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Charles Antzelevitch

Publications and source records attributed to Charles Antzelevitch.

At least 55 records · Page 3Linked to original sources
PubMed2004

Cellular basis for the monophasic action potential. Which electrode is the recording electrode?

BACKGROUND: The cellular basis for the monophasic action potential (MAP) has long been a matter of debate. At the center of the controversy is the issue as to which of the two electrodes is the recording electrode and which is the indifferent electrode. The present study is designed to address this issue. METHODS: Transmembrane action potentials (TAPs) and either intramural MAPs or contact (Franz-like) MAPs were recorded from adjacent sites in canine arterially perfused ventricular wedge preparations. Intramural MAPs were recorded using thin wire electrodes referenced to a KCl electrode. RESULTS: Local cooling or injection of ATX-II into the region subtending the inactivating (contact or KCl) electrode did not affect the MAP. Similar maneuvers at the site of the noninactivating electrode always prolonged the MAP. The intramural MAP always prolonged in proportion to the TAP, whereas the contact MAP did not, often displaying apparent early afterdepolarizations (EADs) or delayed afterdepolarizations (DADs) due to its much wider field of view, which captured activity from the region of prolonged repolarization as well as the remote normal regions. CONCLUSIONS: Our results suggest that (1) it is not the contact or MAP electrode that records the MAP, but rather the noninactivating "indifferent" electrode and (2) intramural MAPs provide more accurate recordings of local activity. The data provide compelling evidence in support of the hypothesis that the MAP represents the extracellular potential difference between active and inactive sites within the heart rather than injury currents flowing at the boundary of the active and inactive zone under the inactivating electrode.

Action Potentials↗
PubMed2004

Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties.

BACKGROUND: Ranolazine is a novel antianginal agent capable of producing antiischemic effects at plasma concentrations of 2 to 6 micromol/L without reducing heart rate or blood pressure. The present study examines its electrophysiological effects in isolated canine ventricular myocytes, tissues, and arterially perfused left ventricular wedge preparations. METHODS AND RESULTS: Transmembrane action potentials (APs) from epicardial and midmyocardial (M) regions and a pseudo-ECG were recorded simultaneously from wedge preparations. APs were also recorded from epicardial and M tissues. Whole-cell currents were recorded from epicardial and M myocytes. Ranolazine inhibited I(Kr) (IC50=11.5 micromol/L), late I(Na), late I(Ca), peak I(Ca), and I(Na-Ca) (IC50=5.9, 50, 296, and 91 micromol/L, respectively) and I(Ks) (17% at 30 micromol/L), but caused little or no inhibition of I(to) or I(K1). In tissues and wedge preparations, ranolazine produced a concentration-dependent prolongation of AP duration of epicardial but abbreviation of that of M cells, leading to reduction or no change in transmural dispersion of repolarization (TDR). At [K+]o=4 mmol/L, 10 micromol/L ranolazine prolonged QT interval by 20 ms but did not increase TDR. Extrasystolic activity and spontaneous torsade de pointes (TdP) were never observed, and stimulation-induced TdP could not be induced at any concentration of ranolazine, either in normal or low [K+]o. Ranolazine (5 to 20 micromol/L) suppressed early afterdepolarizations (EADs) and reduced the increase in TDR induced by the selective I(Kr) blocker d-sotalol. CONCLUSIONS: Ranolazine produces ion channel effects similar to those observed after chronic amiodarone (reduced I(Kr), I(Ks), late I(Na), and I(Ca)). The actions of ranolazine to suppress EADs and reduce TDR suggest that, in addition to its antianginal actions, the drug may possess antiarrhythmic activity.

Acetanilides↗
PubMed2004

Short QT syndrome: pharmacological treatment.

OBJECTIVES: The purpose of this study was to evaluate the efficacy of various antiarrhythmic drugs at prolonging the QT interval into the normal range and preventing ventricular arrhythmias in patients with short QT syndrome. BACKGROUND: Short QT syndrome is a recently described genetic disease characterized by short QT interval, high risk of sudden death, atrial fibrillation, and short refractory periods. METHODS: Six patients with short QT syndrome, five of whom had received an implantable cardioverter-defibrillator (ICD) and one child, were tested with different antiarrhythmic drugs, including flecainide, sotalol, ibutilide, and hydroquinidine, to determine whether they could prolong the QT interval into the normal range and thus prevent symptoms and arrhythmia recurrences. RESULTS: Class IC and III antiarrhythmic drugs did not produce a significant QT interval prolongation. Only hydroquinidine administration caused a QT prolongation, which increased from 263 +/- 12 ms to 362 +/- 25 ms (calculated QT from 290 +/- 13 ms to 405 +/- 26 ms). Ventricular programmed stimulation showed prolongation of ventricular effective refractory period to > or =200 ms, and ventricular fibrillation was no longer induced. CONCLUSIONS: The ability of quinidine to prolong the QT interval has the potential to be an effective therapy for short QT patients. This is particularly important because these patients are at risk of sudden death from birth, and ICD implant is not feasible in very young children.

