- Email: [email protected]
Relation Between Infarct Size in ST-Segment Elevation Myocardial Infarction Treated Successfully by Percutaneous Coronary Intervention and Left Ventricular Ejection Fraction Three Months After the Infarct
Relation Between Infarct Size in ST-Segment Elevation Myocardial Infarction Treated Successfully by Percutaneous Coronary Intervention and Left Ventricular Ejection Fraction Three Months After the Infarct Yuri B. Pride, MDa, Jennifer L. Giuseffi, MDc, Satishkumar Mohanavelu, MSb, Caitlin J. Harrigan, BAb, Warren J. Manning, MDa, C. Michael Gibson, MS, MDa, and Evan Appelbaum, MDa,* The goal of this analysis was to determine the relation between myocardial infarct size and left ventricular (LV) ejection fraction (EF) in patients with ST-segment elevation myocardial infarction (STEMI) after primary percutaneous coronary intervention (pPCI) using cardiovascular magnetic resonance imaging (CMR). After STEMI, LVEF and infarct size correlate with prognosis, but the relation between infarct size and LVEF is incompletely known. Consecutive subjects presenting to a single center with STEMI treated with pPCI were enrolled, and cine functional and late gadolinium enhancement CMR was performed 3 months after presentation. From cine images, LVEF was calculated using volumetric summation of disks method. Infarct size was measured as percent LV myocardial volume with late gadolinium enhancement. In the 78 patients enrolled (mean age 54.5 years, range 42 to 82), median LVEF was 56% (interquartile range 49 to 62) and median infarct size was 11% (interquartile range 5 to 18). Of the 53 patients with infarct size <15%, all had LVEF >40%, and there was no significant relation between infarct size and LVEF (slope ⴚ0.43, R2 ⴝ 0.045, p ⴝ 0.13). In patients with infarct size >15%, there was a significant negative linear association between infarct size and LVEF (slope ⴚ1.21, R2 ⴝ 0.66, p <0.001), such that for every 5% increase in infarct size, there was a 6.1% decrease in LVEF. In conclusion, there is a negative linear relation between infarct size and LVEF for moderate to large infarcts. For small infarcts there is no significant relation between infarct size and LVEF. Up to 15% of LV myocardial volume may be infarcted before there is any appreciable decrease in LVEF. © 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010;106:635–640) Following ST-segment elevation myocardial infarction (STEMI), decreased left ventricular (LV) systolic function has been associated with poor short- and long-term clinical outcomes,1–3 and LV ejection fraction (EF) has gained favor as a prognostic indicator of adverse outcomes.4 Since the introduction of rapid reperfusion therapy for STEMI, however, preserved LV function is more common,5,6 and there is likely a spectrum of risk of adverse events in patients with preserved LVEF. Cardiovascular magnetic resonance imaging (CMR) provides highly accurate, reproducible volumetric data regarding LVEF and infarct size. A larger infarct has been reported to be a better identifier of inducible ventricular tachycardia than LVEF in patients with STEMI and is associated with long-term adverse cardiovascular events.7–9 The association between infarct size and LVEF has not been specifi-
a Cardiovascular Division, bPERFUSE Core Laboratory, and cDepartment of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. Manuscript received January 7, 2010; revised manuscript received and accepted April 15, 2010. This work was supported in part by grants from the American College of Cardiology Foundation, Merck Adult Cardiology Research Fellowship Award, Harvard/Massachusetts Institute of Technology/Pfizer, and the Merck Clinical Investigator Training Program, Boston, Massachusetts. *Corresponding author: Tel: 617-667-2737; fax: 617-667-4833. E-mail address: [email protected] (E. Appelbaum).
0002-9149/10/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2010.04.012
cally evaluated, although the presumption is that it is linear across the spectrum of infarct size. Our hypothesis was that in patients with relatively small infarcts, there would be no appreciable decrease in LVEF. We sought to determine the association between infarct size and LVEF using CMR in patients who underwent successful primary percutaneous coronary intervention (pPCI) for STEMI. Methods Patients who were ⱖ18 years of age were eligible for enrollment on presentation with their first STEMI to a single center and were subsequently treated with pPCI. Evidence of new STEMI required the presence of ⱖ1 of the following: typical symptoms of acute infarction, electrocardiographic evidence of new ST-segment elevation ⱖ1 mm in 2 contiguous leads, creatine phosphokinase levels ⬎2 times the upper limit of normal with ⬎5% creatine kinase-MB, or increased troponin I or T. Exclusion criteria were (1) previous MI, defined by pre-existing pathologic Q waves or previous admission for MI with elevated cardiac biomarkers or previous evidence of a regional wall motion abnormality; (2) nonsinus rhythm; (3) inability to obtain informed consent; or (4) fibrinolytic therapy. Patients’ demographics, Thrombolysis In Myocardial Infarction (TIMI) flow grade, TIMI myocardial perfusion grade, microvascular obstrucwww.ajconline.org
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Table 1 Baseline characteristics (n ⫽ 78) Median age (years) Men Medical history Hypertension Diabetes mellitus Hyperlipidemia Current tobacco abuse Family history of premature coronary artery disease Medications before admission Aspirin  blocker Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker Diuretic Statin Transfer from outside hospital Killip class I II III IV Mean Thrombolysis In Myocardial Infarction risk score Door-to-balloon time (minutes), mean (range) Electrocardiographic changes Anterior location Maximum ST-segment elevation (mm), mean (range) ⬎70% ST-segment resolution at 90 minutes Coronary angiography Culprit lesion location Left anterior descending coronary artery Right coronary artery Left circumflex coronary artery Collateral flow to infarct-related artery Disease extent 1 vessel 2 vessels 3 vessels Following percutaneous coronary intervention Thrombolysis In Myocardial Infarction grade 2/3 flow Median Thrombolysis In Myocardial Infarction myocardial perfusion grade Discharge medications Aspirin Clopidogrel  blocker Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker Diuretic Statin
54.5 67% 52% 13% 63% 50% 31%
10% 12 6% 15% 33% 22%
Figure 1. There was a highly significant correlation between infarct size, as measured by peak creatine kinase serum concentration, and that assessed by percent LV mass by CMR.
