Search

Objective The developer and sponsor of new combination products in US needs to forecast which classification and designation to the regulatory scheme of drug, biological product, or device would be required for the new products by the Food and Drug Administration (FDA). To improve the predictability and acceptability of the designation of new combination products for innovators, developers, and sponsors, and to encourage the development and early access of new combination products, we proposed new visualization models of the designation pathway and group categorization. Method We searched the website of the FDA on 15 November, 2020 to identify the regulatory scheme of the FDA’s 129 capsular decision cases of device–drug and device–biologics combination products and other publicly available cases the FDA designated to the drug/biologic or device regulatory scheme. Results By introducing a new definition for primary intended use (PIU) by developers and sponsors extracted from the classification factors of primary mode of action (PMOA), we developed new visualization models of the designation pathway and two-dimensional group categorization. And applying these models to the cases the FDA designated, we proposed a new group categorization of combination products while focusing on the device component function. Conclusions The new visualization models with PIU and PMOA and the new group categorization focusing on the device component function proposed in this study may increase predictability and acceptability of the classification of newly developed combination products into the regulatory scheme of drug, biological product, and device, for innovators, developers, and sponsors.

The JMA HSPH Taro Takemi Memorial International Symposium "Community Health Systems and Innovations: Building the Foundation for Universal Health Coverage" was held on February 17, 2018. The symposium was co-organized by the Japan Medical Association, Harvard T.H. Chan School of Public Health, the Tokyo Medical Association, and Takemi Memorial Trust for Research of Seizon and Life Sciences. The aim of this symposium was to offer a forum for medical associations, academia, health policy makers, and other stakeholders to discuss the way forward to expand universal health coverage (UHC) in a rapidly changing environment surrounding health and human well-being, a concept that can be traced to the philosophy of late Dr. Taro Takemi. The three keynote lectures provided wide social and ethical as well as historic and global perspectives on health. They were followed by three sessions that each addressed one central theme: lessons learnt from the Japanese experience of responding to unprecedented demographic challenges (Session 1), how innovations can link national and global health policies with people's well-being (Session 2), and how these efforts can be sustained (Session 3). Finally, a concluding lecture attempted to apply the philosophy of Dr. Taro Takemi, known as Seizon and Life Sciences, to UHC based on the discussions of the symposium. In our opinion, Dr. Taro Takemi's foresight and philosophy should be revisited when we attempt to address present and future challenges; therefore, this symposium will be remembered for opening new ways of thinking.

In patients with acute decompensated heart failure (HF), the association of gender and left ventricular ejection fraction (LVEF) with clinical outcomes has not been fully investigated. The aim of this study was to evaluate gender differences in LVEF and adverse outcomes across the full spectrum of LVEF in patients hospitalized for acute decompensated HF. Of the 4,842 patients enrolled in the Acute Decompensated Heart Failure Syndromes registry, 4,231 patients (2,461 men and 1,770 women) discharged alive after hospitalization for acute decompensated HF were investigated to assess the association of gender and LVEF with the primary end point (all-cause death and readmission for HF). Men or women were divided into 5 groups based on the LVEF at hospital discharge (30%, 30% to40%, 40% to50%, 50% to60%, and ≥60%). The median follow-up period after discharge was 523 (384 to 791) days. The frequency of the primary end point did not differ between men and women (36.5% vs 38.1%, p = 0.291). After adjustment for multiple comorbidities, male patients with an LVEF30%, 30% to40%, 40% to50%, or 50% to60% had a significantly higher risk of the primary end point than those with an LVEF ≥60%, indicating an inverse association between LVEF and adverse outcomes. In contrast, the adjusted risk of the primary end point was similar for all 5 LVEF groups of female patients. In conclusions, the association between LVEF and outcomes differs markedly between men and women hospitalized for acute decompensated HF, although event-free survival is similar for both genders.

Background Although an “obesity paradox” exists in patients after myocardial infarction, the association between obesity and the risk of sudden cardiac death (SCD) is limited. The aim of this study was to determine whether obesity is associated with an increased risk of SCD in Japanese survivors of acute myocardial infarction. Methods and Results Pooled data from 2 cohort studies in Japan, JCAD (Japanese Coronary Artery Disease) study and the Heart Institute of Japan Acute Myocardial Infarction‐II (HIJAMI‐II) registry, comprising of 6216 patients (mean age 65±11 years, 75.2% male) with acute myocardial infarction who were discharged alive, were studied. The patients were categorized into the following body mass index (BMI) groups at baseline according to the World Health Organization classification for Asian populations: BMI 2 (n=335), 18.5 to 23 kg/m 2 (n=2371), 23 to 27.5 kg/m 2 (n=2823), and ≥27.5 kg/m 2 (n=687). The main outcomes were all‐cause mortality and SCD. During an average follow‐up period of 3.6±1.4 years, all‐cause mortality was 10.1%, and SCD was 1.2%. Patients with BMI 2 had the highest rate of all‐cause mortality (adjusted hazard ratio, 1.61; 95% confidence interval, 1.20–2.16), but high BMI (≥27.5 kg/m 2 ) was not associated with mortality compared with patients in the group with BMI ≥18.5 and 2 . However, the long‐term risk of SCD was increased in the group with BMI ≥27.5 kg/m 2 (adjusted hazard ratio, 2.97; 95% confidence interval, 1.24–7.15). Multivariate analysis revealed that BMI ≥27.5 kg/m 2 was associated with an increased risk of SCD (hazard ratio, 2.78; 95% confidence interval, 1.35–5.74). Conclusions Obesity (BMI ≥27.5 kg/m 2 ) was associated with the risk of SCD in Japanese patients after myocardial infarction, although an obesity paradox was found for all‐cause mortality.

