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Effects of Nicotine Gum on Coronary Vasomotor Responses During Sympathetic Stimulation in Patients with Coronary Artery Stenosis

Nitenberg, Alain; Antony, Isabelle

Journal of Cardiovascular Pharmacology: November 1999 - Volume 34 - Issue 5 - p 694-699
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Smoking-cessation rates may be improved by nicotine-replacement therapy that reduces withdrawal symptoms. However, nicotine may have adverse effects on coronary circulation. The purpose of this study was to examine the short-term effects of nicotine gum chewing on the dimensions of coronary arteries of patients with coronary artery disease and on the response of coronary vessels to sympathetic stimulation caused by the cold pressor test. In 17 patients who were past chronic cigarette smokers, cross-sectional areas of 32 coronary artery stenoses and 32 adjacent apparently normal segments were measured by using quantitative coronary angiography at baseline and after a cold pressor test before and after nicotine gum chewing. The cold pressor test produces an increase in arterial pressure without any change in heart rate. These changes were similar before and after nicotine gum. Before nicotine gum, the cross-sectional area of coronary stenoses and apparently normal segments was significantly and similarly reduced during the cold pressor test (−11 ± 12% and −11 ± 12%, respectively; both p values <0.0001 vs. baseline). After nicotine gum, baseline cross-sectional area was not modified, and response to the cold pressor test was similar to that observed before nicotine gum (−11 ± 18% and −12 ± 12%, respectively; both p values <0.0001 vs. baseline). In conclusion, nicotine-replacement therapy by using nicotine gum does not reduce the surface area of normal and diseased coronary segments and does not enhance the constricting effect of sympathetic stimulation produced by the cold pressor test. Thus nicotine gum may be considered a relatively safe drug in patients who need nicotine-replacement therapy to stop smoking.

Service de Physiologie et d'Explorations Fonctionnelles, Hôpital Louis Mourier, CHU Xavier-Bichat, Colombes, France

Received April 14, 1999; revision accepted June 29, 1999.

Address correspondence and reprint requests to Dr. A. Nitenberg at Service de Physiologie et d'Explorations, Fonctionnelles, 178, rue des Renouillers, F-92700 Colombes, France.

Prolonged tobacco smoking produces changes in coronary circulation (1). It has adverse effects on coronary artery vasomotion (2,3) and favors progression of coronary atherosclerosis. The increased incidence of cardiac events (4) has been well demonstrated in chronic smokers with coronary artery disease (5,6). Conversely, smoking cessation is followed by an improvement of survival (7) and a reduction of the incidence of myocardial infarction (8,9).

Although psychological and social factors are important, it has been recognized that nicotine is the main factor responsible for tobacco dependence (10,11). Because nicotine chewing gum may reduce withdrawal symptoms, particularly in heavily dependent patients, smoking-cessation rates may be improved by nicotine-replacement therapy (12). However, nicotine may have adverse effects on coronary circulation (13-18), and may increase hematocrit (15), sequestration, and activation of neutrophils (19).

The purpose of this study was to examine the short-term effects of nicotine gum chewing (a) on the dimensions of coronary arteries of past chronic smokers with coronary artery disease and significant coronary stenosis, and (b) on the response of coronary vessels to sympathetic stimulation caused by the cold pressor test.

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METHODS

Patient selection

The study group was composed of 17 patients undergoing diagnostic coronary angiography for evaluation of chest pain. Patients with the following conditions were excluded from the study: history suggestive of unstable angina or myocardial infarction, congestive heart failure, or chest pain during the coronary arteriography. At the time of selective coronary arteriography, all patients had >50% luminal diameter narrowing of at least one major coronary artery. All patients were past chronic cigarette smokers who had smoked >20 cigarettes a day for >10 years, and who had stopped cigarette smoking for ≥1 year. All drugs that may alter coronary vasomotion (β-blocking agents, calcium antagonists, long-acting nitrates, molsidomine, angiotensin-converting enzyme inhibitors) were discontinued 7 days before the investigation with the exception for short-acting nitrates. The study protocol was approved by an institutional review committee. All patients gave written informed consent before cardiac catheterization. Table 1 lists the characteristics of the study group.

