ABSTRACT
Background
The association between preinfarction angina and angiographic findings has not been elucidated in patients with non–ST‐segment elevation myocardial infarction (NSTEMI).
Hypothesis
Patients with preinfarction angina have favorable angiographic findings.
Methods
This retrospective study analyzed 481 patients who underwent coronary angiography within 5 days of presenting NSTEMI. Preinfarction angina was defined as experiencing ≥1 chest‐pain episode within 7 days prior to admission. Infarct size was measured as the peak cardiac troponin I (cTnI) level, and large myocardial infarction (MI) was defined as a peak cTnI level >85th percentile value in the study population. Infarct‐related artery (IRA) patency was defined as Thrombolysis In Myocardial Infarction grade 2 or 3 flow. Clinical and angiographic characteristics and in‐hospital mortality were compared between patients with and without preinfarction angina.
Results
Among 481 patients, 200 (42%) had preinfarction angina. Preinfarction angina was associated with smaller infarct size, indicated by lower peak cTnI levels (P = 0.006) and lower incidence of large MI (P = 0.02), and IRA patency (P = 0.03). There was no significant difference in in‐hospital mortality. On multivariate analysis, both preinfarction angina (odds ratio: 0.53, 95% confidence interval: 0.29‐0.94, P = 0.03) and IRA patency (odds ratio: 0.30, 95% confidence interval: 0.17‐0.52, P < 0.001) were independent negative predictors of large MI.
Conclusion
Our study demonstrates that preinfarction angina is a predictor of smaller infarct size and infarct‐related artery patency in NSTEMI patients, suggesting that NSTEMI patients presenting without preinfarction angina are at increased risk of developing a large MI.
Introduction
Preinfarction angina, defined as an angina episode preceding the onset of myocardial infarction (MI), is associated with smaller infarct size1, 2, 3, 4, 5, 6 and favorable in‐hospital1, 7, 8 and long‐term4, 7, 9 outcomes after ST‐segment elevation myocardial infarction (STEMI) in both the thrombolytic and the percutaneous coronary intervention (PCI) eras. Although data regarding the clinical significance of preinfarction angina in non–ST‐segment elevation myocardial infarction (NSTEMI) patients are limited compared with those in STEMI patients, 2 studies reported that preinfarction angina was associated with smaller infarct size and a lower incidence of in‐hospital ventricular arrhythmia.10, 11
The reduction in infarct size associated with preinfarction angina has been attributed to an ischemic preconditioning phenomenon, which involves a brief episode of ischemia that boosts the tolerance of the heart to a subsequent prolonged ischemic insult.12, 13 However, other confounding factors potentially affect infarct size. In fact, various angiographic factors, including preprocedural coronary blood flow,14, 15, 16, 17 thrombus burden,18 and collateral circulation to the infarct‐related artery (IRA),16, 19, 20 have been reported to affect the infarct size in STEMI patients. Interestingly, STEMI patients with preinfarction angina were reported to have favorable angiographic findings compared with those without preinfarction angina, which included a patent IRA,7, 9, 21, 22 lower thrombus burden,18 and presence of collateral circulation.21, 23
Unlike in STEMI patients, the association between preinfarction angina and those angiographic findings has not been robustly reported in NSTEMI patients. The present study assessed the impact of preinfarction angina on infarct size and the association between preinfarction angina and angiographic findings in NSTEMI patients.
Methods
This retrospective analysis included all patients who had undergone coronary angiography between January 2013 and June 2014 at our institution. Two researchers independently reviewed medical records and identified NSTEMI patients from our angiography database. Myocardial infarction was diagnosed according to the European Society of Cardiology and American College of Cardiology criteria.24 The details of the database were also described in our previously published articles.25, 26
Inclusion criteria were (1) troponin (Tn) value >99th percentile reference value before cardiac catheterization; (2) chest pain (or anginal equivalent) or ischemic change on the electrocardiogram, including horizontal or down‐sloping ST‐segment depression (≥0.05 mV) or T‐wave inversion (≥0.1 mV) in ≥2 contiguous leads; and (3) absence of ST elevation and new left bundle branch block on the electrocardiogram. Exclusion criteria were (1) cardiac catheterization >5 days after presentation; (2) severe aortic stenosis, hypertrophic cardiomyopathy, self‐reported cocaine use within 5 days, cardiac arrest, ventricular tachycardia, supraventricular tachycardia with heart rate >150 bpm, implantable cardioverter‐defibrillator shock, and blood pressure on presentation >230/130 mm Hg; (3) subsequent documented diagnosis of Takotsubo cardiomyopathy, myocarditis, and pulmonary embolism; and (4) insufficient data for analysis.
