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Comparison of Outcomes of Patients With Painless Versus Painful ST-Segment Elevation Myocardial Infarction Undergoing Percutaneous Coronary Intervention
Comparison of Outcomes of Patients With Painless Versus Painful ST-Segment Elevation Myocardial Infarction Undergoing Percutaneous Coronary Intervention Jae Yeong Cho, MDa, Myung Ho Jeong, MDa,*, Young Keun Ahn, MDa, Jong Hyun Kim, MDb, Shung Chull Chae, MDc, Young Jo Kim, MDd, Seung Ho Hur, MDe, In Whan Seong, MDf, Taek Jong Hong, MDg, Dong Hoon Choi, MDh, Myeong Chan Cho, MDi, Chong Jin Kim, MDj, Ki Bae Seung, MDk, Wook Sung Chung, MDk, Yang Soo Jang, MDl, Seung Yun Cho, MDl, Seung Woon Rha, MDm, Jang Ho Bae, MDn, Jeong Gwan Cho, MDa, and Seung Jung Park, MDo, for the Korea Acute Myocardial Infarction Registry Investigators There are few data available on the prognosis of painless ST-segment elevation myocardial infarction (STEMI). The aim of this study was to determine the incidence, clinical characteristics, and outcomes of painless STEMI. We analyzed the Korea Acute Myocardial Infarction Registry (KAMIR) study, which enrolled 7,288 patients with STEMI (61.8 ⴞ 12.8 years old, 74% men; painless STEMI group, n ⴝ 763; painful STEMI group, n ⴝ 6,525). End points were in-hospital mortality and 1-year major adverse cardiac events (MACEs). Patients with painless STEMI were older and more likely to be women, nonsmokers, diabetic, and normolipidemic and to have a higher Killip class. The painless group had more in-hospital deaths (5.9% vs 3.6%, p ⴝ 0.026) and 1-year MACEs (26% vs 19%, p ⴝ 0.002). In Cox proportional hazards analysis, hypotension (hazard ratio [HR] 4.40, 95% confidence interval [CI] 1.41 to 13.78, p ⴝ 0.011), low left ventricular ejection fraction (HR 3.12, 95% CI 1.21 to 8.07, p ⴝ 0.019), and a high Killip class (HR 3.48, 95% CI 1.19 to 10.22, p ⴝ 0.023) were independent predictors of 1-year MACEs in patients with painless STEMI. In conclusion, painless STEMI was associated with more adverse outcomes than painful STEMI and late detection may have contributed significantly to total ischemic burden. These results warrant more investigations for methodologic development in the diagnosis of silent ischemia and painless STEMI. © 2012 Elsevier Inc. All rights reserved. (Am J Cardiol 2012;109:337–343) Nonfatal ST-segment elevation myocardial infarction (STEMI) including painless STEMI can be unrecognized by the patient and discovered only on subsequent routine electrocardiographic examinations or at autopsy examination.
a
Chonnam National University Hospital, Gwangju, South Korea; Busan Hanseo Hospital, Busan, South Korea; cKyungpook National University Hospital, Daegu, South Korea; dYeungnam University Hospital, Daegu, South Korea; eKeimyung University Hospital, Daegu, South Korea; fChungnam National University Hospital, Daejon, South Korea; g Pusan National University Hospital, Busan, South Korea; hYonsei University Severans Hospital, Seoul, South Korea; iChungbuk National University Hospital, Cheongju, South Korea; jKyung hee University Hospital, Seoul, South Korea; kCatholic University Hospital, Seoul, South Korea; l CHA Bundang Medical Center, Sungnam, South Korea; mKorea University Hospital, Seoul, South Korea; nKonyang University Hospital, Daejon, South Korea; oSeoul Asan Medical Center, Seoul, South Korea. Manuscript received August 5, 2011; revised manuscript received and accepted September 13, 2011. This study was supported by a grant from the Korean Society of Circulation, Seoul, Republic of Korea, in celebration of its 50th Anniversary and the Korea Healthcare Technology R&D Project (A084869), Ministry for Health, Welfare and Family Affairs, Seoul, Republic of Korea, and the Cardiovascular Research Foundation Asia, Seoul, Republic of Korea. *Corresponding author: Tel: 82-62-220-6243; fax: ⫹82-62-228-7174. E-mail address: [email protected] (M.H. Jeong). b
0002-9149/12/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2011.09.017
Painless STEMI is often followed by silent myocardial ischemia. Silent myocardial ischemia is defined as an objective documentation of myocardial ischemia in the absence of angina pectoris or angina equivalents.1 Approximately 2.5% of myocardial ischemia in the study population have occurred in the absence of chest pain in several studies.2–5 In a cohort of 1,092 patients undergoing preoperative dobutamine stress echocardiography and noncardiac vascular surgery, unrecognized MI and silent myocardial ischemia were highly prevalent (23% and 28%).6 Silent myocardial ischemia seems to be an independent predictor of future cardiac morbidity and mortality.7 Also, it is estimated that the first manifestation of coronary artery disease in 60% to 70% of patients is sudden death or MI, whereas only a minority present first with angina pectoris or other symptoms of reversible myocardial ischemia.8 Nevertheless, the incidence of painless STEMI is unclear, and currently a paucity of data is available on the outcomes of painless MI. Hence, we aimed to examine the incidence, clinical characteristics, and outcomes of painless STEMI. Methods The Korea Acute Myocardial Infarction Registry (KAMIR), launched in November 2005, is a Korean prospective multicenter data collection registry reflecting realwww.ajconline.org
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Figure 1. Study flow chart. AMI ⫽ acute myocardial infarction; NSTEMI ⫽ non–ST-segment elevation myocardial infarction.
