Advanced Atrioventricular Block in Athletes: Prevalence and Role of Anti-Ro/Sjögren Syndrome-Related Antigen A Antibodies

Abstract

Background: Advanced atrioventricular block (AVB), that is, higher than second-degree Mobitz-1, is an abnormal finding in athletes. Despite intensive investigation, in several cases the pathogenesis remains unknown, but frequently pacemaker implantation is still indicated. Increasing evidence points to circulating anti-Ro/Sjögren syndrome-related antigen A (SSA) antibodies cross-reacting with L-type calcium channel and inhibiting the related current as an epidemiologically relevant and potentially reversible cause of isolated AVB in adults. The aim of the study was to determine the prevalence of anti-Ro/SSA-associated advanced AVBs in a large sample of young athletes.

Methods and results: A total of 2536 consecutive athletes aged <40 years without a history of cardiac diseases/interventions were enrolled in a cross-sectional study. Resting and exercise electrocardiography was performed, and those presenting any AVB were further evaluated by 24-hour Holter ECG. Athletes with second-degree AVBs and their mothers underwent anti-Ro/SSA testing. Moreover, purified immunoglobulin G from subjects with anti-Ro/SSA-positive and anti-Ro/SSA-negative advanced AVB were tested on L-type calcium current and L-type-calcium channel expression using tSA201 cells. The global prevalence of advanced AVB in the overall sample was ≈0.1%, but the risk considerably increased (2%) when intensely trained postpubertal male subjects were selectively considered. While none of the athletes with advanced AVB showed heart abnormalities, in 100% of cases anti-Ro/SSA antibodies were detected. Ex vivo experiments showed that immunoglobulin G from anti-Ro/SSA-positive but not -negative subjects with advanced AVB acutely inhibit L-type calcium current and chronically downregulate L-type-calcium channel expression.

Conclusions: Our study provides evidence that advanced AVB occurs in young athletes, in most cases associated with anti-Ro/SSA antibodies blocking L-type calcium channels. These findings may open new avenues for immunomodulating therapies to reduce the risk of life-threatening events in athletes, avoiding or delaying pacemaker implantation.

Keywords: L‐type calcium channels; advanced atrioventricular block in athletes; anti‐Ro/SSA antibodies; autoimmunity.

Figure 1. Flow diagram showing the overall design of the study and the key ECG findings.

Anti‐Ro/SSA indicates anti‐Ro/Sjögren syndrome–related antigen A antibodies; AVB, atrioventricular block; I°AVB, first‐degree atrioventricular block; ; and II°AVB, second‐degree atrioventricular block.

Figure 2. Representative ECG strips of the 3 athletes showing advanced II°AVB.

A, II°AVB Mobitz 2 in a 16‐year‐old male soccer player (high training level, 5 sessions/wk) with circulating anti‐Ro/SSA 52kD antibodies (acquired form). B, II°AVB 2:1 in a 26‐year‐old male soccer player (medium training level, 4 sessions/wk), whose mother showed circulating anti‐Ro/SSA 52kD antibodies (late progressive congenital form). C, High‐grade II°AVB high‐grade in a 34‐year‐old male cyclist (high training level, 5 sessions/wk) with circulating anti‐Ro/SSA 52kD and 60kD antibodies (acquired form). anti‐Ro/SSA indicates anti‐Ro/Sjögren syndrome–related antigen A; AVB, atrioventricular block; and II°AVB, second‐degree atrioventricular block.

Figure 3. Flow diagram showing the results of anti‐Ro/SSA testing in athletes with II°AVB.

anti‐Ro/SSA indicates anti‐Ro/Sjögren syndrome–related antigen A; anti‐Ro+/−, anti‐Ro/SSA–positive/negative; AVB, atrioventricular block; I°AVB, first‐degree atrioventricular block; and II°AVB, second‐degree atrioventricular block.

Figure 4. Acute and chronic ex vivo effects of purified IgG from patients with AVB on I_CaL in tSA201 cells and Ca_v1.2 protein expression in tSA201 cells.

A, I_CaL recorded from transiently transfected tsA201cells with recombinant expression of Ca_v1.2, before (black) and after (orange) the incubation with purified IgG from the anti‐Ro/SSA–positive athlete with II°AVB high‐grade (75μg/mL for 10 minutes). (a) Representative whole‐cell calcium current traces. I_CaL currents were recorded in the presence of 2 mM CaCl₂ from a holding potential of −100 mV. Time scale was 200 ms and the current amplitude scale is 200 pA, as indicated. (b) Averaged current–voltage relationships before and after IgG treatment (n=7). B, I_CaL recorded from transiently transfected tsA201cells with recombinant expression of Ca_v1.2, before (black) and after (gray) the incubation with purified IgG from a control patient with isolated II°AVB high‐grade but anti‐Ro/SSA negative (75 μg/mL for 10 minutes). (a) Representative whole‐cell calcium current traces. (b) Averaged current–voltage relationships before and after IgG treatment (n=6). C, Plots showing I_CaL current densities recorded at 10 mV before and after treatment with IgG. (a) Anti‐Ro/SSA–positive athlete with AVB (n=7); 2‐tailed paired t test, *P<0.05. (b) Anti‐Ro/SSA–negative control with AVB (n=6); 2‐tailed paired t test, n.s. not significant. D, Ca_v1.2 protein expression in tSA201‐Cav1.2 cells before and after 24‐h treatment with 40 μg/mL purified IgG from the anti‐Ro/SSA–positive athlete with II°AVB high‐grade and the control anti‐Ro/SSA–negative patient with isolated II°AVB high‐grade. (a) Representative western blot for Ca_v1.2 at baseline (B, line 1) and after treatment with IgG from anti‐Ro/SSA–negative (line 2) and anti‐Ro/SSA–positive (line 3) patients. (b) Corresponding histograms of densitometric analysis for Ca_v1.2 normalized to GAPDH (n=3 each). One‐way ANOVA, P<0.001; Tukey–Kramer post hoc multiple comparison test, *P<0.05 vs B and anti‐Ro AVB after IgG treatment. Anti‐Ro+/− indicates anti‐Ro/SSA–positive/negative; AVB, atrioventricular block; IgG, immunoglobulin G; and I_CaL, L‐type calcium current.