Intercalated Disc Abnormalities Are Linked to Arrhythmias in Inflammatory Cardiomyopathy

Peretto, G; Rizzo, S; Menegon, A; Villatore, A; Veeraraghavan, R; Vignale, D; Castoldi, V; Perani, L; Canu, T; Panzeri, MC; Del Rosso, S; Norata, R; Rocchi, M; Della Barbera, M; Rossi, E; Cursi, M; Bergamaschi, A; Campochiaro, C; De Luca, G; Rasponi, M; Di Resta, C; Palmisano, A; Carrera, P; Muzio, L; Pedrocchi, ALG; Leocani, L; Lazzeroni, D; Sanvito, F; Sala, S; Dagna, L; Camici, PG; Martino, G; Fairweather, D; Caforio, ALP; Basso, C; Esposito, A; Cooper, LT; Della Bella, P

doi:10.1016/j.jacep.2025.02.025

Heart failure & cardiomyopathies

Intercalated Disc Abnormalities Are Linked to Arrhythmias in Inflammatory Cardiomyopathy

JACC Clin ElectrophysiolPublished 23 Apr 2025pilot research

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Authors' conclusion

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.

Study context

Population: Humans with inflammatory cardiomyopathy (ICM) investigated for either genetic or autoimmune intercalated disc abnormalities (IDAs); male mice with experimental autoimmune myocarditis (EAM)humans with ICM, 70 (22%) IDA+ · Humans with ICM 316 · Male mice with EAM 12
Participants: 316 humans

Exposure: IDA+ cases compared with IDA- control subjects matched 1:1 by age, sex, and race/ethnicity
IDA+n = 70
Outcome: Occurrence of clinically demanding supraventricular or ventricular arrhythmias, recorded by Holter electrocardiography or implanted devices
Follow-up: 24-month prospective

Methodological detailsreferral center, matched 1:1 by age, sex, and race/ethnicity, 24-month prospective follow-up, comparison with mice with experimental autoimmune myocarditis (EAM)

Referral center
Matched 1:1 by age, sex, and race/ethnicity
24-month prospective follow-up
Comparison with mice with experimental autoimmune myocarditis (EAM)

Main finding

As reported in the abstract

IDA+

44 of 70

events

IDA- control subjects

10 of 70

events

P < 0.001

Observational data: associations, not effects.

Further findings

Major ventricular arrhythmias predicted by IDAs (multivariable model) · 24 months

	← Lower risk ←→ Higher risk →	HR (95% CI)	P value
IDAsMultivariable model	0.10.31310	3.0 (1.4–6.4)	P = 0.004
	0.10.31310Hazard ratio (log scale)

Outcome	IDA+	IDA- control subjects	P value
Average intercellular cleft width (ICW)Greater ICW in IDA+	44 ± 8 nm	28 ± 4 nm	P < 0.001
Clinically demanding arrhythmias at presentation	31 of 70 events	9 of 70 events	P < 0.001
Arrhythmias in miceEAM cases vs control animals			P = 0.038

Increased intercellular cleft width (ICW) in relation to arrhythmias · humans with arrhythmias vs humans without arrhythmias · increased ICW: 32 of 44 with vs 4 of 52 without arrhythmias: P < 0.001
Increased ICW in relation to arrhythmias · mice with arrhythmias vs mice without arrhythmias · increased ICW: 7 of 8 with vs 0 of 4 without arrhythmias: P = 0.010
Increased ICW in relation to arrhythmias · 5 of 6 vs 0 of 6: P = 0.015

Arrhythmias in mice: EAM cases 7 of 12 events
Arrhythmias in mice: control animals 0 of 6 events

Baseline characteristics of humans with ICM · on admission

Mean age: 45 ± 15 years
Male: 63%
IDA+: 70 (22%)
Arrhythmias on admission: 107 (34%)

Original publication

Intercalated Disc Abnormalities Are Linked to Arrhythmias in Inflammatory Cardiomyopathy. JACC Clin Electrophysiol. Published 23 April 2025. doi:10.1016/j.jacep.2025.02.025

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