TABLE 1

TABLE 1

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Catheterization protocol

Patients were studied in the fasting state. No premedication was administered; 1% lidocaine was used for local anesthesia, and 5,000 U i.v. heparin was administered. Coronary arteriography was performed by the percutaneous femoral approach with 6F catheters. After documentation of coronary artery stenoses, in patients with coronary arteriograms suitable for analysis by quantitative coronary arteriography, which required that lesions be clearly seen in two orthogonal views, an additional 5,000 U i.v. heparin was given. Thirty minutes after the diagnostic coronary arteriography, baseline coronary arteriography was realized (Baseline 1). Five minutes later, a cold pressor test was performed, a coronary arteriogram being recorded (CPT 1) after the patient's hands were immersed in ice water for 120 s. The same sequence (Baseline 2 and CPT 2) was repeated 30 min after the patient has chewed a piece of 4-mg nicotine gum (Nicorette; Pharmacia & Upjohn, Saint Quentin en Yvelines, France). This delay corresponds to the peak plasma nicotine concentration after 4-mg nicotine gum chewing (20). Coronary angiograms were performed by using an injection of 8 ml of low-osmolarity contrast medium (meglumine ioxaglate) in the coronary arteries. Heart rate, aortic pressure, and electrocardiogram were continuously monitored throughout the protocol and recorded during each sequence of the procedure.

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Quantitative coronary arteriography

Coronary arteriograms were obtained by electrocardiogram-triggered digital subtraction at a rate of six frames/s on a 512-pixel matrix (General Electric CGR DG 300, General Electric Medical Systems, Waukesha, WI, U.S.A.). The angiographic system was set up in orthogonal positions allowing the best optimal view of the coronary arteries on end-diastolic frames without overlap by side branches. Relations between focal spot, patient, and height of image tube were kept constant throughout the procedure. Analysis of coronary angiograms was performed by a previously validated technique (21,22). The reliability and accuracy of the method were previously established. The accuracy of the technique was 3.6 ± 0.5% (mean ± SD), and the precision, 2.4 ± 0.9%. The maximal error between the actual and the calculated diameters was equal to ±5.7% (R2 = 0.994).

In this study, a segment of the catheter positioned in the coronary artery and filled with saline was placed close to the center of the image and used as a scaling device for calibration before the procedure was begun. Diameter was calculated for each coronary segment, and each segment was defined with anatomic references to measure the same segment reproducibly after each injection. All diameter measurements were corrected by a magnification factor taking into account the distance of the segment from the center of the image. Each angiogram was analyzed at random without knowledge of the sequence of the procedure (Baseline 1, CPT 1, Baseline 2, CPT 2).

The minimal diameter of the stenosed segment and the diameter of the apparently normal portion of the coronary vessel were shown on each angiogram. Cross-sectional area (CSA) of each segment was then calculated from measurements of the two orthogonal diameters (d1 and d2): CSA = π(1/2d1 + 1/2d2)2/4. The percentage area of stenosis was calculated as the ratio of the area of the stenosis to the area of the normal segment.

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Statistical analysis

All data are expressed as mean ± SD. Statistical comparisons of hemodynamic parameters, coronary vessel dimensions under baseline, cold pressor test, before and after the administration of nicotine gum were made by two-way analysis of variance (ANOVA) with repeated measures for experimental condition factor, followed by Fisher's protected least-significant difference test. Statistical significance was assumed if the null hypothesis could be rejected at the 0.05 probability level.

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RESULTS

Patient characteristics

In the study group (Table 1), there was a predominance of male patients. Four of the patients had moderate hypertension, and three patients were diabetics (type II). All patients had normal left ventricular end-diastolic volume, ejection fraction, and left ventricular mass assessed by two-dimensional and M-mode echocardiography (23). Among the patients, seven had one-vessel disease, five had two-vessel disease, and five had three-vessel disease.

