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Biomedical subjects

Charles Antzelevitch

Publications and source records attributed to Charles Antzelevitch.

At least 73 records · Page 4Linked to original sources
PubMed2003

Transmural heterogeneity of calcium activity and mechanical function in the canine left ventricle.

Although electrical heterogeneity within the ventricular myocardium has been the focus of numerous studies, little attention has been directed to the mechanical correlates. This study examines unloaded cell shortening, Ca(2+) transients, and inward L-type Ca(2+) current (I(Ca,L)) characteristics of epicardial, endocardial, and midmyocardial cells isolated from the canine left ventricle. Unloaded cell shortening was recorded using a video edge detector, Ca(2+) transients were measured in cells loaded with 15 microM fluo-3 AM and voltage and current-clamp recordings were obtained using patch-clamp techniques. Time to peak and latency to onset of contraction were shortest in epicardial and longest in endocardial cells; midmyocardial cells displayed an intermediate time to peak. When contraction was elicited using uniform voltage-clamp square waves, epicardial versus endocardial distinctions persisted and midmyocardial cells displayed a time to peak comparable to that of epicardium. The current-voltage relationship for I(Ca,L) and fluorescence-voltage relationship were similar in the three cell types when quantitated using square pulses. However, peak I(Ca,L) and total charge were significantly larger when an epicardial versus endocardial action potential waveform was used to elicit the current under voltage-clamp conditions. Sarcoplasmic reticulum Ca(2+) content, assessed by rapid application of caffeine, was largest in epicardial cells and contributed to a faster time to peak. Our data point to important differences in calcium homeostasis and mechanical function among the three ventricular cell types. These differences serve to synchronize contraction across the ventricular wall. Although these distinctions are conferred in part by differences in electrical characteristics of the three cell types, intrinsic differences in excitation-contraction coupling are evident.

Action Potentials↗
PubMed2003

Cisapride-induced transmural dispersion of repolarization and torsade de pointes in the canine left ventricular wedge preparation during epicardial stimulation.

BACKGROUND: Cisapride, a gastrointestinal prokinetic agent, was recently withdrawn from the market because of its propensity to induce torsade de pointes (TdP) arrhythmias. The present study examines the electrophysiological actions of cisapride in the isolated arterially perfused canine left ventricular wedge preparation. METHODS AND RESULTS: Transmembrane action potentials from epicardial and M regions and a pseudo-ECG were simultaneously recorded. Cisapride (0.1 to 5 micromol/L) was added to the coronary perfusate. Cisapride prolonged the QT interval and increased transmural dispersion of repolarization (TDR) at relatively low but not at high concentrations. TdP could be induced with programmed electrical stimulation only at a low concentration of drug (0.2 micromol/L), when TDR was maximally prolonged. Moreover, TdP could only be induced during epicardial (but not endocardial) activation of the wedge, which was found to augment TDR. At higher concentrations of cisapride, QT was further prolonged, TDR was diminished, and TdP could no longer be induced. Tpeak-Tend interval and Tpeak-Tend area provided reasonable electrocardiographic indices of TDR. CONCLUSIONS: Our data (1) demonstrate a biphasic concentration/response relationship for the effect of cisapride to induce long-QT syndrome and TdP, (2) show the value of the left ventricular wedge preparation in identifying drugs that pose an arrhythmic risk, (3) support the hypothesis that risk for development of TdP is related to the increase in TDR rather than to prolongation of the QT interval, and (4) indicate that epicardial activation of the left ventricle, as occurs during biventricular pacing, can facilitate the development of TdP under long-QT conditions.

Animals↗
PubMed2003

Brugada syndrome: 1992-2002: a historical perspective.

An intriguing new clinical entity characterized by ST-segment elevation in the right precordial electrocardiographic leads and a high incidence of sudden death in individuals with structurally normal hearts was described by Pedro and Josep Brugada in 1992. The past decade has witnessed an exponential rise in the number of reported cases and a dramatic proliferation of papers serving to define the clinical, genetic, cellular, ionic, and molecular aspects of this disease. The purpose of this brief review is to chronicle the historical highlights that have brought us to our present understanding of Brugada syndrome.

