Satoshi Shizuta

Long-Term Clinical and Angiographic Follow-Up After Coronary Stent Placement in Native Coronary Arteries

Background—Although coronary stents have been proved effective in reducing clinical cardiac events for up to 3 to 5 years, longer term clinical and angiographic outcomes have not yet been fully clarified. Methods and Results—To evaluate longer term (7 to 11 years) outcome, clinical and angiographic follow-up information was analyzed in 405 patients with successful stenting in native coronary arteries. Primary or secondary stabilization, which was defined as freedom from death, coronary artery bypass grafting, and target lesion-percutaneous coronary intervention (TL-PCI) during the 14 months after the initial procedure or after the last TL-PCI, was achieved in 373 patients (92%) overall. Only 7 patients (1.7%) underwent TL-PCI more than twice. After the initial 14-month period, freedom from TL-PCI reached a plateau at 84.9% to 80.7% over 1 to 8 years. However, quantitative angiographic analysis in 179 lesions revealed a triphasic luminal response characterized by an early restenosis phase until 6 months, an intermediate-term regression phase from 6 months to 3 years, and a late renarrowing phase beyond 4 years. Minimal luminal diameter in 131 patients with complete serial data were 2.62±0.4 mm immediately after stenting, 2.0±0.49 mm at 6 months, 2.19±0.49 mm at 3 years, and 1.85±0.56 mm beyond 4 years (P <0.0001). Conclusions—The efficacy and safety of coronary stenting seemed to be clinically sustained at 7 to 11 years of follow-up. However, late luminal renarrowing beyond 4 years was common, which demonstrates the need for further follow-up.

A Novel SCN5A Gain-of-Function Mutation M1875T Associated With Familial Atrial Fibrillation

OBJECTIVES This study describes a novel heterozygous gain-of-function mutation in the cardiac sodium (Na+) channel gene, SCN5A, identified in a Japanese family with lone atrial fibrillation (AF). BACKGROUND SCN5A mutations have been associated with a variety of inherited arrhythmias, but the gain-of-function type modulation in SCN5A is associated with only 1 phenotype, long-QT syndrome type 3 (LQTS3). METHODS We studied a Japanese family with autosomal dominant hereditary AF, multiple members of which showed an onset of AF or frequent premature atrial contractions at a young age. RESULTS The 31-year-old proband received radiofrequency catheter ablation, during which time numerous ectopic firings and increased excitability throughout the right atrium were documented. Mutational analysis identified a novel missense mutation, M1875T, in SCN5A. Further investigations revealed the familial aggregation of this mutation in all of the affected individuals. Functional assays of the M1875T Na(+) channels using a whole-cell patch-clamp demonstrated a distinct gain-of-function type modulation; a pronounced depolarized shift (+16.4 mV) in V(1/2) of the voltage dependence of steady-state inactivation; and no persistent Na+ current, which is a defining mechanism of LQTS3. These biophysical features of the mutant channels are potentially associated with increased atrial excitability and normal QT interval in all of the affected individuals. CONCLUSIONS We identified a novel SCN5A mutation associated with familial AF. The mutant channels displayed a gain-of-function type modulation of cardiac Na+ channels, which is a novel mechanism predisposing to increased atrial excitability and familial AF. This is a new phenotype resulting from the SCN5A gain-of-function mutations and is distinct from LQTS3.

KCNE5 (KCNE1L) Variants Are Novel Modulators of Brugada Syndrome and Idiopathic Ventricular Fibrillation