In all the patients, who were past chronic cigarette smokers, percentage of carboxyhemoglobin was used to verify that they had quit cigarette smoking. Carboxyhemoglobin was within the normal range (Table 1) of a group of nonsmoker patients who had coronary arteriography during the same period (1.2 ± 0.4% vs. 1.3 ± 0.2%).

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Hemodynamic changes during the procedure

Cold pressor test resulted in a significant increase in systolic and diastolic aortic pressures. Changes in pressures were similar before and after nicotine-gum administration, and there were no significant differences between values measured at Baselines 1 and 2, and between values measured during cold pressor tests 1 and 2 (Fig. 1). Heart rate was comparable at Baselines 1 and 2, and was not significantly modified during the cold pressor test before and after nicotine gum (CPT 1 and 2; Fig. 1). Thus, rate-pressure product was comparable at Baselines 1 and 2, and was similarly increased during the two cold pressor tests (CPT 1 and 2; Fig. 1).

FIG. 1

FIG. 1

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Changes in cross-sectional area of control segments and stenoses

Before nicotine-gum administration, the cold pressor test (CPT 1) produced a significant decrease in cross-sectional area in most of control segments and the coronary stenoses (Fig. 2). This abnormal response has been reported in patients with coronary artery disease and is due to abnormal endothelium function (24). The percentage decrease was comparable in the control segments and the coronary stenosis (Table 2; both p values <0.0001 vs. baseline). Thus the percentage of stenosis was comparable at baseline and during the cold pressor test (Baseline 1 and CPT 1; Table 2).

FIG. 2

FIG. 2

TABLE 2

TABLE 2

After nicotine-gum administration, the baseline cross-sectional area (Baseline 2) of control segments and stenoses was similar to values measured before nicotine gum (Fig. 2). The percentage decrease in cross-sectional area of both control segments and stenoses during the second cold pressor test (CPT 2) was similar to that observed before the nicotine gum (−12 ± 12% and −11 ± 18%, respectively; both p values <0.0001 vs. baseline), and the percentage of stenosis was not altered after nicotine gum at Baseline 2 and CPT 2 (Table 2).

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DISCUSSION

In patients with coronary artery disease, smoking cessation has been demonstrated to improve the survival rate (7) and to reduce the incidence of myocardial infarction (8,9). However, in heavily dependent smokers, abrupt smoking cessation is responsible for a nicotine-withdrawal syndrome that can cause tobacco relapse. In these patients, nicotine-replacement therapy, by reducing withdrawal symptoms, may improve smoking-cessation rates (12). Although clinical studies have shown that nicotine-replacement therapy has no deleterious effect in patients with coronary artery disease (12,25,26), there is no information about the short-term effects of these drugs on dimensions of atherosclerotic coronary arteries and coronary stenosis, and on coronary vasomotion during sympathetic stimulation.

The main results of this study are that nicotine gum chewing is not followed by any change in dimensions of control and stenosed segments of coronary arteries and does not modify the response to sympathetic stimulation evoked by the cold pressor test. Although constriction of coronary vessels evoked by the cold pressor test is an abnormal response that is currently observed in patients with coronary artery disease (24) and is due to endothelial dysfunction (27), this response is not enhanced after nicotine gum chewing. These results are of importance because nicotine may potentially have adverse effects on coronary circulation (13-18).

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Effects of parenteral nicotine on coronary vasomotion

Indeed, several changes due to nicotine might alter vasomotion. Intravenous administration of nicotine results in α-adrenergic stimulation (15) and increases circulating catecholamines, heart rate, peripheral resistances and systemic arterial pressure, cardiac output, myocardial oxygen demand, and coronary blood flow (13,14,17,28,29). Nicotine also depresses synthesis and release of prostacyclin but does not affect thromboxane production (16), and in vitro, nicotine inhibits formation of prostacyclin-like activity by human vascular tissue (30). Last, intracoronary administration of nicotine stimulates the release of acetylcholine from intrinsic cardiac nerves (31) that may constrict the coronary circulation via a muscarinic mechanism (18), especially in patients with coronary artery disease who have endothelial dysfunction (24).

