Flecainide toxicity: ECG changes associated with supratherapeutic levels in milk-fed infants.

Flecainide is a class 1C antiarrhythmic and is highly effective for treating a wide range of arrhythmias. It is not licensed for children under the age of 12 years, but has been used safely for years in young children, particularly when first-line agents are not effective. Although toxicity does occur in both adult and paediatric populations, there have been very few reported instances of flecainide toxicity in neonates and children. Supratherapeutic levels of flecainide manifests on ECG with prolongation of the PR interval, QRS duration and QT, and can lead to life-threatening arrhythmias. In milk-fed infants receiving flecainide, regular feeding patterns are paramount to achieve a steady therapeutic state, as milk and dairy products are known to reduce the absorption of flecainide. This case series details four milk-fed infants admitted with ECG changes secondary to flecainide toxicity.

Cell-Permeable Succinate Rescues Mitochondrial Respiration in Cellular Models of Amiodarone Toxicity.

Amiodarone is a potent antiarrhythmic drug and displays substantial liver toxicity in humans. It has previously been demonstrated that amiodarone and its metabolite (desethylamiodarone, DEA) can inhibit mitochondrial function, particularly complexes I (CI) and II (CII) of the electron transport system in various animal tissues and cell types. The present study, performed in human peripheral blood cells, and one liver-derived human cell line, is primarily aimed at assessing the concentration-dependent effects of these drugs on mitochondrial function (respiration and cellular ATP levels). Furthermore, we explore the efficacy of a novel cell-permeable succinate prodrug in alleviating the drug-induced acute mitochondrial dysfunction. Amiodarone and DEA elicit a concentration-dependent impairment of mitochondrial respiration in both intact and permeabilized platelets via the inhibition of both CI- and CII-supported respiration. The inhibitory effect seen in human platelets is also confirmed in mononuclear cells (PBMCs) and HepG2 cells. Additionally, amiodarone elicits a severe concentration-dependent ATP depletion in PBMCs, which cannot be explained solely by mitochondrial inhibition. The succinate prodrug NV118 alleviates the respiratory deficit in platelets and HepG2 cells acutely exposed to amiodarone. In conclusion, amiodarone severely inhibits metabolism in primary human mitochondria, which can be counteracted by increasing mitochondrial function using intracellular delivery of succinate.

The inhibitory mechanisms of losartan and vitamin D on amiodarone-induced lung inflammation in rats: Role of mitogen-activated protein kinases/activator protein-1.

Amiodarone (AMD), an antiarrhythmic drug, is used cautiously due to its lung toxicity that is characterized by alveolar inflammation followed by fatal fibrosis. AMD induces lung inflammation via increasing the alveolar macrophages and disturbing the balance of T-helper-1 (Th1) and Th2 cells cytokines. In this study, the role of the mitogen-activated protein kinases (MAPKs)/activator protein-1 (AP-1) pathway in AMD-induced lung inflammation was evaluated. Also, the anti-inflammatory and antifibrotic effects of losartan and/or vitamin D were investigated following 7, 14, and 28 days of AMD administration. AMD resulted in lung injury, inflammatory infiltration, and increased pulmonary levels of inflammatory cytokines starting from Week 1 of exposure. A significant increase in serum levels of interleukin-4 along with a significant reduction of interferon-gamma, in addition to strong expression of CD68, were reported after 14 and 28 days of AMD administration reflecting Th1/Th2 cytokines imbalance and the accumulation of alveolar macrophages, respectively. The phosphorylation of MAPKs (ERK1/2, JNK, p38) and AP-1 was significantly enhanced starting from Week 1 of exposure. Marked expression of transforming growth factor beta-1 and massive deposition of collagen were detected after 28 days reflecting late fibrosis. All these abnormalities were significantly mitigated by vitamin D and its combination with losartan. Losartan alone has less prominent anti-inflammatory effects particularly after 28 days; however, it efficiently prevented late fibrosis. This study concludes that MAPKs/AP-1 pathway is involved in AMD-induced lung inflammation and that vitamin D and/or losartan could be used as a prophylactic agent to prevent AMD-induced lung toxicity.

