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In recent years, transthyretin amyloid cardiomyopathy (ATTR-CM) has received increasing attention; however, the epidemiology of ATTR-CM in Japan is not yet understood. In the Kumamoto Cardiac Amyloid Survey, we evaluated the current incidence, clinical characteristics, diagnostic approaches, and treatment strategies for ATTR-CM and compared tafamidis-prescription hospitals with regional hospitals.We conducted a retrospective multicenter observational cohort study. The registry included patients with ATTR-CM diagnosed in two tafamidis-prescription hospital institutes [Japanese Circulation Society (JCS)-certified facilities] and 15 regional cardiovascular facilities in Kumamoto between January 2018 and December 2020.In total, 174 patients were diagnosed with ATTR-CM. The incidence of ATTR-CM was estimated to be approximately 1 per 10,000 person-years in the elderly population (65 years old) in Kumamoto. Compared with that in the JCS-certified facilities cohort (n=115), age at diagnosis was significantly older (84.5 ± 5.6 vs. 77.5 ± 6.3 years old; p0.01) in the regional hospitals cohort (n=59). Histological (25% vs. 81%; p0.01) and genetic diagnosis (7% vs. 82%) were also less frequently performed. Probable (as indicated by positive bone scintigraphy findings with confirmation of monoclonal protein absence) and possible (as indicated by positive bone scintigraphy findings without confirmation of monoclonal protein absence) ATTR-CM accounted for the majority of cases (75% vs. 19%; p0.01) in the regional hospitals cohort compared to the JCS-certified facilities cohort. There were no cases of hereditary ATTR-CM among the patients who underwent TTR genetic testing (n=98).We confirmed the incidence of ATTR-CM in Kumamoto and the diagnostic approach used in patients with ATTR-CM. Further prospective studies with a larger sample are needed to validate our results and to further shed light on the epidemiology of ATTR-CM in Japan.

Aim Matrix metalloproteinases (MMPs) play critical roles in acute myocardial infarction (AMI). This trial was conducted to determine the potential effects of higher-dose rosuvastatin on circulating MMP levels in patients with AMI. Methods This was a multicenter, open-label, 1:1 randomized, parallel-group study. Patients with AMI were randomly assigned to the appropriate-dose group (10 mg rosuvastatin once daily) or the low-dose group (2.5 mg rosuvastatin once daily) within 24 hours after percutaneous coronary intervention. MMP-2 and MMP-9 levels were measured on day 1 and at week 4, 12, and 24 after enrollment. The primary endpoint was the change in MMP levels at 24 weeks after enrollment. The secondary endpoints were change in MMP levels at day 1 and weeks 4 and 12 after enrollment. Results Between August 2017 and October 2018, 120 patients with AMI from 19 institutions were randomly assigned to either the appropriate-dose or the low-dose group. There were 109 patients who completed the 24-week follow-up. The primary endpoint for both MMP-2 and MMP-9 was not significantly different between the two groups. The change in the active/total ratio of MMP-9 at week 12 after baseline was significantly lower in the appropriate-dose group compared with the low-dose group (0.81 [-52.8-60.1]% vs. 70.1 [-14.5-214.2]%, P=0.004), while the changes in MMP-2 were not significantly different between the two groups during the study period. Conclusions This study could not demonstrate the superiority of appropriate-dose of rosuvastatin in inhibiting serum MMPs levels in patients with AMI.

Cardiovascular and cerebrovascular diseases are considered the principal cause of morbidity and mortality worldwide; the effect of stroke-induced cardiac manifestations is well recognized; however, not enough clinical data have been found about the impact of stroke with underlying cardiac disease. This study's objective is to assess the impact of stroke on the prognosis of patients with underlying IHD, who underwent PCI treatment. This was a multicenter, 1-year observational study in patients undergoing PCI in one of the 17 participating centers across Japan. 18,495 patients were registered on the PCI list; 2481 patients had a prior stroke experience, whereas 15,979 were stroke-free. Our study revealed that stroke patients were significantly older (mean age 73.5 ± 9.6, 69.7(± 11.5), respectively), and suffered from more comorbidities (diabetes, hypertension, and chronic kidney disease, p 0.0001). During the 1-year period, subjects with stroke showed higher incidence of clinical events compared to those without stroke; to illustrate, all-cause death accounted for 6.2% in patients with stroke, in contrast to only 2.8% in stroke-free patients (p 0.0001), cardiac death amounted for 2.2 and 1.2%, respectively (p 0.0001), recurrent stroke for 3.1% and 1.2% (p 0.0001), non-cardiac death for 3.6 and 1.54% (p 0.0001), and finally, hemorrhagic complications with 2.6 and 1.3% (p 0.0001). Kaplan-Meier analysis revealed that stroke patients had a higher probability of all-cause mortality, cardiac death, and recurrent stroke (log-rank p 0.0001). Cox hazard analysis also showed that the presence of stroke is a significant indicator in determining the outcome of cardiac death (HR = 1.457, 95% CI 1.036-2.051, p = 0.031); hence, proving it to be a crucial predictor on cardiac prognosis. History of prior stroke was common in PCI patients, and independently associated with a higher rate of subsequent cardiovascular and cerebrovascular events recurrence. Thus, highlighting an urgent need for comprehensive prevention of cardiac and cerebrovascular diseases.

