Objectives The PAREPET (Prediction of ARrhythmic Events with Positron Emission Tomography) study sought to test the hypothesis that quantifying inhomogeneity in myocardial sympathetic innervation could identify patients at highest risk for sudden cardiac arrest (SCA). Background Left ventricular ejection fraction (LVEF) is the only parameter identifying patients at risk of SCA who benefit from an implantable cardiac defibrillator (ICD). Methods We prospectively enrolled 204 subjects with ischemic cardiomyopathy (LVEF ≤35%) eligible for primary prevention ICDs. Positron emission tomography (PET) was used to quantify myocardial sympathetic denervation (11C-meta-hydroxyephedrine [11C-HED]), perfusion (13N-ammonia) and viability (insulin-stimulated 18F-2-deoxyglucose). The primary endpoint was SCA defined as arrhythmic death or ICD discharge for ventricular fibrillation or ventricular tachycardia >240 beats/min. Results After 4.1 years follow-up, cause-specific SCA was 16.2%. Infarct volume (22 ± 7% vs. 19 ± 9% of left ventricle [LV]) and LVEF (24 ± 8% vs. 28 ± 9%) were not predictors of SCA. In contrast, patients developing SCA had greater amounts of sympathetic denervation (33 ± 10% vs. 26 ± 11% of LV; p = 0.001) reflecting viable, denervated myocardium. The lower tertiles of sympathetic denervation had SCA rates of 1.2%/year and 2.2%/year, whereas the highest tertile had a rate of 6.7%/year. Multivariate predictors of SCA were PET sympathetic denervation, left ventricular end-diastolic volume index, creatinine, and no angiotensin inhibition. With optimized cut-points, the absence of all 4 risk factors identified low risk (44% of cohort; SCA <1%/year); whereas ≥2 factors identified high risk (20% of cohort; SCA ~12%/year). Conclusions In ischemic cardiomyopathy, sympathetic denervation assessed using 11C-HED PET predicts cause-specific mortality from SCA independently of LVEF and infarct volume. This may provide an improved approach for the identification of patients most likely to benefit from an ICD. (Prediction of ARrhythmic Events With Positron Emission Tomography [PAREPET]; NCT01400334)

Background Previous studies have identified multiple risk factors that are associated with total cardiac mortality. Nevertheless, identifying specific factors that distinguish patients at risk of arrhythmic death versus heart failure could better target patients likely to benefit from implantable cardiac defibrillators (ICDs), which have no impact on non-sudden cardiac death (NSCD). Methods and Results We performed a pilot competing risks analysis of the NIH-sponsored PAREPET trial (Prediction of ARrhythmic Events with Positron Emission Tomography). Death from cardiac causes was ascertained in subjects with ischemic cardiomyopathy (n=204) eligible for an ICD for the primary prevention of sudden cardiac arrest (SCA) after baseline clinical evaluation and imaging at enrollment (PET and 2D-echo). Mean age was 67±11 years with an EF of 27±9%, and 90% were male. Over 4.1 years of follow-up, there were 33 SCAs (arrhythmic death or ICD discharge for ventricular fibrillation or ventricular tachycardia >240 bpm) and 36 NSCDs. SCA was correlated with a greater volume of denervated myocardium (defect of the PET norepinephrine analog 11C-hydroxyephedrine), lack of angiotensin inhibition therapy, elevated B-type natriuretic peptide, and larger LV end-diastolic volume index (LVEDVI). In contrast, NSCD was associated with a higher resting heart rate, older age, elevated creatinine, larger left atrial volume index, and larger LVEDVI. Conclusions Distinct clinical, laboratory and imaging variables are associated with cause-specific cardiac mortality in primary prevention candidates with ischemic cardiomyopathy. If prospectively validated, these multi-variable associations may help target specific therapies to those at greatest risk of sudden and non-sudden cardiac death.

Infarct volume independently predicts cardiovascular events. Fragmented QRS complexes (fQRS) may complement Q-waves for identifying infarction; however, their utility in advanced coronary disease is unknown. We tested whether fQRS could improve the ECG prediction of infarct volume by PET in 138 patients with ischemic cardiomyopathy (EF 0.27±0.09). Indices of infarction (pathologic Q-waves, fQRS, and Selvester QRS Score) were analyzed by blinded observers. In patients with QRS duration <120ms, number of leads with pathologic Q-waves (mean 1.6±1.7) correlated weakly with infarct volume (r=0.30, p<0.05). Adding fQRS increased the number of affected leads (3.6±2.5), but the significant correlation with infarct volume was lost (r=0.02, p=0.10). Selvester Score was the most accurate (mean 5.9±4.9 points; r=0.49, p<0.001). fQRS was not predictive of infarct size in patients with QRS duration ≥120ms (r=0.02, p=0.19). Thus in ischemic cardiomyopathy, consideration of fQRS complexes does not improve Q-wave prediction of infarct volume, but Selvester Score was more accurate.

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