Diagnostic Test for CRDS

(DIAGNOSE CRDS Trial)

Recruiting at 17 trial locations

Overseen By Jason Roberts, MD MAS

Age: Any Age

Sex: Any

Trial Phase: Academic

Sponsor: Population Health Research Institute

Must not be taking: Qt prolonging, Class I/III anti-arrhythmics

Disqualifiers: Ventricular cardiomyopathy, Long QT, others

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

400 Participants Needed

Trial Summary

What is the purpose of this trial?

Calcium Release Deficiency Syndrome (CRDS) is a novel inherited arrhythmia syndrome secondary to RyR2 loss-of-function that confers a risk of sudden cardiac death. Diagnosis of CRDS presently requires cellular-based in vitro confirmation that an RyR2 variant causes loss-of-function. We hypothesize that CRDS can be diagnosed clinically through evaluation of the repolarization response to brief tachycardia, mediated by cardiac pacing, and a subsequent pause.

Will I have to stop taking my current medications?

If you are taking a QT prolonging medication or certain anti-arrhythmic drugs, you may need to stop them before participating in the trial, especially during specific procedures. The protocol does not specify a washout period, but you should discuss your current medications with the trial team.

What data supports the effectiveness of the treatment Pacing, Cardiac Pacing, Artificial Pacing, Electrical Stimulation of the Heart for CRDS?

Modern pacemakers, which are used in cardiac pacing, have shown promise in meeting the physiological needs of patients by reducing the incidence of atrial fibrillation (irregular heartbeat) and potentially lowering heart failure hospitalizations. Although specific data for CRDS is not available, these devices have been effective in managing heart rate and improving heart function in other conditions. ^{1 2 3 4 5}

Is cardiac pacing generally safe for humans?

Modern pacemakers, which are used for cardiac pacing, have a reasonable safety margin and are considered safe for fulfilling clinical needs. However, there are rare but significant complications associated with device implantation. ^{1 2 6 7 8}

How is this treatment for CRDS different from other treatments?

The treatment for CRDS involves a diagnostic test using electrophysiologic testing, which is unique because it uses electrode catheters to record electrical activity in the heart and assess arrhythmias. This method is different from standard treatments as it focuses on diagnosing and evaluating the effectiveness of therapies for heart rhythm disturbances. ^{3 9 10 11 12}

Research Team

Wayne Chen, PhD

Principal Investigator

University of Calgary

Ziv Dadon, MD

Principal Investigator

Shaare Zedek Medical Center

Jason D Roberts, MD MAS

Principal Investigator

McMaster University

Eligibility Criteria

This trial is for individuals suspected to have Calcium Release Deficiency Syndrome (CRDS), a genetic heart rhythm disorder that can lead to sudden cardiac death. Participants should be able to undergo a diagnostic test involving brief, controlled increases in heart rate.

Inclusion Criteria

I have a genetic mutation in RyR2 or CASQ2 that affects my heart.

I had a cardiac arrest that remains unexplained even after several heart tests.

I am scheduled for a detailed heart rhythm test.

Exclusion Criteria

I am unable to understand and agree to the study's details on my own.

I am taking medication that affects my heart's rhythm, except for flecainide.

I am currently taking medication that affects my heart's rhythm.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pacing

Separate ventricular and atrial pacing trains are administered at different cycle lengths to evaluate the ventricular repolarization response

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after the pacing procedure

4 weeks

Treatment Details

Interventions

• Pacing

Trial Overview The study aims to evaluate if CRDS can be diagnosed without cellular tests by observing the heart's electrical recovery after it is briefly sped up using a method called pacing. This could simplify and speed up diagnosis.

Participant Groups

Group I: Pacing Experimental Treatment 1 Intervention

Separate ventricular and atrial pacing trains will be administered at different cycle lengths and the ventricular repolarization response on the first sinus beat following the subsequent pause will be evaluated.

Who Is Running the Clinical Trial?

