Kei Nishiyama

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.

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.

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.

Regional cerebral oxygen saturation monitoring for predicting interventional outcomes in patients following out-of-hospital cardiac arrest of presumed cardiac cause: A prospective, observational, multicentre study

AIM This study investigated the value of regional cerebral oxygen saturation (rSO2) monitoring upon arrival at the hospital for predicting post-cardiac arrest intervention outcomes. METHODS We enrolled 1195 patients with out-of-hospital cardiac arrest of presumed cardiac cause from the Japan-Prediction of Neurological Outcomes in Patients Post-cardiac Arrest Registry. The primary endpoint was a good neurologic outcome (cerebral performance categories 1 or 2 [CPC1/2]) 90 days post-event. RESULTS A total of 68 patients (6%) had good neurologic outcomes. We found a mean rSO2 of 21%±13%. A receiver operating characteristic curve analysis indicated an optimal rSO2 cut-off of ≥40% for good neurologic outcomes (area under the curve 0.92, sensitivity 0.81, specificity 0.96). Good neurologic outcomes were observed in 53% (55/103) and 1% (13/1092) of patients with high (≥40%) and low (<40%) rSO2, respectively. Even without return of spontaneous circulation (ROSC) upon arrival at the hospital, 30% (9/30) of patients with high rSO2 had good neurologic outcomes. Furthermore, 16 patients demonstrating ROSC upon arrival at the hospital and low rSO2 had poor neurologic outcomes. Multivariate analyses indicated that high rSO2 was independently associated with good neurologic outcomes (odds ratio=14.07, P<0.001). Patients with high rSO2 showed favourable neurologic prognoses if they had undergone therapeutic hypothermia or coronary angiography (CPC1/2, 69% [54/78]). However, 24% (25/103) of those with high rSO2 did not undergo these procedures and exhibited unfavourable neurologic prognoses (CPC1/2, 4% [1/25]). CONCLUSION rSO2 is a good indicator of 90-day neurologic outcomes for post-cardiac arrest intervention patients.

Direct relationship between aging and overcrowding in the ED, and a calculation formula for demand projection: a cross-sectional study

Objective Although it has been suggested that the increase in older population contributes to overcrowding in emergency departments (EDs), there are limited data defining this relationship. This study examines whether patients’ mean age per day affects length of ED stay. Methods This cross-sectional analysis evaluated how patient age affects length of ED stay. The study was conducted at an ED attached to Fujisawa City Hospital, Japan, between 1 November 2009 and 31 October 2010. Patients scheduled to visit for childbirth and patients under age 15 were excluded. The primary outcome measure was the relationship between length of ED stay and patient age. The secondary outcome was the relationship between patient age and patient dispositions indicated by column chart and 100% staked column chart. Results Over the study period, there were 17 744 patient visits to the ED. The study included 15 840 (89.3%) patients. The mean (SD) age of these patients was 56.9 (21.5) years. In single and multiple linear regression analyses, mean patient age per day was an important factor in length of ED stay for the total number of patients visiting the ED (single linear regression analysis: regression coefficient=1.59 min/year, r2=0.005, p<0.001; multiple linear regression analysis: regression coefficient=0.72 min/year, r2=0.24, p<0.001). The ratio of admitted and transferred patients increased with patient age. Conclusion The increase in older patients visiting the ED has a direct significant negative effect on overcrowding in the ED.

Anisakiasis presenting to the ED: clinical manifestations, time course, hematologic tests, computed tomographic findings, and treatment

