The Geriatric Nutritional Risk Index Predicts Long-Term Survival and Cardiovascular or Limb Events in Peripheral Arterial Disease.

AIM: The Geriatric Nutritional Risk Index (GNRI) was developed to assess the nutritional risk and is associated with mortality. However, there are limited reports on the relationship between the GNRI and overall survival (OS) in peripheral artery disease (PAD). Therefore, the purpose of this study was to examine the relationship between GNRI and OS and cardiovascular or limb events in patients with PAD. METHODS: A prospective cohort study was performed on 1,219 patients with PAD. The baseline GNRI was calculated from the serum albumin level and body mass index obtained at the first visit. The patients were divided into four groups according to the GNRI: G0 (＞98), G1 (92-98), G2 (82-91), and G3 (＜82). The endpoints were OS and freedom from major adverse cardiovascular events (MACE) and MACE plus limb events (MACLE). RESULTS: The median follow-up period was 73 months. There were 626 deaths (51.4%) during the follow-up. The rate of cardiovascular death was 51.3%. OS clearly depended on the GNRI (p＜0.01), with five-year OS rates of 80.8% for G0, 62.0% for G1, 40.0% for G2, and 23.3% for G3. In multivariate analyses, the GNRI, age, ankle-brachial pressure index (ABPI), critical limb ischemia, estimated glomerular filtration rate (eGFR), and C-reactive protein (CRP) were independent factors associated with OS, and GNRI, age, ABPI, coronary artery disease, diabetes mellitus, eGFR, and CRP were associated with MACE and MACLE (all p＜0.05). Statins were found to improve OS, MACE, and MACLE (p＜0.01). CONCLUSIONS: GNRI is an independent predictor for OS, MACE, and MACLE in patients with PAD.

Asymptomatic cerebral infarction is a predictor of long-term survival and vascular or limb events in peripheral arterial disease.

Aims: The purpose of this study was to examine long-term life expectancy including cerebrovascular events (CVE) and fate of the leg in patients with peripheral arterial disease (PAD) with or without cerebral infarction (CI) detected by computed tomography (CT). Methods and results: A prospective cohort study was performed in 932 patients with PAD. The endpoints were overall survival (OS), CVE, stroke-free survival (SFS), freedom from major adverse cardiovascular events (MACE), and freedom from major adverse cardiovascular and limb events (MACLE). The prevalence of CI on CT was 56.8%. There were 413 deaths (44.3%) during follow-up. The rate of cardiovascular deaths among those who died was 53.5%. The 3-, 5-, and 10-year OS rates were 82.0%, 76.9%, and 46.2%, respectively. In Cox multivariate analyses, age, ankle brachial pressure index (ABI), critical limb ischaemia (CLI), estimated glomerular filtration rate (eGFR), albumin level, and CI were independent factors associated with OS (P < 0.05); age, ABI, CLI, atrial fibrillation (AF), and CI were related to CVE (P < 0.05); age, ABI, CLI, diabetes, coronary heart disease (CHD), AF, eGFR, lower albumin, and CI were related to SFS (P < 0.05); age, ABI, CLI, diabetes, CHD, eGFR, lower albumin, and CI were associated with MACE (P < 0.05); and age, ABI, diabetes, CHD, eGFR, lower albumin and CI were related to MACLE (P < 0.05). Statins improved MACE and MACLE (P < 0.05), and AF increased MACLE (P < 0.05). Conclusions: CI on CT was an independent predictor for mortality, CVE, SFS, MACE, and MACLE. Statins improved MACE and MACLE, but AF increased CVE and MACLE in patients with PAD.

Long-term survival and fate of the leg in de novo intermittent claudication.