Takotsubo cardiomyopathy and flecainide toxicity: a case report and brief literature review.

OBJECTIVE: Takotsubo syndrome, also known as stress cardiomyopathy, is predominantly reported in postmenopausal women and it is often triggered by a physical or emotional stressor. CASE REPORT: We present the case of a 44-year-old Caucasian woman admitted to the emergency department after voluntary intake of 20 tablets of flecainide 150 mg to commit suicide. During the in-hospital stay in the Cardiac Intensive Care Unit, the patient developed Takotsubo syndrome. CONCLUSIONS: The relative role of flecainide as a possible trigger of the syndrome is discussed in the context of the current literature evidence.

Silymarin's defensive role against hepatotoxicity induced by amiodarone in albino rats / El efecto defensivo de silimarin contra la hepatotoxicidad inducida por amiodarona en ratas albinas

SUMMARY: Amiodarone (AMD), an orally powerful antidysrhythmic medication that has caused hepatotoxicity on long-term administration, is commonly used across the world. Silymarin ameliorative effects (SLM); this research elucidated the magnitude of the damage to the liver tissue in AMD. We divided 24 albino rats evenly into four groups given daily doses by gastric tube for eight weeks as follows; the 1st group acted as a control group; the 2nd group received SLM; the 3rd group received AMD; and the 4th group received AMD parallel to SLM. Liver tissues prepared for light, electron microscopic and serum samples screened for biomarkers (I)liver injury enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST); (II) oxidative and antioxidant stress, malondialdehyde (MDA) and superoxide dismutase (SOD); and (III) inflammatory markers, tumor necrosis factor-alpha (TNF-a) and interleukin-6 (IL-6). The findings showed that AMD caused hepatic histological changes that included congestion of the blood vessels, leucocytic infiltration and cytoplasmic vacuolation. Ultrastructural degeneration of the mitochondria, endoplasmic reticulum swelling, nuclear pyknosis and increased fat droplets and lysosomes were observed. The biochemical findings showed an increase in the AMD group's ALT and AST activities. The group of rats treated with AMD and SLM, increased the improvements in histology and ultrastructure, while the ALT and AST levels were reduced. Our findings collectively agreed that SLM has a protective impact on AMD hepatotoxicity which can be due to its antioxidant properties.

RESUMEN: La amiodarona (AMD) es un fuerte medicamento antiarrítmico administrado por vía oral que ha causado hepatotoxicidad en la administración a largo plazo utilizado con frecuencia en todo el mundo. Efectos de mejora de la silimarina (SLM); esta investigación analizó la magnitud del daño al tejido hepático en la DMAE. Dividimos 24 ratas albinas de manera uniforme en cuatro grupos que recibieron dosis diarias por sonda gástrica durante ocho semanas de la siguiente manera; el primer grupo fue designado como grupo control; el segundo grupo recibió SLM; el tercer grupo recibió AMD; y el cuarto grupo recibió AMD en paralelo a SLM. Se prepararon tejidos hepáticos para muestras de suero, microscopía de luz y electrónica y se analizaron para biomarcadores (I) enzimas de daño hepático, alanina aminotransferasa (ALT) y aspartato aminotransferasa (AST); (II) estrés oxidativo y antioxidante, malondialdehído (MDA) y superóxido dismutasa (SOD); y (III) marcadores inflamatorios, factor de necrosis tumoral alfa (TNF-a) e interleucina-6 (IL-6). Los hallazgos mostraron que la DMAE genera cambios histológicos hepáticos que incluyen congestión de los vasos sanguíneos, infiltración leucocítica y vacuolación citoplásmica. Se observó una degeneración ultraestructural de las mitocondrias, aumento del retículo endoplásmico, picnosis nuclear y aumento de gotitas de grasa y lisosomas. Los hallazgos bioquímicos mostraron un aumento en las actividades de ALT y AST del grupo AMD. El grupo de ratas tratadas con AMD y SLM, aumentó las mejoras en histología y ultraestructura, mientras que se redujeron los niveles de ALT y AST. Nuestros hallazgos coincidieron colectivamente en que SLM tiene un impacto protector sobre la hepatotoxicidad de AMD debido a sus propiedades antioxidantes.

