BACKGROUND: Recent studies suggest that smokers' coronary endothelial function is impaired because of increased oxidative stress, and their coronary flow velocity reserve (CFVR) is reduced. It is uncertain whether oral antioxidant vitamin C restores impaired CFVR in smokers. Recent technological advances in transthoracic Doppler echocardiography (TTDE) have resulted in the successful measurement of coronary flow velocity and noninvasive CFVR assessment. METHODS: We studied 13 healthy young male smokers and 12 nonsmokers. Coronary flow velocities in the left anterior descending coronary artery (LAD) were recorded with TTDE at rest and during hyperemia induced with intravenous infusion of adenosine triphosphate (ATP). CFVR was calculated as the ratio of hyperemic to basal mean diastolic flow velocity. CFVR and plasma concentrations of vitamin C were assessed at baseline and 2 and 4 hours after oral intake (2 g). RESULTS: Heart rate and blood pressure responses to ATP infusion were not affected by oral vitamin C, but plasma concentrations of vitamin C increased to physiological levels in both groups. CFVR was significantly higher in nonsmokers than in smokers at baseline (4.3 +/- 0.4 vs 3.8 +/- 0.8, P<.05). After oral vitamin C, it was increased significantly in smokers (3.8 +/- 0.8 to 4.5 +/- 0.7, P<.005, 4.5 +/- 0.8, P<.005, respectively), but not in nonsmokers (4.3 +/- 0.4 to 4.3 +/- 0.3, 4.4 +/- 0.7). CONCLUSIONS: This study demonstrated that oral vitamin C restores coronary microcirculatory function and impaired CFVR against oxidative stress in smokers.

OBJECTIVE:To determine the implications of supplemental vitamin C for pregnant tobacco smokers and its effects on the prevalence of pediatric asthma, asthma-related mortality, and associated costs.

STUDY DESIGN:A decision-analytic model built via TreeAge compared the outcome of asthma in a theoretical annual cohort of 480,000 children born to pregnant smokers through 18 years of life. Vitamin C supplementation (500 mg/day) with a standard prenatal vitamin was compared to a prenatal vitamin (60 mg/day). Model inputs were derived from the literature. Deterministic and probabilistic sensitivity analyses assessed the impact of assumptions.

RESULT:Additional vitamin C during pregnancy would prevent 1637 cases of asthma at the age of 18 per birth cohort of pregnant smokers. Vitamin C would reduce asthma-related childhood deaths and save $31,420,800 in societal costs over 18 years per birth cohort.

CONCLUSION:Vitamin C supplementation in pregnant smokers is a safe and inexpensive intervention that may reduce the economic burden of pediatric asthma.

The Japanese diet is high in soy products and fish. A case-control study was conducted in Japan to investigate the relationship between dietary intake of isoflavones and fatty acids and lung function, breathlessness and chronic obstructive pulmonary disease (COPD). A total of 278 referred patients aged 50-75 years with COPD diagnosed within the past 4 years, and 340 community-based controls were assessed for respiratory symptoms and undertook spirometric measurements of lung function. A validated food frequency questionnaire was administered face-to-face to obtain information on habitual food consumption. Dietary intakes of isoflavones and fatty acids were derived from the Japanese food composition tables. The COPD patients had significantly lower habitual intakes of isoflavones (genistein and daidzein) and polyunsaturated fatty acids (PUFA; both omega-3 and omega-6) than control subjects. Lung function measures were found to be positively associated with isoflavones and PUFA intake. Substantial reductions in prevalence of COPD and breathlessness were observed for isoflavones, the respective adjusted odds ratio being 0.36 (95% confidence interval 0.19-0.68) and 0.60 (95% confidence interval 0.33-1.10) for the highest versus lowest levels of total isoflavone intake. The corresponding tests for linear trend were significant. High intakes of PUFA and omega-6 fatty acids (derived from foods excluding oils and fats as seasonings) also appeared to reduce the risks of COPD and breathlessness symptom, but no evidence of association was found for other types of fatty acids. The study provided evidence of possible protective effect of traditional Japanese diet against tobacco carcinogens.

An international, standardised case-control study was established to assess the importance of risk factors for coronary heart disease worldwide. From 52 countries representing every inhabited continent 15152 cases and 14820 controls were enrolled. The relation of smoking, history of hypertension and/or diabetes, waist/hip ratio, dietary patterns, physical activity, consumption of alcohol, blood apolipoproteins and psychosocial factors to myocardial infarction was reported. Odds ratios and their 99% confidence limits for the association of risk factors to acute myocardial infarction and their population attributable risks were calculated. Smoking (odds ratio 2.87 for current vs never, population attributable risk 35.7% for current and former smoker vs never), raised apolipoprotein B / apolipoprotein A1 ratio (3.25 for top vs lowest quintile, population attributable risk 49.2 for top four quintiles vs lowest quintile), history of hypertension (1.91, 17.9%), diabetes (2.37, 9.9%), abdominal obesity (1.12 for top vs lowest tertile and 1.62 for middle vs lowest tertile, 20.1% for top two tertiles vs lowest tertile), psychosocial factors (2.67, 32.5), daily consumption of fruits and vegetables (0.70, 13.7% for lack of daily consumption), regular alcohol consumption (0.91, 6.7%), and regular physical activity (0.86, 12.2%) were all significantly related to acute myocardial infarction (p<0.0001 for all risk factors, and p = 0.03 for alcohol). These associations were noted in men and women, old and young and in all regions of the world. Collectively these nine risk factors accounted for 90% of the population attributable risk in men and 94% in women. This finding suggests that approaches to prevention can be based on similar principles worldwide.

