A Comparative Study of Different Pharmacological Stress

C 2009,the AuthorsJournal compilation C 2009,Wiley Periodicals,Inc.DOI:10.1111/j.1540-8175.2008.00853.xWhich Protocol for Which Segment:A Comparative Study of Different Pharmacological Stress Echocardiography Protocols for Predicting Viability in Segments with Varying Degrees of DyssynergyZainab Abdel-Salam,M.D.and Wail Nammas,M.D.Department of Cardiology,Faculty of Medicine,Ain Shams University Hospitals,Ain Shams University,Cairo,EgyptObjective:Pharmacological stress echocardiography is widely accepted for identifying potential con-tractile recovery after revascularization.We sought to compare the prognostic power of three phar-macological stress protocols for predicting contractile recovery of myocardial segments at varying degrees of dyssynergy.Methods:We enrolled100consecutive patients with significant coronary steno-sis amenable for revascularization and regional wall motion abnormality in the distribution of the affected artery.All patients underwent an assessment of regional wall motion according to the stan-dard16-segment model.The patients underwent three stress echocardiography protocols in separate sessions:low-dose dobutamine,infra-low-dose dipyridamole,and combined protocol.The patients underwent thereafter coronary revascularization either by percutaneous coronary angioplasty or by surgical bypass grafting.A follow-up echocardiography was performed8weeks after revasculariza-tion to assess regional wall motion abnormality.The predicted recovery by any of the three protocols for each category of segments was compared with actual contractility improvement.Results:The combined protocol had a significantly higher sensitivity for predicting contractility recovery in all segment categories compared with the other two protocols.In addition,it had a similar specificity in hypokinetic and dyskinetic segments,though with a lower specificity in akinetic segments when com-pared with the low-dose dobutamine protocol,and a similar specificity in dyskinetic segments,though with a lower specificity in hypokinetic and akinetic segments when compared with the infra-low-dose dipyridamole protocol.Conclusion:In patients with predominantly akinetic/dyskinetic segments,the combined pharmacological stress protocol would better predict functional recovery after revascular-ization,as compared with the low-dose dobutamine and the infra-low-dose dipyridamole protocols. (ECHOCARDIOGRAPHY,Volume26,May2009)stress echocardiography,viability,coronary artery diseaseWith the enormous progress in thefield of myocardial revascularization over the last two decades,the differentiation of viable from non-viable myocardium has acquired paramount clinical importance,particularly in patients All authors have no conflict of interest to declare. Address for correspondence and reprint requests:Wail Nammas,M.D.,Department of Cardiology,Faculty of Medicine,Ain Shams University Hospitals,Ain Shams University,Abbassia,Cairo,Egypt.Fax:+2-02-24820416; E-mail:wnammas@ considered for interventional treatment.1My-ocardial viability represents impairment in contractile function that is potentially re-versible if blood supply is adequately restored.2 Presumably,improving blood supply to dys-functional but viable regions results in sub-sequent improvement of regional and global left ventricular function,heart failure symp-toms,functional capacity,and long-term sur-vival.Thus,an important consideration is whether hypokinetic or akinetic myocardial ar-eas represent viable myocardium with criticallyABDEL-SALAM AND NAMMASendangered blood supply,or irreversibly dam-aged necrotic scar tissue.3This scenario was supported by the results of several studies where only patients with severe left ventricular dysfunction who harbored viable myocardium gained benefit from revascularization.4 Pharmacological stress echocardiography has gained wide acceptance for the identifica-tion of viable myocardium,chiefly because of its feasibility,safety,diagnostic accuracy,and prog-nostic power.5Low-dose dobutamine echocar-diography has emerged as an attractive and increasingly used method of identifying viable myocardium through its ability to elicit a beta-adrenoreceptor-mediated increase in myocar-dial thickening.Low-dose dobutamine response can accurately predict improvement of dysfunc-tional yet viable myocardial regions,and thus identify a subset of patients whose left ventric-ular function will improve following success-ful coronary revascularization.6The problem of inter-and intraobserver variability can be min-imized by stronger adherence to common and new methodological standards.7Dobutamine-responsive wall motion was found specific for predicting reversible dysfunction,but still,its sensitivity is less than ideal.8Experimental