3-N-Butylphthalide Confers Antiarrhythmic Features in Ischemia/Reperfusion Injury of Diabetic Heart by Targeting Mitochondria-Endoplasmic Reticulum Network and Inhibiting Oxidative Stress and Inflammation.

While 3-N-butylphthalide (NBP) has demonstrated notable cardioprotective effects, its precise role in mitigating myocardial arrhythmia following ischemia/reperfusion (IR) injury in diabetes remains unclear. This study aimed to explore the potential mechanisms through which NBP mitigates reperfusion-induced myocardial arrhythmia in diabetic rats, with a particular focus on mitochondrial function and biogenesis, endoplasmic reticulum (ER) stress, and oxidative/inflammatory responses. Sixty Sprague-Dawley rats were divided into non-diabetic and diabetic groups, subjected to in-vivo myocardial IR injury, and treated with NBP (100 mg/kg, intraperitoneally) through different modalities: preconditioning, postconditioning, or a combination of both. Electrocardiography (ECG) was employed to assess the incidence and severity of arrhythmia. Fluorometric, Western blotting and ELISA analyses were utilized to measure the mitochondrial, ER stress, and cellular outcomes. Treatment of non-diabetic rats with NBP in preconditioned, postconditioned, and combined approaches significantly reduced cardiotroponin-I and the frequency and severity of arrhythmias induced by IR injury. However, only the combined preconditioning plus postconditioning approach of NBP had protective and antiarrhythmic effects in diabetic rats, in an additive manner. Moreover, the NBP combined approach improved mitochondrial function and upregulated the expression of PGC-1?, Sirt1, and glutathione while concurrently downregulating ER stress and oxidative and pro-inflammatory-related proteins in diabetic rats. In conclusion, the combined approach of NBP treatment was effective in mitigating myocardial arrhythmia in diabetic rats. This approach coordinates interactions within the mitochondria-endoplasmic reticulum network and inhibits oxidative and inflammatory mediators, offering a promising strategy for managing myocardial arrhythmia in diabetic patients. Key words: Myocardial Infarction, Mitochondria, Arrhythmia, Reperfusion, Diabetes, Ischemia.

Management of atrial fibrillation in older adults.

Most people with atrial fibrillation are older adults, in whom atrial fibrillation co-occurs with other chronic conditions, polypharmacy, and geriatric syndromes such as frailty. Yet most randomized controlled trials and expert guidelines use an age agnostic approach. Given the heterogeneity of aging, these data may not be universally applicable across the spectrum of older adults. This review synthesizes the available evidence and applies rigorous principles of aging science. After contextualizing the burden of comorbidities and geriatric syndromes in people with atrial fibrillation, it applies an aging focused approach to the pillars of atrial fibrillation management, describing screening for atrial fibrillation, lifestyle interventions, symptoms and complications, rate and rhythm control, coexisting heart failure, anticoagulation therapy, and left atrial appendage occlusion devices. Throughout, a framework is suggested that prioritizes patients' goals and applies existing evidence to all older adults, whether atrial fibrillation is their sole condition, one among many, or a bystander at the end of life.

Comparing simultaneous hybrid ablation with stand-alone thoracoscopic surgical ablation for the treatment of non-paroxysmal atrial fibrillation: a prospective randomized controlled trial.

AIMS: Advanced atrial fibrillation (AF) is currently a dilemma for electrophysiologists when choosing a minimally invasive treatment strategy. Previous studies have demonstrated the outcome of either catheter ablation or thoracoscopic surgical ablation (SA) is unsatisfactory in these patients. Whether hybrid ablation (HA) could improve outcomes in these patients is unknown. The purpose of this study was to evaluate the clinical efficacy of HA for the treatment of advanced AF. METHODS AND RESULTS: A randomized controlled trial was designed to enrol patients with persistent AF (PerAF) and enlarged left atrium or long-standing persistent AF (LSPAF) who were randomized to HA or thoracoscopic SA at a 1:1 ratio. The primary endpoint was freedom from any recurrence of AF off antiarrhythmic drugs (AADs) 12 months after operation. The primary endpoint was monitored by 7-day electrocardiogram monitoring devices. One hundred patients were enrolled. The mean age was 58.5 ± 7.6 years, and the mean left atrial diameter (LAD) was 50.1 ± 6.1 mm. At 12 months, freedom from AF off AADs was recorded in 71.4% (35/49) of patients in HA group and 45.8% (22/48) in SA group [odds ratio 2.955, 95% confidence interval (1.275-6.848), P = 0.014]. HA significantly reduced patients' AF burden (30.2% in SA group and 14.8% in HA group, P = 0.048) and the LAD (mean differences: -5.53 ± 4.97 mm in HA group and -3.27 ± 5.20 mm in SA group, P = 0.037) at 12 months after operation. CONCLUSION: In patients with PerAF and enlarged left atrium or LSPAF, HA achieved better freedom from AF after 1 year of follow-up compared with thoracoscopic SA.

