Mamoru Toyofuku

Pulse Wave Velocity Predicts Cardiovascular Mortality

Background Arterial stiffness measurements, generally from pulse wave velocity (PWV), are widely used with little knowledge of their relationship to long-term cardiovascular mortality in general populations. Methods and Results We studied a cohort of 492 Japanese-Americans living in Hawaii (mean age: 63.7 ±8.8 years) to assess the relationship between PWV and cardiovascular disease mortality and all-cause mortality. During the 10-year follow-up, 43 patients died (14 from cardiovascular events). The cohort was divided into 2 groups by the cut-off value of PWV (9.9 m/s) represented in the receiver operating characteristic curve. The risk ratio for PWV values >9.9 m/s to all-cause mortality was 1.28 [95% confidence interval (CI): 1.14-1.42], and adjusted for other risk factors this ratio was 1.42 (95% CI: 0.96-2.11). The corresponding risk ratios for cardiovascular mortality was 4.46 (95% CI: 1.61-12.32) and 4.24 (95% CI: 1.39-12.96), respectively. Conclusions The present study demonstrated that an increased PWV value is associated with future cardiovascular disease death in Japanese-Americans living in Hawaii. (Circ J 2005; 69: 259 - 264)

Three-Year Outcomes After Sirolimus-Eluting Stent Implantation for Unprotected Left Main Coronary Artery Disease Insights From the j-Cypher Registry

Background— Long-term outcomes after stenting of an unprotected left main coronary artery (ULMCA) with drug-eluting stents have not been addressed adequately despite the growing popularity of this procedure. Methods and Results— j-Cypher is a multicenter prospective registry of consecutive patients undergoing sirolimus-eluting stent implantation in Japan. Among 12 824 patients enrolled in the j-Cypher registry, the unadjusted mortality rate at 3 years was significantly higher in patients with ULMCA stenting (n=582) than in patients without ULMCA stenting (n=12 242; 14.6% versus 9.2%, respectively; P<0.0001); however, there was no significant difference between the 2 groups in the adjusted risk of death (hazard ratio 1.23, 95% confidence interval 0.95 to 1.60, P=0.12). Among 476 patients whose ULMCA lesions were treated exclusively with a sirolimus-eluting stent, patients with ostial/shaft lesions (n=96) compared with those with bifurcation lesions (n=380) had a significantly lower rate of target-lesion revascularization for the ULMCA lesions (3.6% versus 17.1%, P=0.005), with similar cardiac death rates at 3 years (9.8% versus 7.6%, P=0.41). Among patients with bifurcation lesions, patients with stenting of both the main and side branches (n=119) had significantly higher rates of cardiac death (12.2% versus 5.5%; P=0.02) and target-lesion revascularization (30.9% versus 11.1%; P<0.0001) than those with main-branch stenting alone (n=261). Conclusions— The higher unadjusted mortality rate of patients undergoing ULMCA stenting with a sirolimus-eluting stent did not appear to be related to ULMCA treatment itself but rather to the patients’ high-risk profile. Although long-term outcomes in patients with ostial/shaft ULMCA lesions were favorable, outcomes in patients with bifurcation lesions treated with stenting of both the main and side branches appeared unacceptable.

Initial Surgical Versus Conservative Strategies in Patients With Asymptomatic Severe Aortic Stenosis.

