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Biomedical subjects

D S Celermajer

Publications and source records attributed to D S Celermajer.

At least 19 recordsLinked to original sources

Evidence-based medicine: how good is the evidence?

The "evidence" in EBM must be of high quality in order to be useful, but this is not always the case. Even the "gold standard" of evidence-based medicine, the randomised clinical trial, is bedevilled by low inclusion rates and potentially important recruitment biases. "Real world" trials often do not give the same results as these highly artificial controlled clinical studies. Meta-analysis, the next most important level of evidence in EBM, may be unreliable, sometimes giving different results to subsequent large randomised trials. There is a bias in the hypotheses tested in large clinical trials, as the costs involved are usually covered by commercially interested companies. For this reason, trials of non-patentable compounds or therapies of no commercial interest may not be performed. The process of journal review and publication is capricious, slow and may have a selection bias towards positive studies, meaning that communication channels for the "evidence" are often unsatisfactory. For many rarer conditions and situations, there is simply no "high level" evidence, such as in paediatrics and subspecialty surgery.

Bias↗

Impaired vascular responses to nitroglycerin in subjects with coronary atherosclerosis.

To study smooth muscle function in atherosclerosis, we calculated dose-response curves in patients with coronary artery disease and in controls by measuring changes in brachial artery diameter after incremental sublingual doses of nitroglycerin. The doses required to produce a 50% maximal dilator response were significantly higher in patients with coronary artery disease than in controls (p <0.002), suggesting smooth muscle dysfunction in atherosclerosis.

Adult↗

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.

Adult↗

The Mediterranean score of dietary habits in Chinese populations in four different geographical areas.

OBJECTIVE: To compare the dietary intake of Chinese people living in Pan Yu, Hong Kong, San Francisco and Sydney with respect to cardiovascular health, using the Mediterranean diet score, examining the effects of age, gender, urbanization and acculturation on the diet score. SUBJECTS: A total of 500 men and 510 women in Hong Kong were recruited as a territory-wide stratified random sample. Subjects were recruited in response to local advertisements for the other three sites: Pan Yu, 58 men, 95 women; San Francisco, 166 men, 192 women; Sydney, 95 men, 73 women. METHOD: Food-frequency questionnaire over a 7 week period. A high/healthy score was taken as > or =4 for men and >3 for women, representing a dietary pattern beneficial for cardiovascular health. RESULTS: In Hong Kong, more women in the middle age group (35-54) had a high score than other age groups, and overall more women had high scores than men. In comparing the four geographical regions, Pan Yu had the highest number of subjects with high score, and Hong Kong had the lowest. With the exception of the younger population and men in Hong Kong, the percentage of the population with a high score in all sites is greater than among elderly Greeks consuming a more traditional heart-healthy Mediterranean diet. CONCLUSION: Considerable variations in Chinese dietary patterns exist with respect to age, gender and geographic location. Overall, the Chinese diet is comparable to the Mediterranean diet and may be expected to have similar health benefits that have been documented for the traditional Mediterranean diet.

Adult↗

Oestradiol improves arterial endothelial function in healthy men receiving testosterone.

OBJECTIVE: 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. PATIENTS AND DESIGN: Twenty-three men (aged 32 +/- 8 years) were randomized to receive depot implants of testosterone (T) alone (group 1, n = 10), or T with either 10 mg (group 2, n = 7) or 20 mg (group 3, n = 6) of oestradiol (E). MEASUREMENTS: Hormone levels, lipids and vascular reactivity were measured before, 1 month and 6 months after hormone implantation. Using high-resolution ultrasound, brachial artery diameter was measured at rest, during reactive hyperaemia (leading to flow-mediated dilatation, FMD, which is endothelium-dependent) and after sublingual nitroglycerin (GTN, an endothelium-independent dilator). RESULTS: Oestradiol produced a dose-dependent increase in plasma oestradiol (at 1 month 96 +/- 7, 149 +/- 6, 192 +/- 23 pmol/l in the 3 groups, respectively, P < 0.001 by ANOVA for trend). Minor side-effects (gynaecomastia, nipple tenderness) indicated that 20 mg oestradiol was the maximum tolerated dose. There was also a dose-dependent increase in FMD with oestradiol dose: at 1 month, - 0.2, + 0.2 and + 1.8% for groups 1-3, respectively (P = 0.31 by ANOVA for trend); and at 6 months, - 0.8, + 0.4 and + 2.2% (P = 0.02). The rise in oestradiol levels following treatment correlated with the improvement in FMD (P = 0.01). GTN responses were similar in the 3 groups throughout the study. CONCLUSION: In healthy young men, oestradiol supplementation is associated with enhanced arterial endothelial function, a key marker of vascular health.

