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Changes of Myocardial Function in Patients with Non-ST-Elevation Acute Coronary Syndrome Awaiting Coronary Angiography
Changes of Myocardial Function in Patients with Non-ST-Elevation Acute Coronary Syndrome Awaiting Coronary Angiography Bjørnar Grenne, MDa, Christian Eek, MDb, Benthe Sjøli, MDa, Helge Skulstad, MD, PhDb, Svend Aakhus, MD, PhDb, Otto A. Smiseth, MD, PhDb, Thor Edvardsen, MD, PhDb, and Harald Brunvand, MD, PhDa,* The optimal timing of coronary angiography in patients with non–ST elevation (NSTE) acute coronary syndromes (ACS) is debated. American Heart Association and American College of Cardiology guidelines recommend an early invasive strategy <12 to 48 hours after the onset of symptoms. The objective of the present study was to determine possible changes in myocardial function in patients with NSTE ACS awaiting coronary angiography. One hundred two patients with suspected NSTE ACS were enrolled, including 56 with NSTE myocardial infarctions (NSTEMIs), 23 with unstable angina pectoris, and 23 with noncoronary chest pain. Global and regional myocardial function was measured as longitudinal and circumferential strain using speckle-tracking echocardiography. Measurements were performed at admission and immediately before coronary angiography (30 ⴞ 16 hours after admission). In patients with NSTEMIs, there was deterioration in longitudinal global strain from ⴚ16.1 ⴞ 2.6% at admission to ⴚ15.0 ⴞ 2.6% before coronary angiography (p <0.001). This was due to deterioration in longitudinal strain in the territory supplied by the infarct-related artery from ⴚ14.2 ⴞ 4.2% to ⴚ12.0 ⴞ 4.1% (p <0.001). Patients with NSTEMIs due to acute coronary occlusion underwent prominent worsening in longitudinal and circumferential strains (ⴚ15.7 ⴞ 2.9% to ⴚ13.9 ⴞ 3.0%, p ⴝ 0.001, and ⴚ16.7 ⴞ 4.0% to ⴚ15.0 ⴞ 3.9%, p ⴝ 0.01, respectively) compared to patients with NSTEMIs without occlusions. There were no changes in strain in patients with unstable angina pectoris or noncoronary chest pain. In patients with NSTEMIs without acute coronary occlusions, myocardial function improved after revascularization, whereas patients with acute occlusions demonstrated no improvement. In conclusion, myocardial function deteriorates in patients with NSTEMIs awaiting coronary angiography. Patients with acute coronary occlusions have the most prominent deterioration, and this subgroup shows no recovery of function after revascularization. © 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010;105:1212–1218) Non–ST elevation (NSTE) acute coronary syndromes (ACS), which comprise NSTE myocardial infarction (NSTEMI) and unstable angina pectoris, are more frequent than myocardial infarctions with ST elevations.1 The American Heart Association and American College of Cardiology guidelines recommend coronary angiography within 12 to 48 hours for risk stratification and planning of revascularization in patients with increased risk,2 whereas the European Society of Cardiology recommends angiography within 72 hours for high- and intermediate-risk patients.1 However, the optimal timing of coronary angiography for patients scheduled to receive this early invasive strategy remains unsolved. The NSTE ACS population is very heterogenous, with pathology ranging from discrete atherosclerosis in small-caliber a
Department of Medicine, Sørlandet Hospital, Arendal, Norway; and Department of Cardiology, Rikshospitalet, University Hospital and University of Oslo, Oslo, Norway. Manuscript received September 16, 2009; revised manuscript received and accepted December 14, 2009. This study was supported by the Southeastern Norway Regional Health Authority, Hamar, Norway; the Norwegian Foundation for Health and Rehabilitation, Oslo, Norway; and Sørlandet Hospital, Arendal, Norway. *Corresponding author: Tel: 47-37014000; fax: 47-37014010. E-mail address: [email protected] (H. Brunvand). b
0002-9149/10/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2009.12.036
coronary arteries to extensive disease with critical stenoses or occlusions of major vessels. Some patients may have ongoing myocardial ischemia until revascularization, and little is known about how this affects myocardial function. New echocardiographic modalities enable the accurate evaluation of global and regional myocardial deformation by strain and can identify abnormal myocardial function due to ischemia and necrosis.3–10 Echocardiography is easily accessible and can be performed repeatedly in the emergency or intensive care room. Consequently, strain by echocardiography is a feasible method for evaluation of myocardial function in patients with NSTE ACS to study changes in function due to ongoing ischemia. The aim of this study was to determine possible changes in myocardial function in terms of strain using speckle-tracking echocardiography in patients with NSTE ACS awaiting coronary angiography. Methods Patients with suspected NSTE ACS admitted to a local hospital were consecutively evaluated for study inclusion. Eligible patients had to fulfill 3 criteria: (1) acute anginal pain lasting ⱖ10 minutes and clinically classified as unstawww.AJConline.org
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Figure 1. Strain measurements. Apical 4-chamber view, showing how the strain measurements were performed. There was reduced systolic strain and postsystolic shortening in the lateral wall.
ble angina pectoris or NSTEMI, (2) a history of chest pain ⬍3 days, and (3) indication for coronary angiography according to current guidelines. Exclusion criteria were (1) age ⬍18 years, (2) previous coronary artery bypass graft or valve surgery, (3) bundle branch block with QRS interval ⬎0.12 seconds, (4) severe valvular dysfunction, (5) atrial fibrillation with heart rate ⬎100 beats/min or continuous severe arrhythmia, and (6) severe mental disorder or short life expectancy because of extracardiac reasons. Because the aim of this study was to assess myocardial function in patients with NSTE ACS awaiting coronary angiography, patients who were planned for very early (⬍10 hours) angiography were not included. All patients received medical treatment according to guidelines.1,2 One hundred two patients were included and retrospectively grouped according to discharge diagnosis. NSTEMI and unstable angina pectoris were diagnosed by convention,11 using a cut-off value of troponin T ⬎0.03 g/L for NSTEMI. Patients without evidence of significant coronary artery disease were classified as having noncoronary chest pain (NCCP). The research protocol was approved by the regional committee for medical research and ethics. All participants gave written informed consent. Echocardiographic examinations were performed using a Vivid 7 scanner (GE Vingmed Ultrasound AS, Horten, Norway). All recordings were digitally stored. Measurements were performed at admission and immediately before coronary angiography. Additionally, 95 patients (93%) were examined using echocardiography 99 ⫾ 20 days after admission. Three consecutive heart cycles from 3 apical imaging planes (4 chamber, 2 chamber, and long axis) and 3 short-axis planes (mitral valve, papillary muscle, and apex) were obtained using 2-dimensional grayscale echocardiography. The mean frame rate was 74 ⫾ 9 frames/s. Mitral inflow velocity was recorded by pulsed Doppler with the sample volume placed between the leaflet tips. Mitral annular velocities were recorded by tissue Doppler using color mode. Early diastolic mitral annular velocity (e=) was calculated by averaging septal and lateral annular velocities. Echocardiographic recordings were analyzed by a single observer blinded to patient data, using EchoPAC version 7 (GE Vingmed Ultrasound AS). Longitudinal strain was computed on the basis of the apical imaging planes and circumferential strain on the basis of the short-axis planes. A 16-segment model of the left ventricle was obtained,12
Table 1 Patient characteristics Variable
NSTEMI (n ⫽ 56)
UAP (n ⫽ 23)
NCCP (n ⫽ 23)
Age (years) Men/women Previous myocardial infarction Previous PCI Time from symptom onset to admission (hours) Time from admission to angiography (hours) Medications before hospitalization Acetylsalicylic acid Clopidogrel  blockers ACE inhibitors/ARBs Calcium inhibitors Statins Medications before coronary angiography Acetylsalicylic acid Clopidogrel Low–molecular weight heparin Glycoprotein IIb/IIIa inhibitors  blockers ACE inhibitors/ARBs Calcium inhibitors Nitroglycerin Statins
67 ⫾ 14* 41:15 7 (13%) 2 (4%)* 9 ⫾ 10
58 ⫾ 11 14:9 7 (30%) 7 (30%) 13 ⫾ 15
56 ⫾ 10 13:10 2 (9%) 6 (26%) 13 ⫾ 18
32 ⫾ 17
32 ⫾ 17
32 ⫾ 17
18 (32%) 3 (5%) 15 (27%) 23 (41%) 6 (11%) 20 (36%)
10 (44%) 4 (17%) 9 (40%) 9 (39%) 1 (4%) 11 (48%)
7 (30%) 2 (9%) 5 (22%) 5 (22%) 1 (4%) 10 (44%)
56 (100%) 56 (100%) 55 (98%) 12 (21%) 49 (88%) 27 (48%) 7 (13%) 29 (52%) 56 (100%)
23 (100%) 22 (96%) 22 (96%) 1 (4%) 19 (83%) 11 (48%) 1 (4%) 9 (39%) 23 (100%)
23 (100%) 23 (100%) 22 (96%) 1 (4%) 16 (70%) 6 (26%) 1 (4%) 7 (30%) 17 (74%)†
Data are expressed as mean ⫾ SD or as numbers (percentage). *p ⬍0.05 vs UAP and NCCP; †p ⬍0.05 vs NSTEMI and UAP. ACE ⫽ angiotensin-converting enzyme; ARB ⫽ angiotensin receptor blocker; PCI ⫽ percutaneous coronary intervention; UAP ⫽ unstable angina pectoris.
