Autoimmune antibodies in arrhythmia: a narrative review of potential therapeutic targets to prevent overtreatment

Introduction

Background

In recent years, with the rapid development of detection and monitoring technologies, the prevalence of autoimmune diseases (ADs) has significantly increased over the past 30 years, with approximately 7.6–9.4% of the global population currently affected (1), a number that is expected to continue rising (2). A study based on the National Health and Nutrition Examination Survey (NHANES) indicated that ADs are common in the United States (3) and often affect the heart, leading to changes in cardiac tissue structure, arrhythmias, and even sudden cardiac death (SCD) (4). It is worth noting that even among individuals with normal cardiac structure, nearly 70% of life-threatening arrhythmia or SCD cases cannot be explained by traditional methods, even after molecular autopsy (5). This suggests that in addition to the known mechanisms such as myocarditis and fibrosis, AD-related pathophysiological mechanisms maybe contribute significantly to the occurrence of arrhythmias (1,6).

Arrhythmias arise as a result of disrupted cardiac electrophysiology, often due to ion channel dysfunction or structural remodeling. Autoimmune antibodies have recently been identified as drivers in this process, directly interacting with receptors and channels to induce arrhythmias independently of traditional risk factors.

A recent study suggested that arrhythmias in patients with dermatomyositis (DM) may be associated with anti-Ro/Sjögren’s syndrome A (SSA)-52 kD positivity, indicating that this antibody may induce arrhythmias by interfering with cardiac electrophysiological activity (7). With the deeper understanding of the interactions between the autoimmune system and cardiovascular diseases, autoimmune antibodies have gradually gained attention as a contributor to the triggering or worsening of arrhythmias. Recent research has focused on how autoimmune antibodies interfere with ion channels and receptor functions to cause arrhythmias (8-10).

Objectives

The relevant reviews in this field have not analyzed the therapeutic targets or examined overtreatment, and thus there is a need for a more comprehensive synthesis of the literature on this subject. Against this background, this review presents the latest progress in understanding the relationship between autoimmune antibodies and arrhythmias, with a focus on clarifying the molecular mechanisms by which these antibodies interfere with cardiac electrophysiological activity, as well as the diagnosis and current treatment of AD-related arrhythmias. In doing so, it is hoped that novel insights into the diagnosis and treatment of such arrhythmias can be shared (Figure 1). We present this article in accordance with the Narrative Review reporting checklist (available at https://cdt.amegroups.com/article/view/10.21037/cdt-2025-173/rc).

Figure 1 Autoantibodies and cardiac arrhythmias. Yellow represents antibodies related to conduction system arrhythmias; black represents antibodies related to atrial arrhythmias; red represents antibodies related to ventricular arrhythmias. Modified from Lee et al. (11). AMA-M2, anti-mitochondrial antibody M2 subtype; anti-Ro/La, anti-Ro antibodies/anti-La antibodies; anti-histone, anti-histone antibodies; ANA, anti-nuclear antibodies; anti-DNA, anti-deoxyribonucleic acid; c-ANCA, cytoplasmic anti-neutrophil cytoplasmic antibodies; CHB, complete heart block; p-ANCA, perinuclear anti-neutrophil cytoplasmic antibodies.

Methods

On February 2025, a search of the as PubMed, Embase, Cochrane Library, and Web of Science databases was conducted with the keywords “autoimmune antibodies” and “arrhythmia” being the core search terms. The literature was screened, and relevant articles were included in the review (the search strategy is outlined in Table 1).

Autoantibody-induced atrial arrhythmias

The relationship between autoantibodies and atrial fibrillation (AF)

AF is being increasingly recognized as a potential autoimmune-mediated disorder. Below, we detail how autoantibodies against myosin, ion channels, and adrenergic/muscarinic receptors drive the pathogenesis of AF through direct cellular interaction and fibrotic remodeling. Figure 2 summarizes the mechanisms by which autoantibodies induce AF, which includes anti-myosin antibodies inducing cardiomyocyte damage, anti-Kir3.4 antibodies altering channel gating, and anti-β1-R/M2-R antibodies promoting fibrosis via transforming growth factor-β1 (TGF-β1) upregulation.

