Effect of Acute and Long-term Smoking on Myocardial Blood Flow and Flow Reserve
Background Cigarette smoking is a major preventable risk factor for coronary artery disease and sudden cardiac death. However, the effect of acute and long-term cigarette smoking on coronary vasodilatory capacity and myocardial flow reserve has not been quantified in humans.
Methods and Results To examine the effect of short-term and long-term smoking, myocardial blood flow was quantified at rest and during dipyridamole-induced hyperemia (0.56 mg/kg) in 12 smokers (10 males and 2 females; mean age, 27±4 years) under baseline conditions (reflecting the effect of long-term smoking) and during short-term cigarette smoking with 13N ammonia, positron emission tomography, and a two-compartment model. Twelve sex- and age-matched nonsmokers served as control subjects. Smoking significantly increased the rate-pressure product at rest from 7525±1290 to 9160±1125 (P<.001 versus baseline), which was paralleled by a proportional increase in myocardial blood flow at rest (0.70±0.17 versus 0.88±0.17 mL · g−1 · min−1; P<.05 versus baseline). In contrast, hyperemic blood flow declined from 2.23±0.35 at baseline (P=NS versus control) to 1.98±0.32 mL · g−1 · min−1 during smoking (P<.01 versus baseline). Accordingly, the myocardial flow reserve declined from 3.36±0.83 in smokers at baseline to only 2.28±0.28 during smoking (P<.0001 versus baseline). Thus, myocardial blood flow and flow reserve were similar in young, long-term smokers and young, healthy nonsmokers.
Conclusions Short-term smoking increases the coronary vasomotor tone during dipyridamole-induced hyperemia and markedly reduces the myocardial flow reserve. In contrast, long-term smoking does not attenuate the coronary vasodilatory capacity in young individuals with a relatively short smoking history. It might be speculated that the short-term reduction in the coronary vasodilatory capacity during smoking could lower the ischemic threshold in smokers with coronary artery disease and contribute to the increased risk for sudden cardiac death.
Cigarette smokers are at increased risk for coronary artery disease and sudden cardiac death.1 2 3 However, the mechanisms through which cigarette smoking exerts its deleterious effects are understood only incompletely.
The effects of short-term smoking on the cardiovascular system are thought to be mediated by an immediate release of catecholamines from local adrenergic nerve terminals followed by a systemic release from the adrenal medulla, as evidenced by an early rise of primarily norepinephrine followed by a rise in epinephrine levels.3 4 Myocardial contractility and heart rate increase as a result of β1-receptor stimulation. Smoking also modulates the coronary vasomotor tone through β2- and α2-receptor stimulation.5 The β1-receptor–mediated increases in heart rate and contractility, together with the β2-receptor–mediated direct coronary vasodilation, would be expected to result in an increase in myocardial blood flow during smoking, which may be opposed, however, by an α2-receptor–mediated increase in coronary vasomotor tone.4
Pharmacological agents such as dipyridamole induce near-maximal vasodilation and uncouple myocardial blood flow from cardiac work.6 The dipyridamole-induced near-maximal vasodilation exceeds the magnitude of vascular smooth muscle relaxation induced by β1- and β2-receptor stimulation. Therefore, a nicotine- or smoking-induced α2-receptor–mediated vasoconstrictor effect would remain unopposed during pharmacological vasodilation, which could be demonstrated by a reduction in hyperemic blood flow.
The net effect of short-term and long-term smoking on myocardial blood flow and flow reserve can now be explored noninvasively with 13N ammonia, positron emission tomography (PET), and an appropriate tracer kinetic model.7 Therefore, the aim of the present study was to quantify noninvasively in healthy young adult smokers the effect of short-term and long-term smoking on myocardial blood flow and on myocardial flow reserve.