In vivo cardiovascular profile of ryanodine receptor 2 inhibitor M201-A: Utility as an anti-atrial fibrillatory drug for patients suffering from heart failure with preserved ejection fraction.

Atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) often coexist; however, clinically available anti-AF drugs can exacerbate symptoms of HFpEF. M201-A suppressed ryanodine receptor-mediated diastolic Ca2+ leakage, possibly inhibiting common pathological processes toward AF and HFpEF. To bridge the basic information to clinical practice, we assessed its cardiohemodynamic, anti-AF and ventricular proarrhythmic profile using halothane-anesthetized dogs (n = 4). M201-A hydrochloride in doses of 0.03, 0.3 and 3 mg/kg/10 min was intravenously administered, providing peak plasma concentrations of 0.09, 0.81 and 5.70 µg/mL, respectively. The high dose of M201-A showed various cardiovascular actions. Namely, M201-A increased mean blood pressure and tended to enhance isovolumetric ventricular relaxation without suppressing ventricular contraction or decreasing cardiac output. M201-A enhanced atrioventricular conduction, but hardy affected intra-atrial/ventricular conduction. Importantly, M201-A prolonged effective refractory period more potently in the atrium than in the ventricle, indicating that it may become an atrial-selective antiarrhythmic drug. Meanwhile, M201-A prolonged QT interval/QTcV, and showed reverse frequency-dependent delay of ventricular repolarization. M201-A prolonged J-Tpeakc without prolonging Tpeak-Tend or terminal repolarization period, indicating the risk of causing torsade de pointes is negligible. Thus, M201-A is expected to become a hopeful therapeutic strategy for patients having pathology of both AF and HFpEF.

Nuciferine analogs block voltage-gated sodium, calcium and potassium channels to regulate the action potential and treat arrhythmia.

Dysfunction of the Nav1.5, Cav1.2, and Kv channels could interfere with the AP and result in arrhythmias and even heart failure. We herein present a novel library of nuciferine analogs that target ion channels for the treatment of arrhythmias. Patch clamp measurements of ventricular myocytes revealed that 6a dramatically blocked both the INa and ICa without altering the currentvoltage relationship (including the activation potential and peak potential), accelerated the inactivation of Nav and Cav channels and delayed the resurrection of these channels after inactivation. Additionally, 6a significantly decreased the APA and RMP without affecting the APD30 or APD50. The IC50 values of 6a against Nav1.5 and Cav1.2 were 4.98 µM and 4.62 µM, respectively. Furthermore, 6a (10 µM) blocked IKs, IK1, and Ito with values of 17.01 %±2.54 %, 9.09 %±2.78 %, and 11.15 %±3.52 %, respectively. Surprisingly, 6a weakly inhibited hERG channels, suggesting a low risk of proarrhythmia. The cytotoxicity evaluation of 6a with the H9c2 cell line indicated that this compound was noncytotoxic. In vivo studies suggested that these novel nuciferine analogs could shorten the time of arrhythmia continuum induced by BaCl2 and normalize the HR, QRS, QT and QTc interval and the R wave amplitude. Moreover, 6a dose-dependently affected aconitine-induced arrhythmias and notably improved the cumulative dosage of aconitine required to evoke VP, VT, VF and CA in rats with aconitine-induced arrhythmia. In conclusion, nuciferine analogs could be promising ion channel blockers that could be further developed into antiarrhythmic agents.

ß-Adrenergic receptor signalling pathway mediated antiarrhythmic activity of s-limonene in the rat heart.

