Propranolol Attenuates Late Sodium Current in a Long QT Syndrome Type 3-Human Induced Pluripotent Stem Cell Model.

BACKGROUND: Long QT syndrome type 3 (LQT3) is caused by gain-of-function mutations in the SCN5A gene, which encodes the α subunit of the cardiac voltage-gated sodium channel. LQT3 patients present bradycardia and lethal arrhythmias during rest or sleep. Further, the efficacy of ß-blockers, the drug used for their treatment, is uncertain. Recently, a large multicenter LQT3 cohort study demonstrated that ß-blocker therapy reduced the risk of life-threatening cardiac events in female patients; however, the detailed mechanism of action remains unclear. OBJECTIVES: This study aimed to establish LQT3-human induced pluripotent stem cells (hiPSCs) and to investigate the effect of propranolol in this model. METHOD: An hiPSCs cell line was established from peripheral blood mononuclear cells of a boy with LQT3 carrying the SCN5A-N1774D mutation. He had suffered from repetitive torsades de pointes (TdPs) with QT prolongation since birth (QTc 680 ms), which were effectively treated with propranolol, as it suppressed lethal arrhythmias. Furthermore, hiPSCs were differentiated into cardiomyocytes (CMs), on which electrophysiological functional assays were performed using the patch-clamp method. RESULTS: N1774D-hiPSC-CMs exhibited significantly prolonged action potential durations (APDs) in comparison to those of the control cells (N1774D: 440 ± 37 ms vs. control: 272 ± 22 ms; at 1 Hz pacing; p < 0.01). Furthermore, N1774D-hiPSC-CMs presented gain-of-function features: a hyperpolarized shift of steady-state activation and increased late sodium current compared to those of the control cells. 5 µM propranolol shortened APDs and inhibited late sodium current in N1774D-hiPSC-CMs, but did not significantly affect in the control cells. In addition, even in the presence of intrapipette guanosine diphosphate ßs (GDPßs), an inhibitor of G proteins, propranolol reduced late sodium current in N1774D cells. Therefore, these results suggested a unique inhibitory effect of propranolol on late sodium current unrelated to ß-adrenergic receptor block in N1774D-hiPSC-CMs. CONCLUSION: We successfully recapitulated the clinical phenotype of LQT3 using patient-derived hiPSC-CMs and determined that the mechanism, by which propranolol inhibited the late sodium current, was independent of ß-adrenergic receptor signaling pathway.

Complex aberrant splicing in the induced pluripotent stem cell-derived cardiomyocytes from a patient with long QT syndrome carrying KCNQ1-A344Aspl mutation.

BACKGROUND: Long QT syndrome type 1 (LQT1) is caused by mutations in KCNQ1, which encodes the α subunit of the slow delayed rectifier potassium current channel. We previously reported that a synonymous mutation, c.1032G>A, p.A344Aspl, in KCNQ1 is most commonly identified in genotyped patients with LQT1 in Japan and the aberrant splicing was analyzed in the lymphocytes isolated from patients' blood samples. However, the mechanisms underlying the observed processes in human cardiomyocytes remain unclear. OBJECTIVE: The purpose of this study was to establish and analyze patient-specific human-induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) model carrying KCNQ1-A344Aspl. METHODS: We generated hiPSCs from the peripheral blood mononuclear cells obtained from a patient with LQT1 carrying KCNQ1-A344Aspl. Using the differentiated cardiomyocytes, we analyzed splicing variants and performed electrophysiology studies. RESULTS: We identified 7 aberrant RNA variants in A344Aspl hiPSC-CMs, which were more complex compared with those in peripheral lymphocytes. Multielectrode array analysis revealed that 1 µM isoproterenol significantly prolonged the duration of the corrected field potential in A344Aspl hiPSC-CMs as compared with that in control hiPSC-CMs. In addition, 100 nM E-4031, which inhibits the rapid component of the delayed rectifier potassium current, was shown to induce early afterdepolarization-like waveforms in A344Aspl hiPSC-CMs. Action potential durations (APDs) did not significantly differ between the hiPSC-CM groups. After administering 500 nM isoproterenol, APDs of A344Aspl hiPSC-CMs were significantly longer than those of the controls. (R)-N-(4-(4-Methoxyphenyl)thiazol-2-yl)-1-tosylpiperidine-2-carboxamide and phenylboronic acid, slow delayed rectifier potassium current activators, ameliorated the APDs of hiPSC-CMs. CONCLUSION: We identified complex aberrant messenger RNA variants in the A344Aspl hiPSC-CM model and successfully recapitulated the clinical phenotypes of the patient with concealed LQT1. This model allows the investigation of the underlying mechanisms and development of novel therapies.