and clinical studies showed that coronary va-sodilator stress can recruit an inotropic reserve in viable segments through a newly designated infra-low-dose dipyridamole regimen that se-lectively explores myocardial viability and has virtually no ischemic potential.Despite being highly specific for predicting reversible dys-function,it is still limited by unsatisfactory sensitivity.9So a theoretically attractive way of in-creasing pharmacological stress echocardiog-raphy sensitivity would be the combination of infra-low-dose dipyridamole and low-dose dobutamine.The two agents act by different—but potentially synergic—mechanisms to re-cruit inotropic reserve in dyssynergic but viable segments.10Combined infra-low-dose dipyri-damole and low-dose dobutamine regimen is gaining increasing acceptance because of its ex-cellent tolerability,low cost,widespread avail-ability,and no radiation involvement,be-sides its superior diagnostic accuracy compared with either forms of stress administered sep-arately.10In a prospective study design,we sought to compare the diagnostic accuracy of the three pharmacological stress protocols for predicting functional recovery after revascular-ization of myocardial segments at varying de-grees of dyssynergy.Patients and Methods PopulationWe included100consecutive patients re-ferred from our catheterization laboratories with significant coronary stenosis during the period from January2004to December2007. The patients were considered eligible for in-clusion if they had regional wall motion ab-normality in the anatomical distribution of the affected artery,as explained later,an affected artery amenable for revascularization,and ev-idence of prior myocardial infarction.Signifi-cant coronary stenosis was defined as at least 70%luminal obstruction of at least one sizable coronary artery(measuring2.5mm or more in diameter),seen in two different projections, or at least50%luminal obstruction of the left main coronary artery.Prior myocardial infarc-tion was defined based on a12-lead electrocar-diogram showing abnormal Q-waves(≥1mm in width)in at least two contiguous leads or labo-ratory evidence of elevated cardiac biomarkers: creatine kinase MB fraction(CK MB)and/or troponin more than twice the upper limit of nor-mal laboratory reference.We excluded patients with postinfarction unstable angina or severe hemodynamic instability,protruding fresh left ventricular thrombus,significant valvular or congenital heart disease,any myocardial dis-ease apart from ischemia,contraindication to dobutamine(e.g.,history of complex ventric-ular arrhythmias and uncontrolled hyperten-sion with blood pressure>180/110),contraindi-cation to dipyridamole(e.g.,bronchial asthma and second-or third-degree heart block),and patients with limited life expectancy due to co-existent disease(e.g.,malignancy).Before in-clusion,an informed consent was obtained from each patient,and the study protocol was re-viewed and approved by our local institutional human research committee,as it conforms to the ethical guidelines of the1975Declaration of Helsinki.Definitions of Risk FactorsThe presence of hypertension was defined as systolic blood pressure≥140mmHg and/or di-astolic blood pressure≥90mmHg,previously recorded by repeated noninvasive office mea-surements,which lead to lifestyle modification or antihypertensive drug therapy.The pres-ence of diabetes mellitus was defined as fast-ing plasma glucose≥126mg/dl,2-hour post-glucose load≥200mg/dl,or specific antidiabeticSTRESS ECHOCARDIOGRAPHY AND VARYING DYSSYNERGYdrug therapy.Dyslipidemia was defined as LDL cholesterol>100mg/dl,serum triglycerides >150mg/dl,and/or HDL and/or cholesterol<40 mg/dl in men and<50mg/dl in women. MethodsThe assessment of regional and global left ventricular systolic function was performed in all patients by transthoracic echocardiography within48hours of admission.Doppler echocar-diography was performed using a Hewlett Packard Sonos5500cardiac ultrasound ma-chine(Hewlett Packard,Andover,MA,USA) equipped with harmonic imaging capabilities. A2.5-MHz phased array probe was used to ob-tain standard two-dimensional,M-mode,and Doppler images.The patients were examined in the left lateral recumbent position using standard parasternal and apical views.The im-ages were digitized in cine-loop format and saved for subsequent playback and analysis. The views were analyzed by a single echocar-diographer employing the software program of the echocardiography machine.Global left ventricular systolic function was assessed in apical four-chamber view using the modified Simpson’s rule.Regional wall motion was as-sessed according to the standard16-segment model recommended by the American Society of Echocardiography.11Individual segments were then subgrouped based on the known vascu-lar