- Email: [email protected]
Does the myocardium become “stunned” after episodes of angina at rest, angina on effort, and coronary angioplasty?
Does the Myocardium Become %tunnedv9 After Episodes of Angina at Rest, Angina on Effort, and Coronary Angioplasty? Paolo Marzullo, MD, Oberdan Parodi, MD, Gianmario Sambuceti, MD, Claudio Marcassa, MD, Alessia Gimelli, MD, Monica Bartoli, RT, Danilo Neglia, MD, and Antonio L’Abbate, MD
To assess wbetber myocardiil stunning occurs & ter brief perids of ischemii, global and re@onal by rmliiuclii ventricular function asses~I ~wasstudiedin52patWts.Patient-s were divided into 3 @oups according to the type of ischemic episodes. Group 1 consisted of 15 pa tients studied before, during and after episodes of angina at rest. Seventeen patients studied im mediately before and after -u@Plasty [email protected] tients with stable an@na studied before, during and after exercise-induced ischemia. Medical ther apy was discontinued 45 hours before the study in all patients except those unaergoing cOcOnacy angioplasty who were receivingdittiqzem i&o mghlay. No difference in baseline ejection h tion was found between @oups, -peakfilling rate was statkthlly lower in @oup 3 ps tients. Evidence of left ventricular dysfunction during ischemia was seen in patii in gulps 1 zmd3,whereastransientischemiawasdocumeW ed by sT+e@nent displacement and/or typical chest pain during ballinnr inflation in gw~~p 2. P* sistence of systolic or diilic dysfunction was notobservedinanyofthe3groupsintherecovcry phase after ischemia. In conclusion, transient ischemia caused either by a primary redu$ion in oxygen ~PPb meat -, -ry mePIin oxygen demand (mna on ty)orbyanincrease efbrt) dii not reproduce the phenomenon of sy* tolic and diiolic stumring observed in animal expefimentq although in all patients the ischemia was of sufficient duration and severity to induce marked ventricular dysfunction. The seamh for stunned myocardium should be extended to other different clinical models draracterized by pr4k longed ischemia such as unst&le angina or myocardial infarction. (Am J Cardiol1993;71:104SlO51)
From the CNR Institute of Clinical Physiology, Pisa, Italy. This study was supported in part by CNR-targeted project “Prevention and Control Disease Factors” and subproject “Control of Cardiovascular Disease” from the National Research Council, Rome, Italy. Manuscript received September 2 1, 1992; revised manuscript received and accepted November 18, 1992. Address for reprints: Paolo Marzullo, MD, CNR Institute of Clinical Physiology, Via P. Savi 8, I-56100 Pisa, Italy.
I
n recent years the phenomenonof “stunned” myocardium has been extensively documentedin experimental works.‘,* It is now well known that prolonged or repeated ischemic episodes may induce, in nonhuman animal experiments,a severereduction in regional wall thickening not associatedwith irreversible myocardial damage.3,4This experimental evidence raises concern on whether transient, short-lasting episodes of myocardial ischemia occurring in patients with coronary artery disease,either causedby a primary reduction in oxygen supply (variant angina, coronary angioplasty) or by an increase in demand (angina on effort), may induce myocardial stunning. In these clinical models, the ischemia that occurs during coronary spasm5or angioplas@ closely resembles that observed in the experimental model of occlusion/reperfusion.Coronary angioplasty has the additional characteristic of repeated periods of occlusion and reperfusion, a sequencethat has been demonstratedto sensitize the myocardium of dogs to the stunning phenomenon.7Ischemia on effort has been investigated in chronic animal preparations with a flow-limiting coronary stenosis8,9 and thesemodels have evidencedthe occurrence of postischemic stunning. Previous studies in humans provided controversial evidence as to the possible occurrence of myocardial stunning. Several studies showed a full recovery of left ventricular function after ischemia,‘@‘* whereasother investigators have reported an incidence of postischemicleft ventricular dysfunction as high as 90%.13,14Furthermore, most studies on ventricular function have been focused on the effect of peak ischemia, and few data are available on the recovery phasein patients with ischemic episodesof different origin. The study of postischemicventricular function may add important information to the natural history of different forms of coronary artery diseaseand address,or limit, the benefits of different cardiologic therapies and interventions. In this study, we investigated the possible development of myocardial stunning in humans by radioisotopit monitoring of ventricular function in different categories of patients with transient ischemia. Study groupe Changes in left ventricular dynamics after transient ischemia were prospectively evaluated in 52 patients. The patients enrolled in the study satisfied the following criteria: absenceof (1) previous myocardial infarction, (2) valvular disease,and (3) left ventricular hypertrophy as assessedby echocardiography.According to the type of ischemic episode studied, patients were divided into 3 groups. Group 1 consistedof 15 paLEFTVENTRICULARDYNAMICSAFTERTRANSIENTISCHEMIA 1045
tients with angina at rest. All were men (mean age 50 + 9 years, range 40 to 67). Group 2 consistedof 17 patients undergoing selectivecoronary angioplasty; 15 men and 2 women (mean age 53 f 5 years, range 46 to 66). Only patients with clear-cut ST-segmentchangesduring coronary occlusion were included in the study. Twenty patients with stable angina and documentedischemia on effort constituted group 3. All were men (mean age 56 + 7 years, range 44 to 65). Medical therapy was discontinued 23 days before the study in all patients except those who underwent coronary angioplasty and were taking diltiazem 180 mg/day. Patients who took oral nitroglycerin within 90 minutes from radionuclide angiography were not studied. Patients from each group gave written informed consent for me relative protocols approved by the local ethical committee on human studies in December 1990. METHODS Radiomdide
an@ography: After in vivo red blood cell labeling, the left anterior oblique projection that best displayed the ventricular septum was maintained throughout the studies. Imaging was performed using a small field mobile camera(Apex 209 MA, Elscint, Israel) equipped with a high-sensitivity, parallel-hole collimator. Data were collected using the minilist mode to compensatefor changes in heart rate variability into a 64 X 64 byte matrix for 24 frames.An averageof 5,000 Kcounts were collected for baseline studies, whereas during transient ischemia (groups 1 and 3) approximately 100 Kcounts/frame were obtained in all studies. Patients in groups 1 and 2 were studied in the supine position, whereaspatients in group 3 were studied in a semisupineposition to reduce discomfort and chest motion during the test. Electrocardiographic (1Zlead) and blood pressure monitoring (cuff manometer) were obtained every minute, and 3 leads (III, aVL and V4) were continuously monitored in all studies. Global ejection fraction was calculated in all patients by semiautomatically drawing end-diastolic and end-systolic contours and end-systolic background for appropriate subtraction. In all patients and in all conditions studied the framing rate was sufficiently high to allow calculation of the diastolic parameters.Accordingly, peak filling rate was calculated by a third order polynomial fit through the first 2/3of diastole. The absolute peak filling rate obtained from the lirst derivative of the regression expression was then referred to end-diastolic counts and expressed as end-diastolic counts per second. The intraobservervariation of ejection fraction and peak filling rate was recalculated in 25 patients and was f 4.4 and f 3.8%, respectively; the interobserver variation was f 4.0% for ejection fraction and + 5.2% for peak tilling rate. Qualitative analysis was performed by 2 experienced observers unaware of the hemodynamic data, who scored5 left ventricular segments(basal septal, apical septal, inferoapical, inferolateral and posterolateral).15The score index used was: 0 = normal; 1 = hypokinesia; and 2 = akinesia or dyskinesia. Discrepancies between the observerswere solved by consensus.
performed in the coronary care unit; the episodesof angina at rest were spontaneousin 8 patients and induced by scalar dosesof ergonovine maleatein the others. Patients in whom the resolution of ischemia required nitrates were not included in the study. Post-ischemia scans were obtained at 8 f 3 minutes from the end of the electrocardiographicchangesand chest pain. Group 2 patients were studied in the catheterization laboratory by baseline radionuclide angiography 10 minutes before and 20 minutes after the angiographic procedure.In patients in group 3, symptom-limited exerciseradionuclide angiography was recorded during the last 2 minutes of a 25 W X 3minute step protocol. Postischemiascans were acquired at 6 minutes after peak exercise.No patient received nitrates or other drugs in the recovery phase of the study. w B aml m All patients underwent coronary angiography in multiple projections within 2 weeks from radioisotopic and echocardiographic studies. Minimal cross-sectionalarea of stenotic arterial segmentswas assessedby computerizedquantitative angiography (Mipron, Kontron, Germany). Digital computer-assisted calipers were used to measure stenotic arterial segmentsthat were quantified as minimal coronary cross-sectionalarea; stenosesof >50% were considered significant. In patients in group 2, coronary angioplasty was performed with a standardsteerableballoon cathetersystem.The procedurewas consideredsuccessful if the tinal lumen reduction was ~50%. In these patients the guide catheter was always removed at the end of the procedure before control scan and all radioisotopic studies were performed in the catheterization laboratory. Statistical analysis: Data are expressedas mean * 1 SD. Differencesin systolic and diastolic functional indexes in different groups were analyzed by analysis of variance (multiple comparison) using the Scheffe’ test. Within each group, differencesbetween different conditions (i.e., baseline and ischemia) were assessedusing the Student’s t test. A probability (p) value co.05 was considered significant. RESULTS
Coronary anatomy: Five patients in group 1 had normal coronary arteries. Six of the remaining patients had l-vessel and 4 multivessel disease.In thesepatients, the average minimal cross-sectionalarea of the ischemia-related coronary artery was 39 f 12%. Coronary spasmwas documentedduring angiography in 8 patients (4 with normal vessels). All patients with coronary angioplasty had l-vessel disease;in 11patients the diseased vessel was the left anterior descending coronary artery, whereasthe remaining 6 patients had right coronary (4 patients) and left circumflex (2 patients) coronary artery narrowing. No patient had completecoronary occlusion. Average minimal cross-sectionalarea was 90 f 10% and 34 f 17% before and after the procedure, respectively (p ~0.01). Eleven patients in group 3 had lvessel and 9 had multivessel disease,respectively. Two patients with 3-vesseldiseasehad complete occlusion of the left anterior descendingcoronary artery with a wellRadioisotopic protocol in different study groups Radionuclide angiography in patients in group 1 was developed collateral circulation in both. Average reduc1046
THE AMERICANJOURNALOF CARDIOLOGY VOLUME71
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TABLE I Individual Patient Data in Group 1
Pt.