58% 33% 6% 3% 1.5 82 (34–183) 45% 3.5 (2.1–7.8) 56%
45% 30% 25% 12% 78% 15% 7% 97% 2
100% 100% 88% 83% 35% 96%
tion, infarct size, and LVEF were assessed. Those who were rehospitalized for MI or repeat revascularization before the 3-month CMR were excluded from the study to avoid possible confounding of multiple MIs causing hibernating myocardium, thus influencing CMR outcomes. Participants provided written informed consent according to the hospital’s committee on clinical investigation. All participants were treated according to the standard of care
Figure 2. There was no significant linear relation between infarct size and LVEF in patients with infarct size ⬍15% (A), but there was a significant negative linear relation between infarct size and LV function in patients with infarct size ⱖ15% (B). ⌬ ⫽ change in.
for STEMI and underwent pPCI with serial sampling of serum cardiac biomarkers. A blinded, experienced observer analyzed all 12-lead electrocardiograms obtained at baseline, 90 minutes after reperfusion, and at 3 months. Each was analyzed for STsegment deviation and presence of pathologic Q waves. TIMI flow grade and TIMI myocardial perfusion grade were assessed at an angiographic core laboratory. All flow and perfusion data were over-read by a single experienced observer blinded to clinical outcomes and CMR data. CMR was performed using a commercial 1.5-T Philips
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Figure 3. In patients with anterior infarct location, there was no significant linear relation between infarct size and LVEF in patients infarct size ⬍15% (A). There was a significant negative linear relation between infarct size and LV function in patients with infarct size ⱖ15% (B). Abbreviation as in Figure 2.
Figure 4. In patients with inferior infarct location, there was no significant linear relation between infarct size and LVEF in patients inferior infarct size ⬍15% (A). There was a significant negative linear relation between infarct size and LV function in patients with inferior infarct size ⱖ15% (B). Abbreviation as in Figure 2.
Gyroscan ACS/NT whole-body scanner (Philips Medical Systems, Best, The Netherlands) with a 60-cm diameter bore, Powertrak 6000 gradients (23 mT/m, 219-ms increase time), and a commercial 5-element cardiac synergy coil. All cine images were acquired with retrospective electrocardiographic gating during end-expiratory breath-holds of approximately 8 seconds. Each of the 9 to 12 contiguous short-axis slices (10 mm thick) was obtained using steadystate free precession methods. Gadolinium-diethylenetriamine penta-acetic acid was then given (total dose gadolinium-diethylenetriamine penta-acetic acid dose 0.20 mmol/ kg) followed by late gadolinium enhancement-CMR 15 minutes later. Optimal inversion time was determined by a real-time interactive scan (Look-Locker) that demonstrates uniform suppression of noninfarcted myocardium. CMR analyses were performed on a commercial workstation (EasyVision 5, Philips Medical Systems). LV mass and LVEF were measured from the cine LV short-axis dataset using standard volumetric techniques. Infarct size was measured from the LV short-axis stack of late gadolinium enhancement images as percent LV myocardial volume with late gadolinium enhancement (defined by pixels ⱖ1/2 maximal signal intensity of infarct area) and expressed in units of percent total LV myocardial volume.10 Data are presented as mean ⫾ SD. All continuous variables were tested for normality using the Shapiro-Wilke test. Continuous, normally distributed variables were expressed as mean ⫾ SD. Continuous, non-normal distributions were expressed
as median and interquartile range. Paired 2-tailed Student’s t test was used to assess for significance in continuous variables. Dichotomous variables were analyzed using Fisher’s exact test. The kappa statistic was employed to measure the agreement between CMR indexes and angiographic indexes. A p value ⬍0.05 was considered statistically significant. All analyses were performed using STATA 8.2 (STATA Corp., College Station, Texas). Results Eighty-three consecutive patients presenting with their first STEMI were enrolled in the study, of whom 5 were excluded because they presented before the 3-month CMR follow-up for repeat MI or revascularization. Thus, 78 patients remained in our study cohort (67% men, mean age 54.5 years, range 42 to 82; Table 1). Anatomic distribution of STEMIs is presented in Table 1. Average maximum ST-segment elevation was 3.5 mm (range 2.1 to 7.8). Most patients (78%) had 1-vessel disease. The culprit lesion was in the left anterior descending coronary artery in 45% of cases, right coronary artery in 30%, and left circumflex artery in 25%. After PCI, TIMI grade 2 or 3 flow was present in 97% of patients. Complete STsegment resolution (⬎70%) occurred in 56% of patients at 90 minutes after PCI. Patients underwent CMR 3 months after initial presentation (median 99 days, range 87 to 110), at which time
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Figure 5. Representatives samples of CMR late gadolinium enhancement images with a single, midventricular slice. (A) Small, subendocardial inferior infarct (white arrow, bright area) (2% of LV volume) with normal LV systolic function (LVEF 68%). (B) Moderate anterior infarct (white arrow) (13% of LV volume, 50% transmural) with preserved LV systolic function (LVEF 51%). (C) Moderate inferior infarct (white arrow) (13% of LV volume, ⬎75% transmural) with preserved LV systolic function (LVEF 49%). (D) Large, transmural anterior infarct (white arrow) with lateral extension (black arrow) (26% of LV volume) with decreased LV systolic function (LVEF 38%). LV ⫽ left ventricle.