Copy number variations of SCN5A in Brugada syndrome.

BACKGROUND: Loss-of-function mutations in SCN5A are associated in ∼20% of Brugada syndrome (BrS) patients. Copy number variations (CNVs) have been shown to be associated with several inherited arrhythmia syndromes. OBJECTIVE: The purpose of this study was to investigate SCN5A CNVs among BrS probands. METHODS: The study cohort consisted of 151 BrS probands who were symptomatic or had a family history of BrS, sudden death, syncope, or arrhythmic diseases. We performed sequence analysis of SCN5A by the Sanger method. For detecting CNVs in SCN5A, we performed multiplex ligation-dependent probe amplification analysis of the 151 BrS probands. RESULTS: We identified pathogenic SCN5A mutations in 20 probands by the Sanger method. In 140 probands in whom multiplex ligation-dependent probe amplification was successfully performed, 4 probands were found to present different CNVs (deletion in 3 and duplication in 1). Three of them had fatal arrhythmia events; the remaining 1 was asymptomatic but had a family history. Mean age at diagnosis was 23 ± 14 years. All of the baseline 12-lead electrocardiograms showed PQ-interval prolongation. The characteristics of these 4 probands with CNVs were similar to those of the probands with mutations leading to premature truncation of the protein or missense mutations causing peak INa reduction >90%. CONCLUSION: We identified SCN5A CNVs in 2.9% of BrS probands who were symptomatic or had a family history.

Gene-Based Risk Stratification for Cardiac Disorders in LMNA Mutation Carriers.

BACKGROUND: Mutations in LMNA (lamin A/C), which encodes lamin A and C, typically cause age-dependent cardiac phenotypes, including dilated cardiomyopathy, cardiac conduction disturbance, atrial fibrillation, and malignant ventricular arrhythmias. Although the type of LMNA mutations have been reported to be associated with susceptibility to malignant ventricular arrhythmias, the gene-based risk stratification for cardiac complications remains unexplored. METHODS AND RESULTS: The multicenter cohort included 77 LMNA mutation carriers from 45 families; cardiac disorders were retrospectively analyzed. The mean age of patients when they underwent genetic testing was 45±17, and they were followed for a median 49 months. Of the 77 carriers, 71 (92%) were phenotypically affected and showed cardiac conduction disturbance (81%), low left ventricular ejection fraction (<50%; 45%), atrial arrhythmias (58%), and malignant ventricular arrhythmias (26%). During the follow-up period, 9 (12%) died, either from end-stage heart failure (n=7) or suddenly (n=2). Genetic analysis showed truncation mutations in 58 patients from 31 families and missense mutations in 19 patients from 14 families. The onset of cardiac disorders indicated that subjects with truncation mutations had an earlier occurrence of cardiac conduction disturbance and low left ventricular ejection fraction, than those with missense mutations. In addition, the truncation mutation was found to be a risk factor for the early onset of cardiac conduction disturbance and the occurrence of atrial arrhythmias and low left ventricular ejection fraction, as estimated using multivariable analyses. CONCLUSIONS: The truncation mutations were associated with manifestation of cardiac phenotypes in LMNA-related cardiomyopathy, suggesting that genetic analysis might be useful for diagnosis and risk stratification.

Very long-term clinical outcomes after radiofrequency catheter ablation for atrial fibrillation: A large single-center experience.

AIMS: Radiofrequency catheter ablation (RFCA) has become widely used for drug-refractory atrial fibrillation (AF). However, there is a paucity of data on the long-term clinical outcomes after RFCA for AF. The aim of the present study was to investigate the very long-term outcomes after RFCA for AF in a large number of consecutive patients. METHODS AND RESULTS: In this retrospective single-center study, we evaluated very long-term follow-up results in 1206 consecutive patients undergoing first RFCA for AF. The primary outcomes were adverse outcomes at 30-day as a safety outcome measure and event-free rates from recurrent atrial tachyarrhythmias as efficacy outcome measures. Final follow-up rate reached 99.3% with a mean follow-up duration of 5.0±2.5years. The incidence of overall 30-day adverse outcomes was 3.6% without death. The 10-year event-free rates from recurrent atrial tachyarrhythmias after the initial and last procedures were 46.9% and 76.4%, respectively. Arrhythmia recurrence occurred most commonly during the first year and decreased beyond 3-year, although it continued to occur at an annual rate of 2.0% and 1.3%, respectively, throughout the 10-year follow-up period. The cumulative 10-year incidences of stroke and major bleeding were 4.2% and 3.5%, respectively, with annual rates of 0.3%. Discontinuation rate of oral anticoagulation at 1-, 3-, and 10-year was 34.6%, 53.4%, 58.0% and 61.9%. CONCLUSIONS: RFCA for AF provided favorable very long-term arrhythmia-free survival without much safety concerns. The 10-year rates of stroke and major bleeding were low even with discontinuation of oral anticoagulation in a large proportion of patients.

