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Background: During acute infections, the risk of malignant ventricular arrhythmias is increased, partly because of a higher propensity to develop QTc prolongation. Although it is generally believed that QTc changes almost exclusively result from concomitant treatment with QT-prolonging antimicrobials, direct effects of inflammatory cytokines on ventricular repolarization are increasingly recognized. We hypothesized that systemic inflammation per se can significantly prolong QTc during acute infections, via cytokine-mediated changes in K + channel expression., Methods: We evaluated (1) the frequency of QTc prolongation and its association with inflammatory markers, in patients with different types of acute infections, during active disease and remission; (2) the prevalence of acute infections in a cohort of consecutive patients with Torsades de Pointes; (3) the relationship between K + channel mRNA levels in ventricles and peripheral blood mononuclear cells and their changes in patients with acute infection over time., Results: In patients with acute infections, regardless of concomitant QT-prolonging antimicrobial treatments, QTc was significantly prolonged but rapidly normalized in parallel to CRP (C-reactive protein) and cytokine level reduction. Consistently in the Torsades de Pointes cohort, concomitant acute infections were highly prevalent (30%), despite only a minority (25%) of these cases were treated with QT-prolonging antimicrobials. KCNJ2 K + channel expression in peripheral blood mononuclear cell, which strongly correlated to that in ventricles, inversely associated to CRP and IL (interleukin)-1 changes in acute infection patients., Conclusions: During acute infections, systemic inflammation rapidly induces cytokine-mediated ventricular electrical remodeling and significant QTc prolongation, regardless concomitant antimicrobial therapy. Although transient, these changes may significantly increase the risk of life-threatening ventricular arrhythmia in these patients. It is timely and warranted to transpose these findings to the current coronavirus disease 2019 (COVID-19) pandemic, in which both increased amounts of circulating cytokines and cardiac arrhythmias are demonstrated along with a frequent concomitant treatment with several QT-prolonging drugs. Graphic Abstract: A graphic abstract is available for this article.

Background Systemic inflammation is a strong predictor of atrial fibrillation. A key role for electrical remodeling is increasingly recognized, and experimental data suggest that inflammatory cytokines can directly affect connexins resulting in gap-junction dysfunction. We hypothesized that systemic inflammation, regardless of its origin, promotes atrial electric remodeling in vivo, as a result of cytokine-mediated changes in connexin expression. Methods and Results Fifty-four patients with different inflammatory diseases and elevated C-reactive protein were prospectively enrolled, and electrocardiographic P-wave dispersion indices, cytokine levels (interleukin-6, tumor necrosis factor-α, interleukin-1, interleukin-10), and connexin expression (connexin 40, connexin 43) were measured during active disease and after reducing C-reactive protein by >75%. Moreover, peripheral blood mononuclear cells and atrial tissue specimens from an additional sample of 12 patients undergoing cardiac surgery were evaluated for atrial and circulating mRNA levels of connexins. Finally, in vitro effects of interleukin-6 on connexin expression were studied in HL-1 mouse atrial myocytes. In patients with active inflammatory diseases, P-wave dispersion indices were increased but rapidly decreased within days when C-reactive protein normalizes and interleukin-6 levels decline. In inflammatory disease patients, both P-wave dispersion indices and interleukin-6 changes were inversely associated with circulating connexin levels, and a positive correlation between connexin expression in peripheral blood mononuclear cells and atrial tissue was demonstrated. Moreover, interleukin-6 significantly reduced connexin expression in HL-1 cells. Conclusions Our data suggest that regardless of specific etiology and organ localization, systemic inflammation, via interleukin-6 elevation, rapidly induces atrial electrical remodeling by down-regulating cardiac connexins. Although transient, these changes may significantly increase the risk for atrial fibrillation and related complications during active inflammatory processes.

