Effect of Coronary Artery Bypass Surgeryon Myocardial Perfusion and Ejection

Fraction Response to InotropicStimulation in Patients Without

Improvement in Resting Ejection FractionAbdou Elhendy, MD, PhD, Jan H. Cornel, MD, PhD, Ron T. van Domburg, PhD,

Jeroen J. Bax, MD, PhD, and Jos R.T.C. Roelandt, MD, PhD

The aim of this study was to assess the effect of coronaryartery bypass grafting (CABG) on myocardial perfusionand left ventricular (LV) contractile reserve in patientswith reduced ejection fraction (EF). We studied 57 pa-tients (age 59 6 8 years, 46 men and 11 women) withEF <40% referred for CABG with dobutamine (up to 40mg/kg/min) stress-reinjection thallium-201 single-pho-ton emission computed tomography, and radionuclideventriculography at rest and at low-dose dobutaminebefore and 3 months after CABG. An increase in restingEF >5% occurred in 12 patients (group A) after CABG (EF34% before and 46% after CABG), whereas no increaseoccurred in the remaining 45 patients (group B) (EF 34%before and 32% after CABG). A significant increase in EFfrom rest to low-dose dobutamine radionuclide ventricu-lography occurred before and after CABG. The magni-tude of increase was more significant after than before

CABG in group A (12% vs 7%) as well as in group B(13% vs 7%, both p <0.001). Patients in both groupshad a significant reduction in stress, rest, and ischemicperfusion scores after CABG. However, the percentageof reduction in resting perfusion defect score was moresignificant in group A than in group B (60% vs 30%,respectively, p <0.01). It is concluded that CABG in-duces a significant improvement in resting myocardialperfusion and EF response to inotropic stimulation, evenin the absence of improved EF at rest. Patients withoutimprovement in resting EF after CABG have mild im-provement in resting myocardial perfusion that may besufficient to increase EF after CABG during inotropicstimulation, but not at rest. We describe the myocardiumwith these characteristics as “the reactive myocardium.”Q2000 by Excerpta Medica, Inc.

(Am J Cardiol 2000;86:490–494)

Coronary artery bypass grafting (CABG) results inimprovement of symptoms, an increase in ejection

fraction (EF), and prolongation of survival in a certainsubset of patients with coronary artery disease and leftventricular (LV) systolic dysfunction.1–8 Previousstudies have used resting LV function as a gold stan-dard for evaluating the outcome of LV myocardiumand for determining the accuracy of various tech-niques employed in assessing myocardial viability.2–13

However, few data are available regarding the con-tractile reserve of the LV myocardium after successfulrevascularization. So far, most of the studies thatinvestigated the effects of CABG on the LV myocar-dium focused on changes in regional and global func-tion as an end point, and little attention was paid to thechanges in myocardial perfusion after revasculariza-tion. The aims of this study were: (1) to assess theeffect of CABG on rest and stress-induced myocardialperfusion abnormalities, as evaluated by dobutamine-

reinjection thallium-201 single-photon emission com-puted tomography, in patients with chronic LV dys-function and reduced EF; and (2) to study the effect ofCABG on LV contractile reserve as assessed by EFresponse to low-dose dobutamine.

METHODSStudy patients: The study was prospectively con-

ducted to evaluate myocardial perfusion and functionand EF response to inotropic stimulation before andafter CABG in patients with chronic LV dysfunctionreferred for CABG. The results of the tests were notused to make the decision of revascularization. Thehospital ethics committee approved the protocol ofthis study. All patients gave informed consent to un-dergo dobutamine thallium imaging and radionuclideventriculography at rest and during low-dose dobut-amine infusion before and 3 months after CABG. Ifadministered,b-blocking agents were discontinued 2days before perfusion and ventriculographic studies.Selection criteria for this study were: (1) LVEF#40%at rest; (2) absence of acute myocardial infarction inthe last 6 months; (3) complete revascularization ofcoronary arteries with significant stenosis; (4) absenceof perioperative infarction; and (5) completion of do-butamine stress thallium testing and ventriculographicstudies before and after CABG. Fifty-seven patientsfulfilled these criteria.