Development of a Patient-Derived Induced Pluripotent Stem Cell Model for the Investigation of SCN5A-D1275N-Related Cardiac Sodium Channelopathy.

BACKGROUND: TheSCN5Agene encodes the α subunit of the cardiac voltage-gated sodium channel, NaV1.5. The missense mutation, D1275N, has been associated with a range of unusual phenotypes associated with reduced NaV1.5 function, including cardiac conduction disease and dilated cardiomyopathy. Curiously, the reported biophysical properties ofSCN5A-D1275N channels vary with experimental system.Methods and Results:First, using a human embryonic kidney (HEK) 293 cell-based heterologous expression system, theSCN5A-D1275N channels showed similar maximum sodium conductance but a significantly depolarizing shift of activation gate (+10 mV) compared to wild type. Second, we generated human-induced pluripotent stem cells (hiPSCs) from a 24-year-old female who carried heterozygousSCN5A-D1275N and analyzed the differentiated cardiomyocytes (CMs). AlthoughSCN5Atranscript levels were equivalent between D1275N and control hiPSC-CMs, both the total amount of NaV1.5 and the membrane fractions were reduced approximately half in the D1275N cells, which were rescued by the proteasome inhibitor MG132 treatment. Electrophysiological assays revealed that maximum sodium conductance was reduced to approximately half of that in control hiPSC-CMs in the D1275N cells, and maximum upstroke velocity of action potential was lower in D1275N, which was consistent with the reduced protein level of NaV1.5. CONCLUSIONS: This study successfully demonstrated diminished sodium currents resulting from lower NaV1.5 protein levels, which is dependent on proteasomal degradation, using a hiPSC-based model forSCN5A-D1275N-related sodium channelopathy.

Allele-specific ablation rescues electrophysiological abnormalities in a human iPS cell model of long-QT syndrome with a CALM2 mutation.

Calmodulin is a ubiquitous Ca2+ sensor molecule encoded by three distinct calmodulin genes, CALM1-3. Recently, mutations in CALM1-3 have been reported to be associated with severe early-onset long-QT syndrome (LQTS). However, the underlying mechanism through which heterozygous calmodulin mutations lead to severe LQTS remains unknown, particularly in human cardiomyocytes. We aimed to establish an LQTS disease model associated with a CALM2 mutation (LQT15) using human induced pluripotent stem cells (hiPSCs) and to assess mutant allele-specific ablation by genome editing for the treatment of LQT15. We generated LQT15-hiPSCs from a 12-year-old boy with LQTS carrying a CALM2-N98S mutation and differentiated these hiPSCs into cardiomyocytes (LQT15-hiPSC-CMs). Action potentials (APs) and L-type Ca2+ channel (LTCC) currents in hiPSC-CMs were analyzed by the patch-clamp technique and compared with those of healthy controls. Furthermore, we performed mutant allele-specific knockout using a CRISPR-Cas9 system and analyzed electrophysiological properties. Electrophysiological analyses revealed that LQT15-hiPSC-CMs exhibited significantly lower beating rates, prolonged AP durations, and impaired inactivation of LTCC currents compared with control cells, consistent with clinical phenotypes. Notably, ablation of the mutant allele rescued the electrophysiological abnormalities of LQT15-hiPSC-CMs, indicating that the mutant allele caused dominant-negative suppression of LTCC inactivation, resulting in prolonged AP duration. We successfully recapitulated the disease phenotypes of LQT15 and revealed that inactivation of LTCC currents was impaired in CALM2-N98S hiPSC model. Additionally, allele-specific ablation using the latest genome-editing technology provided important insights into a promising therapeutic approach for inherited cardiac diseases.

Patient-Specific Human Induced Pluripotent Stem Cell Model Assessed with Electrical Pacing Validates S107 as a Potential Therapeutic Agent for Catecholaminergic Polymorphic Ventricular Tachycardia.

