Brugada phenocopy vs. Brugada syndrome: Delineating the differences for optimal diagnosis and management.

Brugada syndrome (BrS) is a genetic disorder known for its characteristic electrocardiogram (ECG) patterns and increased risk of sudden cardiac death. Brugada phenocopy (BrP) presents similar ECG patterns but is distinguished by its reversible nature when the underlying conditions are resolved. This article delineates the intricacies of BrP, emphasizing its etiology, clinical presentation, diagnosis, treatment, and prognosis. The article categorizes BrP based on various underlying causes, including metabolic disturbances, myocardial infarction, and mechanical compression, among others. It also underscores the critical importance of differentiating BrP from BrS to avoid misdiagnosis and inappropriate treatment, such as unnecessary implantation of cardioverter-defibrillators. The reversible aspect of BrP underlines the necessity for an etiology-specific approach to treatment, which not only prevents cardiac death but also highlights the significance of understanding the dynamic nature of ECG patterns. Through an exploration of case studies and current research, this review advocates for increased awareness and further investigation into BrP. It aims to enhance the diagnostic accuracy and management strategies, thereby improving the prognosis for patients presenting with Brugada-like ECG patterns. The review culminates in a call for further research to close existing knowledge gaps and improve patient outcomes.

Peripartum cardiomyopathy unveiled: Etiology, diagnosis, and therapeutic insights.

Peripartum cardiomyopathy (PPCM) remains a significant challenge in maternal health, marked by its unpredictable onset and varied clinical outcomes. With rising incidence rates globally, understanding PPCM is vital for improving maternal care and prognosis. This review aims to consolidate current knowledge on PPCM, highlighting recent advancements in its diagnosis, management, and therapeutic approaches. This comprehensive review delves into the epidemiology of PPCM, underscoring its global impact and demographic variations. We explore the complex etiology of the condition, examining known risk factors and discussing the potential pathophysiological mechanisms, including oxidative stress and hormonal influences. The clinical presentation of PPCM, often similar yet distinct from other forms of cardiomyopathy, is analyzed to aid in differential diagnosis. Diagnostic challenges are addressed, emphasizing the role of advanced imaging and biomarkers. Current management strategies are reviewed, focusing on the absence of disease-specific treatments and the application of general heart failure protocols. The review also discusses the prognosis of PPCM, factors influencing recovery, and the implications for future pregnancies. Finally, we highlight emerging research directions and the urgent need for disease-specific therapies, aiming to provide a roadmap for future studies and improved patient care. This review serves as a crucial resource for clinicians and researchers, contributing to a deeper understanding and better management of PPCM.

Diagnostic and Therapeutic Approaches for a Diabetic Patient Presenting with Secondary Syphilis and Severe Odynophagia.

Syphilis, an infectious disease caused by the spirochete Treponema pallidum, represents a pervasive global epidemic. Secondary syphilis is typically marked by the emergence of highly contagious mucocutaneous manifestations, including non-pruritic rashes on the palms and soles of the feet, alopecia, mucous patches, and condyloma lata. Here, we report a rare case of a 30-year-old male with newly discovered type 2 diabetes mellitus who presented with severe odynophagia due to secondary syphilis, confirmed by both nontreponemal VDRL/RPR and treponemal TPHA tests. Following the administration of a single-dose intramuscular injection of benzathine penicillin G 2.4 million units, the symptoms gradually decreased, allowing the patient to regain his health.

Transforming clinical cardiology through neural networks and deep learning: A guide for clinicians.

The rapid evolution of neural networks and deep learning has revolutionized various fields, with clinical cardiology being no exception. As traditional methods in cardiology encounter limitations, the integration of advanced computational techniques offers unprecedented opportunities in diagnostics and patient care. This review explores the transformative role of neural networks and deep learning in clinical cardiology, particularly focusing on their applications in electrocardiogram (ECG) analysis, imaging technologies, and cardiac prediction models. Among others, Deep Neural Networks (DNNs) have significantly surpassed traditional approaches in accuracy and efficiency in automatic ECG diagnosis. Convolutional Neural Networks (CNNs) are successfully applied in PET/CT and PET/MR imaging, enhancing diagnostic capabilities. Furthermore, deep learning algorithms have shown potential in improving cardiac prediction models, although challenges in interpretability and clinical integration remain. The review also addresses the 'black box' nature of neural networks and the ethical considerations surrounding their use in clinical settings. Overall, this review underscores the significant impact of neural networks and deep learning in cardiology, providing insights into current applications and future directions in the field.

