Postischemic functional recovery and BMIPP uptake after primary percutaneous transluminal coronary angioplasty in acute myocardial infarction

Postischemic Functional Recovery and BMIPP Uptake After Primary Percutaneous lbansluminal Coronar Angioplasty in Acute Myocardia 1 Infarction Akiyoshi Hashimoto, Shigemichi Tanaka,

MD, Tomoaki Nakata, MD, PhD, Kazufumi Tsuchihashi, MD, PhD, Kenji Fujimori, MD, PhD, and Osamu limura,

MD, PhD, MD, PhD

To correlate asynergic wall motion after primary percutaneous tmnsluminal coronary angioplasty with myocardial perfusion and fatty acid metabolism, uantitative tomogmphies using thallium and mdioi &I inated 15(p-iodophenyl)-3-R,S-methylpentudecanoic acid (BMIPP) were performed during the acute and recovery stages in 56 consecutive patients with acute myocardial infarction, of whom 32 underwent primary percutaneous transluminal coronary an ioplasty (group A) and 24 were conservatively trea tef rou B); 44 patients (79%) had l-vessel disease. RJJ UC myocardial uptakes of thallium and BMIPP and regional wall motion were quantified with a bull’s e e techni ue and a centerline method using contrast lex ventrrcu 4 ogmphy, respective . BMIPPactivity was significantly lower than that of thal‘rium at an acute sta e in both groups. Abnormal BMIPP activities and the 1ifference in thallium and BMIPP abnormalities (perfusion metabolism mismatch) at an acute stage decreased significantly during followupingroupA(111~13toWst:12and30~10to

15 f 10, respectively), and not in group B (129 + 31 vs 118 f 29 and 29 + 13 vs 30 f 10, respectively). Improvement in ional wall motion abnormality cor7i! the improved uptakes of thallium related closely wi and BMIPP (y = 0.64x + 26.4, r = 0.56, p ~0.05; y = 1.1x+ 11.1,r=0.81,pc0.001;respectively).Themismatched uptake of both tracers at an acute stage was significantly related to recovery from asynergic wall motion during follow-up in group A (y = 0.45x + 13.9, r = 0.65, 4.005). In conclusion, despite restored myocardia Pperfusion by primary coronary angioplasty, BMIPP uptake is impaired in salvaged m ocardium at an acute stage of infarction. However, il ed ree and improvement of perFusionmetabolism mismate “9n in acute m ocardial infarction may reflect subsequentrecovery rrom postischemicwall motion abnormality in metabolically impaired but viable myocardium after coronary reperfusion. (Am J Cardiol 1W6;77:25-30)

ositron emission computed tomography has demonstrated increased glucose metabolism and depressed P energy production in viable myocardium after acute

kinetics leading to high-quality imaging.“~~‘U The prcsent study investigates the relation between myocardial perfusion and BMIPP uptake, and correlates perfusion and metabolic alterations with regional left ventricular dysfunction after primary percutaneous transluminal coronary angioplasty (PTCA) in patients with acute myocardial infarction. In particular, this study quantitatively evaluated whether the discordant appearance between myocardial perfusion and BMlPP uptake is related to postischemic functional recovery during several weeks of follow-up.

myocardial infarction. I4 Despite successful coronary reperfusion, prolonged contractile failure with delayed recovery in postischemic, but viable, myocardium has been noted.1” Recently, markedly depressed fatty acid metabolism has been revealed by single-photon emission computed tomography 888 (SPECT) using radioiodinated 15(p-iodophenyl)-3-R,S-methylpentadecanoic acid (BMIPP).9-is A close correlation has been found between impaired metabolism and regional wall motion abnormality rather than myocardial perfusion, but there is still some controversy. l6 Whether alteration of the mismatched appearance of myocardial perfusion and BMIPP uptake correlates with postischemic contractile failure and recovery has not been fully investigated.14.‘” Compared with palmitatelm3 and 15(p-iodophenyl) pentadecanoic acid,‘lIX BMIPP has several advantages for SPECT imaging: greater myocardial retention and lower liver uptake, and appropriate dosimetry and slow irom tne Se
METHODS Patient group: Fifty-six consecutive patients with acute myocardial infarction were recruited. Thirty-two patients (25 men and 7 women, mean age 58 years. range 35 to 78) were treated successfully with PTCA (group A). The remaining 24 (20 men and 4 women, mean age 64 years, range 43 to 84) were treated medically (group B). Primary PTCA was indicated when the onset-toadmission interval was 16 hours or when chest pain remained after admission even if an onset-to-admission interval was >I2 hours: otherwise, conservative medical therapy was selected. No patient underwent thrombolytic therapy. The clinical characteristics of both groups are listed in Table I. There was no statistical difference in the clinical parameters. including age, serum creatine kinase lev-

