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.

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.

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.

Omega-3 Fatty Acids and Arrhythmias.

The pro- and antiarrhythmic effects of omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been extensively studied in preclinical and human trials. Despite early evidence of an antiarrhythmic role of n-3 PUFA in the prevention of sudden cardiac death and postoperative and persistent atrial fibrillation (AF), subsequent well-designed randomized trials have largely not shown an antiarrhythmic benefit. Two trials that tested moderate and high-dose n-3 PUFA demonstrated a reduction in sudden cardiac death, but these findings have not been widely replicated, and the potential of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to reduce arrhythmic death in combination, or as monotherapy, remains uncertain. The accumulated clinical evidence does not support supplementation of n-3 PUFA for postoperative AF or secondary prevention of AF. Several large, contemporary, randomized controlled trials of high-dose n-3 PUFA for primary or secondary cardiovascular prevention have demonstrated a small, significant, dose-dependent increased risk of incident AF compared with mineral oil or corn oil comparator. These findings were reproduced with both icosapent ethyl monotherapy and a mixed EPA+DHA formulation. The proarrhythmic mechanism of increased AF in contemporary cohorts exposed to high-dose n-3 PUFA is unknown. EPA and DHA and their metabolites have pleiotropic cardiometabolic and pro- and antiarrhythmic effects, including modification of the lipid raft microenvironment; alteration of cell membrane structure and fluidity; modulation of sodium, potassium, and calcium currents; and regulation of gene transcription, cell proliferation, and inflammation. Further characterization of the complex association between EPA, EPA+DHA, and DHA and AF is needed. Which formulations, dose ranges, and patient subgroups are at highest risk, remain unclear.

Digoxin is still useful, but is still causing toxicity.

Digoxin, the oldest known cardiovascular drug, is still used today to treat heart failure and atrial fibrillation. Because it has a narrow therapeutic index and multiple interactions, it frequently causes toxicity with a wide range of symptoms and cardiac arrhythmias. More importantly, elevated serum digoxin levels have been linked to a higher risk of death in patients with heart failure or atrial fibrillation, even without signs or symptoms of toxicity. This article reviews the current state of digoxin use, its pharmacologic principles, and the mechanisms, clinical presentation, and management of toxicity.

General anaesthesia compared to conscious sedation for first-time atrial fibrillation catheter ablation-a Danish nationwide cohort study.

AIMS: Catheter ablation (CA) is a well-established treatment option for atrial fibrillation (AF), where sedation and analgesia are pivotal for patient comfort and lesion formation. The impact of anaesthesia type on AF recurrence rates remains uncertain. This study aimed to examine AF recurrence rates depending on conscious sedation (CS) vs. general anaesthesia (GA) during CA. METHODS AND RESULTS: Utilizing nationwide data from the Danish healthcare registries, we conducted this cohort study involving adults (≥18 years) undergoing first-time CA for AF between 2010 and 2018. Patients were categorized by anaesthesia type (CS or GA), with the primary endpoint being AF recurrence, defined by a composite endpoint of either antiarrhythmic drug (AAD) prescriptions, AF-related hospital admissions, electrical cardioversions, or AF re-ablation. The impact of anaesthesia type was evaluated using multivariable Cox proportional hazards analysis. The study cohort comprised 7957 (6421 CS and 1536 GA) patients. Persistent AF, hypertension, and heart failure, as well as use of AAD, were more prevalent in the GA group. Cumulative incidences of recurrent AF were higher in the CS group at 1 (46% vs. 37%) and at 5 (68% vs. 63%) years. Multivariate analysis revealed CS as significantly associated with increased risk of AF recurrence at 5-year follow-up [hazard ratio 1.26 (95% confidence interval 1.15-1.38)], consistent across paroxysmal and persistent AF subtypes. CONCLUSION: This nationwide cohort study suggests a higher risk of AF recurrence with CS during CA compared to GA. These results advocate for considering GA as the preferred anaesthesia type for improved CA outcomes.

Effect of Obesity on the Use of Antiarrhythmics in Adults With Atrial Fibrillation: A Narrative Review.

BACKGROUND: Atrial fibrillation (AF) and obesity coexist in approximately 37.6 million and 650 million people globally, respectively. The anatomical and physiological changes in individuals with obesity may influence the pharmacokinetic properties of drugs. AIM: This review aimed to describe the evidence of the effect of obesity on the pharmacokinetics of antiarrhythmics in people with AF. METHODS: Three databases were searched from inception to June 2023. Original studies that addressed the use of antiarrhythmics in adults with AF and concomitant obesity were included. RESULTS: A total of 4549 de-duplicated articles were screened, and 114 articles underwent full-text review. Ten studies were included in this narrative synthesis: seven cohort studies, two pharmacokinetic studies, and a single case report. Samples ranged from 1 to 371 participants, predominately males (41%-85%), aged 59-75 years, with a body mass index (BMI) of 23-66 kg/m2. The two most frequently investigated antiarrhythmics were amiodarone and dofetilide. Other drugs investigated included diltiazem, flecainide, disopyramide, propafenone, dronedarone, sotalol, vernakalant, and ibutilide. Findings indicate that obesity may affect the pharmacokinetics of amiodarone and sodium channel blockers (e.g., flecainide, disopyramide, and propafenone). Factors such as drug lipophilicity may also influence the pharmacokinetics of the drug and the need for dose modification. DISCUSSION: Antiarrhythmics are not uniformly affected by obesity. This observation is based on heterogeneous studies of participants with an average BMI and poorly controlled confounding factors such as multimorbidity, concomitant medications, varying routes of administration, and assessment of obesity. Controlled trials with stratification at the time of recruitment for obesity are necessary to determine the significance of these findings.