Aims: The long-term life expectancy and fate of the leg, including progression rate to critical limb ischaemia (CLI), were analysed in de novo patients with intermittent claudication (IC). Methods and results: A prospective cohort study was performed in 1107 patients with de novo IC. The endpoints were overall survival (OS), freedom from major adverse cardiovascular events (MACE), freedom from major adverse cardiovascular and limb events (MACLE), and fate of the leg. The 5-, 10-, 15-, and 20-year rates were 73.3, 47.8, 28.1, and 14.9% for OS, and 63.0, 35.6, 18.5, and 5.7% for freedom from MACE, respectively. In Cox multivariable analysis, body mass index, diabetes, haemodialysis, and C-reactive protein (CRP) level were correlated with OS (P < 0.05). Ankle brachial pressure index, diabetes, coronary artery disease, haemodialysis, and CRP level were independently correlated with freedom from MACE and MACLE. Statins improved mortality, MACE, and MACLE (P < 0.05). Revascularization did not improve mortality and MACE, and femoropopliteal revascularization increased MACLE (P < 0.05). There was no deterioration of claudication in 881 patients (79.6%). Worsening claudication was noted in 211 patients (14.8% per 5 years), and 15 patients (1.1% per 5 years) worsened to CLI. Diabetes and haemodialysis were independent predictors of CLI. A history of cerebral infarction and femoropopliteal revascularization tended to increase CLI. Conclusions: Life expectancy in patients with IC was poor, but the rate of IC progression to CLI was low. Statins improved mortality and morbidity, revascularization did not improve mortality and MACE, and femoropopliteal revascularization reduced freedom from MACLE with a risk of CLI.

Lipoprotein(a) is a risk factor for aortic and mitral valvular stenosis in peripheral arterial disease.

AIMS: Lipoprotein(a) (Lp(a)) levels have been associated with aortic valvular calcification and stenosis. The prevalence and risk factors, including Lp(a) level, for valvular heart disease (VHD) were investigated in patients with peripheral arterial disease (PAD). METHODS AND RESULTS: Echocardiography was performed in 861 patients with PAD to detect abnormal cardiac findings. Relationships between VHD and risk factors were analysed. The prevalence of VHD was 43.6%, and the prevalences of aortic valve regurgitation (AR), mitral valve regurgitation (MR), aortic valve stenosis (AS), mitral valve stenosis (MS), and tricuspid regurgitation (TR) were 26.8, 19.7, 5.9, 1.3, and 9.4%, respectively. In stepwise multiple regression analysis, severity of AR was related to age, albumin, and estimated glomerular filtration rate (eGFR); MR was related to eGFR and age; AS was related to eGFR, Lp(a), and age; MS was related to Lp(a) and female gender; and TR was related to age, body mass index, and total cholesterol (all P < 0.05). Lp(a) level was higher in patients with AS compared with those without AS [34.0 (16.7-50.0) vs. 20.0 (11.0-35.0) mg/dL, P = 0.002], in patients with MS compared with those without MS [37.0 (21.5-77.3) vs. 21.0 (11.0-35.0), P = 0.037], and in patients with AS and/or MS compared with those without AS and MS [34.0 (17.3-50.0) vs. 20.0 (11.0-35.0), P = 0.001]. Lp(a) levels were related to low-density lipoprotein cholesterol and high-sensitivity C-reactive protein levels (P = 0.004). CONCLUSIONS: The high prevalence of VHD is found, especially in AR and MR, and the Lp(a) level is associated with increased risks of AS and MS in patients with PAD.

15-Year Patency and Life Expectancy After Primary Stenting Guided by Intravascular Ultrasound for Iliac Artery Lesions in Peripheral Arterial Disease.

OBJECTIVES: The purpose of this study was to evaluate 15-year patency and life expectancy after endovascular treatment (EVT) with primary stenting guided by intravascular ultrasound (IVUS) for iliac artery lesions. BACKGROUND: Fifteen-year patency, factors causing restenosis, and survival after IVUS-guided EVT are unclear based on the TransAtlantic Inter-Society Consensus II (TASC-II) classification in peripheral arterial disease (PAD). METHODS: EVT was performed for 507 lesions in 455 patients with PAD. The 15-year endpoints were primary, primary-assisted, and secondary patency; overall survival; freedom from major adverse cardiovascular events (MACE); and freedom from major adverse cardiovascular and limb events (MACLE). RESULTS: The 5-, 10-, and 15-year primary and secondary patencies were 89%, 83%, and 75%, respectively, and 92%, 91%, and 91%, respectively. There were no significant differences among TASC-II categories. CONCLUSIONS: IVUS-guided stenting for the iliac artery had favorable 15-year patency in all TASC categories. Life expectancy after EVT was poor, but stenting is feasible for patients with PAD.

High-sensitivity C-reactive Protein, Lipoprotein(a) and Homocysteine are Risk Factors for Coronary Artery Disease in Japanese Patients with Peripheral Arterial Disease.