Population Health Research Institute

Lead Sponsor

Trials

165

Recruited

717,000+

Canadian Institutes of Health Research (CIHR)

Collaborator

Trials

1,417

Recruited

26,550,000+

Findings from Research

Modern pacemakers have advanced features that not only help manage arrhythmias but also meet the physiological needs of patients, including dual-chamber pacing and cardiac resynchronization therapy, which can significantly reduce the incidence of atrial fibrillation.

While modern pacemakers show acceptable performance and safety, the reduction in all-cause mortality due to physiological pacing has not yet been proven in randomized trials, indicating that further research is needed to confirm their long-term benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modern pacemakers: hope or hype? DAS, MK., Dandamudi, G., Steiner, HA.[2009]

Artificial pacemakers are crucial for patients with inadequate intrinsic heart rates, as they provide necessary electrical impulses to maintain a normal cardiac rhythm.

Recent advancements in pacemaker technology have made it essential for physicians to understand their use and the potential complications that may arise with these devices.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Artificial cardiac pacemakers. Das, G., Carlblom, D.[2018]

Diagnostic pacing, particularly rapid atrial pacing, is an effective method for stressing the heart in patients with ischemic heart disease, helping to provoke symptoms and assess heart function.

This technique has been valuable in evaluating the effectiveness of treatments for angina and in understanding the mechanisms of heart rhythm disorders, including re-entry supraventricular tachycardias.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diagnostic uses of electrical pacing. Zir, LM., DeSanctis, RW., Harthorne, JW.[2008]

A study of 287 children with congenital heart defects showed that cardiac pacing is generally effective in the long term, with a median follow-up of 5 years, but endocardial systems had significantly better outcomes compared to epicardial systems.

Younger age at the time of implantation was associated with a higher risk of complications and system failure, highlighting the importance of careful patient selection for cardiac pacing in pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiac pacing in paediatric patients with congenital heart defects: transvenous or epicardial? Silvetti, MS., Drago, F., Di Carlo, D., et al.[2013]

The use of a steel wire loop electrode for emergency transthoracic cardiac pacing was successful in capturing heart activity in most patients, with 8 out of 13 cases of cardiac arrest showing effective pacing, especially when performed quickly after arrest.

This method proved to be safe and reliable, particularly when conventional pacing methods failed, suggesting it could significantly improve resuscitation outcomes in critical situations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The clinical application of the emergency remedial transthoracic cardiac pacing used by a steel wire loop electrode]. Ma, J., Su, L., Qiu, J., et al.[2019]

In a study of 22 patients undergoing coronary angiography, atrial pacing induced more positive ECG results for ischemia compared to standard exercise testing, with 94% of patients with significant coronary artery disease (CAD) showing ischemic changes during pacing.

The concordance rate of ECG changes between exercise and pacing tests was high at 90%, suggesting that atrial pacing could be a reliable alternative for detecting CAD, especially given its higher sensitivity in identifying ischemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The pacing stress test: a reexamination of the relation between coronary artery disease and pacing-induced electrocardiographic changes. Heller, GV., Aroesty, JM., McKay, RG., et al.[2019]

In a study of 17 patients with an average age of 67, the 'Crown of Thorns' electrode demonstrated successful long-term physiological pacing in 16 patients over a follow-up period of 4-13 months, indicating its efficacy and reliability.

The study found that while there were some initial failures with specific generators, switching to a more sensitive unit led to successful pacing, suggesting that the electrode can be effectively used with various dual chamber generators.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical evaluation of a single-pass implantable electrode for all modes of pacing. The "Crown of Thorns" lead. Wainwright, R., Crick, J., Sowton, E.[2019]

In a study of 151 patients who received complex cardiac devices (ICD, CRT-P, CRT-D) over two years, the overall procedural success rate was an impressive 99.3%, indicating high efficacy in implantation.