Prediction of the dose range for adverse neurological effects of amiodarone in patients from an in vitro toxicity test by in vitro-in vivo extrapolation.

Amiodarone is an antiarrhythmic agent inducing adverse effects on the nervous system, among others. We applied physiologically based pharmacokinetic (PBPK) modeling combined with benchmark dose modeling to predict, based on published in vitro data, the in vivo dose of amiodarone which may lead to adverse neurological effects in patients. We performed in vitro-in vivo extrapolation (IVIVE) from concentrations measured in the cell lysate of a rat brain 3D cell model using a validated human PBPK model. Among the observed in vitro effects, inhibition of choline acetyl transferase (ChAT) was selected as a marker for neurotoxicity. By reverse dosimetry, we transformed the in vitro concentration-effect relationship into in vivo effective human doses, using the calculated in vitro area under the curve (AUC) of amiodarone as the pharmacokinetic metric. The upper benchmark dose (BMDU) was calculated and compared with clinical doses eliciting neurological adverse effects in patients. The AUCs in the in vitro brain cell culture after 14-day repeated dosing of nominal concentration equal to 1.25 and 2.5 µM amiodarone were 1.00 and 1.99 µg*h/mL, respectively. The BMDU was 385.4 mg for intravenous converted to 593 mg for oral application using the bioavailability factor of 0.65 as reported in the literature. The predicted dose compares well with neurotoxic doses in patients supporting the hypothesis that impaired ChAT activity may be related to the molecular/cellular mechanisms of amiodarone neurotoxicity. Our study shows that predicting effects from in vitro data together with IVIVE can be used at the initial stage for the evaluation of potential adverse drug reactions and safety assessment in humans.

Cardiohemodynamic and Arrhythmogenic Effects of the Anti-Atrial Fibrillatory Compound Vanoxerine in Halothane-Anesthetized Dogs.

While vanoxerine (GBR-12909) is a synaptosomal dopamine uptake inhibitor, it also suppresses IKr, INa and ICa,L in vitro. Based on these profiles on ionic currents, vanoxerine has been developed as a candidate compound for treating atrial fibrillation. To investigate electropharmacological profiles, vanoxerine dihydrochloride was intravenously administered at 0.03 and 0.3 mg/kg to halothane-anesthetized dogs (n = 4), possibly providing subtherapeutic and therapeutic concentrations, respectively. The low dose increased the heart rate and cardiac output, whereas it prolonged the ventricular refractoriness. The high dose decreased the heart rate but increased the total peripheral vascular resistance, whereas it delayed the ventricular repolarization and increased the atrial refractoriness in addition to further enhancing the ventricular refractoriness. The extent of increase in the refractoriness in the atrium was 0.8 times of that in the ventricle. The high dose also prolonged the early and late repolarization periods of the ventricle as well as the terminal repolarization period. Meanwhile, no significant change was detected in the mean blood pressure, ventricular contraction, preload to the left ventricle, or the intra-atrial, intra-ventricular or atrioventricular conductions. The high dose can be considered to inhibit IKr, but it may not suppress INa or ICa in the in situ heart, partly explaining its poor atrial selectivity for increasing refractoriness. The prolongation of early repolarization period may reflect enhancement of net inward current, providing potential risk for intracellular Ca2+ overload. Thus, vanoxerine may provide both trigger and substrate toward torsade de pointes, which would make the drug less promising as an anti-atrial fibrillatory drug.