Adult↗

Inhaled nitric oxide and prevention of pulmonary hypertension after congenital heart surgery: a randomised double-blind study.

BACKGROUND: Pulmonary hypertensive crises (PHTC) are a major cause of morbidity and mortality after congenital heart surgery. Inhaled nitric oxide is frequently used as rescue therapy. We did a randomised double-blind study to investigate the role of routinely administered inhaled nitric oxide to prevent pulmonary hypertension in infants at high risk. METHODS: We enrolled 124 infants (64 male, 60 female; median age 3 months [IQR 1-5]), 76% with large ventricular or atrioventricular septal defects, who had high pulmonary flow, pressure, or both, and were undergoing corrective surgery for congenital heart disease. They were randomly assigned continuous low-dose inhaled nitric oxide (n=63) or placebo (n=61) from surgery until just before extubation. We measured the numbers of PHTC, time on study gas, and hours spent in intensive care. Analysis was done by intention to treat. FINDINGS: Compared with placebo, infants receiving inhaled nitric oxide had fewer PHTC (median four [IQR 0-12] vs seven [1-19]; relative risk, unadjusted 0.66, p<0.001, adjusted for dispersion 0.65, p=0.045) and shorter times until criteria for extubation were met (80 [38-121] vs 112 h [63-164], p=0.019). Time taken to wean infants off study gas was 35% longer in the nitric oxide group than in the placebo group (p=0.19), but the total time on the study gas was still 30 h shorter for the nitric oxide group (87 [43-125] vs 117 h [67-168], p=0.023). No important toxic effects arose. INTERPRETATION: In infants at high risk of pulmonary hypertension, routine use of inhaled nitric oxide after congenital heart surgery can lessen the risk of pulmonary hypertensive crises and shorten the postoperative course, with no toxic effects.

Administration, Inhalation↗

Phytoestrogens do not influence lipoprotein levels or endothelial function in healthy, postmenopausal women.

Plant estrogen or phytoestrogens (PE) are increasingly consumed for the purposes of menopause symptom relief and prevention of cardiovascular and other diseases. The objective of this study was to evaluate the effects of PE on plasma lipids and lipoproteins and on endothelial function. Twenty healthy, postmenopausal women, 50 to 70 years old, and with evidence of endothelial dysfunction, were treated with a soybean PE tablet of 80 mg/day of isoflavones. Endothelial function was assessed noninvasively using brachial ultrasound. A double-blind, placebo-controlled, randomized crossover design was employed. After 3 weeks stabilization on a standard fat-reduced diet, subjects received PE or placebo for 8 weeks in random order, separated by a washout period of 8 weeks. Compared with placebo, there were no significant effects of PE on blood pressure and plasma lipid or lipoprotein concentrations. Flow-mediated endothelium-dependent dilation (FMD) in response to reactive hyperemia was not significantly changed by PE ingestion (3. 3 +/- 0.7% on placebo vs 4.1 +/- 0.7% on PE, p >0.4). Variation in FMD was not correlated with change in plasma isoflavone concentration (r = -0.09, p >0.7). Glyceryl trinitrate endothelium-independent dilation was not significantly changed with PE (15.9 +/- 1.3% vs 13.7 +/- 1.2%, p >0.1). These results fail to show a significant impact of medium-term supplementation with 80 mg/day of isoflavones on lipid and lipoprotein levels or on endothelial function in healthy, postmenopausal women.

Aged↗

A comparison of endothelial function in Caucasian and Chinese women before and after the menopause.

