Congenital Myocardial Sympathetic Dysinnervation (CMSD)—A Structural Defect of Idiopathic Long QT Syndrome

Abstract

Concerning the pathogenetic mechanism of idiopathic long QT syndrome (LQTS), the hypothesis of a specific sympathetic imbalance has gained general acceptance, but its validity has never been proven. To test this hypothesis I-123-MIBG, an analogue of norepinephrine and guanethidine, was used to provide scintigraphic display of the efferent cardiac sympathetic innervation. Twelve members of four LQTS families (mean age 38.2 +/- 17.2 years, eight males) and eight healthy volunteers (mean age 48.2 +/- 13.3 years, five males) were studied by means of I-123-MIBG single photon emission computed tomography (SPECT). A quantitative analysis of all scans was performed. All scans of the healthy volunteers show a uniform tracer uptake with sometimes slightly decreased activity in the apex. (1) All patients with QTc greater than 440 msec (n = 5); (2) all, who had suffered from at least one episode of torsade de pointes, ventricular fibrillation (VF) or syncope (n = 5); and (3) all symptomatic patients with QTc prolongation (n = 4) have reduced or abolished (P less than 0.02) MIBG uptakes in the inferior and inferior septal parts of the left ventricle (congenital myocardial sympathetic dysinnervation [CMSD]). Additionally, one female without symptoms or QTc prolongation (LQT) shows an abnormal MIBG SPECT similar to the one of her daughter, who has LQT and symptoms. One male without LQT, who had suffered from VF shows CMSD similar to his father, who has LQT, but no symptoms. All members of the families with normal MIBG SPECTs have neither LQT nor symptoms. In all families CMSD fulfills the criteria of autosomal-dominant inheritance. Normal QTc-interval predicted only in 57% normal cardiac sympathetic innervation in the present LQTS families. Therefore, quantitative I-123-MIBG SPECT enables to identify myocardial sympathetic dysinnervation as structural defect in LQTS. CMSD is associated with and without LQT and presents a pattern of autosomal-dominant inheritance. LQT at rest or during exercise was specific (100%), but less sensitive (63%) in the assessment of CMSD than I-123-MIBG SPECT.

Scintigraphic evidence for cardiac sympathetic dysinnervation in long-term IDDM patients with and without ECG-based autonomic neuropathy

“…Patients with idiopathic long QT syndrome have been found to demonstrate a reduced myocardial I~3I-MIBG uptake indicating sympathetic dysinnervation [12]. Whether diabetes is associated with a prolonged QT interval is under debate [41,42], but also a shortened QT interval in diabetes has been described [43].…”

“…The guanethidine analogue metaiodobenzylguanidine (MIBG) shares the same active uptake, storage, and release mechanisms as norepinephrine and therefore has a high affinity to chromaffin tissue and adrenergic nerve terminals [8,91. Abnormal 123I-MIBG uptake indicating cardiac sympathetic dysinnervation has been demonstrated after myocardial infarction [10], in cardiomyopathy [11] and in the idiopathic long QT syndrome [12]. Pilot studies in patients with diabetes suggest that the myocardial m3I-MIBG uptake is reduced in diabetic patients with cardiac autonomic neuropathy [13][14][15].…”

Channelopathies and Heart Disease

“…The resting heart rate of Romano-Ward syndrome patients was signifi cantly slower in newborn and children under age 3, due to a right-sided sympathetic defi ciency [ 138 ]. This hypothesis was confi rmed by cardiac SPECT screening with I123-MIBG, an analog of norepinephrine and guanethidine, in fi ve LQTS patients with at least one episode of torsades de pointes, ventricular fi brillation, or syncope, all of them presenting reduced or absent MIBG uptake in the inferior septal parts of the left ventricle compared to a control group [ 139 ]. In a screening study for 5 LQT-associated cardiac channel genes in 541 unrelated patients, Tester et al identifi ed 211 different pathogenic mutations in 272 patients (50 %), of which 29 (11 %) had double LQTS mutations, 16 of them (8 %) in two distinct LQTS genes (biallelic digenic) [ 140 ].…”

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

“…Standard 123 I-MIBG SPECT is restricted to the left ventricle, and thus no direct information on the sympathetic innervation of the right ventricle can currently be provided by SPECT techniques. However, the high incidence of abnormal 123 I-MIBG SPECT not only in ARVC patients but also in patients with known nonstructural LV abnormalities such as RV outflowtract tachycardias (8), or with the Brugada syndrome (7) or long-QT syndrome (13), may underscore the value of 123 I-MIBG SPECT.…”