Dr. Ron’s Research Review – October 13, 2010

This week’s research review contains articles review articles on Coronary Artery Disease; Folate and platelets.

CAD and Thyroid

Overt thyroid dysfunction, hypothyroidism in particular, may lead to coronary artery disease (CAD).

A recent study found free triiodothyronine (fT3) levels were inversely correlated to the presence of CAD and low T3 syndrome conferred an adverse prognosis. (Coceani, Iervasi et al. 2009)

CAD and Hormone Ratios

In animal models the reduced risk of CAD in males administrated with testosterone is due to the conversion of testosterone into estrogen; and sex hormone ratio changes. This suggests the importance of a proper ratio of estrogen:testosterone in the development of CAD. (Yang, Wang et al. 2010)

A lower estradiol to progesterone  (E2-to-P) ratio may be associated with the male disposition to coronary atherosclerosis, whereas lower E2-to-P and E2-to-T ratios may be associated with the same condition in females. (He, Yang et al. 2007)

Folate

High-dose folate may improve platelet function in acute coronary syndrome and other pathologies associated with increased platelet oxidative stress (McCarty 2007)

Dr. Ron


Articles

Thyroid hormone and coronary artery disease: from clinical correlations to prognostic implications

            (Coceani, Iervasi et al. 2009) Download

BACKGROUND: Overt thyroid dysfunction, hypothyroidism in particular, may lead to coronary artery disease (CAD). Whether more subtle anomalies of thyroid hormone metabolism influence the progression of CAD remains a matter of speculation. HYPOTHESIS: The occurrence of CAD and long-term prognosis in patients without a history of either primary thyroid disease, myocardial infarction, or chronic heart failure is related to serum levels of biologically active free triiodothyronine (fT3). METHODS: The cohort consisted of 1047 clinically and biochemically euthyroid patients (median age 65.6 y and 69% male) who underwent coronary angiography in our institute for suspected CAD. RESULTS: Lower fT3 levels were predictive of both single-vessel (p = 0.012) and multivessel (p = 0.009) CAD. Through a multivariate logistic regression analysis, fT3 was still linked to the presence of CAD (hazard ratio [HR]: 0.48, 95% confidence interval [CI]: 0.34-0.68, p < 0.001). After a mean follow-up of 31 months, the survival rate was 95% and total mortality (log-rank 6.75, p = 0.009), as well as cardiac mortality (log-rank 8.26, p = 0.004), was greater among patients with low T3 (fT3 < 2.10 pg/mL) syndrome. At subsequent multivariate Cox regression analysis, the association between low T3 syndrome and survival was maintained (total mortality HR: 1.80, 95% CI: 1.05-3.10, p = 0.034; cardiac mortality HR: 2.58, 95% CI: 1.13-5.93, p = 0.025). CONCLUSIONS: In this selected population, fT3 levels were inversely correlated to the presence of CAD and low T3 syndrome conferred an adverse prognosis, even after adjusting for traditional coronary risk factors.

Prevention of coronary artery disease in men: Male hormone, female hormone, or both?

            (Yang, Wang et al. 2010) Download

Sex hormones play an important role in coronary artery disease. Although both male and female hormones have been well-documented to be able to influence vascular biology, the preventive use of sex hormones in CAD is not established. Recent progress suggests a necessity of rethinking of the use of sex hormones for CAD in both sexes. We hypothesize that a long-term and appropriate low-dose combination of male hormone and female hormone could be an effective preventive strategy for men with a high risk of but not developed CAD. This hypothesis is supported by the fact that estrogen has favorable profiles on several key CAD-associated risk factors regardless of sexes. Testosterone supplementation has been linked to a reduced risk of CAD specifically in men. In animal models the reduced risk of CAD in males administrated with testosterone is due to the conversion of testosterone into estrogen; and sex hormone ratio changes rather than each individual sex hormone were found to be the predictor of CAD in a human study, suggesting the importance of a proper ratio of estrogen:testosterone in the development of CAD. In addition, the controversy surrounding the use of hormone replacement therapy in women in turn indicates a potential beneficial effect of sex hormones in men in the prevention of CAD because of the fundamental difference between sexes. Therefore, the combined use of estrogen and testosterone for CAD in men deserves a full investigation and could provide useful information in understanding of the preventive and/or therapeutic application of sex hormones in both sexes.

