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Effect of Acute Cigarette Smoking on Endothelium-Dependent Brachial Artery Dilatation in Healthy Individuals
Effect of Acute Cigarette Smoking on EndotheliumDependent Brachial Artery Dilatation in Healthy Individuals John Lekakis, MD, Christos Papamichael, MD, Costas Vemmos, MD, John Nanas, MD, Dimitrios Kontoyannis, MD, Stamatios Stamatelopoulos, MD, and Spyridon Moulopoulos, igarette smoking is an important risk factor for the development of atherosclerosis in coronary, C cerebral, and peripheral arteries. Endothelial dysfunction, an early phenomenon in atherogenesis, has been described in brachial arteries of healthy chronic1 and passive2 smokers. Less information is available regarding the effect of short-term smoking on vascular tone; a very strong association between cigarette smoking and pure coronary spasm has been described in young women,3 whereas short-term smoking increased coronary vasomotor tone during dipyridamole-induced hyperemia and markedly reduced myocardial flow reserve.4 The effect of acute smoking on large peripheral artery tone has not been described. The present study evaluates, by high-resolution ultrasound imaging, the effect of short-term smoking on endothelium-dependent and endothelium-independent vasodilation of the brachial artery. jjj The study group was composed of 27 healthy volunteers (9 men and 18 women, mean age 33 { 6 years, range 22 to 47). Ten subjects were nonsmokers, whereas 17 were smokers with a 13 { 4.5 packyear history of smoking. No participant had diabetes mellitus systemic hypertension, cholesterol level ú240 mg/dl, or any cardiac disease. Subjects were not taking any cardioactive medications or other medicines known to affect vasoreactivity. All participants gave informed consent before entering the study. All subjects underwent a noninvasive study of the right brachial artery to assess endothelial and smooth muscle responses, as has been previously described by Celermajer et al.1 A 7.0-MHz linear array transducer of a computed sonography system (Acuson 128 XP; Mountain View, California) was used. In all studies, scans were taken at rest, during reactive hyperemia (an endothelium-dependent stimulus to vasodilation), again at rest, and after sublingual isosorbide dinitrate (an endothelium-independent vasodilator). The subject rested quietly for 10 minutes before the scan. When a satisfactory position was found, the skin was marked; a resting scan was recorded, and arterial flow velocity was measured using a pulsed-Doppler signal at a 607 angle in the center of the artery. Blood flow through the brachial artery was altered with an occluding cuff placed on From the Department of Clinical Therapeutics, Alexandra University Hospital, Athens, Greece. Dr. Lekakis’s address is: 86 Alkionis Street, P. Faliron, 17562, Athens, Greece. Manuscript received July 1, 1996; revised manuscript received and accepted September 25, 1996.
the forearm approximately 8 cm distal to the site of brachial artery measurement.5 By inflating the cuff to 250 to 300 mm Hg, flow was reduced through the brachial artery measured proximal to the cuff. By deflating the cuff after 5 minutes of inflation, flow was increased through the brachial artery (reactive hyperemia). The brachial artery was scanned continuously 30 seconds before and 90 seconds after cuff deflation. Ten minutes later, a second rest scan was recorded. Isosorbide dinitrate (5 mg) was then administered sublingually, and the artery was scanned 5 minutes later. Artery diameter was measured by consensus of 2 observers (J.L. and C.P.) unaware of the stage of experiment. Measurements were obtained at end-diastole (peak of R wave of the electrocardiogram); 5 cardiac cycles were analyzed and measurements were averaged, and volume flow was calculated by multiplying the time-averaged velocity of the Doppler flow signal by heart rate and vessel cross-sectional area (pr2).1 Flow-mediated dilatation was calculated as percent increase in arterial diameter during hyperemia compared with the corresponding resting value. Nitrate-induced dilatation was calculated similarly. Reactive hyperemia was calculated as maximum flow during the first 15 seconds after cuff deflation, divided by the corresponding rest flow.1 Next morning (day 2) subjects returned to the laboratory and rest scans were repeated. All participants were then asked to smoke a cigarette (1.1 mg nicotine, 15 mg tar); 5 minutes later, rest scans were repeated. By inflating and deflating the cuff, hyperemia was produced and recorded as described above. Finally, isosorbide dinitrate was used to test endothelium-independent vasodilation. Flow-mediated and endothelium-independent dilatation were calculated as previously described. All subjects abstained from smoking for at least 8 hours before the start of the investigations; subjects could smoke between days 1 and 2 as long as they smoked their last cigarette 8 hours before the day 2 study. Values are expressed as mean { SD. Paired t test was used to compare values in the pre- and postsmoking studies. Probability levels õ0.05 were considered statistically significant. Baseline flow on day 2 was 144 { 50 ml/min and baseline brachial diameter was 3.4 { 0.5 mm; these values were not different from day 1 baseline flow and diameter (132 { 72 ml/min and 3.5 { 0.6 mm, respectively, p Å NS) [Table I]). Resting diameter before sublingual isosorbide dinitrate was similar to that measured before reactive hyperemia (p Å NS).