distribution into left anterior descending territory,left circumflex territory,right coro-nary artery territory,and overlap segments.11 Regional wall motion was visually assessed for each segment individually,considering both endocardial excursion and systolic thickening, and each segment was graded according to the semiquantitative scoring system described by Knudsen et al.12Segments with poorly de-fined endocardial borders for50%or more of their length were considered nonvisualized and assigned a score of0.13Wall thicken-ing was assessed at a distance of at least 1cm from the adjacent segment to minimize the effect of tethering.14Wall motion in a vascular territory was considered abnormal if wall thick-ening was abnormal in at least two contiguous nonoverlap segments.11Wall motion score in-dex was derived by dividing the sum of indi-vidual segment scores by the number of inter-pretable segments.Stress Echocardiographic ProtocolsThe patients underwent the following stress echocardiographic protocols in separate ses-sions:1.Low-dose dobutamine:dobutamine wasinfused starting at5μg/kg/min,and thenincreased to10μg/kg/min in3-minutestages.2.Infra-low-dose dipyridamole:dipyri-damole was given intravenously at a doseof0.28mg/kg over4minutes.bined protocol:infra-low-dose dipyri-damole was given,immediately followedby low-dose dobutamine infusion as before. Standard views were recorded at baseline, during each stage of the infusion protocol,as well as during recovery.Visual assessment of wall motion and thickening was performed by the same echocardiographer as before.Global left ventricular systolic function and wall mo-tion score index were evaluated at rest and at the end of each stage.Viability was defined by improvement of regional wall motion score by at least one grade in at least two contiguous nonoverlap segments along with at least20% reduction in global wall motion score index com-pared with baseline evaluation.14Our stress test protocols were performed with the patients on their full anti-ischemic and antifailure medications,and before infra-low-dose dipyridamole,all caffeine beverages and theophylline-containing preparations were stopped for at least24hours.Coronary RevascularizationAll patients underwent coronary revascular-ization either by percutaneous coronary angio-plasty or by surgical bypass grafting,according to the operator’s decision.The operator’s de-cision was based on the clinical presentation, coronary anatomy,and evidence of ischemia, but not on the presence or absence of contrac-tile reserve by any of the stress test protocols. Echocardiographic Follow-UpA follow-up echocardiographic reassessment was performed(by the same operator)8weeks after revascularization to evaluate regional and global left ventricular systolic function,asABDEL-SALAM AND NAMMASTABLE IBaseline Clinical,Echocardiographic,and AngiographicCharacteristics of the Study GroupsStudy Cohort (n =100)Age (years)52.6±8.8Males 85(85)Smoking 77(77)Diabetes33(33)Hypertension 50(50)Dyslipidemia 75(75)FH of IHD 23(23)Infarction site Anterior 52(52)Inferior 40(40)Lateral 8(8)Echo data LV EF 38.5±8.1WMSI2.04±0.38Mitral regurgitation 33(33)Angiographic data SVD 37(37)DVD 28(28)MVD35(35)All continuous variables are presented as mean ±SD,whereas categorical variables are presented as numbers (percentage).FH =family history;IHD =ischemic heart disease;LV EF =left ventricular ejection fraction;WMSI =wall motion score index;SVD =single-vessel disease;DVD =double-vessel disease;MVD =multivessel disease.described before.The viability was defined as before.Significant improvement of global left ventricular systolic function was defined as a 5%or more increase in the ejection fraction at follow-up compared with baseline evalua-tion.During follow-up,the patients were inter-rogated for the occurrence of new myocardial infarction or congestive heart failure by clinical visits,telephone calls,hospital chart reviews,or personal communication with the referring physician.TABLE IISensitivity ,Specificity ,Positive and Negative Predictive Values,and Diagnostic Accuracy of the Three PharmacologicalStress Echocardiography Protocols for Predicting Recovery of Basally Dyssynergic Segments Stress ProtocolSensitivitySpecificity PPV NPV Accuracy Low-dose dobutamine76%94%96%67%82%Infra-low-dose dipyridamole 72%97%98%64%80%Combined protocol95%87%94%90%92%Statistical AnalysisAll continuous variables were presented as mean ±standard deviation (SD),if they were normally distributed.Differences in the normally distributed variables were assessed using the t -test and the paired t -test for depen-dent variables.Categorical variables were de-scribed with absolute and relative (percentage)frequencies.The sensitivity ,specificity ,positive and negative predictive values,and diagnos-tic