Afferent Block for Heart Failure

Overseen By Misti R Seppi, MBA BS AAS

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: VA Office of Research and Development

Disqualifiers: Heart failure with reduced ejection

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how exercise can benefit veterans with heart failure who have preserved ejection fraction (HFpEF), a condition where the heart pumps normally but doesn't relax well. Researchers focus on the role of nerves in the muscles that might affect exercise performance and fatigue resistance. The trial employs various approaches, such as blocking certain nerve signals (afferent block) and engaging in regular exercise, to assess their impact on muscle and blood flow. Veterans with heart failure but normal pumping function who struggle with exercise might be suitable candidates for this study. The goal is to enhance their exercise capacity and overall quality of life. As an unphased trial, this study offers veterans the chance to contribute to groundbreaking research that could improve their exercise capacity and quality of life.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications.

What prior data suggests that this afferent block is safe for heart failure patients?

Research has shown that treatments affecting the autonomic nervous system, such as the afferent block, have been studied for heart failure. Similar treatments, like vagal nerve stimulation, are generally well-tolerated. Studies suggest that while some patients may experience mild side effects, serious problems are rare. However, specific information about the afferent block for heart failure with preserved ejection fraction (HFpEF) remains limited, leaving questions about its safety. Researchers are testing this treatment to see if it can help veterans with HFpEF who struggle with exercise. This research phase typically does not focus on early human safety, indicating reasonable confidence in its safety based on earlier studies. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about afferent block for heart failure because it targets group III/IV muscle afferents, which could influence blood flow and muscle fatigue in a novel way. Unlike traditional treatments for heart failure, which often rely on medications like ACE inhibitors or beta-blockers to manage symptoms, this approach focuses on the nervous system's role in regulating blood flow during exercise. By potentially improving limb blood flow and reducing exercise-induced fatigue, afferent block could offer a new avenue for enhancing the quality of life in heart failure patients.

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

Research has shown that cardiac rehabilitation, including exercise programs, greatly benefits people with heart failure. Studies have found that these programs lower the risk of death from any cause by 27% and reduce the risk of death specifically from heart issues by 31%. Regular exercise also improves exercise capacity and enhances the quality of life for heart failure patients. In this trial, one arm will focus on the "afferent block" to explore how blocking certain nerves might reduce tiredness and improve blood flow during exercise. Better blood flow and less fatigue can make exercise more effective for heart failure patients. ^{6 7 8 9 10}

Who Is on the Research Team?

Markus Amann, 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 Veterans with a type of heart failure where the heart muscle pumps out a normal amount of blood (HFpEF). It's not for those whose hearts can't pump enough blood (reduced ejection fraction). Participants will explore how exercise affects their condition.

Inclusion Criteria

My heart pumps well but is stiff.

Exclusion Criteria

My heart pumps less blood than normal.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo a supervised 12-week knee-extension exercise training program to evaluate the effect of chronic exercise on muscle afferents and exercise tolerance

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after the exercise training program

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Afferent block

Trial Overview

The study tests whether blocking certain nerves in limb muscles can improve exercise tolerance and fatigue resistance in patients. The focus is on regular physical activity as an alternative treatment to enhance quality of life.

How Is the Trial Designed?

Group I: Effect of cardiac rehab Experimental Treatment 1 Intervention

Evaluate effect of chronic exercise on influence of muscle afferents on limb blood flow

Group II: Afferent effect on hemodynamics Experimental Treatment 1 Intervention

Evaluate impact of group III/IV muscle afferents on femoral blood flow

Group III: Afferent effect on fatigue Experimental Treatment 1 Intervention

Evaluate impact of group III/IV muscle afferents on exercise-induced changes in quadriceps twitch force

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

Published Research Related to This Trial

In a study involving 3991 patients with chronic heart failure, metoprolol CR/XL significantly reduced total mortality and hospitalizations compared to placebo, demonstrating a 19% reduction in all-cause hospitalizations and a 31% reduction in hospitalizations due to worsening heart failure.

Patients taking metoprolol CR/XL also showed improvements in their functional status and quality of life, as indicated by better NYHA class ratings and patient-reported outcomes, highlighting its efficacy in managing heart failure symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive heart failure (MERIT-HF). MERIT-HF Study Group. Hjalmarson, A., Goldstein, S., Fagerberg, B., et al.[2022]

Beta-adrenergic blocking agents significantly reduce overall mortality and cardiovascular mortality in heart failure patients, with a notable decrease in sudden death and pump failure mortality by 34% to 39%, based on a meta-analysis of 21 trials involving 5,849 patients.