BACKGROUND Current guidelines generally recommend watchful waiting until symptoms emerge for aortic valve replacement (AVR) in asymptomatic patients with severe aortic stenosis (AS). OBJECTIVES The study sought to compare the long-term outcomes of initial AVR versus conservative strategies following the diagnosis of asymptomatic severe AS. METHODS We used data from a large multicenter registry enrolling 3,815 consecutive patients with severe AS (peak aortic jet velocity >4.0 m/s, or mean aortic pressure gradient >40 mm Hg, or aortic valve area <1.0 cm(2)) between January 2003 and December 2011. Among 1,808 asymptomatic patients, the initial AVR and conservative strategies were chosen in 291 patients, and 1,517 patients, respectively. Median follow-up was 1,361 days with 90% follow-up rate at 2 years. The propensity score-matched cohort of 582 patients (n = 291 in each group) was developed as the main analysis set for the current report. RESULTS Baseline characteristics of the propensity score-matched cohort were largely comparable, except for the slightly younger age and the greater AS severity in the initial AVR group. In the conservative group, AVR was performed in 41% of patients during follow-up. The cumulative 5-year incidences of all-cause death and heart failure hospitalization were significantly lower in the initial AVR group than in the conservative group (15.4% vs. 26.4%, p = 0.009; 3.8% vs. 19.9%, p < 0.001, respectively). CONCLUSIONS The long-term outcome of asymptomatic patients with severe AS was dismal when managed conservatively in this real-world analysis and might be substantially improved by an initial AVR strategy. (Contemporary Outcomes After Surgery and Medical Treatment in Patients With Severe Aortic Stenosis Registry; UMIN000012140).

Effects of genetic ablation of bach1 upon smooth muscle cell proliferation and atherosclerosis after cuff injury

Bach1 is a transcriptional repressor of the cytoprotective enzyme heme oxygenase‐1 (HO‐1). Although HO‐1 protects against atherosclerosis, the function of Bach1 in this process is poorly understood. We isolated peritoneal macrophages and aortic smooth muscle cells (SMC) from wild‐type and bach1‐deficient mice. bach1‐deficient macrophages expressed increased levels of HO‐1 and showed elevated phagocytic activity when incubated with 0.75 µm microspheres. In SMC, bach1‐ablation resulted in increased expression of HO‐1 and decreased proliferation in bromodeoxyuridine incorporation assay as compared with wild‐type cells. The up‐regulated phagocytic activity and reduced SMC proliferation of bach1‐deficient cells were not restored by Zinc (II) protoporphyrin IX, an inhibitor of HO, suggesting that HO‐independent mechanisms are also involved in the regulation of phagocytosis of macrophages and proliferation of SMC by Bach1. In wild‐type mice, cuff placement around femoral artery caused pronounced intimal proliferation without affecting the media, thus resulting in intimal to medial (I/M) volume ratio of 65.6%. bach1‐deficient mice had less degree of intimal growth (I/M ratio of 45.6%). These results indicate that Bach1 plays a critical role in the regulation of HO‐1 expression, macrophage function, SMC proliferation and neointimal formation. Bach1 may regulate gene expression in these cells during inflammation and atherogenesis.

Influence of type 2 diabetes mellitus on cardiovascular disease mortality: findings from the Hawaii-Los Angeles-Hiroshima study.

The present study addressed whether diabetes mellitus was a strong risk factor for cardiovascular disease (CVD) death. Between 1976 and 1984, 927 (404 men) Japanese-Americans in Hawaii aged 40-79 years participated at baseline examination including a 75 g oral glucose tolerance test. Diabetes was defined as fasting serum glucose >or=140 mg/dl, 2 h postload glucose >or=180 mg/dl, or the use of drugs for diabetes. Causes of death were classified by ICD-9 codes on the reports from the Hawaii State Public Health Bureau. Until 1994, 178 individuals suffered death; 81 were attributed to CVD and 43 to coronary heart disease (CHD). The age-adjusted and coronary risk factors-adjusted relative risks for CHD and CVD mortality were significant for diabetes both in men and women. The impact of diabetes on CHD mortality was greater for women. However, no gender difference in the contribution of diabetes to fatal CVD was observed. Serum fasting glucose levels tended to be associated with CHD death and were associated with CVD death in diabetic subjects. In conclusion, diabetes is a strong independent risk factor for CVD mortality in Japanese-American men and women. Hyperglycemia is associated with CVD mortality in diabetic subjects.