The study population consisted of 12 healthy smokers (10 males, 2 females; mean age, 27±4 years) with a 6±3 pack-year history of smoking and 12 age- and sex-matched, healthy nonsmokers (10 males, 2 females; mean age, 27±5 years). None of the participants had diabetes, hypertension, or any cardiac disease. All participants had normal ECGs at rest and during dipyridamole-induced hyperemia. No subjects were on any medication before or during the study, and all refrained from intake of caffeine-containing food or beverages for at least 12 hours before the study.8 All abstained from smoking for at least 3 hours before the blood flow measurements by PET.3 4 Each participant signed an informed consent form approved by the University of California, Los Angeles, Human Subject Protection Committee.
All smokers (study group) underwent two resting and two hyperemic blood flow studies (0.56 mg/kg IV dipyridamole) with 13N ammonia on 2 separate days (mean time interval, 11±7 days). One of the two resting and one of the two hyperemic blood flow studies were performed while the participants inhaled the smoke of one cigarette of their choice. Thus, the two 13N ammonia studies during smoking were performed to assess the effect of short-term smoking, while the two blood flow studies under baseline conditions were performed to examine the effect of long-term smoking on myocardial blood flow and flow reserve.
To allow for the decay of radiotracer activity, the two 13N ammonia blood flow studies were conducted at least 50 minutes apart. This time interval also allowed smoking-induced increases in catecholamine levels to return to baseline. Therefore, when blood flow was measured first during smoking, the effect of smoking had dissipated during the repeated flow measurement.3 4 The studies were performed in random order. For example, blood flow was measured at rest during smoking followed by a hyperemic flow measurement without smoking. Alternatively, blood flow was measured at rest without smoking and then again during hyperemia during smoking.
In the group of nonsmokers (control group), myocardial blood flow was measured only once at rest and once during dipyridamole-induced hyperemia.
For the resting blood flow study during cigarette smoking, the participants began smoking 3 minutes before the injection of 13N ammonia and continued to smoke for the first 2 minutes of the dynamic image acquisition. For the hyperemic blood flow study during smoking, 0.56 mg/kg dipyridamole was infused intravenously over 4 minutes by an infusion pump. The volunteers began smoking 1 minute after the end of the dipyridamole infusion; a repeated injection of 13N ammonia followed 3 minutes later while the participants continued smoking for another 2 minutes. Subjects continued to smoke during the initial 2 minutes after tracer injection to allow us to ascertain steady-state conditions during the time of 13N ammonia uptake into the myocardium.9
Throughout each of the four 13N ammonia blood flow studies, a 3-lead ECG was obtained continuously; 12-lead ECGs, heart rate, and blood pressure (cuff measurements) were measured at 1-minute intervals.
Myocardial blood flow was measured with a Siemens/CTI 931/08-12 tomograph that acquires 15 transaxial images simultaneously. The device has an intrinsic in-plane spatial resolution of 6.5-mm full-width half-maximum (FWHM), an interplane spacing of 6.7 mm, and a 10-cm axial field of view.10 The transaxial images were reconstructed by use of a Shepp filter with a cutoff frequency of 0.3 Nyquist, resulting in an effective in-plane resolution of 11-mm FWHM.
The image acquisition protocol was identical in all four (study group) and two (control group) 13N ammonia blood flow studies. To correct for photon attenuation, a 20-minute transmission image was acquired before each of the two paired 13N ammonia blood flow studies. 13N ammonia (10 to 15 mCi) was then injected intravenously over 30 seconds while the imaging sequence started. The dynamic imaging protocol consisted of twelve 10-second, two 30-second, one 60-second, and one 15-minute images.
To minimize motion during image acquisition, the participants were secured to the table by Velcro straps across the chest. Moreover, the chests were marked with a felt pen, and position was controlled with a light beam.
Semiquantitative Image Analysis
The serially acquired sets of 15 transaxial images were reoriented into 6 short-axis planes as described previously.11 To rule out possible flow abnormalities, the short-axis images were assembled into polar maps of the 13N ammonia activity distribution and compared with a database of normal.12
Placement of Regions of Interest and Quantification of Blood Flow
Three 70° to 90° regions of interest were approximated in the territory of the left anterior descending coronary artery, the left circumflex artery, and the right coronary artery on three short-axis images (one basilar, one midventricular, and one apical image) as described previously.13 The regions of interest were identical for all four (study group) or two (control group) blood flow studies. This was achieved by use of the same anatomic landmark (the insertion of the right ventricle into the intraventricular septum) as the starting point for the placement of regions in all four studies. The regions were then copied to the first 120 seconds (12 frames) of the dynamic imaging sequence to obtain tissue time activity curves.
