Showing papers by "Charles Antzelevitch published in 2010"

Mode of onset of ventricular fibrillation in patients with early repolarization pattern vs. Brugada syndrome.

Abstract: Aims The aim of the present study was to identify specific electrocardiogram (ECG) features that predict the development of multiple episodes of ventricular fibrillation (VF) in patients with an early repolarization (ER) pattern and to compare the mode of VF initiation with that observed in typical cases of Brugada syndrome (BrS). Methods and results The mode of the onset and the coupling intervals of the premature ventricular contractions (PVCs) initiating VF episodes were analysed in patients with BrS ( n = 8) or ER who experienced sudden cardiac death/syncope or repeated appropriate implantable cardioverter defibrillator shocks. Among the 11 patients with ER, 5 presented with electrical storm (ES, four or more recurrent VF episodes/day). The five ES patients displayed a dramatic but very transient accentuation of J waves across the precordial and limb leads prior to the development of ES. Ventricular fibrillation episodes were more commonly initiated by PVCs with a short–long–short (SLS) sequence in ER (42/58, 72.4%) vs. BrS patients (13/86, 15.1%, P < 0.01). Coupling intervals were significantly shorter in the ER group compared with those with BrS [328 (320, 340) ms vs. 395 (350, 404) ms, P < 0.01]. Conclusion Our study provides additional evidence in support of the hypothesis that ER pattern in the ECG is not always benign. Transient augmentation of global J waves may be indicative of a highly arrhythmogenic substrate heralding multiple episodes of VF in patients with ER pattern. Ventricular tachycardia/VF initiation is more commonly associated with an SLS sequence, and PVCs display a shorter coupling interval in patients with ER pattern compared with those with BrS.

Short QT Syndrome: From Bench to Bedside

Abstract: Short QT syndrome (SQTS) is an inheritable primary electric disease of the heart characterized by abnormally short QT intervals on the ECG and an increased propensity to develop atrial and ventricular tachyarrhythmias.1,–,3 It is a relatively recent addition to the list of inherited channelopathies responsible for sudden cardiac death (SCD) in individuals with structurally normal hearts. Cases of SQTS have been reported with presentation as early as in the first year of life, suggesting that it could be one of the etiologies underlying sudden infant death syndrome.4 SQTS was first described as a new clinical entity by Gussak et al in 2000.1 The familial nature and arrhythmic potential of the disease was further highlighted by Gaita et al.5 They described 6 patients of SQTS in 2 unrelated European families with strong family history of sudden death in association with short QT intervals on the ECG. Since its initial introduction in 2000, significant progress has been made in defining the clinical, genetic,6 and ionic basis of the disease as well as approaches to therapy. The purpose of this review is to summarize the available data concerning SQTS from bench to bedside. The definition of a pathophysiologic long QT interval evolved over a period of several decades and it may take some time to define what constitutes a pathophysiologic short QT interval. Several large scale population studies have shown that the corrected QT interval (QTc, using the Bazett formula) of healthy individuals conforms to a gaussian normal distribution, that is, a bell-shaped curve.7,–,10 Based on this distribution, the “normal QTc” interval may be defined as values that fall within 2 standard deviations (SD) from the mean. This approach will categorize 95% of the population as having normal QTc …

Induced Pluripotent Stem Cells as a Model for Accelerated Patient- and Disease-specific Drug Discovery

Abstract: Human induced pluripotent stem (iPS) cells hold great promise for therapy of a number of degenerative diseases such as ischemic heart failure, Parkinson's disease, Alzheimer's disease, diabetes mellitus, sickle cell anemia and Huntington disease. They also have the potential to accelerate drug discovery in 3 ways. The first involves the delineation of chemical components for efficient reprogramming of patient's blood cells or cells from biopsies, obviating the need for cellular delivery of reprogramming exogenous transgenes, thereby converting hope into reality for patients suffering from degenerative diseases. Patients worldwide stand to benefit from the clinical applicability of iPS cell-based cell replacement therapy for a number of degenerative diseases. The second is the potential for discovering novel drugs in a high throughput manner using patient-specific iPS cell-derived somatic cells possessing the etiology of the specific disease. The third is their suitability for toxicological testing of drugs and environmental factors. This review focuses on these potential applications of iPS cells with special emphasis on recent updates of iPS cell research contributing to the accelerated drug discovery.

