Gene mutations in cardiac arrhythmias: a review of recent evidence in ion channelopathies.

Over the past 15 years, molecular genetic studies have linked gene mutations to many inherited arrhythmogenic disorders, in particular, "ion channelopathies", in which mutations in genes encode functional units of ion channels and/or their transporter-associated proteins in patients without primary cardiac structural abnormalities. These disorders are exemplified by congenital long QT syndrome (LQTS), short QT syndrome, Brugada syndrome (BrS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). Functional and pathophysiological studies have led to better understanding of the clinical spectrum, ion channel structures and cellular electrophysiology involving dynamics of intracellular calcium cycling in many subtypes of these disorders and more importantly, development of potentially more effective pharmacological agents and even curative gene therapy. In this review, we have summarized (1) the significance of unveiling mutations in genes encoding transporter-associated proteins as the cause of congenital LQTS, (2) the technique of catheter ablation applied at the right ventricular outflow tract may be curative for severely symptomatic BrS, (3) mutations with channel function modulated by protein Kinase A-dependent phosphorylation can be the culprit of CPVT mimicry in Andersen-Tawil syndrome (LQT7), (4) ablation of the ion channel anchoring protein may prevent arrhythmogenesis in Timothy syndrome (LQT8), (5) altered intracellular Ca2+ cycling can be the basis of effective targeted pharmacotherapy in CPVT, and (6) the technology of induced pluripotent stem cells is a promising diagnostic and research tool as it has become a new paradigm for pathophysiological study of patient- and disease-specific cells aimed at screening new drugs and eventual clinical application of gene therapy. Lastly, we have discussed (7) genotype-phenotype correlation in relation to risk stratification of patients with congenital LQTS in clinical practice.

Left Atrial Diastolic Dysfunction following Catheter Ablation of Atrial Fibrillation.

Radiofrequency catheter ablation (RFCA)-induced thermal injury may cause and/or worsen left atrial (LA) diastolic dysfunction leading to pulmonary hypertension and heart failure in patients with atrial fibrillation (AF), the incidence of which is probably more common than is generally realized. Biplane 2-dimensional echocardiography coupled with tissue Doppler (velocity) imaging and Doppler-derived strain (rate) imaging can be applied to provide quantitative assessment of the LA function (both systolic and diastolic) relative to pulmonary venous circulation and left ventricular function. Information so obtained is useful for guiding follow-up management of patients undergoing RFCA of AF.

Targeting intracellular calcium cycling in catecholaminergic polymorphic ventricular tachycardia: a theoretical investigation.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a malignant arrhythmogenic disorder linked to mutations in the cardiac ryanodine receptor (RyR2) and calsequestrin, predisposing the young to syncope and cardiac arrest. To define the role of ß-adrenergic stimulation (BAS) and to identify potential therapeutic targeted sites relating to intracellular calcium cycling, we used a Luo-Rudy dynamic ventricular myocyte model incorporated with interacting Markov models of the L-type Ca(2+) channel (I(Ca,L)) and RyR2 to simulate the heterozygous state of mouse RyR2 R4496C mutation (RyR2(R4496C+/-)) comparable with CPVT patients with RyR2 R4497C mutation. Characteristically, in simulated cells, pacing at 4 Hz or faster or pacing at 2 Hz under BAS with effects equivalent to those of isoproterenol at ≥ 0.1 µM could readily induce delayed afterdepolarizations (DADs) and DAD-mediated triggered activity (TA) in RyR2(R4496C+/-) but not in the wild-type via enhancing both I(Ca,L) and sarcoplasmic reticulum (SR) Ca(2+) ATPase (I(UP)). Moreover, with the use of steady state values of isolated endocardial (Endo), mid-myocardial (M), and epicardial (Epi) cells as initial data for conducting single cell and one-dimensional strand studies, the M cell was more vulnerable for developing DADs and DAD-mediated TA than Endo and Epi cells, and the gap junction coupling represented by diffusion coefficient (D) of ≤ 0.000766*98 cm(2)/ms was required for generating DAD-mediated TA in RyR2(R4496C+/-). Whereas individual reduction of Ca(2+) release channel of SR and Na-Ca exchanger up to 50% was ineffective, 30% or more reduction of either I(Ca,L) or I(UP) could totally suppress the inducibility of arrhythmia under BAS. Of note, 15% reduction of both I(Ca,L) and I(UP) exerted a synergistic antiarrhythmic efficacy. Findings of this model study confirm that BAS facilitates induction of ventricular tachyarrhythmias via its action on intracellular Ca(2+) cycling and a pharmacological regimen capable of reducing I(Ca,L) could be an effective adjunctive to ß-adrenergic blockers for suppressing ventricular tachyarrhythmias during CPVT.