world treatment practices and outcomes in Asian patients diagnosed with acute infarction. The registry includes 50 community and teaching hospitals with facilities for primary percutaneous coronary intervention (PCI) and on-site cardiac surgery. It is the largest acute MI registry in Korea and, to the best of our knowledge, 1 of the largest in the world. From November 2005 to December 2007, 14,885 patients with acute MI were enrolled in the KAMIR. Data were collected by a trained study coordinator using a standardized case-report form and protocol. The study protocol was approved by the ethics committee at each participating institution. In the present study, patients with STEMI were selected (61.8 ⫾ 12.8 years old, 74% men) and constituted the eligible 7,288 of the 14,885 total registered patients. Patients were grouped into the painless STEMI group (n ⫽ 763) and the painful STEMI group (n ⫽ 6,525) based on the presence of chest pain around the time of their visit to the emergency room (Figure 1). All patients received aspirin ⱖ100 mg and a loading dose of clopidogrel 300 to 600 mg and heparin. The maintenance dose was aspirin 100 mg/day and clopidogrel 75 mg/day. Aspirin and clopidogrel was administered to all patients for ⱖ6 months according to existing guidelines. Postintervention medication included aspirin, clopidogrel,  blockers, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers. After discharge, the patients continued to receive the same medications that they received during hospitalization with the exception of some intravenous or temporary medications. Coronary interventions were performed using standard techniques. The decisions for predilation, direct stenting, postadjunctive balloon inflation, and the administration of glycoprotein IIb/IIIa receptor blockers were left to the discretion of individual
operators. Clinical follow-up was performed at 1 month and 6, and 12 months and when anginalike symptoms occurred. Acute MI was defined as the presence of ⱖ2 of the following 3 conditions: (1) ischemic symptoms, (2) increase of cardiac markers ⱖ2 times the upper limit of normal, or (3) new ST-segment elevation. STEMI was defined as a clinical presentation consistent with an acute MI and an electrocardiogram with ST-segment elevation ⱖ0.1 mV in ⱖ2 contiguous leads, Q wave, or new left bundle branch block. Painless STEMI was defined as STEMI without pain symptoms and dyspnea, which is an accepted angina equivalent.1 Data on other cardiovascular risk factors such as hypertension, smoking, and previous ischemic heart disease were also reported by the patients themselves, with the exception of dyslipidemia, which was defined as a composite of selfreported history, previous statin usage, and a fasting cholesterol level ⱖ200 mg/dl. Angiographic parameters such as Thrombolysis In Myocardial Infarction (TIMI) flow grade or American College of Cardiology/American Heart Association lesion type were assessed by the operator. A successful procedure was defined as ⬍20% residual stenosis after the procedure in this study. In-hospital deaths from all causes and 1-year major adverse cardiac events (MACEs) were considered primary outcomes. A MACE was defined as a composite of cardiac death, noncardiac death, nonfatal reinfarction, and coronary artery revascularization. Target vessel revascularization was defined as any repeated intervention driven by lesions in the treated vessel within and beyond the target lesion limits. Continuous variables with normal distributions are presented as mean ⫾ SD and were compared using Student’s t test or Mann–Whitney U test when group distributions were skewed. Categorical variables were compared using chisquare test or Fisher’s exact test, where appropriate. Cumulative mortality, death and nonfatal MIs, revascularization, and composite MACE rates were evaluated using the Kaplan–Meier method and compared using log-rank test. Cox regression analysis was performed to identify independent predictors of 1-year mortality and MACEs in painless STEMI. Variables with a p value ⬍0.1 in univariate Cox analysis were tested. All statistical tests were 2-tailed and a p value ⬍0.05 was considered statistically significant. All analyses were performed using SPSS 17.0 (SPSS, Inc., Chicago, Illinois). Results Baseline demographic characteristics are listed in Table 1. Painless STEMI comprised 11% of total patients with STEMI. Patients in the painless group were older, were more likely to be women, and were more likely to have diabetes, but were less likely to have hyperlipidemia, to have a family history, and to be a smoker. The painless group had fewer previous MIs and no significant differences in left ventricular function were observed between the 2 groups. The painless group was less likely to be given primary PCI. The painless group had comparable blood pressure to the painful group but the painless group had faster heart rates. With regard to door-to-balloon time, the
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Table 1 Demographic findings Variable Age (years) Men Body mass index (kg/m2) Diabetes mellitus Hypertension Hyperlipidemia Smoker Family history of coronary disease Previous myocardial infarction Left ventricular ejection fraction (%) Killip class III on presentation Systolic blood pressure (mm Hg) Heart rate (beats/min) Primary percutaneous coronary intervention Door-to-balloon time (minutes) Q wave Left bundle branch block Glomerular filtration rate (ml/min) Glucose (mg/dl) High-sensitivity C-reactive protein (mg/dl) Amino-terminal pro–B-type natriuretic peptide (pg/ml) Maximum creatine kinase (IU/L) Maximum creatine kinase-MB (IU/L) Maximum cardiac troponin I (ng/ml) Total cholesterol (mg/dl) Triglycerides (mg/dl) High-density lipoprotein cholesterol (mg/dl) Low-density lipoprotein cholesterol (mg/dl)
Painless (n ⫽ 763)
Painful (n ⫽ 6,525)
p Value
65.2 ⫾ 12.8 531 (70%) 23.8 ⫾ 8.1 219 (29%) 369 (49%) 232 (33%) 438 (58%) 33 (4.7%) 269 (36%) 50.2 ⫾ 13.0 89 (12%) 127.8 ⫾ 40.9 80.4 ⫾ 39.0 454 (61%) 133.5 ⫾ 136.1 247 (32%) 9 (1.2%) 67.0 ⫾ 36.1 172.0 ⫾ 87.0 12.6 ⫾ 72.5 3,755.3 ⫾ 6,960.6 1,464.8 ⫾ 2,345.9 111.6 ⫾ 185.7 50.8 ⫾ 77.6 177.5 ⫾ 44.5 117.4 ⫾ 94.1 45.1 ⫾ 12.8 113.5 ⫾ 39.2
61.4 ⫾ 12.8 4,883 (75%) 24.1 ⫾ 5.2 1,549 (24%) 2,918 (45%) 2,318 (39%) 4,041 (63%) 451 (7.8%) 2,538 (39%) 50.6 ⫾ 11.6 454 (7.2%) 127.5 ⫾ 31.3 77.0 ⫾ 26.3 4,861 (77%) 88.4 ⫾ 94.8 1,053 (16%) 39 (0.6%) 75.7 ⫾ 41.2 171.3 ⫾ 74.5 14.9 ⫾ 75.4 1,802.3 ⫾ 4,575.8 1,813.1 ⫾ 2,064.9 197.7 ⫾ 314.1 65.9 ⫾ 180.3 184.0 ⫾ 43.9 126.5 ⫾ 113.2 45.3 ⫾ 22.7 118.4 ⫾ 43.9
⬍0.001 0.001 0.164 0.003 0.074 0.002 0.009 0.004 0.043 0.466 ⬍0.001 0.798 0.022 ⬍0.001 ⬍0.001 ⬍0.001 0.060 ⬍0.001 0.826 0.463 ⬍0.001 ⬍0.001 ⬍0.001 0.025 ⬍0.001 0.017 0.819 0.005
Data are presented as number of patients (percentage) or mean ⫾ SD.
