Prediction of ARrhythmic Events With Positron Emission Tomography

Study Overview
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Brief Summary
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The hypothesis of PAREPET is that hibernating myocardium (viable myocardium with reduced resting flow) and/or viable but denervated myocardium can predict the risk of sudden death in subjects with ischemic cardiomyopathy.

Detailed Description
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Currently available electrophysiological approaches are limited in their ability to identify the majority of patients with CAD and LV dysfunction that succumb to sudden cardiac death (SCD). Half of the patients developing SCD are not inducible at electrophysiological testing underscoring the need for new ways to identify substrates leading to arrhythmic death. Viable chronically dysfunctional with reduced resting flow, or hibernating myocardium, not amenable to revascularization appears to be a major risk factor for subsequent cardiac death and is present in up to 60% of patients with ischemic cardiomyopathy. Cause specific mortality data is limited but appears to be arrhythmic rather than from fatal myocardial infarction or progressive heart failure. Revascularization improves survival but most patients with hibernating myocardium are managed medically due to prohibitive procedural risks or technical limitations. Basic studies in swine with hibernating myocardium demonstrate SCD arising from VT/VF in the absence of myocardial scar or heart failure. The central hypothesis of this proposal is that the presence of hibernating myocardium as opposed to scar identifies a large subset of patients with ischemic cardiomyopathy that are at high risk for SCD. We further hypothesize that this risk is related to inhomogeneity in sympathetic innervation arising from chronic repetitive ischemia. PAREPET is a prospective observational study that will enroll patients with coronary disease, Class I-III heart failure and an ejection fraction ≤35%. Using positron emission tomography (PET), the frequency and amount of hibernating myocardium will be quantified in patients that are not candidates for coronary revascularization. Three Specific Aims are proposed. Aim 1 will determine whether imaging the mismatch between viability (preserved 18F-2-deoxyglucose) and reduced resting flow (13NH3) can predict an increased risk of SCD (or ICD discharge for VT/VF as a surrogate end-point) in hibernating myocardium. Aim 2 will image norepinephrine uptake using 11C-hydroxyephedrine to determine whether inhomogeneity in myocardial sympathetic innervation predicts SCD risk better than viability testing. Aim 3 will identify whether the substrate identified by PET is stable after an aborted SCD event by evaluating temporal changes in function, viability and sympathetic innervation in patients with an ICD. Our long-term objective is to develop better approaches to identify patients with CAD who are most likely to benefit from primary prevention of SCD with placement an ICD.

Official Title
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Hibernating Myocardium and Sudden Cardiac Death

Conditions
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Ischemic Cardiomyopathy, Hibernating Myocardium, Nerve; Disorder, Sympathetic

Intervention / Treatment
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* Radiation: Positron Emission Tomography


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: LV EF ≤35% (by nuclear imaging, cardiac catheterization or echocardiography) Coronary artery disease documented by cardiac catheterization, a history of definite myocardial infarction, or reversible ischemia on nuclear imaging New York State Heart Association functional Class I-III heart failure Not a candidate for surgical or percutaneous coronary revascularization at the time of enrollment Exclusion Criteria: History of resuscitated sudden cardiac death, sustained ventricular tachycardia, appropriate implantable cardiac defibrillator (ICD) discharge, or unexplained syncope Myocardial infarction within 30 days Coronary artery bypass grafting within 1 year Percutaneous intervention within 3 months Claustrophobia or physical limitation that would preclude PET scanning Pregnancy Tricyclic antidepressant drug therapy Comorbidities that would be expected to result in noncardiac death within 2 years Inability to provide informed consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Ischemic Cardiomyopathy<br>Subjects with ischemic cardiomyopathy [pre-enrollment left ventricular ejection fraction ≤0.35, with coronary artery disease documented by cardiac catheterization, a history of definite myocardial infarction, or reversible ischemia on nuclear imaging] who are considered eligible to receive an implantable cardiac defibrillator for the primary prevention of sudden cardiac death. | Radiation: Positron Emission Tomography<br>* Quantification of cardiac function using positron emission tomography and: a)11C-meta-hydroxyephedrine [HED, 20 mCi (740 MBq)] to quantify sympathetic nerve function, b) 13N-ammonia [NH3, 20 mCi (740 MBq)] for regional perfusion, and c) 18F-2-deoxyglucose [FDG; 6.5 mCi (241 MBq)] administered during a hyperinsulinemic-euglycemic clamp to assess viability.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sudden Cardiac Death | Adjudicated sudden cardiac death and implantable cardiac defibrillator therapy for fast ventricular tachycardia (>240 bpm) or ventricular fibrillation. | every 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiac Death | Sudden cardiac death and adjudicated non-sudden cardiac death | every 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ischemic Cardiomyopathy, Sudden Cardiac Death, Positron Emission Tomography, Hibernating Myocardium, Denervated Myocardium