- Email: [email protected]
Temporal response of brachial artery dilation after occlusion and nitroglycerin
tobacco use in addition to cocaine. Cigarette smoking has been shown to potentiate the negative effects of cocaine on myocardial oxygen supply and demand.4 Tobacco and cocaine have the synergistic effect of reducing the diameters of coronary arterial segments while increasing the rate-pressure product that serves as an estimate of myocardial oxygen demand.4 Similarly, cocaine-induced vasoconstriction may be more pronounced in patients with coronary atherosclerosis, particularly cigarette smokers.4,5 In conclusion, the CPC appears to provide an important alternative to hospital admission for patients with cocaine-associated chest pain. In our setting, patients without evidence of myocardial necrosis, evidence of ST-segment elevation or isch-
emia by 12-lead electrocardiogram, or hemodynamic instability could be effectively and safely evaluated in a CPC. 1. Hollander JE, Hoffman RS, Gennis P, Fairweather P, Feldman JA, Fish SS,
DiSano MJ, Schumb DA, Dyer S. Cocaine-associated chest pain: one-year follow-up. Acad Emerg Med 1995;2:179 –184. 2. Gibler WB, Runyon JP, Levy RC, Sayre MR, Kacich R, Hattemer CR, Hamilton CA, Gerlach JW, Walsh RA. A rapid diagnostic and treatment center for patients with chest pain in the emergency department. Ann Emerg Med 1995;25:1– 8. 3. Hollander JE, Levitt MA, Young GP, Briglia E, Wetli CW, Gawad Y. Effect of recent cocaine use on the specificity of cardiac markers for diagnosis of acute myocardial infarction. Am Heart J 1998;135:245–252. 4. Moliterno DJ, Willard JE, Lange RA, Negus BH, Boehrer JD, Glamann DB, Landau C, Rossen JD, Winniford MD, Hillis LD. Coronary-artery vasoconstriction induced by cocaine, cigarette smoking, or both. N Engl J Med 1994;330: 454 – 459. 5. Flores ED, Lange RA, Cigarroa RG, Hillis LD. Effect of cocaine on coronary artery dimensions in atherosclerotic coronary artery disease: enhanced vasoconstriction at sites of significant stenoses. J Am Coll Cardiol 1990;16:74 –79.
Temporal Response of Brachial Artery Dilation After Occlusion and Nitroglycerin Brian Bressler, Sammy Chan, ndothelial dysfunction is seen early in the develE opment of atherosclerosis and can precede structural abnormalities. It is due to an abnormal bio-
MD,
and G.B. John Mancini,
TABLE I Reproducibility
1,2
availability of nitric oxide.3 The actions of nitric oxide consist of vasodilation, inhibition of interactions between platelets, leukocytes, and the vessel wall, and inhibition of smooth muscle migration and proliferation.4 This dysfunction has been shown to exist in patients both with coronary atherosclerosis,5 and with risk factors for this disease.6 Celermajer et al7 established a test for noninvasive assessment of endothelial function by ultrasonography. This procedure evaluates the flow-mediated dilation of the brachial artery as an indicator of endothelium-dependent response to shear stress. It also looks at the endothelium-independent response of the artery by measuring peak dilation after administration of nitroglycerin. The latter is required to ensure that abnormalities of flow-mediated dilation are due truly to endothelial dysfunction and not to smooth muscle insensitivity to nitric oxide. This technique has already been used to look at the effects of management of atherosclerosis or its risk factors8 and as a marker for the disease in patients with predisposing risk factors for atherosclerosis.7,9 –12 All studies using this technique center on measurement of the response of the brachial artery to the 2 procedures yielding vasodilation. For flow-mediated dilation, the From the University of British Columbia, Department of Medicine, Division of Cardiology, St. Paul’s Hospital Atherosclerosis Reversal Clinic; and the Jack Bell Research Centre, Vancouver, Canada. Dr. Mancini’s address is: Vancouver Hospital & Health Sciences Centre, 3300-950 West 10th Avenue, Vancouver, British Columbia V5E 4Z3. E-mail: [email protected]. Manuscript received June 21, 1999; revised manuscript received September 7, 1999, and accepted September 8.
