Effects of Intravenous Dobutamine on Coronary Vasomotion in Humans Emanuele Barbato, MD, Jozef Bartunek, MD, PHD, Eric Wyffels, MD, William Wijns, MD, PHD, Guy R

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View metadata, citation and similar papers at core.ac.uk brought to you by CORE Journal of the American College of Cardiology providedVol. by Elsevier 42, No. - 9,Publisher 2003 Connector © 2003 by the American College of Cardiology Foundation ISSN 0735-1097/03/$30.00 Published by Elsevier Inc. doi:10.1016/S0735-1097(03)01078-7 Pharmacologic Effects of Dobutamine Effects of Intravenous Dobutamine on Coronary Vasomotion in Humans Emanuele Barbato, MD, Jozef Bartunek, MD, PHD, Eric Wyffels, MD, William Wijns, MD, PHD, Guy R. Heyndrickx, MD, PHD, Bernard De Bruyne, MD, PHD Aalst, Belgium

OBJECTIVES We sought to investigate the vascular mechanisms of dobutamine-induced myocardial ischemia. BACKGROUND Dobutamine stress is often used as a surrogate for exercise. The effects of dobutamine on the epicardial arteries are incompletely understood and possibly different from those of physical exercise. METHODS Intravenous (IV) dobutamine (40 ␮g/kg per min) was administered in 19 patients with normal, 23 patients with mildly atherosclerotic, and 12 patients with stenotic coronary arteries. In another two groups of patients with stenotic arteries, IV dobutamine was preceded by 1) an intracoronary (IC) bolus of the alpha-adrenergic blocker phentolamine (12 ␮g/kg, n ϭ 12); and 2) an IC infusion of the nitric oxide substrate L-arginine (150 ␮mol/l per min for 20 min, n ϭ 11). Intravenous saline instead of dobutamine was infused into eight patients with normal arteries. After dobutamine (or saline), an IC bolus of isosorbide dinitrate (ISDN, 0.2 mg) was given. Coronary vasomotion was evaluated by quantitative coronary angiography on angiograms obtained after each dose of dobutamine, saline, phentolamine, L-arginine, and ISDN. RESULTS Dobutamine increased the rate–pressure product and heart rate similarly in all patients except those who received saline. Dobutamine induced vasodilation in normal (change in luminal diameter [⌬LD] vs. baseline: 19 Ϯ 2%) and in mildly atherosclerotic arteries (⌬LD: 8 Ϯ 2%, p Ͻ 0.05 vs. normal). In stenotic arteries, dobutamine did not induce signiﬁcant vasomotion (⌬LD: Ϫ3 Ϯ 3%); the latter was improved by L-arginine (⌬LD: 10 Ϯ 3%, p Ͻ 0.05 vs. stenotic arteries) and fully restored by phentolamine (⌬LD: 19 Ϯ 3%, p Ͻ 0.05 vs. stenotic arteries). CONCLUSIONS Endothelial dysfunction and enhanced alpha-adrenergic tone contribute to the loss of dobutamine-induced vasodilation in coronary atherosclerosis. In contrast to physical exercise, dobutamine does not induce “paradoxical vasoconstriction” of atherosclerotic coronary arteries. (J Am Coll Cardiol 2003;42:1596–601) © 2003 by the American College of Cardiology Foundation

Dobutamine stress echocardiography (DSE) is an accepted sclerotic epicardial coronary arteries, an effect not observed surrogate for exercise stress testing to detect significant during physical exercise. The latter induces “paradoxical” coronary atherosclerotic disease (1,2). Several studies have vasoconstriction of atherosclerotic arteries due to endothe- shown that high-dose intravenous (IV) dobutamine can lial dysfunction and enhanced alpha-adrenergic receptor induce a mechanical dysfunction when an increase in oxygen responsiveness (6–11). Dobutamine-induced vasomotion is thus the net result between dilatory forces (the endothelial See page 1602 component, through a flow-mediated metabolic response, demand induced by myocardial beta-adrenergic receptor and the direct stimulation of vascular and cardiac beta1- and stimulation is not matched by an adequate increase in beta2-adrenergic receptors [12–14]) and constrictive forces coronary blood flow. In addition, IV dobutamine was shown (the direct stimulation of alpha1-adrenergic receptors of the to decrease the microvascular resistance to the same extent vascular wall [13]). as intracoronary adenosine (3,4). Accordingly, in the present study, we investigated the Nevertheless, DSE is clouded by a large number of vasomotion of epicardial