Validation of lactate level as a predictor of early mortality in acute decompensated heart failure patients who entered intensive care unit

BACKGROUND The significance of routine measurement of lactate level is unclear in patients with critical acute decompensated heart failure (ADHF). METHODS AND RESULTS Consecutive 754 patients who were admitted to the intensive care unit (ICU) in our hospital from January 2007 to March 2012 and given a diagnosis of ADHF were eligible for retrospective entry into the registry. Lactate level was measured on admission from routine arterial blood sample and we investigated by comparing the lactate level and parameters of conventional in-hospital mortality predictors. Among the patients, 88 (12%) died during hospitalization. The lactate level had great power to predict in-hospital mortality, as suggested by the c-statistics of 0.71. The occurrence of in-hospital death was more pronounced in patients with high levels of lactate (>3.2mmol/l) and the tendency was observed in patients in both the acute coronary syndrome (ACS) group and non-ACS group. In multivariate analysis, elevated lactate levels remained an independent predictor of in-hospital death (odds ratio, 2.14; 95% confidence interval, 1.10-4.21; p=0.03). CONCLUSIONS Elevated levels of arterial lactate on admission were related to worse in-hospital mortality in patients with ADHF either with or without ACS, suggesting that the presence of high lactate in patients who enter the ICU with ADHF could help stratify the initial risk of early mortality.

Comparison of heart-type fatty acid binding protein and sensitive troponin for the diagnosis of early acute myocardial infarction

BACKGROUND The current development of serological biomarkers allows detection of smaller myocardial necrosis and early acute myocardial infarction (AMI). We evaluated the relevance of the heart-type fatty acid binding protein (H-FABP) assay, which has recently been approved in Japan, for early diagnosis of AMI as compared with the sensitive troponin assay. METHODS This is an observational study in a single center. From 2010 July to 2011 January, 114 patients who presented with symptoms suggestive of AMI were enrolled. RESULTS AMI was adjudicated in 45 patients (40%). The diagnostic accuracy of measurements obtained at presentation for AMI, as quantified by the area under the receiver-operating-characteristic curve (AUC), was significantly lower with H-FABP assay than the sensitive troponin assay [AUC for H-FABP, 0.59; 95% confidence interval (CI) 0.48-0.70; and for troponin I, 0.89; 95% CI, 0.83-0.94; P<.0001]. Among patients who presented within 2h after the onset of chest pain, the AUC for H-FABP was even low as compared with sensitive troponin (0.55; 0.39-0.72 vs. 0.89; 0.80-0.98, p<0.001). The clinical sensitivity for the diagnosis of AMI with the cutoff point of 99 th percentile was similar in both assays (81% and 81%, respectively), however, the specificity was extremely low in the H-FABP assay as compared with sensitive troponin assay (19% and 79%, respectively). CONCLUSION The measurement of H-FABP in 114 consecutive patients with chest pain suggestive of AMI showed no improvement of diagnosis for early AMI as compared with the current sensitive troponin assay because of its extremely low specificity.

Exogenous adenosine triphosphate disodium administration during primary percutaneous coronary intervention reduces no-reflow and preserves left ventricular function in patients with acute anterior myocardial infarction: A study using myocardial contrast echocardiography

BACKGROUND It is unknown whether adenosine triphosphate disodium (ATP) administration during primary percutaneous coronary intervention (PCI) is useful in anterior acute myocardial infarction (AMI). METHODS The study was a prospective, non-randomized, open-label trial. Primary PCI was successfully performed in 204 consecutive patients with first anterior AMI. ATP at a mean dose of 117 microg/kg/min for 45 min on an average was infused intravenously during PCI in 100 patients (Group 1). In the other 104 patients, normal saline was administered (Group 2). ST-segment resolution (STR) was estimated 90 min after recanalization. The no-reflow ratio was measured 2 weeks later, using intravenous myocardial contrast echocardiography. Left ventricular ejection fraction (LVEF), LV regional wall motion (LVRWM), and LV end-diastolic volume index (LVEDVI) were measured 6 months later. RESULTS Baseline patient characteristics of the two groups were similar, including TIMI risk scores. Significant STR (> or =50% resolution compared to baseline) (66% versus 50%; Group 1 versus Group 2, p=0.02), no-reflow ratio (24% versus 34%, indicated by mean values, p=0.02), LVEF (61% versus 55%, p=0.0007), LVRWM (-1.56 versus -2.05, using the SD/chord, p=0.0001), and LVEDVI (60 ml/m(2) versus 71 ml/m(2), p=0.0007) were significantly better in Group 1, and the no-reflow ratio, LVEF, LVRWM and LVEDVI were significantly better in ATP-administered patients, regardless of antecedent angina or advanced age. ATP Administration was consistently identified as a significant determinant for STR, no-reflow ratio, LVEF, LVRWM, and LVEDVI. CONCLUSIONS Intravenous ATP administration during reperfusion is an independent determinant of STR and the no-reflow ratio, and LVEF, LVRWM, and LVEDVI at 6 months after primary PCI.