The present study complied with the Declaration of Helsinki and was approved by the institutional review board of our hospital. Patients' demographic data and risk factors, along with admission characteristics, were obtained. Laboratory data on admission were recorded. Cardiac troponin I (cTnI) level was measured using the second‐generation Vitros TnI assay (Ortho‐Clinical Diagnostics Inc., Raritan, NJ). The upper limit of normal for cTnI was 0.034 µg/L, which represented the 99th percentile reference value. The cTnI level was measured serially at approximately a 6‐hour interval before and after catheterization, as clinically indicated, with the highest level designated as the peak cTnI. Transthoracic echocardiography was performed during hospitalization. Left ventricular ejection fraction was calculated by either the Teichholz or biplane Simpson method.
Preinfarction angina was defined as ≥1 separate episode of chest pain or anginal equivalent, similar to the symptoms that lead to the hospital presentation, within 7 days before the admission. We used this cutoff of 7 days in line with a previous study in NSTEMI patients.11 Patients were categorized into 2 groups: those with and without documented preinfarction angina.
All patients had undergone cardiac catheterization within 5 days after presentation. We used the cutoff of 5 days because angiography performed later is less likely to represent the actual coronary flow at the time of the event. An independent cardiologist blinded to the clinical data reviewed all coronary angiography findings, and the assessment was compared with the primary assessment by the treating cardiologist. In case of a discrepancy in assessments, a third investigator performed the final interpretation. In line with the standard definition of flow‐limiting stenosis,27, 28 obstructive coronary artery disease was defined as stenosis ≥70% (≥50% for the left main coronary artery). Angiographic findings including the number of diseased vessels, definite stent thrombosis as defined by the Academic Research Consortium,29 and revascularization procedures were recorded. Coronary blood flow was graded according to the Thrombolysis In Myocardial Infarction (TIMI) criteria.30 Collateral circulation to the IRA was graded according to the Rentrop grade classification.31 Thrombus burden was graded according to the TIMI classification.32 The primary outcomes were peak cTnI level, used as a surrogate of infarct size as previously validated,33, 34 and large MI defined by a peak cTnI level >85th percentile of the study population (10.8 µg/L). The cutoff level was determined based on a previous study demonstrating that patients with a peak Tn level >90th percentile of the study population had the worst prognosis.35 The 85th percentile cutoff level instead of the 90th percentile cutoff level was adopted to maintain a sufficient number of events for a prediction model. The secondary outcome was in‐hospital mortality. In addition, in‐hospital recurrent MI, heart failure, sustained ventricular tachycardia or ventricular fibrillation, and cardiogenic shock were recorded. These outcomes were also analyzed in the subgroup of patients with an obstructive lesion on angiography.
Statistical Analysis
Data are expressed as number (%) or median (interquartile range). Continuous variables were compared using either the Student t test or Wilcoxon rank sum test, as appropriate. Dichotomous variables were compared using the χ2 test or Fisher exact test. The following potential confounding variables were evaluated first in a univariate model to assess the independent predictors of large MI: age, sex, obesity, preinfarction angina, hypertension, diabetes mellitus, hyperlipidemia, current smoking, previous MI, previous coronary artery bypass graft, previous PCI, estimated glomerular filtration rate, TIMI grade 2 or 3 flow, angiographic thrombus (grade 1–5), and collateral circulation to the IRA with Rentrop grade 2 or 3. Significant variables with a P value <0.15 in the univariate analysis were then entered into a multivariate logistic‐regression analysis using backward stepwise selection. A significance level of 0.10 was required to allow a variable to stay in the model. Univariate and multivariate logistic regression analyses were also performed in the subgroup of the patients with an obstructive lesion on angiography. Two‐sided P values <0.05 were considered statistically significant. All statistical analyses were performed with R software version 3.0.1 (http://www.r‐project.org).
Results
Among 728 patients who met the inclusion criteria, 247 were excluded. Thus, 481 patients were included in the final analysis. Baseline characteristics are summarized in Table 1. Among 481 patients, 200 (42%) had documented preinfarction angina. Patients with preinfarction angina were significantly younger than those without preinfarction angina. Regarding demographic data and risk factors, there was no significant difference except for age. Patients with preinfarction angina had significantly lower peak cTnI levels than patients without preinfarction angina.
Table 1.
