Bela Szabo

Progress in the understanding of cardiac early afterdepolarizations and torsades de pointes: time to revise current concepts

Time for primary review 19 days. Afterdepolarizations are oscillations of the transmembrane potential that depend on the preceding action potential (AP) for their generation and can give rise to new APs when they reach a critical threshold for activation of a depolarizing current. This form of abnormal impulse generation is called ‘triggered activity’ [1]. Two types of afterdepolarizations have been distinguished: delayed (DADs) and early afterdepolarizations (EADs). DADs have been defined as “oscillations in membrane potential that occur after repolarization of an action potential” [2]. EADs are generated during the AP and have been defined as “oscillations at the plateau level of membrane potential or later during phase 3 of repolarization” [2]. Depending on the level of the membrane potential at which they are generated, EADs can trigger new APs that may appear as ectopic beats on the ECG. EADs can also augment electrical heterogeneity in regions of neighboring myocardium, which can lead to the formation of new APs via electrotonic interaction between areas that are still inexcitable and those that have already recovered from refractoriness [3]. Although the latter mechanism is reentrant rather than triggered activity, the occurrence of EADs is of pivotal importance for arrhythmogenesis under these circumstances. The clinical significance of EADs lies in their capacity to provide both the trigger (premature ectopic beats) and the substrate (electrical heterogeneity with nonuniform repolarization and refractoriness) for the initiation and perpetuation of torsades de pointes. In this article, we discuss the evidence for a new concept of EAD formation, which includes an important role for cytoplasmic-[Ca2+]-dependent mechanisms, as schematically illustrated in Fig. 1. As a background, we will first review the recent literature on cellular Ca2+ homeostasis. Then, we introduce the classical view on EAD formation with a discussion of the … * Corresponding author. Tel.: +31-43-3875093; fax: +31-43-3875104 p.volders{at}cardio.azm.nl

Similarities between early and delayed afterdepolarizations induced by isoproterenol in canine ventricular myocytes

OBJECTIVES This study aims at clarifying the role of cellular Ca2+ overload and spontaneous sarcoplasmic reticulum (SR) Ca2+ release in the generation of early afterdepolarizations (EAD) by isoproterenol. The involvement of a Ca(2+)-activated membrane current in isoproterenol-induced EAD is investigated. METHODS Membrane potential and contraction (an indicator of SR Ca2+ release) were recorded in canine left ventricular myocytes at pacing cycle lengths (CL) of 300-4000 ms. Threshold concentration for EAD was 20-50 mmol/l isoproterenol. Ni2+ (2.0-5.0 mmol/l) was used at normal and high (5.4 mmol/l) [Ca2+]o to examine the role of Ca2+ current and/or Na(+)-Ca2+ exchange (1Na-Ca) in EAD. RESULTS In all cells delayed afterdepolarizations (DAD) appeared during isoproterenol. In most (approximately equal to 70%) cells EAD were also generated, which were fast-pacing dependent, occurring only at CL of 400-1000 ms. EAD were always initiated by a delay in repolarization. Early aftercontractions preceded the EAD upstrokes, often occurring without them. They coincided with the initial delays in repolarization. During treatment with isoproterenol, Ni2+ and high [Ca2+]o, EAD and DAD were suppressed despite the continued presence of early and delayed aftercontractions. CONCLUSIONS Our data indicate that beta-adrenergic EAD share a common ionic mechanism with DAD in terms of cellular Ca2+ overload and spontaneous SR Ca2+ release. beta-Adrenergic EAD consist of two phases: (1) a conditional phase coinciding with the onset of an early aftercontraction, often followed by (2) an EAD upstroke. A Ca2(+)-activated membrane current, probably I Na-Ca, is necessary at least for the initiation of these EAD.

Ventricular Tachyarrhythmias Related to Early Afterdepolarizations and Triggered Firing: Relationship to QT Interval Prolongation and Potential Therapeutic Role for Calcium Channel Blocking Agents

The ventricular tachyarrhythmias associated with the long QT syndromes have remained enigmatic because of the striking heterogeneity in the events precipitating the arrhythmia (intense sympathetic stimulation vs drug administration or electrolyte abnormalities which prolong repolarization). The absence of comprehensive diagnostic criteria and rational therapy stems from a poor understanding of the mechanistic bases for these arrhythmias. The purpose of this report is to demonstrate the use of current tool s (pacing, monophasic action potential recordings and drugs) to explore new characteristics of these arrhythmias in patients which might be compared to those observed in experimental models. Although limited in scope, recent experimental observations suggest that arrhythmias with many of these characteristics might result from triggered firing associated with early afterdepolarizations (Brachmann , et al., 1983; Da-