As demonstrated previously, myocardial blood flows in the three coronary territories in healthy volunteers are similar.13 Therefore, the regional time activity curves were averaged, and a single mean myocardial time activity curve was obtained for each study in each individual. The arterial input function was derived from a small region of interest that was centered in the left ventricular blood pool and copied to the serially acquired images.14
The myocardial time activity curves were corrected for partial volume effects by assuming a uniform myocardial wall thickness of 1 cm.15 Both the blood pool and myocardial time activity curves were corrected for physical decay. They were then fitted with a previously validated two-compartment model, which corrects for spillover of activity from the blood pool into the left ventricular myocardium.7 16 17
Values are mean±SD. The paired t test was used to compare baseline myocardial blood flow conditions to those during smoking. One-way ANOVA was used to assess differences in hemodynamic parameters and blood flow between smokers and control subjects. Probability levels of <.05 were considered statistically significant.
Semiquantitative Polar Map Analysis
Polar map analysis of the reoriented short-axis images and comparison to a database of normal revealed normal uptake of 13N ammonia in the left ventricular myocardium of all study participants. The absence of regional flow reductions at rest and during dipyridamole-induced hyperemia argues against significant coronary artery disease in this population of young smokers.18 19 20
Table 1⇓ lists heart rate, blood pressure, and rate-pressure product at baseline and during smoking in the study and control groups. Baseline systolic blood pressure did not increase with smoking (P=NS versus baseline and control subjects). However, diastolic blood pressure, mean aortic blood pressure, heart rate, and rate-pressure product were higher during smoking (P<.05 versus baseline and control subjects).
During pharmacological vasodilation, systolic, diastolic, and mean aortic blood pressure did not differ (P=NS versus baseline and control subjects), while heart rate and rate-pressure product were higher during smoking than under baseline conditions and in nonsmoking control subjects (P<.05).
Myocardial Blood Flow and Flow Reserve
Table 2⇓ lists the individual flow measurements. Resting myocardial blood flow averaged 0.62±0.10 and 0.70±0.17 mL · g−1 · min−1 in the control and study groups, respectively, under baseline conditions (P=NS). While subjects were smoking, it increased to 0.88±0.17 mg/min (P<.01 versus control and P<.05 versus baseline; the Figure⇓, panel A). The smoking-induced changes in myocardial blood flow were significantly correlated to changes in rate-pressure product (y=0.59x+0.47; r=.84; P<.001). Thus, smoking induced proportional increases in myocardial blood flow and cardiac work.
Hyperemic myocardial blood flow averaged 2.31±0.47 mL · g−1 · min−1 in the control group. It was similar in the smokers at baseline (2.23±0.35 mL · g−1 · min−1; P=NS) but declined to 1.98±0.32 during short-term smoking (P<.05 versus baseline; the Figure⇑, panel B).
The myocardial flow reserve averaged 3.82±0.71 in the control group and 3.36±0.83 in the study group under baseline conditions (P=.16). The increase in resting blood flow, together with the reduction in hyperemic blood flow during smoking in the study group, resulted in a significant reduction of the myocardial flow reserve to 2.28±0.28 (P<.0001 versus control and baseline condition; the Figure⇑, panel C).
Coronary Vascular Resistance
To account for individual differences in coronary driving pressure, an index of coronary vascular resistance was computed from the ratio of mean aortic blood pressure (millimeters of mercury) to myocardial blood flow (milliliters per gram per minute).
At rest, this index did not differ between control subjects and smokers at baseline (118±28 versus 139±25 mm Hg · mL−1 · g−1 · min−1) but was lower during short-term smoking (98±22 mm Hg · mL−1 · g−1 · min−1; P<.05). Furthermore, coronary resistance during pharmacological vasodilation was similar in the control and study groups (38±8 versus 38±9 mm Hg · mL−1 · g−1 · min−1). However, short-term smoking resulted in an increase in coronary vascular resistance during pharmacological vasodilation to 43±9 mm Hg · mL−1 · g−1 · min−1 (P<.05).