arteries during dobutamine infu- false-negative results as compared with hemodynamic as- sion in patients with normal, mildly atherosclerotic, and sessment of coronary stenosis (5). This may be partly due to stenotic coronary arteries. In the latter setting, we further the inability to detect regional wall motion abnormalities tested the hypothesis that paradoxical vasoconstriction to that occur in small territories. Alternatively, this might be dobutamine does not occur. due to a direct vasodilatory effect of dobutamine on athero- METHODS From the Cardiovascular Center, OLV Ziekenhuis, Aalst, Belgium. Manuscript received January 8, 2003; revised manuscript received February 27, Patients and protocol. The study population consisted of 2003, accepted March 19, 2003. 85 patients (24 women) with a normal left ventricular JACC Vol. 42, No. 9, 2003 Barbato et al. 1597 November 5, 2003:1596–601 Dobutamine and Coronary Vasomotion

segments analyzed) with the same angiographic criteria as Abbreviations and Acronyms groups 4 and 5 (%DS: 47 Ϯ 4; p ϭ NS vs. groups 4 and 5), ACE ϭ angiotensin-converting enzyme but, 8 min before IV dobutamine, an IC infusion (1.5 ϭ DS diameter stenosis ml/min) of the nitric oxide (NO) precursor L-arginine (150 ϭ DSE dobutamine stress echocardiography ␮mol/l per min for 20 min) (10,11) was started and IC ϭ intracoronary ISDN ϭ isosorbide dinitrate maintained during dobutamine. IV ϭ intravenous Catheterization protocol. A 6F sheath was introduced LD ϭ luminal diameter into the femoral artery, and a 6F guiding catheter was NO ϭ nitric oxide engaged into the coronary ostium. Heparin (5,000 U) was ϭ RD reference diameter given to all patients, and in case of a coronary intervention, the dose was adjusted according to the body weight and need for glycoprotein IIb/IIIa receptor antagonists. On ejection fraction referred for coronary angiography or per- average, the duration of the protocol was 30 min, and the cutaneous coronary intervention. In all patients, cardiac protocol was well tolerated by the patients. Informed medications, except for aspirin and statins, were withheld consent was obtained from all patients before the diagnostic for more than 36 h before the protocol, and no significant catheterization, in accordance with the protocol approved by differences in the therapeutic regimen (e.g., angiotensin- the local ethical committee. converting enzyme [ACE] inhibitors, statins) were observed Data acquisition. Figure 1 summarizes the study proto- between groups of patients with stenotic coronary arteries cols. An angiogram was acquired at baseline, 3 min after IC (groups 4, 5, and 6). Patients with valvular heart disease, administration of phentolamine in group 5, 8 min after the unstable angina, a recent myocardial infarction, conduction start of IC infusion of L-arginine in group 6, during the last system disease, or clinical evidence of heart failure were 15 s of each dosage of dobutamine (or saline) infusion, and excluded. 1 min after IC administration of ISDN. In each patient, an The patients were classified into six groups according to average of 4.1 segments were selected in one projection on the angiographic data and pharmacologic protocol: group 1 the baseline angiogram. The coronary segments were con- consisted of 19 patients (83 coronary segments analyzed) sidered as follows: in the left anterior descending coronary with angiographically smooth coronary arteries (reference artery, the proximal (from the ostium to first septal branch), diameter [RD]: 2.2 Ϯ 0.1 mm). In these patients, angio- the mid (from the first to second septal branch), and the graphic and hemodynamic data were recorded at baseline, distal segment (after the second septal branch); in the left during infusion of dobutamine (increasing dosages of 10, circumflex coronary artery, the proximal (from the ostium to 20, 30, and 40 ␮g/kg per min for 3 min each step), as well first marginal branch), the mid (after the first marginal as 1 min after IC isosorbide dinitrate (ISDN; 0.2 mg) given branch), and the proximal segment of the first marginal 10 min after cessation of the infusion of dobutamine, when branch (the first 10 mm of the