Prediction of ARrhythmic Events With Positron Emission Tomography

Hibernating Myocardium and Sudden Cardiac Death

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.

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.

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