S-Limonene (s-Lim) is a monocyclic monoterpene found in a variety of plants and has been shown to present antioxidant and cardioprotective activity in experimental models of myocardial infarction. The aim of this study was to evaluate the potential mechanism by which s-Lim exerts its antiarrhythmic effect, focusing on the blockade of ß-adrenoceptor (ß-AR) and its effects on various in vivo and in vitro parameters, including electrocardiogram (ECG) measurements, left ventricular developed pressure (LVDP), the ß-adrenergic pathway, sarcomeric shortening and L-type calcium current (ICa,L). In isolated hearts, 10 µM of s-Lim did not alter the ECG profile or LVPD. s-Lim increased the heart rate corrected QT interval (QTc) (10.8%) at 50 µM and reduced heart rate at the concentrations of 30 (12.4%) and 50 µM (16.6%). s-Lim (10 µM) also inhibited the adrenergic response evoked by isoproterenol (ISO) (1 µM) reducing the increased of heart rate, LVDP and ECG changes. In ventricular cardiomyocyte, s-Lim antagonized the effect of dobutamine by preventing the increase of sarcomeric shortening, demonstrating a similar effect to atenolol (blocker ß1-AR). In vivo, s-Lim antagonized the effect of ISO (agonists ß1-AR), presenting a similar effect to propranolol (a non-selective blocker ß-AR). In ventricular cardiomyocyte, s-Lim did not alter the voltage dependence for ICa,L activation or the ICa,L density. In addition, s-Lim did not affect changes in the ECG effect mediated by 5 µM forskolin (an activator of adenylate cyclase). In an in vivo caffeine/ISO-induced arrhythmia model, s-Lim (1 mg/kg) presented antiarrhythmic action verified by a reduced arrhythmia score, heart rate, and occurrence of ventricular premature beats and inappropriate sinus tachycardia. These findings indicate that the antiarrhythmic activity of s-Lim is related to blockade of ß-AR in the heart.

MULTIPLE KERATINOCYTIC CANCERS AFTER INTAKE OF ANTIHYPERTENSIVES (LISINOPRIL/BISOPROLOL/HCT) AND ANTIARRHYTMICS (PROPAFENONE): THE IMPORTANT NEW LINKS TO THE NITROSO-CONTAMINATION AND THE METABOLIC REPROGRAMMING OF THE FUTURE CANCER CELL.

The pathogenesis of cutaneous tumors has been known for decades yet remains largely unexplained or incompletely understood. The reason for this mystery lies in the concepts of photosensitivity and phototoxicity: how do they arise or what actually causes them? Recently published data in the medical literature link certain nitrosamines such as nitrosomorpholine, for example, to gene and phototoxicity in humans. A number of other nitrosamines analogous in action and structure are found as contaminants in about 300 of the most widely distributed pharmaceuticals worldwide: NDEA, NDMA, NMBA and many others. These contaminated drugs include beta blockers/ bisoprolol/, thiazide diuretics/ hydrochlorothiazide/, antiarrhythmics/ propafenone/, ACE inhibitors/ lisinopril/, but also a number of other drugs which are, according to the FDA, found to have contaminants with a certain carcinogenic potency ranging between 1 and 5. The phototoxicity and genotoxicity of these contaminants, attributed to the pathogenesis of skin tumors, still remain a mystery. The problems of the intake of the above-mentioned groups of drugs arise mainly on the basis of the official bulletins of the regulatory bodies, namely that: in practice, the intake of polymedication could in many cases also be considered as regular, permanent, long-term intake of contaminants/carcinogens/mutagens of heterogeneous type, also known as nitrosamines or NDSRIs. Nitrosamines are genome modifiers in humans and cause acquired mutations. Their concomitant administration in the context of standard, but currently not yet officially declared as contaminated polymedication, would be able to block certain tumor suppressor genes (p53) as well as activate RAS oncogenes. Or in practice- daily administration of a particular combination of drugs could activate the cascades of carcinogenesis regulating the genesis of skin cancer. Precisely because of this fact, it should not be surprising to anyone that the concurrent intake of the aforementioned drugs could also be associated with the clinical manifestation of multiple keratinocytic tumors. We describe a consecutive case of a patient who developed 4 keratinocytic tumors: 2 basal cell carcinomas, 1 keratoacanthoma, and 1 squamous cell carcinoma on a background of potentially contaminated polymedication with propafenone, lisinopril, hydrochlorothiazide, and bisoprolol. Recently published innovative international data on the topic are discussed in the context of concepts such as drug-mediated nitrosogenesis, photonitrosо-carcinogenesis and metabolic programming/ reprogramming of the tumor cell.