painless group was given primary PCI significantly later than the painful group. On electrocardiogram a Q wave was more frequently seen in the painless group than in the painful group. Laboratory testing indicated that renal function was worse in the painless group. There were no differences in high-sensitivity C-reactive protein level but the N-terminal pro–B-type natriuretic peptide level was much higher in the painless group. The lipid profile was better in the painless group: total cholesterol, triglyceride, and lowdensity lipoprotein cholesterol levels were lower than those in the painful group. Coronary angiographic findings are presented in Table 2. There were no significant differences between groups in culprit lesions. The painless group had more multivessel disease but less TIMI grade 0 flows before the procedure and complex lesions. Drug-eluting stents were used less frequently in the painless group and physicians used paclitaxel-eluting stents more in patients in the painless group than in those in the painful group. Clinical outcomes in patients who underwent primary PCI are presented in Table 3. The painless group had a larger number of in-hospital deaths. Other hospital outcomes including heart failure, acute renal failure, and bleeding tended to be worse and cardiogenic shock and stroke were significantly more frequent in the painless group. Long-term outcome analyses indicated that the composite MACE was greater in the painless group than in the painful group. In detail, all-cause death and any revascularization
tended to be higher in percentages than in the painful STEMI group, although this was not statistically significant. In contrast, death, nonfatal MI, and target lesion revascularization rates were higher in the painless group. Kaplan– Meier analysis indicated that patients with painless STEMI had worse outcomes in death, MI, and composite MACE (p ⫽ 0.019 and 0.005, log-rank test, respectively). In contrast, all-cause death or revascularization rate did not show more than a trend to be worse in the painless group (Figure 2). In multivariable Cox proportional hazard analysis, hypotension (hazard ratio [HR] 4.40, 95% confidence interval [CI] 1.41 to 13.78, p ⫽ 0.011), low left ventricular ejection fraction (HR 3.12, 95% CI 1.21 to 8.07, p ⫽ 0.019), and Killip class III (HR 3.48, 95% CI 1.19 to 10.22, p ⫽ 0.023) were independent predictors of 1-year MACEs in patients with painless STEMI. However, low left ventricular ejection fraction was not 1 of the predictors of 1-year mortality (Figure 3). Discussion The present study definitively showed that patients with painless STEMI had worse short-term and long-term outcomes than patients with painful STEMI. In addition, hypotension, low left ventricular ejection fraction, and high Killip class were independent predictors of 1-year MACEs for patients with painless STEMI after PCI.
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Table 2 Coronary angiographic findings Variable Culprit coronary lesion Left main coronary artery Left anterior descending coronary artery Left circumflex coronary artery Right coronary artery Multivessel coronary disease Thrombolysis In Myocardial Infarction grade flow 0 (total occlusion) before procedure 0 (no reflow) after procedure 3 Lesion complexity* Stent profile Use of drug-eluting stent Sirolimus-eluting stent Paclitaxel-eluting stent Everolimus-eluting stent Other drug-eluting stent Use of bare metal stent Stent diameter (mm) Stent length (mm)
Painless (n ⫽ 763)
Painful (n ⫽ 6,525)
p Value
12 (1.8%) 360 (54%) 54 (8.1%) 243 (36%) 395 (59%)
78 (1.3%) 3,180 (52%) 609 (9.9%) 2,277 (37%) 3,239 (53%)
0.259 0.313 0.127 0.707 0.003
288 (45%) 13 (1.7%) 566 (71%) 446 (71%)
3,131 (53%) 116 (1.8%) 5,254 (92%) 4,486 (78%)
⬍0.001 0.883 0.679 ⬍0.001
504 (86%) 168 (29%) 253 (43%) 43 (7.4%) 40 (6.8%) 81 (14%) 3.2 ⫾ 0.4 24.9 ⫾ 6.0
4,986 (91%) 2,399 (44%) 1,665 (31%) 576 (11%) 346 (6.3%) 469 (8.6%) 3.2 ⫾ 0.4 25.1 ⫾ 6.3
⬍0.001 ⬍0.001 ⬍0.001 0.015 0.642 ⬍0.001 0.128 0.326
Data are presented as number of patients (percentage) or mean ⫾ SD. * Lesion types B2 to C according to the American College of Cardiology/American Heart Association. Table 3 Clinical outcomes in patients who underwent primary percutaneous coronary intervention
In-hospital outcomes Patients In-hospital death Heart failure Acute renal failure Cardiogenic shock Stroke Bleeding Coronary care unit stay (days) 1-Year outcomes Patients All-cause death Death and nonfatal myocardial infarction Target lesion revascularization Target vessel revascularization Coronary artery bypass grafting Revascularization Composite major adverse cardiac events
Painless
Painful
p Value
454 27 (5.9%) 3 (0.7%) 4 (0.9%) 33 (7.3%) 5 (1.1%) 3 (0.7%) 3.3 ⫾ 4.3
4,861 185 (3.6%) 22 (0.5%) 17 (0.4%) 189 (3.9%) 18 (0.4%) 18 (0.4%) 3.3 ⫾ 3.4
0.026 0.468 0.099 0.001 0.041 0.418 0.970
355 43 (12%) 51 (14%) 24 (35%) 32 (46%) 0 (0%) 42 (12%) 93 (26%)
3,030 283 (9.2%) 312 (10%) 82 (19%) 114 (26%) 11 (0.4%) 276 (8.9%) 588 (19%)
0.082 0.016 0.002 ⬍0.001 0.618 0.085 0.002
Data are presented as number of patients (percentage) or mean ⫾ SD.
In the present study, patients with painless STEMI were less hyperlipidemic. The older age and predominance of women in the painless group may have contributed to the antidyslipidemic feature of this group because low-density lipoprotein cholesterol levels tend to be lower in women and tend to decrease with increasing age.9 However, a direct relation between the cardiac pain mechanism and a lipid profile is currently unknown. In addition, there were fewer TIMI grade 0 flows before the procedure and American College of Cardiology/American Heart Association type B2/C lesions in patients with painless STEMI. These results
are consistent with the intensity theory, which postulates that more intense or more prolonged episodes of myocardial ischemia elicit pain, whereas less intense or shorter episodes are silent.10,11 Despite the favorable lesion characteristics, clinical outcomes of painless STEMI were worse. This may suggest that ischemic duration representing total ischemic burden might be more important in painless STEMI.12 There is lack of data directly explaining the consequences of painless MI. However, some studies have identified the prognostic importance of silent myocardial ischemia in various populations of patients with coronary artery
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Figure 2. Cumulative incidence of all-cause death (A), death and myocardial infarction (B), revascularization (C), and major adverse cardiac events (D) in the study population. Patients with painless ST-segment elevation myocardial infarction had worse outcomes in all-cause death, death and myocardial infarction, and composite major adverse cardiac events. However, there was no significant difference between groups in revascularization rate.
disease. Gill et al13 reported that myocardial ischemia was detected in 23% of ⱖ400 patients before discharge after MI. MACEs at 1-year follow-up were almost threefold higher in patients with silent ischemia on Holter electrocardiogram than in those without. However, Klein et al14 suggested that silent ischemia is prognostically worse in populations with more intense ischemia. Narins et al15 also found that in patients with stable coronary artery disease, adverse outcomes were more prevalent in patients with painful versus silent ischemia. However, the prognostic value of silent ischemia was greater in high-risk cohorts such as patients after infarction or those with acute coronary syndromes.