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artery before smoking dilated 13.5 { 5% in response to increasing Day 2 flow. Short-term smoking led to (After Smoking) a significant decrease in flowmediated dilatation (6.9 { 4%, 3.4 { 0.5 150 { 70 p õ0.001). In absolute terms, 130 { 14* diameter of the vessel changed from 86 { 6* 3.4 { 0.5 mm to 3.9 { 0.6 mm dur89 { 9* ing hyperemia before smoking (p õ0.01) and from 3.4 { 0.5 mm to 3.6 { 0.6 mm after smoking (p Å NS) (Figure 1). Significant changes in flow-mediated dilatation after smoking were observed in all subgroups: men (11 { 1% to 6 { 1%, p õ0.001); women (14.5 { 6% to 7.3 { 5%, p õ0.001); smokers (12 { 4% to 6.5 { 5%, p õ0.001), and nonsmokers (14.8 { 8% to 7.6 { 4%, p õ0.05 [Table II]). Nitrate-induced dilatation before smoking was 24 { 7%, and did not change significantly after smoking (21 { 6%, p Å NS). jjj The present study demonstrates for the first time that short-term smoking markedly reduces flow-dependent vasodilation in the brachial artery, whereas the capacity of the artery to dilate in response to nitrates is preserved. Flow-dependent vasodilation in systemic as well as coronary arteries is mediated by the endothelium through the release of dilator substances that act on the underlying smooth muscle; these endotheliumderived relaxing factors have been identified as nitric oxide6; hyperpolarizing factor may also contribute to flow-dependent vasodilation.7 Increasing flow causes dilatation, which is abolished by removal of the endothelium8; this mechanism fails with endothelial dysfunction.9 Although reduced flow-mediated dilatation after smoking observed in this study is compatible with endothelial dysfunction, it could alternatively reflect an intrinsic impairment of the capacity of smooth muscle cells to relax. To distinguish dysfunction from intrinsic smooth muscle dysfunction, we used isosorbide dinitrate, an endothelium-independent vasodilator.10 Our results demonstrate that the response to nitrates was similar before and after smoking, suggesting that short-term smoking does not affect the arterial smooth muscle. Impaired endothelium-independent vasodilation has been observed in atherosclerotic arteries,11 whereas it is mildly impaired in adults who are long-term smokers.1 It is known that acute cigarette smoking increases heart rate, blood pressure, and cardiac output12; in our study, flow at rest in the brachial artery did not increase significantly after smoking; this could be due to downstream vasoconstriction, although it is known that flow volume measurements performed using ultrasound are vulnerable to minor errors.13 There is accumulating evidence that impairment of endothelium-mediated vasodilation is an important feature of vascular disease not only in subjects with established atherosclerosis, but also in humans with risk factors for vascular disease before the an-
TABLE I Hemodynamics, Vessel Size, and Flow at Rest Before and After Smoking Day 1 Vessel size (mm) Flow at rest (ml/min) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Heart rate (beats/min)
3.5 132 119 78 75
{ 0.6 { 72 { 11 {6 {7
Day 2 (Before Smoking) 3.4 144 118 76 74
{ 0.5 { 50 { 10 {6 {7
* p õ0.001.
FIGURE 1. Brachial artery diameter at rest and during hyperemia before and after smoking.
