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-Although humans and swine with hibernating myocardium have an increased risk of sudden death, the contribution of chronic alterations in sympathetic nerve function is unknown. Acute transmural ischemia causes inhomogeneity in sympathetic innervation that may lead to lethal arrhythmias, but it is unclear whether similar abnormalities develop in response to chronic reversible ischemia. Methods and Results-Swine were chronically instrumented with a left anterior descending coronary artery (LAD) stenosis that produced hibernating myocardium after 3 months. Resting subendocardial flow (LAD 0.75Ϯ0.14 versus 1.19Ϯ0.14 mL · min Ϫ1 · g Ϫ1 , PϽ0.05) and wall thickening (LAD 15Ϯ3% versus 40Ϯ2%, PϽ0.05) were reduced compared with normal remote regions, without triphenyltetrazolium chloride evidence of necrosis.131 I-metaiodobenzylguanidine (MIBG) was used to assess integrity of the norepinephrine uptake-1 mechanism, and the spatial and transmural distributions were quantified by ex vivo counting. In hibernating myocardium, MIBG deposition was decreased in each layer, with the greatest reduction in the subendocardium (LAD subendocardium 0.28Ϯ0.02 versus 0.42Ϯ0.04 mL · g Ϫ1 · min Ϫ1 in normal, PϽ0.05; LAD subepicardium 0.31Ϯ0.03 versus 0.38Ϯ0.04 mL · g Ϫ1 · min Ϫ1 in normal, PϽ0.05). In contrast, there were no spatial alterations of MIBG deposition in sham-instrumented animals. Conclusions-The sympathetic norepinephrine uptake-1 mechanism is impaired in hibernating myocardium. These findings raise the possibility that chronic alterations in sympathetic innervation contribute to the excess mortality seen in the setting of hibernating myocardium. Key Words: hibernation Ⅲ myocardial stunning Ⅲ nervous system, sympathetic Ⅲ death, sudden Ⅲ ischemia S patial variations in regional sympathetic innervation lead to inhomogeneity in cardiac repolarization and may increase the risk of arrhythmic sudden death. 1-3 Regional denervation occurs after myocardial infarction, and lethal arrhythmias may be related to nerve sprouting during reinnervation. 4 Functional denervation has also been observed after brief coronary occlusions, 5,6 as well as in viable risk areas of reperfused myocardial infarcts, 7 which supports the view that sympathetic nerve function is exquisitely sensitive to ischemia.Although transmural ischemia causes cardiac denervation, it is uncertain whether reversible subendocardial ischemia could chronically affect sympathetic nerve function and contribute to the risk of sudden death in patients with chronic ischemic heart disease. In support of this, clinical studies have demonstrated an increased mortality when patients with hibernating myocardium are not revascularized, and the excess risk is largely related to sudden death. 8 This increased mortality is also seen in animal studies of chronic hibernating myocardium, in which the cumulative incidence of sudden death approaches 50% over 5 months. 9 We hypothesized that hibernating myocardium exhibits regional inhomogeneity in sympathetic innervation that arise...
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.
Background Positron emission tomography (PET) with insulin-stimulated 18F-2-deoxyglucose (FDG) uptake is the gold standard for myocardial viability. However, insulin stimulation is infrequently performed due to time and inconvenience. We therefore assessed the clinical applicability of an abbreviated hyperinsulinemic-euglycemic clamp. Methods and Results Dynamic FDG PET was performed in 50 patients with ischemic cardiomyopathy (ejection fraction: .30 ± .10) using an abbreviated hyperinsulinemic-euglycemic clamp with separate Non-Diabetic (n = 26) and Diabetic (n = 24) protocols (American Society of Nuclear Cardiology guidelines), and supplemental potassium. In regions with normal resting perfusion (13N-ammonia uptake ≥80% maximal segment), there were no differences in either maximal (Non-Diabetic: .60 ± .20 vs Diabetic: .60 ± .17 μmol/min/g, P = .93) or mean rates of myocardial glucose uptake (MGU) (Non-Diabetic: .52 ± .18 vs Diabetic: .52 ± .14 μmol/min/g, P = .63) between the protocols. Multivariate analysis showed that diastolic blood pressure alone (maximal MGU, r2 = .20, P = .001) or with NYHA Heart Failure Class (mean MGU, r2 = .25, P = .003) could account for some of the variability in normal-region MGU. Potassium supplementation safely attenuated the decline in plasma levels. Conclusions This abbreviated hyperinsulinemic-euglycemic clamp produced similar MGU values in normal resting myocardium in non-diabetic and diabetic subjects, which are no different than published rates with a standard insulin clamp. Thus, this abbreviated approach is sufficient to overcome myocardial insulin resistance.
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