INTRODUCTION: Human induced pluripotent stem cells (hiPSCs) offer a unique opportunity for disease modeling. However, it is not invariably successful to recapitulate the disease phenotype because of the immaturity of hiPSC-derived cardiomyocytes (hiPSC-CMs). The purpose of this study was to establish and analyze iPSC-based model of catecholaminergic polymorphic ventricular tachycardia (CPVT), which is characterized by adrenergically mediated lethal arrhythmias, more precisely using electrical pacing that could promote the development of new pharmacotherapies. METHOD AND RESULTS: We generated hiPSCs from a 37-year-old CPVT patient and differentiated them into cardiomyocytes. Under spontaneous beating conditions, no significant difference was found in the timing irregularity of spontaneous Ca2+ transients between control- and CPVT-hiPSC-CMs. Using Ca2+ imaging at 1 Hz electrical field stimulation, isoproterenol induced an abnormal diastolic Ca2+ increase more frequently in CPVT- than in control-hiPSC-CMs (control 12% vs. CPVT 43%, p<0.05). Action potential recordings of spontaneous beating hiPSC-CMs revealed no significant difference in the frequency of delayed afterdepolarizations (DADs) between control and CPVT cells. After isoproterenol application with pacing at 1 Hz, 87.5% of CPVT-hiPSC-CMs developed DADs, compared to 30% of control-hiPSC-CMs (p<0.05). Pre-incubation with 10 µM S107, which stabilizes the closed state of the ryanodine receptor 2, significantly decreased the percentage of CPVT-hiPSC-CMs presenting DADs to 25% (p<0.05). CONCLUSIONS: We recapitulated the electrophysiological features of CPVT-derived hiPSC-CMs using electrical pacing. The development of DADs in the presence of isoproterenol was significantly suppressed by S107. Our model provides a promising platform to study disease mechanisms and screen drugs.

Effect of vitamin K2 on the anticoagulant activity of warfarin during the perioperative period of catheter ablation: Population analysis of retrospective clinical data.

BACKGROUND: Catheter ablation is a non-medication therapy for atrial fibrillation, and during the procedure, warfarin is withdrawn in the preoperative period to prevent the risk of bleeding. In case of emergency, vitamin K2 can be intravenously administered to antagonize the anticoagulant activity of warfarin. The aims of this study were to conduct population pharmacokinetic/pharmacodynamic modeling for retrospective clinical data and to investigate the effect of vitamin K2 on the anticoagulant activity of warfarin in the perioperative period of catheter ablation. METHODS: A total of 579 international normalized ratio (INR) values of prothrombin time from 100 patients were analyzed using the nonlinear mixed-effects modeling program NONMEM. A 1-compartment model was adapted to the pharmacokinetics of warfarin and vitamin K2, and the indirect response model was used to investigate the relationship between plasma concentration and the pharmacodynamic response of warfarin and vitamin K2. Since no plasma concentration data for warfarin and vitamin K2 were available, 3 literally available pharmacokinetic parameters were used to simultaneously estimate 1 pharmacokinetic parameter and 5 pharmacodynamic parameters. RESULTS: The population parameters obtained not only successfully explained the observed INR values, but also indicated an increase in sensitivity to warfarin in patients with reduced renal function. Simulations using these parameters indicated that vitamin K2 administration of more than 20 mg caused a slight dose-dependent decrease in INR on the day of catheter ablation and a delayed INR elevation after warfarin re-initiation. CONCLUSIONS: A pharmacokinetic/pharmacodynamic model was successfully built to explain the retrospective INR data during catheter ablation. Simulation studies suggest that vitamin K2 should be administered with care and that more than 20 mg is unnecessary in the preoperative period of catheter ablation.

Cardiac sodium channel mutation associated with epinephrine-induced QT prolongation and sinus node dysfunction.

BACKGROUND: Long-QT syndrome (LQTS) is an inherited arrhythmia characterized by prolonged ventricular repolarization and malignant tachyarrhythmias. LQT1, LQT2, and LQT3 are caused by mutations in KCNQ1 (LQT1), KCNH2 (LQT2), and SCN5A (LQT3), which account for approximately 90% of genotyped LQTS patients. Most cardiac events in LQT1 patients occur during exercise, whereas patients with LQT3 tend to have arrhythmic events during rest or asleep. OBJECTIVE: The study aimed to identify a genetic mutation in a Japanese man who presented with sinus node dysfunction and prolonged QT interval on exercise and epinephrine stress tests, as well as to clarify the electrophysiological properties of mutant channels. METHODS: LQTS-related genes were screened in this patient. Electrophysiological functional assays were conducted with a heterologous expression system. RESULTS: We identified a heterozygous missense SCN5A mutation, V2016M, which changes the last amino acid of the cardiac sodium channel. Electrophysiological analyses revealed that the mutant channels exhibited a loss-of-function feature, decreased peak sodium current densities (wild type 175.2 ± 17.6 pA/pF; V2016M 97.2 ± 16.0 pA/pF; P < .01). In addition, the mutant channels showed gain-of-function features: increased late sodium currents by protein kinase A activation (wild type 0.07 ± 0.01%; V2016M 0.17 ± 0.03%; P < .05) and impaired inactivation of sodium channels by protein kinase A or C activation. CONCLUSION: We identified an SCN5A mutation in a patient with sinus node dysfunction and epinephrine-induced QT prolongation, which was an atypical phenotype for LQT3. The electrophysiological properties of the mutant channels might be associated with the overlapping clinical features of the patient.