TABLE II Brachial Artery Dilatation in Response to Hyperemia or Nitrates Before and After Smoking Day 1 Hyperemia (%) Flow-mediated dilation (%) Men Women Smokers Nonsmokers Nitrate-induced dilation (%) * p õ0.001;
†
558 13.5 11 14.5 12 14.8 24
{ 230 {5 {1 {6 {4 {8 {7
Day 2 (After Smoking) 526 { 207 6.9 { 4* 6 { 1* 7.3 { 5* 6.5 { 5* 7.6 { 4† 21 { 6
p õ0.05.
Table I lists the hemodynamic findings before and after smoking on day 2. Short-term smoking caused a significant increase in systolic blood pressure (118 { 10 to 130 { 14 mm Hg, p õ0.001), diastolic blood pressure (76 { 6 to 86 { 6 mm Hg, p õ0.001), and heart rate (74 { 7 to 89 { 9 beats/min, p õ 0.001). Baseline brachial diameter did not change significantly after smoking (3.4 / 0.5 to 3.4 { 0.5 mm, p Å NS). No significant changes were induced by smoking on baseline flow (144 { 50 to 150 { 70 ml/min, p Å NS). Reactive hyperemia on day 1 (before smoking) was 558 { 230% and did not change significantly after smoking (day 2, 526 { 207%, p Å NS). The 530
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atomic evidence of atherosclerosis.14 – 16 Abnormal endothelial function may result in abnormal reactions between the vessel wall, platelets, and leukocytes, leading to atherosclerosis. Tolerance is a well-known phenomenon in smoking; analysis of the acceleration of the heart rate indicates a half-life of development and regression in tolerance of 35 minutes17; these observations explain why the heart rate in smokers increases most with the first few cigarettes of the day but does not vary thereafter in relation to the amount of nicotine consumed. It remains to be seen if this phenomenon also applies to endothelial function. This study does not provide insight on how long the effect of smoking on endothelial function lasted. Serial measurements after smoking will be required to clarify this question. In conclusion, our results indicate for the first time that flow-dependent dilatation of systemic arteries is impaired after short-term smoking. This reduction in vasodilatory capacity might lower the threshold for ischemia when the metabolic demand increases in patients with peripheral vascular disease. 1. Celermajer DS, Sorensen KE, Georgakopoulos D, Bull C, Thomas O, Rob-
inson J, Deanfield JE. Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilatation in healthy young adults. Circulation 1993;88(part 1):2149–2155. 2. Celermajer DS, Adams MR, Clarkson P, Robinson J, McCredie R, Donald A, Deanfield JE. Passive smoking and impaired endothelium-dependent arterial dilatation in healthy young adults. N Engl J Med 1996;334:150–154.
3. Caralis DG, Deligonul U, Kern MJ, Cohen JD. Smoking is a risk factor for coronary spasm in young women. Circulation 1992;85:905–909. 4. Czermin J, Sun K, Bruken R, Bottcher M, Phelps M, Schelbert H. Effect of acute and long-term smoking on myocardial blood flow and flow reserve. Circulation 1995;91:2891–2897. 5. Anderson EA, Mark AL. Flow-mediated and reflex changes in large peripheral artery tone in humans. Circulation 1989;79:93–100. 6. Palmer RMJ, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987;327:524–526. 7. Feletou M, Vanhoutte PM. Endothelium-dependent hyperpolarization of canine coronary smooth muscle. Br J Pharmacol 1988;93:515–524. 8. Rubanyi GM, Romero JC, Vanhoutte PJ. Flow-induced release of endothelium-derived relaxing factor. Am J Physiol 1986;250:H1145–H1149. 9. Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, Lloyd JK, Deanfield JE. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 1992;340:1111– 1115. 10. Katz SD, Biasucci L, Sabba C, Storm JA, Jondeau G, Galvao M, Solomon S, Nicolic SD, Forman R, Lejemtel TH. Impaired endothelium-mediated vasodilatation in the peripheral vasculature of patients with congestive heart failure. J Am Coll Cardiol 1992;19:981–925. 11. Zeiher AM, Drexler H, Wollschlager H, Just H. Modulation of coronary vasomotor tone in humans: progressive endothelial dysfunction with different early stages of coronary atherosclerosis. Circulation 1991;83:391–401. 12. Nicod P, Rehr R, Winniford MD, Campbell WB, Firth BG, Hillis LD. Acute systemic and coronary hemodynamic and serologic responses to cigarette smoking in long-term smokers with atherosclerotic coronary artery disease. J Am Coll Cardiol 1984;4:964–971. 13. Scho¨ning M, Walter J, Scheel P. Estimation of cerebral blood flow through color duplex sonography of the carotid and vertebral arteries in healthy adults. Stroke 1994;25:17–22. 14. Antony I, Lerebours G, Nitenber A. Loss of flow-dependent coronary artery dilatation in patients with hypertension. Circulation 1995;91:1624–1628. 15. Sorensen KE, Celermajer DS, Georgakopoulos D, Hatcher G, Betteridge DJ, Deanfield JE. Impairment of endothelium-dependent dilatation is an early event and is related to the lipoprotein (a) level. J Clin Invest 1994;93:50–55. 16. Johnstone MT, Creager SJ, Scales KM, Cusco JA, Lee BK, Creager MA. Impaired endothelium-dependent vasodilatation in patients with insulin-dependent diabetes mellitus. Circulation 1993;88:2510–2516. 17. Benowitz NL. Pharmacologic aspects of cigarette smoking and nicotine addiction. N Engl J Med 1988;319:1318–1330.
