Kaye A. Griffiths

Aortic wall thickness in newborns with intrauterine growth restriction

Much epidemiological evidence has linked low birthweight with late cardiovascular risk. We measured aortic wall thickness (a marker of early atherosclerosis) by ultrasonography in 25 newborn babies with intrauterine growth restriction and 25 with normal birthweight. Maximum aortic thicknesses were significantly higher in the babies with intrauterine growth restriction (810 microm [SD 113]) than in those without (743 microm [76], p=0.02), more so after adjustment for birthweight (300 microm/kg [45] vs 199 microm/kg [29], p<0.0001). Newborn babies with growth restriction have significant aortic thickening, suggesting that prenatal events might predispose to later cardiovascular risk.

Vascular Reactivity Is Impaired in Genetic Females Taking High-Dose Androgens

OBJECTIVE To assess the vascular effects of high-dose androgen treatment in genetic females. BACKGROUND Male gender is an independent risk factor for coronary artery disease, suggesting either a protective effect of estrogens and/or a deleterious effect of androgens. We have recently demonstrated that androgen deprivation is associated with enhanced vascular reactivity in adult men, however, the effects of androgen excess on vascular function in humans has not been reported previously. METHODS We studied vascular reactivity in two groups of genetic females: 12 female-to-male transsexuals receiving long-term high-dose androgens, and 12 healthy female control subjects, matched for age and smoking history. Using external vascular ultrasound, brachial artery diameter was measured at rest, after flow increase (leading to flow-mediated dilatation [FMD], which depends on normal endothelial function) and after sublingual nitroglycerin (NTG), an endothelium-independent dilator. RESULTS Testosterone levels were higher (15.2+/-8.7 vs. 1.9+/-1.3 mmol/L, p < 0.001) and high-density lipoprotein cholesterol levels were lower (1.2+/-0.2 vs. 1.6+/-0.4 mmol/L, p=0.02) in the transsexuals compared with the control subjects. In each group, nine of 12 subjects were current or ex-smokers, leading to impaired FMD in both groups (5.1+/-3.7% in the transsexuals vs. 6.9+/-4.1% in controls, p=0.28). The NTG response was significantly decreased in the transsexuals (15.9+/-4.9% vs. 22+/-5.8% in controls, p=0.01), independent of the effects of age, cholesterol or vessel size. CONCLUSIONS Long-term treatment with high-dose androgens is associated with impaired vascular reactivity in genetic females, consistent with a deleterious effect of androgen excess on arterial physiology.

Androgenic anabolic steroids and arterial structure and function in male bodybuilders.

OBJECTIVES The study examined arterial and cardiac structure and function in bodybuilders using androgenic anabolic steroids (AAS), compared to non-steroid-using bodybuilder controls. BACKGROUND Adverse cardiovascular events have been reported in bodybuilders taking anabolic steroids. The cardiovascular effects of AAS, however, have not been investigated in detail. METHODS We recruited 20 male bodybuilders (aged 35 +/- 3 years), 10 actively using AAS and 10 who denied ever using steroids. Serum lipid and hormone levels, carotid intima-media thickness (IMT), arterial reactivity, and left ventricular (LV) dimensions were measured. Vessel diameter was measured by ultrasound at rest, during reactive hyperemia (an endothelium-dependent response, leading to flow-mediated dilation, FMD), and after sublingual nitroglycerin (GTN, an endothelium-independent dilator). Arterial reactivity was also measured in 10 age-matched non-bodybuilding sedentary controls. RESULTS Use of AAS was associated with significant decreases in high density lipoprotein cholesterol, sex hormone binding globulin, testosterone and gonadotrophin levels, and significant increases in LV mass and self-reported physical strength (p < 0.05). Carotid IMT (0.60 +/- 0.04 mm vs. 0.63 +/- 0.07 mm), arterial FMD (4.7 +/- 1.4% vs. 4.1 +/- 0.7%) and GTN responses (11.0 +/- 1.9% vs. 14.4 +/- 1.7%) were similar in both bodybuilding groups (p > 0.2). The GTN responses were significantly lower and carotid IMT significantly higher in both bodybuilding groups, however, compared with the non-bodybuilding sedentary controls (p = 0.01). CONCLUSIONS Although high-level bodybuilding is associated with impaired vascular reactivity and increased arterial thickening, the use of AAS per se is not associated with significant abnormalities of arterial structure or function.

Enhanced peripheral vasodilation in humans after a fatty meal.