No.
Age (yr)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
54 61 53 56 52 52 62 51 56 45 67 50 45 59 52
No. of Coronary Arteries Narrowed > 50% 0 1* 1* 0* 2* 0* 1 2 1* 1* 1 2 0* 3 0
Wall Motion Score
Ejectlon Fraction
Peak Fillmg Rate
Bas.
Isch.
Rec.
Bas.
Isch.
Rec.
Bas.
Isch.
Rec.
53 55 51 59 42 57 56 59 56 70 57 61 66 55 56
38 43 49 52 19 43 49 32 40 66 45 27 49 31 31
54 54 52 67 40 56 56 58 55 70 55 60 58 55 57
0 0 0 0 1 0 0 0 1 0 2 0 0 1 0
3 2 2 3 3 2 3 4 2 1 2 4 1 2 3
0 0 0 1 0 0 0 0 1 0 2 0 0 1 0
1.88 2.32 1.78 1.90 2.11 2.26 2.39 2.15 1.58 2.00 2.32 2.08 2.58 1.75 2.68
0.81 0.56 1.00 1.23 1.34 0.92 1.20 1.14 0.45 1.01 1.28 1.35 1.45 0.90 1.87
1.95 2.10 1.70 2.08 2.45 2.21 2.85 2.28 1.67 2.11 2.40 2.22 2.50 1.60 2.72
*Documented vasospasm by anglography. Bas. = basehne;lsch. = ischemla at rest; Rec. = 6.minute recovery.
tion in relative minimal cross-sectional area of the ischemia-relatedcoronary artery was 78 f 12%. Clinicalmzakersoftmmiemtisdmniainthedii
ent groups: Among patients in group 1, 8 had multiple episodes characterized by ST-segment elevation (anterior in 6 and inferior in 2 patients) and 7 had episodes with ST-segment depression (anterior in all patients). The average duration of the ST-segmentdisplacement during the ischemic episodes, and therefore the duration of the radioisotopic acquisition, was 134 + 48 seconds.Ejection fraction during ischemia declined by 16 ejection fraction units, peak filling rate by 48%, and regional wall motion score increased by 80%. An example of such a responseis shown in Figure 1. No serious arrhythmias were observed during ischemia and recovery in any patients. Clinical and radioisotopic data are listed in Table I. Because of the short-lasting ischemic episodesinduced by coronary angioplasty,radioisotopic monitoring was not performed in group 2 patients. The occurrence of ischemia, a prerequisite for myocardial stunning, was documented in 10 patients by transient ST-segment elevation (anterior, inferior and posterior in 7, 2 and 1 patients, respectively), in 4 by ST-segmentdepression(anterior in all patients), and in 3 by typical chest pain not associatedwith electrocardiographic changes.Total occlusion time was 120 k 60 seconds,and the average number of inIIations was 2.8 + 1.2. Clinical and radioisotopic data are listed in Table II. In group 3 patients, ST-segmentdepressionwas documented in 17 patients, whereastypical chest pain in the absenceof significant ST segmentshift was experienced by 3. Average ejection fraction declined by 6 ejection fraction units, and peak filling rate increasedbelow the lower normal exerciserange of our laboratory (3.35 enddiastolic counts per second)in 14 of 20 patients.Regional wall motion score increasedby 21%. An example of ventricular dysfunction occurring at peak ischemia is shown in Figure 2. The averageduration of radioisotopic acquisition at peak exercise was 155 + 20 seconds. Radionuclide angiography during the recovery period
was started at the sixth minute in all patients. Clinical and radioisotopic data of patients in group 3 are listed in Table III. Comparison of baseline systolic and diastolic function in the three groups: Baseline left ventricu-
lar ejection fraction did not differ significantly among the 3 groups (Figure 3). An abnormal systolic function, defined as 2 SD below normal values of our laboratory (<55%), was found in 20, 18 and 41% of patients in the 3 groups, respectively. This tinding correlated with the higher prevalenceof multivessel diseasein group 3 patients (45%) comparedwith group 1 patients, and 2 who
FlWBE
1. Equilihium
radhuclii
angim
petiemt 1 of group 1 before (BABEUNE), ‘5
obtdned in (BT ELEVA-
noN)wdaftew(KsTlscHEMlA)wi!stchwclttadcatrest chaacterized by smegmnt elevatien. ElmMaw& (ED) andencky8Mic(EB)~areshownto@thwwith~ tii fracth (EF) and peak filling rate (PFB) exptwsed as enrhliastelic ceunts/secwd (EBC/S). Buring isclmmia, left venbicular&dationisaswdtedwilhadeweaseinejectbn l?actian,peakfiHingrateandwiththedevelqlmentdre ghnlal wall motion dlnonnaliies. cwlplete nemlali?atii ef ventricular dynamics is evident in the recovery phase.
LEFTVENTRICULARDYNAMICSAFTERTRANSIENTISCHEMIA 1047
TABLE II
Individual
Patient
Data in Group 2 with One-Vessel
Ejection Fraction
Peak Filling Rate
Disease PTCA
Pt. No.
Age (yr)
Bas.
Rec.
Bas.
Rec.
Vessel
ST Changes
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
58 51 53 62 56 57 53 66 53 55 47 54 48 46 48 53 50
45 51 62 57 60 59 62 57 65 60 57 56 59 62 45 55 56
43 49 56 57 60 64 60 58 60 60 53 53 54 64 46 53 56
1.20 1.50 2.10 2.08 1.90 2.13 1.32 3.06 2.45 1.76 2.10 1.36 2.20 2.12 1.23 1 .oo 1.73
1.70 1.40 1.32 2.21 2.83 2.20 1.26 2.50 2.22 2.13 1.79 1.09 1.97 2.08 2.15 0.95 1.45
LAD RCA RCA LAD LAD LAD
Elevation Elevation Elevation Elevation Elevation Elevation Elevation Elevation Elevation Elevation Depression Depression Depression Depression -
lxx
LAD LAD LAD RCA LAD IAD LAD LCX LAD RCA
Chest Pain 0 + + + 0 + + + 0 + 0 + 0 0 + + +
Bas. = baselk; Chest Pain = typlcal cardiac pan dung coronary occlusion; LAD = left anterior descending coronary artery; LCX = left wcumflex coronary artery; PTCA = percutaneous translumlnal coronary angoplasty; RCA = right coronary arterv: Rec. = 20.mmute recoverv: ST chaws = twe of ST-T changes during percutaneous transluminal coronary angi-
ment depression during angina at rest. In this patient, ejection fraction decreasedby >5 U in the recovery phase. Although reduced when compared with control, ejection fraction was still within normal limits (58%) and diastolic function was unchanged before and after ischemia (Table I). According to thesedata,patients with angina at rest did not have any left ventricular stunning bRvBtMallardynamibefDre4anddteriBchemia: GROUP I: Baseline ejection fraction and peak filling 6 minutes after an ischemic episode of sufficient durarate were not statistically different from baseline values tion to induce severeleft ventricular dysfunction. GROUP 2: In patients in group 2, left ventricular dy(p = NS, Figure 3). Only 1 patient in this group (no. 13) with normal coronary arterieshad documentedspasmof namics before and after coronary angioplasty were unthe left anterior descendingcoronary artery and ST-seg- changed(Figure 3). Regional wall motion score was not statistically different (0.3 + 0.6 and 0.4 f 0.6 segment per patient, p = NS). When individual patient data were analyzed,a decreasein ejection fraction >5 U was found in 1 patient (patient 3 in Table II). Although reduced when compared with the relative control value, postangioplasty ejection fraction in this patient was 56%. The same patient had a reduction in peak filling rate, from 2.10 to 1.30 end-diastolic counts per second. As observed in patients in group 1, no significant systolic or diastolic postischemicventricular impairment was found in patients undergoing coronary angioplasty. GROUP 3: In patients in group 3, ejection fraction and peak filling rate before and after exercise were unchanged as well as regional wall motion score (Table III). Despite patients with multivessel diseasehaving a higher wall motion score during exercise, no significant difference was found betweenejection fraction and peak filling rate in the 2 subgroupsof patients with ischemia on effort (Table IV). When individual patient data were FlDlJBB 2. kplilibrium radi0nuclii B obtained in analyzed,only 1 patient (patient 13, Table III) with mulpatient 19 of #oup 2 before (BASEUNE), during (PEAK EXtivessel diseasehad a reduction in ejection fraction, from ERCISE) and at 6 minutes after ischemia (PDST BXERCISE) 65 to 58% in the recovery phase. In this patient the (ED) and en& induced by exercise rhtrs test. Enddbtolic reduced ejection fraction was still within normal limits systolic (EB) frames (y8 shown together with ejection m tion(EF)andpeiafilliJrate(PPlt)e~asand was not associatedwith persistent abnormalities of stolii counts/seawxl @DC/S). During &hernia, left ventrio diastolic relaxation. Two patients in this group (patients ular dilatia41 and re@ad wall motion abnomdiies are 5 and 12) had a slight reduction in peak filling rate after evident, with cemplete normdixation of ventricular dynam peak exercise without any abnormality in systolic funcits in the recovery phese.
had l-vessel disease.Thesepatients also had a more depresseddiastolic function under basal conditions (Figure 3). Wall motion abnormalities at rest were equally distributed among the 3 groups. Patientswith angina at rest had the highest ejection fraction and peak filling rate and the lowest impairment of regional wall motion at rest.
