Blood Flow Improvement Drugs + Supplements for Heart Failure

(MPMA Trial)

Overseen By Cassandra Demastus, NP

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Pennsylvania

Must not be taking: Organic nitrates, Phosphodiesterase inhibitors

Disqualifiers: Pregnancy, Uncontrolled atrial fibrillation, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 6 weeks

53 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will test whether pharmacologic agents that increase perfusion \[Potassium Nitrate (KNO3)\], with and without additional supplements that may improve mitochondrial function \[Propionyl-L-Carnitine (PLC) and Nicotinamide Riboside (NR)\], improve submaximal exercise endurance and skeletal muscle oxidative phosphorylation capacity (SkM OxPhos) in participants with Heart Failure with Preserved Ejection Fraction (HFpEF).

Will I have to stop taking my current medications?

The trial requires that you stop taking organic nitrates or phosphodiesterase inhibitors if they cannot be interrupted. For other medications, the protocol does not specify, so it's best to discuss with the study team.

What data supports the effectiveness of the drug Potassium Nitrate for heart failure?

Research suggests that nitrates, like Potassium Nitrate, can help improve heart function by reducing heart pressure and increasing blood flow, which may ease symptoms and improve exercise tolerance in heart failure patients. ^{1 2 3 4 5}

Is the treatment with nitrates and supplements generally safe for humans?

Nitrates, used in various forms, are generally well-tolerated and effective for heart conditions, but they can cause side effects like headache, dizziness, and nausea. They are widely used for heart failure and other cardiovascular diseases, although some patients may develop resistance or tolerance to their effects. ^{1 2 4 6 7}

How is the drug Potassium Nitrate + Propionyl-L-Carnitine + Nicotinamide Riboside unique for heart failure?

This treatment is unique because it combines potassium nitrate, which can increase nitric oxide levels to improve blood flow, with supplements like Propionyl-L-Carnitine and Nicotinamide Riboside, potentially enhancing energy production in heart cells. Unlike standard treatments, this combination aims to address both blood flow and cellular energy, offering a novel approach to managing heart failure. ^{1 4 5 7 8}

Research Team

Payman Zamani, MD

Principal Investigator

University of Pennsylvania

Eligibility Criteria

This trial is for adults with Heart Failure with Preserved Ejection Fraction (HFpEF), who have been on stable heart medication for at least a month. They should have certain signs of heart stress, like specific ratios in their echocardiogram or history of acute heart failure. Excluded are those under 18, pregnant women, people with severe other diseases or conditions that could interfere with the study, and those taking conflicting medications.

Inclusion Criteria

You have signs of high pressure in your blood vessels.

Your heart has certain measurements and pressures that show it may not be working properly, or you've had a previous episode of acute heart failure requiring intravenous diuretics.

My current medication has been the same for at least 1 month.

Exclusion Criteria

Your methemoglobin level is higher than 5%.

Any condition that, in the opinion of the investigator, will interfere with the performance and completion of the study.

I have severe lung disease or need extra oxygen.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Potassium Nitrate (KNO3) with or without additional supplements (Propionyl-L-Carnitine and Nicotinamide Riboside) to test improvements in exercise endurance and skeletal muscle oxidative phosphorylation capacity

6 weeks

Regular visits for monitoring and assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Potassium Nitrate
• Potassium Nitrate + Propionyl-L-Carnitine + Nicotinamide Riboside

Trial Overview The study tests if Potassium Nitrate alone or combined with Propionyl-L-Carnitine and Nicotinamide Riboside can improve exercise endurance and muscle function in HFpEF patients. It compares these treatments to Potassium Chloride to see which is better at increasing blood flow and enhancing mitochondrial function.

Participant Groups

Group I: Potassium Nitrate Active Control 1 Intervention

Potassium Nitrate (KNO3) 6 mmol three times daily

Group II: Potassium Nitrate + Propionyl-L-Carnitine + Nicotinamide Riboside Active Control 1 Intervention

Potassium Nitrate (KNO3) 6 mmol three times daily + Propionyl-L-Carnitine (PLC) 1000 mg twice daily + Nicotinamide Riboside (NR) 300 mg three times daily

Group III: Potassium Chloride Placebo Group 1 Intervention

Potassium Chloride (KCl) 6 mmol three times daily

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

Findings from Research

A pilot trial is being conducted to evaluate the feasibility of using oral sodium nitrate as a treatment for acute heart failure (AHF), which is characterized by impaired vasorelaxation and reduced nitric oxide levels.

The study aims to determine if sodium nitrate can increase levels of nitric oxide precursors in the blood and improve vasorelaxation without causing significant drops in blood pressure, potentially offering a new treatment option for AHF.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inorganic nitrate as a treatment for acute heart failure: a protocol for a single center, randomized, double-blind, placebo-controlled pilot and feasibility study. Falls, R., Seman, M., Braat, S., et al.[2018]

Nitrates, such as isosorbide dinitrate, can improve heart failure symptoms and exercise tolerance by reducing cardiac filling pressures and increasing cardiac output, as shown in studies combining them with digoxin and diuretics.

