Cardiac Pacing for Heart Failure

(HeartExcel Trial)

Overseen By Denice Hodgson-Zingman, MD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Denice Hodgson-Zingman, MD

Disqualifiers: Atrial arrhythmias, Valve disease, Pregnancy, others

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

Compensation: Varies

Number of Visits: 21

Duration: 6 weeks

52 Participants Needed

Trial Summary

What is the purpose of this trial?

A clinical trial of exercise-similar heart rate acceleration delivered via cardiac pacing vs. sham intervention in subjects at rest will be performed. The study population comprises subjects with guideline-directed medically managed left ventricular dysfunction due to ischemic or non-ischemic cardiomyopathy and an existing implantable cardioverter defibrillator or biventricular implantable cardioverter defibrillator. The purpose of the study is to understand how the heart rate pattern of exercise contributes to the considerable cardiac conditioning effects of exercise and estimate whether the pacing approach may have translational clinical applicability. Fifty-two subjects will be randomized, single-blinded, to either the pacing intervention or a sham intervention which they will receive once daily, 3 days/week for 6 weeks. Baseline symptoms and clinical test results will be compared to the same measures at 2 weeks, 4 weeks and 6 weeks of intervention/sham and at 3 months and one-year post-intervention. The primary endpoint will be the change in left ventricular ejection fraction from baseline in intervention vs. sham groups (mixed effects linear regression with time and treatment arm as fixed effects and pre-specified covariates of sex and cardiomyopathy type as random effects). Secondary endpoints will include changes in quality of life, 6-minute walk distance, cardiopulmonary exercise test (CPET) measures, daily activity and major adverse cardiac events (MACE) at 3 and 12 months between pacing and sham groups. A "dose-response" analysis of outcomes at 2, 4, and 6 weeks of the intervention vs. sham compared with baseline will be performed.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It is best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment Paced Heart Rate Acceleration, Exercise-Similar Heart Rate Acceleration, Cardiac Pacing for Cardiac Conditioning?

Research shows that pacing therapies can improve heart function and exercise capacity in patients with heart failure by increasing heart rate and improving blood flow. Studies indicate that rate-adaptive pacing, which adjusts the heart rate based on activity, can enhance exercise tolerance and provide more efficient heart function compared to fixed-rate pacing. ^{1 2 3 4 5}

Is cardiac pacing generally safe for humans?

Cardiac pacing has been used for many years, but some studies show that certain types, like right ventricular pacing, can worsen heart health over time. However, rate-responsive pacing, which adjusts the heart rate based on activity, may offer better heart function and exercise tolerance. ^{3 5 6 7 8}

How is the Paced Heart Rate Acceleration treatment different from other heart failure treatments?

Paced Heart Rate Acceleration is unique because it uses cardiac pacing to mimic the heart rate increase seen during exercise, potentially improving heart function and quality of life in heart failure patients. Unlike traditional treatments, it focuses on synchronizing heart contractions and optimizing heart rate response to improve overall cardiac performance. ^{1 4 9 10 11}

Research Team

Denice Hodgson-Zingman, MD

Principal Investigator

University of Iowa

Eligibility Criteria

This trial is for adults over 18 with severe left ventricular dysfunction who have had an implantable cardioverter defibrillator for more than 3 months. They should be experiencing mild to moderate heart failure symptoms despite treatment and must commit to the study schedule.

Inclusion Criteria

I have signed and dated the consent form.

I am willing and able to follow all study rules and be available for its duration.

I am either male or female.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2 weeks

Baseline Testing

Baseline testing including plasma collection, echocardiographic measurements, and quality of life assessments

1 week

1 visit (in-person)

Treatment

Participants receive either pacing intervention or sham intervention once daily, 3 days per week for 6 weeks

6 weeks

18 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment with assessments at 3 and 12 months

12 months

2 visits (in-person)

Treatment Details

Interventions

• Paced Heart Rate Acceleration

Trial Overview The trial tests if a special type of cardiac pacing that mimics exercise can improve heart function in people at rest, compared to a sham (fake) procedure. Participants will receive their assigned intervention three times weekly for six weeks and be monitored up to one year.