Beta-adrenergic modulation of arrhythmogenesis and identification of targeted sites of antiarrhythmic therapy in Timothy (LQT8) syndrome: a theoretical study.

Timothy syndrome (TS) is a malignant form of congenital long QT syndrome with a mode of arrhythmia onset often triggered by enhanced sympathetic tone. We sought to explore mechanisms by which beta-adrenergic stimulation (BAS) modulates arrhythmogenesis and to identify potential targeted sites of antiarrhythmic therapy in TS. Using a dynamic Luo-Rudy ventricular myocyte model incorporated with detailed intracellular Ca(2+) cycling, along with its one-dimensional multicellular strand, we simulated various clinical scenarios of TS, with stepwise increase in the percentage of G406R Ca(v)1.2 channels from 0 to 11.5 and 23%, and to 38.5 and 77%, respectively, for heterozygous and homozygous states of TS1 and TS2. Progressive prolongation of action potential duration (APD) and QT interval, accompanied by amplification of transmural dispersion of repolarization, steepening of APD restitution, induction of delayed afterdepolariztions (DADs), and both DAD and phase 3 early afterdepolariztion-mediated triggered activities, correlated well with the extent of G406R Ca(v)1.2 channel mutation. BAS amplified transmural dispersion of repolarization, steepened APD restitution, and facilitated inducibility of DAD-mediated triggered activity. Systematic analysis of intracellular Ca(2+) cycling revealed that sarcoplasmic reticulum Ca(2+) ATPase (uptake current) played an essential role in BAS-induced facilitation of DAD-mediated triggered activity and, in addition to L-type calcium current, it could be an effective site of antiarrhythmic therapy under the influence of BAS. Thus G406R Ca(v)1.2 channel mutation confers not only a trigger, but also a substrate for lethal ventricular arrhythmias, which can be exaggerated by BAS. It is suggested that, besides beta-adrenergic blockers and L-type calcium current channel blockers, an agent aimed at reduction of sarcoplasmic reticulum Ca(2+) ATPase uptake current may provide additional antiarrhythmic effect in patients with TS.

Time-dependent block of ultrarapid-delayed rectifier K+ currents by aconitine, a potent cardiotoxin, in heart-derived H9c2 myoblasts and in neonatal rat ventricular myocytes.

Aconitine (ACO), a highly toxic diterpenoid alkaloid, is recognized to have effects on cardiac voltage-gated Na(+) channels. However, it remains unknown whether it has any effects on K(+) currents. The effects of ACO on ion currents in differentiated clonal cardiac (H9c2) cells and in cultured neonatal rat ventricular myocytes were investigated in this study. In H9c2 cells, ACO suppressed ultrarapid-delayed rectifier K(+) current (I(Kur)) in a time- and concentration-dependent fashion. The IC(50) value for ACO-induced inhibition of I(Kur) was 1.4 microM. ACO could accelerate the inactivation of I(Kur) with no change in the activation time constant of this current. Steady-state inactivation curve of I(Kur) during exposure to ACO could be demonstrated. Recovery from block by ACO was fitted by a single-exponential function. The inhibition of I(Kur) by ACO could still be observed in H9c2 cells preincubated with ruthenium red (30 microM). Intracellular dialysis with ACO (30 microM) had no effects on I(Kur). I(Kur) elicited by simulated action potential (AP) waveforms was sensitive to block by ACO. Single-cell Ca(2+) imaging revealed that ACO (10 microM) alone did not affect intracellular Ca(2+) in H9c2 cells. In cultured neonatal rat ventricular myocytes, ACO also blocked I(Kur) and prolonged AP along with appearance of early afterdepolarizations. Multielectrode recordings on neonatal rat ventricular tissues also suggested that ACO-induced electrocardiographic changes could be associated with inhibition of I(Kur). This study provides the evidence that ACO can produce a depressant action on I(Kur) in cardiac myocytes.

