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Pietro Enea Lazzerini,1 Pier Leopoldo Capecchi,1 Giacomo Maria Guidelli,1 Enrico Selvi,1 Maurizio Acampa,2 Franco Laghi-Pasini1 1Department of Medical Sciences, Surgery and Neurosciences, University of Siena, 2Stroke Unit, University Hospital of Siena, Siena, Italy Abstract: Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease primarily affecting synovial joints and is characterized by persistent high-grade systemic inflammation. Proinflammatory cytokines, particularly interleukin-6 (IL-6), are of crucial importance in the pathogenesis of the disease, driving both joint inflammation and extra-articular comorbidities. Tocilizumab, a humanized IL-6 receptor-inhibiting monoclonal antibody, has been the first, and, to date, the only, IL-6 inhibitor approved for the treatment of RA. Many studies have demonstrated the potency and effectiveness of tocilizumab in controlling disease activity and radiological progression of RA. These successful results have encouraged the development of novel IL-6 inhibitors, among which a promising agent is sirukumab (SRK), a human anti-IL-6 monoclonal antibody currently under evaluation in Phase II/III studies in patients with RA, systemic lupus erythematosus, giant-cell arteritis, and major depressive disorder. The evidence to date indicates SRK as an effective and well-tolerated new therapeutic tool for patients with active RA, with some preliminary data suggesting a specific beneficial impact on relevant systemic complications associated with the disease, such as depression and cardiovascular disease. Conversely, although pathophysiological considerations make plausible the hypothesis that IL-6 blockade with SRK may also be beneficial in the treatment of many diseases other than RA (either autoimmune or not), available clinical data in patients with systemic lupus erythematosus do not seem to support this view, also giving rise to potentially relevant concerns about drug safety. If large Phase III clinical trials currently in progress in patients with RA confirm the efficacy and tolerability of SRK, then in the long term, this drug could, in the near future, occupy a place in the treatment of the disease, potentially also opening the doors to a more extended use of SRK in a wide range of disorders in which IL-6 plays a key pathogenic role. Keywords: sirukumab, rheumatoid arthritis, interleukin-6, tocilizumab, systemic lupus erythematosus, cardiovascular disease, interleukin-6

Competing Interests: The authors report no conflicts of interest.

Takotsubo syndrome (TTS) is a reversible form of acute myocardial injury due to a neurocardiogenic mechanism associated with a relevant risk for life-threatening ventricular arrhythmias, occurring in up to 25% of all patients and including both ventricular arrhythmias (especially) in the context of QT prolongation and atrial tachy- or bradyarrhythmias. The pathogenetic mechanisms of TTS-related arrhythmic complications are not completely understood, and there are no randomized clinical trials addressing the pharmacologic and nonpharmacologic management in this specific setting. In this narrative review, the authors provide an overview of the pathogenesis and the therapeutic management of arrhythmic complications in patients with TTS, along with the future perspectives and the remaining knowledge gaps in this field., Competing Interests: Funding Support and Author Disclosures Dr Abbate has received consulting fees from Cardiol, Implicit Biosciences, Novo Nordisk, Kiniksa, Olatec, and Serpin Pharma. Dr Sanna is a consultant for Medtronic. Dr Lazzerini has received a grant from Roche Italia outside the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Dr. Pietro Enea Lazzerini received a grant from Roche Italia S.p.A. outside the submitted work, in 2018. The other authors declare no competing interests., (© 2024 The Author(s). Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of Japanese Heart Rhythm Society.)

Background/Objectives : Arterial stiffness (AS) is an independent predictor of cardiovascular events and is associated with a poor prognosis. While AS may represent a novel therapeutic target, recent evidence shows that it is sexually dimorphic. The aim of this study was to evaluate relative sex differences in arterial stiffness and their possible impact on the outcome of acute ischemic stroke. Methods : We retrospectively evaluated a cohort of adult patients with the following inclusion criteria: acute ischemic stroke, which occurred within 24 h from the onset of symptoms, confirmed through neuroimaging examinations, additional evaluations including extracranial and transcranial arterial ultrasound examinations, transthoracic echocardiography, a 12-lead resting ECG, and continuous 24 h in-hospital blood pressure monitoring. Based on the 24 h blood pressure monitoring, the following parameters were evaluated: systolic blood pressure, diastolic blood pressure, mean blood pressure, pulse pressure, and arterial stiffness index (ASI). The modified Rankin scale (mRS) was assessed at 90 days to evaluate the 3-month clinical outcome, defining an unfavorable outcome as an mRS score ≥ 3. To assess the factors associated with unfavorable outcomes, a stepwise logistic regression model was performed on the total sample size, and the analyses were replicated after stratifying by sex. Results : A total of 334 patients (176 males, 158 females) were included in the analysis. There was a significant sex-dependent impact of ASI on the 90-day unfavorable Rankin score (mRS score ≥ 3) as only men had a reduced likelihood of favorable outcomes with increasing arterial stiffness (OR:1.54, 95% CI: 1.06-2.23; P-interaction = 0.023). Conclusions : The influence of ASI on the 3-month functional outcome after acute ischemic stroke is at least in part sex-related, suggesting that, in males, higher ASI values are associated with a worse outcome.