These results imply that a severe ischemia such as painless MI has a close association with adverse outcomes, whereas mild episodes do not. These observations are consistent with the results of our study indicating that patients with painless STEMI have more adverse short-term and longterm outcomes than those with painful STEMI. Although the specific reason for worse outcomes of painless STEMI is not known, 1 possibility might be that the painless group had ischemia for much longer owing to a lack of pain symptoms at the time they had revascularization and thus little to gain. Electrocardiographic findings supported that assumption. The presence of Q waves in
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Figure 3. Independent predictors of cumulative mortality (A) and major adverse cardiac events (B) in patients with painless ST-segment elevation myocardial infarction. HR ⫽ heart rate; LVEF ⫽ left ventricular ejection fraction; SBP ⫽ systolic blood pressure.
addition to ST-segment elevations can provide information on the onset of infarction. There were definitely more Q waves in the painless group than in the painful group (32% vs 16%, p ⬍0.001). Moreover, this phenomenon might be explained by adenosine, a purine nucleoside mainly derived from adenosine 5=-triphosphate metabolism. Its extracellular concentration in body fluids may increase 100-fold during periods of oxygen depletion and ischemia.16 It has been reported that sustained elevation of myocardial adenosine can impair cardiac sympathetic neurotransmission.17 This supports the mechanism of the neural stunning theory18 in painless myocardial ischemia. Also, adenosine exerts potent cardioprotective effects on the ischemic/reperfused heart, decreasing reversible and irreversible myocardial injury.19 Its protective effects before and after ischemic conditioning are available if the occupancy of adenosine receptors is guaranteed.20 Repetitive mild episodes of myocardial ischemia may cause neural stunning and an ischemic preconditioning-like ischemic/reperfusion state. Taken together, we assumed that some portion of patients with STEMI might have downregulated adenosine receptors associated with a failure of the cardiac pain sensation and insufficient cardioprotective effects that led to worse outcomes in patients with painless STEMI. The regulation of adenosine receptor concentration in patients with painless STEMI remains to be clearly established by future molecular biological studies. Several methods have been reported for recognizing silent myocardial ischemia including ambulatory electrocardiographic monitoring, bedside electrocardiographic monitoring, exercise stress testing, radionuclide imaging techniques, continuous intracardiac monitoring, near-
infrared spectroscopy, computed tomography, tissue oxygen tension, and intramyocardial temperature monitoring.21 None of them, however, are easy to use in the emergency setting. Another way to solve this problem is the pharmacologic approach, which increases pain perception in the heart by decreasing neural stunning and cardiac pain thresholds and directly reinforcing cardiac pain perception. The neural stunning theory states that sustained cardiac increases in adenosine cause sympathetic neural conduction impairment. This phenomenon has been prevented by adenosine deaminase or 8-sulfophenyltheophylline, an adenosine receptor blocker.17 The present study has several limitations. First, this is a nonrandomized registry-based study and was therefore subject to the limitations pertinent to this type of clinical investigation. Second, specific symptoms of which patients complained at presentation were not recorded in detail in the KAMIR, although chest pain and dyspnea were described well. Various symptoms in painless MI have been described elsewhere as dyspnea, dizziness, nausea, hypotension, appetite loss, loss of consciousness, or no symptoms.22 Third, it was unfeasible to evaluate the symptom-to-balloon time because of a lack of painful symptoms. Door-to-balloon time therefore was the only variable that reflected ischemic duration. Fourth, there was a lack of long-term follow-up data. Further observation is needed to draw more definite conclusions on long-term clinical outcomes. Fifth, symptoms that had brought patients with painless STEMI to the hospital were not clear because of insufficient symptom data in the KAMIR. However, surely they did not have any pain symptoms or angina equivalents. Appendix KAMIR study group of the Korean Circulation Society: Myung Ho Jeong, Young Jo Kim, Chong Jin Kim, Myeong Chan Cho, Youngkeun Ahn, Jong Hyun Kim, Shung Chull Chae, Seung Ho Hur, In Whan Seong, Taek Jong Hong, Dong Hoon Choi, Jei Keon Chae, Jae Young Rhew, Doo Il Kim, In Ho Chae, Jung Han Yoon, Bon Kwon Koo, Byung Ok Kim, Myoung Yong Lee, Kee Sik Kim, Jin Yong Hwang, Seok Kyu Oh, Nae Hee Lee, Kyoung Tae Jeong, Seung Jea Tahk, Jang Ho Bae, Seung Woon Rha, Keum Soo Park, Kyoo Rok Han, Tae Hoon Ahn, Moo Hyun Kim, Joo Young Yang, Chong Yun Rhim, Hyeon Cheol Gwon, Seong Wook Park, Young Youp Koh, Seung Jae Joo, Soo Joong Kim, Dong Kyu Jin, Jin Man Cho, Wook Sung Chung, Yang Soo Jang, Jeong Gwan Cho, Ki Bae Seung, and Seung Jung Park. 1. Cohn PF, Fox KM, Daly C. Silent myocardial ischemia. Circulation 2003;108:1263–1277. 2. Froelicher VF, Thompson AJ, Longo MR Jr, Triebwasser JH, Lancaster MC. Value of exercise testing for screening asymptomatic men for latent coronary artery disease. Prog Cardiovasc Dis 1976;18:265– 276. 3. Thaulow E, Erikssen J, Sandvik L, Erikssen G, Jorgensen L, Cohn PF. Initial clinical presentation of cardiac disease in asymptomatic men with silent myocardial ischemia and angiographically documented coronary artery disease (the Oslo Ischemia Study). Am J Cardiol 1993;72:629 – 633. 4. Fleg JL, Gerstenblith G, Zonderman AB, Becker LC, Weisfeldt ML, Costa PT Jr, Lakatta EG. Prevalence and prognostic significance of
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exercise-induced silent myocardial ischemia detected by thallium scintigraphy and electrocardiography in asymptomatic volunteers. Circulation 1990;81:428 – 436. He ZX, Hedrick TD, Pratt CM, Verani MS, Aquino V, Roberts R, Mahmarian JJ. Severity of coronary artery calcification by electron beam computed tomography predicts silent myocardial ischemia. Circulation 2000;101:244 –251. Feringa HH, Karagiannis SE, Vidakovic R, Elhendy A, ten Cate FJ, Noordzij PG, van Domburg RT, Bax JJ, Poldermans D. The prevalence and prognosis of unrecognized myocardial infarction and silent myocardial ischemia in patients undergoing major vascular surgery. Coron Artery Dis 2007;18:571–576. Raby KE, Goldman L, Cook EF, Rumerman J, Barry J, Creager MA, Selwyn AP. Long-term prognosis of myocardial ischemia detected by Holter monitoring in peripheral vascular disease. Am J Cardiol 1990; 66:1309 –1313. Oberman A, Kouchoukos NT, Holt JH Jr, Russell RO Jr. Long-term results of the medical treatment of coronary artery disease. Angiology 1977;28:160 –168. Schaefer EJ, Lamon-Fava S, Cohn SD, Schaefer MM, Ordovas JM, Castelli WP, Wilson PW. Effects of age, gender, and menopausal status on plasma low density lipoprotein cholesterol and apolipoprotein B levels in the Framingham Offspring Study. J Lipid Res 1994; 35:779 –792. Nihoyannopoulos P, Marsonis A, Joshi J, Athanassopoulos G, Oakley CM. Magnitude of myocardial dysfunction is greater in painful than in painless myocardial ischemia: an exercise echocardiographic study. J Am Coll Cardiol 1995;25:1507–1512. Taki J, Yasuda T, Flamm SD, Hutter A, Gold HK, Leinbach R, Strauss HW. Comparison of painful and painless left ventricular dysfunction recorded during ambulatory ventricular function monitoring in angina pectoris secondary to coronary artery disease. Am J Cardiol 1992;70: 1555–1558. Cohn PF. Total ischemic burden: definition, mechanisms, and therapeutic implications. Am J Med 1986;81:2– 6.