BRIEF REPORTS
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the forearm approximately 8 cm distal to the site of brachial artery measurement.5 By inflating the cuff to 250 to 300 mm Hg, flow was reduced through the brachial artery measured proximal to the cuff. By deflating the cuff after 5 minutes of inflation, flow was increased through the brachial artery (reactive hyperemia). The brachial artery was scanned continuously 30 seconds before and 90 seconds after cuff deflation. Ten minutes later, a second rest scan was recorded. Isosorbide dinitrate (5 mg) was then administered sublingually, and the artery was scanned 5 minutes later. Artery diameter was measured by consensus of 2 observers (J.L. and C.P.) unaware of the stage of experiment. Measurements were obtained at end-diastole (peak of R wave of the electrocardiogram); 5 cardiac cycles were analyzed and measurements were averaged, and volume flow was calculated by multiplying the time-averaged velocity of the Doppler flow signal by heart rate and vessel cross-sectional area (pr2).1 Flow-mediated dilatation was calculated as percent increase in arterial diameter during hyperemia compared with the corresponding resting value. Nitrate-induced dilatation was calculated similarly. Reactive hyperemia was calculated as maximum flow during the first 15 seconds after cuff deflation, divided by the corresponding rest flow.1 Next morning (day 2) subjects returned to the laboratory and rest scans were repeated. All participants were then asked to smoke a cigarette (1.1 mg nicotine, 15 mg tar); 5 minutes later, rest scans were repeated. By inflating and deflating the cuff, hyperemia was produced and recorded as described above. Finally, isosorbide dinitrate was used to test endothelium-independent vasodilation. Flow-mediated and endothelium-independent dilatation were calculated as previously described. All subjects abstained from smoking for at least 8 hours before the start of the investigations; subjects could smoke between days 1 and 2 as long as they smoked their last cigarette 8 hours before the day 2 study. Values are expressed as mean { SD. Paired t test was used to compare values in the pre- and postsmoking studies. Probability levels õ0.05 were considered statistically significant. Baseline flow on day 2 was 144 { 50 ml/min and baseline brachial diameter was 3.4 { 0.5 mm; these values were not different from day 1 baseline flow and diameter (132 { 72 ml/min and 3.5 { 0.6 mm, respectively, p Å NS) [Table I]). Resting diameter before sublingual isosorbide dinitrate was similar to that measured before reactive hyperemia (p Å NS).
Q1997 by Excerpta Medica, Inc.
0002-9149/97/$17.00 PII S0002-9149(96)00805-3
All rights reserved.