Background: Advanced atrioventricular block (AVB), that is, higher than second-degree Mobitz-1, is an abnormal finding in athletes. Despite intensive investigation, in several cases the pathogenesis remains unknown, but frequently pacemaker implantation is still indicated. Increasing evidence points to circulating anti-Ro/Sjögren syndrome-related antigen A (SSA) antibodies cross-reacting with L-type calcium channel and inhibiting the related current as an epidemiologically relevant and potentially reversible cause of isolated AVB in adults. The aim of the study was to determine the prevalence of anti-Ro/SSA-associated advanced AVBs in a large sample of young athletes., Methods and Results: A total of 2536 consecutive athletes aged <40 years without a history of cardiac diseases/interventions were enrolled in a cross-sectional study. Resting and exercise electrocardiography was performed, and those presenting any AVB were further evaluated by 24-hour Holter ECG. Athletes with second-degree AVBs and their mothers underwent anti-Ro/SSA testing. Moreover, purified immunoglobulin G from subjects with anti-Ro/SSA-positive and anti-Ro/SSA-negative advanced AVB were tested on L-type calcium current and L-type-calcium channel expression using tSA201 cells. The global prevalence of advanced AVB in the overall sample was ≈0.1%, but the risk considerably increased (2%) when intensely trained postpubertal male subjects were selectively considered. While none of the athletes with advanced AVB showed heart abnormalities, in 100% of cases anti-Ro/SSA antibodies were detected. Ex vivo experiments showed that immunoglobulin G from anti-Ro/SSA-positive but not -negative subjects with advanced AVB acutely inhibit L-type calcium current and chronically downregulate L-type-calcium channel expression., Conclusions: Our study provides evidence that advanced AVB occurs in young athletes, in most cases associated with anti-Ro/SSA antibodies blocking L-type calcium channels. These findings may open new avenues for immunomodulating therapies to reduce the risk of life-threatening events in athletes, avoiding or delaying pacemaker implantation.

Competing Interests: Funding Support and Author Disclosures Dr Abbate has received research support or consultant fees from CardiolRx, Implicit Biosciences, Kiniksa, Novo Nordisk, and Olatec. Dr Lazzerini has reported that he has no relationships relevant to the contents of this paper to disclose.

Background: Although accumulating data indicate that IL-6 (interleukin-6) can promote heart rate-corrected QT interval (QTc) prolongation via direct and indirect effects on cardiac electrophysiology, current evidence comes from basic investigations and small clinical studies only. Therefore, IL-6 is still largely ignored in the clinical management of long-QT syndrome and related arrhythmias. The aim of this study was to estimate the risk of QTc prolongation associated with elevated IL-6 levels in a large population of unselected subjects., Methods and Results: An observational study using the Veterans Affairs Informatics and Computing Infrastructure was performed. Participants were US veterans who had an ECG and were tested for IL-6. Descriptive statistics and univariate and multivariate regression analyses were performed to study the relationship between IL-6 and QTc prolongation risk. Study population comprised 1085 individuals, 306 showing normal (<5 pg/mL), 376 moderately high (5-25 pg/mL), and 403 high (>25 pg/mL) IL-6 levels. Subjects with elevated IL-6 showed a concentration-dependent increase in the prevalence of QTc prolongation, and those presenting with QTc prolongation exhibited higher circulating IL-6 levels. Stepwise multivariate regression analyses demonstrated that increased IL-6 level was significantly associated with a risk of QTc prolongation up to 2 times the odds of the reference category of QTc (e.g. QTc >470 ms men/480 ms women ms: odds ratio, 2.28 [95% CI, 1.12-4.50] for IL-6 >25 pg/mL) regardless of the underlying cause. Specifically, the mean QTc increase observed in the presence of elevated IL-6 was quantitatively comparable (IL-6 >25 pg/mL:+6.7 ms) to that of major recognized QT-prolonging risk factors, such as hypokalemia and history of myocardial infarction., Conclusions: Our data provide evidence that a high circulating IL-6 level is a robust risk factor for QTc prolongation in a large cohort of US veterans, supporting a potentially important arrhythmogenic role for this cytokine in the general population.