1048
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TABLE III Individual Patient Data in Group 3 Wall Pt. No.
Age (yr)
No. of Coronary Arteries Narrowed > 50%
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
65 44 53 56 63 59 65 49 64 63 61 48 48 53 51 53 63 58 61 44
1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 3 3 3 3
Abbreviations
Peak Filling Rate
Motion Score
Ejection Fractron Bas.
Isch.
Rec.
Bas.
Isch.
Rec.
Bas.
Isch.
Rec.
54 68 60 49 66 43 64 56 65 72 53 59 65 41 39 52 73 59 52 58
51 53 52 36 60 42 63 56 65 71 45 55 58 38 34 35 67 55 35 56
58 67 57 56 63 43 64 60 62 67 55 66 58 45 40 50 71 58 53 58
0 0 0 0 0 0 2 0 2 0 0 1 0 1 1 1 1 1 1 0
1 1 1 2 1 1 3 2 3 1 1 4 1 3 3 3 3 3 3 2
0 0 0 0 0 0 2 0 2 0 0 1 0 1 1 1 1 1 1 0
1.75 2.24 2.67 1.20 1.25 1.25 1.52 1.20 1.13 1.04 0.94 2.00 1.60 0.97 1.34 0.99 1.63 1.48 0.94 1.59
3.84 4.56 2.94 2.00 2.51 2.51 3.52 2.96 2.74 2.49 1.86 5.50 6.32 2.26 3.35 2.90 3.12 2.29 2.13 2.13
2.24 3.35 2.85 1.37 1.12 1.12 1.43 1.35 1.96 1.08 1.04 1.60 2.30 1.27 1.71 1 .oo 1.65 1.79 1.06 1.72
as in Table I.
tion. Also, no significant persistent postischemic dys- ments, Nicklas” and Schroeder’ and their co-workers function was detectedby radionuclide angiography after showed that with subsequentocclusions the additional peak ischemia in this group. decrement in mechanical performance of the stunned myocardium became progressively smaller. Homanss DISCUSSION and Tomoike9and their co-workers demonstratedthat in Myocadial stunning in humans: The main purpose animals with a coronary stenosisthat reduced coronary of our investigation was to study the effects of short- blood flow at rest, exercise provoked long-lasting islasting ischemic episodeson left ventricular dynamics in chemic contractile abnormalities persisting even after the patients with different types of ischemia, i.e., angina at releaseof the stenosis. rest, on effort and with transient and repeatedblood flow interruptions caused by coronary angioplasty. For the most part, our results were in agreementwith several Ischemia at rest Ischemia on effort PTCA measured indexes of left ventricular function and in801 807 801 dicated that in these patients no systolic or diastolic stunning occurs after brief ischemic episodes. Dylerimantalmode4lsdpostischemivenbicular dysfunction: The most common experimental model of myocardial stunning, basedon a sequenceof occlusions at rest followed by reperfusion, induces a persistent systolic and diastolic dysfunction.t6 In different experiTABLE IV Systolic and Diastolic Function 3: Single Versus Multivessel Disease
Ejection fraction Baselrne lschemic Recovery Peak filling rate Baseline lschemic Recovery Wall motion score Baseline lschemic Recovery
in Patients
in Group
One-Vessel Disease (11 patients)
Multivessel Disease (9 patrents)
p Value
59 + 8 55 k 10 59 k 8
545 10 47 2 10 54 -c 9
NS NS
1.53 + 0.50 2.80 + 0.84 1.80 ‘- 0.85
1.33 2 0.39 3.28 t 1.57 1.48 1 0.44
NS NS NS
0.2 2 0.6 1.3 r 0.6 0.2 + 0.6
0.8 + 0.4 2.8 t 0.8 0.8 2 0.4
p <0.05 p <0.05 p < 0.05
NS
[a
Baseline
0 Post &hernia
1
RGURE 3. Chmges in ejdion hcti011 (EF), peak filling rate (PPR)andwallmotionscom(WMS)ineach#oupatbese line (&ted ibarr) and after ischemia (open rbars). No sign@ cmtpenirtentpostischemii lanannari is evident in each ~~i.ls PTCA = pe -stransh8lwi.
LEFT VENTRICULAR DYNAMICS AFTER TRANSIENT ISCHEMIA
1049
Clinical cotMate
of myocadial
stunningt In our
study group, the mode of ischemia was similar to that of experimental preparations.Ischemia at rest and coronary angioplasty resembledcoronary occlusion and reperfusion, and ischemia on effort was similar to experiments in which an increased myocardial demand was induced by exercise. In particular, vasospasticischemia in group 1 patients had the same features as those induced by a single ischemic episode in dogs, whereasischemia induced by coronary angioplasty was similar to that obtained experimentally by a sequenceof brief coronary occlusions. Similar to the animal model, all our patients had evidence of transient ischemia documented by the abnormal systolic and diastolic function during ischemia or by the development of ST-segmentabnormalities, or both. Despite these similarities, we were unable to demonstratethe occurrence of significant postischemic ventricular dysfunction in the 3 study groups. Several factors may explain why there are discrepancies between the experimental and the clinical model, the most striking being duration of ischemia. A common feature of animal experiments is that in these studies ischemia lasts for periods ranging from 5 to 20 minutes, which probably never occurs in patients during episodes of angina either at rest, on effort or during coronary angioplasty. The average duration of ischemia in our study groups was 120 to 180 seconds,an interval that can be consideredreasonablylong from a clinical viewpoint but extremely short when compared with animal studies. Additional variables such as differencesin myocat-dial vulnerability to ischemia among species may help to clarify why no myocardial stunning was detected in our study population. correlation with previous clinical studies In patients with angina at test, several studies have demonstratedthat wall motion abnormalities and ejection fraction return to baseline values in the recovery phase of episodes characterized by ST-segment elevation or depression. Radioisotopic monitoringto demonstrated that systolic function fully recovers after ischemia, both spontaneouslyand after isosorbide dinitrate administration. Echocardiographic18and hemodynamic studies19 also showed that recovery of function in these patients occurs soon after the resolution of the ischemic episodes. Most patients enrolled in these studies experiencedseveral symptomatic and asymptomatic attacks of resting angina each day and all of them showed a normal left ventricular function at rest without stable wall motion abnormalities or hemodynamic changes. Beyond confirming these data, our results also showed that an absolute, reversible reduction in diastolic relaxation usually parallels systolic dysfunction (Figure 2). Myocardial stunning in thesepatients does not appearto representa relevant clinical problem. Most studies performed in the catheterization laboratory shortly after coronary dilation failed to show any persistentsystolic or diastolic ventricular dysfunction after transient, repeated coronary occlusions.11,2@23 Our data are in apparent disagreement with the study by Wijns et al22 who reported the persistenceof diastolic dysfunction at 12 minutes after the end of the procedure in a group of patients treated with a combination of cal1050
THE AMERICANJOURNALOF CARDIOLOGY VOLUME71
cium antagonists/l3blockers and nitrates. The negative effectsof /3 blockers on diastolic function and the shorter interval between angioplasty and control could partly explain this discrepancy. The occurrence of severe ventricular dysfunction during coronary angioplasty has been recently challenged by Verani et al.24In this study,they showed signihcant left ventricular dysfunction during coronary angioplasty mainly in patients who underwent left anterior descendingcoronary artery dilation. If ventricular dysfunction does not occur in patients with right or left circumllex coronary artery stenosis, myocardial stunning cannot be detectedin this subgroup of patients as a logical consequence.However, in our study population, 68% of angioplasty patients had left anterior descending coronary artery disease and all group 2 patients had electrocardiographic changes or typical chest pain, or both, during the procedure. Thus, in the present study, systolic and diastolic dysfunction do not appear to be relevant in the immediate postangioplastyphasein most patients studied. Radioisotopic and echocardiographic studies have been performed in patients with angina on effort mainly at peak exercise, and only few data are available on the postexerciseventricular dynamics. Our data are in agreementwith those of Dymond et alI2 who studied left ventricular function by first-passradionuclide angiography in ischemic patients and did not report any persistent dysfunction at 1 minute after peak exercise.Similarly, Schneider et alI3 reported a normalized ejection fraction 6 minutes into the recovery phase in all their study groups. On the other hand, echocardiographicevidenceof persistentleft ventricular dysfunction alier peak exercise has been demonstratedby Robertson et al25in 35% of their study population. In particular, myocardial stunning was detectedin 1 patient with normal coronary vesselsand in 6 of 10 patients with multivessel disease. Kloner et all4 showed by 2dimensional echocardiography the persistenceof stress-inducedwall motion abnormalities in 90% of patients at 30 minutes after peak exercise in a similar study group. These studies are in apparent contrast to those supporting the concept that echocardiographyafter exercise frequently fails to identify patients with effort ischemia because of the rapid resolution of wall motion abnormalities after termination of exercise26T27 as well as the less-than-perfectdiagnostic accuracy of exercise echocardiography. study limitatbns We used radionuclide angiography to assessglobal and regional left ventricular function. Some limitations of this technique should be mentioned. In all studies performed during ischemia we operated at the lower limit of the temporal resolution of the technique and this may have generatedinaccuracies in the relative measurements;furthermore, we used semiquantitative analysis of regional wall motion and no regional ejection fractions were calculated. In patients with angina at rest, ischemic episodes were induced by ergonovine maleatein 7 of 15 patients. A different degree of ventricular dysfunction could be hypothesized in ergonovine-induced episodes although previous studies failed to show any difference between spontaneousand induced ischemic attacks.10J8,19