The Efficacy and Safety of Monoclonal Antibody Treatments Against COVID-19: A Systematic Review and Meta-analysis of Randomized Clinical Trials.

BACKGROUND: The use of monoclonal antibody as the proposed treatment of COVID-19 showed different results in various prior studies, and Efficacy remains open in literature. This study aimed to comprehensively determine the effect of monoclonal antibodies on clinical, laboratory, and safety outcomes in COVID-19 patients. METHODS: Sixteen RCTs were analyzed in this meta-analysis using RevMan 5.4 to measure the pooled estimates of risk ratios (RRs) and standardized mean differences (SMDs) with 95% CIs. RESULTS: The pooled effect of Monoclonal antibodies demonstrated efficacy on mortality risk reduction (RR=0,89 (95%CI 0.82-0.96), I2=13%, fixed-effect), Tocilizumab also show efficacy on mortality risk reduction for severe-critical disease (RR=0.90 (95%CI 0.83-0.97), I2=12%, fixed-effect)), need for mechanical ventilation (RR=0.76 (95%CI 0.62-0.94), I2=42%, random-effects), and hospital discharge (RR=1.07 (95%CI 1.00-1.14), I2=60%, random-effects). Bamlanivimab monotherapy did not reduce viral load (SMD=-0.07 (95%CI -0.21-0.07), I2=44%, fixed-effect). Monoclonal antibodies did not differ from placebo/standard therapy for hospital discharge at day 28-30 (RR=1.05 (95%CI 0.99-1.12), I2=71%, random-effects) and safety (RR=1.04 (95%CI 0.76-1.43), I2=54%, random-effects). CONCLUSION: Tocilizumab should be used for severe to critical COVID-19 because it is not harmful and can improve mortality risk, mechanical ventilation, and hospital discharge. Bamlanivimab-Etesevimab and REGN-COV2 reduced viral load in mild-moderate outpatients.

Current Insights into Cellular Determinants of Peritoneal Fibrosis in Peritoneal Dialysis: A Narrative Review.

Peritoneal fibrosis is the final process of progressive changes in the peritoneal membrane due to chronic inflammation and infection. It is one of the main causes of discontinuation of peritoneal dialysis (PD), apart from peritonitis and cardiovascular complications. Over time, morphological changes occur in the peritoneal membranes of patients who use PD. Of those are mesothelial-to-mesenchymal transition (MMT), neoangiogenesis, sub-mesothelial fibrosis, and hyalinizing vasculopathy. Several key molecules are involved in the complex pathophysiology of peritoneal fibrosis, including advanced glycosylation end products (AGEs), transforming growth factor beta (TGF-ß), and vascular endothelial growth factor (VEGF). This narrative review will first discuss the physiology of the peritoneum and PD. Next, the multifaceted pathophysiology of peritoneal fibrosis, including the effects of hyperglycemia and diabetes mellitus on the peritoneal membrane, and the promising biomarkers of peritoneal fibrosis will be reviewed. Finally, the current and future management of peritoneal fibrosis will be discussed, including the potential benefits of new-generation glucose-lowering medications to prevent or slow down the progression of peritoneal fibrosis.

Complex Refractory Esophageal Stricture Due to Chronic Gasoline Ingestion: A Case Report.

Esophageal stricture is a narrowing of the esophageal lumen which is often characterized by impaired swallowing or dysphagia. It can be induced by inflammation, fibrosis or neoplasia which damages the mucosa and/or submucosa of the esophagus. Corrosive substance ingestion is one of the major causes of esophageal stricture, particularly in children and young adults. For instance, accidental ingestion or attempted suicide with corrosive household products is not uncommon. Gasoline is a liquid mixture of aliphatic hydrocarbons derived from the fractional distillation of petroleum, which is then combined with additives such as isooctane and aromatic hydrocarbons (e.g., toluene and benzene). Gasoline also contains several other additives including ethanol, methanol and formaldehyde, which make it a corrosive agent. Interestingly, to the best of our knowledge, the incidence of esophageal stricture caused by chronic gasoline ingestion has not been reported. In this paper, we report the case of a patient with dysphagia due to complex esophageal stricture due to chronic gasoline ingestion who underwent a series of esophago-gastro-duodenoscopy (EGD) procedures and repeated esophageal dilation.