Baseline Characteristics of Patients Included in the Study
| Preinfarction Angina, n = 200 | No Preinfarction Angina, n = 281 | P Value | |
|---|---|---|---|
| Baseline characteristics and risk factors | |||
| Age, y | 64 (56–71) | 68 (58–79) | <0.001 |
| Male sex | 131 (66) | 167 (59) | 0.18 |
| HTN | 154 (77) | 208 (74) | 0.46 |
| DM | 80 (40) | 109 (39) | 0.79 |
| Hyperlipidemia | 114 (57) | 162 (58) | 0.89 |
| Current smoking | 44 (22) | 63 (22) | 0.91 |
| Family history | 39 (20) | 60 (21) | 0.62 |
| Previous MI | 33 (17) | 48 (17) | 0.87 |
| Previous PCI | 64 (32) | 84 (30) | 0.62 |
| Previous CABG | 20 (10) | 41 (15) | 0.14 |
| TIMI risk score | 0.08 | ||
| Low risk, 0–2 | 46 (23) | 42 (15) | |
| Intermediate risk, 3–4 | 94 (47) | 148 (53) | |
| High risk, 5–7 | 60 (30) | 91 (32) | |
| Treatment before presentation | |||
| ASA | 106 (53) | 155 (55) | 0.64 |
| Thienopyridine | 48 (24) | 58 (21) | 0.38 |
| ACEI | 47 (24) | 81 (29) | 0.19 |
| ARB | 30 (15) | 45 (16) | 0.76 |
| Nitrate | 19 (10) | 21 (7) | 0.43 |
| β‐Blocker | 86 (43) | 130 (46) | 0.48 |
| Hemodynamic, laboratory, and echocardiographic data | |||
| Killip class >1 on admission | 24 (12) | 43 (15) | 0.3 |
| Killip class | 0.29 | ||
| 1 | 176 (88) | 238 (85) | |
| 2 | 19 (10) | 34 (12) | |
| 3 | 5 (3) | 5 (2) | |
| 4 | 0 (0) | 4 (1) | |
| SBP, mm Hg | 144 (127–159) | 142 (123–158) | 0.19 |
| DBP, mm Hg | 81 (73–94) | 79 (70–90) | 0.07 |
| Heart rate, bpm | 80 (71–94) | 80 (69–94) | 0.98 |
| WBC count, 109/L | 8.0 (6.6–10.0) | 8.7 (6.9–10.6) | 0.11 |
| Hemoglobin, g/L | 134 (119–142) | 129 (116–141) | 0.07 |
| Glucose, mmol/L | 6.2 (5.3–8.8) | 6.6 (5.6–9.5) | 0.05 |
| eGFR, mL/min/1.73 m2 | 77 (58–90) | 68 (50–88) | 0.02 |
| Peak Tn I, µg/L) | 0.40 (0.07–4.49) | 0.92 (0.15–6.31) | 0.006 |
| LVEF, % | 60 (43–63) | 60 (45–64) | 0.55 |
| In‐hospital treatment | |||
| ASA | 192 (96) | 276 (98) | 0.14 |
| Thienopyridine | 142 (71) | 199 (71) | 0.97 |
| ACEI | 113 (57) | 138 (49) | 0.11 |
| ARB | 21 (11) | 41 (15) | 0.19 |
| β‐Blocker | 180 (90) | 241 (86) | 0.17 |
| Statin | 191 (96) | 263 (94) | 0.37 |
| Heparin infusion | 132 (66) | 200 (71) | 0.23 |
| Enoxaparin | 14 (7) | 15 (5) | 0.45 |
| Thienopyridine loading | 61 (31) | 88 (31) | 0.85 |
Abbreviations: ACEI, angiotensin‐converting enzyme inhibitor; ARB, angiotensin II receptor blocker; ASA, aspirin; CABG, coronary artery bypass grafting; DBP, diastolic blood pressure; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; HTN, hypertension; IQR, interquartile range; LVEF, left ventricular ejection fraction; MI, myocardial infarction; PCI, percutaneous coronary intervention; SBP, systolic blood pressure; TIMI, Thrombolysis In Myocardial Infarction; Tn, troponin; WBC, white blood cell.
Data are presented as n (%) or median (IQR).
Angiographic findings are summarized in Table 2. Among the 481 patients, 378 (79%) had obstructive coronary artery disease. There was no significant difference between the 2 groups in the number of diseased vessels, location of the IRA, and the rate of in‐stent restenosis and definite stent thrombosis. Patients with preinfarction angina were more likely to have a patent IRA than those without preinfarction angina. The overall incidence of angiographic thrombus (TIMI grade 1–5) was similar between the 2 groups. However, among patients with angiographic evidence of thrombus, patients with preinfarction angina were less likely to have higher thrombus burden (TIMI grade 4–5) than those without preinfarction angina. The rate of collateral circulation to the IRA with Rentrop grade 2 or 3 was comparable between the 2 groups. Patients with preinfarction angina had a significantly higher rate of in‐hospital revascularization driven by a significantly higher rate of PCI.
Table 2.
