In vivo tebuconazole administration impairs heart electrical function and facilitates the occurrence of dobutamine-induced arrhythmias: involvement of reactive oxygen species.

Tebuconazole (TEB), a widely used pesticide in agriculture to combat fungal infections, is commonly detected in global food, potable water, groundwater, and human urine samples. Despite its known in vivo toxicity, its impact on heart function remains unclear. In a 28-day study on male Wistar rats (approximately 100 g), administering 10 mg/kg/day TEB or a vehicle (control) revealed no effect on body weight gain or heart weight, but an increase in the infarct area in TEB-treated animals. Notably, TEB induced time-dependent changes in in vivo electrocardiograms, particularly prolonging the QT interval after 28 days of administration. Isolated left ventricular cardiomyocytes exposed to TEB exhibited lengthened action potentials and reduced transient outward potassium current. TEB also increased reactive oxygen species (ROS) production in these cardiomyocytes, a phenomenon reversed by N-acetylcysteine (NAC). Furthermore, TEB-treated animals, when subjected to an in vivo dobutamine (Dob) and caffeine (Caf) challenge, displayed heightened susceptibility to severe arrhythmias, a phenotype prevented by NAC. In conclusion, TEB at the no observed adverse effect level (NOAEL) dose adversely affects heart electrical function, increases arrhythmic susceptibility, partially through ROS overproduction, and this phenotype is reversible by scavenging ROS with NAC.

Efficacy and safety of ciprofol versus propofol for anesthesia induction in adult patients received elective surgeries: a meta­analysis.

BACKGROUND: Propofol is use widely used in anesthesia, known for its effectiveness, may lead to cardiopulmonary issues in some patients. Ciprofol has emerged as a possible alternative to propofol because it can achieve comparable effects to propofol while causing fewer adverse events at lower doses. However, no definitive conclusion has been reached yet. This meta-analysis aimed to evaluate the efficacy and safety of ciprofol versus propofol in adult patients undergoing elective surgeries under general anesthesia. METHODS: We searched PubMed, EMBASE, the Cochrane library, Web of Science, and Chinese National Knowledge Infrastructure (CNKI) to identify potentially eligible randomized controlled trials (RCT) comparing ciprofol with propofol in general anesthesia until September 30, 2023. The efficacy outcomes encompassed induction success rate, time to onset of successful induction, time to disappearance of eyelash reflex, and overall estimate means in Bispectral Index (BIS). Safety outcomes were assessed through time to full alertness, incidence of hypotension, incidence of arrhythmia, and incidence of injection-site pain. Continuous variables were expressed as mean difference (MD) with 95% confidence interval (CI), and dichotomous variables were expressed as risk ratio (RR) with 95% CI. Statistical analyses were performed using RevMan 5.4 and STATA 14.0. The quality of the evidence was rated through the grading of recommendations, assessment, development and evaluation (GRADE) system. RESULTS: A total of 712 patients from 6 RCTs were analyzed. Meta-analysis suggested that ciprofol was equivalent to propofol in terms of successful induction rate, time to onset of successful induction, time to disappearance of eyelash reflex, time to full alertness, and incidence of arrhythmia, while ciprofol was better than propofol in overall estimated mean in BIS (MD: -3.79, 95% CI: -4.57 to -3.01, p < 0.001), incidence of hypotension (RR: 0.63, 95% CI: 0.42 to 0.94, p = 0.02), and incidence of injection-site pain (RR: 0.26, 95% CI: 0.14 to 0.47, p < 0.001). All results were supported by moderate to high evidence. CONCLUSIONS: Ciprofol may be a promising alternative to propofol because it facilitates achieving a satisfactory anesthesia depth and results in fewer hypotension and injection-site pain. However, we still recommend conducting more studies with large-scale studies to validate our findings because only limited data were accumulated in this study. TRIAL REGISTRATION: PROSPERO 2023 CRD42023479767.

Protective effect of ginsenoside Rb1 against aconitine cardiotoxicity studied by myocardial injury, action potential, and calcium signaling.

Aconitine is the main active component of Aconitum plants. Although aconitine has effects that include strengthening the heart, analgesia, anti-tumor, and immune-regulating effects, aconitine has both efficacy and toxicity, especially cardiotoxicity. Severe effects can include arrhythmia and cardiac arrest, which limits the clinical application of aconitine-containing traditional Chinese medicine. Ginsenoside Rb1(Rb1) is mainly found in plants, such as ginseng and Panax notoginseng, and has cardiovascular-protective and anti-arrhythmia effects. This study aimed to investigate the detoxifying effects of Rb1 on aconitine cardiotoxicity and the electrophysiological effect of Rb1 on aconitine-induced arrhythmia in rats. Pathological analysis, myocardial enzymatic indexes, and Western blotting were used to investigate the ameliorating effect of Rb1 on aconitine cardiotoxicity. Optical mapping was used to evaluate the effect of Rb1 on action potential and calcium signaling after aconitine-induced arrhythmia. Rb1 inhibited pathological damage caused by aconitine, decreased myocardial enzyme levels, and restored the balance of apoptotic protein expression by reducing the expression of Bax and cleaved caspase 3 and increasing the expression of Bcl-2, thereby reducing myocardial damage caused by aconitine. Rb1 also reduced the increase in heart rate caused by aconitine, accelerated action potential conduction and calcium signaling, and reduced the dispersion of action potential and calcium signal conduction. Rb1 reduced the cardiotoxicity of aconitine by attenuating aconitine-induced myocardial injury and inhibiting the aconitine-induced retardation of ventricular action potential and calcium signaling in rats.

