Real-life Clinical Outcomes of Low-voltage Isolation and Spatiotemporal Dispersion Ablation Strategies for Persistent Atrial Fibrillation.

Multiple techniques have been developed in addition to pulmonary vein isolation (PVI) to improve the outcomes of catheter ablation in patients with persistent atrial fibrillation (AF). We sought to evaluate the long-term efficacy of alternative techniques used in our laboratory for the treatment of persistent AF, including spatiotemporal dispersion (SD) and low-voltage isolation (LVI). Consecutive patients with persistent AF who underwent catheter ablation with the studied techniques between July 2016 and December 2019 were included in the study. PVI alone was compared with PVI plus SD and PVI plus LVI in terms of long-term freedom from atrial tachycardia (AT) and AF recurrence. Follow-up data were obtained from clinical records and hospital visits, which included a 7-day Holter monitor and electrocardiograms. The study was approved by the institutional review board of Rhode Island Hospital. A total of 382 patients underwent catheter ablation at our institution during the study period. One hundred seventy-two patients had paroxysmal AF and were excluded from the study. The remaining 210 patients had persistent AF and were included in the study. One hundred and three patients underwent PVI alone, while 48 had the addition of LVI and 59 had SD. Additionally, freedom from AT/AF recurrence at 18 months was 68% in the group that underwent LVI, 49% in the SD group, and 40% in the group that underwent PVI alone (log-rank P = .014). Freedom from AF recurrence was 74% in the LVI group, 71% in the SD group, and 43% in the PVI-alone group (log-rank P = .002). On multivariate Cox regression, LVI and left atrial size were found to be independent predictors of recurrence (hazard ratio, 0.39; 95% confidence interval, 0.206-0.760; P = .005 and hazard ratio, 1.4; 95% confidence interval, 1.105-1.923; P = .008, respectively). LVI and SD in addition to PVI were associated with greater freedom from AT/AF recurrence at 18 months compared to PVI alone.

Mechanisms of cardiac arrhythmias and sudden death in transgenic rabbits with long QT syndrome.

Long QT syndrome (LQTS) is a heritable disease associated with ECG QT interval prolongation, ventricular tachycardia, and sudden cardiac death in young patients. Among genotyped individuals, mutations in genes encoding repolarizing K+ channels (LQT1:KCNQ1; LQT2:KCNH2) are present in approximately 90% of affected individuals. Expression of pore mutants of the human genes KCNQ1 (KvLQT1-Y315S) and KCNH2 (HERG-G628S) in the rabbit heart produced transgenic rabbits with a long QT phenotype. Prolongations of QT intervals and action potential durations were due to the elimination of IKs and IKr currents in cardiomyocytes. LQT2 rabbits showed a high incidence of spontaneous sudden cardiac death (>50% at 1 year) due to polymorphic ventricular tachycardia. Optical mapping revealed increased spatial dispersion of repolarization underlying the arrhythmias. Both transgenes caused downregulation of the remaining complementary IKr and IKs without affecting the steady state levels of the native polypeptides. Thus, the elimination of 1 repolarizing current was associated with downregulation of the reciprocal repolarizing current rather than with the compensatory upregulation observed previously in LQTS mouse models. This suggests that mutant KvLQT1 and HERG interacted with the reciprocal wild-type alpha subunits of rabbit ERG and KvLQT1, respectively. These results have implications for understanding the nature and heterogeneity of cardiac arrhythmias and sudden cardiac death.

Cardiac Resynchronization and Circulating Markers of Sarcoplasmic Reticulum Calcium Handling and Sudden Death Risk.

Cardiac resynchronization therapy (CRT) can improve heart function and decrease arrhythmic events. We tested whether CRT altered circulating markers of calcium handling and sudden death risk. Circulating cardiac sodium channel messenger RNA (mRNA) splicing variants indicate arrhythmic risk, and a reduction in sarco/endoplasmic reticulum calcium adenosine triphosphatase 2a (SERCA2a) is thought to diminish contractility in heart failure. CRT was associated with a decreased proportion of circulating, nonfunctional sodium channels and improved SERCA2a mRNA expression. Patients without CRT did not have improvement in the biomarkers. These changes might explain the lower arrhythmic risk and improved contractility associated with CRT.

Electrophysiological studies of transgenic long QT type 1 and type 2 rabbits reveal genotype-specific differences in ventricular refractoriness and His conduction.

