Pathogenesis of the Novel Autoimmune-Associated Long-QT Syndrome

Yue, Yuankun; Castrichini, Monica; Srivastava, Ujala; Fabris, Frank; Shah, Krupa; Li, Zhiqiang; Qu, Yongxia; El‐Sherif, Nabil; Zhou, Zhengfeng; January, Craig T.; Hussain, M. Mahmood; Jiang, Xian Cheng; Sobie, Eric A.; Wahren‐Herlenius, Marie; Chahine, Mohamed; Capecchi, Pier Leopoldo; Laghi-Pasini, Franco; Lazzerini, Pietro Enea; Boutjdir, Mohamed

doi:10.1161/circulationaha.115.009800

Cited by 66 publications

(77 citation statements)

References 43 publications

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“…14 Mounting evidence indicates that the hERG-channel is also a specific molecular target for anti-Ro/SSA, thereby responsible for a novel form of acquired LQTS mediated by an autoimmune origin. 7,13 Although anti-Ro/SSA-positive CTD patients frequently display QTc prolongation and complex ventricular arrhythmias, 4,6,25 anti-Ro/SSA are also silently present in a significant proportion of asymptomatic subjects of the general population. [8][9][10][11][12] An emblematic case of an anti-Ro/ SSA-associated TdP in an apparently healthy young woman has been recently reported in which clear evidence of a direct mechanistic link between circulating anti-Ro/SSA and QTc prolongation was provided.…”

Section: Discussionmentioning

confidence: 99%

“…Experiments were performed on HEK293 cells stably expressing the hERG channel as previously described 7 and detailed in Methods in the Data Supplement.…”

Section: Electrophysiological Studymentioning

confidence: 99%

“…Figure 6A shows that anti-Ro/SSA-positive IgG from patients 6 and 3 did not recognize any bands in untransfected HEK293 cells (lanes 1 and 3) but recognized 2 bands at ≈155 and 135 kDa in transfected HEK293 cells (lanes 2 and 4) corresponding to the glycosylated and endoplasmic reticulumretained hERG channel consistent with previous reports. 7,21,22 Figure 6B shows no bands when anti-Ro/SSA-negative IgG from patients numbers 16 and 18 was used in both untransfected HEK293 cells (lanes 1 and 3) and transfected HEK293 cells expressing hERG channels (lanes 2 and 4). Because of the previously demonstrated 7 homology between 52-kD Ro protein (aa302-aa321) and hERG α 1 -subunit (aa574-aa598) at the pore region, we tested the reactivity of patients' sera with the E-pore peptide and its scrambled form.…”

Section: Anti-ro/ssa-positive But Not Anti-ro-negative Igg Cross-reacmentioning

confidence: 99%

“…7,21,22 Figure 6B shows no bands when anti-Ro/SSA-negative IgG from patients numbers 16 and 18 was used in both untransfected HEK293 cells (lanes 1 and 3) and transfected HEK293 cells expressing hERG channels (lanes 2 and 4). Because of the previously demonstrated 7 homology between 52-kD Ro protein (aa302-aa321) and hERG α 1 -subunit (aa574-aa598) at the pore region, we tested the reactivity of patients' sera with the E-pore peptide and its scrambled form. Sera of each patient were tested in triplicates.…”

Section: Anti-ro/ssa-positive But Not Anti-ro-negative Igg Cross-reacmentioning

confidence: 99%

“…7 In addition, 52-kD Ro/SSA antigenimmunized guinea pigs showed QTc prolongation on ECG after developing high titers of anti-Ro/SSA. 7 Several studies have demonstrated that anti-Ro/SSA are the most frequent autoantibodies found in the general population with a frequency ranging from 0.5% to 2.7%. [8][9][10] Notably, this rate increases to ≈15% when the laboratory method used is immuno-Western blotting.…”

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confidence: 98%

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Arrhythmogenicity of Anti-Ro/SSA Antibodies in Patients With Torsades de Pointes