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.

Stem cell models of inherited arrhythmias.

Inherited arrhythmias are a heterogeneous group of conditions that confer risk of sudden death. Many inherited arrhythmias have been linked to pathogenic genetic variants that result in ion channel dysfunction, although current genetic testing panels fail to identify variants in many patients, potentially secondary to their underlying substrates being oligogenic or polygenic. Here we review the current state of knowledge surrounding the cellular mechanisms of inherited arrhythmias generated from stem cell models with a focus on integrating genetic and mechanistic data. The utility and limitations of human induced pluripotent stem cell models in disease modeling and drug development are also explored with a particular focus on examples of pharmacogenetics and precision medicine. We submit that progress in understanding inherited arrhythmias is likely to be made by using human induced pluripotent stem cells to model probable polygenic cases as well as to interrogate the diverse and potentially complex molecular networks implicated by genome-wide association studies.

Evaluation of the management of a first crisis of atrial fibrillation in a group of Cameroon's urban setting subjects.

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice. When atrial fibrillation is first diagnosed, it tends to be permanent and associated with significant morbidity and mortality. We aimed to study the management of a first episode of atrial fibrillation in a group of patients in Yaounde, Cameroon. METHODS: We conducted a retrospective study with data collected from the Cardiology department of Yaounde Central Hospital and the internal medicine department of Yaounde General Hospital over five years (January 2017 to December 2021), for a duration of 4 months, from February 2022 to May 2022. All patients older than 15 years with a first episode of atrial fibrillation were included, and all patients with incomplete medical records were excluded. The association between different variables was assessed using a χ² test and logistic regression method with a significance threshold of p < 0.05. RESULTS: Of the 141 patients recruited, the mean age was 68.5 ± 10.6 years. The sex ratio (M/F) was 0.7. The main associated factors and co-morbidities were hypertension in 70.2% (99) patients, heart failure in 36.9% (52) patients and a sedentary lifestyle in 33.3% (47) patients. The most common anticoagulant treatment was AntiVitamin K, used in 64.5% (91) of patients. Heart rate control was the most commonly used symptom control strategy in 85.1% (120) patients, mainly with beta-blockers in 52.5% (74). We found 1.4% (2) participants who were not treated with antithrombotics as recommended. Treatment of arrhythmia due to co-morbidities was not always recommended. The complication rate was 94.3% (133) patients. Control of the bleeding risk due to antithrombotic therapy and monitoring of anticoagulant therapy were not optimal. The heart rate control strategy had a higher success rate, and the sinus rhythm maintenance rate at one year was 61.7% (37) participants. CONCLUSION: The management of a first episode of atrial fibrillation at Yaoundé's Central and General Hospitals is not always performed according to current recommendations and is far from optimal. However, nearly two out of three patients maintained sinus rhythm for one year.

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.

Insights into the prospects of nanobiomaterials in the treatment of cardiac arrhythmia.

Cardiac arrhythmia, a disorder of abnormal electrical activity of the heart that disturbs the rhythm of the heart, thereby affecting its normal function, is one of the leading causes of death from heart disease worldwide and causes millions of deaths each year. Currently, treatments for arrhythmia include drug therapy, radiofrequency ablation, cardiovascular implantable electronic devices (CIEDs), including pacemakers, defibrillators, and cardiac resynchronization therapy (CRT). However, these traditional treatments have several limitations, such as the side effects of medication, the risks of device implantation, and the complications of invasive surgery. Nanotechnology and nanomaterials provide safer, effective and crucial treatments to improve the quality of life of patients with cardiac arrhythmia. The large specific surface area, controlled physical and chemical properties, and good biocompatibility of nanobiomaterials make them promising for a wide range of applications, such as cardiovascular drug delivery, tissue engineering, and the diagnosis and therapeutic treatment of diseases. However, issues related to the genotoxicity, cytotoxicity and immunogenicity of nanomaterials remain and require careful consideration. In this review, we first provide a brief overview of cardiac electrophysiology, arrhythmia and current treatments for arrhythmia and discuss the potential applications of nanobiomaterials before focusing on the promising applications of nanobiomaterials in drug delivery and cardiac tissue repair. An in-depth study of the application of nanobiomaterials is expected to provide safer and more effective therapeutic options for patients with cardiac arrhythmia, thereby improving their quality of life.

Body Surface Potential Mapping during Atrial Depolarization in Rats with Post-Infarction Chronic Heart Failure against the Background of Fabomotizole Therapy.

Cardiac remodeling in rats with post-infarction chronic heart failure caused by anterior transmural myocardial infarction leads to an atypical location of areas of positive and negative cardioelectric potentials on the body surface before the onset of the PII-wave on the ECG in the limb leads, which is a sign of increased heterogeneity of atrial depolarization associated with the appearance of additional excitation focus in the left atrium. A course of therapy with fabomotizole leads to a decrease in the heterogeneity of atrial depolarization at the initial stages of the formation of the cardioelectric field of the atria on the body surface before the onset of the PII-wave, thereby producing an antiarrhythmic effect.