Effects of Chronic Tobacco Smoking on the Coronary Circulation

J AM cou, CARDIOl 421 1983 .1(2)421-6

LLOYD W. KLEIN, MD, AUGUSTO D. PICHARD, MD, FACC, JAMES HOLT, MA, HARRY SMITH, PhD, RICHARD GORLIN, MD, FACC, LOUIS E. TEICHHOLZ, MD, FACC New York. New York

The effects of chronic smoking on the coronary circu• was 74.1 ± 20.1% in the smokers versus 117.1 ± 45.1% lation were studied by evaluating the coronary vascular in the nonsmokers (p < 0.02). In patients who smoked reserve in 12 chronic smokers (group 1) and 10 non• 1 pack a day or less and in those who smoked more than smokers (group 2). All patients were referred to cardiac 1 pack a day, the mean coronary reserve was 89.5 and catheterization for evaluation of chest pain and were 64.9%, respectively (p < 0.05). Additionally, of 20 pa• found to have normal coronary and left ventricular an• tients followed up for an average of 20 months, 7 of 10 giograms. Coronary vascular reserve was measured by smokers and 1 of 10 nonsmokers continued to have chest analyzing the hyperemic response to selective coronary pain (p < 0.03). The cause for the chest pain has not injection of contrast agent. There was no statistically been established in these patients. These results suggest significantdifference between groups 1and 2 with regard that coronary vascular reserve is significantly less in to age, baseline electrocardiogram or response to tread• chronic smokers than in nonsmokers, and that this de• mill or thallium·201 exercise tests. crease is more pronounced in heavy smokers. The mean coronary reserve (± standard deviation)

The immediate physiologic response to cigarette smoking vascular reserve, or capacity of the coronary arteries to dilate has been extensively studied in healthy human subjects (1,2) and increase blood flow on increased demand, in chronic and includes increases in blood pressure, heart rate and smokers. The coronary reserve alIows for an increase in the cardiac output. Increased coronary blood flow has been gen• coronary blood flow of at least 200 to 400% to meet the erally observed, in both animal (3-7) and human subjects increased myocardial oxygen requirements associated with (8), accompanying the augmentation in cardiac work. In exercise or other stresses (13) . This constitutes an important patients with coronary artery disease (9) and in animal models physiologic adaptive mechanism, because the myocardial with experimental coronary artery narrowing (10-12), cor• oxygen extraction is large (± 75%) and nearly maximal onary blood flow may not change or may actually decrease. under resting conditions (14, IS) . These acute alterations in coronary blood flow produced by cigarette smoking occur both in response to increased myo• cardial oxygen demand and through neurally mediated Methods mechanisms that affect coronary artery dynamics. It is pos• Patient Selection sible that chronic smoking may produce long-term changes All patients were referred for diagnosticcardiac catheterization in coronary artery reactivity. and coronary angiographyfor a chest pain syndrome. Twenty-two To assess this hypothesis, we evaluated the coronary consecutive patients with normal coronary arteries (as defined by selective coronary arteriography) and normal left ventricular and aortic pressures were entered in the study. There were 13 men and From the Division of Cardiology, Department of Medicine, and the 9 women with a mean age of 48 years (range 29 to 65). Department of Biostaustics, Mount Sinai Medical Center. New York . New Twelve patients who were chronic smokers (group I) were York . Manuscript received July 13, 1982; revised manuscript received compared with a control group of 10 nonsmokers (group 2). All August 9. 1982. accepted August 19. 1982. subjects considered chronic smokers had smoked for at least 10 Address for reprints: Lloyd W. Klein, MD, Division of Cardiology. Mount Sinal Medical Center. I Gustave L. Levy Place. New York. New years, and no subjects considered nonsmokers had ever smoked York 10029 . cigarettes for any length of time. We then further separated the