and longitudinal and circumferential global strain was calculated by averaging all segmental peak systolic longitudinal and circumferential strain values.9 Longitudinal and circumferential territorial strain was calculated on the basis of the perfusion areas of the 3 major coronary arteries, as proposed by Cerqueira et al,12 by averaging all segmental peak systolic longitudinal and circumferential strain values within each territory. Segments not belonging to the culprit territory were averaged and defined as the remote area.
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Table 2 Changes in clinical and echocardiographic parameters from admission to coronary angiography Variable
Systolic blood pressure (mm Hg) Heart rate (beats/min) Left ventricular ejection fraction (%) End-diastolic volume (ml) E/e= ratio
NSTEMI
UAP
NCCP
Admission
CA
Admission
CA
Admission
CA
137 ⫾ 25 70 ⫾ 12 53 ⫾ 6 107 ⫾ 30 10 ⫾ 4
134 ⫾ 19 70 ⫾ 19 51 ⫾ 7 106 ⫾ 32 11 ⫾ 4†
140 ⫾ 25 66 ⫾ 10 54 ⫾ 8 103 ⫾ 29 9⫾2
133 ⫾ 23 66 ⫾ 9 54 ⫾ 6 110 ⫾ 40 9⫾2
135 ⫾ 17 69 ⫾ 11 59 ⫾ 7* 103 ⫾ 24 8⫾3
129 ⫾ 16 64 ⫾ 12 59 ⫾ 5 106 ⫾ 16 8⫾2
Data are expressed as mean ⫾ SD. * p ⬍0.05 vs NSTEMI and UAP at admission; † p ⬍0.01 vs admission and p ⬍0.01 vs UAP and NCCP. CA ⫽ coronary angiography. Other abbreviation as in Table 1.
Table 3 Global strain at admission and before coronary angiography Variable NSTEMI (n ⫽ 56) Longitudinal strain (%) Circumferential strain (%) UAP (n ⫽ 23) Longitudinal strain (%) Circumferential strain (%) NCCP (n ⫽ 23) Longitudinal strain (%) Circumferential strain (%)
⌬Strain
Admission
CA
⫺16.1 ⫾ 2.6† ⫺18.4 ⫾ 5.1†
⫺15.0 ⫾ 2.6†‡ ⫺18.2 ⫾ 5.4†
⫺17.2 ⫾ 3.0† ⫺19.8 ⫾ 4.6
⫺17.6 ⫾ 2.4 ⫺19.3 ⫾ 3.9
⫺0.4 (⫺1.0 to 0.2) 0.5 (⫺0.4 to 1.4)
0.20 0.23
⫺19.5 ⫾ 2.0 ⫺22.0 ⫾ 3.1
⫺19.3 ⫾ 2.1 ⫺22.2 ⫾ 3.0
0.2 (⫺0.4 to 0.8) ⫺0.2 (⫺1.1 to 0.7)
0.44 0.63
1.1 (0.7 to 1.5)†‡ 0.2 (⫺0.6 to 1.1)
p Value* ⬍0.001 0.53
Data are expressed as mean ⫾ SD or as mean (95% confidence interval). * Difference from admission to CA. † p ⬍0.01 vs NCCP; ‡ p ⬍0.01 vs UAP. ⌬Strain ⫽ change in strain from admission to CA. Other abbreviations as in Tables 1 and 2.
Normal segmental strain was defined as the average segmental strain in 17 patients without a history of heart disease, discharge diagnoses of NCCP, and no other serious conditions with possible influence on myocardial contractility. We defined hypercontraction as absolute segmental strain ⬎1 SD from the normal segmental strain value. The percentage of segments within the remote area with evidence of hypercontraction was calculated for each patient. The influence of single- versus multivessel disease was studied in patients without a history of myocardial infarctions. Longitudinal postsystolic shortening was calculated on a segmental basis as the difference between longitudinal peak postsystolic strain and longitudinal end-systolic strain (Figure 1). Longitudinal global postsystolic shortening was obtained by averaging all segmental postsystolic shortening values. Peak systolic strain was defined as the maximum absolute value of peak positive or peak negative strain during systole. End-systole was defined by aortic valve closure in the apical long-axis view. We analyzed 97.2% of the longitudinal and 92.0% of the circumferential segments. The left ventricular ejection fraction and end-diastolic volume were assessed using Simpson’s biplane method. The ratio of peak early mitral inflow velocity (E) divided by e= was used as a noninvasive estimate of left ventricular diastolic filling pressure.13 Coronary angiograms were interpreted by experienced operators. The culprit lesion was described on the basis of the association between angiographic lesion morphology14 and electrocardiographic changes.
The data were analyzed using standard statistical software (SPSS version 16.0; SPSS, Inc., Chicago, Illinois). Values are presented as number (percentage) or as mean ⫾ SD. Differences between groups were analyzed using 1-way analysis of variance for continuous variables, and Bonferroni’s correction was applied for post hoc tests. For categorical variables, differences between groups were analyzed using chi-square or Fisher’s exact tests. Assessments of changes in strain within groups were performed using paired Student’s t tests. Differences between groups regarding change in strain, echocardiographic, and clinical parameters were tested with general linear models, and Bonferroni’s correction for multiple comparisons was applied. Relations between the levels of biomarkers and the level of strain were tested using linear regression. Reproducibility was calculated by intraclass correlation in 10 randomly selected patients. For all analyses, p values ⬍0.05 were considered significant. Results Baseline characteristics are listed in Table 1. Clinical and conventional echocardiographic parameters at admission and before coronary angiography are given in Table 2. There were no differences between the 3 groups in time from symptom onset to admission or from admission to coronary angiography. Furthermore, there were no differences between patients with NSTEMIs with and without acute coronary occlusions with regard to these time intervals (time to admission
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Table 4 Strains in non–ST elevation myocardial infarction subgroups Variable Global strain, culprit lesion occluded (n ⫽ 16) Longitudinal strain (%) Circumferential strain (%) Global strain, nonocclusion (n ⫽ 40) Longitudinal strain (%) Circumferential strain (%) Strain, culprit territory (n ⫽ 47) Longitudinal strain (%) Circumferential strain (%) Strain, remote area (n ⫽ 47) Longitudinal strain (%) Circumferential strain (%)
Admission
CA
⌬Strain
⫺15.7 ⫾ 2.9 ⫺16.7 ⫾ 4.0
⫺13.9 ⫾ 3.0 ⫺15.0 ⫾ 3.9
1.8 (0.9 to 2.7) 1.8 (0.5 to 3.1)
⫺16.3 ⫾ 2.5 ⫺19.1 ⫾ 5.4
⫺15.4 ⫾ 2.3 ⫺19.5 ⫾ 5.3
0.9 (0.4 to 1.3) ⫺0.4 (⫺1.4 to 0.6)
⬍0.001 0.42
⫺14.2 ⫾ 4.2 ⫺13.6 ⫾ 8.4
⫺12.0 ⫾ 4.1 ⫺13.2 ⫾ 9.4
2.2 (1.4 to 3.0) 0.4 (⫺0.9 to 1.7)
⬍0.001 0.55
⫺16.7 ⫾ 2.7 ⫺20.6 ⫾ 4.9
⫺16.3 ⫾ 2.7 ⫺20.6 ⫾ 4.5
0.4 (⫺0.1 to 0.9) 0.0 (⫺1 to 1)
0.09 0.96
p Value* 0.001 0.01
Data are expressed as mean ⫾ SD or as mean (95% confidence interval). *Difference from admission to CA. Abbreviations as in Tables 2 and 3.