A case of digoxin intoxication caused by short-term massive overdose: Case report.

RATIONALE: Digoxin is a frequently prescribed medication for the management of both acute and chronic cardiac insufficiency. The overdose ingestion of digoxin can result in a range of arrhythmias, with severe cases potentially leading to malignant arrhythmias and fatal outcomes. To date, there is a lack of documented cases related to acute digoxin intoxication resulting from the administration of massive digoxin overdose in the short term. PATIENT CONCERNS: A 37-year-old female patient was admitted to the emergency department following a suicide attempt involving the administration of 330 tablets of digoxin (each tablet containing 0.25 mg). The patient exhibited symptoms of confusion, nausea, and vomiting for around 30 minutes. The patient had a history of depression. DIAGNOSES: The patient was diagnosed with digoxin intoxication. INTERVENTIONS: The patient underwent many medical interventions including stomach lavage, administration of laxatives, correction of cardiac arrhythmias, provision of myocardial nutrition, diuresis, correction of acid-base balance, and management of electrolyte disturbances, among others. OUTCOMES: Following a treatment of 9 days, the patient exhibited no signs of discomfort, maintained consciousness, and the serum concentration of digoxin was indeterminable. Upon reevaluation of the electrocardiogram, it was determined that no arrhythmia was present. Consequently, the patient was authorized to be discharged from the hospital. CONCLUSIONS: There is currently no documented evidence of cases involving a significant overdose of digoxin resulting in intoxication. The patient had a comprehensive treatment regimen consisting of stomach lavage, administration of a laxative, correction of cardiac arrhythmias, provision of myocardial nutrition, fluid replacement, diuresis, and supportive therapy, resulting in successful outcomes. LESSONS: There have been no known cases of intoxication resulting from a significant overdose of digoxin, specifically with the consumption of 330 tablets (0.25 mg/tablet). However, in the event of ingesting excessive amounts of digoxin, it is imperative to promptly administer stomach lavage, administration of a laxative, and arrhythmia correction. The administration of temporary pacemaker therapy is recommended for patients presenting with high atrioventricular block, whereas hemoperfusion is advised for patients with renal insufficiency as a means to eliminate digoxin from the body.

Major cardiovascular adverse events in older adults with early-stage triple-negative breast cancer treated with adjuvant taxane + anthracycline versus taxane-based chemotherapy regimens: A SEER-medicare study.

BACKGROUND: Triple-negative breast cancer (TNBC) is more aggressive as compared to other subtypes of breast cancer with characteristic metastatic patterns and a poor prognosis. The standard of care for early-stage TNBC is historically anthracycline and taxane-based chemotherapy (ATAX). Despite the effectiveness of this regimen, anthracyclines carry a small but important risk of cardiotoxicity, which is specifically a concern in the older population. This study evaluates major adverse cardiovascular events (MACE) in older women with TNBC treated with ATAX compared to taxane-based chemotherapy (TAX). METHODS: Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, we identified women aged 66 and older with TNBC diagnosed between 2010 and 2015 (N = 2215). We compared patient and clinical characteristics according to adjuvant chemotherapy regimen (chemotherapy versus no chemotherapy and ATAX versus TAX). Logistic regression was performed to estimate the odds ratios (OR) and 95% confidence intervals (CIs), Kaplan-Meier survival curves were generated to estimate three-year overall survival (OS) and cancer specific survival (CSS). Cox proportional hazards models were used to analyze OS and CSS while controlling for patient and tumor characteristics. MACE was defined as acute myocardial infarction, heart failure, potentially fatal arrhythmia, and cerebral vascular incidence. Few patients experienced a cardiac death and therefore this was excluded in the analysis. RESULTS: Of the 2215 patients in our cohort, most patients (n = 1334; 60.26%) received TAX compared to ATAX (n = 881; 39.78%). Patients who received ATAX were not statistically significantly more likely than those who received TAX to experience acute myocardial infarction, cerebral vascular accident (CVA), or potentially fatal arrhythmia when controlling for traditional risk factors. Among patients who experienced MACE, there was no difference in OS or CSS in patients who received TAX vs ATAX. Patients who received ATAX were less likely to develop heart failure than those who received TAX (OR 0.63, 95% CI [0.45-0.88], p < 0.01). Patients who developed MACE and who were > 76 years old had worse OS compared to those who experienced MACE and were age 66-75 years old (HR 1.67, 95% CI [1.07-2.62], p = 0.02). CONCLUSION: Among older women with TNBC, receipt of adjuvant chemotherapy with ATAX was not associated with increased risk of major adverse cardiac events. For those who experienced a cardiac event, there was no difference in survival amongst those who received TAX vs ATAX. Other factors including additional chemotherapy toxicities should be investigated as a potential etiology for the inferior OS previously observed with ATAX vs TAX in older women with node negative or 1-3 positive lymph nodes.