Adolescent↗
PubMed2004

Epicardial activation of left ventricular wall prolongs QT interval and transmural dispersion of repolarization: implications for biventricular pacing.

BACKGROUND: Epicardial pacing of the left ventricle (LV) has been shown to prolong the QT interval and predispose to the development of torsade de pointes arrhythmias. The present study examines the cellular basis for QT prolongation and arrhythmogenesis after reversal of the direction of activation of the LV wall. METHODS AND RESULTS: A transmural ECG and transmembrane action potentials were simultaneously recorded from epicardial, M, and endocardial cells of arterially perfused canine LV wedge preparations. QT interval increased from 297.6+/-3.9 to 314.0+/-5.7 ms (n=12; P<0.001) and transmural dispersion of repolarization (TDR) increased from 35.5+/-5.2 to 70.3+/-6.2 ms (n=12; P<0.001) as pacing was shifted from endocardium to epicardium. Conduction time between M and epicardial cells increased from 12.1+/-1.2 to 24.2+/-1.5 ms (n=12; P<0.001). Amplification of TDR was further accentuated in the presence of rapidly activating delayed rectifier potassium current blockers (E-4031 and cisapride), increasing from 50.5+/-7.6 to 86.1+/-6.2 ms (n=8; P<0.01). Torsade de pointes arrhythmias could be induced during epicardial, but not endocardial, pacing of LV in the presence of rapidly activating delayed rectifier potassium current blockade. CONCLUSIONS: Reversal of the direction of activation of the LV wall, as occurs during biventricular pacing, leads to a prominent increase in QT and TDR as a result of earlier repolarization of epicardium and delayed activation and repolarization of the midmyocardial M cells. The increase in TDR creates the substrate for the development of torsade de pointes under long-QT conditions.

Action Potentials↗
PubMed2004

Antiarrhythmic effects of ranolazine in a guinea pig in vitro model of long-QT syndrome.

Prolongation of the QT interval of the ECG is associated with increased risk of torsades de pointes ventricular tachycardia. Ranolazine, a novel antianginal agent, is reported to decrease the delayed rectifier potassium current, I(Kr), and to increase action potential duration (APD) and the QT interval. However, ranolazine is also reported to reduce late sodium current (late I(Na)), a depolarizing current that contributes to prolongation of the plateau of the ventricular action potential. We hypothesized that ranolazine would decrease APD and the occurrence of arrhythmias when late I(Na) is increased. Therefore, we measured the effects of ranolazine alone and in the presence of anemone toxin (ATX)-II, whose action mimics the sodium channelopathy associated with long-QT3 syndrome, on epicardial monophasic action potentials and ECGs recorded from guinea pig isolated hearts. Ranolazine (0.1-50 microM) prolonged monophasic APD at 90% repolarization (MAPD(90)) by up to 22% but did not cause either early afterdepolarizations (EADs) or ventricular tachycardia (VT). ATX-II (1-20 nM) markedly increased APD and caused EADs and VT. Ranolazine (5-30 microM) significantly attenuated increases in MAPD(90) and reduced episodes of EADs and VT produced by ATX-II. Ranolazine also attenuated the synergistic effect of MAPD(90) increase caused by combinations of ATX-II and blockers of I(K) [E-4031; 1-[2-(6-methyl-2-pyridyl)ethyl]-4-methylsulfonylaminobenzoyl)piperidine]. Thus, although ranolazine alone prolonged APD, it reduced APD and ventricular arrhythmias caused by agents that increased late I(Na) and decreased I(K).

Acetanilides↗
PubMed2004

Role of sodium and calcium channel block in unmasking the Brugada syndrome.