The activation by estrogen receptor agonists of the BK(Ca)-channel in human cardiac fibroblasts.

The agonists selective for estrogen receptor (ER)-alpha (4,4',4''-(4-propyl-[(1)H]-pyrazole-1,3,5-triyl) tris-phenol, PPT) and ER-beta (2,3-bis(4-hydroxyphenyl)-propionitrile, DPN) are known to stimulate ER-alpha and ER-beta receptors, respectively. It remains unknown whether these two agents regulate the activity of ion channels via a direct stimulation. In this study, we tested the hypothesis that DPN or PPT stimulates the large-conductance Ca(2+)-activated K(+) (BK(Ca)) channels in cultured human cardiac fibroblasts (HCFs). In whole-cell configuration, depolarizing pulses evoked K(+) outward currents in an outward rectification in HCFs, the amplitude of which was increased in the presence of DPN or PPT. In inside-out patches, the activity of BK(Ca)-channel with a conductance of 167+/-8 pS was observed in these cells. PPT or DPN applied to the intracellular face of the membrane enhanced the activity of BK(Ca) channels with no change in single-channel conductance. DPN and PPT increased BK(Ca)-channel activity with an EC(50) value of 2.3 and 2.6 microM, respectively. The mean closed time of these channels during the exposure to these compounds was reduced with no change in the gating charge of the channels. Intracellular Ca(2+) was not altered by these two compounds. RT-PCR analysis revealed that no change in the transcriptional level of the BK(Ca)-channel alpha-subunit was observed in chronic treatment with these two compounds. PPT- and DPN-stimulated increase in BK(Ca) channels reveal novel pharmacological properties attributable to the activity of these channels, and their increase in BK(Ca) channels activity in HCFs may contribute to cell function.

Identification of two types of ATP-sensitive K+ channels in rat ventricular myocytes.

The ATP-sensitive K(+) (K(ATP)) channels are known to provide a functional linkage between the electrical activity of the cell membrane and metabolism. Two types of inwardly rectifying K(+) channel subunits (i.e., Kir6.1 and Kir6.2) with which sulfonylurea receptors are associated were reported to constitute the K(ATP) channels. In this study, we provide evidence to show two types of K(ATP) channels with different biophysical properties functionally expressed in isolated rat ventricular myocytes. Using patch-clamp technique, we found that single-channel conductance for the different two types of K(ATP) channels in these cells was 57 and 21 pS. The kinetic properties, including mean open time and bursting kinetics, did not differ between these two types of K(ATP) channels. Diazoxide only activated the small-conductance K(ATP) channel, while pinacidil and dinitrophenol stimulated both channels. Both of these K(ATP) channels were sensitive to block by glibenclamide. Additionally, western blotting, immunochemistry, and RT-PCR revealed two types of Kir6.X channels, i.e., Kir6.1 and Kir6.2, in rat ventricular myocytes. Single-cell Ca(2+) imaging also revealed that similar to dinitrophenol, diazoxide reduced the concentration of intracellular Ca(2+). The present results suggest that these two types of K(ATP) channels may functionally be related to the activity of heart cells.

Myocardial ischemia and ventricular fibrillation: pathophysiology and clinical implications.