The present study demonstrates that short-term smoking markedly reduces the myocardial flow reserve. The reduction results from a smoking-induced increase in resting blood flow and a decrease in hyperemic blood flow. In this group of young smokers with relatively short histories of smoking, however, the coronary vasodilator capacity and coronary vasomotion under basal conditions were found to be similar to those in nonsmokers and thus appeared to be unaffected by long-term smoking.
Effect of Short-term Smoking on Myocardial Blood Flow at Rest
Using coronary sinus blood flow measurements, Winniford et al21 demonstrated the complex interaction between β-receptor–mediated vasodilation and α2-receptor–mediated vasoconstriction in patients with coronary artery disease during short-term smoking. They observed a 32±17% increase in coronary sinus blood flow when α-receptors were blocked with phentolamine during smoking. In contrast, coronary sinus blood flow fell by 12±5% after administration of the nonselective β-blocker propanolol. Smoking apparently exerts different effects on the vasomotor tone in healthy humans and patients with coronary artery disease. The interactions between β1-, β2-, and α2-receptors result in increases in22 23 24 25 or do not affect26 myocardial blood flow in apparently healthy humans. In contrast, in patients with coronary artery disease, smoking reduces blood flow.24 27 28 29 30
Kaijser and Berglund23 observed in healthy humans proportional increases of about 20% in cardiac work and coronary sinus blood flow during smoking, which is similar to the smoking-induced 20% increase in cardiac work and coronary sinus blood flow reported by Nicod et al.24 The latter investigators reported an attenuated or even no increase in blood flow despite an increase in cardiac work during smoking in patients with coronary artery disease. This is consistent with observations with intracoronary flow probes showing that short-term smoking caused an approximate 7% decrease in coronary flow velocity and a 10% increase in coronary resistance in patients with coronary artery disease.30 Additionally, with coronary sinus flow probes, coronary vascular resistance was found to increase in patients with coronary artery disease but to decline in angiographically normal coronary arteries. Patients with modest coronary arteriosclerosis had smaller smoking-induced increases in coronary resistance than those with more severe coronary artery disease.28
Thus, the present finding of smoking-induced, proportional increases in cardiac work and myocardial blood flow by approximately 20%, together with the reduction in coronary vascular resistance at rest, is consistent with previous invasive blood flow measurements in healthy humans. It most likely reflects the demand-induced coronary vasodilation that in part offsets the α2-receptor–mediated vasoconstriction in young smokers with presumably normal endothelial function. The reason for the differential effect of smoking on myocardial blood flow in patients and in nonsmoking control subjects remains uncertain. In normal coronary arteries, the direct vasoconstrictor effect of norepinephrine is presumably counteracted by release of endothelium-derived vasodilatory substances.31 This compensatory mechanism appears to be impaired in patients at risk for32 or with documented33 34 coronary artery disease and endothelial dysfunction of the coronary circulation. The proportional increases in the rate-pressure product and blood flow in the present study suggest that adequate vasomotor control and endothelial function are maintained in young smokers with relatively short histories of smoking.
Effect of Short-term Smoking on Hyperemic Blood Flow
Experiments in isolated heart preparations demonstrated the dependency of hyperemic blood flow on perfusion pressure.35 Smoking-induced increases in mean arterial blood pressure might therefore increase blood flow during pharmacological vasodilation in humans. However, the catecholamine-induced, β1-receptor–mediated increase in cardiac work or the β2-receptor–mediated vascular smooth muscle relaxation is unlikely to further increase flow in coronary arteries that are already nearly maximally dilated. Thus, the unopposed α2-receptor–mediated increase in the coronary vasomotor tone4 might be uncovered during pharmacological vasodilation.
