Anti-Ro52 antibody acts on the S5-pore linker of hERG to chronically reduce channel expression

Szendrey, John A.; Lamothe, Shawn M.; Vanner, S; Guo, Jun; Yang, Tonghua; Li, Wentao; Davis, Jordan H.; Joneja, M. G.; Baranchuk, Adrián; Zhang, Shetuan

doi:10.1093/cvr/cvy310

Cited by 5 publications

(10 citation statements)

References 25 publications

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“…Several factors may account for these discrepancies, also possibly contributing to the significant variability in anti-Ro/SSA-associated QTc prolongation frequencies even reported by positive association studies (~10-60%) ( 25 , 66 ). Firstly, given that the QT-prolonging effects seems to be specifically due to the anti-Ro/SSA-52kD subtype, and in a concentration-dependent manner ( 23 , 24 , 27 , 66 , 69 , 70 ), it is likely that patients in these cohorts did not present circulating levels of this autoantibody sufficient to produce measurable electrocardiographic changes. Indeed, among different CTDs, a wide variability exists in terms of anti-Ro/SSA-52kD concentrations (for example, in systemic sclerosis patients the antibody level is typically low) ( 85 , 88 , 89 ), and in most of the negative association studies specific subtype assessment was not executed.…”

Section: Anti-ro/ssa-associated Long-qt Syndromementioning

confidence: 99%

“…Accumulating data from experimental studies based on in-vitro, ex-vivo , and in-vivo models ( Table 2 ) ( 23 , 24 , 26 , 27 , 33 ) demonstrated that the QT-prolonging effect of anti-Ro/SSA-antibodies, specifically the anti-Ro/SSA-52kD subtype, is due to a specific cross-reaction with the cardiac hERG-K + channel leading to an inhibition of the related current, I Kr ( 21 ). The direct electrophysiological nature of such an effect can well explain why circulating anti-Ro/SSA-antibodies are per se associated with an increased risk of QTc prolongation/TdP in the clinical setting, regardless of the presence or not of an overt AD ( 24 , 31 ).…”

Section: Anti-ro/ssa-associated Long-qt Syndromementioning

confidence: 99%

“…Consistently, the immunization of guinea-pigs with a 31-amino acid peptide corresponding to this region of the hERG-K + -channel resulted in high levels antibodies able to block I Kr , prolong APD and QTc, in the absence of any structural change at the pathology examination of the myocardium ( 26 ). In addition, a recent Canadian study provided further mechanistic insights into anti-Ro/SSA-associated QTc prolongation, explaining its long-lasting persistence as observed in the clinical setting ( 27 ). In fact, these authors demonstrated that prolonged incubation of HEK293-hERG cells with anti-Ro/SSA-52kD-positive sera from patients with rheumatic diseases significantly decreased I Kr compared to cells treated with autoantibody-negative patients' sera ( 27 ).…”

Section: Anti-ro/ssa-associated Long-qt Syndromementioning

confidence: 99%

“…In addition, a recent Canadian study provided further mechanistic insights into anti-Ro/SSA-associated QTc prolongation, explaining its long-lasting persistence as observed in the clinical setting ( 27 ). In fact, these authors demonstrated that prolonged incubation of HEK293-hERG cells with anti-Ro/SSA-52kD-positive sera from patients with rheumatic diseases significantly decreased I Kr compared to cells treated with autoantibody-negative patients' sera ( 27 ). Moreover, they showed that anti-Ro/SSA-52kD antibodies chronically facilitated hERG endocytic degradation by targeting the extracellular S5-pore linker region of the channel, and that these changes were associated with persistent I Kr reduction and APD prolongation in neonatal rat ventricular myocytes ( 27 ).…”

Section: Anti-ro/ssa-associated Long-qt Syndromementioning

confidence: 99%

“…Regarding the autoimmune LQTS, the most investigated form is associated to the presence of circulating anti-Ro/SSA-antibodies, responsible for one of the first identified arrhythmogenic autoantibody-induced channelopathies ( autoimmune cardiac channelopathies ) ( 19 , 21 , 22 ). In fact, accumulating evidence exists that anti-Ro/SSA-antibodies exert significant electrophysiological effects on the heart via an inhibitory cross-reaction with the extracellular pore region of the hERG-K + channel ( 23 – 27 ), leading to a higher propensity of developing LQTS ( 28 – 31 ) and VAs/TdP ( 24 , 32 , 33 ) in anti-Ro/SSA-antibody positive adults and newborns subjects. In this review, we highlight the current knowledge on this autoimmune associated LQTS form providing complementary basic, clinical and population health perspectives.…”

