Diabetes is a leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in developed nations, including Japan and the United States. Japan has the unenviable distinction of having one of the world’s highest rates of dialysis: in 2011, there were over 300,000 dialysis patients (2,383 per million people), with diabetic patients accounting for almost half of all incident cases. Concomitance of CKD and diabetes predicts a greater risk of cardiovascular disease (CVD) than either condition in isolation. Hence, appropriate management of modifiable cardiovascular (CV) risk factors, including dyslipidemia, is paramount in this high-risk group. The United States and Japan have distinct approaches to cholesterol management, with more stringent therapeutic targets for lipid control advocated in US guidelines. However, upward trends in cholesterol levels and coronary heart disease incidence in Japan may provide justification for more intensive CV risk factor management strategies by Japanese physicians to achieve maximum benefit. Attainment of recommended lipid goals in Japan is poor, particularly in patients with diabetes and/or CKD in whom CV risk factors are often undertreated. Statin therapy has been shown to be safe and effective in reducing CV risk in patients with diabetes and/or CKD stages 1-5. Moreover, statins may impart a renoprotective effect by preventing or delaying progressive loss of kidney function. This review summarizes evidence from studies in Western and Japanese populations to highlight the CV and renal benefits of lipid-lowering agents in CKD patients, including those with diabetes.
Aim: Paracrine interaction between macrophages and adipocytes in obese visceral fat tissues is thought to be a trigger of chronic inflammation. The immunomodulatory effect of the short chain fatty acid, butyric acid, has been demonstrated. We hypothesize that sodium butyrate (butyrate) attenuates inflammatory responses and lipolysis generated by the interaction of macrophages and adipocytes. Methods: Using contact or transwell co-culture methods with differentiated 3T3-L1 adipocytes and RAW264.7 macrophages, we investigated the effects of butyrate on the production of tumor necrosis factor alpha (TNF-α), monocyte chemoattractant protein 1 (MCP-1), interleukin 6 (IL-6), and the release of free glycerol, free fatty acids (FFAs) into the medium. We also examined the activity of nuclear factor-kappaB (NF-κB) and the phosphorylation of mitogen-activated protein kinases (MAPKs) in co-cultured macrophages, as well as lipase activity and expression in co-cultured adipocytes. Results: We found increased production of TNF-α, MCP-1, IL-6, and free glycerol, FFAs in the co-culture medium, and butyrate significantly reduced them. Butyrate inhibited the phosphorylation of MAPKs, the activity of NF-κB in co-cultured macrophages, and suppressed lipase activity in co-cultured adipocytes. Lipase inhibitors significantly attenuated the production of TNF-α, MCP-1 and IL-6 in the co-culture medium as effectively as butyrate. Butyrate suppressed the protein production of adipose triglyceride lipase, hormone sensitive lipase, and fatty acid-binding protein 4 in co-cultured adipocytes. Pertussis toxin, which is known to block GPR41 completely, inhibited the antilipolysis effect of butyrate. Conclusion: Butyrate suppresses inflammatory responses generated by the interaction of adipocytes and macrophages through reduced lipolysis and inhibition of inflammatory signaling.
Aim: The cardio-ankle vascular index (CAVI) is a novel non-invasive marker of arterial stiffness and atherosclerosis. The aim of this work was to examine whether the CAVI value in patients with dyslipidaemia (DLP) is increased by the presence of other cardiovascular risk factors: hypertension, diabetes mellitus, and smoking. Methods: A total of 392 subjects with DLP (166 male, 226 female), with a median age of 58.5 and 5-95 percentile range 32.2-73.9 years were examined. CAVI was measured using the VaSera 1500 system. Results: CAVI correlated significantly with age (p<0.001) and both systolic (p<0.001) and diastolic (p=0.002) blood pressure; higher values were found in men (p=0.034) than in women in the 56-65 age group. There was no significant difference in CAVI between smokers and non-smokers (p= 0.217) and between subjects with and without diabetes mellitus (p= 0.424). CAVI was significantly higher in subjects with hypertension than in the normotensive group (p<0.001) and in statin-treated subjects than in those without statins (p<0.001); however, CAVI values adjusted for age and sex did not differ significantly between these groups. Adjusted CAVI values were higher only in smokers than in non-smokers (former smokers) (p<0.001). Conclusion: The study proves conclusively that the CAVI value in DLP patients is not significantly affected by hypertension and diabetes mellitus, but it is increased by smoking.