BACKGROUND The prevalence of anisakiasis is rare in the United States and Europe compared with that in Japan, with few reports of its presentation in the emergency department (ED). This study describes the clinical, hematologic, computed tomographic (CT) characteristics, and treatment in gastric and small intestinal anisakiasis patients in the ED. METHODS We retrospectively reviewed the data of 83 consecutive anisakiasis presentations in our ED between 2003 and 2012. Gastric anisakiasis was endoscopically diagnosed with the Anisakis polypide. Small intestinal anisakiasis was diagnosed based on both hematologic (Anisakis antibody) and CT findings. RESULTS Of the 83 cases, 39 had gastric anisakiasis and 44 had small intestinal anisakiasis based on our diagnostic criteria. Although all patients had abdominal pain, the gastric anisakiasis group developed symptoms significantly earlier (peaking within 6 hours) than the small intestinal anisakiasis group (peaking within 48 hours), and fewer patients with gastric anisakiasis needed admission therapy (5% vs 57%, P<.01). All patients in the gastric and 40 (91%) in the small intestinal anisakiasis group had a history of raw seafood ingestion. Computed tomographic findings revealed edematous wall thickening in all patients, and ascites and phlegmon of the mesenteric fat were more frequently observed in the small intestinal anisakiasis group. CONCLUSIONS In the ED, early and accurate diagnosis of anisakiasis is important to treat and explain to the patient, and diagnosis can be facilitated by a history of raw seafood ingestion, evaluation of the time-to-symptom development, and classic CT findings.

Sudden cardiac death after PCI and CABG in the bare-metal stent era: Incidence, prevalence, and predictors

BACKGROUND Few prospective cohort studies have examined the relationship between reduced left ventricular ejection fraction (LVEF) and other comorbidities for precise risk stratification of sudden cardiac death (SCD) after coronary revascularization. METHODS We analyzed 9877 consecutive patients who underwent first elective percutaneous coronary intervention (PCI) (n=6878) and coronary artery bypass grafting (CABG) (n=2999) between 2000 and 2002 at 30 institutions registered under the CREDO-Kyoto registry. RESULTS During the long-term follow-up (median follow-up period=42.8 months), 906 patients (9.4%) died; death from cardiovascular causes was observed in 517 (5.7%) patients; cardiac death, in 376 (3.9%) patients; and SCD, in 140 (1.5%) patients. The rates of SCD were 0.5%, 0.9%, and 1.3% at 1, 2, and 3 years of follow-up, respectively. Multivariate analyses indicated that dialysis (hazard ratio=2.51), chronic obstructive pulmonary disease (hazard ratio=2.04), congestive heart failure (hazard ratio=1.63), reduced LVEF (LVEF ≤ 30%; hazard ratio=1.55), chronic total occlusion of coronary artery (hazard ratio=1.38), diabetes with insulin therapy (hazard ratio=1.33), chronic renal disease (hazard ratio=1.29), and peripheral artery disease (hazard ratio=1.27) were independent predictors of SCD. CONCLUSIONS The method of revascularization had no influence on the incidence of SCD, and the adjusted hazard ratio of reduced LVEF was smaller than that observed in dialysis, chronic obstructive pulmonary disease, and congestive heart failure. This indicated that the risk of SCD depends on multiple variables in addition to LVEF.

Characteristics of regional cerebral oxygen saturation levels in patients with out-of-hospital cardiac arrest with or without return of spontaneous circulation: A prospective observational multicentre study.

AIM Our study aimed at filling the fundamental knowledge gap on the characteristics of regional brain oxygen saturation (rSO2) levels in out-of-hospital cardiac arrest (OHCA) patients with or without return of spontaneous circulation (ROSC) upon arrival at the hospital for estimating the quality of cardiopulmonary resuscitation and neurological prognostication in these patients. METHODS We enrolled 1921 OHCA patients from the Japan - Prediction of Neurological Outcomes in Patients Post-cardiac Arrest Registry and measured their rSO2 immediately upon arrival at the hospital by near-infrared spectroscopy using two independent forehead probes (right and left). We also assessed the percentage of patients with a good neurological outcome (defined as cerebral performance categories 1 or 2) 90 days post cardiac arrest. RESULTS After 90 days, 79 (4%) patients had good neurological outcomes and a median lower rSO2 level of 15% (15-20%). Compared to patients without ROSC upon arrival at the hospital, those with ROSC had significantly higher rSO2 levels (56% [39-65%] vs. 15% [15-17%], respectively; P<0.01), and significantly correlated right- and left-sided regional brain oxygen saturation levels (R=0.94 vs. 0.66, respectively). In both groups, the percentage of patients with a good 90-day neurological outcome increased significantly in proportion to their rSO2 levels upon arrival at the hospital (P<0.01). CONCLUSION Our data indicate that measuring rSO2 levels might be effective for both monitoring the quality of resuscitation and neurological prognostication in patients with OHCA.