From the Thoraxcenter, Rotterdam, The Netherlands; and the Divisionof Cardiovascular Diseases and Internal Medicine, Mayo Clinic,Rochester, Minnesota. This study was supported in part by the Depart-ment of Cardiology, Cairo University Hospital, Cairo, Egypt. Manu-script received January 24, 2000; revised manuscript received andaccepted March 21, 2000.

Address for reprints: Abdou Elhendy, MD, PhD, Mayo Clinic,Plummer Building A1, 200 First Street SW, Rochester, Minnesota55905. E-mail: Elhendy.Abdou@mayo.edu.

490 ©2000 by Excerpta Medica, Inc. All rights reserved. 0002-9149/00/$–see front matterThe American Journal of Cardiology Vol. 86 September 1, 2000 PII S0002-9149(00)00999-1

Dobutamine stress test: Dobutamine was infusedthrough the antecubital vein starting at a dose of 5followed by 10mg/kg/min (3-minute stages), increas-ing by 10mg/kg/min every 3 minutes to a maximumof 40 mg/kg/min. Atropine (up to 1 mg) was given topatients not achieving 85% of age-predicted maximalheart rate.13,14

Thallium-201 imaging: The test was performed at amean of 10 days before and 90 days after CABG.Myocardial perfusion was assessed using the dobut-amine stress-reinjection technique described previous-ly.13,14Approximately 1 minute before termination ofthe dobutamine stress test, an intravenous dose of 74MBq of thallium-201 was administered. The acquisi-tion of stress single-photon emission computed tomo-graphic images was started immediately after the test.For the reinjection studies, imaging was acquired 4hours after the stress test (20 minutes after the rein-jection of 37 MBq of 201 thallium). For each study 6oblique (short-axis) slices from the apex to the baseand 3 sagittal (vertical long-axis) slices from the sep-tum to the lateral wall were defined. Each of the 6short-axis slices was divided into 8 equal segments.The interpretation of the scan was performed by visualanalysis assisted by the circumferential profiles anal-ysis. All tomographic views were reviewed in side-by-side pair by an experienced observer who wasunaware of the patients’ clinical or angiographic data.A reversible perfusion defect was defined as a perfu-sion defect on stress images that partially or com-pletely resolved at reinjection images in$2 contigu-ous segments or slices. This was considered diagnos-tic of ischemia. A fixed perfusion defect was definedas a perfusion defect on stress images in$2 contig-uous segments or slices that persist on reinjectionimages. For visual quantification of perfusion, 6 majormyocardial segments were identified: anterior, infe-rior, septal anterior, septal posterior, posterolateral,and apical. Each of the 6 major LV segments wasscored using a 4-grade score method (05 normal, 15slightly reduced, 25 moderately reduced, 35 se-verely reduced or absent uptake). Perfusion score wasderived by the summation of the score of the 6 myo-cardial segments. Ischemic score was obtained bysubtracting rest (reinjection) from stress score. Rest(fixed perfusion defect) score was considered as in-farction score.14 To assess perfusion defect size quan-titatively, perfusion defect score was calculated by

measuring the area between thelower limit of normal values (6 2SDs) and the actual circumferentialprofile of the patient at reinjectionand stress images. Ischemic perfu-sion score was derived by subtract-ing rest from stress score in segmentswith reversible defects.14

Multigated radionuclide ventricu-lography: The study was performedwithin 4 days from the dobutaminestress test before and after CABG.Radionuclide ventriculography wasperformed at rest in the 45° left an-

terior oblique view after in vitro labeling of the redblood cells with 15 mCi (540 MBq) of technetium-99m. Acquisition was performed during a 6-minuteperiod with a Siemens (Orbiter, Siemens Corp., Iselin,New Jersey) gamma camera equipped with a low-energy, all-purpose collimator. The data were pre-sented with standard software and background correc-tion, and LVEF was computed from end-systolic andend-diastolic images at rest as previously described.15

Dobutamine was then infused through the antecubitalvein starting at a dose of 5mg/kg/min for 5 minutes.Image acquisition was repeated after 5 minutes anddobutamine infusion was continued. The dose of do-butamine was then increased to 10mg/kg/min for 5minutes and another acquisition was performed withcontinuation of dobutamine infusion.