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13. Gill JB, Cairns JA, Roberts RS, Costantini L, Sealey BJ, Fallen EF, Tomlinson CW, Gent M. Prognostic importance of myocardial ischemia detected by ambulatory monitoring early after acute myocardial infarction. N Engl J Med 1996;334:65–70. 14. Klein J, Chao SY, Berman DS, Rozanski A. Is ‘silent’ myocardial ischemia really as severe as symptomatic ischemia? The analytical effect of patient selection biases. Circulation 1994;89:1958 – 1966. 15. Narins CR, Zareba W, Moss AJ, Goldstein RE, Hall WJ. Clinical implications of silent versus symptomatic exercise-induced myocardial ischemia in patients with stable coronary disease. J Am Coll Cardiol 1997;29:756 –763. 16. Schulte G, Fredholm BB. Signalling from adenosine receptors to mitogen-activated protein kinases. Cell Signal 2003;15:813– 827. 17. Pettersen MD, Abe T, Morgan DA, Gutterman DD. Role of adenosine in postischemic dysfunction of coronary innervation. Circ Res 1995; 76:95–101. 18. Gutterman DD. Silent myocardial ischemia. Circ J 2009;73:785–797. 19. McIntosh VJ, Lasley RD. Adenosine receptor-mediated cardioprotection: are all 4 subtypes required or redundant? J Cardiovasc Pharmacol Ther 2011. [Epub ahead of print]. 20. Yang XM, Philipp S, Downey JM, Cohen MV. Postconditioning’s protection is not dependent on circulating blood factors or cells but involves adenosine receptors and requires PI3-kinase and guanylyl cyclase activation. Basic Res Cardiol 2005;100:57– 63. 21. Ahmed AH, Shankar K, Eftekhari H, Munir M, Robertson J, Brewer A, Stupin IV, Casscells SW. Silent myocardial ischemia: current perspectives and future directions. Exp Clin Cardiol 2007;12:189 – 196. 22. Komukai K, Ogawa T, Yagi H, Date T, Suzuki K, Sakamoto H, Miyazaki H, Takatsuka H, Shibayama K, Ogawa K, Kanzaki Y, Kosuga T, Kawai M, Hongo K, Yoshida S, Taniguchi I, Mochizuki S. Renal insufficiency is related to painless myocardial infarction. Circ J 2007;71:1366 –1369.
a
Chonnam National University Hospital, Gwangju, South Korea; Busan Hanseo Hospital, Busan, South Korea; cKyungpook National University Hospital, Daegu, South Korea; dYeungnam University Hospital, Daegu, South Korea; eKeimyung University Hospital, Daegu, South Korea; fChungnam National University Hospital, Daejon, South Korea; g Pusan National University Hospital, Busan, South Korea; hYonsei University Severans Hospital, Seoul, South Korea; iChungbuk National University Hospital, Cheongju, South Korea; jKyung hee University Hospital, Seoul, South Korea; kCatholic University Hospital, Seoul, South Korea; l CHA Bundang Medical Center, Sungnam, South Korea; mKorea University Hospital, Seoul, South Korea; nKonyang University Hospital, Daejon, South Korea; oSeoul Asan Medical Center, Seoul, South Korea. Manuscript received August 5, 2011; revised manuscript received and accepted September 13, 2011. This study was supported by a grant from the Korean Society of Circulation, Seoul, Republic of Korea, in celebration of its 50th Anniversary and the Korea Healthcare Technology R&D Project (A084869), Ministry for Health, Welfare and Family Affairs, Seoul, Republic of Korea, and the Cardiovascular Research Foundation Asia, Seoul, Republic of Korea. *Corresponding author: Tel: 82-62-220-6243; fax: ⫹82-62-228-7174. E-mail address: [email protected] (M.H. Jeong). b
0002-9149/12/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2011.09.017
Painless STEMI is often followed by silent myocardial ischemia. Silent myocardial ischemia is defined as an objective documentation of myocardial ischemia in the absence of angina pectoris or angina equivalents.1 Approximately 2.5% of myocardial ischemia in the study population have occurred in the absence of chest pain in several studies.2–5 In a cohort of 1,092 patients undergoing preoperative dobutamine stress echocardiography and noncardiac vascular surgery, unrecognized MI and silent myocardial ischemia were highly prevalent (23% and 28%).6 Silent myocardial ischemia seems to be an independent predictor of future cardiac morbidity and mortality.7 Also, it is estimated that the first manifestation of coronary artery disease in 60% to 70% of patients is sudden death or MI, whereas only a minority present first with angina pectoris or other symptoms of reversible myocardial ischemia.8 Nevertheless, the incidence of painless STEMI is unclear, and currently a paucity of data is available on the outcomes of painless MI. Hence, we aimed to examine the incidence, clinical characteristics, and outcomes of painless STEMI. Methods The Korea Acute Myocardial Infarction Registry (KAMIR), launched in November 2005, is a Korean prospective multicenter data collection registry reflecting realwww.ajconline.org
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Figure 1. Study flow chart. AMI ⫽ acute myocardial infarction; NSTEMI ⫽ non–ST-segment elevation myocardial infarction.