smokers into subjects who smoked I pack a day or less (group Echocardiographic measurements. Echocardiograrns were IA) and those who smoked more than I pack a day (group IB). obtained within 24 hours of the cathetenzation. All tracings were The one cigar smoker could not be classified in either group, and of excellent quality. All measurements of left ventricular posterior was deleted from this section of the analysis. These subgroups wall thickness (LVPW), septum (IVS ct) and left ventricular cavity were defined by having regularly smoked the specified amount for (LVIDd ) were made according to standard convention (19), and at least 5 years before the study. This classification, by number during diastole before the A wave. Left ventricular (LV) mass was of packs smoked a day, is somewhat artificial. It is necessary calculated using the formula (17): because of the wide variation among smokers in the volume of LV mass (g) cigarette smoke inhaled and in the nicotine content of the brand 0.77 x W [(LVID + LVPW + IVS )3 - (LVID )3] + 2.4 of cigarette smoked. All patients signed informed consent before d d ct d cardiac catheterization and agreed to have coronary sinus flow Echocardiographic dimensions were measured by an investigator measurements performed according to a protocol approved by the who had no knowledge of the results of the coronary sinus flow Mount Sinai Medical Center Research Administrative Committee. measurements. Statistical analysis. The data were maintained and analyzed using SAS (Statistical Analysis System) on an IBM/370 at the City University of New York Computing Center. Means and standard Procedure and Measurements deviations were calculated for all groups by utilizing the maximal Patients were premedicated with 10 mg of oral diazepam and percent increase in coronary sinus flow for each patient. fasted for at least 10 hours before catheterization. Cigarettes were t-Tests were performed when comparing continuous variables withheld for at least I hour before introduction of the coronary between two groups. Analysis of variance was performed when flow studies. Nitrites, beta-receptor blocking agents, calcium an• comparing more than two groups. Duncan multiple range tests tagonists and antiarrhythmic agents were withheld for at least 12 were performed at a = 0.05 with the analysis of variance. Pearson hours before coronary sinus blood flow measurements were made. correlation coefficients were calculated when testing relations be• Pressures were measured in the aorta and the left ventricle before tween two continuous variables; the chi-square test was performed and during contrast injection. when testing two categorical variables. Coronary sinus blood flow measurements. Placement of the coronary sinus catheter was performed after one selective injection of contrast agent into each coronary artery to confirm that the Results coronary arteries were normal. The procedure used for verification Table 1 summarizes the pertinent clinical and hemody• of position in the coronary sinus has been described previously namic data of the 12 chronic smokers (group I) and 10 (16). Coronary sinus blood flow was determined with the contin• uous thermodilution technique of Ganz et al. (17) using a preshaped nonsmokers (group 2). There was no statistically significant coronary sinus catheter with two thermistors and two pacing elec• difference between these groups with respect to age (47 trodes (Wilton Webster Laboratories). Coronary sinus flow at rest versus 47 years), sex (7 of 12 versus 6 of 10 male subjects), was measured before any further intervention. Hyperemic flow abnormal resting electrocardiogram (7 of 12 versus 3 of 10, was defined as the maximal flow recorded after the injection of 6 respectively), abnormal exercise treadmill test (5 of 10 ver• to 8 cc of contrast medium into the left coronary artery; 3 to 5 sus 4 of 9), or abnormal exercise thallium tests (3 of 4 injections of contrast medium were given. The largest increase in versus 5 of 7). All patients had normal calculated left ven• coronary flow was chosen for analysis so as to more closely ap• tricular mass, volumes and pressures. There was no cor• proximate maximal vasodilation. The average variance in these relation between the coronary vascular reserve and any of values was within the 7 to 10% range as previously described (16). these variables. The percent increase in coronary sinus flow was calculated as follows: coronary vascular reserve = (Hyperemic flow - Resting The nonsmokers had a significantly higher mean coronary flow)/(Resting flow) x 100. Contrast-induced hyperemia may not vascular reserve (117 ± 45. 1%) than the smokers (74. I ± represent maximal coronary flow, as discussed extensively else• 20.1 %) (p < 0.02) (Fig. 1). When patients in group 1 were where (16). Data from the coronary sinus flow measurements were classified into those who smoked 1 pack a day or less recorded on an Electronics for Medicine recorder at a paper speed (group l A) and those who smoked more than I pack a day of 2.5 or 5 mm/s. Coronary sinus flow and percent increase in (group IB), a significant difference in coronary vascular coronary sinus flow were calculated by computer. reserve was revealed between moderate and heavy smokers Errors In the measurement of coronary sinus flow may result (89.5 ± 16.9 versus 64.9 ± 15.1,respectively)(p < 0.05) if the posterior ventricular vein drains very near the ostium of the (Fig. 2). coronary sinus. In such cases, the flow of that vein would not be Follow-up data. Twenty patients were followed for 3 to included in the measurements obtained. Also, the flow measured would be artificially decreased if the thermodilution catheter were 47 months (average 20 months); two in the smokers group positioned too far into the coronary sinus, or artificially increased were lost to this follow-up study. All smokers continued to if it were too close to the right atrium (18). These considerations smoke, and 7 of the 10 continued to have chest pain. Only would not influence the conclusions of our study because our I of 10 nonsmokers had persistence of symptoms (p < analysis is based on the percent change III flow during hyperemia 0.03). No cause for the chest pain syndrome was found in recorded at any constant venous drainage site. these patients despite comprehensive diagnostic evaluation. CORONARY EFFECTS OF CHRONIC SMOKING J AM cou. CARDIOl 423 1983,1(2) 421-6