Refractory amiodarone-induced thyrotoxicosis requiring adjunctive cholestyramine treatment.

Amiodarone is an antiarrhythmic drug which may be associated with thyroid dysfunction. Type I amiodarone-induced thyrotoxicosis (AIT) is treated with thionamides and type II AIT is treated with glucocorticoids. Combined therapy is used in mixed or indeterminate forms. When medical treatment is unsuccessful, radioiodine ablation or thyroidectomy is considered. This report reviews a case of AIT refractory to conventional treatment. Despite high doses of methimazole and prednisone, the patient remained clinically and biochemically thyrotoxic. Cholestyramine, a bile salt sequestrant, was used as an off-label adjunctive treatment resulting in significant improvement and achievement of euthyroidism that may also be in part due to the expected natural timeline of recovery from AIT after several months. The patient subsequently trended towards hypothyroidism with symptomatic weight gain and cold intolerance for which he was initiated on levothyroxine.

The Effects of Silymarin on Calcium Chloride-Induced Arrhythmia in Male Rat.

Antioxidants play an important role in protecting cardiac arrhythmias. Silymarin, strong antioxidant, is effective in reducing the complications caused by arrhythmias. This study was conducted to determine the effect of silymarin on the prevention and treatment of calcium chloride-induced arrhythmia. In total, 48 male rats were randomly divided into six groups: the first control group for acute administration received intravenous injection of 0.2 mL of dimethylsulfoxide, a cosolvent, immediately after induction of arrhythmia; the second control group for chronic administration, daily gavage of dimethylsulfoxide for 2 weeks before induction of arrhythmia; acute silymarin group, 100 mg/kg intravenous, immediately after the occurrence of arrhythmia; chronic silymarin group, daily gavage of 50 mg/kg for 2 weeks before induction of arrhythmia; amiodarone standard treatment, 5 mg/kg intravenous, immediately after induction of arrhythmia; and quinidine standard treatment, 10 mg/kg intravenous, immediately after induction of arrhythmia. Calcium chloride (140 mg/kg, i.v.) was used to induce arrhythmia. Electrocardiogram was recorded and monitored by PowerLab™ system. The incidence rates of premature ventricular beat (PVB), ventricular tachycardia (VT), and ventricular fibrillation (VF) were calculated. The antiarrhythmic effect of silymarin was observed with a significant decrease in the incidence of premature ventricular beat (22.56 ± 1.04%, P < 0.001), ventricular tachycardia (34.150 ± 1.59%, P < 0.001), and ventricular fibrillation (24.31 ± 1.02%, P < 0.001) compared with the control group (100%). These effects were comparable to antiarrhythmic drugs such as quinidine (29.23% ± 1.24%, 52.23% ± 1.13%, 66.31% ± 1.81%) and amiodarone (22.91% ± .72%, 41.09% ± 1.66%, 61.59% ± 1.11%). Silymarin exerts a potent antioxidant effect, thereby mitigating the risk of VT, VF, and PVC.

Advanced Interatrial block induced by flecainide.

We present a case of advanced interatrial block induced by flecainide toxicity. We discuss the implications of this conduction abnormality.

Can the efficacy of a medical treatment be predicted based on the type of idiopathic premature ventricular contraction?