Bundle-Branch Block↗
PubMed2003

Reinduction of atrial fibrillation immediately after termination of the arrhythmia is mediated by late phase 3 early afterdepolarization-induced triggered activity.

BACKGROUND: Atrial fibrillation (AF) at times recurs immediately after termination of the arrhythmia. The mechanism(s) responsible for the extrasystole that reinduces AF is largely unknown. We hypothesized that abbreviation of action potential duration (APD) would permit very rapid rates of excitation, known to induce intracellular calcium loading, which in turn could promote delayed and/or early afterdepolarizations (EADs). METHODS AND RESULTS: Acetylcholine (ACh, 1 micromol/L) was used to abbreviate atrial APD and permit rapid-pacing induction of AF in isolated coronary-perfused canine right atria. Transmembrane action potentials, pseudo-ECG, and tension development were recorded. AF or rapid pacing was associated with an increase in tonic tension. Termination of AF or rapid pacing (cycle length, 150 to 80 ms) resulted in a dramatic rise of phasic tension, prolongation of repolarization of the initial beats at the regular rate (cycle length, 700 ms), and the development of late phase 3 EADs and extrasystoles. These extrasystoles initiated AF in 15 cases (involving 9 right atria) within the first 11 seconds after termination of AF or rapid pacing. This novel EAD mechanism is observed only in association with marked APD abbreviation. The calcium channel blocker nifedipine reduced, and the sarcoplasmic reticulum calcium release blocker ryanodine eliminated, the post-rapid pacing-induced increase in phasic tension, late phase 3 EADs, and extrasystoles that initiate AF. CONCLUSIONS: These data suggest that calcium overload conditions present after termination of vagally mediated AF contribute to the development of late phase 3 EAD-induced triggered activity and that this mechanism may be responsible for the extrasystolic activity that reinitiates AF.

Acetylcholine↗
PubMed2003

Effect of epicardial or biventricular pacing to prolong QT interval and increase transmural dispersion of repolarization: does resynchronization therapy pose a risk for patients predisposed to long QT or torsade de pointes?

BACKGROUND: The present study examined pacing site-dependent changes in QT interval and transmural dispersion of repolarization (TDR) and their potential role in the development of torsade de pointes (TdP). METHODS AND RESULTS: In humans, the QT interval, JT interval, and TDR were measured in 29 patients with heart failure during right ventricular endocardial pacing (RVEndoP), biventricular pacing (BiVP), and left ventricular epicardial pacing (LVEpiP). In animal experiments, pacing site--dependent changes in ventricular repolarization were examined with a rabbit left ventricular wedge preparation in which action potentials from endocardium and epicardium could be simultaneously recorded with a transmural ECG. In humans, LVEpiP and BiVP led to significant QT and JT prolongation. LVEpiP also enhanced TDR. Frequent R-on-T extrasystoles generated by BiVP and LVEpiP but completely inhibited by RVEndoP occurred in 4 patients, of whom 1 developed multiple episodes of nonsustained polymorphic ventricular tachycardia and another suffered incessant TdP. In rabbit experiments, switching from endocardial to epicardial pacing produced a net increase in QT interval and TDR by 17+/-5 and 22+/-5 ms, respectively (n=6, P<0.01), without parallel increases in ventricular transmembrane action potential durations. Epicardial pacing facilitated transmural propagation of early afterdepolarization, leading to the development of R-on-T extrasystoles and TdP in the presence of action potential duration-prolonging agents. CONCLUSIONS: LVEpiP and BiVP increase QT, JT, and TDR by altering the transmural sequence of activation of the intrinsically heterogeneous ventricular myocardium. Our data suggest that the resultant exaggeration of arrhythmic substrates can lead to the development of TdP in a subset of patients.

Action Potentials↗
PubMed2003

Cellular basis for ST-segment changes observed during ischemia.