Angiographic Findings of Patients With and Without Preinfarction Angina
| Preinfarction Angina, n = 200 | No Preinfarction Angina, n = 281 | P Value | |
|---|---|---|---|
| Interval, da | 1.1 (0.6–2.1) | 1.2 (0.7–2.3) | 0.27 |
| Catheterization within 24 h | 89 (45) | 119 (42) | 0.64 |
| No. of diseased vessels | 0.44 | ||
| 0 | 37 (19) | 66 (23) | |
| 1 | 58 (29) | 67 (24) | |
| 2 | 55 (28) | 81 (29) | |
| 3 | 50 (25) | 67 (24) | |
| IRA | 0.56 | ||
| LAD | 49 (25) | 66 (23) | |
| LCX | 41 (21) | 50 (18) | |
| RCA | 43 (22) | 50 (18) | |
| LMCA | 8 (4) | 8 (3) | |
| Graft | 6 (3) | 6 (2) | |
| Multi‐territory ischemia | 16 (8) | 35 (12) | |
| ≥70% stenosis | |||
| LAD | 116 (58) | 153 (54) | 0.44 |
| LCX | 96 (48) | 138 (49) | 0.81 |
| RCA | 101 (51) | 135 (48) | 0.6 |
| LMCA (≥50%) | 14 (7) | 16 (6) | 0.56 |
| In‐stent restenosis | 24 (12) | 33 (12) | 0.93 |
| Stent thrombosis | 3 (2) | 9 (3) | 0.37 |
| TIMI flow grade | 0.03 | ||
| 0–1 | 38 (19) | 77 (27) | |
| 2–3 | 161 (81) | 204 (73) | |
| Thrombus (TIMI grade 1–5) | 74 (37) | 88 (31) | 0.19 |
| Thrombus gradeb | 0.02 | ||
| High‐grade thrombus (TIMI grade 4–5) | 25 (34) | 46 (52) | |
| Low‐grade thrombus (TIMI grade 1–3) | 49 (66) | 42 (48) | |
| Collateral circulation (Rentrop grade 2–3) | 37 (19) | 62 (22) | 0.34 |
| In‐hospital revascularization | 138 (69) | 155 (55) | 0.002 |
| In‐hospital PCI | 117 (59) | 133 (47) | 0.02 |
| In‐hospital CABG | 21 (11) | 22 (8) | 0.31 |
Abbreviations: CABG, coronary artery bypass grafting; IQR, interquartile range; IRA, infarct‐related artery; LAD, left anterior descending artery; LMCA, left main coronary artery; LCX, left circumflex artery; PCI, percutaneous coronary intervention; RCA, right coronary artery; TIMI, Thrombolysis In Myocardial Infarction.
Data are presented as n (%) or median (IQR).
Interval from presentation to catheterization.
Analysis among patients with thrombus.
In‐hospital outcomes are shown in Table 3. Patients with preinfarction angina had a significantly lower incidence of a large MI than those without preinfarction angina. There was no significant difference in in‐hospital mortality between the groups. The association between preinfarction angina and lower incidence of a large MI remained statistically significant in the subgroup of patients who had an obstructive coronary lesion.
Table 3.
In‐hospital Outcomes of the Patients Recruited in the Study
| In‐hospital Outcomes of All Patients, n = 481 | Preinfarction Angina, n = 200 | No Preinfarction Angina, n = 281 | P Value |
|---|---|---|---|
| Large MI | 21 (11) | 51 (18) | 0.02 |
| In‐hospital all‐cause death | 2 (1) | 5 (2) | 0.7 |
| In‐hospital recurrent MI | 0 (0) | 2 (0.7) | 0.51 |
| In‐hospital HF | 27 (14) | 46 (16) | 0.39 |
| In‐hospital cardiogenic shock | 5 (3) | 10 (4) | 0.51 |
| In‐hospital VT/VF | 4 (2) | 3 (1) | 0.46 |
| Length of stay, d | 4.1 (2.5–7.2) | 4.9 (2.7–8.0) | 0.16 |
| In‐hospital Outcomes of Patients With Obstructive Lesion, n = 378 | Preinfarction Angina, n = 163 | No Preinfarction Angina, n = 215 | P Value |
| Large MI | 20 (12) | 51 (24) | 0.005 |
| In‐hospital all‐cause death | 2 (1) | 5 (2) | 0.7 |
| In‐hospital recurrent MI | 0 (0) | 2 (0.9) | 0.51 |
| In‐hospital HF | 25 (15) | 39 (18) | 0.47 |
| In‐hospital cardiogenic shock | 5 (3) | 10 (5) | 0.43 |
| In‐hospital VT/VF | 3 (2) | 3 (1) | 1 |
| Length of stay, d | 4.2 (2.4–7.8) | 5.4 (3.0–8.9) | 0.047 |
Abbreviations: HF, heart failure; IQR, interquartile range; MI, myocardial infarction; VT/VF, sustained ventricular tachycardia/ventricular fibrillation.
Data are presented as n (%) or median (IQR).
Tables 4 and 5 show univariate and multivariate analyses findings of potential predictors of large MI. Multivariate analysis indicated preinfarction angina as an independent negative predictor of large MI in all patients and the subgroup of the patients with an obstructive lesion. Moreover, IRA patency was an independent negative predictor of large MI in all patients and the subgroup of the patients with an obstructive lesion. In contrast, angiographic thrombus (TIMI grade 1–5) was an independent positive predictor of large MI in all patients and the subgroup of the patients with an obstructive lesion.