Figure 2 The relationship between autoantibodies and atrial fibrillation. Anti-myosin heavy chain antibodies, anti-Kir3.4 protein antibodies, anti-31-R antibodies and anti-M2-R antibodies. Modified from Zygadło et al. (10). anti-β1-R antibodies, anti-β1-adrenergic receptor antibodies; anti-Kir3.4 protein antibodies, anti-inwardly rectifying potassium channel subfamily Kir3 member 4 protein antibodies; anti-M2-R antibodies, anti-muscarinic acetylcholine receptor M2 subtype antibodies.

Autoantibodies against myosin heavy chain

Studies have shown that α-myosin heavy chain significantly affect myocardial pathological changes studies collectively emphasize the importance of α-myosin heavy chain in myocardial lesions (12,13). The earliest study suggesting a potential link between atrial arrhythmia and autoantibodies against cardiac myosin heavy chain was a small-scale case-control study conducted by Maixent et al. (14). This study used SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis) technology and applied homogenates and membrane fractions from human left ventricle and atrial specimens as antigens for Western blotting to analyze the serum of 10 patients with idiopathic paroxysmal AF and 10 age-matched healthy controls. Circulating immunoglobulin G (IgG) reactivity against cardiac myosin heavy chain was detected in the serum of 1 (10%) control participant and 6 (60%) patients, with this difference being statistically significant (P<0.05). Moreover, it was found that circulating autoantibodies against myosin heavy chain were present in patients with idiopathic paroxysmal AF (14), suggesting an association between anti-myosin antibodies and AF.

Autoantibodies against Kir3.4 protein

In AF research, the Kir3.4 protein, an inwardly rectifying potassium channel encoded by the KCNJ5 gene, has emerged as a pivotal player. Dysfunctions in this protein have been closely linked to the pathogenesis of various arrhythmias. Studies have demonstrated that Kir3.4 operates within atrial-specific ion channels, regulating the induction, dynamics, and termination of AF (15). Modulation of these channels holds considerable promise for advancing both the treatment and greater understanding of AF. Notably, Kir3.4 complexes with Kir3.1 to form the acetylcholine-activated inward rectifier potassium channel (IKACh), which is uniquely expressed in atrial tissues and plays a critical role in the pathophysiology of AF (16,17). Furthermore, genetic mutations in the Kir3.4 protein have been directly implicated in arrhythmogenesis (18).

The aforementioned research has unequivocally established that the Kir3.4 protein and the IKACh channel it forms play pivotal roles in the pathophysiological processes of AF. Both the functional abnormalities and genetic mutations of Kir3.4 are significant contributors to the onset of various arrhythmias. In recent years, with the deepening of research, the role of autoantibodies in the pathogenesis of AF has garnered heightened attention. In particular, the association between autoantibodies targeting the Kir3.4 protein and AF has emerged as a new focal point in research.

A recent study combining clinical and basic experiments further confirmed the role of autoantibodies in AF. Maguy et al. detected a common autoantibody response against the Kir3.4 protein in the serum of patients with AF. Purified anti-Kir3.4 IgG was found to shorten the action potential duration of human-induced pluripotent stem cell-derived atrial cardiomyocytes and enhance the constitutive activation of IKACh. In terms of mechanism, this antibody may directly bind to the extracellular domain of the Kir3.4 protein, inducing conformational changes in the channel that keep the IKACh channel partially open without acetylcholine stimulation (19). In a mouse model of Kir3.4 autoimmunity, although Kir3.4 autoantibodies had no significant effect on cardiac structure (such as left atrial size) or overall function (such as left ventricular ejection fraction), and all mice maintained sinus rhythm with no differences in electrocardiographic parameters between groups, intracardiac electrophysiological experiments showed that the atrial effective refractory period (AERP) was significantly shortened in experimental mice, with the AF induction rate increased by 2.8-fold compared to the control group (80% vs. 28%). These results suggest that anti-Kir3.4 autoantibodies may participate in a key pathogenic process of AF, shortening atrial repolarization and reducing the threshold for AF initiation.