Rationale & Objective Epidemiologic and clinical studies have suggested that urate-lowering therapy may slow the progression of chronic kidney disease (CKD). However, definitive evidence is lacking. Study Design Randomized, double-blind, placebo-controlled trial. Setting & Participants 467 patients with stage 3 CKD and asymptomatic hyperuricemia at 55 medical institutions in Japan. Intervention Participants were randomly assigned in a 1:1 ratio to receive febuxostat or placebo for 108 weeks. Outcomes The primary end point was the slope (in mL/min/1.73 m2 per year) of estimated glomerular filtration rate (eGFR). Secondary end points included changes in eGFRs and serum uric acid levels at 24, 48, 72, and 108 weeks of follow-up and the event of doubling of serum creatinine level or initiation of dialysis therapy. Results Of 443 patients who were randomly assigned, 219 and 222 assigned to febuxostat and placebo, respectively, were included in the analysis. There was no significant difference in mean eGFR slope between the febuxostat (0.23 ± 5.26 mL/min/1.73 m2 per year) and placebo (−0.47 ± 4.48 mL/min/1.73 m2 per year) groups (difference, 0.70; 95% CI, −0.21 to 1.62; P = 0.1). Subgroup analysis demonstrated a significant benefit from febuxostat in patients without proteinuria (P = 0.005) and for whom serum creatinine concentration was lower than the median (P = 0.009). The incidence of gouty arthritis was significantly lower (P = 0.007) in the febuxostat group (0.91%) than in the placebo group (5.86%). Adverse events specific to febuxostat were not observed. Limitations GFR was estimated rather than measured, and patients with stages 4 and 5 CKD were excluded. Conclusions Compared to placebo, febuxostat did not mitigate the decline in kidney function among patients with stage 3 CKD and asymptomatic hyperuricemia. Funding Funded by Teijin Pharma Limited. Trial Registration Registered at the UMIN (University Hospital Medical Information Network) Clinical Trials Registry with study number UMIN000008343.

Human cells and tissue products belong to a relatively new class of medical products. Therefore, limited information is available on the classification and premarket evaluation of human cells and tissue products in the United States (US), the European Union (EU), and Japan. In this study, the definition, legislation, and approval system of these products were surveyed. A total of nine autologous human cells and tissue products approved until October 2013 were collected. The definitions of human cells and tissue products were compatible among the US, the EU and Japan. The products were classified as human cells, tissue, and cellular and tissue-based products (HCT/Ps) in the US, advanced therapy medicinal products (ATMPs) in the EU, and cell/tissue-engineered products in Japan. These products were categorized as biologics and medical device in the US and Japan, and drug in the EU. The issuance of new guidance induced regulatory impact for manufacturer, especially in the US. These products are subjected to the accelerated approval of biological product, the humanitarian device exemption approval, the premarket application approval, the biologics license application approval, and new drug application approval with specific targeting of postapproval registry or surveillance. Of nine autologous human cells and tissue products, four products had been evaluated using clinical experiences or open clinical trials with small subjects, although the rests of products had been evaluated using comparative clinical trials with control treatment. Our survey suggests that autologous human cells and tissue products would need postmarket-oriented evaluation rather than premarket-oriented evaluation for doctors and patients.

In patients with acute decompensated heart failure (HF), the influence of gender on anemia, left ventricular ejection fraction (EF), and outcomes is unclear. We evaluated the association of anemia and left ventricular EF with survival in men or women hospitalized for acute decompensated HF. Of the 4,842 patients enrolled in the Acute Decompensated Heart Failure Syndromes registry, 4,215 patients (2,450 men and 1,765 women) discharged alive after hospitalization for acute decompensated HF were enrolled to evaluate the association of gender, anemia (hemoglobin

The current definition of biomaterials differs vastly from it of just a decade ago. According to advancing technologies, it encompasses unpredictable materials such as engineered human cells and tissue. These biomaterials also have to be approved to use in health care business by regulatory authority, which are defined as drug, medical device, or biologics in the regulation. This Leading Opinion Paper addresses the regulatory issues of engineered human cells and tissue products using allogeneic cells that should have a great possibility to develop therapeutics for life-threating diseases or orphan diseases. Six allogeneic human cells and tissue products derived from neonatal or infant fibroblasts and/or keratinocytes were approved as medical devices or biologics in the United States as well as a hematopoietic cell product. For five of the seven products, well-controlled comparative clinical trials were conducted as pre-approval evaluation followed by post-approval evaluation. Although these products avoid a sterilization process usually used for medical devices, no serious malfunction that would lead to class 1 recall was reported. This article would provide insight for development of the engineered human cells and tissue.

The Japanese medical device industry's stagnation over the years can be attributed to the uncertainty related to device development. The purpose of this study is to identify the major factors that impact development. We studied the ventricular assist device EVAHEART through interviews with the persons involved and created a development model using system dynamics. There are at least six stages in the device development process, including interactions with academia and the government. Through a simulation and comparison to Novacor, it was determined that the satisfaction of academia leads to government action in the subsequent measures. Our trial simulation of EVAHEART suggests that it has the potential to clarify unclear relationships in the development of devices.

Risk stratification of lethal arrhythmias is important for the management of ischemic heart disease. Recently, we developed a novel 187-channel signal-averaged vector-projected high-resolution electrocardiograph (187-ch SAVP-ECG) with a Mason–Likar lead system with 10 electrodes. The purpose of this study was to examine the feasibility of a noninvasive evaluation of the spatial distribution of high-frequency late potentials (HFLPs) in patients with myocardial infarction (MI) by using the 187-ch SAVP-ECG. Sixty-four MI patients (7 women and 57 men), between the age of 39 and 84 years (mean 67.7±9.7 years), with positive ventricular late potentials defined by an X, Y, Z-lead ECG were studied. The integrated ventricular 187-ch SAVP-ECG could identify the area of HFLPs that was projected virtually by mathematically calculated 187 electrograms on the body surface in all patients, and differentiate the locations of MI. The 187-ch SAVP-ECG can be a practical and noninvasive examination tool for identifying the location of infarction areas and possible arrhythmogenic substrates with slow conduction properties in patients with MI.

In the setting of acute decompensated heart failure (HF), relations among the etiology of HF, left ventricular systolic function, and outcomes are unclear. The aim of this study was to investigate the association of HF etiology with outcomes in patients with acute decompensated HF with a preserved or reduced ejection fraction (EF). Of the 4,842 patients enrolled in the Acute Decompensated Heart Failure Syndromes registry, 3,810 patients (1,601 with a preserved EF and 2,209 with a reduced EF) who had a hypertensive, ischemic, valvular, or idiopathic dilated etiology of HF were investigated to assess the association of etiology with a composite end point (all-cause mortality and readmission for HF). The median follow-up period after admission was 502 (381 to 759) days. The composite end point was reached in 44.6% and 41.7% of the preserved and reduced EF groups, respectively. After adjustment for multiple co-morbidities, the risk of the composite end point was comparable among hypertensive, ischemic, and valvular etiologies in the preserved EF group. In contrast, in the reduced EF group, ischemic etiology was associated with a tendency toward greater risk of the composite end point than hypertensive etiology (but this difference was not significant), whereas valvular etiology was associated with a significantly greater risk of the composite end point relative to hypertensive or idiopathic dilated etiology. In conclusion, this study demonstrated that taking the etiology of HF into account may help to reduce the heterogeneity of acute decompensated HF and assist in identifying patients at risk of adverse outcomes, especially among patients with reduced EF.