Role of Na+:Ca2+ Exchange Current in Cs+‐Induced Early Afterdepolarizations in Purkinje Fibers

Na+:Ca2+ Exchanger and EADs. Introduction: The ionic mechanisms for early afterdepolarizations (EADs) have not been fully clarified. It has been suggested that L‐type Ca2+ current (IcaL) is the primary current generating EADs that occur near the plateau level (E‐EADs) of the membrane potential (Vm) when IcaL is enhanced. The purpose of these studies was to determine accurately the range of Vm at which EADs occur in Purkinje fibers with K+ currents blocked by Cs+ and to investigate the importance of Na+:Ca2+ exchange current (INa:ca) as opposed to lCaL and other currents in the generation of EADs occurring later during repolarization (L‐EADs).

Role of calcium loading in early afterdepolarizations generated by Cs+ in canine and guinea pig Purkinje fibers.

Ca2+‐Loading and EAD. introduction: Our previous observations indicate that the Na2+:Ca2+ exchange current (INa:Ca) plays an important role in early afterdepolarizations occurring at more negative Vm (L‐EAD). The purpose of these studies was to examine the role of Ca2+‐loading, which stimulates INa:Ca, in generation of L‐EAD.

Opposing cardiac effects of autoantibody activation of beta-adrenergic and M2 muscarinic receptors in cardiac-related diseases

BACKGROUND Activating autoantibodies to β-adrenergic receptors (AAβ1/2AR) and M2 muscarinic receptors (AAM2R) have been reported in several cardiac diseases and may have pathophysiologic relevance. However, the interactions and relative effects of AAβ1AR, AAβ2AR and AAM2R on contractile function have not been characterized. METHODS The inotropic effects of IgG from 18 selected patients with cardiomyopathy and/or atrial tachyarrhythmias positive by ELISA for antibodies to β1/2AR were studied using an isolated canine Purkinje fiber contractility assay. M2R-blockade was tested using atropine while selective β1AR and β2AR blockade used CGP-20712A and ICI-118551 respectively. RESULTS Fifteen of the 18 anti-β1/2AR ELISA-positive samples demonstrated evidence for negative inotropic muscarinic effects which were blocked using atropine. Atropine failed to uncover a positive inotropic response in 2 of the 18 IgG samples (false positive ELISA for AAβAR). In the remaining 16 AAβAR true-positive subjects, the β1AR-induced increase in contractility (concurrent M2/β2 blockade) was augmented to 140.5±12.2% of baseline compared to 127.4±7.2% of baseline with M2 blockade (atropine) only (p<0.001, n=16). The β2AR-induced increase in contractility (concurrent M2/β1 blockade) was only 114.5±4.3% of baseline (p<0.001, n=16). Combined M2 and β1/β2 blockade eliminated any increase in contractility. CONCLUSIONS The inherently positive inotropic effect of AAβ1AR was negatively modulated by AAM2R and AAβ2AR. These opposing effects of receptor-activating autoantibodies may alter cardiac performance and influence clinical outcome depending on their receptor type and relative contractile activity.

Facilitation of Epinephrine-Induced Afterdepolarizations by Class III Antiarrhythmic Drugs

The electrophysiologic actions of epinephrine (10(-9) M, 10(-8) M, and 10(-7) M) were evaluated in canine Purkinje fibers pretreated with the class III antiarrhythmic drugs clofilium (10(-7) M) or d,l-sotalol (10(-6) M). Clofilium and d,l-sotalol prolonged action potential duration at 50% and 90% of repolarization without provoking early afterdepolarization (EAD) or delayed afterdepolarization (DAD). Subsequent administration of epinephrine provoked both bradycardia-dependent EADs and tachycardia-dependent DADs in clofilium-treated Purkinje fibers, with predominantly EADs observed in d,l-sotalol-treated Purkinje fibers. A temporary increase in Ca0(+2) from 1.35 mM to 5 mM suppressed both EADs and DADs. The data demonstrate facilitation of epinephrine-induced EADs and DADs by class III antiarrhythmic drugs. The acute suppression of both EADs and DADs observed following an acute increase in Ca0(+2) suggests inward Na(+)-Ca0(+2) exchange current as a basis for both EADs and DADs observed in the presence of class III antiarrhythmic drugs and epinephrine.

