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Green DJ, O'Driscoll JG, Maiorana A, Scrimgeour NB, Weerasooriya R, Taylor RR.

Department of Human Movement, University of Western Australia, Australia.

1. 'Chelation therapy' with EDTA is being frequently used in patients with cardiovascular disease, despite limited objective evidence of effectiveness. Depressed nitric oxide (.NO)-related endothelial function accompanies atherosclerosis, and even the vascular risk factors alone, and is improved by numerous interventions that also improve prognosis in vascular disease. 2. The aim of the present study was to determine the influence of chelation therapy with EDTA alone and EDTA in combination with B vitamins on endothelial function. 3. After a control series of saline infusions, we examined the effects of a series of EDTA infusions (1.5 g, 10 times over 6 weeks) in eight subjects with coronary artery disease. In addition, because EDTA is commonly supplemented by other components, particularly B group vitamins, we subsequently examined the effect of a similar series of vitamin-supplemented EDTA infusions. 4. Forearm blood flow (FBF) was assessed by plethysmography and graded intrabrachial infusions of the endothelium-dependent vasodilator acetylcholine (ACh) and the endothelium-independent dilator sodium nitroprusside (SNP). 5. There was no difference in vasodilation to either drug after EDTA alone compared with the control periods, but the response to ACh was augmented after combined therapy (P < 0.03, ANOVA). The latter was accompanied by a small but consistent mean (+/- SEM) fall in plasma homocysteine of 1.6 +/- 0.5 mumol/L (P < 0.05). 6. The selective increase in the vasodilator response to ACh after therapy with EDTA and several B group vitamins indicates that NO-related endothelial function was improved. The absence of response to EDTA alone suggests that the supplementary vitamins were necessary for this benefit, which may have been related to the accompanying decrease in plasma homocysteine. These results, along with the current interest in the possible cardioprotective effects of vitamins and the increasing administration of 'chelation therapy', call for more definitive studies on these aspects of 'alternative medicine'.

PMID: 10561804 [PubMed - indexed for MEDLINE]

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January 18, 2002 - Nicotine alone causes acute endothelial dysfunction, though to a lesser extent than does the same amount in a smoked cigarette.

The precise mechanisms by which the drug leads to this altered vascular reactivity, however, remain unclear.

Objective of this study was to determine whether nicotine, a constituent of cigarette smoke, contributes to acute endothelial dysfunction after the smoking of one cigarette. That nicotine might cause an impairment of endothelium-dependent vasodilation via an increase in oxidative stress has been suggested in animal studies.

Sixteen healthy smokers participated in this randomised, observer-blind crossover study comparing the effects of nicotine nasal spray (1 mg nicotine) and cigarette smoke (1 mg nicotine, 12 mg tar) on vascular reactivity in the brachial artery.

Researchers used high-resolution ultrasound to assess flow-mediated dilation (FMD) and endothelium-independent, nitroglycerin-induced dilation. These measures were taken at baseline and 20 minutes after administration of the nicotine in the spray or cigarette form.

In response to similar increases in nicotine serum levels, FMD values declined from 10.2 4.4 percent to 6.7 4 percent after the spray. After the cigarette, these FMD values declined from 9.4 3.8 percent to 4.3 2.8 percent.

Nitroglycerin-induced dilation remained similar within both periods.

When researchers performed a period-effect analysis of variance, a significant influence on FMD was found for the mode of administration and the baseline value.

Effect on FMD was more pronounced after the cigarette than after the spray (estimated average effect difference: 1.9 percent FMD).

Oxidation parameters did not increase significantly after nicotine spray or tobacco exposure.

Although just how nicotine alters vascular reactivity remain unclear, these findings demonstrate it does cause acute endothelial dysfunction on its own, although to a lesser extent than would the same amount taken in a cigarette, these authors conclude.

T Neunteufl and colleagues from the Department of Cardiology, University of Vienna, Vienna, Austria did work.

J Am Coll Cardiol 2002 Jan 16;39(2):251-6.
"Contribution of nicotine to acute endothelial dysfunction in long-term smokers"

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Endothelial dysfunction in obesity: new therapeutic role for antioxidants?

Original article:
Obesity and body fat distribution induce endothelial dysfunction by oxidative stress. Protective effect of vitamin C. Perticone F, Ceravolo R, Candigliota M et al. Diabetes 2001; 50: 159–65.