Noninvasive measurement of hemodynamic parameter was undertaken in 240 patients with untreated primary hypertension using impedance cardiography (ICG) in outpatient clinics. High output was defined as a cardiac index (CI) >3.6 L/minute/m(2) and high resistance was defined as the total peripheral resistance index (TPRI) >2700 dyne·s·m(2)/cm(5). Of all patients, 67% had high-resistance hypertension (high TPRI with normal or low CI), and 16% had high-output hypertension (high CI with normal TPRI). Treatment with β-blockers for high-output hypertension and with calcium channel blockers for high-resistance hypertension reduced blood pressure equally, and restored normal hemodynamic balance, as reported in studies using invasive monitoring methods. These findings suggest that it is appropriate to use noninvasive ICG measurements to guide antihypertensive therapy. Multivariate analysis showed that female gender, tachycardia, and low body mass index (BMI) were associated with high-output hypertension, but age was not. Heterogeneity of hemodynamic parameters is thought to be one of the reasons why the efficacies of antihypertensive agents differ between patients. It may be feasible to predict which antihypertensive agent would be the most effective for a particular patient based on hemodynamic measurements or combination of gender, heart rate, and BMI.

Agaricus blazei (A. blazei) Murrill mycelia-dikaryon has attracted the attention of scientists and clinicians worldwide owing to its potential for the treatment of cancer. However, little is known about its effect on other pathologies. This study sought to extend the potential medical usefulness of A. blazei for preventing vascular damage and to unravel its mechanism of action. The A. blazei extract showed estrogen-like activity in both gene expression profiling and a luciferase assay. Indeed, the extract inhibited oxidized low-density lipoprotein-stimulated activation of Erk1/2, Akt and p38 in HUVECs and macrophage-derived TIB-67 cells. Moreover, the extract enhanced transcription of the glutathione peroxidase 3 (GPX3), α-synuclein (SNCA) and endothelial nitrogen-oxide synthase (eNOS) genes. Furthermore, atherosclerotic lesions in rabbits were reduced by intake of A. blazei powder. Therefore, A. blazei may be useful for preventing atherosclerosis via dual roles in cell signaling, suppression of macrophage development and the recovery of endothelial cells from vascular damage.

Background: For stable patients suspected of having coronary artery disease (CAD), myocardial perfusion imaging (MPI) or computed tomographic angiography (CT) is used for initial evaluation, while coronary angiography (CAG) is used for confirming the diagnosis. The choice of the initial diagnostic test might influence the treatment strategy. Methods and Results: Patients scheduled for MPI, CT, or CAG as the initial diagnostic test were enrolled. The primary and secondary end-points were a major adverse cardiac event (MACE) and revascularization, respectively. Of the 2,878 patients enrolled, 2,825 underwent initial diagnostic tests, and 2,780 were followed up for 1.42±0.49 years. After adjustment for CAD severity, Cox proportional hazard regression analysis showed that the risk of MACE in the MPI and CT groups were similar and significantly less than that in the CAG group (hazard ratio, 0.82 vs. 2.19; 95% confidence interval [CI], 0.43–1.58 vs. 1.40–3.44). Furthermore, the rate of revascularization in the MPI group was less than that of the CT (odds ratio, 1.62; 95% CI, 1.20–2.18) and CAG (odds ratio, 5.36; 95% CI, 4.07–7.05) groups. Conclusions: These data indicate that for stable patients with suspected CAD, the use of MPI or CT as the initial diagnostic test was associated with better prognosis than the use of CAG, and that initial evaluation with MPI was associated with a lower requirement of coronary intervention. (Circ J 2012; 76: 2832–2839)

Background: Recent studies have suggested that esmolol is the first choice for rate control in patients with postoperative atrial fibrillation (AF) after coronary artery bypass surgery, but side-effects of esmolol such as hypotension are problematic. To overcome this problem, landiolol, an ultra-short-acting β1-blocker with a less negative inotropic effect than esmolol, has been developed. The aim of the present study was to investigate whether landiolol was effective for both rate control and conversion to normal sinus rhythm (NSR). Methods and Results: A prospective, randomized, open-label comparison between i.v. landiolol and diltiazem in patients with postoperative AF was undertaken between January 2008 and June 2009 in Japan. Of 335 patients included in the analysis, 71 patients went into AF. Among these 71 patients, conversion to NSR within 8h after onset of AF occurred in 19 of 35 patients (54.3%) in the landiolol group vs. 11 of 36 patients (30.6%) in the diltiazem group (P

It remains unclear whether end-stage hypertrophic cardiomyopathy (HCM) is associated with as high a rate of sudden death as occurs among HCM patients with preserved left ventricular (LV) systolic function. The purpose of this study was to evaluate the incidence of sudden death among patients with end-stage HCM and to identify high-risk end-stage patients.A total of 490 consecutive patients with HCM, who were diagnosed and followed-up at our hospital, were analyzed retrospectively. End-stage HCM was defined by an LV ejection fraction50% on echocardiography during follow-up. Among the 490 HCM patients, 43 patients (8.8%) were diagnosed as having end-stage HCM during a mean follow-up period of 12 ± 7 years after the initial diagnosis. During a mean follow-up period of 5 ± 3 years after progression to end-stage HCM, sudden death occurred in 21 of 43 patients (47%). Cox proportional hazards analysis identified syncope as an independent predictor of sudden death (hazard ratio = 6.15; 95% confidence interval, 2.40-15.75; P.001).This study demonstrated that patients with end-stage HCM have a high incidence of sudden death. Therefore, it is suggested that an aggressive therapeutic strategy to counter sudden death should be considered for patients with end-stage HCM.

Background: Several studies have suggested that depression poses a risk in cardiovascular patients. The aim of the present study was to evaluate the prevalence of depression and its effect on cardiovascular events and mortality in Japanese inpatients with cardiovascular disease. Methods and Results: A total of 505 patients hospitalized with cardiovascular disease (28% female; mean age, 61±14 years; 31% ischemic heart disease; 47% New York Heart Association [NYHA] class II-IV; 25% implantation of pacing devices) were enrolled in the present prospective observational study. The Zung Self-Rating Depression Scale (SDS) was used to screen for depression. The primary outcome was the time to death or cardiovascular event, and the secondary outcome was death. In total, 109 patients (22%) were diagnosed with depression (Zung SDS index score ≥60). NYHA class III/IV, defibrillator implantation, and being unmarried were independently associated with depression. During an average follow-up period of 38±15 months, 92 patients (18%) reached the primary outcome. There was a higher incidence of the primary outcome in patients with depression than in those who were not depressed (P