OBJECTIVE: Arterial endothelial dysfunction is a key atherogenic event that may be related to oestrogen status. We therefore aimed to compare menopause-related changes in endothelial physiology in Chinese and Caucasian females. METHODS: We studied 40 female subjects; 20 Chinese from a rural region of Southern China (ten premenopausal, aged 20-35 years, and ten postmenopausal, aged 55-66 years), and 20 age-matched Caucasian females from Sydney, Australia. All women had a clinical history, resting blood pressure and fasting lipids measured, and endothelial function assessed. Using high-resolution external vascular ultrasound, brachial artery diameter was measured at rest, after flow increase (causing endothelium-dependent dilatation) and after sublingual glyceryl trinitrate (GTW) (an endothelium-independent dilator). RESULTS: There was a significant decline in endothelium-dependent dilatation (EDD) comparing Caucasian females from the premenopausal versus postmenopausal groups (8.4+/-2.7% versus 2.7+/-2.9%; P<0.001). In contrast, there was no significant difference in EDD between pre- and postmenopausal Chinese (9.8+/-3.3% versus 8.3+/-1.7%; P=0.22). On multivariate analysis, postmenopausal status was associated with impaired EDD in Caucasian females (P<0.002) independent of serum cholesterol, blood pressure and vessel size. In contrast, EDD in the Chinese females was not significantly influenced by any of these factors. GTW-induced dilatation was also impaired in the older Caucasian females, a finding explained on multivariate analysis by the increased vessel size in this patient group (P=0.03). CONCLUSION: Menopause is associated with impaired arterial endothelial function in Caucasian but not Chinese women. This suggests possible ethnic differences in menopause-related vascular changes.

Adult↗

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.

Adolescent↗

Androgen receptor expression is greater in macrophages from male than from female donors. A sex difference with implications for atherogenesis.

BACKGROUND: Male sex is an independent risk factor for the extent and severity of atherosclerosis. The influence of androgens on foam cell formation, a key event in atherogenesis, has not yet been investigated. METHODS AND RESULTS: Primary human monocytes were allowed to differentiate into macrophages. RNA was then extracted from healthy male-donor (n=8) and premenopausal female-donor (n=8) macrophages, and message for the androgen receptor (AR) was examined by RT-PCR. There was a significantly higher level of AR mRNA in macrophages isolated from men than in those from women (0.64+/-0.06 versus 0.15+/-0.02 amol/microgram total RNA; P<0.001). AR mRNA levels were similar in macrophages from postmenopausal and premenopausal women (P=0.16). The functional consequence of this sex difference was then explored. Lipid-loading studies were performed on male (n=9) macrophages treated with the androgen dihydrotestosterone (DHT) and/or the AR antagonist hydroxyflutamide. These showed that DHT caused a dose-dependent and receptor-mediated increase in macrophage cholesteryl ester content (109+/-10%, 117+/-3%, and 120+/-4% for 4, 40, and 400 nmol/L DHT, respectively, as a percentage of control, P=0.002; 95+/-8% for DHT with hydroxyflutamide, P=0.58 versus controls). By contrast, there was no significant effect of androgen on lipid loading in female-donor macrophages (P>0.2 versus controls). CONCLUSIONS: Sex differences in androgen-mediated macrophage lipid loading may contribute to the greater prevalence and severity of atherosclerosis in men.

Adult↗

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.

Administration, Oral↗

Role of ischemia and infarction in late right ventricular dysfunction after atrial repair of transposition of the great arteries.