median LVEF was 56% (interquartile range 49 to 62). There were 25 patients with LVEF ⱕ40% and 4 with LVEF ⬍30%. The remaining patients had relatively preserved LV function (LVEF ⬎40%). Median infarct size was 11% of LV mass (interquartile range 5 to 18). Most patients (n ⫽ 53, 68.0%) had infarct size ⬍15%, and 12 had infarct size ⱖ25%. Infarct size, as measured by peak creatine kinase release, correlated very strongly with infarct size as assessed by percent LV mass (Figure 1). Of the 53 patients with infarct size ⬍15%, all had LVEF ⬎40%; of patients with infarct size ⱖ15%, 11 (44%) had LVEF ⱕ40% (p ⬍0.001). In those patients with smaller infarcts (⬍15%), there was no significant relation between infarct size and LVEF (R2 ⫽ 0.045, p ⫽ 0.13; Figure 2). For those patients with infarct size ⱖ15%, there was a significant negative linear association between infarct size and LVEF (R2 ⫽ 0.66, p ⬍0.001), such that for every 5% increase in infarct size, there was a 6.1% decrease in LVEF.
Patients were further stratified by infarct location. In patients with anterior infarcts, there was no significant relation between infarct size and LVEF in patients with infarct size ⬍15% (R2 ⫽ 0.070, p ⫽ 0.38); in those with large anterior infarcts (ⱖ15%), there was a significant negative linear relation (R2 ⫽ 0.64, p ⫽ 0.03; Figure 3). Similar results were observed in patients with small (⬍15%) inferior infarcts (R2 ⫽ 0.081, p ⫽ 0.08) and large (ⱖ15%) inferior infarcts (R2 ⫽ 0.69, p ⬍0.001; Figure 4). Figure 5 displays representative late gadolinium enhancement images from patients enrolled in the study. Discussion In this prospective cohort study of patients presenting with their first STEMI treated with pPCI, more than 2/3 of patients had preserved LVEF. CMR infarct size was not linearly associated with LVEF across the spectrum of LVEF. Moreover, no patient with an infarct size ⬍15% had
Coronary Artery Disease/Infarct Size and LVEF in STEMI
a significantly decreased LVEF, and, in this population, there was no significant relation between infarct size and LVEF. In patients with larger infarcts (ⱖ15%), nearly half had LV systolic dysfunction, with a significant negative linear relation between infarct size and LVEF. Patients with systolic dysfunction after STEMI have poor short- and long-term clinical outcomes, including a higher incidence of congestive heart failure and arrhythmic events.11 Symptomatic congestive heart failure, arrhythmic events, and mortality have been strongly associated with LVEF.12 However, because of an increase in the use of early reperfusion and other data-driven therapies for STEMI, the incidence of decreased LVEF is decreasing.5,6 Although this is likely to decrease the burden of pump failure, its effect on the incidence of ventricular arrhythmia is unknown. As such, determination of prognostic factors in this growing population of patients with preserved LVEF is desirable. Enzymatic infarct size, as determined by peak serum concentration of creatine kinase or creatine kinase-MB or the area under the curve of these biomarkers, has been associated with adverse outcomes, including cardiogenic shock,13 congestive heart failure,14,15 and short- and longterm mortality.16 –19 A significant association between infarct size and ventricular arrhythmia, even in patients with preserved LVEF, has also been reported. In a post hoc analysis of the Clopidogrel as Adjunctive Reperfusion Therapy–Thrombolysis In Myocardial Infarction (CLARITY-TIMI) 28 study, infarct size measured by peak creatine kinase-MB was significantly associated with ventricular arrhythmia, even in patients with preserved systolic function.20 The prognostic ability of CMR has also been established, although in smaller studies. Infarct size, as assessed by late gadolinium enhancement CMR, has been significantly associated with inducible monomorphic ventricular tachycardia, and infarct mass and surface area have been reported to be better predictors of inducible monomorphic ventricular tachycardia than LVEF.7 In addition, the association between infarct tissue heterogeneity and inducible ventricular tachycardia has been described.8 Moreover, in a prospective cohort study of patients with STEMI undergoing pPCI, infarct size on late gadolinium enhancement CMR correlated more strongly to the composite of death, recurrent MI, and heart failure than did LVEF.21 Taken together, these previous studies suggest that in the growing population of patients with STEMI and relatively preserved LVEF, there is still a significant burden of adverse cardiovascular outcomes, including ventricular