However, alterations in heart rate, blood pressure, and contractility induced by short-term smoking might affect hyperemic myocardial blood flow. For instance, increases in heart rate and contractility might attenuate the hyperemic response by shortening the diastolic phase of high coronary flow36 or by increasing extravascular resistive forces.37 However, 100% increases in heart rate were required in animal experimental studies to reduce significantly hyperemic blood flow.36 The modest, smoking-induced, 20% increase in heart rate in the current study probably did not contribute to the reduction in hyperemic blood flow. Systolic blood pressure did not change significantly during smoking. Therefore, increases in myocardial contractility and thus in extravascular compressive forces are also unlikely to explain the attenuated hyperemic flow response during smoking. Thus, the reduction in hyperemic blood flow during smoking was most likely related to a smoking-induced, α2-receptor–mediated vasoconstriction.
Effect of Short-term Smoking on the Myocardial Flow Reserve
The significant smoking-induced increase in resting blood flow, which can be attributed largely to the increase in cardiac work and the increased vasomotor tone during hyperemia, resulted in an approximate 30% reduction in myocardial flow reserve. Plasma catecholamine levels have been shown to peak within 10 minutes of smoking a cigarette, but increased levels might persist for 30 minutes.4 Thus, the reduction in the coronary reserve and in turn a lower threshold for ischemic events might persist during this time interval after a cigarette is smoked and might contribute to the pathogenesis of severe ischemic events in smokers with coronary artery disease.
Effect of Long-term Smoking on Myocardial Blood Flow and Flow Reserve
Two previous studies examined the effect of long-term smoking on endothelium-dependent vasomotion. Celermajer et al38 found a marked reduction in both flow-mediated, endothelium-dependent and nitroglycerin-induced, endothelium-independent vasodilation of the forearm arteries in smokers. In contrast, Vita et al32 measured the coronary response to intracoronary acetylcholine but failed to observe a correlation between changes in coronary artery diameter and smoking as a coronary risk factor.
In the present study, resting blood flow in smokers under baseline conditions did not differ from that in nonsmoking control subjects. Thus, coronary vasomotion in response to long-term smoking appeared to be unaltered at rest in young smokers with relatively brief smoking histories. This finding argues for a preserved regulation of the coronary vasomotor tone in these individuals. The modest but statistically insignificant lower myocardial flow reserve in long-term smokers (3.36±0.83 versus 3.82±0.71) was due to the somewhat higher resting rate-pressure product and resting blood flow in long-term smokers, while the hyperemic flow did not differ between long-term smokers and control subjects. Therefore, this modest but statistically insignificant difference is probably unrelated to an altered coronary circulation. Rather, it may be related to differences in physical condition and lifestyles between control subjects and long-term smokers.39
This study has several limitations. First, the effect of long-term smoking was assessed only in young smokers. In this population, the myocardial flow reserve only tended to but did not differ significantly from that in young control subjects with similar demographic characteristics. However, the effect of longer-term exposure to smoking on myocardial blood flow and flow reserve was not addressed in the present study. Moreover, because of ethical considerations, the effect of smoking on myocardial blood flow was not assessed in nonsmokers.
Second, only healthy subjects were enrolled in this study. Thus, the effect of smoking on resting and hyperemic blood flow in patients with coronary artery disease was not examined.
Third, no measurements of catecholamine levels were performed. However, the literature provides sufficient evidence that the hemodynamic and blood flow alterations observed in the present study are secondary to an increase in circulating and locally released and in circulating catecholamines.3 4 Cryer et al4 reported prompt increases in systolic blood pressure and heart rate 2.5 minutes after the start of smoking, with a maximal hemodynamic response to smoking within 5 minutes. Interestingly, increases in serum norepinephrine and epinephrine levels were preceded by the changes in hemodynamic parameters, suggesting that local release precedes systemic catecholamine release. In this study, catecholamine levels and hemodynamic parameters returned to baseline levels 30 minutes after the start of smoking. This observation further suggests that a time interval of 50 minutes is sufficient to rule out a significant effect of smoking on the second 13N ammonia blood flow study.3 4
Another limitation is that the hemodynamic conditions and, by inference, myocardial blood flow might not have been stable during the first 2 minutes of the dynamic image acquisition. However, no significant differences in the rate-pressure product measured twice during the first 2 minutes of the dynamic imaging sequence were observed, suggesting steady-state conditions during the quantitative blood flow studies.