Statistical analysis: Unless specified, data are pre-sented as mean values6 SD. The chi-square test wasused to compare differences between proportions. TheStudent’st test was used for analysis of continuousdata. A p value,0.05 was considered statisticallysignificant.

RESULTSClinical features: The study included 46 men and 11

women (mean age was 596 8 years). All patients hada previous myocardial infarction. Mean time after theinfarction was 4.26 4.4 years. Ten patients hadnon–Q-wave and 47 patients had Q-wave infarction,which was anterior (or anterolateral) in 20 patients,inferior (or inferolateral) in 17 patients, and anteriorand inferior in 10 patients. Before CABG, 52 patientshad typical angina, whereas the remaining 5 patientshad atypical chest pain or anginal equivalent symp-toms. Angiotensin-converting enzyme inhibitors wereadministered to 40 patients (70%) before and to 37(65%) after CABG. Calcium channel blockers wereadministered to 20 patients (35%) before and to 11(19%) after CABG.

Dobutamine stress test: No patient had myocardialinfarction or worsening of symptoms during the studyperiod. Table I lists the hemodynamics, symptoms,and electrocardiographic changes during dobutaminestress testing before and after CABG. The prevalenceof angina and ST-segment depression was markedlyreduced after CABG. Resting heart rate and peakrate-pressure product did not differ before and afterCABG. A modest but significant increase in peak

TABLE I Hemodynamic Data of Dobutamine Stress Test Before and After CABG

Before CABG After CABG p Value

Rest heart rate 70 6 12 72 6 13 0.5Stress heart rate 139 6 15 143 6 12 0.03Rest systolic blood pressure 127 6 20 128 6 21 0.7Stress systolic blood pressure 126 6 26 126 6 27 0.9Stress rate-pressure product 17,319 6 3,973 18,120 6 4,056 0.5Dobutamine dose (mg/kg/min) 35.8 6 7.4 36.7 6 6.1 0.5Atropine given (pts.) 17 (30%) 15 (26%) 0.4Target heart rate reached (pts.) 40 (70%) 45 (79%) 0.8Angina during the test (pts.) 40 (70%) 2 (4%) 0.0001ST-segment depression (pts.) 21 (37%) 2 (4%) 0.0001

CORONARY ARTEY DISEASE/MYOCARDIAL PERFUSION AND FUNCTION AFTER CABG 491

stress heart rate occurred after CABG. In the 20 pa-tients who gave consent to undergo follow-up coro-nary angiography, no significant graft stenosis or newlesions distal to the grafts or in nongrafted arterieswere detected.

Dobutamine thallium-201 imaging: Dobutaminestress and resting myocardial perfusion defect scoresbefore and after CABG are listed in Table II. Therewas a significant reduction in rest, stress, and revers-ible perfusion defect scores after CABG by visual andcircumferential profile analysis.

Ejection fraction at rest and at low-dose dobutamine:In the entire group, there was no significant change inmean resting EF after CABG (Table III). An increasein resting EF$5% occurred in 12 patients (21%) afterCABG (group A), whereas no such increase was seenin the remaining 45 patients (group B). No angina orST-segment depression occurred during low-dose do-butamine radionuclide ventriculography before or af-ter CABG. A significant increase in EF from rest tolow-dose dobutamine occurred before and afterCABG. However, the magnitude of increase was moresignificant after than before CABG.

Comparison of patients with and without improve-ment in resting ejection fraction: Before CABG, pa-tients in group A had a lower rest defect score byvisual and quantitative analysis (Table II). Patients inboth groups had a significant reduction in stress, rest,and ischemic scores after CABG by visual and quan-titative analysis. However, the percentage of reduc-tions in resting perfusion defect score was more sig-nificant in group A than in group B (38% vs 19% byvisual analysis and 60% vs 30% by quantitative anal-ysis, respectively, p,0.01 for both). Patients in bothgroups had a significant increase in EF during low-

dose dobutamine-radionuclide ventriculography be-fore and after CABG. However, the magnitude ofincrease in EF during low-dose dobutamine was moresignificant after than before CABG (Table III). Therewas no significant difference between both groupsregarding the magnitude of improvement in EF re-sponse to low-dose dobutamine after CABG.