Ventricular fibrillation (VF) and myocardial ischemia are inseparable. The first clinical manifestation of myocardial ischemia or infarction may be sudden cardiac death in 20-25% of patients. The occurrence of potentially lethal arrhythmia is the end result of a cascade of pathophysiological abnormalities that result from complex interactions between coronary vascular events, myocardial injury, and changes in autonomic tone, metabolic conditions and ionic state of the myocardium. It is also related to the time from the onset of ischemia. Within the first few minutes there is abundant ventricular arrhythmogenesis usually lasting for 30 min. Triggers for ischemic VF occur at the border zone or regionally ischemic heart. The border zone of ischemia is the predominant site of fragmentation. Acute ischemia opens K(ATP) channels and causes acidosis and hypoxia of myocardial cells leading to a large dispersion in repolarization across the border zone. Abnormalities of intracellular Ca2+ handling also occur in the first few minutes of acute myocardial ischemia and may be an important cause of arrhythmias in human coronary artery disease. Substrate on the other hand transforms triggers into VF and serves to maintain it through fragmentation of waves in the ischemic zone. Thrombin levels, stretch, catecholamine, genetic predisposition, etc. are some of these factors. Reentry models described are spiral wave reentry, 3 dimensional rotors, reentry around 'M' cells and figure-of-eight reentry. Continuing efforts to better understand these arrhythmias will help identify patients of myocardial ischemia prone to arrhythmias.

Electrophysiological mechanisms of ventricular arrhythmias in relation to Andersen-Tawil syndrome under conditions of reduced IK1: a simulation study.

Patients with Andersen-Tawil syndrome (ATS) mostly have mutations on the KCNJ2 gene, producing loss of function or dominant-negative suppression of the inward rectifier K(+) channel Kir2.1. However, clinical manifestations of ATS including dysmorphic features, periodic paralysis (hypo-, hyper-, or normokalemic), long QT, and ventricular arrhythmias (VAs) are considerably variable. Using a modified dynamic Luo-Rudy simulation model of cardiac ventricular myocytes, we attempted to elucidate mechanisms of VA in ATS by analyzing effects of the inward rectifier K(+) channel current (I(K1)) on the action potential (AP). During pacing at 1.0 Hz with extracellular K(+) concentration ([K(+)](o)) at 4.5 mM, a stepwise 10% reduction of Kir2.1 channel conductance progressively prolonged the terminal repolarization phase of the AP along with gradual depolarization of the resting membrane potential (RMP). At 90% reduction, early afterdepolarizations (EADs) became inducible and RMP was depolarized to -52.0 mV (control: -89.8 mV), followed by emergence of spontaneous APs. Both EADs and spontaneous APs were facilitated by a decrease in [K(+)](o) and suppressed by an increase in [K(+)](o). Simulated beta-adrenergic stimulation enhanced delayed afterdepolarizations (DADs) and could also facilitate EADs as well as spontaneous APs in the setting of low [K(+)](o) and reduced Kir2.1 channel conductance. In conclusion, the spectrum of VAs in ATS may include 1) triggered activity mediated by EADs and/or DADs and 2) abnormal automaticity manifested as spontaneous APs. These VAs can be aggravated by a decrease in [K(+)](o) and beta-adrenergic stimulation and may potentially induce torsade de pointes and cause sudden death. In patients with ATS, the hypokalemic form of periodic paralysis should have the highest propensity to VAs, especially during physical activity.

Cocaine-induced inhibition of ATP-sensitive K+ channels in rat ventricular myocytes and in heart-derived H9c2 cells.

Cocaine use may cause coronary artery spasm and acute myocardial ischaemia/infarction. However, its effects on ATP-sensitive K+ (KATP) channel, an ion channel responsible for ischaemic preconditioning, remain unknown. In isolated rat ventricular myocytes with whole-cell experiments, cocaine can reverse action potential shortening and increased K+ current caused by the openers of ATP-sensitive K+ (KATP) channels. In inside-out patches, cocaine applied to intracellular surface suppressed KATP-channel activity in a concentration-dependent manner with an IC50 value of 9.2 microM; however, it did not modify the single-channel conductance of this channel. The change in the kinetic behaviour of KATP channels caused by cocaine is primarily the result of an increase in mean closed time and a decrease in mean open time. Cocaine-induced inhibition of KATP channels is independent of change in intracellular ATP concentrations. In heart-derived H9c2 cells, cocaine is also capable of suppressing KATP-channel activity. The present study provides evidence that cocaine can produce a depressant action on KATP channels in cardiac myocytes, and thus disturb ischaemic preconditioning in clinical settings.

