Arrhythmia Models Research Articles

The Current Model of Cardiac Arrhythmia Based on an Autonomous Dynamical System with A Smale - Williams Hyperbolic Attractor

The Current Model of Cardiac Arrhythmia Based on an Autonomous Dynamical System with A Smale - Williams Hyperbolic Attractor

Reduced cardiomyocyte Na+ current in the age-dependent murine Pgc-1β-/- model of ventricular arrhythmia.

Peroxisome proliferator‐activated receptor‐γ coactivator‐1 deficient (Pgc‐1β −/−) murine hearts model the increased, age‐dependent, ventricular arrhythmic risks attributed to clinical conditions associated with mitochondrial energetic dysfunction. These were accompanied by compromised action potential (AP) upstroke rates and impaired conduction velocities potentially producing arrhythmic substrate. We tested a hypothesis implicating compromised Na+ current in these electrophysiological phenotypes by applying loose patch‐clamp techniques in intact young and aged, wild‐type (WT) and Pgc‐1β −/−, ventricular cardiomyocyte preparations for the first time. This allowed conservation of their in vivo extracellular and intracellular conditions. Depolarising steps elicited typical voltage‐dependent activating and inactivating inward Na+ currents with peak amplitudes increasing or decreasing with their respective activating or preceding inactivating voltage steps. Two‐way analysis of variance associated Pgc‐1β −/− genotype with independent reductions in maximum peak ventricular Na+ currents from −36.63 ± 2.14 (n = 20) and −35.43 ± 1.96 (n = 18; young and aged WT, respectively), to −29.06 ± 1.65 (n = 23) and −27.93 ± 1.63 (n = 20; young and aged Pgc‐1β −/−, respectively) pA/μm2 (p < 0.0001), without independent effects of, or interactions with age. Voltages at half‐maximal current V*, and steepness factors k in plots of voltage dependences of both Na+ current activation and inactivation, and time constants for its postrepolarisation recovery from inactivation, remained indistinguishable through all experimental groups. So were the activation and rectification properties of delayed outward (K+) currents, demonstrated from tail currents reflecting current recoveries from respective varying or constant voltage steps. These current–voltage properties directly implicate decreases specifically in maximum available Na+ current with unchanged voltage dependences and unaltered K+ current properties, in proarrhythmic reductions in AP conduction velocity in Pgc‐1β−/− ventricles.

Transcripts of Kv7.1 and MinK channels and slow delayed rectifier K+ current (IKs) are expressed in zebrafish (Danio rerio) heart.

Zebrafish are increasingly used as a model for human cardiac electrophysiology, arrhythmias, and drug screening. However, K+ ion channels of the zebrafish heart, which determine the rate of repolarization and duration of cardiac action potential (AP) are still incompletely known and characterized. Here, we provide the first evidence for the presence of the slow component of the delayed rectifier K+channels in the zebrafish heart and characterize electrophysiological properties of the slow component of the delayed rectifier K+current, IKs. Zebrafish atrium and ventricle showed strong transcript expression of the kcnq1 gene, which encodes the Kv7.1 α-subunit of the slow delayed rectifier K+ channel. In contrast, the kcne1 gene, encoding the MinK β-subunit of the delayed rectifier, was expressed at 21 and 17 times lower level in ventricle and atrium, respectively, in comparison to the kcnq1. IKs was observed in 62% of ventricular myocytes with mean (± SEM) density of 1.23 ± 0.37 pA/pF at + 30mV.Activation rate of IKs was 38% faster (τ50 = 1248 ± 215ms) than kcnq1:kcne1channels (1725 ± 792ms) expressed in 3:1 ratio in Chinese hamster ovary cells. Microelectrode experiments demonstrated the functional relevance of IKs in the zebrafish heart, since 100μM chromanol 293B produced a significant prolongation of AP in zebrafish ventricle. We conclude that AP repolarization in zebrafish ventricle is contributed by IKs, which is mainly generated by homotetrameric Kv7.1 channels not coupled to MinK ancillaryβ-subunits. This is a clear difference to the human heart, where MinK is an essential component of the slow delayed rectifier K+channel.