396
©2000 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 85 February 1, 2000
MD
Observer A Peak FMD
Observer B
Peak Dilation to Nitroglycerin
Peak FMD
Peak Dilation to Nitroglycerin
Intraobserver Variability r 0.82 Accuracy* ⫺0.31% † Precision 1.97% MAD 1.63%
0.94 0.16% 2.45% 1.64%
0.87 ⫺0.57% 1.50% 1.11%
0.94 ⫺1.27% 3.97% 2.44%
Interobserver Variability r Accuracy* Precision† MAD
0.97 0.50% 0.83% 0.79%
0.92 ⫺1.41% 3.68% 2.73%
*Mean of differences (all values are not different from 0). †SD of differences. MAD ⫽ mean absolute difference; FMD ⫽ flow-mediated dilation; r ⫽ Pearson’s linear regression coefficient.
values have been obtained at approximately 60 seconds after occlusion. Vasodilation after nitroglycerin has been recorded 3 to 5 minutes after drug administration. This study characterizes the temporal response of the brachial artery after occlusion and after giving nitroglyercin. The results suggest that the time at which measurements are often being made is not indicative of the true peak dilatory response. •••
Fifty-two adult volunteers (46 men and 6 women) were recruited for this study. All had clinical evidence of coronary artery disease and were enrolled in the Atherosclerosis Reversal Clinic at St. Paul’s Hospital in Vancouver, British Columbia, Canada. Each sub0002-9149/00/$–see front matter PII S0002-9149(99)00756-0
FIGURE 1. Relation between time after cuff deflation (seconds) and percent flow-mediated dilation. Line represents average response of all 52 patients. Error bars are ⴞ 1 SE. The bracket indicates the time interval during which dilation was maximal.
ject underwent 1 study to assess brachial artery response to flow-mediated dilation and to sublingual nitroglycerin (0.3 mg). They were instructed to refrain from caffeine intake for 24 hours before the study and to not eat, drink, or take medications for 4 hours before the scans. Ultrasound scans were obtained with the patient supine, at rest, and at ambient temperatures between 20°C and 26°C. The electrocardiogram was continuously monitored. The subject’s right arm was comfortably immobilized in the extended position. Each patient’s brachial artery was scanned in the longitudinal section between 5 and 10 cm above the antecubital fossa with a 10.0-MHz linear array transducer and an HP SONOS 5500 system (Andover, Massachusetts) by the same sonographer. The center of the artery was identified when the clearest pictures of the anterior and posterior intimal layers were obtained. Depth and gain settings were optimized to identify the lumen-tovessel wall interface, and were kept constant during each experiment. Subjects rested for about 10 minutes in a quiet dark room before baseline measurements were obtained. Fifteen to 45 seconds before the cuff was inflated, a baseline recording of the brachial artery diameter was undertaken. The pneumatic cuff was placed around the forearm distal to the imaged brachial artery segment, and was inflated to 300 mm Hg for 5 minutes. The cuff was released and the artery was scanned continuously for 5 minutes. Ten minutes later, a second rest scan was done. Nitroglycerin 0.3 mg (Nitrostat [Parke-Davis, Scarborough, Ontario, Canada]) or Nitrospray 0.4 mg (nitrolingual spray [Rhone-Poulenc Rorer, Ville St. Laurent, Quebec, Canada]) were given sublingually, and the artery was scanned continuously for at least 7 minutes after drug administration. The scans were recorded on super VHS videotapes.
Measurements were obtained at 20-second intervals starting from the release of the cuff in the first part and 2 minutes after the administration of the nitroglycerin in the second part. At a fixed distance, the observer measured media-to-media diameter averaged over a 1-cm length at the peak of the R wave for 3 consecutive heart beats. These values were averaged. All these measurements were obtained with the use of the Prosound software (Los Angeles, California) with automatic edge detection.13 Two technicians independently analyzed studies from 7 patients and repeated their analyses after 3 to 6 months. The reproducibility of measures of peak percent flow-mediated dilation and peak percent dilation induced with nitroglycerin are excellent (Table I). None of the accuracy measurements were significantly different from zero. Virtually identical results were achieved when 1-minute values were analyzed. Data were analyzed using SPSS version 8 (Chicago, Illinois). All descriptive data are expressed as mean value ⫾ SD. Analysis of variance was performed initially, followed by t testing with Bonferroni correction. Results were considered significant when the p value was ⬍0.05. Fifty-two studies were performed. One patient was withdrawn from the nitroglycerin part of the study because the subject was only evaluated for 2 minutes compared with the usual minimum of 7. Flow-mediated dilation after cuff deflation is depicted in Figure 1. This figure shows the aggregate response of all subjects. The highest average dilation (3.5 ⫾ 3.0%) occurred at 60 seconds. Values greater than baseline occur between 40 and 140 seconds, but individual values were not different from one another. Figure 2 shows the cumulative frequency of the time at which true, peak dilation occurred in individual patients. By 140 seconds ⬎90% reached their maximum response. BRIEF REPORTS
397
FIGURE 2. The frequency (bars) and cumulative frequency (line) plots of true, individual peak dilation at time intervals after cuff deflation. The time intervals are the time from the previous 10 seconds to the current one (e.g., “10” ⴝ 0 to 10 seconds).