We have generated transgenic rabbits lacking cardiac slow delayed-rectifier K(+) current [I(Ks); long QT syndrome type 1 (LQT1)] or rapidly activating delayed-rectifier K(+) current [I(Kr); long QT syndrome type 2 (LQT2)]. Rabbits with either genotype have prolonged action potential duration and QT intervals; however, only LQT2 rabbits develop atrioventricular (AV) blocks and polymorphic ventricular tachycardia. We therefore sought to characterize the genotype-specific differences in AV conduction and ventricular refractoriness in LQT1 and LQT2 rabbits. We carried out in vivo electrophysiological studies in LQT1, LQT2, and littermate control (LMC) rabbits at baseline, during isoproterenol infusion, and after a bolus of dofetilide and ex vivo optical mapping studies of the AV node/His-region at baseline and during dofetilide perfusion. Under isoflurane anesthesia, LQT2 rabbits developed infra-His blocks, decremental His conduction, and prolongation of the Wenckebach cycle length. In LQT1 rabbits, dofetilide altered the His morphology and slowed His conduction, resulting in intra-His block, and additionally prolonged the ventricular refractoriness, leading to pseudo-AV block. The ventricular effective refractory period (VERP) in right ventricular apex and base was significantly longer in LQT2 than LQT1 (P < 0.05) or LMC (P < 0.01), with a greater VERP dispersion in LQT2 than LQT1 rabbits. Isoproterenol reduced the VERP dispersion in LQT2 rabbits by shortening the VERP in the base more than in the apex but had no effect on VERP in LQT1. EPS and optical mapping experiments demonstrated genotype-specific differences in AV conduction and ventricular refractoriness. The occurrence of infra-His blocks in LQT2 rabbits under isoflurane and intra-His block in LQT1 rabbits after dofetilide suggest differential regional sensitivities of the rabbit His-Purkinje system to drugs blocking I(Kr) and I(Ks).

Incidence and Risk Factors for Atrial Fibrillation Recurrence after Ablation of Nodal and Atrioventricular Reentrant Tachycardia: A Meta-analysis.

Introduction Atrioventricular nodal reentrant tachycardia (AVNRT) and atrioventricular reentrant tachycardia (AVRT) are frequently associated with atrial fibrillation (AF). Targeting the slow or accessory pathways has been advocated as therapy for coexisting AF. But in practice, AF has frequently recurred after ablation, possibly because of various risk factors. The objective of this study is to investigate these risk factors and check for their significance in AF recurrence. Materials and methods A systematic review of Medline, Cochrane, and ClinicalTrials.gov databases was conducted. Articles that studied AF recurrence after either AVNRT or AVRT ablation were reviewed. Publication bias was adequately assessed, and the random method was applied for all dichotomous values. Finally, the odds ratio (OR) and confidence intervals (CI) were calculated for each risk factor. Results Four studies were included, with a total of 1,308 participants. Only 218 participants had dual tachycardia (AF with either AVNRT or AVRT). The mean follow-up time was 29 +/- 3.3 months. The mean age was 56 +/- 15 years. Age constituted the only significant risk factor for AF recurrence (OR: 3.4, CI: 2.1-5.3, p<0.001). Atrial vulnerability did not significantly correlate with a higher risk of AF recurrence (OR: 4.8, CI: 0.7-29, p<0.008). Again, neither male gender (OR: 1.5, CI: 0.8-2.8, p<0.16) nor left atrial diameter (OR: 1.5, CI: 0.2-10, p<0.67) were significant risk factors for recurrence of AF. Conclusion Older age was the only significant predictor of AF recurrence after ablation of AVNRT or AVRT. Further studies are needed to determine the age cut-off at which concomitant pulmonary vein isolation would be beneficial in patients undergoing ablation of AVNRT/AVRT.

True bipolar defibrillator leads have increased sensing latency and threshold compared with the integrated bipolar configuration.