MAY 1,1993
We did not obtain measurementsduring balloon inflation in patients undergoing coronary angioplasty,and the occurrence of ischemia was documented in all patients by electrocardiographicchangesand chest pain. In these patients, no assumption can be made about the degree of left ventricular dysfunction and the relative depression of global ejection fraction and peak filling rate during ischemia. Patients with previous myocardial infarction were not studied to avoid any interference with transient ischemia and postischemicventricular dysfunction. Whether myocardial stunning occurs in patients with baselinewall motion abnormalitiesneedsfurther investigation in a different study population. Finally, all patients were studied at baseline, during ischemia (except patients in group 2) and at different time intervals after ischemia.Patientsin groups 1 and 3 were studied starting at 6 minutes after ischemia resolution, whereas patients in group 2 were studied 20 minutes after angioplasty.No conclusion can be drawn as to the possible occurrenceof myocardial stunning earlier in the recovery phase after angioplasty. In conclusion, our data demonstratethat in most patients with transient ischemic ventricular dysfunction of short duration (2 to 4 minutes), recovery of systolic and diastolic function is complete within a few minutes and that the phenomenonof persistent postischemicventricular dysfunction does not play any clinical role; the searchfor myocardial stunning should be directed to different models characterizedby more prolonged ischemia such as unstable angina,28cardiac surgery29and acute myocardial infarction.30 1. Braunwald E, Kloner RA. The stunned myccardium: prolonged, postischemic ventricular dysfunction. Circulation 1982;66:1146-1149. 2. Pagani M, Vatner SF, Baig H, Braunwald E. Initial myocardial adjushnent to brief periods of ischemia and reperfusion in the conscious dog. Circ Res 198243: 83-92. 3. Heyndrickx GR, Millard RW, McRichtie RJ, Maroko PR, Vamer SF. Regional myocardial functional and electmphysiological alterations after brief coronary artery occlusion in conscious dogs. J Clin lnvesr 1975;56:978-985. 4. Bush LR, Buja LM, Samowitz W, Rude RE, W&en M, Tilton G, Willerson IT. Recovery of left ventricular segmental function after long term reperfusion folIpwing tempaxty coronary occlusion in conscious dogs. Circ Res 1983;53:248-263. 5. Masai A, Severi S, De Nes M, L’Abbate A, Chierchia S, Marzilli M, Ballestra AM, Pa&i 0, Biagini A, Distante A. “Variant angina”: one aspect of a continuous spectrum of vasospastic myocardial &hernia. Am J Cardiol1978;42:1019-1035. 6. Gruntzig AR, Seming A, Siegenthaler WE. Non-operative dilation of coronaryartery stenosis: percutaneous tnmsluminal angioplasty. N En,@ J Med 1979;301: 6148. 7. Schtier ES, Sims SJ, Kieso RA, Kerber RE. Sensitization of reperfosed myocaniiurn to subsequent coronary flow reductions. An extension of the concept of mywardial stunning. Circularion 1988;78:717-728. 8. Homans DC, Sublett E, Dai XZ, Bathe RJ. Persistence of regional left venhicular dysfunction after exercise-induced myocardial &hernia. J Clin Invest 198677: 66-73. 9. Tom&e HD, Franklii D, McKown D, Kemper WS, Goberek M, Ross J Jr. Regional myocardial dysfunction and hemcdynamic abnormalities during strenuous exercise in dogs with limited coronary flow. Circ Res 1978;42:4874%. 10. Marzullo P, Parodi 0, Schelbert HR, L’Abbate A. Regional myocardial dys-
function and response to isosorbide dinitrate assessed by phase analysis of radionuelide venbiculogratns. J Am Coil Cardiol 1984;3: 1357-1366. 11. Hauser AM, Gangadharan V, Ramos RG, Gordon S, Timmis GC, Dudlets P. Sequence of mechanical, electrocardiographic and clinical effects of repeated corenary artery occlusion in human beiigs: echocardiographic observations during coronary angioplasty. J Am CON Cardiol 1985;5:193-197. 12. Dymond DS, Foster C, Grenier RP, Carpemter J, Schmidt DH. Peak exercise and immediate postexercise imaging for the detection of left ventricular functional abnormalities in coronary atery disease. Am J Cardiol 1984:53:1532-1537. 13. Schneider RM, Weintraub WS, Klein LW, Se&us PA, Agawal JB, Helfant RH. Rate of left ventricular functional recovery by radionuclide angiography after exercise in coronary artery disease. Am J Car&l 1986;57:927-932. l4. Kloner RA, Allen J, Cox TA, Zheng Y, Ruiz C. Stunned left ventricular myoardium after exercise treadmill testing in coronary artery disease. Am J Cardial 1991;68:32!&334. 15. Zxet BL, Wackers FJT, Tenin ML, Ross R, Weiss M, Slater I, Morrison J, Bourge RC, Pawmani E, Knatterud G, Braunwald E. Assessment of global and regional left ventricular performance at rest and during exercise after thrombolytic therapy for acute myocardial infarction: results of the thmmbolysis in myocardial infarction (TIMI II) study. Am J Cardiol 199269: l-9. 16. Charlat ML, O’Neill PG, Hartley CJ, Roberts R, Bolli R. Prolonged abnormalities of left ventricular diastolic wall thinning in the “stunned” myocardium in conscious dogs: time-course and relation to systolic function. .I Am Coil Cardiol 1989;13:185-194. 17. Nicklas JM, Becker LC, Bulkley BH. Effects of repeated brief coronary occlusion on regional left ventricular function and dimension in dogs. Am J Cardiol 1985:56:47+l78. 18. D&ante A, Rovai D, F&no E, Moscarelli E, Palombo C, Morales MA, Michelassi C, L’ Abbate A. Transient changes in left ventricular mechanics during attacks of F’rinametal’s angina: an M-mode echwxdiographic study. Am Heart J 1984;107:465-474, 19. Chierchia S, Btunelli C, Simon& I, Lazui M, Maseri A. Sequence of events in angina at rest: primary reduction in cornnary flow. CircuUon 1980,61:759-768. 20. Piscione F, Hugenholtz PG. Senuys PW. Impaired left ventricular filling dynanits during percutaneous tmnsluminaJ angioplasty for coronary artery disease. Am J Cardiol 1987;59:29-37. 21. Carlson EB, Hinohxa T, Morris KG. Recovery of systolic and diastolic left ventricular function after 6C-second coronary arterial occlusion during percutaneous ~ansluminal coronary angioplasty for angina pectmis. Am J Cardiol 1987;60: 460-466. 22. Wijns W, Senuys PW, Slager CJ, Grimm J, Krayenbuehl HP, Hugenholtz PG, Hess OM. Effect of coronary occlusion during percutaneous tmnsluminal angioplasty in humans on left ventricular chamber stiffness and regional diastolic pressure-ratio relations. J Am Co/l CardioI 1986;7:45S463. 23. De Feyter PJ, Suyapranata H, Senuys PW, Beatt K, Van der Brand M, Hugenholtz PG. Effects of successful percutaneous transluminal coronary angioplasty on global and regional left ventticulx function in unstable angina pectmis. Am J Cardial 1987;60993-997. 24. Verani MS, Lacy JL, Guidty GW, Nishimnra S, Mahmarian JJ, Athanasoulis T, Roberts R. Quantification of left ventricular performance during aansient cornnary occlusion at various anatomic sites in humans: a study using Tantalum-178 and a multiwire gamma camera. J Am Co/l Cardiol 1992: 19297-306. 25. Robertson WS, Feigenbaum H, Armstrong WF, Dillon JC, O’Donnel JO, McHemy PW. Exercise echocardiography: a clinically practical addition in the eviluation of coronary artery disease. J Am Co0 Cardinl 1983;6:1085-1091. 26. Iliceto S. D’Ambrosio G, Sotino M, Papa A, Amico A, Ricci A, Rizzon P. Comparison of patexercise and tramesophageal attial pacing two-dimensional echocardiography for detection of coronary artery disease. Am J Cardio/ 198657: 547-553. 27. Presti CF. Armstrong WF, Feigenbaum H. Comparison of peak and post-exacise echocardiographic imaging in evaluation of coronary artery disease (abstr). J Am Co/l Cardiol 1987;9:217A. 28. Nixon JV, Brown CN, Smitherman TC. Identiication of transient and persistent segmental wall motion abnormalities in patients with unstable angina by twodimensional echocardiography. Circulation 198265: 1497-1503. 29. Rankin JS, Newman GE, Muhlbaier LH, Behar VS, Fedor JM, Sabisten DC Jr. The effect of coronary revascularization on LV function in ischemic heart disease. .I Thorac Cardiovasc Surg 1985;90:818-832. 30. Wackers FJT. Thrombolytic therapy for myocardial infarction: assessment of efficacy by myocardial perfusion imaging with technetium-99m Sestatnibi. Am J Cardiol 1990;66:36E-41E.