Autoantibodies against β1-adrenergic receptor (β1-R) and M2-cholinergic receptor (M2-R)

Multiple studies have shown a significant correlation between the levels of autoantibodies against β1-R, M2-R, interleukin-6 (IL-6), heat shock protein 65, and AF in circulating serum (6,10,20-25). Yalcin et al. examined 75 patients with isolated paroxysmal AF and 75 matched controls in their study, measuring and comparing serum levels of anti-M2-R and anti-β1-R using enzyme-linked immunosorbent assay. They found that anti-β1-R and anti-M2-R autoantibodies (M2-AABs) were independent biomarkers for the occurrence of paroxysmal AF in patients without cardiovascular disease (26). Moreover, it was reported that M2-AABs may play a role in the occurrence of AF in patients with dilated cardiomyopathy (DCM) (27). Additionally, anti-β1-R autoantibodies are associated with increased expression levels of TGF-β1, collagen I, and collagen III in the left atrium, and M2-AABs are correlated with the elevated expression levels of TGF-β1 and connective tissue growth factor (CTGF) in the left atrium (28,29). These changes promote atrial fibrosis, thereby increasing the risk of AF.

The relationship between inflammation and AF

Inflammation plays a key role in the onset and progression of AF, interacting with autoimmune mechanisms, thereby affecting the function of atrial ion channels and ultimately leading to electrical remodeling. Inflammation is one of the core features of atrial remodeling associated with AF and thus is closely linked to AF. Inflammatory factors such as matrix metalloproteinase-9 (MMP-9), high-sensitivity C-reactive protein (hs-CRP), and IL-6 are known to influence signaling pathways, thereby contributing to the development of AF. Additionally, systemic inflammation triggered by ADs can affect cardiac structure and function through multiple mechanisms, further exacerbating pathological changes such as AF and significantly increasing the risk of AF (21). One study found that patients with chronic inflammatory ADs [e.g., rheumatoid arthritis and systemic lupus erythematosus (SLE)] have a significantly higher risk of AF, with inflammatory markers (IL-6 and CRP) directly correlating with AF incidence. Autoimmune antibodies that have been linked to the pathophysiological process underlying the association between chronic inflammatory ADs (e.g., rheumatoid arthritis, SLE) and the development of AF include anti-Ro/SSA, anti-La/SSB [linked to congenital heart block (CHB)], and anti-myocardial antibodies, but not anti-M2-R. Key inflammatory factors include IL-6, TNF-α, and CRP (22). Autoimmune antibodies and inflammatory factors jointly drive the electrophysiological changes in AF, forming a vicious cycle of immune inflammation in conjunction with electrical remodeling. This mechanism suggests that targeting the inhibition of inflammatory signaling pathways and autoantibodies may be a valuable strategy for treating AF.

The role of humoral immunity in atrial arrhythmias has recently attracted interest. Autoantibodies alter the electrophysiological properties of the heart by binding to specific cardiac antigens, leading to atrial electrical instability. For example, anti-Kir3.4 autoantibodies shorten the AERP, increasing the susceptibility to AF; and anti-β1-R and anti-M2-R autoantibodies promote atrial fibrosis, further exacerbating the occurrence of AF.

Autoantibodies-induced damage to the cardiac conduction system

Congenital cardiac conduction disorder

CHB is a passively acquired AD associated with maternal ADs. In 1928, Aylward was to report a case of CHB associated with maternal Mikulicz disease (30). The occurrence of CHB is closely related to the presence of Ro/La (SSA/SSB) autoantibodies in the maternal body.