AIM: The goal of the study was to investigate the relationships between coronary artery disease (CAD) and risk factors, including the serum levels of high-sensitivity C-reactive protein (hs-CRP), lipoprotein(a) (Lp(a)) and homocysteine, in Japanese patients with peripheral arterial disease (PAD). METHODS: Coronary angiography was performed in 451 patients with PAD, among whom the prevalence and clinical characteristics of CAD were analyzed. A multiple logistic analysis was used to evaluate the relationships between CAD and the risk factors. The relationships between the severity of coronary arterial lesions and the risk factors were evaluated using multiple regression analysis. RESULTS: The prevalence of CAD (≥70% luminal diameter narrowing or a history of CAD) and coronary artery stenosis (≥50%) was 55.9% and 74.1%, respectively, and the rate of CAD (≥70%) with single-, double- and triple-vessel disease was 25.9%, 13.5% and 10.6%, respectively. The prevalence of diabetes was higher among the patients with CAD than among those without. The serum levels of hs-CRP, Lp(a), and homocysteine were higher in the patients with CAD, whereas the estimated glomerular filtration rates and HDL-cholesterol levels were lower in these patients. According to the multiple logistic analysis, CAD was related to diabetes (hazard ratio [HR]: 2.253; 95% confidence interval [CI]: 1.137-4.464, p=0.020), hs-CRP (HR: 1.721; 95% CI: 1.030-2.875, p=0.038), Lp(a) (HR: 1.015; 95% CI: 1.001-1.029, p=0.041) and homocysteine (HR: 1.084; 95% CI: 1.012-1.162, p=0.021). Furthermore, diabetes and the D-dimer and LDL-cholesterol levels exhibited significant relationships with the number of stenotic coronary lesions in the stepwise multiple regression analysis (p＜0.05). CONCLUSIONS: Diabetes, hs-CRP, Lp(a), homocysteine and lipid abnormalities are critical risk factors for CAD in Japanese patients with PAD.

Differences in brain natriuretic peptide and other factors between Japanese peripheral arterial disease patients with critical limb ischemia and intermittent claudication.

AIM: The goal of this study was to analyze differences in risk factors, including the level of brain natriuretic peptide (BNP) and the distribution of lesions, between cases of critical limb ischemia (CLI) and intermittent claudication (IC) among patients with peripheral arterial disease. METHODS: Risk factors and clinical characteristics were prospectively investigated in 817 consecutive patients, including 185 patients with CLI and 632 patients with IC. RESULTS: The patients in the CLI group were older than those in the IC group (p＜0.001). The prevalence of diabetes and cerebral infarction and the proportion of women were higher in the CLI group (p＜0.05). The plasma BNP levels in the CLI group were higher than those observed in the IC group (333±538 vs. 136±354 pg/mL, p＜0.001). In contrast, the levels of homocysteine and fibrinogen were higher and the levels of albumin and the estimated glomerular filtration rate were lower in the CLI group (p＜0.05). According to a multiple logistic analysis, the BNP level, diabetes, female gender, the albumin level, body mass index (BMI) and ankle-brachial pressure index (ABI) were associated with CLI (p＜0.05). Aortoiliac artery lesions were less common, whereas femoropopliteal and below-the-knee (BK) lesions were more common, in the CLI group (p＜0.05). The number of affected BK arteries was also higher in the CLI group (p＜0.001). Correlations were found between the presence of aortoiliac lesions and smoking and a low HDL cholesterol level, while femoropopliteal lesions were found to correlate with age, BMI and hypertension and BK lesions were found to correlate with diabetes, age, female gender and BMI (p＜0.05). The plasma BNP level correlated with the number of affected BK arteries (p＜0.05). CONCLUSIONS: A high BNP level, diabetes, female gender, a low albumin level, ABI and BMI are risk factors for CLI. In this study, differences in the levels of anatomical lesions and correlated risk factors were found between the CLI and IC groups.

A successful surgical repair of pulmonary stenosis caused by isolated pulmonary Takayasu's arteritis.