This study probes the cellular basis for ischemia-induced ST-segment elevation with the isolated arterially perfused canine ventricular wedge preparation. Transmembrane action potentials (AP) from epicardial (Epi) and endocardial (Endo) regions, a pseudo-electrocardiogram (ECG), and 5 intramural unipolar electrograms were simultaneously recorded at a basic cycle length of 800 or 2,000 ms. Global ischemia was induced by an abrupt interruption of coronary flow for 30 minutes. Under control conditions, the ST segment was isoelectric because of the absence of voltage gradients at the level of AP plateau among the cells spanning the ventricular wall. Global ischemia could cause an all-or-none repolarization at the end of phase 1 of the AP in Epi but not Endo leading to ST-segment elevation and extrasystolic activity secondary to phase 2 re-entry. In the majority of preparations, global ischemia resulted in a progressive increase in transmural conduction time after 25 to 30 minutes of interruption of flow caused by a step delay of impulse transmission in the midmyocardium. The ECG assumed a "tombstone" configuration. Correlation of the APs and ECG activity revealed that the apparent severe ST-segment elevation encountered under these conditions is actually a markedly prolonged R wave. In control, Endo repolarized after Epi yielding upright T waves in the ECG. After 30 minutes of ischemia Epi repolarized after Endo causing reversal of repolarization gradients and T-wave inversion. The ischemia-induced electrophysiologic changes returned to nearly control values within 5 minutes of reperfusion. Our results indicate that 2 distinctly different mechanisms involving 1) loss of the epicardial action potential dome and 2) markedly delayed transmural conduction underlie the apparent ST-segment elevation encountered during acute ischemia.

Action Potentials↗
PubMed2003

Cellular and ionic basis for the sex-related difference in the manifestation of the Brugada syndrome and progressive conduction disease phenotypes.

UNLABELLED: The Brugada syndrome (BS) has been linked to mutations in SCN5A. Despite equal hereditary transmission of the mutation between the sexes, the syndrome is 8 to 10 times more likely to occur in males. As recently reported, SCN5A mutations such as G1406R lead to development of BS phenotype principally in males and conduction disease phenotype in females. We hypothesized that these differences may be related to a larger transient outward current (Ito)-mediated right ventricular (RV) epicardial (Epi) action potential (AP) notch in males versus females, resulting in a higher incidence of all-or-none repolarization at the end of phase 1 and phase 2 re-entry (P2R) when challenged with sodium and calcium channel block. Using canine RV wedge preparations, we developed an experimental model of the BS using terfenadine to depress the AP dome in RV Epi. RESULTS: RV Epi AP phase 1 amplitude corrected to phase 2 amplitude was 12% smaller in males (n=18) compared to females (n=8, P<.05) at a cycle length of 2,000 ms. When exposed to 5 microM terfenadine for up to 2 hours, 6 of 7 male but only 2 of 7 female preparations exhibited spontaneous P2R, generating a closely coupled extrasystole. Two of 6 male and 1 of 2 female preparations displaying P2R developed polymorphic VT/VF. Female and male preparations that failed to develop P2R displayed progressive conduction impairment with continued exposure to terfenadine and developed polymorphic and monomorphic VT/VF when paced at rapid rates. Male preparations pretreated with 4-aminopyridine to inhibit Ito displayed progressive conduction impairment but not Brugada syndrome. CONCLUSION: Our data suggest that the presence of a more prominent Ito-mediated notch in the Epi of males predisposes males to the development of the Brugada phenotype and that a smaller Epi notch in females relegates them to development of progressive conduction problems under conditions in which inward currents are compromised.

Animals↗
PubMed2003

Assessing predictors of drug-induced torsade de pointes.

Torsades de pointes (TdP) is a malignant polymorphic ventricular tachyarrhythmia that can be caused by drugs that induce electrophysiological changes. Although the number of drugs known to cause TdP has increased in recent years, there is no cell-based assay, in vitro heart preparation or animal model that predicts the potential of a drug to induce TdP in humans. Nevertheless, certain electrophysiological events are known to be associated with the development of TdP. For example, a drug that prolongs action potential duration, induces early afterdepolarizations and ectopic beats, and increases dispersion of ventricular repolarization is likely to cause TdP. By contrast, a drug that does not induce these changes is unlikely to cause TdP. The exact relationship between these electrophysiological events and the development of TdP has not been defined, but the potential of a drug to elicit these events might predict its pro-arrhythmic risk.

