Animal models that closely resemble both human disease findings and their onset mechanism have contributed to the advancement of biomedical science. The Watanabe heritable hyperlipidemic (WHHL) rabbit and its advanced strains (the coronary atherosclerosis-prone and the myocardial infarction-prone WHHL rabbits) developed at Kobe University (Kobe, Japan), an animal model of human familial hypercholesterolemia, have greatly contributed to the elucidation of the pathophysiology of human lipoprotein metabolism, hypercholesterolemia, atherosclerosis, and coronary heart disease, as described below. 1) The main part of human lipoprotein metabolism has been elucidated, and the low-density lipoprotein (LDL) receptor pathway hypothesis derived from studies using fibroblasts was proven in vivo. 2) Oxidized LDL accumulates in the arterial wall, monocyte adhesion molecules are expressed on arterial endothelial cells, and monocyte-derived macrophages infiltrate the arterial intima, resulting in the formation and progression of atherosclerosis. 3) Coronary lesions differ from aortic lesions in lesion composition. 4) Factors involved in the development of atherosclerosis differ between the coronary arteries and aorta. 5) The rupture of coronary lesions requires secondary mechanical forces, such as spasm, in addition to vulnerable plaques. 6) Specific lipid molecules in the blood have been identified as markers of the progression of coronary lesions. At the end of the breeding of the WHHL rabbit family at Kobe University, this review summarizes the history of the development of the WHHL rabbit family and their contribution to biomedical science.

A number of effective drugs have been developed through animal experiments, contributing to the health of many patients. In particular, the WHHL rabbit family (WHHL rabbits and its advanced strains (coronary atherosclerosis-prone WHHL-CA rabbits and myocardial infarction-prone WHHLMI rabbits) developed at Kobe University (Kobe, Japan) contributed greatly in the development of cholesterol-lowering agents. The WHHL rabbit family is animal models for human familial hypercholesterolemia, coronary atherosclerosis, and coronary heart disease. At the end of breeding of the WHHL rabbit family, this review summarizes the contribution of the WHHL rabbit family to the development of lipid-lowering agents and anti-atherosclerosis agents. Studies using the WHHL rabbit family demonstrated, for the first time in the world, that lowering serum cholesterol levels or preventing LDL oxidation can suppress the progression and destabilization of coronary lesions. In addition, the WHHL rabbit family contributed to the development of various compounds that exhibit lipid-lowering and anti-atherosclerotic effects and has also been used in studies of gene therapeutics. Furthermore, this review also discusses the causes of the increased discrepancy in drug development between the results of animal experiments and clinical studies, which became a problem in recent years, and addresses the importance of the selection of appropriate animal models used in studies in addition to an appropriate study design.

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.

Aims: Low-density lipoprotein (LDL)-lowering statin therapy is an established secondary stroke prevention strategy. However, the differential impact of key non-LDL levels on recurrent stroke risk, while on lipid-modifying therapy (LT), remains unclear.

Methods: We analyzed the dataset of a multicenter trial involving 3640 recent (＜4 months) noncardioembolic stroke patients followed for 2 years. Participants were categorized into four groups of presumed improving lipid profile: level 0, no LT prescribed; level I, LT use with low high-density lipoprotein cholesterol (HDL-C) (＜40 mg/dL for men; ＜50 mg/dL for women); level II, LT use with high HDL-C (≥ 40 mg/dL and ≥ 50 mg/dL, respectively); and level III, level II with low triglycerides (＜150 mg/dL). Independent associations of LT category with stroke, major vascular events (MVEs; stroke/coronary heart disease/vascular death), and all-cause death were assessed.

Results: LTs were mostly statins (＞95%). The unadjusted recurrent stroke rate declined with LT category level (9.2% for level 0; 8.4% for level I; 7.5% for level II; and 5.7% for level III). Compared with level 0, the adjusted hazard ratio of stroke for level I was 0.78 (95% confidence interval (CI), 0.59–1.03), level II 0.80 (0.54–1.18), and level III 0.63 (0.43–0.91). Multivariable analyses of MVEs and all-cause death followed a similar pattern of declining risk with higher LT category level.

Conclusions: Compared with the nonuse of LT, there may be a hierarchy of residual vascular risk after stroke by non-LDL type and target, while on LT. Particularly, stroke patients with low HDL-C levels on LT may benefit from additional therapeutic strategies to improve their outcomes.