OBJECTIVES We sought to study the effects of a fatty meal on vascular reactivity, including endothelial function and maximal vasodilation. BACKGROUND Recent reports regarding the physiological changes in peripheral vasculature after eating a fatty meal have been controversial. METHODS Twelve volunteers were studied before, 3 h after, and 6 h after a high-fat meal (1030 kcal, 61 g fat) rich in saturated fatty acids, and 10 were restudied after a similar meal rich in monounsaturated fatty acids. Endothelial function was assessed as flow-mediated dilatation (FMD) in the brachial artery using ultrasound. Resting and postischemic forearm blood flow (FBF) were recorded using venous occlusion strain-gauge plethysmography, before, and every 10 to 15 s after, 5 min upper arm ischemia. RESULTS Brachial artery basal diameter, resting FBF and postischemic hyperemia increased after high-fat meals (all p<0.001), whereas FMD did not change. The increase in resting FBF correlated with increases in postprandial insulin (r = 0.80, p<0.002) and triglyceride (r = 0.77, p<0.005) levels. CONCLUSIONS We concluded that eating a fatty meal induces vasodilation and increases resting and stimulated FBF and that these observations are probably mediated by postprandial changes in insulin and/or triglyceride levels. The metabolic changes that occur after meals are not associated with impaired endothelial nitric oxide release in the conduit arteries.

Oral vitamin C and endothelial function in smokers: short-term improvement, but no sustained beneficial effect

OBJECTIVES To test the hypothesis that antioxidant therapy would improve endothelial function in smokers. BACKGROUND Several studies have documented a beneficial effect of short-term oral or parenteral vitamin C on endothelial physiology in subjects with early arterial dysfunction. Possible long-term effects of vitamin C on endothelial function, however, are not known. METHODS We studied the effects of short- and long-term oral vitamin C therapy on endothelial function in 20 healthy young adult smokers (age 36 +/- 6 years, 8 male subjects, 21 +/- 10 pack-years). Each subject was studied at baseline, 2 h after a single dose of 2 g vitamin C and 8 weeks after taking 1 g vitamin C daily, and after placebo, in a randomized double-blind crossover study. Blood samples were analyzed for plasma ascorbate levels and endothelial function was measured as flow-mediated dilation of the brachial artery, using high resolution ultrasound. Nitroglycerin-mediated dilation (endothelium-independent) was also measured at each visit. RESULTS At baseline, plasma ascorbate level was low in the smokers (42 +/- 21 micromol/liter; normal range, 50 to 150 micromol/liter), increased with vitamin C therapy after 2 h to 120 +/- 54 micromol/liter (p < 0.001) and remained elevated after eight weeks of supplementation at 92 +/- 32 micromol/liter (p < 0.001, compared with placebo). Flow-mediated dilation, however, increased at 2 h (from 2.8 +/- 2.0% to 6.3 +/- 2.8%, p < 0.001), but there was no sustained beneficial effect after eight weeks (3.9 +/- 3.2%, p = 0.26). Nitroglycerin-mediated dilation was unchanged throughout. CONCLUSION Oral vitamin C therapy improves endothelial dysfunction in the short term in healthy young smokers, but it has no beneficial long-term effect, despite sustained elevation of plasma ascorbate levels.

Long-Term Effects of Dihydrotestosterone Treatment on Prostate Growth in Healthy, Middle-Aged Men Without Prostate Disease: A Randomized, Placebo-Controlled Trial

BACKGROUND Benign prostatic hypertrophy increases with age and can result in substantially decreased quality of life for older men. Surgery is often required to control symptoms. It has been hypothesized that long-term administration of a nonamplifiable pure androgen might decrease prostate growth, thereby decreasing or delaying the need for surgical intervention. OBJECTIVE To test the hypothesis that dihydrotestosterone (DHT), a nonamplifiable and nonaromatizable pure androgen, reduces late-life prostate growth in middle-aged men. DESIGN Randomized, placebo-controlled, parallel-group trial. (Australian New Zealand Clinical Trials Registry number: ACTRN12605000358640) SETTING: Ambulatory care research center. PARTICIPANTS Healthy men (n = 114) older than 50 years without known prostate disease. INTERVENTION Transdermal DHT (70 mg) or placebo gel daily for 2 years. MEASUREMENTS Prostate volume was measured by ultrasonography; bone mineral density (BMD) and body composition were measured by dual-energy x-ray absorptiometry; and blood samples and questionnaires were collected every 6 months, with data analyzed by mixed-model analysis for repeated measures. RESULTS Over 24 months, there was an increase in total (29% [95% CI, 23% to 34%]) and central (75% [CI, 64% to 86%]; P < 0.01) prostate volume and serum prostate-specific antigen level (15% [CI, 6% to 24%]) with time on study, but DHT had no effect (P > 0.2). Dihydrotestosterone treatment decreased spinal BMD (1.4% [CI, 0.6% to 2.3%]; P < 0.001) at 24 months but not hip BMD (P > 0.2) and increased serum aminoterminal propeptide of type I procollagen in the second year of the study compared with placebo. Dihydrotestosterone increased serum DHT levels and its metabolites (5α-androstane-3α,17β-diol and 5α-androstane-3β,17β-diol) and suppressed serum testosterone, estradiol, luteinizing hormone, and follicle-stimulating hormone levels. Dihydrotestosterone increased hemoglobin levels (7% [CI, 5% to 9%]), serum creatinine levels (9% [CI, 5% to 11%]), and lean mass (2.4% [CI, 1.6% to 3.1%) but decreased fat mass (5.2% [CI, 2.6% to 7.7%]) (P <0.001 for all). Protocol-specific discontinuations due to DHT were asymptomatic increased hematocrit (n = 8), which resolved after stopping treatment, and increased prostate-specific antigen levels (n = 3; none with prostate cancer) in the DHT group. No serious adverse effects due to DHT occurred. LIMITATION Negative findings on prostate growth cannot exclude adverse effects on the natural history of prostate cancer. CONCLUSION Dihydrotestosterone treatment for 24 months has no beneficial or adverse effect on prostate growth but causes a decrease in spinal but not hip BMD. These findings have important implications for the wider use of nonsteroidal pure androgens in older men. PRIMARY FUNDING SOURCE BHR Pharma.