Background—Brugada syndrome (BrS) has a significantly higher incidence among the male sex. Among genes coding ion channels and their modulatory proteins, KCNE5 (KCNE1L) is located in the X chromosome and encodes an auxiliary &bgr;-subunit for K channels. KCNE5 has been shown to modify the transient outward current (Ito), which plays a key role in determining the repolarization process in the myocardium. This study investigated whether KCNE5 mutations could be responsible for BrS and other idiopathic ventricular fibrillation (IVF). Methods and Results—In 205 Japanese patients with BrS or IVF who tested negative for SCN5A mutation, we conducted a genetic screen for KCNE5 variants. We identified 2 novel KCNE5 variants: p.Y81H in 3 probands and p.[D92E;E93X] in 1 proband from 4 unrelated families. Y81H was identified in 1 man and 2 women; D92E;E93X was found in a 59-year-old man. All probands received implantable cardioverter-defibrillators. Functional consequences of the KCNE5 variants were determined through biophysical assay using cotransfection with KCND3 or KCNQ1. In the experiments with KCND3, which encodes Kv4.3, Ito was significantly increased for both KCNE5 variants compared to wild type. In contrast, there were no significant changes in current properties reconstructed by KCNQ1+ wild type KCNE5 and the 2 variants. With the simulation model, both variants demonstrated notch-and-dome or loss-of-dome patterns. Conclusions—KCNE5 modulates Ito, and its novel variants appeared to cause IVF, especially BrS, in male patients through gain-of-function effects on Ito. Screening for KCNE5 variants is relevant for BrS or IVF.

Long-Term Outcomes of Coronary-Artery Bypass Graft Surgery Versus Percutaneous Coronary Intervention for Multivessel Coronary Artery Disease in the Bare-Metal Stent Era

Background— Observational registries comparing coronary artery bypass graft (CABG) surgery and percutaneous coronary intervention (PCI) have reported long-term survival results that are discordant with those of randomized trials. Methods and Results— We conducted a multicenter study in Japan enrolling consecutive patients undergoing first CABG or PCI between January 2000 and December 2002. Among 9877 patients enrolled, 5420 (PCI: 3712, CABG: 1708) had multivessel disease without left main involvement. Because age is an important determinant when choosing revascularization strategies, survival analysis was stratified by either age ≥75 or <75 years. Analyses were also performed in other relevant subgroups. Median follow-up interval was 1284 days with 95% follow-up rate at 2 years. At 3 years, unadjusted survival rates were 91.7% and 89.6% in the CABG and PCI groups, respectively (log rank P=0.26). After adjustment for baseline characteristics, survival outcome tended to be better after CABG (hazard ratio for death after PCI versus CABG [HR], 95% confidence interval [CI]: 1.23 [0.99-1.53], P=0.06). Adjusted survival outcomes also tended to be better for CABG among elderly patients (HR [95%CI]: 1.37 [0.98-1.92] P=0.07), but not among nonelderly patients (HR [95% CI]: 1.09 [0.82-1.46], P=0.55). Unadjusted and adjusted survival outcome for CABG and PCI were not significantly different in any subgroups when elderly patients were excluded from analysis. Conclusions— In the CREDO-Kyoto registry, survival outcomes among patients <75 years of age were similar after PCI and CABG, a result that is consistent with those of randomized trials.

Adenosine triphosphate-guided pulmonary vein isolation for atrial fibrillation: the UNmasking Dormant Electrical Reconduction by Adenosine TriPhosphate (UNDER-ATP) trial.

AIMS Most of recurrent atrial tachyarrhythmias after pulmonary vein isolation (PVI) for atrial fibrillation (AF) are due to reconnection of PVs. The aim of the present study was to evaluate whether elimination of adenosine triphosphate (ATP)-induced dormant PV conduction by additional energy applications during the first ablation procedure could reduce the incidence of recurrent atrial tachyarrhythmias. METHODS AND RESULTS We randomly assigned 2113 patients with paroxysmal, persistent, or long-lasting AF to either ATP-guided PVI (1112 patients) or conventional PVI (1001 patients). The primary endpoint was recurrent atrial tachyarrhythmias lasting for >30 s or those requiring repeat ablation, hospital admission, or usage of Vaughan Williams class I or III antiarrhythmic drugs at 1 year with the blanking period of 90 days post ablation. Among patients assigned to ATP-guided PVI, 0.4 mg/kg body weight of ATP provoked dormant PV conduction in 307 patients (27.6%). Additional radiofrequency energy applications successfully eliminated dormant conduction in 302 patients (98.4%). At 1 year, 68.7% of patients in the ATP-guided PVI group and 67.1% of patients in the conventional PVI group were free from the primary endpoint, with no significant difference (adjusted hazard ratio [HR] 0.89; 95% confidence interval [CI] 0.74-1.09; P = 0.25). The results were consistent across all the prespecified subgroups. Also, there was no significant difference in the 1-year event-free rates from repeat ablation for any atrial tachyarrhythmia between the groups (adjusted HR 0.83; 95% CI 0.65-1.08; P = 0.16). CONCLUSION In the catheter ablation for AF, we found no significant reduction in the 1-year incidence of recurrent atrial tachyarrhythmias by ATP-guided PVI compared with conventional PVI.