A 48-year-old man underwent surgery to treat pulmonary stenoses of unknown origin. The right main pulmonary artery was severely stenotic, and the orifice of the left pulmonary artery was focally constricted. The patient was nearly asymptomatic, despite marked pulmonary hypertension and right heart strain. The pressure gradients beyond the stenotic regions were 88 mmHg bilaterally. The cause of the stenoses could not be established before operation. The right main pulmonary artery and ascending aorta were successfully replaced. It was suspected that the ascending aorta was involved because it was markedly thickened and adhered tightly to the right pulmonary artery. It was therefore also replaced. However, only the transected right pulmonary artery showed histological evidence consistent with a diagnosis of Takayasu's arteritis. The postoperative course was uneventful. The patient was completely free of symptoms six months after the operation. To our knowledge, this is the thirteenth surgically treated case of isolated pulmonary Takayasu's arteritis to be reported.

Prevalence and risk factors for cerebral infarction and carotid artery stenosis in peripheral arterial disease.

OBJECTIVE: The purpose of the study was to examine the prevalence and risk factors for cerebral infarction (CI) and carotid artery stenosis (CAS) in patients with peripheral arterial disease (PAD) compared with normal controls. METHOD: A cross-sectional analysis was performed in 857 subjects (PAD: 543, controls: 314). CI and lacunar infarction (LI) were evaluated using brain computed tomography. Intima-media thickening (IMT) and CAS were measured with ultrasound. RESULTS: The prevalences of CI and LI were higher in patients with PAD than in controls (15.0% vs. 9.8%, 41.0% vs. 13.4%, respectively, p < 0.05). In multiple logistic analysis, CI was associated with diabetes mellitus, low HDL cholesterol and CAS ≥ 70% (p < 0.05). LI was associated with age, PAD, diabetes mellitus, and estimated glomerular filtration rate (p < 0.05). The prevalences of CAS ≥ 70% and CAS ≥ 50% were higher in patients with PAD than in controls (5.2% vs. 0.6%, 17.6% vs. 3.8%, respectively, p < 0.01). Mean and max IMT differed significantly between the two groups (PAD vs. controls: 1.01 ± 0.45 vs. 0.90 ± 0.28, 2.67 ± 2.00 vs. 1.73 ± 1.05 mm, respectively, p < 0.001). CAS ≥ 70% correlated with high LDL cholesterol, and CAS ≥ 50% with age and PAD. IMT was positively correlated with PAD, high LDL cholesterol, age, and hypertension (p < 0.05). CONCLUSIONS: Prevalences of CI and CAS were markedly higher in patients with PAD than in controls, indicating that PAD is a meaningful risk factor for CI, LI, and CAS. This suggests that screening for CI and CAS is important for managements in PAD, as with screening for PAD in patients with stroke.

Sex-related differences in Japanese patients with peripheral arterial disease.

OBJECTIVE: The goal of the study was to examine possible sex-related differences in the clinical characteristics and risk factors in Japanese patients with peripheral arterial disease (PAD). METHODS: Sex-related differences in clinical profiles, risk factors and treatments were examined in 730 consecutive patients with PAD (148 women (20.3%) and 582 men (79.7%)). RESULTS: The mean age of the women was higher than that of the men (73.6 ± 11.2 vs. 70.9 ± 9.1 years old, p = 0.002) and the proportion of subjects aged ≥ 75 years old was also higher in women (P=0.005). Women more frequently had critical limb ischemia (P < 0.001) and diabetes mellitus (P = 0.026), but less frequent smoking and alcohol intake, compared to men (P< 0.001). Total cholesterol (P < 0.001) and LDL cholesterol (P = 0.014) were higher in women. Fontaine stages were correlated with age, diabetes, cerebral infarction and women (p < 0.001). The prevalence of iliac artery lesions was higher in men (p< 0.001), whereas that for below the knee lesions was higher in women (p < 0.001). The number of affected below the knee arteries was also higher in women than in men (p < 0.001). The prevalence of medical treatment was higher in women (P = 0.009) and major amputation tended to be higher in women (p = 0.056). CONCLUSIONS: Women had more severe symptomatic states and uncontrolled risk factors. The prevalence of iliac artery lesions was lower, but below the knee lesions were more severe in women.

Prevalence and risk factors for renal artery stenosis and chronic kidney disease in Japanese patients with peripheral arterial disease.

