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Biomedical subjects

D C Wheeler

Publications and source records attributed to D C Wheeler.

At least 19 recordsLinked to original sources
PubMed2001

A randomized double-blind placebo-controlled trial of the effect of homocysteine-lowering therapy with folic acid on endothelial function in patients with coronary artery disease.

OBJECTIVES: This study was designed to determine the effects of folic acid therapy on endothelial function in patients with coronary artery disease (CAD). BACKGROUND: Hyperhomocysteinemia, a risk factor for CAD, may cause atherosderosis by oxidative endothelial injury. Folic acid reduces plasma homocysteine, but the effect on adverse vascular events is unknown. METHODS: In a double-blind placebo-controlled trial, 90 patients (mean age [range] 63 [46 to 79] years, 79 men) with CAD were randomized to either folic acid 5 mg or placebo daily for 12 weeks. Endothelial function was assessed by measuring: 1) flow-mediated endothelium-dependent dilation (EDD) of the brachial artery; 2) combined serum nitrite/nitrate (NOx) concentrations and; 3) plasma von Willebrand factor (vWF) concentration. RESULTS: At the end of the study, plasma homocysteine was lower in the folic acid group compared with the placebo group (mean [95% confidence interval] 9.3 (8.5 to 10.1) vs. 12.3 [11.3 to 13.4] micromol/l, p < 0.001). Although there were no significant differences in EDD, serum NOx or plasma vWF between the two groups, there was a greater increase in EDD from baseline in the folic acid group compared to placebo (1.2 [0.7 to 1.8] vs. 0.4 [-0.3 to 1.1]%, p = 0.07). CONCLUSIONS: Folic acid reduced plasma homocysteine and was associated with a trend toward improved endothelial function in patients with CAD. The absence of an unequivocally positive result may have been due to inadequate sample size or chance. This reinforces the need for the results of large randomized controlled trials before the implementation of routine folic acid supplementation.

Aged↗
PubMed2001

Epidemiological evaluation of known and suspected cardiovascular risk factors in chronic renal impairment.

Patients with chronic renal impairment (CRI) are at greatly increased risk for premature vascular disease; however, little is known about its evolution. This paper describes a cohort of patients with CRI and reports study design, baseline demographic and biochemical data, and comparisons with two contemporaneous age- and sex-matched control groups, one with established coronary artery disease and the other without overt vascular disease. Among 369 individuals (median age, 63 years; range, 18 to 88 years; 67% men) with CRI, 34% had a history of vascular disease and 21% had electrocardiographic left ventricular hypertrophy (LVH). Even in those with mild renal impairment (serum creatinine < 2.1 mg/dL), approximately one third had vascular disease and 12% had LVH. A history of hypertension was present in 76% of the CRI group, but as compared with controls, systolic and diastolic blood pressures were not elevated. Low-density lipoprotein (LDL) cholesterol concentration also was not elevated, but CRI was associated with elevated serum triglyceride and plasma homocysteine levels and reduced high-density lipoprotein (HDL) cholesterol, hemoglobin, and serum albumin concentrations. Across the spectrum of CRI, more severe renal dysfunction was associated with lower levels of diastolic blood pressure, LDL and HDL cholesterol, albumin, and hemoglobin, but increased levels of plasma homocysteine. This cross-sectional analysis shows that vascular disease is common in individuals with mild CRI attending a nephrology program and also suggests trends in the levels of a number of potential vascular risk factors with respect to severity of renal dysfunction. These results will be further quantified in a prospective biennial follow-up.

Adolescent↗
PubMed2000

Evolution and etiology of cardiovascular diseases in renal transplant recipients.

The mortality rates for CVDs in transplant recipients are greater than those in the general population (13). CVDs are a major cause of both patient and graft loss in renal transplant recipients, and improving cardiovascular health may help to extend both patient and graft survival. A complication of chronic renal failure, CVDs are frequently present in patients being considered for transplantation. Pretransplant screening, based on risk stratification, may detect pre-existing disease and identify patients likely to benefit from therapeutic strategies designed to reduce CVDs prevalence. Further studies are needed to better define the risk factors for CVDs in the renal transplant population and to evaluate the effectiveness of risk modification on the related morbidity and mortality. Risk-factor management initiated early in the course of chronic renal failure might reduce the burden of CVDs in both dialysis and transplant populations.

Adult↗
PubMed2000

Does folic acid decrease plasma homocysteine and improve endothelial function in patients with predialysis renal failure?