A potential pitfall of the modified 12 lead electrocardiogram (Mason-Likar modification) in catheter ablation of idiopathic ventricular arrhythmias originating from the outflow tract.

AIMS: The Mason-Likar modified electrocardiogram (ML-ECG) can be interchanged with standard 12 lead ECG electrode positions (standard ECG) without affecting the diagnostic interpretation during sinus rhythm, but the morphological differences during ventricular arrhythmias have not been sufficiently evaluated. This study aimed to elucidate the morphological changes in the ML-ECG precordial leads. METHODS AND RESULTS: In 53 consecutive patients with premature ventricular contractions predicted to originate from the outflow tract (OT-PVCs), the arrhythmias were analysed by those two ECG methods. The OT-PVC origin sites, which were predicted by currently published criteria with the respective ECG methods prior to catheter ablation, were compared with the successful ablation sites. Compared with the standard-ECG, S-waves in the ML-ECG became shallower in leads V1-4 (P < 0.05 in lead V1; P < 0.001 in leads V2-4), and pseudo-R-waves in lead V1 appeared in seven patients. The precordial leads transition zone shifted counter-clockwise in 18 patients in the ML-ECG. In leads I and aVL, the negative deflection amplitudes of the ML-ECG were greater than those of the standard ECG (P < 0.001), and polarity reversals in lead I appeared in 18 patients. The R-wave amplitudes in all ML-ECG inferior leads were greater than those in the standard-ECG leads (all for P < 0.001). Those changes had an effect on the diagnostic indexes for the localization, and the specificity of the criteria for the ML-ECG was poorer than that for the standard-ECG. CONCLUSION: Great differences were found between those two ECG methods. Predicting OT-PVC origins by diagnostic criteria with the ML-ECG might result in a misdiagnosis and inefficient ablation.

Antiplatelet therapy discontinuation and the risk of serious cardiovascular events after coronary stenting: observations from the CREDO-Kyoto Registry Cohort-2.

Relation of antiplatelet therapy (APT) discontinuation with the risk of serious cardiovascular events has not been fully addressed yet. This study is aimed to evaluate the risk of ischemic event after APT discontinuation based on long-term APT status of large cohort. In the CREDO-Kyoto Registry Cohort-2 enrolling 15939 consecutive patients undergoing first coronary revascularization, 10470 patients underwent percutaneous coronary intervention either with bare-metal stents (BMS) only (N=5392) or sirolimus-eluting stents (SES) only (N=5078). Proportions of patients taking dual-APT were 67.3% versus 33.4% at 1-year, and 48.7% versus 24.3% at 5-year in the SES and BMS strata, respectively. We evaluated daily APT status (dual-, single- and no-APT) and linked the adverse events to the APT status just 1-day before the events. No-APT as compared with dual- or single-APT was associated with significantly higher risk for stent thrombosis (ST) beyond 1-month after SES implantation (cumulative incidence rates beyond 1-month: 1.23 versus 0.15/0.29, P<0.001/P<0.001), while higher risk of no-APT for ST was evident only until 6-month after BMS implantation (incidence rates between 1- and 6-month: 8.43 versus 0.71/1.20, P<0.001/P<0.001, and cumulative incidence rates beyond 6-month: 0.31 versus 0.11/0.08, P=0.16/P=0.08). No-APT as compared with dual- or single-APT was also associated with significantly higher risk for spontaneous myocardial infarction (MI) and stroke regardless of the types of stents implanted. Single-APT as compared with dual-APT was not associated with higher risk for serious adverse events, except for the marginally higher risk for ST in the SES stratum. In conclusion, discontinuation of both aspirin and thienopyridines was associated with increased risk for serious cardiovascular events including ST, spontaneous MI and stroke beyond 1-month after coronary stenting.