A tissue-engineered scale model of the heart ventricle.

Laboratory studies of the heart use cell and tissue cultures to dissect heart function yet rely on animal models to measure pressure and volume dynamics. Here, we report tissue-engineered scale models of the human left ventricle, made of nanofibrous scaffolds that promote native-like anisotropic myocardial tissue genesis and chamber-level contractile function. Incorporating neonatal rat ventricular myocytes or cardiomyocytes derived from human induced pluripotent stem cells, the tissue-engineered ventricles have a diastolic chamber volume of ~500 μL (comparable to that of the native rat ventricle and approximately 1/250 the size of the human ventricle), and ejection fractions and contractile work 50–250 times smaller and 104–108 times smaller than the corresponding values for rodent and human ventricles, respectively. We also measured tissue coverage and alignment, calcium-transient propagation and pressure/volume loops in the presence or absence of test compounds. Moreover, we describe an instrumented bioreactor with ventricular-assist capabilities, and provide a proof-of-concept disease model of structural arrhythmia. The model ventricles can be evaluated with the same assays used in animal models and in clinical settings.

Mouse Models of Cardiac Arrhythmias.

Mouse models have been invaluable for delineating the contributions of specific genes and signaling pathways to the pathogenesis of cardiac arrhythmias. Considering that there are important differences between mice and humans, here we discuss the strengths and limitations of mouse models of cardiac arrhythmias.

2-phenyl-1-(3-pyrrolidin-1-il-propyl)-1 H-indole hydrochloride (SS-68): Antiarrhythmic and cardioprotective activity and its molecular mechanisms of action (Part I)

Introduction. The problem of heart rhythm disturbances is one of the most urgent topics of modern cardiology. According to the currently available concepts, 1,2- and 1,3-disubstituted aminoindole derivatives, which compound 2-phenyl-1-(3-pyrrolidin-1-il-propyl)-1H-indole hydrochloride (SS-68) belongs to, are a promising chemical group in terms of their cardio-pharmacological activity.&#x0D; Materials and methods. To study the anti-arrhythmic activity of SS-68 compound, the following models were used: 1) Models of cardiogenic arrhythmia: aconitine-inducedic, calcium chloride-induced, barium chloride-induced, cesium chloride-induced, adrenaline model of arrhythmia, strophanthine-induced arrhythmias, as well as arrhythmias caused by electrostimulation and acute myocardial ischemia; 2) neurogenic arrhythmias: arrhythmias caused by administration of aconitine, strophanthine K, cesium chloride into the IV ventricle of the brain and also by applying carbachol on the somatosensory cortex. To assess the antianginal activity of SS-68 in various models, the effect of this drug and comparators on the intact and ischemic myocardium was studied.&#x0D; Results. It was found that with cardiogenic arrhythmias, SS-68 compound exhibits a pronounced antiarrhythmic effect and brings to normal the electrophysiological pattern of the heart, in most cases exceeding the analogous effect of reference drugs (amiodarone, lidocaine, aymaline, ethacizine, etmozine, quinidine anaprilin). In neurogenic arrhythmias, SS-68 also had a stopping effect, and, in addition, reduced the epileptiform activity of the brain in the model with the application of carbachol on the somatosensory cortex. In the study of antianginal and coronary vasolidating activities, SS-68 demonstrated pronounced thrombolytic and anti-ischemic activities, manifested in an increase in the coronary blood flow, a positive effect on ST-segment depression, and a decrease in the area of necrosis in experimental myocardial infarction.&#x0D; Discussion. The antiarrhythmic and antianginal activities of SS-68 compound create the prerequisites for further study of the pharmacological properties of this molecule. In addition, it seems appropriate to continue studying the pharmacodynamics, pharmacokinetics and molecular mechanisms of SS-68 action.&#x0D; Conclusions. SS-68 compound is a promising pharmacological agent with a high activity towards various electrophysiological disorders in the heart, and, in addition, it has significant antiischemic and coronary vasolidating properties.