12 ⫾ 14 vs 8 ⫾ 8 hours, time from admission to coronary angiography 29 ⫾ 15 vs 34 ⫾ 18 hours). The culprit lesions were identified and localized to major coronary vessels in 47 patients with NSTEMIs and in 15 with unstable angina pectoris. Lesions were equally distributed among the 3 major coronary territories (left anterior descending coronary artery n ⫽ 21, circumflex coronary artery n ⫽ 19, and right coronary artery n ⫽ 22). In the NSTEMI group, 16 patients (29%) had acute coronary occlusions, and 27 (48%) had ⱖ90% stenoses. Percutaneous coronary intervention was performed in 39 patients with NSTEMIs (70%) and in 9 patients with unstable angina pectoris (39%), whereas coronary artery bypass grafting was performed in 8 (14%) and 5 (22%) patients, respectively. The average longitudinal and circumferential segmental strain in healthy subjects were ⫺19.6 ⫾ 4.2% and ⫺21.9 ⫾ 7.3%, respectively. The main results of the study are listed in Tables 3 and 4. At admission, longitudinal and circumferential strain were impaired in patients with NSTEMIs compared to those with NCCP. Longitudinal global strain deteriorated from admission to coronary angiography in patients with NSTEMIs. In patients with NSTEMIs and acute coronary occlusions, there was a pronounced deterioration of longitudinal and circumferential global strain from admission to coronary angiography, both significantly more prominent than in patients with nonocclusive disease (Table 4). Additionally, peak troponin T and creatine kinase-MB in patients with acute occlusions were considerably higher than in patients with NSTEMIs without occlusions (troponin T 3.3 ⫾ 2.5 vs 0.9 ⫾ 1.3 g/L, p ⬍0.001; creatine kinase-MB 107 ⫾ 78 vs 38 ⫾ 40 g/L, p ⬍0.001). Peak troponin T and creatine kinase-MB were significantly related to strain in the culprit territory before coronary angiography (troponin T vs culprit territorial longitudinal strain R ⫽ 0.59, p ⬍0.001; creatine kinase-MB vs culprit territorial longitudinal strain R ⫽ 0.52, p ⬍0.001). No changes in circumferential global strain were observed in patients with NSTEMIs without acute coronary occlusions, in patients with unstable angina pectoris, or in those with NCCP. The extent of deterioration in longitudinal global strain in patients with NSTEMIs was not associated with which perfusion territory was affected
Figure 2. Changes in myocardial function. Longitudinal (top) and circumferential (bottom) global strain (mean ⫾ SEM percentage) in revascularized patients with NSTEMIs with and without acute coronary occlusions (n ⫽ 16 and n ⫽ 27, respectively). *p ⬍0.05 compared to admission. † p ⬍0.05 compared to coronary angiography (CA).
(changes in longitudinal global strain: left anterior descending coronary artery 1.5 ⫾ 1.8%, circumflex coronary artery 1.4 ⫾ 1.4%, right coronary artery 1.2 ⫾ 1.4%; p ⫽ 0.88). There were no differences in longitudinal or circumferential global strain with regard to which coronary territory was affected (p ⫽ 0.47 and p ⫽ 0.64, respectively). Analyses of territorial strain in patients with NSTEMI revealed a prominent deterioration of longitudinal strain in the territory supplied by the infarct-related artery, whereas strain in the remote area remained unchanged (Table 4). There was no evidence of compensatory increase in myocardial function in the remote area from admission to coronary angiography, with neither single- nor multivessel
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disease (percentage longitudinal hyperdynamic segments: single-vessel disease 3 ⫾ 6% vs 5 ⫾ 6%, p ⫽ 0.37; multivessel disease 8 ⫾ 11% vs 6 ⫾ 8%, p ⫽ 0.33). Because of the low frequency of high-grade coronary lesions in patients with unstable angina pectoris compared to those with NSTEMIs, the 10 patients with unstable angina pectoris and ⱖ90% stenoses were analyzed separately. Even in these patients, there were no changes in longitudinal or circumferential global strain from admission to coronary angiography (longitudinal ⫺16.7 ⫾ 1.8% vs ⫺17.0 ⫾ 1.4%, p ⫽ 0.56; circumferential ⫺18.1 ⫾ 3.7% vs ⫺18.2 ⫾ 3.2%, p ⫽ 0.76). Longitudinal and circumferential global strain 3 months after discharge were ⫺17.1 ⫾ 3.1% and ⫺20.2 ⫾ 4.4%, ⫺19.5 ⫾ 1.7% and ⫺22.6 ⫾ 4.0%, and ⫺20.2 ⫾ 1.7% and ⫺23.3 ⫾ 2.6% for patients with NSTEMIs, those with unstable angina pectoris, and those with NCCP, respectively. In patients revascularized by percutaneous coronary intervention or coronary artery bypass grafting, there were improvements in longitudinal and circumferential global strain in the NSTEMI group (Figure 2). These improvements were explained by better myocardial function in the culprit territories. In the subgroup with acute coronary occlusions, however, no significant improvements in function were observed after revascularization. In the NSTEMI group, 9 patients (16%) were not eligible for revascularization, because of the small caliber of the culprit vessel or stenosis diameter ⬍50%. Longitudinal and circumferential global strain after 3 months in these patients were comparable to those in revascularized patients (longitudinal ⫺17.6 ⫾ 3.4% vs ⫺17.1 ⫾ 3.0%, p ⫽ 0.63; circumferential ⫺21.7 ⫾ 4.6% vs ⫺19.8 ⫾ 4.3%, p ⫽ 0.23). However, these patients had very small infarctions (peak troponin T 0.2 ⫾ 0.1 g/L). Similarly, strain in the 9 patients with unstable angina pectoris (39%) not eligible for revascularization was comparable to values in revascularized patients (longitudinal ⫺19.9 ⫾ 1.8% vs ⫺20.2 ⫾ 1.6%, p ⫽ 0.38; circumferential ⫺23.5 ⫾ 4.9% vs ⫺22.1 ⫾ 3.6%, p ⫽ 0.50). Before coronary angiography, longitudinal postsystolic shortening was more pronounced in patients with NSTEMIs than in those with unstable angina pectoris (1.1 ⫾ 0.7% vs 0.7 ⫾ 0.4%, p ⫽ 0.01). Three months after revascularization, patients with NSTEMIs had less postsystolic shortening compared to before coronary angiography (0.9 ⫾ 0.7%, p ⫽ 0.03), whereas postsystolic shortening in patients with unstable angina pectoris was unchanged (0.7 ⫾ 0.5%, p ⫽ 0.67). Reproducibility was excellent for longitudinal and circumferential global strain and for longitudinal and circumferential territorial strain. Intraclass correlations for intraobserver variability were 0.94, 0.94, 0.94, and 0.91, respectively, and for interobserver variability were 0.92, 0.79, 0.92, and 0.83, respectively. Discussion The present study is the first to demonstrate progressive impairment of myocardial function in the culprit territories in patients with NSTEMIs awaiting coronary angiography, most prominent in patients with acute coronary occlusions.