BACKGROUND:Peripheral arterial disease (PAD) is a severe atherosclerotic condition frequently accompanied by inflammation and oxidative stress. We hypothesized that vitamin C antioxidant levels might be low in PAD and are related to inflammation and disease severity.

METHODS AND RESULTS:We investigated vitamin C (L-ascorbic acid) levels in 85 PAD patients, 106 hypertensives without PAD, and 113 healthy subjects. Serum L-ascorbic acid concentrations were low among PAD patients (median, 27.8 micromol/L) despite comparable smoking status and dietary intake with the other groups (P<0.0001). Subclinical vitamin C deficiency (<11.4 micromol/L), confirmed by low serum alkaline phosphatase activity, was found in 14% of the PAD patients but not in the other groups. Serum C-reactive protein (CRP) concentrations were significantly higher in PAD patients (P<0.0001) and negatively correlated with L-ascorbic acid levels (r=-0.742, P<0.0001). In stepwise multivariate analysis, low L-ascorbic acid concentration in PAD patients was associated with high CRP level (P=0.0001), smoking (P=0.0009), and shorter absolute claudication distance on a standardized graded treadmill test (P=0.029).

CONCLUSIONS:Vitamin C concentrations are lower in intermittent claudicant patients in association with higher CRP levels and severity of PAD. Future studies attempting to relate vitamin C levels to disease occurrence should include in their analysis an inflammatory marker such as CRP.

Vitamin D may protect against several cancers, but data about the association between circulating vitamin D and bladder cancer are limited. Within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, a randomized controlled trial conducted to determine the effects ofα-tocopherol and β-carotene supplements on cancer incidence in male smokers, 250 bladder cancer cases were randomly sampled by month of blood collection. Controls were matched 1:1 to cases on age at randomization and date of blood collection. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) of bladder cancer by a priori categories of baseline serum 25-hydroxyvitamin D [25(OH)D; i.e.,<25, 25 to<37.5, 37.5 to<50,≥50 nmol/L] and by season-specific quartiles. After multivariable adjustment, we found that lower 25(OH)D was associated with a statistically significantly increased risk of bladder cancer (versus ≥50 nmol/L;<25 nmol/L: OR, 1.73; 95% CI, 1.03-2.91; 25 to<37.5 nmol/L: OR, 1.81; 95% CI, 1.05-3.14; 37.5 to<50 nmol/L: OR, 1.76; 95% CI, 1.02-3.02; P trend=0.04). Similarly, increased risks for the lowest vitamin D category were observed when season-specific quartiles were used (Q1 versus Q4: OR, 1.63; 95% CI, 0.96-2.75; P trend=0.03). In this prospective study of male smokers, lower serum 25(OH)D was associated with an increased risk of bladder cancer. Future studies should examine the association in other populations, especially nonsmokers and women.

BACKGROUND:Infants whose mothers smoked during pregnancy demonstrate lifelong decreases in pulmonary function. DNA methylation changes associated with maternal smoking during pregnancy have been described in placenta and cord blood at delivery, in fetal lung, and in buccal epithelium and blood during childhood. We recently demonstrated in a randomized clinical trial (NCT00632476) that vitamin C supplementation to pregnant smokers can lessen the impact of maternal smoking on offspring pulmonary function and decrease the incidence of wheeze at one year of age.

OBJECTIVES:To determine if vitamin C supplementation reduces changes in offspring methylation in response to maternal smoking and whether methylation at specific CpGs is also associated with respiratory outcomes.

METHODS:Targeted bisulfite sequencing was performed using a subset of placentas, cord bloods and buccal samples collected during the NCT00632476 trial followed by independent validation of selected cord blood DMRs using bisulfite amplicon sequencing.

RESULTS:The majority (69.03%) of CpGs with≥ 10% methylation difference between placebo and non-smoker groups were restored (by at least 50%) towards non-smoker levels with vitamin C treatment. A significant proportion of restored CpGs were associated with phenotypic outcome with greater enrichment among hypomethylated CpGs.

CONCLUSIONS:We identified a pattern of normalization in DNA methylation by vitamin C supplementation across multiple loci. The consistency of this pattern across tissues and time suggests a systemic and persistent effect on offspring DNA methylation. Further work is necessary to determine how genome-wide changes in DNA methylation may mediate or reflect persistent effects of maternal smoking on lung function.

Analyses in nutritional epidemiology usually assume a uniform effect of a nutrient. Previously, four subgroups of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study of Finnish male smokers aged 50-69 years were identified in which vitamin E supplementation either significantly increased or decreased the risk of pneumonia. The purpose of this present study was to quantify the level of true heterogeneity in the effect of vitamin E on pneumonia incidence using the I 2 statistic. The I 2 value estimates the percentage of total variation across studies that is explained by true differences in the treatment effect rather than by chance, with a range from 0 to 100 %. The I 2 statistic for the effect of vitamin E supplementation on pneumonia risk for five subgroups of the ATBC population was 89 % (95 % CI 78, 95 %), indicating that essentially all heterogeneity was true variation in vitamin E effect instead of chance variation. The I 2 statistic for heterogeneity in vitamin E effects on pneumonia risk was 92 % (95 % CI 80, 97 %) for three other ATBC subgroups defined by smoking level and leisure-time exercise level. Vitamin E decreased pneumonia risk by 69 % among participants who had the least exposure to smoking and exercised during leisure time (7·6 % of the ATBC participants), and vitamin E increased pneumonia risk by 68 % among those who had the highest exposure to smoking and did not exercise (22 % of the ATBC participants). These findings refute there being a uniform effect of vitamin E supplementation on the risk of pneumonia.