The Detrimental Effect of Pre-Treatment with Ivermectin on Myocardial Ischemia.

INTRODUCTION: Ivermectin (IVM) is a broad-spectrum anti-parasitic agent with potential antibacterial, antiviral, and anti-cancer effects. There are limited studies on the effects of IVM on cardiovascular diseases, so the present study sought to determine the effects of pre-treatment with IVM on myocardial ischemia in both ex vivo and in vivo. METHODS: In the ex vivo part, two groups of control and treated rats with IVM (0.2 mg/kg) were examined for cardiac function and arrhythmias by isolated heart perfusion. In the in vivo part, four groups, namely, control, IVM, Iso (MI), and Iso + IVM 0.2 mg/kg were used. Subcutaneous injection of isoproterenol (100 mg/kg/day) for 2 consecutive days was used for the induction of myocardial infarction (MI) in male Wistar rats. Then electrocardiogram, hemodynamic factors, cardiac hypertrophy, and malondialdehyde (MDA) levels were investigated. RESULTS: The ex vivo results showed that administration of IVM induces cardiac arrhythmia and decreases the left ventricular maximal rate of pressure increase (contractility) and maximal rate of pressure decline (relaxation). The isoproterenol-induced MI model used as an in vivo model showed that cardiac hypertrophy were increased with no improvement in the hemodynamic and electrocardiogram pattern in the IVM-treated group in comparison to MI (Iso) group. However, the MDA level was lower in the IVM-treated group. CONCLUSION: IVM pre-treatment demonstrates detrimental effects in cardiac ischemia through exacerbation of cardiac arrhythmia, myocardial dysfunction, and increased cardiac hypertrophy. Therefore, the use of IVM in ischemic heart patients should be done with great caution.

Recurrent malignant ventricular arrhythmias and paresthesia-a mystery revealed as aconitine poisoning: a case report.

BACKGROUND: We report a case of a clinical challenge lasting for 12 months, with severe and unresolved clinical features involving several medical disciplines. CASE PRESENTATION: A 53-year-old Caucasian male, who had been previously healthy apart from a moderate renal impairment, was hospitalized 12 times during a 1-year period for a recurrent complex of neurological, cardiovascular, and gastrointestinal symptoms and signs, without any apparent etiology. On two occasions, he suffered a cardiac arrest and was successfully resuscitated. Following the first cardiac arrest, a cardiac defibrillator was inserted. During the 12th admission to our hospital, aconitine poisoning was suspected after a comprehensive multidisciplinary evaluation and confirmed by serum and urine analyses. Later, aconitine was also detected in a hair segment, indicating exposure within the symptomatic period. After the diagnosis was made, no further episodes occurred. His cardiac defibrillator was later removed, and he returned to work. A former diagnosis of epilepsy was also abandoned. Criminal intent was suspected, and his wife was sentenced to 11 years in prison for attempted murder. To make standardized assessments of the probability for aconitine poisoning as the cause of the eleven prior admissions, an "aconitine score" was established. The score is based on neurological, cardiovascular, gastrointestinal, and other clinical features reported in the literature. We also make a case for the use of hair analysis to confirm suspected poisoning cases evaluated after the resolution of clinical features. CONCLUSION: This report illustrates the medical challenge raised by cases of covert poisoning. In patients presenting with symptoms and signs from several organ systems without apparent cause, poisoning should always be suspected. To solve such cases, insight into the effects of specific toxic agents is needed. We present an "aconitine score" that may be useful in cases of suspected aconitine poisoning.

Synthesis and In Vivo Antiarrhythmic Activity Evaluation of Novel Scutellarein Analogues as Voltage-Gated Nav1.5 and Cav1.2 Channels Blockers.