Disentangling the Pathogenesis of Systemic Lupus Erythematosus: Close Ties between Immunological, Genetic and Environmental Factors.

Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease that attacks various organ systems with a variety of clinical implications, ranging from mild skin and mucosal manifestations to severe central nervous system manifestations and death. Cases of SLE have been documented nearly two centuries ago when scholars used the terms 'erythema centrifugum' and 'seborrhea congestiva' to describe the discoid skin lesions and the butterfly or malar rash in SLE. Since then, knowledge about this disease has developed rapidly, especially knowledge related to the underlying pathogenesis of SLE. To date, it is known that immune system dysregulation, supported by genetic and environmental predisposition, can trigger the occurrence of SLE in a group of susceptible individuals. Various inflammatory mediators, cytokines and chemokines, as well as intra- and intercellular signaling pathways, are involved in the pathogenesis of SLE. In this review, we will discuss the molecular and cellular aspects of SLE pathogenesis, with a focus on how the immune system, genetics and the environment interact and trigger the various clinical manifestations of SLE.

Risk of Thrombosis during and after a SARS-CoV-2 Infection: Pathogenesis, Diagnostic Approach, and Management.

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.

Electrophysiological and calcium-handling development during long-term culture of human-induced pluripotent stem cell-derived cardiomyocytes.

Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are increasingly used for personalised medicine and preclinical cardiotoxicity testing. Reports on hiPSC-CM commonly describe heterogenous functional readouts and underdeveloped or immature phenotypical properties. Cost-effective, fully defined monolayer culture is approaching mainstream adoption; however, the optimal age at which to utilise hiPSC-CM is unknown. In this study, we identify, track and model the dynamic developmental behaviour of key ionic currents and Ca2+-handling properties in hiPSC-CM over long-term culture (30-80 days). hiPSC-CMs > 50 days post differentiation show significantly larger ICa,L density along with an increased ICa,L-triggered Ca2+-transient. INa and IK1 densities significantly increase in late-stage cells, contributing to increased upstroke velocity and reduced action potential duration, respectively. Importantly, our in silico model of hiPSC-CM electrophysiological age dependence confirmed IK1 as the key ionic determinant of action potential shortening in older cells. We have made this model available through an open source software interface that easily allows users to simulate hiPSC-CM electrophysiology and Ca2+-handling and select the appropriate age range for their parameter of interest. This tool, together with the insights from our comprehensive experimental characterisation, could be useful in future optimisation of the culture-to-characterisation pipeline in the field of hiPSC-CM research.

Myocarditis and coronavirus disease 2019 vaccination: A systematic review and meta-summary of cases.

Vaccination is significant to control, mitigate, and recover from the destructive effects of coronavirus disease 2019 (COVID-19). The incidence of myocarditis following COVID-19 vaccination has been increasing and growing public concern; however, little is known about it. This study aimed to systematically review myocarditis following COVID-19 vaccination. We included studies containing individual patient data of myocarditis following COVID-19 vaccination published between January 1, 2020 and September 7, 2022 and excluded review articles. Joanna Briggs Institute critical appraisals were used for risk of bias assessment. Descriptive and analytic statistics were performed. A total of 121 reports and 43 case series from five databases were included. We identified 396 published cases of myocarditis and observed that the majority of cases was male patients, happened following the second dose of mRNA vaccine administration, and experienced chest pain as a symptom. Previous COVID-19 infection was significantly associated (p < 0.01; OR, 5.74; 95% CI, 2.42-13.64) with the risk of myocarditis following the administration of the first dose, indicating that its primary mechanism is immune-mediated. Moreover, 63 histopathology examinations were dominated by non-infective subtypes. Electrocardiography and cardiac marker combination is a sensitive screening modality. However, cardiac magnetic resonance is a significant noninvasive examination to confirm myocarditis. Endomyocardial biopsy may be considered in confusing and severe cases. Myocarditis following COVID-19 vaccination is relatively benign, with a median length of hospitalization of 5 days, intensive care unit admission of <12%, and mortality of <2%. The majority was treated with nonsteroidal anti-inflammatory drugs, colchicine, and steroids. Surprisingly, deceased cases had characteristics of being female, older age, non-chest pain symptoms, first-dose vaccination, left ventricular ejection fraction of <30%, fulminant myocarditis, and eosinophil infiltrate histopathology.