arrhythmia. Development of tools to risk stratify this population is therefore desirable. As demonstrated in the present study, patients with normal LVEF after STEMI have a wide range of infarct sizes. Consequently, CMR determination of infarct size may be 1 tool to risk stratify patients with preserved LV function. There are several limitations to this study. The sample is small and predominately male. All these participants presented to a single center. These limitations may have influenced some confounders regarding demographics and treatment, particularly prior to presentation. Also, the patients who were eligible for the 3-month CMR follow-up were relatively healthy. It may be difficult to apply these data to
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all patients in practice given the strict enrollment criteria used. Although there may be an association between infarct size and adverse cardiovascular events independent of LVEF, long-term clinical outcomes were not assessed in this study. 1. Dewhurst NG, Hannan WJ, Muir AL. Prognostic value of radionuclide ventriculography after myocardial infarction. Q J Med 1980;49:479 – 490. 2. Sanz G, Castaner A, Betriu A, Magrina J, Roig E, Coll S, Pare JC, Navarro-Lopez F. Determinants of prognosis in survivors of myocardial infarction: a prospective clinical angiographic study. N Engl J Med 1982;306:1065–1070. 3. Schulze RA Jr, Humphries JO, Griffith LS, Ducci H, Achuff S, Baird MG, Mellits ED, Pitt B. Left ventricular and coronary angiographic anatomy. Relationship to ventricular irritability in the late hospital phase of acute myocardial infarction. Circulation 1977;55:839 – 843. 4. Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R, Domanski M, Troutman C, Anderson J, Johnson G, McNulty SE, Clapp-Channing N, Davidson-Ray LD, Fraulo ES, Fishbein DP, Luceri RM, Ip JH. Amiodarone or an implantable cardioverterdefibrillator for congestive heart failure. N Engl J Med 2005;352: 225–237. 5. Hellermann JP, Goraya TY, Jacobsen SJ, Weston SA, Reeder GS, Gersh BJ, Redfield MM, Rodeheffer RJ, Yawn BP, Roger VL. Incidence of heart failure after myocardial infarction: is it changing over time? Am J Epidemiol 2003;157:1101–1107. 6. Hellermann JP, Reeder GS, Jacobsen SJ, Weston SA, Killian JM, Roger VL. Longitudinal trends in the severity of acute myocardial infarction: a population study in Olmsted County, Minnesota. Am J Epidemiol 2002;156:246 –253. 7. Bello D, Fieno DS, Kim RJ, Pereles FS, Passman R, Song G, Kadish AH, Goldberger JJ. Infarct morphology identifies patients with substrate for sustained ventricular tachycardia. J Am Coll Cardiol 2005; 45:1104 –1108. 8. Schmidt A, Azevedo CF, Cheng A, Gupta SN, Bluemke DA, Foo TK, Gerstenblith G, Weiss RG, Marban E, Tomaselli GF, Lima JA, Wu KC. Infarct tissue heterogeneity by magnetic resonance imaging identifies enhanced cardiac arrhythmia susceptibility in patients with left ventricular dysfunction. Circulation 2007;115:2006 – 2014. 9. Wu KC, Zerhouni EA, Judd RM, Lugo-Olivieri CH, Barouch LA, Schulman SP, Blumenthal RS, Lima JA. Prognostic significance of microvascular obstruction by magnetic resonance imaging in patients with acute myocardial infarction. Circulation 1998;97:765– 772. 10. Amado LC, Gerber BL, Gupta SN, Rettmann DW, Szarf G, Schock R, Nasir K, Kraitchman DL, Lima JA. Accurate and objective infarct sizing by contrast-enhanced magnetic resonance imaging in a canine myocardial infarction model. J Am Coll Cardiol 2004;44: 2383–2389. 11. Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, Daubert JP, Higgins SL, Brown MW, Andrews ML. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002;346:877– 883. 12. Curtis JP, Sokol SI, Wang Y, Rathore SS, Ko DT, Jadbabaie F, Portnay EL, Marshalko SJ, Radford MJ, Krumholz HM. The association of left ventricular ejection fraction, mortality, and cause of death in stable outpatients with heart failure. J Am Coll Cardiol 2003;42: 736 –742. 13. Grande P, Christiansen C, Hansen BF. Myocardial infarct size and cardiogenic shock. Eur Heart J 1983;4:289 –294. 14. Christenson RH, Vollmer RT, Ohman EM, Peck S, Thompson TD, Duh SH, Ellis SG, Newby LK, Topol EJ, Califf RM. Relation of temporal creatine kinase-MB release and outcome after thrombolytic therapy for acute myocardial infarction. TAMI Study Group. Am J Cardiol 2000;85:543–547. 15. Turer AT, Mahaffey KW, Gallup D, Weaver WD, Christenson RH, Every NR, Ohman EM. Enzyme estimates of infarct size correlate with functional and clinical outcomes in the setting of ST-segment elevation myocardial infarction. Curr Control Trials Cardiovasc Med 2005; 6:12.
