Acacetin suppresses the electrocardiographic and arrhythmic manifestations of the J wave syndromes.

BACKGROUND: J wave syndromes (JWS), including Brugada (BrS) and early repolarization syndromes (ERS), are associated with increased risk for life-threatening ventricular arrhythmias. Pharmacologic approaches to therapy are currently very limited. Here, we evaluate the effects of the natural flavone acacetin. METHODS: The effects of acacetin on action potential (AP) morphology and transient outward current (Ito) were first studied in isolated canine RV epicardial myocytes using whole-cell patch clamp techniques. Acacetin's effects on transmembrane APs, unipolar electrograms and transmural ECGs were then studied in isolated coronary-perfused canine RV and LV wedge preparations as well as in whole-heart, Langendorff-perfused preparations from which we recorded a 12 lead ECG and unipolar electrograms. Using floating glass microelectrodes we also recorded transmembrane APs from the RVOT of the whole-heart model. The Ito agonist NS5806, sodium channel blocker ajmaline, calcium channel blocker verapamil or hypothermia (32°C) were used to pharmacologically mimic the genetic defects and conditions associated with JWS, thus eliciting prominent J waves and provoking VT/VF. RESULTS: Acacetin (5-10 µM) reduced Ito density, AP notch and J wave area and totally suppressed the electrocardiographic and arrhythmic manifestation of both BrS and ERS, regardless of the experimental model used. In wedge and whole-heart models of JWS, increasing Ito with NS5806, decreasing INa or ICa (with ajmaline or verapamil) or hypothermia all resulted in accentuation of epicardial AP notch and ECG J waves, resulting in characteristic BrS and ERS phenotypes. Phase 2-reentrant extrasystoles originating from the RVOT triggered VT/VF. The J waves in leads V1 and V2 were never associated with a delay of RVOT activation and always coincided with the appearance of the AP notch recorded from RVOT epicardium. All repolarization defects giving rise to VT/VF in the BrS and ERS models were reversed by acacetin, resulting in total suppression of VT/VF. CONCLUSIONS: We present experimental models of BrS and ERS capable of recapitulating all of the ECG and arrhythmic manifestations of the JWS. Our findings provide definitive support for the repolarization but not the depolarization hypothesis proposed to underlie BrS and point to acacetin as a promising new pharmacologic treatment for JWS.

Epicardial Substrate as a Target for Radiofrequency Ablation in an Experimental Model of Early Repolarization Syndrome.

BACKGROUND: Early repolarization syndrome (ERS) is an inherited cardiac arrhythmia syndrome associated with sudden cardiac death. Approaches to therapy are currently very limited. This study probes the mechanisms underlying the electrocardiographic and arrhythmic manifestation of experimental models of ERS and of the ameliorative effect of radiofrequency ablation. METHODS: Action potentials, bipolar electrograms, and transmural pseudo-ECGs were simultaneously recorded from coronary-perfused canine left ventricular wedge preparations (n=11). The Ito agonist NS5806 (7-10 µmol/L), calcium channel blocker verapamil (3 µmol/L), and acetylcholine (1-3 µmol/L) were used to pharmacologically mimic the effects of genetic defects associated with ERS. RESULTS: The provocative agents induced prominent J waves in the ECG secondary to accentuation of the action potential notch in epicardium but not endocardium. Bipolar recordings displayed low-voltage fractionated potentials in epicardium because of temporal and spatial variability in appearance of the action potential dome. Concealed phase 2 reentry developed when action potential dome was lost at some epicardial sites but not others, appearing in the bipolar electrogram as discrete high-frequency spikes. Successful propagation of the phase 2 reentrant beat precipitated ventricular tachycardia/ventricular fibrillation. Radiofrequency ablation of the epicardium destroyed the cells displaying abnormal repolarization and thus suppressed the J waves and the development of ventricular tachycardia/ventricular fibrillation in 6/6 preparations. CONCLUSIONS: Our findings suggest that low-voltage fractionated electrical activity and high-frequency late potentials recorded from the epicardial surface of the left ventricle can identify regions of abnormal repolarization responsible for ventricular tachycardia/ventricular fibrillation in ERS and that radiofrequency ablation of these regions in left ventricular epicardium can suppress ventricular tachycardia/ventricular fibrillation by destroying regions of ER.