Dynamic features of cardiac vector as alternative markers of drug-induced spatial dispersion.

INTRODUCTION: The abnormal amplification of ventricular repolarization dispersion (VRD) has long been linked to proarrhythmia risk. Recently, the measure of VRD through electrocardiogram intervals has been strongly questioned. The search for an efficient and non-invasive surrogate marker of drug-induced dispersion effects constitute an urgent research challenge. METHODS: Herein, drug-induced ventricular dispersion is generated by d-Sotalol supply in an In-vitro rabbit heart model. A cilindrical chamber simulates the thorax and a multi-electrode net is used to obtain spatial electrocardiographic signals. Cardiac vector dynamics is captured by novel velocity cardiomarkers obtained by quaternion methods. Through statistical analysis and machine learning technics, we compute potential dispersion markers that could define proarrhythmic risk. RESULTS: The cardiomarkers with the greatest statistical significance, both obtained from the electrical cardiac vector, were: the QTω, which is the difference between first and last maxima of angular velocity and λ21vT, the roundness of linear velocity. When comparing with the performance of the current standards (89%), this pair was able to correctly separate 21 out of 22 experiments achieving a performance of 95%. Moreover, the QTω computes in a much more robust basis the QT interval, the current index for drug regulation. DISCUSSION: These velocity markers circumvent the problems of accuratelly finding the fiducial points such as the always tricky T-wave end. Given the high performance they achieved, it is provided a promising outcome for future applications to the detection of anomalous changes of heterogeneity that may be useful for the purposes of torsadogenic toxicity studies.

Traditional Chinese medicine practices used in COVID-19 (Sars-cov 2/Coronavirus-19) treatment in clinic and their effects on the cardiovascular system.

OBJECTIVE: The aim of this study was to evaluate the effectiveness of plants used in the formulations of traditional Chinese medicine (TCM), which were also used in clinical trials to treat patients with the novel coronavirus COVID-19, and to assess their effects on the cardiovascular system. METHODS: A literature review of PubMed, ResearchGate, ScienceDirect, the Cochrane Library, and TCM monographs was conducted and the effects of the plants on the cardiovascular system and the mechanisms of action in COVID-19 treatment were evaluated. RESULTS: The mechanism of action, cardiovascular effects, and possible toxicity of 10 plants frequently found in TCM formulations that were used in the clinical treatment of COVID-19 were examined. CONCLUSION: TCM formulations that had been originally developed for earlier viral diseases have been used in COVID-19 treatment. Despite the effectiveness seen in laboratory and animal studies with the most commonly used plants in these formulations, the clinical studies are currently insufficient according to standard operating procedures. More clinical studies are needed to understand the safe clinical use of traditional plants.

The Case of Flecainide Toxicity: What to Look for and How to Treat.

BACKGROUND: Flecainide is a class Ic antidysrhythmic agent used to prevent and treat both ventricular and supraventricular tachycardias, including atrial fibrillation, atrioventricular nodal re-entrant tachycardia, and Wolff-Parkinson-White syndrome. Flecainide can cause serious side effects, including cardiac arrest, dysrhythmias, and heart failure. Despite its growing use, the presenting signs and symptoms of flecainide toxicity are not familiar to most clinicians. In particular, our patient's particular presentation of acute kidney injury (AKI) resulting in flecainide accumulation is high risk for missed diagnosis in the emergency department. CASE REPORT: A 58-year-old woman presented with altered mental status and hypoxia that was later found to be secondary to sepsis. Medical history was notable for atrial fibrillation, for which she was on flecainide. Laboratory results were notable for hypokalemia and an AKI. Her wide complex tachycardia on admission was ultimately attributed to flecainide toxicity in the setting of AKI. Six days after presentation, it was found that her flecainide level was in the toxic range at 2.02 µg/mL (normal range 0.20-1.00 µg/mL, toxic >1.50 µg/mL). WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Flecainide intoxication is rare but serious due to the potential for cardiogenic shock. Its diagnosis can be difficult, as the flecainide serum level may take days to result. This case demonstrates the necessity of keeping flecainide toxicity on the physician's differential for patients who are taking the drug, as well as what electrocardiogram findings suggest it as the etiology. Treatment can be lifesaving if initiated promptly.