branch); and in the right the heart rate and blood pressure had returned to baseline. coronary artery, the proximal (from the ostium to first acute Group 2 consisted of eight patients (34 coronary segments marginal branch), the mid (from the first to second acute analyzed) with smooth coronary arteries (RD: 2.2 Ϯ 0.1 marginal branch), and the distal segment (after the second mm; p ϭ NS vs. group 1). The protocol was identical to that acute marginal branch). In dominant right coronary arteries, of group 1, except that dobutamine was replaced by saline. the proximal 10 mm of the right posterior descending artery This was done to rule out the potential influence of the was also considered. In groups 4, 5, and 6 (stenotic arteries), contrast medium itself on epicardial vasomotion. Group 3 besides the stenosis, whenever possible, at least one segment consisted of 23 patients (83 coronary segments analyzed) proximal and one segment distal to the stenosis were with diffuse, mildly atherosclerotic coronaries (Ͻ30% diam- obtained. In case of ostial stenosis, two or more segments eter stenosis; RD: 2.0 Ϯ 0.1 mm). The pharmacologic distal to the stenosis were obtained. For each segment, the protocol and regimen were identical to that of group 1. luminal diameter (LD) was measured at end diastole by Group 4 consisted of 12 patients (36 coronary segments quantitative coronary angiography using the catheter as a analyzed) with angiographically documented stenosis in at scaling device (3). In case of stenotic coronary arteries, least one coronary artery (percent diameter stenosis [%DS]: changes in LD of the stenosis itself were first analyzed 49 Ϯ 4%). The coronary segments studied in this group all separately from the changes of the adjacent reference seg- belonged to the stenotic artery. The pharmacologic protocol ments. For groups 4, 5, and 6, the data from the stenotic was identical to that of groups 1 and 3. Group 5 consisted and adjacent reference segments were pooled, as a uniform of 12 patients (55 coronary segments analyzed) who fulfilled response to dobutamine was observed. the same angiographic criteria as patients of group 4 (%DS: To ensure proper filling of the coronaries with contrast 47 Ϯ 4; p ϭ NS vs. group 4), but, 3 min before the start of medium, even during high-flow situations, an angioplasty dobutamine infusion, an IC bolus of phentolamine (12 guiding catheter was used in every case. Exactly the same ␮g/kg), a nonselective alpha-adrenergic blocking agent, was projection was used at the different stages of the protocol. given (9). Group 6 consisted of 11 patients (63 coronary Based on the emergence of side branches, exactly the same 1598 Barbato et al. JACC Vol. 42, No. 9, 2003 Dobutamine and Coronary Vasomotion November 5, 2003:1596–601

Figure 1. Study protocols. BL ϭ baseline; DOB ϭ dobutamine; IC ϭ intracoronary; ISDN ϭ isosorbide dinitrate; IV ϭ intravenous; Phento ϭ phentolamine; QCA ϭ quantitative coronary angiography; REC ϭ recovery period; SAL ϭ saline. segments were analyzed at the different stages of the uct in groups 1, 3, 4, 5, and 6. As expected, the adminis- protocol. Angiograms were recorded at 25 frames/s. Heart tration of saline (instead of dobutamine) in group 2 patients rate and blood pressures were digitally recorded (Notocord, did not produce any hemodynamic changes. The IC admin- France) during the entire study protocol. istration of ISDN after the end of the dobutamine/saline The contrast medium used for all patients was the infusion was associated with a significant decrease of the nonionic monomer, hypo-osmolar ioversol. rate–pressure product in all but group 2. In group 5, Statistical analysis. Data are expressed as the mean value phentolamine administration produced a transient and non- Ϯ SEM. Statistical comparison was made by analysis of significant reduction in blood pressure that was completely variance (ANOVA) for repeated measurements to compare, normalized after 3 min, when dobutamine infusion was within each group of patients, the effects of different doses started. No significant hemodynamic changes were observed of the drugs being tested. One-way ANOVA was used to during IC infusion of