Increased proinflammatory interleukin-6 (IL-6) levels are associated with acquired long QT-syndrome (LQTS) in patients with systemic inflammation, leading to higher risks for life-threatening polymorphic ventricular tachycardia such as Torsades de Pointes. However, the functional and molecular mechanisms of this association are not known. In most cases of acquired LQTS, the target ion channel is the human ether-á-go-go-related gene (hERG) encoding the rapid component of the delayed rectifier K current, IKr, which plays a critical role in cardiac repolarization. Here, we tested the hypothesis that IL-6 may cause QT prolongation by suppressing IKr. Electrophysiological and biochemical assays were used to assess the impact of IL-6 on the functional expression of IKr in HEK293 cells and adult guinea-pig ventricular myocytes (AGPVM). In HEK293 cells, IL-6 alone or in combination with the soluble IL-6 receptor (IL-6R), produced a significant depression of IKr peak and tail current densities. Block of IL-6R or Janus kinase (JAK) reversed the inhibitory effects of IL-6 on IKr. In AGPVM, IL-6 prolonged action potential duration (APD) which was further prolonged in the presence of IL-6R. Similar to heterologous cells, IL-6 reduced endogenous guinea pig ERG channel mRNA and protein expression. The data are first to demonstrate that IL-6 inhibition of IKr and the resulting prolongation of APD is mediated via IL-6R and JAK pathway activation and forms the basis for the observed clinical QT interval prolongation. These novel findings may guide the development of targeted anti-arrhythmic therapeutic interventions in patients with LQTS and inflammatory disorders., Competing Interests: The authors have declared that no competing interests exist.

Polymyalgia rheumatica (PMR) represents the most common inflammatory rheumatic disease of the elderly. It is characterized by synovitis of proximal joints and extra-articular synovial structures, along with chronic high-grade systemic inflammation. PMR is closely related to giant cell arteritis (GCA), a large-vessel vasculitis that involves the major branches of the aorta, particularly the extracranial branches of carotid artery including temporal arteries. It is currently believed that PMR and GCA may represent different manifestations of the same disease process. Chronic systemic inflammation is presently recognized as one of the key pathogenic mechanisms underlying cardiovascular disease and associated complications, including cardiac arrhythmias and sudden death. In this regard, several studies demonstrated that besides promoting structural heart disease, inflammatory activation may also be per se arrhythmogenic, via cytokine-mediated effects on cardiac electrophysiology. In particular, increasing evidence points to inflammation as a novel risk factor for QTc prolongation and related life-threatening arrhythmias, specifically Torsade de Pointes (TdP). Starting from the report of two cases of TdP occurring in PMR patients with active disease and elevated circulating IL-6 levels, we here reviewed literature data regarding heart involvement and arrhythmic events in PMR/GCA, as well as TdP risk in inflammatory diseases. Potential underlying mechanisms were dissected, by focusing on the driving role of inflammatory activation., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Objective: Increasing evidence indicates systemic inflammation as a new potential cause of acquired long QT syndrome (LQTS), via cytokine-mediated changes in cardiomyocyte ion channels. Torsade de pointes (TdP) is a life-threatening polymorphic ventricular tachycardia occurring in patients with LQTS, usually when multiple QT-prolonging factors are simultaneously present. Since classical risk factors cannot fully explain TdP events in a number of patients, we hypothesised that systemic inflammation may represent a currently overlooked risk factor contributing to TdP development in the general population., Methods: Forty consecutive patients who experienced TdP (TdP cohort) were consecutively enrolled and circulating levels of C-reactive protein (CRP) and proinflammatory cytokines (interleukin-6 (IL-6), tumour necrosis factor alpha (TNFα), interleukin-1 (IL-1)) were compared with patients with active rheumatoid arthritis (RA), comorbidity or healthy controls. An additional 46 patients with different inflammatory conditions (acute infections, n=31; immune-mediated diseases, n=12; others, n=3) and elevated CRP (inflammatory cohort) were prospectively enrolled, and corrected QT (QTc) and cytokine levels were measured during active disease and after a CRP decrease of >75% subsequent to therapy., Results: In the TdP cohort, 80% of patients showed elevated CRP levels (median: ~3 mg/dL), with a definite inflammatory disease identifiable in 18/40 cases (acute infections, n=12; immune-mediated diseases, n=5; others, n=1). In these subjects, IL-6, but not TNFα and IL-1, was ~15-20 times higher than in controls, and comparable to RA patients. In the inflammatory cohort, where QTc prolongation was common (mean values: 456.6±30.9 ms), CRP reduction was associated with IL-6 level decrease and significant QTc shortening (-22.3 ms)., Conclusion: The data are first to show that systemic inflammation via elevated IL-6 levels may represent a novel QT-prolonging risk factor contributing to TdP occurrence in the presence of other classical risk factors. If confirmed, this could open new avenues in antiarrhythmic therapy., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Hyperhomocysteinemia is independently associated with the development of coronary, cerebral and peripheral vascular disease and deep-vein thrombosis in the general population. The evidence that cardiovascular involvement is particularly frequent and advanced in patients affected with several autoimmune diseases (AD), in which hyperhomocysteinemia represent a common finding, led to an intensive investigation on homocysteine (Hcy) as a putative risk factor for the development of cardiovascular disease in such subjects. Indeed, recent data intriguingly expanded the spectrum of the possible pathogenetic implications for hyperhomocysteinemia in the course of AD. In fact, a bi-directional link seems to connect Hcy and the immuno-inflammatory activation characterizing AD, in which immuno-inflammatory activation may contribute to Hcy increase, and Hcy, in its turn, may act as a pro-inflammatory and immuno-stimulating molecule putatively cooperating to the injury of the disease-specific target organs, at least in rheumatoid arthritis and inflammatory bowel disease. Moreover, Hcy may be also a trigger of autoimmune reactions through its capability to bind and structurally modify specific proteins, then resulting in neoantigens formation potentially relevant either in the onset of specific AD and in the progression of the associated cardiovascular damage. More investigation is necessary to fully define the clinical relevance of such phenomena.