Synergistic Electrophysiologic and Antiarrhythmic Effects of the Combination of Ranolazine and Chronic Amiodarone in Canine Atria

Abstract: Background— Amiodarone and ranolazine have been characterized as inactivated- and activated-state blockers of cardiac sodium channel current (INa), respectively, and shown to cause atrial-selective depression of INa-related parameters. This study tests the hypothesis that their combined actions synergistically depress INa-dependent parameters in atria but not ventricles. Methods and Results— The effects of acute ranolazine (5 to 10 μmol/L) were studied in coronary-perfused right atrial and left ventricular wedge preparations and superfused left atrial pulmonary vein sleeves isolated from chronic amiodarone-treated (40 mg/kg daily for 6 weeks) and untreated dogs. Floating and standard microelectrode techniques were used to record transmembrane action potentials. When studied separately, acute ranolazine and chronic amiodarone caused atrial-predominant depression of INa-dependent parameters. Ranolazine produced a much greater reduction in Vmax and much greater increase in diastolic threshold of excitation and effective refractory period in atrial preparations isolated from amiodarone-treated versus untreated dogs, leading to a marked increase in postrepolarization refractoriness. The drug combination effectively suppressed triggered activity in pulmonary vein sleeves but produced relatively small changes in INa-dependent parameters in the ventricle. Acetylcholine (0.5 μmol/L) and burst pacing induced atrial fibrillation in 100% of control atria, 75% of ranolazine-treated (5 μmol/L) atria, 16% of atria from amiodarone-treated dogs, and in 0% of atria from amiodarone-treated dogs exposed to 5 μmol/L ranolazine. Conclusions— The combination of chronic amiodarone and acute ranolazine produces a synergistic use-dependent depression of INa-dependent parameters in isolated canine atria, leading to a potent effect of the drug combination to prevent the induction of atrial fibrillation. Received June 12, 2009; accepted November 11, 2009.

A novel mutation in the HCN4 gene causes symptomatic sinus bradycardia in Moroccan Jews.

Abstract: Objectives To conduct a clinical, genetic and functional analysis of three unrelated families with familial sinus bradycardia (FSB).

New developments in atrial antiarrhythmic drug therapy

Abstract: Atrial fibrillation (AF) has multifactorial intracardiac and extracardiac causes. Current development of anti-AF agents is focused on modulation of ion channel activity as well as on upstream therapies that reduce structural substrates. In this Review, Burashnikov and Antzelevitch examine new and emerging pharmacological approaches to rhythm control in patients with AF and summarize the available data on these drugs.

A common single nucleotide polymorphism can exacerbate long-QT type 2 syndrome leading to sudden infant death.

Abstract: Background— Identification of infants at risk for sudden arrhythmic death remains one of the leading challenges of modern medicine. We present a family in which a common polymorphism (single nucleotide polymorphism) inherited from the father, combined with a stop codon mutation inherited from the mother (both asymptomatic), led to 2 cases of sudden infant death. Methods and Results— KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, CACNA1c, CACNB2b , and KCNJ2 genes were amplified and analyzed by direct sequencing. Functional electrophysiological studies were performed with the single nucleotide polymorphism and mutation expressed singly and in combination in Chinese ovary (CHO-K1) and COS-1 cells. An asymptomatic woman presenting after the death of her 2-day-old infant and spontaneous abortion of a second baby in the first trimester was referred for genetic analysis. The newborn infant had nearly incessant ventricular tachycardia while in utero and a prolonged QTc (560 ms). The mother was asymptomatic but displayed a prolonged QTc. Genetic screening of the mother revealed a heterozygous nonsense mutation (P926AfsX14) in KCNH2 , predicting a stop codon. The father was asymptomatic with a normal QTc but had a heterozygous polymorphism (K897T) in KCNH2 . The baby who died at 2 days of age and the aborted fetus inherited both K897T and P926AfsX14. Heterologous coexpression of K897T and P926AfsX14 led to loss of function of HERG current much greater than expression of K897T or P926AfsX14 alone. Conclusions— Our data suggest that a common polymorphism (K897T) can markedly accentuate the loss of function of mildly defective HERG channels, leading to long-QT syndrome–mediated arrhythmias and sudden infant death. Received July 30, 2009; accepted February 10, 2010. # CLINICAL PERSPECTIVE {#article-title-2}