L-arginine. compare the data between different groups. Post hoc anal- Epicardial coronary vasomotion. The results of the drug ysis was performed with the Newman-Keuls test. Statistical regimen in the different groups are shown in Table 1 and analysis was performed with GraphPad Prism, version 2.0. Figures 3 and 4. In group 1 patients (normal coronary P values Ͼ0.05 were considered nonsignificant. arteries), a significant dose-dependent increase in LD was observed during infusion of dobutamine. No further in- RESULTS crease in LD was observed after ISDN. In group 2 patients Systemic hemodynamics (Fig. 2). Dobutamine induced a (normal coronary arteries), saline infusion did not result in similar dose-dependent increase in the rate–pressure prod- any change in LD, whereas ISDN significantly increased

Table 1. Changes in Luminal Diameter in the Different Groups of Patients Dob 10 Dob 20 Dob 30 Dob 40 ISDN Group 1 (normal arteries) 3 Ϯ 1* 8 Ϯ 1*† 16 Ϯ 2*† 19 Ϯ 2* 22 Ϯ 2* Group 2 (normal arteries, but dobutamine replaced by saline) 0 Ϯ 12Ϯ 1 Ϫ2 Ϯ 12Ϯ 116Ϯ 2*† Group 3 (mildly atherosclerotic arteries) Ϫ1 Ϯ 14Ϯ 2* 7 Ϯ 2* 8 Ϯ 2* 17 Ϯ 2*† Group 4 (stenotic arteries) Ϫ6 Ϯ 2* Ϫ1 Ϯ 2 Ϫ1 Ϯ 3 Ϫ3 Ϯ 318Ϯ 3*† Group 5 (stenotic arteries pretreated with phentolamine) 2 Ϯ 210Ϯ 2*† 15 Ϯ 2* 19 Ϯ 3* 20 Ϯ 2* Group 6 (stenotic arteries pretreated with L-arginine) Ϫ1 Ϯ 26Ϯ 2* 5 Ϯ 3* 10 Ϯ 3* 15 Ϯ 3*†

*p Ͻ 0.05 vs. baseline (BL). †p Ͻ 0.05 vs. preceding value. Data are presented as the mean value Ϯ SEM in percent changes compared with baseline. DOB 10, 20, 30, and 40 ϭ dobutamine at 10, 20, 30, and 40 ␮g/kg per min; ISDN ϭ isosorbide dinitrate. JACC Vol. 42, No. 9, 2003 Barbato et al. 1599 November 5, 2003:1596–601 Dobutamine and Coronary Vasomotion

Figure 4. Effect of dobutamine on luminal diameter (LD) changes in Figure 2. Effect of dobutamine (DOB) and saline on the rate–pressure group 4 (stenotic coronary arteries), group 5 (stenotic coronary arteries, Ͻ product (RPP). *p 0.05 vs. baseline (BL) for dobutamine 20, 30, and 40 pretreated with phentolamine), and group 6 (stenotic coronary arteries, ␮ ␮ g/kg per min in groups 1, 3, 4, and 6; for dobutamine 30 and 40 g/kg pretreated with L-arginine). *p Ͻ 0.05 vs. group 4. †p Ͻ 0.05 vs. group 6. Ͻ per min in group 5; and for ISDN in group 1. †p 0.05 vs. preceding value For an explanation of symbols and abbreviations, see Figure 2. in groups 1, 3, 4, 5, and 6. White boxes represent group 1 (normal coronary arteries); white circles ϭ group 2 (normal coronary arteries, but dobutamine replaced by saline); blue diamonds ϭ group 3 (mildly In group 4 patients (with angiographically significant ste- atherosclerotic coronary arteries); black triangles ϭ group 4 (stenotic nosis), apart from transient, minor vasoconstriction occur- ϭ coronary arteries); white triangles group 5 (stenotic coronary arteries, ring at 10 ␮g/kg per min, no significant vasomotion was pretreated with phentolamine); blue triangles ϭ group 6 (stenotic coronary arteries, pretreated with L-arginine). observed. A significant increase in LD after ISDN could be detected. In group 5 patients (with angiographically signif- LD. In group 3 patients (mildly irregular coronary arteries), icant stenosis), no changes in LD were observed after IC a significant dose-dependent increase in LD was observed administration of phentolamine (change in LD of 1 Ϯ 1% during infusion of dobutamine. Yet, this increase was vs. baseline; p ϭ NS). However, after alpha-blockade, the significantly blunted as compared with group 1. Neverthe- infusion of dobutamine induced dose-dependent vaso- less, administration of ISDN resulted in a similar increase in dilation similar to that observed in normal arteries. Finally, LD as compared with the two previous groups. The data of in group 6 patients (with angiographically significant groups 4, 5, and 6 take into account the stenosis and stenosis), no changes in LD were observed after 8 min of adjacent reference segments of the stenotic coronary artery. IC infusion of L-arginine (change in LD of Ϫ2 Ϯ 2% vs. baseline; p ϭ NS). Nevertheless, simultaneous administration of L-arginine and dobutamine was associated with improved vasodilation.