Table 4.
Univariate and Multivariate Analyses of Predictors for Large MI in All Patients (n = 481)
| OR | 95% CI | P Value | |
|---|---|---|---|
| Univariate analysis | |||
| Age (per decade increase) | 1.14 | 0.94‐1.39 | 0.18 |
| Male sex | 1.18 | 0.71‐2.02 | 0.53 |
| Preinfarction angina | 0.53 | 0.30‐0.90 | 0.02 |
| HTN | 0.9 | 0.52‐1.63 | 0.73 |
| DM | 0.69 | 0.40‐1.16 | 0.17 |
| Hyperlipidemia | 0.75 | 0.45‐1.25 | 0.27 |
| Current smoking | 0.66 | 0.33‐1.24 | 0.22 |
| Previous MI | 0.58 | 0.25‐1.19 | 0.16 |
| Previous PCI | 0.66 | 0.36‐1.15 | 0.16 |
| Previous CABG | 1.66 | 0.82‐3.17 | 0.14 |
| eGFR (per 10 mL/min/1.73 m2 increase) | 0.96 | 0.88‐1.04 | 0.32 |
| TIMI grade 2–3 flow | 0.21 | 0.12‐0.35 | <0.001 |
| Angiographic thrombus | 3.88 | 2.32‐6.58 | <0.001 |
| Collateral (Rentrop grade 2–3) | 2.23 | 1.27‐3.83 | 0.004 |
| Multivariate analysis | |||
| Preinfarction angina | 0.53 | 0.29‐0.94 | 0.03 |
| TIMI grade 2–3 flow | 0.30 | 0.17‐0.52 | <0.001 |
| Angiographic thrombus | 2.99 | 1.71‐5.25 | <0.001 |
Abbreviations: CABG, coronary artery bypass grafting; CI, confidence interval; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; HTN, hypertension; MI, myocardial infarction; OR, odds ratio; PCI, percutaneous coronary intervention, TIMI, Thrombolysis In Myocardial Infarction.
Table 5.
Univariate and Multivariate Analyses of Predictors for Large MI in Patients With Obstructive Lesion (n = 378)
| OR | 95% CI | P Value | |
|---|---|---|---|
| Univariate analysis | |||
| Age (per decade increase) | 1.10 | 0.89‐1.36 | 0.39 |
| Male sex | 1.01 | 0.59‐1.76 | 0.96 |
| Preinfarction angina | 0.45 | 0.25‐0.78 | 0.005 |
| HTN | 0.82 | 0.46‐1.53 | 0.52 |
| DM | 0.64 | 0.37‐1.10 | 0.11 |
| Hyperlipidemia | 0.71 | 0.42‐1.19 | 0.19 |
| Current smoking | 0.60 | 0.29‐1.13 | 0.13 |
| Previous MI | 0.50 | 0.21‐1.05 | 0.09 |
| Previous PCI | 0.52 | 0.28‐0.92 | 0.03 |
| Previous CABG | 1.30 | 0.64‐2.52 | 0.44 |
| eGFR (per 10 mL/min/1.73 m2 increase) | 0.94 | 0.86‐1.03 | 0.19 |
| TIMI grade 2–3 flow | 0.29 | 0.17‐0.49 | <0.001 |
| Angiographic thrombus | 2.61 | 1.54‐4.48 | <0.001 |
| Collateral (Rentrop grade 2–3) | 1.58 | 0.90‐2.74 | 0.11 |
| Multivariate analysis | |||
| Preinfarction angina | 0.45 | 0.24‐0.81 | 0.009 |
| Current smoking | 0.53 | 0.25‐1.04 | 0.08 |
| Previous PCI | 0.56 | 0.29‐1.03 | 0.07 |
| TIMI grade 2–3 flow | 0.37 | 0.21‐0.64 | <0.001 |
| Angiographic thrombus | 2.29 | 1.31‐4.08 | 0.004 |
Abbreviations: CABG, coronary artery bypass grafting; CI, confidence interval; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; HTN, hypertension; MI, myocardial infarction; OR, odds ratio; PCI, percutaneous coronary intervention; TIMI, Thrombolysis In Myocardial Infarction.
Discussion
The primary findings of our study are: (1) preinfarction angina was associated with smaller infarct size, as indicated by a lower peak cTnI level and lower incidence of large MI; (2) preinfarction angina was associated with a patent IRA; and (3) both preinfarction angina and IRA patency were independent negative predictors of large MI.