Complications occurred in 9.3% of cases, with lead displacement being the most common issue (5.3%), but there were no procedure-related deaths, highlighting the safety of these procedures when performed by experienced clinicians.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complex cardiac pacing in the setting of a district general hospital: procedural success and complications. Rahbi, H., El-Din, M., Salloum, M., et al.[2020]

Electrophysiologic testing, which involves placing electrode catheters in the heart to record electrical activity, is crucial for diagnosing arrhythmias and assessing treatment options in patients with various heart rhythm disorders.

This testing is particularly beneficial for patients with conditions like sinus node dysfunction, ventricular tachycardia, and those who have experienced cardiac arrest, as it helps evaluate the effectiveness of therapies such as antiarrhythmic drugs and procedures like transcatheter ablation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical intracardiac electrophysiologic testing: technique, diagnostic indications, and therapeutic uses. Hammill, SC., Sugrue, DD., Gersh, BJ., et al.[2019]

In a study of 26 patients with implanted pacemakers, non-invasive programmed ventricular stimulation successfully induced complex ventricular arrhythmias in 42% of cases, allowing for tailored treatment options based on the type of arrhythmia observed.

This method is a safe and repeatable alternative for assessing cardiac stability without the need for fluoroscopy, although it has limitations such as not being able to pace from the right ventricle outflow tract.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Electric programmed ventricular stimulation using a permanent cardiac pacing system--a noninvasive method in arrhythmia]. Novotný, T., Dvorák, R., Lábrová, R., et al.[2009]

The novel pacing guidewire demonstrated strong accuracy in measuring pacing thresholds and R-wave sensing during cardiac resynchronization therapy (CRT) procedures, particularly at basal and middle left ventricular sites, with significant correlations to LV lead measurements (r values up to 0.930).

The guidewire can effectively predict the presence of phrenic nerve stimulation at high pacing outputs with an 87% concordance rate, indicating its potential utility in optimizing CRT implantation sites.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Utility of a novel pacing guidewire in pre-implantation testing at different left ventricular sites in cardiac resynchronization therapy procedures. Chan, NY., Choy, CC., Lau, CL., et al.[2021]

Atrial pacing is a safe and effective method for assessing patients with angina pectoris, providing valuable information for clinical decision-making.

This technique is particularly useful for patients with uncertain diagnoses of angina or those being evaluated for potential surgical interventions for ischemic heart disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical use of atrial pacing test in angina pectoris. Balcon, R., Maloy, WC., Sowton, E.[2019]

References

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

Modern pacemakers: hope or hype? [2009]

2. Germany pubmed.ncbi.nlm.nih.gov

Artificial cardiac pacemakers. [2018]

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

Diagnostic uses of electrical pacing. [2008]

4. England pubmed.ncbi.nlm.nih.gov

Cardiac pacing in paediatric patients with congenital heart defects: transvenous or epicardial? [2013]

5. China pubmed.ncbi.nlm.nih.gov

[The clinical application of the emergency remedial transthoracic cardiac pacing used by a steel wire loop electrode]. [2019]

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

The pacing stress test: a reexamination of the relation between coronary artery disease and pacing-induced electrocardiographic changes. [2019]

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

Clinical evaluation of a single-pass implantable electrode for all modes of pacing. The "Crown of Thorns" lead. [2019]

8. England pubmed.ncbi.nlm.nih.gov

Complex cardiac pacing in the setting of a district general hospital: procedural success and complications. [2020]

9. England pubmed.ncbi.nlm.nih.gov

Clinical intracardiac electrophysiologic testing: technique, diagnostic indications, and therapeutic uses. [2019]

10. Czech Republic pubmed.ncbi.nlm.nih.gov

[Electric programmed ventricular stimulation using a permanent cardiac pacing system--a noninvasive method in arrhythmia]. [2009]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Utility of a novel pacing guidewire in pre-implantation testing at different left ventricular sites in cardiac resynchronization therapy procedures. [2021]

12. England pubmed.ncbi.nlm.nih.gov

Clinical use of atrial pacing test in angina pectoris. [2019]