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Since torcetrapib, an inhibitor of cholesteryl ester transfer protein, markedly increases levels of high-density lipoprotein cholesterol and lowers levels of low-density lipoprotein cholesterol, in principle it might have a beneficial effect on atherosclerosis. However, in this clinical trial, torcetrapib had no beneficial effect on carotid atherosclerosis, as assessed by ultrasonographic measurement of carotid intima–media thickness. The reasons for this finding are unclear, but the drug did increase blood pressure slightly. In this clinical trial, torcetrapib had no beneficial effect on carotid atherosclerosis, as assessed by ultrasonographic measurement of carotid intima–media thickness.Published Online March 26, 2007 (DOI:10.1056/NEJMoa071359) Guidelines for the prevention and management of cardiovascular disease focus on reducing levels of low-density lipoprotein (LDL) cholesterol by means of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (collectively referred to as statins). 1 , 2 However, recent meta-analyses have shown that even with the most aggressive treatment, 3 , 4 these drugs reduce the risk of a major coronary event by only 30%. 5 This finding, combined with an estimation that mortality from cardiovascular causes will increase worldwide by 90% by the year 2020, as compared with that in 1990, 6 illustrates the need for new efficacious treatments. A review of four large, prospective epidemiologic studies . . .

Objective. To evaluate the long-term effects of a Mediterranean diet (MeDiet) intervention on the plasma concentrations of inflammatory and plaque stability-related molecules in elderly people at high risk for cardiovascular disease. Design and Setting. 66 participants from primary care centers affiliated with the Hospital Clinic of Barcelona were randomized into 3 groups: MeDiet plus extra virgin olive oil (EVOO) or nuts and a low-fat diet (LFD). At baseline and at 3 and 5 years, we evaluated the changes in the plasma concentrations of 24 inflammatory biomarkers related to the different stages of the atherosclerotic process by Luminex®. Results. At 3 and 5 years, both MeDiet groups showed a significant reduction of IL-6, IL-8, MCP-1, and MIP-1β (P<0.05; all) compared to LFD. IL-1β, IL-5, IL-7, IL-12p70, IL-18, TNF-α, IFN-γ, GCSF, GMCSF, and ENA78 (P<0.05; all) only decreased in the MeDiet+EVOO group and E-selectin and sVCAM-1 (P<0.05; both) in the MeDiet+nuts group. Conclusions. Long-term adherence to MeDiet decreases the plasma concentrations of inflammatory biomarkers related to different steps of atheroma plaque development in elderly persons at high cardiovascular risk.

Abstract Context Testosterone increases skeletal muscle mass and strength, but long-term effects of testosterone supplementation on aerobic capacity, or peak oxygen uptake (V̇O2peak), in healthy older men with low testosterone have not been evaluated. Objective To determine the effects of testosterone supplementation on V̇O2peak during incremental cycle ergometry. Design A double-blind, randomized, placebo-controlled, parallel-group trial (Testosterone’s Effects on Atherosclerosis Progression in Aging Men). Setting Exercise physiology laboratory. Participants Healthy men aged ≥ 60 years with total testosterone levels of 100 to 400 ng/dL (3.5 to 13.9 nmol/L) or free testosterone levels < 50 pg/mL (174 pmol/L). Interventions Randomization to 1% transdermal testosterone gel adjusted to achieve serum levels of 500 to 950 ng/dL or placebo applied daily for 3 years. Main Outcome Measures Change in V̇O2peak. Results Mean (±SD) baseline V̇O2peak was 24.2 ± 5.2 and 23.6 ± 5.6 mL/kg/min for testosterone and placebo, respectively. V̇O2peak did not change in men treated with testosterone but fell significantly in men receiving placebo (average 3-year decrease, 0.88 mL/kg/min; 95% CI, −1.39 to 0.38 mL/kg/min; P = 0.035); the difference in change in V̇O2peak between groups was significant (average 3-year difference, 0.91 mL/kg/min; 95% CI, 0.010 to 0.122 mL/kg/min; P = 0.008). The 1-g/dL mean increase in hemoglobin (P < 0.001) was significantly associated with changes in V̇O2peak in testosterone-treated men. Conclusion The mean 3-year change in V̇O2peak was significantly smaller in men treated with testosterone than in men receiving placebo and was associated with increases in hemoglobin. The difference in V̇O2peak change between groups may indicate attenuation of its expected age-related decline; the clinical meaningfulness of the modest treatment effect remains to be determined. Three years of testosterone supplementation in older men attenuated the age-related decline in aerobic capacity. This effect may be explained, at least in part, by changes in hemoglobin levels.