Background: An exuberant and dysregulated inflammatory response contributes to the development and progression of cardiovascular diseases (CVDs)., Methods: This narrative review includes original articles and reviews published over the past 20 years and found through PubMed. The following search terms (or combination of terms) were considered: "acute pericarditis," "recurrent pericarditis," "myocarditis," "cardiac sarcoidosis," "atherosclerosis," "acute myocardial infarction," "inflammation," "NLRP3 inflammasome," "Interleukin-1" and "treatment.", Results: Recent evidence supports the role of inflammation across a wide spectrum of CVDs including myocarditis, pericarditis, inflammatory cardiomyopathies (i.e. cardiac sarcoidosis) as well as atherosclerotic CVD and heart failure. Interleukins (ILs) are the signalling mediators of the inflammatory response. The NACHT, leucine-rich repeat and pyrin-domain containing protein 3 (NLRP3) inflammasome play a key role in producing IL-1β, the prototypical pro-inflammatory cytokine involved in CVDs. Other pro-inflammatory cytokines (e.g. tumour necrosis factor) have been implicated in cardiac sarcoidosis. As a proof of this, IL-1 blockade has been proven efficacious in pericarditis and chronic coronary syndrome., Conclusion: Tailored strategies aiming at quenching the inflammatory response have emerged as promising to treat CVDs. In this review article, we summarize recent evidence regarding the role of inflammation across a broad spectrum of CVDs. We also review novel evidence regarding targeted therapeutic strategies., (© 2023 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Background: Adoption and outcomes for conduction system pacing (CSP), which includes His bundle pacing (HBP) or left bundle branch area pacing (LBBAP), in real-world settings are incompletely understood. We sought to describe real-world adoption of CSP lead implantation and subsequent outcomes., Methods: We performed an online cross-sectional survey on the implantation and outcomes associated with CSP, between November 15, 2020, and February 15, 2021. We described survey responses and reported HBP and LBBAP outcomes for bradycardia pacing and cardiac resynchronization CRT indications, separately., Results: The analysis cohort included 140 institutions, located on 5 continents, who contributed data to the worldwide survey on CSP. Of these, 127 institutions (90.7%) reported experience implanting CSP leads. CSP and overall device implantation volumes were reported by 84 institutions. In 2019, the median proportion of device implants with CSP, HBP, and/or LBBAP leads attempted were 4.4% (interquartile range [IQR], 1.9-12.5%; range, 0.4-100%), 3.3% (IQR, 1.3-7.1%; range, 0.2-87.0%), and 2.5% (IQR, 0.5-24.0%; range, 0.1-55.6%), respectively. For bradycardia pacing indications, HBP leads, as compared to LBBAP leads, had higher reported implant threshold (median [IQR]: 1.5 V [1.3-2.0 V] vs 0.8 V [0.6-1.0 V], p = 0.0008) and lower ventricular sensing (median [IQR]: 4.0 mV [3.0-5.0 mV] vs. 10.0 mV [7.0-12.0 mV], p < 0.0001)., Conclusion: In conclusion, CSP lead implantation has been broadly adopted but has yet to become the default approach at most surveyed institutions. As the indications and data for CSP continue to evolve, strategies to educate and promote CSP lead implantation at institutions without CSP lead implantation experience would be necessary., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: In ∼50% of severe atrioventricular blocks (AVBs) occurring in adults <50 years, the underlying etiology remains unknown. Preliminary evidence from case reports suggests that autoimmunity, specifically the presence of circulating anti-Ro/SSA antibodies in the patient (acquired form), in the patient's mother (late-progressive congenital form), or in both (mixed form), could be involved in a fraction of idiopathic AVBs in adults by possibly targeting the L-type calcium channel (Ca v 1.2) and inhibiting the related current (I CaL )., Objectives: The purpose of this study was to evaluate whether anti-Ro/SSA antibodies are causally implicated in the development of isolated AVBs in adults., Methods: Thirty-four consecutive patients with isolated AVB of unknown origin and 17 available mothers were prospectively enrolled in a cross-sectional study. Anti-Ro/SSA antibodies were assessed by fluoroenzyme-immunoassay, immuno-Western blotting, and line-blot immunoassay. Purified immunoglobulin-G (IgG) from anti-Ro/SSA-positive and anti-Ro/SSA-negative subjects were tested on I CaL and Ca v 1.2 expression using tSA201 and HEK293 cells, respectively. Moreover, in 13 AVB patients, the impact of a short course of steroid therapy on AV conduction was evaluated., Results: Anti-Ro/SSA antibodies, particularly anti-Ro/SSA-52kD, were found in 53% of AVB-patients and/or in their mothers, most commonly an acquired or mixed form (two-thirds of cases) without history of autoimmune diseases. Purified IgG from anti-Ro/SSA-positive but not anti-Ro/SSA-negative AVB patients acutely inhibited I CaL and chronically down-regulated Ca v 1.2 expression. Moreover, anti-Ro/SSA-positive sera showed high reactivity with peptides corresponding to the Ca v 1.2 channel pore-forming region. Finally, steroid therapy rapidly improved AV conduction in AVB-patients with circulating anti-Ro/SSA antibodies but not in those without., Conclusions: Our study points to anti-Ro/SSA antibodies as a novel, epidemiologically relevant and potentially reversible cause of isolated AVB in adults, via an autoimmune-mediated functional interference with the L-type calcium channels. These findings have significant impact on antiarrhythmic therapies by avoiding or delaying pacemaker implantation., Competing Interests: Funding Support and Author Disclosures This work was supported by Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR), Progetti di Rilevante Interesse Nazionale (PRIN), and Bando 2017, protocollo 2017XZMBYX (to Dr Lazzerini and Dr Capecchi); a Merit Review grant I01 BX002137 from Biomedical Laboratory Research & Development Service of Veterans Affairs Office of Research and Development (to Dr Boutjdir); National Heart, Lung, and Blood Institute grant 1R01HL164415-01 (to Dr Boutjdir); and U.S. Department of Defense award number W81XWH-21-1-0424 (to Dr Boutjdir). Dr Lazzerini has received a grant from Roche Italia S.p.A. outside the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: 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)., Methods: 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., Results: 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., Conclusions: 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., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Nabil El-Sherif reports financial support was provided by Narrows Institute for Biomedical Research and Education, Inc. Mohamed Boutjdir reports financial support was provided by Biomedical Laboratory Research & Development Service of Veterans Affairs Office of Research and Development. Mohamed Boutjdir reports financial support was provided by National Heart Lung and Blood Institute. Mohamed Boutjdir reports financial support was provided by US Department of Defense., (Published by Elsevier Inc.)