Summary
Endothelium-dependent and -independent microcirculatory function of the forearm in response to intra-arterial administration of acetylcholine (ACh) and sodium nitroprusside (SNP), respectively, was studied in 76 healthy subjects (50 men and 26 women aged 21–45 years) with a wide range of body weights and insulin resistance. The acute effects of intra-
arterial infusions of vitamin C and indomethacin were also studied.
A significant inverse correlation was found between forearm blood flow response to ACh and BMI (r = -0.676, p < 0.0001) (Fig. 1), waist-hip ratio (r = -0.631, p < 0.0001), and insulin resistance estimated by homeostasis model assessment (r = -0.633, p < 0.0001).

Fig. 1: Peak percent increases in forearm blood flow after ACh infusion vs. BMI in all subjects and subdivided by sex.

These associations were seen in both men and women and were independent of blood pressure and fasting plasma concentrations of glucose, cholesterol and triglycerides. No correlations were found between adiposity and forearm blood flow responses to SNP. Accordingly, the group of obese subjects, consisting of 24 men and 13 women with a BMI ³30 kg/m2, had threefold lower forearm vasodilatation to ACh than did lean subjects (p < 0.0001), but preserved responses to SNP. In the overweight/ obese group, both vitamin C (Fig. 2) and indomethacin improved (p < 0.0001) but did not normalize the impaired vasodilatation to ACh; SNP responses were unchanged.

Fig. 2: Forearm blood flow (FBF) and vascular resistance during ACh and SNP infusions, before and during coinfusion of vitamin C. Group A: n = 15 (10 men, 5 women), BMI <25 kg/m2; group B: n = 24 (16 men, 8 women), BMI 25–29 kg/m2; group C: n = 37 (24 men, 13 women), BMI ³30 kg/m2.

The authors concluded that obese subjects have impaired peripheral microcirculatory endothelial function and that this is related to both the degree of adiposity and to insulin resistance. The reversal of peripheral endothelial dysfunction with vitamin C and indomethacin was interpreted as supporting the hypothesis that oxidative stress contributes to vascular dysfunction in human obesity.