The paradoxical association of obesity with mortality, named the "obesity paradox", has been inconsistent, possibly due to a difference between body mass index (BMI) and central obesity, estimated by waist circumference (WC) as patterns of adiposity.We enrolled 8513 participants from the Kumamoto Intervention Conference Study, a multicenter registry that included consecutive patients undergoing percutaneous coronary intervention (PCI) at 18 centers between 2008 and 2017 in Japan. Patients were divided into quartiles in ascending order of the BMI or WC. The primary endpoints were all-cause mortality and cardiovascular death within a year.There were 186 deaths (case fatality rate, 22.1/1000 person-years) during the follow-up period. The lowest group (1st quartile) of BMI or WC had the worst prognosis among the quartiles (1st quartile, 4.2%; 2nd quartile, 1.9%; 3rd quartile, 1.5%; 4th quartile, 1.1%; P 0.001 (χThe obesity paradox was observed in patients after PCI, and single-use of BMI (or WC) was sufficient to predict the prognosis of patients after PCI.

Percutaneous coronary intervention (PCI) has significantly advanced over the last 40 years, but it is not clear whether there have been any changes in prognosis in recent years. The Kumamoto Intervention Conference Study Real-World Registry is a multi-center registry that enrolls consecutive patients undergoing PCI in 17 centers in Kyushu, Japan. To elucidate the clinical impact of recent changes in treatment strategies, 8841 consecutive participants (historical PCI: n = 4038, enrolled between January 2013 and December 2014, and current PCI: n = 4803, between January 2015 and March 2017) with 1-year follow-up data were analyzed. The incidences of major adverse cardiovascular and other clinical events were comparable between historical PCI and current PCI, even though complex lesions were more frequent during the more recent period. During this period, the use of radial approaches, drug eluting stents, and coronary imaging was greater. The use of prasugrel was more frequent (P

An 82-year-old man who had previously undergone a proximal gastrectomy with jejunal interposition surgery for stomach cancer was transferred to our hospital for massive hematemesis and hypotension. His electrocardiogram showed ST-segment elevation in lead ΙΙ, ΙΙΙ, aVF, which confirmed inferior myocardial infarction. Due to active hematemesis, upper endoscopy was performed initially. A visible vessel of gastric ulceration was discovered, and hemostasis was achieved using hemoclips. Subsequently, coronary angiography was performed since the right coronary artery (RCA) segment 4 atrioventricular (AV) was occluded. After thrombectomy and intravascular ultrasound (IVUS), 2.0 mm balloon angioplasty was done, and coronary perforation occurred. During coronary angiography, extravasation of the contrast material into the gastrointestinal cavity was noted. A covered stent was placed across segment 3 to segment 4 descending posteriorly (PD) to stop the blood supply to the perforation site of segment 4 AV. After stenting, adequate re-hemostasis was achieved. The patient was discharged after 28 days. This is the first report of a coronary artery perforation into the gastrointestinal cavity.

Although there is accumulating evidence for the usefulness of imaging-guided percutaneous coronary intervention (PCI), there are few studies for acute coronary syndrome (ACS), and the impact of the frequency of use has not been well addressed. From the Kumamoto Intervention Conference Study; a Japanese registry comprising 17 institutions, consecutive patients undergoing successful PCI from April 2008 through March 2014 were enrolled. Subjects were divided into two groups: imaging-guided PCI and angiography-guided PCI. Clinical outcome was a composite of cardiac death, non-fatal myocardial infarction, and stent thrombosis within 1 year. A total of 6025 ACS patients were enrolled: 3613 and 2412 patients with imaging- and angiography-guided PCI, respectively. Adverse cardiac events were significantly lower in the imaging-guided PCI group (long-rank P P = 0.004). To assess the effects of frequency of imaging usage, we divided the 17 institutions into six low-, six moderate-, and five high-frequency groups. The event rates decreased depending on the frequency, seemingly driven by stepwise event suppression in angiography-guided PCI. In Japanese ACS patients, the incidence of adverse clinical events in patients treated with imaging-guided PCI were significantly lower than that in patients with angiography-guided PCI. Better clinical result was found in the institutions using intravascular imaging more frequently. University Hospital Medical Information Network (UMIN)-CTR (http://www.umin.ac.jp/ctr/). Identifier: KICS (UMIN000015397).

The low-density lipoprotein-cholesterol (LDL-C) level of a 38-year-old man diagnosed with acute coronary syndrome was 257 mg/dL. The administration of a proprotein convertase subtilisin-kexin type 9 (PCSK9) antibody in addition to rosuvastatin plus ezetimibe was initiated, reducing his LDL-C level to 37 mg/dL. A genetic analysis revealed both an LDL receptor (LDLR) mutation and a PCSK9 V4I mutation. Nine months after revascularization, intravascular ultrasound revealed plaque regression in the coronary arteries. LDLR/PCSK9 mutation carriers are prone to coronary artery disease. Intensive LDL-C lowering by including PCSK9 antibody was associated with coronary plaque regression, suggesting the expectation of prognosis improvement.