Aims: To investigate the clinical predictors of coronary atherosclerosis and to assess the utility of maximum-IMT for predicting coronary atherosclerosis in asymptomatic type 2 diabetic patients. Methods: One hundred one Japanese patients with type 2 diabetes underwent computed tomography coronary angiography. Definitions of coronary artery stenosis and vulnerable coronary plaque were luminal narrowing of ≥50% and any coronary plaque with positive vessel remodeling and low attenuation, respectively. Carotid intima-media thickness (IMT) was assessed using B-mode ultrasound. Results: Of the 101 patients, 40 had coronary artery stenosis without vulnerable coronary plaque, 7 had vulnerable coronary plaque without coronary artery stenosis, and 23 had coronary artery stenosis with vulnerable coronary plaque. Male sex (p=0.031), duration of diabetes (p=0.024), systolic blood pressure (SBP) (p=0.039), and the LDL/HDL ratio (LDL/HDL) (p=0.013) were independent predictors of coronary artery stenosis and the LDL/HDL (p=0.042) independently predicted vulnerable coronary plaque by logistic regression analyses. Areas under the curves in receiver operating characteristic curve analysis of the maximum-IMT, LDL/HDL, and these two parameters combined were 0.711 (95% CI 0.601-0.820), 0.618 (0.508-0.728), and 0.732 (0.632-0.831), respectively, for predicting coronary artery stenosis and 0.655 (0.537-0.773), 0.629 (0.504-0.754), and 0.710 (0.601-0.818), respectively, for predicting vulnerable coronary plaque. Conclusions: Male sex, duration of diabetes, elevated SBP, and LDL/HDL were independent predictors of coronary artery stenosis. LDL/HDL was an independent predictor of vulnerable coronary plaque. Maximum-IMT predicted both coronary stenosis and vulnerable coronary plaque. Adding LDL/HDL improved the prediction of coronary artery stenosis and vulnerable coronary plaque.
Aim: At present, limited in vivo information is available on the prevalence and severity of coronary atherosclerosis in asymptomatic healthy subjects. The aim of this study was to examine the prevalence, extent and severity of coronary atherosclerosis in healthy individuals. Methods: We performed an intravascular ultrasound (IVUS) examination on 198 heart transplant recipients 4 weeks after transplantation. The donor population consisted of 147 men and 51 women (31.4±11.0 years). The left anterior descending coronary artery was imaged in all patients, and 3 vessel images were obtained for 99 patients. Results: Angiographic appearance was completely normal in 177 of the 198 subjects (89.4%), while atherosclerotic luminal irregularities were observed in the remaining individuals. IVUS revealed that atherosclerotic lesions (defined as intimal thickness ≥0.5 mm at any site) were present in 96 patients (48.5%). The prevalence of coronary atherosclerosis rapidly increased with age (10-19 years, 5.9%; 20-29 years, 31.1%; 30-39 years, 59.0%; 40-49 years, 78.4%). In the diseased subgroup, atherosclerotic lesions were mostly eccentric (92.7%), with maximal intimal thickness of 0.99±0.42 mm (area stenosis, 32.2±11.7%). All coronary arteries were predominantly located in the proximal third of each vessel. Donor age, male sex, and hypertension were the determinants of coronary atherosclerosis measured by IVUS examination. As more risk factors were present, the risk of atherosclerosis increased. Conclusion: Coronary atherosclerosis is common in asymptomatic young healthy adults, supporting the need for preventive cardiology in the early stages of life.
Aim: Few multicenter studies have assessed the effects of angiotensin receptor blockers on cardiovascular events after drug-eluting stent implantation in patients with ischemic heart disease. Methods: An open-label multicenter randomized prospective study is in progress to evaluate the effects of candesartan on cardiovascular events in patients with ischemic heart disease after implantation of sirolimus- and/or paclitaxel-eluting stents. Results: A total of 1,145 patients were enrolled at 39 institutes in the Candesartan for prevention of Cardiovascular events after CYPHER or TAXUS Coronary stenting (4C trial). Patients were randomized into a group treated with candesartan (n=602) and a group treated with standard medical therapy without candesartan (n=543). The primary endpoint of the 4C trial is a composite of all-cause death, successful resuscitation after cardiopulmonary arrest and cardiovascular events including non-fatal myocardial infarction, unstable angina requiring emergent hospitalization, congestive heart failure requiring emergent hospitalization and cerebrovascular attacks. All patients will be followed-up for 36 months. Conclusions: The 4C trial will be the first multicenter study to elucidate the effects of candesartan after drug-eluting stent implantation and may provide new information to optimize medical therapy after percutaneous coronary interventions.
