IL-1 provokes electrical abnormalities in rat atrial myocardium

Mitrokhin, Vadim; Kamkin, Andre

doi:10.1016/j.intimp.2015.08.006

Cited by 13 publications

(4 citation statements)

References 26 publications

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“…Even though poorly correlated to survival in COVID19 [ 27 ], especially IL-1β has been shown to decrease the beta-adrenergic responsiveness of L-type Ca 2+ channels in a cAMP-independent mechanism, potentially decreasing cellular inotropic response [ 28 ]. This is in line with our observed altered cytosolic [Ca 2+ ] at 60 minutes serum incubation and further supported by results from Mitrokhin et al [ 29 ], associating electrical abnormalities and action potential prolongations with IL-1.…”

Section: Discussionsupporting

confidence: 93%

COVID19-associated cardiomyocyte dysfunction, arrhythmias and the effect of Canakinumab

et al. 2021

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Background Cardiac injury associated with cytokine release frequently occurs in SARS-CoV-2 mediated coronavirus disease (COVID19) and mortality is particularly high in these patients. The mechanistic role of the COVID19 associated cytokine-storm for the concomitant cardiac dysfunction and associated arrhythmias is unclear. Moreover, the role of anti-inflammatory therapy to mitigate cardiac dysfunction remains elusive. Aims and methods We investigated the effects of COVID19-associated inflammatory response on cardiac cellular function as well as its cardiac arrhythmogenic potential in rat and induced pluripotent stem cell derived cardiomyocytes (iPS-CM). In addition, we evaluated the therapeutic potential of the IL-1β antagonist Canakinumab using state of the art in-vitro confocal and ratiometric high-throughput microscopy. Results Isolated rat ventricular cardiomyocytes were exposed to control or COVID19 serum from intensive care unit (ICU) patients with severe ARDS and impaired cardiac function (LVEF 41±5%; 1/3 of patients on veno-venous extracorporeal membrane oxygenation; CK 154±43 U/l). Rat cardiomyocytes showed an early increase of myofilament sensitivity, a decrease of Ca2+ transient amplitudes and altered baseline [Ca2+] upon exposure to patient serum. In addition, we used iPS-CM to explore the long-term effect of patient serum on cardiac electrical and mechanical function. In iPS-CM, spontaneous Ca2+ release events were more likely to occur upon incubation with COVID19 serum and nuclear as well as cytosolic Ca2+ release were altered. Co-incubation with Canakinumab had no effect on pro-arrhythmogenic Ca2+ release or Ca2+ signaling during excitation-contraction coupling, nor significantly influenced cellular automaticity. Conclusion Serum derived from COVID19 patients exerts acute cardio-depressant and chronic pro-arrhythmogenic effects in rat and iPS-derived cardiomyocytes. Canakinumab had no beneficial effect on cellular Ca2+ signaling during excitation-contraction coupling. The presented method utilizing iPS-CM and in-vitro Ca2+ imaging might serve as a novel tool for precision medicine. It allows to investigate cytokine related cardiac dysfunction and pharmacological approaches useful therein.

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Section: Discussionsupporting

confidence: 93%

COVID19-associated cardiomyocyte dysfunction, arrhythmias and the effect of Canakinumab

et al. 2021

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“…In 1993, IL-1 (not the mature IL-1β) was shown to increase the duration of the AP51 . Another study described acute effects of IL-1β on atrial preparations, and did not find any effects on APD52. Herein we demonstrate that IL-1β creates a pro-arrhythmic environment both in rodent and human cells by reducing the repolarizing K + current (I to ), by increasing CaMKII oxidation/ phosphorylation and Ca 2+ spark frequency.…”