Tetrodotoxin-sensitive Navs contribute to early and delayed afterdepolarizations in long QT arrhythmia models.

Recent evidence suggests that neuronal Na+ channels (nNavs) contribute to catecholamine-promoted delayed afterdepolarizations (DADs) and catecholaminergic polymorphic ventricular tachycardia (CPVT). The newly identified overlap between CPVT and long QT (LQT) phenotypes has stoked interest in the cross-talk between aberrant Na+ and Ca2+ handling and its contribution to early afterdepolarizations (EADs) and DADs. Here, we used Ca2+ imaging and electrophysiology to investigate the role of Na+ and Ca2+ handling in DADs and EADs in wild-type and cardiac calsequestrin (CASQ2)-null mice. In experiments, repolarization was impaired using 4-aminopyridine (4AP), whereas the L-type Ca2+ and late Na+ currents were augmented using Bay K 8644 (BayK) and anemone toxin II (ATX-II), respectively. The combination of 4AP and isoproterenol prolonged action potential duration (APD) and promoted aberrant Ca2+ release, EADs, and DADs in wild-type cardiomyocytes. Similarly, BayK in the absence of isoproterenol induced the same effects in CASQ2-null cardiomyocytes. In vivo, it prolonged the QT interval and, upon catecholamine challenge, precipitated wide QRS polymorphic ventricular tachycardia that resembled human torsades de pointes. Treatment with ATX-II produced similar effects at both the cellular level and in vivo. Importantly, nNav inhibition with riluzole or 4,9-anhydro-tetrodotoxin reduced the incidence of ATX-II-, BayK-, or 4AP-induced EADs, DADs, aberrant Ca2+ release, and VT despite only modestly mitigating APD prolongation. These data reveal the contribution of nNaVs to triggered arrhythmias in murine models of LQT and CPVT-LQT overlap phenotypes. We also demonstrate the antiarrhythmic impact of nNaV inhibition, independent of action potential and QT interval duration, and provide a basis for a mechanistically driven antiarrhythmic strategy.

The study of the functionality of cardiomyocytes obtained from induced pluripotent stem cells for the modeling of cardiac arrhythmias based on long QT syndrome

There are risk factors that lead the normal conduction of excitation in the heart into a chaotic one. These factors include hereditary and acquired channelopathies. Many dangerous changes in the work of the heart can be identified using the patient’s electrocardiogram. Such relatively easily detectable changes include the long QT interval syndrome (LQTS). Despite a relatively high prevalence of hereditary LQTS, to which it is necessary to add both hereditary and induced LQTS as well as the ease of detection on the ECG, the mechanism of reentry formation in this syndrome is still un­known. What should be noted is a high variability of the hereditary syndrome and the fact of the connection between the increase in the heart rate and the risk of cardiac arrest. After an electrophysiological study on individual cardiac cells from patients with the LQT syndrome, it became apparent that the search for a mechanism for the transition of the normal heart rhythm to chaotic and fibrillation cannot be limited to recording ion currents in single cells. To solve this problem, we need a model of the behavior of cardiac tissue which reflects the relationship of various factors and the risk of reentry. In order to create an experimental model of LQTS in our work, the iPSC of a pati­ent-specific line from a healthy patient was differentiated into a monolayer of cardiac cells and the parameters of the excitation propagation were studied depending on the stage of differentiation. It was shown that a stable value of the propagation velocity and the response to periodic stimulation in the range of physiological values, are reached after the 30th day of dif­ferentiation.

P801Arrhythmogenic mechanisms in ageing: insights from murine models of arrhythmia

P801Arrhythmogenic mechanisms in ageing: insights from murine models of arrhythmia

MUSCLEMOTION: A Versatile Open Software Tool to Quantify Cardiomyocyte and Cardiac Muscle Contraction In Vitro and In Vivo.

