Development of the Rabbit NASH Model Resembling Human NASH and Atherosclerosis.

Non-alcoholic steatohepatitis (NASH) is a chronic liver disease which may progress into liver fibrosis and cancer. Since NASH patients have a high prevalence of atherosclerosis and ensuing cardiovascular diseases, simultaneous management of NASH and atherosclerosis is required. Currently, rodents are the most common animal models for NASH and accompanying liver fibrosis, but there are great differences in lipoprotein profiles between rodents and humans, which makes it difficult to reproduce the pathology of NASH patients with atherosclerosis. Rabbits can be a promising candidate for assessing NASH and atherosclerosis because lipoprotein metabolism is more similar to humans compared with rodents. To develop the NASH model using rabbits, we treated the Japanese White rabbit with a newly developed high-fat high-cholesterol diet (HFHCD) containing palm oil 7.5%, cholesterol 0.5%, and ferrous citrate 0.5% for 16 weeks. HFHCD-fed rabbits exhibited NASH at 8 weeks after commencing the treatment and developed advanced fibrosis by the 14th week of treatment. In addition to hypercholesterolemia, atherosclerotic lesion developed in the aorta after 8 weeks. Therefore, this rabbit NASH model might contribute to exploring the concurrent treatment options for human NASH and atherosclerosis.

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.