accuracy were calculated according to the standard definitions for each of the three stress echocardiography protocols to predict viability (contractility improvement after revasculariza-tion).The segments were subdivided accord-ing to the severity of dyssynergy into three subgroups,namely ,hypokinetic,akinetic,and dyskinetic.The above statistical values were then calculated individually for each of the three stress echocardiographic protocols in each subgroup of segments.Differences between the three stress echocardiography protocols regard-ing these values were compared using the Pear-son chi-square test.Twenty cases were ran-domly selected for the analysis of intraobserver variability .An assessment of variability was performed using a linear regression analysis.A probability value of P <0.05was considered statistically significant.The analyses were per-formed with SPSS version 12.0statistical pack-age (SPSS,Inc.,Chicago,IL,USA).ResultsA total of 100consecutive patients with ev-idence of prior myocardial infarction were in-cluded in the current study who underwent coronary revascularization for significant coro-nary stenosis.The baseline characteristics of the cohort are shown in Table I.The mean age was 52.6±8.8years,85%being male.Table II shows the sensitivity ,specificity ,positive and negative predictive values,andSTRESS ECHOCARDIOGRAPHY AND VARYING DYSSYNERGYTABLE IIISensitivity ,Specificity ,Positive and Negative Predictive Values,and Diagnostic Accuracy of the Three PharmacologicalStress Echocardiography Protocols for Predicting Recovery of Basally Hypokinetic Segments Stress ProtocolSensitivitySpecificity PPV NPV Accuracy Low-dose dobutamine86%88%96%66%86%Infra-low-dose dipyridamole 82%93%97%61%85%Combined protocol98%86%96%92%95%diagnostic accuracy of the three stress echocar-diographic protocols to predict viability (con-tractility improvement after revasculariza-tion).The sensitivity of the combined protocol was significantly higher when compared with either of the other two protocols (P <0.001for each),whereas the difference was insignifi-cant between the low-dose dobutamine and the infra-low-dose dipyridamole protocols.Yet,the specificity of the combined protocol was lower when compared with either of these two proto-cols (P >0.05vs low-dose dobutamine,and P <0.05vs infra-low-dose dipyridamole).The pos-itive predictive value was similar between the three protocols;however,the negative predic-tive value of the combined protocol was signifi-cantly higher when compared with either of the other two protocols (P <0.001for both).Finally ,the diagnostic accuracy of the combined pro-tocol was significantly higher when compared with either of the other two protocols (P <0.05for both).Table III shows the sensitivity ,specificity ,positive and negative predictive values,and diagnostic accuracy of the three stress echocar-diographic protocols to predict viability (con-tractility improvement after revascularization)individually for the hypokinetic segments.The sensitivity of the combined protocol was signifi-cantly higher when compared with either of the other two protocols (P <0.05for both),whereas the difference was insignificant between the low-dose dobutamine and the infra-low-dose dipyridamole protocols.Yet,the specificity of TABLE IVSensitivity ,Specificity ,and Positive and Negative Predictive Values,and Diagnostic Accuracy of the Three PharmacologicalStress Echocardiography Protocols for Predicting Recovery of Basally Akinetic Segments Stress ProtocolSensitivitySpecificity PPV NPV Accuracy Low-dose dobutamine61%98%97%65%77%Infra-low-dose dipyridamole 58%99%99%64%75%Combined protocol91%87%91%87%89%both the low-dose dobutamine and the com-bined protocols was significantly lower when compared with the infra-low-dose dipyridamole protocol (P <0.05for both).The positive predic-tive value was similar between the three proto-cols;however,the negative predictive value of the combined protocol was significantly higher when compared with either of the other two pro-tocols (P <0.05for both).Finally ,the diagnostic accuracy of the combined protocol was signifi-cantly higher when compared with either of the other two protocols (P <0.05for both).Table IV shows the sensitivity ,specificity ,positive and negative predictive values,and di-agnostic accuracy of the three stress echocar-diographic protocols to predict viability (con-tractility improvement after revascularization)individually for the akinetic segments.The sen-sitivity of the combined protocol was signifi-cantly higher when compared with either of the other two protocols (P <0.001for both),whereas the difference was insignificant be-tween the low-dose dobutamine and the infra-low-dose dipyridamole protocols.Yet,the speci-ficity of the combined protocol was significantly