Incidence and outcome of surgical procedures after coronary artery bypass grafting compared with those after percutaneous coronary intervention: a report from the Coronary Revascularization Demonstrating Outcome Study in Kyoto PCI/CABG Registry Cohort-2.

BACKGROUND: Noncardiac surgery after percutaneous coronary intervention (PCI) has been reported to be carrying high risk for both ischemic and bleeding complications. However, there has been no report comparing the incidence and outcomes of surgical procedures after coronary artery bypass grafting (CABG) with those after PCI. METHODS AND RESULTS: Among 14 383 patients undergoing first coronary revascularization (PCI, n=12 207; CABG, n=2176) enrolled in the Coronary Revascularization Demonstrating Outcome Study in Kyoto (CREDO-Kyoto) PCI/CABG Registry Cohort-2, surgical procedures were performed more frequently after CABG (n=560) than after PCI (n=2398; cumulative 3-year incidence: 27% versus 22%; unadjusted P<0.0001), particularly <6 months of coronary revascularization. The risk for the primary ischemic outcome measure (death/myocardial infarction) at 30-day postsurgical procedures was not significantly different between the CABG and PCI groups (cumulative incidence: 3.1% versus 3.2%; unadjusted P=0.9; adjusted hazard ratio, 0.97; 95% confidence interval, 0.47-1.89; P=0.9). The risk for the primary bleeding outcome measure (moderate or severe bleeding by Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries classification) was lower in the CABG groups than in the PCI group (cumulative incidence: 1.3% versus 2.6%; unadjusted P=0.07; adjusted hazard ratio, 0.36; 95% confidence interval, 0.12-0.87; P=0.02). There were no interactions between the timing of surgery and the types of coronary revascularization (CABG/PCI) for both ischemic and bleeding outcomes. CONCLUSIONS: Surgical procedures were performed significantly more frequently after CABG than after PCI, particularly <6 months after coronary revascularization. Surgical procedures after CABG as compared with those after PCI were associated with similar risk for ischemic events and lower risk for bleeding events, regardless of the timing after coronary revascularization.

Late adverse events after implantation of sirolimus-eluting stent and bare-metal stent: long-term (5-7 years) follow-up of the Coronary Revascularization Demonstrating Outcome study-Kyoto registry Cohort-2.

BACKGROUND: Late adverse events such as very late stent thrombosis (VLST) or late target-lesion revascularization (TLR) after first-generation sirolimus-eluting stents (SES) implantation have not been yet fully characterized at long term in comparison with those after bare-metal stent (BMS) implantation. METHODS AND RESULTS: Among 13 058 consecutive patients undergoing first percutaneous coronary intervention in the Coronary REvascularization Demonstrating Outcome study-Kyoto registry Cohort-2, 5078 patients were treated with SES only, and 5392 patients were treated with BMS only. During 7-year follow-up, VLST and late TLR beyond 1 year after SES implantation occurred constantly and without attenuation at 0.24% per year and at 2.0% per year, respectively. Cumulative 7-year incidence of VLST was significantly higher in the SES group than that in the BMS group (1.43% versus 0.68%, P<0.0001). However, there was no excess of all-cause death beyond 1 year in the SES group as compared with that in the BMS group (20.8% versus 19.6%, P=0.91). Cumulative incidences of late TLR (both overall and clinically driven) were also significantly higher in the SES group than in the BMS group (12.0% versus 4.1%, P<0.0001 and 8.5% versus 2.6%, P<0.0001, respectively), leading to late catch-up of the SES group to the BMS group regarding TLR through the entire 7-year follow-up (18.8% versus 25.2%, and 10.6% versus 10.2%, respectively). Clinical presentation as acute coronary syndrome was more common at the time of late SES TLR compared with early SES TLR (21.2% and 10.0%). CONCLUSIONS: Late catch-up phenomenon regarding stent thrombosis and TLR was significantly more pronounced with SES than that with BMS. This limitation should remain the target for improvements of DES technology.

Optimal observation time after completion of circumferential pulmonary vein isolation for atrial fibrillation to prevent chronic pulmonary vein reconnections.

