Exercise + BH4 for Heart Failure

Overseen By David W Wray, PhD

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: VA Office of Research and Development

Must be taking: Ace inhibitors, Beta blockers

Must not be taking: Hormone replacement therapy

Disqualifiers: Atrial fibrillation, Dementia, COPD, Diabetes, others

Compensation: Varies

Number of Visits: Unknown

Duration: 8 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to find better ways to help people with heart failure improve their ability to exercise and slow the disease's progression. Researchers are testing an exercise program and an oral antioxidant treatment, including Tetrahydrobiopterin (BH4), to determine if they can enhance blood flow to muscles and improve heart function. Participants should have stable heart failure with symptoms affecting daily life, such as difficulty with physical activities, and should not have engaged in regular exercise for at least six months.

As an Early Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment approach.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop your current medications. However, it mentions that participants should have been on optimal heart failure treatment, including certain medications, for at least 6 weeks before joining. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Past studies have found exercise programs safe for people with heart failure. Research shows these programs can improve heart health and quality of life. When done with proper evaluation and guidance, no major safety issues have been reported.

For oral treatment with tetrahydrobiopterin (BH4), research indicates it is generally well-tolerated. Studies on a similar compound, sapropterin, reported some minor side effects but no serious safety concerns. BH4 may benefit heart health.

Antioxidants are also under study, and evidence suggests they might help lower the risk of heart disease. Antioxidants from food have been linked to better heart health. Typical antioxidant use has not raised major safety concerns.

Overall, these treatments have been studied and appear safe, but participation in trials should occur under medical supervision. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they explore new ways to tackle heart failure. Unlike standard treatments that often involve medications like ACE inhibitors or beta-blockers, this trial focuses on a combination of exercise training and innovative oral treatments. The study uses tetrahydrobiopterin (BH4), which may enhance blood flow and heart function, and an oral antioxidant treatment, which could reduce oxidative stress, a factor in heart damage. These approaches aim to improve heart health by targeting mechanisms not typically addressed by conventional therapies, offering potential new hope for heart failure patients.

What evidence suggests that this trial's treatments could be effective for heart failure?

This trial will evaluate the effects of different treatments on heart failure. Research has shown that exercise, which participants in this trial may undergo, can greatly benefit people with heart failure, including those with reduced ejection fraction (HFrEF). Studies have found that exercise can improve exercise capacity, heart function, and overall quality of life by reducing stress on the body and easing physical activity.

Another treatment option in this trial is oral antioxidants. Researchers hope they might reduce heart failure risks by lowering stress on the body. However, results have been mixed. Some studies suggest they might help, but the evidence remains inconclusive.

Tetrahydrobiopterin (BH4) is also under study in this trial. Research indicates it can improve blood flow to muscles and reduce stress on the heart. Early studies suggest it might help with heart failure symptoms, but further research is needed to confirm its effectiveness. ^{3 6 7 8 9}

Who Is on the Research Team?

David W. Wray, PhD

Principal Investigator

VA Salt Lake City Health Care System, Salt Lake City, UT

Are You a Good Fit for This Trial?

This trial is for stable cardiomyopathy patients aged 45-75 who've been on optimal heart failure treatment for at least 6 weeks. They should have severe heart function reduction, minimal smoking history, and be able to exercise without orthopedic limits. Excluded are those with extreme obesity, uncontrolled high blood pressure, severe kidney issues, sedentary lifestyle, certain heart rhythm problems or diseases causing their heart failure.

Inclusion Criteria

You can only join the study if you have specific heart symptoms, low heart function, hardly smoke, and do not have a pacemaker.

I am on heart failure treatment as per AHA/ACC/HFSA guidelines or have a valid reason for not following them.

I have had a stable heart condition for over 3 months, despite treatment.

Exclusion Criteria

My heart failure is not due to untreated major valve problems, except for issues caused by a weak left ventricle.

I am currently on hormone replacement therapy.