lower when compared with either the low-dose dobutamine or the infra-low-dose dipyridamole protocol (P <0.05for both).Similarly ,the pos-itive predictive value of the combined protocol was significantly lower and its negative predic-tive value was significantly higher when com-pared with either of the other two protocols (P <0.05for all).Finally ,the diagnostic accuracy of the combined protocol was significantly higherABDEL-SALAM AND NAMMASTABLE VSensitivity,Specificity,and Positive and Negative Predictive Values,and Diagnostic Accuracy of the Three Pharmacological Stress Echocardiography Protocols for Predicting Recovery of Basally Dyskinetic SegmentsStress Protocol Sensitivity Specificity PPV NPV Accuracy Low-dose dobutamine60%100%100%90%91% Infra-low-dose dipyridamole40%100%100%86%87% Combined protocol100%100%100%100%100%when compared with either of the other two protocols(P<0.05for both).Table V shows the sensitivity,specificity, positive and negative predictive values,and diagnostic accuracy of the three stress echocar-diographic protocols to predict viability(con-tractility improvement after revascularization) individually for the dyskinetic segments.The sensitivity of the combined protocol was signifi-cantly higher when compared with either of the other two protocols(P<0.001for each),and the difference was also significant between the low-dose dobutamine and the infra-low-dose dipyri-damole protocols(60%vs40%,respectively,P <0.05).Yet,both the specificity and the posi-tive predictive value were similar between the three protocols(P>0.05for all).Neverthe-less,the negative predictive value of the com-bined protocol was significantly higher when compared with either of the other two protocols (P<0.05for both).Finally,the diagnostic accu-racy of the combined protocol was significantly higher when compared with either of the other two protocols(P<0.05for both).The analysis of intraobserver variability re-vealed a close correlation between repeated measurements of regional wall motion by the single operator,with a correlation coefficient r=0.92.DiscussionOur results suggest that contractile improve-ment in akinetic/dyskinetic segments in re-sponse to pharmacological stress testing is highly specific but moderately sensitive for pre-dicting functional recovery in these segments after revascularization,whereas improvement in hypokinetic segments is less specific but more sensitive.Thefinding that hypokintic segments are more likely to manifest contractile improve-ment in response to pharmacological stress testing is consistent with histopathology stud-ies showing that these segments harbor a mix-ture of scar tissue and normal and hibernat-ing myocardium in variable proportions,where fibrosis is usually minimal and myocardial vi-ability is more common.15Nevertheless,some hypokinetic segments that improved with phar-macological stress testing did not recover con-tractile function following revascularization. This coincides with the hypothesis that hypoki-netic segments may not always represent hiber-nating myocardium,but instead,they might be the result of a nontransmural infarction,leav-ing a heterogeneous mixture of necrotic and al-ready well perfused,functioning myocardium that would not further improve its contractility after revascularization.Alternatively,hypoki-netic segments may represent tethering of a severely dysfunctional region by an adjacent well-perfused,functioning segment,or might reflect an area of subendocardial scar with the overlying middle and epicardial layers of the myocardium being well perfused and well func-tioning.16These factors would contribute to a higher false-positive response rate,and conse-quently,a lower specificity for predicting func-tional recovery in hypokinetic segments follow-ing revascularization.In contrast,pharmacological stress testing demonstrated a lower sensitivity to predict via-bility in akinetic/dyskinetic segments.This can be attributed to thefinding that these segments are mostly supplied by critically stenosed or to-tally occluded coronaries with such exhausted coronaryflow reserve that even at low lev-els of pharmacological stress they fail to im-prove their contractility,despite the presence of viable myocardium that would actually im-prove its contractility after revascularization.17 Furthermore,the prediction of reversible con-tractile dysfunction in akinetic/dyskinetic seg-ments might be difficult with the standard dosage of dobutamine and the standard dura-tion of infra-low-dose dipyridamole owing to the usual presence of a large infarct size in these regions.18,19Few previous studies segregated myocardial segments according to the severity of theirSTRESS ECHOCARDIOGRAPHY AND VARYING DYSSYNERGYbaseline dyssynergy(hypokinesis,akinesis,or dyskinesis)when reporting