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

Abstract

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).

Keywords: (11)C-HED; (11)C-meta-hydroxyephedrine; (123)I-meta-iodobenzylguanidine; (18)F-2-deoxyglucose; (18)FDG; B-type natriuretic peptide; BNP; ICD; LV; LVEF; MIBG; MRI; PET; SCA; VF; VT; implantable cardiac defibrillator; left ventricle; left ventricular ejection fraction; magnetic resonance imaging; myocardial viability; positron emission tomography; sudden cardiac arrest; sympathetic denervation; ventricular fibrillation; ventricular tachycardia.

Figure 1. PET imaging of Flow, Viability, and Sympathetic Innervation

(A) A subject experiencing sudden cardiac arrest (SCA). There is a mismatch in infarct size (reduced ¹⁸F-2-deoxyglucose [¹⁸FDG]), which was smaller than the volume of sympathetic denervation (reduced ¹¹C-meta-hydroxyephedrine [¹¹C-HED]). There was also reduced perfusion (¹³N-ammonia [¹³NH₃]) with preserved ¹⁸FDG indicating hibernating myocardium. In contrast, B shows a subject with matched reductions in flow, infarct volume, and sympathetic denervation. ANT = anterior; INF = inferior; LAT = lateral; PET = positron emission tomography; SEP = septum.

Figure 2. PET Parameters and SCA

Kaplan-Meier curves show the incidence of SCA for tertiles of PET-defined myocardial substrates (median follow-up 4.1 years). As continuous variables, the total volume of denervated myocardium, as well as viable denervated myocardium, predicted SCA. Neither infarct volume nor hibernating myocardium was significant as continuous variables. Abbreviations as in Figure 1.

Figure 3. Predictors of SCA by Multivariate Analysis

Kaplan-Meier curves illustrating the incidence of SCA greater than and less than the optimal cut-point for denervated myocardium (>37.6% of left ventricle [LV]), left ventricular end-diastolic volume index (LVEDVI >99 ml/m²), creatinine (>1.49 mg/dl), and no angiotensin inhibition therapy. The hazard ratio (HR) for each parameter was derived from the multivariate analysis. ACEI/ARA = angiotensin-converting-enzyme inhibitor/angiotensin receptor antagonist. Abbreviations as in Figure 1.

Figure 4. SCA Risk Factor Model

Kaplan-Meier curves illustrating highly significant differences in the incidence of SCA in relation to the number of risk factors present (p < 0.0001). Subjects with no risk factor (blue, 44% of cohort) had an annual rate of SCA <1%. With 2 or more risk factors (red, 20% of cohort), the annual risk of SCA increased to ~12%. Patients with 1 risk factor (green, 36% of cohort) had an intermediate risk of SCA (~4%/year). Abbreviations as in Figure 1.