Malignant cardiac arrhythmias with high morbidity and mortality have posed a significant threat to our human health. Scutellarein, a metabolite of Scutellarin which is isolated from Scutellaria altissima L., presents excellent therapeutic effects on cardiovascular diseases and could further be metabolized into methylated forms. A series of 22 new scutellarein derivatives with hydroxyl-substitution based on the scutellarin metabolite in vivo was designed, synthesized via the conjugation of the scutellarein scaffold with pharmacophores of FDA-approved antiarrhythmic medications and evaluated for their antiarrhythmic activity through the analyzation of the rat number of arrhythmia recovery, corresponding to the recovery time and maintenance time in the rat model of barium chloride-induced arrhythmia, as well as the cumulative dosage of aconitine required to induce VP, VT, VF and CA in the rat model of aconitine-induced arrhythmia. All designed compounds could shorten the time of the arrhythmia continuum induced by barium chloride, indicating that 4'-hydroxy substituents of scutellarein had rapid-onset antiarrhythmic effects. In addition, nearly all of the compounds could normalize the HR, RR, QRS, QT and QTc interval, as well as the P/T waves' amplitude. The most promising compound 10e showed the best antiarrhythmic activity with long-term efficacy and extremely low cytotoxicity, better than the positive control scutellarein. This result was also approved by the computational docking simulation. Most importantly, patch clamp measurements on Nav1.5 and Cav1.2 channels indicated that compound 10e was able to reduce the INa and ICa in a concentration-dependent manner and left-shifted the inactivation curve of Nav1.5. Taken together, all compounds were considered to be antiarrhythmic. Compound 10e even showed no proarrhythmic effect and could be classified as Ib Vaughan Williams antiarrhythmic agents. What is more, compound 10e did not block the hERG potassium channel which highly associated with cardiotoxicity.

Nitric Oxide Modulates Ca2+ Leak and Arrhythmias via S-Nitrosylation of CaMKII.

BACKGROUND: Nitric oxide (NO) has been identified as a signaling molecule generated during ß-adrenergic receptor stimulation in the heart. Furthermore, a role for NO in triggering spontaneous Ca2+ release via S-nitrosylation of CaMKIIδ (Ca2+/calmodulin kinase II delta) is emerging. NO donors are routinely used clinically for their cardioprotective effects on the heart, but it is unknown how NO donors modulate the proarrhythmic CaMKII to alter cardiac arrhythmia incidence. We test the role of S-nitrosylation of CaMKIIδ at the Cysteine-273 inhibitory site and cysteine-290 activating site in cardiac Ca2+ handling and arrhythmogenesis before and during ß-adrenergic receptor stimulation. METHODS: We measured Ca2+-handling in isolated cardiomyocytes from C57BL/6J wild-type (WT) mice and mice lacking CaMKIIδ expression (CaMKIIδ-KO) or with deletion of the S-nitrosylation site on CaMKIIδ at cysteine-273 or cysteine-290 (CaMKIIδ-C273S and -C290A knock-in mice). Cardiomyocytes were exposed to NO donors, S-nitrosoglutathione (GSNO; 150 µM), sodium nitroprusside (200 µM), and ß-adrenergic agonist isoproterenol (100 nmol/L). RESULTS: Both WT and CaMKIIδ-KO cardiomyocytes responded to isoproterenol with a full inotropic and lusitropic Ca2+ transient response as well as increased Ca2+ spark frequency. However, the increase in Ca2+ spark frequency was significantly attenuated in CaMKIIδ-KO cardiomyocytes. The protection from isoproterenol-induced Ca2+ sparks and waves was mimicked by GSNO pretreatment in WT cardiomyocytes but lost in CaMKIIδ-C273S cardiomyocytes. When GSNO was applied after isoproterenol, this protection was not observed in WT or CaMKIIδ-C273S but was apparent in CaMKIIδ-C290A. In Langendorff-perfused isolated hearts, GSNO pretreatment limited isoproterenol-induced arrhythmias in WT but not CaMKIIδ-C273S hearts, while GSNO exposure after isoproterenol sustained or exacerbated arrhythmic events. CONCLUSIONS: We conclude that prior S-nitrosylation of CaMKIIδ at cysteine-273 can limit subsequent ß-adrenergic receptor-induced arrhythmias, but that S-nitrosylation at cysteine-290 might worsen or sustain ß-adrenergic receptor-induced arrhythmias. This has important implications for the administration of NO donors in the clinical setting.

Facilitation of hERG Activation by Its Blocker: A Mechanism to Reduce Drug-Induced Proarrhythmic Risk.

Modulation of the human Ether-à-go-go-Related Gene (hERG) channel, a crucial voltage-gated potassium channel in the repolarization of action potentials in ventricular myocytes of the heart, has significant implications on cardiac electrophysiology and can be either antiarrhythmic or proarrhythmic. For example, hERG channel blockade is a leading cause of long QT syndrome and potentially life-threatening arrhythmias, such as torsades de pointes. Conversely, hERG channel blockade is the mechanism of action of Class III antiarrhythmic agents in terminating ventricular tachycardia and fibrillation. In recent years, it has been recognized that less proarrhythmic hERG blockers with clinical potential or Class III antiarrhythmic agents exhibit, in addition to their hERG-blocking activity, a second action that facilitates the voltage-dependent activation of the hERG channel. This facilitation is believed to reduce the proarrhythmic potential by supporting the final repolarizing of action potentials. This review covers the pharmacological characteristics of hERG blockers/facilitators, the molecular mechanisms underlying facilitation, and their clinical significance, as well as unresolved issues and requirements for research in the fields of ion channel pharmacology and drug-induced arrhythmias.