The result of the present study further supports existing data that preinfarction angina was associated with smaller infarct size indicated by lower peak creatine kinase level in patients with NSTEMI.10, 11 In addition, our study demonstrated that preinfarction angina was associated with IRA patency defined as having a TIMI grade 2 or 3 flow, suggesting that IRA patency is one of the mechanisms of cardioprotection associated with preinfarction angina in the setting of NSTEMI. Preprocedural TIMI grade 0 or 1 flow is associated with larger scintigraphic infarct size in STEMI patients.15, 16 The association between preinfarction angina and IRA patency has been reported in the STEMI population,7, 9, 21, 22 though not all studies supported this association.23, 36 To the best of our knowledge, this is the first study that evaluated the association between preinfarction angina and various angiographic findings in the NSTEMI population. Our findings suggest that NSTEMI patients presenting without preinfarction angina are at increased risk of developing a large MI.
Another interesting finding of our study was that preinfarction angina was associated with lower thrombus burden among patients with angiographic thrombus, although the overall incidence of angiographic thrombus was similar between the 2 groups. The association between preinfarction angina and lower thrombus burden has also been demonstrated in the STEMI population.18 This association was consistent with that in a previous study37 that demonstrated that the culprit plaques of patients with preinfarction angina had less necrotic core component, which has been shown to be the most thrombogenic component in human atherosclerotic plaques,38 than those of patients without preinfarction angina. In addition, the association between preinfarction angina and lower thrombus burden was consistent with the findings of previous reports showing that STEMI patients with preinfarction angina had a faster reperfusion after thrombolysis39 and a higher successful rate of reperfusion after thrombolysis7 than those without preinfarction angina. Although preinfarction angina was associated with collateral circulation in STEMI patients,21, 23 there was no statistically significant association between preinfarction angina and collateral circulation to the IRA in our patient population.
Regarding the association between preinfarction angina and IRA patency, whether the cardioprotective effect associated with preinfarction angina is related to patency of the IRA is worth considering. In this context, we assessed the impact of potential confounding variables on large infarct size and found that both preinfarction angina and IRA patency were independent negative predictors of large MI. This finding was consistent with that of a previous report demonstrating a cardioprotective effect of preinfarction angina, as indicated by a lower 5‐year all‐cause mortality, in the subgroup of the patients with both TIMI grade 0 flow and TIMI grade 1–3 flow in the STEMI population.9 Our results suggest that the cardioprotective effects observed in patients with preinfarction angina were associated with both an ischemic preconditioning phenomenon and IRA patency. Preconditioning phenomenon can be divided into 2 phases, and delayed preconditioning (second phase) reappears 12 to 24 hours later and lasts for 3 to 4 days.40 Coronary circulation is a major determinant of cardioprotection associated with preconditioning phenomenon.41
Study Limitations
Our study has several limitations. First, it is subject to the usual limitations associated with a retrospective observational study. We cannot exclude the possibility that some patients might have had undocumented preinfarction angina. Although we reviewed all patients who had undergone cardiac catheterization, selection bias might have affected the results. Second, we used a peak Tn value as a surrogate of infarct size instead of an imaging study. It should be noted that Tn value could be affected by various clinical factors, such as age, renal function, and heart failure. Third, the higher rate of in‐hospital revascularization in patients with preinfarction angina might have contributed to smaller infarct size in patients with preinfarction angina. The association between the infarct size and impaired coronary flow may not be causal.42 Finally, our study evaluated only in‐hospital clinical outcomes; therefore, the impact of preinfarction angina on long‐term outcomes was not assessed.
Conclusion
Our study demonstrated that preinfarction angina was associated with smaller infarct size and IRA patency in NSTEMI patients. Both preinfarction angina and IRA patency were independent negative predictors of large MI. Our study suggests that NSTEMI patients presenting without preinfarction angina are at increased risk of developing a large MI.
The authors have no funding, financial relationships, or conflicts of interest to disclose.