FIGURE 3. Left, comparison of the percent dilation after 60 seconds with the maximum response; right, comparison of the maximum nitroglycerin response to responses at 3 and 5 minutes.
The longest time for this to occur was 290 seconds. The time it took for the subjects to reach their maximum response did not correlate with peak dilatation (r ⫽ 0.14, p ⫽ 0.31). The average time for the true peak response to occur was 81 ⫾ 56 seconds. This peak percent dilation was significantly greater than at 398 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 85
60 seconds (5.2 ⫾ 2.6% vs 3.5 ⫾ 3.0%, p ⬍0.0005) (Figure 3). Nitroglycerin-induced dilation is depicted in Figure 4. Values greater than baseline occur between 180 and 420 seconds (p ⬍0.0005), but individual values were not different from each other. The percent dilaFEBRUARY 1, 2000
FIGURE 4. Relation between time after nitroglycerin administration (seconds) and percent dilation. Line represents average response of 51 patients. Error bars are ⴞ 1 SE. The bracket indicates the time interval during which dilation was maximal.
FIGURE 5. The frequency (bars) and cumulative frequency (line) plots of true, peak dilation at time intervals after nitroglycerin administration.
tions induced by nitroglycerin after 3 and 5 minutes were 10 ⫾ 6% and 12 ⫾ 6%, respectively. Both values are significantly less than the maximum percent dilation of 15 ⫾ 6% (at 350 ⫾ 102 seconds; p ⫽
0.0005 and p ⫽ 0.025, respectively). Figure 5 shows the cumulative frequency of peak responses (90% occurred by 480 seconds; the longest was at 620 seconds). BRIEF REPORTS
399
•••
Groups previously using this technique have estimated the maximum dilation to occur in the range of 60 seconds. Our results showed that the peak percent dilation response overall did indeed occur at 60 seconds, but values between 40 and 140 seconds showed no statistically significant differences. Moreover, only about half of the subjects reached their maximum response by 60 seconds, and it took until 140 seconds after cuff deflation for ⬎90% to reach their highest level of dilation. Thus, the values typically recorded at 60 seconds may not be representative of the true, maximum response. The time at which the peak percent dilation occurred (81 ⫾ 56 seconds) was significantly delayed compared with the 1-minute mark (p ⫽ 0.008). Furthermore, when investigating the relation between the percent response and the time it took to reach this level, there appeared to be no relation. Corretti et al14 determined that peak responses occurred at 1 minute. However, their measurements were performed at only 1-minute intervals in contrast to the 20-second intervals in our study. Thus, it is conceivable that those investigators missed the true peak at about 80 seconds because of too infrequent sampling. The second part of this experiment studied the nonendothelial dependent response of the brachial artery to the exogenous nitrate. Many peak responses occurred within the 3- to 5-minute period that corresponds to the time of reporting in prior studies. However, the true peak responses occurred significantly later. In conclusion, this report suggests that a set time after cuff deflation or after nitroglycerin may not be adequate to capture peak responses of individual patients. This observation provides an important impetus for developing automated, contin-
400 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 85
