Acute Effects of Inorganic Nitrite on Cardiovascular Hemodynamics in Heart Failure With Preserved Ejection Fraction

Phase 2

Completed

Conditions: Heart Disease
Exercise Intolerance
Heart Failure With Preserved Ejection Fraction
Pulmonary Hypertension

Interventions: Drug: Saline Placebo for Nitrite
Drug: Nitrite

Registration Number: NCT01932606

Lead Sponsor: Barry Borlaug

Brief Summary: Heart failure with preserved ejection fraction (HFpEF) is a major public health problem that has no proven effective treatment. This study assessed the effects of acute nitrite administration on resting and exercise hemodynamics in patients with HFpEF.

Detailed Description: Subjects were studied on their long-term medications in the post-absorptive state and supine position. Right heart catheterization was performed with simultaneous expired gas analysis at rest and during supine exercise at a 20 Watts workload for 5 minutes. After the first exercise phase (before any drug administration) and after return to steady-state baseline hemodynamic values, subjects were randomized. Study drug or placebo was infused for 5 minutes. After a 10 minute observation period, hemodynamic measurements were repeated at rest, followed by repeat supine exercise at a 20 Watts workload for 5 minutes, identical to the study's first phase. Arterial and venous blood samples and hemodynamic and expired gas data were acquired during each stage of the protocol.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 28

Inclusion Criteria

Scheduled to undergo a cardiac catheterization procedure.
Clinical symptoms of shortness of breath and fatigue
Normal left ventricular ejection fraction (≥50%)
Elevated left ventricular filling pressures at cardiac catheterization (defined as resting pulmonary capillary wedge pressure (PCWP)>15 mmHg and/or PCWP≥25 mmHg during exercise)

Exclusion Criteria

Systolic BP <120 mmHg
Prior nitrate therapy (within previous 2 weeks)
Glucose 6-phosphate dehydrogenase (G6PD) deficiency
Other "non-HFpEF" specific causes of heart failure such as significant valvular disease (>moderate left-sided regurgitation, >mild stenosis), severe pulmonary disease, unstable coronary disease or coronary spasm, primary renal or hepatic disease, constrictive pericarditis, or infiltrative, restrictive, or hypertrophic cardiomyopathies

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Saline	Saline Placebo for Nitrite	Saline Placebo for Nitrite will be infused for 5 minutes during the cardiac catheterization procedure.
Nitrite	Nitrite	Study drug (NaNO_2 50 mcg/kg/min) will be infused for 5 minutes during the cardiac catheterization procedure.

Primary Outcome Measures

Name	Time	Method
Exercise Pulmonary Capillary Wedge Pressure (PCWP)	during repeat exercise run, approximately 30 minutes after study drug administration	Pulmonary capillary wedge pressure (PCWP) provides an indirect estimate of left atrial pressure (LAP). PCWP is the pressure measured by wedging a pulmonary catheter with an inflated balloon into a small pulmonary arterial branch.