No deterioration in myocardial function was observed in patients with unstable angina pectoris or those with NCCP. A number of mechanisms may explain the observed deterioration in myocardial function. Most patients with NSTEMIs had ⱖ90% stenosis or occlusions of major vessels, which may cause sustained ischemia until flow is restored. Persistent ischemia may lead to reversible or irreversible myocardial injury, with a decrease in myocardial function as a result. Whether irreversible myocardial injury develops depends on the severity and duration of ischemia. We demonstrated that in acute coronary occlusions, longitudinal and circumferential myocardial function deteriorated, whereas only longitudinal myocardial function changed in patients with nonocclusive disease. This discrepancy may be due to the helical structure of myocardial fibers, with subendocardial fibers having a dominant longitudinal direction, whereas midmyocardial fibers are more circumferentially oriented.15 As more pronounced ischemia causes increasing transmural dysfunction,16 nonocclusive lesions are likely to result in predominantly subendocardial hypokinesia, whereas acute coronary occlusions may cause transmural dysfunction. The observed improvement in myocardial function after revascularization in patients with NSTEMIs and nonocclusive culprit lesions further supports that these patients have mainly reversible injuries because of subendocardial ischemia before revascularization. In contrast, we did not find improvements in myocardial function after revascularization in patients with acute coronary occlusions, supporting more irreversible myocardial injuries in these patients. Finally, we found that patients with acute coronary occlusions had significantly higher levels of cardiac biomarkers than patients with nonocclusive lesions. Thus, myocardial strain measurements and cardiac biomarkers demonstrate more pronounced myocardial injuries in patients with acute coronary occlusions. In addition to deterioration of myocardial function, possible persistent ischemia before revascularization would be supposed to influence left ventricular filling pressure. This was suggested in our study by higher E/e= ratios in the NSTEMI group, with a small but significant increase in the E/e= ratio, which is consistent with an increase in left ventricular filling pressure.13 Ischemia may also cause longitudinal postsystolic shortening.17 Therefore, the finding of more postsystolic shortening in patients with NSTEMIs than in those with unstable angina pectoris and NCCP before revascularization supports that patients with NSTEMIs have more severe ischemia. In patients with unstable angina pectoris, longitudinal and circumferential strains remained unchanged, even when the culprit lesion was ⱖ90% stenosis. This indicates that progressive impairment of myocardial function is not only related to the angiographic severity of the culprit lesion, which may be in accordance with dobutamine stress echocardiographic results, in which myocardial function is found to be more closely related to functional than the angiographic severity of coronary artery stenosis.18 Our results indicate progressive impairment of myocardial function until revascularization in patients with NSTEMIs. Although relatively small, this deterioration adds to the impairment already present at admission. Particularly in patients with acute coronary occlusions, in whom there was evidence of more pronounced myocardial injury, the present
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findings may suggest benefit from immediate revascularization to relieve ischemia, thereby preventing further myocardial damage. Additionally, even without necrosis, severe ischemia is an unfavorable condition.19 Thus, the present findings reveal a need for further studies to clarify some emerging issues. First, methods for the early identification of patients with NSTEMIs and occluded coronary arteries are required, because these patients seem to be at high risk for developing irreversible myocardial injuries while awaiting coronary angiography. Strain by echocardiography, which measures regional myocardial deformation, may be performed by tissue Doppler imaging or, more recently, by speckletracking imaging based on standard grayscale images.20 Strain has previously been shown to correlate well with infarct size9,10,21 and may be a valuable tool in the evaluation of myocardial injury in patients with NSTEMIs. Echocardiography is a feasible method for the evaluation of patients with NSTE ACS, and strain may have the potential for early detection of high-risk patients who would possibly benefit from urgent coronary angiography. Second, investigation of the relation between the decrease in myocardial function and long-term prognosis would possibly answer whether the present finding represents clinically important myocardial injury. Third, the NSTE ACS population is very heterogenous, and studies should be performed to find the optimal timing of coronary angiography in different risk groups. Our study suggests that patients with NSTEMIs and acute coronary occlusions may be high-risk patients who are likely to benefit from urgent revascularization. Small baseline differences between the groups in age and previous percutaneous coronary intervention could possibly influence strain values but are unlikely to affect the degree of change in strain from admission to coronary angiography. Similarly, patients with a history of myocardial infarctions were not excluded from this study, because myocardial segments with scar can cause reductions in strain but are not likely to affect the degree of change. Moreover, if any possible bias was introduced by baseline differences, we would expect change of myocardial function in the culprit territory and remote area. The described method for assessment of coronary territories does not take into account individual variations in coronary anatomy or the size of the area at risk. Noninvasive measurement of the area at risk is difficult and with echocardiography is only feasible using contrast. Although some overlap between area at risk and remote myocardium is expected with the present model, we demonstrated marked differences between the culprit territory and remote area. The timing of coronary angiography was not a primary objective of this study, and angiography was scheduled solely for clinical and logistic reasons. Therefore, we could not explore in detail the relation among the degree of change in myocardial function, time from onset of symptoms, and the timing of coronary angiography. Finally, the study lacked a definitive method to separate ischemia from necrosis. Troponin T and creatine kinase-MB are elevated within a few hours of symptom onset in all patients with NSTEMIs and could not be used to detect any possible low-grade succeeding necrosis. However, on the basis of the combination of higher levels of cardiac biomarkers, more impaired strain, more pronounced deterioration of strain,
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and an absence of reversibility in patients with acute coronary occlusions, it is reasonable to suggest that the deterioration of myocardial function is caused by ischemia and necrosis. 1. Task Force for Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of European Society of Cardiology, Bassand JP, Hamm CW, Ardissino D, Boersma E, Budaj A, Fernández-Avilés F, Fox KA, Hasdai D, Ohman EM, Wallentin L, Wijns W. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. Eur Heart J 2007;28:1598 –1660. 2. Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE Jr, Chavey WE, II, Fesmire FM, Hochman JS, Levin TN, Lincoff AM, Peterson ED, Theroux P, Wenger NK, Wright RS, Smith SC Jr, Jacobs AK, Halperin JL, Hunt SA, Krumholz HM, Kushner FG, Lytle BW, Nishimura R, Ornato JP, Page RL, Riegel B. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction. J Am Coll Cardiol 2007;50:e1– e157. 3. Urheim S, Edvardsen T, Torp H, Angelsen B, Smiseth OA. Myocardial strain by Doppler echocardiography: validation of a new method to quantify regional myocardial function. Circulation 2000;102:1158 – 1164. 4. Edvardsen T, Skulstad H, Aakhus S, Urheim S, Ihlen H. Regional myocardial systolic function during acute myocardial ischemia assessed by strain Doppler echocardiography. J Am Coll Cardiol 2001; 37:726 –730. 5. Gotte MJ, van Rossum AC, Twisk JWR, Kuijer JPA, Marcus JT, Visser CA. Quantification of regional contractile function after infarction: strain analysis superior to wall thickening analysis in discriminating infarct from remote myocardium. J Am Coll Cardiol 2001;37: 808 – 817. 6. Amundsen BH, Helle-Valle T, Edvardsen T, Torp H, Crosby J, Lyseggen E, Stoylen A, Ihlen H, Lima JA, Smiseth OA, Slordahl SA. Noninvasive myocardial strain measurement by speckle tracking echocardiography: validation against sonomicrometry and tagged magnetic resonance imaging. J Am Coll Cardiol 2006;47:789 –793. 7. Cho GY, Chan J, Leano R, Strudwick M, Marwick TH. Comparison of two-dimensional speckle and tissue velocity based strain and validation with harmonic phase magnetic resonance imaging. Am J Cardiol 2006;97:1661–1666. 8. Gjesdal O, Hopp E, Vartdal T, Lunde K, Helle-Valle T, Aakhus S, Smith HJ, Ihlen H, Edvardsen T. Global longitudinal strain measured by two-dimensional speckle tracking echocardiography is closely related to myocardial infarct size in chronic ischaemic heart disease. Clin Sci 2007;113:287–296. 9. Vartdal T, Brunvand H, Pettersen E, Smith HJ, Lyseggen E, HelleValle T, Skulstad H, Ihlen H, Edvardsen T. Early prediction of infarct size by strain Doppler echocardiography after coronary reperfusion. J Am Coll Cardiol 2007;49:1715–1721. 10. Sjøli B, Ørn S, Grenne B, Ihlen H, Edvardsen T, Brunvand H. Diagnostic capability and reproducibility of strain by Doppler and by speckle tracking in patients with acute myocardial infarction. J Am Coll Cardiol Img 2009;2:24 –33. 11. Thygesen K, Alpert JS, White HD, on behalf of the Joint ESC/ACCF/ AHA/WHF Task Force for the Redefinition of Myocardial Infarction. Universal definition of myocardial infarction. J Am Coll Cardiol 2007; 50:2173–2195. 12. Cerqueira MD, Weissman NJ, Dilsizian V, Jacobs AK, Kaul S, Laskey WK, Pennell DJ, Rumberger JA, Ryan T, Verani MS. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart: a statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Circulation 2002;105:539 –542. 13. Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA, Waggoner AD, Flachskampf FA, Pellikka PA, Evangelista A. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. J Am Soc Echocardiogr 2009;22:107–133. 14. Early effects of tissue-type plasminogen activator added to conventional therapy on the culprit coronary lesion in patients presenting with ischemic cardiac pain at rest. Results of the Thrombolysis in Myocardial Ischemia (TIMI IIIA) trial. Circulation 1993;87:38 –52.
