林 睦晴

Background: Atrial fibrillation (AF) is associated with a prothrombotic state. The aim of this study was to analyze platelet activation and tissue factor (TF) induction in mononuclear cells (MNCs) and granulocytes downstream of cell-cell interactions in AF patients. Methods: Blood samples were obtained from patients with paroxysmal AF (n = 14) at sinus rhythm and at 15 min after induction of AF during an electrophysiological study, and from control subjects (n = 13) and patients with chronic AF (n = 14) in the outpatient clinic. The expression of CD41a, CD42b, P-selectin, and P-selectin glycoprotein ligand-1 (PSGL-1) on platelets and microparticles in platelet-rich plasma (PRP), and on MNCs and granulocytes in whole blood were examined by flow cytometry. MNC-platelet interaction was investigated ex vivo. Results: The expression of CD41a and CD42b on platelets and microparticles was comparable between the control and chronic AF groups, and unchanged after AF induction. Acute induction of AF significantly increased the expression of P-selectin on platelets and microparticles, and to a similar extent, P-selectin-positive MNCs and granulocytes and P-selectin/PSGL-1-double positive MNCs. However, AF induction had no effect on platelet-MNC interactions ex vivo or TF expression on MNCs and granulocytes. Only patients with chronic AF showed platelet-MNC interaction ex vivo and TF overexpression on MNCs. Conclusions: Acute-onset AF activates platelets within minutes to initiate platelet-MNC interaction. The subsequent platelet binding induced TF expression in patients with chronic AF. These findings support the efficacy of anticoagulant therapeutics in chronic AF and suggest the underlying utility of antiplatelet therapeutics in early phase of AF occurrence. (C) 2011 Elsevier Ltd. All rights reserved.

Measuring sodium excretion in a 24-h urine collection is the most reliable method of estimating salt intake, but it is not applicable to all patients. As an alternative, equations for estimating Na excretion from Japanese by a spot urine sample were created, but they have not been validated in patients with chronic kidney disease (CKD), which are frequently associated with nocturia and medication. We enrolled 136 patients with CKD and collected both 24-h urine and the first morning urine. Na excretion was estimated from the first morning urine by Kawasaki's equation, which was originally used for the second morning urine, and Tanaka's equation, which is applied for spot urine samples taken at any time from 9 am to 7 pm. We evaluated the two equations for bias, RMSE and accuracy within 30 and 50% of the measured Na excretion. Bias, RMSE and accuracy within 30% of the estimated Na excretion were 48 +/- A 69 and 2 +/- A 69 mmol/day, 84 and 69 mmol/day, and 35 and 49% using Kawasaki's equation and Tanaka's equation, respectively. Na excretion in the first morning urine was accurately estimated by Tanaka's equation, but it was overestimated by Kawasaki's equation. Nocturia and medication such as diuretics and ACE inhibitor or angiotensin receptor blocker did not affect the accuracy with which Na excretion was estimated by Tanaka's equation substantially. Tanaka's equation for estimating Na excretion from the first morning urine in patients with CKD is accurate enough for use in clinical practice.

The relationship between mild-to-moderate renal dysfunction and cardiac diastolic dysfunction and cardiac events in patients with nonischemic dilated cardiomyopathy (NDCM) has not been fully elucidated. The aim of this study was to investigate the relationship between renal and cardiac function, as well as clinical outcome in patients with NDCM. We measured plasma BNP and eGFR, and performed cardiac catheterization in 135 patients with NDCM. LV dP/dt(max) and T-1/2 were determined as indexes of LV contractility and isovolumic relaxation, respectively. During a mean follow-up of 4.8 years, we monitored all patients for the occurrence of cardiac events, which were defined as cardiac death (from worsening HF or sudden death) and unscheduled admission for decompensated HF. Patients were classified into 3 groups on the basis of eGFR (mL min(-1) 1.73 m(-2)): eGFR >= 90 (n = 23, group A), 60 <= eGFR < 90 (n = 70, group B), and 30 <= eGFR < 60 (n = 42, group C). Whereas LV dP/dt(max) did not significantly differ among the 3 groups, T-1/2 was significantly longer in groups B and C than in group A (P < 0.01). Event-free survival in group C was significantly lower than that in groups A and B (P = 0.014, log-rank test). These results suggest that even mild renal dysfunction is associated with LV isovolumic relaxation impairment. In addition, moderate impairment of renal function is independently associated with cardiac events in patients with NDCM. (Int Heart J 2011; 52: 366-371)