/ 2w19 0791 Mp
529
Wednesday Jan 15 12:19 AM
MD
EL–AJC (v. 79, no. 4 ’97)
0791
529
artery before smoking dilated 13.5 { 5% in response to increasing Day 2 flow. Short-term smoking led to (After Smoking) a significant decrease in flowmediated dilatation (6.9 { 4%, 3.4 { 0.5 150 { 70 p õ0.001). In absolute terms, 130 { 14* diameter of the vessel changed from 86 { 6* 3.4 { 0.5 mm to 3.9 { 0.6 mm dur89 { 9* ing hyperemia before smoking (p õ0.01) and from 3.4 { 0.5 mm to 3.6 { 0.6 mm after smoking (p Å NS) (Figure 1). Significant changes in flow-mediated dilatation after smoking were observed in all subgroups: men (11 { 1% to 6 { 1%, p õ0.001); women (14.5 { 6% to 7.3 { 5%, p õ0.001); smokers (12 { 4% to 6.5 { 5%, p õ0.001), and nonsmokers (14.8 { 8% to 7.6 { 4%, p õ0.05 [Table II]). Nitrate-induced dilatation before smoking was 24 { 7%, and did not change significantly after smoking (21 { 6%, p Å NS). jjj The present study demonstrates for the first time that short-term smoking markedly reduces flow-dependent vasodilation in the brachial artery, whereas the capacity of the artery to dilate in response to nitrates is preserved. Flow-dependent vasodilation in systemic as well as coronary arteries is mediated by the endothelium through the release of dilator substances that act on the underlying smooth muscle; these endotheliumderived relaxing factors have been identified as nitric oxide6; hyperpolarizing factor may also contribute to flow-dependent vasodilation.7 Increasing flow causes dilatation, which is abolished by removal of the endothelium8; this mechanism fails with endothelial dysfunction.9 Although reduced flow-mediated dilatation after smoking observed in this study is compatible with endothelial dysfunction, it could alternatively reflect an intrinsic impairment of the capacity of smooth muscle cells to relax. To distinguish dysfunction from intrinsic smooth muscle dysfunction, we used isosorbide dinitrate, an endothelium-independent vasodilator.10 Our results demonstrate that the response to nitrates was similar before and after smoking, suggesting that short-term smoking does not affect the arterial smooth muscle. Impaired endothelium-independent vasodilation has been observed in atherosclerotic arteries,11 whereas it is mildly impaired in adults who are long-term smokers.1 It is known that acute cigarette smoking increases heart rate, blood pressure, and cardiac output12; in our study, flow at rest in the brachial artery did not increase significantly after smoking; this could be due to downstream vasoconstriction, although it is known that flow volume measurements performed using ultrasound are vulnerable to minor errors.13 There is accumulating evidence that impairment of endothelium-mediated vasodilation is an important feature of vascular disease not only in subjects with established atherosclerosis, but also in humans with risk factors for vascular disease before the an-
TABLE I Hemodynamics, Vessel Size, and Flow at Rest Before and After Smoking Day 1 Vessel size (mm) Flow at rest (ml/min) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Heart rate (beats/min)
3.5 132 119 78 75
{ 0.6 { 72 { 11 {6 {7
Day 2 (Before Smoking) 3.4 144 118 76 74
{ 0.5 { 50 { 10 {6 {7
* p õ0.001.
FIGURE 1. Brachial artery diameter at rest and during hyperemia before and after smoking.
TABLE II Brachial Artery Dilatation in Response to Hyperemia or Nitrates Before and After Smoking Day 1 Hyperemia (%) Flow-mediated dilation (%) Men Women Smokers Nonsmokers Nitrate-induced dilation (%) * p õ0.001;
†
558 13.5 11 14.5 12 14.8 24
{ 230 {5 {1 {6 {4 {8 {7
Day 2 (After Smoking) 526 { 207 6.9 { 4* 6 { 1* 7.3 { 5* 6.5 { 5* 7.6 { 4† 21 { 6
p õ0.05.