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15. Greenbaum RA, Ho SY, Gibson DG, Becker AE, Anderson RH. Left ventricular fibre architecture in man. Br Heart J 1981;45:248 – 263. 16. Birkeland S, Hexeberg E, Matre K, Kvitting P, Westby J, Lekven J, Grong K. Gradual reduction of coronary perfusion pressure in cats: changes in transmural distribution of blood flow. Scand J Clin Lab Invest 1990;50:787–796. 17. Skulstad H, Edvardsen T, Urheim S, Rabben SI, Stugaard M, Lyseggen E, Ihlen H, Smiseth OA. Postsystolic shortening in ischemic myocardium: active contraction or passive recoil? Circulation 2002; 106:718 –724. 18. Bartunek J, Marwick TH, Rodrigues AC, Vincent M, Van Schuerbeeck E, Sys SU, de Bruyne B. Dobutamine-induced wall motion abnormalities: Correlations with myocardial fractional flow reserve and quantitative coronary angiography. J Am Coll Cardiol 1996;27: 1429 –1436.
19. Shaw LJ, Berman DS, Maron DJ, Mancini GBJ, Hayes SW, Hartigan PM, Weintraub WS, O’Rourke RA, Dada M, Spertus JA, Chaitman BR, Friedman J, Slomka P, Heller GV, Germano G, Gosselin G, Berger P, Kostuk WJ, Schwartz RG, Knudtson M, Veledar E, Bates ER, McCallister B, Teo KK, Boden WE, for the COURAGE Investigators. Optimal medical therapy with or without percutaneous coronary intervention to reduce ischemic burden: results from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial nuclear substudy. Circulation 2008;117:1283– 1291. 20. Marwick TH. Measurement of strain and strain rate by echocardiography: ready for prime time? J Am Coll Cardiol 2006;47:1313–1327. 21. Sjøli B, Ørn S, Grenne B, Vartdal T, Smiseth OA, Edvardsen T, Brunvand H. Comparison of left ventricular ejection fraction and left ventricular global strain as determinants of infarct size in patients with acute myocardial infarction. J Am Soc Echocardiogr 2009;22:1232–1238.
Department of Medicine, Sørlandet Hospital, Arendal, Norway; and Department of Cardiology, Rikshospitalet, University Hospital and University of Oslo, Oslo, Norway. Manuscript received September 16, 2009; revised manuscript received and accepted December 14, 2009. This study was supported by the Southeastern Norway Regional Health Authority, Hamar, Norway; the Norwegian Foundation for Health and Rehabilitation, Oslo, Norway; and Sørlandet Hospital, Arendal, Norway. *Corresponding author: Tel: 47-37014000; fax: 47-37014010. E-mail address: [email protected] (H. Brunvand). b
0002-9149/10/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2009.12.036
coronary arteries to extensive disease with critical stenoses or occlusions of major vessels. Some patients may have ongoing myocardial ischemia until revascularization, and little is known about how this affects myocardial function. New echocardiographic modalities enable the accurate evaluation of global and regional myocardial deformation by strain and can identify abnormal myocardial function due to ischemia and necrosis.3–10 Echocardiography is easily accessible and can be performed repeatedly in the emergency or intensive care room. Consequently, strain by echocardiography is a feasible method for evaluation of myocardial function in patients with NSTE ACS to study changes in function due to ongoing ischemia. The aim of this study was to determine possible changes in myocardial function in terms of strain using speckle-tracking echocardiography in patients with NSTE ACS awaiting coronary angiography. Methods Patients with suspected NSTE ACS admitted to a local hospital were consecutively evaluated for study inclusion. Eligible patients had to fulfill 3 criteria: (1) acute anginal pain lasting ⱖ10 minutes and clinically classified as unstawww.AJConline.org
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Figure 1. Strain measurements. Apical 4-chamber view, showing how the strain measurements were performed. There was reduced systolic strain and postsystolic shortening in the lateral wall.
ble angina pectoris or NSTEMI, (2) a history of chest pain ⬍3 days, and (3) indication for coronary angiography according to current guidelines. Exclusion criteria were (1) age ⬍18 years, (2) previous coronary artery bypass graft or valve surgery, (3) bundle branch block with QRS interval ⬎0.12 seconds, (4) severe valvular dysfunction, (5) atrial fibrillation with heart rate ⬎100 beats/min or continuous severe arrhythmia, and (6) severe mental disorder or short life expectancy because of extracardiac reasons. Because the aim of this study was to assess myocardial function in patients with NSTE ACS awaiting coronary angiography, patients who were planned for very early (⬍10 hours) angiography were not included. All patients received medical treatment according to guidelines.1,2 One hundred two patients were included and retrospectively grouped according to discharge diagnosis. NSTEMI and unstable angina pectoris were diagnosed by convention,11 using a cut-off value of troponin T ⬎0.03 g/L for NSTEMI. Patients without evidence of significant coronary artery disease were classified as having noncoronary chest pain (NCCP). The research protocol was approved by the regional committee for medical research and ethics. All participants gave written informed consent. Echocardiographic examinations were performed using a Vivid 7 scanner (GE Vingmed Ultrasound AS, Horten, Norway). All recordings were digitally stored. Measurements were performed at admission and immediately before coronary angiography. Additionally, 95 patients (93%) were examined using echocardiography 99 ⫾ 20 days after admission. Three consecutive heart cycles from 3 apical imaging planes (4 chamber, 2 chamber, and long axis) and 3 short-axis planes (mitral valve, papillary muscle, and apex) were obtained using 2-dimensional grayscale echocardiography. The mean frame rate was 74 ⫾ 9 frames/s. Mitral inflow velocity was recorded by pulsed Doppler with the sample volume placed between the leaflet tips. Mitral annular velocities were recorded by tissue Doppler using color mode. Early diastolic mitral annular velocity (e=) was calculated by averaging septal and lateral annular velocities. Echocardiographic recordings were analyzed by a single observer blinded to patient data, using EchoPAC version 7 (GE Vingmed Ultrasound AS). Longitudinal strain was computed on the basis of the apical imaging planes and circumferential strain on the basis of the short-axis planes. A 16-segment model of the left ventricle was obtained,12
Table 1 Patient characteristics Variable
NSTEMI (n ⫽ 56)
UAP (n ⫽ 23)
NCCP (n ⫽ 23)
Age (years) Men/women Previous myocardial infarction Previous PCI Time from symptom onset to admission (hours) Time from admission to angiography (hours) Medications before hospitalization Acetylsalicylic acid Clopidogrel  blockers ACE inhibitors/ARBs Calcium inhibitors Statins Medications before coronary angiography Acetylsalicylic acid Clopidogrel Low–molecular weight heparin Glycoprotein IIb/IIIa inhibitors  blockers ACE inhibitors/ARBs Calcium inhibitors Nitroglycerin Statins
67 ⫾ 14* 41:15 7 (13%) 2 (4%)* 9 ⫾ 10
58 ⫾ 11 14:9 7 (30%) 7 (30%) 13 ⫾ 15
56 ⫾ 10 13:10 2 (9%) 6 (26%) 13 ⫾ 18
32 ⫾ 17
32 ⫾ 17
32 ⫾ 17
18 (32%) 3 (5%) 15 (27%) 23 (41%) 6 (11%) 20 (36%)
10 (44%) 4 (17%) 9 (40%) 9 (39%) 1 (4%) 11 (48%)
7 (30%) 2 (9%) 5 (22%) 5 (22%) 1 (4%) 10 (44%)
56 (100%) 56 (100%) 55 (98%) 12 (21%) 49 (88%) 27 (48%) 7 (13%) 29 (52%) 56 (100%)
23 (100%) 22 (96%) 22 (96%) 1 (4%) 19 (83%) 11 (48%) 1 (4%) 9 (39%) 23 (100%)
23 (100%) 23 (100%) 22 (96%) 1 (4%) 16 (70%) 6 (26%) 1 (4%) 7 (30%) 17 (74%)†
Data are expressed as mean ⫾ SD or as numbers (percentage). *p ⬍0.05 vs UAP and NCCP; †p ⬍0.05 vs NSTEMI and UAP. ACE ⫽ angiotensin-converting enzyme; ARB ⫽ angiotensin receptor blocker; PCI ⫽ percutaneous coronary intervention; UAP ⫽ unstable angina pectoris.
and longitudinal and circumferential global strain was calculated by averaging all segmental peak systolic longitudinal and circumferential strain values.9 Longitudinal and circumferential territorial strain was calculated on the basis of the perfusion areas of the 3 major coronary arteries, as proposed by Cerqueira et al,12 by averaging all segmental peak systolic longitudinal and circumferential strain values within each territory. Segments not belonging to the culprit territory were averaged and defined as the remote area.