Background: A high low-density lipoprotein cholesterol (LDL-C) to a high-density lipoprotein cholesterol (HDL-C) ratio is associated with cardiac events, while the left main coronary artery (LMCA) is considered to be an important target of atherosclerotic plaque accumulation. This aim of the present study was to investigate the relationship between a LDL-C/HDL-C ratio and the characteristics of tissue components of LMCA plaque. Methods and Results: One-hundred-twenty consecutive patients with stable angina pectoris who received chronic statin treatment underwent percutaneous coronary intervention for the left coronary artery. We prospectively performed integrated backscatter (IB) intravascular ultrasound (NUS) to their LMCAs and evaluated the tissue characteristics. According to the median value of their LDL-C/HDL-C ratios (2.4), they were divided into 2 groups [high LDL-C/HDL-C ratio (>2.4) (n=60) or low LDL-C/HDL-C ratio (<= 2.4) (n=60)]. There was no significant difference in the data analyzed using conventional IVUS between the 2 groups. In the IB-IVUS analysis, patients with a high LDL-C/HDL-C ratio had a larger lipid volume and a smaller fibrous volume compared to patients with a low LDL-C/HDL-C ratio (52 +/- 10% vs. 48 +/- 10%, P=0.014 and 45 +/- 9% vs. 50 +/- 10%, P=0.010). Conclusions: A high LDL-C/HDL-C ratio was associated with a high percentage of lipid volume and a low percentage of fibrous volume in LMCA lesions. Our findings might well suggest the increased risk of cardiovascular events in patients with a high LDL-C/HDL-C ratio. (Circ J 2011; 75: 1960-1967)

Background: Noninvasive assessment of coronary plaque is important for coronary risk stratification. Whereas integrated backscatter intravascular ultrasound (IB-IVUS) has proven effective for analysis of the tissue components of coronary plaque, plaque assessment by 64-slice multidetector computed tomography (MDCT) has not been established. We therefore evaluated the accuracy of MDCT compared with IB-IVUS for identification of coronary plaque components and determination of plaque volume. Methods: Thirty-one sites in 17 coronary vessels (7 left anterior descending, 5 left circumflex, and 5 right coronary arteries) with substantial stenosis were visualized by both 64-slice MDCT and IB-IVUS. Coronary plaque was evaluated by MDCT and the findings were compared with those of IB-IVUS at the same sites and for the same vessel lengths. Plaque was classified as low-attenuated, fibrous, or calcified, and the volume of each plaque component and total plaque volume were calculated. Results: Total plaque volume per vessel determined by MDCT was significantly correlated with that determined by IB-IVUS (r = 0.704, P < 0.05, n = 17). However, the volumes of individual plaque components determined by the two approaches were not correlated. The predominant plaque morphology as determined by the two approaches was consistent in 12 of the 17 vessels (70.6%), whereas calcified and low-attenuated plaques were overestimated by MDCT in the remaining vessels. Conclusions: MDCT is a promising approach for noninvasive detection of different types of coronary plaque and may therefore contribute to coronary risk stratification. The ability of MDCT to determine the volume of individual plaque components, however, is limited. (c) 2010 Elsevier Ireland Ltd. All rights reserved.