These antibodies enter the fetal circulation through the placenta and cross the placental barrier via FcγRn, damaging the fetal cardiac conduction tissue, which results in inflammation, calcification, and fibrosis, ultimately obstructing the cardiac conduction signaling pathway (31-33). In pregnancies positive for anti-Ro/SSA and/or anti-La/SSB antibodies, the incidence of CHB is approximately 2–5%, and the recurrence rate in subsequent pregnancies can be as high as 12–25% (34-36). The mother may have rheumatic ADs, such as Sjögren syndrome or SLE, or may be asymptomatic (37) (Figure 3).

Figure 3 The mechanisms of congenital heart block. The diagram at the bottom shows electrocardiograms of varying degrees of AV conduction block. Modified from Ambrosi et al. (31). AV, atrioventricular; AVN, atrioventricular node.

The immune mechanism of CHB

Studies have shown that the presence of anti-Ro/La autoantibodies in the mother’s body, particularly antibodies against the 52-kDa Ro and 48-kDa La proteins, significantly increases the risk of the offspring developing isolated congenital complete atrioventricular block (AVB) (38-41). Approximately two-thirds of CHB fetuses die in utero, and 70–80% of newborns require the implantation of a permanent pacemaker to maintain normal cardiac function (42-45). Lisney et al. were the first to report that mothers of children with autoimmune CHB exhibit significantly elevated plasma interferon (IFN) levels as compared to mothers with Sjögren syndrome or SLE who carry anti-Ro/La antibodies but have unaffected children (46). Additionally, activation of the type I IFN system and increased expression of siglec1 have been observed in the umbilical cord blood mononuclear cells of neonates from anti-Ro/La antibody-positive mothers (47), as well as in the cardiac tissue of fetuses that have died from autoimmune CHB (48-50). Siglec1 is a protein induced by type I IFN and expressed on bone marrow cells, with its cell surface expression being most significantly upregulated in the IFN signaling of patients with SLE or Sjögren syndrome, and it is associated with disease activity (51-54). Although it is unclear whether siglec1 directly participates in the pathogenesis of CHB, one study suggested that it may indirectly affect disease progression by promoting the expression of TGF-β and potential downstream pro-fibrotic effects (37).

Ion channel dysfunction and apoptosis in CHB

Multiple studies related to CHB consistently indicate that anti-Ro52-kD and anti-La/SSB antibodies may be strongly associated with CHB (55-58). Boutjdir et al. provided strong evidence through human and animal experiments that anti-Ro52-kD antibodies cause the occurrence of CHB and that the L-type Ca²⁺ channel may be one of the key pathogenic factors [the electrophysiological generation of the atrioventricular node (AVN) mainly depends on ICa]. In a previously reported study, anti-Ro52-kD antibodies purified from CHB-affected mothers’ sera inhibited the L-type calcium channels (LCCs) in human fetal cardiomyocytes, disrupting AVN conduction. In mouse models, maternal immunization with these antibodies induced AVB and fetal cardiac fibrosis (59). The study by Lee et al., in line with the work of Boutjdir et al., found that the autoantibodies causing CHB also lead to gradual damage of the AVN, ultimately resulting in fibrosis and calcification (11). Moreover, the Xiao et al. reported findings similar to those of Boutjdir et al. and Lee et al., as they discovered that maternal sera with Ro/SSA and La/SSB antibodies (positive IgG) could inhibit LCCs in isolated cardiomyocytes and induce sinus bradycardia in a mouse CHB model (60).

In conclusion, these studies confirm that anti-Ro52 (61) and anti-La/SSB antibodies may have a strong correlation with CHB, and Ca²⁺ channels are likely to play an important role in this process.

In the cardiac tissue of fetuses with CHB, significant apoptosis has been observed (62), which may be due to the uncontrolled apoptosis process or defects in the clearance mechanism (63). When macrophages are cocultured with activated apoptotic fetal cardiomyocytes, they may react with anti-SSA/Ro antibodies, thereby promoting an increase in TGF-β secretion. Prolonged excessive secretion of TGF-β may lead to the transformation of cardiac fibroblasts into myofibroblasts, subsequently causing the formation of extensive scar tissue (64,65). The abnormal apoptosis phenomenon and excessive secretion of TGF-β in the cardiac tissue of fetuses with CHB may play an important role in the process of cardiac scar formation. This mechanism provides new insights into the occurrence and development of fetal cardiac lesions and may offer potential targets for future clinical intervention strategies.