Inflammatory activation is increasingly recognized as a nonconventional risk factor for arrhythmias, and experimental studies provided robust evidence that this association is mediated by direct arrhythmogenic effects of proinflammatory cytokines on cardiac cells. Additionally, inflammatory cytokines can favor arrhythmias indirectly through multiple systemic effects. Accumulating data confirm the clinical relevance of these mechanisms; the largest evidence being available for atrial fibrillation, acquired long-QT syndrome, and ventricular arrhythmias. However, clinical management of arrhythmias largely neglects inflammatory cytokines. This review integrates basic science and clinical research to present an updated overview of the topic and provides future directions for patient's management., Competing Interests: This work was supported by Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR), Progetti di Rilevante Interesse Nazionale (PRIN), and Bando 2017, protocollo 2017XZMBYX (to Drs Lazzerini and Capecchi); Bando Ricerca COVID-19 Toscana–2021, Progetto PRECARVID (to Drs Lazzerini and Capecchi); Biomedical Laboratory Research and Development Service of Veterans Affairs Office of Research and Development, Merit Review grant I01 BX002137 (to Dr Boutjdir); National Heart, Lung, and Blood Institute 1R01HL164415-01 (to Dr Boutjdir); and US Department of Defense Award Number W81XWH-21-1-0424 (to Dr Boutjdir). Dr Lazzerini received a grant from Roche Italia SpA outside the submitted work, in 2018. Dr Abbate has served as a consultant for Cardiol, Implicit Biosciences, Kiniksa, Novartis, Novo-Nordisk, Olatec, R-Pharm, Sanofi, and Serpin Pharma, unrelated to the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Background and Purpose: The current definition of embolic strokes of undetermined source (ESUS) seems to be too broad, including strokes due to heterogeneous mechanisms, such as atrial cardiopathy and other occult cardiac conditions, aortic arch plaques, and non-stenosing atherosclerosis, that can be differently associated with clinical stroke severity at the time of presentation. The aim of our study was to assess the possible association between neurological deficit severity and presence of markers of atrial cardiopathy in ESUS., Methods: We retrospectively reviewed the medical records of a cohort of 226 ESUS patients (105 M, 121 F), that were divided into two groups according to the severity of neurological deficit (99 mild strokes with NIHSS ≤ 5 and 127 severe strokes with NIHSS >5). The following indices of atrial cardiopathy were evaluated: P wave dispersion, P wave max, P wave min, P wave mean, P wave index, P wave axis, left atrial size., Results: Patients with severe ESUS were significantly older (74 ± 12 vs. 67 ± 14 years, P < 0.001) and female sex was prevalent (67 vs. 36%, P > 0.001); they had higher values of P-wave-dispersion (51 ± 14 vs. 46 ± 13, P = 0.01), P-wave-max (131 ± 20 vs. 125 ± 15 ms, P = 0.01), P-wave-index (16 ± 5 vs. 15 ± 5 ms, P = 0.01), left atrial size (20 ± 6 vs. 18 ± 4 cm 2 , P = 0.01), left atrial volume index (31 ± 14 vs. 27 ± 11 ml/m 2 , P = 0.04), in comparison with mild ESUS. An abnormal P wave axis was detected more frequently in severe ESUS (21 vs. 9%, P = 0.01). Furthermore, multivariate logistic regression showed that age (OR = 1.21 for each 5-year increase, 95% CI 1.09-1.35), sex (OR = 3.24 for female sex, 95% CI 1.82-5.76) and PWD (OR = 1.32 for each 10-ms increase, 95% CI 1.07-1.64) were the best subset of associated variables for severe ESUS., Conclusions: Our findings shed light on specific clinical characteristics of severe ESUS including the presence of atrial cardiopathy that could play a pathogenic role in this subgroup of patients. Searching for atrial fibrillation in these patients is especially important to perform the most appropriate therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Acampa, Cartocci, Domenichelli, Tassi, Guideri, Lazzerini and Martini.)

