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From the Townsend Letter
May 2013

Literature Review & Commentary
by Alan R. Gaby, MD
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Vitamin D and Congestive Heart Failure
In a study of patients in a health maintenance organization in Israel, the median serum 25-hydroxyvitamin D (25[OH]D) level was significantly lower in 3009 patients with heart failure than in 46,825 controls without heart failure (36.9 vs. 40.7 nmol/L; p < 0.00001). The percentage of patients with vitamin D deficiency (25(OH)D level < 25 nmol/L) was higher in heart failure patients than in controls (28% vs. 22%, p < 0.00001). During a median follow-up period of 17 months, vitamin D deficiency was an independent predictor of increased mortality in patients with heart failure (hazard ratio [HR] = 1.52; p < 0.001) and also in people without heart failure (HR = 1.91; p < 0.00001). Vitamin D supplementation (usually 800–1000 IU per day) was associated with reduced mortality in heart failure patients (HR = 0.68; p < 0.0001).

Comment: The results of this study indicate that low serum 25(OH)D concentrations are associated with worse outcomes, both in people with and without heart failure. In addition, vitamin D supplementation of heart failure patients was associated with reduced mortality. There are several limitations to this study. First, serum 25(OH)D levels are influenced by how much time people spend outdoors. There are differences between people who do and do not go outside, and some of those other differences, rather than vitamin D status per se, might be responsible for the observed differences in mortality. Second, sunlight exposure has a number of potentially beneficial biochemical effects other than vitamin D synthesis (such as the production of corticotropin-releasing hormone); therefore, some of the biochemical effects of sunlight cannot be duplicated by vitamin D supplementation. Third, while vitamin D supplementation of heart failure patients was associated with better outcomes, vitamin D supplementation might simply be a marker for more conscientious overall medical care. Although there is little risk in giving heart failure patients 800 to 1000 IU per day of vitamin D, randomized controlled trials are needed to prove that such treatment reduces mortality.

Gotsman I et al. Vitamin D deficiency is a predictor of reduced survival in patients with heart failure; vitamin D supplementation improves outcome. Eur J Heart Fail. 2012;14:357–366.

Fish Oil for Atrial Fibrillation
One hundred seventy-eight patients (mean age, 62 years) with persistent atrial fibrillation for more than 1 month were randomly assigned to a control group or to receive 6 g per day of fish oil, in open-label fashion. At least 1 month (mean, 56 days) after the start of supplementation, patients underwent electrical cardioversion. Fish oil was continued until atrial fibrillation returned or for a maximum of 1 year. Concurrent use of antiarrhythmic drugs (sotalol or amiodarone) was permitted. Mean duration of fish oil use after cardioversion was 186 days. Ninety days after cardioversion, the recurrence rate of atrial fibrillation was significantly lower in the fish oil group than in the control group (38.5% vs. 77.5%; p < 0.001). Fish oil significantly reduced recurrence rates both in patients who were and were not using antiarrhythmic drugs.

Comment: Persistent atrial fibrillation is associated with a high risk of recurrence after electrical cardioversion. The results of the present study demonstrate that starting fish oil supplementation more than 1 month before electrical cardioversion and continuing it afterwards can reduce the recurrence rate of persistent atrial fibrillation.

Kumar S et al. Long-term omega-3 polyunsaturated fatty acid supplementation reduces the recurrence of persistent atrial fibrillation after electrical cardioversion. Heart Rhythm. 2012;9:483–491.

Nutrients for Age-Related Macular Degeneration
One hundred forty-five patients (mean age, 73 years) with dry age-related macular degeneration were randomly assigned to receive daily, in open-label fashion, a nutritional supplement (10 mg of lutein, 1 mg of zeaxanthin, 4 mg of astaxanthin, 180 mg of vitamin C, 30 mg of vitamin E, 22.5 mg of zinc, and 1 mg of copper) or no supplement for 2 years. After 2 years, the active-treatment group showed stabilization of visual acuity, with a significantly better mean visual acuity score compared with the control group (81.4 vs. 76.8; p = 0.003). Contrast sensitivity improved in the active-treatment group and deteriorated in the control group (p = 0.001 for the difference in the change between groups). Compared with the control group, the active-treatment group also showed a significantly better composite score on the National Eye Institute Visual Functioning Questionnaire.