Table 1. Summary of Results in 22 Patients

Group I Group 2 (smokers) (nonsmokers)

Patients (n) 12 10 Age (yr) 46.8 ± 8.5 47.4 ± 9.7 Sex (male subjects/total) 7 of 12 6 of 10 Resting ECG (abnormalltotal) 7 of 12 3 of 10 Exercise treadmill test (abnormalltotal) 5 of \0 4 of 9 Exercise thallium test (abnormal/total) 3 of 4 5 of 7 Heart rate (beats/min) 72.6 ± 9.0 71.3 ± 5.7 LV systolic pressure (mm Hg) 1204 ± 19.2 \33.3 ± 22.3 LV mid diastolic pressure (mm Hg) 6.3 ± 4.0 10.4 ± 3.4 LV end diastolic pressure (mm Hg) 12.6 ± 4.0 14.2 ± 4.3 Aortic diastolic pressure (mm Hg) 71.4 ± 8.2 76.7 :! 75 LV mass (by echocardiogram) (g) \17 5 ± 21.9 1232 ± 43.\ Coronary smus flow 112.5 ± 52.0 117.2 ± 67.4 At rest during hyperemia 190.7 ± 77.2 238.1 ± 108.1 Hyperemic flow mmus resting flow* 78.2 ± 30.2 120.9 ± 46.2 Coronary vascular reserve (%)* 74.1 ± 20.1 117.1 ± 45.\ Persistence of pain (presentltotal)t 7 of 10 \ of \0

Values represent mean values ± standard devianon except where noted. ECG = electrocardiogram. lV = left ventncular *p < 0 02. tp < 0 03

Discussion for 10 to 15 minutes after smoking. Long-term hemody• Hemodynamic effects of smoking. The hemodynamic namic alterations in chronic smokers at rest or with stressful response to smoking is the result of a number of effects on interventions have not been observed (34). autonomic and peripheral ganglia, systemic hormonal re• Effects of smoking on coronary blood flow. An in• lease and myocardial wall stress and contractility. Cigarette crease in coronary blood flow follows the administration of smoke has been analyzed extensively (20,21); nicotine and cigarette smoke or nicotine in dogs (3-6), heart-lung prep• carbon monoxide are the components of most pharmaco• arations (6) or rabbits (7), but only when there is a significant logic interest with respect to the cardiovascular system (22). change in cardiac output or blood pressure (3). Bargeron et The administration of nicotine intravenously has been shown al. (8) first investigated changes in coronary blood flow in to approximate closely the acute hemodynamic effects of normal human subjects utilizing the nitrous oxide desatu• smoking in human beings (23) and in animals (3). The ration method and found an increase in flow during smoking. primary action of nicotine consists of the stimulation of all Regan et al. (9,35) studied smoking in patients with and sympathetic ganglia (24) resulting in the release of norep• without coronary artery disease and found that, despite in• inephrine from postganglionic adrenergic axon terminals creases in heart rate, cardiac output and blood pressure, (25,26). Consequently, vasoconstriction is produced from coronary blood flow did not increase in either group. Thus, direct peripheral ganglion stimulation (27,28), by facilita• smoking increases myocardial work and oxygen demand, tion of transmission of impulses through ganglia (29), and but does not exert a direct action on coronary flow. from activation of chemoreceptors in the medulla and in the Studies of nicotine administration directly into the cor• aortic and carotid bodies (29). As a result, there is a net onary arteries of dogs have shown similar results (36,37). increased peripheral resistance, increased heart rate and el• Injection of nicotine into the left anterior descending artery evated blood pressure. In addition, there is stimulation of did not alter coronary flow. When positive chronotropic or the hypothalamus (25) and the pituitary and adrenal gland inotropic effects, or both, were produced during left cir• resulting in the systemic release of antidiuretic hormone cumflex artery injections, there was invariably an increase (ADH) (30), catecholamines and glucocorticoids (26). The in coronary flow. serum levels of epinephrine and norepinephrine have been Carbon monoxide interferes with oxygen transport, both shown (26,31-33) to increase soon after the peripheral cir• by displacing oxygen from the hemoglobin molecule and culatory response has started. The catecholamines mediate by shifting the oxyhemoglobin dissociation curve. By in• increases in heart rate and contractility;thus, although changes terfering with oxygen release at the tissue level in the myo• in stroke volume and pulse pressure may vary from indi• cardium, oxygen demands are further increased, necessi• vidual to individual, cardiac output increases principally tating a compensatory increase in coronary blood flow. because of the increased heart rate (1,2). These effects last Ayres et al. (38) used carbon monoxide inhalation to raise 424 J AM COLL CARDIOL KLEIN ET AL 1983;1(2) 421-6