Physiological testosterone replacement and arterial endothelial function in men

objective The vascular effects of fluctuations in testosterone levels within the physiological range in otherwise healthy men are not known. We therefore aimed to study arterial function in hypogonadal men receiving long‐term physiological androgen replacement therapy, at trough and peak testosterone levels.

Oestradiol improves arterial endothelial function in healthy men receiving testosterone

To assess prospectively the effects of low dose oestradiol on arterial endothelial and smooth muscle function in healthy men. Oestrogen use is associated with reduced cardiovascular disease in oestrogen‐deficient women, however, the vascular effects of low‐dose oestradiol in healthy men have not been investigated previously.

Effects of raloxifene on endothelium-dependent dilation, lipoproteins, and markers of vascular function in postmenopausal women with coronary artery disease

OBJECTIVES We sought to assess the effects of raloxifene, a selective estrogen receptor modulator, on arterial physiology and biology in postmenopausal women with coronary artery disease (CAD). BACKGROUND Raloxifene improves endothelial function and markers of vascular health in vitro in experimental animals and in healthy postmenopausal women. In women whose arteries are affected by advanced atherosclerosis, however, the vascular effects of estrogen receptor modulation are unknown. METHODS We conducted a prospective, randomized, double-blinded, placebo-controlled, crossover trial of raloxifene, 60 mg/day for 8 weeks, in 33 consecutively eligible and consenting postmenopausal women age 50 to 75 years with known CAD. Parameters measured at the beginning and end of each treatment period included brachial artery flow-mediated dilation (FMD), the primary end point, as well as nitroglycerin-induced dilation, peripheral artery tonometry, serum lipoprotein levels, and markers of vascular function, including urinary prostaglandin, serum endothelin-1, and fibrinogen levels. RESULTS Baseline FMD was impaired in these women, as expected (2.84 +/- 0.60%), but there was no significant difference between the effect of raloxifene (0.26 +/- 0.66% increase) and placebo (0.01 +/- 0.63% decrease) on this marker of endothelial function (p = 0.82). No significant raloxifene-related effects were observed on derived aortic pressure, pulse pressure, augmentation index, total cholesterol or low- and high-density lipoprotein subfractions, markers of thrombosis, or vasoconstrictor or vasodilator substances. CONCLUSIONS In postmenopausal women with treated CAD, selective estrogen receptor modulation with raloxifene does not improve a comprehensive set of parameters examining vascular function and serum lipoprotein levels.

Coenzyme Q improves LDL resistance to ex vivo oxidation but does not enhance endothelial function in hypercholesterolemic young adults.

Oxidative modification of low-density lipoprotein (LDL) may cause arterial endothelial dysfunction in hyperlipidemic subjects. Antioxidants can protect LDL from oxidation and therefore improve endothelial function. Dietary supplementation with coenzyme Q (CoQ(10)) raises its level within LDL, which may subsequently become more resistant to oxidation. Therefore, the aim of this study was to assess whether oral supplementation of CoQ(10) (50 mg three times daily) is effective in reducing ex vivo LDL oxidizability and in improving vascular endothelial function. Twelve nonsmoking healthy adults with hypercholesterolemia (age 34+/-10 years, nine women and three men, total cholesterol 7.4+/-1.1 mmol/l) and endothelial dysfunction (below population mean) at baseline were randomized to receive CoQ(10) or matching placebo in a double-blind crossover study (active/placebo phase 4 weeks, washout 4 weeks). Flow-mediated (FMD, endothelium-dependent) and nitrate-mediated (NMD, smooth muscle-dependent) arterial dilatation were measured by high-resolution ultrasound. CoQ(10) treatment increased plasma CoQ(10) levels from 1.1 +/-0.5 to 5.0+/-2.8 micromol/l (p =.009) but had no significant effect on FMD (4.3+/-2.4 to 5.1+/-3.6 %, p =.99), NMD (21.6+/-6.1 to 20.7+/-7.8 %, p = .38) or serum LDL-cholesterol levels (p = .51). Four subjects were selected randomly for detailed analysis of LDL oxidizability using aqueous peroxyl radicals as the oxidant. In this subgroup, CoQ(10) supplementation significantly increased the time for CoQ(10)H(2) depletion upon oxidant exposure of LDL by 41+/-19 min (p = .04) and decreased the extent of lipid hydroperoxide accumulation after 2 hours by 50+/-37 micromol/l (p =.04). We conclude that dietary supplementation with CoQ(10) decreases ex-vivo LDL oxidizability but has no significant effect on arterial endothelial function in patients with moderate hypercholesterolemia.