Background: Severely ill patients with coronavirus disease 2019 (COVID‐19) show an increased risk of new‐onset atrioventricular blocks (AVBs), associated with high rates of short‐term mortality. Recent data suggest that the uncontrolled inflammatory activation observed in these patients, specifically interleukin (IL)‐6 elevation, may play an important pathogenic role by directly affecting cardiac electrophysiology. The aim of our study was to assess the acute impact of IL‐6 changes on electrocardiographic indices of atrioventricular conduction in severe COVID‐19. Methods: We investigated (1) the behavior of PR‐interval and PR‐segment in patients with severe COVID‐19 during active phase and recovery, and (2) their association with circulating IL‐6 levels over time. Results: During active disease, COVID‐19 patients showed a significant increase of PR‐interval and PR‐segment. Such atrioventricular delay was transient as these parameters rapidly normalized during recovery. PR‐indices significantly correlated with circulating IL‐6 levels over time. All these changes and correlations persisted also in the absence of laboratory signs of cardiac strain/injury or concomitant treatment with PR‐prolonging drugs, repurposed or not. Conclusions: Our study provides evidence that in patients with severe COVID‐19 and high‐grade systemic inflammation, IL‐6 elevation is associated with a significant delay of atrioventricular conduction, independent of concomitant confounding factors. While transient, such alterations may enhance the risk of severe AVB and associated short‐term mortality. Our data provide further support to current anti‐inflammatory strategies for severe COVID‐19, including IL‐6 antagonists. [ABSTRACT FROM AUTHOR]

Cardiac K+ channelopathies account for a significant proportion of arrhythmias and sudden cardiac death (SCD) in subjects without structural heart disease. It is well recognized that genetic defects are key factors in many cases, and in practice, the term cardiac channelopathies currently coincides with inherited cardiac channelopathies. However, mounting evidence demonstrate that not only genetic alterations but also autoimmune and inflammatory factors can cause cardiac K+-channel dysfunction and arrhythmias in the setting of a structurally normal heart. In particular, it has been demonstrated that specific autoantibodies as well as inflammatory cytokines can modulate expression and/or function of different K+ channels in the heart, resulting in a disruption of the cardiac action potential and arrhythmias/sudden cardiac death. Awareness about the existence of these newly recognized forms is essential to identify and adequately manage affected patients. In the present review, we focus on autoimmune and inflammatory K+ channelopathies as a novel mechanism for cardiac arrhythmias and analyze the recent advancements in this topic, providing complementary basic, clinical, and population health perspectives. [ABSTRACT FROM AUTHOR]