LEFTVENTRICULARDYNAMICSAFTERTRANSIENTISCHEMIA 1051
To assess wbetber myocardiil stunning occurs & ter brief perids of ischemii, global and re@onal by rmliiuclii ventricular function asses~I ~wasstudiedin52patWts.Patient-s were divided into 3 @oups according to the type of ischemic episodes. Group 1 consisted of 15 pa tients studied before, during and after episodes of angina at rest. Seventeen patients studied im mediately before and after -u@Plasty [email protected] tients with stable an@na studied before, during and after exercise-induced ischemia. Medical ther apy was discontinued 45 hours before the study in all patients except those unaergoing cOcOnacy angioplasty who were receivingdittiqzem i&o mghlay. No difference in baseline ejection h tion was found between @oups, -peakfilling rate was statkthlly lower in @oup 3 ps tients. Evidence of left ventricular dysfunction during ischemia was seen in patii in gulps 1 zmd3,whereastransientischemiawasdocumeW ed by sT+e@nent displacement and/or typical chest pain during ballinnr inflation in gw~~p 2. P* sistence of systolic or diilic dysfunction was notobservedinanyofthe3groupsintherecovcry phase after ischemia. In conclusion, transient ischemia caused either by a primary redu$ion in oxygen ~PPb meat -, -ry mePIin oxygen demand (mna on ty)orbyanincrease efbrt) dii not reproduce the phenomenon of sy* tolic and diiolic stumring observed in animal expefimentq although in all patients the ischemia was of sufficient duration and severity to induce marked ventricular dysfunction. The seamh for stunned myocardium should be extended to other different clinical models draracterized by pr4k longed ischemia such as unst&le angina or myocardial infarction. (Am J Cardiol1993;71:104SlO51)
From the CNR Institute of Clinical Physiology, Pisa, Italy. This study was supported in part by CNR-targeted project “Prevention and Control Disease Factors” and subproject “Control of Cardiovascular Disease” from the National Research Council, Rome, Italy. Manuscript received September 2 1, 1992; revised manuscript received and accepted November 18, 1992. Address for reprints: Paolo Marzullo, MD, CNR Institute of Clinical Physiology, Via P. Savi 8, I-56100 Pisa, Italy.
I
n recent years the phenomenonof “stunned” myocardium has been extensively documentedin experimental works.‘,* It is now well known that prolonged or repeated ischemic episodes may induce, in nonhuman animal experiments,a severereduction in regional wall thickening not associatedwith irreversible myocardial damage.3,4This experimental evidence raises concern on whether transient, short-lasting episodes of myocardial ischemia occurring in patients with coronary artery disease,either causedby a primary reduction in oxygen supply (variant angina, coronary angioplasty) or by an increase in demand (angina on effort), may induce myocardial stunning. In these clinical models, the ischemia that occurs during coronary spasm5or angioplas@ closely resembles that observed in the experimental model of occlusion/reperfusion.Coronary angioplasty has the additional characteristic of repeated periods of occlusion and reperfusion, a sequencethat has been demonstratedto sensitize the myocardium of dogs to the stunning phenomenon.7Ischemia on effort has been investigated in chronic animal preparations with a flow-limiting coronary stenosis8,9 and thesemodels have evidencedthe occurrence of postischemic stunning. Previous studies in humans provided controversial evidence as to the possible occurrence of myocardial stunning. Several studies showed a full recovery of left ventricular function after ischemia,‘@‘* whereasother investigators have reported an incidence of postischemicleft ventricular dysfunction as high as 90%.13,14Furthermore, most studies on ventricular function have been focused on the effect of peak ischemia, and few data are available on the recovery phasein patients with ischemic episodesof different origin. The study of postischemicventricular function may add important information to the natural history of different forms of coronary artery diseaseand address,or limit, the benefits of different cardiologic therapies and interventions. In this study, we investigated the possible development of myocardial stunning in humans by radioisotopit monitoring of ventricular function in different categories of patients with transient ischemia. Study groupe Changes in left ventricular dynamics after transient ischemia were prospectively evaluated in 52 patients. The patients enrolled in the study satisfied the following criteria: absenceof (1) previous myocardial infarction, (2) valvular disease,and (3) left ventricular hypertrophy as assessedby echocardiography.According to the type of ischemic episode studied, patients were divided into 3 groups. Group 1 consistedof 15 paLEFTVENTRICULARDYNAMICSAFTERTRANSIENTISCHEMIA 1045
tients with angina at rest. All were men (mean age 50 + 9 years, range 40 to 67). Group 2 consistedof 17 patients undergoing selectivecoronary angioplasty; 15 men and 2 women (mean age 53 f 5 years, range 46 to 66). Only patients with clear-cut ST-segmentchangesduring coronary occlusion were included in the study. Twenty patients with stable angina and documentedischemia on effort constituted group 3. All were men (mean age 56 + 7 years, range 44 to 65). Medical therapy was discontinued 23 days before the study in all patients except those who underwent coronary angioplasty and were taking diltiazem 180 mg/day. Patients who took oral nitroglycerin within 90 minutes from radionuclide angiography were not studied. Patients from each group gave written informed consent for me relative protocols approved by the local ethical committee on human studies in December 1990. METHODS Radiomdide
an@ography: After in vivo red blood cell labeling, the left anterior oblique projection that best displayed the ventricular septum was maintained throughout the studies. Imaging was performed using a small field mobile camera(Apex 209 MA, Elscint, Israel) equipped with a high-sensitivity, parallel-hole collimator. Data were collected using the minilist mode to compensatefor changes in heart rate variability into a 64 X 64 byte matrix for 24 frames.An averageof 5,000 Kcounts were collected for baseline studies, whereas during transient ischemia (groups 1 and 3) approximately 100 Kcounts/frame were obtained in all studies. Patients in groups 1 and 2 were studied in the supine position, whereaspatients in group 3 were studied in a semisupineposition to reduce discomfort and chest motion during the test. Electrocardiographic (1Zlead) and blood pressure monitoring (cuff manometer) were obtained every minute, and 3 leads (III, aVL and V4) were continuously monitored in all studies. Global ejection fraction was calculated in all patients by semiautomatically drawing end-diastolic and end-systolic contours and end-systolic background for appropriate subtraction. In all patients and in all conditions studied the framing rate was sufficiently high to allow calculation of the diastolic parameters.Accordingly, peak filling rate was calculated by a third order polynomial fit through the first 2/3of diastole. The absolute peak filling rate obtained from the lirst derivative of the regression expression was then referred to end-diastolic counts and expressed as end-diastolic counts per second. The intraobservervariation of ejection fraction and peak filling rate was recalculated in 25 patients and was f 4.4 and f 3.8%, respectively; the interobserver variation was f 4.0% for ejection fraction and + 5.2% for peak tilling rate. Qualitative analysis was performed by 2 experienced observers unaware of the hemodynamic data, who scored5 left ventricular segments(basal septal, apical septal, inferoapical, inferolateral and posterolateral).15The score index used was: 0 = normal; 1 = hypokinesia; and 2 = akinesia or dyskinesia. Discrepancies between the observerswere solved by consensus.
performed in the coronary care unit; the episodesof angina at rest were spontaneousin 8 patients and induced by scalar dosesof ergonovine maleatein the others. Patients in whom the resolution of ischemia required nitrates were not included in the study. Post-ischemia scans were obtained at 8 f 3 minutes from the end of the electrocardiographicchangesand chest pain. Group 2 patients were studied in the catheterization laboratory by baseline radionuclide angiography 10 minutes before and 20 minutes after the angiographic procedure.In patients in group 3, symptom-limited exerciseradionuclide angiography was recorded during the last 2 minutes of a 25 W X 3minute step protocol. Postischemiascans were acquired at 6 minutes after peak exercise.No patient received nitrates or other drugs in the recovery phase of the study. w B aml m All patients underwent coronary angiography in multiple projections within 2 weeks from radioisotopic and echocardiographic studies. Minimal cross-sectionalarea of stenotic arterial segmentswas assessedby computerizedquantitative angiography (Mipron, Kontron, Germany). Digital computer-assisted calipers were used to measure stenotic arterial segmentsthat were quantified as minimal coronary cross-sectionalarea; stenosesof >50% were considered significant. In patients in group 2, coronary angioplasty was performed with a standardsteerableballoon cathetersystem.The procedurewas consideredsuccessful if the tinal lumen reduction was ~50%. In these patients the guide catheter was always removed at the end of the procedure before control scan and all radioisotopic studies were performed in the catheterization laboratory. Statistical analysis: Data are expressedas mean * 1 SD. Differencesin systolic and diastolic functional indexes in different groups were analyzed by analysis of variance (multiple comparison) using the Scheffe’ test. Within each group, differencesbetween different conditions (i.e., baseline and ischemia) were assessedusing the Student’s t test. A probability (p) value co.05 was considered significant. RESULTS
Coronary anatomy: Five patients in group 1 had normal coronary arteries. Six of the remaining patients had l-vessel and 4 multivessel disease.In thesepatients, the average minimal cross-sectionalarea of the ischemia-related coronary artery was 39 f 12%. Coronary spasmwas documentedduring angiography in 8 patients (4 with normal vessels). All patients with coronary angioplasty had l-vessel disease;in 11patients the diseased vessel was the left anterior descending coronary artery, whereasthe remaining 6 patients had right coronary (4 patients) and left circumflex (2 patients) coronary artery narrowing. No patient had completecoronary occlusion. Average minimal cross-sectionalarea was 90 f 10% and 34 f 17% before and after the procedure, respectively (p ~0.01). Eleven patients in group 3 had lvessel and 9 had multivessel disease,respectively. Two patients with 3-vesseldiseasehad complete occlusion of the left anterior descendingcoronary artery with a wellRadioisotopic protocol in different study groups Radionuclide angiography in patients in group 1 was developed collateral circulation in both. Average reduc1046
THE AMERICANJOURNALOF CARDIOLOGY VOLUME71
MAY 1,1993
TABLE I Individual Patient Data in Group 1
Pt.