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16. Nienhuis MB, Ottervanger JP, de Boer MJ, Dambrink JH, Hoorntje JC, Gosselink AT, Suryapranata H, van’t Hof AW. Prognostic importance of creatine kinase and creatine kinase-MB after primary percutaneous coronary intervention for ST-elevation myocardial infarction. Am Heart J 2008;155:673– 679. 17. Grande P, Christiansen C, Pedersen A. Influence of acute myocardial infarct size on acute and one-year mortality. Eur Heart J 1983;4:20–25. 18. Grande P, Nielsen A, Wagner GS, Christiansen C. Quantitative influence of serum creatine kinase isoenzyme MB estimated infarct size and other prognostic variables on one-year mortality after acute myocardial infarction. Br Heart J 1985;53:9 –15. 19. Halkin A, Stone GW, Grines CL, Cox DA, Rutherford BD, Esente P, Meils CM, Albertsson P, Farah A, Tcheng JE, Lansky AJ, Mehran R. Prognostic implications of creatine kinase elevation after primary
percutaneous coronary intervention for acute myocardial infarction. J Am Coll Cardiol 2006;47:951–961. 20. Pride YB, Appelbaum E, Lord EE, Sloan S, Cannon CP, Sabatine MS, Gibson CM. Relation between myocardial infarct size and ventricular tachyarrhythmia among patients with preserved left ventricular ejection fraction following fibrinolytic therapy for STsegment elevation myocardial infarction. Am J Cardiol 2009;104: 475– 479. 21. Wu E, Ortiz JT, Tejedor P, Lee DC, Bucciarelli-Ducci C, Kansal P, Carr JC, Holly TA, Lloyd-Jones D, Klocke FJ, Bonow RO. Infarct size by contrast enhanced cardiac magnetic resonance is a stronger predictor of outcomes than left ventricular ejection fraction or end-systolic volume index: prospective cohort study. Heart 2008; 94:730 –736.
a Cardiovascular Division, bPERFUSE Core Laboratory, and cDepartment of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. Manuscript received January 7, 2010; revised manuscript received and accepted April 15, 2010. This work was supported in part by grants from the American College of Cardiology Foundation, Merck Adult Cardiology Research Fellowship Award, Harvard/Massachusetts Institute of Technology/Pfizer, and the Merck Clinical Investigator Training Program, Boston, Massachusetts. *Corresponding author: Tel: 617-667-2737; fax: 617-667-4833. E-mail address: [email protected] (E. Appelbaum).
0002-9149/10/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2010.04.012
cally evaluated, although the presumption is that it is linear across the spectrum of infarct size. Our hypothesis was that in patients with relatively small infarcts, there would be no appreciable decrease in LVEF. We sought to determine the association between infarct size and LVEF using CMR in patients who underwent successful primary percutaneous coronary intervention (pPCI) for STEMI. Methods Patients who were ⱖ18 years of age were eligible for enrollment on presentation with their first STEMI to a single center and were subsequently treated with pPCI. Evidence of new STEMI required the presence of ⱖ1 of the following: typical symptoms of acute infarction, electrocardiographic evidence of new ST-segment elevation ⱖ1 mm in 2 contiguous leads, creatine phosphokinase levels ⬎2 times the upper limit of normal with ⬎5% creatine kinase-MB, or increased troponin I or T. Exclusion criteria were (1) previous MI, defined by pre-existing pathologic Q waves or previous admission for MI with elevated cardiac biomarkers or previous evidence of a regional wall motion abnormality; (2) nonsinus rhythm; (3) inability to obtain informed consent; or (4) fibrinolytic therapy. Patients’ demographics, Thrombolysis In Myocardial Infarction (TIMI) flow grade, TIMI myocardial perfusion grade, microvascular obstrucwww.ajconline.org
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Table 1 Baseline characteristics (n ⫽ 78) Median age (years) Men Medical history Hypertension Diabetes mellitus Hyperlipidemia Current tobacco abuse Family history of premature coronary artery disease Medications before admission Aspirin  blocker Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker Diuretic Statin Transfer from outside hospital Killip class I II III IV Mean Thrombolysis In Myocardial Infarction risk score Door-to-balloon time (minutes), mean (range) Electrocardiographic changes Anterior location Maximum ST-segment elevation (mm), mean (range) ⬎70% ST-segment resolution at 90 minutes Coronary angiography Culprit lesion location Left anterior descending coronary artery Right coronary artery Left circumflex coronary artery Collateral flow to infarct-related artery Disease extent 1 vessel 2 vessels 3 vessels Following percutaneous coronary intervention Thrombolysis In Myocardial Infarction grade 2/3 flow Median Thrombolysis In Myocardial Infarction myocardial perfusion grade Discharge medications Aspirin Clopidogrel  blocker Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker Diuretic Statin
54.5 67% 52% 13% 63% 50% 31%
10% 12 6% 15% 33% 22%
Figure 1. There was a highly significant correlation between infarct size, as measured by peak creatine kinase serum concentration, and that assessed by percent LV mass by CMR.