When compared to the general population, patients with rheumatoid arthritis (RA) have an overall standard mortality ratio of approximately two, with more than 50% of premature deaths attributable to cardiovascular disease (CVD). Moreover, RA patients were twice as likely to experience sudden cardiac death (SCD) compared with non-RA subjects, as a putative consequence of an increased incidence of malignant arrhythmias. Accordingly, mounting data indicate that in patients affected with RA the risk of developing rhythm disturbances, particularly tachyarrhythmias, is high. Although a number of papers reviewing the problem of cardiovascular involvement in RA are currently available, the main focus is on the mechanisms of accelerated atherosclerosis and related ischemic consequences in the clinical setting. On the contrary, only little consideration has been specifically given to the arrhythmic risk so far. In the light of this concern, in the present paper we reviewed the topic with the aim to put together the apparently fragmentary existing information, with particular attention to the putative role of chronic systemic inflammation characterizing the disease. In fact, although the underlying mechanisms accounting the arrhythmogenic substrate in RA are probably intricate, the leading role seems to be played by inflammatory activation, able to promote arrhythmias either indirectly, by accelerating the development of structural CVD, and directly by affecting cardiac electrophysiology. In this view, lowering inflammatory burden through an increasingly tight control of disease activity may represent the most effective intervention to reduce arrhythmic risk and prevent life-threatening complications in these patients. [ABSTRACT FROM AUTHOR]

COVID-19, Arrhythmic Risk, and Inflammation: Mind the Gap! Keywords: arrhythmia; COVID-19; inflammation EN arrhythmia COVID-19 inflammation 7 9 3 07/08/20 20200707 NES 200707 Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).[1] Besides direct tissue invasion, SARS-CoV-2 can also elicit an exaggerated host immune response, frequently leading to a cytokine storm, which significantly contributes to multiorgan dysfunction.[1] Indeed, high levels of circulating cytokines, particularly interleukin (IL)-6, are commonly found in patients with COVID-19, also associating with in-hospital death.[1] Accumulating data point to an increased cardiovascular disease morbidity and mortality in these patients.[1] In particular, growing evidence suggest that COVID-19 is burdened by a higher risk of arrhythmic events, with important implications for survival.[1] Heart palpitations were reported as one of the most common initial symptom of the disease (7.3%).[1] In 138 hospitalized patients with COVID-19, arrhythmias represented the leading complication (19.6%) after acute distress respiratory syndrome, particularly in those admitted to intensive care unit where the prevalence rose to 44.4%.[1] Specifically, malignant ventricular arrhythmias (ie, ventricular tachycardia/fibrillation) were found in 5.9% of cases.[1] It is currently believed that myocardial damage might represent a main driver of enhanced arrhythmic risk in these patients.[1] Cardiac myocyte injury, reflected by increased troponin levels, was demonstrated in many individuals, particularly in those with severe disease. [Extracted from the article]

Torsade de pointes is a potentially lethal polymorphic ventricular tachyarrhythmia that can occur in the setting of long QT syndrome (LQTS). LQTS is multi-hit in nature and multiple factors combine their effects leading to increased arrhythmic risk. While hypokalemia and multiple medications are accounted for in LQTS, the arrhythmogenic role of systemic inflammation is increasingly recognized but often overlooked. We tested the hypothesis that the inflammatory cytokine interleukin(IL)-6 will significantly increase the incidence of arrhythmia when combined with other pro-arrhythmic conditions (hypokalemia and the psychotropic medication, quetiapine). Guinea pigs were injected intraperitoneally with IL-6/soluble IL-6 receptor and QT changes were measured in vivo. Subsequently, hearts were cannulated via Langendorff perfusion for ex vivo optical mapping measurements of action potential duration (APD 90) and arrhythmia inducibility. Computer simulations (MATLAB) were performed to investigate I Kr inhibition at varying IL-6 and quetiapine concentrations. IL-6 prolonged QTc in vivo guinea pigs from 306.74 ± 7.19 ms to 332.60 ± 8.75 ms (n = 8, p =.0021). Optical mapping on isolated hearts demonstrated APD prolongation in IL-6- vs saline groups (3Hz APD 90 :179.67 ± 2.47 ms vs 153.5 ± 7.86 ms, p =.0357). When hypokalemia was introduced, the APD 90 increased to 195.8 ± 5.02 ms[IL-6] and 174.57 ± 10.7 ms[saline] (p =.2797), and when quetiapine was added to hypokalemia to 207.67 ± 3.03 ms[IL-6] and 191.37 ± 9.49 ms[saline] (p =.2449). After the addition of hypokalemia ± quetiapine, arrhythmia was induced in 75% of IL-6-treated hearts (n = 8), while in none of the control hearts (n = 6). Computer simulations demonstrated spontaneous depolarizations at ∼83% aggregate I Kr inhibition. Our experimental observations strongly suggest that controlling inflammation, specifically IL-6, could be a viable and important route for reducing QT prolongation and arrhythmia incidence in the clinical setting. • Inflammation is often overlooked in treatment of Long QT Syndrome. • Patients taking psychotropic medication are at increased risk for arrhythmia. • Interleukin-6 can increase action potential duration and QT interval. • Our data shows IL-6 could be a novel therapeutic target for reducing arrhythmia risk. [ABSTRACT FROM AUTHOR]

