Mamoru Hayano

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.

Combined Dominant Frequency and Complex Fractionated Atrial Electrogram Ablation After Circumferential Pulmonary Vein Isolation of Atrial Fibrillation

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.

Incidence and Outcome of Surgical Procedures After Coronary Bare-Metal and Drug-Eluting Stent Implantation A Report From the CREDO-Kyoto PCI/CABG Registry Cohort-2

Background— There still remain safety concerns on surgical procedures after coronary drug-eluting stents (DES) implantation, and optimal management of perioperative antiplatelet therapy (APT) has not been yet established. Methods and Results— During 3-year follow-up of 12 207 patients (DES=6802 patients and bare-metal stent [BMS] only=5405 patients) who underwent coronary stent implantation in the CREDO-Kyoto registry cohort-2, surgical procedures were performed in 2398 patients (DES=1295 patients and BMS=1103 patients). Surgical procedures (early surgery in particular) were more frequently performed in the BMS group than in the DES group (4.4% versus 1.9% at 42-day and 23% versus 21% at 3-year, log-rank P=0.0007). Cumulative incidences of death/myocardial infarction (MI)/stent thrombosis (ST) and bleeding at 30 days after surgery were low, without differences between BMS and DES (3.5% versus 2.9%, P=0.4 and 3.2% versus 2.1%, P=0.2, respectively). The adjusted risks of DES use relative to BMS use for death/MI/ST and bleeding were not significant (hazard ratio: 1.63, 95% confidence interval: 0.93 to 2.87, P=0.09 and hazard ratio: 0.6, 95% confidence interval: 0.34 to 1.06, P=0.08, respectively). The risks of perioperative single- and no-APT relative to dual-APT for both death/MI/ST and bleeding were not significant; single-APT as compared with dual-APT tended to be associated with lower risk for death/MI/ST (hazard ratio: 0.4, 95% confidence interval: 0.13 to 1.01, P=0.053). Conclusions— Surgical procedures were commonly performed after coronary stent implantation, and the risk of ischemic and bleeding complications in surgical procedures was low. In patients selected to receive DES or BMS, there were no differences in outcomes. Perioperative administration of dual-APT was not associated with lower risk for ischemic events.

Comparison of Long-Term Outcome After Percutaneous Coronary Intervention Versus Coronary Artery Bypass Grafting in Patients With Unprotected Left Main Coronary Artery Disease (from the CREDO-Kyoto PCI/CABG Registry Cohort-2)

The long-term outcome of percutaneous coronary intervention (PCI) compared to coronary artery bypass grafting (CABG) for unprotected left main coronary artery disease (ULMCAD) remains to be investigated. We identified 1,005 patients with ULMCAD of 15,939 patients with first coronary revascularization enrolled in the CREDO-Kyoto PCI/CABG Registry Cohort-2. Cumulative 3-year incidence of a composite of death/myocardial infarction (MI)/stroke was significantly higher in the PCI group than in the CABG group (22.7% vs 14.8%, p = 0.0006, log-rank test). However, the adjusted outcome was not different between the PCI and CABG groups (hazard ratio [HR] 1.30, 95% confidence interval [CI] 0.79 to 2.15, p = 0.30). Stratified analysis using the SYNTAX score demonstrated that risk for a composite of death/MI/stroke was not different between the 2 treatment groups in patients with low (<23) and intermediate (23 to 33) SYNTAX scores (adjusted HR 1.70, 95% CI 0.77 to 3.76, p = 0.19; adjusted HR 0.86, 95% CI 0.37 to 1.99, p = 0.72, respectively), whereas in patients with a high SYNTAX score (≥33), it was significantly higher after PCI than after CABG (adjusted HR 2.61, 95% CI 1.32 to 5.16, p = 0.006). In conclusion, risk of PCI for serious adverse events seemed to be comparable to that after CABG in patients with ULMCAD with a low or intermediate SYNTAX score, whereas PCI compared with CABG was associated with a higher risk for serious adverse events in patients with a high SYNTAX score.

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

&NA; 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.

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.

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.

Clinical Efficacy of Thrombus Aspiration on 5‐Year Clinical Outcomes in Patients With ST‐Segment Elevation Acute Myocardial Infarction Undergoing Percutaneous Coronary Intervention

Background Adjunctive thrombus aspiration (TA) during primary percutaneous coronary intervention (PCI) was reported to promote better coronary and myocardial reperfusion. However, long-term mortality benefit of TA remains controversial. The objective of this study is to investigate the clinical impact of TA on long-term clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary PCI. Methods and Results The CREDO-Kyoto AMI Registry is a large-scale cohort study of acute myocardial infarction patients undergoing coronary revascularization in 2005–2007 at 26 hospitals in Japan. Among 5429 patients enrolled in the registry, the current study population consisted of 3536 patients who arrived at the hospital within 12 hours after the symptom onset and underwent primary PCI. Clinical outcomes were compared between the 2 patient groups with or without TA. During primary PCI procedures, 2239 out of 3536 (63%) patients underwent TA (TA group). The cumulative 5-year incidence of all-cause death was significantly lower in the TA group than in the non-TA group (18.5% versus 23.9%, log-rank P<0.001). After adjusting for confounders, however, the risk for all-cause death in the TA group was not significantly lower than that in the non-TA group (hazard ratio: 0.90, 95% CI: 0.76 to 1.06, P=0.21). The adjusted risks for cardiac death, myocardial infarction, stroke, and target-lesion revascularization were also not significantly different between the 2 groups. Conclusions Adjunctive TA during primary PCI was not associated with better 5-year mortality in STEMI patients.

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.