Background: Heart rate-corrected QT interval (QTc) prolongation is prevalent in patients with severe coronavirus disease 2019 (COVID-19) and is associated with poor outcomes. Recent evidence suggests that the exaggerated host immune-inflammatory response characterizing the disease, specifically interleukin-6 (IL-6) increase, may have an important role, possibly via direct effects on cardiac electrophysiology. The aim of this study was to dissect the short-term discrete impact of IL-6 elevation on QTc in patients with severe COVID-19 infection and explore the underlying mechanisms., Methods: We investigated the following mechanisms: (1) the QTc duration in patients with COVID-19 during the active phase and recovery, and its association with C-reactive protein (CRP) and IL-6 levels; (2) the acute impact of IL-6 administration on QTc in an in vivo guinea pig model; and (3) the electrophysiological effects of IL-6 on ventricular myocytes in vitro ., Results: In patients with active severe COVID-19 and elevated IL-6 levels, regardless of acute myocardial injury/strain and concomitant QT-prolonging risk factors, QTc was significantly prolonged and rapidly normalized in correlation with IL-6 decrease. The direct administration of IL-6 in an in vivo guinea pig model acutely prolongs QTc duration. Moreover, ventricular myocytes incubated in vitro with IL-6 show evident prolongation in the action potential, along with significant inhibition in the rapid delayed rectifier potassium current (I Kr )., Conclusion: For the first time, we demonstrated that in severe COVID-19, systemic inflammatory activation can per se promote QTc prolongation via IL-6 elevation, leading to ventricular electric remodeling. Despite being transitory, such modifications may significantly contribute to arrhythmic events and associated poor outcomes in COVID-19. These findings provide a further rationale for current anti-inflammatory treatments for COVID-19, including IL-6-targeted therapies., Competing Interests: PL received a grant from Roche Italia S.p.A. outside the submitted work in 2018. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lazzerini, Accioli, Acampa, Zhang, Verrengia, Cartocci, Bacarelli, Xin, Salvini, Chen, Salvadori, D’errico, Bisogno, Cevenini, Marzotti, Capecchi, Laghi-Pasini, Chen, Capecchi and Boutjdir.)

This study aimed to characterize adverse drug reactions (ADRs) to hydroxychloroquine in the setting of COVID-19, occurring in Italy in the period March to May 2020. The analysis of the combination therapy with azithromycin or/and lopinavir/ritonavir as well as a comparison with ADRs reported throughout 2019 was performed. ADRs collected by the Italian National Network of Pharmacovigilance were analyzed for their incidence, seriousness, outcome, coadministered drugs, and Medical Dictionary for Regulatory Activities classification. A total of 306 reports were gathered for the quarter of 2020: 54% nonserious and 46% serious, and half of the latter required either the hospitalization or its prolongation. However, most of them were either completely recovered (26%) or in the process of recovery (45%), except for 9 fatal cases. Throughout 2019, 38 reports were collected, 53% nonserious and 47% serious, but no deaths had been reported. Diarrhea, prolonged QT interval, and hypertransaminasemia were the most frequently ADRs reported in 2020, significantly higher than 2019 and specific for COVID-19 subjects treated with hydroxychloroquine. The logistic regression analyses demonstrated that the likelihood of serious ADRs, QT prolongation, and diarrhea significantly increased with hydroxychloroquine dosage. Coadministration of lopinavir/ritonavir and hydroxychloroquine showed a positive correlation with diarrhea and hypertransaminasemia and a negative relationship with the ADR seriousness. The combination therapy with azithromycin was another independent predictor of a serious ADR. Off-label use of hydroxychloroquine for COVID-19, alone or in combination regimens, was associated with increased incidence and/or seriousness of specific ADRs in patients with additional risk factors caused by the infection., (© 2021, The American College of Clinical Pharmacology.)