correlate significantly with chronic smoking is the change 220 p< .02 in the coronary flow with contrast injection-that is, hy• 0 peremic flow minus resting flow (or ".:l coronary flow"). This difference is significant (p < 0.02) (Table I). 200 e :5 Ipock perday A > I pock perday Clinical implications. Although the reduced coronary • Cigars reserve is important and intriguing from the physiologic 180 standpoint, its clinical significance remains to be explored. 0 What role does it play in explaining the commonly noted w > ------complaints of decreased exercise tolerance and easy fati• a:: 160 w gability of chronic smokers? How does it participate in the en w pathogenesis of the chest pain syndrome with normal cor• a:: 140 onary arteries? The clinical characteristics of the chest pain a:: 0 syndrome were similar in smokers and nonsmokers in our <{ ...J study, but the smokers had a significantly greater incidence ::> 120 0 e 0 of persistent pain on long-term follow-up study. The reason enU <{ for this finding is not known. > 100 The work by Opherk et al. (40) suggests that patients ------0 >- e 0 with a chest pain syndrome suggestive of angina pectoris a:: e <{ 0 and abnormal exercise tests have less coronary vascular Z e 0 0 80 reserve than those with atypical chest pain and normal ex• a:: ~J------0 ercise tests. However, we found no correlation between 0 A u 60 coronary vascular reserve and pain characteristics or results ---.--- of exercise stress tests in our study. Interaction between nicotine and the neural control of 40 A the coronary vasculature may explain a decreased coronary vascular reserve in chronic smokers. Coronary arteries have 20 both alpha (vasoconstrictor)- and beta, (vasodilator)-adre• 01 i nergic receptors (41,42). These arteries dilate in response SMOKERS NON-SMOKERS to sympathetic nerve stimulation (41) and to catecholamines with beta-adrenergic activity (43). The predominant factor

Figure 1. Coronary vascular reserve In 12 subjects who smoked for more (44) in the response to metabolically induced stimulation is than 10 years and in 10 nonsmokers.

Figure 2. Coronary vascular reserve In five subjects who smoked about carboxyhemoglobin levels to those developed with smoking. I pack a day or less and In six subjects who smoked more than I pack a They found that both cardiac output and coronary blood day for at least 5 years before the study. flow increased substantially, despite the known negatively inotropic properties of carbon monoxide (39). p<.05 In no human or animal study has coronary vasoconstric• w > tion or decreased coronary flow been observed in response a:: 120 • to smoking, nicotine administration or carbon monoxide w (f) ------inhalation in the absence ofcoronary artery obstruction. This w 100 a:: __e__ is of clinical importance in that there has never been a a:: documented case of coronary spasm directly attributable to <{ • ...J ------smoking. ::> 80 • u ---e--- AA.. Coronary vascular reserve in chronic smoking. We en .. <[ found in this study that the coronary vascular reserve is > 60 -.- significantly decreased in chronic smokers as compared with >- a:: ------nonsmokers, and that this decrease is more pronounced in <[ z 40 heavy smokers (Fig. 1 and 2). Our finding that chronic 0 .. a:: smoking has a measurable impact on coronary vascular dy• 0 namics suggests that during maximal metabolic demand, o 20 chronic smokers may be less able than nonsmokers to aug• 01' 1 ment coronary blood flow, and hence oxygen delivery to s I PACK > I PACK the myocardium. The factor that makes the coronary reserve PER DAY PER DAY CORONARY EFFECTS OF CHRONIC SMOKING J AM cou, CARDlOl 425 1983;1(2):421-6

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