Contribution of BK(Ca)-channel activity in human cardiac fibroblasts to electrical coupling of cardiomyocytes-fibroblasts.

Cardiac fibroblasts are involved in the maintenance of myocardial tissue structure. However, little is known about ion currents in human cardiac fibroblasts. It has been recently reported that cardiac fibroblasts can interact electrically with cardiomyocytes through gap junctions. Ca(2+)-activated K(+) currents (I (K[Ca])) of cultured human cardiac fibroblasts were characterized in this study. In whole-cell configuration, depolarizing pulses evoked I (K(Ca)) in an outward rectification in these cells, the amplitude of which was suppressed by paxilline (1 microM: ) or iberiotoxin (200 nM: ). A large-conductance, Ca(2+)-activated K(+) (BK(Ca)) channel with single-channel conductance of 162 +/- 8 pS was also observed in human cardiac fibroblasts. Western blot analysis revealed the presence of alpha-subunit of BK(Ca) channels. The dynamic Luo-Rudy model was applied to predict cell behavior during direct electrical coupling of cardiomyocytes and cardiac fibroblasts. In the simulation, electrically coupled cardiac fibroblasts also exhibited action potential; however, they were electrically inert with no gap-junctional coupling. The simulation predicts that changes in gap junction coupling conductance can influence the configuration of cardiac action potential and cardiomyocyte excitability. I (k(Ca)) can be elicited by simulated action potential waveforms of cardiac fibroblasts when they are electrically coupled to cardiomyocytes. This study demonstrates that a BK(Ca) channel is functionally expressed in human cardiac fibroblasts. The activity of these BK(Ca) channels present in human cardiac fibroblasts may contribute to the functional activities of heart cells through transfer of electrical signals between these two cell types.

Pleomorphic ventricular tachycardia: an uncommon presentation in idiopathic left ventricular tachycardia.

Idiopathic left ventricular tachycardia (ILVT) is a distinct entity that arises in the left ventricle, may have reentrant mechanism and is verapamil-sensitive. Pleomorphism as defined by multiple ventricular tachycardia morphologies is usually associated with either coronary artery disease or cardiomyopathy but very rare in cases of ILVT. In this case report, we describe an unusual case of ILVT with two ECG morphologies of the opposite axis that were successfully eliminated with radiofrequency ablation. The successful ablation sites were closely located to each other in the left lower ventricular septum.

Unusual features of an idiopathic ventricular tachycardia arising from the left ventricular outflow tract.

We encountered a 40-year-old man with recurrent symptomatic palpitations manifested as monomorphic ventricular tachycardia (VT) of a right bundle branch block (RBBB) pattern with an inferior frontal axis. Physical examination, chest roentgenogram, and echocardiogram were unremarkable. The VT could be provoked by treadmill exercise testing. Electrophysiologic study revealed that the VT could be reproducibly initiated with either atrial or ventricular pacing at cycle lengths between 500 and 400 ms. With overdrive ventricular pacing, the VT could be terminated. Of note was the observation that intravenous adenosine was not effective, but intravenous verapamil could interrupt the VT. The VT was pace mapped to be arising from a site at the left ventricular outlet tract (LVOT). Notably, during pace mapping, the pacing spike was immediately followed by the beginning of the paced QRS complex, and during VT, there was no time delay between the earliest local activation and the onset of QRS complex. Furthermore, there was no mid-diastolic activity or Purkinje potential that could be recorded during sinus rhythm and VT. Subsequently, the VT was successfully ablated with radiofrequency energy as guided by pace mapping. In summary, an idiopathic VT arising from the LVOT was found to be cycle lengths- and catecholamine-dependent, adenosine-insensitive but verapamil responsive. These unusual features suggest that either microreentry or triggered activity could be the underlying mechanism.