TABLE I Clinical

Characteristics

of Both

Groups Group A (n = 32)

be (yd Gender (men/women) Infarct-related coronary artery LAD/K/right Coronary narrowings 1 -VD/2-VD/3VD Peak serum creatine kinase level (tU/t) Onset-tc-first study interval (d) Thallium scan BMIPP scan Contrast left ventriculography Onset-tasecond study interval (d) Thallium scan BMIPP scan Contrast left ventriculography Onset to recanalization (hr)

58

i 2 (35-78) 25/7 19/9/4

28/2/2 2,432 ct 382

Values ore expressed as mean * SEM. IAD = left anterior descending artery; LC = left circumflex

13 i2 13 *2 16*2 102 104 132

f 15 f 15 * 18 6il coronary

artery;

el, and any study interval. The inclusion criteria were: (1) acute myocardial infarction; (2) onset of infarction determined by typical symptoms or electrocardiographic findings; (3) thallium and fatty acid imagings performed simultaneously or within a 2-day interval within 30 days after onset of infarction; and (4) regional wall motion assessed by contrast left ventriculography or echocardiography at an acute stage of infarction. In group A, successful primary PTCA was defined as successful dilatation, no residual luminal narrowing of >50%, and Thrombolysis in Myocardial Infarction trial grade 3 coronary flow without major complications (such as emergent coronary artery bypass grafting, repeated angioplasty for reocclusion or restenosis, and recurrence of myocardial infarction or angina). Patients were excluded by the following criteria: (1) postinfarction angi-

VD

na prolonged >l day after admission; (2) postinfarction cardiogenic shock or Group B uncontrollable congestive heart fail(n = 24) ure; (3) coronaty restenosis after primary PTCA; (4) bypass surgery or in64 LIZ 2 (43-84) 20/4 traaortic balloon pumping after admission; (5). valvular or congenital heart 12/4/8 disease and cardiomyopathy; (6) previous coronary artery bypass grafting 16/5/3 2,524 sz 559 or PTCA; and (7) systemic disorders, such as hormonal disturbances, renal 15i2 failure, severe diabetes mellitus, or ma17*2 lignancies. The diagnosis of acute myo20 * 2 cardial infarction was made by at least 75 f 13 3 of the following findings: prolonged 74* 12 severe chest pain, elevated ST-seg111 * 17 ments in 22 leads, elevation of creak-1 tine phosphokinase, and a coronary lesion angiographically determined with= vessel disease. in several hours after admission. In all patients, coronary angiography was performed before discharge; infarct-related coronary artery and the presence or absence of coronary restenosis, if primary PTCA was performed, were evaluated. Study protocol: Thallium and BMIPP SPECT were performed within 30 days after the onset of infarction with mean onset-to-scan intervals of 13 days in group A and 15 to 17 days in group B (Table I). Thallium and fatty acid imagings were repeated in 23 of 32 patients (72%) undergoing primary PTCA and in 14 medically treated patients (58%) with a mean onset-to-scan interval of 102 to 104 days and 74 to 75 days, respectively (Table I). During rest and overnight fasting, thallium-201 (111 MBq) and iodine-123-labeled BMIPP (111 MBq) (provided by Nihon Mediphysics Ltd., Osaka, Japan) were injected intravenously on the same day or within 2 days. Thirty minutes later, SPECT data were acquired

FIGURE 1. Thallium and 15(piadophenyl)-3-R,S-methylpentadecanoic acid (BMIPP) bull’s-eye displv and contrast left venhiculograms performed 3 weeks and 3 months after onset in a 42-year-dd man with acute antero I mfarction undergoing primary percutaneous transluminal coronary angioplas . The larger BMIPP defect relative to that of tha T lium at the acute sta e suggests a perfusion fatty acid metabolism mismatch. At x e recovery stage, the fa acid uptake and regionally depressed wa a motion definitdy improved in the infarct-related segments despite no change of thal1 ium uptake in the corresponding anteroapical region.