DISCUSSION The present study demonstrates that atherosclerosis is associated with a progressive loss of dobutamine-induced coronary vasodilation. However, “paradoxical” vasoconstriction, as reported in patients with atherosclerosis during various forms of stress, was not observed with dobutamine. Dobutamine-induced vasodilation in patients with severe atherosclerosis is partially improved by pretreatment with L-arginine, an NO precursor, and fully restored by phentol-

amine, an alpha1- and alpha2-receptor blocker. Effects of dobutamine in normal coronary arteries. Our data show that high-dose dobutamine induces a dose- dependent dilation of the normal coronary arteries, similar to intracoronary nitrates. The vasomotor response to dobutamine in group 1 is the consequence of direct and indirect Figure 3. Effect of dobutamine on luminal diameter (LD) changes in mechanisms: dobutamine causes vasodilation by direct group 1 (normal coronary arteries), group 3 (mildly atherosclerotic coronary arteries), and group 4 (stenotic coronary arteries). *p Ͻ 0.05 vs. group stimulation of alpha1-, beta1-, and beta2-adrenergic recep- 1. For an explanation of symbols and abbreviations, see Figure 2. tors of the coronary vascular wall (12–14). Coronary beta- 1600 Barbato et al. JACC Vol. 42, No. 9, 2003 Dobutamine and Coronary Vasomotion November 5, 2003:1596–601 adrenergic relaxation is partly mediated by NO release dobutamine is not due to vessel stiffness, and that the activation both in conductance (15) and resistive vessels vascular smooth muscle cell component of the coronary wall (16). However, Ghaleh et al. (17) reported that the vascular is still working, allowing the diseased vessel to be responsive smooth muscle cell component of beta-receptors is the main to constrictive or dilatory stimulation. regulator of epicardial coronary vasomotion, and endothe- Role of the coronary endothelium. Progressive endothelium plays only an indirect role by enhancing the vasodila- lial dysfunction could contribute to the loss of vasodilatory tion via a flow-mediated mechanism. Of note, the distribu- response to dobutamine. This can be related to the impair- tion of beta-adrenergic receptors on coronary vascular wall is ment of both the endothelial beta-adrenergic receptor com- heterogeneous, as beta1-adrenergic receptors are crucial in ponent and the flow-mediated component of dobutamine- the regulation of coronary vasomotion in epicardial coronary induced vasodilation. In fact, pretreatment with the NO arteries, whereas beta2-adrenergic receptors become more precursor L-arginine of the stenotic coronary arteries im- important in the regulation of resistance coronaries (16,17). proved coronary vasodilation to dobutamine, yet did not In addition, dobutamine, by increasing contractility and fully restore it. myocardial oxygen consumption (18), leads to a release of Effects of alpha-receptor blockers. Several studies have vasodilatory substances such as adenosine, which acts on suggested that paradoxical epicardial vasoconstriction in the epicardial arteries and microvasculature (19). Finally, do- presence of atherosclerosis is mediated by an unmasked butamine, by increasing the heart rate, induces flow- alpha-adrenergic vasoconstriction (22,28,29). In patients mediated epicardial vasodilation (7). with normal coronaries, no significant resting alpha- Interestingly, other stress stimuli, including physical ex- adrenergic tone has been found (13). Mildly atherosclerotic ercise, cold pressor testing, atrial pacing, and mental stress, coronary arteries exhibit a more pronounced vasoconstric- induce vasodilation of normal coronaries, mainly via a tion to the selective alpha1-agonist phenylephrine. The flow-mediated mechanism (6–8). latter is paralleled by a vasoconstriction to acetylcholine, Epicardial vasomotion in atherosclerosis. In contrast, in suggesting that endothelial dysfunction