uous monitoring methods to simplify identification of peak responses and to standardize reporting. 1. Reddy K, Nair R, Sheehan H, Hodgson JM. Evidence that selective endothelial dysfunction may occur in the absence of angiographic or ultrasound atherosclerosis in patients with risk factors for atherosclerosis. J Am Coll Cardiol 1994; 23:833– 843. 2. Zeiher A, Drexler H, Wolschlager 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. 3. Playford D, Watts G. Non-invasive measurement of endothelial function. Clinical and experimental pharmacology and physiology. 1998;25:640 – 643. 4. Cook J, Tsao P. Is NO an anti-atherogenic molecule? Arterioscler Thromb Vasc Biol 1994;14:653– 655. 5. Sorensen K, Kristensen I. Atherosclerosis in the human brachial artery. J Am Coll Cardiol 1997;28:318 –322. 6. Celermajer D, Sorensen K, Bull C, Robinson J, Deanfield J. Endotheliumdependent dilation in the systemic arteries of asymptomatic subjects relates to coronary risk factors and their interactions. J Am Coll Cardiol 1994;24:1468 – 1474. 7. Celermajer D, Sorensen K, Gooch V, Spielgelhalter D, Miller O, Sullivan I, Lloyd J, Deanfield J. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 1992;340:1111–1115. 8. Jodoin I, Bussieres L, Tardif J, Juneau M. Effect of a short term primary prevention program on endothelium-dependent vasodilation in adults at risk for atherosclerosis. Can J Cardiol 1999;15:83– 88. 9. Georgapoulos D, Celermajer D, Thomas O, Robinson J, Betteridge J, Deanfield J. Endothelium-dependent dilatation is impaired in the large arteries of healthy young adult type 1 diabetics and is related to the presence of microalbuminuria. J Am Coll Cardiol 1994;(suppl):484A-484A. 10. Panza J, Garcia C, Kilcoyne C, Quyyumi A, Cannon RO. Impaired endothelium dependent vasodilation in patients with essential hypertension. Circulation 1995;91:1732–1738. 11. Vogel R, Corretti M, Plotnick G. Changes in flow-mediated brachial artery vasoactivity iwth lowering of desirable cholesterol levels in middle-aged men. Am J Cardiol 1996;77:37– 40. 12. Celermajer D, Sorensen K, Spielgelhalter D, Georgapoulos D, Robinson J, Deanfield J. Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women. J Am Coll Cardiol 1994;24:471– 476. 13. Selzer R, Hodis H, Kwong-Fu H, Mack W, Lee P, Liu C, Liu C. Evaluation of computerized edge tracking for quantifying intima-media thickness of the common carotid artery from B-mode ultrasound images. Atherosclerosis 1994; 111:1–11. 14. Corretti MC, Plotnick GD, Vogel RA. Technical aspects of evaluating brachial artery vasodilatation using high-frequency ultrasound. Am J Physiol 1995;268:H1397–H1404.
FEBRUARY 1, 2000
emia by 12-lead electrocardiogram, or hemodynamic instability could be effectively and safely evaluated in a CPC. 1. Hollander JE, Hoffman RS, Gennis P, Fairweather P, Feldman JA, Fish SS,
DiSano MJ, Schumb DA, Dyer S. Cocaine-associated chest pain: one-year follow-up. Acad Emerg Med 1995;2:179 –184. 2. Gibler WB, Runyon JP, Levy RC, Sayre MR, Kacich R, Hattemer CR, Hamilton CA, Gerlach JW, Walsh RA. A rapid diagnostic and treatment center for patients with chest pain in the emergency department. Ann Emerg Med 1995;25:1– 8. 3. Hollander JE, Levitt MA, Young GP, Briglia E, Wetli CW, Gawad Y. Effect of recent cocaine use on the specificity of cardiac markers for diagnosis of acute myocardial infarction. Am Heart J 1998;135:245–252. 4. Moliterno DJ, Willard JE, Lange RA, Negus BH, Boehrer JD, Glamann DB, Landau C, Rossen JD, Winniford MD, Hillis LD. Coronary-artery vasoconstriction induced by cocaine, cigarette smoking, or both. N Engl J Med 1994;330: 454 – 459. 5. Flores ED, Lange RA, Cigarroa RG, Hillis LD. Effect of cocaine on coronary artery dimensions in atherosclerotic coronary artery disease: enhanced vasoconstriction at sites of significant stenoses. J Am Coll Cardiol 1990;16:74 –79.