Symptomatic digoxin toxicity in a patient on haemodialysis.

We present a man undergoing regular haemodialysis sessions, who presented with non-specific symptoms of nausea, vomiting and light-headedness. He was found to have significantly raised serum digoxin concentrations, as well as a heart rate of 30 beats per minutes. An ECG showed complete heart block. He has a history of non-ischaemic dilated cardiomyopathy with resistant supraventricular and ventricular tachycardias and was on concomitant beta-blockade and digoxin. On questioning, he reported a gradual decline in his residual urine output over the past 6 months. He was reviewed by the cardiology team and required both pharmacological therapy for reversal of digoxin toxicity and temporary pacing in view of significant bradyarrhythmias. The beta-blockade and digoxin were discontinued. He was kept on continuous monitoring at the Cardiac Critical Care Unit. His symptoms resolved spontaneously once digoxin-specific antibody fragments were administered and temporary pacing successfully performed.

Pilsicainide Intoxication with Neuropsychiatric Symptoms Treated with Continuous Hemodiafiltration.

A 72-year-old lady with atrial fibrillation and chronic renal failure was hospitalized due to bradycardic shock with electrocardiographic QRS prolongation. She had experienced limb shaking two days before hospitalization, and additionally developed hallucinations one day before admission. Pilsicainide intoxication was diagnosed from a review of her medications and electrocardiographic findings. Consequently, continuous hemodiafiltration was performed resulting in a resolution of the hallucinations and the QRS prolongation. This is a rare case of psychiatric symptoms caused by pilsicainide intoxication. It is important to know the mode of excretion of a drug and to adjust its dose, so that such drug-related incidents can be avoided.

Flecainide toxicity: a presentation to the emergency department with literature review.

Flecainide toxicity can result in increased cardiovascular instability which can significantly alter patient outcome if not recognised early. In this case report, the management of a 68-year-old woman who took an unintentional overdose of flecainide is detailed. We look at the management she received in the emergency department and her successful recovery and follow-up since the admission. In addition, the case report outlines the ECG changes that are most commonly documented in flecainide overdose and reviews the frequently used treatment methods for the overdose as summarised in current literature.

Dose-Dependent Effects of Ranolazine on Reentrant Ventricular Arrhythmias Induced After Subacute Myocardial Infarction in Rabbits.

Ranolazine has been found to prevent ventricular arrhythmias (VAs) during acute myocardial infarction (AMI). This study aimed to investigate its efficacy on VAs induced several days post-MI. For this purpose, 13 anesthetized rabbits underwent coronary artery ligation. Ten of these animals that survived AMI were reanesthetized 3 to 7 days later for electrophysiologic testing. An endocardial monophasic action potential combination catheter was placed in the right ventricle for simultaneous pacing and recording. Monophasic action potential duration, ventricular effective refractory period (VERP), and VAs induced by programmed stimulation were assessed. Measurements were performed during control pacing, and following an intravenous infusion of either a low-dose ranolazine (2.4 mg/kg, R1) or a higher dose ranolazine (4.8 mg/kg cumulative dose, R2). During control stimulation, 2 animals developed primary ventricular fibrillation (VF), 6 sustained ventricular tachycardia (sVT), and 2 nonsustained VT (nsVT). R1 did not prevent the appearance of VAs in any of the experiments; in contrast, it aggravated nsVT into sVT and complicated sVT termination in 2 of 6 animals. Sustained ventricular tachycardia cycle length and VERP were only slightly decreased after R1 (112 ± 5 vs 110 ± 6 ms and 101 ± 11 vs 98 ± 10 ms, respectively). R2 suppressed inducibility of control nsVT, VF, and sVT in 2 animals. In 4 animals with still inducible sVT, R2 significantly prolonged VT cycle length by 150 ± 23 ms (P < .01), and VERP by 120 ± 7 ms (P < .001) versus control. In conclusion, R2 exerted antiarrhythmic efficacy against subacute-MI VAs, whereas R1 rather aggravated than prevented these arrhythmias. Ventricular effective refractory period prolongation could partially explain the antiarrhythmic action of R2 in this rabbit model.