Arterial wall thickening, stimulated by low-grade systemic inflammation, underlies many cardiovascular events. As diet is a significant moderator of systemic inflammation, the dietary inflammatory index (DIITM) has recently been devised to assess the overall inflammatory potential of an individual’s diet. The primary objective of this study was to assess the association of the DII with common carotid artery–intima-media thickness (CCA–IMT) and carotid plaques. To substantiate the clinical importance of these findings we assessed the relationship of DII score with atherosclerotic vascular disease (ASVD)-related mortality, ischaemic cerebrovascular disease (CVA)-related mortality and ischaemic heart disease (IHD)-related mortality more. The study was conducted in Western Australian women aged over 70 years (n 1304). Dietary data derived from a validated FFQ (completed at baseline) were used to calculate a DII score for each individual. In multivariable-adjusted models, DII scores were associated with sub-clinical atherosclerosis: a 1 sd (2·13 units) higher DII score was associated with a 0·013-mm higher mean CCA–IMT (P=0·016) and a 0·016-mm higher maximum CCA–IMT (P=0·008), measured at 36 months. No relationship was seen between DII score and carotid plaque severity. There were 269 deaths during follow-up. High DII scores were positively associated with ASVD-related death (per sd, hazard ratio (HR): 1·36; 95 % CI 1·15, 1·60), CVA-related death (per sd, HR: 1·30; 95 % CI 1·00, 1·69) and IHD-related death (per sd, HR: 1·40; 95 % CI 1·13, 1·75). These results support the hypothesis that a pro-inflammatory diet increases systemic inflammation leading to development and progression of atherosclerosis and eventual ASVD-related death.

Exposure to particulate matter is associated with risk of cardiovascular events, possibly through endothelial dysfunction, and indoor air may be most important. We investigated effects of controlled exposure to indoor air particles on microvascular function (MVF) as the primary endpoint and biomarkers of inflammation and oxidative stress as secondary endpoints in a healthy elderly population. A total of 21 nonsmoking couples participated in a randomized, double-blind, crossover study with two consecutive 48-hour exposures to either particle-filtered or nonfiltered air (2,533-4,058 and 7,718-12,988 particles/cm(3), respectively) in their homes. MVF was assessed noninvasively by measuring digital peripheral artery tone after arm ischemia. Secondary endpoints included hemoglobin, red blood cells, platelet count, coagulation factors, P-selectin, plasma amyloid A, C-reactive protein, fibrinogen, IL-6, tumor necrosis factor-alpha, protein oxidation measured as 2-aminoadipic semialdehyde in plasma, urinary 8-iso-prostaglandin F(2alpha), and blood pressure. Indoor air filtration significantly improved MVF by 8.1% (95% confidence interval, 0.4-16.3%), and the particulate matter (diameter < 2.5 mum) mass of the indoor particles was more important than the total number concentration (10-700 nm) for these effects. MVF was significantly associated with personal exposure to iron, potassium, copper, zinc, arsenic, and lead in the fine fraction. After Bonferroni correction, none of the secondary biomarkers changed significantly. Reduction of particle exposure by filtration of recirculated indoor air for only 48 hours improved MVF in healthy elderly citizens, suggesting that this may be a feasible way of reducing the risk of cardiovascular disease.