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Table 2 Changes in clinical and echocardiographic parameters from admission to coronary angiography Variable
Systolic blood pressure (mm Hg) Heart rate (beats/min) Left ventricular ejection fraction (%) End-diastolic volume (ml) E/e= ratio
NSTEMI
UAP
NCCP
Admission
CA
Admission
CA
Admission
CA
137 ⫾ 25 70 ⫾ 12 53 ⫾ 6 107 ⫾ 30 10 ⫾ 4
134 ⫾ 19 70 ⫾ 19 51 ⫾ 7 106 ⫾ 32 11 ⫾ 4†
140 ⫾ 25 66 ⫾ 10 54 ⫾ 8 103 ⫾ 29 9⫾2
133 ⫾ 23 66 ⫾ 9 54 ⫾ 6 110 ⫾ 40 9⫾2
135 ⫾ 17 69 ⫾ 11 59 ⫾ 7* 103 ⫾ 24 8⫾3
129 ⫾ 16 64 ⫾ 12 59 ⫾ 5 106 ⫾ 16 8⫾2
Data are expressed as mean ⫾ SD. * p ⬍0.05 vs NSTEMI and UAP at admission; † p ⬍0.01 vs admission and p ⬍0.01 vs UAP and NCCP. CA ⫽ coronary angiography. Other abbreviation as in Table 1.
Table 3 Global strain at admission and before coronary angiography Variable NSTEMI (n ⫽ 56) Longitudinal strain (%) Circumferential strain (%) UAP (n ⫽ 23) Longitudinal strain (%) Circumferential strain (%) NCCP (n ⫽ 23) Longitudinal strain (%) Circumferential strain (%)
⌬Strain
Admission
CA
⫺16.1 ⫾ 2.6† ⫺18.4 ⫾ 5.1†
⫺15.0 ⫾ 2.6†‡ ⫺18.2 ⫾ 5.4†
⫺17.2 ⫾ 3.0† ⫺19.8 ⫾ 4.6
⫺17.6 ⫾ 2.4 ⫺19.3 ⫾ 3.9
⫺0.4 (⫺1.0 to 0.2) 0.5 (⫺0.4 to 1.4)
0.20 0.23
⫺19.5 ⫾ 2.0 ⫺22.0 ⫾ 3.1
⫺19.3 ⫾ 2.1 ⫺22.2 ⫾ 3.0
0.2 (⫺0.4 to 0.8) ⫺0.2 (⫺1.1 to 0.7)
0.44 0.63
1.1 (0.7 to 1.5)†‡ 0.2 (⫺0.6 to 1.1)
p Value* ⬍0.001 0.53
Data are expressed as mean ⫾ SD or as mean (95% confidence interval). * Difference from admission to CA. † p ⬍0.01 vs NCCP; ‡ p ⬍0.01 vs UAP. ⌬Strain ⫽ change in strain from admission to CA. Other abbreviations as in Tables 1 and 2.
Normal segmental strain was defined as the average segmental strain in 17 patients without a history of heart disease, discharge diagnoses of NCCP, and no other serious conditions with possible influence on myocardial contractility. We defined hypercontraction as absolute segmental strain ⬎1 SD from the normal segmental strain value. The percentage of segments within the remote area with evidence of hypercontraction was calculated for each patient. The influence of single- versus multivessel disease was studied in patients without a history of myocardial infarctions. Longitudinal postsystolic shortening was calculated on a segmental basis as the difference between longitudinal peak postsystolic strain and longitudinal end-systolic strain (Figure 1). Longitudinal global postsystolic shortening was obtained by averaging all segmental postsystolic shortening values. Peak systolic strain was defined as the maximum absolute value of peak positive or peak negative strain during systole. End-systole was defined by aortic valve closure in the apical long-axis view. We analyzed 97.2% of the longitudinal and 92.0% of the circumferential segments. The left ventricular ejection fraction and end-diastolic volume were assessed using Simpson’s biplane method. The ratio of peak early mitral inflow velocity (E) divided by e= was used as a noninvasive estimate of left ventricular diastolic filling pressure.13 Coronary angiograms were interpreted by experienced operators. The culprit lesion was described on the basis of the association between angiographic lesion morphology14 and electrocardiographic changes.
The data were analyzed using standard statistical software (SPSS version 16.0; SPSS, Inc., Chicago, Illinois). Values are presented as number (percentage) or as mean ⫾ SD. Differences between groups were analyzed using 1-way analysis of variance for continuous variables, and Bonferroni’s correction was applied for post hoc tests. For categorical variables, differences between groups were analyzed using chi-square or Fisher’s exact tests. Assessments of changes in strain within groups were performed using paired Student’s t tests. Differences between groups regarding change in strain, echocardiographic, and clinical parameters were tested with general linear models, and Bonferroni’s correction for multiple comparisons was applied. Relations between the levels of biomarkers and the level of strain were tested using linear regression. Reproducibility was calculated by intraclass correlation in 10 randomly selected patients. For all analyses, p values ⬍0.05 were considered significant. Results Baseline characteristics are listed in Table 1. Clinical and conventional echocardiographic parameters at admission and before coronary angiography are given in Table 2. There were no differences between the 3 groups in time from symptom onset to admission or from admission to coronary angiography. Furthermore, there were no differences between patients with NSTEMIs with and without acute coronary occlusions with regard to these time intervals (time to admission
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Table 4 Strains in non–ST elevation myocardial infarction subgroups Variable Global strain, culprit lesion occluded (n ⫽ 16) Longitudinal strain (%) Circumferential strain (%) Global strain, nonocclusion (n ⫽ 40) Longitudinal strain (%) Circumferential strain (%) Strain, culprit territory (n ⫽ 47) Longitudinal strain (%) Circumferential strain (%) Strain, remote area (n ⫽ 47) Longitudinal strain (%) Circumferential strain (%)
Admission
CA
⌬Strain
⫺15.7 ⫾ 2.9 ⫺16.7 ⫾ 4.0
⫺13.9 ⫾ 3.0 ⫺15.0 ⫾ 3.9
1.8 (0.9 to 2.7) 1.8 (0.5 to 3.1)
⫺16.3 ⫾ 2.5 ⫺19.1 ⫾ 5.4
⫺15.4 ⫾ 2.3 ⫺19.5 ⫾ 5.3
0.9 (0.4 to 1.3) ⫺0.4 (⫺1.4 to 0.6)
⬍0.001 0.42
⫺14.2 ⫾ 4.2 ⫺13.6 ⫾ 8.4
⫺12.0 ⫾ 4.1 ⫺13.2 ⫾ 9.4
2.2 (1.4 to 3.0) 0.4 (⫺0.9 to 1.7)
⬍0.001 0.55
⫺16.7 ⫾ 2.7 ⫺20.6 ⫾ 4.9
⫺16.3 ⫾ 2.7 ⫺20.6 ⫾ 4.5
0.4 (⫺0.1 to 0.9) 0.0 (⫺1 to 1)
0.09 0.96
p Value* 0.001 0.01
Data are expressed as mean ⫾ SD or as mean (95% confidence interval). *Difference from admission to CA. Abbreviations as in Tables 2 and 3.