Background: Cardiac implantable electronic device (CIED) implantation rates as well as the clinical and procedural characteristics and outcomes in patients with known active coronavirus disease 2019 (COVID-19) are unknown., Objective: The purpose of this study was to gather information regarding CIED procedures during active COVID-19, performed with personal protective equipment, based on an international survey., Methods: Fifty-three centers from 13 countries across 4 continents provided information on 166 patients with known active COVID-19 who underwent a CIED procedure., Results: The CIED procedure rate in 133,655 hospitalized COVID-19 patients ranged from 0 to 16.2 per 1000 patients (P <.001). Most devices were implanted due to high-degree/complete atrioventricular block (112 [67.5%]) or sick sinus syndrome (31 [18.7%]). Of the 166 patients in the study survey, the 30-day complication rate was 13.9% and the 180-day mortality rate was 9.6%. One patient had a fatal outcome as a direct result of the procedure. Differences in patient and procedural characteristics and outcomes were found between Europe and North America. An older population (76.6 vs 66 years; P <.001) with a nonsignificant higher complication rate (16.5% vs 7.7%; P = .2) was observed in Europe vs North America, whereas higher rates of critically ill patients (33.3% vs 3.3%; P <.001) and mortality (26.9% vs 5%; P = .002) were observed in North America vs Europe., Conclusion: CIED procedure rates during known active COVID-19 disease varied greatly, from 0 to 16.2 per 1000 hospitalized COVID-19 patients worldwide. Patients with active COVID-19 infection who underwent CIED implantation had high complication and mortality rates. Operators should take these risks into consideration before proceeding with CIED implantation in active COVID-19 patients., (Copyright © 2021 Heart Rhythm Society. All rights reserved.)

Inflammatory diseases including COVID-19 are associated with a cytokine storm characterized by high interleukin-6 (IL-6) titers. In particular, while recent studies examined COVID-19 associated arrhythmic risks from cardiac injury and/or from pharmacotherapy such as the combination of azithromycin (AZM) and hydroxychloroquine (HCQ), the role of IL-6 per se in increasing the arrhythmic risk remains poorly understood. The objective is to elucidate the electrophysiological basis of inflammation-associated arrhythmic risk in the presence of AZM and HCQ. IL-6, AZM and HCQ were concomitantly administered to guinea pigs in-vivo and in-vitro. Electrocardiograms, action potentials and ion-currents were analyzed. IL-6 alone or the combination AZM + HCQ induced mild to moderate reduction in heart rate, PR-interval and corrected QT (QTc) in-vivo and in-vitro. Notably, IL-6 alone was more potent than the combination of the two drugs in reducing heart rate, increasing PR-interval and QTc. In addition, the in-vivo or in-vitro combination of IL-6 + AZM + HCQ caused severe bradycardia, conduction abnormalities, QTc prolongation and asystole. These electrocardiographic abnormalities were attenuated in-vivo by tocilizumab (TCZ), a monoclonal antibody against IL-6 receptor, and are due in part to the prolongation of action potential duration and selective inhibition of Na + , Ca 2+ and K + currents. Inflammation confers greater risk for arrhythmia than the drug combination therapy. As such, in the setting of elevated IL-6 during inflammation caution must be taken when co-administering drugs known to predispose to fatal arrhythmias and TCZ could be an important player as a novel anti-arrhythmic agent. Thus, identifying inflammation as a critical culprit is essential for proper management., (© 2022. The Author(s).)

Background Systemic inflammation and male hypogonadism are 2 increasingly recognized "nonconventional" risk factors for long-QT syndrome and torsades de pointes (TdP). Specifically, inflammatory cytokines prolong, while testosterone shortens the heart rate-corrected QT interval (QTc) via direct electrophysiological effects on cardiomyocytes. Moreover, several studies demonstrated important interplays between inflammation and reduced gonad function in men. We hypothesized that, during inflammatory activation in men, testosterone levels decrease and that this enhances TdP risk by contributing to the overall prolonging effect of inflammation on QTc. Methods and Results We investigated (1) the levels of sex hormones and their relationship with inflammatory markers and QTc in male patients with different types of inflammatory diseases, during active phase and recovery; and (2) the association between inflammatory markers and sex hormones in a cohort of male patients who developed extreme QTc prolongation and TdP, consecutively collected over 10 years. In men with active inflammatory diseases, testosterone levels were significantly reduced, but promptly normalized in association with the decrease in C-reactive protein and interleukin-6 levels. Reduction of testosterone levels, which also inversely correlated with 17-β estradiol over time, significantly contributed to inflammation-induced QTc prolongation. In men with TdP, both active systemic inflammation and hypogonadism were frequently present, with significant correlations between C-reactive protein, testosterone, and 17-β estradiol levels; in these patients, increased C-reactive protein and reduced testosterone were associated with a worse short-term outcome of the arrhythmia. Conclusions During systemic inflammatory activation, interleukin-6 elevation is associated with reduced testosterone levels in males, possibly deriving from an enhanced androgen-to-estrogen conversion. While transient, inflammatory hypotestosteronemia is significantly associated with an increased long-QT syndrome/TdP risk in men.