My heart condition is due to atrial fibrillation.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo 8 weeks of oral antioxidant treatment, oral tetrahydrobiopterin treatment, or knee-extensor exercise training

8 weeks

Rehabilitation

Participants engage in an 8-week clinical cardiac rehabilitation program to assess adherence improvements

8 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Antioxidant
• Exercise training
• Tetrahydrobiopterin (BH4)

Trial Overview The study tests if antioxidants and a compound called Tetrahydrobiopterin (BH4), along with exercise training can improve muscle blood flow and exercise tolerance in people with reduced ejection fraction heart failure (HFrEF). The goal is to slow disease progression and enhance quality of life.

How Is the Trial Designed?

Group I: Oral BH4 Experimental Treatment 1 Intervention

8 week oral tetrahydrobiopterin treatment

Group II: Oral AOx Experimental Treatment 1 Intervention

8 week oral antioxidant treatment

Group III: Ex training Experimental Treatment 1 Intervention

8-week knee-extensor exercise training program

Group IV: Oral BH4 (placebo) Placebo Group 1 Intervention

Placebo for arm 3

Group V: Oral AOx (placebo) Placebo Group 1 Intervention

Placebo for arm 1

Group VI: Ex training (attn con) Placebo Group 1 Intervention

Attention control for arm 5

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

University of Utah

Collaborator

Trials

1,169

Recruited

1,623,000+

Published Research Related to This Trial

Regular exercise training is highly recommended for heart failure patients, supported by strong evidence, yet many patients remain inactive due to various barriers.

Home telerehabilitation is proposed as an effective solution to encourage physical activity among heart failure patients, addressing the limitations of traditional outpatient rehabilitation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

How to do: telerehabilitation in heart failure patients. Piotrowicz, E.[2019]

Exercise training (ET) is recognized as a beneficial component of heart failure (HF) care, improving quality of life and functional capacity, but evidence for its routine inclusion in rehabilitation programs is inconsistent due to variability in existing studies.

This review aims to clarify the mixed evidence surrounding ET in HF and proposes a new in-hospital exercise rehabilitation program to enhance patient care alongside existing HF clinics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exercise training in heart failure. Abela, M.[2018]

A 12-week concurrent exercise training program combining aerobic and resistance exercises significantly improved functional capacity and muscular strength in 95 male patients with chronic heart failure, compared to traditional aerobic training alone.

Patients in the concurrent training group experienced greater improvements in quality of life and lower body strength, with no reported side effects leading to discontinuation of the training program.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Concurrent, Within-Session, Aerobic and Resistance Exercise Training on Functional Capacity and Muscle Performance in Elderly Male Patients with Chronic Heart Failure. Volterrani, M., Caminiti, G., Perrone, MA., et al.[2023]

The HF-ACTION trial aims to determine if exercise training can reduce all-cause mortality and hospitalization in patients with heart failure, involving 36 supervised sessions followed by home-based exercise over a 4-year period.

Exercise training is a low-cost and accessible intervention that may improve health outcomes for heart failure patients, with various physiological and quality-of-life measures being assessed throughout the study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Heart failure and a controlled trial investigating outcomes of exercise training (HF-ACTION): design and rationale. Whellan, DJ., O'Connor, CM., Lee, KL., et al.[2007]

Supervised exercise training and individual physical activity are strongly recommended for all patients with heart failure, starting in the hospital after stabilization and continuing in rehabilitation programs post-discharge.

These exercise programs, which include endurance, resistance, and respiratory training, not only help improve physical fitness but also aim to enhance health literacy for better long-term adherence to physical activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Exercise Training and Physical Activity in Patients with Heart Failure]. Wilhelm, M.[2018]

In a study of 82 heart failure patients, those who participated in supervised hospital-based exercise training showed significant improvements in functional capacity, with peak oxygen consumption increasing from 19.4 to 21.4 mL/min/kg, while home-based training did not show similar benefits.

Quality of life also improved significantly in the hospital-based group, but there were no significant differences in cardiac events between the two groups after one year, suggesting that while hospital-based training is more effective for immediate functional improvements, both training types have similar long-term safety outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of Supervised Hospital-based versus Educated Home-based Exercise Training in Korean Heart Failure Patients. Kim, M., Kim, MS., Lim, SJ., et al.[2020]

A supervised exercise training program for 12 patients with heart failure was found to be feasible and safe, with no cardiovascular events occurring during the training year.