Coexistence of atrioventricular accessory pathways and drug-induced type 1 Brugada pattern.

BACKGROUND: Atrial arrhythmias, particularly atrioventricular nodal reentrant tachycardia, can coexist with drug-induced type 1 Brugada electrocardiogram (ECG) pattern (DI-Type1-BrP). The present study was designed to determine the prevalence of DI-Type1-BrP in patients with atrioventricular accessory pathways (AV-APs) and to investigate the clinical, electrocardiographic, electrophysiologic, and genetic characteristics of these patients. METHODS: One-hundred twenty-four consecutive cases of AV-APs and 84 controls underwent an ajmaline challenge test to unmask DI-Type1-BrP. Genetic screening and analysis was performed in 55 of the cases (19 with and 36 without DI-Type1-BrP). RESULTS: Patients with AV-APs were significantly more likely than controls to have a Type1-BrP unmasked (16.1 vs 4.8%, P = 0.012). At baseline, patients with DI-Type1-BrP had higher prevalence of chest pain, QR/rSr' pattern in V1 and QRS notching/slurring in V2 and aVL during preexcitation, rSr' pattern in V1 -V2 , and QRS notching/slurring in aVL during orthodromic atrioventricular reentrant tachycardia (AVRT) compared to patients without DI-Type1-BrP. Abnormal QRS configuration (QRS notching/slurring and/or fragmentation) in V2 during preexcitation was present in all patients with DI-Type1 BrP. The prevalence of spontaneous preexcited atrial fibrillation (AF) and history of AF were similar (15% vs 18.3%, P = 0.726) in patients with and without DI-Type1-BrP, respectively. The prevalence of mutations in Brugada-susceptibility genes was higher (36.8% vs 8.3%, P = 0.02) in patients with DI-Type1-BrP compared to patients without DI-Type1-BrP. CONCLUSIONS: DI-Type1-BrP is relatively common in patients with AV-APs. We identify 12-lead ECG characteristics during preexcitation and orthodromic AVRT that point to an underlying type1-BrP, portending an increased probability for development of malignant arrhythmias.

Mechanisms underlying atrial-selective block of sodium channels by Wenxin Keli: Experimental and theoretical analysis.

INTRODUCTION: Atrial-selective inhibition of cardiac sodium channel current (INa) and INa-dependent parameters has been shown to contribute to the safe and effective management of atrial fibrillation. The present study was designed to examine the basis for the atrial-selective actions of Wenxin Keli. METHODS: Whole cell INa was recorded at room temperature in canine atrial and ventricular myocytes. Trains of 40 pulses were elicited over a range of pulse durations and interpulse intervals to determine tonic and use-dependent block. A Markovian model for INa that incorporates interaction of Wenxin Keli with different states of the channel was developed to examine the basis for atrial selectivity of the drug. RESULTS: Our data indicate that Wenxin Keli does not bind significantly to either closed or open states of the sodium channel, but binds very rapidly to the inactivated state of the channel and dissociates rapidly from the closed state. Action potentials recorded from atrial and ventricular preparations in the presence of 5g/L Wenxin Keli were introduced into the computer model in current clamp mode to simulate the effects on maximum upstroke velocity (Vmax). The model predicted much greater inhibition of Vmax in atrial vs. ventricular cells at rapid stimulation rates. CONCLUSION: Our findings suggest that atrial selectivity of Wenxin Keli to block INa is due to more negative steady-state inactivation, less negative resting membrane potential, and shorter diastolic intervals in atrial vs. ventricular cells at rapid activation rates. These actions of Wenxin Keli account for its relatively safe and effective suppression of atrial fibrillation.

Risk stratification in Brugada syndrome: Clinical characteristics, electrocardiographic parameters, and auxiliary testing.

Risk stratification in Brugada syndrome remains a clinical challenge because the event rate is low but the presenting symptom is often cardiac arrest (CA). We review the data on risk stratification. A history of CA or malignant syncope is a strong predictor of spontaneous ventricular fibrillation (VF), whereas the prognostic value of a history of familial sudden death and the presence of a SCN5A mutation are less well defined. On the electrocardiogram, the presence of spontaneous type I electrocardiogram increases the risk for VF in all studies, whereas the presence of fragmented QRS complexes and early repolarization correlates with increased risk in several studies. Signal-averaged techniques using late potentials and microscopic T-wave alternans show some promising results in small studies that need to be confirmed. The value of electrophysiologic studies for predicting spontaneous VF remains controversial, and this includes programmed stimulation protocols that avoid a third extrastimuli or stimulation from the right ventricular outflow. Risk prediction is particularly challenging in children and women.