Comment
The pathogenesis of vascular disease in obesity remains unclear but probably relates to the impact of the metabolic syndrome (insulin resistance, dyslipidaemia, hyperoxidative stress, hypertension) on the biology of endothelial-derived nitric oxide. This study confirms previous reports of vascular dysfunction in obesity [1, 2] but extends these findings by showing that the effects of adiposity occur in both men and women and that the vascular dysfunction is potentially reversible with antioxidants such as ascorbic acid (vitamin C).
The study was carefully performed using a standard protocol for measuring peripheral endothelial function in the forearm microcirculation. Impressively, the findings were based on a large number of observations, by comparison with other studies of this type in which the sample sizes have been much smaller. The acute experiments involving the intrabrachial administration of vitamin C and indomethacin were well controlled, but the specificity of the vascular improvement with these agents for endogenous release of nitric oxide was not tested with a co-infusion of a nitric oxide synthase inhibitor such as NG-monomethyl-L-arginine. To fully infer that the therapeutic agents operated through reduction in oxidative stress, it would also have been pertinent to have assayed plasma or urinary isoprostanes, which are measures of free radical load.
The relationship between insulin resistance and endothelial dysfunction in this paper confirms physiological studies showing that the vasodilatory effect of insulin in skeletal muscle is mediated by nitric oxide [3]. Impairment in vascular insulin sensitivity may arise as a consequence of an increase in oxidative stress that depresses the endogenous release of nitric oxide and/or enhances its oxidative catabolism [4]. In this respect, it was surprising that abnormalities to SNP infusions were not detected in the present study, as demonstrated in patients with type 2 diabetes. The notion of increased oxidative stress in central obesity is based on an expansion of the cytosolic triglyceride storage pool in non-adipose tissue [5]. The accumulation of long-chain fatty acyl-coenzyme A esters is hypothesized to inhibit mitochondrial adenosine translocation, with subsequent overproduction of oxygen free radicals such as superoxide. Abundant evidence is accumulating that anti-oxidants may improve insulin resistance [6] and endothelial dysfunction, and the present study adds to the body of data. Whilst the effects of vitamin C may be mostly related to its anti-
oxidant properties, improvement in endothelial function could involve other mechanisms including increased release of nitric oxide from S-nitroso-glutathione. The suggestion that indomethacin has an antioxidant effect is tenuous and at variance with the concept that inhibition of cyclo-oxygenase decreases the release of prostacyclins with a potential vasotonic effect. In both diabetic and non-diabetic subjects indomethacin has been shown to decrease forearm blood flow responses to ACh [7]. The indomethacin findings could, however, be due to an acute anti-inflammatory effect or to net reduction in the release of vasoconstrictor prostanoids.
A surprising finding in this study was also that the obese patients were not hypertriglyceridaemic compared with the lean group and that no data on HDL cholesterol were reported. Hypertriglyceridaemia and low HDL cholesterol have been reported to be associated with endothelial dysfunction and insulin resistance in type 2 diabetes [1, 4]. The effects of hypertriglyceridaemia on endothelial function may be a consequence of the accumulation of chylomicron remnants and small, dense LDL that collectively disturb the endogenous release of nitric oxide [4]. Low HDL may also be causally implicated in endothelial dysfunction, principally owing to its pro-oxidant and pro-inflammatory properties. From a lipoprotein perspective, it is noteworthy that postprandial hypertriglyceridaemia has been suggested to increase oxidative stress and impair endothelial function and that these responses may be attenuated with antioxidant therapy [8, 9]. There is also emerging evidence that non-esterified fatty acids induce both insulin resistance and endothelial dysfunction in humans [10], and it would have been pertinent in the present context to report their contribution to endothelial dysfunction in the obese group. These additional key components of the metabolic syndrome might have explained half the variance in the ACh responses unaccounted for by adiposity or insulin resistance. Some of this variance might also have been attributed to increased sympathetic tone, as previously described in obesity.
Endothelial function of peripheral arteries provides a surrogate for the coronary circulation [11], and the present study suggests that anti-oxidant therapy with vitamin C may potentially be useful in the reversal and prevention of coronary disease in obesity. This suggestion will, however, need to be formally tested in a controlled trial of the effect of long-term, oral vitamin C, with or without other antioxidants, on clinical endpoints [12]. Ascorbic acid is a highly effective water-soluble antioxidant that vigorously scavenges a wide variety of radical species and oxidants including superoxide. It may have particular merits over other antioxidants such as the lipid-soluble a-tocopherol that in high doses may have a pro-oxidant effect [12]. Whilst consumption of vitamin C will be safe for obese patients, the same cannot be said for consumption of indomethacin. Extensive reports show that in common with other non-steroidal anti-inflammatory agents, indomethacin interferes with the regulatory effects of a number of antihypertensive agents by mechanisms that involve renal sodium retention and inhibition of the release of vasodilator prostanoids [13]. This diminishes the significance of the indomethacin findings in the present study. A wide variety of therapeutic approaches have been shown to improve endothelial dysfunction, including weight reduction, exercise, fish oils, fibrates, statins, glitazones and ACE inhibitors [14]. Hence, an important question for the future is whether in obese, insulin-resistant and diabetic patients the use of ascorbic acid alone, or in an antioxidant cocktail, improves vascular function over and above that seen with other therapeutic measures. Finally, on the basis of clinical trial data [12], it is premature to recommend that obese patients should routinely take antioxidant supplements.