Background Atherosclerosis has been widely accepted as an inflammatory disease of vascular, adhesion molecules play an important role in the early progression of it. The aim of the present study was to evaluate the effect of kaempferol on the inflammatory molecules such as E-selectin (E-sel), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesionmolecule-1 (VCAM-1) and monocyte chemotactic protein-1 (MCP-1) in high cholesterol induced atherosclerosis rabbit models. Methods Thirty male New Zealand white (NZW) rabbits were randomly divided into five groups, control group, model group, fenofibrate (12mg/kg) group and kaempferol groups (150 mg/kg and 30 mg/kg). The rabbits were fed with a normal diet or a high cholesterol diet for 10 weeks. Levels of blood lipids, serum tumour-necrosis factor-alpha (TNF-α) and serum interleukin-1beta (IL-1β) were detected at the end of the sixth and tenth week. Malonaldehyde (MDA) level and superoxide dismutase (SOD) activity in serum were also determined. Lesion areas of the aorta were measured with morphometry analysis after ten weeks. Gene expression of E-sel, ICAM-1, VCAM-1 and MCP-1 in aortas was determined by RT-PCR (reverse transcription-polymerase chain reaction). Immunohistochemical staining was employed to measure protein expression of E-sel, ICAM-1, VCAM-1 and MCP-1. Results Model rabbits fed with ten weeks of high-cholesterol diet developed significant progression of atherosclerosis. Compared with the control, levels of blood lipids, TNF-α, IL-1β and MDA increased markedly in serum of model rabbits, while SOD levels decreased. Gene and protein expressions of E-sel, ICAM-1, VCAM-1 and MCP-1 in atherosclerotic aortas increased remarkably in model group. However, comparing to the model rabbits, levels of TNF-α, IL-1β and MDA decreased significantly and serum SOD activity increased, gene and protein expressions of E-sel, ICAM-1, VCAM-1 and MCP-1 in aortas decreased significantly with the treatment of kaempferol. Conclusion Kaempferol shows anti-atherosclerotic effect by modulating the gene and protein expression of inflammatory molecules.

Background Subjects with type 2 diabetes (T2D) have a higher risk of in-stent restenosis and stent thrombosis. The activation of the glucagon-like peptide-1 receptor (GLP-1R) has been suggested to induce several effects on the vasculature that may reduce the risk of stent failure following an angioplasty. The aim of this study is to evaluate the effect of the GLP-1R agonist exenatide on endothelialization of a modern drug-eluting stent (DES) in subjects with T2D. Methods 38 subjects with T2D who were eligible for revascularization with implantation of DES were randomized to treatment with exenatide (once weekly) plus standard treatment, or to standard treatment alone. After 12 weeks, a new coronary angiography was performed to evaluate the percentage of strut coverage (primary endpoint) and the presence of neo-atherosclerosis by optical coherence tomography. This study was approved by the Stockholm’s Ethical Review Board. Results The two groups were well balanced regarding baseline clinical characteristics. Strut coverage was 95% (88.7–98.5%) in the exenatide group and 91.4% (88.8–98.5%) in the control group (p = 0.692). There were no significant differences between groups neither in the thickness of neo-intima (0.2 mm in both groups, p = 0.471), nor the maximal in-stent obstruction by neo-intima (15.5% in exenatide group vs 14.7% in control group, p = 0.801). No significant differences were detected in the rate of target lesion revascularization between groups (p = 0.224). Conclusion Twelve weeks treatment with exenatide did not lead to a significantly better stent coverage in people with T2D. No significant differences in the occurrence of neo-atherosclerosis were detected between groups. Trial registration: The study was registered at www.clinicaltrials.gov (Rebuild Study, NCT02621489).

Introduction. Randomized clinical trials have not shown an additional clinical benefit of sitagliptin treatment over conventional treatment alone. However, studies of sitagliptin treatment have not examined the relationship between anemia and treatment group outcomes. Methods. The PROLOGUE study is a prospective clinical trial of 442 participants with type 2 diabetes mellitus (T2DM) randomized to sitagliptin treatment or conventional treatment which showed no treatment differences [Estimated mean (± standard error) common carotid intima-media thickness (CIMT) was 0.827±0.007 mm and 0.837±0.007 mm, respectively, with a mean difference of -0.009 mm (97.2% CI −0.028 to 0.011, p=0.309) at 24 mo of follow-up]. This is a post hoc subanalysis using data obtained from the PROLOGUE study; the study population was divided into anemic groups (n=94) and nonanemic group (n=343) based on hemoglobin level. And we analyzed for the changes in each CIMT parameter from baseline to 24 months in subgroups. Results. The treatment group difference in baseline-adjusted mean common carotid artery- (CCA-) IMT at 24 months was −0.003 mm (95% CI −0.022 to 0.015, p=0.718) in the nonanemic subgroup and −0.007 mm (95% CI −0.043 to 0.030, p=0.724) in the anemic subgroup. Although there were no significant differences in the other CIMT parameters between the treatment groups in the anemic subgroup, the changes in mean and max ICA-IMT at 24 months in the nonanemic subgroup were significantly lower in the sitagliptin group than the conventional group [−0.104 mm (95% CI −0.182 to −0.026), p=0.009 and −0.142 mm (−0.252 to −0.033), p=0.011, respectively]. Conclusion. These data suggest that nonanemia may indicate a potentially large subgroup of those with T2DM patients that sitagliptin therapy has a better antiatherosclerotic effect than conventional therapy. Further research is needed to confirm these preliminary observations.