functional recov-ery after revascularization.Yet,all of them ad-dressed the predictive accuracy of dobutamine stress echocardiography.To our knowledge,no studies to date have reported similar data for the infra-low-dose dipyridamole or the com-bined protocols.In concordance with our re-sults,many reported that the low-dose dobu-tamine protocol exhibits a higher sensitivity and lower specificity for predicting functional recovery after revascularization in hypokinetic segments as compared with akinetic ones.19–22 Our results showed a modest sensitivity for dobutamine stress echocardiography for pre-dicting functional recovery after revascular-ization of akinetic and dyskinetic segments (61%and60%,respectively).Many previous reports observed an even worse sensitivity (range from11%to47%)for predicting func-tional recovery by dobutamine stress echocar-diography in akinetic segments.17,19,23–25Fur-thermore,one study even reported a modest specificity(68%)for dobutamine stress echocar-diography in these segments.26Finally,our data showed that the combined protocol had a significantly higher sensitivity for predicting functional recovery in all seg-ment categories compared with the low-dose dobutamine protocol,in addition to a simi-lar specificity in hypokinetic and dyskinetic segments,though with a lower specificity in akinetic segments.ConclusionIn patients with predominantly akinetic and dyskinetic segments,the combined pharmaco-logical stress echocardiography protocol would offer a better diagnostic accuracy for predict-ing functional recovery after revascularization, as compared with the low-dose dobutamine and the infra-low-dose dipyridamole protocols.Limitations of the StudyOurfindings are based on a single center study with a relatively small sample size of the cohort,a fact that makes it difficult to general-ize our results to all patients undergoing risk stratification for predicting functional recov-ery after revascularization.Multicenter stud-ies using the same protocol and examining a larger number of patients are needed.More-over,the follow-up period of8weeks might have been inadequate to allow recovery of some dyssynergic but viable segments,thereby un-derestimating the specificity of the observed functional recovery.Delayed recovery can fur-ther occur in a substantial number of segments up to a median of14months following revas-cularization,a fact that warrants repeated assessment after longer periods of follow-up. Finally,follow-up coronary angiography was not done;therefore,restenosis or reocclusion cannot be definitely excluded,something that would hazard the achieved functional im-provement and again underestimate the speci-ficity.However,no patient reported any clinical events during the period from revascularization to follow-up echocardiographic evaluation.Fur-thermore,the specificity was already relatively high for all the three protocols in all segment categories.References1.Dilsizian V,Bonow RO:Current diagnostic tech-niques of assessing myocardial viability in patients with hibernating and stunned myocardium.Circula-tion1993;87(1):1–20.2.Hoffmann R:Stress echocardiography before and afterinterventional therapy.In Marwick TH(ed):Cardiac Stress Testing and Imaging.A Clinician’s Guide.New York:Churchill Livingston,1996,pp.355–367.3.Beller GA:Comparison of201Tl scintigraphy and low-dose dobutamine echocardiography for the noninva-sive assessment of myocardial viability.Circulation 1996;94(11):2712–2719.4.Jim´e nez Borreguero LJ,Ruiz-Salmer´o n R:Assessmentof myocardial viability in patients before revascular-ization.Rev Esp Cardiol2003;56(7):721–733.5.Marwick TH:Stress echocardiography.Heart2003;89(1):113–118.6.Yao SS,Chaudhry FA:Assessment of myocardial vi-ability with dobutamine stress echocardiography in patients with ischemic left ventricular dysfunction.Echocardiography2005;22(1):71–83.7.Krenning BJ,Geleijnse ML,Poldermans D,et al:Methodological analysis of diagnostic dobutamine stress echocardiography studies.Echocardiography 2004;21(8):725–736.8.Grayburn PA:Defining the threshold of myocardial vi-ability by dobutamine echocardiography.Int J Cardiol 2003;90(1):31–32.9.Varga A,Ostojic M,Djordjevic-Dikic A,et al:Infra-lowdose dipyridamole test.A novel dose regimen for selec-tive assessment of myocardial viability by vasodilator stress echocardiography.Eur Heart J1996;17(4):629–634.10.Picano E,Ostojic M,Varga A,et al:Combined lowdose dipyridamole-dobutamine stress echocardiogra-phy to identify myocardial viability.J Am Coll Cardiol 1996;27(6):1422–1428.11.Carlos ME,Smart SC,Wynsen JC,et al:Dobutaminestress echocardiography for risk stratification after my-ocardial infarction.Circulation1997;95(6):1402–1410.12.Knudsen AS,Darwish AZ,Nørgaard A,et al:Timecourse of myocardial viability after acute myocardial。