INDIE-HFpEF (Inorganic Nitrite Delivery to Improve Exercise Capacity in Heart Failure With Preserved Ejection Fraction): Rationale and Design

Abstract

Approximately half of patients with heart failure have preserved ejection fraction. There is no proven treatment that improves outcome. The pathophysiology of heart failure with preserved ejection fraction is complex and includes left ventricular systolic and diastolic dysfunction, pulmonary vascular disease, endothelial dysfunction, and peripheral abnormalities. Multiple lines of evidence point to impaired nitric oxide (NO)-cGMP bioavailability as playing a central role in each of these abnormalities. In contrast to traditional organic nitrate therapies, an alternative strategy to restore NO-cGMP signaling is via inorganic nitrite. Inorganic nitrite, previously considered to be an inert byproduct of NO metabolism, functions as an important in vivo reservoir for NO generation, particularly under hypoxic and acidosis conditions. As such, inorganic nitrite becomes most active at times of greater need for NO signaling, as during exercise when left ventricular filling pressures and pulmonary artery pressures increase. Herein, we present the rationale and design for the INDIE-HFpEF trial (Inorganic Nitrite Delivery to Improve Exercise Capacity in Heart Failure with Preserved Ejection Fraction), which is a multicenter, randomized, double-blind, placebo-controlled cross-over study assessing the effect of inhaled inorganic nitrite on peak exercise capacity, conducted in the National Heart, Lung, and Blood Institute-sponsored Heart Failure Clinical Research Network.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02742129.

Keywords: clinical trial; exercise; heart failure; heart failure with preserved ejection fraction; metabolism; nitric oxide.

Figure 1. Pathophysiology of HFpEF

Symptoms of dyspnea and fatigue in HFpEF originate from hemodynamic and metabolic perturbations that are both central and peripheral. Central limitations exist in the heart and great arteries and cause elevation in cardiac filling pressures and limited increases in cardiac output with exertion (decreased convective O₂ conductance). Peripheral limitations exist in the peripheral vasculature and skeletal muscle and lead to impaired O2 delivery (diffusive O₂ conductance) and utilization in the tissues. Tissue/organ-level abnormalities that are present in HFpEF patients that are expected to targeted/ameliorated with nitrite are colored in blue. Afib, atrial fibrillation; LA, left atrial; HR, heart rate; LV, left ventricular; RV, right ventricular.

Figure 2. Hemodynamic effects of nitrite in HFpEF

[A] Acute administration of inhaled and intravenous nitrite leads to reductions in right atrial pressure (RAP), pulmonary capillary wedge pressure (PCWP), and mean pulmonary artery (PA) pressure (mPAP) at rest, with improvement in PA compliance (PAC). [B, C] Reductions in PCWP during exercise are significantly greater because of greater conversion of nitrite to NO during stress. [D] Nitrite administration decreases the slope of the PA pressure-flow relationship, with lower PA pressure for any cardiac output (CO), while improving CO reserve during exercise [E, F], measured by the increase in CO, or the increase in CO relative to total body O2 consumption (ΔCO/ΔVO₂). Figures adapted with permission from references 8 and 13.

Figure 3. INDIE Study Flow Diagram

See text for details. CPET, cardiopulmonary exercise test; ECG, electrocardiogram; KCCQ, Kansas City Cardiomyopathy Questionnaire; AXM, accelerometer; echo, echocardiogram. A follow up phone call (not depicted) will be performed 2 weeks following the final visit to assess for adverse events. *Subjects not tolerating higher dose study drug will continue on low dose for final 3 weeks.

Figure 4. The nebulizer device used for nitrite delivery (Philips I-neb AAD)