Effect of KNO3 Compared to KCl on Oxygen UpTake in Heart Failure With Preserved Ejection Fraction (KNO3CK OUT HFPEF)

University of Pennsylvania84 enrolled

Overview

This trial seeks to assess if potassium nitrate (KNO3) therapy improves exercise capacity and oxygen uptake in heart failure patients with preserved ejection fraction (HFpEF).

Approximately 50% of heart failure patients exhibit preserved left ventricular (LV) ejection fraction (EF), and therefore have HF with preserved EF (HFpEF). There are currently no proven effective pharmacologic interventions. Exercise intolerance with reduced aerobic capacity is the hallmark of HFpEF and greatly impairs quality of life (QOL). During exercise, blood vessels within active muscle vasodilator, increasing perfusion to the muscle bed. Nitric oxide is a chief mediator of this process. Inorganic nitrate can ultimately be converted to nitric oxide. This conversion occurs preferentially at the site of exercising muscle, allowing for vasodilation to occur, hence increasing blood flow to the working muscle. Preliminary data suggest that inorganic nitrate improves exercise tolerance in HFpEF. The investigator will aim to test this hypothesis in a larger group.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Heart Failure

Interventions

Potassium Nitrate (KNO3)DRUG

The effect of potassium nitrate (KNO3) supplementation on exercise capacity and peak oxygen consumption in HFpEF will be assessed.

Potassium Chloride (KCl)DRUG

Potassium Chloride (KCl) is the matching placebo control drug in this trial.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 90 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Adults aged 18-90 years of age 2. A diagnosis of heart failure with NYHA Class II-III symptoms 3. LV ejection fraction \>50% during baseline echocardiography 4. Stable medical therapy: no addition/removal/changes in antihypertensive medications, or beta-blockers in the preceding 30 days 5. Elevated filling pressures as evidenced by at least 1 of the following: 1. Mitral E/e' ratio \> 8 (either lateral or septal), with low e' velocity (septal e'\<7 cm/sec or lateral e'\< 10 cm/sec), in addition to one of the following: i Enlarged left atrium (LA volume index \>34 ml/m2) ii Chronic loop diuretic use for control of symptoms iii Elevated natriuretic peptides (BNP levels \>100 ng/L or NT-proBNP levels \>300 ng/L) 2. Mitral E/e' ratio \> 14 (either lateral or septal) 3. Elevated invasively-determined filling pressures previously (resting LVEDP\>16 mmHg or mean pulmonary capillary wedge pressure \[PCWP\] \> 12 mmHg; or PCWP/LVEDP≥25 mmHg with exercise) 4. Acute heart failure decompensation requiring IV diuretics Exclusion Criteria: 1. Supine systolic blood pressure \<100 mm Hg 2. Pregnancy: Women of childbearing potential will undergo a pregnancy test during the screening visit 3. Orthostatic hypotension defined as \>20 mm Hg decrease in systolic blood pressure 3-5 minutes following the transition from the supine to standing position 4. Uncontrolled atrial fibrillation, as defined by a resting heart rate\>100 beats per minute 5. Hemoglobin \< 10 g/dL 6. Inability/unwillingness to exercise 7. Moderate or greater left sided valvular disease (mitral regurgitation, aortic stenosis, aortic regurgitation), any degree of mitral stenosis, severe right-sided valvular disease, or presence of a prosthetic valve in the mitral position 8. Hypertrophic, infiltrative, or inflammatory cardiomyopathy 9. Clinically significant pericardial disease, as per investigator judgement. 10. Current angina 11. Acute coronary syndrome or coronary intervention within the past 2 months 12. Primary pulmonary arteriopathy 13. Clinically significant lung disease as defined by: Chronic Obstructive Pulmonary Disease meeting Stage III or greater GOLD criteria, treatment with oral steroids within the past 6 months for an exacerbation of obstructive lung disease, or the use of daytime supplemental oxygen 14. Ischemia on stress testing without either (1) subsequent revascularization, or; (2) a subsequent angiogram demonstrating the absence of clinically significant epicardial coronary artery disease, as per investigator judgement. 15. Left ventricular ejection fraction \<45% in any prior echocardiogram or cardiac MRI, unless this was in the setting of uncontrolled atrial fibrillation. 16. Treatment with phosphodiesterase inhibitors that cannot be withheld 17. Treatment with organic nitrates 18. Significant liver disease impacting synthetic function or volume control (ALT/AST \> 3x ULN, Albumin \<3.0 g/dL) 19. eGFR \< 30 mL/min/1.73m2 20. G6PD deficiency. In males of African, Asian or Mediterranean decent, this will be formally evaluated by enzyme testing prior to drug administration. A negative screening test for G6PD will be required in these subjects for inclusion in the study. If a quantitative test is being performed, a clinically significant reduction in G6PD activity (\<60% of normal) will exclude subjects. 21. Methemoglobinemia - baseline methemoglobin level \>5% 22. Serum K\>5.0 mEq/L 23. Severe right ventricular dysfunction 24. Any medical condition that, in the opinion of the investigator, will interfere with the safe completion of the study. 25. Contraindications to MRI (except as noted below), including the presence of a pacemaker, metal implants, claustrophobia, or that have known medical conditions which can be exacerbated by stress such as anxiety or panic attacks. Inability to lie flat in the MRI scanner for 90 minutes is also an exclusion criterion.

Locations (3)

Northwestern Medical Center

Evanston, Illinois, United States

Corporal Michael J Crescenz Veterans Affairs Medical Center (VA)

Philadelphia, Pennsylvania, United States

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, United States

Outcomes

Primary Outcomes

Difference in Peak Oxygen Consumption (Vo2) Between KNO3 and KCl Phases

Subjects will perform a maximal-effort peak oxygen consumption test using a supine bicycle exercise test with expired gas analysis.

Time frame: 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control)

Change in Total Work Performed During a Maximal-effort Exercise Test From Phase 1 to Phase 2

Subjects will perform a maximal-effort supine bicycle exercise test.

Time frame: 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control)

Secondary Outcomes

Effect of Potassium Nitrate (KNO3) on Quality of Life (QOL)

QOL will be assessed with the Kansas City Cardiomyopathy Questionnaire (KCCQ). The overall summary score from the KCCQ ranges from 0-100, where higher scores indicate a better quality of life.

Time frame: All three visits: Baseline (first) visit; 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control)

Effect of KNO3 on the Percent Change of Systemic Vasodilatory Response to Exercise: The Change in Systemic Vascular Resistance Reserve During Exercise During a Maximal Effort Exercise Test

We measured the Systematic vasodilatory response at rest and peak maximal exercise using corresponding echo parameters and blood pressures for each visit. This measure depicts the change from rest and exercise.

Time frame: 6 weeks after start of phase 1 (experimental drug or control); 6 weeks after start of phase 2 (experimental drug or control)

Effect of Potassium Nitrate (KNO3) on Muscle Phosphocreatine (PCr) Recovery Kinetics Following a Standardized Plantar Flexor Exercise Protocol

Muscle PCr recovery kinetics were measured using MRI and a standardized plantar flexor exercise protocol with a high resolution spatial mapping of creatine in muscle to analyze creatine chemical exchange saturation transfer and quantify the recovery kinetics of creatine levels. Exercise induces increases in the rate of O2 consumption, which upon cessation of exercise, declines towards baseline in a mono-exponential fashion. This is characterized by a time constant (τ, tau) that corresponds to the time constant of PCr recovery kinetics. Muscle PCr is a marker of oxidative capacity. This outcome measure relates to the half-time derived from linear regression, where a lower value depicts a faster PCr recovery.

Data from ClinicalTrials.gov

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