Animals↗
PubMed2003

HMR 1556, a potent and selective blocker of slowly activating delayed rectifier potassium current.

The slowly activating delayed rectifier potassium current (IKs) contributes prominently to ventricular repolarization of the cardiac action potential. Development of a selective IKs blocker is important for the elucidation of the physiologic and pathophysiologic relevance of IKs and the development of antiarrhythmic strategies. HMR 1556 [(3R,4S)-(+)-N-[3-hydroxy-2,2-dimethyl-6-(4,4,4-trifluorobutoxy) chroman-4-yl]-N-methylmethanesulfonamide] is a new chromanol derivative developed as a selective IKs blocker. Chromanol 293B, the most specific IKs blocker currently available, also inhibits the transient outward current (Ito). HMR 1556 was examined for its effects on IKs compared with rapidly activating delayed rectifier (IKr), inward rectifier (IK1), Ito, and L-type calcium (ICa.L) currents in canine left ventricular myocytes. HMR 1556 (0.5-500 nM ) inhibited IKs in a concentration-dependent manner (IC50 of 10.5 nM, compared with chromanol 293B's IC50 of 1.8microM). Inhibition of Ito was observed only at relatively high concentrations (IC50 of 33.9 microM comparable to chromanol 293B's IC of 38 microM). High concentrations of HMR 1556 also inhibited ICa.L (IC of 27.5 microM) and IKr (IC50 of 12.6 microM) while IK1 was unaffected. Our results indicate that HMR 1556 is superior to chromanol 293B in its potency and specificity for inhibition of IKs, making it a valuable experimental tool and a potential therapeutic agent.

Action Potentials↗
PubMed2003

Brugada syndrome: clinical, genetic, molecular, cellular and ionic aspects.

Brugada syndrome, first described as a new clinical entity by Pedro and Josep Brugada in 1992, has attracted great interest because of its high prevalence in many regions of the world and its association with high risk for sudden death. The syndrome has captured the attention of the cardiac electrophysiology community because it serves as a paradigm for our understanding of the role of spatial dispersion of repolarization in the development of cardiac arrhythmias. The past decade has witnessed an exponential rise in the number of reported cases and a striking proliferation of papers serving to define the clinical, genetic, cellular, ionic and molecular aspects of this disease. This brief review summarizes the key clinical and experimental milestones that have brought us to our current understanding and approach to therapy of the Brugada syndrome.

Bundle-Branch Block↗
PubMed2002

Ionic and cellular basis for the predominance of the Brugada syndrome phenotype in males.

BACKGROUND: The Brugada syndrome displays an autosomal dominant mode of transmission with low penetrance. Despite equal genetic transmission of the disease, the clinical phenotype is 8 to 10 times more prevalent in males than in females. The basis for this intriguing sex-related distinction is unknown. The present study tests the hypothesis that the disparity in expression of the Brugada phenotype is a result of a more prominent I(to)-mediated action potential notch in the right ventricular (RV) epicardium of males versus females. METHODS AND RESULTS: We studied epicardial tissue slices, arterially perfused wedge preparations, and dissociated epicardial myocytes isolated from male and female canine hearts. RV epicardium action potential phase 1 amplitude was 64.8+/-2.0% of that of phase 2 in males compared with 73.8+/-4.4% in females (P<0.05) at a cycle length of 2000 ms. I(to) density was 26% smaller and time constant for inactivation 17% smaller at +40 mV in female versus male RV epicardial cells (P<0.05). The other functional characteristics of I(to), including the voltage dependence of inactivation and time course of reactivation, were no different between the sexes. Pinacidil caused loss of action potential dome in male, but not female, RV epicardial tissue slices. Terfenadine (5 micromol/L) induced phase 2 reentry in 6 of 7 male but only 2 of 7 female arterially perfused wedge preparations. Two of 6 male and 1 of 2 female preparations developed polymorphic ventricular tachycardia/ventricular fibrillation. CONCLUSIONS: Our results suggest that the predominance of the Brugada phenotype in males is a result of the presence of a more prominent I(to) in males versus females.

Action Potentials↗