Background/Aims: Adiponectin is an adipocyte-derived protein with antiatherogenic properties. Chronic kidney disease (CKD) is one of the risk factors for cardiovascular disease. We investigated the potential association between adiponectin and carotid arteriosclerosis in patients with predialysis CKD. Methods: We enrolled 95 CKD patients without dialysis and 81 non-CKD patients. Intima-media thickness (IMT) and plaque score (PS) in the common carotid artery were measured using an ultrasound system. Carotid arteriosclerosis was defined as IMT > 1.2 mm and/or PS > 5.0 mm. Results: The prevalence of CKD was independently associated with carotid arteriosclerosis after adjustment for other risk factors. Higher adiponectin levels were observed in CKD patients compared with non-CKD patients. Adiponectin levels were not independently correlated with the presence of carotid arteriosclerosis in all subjects. To evaluate the association between adiponectin and carotid arteriosclerosis among a CKD population, we divided the CKD patients into 2 groups according to a cutoff level of adiponectin determined by ROC analysis. The prevalence of carotid arteriosclerosis was significantly higher in the low-adiponectin group than in the high-adiponectin group among CKD patients. After adjusting for other risk factors, low levels of adiponectin were independently correlated with carotid arteriosclerosis in CKD patients. Conclusion: Our data document that adiponectin is associated with increased risk of carotid atherosclerosis in a predialysis CKD population. Copyright (C) 2011 S. Karger AG, Basel

Background: F-18 fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) is a useful tool for the detection of local inflamed atherosclerotic lesions. Objective: This study used hybrid PET/computed tomography (CT) to examine the effects of 2 doses of atorvastatin on (18)F-FDG uptake in atherosclerotic plaques in Japanese adults with stable angina pectoris who were scheduled to undergo percutaneous coronary intervention (PCI). Methods: This was a prospective, randomized, investigator-blinded, open-label study in patients with dyslipidemia (total cholesterol >= 220 mg/dL and/or LDL-C >= 140 mg/dL) who were scheduled to undergo PCI for stable angina pectoris and had not received any lipid-lowering drugs within 1 year before enrollment. Patients were randomly allocated to receive atorvastatin 5 or 20 mg/d for 6 months. At baseline (the day after PCI), (18)F-FDG uptake in the ascending aorta and femoral artery was determined using PET/CT imaging, and the mean target-to-background ratio (TBR) was calculated in individual plaques. The same regions were assessed by PET/CT after 6 months of treatment. Changes from baseline to follow-up in the lipid profile, serum malondialdehyde-modified LDL-C (MDA-LDL-C), and serum high-sensitivity C-reactive protein (hs-CRP) were also examined. Drug adherence, adverse events, and changes in medications were monitored at monthly outpatient visits. Results: Of 32 patients initially screened, 2 were excluded due to newly diagnosed cancer; thus, 30 patients were randomly assigned to treatment, 15 in each group. Patients were predominantly male (18 [60%]), with a mean (SD) age of 54 (11) years, mean body weight of 65 (12) kg, and mean total cholesterol, HDL-C, and triglyceride concentrations of 240 (29), 48 (14), and 180 (102) mg/dL, respectively. After 6 months, the 20-mg group had significant reductions from baseline in mean (SD) TBR in the ascending aorta (from 1.15 [0.14] to 1.05 [0.12]; percent change, -7.9% [9.4%]; P = 0.007) and the femoral artery (from 1.12 [0.11] to 1.02 [0.11]; percent change, -9.9% [13.8%]; P = 0.012). The corresponding changes from baseline were not statistically significant in the 5-mg group. The differences in percent change in TBR in the 2 locations were not significant between groups. When data from the 2 groups were combined, the overall reduction in TBR from baseline to 6 months was significant in both the ascending aorta (P = 0.003) and the femoral artery (P = 0.021). The decreases in TBR in both arteries were significantly correlated with reductions in LDL-C (ascending aorta: r(2) = 0.230 [P = 0.012]; femoral artery: r(2) = 0.338 [P = 0.003]), MDA-LDL-C (ascending aorta: r(2) = 0.183 [P = 0.028]; femoral artery: r(2) = 0.247 [P = 0.010]), and hs-CRP (ascending aorta: r(2) = 0.132 [P = 0.048]; femoral artery: r(2) = 0.271 [P = 0.007]). One patient in the 5-mg group and 2 patients in the 20-mg group had similar to 2-fold increases in serum aminotransferases on a single occasion; however, no specific musculoskeletal or hepatic adverse events were observed, and aminotransferase values decreased to within normal ranges without changes in the atorvastatin dose. Conclusion: Six months of treatment with atorvastatin 20 mg, but not 5 mg, was associated with a significant reduction in TBR in the ascending aorta and femoral artery in these Japanese adults with dyslipidemia undergoing PCI for stable angina pectoris. University Hospital Medical Information Network Clinical Trials Registry identifier: C000000371. (Clin Ther. 2010;32:2337-2347) (C) 2010 Elsevier HS Journals, Inc.