References
- 1. Kloner RA, Shook T, Przyklenk K, et al. Previous angina alters in‐hospital outcome in TIMI 4: a clinical correlate to preconditioning? Circulation. 1995;91:37–45. [DOI] [PubMed] [Google Scholar]
- 2. Anzai T, Yoshikawa T, Asakura Y, et al. Preinfarction angina as a major predictor of left ventricular function and long‐term prognosis after a first Q wave myocardial infarction. J Am Coll Cardiol. 1995;26:319–327. [DOI] [PubMed] [Google Scholar]
- 3. Ottani F, Galvani M, Ferrini D, et al. Prodromal angina limits infarct size: a role for ischemic preconditioning. Circulation. 1995;91:291–297. [DOI] [PubMed] [Google Scholar]
- 4. Bahr RD, Leino EV, Christenson RH. Prodromal unstable angina in acute myocardial infarction: prognostic value of short‐ and long‐term outcome and predictor of infarct size. Am Heart J. 2000;140:126–133. [DOI] [PubMed] [Google Scholar]
- 5. Solomon SD, Anavekar NS, Greaves S, et al. Angina pectoris prior to myocardial infarction protects against subsequent left ventricular remodeling. J Am Coll Cardiol. 2004;43:1511–1514. [DOI] [PubMed] [Google Scholar]
- 6. Reiter R, Henry TD, Traverse JH. Preinfarction angina reduces infarct size in ST‐elevation myocardial infarction treated with percutaneous coronary intervention. Circ Cardiovasc Interv. 2013;6:52–58. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Ishihara M, Sato H, Tateishi H, et al. Implications of prodromal angina pectoris in anterior wall acute myocardial infarction: acute angiographic findings and long‐term prognosis. J Am Coll Cardiol. 1997;30:970–975. [DOI] [PubMed] [Google Scholar]
- 8. Kobayashi Y, Miyazaki S, Itoh A, et al. Previous angina reduces in‐hospital death in patients with acute myocardial infarction. Am J Cardiol. 1998;81:117–122. [DOI] [PubMed] [Google Scholar]
- 9. Taniguchi T, Shiomi H, Toyota T, et al. Effect of preinfarction angina pectoris on long‐term survival in patients with ST‐segment elevation myocardial infarction who underwent primary percutaneous coronary intervention. Am J Cardiol. 2014;114:1179–1186. [DOI] [PubMed] [Google Scholar]
- 10. Papadopoulos CE, Karvounis HI, Gourasas IT, et al. Evidence of ischemic preconditioning in patients experiencing first non–ST‐segment elevation myocardial infarction (NSTEMI). Int J Cardiol. 2003;92:209–217. [DOI] [PubMed] [Google Scholar]
- 11. Lorgis L, Gudjoncik A, Richard C, et al. Pre‐infarction angina and outcomes in non‐ST‐segment elevation myocardial infarction: data from the RICO survey. PLoS One. 2012;7:e48513. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986;74:1124–1136. [DOI] [PubMed] [Google Scholar]
- 13. Kloner RA, Jennings RB. Consequences of brief ischemia: stunning, preconditioning, and their clinical implications: part 2. Circulation. 2001;104:3158–3167. [DOI] [PubMed] [Google Scholar]
- 14. Ndrepepa G, Kastrati A, Schwaiger M, et al. Relationship between residual blood flow in the infarct‐related artery and scintigraphic infarct size, myocardial salvage, and functional recovery in patients with acute myocardial infarction. J Nucl Med. 2005;46:1782–1788. [PubMed] [Google Scholar]
- 15. De Luca G, Parodi G, Sciagrà R, et al. Preprocedural TIMI flow and infarct size in STEMI undergoing primary angioplasty. J Thromb Thrombolysis. 2014;38:81–86. [DOI] [PubMed] [Google Scholar]
- 16. Ortiz‐Pérez JT, Lee DC, Meyers SN, et al. Determinants of myocardial salvage during acute myocardial infarction: evaluation with a combined angiographic and CMR myocardial salvage index. JACC Cardiovasc Imaging. 2010;3:491–500. [DOI] [PubMed] [Google Scholar]
- 17. Brodie BR, Stuckey TD, Hansen C, et al. Benefit of coronary reperfusion before intervention on outcomes after primary angioplasty for acute myocardial infarction. Am J Cardiol. 2000;85:13–18. [DOI] [PubMed] [Google Scholar]
- 18. Ahmed TA, Sorgdrager BJ, Cannegieter SC, et al. Pre‐infarction angina predicts thrombus burden in patients admitted for ST‐segment elevation myocardial infarction. EuroIntervention. 2012;7:1396–1405. [DOI] [PubMed] [Google Scholar]
- 19. Elsman P, van 't Hof AW, de Boer MJ, et al. Role of collateral circulation in the acute phase of ST‐segment elevation myocardial infarction treated with primary coronary intervention. Eur Heart J. 2004;25:854–858. [DOI] [PubMed] [Google Scholar]
- 20. Desch S, Eitel I, Schmitt J, et al. Effect of coronary collaterals on microvascular obstruction as assessed by magnetic resonance imaging in patients with acute ST‐elevation myocardial infarction treated by primary coronary intervention. Am J Cardiol. 2009;104:1204–1209. [DOI] [PubMed] [Google Scholar]
- 21. Gheeraert PJ, Henriques JP, De Buyzere ML, et al. Preinfarction angina protects against out‐of‐hospital ventricular fibrillation in patients with acute occlusion of the left coronary artery. J Am Coll Cardiol. 2001;38:1369–1374. [DOI] [PubMed] [Google Scholar]