Temporal Response of Brachial Artery Dilation After Occlusion and Nitroglycerin Brian Bressler, Sammy Chan, ndothelial dysfunction is seen early in the develE opment of atherosclerosis and can precede structural abnormalities. It is due to an abnormal bio-
MD,
and G.B. John Mancini,
TABLE I Reproducibility
1,2
availability of nitric oxide.3 The actions of nitric oxide consist of vasodilation, inhibition of interactions between platelets, leukocytes, and the vessel wall, and inhibition of smooth muscle migration and proliferation.4 This dysfunction has been shown to exist in patients both with coronary atherosclerosis,5 and with risk factors for this disease.6 Celermajer et al7 established a test for noninvasive assessment of endothelial function by ultrasonography. This procedure evaluates the flow-mediated dilation of the brachial artery as an indicator of endothelium-dependent response to shear stress. It also looks at the endothelium-independent response of the artery by measuring peak dilation after administration of nitroglycerin. The latter is required to ensure that abnormalities of flow-mediated dilation are due truly to endothelial dysfunction and not to smooth muscle insensitivity to nitric oxide. This technique has already been used to look at the effects of management of atherosclerosis or its risk factors8 and as a marker for the disease in patients with predisposing risk factors for atherosclerosis.7,9 –12 All studies using this technique center on measurement of the response of the brachial artery to the 2 procedures yielding vasodilation. For flow-mediated dilation, the From the University of British Columbia, Department of Medicine, Division of Cardiology, St. Paul’s Hospital Atherosclerosis Reversal Clinic; and the Jack Bell Research Centre, Vancouver, Canada. Dr. Mancini’s address is: Vancouver Hospital & Health Sciences Centre, 3300-950 West 10th Avenue, Vancouver, British Columbia V5E 4Z3. E-mail: [email protected]. Manuscript received June 21, 1999; revised manuscript received September 7, 1999, and accepted September 8.
396
©2000 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 85 February 1, 2000
MD
Observer A Peak FMD
Observer B
Peak Dilation to Nitroglycerin
Peak FMD
Peak Dilation to Nitroglycerin
Intraobserver Variability r 0.82 Accuracy* ⫺0.31% † Precision 1.97% MAD 1.63%
0.94 0.16% 2.45% 1.64%
0.87 ⫺0.57% 1.50% 1.11%
0.94 ⫺1.27% 3.97% 2.44%
Interobserver Variability r Accuracy* Precision† MAD
0.97 0.50% 0.83% 0.79%
0.92 ⫺1.41% 3.68% 2.73%
*Mean of differences (all values are not different from 0). †SD of differences. MAD ⫽ mean absolute difference; FMD ⫽ flow-mediated dilation; r ⫽ Pearson’s linear regression coefficient.
values have been obtained at approximately 60 seconds after occlusion. Vasodilation after nitroglycerin has been recorded 3 to 5 minutes after drug administration. This study characterizes the temporal response of the brachial artery after occlusion and after giving nitroglyercin. The results suggest that the time at which measurements are often being made is not indicative of the true peak dilatory response. •••
Fifty-two adult volunteers (46 men and 6 women) were recruited for this study. All had clinical evidence of coronary artery disease and were enrolled in the Atherosclerosis Reversal Clinic at St. Paul’s Hospital in Vancouver, British Columbia, Canada. Each sub0002-9149/00/$–see front matter PII S0002-9149(99)00756-0
FIGURE 1. Relation between time after cuff deflation (seconds) and percent flow-mediated dilation. Line represents average response of all 52 patients. Error bars are ⴞ 1 SE. The bracket indicates the time interval during which dilation was maximal.
ject underwent 1 study to assess brachial artery response to flow-mediated dilation and to sublingual nitroglycerin (0.3 mg). They were instructed to refrain from caffeine intake for 24 hours before the study and to not eat, drink, or take medications for 4 hours before the scans. Ultrasound scans were obtained with the patient supine, at rest, and at ambient temperatures between 20°C and 26°C. The electrocardiogram was continuously monitored. The subject’s right arm was comfortably immobilized in the extended position. Each patient’s brachial artery was scanned in the longitudinal section between 5 and 10 cm above the antecubital fossa with a 10.0-MHz linear array transducer and an HP SONOS 5500 system (Andover, Massachusetts) by the same sonographer. The center of the artery was identified when the clearest pictures of the anterior and posterior intimal layers were obtained. Depth and gain settings were optimized to identify the lumen-tovessel wall interface, and were kept constant during each experiment. Subjects rested for about 10 minutes in a quiet dark room before baseline measurements were obtained. Fifteen to 45 seconds before the cuff was inflated, a baseline recording of the brachial artery diameter was undertaken. The pneumatic cuff was placed around the forearm distal to the imaged brachial artery segment, and was inflated to 300 mm Hg for 5 minutes. The cuff was released and the artery was scanned continuously for 5 minutes. Ten minutes later, a second rest scan was done. Nitroglycerin 0.3 mg (Nitrostat [Parke-Davis, Scarborough, Ontario, Canada]) or Nitrospray 0.4 mg (nitrolingual spray [Rhone-Poulenc Rorer, Ville St. Laurent, Quebec, Canada]) were given sublingually, and the artery was scanned continuously for at least 7 minutes after drug administration. The scans were recorded on super VHS videotapes.