The aim of this phase I, dose-escalating study was to evaluate the pharmacokinetics, electrocardiographic effect and safety of amiodarone after a single intravenous administration in Japanese subjects. Thirty-two healthy Japanese male volunteers (20-32 years) were randomized to three single-dose groups (1.25, 2.5 and 5.0 mg/kg). In each group, six (1.25 mg/kg) or ten (2.5 and 5.0 mg/kg) subjects received a single 15-min infusion of intravenous amiodarone, and two subjects received glucose solution as control. The pharmacokinetic profile, blood pressure and electrocardiographic analyses were obtained on a timely basis after up to 77 days. The maximum plasma concentration (C (max)) and area under the concentration-time curve (AUC(0-96)) for amiodarone 1.25, 2.5 and 5.0 mg/kg displayed dose-dependent characteristics: mean C (max) was 2,920 ± 610, 7,140 ± 1,480 and 13,660 ± 3,410 ng/ml, respectively; the mean AUC(0-96) was 3,600 ± 700, 8,100 ± 1,600 and 16,600 ± 4,300 ng h/ml, respectively. A long serum half-life (14 days) was observed for amiodarone and desethylamiodarone. PR intervals were prolonged at 15 min (0.16 ± 0.0.1 vs. 0.15 ± 0.01 s, p = 0.03) and 18 min (0.17 ± 0.01 vs. 0.15 ± 0.01 s, p = 0.03) with the 5.0 mg/kg dose compared with baseline. No other significant changes in electrocardiographic parameters, pulse rate or blood pressure were observed. A needle-pain-induced vasovagal effect appeared in a volunteer, and three volunteers experienced pain at the drug infusion site. After a single infusion of amiodarone at doses of 1.25-5.0 mg/kg, serum concentrations increased in a dose-dependent manner. A single intravenous amiodarone dose barely affected the electrocardiographic parameters and was well tolerated.

Background: It is unclear whether depression persists in patients with implantable cardioverter defibrillators (ICDs). We evaluated the prevalence and persistence of depression in ICD patients over a 2-year period. Methods: The study included 90 consecutively hospitalized patients. Patients underlying heart disease was 24% coronary artery disease, 29% idiopathic dilated cardiomyopathy, 24% hypertrophic cardiomyopathy, 13% idiopathic VF/long QT syndrome and miscellaneous conditions 11%. A secondary indication for ICD implantation was present in 20 patients. All patients completed the Zung Self-Rating Depression Scale (SDS) at study baseline and at the their routine follow-up visit 2 years after the baseline questionnaire. Delivery of ICD therapies was tracked throughout the 2 years. Results: Depression, indicated by a Zung SDS index score exceeding 60, was present in 29 (32%) of patients at study baseline. Depression was present in 11/51 (21%) patients scheduled to undergo ICD implantation, 2/2 (100%) patients whose device was upgraded to a CRT-D, 3/14 (21%) patients who had undergone pulse generator replacement, 7/14 (50%) patients who experienced electrical storm and 6/9 (66%) patients hospitalized with acute decompensated heart failure. NYHA functional class III was significantly associated with depression at baseline (HR 6.7, 95% CI 1.68–27.2, p = 0.0007). No differences were noted for female gender, demographics, β-blocker use, or LVEF ≤35% (p = ns). Depression was present in 25 (28%) of patients at 2 years follow-up, persisting in 21 (72%) of patients whose Zung SDS scores were elevated at baseline. The median time from ICD shock therapy to completion of the 2 year questionnaire was 9 months (range, 1–22). Patients who were depressed (9/25, 36%) experienced more shocks than non-depressed patients (6/65, 9%) after 2 years (p = 0.002). Conclusions: Depression is not uncommon among patients who meet criteria for ICD implantation and persists over time particularly when functional status is impaired. Depression is associated with a higher incidence shock therapy. (PACE 2010; 33:1455–1461)

Combination therapy with calcium channel blockers and angiotensin II receptor blockers is recommended as one of the effective therapies for hypertension. However, it remains unclear whether this combination reduces major adverse cardiovascular events (MACEs) in patients with hypertension with coronary artery disease (CAD). The purpose of the present study was to examine the effects of amlodipine plus candesartan on MACEs in patients with hypertension with CAD. The study population was drawn from The Heart Institute of Japan Candesartan Randomized Trial for Evaluation in Coronary Artery Disease (HIJ-CREATE), which was a multicenter, prospective, randomized controlled trial including 2,049 patients with hypertension with angiographically documented CAD. Subgroup analysis was performed in patients treated with amlodipine at baseline (n = 388). The median follow-up period was 4.3 years. Treatment using amlodipine plus candesartan reduced the risk for MACEs by 39% (p = 0.015) compared to that using amlodipine without angiotensin II receptor blockers. Among the individual events constituting MACEs, the incidence of unstable angina pectoris requiring hospitalization was significantly lower, by 52% (p = 0.007). In conclusion, amlodipine plus candesartan demonstrated a more favorable effect on reducing cardiovascular events in patients with hypertension with CAD compared to amlodipine-based therapy without candesartan.

The aim of this study was to assess the effects of angiotensin receptor blocker (ARB)-based therapy on cardiovascular events in high-risk hypertensive patients with coronary artery disease (CAD) and impaired renal function in post hoc analysis of HIJ-CREATE (Heart Institute of Japan Candesartan Randomized Trial for Evaluation in Coronary Artery Disease). Patients (n=2049) were randomly assigned to candesartan-based or non-ARB treatment arms; 1022 patients (age 70 ± 6 years, 28% female) with impaired renal function, defined as creatinine clearance

Previous studies indicated that women were less likely to experience ventricular arrhythmia recurrence than men among patients with coronary artery disease and implantable cardioverter defibrillator (ICD). However, it is not clear whether the risk for ventricular tachyarrhythmia is gender-dependent in patients with nonischemic dilated cardiomyopathy. This study included 173 consecutive nonischemic dilated cardiomyopathy patients with a left ventricular ejection fraction of45% (122 men and 51 women), who received ICD therapy between 1990 and 2008. The average follow-up period was 33 +/- 28 months. There was no significant difference in event-free rates of appropriate ICD therapy between genders for all patients (P = 0.15) and by indication of ICD (primary prevention: P = 0.43, secondary prevention: P = 0.24). There was also no significant difference in event-free rates of electrical storm between genders (P = 0.17). In high-risk patients with nonischemic dilated cardiomyopathy who received ICD, there was no gender difference in the incidence of appropriate ICD therapy or electrical storm.