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at 5” increments for 30 seconds per increment during a 180” rotation from the 45” left anterior to 45” right anterior oblique views with a large field-of-view rotating gamma camera (Shimadzu SNC 51OOR/Scintipac 24000, Tokyo, Japan, or GE 4OOOXC/T General Electric Medical Systems, Milwaukee, Wisconsin) with a high-resolution parallel-hole collimator. Based on preliminary results obtained from cardiac phantom experiments in our nuclear medicine laboratory, 2 energy windows were selected: the 159 keV photopeak of iodine-123 with a 20% window and the 75 keV photopeak of thallium-201 with a 20% window. Data were stored in a 64 X 64 word matrix nuclear medicine computer system. After transaxial tomograms were reconstructed using a filtered backprojection algorithm using Shepp and Logan’s filter, short-, vertical-, and horizontal long-axis tomograms were obtained. Furthermore, the circumferential profile analysis using short-axis tomograms was performed to obtain a bull’s-eye display as previously reported.21 No attenuation or cross-talk correction was performed because there is no established method for doing so. Quantitative analysis of thallium and BMIPP single-photon emission computed tomography: Quantitative analy-

sis of thallium and BMIPP SPECT was performed using the bull’s-eye method. *’ Normal files were derived from data from 8 control subjects (4 men and 4 women) without cardiac dysfunction or any other systemic disorders, and a standard bull’s-eye map was created. By comparing normal files with the standardized bull’s-eye map, the severity of abnormal activities of thallium and BMIPP was calculated as a severity score using the following formula: Severity score = Z h count (normal count - abnormal count)/total points [60 X (number of short-axis slices)], where 60 is the number of points per short-axis slice and an abnormal count is one that is below the lower limit (mean minus 2 SDS) of the normal range for the 8 control subjects. Quantitative

assessment

of regional

wall

motion:

Statistical analysis: In the present study, all data are continuous variables and all measures are expressed as mean f SEM. The mean differences in groups A and B were compared using the Student’s t test, and comparisons between acute and recovery stages were performed using the paired Student’s r test in each group. Correlations of wall motion abnormality index (SD/chord) with the severity scores of thallium and BMIPP or with changes during follow-up intervals were analyzed using a linear regression analysis. A p value co.05 was considered signilicant.

RESULTS Case example: Thallium and BMIPP bull’s-eye displays and contrast left ventriculograms in a typical patient undergoing primary PTCA are shown in Figure I. The SPECT images 3 weeks and 3 months after onset in a 42-year-old man with acute anteroseptal infarction clearly demonstrate that BMIPP defect is larger than that of thallium (Figure l), suggesting a perfusion fatty acid metabolism mismatch in the infarct-related region. At the recovery stage, BMIPP uptake is definitely improved despite no improvement in thallium uptake in the infarcted region. Contrast left ventriculography reveals improved asynergic wall motion in the anterior and apical segments. Comparison of thallium and BMIPP severity scores during acute and recovery stages of myocardial infarction:

The BMIPP severity score was significantly greater than that of thallium at an acute stage in both groups A (111 +_13 vs 81 + 11, p <0.05) and B (129 + 31 vs 99 + 24, p ~0.05) (Figure 2Aj. In contrast, the BMIPP severity score at an acute stage was significantly reduced (p ~0.05) at a recovery stage in group A, from 111f 13 to 99 f 12. A significant difference (p <0.05), therefore, in thallium and BMIPP scores at a recovery stage remained in group B (118 f 29 vs 88 + 24, p ~0.05) but not in group A (99 f 12 vs 86 f 13. p = NS) (Figure 2A). No

Regional wall motion of the left ventricle was quantified by a modified centerline method using contrast left ventriculography.22 160 The angiographic normal ftle derived from 50 control subjects 1 was compared with normal left ventricular function in our laboratory, and regional wall motion abnormality was quantified as the score of CSD in areas showing the SD chord c-l.5 SD of a normal tile. The first contrast left ventriculogrdphy was performed within 30 days after onset of infarction. Mean intervals were 16 days in group A and 20 days in 60’ -20’ Acute Recovery Acute Recovery ThaIbUm BMIPP Thallium BMIPP group B (Table I). The second stage stag8 stage stage Group A Group B Group A Group B examination wasperformed when I follow-up catheterization was llr*ac 2. A, comparisons of severity scores of thallium (c/o& circles~ and 15(ppossible, with mean n---- intervals :-*, of FIGURE iodophenyl)-3-R,S-melhylpentodecanoic acid (BMIPP) {open ci&s~ at acute and recov 132 days in .21 of c 32 patients in stages of myocardial infarction in both groups. 6, comparisons of the diirence in thal7 __. RI group A and 111days in 11 of 24 urn or BMIPP severity score between acute and recovery stages of myocadial infarction in both patient groups. l p 4.05; A q change. patients in group B (Table I).