58% 33% 6% 3% 1.5 82 (34–183) 45% 3.5 (2.1–7.8) 56%
45% 30% 25% 12% 78% 15% 7% 97% 2
100% 100% 88% 83% 35% 96%
tion, infarct size, and LVEF were assessed. Those who were rehospitalized for MI or repeat revascularization before the 3-month CMR were excluded from the study to avoid possible confounding of multiple MIs causing hibernating myocardium, thus influencing CMR outcomes. Participants provided written informed consent according to the hospital’s committee on clinical investigation. All participants were treated according to the standard of care
Figure 2. There was no significant linear relation between infarct size and LVEF in patients with infarct size ⬍15% (A), but there was a significant negative linear relation between infarct size and LV function in patients with infarct size ⱖ15% (B). ⌬ ⫽ change in.
for STEMI and underwent pPCI with serial sampling of serum cardiac biomarkers. A blinded, experienced observer analyzed all 12-lead electrocardiograms obtained at baseline, 90 minutes after reperfusion, and at 3 months. Each was analyzed for STsegment deviation and presence of pathologic Q waves. TIMI flow grade and TIMI myocardial perfusion grade were assessed at an angiographic core laboratory. All flow and perfusion data were over-read by a single experienced observer blinded to clinical outcomes and CMR data. CMR was performed using a commercial 1.5-T Philips
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Figure 3. In patients with anterior infarct location, there was no significant linear relation between infarct size and LVEF in patients infarct size ⬍15% (A). There was a significant negative linear relation between infarct size and LV function in patients with infarct size ⱖ15% (B). Abbreviation as in Figure 2.
Figure 4. In patients with inferior infarct location, there was no significant linear relation between infarct size and LVEF in patients inferior infarct size ⬍15% (A). There was a significant negative linear relation between infarct size and LV function in patients with inferior infarct size ⱖ15% (B). Abbreviation as in Figure 2.
Gyroscan ACS/NT whole-body scanner (Philips Medical Systems, Best, The Netherlands) with a 60-cm diameter bore, Powertrak 6000 gradients (23 mT/m, 219-ms increase time), and a commercial 5-element cardiac synergy coil. All cine images were acquired with retrospective electrocardiographic gating during end-expiratory breath-holds of approximately 8 seconds. Each of the 9 to 12 contiguous short-axis slices (10 mm thick) was obtained using steadystate free precession methods. Gadolinium-diethylenetriamine penta-acetic acid was then given (total dose gadolinium-diethylenetriamine penta-acetic acid dose 0.20 mmol/ kg) followed by late gadolinium enhancement-CMR 15 minutes later. Optimal inversion time was determined by a real-time interactive scan (Look-Locker) that demonstrates uniform suppression of noninfarcted myocardium. CMR analyses were performed on a commercial workstation (EasyVision 5, Philips Medical Systems). LV mass and LVEF were measured from the cine LV short-axis dataset using standard volumetric techniques. Infarct size was measured from the LV short-axis stack of late gadolinium enhancement images as percent LV myocardial volume with late gadolinium enhancement (defined by pixels ⱖ1/2 maximal signal intensity of infarct area) and expressed in units of percent total LV myocardial volume.10 Data are presented as mean ⫾ SD. All continuous variables were tested for normality using the Shapiro-Wilke test. Continuous, normally distributed variables were expressed as mean ⫾ SD. Continuous, non-normal distributions were expressed
as median and interquartile range. Paired 2-tailed Student’s t test was used to assess for significance in continuous variables. Dichotomous variables were analyzed using Fisher’s exact test. The kappa statistic was employed to measure the agreement between CMR indexes and angiographic indexes. A p value ⬍0.05 was considered statistically significant. All analyses were performed using STATA 8.2 (STATA Corp., College Station, Texas). Results Eighty-three consecutive patients presenting with their first STEMI were enrolled in the study, of whom 5 were excluded because they presented before the 3-month CMR follow-up for repeat MI or revascularization. Thus, 78 patients remained in our study cohort (67% men, mean age 54.5 years, range 42 to 82; Table 1). Anatomic distribution of STEMIs is presented in Table 1. Average maximum ST-segment elevation was 3.5 mm (range 2.1 to 7.8). Most patients (78%) had 1-vessel disease. The culprit lesion was in the left anterior descending coronary artery in 45% of cases, right coronary artery in 30%, and left circumflex artery in 25%. After PCI, TIMI grade 2 or 3 flow was present in 97% of patients. Complete STsegment resolution (⬎70%) occurred in 56% of patients at 90 minutes after PCI. Patients underwent CMR 3 months after initial presentation (median 99 days, range 87 to 110), at which time
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Figure 5. Representatives samples of CMR late gadolinium enhancement images with a single, midventricular slice. (A) Small, subendocardial inferior infarct (white arrow, bright area) (2% of LV volume) with normal LV systolic function (LVEF 68%). (B) Moderate anterior infarct (white arrow) (13% of LV volume, 50% transmural) with preserved LV systolic function (LVEF 51%). (C) Moderate inferior infarct (white arrow) (13% of LV volume, ⬎75% transmural) with preserved LV systolic function (LVEF 49%). (D) Large, transmural anterior infarct (white arrow) with lateral extension (black arrow) (26% of LV volume) with decreased LV systolic function (LVEF 38%). LV ⫽ left ventricle.