No.
Age (yr)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
54 61 53 56 52 52 62 51 56 45 67 50 45 59 52
No. of Coronary Arteries Narrowed > 50% 0 1* 1* 0* 2* 0* 1 2 1* 1* 1 2 0* 3 0
Wall Motion Score
Ejectlon Fraction
Peak Fillmg Rate
Bas.
Isch.
Rec.
Bas.
Isch.
Rec.
Bas.
Isch.
Rec.
53 55 51 59 42 57 56 59 56 70 57 61 66 55 56
38 43 49 52 19 43 49 32 40 66 45 27 49 31 31
54 54 52 67 40 56 56 58 55 70 55 60 58 55 57
0 0 0 0 1 0 0 0 1 0 2 0 0 1 0
3 2 2 3 3 2 3 4 2 1 2 4 1 2 3
0 0 0 1 0 0 0 0 1 0 2 0 0 1 0
1.88 2.32 1.78 1.90 2.11 2.26 2.39 2.15 1.58 2.00 2.32 2.08 2.58 1.75 2.68
0.81 0.56 1.00 1.23 1.34 0.92 1.20 1.14 0.45 1.01 1.28 1.35 1.45 0.90 1.87
1.95 2.10 1.70 2.08 2.45 2.21 2.85 2.28 1.67 2.11 2.40 2.22 2.50 1.60 2.72
*Documented vasospasm by anglography. Bas. = basehne;lsch. = ischemla at rest; Rec. = 6.minute recovery.
tion in relative minimal cross-sectional area of the ischemia-relatedcoronary artery was 78 f 12%. Clinicalmzakersoftmmiemtisdmniainthedii
ent groups: Among patients in group 1, 8 had multiple episodes characterized by ST-segment elevation (anterior in 6 and inferior in 2 patients) and 7 had episodes with ST-segment depression (anterior in all patients). The average duration of the ST-segmentdisplacement during the ischemic episodes, and therefore the duration of the radioisotopic acquisition, was 134 + 48 seconds.Ejection fraction during ischemia declined by 16 ejection fraction units, peak filling rate by 48%, and regional wall motion score increased by 80%. An example of such a responseis shown in Figure 1. No serious arrhythmias were observed during ischemia and recovery in any patients. Clinical and radioisotopic data are listed in Table I. Because of the short-lasting ischemic episodesinduced by coronary angioplasty,radioisotopic monitoring was not performed in group 2 patients. The occurrence of ischemia, a prerequisite for myocardial stunning, was documented in 10 patients by transient ST-segment elevation (anterior, inferior and posterior in 7, 2 and 1 patients, respectively), in 4 by ST-segmentdepression(anterior in all patients), and in 3 by typical chest pain not associatedwith electrocardiographic changes.Total occlusion time was 120 k 60 seconds,and the average number of inIIations was 2.8 + 1.2. Clinical and radioisotopic data are listed in Table II. In group 3 patients, ST-segmentdepressionwas documented in 17 patients, whereastypical chest pain in the absenceof significant ST segmentshift was experienced by 3. Average ejection fraction declined by 6 ejection fraction units, and peak filling rate increasedbelow the lower normal exerciserange of our laboratory (3.35 enddiastolic counts per second)in 14 of 20 patients.Regional wall motion score increasedby 21%. An example of ventricular dysfunction occurring at peak ischemia is shown in Figure 2. The averageduration of radioisotopic acquisition at peak exercise was 155 + 20 seconds. Radionuclide angiography during the recovery period
was started at the sixth minute in all patients. Clinical and radioisotopic data of patients in group 3 are listed in Table III. Comparison of baseline systolic and diastolic function in the three groups: Baseline left ventricu-
lar ejection fraction did not differ significantly among the 3 groups (Figure 3). An abnormal systolic function, defined as 2 SD below normal values of our laboratory (<55%), was found in 20, 18 and 41% of patients in the 3 groups, respectively. This tinding correlated with the higher prevalenceof multivessel diseasein group 3 patients (45%) comparedwith group 1 patients, and 2 who
FlWBE
1. Equilihium
radhuclii
angim
petiemt 1 of group 1 before (BABEUNE), ‘5
obtdned in (BT ELEVA-
noN)wdaftew(KsTlscHEMlA)wi!stchwclttadcatrest chaacterized by smegmnt elevatien. ElmMaw& (ED) andencky8Mic(EB)~areshownto@thwwith~ tii fracth (EF) and peak filling rate (PFB) exptwsed as enrhliastelic ceunts/secwd (EBC/S). Buring isclmmia, left venbicular&dationisaswdtedwilhadeweaseinejectbn l?actian,peakfiHingrateandwiththedevelqlmentdre ghnlal wall motion dlnonnaliies. cwlplete nemlali?atii ef ventricular dynamics is evident in the recovery phase.
LEFTVENTRICULARDYNAMICSAFTERTRANSIENTISCHEMIA 1047
TABLE II
Individual
Patient
Data in Group 2 with One-Vessel
Ejection Fraction
Peak Filling Rate
Disease PTCA
Pt. No.
Age (yr)
Bas.
Rec.
Bas.
Rec.
Vessel
ST Changes
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
58 51 53 62 56 57 53 66 53 55 47 54 48 46 48 53 50
45 51 62 57 60 59 62 57 65 60 57 56 59 62 45 55 56
43 49 56 57 60 64 60 58 60 60 53 53 54 64 46 53 56
1.20 1.50 2.10 2.08 1.90 2.13 1.32 3.06 2.45 1.76 2.10 1.36 2.20 2.12 1.23 1 .oo 1.73
1.70 1.40 1.32 2.21 2.83 2.20 1.26 2.50 2.22 2.13 1.79 1.09 1.97 2.08 2.15 0.95 1.45
LAD RCA RCA LAD LAD LAD
Elevation Elevation Elevation Elevation Elevation Elevation Elevation Elevation Elevation Elevation Depression Depression Depression Depression -
lxx
LAD LAD LAD RCA LAD IAD LAD LCX LAD RCA
Chest Pain 0 + + + 0 + + + 0 + 0 + 0 0 + + +
Bas. = baselk; Chest Pain = typlcal cardiac pan dung coronary occlusion; LAD = left anterior descending coronary artery; LCX = left wcumflex coronary artery; PTCA = percutaneous translumlnal coronary angoplasty; RCA = right coronary arterv: Rec. = 20.mmute recoverv: ST chaws = twe of ST-T changes during percutaneous transluminal coronary angi-
ment depression during angina at rest. In this patient, ejection fraction decreasedby >5 U in the recovery phase. Although reduced when compared with control, ejection fraction was still within normal limits (58%) and diastolic function was unchanged before and after ischemia (Table I). According to thesedata,patients with angina at rest did not have any left ventricular stunning bRvBtMallardynamibefDre4anddteriBchemia: GROUP I: Baseline ejection fraction and peak filling 6 minutes after an ischemic episode of sufficient durarate were not statistically different from baseline values tion to induce severeleft ventricular dysfunction. GROUP 2: In patients in group 2, left ventricular dy(p = NS, Figure 3). Only 1 patient in this group (no. 13) with normal coronary arterieshad documentedspasmof namics before and after coronary angioplasty were unthe left anterior descendingcoronary artery and ST-seg- changed(Figure 3). Regional wall motion score was not statistically different (0.3 + 0.6 and 0.4 f 0.6 segment per patient, p = NS). When individual patient data were analyzed,a decreasein ejection fraction >5 U was found in 1 patient (patient 3 in Table II). Although reduced when compared with the relative control value, postangioplasty ejection fraction in this patient was 56%. The same patient had a reduction in peak filling rate, from 2.10 to 1.30 end-diastolic counts per second. As observed in patients in group 1, no significant systolic or diastolic postischemicventricular impairment was found in patients undergoing coronary angioplasty. GROUP 3: In patients in group 3, ejection fraction and peak filling rate before and after exercise were unchanged as well as regional wall motion score (Table III). Despite patients with multivessel diseasehaving a higher wall motion score during exercise, no significant difference was found betweenejection fraction and peak filling rate in the 2 subgroupsof patients with ischemia on effort (Table IV). When individual patient data were FlDlJBB 2. kplilibrium radi0nuclii B obtained in analyzed,only 1 patient (patient 13, Table III) with mulpatient 19 of #oup 2 before (BASEUNE), during (PEAK EXtivessel diseasehad a reduction in ejection fraction, from ERCISE) and at 6 minutes after ischemia (PDST BXERCISE) 65 to 58% in the recovery phase. In this patient the (ED) and en& induced by exercise rhtrs test. Enddbtolic reduced ejection fraction was still within normal limits systolic (EB) frames (y8 shown together with ejection m tion(EF)andpeiafilliJrate(PPlt)e~asand was not associatedwith persistent abnormalities of stolii counts/seawxl @DC/S). During &hernia, left ventrio diastolic relaxation. Two patients in this group (patients ular dilatia41 and re@ad wall motion abnomdiies are 5 and 12) had a slight reduction in peak filling rate after evident, with cemplete normdixation of ventricular dynam peak exercise without any abnormality in systolic funcits in the recovery phese.
had l-vessel disease.Thesepatients also had a more depresseddiastolic function under basal conditions (Figure 3). Wall motion abnormalities at rest were equally distributed among the 3 groups. Patientswith angina at rest had the highest ejection fraction and peak filling rate and the lowest impairment of regional wall motion at rest.
