Vitamin D and progression of carotid intima-media thickness in HIV-positive Canadians.

OBJECTIVES: Based on a growing body of evidence implicating low vitamin D status in the development of cardiovascular disease (CVD), we hypothesized that in Canadian HIV-positive adults, low 25-hydroxyvitamin D (25(OH)D) concentration would be associated with increased subclinical vascular disease progression. METHODS: We prospectively studied the relationship between baseline 25(OH)D and subsequent progression of carotid intima-media thickness (CIMT) between 2002 and 2011, in the Canadian HIV Vascular Study using stored blood specimens. RESULTS: Of the 128 participants, 89.1% were men, the mean age (standard deviation [SD]) was 46.5 (8.2) years, 93.8% were white, and 36.7% were current smokers. Mean (SD) annual CIMT follow-up was 5.9 (1.8) years (maximum 8.5 years), providing approximately 750 patient-years of follow-up. Mean (SD) CIMT progression was 0.027 (0.030) mm/year. Mean (SD) 25(OH)D was 95.0 (46.9) nmol/L. Only 13.3% of participants were vitamin D deficient (25(OH)D < 50 nmol/L), whereas 61.7% had a 25(OH)D exceeding the sufficiency threshold (75 nmol/L). Vitamin D quartiles were inversely associated with body mass index (BMI) (P = 0.034), total cholesterol to high-density lipoprotein (HDL) cholesterol ratio (P = 0.001) and parathyroid hormone concentration (P = 0.003), but not efavirenz exposure (P = 0.141). In linear regression analyses, baseline 25(OH)D as a continuous variable was inversely associated with CIMT progression in univariable (P < 0.001) and multivariable (P < 0.001) models. CONCLUSIONS: Baseline 25(OH)D was associated with CIMT progression in this relatively vitamin D replete, predominately white and male, Canadian HIV-positive population. Future research needs to establish causality as this may warrant more targeted screening or supplementation.

Is there a role for antioxidant vitamins in the prevention of cardiovascular diseases? An update on epidemiological and clinical trials data.

OBJECTIVES: To review prospective epidemiological studies and randomized clinical trials regarding the role of antioxidant vitamins (vitamins E and C and beta-carotene) in the prevention of cardiovascular diseases. DATA SOURCES: Computerized (MEDLINE and Science Citation Index) and manual searches on the role of antioxidant vitamins in cardiovascular disease management. STUDY SELECTION: Only prospective epidemiological studies and double-blind, controlled, randomized clinical trials, including at least 100 participants and providing sufficient data to allow quantitative estimation of the effects of vitamin intake were included. Retrospective epidemiological evaluations and other retrospective studies were excluded. Geographic correlation studies of population-based intake of antioxidants and cardiovascular disease rates were also excluded due to the potential large impact of confounders in cross-sectional analyses. DATA SYNTHESIS: Relative risk was evaluated for all prospective epidemiological studies. Relative risk reductions were evaluated for clinical trials. The Mantel-Haenszel method was used to estimate the relative risk reduction in clinical trials when not calculated in the original publication. A formal meta-analysis was not performed because very significant differences among study populations, type (supplemental versus dietary) and dosage of antioxidant vitamins, duration of follow-up and overall study design exist for both epidemiological investigations and clinical trials, and the pooling of study results could be misleading. CONCLUSIONS: Prospective epidemiological investigations suggest a reduction in cardiovascular risk associated with increased intake of antioxidant vitamins, particularly vitamin E. Randomized clinical trials remain inconclusive with regard to the role of vitamin E in cardiovascular protection. The large, randomized clinical trials of beta-carotene in primary prevention show no effect and potential for harm associated with the use of beta-carotene. There are inconclusive and insufficient epidemiological and clinical trial data with regard to the role of vitamin C in cardiovascular protection. Overall, it is recommended that wide-spread use of antioxidant vitamins in cardiovascular protection should not be instituted and should await the results of further ongoing clinical trials.

Study design and baseline characteristics of the study to evaluate carotid ultrasound changes in patients treated with ramipril and vitamin E: SECURE.

Atherosclerotic cardiovascular disease remains a major cause of mortality and morbidity in most developed countries. Experimental and clinical evidence suggests that angiotensin-converting enzyme inhibitors and vitamin E therapy may retard the atherosclerotic process; however, definitive proof in humans is lacking. The Study to Evaluate Carotid Ultrasound Changes in Patients Treated with Ramipril and Vitamin E (SECURE) is designed to assess the effects of ramipril--an angiotensin-converting enzyme inhibitor, at 2 doses: 2.5 mg daily (which has little effect on lowering blood pressure) and 10 mg daily--and the antioxidant vitamin E, 400 IU daily, on atherosclerosis progression in 732 patients using a factorial 3 x 2 study design. High-risk patients with a documented history of significant cardiovascular disease or with diabetes and additional risk factors were enrolled and will be followed for 4 years. The extent and progression of atherosclerosis are assessed noninvasively by B-mode carotid ultrasonography. The SECURE trial is a substudy of the larger Heart Outcomes Prevention Evaluation (HOPE) study of 9,541 high-risk patients evaluating the effects of ramipril and vitamin E on major cardiovascular events (cardiovascular death, myocardial infarction, and stroke). The 2 studies are complementary. Whereas HOPE is expected to provide information on major clinical outcomes, SECURE will shed light on the mechanisms by which these effects may be mediated.