There are several methods to measure cardiomyocyte and muscle contraction, but these require customized hardware, expensive apparatus, and advanced informatics or can only be used in single experimental models. Consequently, data and techniques have been difficult to reproduce across models and laboratories, analysis is time consuming, and only specialist researchers can quantify data. Here, we describe and validate an automated, open-source software tool (MUSCLEMOTION) adaptable for use with standard laboratory and clinical imaging equipment that enables quantitative analysis of normal cardiac contraction, disease phenotypes, and pharmacological responses. MUSCLEMOTION allowed rapid and easy measurement of movement from high-speed movies in (1) 1-dimensional in vitro models, such as isolated adult and human pluripotent stem cell-derived cardiomyocytes; (2) 2-dimensional in vitro models, such as beating cardiomyocyte monolayers or small clusters of human pluripotent stem cell-derived cardiomyocytes; (3) 3-dimensional multicellular in vitro or in vivo contractile tissues, such as cardiac "organoids," engineered heart tissues, and zebrafish and human hearts. MUSCLEMOTION was effective under different recording conditions (bright-field microscopy with simultaneous patch-clamp recording, phase contrast microscopy, and traction force microscopy). Outcomes were virtually identical to the current gold standards for contraction measurement, such as optical flow, post deflection, edge-detection systems, or manual analyses. Finally, we used the algorithm to quantify contraction in in vitro and in vivo arrhythmia models and to measure pharmacological responses. Using a single open-source method for processing video recordings, we obtained reliable pharmacological data and measures of cardiac disease phenotype in experimental cell, animal, and human models.

Effects of ageing on pro-arrhythmic ventricular phenotypes in incrementally paced murine Pgc-1\u03b2\u2212/\u2212 hearts

A range of chronic clinical conditions accompany cardiomyocyte energetic dysfunction and constitute independent risk factors for cardiac arrhythmia. We investigated pro-arrhythmic and arrhythmic phenotypes in energetically deficient C57BL mice with genetic ablation of the mitochondrial promoter peroxisome proliferator-activated receptor-γ coactivator-1β (Pgc-1β), a known model of ventricular arrhythmia. Pro-arrhythmic and cellular action potential (AP) characteristics were compared in intact Langendorff-perfused hearts from young (12–16 week) and aged (> 52 week), wild-type (WT) and Pgc-1β−/− mice. Simultaneous electrocardiographic and intracellular microelectrode recordings were made through successive trains of 100 regular stimuli at progressively incremented heart rates. Aged Pgc-1β−/− hearts displayed an increased incidence of arrhythmia compared to other groups. Young and aged Pgc-1β−/− hearts showed higher incidences of alternans in both AP activation (maximum AP upshoot velocity (dV/dt)max and latency), recovery (action potential duration (APD90) and resting membrane potential (RMP) characteristics compared to WT hearts. This was particularly apparent at lower pacing frequencies. These findings accompanied reduced (dV/dt)max and increased AP latency values in the Pgc-1β−/− hearts. APs observed prior to termination of the protocol showed lower (dV/dt)max and longer AP latencies, but indistinguishable APD90 and RMPs in arrhythmic compared to those in non-arrhythmic hearts. APD restitution analysis showed that Pgc-1β−/− and WT hearts showed similar limiting gradients. However, Pgc-1β−/− hearts had shortened plateau AP wavelengths, particularly in aged Pgc-1β−/− hearts. Pgc-1β−/− hearts therefore show pro-arrhythmic instabilities attributable to altered AP conduction and activation rather than recovery characteristics.

Rat Models of Ventricular Fibrillation Following Acute Myocardial Infarction.

A number of animal models have been designed in order to unravel the underlying mechanisms of acute ischemia-induced arrhythmias and to test compounds and interventions for antiarrhythmic therapy. This is important as acute myocardial infarction (AMI) continues to be the major cause of sudden cardiac death, and we are yet to discover safe and effective treatments of the lethal arrhythmias occurring in the acute setting. Animal models therefore continue to be relevant for our understanding and treatment of acute ischemic arrhythmias. This review discusses the applicability of the rat as a model for ventricular arrhythmias occurring during the acute phase of AMI. It provides a description of models developed, advantages and disadvantages of rats, as well as an overview of the most important interventions investigated and the relevance for human pathophysiology.