Background Acute myocardial infarction (AMI) is mainly characterized by the rupture of lipid-rich vulnerable atherosclerotic plaque. The matrix metalloproteinases (MMPs) have been shown to play a critical role in inflammatory processes underlying plaque rupture. Some reports suggested statins inhibit the increased MMP levels after AMI. However, there are a few comparison studies between the different dosages of the same statin and circulating levels of MMPs. Purpose This study will preliminarily investigate the potential effects of appropriate or low dose of rosuvastatin on circulating MMPs levels in AMI patients. Moreover, we will also obtain plasma from patients while undergoing diagnostic angiography to determine differences in various cardiac sites and peripheral vessels. Methods This study is a multicenter, open-label, randomized, parallel-group study to be conducted to compare the appropriate or low dose of rosuvastatin in the effect on serum levels of inflammatory markers in AMI patients. The eligible patients undergoing percutaneous coronary intervention (PCI) will be randomly assigned to receive either appropriate or low-dose rosuvastatin daily using a web-based randomization software within 24 h after PCI. The low-dose group will be treated with rosuvastatin 2.5 mg once daily with a follow-up. The appropriate-dose group will begin treatment with rosuvastatin 5 mg once daily, and the dose of rosuvastatin will be titrated to 10 mg within 4 weeks. During administration of the study treatment, subjects will undergo laboratory testing including MMPs and be monitored for the occurrence of adverse events up to 24 weeks. The primary endpoint will be the change rate of MMPs at 24 weeks after administration. Conclusions INVITATION will compare the appropriate or low dose of rosuvastatin in the effects on serum levels of inflammatory markers including MMPs in AMI patients. This study will provide significant information on rosuvastatin as an anti-inflammatory agent for AMI.

Background Experimental studies suggest that angiotensin II-receptor blockers can influence atrial remodeling and may prevent atrial fibrillation (AF). Therefore, we hypothesized that irbesartan may prevent the recurrence of AF following either catheter ablation or electrical cardioversion of AF. Methods Study on the Effect of Irbesartan on Atrial Fibrillation Recurrence in Kumamoto (SILK study) is a prospective, multicenter, randomized, and open-label comparative evaluation of the effects of irbesartan and amlodipine on AF recurrence in hypertensive patients with AF who are scheduled to undergo catheter ablation or electrical cardioversion of AF. The primary end point was either AF or atrial tachycardia (AT) recurrence. AF/AT recurrence was evaluated for 6 months using 24-h Holter electrocardiogram and portable electrocardiogram. The secondary endpoints included the change in blood pressure, the interval from the procedure to the first AF/AT recurrence, cardiovascular events, left atrial diameter (LAD), left ventricular ejection fraction (LVEF), and changes in the biomarkers [brain natriuretic polypeptide (BNP), high-sensitivity C-reactive protein (hs-CRP), urinary albumin/creatinine]. Results The study enrolled 98 patients (irbesartan; n = 47, amlodipine; n = 51). The recurrence of AF/AT was observed in 8 patients (17.0%) in the irbesartan group and in 10 patients (19.6%) in the amlodipine group. There was no significant difference in the AF/AT recurrence between the irbesartan and amlodipine groups. Blood pressure decreased similarly in both groups. There were no significant differences between the two groups as regards to the interval from the procedure to the first AF/AT recurrence, occurrence of cardiovascular events, changes in LAD and LVEF. BNP and urinary albumin/creatinine significantly decreased similarly in both groups, but no significant difference was found in hs-CRP between the two groups. Conclusions In hypertensive patients with AF, treatment with irbesartan did not have any advantage over amlodipine in the reduction of AF/AT recurrence after catheter ablation or electrical cardioversion.

Clinical outcomes of percutaneous coronary intervention (PCI) at hospital with or without onsite cardiac surgery backup Tomonori Akasaka , Seiji Hokimoto ⁎, Shuichi Oshima , Koichi Nakao , Kazuteru Fujimoto , Yuji Miyao , Hideki Shimomura , Ryusuke Tsunoda , Toyoki Hirose , Ichiro Kajiwara , Toshiyuki Matsumura , Natsuki Nakamura , Nobuyasu Yamamoto , Shunichi Koide , Hideki Oka , Yasuhiro Morikami , Naritsugu Sakaino , Koichi Kaikita , Sunao Nakamura , Kunihiko Matsui , Hisao Ogawa , on behalf of, Kumamoto Intervention Conference Study (KICS) Investigators

Background Based on the 2011 American College of Cardiology/American Heart Association percutaneous coronary intervention (PCI) guideline, it is recommended that PCI should be performed at hospital with onsite cardiac surgery. But, data suggest that there is no significant difference in clinical outcomes following primary or elective PCI between the two groups. We examined the impact of with or without onsite cardiac surgery on clinical outcomes following PCI for acute coronary syndrome (ACS). Methods and results From August 2008 to March 2011, subjects ( n = 3241) were enrolled from the Kumamoto Intervention Conference Study (KICS). Patients were assigned to two groups treated in hospitals with ( n = 2764) or without ( n = 477) onsite cardiac surgery. Clinical events were followed up for 12 months. Primary endpoint was in-hospital death, cardiovascular death, myocardial infarction, and stroke. And we monitored in-hospital events, non-cardiovascular deaths, bleeding complications, revascularizations, and emergent coronary artery bypass grafting (CABG). There was no overall significant difference in primary endpoint between hospitals with and without onsite cardiac surgery [ACS, 7.6% vs. 8.0%, p = 0.737; ST-segment elevation myocardial infarction (STEMI), 10.4% vs. 7.5%, p = 0.200]. There was also no significant difference when events in primary endpoint were considered separately. In other events, revascularization was more frequently seen in hospitals with onsite surgery (ACS, 20.0% vs. 13.0%, p p = 0.009). We performed propensity score matching analysis to correct for the disparate patient numbers between the two groups, and there was also no significant difference for primary endpoint (ACS, 8.6% vs. 7.5%, p = 0.547; STEMI, 11.2% vs. 7.5%, p = 0.210). Conclusions There is no significant difference in clinical outcomes following PCI for ACS between hospitals with and without onsite cardiac surgery backup in Japan.