Aims/Introduction Type 2 diabetes mellitus is correlated with systemic atherosclerosis. Statin therapies have been proved to reduce low‐density lipoprotein cholesterol (LDL‐C) level, protecting type 2 diabetes mellitus patients from cardiovascular events. Recently, more interest has been focused on the regression of lower extremity atherosclerotic disease (LEAD) for the potential prevention of amputation. However, the effects of pitavastatin and atorvastatin on LEAD in type 2 diabetes mellitus patients have not been directly compared. Materials and Methods This study compared the effects of pitavastatin and atorvastatin on femoral total plaque areas (FTPA), and lipids and glucose metabolism in type 2 diabetes mellitus patients with elevated LDL‐C level and LEAD. Type 2 diabetes mellitus patients with LDL‐C level >2.6 mmol/L and LEAD were randomly assigned to receive either pitavastatin 2 mg/day or atorvastatin 10 mg/day for 48 weeks. FTPA were measured at baseline and the end of the study. Levels of glucose and lipids profile were measured periodically. The efficacy was evaluated in 63 patients. Results The percentage change in FTPA measurements was similar between the pitavastatin group and atorvastatin group (−17.79 ± 21.27% vs −14.34 ± 16.33%), as were the changes in LDL‐C (−44.0 ± 18.0% vs −40.3 ± 18.2%) and triglyceride (17.6 ± 20.0% vs 16.2 ± 17.0%). However, the level of high‐density lipoprotein cholesterol was significantly higher in the pitavastatin group compared with the atorvastatin group after 48 weeks of treatment (12.9 ± 10.3% vs 7.2 ± 11.7%, P < 0.05). There were no significant differences between groups for the measurements of glucose metabolism. Conclusion In type 2 diabetes mellitus patients with elevated LDL‐C level and LEAD, 48 weeks of treatment with either pitavastatin or atorvastatin was associated with significant regression of FTPA. Pitavastatin treatment resulted in a significantly higher high‐density lipoprotein cholesterol level compared with atorvastatin treatment. Forty‐eight weeks of treatment with either pitavastatin or atorvastatin was associated with significant regression of femoral total plaque areas. However, pitavastatin treatment resulted in a significantly higher high‐density lipoprotein cholesterol level compared with atorvastatin treatment. It seemed that pitavastatin might be superior in the control of dyslipidemia in diabetes patients.

Test whether angiographically-documented changes in percent stenosis and clinical endpoints (coronary-related deaths, myocardial infarctions, stroke, revascularization for worsening ischemia) in the HDL-Atherosclerosis Treatment Study (HATS) were attributable to specific LDL-subclasses. Gradient gel electrophoresis of on-study LDL-subclass cholesterol concentrations were measured in 32 placebo, 33 simvastatin-niacin, 38 antioxidant, and 39 simvastatin-niacin & antioxidant treated participants. The prespecified primary end point was the mean change per patient from the initial arteriogram to the final arteriogram in the percent stenosis caused by the most severe lesion in each of the nine proximal coronary segments. The change in the percent stenosis of the most severe proximal lesions increased in association with higher concentrations of the small LDL subfractions LDL-IIIb (24.2-24.6 nm) and LDL-IVa (23.3-24.1 nm) before (both P = 0.002) and after (P = 0.01 and P = 0.03 respectively) adjustment for treatment group and on-study HDL-cholesterol, LDL-cholesterol, and triglyceride concentrations. The associations appeared specific to lesions with <30% baseline stenosis. When adjusted for age, sex, baseline BMI and cigarette use, the odds for primary clinical endpoints (death from coronary causes, nonfatal myocardial infarction, stroke, or revascularization for worsening ischemia) were significantly greater in subjects with higher on-study LDL-IIIb levels both before (P = 0.01) and after (P = 0.03) adjustment for treatment group and the standard lipid values. Plasma LDL-IIIb cholesterol concentrations were related to changes in coronary artery stenosis and cardiovascular events in patients with coronary artery disease and low HDL-cholesterol. ClinicalTrials.gov NCT00000553.