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Effects of oral nicotine on coronary vasomotion

In our study, it is very interesting to note that oral administration of nicotine did not result in any change at baseline in heart rate, arterial pressure, and rate-pressure product, which is an estimate of myocardial oxygen demand. These results are similar to those obtained after transdermal nicotine in patients with coronary artery disease in whom systolic and diastolic arterial pressures were not modified (25). The differences between results obtained after parenteral administration of nicotine and those observed after oral or transdermal administration may result from the slower onset of nicotine action after the two latter drugs. Indeed, it is only 30 min after 4-mg nicotine gum chewing that nicotine blood concentration progressively reaches a plateau similar to the nicotine concentration reached 30 min after smoking one cigarette (20). However, the kinetics of nicotine blood concentration after smoking one cigarette or after nicotine administered through a parenteral route is very different from the kinetics of nicotine after nicotine gum. Indeed, nicotine blood concentration peaks ∼5 min after smoking and decreases progressively thereafter (20,32).

On the other hand, heart rate was not significantly increased by the cold pressor test both before and after nicotine gum. Although this result may be surprising, it can be explained by the baroreflex in patients whose average arterial pressure increase was ∼30 mm Hg.

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Comparative effects of nicotine gum and cigarette smoking on coronary vasomotion

Our data also show that the effect of nicotine on coronary vessels is strikingly different from the effects resulting from cigarette smoking, which results in coronary constriction (33-36), decrease in coronary blood flow in patients with proximal coronary artery stenoses due to the increase in coronary artery tone at the site of stenosis, limiting the coronary flow (33,34), and abnormal coronary endothelium-dependent coronary vasodilation (2,3). This is in accordance with the fact that the deleterious effects of cigarette smoke on the coronary vasomotion are not mediated by nicotine (37-41), which is only one among ∼3,000 components of cigarette smoke (42), and among them, superoxide anions and hydrogen peroxide (38), which are known to inactivate nitric oxide (39), might play a major role (37).

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Methodologic limitations

In this study, the assessment of vasomotor responses might be limited by the precision of measurements, especially at the level of stenosis, because the range of the observed responses to the cold pressor test lies within the relative error of the method. However, it must be pointed out that in our study, constriction in response to the cold pressor test was observed in almost all of the control segments and stenoses. It seems highly improbable that this result might be due only to the imprecision of the method, whose accuracy and precision have been established on calibrated catheters ranging from 3F to 9F filled with contrast medium.

We observed only the short-term effects of nicotine gum on coronary vasomotion, and long-term administration of nicotine might be different. However, our study provides information on coronary vasomotor responses to sympathetic stimulation that confirm publications that have shown that the nicotine patch is safe in patients with cardiac disease (12,25,26).

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Clinical implications

This study shows that nicotine-replacement therapy with nicotine gum does not reduce the surface area of normal and diseased coronary arteries and does not enhance the constricting effect of sympathetic stimulation by the cold pressor test. These results confirm data that have shown that nicotine patches improve exercise thallium-201 single-photon emission computed tomography (SPECT) (43) because exercise also results in sympathetic stimulation. Thus nicotine gum may be considered a relatively safe drug in patients who need nicotine-replacement therapy to stop smoking. Nevertheless, nicotine may have other deleterious effects that have not been investigated in our study, such as enhancement of platelet aggregation and increased hematocrit (15), and sequestration and activation of neutrophils (19).

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Keywords:

Coronary artery stenosis; Cross-sectional area; Nicotine gum; Cold pressor test

© 1999 Lippincott Williams & Wilkins, Inc.