The aim of this study was to examine the effects of different statins on the clinical outcomes of Japanese patients with coronary stent implants.This study included 5,801 consecutive patients (males, 4,160; age, 69.7±11.1 years, mean±SD) who underwent stent implantation between April 2008 and March 2011. They were treated with a strong statin (n=3,042, 52%, atorvastatin, pitavastatin, or rosuvastatin), a regular statin (n=1,082, 19%, pravastatin, simvastatin, or fluvastatin) or no statin (n=1,677, 29%). The patients with chronic kidney disease (CKD) were divided into mild-to-moderate CKD (30≤eGFR60, n=1,956) and severe CKD (eGFR30, n=559). Primary endpoints included cardiovascular death and nonfatal myocardial infarction, including stent thrombosis and ischemic stroke. The clinical outcome for the primary endpoint in mild-to-moderate CKD patients treated with a strong statin (hazard ratio 0.50, 95% confidence interval 0.31-0.81; P=0.005) was significantly lower than in those on no statins, but that in the patients treated with a regular statin was not (P=0.160). The clinical outcome for the primary endpoint in severe CKD patients treated with a strong or regular statin was no different than not being on statin therapy (P=0.446, P=0.194, respectively).In patients with mild-to-moderate CKD, only strong statins were associated with lower risk compared with no statin, but regular statins were not. It is possible that taking a strong statin from the early stage of CKD is useful for suppression of cardiovascular events.

Plasma levels of human thioredoxin are indicative of the responses against oxidative stress. We measured the plasma thioredoxin levels in patients with unstable angina in order to examine the relationships between subsequent clinical course and plasma thioredoxin levels before and after treatment for unstable angina. Blood was sampled both on admission and after treatment in 44 patients with unstable angina. In addition, blood samples were obtained from 41 patients with stable exertional angina and 41 patients with chest pain syndrome after admission. The plasma levels of thioredoxin were the highest in the unstable angina group among three groups (p

To determine whether plasma levels of thioredoxin are associated with coronary spasm, we measured the plasma levels of thioredoxin in 170 patients who had

Oxidative stress is thought to play an important role in atherosclerotic vascular disease. Recently, it has become possible to quantitatively measure thioredoxin, a marker of oxidative stress in human plasma. A platelet aggregometer that uses laser-light scattering enables minimal changes in platelet aggregability to be monitored; however, the relationship between oxidative stress and platelet aggregability in vivo is not well understood.We investigated plasma thioredoxin levels and platelet aggregability, in particular small platelet aggregates, in 45 patients with acute myocardial infarction (AMI); we compared the results with 33 patients with stable exertional angina (SEA) and 30 patients with chest pain syndrome (CPS).The plasma thioredoxin levels and the degree of small platelet aggregates were higher in the AMI group than in the SEA and the CPS groups: in the AMI group, at 4 weeks after admission, both of those parameters were significantly decreased (P.01), but they were still higher (P.05) than in the SEA or the CPS group. There was a significant positive correlation between small platelet aggregates and plasma thioredoxin levels (rho = 0.354, P =.0002). We divided the AMI patients into 2 groups according to the 75 percentile of plasma thioredoxin levels on admission. At the chronic phase, the left ventricular ejection fraction was significantly higher in the lower thioredoxin group than in the higher thioredoxin group.We showed that plasma thioredoxin levels and platelet aggregability increased concomitantly in patients with AMI. In these patients, increased plasma thioredoxin was associated with platelet hyperaggregability and lower left ventricular ejection fraction.

Background— Coronary artery spasm plays an important role in the pathogenesis of ischemic heart diseases such as unstable angina (UA) and acute myocardial infarction. Nitric oxide (NO) plays an important role in coronary artery spasm. We previously reported a deficiency in NO activity in the spasm arteries of patients with coronary spastic angina (CSA). Others have reported that NO influences the immune response. Therefore, we investigated the balance between T-helper type 1 (Th1) and 2 (Th2) responses in patients with CSA by evaluating the frequencies of interferon (IFN)-γ–producing T cells and interleukin (IL)-4–producing T cells in the peripheral blood of such patients. Methods and Results— Peripheral blood mononuclear cells were collected from 50 consecutive patients with CSA, 23 consecutive patients with UA, 36 patients with stable angina (SA), and 21 patients with chest pain syndrome (CPS). Cytokine-producing CD4+ T cells were quantified by 3-color flow cytometry after stimulation with phorbol myristate acetate and ionomycin. UA and CSA were associated with a significant increase in the frequency of CD4+ T cells that produced IFN-γ, whereas these conditions caused no significant difference in the frequency of CD4+ T cells that produced IL-4. Culturing with an NO donor compound for 24 hours before stimulation inhibited the increase in the frequency of CD4+ T cells that produced IFN-γ. Conclusions— We demonstrated that there was a preference toward the Th1-type response in patients with CSA and that T cells showed a reduced Th1-type response after being treated with NO.