Objective To compare the efficacy and safety of nifekalant, a pure class III anti-arrhythmic drug, and lidocaine in patients with shock-resistant in-hospital ventricular fibrillation (VF) or ventricular tachycardia (VT). Patients and methods Between August 2005 and March 2008, we conducted a prospective, two-arm, cluster observational study, in which participating hospitals were pre-registered either to the nifekalant arm or the lidocaine arm. Patients were enrolled if they had in-hospital VF or VT resistant to at least two defibrillation shocks. Congenital or drug-induced long QT syndrome was excluded. The primary end-point was termination of VF or VT with/without additional shock. The secondary end-points were return of spontaneous circulation (ROSC), 1-month survival and survival to hospital discharge. We also assessed the frequency of adverse events, including asystole, pulseless electrical activity and torsade de pointes. Results In total, 55 patients were enrolled. After nifekalant, 22 of 27 patients showed termination of VF or VT, as compared with 15 of 28 patients treated with lidocaine with/without additional shock (odds ratio (OR): 3.8; 95% confidence interval (CI): 1.1–13.0; P = 0.03). Twenty-three of 27 patients given nifekalant showed ROSC, as compared with 15 of 28 patients given lidocaine (OR: 5.0; 95% CI: 1.4–18.2; P = 0.01). There was no difference in 1-month survival or survival to hospital discharge between the nifekalant and lidocaine arms. There was a higher incidence of asystole with lidocaine (7 of 28 patients) than with nifekalant (0 of 27 patients) ( P = 0.005). Torsade de pointes was not observed. Conclusion Nifekalant was more effective than lidocaine for termination of arrhythmia and for ROSC in patients with shock-resistant in-hospital VF or VT (umin-CTR No. UMIN 000001781).

In patients with acute decompensated heart failure (ADHF) and left ventricular systolic dysfunction (LVSD), the role of initial vasodilator therapy remains uncertain. The present study aimed to evaluate the acute efficacy of initial carperitide therapy and to predict its response in ADHF patients with LVSD.Twenty-four consecutive patients with ADHF and LVSD were enrolled. Inclusion criteria were a left ventricular ejection fraction40%, systolic blood pressure (BP)90 mm Hg, and pulmonary capillary wedge pressureor=18 mm Hg at baseline. Hemodynamic parameters were evaluated by right heart catheterization before and after carperitide infusion. Responders were defined as aor=30% reduction of pulmonary capillary wedge pressure (PCWP) or a decrease to16 mm Hg within 6 h after carperitide infusion.Seventeen (71%) of the 24 patients were responders for initial carperitide therapy. The responders had significantly higher systolic BP and cardiac index at baseline compared with nonresponders. The area under the curve (AUC) for systolic BP was 0.93 and a cut-off value of 120 mm Hg had a sensitivity of 94% and specificity of 86% for predicting the efficacy of carperitide. The AUC for the cardiac index was 0.88 and a cut-off value of 2.30 L/min/m(2) had a sensitivity of 65% and a specificity of 100% for predicting the response to carperitide.The initial use of carperitide therapy safely reduces PCWP in ADHF patients with LVSD and baseline systolic BP may be useful for predicting the response to initial carperitide therapy for ADHF with LVSD.

Objectives and background Recent evidence has revealed that aldosterone (ALDO) is produced in the vasculature, and acts directly in the cardiovascular system. This study was designed to examine the role of ALDO in the process of long-term renin–angiotensin system (RAS) induced vascular remodeling. Material and method Hypertensive transgenic mice that overproduce angiotensin II (AngII), i.e., Tsukuba-Hypertensive-Mice (THM), were given tap water or 1% salt water and treated with or without Spironolactone (SPRL: 20 mg/kg/day) for 4 weeks. We also employed A7r5 cells and investigated the effect of SPRL on the AngII mediated signal transduction in the vascular smooth muscle cells. Results Intimal hyperplasia, medial hypertrophy and degradation of medial elastic laminae were observed in the abdominal aorta, independent of blood pressure. Taking 1% salt water markedly enhanced these changes. In contrast, SPRL-treated THM showed almost complete disappearance of these intimal hyperplasia and medial hypertrophy. Osteopontin (OPN) was markedly up-regulated in the intima and media. However, it was inhibited by SPRL treatment in spite of high level of AngII. In A7r5 cells, AngII (10 −7 μM) induced OPN expression and pretreatment with MEK, PI3K, and EGFR inhibitor suppressed it. SPRL pretreatment also inhibited AngII-induced ERK and AKT phosphorylation, and resulted in the suppression of AngII-induced OPN expression. Conclusions ALDO blockade by SPRL restores the vascular remodeling caused by the long-term RAS enhancement even in the high level of AngII, independent of blood pressure. Blocking AngII alone may not be sufficient, and direct ALDO blockade is also important to prevent vascular disease.

Objective Although recent clinical trials have suggested that angiotensin II type 1 receptor blockers (ARBs) reduced cardiovascular events, the precise mechanisms involved are still unknown. Telmisartan, an ARB, has recently been identified as a ligand of peroxisome proliferator-activated receptor-gamma (PPARγ). On the other hand, since endothelial progenitor cells (EPCs) are thought to play a critical role in ischemic diseases, we investigated effects of telmisartan on proliferation of EPCs. Methods and results Human peripheral blood mononuclear cells were isolated from healthy volunteers, and cultured on fibronectin-coated dishes in the presence or absence of telmisartan. Four days after starting culture, adherent cells were collected, and equal numbers of cells were reseeded into methylcellulose medium with or without telmisartan. In the presence of telmisartan, numbers of colonies increased in a dose-dependent manner. DiI-AcLDL uptake and lectin and CD31, CD34 staining revealed that these colonies were EPCs. Increase in colony number by treatment with telmisartan was absolutely inhibited when cultured with a specific inhibitor of PPARγ. In addition, we observed that specific inhibitors of phosphoinositide-3 kinase (PI3K) abolished telmisartan-stimulated increase of monocytic EPC-like cells and telmisartan induced phosphorylation of Akt. Furthermore, mRNA expression of p21 was downregulated in a dose dependent manner, suggesting that growth inductive effects of telmisartan might be regulated by the PI3K/Akt and p21 signaling pathway. Conclusions These findings suggest that telmisartan might contribute to endothelial integrity and vasculogenesis in ischemic regions by increasing numbers of EPCs.