BACKGROUND: Considerable evidence suggests that hyperhomocysteinemia is an independent vascular risk factor that promotes atherosclerosis by inducing endothelial dysfunction. Although folic acid reduces hyperhomocysteinemia, the effect on adverse vascular events is unknown. We hypothesized that in patients with chronic renal failure, a condition associated with both hyperhomocysteinemia and atherosclerosis, treatment with folic acid would improve endothelial function. METHODS AND RESULTS: In a prospective, double-blind protocol, 100 patients (mean age 62 years, 67 men) with predialysis chronic renal failure were randomized to 5 mg folic acid or placebo daily for 12 weeks. Endothelial function was assessed by measuring (1) endothelium-dependent dilation of the brachial artery, (2) combined serum nitrite/nitrate concentrations, and (3) plasma von Willebrand factor concentration. Baseline characteristics of the 2 groups were similar. At the end of the study, both serum and red cell folate concentrations were greater in the folic acid group than the placebo group [mean (95% CI) 39.0 (29.8 to 51.0) versus 7.7 (6.6 to 8.9) microg/L and 739 (613 to 891) versus 220 (184 to 262) microg/L, respectively; both P<0.001]. Despite a reduction in hyperhomocysteinemia in the folic acid group compared with the placebo group [15.1 (14.1 to 16.2) versus 20.1 (18.2 to 22.2) micromol/L; P<0.001], there were no significant differences in endothelium-dependent dilation, combined serum nitrite/nitrate concentrations, or plasma von Willebrand factor concentration between the 2 groups. CONCLUSIONS: High-dose folic acid lowers but fails to normalize hyperhomocysteinemia in patients with predialysis chronic renal failure. This was not accompanied by an improvement of endothelial function and suggests that treatment with folic acid may not reduce the burden of vascular disease in uremia.

Aged↗
PubMed2000

Low-density lipoprotein stimulates mesangial cell proteoglycan and hyaluronan synthesis.

BACKGROUND: Hyperlipidaemia leads to glomerulosclerosis in small mammals and may contribute to progressive renal disease in man. One prominent feature of lipid-induced glomerular injury in animal models is the accumulation of mesangial matrix. These studies were designed to investigate whether low-density lipoprotein (LDL) enhanced mesangial cell (MC) matrix deposition by modulating the production of proteoglycans (PG) and hyaluronan (HA). METHODS: Growth arrested human MC were metabolically labelled with either 50 microCi/ml Na(2)[(35)S]sulphate or 25 microCi/ml [(3)H]glucosamine and stimulated with LDL (10-100 microg/ml). The radiolabelled PG and HA extracted from the cell layer and the culture medium were isolated, quantified and characterized. Comparison of the PG core proteins synthesized by MC was carried out using Western blot analysis. RESULTS: LDL stimulation led to a dose- and time-dependent increase in [(35)S]sulphate incorporation into PG in the culture medium and to a lesser extent in the cell layer. Analysis of the glycosaminoglycan (GAG) chains showed no difference in either their size or charge. Enzyme digestion studies demonstrated that the synthesis of both chondroitin sulphate PG (CSPG) and heparan sulphate PG (HSPG) was enhanced as was the production of the core proteins of versican (a large CSPG), perlecan (a basement membrane HSPG) and to a lesser extent decorin (a small dermatan sulphate PG (DSPG)). An increase in HA synthesis was also demonstrated in [(3)H]glucosamine labelled cells following LDL stimulation. CONCLUSION: LDL selectively enhances the synthesis of specific PG and HA by mesangial cells. Such effects may contribute to the expansion of the mesangial matrix and modify cell-matrix interactions in lipid-induced renal damage.

Blotting, Western↗
PubMed2000

Abnormalities of endothelial function in patients with predialysis renal failure.

BACKGROUND: Endothelial dysfunction plays an important role in the development of atherosclerotic vascular disease, which is the leading cause of mortality in patients with chronic renal failure. OBJECTIVE: To examine the relation between predialysis renal failure and endothelial function. DESIGN: Two groups were studied: 80 patients with non-diabetic chronic renal failure and 26 healthy controls, with similar age and sex distributions. Two indices of endothelial function were assessed: high resolution ultrasonography to measure flow mediated endothelium dependent dilatation of the brachial artery following reactive hyperaemia, and plasma concentration of von Willebrand factor. Endothelium independent dilatation was also assessed following sublingual glyceryl trinitrate. The patients were divided into those with and without overt atherosclerotic vascular disease. RESULTS: Although patients with chronic renal failure had significantly impaired endothelium dependent dilatation compared with controls (median (interquartile range), 2.6% (0.7% to 4.8%) v 6.5% (4.8% to 8.3%); p < 0.001) and increased von Willebrand factor (254 (207 to 294) v 106 (87 to 138) iu/dl; p < 0.001), there was no difference between renal failure patients with and without atherosclerotic vascular disease. Within the chronic renal failure group, endothelium dependent dilatation and von Willebrand factor were similar in patients in the upper and lower quartiles of glomerular filtration rate (2.7% (0.7% to 6.7%) v 2.8% (1.1% to 5.0%); and 255 (205 to 291) v 254 (209 to 292) iu/dl, respectively). Endothelium independent dilatation did not differ between the renal failure or control groups and was also similar in patients with renal failure irrespective of the degree of renal failure or the presence of atherosclerotic vascular disease. CONCLUSIONS: Endothelial function is abnormal in chronic renal failure, even in patients with mild renal insufficiency and those without atherosclerotic vascular disease, suggesting that uraemia may directly promote the development of atherosclerosis early in the progression of chronic renal failure.

Arteriosclerosis↗
PubMed1999

Fibronectin augments monocyte adhesion to low-density lipoprotein-stimulated mesangial cells.