Acquired arrhythmias related to the cardiac conduction system

Anti-Ro/La antibodies and adult arrhythmias

A study in China revealed that anti-SSA is independently associated with AVB and bundle branch block (BBB) in patients with heart failure (HF) (66). Akuka et al. conducted a population-based cross-sectional study involving 17,231 individuals serum-positive for anti-Ro/La antibody and 84,368 control participants. The study found that serum anti-Ro positivity, regardless of the presence of ADs, was positively correlated with adult cardiac conduction disorders (67) and may be closely associated with anti-Ro/SSA 52-kD antibodies (68-70). Additionally, it was associated with a particularly high risk of arrhythmias, which could even be life-threatening (71,72). However, the effects of anti-Ro/SSA and anti-La/SSB antibodies on the adult cardiac conduction system remain controversial (73), as it was reported that some patients who are only positive for anti-La (SSB antibodies) do not seem to have a significant association with arrhythmias (66,67). However, Lodde et al. found a certain association between La antibodies and the occurrence of first-degree heart block in adults with primary Sjögren syndrome who were positive for anti-La/SSB antibodies (74). Garcia et al. found that anti-Ro/SSA antibodies or anti-La/SSB antibodies were present in the serum IgG of patients with SLE (61). These antibodies may induce cardiac conduction disorders by cross-reacting with multiple cardiac ion channels (especially L-type and T-type calcium channels) and potassium channels [such as human ether-a-go-go related gene (hERG)] through inhibitory cross-reactions (75-77). Despite this research, the mechanisms underlying the effect of anti-Ro/La antibodies on the cardiac conduction system remain to be fully clarified, and doing so may provide definitive evidence for clinical diagnosis and treatment.

Autoimmune-related cardiac calcium channel abnormalities have been confirmed in anti-Ro/La antibody-positive patients, manifesting as sinoatrial node (SAN) dysfunction, atrioventricular conduction block, and ventricular arrhythmias in patients with DCM (11,78,79). In the heart, there are primarily L-type and T-type calcium channels, which are voltage-gated and have different characteristics: LCCs are high-voltage-activated and persistent, while T-type channels are low-voltage-activated and transient (80-82). The α1c subtype of the LCC is widely expressed in the heart and plays a crucial role in excitation-contraction coupling, SAN impulse generation, and AVN conduction (83,84). Lazzerini et al. identified interference with LCC function by anti-Ro/SSA antibodies as a novel pathological mechanism for adult isolated AVB, which is epidemiologically relevant and may be reversible (85). This finding provides new insights into avoiding or delaying pacemaker implantation and may have a significant impact on the treatment of arrhythmias. Therefore, research on conduction system-related arrhythmias mediated by AD antibodies, with a focus on antigen antibody interaction with ion channels, may lead to new breakthroughs.

Other ADs and cardiac conduction block

A retrospective clinical study included 32 patients with complete cardiac conduction block and SLE, 25 of whom were tested for antinuclear antibodies and all found positive; 16 out of 19 were positive for anti-DNA antibodies (86). These two types of antibodies may be involved in the occurrence of complete cardiac conduction block in SLE.

A small number case reports have indicated that perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA)-associated vasculitis can lead to various cardiac conduction system abnormalities (87,88). Other case reports suggest that c-ANCA-associated systemic vasculitis can lead to aneurysm formation, thrombosis, or coronary artery dissection (89), which can then trigger coronary arteritis and cardiac arrest (90,91), with a portion of these patients also presenting with complete cardiac conduction block (92-95).