We examined the relation between oxidative stress and cardiac events in patients with acute myocardial infarction (AMI). There is now increasing evidence that reactive oxygen species cause reperfusion injury to the previously ischemic myocardium after reperfusion. We measured urinary biopyrrin/creatinine levels, an oxidative stress marker, in 41 patients with AMI, 34 patients with stable angina pectoris (SAP), and 29 control subjects. In the patients with AMI, urine samples were taken before, at 4 and 24 hours, and at 1 and 2 weeks after reperfusion therapy. Of these 41 patients with AMI, 38 received reperfusion therapy, and the urinary biopyrrin/creatinine levels (micromol/g.creatinine) before reperfusion were significantly higher than those of the other 2 groups (AMI 4.24 +/- 0.49, SAP 2.45 +/- 0.15, control subjects 2.31 +/- 0.16; p = 0.0003 vs AMI). The onset of reperfusion significantly increased the levels of urinary biopyrrins/creatinine, and this time course was mapped out, peaking at 4 hours (8.21 +/- 0.96 vs 4.24 +/- 0.49 before, p = 0.0001), and decreasing to control levels between 24 hours and 7 days. The peak levels of urinary biopyrrins/creatinine were higher in the positive cardiac event group than in the negative cardiac event group (11.89 +/- 1.77 vs 7.57 +/- 1.00 micromol/g.creatinine, p = 0.029). These findings add further evidence that oxidative stress contributes to the complications of reperfusion injury, and suggest that urinary assessment of biopyrrins may be useful in predicting subsequent cardiac events after reperfusion in AMI.

Oxidized low-density lipoproteins are important in the progression of atherosclerosis. Autoantibodies against malondialdehyde-modified low-density lipoproteins have been reported to be predictive of the progression of atherosclerosis. This study sought to examine whether plasma levels of autoantibodies against oxidized low-density lipoprotein increase in the coronary circulation in patients with coronary spastic angina. The authors examined plasma antioxidized low-density lipoprotein antibody levels (activity unit values (AcU)/mL) simultaneously in the coronary sinus and the aortic root in 20 patients with coronary spastic angina, 23 patients with stable exertional angina, and 15 control subjects by measuring plasma levels of immunoglobulin G (IgG) autoantibodies against malondialdehyde-modified low-density lipoproteins by enzyme-linked immunosorbent assay. The plasma antioxidized low-density lipoprotein antibody levels (AcU/mL) in the coronary sinus increased in coronary spastic angina (38 +/- 16) compared with stable exertional angina (23 +/- 7) and control subjects (20 +/- 6) (p < or = 0.0001). The levels (AcU/mL) in the aortic root also increased in coronary spastic angina (33 +/- 12) compared with stable exertional angina (23 +/- 7) and control subjects (20 +/- 6) (p < 0.005). Furthermore, the coronary sinus-arterial differences of the levels (AcU/mL) were also higher in coronary spastic angina (5 +/- 9) than in stable exertional angina (0 +/- 6) and healthy subjects (-1 +/- 5) (p < 0.05). The generation of malondialdehyde-modified low-density lipoproteins is reported to be associated with atherothrombosis. These findings suggest that elevated levels of autoantibodies against malondialdehyde-modified oxidized low-density lipoproteins in coronary circulation are associated with the development of atherothrombosis from the progression of atherosclerosis rather than with the extent of coronary atherosclerosis in patients with coronary spastic angina.

Coronary thrombosis has been implicated in the pathogenesis of acute coronary syndromes, and platelet activation plays a pivotal role in the pathogenesis of coronary thrombus. A new platelet aggregometer using a laser-light scattering beam was trialled for assessment of platelet aggregation. Platelet aggregability, especially small-sized platelet aggregates, was investigated on admission using the laser-light scattering method and again after treatment in 23 patients with acute coronary syndromes. The platelet aggregability in 14 patients with stable exertional angina and in 14 control subjects was also examined. On admission, the number of small- and medium-sized platelet aggregates in the acute coronary syndromes group was significantly greater than in the stable exertional angina group or control group. However, the number of large-sized platelet aggregates on admission was not increased in the acute coronary syndromes group. Furthermore, the number of small- and medium-sized platelet aggregates decreased significantly after treatment in the acute coronary syndromes group. The increased number of small-sized platelet aggregates may sensitively reflect attacks of thrombosis in patients suffering acute coronary syndromes.

We report the first case of angiosarcoma in the kidney occurring in a woman; the tumor was initially believed to be renal cell carcinoma. This malignant tumor was discovered in a patient with macrohematuria. The final diagnosis was confirmed by histologic and immunohistochemical findings. A review of the literature on this tumor is also included in the discussion.

The role of infiltrating macrophages in the pathogenesis of acute rejection was investigated in biopsy specimens obtained from human transplanted kidneys using immunohistochemical methods. Thirty-one allograft tissue specimens obtained from 26 patients were histologically classified into 18 with acute rejection, 7 with borderline change and 6 with chronic rejection according to the Banff working classification (1993). These specimens were analyzed by avidin-biotin peroxidase complex method on frozen sections in order to examine the utility of some antimonocyte/macrophage monoclonal antibodies in differentiating acute rejection from other conditions. The ratio of CD68, CD11b, LeuM3, OKM5 and HAM56-positive infiltrating monocytes/macrophages to leukocyte common antigen (LCA)-positive cells in the renal cortex were calculated. As a result, the ratio of the positive cells for CD68, which stains mature macrophages, significantly increased in the cases of acute rejection compared with those of other groups. In addition, a strong expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) was observed in the acute rejection group. In our study, the expression of class II major histocompatibility antigens (HLA-DR) in the proximal epithelial tubules was also strongly observed in the cases of acute rejection. It was thus concluded that the increase of CD68-positive infiltrating cells and the expression of GM-CSF may play a possible role as a reaction effector in the process of acute renal allograft rejection.