is responsible for patients with atherosclerosis, the latter stimuli were shown the alpha-adrenergic hyper-responsiveness (23). Accord- to induce paradoxical vasoconstriction, presumably due to ingly, vasoconstriction in response to the cold pressor test unopposed alpha-adrenergic vasoconstriction (20–23). The (28), exercise (29), or smoking (22) was abolished by exercise-induced dilation of normal arteries is attenuated nonselective alpha- or selective alpha1-blockers in patients already at early stages of atherosclerosis in the presence of with coronary artery disease. hypercholesterolemia (24) and hypertension (25) and with Our data demonstrate that the blunted vasodilatory smoking (26). In the setting of angiographically docu- response to dobutamine is also the consequence of enhanced mented coronary atherosclerosis, exercise is typically asso- alpha-adrenergic receptor tone. In patients with docu- ciated with vasoconstriction (8). Likewise, cold pressor mented coronary stenosis, alpha-blockade, at dosages that testing and atrial pacing were characterized by a reversal of evoke mainly a local effect (9), restored vasomotion in vasodilation to vasoconstriction with increasing severity of severely diseased coronary segments. coronary atherosclerosis (6,7). Furthermore, mental stress Clinical implications. Several studies have suggested that and smoking have been demonstrated to have a similar the sensitivity of exercise echocardiography was superior to vasoconstrictive response in atherosclerotic coronaries that of DSE (30,31). This might be related to a higher level (22,27). of oxygen consumption reached by physical exercise. In Our data suggest a progressive abolition of dobutamine- addition, as suggested by the present data, it might be induced coronary vasodilation as a function of the severity of related to the exercise-induced vasoconstriction that is not atherosclerosis. In contrast to what is observed during observed during dobutamine. Finally, the concomitant physical exercise, paradoxical vasoconstriction was not ob- treatment with alpha-blockers of patients undergoing DSE served during high doses of dobutamine, not even in could further contribute to false-negative results. patients with angiographically significant stenoses. The Study limitations. Some of the variables that might influ- small constriction at the lowest dose of dobutamine could be ence the inter- and intra-individual vascular response to explained by a local vascular response through the alpha- dobutamine have not been addressed in the present study. adrenergic receptor stimulation, as supported by the fact Concomitant medical therapy, even though mostly with- that this constriction is turned into a dilation after alpha- drawn 36 h before, might have influenced the vasomotor blockade (group 5). It can be speculated that a dynamic response to dobutamine. In particular, drugs like ACE equilibrium between vasoconstrictive forces (alpha- inhibitors and statins, which improved the endothelial adrenergic receptors, endothelial dysfunction) and vasodila- function, could enhance the vasodilation to dobutamine. tory forces (beta-adrenergic receptors, both vascular and However, in the groups of patients with stenotic coronary cardiac) is responsible for the absence of vasoconstriction arteries (groups 4, 5, and 6), no significant differences were during high-dose dobutamine. The significant additional observed concerning concomitant drug categories. vasodilation induced by IC nitrates (group 4, stenotic Diurnal variations of the endothelial vasomotor response arteries) suggests that the absence of vasomotion during have been reported (32,33). In particular, coronary seg- JACC Vol. 42, No. 9, 2003 Barbato et al. 1601 November 5, 2003:1596–601 Dobutamine and Coronary Vasomotion ments with dysfunctional endothelium showed a hyper- 11. 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