Table I lists the hemodynamic findings before and after smoking on day 2. Short-term smoking caused a significant increase in systolic blood pressure (118 { 10 to 130 { 14 mm Hg, p õ0.001), diastolic blood pressure (76 { 6 to 86 { 6 mm Hg, p õ0.001), and heart rate (74 { 7 to 89 { 9 beats/min, p õ 0.001). Baseline brachial diameter did not change significantly after smoking (3.4 / 0.5 to 3.4 { 0.5 mm, p Å NS). No significant changes were induced by smoking on baseline flow (144 { 50 to 150 { 70 ml/min, p Å NS). Reactive hyperemia on day 1 (before smoking) was 558 { 230% and did not change significantly after smoking (day 2, 526 { 207%, p Å NS). The 530
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atomic evidence of atherosclerosis.14 – 16 Abnormal endothelial function may result in abnormal reactions between the vessel wall, platelets, and leukocytes, leading to atherosclerosis. Tolerance is a well-known phenomenon in smoking; analysis of the acceleration of the heart rate indicates a half-life of development and regression in tolerance of 35 minutes17; these observations explain why the heart rate in smokers increases most with the first few cigarettes of the day but does not vary thereafter in relation to the amount of nicotine consumed. It remains to be seen if this phenomenon also applies to endothelial function. This study does not provide insight on how long the effect of smoking on endothelial function lasted. Serial measurements after smoking will be required to clarify this question. In conclusion, our results indicate for the first time that flow-dependent dilatation of systemic arteries is impaired after short-term smoking. This reduction in vasodilatory capacity might lower the threshold for ischemia when the metabolic demand increases in patients with peripheral vascular disease. 1. Celermajer DS, Sorensen KE, Georgakopoulos D, Bull C, Thomas O, Rob-
inson J, Deanfield JE. Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilatation in healthy young adults. Circulation 1993;88(part 1):2149–2155. 2. Celermajer DS, Adams MR, Clarkson P, Robinson J, McCredie R, Donald A, Deanfield JE. Passive smoking and impaired endothelium-dependent arterial dilatation in healthy young adults. N Engl J Med 1996;334:150–154.
3. Caralis DG, Deligonul U, Kern MJ, Cohen JD. Smoking is a risk factor for coronary spasm in young women. Circulation 1992;85:905–909. 4. Czermin J, Sun K, Bruken R, Bottcher M, Phelps M, Schelbert H. Effect of acute and long-term smoking on myocardial blood flow and flow reserve. Circulation 1995;91:2891–2897. 5. Anderson EA, Mark AL. Flow-mediated and reflex changes in large peripheral artery tone in humans. Circulation 1989;79:93–100. 6. Palmer RMJ, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987;327:524–526. 7. Feletou M, Vanhoutte PM. Endothelium-dependent hyperpolarization of canine coronary smooth muscle. Br J Pharmacol 1988;93:515–524. 8. Rubanyi GM, Romero JC, Vanhoutte PJ. Flow-induced release of endothelium-derived relaxing factor. Am J Physiol 1986;250:H1145–H1149. 9. Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, Lloyd JK, Deanfield JE. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 1992;340:1111– 1115. 10. Katz SD, Biasucci L, Sabba C, Storm JA, Jondeau G, Galvao M, Solomon S, Nicolic SD, Forman R, Lejemtel TH. Impaired endothelium-mediated vasodilatation in the peripheral vasculature of patients with congestive heart failure. J Am Coll Cardiol 1992;19:981–925. 11. Zeiher AM, Drexler H, Wollschlager H, Just H. Modulation of coronary vasomotor tone in humans: progressive endothelial dysfunction with different early stages of coronary atherosclerosis. Circulation 1991;83:391–401. 12. Nicod P, Rehr R, Winniford MD, Campbell WB, Firth BG, Hillis LD. Acute systemic and coronary hemodynamic and serologic responses to cigarette smoking in long-term smokers with atherosclerotic coronary artery disease. J Am Coll Cardiol 1984;4:964–971. 13. Scho¨ning M, Walter J, Scheel P. Estimation of cerebral blood flow through color duplex sonography of the carotid and vertebral arteries in healthy adults. Stroke 1994;25:17–22. 14. Antony I, Lerebours G, Nitenber A. Loss of flow-dependent coronary artery dilatation in patients with hypertension. Circulation 1995;91:1624–1628. 15. Sorensen KE, Celermajer DS, Georgakopoulos D, Hatcher G, Betteridge DJ, Deanfield JE. Impairment of endothelium-dependent dilatation is an early event and is related to the lipoprotein (a) level. J Clin Invest 1994;93:50–55. 16. Johnstone MT, Creager SJ, Scales KM, Cusco JA, Lee BK, Creager MA. Impaired endothelium-dependent vasodilatation in patients with insulin-dependent diabetes mellitus. Circulation 1993;88:2510–2516. 17. Benowitz NL. Pharmacologic aspects of cigarette smoking and nicotine addiction. N Engl J Med 1988;319:1318–1330.
BRIEF REPORTS
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Wednesday Jan 15 12:19 AM
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