Cardiac Sympathetic Dysfunction in Genotyped Patients with Arrhythmogenic Right Ventricular Cardiomyopathy and Risk of Recurrent Ventricular Tachyarrhythmias

Abstract

Patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) typically present with ventricular tachyarrhythmias preferentially triggered by an elevated sympathetic tone. Previous studies demonstrated an impairment of the presynaptic catecholamine reuptake as assessed by 123 I-labeled norepinephrine analog on metaiodobenzylguanidine ( 123 I-MIBG) SPECT. Mutations in the gene encoding for plakophilin-2 (PKP-2) are the most common cause of autosomal dominant ARVC (ARVC-9). In this study, we investigated the potential role of adrenergic dysfunction on the arrhythmia profile in patients with ARVC and correlated these findings with the causative genotype. Methods: 123 I-MIBG SPECT was performed for 42 patients with definite ARVC (10 women, 32 men; mean age 6 SD, 43 6 14 y). Images were acquired at 4 h after injection and analyzed for regional 123 I-MIBG uptake in a standardized 33-segment polar map. Results were compared with those obtained from 10 control subjects (5 women, 5 men; mean age 6 SD, 43 6 12 y). Results: An abnormal tracer uptake was detected in 25 patients with ARVC (59%). The extents of right ventricular dilation and regional wall motion abnormalities as well as electrocardiographic markers of de-or repolarization were not significantly different between patients with normal and abnormal 123 I-MIBG SPECT findings. However, during long-term follow-up of 11.9 6 4.1 y, patients with abnormal 123 I-MIBG SPECT findings experienced life-threatening ventricular tachyarrhythmias significantly more often (22/25 patients [88%]) and independent of the extent of right ventricular dysfunction than those with a normal sympathetic innervation (6/17 patients [35%]; P , 0.0005). Mutations in PKP-2 were identified in 17 patients (40%) but were not correlated with the degree of adrenergic dysfunction. Conclusion: In patients with ARVC, an impairment of adrenergic innervation independent of the underlying genotype is associated with a higher incidence for future recurrences of ventricular tachyarrhythmias. This finding may suggest a potential role of 123 I-MIBG SPECT for individualized risk stratification in ARVC patients and asymptomatic PKP-2 mutation carriers alike.

ASNC imaging guidelines for SPECT nuclear cardiology procedures: Stress, protocols, and tracers

“…Cardiac 123 I-mIBG imaging is currently indicated for ''scintigraphic assessment of sympathetic innervation of the myocardium in patients with New York Heart Association [NYHA] class II or class III HF and left ventricular ejection fraction [LVEF] B35% … and to help identify patients with lower oneand two-year mortality risks, as indicated by an [HMR] ratio C1.6.'' Nevertheless, much literature suggests a potential broader use, 91 including identification of patients at increased risk of lethal cardiac arrhythmias in the setting of HF, [92][93][94][95] evaluating primary arrhythmic conditions, [96][97][98][99][100] assessing the presence and risk of ischemic heart disease, 101,102 including in situations of hibernating myocardium 103,104 and post-infarction, [105][106][107] evaluating pre-and post-cardiac transplant patients, [108][109][110] identifying diabetic patients at increased risk from cardiac autonomic dysfunction, 111,112 and monitoring toxicity from chemotherapy. 113 However, based on currently available literature, published guidelines, and the FDA package insert, the following indications can be recommended: 114 • For patients with NYHA class II or III heart failure with LVEF B35% to help stratify risk and to promote more informed clinical decision-making when the result of 123 I-mIBG study is likely to influence the decision regarding ICD implant.…”

Genes Causing Inherited Forms of Cardiomyopathies

“…Comprehensive screening of all known and potentially causative genes is likely to place the mutation detection rate in ARVC probands in a 40-50% range [85]. The majority of reported mutations are heterozygous missense mutations causing a nonsynonymous amino acid substitution mainly in desmosomal proteins [74]. Desmosomes are major cell adhesion junctions, particularly prominent in the epidermis and cardiac tissue, and are important for the rigidity and strength of the cells for cell-to-cell contact and cell signaling.…”

“…In general, overlap of ARVC with other cardiomyopathies is not a general problem to distinguish ARVC from DCM or noncompaction cardiomyopathy (NCMP) or other right ventricular disorders [73,74]. In rare instances, ARVC may have a left ventricular involvement [32,33,40,45,53,59,89,94] due to a rare mutation in an ARVC gene (DSP-2) [69].…”

Resolution and noise properties of ¹²³I MIBG SPECT with collimator-detector response modeling

“…It has proven useful for the detection of neuroendocrine tumors, as well as to image the sympathetic innervation of the heart. Although its primary clinical applica tion is currently tumor detection, this tracer has recently shown promise as a prognostic indicator of heart failure progression and future risk of cardiac arrhythmic events [2]- [4].…”