Measurements were obtained at 20-second intervals starting from the release of the cuff in the first part and 2 minutes after the administration of the nitroglycerin in the second part. At a fixed distance, the observer measured media-to-media diameter averaged over a 1-cm length at the peak of the R wave for 3 consecutive heart beats. These values were averaged. All these measurements were obtained with the use of the Prosound software (Los Angeles, California) with automatic edge detection.13 Two technicians independently analyzed studies from 7 patients and repeated their analyses after 3 to 6 months. The reproducibility of measures of peak percent flow-mediated dilation and peak percent dilation induced with nitroglycerin are excellent (Table I). None of the accuracy measurements were significantly different from zero. Virtually identical results were achieved when 1-minute values were analyzed. Data were analyzed using SPSS version 8 (Chicago, Illinois). All descriptive data are expressed as mean value ⫾ SD. Analysis of variance was performed initially, followed by t testing with Bonferroni correction. Results were considered significant when the p value was ⬍0.05. Fifty-two studies were performed. One patient was withdrawn from the nitroglycerin part of the study because the subject was only evaluated for 2 minutes compared with the usual minimum of 7. Flow-mediated dilation after cuff deflation is depicted in Figure 1. This figure shows the aggregate response of all subjects. The highest average dilation (3.5 ⫾ 3.0%) occurred at 60 seconds. Values greater than baseline occur between 40 and 140 seconds, but individual values were not different from one another. Figure 2 shows the cumulative frequency of the time at which true, peak dilation occurred in individual patients. By 140 seconds ⬎90% reached their maximum response. BRIEF REPORTS
397
FIGURE 2. The frequency (bars) and cumulative frequency (line) plots of true, individual peak dilation at time intervals after cuff deflation. The time intervals are the time from the previous 10 seconds to the current one (e.g., “10” ⴝ 0 to 10 seconds).
FIGURE 3. Left, comparison of the percent dilation after 60 seconds with the maximum response; right, comparison of the maximum nitroglycerin response to responses at 3 and 5 minutes.
The longest time for this to occur was 290 seconds. The time it took for the subjects to reach their maximum response did not correlate with peak dilatation (r ⫽ 0.14, p ⫽ 0.31). The average time for the true peak response to occur was 81 ⫾ 56 seconds. This peak percent dilation was significantly greater than at 398 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 85
60 seconds (5.2 ⫾ 2.6% vs 3.5 ⫾ 3.0%, p ⬍0.0005) (Figure 3). Nitroglycerin-induced dilation is depicted in Figure 4. Values greater than baseline occur between 180 and 420 seconds (p ⬍0.0005), but individual values were not different from each other. The percent dilaFEBRUARY 1, 2000
FIGURE 4. Relation between time after nitroglycerin administration (seconds) and percent dilation. Line represents average response of 51 patients. Error bars are ⴞ 1 SE. The bracket indicates the time interval during which dilation was maximal.
FIGURE 5. The frequency (bars) and cumulative frequency (line) plots of true, peak dilation at time intervals after nitroglycerin administration.