Vasodilating beta-blockers are more effective than nonvasodilating agents in reducing overall mortality, particularly in patients without ischemic heart disease, showing a 45% reduction compared to 27% for nonvasodilating agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beta-adrenergic blocking agents in heart failure: benefits of vasodilating and non-vasodilating agents according to patients' characteristics: a meta-analysis of clinical trials. Bonet, S., Agustí, A., Arnau, JM., et al.[2019]

Chronic ablation of cardiac sympathetic afferent reflex (CSAR) afferents significantly reduced the strength of the muscle metaboreflex in both normal and heart failure conditions, indicating that CSAR amplifies sympathetic activity during exercise intolerance.

In a canine model, the study demonstrated that the muscle metaboreflex, which controls blood pressure and heart rate, is negatively impacted by the CSAR, contributing to the oxygen delivery and demand imbalance seen in heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Muscle metaboreflex stimulates the cardiac sympathetic afferent reflex causing positive-feedback amplification of sympathetic activity: effect of heart failure. Mannozzi, J., Senador, D., Kaur, J., et al.[2023]

Beta-blockers, such as metoprolol and bisoprolol, have been shown to improve heart function in patients with heart failure, suggesting that reducing sympathetic stimulation can be beneficial.

The CIBIS trial indicated a survival benefit in non-ischaemic heart failure patients treated with bisoprolol, but this finding needs further confirmation from additional studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Adrenergic betablockers and heart failure]. Lechat, P.[2013]

In a study of patients with chronic heart failure, both metoprolol and carvedilol significantly improved left ventricular ejection fraction (LVEF) after 12 weeks, with increases of +6% in sinus rhythm (SR) and +11% in atrial fibrillation (AF).

Despite improvements in LVEF for both groups, only patients in sinus rhythm experienced significant enhancements in symptoms and exercise capacity, indicating that beta-blockers may be less effective for symptom relief in heart failure patients with atrial fibrillation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is beta-blockade useful in heart failure patients with atrial fibrillation? An analysis of data from two previously completed prospective trials. Fung, JW., Chan, SK., Yeung, LY., et al.[2019]

In a study of 122 patients with high-grade atrioventricular block (AVB), 23% presented with heart failure (HF), primarily linked to decreased cardiac output and impaired left ventricular compliance.

The occurrence of HF in these patients was significantly associated with increased diastolic mitral regurgitation volume, rather than heart rate or left ventricular ejection fraction, suggesting that poor LV compliance and high diastolic MR volume contribute to heart failure during AVB.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Heart Failure Due to High-Degree Atrioventricular Block: How Frequent Is It and What Is the Cause? Viskin, D., Halkin, A., Sherez, J., et al.[2021]

Beta-blockers have been shown to significantly improve heart function, increase exercise capacity, and reduce mortality in patients with heart failure, regardless of other treatments like digoxin or ACE inhibitors, based on 20 years of cumulative evidence.

Approximately 90% of heart failure patients respond positively to beta-blockers, although there are no specific indicators to predict who will benefit, and the positive effects develop gradually but can last for years.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beta-blocker therapy in heart failure: myths or realities. Kelly, DT.[2019]

Beta-blockers, like metoprolol and bisoprolol, have been shown to improve heart function in patients with heart failure, as confirmed by two large-scale studies (MDC and CIBIS).

The CIBIS trial specifically noted a survival benefit in non-ischemic heart failure patients, suggesting that further research is needed to validate these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Beta-blockers and heart failure]. Lechat, P.[2013]

In a study of 934 chronic heart failure patients, including 255 very old patients (≥80 years), the use of beta-blockers was associated with increased survival rates in both very old and younger patients, indicating their efficacy in improving outcomes in heart failure.

Renin-angiotensin system inhibitors also showed a survival benefit, particularly in younger patients, suggesting that neurohormonal modulation therapy is beneficial for older patients with chronic heart failure, despite their higher risk of mortality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prognostic impact of neurohormonal modulation in very old patients with chronic heart failure. Silva, JE., Melo, N., Ferreira, AI., et al.[2022]

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Renal afferent nerves project directly into many areas within the CNS, controlling the SNS outflow activity. Resistant hypertension with systolic HF was not an ...

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This review will focus on the three most studied device-based ART modalities in the setting of HFrEF: cervical vagal nerve stimulation (cVNS), baroreflex ...

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