Background and objectives: Cardiac failure is directly affected by left ventricular (LV) dysfunction, and particularly LV systolic dysfunction is strongly associated with survival in ESRD patients. The aim of this study was to determine the prognostic value of reduced LV ejection fraction (LVEF) measured at the time of initiation of hemodialysis (HD) in incident HD patients. Design, setting, participants, & measurements: 1254 consecutive ESRD patients who electively started HD therapy were screened by echocardiography within 1 month after its inception. They were divided into five groups according to LVEF levels with a decrease of 0.1 each and were followed up for up to 7 years. Survival was examined with the Kaplan-Meier method and compared using the log-rank test. Results: Among the 1254 patients, LVEF levels >= 0.6, 0.5 to 0.6, 0.4 to 0.5, 0.3 to 0.4, and <0.3 were seen in 842 (67.1%), 247 (19.7%), 107 (8.5%), 41 (3.3%), and 17 (1.4%) patients, respectively. On Kaplan-Meier analysis, 7-year event-free rates from cardiovascular death were 84.2, 83.7, 73.6, 59.4, and 30.9% in order of groups with decreasing LVEF of 0.1 each, respectively. Seven-year event-free rates from all-cause death were 69.2, 61.7, 57.1, 45.9, and 23.1% in the respective groups. Even after adjustment for other risk factors, decreasing LVEF was a strong independent predictor for cardiovascular death. Conclusions: Reduced LVEF on starting HD therapy could stratify risk of cardiovascular and all-cause mortality in ESRD patients. Screening by echocardiography at start of HD therapy might be recommended to predict prognosis in patients with ESRD. Clin J Am Soc Nephrol 5: 1793-1798, 2010. doi: 10.2215/CJN.00050110

Methods. We prospectively performed IB-IVUS before elective PCI in 89 consecutive patients with stable angina. According to estimated glomerular filtration rate (eGFR), they were divided into two groups (eGFR < 60 ml/min/ 1.73 m(2) or eGFR >= 60 ml/min/1.73 m(2)). The tissue characteristics of the coronary plaque at each target stenotic site were evaluated by three-dimensional (3D) IB-IVUS just before PCI procedure. Results. The patients with eGFR < 60 ml/min/1.73 m(2) had higher percentage of lipid volume and lower percentage of fibrous volume compared to the patients with eGFR >= 60 ml/min/1.73 m(2) on the 3D IB-IVUS images (36.7 +/- 10.6% versus 28.7 +/- 9.3%, P < 0.001 and 59.1 +/- 8.7% versus 66.3 +/- 8.3%, P < 0.001, respectively). eGFR showed a significant negative correlation with lipid volume and had a significant positive correlation with fibrous volume in coronary plaques (r = -0.44, P < 0.0001, and r = 0.46, P < 0.0001, respectively). Conclusions. Impaired renal function was related to higher percentage of lipid volume and lower percentage of fibrous volume in coronary plaque. Our findings may explain the increasing risk of cardiovascular events in patients with renal dysfunction.