Background Recent data suggest that systemic inflammation can negatively affect atrioventricular conduction, regardless of acute cardiac injury. Indeed, gap-junctions containing connexin43 coupling cardiomyocytes and inflammation-related cells (macrophages) are increasingly recognized as important factors regulating the conduction in the atrioventricular node. The aim of this study was to evaluate the acute impact of systemic inflammatory activation on atrioventricular conduction, and elucidate underlying mechanisms. Methods and Results We analyzed: (1) the PR-interval in patients with inflammatory diseases of different origins during active phase and recovery, and its association with inflammatory markers; (2) the existing correlation between connexin43 expression in the cardiac tissue and peripheral blood mononuclear cells (PBMC), and the changes occurring in patients with inflammatory diseases over time; (3) the acute effects of interleukin(IL)-6 on atrioventricular conduction in an in vivo animal model, and on connexin43 expression in vitro. In patients with elevated C-reactive protein levels, atrioventricular conduction indices are increased, but promptly normalized in association with inflammatory markers reduction, particularly IL-6. In these subjects, connexin43 expression in PBMC, which is correlative of that measured in the cardiac tissue, inversely associated with IL-6 changes. Moreover, direct IL-6 administration increased atrioventricular conduction indices in vivo in a guinea pig model, and IL-6 incubation in both cardiomyocytes and macrophages in culture, significantly reduced connexin43 proteins expression. Conclusions The data evidence that systemic inflammation can acutely worsen atrioventricular conduction, and that IL-6-induced down-regulation of cardiac connexin43 is a mechanistic pathway putatively involved in the process. Though reversible, these alterations could significantly increase the risk of severe atrioventricular blocks during active inflammatory processes.

Objectives: Microcrystal-induced arthritis is still an unresolved paradigm for medicine. Overt inflammation may be absent even when crystals occur in SF. Recently, the production of neutrophil extracellular traps (NETs) embedding MSU crystals has been proposed as a possible mechanism of the auto-resolution of the inflammatory phase during gout. We aimed to verify and quantify the release of NETs in SFs during gout and pseudogout attacks and to compare any differences with respect to crystals and neutrophils number, and to analyse activation of necroptosis pathway in SF from crystal-induced arthritis., Methods: SF samples were obtained by arthrocentesis from 22 patients presenting acute crystal-induced arthritis, gout or pseudogout (n = 11 each group), and from 10 patients with acute non-crystal arthritis as controls. NETosis was quantified in SF by nucleic acid stain and by quantification of human neutrophil elastase. Activation of phosphorylated MLKL was assessed by western blot., Results: We observed that SF neutrophils encountering MSU and CPPD crystals during episodes of gout and pseudogout release NETs in relation to the number of crystals in SF and irrespective of neutrophil density and type of crystal. This release was accompanied by necroptosis through the activation of the MLKL pathway., Conclusions: Our findings suggest that a role of NETs in crystal-induced arthritis is to 'trap extracellular particles', including microcrystals. Embedding crystals in aggregates of NETs may be the basis of tophi and CPPD deposition, and may have implications for disease evolution rather than for spontaneous resolution of the acute attack., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lazzerini, Laghi-Pasini, Boutjdir and Capecchi.)

Objective: The primary objectives of this prospective cross-sectional study were to estimate the prevalence of drug-related long QT syndrome (LQTS) and the prevalence of use of QT-prolonging drugs in older patients admitted to an internal medicine unit., Methods: We screened consecutive patients hospitalized in an internal medicine unit over a 2-year period. A 12-lead electrocardiogram using an electrocardiograph with automated measurement of QT interval was recorded. Patient characteristics (age, sex, body mass index), drug treatments, and variables associated with QT interval prolongation, including hypothyroidism, type 2 diabetes mellitus, and cardiac disease, were also recorded. In addition, we also measured serum levels of potassium, calcium, magnesium, and creatinine at admission. The list of medications known to cause or to contribute to LQTS was obtained from CredibleMeds ® ., Results: A total of 243 patients were enrolled: mean ± standard deviation age, 79.65 ± 8.27 years; males, n = 121 (40.8%); mean corrected QT (QTc) interval, 453.70 ± 43.77 ms. Overall, 89/243 (36.6%) patients had a prolonged QTc interval, with 29/243 (11.9%) having QTc interval prolongation > 500 ms (11.9%). A vast majority were prescribed at least one QT-prolonging drug (218/243 [89.7%]), whereas 74/218 (30.5%) were receiving at least one medication with a known risk of Torsades des Pointes (TdP). Proton pump inhibitors were the second most commonly prescribed class of drugs. After logistic regression, male sex was independently associated with LQTS (odds ratio 2.85; 95% confidence interval 1.56-5.22; p = 0.001)., Conclusions: The prevalence of LQTS with QTc interval > 500 ms in geriatric inpatients was > 10%, and QT-prolonging drugs were frequently used on admission (more than 30% of patients were receiving drugs with a known risk of TdP)., (© 2021. The Author(s).)