Aims To test whether angiotensin II receptor blockers (ARBs) therapy can reduce the incidence of cardiovascular events compared with non-ARB-based standard pharmacotherapy in coronary artery disease (CAD) patients with hypertension. Methods and results Angiographically documented CAD patients with hypertension were randomly assigned to receive either candesartan-based ( n = 1024) or non-ARB-based pharmacotherapy including angiotensin-converting enzyme-inhibitors ( n = 1025). The primary endpoint was the occurrence of a first major adverse cardiovascular event (MACE). There were 552 primary events during a median follow-up of 4.2 years: 264 (25.8%) in the candesartan group and 288 (28.1%) in the non-ARB group (hazard ratio, 0.89; 95% confidence interval, 0.76–1.06). No significant differences existed between groups in terms of cardiovascular death (2.7 vs. 2.4%, 1.14; 0.66–1.95), non-fatal myocardial infarction (2.8 vs. 2.5%, 1.12; 0.66–1.88), or heart failure (3.9 vs. 4.3%, 0.91; 0.59–1.40). New-onset diabetes was diagnosed significantly less frequently with candesartan than with non-ARBs (0.37; 0.16–0.89). Incidence of study drug discontinuation due to adverse events was lower with candesartan than with non-ARBs (5.7 vs. 12.2%, P < 0.001). Conclusion Although candesartan showed no significant differences in MACE compared with the non-ARB treatment group, the drug significantly reduced the incidence of new-onset diabetes and was better tolerated. This study is registered as International Standard Randomised Controlled Trial No. UMIN000000790.

The aims of the present study are to: (1) clarify the angiographic follow-up (AFU) rate after discharge; (2) elucidate the characteristics of those undergoing it; and (3) determine the impact of AFU on subsequent revascularization procedures among patients with acute myocardial infarction (AMI). Three thousand and twenty-one consecutive patients presenting within 48 h of AMI onset were enrolled from 17 centers in Japan between January 1999 and June 2001. To clarify the frequency of AFU and their characteristics, 2736 patients who survived at discharge were analyzed. Among 1160 patients matched by propensity score, the impact of AFU on subsequent revascularization was analyzed. Of 2736 patients, 1367 (50%) underwent AFU and constituted the lower-risk population. Of the 580 matched patient pairs, 120 (21%) in the clinical follow-up group and 198 (34%) in the AFU group underwent subsequent revascularization (hazard ratio 7.54; 95% confidence interval 5.74-9.91). Of the 198 patients in the AFU group, 157 (79%) underwent revascularization at the discretion of the responsible physician based on angiographic findings. Angiographic follow-up led to more subsequent revascularization. More evidence would be necessary to determine the effectiveness and the methods by which patients are selected.

We conducted a prospective multicenter case-control study to confirm the clinical efficacy and safety of Waon therapy on chronic heart failure (CHF).Patients (n=188) with CHF were treated with standard therapy for at least 1 week, and then were randomized to Waon therapy (n=112) or a control group (n=76). All patients continued conventional treatment for an additional 2 weeks. The Waon therapy group was treated daily with a far infrared-ray dry sauna at 60 degrees C for 15 min and then kept on bed rest with a blanket for 30 min for 2 weeks. Chest radiography, echocardiography, and plasma levels of brain natriuretic peptide (BNP) were measured before and 2 weeks after treatment.NYHA functional class significantly decreased after 2 weeks of treatment in both groups. Chest radiography also showed a significant decrease of the cardiothoracic ratio in both groups (Waon therapy: 57.2+/-8.0% to 55.2+/-8.0%, p0.0001; control: 57.0+/-7.7% to 56.0+/-7.1%, p0.05). Echocardiography demonstrated that left ventricular diastolic dimension (LVDd), left atrial dimension (LAD), and ejection fraction (EF) significantly improved in the Waon therapy group (LVDd: 60.6+/-7.6 to 59.1+/-8.4 mm, p0.0001; LAD: 45.4+/-9.3 mm to 44.1+/-9.4 mm, p0.05; EF: 31.6+/-10.4% to 34.6+/-10.6%, p0.0001), but not in the control group (LVDd: 58.4+/-10.3 mm to 57.9+/-10.4 mm; LAD: 46.3+/-9.7 mm to 46.2+/-10.1 mm; EF: 36.6+/-14.1% to 37.3+/-14.0%). The plasma concentration of BNP significantly decreased with Waon therapy, but not in the control group (Waon: 542+/-508 pg/ml to 394+/-410 pg/ml, p0.001; control: 440+/-377 pg/ml to 358+/-382 pg/ml).Waon therapy is safe, improves clinical symptoms and cardiac function, and decreases cardiac size in CHF patients. Waon therapy is an innovative and promising therapy for patients with CHF.

Risk stratification among patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) has been made by clinical scoring. Recently, multiple-detector computed tomography (MDCT) appeared to provide noninvasive coronary angiography (CAG). To clarify the prognostic significance of MDCT, we aimed to evaluate the clinical utility of MDCT in the early management and in predicting the long-term prognosis of NSTE-ACS with low to intermediate risk. Among 84 consecutive patients with NSTEACS, risk stratification using a TIMI risk score was done. A total of 48 patients were categorized as low to intermediate risk. Multiple-detector CT was performed in 30 patients using 16-slice MDCT. MDCT detected coronary stenoses in 18 patients. Compared to invasive CAG, MDCT successfully depicted the coronary stenosis (P < 0.005), with sensitivity of 100% and specificity of 86%. The incidence of in-hospital major adverse clinical events (death, subsequent myocardial infarction, revascularization) was significantly higher in patients with a positive MDCT than in those with a negative MDCT test (44% vs 0%, P < 0.005). Moreover, a Kaplan-Meier analysis showed a significant difference in the event — free survival between MDCT positive and negative groups (33% vs 100%, respectively, P < 0.0001) during the mean follow-up period of 9.9 ± 7.5 months. Sixteen-slice MDCT in conjunction with a TIMI risk score appeared to demonstrate prognostic significance in patients with NSTE-ACS.