Execution of Diagnostic Testing Has a Stronger Effect on Emergency Department Crowding than Other Common Factors: A Cross-Sectional Study

Study Objective We compared the effects of execution of diagnostic tests in the emergency department (ED) and other common factors on the length of ED stay to identify those with the greatest impacts on ED crowding. Methods Between February 2010 and January 2012, we conducted a cross-sectional, single-center study in the ED of a large, urban, teaching hospital in Japan. Patients who visited the ED during the study period were enrolled. We excluded (1) patients scheduled for admission or pharmaceutical prescription, and (2) neonates requiring intensive care transferred from other hospitals. Multivariate linear regression was performed on log-transformed length of ED stay in admitted and discharged patients to compare influence of diagnostic tests and other common predictors. To quantify the range of change in length of ED stay given a unit change of the predictor, a generalized linear model was used for each group. Results During the study period, 55,285 patients were enrolled. In discharged patients, laboratory blood tests had the highest standardized β coefficient (0.44) among common predictors, and increased length of ED stay by 72.5 minutes (95% CI, 72.8–76.1 minutes). In admitted patients, computed tomography (CT) had the highest standardized β coefficient (0.17), and increased length of ED stay by 32.7 minutes (95% CI, 40.0–49.9 minutes). Although other common input and output factors were significant contributors, they had smaller standardized β coefficients in both groups. Conclusions Execution of laboratory blood tests and CT had a stronger influence on length of ED stay than other common input and output factors.

Association between shelter crowding and incidence of sleep disturbance among disaster evacuees: a retrospective medical chart review study

Objectives We determined whether crowding at emergency shelters is associated with a higher incidence of sleep disturbance among disaster evacuees and identified the minimum required personal space at shelters. Design Retrospective review of medical charts. Setting 30 shelter-based medical clinics in Ishinomaki, Japan, during the 46 days following the Great Eastern Japan Earthquake and Tsunami in 2011. Participants Shelter residents who visited eligible clinics. Outcome measures Based on the result of a locally weighted scatter-plot smoothing technique assessing the relationship between the mean space per evacuee and cumulative incidence of sleep disturbance at the shelter, eligible shelters were classified into crowded and non-crowded shelters. The cumulative incidence per 1000 evacuees was compared between groups, using a Mann-Whitney U test. To assess the association between shelter crowding and the daily incidence of sleep disturbance per 1000 evacuees, quasi–least squares method adjusting for potential confounders was used. Results The 30 shelters were categorised as crowded (mean space per evacuee <5.0 m2, 9 shelters) or non-crowded (≥5.0 m2, 21 shelters). The study included 9031 patients. Among the eligible patients, 1079 patients (11.9%) were diagnosed with sleep disturbance. Mean space per evacuee during the study period was 3.3 m2 (SD, 0.8 m2) at crowded shelters and 8.6 m2 (SD, 4.3 m2) at non-crowded shelters. The median cumulative incidence of sleep disturbance did not differ between the crowded shelters (2.3/1000 person-days (IQR, 1.6–5.4)) and non-crowded shelters (1.9/1000 person-days (IQR, 1.0–2.8); p=0.20). In contrast, after adjusting for potential confounders, crowded shelters had an increased daily incidence of sleep disturbance (2.6 per 1000 person-days; 95% CI 0.2 to 5.0/1000 person-days, p=0.03) compared to that at non-crowded shelters. Conclusions Crowding at shelters may exacerbate sleep disruptions in disaster evacuees; therefore, appropriate evacuation space requirements should be considered.