High prevalence of concealed Brugada syndrome in patients with atrioventricular nodal reentrant tachycardia.

BACKGROUND: Atrioventricular nodal reentrant tachycardia (AVNRT) may coexist with Brugada syndrome (BrS). OBJECTIVES: The present study was designed to determine the prevalence of drug-induced type 1 Brugada ECG pattern (concealed BrS) in patients presenting with clinical spontaneous AVNRT and to investigate their electrocardiographic, electrophysiological, and genetic characteristics. METHODS: Ninety-six consecutive patients without any sign of BrS on baseline electrocardiogram undergoing electrophysiological study and ablation for symptomatic, drug-resistant AVNRT and 66 control subjects underwent an ajmaline challenge to unmask BrS. Genetic screening was performed in 17 patients displaying both AVNRT and BrS. RESULTS: A concealed BrS electrocardiogram was uncovered in 26 of 96 patients with AVNRT (27.1%) and in 3 of 66 control subjects (4.5%) (P ≤ .001). Patients with concealed BrS were predominantly female patients (n=23 [88.5%] vs n=44 [62.9%], P = .015), had higher prevalence of chest pain (n=10 [38.5%] vs n=13 [18.6%], p=0.042), migraine headaches (n=10 [38.5%] vs n=10 [14.2%], p=0.008), and drug-induced initiation and/or worsening of duration and/or frequency of AVNRT (n=4 [15.4%] vs n=1 [1.4%], p=0.006) as compared to patients with AVNRT without BrS. Genetic screening identified 19 mutations or rare variants in 13 genes in 13 of 17 patients with both AVNRT and BrS (yield = 76.5%). Ten of these 13 genotype-positive patients (76.9%) harbored genetic variants known or suspected to cause a loss of function of cardiac sodium channel current (SCN5A, SCN10A, SCN1B, GPD1L, PKP2, and HEY2). CONCLUSION: Our results suggest that spontaneous AVNRT and concealed BrS co-occur, particularly in female patients, and that genetic variants that reduce sodium channel current may provide a mechanistic link between AVNRT and BrS and predispose to expression of both phenotypes.

PQ segment depression in patients with short QT syndrome: a novel marker for diagnosing short QT syndrome?

BACKGROUND: Patients with short QT syndrome (SQTS) have an increased risk for atrial tachyarrhythmias, ventricular tachyarrhythmias, and/or sudden cardiac death. PQ segment depression (PQD) is related to atrial fibrillation and carries a poor prognosis in the setting of acute inferior myocardial infarction and is a well-defined electrocardiographic (ECG) marker of acute pericarditis. OBJECTIVE: To evaluate the prevalence of PQD in SQTS and to analyze the association with atrial arrhythmias. METHODS: Digitalized 12-lead ECGs of SQTS patients were evaluated for PQD in all leads and for QT intervals in leads II and V5. PQD was defined as ≥0.05 mV (0.5 mm) depression from the isoelectric line. RESULTS: A total of 760 leads from 64 SQTS patients (mean age 36 ± 18 years; 48 [75%] men) were analyzed. PQD was seen in 265 (35%) leads from 52 (81%) patients and was more frequent in leads II, V3, aVF, V4, and I (n = 43 [67%], n = 30 [47%], n = 27 [42%], n = 25 [39%], and n = 25 [39%], respectively). Nine of 64 (14%) patients presented with atrial tachyarrhythmias, and all of them had PQD. CONCLUSION: Fifty-two of 64 (81%) patients with SQTS reveal PQD. As PQD is rarely observed in healthy individuals, this ECG stigma may constitute a novel marker for SQTS in addition to a short QT interval.

Effect of Wenxin Keli and quinidine to suppress arrhythmogenesis in an experimental model of Brugada syndrome.