References
1. Steinberg HO, Chaker H, Leaming R et al. Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. J Clin Invest 1996; 97: 2601–10.
2. Nestel P, Yamashita T, Sasahara T et al. Control of the forearm microcirculation: interactions with measures of obesity and noradrenaline kinetics. Clin Sci 1998; 95: 203–12.
3. Sherrer U, Randin D, Vollenweider L, Nicod P. Nitric oxide release accounts for insulin’s vascular effects. J Clin Invest 1994; 94: 2511–5.
4. Watts GF, Playford DA. Dyslipoproteinaemia and hyperoxidative stress in the pathogenesis of endothelial dysfunction in non-insulin dependent diabetes mellitus; an hypothesis. Atherosclerosis 1998; 141: 17–30.
5. Bakker SJ, Ijzerman RG, Teerlink T et al. Cytosolic triglycerides and oxidative stress in central obesity: the missing link between excessive atherosclerosis, endothelial dysfunction and beta-cell failure? Atherosclerosis 2000; 148: 17–21.
6. Paolisso G, Giugliano D. Oxidative stress and insulin action: is there a relationship? Diabetologia 1996; 39: 357–63.
7. Meeking DR, Browne DL, Allard S et al. Effects of cyclo-oxygenase inhibition on vasodilatory response to acetylcholine in patients with type 1 diabetes and nondiabetic subjects. Diabetes Care 2000; 23: 1840–3.
8. Plotnick GD, Corretti MC, Vogel RA. Effect of anti-oxidant vitamins on the transient impairment of endothelium-dependent brachial artery vasoactivity
following a single high-fat meal. J Am Med Assoc 1997; 278: 1682–6.
9. Anderson RA, Evans ML, Ellis GR et al. The relationship between post-prandial lipaemia, endothelial function and oxidative stress in healthy individuals and patients with type 2 diabetes. Atherosclerosis 2001; 154: 475–83.
10. Steinberg HO, Paradisi G, Hook ZG et al. Free fatty acid elevation impairs insulin-mediated vasodilation and nitric oxide production. Diabetes 2000; 49: 1231–8.
11. Sax FL, Cannon RD, Hanson C, Epstein SE. Impaired forearm vasodilator reserve in patients with microvascular angina: evidence of a generalized disorder of vascular function? N Engl J Med 1987; 317: 1366–70.
12. Stocker R. Dietary and pharmacological antioxidants in atherosclerosis. Curr Opin Lipidol 1999; 10: 589–97.
13. Watts GF. Non-steroidal anti-inflammatory drugs and blood pressure control in the elderly. Aust J Cardiovasc Med 2001; 2: 16–7.
14. Anderson TJ. Assessment and treatment of endothelial dysfunction in humans. J Am Coll Cardiol 1999; 34: 631–8.

Summary and Comment:
Gerald F. Watts, University of
Western Australia, Perth, WA, Australia

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Stanton A. Glantz, PhD; William W. Parmley, MD

As more and more nonsmokers have come to understand the dangers associated with breathing secondhand smoke,(1), (2) the number of communities enacting ordinances requiring smoke-free workplaces and public places has increased rapidly. As of May 2001, hundreds of communities had enacted laws requiring smoke-free workplaces, smoke-free restaurants, and smoke-free bars. California requires all workplaces, including restaurants and bars, to be smoke-free.(3), (4) The theme for the World Health Organization's World No Tobacco Day in 2001 was "clean indoor air" and communities throughout the world are beginning to clear the air of secondhand smoke. Not only do the laws protect nonsmokers from the toxins in secondhand smoke, but they also create an environment that helps smokers cut down or stop smoking. (5)

The tobacco industry's efforts to slow the spread of smoke-free environments has included a systematic effort to attempt to undermine the scientific evidence that passive smoking causes disease.6-8 One common theme is that the dose of toxins a nonsmoker inhales is tiny compared with the dose the smoker receives, implying that the risks are trivial or nonexistent. Such statements are based on measuring the delivered dose of 1 or more of the 4000 chemicals in secondhand smoke. The problem with such calculations is they can be manipulated by selecting the particular constituent of smoke to be the one that has low absorption or rapid clearance.(1) The real measure of effect should not be the dose of one chemical or another, but rather the biological effect of breathing the secondhand smoke.

The article by Otsuka and colleagues (9) in this issue of THE JOURNAL adds substantially to the case that short-term passive smoking adversely affects endothelial function in ways that immediately compromise the cardiovascular system. (10) The investigators demonstrated that, in healthy young volunteers, just 30 minutes of exposure to secondhand smoke compromised the endothelial function in coronary arteries of nonsmokers in a way that made the endothelial response of nonsmokers indistinguishable from that of habitual smokers.

The investigators measured blood pressure, heart rate, and coronary flow velocity reserve before and after administering adenosine triphosphate using transthoracic Doppler echocardiography of the left anterior descending coronary artery. This innovative noninvasive approach to measuring coronary endothelial function appears to be ideal in these individuals, who have no evidence of coronary disease. Significantly, these substantial changes in endothelial function were not associated with changes in heart rate or blood pressure.