Comment: Previous studies have shown that zinc supplementation can slow the rate of deterioration and that lutein can improve visual function in patients with age-related macular degeneration. Antioxidant nutrients such as vitamin C and vitamin E might also be beneficial by decreasing the amount of oxidative damage in retinal tissue. From this study and others, it is clear that nutritional supplements should be included as part of a comprehensive treatment program for patients with dry age-related macular degeneration.

Piermarocchi S et al. Carotenoids in Age-related Maculopathy Italian Study (CARMIS): two-year results of a randomized study. Eur J Ophthalmol. 2012;22:216–225.

B Vitamins and Heart Disease: Interaction with Antiplatelet Medications
In the VITATOPS trial, 8164 patients with a recent stroke or transient ischemic attack were randomly assigned to receive, in double-blind fashion, placebo or daily B vitamins (2 mg of folic acid, 25 mg vitamin B6, and 500 mcg vitamin B12) and were followed up for a median 3.4 years. The primary outcome measure was a composite of stroke, myocardial infarction, or death from vascular causes. This post hoc analysis examined whether there was an interaction between antiplatelet therapy and the effect of B vitamins on the primary outcome. Among the 6609 patients taking antiplatelet drugs at baseline, B vitamins had no significant effect on the incidence of the primary outcome (15% vs. 16%; hazard ratio [HR] = 0.94; 95% CI, 0.83–1.07). Among the 1463 participants not taking antiplatelet drugs at baseline, B vitamins significantly decreased the incidence of the primary outcome (17% vs. 21%; HR = 0.76; 95% CI, 0.60–0.96). The interaction between antiplatelet therapy and the effect of B vitamins was significant after adjusting for imbalance in the baseline variables (p = 0.02).

Comment: Homocysteine, a metabolite of methionine, appears to be toxic to the cardiovascular system. Folic acid, vitamin B6, and vitamin B12 can lower homocysteine levels. Numerous studies have examined whether supplementing with these vitamins can prevent cardiovascular events such as heart attack or stroke, and the results have been conflicting. In the present study, B vitamins were most effective in people not taking antiplatelet drugs; in those who were taking such drugs, the benefits of B vitamins were modest at best. This modulating effect of antiplatelet drugs on the efficacy of B vitamins might be explainable by the observation that the adverse effect of homocysteine on the cardiovascular system is mediated in part by increased platelet aggregation. Consequently, in patients taking antiplatelet drugs, there may be “less room” for a beneficial effect of B vitamins.

Hankey GJ et al. Antiplatelet therapy and the effects of B vitamins in patients with previous stroke or transient ischaemic attack: a post-hoc subanalysis of VITATOPS, a randomised, placebo-controlled trial. Lancet Neurol. 2012;11:512–520.

Green Tea Extract Lowers LDL-Cholesterol Levels
One hundred three healthy postmenopausal women (mean age, 60 years) were randomly assigned to receive, in double-blind fashion, Polyphenon E (a green tea extract, providing 400 or 800 mg per day of epigallocatechin gallate [EGCG]; equivalent to about 5 or 10 cups per day of green tea) or placebo for 2 months. The mean serum concentration of LDL cholesterol decreased by 7.7% with 400 mg per day of EGCG, decreased by 6.5% with 800 mg per day of EGCG, and increased by 0.8% in the placebo group (p = 0.02 for the difference in the change between the combined active-treatment groups and placebo).

Comment: Other studies have shown that supplementation with green tea extract can decrease systolic and diastolic blood pressure and serum levels of C-reactive protein, while increasing insulin sensitivity. Each of these effects would be expected to decrease the risk of developing cardiovascular disease. The results of the present study indicate that green tea can protect the heart and blood vessels by yet another mechanism.

Wu AH et al. Effect of 2-month controlled green tea intervention on lipoprotein cholesterol, glucose, and hormone levels in healthy postmenopausal women. Cancer Prev Res. 2012;5:393–402.