BACKGROUND: Glomerular monocyte infiltration is an early feature of lipid-mediated renal injury in animal models. Interactions between mesangial and infiltrating mononuclear cells may contribute to the development of glomerular scarring. METHODS: Adherence of U-937 monocytes to low-density lipoprotein (LDL)- or tumor necrosis factor alpha (TNFalpha)-prestimulated human mesangial cells was assessed by colorimetry of nuclear staining with crystal violet. Blocking antibodies were added to examine the mechanisms of binding. Adhesion molecule expression and fibronectin synthesis were measured by ELISA. RESULTS: Preincubation of mesangial cells for 24 hours with LDL (100 micrograms/ml) or mildly oxidized (minimally modified) LDL (MM-LDL) increased monocyte adhesion by 207% and 240%, respectively, compared with control nonstimulated cells (100%). TNFalpha (100 U/ml) enhanced binding by 335% and up-regulated intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression by 505% and 179%, respectively, as compared with MM-LDL (120% and 116%) and LDL, which had no effect. Blocking antibodies to these adhesion molecules inhibited monocyte binding to TNFalpha- and, to a lesser extent, MM-LDL-primed mesangial cells, but had no effect after LDL pretreatment. In contrast to TNFalpha, MM-LDL and LDL increased mesangial cell-associated fibronectin, whereas antibodies to fibronectin inhibited monocyte binding to lipoprotein-stimulated but not TNFalpha-stimulated cells. CONCLUSIONS: Although enhanced monocyte adhesion to TNFalpha- and, to a lesser extent, MM-LDL-stimulated mesangial cells is mediated by changes in ICAM-1 and VCAM-1 expression, both LDL and MM-LDL promote similar cellular interactions as a result of increased fibronectin production.

Cell Adhesion↗
PubMed1998

Low-density lipoprotein subfraction profiles in chronic renal failure.

BACKGROUND: Small low-density lipoprotein (LDL) particle size, a newly recognized risk factor for cardiovascular disease in the general population, is frequently associated with hypertriglyceridaemia, the predominant plasma lipid abnormality present in uraemia. METHODS: Plasma lipids and LDL subfraction profiles were examined in 33 non-dialysed patients with chronic renal failure (predial), 40 patients on continuous ambulatory peritoneal dialysis (CAPD), 42 haemodialysis patients (HD), 47 renal transplant recipients (RTR), and 44 controls. LDL subfractions separated by gel electrophoresis were scored by densitometric analysis (higher scores indicate profiles comprising smaller particles). RESULTS: All groups with renal failure had significantly elevated (mean+/-SD) LDL scores (predial 1.36+/-0.6, CAPD 1.71+/-0.9, HD 1.68+/-0.9, RTR 1.92+0.8 vs control 0.87+0.4, all P<0.001), this being the only lipid abnormality detected in the predialysis patients. In CAPD and HD patients, LDL scores were associated with serum triglyceride (r=0.81, P<0.001 and r=0.70, P<0.001 respectively), cholesterol (r=0.55, P<0.001 and r=0.49, P<0.01) and HDL-cholesterol (r= -0.43, P<0.01 and r= -0.51, P<0.01), whilst no such relationship was seen in the predialysis and RTR groups, suggesting that other factors were important. CONCLUSIONS: The presence of small LDL particles appears to be an early and unexplained feature of the uraemic dyslipidaemia. This abnormality persists after renal transplantation and may represent an important atherogenic risk factor.

Adrenergic beta-Antagonists↗
PubMed1998

Statins and the kidney.

Experience to date suggests that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors or statins can be used relatively safely and effectively to treat dyslipidaemia complicating renal disease. Recent studies suggest that in addition to lowering plasma lipid levels, these drugs modify other factors that contribute to vascular injury. Furthermore, statins could slow the progression of chronic renal failure and may augment the action of immunosuppressive therapy after renal transplantation. Such newly defined actions, some of which could be unrelated to lipid lowering, are likely to extend the applications of statins in nephrology.

Animals↗
PubMed1998

Are there potential non-lipid-lowering uses of statins?

Recent clinical trials have demonstrated beyond doubt that statins are effective in the prevention of acute coronary events. Critical analysis of these studies suggests that the benefits of statin therapy cannot be fully explained on the basis of reductions in plasma cholesterol levels. Accumulating knowledge of the actions of these drugs shows that they may prevent several processes that eventually lead to plaque rupture and the development of occlusive thrombosis, the basis of acute coronary events. Hence, statins may correct endothelial dysfunction (thus protecting against ischaemic injury), stabilise existing plaques and modify the coagulation pathway, thereby reducing the likelihood of a sudden vascular event. At a cellular level, these drugs inhibit the synthesis not just of cholesterol, but of other compounds important in cell proliferation. Antiproliferative effects have been demonstrated in vitro and may broaden the applications of statins to the treatment of noncardiovascular diseases. Finally, preliminary clinical studies indicate that as a result of immunosuppressive actions, statins may reduce the incidence of rejection following organ transplantation.

Animals↗