Sex hormone ratio changes in men and postmenopausal women with coronary artery disease

            (He, Yang et al. 2007) Download

OBJECTIVE: The goal of this study was to investigate the potential role of sex hormones in coronary atherosclerosis in both men and postmenopausal women. DESIGN: A total of 258 male and 236 female postmenopausal participants with angiographically defined stable coronary artery disease (CAD) were enrolled. We measured the levels of estradiol (E2), progesterone (P), testosterone (T), follicle-stimulating hormone, and luteinizing hormone in the participants and in 156 male and 132 female disease-free and age-matched controls using commercially available radioimmunoassay kits. RESULTS: In the male study participants and control subjects, the levels of E2 and P differed slightly in opposing directions; however, these differences were not significantly different, nor were there significant differences in T. However, the ratio of E2 to P in participants was significantly (P < 0.01) lower (even after adjustments for age and body mass index) than in the control subjects (mean +/- SEM: 70.2 +/- 56.4 vs 90.7 +/- 59.5, respectively). In the postmenopausal women, a slight decrease in E2 and increases in P and T in participants were not significantly different from levels in the control group. However, the E2 to P and E2 to T ratios were significantly (P < 0.01) lower (before and after adjustments for age and body mass index adjustments) in the participants relative to the control subjects (38.7 +/- 28.4 vs 49.6 +/- 36.3 and 46.5 +/- 37.6 vs 60.6 +/- 40.8, respectively). Correlation analyses demonstrated that the sex hormone ratio changes in both men and postmenopausal women were related with atherogenic blood lipoprotein changes. In both the male and female groups, levels of follicle-stimulating hormone and luteinizing hormone did not differ significantly between the participants and controls, and correlation analyses revealed no association between these hormones and the ratio of E2 to P in males and the ratios of E2 to P and E2 to T in females (r < 0.2, P > 0.05). Multiple regression analyses demonstrated that age and the presence of CAD were significantly and independently associated with the E2-to-P ratio in men and the E2-to-P and E2-to-T ratios in women and that E2-to-P ratio and low-density lipoprotein cholesterol level were significant independent predictors of CAD in males; E2-to-P and E2-to-T ratios and low-density lipoprotein cholesterol level were significant predictors of CAD in women. CONCLUSIONS: In both men and postmenopausal women with angiographic CAD, there were significant differences (relative to age-matched control subjects) in sex hormone ratios, suggesting an abnormality that could influence coronary health. A lower E2-to-P ratio may be associated with the male disposition to coronary atherosclerosis, whereas lower E2-to-P and E2-to-T ratios may be associated with the same condition in females.

High-dose folate may improve platelet function in acute coronary syndrome and other pathologies associated with increased platelet oxidative stress

(McCarty 2007) Download

Although nitric oxide of endothelial origin plays a major role in warding off inappropriate thrombus formation, platelets also express the "constitutive" isoform of nitric oxide synthase (cNOS). Activation of this enzyme by calcium influx during platelet aggregation provides an important feedback signal that dampens platelet recruitment. Platelets also express a membrane-bound NAD(P)H oxidase complex, activated by collagen receptors, that produces superoxide. Superoxide can directly quench NO; moreover, by giving rise to peroxynitrite, it can oxidize the cNOS cofactor tetrahydrobiopterin (BH4), thereby suppressing cNOS activity and converting it to superoxide generator. In a canine model of acute coronary syndrome, infusion of BH4 has been shown to prevent thrombus formation. Platelets from patients with acute coronary syndrome produce markedly less NO than do control platelets. A reasonable explanation for these findings is that episodic contact with collagen boosts platelet superoxide production, oxidizing BH4. Since 5-methyltetrahydrofolate can reduce oxidized BH4, or otherwise compensate for its deficiency, supplementation with its precursor folic acid may improve platelet function in acute coronary syndrome and possibly reduce risk for coronary thrombosis in other at-risk patients. Other research demonstrates that superoxide production is increased, and nitric oxide production diminished, in platelets of diabetics; the ability of glutathione--a peroxynitrite scavenger--to largely ameliorate these abnormalities, is consistent with a prominent role for BH4 deficiency in diabetic platelet malfunction. Reports that platelet NO production is decreased, and/or superoxide production increased, in patients with disorders associated with insulin resistance syndrome, suggest that BH4 deficiency--potentially remediable with high-dose folate--may likewise contribute to the platelet hyperreactivity noted in these disorders. Supplemental vitamin C and arginine also have the potential to boost platelet production of NO Increased intakes of taurine, magnesium, gamma-tocopherol, fish oil, and garlic may help to stabilize platelets by additional mechanisms. As a complement to the proven benefits of low-dose aspirin, a supplemental regimen emphasizing these nutrients in appropriate doses may act directly on platelets to further diminish risk for thrombotic episodes.


References

Coceani, M., G. Iervasi, et al. (2009). "Thyroid hormone and coronary artery disease: from clinical correlations to prognostic implications." Clin Cardiol 32(7): 380-5.

He, H., F. Yang, et al. (2007). "Sex hormone ratio changes in men and postmenopausal women with coronary artery disease." Menopause 14(3 Pt 1): 385-90.

McCarty, M. F. (2007). "High-dose folate may improve platelet function in acute coronary syndrome and other pathologies associated with increased platelet oxidative stress." Med Hypotheses 69(1): 12-9.

Yang, C., X. Wang, et al. (2010). "Prevention of coronary artery disease in men: Male hormone, female hormone, or both?" Med Hypotheses.