Effectiveness of COVID-19 Vaccines against SARS-CoV-2 Omicron Variant (B.1.1.529): A Systematic Review with Meta-Analysis and Meta-Regression.

Vaccine effectiveness (VE) and the urgency of booster vaccination against SARS-CoV-2 Omicron variant need evaluation. A systematic search was conducted from 1−6 April, 2022. VE difference (VED) estimates were assessed using random-effects and meta-regression analyses were performed for evaluating VE over time. Compared to full dose, booster dose of overall vaccines provided better protection against any and severe Omicron infections within 3 months (p < 0.001), and within 3 months or more in any, severe, and symptomatic infections (p < 0.001). From meta-regression analysis of overall vaccines, the full-dose VE against any and symptomatic Omicron infections reduced per month by 2.45% and 5.5%, respectively; whereas booster dose effectiveness against any and symptomatic Omicron infections reduced per month by 1.79% and 1.14%, respectively. The VE estimates of booster dose provide excellent protection against symptomatic infection compared to full dose. The VE estimates of Ad26.COV2.S, BNT162b2, ChAdOx1 nCov-19, and mRNA-1273 against Omicron infection are generally moderate, despite the VE estimates declining over time.

Clinical outcomes of opioid administration in acute and chronic heart failure: A meta-analysis.

BACKGROUND AND AIMS: Opioid use in heart failure (HF) management is controversial, and whether rapid symptomatic relief outweighs the risks of opioid use in HF remains unknown. This study aimed to explore the clinical outcomes of opioid administration in patients with acute or chronic HF. METHODS: A systematic search for eligible studies was conducted in databases (MEDLINE, Scopus, Web of Science, EBSCO) and registries (ClinicalTrials.gov, WHO Clinical Trial Registry) until June 8, 2022. Odds ratios (ORs) or adjusted OR (aORs) and mean difference (MD) or standardized MD were quantified for binary and continuous outcomes, respectively. Meta-regression was performed using the restricted maximum likelihood method. RESULTS: A total of 20 studies (154,736 participants) were included. In acute HF, opioid use presented a high risk for in-hospital mortality (OR = 2.35; 95% confidence interval (CI): 1.03-5.38; I2 = 97%), invasive (OR = 2.78; 95%CI: 1.17-6.61; I2 = 93%) and noninvasive (OR = 2.97; 95%CI: 1.06-8.28; I2 = 95%) ventilations, intensive care unit admission (OR = 3.62; 95%CI: 3.11-4.21; I2 = 6%), and inotrope use (OR = 2.54; 95%CI: 1.94-3.32; I2 = 63%). In chronic HF New York Heart Association (NYHA) Class II/III, opioid use improved ventilatory efficiency (MD = -3.16; 95%CI: (-4.78)-(-1.54); I2 = 0%), and exercise test duration (MD = 69.24; 95%CI: 10.11-128.37; I2 = 89%). CONCLUSIONS: Opioids are not recommended for acute HF management; however, they showed an advantage in exercise testing by improving ventilatory efficiency, chemosensitivity, and exercise test duration in stable patients with chronic HF NYHA Class II/III. Nonetheless, larger randomized controlled trials and individual patient-level data meta-analyses are warranted.

Grapefruit Flavonoid Naringenin Sex-Dependently Modulates Action Potential in an In Silico Human Ventricular Cardiomyocyte Model.

