Pathophysiology and Natural History Coronary Artery Disease

In patients with atherosclerotic coronary artery disease, cigarette smoking increases myocardial oxygen demand but may cause an inappropriate decrease in coronary blood flow and myocardial oxgyen supply. This study was performed to explore the mechanism of smoking-induced coronary vasoconstriction and, specifically, to determine if smoking causes an ct-adrenergically mediated increase in coronary artery tone. In 36 chronic smokers with coronary artery disease (27 men and nine women, 50 9 [mean + SD] years old), heart rate-systolic arterial pressure double product and coronary sinus blood flow (by thermodilution) were measured before and during smoking both before and after (1) normal saline (n = 5, control subjects), (2) an at-adrenergic-blocking agent, phentolamine, 5 mg (n 15), (3) a /3-adrenergic-blocking agent, propranolol, 0.1 mg/kg (n = 12), or (4) sodium nitroprusside, 0.4 to 0.8 g.g/kg/min, given in a dose sufficient to diminish systolic arterial pressure by 15% (n 4). During the initial smoking period, rate-pressure product increased and coronary sinus blood flow was unchanged by smoking in all groups. After 30 to 75 min, saline, phentolamine, propranolol, or sodium nitroprusside was given, and measurements were repeated. In the control subjects, rate-pressure product and coronary sinus blood flow responded in a similar manner to that observed previously. In those receiving phentolamine, rate-pressure product was unchanged, but coronary sinus blood flow rose substantially with smoking (percent change + 2 + 15% during the first smoking period [before phentolamine] and +32 + 17% during the second smoking period [after phentolamine]; p < .01). In the 12 patients who received propranolol, rate-pressure product was unchanged, but coronary sinus blood flow fell with smoking (percent change + 5 + 14% during the first smoking period [before propranolol], -12 + 5% during the second smoking period [after propranolol]; p < .01). In those who received sodium nitroprusside, rate-pressure product fell slightly, and coronary sinus blood flow responded in a similar manner to that observed previously. Thus, smoking-induced coronary vasoconstriction is due to an ca-adrenergically mediated increase in coronary artery tone. Circulation 73, No. 4, 662-667, 1986. SEVERAL RECENT STUDIES in patients with atherosclerotic coronary artery disease have shown that cigarette smoking increases myocardial oxygen demand but may cause an inappropriate decrease in From the Department of Internal Medicine (Cardiovascular Division), the University of Texas Health Science Center, Dallas. Supported in part by Ischemic SCOR grant HL-17669 from the National Institutes of Health, Bethesda, and by a grant from the Texas affiliate of the American Heart Association. Address for correspondence: Dr. L. David Hillis, Room L5.134, University of Texas Health Science Center, 5323 Harry Hines Blvd., Dallas, TX 75235. Received July 9, 1985; revision accepted Jan. 2, 1986. Dr. Hillis is an Established Investigator of the American Heart Association, Dallas. coronary blood flow and myocardial oxygen supply.1-' Although the pathogenesis of smoking-induced coronary vasoconstriction is unknown, several mechanisms have been suggested, including (1) an increase in arginine vasopressin, (2) an imbalance of the intracoronary concentrations of thromboxane and prostacyclin, and (3) an oa-adrenergically mediated increase in coronary artery tone.4 We have previously demonstrated that the changes in coronary blood flow caused by smoking bear no clear relationship to alterations in the plasma concentration of arginine vasopressin' or the stable metabolities of thromboxane and prostacyclin.2 The present study was performed to determine if smokCIRCULATION 662 by gest on July 5, 2017 http://ciajournals.org/ D ow nladed from PATHOPHYSIOLOGY AND NATURAL HISTORY-CORONARY ARTERY DISEASE ing-induced coronary vasoconstriction is mediated by a-adrenergic stimulation. Materials and methods Patient population. From January to October 1985, 40 patients (29 men and 11 women, 33 to 71 years old) who underwent cardiac catheterization for the evaluation of chest pain at Parkland Memorial Hospital were studied (table 1). The protocol was approved by the Human Subjects Review Committee of the University of Texas Health Science Center, and all patients gave written informed consent. All had smoked more than 10 cigarettes a day for more than 10 years. Antianginal medications (/3-adrenergic-blocking agents, calcium antagonists, and longacting nitrates) were discontinued more than 24 hr before study. The experimental protocol was undertaken in patients in the fasting state after premedication with 10 mg oral diazepam. All hemodynamic measurements were obtained before the introduction of iodinated contrast material. All subjects had refrained from smoking for more than 4 hr before study. Experimental protocol. In each patient, a thermodilution catheter (model CCS-7U-90B, Wilton Webster Laboratories, Altadena, CA) was advanced to the coronary sinus from the basilic vein, and its position was confirmed fluoroscopically and oximetrically. Coronary sinus blood flow was measured with the continuous thermodilution technique.6 Systemic arterial pressure was recorded through a percutaneous brachial or femoral arterial cannula. After placement of the catheter, atrial pacing was begun at 12 to 20 beats/min above resting heart rate. Three minutes later, coronary sinus blood flow and systemic arterial pressure were recorded. The patient then smoked a cigarette, and coronary sinus blood flow and systemic arterial pressure were measured during the last minute of smoking. After these measurements were obtained, smoking and atrial pacing were discontinued. After 30 to 75 (average 53 + 10) min (during which routine right and left heart catheterization and measurement of cardiac output were accomplished), each patient was assigned to receive one of the following: normal saline, 5 mg iv phentolamine over 1 min, 0.1 mg/kg iv propranolol given at a rate of 1 'mg/min, or 0.4 to 0.8 gug/kg/min sodium nitroprusside given in a dose sufficient to reduce systolic arterial pressure by 15%. After 3 to 5 min, atrial pacing was begun at the same rate used previously and coronary sinus blood flow and systemic arterial pressure were recorded before and during smoking (in an identical manner to that 30 to 75 min previously). Thus, the response of coronary sinus blood flow and systemic arterial pressure to cigarette smoking was assessed before and after normal saline (n = 5, control subjects); an a-adrenergic-blocking agent, phentolamine, S mg (n = 17); a S3-adrenergic-blocking agent, propranolol, 0.1 mg/kg (n = 14); or sodium nitroprusside, 0.4 to 0.8 gug/kg/min (n = 4). In nine patients (five who received phentolamine and four who received propranolol), systemic arterial and coronary sinus blood was obtained before and during the second smoking period, and its oxygen content was measured with a Lex-02-Con (Lexington Instruments, Lexington, MA).7 The difference between systemic arterial and coronary sinus oxygen content was expressed in milliters per deciliter. Analysis of data. All results are reported as mean + 1 SD. For each patient, the heart rate-systolic arterial pressure product before and during smoking was calculated and was considered to reflect myocardial oxygen demand. Changes from before to after saline, phentolamine, propranolol, or sodium nitroprusside within each group were assessed with a paired t test.8 The four groups were compared with the use of an analysis of variVol. 73, No. 4, April 1986 ance.1 For all analyses, a p value < .05 was considered indicative of a significant difference.