Section: Discussionmentioning

confidence: 59%

Macrophage-dependent IL-1β production induces cardiac arrhythmias in diabetic mice

et al. 2016

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Diabetes mellitus (DM) encompasses a multitude of secondary disorders, including heart disease. One of the most frequent and potentially life threatening disorders of DM-induced heart disease is ventricular tachycardia (VT). Here we show that toll-like receptor 2 (TLR2) and NLRP3 inflammasome activation in cardiac macrophages mediate the production of IL-1β in DM mice. IL-1β causes prolongation of the action potential duration, induces a decrease in potassium current and an increase in calcium sparks in cardiomyocytes, which are changes that underlie arrhythmia propensity. IL-1β-induced spontaneous contractile events are associated with CaMKII oxidation and phosphorylation. We further show that DM-induced arrhythmias can be successfully treated by inhibiting the IL-1β axis with either IL-1 receptor antagonist or by inhibiting the NLRP3 inflammasome. Our results establish IL-1β as an inflammatory connection between metabolic dysfunction and arrhythmias in DM.

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“…Moreover, a huge amount of data demonstrated that inflammatory cytokines play a key pathophysiological role in AF by promoting both structural and electrical atrial remodelling through several mechanisms [85], including atrial fibroblast activation [86][87][88][89], gap junction impairment via changes in connexins [88,90,91], and intracellular calcium-handling abnormalities [86,92,93]. These phenomena, by both increasing ectopic activity [86,94,95] and slowing atrial conduction [86], impair the homogeneity of impulse propagation throughout the atrium and promote reentry, a key electrophysiological alteration for AF development [96](Figure 4). In accordance with these data, P-wave dispersion (PWD), an electrocardiographic marker of inhomogeneous propagation of sinus impulses in the atrial myocardium representing a sensitive and specific clinical predictor of AF by reflecting the risk of reentry occurrence [97], was found to be increased in RA, and correlated with CRP and disease duration [98,99].…”

Section: 2pathogenic Mechanisms and Pathophysiologymentioning

confidence: 99%

Systemic inflammation and arrhythmic risk: lessons from rheumatoid arthritis

Lazzerini¹,

Capecchi²,

2016

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Rheumatoid arthritis (RA) is a chronic immuno-mediated disease primarily affecting the joints, characterized by persistent high-grade systemic inflammation. Cardiovascular morbidity and mortality are significantly increased in RA, with >50% of premature deaths attributable to cardiovascular disease. In particular, RA patients were twice as likely to experience sudden cardiac death compared with non-RA subjects, pointing to an increased propensity to develop malignant ventricular arrhythmias. Indeed, ventricular repolarization (QT interval) abnormalities and cardiovascular autonomic nervous system dysfunction, representing two well-recognized risk factors for life-threatening ventricular arrhythmias in the general population, are commonly observed in RA. Moreover, large population-based studies seem to indicate that also the prevalence of atrial fibrillation is significantly higher in RA subjects than in the general population, thus suggesting that these patients are characterized by an abnormal diffuse myocardial electrical instability. Although the underlying mechanisms accounting for the pro-arrhythmogenic substrate in RA are probably intricate, the leading role seems to be played by chronic systemic inflammatory activation, able to promote arrhythmias both indirectly, by accelerating the development of ischaemic heart disease and congestive heart failure, and directly, by affecting cardiac electrophysiology. In this integrated mechanistic view, lowering the inflammatory burden through an increasingly tight control of disease activity may represent the most effective intervention to reduce arrhythmic risk in these patients. Intriguingly, these considerations could be more generally applicable to all the diseases characterized by chronic systemic inflammation, and could help elucidate the link between low-grade chronic inflammation and arrhythmic risk in the general population.

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IL-1 provokes electrical abnormalities in rat atrial myocardium

Cited by 13 publications

References 26 publications

COVID19-associated cardiomyocyte dysfunction, arrhythmias and the effect of Canakinumab

COVID19-associated cardiomyocyte dysfunction, arrhythmias and the effect of Canakinumab

Macrophage-dependent IL-1β production induces cardiac arrhythmias in diabetic mice

Systemic inflammation and arrhythmic risk: lessons from rheumatoid arthritis

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