Anthracyclines and the risk of arrhythmias: A systematic review and meta-analysis.

BACKGROUND: There have been controversial findings from recent studies regarding anthracyclines use and the subsequent risk of arrhythmias. This study aimed to evaluate the existing evidence of the risk of arrhythmias in patients treated with anthracyclines. METHODS: PubMed, Scopus, and Web of Science databases were searched up to April 2022 using keywords such as "anthracycline" and "arrhythmia." Dichotomous data were presented as relative risk (RR) and confidence interval (CI), while continuous data were presented as mean difference (MD) and CI. Revman software version 5.4 was used for the analysis. RESULTS: Thirteen studies were included with a total of 26891 subjects. Pooled analysis showed that anthracyclines therapy was significantly associated with a higher risk of arrhythmia (RR: 1.58; 95% CI: 1.41-1.76; P < .00001), ST segment and T wave abnormalities (RR: 1.73, 95% CI: 1.18-2.55, P = .005), conduction abnormalities and AV block (RR = 1.86, 95% CI = 1.06-3.25, P = .03), and tachycardia (RR: 1.736, 95% CI: 1.11-2.69, P = .02). Further analyses of the associations between anthracyclines and atrial flutter (RR = 1.30, 95% CI = 0.29-5.89, P = .74), atrial ectopic beats (RR: 1.27, 95% CI: 0.78-2.05, P = .34), and ventricular ectopic beats (RR: 0.93, 95% CI: 0.53-1.65, P = .81) showed no statistically significant results. Higher doses of anthracycline were associated with a higher risk of arrhythmias (RR: 1.49; 95% CI: 1.08-2.05; P = .02) compared to the lower doses (RR: 1.36; 95% CI: 1.00-1.85; P = .05). Newer generations of Anthracycline maintained the arrhythmogenic properties of previous generations, such as Doxorubicin. CONCLUSION: Anthracyclines therapy was significantly associated with an increased risk of arrhythmias. Accordingly, Patients treated with anthracyclines should be screened for ECG abnormalities and these drugs should be avoided in patients susceptible to arrhythmia. The potential benefit of the administration of prophylactic anti-fibrotic and anti-arrhythmic drugs should also be explored.

Bevacizumab-induced arrhythmia in a patient with lung adenocarcinoma: A case report.

RATIONALE: Cardiotoxicity is an important side effect of vascular endothelial growth factor inhibitors therapy in the treatment of cancer. Massive studies have shown bevacizumab-related hypertension, venous, and arterial thrombosis. PATIENT CONCERNS: A 56-year-old female patient was treated with bevacizumab monotherapy for lung adenocarcinoma. The patient was detected a poor R-wave increase with slight ST segment elevation in V1-V3 leads, and ventricular arrhythmia. DIAGNOSIS: The incidental arrhythmia caused by bevacizumab was considered. INTERVENTIONS: The patients received aspirin and amiodarone (0.2 g tid) to treat arrhythmia. After consultation with the cardiology department, the patient received a diagnostic coronary angiography. Coronary angiography showed 30% of the right coronary artery stenoses and no obvious organic stenosis in the left main artery, left anterior ascending, or left circumflex. OUTCOMES: The patient exhibited disappearance of chest tightness and rapid heartbeat after the treatment of amiodarone. Electrocardiogram monitoring results returning to normal. LESSONS: This is the first reported case of bevacizumab-associated arrhythmia. It is advisable to consider the risk of arrhythmia in bevacizumab monotherapy or combines treatment.

COVID-19 Vaccination and Cardiac Arrhythmias: A Review.

PURPOSE OF REVIEW: In this review, we aim to delve into the existing literature, seeking to uncover the mechanisms, investigate the electrocardiographic changes, and examine the treatment methods of various cardiac arrhythmias that occur after administration of the COVID-19 vaccine. RECENT FINDINGS: A global survey has exposed an incidence of arrhythmia in 18.27% of hospitalized COVID-19 patients. Furthermore, any type of COVID-19 vaccine - be it mRNA, adenovirus vector, whole inactivated, or protein subunit - appears to instigate cardiac arrhythmias. Among the cardiac adverse events reported post-COVID-19 vaccination, myocarditis emerges as the most common and is thought to be a potential cause of bradyarrhythmia. When a patient post-COVID-19 vaccination presents a suspicion of cardiac involvement, clinicians should perform a comprehensive history and physical examination, measure electrolyte levels, conduct ECG, and carry out necessary imaging studies. In our extensive literature search, we uncovered various potential mechanisms that might lead to cardiac conduction abnormalities and autonomic dysfunction in patients who have received the COVID-19 vaccine. These mechanisms encompass direct viral invasion through molecular mimicry/spike (S) protein production, an escalated inflammatory response, hypoxia, myocardial cell death, and the eventual scar/fibrosis. They correspond to a range of conditions including atrial tachyarrhythmias, bradyarrhythmia, ventricular arrhythmias, sudden cardiac death, and the frequently occurring myocarditis. For treating these COVID-19 vaccination-induced arrhythmias, we should incorporate general treatment strategies, similar to those applied to arrhythmias from other causes.