The prevalence and risk factors for renal artery stenosis (RAS) and chronic kidney disease (CKD) are unclear in Japanese patients with peripheral arterial disease (PAD). To examine these issues, we performed renal angiography in 410 patients with PAD. Renal function and damage were assessed using the estimated glomerular filtration rate (eGFR) and urinary level of microalbumin (MA). Multiple logistic and multiple regression analyses were used to examine the relationships of potential risk factors with RAS and CKD. In all, 94 subjects (22.9%) had RAS >50% and 45 subjects (11.0%) had RAS >75%. The incidences of an abnormal level of MA and renal insufficiency (eGFR <60 ml min(-1) per 1.73 m(2)) were 37.0 and 60.7%, respectively. RAS > or =50% was associated with critical limb ischemia (CLI; hazard ratio (HR) 2.519; 95% confidence interval (CI) 1.203-5.276, P=0.014), coronary heart disease (CHD; HR 2.143; 95% CI 1.129-4.069; P=0.020) and hypertension (HR 1.907; 95% CI 1.009-3.628; P=0.045). RAS > or =75% had a relationship with hypertension (HR 3.093; 95% CI 1.002-9.548; P=0.048). eGFR was negatively correlated with age, uric acid and CHD (P=0.013), and MA had a significant positive correlation with low-density lipoprotein cholesterol, CLI, age, CHD and diabetes (P<0.001). These results show that the prevalences of RAS and CKD are very high in Japanese patients with PAD; that CLI and CHD are major risk factors for RAS; and that hyperuricemia, hypercholesterolemia and diabetes are risk factors for CKD in PAD. We also found that MA is a simple and noninvasive marker of renal dysfunction and general vascular damage.

The influence of the obesity paradox and chronic kidney disease on long-term survival in a Japanese cohort with peripheral arterial disease.

BACKGROUND: This study analyzed risk factors for mortality in peripheral arterial disease (PAD), including body mass index (BMI) and estimated glomerular filtration rate (eGFR). Risk factors for long-term survival are unclear in patients with PAD. The origin of the obesity paradox, a paradoxical decrease in mortality with increasing BMI, is also uncertain in these patients. METHODS: A prospective cohort study was performed in 652 patients (aged 71.3 +/- 9.4 years old) with PAD. RESULTS: The 1-, 5-, 10- and 15-year survival rates were 94.5%, 70.4%, 45.2%, and 21.1%, respectively, in patients with intermittent claudication, and 72.7%, 27.2%, 11.6%, and 5.8%, respectively, in those with critical limb ischemia (CLI). In Cox multivariate analysis, a significant association with all-cause mortality was found for CLI (hazard ratio [HR], 1.931; 95% confidence interval [CI], 1.089-3.422; P = .024), diabetes (HR, 2.111; 95% CI, 1.247-3.572; P = .005), BMI (HR, 0.879; 95% CI, 0.804-0.962; P = .005), and eGFR (HR, 0.985; 95% CI, 0.971-0.998l; P = .028). These parameters were also significant risk factors for cardiovascular mortality. Fibrinogen (HR, 1.003; 95% CI, 1.001-1.005; P = .014) and cerebrovascular disease (HR, 1.730; 95% CI, 1.021-2.930; P = .045) were identified as risk factors for all-cause mortality. The adjusted HR for mortality of BMI <21.5 vs >or=21.5 kg/m(2) was 1.772 (95% CI, 1.378-2.279; P < .001). BMI had positive correlations with triglyceride and albumin concentrations and negative correlations with the fibrinogen level and chronic obstructive pulmonary disease (P = .005). CONCLUSIONS: Low BMI, eGFR, CLI, and diabetes are significant risk factors for mortality in PAD. The obesity paradox was verified and may be partly explained by low BMI mediated by malnutrition and systemic inflammation due to PAD or chronic obstructive pulmonary disease.

Effects of raloxifene on brachial arterial endothelial function, carotid wall thickness, and arterial stiffness in osteoporotic postmenopausal women.