M Cells in the Human Heart

Abstract: See related articles, pages 981–991 Dispersion of repolarization across the ventricular wall has been suggested to underlie the inscription of the normal electrocardiographic T wave and when amplified to contribute prominently to the development of cardiac arrhythmias.1–3 The magnitude of transmural dispersion of repolarization (TDR) is attributable to intrinsic differences in the action potential duration (APD) of the 3 principal cell types that comprise the ventricular myocardium and the extent to which these repolarization differences are damped by electrotonic forces. An increase in tissue resistivity in the deep subepicardium,4 attributable to a sharp transition in cell orientation,3 reduced expression of connexin 435,6 and increased density of collagen7 in this region, contributes to the expression of repolarization heterogeneities across the ventricular wall by limiting the degree of electrotonic interaction between the myocardial layers. Thus, the degree of electrotonic coupling, together with the intrinsic differences in APD, determines the extent to which TDR is expressed and its impact on arrhythmogenesis, as well as on the morphology of the T wave. It is noteworthy that even in the absence of any difference in final repolarization time, electrotonic forces generated by transmural differences in the shape of the action potential can inscribe an upright T wave in the ECG. Theoretical studies have also been helpful in our understanding of the role of electrical coupling in the expression of TDR.8 TDR is in large part attributable to the presence of M cells between the endocardial and epicardial layers of the heart. The M cell, discovered in the early 1990s and named in memory of Gordon K. Moe,9,10 has as its hallmark the ability to prolong its action potential more than that of normal epicardium or endocardium in response to a slowing of rate or exposure to agents …

Transseptal Dispersion of Repolarization and Its Role in the Development of Torsade de Pointes Arrhythmias

Abstract: Transseptal Dispersion and TdP. Objective: This study was designed to quantitate transseptal dispersion of repolarization (DR) and delineate its role in arrhythmogenesis using the calcium agonist BayK 8644 to mimic the gain of function of calcium channel current responsible for Timothy syndrome. Background: Amplification of transmural dispersion of repolarization (TDR) has been shown to contribute to development of Torsade de Pointes (TdP) arrhythmias under long-QT conditions. Methods: An arterially perfused septal wedge preparation was developed via cannulation of the septal artery. Action potentials (APs) were recorded using floating microelectrodes together with a transseptal electrocardiogram (ECG). These data were compared to those recorded from arterially perfused canine left ventricular (LV) wedge preparations. Results: Under control conditions, the shortest AP duration measured at 90% repolarization (APD90) was observed in right ventricular (RV) endocardium (181.8 ± 15 ms), APD90 peaked close to midseptum (278.0 ± 32 ms), and abbreviated again as LV endocardium was approached (207.3 ± 9 ms). Transseptal DR averaged 106 ± 24 ms and Tpeak–Tend 84 ± 7 ms (n = 6). TDR and Tpeak–Tend recorded from LV wedge were 36 ± 9 ms and 34 ± 19 ms, respectively (n = 30). BayK 8644 increased transseptal DR to 123.2 ± 35 ms (n = 5) and induced early and delayed afterdepolarizations (3/5), rate-dependent ST-T-wave alternans (5/5), and TdP arrhythmias (3/5). Conclusions: Our data indicate that dispersion of repolarization across the interventricular septum is twice that of the LV free wall, predisposing to development of TdP under long-QT conditions. Our findings suggest that the coronary-perfused ventricular septal preparation may be a sensitive model in which to assess the potential arrhythmogenic effects of drugs and pathophysiological conditions. (J Cardiovasc Electrophysiol, Vol. 21, pp. 441–447, April 2010)

Dual variation in SCN5A and CACNB2b underlies the development of cardiac conduction disease without Brugada syndrome.

Abstract: Background Inherited loss of function mutations in SCN5A have been linked to overlapping syndromes including cardiac conduction disease and Brugada syndrome (BrS). The mechanisms responsible for the development of one without the other are poorly understood.

The Contribution of HCN4 to normal sinus node function in humans and animal models.