Significance of inducible ventricular flutter/fibrillation in risk stratification in patients with coronary artery disease.

BACKGROUND: Although inducible ventricular fibrillation (VF) has been used as an indication for prophylactic implantation of cardioverter-defibrillators (ICDs) in patients with coronary artery disease (CAD), the significance of inducible VF remains controversial. METHODS: Among 364 CAD patients who underwent electrophysiologic (EP) study for risk stratification, 23 patients, 12 without any history of VF or cardiac arrest (group A) and 11 with previously documented VF or cardiac arrest (group B), exhibited inducible ventricular flutter (VFL) or VF and subsequently underwent ICD implantation. Additionally, 11 CAD patients without previous VF or cardiac arrest, who had no inducible ventricular tachyarrhythmias but received an ICD, were included for comparison (group C). RESULTS: During 2 years of follow-up, 1 (8%), 5 (45%), and 1 (9%) patients had appropriate ICD shocks in groups A, B, and C, respectively. The survival free from appropriate ICD shocks was significantly lower in group B compared to groups A and C (p<0.05). There were no significant differences in age, sex, ejection fraction (EF), or induction protocol between groups A and B or between groups A and C. CONCLUSIONS: In CAD patients with inducible VFL/VF, patients without any history of VF or cardiac arrest had significantly lower incidence of appropriate ICD shocks when compared to those with such clinical events. Conversely, in CAD patients without any history of VF or cardiac arrest, incidence of appropriate ICD shocks was similar regardless of inducible VFL/VF. Inducible VFL/VF is therefore not useful as an indication for prophylactic ICD implantation in this patient population.

Seasonal variation of mortality in the Antiarrhythmics Versus Implantable Defibrillators (AVID) study registry.

OBJECTIVES: We postulated that the pattern of death would be nonrandom with respect to temporal variables. BACKGROUND: Previous studies have demonstrated increased sudden death is associated with periods of relative stress, and overall mortality is associated with temporal variables. METHODS: In the Antiarrhythmics Versus Implantable Defibrillators (AVID) registry, vital status was obtained for 4,450 patients (who had a recent episode of sustained ventricular arrhythmias or unexplained syncope and inducible ventricular tachycardia) through the National Death Index Service as of December 31, 1997 (follow-up 25.5 +/- 13.7 months). RESULTS: Mortality was not associated with the day of the week or with holidays but was associated with season (P = .033). Seasonal variation was present both in northern and southern sites. Mortality was higher during the winter months compared to the remaining months (111.2% in winter vs 96.5% in other months, P = .036). In addition, increased mortality was associated with a high-risk season variable defined (prior to evaluation of treatment arm associations) as spring in the north and winter in the south (P < .001). The hazard ratio for death associated with this "high-risk season" measured 1.25 (P = .001) compared to the other seasons in each region. A test of interaction between "high-risk" season and implantable cardioverter-defibrillator (ICD) status suggested that the group with ICDs experienced reduced mortality during the "high-risk season" compared to the group without ICDs (P = .047). CONCLUSIONS: Mortality was higher in the winter months and in the respective regional "high-risk" seasons. Furthermore, seasonal variation in mortality may have been due to variation in sudden arrhythmic death, and associated increases in mortality were reduced by ICD therapy.

Spatial heterogeneity of action potential alternans during global ischemia in the rabbit heart.