tions induced by nitroglycerin after 3 and 5 minutes were 10 ⫾ 6% and 12 ⫾ 6%, respectively. Both values are significantly less than the maximum percent dilation of 15 ⫾ 6% (at 350 ⫾ 102 seconds; p ⫽
0.0005 and p ⫽ 0.025, respectively). Figure 5 shows the cumulative frequency of peak responses (90% occurred by 480 seconds; the longest was at 620 seconds). BRIEF REPORTS
399
•••
Groups previously using this technique have estimated the maximum dilation to occur in the range of 60 seconds. Our results showed that the peak percent dilation response overall did indeed occur at 60 seconds, but values between 40 and 140 seconds showed no statistically significant differences. Moreover, only about half of the subjects reached their maximum response by 60 seconds, and it took until 140 seconds after cuff deflation for ⬎90% to reach their highest level of dilation. Thus, the values typically recorded at 60 seconds may not be representative of the true, maximum response. The time at which the peak percent dilation occurred (81 ⫾ 56 seconds) was significantly delayed compared with the 1-minute mark (p ⫽ 0.008). Furthermore, when investigating the relation between the percent response and the time it took to reach this level, there appeared to be no relation. Corretti et al14 determined that peak responses occurred at 1 minute. However, their measurements were performed at only 1-minute intervals in contrast to the 20-second intervals in our study. Thus, it is conceivable that those investigators missed the true peak at about 80 seconds because of too infrequent sampling. The second part of this experiment studied the nonendothelial dependent response of the brachial artery to the exogenous nitrate. Many peak responses occurred within the 3- to 5-minute period that corresponds to the time of reporting in prior studies. However, the true peak responses occurred significantly later. In conclusion, this report suggests that a set time after cuff deflation or after nitroglycerin may not be adequate to capture peak responses of individual patients. This observation provides an important impetus for developing automated, contin-
400 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 85
uous monitoring methods to simplify identification of peak responses and to standardize reporting. 1. Reddy K, Nair R, Sheehan H, Hodgson JM. Evidence that selective endothelial dysfunction may occur in the absence of angiographic or ultrasound atherosclerosis in patients with risk factors for atherosclerosis. J Am Coll Cardiol 1994; 23:833– 843. 2. Zeiher A, Drexler H, Wolschlager 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. 3. Playford D, Watts G. Non-invasive measurement of endothelial function. Clinical and experimental pharmacology and physiology. 1998;25:640 – 643. 4. Cook J, Tsao P. Is NO an anti-atherogenic molecule? Arterioscler Thromb Vasc Biol 1994;14:653– 655. 5. Sorensen K, Kristensen I. Atherosclerosis in the human brachial artery. J Am Coll Cardiol 1997;28:318 –322. 6. Celermajer D, Sorensen K, Bull C, Robinson J, Deanfield J. Endotheliumdependent dilation in the systemic arteries of asymptomatic subjects relates to coronary risk factors and their interactions. J Am Coll Cardiol 1994;24:1468 – 1474. 7. Celermajer D, Sorensen K, Gooch V, Spielgelhalter D, Miller O, Sullivan I, Lloyd J, Deanfield J. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 1992;340:1111–1115. 8. Jodoin I, Bussieres L, Tardif J, Juneau M. Effect of a short term primary prevention program on endothelium-dependent vasodilation in adults at risk for atherosclerosis. Can J Cardiol 1999;15:83– 88. 9. Georgapoulos D, Celermajer D, Thomas O, Robinson J, Betteridge J, Deanfield J. Endothelium-dependent dilatation is impaired in the large arteries of healthy young adult type 1 diabetics and is related to the presence of microalbuminuria. J Am Coll Cardiol 1994;(suppl):484A-484A. 10. Panza J, Garcia C, Kilcoyne C, Quyyumi A, Cannon RO. Impaired endothelium dependent vasodilation in patients with essential hypertension. Circulation 1995;91:1732–1738. 11. Vogel R, Corretti M, Plotnick G. Changes in flow-mediated brachial artery vasoactivity iwth lowering of desirable cholesterol levels in middle-aged men. Am J Cardiol 1996;77:37– 40. 12. Celermajer D, Sorensen K, Spielgelhalter D, Georgapoulos D, Robinson J, Deanfield J. Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women. J Am Coll Cardiol 1994;24:471– 476. 13. Selzer R, Hodis H, Kwong-Fu H, Mack W, Lee P, Liu C, Liu C. Evaluation of computerized edge tracking for quantifying intima-media thickness of the common carotid artery from B-mode ultrasound images. Atherosclerosis 1994; 111:1–11. 14. Corretti MC, Plotnick GD, Vogel RA. Technical aspects of evaluating brachial artery vasodilatation using high-frequency ultrasound. Am J Physiol 1995;268:H1397–H1404.
FEBRUARY 1, 2000