1048
THE AMERICANJOURNALOF CARDIOLOGY VOLUME71
MAY 1,1993
TABLE III Individual Patient Data in Group 3 Wall Pt. No.
Age (yr)
No. of Coronary Arteries Narrowed > 50%
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
65 44 53 56 63 59 65 49 64 63 61 48 48 53 51 53 63 58 61 44
1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 3 3 3 3
Abbreviations
Peak Filling Rate
Motion Score
Ejection Fractron Bas.
Isch.
Rec.
Bas.
Isch.
Rec.
Bas.
Isch.
Rec.
54 68 60 49 66 43 64 56 65 72 53 59 65 41 39 52 73 59 52 58
51 53 52 36 60 42 63 56 65 71 45 55 58 38 34 35 67 55 35 56
58 67 57 56 63 43 64 60 62 67 55 66 58 45 40 50 71 58 53 58
0 0 0 0 0 0 2 0 2 0 0 1 0 1 1 1 1 1 1 0
1 1 1 2 1 1 3 2 3 1 1 4 1 3 3 3 3 3 3 2
0 0 0 0 0 0 2 0 2 0 0 1 0 1 1 1 1 1 1 0
1.75 2.24 2.67 1.20 1.25 1.25 1.52 1.20 1.13 1.04 0.94 2.00 1.60 0.97 1.34 0.99 1.63 1.48 0.94 1.59
3.84 4.56 2.94 2.00 2.51 2.51 3.52 2.96 2.74 2.49 1.86 5.50 6.32 2.26 3.35 2.90 3.12 2.29 2.13 2.13
2.24 3.35 2.85 1.37 1.12 1.12 1.43 1.35 1.96 1.08 1.04 1.60 2.30 1.27 1.71 1 .oo 1.65 1.79 1.06 1.72
as in Table I.
tion. Also, no significant persistent postischemic dys- ments, Nicklas” and Schroeder’ and their co-workers function was detectedby radionuclide angiography after showed that with subsequentocclusions the additional peak ischemia in this group. decrement in mechanical performance of the stunned myocardium became progressively smaller. Homanss DISCUSSION and Tomoike9and their co-workers demonstratedthat in Myocadial stunning in humans: The main purpose animals with a coronary stenosisthat reduced coronary of our investigation was to study the effects of short- blood flow at rest, exercise provoked long-lasting islasting ischemic episodeson left ventricular dynamics in chemic contractile abnormalities persisting even after the patients with different types of ischemia, i.e., angina at releaseof the stenosis. rest, on effort and with transient and repeatedblood flow interruptions caused by coronary angioplasty. For the most part, our results were in agreementwith several Ischemia at rest Ischemia on effort PTCA measured indexes of left ventricular function and in801 807 801 dicated that in these patients no systolic or diastolic stunning occurs after brief ischemic episodes. Dylerimantalmode4lsdpostischemivenbicular dysfunction: The most common experimental model of myocardial stunning, basedon a sequenceof occlusions at rest followed by reperfusion, induces a persistent systolic and diastolic dysfunction.t6 In different experiTABLE IV Systolic and Diastolic Function 3: Single Versus Multivessel Disease
Ejection fraction Baselrne lschemic Recovery Peak filling rate Baseline lschemic Recovery Wall motion score Baseline lschemic Recovery
in Patients
in Group
One-Vessel Disease (11 patients)
Multivessel Disease (9 patrents)
p Value
59 + 8 55 k 10 59 k 8
545 10 47 2 10 54 -c 9
NS NS
1.53 + 0.50 2.80 + 0.84 1.80 ‘- 0.85
1.33 2 0.39 3.28 t 1.57 1.48 1 0.44
NS NS NS
0.2 2 0.6 1.3 r 0.6 0.2 + 0.6
0.8 + 0.4 2.8 t 0.8 0.8 2 0.4
p <0.05 p <0.05 p < 0.05
NS
[a
Baseline
0 Post &hernia
1
RGURE 3. Chmges in ejdion hcti011 (EF), peak filling rate (PPR)andwallmotionscom(WMS)ineach#oupatbese line (&ted ibarr) and after ischemia (open rbars). No sign@ cmtpenirtentpostischemii lanannari is evident in each ~~i.ls PTCA = pe -stransh8lwi.
LEFT VENTRICULAR DYNAMICS AFTER TRANSIENT ISCHEMIA
1049
Clinical cotMate
of myocadial
stunningt In our
study group, the mode of ischemia was similar to that of experimental preparations.Ischemia at rest and coronary angioplasty resembledcoronary occlusion and reperfusion, and ischemia on effort was similar to experiments in which an increased myocardial demand was induced by exercise. In particular, vasospasticischemia in group 1 patients had the same features as those induced by a single ischemic episode in dogs, whereasischemia induced by coronary angioplasty was similar to that obtained experimentally by a sequenceof brief coronary occlusions. Similar to the animal model, all our patients had evidence of transient ischemia documented by the abnormal systolic and diastolic function during ischemia or by the development of ST-segmentabnormalities, or both. Despite these similarities, we were unable to demonstratethe occurrence of significant postischemic ventricular dysfunction in the 3 study groups. Several factors may explain why there are discrepancies between the experimental and the clinical model, the most striking being duration of ischemia. A common feature of animal experiments is that in these studies ischemia lasts for periods ranging from 5 to 20 minutes, which probably never occurs in patients during episodes of angina either at rest, on effort or during coronary angioplasty. The average duration of ischemia in our study groups was 120 to 180 seconds,an interval that can be consideredreasonablylong from a clinical viewpoint but extremely short when compared with animal studies. Additional variables such as differencesin myocat-dial vulnerability to ischemia among species may help to clarify why no myocardial stunning was detected in our study population. correlation with previous clinical studies In patients with angina at test, several studies have demonstratedthat wall motion abnormalities and ejection fraction return to baseline values in the recovery phase of episodes characterized by ST-segment elevation or depression. Radioisotopic monitoringto demonstrated that systolic function fully recovers after ischemia, both spontaneouslyand after isosorbide dinitrate administration. Echocardiographic18and hemodynamic studies19 also showed that recovery of function in these patients occurs soon after the resolution of the ischemic episodes. Most patients enrolled in these studies experiencedseveral symptomatic and asymptomatic attacks of resting angina each day and all of them showed a normal left ventricular function at rest without stable wall motion abnormalities or hemodynamic changes. Beyond confirming these data, our results also showed that an absolute, reversible reduction in diastolic relaxation usually parallels systolic dysfunction (Figure 2). Myocardial stunning in thesepatients does not appearto representa relevant clinical problem. Most studies performed in the catheterization laboratory shortly after coronary dilation failed to show any persistentsystolic or diastolic ventricular dysfunction after transient, repeated coronary occlusions.11,2@23 Our data are in apparent disagreement with the study by Wijns et al22 who reported the persistenceof diastolic dysfunction at 12 minutes after the end of the procedure in a group of patients treated with a combination of cal1050
THE AMERICANJOURNALOF CARDIOLOGY VOLUME71
cium antagonists/l3blockers and nitrates. The negative effectsof /3 blockers on diastolic function and the shorter interval between angioplasty and control could partly explain this discrepancy. The occurrence of severe ventricular dysfunction during coronary angioplasty has been recently challenged by Verani et al.24In this study,they showed signihcant left ventricular dysfunction during coronary angioplasty mainly in patients who underwent left anterior descendingcoronary artery dilation. If ventricular dysfunction does not occur in patients with right or left circumllex coronary artery stenosis, myocardial stunning cannot be detectedin this subgroup of patients as a logical consequence.However, in our study population, 68% of angioplasty patients had left anterior descending coronary artery disease and all group 2 patients had electrocardiographic changes or typical chest pain, or both, during the procedure. Thus, in the present study, systolic and diastolic dysfunction do not appear to be relevant in the immediate postangioplastyphasein most patients studied. Radioisotopic and echocardiographic studies have been performed in patients with angina on effort mainly at peak exercise, and only few data are available on the postexerciseventricular dynamics. Our data are in agreementwith those of Dymond et alI2 who studied left ventricular function by first-passradionuclide angiography in ischemic patients and did not report any persistent dysfunction at 1 minute after peak exercise.Similarly, Schneider et alI3 reported a normalized ejection fraction 6 minutes into the recovery phase in all their study groups. On the other hand, echocardiographicevidenceof persistentleft ventricular dysfunction alier peak exercise has been demonstratedby Robertson et al25in 35% of their study population. In particular, myocardial stunning was detectedin 1 patient with normal coronary vesselsand in 6 of 10 patients with multivessel disease. Kloner et all4 showed by 2dimensional echocardiography the persistenceof stress-inducedwall motion abnormalities in 90% of patients at 30 minutes after peak exercise in a similar study group. These studies are in apparent contrast to those supporting the concept that echocardiographyafter exercise frequently fails to identify patients with effort ischemia because of the rapid resolution of wall motion abnormalities after termination of exercise26T27 as well as the less-than-perfectdiagnostic accuracy of exercise echocardiography. study limitatbns We used radionuclide angiography to assessglobal and regional left ventricular function. Some limitations of this technique should be mentioned. In all studies performed during ischemia we operated at the lower limit of the temporal resolution of the technique and this may have generatedinaccuracies in the relative measurements;furthermore, we used semiquantitative analysis of regional wall motion and no regional ejection fractions were calculated. In patients with angina at rest, ischemic episodes were induced by ergonovine maleatein 7 of 15 patients. A different degree of ventricular dysfunction could be hypothesized in ergonovine-induced episodes although previous studies failed to show any difference between spontaneousand induced ischemic attacks.10J8,19