12 ⫾ 14 vs 8 ⫾ 8 hours, time from admission to coronary angiography 29 ⫾ 15 vs 34 ⫾ 18 hours). The culprit lesions were identified and localized to major coronary vessels in 47 patients with NSTEMIs and in 15 with unstable angina pectoris. Lesions were equally distributed among the 3 major coronary territories (left anterior descending coronary artery n ⫽ 21, circumflex coronary artery n ⫽ 19, and right coronary artery n ⫽ 22). In the NSTEMI group, 16 patients (29%) had acute coronary occlusions, and 27 (48%) had ⱖ90% stenoses. Percutaneous coronary intervention was performed in 39 patients with NSTEMIs (70%) and in 9 patients with unstable angina pectoris (39%), whereas coronary artery bypass grafting was performed in 8 (14%) and 5 (22%) patients, respectively. The average longitudinal and circumferential segmental strain in healthy subjects were ⫺19.6 ⫾ 4.2% and ⫺21.9 ⫾ 7.3%, respectively. The main results of the study are listed in Tables 3 and 4. At admission, longitudinal and circumferential strain were impaired in patients with NSTEMIs compared to those with NCCP. Longitudinal global strain deteriorated from admission to coronary angiography in patients with NSTEMIs. In patients with NSTEMIs and acute coronary occlusions, there was a pronounced deterioration of longitudinal and circumferential global strain from admission to coronary angiography, both significantly more prominent than in patients with nonocclusive disease (Table 4). Additionally, peak troponin T and creatine kinase-MB in patients with acute occlusions were considerably higher than in patients with NSTEMIs without occlusions (troponin T 3.3 ⫾ 2.5 vs 0.9 ⫾ 1.3 g/L, p ⬍0.001; creatine kinase-MB 107 ⫾ 78 vs 38 ⫾ 40 g/L, p ⬍0.001). Peak troponin T and creatine kinase-MB were significantly related to strain in the culprit territory before coronary angiography (troponin T vs culprit territorial longitudinal strain R ⫽ 0.59, p ⬍0.001; creatine kinase-MB vs culprit territorial longitudinal strain R ⫽ 0.52, p ⬍0.001). No changes in circumferential global strain were observed in patients with NSTEMIs without acute coronary occlusions, in patients with unstable angina pectoris, or in those with NCCP. The extent of deterioration in longitudinal global strain in patients with NSTEMIs was not associated with which perfusion territory was affected
Figure 2. Changes in myocardial function. Longitudinal (top) and circumferential (bottom) global strain (mean ⫾ SEM percentage) in revascularized patients with NSTEMIs with and without acute coronary occlusions (n ⫽ 16 and n ⫽ 27, respectively). *p ⬍0.05 compared to admission. † p ⬍0.05 compared to coronary angiography (CA).
(changes in longitudinal global strain: left anterior descending coronary artery 1.5 ⫾ 1.8%, circumflex coronary artery 1.4 ⫾ 1.4%, right coronary artery 1.2 ⫾ 1.4%; p ⫽ 0.88). There were no differences in longitudinal or circumferential global strain with regard to which coronary territory was affected (p ⫽ 0.47 and p ⫽ 0.64, respectively). Analyses of territorial strain in patients with NSTEMI revealed a prominent deterioration of longitudinal strain in the territory supplied by the infarct-related artery, whereas strain in the remote area remained unchanged (Table 4). There was no evidence of compensatory increase in myocardial function in the remote area from admission to coronary angiography, with neither single- nor multivessel
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disease (percentage longitudinal hyperdynamic segments: single-vessel disease 3 ⫾ 6% vs 5 ⫾ 6%, p ⫽ 0.37; multivessel disease 8 ⫾ 11% vs 6 ⫾ 8%, p ⫽ 0.33). Because of the low frequency of high-grade coronary lesions in patients with unstable angina pectoris compared to those with NSTEMIs, the 10 patients with unstable angina pectoris and ⱖ90% stenoses were analyzed separately. Even in these patients, there were no changes in longitudinal or circumferential global strain from admission to coronary angiography (longitudinal ⫺16.7 ⫾ 1.8% vs ⫺17.0 ⫾ 1.4%, p ⫽ 0.56; circumferential ⫺18.1 ⫾ 3.7% vs ⫺18.2 ⫾ 3.2%, p ⫽ 0.76). Longitudinal and circumferential global strain 3 months after discharge were ⫺17.1 ⫾ 3.1% and ⫺20.2 ⫾ 4.4%, ⫺19.5 ⫾ 1.7% and ⫺22.6 ⫾ 4.0%, and ⫺20.2 ⫾ 1.7% and ⫺23.3 ⫾ 2.6% for patients with NSTEMIs, those with unstable angina pectoris, and those with NCCP, respectively. In patients revascularized by percutaneous coronary intervention or coronary artery bypass grafting, there were improvements in longitudinal and circumferential global strain in the NSTEMI group (Figure 2). These improvements were explained by better myocardial function in the culprit territories. In the subgroup with acute coronary occlusions, however, no significant improvements in function were observed after revascularization. In the NSTEMI group, 9 patients (16%) were not eligible for revascularization, because of the small caliber of the culprit vessel or stenosis diameter ⬍50%. Longitudinal and circumferential global strain after 3 months in these patients were comparable to those in revascularized patients (longitudinal ⫺17.6 ⫾ 3.4% vs ⫺17.1 ⫾ 3.0%, p ⫽ 0.63; circumferential ⫺21.7 ⫾ 4.6% vs ⫺19.8 ⫾ 4.3%, p ⫽ 0.23). However, these patients had very small infarctions (peak troponin T 0.2 ⫾ 0.1 g/L). Similarly, strain in the 9 patients with unstable angina pectoris (39%) not eligible for revascularization was comparable to values in revascularized patients (longitudinal ⫺19.9 ⫾ 1.8% vs ⫺20.2 ⫾ 1.6%, p ⫽ 0.38; circumferential ⫺23.5 ⫾ 4.9% vs ⫺22.1 ⫾ 3.6%, p ⫽ 0.50). Before coronary angiography, longitudinal postsystolic shortening was more pronounced in patients with NSTEMIs than in those with unstable angina pectoris (1.1 ⫾ 0.7% vs 0.7 ⫾ 0.4%, p ⫽ 0.01). Three months after revascularization, patients with NSTEMIs had less postsystolic shortening compared to before coronary angiography (0.9 ⫾ 0.7%, p ⫽ 0.03), whereas postsystolic shortening in patients with unstable angina pectoris was unchanged (0.7 ⫾ 0.5%, p ⫽ 0.67). Reproducibility was excellent for longitudinal and circumferential global strain and for longitudinal and circumferential territorial strain. Intraclass correlations for intraobserver variability were 0.94, 0.94, 0.94, and 0.91, respectively, and for interobserver variability were 0.92, 0.79, 0.92, and 0.83, respectively. Discussion The present study is the first to demonstrate progressive impairment of myocardial function in the culprit territories in patients with NSTEMIs awaiting coronary angiography, most prominent in patients with acute coronary occlusions.