d-Limonene complexed with cyclodextrin attenuates cardiac arrhythmias in an experimental model of doxorubicin-induced cardiotoxicity: Possible involvement of calcium/calmodulin-dependent protein kinase type II.

BACKGROUND: Arrhythmias are one manifestation of the cardiotoxicity that results from doxorubicin (Doxo) administration. Although cardiotoxicity is an anticipated outcome in anticancer therapies, there is still a lack of treatment options available for its effective management. This study sought to evaluate the possible cardioprotective effect of complex d-limonene (DL) plus hydroxypropyl-ß-cyclodextrin (HßDL) during treatment with Doxo, focusing on the arrhythmic feature. METHODS: Cardiotoxicity was induced in Swiss mice with Doxo 20 mg/kg, with 10 mg/kg of HßDL being administered 30 min before the Doxo. Plasma CK-MB and LDH levels were analyzed. Cellular excitability and susceptibility to cardiac and cardiomyocyte arrhythmias were evaluated using in vivo (pharmacological cardiac stress) and in vitro (burst pacing) ECG protocols. Ca2+ dynamics were also investigated. The expression of CaMKII and its activation by phosphorylation and oxidation were evaluated by western blot, and molecular docking was used to analyze the possible interaction between DL and CaMKII. RESULTS: Electrocardiograms showed that administration of 10 mg/kg of HßDL prevented Doxo-induced widening of the QRS complex and QT interval. HßDL also prevented cardiomyocyte electrophysiological changes that trigger cellular arrhythmias, such as increases in action potential duration and variability; decreased the occurrence of delayed afterdepolarizations (DADs) and triggered activities (TAs), and reduced the incidence of arrhythmia in vivo. Ca2+ waves and CaMKII overactivation caused by phosphorylation and oxidation were also decreased. In the in silico study, DL showed potential inhibitory interaction with CaMKII. CONCLUSION: Our results show that 10 mg/kg of ßDL protects the heart against Doxo-induced cardiotoxicity arrhythmias, and that this is probably due to its inhibitory effect on CaMKII hyperactivation.

Clinical and electrocardiographic factors associated with adverse cardiovascular events in bupropion exposures.

INTRODUCTION: Bupropion toxicity can cause cardiogenic shock, ventricular dysrhythmias, and death. Clinical and electrocardiographic factors associated with adverse cardiovascular events in bupropion toxicity have not been well-studied. This study aimed to identify factors associated with adverse cardiovascular events in adult patients with isolated bupropion exposures. METHODS: This retrospective cohort study queried the National Poison Data System from 2019 through 2020. We included patients 20 years or older with acute or acute-on-chronic single-agent bupropion exposures evaluated in a healthcare facility. Exclusion criteria were confirmed non-exposure, withdrawal as a reason for exposure, lack of follow-up, documentation that exposure was probably not responsible for the effects, and missing data. The primary outcome was adverse cardiovascular events, defined as the presence of any of the following: vasopressor use, ventricular dysrhythmia, myocardial injury, or cardiac arrest. Independent variables were age, the intentionality of exposure, seizures, tachycardia, QRS widening, and QTc prolongation. Multivariable logistic regression was performed to test for independent associations between independent variables and adverse cardiovascular events. RESULTS: Of 4,640 patients included in the final analysis (56.7% female, 56.5% suspected suicidal intent), 68 (1.47%) experienced an adverse cardiovascular event. Age (odds ratio 1.03; 95% confidence intervals 1.02-1.05), single seizure (odds ratio 9.18; 95% confidence intervals 4.24-19.9) and complicated seizures (odds ratio 38.9; 95% confidence intervals 19.3-78.1), QRS widening (odds ratio 3.01; 95% confidence intervals 1.62-5.59), and QTc prolongation (odds ratio 1.76; 95% confidence intervals 1.00-3.10) were independently associated with adverse cardiovascular events. No patients with unintentional exposure experienced adverse cardiovascular events, prohibiting intentionality from inclusion in the regression model. In the post hoc subgroup analysis of intentional exposures, age, single and complicated seizures, and QRS widening remained independently associated with adverse cardiovascular events. CONCLUSIONS: Increasing age, seizures, QRS widening, and QTc prolongation were associated with adverse cardiovascular events in bupropion exposures. Adverse cardiovascular events did not occur in unintentional exposures. Further research is needed to develop screening tools and treatments for bupropion cardiotoxicity.