Lazzerini

Yue

Srivastava

et al. 2016

Circ: Arrhythmia and Electrophysiology

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Background— In patients with autoimmune disease, anti-Ro/SSA antibodies (anti-Ro/SSA) are responsible for a novel autoimmune-associated long-QT syndrome by targeting the hERG potassium channel and inhibiting the related current ( I Kr ). Because anti-Ro/SSA are also present in a significant proportion of healthy subjects and may be associated with torsades de pointes (TdP) arrhythmia, we tested the hypothesis that anti-Ro/SSA may represent a silent risk factor in patients developing TdP. Methods and Results— Twenty-five consecutive patients who experienced TdP were prospectively collected independent of ongoing therapies and concomitant diseases. Anti-Ro/SSA were detected by fluoroenzyme immunoassay, immuno–Western blotting, and line-blot immunoassay. Purified IgGs from anti-Ro/SSA-positive and anti-Ro/SSA-negative patients were tested on I Kr using HEK293 cells stably expressing the hERG channel. As expected, in TdP patients, many known corrected QT interval–prolonging risk factors were simultaneously present, including hypokalemia that was the most common (52%). Anti-Ro/SSA were present in 60% of the subjects, mostly the anti-Ro/SSA-52-kD subtype detected by immuno–Western blotting only. A history of autoimmune disease was found in only 2 of anti-Ro/SSA-positive patients. Experimental data demonstrated that purified anti-Ro/SSA-positive IgGs significantly inhibited I Kr and cross reacted with hERG-channel proteins. Moreover, anti-Ro/SSA-positive sera exhibited high reactivity with a peptide corresponding to the hERG-channel pore-forming region. Conclusions— Anti-Ro/SSA may represent a clinically silent novel risk factor for TdP development via an autoimmune-mediated electrophysiological interference with the hERG channel. We propose that TdP patients may benefit from specific anti-Ro/SSA testing even in the absence of autoimmune diseases as immunomodulating therapies may be effective in shortening corrected QT interval and reducing TdP recurrence risk.

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Section: Discussionmentioning

confidence: 99%

“…Experiments were performed on HEK293 cells stably expressing the hERG channel as previously described 7 and detailed in Methods in the Data Supplement.…”

Section: Electrophysiological Studymentioning

confidence: 99%

Section: Anti-ro/ssa-positive But Not Anti-ro-negative Igg Cross-reacmentioning

confidence: 99%

Section: Anti-ro/ssa-positive But Not Anti-ro-negative Igg Cross-reacmentioning

confidence: 99%

mentioning

confidence: 98%

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Arrhythmogenicity of Anti-Ro/SSA Antibodies in Patients With Torsades de Pointes

Lazzerini

Yue

Srivastava

et al. 2016

Circ: Arrhythmia and Electrophysiology

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American College of Rheumatology White Paper on Antimalarial Cardiac Toxicity

Desmarais

Rosenbaum

Costenbader

et al. 2021

Arthritis & Rheumatology

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Hydroxychloroquine (HCQ) and chloroquine (CQ) are well-established medications used in treating systemic lupus erythematosus and rheumatoid arthritis, as well as skin conditions such as cutaneous lupus erythematosus. In rare cases, arrhythmias and conduction system abnormalities, as well as cardiomyopathy, have been reported in association with HCQ/CQ use. Recently, however, the corrected QT interval (QTc)-prolonging potential of these medications, and risk of torsade de pointes (TdP) in particular, have been highlighted in the setting of their experimental use for COVID-19 infection. This report was undertaken to summarize the current understanding of HCQ/CQ cardiac toxicity, describe QTc prolongation and TdP risks, and discuss areas of priority for future research. A working group of experts across rheumatology, cardiology, and dermatology performed a nonsystematic literature review and offered a consensus-based expert opinion. Current data clearly indicate that HCQ and CQ are invaluable medications in the management of rheumatic and dermatologic diseases, but they are associated with QTc prolongation by directly affecting cardiac repolarization. Prescribing clinicians should be cognizant of this small effect, especially in patients taking additional medications that prolong the QTc interval. Long-term use of HCQ/CQ may lead to a cardiomyopathy associated with arrhythmias and heart failure. Risk and benefit assessment should be considered prior to initiation of any medication, and both initial and ongoing risk-benefit assessments are important with regard to prescription of HCQ/CQ. While cardiac toxicity related to HCQ/CQ treatment of rheumatic diseases is rarely reported, it can be fatal. Awareness of the potential adverse cardiac effects of HCQ and CQ can increase the safe use of these medications. There is a clear need for additional research to allow better understanding of the cardiovascular risk and safety profile of these therapies used in the management of rheumatic and cutaneous diseases.

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