Background: Percutaneous transluminal angioplasty (PTA) for femoropopliteal lesions in peripheral artery disease has been performed in patients undergoing hemodialysis as well as in the general population. Cilostazol, a selective inhibitor of phosphodiesterase 3, has been reported to reduce target lesion revascularization after PTA for femoropopliteal lesions in the general population. Objective: This study investigated the effects of cilostazol use on long-term patency after PTA in patients with femoropopliteal disease undergoing hemodialysis. Methods: fit this retrospective study, data from patients undergoing hemodialysis who underwent successful PTA for femoropopliteal disease, defined as a final luminal diameter stenosis <30%, without angiographically Visual arterial dissection and no in-hospital complications, were included. One Study group received long-term treatment with oral cilostazol 100 mg BID after PTA; the control group did not. The duration of follow-tip was ! 6 years. The primary outcome of interest Was cumulative patency, as measured by the event-free rate 6 years after PTA, with event defined as restenosis of >50% of the vessel diameter in femoropophreal lesions. Data on baseline characteristics, patency, and covariates (diabetes, hypertension, hyperlipidemia, smoking, coronary artery disease, critical limb ischemia, TransAtlantic Inter-Society Consensus classification, and stenting) were obtained from electronic medical records and tele-phone interviews with patients. To minimize the effects of selection bias for cilostazol administration, a propensity-matched analysis using Cox univariate and multivariate models including the previously mentioned covariates was conducted. The propensity, scores of the 2 groups were matched 1:1 (AUC = 0.69 [receiving operating characteristics analysis]). Data were obtained from electronic medical records and telephone interviews with patients by trained personnel who were blinded to treatment assignment. Results: A total of 358 consecutive lesions of 1,74 patients undergoing hemodialysis were Included (103 men, 7.1 women; mean [SD] age, 66 [11] years; cilostazol group, 61. patients, 121 lesions; control group, I 13 patients, 237 lesions). The mean duration of follow-Lip was 37 (27) months. The 6-year event-free rate of restenosis of >50% of the vessel diameter was significantly higher in the cilostazol group than in the control group (72/121 [59.5%] vs 120/237 [50.6%,]; P = 0.005 [log-rank test]; hazard ratio [HR] = 0.63; 95% CI, 0.45-0.88; P = 0.008 [Cox univariate analysis]). Also, event-free rates of target lesion revascularization and limb amputation were significantly higher in the cilostazol group than in the control group (40/61 [65.6%] vs 57/113 [50.4%]; P = 0.013 [log-rank test] and 54161 [88.5%] vs 90/113 [79.6%]; P = 0.047 [log-rank test], respectively). On propensity score matching (105 lesions), the baseline characteristics were comparable between the 2 groups. The 6-year event-free rate of restenosis was significantly higher in the cilostazol group than in the control group (66/105 [62.9%] vs 52/105 [49.5%]; HR = 0.58; 95% CI, 0.38-0.88; P = 0.012 [Cox univariate analysis]). On propensity-matched (COX multivariate) analysis, cilostazol (HR = 0.51; 95% CI, 0.27-0.84; P = 0.008), age (HR = 1.01; 95% CI, 1.01-1.04; P = 0.031), and critical limb ischemia (HR = 2.21; 95% CI, 1.39-3.53; P = 0.001) were independent predictors of restenosis. None of the patients in the cilostazol group discontinued cilostazol treatment during the follow-up period. Four patients (6.6%) experienced mild headache. Conclusion: This study found that ill these patients with femoropopliteal lesions in peripheral artery disease who were undergoing hemodialysis, those treated with cilostazol 100 mg BID after PTA had a higher mean rate of cumulative patency after PTA than those in the control group. (Clin Ther. 2010;32:24-33) (C) 2010 Excerpta Medica Inc.