DISCUSSIONOur study demonstrated that in patients with

chronic LV dysfunction referred for CABG, restingmyocardial perfusion greatly improves after revascu-larization as demonstrated by a 34% reduction in theperfusion defect score at rest using quantitative anal-ysis of thallium-201 tomographic images. Althoughthe mean EF at rest did not improve significantly afterCABG in the entire group, EF response to inotropicstimulation increased as demonstrated by a 13% in-crease in EF at low-dose dobutamine radionuclideventriculography after CABG compared with 7% be-fore CABG. An improvement in resting EF$5% afterCABG occurred in 21% of patients. The increase inEF response to low-dose dobutamine was equallyachieved in patients with and without improvement inresting EF after CABG. Improvement in resting myo-cardial perfusion was greater among patients who hadan increased EF at rest than those who did not (60% vs30%). From these findings, it appears that a markedimprovement in myocardial perfusion as a conse-quence of revascularization is required before an im-provement in resting EF could be observed.

Previous studies have demonstrated that CABGimproves survival in patients with multivessel coro-nary artery disease and reduced EF.1–3 Possible con-tributing factors are improvement in resting LV func-

TABLE II Myocardial Perfusion Abnormalities Assessed by Dobutamine Stress and Reinjection (rest) Thallium-201 TomographyBefore and Three Months After CABG in Patients With (group A) and Without (group B) an Increase in Resting EF $5% AfterCABG

Defect Scores

All Patients Group A Group B

Before After p Value Before After p Value Before After p Value

VisualStress 10.4 6 4.2 5.9 6 4.4 ,0.0001 9.4 6 4.1 3.4 6 3.8 ,0.001 10.6 6 4.4 6.5 6 4.5* ,0.001Rest 6.4 6 3.1 5 6 3.2 ,0.005 4.2 6 2.3 2.6 6 2.3 ,0.01 6.9 6 3.3* 5.6 6 3.4† ,0.05Reversible 4 6 2.9 0.9 6 0.8 ,0.0001 5.2 6 3.0 0.8 6 0.7 ,0.001 3.7 6 2.8 0.9 6 0.8 ,0.001

QuantitativeStress 3,077 6 1,350 1,441 6 850 ,0.0001 2,802 6 1,010 826 6 546 ,0.001 3,150 6 1,445 1,607 6 1,009* ,0.001Rest 1,829 6 1,050 1,204 6 830 ,0.001 1,331 6 893 536 6 721 ,0.001 1,962 6 1,123* 1,382 6 897† ,0.01Reversible 1,248 6 840 237 6 205 ,0.0001 1,471 6 756 290 6 210 ,0.001 1,188 6 875 225 6 198 ,0.001

*p ,0.05; †p ,0.01 versus group A.

TABLE III EF at Rest and at Low-Dose Dobutamine (LDD) as Assessed by Radionuclide Ventriculography Before and After CABG inPatients With (group A) and Without (group B) Increase in Resting EF $5% After CABG

EF

All Patients Group A Group B

Before After p Value Before After p Value Before After p Value

Rest 34 6 11 35 6 9 0.6 34 6 11 46 6 9 ,0.001 34 6 11 32 6 9 0.07LDD 41 6 13 48 6 12 ,0.0001 41 6 12 58 6 13 ,0.01 41 6 13 45 6 11 ,0.01LDD at rest 7 6 6 13 6 7 ,0.0001 7 6 8 12 6 7 ,0.001 7 6 5 13 6 7 ,0.001

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tion and amelioration of ischemia. However, improve-ment in resting function was shown in most of thestudies to be modest, and often involved segmentalrather than global function. Therefore, other mecha-nisms may additionally play a role in the improvedsurvival and functional status after CABG. This studydemonstrates that in addition to the marked reductionin ischemia, improvement in resting perfusion alsooccurs. This improvement can potentially have animpact on structural and functional properties of themyocardium, even if resting function did not improve.Improvement in perfusion may be associated withmore favorable remodeling or may contribute to theprevention of arrhythmia after CABG as suggestedrecently by Beller10 and Bonow.11 An important find-ing in our study that supports this hypothesis is thesignificant improvement in EF response to low-dosedobutamine after CABG. This finding indicates thatimprovement in resting perfusion may be coupledwith structural changes that render the myocardiummore responsive to inotropic stimulation. Lee et al16

demonstrated that contractile response to dobutaminedepends on the level of myocardial blood flow at restand during inotropic stimulation. Melon et al17 andSawada et al18 reported similar findings. Our studysupports this conclusion since both resting myocardialperfusion and EF response to dobutamine improvedafter CABG.

