Rationale: Postoperative atrial fibrillation (POAF) is a common and troublesome complication of cardiac surgery. POAF is generally believed to occur when postoperative triggers act on a preexisting vulnerable substrate, but the underlying cellular and molecular mechanisms are largely unknown. Objective: To identify cellular POAF mechanisms in right atrial samples from patients without a history of atrial fibrillation undergoing open-heart surgery. Methods and Results: Multicellular action potentials, membrane ion-currents (perforated patch-clamp), or simultaneous membrane-current (ruptured patch-clamp) and [Ca ²⁺ ] _i -recordings in atrial cardiomyocytes, along with protein-expression levels in tissue homogenates or cardiomyocytes, were assessed in 265 atrial samples from patients without or with POAF. No indices of electrical, profibrotic, or connexin remodeling were noted in POAF, but Ca ²⁺ -transient amplitude was smaller, although spontaneous sarcoplasmic reticulum (SR) Ca ²⁺ -release events and L-type Ca ²⁺ -current alternans occurred more frequently. CaMKII (Ca ²⁺ /calmodulin-dependent protein kinase-II) protein-expression, CaMKII-dependent phosphorylation of the cardiac RyR2 (ryanodine-receptor channel type-2), and RyR2 single-channel open-probability were significantly increased in POAF. SR Ca ²⁺ -content was unchanged in POAF despite greater SR Ca ²⁺ -leak, with a trend towards increased SR Ca ²⁺ -ATPase activity. Patients with POAF also showed stronger expression of activated components of the NLRP3 (NACHT, LRR, and PYD domains-containing protein-3)-inflammasome system in atrial whole-tissue homogenates and cardiomyocytes. Acute application of interleukin-1β caused NLRP3-signaling activation and CaMKII-dependent RyR2/phospholamban hyperphosphorylation in an immortalized mouse atrial cardiomyocyte cell-line (HL-1-cardiomyocytes) and enhanced spontaneous SR Ca ²⁺ -release events in both POAF cardiomyocytes and HL-1-cardiomyocytes. Computational modeling showed that RyR2 dysfunction and increased SR Ca ²⁺ -uptake are sufficient to reproduce the Ca ²⁺ -handling phenotype and indicated an increased risk of proarrhythmic delayed afterdepolarizations in POAF subjects in response to interleukin-1β. Conclusions: Preexisting Ca ²⁺ -handling abnormalities and activation of NLRP3-inflammasome/CaMKII signaling are evident in atrial cardiomyocytes from patients who subsequently develop POAF. These molecular substrates sensitize cardiomyocytes to spontaneous Ca ²⁺ -releases and arrhythmogenic afterdepolarizations, particularly upon exposure to inflammatory mediators. Our data reveal a potential cellular and molecular substrate for this important clinical problem.

Calcium (Ca2+) plays a central role in cardiomyocyte excitation-contraction coupling. To ensure an optimal electrical impulse propagation and cardiac contraction, Ca2+ levels are regulated by a variety of Ca2+-handling proteins. In turn, Ca2+ modulates numerous electrophysiological processes. Accordingly, Ca2+-handling abnormalities can promote cardiac arrhythmias via various mechanisms, including the promotion of afterdepolarizations, ion-channel modulation and structural remodeling. In the last 30 years, significant improvements have been made in the computational modeling of cardiomyocyte Ca2+ handling under physiological and pathological conditions. However, numerous questions involving the Ca2+-dependent regulation of different macromolecular complexes, cross-talk between Ca2+-dependent regulatory pathways operating over a wide range of time scales, and bidirectional interactions between electrophysiology and mechanics remain to be addressed by in vitro and in silico studies. A better understanding of disease-specific Ca2+-dependent proarrhythmic mechanisms may facilitate the development of improved therapeutic strategies. In this review, we describe the fundamental mechanisms of cardiomyocyte Ca2+ handling in health and disease, and provide an overview of currently available computational models for cardiomyocyte Ca2+ handling. Finally, we discuss important uncertainties and open questions about cardiomyocyte Ca2+ handling and highlight how synergy between in vitro and in silico studies may help to answer several of these issues.