world treatment practices and outcomes in Asian patients diagnosed with acute infarction. The registry includes 50 community and teaching hospitals with facilities for primary percutaneous coronary intervention (PCI) and on-site cardiac surgery. It is the largest acute MI registry in Korea and, to the best of our knowledge, 1 of the largest in the world. From November 2005 to December 2007, 14,885 patients with acute MI were enrolled in the KAMIR. Data were collected by a trained study coordinator using a standardized case-report form and protocol. The study protocol was approved by the ethics committee at each participating institution. In the present study, patients with STEMI were selected (61.8 ⫾ 12.8 years old, 74% men) and constituted the eligible 7,288 of the 14,885 total registered patients. Patients were grouped into the painless STEMI group (n ⫽ 763) and the painful STEMI group (n ⫽ 6,525) based on the presence of chest pain around the time of their visit to the emergency room (Figure 1). All patients received aspirin ⱖ100 mg and a loading dose of clopidogrel 300 to 600 mg and heparin. The maintenance dose was aspirin 100 mg/day and clopidogrel 75 mg/day. Aspirin and clopidogrel was administered to all patients for ⱖ6 months according to existing guidelines. Postintervention medication included aspirin, clopidogrel,  blockers, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers. After discharge, the patients continued to receive the same medications that they received during hospitalization with the exception of some intravenous or temporary medications. Coronary interventions were performed using standard techniques. The decisions for predilation, direct stenting, postadjunctive balloon inflation, and the administration of glycoprotein IIb/IIIa receptor blockers were left to the discretion of individual
operators. Clinical follow-up was performed at 1 month and 6, and 12 months and when anginalike symptoms occurred. Acute MI was defined as the presence of ⱖ2 of the following 3 conditions: (1) ischemic symptoms, (2) increase of cardiac markers ⱖ2 times the upper limit of normal, or (3) new ST-segment elevation. STEMI was defined as a clinical presentation consistent with an acute MI and an electrocardiogram with ST-segment elevation ⱖ0.1 mV in ⱖ2 contiguous leads, Q wave, or new left bundle branch block. Painless STEMI was defined as STEMI without pain symptoms and dyspnea, which is an accepted angina equivalent.1 Data on other cardiovascular risk factors such as hypertension, smoking, and previous ischemic heart disease were also reported by the patients themselves, with the exception of dyslipidemia, which was defined as a composite of selfreported history, previous statin usage, and a fasting cholesterol level ⱖ200 mg/dl. Angiographic parameters such as Thrombolysis In Myocardial Infarction (TIMI) flow grade or American College of Cardiology/American Heart Association lesion type were assessed by the operator. A successful procedure was defined as ⬍20% residual stenosis after the procedure in this study. In-hospital deaths from all causes and 1-year major adverse cardiac events (MACEs) were considered primary outcomes. A MACE was defined as a composite of cardiac death, noncardiac death, nonfatal reinfarction, and coronary artery revascularization. Target vessel revascularization was defined as any repeated intervention driven by lesions in the treated vessel within and beyond the target lesion limits. Continuous variables with normal distributions are presented as mean ⫾ SD and were compared using Student’s t test or Mann–Whitney U test when group distributions were skewed. Categorical variables were compared using chisquare test or Fisher’s exact test, where appropriate. Cumulative mortality, death and nonfatal MIs, revascularization, and composite MACE rates were evaluated using the Kaplan–Meier method and compared using log-rank test. Cox regression analysis was performed to identify independent predictors of 1-year mortality and MACEs in painless STEMI. Variables with a p value ⬍0.1 in univariate Cox analysis were tested. All statistical tests were 2-tailed and a p value ⬍0.05 was considered statistically significant. All analyses were performed using SPSS 17.0 (SPSS, Inc., Chicago, Illinois). Results Baseline demographic characteristics are listed in Table 1. Painless STEMI comprised 11% of total patients with STEMI. Patients in the painless group were older, were more likely to be women, and were more likely to have diabetes, but were less likely to have hyperlipidemia, to have a family history, and to be a smoker. The painless group had fewer previous MIs and no significant differences in left ventricular function were observed between the 2 groups. The painless group was less likely to be given primary PCI. The painless group had comparable blood pressure to the painful group but the painless group had faster heart rates. With regard to door-to-balloon time, the
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Table 1 Demographic findings Variable Age (years) Men Body mass index (kg/m2) Diabetes mellitus Hypertension Hyperlipidemia Smoker Family history of coronary disease Previous myocardial infarction Left ventricular ejection fraction (%) Killip class III on presentation Systolic blood pressure (mm Hg) Heart rate (beats/min) Primary percutaneous coronary intervention Door-to-balloon time (minutes) Q wave Left bundle branch block Glomerular filtration rate (ml/min) Glucose (mg/dl) High-sensitivity C-reactive protein (mg/dl) Amino-terminal pro–B-type natriuretic peptide (pg/ml) Maximum creatine kinase (IU/L) Maximum creatine kinase-MB (IU/L) Maximum cardiac troponin I (ng/ml) Total cholesterol (mg/dl) Triglycerides (mg/dl) High-density lipoprotein cholesterol (mg/dl) Low-density lipoprotein cholesterol (mg/dl)
Painless (n ⫽ 763)
Painful (n ⫽ 6,525)
p Value
65.2 ⫾ 12.8 531 (70%) 23.8 ⫾ 8.1 219 (29%) 369 (49%) 232 (33%) 438 (58%) 33 (4.7%) 269 (36%) 50.2 ⫾ 13.0 89 (12%) 127.8 ⫾ 40.9 80.4 ⫾ 39.0 454 (61%) 133.5 ⫾ 136.1 247 (32%) 9 (1.2%) 67.0 ⫾ 36.1 172.0 ⫾ 87.0 12.6 ⫾ 72.5 3,755.3 ⫾ 6,960.6 1,464.8 ⫾ 2,345.9 111.6 ⫾ 185.7 50.8 ⫾ 77.6 177.5 ⫾ 44.5 117.4 ⫾ 94.1 45.1 ⫾ 12.8 113.5 ⫾ 39.2
61.4 ⫾ 12.8 4,883 (75%) 24.1 ⫾ 5.2 1,549 (24%) 2,918 (45%) 2,318 (39%) 4,041 (63%) 451 (7.8%) 2,538 (39%) 50.6 ⫾ 11.6 454 (7.2%) 127.5 ⫾ 31.3 77.0 ⫾ 26.3 4,861 (77%) 88.4 ⫾ 94.8 1,053 (16%) 39 (0.6%) 75.7 ⫾ 41.2 171.3 ⫾ 74.5 14.9 ⫾ 75.4 1,802.3 ⫾ 4,575.8 1,813.1 ⫾ 2,064.9 197.7 ⫾ 314.1 65.9 ⫾ 180.3 184.0 ⫾ 43.9 126.5 ⫾ 113.2 45.3 ⫾ 22.7 118.4 ⫾ 43.9
⬍0.001 0.001 0.164 0.003 0.074 0.002 0.009 0.004 0.043 0.466 ⬍0.001 0.798 0.022 ⬍0.001 ⬍0.001 ⬍0.001 0.060 ⬍0.001 0.826 0.463 ⬍0.001 ⬍0.001 ⬍0.001 0.025 ⬍0.001 0.017 0.819 0.005
Data are presented as number of patients (percentage) or mean ⫾ SD.
painless group was given primary PCI significantly later than the painful group. On electrocardiogram a Q wave was more frequently seen in the painless group than in the painful group. Laboratory testing indicated that renal function was worse in the painless group. There were no differences in high-sensitivity C-reactive protein level but the N-terminal pro–B-type natriuretic peptide level was much higher in the painless group. The lipid profile was better in the painless group: total cholesterol, triglyceride, and lowdensity lipoprotein cholesterol levels were lower than those in the painful group. Coronary angiographic findings are presented in Table 2. There were no significant differences between groups in culprit lesions. The painless group had more multivessel disease but less TIMI grade 0 flows before the procedure and complex lesions. Drug-eluting stents were used less frequently in the painless group and physicians used paclitaxel-eluting stents more in patients in the painless group than in those in the painful group. Clinical outcomes in patients who underwent primary PCI are presented in Table 3. The painless group had a larger number of in-hospital deaths. Other hospital outcomes including heart failure, acute renal failure, and bleeding tended to be worse and cardiogenic shock and stroke were significantly more frequent in the painless group. Long-term outcome analyses indicated that the composite MACE was greater in the painless group than in the painful group. In detail, all-cause death and any revascularization
tended to be higher in percentages than in the painful STEMI group, although this was not statistically significant. In contrast, death, nonfatal MI, and target lesion revascularization rates were higher in the painless group. Kaplan– Meier analysis indicated that patients with painless STEMI had worse outcomes in death, MI, and composite MACE (p ⫽ 0.019 and 0.005, log-rank test, respectively). In contrast, all-cause death or revascularization rate did not show more than a trend to be worse in the painless group (Figure 2). In multivariable Cox proportional hazard analysis, hypotension (hazard ratio [HR] 4.40, 95% confidence interval [CI] 1.41 to 13.78, p ⫽ 0.011), low left ventricular ejection fraction (HR 3.12, 95% CI 1.21 to 8.07, p ⫽ 0.019), and Killip class III (HR 3.48, 95% CI 1.19 to 10.22, p ⫽ 0.023) were independent predictors of 1-year MACEs in patients with painless STEMI. However, low left ventricular ejection fraction was not 1 of the predictors of 1-year mortality (Figure 3). Discussion The present study definitively showed that patients with painless STEMI had worse short-term and long-term outcomes than patients with painful STEMI. In addition, hypotension, low left ventricular ejection fraction, and high Killip class were independent predictors of 1-year MACEs for patients with painless STEMI after PCI.