The beneficial effects of raloxifene, a selective estrogen receptor modulator, on cardiovascular risks and events have been investigated. Brachial arterial flow-mediated vasodilatation (FMD), carotid intima-media thickness (IMT), and pulse wave velocity (PWV) have been widely used in clinical settings as surrogate markers of atherosclerosis. This study investigated the simultaneous effects of raloxifene on brachial arterial FMD, carotid IMT, and PWV in osteoporotic postmenopausal women. A total of 31 postmenopausal women with osteoporosis or osteopenia were divided into 2 groups: a raloxifene group (n = 15; mean age +/- SD, 66.1 +/- 8.2 years) was treated with raloxifene hydrochloride (60 mg/day) orally for 12 months, and an untreated control group (n = 16; 64.1 +/- 7.8 years). Brachial arterial FMD, carotid IMT, and brachial-ankle PWV (baPWV) were measured at baseline and at 12 months after the start of the study. The brachial arterial FMD increased significantly, from 4.5 +/- 1.8% to 9.2 +/- 3.0%, in the raloxifene group (P < 0.01) but did not change in the control group. Nitroglycerin-induced vasodilatation did not change in either group. The carotid IMT decreased significantly, from 0.82 +/- 0.15 mm to 0.72 +/- 0.11 mm, in the raloxifene group (P < 0.01) but did not change in the control group. The baPWV did not change in either group. In conclusion, raloxifene may have beneficial effects on brachial arterial endothelial function and carotid wall thickness in osteoporotic postmenopausal women.

Characterization of gamma-Ga2O3-Al2O3 prepared by solvothermal method and its performance for methane-SCR of NO.

The gamma-Ga(2)O(3)-Al(2)O(3) mixed oxides with a spinel structure were prepared by the solvothermal reaction of gallium acetylacetonate and aluminum isopropoxide in diethylenetriamine. In the crystal structures of the catalysts obtained by the calcination of these mixed oxides, Ga(3+) and Al(3+) ions preferentially occupied tetrahedral and octahedral sites, respectively. The catalysts with low Ga contents had a unique structure with high surface areas and a concentration gradient of decreasing Ga content from the surface to the bulk. In methane-selective catalytic reduction (SCR) of NO, higher NO conversion to N(2) was attained on the catalyst with high occupation of Ga(3+) ions at tetrahedral sites and Al(3+) ions at octahedral sites. For the gamma-Ga(2)O(3)-Al(2)O(3) mixed oxide with a charged Ga molar content of 0.3 (ST(0.3)), tetrahedral and octahedral sites were solely occupied by Ga(3+) and Al(3+) ions, respectively, and the catalyst exhibited the highest NO conversion to N(2). Therefore, it was concluded that the active site for methane-SCR of NO is tetrahedral Ga(3+) ion and octahedral Al(3+) ion, which are linked to each other. Nitrogen monoxide is adsorbed on the isolated hydroxyl group attached to Al(3+) ions and then oxidized by O(2) yielding surface nitrate species. Tetrahedral Ga(3+) ions work as Lewis acid sites for the activation of methane because of their coordinative unsaturation. The Ga(3+) ions in the gamma-Ga(2)O(3)-Al(2)O(3) catalyst have a redox property, which plays important roles in both the oxidation of NO to surface nitrate species and the activation of methane. The most important factor for this catalyst is that the sites for the formation of surface nitrate species reside next to the methane activation sites, which facilitates the reaction between surface nitrate species and the activated species derived from methane, thus mitigating the consumption of methane by simple combustion with O(2). Therefore, ST(0.3), which has the largest number of ensembles of the tetrahedral Ga(3+) ions and octahedral Al(3+) ions, shows the highest activity for methane-SCR of NO.

Ten-year patency and factors causing restenosis after endovascular treatment of iliac artery lesions.

BACKGROUND: Long-term outcome and the factors associated with restenosis after endovascular treatment (EVT) for iliac artery lesions in peripheral arterial disease (PAD) were evaluated. METHODS AND RESULTS: EVT was performed for 487 lesions (TransAtlantic Inter-Society Consensus-II (TASC-II) Type-A: 275, B: 115, C: 37, and D: 60) in 436 PAD patients. The initial success rates for Type-B and Type-D lesions were lower than for Type-A lesions (P<0.05). The 3-, 5- and 10-year patency rates were 67%, 54% and 50%, respectively, with plain-old balloon angioplasty (POBA), and 88%, 82% and 75%, respectively, for stenting after suboptimal POBA, showing a significantly higher patency after treatment with a stent (P<0.001). With POBA, the long-term patency for Type-C/D lesions was lower than for Type-A/B lesions (P<0.05), but the patency after stenting did not differ significantly between Type-C/D and A/B. In the univariate analysis, the TASC-II classification, lesion length, pre- and post-procedural stenosis rates and stent use were found to be significant factors associated with restenosis (P<0.05). In the multivariate analysis, stent use (hazard ratio (HR) 0.345, confidence interval (CI) 0.193-0.616, P<0.001) and the post-procedural stenosis rate (HR 1.015, CI 1.001-1.030, P<0.05) were significantly associated with restenosis. CONCLUSIONS: Stent use and a low residual stenosis rate are significantly associated with patency, and favorable long-term patency can be obtained with stent placement for selected TASC-II Type-C/D lesions.