Borges et al. reported a case of a patient with systemic sclerosis (SSc) without SSc-related manifestations, who was positive for both antinuclear antibodies and anticentromere antibodies, with an electrocardiogram (ECG) showing left BBB (96). Another study reported that 59% of patients with SSc had right BBB (97), whereas only 32% of patients with rheumatoid arthritis exhibited conduction abnormalities (97); furthermore, there was a certain correlation between the positive rate of cardiac conduction tissue antibodies and conduction abnormalities in patients with rheumatoid arthritis (98). Patients with myocarditis associated with idiopathic inflammatory myopathies often present with left anterior fascicular block, pathological Q waves, and prolonged QRS duration, which may be related to cardiac remodeling, inflammation, and fibrosis in the conduction system. However, whether this is related to the positivity rate of anti-mitochondrial antibody M2 subtype (AMA-M2) antibodies requires further study (99). Collectively, this research suggests that autoimmune antibodies may play an important role in the occurrence and development of adult cardiac conduction block, but the specific pathophysiological mechanisms and their relationships need to be examined further (Table 2).

Autoantibodies and ventricular arrhythmias

Autoantibodies in ADSs may directly affect the myocardium, leading to various arrhythmias, especially ventricular arrhythmias. A study by Gawałko et al. found that the incidence of ventricular arrhythmias was significantly increased in patients with rheumatic ADs such as sarcoidosis, SSc, polymyositis (PM), and DM (1). These arrhythmias may be related to certain autoantibodies, especially anti-β1-R autoantibodies and anti-calcium channel autoantibodies. Among the patients, long QT syndrome was closely associated with β1-R and anti-calcium channel antibodies. These antibodies prolong ventricular action potential duration by enhancing LCCs and reducing potassium currents (IK1 and Ito), thereby increasing the risk of torsade de pointes. The details of the mechanisms are provided in Figure 4.

Figure 4 Autoantibody and ventricular arrhythmia. Anti-β1-AR antibodies enhance LCCs and reduce potassium currents (such as IK1 and Ito) by binding to β1-AR in the ventricular myocardium, affecting phases 1, 2, and 3 of the ventricular action potential, thereby prolonging the QT interval and triggering ventricular arrhythmias. Anti-calcium channel antibodies may bind to calcium channel receptors in the ventricular myocardium, further enhancing CCs, prolonging phase 2 of the ventricular action potential, and leading to QT interval prolongation, which in turn causes the occurrence of ventricular arrhythmias. Modified from Lazzerini PE, Capecchi PL, Laghi-Pasini F. Long QT Syndrome: An Emerging Role for Inflammation and Immunity. Front Cardiovasc Med. 2015 May 27;2:26. PMID: 26798623. Anti-β1-AR antibodies, anti-β1-adrenergic receptor antibodies; AP, action potential; β1-AR, β1-adrenergic receptor; CC, calcium currents; ECG, electrocardiogram; IK1, inward rectifier potassium current 1; Ito, transient outward potassium current; LCC, L-type calcium channel.

Anti-β1-R autoantibodies and ventricular arrhythmias

A study involving 104 patients with DCM showed that patients who tested positive for anti-β1-R autoantibodies were more prone to ventricular tachycardia (VT) and premature ventricular contractions. The presence of these antibodies, along with a low left ventricular ejection fraction, was identified as an independent predictor of VT (100). In patients with normal cardiac structure but ventricular electrical instability, anti-β1-R autoantibodies were detected in approximately 48% to 72% of patients (8), suggesting that anti-β1-R autoantibodies may be an important factor influencing in ventricular arrhythmias. Xiao et al. found through animal experiments that an increase in anti-β1-R antibodies could prolong action potential duration and promote early repolarization, thus increasing the risk of ventricular arrhythmias and potentially raising the incidence of SCD (78). Another in vitro experiment revealed the specific molecular mechanism by which β1-R autoantibodies induce arrhythmias. The study reported that β1 antibodies enhanced LCCs and reduced potassium currents (such as IK1 and Ito), thereby prolonging the QT interval in rat ventricular myocytes and triggering arrhythmias (101), providing direct evidence for the mechanism of β1-AR antibody-induced arrhythmias. These findings suggest that anti-β1-R autoantibodies in patients with DCM may increase the risk of ventricular arrhythmias by affecting myocardial electrophysiological properties, especially ventricular electrical activity. This suggests the participation of antibodies in the occurrence of arrhythmias and provides a new research direction for clinical interventions.