Participant Groups

Group I: Exercise-similar cardiac pacing Experimental Treatment 1 Intervention

Atrial pacing to replicate exercise heart rate envelope once daily, 3 days per week, over 6 weeks while symptoms and vital signs are monitored and outcome measures assessed.

Group II: Sham cardiac pacing Placebo Group 1 Intervention

Sham pacing to replicate exercise heart rate envelope once daily, 3 days per week, over 6 weeks while symptoms and vital signs are monitored and outcome measures assessed.

Who Is Running the Clinical Trial?

Denice Hodgson-Zingman, MD

Lead Sponsor

Trials

1

Recruited

50+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

The Cleveland Clinic

Collaborator

Trials

1,072

Recruited

1,377,000+

Findings from Research

In a study involving 10 patients with left ventricular dysfunction, atrial rate-adaptive pacing (AAIR) did not show any significant improvement in peak oxygen consumption (VO2) compared to ventricular demand pacing (VVI), indicating that AAIR may not enhance exercise capacity in this population.

Although heart rate was higher during AAIR pacing, there were no differences in other key exercise performance measures such as anaerobic threshold, perceived exertion, or exercise duration, suggesting that AAIR pacing may not provide additional benefits over VVI in patients without pacing indications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of rate-adaptive atrial pacing versus ventricular backup pacing on exercise capacity in patients with left ventricular dysfunction. Passman, R., Banthia, S., Galvez, D., et al.[2009]

Most rate-responsive pacing systems do not accurately match heart rate to the level of physical effort, with P-wave driven pacing often resulting in a heart rate that is too fast and QT-driven pacing resulting in a heart rate that is too slow for the workload.

While there are some improvements in heart rate response compared to fixed rate pacing, the benefits are not as significant as anticipated, and achieving atrioventricular (AV) synchrony does not provide additional advantages beyond simply increasing the heart rate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exercise testing in the indication and evaluation of pacemaker treatment. Sowton, E.[2019]

In a study of 108 participants (81 with heart failure or hypertension and 27 normal subjects), it was found that heart rate increases linearly with exercise, particularly in patients with more severe heart failure, indicating a strong heart rate-oxygen uptake relationship.

Mixed venous oxygen saturation (SvO2) was identified as a highly reliable predictor of heart rate during exercise, suggesting it could be used as a sensor for rate-responsive cardiac pacemakers in patients with heart conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Physiologic correlates of the heart rate response to upright isotonic exercise: relevance to rate-responsive pacemakers. McElroy, PA., Janicki, JS., Weber, KT.[2019]

The PATH-CHF study is evaluating the effects of pacing therapy in patients with moderate-to-severe congestive heart failure, with 42 patients enrolled so far and a focus on both acute hemodynamic function and chronic clinical benefits over a planned 3-year period.

Initial results indicate trends toward improvement in key measures such as oxygen consumption during exercise and quality of life, suggesting that pacing may help alleviate symptoms in CHF patients compared to periods without pacing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Pacing Therapies for Congestive Heart Failure (PATH-CHF) study: rationale, design, and endpoints of a prospective randomized multicenter study. Auricchio, A., Stellbrink, C., Sack, S., et al.[2019]

An adequate increase in heart rate is crucial for improving cardiac output and exercise tolerance, regardless of whether atrioventricular synchronization is present, highlighting the importance of heart rate variability in pacing modalities.

Rate-adaptive ventricular pacing is more efficient than fixed rate pacing, as it maintains higher cardiac output without increasing myocardial oxygen consumption, suggesting it may be safer and more beneficial for long-term myocardial function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hemodynamics and exercise capacity during pacemaker stimulation. Nordlander, R., Hedman, A.[2007]

In a study of 22 subjects with dual-chamber pacemakers, maximal right ventricular pacing (RVP-max) significantly worsened endothelial function compared to minimal right ventricular pacing (RVP-min), indicating potential cardiovascular risks associated with higher pacing levels.