Cardiac arrhythmias associated with anaplastic lymphoma kinase (ALK) inhibitors: an analysis of the FDA Adverse Event Reporting System (FAERS).

BACKGROUND: Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) may provoke cardiac arrhythmias. We conducted this pharmacovigilance analysis to research cardiac arrhythmias associated with ALK-TKIs using the Food and Drug Administration Adverse Event Reporting System (FAERS). RESEARCH DESIGN AND METHODS: The first ALK-TKI, named crizotinib, was approved by the Food and Drug Administration (FDA) on 26 August 2011 for the treatment of ALK-rearranged non-small cell lung cancer (NSCLC). We evaluated ALK-TKIs-induced cardiac arrhythmias, by using the reporting odds ratio (ROR) and information component (IC) for mining the adverse event report signals in the FAERS database between January 2016 and June 2022. RESULTS: We identified a total of 362 ALK-TKIs-related cardiac arrhythmia reports which appeared to influence more men (64.44%) than women (30.76%), with a median age of 68 (interquartile range [IQR] 7-74) years. Compared with the full database, ALK-TKIs were detected with pharmacovigilance of cardiac arrhythmias (ROR025 = 1.26, IC025 = 0.26). Crizotinib and alectinib were found to be related to higher reporting of arrhythmias. The median time to onset (TTO) among five ALK-TKI therapies was significantly different (p = 0.044). CONCLUSION: ALK-TKIs present different frequencies of cardiac arrhythmias reporting, with only crizotinib and alectinib producing positive signals in high-level group term (HLGT) level arrhythmia. The time interval between the initial of drug treatment to the onset of arrhythmia varies greatly and cannot be predicted.

Index of cardiac-electrophysiological balance in relapsing-remitting multiple sclerosis patients treated with fingolimod.

BACKGROUND: Fingolimod is indicated for the treatment of relapsing-remitting multiple sclerosis (RRMS) and also targets cardiovascular system due to receptors on cardiomyocytes. Results of previous studies are controversial for the effect of fingolimod in terms of ventricular arrhythmias. Index of cardio-electrophysiological balance (iCEB) is a risk marker for predicting malignant ventricular arrhythmia. There is no evidence on the effect of fingolimod on iCEB in patients with relapsing-remitting multiple sclerosis (RRMS). The aim of this study was to evaluate iCEB in patients with RRMS treated with fingolimod . METHODS: A total of 86 patients with RRMS treated with fingolimod were included in the study. All patients underwent a standard 12-lead surface electrocardiogram at initiation of treatment and 6 h after treatment. Heart rate, RR interval, QRS duration, QT, QTc (heart rate corrected QT), T wave peak-to-end (Tp-e) interval, Tp-e/QT, Tp-e/QTc, iCEB (QT/QRS) and iCEBc (QTc/QRS) ratios were calculated from the electrocardiogram. QT correction for heart rate was performed using both the Bazett and Fridericia formulas. Pre-treatment and post-treatment values were compared. RESULTS: Heart rate was significantly lower after fingolimod treatment (p< 0.001). While the post-treatment values of RR and QT intervals were significantly longer (p< 0.001) and post-treatment iCEB was higher (median [Q1-Q3], 4.23 [3.95-4.50] vs 4.53 [4.18-5.14]; p< 0.001), it was found that there was no statistically significant change in iCEB and other study parameters derived using QT after correcting for heart rate using both of two formulas. CONCLUSIONS: In this study, it was found that fingolimod did not statistically significantly change any of the heart rate-corrected ventricular repolarization parameters, including iCEBc, and it is safe in terms of ventricular arrhythmia.

Investigation of cardiac arrhythmia events in patients treated with lamotrigine: FDA adverse event reporing system analysis.