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BACKGROUND Recently, some case reports have been published on the macrolide antimicrobials azithromycin and clarithromycin as the cause of thrombocytopenia. The publicly accessible databases of the European Medicine Agency and the WHO drug monitoring program contain dozens of reports of roxithromycin-associated thrombocytopenia. CASE REPORT We described the case of a 78-year-old woman presenting to our unit with petechial lesions of the palate, 2 hematomas of the tongue, and purpuric macules in the abdomen and in the left lower limb 4 days after a course of roxithromycin. She presented to the Emergency Department with 3 out-of-range blood test results: neutrophils (11 960/mL; range: 1500-7000/mL), platelet count (3000/mL; range: 150 000-400 000/mL), and lactate dehydrogenase (379 IU/L; range: 135-225 IU/L). Thrombocytopenia occurred in the absence of aggregates and observed nucleolated lymphocytes. Lymphoproliferative pathologies and thrombotic microangiopathy were excluded by the hematologist. To rule out neoplastic lesions, an abdominal ultrasound examination was made. Antibody screening was performed for antinuclear antibodies, extractable nuclear antigen, antineutrophil cytoplasmic antibodies (all negative), and for Parvovirus B-19 (IgM negative, IgG positive), as well as HHV-6 and HHV-8 (both negative), to exclude an autoimmune or viral etiology. She recovered after intravenous methylprednisolone 60 mg/day and intravenous-immunoglobulin therapy 400 mg/kg/day. After 9 days, the patient was discharged with resolution of skin and buccal lesions. Her platelet count was 515 000/mL. CONCLUSIONS To the best of our knowledge, this is the first case of roxithromycin-associated acute autoimmune thrombocytopenia reported in the medical literature. We suggest that clinicians should consider this drug to be among the possible causes of drug-induced thrombocytopenia.

Background: Subarachnoid haemorrhage (SAH) accounts for 5-10% of strokes and its prognosis may be influenced by different complications, including delayed cerebral ischaemia (DCI). The pathophysiology of DCI is complex and still unknown. Many different mechanisms may contribute to the occurrence of DCI. Arterial stiffness (AS), a well-known risk factor for cardiovascular events, also associated with the development and rupture of cerebral aneurysms, may represent a novel contributing risk factor. The aim of our study was to investigate a possible link between AS and DCI after SAH., Method: Fifty-nine (59) patients with SAH (age [mean±standard deviation], 62±12 years) underwent neuroimaging examination, and 24-hour heart rate and blood pressure monitoring, including AS index (ASI) measurement., Results: Of 59 patients, DCI occurred in 12. ASI was significantly higher in patients with DCI than in patients without it (0.70±0.1 vs 0.62±0.1; p=0.03). ASI was a significant predictor for DCI (odds ratio [for an increase of 0.20 points in ASI], 5.99; 95% confidence interval, 1.23-29.22; p=0.03)., Conclusions: Arterial stiffness index is a simple and inexpensive tool that is able to predict the risk of DCI in patients with SAH. This marker can impact on intensive care unit monitoring, early recognition, and treatment, contributing to optimal acute management of patients with SAH., (Copyright © 2020 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

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Background Anti-Sjögren's syndrome-related antigen A-antibodies (anti-Ro/SSA-antibodies) are responsible for a novel form of acquired long-QT syndrome, owing to autoimmune-mediated inhibition of cardiac human ether-a-go-go-related gene-potassium channels. However, current evidence derives only from basic mechanistic studies and relatively small sample-size clinical investigations. Hence, the aim of our study is to estimate the risk of QTc prolongation associated with the presence of anti-Ro/SSA-antibodies in a large population of unselected subjects. Methods and Results This is a retrospective observational cohort study using the Veterans Affairs Informatics and Computing Infrastructure. Participants were veterans who were tested for anti-Ro/SSA status and had an ECG. Descriptive statistics and univariate and multivariate logistic regression analyses were performed to identify risk factors for heart rate-corrected QT interval (QTc) prolongation. The study population consisted of 7339 subjects (61.4±12.2 years), 612 of whom were anti-Ro/SSA-positive (8.3%). Subjects who were anti-Ro/SSA-positive showed an increased prevalence of QTc prolongation, in the presence of other concomitant risk factors (crude odds ratios [OR], 1.67 [1.26-2.21] for QTc >470/480 ms; 2.32 [1.54-3.49] for QTc >490 ms; 2.77 [1.66-4.60] for QTc >500 ms), independent of a connective tissue disease history. Adjustments for age, sex, electrolytes, cardiovascular risk factors/diseases, and medications gradually attenuated QTc prolongation estimates, particularly when QT-prolonging drugs were added to the model. Nevertheless, stepwise-fully adjusted OR for the higher cutoffs remained significantly increased in anti-Ro/SSA-positive subjects, particularly for QTc >500 ms (2.27 [1.34-3.87]). Conclusions Anti-Ro/SSA-antibody positivity was independently associated with an increased risk of marked QTc prolongation in a large cohort of US veterans. Our data suggest that within the general population individuals who are anti-Ro/SSA-positive may represent a subgroup of patients particularly predisposed to ventricular arrhythmias/sudden cardiac death.