BACKGROUND: Wenxin Keli (WK), a Chinese herb extract, is reported to be effective in the treatment of atrial and ventricular cardiac arrhythmias. Recent studies suggest that WK inhibits the transient potassium outward current (I(to)). OBJECTIVE: To examine the effectiveness of WK, alone and in combination with quinidine, to suppress arrhythmogenesis in an experimental model of Brugada syndrome (BrS). METHODS: Action potential and electrocardiographic recordings were obtained from epicardial and endocardial sites of coronary-perfused canine right ventricular wedge preparations. The Ito agonist NS5806 (10-15 µM) was used to pharmacologically mimic a genetic predisposition to BrS. RESULTS: The Ito agonist induced Phase 2 reentry (P2R) in 13/19 preparations and polymorphic ventricular tachycardia (pVT) in 11/19 wedge preparations. WK (10 g/L) suppressed P2R and pVT in 100% (3/3) of preparations. A lower concentration of WK (5 g/L) suppressed P2R in 60% (3/5) and pVT in 50% (2/4), but in combination with a low concentration of quinidine (5 µM), was 100% effective in suppressing P2R and pVT. Quinidine alone suppressed P2R and pVT in 60% (3/5) and 50% (2/4), respectively, and in combination with WK (5 g/L) suppressed P2R and pVT by 80% (4/5) and 75% (3/4), respectively. WK reduced Ito, the L-type calcium current, and contractility in single cardiomyocytes, but dose-dependently increased contractility in intact wedge preparations, an effect mimicked by tyramine. CONCLUSIONS: Our data provide support for the hypothesis that WK, particularly in combination with quinidine, effectively suppresses arrhythmogenesis in an experimental model of BrS via inhibition of Ito and indirect adrenergic sympathomimetic effects.

Torsades de pointes following acute myocardial infarction: evidence for a deadly link with a common genetic variant.

BACKGROUND: Although QT prolongation following myocardial infarction (MI) is generally moderate, cases with marked QT prolongation leading to life-threatening torsades de pointes (TdP) have been described. OBJECTIVE: To investigate the genetic substrate of this phenomenon. METHODS: We studied 13 patients who developed TdP in the subacute phase of MI (2-11 days) and a group of 133 ethnically matched controls with uncomplicated MI. Long QT syndrome genes and the KCNH2-K897T polymorphism were screened by using denaturing high-performance liquid chromatography plus direct sequencing and a specific TaqMan assay, respectively. RESULTS: Two of the 13 patients (15%) who presented with QT prolongation and TdP were found to carry long QT syndrome mutations (KCNH2-R744X and SCN5A-E446K). Nine of the remaining 11 patients (82%) carried the KCNH2-K897T polymorphism, which was present in 35% of the controls (P = .0035). Thus, patients with an acute MI carrying the KCNH2-K897T polymorphism had an 8-fold greater risk of experiencing TdP compared with controls (95% confidence interval = 2-40). CONCLUSIONS: Our data suggest that the common K897T polymorphism is associated with an increased risk of TdP developing in the subacute phase of MI. Our findings support the concept that the electrical remodeling associated with this healing phase of MI may unmask a genetic substrate predisposing to a time-limited development of life-threatening arrhythmias. They also provide the first line of evidence in support of the hypothesis that a common polymorphism, previously described as a modifier of the severity of LQTS, may increase the risk of life-threatening arrhythmias in a much more prevalent cardiac disease such as myocardial infarction.

Identification of specific pluripotent stem cell death--inducing small molecules by chemical screening.

A potential application of embryonic and inducible pluripotent stem cells for the therapy of degenerative diseases involves pure somatic cells, free of tumorigenic undifferentiated embryonic and inducible pluripotent stem cells. In complex collections of chemicals with pharmacological potential we expect to find molecules able to induce specific pluripotent stem cell death, which could be used in some cell therapy settings to eliminate undifferentiated cells. Therefore, we have screened a chemical library of 1120 small chemicals to identify compounds that induce specifically apoptotic cell death in undifferentiated mouse embryonic stem cells (ESCs). Interestingly, three compounds currently used as clinically approved drugs, nortriptyline, benzethonium chloride and methylbenzethonium chloride, induced differential effects in cell viability in ESCs versus mouse embryonic fibroblasts (MEFs). Nortriptyline induced apoptotic cell death in MEFs but not in ESCs, whereas benzethonium and methylbenzethonium chloride showed the opposite effect. Nortriptyline, a tricyclic antidepressant, has also been described as a potent inhibitor of mitochondrial permeability transition, one of two major mechanisms involved in mitochondrial membrane permeabilization during apoptosis. Benzethonium chloride and methylbenzethonium chloride are quaternary ammonium salts used as antimicrobial agents with broad spectrum and have also been described as anticancer agents. A similar effect of benzethonium chloride was observed in human induced pluripotent stem cells (hiPSCs) when compared to both primary human skin fibroblasts and an established human fibroblast cell line. Human fibroblasts and hiPSCs were similarly resistant to nortriptyline, although with a different behavior. Our results indicate differential sensitivity of ESCs, hiPSCs and fibroblasts to certain chemical compounds, which might have important applications in the stem cell-based therapy by eliminating undifferentiated pluripotent stem cells from stem cell-derived somatic cells to prevent tumor formation after transplantation for therapy of degenerative diseases.