Effects of a stable prostacyclin analogue beraprost sodium on VEGF and PAI-1 gene expression in vascular smooth muscle cells.

BACKGROUND: Beraprost sodium, an orally active prostacyclin analogue, has proved to be beneficial for the patients with primary pulmonary hypertension and obstructive peripheral arterial disease. METHODS: In this study, we examined the effects of BPS on the expression of the VEGF and PAI-1 genes in vascular smooth muscle cells. RESULTS: The mRNA levels for VEGF were increased by BPS in C2/2 cells and cultured rat aortic smooth muscle cells. In contrast, PAI-1 mRNA levels were significantly decreased by BPS. Luciferase assays and mRNA decay assays showed that BPS increases VEGF promoter activity and has no effects on its mRNA stability. Likewise, BPS decreases PAI-1 promoter activity without affecting its mRNA stability. Experiments using various pharmacological inhibitors for protein kinases showed that activation of cAMP-dependent protein kinase (PKA) was involved in BPS-mediated regulation of VEGF and PAI-1 mRNA expression. Overexpression of CREB (cAMP-responsive element binding protein) induces VEGF promoter and reduces PAI-1 promoter activities. CREMepsilon, a dominant negative form of CREB, inhibits BPS-mediated changes in VEGF and PAI-1 promoter activities. While BPS augmented hypoxia-induced VEGF mRNA expression, it blunted hypoxia-induced PAI-1 mRNA expression. CONCLUSION: These results suggest that BPS increases VEGF and decreases PAI-1 gene expression through PKA/CREB-dependent mechanisms in vascular smooth muscle cells. Because these effects are observed more prominently under the hypoxic condition compared to normoxic condition, BPS may have a potential to relieve hypoxia by inducing neovasculization and by reducing thrombosis.

Intravascular Ultrasound Analysis of Correlation between Plaque-Morphology and Risk Factors in Peripheral Arterial Disease.

OBJECTIVE: To analyze relationships between plaque-morphology classified by intravascular ultrasound (IVUS) and risk factors in patients with peripheral arterial disease (PAD). METHODS: We performed IVUS in 203 patients with PAD. Multiple regression and logistic analysis were used to assess relationships between plaque-morphology (degree of calcification, presence of a lipid core, intimal flap and thrombus) and risk factors including diabetes mellitus, hypertension, dyslipidemia, estimated glomerular filtration rate (eGFR), HbA1c and the homeostasis model assessment-insulin resistance ratio (HOMA-IR). RESULTS: IVUS data led to 22% of lesions being classified as soft, 18% as fibrous, 32% as calcified, and 28% as mixed. Calcification was present in the superficial and deep layers in 65% and 35% of cases, respectively, and a lipid core, intimal flap and thrombus were found in 31%, 5.4% and 3.0%, respectively. The calcified angle correlated with HbA1c and eGFR (p < 0.05). Associations were found between deep calcification and HOMA-IR (odds ratio: 4.4, p < 0.05) and a lipid core and hypercholesterolemia (odds ratio: 3.2, p < 0.05). The odds ratio for intimal flap was 15.6 times with hypercholesterolemia (p < 0.05) and 16.9 times with a high HOMA-IR (p < 0.01). CONCLUSION: Plaque calcification and morphology are associated with chronic kidney disease, insulin resistance and dyslipidemia in PAD patients.

Effects of antiplatelet agents and other factors on neointimal proliferation in iliac artery stenting: intravascular ultrasound analysis.