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Table 2 Coronary angiographic findings Variable Culprit coronary lesion Left main coronary artery Left anterior descending coronary artery Left circumflex coronary artery Right coronary artery Multivessel coronary disease Thrombolysis In Myocardial Infarction grade flow 0 (total occlusion) before procedure 0 (no reflow) after procedure 3 Lesion complexity* Stent profile Use of drug-eluting stent Sirolimus-eluting stent Paclitaxel-eluting stent Everolimus-eluting stent Other drug-eluting stent Use of bare metal stent Stent diameter (mm) Stent length (mm)
Painless (n ⫽ 763)
Painful (n ⫽ 6,525)
p Value
12 (1.8%) 360 (54%) 54 (8.1%) 243 (36%) 395 (59%)
78 (1.3%) 3,180 (52%) 609 (9.9%) 2,277 (37%) 3,239 (53%)
0.259 0.313 0.127 0.707 0.003
288 (45%) 13 (1.7%) 566 (71%) 446 (71%)
3,131 (53%) 116 (1.8%) 5,254 (92%) 4,486 (78%)
⬍0.001 0.883 0.679 ⬍0.001
504 (86%) 168 (29%) 253 (43%) 43 (7.4%) 40 (6.8%) 81 (14%) 3.2 ⫾ 0.4 24.9 ⫾ 6.0
4,986 (91%) 2,399 (44%) 1,665 (31%) 576 (11%) 346 (6.3%) 469 (8.6%) 3.2 ⫾ 0.4 25.1 ⫾ 6.3
⬍0.001 ⬍0.001 ⬍0.001 0.015 0.642 ⬍0.001 0.128 0.326
Data are presented as number of patients (percentage) or mean ⫾ SD. * Lesion types B2 to C according to the American College of Cardiology/American Heart Association. Table 3 Clinical outcomes in patients who underwent primary percutaneous coronary intervention
In-hospital outcomes Patients In-hospital death Heart failure Acute renal failure Cardiogenic shock Stroke Bleeding Coronary care unit stay (days) 1-Year outcomes Patients All-cause death Death and nonfatal myocardial infarction Target lesion revascularization Target vessel revascularization Coronary artery bypass grafting Revascularization Composite major adverse cardiac events
Painless
Painful
p Value
454 27 (5.9%) 3 (0.7%) 4 (0.9%) 33 (7.3%) 5 (1.1%) 3 (0.7%) 3.3 ⫾ 4.3
4,861 185 (3.6%) 22 (0.5%) 17 (0.4%) 189 (3.9%) 18 (0.4%) 18 (0.4%) 3.3 ⫾ 3.4
0.026 0.468 0.099 0.001 0.041 0.418 0.970
355 43 (12%) 51 (14%) 24 (35%) 32 (46%) 0 (0%) 42 (12%) 93 (26%)
3,030 283 (9.2%) 312 (10%) 82 (19%) 114 (26%) 11 (0.4%) 276 (8.9%) 588 (19%)
0.082 0.016 0.002 ⬍0.001 0.618 0.085 0.002
Data are presented as number of patients (percentage) or mean ⫾ SD.
In the present study, patients with painless STEMI were less hyperlipidemic. The older age and predominance of women in the painless group may have contributed to the antidyslipidemic feature of this group because low-density lipoprotein cholesterol levels tend to be lower in women and tend to decrease with increasing age.9 However, a direct relation between the cardiac pain mechanism and a lipid profile is currently unknown. In addition, there were fewer TIMI grade 0 flows before the procedure and American College of Cardiology/American Heart Association type B2/C lesions in patients with painless STEMI. These results
are consistent with the intensity theory, which postulates that more intense or more prolonged episodes of myocardial ischemia elicit pain, whereas less intense or shorter episodes are silent.10,11 Despite the favorable lesion characteristics, clinical outcomes of painless STEMI were worse. This may suggest that ischemic duration representing total ischemic burden might be more important in painless STEMI.12 There is lack of data directly explaining the consequences of painless MI. However, some studies have identified the prognostic importance of silent myocardial ischemia in various populations of patients with coronary artery
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Figure 2. Cumulative incidence of all-cause death (A), death and myocardial infarction (B), revascularization (C), and major adverse cardiac events (D) in the study population. Patients with painless ST-segment elevation myocardial infarction had worse outcomes in all-cause death, death and myocardial infarction, and composite major adverse cardiac events. However, there was no significant difference between groups in revascularization rate.
disease. Gill et al13 reported that myocardial ischemia was detected in 23% of ⱖ400 patients before discharge after MI. MACEs at 1-year follow-up were almost threefold higher in patients with silent ischemia on Holter electrocardiogram than in those without. However, Klein et al14 suggested that silent ischemia is prognostically worse in populations with more intense ischemia. Narins et al15 also found that in patients with stable coronary artery disease, adverse outcomes were more prevalent in patients with painful versus silent ischemia. However, the prognostic value of silent ischemia was greater in high-risk cohorts such as patients after infarction or those with acute coronary syndromes.