Anti-calcium channel autoantibodies and ventricular arrhythmias

A prospective case follow-up study found that among 80 patients with DCM, positivity for anti-calcium channel autoantibodies was the only independent predictor of VT (102). The α1c subtype of LCCs is widely expressed in the heart and participates in excitation-contraction coupling, SAN impulse generation, and AVN conduction. Similar to anti-Ro/La antibodies in fetal conduction systems (Section “Ion channel dysfunction and apoptosis in CHB”), anti-β1-R and anti-calcium channel antibodies in adults enhance LCCs, prolonging ventricular action potential duration and increasing arrhythmia risk. This finding suggests that the presence of anti-calcium channel autoantibodies may induce malignant arrhythmias by affecting the heart’s electrophysiological processes, making it an important risk factor in patients with DCM.

Other autoantibodies and ventricular arrhythmias

In addition to causing the conduction system lesions—as mentioned above—anti-Ro/SSA may be associated with prolonged QTc intervals in patients with connective tissue diseases. A study found that about half of the anti-Ro/SSA-positive patients with connective tissue diseases had prolonged QTc intervals, while only 0–5% of anti-Ro/SSA-negative patients exhibit did. Even without structural heart abnormalities, the incidence of complex ventricular arrhythmias was significantly higher in positive patients than in negative ones (50% vs. 10%) (11).

Plastiras et al. found that the probability of VT in patients with SSc was as high as 67%, and this phenomenon may be related to the presence of specific autoantibodies (4). A study by Vacca et al. further confirmed that 90% of patients with SSc showed ventricular arrhythmias in a 24-hour Holter ECG (103), which also supports the significant role of autoimmune-related factors in arrhythmias in patients with SSc.

A retrospective study conducted in China analyzed 75 patients PM or DM with mild cognitive impairment admitted to Peking Union Medical College Hospital from October 1997 to April 2019, finding that positivity for antimitochondrial antibodies was closely related to ventricular arrhythmias in these patients (104). The autoantibodies associated with the occurrence of ventricular arrhythmias are summarized in Table 3. It was further reported that 30–70% of PM/DM patients exhibited ECG abnormalities, with 76.7% showing ventricular arrhythmias and 53.3% showing atrial arrhythmias (99). These studies suggest that antimitochondrial antibodies may be an important risk factor for ventricular arrhythmias in patients with PM or DM.

Antibodies in connective tissue diseases and immune-related diseases (such as anti-Ro/SSA antibodies, anti-β1-R antibodies, and antimitochondrial antibodies) are closely associated with the occurrence of ventricular arrhythmias, especially in patients with abnormal ECGs or no apparent structural heart abnormalities. These antibodies may increase the risk of arrhythmias by interfering with cardiac electrophysiological processes, causing fibrosis, or disrupting autonomic nerve function, highlighting the significance of these diseases in cardiac electrophysiology.

Therapeutic strategies for autoimmune antibody-induced arrhythmias

For the treatment of CHB, early interventions include fluorinated steroids or high-dose intravenous immunoglobulin for second-degree AVB, which can prevent disease progression and achieve a lower degree of block (105-107). Recent clinically relevant studies have shown that the use of hydroxychloroquine during pregnancies exposed to anti-SSA/Ro can prevent the occurrence and recurrence of CHB (108-110).