The present study was designed to determine whether the administration of free radical scavengers, superoxide dismutase (SOD), catalase or dimethylsulfoxide (DMSO) is able to ameliorate ischemia/reperfusion injury in the canine kidney and also ascertain whether or not a relationship exists between oxygen free radicals and membrane-bound Na(+)-K(+)-ATPase activity. In 23 dogs, the vascular pedicle of the left kidney was clamped for 75 min at room temperature. The experimental animals received free radical scavengers for 30 min starting at 2 min prior to reperfusion. Renal tissue specimens were enzyme-histochemically examined regarding the activity of membrane-bound Na(+)-K(+)-ATPase, and a marked reduction just before reperfusion was revealed. The SOD- and the DMSO-treated groups showed a marked recovery of the membrane-bound Na(+)-K(+)-ATPase activity; however, the untreated and the catalase-treated groups still demonstrated a marked reduction 1 day after reperfusion. At the same time, widespread acute tubular necrosis in the cortex was observed in the untreated and catalase groups in comparison with the SOD and the DMSO groups. In addition, the SOD and the DMSO groups significantly preserved better renal function. Based on these findings, it was thus concluded that free radical scavengers ameliorate the recovery of depressed membrane-bound Na(+)-K(+)-ATPase activity and ischemia/reperfusion injury in the canine kidney.

We investigated the effect of statin therapy on T-cell activation in patients who underwent percutaneous coronary intervention by using flow cytometric analysis. The increased frequency of interferon-γ–positive CD4 + T cells after percutaneous coronary intervention was significant in the group treated without statins but not in the group treated with statins.

The present study has been carried out to clarify relationship between phimosis and urinary tract infection or vesicoureteral reflux. The subjects consisted of 654 boys up to 15 years old with phimosis who had been treated at the outpatient division, Fukuoka University Hospital during 13 years from 1974; 393 boys (60%) with false phimosis, 261 boys (40%) with true phimosis. Thirty three cases (5%) had abnormal voiding (weak stream, preputial ballooning, dribbling etc.) Boys with true phimosis without abnormal voiding showed high incidence of urinary tract infection compared with normal subject, and if these boys had abnormal voiding symptoms as well, the incidence of urinary tract infection, particularly in the form of pyelonephritis, was noted to be high. Therefore, we suggest that boys with phimosis should be treated surgically. The incidence of urinary tract infection in boys with false phimosis were similar to normal group. All cases except one of vesicoureteral reflux accompanied by true phimosis was diagnosed as primary reflux cystoscopically. Therefore in most cases of phimosis associated with reflux, phimosis is determined to be only an accessory factor of vesicoureteral reflux. And refluxing patients should be worked up for urinary tract infection after they have had circumcision. Only in one boy with phimosis and reflux, was the reflux thought to be secondary reflux caused by phimotic obstruction.

Serotonin is secreted from platelets at sites of endothelial injury, where it promotes thrombogenic reactions. Serotonin is reported to be associated with not only coronary artery disease but also cardiac events.We studied 33 patients with stable effort angina (SEA) (11 patients with multivessel disease (MVD) and 22 patients with single vessel disease (SVD)) and 25 patients with chest pain syndrome (CPS). Sarpogrelate was administered to 22 of 33 patients with SEA in addition to aspirin therapy, and platelet aggregation, plasma serotonin concentration, and plasma plasminogen activator inhibitor (PAI) activity were measured before and 1 week after administration.Serotonin level was higher in patients with MVD than in those with SVD (p0.05) and in those with CPS (p0.001). The formation of small-sized platelet aggregates was significantly higher in the high serotonin group than in the low serotonin group of SEA patients. The formation of large-sized platelet aggregates was significantly decreased by administration of sarpogrelate (P0.05). The formation of small- or medium-sized aggregates was not significantly decreased. Plasma PAI activity decreased significantly (P0.05) although the plasma serotonin concentration did not show significant change by administration of sarpogrelate. Plasma serotonin level is increased in relation to severity of coronary artery disease and plasma serotonin level is associated with increased platelet aggregation. Administration of sarpogrelate in addition to aspirin therapy reduces the increased platelet aggregation and PAI activity, and it may indicate that additional administration of sarpogrelate is useful for patients with SEA.

High-sensitivity C-reactive protein (hsCRP) levels can predict cardiovascular events among apparently healthy individuals and patients with coronary artery disease (CAD). However, hsCRP levels vary among ethnic populations. We previously reported hsCRP levels in Japanese to be much lower than in Western populations. We investigated the prognostic value of hsCRP levels in Japanese patients with stable CAD. The hsCRP levels were measured in 373 Japanese patients who underwent elective coronary angiography and thereafter decided to receive only medical treatment. Patients were followed up for 2.9+/-1.5 years for major cardiovascular events (death, myocardial infarction, unstable angina, stroke, aortic disease, peripheral arterial disease, or heart failure). The median hsCRP level was 0.70 mg/l. During the follow-up, cardiovascular events occurred in 53 (14%) of the 373 patients. Compared with 320 patients without events, 53 with events had higher hsCRP levels (median 1.06 vs. 0.67 mg/l, P0.05). To clarify the association between hsCRP levels and cardiovascular events, the 373 study patients were divided into tertiles according to hsCRP levels: lower (0.4 mg/l), middle (0.4-1.2mg/l), and higher (1.2mg/l). The Kaplan-Meier analysis demonstrated a significant difference in the event-free survival rate between higher vs. middle or lower tertiles (P0.05). In multivariate Cox regression analysis, the hsCRP level of1.0mg/l was an independent predictor for cardiovascular events (hazard ratio, 2.0; 95%CI, 1.1-3.4; P0.05). Thus, in Japanese patients with stable CAD who received only medical treatment, higher hsCRP levels, even1.0mg/l, were found to be associated with a significantly increased risk for further cardiovascular events.