These results imply that a severe ischemia such as painless MI has a close association with adverse outcomes, whereas mild episodes do not. These observations are consistent with the results of our study indicating that patients with painless STEMI have more adverse short-term and longterm outcomes than those with painful STEMI. Although the specific reason for worse outcomes of painless STEMI is not known, 1 possibility might be that the painless group had ischemia for much longer owing to a lack of pain symptoms at the time they had revascularization and thus little to gain. Electrocardiographic findings supported that assumption. The presence of Q waves in
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Figure 3. Independent predictors of cumulative mortality (A) and major adverse cardiac events (B) in patients with painless ST-segment elevation myocardial infarction. HR ⫽ heart rate; LVEF ⫽ left ventricular ejection fraction; SBP ⫽ systolic blood pressure.
addition to ST-segment elevations can provide information on the onset of infarction. There were definitely more Q waves in the painless group than in the painful group (32% vs 16%, p ⬍0.001). Moreover, this phenomenon might be explained by adenosine, a purine nucleoside mainly derived from adenosine 5=-triphosphate metabolism. Its extracellular concentration in body fluids may increase 100-fold during periods of oxygen depletion and ischemia.16 It has been reported that sustained elevation of myocardial adenosine can impair cardiac sympathetic neurotransmission.17 This supports the mechanism of the neural stunning theory18 in painless myocardial ischemia. Also, adenosine exerts potent cardioprotective effects on the ischemic/reperfused heart, decreasing reversible and irreversible myocardial injury.19 Its protective effects before and after ischemic conditioning are available if the occupancy of adenosine receptors is guaranteed.20 Repetitive mild episodes of myocardial ischemia may cause neural stunning and an ischemic preconditioning-like ischemic/reperfusion state. Taken together, we assumed that some portion of patients with STEMI might have downregulated adenosine receptors associated with a failure of the cardiac pain sensation and insufficient cardioprotective effects that led to worse outcomes in patients with painless STEMI. The regulation of adenosine receptor concentration in patients with painless STEMI remains to be clearly established by future molecular biological studies. Several methods have been reported for recognizing silent myocardial ischemia including ambulatory electrocardiographic monitoring, bedside electrocardiographic monitoring, exercise stress testing, radionuclide imaging techniques, continuous intracardiac monitoring, near-
infrared spectroscopy, computed tomography, tissue oxygen tension, and intramyocardial temperature monitoring.21 None of them, however, are easy to use in the emergency setting. Another way to solve this problem is the pharmacologic approach, which increases pain perception in the heart by decreasing neural stunning and cardiac pain thresholds and directly reinforcing cardiac pain perception. The neural stunning theory states that sustained cardiac increases in adenosine cause sympathetic neural conduction impairment. This phenomenon has been prevented by adenosine deaminase or 8-sulfophenyltheophylline, an adenosine receptor blocker.17 The present study has several limitations. First, this is a nonrandomized registry-based study and was therefore subject to the limitations pertinent to this type of clinical investigation. Second, specific symptoms of which patients complained at presentation were not recorded in detail in the KAMIR, although chest pain and dyspnea were described well. Various symptoms in painless MI have been described elsewhere as dyspnea, dizziness, nausea, hypotension, appetite loss, loss of consciousness, or no symptoms.22 Third, it was unfeasible to evaluate the symptom-to-balloon time because of a lack of painful symptoms. Door-to-balloon time therefore was the only variable that reflected ischemic duration. Fourth, there was a lack of long-term follow-up data. Further observation is needed to draw more definite conclusions on long-term clinical outcomes. Fifth, symptoms that had brought patients with painless STEMI to the hospital were not clear because of insufficient symptom data in the KAMIR. However, surely they did not have any pain symptoms or angina equivalents. Appendix KAMIR study group of the Korean Circulation Society: Myung Ho Jeong, Young Jo Kim, Chong Jin Kim, Myeong Chan Cho, Youngkeun Ahn, Jong Hyun Kim, Shung Chull Chae, Seung Ho Hur, In Whan Seong, Taek Jong Hong, Dong Hoon Choi, Jei Keon Chae, Jae Young Rhew, Doo Il Kim, In Ho Chae, Jung Han Yoon, Bon Kwon Koo, Byung Ok Kim, Myoung Yong Lee, Kee Sik Kim, Jin Yong Hwang, Seok Kyu Oh, Nae Hee Lee, Kyoung Tae Jeong, Seung Jea Tahk, Jang Ho Bae, Seung Woon Rha, Keum Soo Park, Kyoo Rok Han, Tae Hoon Ahn, Moo Hyun Kim, Joo Young Yang, Chong Yun Rhim, Hyeon Cheol Gwon, Seong Wook Park, Young Youp Koh, Seung Jae Joo, Soo Joong Kim, Dong Kyu Jin, Jin Man Cho, Wook Sung Chung, Yang Soo Jang, Jeong Gwan Cho, Ki Bae Seung, and Seung Jung Park. 1. Cohn PF, Fox KM, Daly C. Silent myocardial ischemia. Circulation 2003;108:1263–1277. 2. Froelicher VF, Thompson AJ, Longo MR Jr, Triebwasser JH, Lancaster MC. Value of exercise testing for screening asymptomatic men for latent coronary artery disease. Prog Cardiovasc Dis 1976;18:265– 276. 3. Thaulow E, Erikssen J, Sandvik L, Erikssen G, Jorgensen L, Cohn PF. Initial clinical presentation of cardiac disease in asymptomatic men with silent myocardial ischemia and angiographically documented coronary artery disease (the Oslo Ischemia Study). Am J Cardiol 1993;72:629 – 633. 4. Fleg JL, Gerstenblith G, Zonderman AB, Becker LC, Weisfeldt ML, Costa PT Jr, Lakatta EG. Prevalence and prognostic significance of
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13. Gill JB, Cairns JA, Roberts RS, Costantini L, Sealey BJ, Fallen EF, Tomlinson CW, Gent M. Prognostic importance of myocardial ischemia detected by ambulatory monitoring early after acute myocardial infarction. N Engl J Med 1996;334:65–70. 14. Klein J, Chao SY, Berman DS, Rozanski A. Is ‘silent’ myocardial ischemia really as severe as symptomatic ischemia? The analytical effect of patient selection biases. Circulation 1994;89:1958 – 1966. 15. Narins CR, Zareba W, Moss AJ, Goldstein RE, Hall WJ. Clinical implications of silent versus symptomatic exercise-induced myocardial ischemia in patients with stable coronary disease. J Am Coll Cardiol 1997;29:756 –763. 16. Schulte G, Fredholm BB. Signalling from adenosine receptors to mitogen-activated protein kinases. Cell Signal 2003;15:813– 827. 17. Pettersen MD, Abe T, Morgan DA, Gutterman DD. Role of adenosine in postischemic dysfunction of coronary innervation. Circ Res 1995; 76:95–101. 18. Gutterman DD. Silent myocardial ischemia. Circ J 2009;73:785–797. 19. McIntosh VJ, Lasley RD. Adenosine receptor-mediated cardioprotection: are all 4 subtypes required or redundant? J Cardiovasc Pharmacol Ther 2011. [Epub ahead of print]. 20. Yang XM, Philipp S, Downey JM, Cohen MV. Postconditioning’s protection is not dependent on circulating blood factors or cells but involves adenosine receptors and requires PI3-kinase and guanylyl cyclase activation. Basic Res Cardiol 2005;100:57– 63. 21. Ahmed AH, Shankar K, Eftekhari H, Munir M, Robertson J, Brewer A, Stupin IV, Casscells SW. Silent myocardial ischemia: current perspectives and future directions. Exp Clin Cardiol 2007;12:189 – 196. 22. Komukai K, Ogawa T, Yagi H, Date T, Suzuki K, Sakamoto H, Miyazaki H, Takatsuka H, Shibayama K, Ogawa K, Kanzaki Y, Kosuga T, Kawai M, Hongo K, Yoshida S, Taniguchi I, Mochizuki S. Renal insufficiency is related to painless myocardial infarction. Circ J 2007;71:1366 –1369.