The treatment for arrhythmias caused by adult autoimmune-related antibodies is still in the exploration stage. Lazzerini et al. reported a case in which a 65-year-old male with hypertension developed fatigue and dizziness after taking olmesartan. The ECG showed high-degree AVB, and the patient was positive for the anti-Ro/SSA-52 kD antibody. Patch-clamp technique and Western blot confirmed the presence of anti-Cav1.2 antibodies in his IgG. Intravenous methylprednisolone (1 mg/kg/day) rapidly improved symptoms and was later switched to oral prednisone (1 mg/kg/day) with the addition of hydroxychloroquine (400 mg/day). Prednisone was discontinued after 10 months, and hydroxychloroquine was continued for maintenance therapy. Follow-up indicated the patients was anti-Ro/SSA-52 kD antibody-negative, and only three asymptomatic long intervals were noted on the ECG over 25 months. This case suggests that hydroxychloroquine monotherapy may be a safe and effective alternative to pacemaker treatment for atrioventricular valve (AVV) induced by anti-Cav1.2 antibodies (111). Autoantibodies can play a role in the occurrence of arrhythmias such as AF by inhibiting or stimulating various cardiac ion channels, such as depolarization-related INa and ICaL currents and repolarization-related IK currents. This finding opens novel avenues for developing personalized antiarrhythmic treatment strategies (112). Additionally, a recent study found that neutralizing anti-β1 and anti-M2 antibodies could block the induction of AF. Therefore, it is necessary to conduct further in vivo and in vitro studies to determine the application of decoy peptide therapy and promote its clinical translation (10).

Discussion and summary

Key findings

This review summarizes the link between autoantibodies and arrhythmias, describing the mechanisms underlying their interference with cardiac ion channels, receptors, and cellular structures. In atrial arrhythmias, multiple antibodies increase the risk of AF via cell damage, shortened refractory periods, or fibrosis. Maternal anti-Ro/SSA antibodies cause fetal CHB (12–25% recurrence) and adult conduction disorders. Ventricular arrhythmias are induced by anti-β1-R and calcium channel antibodies via ion channel effects. In terms of treatment, hydroxychloroquine reduces CHB recurrence and may replace pacemakers in select adult cases. The review highlights autoantibodies as key pathogenic factors that hold considerable therapeutic implications.

Study limitations

Although studies have revealed the interaction between antibodies and ion channels, the specific signal transduction pathways have not yet been fully clarified. There are significant differences in antibody detection methods, population cohorts, and follow-up times across different studies, which limits the comparability of the results. Current treatment strategies are mostly based on case reports or small sample studies, and validation in large-scale randomized controlled trials remains lacking.

Conclusions

This review highlights autoantibodies’ core role in the occurrence of arrhythmia. Clinically, clinicians should test for autoantibodies in patients with unexplained arrhythmia, especially those with AD. Hydroxychloroquine may offer alternatives to traditional pacing. Recommendations include establishing multicenter databases, standardizing antibody detection, and promoting personalized treatment. Policy support for single-cell technology and novel biologics is advised to reduce complications and mortality. As a cross-disciplinary target, autoantibodies may represent a novel approach in the precision treatment of patients arrhythmias and aid in improving outcomes.

The following are the potential avenues of research in this field: first, elucidating the precise binding sites of antibody-antigen interactions; second, clarifying the interaction between inflammation and immune pathways based on single-cell transcriptome sequencing technology (113); third, screening for cell subpopulation markers related to arrhythmias to improve the early diagnosis rate of autoimmune arrhythmias; fourth, developing blockers targeting antibody-receptor interactions; and finally, exploring the clinical application of bispecific antibodies in inhibiting pathogenic antibodies (114).

Acknowledgments

We would like to thank Professor Baopeng Tang for his invaluable guidance, insightful suggestions, and constant encouragement throughout the entire research process, as well as his profound expertise and rigorous academic attitude that have greatly inspired us and contributed significantly to the completion of this work. We would also like to thank all the members of the research team for their excellent collaboration, dedicated efforts, and constructive discussions. Without the collective wisdom and hard work of each team member, the success of this study would not have been possible.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://cdt.amegroups.com/article/view/10.21037/cdt-2025-173/rc

Peer Review File: Available at https://cdt.amegroups.com/article/view/10.21037/cdt-2025-173/prf

Funding: This study was supported by Top Young Scientific and Technological Talents of Tianshan Talent Cultivation Program in Xinjiang (No. 2022TSYCCX0101).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-2025-173/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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(English Language Editor: J. Gray)