Abstract: Although sinus node bradycardia is a very common clinical condition, the cellular mechanisms contributing to abnormal sinus node function are not clearly delineated. In recent publications, mutations in the hyperpolarization-activated, cyclic nucleotide-gated (HCN) 4 channels have been associated with sinus bradycardia. These channels are thought to be crucial in generating the spontaneous sinus node action potential, in accelerating the heart rate during sympathetic drive, and decelerating heart rate during vagal stimulation. Humans carrying HCN4 mutations indeed display significant bradycardia. Recent studies generating HCN4 knock out mice suggested that although HCN4 is crucial in early development, other mechanisms may also play a role in the accelerated heat rate achieved during sympathetic drive. In this review, we focus on genotype-phenotype correlation of these mutations and discuss the relative contribution of various ion channels to sinus node function. We also discuss the importance of HCN in treating clinical conditions such as brady- and tachycardia.

Atrial-selective sodium channel block as a novel strategy for the management of atrial fibrillation.

Abstract: Safe and effective pharmacologic management of atrial fibrillation (AF) is one of the greatest challenges facing an aging society. Currently available pharmacologic strategies for rhythm control of AF are associated with ventricular arrhythmias and in some cases multi-organ toxicity. Consequently, drug development has focused on atrial-selective agents such as IKur blockers. Recent studies suggest that IKur block alone may be ineffective for suppression of AF and may promote AF in healthy hearts. Recent experimental studies have demonstrated other important electrophysiologic differences between atrial and ventricular cells, particularly with respect to sodium channel function, and have identified sodium channel blockers that exploit these electrophysiologic distinctions. Atrial-selective sodium channel blockers, such as ranolazine and amiodarone, effectively suppress and/or prevent the induction of AF in experimental models, while producing little to no effect on ventricular myocardium. These findings suggest that atrial-selective sodium channel block may be a fruitful new strategy for the management of AF.

AZD1305 exerts atrial predominant electrophysiological actions and is effective in suppressing atrial fibrillation and preventing its reinduction in the dog.

Abstract: Recent development of drugs for the treatment of atrial fibrillation (AF) has focused on atrial selective agents. We examined the atrioventricular differences in sodium channel block of the antiarrhythmic agent AZD1305 in atria and ventricles of anesthetized dogs in vivo, canine isolated arterially perfused preparations in vitro, and isolated myocytes using whole-cell patch-clamp techniques. AZD1305 did not change heart rate or blood pressure in vivo but prolonged action potential duration and increased effective refractory period, diastolic threshold of excitation, and conduction time preferentially in atria both in vitro and in vivo. AZD1305 reduced the maximum rate of rise of the action potential upstroke (V(max)) predominantly in atria (-51% +/- 10% in atria vs. -31% +/- 23% in ventricles; 3 microM; cycle length = 500 milliseconds). Fast sodium current (I(Na)) was blocked by AZD1305 to a greater degree in atrial versus ventricular myocytes (particularly tonic inhibition). In coronary-perfused right atria, AZD1305 very effectively prevented induction of persistent acetylcholine-mediated AF and, in a different set of atria, terminated persistent AF (in 5 of 5 and 7 of 8 atria, respectively). In conclusion, AZD1305 exerts atrial predominant sodium channel-blocking effects in vitro and in vivo and effectively suppresses AF.