Despite significant advances in its detection, understanding and management, atrial fibrillation (AF) remains a highly prevalent cardiac arrhythmia with a major impact on morbidity and mortality of millions of patients. AF results from complex, dynamic interactions between risk factors and comorbidities that induce diverse atrial remodelling processes. Atrial remodelling increases AF vulnerability and persistence, while promoting disease progression. The variability in presentation and wide range of mechanisms involved in initiation, maintenance and progression of AF, as well as its associated adverse outcomes, make the early identification of causal factors modifiable with therapeutic interventions challenging, likely contributing to suboptimal efficacy of current AF management. Computational modelling facilitates the multilevel integration of multiple datasets and offers new opportunities for mechanistic understanding, risk prediction and personalized therapy. Mathematical simulations of cardiac electrophysiology have been around for 60 years and are being increasingly used to improve our understanding of AF mechanisms and guide AF therapy. This narrative review focuses on the emerging and future applications of computational modelling in AF management. We summarize clinical challenges that may benefit from computational modelling, provide an overview of the different in silico approaches that are available together with their notable achievements, and discuss the major limitations that hinder the routine clinical application of these approaches. Finally, future perspectives are addressed. With the rapid progress in electronic technologies including computing, clinical applications of computational modelling are advancing rapidly. We expect that their application will progressively increase in prominence, especially if their added value can be demonstrated in clinical trials.

Coronavirus disease 2019 (COVID-19) increases the risk of thromboembolic events, especially in patients with severe infections requiring intensive care and cardiorespiratory support. COVID-19 patients with thromboembolic complications have a higher risk of death, and if they survive, these complications are expected to negatively affect these patients’ quality of life. Moreover, recent data reported that the risk of thromboembolism remains high months after a COVID-19 infection. Therefore, understanding the pathogenesis of thrombosis in the setting of COVID-19 may facilitate the early prevention and treatment of COVID-19-associated thromboembolism to reduce concomitant morbidity, mortality, and disability. This review will first discuss the clinical characteristics of COVID-19 infections, particularly with regard to the underlying pathophysiology. Then, the pathogenesis of COVID-19-associated thrombosis at the molecular and cellular levels will be comprehensively reviewed. Next, the clinical manifestations of venous and arterial thromboembolism in COVID-19 as well as the potential benefits of several laboratory markers of thrombosis will be further discussed. Lastly, the preventive and therapeutic management of thromboembolism during and after COVID-19 will also be explained.

TASK-1 (K_2P3.1) two-pore-domain potassium channels are atrial-specific and significantly up-regulated in atrial fibrillation (AF) patients, contributing to AF-related electrical remodelling. Inhibition of TASK-1 in cardiomyocytes of AF patients was shown to counteract AF-related action potential duration shortening. Doxapram was identified as a potent inhibitor of the TASK-1 channel. In this study, we investigated the antiarrhythmic efficacy of doxapram in a porcine model of AF. Doxapram successfully cardioverted pigs with artificially induced episodes of AF. We established a porcine model of persistent AF in domestic pigs via intermittent atrial burst stimulation using implanted pacemakers. All pigs underwent catheter-based electrophysiological investigations prior to and after 14 days of doxapram treatment. Pigs in the treatment group received intravenous administration of doxapram once per day. In doxapram-treated AF pigs, the AF burden was significantly reduced. After 14 days of treatment with doxapram, TASK-1 currents were still similar to values of sinus rhythm animals. Doxapram significantly suppressed AF episodes and normalized cellular electrophysiology by inhibition of the TASK-1 channel. Patch-clamp experiments on human atrial cardiomyocytes, isolated from patients with and without AF could reproduce the TASK-1 inhibitory effect of doxapram. Repurposing doxapram might yield a promising new antiarrhythmic drug to treat AF in patients.

Cardiovascular diseases (CVDs) are the leading cause of death worldwide and obesity is a major risk factor that increases the morbidity and mortality of CVDs. Lifestyle modifications (e.g., diet control, physical exercise and behavioral changes) have been the first-line managements of obesity for decades. Nonetheless, when such interventions fail, pharmacotherapies and bariatric surgery are considered. Interestingly, a sudden weight loss (e.g., due to bariatric surgery) could also increase mortality. Thus, it remains unclear whether the bariatric surgery-associated weight reduction in patients with obesity and CVDs is beneficial for the reduction of Major Adverse Cardiovascular Events (MACE). Here, we performed a systematic literature search and meta-analysis of published studies comparing MACE in patients with obesity and CVDs who underwent bariatric surgery with control patients (no surgery). Eleven studies, with a total of 1,772,305 patients, which consisted of 74,042 patients who underwent any form of bariatric surgery and 1,698,263 patients with no surgery, were included in the systematic review. Next, the studies’ data, including odds ratio (OR) and adjusted hazard ratio (aHR), were pooled and analyzed in a meta-analysis using a random effect model. The meta-analysis of ten studies showed that the bariatric surgery group had significantly lower odds of MACE as compared to no surgery (OR = 0.49; 95% CI 0.40–0.60; p < 0.00001; I² = 93%) and the adjustment to confounding variables in nine studies revealed consistent results (aHR = 0.57; 95% CI 0.49–0.66; p < 0.00001; I² = 73%), suggesting the benefit of bariatric surgery in reducing the occurrence of MACE in patients with obesity and CVDs (PROSPERO ID: CRD42021274343).