T-Cell–Mediated Inflammatory Activity in the Stellate Ganglia of Patients With Ion-Channel Disease and Severe Ventricular Arrhythmias

Abstract

Background-Long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) are electric diseases characterized by catecholamine-induced ventricular arrhythmias. Unbalanced autonomic innervation of the heart may trigger arrhythmic events and stellectomy is a treatment option for patients who are resistant to pharmacological drugs. We analyzed left stellectomy specimens of LQTS and CPVT patients for signs of inflammatory activity. Methods and Results-Stellate ganglia were retrieved from 12 consecutive patients (8F; 4 mol/L; mean age, 23.4±17 years) with either LQTS (n=8) or CPVT (n=4) and serious arrhythmias. Control stellate ganglia were obtained from 10 accidently deceased patients (6F; 4 mol/L; mean age, 35±17.6 years). Sections were immunostained with antibodies against T cells (CD3, CD4, CD8, CD20, Granzyme B), CD68 (macrophages), and HLA-DR (human leukocyte antigen-DR) antigens (activation marker). Immunopositive cells were quantified as cells/mm 2 . Polymerase chain reaction (PCR) and reverse transcription PCR were performed to screen for herpes virus DNA. Stellate ganglia of all 12 LQTS/CPVT patients revealed mild but distinct inflammatory infiltrates composed of T lymphocytes and macrophages, which were diffusely spread, but also clustered in small foci opposed to ganglion cells, interpreted as T-cell-mediated ganglionitis. Morphometric analysis showed that CD3+ and CD8+ T cells/mm 2 were significantly higher in the ganglia of LQTS/CPVT cases than in healthy controls (P=0.0018 and P=0.0009, respectively). Molecular analyses were negative for neurotropic viruses. Conclusions-T-cell-mediated cytotoxicity toward ganglion cells may boost adrenergic activity as to trigger or enhance electric instability in LQTS/CPVT patients who are already genetically predisposed to arrhythmias. (Circ Arrhythm Electrophysiol. 2014;7:224-229.)

Inflammation, oxidative stress, and glial cell activation characterize stellate ganglia from humans with electrical storm

“…Morphological size of SGNs along with synaptic density are increased in patients with cardiomyopathy (CMY) and arrhythmias (3). Further, in patients with inherited channelopathies undergoing sympathectomy for recurrent ventricular arrhythmias, evidence of inflammation was demonstrated (7). The neurochemical properties of SGNs from humans with CMY and arrhythmias, in whom chronic sympathoexcitation is characteristic, remain unknown.…”

Ganglionitis and Genetic Cardiac Arrhythmias

“…Of course, our comments are speculative, but we suspect the ganglionic findings are minor and are not playing a causal role in the disease process. However, cervical thoracic ganglionectomy should dramatically reduce normal sympathetic traffic to the heart with resultant rhythm stabilization, and this is what was observed in almost all the patients reported in the article by Rizzo et al 6 The type of gangliocytic injury described by the authors as vacuolation may be subtle and is difficult to discern from figures provided. 6 Vacuolation of ganglion cells has been described in several instances from toxic exposure, to trauma, to aging and is considered nonspecific.…”

“…However, cervical thoracic ganglionectomy should dramatically reduce normal sympathetic traffic to the heart with resultant rhythm stabilization, and this is what was observed in almost all the patients reported in the article by Rizzo et al 6 The type of gangliocytic injury described by the authors as vacuolation may be subtle and is difficult to discern from figures provided. 6 Vacuolation of ganglion cells has been described in several instances from toxic exposure, to trauma, to aging and is considered nonspecific. 10,11 It should be noted that stellate and thoracic ganglia are not routinely examined in postmortem examination by pathologists, so there is a paucity of available data on the histological findings in these tissues among patients who die suddenly from cardiac arrhythmias.…”

“…Furthermore, the authors speculated that the ganglionic inflammation might contribute to the cardiac electric instability in subjects with LQTS/CPVT, and particularly in those who are heavily symptomatic. 6 There is no question about the presence of the low-grade ganglionitis as documented in the publication by Rizzo et al 6 in the 12 patients with life-threatening arrhythmogenic cardiac events in 2 very different genetic cardiac disorders. So how do we explain the presence of the ganglionitis in these patients?…”

“…In the current publication by Rizzo et al 6 from the Amsterdam group, the lower half of the left stellate ganglion and the left second through fourth thoracic ganglia were removed through a videoscopic transthoracic approach in 8 patients with LQTS and 4 patients with catecholaminergic polymorphic ventricular tachycardia (CPVT). All patients were severely symptomatic before the ganglionectomy and had experienced multiple syncopal episodes, with 7 of the 12 patients having had multiple shocks from a previously implantable cardioverter defibrillator.…”