BACKGROUND: Dual-coil implantable defibrillator (ICD) leads with true bipolar pacing and sensing (quadripolar leads) have been introduced to provide improved sensing characteristics without sacrificing defibrillation efficacy. Electrode configuration has been shown to have little effect on the amplitude or slew rate of the intracardiac electrogram, but does have an effect on the duration of the sensed electrogram. Closer spacing of the electrodes and smaller surface area of the anode may, therefore, result in a different latency of sensing relative to the onset of the QRS complex. METHODS: We tested the difference in ventricular sensing latency between integrated bipolar and true bipolar electrode configurations in 40 patients undergoing ICD implantation for standard indications (Medtronic Sprint Quattro lead in 26 and St. Jude Riata in 16). In addition, we compared R wave amplitude, pacing threshold, impedance, and slew rate. RESULTS: Sensing latency was significantly longer in the true bipolar configuration (Medtronic Sprint Quattro 45.2 +/- 14.7 msec in the true bipolar configuration, vs 37.4 +/- 18.2 msec in the integrated bipolar configuration, and St. Jude Riata, 43.5 +/- 9.8 msec true bipolar, vs 33.8 +/- 10.1 msec integrated bipolar, P < 0.01). There was no difference in R wave amplitude or slew rate. Pacing threshold and impedance were also greater in the true bipolar configuration than in the integrated bipolar configuration. CONCLUSION: The true bipolar configuration has a longer sensing latency than the integrated bipolar configuration. In some patients, this may require a longer programmed AV delay to avoid ventricular pseudofusion.

Coronary sinus and fossa ovalis ablation: effect on interatrial conduction and atrial fibrillation.

BACKGROUND: Interatrial conduction occurs via discrete pathways along the coronary sinus musculature, fossa ovalis region, and Bachman's bundle. We assessed the feasibility of altering interatrial conduction by selectively ablating two of these conduction pathways using a novel mesh electrode ablation catheter. METHODS: Circular radiofrequency energy catheter ablation lesions were created in the proximal coronary sinus in four dogs and in both the fossa ovalis and the proximal coronary sinus regions in seven pigs. Interatrial conduction was assessed by analyzing intracardiac electrogram and noncontact isopotential mapping data. Inducibility of atrial fibrillation was assessed before and after ablation (in six pigs). RESULTS: Ablation lesions in the proximal coronary sinus eliminated interatrial conduction along the coronary sinus musculature in four dogs and five of seven pigs. Ablation lesions in the fossa ovalis region eliminated interatrial conduction via midseptal pathways in six of seven pigs. Atrial fibrillation, inducible in five of seven pigs at baseline, was rendered noninducible in all five. There was no adverse effect on AV nodal conduction. CONCLUSIONS: (1) Using a novel mesh electrode ablation catheter, we were able to ablate interatrial conduction pathways along the proximal coronary sinus and fossa ovalis regions. (2) This altered interatrial conduction and altered atrial fibrillation inducibility and maintenance. (3) Catheter ablation of interatrial conduction pathways may be useful in the therapy of atrial fibrillation.

The impact of cardiac resynchronization therapy on obstructive sleep apnea in heart failure patients: a pilot study.

BACKGROUND: Cardiac resynchronization therapy (CRT) has been shown to improve cardiac function and reduce Cheyne-Stokes respiration but has not been evaluated in patients with obstructive sleep apnea (OSA). In this pilot study, we investigated the impact of both CRT and CRT plus increased rate pacing in heart failure (ie, congestive heart failure [CHF]) patients with OSA. We hypothesized that through increased cardiac output CRT/pacing would reduce obstructive events and daytime symptoms of sleepiness. METHODS: Full polysomnograms were performed on CHF patients who were scheduled for CRT, and those patients with an apnea-hypopnea index (AHI) of > 5 events per hour were approached about study enrollment. Patients had a pre-CRT implant baseline echocardiogram and an echocardiogram a mean (+/- SEM) duration of 6.6 +/- 1.4 months post-CRT implant; polysomnography; and responded to the Minnesota Living with Heart Failure questionnaire, the Epworth sleepiness scale, and the Functional Outcomes of Sleep Questionnaire. An additional third polysomnography was performed combining CRT with a pacing rate of 15 beats/min above the baseline sleeping heart rate within 1 week of the second polysomnography. Assessments for the change in cardiac output during the polysomnography were performed using circulation time to pulse oximeter as a surrogate. RESULTS: Twenty-four patients were screened, and 13 patients (mean age, 68.6 years; body mass index, 28.7 kg/m(2)) had evidence of OSA. The mean AHI decreased from 40.9 +/- 6.4 to 29.5 +/- 5.9 events per hour with CRT (p = 0.04). The mean baseline ejection fraction was 22 +/- 1.7% and increased post-CRT to 33.6 +/- 2.0% (p < 0.05). The reduction in AHI with CRT closely correlated with a decrease in circulation time (r = 0.89; p < 0.001) with CRT. Increased rate pacing made no additional impact on the AHI or circulation time. CRT had a limited impact on sleep architecture or daytime symptom scores. CONCLUSIONS: CRT improved cardiac function and reduced the AHI. Reduced circulatory delay likely stabilized ventilatory control systems and may represent a new therapeutic target in OSA.