Contractile reserve after CABG: The improvement incontractile response to inotropic stimulation despitethe absence of improvement in the mean resting EFafter CABG may be explained by partial recovery ofperformance characteristics of the LV myocardium,which is manifest during inotropic stimulation but notsufficient to demonstrate improvement in function atrest. We describe the myocardium with such charac-teristics as “the reactive myocardium,” because thedefinition of myocardial hibernation and stunning donot apply in this case. It has been suggested that theabsence of improvement in resting function afterCABG in some segments identified as viable shouldnot always be considered as a false-positive diagnosisof viability, because an increased thickening afterrevascularization may be hindered by adjacent scarredsegments.10 Viable reperfused myocardium may over-come these confounding mechanisms only during ino-tropic stimulation. Some of the previous studies havefound a discrepancy between the diagnosis of myo-cardial viability and recovery of function.10–13,19,20

Therefore, some investigators stated that the definitionof myocardial viability should not be recognized asthe analog for functional recovery, since some myo-cardial regions may retain metabolic evidence of via-bility after revascularization without actual change inresting function.10–12

Another explanation for our findings is that thepresence of severe ischemia impairs the increase inEF during low-dose dobutamine before but not afterCABG.21 Bonow11 recently suggested that someregions with hibernating myocardium are so deli-cately balanced between the reduction in flow andfunction, with exhausted coronary flow reserve, that

any catecholamine stimulation will result in isch-emia and inability to enhance contractile function.Afridi et al22 reported that in patients with LVdysfunction studied with dobutamine echocardiog-raphy before and after coronary angioplasty, thosewithout recovery of resting function have improvedfunction during dobutamine echocardiography, par-ticularly when there was evidence of ischemia be-fore revascularization. Similar findings were re-ported by Lombardo et al.23 Improvement in EFresponse to low-dose dobutamine after CABG with-out improvement in resting EF could possibly be amanifestation of myocardial stunning induced bythe operative procedure.24 The time course for suchmyocardial stunning is not clearly defined. Finally,CABG may have improved the delivery of dobut-amine to myocardial tissues, with subsequent im-provement in EF response to dobutamine. In thiscase, such increase of dobutamine delivery to myo-cardial tissues may translate into improvement inmyocardial response to circulating catecholaminesduring exercise after CABG or improved responseto dobutamine in patients who may require inotro-pic support. The improvement of contractile reserveafter CABG may precede a late improvement inresting function. Its persistence may translate intobetter ventricular remodeling or improvement infunctional capacity. Bonow has recently indicatedthat the apparently low specificity of current tech-niques used in evaluating myocardial viabilityshould be reexamined against end points other thanimprovement in resting LV function alone becausethe latter may not be the only benefit of revascular-ization of viable myocardium.11,12 The investigatorsuggested that even in the absence of improved LVsystolic function, revascularization might provideclinical benefit by attenuation of LV dilatation andremodeling, reducing the risk of arrhythmia andfatal ischemic events.

Samady et al25 recently reported that the lack ofimprovement of global LVEF after CABG is not as-sociated with power outcome compared with that ofpatients with improved LVEF, presumably becauseeffective revascularization of ischemic myocardium,even without improvement in ventricular function,protects against future infarction and death. The re-sults of our study provide further explanation of theirfindings because patients without improvement inresting EF had a 30% improvement in resting perfu-sion and a marked increase in EF response to low-dosedobutamine after CABG.

Evidence of the reactive myocardium:. Our datademonstrated that in addition to the hibernating andthe stunned myocardium, another category of the vi-able myocardium may exist. We describe this as thereactive myocardium, defined as the myocardium thatdemonstrates improvement in perfusion and responseto inotropic stimulation without improvement in rest-ing function after revascularization. Further studiesare required to investigate the prognostic significanceof these findings.

CORONARY ARTEY DISEASE/MYOCARDIAL PERFUSION AND FUNCTION AFTER CABG 493

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