OBJECTIVES: In October 2020 and March 2021, the U.S. Food and Drug Administration (FDA) classified lamotrigine as a class IB antiarrhythmic, announcing an increased risk of heart rhythm problems. We sought to investigate the nature of the arrhythmia signal with lamotrigine use compared to anticonvulsants with sodium-blocking and non-sodium-blocking mechanisms. METHODS: This retrospective pharmacovigilance case-non-case study used disproportionality analysis to detect signals of adverse reaction of interest reported with lamotrigine to the FDA Adverse Event Reporting System (FAERS) between 1998 and 2022. Our regression model adjusted for interacting concomitant medications. Sensitivity analyses included stratifying by indication and publication date. RESULTS: Overall, 2917 cases of heart rhythm problems with anticonvulsants were analyzed (1557 female [58.4%] and 1109 male [41.6%]). The mean age ± standard deviation (SD) was 43 ± 19, the groups did not differ significantly by age. Forty cases (7.91%) in the epileptic indication included more than one concomitant medication that influences cardiac conduction. The disproportionality signal for cardiac arrest did not differ for lamotrigine compared with other anticonvulsants, adjusted reporting odds ratio (adj.ROR, .88; 95% CI, .59-1.29) in the epileptic indication. A significantly lower reporting risk for bradyarrhythmia was identified with lamotrigine users in the epileptic population, (adj.ROR, .45; 95% confidence interval [CI], .29-.68). The psychiatric indication demonstrated a sixfold reporting risk for cardiac arrest compared to the epileptic indication. Concomitant medications that affect cardiac conduction, as well as reports on overdose and suicide attempts, were significant variables in psychiatric patients (ROR, 2.45; 95% CI, 2.21-2.71) and (ROR, 1.44; 95% CI, 1.34-1.55), respectively. SIGNIFICANCE: Our results do not support a significant difference in the reporting risk for cardiac arrest, syncope, tachyarrhythmia, and bradyarrhythmia with lamotrigine in the epileptic indication. Signals of cardiac arrest in lamotrigine could be explained by confounding factors in the psychiatric indication, such as greater concomitant use of medications with cardiac adverse events, and greater reports on overdose and suicide attempts. We recommend that patients with polypharmacy undergo clinical and electrocardiographic monitoring. We illustrate the importance of examining signals for separate indications.

Quantitative cardiovascular magnetic resonance findings and clinical risk factors predict cardiovascular outcomes in breast cancer patients.

BACKGROUND: Cardiac magnetic resonance (CMR) global longitudinal strain and circumferential strain abnormalities have been associated with left ventricular ejection fraction (LVEF) reduction and cardiotoxicity from oncologic therapy. However, few studies have evaluated the associations of strain and cardiovascular outcomes. OBJECTIVES: To assess CMR circumferential and global longitudinal strain (GLS) correlations with cardiovascular outcomes including myocardial infarction, systolic dysfunction, diastolic dysfunction, arrhythmias and valvular disease in breast cancer patients treated with and without anthracyclines and/or trastuzumab therapy. METHODS: Breast cancer patients with a CMR from 2013-2017 at Yale New Haven Hospital were included. Patient co-morbidities, medications, and cardiovascular outcomes were obtained from chart review. Biostatistical analyses, including Pearson correlations, competing risk regression model, and competing risk survival curves comparing the two groups were analyzed. RESULTS: 116 breast cancer with CMRs were included in our analysis to assess differences between Anthracycline/Trastuzumab (AT) (62) treated versus non anthracycline/trastuzumab (NAT) (54) treated patients in terms of imaging characteristics and outcomes. More AT patients 17 (27.4%) developed systolic heart failure compared to the NAT group 6 (10.9%), p = 0.025. Statin use was associated with a significant reduction in future arrhythmias (HR 0.416; 95% CI 0.229-0.755, p = 0.004). In a sub-group of 13 patients that underwent stress CMR, we did not find evidence of microvascular dysfunction by sub-endocardial/sub-epicardial myocardial perfusion index ratio after adjusting for ischemic heart disease. CONCLUSIONS: In our study, CMR detected signs of subclinical cardiotoxicity such as strain abnormalities despite normal LV function and abnormal circumferential strain was associated with adverse cardiovascular outcomes such as valvular disease and systolic heart failure. Thus, CMR is an important tool during and after cancer treatment to identity and prognosticate cancer treatment-related cardiotoxicity.

CaMKII regulates the proteins TPM1 and MYOM2 and promotes diacetylmorphine-induced abnormal cardiac rhythms.

Although opioids are necessary for the treatment of acute pain, cancer pain, and palliative care, opioid abuse is a serious threat to society. Heroin (Diacetylmorphine) is the most commonly abused opioid, and it can have a variety of effects on the body's tissues and organs, including the well-known gastrointestinal depression and respiratory depression; however, there is little known about the effects of diacetylmorphine on cardiac damage. Here, we demonstrate that diacetylmorphine induces abnormal electrocardiographic changes in rats and causes damage to cardiomyocytes in vitro by an underlying mechanism of increased autophosphorylation of CaMKII and concomitant regulation of myocardial contractile protein TPM1 and MYOM2 protein expression. The CaMKII inhibitor KN-93 was first tested to rescue the toxic effects of heroin on cardiomyocytes in vitro and the abnormal ECG changes caused by heroin in SD rats, followed by the TMT relative quantitative protein technique to analyze the proteome changes. Diacetylmorphine causes increased phosphorylation at the CaMKII Thr287 site in myocardium, resulting in increased autophosphorylation of CaMKII and subsequent alterations in myocardial contractile proteins, leading to myocardial rhythm abnormalities. These findings provide a theoretical basis for the treatment and prevention of patients with arrhythmias caused by diacetylmorphine inhalation and injection.