A 60 year-old man with atherosclerosis obliterans had received a bypass operation twice, but came to notice resting pain in the left calf. As it was not possible to perform further bypass operations (resulys of arteriography), we conducted conservative treatments. We therefore performed therapeutic angiogenesis by autologous transplantation of bone marrow mononuclear cells since the symptoms were not improved at all. Resting pain was improved the next day after the operation and completely disappeared on the third day. The patient was only able to walk 180m in the preoperative state by crutch-assisted, but walked 180m without a stick on the second day and 900m on the fourth day. This treatment did not cause any inconvenience in everyday life and the patient showed no resting pain eight weeks later. In addition, the ankle-brachial index improved to 0.48 from the preoperation level of 0.36 after two months.

Background— Nitrates are widely used to treat coronary artery disease, but their therapeutic value is compromised by the rapid development of tolerance. Recently, the renin-angiotensin system has been suggested to play an important role in the development of nitrate tolerance. Methods and Results— Sixty-four patients with coronary spastic angina were investigated to clarify the effect of angiotensin II type 1 receptor blocker (ARB) therapy on nitrate tolerance. Transdermal nitroglycerin (10 mg/d) and an ARB (candesartan, 8 mg/d) were administered to 21 patients (GTN+ARB group) for 3 days, whereas transdermal nitroglycerin and placebo were administered to 19 patients (GTN group). Another 18 patients were treated with placebo skin patches and placebo tablets for 3 days (control group). The brachial artery response to incremental doses of intravenous nitroglycerin (0.01, 0.1, and 1.0 μg/kg) was measured by ultrasound before and after transdermal nitroglycerin therapy. Before treatment, the arterial diameter was increased by nitroglycerin injection in each group. After treatment, the increase of arterial diameter was significantly suppressed in the GTN group but not in the control or GTN+ARB groups. The plasma level of thioredoxin (a marker of oxidative stress) was increased in the GTN group after treatment ( P Conclusions— An ARB suppressed the development of nitrate tolerance during transdermal nitroglycerin therapy. These results suggest that increased oxidative stress induced by activation of angiotensin II may play an important role in the development of nitrate tolerance.

Objectives We investigated the relationship between the urinary levels of biopyrrins and the severity of heart failure (HF). Background Oxidative stress is evident in heart disease and contributes to the development of ventricular dysfunction in patients with HF. Biopyrrins, oxidative metabolites of bilirubin, have been discovered as potential markers of oxidative stress. Methods We measured the levels of urinary biopyrrins and plasma B-type natriuretic peptide (BNP) in 94 patients with HF (59 men; mean age 65 years) and 47 control subjects (30 men; mean age 65 years). Urine and blood samples were taken after admission in all subjects. Further urine samples were obtained from 40 patients after treatment of HF. Results The urinary biopyrrins/creatinine levels (μmol/g creatinine) were the highest in patients in New York Heart Association (NYHA) class III/IV (n = 26; 17.05 [range 7.85 to 42.91]). The urinary biopyrrins/creatinine levels in patients in NYHA class I (n = 35; 3.46 [range 2.60 to 5.42]) or II (n = 33; 5.39 [range 3.37 to 9.36]) were significantly higher than those in controls (2.38 [range 1.57 to 3.15]). There were significant differences in urinary biopyrrins/creatinine levels among each group. The treatment of HF significantly decreased both urinary biopyrrins/creatinine levels (from 7.43 [range 3.84 to 17.05] to 3.07 [range 2.21 to 5.71]) and NYHA class (from 2.5 ± 0.1 to 1.7 ± 0.1). Log biopyrrins/creatinine levels were positively correlated with log BNP levels (r = 0.650, p Conclusions These results indicate that urinary biopyrrins levels are increased in patients with HF and are elevated in proportion to its severity.

The left ventricular ejection fraction (LVEF) is one of the major prognostic factors after acute myocardial infarction (AMI) and matrix metalloproteinase-1 (MMP-1) is an enzyme responsible for extracellular collagen degradation and remodeling. The present study investigated whether the concentration of serum MMP-1 was associated with the LVEF after AMI. Blood was sampled on admission, and at 24 h, 3 days, 7 days, 2 weeks and 4 weeks in 24 patients with their first AMI. Left ventriculography was performed 4 weeks after the onset of AMI and the LVEF was calculated by center line method. MMP-1 concentrations were higher at 7 days and at 2 weeks than on admission (p

Background: Platelet aggregation, blood coagulation, and fibrinolysis play a pivotal role in the pathogenesis of unstable angina. Methods: Platelet aggregability was examined on admission and after 2 weeks of treatment in 22 patients with unstable angina, in particular with regard to small-sized platelet aggregates, plasma tissue factor (TF) antigen levels as a marker of blood coagulation, and plasma plasminogen activator inhibitor (PAI) activity levels as an indicator of fibrinolysis. We also examined the same parameters in 19 patients with stable exertional angina and 17 patients with chest pain syndrome. Results: The number of small-sized platelet aggregates increased more significantly in the unstable angina group than in the stable exertional angina and chest pain syndrome groups. In the unstable angina group, the number of small-sized platelet aggregates decreased significantly after 2 weeks of treatment, but was still higher than that in the stable exertional angina and chest pain syndrome groups. Plasma TF antigen and PAI activity were higher in the unstable angina group than in the stable exertional angina and chest pain syndrome groups. TF and PAI activity decreased to normal ranges after 2 weeks of treatment in the unstable angina group. There were significant positive correlations among the three parameters on admission. Conclusions: It was demonstrated that small-sized platelet aggregates, plasma TF antigen and PAI activity levels increased concomitantly in the unstable angina group. While the blood coagulation and fibrinolytic parameters decreased after stabilization of the clinical symptoms, platelet hyperaggregability still persisted. These results suggest that continuous antiplatelet therapy is essential for the treatment of unstable angina.