Abstract: Background: The risk of sudden cardiac death is increased in chronic inflammatory arthritis, particularly rheumatoid arthritis (RA). To evaluate the putative effect of systemic inflammation on heart rate variability (HRV) and ventricular repolarization in chronic inflammatory arthritis, we analyzed in these patients the possible relationship among HRV parameters, QT interval, and high sensitivity C-reactive protein (hsCRP). Methods: One hundred-one patients with chronic inflammatory arthritis underwent a 15-minute ambulatory twelve-channel electrocardiogram-recording, to evaluate HRV and QT interval, as well as a venous withdrawal for hsCRP as an estimation of ongoing systemic inflammation. Results: In patients with chronic inflammatory arthritis, hsCRP is inversely correlated with HRV and directly with QTc duration, but while hsCRP is associated with HRV independently from any other investigated factor, the association between hsCRP and QTc seems to be an indirect consequence of the autonomic dysfunction itself. Within the whole cohort of patients, those subjects having elevated hsCRP levels displayed both a significant reduction in HRV and a prolongation of QTc with respect to patients with a normal hsCRP value. A similar, although less marked, degree of HRV depression and QTc prolongation was found in RA patients when compared to subjects with spondyloarthritis (SpA) and healthy controls. Conclusions: These data provide evidence of a link between systemic inflammation and the arrhythmic risk in patients with chronic inflammatory arthritis, also putatively explaining, at least in part, how the different inflammatory load characterizing RA and SpA parallels the different risks of cardiovascular death in these two conditions. [Copyright &y& Elsevier]

Abstract: Objective: Experimental and clinical data suggest that statins may protect bone by inhibiting bone resorption and/or stimulating bone formation. Interleukin-6 (IL-6) is produced by osteoblasts, and potently stimulates osteoclast activation playing a key role in normal bone resorption as well as in post-menopausal and inflammation-driven osteoporosis. Although statins inhibit IL-6 production from different cell types, currently no data exist on osteoblasts. The aim of the study was to evaluate the effect of rosuvastatin on IL-6 production by human osteoblasts. Methods: Osteoblasts from osteoarthritic patients were incubated with rosuvastatin (0.1–10μmol/L)±IL-1β, and IL-6 production was evaluated as cytokine concentration in the culture medium (ELISA), as well as mRNA expression in the cells (qPCR). Putative intracellular mechanisms of the drug, such as blocking HMG-CoA-reductase, and interference in the prenylation process were investigated by the addition of mevalonate and isoprenoids. The effect of rosuvastatin±IL-1β on the anti-resorptive molecule osteoprotegerin (OPG) was also assessed (ELISA). Results: Rosuvastatin significantly reduced IL-6 levels in the osteoblast culture medium, both in unstimulated and IL-1β-stimulated cells. This effect was reversed by mevalonate or geranylgeraniol, but not farnesol. Moreover, the drug decreased both spontaneous and IL-1β-induced IL-6 mRNA expression in osteoblasts. Conversely, rosuvastatin did not affect OPG levels in the culture medium. Conclusion: Our results show that rosuvastatin decreases IL-6 production by osteoblasts, thereby suggesting a possible inhibiting activity on osteoclast function in an indirect way. These data may provide further rationale for employing rosuvastatin to beneficially affect bone metabolism in post-menopausal women and possibly in inflammation-driven osteoporosis. [Copyright &y& Elsevier]