Section: Introductionmentioning

confidence: 99%

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Anti-Ro/SSA Antibodies and the Autoimmune Long-QT Syndrome

et al. 2021

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Autoimmunity is increasingly recognized as a novel pathogenic mechanism for cardiac arrhythmias. Several arrhythmogenic autoantibodies have been identified, cross-reacting with different types of surface proteins critically involved in the cardiomyocyte electrophysiology, primarily ion channels (autoimmune cardiac channelopathies). Specifically, some of these autoantibodies can prolong the action potential duration leading to acquired long-QT syndrome (LQTS), a condition known to increase the risk of life-threatening ventricular arrhythmias, particularly Torsades de Pointes (TdP). The most investigated form of autoimmune LQTS is associated with the presence of circulating anti-Ro/SSA-antibodies, frequently found in patients with autoimmune diseases (AD), but also in a significant proportion of apparently healthy subjects of the general population. Accumulating evidence indicates that anti-Ro/SSA-antibodies can markedly delay the ventricular repolarization via a direct inhibitory cross-reaction with the extracellular pore region of the human-ether-a-go-go-related (hERG) potassium channel, resulting in a higher propensity for anti-Ro/SSA-positive subjects to develop LQTS and ventricular arrhythmias/TdP. Recent population data demonstrate that the risk of LQTS in subjects with circulating anti-Ro/SSA antibodies is significantly increased independent of a history of overt AD, intriguingly suggesting that these autoantibodies may silently contribute to a number of cases of ventricular arrhythmias and cardiac arrest in the general population. In this review, we highlight the current knowledge in this topic providing complementary basic, clinical and population health perspectives.

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Section: Anti-ro/ssa-associated Long-qt Syndromementioning

confidence: 99%

Section: Anti-ro/ssa-associated Long-qt Syndromementioning

confidence: 99%

Section: Anti-ro/ssa-associated Long-qt Syndromementioning

confidence: 99%

Section: Anti-ro/ssa-associated Long-qt Syndromementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Anti-Ro/SSA Antibodies and the Autoimmune Long-QT Syndrome

et al. 2021

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Hydroxychloroquine and Chloroquine-Induced Cardiac Arrhythmias and Sudden Cardiac Death in Patients with Systemic Autoimmune Rheumatic Diseases: A Systematic Review and Meta-Analysis

Nikolic,

Virk,

Buhler

et al. 2024

Journal of Cardiovascular Pharmacology

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Hydroxychloroquine (HCQ) and chloroquine (CQ) are foundational treatments for several systemic autoimmune rheumatic diseases, including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Concerns regarding the risk of cardiac arrhythmia and death have been raised, yet the burden of HCQ and CQ-related cardiac toxicities remains unclear. A systematic literature search was conducted in the MEDLINE and Embase databases for articles published between the earliest date and April 2023 reporting cardiac conduction abnormalities in patients with systemic autoimmune rheumatic diseases taking HCQ or CQ. Meta-analysis was performed to calculate the difference in mean QTc and odds ratio of prolonged QTc in those taking HCQ or CQ versus not. Of 2673 unique records, 34 met the inclusion criteria, including 70,609 subjects. Thirty-three studies reported outcomes in HCQ and 9 in CQ. Five studies reported outcomes in RA, 11 in SLE, and 18 in populations with mixed rheumatic diseases. Eleven studies reported mean QTc and OR for prolonged QTc for meta-analysis, all reporting outcomes in HCQ. There was a significant increase in mean QTc among HCQ users in patients with RA (10.29 ms, p = 0.458). There was no difference in mean QTc between HCQ and non-HCQ users in other systemic autoimmune rheumatic diseases. When rheumatic diseases were pooled, HCQ users were more likely to have prolonged QTc (odds ratio 1.57, 95%CI: 1.19, 2.08). QTc prolongation was more likely in patients with systemic autoimmune rheumatic diseases. Clinicians should be aware of potential adverse cardiac events of HCQ and consider QTc monitoring.

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Evaluating pro-arrhythmogenic effects of the T634S-hERG mutation: insights from a simulation study

Hu,

Zhang,

Zhang

et al. 2023

Interface Focus.

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A mutation to serine of a conserved threonine (T634S) in the hERG K + channel S6 pore region has been identified as a variant of uncertain significance, showing a loss-of-function effect. However, its potential consequences for ventricular excitation and arrhythmogenesis have not been reported. This study evaluated possible functional effects of the T634S-hERG mutation on ventricular excitation and arrhythmogenesis by using multi-scale computer models of the human ventricle. A Markov chain model of the rapid delayed rectifier potassium current (I Kr ) was reconstructed for wild-type and T634S-hERG mutant conditions and incorporated into the ten Tusscher et al . models of human ventricles at cell and tissue (1D, 2D and 3D) levels. Possible functional impacts of the T634S-hERG mutation were evaluated by its effects on action potential durations (APDs) and their rate-dependence (APDr) at the cell level; and on the QT interval of pseudo-ECGs, tissue vulnerability to unidirectional conduction block (VW), spiral wave dynamics and repolarization dispersion at the tissue level. It was found that the T634S-hERG mutation prolonged cellular APDs, steepened APDr, prolonged the QT interval, increased VW, destablized re-entry and augmented repolarization dispersion across the ventricle. Collectively, these results imply potential pro-arrhythmic effects of the T634S-hERG mutation, consistent with LQT2.

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Anti-Ro52 antibody acts on the S5-pore linker of hERG to chronically reduce channel expression

Cited by 5 publications

References 25 publications

Anti-Ro/SSA Antibodies and the Autoimmune Long-QT Syndrome

Anti-Ro/SSA Antibodies and the Autoimmune Long-QT Syndrome

Hydroxychloroquine and Chloroquine-Induced Cardiac Arrhythmias and Sudden Cardiac Death in Patients with Systemic Autoimmune Rheumatic Diseases: A Systematic Review and Meta-Analysis

Evaluating pro-arrhythmogenic effects of the T634S-hERG mutation: insights from a simulation study

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