Effects of selective autonomic blockade on T-wave alternans in humans.

BACKGROUND: T-wave alternans (TWA) is an important noninvasive measure of ventricular arrhythmia vulnerability. This study tested the hypothesis that the autonomic nervous system influences TWA measurement in high-risk subjects with coronary artery disease. METHODS AND RESULTS: T-wave alternans was measured in 60 patients with coronary artery disease, left ventricular dysfunction, and inducible sustained ventricular tachycardia during electrophysiological studies. All patients had TWA measured at baseline with atrial pacing at 100 bpm (600 ms), 109 bpm (550 ms), and 120 bpm (500 ms). After a 10-minute recovery period, TWA was measured again after sympathetic blockade (esmolol, n=20), parasympathetic blockade (atropine, n=20), or no intervention (control subjects, n=20). The prevalence of significant TWA was unchanged compared with baseline after atropine infusion and in the control group. In contrast, the amplitude of TWA in the vector magnitude lead was significantly reduced after esmolol infusion (P<0.001), and the number of positive TWA tests was reduced by 50% (70% versus 35%, P<0.05). CONCLUSIONS: Our findings have important implications for the use of TWA to risk-stratify patients for life-threatening ventricular arrhythmias and provide a new potential mechanism for the reduction in sudden cardiac death conferred by beta-blockers among patients with coronary artery disease and congestive heart failure.

Primary prevention of sudden cardiac death: trials in patients with coronary artery disease.

Over the past decade, four randomized, controlled trials have evaluated therapies for prevention of sudden cardiac death in patients with coronary disease. Three of the four trials have shown significant reductions in mortality with implanted defibrillators. Two studies failed to demonstrate any benefit from pharmacologic antiarrhythmic therapy. The results of these studies in similar patient populations have erased any doubt regarding the ability of implanted defibrillators to reduce the risk of sudden death in patients with coronary disease. Our major challenge at this time is understanding how best to utilize this therapy in order to bring the benefit to the maximum number of patients while minimizing expense.

Anticoagulation in atrial fibrillation.

Anticoagulation with warfarin is the most effective means of reducing stroke in AF. The generally recommended INR goal is 2-3. Aspirin provides a modest degree of stroke protection in AF but is inferior to warfarin. Assessment of stroke risk is critical in determining whether to prescribe warfarin therapy to a patient with AF. The most important risk factors for stroke in AF are age over 65 years, hypertension, prior stroke, and left ventricular dysfunction or heart failure. The risk of warfarin may be less than commonly believed, but increases when warfarin is combined with aspirin. Patients with paroxysmal AF are not at lower risk of stroke than those with persistent AF and should be treated with warfarin. Apparently successful therapy with antiarrhythmic agents does not eliminate the need for anticoagulation. New antithrombotic therapies are being studied and may soon provide an alternative to warfarin.

The ABCD (Alternans Before Cardioverter Defibrillator) Trial: strategies using T-wave alternans to improve efficiency of sudden cardiac death prevention.

OBJECTIVES: Because risk stratification with electrophysiological study (EPS) improves efficiency but is invasive, we sought to determine whether noninvasive microvolt T-wave alternans (MTWA) testing could identify patients who benefit from implantable cardioverter-defibrillators (ICDs) as well as EPS. BACKGROUND: Prevention of sudden cardiac death on the basis of left ventricular ejection fraction (LVEF) alone is inefficient, because most ICDs never deliver therapy. METHODS: The ABCD (Alternans Before Cardioverter Defibrillator) trial is a multicenter prospective study that enrolled patients with ischemic cardiomyopathy (LVEF < or =0.40) and nonsustained ventricular tachycardia. All patients underwent MTWA and EPS. ICDs were mandated if either test was positive. RESULTS: Of 566 patients followed for a median of 1.9 years, 39 (7.5%) met the primary end point of appropriate ICD discharge or sudden death at 1 year. As hypothesized, primary analysis showed that MTWA achieved 1-year positive (9%) and negative (95%) predictive values that were comparable to EPS (11% and 95%, respectively). In addition, secondary analysis showed that at the pre-specified 1-year end point, event rates were significantly higher in patients with both a positive MTWA-directed strategy (hazard ratio: 2.1, p = 0.03) and a positive EPS-directed strategy (hazard ratio: 2.4, p = 0.007). Moreover, the event rate in patients with both negative MTWA test and EPS was lower than in those with 2 positive tests (2% vs. 12%; p = 0.017). CONCLUSIONS: The ABCD study is the first trial to use MTWA to guide prophylactic ICD insertion. Risk stratification strategies using noninvasive MTWA versus invasive EPS are comparable at 1 year and complementary when applied in combination. Strategies employing MTWA, EPS, or both might identify subsets of patients least likely to benefit from ICD insertion. (Study to Compare TWA Test and EPS Test for Predicting Patients at Risk for Life-Threatening Heart Rhythms [ABCD Study]; NCT00187291).