BACKGROUND: Outcomes after percutaneous coronary intervention (PCI) for patients with acute myocardial infarction (AMI) complicated by renal insufficiency have not been well described. The aims of this study were to evaluate the association of estimated glomerular filtration rate (GFR) and risk of unsuccessful PCI for AMI, and to evaluate the prognostic importance of PCI success in patients with renal insufficiency. METHODS AND RESULTS: From the Heart Institute of Japan Acute Myocardial Infarction (HIJAMI) registry, 1,706 patients undergoing primary PCI were analyzed. The adjusted odds ratios for unsuccessful PCI of GFR 30-60 and

The purpose of this study was to verify the spatial distribution of myocardial repolarization heterogeneity using a newly developed 187-channel signal-averaged vector-projected ECG (187-ch SAVP-ECG). We constructed corrected recovery time (RTc) and Tpeak-end (corrected Tp-e) dispersion maps using a 187-ch SAVP-ECG based on vector-projection theory using a Mason-Likar lead system. We compared the spatial distribution and quantitative values of dispersion maps by 187-ch SAVP-ECG with those by 64-ch magnetocardiography (MCG) in 27 normal controls (control) and 16 patients (12 myocardial infarction (MI), and 4 dilated cardiomyopathy (DCM)). The wave pattern of the 187-ch SAVP-ECG in the representative cases was similar to those in 64-ch MCG. Spatial distribution increased RTc and corrected Tp-e dispersion maps defined by 187-ch SAVP-ECG were in agreement with those by 64-ch MCG. The value of RTc dispersion in MI was higher than that in control (41 +/- 21 ms in MI versus 30 +/- 12 ms in control, P0.05). The value of corrected Tp-e dispersion in DCM was higher than that in control (58 +/- 12 ms in DCM versus 30 +/- 13 ms in control, P0.001). There was a good correlation between RTc and corrected Tp-e dispersion values determined by 187-ch SAVP-ECG and 64-ch MCG modalities (y = 0.46x + 18, r = 0.62, P = 0.02 for RTc dispersion; y = 0.52x + 15, r = 0.63, P = 0.01 for corrected Tp-e dispersion). RTc and corrected Tp-e dispersion maps by 187-ch SAVP-ECG based on vector-projection theory can evaluate the spatial distribution of myocardial repolarization heterogeneity.

We report the treatment of four thyrotoxic patients. Two were cases of type I amiodarone-induced thyrotoxicosis (AIT) treated with methimazole. The third Graves' disease patient, who became hypothyroid 25 years after subtotal thyroidectomy, developed type II AIT. Furthermore, one case with heart failure and ventricular tachycardia, who developed an adverse reaction to antithyroid agents and was prescribed amiodarone, underwent total thyroidectomy. The clinical course was uneventful, and the patient is doing well. Since amiodarone contains a large amount of iodine, it is frequently difficult to make a differential diagnosis. Surgical treatment of Graves' disease patients is recommended when immediate control of hyperthyroidism and heart failure is required.

Background Because there is insufficient evidence to support primary percutaneous coronary intervention (PPCI) as the treatment of acute myocardial infarction (AMI), this study elucidated the efficacy of PPCI according to disease severity. Methods and Results Between January 1999 and June 2001, 3,021 AMI patients were registered at Tokyo Women's Medical University and 17 affiliated institutions. Of these, 1,994 patients with ST-elevation AMI were admitted within 12 h of onset. PPCI was performed in 1,143 and 294 were treated conservatively. The 1,437 patients were grouped according to Thrombolysis In Myocardial Infarction-risk score: PPCI was performed in 59.5% of the low-risk group, 61.8% of the moderate-risk group, and 56.2% of the high-risk group. Cardiac death was the primary outcome. In the low-risk group, no significant differences were observed between PPCI and conservative therapy for 30-day and long-term cardiac mortality rates. In the moderate-risk group, the 30-day cardiac mortality rate for PPCI was significantly lower; however, no significant intergroup differences were observed for long-term cardiac mortality. In the high-risk group, 30-day and long-term cardiac mortality for PPCI were significantly more favourable than for conservative therapy (p

Background Heart failure (HF) represents a major public health issue in an aging population. Although HF is a leading cause of morbidity and mortality in developed countries, the clinical features of HF in Japan remain unclear. Methods and Results This observational cohort study analyzed data from the Heart Institute of Japan - Department of Cardiology (HIJC)-HF Registry, which is based on a nationwide survey by the HIJC, Tokyo Women's Medical University and its affiliated hospitals. Of 3,578 consecutive patients (average age, 69.8 years; females 40.7%) hospitalized for HF between January 2001 and December 2002, 95.0% were followed up until the end of 2005 (median, 2.8 years). The 1- and 3-year mortality rates were 11.3% and 29.2%, respectively. Multivariate analysis revealed that advanced age (hazard ratio 1.71 [95% confidence interval 1.38-2.12]; p

The aim of this study was to investigate whether cilnidipine, an N- and L-type calcium channel blocker, and nisoldipine, an L-type calcium channel blocker, have different effects on sympathetic activity, using an identical group of healthy male subjects. Eight healthy men (22-28 years) were given 10 mg of cilnidipine or 10 mg of nisoldipine in a randomized crossover design. In each trial, in subjects without medication on day 1 (control) and with medication on day 2, we measured heart rate (HR), low frequency (LF)/high frequency (HF) of HR variability, and plasma noradrenaline (NA) in a resting supine position and during head-up tilt, and palmar sweating during a mental arithmetic test, before and at 1, 2, 4, 6, and 8 h after administration. Time-plasma concentration profiles of the two drugs were similar. Measurements in controls on the two days showed no significant difference in any of these parameters. Nisoldipine, but not cilnidipine, slightly increased HR and LF/HF at rest. Head-up tilt increased HR, LF/HF, and plasma NA. As evaluated with repeated-measures analysis of variance, head-up tilt induced a significant increase in LF/HF, but not HR or plasma NA, and the effect of cilnidipine was significantly less than that of nisoldipine (P = 0.017). Postural hypotension was not observed. There was no difference in mental arithmetic-induced sweating between the two drugs. Cilnidipine, but not nisoldipine, might have a weak inhibitory effect on reflex sympathetic activity.

It has been reported that (123)I-metaiodobenzylguanidine (MIBG) scintigraphy can predict the poor prognosis in patients with dilated cardiomyopathy (DCM). However, the prognostic significance of MIBG is still unknown in patients with other heart diseases. In this study, we compared the prognosis and MIBG findings in various heart diseases.Consecutive 565 patients undergoing MIBG scintigraphy were enrolled (392 men, 52 +/- 16 years). Indications were that 127 had ischemic heart disease (IHD), 120 DCM, 101 hypertrophic cardiomyopathy (HCM), 21 hypertensive heart disease (HHD), 58 volume-load valvular disease (VVD), 38 pressure-load valvular disease (PVD), and 101 ventricular tachycardia or fibrillation (VTF). Heart-to-mediastinum ratio (H/M) and washout rate (WR) of MIBG were evaluated. Cardiac events were defined as sudden cardiac death, heart failure, and acute ischemic event (follow-up, 22.7 +/- 17.0 months).A total of 106 cardiac events including 40 cardiac deaths occurred. Cox hazard model analysis showed that in the IHD, HCM, and DCM groups, H/M and WR were associated with cardiac death, but not in the HHD, PVD, VVD, or VTF groups. Only death and congestive heart failure (CHF) episodes were related to H/M and WR. On the other hand, fatal arrhythmia, myocardial infarction, or angina pectoris were not related to H/M and WR. The data indicated that WR or H/M may predict death and CHF but does not predict fatal arrhythmia or acute ischemic event.MIBG WR and H/M were associated with heart failure, sudden death, and cardiac death events, and were useful to predict the prognosis in DCM, HCM, and IHD. In contrast, fatal arrhythmia events were not associated with MIBG indices, and thus it does not appear to be useful in predicting cardiac events in patients with VTF.