Cardiac ischemia causes beat-to-beat fluctuation in action potential duration (APD) alternans, which leads to T wave alternans and arrhythmias. Occurrence of APD alternans that is out of phase at two sites is especially important, but most APD alternans studies have involved rapid pacing of normal myocardium rather than ischemia. To determine the spatial features of APD alternans during ischemia, blood-perfused rabbit hearts were stained with 4-[beta-[2(di-n-butylamino)-6-napthyl]vinyl]pyridinium (di-4-ANEPPS) and imaged with a high-resolution camera. Hearts were perfused with oxygenated Tyrode solution at 37 degrees C for staining and then switched to a 50:50% blood/Tyrode mixture. Hearts were paced from the right ventricle at 3/s, and made ischemic by stopping flow for 6 min. Images of 10,000 pixels were obtained at 300 frames/s. Motion artifact was controlled by immobilization and by manual selection of undistorted single-pixel records. Upstroke propagation and conduction isochrones were displayed by computerized image processing. APD alternans was demonstrated in six of seven hearts, and was out of phase in different regions of the image in three hearts. The largest spatial variation in the onset of depolarization to 50% repolarization (APD50) was 155%. This caused beat-to-beat reversal of repolarization. An alternans map could be constructed for well-immobilized portions of the image. There were discrete regions of APD alternans separated by a boundary, as occurs with intracellular Ca2+ concentration alternans. Pixels as close together as 1.1 mm showed an APD alternans that was out of phase. The out-of-phase APD alternans was not due to conduction alternans, as shown by upstroke intervals and conduction isochrones. This contrasts with rapid pacing, where a causal relationship appears to exist. These new observations suggest distinct mechanisms for the genesis of arrhythmias during ischemia.

Limited predictive value of inducible sustained ventricular tachycardia for future occurrence of spontaneous ventricular tachycardia in patients with coronary artery disease and relatively preserved cardiac function.

To evaluate the significance of inducible sustained ventricular tachycardia (VT) in patients with coronary artery disease and relatively preserved cardiac function, 33 patients who met the following criteria were studied; documented nonsustained VT but no history of life-threatening arrhythmia, inducible sustained VT at electrophysiologic study, and implantation of a cardioverter-defibrillator. Eighteen patients developed clinical sustained VT within 2 years. By univariate analysis, left ventricular ejection fraction (EF) and the cycle length of induced VT were associated with clinical VT occurrence. By multivariate analysis, however, EF was the only independent predictor. Among 23 patients with EF 40% (P <.01). In coronary artery disease patients with relatively preserved EF, the incidence of clinical VT is considerably low even though sustained VT is inducible. Inducible VT is therefore not appropriate for risk stratification in this patient population.

Facilitating electrical cardioversion of persistant atrial fibrillation by antiarrhythmic drugs: update on clinical trial results.

Results from clinical trials suggest that antiarrhythmic drugs (AD) can facilitate electrical cardioversion (EC) for persistent atrial fibrillation (AF) (duration >48 hours, no spontaneous termination) by suppression of immediate reinitiation of AF following the procedure. Class IC agents may increase the atrial defibrillation threshold (DFT) by significantly reducing the availability of Na+-channel for depolarization. In contrast, class III agents may decrease the atrial DFT by markedly prolonging atrial refractoriness. Among all AD, ibutilide and amoidarone have been shown to be most effective in enhancing the acute outcome of EC. In patients who are over 65 years of age at high risks of stroke (e.g., atherosclerotic cardiovascular disease, diabetes, hypertension, previous thromboembolism, etc.), the rhythm control strategy offers no survival advantage over the rate control strategy and frequently subjects patients to serious adverse effects of AD therapy. It can not be overemphasized that adequate anticoagulation (INR 2.0-3.0) with warfarin is needed regardless of whichever strategy is chosen unless there are contraindications. On the other hand, in patients who are under 65 years of age without structural heart disease or other risk factors of stroke, rhythm control can be the treatment of choice. Specifically, if a patient has failed EC alone or if the patient has characteristics (e.g., duration of AF >6 months, left atrium >50 mm, etc.) that EC could fail, AD may be given before the procedure to facilitate EC. In the subgroup of patients who are symptomatic with hypertrophic cardiomyopathy and severe diastolic dysfunction requiring maintenance of sinus rhythm to have sufficient ventricular function for optimization of cardiac output, an aggressive approach for rhythm control with amiodarone along with adequate anticoagulation with warfarin should be encouraged.