Atrial-selective inhibition of sodium-channel current by Wenxin Keli is effective in suppressing atrial fibrillation.

BACKGROUND: Wenxin Keli is a Chinese herb extract reported to be of benefit in the treatment of cardiac arrhythmias, cardiac inflammation, and heart failure. METHODS AND RESULTS: We evaluated the electrophysiologic effects of Wenxin Keli in isolated canine arterially perfused right atrial preparations with a rim of right ventricular tissue (n = 11). Transmembrane action potentials and a pseudoelectrocardiogram were simultaneously recorded. Acetylcholine (1 µM) was used to induce atrial fibrillation (AF) and to test the anti-AF potential of Wenxin Keli (5 g/L). Wenxin Keli produced preferential abbreviation of action potential duration measured at 90% repolarization (APD(90)) in atria, but caused atrial-selective prolongation of the effective refractory period, due to the development of postrepolarization refractoriness. The maximum rate of rise of the action potential upstroke was preferentially reduced in atria. The diastolic threshold of excitation increased in both atria and ventricles, but much more in atria. The duration of the "P wave" (index of atrial conduction time) was prolonged to a much greater extent than the duration of the "QRS complex" (index of ventricular conduction time). Wenxin Keli significantly reduced I(Na) and shifted steady-state inactivation to more negative potentials in HEK293 cells stably expressing SCN5A. Wenxin Keli prevented the induction of persistent AF in 100% atria (6/6) and, in another experimental series, was found to terminate persistent acetylcholine-mediated AF in 100% of atria (3/3). CONCLUSION: Wenxin Keli produces atrial-selective depression of I(Na)-dependent parameters in canine isolated coronary-perfused preparations via a unique mechanism and is effective in suppressing AF and preventing its induction, with minimal effects on the ventricular electrophysiology.

Electrophysiologic basis for the antiarrhythmic actions of ranolazine.

Ranolazine is a Food and Drug Administration-approved antianginal agent. Experimental and clinical studies have shown that ranolazine has antiarrhythmic effects in both ventricles and atria. In the ventricles, ranolazine can suppress arrhythmias associated with acute coronary syndrome, long QT syndrome, heart failure, ischemia, and reperfusion. In atria, ranolazine effectively suppresses atrial tachyarrhythmias and atrial fibrillation (AF). Recent studies have shown that the drug may be effective and safe in suppressing AF when used as a pill-in-the pocket approach, even in patients with structurally compromised hearts, warranting further study. The principal mechanism underlying ranolazine's antiarrhythmic actions is thought to be primarily via inhibition of late I(Na) in the ventricles and via use-dependent inhibition of peak I(Na) and I(Kr) in the atria. Short- and long-term safety of ranolazine has been demonstrated in the clinic, even in patients with structural heart disease. This review summarizes the available data regarding the electrophysiologic actions and antiarrhythmic properties of ranolazine in preclinical and clinical studies.

Antiarrhythmic effects of simvastatin in canine pulmonary vein sleeve preparations.