Background-Percutaneous coronary intervention (PCI) using drug-eluting stents significantly reduces the risk of restenosis in the general population. However, in patients on hemodialysis, adverse cardiac events are frequently seen even if treated with drug-eluting stents. Recent studies suggest that C-reactive protein (CRP) reflects vascular wall inflammation and can predict adverse cardiac events. We evaluated possible prognostic values of CRP on outcomes in patients on hemodialysis undergoing PCI with drug-eluting stents. Methods and Results-A total of 167 patients undergoing PCI with sirolimus-eluting stents for stable angina (322 lesions) were enrolled. They were divided into tertiles according to serum CRP levels. We analyzed the incidence of major adverse cardiovascular events including cardiovascular death, nonfatal myocardial infarction, and target lesion revascularization after PCI as well as quantitative coronary angiographic data. The mean follow-up was 31 months (SD, 14). Major adverse cardiac events occurred in 11 patients (19.6%) of the lowest tertile, in 22 patients (39.3%) of the middle tertile, and in 28 patients (50.9%) of the highest tertile during follow-up period (P=0.0009). There was a progressive increase in neointimal growth after sirolimus-eluting stent implantation during follow-up because preprocedural CRP levels were higher, despite similar angiographic data just after PCI. Angiographic restenosis at 6 to 8 months after PCI was seen in 10.6% in the lowest tertile, 17.9% in the middle tertile, and 32.0% in the highest tertile (P=0.0007). Conclusions-Increased preprocedural serum CRP levels would predict higher major adverse cardiac events and restenosis rates after sirolimus-eluting stents implantation in patients on hemodialysis. (Circ Cardiovasc Interv. 2009; 2: 513-518.)

Background: Studies have found an association between treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins") and reductions in procedure-related complications in percutaneous coronary intervention (PCI). Objective: This study investigated the effects of long-term statin treatment before elective PCI on coronary plaque composition at the anglographically severe target stenotic lesions. Methods: This nonrandomized, observational study was conducted at Nagoya University Hospital, Nagoya, Japan. Data were collected from the electronic medical records of patients with stable angina pectoris who underwent PCI guided by intravascular ultrasound (IVUS). Patients were stratified into 2 groups: those who received long-term statin treatment for <= 6 months before PCI (statin group) and those who did not (nonstatin group). The tissue characteristics of the coronary plaque at each target stenotic site were analyzed using 3-dimensional integrated backscatter IVUS immediately before PCI. Results: Data from 100 patients were included (91 men, 9 women; mean [SD] age, 67 110] years; statin group, 44 patients; nonstatin group, 56). The clinical characteristics of the 2 groups were not significantly different, with the exception of the prevalence of hyperlipidemia (statin vs nonstatin, 100% vs 51.8%; P < 0.001). There were no significant between-group differences in serum lipid profiles. The statin group had a significantly greater mean (SD) percentage decrease in lipid volume (28.7% [10.0%] vs 34.7% [9.8%]; P = 0.003) and a significantly greater increase in fibrous volume (66.5% [8.5%] vs 60.9%[8.6%]; P = 0.001) compared with the nonstatin group. Conclusion: This study found a significant difference in lipid and fibrous volumes in anglographically severe coronary stenotic lesions in these patients with stable angina who received long-term statin treatment before PCI versus those who did not. (Clin Ther. 2009;31:6473) (C) 2009 Excerpta Medica Inc.