Pharmacogenomics of anesthetic drugs in transgenic LQT1 and LQT2 rabbits reveal genotype-specific differential effects on cardiac repolarization.

Anesthetic agents prolong cardiac repolarization by blocking ion currents. However, the clinical relevance of this blockade in subjects with reduced repolarization reserve is unknown. We have generated transgenic long QT syndromes type 1 (LQT1) and type 2 (LQT2) rabbits that lack slow delayed rectifier K+ currents (IKs) or rapidly activating K+ currents (IKr) and used them as a model system to detect the channel-blocking properties of anesthetic agents. Therefore, LQT1, LQT2, and littermate control (LMC) rabbits were administered isoflurane, thiopental, midazolam, propofol, or ketamine, and surface ECGs were analyzed. Genotype-specific heart rate correction formulas were used to determine the expected QT interval at a given heart rate. The QT index (QTi) was calculated as percentage of the observed QT/expected QT. Isoflurane, a drug that blocks IKs) prolonged the QTi only in LQT2 and LMC but not in LQT1 rabbits. Midazolam, which blocks inward rectifier K+ current (IK1), prolonged the QTi in both LQT1 and LQT2 but not in LMC. Thiopental, which blocks both IKs and IK1, increased the QTi in LQT2 and LMC more than in LQT1. By contrast, ketamine, which does not block IKr, IKs, or IK1, did not alter the QTi in any group. Finally, anesthesia with isoflurane or propofol resulted in lethal polymorphic ventricular tachycardia (pVT) in three out of nine LQT2 rabbits. Transgenic LQT1 and LQT2 rabbits could serve as an in vivo model in which to examine the pharmacogenomics of drug-induced QT prolongation of anesthetic agents and their proarrhythmic potential. Transgenic LQT2 rabbits developed pVT under isoflurane and propofol, underlining the proarrhythmic risk of IKs blockers in subjects with reduced IKr.

Effect of an active abdominal pulse generator on defibrillation thresholds with a dual-coil, transvenous ICD lead system.

INTRODUCTION: Many patients with implantable cardioverter defibrillators (ICDs) have older lead systems, which are usually not replaced at the time of pulse generator replacement unless a malfunction is noted. Therefore, optimization of defibrillation with these lead systems is clinically important. The objective of this prospective study was to determine if an active abdominal pulse generator (Can) affects chronic defibrillation thresholds (DFTs) with a dual-coil, transvenous ICD lead system. METHODS AND RESULTS: The study population consisted of 39 patients who presented for routine abdominal pulse generator replacement. Each patient underwent two assessments of DFT using a step-down protocol, with the order of testing randomized. The distal right ventricular (RV) coil was the anode for the first phase of the biphasic shocks. The proximal superior vena cava (SVC) coil was the cathode for the Lead Alone configuration (RV --> SVC). For the Active Can configuration, the SVC coil and Can were connected electrically as the cathode (RV --> SVC + Can). The Active Can configuration was associated with a significant decrease in shock impedance (39.5 +/- 5.8 Omega vs. 50.0 +/- 7.6 Omega, P < 0.01) and a significant increase in peak current (8.3 +/- 2.6 A vs. 7.2 +/- 2.4 A, P < 0.01). There was no significant difference in DFT energy (9.0 +/- 4.6 J vs. 9.8 +/- 5.2 J) or leading edge voltage (319 +/- 86 V vs. 315 +/- 83 V). An adequate safety margin for defibrillation (> or =10 J) was present in all patients with both shocking configurations. CONCLUSION: DFTs are similar with the Active Can and Lead Alone configurations when a dual-coil, transvenous lead is used with a left abdominal pulse generator. Since most commercially available ICDs are only available with an active can, our data support the use of an active can device with this lead system for patients who present for routine pulse generator replacement.