Pharmacological activation of IKr in models of long QT Type 2 risks overcorrection of repolarization.

AIMS: Current treatment for congenital long QT syndrome Type 2 (cLQTS2), an electrical disorder that increases the risk of life-threatening cardiac arrhythmias, is aimed at reducing the incidence of arrhythmia triggers (beta-blockers) or terminating the arrhythmia after onset (implantable cardioverter-defibrillator). An alternative strategy is to target the underlying disease mechanism, which is reduced rapid delayed rectifier current (IKr) passed by Kv11.1 channels. Small molecule activators of Kv11.1 have been identified but the extent to which these can restore normal cardiac signalling in cLQTS2 backgrounds remains unclear. Here, we examined the ability of ICA-105574, an activator of Kv11.1 that impairs transition to the inactivated state, to restore function to heterozygous Kv11.1 channels containing either inactivation enhanced (T618S, N633S) or expression deficient (A422T) mutations. METHODS AND RESULTS: ICA-105574 effectively restored Kv11.1 current from heterozygous inactivation enhanced or expression defective mutant channels in heterologous expression systems. In a human-induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) model of cLQTS2 containing the expression defective Kv11.1 mutant A422T, cardiac repolarization, estimated from the duration of calcium transients in isolated cells and the rate corrected field potential duration (FPDc) in culture monolayers of cells, was significantly prolonged. The Kv11.1 activator ICA-105574 was able to reverse the prolonged repolarization in a concentration-dependent manner. However, at higher doses, ICA-105574 produced a shortening of the FPDc compared to controls. In vitro and in silico analysis suggests that this overcorrection occurs as a result of a temporal redistribution of the peak IKr to much earlier in the plateau phase of the action potential, which results in early repolarization. CONCLUSION: Kv11.1 activators, which target the primary disease mechanism, provide a possible treatment option for cLQTS2, with the caveat that there may be a risk of overcorrection that could itself be pro-arrhythmic.

Heterotropic activation of flavonoids on cytochrome P450 3A4: A case example of alleviating dronedarone-induced cytotoxicity.

The clinical drug-drug interactions mediated by heterotropic activation on cytochrome P450 (CYP450) kinetics, especially CYP3A4, have received wide concern in recent years. Flavonoids, a group of important natural substances with various pharmacological activities, distribute widely among vegetables, fruits and herbs. The frequent and numerous uses of flavonoids may increase the risk of food/herb-drug interactions. However, little is known about activation effects of flavonoids on CYP3A4. The aim of this study was to investigate activation of CYP3A4 by flavonoids, explore the molecular mechanism, and assess the biological effects on dronedarone (DND) induced toxicity. The results showed that flavone, tangeretin, sinensetin and 6-hydroxyflavone increased the cell viability by decreasing DND-induced cytotoxicity. These four flavonoids could activate the metabolism of DND in hamster pharmacokinetics study. Furthermore, both molecular docking and circular dichroism analysis partially illustrated the molecular mechanism of heterotropic activation. Finally, the pharmacophore model suggested B aromatic ring, hydrophobic groups at 7-position and hydrogen bond acceptors at 4-position may play a vital role in activation of flavonoids on CYP3A4. Taken together, our findings would provide useful information for predicting the potential risks of flavonoid-containing food/herb-drug interactions in humans.

Pulmonary Responses Following Quercetin Administration in Rats After Intratracheal Instillation of Amiodarone.