Recent in vitro studies showed that grapefruit (Citrus × paradisi) flavonoid naringenin alters the function of cardiac ion channels. Here, we explored the effect of naringenin on cardiomyocyte action potentials (APs) using a detailed in silico model of ventricular electrophysiology. Concentration-dependent effects of naringenin on seven major cardiac ion channels were incorporated into the Tomek-Rodriguez modification of O'Hara-Rudy (ToR-ORd) human ventricular endocardium model. To investigate the sex-dependent effect of naringenin, previously reported sex-specific ionic modifications were implemented into the model. Next, populations of 1000 models accommodating intercellular variability were generated. The results show, naringenin at various concentrations prolonged AP duration (APD) in male and female cardiomyocytes. Pacing cells at higher frequencies abbreviated APD differently in males versus females; for example, at 3 Hz, 50 µM naringenin induced AP and calcium alternans only in the female cardiomyocyte. Finally, a population modeling approach corroborated that naringenin significantly prolonged APD in a concentration-dependent manner, with a larger effect in females than in males. In conclusion, our study demonstrates that the APD-prolonging effect of naringenin was larger in females, and that pacing at faster rates induces AP alternation earlier in females, suggesting a potentially higher proarrhythmic risk of naringenin in females than in males.

Ozone as an adjuvant therapy for COVID-19: A systematic review and meta-analysis.

OBJECTIVE: Ozone adjuvant in COVID-19 management showed conflicting results in prior studies. Here, we aimed to comprehensively evaluate benefits and side effects of ozone as adjuvant therapy in COVID-19 patients. METHODS: Systematic searches were conducted in MEDLINE, ScienceDirect, Cochrane Library, Springer, medRxiv, and ProQuest for articles investigating ozone as adjuvant therapy in COVID-19. Clinical and laboratory outcomes, mortality, length of hospital stay, intensive care unit (ICU) admission, and adverse events were assessed. RESULTS: Thirteen studies were included in this review. Case-control studies, but not randomized controlled trials (RCTs), showed a decrease in mortality following ozone therapy (OR = 0.24 (95% CI [0.07-0.76]), p = 0.02, I2 = 0%, fixed-effect). However, ozone therapy did not improve the length of hospital stay (SMD = -0.99 (95 %CI -2.44 to 0.45), p = 0.18, I2 = 84%, random-effects) and ICU admission (RR = 0.57 (95 %CI [0.05-6.71]), I2 = 73%, p = 0.65, random-effects). Consecutive case control studies suggested that ozone therapy significantly improved levels of D-dimer (p = 0.0060), lactate dehydrogenase (LDH; p = 0.0209), C-reactive protein (CRP; p = 0.0040) and interleukin (IL)-6 (p = 0.0048) as compared to standard therapy alone. CONCLUSIONS: The beneficial effect of ozone in COVID-19 management seems to be limited to the improvements of laboratory parameters among severe patients, including the reduction of IL-6, LDH, CRP, and D-dimer levels. Meanwhile, other study endpoints, such as mortality, length of stay and ICU admission, were not improved following ozone therapy, although it may partly be due to a shorter duration of viral clearance. Furthermore, no serious adverse event was reported following ozone therapy, suggesting its high safety profile. (PROSPERO ID: CRD42021278018).

Multi-Scale Computational Modeling of Spatial Calcium Handling From Nanodomain to Whole-Heart: Overview and Perspectives.

Regulation of intracellular calcium is a critical component of cardiac electrophysiology and excitation-contraction coupling. The calcium spark, the fundamental element of the intracellular calcium transient, is initiated in specialized nanodomains which co-locate the ryanodine receptors and L-type calcium channels. However, calcium homeostasis is ultimately regulated at the cellular scale, by the interaction of spatially separated but diffusively coupled nanodomains with other sub-cellular and surface-membrane calcium transport channels with strong non-linear interactions; and cardiac electrophysiology and arrhythmia mechanisms are ultimately tissue-scale phenomena, regulated by the interaction of a heterogeneous population of coupled myocytes. Recent advances in imaging modalities and image-analysis are enabling the super-resolution reconstruction of the structures responsible for regulating calcium homeostasis, including the internal structure of nanodomains themselves. Extrapolating functional and imaging data from the nanodomain to the whole-heart is non-trivial, yet essential for translational insight into disease mechanisms. Computational modeling has important roles to play in relating structural and functional data at the sub-cellular scale and translating data across the scales. This review covers recent methodological advances that enable image-based modeling of the single nanodomain and whole cardiomyocyte, as well as the development of multi-scale simulation approaches to integrate data from nanometer to whole-heart. Firstly, methods to overcome the computational challenges of simulating spatial calcium dynamics in the nanodomain are discussed, including image-based modeling at this scale. Then, recent whole-cell models, capable of capturing a range of different structures (such as the T-system and mitochondria) and cellular heterogeneity/variability are discussed at two different levels of discretization. Novel methods to integrate the models and data across the scales and simulate stochastic dynamics in tissue-scale models are then discussed, enabling elucidation of the mechanisms by which nanodomain remodeling underlies arrhythmia and contractile dysfunction. Perspectives on model differences and future directions are provided throughout.