OBJECTIVE: We hypothesized that a combination of I(Na) and I(Ca) blockade may be more effective in causing loss of the epicardial action potential (AP) dome and precipitating the Brugada syndrome (BS). The present study was designed to test this hypothesis in an in vitro model of BS. BACKGROUND: The Brugada syndrome is characterized by an ST segment elevation in the right precordial ECG leads and a high risk of sudden death. The ECG sign of BS is often concealed, but can be unmasked with potent sodium channel blockers. Using canine right ventricular (RV) wedge preparations, we previously developed an experimental model of BS using flecainide to depress the AP dome in RV epicardium. METHODS: Intracellular APs and a transmural ECG were simultaneously recorded from canine RV wedge preparations. RESULTS: Terfenadine (5-10 microM)-induced block of I(Ca) and I(Na) caused heterogeneous loss of the epicardial AP dome, resulting in ST segment elevation, phase 2 reentry (12/16), and spontaneous polymorphic VT/VF (6/16). Flecainide (</=7.5 microM), ajmaline (</=20 microM), and procainamide (</=300 microM) failed to generate polymorphic VT in any preparation except when combined with a calcium channel blocker (verapamil, </=20 microM). Terfenadine-induced ST segment elevation was normalized and arrhythmias suppressed following I(to) block with 4-aminopyridine (0.5-2 mM). CONCLUSION: Our data suggest that combined sodium and calcium channel block may be more effective than sodium channel block alone in unmasking the Brugada syndrome and that pharmacologic agents that inhibit I(to) may be useful in preventing lethal arrhythmias in patients with the syndrome.

Ajmaline↗
PubMed2004

Arrhythmogenic mechanisms of QT prolonging drugs: is QT prolongation really the problem?

Torsade de Pointes (TdP) is an atypical ventricular arrhythmias associated with the acquired and congenital forms of the long QT syndrome. The substrate for the arrhythmia develops as a consequence of the amplification of electrical heterogeneities intrinsic to the ventricular myocardium. These heterogeneities exist because of differences in the time course of repolarization of the three predominant cell types that make up the ventricular myocardium, giving rise to transmural voltage gradients and a dispersion of repolarization responsible for the inscription of the electrocardiographic T wave. A wide variety of drugs are capable of reducing net repolarizing current and thus amplifying the intrinsic spatial dispersion of repolarization, so as to create the substrate for the development of re-entry. The result is a prolongation of the QT interval, abnormal T waves, and development of polymorphic re-entrant ventricular tachycardia displaying characteristics of TdP. Recent studies demonstrate that prolongation of the QT interval is not the sole determinant of the potential of a drug to cause TdP; agents that do not increase transmural dispersion of repolarization have little or no potential to induce the arrhythmia despite their ability to prolong the QT interval. Moreover, drugs such as sodium pentobarbital, which reduce transmural dispersion of repolarization, can diminish the likelihood of TdP, despite their ability to prolong the QT interval.

Action Potentials↗
PubMed2004

Phenotypic characterization of a large European family with Brugada syndrome displaying a sudden unexpected death syndrome mutation in SCN5A:.

INTRODUCTION: Brugada syndrome is characterized by sudden death secondary to malignant arrhythmias and the presence of ST segment elevation in leads V(1) to V(3) of patients with structurally normal hearts. This ECG pattern often is concealed but can be unmasked using potent sodium channel blockers. Like congenital long QT syndrome type 3 (LQT3) and sudden unexpected death syndrome, Brugada syndrome has been linked to mutations in SCN5A. METHODS AND RESULTS: We screened a large European family with Brugada syndrome. Three members (two female) had suffered malignant ventricular arrhythmias. Ten members showed an ECG pattern characteristic of Brugada syndrome at baseline, and eight showed the pattern only after administration of ajmaline (total 12 female). Haplotype analysis revealed that all individuals with positive ECG at baseline shared the SCN5A locus. Sequencing of SCN5A identified a missense mutation, R367H, previously associated with sudden unexpected death syndrome. Two of the eight individuals who displayed a positive ECG after the administration of ajmaline, but not before, did not have the R367H mutation, and sequencing analysis failed to identify any other mutation in SCN5A. The R367H mutation failed to generate any current when heterologously expressed in HEK cells. CONCLUSION: Our results support the hypothesis that (1) sudden unexpected death syndrome and Brugada syndrome are the same disease; (2) male predominance of the phenotype observed in sudden unexpected death syndrome does not apply to this family, suggesting that factors other than the specific mutation determine the gender distinction; and (3) ajmaline may provide false-positive results. These findings have broad implications relative to the diagnosis and risk stratification of family members of patients with the Brugada syndrome.

Adult↗
PubMed2004

Drug-induced torsades de pointes and implications for drug development.