OBJECTIVES: The purpose of this study was to determine the electrophysiologic effects of simvastatin in canine pulmonary vein (PV) sleeve preparations. BACKGROUND: Ectopic activity arising from the PV plays a prominent role in the development of atrial fibrillation. METHODS: Transmembrane action potentials were recorded from canine superfused left superior or inferior PV sleeves using standard microelectrode techniques. Acetylcholine (1 µM), isoproterenol (1 µM), high calcium ([Ca(2+)](o) = 5.4 mM), or a combination was used to induce early afterdepolarizations or delayed afterdepolarizations and triggered activity. Voltage clamp experiments were performed in the left atrium measuring fast and late sodium currents. RESULTS: Under steady-state conditions, simvastatin (10 nM, n = 9) induced a small increase in action potential duration measured at 85% repolarization and a significant decrease in action potential amplitude, take-off potential, and maximum rate of rise of action potential upstroke at the fastest rates. The V(max) decreased from 175.1 ± 34 V/s to 151.7 ± 28 V/s and from 142 ± 47 V/s to 97.4 ± 39 V/s at basic cycle lengths of 300 and 200 ms, respectively. Simvastatin (10 to 20 nM) eliminated delayed afterdepolarizations and delayed afterdepolarization-induced triggered activity in 7 of 7 PV sleeve preparations and eliminated or reduced late-phase 3 early afterdepolarizations in 6 of 6 PV sleeve preparations. Simvastatin (20 nM) did not affect late or fast sodium currents measured using voltage clamp techniques. CONCLUSIONS: Our data suggest that in addition to its upstream actions to reduce atrial structural remodeling, simvastatin exerts a direct antiarrhythmic effect by suppressing triggers responsible for the genesis of atrial fibrillation.

Unraveling the Enigma of Bangungut: Is Sudden Unexplained Nocturnal Death Syndrome (SUNDS) in the Philippines a Disease Allelic to the Brugada Syndrome?

BACKGROUND: Sudden unexplained nocturnal death syndrome (SUNDS) has been reported worldwide. SUNDS is endemic in Southeast Asia and is colloquially known as Bangungut in the Philippines, Lai Tai in Thailand, and Pokkuri in Japan. Although SUNDS in Thailand and Japan have been determined to be phenotypically, genetically and functionally identical to the Brugada syndrome, the relationship between Bangungut/SUNDS in the Philippines and the Brugada syndrome has not been clarified. This paper explores the concordance between Bangungut/SUNDS and the Brugada syndrome. METHODS: We summarized autopsy studies on Bangungut retrieved from PubMed since 1917 and current epidemiological data on Philippine SUNDS to clarify its diagnostic features. We also reviewed current hypotheses of the pathophysiological mechanism of the Brugada syndrome to explore its applicability to Bangungut/SUNDS. RESULTS: The use of the term Bangungut is confusing as it includes many diseases that may cause SUNDS. However, our review reveals a notable subset of Bangungut, identified as Bangungut/SUNDS with no gross cardiac pathology that conforms to the clinical picture of the folk-belief of Bangungut and of the Brugada syndrome, namely: predominance among male in the 20-40 age range; sudden death during sleep or at rest, usually following ingestion of a large meal at night; and victims were in apparent good health prior to their demise. Current pathophysiological mechanisms of Brugada syndrome seemed plausible explanations for a majority of this subset of Bangungut/SUNDS. CONCLUSION: Bangungut/SUNDS and the Brugada syndrome appear closely related. Pathophysiological mechanisms of the Brugada syndrome may explain the enigma of Bangungut/SUND. Whether Bangungut/SUNDS is phenotypically, genetically and functionally an allele of the Brugada syndrome remains inconclusive due to lack of research data. We therefore proposed a research agenda including genetic testing and pharmacological challenge of probands and their family members suspected of SUNDS to conclusively establish the relationship between these two syndromes.

Mutations in the cardiac L-type calcium channel associated with inherited J-wave syndromes and sudden cardiac death.

BACKGROUND: L-type calcium channel (LTCC) mutations have been associated with Brugada syndrome (BrS), short QT (SQT) syndrome, and Timothy syndrome (LQT8). Little is known about the extent to which LTCC mutations contribute to the J-wave syndromes associated with sudden cardiac death. OBJECTIVE: The purpose of this study was to identify mutations in the α1, ß2, and α2δ subunits of LTCC (Ca(v)1.2) among 205 probands diagnosed with BrS, idiopathic ventricular fibrillation (IVF), and early repolarization syndrome (ERS). CACNA1C, CACNB2b, and CACNA2D1 genes of 162 probands with BrS and BrS+SQT, 19 with IVF, and 24 with ERS were screened by direct sequencing. METHODS/RESULTS: Overall, 23 distinct mutations were identified. A total of 12.3%, 5.2%, and 16% of BrS/BrS+SQT, IVF, and ERS probands displayed mutations in α1, ß2, and α2δ subunits of LTCC, respectively. When rare polymorphisms were included, the yield increased to 17.9%, 21%, and 29.1% for BrS/BrS+SQT, IVF, and ERS probands, respectively. Functional expression of two CACNA1C mutations associated with BrS and BrS+SQT led to loss of function in calcium channel current. BrS probands displaying a normal QTc had additional variations known to prolong the QT interval. CONCLUSION: The study results indicate that mutations in the LTCCs are detected in a high percentage of probands with J-wave syndromes associated with inherited cardiac arrhythmias, suggesting that genetic screening of Ca(v) genes may be a valuable diagnostic tool in identifying individuals at risk. These results are the first to identify CACNA2D1 as a novel BrS susceptibility gene and CACNA1C, CACNB2, and CACNA2D1 as possible novel ERS susceptibility genes.