The study also found that cardiac output during peak exercise was significantly lower with RVP-max, suggesting that right ventricular pacing negatively impacts cardiac reserve and overall heart health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Right ventricular pacing impairs endothelial function in man. Choy, AM., Su, HH., Elder, DH., et al.[2011]

Patients with atrial demand mode pacemakers (AAIR) showed better cardiac function during exercise, with significant increases in cardiac index and left ventricular ejection fraction compared to those with ventricular demand mode pacemakers (VVIR).

The study highlights the importance of atrioventricular synchrony in pacing, as VVIR pacing led to increased levels of atrial natriuretic peptide, indicating atrial overload, while AAIR pacing maintained better overall cardiac dynamics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiodynamic and neurohormonal importance of atrial contribution in rate-responsive pacing. Seino, Y., Shimai, S., Nagae, Y., et al.[2019]

Prolonged stimulation of the right ventricular apex in cardiac pacing can lead to significant adverse effects, highlighting the need for careful consideration in pacing strategies.

The commentary discusses potential modifications in contemporary pacing techniques to mitigate these adverse effects, reflecting the evolution of cardiac pacing practices over the past 50 years.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fifty years of cardiac pacing: the dark side of the moon? de Cock, CC.[2021]

Recent multicenter trials have shown that physiologic pacing, particularly biventricular pacing, can significantly improve heart function and quality of life in patients with congestive heart failure (CHF), as evidenced by better peak exercise oxygen consumption and ejection fraction.

Ongoing studies aim to address safety concerns, such as pacing-induced arrhythmias, and explore the potential benefits of pacing for a broader range of CHF patients beyond those with specific conduction abnormalities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Congestive heart failure treatment: the pacing approach. Dresing, TJ., Natale, A.[2019]

Rate adaptive cardiac pacing (RAP) significantly increased peak heart rate (HR) by 15 bpm compared to fixed rate pacing in patients with chronic heart failure, based on a systematic review of 14 studies.

Despite the increase in peak HR, RAP did not lead to a significant improvement in peak exercise capacity (peak VO2), suggesting that while RAP enhances heart rate response, it may primarily benefit cardiac output at lower exercise intensities rather than overall peak performance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rate adaptive pacing in people with chronic heart failure increases peak heart rate but not peak exercise capacity: a systematic review. Clark, HI., Pearson, MJ., Smart, NA.[2023]

In patients with heart failure and depressed left ventricular (LV) function, switching from dual-chamber pacing to ventricular pacing during exercise improved cardiac function, as indicated by increased LV ejection fraction and stroke volume, without affecting overall cardiac output.

Conversely, in patients with normal LV function, ventricular pacing led to a significant decrease in cardiac output during physical activity, suggesting that the benefits of ventricular pacing may be limited to those with impaired heart function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Haemodynamic effects of dual-chamber pacing versus ventricular pacing during a walk test in patients with depressed or normal left ventricular function. Ferro, A., Duilio, C., Santomauro, M., et al.[2018]

References

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

The effects of rate-adaptive atrial pacing versus ventricular backup pacing on exercise capacity in patients with left ventricular dysfunction. [2009]

2. England pubmed.ncbi.nlm.nih.gov

Exercise testing in the indication and evaluation of pacemaker treatment. [2019]

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

Physiologic correlates of the heart rate response to upright isotonic exercise: relevance to rate-responsive pacemakers. [2019]

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

The Pacing Therapies for Congestive Heart Failure (PATH-CHF) study: rationale, design, and endpoints of a prospective randomized multicenter study. [2019]

5. Germany pubmed.ncbi.nlm.nih.gov

Hemodynamics and exercise capacity during pacemaker stimulation. [2007]

6. England pubmed.ncbi.nlm.nih.gov

Right ventricular pacing impairs endothelial function in man. [2011]

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

Cardiodynamic and neurohormonal importance of atrial contribution in rate-responsive pacing. [2019]

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

Fifty years of cardiac pacing: the dark side of the moon? [2021]

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

Congestive heart failure treatment: the pacing approach. [2019]

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

Rate adaptive pacing in people with chronic heart failure increases peak heart rate but not peak exercise capacity: a systematic review. [2023]

11. Germany pubmed.ncbi.nlm.nih.gov

Haemodynamic effects of dual-chamber pacing versus ventricular pacing during a walk test in patients with depressed or normal left ventricular function. [2018]