Sudden death in ischemic heart disease – 2017

At this time, we find ourselves with an abundance of guidelines for management of patients with manifest ventricular tachyarrhythmias, or at risk for such arrhythmias, in patients with coronary heart disease (CHD). The guidelines are focused primarily on the “appropriate use” of the implantable cardioverter/defibrillator (ICD). Unfortunately, the bulk of the guidelines have very little basis in the underlying pathophysiology responsible for sudden cardiac death (SCD) in patients with CHD. Rather, they are based primarily on the results of randomized clinical trials that merely sought to take broad populations at elevated total mortality risk and determining whether the ICD can reduce overall mortality. The trials were not aimed at elucidating or exploiting the varying pathophysiology responsible for the ventricular arrhythmias responsible for most sudden deaths in this setting. The goal of the trials is appropriate – to improve the survival. The problem with promoting trials that solely determine whether a broad-based population (identified by one parameter such as ejection fraction that bears no direct relation to the pathogenesis of arrhythmias) derives a survival benefit from a therapy such as the ICD, is that many patients that could benefit from the ICD are missed (not covered by the guidelines), and many patients that will never benefit from the ICD are exposed to its risks and costs.How can we advance the use of potent, but expensive therapies that carry risk such as the ICD to improve survival of patients with CHD today? There are several avenues worth pursuing, both for short-term as well as long-term gain. First, there are several models shown to have the potential to identify patients currently covered by the guidelines for ICD use, that are highly unlikely to benefit, because of the existing co-morbidities. These models are likely to be valid because there is significant overlap in the parameters identified in each model, and they have been tested retrospectively in a variety of study populations. These models are not likely to be incorporated into use guidelines, until they have been tested prospectively in a randomized trial in a contemporary patient population. This can, and should be done. Use of such a model, based on noninvasive, readily available clinical markers offers the possibility of improving the efficiency with which ICDs are used to reduce the risk of SCD in CHD patients.Second, we need to recognize the fact that SCD in this population is a result of multiple potential mechanisms. And, the electrophysiologic substrates underlying these mechanisms are influenced by interactions with the autonomic nervous system and hemodynamic conditions. While most out-of-hospital cardiac arrests do not occur in persons with overt heart failure, the presence of heart failure clearly increases the risk for SCD, likely by a variety of mechanisms. There is increasing evidence that altered left ventricular geometry may not only reduce LV mechanical efficiency, but may also have direct effects on the electrophysiologic substrate. Although there is an abundance of evidence supporting the importance of autonomic interactions in the genesis of spontaneous arrhythmias, the utility of prospectively measuring autonomic indices to predict future arrhythmic events has to date not proven to be useful. Of course, that is not to discount the significant impact of beta-adrenergic blockade on survival and reducing arrhythmic events. Future works must focus more on both animal models of post-infarction arrhythmias, as well as integrating findings from such studies into human physiology, with subsequent testing in the form of randomized clinical trials.

Suppression of Arrhythmia by Enhancing Mitochondrial Calcium Uptake in Experimental Models of Catecholaminergic Ventricular Tachycardia