A recently developed platelet aggregometer using a laser light scattering method is capable of monitoring the increase in size of small-sized platelet aggregates (diameter 9-25 microm), which cannot be detected with the conventional methods. Whether coronary spasm can cause platelet aggregation in the coronary circulation is unknown. We investigated platelet aggregation, especially small-sized platelet aggregates, simultaneously in the coronary sinus and the aortic root in 18 patients with coronary spastic angina before and after a left coronary artery spasm induced by intracoronary injection of acetylcholine, and in 15 patients with stable exertional angina before and after acute myocardial ischemia induced by rapid right atrial pacing. Platelet aggregation in 12 patients with chest pain syndrome was also examined before and after coronary spasms provoked by acetylcholine. The number of small-sized platelet aggregates increased significantly in the coronary sinus [2.0+/-0.6 x 104 to 4.1+/-1.0 x 104 (V), P

Platelet activation plays a pivotal role in the pathogenesis of acute coronary syndromes. This study was designed to evaluate the platelet aggregability in patients with unstable angina using a new aggregometer with laser-light scattering. We also examined whether there was a relationship between these platelet aggregabilities and unfavorable outcome during in-hospital stay. We measured platelet aggregability, in particular small-sized platelet aggregates in 31 patients with unstable angina, 31 patients with stable exertional angina, and 30 patients with chest pain syndrome. The patients with unstable angina were divided into two groups by their cardiac events during in-hospital stay, cardiac events (+)(n=11) group and cardiac events (-)(n=20) group. On admission, the number of small-sized platelet aggregates (V) was higher in patients with unstable angina (3.0+/-0.5x10(4)) than in those with stable exertional angina (1.4+/-0.3x10(4), P=.017) and chest pain syndrome (0.7+/-0.2x10(4), P=.0003). The number of small-sized platelet aggregates was higher in the cardiac events (+) group than in the cardiac events (-) group (5.5+/-0.9x10(4) vs. 1.6+/-0.4x10(4), P=.0001). A previous study elucidated that small-sized platelet aggregates ultimately developed into medium-sized and large-sized aggregates as platelet aggregation proceeds. Therefore, the production of small-sized platelet aggregates is more sensitive for hyperaggregability. Furthermore, the production of small-sized platelet aggregates increased significantly in patients with unstable angina than in those with stable exertional angina and chest pain syndrome. These findings suggest that a tendency toward thrombus formation increases markedly in patients with unstable angina and increased number of small-sized platelet aggregates on admission predicts poor prognosis during in-hospital stay in patients with unstable angina.

Vascular endothelial growth factor (VEGF) is a growth factor for vascular endothelial cells in vitro. The present study was designed to determine whether serum VEGF levels increase in patients with acute myocardial infarction (AMI) compared with patients with stable exertional angina and control subjects, and to examine the serial changes of serum VEGF levels in patients with AMI. We examined serum VEGF levels by using antibody prepared from serum immunized with human VEGF121. The serum VEGF level (pg/ml) was higher (p < 0.0001) on admission in the patients with AMI (177 ± 19) than in those with stable exertional angina (61 ± 7) and control subjects (62 ± 6). The serum VEGF level (pg/ml) of the patients with AMI was 177 ± 19 on admission, 125 ± 9 on day 3, 137 ± 11 on day 5, 242 ± 18 at 1 week, and 258 ± 22 at 2 weeks after admission. The value was higher on admission than on day 3 after admission (p = 0.014), the values were higher at 1 week and 2 weeks than on admission, on day 3, and 5 (p < 0.01). Furthermore, there were correlations between peak VEGF levels at 1 week or 2 weeks after admission and peak creatine kinase levels. The increase of VEGF on admission in the patients with AMI may be due to the hypoxia of acute myocardial ischemia. The elevation at 1 week and 2 weeks from the onset may cause the development of collateral circulation in relation to the healing of the infarction site.

The interfacial tension of aqueous sodium perfluorooctanoate (SPFO) solution against hexane was measured as a function of temperature at various concentrations around the critical micelle concentration (c.m.c.). The interfacial density and the entropy and energy of adsorption were evaluated by applying the thermodynamic relations developed previously. It was observed that the surface pressure versus area curves of SPFO, dodecylammonium chloride (DAC), and sodium dodecyl sulfate (SDS) are in the order of the cross-sectional area of the polar head group at high pressure. Further, the entropy and energy of adsorption of SPFO were found to be larger than those of DAC and SDS. These results were attributed to a weak mutual interaction between the fluorocarbon chain and the hexane molecule as well as the strong hydrophobicity of SPFO. It was demonstrated that the micelle formation of SPFO can also be treated approximately the same as a macroscopic bulk phase in the range of concentration near the c.m.c.