Comment on “Absence of an association between anti-Ro antibodies and prolonged QTc interval in systemic sclerosis: A multicenter study of 689 patients”

Lazzerini, Pietro Enea; Capecchi, Pier Leopoldo; Boutjdir, Mohamed; Laghi-Pasini, Franco

doi:10.1016/j.semarthrit.2014.10.002

Cited by 7 publications

(4 citation statements)

References 10 publications

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“…Previous studies have shown that circulating IL-6 levels are elevated in patients with autoimmune diseases (Adlan et al, 2015; Lazzerini et al, 2015a,c, 2017a) and are associated with the prolongation of corrected QT (QT c ) or LQTS, a serious condition which increases vulnerability to fatal arrhythmias including Torsades de Pointes ( TdP ). These results were obtained by accumulating data from patients with myo/endocarditis (Ukena et al, 2011; Lazzerini et al, 2015b) and systemic autoimmune diseases, particularly rheumatoid arthritis (Lazzerini et al, 2014, 2017a; Adlan et al, 2015) and connective tissue disease (Lazzerini et al, 2015c). There have also been reports of an association between elevated serum IL-6 concentrations and increased susceptibility to spontaneous ventricular tachyarrhythmia in patients with coronary artery disease (Streitner et al, 2007).…”

Section: Molecular Signaling Pathways Of Cardiolipotoxicity That Prommentioning

confidence: 99%

Cardiolipotoxicity, Inflammation, and Arrhythmias: Role for Interleukin-6 Molecular Mechanisms

2019

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Fatty acid infiltration of the myocardium, acquired in metabolic disorders (obesity, type-2 diabetes, insulin resistance, and hyperglycemia) is critically associated with the development of lipotoxic cardiomyopathy. According to a recent Presidential Advisory from the American Heart Association published in 2017, the current average dietary intake of saturated free-fatty acid (SFFA) in the US is 11–12%, which is significantly above the recommended <10%. Increased levels of circulating SFFAs (or lipotoxicity) may represent an unappreciated link that underlies increased vulnerability to cardiac dysfunction. Thus, an important objective is to identify novel targets that will inform pharmacological and genetic interventions for cardiomyopathies acquired through excessive consumption of diets rich in SFFAs. However, the molecular mechanisms involved are poorly understood. The increasing epidemic of metabolic disorders strongly implies an undeniable and critical need to further investigate SFFA mechanisms. A rapidly emerging and promising target for modulation by lipotoxicity is cytokine secretion and activation of pro-inflammatory signaling pathways. This objective can be advanced through fundamental mechanisms of cardiac electrical remodeling. In this review, we discuss cardiac ion channel modulation by SFFAs. We further highlight the contribution of downstream signaling pathways involving toll-like receptors and pathological increases in pro-inflammatory cytokines. Our expectation is that if we understand pathological remodeling of major cardiac ion channels from a perspective of lipotoxicity and inflammation, we may be able to develop safer and more effective therapies that will be beneficial to patients.

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Section: Molecular Signaling Pathways Of Cardiolipotoxicity That Prommentioning

confidence: 99%

Cardiolipotoxicity, Inflammation, and Arrhythmias: Role for Interleukin-6 Molecular Mechanisms

2019

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“…Although the majority of the data point to an association between anti-Ro/SSA and QTc prolongation, there are conflicting results from other studies, either in children ( 123 , 125 ) and adults ( 27 , 35 , 37 ). However, it should be noted that one of these studies ( 37 ) was performed in SSc patients, who frequently display anti-Ro/SSA but at a low level ( 127 ), thus possibly not high enough for the threshold level required for QTc prolongation manifestation ( 29 , 128 ); in another one ( 35 ), involving SLE patients, the authors used a cutoff for QTc prolongation (>500 ms) probably not adequate to detect the phenomenon in this setting, as previous studies consistently demonstrated that in the large majority of the anti-Ro/SSA-positive CTD patients with QTc prolongation values ranged from 440 to 500 ms.…”

Section: Autoimmunity As a Cause Of Acquired Lqtsmentioning

confidence: 99%

“…A block of the inward ICaL during the plateau phase shortens, while an inhibition of outward IKr during repolarization prolongs APD ( 160 ). Thus, it is conceivable that a concomitant inhibitory effect of anti-Ro/SSA on calcium channels can partially counteract the IKr inihibition-dependent APD prolonging effects in vivo , thus reducing the actual extent of QTc prolongation observed ( 128 ). In this view, intrinsic (inherited or acquired) differences in potassium and calcium channel expression on patient’s cardiomyocytes may participate in the QTc variability observed.…”

Section: Autoimmunity As a Cause Of Acquired Lqtsmentioning

confidence: 99%

Long QT Syndrome: An Emerging Role for Inflammation and Immunity

Lazzerini

Capecchi

Laghi‐Pasini

2015

Front. Cardiovasc. Med.

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134

123

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The long QT syndrome (LQTS), classified as congenital or acquired, is a multi-factorial disorder of myocardial repolarization predisposing to life-threatening ventricular arrhythmias, particularly torsades de pointes. In the latest years, inflammation and immunity have been increasingly recognized as novel factors crucially involved in modulating ventricular repolarization. In the present paper, we critically review the available information on this topic, also analyzing putative mechanisms and potential interplays with the other etiologic factors, either acquired or inherited. Accumulating data indicate inflammatory activation as a potential cause of acquired LQTS. The putative underlying mechanisms are complex but essentially cytokine-mediated, including both direct actions on cardiomyocyte ion channels expression and function, and indirect effects resulting from an increased central nervous system sympathetic drive on the heart. Autoimmunity represents another recently arising cause of acquired LQTS. Indeed, increasing evidence demonstrates that autoantibodies may affect myocardial electric properties by directly cross-reacting with the cardiomyocyte and interfering with specific ion currents as a result of molecular mimicry mechanisms. Intriguingly, recent data suggest that inflammation and immunity may be also involved in modulating the clinical expression of congenital forms of LQTS, possibly triggering or enhancing electrical instability in patients who already are genetically predisposed to arrhythmias. In this view, targeting immuno-inflammatory pathways may in the future represent an attractive therapeutic approach in a number of LQTS patients, thus opening new exciting avenues in antiarrhythmic therapy.

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“…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. In addition, most of these studies were retrospective and utilized different cutoffs to define QTc prolongation, these factors also potentially contributing to inconsistencies.…”

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

confidence: 99%

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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Comment on “Absence of an association between anti-Ro antibodies and prolonged QTc interval in systemic sclerosis: A multicenter study of 689 patients”

Cited by 7 publications

References 10 publications

Cardiolipotoxicity, Inflammation, and Arrhythmias: Role for Interleukin-6 Molecular Mechanisms

Cardiolipotoxicity, Inflammation, and Arrhythmias: Role for Interleukin-6 Molecular Mechanisms

Long QT Syndrome: An Emerging Role for Inflammation and Immunity

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

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