Long-term use of nitrates has been associated with improved survival rates and left ventricular ejection fraction, suggesting they may help prevent harmful changes in the heart's structure, although the best dosing strategies for heart failure patients are still being researched.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mechanisms of action and efficacy of nitrates in heart failure. Cohn, JN.[2019]

In a study of 19,047 patients with heart failure and preserved ejection fraction (HFpEF), nitrates did not improve all-cause mortality or reduce heart failure hospitalizations, showing a hazard ratio of 1.06 when compared to untreated patients.

Despite initial expectations that nitrates could enhance heart function, the data indicated that their use was associated with worse outcomes, including a higher risk of hospitalization and lower event-free survival rates in the matched cohort.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association Between Use of Long-Acting Nitrates and Outcomes in Heart Failure With Preserved Ejection Fraction. Lim, SL., Benson, L., Dahlström, U., et al.[2017]

A survey of Heart Failure Society of America members found that nitrates are commonly used in chronic congestive heart failure (CHF) patients despite not being FDA-approved, with 90% using them for ischemic and 81% for nonischemic CHF.

Nitrates are primarily used to alleviate symptoms (96% of respondents), improve hemodynamics (74%), and enhance exercise tolerance (65%), but only a small percentage (14%) use them for left ventricular remodeling.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Survey of the use of organic nitrates for the treatment of chronic congestive heart failure in the United States. Bitar, F., Akhter, MW., Khan, S., et al.[2015]

Nitroglycerin and its derivatives effectively treat severe heart failure by reducing the heart's preload and afterload, which improves cardiac output and alleviates symptoms for patients.

Intravenous nitrates are particularly useful in acute situations like myocardial infarction and worsening left ventricular failure, while oral and transdermal forms are prescribed for chronic heart failure in advanced stages (NYHA class III and IV).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Use of nitroglycerin in the treatment of congestive heart failure]. Curyło, AM.[2013]

Nitrates are effective in treating various cardiovascular conditions, such as stable and unstable angina, by dilating blood vessels and reducing heart workload, with their clinical effects primarily stemming from systemic venodilatation and decreased vascular resistance.

Nitrate therapy is generally safe and well-tolerated, with common side effects including headache and dizziness, and it is recommended to start with low doses and adjust as needed, making it an effective and inexpensive option for patients with cardiovascular disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nitroglycerin and long-acting nitrates in clinical practice. Abrams, J.[2019]

Organic nitrates are effective in treating chronic congestive heart failure (CHF) by improving exercise capacity and reducing symptoms, and they can prolong life when combined with hydralazine in patients with mild-to-moderate symptoms.

However, many patients develop resistance to the hemodynamic effects of nitrates and early tolerance, which may limit their long-term benefits in CHF treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nitrate resistance and tolerance: potential limitations in the treatment of congestive heart failure. Elkayam, U., Mehra, A., Shotan, A., et al.[2019]

In a study of 31 patients with acute heart failure (AHF), intravenous nicorandil significantly reduced levels of B-type natriuretic peptide (BNP) and showed a trend towards decreasing N-terminal-pro-BNP, indicating its efficacy in lowering cardiac stress markers.

Nicorandil improved hemodynamics in patients with high systolic blood pressure while being safe for those with low systolic blood pressure, suggesting it can be effectively used across different patient profiles in AHF.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of nicorandil therapy in patients with acute heart failure. Shirakabe, A., Hata, N., Yokoyama, S., et al.[2015]

References

1. England pubmed.ncbi.nlm.nih.gov

Inorganic nitrate as a treatment for acute heart failure: a protocol for a single center, randomized, double-blind, placebo-controlled pilot and feasibility study. [2018]

2. United States pubmed.ncbi.nlm.nih.gov

Mechanisms of action and efficacy of nitrates in heart failure. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

Association Between Use of Long-Acting Nitrates and Outcomes in Heart Failure With Preserved Ejection Fraction. [2017]

4. United States pubmed.ncbi.nlm.nih.gov

Survey of the use of organic nitrates for the treatment of chronic congestive heart failure in the United States. [2015]

5. Poland pubmed.ncbi.nlm.nih.gov

[Use of nitroglycerin in the treatment of congestive heart failure]. [2013]

6. United States pubmed.ncbi.nlm.nih.gov

Nitroglycerin and long-acting nitrates in clinical practice. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

Nitrate resistance and tolerance: potential limitations in the treatment of congestive heart failure. [2019]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Efficacy and safety of nicorandil therapy in patients with acute heart failure. [2015]