PURPOSE: To identify predictors of chronic pulmonary vein (PV) reconnection (CPVR) after successful circumferential PV isolation (CPVI) for atrial fibrillation (AF). MATERIALS AND METHODS: A total of 718 PVs from 181 consecutive AF patients (141 males, median age 61 years, 92 paroxysmal AF) who underwent a second ablation procedure for recurrent AF were retrospectively analyzed. RESULTS: During the second procedure, a CPVR was observed in 477 PVs (66.4%) among 169 patients. In a multiple logistic regression analysis, the observation time after the final completion of the PVI (OT-final) was a significant negative predictor (odds ratio 0.980; P<0.001). A receiver operating characteristic analysis demonstrated that the greatest area under the curve was for the OT-final (0.670). At an optimal cutoff of 35 min, the sensitivity and specificity for predicting a CPVR were 66.9% and 60.6%, respectively. By Kaplan Meier analysis, CPVR was more frequent in PVs with an OT-final of <35 min than ≥35 min (log-rank test, P=0.018). In a vessel-by-vessel analysis, the OT-final at all PV sites was a significant negative predictor, while male gender in the right PVs and left-inferior PV, number of RF applications for the ipsilateral CPVI in the right PVs and left-superior PV, and major PV diameter in the left-superior PV were significant positive predictors of a CPVR (all P<0.05). CONCLUSIONS: An optimal observation time (≥35 min in this study) to determine whether PVI is successfully completed during the initial CPVI for AF may be needed to prevent a CPVR and subsequent AF recurrence thereafter.

Combined dominant frequency and complex fractionated atrial electrogram ablation after circumferential pulmonary vein isolation of atrial fibrillation.

INTRODUCTION: Atrial substrates with high-dominant frequency (DF) and complex fractionated atrial electrogram (CFAE) sites have sources maintaining atrial fibrillation (AF) and are potential AF ablation targets. This study aimed to evaluate an approach of circumferential pulmonary vein isolation (PVI) followed by a DF and CFAE site ablation. METHODS AND RESULTS: Fifty consecutive AF patients (23 paroxysmal, 9 persistent, and 18 longstanding persistent) underwent ablation, using NavX. When AF continued after circumferential PVI, high-DF sites of ≥ 8 Hz and then continuous left atrial (LA) CFAE sites defined by fractionated intervals (FI) of ≤50 milliseconds including the coronary sinus and right atrium were targeted. A total of 45.1% of high-DF and 48.1% of continuous CFAE sites significantly decreased after PVI (P < 0.001). The mean LA DF and FI significantly decreased and prolonged, respectively, after PVI (P < 0.001). Only 14.1% of all high-DF sites after PVI overlapped with continuous CFAE sites. AF terminated at high-DF sites in 11 (22%) patients and continuous CFAE sites in 1 (2%). AF could be induced in only 8% of patients after the procedure. The mean LA DF value before ablation was significantly lower in those without recurrence (P = 0.003). AF freedom on antiarrhythmic drugs was 96% and 59%, respectively, in the paroxysmal and nonparoxysmal AF patients (89% persistent and 44% longstanding persistent) after 1 procedure over a 12-month follow-up. CONCLUSIONS: A combined high-DF and continuous CFAE site ablation in all chambers after circumferential PVI may be effective in the paroxysmal and persistent AF patients.

Pre-procedural prediction of termination of persistent atrial fibrillation by catheter ablation as an indicator of reverse remodeling of the left atrium.

BACKGROUND: The pre-procedural prediction of atrial fibrillation (AF) termination by catheter ablation in patients with persistent AF has not been evaluated fully. The aim of this study was to evaluate the pre-procedural predictors of persistent AF termination by ablation associated with the possibility of reverse remodeling of the left atrium (LA). METHODS AND RESULTS: Seventy consecutive patients (mean age, 62±8 years) with persistent or long-standing persistent AF underwent ablation. They were divided into 2 groups: those with AF terminated by ablation (n=14; group 1) and those with AF terminated by cardioversion after ablation (n=56; group 2). The left atrial appendage (LAA) contraction velocity determined on transesophageal echocardiography was significantly decreased in group 2 as compared to group 1 (P<0.001). Kaplan-Meier analysis showed that the group 1 patients had a higher AF-free survival rate than those in group 2 during 12±4.1 months of follow-up (P=0.048). The LA reverse remodeling ratio, given as the volume difference between before and 3 months after ablation in group 1, was significantly greater after ablation than that in group 2 (25.8±13% vs. 15.0±15%, P=0.015). Multivariate logistic regression analysis indicated that the LAA contraction velocity was an independent predictor of persistent AF termination by ablation (P=0.018). CONCLUSIONS: The LAA contraction velocity was the only non-invasive pre-procedural predictor of persistent AF termination by ablation, indicating the possibility of reverse remodeling of the LA.

Influence of initial acute myocardial infarction presentation on the outcome of surgical procedures after coronary stent implantation: a report from the CREDO-Kyoto PCI/CABG Registry Cohort-2.