Vitamin D and Cardiovascular Disease: Racial Differences
Serum 25-hydroxyvitamin D (25[OH]D) levels were measured at baseline in 5001 white and 2980 black adults participating in the Third National Health and Nutrition Examination Survey, 1988–1994. During a median of 14.1 years of follow-up, there were 116 and 60 fatal strokes in whites and blacks, respectively. The risk of fatal stroke was 60% higher in blacks than in whites, after adjustment for socioeconomic status and cardiovascular disease risk factors. The mean baseline 25(OH)D level was significantly lower in blacks than in whites (19.4 vs. 30.8 ng/ml). After adjustment for potential confounding variables, 25(OH)D levels below 15 ng/ml were associated with an increased risk of fatal stroke in whites (hazard ratio [HR] = 2.13; 95% confidence interval [CI], 1.01–4.50) but not in blacks (HR = 0.93; 95% CI, 0.49–1.80).

Comment: Vitamin D metabolism and vitamin D requirements of Caucasians appear to differ from those of African Americans, and possibly from those Asians and certain other racial/ethnic groups. For example, in one study, low serum 25(OH)D levels were associated with an increased risk of fractures in Caucasians, but with a decreased fracture risk in African Americans and Asians. The results of the present study suggest that low vitamin D status may increase the risk of stroke in Caucasians, whereas low vitamin D status has no effect or a modest protective effect against stroke in African Americans. While observational studies do not prove causality, these studies raise the possibility that aggressive vitamin D supplementation is inappropriate for certain racial/ethnic groups.

Michos ED et al. 25-hydroxyvitamin D deficiency is associated with fatal stroke among whites but not blacks: The NHANES-III linked mortality files. Nutrition. 2012;28:367–371.

Saturated Fat and Heart Disease: Does the Food Source Matter?
The association between saturated fat intake from different food sources and incidence of cardiovascular disease was examined in a multiethnic population of 5209 US adults (aged 45–84 years). During a 10-year follow-up period, 316 cases of cardiovascular disease were documented. After adjustment for demographics, lifestyle, and dietary confounders, higher intake of dairy saturated fat was associated with lower cardiovascular disease risk. In contrast, a higher intake of saturated fat from meat was associated with greater cardiovascular disease risk. The substitution of 2% of energy from meat saturated fat with energy from dairy saturated fat was associated with a statistically significant 25% lower cardiovascular disease risk. Ad hoc analysis of various dairy sources suggested that the inverse association between dairy saturated fat and cardiovascular disease may be driven by associations for whole-fat cheese rather than for low- or whole-fat milk.

Comment: Although saturated fat intake has historically been thought to contribute to the development of heart disease, the totality of the evidence suggests that saturated fat intake may have a minimal effect, if any, on cardiovascular disease risk. The results of the present study suggest that some foods high in saturated fat are harmful, whereas others are beneficial. If cheese is a cardioprotective food, its effect might be due to constituents other than saturated fat, such as vitamin K2. In addition, the effect of foods high in saturated fat may depend on how they are cooked. For example, high-temperature cooking of meat leads to the formation of relatively large amounts of cardiotoxic cholesterol oxides and advanced glycation end products, whereas less of these compounds are produced when meat is cooked at lower temperatures.

Oliveira Otto MC et al. Dietary intake of saturated fat by food source and incident cardiovascular disease: the Multi-Ethnic Study of Atherosclerosis. Am J Clin Nutr. 2012;96:397–404.

Breakfast and Diabetes
Eating patterns were assessed in 1992 in a cohort of 29,206 US men in the Health Professionals Follow-Up Study who were free of type 2 diabetes. During 16 years of follow-up, 1944 cases of type 2 diabetes were documented. After adjustment for known risk factors, including body mass index (BMI), men who skipped breakfast had a 21% higher risk of type 2 diabetes than did men who consumed breakfast (relative risk [RR] = 1.21; 95% confidence interval [CI], 1.07–1.35). Compared with men who ate 3 times per day, men who ate 1 or 2 times per day had a higher risk of type 2 diabetes (RR = 1.25; 95% CI, 1.08–1.45). These findings persisted after stratification by BMI and diet quality.

Comment: In an earlier randomized, controlled trial, skipping breakfast resulted in a decrease in insulin sensitivity among healthy volunteers. The results of the present study suggest that skipping breakfast can promote the development of type 2 diabetes. Omitting breakfast has also been associated with deleterious changes in serum lipid profiles, decreased cognitive function, and weight gain. Thus, there are many reasons to start your day off with a good breakfast.

Mekary RA et al. Eating patterns and type 2 diabetes risk in men: breakfast omission, eating frequency, and snacking. Am J Clin Nutr. 2012;95:1182–1189.

Alan R. Gaby, MD

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