Acute dronedarone is inferior to amiodarone in terminating and preventing atrial fibrillation in canine atria.

BACKGROUND: Dronedarone is approved by the U.S. Food and Drug Administration for the treatment of patients with atrial fibrillation (AF) as a safe alternative to amiodarone. There are no full-length published reports describing the effectiveness of acute dronedarone use against AF in experimental or clinical studies. OBJECTIVE: The purpose of this study was to determine the effect of acute dronedarone and amiodarone on electrophysiological parameters, and their anti-AF efficacy in canine isolated arterially perfused right atria. METHODS: Transmembrane action potentials and pseudoelectrocardiograms were recorded. Acetylcholine (ACh, 1.0 muM) was used to induce persistent AF. RESULTS: Amiodarone-induced changes were much more pronounced than those of dronedarone on (1) action potential duration (DeltaAPD(90), +51 +/- 17 ms vs. 4 +/- 6 ms, P >.01), (2) effective refractory period (DeltaERP, +84 +/- 23 ms vs. 18 +/- 9 ms, P <.001), (3) diastolic threshold of excitation (DeltaDTE, +0.32 +/- 0.11 mA vs. 0.03 +/- 0.02 mA, P <.001), and (4) V(max) (DeltaV(max), -43 +/- 14% vs. -11 +/- 4%, P <.01, n = 5 to 6; all recorded at 10 muM, cycle length = 500 ms). Persistent AF was induced in 10 of 10 atria exposed to ACh alone; subsequent addition of dronedarone or amiodarone terminated AF in 1 of 7 and 4 of 5 atria, respectively. Persistent ACh-mediated AF was induced in 5 of 6 and 0 of 5 atria pretreated with dronedarone and amiodarone, respectively. CONCLUSION: The electrophysiological effects and anti-AF efficacy of acute dronedarone are much weaker than those of amiodarone in a canine model of AF. The efficacy of acute dronedarone to prevent induction of acetylcholine-mediated AF as well as to terminate persistent AF in canine right atria is relatively poor. Our data suggest that acute dronedarone is a poor substitute for amiodarone for acute cardioversion of AF or prevention of AF recurrence.

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

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. METHODS: Direct sequencing was performed in a family with cardiac conduction disease. Wild-type (WT) and mutant channels were expressed in TSA201 cells for electrophysiological study. Green fluorescent protein (GFP)-fused WT or mutant genes were used to assess channel trafficking. RESULTS: A novel SCN5A mutation, P1008S, was identified in all family members displaying first-degree atrioventricular block, but not in unaffected family members nor in 430 reference alleles. Peak P1008S current was 11.77% of WT (P < 0.001). Confocal microscopy showed that WT channels tagged with GFP were localized on the cell surface, whereas GFP-tagged P1008S channels remained trapped in intracellular organelles. Trafficking could be rescued by incubation at room temperature, but not by incubation with mexiletine (300 muM) at 37 degrees C. We also identified a novel polymorphism (D601E) in CACNB2b that slowed inactivation of L-type calcium current (I(Ca,L)), significantly increased total charge. Using the Luo-Rudy action potential (AP) model, we show that the reduction in sodium current (I(Na)) can cause loss of the right ventricular epicardial AP dome in the absence but not in the presence of the slowed inactivation of I(Ca,L). Slowed conduction was present in both cases. CONCLUSIONS: Our results suggest genetic variations leading to a loss-of-function in I(Na) coupled with a gain of function in I(Ca,L) may underlie the development of cardiac conduction disease without BrS.