Torsades de pointes is a potentially lethal arrhythmia that occasionally appears as an adverse effect of pharmacotherapy. Recently developed understanding of the underlying electrophysiology allows better estimation of the drug-induced risks and explains the failures of older approaches through the surface ECG. This article expresses a consensus reached by an independent academic task force on the physiologic understanding of drug-induced repolarization changes, their preclinical and clinical evaluation, and the risk-to-benefit interpretation of drug-induced torsades de pointes. The consensus of the task force includes suggestions on how to evaluate the risk of torsades within drug development programs. Individual sections of the text discuss the techniques and limitations of methods directed at drug-related ion channel phenomena, investigations aimed at action potentials changes, preclinical studies of phenomena seen only in the whole (or nearly whole) heart, and interpretation of human ECGs obtained in clinical studies. The final section of the text discusses drug-induced torsades within the larger evaluation of drug-related risks and benefits.

Anti-Arrhythmia Agents↗
PubMed2004

Cellular basis and mechanism underlying normal and abnormal myocardial repolarization and arrhythmogenesis.

Regional differences in repolarization characteristics of distinct cell types are responsible for the inscription of the J wave and T wave of the electrocardiogram (ECG). Amplification of these electrical heterogeneities contributes to the development of a variety of cardiac arrhythmias. This brief review examines the ionic and cellular basis for these heterogeneities and their role in the Brugada and long-QT syndromes. Both cases involve an accentuation of transmural dispersion of repolarization (TDR). In the case of the Brugada syndrome. TDR is accentuated as a result of a preferential abbreviation of the right ventricular epicardial action potential, whereas in the long-QT syndrome, accentuation of TDR is secondary to a preferential prolongation of the action potential of the M cell.

Action Potentials↗
PubMed2004

Autonomic aspects of arrhythmogenesis: the enduring and the new.

PURPOSE OF REVIEW: Recent progress in understanding the role of the autonomic nervous system in the development of cardiac arrhythmias is reviewed. The focus is on the translation of basic principles of neural control of heart rhythm that have emerged from experimental studies to clinical applications. RECENT FINDINGS: Recent studies have made significant strides in defining the function of intrinsic cardiac innervation and the importance of nerve sprouting in electrical remodeling. A recurring theme is that heterogeneity of sympathetic innervation in response to injury is highly arrhythmogenic. In addition, both sympathetic and parasympathetic influences on ion channel activity have been found to accentuate electrical heterogeneities and thus to contribute to arrhythmogenesis in the long QT and Brugada syndromes. In the clinic, heart rate variability continues to be a useful tool in delineating pathophysiologic changes that result from the progression of heart disease and the impact of diabetic neuropathy. Heart rate turbulence, a noninvasive indicator of baroreceptor sensitivity, has emerged as a simple, practical tool to assess risk for cardiovascular mortality in patients with ischemic heart disease and heart failure. Evidence of the proarrhythmic influence of behavioral stress has been further bolstered by defibrillator discharge studies and ambulatory ECG-based T-wave alternans measurement. SUMMARY: The results of recent investigations underscore the importance of the autonomic influences as triggers of arrhythmia and provide important mechanistic insights into the ionic and cellular mechanisms involved.

Arrhythmias, Cardiac↗
PubMed2004

Transmembrane action potential heterogeneity in the canine isolated arterially perfused right atrium: effect of IKr and IKur/Ito block.

The role of electrical heterogeneity in development of cardiac arrhythmias is well recognized. The extent to which transmembrane action potential (TAP) heterogeneity contributes to the normal electrophysiology of well-oxygenated atria is not well defined. The principal objective of the present study was to define regional and transmural differences in characteristics of the TAP in isolated superfused and arterially perfused canine right atrial (RA) preparations under baseline, rapidly activating delayed rectifier K(+) current (I(Kr)) block, and combined block of ultrarapid delayed rectifier and transient outward K(+) current (I(Kur)/I(to) block). Superfused preparations that survived generally displayed a triangle-shaped TAP. Exceptions included cells from the crista terminalis, where TAPs with a normal plateau could be recorded. In contrast, most TAPs recorded from throughout the perfused RA displayed a spike-and-dome and/or plateau morphology. The perfused RA displayed a heterogeneous distribution of repolarization, V(max), and spike-and-dome morphology along the epicardial and endocardial surfaces as well as transmurally, in the region of the upper crista terminalis. I(Kr) block with E-4031 prolonged repolarization homogeneously in the perfused RA, whereas I(Kur)/I(to) block using low concentrations of 4-aminopyridine abbreviated action potential duration at 90% repolarization heterogeneously, leading to a reduction in dispersion of repolarization. Our data indicate that the electrical heterogeneities, previously described for the canine ventricle, also exist within the atria and that I(Kr) block does not accentuate and I(Kur)/I(to) block reduces RA dispersion of repolarization. Our study also points to major differences in the transmembrane activity recorded using superfused vs. arterially perfused atrial preparations.