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.

Lack of Effect of Oral Beta-Blocker Therapy at Discharge on Long-Term Clinical Outcomes of ST-Segment Elevation Acute Myocardial Infarction After Primary Percutaneous Coronary Intervention

Beta-blocker therapy is recommended after ST-segment elevation acute myocardial infarction (STEMI) in current guidelines, although its efficacy in those patients who have undergone primary percutaneous coronary intervention (PCI) has not been adequately evaluated. Of 12,824 consecutive patients who underwent sirolimus-eluting stent implantation in the J-Cypher registry, we identified 910 patients who underwent PCI within 24 hours from onset of STEMI. Three-year outcomes were evaluated according to use of β blockers at hospital discharge (349 patients in β-blocker group and 561 patients in no-β-blocker group). Patients in the β-blocker group more frequently had hypertension, low left ventricular ejection fraction (LVEF), a left anterior descending artery infarct, and statin use than those in the no-β-blocker group. No difference was observed between the β-blocker and no-β-blocker groups in mortality (6.6% vs 6.6%, p = 0.85; propensity score adjusted hazard ratio 1.10, 95% confidence interval 0.64 to 1.90, p = 0.70) or in incidence of major adverse cardiac events (all-cause death, recurrent myocardial infarction, and heart failure hospitalization, 13.5% vs 12.1%, p = 0.91; hazard ratio 1.13, 95% confidence interval 0.76 to 1.66, p = 0.53). Better outcomes were observed in the β-blocker group than in the no-β-blocker group in a subgroup of patients with LVEF ≤40% (n = 125, death 6.4% vs 17.4%, p = 0.04; major adverse cardiac events 14.5% vs 31.8%, p = 0.009). In conclusion, β-blocker therapy was not associated with better 3-year clinical outcomes in patients with STEMI who underwent primary PCI and had preserved LVEF.

Duration of Dual Antiplatelet Therapy and Long-Term Clinical Outcome After Coronary Drug-Eluting Stent Implantation Landmark Analyses From the CREDO-Kyoto PCI/CABG Registry Cohort-2

Background— Optimal duration of dual antiplatelet therapy (DAPT) after drug-eluting stent (DES) implantation has not been yet fully elucidated. Methods and Results— We assessed the influence of prolonged thienopyridine therapy on clinical outcomes with landmark analysis at 4 and 13 months after DES implantation. Among 6802 patients with at least 1 DES implantation in the CREDO-Kyoto Registry Cohort-2, 6309 patients (on thienopyridine, 5438 patients; off thienopyridine, 871 patients) and 5901 patients (on thienopyridine, 4098 patients; off thienopyridine, 1803 patients) were eligible for the 4- and 13-month landmark analyses, respectively. The majority of patients had stable coronary artery disease (73%) and received sirolimus-eluting stents (93%), and approximately 90% of thienopyridine was ticlopidine. Patients taking thienopyridine had more complex comorbidities and more complex lesion and procedural characteristics as compared with patients not taking thienopyridine. After adjusting for confounders, thienopyridine use was not associated with decreased risk for death/myocardial infarction/stroke (hazard ratio [HR], 1.13; 95% confidence interval [CI], 0.89–1.43, P=0.32 in the 4-month landmark analysis; HR, 1.14; 95% CI, 0.90–1.45, P=0.29 in the 13-month landmark analysis, respectively), whereas the risk for GUSTO moderate/severe bleeding tended to be higher in patients taking thienopyridine (HR, 1.51; 95% CI, 1.00–2.23, P=0.049 in the 4-month landmark analysis; HR, 1.44; 95% CI, 0.99–2.09, P=0.057 in the 13-month landmark analysis, respectively). Conclusions— Prolonged thienopyridine therapy beyond 4 and 13 months appeared not to be associated with reduction in ischemic events but to be associated with a trend toward increased bleeding. Optimal duration of DAPT after DES implantation might be shorter than the currently recommended 1-year interval.