MAY 1,1993
We did not obtain measurementsduring balloon inflation in patients undergoing coronary angioplasty,and the occurrence of ischemia was documented in all patients by electrocardiographicchangesand chest pain. In these patients, no assumption can be made about the degree of left ventricular dysfunction and the relative depression of global ejection fraction and peak filling rate during ischemia. Patients with previous myocardial infarction were not studied to avoid any interference with transient ischemia and postischemicventricular dysfunction. Whether myocardial stunning occurs in patients with baselinewall motion abnormalitiesneedsfurther investigation in a different study population. Finally, all patients were studied at baseline, during ischemia (except patients in group 2) and at different time intervals after ischemia.Patientsin groups 1 and 3 were studied starting at 6 minutes after ischemia resolution, whereas patients in group 2 were studied 20 minutes after angioplasty.No conclusion can be drawn as to the possible occurrenceof myocardial stunning earlier in the recovery phase after angioplasty. In conclusion, our data demonstratethat in most patients with transient ischemic ventricular dysfunction of short duration (2 to 4 minutes), recovery of systolic and diastolic function is complete within a few minutes and that the phenomenonof persistent postischemicventricular dysfunction does not play any clinical role; the searchfor myocardial stunning should be directed to different models characterizedby more prolonged ischemia such as unstable angina,28cardiac surgery29and acute myocardial infarction.30 1. Braunwald E, Kloner RA. The stunned myccardium: prolonged, postischemic ventricular dysfunction. Circulation 1982;66:1146-1149. 2. Pagani M, Vatner SF, Baig H, Braunwald E. Initial myocardial adjushnent to brief periods of ischemia and reperfusion in the conscious dog. Circ Res 198243: 83-92. 3. Heyndrickx GR, Millard RW, McRichtie RJ, Maroko PR, Vamer SF. Regional myocardial functional and electmphysiological alterations after brief coronary artery occlusion in conscious dogs. J Clin lnvesr 1975;56:978-985. 4. Bush LR, Buja LM, Samowitz W, Rude RE, W&en M, Tilton G, Willerson IT. Recovery of left ventricular segmental function after long term reperfusion folIpwing tempaxty coronary occlusion in conscious dogs. Circ Res 1983;53:248-263. 5. Masai A, Severi S, De Nes M, L’Abbate A, Chierchia S, Marzilli M, Ballestra AM, Pa&i 0, Biagini A, Distante A. “Variant angina”: one aspect of a continuous spectrum of vasospastic myocardial &hernia. Am J Cardiol1978;42:1019-1035. 6. Gruntzig AR, Seming A, Siegenthaler WE. Non-operative dilation of coronaryartery stenosis: percutaneous tnmsluminal angioplasty. N En,@ J Med 1979;301: 6148. 7. Schtier ES, Sims SJ, Kieso RA, Kerber RE. Sensitization of reperfosed myocaniiurn to subsequent coronary flow reductions. An extension of the concept of mywardial stunning. Circularion 1988;78:717-728. 8. Homans DC, Sublett E, Dai XZ, Bathe RJ. Persistence of regional left venhicular dysfunction after exercise-induced myocardial &hernia. J Clin Invest 198677: 66-73. 9. Tom&e HD, Franklii D, McKown D, Kemper WS, Goberek M, Ross J Jr. Regional myocardial dysfunction and hemcdynamic abnormalities during strenuous exercise in dogs with limited coronary flow. Circ Res 1978;42:4874%. 10. Marzullo P, Parodi 0, Schelbert HR, L’Abbate A. Regional myocardial dys-
function and response to isosorbide dinitrate assessed by phase analysis of radionuelide venbiculogratns. J Am Coil Cardiol 1984;3: 1357-1366. 11. Hauser AM, Gangadharan V, Ramos RG, Gordon S, Timmis GC, Dudlets P. Sequence of mechanical, electrocardiographic and clinical effects of repeated corenary artery occlusion in human beiigs: echocardiographic observations during coronary angioplasty. J Am CON Cardiol 1985;5:193-197. 12. Dymond DS, Foster C, Grenier RP, Carpemter J, Schmidt DH. Peak exercise and immediate postexercise imaging for the detection of left ventricular functional abnormalities in coronary atery disease. Am J Cardiol 1984:53:1532-1537. 13. Schneider RM, Weintraub WS, Klein LW, Se&us PA, Agawal JB, Helfant RH. Rate of left ventricular functional recovery by radionuclide angiography after exercise in coronary artery disease. Am J Car&l 1986;57:927-932. l4. Kloner RA, Allen J, Cox TA, Zheng Y, Ruiz C. Stunned left ventricular myoardium after exercise treadmill testing in coronary artery disease. Am J Cardial 1991;68:32!&334. 15. Zxet BL, Wackers FJT, Tenin ML, Ross R, Weiss M, Slater I, Morrison J, Bourge RC, Pawmani E, Knatterud G, Braunwald E. Assessment of global and regional left ventricular performance at rest and during exercise after thrombolytic therapy for acute myocardial infarction: results of the thmmbolysis in myocardial infarction (TIMI II) study. Am J Cardiol 199269: l-9. 16. Charlat ML, O’Neill PG, Hartley CJ, Roberts R, Bolli R. Prolonged abnormalities of left ventricular diastolic wall thinning in the “stunned” myocardium in conscious dogs: time-course and relation to systolic function. .I Am Coil Cardiol 1989;13:185-194. 17. Nicklas JM, Becker LC, Bulkley BH. Effects of repeated brief coronary occlusion on regional left ventricular function and dimension in dogs. Am J Cardiol 1985:56:47+l78. 18. D&ante A, Rovai D, F&no E, Moscarelli E, Palombo C, Morales MA, Michelassi C, L’ Abbate A. Transient changes in left ventricular mechanics during attacks of F’rinametal’s angina: an M-mode echwxdiographic study. Am Heart J 1984;107:465-474, 19. Chierchia S, Btunelli C, Simon& I, Lazui M, Maseri A. Sequence of events in angina at rest: primary reduction in cornnary flow. CircuUon 1980,61:759-768. 20. Piscione F, Hugenholtz PG. Senuys PW. Impaired left ventricular filling dynanits during percutaneous tmnsluminaJ angioplasty for coronary artery disease. Am J Cardiol 1987;59:29-37. 21. Carlson EB, Hinohxa T, Morris KG. Recovery of systolic and diastolic left ventricular function after 6C-second coronary arterial occlusion during percutaneous ~ansluminal coronary angioplasty for angina pectmis. Am J Cardiol 1987;60: 460-466. 22. Wijns W, Senuys PW, Slager CJ, Grimm J, Krayenbuehl HP, Hugenholtz PG, Hess OM. Effect of coronary occlusion during percutaneous tmnsluminal angioplasty in humans on left ventricular chamber stiffness and regional diastolic pressure-ratio relations. J Am Co/l CardioI 1986;7:45S463. 23. De Feyter PJ, Suyapranata H, Senuys PW, Beatt K, Van der Brand M, Hugenholtz PG. Effects of successful percutaneous transluminal coronary angioplasty on global and regional left ventticulx function in unstable angina pectmis. Am J Cardial 1987;60993-997. 24. Verani MS, Lacy JL, Guidty GW, Nishimnra S, Mahmarian JJ, Athanasoulis T, Roberts R. Quantification of left ventricular performance during aansient cornnary occlusion at various anatomic sites in humans: a study using Tantalum-178 and a multiwire gamma camera. J Am Co/l Cardiol 1992: 19297-306. 25. Robertson WS, Feigenbaum H, Armstrong WF, Dillon JC, O’Donnel JO, McHemy PW. Exercise echocardiography: a clinically practical addition in the eviluation of coronary artery disease. J Am Co0 Cardinl 1983;6:1085-1091. 26. Iliceto S. D’Ambrosio G, Sotino M, Papa A, Amico A, Ricci A, Rizzon P. Comparison of patexercise and tramesophageal attial pacing two-dimensional echocardiography for detection of coronary artery disease. Am J Cardio/ 198657: 547-553. 27. Presti CF. Armstrong WF, Feigenbaum H. Comparison of peak and post-exacise echocardiographic imaging in evaluation of coronary artery disease (abstr). J Am Co/l Cardiol 1987;9:217A. 28. Nixon JV, Brown CN, Smitherman TC. Identiication of transient and persistent segmental wall motion abnormalities in patients with unstable angina by twodimensional echocardiography. Circulation 198265: 1497-1503. 29. Rankin JS, Newman GE, Muhlbaier LH, Behar VS, Fedor JM, Sabisten DC Jr. The effect of coronary revascularization on LV function in ischemic heart disease. .I Thorac Cardiovasc Surg 1985;90:818-832. 30. Wackers FJT. Thrombolytic therapy for myocardial infarction: assessment of efficacy by myocardial perfusion imaging with technetium-99m Sestatnibi. Am J Cardiol 1990;66:36E-41E.
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