Regional myocardial sympathetic denervation predicts the risk of sudden cardiac arrest in ischemic cardiomyopathy.

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 ((11)C-meta-hydroxyephedrine [(11)C-HED]), perfusion ((13)N-ammonia) and viability (insulin-stimulated (18)F-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 (11)C-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).

An abbreviated hyperinsulinemic-euglycemic clamp results in similar myocardial glucose utilization in both diabetic and non-diabetic patients with ischemic cardiomyopathy.

BACKGROUND: Positron emission tomography (PET) with insulin-stimulated (18)F-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 ((13)N-ammonia uptake >or=80% maximal segment), there were no differences in either maximal (Non-Diabetic: .60 +/- .20 vs Diabetic: .60 +/- .17 micromol/min/g, P = .93) or mean rates of myocardial glucose uptake (MGU) (Non-Diabetic: .52 +/- .18 vs Diabetic: .52 +/- .14 micromol/min/g, P = .63) between the protocols. Multivariate analysis showed that diastolic blood pressure alone (maximal MGU, r (2) = .20, P = .001) or with NYHA Heart Failure Class (mean MGU, r (2) = .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.

The Selvester QRS Score is more accurate than Q waves and fragmented QRS complexes using the Mason-Likar configuration in estimating infarct volume in patients with ischemic cardiomyopathy.

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 electrocardiographic prediction of infarct volume by positron emission tomography in 138 patients with ischemic cardiomyopathy (ejection fraction, 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 less than 120 milliseconds, number of leads with pathologic Q waves (mean, 1.6 +/- 1.7) correlated weakly with infarct volume (r = 0.30, P < .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 = .10). Selvester Score was the most accurate (mean, 5.9 +/- 4.9 points; r = 0.49; P < .001). Fragmented QRS was not predictive of infarct size in patients with QRS duration of at least 120 milliseconds (r = 0.02, P = .19). Thus, in ischemic cardiomyopathy, consideration of fQRS complexes does not improve Q wave prediction of infarct volume; but Selvester Score was more accurate.

Prediction of arrhythmic events with positron emission tomography: PAREPET study design and methods.

BACKGROUND: In medically-treated patients with ischemic cardiomyopathy, myocardial viability is associated with a worse prognosis than scar. The risk is especially great with hibernating myocardium (chronic regional dysfunction with reduced resting flow), and the excess mortality appears to be due to sudden cardiac death (SCD). Hibernating myocardium also results in sympathetic nerve dysfunction, which has been independently associated with risk of SCD. OBJECTIVES: PAREPET is a prospective, observational cohort study funded by NHLBI. It is designed to determine whether hibernating myocardium and/or inhomogeneity of sympathetic innervation by positron emission tomography imaging identifies patients with ischemic cardiomyopathy who are at high risk for SCD and cardiovascular mortality. METHODS: Patients with documented ischemic cardiomyopathy, an ejection fraction of

Regional 11C-hydroxyephedrine retention in hibernating myocardium: chronic inhomogeneity of sympathetic innervation in the absence of infarction.

UNLABELLED: We have previously shown that ex vivo counting of (131)I-metaiodobenzylguanidine can identify regional reductions in sympathetic norepinephrine uptake in pigs with hibernating myocardium. However, nonneuronal uptake limited relative differences between regions and would preclude accurate assessment with conventional imaging. We therefore hypothesized that the superior specificity of the positron-emitting isotope (11)C-hydroxyephedrine (HED) would facilitate the imaging of regional differences, and we designed this study to determine whether altered uptake of norepinephrine by sympathetic nerves in viable, dysfunctional myocardium can be imaged in vivo and to determine the temporal progression and stability of sympathetic dysinnervation in hibernating myocardium. METHODS: Pigs (n = 15) were chronically instrumented with a 1.5-mm stenosis of the left anterior descending coronary artery, a procedure that we have previously shown to produce viable chronically dysfunctional myocardium with reduced resting flow, or hibernating myocardium, after 3 mo. Physiologic studies and HED PET were performed 1-5 mo later with the animals in the closed-chest sedated state. One animal with a myocardial infarct was analyzed separately. RESULTS: After 3 mo, anterior hypokinesis developed (wall thickening, 32% +/- 4% vs. 60% +/- 4%, P < 0.001), with reductions in resting flow (subendocardial flow, 0.81 +/- 0.11 vs. 1.20 +/- 0.18 mL/min/g, P < 0.05) and a critical reduction in subendocardial flow reserve (subendocardial adenosine flow, 0.53 +/- 0.20 vs. 3.96 +/- 0.43 mL/min/g, P < 0.001). Extensive defects in HED uptake were found for hibernating myocardium, with regional retention approximately 50% lower than that in normally perfused remote myocardium (0.035 +/- 0.002 vs. 0.066 +/- 0.002 min(-1), P < 0.001). Relative HED uptake (left anterior descending coronary artery/remote) was lower in chronically instrumented animals than in control animals (n = 4, P < 0.001) and animals studied 1 mo after instrumentation (n = 2, P < 0.05). The regional reduction in sympathetic nerve function was persistent and unaltered for at least 2 mo after the development of hibernating myocardium. CONCLUSION: Hibernating myocardium is associated with persistent reductions in regional uptake of norepinephrine by sympathetic nerves. The inhomogeneity in sympathetic innervation in viable dysfunctional myocardium is similar to that occurring after myocardial infarction and may contribute to arrhythmic death in patients with ischemic cardiomyopathy.

Spatial inhomogeneity of sympathetic nerve function in hibernating myocardium.

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 0.75+/-0.14 versus 1.19+/-0.14 mL. min(-1) x g(-1), P<0.05) and wall thickening (LAD 15+/-3% versus 40+/-2%, P<0.05) were reduced compared with normal remote regions, without triphenyltetrazolium chloride evidence of necrosis. 131I-meta-iodobenzylguanidine (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 0.28+/-0.02 versus 0.42+/-0.04 mL x g(-1) x min(-1) in normal, P<0.05; LAD subepicardium 0.31+/-0.03 versus 0.38+/-0.04 mL x g(-1) x min(-1) in normal, P<0.05). 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.