The antioxidant vitamins and cardiovascular disease. A critical review of epidemiologic and clinical trial data.

PURPOSE: To review prospective epidemiologic studies and randomized trials regarding the role of antioxidant vitamins (vitamins E and C and beta-carotene) in the prevention of cardiovascular disease, with emphasis on differences in results obtained by these two types of studies. DATA SOURCES: Computerized and manual searches of the literature on antioxidant vitamins and cardiovascular disease. STUDY SELECTION: Prospective epidemiologic studies and randomized trials that included 100 or more participants and provided quantified estimates of antioxidant vitamin intake. DATA SYNTHESIS: Comparisons of relative risk reductions (RRR) across observational studies and randomized trials, including assessment of dose-response relations. RESULTS: All three large epidemiologic cohort studies of vitamin E noted that high-level vitamin E intake or supplementation was associated with a significant reduction in cardiovascular disease (RRR range, 31% to 65%), as measured by various fatal and nonfatal cardiovascular end points. To obtain these reductions, vitamin E supplementation must last at least 2 years. Less consistent reductions were seen in studies of beta-carotene (RRR range, -2% to 46%) and vitamin C (RRR range, -25% to 51%). Considerable biases in observational studies, such as different health behaviors of persons using antioxidants, may account for the observed benefit. By contrast, none of the completed randomized trials showed any clear reduction in cardiovascular disease with vitamin E, vitamin C, or beta-carotene supplementation. The trials were not specifically designed to assess cardiovascular disease, did not provide data on nonfatal cardiovascular end points, may have had insufficient treatment durations, and used suboptimal vitamin E doses. The completed trials were of adequate size to indicate that the true therapeutic benefit of vitamin E and other antioxidants in reducing fatal cardiovascular disease (a survival benefit as long as 5 years) is probably more modest than the epidemiologic data suggest. CONCLUSION: The epidemiologic data suggest that antioxidant vitamins reduce cardiovascular disease, with the clearest effect for vitamin E; however, completed randomized trials do not support this finding. Much of this controversy should be resolved by the ongoing large-scale and long-term randomized trials designed specifically to evaluate effects on cardiovascular disease.

Effects of oxygen free radicals and scavengers on the cardiac extracellular collagen matrix during ischemia-reperfusion.

OBJECTIVE: Collagen is lysed early during ischemia-reperfusion, but whether this is due to ischemia or reperfusion injury is not known. The effect of oxygen free radicals and free radical scavengers on left ventricular hemodynamics, myocardial morphology and collagen content were studied in an isolated, Langendorff-perfused rat heart model of regional ischemia-reperfusion. METHODS: All hearts received left anterior descending coronary artery ischemia for 20 mins. Group 1 had ischemia only; group 2 had ischemia followed by reperfusion with oxygenated Krebs-Henseleit buffer for 20 mins; group 3 had oxygen free radicals generated by hypoxanthine and xanthine oxidase during reperfusion; group 4 had free radical scavengers with superoxide dismutase plus catalase; group 5 had both oxygen free radicals and free radical scavengers during reperfusion. RESULTS: Left ventricular developed pressure decreased significantly in group 3 during ischemia followed by reperfusion (58 +/- 3.1 mmHg versus 42 +/- 2.4 mmHg, P = 0.004), but did not change significantly in any of the other groups. Necrosis score on pathology was highest in group 3; this score also was higher than that in group 5 with free radical scavengers added (3.0 +/- 0.3 versus 2.0 +/- 0.4, P = 0.07) and higher than that of group 2 with reperfusion with buffer only (3.0 +/- 0.3 versus 1.4 +/- 0.5, P < 0.05). Collagen content decreased significantly compared with control in group 3 only with ischemia followed by reperfusion with the addition of oxygen free radicals (18.4 +/- 1.5 versus 11.9 +/- 1.7 g/mg protein, P < 0.05). The addition of free radical scavengers in group 5 mainly attenuated the collagen loss. Scanning electron microscopy revealed profound structural changes of the extracellular collagen matrix in numerous regions of 'stunning' independent of tissue necrosis. CONCLUSIONS: We conclude that: first, oxygen free radicals trigger significant collagen damage and left ventricular dysfunction during reperfusion; second, these changes extend beyond the ischemic damage alone; and third, free radical scavengers can effectively limit oxygen free radical-induced collagen loss and left ventricular dysfunction.