The role of local voltage potentials in outflow tract ectopy

Abstract: Aims Discrete, fragmented, local voltage potentials (LVPs) have been observed in electrograms recorded at the ablation site in patients undergoing radiofrequency ablation for arrhythmias originating in both the right and left ventricular outflow tract; however, the incidence and the significance of the LVP with respect to arrhythmogenesis is uncertain. Methods and results We studied 25 patients with outflow tract arrhythmias referred for radiofrequency catheter ablation and recorded high-amplified intracardiac electrograms close to the site of origin of the arrhythmia. Ten patients undergoing ablation for supraventricular arrhythmias served as controls. During sinus rhythm, LVPs were recorded in 24 of the 25 patients, 10–85 ms (41 ± 19 ms) after the onset of the QRS complex, duration 33 ± 11 ms, voltage 2.0 ± 1.5 mV. The same potential was recorded 10–52 ms (mean 37 ± 11 ms) prior to the V potential in the ventricular premature beats. In 10 patients, ventricular parasystole was suggested by varying coupling intervals >100 ms, and fusion beats allowing for the estimation of the least common denominator of R-R intervals. In 23 of the 25 patients, the 12-lead electrocardiogram (ECG) and intracardiac contact mapping located the arrhythmias to an area of 3–4 cm2 in the septal region of the right ventricular outflow tract; in two patients, the site of origin was in the left coronary cusp. Radiofrequency ablation carried out in 24 of the 25 patients was successful in 21 patients, and after successful ablation, the LVP could still be recorded in all these 21 patients. The LVP was not present in 10 controls. Conclusion Local potentials are recorded close to the site of origin of ventricular ectopy in >90% of patients with idiopathic outflow tract ectopy and imply successful ablation. The potentials may reflect an area of depressed conductivity known to be a prerequisite for experimental ventricular ectopy including parasystole.

Overlapping LQT1 and LQT2 phenotype in a patient with long QT syndrome associated with loss-of-function variations in KCNQ1 and KCNH2.

Abstract: Long QT syndrome (LQTS) is an inherited disorder characterized by prolonged QT intervals and potentially life-threatening arrhythmias. Mutations in 12 different genes have been associated with LQTS. Here we describe a patient with LQTS who has a mutation in KCNQ1 as well as a polymorphism in KCNH2. The proband (MMRL0362), a 32-year-old female, exhibited multiple ventricular extrasystoles and one syncope. Her ECG (QT interval corrected for heart rate (QTc) = 518ms) showed an LQT2 morphology in leads V4–V6 and LQT1 morphology in leads V1–V2. Genomic DNA was isolated from lymphocytes. All exons and intron borders of 7 LQTS susceptibility genes were amplified and sequenced. Variations were detected predicting a novel missense mutation (V110I) in KCNQ1, as well as a common polymorphism in KCNH2 (K897T). We expressed wild-type (WT) or V110I Kv7.1 channels in CHO-K1 cells cotransfected with KCNE1 and performed patch-clamp analysis. In addition, WT or K897T Kv11.1 were also studied by patch clamp. Current–voltage...

Electrophysiologic and Antiarrhythmic Effects of AZD1305 in Canine Pulmonary Vein Sleeves

Abstract: The objective of this study was to examine the electrophysiologic and antiarrhythmic effects of the new antiarrhythmic agent tert-butyl (2-{7-[2-(4-cyano-2-fluorophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non3-yl}ethyl)carbamate (AZD1305) in canine pulmonary vein (PV) sleeve preparations isolated from untreated and long-term amiodarone-treated animals. Ectopic activity arising from PV sleeves plays a prominent role in the development of atrial fibrillation (AF). Delayed afterdepolarizations (DADs) and late phase 3 early afterdepolarizations (EADs), originating from the PV have been proposed as potential triggers in initiation of AF. Action potentials were recorded from canine superfused PV sleeves using standard microelectrode techniques. Acetylcholine (1 μM), isoproterenol (1 μM), or their combination was used to induce EADs, DADs, and triggered activity (TA). The effects of AZD1305 (0.1–10 μM) were evaluated in PV sleeve preparations isolated from untreated and amiodarone-treated (40 mg/kg daily for 6 weeks) dogs. AZD1305 (0.1–10 μM, 30 min) significantly prolonged action potential duration and reduced excitability. Abbreviating basic cycle length from 1000 to 300 ms resulted in a decrease of Vmax from 314 ± 79 to 251 ± 55 V/s (Δ = −20%) in control and from 177 ± 53 to 76.5 ± 33 V/s (Δ = −57%) after AZD1305 (n = 6, p < 0.05). AZD1305 markedly attenuated or suppressed DADs and DAD-induced TA, but not late phase 3 EADs. AZD1305-induced attenuation of excitability, leading to activation failure at much longer cycle lengths, was much more pronounced in PV from amiodarone-treated dogs. Potent effects of AZD1305 to depress excitability, prolong action potential duration, and suppress DAD-induced triggered activity in canine PV sleeve preparations may be effective in suppressing triggers responsible for the genesis of AF and other atrial arrhythmias.