Intercalated Disc Abnormalities Are Linked to Arrhythmias in Inflammatory Cardiomyopathy.
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Peretto Giovanni, Rizzo Stefania, Menegon Andrea, Villatore Andrea, Veeraraghavan Rengasayee, Vignale Davide, Castoldi Valerio, Perani Laura, Canu Tamara, Panzeri Maria Carla, Del Rosso Stefania, Norata Rossana, Rocchi Martina, Della Barbera Mila, Rossi Elena, Cursi Marco, Bergamaschi Andrea, Campochiaro Corrado, De Luca Giacomo, Rasponi Marco, Di Resta Chiara, Palmisano Anna, Carrera Paola, Muzio Luca, Pedrocchi Alessandra Laura Giulia, Leocani Letizia, Lazzeroni Davide, Sanvito Francesca, Sala Simone, Dagna Lorenzo, Camici Paolo Guido, Martino Gianvito, Fairweather DeLisa, Caforio Alida Linda Patrizia, Basso Cristina, Esposito Antonio, Cooper Leslie T, Della Bella Paolo
Аннотация
OBJECTIVES: This study presents a pilot research that aimed to: 1) investigate the link between IDAs and arrhythmias in humans with ICM; and 2) compare findings in humans and mice with experimental autoimmune myocarditis (EAM).
METHODS: Humans with ICM (N = 316) investigated for either genetic or autoimmune IDAs were identified at a referral center. Ultrastructural analysis on biobanked tissue was performed to determine the average intercellular cleft width (ICW) between cardiac myocytes. IDA+ cases were compared with IDA- control subjects matched 1:1 by age, sex, and race/ethnicity. The primary endpoint was the occurrence of clinically demanding supraventricular or ventricular arrhythmias, recorded either by Holter electrocardiography or implanted devices during a 24-month prospective follow-up. The relationships between ICW and arrhythmias were compared in humans and male mice with EAM (n = 12).
RESULTS: Of 316 humans with ICM (mean age 45 ± 15 years, 63% male), 70 (22%) were IDA+ and 107 (34%) had arrhythmias on admission. IDA+ patients had greater ICW than control subjects (44 ± 8 nm vs 28 ± 4 nm; P < 0.001) and higher incidence of clinically demanding arrhythmias both at presentation (31 of 70 vs 9 of 70; P < 0.001) and during follow-up (44 of 70 vs 10 of 70; P < 0.001). In a multivariable model, IDAs predicted the occurrence of major ventricular arrhythmias by 24 months (HR: 3.0; 95% CI: 1.4-6.4; P = 0.004). In mice, arrhythmias were documented in 7 of 12 EAM cases and 0 of 6 control animals (P = 0.038). Increased ICW was found in close relationship with arrhythmias in both species (humans: 32 of 44 with vs 4 of 52 without arrhythmias; P < 0.001; mice: 7 of 8 with vs 0 of 4 without arrhythmias; P = 0.010), as well as with abnormal ventricular electrograms on viable murine myocardial tissue (5 of 6 vs 0 of 6; P = 0.015).
CONCLUSIONS: As a shared trait between genetic and autoimmune ICM, IDAs are linked to arrhythmias in humans and find promising applications in the EAM mouse model.