No deterioration in myocardial function was observed in patients with unstable angina pectoris or those with NCCP. A number of mechanisms may explain the observed deterioration in myocardial function. Most patients with NSTEMIs had ⱖ90% stenosis or occlusions of major vessels, which may cause sustained ischemia until flow is restored. Persistent ischemia may lead to reversible or irreversible myocardial injury, with a decrease in myocardial function as a result. Whether irreversible myocardial injury develops depends on the severity and duration of ischemia. We demonstrated that in acute coronary occlusions, longitudinal and circumferential myocardial function deteriorated, whereas only longitudinal myocardial function changed in patients with nonocclusive disease. This discrepancy may be due to the helical structure of myocardial fibers, with subendocardial fibers having a dominant longitudinal direction, whereas midmyocardial fibers are more circumferentially oriented.15 As more pronounced ischemia causes increasing transmural dysfunction,16 nonocclusive lesions are likely to result in predominantly subendocardial hypokinesia, whereas acute coronary occlusions may cause transmural dysfunction. The observed improvement in myocardial function after revascularization in patients with NSTEMIs and nonocclusive culprit lesions further supports that these patients have mainly reversible injuries because of subendocardial ischemia before revascularization. In contrast, we did not find improvements in myocardial function after revascularization in patients with acute coronary occlusions, supporting more irreversible myocardial injuries in these patients. Finally, we found that patients with acute coronary occlusions had significantly higher levels of cardiac biomarkers than patients with nonocclusive lesions. Thus, myocardial strain measurements and cardiac biomarkers demonstrate more pronounced myocardial injuries in patients with acute coronary occlusions. In addition to deterioration of myocardial function, possible persistent ischemia before revascularization would be supposed to influence left ventricular filling pressure. This was suggested in our study by higher E/e= ratios in the NSTEMI group, with a small but significant increase in the E/e= ratio, which is consistent with an increase in left ventricular filling pressure.13 Ischemia may also cause longitudinal postsystolic shortening.17 Therefore, the finding of more postsystolic shortening in patients with NSTEMIs than in those with unstable angina pectoris and NCCP before revascularization supports that patients with NSTEMIs have more severe ischemia. In patients with unstable angina pectoris, longitudinal and circumferential strains remained unchanged, even when the culprit lesion was ⱖ90% stenosis. This indicates that progressive impairment of myocardial function is not only related to the angiographic severity of the culprit lesion, which may be in accordance with dobutamine stress echocardiographic results, in which myocardial function is found to be more closely related to functional than the angiographic severity of coronary artery stenosis.18 Our results indicate progressive impairment of myocardial function until revascularization in patients with NSTEMIs. Although relatively small, this deterioration adds to the impairment already present at admission. Particularly in patients with acute coronary occlusions, in whom there was evidence of more pronounced myocardial injury, the present
Coronary Artery Disease/Myocardial Function in NSTE ACS
findings may suggest benefit from immediate revascularization to relieve ischemia, thereby preventing further myocardial damage. Additionally, even without necrosis, severe ischemia is an unfavorable condition.19 Thus, the present findings reveal a need for further studies to clarify some emerging issues. First, methods for the early identification of patients with NSTEMIs and occluded coronary arteries are required, because these patients seem to be at high risk for developing irreversible myocardial injuries while awaiting coronary angiography. Strain by echocardiography, which measures regional myocardial deformation, may be performed by tissue Doppler imaging or, more recently, by speckletracking imaging based on standard grayscale images.20 Strain has previously been shown to correlate well with infarct size9,10,21 and may be a valuable tool in the evaluation of myocardial injury in patients with NSTEMIs. Echocardiography is a feasible method for the evaluation of patients with NSTE ACS, and strain may have the potential for early detection of high-risk patients who would possibly benefit from urgent coronary angiography. Second, investigation of the relation between the decrease in myocardial function and long-term prognosis would possibly answer whether the present finding represents clinically important myocardial injury. Third, the NSTE ACS population is very heterogenous, and studies should be performed to find the optimal timing of coronary angiography in different risk groups. Our study suggests that patients with NSTEMIs and acute coronary occlusions may be high-risk patients who are likely to benefit from urgent revascularization. Small baseline differences between the groups in age and previous percutaneous coronary intervention could possibly influence strain values but are unlikely to affect the degree of change in strain from admission to coronary angiography. Similarly, patients with a history of myocardial infarctions were not excluded from this study, because myocardial segments with scar can cause reductions in strain but are not likely to affect the degree of change. Moreover, if any possible bias was introduced by baseline differences, we would expect change of myocardial function in the culprit territory and remote area. The described method for assessment of coronary territories does not take into account individual variations in coronary anatomy or the size of the area at risk. Noninvasive measurement of the area at risk is difficult and with echocardiography is only feasible using contrast. Although some overlap between area at risk and remote myocardium is expected with the present model, we demonstrated marked differences between the culprit territory and remote area. The timing of coronary angiography was not a primary objective of this study, and angiography was scheduled solely for clinical and logistic reasons. Therefore, we could not explore in detail the relation among the degree of change in myocardial function, time from onset of symptoms, and the timing of coronary angiography. Finally, the study lacked a definitive method to separate ischemia from necrosis. Troponin T and creatine kinase-MB are elevated within a few hours of symptom onset in all patients with NSTEMIs and could not be used to detect any possible low-grade succeeding necrosis. However, on the basis of the combination of higher levels of cardiac biomarkers, more impaired strain, more pronounced deterioration of strain,
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and an absence of reversibility in patients with acute coronary occlusions, it is reasonable to suggest that the deterioration of myocardial function is caused by ischemia and necrosis. 1. Task Force for Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of European Society of Cardiology, Bassand JP, Hamm CW, Ardissino D, Boersma E, Budaj A, Fernández-Avilés F, Fox KA, Hasdai D, Ohman EM, Wallentin L, Wijns W. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. Eur Heart J 2007;28:1598 –1660. 2. Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE Jr, Chavey WE, II, Fesmire FM, Hochman JS, Levin TN, Lincoff AM, Peterson ED, Theroux P, Wenger NK, Wright RS, Smith SC Jr, Jacobs AK, Halperin JL, Hunt SA, Krumholz HM, Kushner FG, Lytle BW, Nishimura R, Ornato JP, Page RL, Riegel B. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction. J Am Coll Cardiol 2007;50:e1– e157. 3. Urheim S, Edvardsen T, Torp H, Angelsen B, Smiseth OA. Myocardial strain by Doppler echocardiography: validation of a new method to quantify regional myocardial function. Circulation 2000;102:1158 – 1164. 4. Edvardsen T, Skulstad H, Aakhus S, Urheim S, Ihlen H. Regional myocardial systolic function during acute myocardial ischemia assessed by strain Doppler echocardiography. J Am Coll Cardiol 2001; 37:726 –730. 5. Gotte MJ, van Rossum AC, Twisk JWR, Kuijer JPA, Marcus JT, Visser CA. Quantification of regional contractile function after infarction: strain analysis superior to wall thickening analysis in discriminating infarct from remote myocardium. J Am Coll Cardiol 2001;37: 808 – 817. 6. Amundsen BH, Helle-Valle T, Edvardsen T, Torp H, Crosby J, Lyseggen E, Stoylen A, Ihlen H, Lima JA, Smiseth OA, Slordahl SA. Noninvasive myocardial strain measurement by speckle tracking echocardiography: validation against sonomicrometry and tagged magnetic resonance imaging. J Am Coll Cardiol 2006;47:789 –793. 7. Cho GY, Chan J, Leano R, Strudwick M, Marwick TH. Comparison of two-dimensional speckle and tissue velocity based strain and validation with harmonic phase magnetic resonance imaging. Am J Cardiol 2006;97:1661–1666. 8. Gjesdal O, Hopp E, Vartdal T, Lunde K, Helle-Valle T, Aakhus S, Smith HJ, Ihlen H, Edvardsen T. Global longitudinal strain measured by two-dimensional speckle tracking echocardiography is closely related to myocardial infarct size in chronic ischaemic heart disease. Clin Sci 2007;113:287–296. 9. Vartdal T, Brunvand H, Pettersen E, Smith HJ, Lyseggen E, HelleValle T, Skulstad H, Ihlen H, Edvardsen T. Early prediction of infarct size by strain Doppler echocardiography after coronary reperfusion. J Am Coll Cardiol 2007;49:1715–1721. 10. Sjøli B, Ørn S, Grenne B, Ihlen H, Edvardsen T, Brunvand H. Diagnostic capability and reproducibility of strain by Doppler and by speckle tracking in patients with acute myocardial infarction. J Am Coll Cardiol Img 2009;2:24 –33. 11. Thygesen K, Alpert JS, White HD, on behalf of the Joint ESC/ACCF/ AHA/WHF Task Force for the Redefinition of Myocardial Infarction. Universal definition of myocardial infarction. J Am Coll Cardiol 2007; 50:2173–2195. 12. Cerqueira MD, Weissman NJ, Dilsizian V, Jacobs AK, Kaul S, Laskey WK, Pennell DJ, Rumberger JA, Ryan T, Verani MS. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart: a statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Circulation 2002;105:539 –542. 13. Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA, Waggoner AD, Flachskampf FA, Pellikka PA, Evangelista A. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. J Am Soc Echocardiogr 2009;22:107–133. 14. Early effects of tissue-type plasminogen activator added to conventional therapy on the culprit coronary lesion in patients presenting with ischemic cardiac pain at rest. Results of the Thrombolysis in Myocardial Ischemia (TIMI IIIA) trial. Circulation 1993;87:38 –52.
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