Aim: Obesity and metabolic syndrome (MetS) frequently coexist and are both important risk factors for cardiovascular disease. However, the pathophysiological role of obesity without MetS, also referred to as metabolically healthy obesity (MHO), remains unclear. In this study, we aim to clarify the effect of MHO on the development of carotid plaque using a community-based cohort.

Methods: We examined 1,241 subjects who underwent health checkups at our institute. Obesity was defined as body mass index of ≥ 25.0 kg/m². Subjects were divided into three groups: non-obese, MHO, and metabolically unhealthy obesity (MUO).

Results: The prevalence of carotid plaque, defined as intima-media thickness (IMT) ≥ 1.1 mm, was higher in subjects with MUO and MHO than in non-obese subjects. Multivariable analysis demonstrated that MHO (odds ratio 1.6, p=0.012) and MUO (odds ratio 1.9, p=0.003) as well as age of ≥ 65 years, male sex, hypertension, and diabetes mellitus were independently associated with carotid plaque formation. A similar trend was observed in each subgroup according to age and sex.

Conclusions: MHO increased the prevalence of carotid plaque when compared with non-obese subjects, suggesting the potential significance of MHO in the development of subsequent cardiovascular diseases.

Aim: Paclitaxel-eluting stents' (Eluvia and Zilver PTX) effectiveness has been recently reported for femoropopliteeal (FP) lesions. However, there is no evaluation of one-year late lumen loss (LLL). Therefore, we evaluated one-year LLL after implantation with Eluvia or Zilver PTX.

Methods: This was a multicenter, prospective study. Patients who had symptomatic de novo lesions in the native FP artery were enrolled. The primary endpoint was one-year angiographic LLL, and the secondary endpoints were binary restenosis and target lesion revascularization (TLR) at one year.

Results: From December 2015 to December 2016, 48 patients (Eluvia, 36 patients; Zilver PTX, 12 patients) were enrolled. No significant difference was found in baseline and lesion characteristics between both groups. One-year, LLL was significantly lower in the Eluvia group (0.60 {plus minus}0.80 mm) than in the Zilver PTX group (1.74 {plus minus}0.89 mm) (P=0.0003). Negative LLL was observed only in the Eluvia group (0% vs. 23%, p=0.096). The binary restenosis rate was significantly lower than in the Zilver PTX group (0% vs. 16.7%, P=0.012). The one-year TLR in the Eluvia group tended to be lower (0% vs. 8.3%, P=0.08). Stent thrombosis was not observed in either group.

Conclusion: One-year LLL in the Eluvia group was significantly lower than that in the Zilver PTX group for FP lesions.

Aim: Takayasu arteritis (TAK) is a rare inflammatory large-vessel vasculitis with increased cardiovascular morbidity and mortality. Brachial-ankle pulse wave velocity (ba-PWV) is a widely used measure of arterial stiffness and serves as an indicator of either cardiovascular risk or severity of vascular damage. However, the studies about the relationship between TAK and ba-PWV are limited. This study aimed to investigate the use of ba-PWV in the patients with TAK.

Methods: Sixty-seven patients with TAK and 67 age and sex matched healthy controls were recruited. Patients with TAK were grouped according to disease activity. The routine hematological parameters and ba-PWV were summarized.

Results: Ba-PWV was significantly higher in the patients with TAK than in the healthy controls (P＜0.001). Ba-PWV was significantly higher in the patients with active TAK than in the patients with inactive TAK (P= 0.04). Multiple liner regression analysis indicated that TAK (β=363.97, P=0.013), and mean arterial pressure (MAP) (β=8.52, P=0.012) were independently related to ba-PWV. Ba-PWV did not correlate with C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) in overall patients with TAK (both P＞0.05). In patients with TAK without immunosuppressive therapy, ba-PWV significantly correlated with CRP (r=0.419, P=0.008) but not ESR (P＞0.05). Multiple logistic regression analysis indicated that ba-PWV was an independent predictor of active TAK in overall patients with TAK (OR=1.003, 95% CI=1.000–1.007; P=0.040) and patients with TAK without immunosuppressive therapy (OR=1.006, 95% CI=1.001–1.012; P=0.031).

Conclusions: Being significantly increased in patients with TAK, ba-PWV is significantly associated with TAK disease activity, and it probably correlates with systematic inflammation.