Inflammatory and immunological mechanisms are implicated in the development of idiopathic dilated cardiomyopathy (DCM). Since activated T lymphocytes express surface HLA-DR antigens, an increased level of these cells in the circulation could indicated an ongoing immune response. While the role of activated T lymphocytes in experimental myocarditis has been elucidated, the contribution of T lymphocyte activation in clinical DCM remains unclear. We therefore examined the role of T-cell activation in peripheral blood samples obtained from 10 patients with DCM (mean age, 49 +/- 12 years) and from 10 age-matched healthy controls. Citrated whole blood was mixed with fluorescein isothiocyanate- or phycoerythrin-conjugated specific monoclonal antibodies and analyzed using a fluorescence-activated cell sorter (FACS). The ratio (%) of histocompatibility leukocyte antigen (HLA)-DR positive cells in the FACS gated lymphocyte population was significantly higher in DCM patients than in controls (7.9% +/- 5.3% vs 2.0% +/- 0.9%; P < 0.01). The expression of CD40L on T cells determined as mean fluorescence intensity (MFI) was also significantly higher in DCM patients than in controls (3.6 +/- 2.1 vs 1.8 +/- 0.4 MFI; P < 0.05). Furthermore, the ratios of T cells expressing HLA-DR and serum brain natriuretic peptide (BNP) levels closely correlated (P = 0.0008). We showed that HLA-DR on peripheral T cells significantly correlated with serum BNP levels and that high CD40L expression on T cells was concomitant with increased BNP levels (P < 0.05). Therefore the magnitude of T-cell expression, such as increased expression of HLA-DR and CD40L, contributes to myocardial dysfunction in DCM.

Junctophilin subtypes, designated as JPH1 approximately 4, are protein components of junctional complexes and play essential roles in cellular Ca2+ signaling in excitable cells. Knockout mice lacking the cardiac-type Jph2 die of embryonic cardiac arrest, and the mutant cardiac myocytes exhibit impaired formation of peripheral couplings and arrhythmic Ca2+ signaling caused by functional uncoupling between dihydropyridine and ryanodine receptor channels. Based on these observations, we hypothesized that mutations of JPH2 could cause human genetic cardiac diseases. Among 195 Japanese patients (148 index cases and 47 affected family members) with hypertrophic cardiomyopathy (HCM), two heterozygous nonsynonymous nucleotide transitions, G505S and R436C, were newly found in JPH2. When Fisher's exact test was used to compare index cases with HCM to unrelated Japanese healthy controls in the frequencies of mutant alleles, only the G505S mutation showed statistical significance (4/296 HCM patients and 0/472 control individuals, P=0.022). This result was still significant after Bonferroni's correction for multiple comparisons (P=0.044). To the best of our knowledge, this is the first report on JPH2 mutation associated with HCM.

The purpose of this study was to evaluate delayed enhancement (DE) of the aortic wall of atherosclerotic aneurysms using computed tomography and to evaluate the relationships between DE and wall thickness of abdominal aortic aneurysm (AAA), diameter of AAA, serum levels of C-reactive protein (CRP) which indicate inflammation status, and pathological findings. Computed tomographic images of atherosclerotic AAA in 110 patients were studied between July 2001 and March 2003. Computed tomography (CT) scanning included unenhanced, enhanced early, and enhanced delayed phases. Pathological findings were obtained from 19 of the 110 patients. We determined DE of the AAA wall and assessed the association between DE and AAA wall thickness, AAA diameter, serum levels of CRP, and pathological findings. Delayed enhancement on CT was demonstrated in 66 of 110 patients with atherosclerotic AAA (60.0%). Patients with DE demonstrated significantly larger AAA diameter (4.8 +/- 0.9 versus 3.9 +/- 0.6 cm, P0.0001) and significantly higher levels of CRP (5.0 +/- 6.0 versus 2.3 +/- 2.9 mg/l, P = 0.033) than those patients without DE. Patients with DE also had significantly thicker and more severe atheroma and a tendency toward more prominent inflammation and vascularity in pathologic findings. There was no significant difference in wall thickness between AAA with and without DE (1.44 +/- 0.7 versus 1.24 +/- 0.22 mm, P = 0.352). Delayed enhancement on CT demonstrated in over half of atherosclerotic AAA may be associated with chronic inflammation by atherosclerosis.

Background Several reports have suggested a possible link between bronchial asthma and coronary spasm, but the possibility of a relationship in coronary spastic angina (CSA) has not been clarified. Methods and Results Airway responsiveness to methacholine and coronary spasticity to acetylcholine were examined in 42 patients with CSA and 36 patients with chest pain syndrome (CP). Furthermore, 18 control subjects were examined and their airway responsiveness compared with that of the CSA and CP patients. The incidence of airway hyperresponsiveness was significantly higher in the CSA group (74%) than in the CP (19%) and control (17%) groups (p

Background The basic mechanisms of thromboembolism in cyanotic congenital heart disease (CCHD) have not been well clarified. P-selectin on the platelets reflects platelet activation. Thrombomodulin is a critical cofactor for thrombin-mediated activation of protein C and reflects the anticoagulant activity of the endothelium. The present study was performed to evaluate whether platelet activation exists in patients with CCHD. Methods and results Platelet P-selectin as a marker of platelet activation, plasma thrombomodulin level and protein C activity as markers of anticoagulant activity of the endothelium and thrombin - antithrombin complex III (TAT) were examined in 35 patients with CCHD. Plasma thrombomodulin level (1.1+/-0.9 vs 2.2+/-0.3 FU/ml) and protein C activity (71.1+/-29.8 vs 117.8+/-24.8%) were significantly lower in patients with CCHD as compared with the control subjects. The levels of plasma TAT (255+/-811 vs 1.9+/-0.9 ng/ml) and P-selectin on platelets (6.3 +/-4.5 vs 3.3+/-0.3 mean fluorescence intensity) were significantly higher in the patients with CCHD than in the controls. Four of the CCHD patients who experienced thromboembolic events had elevated levels of platelet P-selectin (p=0.02) compared with CCHD patients without thromboembolic events. Conclusion Platelet activation exists in patients with CCHD and it may play an important role in the thromboembolic events in CCHD.