median LVEF was 56% (interquartile range 49 to 62). There were 25 patients with LVEF ⱕ40% and 4 with LVEF ⬍30%. The remaining patients had relatively preserved LV function (LVEF ⬎40%). Median infarct size was 11% of LV mass (interquartile range 5 to 18). Most patients (n ⫽ 53, 68.0%) had infarct size ⬍15%, and 12 had infarct size ⱖ25%. Infarct size, as measured by peak creatine kinase release, correlated very strongly with infarct size as assessed by percent LV mass (Figure 1). Of the 53 patients with infarct size ⬍15%, all had LVEF ⬎40%; of patients with infarct size ⱖ15%, 11 (44%) had LVEF ⱕ40% (p ⬍0.001). In those patients with smaller infarcts (⬍15%), there was no significant relation between infarct size and LVEF (R2 ⫽ 0.045, p ⫽ 0.13; Figure 2). For those patients with infarct size ⱖ15%, there was a significant negative linear association between infarct size and LVEF (R2 ⫽ 0.66, p ⬍0.001), such that for every 5% increase in infarct size, there was a 6.1% decrease in LVEF.
Patients were further stratified by infarct location. In patients with anterior infarcts, there was no significant relation between infarct size and LVEF in patients with infarct size ⬍15% (R2 ⫽ 0.070, p ⫽ 0.38); in those with large anterior infarcts (ⱖ15%), there was a significant negative linear relation (R2 ⫽ 0.64, p ⫽ 0.03; Figure 3). Similar results were observed in patients with small (⬍15%) inferior infarcts (R2 ⫽ 0.081, p ⫽ 0.08) and large (ⱖ15%) inferior infarcts (R2 ⫽ 0.69, p ⬍0.001; Figure 4). Figure 5 displays representative late gadolinium enhancement images from patients enrolled in the study. Discussion In this prospective cohort study of patients presenting with their first STEMI treated with pPCI, more than 2/3 of patients had preserved LVEF. CMR infarct size was not linearly associated with LVEF across the spectrum of LVEF. Moreover, no patient with an infarct size ⬍15% had
Coronary Artery Disease/Infarct Size and LVEF in STEMI
a significantly decreased LVEF, and, in this population, there was no significant relation between infarct size and LVEF. In patients with larger infarcts (ⱖ15%), nearly half had LV systolic dysfunction, with a significant negative linear relation between infarct size and LVEF. Patients with systolic dysfunction after STEMI have poor short- and long-term clinical outcomes, including a higher incidence of congestive heart failure and arrhythmic events.11 Symptomatic congestive heart failure, arrhythmic events, and mortality have been strongly associated with LVEF.12 However, because of an increase in the use of early reperfusion and other data-driven therapies for STEMI, the incidence of decreased LVEF is decreasing.5,6 Although this is likely to decrease the burden of pump failure, its effect on the incidence of ventricular arrhythmia is unknown. As such, determination of prognostic factors in this growing population of patients with preserved LVEF is desirable. Enzymatic infarct size, as determined by peak serum concentration of creatine kinase or creatine kinase-MB or the area under the curve of these biomarkers, has been associated with adverse outcomes, including cardiogenic shock,13 congestive heart failure,14,15 and short- and longterm mortality.16 –19 A significant association between infarct size and ventricular arrhythmia, even in patients with preserved LVEF, has also been reported. In a post hoc analysis of the Clopidogrel as Adjunctive Reperfusion Therapy–Thrombolysis In Myocardial Infarction (CLARITY-TIMI) 28 study, infarct size measured by peak creatine kinase-MB was significantly associated with ventricular arrhythmia, even in patients with preserved systolic function.20 The prognostic ability of CMR has also been established, although in smaller studies. Infarct size, as assessed by late gadolinium enhancement CMR, has been significantly associated with inducible monomorphic ventricular tachycardia, and infarct mass and surface area have been reported to be better predictors of inducible monomorphic ventricular tachycardia than LVEF.7 In addition, the association between infarct tissue heterogeneity and inducible ventricular tachycardia has been described.8 Moreover, in a prospective cohort study of patients with STEMI undergoing pPCI, infarct size on late gadolinium enhancement CMR correlated more strongly to the composite of death, recurrent MI, and heart failure than did LVEF.21 Taken together, these previous studies suggest that in the growing population of patients with STEMI and relatively preserved LVEF, there is still a significant burden of adverse cardiovascular outcomes, including ventricular arrhythmia. Development of tools to risk stratify this population is therefore desirable. As demonstrated in the present study, patients with normal LVEF after STEMI have a wide range of infarct sizes. Consequently, CMR determination of infarct size may be 1 tool to risk stratify patients with preserved LV function. There are several limitations to this study. The sample is small and predominately male. All these participants presented to a single center. These limitations may have influenced some confounders regarding demographics and treatment, particularly prior to presentation. Also, the patients who were eligible for the 3-month CMR follow-up were relatively healthy. It may be difficult to apply these data to