BACKGROUND: Premature ventricular contractions (PVCs) are common arrhythmias with diverse clinical implications. This retrospective study aimed to evaluate the efficacy of medical treatments using various clinical, imaging, and electrocardiographic parameters in patients with idiopathic PVCs. METHODS: A total of 1051 patients with idiopathic PVCs were retrospectively analyzed. Patients were categorized into three groups based on treatment response: beta-blocker (BB) responders (479 patients), calcium-channel blocker (CCB) responders (335 patients), and class 1c antiarrhythmic (AA) responders (237 patients). Clinical, imaging, and electrocardiographic data were collected and analyzed to assess the factors influencing treatment response. RESULTS: Age, left ventricular ejection fraction (LVEF), PVC QRS duration, CI variability, and multiple PVC morphologies were identified as significant factors affecting treatment response. Older age and lower LVEF were associated with better response to BB treatment, whereas CCB responders showed narrower QRS complexes. BB responders also exhibited higher CI variability, possibly linked to automaticity mechanisms. Moreover, the BB responder group had a higher frequency of multiple PVC morphologies. CONCLUSION: These findings emphasize the importance of tailored treatment approaches based on individual patient characteristics.

Safety of different therapies for atrial fibrillation: a network meta-analysis.

OBJECTIVE: Most published studies have aimed to compare the effectiveness of different treatment strategies for atrial fibrillation (AF), while few articles have comprehensively compared the safety of therapeutic measures.The aim of the article was to assess the safety of different therapeutic measures (different ablation techniques, antiarrhythmic drugs and surgery) in patients with AF. METHOD: A comprehensive and systematic search was undertaken across various databases, namely PubMed, Embase, Cochrane Library, and Web of Science, with the aim of identifying pertinent randomized controlled trials (RCTs) that delve into the safety aspects of diverse atrial fibrillation treatment strategies. The search was conducted up until December 1st, 2023. R4.2.3 software gemtc package was used for data analysis, Review Manager 5.3 was used for quality assessment of included studies, and stata15.0 was used for publication bias.Safety is defined as the adverse outcomes that occur in different treatment strategies for atrial fibrillation, with specific adverse events as described below. RESULT: 22 RCTs (involving 5073 subjects) with interventions including cryoballoon ablation (CA), radiofrequency ablation (RF), laser balloon ablation (LB), pulmonary vein ablation catheter (PVAC), antiarrhythmic drugs (AADS), and surgery (SA) were included in this study. In this article, medication and surgery were combined into the same intervention (non-traditional treatment measure, UT). UT was not associated with pericardial effusion (OR:4.27e-10, 95%CI:4.91e-30-0.0663), infections (OR:0.248, 95%CI:0.0584-0.89), arrhythmias (OR:0.609,95%CI:0.393-0.936), pseudoaneurysms (OR:5.57e-10, 95%CI:1.16e-31-0.934) and pulmonary vein stenosis (OR:1.16e-09, 95%CI:6.56e-24-0.194). Complications of the procedure were mainly mechanical injuries. Among the various ablation strategies, radiofrequency ablation had a lower incidence of phrenic nerve palsy and pain (OR:4.01e-06, 95%CI:1.18e-17-0.710) than cryoballoon ablation, which was superior to radiofrequency ablation in terms of infection rates. Finally, there were no significant differences between the various ablation techniques in terms of other complication rates. CONCLUSION: Because the interventions in the UT group were predominantly AADS and antiarrhythmic drug therapy didn't have some of the common aggressive complications of ablation strategies, the UT group had a low rate of complications such as pericardial effusion, postprocedural arrhythmia, pseudoaneurysm, and pulmonary vein stenosis compared with various catheter ablation strategies. Additionally, we also discovered between the various ablation technology groups, there was no significant difference in the incidence of major adverse events. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registry number:CRD42024566530.

Investigative agents for atrial fibrillation: agonists and stimulants, progress and expectations.

INTRODUCTION: Atrial fibrillation (AF) is the most common type of cardiac arrhythmia. Its prevalence has increased due to worldwide populations that are aging in combination with the growing incidence of risk factors associated. Recent advances in our understanding of AF pathophysiology and the identification of nodal players involved in AF-promoting atrial remodeling highlights potential opportunities for new therapeutic approaches. AREAS COVERED: This detailed review summarizes recent developments in the field antiarrhythmic drugs in the field AF. EXPERT OPINION: The current situation is far than optimal. Despite clear unmet needs in drug development in the field of AF treatment, the current development of new drugs is absent. The need for a molecule with absence of cardiac and non-cardiac toxicity in the short and long term is a limitation in the field. Improvement in the understanding of AF genetics, pathophysiology, molecular alterations, big data and artificial intelligence with the objective to provide a personalized AF treatment will be the cornerstone of AF treatment in the coming years.