We have recently identified a critical role of mitochondria to shape intracellular Ca2+ signals and to regulate cardiac rhythmicity. Activation of mitochondrial Ca2+ uptake by efsevin, an agonist of the voltage-dependent anion channel 2 in the outer mitochondrial membrane, restored rhythmic cardiac contractions in a zebrafish cardiac arrhythmia model. Here we investigated the potential of pharmacological activation of mitochondrial Ca2+ uptake as a novel pharmacological strategy for human cardiac arrhythmia in a translational approach. To this aim we first used a murine model of ryanodine receptor 2 (RyR2)-mediated catecholaminergic polymorphic ventricular tachycardia (CPVT). In freshly isolated cardiomyocytes of RyR2R4496C/WT mice, harboring the human RyR2R4496C mutation associated with CPVT, efsevin restricted diastolic Ca2+ sparks and prevented the formation of propagating Ca2+ waves and spontaneous, diastolic action potentials. This anti-arrhythmic effect was abolished in the presence of mitochondrial Ca2+ uniporter (MCU) blocker Ru360 , but could be reproduced with the MCU activator kaempferol, demonstrating an immediate role of mitochondrial Ca2+ uptake for the anti-arrhythmic effect of efsevin. In RyR2R4496C/WT mice both mitochondrial Ca2+ uptake enhancers (MiCUps), efsevin and kaempferol, significantly reduced episodes of ventricular tachycardia after catecholaminergic stimulation by a bolus injection of epinephrine and caffeine in vivo while baseline ECG was unaffected. Finally, we used stem cell-derived cardiomyocytes from a CPVT patient to show efficacy of MiCUps in a human model. Both MiCUps abolished arrhythmogenic events in human CPVT cardiomyocytes. Our results demonstrate that enhancement of mitochondrial Ca2+ uptake by MiCUps is a promising pharmacological strategy for treatment and prevention of Ca2+-triggered arrhythmias, such as CPVT.

Instrumento para la evaluación del riesgo de arritmias durante el entrenamiento no aeróbico en pacientes con enfermedad cardiovascular

AimNon-aerobic physical training (NAPhT) sessions with strength, flexibility, coordination, proprioception and neuromuscular balance exercises is recommended in cardiac rehabilitation programs. However, some patients have arrhythmias that are not detected in the risk stratification. The aim of this study was to make a prediction model of arrhythmias during NAPhT sessions. Material and methodWe studied a cohort of patients (n=412) undergoing NAPhT for 30min, 3 times a week, with a moderate intensity. A cardiologist monitored the electrocardiographic signal. The occurrence of arrhythmia during NAPhT was compared with its presence in the risk stratification stress testing. All P values<.05 were considered significant. Multivariate logistic regression model was also performed. ResultsFrom a total of 412 patients, 270 (65%) showed arrhythmias in NAPhT, without major complications. Relative risk of arrhythmia in NAPhT was 1.89 (95% CI 1.25-2.86, P<.01), when arrhythmia was present during stress testing. In the bivariate analysis, other variables associated were dilated cardiomyopathy, low ejection fraction, use of digoxin, diuretics, low peak oxygen uptake and low ventilatory efficiency. In the regression model, 3 variables remained significant: arrhythmias in stress test, peak oxygen uptake and diuretic. ConclusionThe presence of arrhythmias during NAPhT sessions in patients with heart disease is elevated, and they are associated with diuretic use, peak oxygen uptake values and the presence of arrhythmias in stress testing. Therefore, continuous electrocardiographic monitoring is recommended in these kind of patients.

Gene Therapy for Post-infarction Ventricular Tachycardia.

Cardiac arrhythmias are a leading cause of morbidity and mortality in the developed world. In particular, cardiac arrest or sudden cardiac death is the leading cause of death in these countries. Death generally results from a ventricular tachyarrhythmia, and pathology data have shown that cardiac arrest victims very frequently have evidence of coronary atherosclerosis with either acute ischemia or healed myocardial infarction. In this work, we describe an animal model that reproducibly has inducible ventricular tachyarrhythmias after healing of a myocardial infarction scar and a gene delivery method that allows gene transfer to the scar and surrounding myocardial tissues. Use of the method allows gene delivery to the arrhythmia model for testing of hypotheses related to ventricular tachyarrhythmia mechanisms and for efficacy testing of proposed gene therapies. To date, all work in this area has been preclinical, but it is our hope that continued development in this area will 1 day allow translation of this method into clinical practice.

Synthesis and Structure-Activity Relationships of a Series of Aporphine Derivatives with Antiarrhythmic Activities and Acute Toxicity.