Several previous publications have consistently reported that surgical procedures performed early after coronary stenting were associated with significantly higher risk for ischemic events than those performed late. In the current post hoc analysis of the Coronary REvascularization Demonstrating Outcome Study in Kyoto PCI/coronary artery bypass grafting Registry Cohort-2, we compared the outcomes of early (within 42 days) versus late surgery (beyond 42 days) after coronary stenting stratified by the initial clinical presentations [acute myocardial infarction (AMI) [early N = 153, and late N = 586] and non-AMI (early N = 202, and late N = 1457)]. Cumulative incidence of death/myocardial infarction/stent thrombosis at 30 days after surgery was significantly higher in the early group than in the late group in the AMI stratum [18.4 vs. 2.6 %, P < 0.0001, and adjusted HR 5.65 (95 % CI 2.42-13.5), P < 0.0001], but not in the non-AMI stratum [3.0 vs. 1.8 %, P = 0.3, and adjusted HR 1.52 (95 % CI 0.47-4.17), P = 0.5]. There was a significant interaction for the risk of ischemic events between the clinical presentation and the timing of surgery (P interaction = 0.03). Deaths in patients with early surgery in the AMI stratum were mostly related to preoperative complications of AMI (76 %), but not related to perioperative stent-related complications (4.0 %). In conclusion, significantly higher risk of early versus late surgery for perioperative ischemic events was seen only in patients with initial AMI presentation, but not in patients with non-AMI presentation. Previous observations suggesting higher risk in early surgery might not be related to the timing after stent implantation per se, but related to more morbid preoperative conditions in patients who underwent early surgery.

ß-Blocker therapy and cardiovascular outcomes in patients who have undergone percutaneous coronary intervention after ST-elevation myocardial infarction.

The effect of ß-blockers in ST-elevation myocardial infarction (STEMI) patients who have undergone primary percutaneous coronary intervention (PCI) has not been adequately evaluated. Using a large multi-center registry in Japan, we identified 3,692 patients who underwent PCI within 24 h from onset of STEMI and were discharged alive from 2005 to 2007. Three-year cardiovascular outcomes were compared between the 2 groups of patients with (N = 1,614) or without (N = 2,078) ß-blocker prescription at discharge. Compared with patients in the no-ß group, patients in the ß group were younger, more frequently male, more often had hypertension and atrial fibrillation but less often had chronic obstructive pulmonary disease than in the no-ß group. Statins and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers were more frequently prescribed in the ß group. Crude incidence of cardiac death and/or recurrent myocardial infarction (cardiac death/MI) tended to be higher in the ß group (7.6 vs. 6.2%, log-rank p = 0.1). After adjusting for potential confounders, ß-blockers were associated with significantly higher risk for cardiac death/MI (hazard ratio 1.43, 95% CI: 1.06-1.94, p = 0.01). ß-Blocker prescription at discharge was not associated with better cardiovascular outcomes in patients who underwent PCI after STEMI. Large-scale randomized controlled trials are needed to evaluate the role of ß-blocker therapy in these patients.

Efficacy and safety of periprocedural dabigatran in patients undergoing catheter ablation of atrial fibrillation.

BACKGROUND: Periprocedural anticoagulation using uninterrupted warfarin could reduce the risk of thromboembolic complications of atrial fibrillation (AF) ablation. Few studies, however, have evaluated the efficacy and safety of periprocedural dabigatran in AF ablation. METHODS AND RESULTS: A total of 211 consecutive patients who underwent AF ablation, including 110 patients who received 110mg dabigatran twice daily (group D) and 101 patients who received dose-adjusted warfarin (international normalized ratio, 2.0-3.0; group W), were evaluated. Dabigatran was discontinued on the morning of the procedure, and resumed on the next morning. Warfarin was continued throughout the procedure. During the procedure, heparin infusion was maintained to achieve an activated clotting time of >300s. Postprocedural cerebral magnetic resonance imaging (MRI) was performed in 60 patients (group D, n=31; group W, n=29). No periprocedural deaths or symptomatic thromboembolic complications were observed in either group. MRI indicated a silent cerebral infarction in 1 patient in each group. Five patients in group D and 11 in group W had minor bleeding (P=0.12). Cardiac tamponade occurred in 2 patients in group W, but in none in group D. Total bleeding complications occurred less frequently in group D (4.5%) than in group W (12.9%; P<0.05). CONCLUSIONS: Dabigatran at a dose of 110mg twice daily was safe for AF ablation in patients with a relatively low risk of thromboemboli, suggesting that it may become an alternative to warfarin in those patients.