Endothelial dysfunction may be at the heart of the development of atherosclerosis. Normal endothelial cells promote vasodilation and inhibit atherosclerosis and thrombosis, in part because of the release of nitric oxide.(11) Dysfunctional cells, on the other hand, contribute to vasoconstriction, atherogenesis, and thrombosis. Risk factors contribute individually to endothelial dysfunction and appear to be additive. One possible unifying hypothesis for the effects of risk factors is that they increase oxidative stress that mediates these effects. (12) Thus, reduction of risk factors improves endothelial function and reduces clinical coronary events. For example, in patients with hyperlipidemia, lipid lowering improves endothelial function both acutely (13) and chronically.(14)

The findings of Otsuka et al (9) are important not only because they illustrate the importance of preventing nonsmokers from any exposure to secondhand smoke, but also because they help to explain the relatively large risk of death and other cardiac events associated with passive smoking compared with active smoking. Passive smoking increases the risk of cardiac death or morbidity about 30% (15-21) compared with a doubling to quadrupling of risk associated with active smoking. Thus, the effect of passive smoking is as high as one third the effect of active smoking even though the dose of at least some of the constituents is much less than what the smoker inhales.(1)

The first evidence that nonsmokers were sensitive to a component of tobacco smoke came from studies showing that short-term (30-minute) exposure to secondhand smoke activated nonsmokers' platelets to nearly the extent that they were activated in smokers (22), (23) and that passive smoking increased the presence of endothelial cell morbidity in the blood. (23) These immediate effects on platelets probably act synergistically with the effects on endothelial function. The platelet effects convinced epidemiologists that the dose-response curve for cardiovascular effects associated with tobacco smoke exposure was not linear, but exhibited substantial effects at relatively low doses (at least compared with an active smoker; the doses are high when measured against other environmental toxins) that a passive smoker receives.(18), (20) In addition, animal studies demonstrated that exposure to the secondhand smoke from a single cigarette daily induced atherosclerotic changes. (24) The fact that passive smoking does not induce additional effects in smokers (9), (22) suggests that the underlying biochemical and cellular processes saturate at the doses involuntary smokers experience.

While most people think of cancer when they think of active and passive smoking, it is important to emphasize that heart disease is also an important consequence of tobacco smoke exposure. This situation is particularly true for passive smoking; heart disease accounts for about 37,000 of the estimated 53,000 annual deaths attributed to involuntary smoking in the United States.18 Another important difference between the effects of smoking on risk of cancer compared with risk of heart disease is that the effects on cancer develop and resolve slowly (over a period of years) whereas the effects of smoking on the cardiovascular system occur rapidly.

The findings of the study by Otsuka et al (9) add to the evidence suggesting that everyone should be protected from even short-term exposure to the toxins in secondhand smoke. Communities should continue to require that workplaces, including restaurants and bars, be smoke-free and mount public education campaigns to encourage smoke-free homes. Not only will everyone breathe better, (25) but they will also have healthier hearts.

Author/Article Information

Author Affiliation: Division of Cardiology, Department of Medicine, University of California, San Francisco.

Corresponding Author and Reprints: Stanton A. Glantz, PhD, Division of Cardiology, University of California School of Medicine, 505 Parnassus, Room 1317M, Box 0130, San Francisco, CA 94143-0130 (e-mail: glantz@medicine.ucsf.edu). Editorials represent the opinions of the authors and THE JOURNAL and not those of the American Medical Association.

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Health effects of exposure to environmental tobacco smoke: the report of the California Environmental Protection Agency.

Smoking and Tobacco Control Monograph No. 10. Bethesda, Md: US Dept of Health and Human Services, National Cancer Institute, National Institute of Health; 1999. Publication NIH 99-4645. Available at: http://rex.nci.nih.gov/NCI_MONOGRAPHS/MONO10/M10-Ch.7.pdf . Accessibility verified June 21, 2001.

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The Tobacco War: Inside the California Battles.

Berkeley: University of California Press; 2000.

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Acute effects of passive smoking on the coronary circulation in healthy young adults.

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ABSTRACT | FULL TEXT | PDF | MEDLINE

(10) Celermajer D, Adams MR, Clarkson P, et al.

Passive smoking and impaired endothelium-dependent arterial dilation in healthy young adults.

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Cellular and molecular mechanisms of endothelial dysfunction.

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(21) He J, Vupputuri S, Allen K, Prerost MR, Hughes J, Whelton PK.

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(22) Burghuber O, Punzengruber C, Sinzinger H, Haber P, Silberbauer K.

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(23) Davis JW, Shelton L, Watanabe IS, Arnold J.

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(24) Penn A, Chen LC, Snyder CA.

Inhalation of steady-state sidestream smoke from one cigarette promotes atherosclerotic plaque development.

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