Some aporphine alkaloids, such as crebanine, were found to present arrhythmic activity and also higher toxicity. A series of derivatives were synthesized by using three kinds of aporphine alkaloids (crebanine, isocorydine, and stephanine) as lead compounds. Chemical methods, including ring-opening reaction, bromination, methylation, acetylation, quaternization, and dehydrogenation, were adopted. Nineteen target derivatives were evaluated for their antiarrhythmic potential in the mouse model of ventricular fibrillation (VF), induced by CHCl3, and five of the derivatives were investigated further in the rat model of arrhythmia, induced by BaCl2. Meanwhile, preliminary structure-activity/toxicity relationship analyses were carried out. Significantly, N-acetamidesecocrebanine (1d), three bromo-substituted products of crebanine (2a, 2b, 2c), N-methylcrebanine (2d), and dehydrostephanine (4a) displayed antiarrhythmic effects in the CHCl3-induced model. Among them, 7.5 mg/kg of 2b was able to significantly reduce the incidence of VF induced by CHCl3 (p < 0.05), increase the number of rats that resumed sinus rhythm from arrhythmia, induced by BaCl2 (p < 0.01), and the number of rats that maintained sinus rhythm for more than 20 min (p < 0.01). Therefore, 2b showed remarkably higher antiarrhythmic activity and a lower toxicity (LD50 = 59.62 mg/kg, mice), simultaneously, indicating that 2b could be considered as a promising candidate in the treatment of arrhythmia. Structural-activity analysis suggested that variationsin antiarrhythmic efficacy and toxicity of aporphines were related to the C-1,C-2-methylenedioxy group on ring A, restricted ring B structural conformation, N-quaternization of ring B, levoduction of 6a in ring C, and the 8-, 9-, 10-methoxy groups on ring D on the skeleton.

Influence of total flavonoids derived from Choerospondias axillaris folium on aconitine-induced antiarrhythmic action and hemodynamics in Wistar rats

ABSTRACTIt is well known that various traditional Chinese medicines produce antiarrhythmic actions. The aims of this study were to examine whether total flavones derived from Choerospondias axillaris folium (TFCF) also produced antiarrhythmic effects using a rat model of aconitine-induced arrhythmia and to compare these observations with the effects of total flavones of Choerospondias axillaris fructus (TFC). Wistar rats were orally administered TFC (0.2 g/kg) or TFCF (0.1, 0.2, or 0.4 g/kg) daily for 7 d. Subsequently, aconitine iv at 25 µg/kg was used to induce arrhythmia in these animals. Control (C) physiological saline and positive verapamil rats were also administered orally. The starting times of ventricular ectopic beats (VE), ventricular tachycardia (VT), ventricular fibrillation (VF), and heart arrest (HA) were recorded. In comparison to C, TFCF and TFC significantly prolonged the starting time of VE, VT, VF, and HA induced by aconitine. With respect to hemodynamics, TFC and high-dose TFCF were effective in reducing HR without associated changes in BP in all groups. TFC and TFCF decreased left ventricular systolic pressure (LVSP) and maximal velocity rate of ventricular pressure (+dp/dt max and –dp/dt min) with no marked effect on left ventricular end diastolic pressure (LVEDP) and –dp/dtmin. Data demonstrated that TFCF and TFC were equally effective in diminishing the aconitine-mediated arrhythmias. In addition, TFCF and TFC produced a similar reduction in HR with no accompanying change in BP. These findings indicate that the TFCF- and TFC-induced alterations may be attributed to inhibition of ventricular contraction without altering ventricular diastolic function.

Chemically Homogenous Compounds with Antagonistic Properties at All α1-Adrenoceptor Subtypes but not β1-Adrenoceptor Attenuate Adrenaline-Induced Arrhythmia in Rats

