pulmonary arterial hypertension patients on background PH-specific therapy, and 6 Group 3 PH). Drug administration was well tolerated. Nitrite inhalation significantly lowered pulmonary, right atrial, and pulmonary capillary wedge pressures, most pronounced in patients with PH-HFpEF. There was a modest decrease in cardiac output and systemic blood pressure. Pulmonary vascular resistance decreased only in Group 3 PH patients. There was substantial increase in pulmonary artery compliance, most pronounced in patients with PH-HFpEF.

Conclusions: Inhaled nitrite is safe in PH patients and may be efficacious in PH-HFpEF and Group 3 PH primarily via improvements in left and right ventricular filling pressures and pulmonary artery compliance. The lack of change in pulmonary vascular resistance likely may limit efficacy for Group 1 patients.

Trial registration: ClinicalTrials.gov NCT01431313 FUNDING. This work was supported in part by the NIH grants P01HL103455 (to MAS and MTG), R01HL098032 (to MTG), and R01HL096973 (to MTG), and Mast Therapeutics, Inc.

Conflict of interest statement

M.A. Simon has received consultancy fees from United Therapeutics and Gilead. E.L. Parsley is an employee of Mast Therapeutics, Inc. M.T. Gladwin is a coinventor of awarded patent (number 9,387,224) for nitrite therapy for cardiovascular indications. M.T. Gladwin receives sponsored research support for the inhaled nitrite clinical trial (note: M.T.G. does not receive consulting fees from Mast Therapeutics).

Figures

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.

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 nitric oxide (iNO) or nitrite compared with baseline; ‡P < 0.05 for effect of nitrite compared with effect of iNO, all by Hausman specification test.

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; ‡P < 0.05 for effect of nitrite compared with effect of iNO, all by Hausman specification test.

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; ‡P < 0.05 for effect of nitrite compared with effect of iNO, all by Hausman specification test.

Figure 5. Resistance-compliance relationship at baseline and after aerosolized sodium nitrite.

Data were fit to an inverse hyperbolic model with the following equations, in which C is pulmonary artery compliance and R is pulmonary vascular resistance: PH-HFpEF baseline, C = 0.59/(0.03 + R), r2 = 0.44; PH-HFpEF nitrite, C = 0.99/(0.03 + R), r2 = 0.25; Group 1 PAH baseline, C = 0.81/(0.10 + R), r2 = 0.61; Group 1 PAH nitrite, C = 1.18/(0.21 + R), r2 = 0.49; Group 3 PH baseline, C = 0.63/(0.04 + R), r2 = 0.71; Group 3 PH nitrite, C = 0.88/(0.09 + R), r2 = 0.69. The resistance-compliance relationship was not significantly altered in any group, although there was a trend in PH-HFpEF (P = 0.14; Group 1 P = 0.22; Group 3 P = 0.27; extra sum-of-squares F test). PH-HFpEF, pulmonary hypertension associated with heart failure with preserved ejection fraction; PAH, pulmonary arterial hypertension; PH, pulmonary hypertension; PA, pulmonary artery; PVR, pulmonary vascular resistance.

Figure 6. Protocol design.

Baseline hemodynamics (baseline 1) were initially recorded followed by administration of inhaled nitric oxide (iNO) for 10 minutes, at which time hemodynamics were recorded again. NO was then turned off, allowed to wear off for 10 minutes, and then baseline hemodynamics (baseline 2) were recorded. Next, aerosolized sodium nitrite was administered at the first dose of 45 mg (dose 1). Hemodynamics were recorded 15 minutes after completion of the inhaled dose, and then at 30, 45, and 60 minutes after completion of dose 1. Dose 2 (90 mg) of aerosolized sodium nitrite was administered next. Hemodynamics were recorded 15 minutes after completion of the inhaled dose, and then at 30, 45, and 60 minutes after completion of dose 2.