OBJECTIVES: This study was conducted to assess whether myocardial ischemia and/or infarction are involved in the pathogenesis of late right ventricular dysfunction in adult survivors of atrial baffle repair for transposition of the great arteries in infancy. BACKGROUND: The medium-term success of intraatrial baffle repair for transposition of the great arteries is good, with many patients surviving into adult life, but prognosis can be limited by progressive right ventricular dysfunction. We hypothesized that ongoing myocardial ischemia and/or infarction are important factors in the pathogenesis of this complication. Radionuclide techniques offer an opportunity to study both myocardial perfusion and concomitant ventricular wall motion. METHODS: Dipyridamole sestamibi single-photon emission computed tomography followed by rest sestamibi single-photon emission computed tomography was used to assess right ventricular myocardial perfusion, wall motion, wall thickening and ejection fraction in 22 adolescents/young adults who had undergone atrial baffle repair for simple transposition of the great arteries at median 6.7 (range 0.5 to 54) months of age. The patients were aged 10 to 25 (median 15.5) years; 19 in New York Heart Association class I, 2 in class II and 1 in class III. All were in a regular cardiac rhythm during the studies. The right ventricular tomographic images were examined in three parallel and two orthogonal planes, analyzed in 12 segments. RESULTS: Perfusion defects were evident in all patients in at least one segment, in either the rest or stress images. Twelve patients (55%) demonstrated fixed defects only, nine (41%) had fixed and reversible defects and one (4.5%) had reversible defects only. Concomitant wall-thickening abnormalities occurred in 83% of segments with fixed perfusion defects, mirrored by a reduction in wall motion in 91% of segments analyzed. Right ventricular ejection fraction was correlated with age (R = 0.62; p = 0.002), and with wall-thickening abnormalities (R = 0.60; p < 0.005). CONCLUSIONS: Reversible and fixed perfusion defects with concordant regional wall motion abnormalities occur in the right (systemic) ventricle 10 to 20 years after Mustard repair for transposition of the great arteries; this may be important in the pathogenesis of late right ventricular dysfunction in this group.

Adolescent↗

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.

Adolescent↗

The impact of heavy passive smoking on arterial endothelial function in modernized Chinese.

OBJECTIVES: The study evaluated whether heavy exposure to environmental tobacco smoke (passive smoking) might damage arterial function in modernized Chinese. BACKGROUND: Heavy passive smoking is associated with arterial endothelial dysfunction in Caucasian, but not rural Chinese, subjects. METHODS: We studied 20 young (mean age 36.6 +/- 7.0 years) nonsmoking asymptomatic casino workers (9 men) in Macau who were exposed to environmental tobacco smoke for over 8 h/day for at least two years and 20 normal subjects (control subjects). These two groups were carefully matched for age, gender, body mass index (BMI), blood pressure, vessel diameter, cholesterol and glucose levels. Brachial artery diameter was measured by high-resolution B-mode ultrasound at rest, after flow increase (causing flow-mediated endothelium-dependent dilation) and after sublingual nitroglycerin (an endothelium-independent dilator). RESULTS: Flow-mediated dilation (mean +/- SD% of diameter changes) was significantly lower in passive smokers (6.6 +/- 3.4%) compared with the controls (10.6 +/- 2.3%) (p < 0.0001). Nitroglycerin-induced dilation of the two groups were similar. Upon multivariate analysis, passive smoking exposure was the strongest independent predictor (beta = -0.59; p = 0.0001) for impaired flow-mediated endothelium-dependent dilation (model R2 = 0.75, F value = 6.1, p = 0.0001). CONCLUSIONS: In modernized Chinese, as in Caucasians, exposure to heavy environmental tobacco smoke causes arterial endothelial dysfunction, a key early event in atherosclerosis. This may have serious implications for cardiovascular health in China, currently in a process of rapid modernization.

Administration, Sublingual↗

Flow-mediated dilatation.

Arterial endothelial dysfunction is one of the key early events in atherogenesis, preceding structural atherosclerotic changes. It is also important in the late stages of obstructive atherosclerosis, predisposing to constriction and/or thrombosis. Endothelial function can be measured in coronary arteries and in the periphery by measuring vasomotor function after intra-arterial infusion of pharmacologic substances which enhance the release of endothelial nitric oxide. The disadvantage of these methods is their invasive nature, which generally makes them unsuitable for studies involving asymptomatic subjects. For this reason, noninvasive tests of endothelial function have been developed. In the most widely used of these, an ultrasound-based method, arterial diameter is measured in response to an increase in shear stress, which causes endothelium-dependent dilatation. Endothelial function assessed by this method correlates with invasive testing of coronary endothelial function, as well as with the severity and extent of coronary atherosclerosis. This noninvasive endothelial function testing has provided valuable insights into early atherogenesis, as well as into the potential reversibility of endothelial dysfunction by various strategies, including pharmacological agents (lipid lowering, ACE inhibition), L-arginine, antioxidants and hormones.

Arteries↗