Aim: Familial apolipoprotein C-II (apoC-II) deficiency is a rare autosomal recessive disorder with marked hypertriglyceridemia resulting from impaired activation of lipoprotein lipase. In most cases of apoC-II deficiency, causative mutations have been found in the protein-coding region of APOC2; however, several atypical cases of apoC-II deficiency were reported to have markedly reduced, but detectable levels of plasma apoC-II protein (hereafter referred to as hypoapoC-II), which resulted from decreased promoter activity or improper splicing of apoC-II mRNA due to homozygous mutations in APOC2. Here we aim to dissect the molecular bases of a new case of hypoapoC-II. Methods: We performed detailed biochemical/genetic analyses of our new case of hypoapoC-II, manifesting severe hypertriglyceridemia (plasma triglycerides, 3235 mg·dL-1) with markedly reduced levels of plasma apoC-II (0.6 mg·dL-1). Results: We took advantage of a monocyte/macrophage culture system to prove that transcription of apoC-II mRNA was decreased in the patient’s cells, which is compatible with the reported features of hypoapoC-II. Concomitantly, transcriptional activity of the minigene reporter construct of the patient’s APOC2 gene was decreased; however, no rare variant was detected in the patient’s APOC2 gene. Fifty single nucleotide variants were detected in the patient’s APOC2, but all were common variants (allele frequencies ＞35%) that are supposedly not causative. Conclusions: A case of apoC-II deficiency was found that is phenotypically identical to hypoapoC-II but with no causative mutations in APOC2, implying that other genes regulate apoC-II levels. The clinical entity of hypoapoC-II is discussed.
Aim: Probucol has antioxidant as well as cholesterol-lowering effects. We examined the effect of probucol on the progression of diabetic nephropathy. We named this study ‘Sakura Study’ after our hospital and city. Methods: We performed a randomized, open trial on 162 type 2 diabetic patients with clinical albuminuria (urinary albumin excretion >300 mg/g creatinine). Eighty patients were assigned to probucol treatment (500 mg/day) and 82 patients to no probucol treatment. All patients were followed for five years. The primary outcome was the time to renal dysfunction events, defined as the initiation of chronic hemodialysis therapy and renal dysfunction-related death. Results: Probucol decreased total cholesterol, HDL-cholesterol, and LDL-cholesterol compared to the control group. The serum creatinine increase rate was significantly lower (p= 0.015) in the probucol group (0.066 mg/dL/month) than in the non-probucol group (0.116 mg/dL/month). Renal dysfunction events occurred in 72 patients during this study. The 69 patients who were initiated on chronic hemodialysis comprised 42 in the non-probucol group and 27 in the probucol group. Three patients in the non-probucol group, but no patients in the probucol group died of renal dysfunction. The renal dysfunction event-free survival rate was significantly higher (log-rank: p= 0.02) in the probucol group than in the non-probucol group. Conclusion: Probucol suppressed the progression of diabetic nephropathy and renal dysfunction events.
Aims: The incidence of cardiovascular events increases after a large earthquake, but the mechanism is not fully understood. The cardio-ankle vascular index (CAVI) reflects the stiffness of the artery from the origin of the aorta to the ankles and is independent of blood pressure. To determine the effect of a major earthquake on CAVI in healthy volunteers and in patients with cardiovascular risks. Methods and Results: Our hospital is situated about 300 km from the epicenter of the earthquake that occurred in Japan in 2011. In study 1, healthy volunteers were included. In study 2, patients with cardiovascular factors were included. In study 1, the mean CAVI was 7.3±1.0 just after the earthquake. After 7-14 days, the mean CAVI had decreased to 6.8±1.1 (compared to firstt measurement, p<0.05). Furthermore, the CAVI value 30 days after the earthquake was 7.0±1.1. The blood pressure did not change during these 30 days. In study 2, the mean CAVI 12 and 6 months before the earthquake were 8.95±0.76 and 8.99±0.83, respectively. The CAVI was 9.34±1.0 just after the earthquake and had decreased to 8.83±0.76 6 months later (compared to after the earthquake, p< 0.05). The blood pressure increased slightly at the time of earthquake, but was not significantly different from before the earthquake. Conclusions: CAVI increased in healthy people and also in patients with cardiovascular risks just after the earthquake, even far from the epicenter.