Action Potentials↗
PubMed2004

Electrophysiologic properties and antiarrhythmic actions of a novel antianginal agent.

Ranolazine is a novel antianginal agent capable of producing anti-ischemic effects at plasma concentrations of 2 to 6 microM without a significant reduction of heart rate or blood pressure. This review summarizes the electrophysiologic properties of ranolazine. Ranolazine significantly blocks I(Kr) (IC(50) = 12 microM), late I(Na), late I(Ca), peak I(Ca), I(Na-Ca) (IC(50) = 5.9, 50, 296, and 91 microM, respectively) and I(Ks) (17% at 30 microM), but causes little or no inhibition of I(to) or I(K1). In left ventricular tissue and wedge preparations, ranolazine produces a concentration-dependent prolongation of action potential duration (APD) in epicardium, but abbreviation of APD of M cells, leading to either no change or a reduction in transmural dispersion of repolarization (TDR). The result is a modest prolongation of the QT interval. Prolongation of APD and QT by ranolazine is fundamentally different from that of other drugs that block I(Kr) and induce torsade de pointes in that APD prolongation is rate-independent (ie, does not display reverse rate-dependent prolongation of APD) and is not associated with early after depolarizations, triggered activity, increased spatial dispersion of repolarization, or polymorphic ventricular tachycardia. Torsade de pointes arrhythmias were not observed spontaneously nor could they be induced with programmed electrical stimulation in the presence of ranolazine at concentrations as high as 100 microM. Indeed, ranolazine was found to possess significant antiarrhythmic activity, acting to suppress the arrhythmogenic effects of other QT-prolonging drugs. Ranolazine produces ion channel effects similar to those observed after chronic exposure to amiodarone (reduced late I(Na), I(Kr), I(Ks), and I(Ca)). Ranolazine's actions to reduce TDR and suppress early after depolarization suggest that in addition to its anti-anginal actions, the drug possesses antiarrhythmic activity.

Acetanilides↗
PubMed2004

Brugada syndrome: 12 years of progression.

Brugada syndrome is increasingly being recognized in clinical medicine. What started as an electrocardiographic curiosity has become an important focus of attention for individuals working in the different disciplines related to sudden cardiac death, from basic scientists to clinical cardiac electrophysiologists. In just 12 years, since the description of the disease, clinically relevant information is continuously being provided to physicians to help protect the individuals with Brugada syndrome to the best of our ability. And this information has been gathered thanks to the effort of hundreds of basic scientists, physicians and patients who continue to give their time, effort and data to help understand how the electrocardiographic pattern may cause sudden cardiac death. There are still many unanswered questions, both at the clinical and basic field. However, with the further collection of data, the longer follow-up and the continued interest from the basic science world we will have the necessary tools to the successful unraveling of the disease.

Arrhythmias, Cardiac↗
PubMed2003

Sudden death associated with short-QT syndrome linked to mutations in HERG.

BACKGROUND: Sudden cardiac death takes the lives of more than 300 000 Americans annually. Malignant ventricular arrhythmias occurring in individuals with structurally normal hearts account for a subgroup of these sudden deaths. The present study describes the genetic basis for a new clinical entity characterized by sudden death and short-QT intervals in the ECG. METHODS AND RESULTS: Three families with hereditary short-QT syndrome and a high incidence of ventricular arrhythmias and sudden cardiac death were studied. In 2 of them, we identified 2 different missense mutations resulting in the same amino acid change (N588K) in the S5-P loop region of the cardiac IKr channel HERG (KCNH2). The mutations dramatically increase IKr, leading to heterogeneous abbreviation of action potential duration and refractoriness, and reduce the affinity of the channels to IKr blockers. CONCLUSIONS: We demonstrate a novel genetic and biophysical mechanism responsible for sudden death in infants, children, and young adults caused by mutations in KCNH2. The occurrence of sudden cardiac death in the first 12 months of life in 2 patients suggests the possibility of a link between KCNH2 gain of function mutations and sudden infant death syndrome. KCNH2 is the binding target for a wide spectrum of cardiac and noncardiac pharmacological compounds. Our findings may provide better understanding of drug interaction with KCNH2 and have implications for diagnosis and therapy of this and other arrhythmogenic diseases.

Adult↗