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

140 Participants Needed

Trial Summary

What is the purpose of this trial?

Heart disease is the leading cause of death in the United States, accounting for one in every four deaths in 2010 and costing over $300 billion annually in health care, medication, and lost productivity. Heart failure with a reduced ejection fraction (HFrEF), a clinical syndrome that develops as a consequence of heart disease, now affects almost 6 million Americans. Within the VA Health Care System, HFrEF hospital admission rates continue to rise, and remain the number one reason for discharge from VA hospitals nationwide. Unfortunately, over one-third of all Veterans suffering from HFrEF die within two years of discharge despite optimized drug therapy, an unacceptably high number. This proposal is focused on how impaired muscle blood flow contributes to exercise intolerance in HFrEF, and on subsequently developing strategies for restoring exercise tolerance and slowing disease progression in this patient group. It is anticipated that knowledge gained from these studies will contribute to improved standard of care, quality of life, and prognosis in this VA patient group.

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.

What data supports the effectiveness of this treatment for heart failure?

Research shows that exercise training can improve fitness levels, relieve symptoms, and potentially reduce hospitalizations and mortality in heart failure patients. Regular exercise is recommended for heart failure patients as it enhances quality of life and survival. ^{1 2 3 4 5}

Is exercise training safe for heart failure patients?

Exercise training is generally considered safe for heart failure patients when they are properly evaluated and monitored. Studies suggest that it can be safely performed and may even improve fitness and symptoms in these patients. ^{1 3 4 6 7}

How does the treatment Exercise training differ from other treatments for heart failure?

Exercise training for heart failure is unique because it focuses on improving physical fitness through supervised activities like endurance and resistance exercises, which can start in the hospital and continue at home. Unlike medications, this treatment enhances blood flow, muscle function, and quality of life without directly altering heart function, and it can be as effective as the best drug treatments in improving exercise capacity. ^{4 8 9 10 11}

Research Team

David W. Wray, PhD

Principal Investigator

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

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

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

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

2. Netherlands pubmed.ncbi.nlm.nih.gov

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

3. Korea (South) pubmed.ncbi.nlm.nih.gov

Comparison of Supervised Hospital-based versus Educated Home-based Exercise Training in Korean Heart Failure Patients. [2020]

4. Poland pubmed.ncbi.nlm.nih.gov

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

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

Heart failure and a controlled trial investigating outcomes of exercise training (HF-ACTION): design and rationale. [2007]

6. Germany pubmed.ncbi.nlm.nih.gov

Establishing a cardiac training group for patients with heart failure: the "HIP-in-Würzburg" study. [2022]

7. England 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) [2007]

8. Switzerland pubmed.ncbi.nlm.nih.gov

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

9. Germany pubmed.ncbi.nlm.nih.gov

[Physical activity and training in heart failure]. [2019]

10. Switzerland 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. [2023]

11. England pubmed.ncbi.nlm.nih.gov

Exercise training in heart failure. [2018]