Intravenous administration of quinidine and metoprolol for treatment of atrial fibrillation in 2 neonatal foals.

Atrial fibrillation (AF) is a rarely reported arrhythmia in otherwise healthy newborn foals, with a single case of cardioversion using procainamide administration described in the literature. Two neonatal Thoroughbred colts were presented to an equine hospital because of an irregularly irregular tachyarrhythmia and poor latching when trying to nurse. History, physical examination, and initial diagnostic testing including ECG and echocardiography confirmed AF without structural heart disease. The 1st foal converted into normal sinus rhythm after treatment with IV metoprolol and quinidine. The 2nd foal converted to normal sinus rhythm after a single IV dose of metoprolol, intended for rate control. Demeanor and nursing behavior improved markedly after conversion. The 2 foals had normal heart rates and sinus rhythm that persisted for 6 weeks until euthanasia in the 1st foal and for 2 years in the 2nd foal. Rate control and cardioversion should be considered as a treatment for persistent lone AF in neonatal foals.

Drug-induced QT interval prolongation in patients with heart failure with preserved ejection fraction.

Heart failure (HF) with reduced ejection fraction (HFrEF) is a risk factor for drug-induced QT interval prolongation. It is unknown if HF with preserved ejection fraction (HFpEF) is also associated with an increased risk. Dofetilide and sotalol are potent QT interval-prolonging agents that are frequently used in patients with HFpEF, in whom atrial fibrillation is a common comorbidity. We tested the hypothesis that the risk of QT interval prolongation associated with dofetilide and sotalol is increased in patients with HFpEF. We conducted a retrospective cohort study conducted using electronic health records from the Indiana Network for Patient Care (January 31, 2010 -May 3, 2021). After removing patients with overlapping diagnoses of HFpEF and HFrEF, no diagnosis code, and absence of QT interval records, we identified patients taking dofetilide or sotalol among three groups: HFrEF (n = 138), HFpEF (n = 109), and no HF (n = 729). QT prolongation was defined as heart rate-corrected QT (QTc) > 500 ms during dofetilide/sotalol therapy. Unadjusted odds ratios (OR) for QT prolongation were determined by univariate analysis. Adjusted ORs were determined by generalized estimating equations (GEE) with logit link to account for an individual cluster with different times of hospitalization and covariates. QTc prolongation associated with dofetilide or sotalol occurred in 53.2%, 71.7% and 30.0% of patients with HFpEF, HFrEF, and patients with no HF, respectively. After adjusting for age, sex, race, serum potassium and magnesium concentrations, kidney function, concomitant drug therapy, and comorbid conditions, the adjusted odds of QTc prolongation were significantly higher in patients with HFpEF [OR = 1.98 (95% CI 1.17-3.33)], and in those with HFrEF [OR = 5.23, (3.15-8.67)], compared to those with no evidence of HF. The odds of QT prolongation among inpatients receiving dofetilide or sotalol were increased in patients with HFpEF and HFrEF compared to those who did not have HF.

Cellular heterogeneity of pluripotent stem cell-derived cardiomyocyte grafts is mechanistically linked to treatable arrhythmias.

Preclinical data have confirmed that human pluripotent stem cell-derived cardiomyocytes (PSC-CMs) can remuscularize the injured or diseased heart, with several clinical trials now in planning or recruitment stages. However, because ventricular arrhythmias represent a complication following engraftment of intramyocardially injected PSC-CMs, it is necessary to provide treatment strategies to control or prevent engraftment arrhythmias (EAs). Here, we show in a porcine model of myocardial infarction and PSC-CM transplantation that EAs are mechanistically linked to cellular heterogeneity in the input PSC-CM and resultant graft. Specifically, we identify atrial and pacemaker-like cardiomyocytes as culprit arrhythmogenic subpopulations. Two unique surface marker signatures, signal regulatory protein α (SIRPA)+CD90-CD200+ and SIRPA+CD90-CD200-, identify arrhythmogenic and non-arrhythmogenic cardiomyocytes, respectively. Our data suggest that modifications to current PSC-CM-production and/or PSC-CM-selection protocols could potentially prevent EAs. We further show that pharmacologic and interventional anti-arrhythmic strategies can control and potentially abolish these arrhythmias.