(A)

CORONARY

ARTCRY DISEASE/BMIPP

UPTAKE AND

POSTISCHEMIC

DYSFUNCTION

I-

27

significant difference in thallium or BMIPP severity score at an acute or recovery stage was found between groups A and B. The difference in the BMIPP severity score between acute and recovery stages of myocardial infarction was significantly greater (p ~0.05) than that in the thallium score in group A (10 + 5 vs -5 + 6, p ~0.05). However, no significant difference was found in thallium and BMIPP scores in group B (11 f 9 vs 10 f 7, p = NS) (Figure 2B). Figure 3 shows comparisons of the differences in severity scores of thallium and BMIPP (i.e., the degree of thallium/BMIPP mismatch) between acute and recovery stages of myocardial infarction in both patient groups. In group A, the degree of thallium/BMTPP mismatch was significantly reduced, from 30 + 10 to 15 + 10 (p ~0.05) during the follow-up interval, but not in group B (29 f 13 to 30 + 10, p = NS). Correlation of xintigruphic scores with regional wall motion abnormality: Regional wall motion abnormality

index (SD/chord) was significantly reduced, from 108 f 10 to 78 + 9 (p
1

0’

Acute recovery Acute recovery stage stage stage stage

Group A

Group B

FIGURE3. Comparisons

of the diince in severi scores of and 15( -iodophenyi)-3-R,S-methylpenta r ecanoic acid (BMIPP) (i.e, the c&gree of thallium/BMIPP mismatch) between acute and recovery stages of myocardial infarction in groups A and B. *p -zO.O5. thallium

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group A. The regression line was: y = 0.45x + 13.9, r = 0.65, p <0.005 (Figure 5B). However, there was no significant correlation between improvement in regional wall motion and the improved scores of thallium and BMIPP abnormalities or the difference in group B. DISCUSSION Myocardial perfusion and BMIPP uptake in acute myocardial infarction: The present study has clearly demon-

strated the sustained metabolic abnormalities found in salvaged myocardium after acute myocardial ischemia and reperfusion by primary PTCA. Furthermore, quantitative assessment of alterations of thallium and BMJPP abnormalities and regional wall abnormalities revealed that the perfusion metabolism mismatch is definitely associated with the severity of postischemic myocardial dysfunction and its recovery during a 2- to 3-month interval after acute myocardial infarction. The perfusion metabolism mismatch in survived myocardium seems consistent with the concept of initial manifestation of metabolic derangements due to ischemia (i.e., depressed fatty acid oxidation and high-energy phosphate depletion).2”-25 The close correlation between BMIPP activity and intracellular adenosine triphosphate levels26 suggests that fatty acid metabolism and energy production can be partially assessed by BMIPP despite the limited estimation of overall energy production. The presence of thallium activity at rest represents restored myocardial perfusion and cell viability in an infarct-related segment, and the reduced fatty acid uptake reflects metabolic alternations in both viable and nonviable myocardium. The regions where acute ischemia and coronary reperfusion occur would contain inhomogeneous abnormalities in perfusion and metabolic states; in other words, there is necrotic, surviving, but metabolically damaged and fully recovered, myocardium showing various functional abnormalities. This is the rationale for the combined assessment of thallium and BMIPP uptakes and regional wall motion in postischemic myocardium. Primary PTCA contributed to full recovery of coronary perfusion without sustained myocardial ischemia or major complications27-29 and to a clearer evaluation of the perfusion and metabolic correlation. In the primary PTCA group, significantly preserved perfusion relative to the BMIPP uptake and more profound perfusion metabolism mismatch were observed at an acute stage of myocardial infarction than at a recovery stage (Figure 2A), indicating that perfusion metabolism mismatch can be augmented by successful coronary reperfusion despite prolonged impairment of fatty acid uptake and regional wall motion. In contrast, in the medically treated group, both perfusion and fatty acid uptake slightly, but not significantly, improved. In addition to variations of residual coronary lesions and perfusion state, recovery from ischemia may have been different in each patient in this group. Discordant uptake of thallium and the metabolic tracer were more predominant in patients undergoing coronary artery bypass grafting than in those treated with conservative medical therapy.9~ii~‘“~‘s Thus, impaired fatty acid uptake relative to myocardial perfusion indicates the presence of metabolically impaired but salvaged myocardium as a result of coronary recanalJANUARY