Background: We previously reported that the targeted disruption of murine antithrombin (AT) gene resulted in embryonic lethality before 16.5 gestational days (gd) because of severe cardiac and hepatic thrombosis. Objective and Methods: To investigate the influences of lowered tissue factor (TF) activity upon hypercoagulation of AT(-/-) embryos, we crossed AT(+/-) with low TF (mTF(-/-)hTF(+)) mice to yield homozygous AT-deficient mice with the extremely low TF activity, that is expressed from the inserted human TF mini gene. Results: AT(-/-) embryos either with 50% TF (AT(-/-)mTF(+/-)hTF(+)) or with low (similar to 1% TF, AT(-/-)mTF(-/-)hTF(+)) were not born, although the survival was prolonged until 18.5 gd. In both genotypes, histological examination showed disseminated thrombosis in hepatic sinusoidal space or in the portal veins, suggesting that the thrombogenesis caused loss of hepatic blood flow. As in original AT(-/-), AT(-/-)mTF(+/-)hTF(+) showed subcutaneous (s.c.) bleeding and also suffered from the myocardial degeneration apparently because of coronary thrombus formation. However, AT(-/-)mTF(-/-)hTF(+) had no skin hemorrhage and the thrombosis and degeneration were completely abolished in the heart. Myocardium of adult low TF mice had exhibited fibrosis secondary to hemorrhage; however, it was significantly decreased in low TF mice with AT(+/-). Conclusions: Our current model suggests that, in the heart, TF plays an important role in the thrombogenesis and it counterbalances AT-dependent anticoagulation. AT may be a potent anticoagulant during mice development and the activation and subsequent regulation of TF-procoagulant activity take place differently between the liver and the heart. These differences appear to point to local regulatory mechanisms in murine hemostasis.

Among three different isoforms of non-muscle myosin heavy chains (NMMHCs), only NMMHCA is associated with inherited human disease, called MYH9 disorders, characterized by macrothrombocytopenia and characteristic granulocyte inclusions. Here targeted gene disruption was performed to understand fundamental as well as pathological role of the gene for NMMHCA, MYH9. Heterozygous intercrosses yielded no homozygous animals among 552 births, suggesting that MYH9 expression is required for embryonic development. In contrast, MYH9+/- mice were viable and fertile without gross anatomical, hematological, and nephrological abnormalities. Immunofluorescence analysis also showed the normal cytoplasmic distribution of NMMHCA. We further measured the auditory brainstem response and found two of six MYH9+/- mice had hearing losses, whereas the remaining four were comparable to wild-type mice. Such observation may parallel the diverse expression of Alport's manifestations of human individuals with MYH9 disorders and suggest the limited requirement of the gene for maintenance and function of specific organs. (C) 2004 Elsevier Inc. All rights reserved.

Plasminogen activator inhibitor-1 (PAI-1) plays a critical role in tissue fibrosis by inactivating matrix metalloproteinases, which might effect on the progression of left ventricular dysfunction. However, little has been known about the expression of PAI-1 during cardiac remodeling. We used a mouse model of myocardial infarction (MI) by coronary ligation, in which the progression of left ventricular remodeling was confirmed by echocardiography. Histological examination showed that interstitial and perivascular fibrosis progressed in the post-All (PMI) heart at 4 weeks after the procedure. We observed the dramatic induction of cardiac PAI-1 mRNA and PAI-1 antigen in plasma in the PMI mice, as compared with the shamoperated (sham) mice. In situ hybridization analysis demonstrated that strong signals for PAI-1 mRNA were localized to cardiomyocytes in the boarder of infarct area and around fibrous lesions, and to perivascular mononuclear cells, which seemed to be mast cells, only in hearts of the PMI mice. Importantly, less development of cardiac fibrosis after MI was observed in mice deficient in PAI-1 as compared to wild-type mice. The mRNA expression of cytokines, transforming growth factor-beta, and tumor necrosis factor-alpha, was also increased in hearts of the PMI mice, but not in the sham mice. These observations suggest that cardiomyocytes and mast cells contribute to the increased PAI-1 expression, resulting in the development of interstitial and perivascular fibrosis in the PMI heart, and that the regional induction of cytokines may be involved in this process.

流血中には、骨髄より由来した内皮前駆細胞が流れている。この内皮前駆細胞の数は、冠動脈硬化の危険因子や血管内皮機能と関連することが報告されている。しかしながら、喫煙習慣と流血中血管内皮細胞の数との関係はこれまでに報告されていなかった。本研究で我々は、慢性の喫煙者では血中の内皮前駆細胞数が少ないことを初めて示した。又、喫煙者が１ヶ月間禁煙することによって、これらの細胞が非喫煙者とほぼ同レベルにまで改善することを示した。