Adrenergic Induction of Delayed Afterdepolarizations in Ventricular Myocardial Cells: β Induction and α Modulation

Adrenergic Afterdepolarizations in Ventricular Cells. Introduction: The purpose of these studies was to expose canine multicellular ventricular endocardial preparations and disaggregated myocytes to adrenergic agonists and antagonists, and to investigate the generation of delayed afterdepolarizations and triggered action potentials. Methods and Results: We used multicellular preparations and disaggregated myocytes from canine ventricles. The threshold concentration for induction of delayed afterdepolarizations in isolated myocytes for norepinephrine was between 1 × 10−8 M and 5 × 10−5 M, with 50% of the cells showing delayed afterdepolarizations at 4.3 × 10−8 M. Higher concentrations of epinephrine are required with 50% of the cells responding to 8.3 × 10−8 M. The threshold concentrations for induction of delayed afterdepolarizations in myocardial cells of multicellular preparations were an order of magnitude higher. Delayed afterdepolarizations could not be induced in Purkinje fibers with concentrations up to 10−4 M with norepinephrine. Adrenergic delayed afterdepolarizations were inhibited promptly by reduction of pO2 in superfusate that was equilibrated with N2 (95%) in place of O2. The amplitudes of adrenergic delayed afterdepolarizations and the propensity to triggered action potentials were inversely related to cycle length down to the shortest cycle length tested (330 msec). Adrenergic delayed afterdepolarizations were induced by isoproterenol but not by α‐adrenergic agonists (methoxamine or phenylephrine). They were inhibited by a β antagonist (propranolol) but not by α antagonists (prazosin or yohimbine). Delayed afterdepolarizations induced by isoproterenol were inhibited by α agonists (methoxamine or phenylephrine). The α‐adrenergic inhibitory effects on β‐adrenergic delayed afterdepolarizations could be reversed by prazosin, but not by yohimbine. Conclusions: We conclude the natural catecholamines norepinephrine and epinephrine generate delayed afterdepolarizations in myocardial cells, but not in Purkinje cells, by activating β receptors, but activation of α1 receptors inhibits adrenergic delayed afterdepolarizations. Individual myocytes exhibit widely varying sensitivities for induction of adrenergic delayed afterdepolarizations, but some cells respond to concentrations similar to those that may exist in vivo. Therefore, sympathetic activation in vivo may generate delayed afterdepolarizations, triggered action potentials, and arrhythmias.

Canine Ventricular Myocyte β2‐Adrenoceptors Are Not Functionally Coupled to L‐Type Calcium Current

Selective Stimulation of β AR Subtypes and ICaL. Introduction: To establish the functional coupling of beta adrenoceptor (βAR) subtypes β1, AR and β2AR to L‐type calcium current (ICaL)we investigated the nonselective agonist isoproterenol (ISO) and the relatively selective β1AR antagonists zinterol (ZIN) and salbutamol (SAL) on ICaL in isolated canine ventricular myocytes in the presence and absence of CGP 20712A (CGP) and atenolol (AT), selective β1AR antagonists, and ICI 118,551 (ICI) a selective β2AR antagonist.

Autoimmune Hypertensive Syndrome

Intravenous infusion of epinephrine or norepinephrine produces hypertension and symptoms similar to a pheochromocytoma.1,2 The sequelae are predictable on the basis of continuous infusion of agonists that activate β and α adrenergic receptors (ARs). These monoamine agonists, however, are not the only means by which β-ARs can be activated. Activating autoantibodies (AAs) directed toward the β1AR and/or the β2AR have been demonstrated in some patients with idiopathic dilated cardiomyopathy,3–5 Chagas’ disease,6,7 and other forms of cardiomyopathy.8,9 Several studies have demonstrated that these antibodies possess the ability to activate the intrinsic βAR signal transduction system; however, these studies have focused only on the possible relationship of the AAβAR agonist effects on cardiomyopathy. Because β-agonist excess also produces changes in systemic blood pressure, one would expect the presence of AAβAR to produce a phenotype including some features observed in patients with an epinephrine-only secretory neuroendocrine tumor. Isolated studies have reported the concurrence of activating autoantibodies to the α1AR10,11 or to the angiotensin receptor (AT1)12,13 in a few patients with associated hypertension. Herein, we present a hypertensive patient with no clinical evidence for a pheochromocytoma secreting excess catecholamine(s). However, in year 2000, there was conclusive evidence for anti-βAR autoantibodies, which in vitro activate the βAR signal transduction system independent of the intrinsic hormone-mediated system. Subsequent study in sera obtained in 2006 confirmed these data. These autoantibodies, as a result of their peptide sequence specificity, do not activate the α-adrenergic transduction system, as would norepinephrine or epinephrine at higher dosages. The evidence that these antibodies possess all of the β-activation potential of epinephrine is not unlike that expected with an epinephrine-only secreting pheochromocytoma but without a secretory tumor. The patient may represent the prototype of a new hypertensive syndrome that has an …