Amiodarone, a drug that treats arrhythmias induces pulmonary toxicity through interplay between oxidative stress and inflammation. Quercetin, a flavonoid widely occurring in natural products possesses antioxidant and anti-inflammatory properties. The aim of the present study was to evaluate the effects of quercetin on pulmonary responses in rats after amiodarone intra-tracheal instillation. Eighteen female Wistar rats (150-250 g) were randomly assigned into three groups of six animals each namely; control, amiodarone (AMI) and amiodarone + Quercetin (AMI + Quercetin) groups. AMI group received 2 intra-tracheal instillations of amiodarone (6.25mg/kg in 0.3ml of water) on days 0 and 2 and 0.4ml of 2% DMSO (Dimethyl sulfoxide) orally from day 0 for 3 weeks. AMI + Quercetin group was administered 2 intratracheal instillations of amiodarone on days 0 and 2 and 20mg/kg body weight of quercetin in 2% DMSO from day 0 for 3 weeks. Thereafter, the animals were sacrificed and bronchoalveolar lavage fluid (BALF) was collected to determine total cell polymorphonuclear (PMN) cell and macrophage counts. Inflammation of the lung tissues was also assessed. Macrophage count of AMI + Quercetin group was significantly lowered (p<0.01) compared to AMI group. Inflammation rate of the AMI + Quercetin group was significantly reduced compared to AMI group (p<0.01). Quercetin treatment markedly suppressed amiodarone induced toxicity in the pulmonary tissues.

Renal failure, shock, and loss of pacemaker capture: A case of flecainide intoxication.

Flecainide intoxication is a severe intoxication that can lead to cardiogenic shock. We report on a 68-year-old female patient, who presented with a flecainide intoxication in the setting of renal failure. She was managed with invasive supportive therapy at the ICU and infusion of sodium bicarbonate and intravenous lipid emulsion (ILE, intralipid 20%), after which she made a complete recovery.

Intravenous Amiodarone and Sotalol Impair Contractility and Cardiac Output, but Procainamide Does Not: A Langendorff Study.

INTRODUCTION: Direct comparison of the effects of antiarrhythmic agents on myocardial performance may be useful in choosing between medications in critically ill patients. Studies directly comparing multiple antiarrhythmic medications are lacking. The use of an experimental heart preparation permits examination of myocardial performance under constant loading conditions. METHODS: Hearts of Sprague Dawley rats (n = 35, 402-507 g) were explanted and cannulated in working heart model with fixed preload and afterload. Each heart was then exposed to a 3-hour infusion of procainamide (20 µg/kg/min), esmolol (100 or 200 µg/kg/min), amiodarone (10 or 20 mg/kg/d), sotalol (80 mg/m2/d), or placebo infusions (n = 5 per dose). Cardiac output, contractility (dP/dTmax), diastolic performance (dP/dTmin), and heart rate were compared between groups over time by linear mixed modeling. RESULTS: Compared with placebo, sotalol decreased contractility by an average of 24% ( P < .001) over the infusion period, as did amiodarone (low dose by 13%, P = .029; high dose by 14%, P = .013). Compared with placebo, mean cardiac output was significantly lower in animals treated with sotalol (by 22%, P = .016) and esmolol 200 µg/kg/min (by 23%, P = .012). Over time, amiodarone decreased cardiac output (20 mg/kg/d, ß = -89 [-144, -33] µL/min2 decrease, P = .002) and also worsened diastolic function, decreasing dP/dTmin by ∼18% and 22% ( P = .032 and P = .011, low and high doses, respectively). Procainamide did not have a significant effect on any measures of systolic or diastolic performance. CONCLUSIONS: In isolated hearts, amiodarone and sotalol depressed myocardial contractility, cardiac output, and diastolic function. However, procainamide did not negatively affect myocardial performance and represents a favorable agent in settings of therapeutic equivalence.