Chronic obstructive pulmonary disease—An independent risk factor for long-term cardiac and cardiovascular mortality in patients with ischemic heart disease

BACKGROUND Limited data are available on long-term mortality and morbidity of patients with chronic obstructive pulmonary disease (COPD) and ischemic heart disease. We examined how COPD affects long-term mortality and morbidity after undergoing percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG). METHODS We analyzed 9877 consecutive patients who underwent their first elective PCI (n=6878) and CABG (n=2999) in 2000-2002 at 30 institutions listed in the CREDO-Kyoto registry. RESULTS COPD was diagnosed in 240 patients (2.4%). In-hospital mortality (1.3% vs. 1.2%, p=0.972) did not differ between patients with and without COPD. During long-term follow-up (42. 8 month s), 906 patients (9.4%) died, 517 (5.3%) of whom died of cardiovascular death and 376 (3.9%), of cardiac death. At 3 years, the unadjusted survival rate and the rates of freedom from cardiovascular death and cardiac death were 92.1%, 95.3%, and 96.5% in the total population and 82.8%, 91.7%, and 92.1% in patients with COPD respectively. Log-rank test indicated that COPD was associated with higher incidence of all-cause mortality (p<0.0001), cardiovascular death (p=0.0002), and cardiac death (p<0.0001). Multivariate analyses indicated that COPD was an independent predictor of all-cause mortality (hazard ratio 1.36, p=0.0003), cardiovascular death (hazard ratio 1.28, p=0.0407), and cardiac death (hazard ratio 1.48, p=0.003). CONCLUSIONS COPD is an independent risk factor for long-term cardiac and cardiovascular mortality in patients with ischemic heart disease.

Efficacy of Antiarrhythmic Drugs Short-Term Use After Catheter Ablation for Atrial Fibrillation (EAST-AF) trial

AIMS Substantial portion of early arrhythmia recurrence after catheter ablation for atrial fibrillation (AF) is considered to be due to irritability in left atrium (LA) from the ablation procedure. We sought to evaluate whether 90-day use of antiarrhythmic drug (AAD) following AF ablation could reduce the incidence of early arrhythmia recurrence and thereby promote reverse remodelling of LA, leading to improved long-term clinical outcomes. METHODS AND RESULTS A total of 2038 patients who had undergone radiofrequency catheter ablation for paroxysmal, persistent, or long-lasting AF were randomly assigned to either 90-day use of Vaughan Williams class I or III AAD (1016 patients) or control (1022 patients) group. The primary endpoint was recurrent atrial tachyarrhythmias lasting for >30 s or those requiring repeat ablation, hospital admission, or usage of class I or III AAD at 1 year, following the treatment period of 90 days post ablation. Patients assigned to AAD were associated with significantly higher event-free rate from recurrent atrial tachyarrhythmias when compared with the control group during the treatment period of 90 days [59.0 and 52.1%, respectively; adjusted hazard ratio (HR) 0.84; 95% confidence interval (CI) 0.73-0.96; P = 0.01]. However, there was no significant difference in the 1-year event-free rates from the primary endpoint between the groups (69.5 and 67.8%, respectively; adjusted HR 0.93; 95% CI 0.79-1.09; P = 0.38). CONCLUSION Short-term use of AAD for 90 days following AF ablation reduced the incidence of recurrent atrial tachyarrhythmias during the treatment period, but it did not lead to improved clinical outcomes at the later phase.