As a technical limitation, the assumption of a homogeneous 1-cm left ventricular wall thickness represents a simplification that might induce a systematic error in absolute flow estimates. However, wall thickness would not be expected to differ between the baseline and the smoking study. Thus, while a systematic error cannot be excluded, it would not affect the finding of a reduced flow reserve during short-term smoking.
The current study demonstrates for the first time a short-term impairment of the vasodilator capacity during smoking. The significant reduction in vasodilator capacity in apparently healthy young subjects might have important clinical implications. The short-term reduction in vasodilator capacity might limit the available flow reserve in patients with coronary artery disease and might lower the threshold for ischemic events. It is therefore conceivable that ischemic changes induced by smoking contribute to the increased risk of sudden cardiac death in smokers with coronary artery disease.
The Laboratory of Structural Biology and Molecular Medicine at the University of California, Los Angeles, is operated for the US Department of Energy by the University of California under contract DE-FC03-87ER60615. This work was supported in part by the Director of the Office of Energy Research, Office of Health and Environmental Research, Washington, DC; by research grants HL-29845 and HL-33177 from the NIH, Bethesda, Md; and by an Investigative Group Award by the Greater Los Angeles (Calif) Affiliate of the American Heart Association. We want to thank Ron Sumida, Larry Pang, Francine Aguilar, Derjenn Liu, and Marc Hulgan for their technical assistance; Diane Martin for preparing the figure and tables; and Eileen Rosenfeld for her assistance in preparing this manuscript.
- Received October 26, 1994.
- Revision received December 6, 1994.
- Accepted December 18, 1994.
- Copyright © 1995 by American Heart Association
Kannel WB, Higgins M. Smoking and hypertension as predictors of cardiovascular risk in population studies. J Hypertens. 1990;8(suppl 5):S3-S8.
Groppelli A, Omboni S, Parati G, Mancia G. Blood pressure and heart rate response to repeated smoking before and after beta-blockade and selective alpha 1 inhibition. J Hypertens. 1990;8(suppl 5):S35-S40.
West J, Bellet S, Manzoli U, Müller O. Effects of Persantine (RA8), a new coronary vasodilator, on coronary flow and cardiac dynamics in the dog. Circ Res. 1962;10:5-42.
Kuhle W, Porenta G, Huang S-C, Buxton D, Gambhir S, Hansen H, Phelps M, Schelbert H. Quantification of regional myocardial blood flow using 13N-ammonia and reoriented dynamic positron emission tomographic imaging. Circulation. 1992;86:1004-1017.
Spinks TJ, Guzzardi R, Bellina CR. Performance characteristics of a whole-body positron tomograph. J Nucl Med. 1988;29:1833-1841.
Kuhle W, Porenta G, Huang S-C, Phelps M, Schelbert H. Issues in the quantitation of reoriented cardiac PET images. J Nucl Med. 1992;33:1235-1242.
Porenta G, Kuhle W, Czernin J, Ratib O, Brunken R, Phelps M, Schelbert H. Semiquantitative assessment of myocardial viability and perfusion utilizing polar map displays of cardiac PET images. J Nucl Med. 1992;33:1623-1631.
Czernin J, Müller P, Chan S, Brunken R, Porenta G, Krivokapich J, Chen K, Chan A, Phelps M, Schelbert H. Influence of age and hemodynamics on myocardial blood flow and flow reserve. Circulation. 1993;88:62-69.
Weinberg IN, Huang SC, Hoffman EJ, Araujo L, Nienaber C, Grover-McKay M, Dahlbom M, Schelbert H. Validation of PET-acquired functions for cardiac studies. J Nucl Med. 1988;29:241-247.