Clinical usefulness of drug-eluting stents in the treatment of dialysis patients with coronary artery disease

AIMS To investigate the clinical outcomes of paclitaxel-eluting stents (PES) and sirolimus-eluting stents (SES) in patients on dialysis. METHODS AND RESULTS Between May 2004 and December 2008, 95 patients on dialysis with 124 lesions were treated with PES alone, and were compared to 184 patients on dialysis with 244 lesions treated with SES alone, retrospectively. One-year major adverse cardiac event (MACE) including stent thrombosis, target lesion revascularisation (TLR), myocardial infarction (MI) and cardiac death were compared. Baseline characteristics were similar except for previous CABG (p = 0.02) and reference vessel diameter (p = 0.04). During hospitalisation, all cause death was more frequently observed in the PES group (p = 0.004). In-hospital MACE was not significantly different (p = 0.8). The incidence of 1-year MACE in the PES group was lower than that in the SES group (14.7%, 28.3%, p = 0.04), mainly due to the reduction of TLR (11.6%, 25.0%, p = 0.03). Rates of stent thrombosis (0%, 2.7%, p = 0.1), MI (1.1%, 3.8%, p = 0.2), and cardiac death (3.2%, 4.4%, p = 0.6) were not significantly different. CONCLUSIONS PES appears to be more efficient in reducing angiographic and clinical restenosis in dialysis patients compared with SES.

Comparison of 5-year outcomes in patients with and without unprotected left main coronary artery disease after treatment with sirolimus-eluting stents: insights from the j-Cypher registry.

OBJECTIVES This study assessed 5-year outcomes after implantation of sirolimus-eluting stents (SES) for unprotected left main coronary artery (ULMCA) disease in comparison with that for non-left main disease. BACKGROUND More information on long-term outcomes after ULMCA stenting is needed. METHODS The j-Cypher is a multicenter prospective registry of consecutive patients undergoing SES implantation in Japan. RESULTS Among 12,812 patients enrolled in the j-Cypher registry, the unadjusted mortality rate at 5 years was significantly higher in patients with ULMCA stenting than in patients without ULMCA stenting (22.8% vs. 14.1%; p < 0.0001); however, the risk for death with ULMCA stenting was no longer significant after adjusting for confounders (hazard ratio: 1.18, 95% confidence interval: 0.95 to 1.46; p = 0.14). In the lesion-level comparison, the nonbifurcation ULMCA lesions treated exclusively with SES had a significantly lower rate of target lesion revascularization (TLR) than those in non-ULMCA nonbifurcation lesions (2.4% vs. 12.7%; p = 0.04). Among bifurcation lesions, those treated with a provisional 2-stent approach had similar rates of TLR (12.1% vs. 11.4%; p = 0.79) between the ULMCA and non-ULMCA groups. Lesions treated with an elective 2-stent approach had higher TLR rates in the ULMCA group as compared with the non-ULMCA group (33.5% vs. 19.7%; p = 0.002). CONCLUSIONS The safety of ULMCA stenting relative to non-LMCA stenting was maintained through 5 years follow-up. In terms of efficacy, SES implantation in nonbifurcation ULMCA lesions was associated with an extremely low cumulative incidence of TLR, whereas the elective 2-stent approach for ULMCA bifurcation lesions was associated with a markedly higher cumulative incidence of TLR as compared with that for non-ULMCA bifurcation lesions.