Studies proved that among all α1-adrenoceptors, cardiac myocytes functionally express only α1A- and α1B-subtype. Scientists indicated that α1A-subtype blockade might be beneficial in restoring normal heart rhythm. Therefore, we aimed to determine the role of α1-adrenoceptors subtypes (i.e., α1A and α1B) in antiarrhythmic effect of six structurally similar derivatives of 2-methoxyphenylpiperazine. We compared the activity of studied compounds with carvedilol, which is β1- and α1-adrenoceptors blocker with antioxidant properties. To evaluate the affinity for adrenergic receptors, we used radioligand methods. We investigated selectivity at α1-adrenoceptors subtypes using functional bioassays. We tested antiarrhythmic activity in adrenaline-induced (20 μg/kg i.v.), calcium chloride-induced (140 and 25 mg/kg i.v.) and barium chloride-induced (32 and 10 mg/kg i.v.) arrhythmia models in rats. We also evaluated the influence of studied compounds on blood pressure in rats, as well as lipid peroxidation. All studied compounds showed high affinity toward α1-adrenoceptors but no affinity for β1 receptors. Biofunctional studies revealed that the tested compounds blocked α1A-stronger than α1B-adrenoceptors, but except for HBK-19 they antagonized α1A-adrenoceptor weaker than α1D-subtype. HBK-19 showed the greatest difference in pA2 values—it blocked α1A-adrenoceptors around seven-fold stronger than α1B subtype. All compounds showed prophylactic antiarrhythmic properties in adrenaline-induced arrhythmia, but only the activity of HBK-16, HBK-17, HBK-18, and HBK-19 (ED50 = 0.18–0.21) was comparable to that of carvedilol (ED50 = 0.36). All compounds reduced mortality in adrenaline-induced arrhythmia. HBK-16, HBK-17, HBK-18, and HBK-19 showed therapeutic antiarrhythmic properties in adrenaline-induced arrhythmia. None of the compounds showed activity in calcium chloride- or barium chloride-induced arrhythmias. HBK-16, HBK-17, HBK-18, and HBK-19 decreased heart rhythm at ED84. All compounds significantly lowered blood pressure in normotensive rats. HBK-18 showed the strongest hypotensive properties (the lowest active dose: 0.01 mg/kg). HBK-19 was the only compound in the group, which did not show hypotensive effect at antiarrhythmic doses. HBK-16, HBK-17, HBK-18, HBK-19 showed weak antioxidant properties. Our results indicate that the studied 2-methoxyphenylpiperazine derivatives that possessed stronger α1A-adrenolytic properties (i.e., HBK-16, HBK-17, HBK-18, and HBK-19) were the most active compounds in adrenaline-induced arrhythmia. Thus, we suggest that the potent blockade of α1A-receptor subtype is essential to attenuate adrenaline-induced arrhythmia.

Ischemia–reperfusion destabilizes rhythmicity in immature atrioventricular pacemakers: A predisposing factor for postoperative arrhythmias in neonate rabbits

Postoperative arrhythmias such as junctional ectopic tachycardia and atrioventricular block are serious postoperative complications for children with congenital heart disease. We hypothesize that ischemia-reperfusion (I/R) related changes exacerbate these postoperative arrhythmias in the neonate heart and administration of postoperative inotropes is contributory. The purpose of this study was to study the effects of I/R and postischemic dopamine application on automaticity and rhythmicity in immature and mature pacemaker cells and whole heart preparations. Single pacemaker cells and whole heart models of postoperative arrhythmias were generated in a rabbit model encompassing 3 primary risk factors: age, I/R exposure, and dopamine application. Single cells were studied using current clamp and line scan confocal microscopy, whereas whole hearts were studied using optical mapping. Four responses were observed in neonatal atrioventricular nodal cells (AVNCs): slowing of AVNC automaticity (from 62±10 to 36 ± 12 action potentials per minute, P<.05); induction of arrhythmicity or increased beat-to-beat variability (0.08 ± 0.04 to 3.83 ± 1.79, P<.05); altered automaticity (subthreshold electrical fluctuations); and disruption of calcium transients. In contrast, these responses were not observed in mature AVNCs or neonatal sinoatrial cells. In whole heart experiments, neonatal hearts experienced persistent postischemia arrhythmias of varying severity, whereas mature hearts exhibited no arrhythmias or relatively transient ones. Neonatal pacemaker cells and whole hearts demonstrate a susceptibility to I/R insults resulting in alterations in automaticity, which may predispose neonates to postoperative arrhythmias such as junctional ectopic tachycardia and atrioventricular block.