Secondary Outcome Measures

Name	Time	Method
Change in Central Pressures After Study Drug (Resting)	baseline, approximately 30 minutes after study drug administration	Values are resting values after receiving study drug minus resting values before study drug (on the same day.)
Change in Heart Rate After Study Drug (Resting)	baseline, approximately 30 minutes after study drug administration	Values are resting values after receiving study drug minus resting values before study drug (on the same day.)
Change in Blood Pressure After Study Drug (Resting)	baseline, approximately 30 minutes after study drug administration	Values are resting values after receiving study drug minus resting values before study drug (on the same day.)
Change in Pulmonary Vascular Resistance (PVR) After Study Drug (Resting)	baseline, approximately 30 minutes after study drug administration	Values are resting values after receiving study drug minus resting values before study drug (on the same day.) Pulmonary Vascular Resistance (PVR) is the resistance to flow that must be overcome to push blood through the pulmonary vasculature. Acute and chronic lung disease can both cause an increase in PVR. Chronic PVR can lead to right sided heart failure.
Change in Pulmonary Artery (PA) Compliance After Study Drug (Resting)	baseline, approximately 30 minutes after study drug administration	Values are resting values after receiving study drug minus resting values before study drug (on the same day.) Pulmonary artery compliance is an index of the elasticity of the blood vessel, an indication of arterial stiffness.
Change in Systemic Vascular Resistance (SVR) After Study Drug (Resting)	baseline, approximately 30 minutes after study drug administration	Values are resting values after receiving study drug minus resting values before study drug (on the same day.) Systemic vascular resistance (SVR) refers to the resistance to blood flow offered by all of the systemic vasculature, excluding the pulmonary vasculature.
Change in Left Ventricular Stroke Work (LVSW) After Study Drug (Resting)	baseline, approximately 30 minutes after study drug administration	Values are resting values after receiving study drug minus resting values before study drug (on the same day.) Stroke work refers to the work done by the ventricle to eject a volume of blood (i.e., stroke volume) into the aorta. Ventricular stroke work can be estimated as the product of stroke volume and mean aortic pressure during ejection.
Change in Oxygen Consumption (VO_2) After Study Drug (Resting)	baseline, approximately 30 minutes after study drug administration	Values are resting values after receiving study drug minus resting values before study drug (on the same day.)
Change in Arteriovenous Oxygen Content Difference After Study Drug (Resting)	baseline, approximately 30 minutes after study drug administration	Values are resting values after receiving study drug minus resting values before study drug (on the same day.) Arteriovenous oxygen difference is the difference in the oxygen content of the blood between the arterial blood and the venous blood. It is an indication of how much oxygen is removed from the blood in capillaries as the blood circulates in the body.
Change in Cardiac Output After Study Drug (Resting)	baseline, approximately 30 minutes after study drug administration	Values are resting values after receiving study drug minus resting values before study drug (on the same day.) The volume of blood pumped per minute by each ventricle of the heart. Cardiac output is equal to the stroke volume (the amount of blood pumped from a ventricle in a single heartbeat) times the heart rate.
Change in Stroke Volume After Study Drug (Resting)	baseline, approximately 30 minutes after study drug administration	Values are resting values after receiving study drug minus resting values before study drug (on the same day.) Stroke volume is the amount of blood pumped out of the heart (left ventricle - to the body) during each contraction.
Change in Central Pressures After Study Drug (Exercise)	baseline, approximately 30 minutes after study drug administration	Values are exercise values after receiving study drug minus exercise values before study drug (on the same day.)
Change in Heart Rate After Study Drug (Exercise)	baseline, approximately 30 minutes after study drug administration	Values are exercise values after receiving study drug minus exercise values before study drug (on the same day.)
Change in Blood Pressure After Study Drug (Exercise)	baseline, approximately 30 minutes after study drug administration	Values are exercise values after receiving study drug minus exercise values before study drug (on the same day.)
Change in PVR After Study Drug (Exercise)	baseline, approximately 30 minutes after study drug administration	Values are exercise values after receiving study drug minus exercise values before study drug (on the same day.) Pulmonary Vascular Resistance (PVR) is the resistance to flow that must be overcome to push blood through the pulmonary vasculature. Acute and chronic lung disease can both cause an increase in PVR. Chronic PVR can lead to right sided heart failure.
Change in PA Compliance After Study Drug (Exercise)	baseline, approximately 30 minutes after study drug administration	Values are exercise values after receiving study drug minus exercise values before study drug (on the same day.) Pulmonary artery compliance is an index of the elasticity of the blood vessel, an indication of arterial stiffness.
Change in SVR After Study Drug (Exercise)	baseline, approximately 30 minutes after study drug administration	Values are exercise values after receiving study drug minus exercise values before study drug (on the same day.) Systemic vascular resistance (SVR) refers to the resistance to blood flow offered by all of the systemic vasculature, excluding the pulmonary vasculature.
Change in LVSW After Study Drug (Exercise)	baseline, approximately 30 minutes after study drug administration	Values are exercise values after receiving study drug minus exercise values before study drug (on the same day.) Stroke work refers to the work done by the ventricle to eject a volume of blood (i.e., stroke volume) into the aorta. Ventricular stroke work can be estimated as the product of stroke volume and mean aortic pressure during ejection.
Change in Oxygen Consumption (VO_2) After Study Drug (Exercise)	baseline, approximately 30 minutes after study drug administration	Values are exercise values after receiving study drug minus exercise values before study drug (on the same day.)
Change in Arteriovenous Oxygen Difference After Study Drug (Exercise)	baseline, approximately 30 minutes after study drug administration	Arteriovenous oxygen difference is the difference in the oxygen content of the blood between the arterial blood and the venous blood. It is an indication of how much oxygen is removed from the blood in capillaries as the blood circulates in the body.
Change in Cardiac Output After Study Drug (Exercise)	baseline, approximately 30 minutes after study drug administration	Values are exercise values after receiving study drug minus exercise values before study drug (on the same day.) Cardiac output is equal to the stroke volume (the amount of blood pumped from a ventricle in a single heartbeat) times the heart rate.
Change in Stroke Volume After Study Drug (Exercise)	baseline, approximately 30 minutes after study drug administration	Values are exercise values after receiving study drug minus exercise values before study drug (on the same day.) Stroke volume is the amount of blood pumped out of the heart (left ventricle - to the body) during each contraction.