Management of the non-inducible patient.

Management of the patient without inducible arrhythmias is dictated by the clinical setting in which the arrhythmias occur. Decisions must be based on whether the patient is being treated for symptomatic arrhythmias, or is undergoing evaluation of risk for potentially lethal arrhythmias. The management is influenced by the anatomic substrate, as well as the clinical presentation. As with all diagnostic tests, the significance of the electrophysiology study depends on the clinical context, and this type of test reflects but one mechanism for tachycardia. Finally, it is critical to remember that the results of published clinical trials can be used to guide management decisions, only when the same stimulation protocol utilized in the trials is employed, and the patient has the same characteristics as those enrolled in the trial.

Role of the transverse-axial tubule system in generating calcium sparks and calcium transients in rat atrial myocytes.

Cardiac atrial cells lack a regular system of transverse tubules like that in cardiac ventricular cells. Nevertheless, many atrial cells do possess an irregular internal transverse-axial tubular system (TATS). To investigate the possible role of the TATS in excitation-contraction coupling in atrial myocytes, we visualized the TATS (labelled with the fluorescent indicator, Di-8-ANEPPS) simultaneously with Ca2+ transients and/or Ca2+ sparks (fluo-4). In confocal transverse linescan images of field-stimulated cells, whole-cell Ca2+ transients had two morphologies: 'U-shaped' transients and irregular or 'W-shaped' transients with a varying number of points of origin of the Ca2+ transient. About half (54 %, n =289 cells, 13 animals) of the cells had a TATS. Cells with TATS had a larger mean diameter (13.2 +/- 2.8 microm) than cells without TATS (11.7 +/- 2.0 microm) and were more common in the left atrium (n = 206 cells; left atrium: 76 with TATS, 30 without TATS; right atrium: 42 with TATS, 58 without TATS). Simultaneous measurement of Ca2+ sparks and sarcolemmal structures showed that cells without TATS had U-shaped transients that started at the cell periphery, and cells with TATS had W-shaped transients that began simultaneously at the cell periphery and the TATS. Most (82 out of 102 from 31 cells) 'spontaneous' (non-depolarized) Ca2+ sparks occurred within 1 microm of a sarcolemmal structure (cell periphery or TATS), and 33 % occurred within 1 pixel (0.125 microm). We conclude that the presence of a sarcolemmal membrane either at the cell periphery or in the TATS in close apposition to the sarcoplasmic reticulum is required for the initiation of an evoked Ca2+ transient and for spontaneous Ca2+ sparks.

Enhanced detection of arrhythmia vulnerability using T wave alternans, left ventricular ejection fraction, and programmed ventricular stimulation: a prospective study in subjects with chronic ischemic heart disease.

INTRODUCTION: In previous studies, the prognostic value of T wave alternans (TWA) was similar to that of programmed ventricular stimulation (PVS). However, presently it is unclear if TWA and PVS identify the same patients or provide complementary risk stratification information. In addition, the effects of left ventricular ejection fraction (LVEF) on the prognostic value of TWA are unknown. The aim of this study was to determine if combined assessment of TWA, LVEF, and PVS improves arrhythmia risk stratification. METHODS AND RESULTS: This was a prospective study of 144 patients with coronary artery disease and LVEF < or =40% who were referred for PVS for standard clinical indications. The endpoint was the combined incidence of death, sustained ventricular arrhythmias, and appropriate implantable cardioverter defibrillator (ICD) therapy. TWA (hazard ratio 2.2, P = 0.03) and PVS (hazard ratio 1.9, P = 0.05) both were significant predictors of endpoint events, and TWA was the only independent predictor. LVEF markedly influenced the prognostic value of TWA, which was a potent predictor of events in subjects with LVEF between 30% and 40% (event rates: TWA+ 36%, TWA- 0%, P = 0.001) but did not predict events in subjects with LVEF <30% (hazard ratio 1.1, P > 0.5). PVS successfully identified additional low-risk patients within the cohort with negative or indeterminate TWA results (hazard ratio 4.7, P = 0.015) but did not provide incremental prognostic information for TWA+ patients (hazard ratio 0.9, P > 0.5). CONCLUSION: The combined use of TWA, LVEF, and PVS is a promising new approach to arrhythmia risk stratification that permits identification of high-risk and very-low-risk patients.