Integrative Computational Modeling of Cardiomyocyte Calcium Handling and Cardiac Arrhythmias: Current Status and Future Challenges.

Cardiomyocyte calcium-handling is the key mediator of cardiac excitation-contraction coupling. In the healthy heart, calcium controls both electrical impulse propagation and myofilament cross-bridge cycling, providing synchronous and adequate contraction of cardiac muscles. However, calcium-handling abnormalities are increasingly implicated as a cause of cardiac arrhythmias. Due to the complex, dynamic and localized interactions between calcium and other molecules within a cardiomyocyte, it remains experimentally challenging to study the exact contributions of calcium-handling abnormalities to arrhythmogenesis. Therefore, multiscale computational modeling is increasingly being used together with laboratory experiments to unravel the exact mechanisms of calcium-mediated arrhythmogenesis. This article describes various examples of how integrative computational modeling makes it possible to unravel the arrhythmogenic consequences of alterations to cardiac calcium handling at subcellular, cellular and tissue levels, and discusses the future challenges on the integration and interpretation of such computational data.

Individual Contributions of Cardiac Ion Channels on Atrial Repolarization and Reentrant Waves: A Multiscale In-Silico Study.

The excitation, contraction, and relaxation of an atrial cardiomyocyte are maintained by the activation and inactivation of numerous cardiac ion channels. Their collaborative efforts cause time-dependent changes of membrane potential, generating an action potential (AP), which is a surrogate marker of atrial arrhythmias. Recently, computational models of atrial electrophysiology emerged as a modality to investigate arrhythmia mechanisms and to predict the outcome of antiarrhythmic therapies. However, the individual contribution of atrial ion channels on atrial action potential and reentrant arrhythmia is not yet fully understood. Thus, in this multiscale in-silico study, perturbations of individual atrial ionic currents (INa, Ito, ICaL, IKur, IKr, IKs, IK1, INCX and INaK) in two in-silico models of human atrial cardiomyocyte (i.e., Courtemanche-1998 and Grandi-2011) were performed at both cellular and tissue levels. The results show that the inhibition of ICaL and INCX resulted in AP shortening, while the inhibition of IKur, IKr, IKs, IK1 and INaK prolonged AP duration (APD). Particularly, in-silico perturbations (inhibition and upregulation) of IKr and IKs only minorly affected atrial repolarization in the Grandi model. In contrast, in the Courtemanche model, the inhibition of IKr and IKs significantly prolonged APD and vice versa. Additionally, a 50% reduction of Ito density abbreviated APD in the Courtemanche model, while the same perturbation prolonged APD in the Grandi model. Similarly, a strong model dependence was also observed at tissue scale, with an observable IK1-mediated reentry stabilizing effect in the Courtemanche model but not in the Grandi atrial model. Moreover, the Grandi model was highly sensitive to a change on intracellular Ca2+ concentration, promoting a repolarization failure in ICaL upregulation above 150% and facilitating reentrant spiral waves stabilization by ICaL inhibition. Finally, by incorporating the previously published atrial fibrillation (AF)-associated ionic remodeling in the Courtemanche atrial model, in-silico modeling revealed the antiarrhythmic effect of IKr inhibition in both acute and chronic settings. Overall, our multiscale computational study highlights the strong model-dependent effects of ionic perturbations which could affect the model's accuracy, interpretability, and prediction. This observation also suggests the need for a careful selection of in-silico models of atrial electrophysiology to achieve specific research aims.