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

Primary Purpose

Heart Disease, Heart Failure With Preserved Ejection Fraction, Exercise Intolerance

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Nitrite
Saline Placebo for Nitrite
Sponsored by
Barry Borlaug
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Heart Disease

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Mayo Clinic in Rochester

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Nitrite

Saline

Arm Description

Study drug (NaNO_2 50 mcg/kg/min) will be infused for 5 minutes during the cardiac catheterization procedure.

Saline Placebo for Nitrite will be infused for 5 minutes during the cardiac catheterization procedure.

Outcomes

Primary Outcome Measures

Exercise Pulmonary Capillary Wedge Pressure (PCWP)
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

Change in Central Pressures After Study Drug (Resting)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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.

Full Information

First Posted
August 27, 2013
Last Updated
February 15, 2016
Sponsor
Barry Borlaug
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1. Study Identification

Unique Protocol Identification Number
NCT01932606
Brief Title
Acute Effects of Inorganic Nitrite on Cardiovascular Hemodynamics in Heart Failure With Preserved Ejection Fraction
Official Title
Acute Effects of Inorganic Nitrite on Cardiovascular Hemodynamics in Heart Failure With Preserved Ejection Fraction
Study Type
Interventional

2. Study Status

Record Verification Date
February 2016
Overall Recruitment Status
Completed
Study Start Date
August 2013 (undefined)
Primary Completion Date
October 2014 (Actual)
Study Completion Date
October 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Barry Borlaug

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Heart Disease, Heart Failure With Preserved Ejection Fraction, Exercise Intolerance, Pulmonary Hypertension

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
28 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Nitrite
Arm Type
Experimental
Arm Description
Study drug (NaNO_2 50 mcg/kg/min) will be infused for 5 minutes during the cardiac catheterization procedure.
Arm Title
Saline
Arm Type
Placebo Comparator
Arm Description
Saline Placebo for Nitrite will be infused for 5 minutes during the cardiac catheterization procedure.
Intervention Type
Drug
Intervention Name(s)
Nitrite
Intervention Description
Study drug (NaNO_2 50 mcg/kg/min) will be infused for 5 minutes during the cardiac catheterization procedure.
Intervention Type
Drug
Intervention Name(s)
Saline Placebo for Nitrite
Intervention Description
Normal saline placebo will be infused for 5 minutes during the cardiac catheterization procedure. Hemodynamics will then be measured at baseline after study drug infusion and again during low level exercise (20 Watts).
Primary Outcome Measure Information:
Title
Exercise Pulmonary Capillary Wedge Pressure (PCWP)
Description
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.
Time Frame
during repeat exercise run, approximately 30 minutes after study drug administration
Secondary Outcome Measure Information:
Title
Change in Central Pressures After Study Drug (Resting)
Description
Values are resting values after receiving study drug minus resting values before study drug (on the same day.)
Time Frame
baseline, approximately 30 minutes after study drug administration
Title
Change in Heart Rate After Study Drug (Resting)
Description
Values are resting values after receiving study drug minus resting values before study drug (on the same day.)
Time Frame
baseline, approximately 30 minutes after study drug administration
Title
Change in Blood Pressure After Study Drug (Resting)
Description
Values are resting values after receiving study drug minus resting values before study drug (on the same day.)
Time Frame
baseline, approximately 30 minutes after study drug administration
Title
Change in Pulmonary Vascular Resistance (PVR) After Study Drug (Resting)
Description
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.
Time Frame
baseline, approximately 30 minutes after study drug administration
Title
Change in Pulmonary Artery (PA) Compliance After Study Drug (Resting)
Description
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.
Time Frame
baseline, approximately 30 minutes after study drug administration
Title
Change in Systemic Vascular Resistance (SVR) After Study Drug (Resting)
Description
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.
Time Frame
baseline, approximately 30 minutes after study drug administration
Title
Change in Left Ventricular Stroke Work (LVSW) After Study Drug (Resting)
Description
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.
Time Frame
baseline, approximately 30 minutes after study drug administration
Title
Change in Oxygen Consumption (VO_2) After Study Drug (Resting)
Description
Values are resting values after receiving study drug minus resting values before study drug (on the same day.)
Time Frame
baseline, approximately 30 minutes after study drug administration
Title
Change in Arteriovenous Oxygen Content Difference After Study Drug (Resting)
Description
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.
Time Frame
baseline, approximately 30 minutes after study drug administration
Title
Change in Cardiac Output After Study Drug (Resting)
Description
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.
Time Frame
baseline, approximately 30 minutes after study drug administration
Title
Change in Stroke Volume After Study Drug (Resting)
Description
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.
Time Frame
baseline, approximately 30 minutes after study drug administration
Title
Change in Central Pressures After Study Drug (Exercise)
Description
Values are exercise values after receiving study drug minus exercise values before study drug (on the same day.)
Time Frame
baseline, approximately 30 minutes after study drug administration
Title
Change in Heart Rate After Study Drug (Exercise)
Description
Values are exercise values after receiving study drug minus exercise values before study drug (on the same day.)
Time Frame
baseline, approximately 30 minutes after study drug administration
Title
Change in Blood Pressure After Study Drug (Exercise)
Description
Values are exercise values after receiving study drug minus exercise values before study drug (on the same day.)
Time Frame
baseline, approximately 30 minutes after study drug administration
Title
Change in PVR After Study Drug (Exercise)
Description
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.
Time Frame
baseline, approximately 30 minutes after study drug administration
Title
Change in PA Compliance After Study Drug (Exercise)
Description
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.
Time Frame
baseline, approximately 30 minutes after study drug administration
Title
Change in SVR After Study Drug (Exercise)
Description
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.
Time Frame
baseline, approximately 30 minutes after study drug administration
Title
Change in LVSW After Study Drug (Exercise)
Description
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.
Time Frame
baseline, approximately 30 minutes after study drug administration
Title
Change in Oxygen Consumption (VO_2) After Study Drug (Exercise)
Description
Values are exercise values after receiving study drug minus exercise values before study drug (on the same day.)
Time Frame
baseline, approximately 30 minutes after study drug administration
Title
Change in Arteriovenous Oxygen Difference After Study Drug (Exercise)
Description
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.
Time Frame
baseline, approximately 30 minutes after study drug administration
Title
Change in Cardiac Output After Study Drug (Exercise)
Description
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.
Time Frame
baseline, approximately 30 minutes after study drug administration
Title
Change in Stroke Volume After Study Drug (Exercise)
Description
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.
Time Frame
baseline, approximately 30 minutes after study drug administration

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Barry Borlaug, MD
Organizational Affiliation
Mayo Clinic
Official's Role
Principal Investigator
Facility Information:
Facility Name
Mayo Clinic in Rochester
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
26449137
Citation
Borlaug BA, Koepp KE, Melenovsky V. Sodium Nitrite Improves Exercise Hemodynamics and Ventricular Performance in Heart Failure With Preserved Ejection Fraction. J Am Coll Cardiol. 2015 Oct 13;66(15):1672-82. doi: 10.1016/j.jacc.2015.07.067.
Results Reference
result
PubMed Identifier
33421267
Citation
Reddy YNV, Stewart GM, Obokata M, Koepp KE, Borlaug BA. Peripheral and pulmonary effects of inorganic nitrite during exercise in heart failure with preserved ejection fraction. Eur J Heart Fail. 2021 May;23(5):814-823. doi: 10.1002/ejhf.2093. Epub 2021 Feb 1.
Results Reference
derived

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

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