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ization for acutely or chronically progressive myocardial ischemia. The identification of myocardium that has a perfusion metabolism mismatch is particularly important in the recanalization era to clarify the effect of coronary reperfusion therapy, myocardial viability, and underlying metabolic injury. Perfusion BMIPP upbke and postischemic cardiac dysfunction: Reduced methyl-branched fatty acid uptake rel-

ative to myocardial perfusion correlated closely with improvement of regional cardiac function during a 2- to 3month follow-up interval after successful primary PTCA. Previous observations9-“,‘~1-5 have shown that impaired fatty acid uptake correlates with ischemia-induced cardiac dysfunction. These findings suggest that

the mismatched appearance of thallium and fatty acid imagings in salvaged myocardium is closely related to perfusion contraction mismatch and postischemic functional recovery. Increased glucose utilization was clinically observed in viable myocardium showing asynergic wall motion, ischemia, and impaired BMIPP uptake.9,‘2 In addition to impairment of energy production and utilization, there are several possible mechanisms underlying postischemic dysfunction or myocardial stunning: calcium overload, insensitivity of myolilaments to calcium, excitation-contraction uncoupling, oxyradical generation, and so forth.’ However, none of these mechanisms can explain the entire process of postischemic dysfunction by itself, and many of the hypotheses were

Group A

100 FIGURE between

4. Correlations wall motion abnormality (WMA) index (SD/chord) and severity scores of thallium and 15

Group B infarction in both change.

300

groups.

A=

I

.

I

Q: 200 I

5

loo

0

200

l

.‘*.

#?

l

0

.

.

z

100

ns

b

FIGURE 5. A, correlation between improvement in regional wall motion abnormality (WY

0 Thallium y = 0.64x+26.4 r=0.56

(sJ$ypt:;c i

or 15 7 piodophenyl)9R,S-meth pentadecanoic acid (BM r PP) during a follow-up interval in roup A. B, correlation Bthe difference in thallium and BMIPP severity scores at an acute stage and wall motion abnormality during a follow-up interval in group A. A = change.

Bloo I

r::y;”

g 0

/A

u,

0

l

60

l

60

s

l

3 40 a

l

--l I/ l

l

l @

~~oq.sx+13.9 I

i -20P

everity score between acute and recovery stages

CORONARY

ARTLRY EISEASE/BMIPP

UPIAYE

ANI

Difference in thallium and BMIPP severity scores

PCXTISC‘HLMIC

3YSFUNClION

29

derived from various studies using different animal species and experimental protocols with relatively brief ischemia. The underlying mechanisms of prolonged but reversible postischemic dysfunction are still not clear and appear to be more complicated in clinical than in experimental situations.7 In the present study, incomplete, but not full, recovery from postischemic dysfunction was observed during a 2- to 3-month follow-up interval. We speculate that the time course and magnitude of postischemic functional recovery depend on the severity of ischemia-reperfusion-induced myocardial injury which, in turn, is determined by an ischemic interval, residual myocardial flow, and the pattern of coronary reperfusion.ls There would be necrosis and salvaged but stunned myocardium, both of which can interact with each other and contribute to prolonged postischemic contractile failure. These possibilities may explain the mechanisms behind the partial recovery from dysfunction and a necessity of a longer period for full recovery in patients with acute myocardial infarction. Study limitaiions: Highly reduced fatty acid activity relative to myocardial perfusion was related to recovery of functional derangement in patients undergoing primary PTCA. This correlation, however, is not clear in the medically treated patients (group B) despite the presence of perfusion metabolism mismatch and slightly decreased abnormalities in thallium and BMIPP uptakes during follow-up (Figure 2). The few patients and the relatively short follow-up interval make the results inconclusive. Regional wall motion abnormalities would change for hours, days, or weeks after ischemia and reperfusion,7s suggesting the necessity for time-course analysis of myocardial perfusion and fatty acid uptake during a longer follow-up interval. Finally, a large patient population is needed to establish the clinical implications and prognostic value of combined perfusion and fatty acid imagings, particularly in patients showing sustained mismatch between perfusion and fatty acid uptake and prolonged postischemic cardiac dysfunction. Acl
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