Participants showed improvements in quality of life and reductions in NT-proBNP levels, indicating a potential decrease in heart failure severity, while also experiencing a slight increase in left ventricular ejection fraction (LVEF).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Establishing a cardiac training group for patients with heart failure: the "HIP-in-Würzburg" study. Güder, G., Wilkesmann, J., Scholz, N., et al.[2022]

Exercise training in chronic heart failure patients has shown significant improvements in exercise capacity, comparable to the best pharmacological treatments, without deteriorating cardiac function.

Despite the lack of definitive evidence on improved survival rates, exercise training is recommended for selected heart failure patients, as it enhances muscle function, reduces ventilation during exercise, and improves overall quality of life when supervised properly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Physical activity and training in heart failure]. Weber, T., Kirchgatterer, A., Auer, J., et al.[2019]

Exercise training is effective and safe for heart failure (HF) patients, improving their fitness levels and symptoms, and may even reduce mortality and morbidity.

The review supports prescribing exercise training for patients with NYHA functional classes II-III and suggests that stable NYHA IV patients who are asymptomatic at rest could also benefit from training.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exercise training in patients with heart failure: clinical outcomes, safety, and indications. McKelvie, RS.[2021]

Regular exercise training significantly improves quality of life and survival rates in both healthy individuals and patients with cardiovascular diseases, including those with stable heart failure.

In patients with heart failure classified as NYHA functional classes II and III, exercise training alleviates symptoms, enhances exercise capacity, and may reduce hospitalizations and mortality, highlighting its importance as a recommended treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exercise training in chronic heart failure: mechanisms and therapies. Piepoli, MF.[2022]

A study involving 80 patients with chronic heart failure showed that a structured endurance training program was safe, with no reported adverse events, and led to significant improvements in exercise time and quality of life.

The training increased the anaerobic threshold and decreased the ventilatory equivalent for carbon dioxide during submaximal exercise, indicating enhanced exercise capacity, although it did not significantly improve peak oxygen consumption.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and effects of physical training in chronic heart failure. Results of the Chronic Heart Failure and Graded Exercise study (CHANGE) Wielenga, RP., Huisveld, IA., Bol, E., et al.[2007]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12561675/

Implications for Disease Modeling Using Cardiac Organoids Despite strong rationales and positive preclinical results, antioxidant therapy in cardiovascular disease has faced significant challenges.

2. nature.com nature.com/articles/s41598-022-05632-x

Associations between dietary antioxidant intakes and ... Our study suggests an inverse association between vitamin E intake and the risk of CVD, emphasizing the potential protective role of fruit and vegetable in the ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S0261561422001510

Antioxidant effects of vitamin E and risk of cardiovascular ... Currently available data suggest that vitamin E may be essential in preventing CVD, especially in coronary heart disease and atherosclerosis.

4. jacc.org jacc.org/doi/10.1016/j.jacc.2022.10.011

Antioxidant Supplementation in Cardiovascular Prevention For decades, the association between antioxidant supplementation and cardiovascular prevention has been controversial.

5. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/10.1002/mnfr.70249?af=R

Predictive Modeling of Heart Failure Risk Based on Dietary ... The results that dietary antioxidants, including metal ions, vitamins, and other compounds, significantly reduced HF risk by reducing oxidative ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10716306/

Composite dietary antioxidant index and the risk of heart ... In this study, we investigated the relationship between CDAI and HF risk using National Health and Nutritional Examination Survey (NHANES) data.

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0147956324000311

Dietary antioxidant intake is associated with heart failure In this study, the CDAI is found to be negatively associated with HF by using the NHANES 2003–2019 data, indicating that vitamin A, vitamin C, vitamin E, zinc, ...

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38457967/

Dietary antioxidant intake is associated with heart failure Background: Growing evidence has shown that antioxidant diets protect against heart failure (HF). However, the association between the composite ...

9. ahajournals.org ahajournals.org/doi/10.1161/01.cir.99.4.591

Antioxidant Consumption and Risk of Coronary ... This report provides a brief overview of evidence concerning a role for dietary antioxidants in disease prevention, with emphasis on studies in human ...