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all patients in practice given the strict enrollment criteria used. Although there may be an association between infarct size and adverse cardiovascular events independent of LVEF, long-term clinical outcomes were not assessed in this study. 1. Dewhurst NG, Hannan WJ, Muir AL. Prognostic value of radionuclide ventriculography after myocardial infarction. Q J Med 1980;49:479 – 490. 2. Sanz G, Castaner A, Betriu A, Magrina J, Roig E, Coll S, Pare JC, Navarro-Lopez F. Determinants of prognosis in survivors of myocardial infarction: a prospective clinical angiographic study. N Engl J Med 1982;306:1065–1070. 3. Schulze RA Jr, Humphries JO, Griffith LS, Ducci H, Achuff S, Baird MG, Mellits ED, Pitt B. Left ventricular and coronary angiographic anatomy. Relationship to ventricular irritability in the late hospital phase of acute myocardial infarction. Circulation 1977;55:839 – 843. 4. Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R, Domanski M, Troutman C, Anderson J, Johnson G, McNulty SE, Clapp-Channing N, Davidson-Ray LD, Fraulo ES, Fishbein DP, Luceri RM, Ip JH. Amiodarone or an implantable cardioverterdefibrillator for congestive heart failure. N Engl J Med 2005;352: 225–237. 5. Hellermann JP, Goraya TY, Jacobsen SJ, Weston SA, Reeder GS, Gersh BJ, Redfield MM, Rodeheffer RJ, Yawn BP, Roger VL. Incidence of heart failure after myocardial infarction: is it changing over time? Am J Epidemiol 2003;157:1101–1107. 6. Hellermann JP, Reeder GS, Jacobsen SJ, Weston SA, Killian JM, Roger VL. Longitudinal trends in the severity of acute myocardial infarction: a population study in Olmsted County, Minnesota. Am J Epidemiol 2002;156:246 –253. 7. Bello D, Fieno DS, Kim RJ, Pereles FS, Passman R, Song G, Kadish AH, Goldberger JJ. Infarct morphology identifies patients with substrate for sustained ventricular tachycardia. J Am Coll Cardiol 2005; 45:1104 –1108. 8. Schmidt A, Azevedo CF, Cheng A, Gupta SN, Bluemke DA, Foo TK, Gerstenblith G, Weiss RG, Marban E, Tomaselli GF, Lima JA, Wu KC. Infarct tissue heterogeneity by magnetic resonance imaging identifies enhanced cardiac arrhythmia susceptibility in patients with left ventricular dysfunction. Circulation 2007;115:2006 – 2014. 9. Wu KC, Zerhouni EA, Judd RM, Lugo-Olivieri CH, Barouch LA, Schulman SP, Blumenthal RS, Lima JA. Prognostic significance of microvascular obstruction by magnetic resonance imaging in patients with acute myocardial infarction. Circulation 1998;97:765– 772. 10. Amado LC, Gerber BL, Gupta SN, Rettmann DW, Szarf G, Schock R, Nasir K, Kraitchman DL, Lima JA. Accurate and objective infarct sizing by contrast-enhanced magnetic resonance imaging in a canine myocardial infarction model. J Am Coll Cardiol 2004;44: 2383–2389. 11. Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, Daubert JP, Higgins SL, Brown MW, Andrews ML. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002;346:877– 883. 12. Curtis JP, Sokol SI, Wang Y, Rathore SS, Ko DT, Jadbabaie F, Portnay EL, Marshalko SJ, Radford MJ, Krumholz HM. The association of left ventricular ejection fraction, mortality, and cause of death in stable outpatients with heart failure. J Am Coll Cardiol 2003;42: 736 –742. 13. Grande P, Christiansen C, Hansen BF. Myocardial infarct size and cardiogenic shock. Eur Heart J 1983;4:289 –294. 14. Christenson RH, Vollmer RT, Ohman EM, Peck S, Thompson TD, Duh SH, Ellis SG, Newby LK, Topol EJ, Califf RM. Relation of temporal creatine kinase-MB release and outcome after thrombolytic therapy for acute myocardial infarction. TAMI Study Group. Am J Cardiol 2000;85:543–547. 15. Turer AT, Mahaffey KW, Gallup D, Weaver WD, Christenson RH, Every NR, Ohman EM. Enzyme estimates of infarct size correlate with functional and clinical outcomes in the setting of ST-segment elevation myocardial infarction. Curr Control Trials Cardiovasc Med 2005; 6:12.
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