OBJECTIVE: To use intravascular ultrasound to investigate the effects of antiplatelet agents and other factors on neointimal proliferation after stent implantation for iliac artery stenosis. PATIENTS AND METHODS: The subjects were 109 patients with peripheral arterial disease who underwent stent implantation in the iliac artery. Intravascular ultrasound was performed to evaluate lesion area, stent dilatation and neointimal proliferation before, just after, and six months after stenting. Multiple regression analysis was performed to examine the relationship of the neointimal proliferation rate with antiplatelet agents and other factors. RESULTS: At the time of stent implantation, a Palmaz stent resulted in a significant increase in lumen area compared with a Wallstent (p < 0.05). Six months later, self-expanding Wallstent and Luminexx stents showed a significant increase in the stent-lumen area (p < 0.05). The neointimal proliferation rate showed a significant negative correlation with beraprost and cilostazol (p < 0.05) and a significant positive correlation with serum creatinine (p < 0.01). There was no significant difference in the vessel lumen area including the proliferated intima among the three stents. CONCLUSION: Suppression of neointimal proliferation can be achieved with beraprost or cilostazol whereas renal dysfunction may increase neointimal proliferation following stent implantation in iliac artery lesions.

HERP1 inhibits myocardin-induced vascular smooth muscle cell differentiation by interfering with SRF binding to CArG box.

OBJECTIVE: Myocardin is a coactivator of serum response factor (SRF) required for vascular smooth muscle cell (VSMC) differentiation. HERP1 is a transcriptional repressor, which is abundantly expressed in vascular system and is known to function as a target gene of Notch. However, the role of HERP1 in the pathogenesis of vascular lesions remains unknown. The present study characterizes the expression of HERP1 in normal and diseased vessels, and tests the hypothesis that HERP1 inhibits SRF/myocardin-dependent SMC gene expression. METHODS AND RESULTS: Immunohistochemistry revealed that HERP1 and myocardin expression was localized to SMC in the neointima of balloon-injured rat aorta and in human coronary atherosclerotic lesions. Expression of both HERP1 and myocardin was elevated in cultured VSMCs compared with medial SMC. Overexpressed HERP1 inhibited the myocardin-induced SMC marker gene expression in 10T1/2 cells. HERP1 protein interfered with the SRF/CArG-box interaction in vivo and in vitro. Immunoprecipitation assays showed that HERP1 physically interacts with SRF. CONCLUSIONS: HERP1 expression was associated with the SMC proliferation and dedifferentiation in vitro and in vivo. HERP1 may play a role in promoting the phenotypic modulation of VSMCs during vascular injury and atherosclerotic process by interfering with SRF binding to CArG-box through physical association between HERP1 and SRF.

Mitochondrial reactive oxygen species and c-Src play a critical role in hypoxic response in vascular smooth muscle cells.

OBJECTIVE: Thickened atherosclerotic plaques are prone to be hypoxic because of poor perfusion. In this study, we tested (a) whether reactive oxygen species (ROS) and c-Src play roles in hypoxic induction of HIF-1alpha protein and PAI-1 gene expression in the rabbit aortic smooth muscle cell line C2/2 cells and primary cultures of rat aortic smooth muscle cells, and (b) how mitochondria act on the hypoxia-induced signaling mechanism. METHODS AND RESULTS: Hypoxic exposure of C2/2 cells increased H2O2 generation, c-Src phosphorylation, HIF-1alpha protein expression, and PAI-1 gene expression. Catalase, a scavenger of H2O2, inhibited the hypoxia-induced ROS generation and PAI-1 gene expression. Src kinase inhibitors PP1 and PP2 inhibited hypoxia-induced HIF-1alpha protein and PAI-1 gene expression. Ablation of mitochondrial respiration by rotenone abolished hypoxia-induced ROS generation, c-Src phosphorylation, HIF-1alpha protein expression, and PAI-1 gene expression. CONCLUSION: Induction of HIF-1alpha protein and PAI-1 gene expression in response to hypoxia was regulated by ROS production and c-Src activation in vascular smooth muscle cells. Mitochondria linked the hypoxic signal to c-Src, which in turn led to HIF-1alpha protein and PAI-1 gene expression. These results provide evidence that hypoxia induces the ROS-mediated and c-Src-dependent signaling cascades which are closely associated with angiogenesis and thrombosis in atherosclerotic vasculature.