Gambhir SS, Schwaiger M, Huang SC, Krivokapich J, Schelbert HR, Nienaber CA, Phelps ME. Simple noninvasive quantification method for measuring myocardial glucose utilization in humans employing positron emission tomography and fluorine-18 deoxyglucose. J Nucl Med. 1989;30:359-366.
Krivokapich J, Smith GT, Huang SC, Hoffman EJ, Ratib O, Phelps ME, Schelbert HR. 13N ammonia myocardial imaging at rest and with exercise in normal volunteers: quantification of absolute myocardial perfusion with dynamic positron emission tomography. Circulation. 1989;80:1328-1337.
Go RT, Marwick TH, MacIntyre WJ, Saha GB, Neumann DR, Underwood DA, Simpfendorfer CC. A prospective comparison of rubidium-82 PET and thallium-201 SPECT myocardial perfusion imaging utilizing a single dipyridamole stress in the diagnosis of coronary artery disease. J Nucl Med. 1990;31:1899-1905.
Demer LL, Gould KL, Goldstein RA, Kirkeeide RL, Mullani NA, Smalling RW, Nishikawa A, Merhige ME. Assessment of coronary artery disease severity by positron emission tomography: comparison with quantitative arteriography in 193 patients. Circulation. 1989;79:825-835.
Winniford MD, Wheelan KR, Kremers MS, Ugolini V, Van Den Berg E, Niggemann EH, Jansen DE, Hillis DL. Smoking induced vasoconstriction in patients with atherosclerotic coronary artery disease: evidence for adrenergically mediated alterations in coronary artery tone. Circulation. 1986;4:662-667.
Bargeron LM, Ehmke D, Gonlubol F, Castellanos A, Siegel A, Bing RJ. Effect of cigarette smoking on coronary blood flow and myocardial metabolism. Circulation. 1957;15:251-257.
Winniford M. Smoking and cardiovascular function. J Hypertens. 1990;8(suppl 5):S17-S23.
Regan TJ, Frank MJ, McGinty JF, Zobl E, Hellems HK, Bing RJ. Myocardial response to cigarette smoking in normal subjects and patients with coronary artery disease. Circulation. 1961;23:365-369.
Harrison DG. From isolated vessels to the catheterization laboratory: studies of endothelial function in the coronary circulation of humans. Circulation. 1989;80:703-706.
Vita JA, Treasure CB, Nabel EG, McLenachan JM, Fish D, Yeung AC, Vekshtein VI, Selwyn AP, Ganz P. Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease. Circulation. 1990;81:491-497.
Zeiher AM, Drexler H, Wollschläger H, Just HJ. Endothelial dysfunction of the coronary microvasculature is associated with impaired coronary blood flow regulation in patients with early atherosclerosis. Circulation. 1991;84:1984-1992.
Vita J, Treasure C, Yeung A, Vekshtein V, Fantasia G, Fish R, Ganz P, Selwyn A. Patients with evidence of coronary endothelial dysfunction as assessed by acetylcholine infusion demonstrate marked increase in sensitivity to constrictor effects of catecholamines. Circulation. 1992;85:1390-1397.
Hoffman E. Maximal coronary flow and the concept of coronary vascular reserve. Circulation. 1984;70:153-165.
Bache R, Cobb F. Effect of maximal coronary vasodilation on transmural myocardial perfusion during tachycardia in the awake dog. Circ Res. 1977;41:648-653.
Marzilli M, Goldstein S, Sabbah H, Lee T, Stein P. Modulating effect of regional myocardial performance on local myocardial perfusion in the dog. Circ Res. 1979;45:634-643.
Celermajer DS, Sorensen KE, Georgakopoulos D, Bull C, Thomas O, Robinson J, Deanfield J. Cigarette smoking is associated with dose related and potentially reversible impairment of endothelium dependent dilation in healthy young adults. Circulation. 1993;88(suppl I):I-2149-I-2155.
Czernin J, Barnard J, Sun K, Krivokapich J, Brunken R, Porenta G, Phelps M, Schelbert H. Beneficial effect of cardiovascular conditioning on myocardial blood flow and coronary vasodilator capacity. Circulation. 1993;88:I-51. Abstract.