- 22. Tomoda H, Aoki N. Coronary blood flow in evolving myocardial infarction preceded by preinfarction angina: a critical reevaluation of preconditioning effects in clinical cases. Angiology. 2004;55:9–15. [DOI] [PubMed] [Google Scholar]
- 23. Lønborg J, Kelbæk H, Vejlstrup N, et al. Influence of pre‐infarction angina, collateral flow, and pre‐procedural TIMI flow on myocardial salvage index by cardiac magnetic resonance in patients with ST‐segment elevation myocardial infarction. Eur Heart J Cardiovasc Imaging. 2012;13:433–443. [DOI] [PubMed] [Google Scholar]
- 24. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. J Am Coll Cardiol. 2012;60:1581–1598. [DOI] [PubMed] [Google Scholar]
- 25. Misumida N, Kobayashi A, Saeed M, et al. Electrocardiographic left ventricular hypertrophy as a predictor for nonsignificant coronary artery disease in patients with non–ST‐segment elevation myocardial infarction [published online ahead of print March 3, 2015]. Angiology. doi: 10.1177/0003319715574803. [DOI] [PubMed] [Google Scholar]
- 26. Misumida N, Kobayashi A, Fox JT, et al. Predictive value of ST‐segment elevation in lead aVR for left main and/or three‐vessel disease in non–ST‐segment elevation myocardial infarction [published online ahead of print April 17, 2015]. Ann Noninvasive Electrocardiol. doi: 10.1111/anec.12272. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Wilson RF, Marcus ML, White CW. Prediction of the physiologic significance of coronary arterial lesions by quantitative lesion geometry in patients with limited coronary artery disease. Circulation. 1987;75:723–732. [DOI] [PubMed] [Google Scholar]
- 28. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI Guideline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation. 2011;124:e574–e651. [DOI] [PubMed] [Google Scholar]
- 29. Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation. 2007;115:2344–2351. [DOI] [PubMed] [Google Scholar]
- 30. TIMI Study Group . The Thrombolysis in Myocardial Infarction (TIMI) trial: phase I findings. N Engl J Med. 1985;312:932–936. [DOI] [PubMed] [Google Scholar]
- 31. Rentrop KP, Thornton JC, Feit F, et al. Determinants and protective potential of coronary arterial collaterals as assessed by an angioplasty model. Am J Cardiol. 1988;61:677–684. [DOI] [PubMed] [Google Scholar]
- 32. Gibson CM, de Lemos JA, Murphy SA, et al. Combination therapy with abciximab reduces angiographically evident thrombus in acute myocardial infarction: a TIMI 14 substudy. Circulation. 2001;103:2550–2554. [DOI] [PubMed] [Google Scholar]
- 33. Tzivoni D, Koukoui D, Guetta V, et al. Comparison of troponin T to creatine kinase and to radionuclide cardiac imaging infarct size in patients with ST‐elevation myocardial infarction undergoing primary angioplasty. Am J Cardiol. 2008;101:753–757. [DOI] [PubMed] [Google Scholar]
- 34. Byrne RA, Ndrepepa G, Braun S, et al. Peak cardiac troponin‐T level, scintigraphic myocardial infarct size and one‐year prognosis in patients undergoing primary percutaneous coronary intervention for acute myocardial infarction. Am J Cardiol. 2010;106:1212–1217. [DOI] [PubMed] [Google Scholar]
- 35. Chin CT, Wang TY, Li S, et al. Comparison of the prognostic value of peak creatine kinase‐MB and troponin levels among patients with acute myocardial infarction: a report from the Acute Coronary Treatment and Intervention Outcomes Network Registry–Get With the Guidelines. Clin Cardiol. 2012;35:424–429. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36. Kosuge M, Kimura K, Kojima S, et al. Effects of preinfarction angina pectoris on infarct size and in‐hospital mortality after coronary intervention for acute myocardial infarction. Am J Cardiol. 2003;92:840–843. [DOI] [PubMed] [Google Scholar]
- 37. Higashikuni Y, Tanabe K, Tanimoto S, et al. Difference of culprit plaque composition between patients with and without pre‐infarction angina: an intravascular ultrasound radiofrequency analysis. EuroIntervention. 2009;5:363–369. [DOI] [PubMed] [Google Scholar]
- 38. Fernández‐Ortiz A, Badimon JJ, Falk E, et al. Characterization of the relative thrombogenicity of atherosclerotic plaque components: implications for consequences of plaque rupture. J Am Coll Cardiol. 1994;23:1562–1569. [DOI] [PubMed] [Google Scholar]
- 39. Andreotti F, Pasceri V, Hackett DR, et al. Preinfarction angina as a predictor of more rapid coronary thrombolysis in patients with acute myocardial infarction. N Engl J Med. 1996;334:7–12. [DOI] [PubMed] [Google Scholar]
- 40. Heusch G. Nitroglycerin and delayed preconditioning in humans: yet another new mechanism for an old drug? Circulation. 2001;103:2876–2878. [DOI] [PubMed] [Google Scholar]
- 41. Heusch G, Kleinbongard P, Skyschally A, et al. The coronary circulation in cardioprotection: more than just one confounder. Cardiovasc Res. 2012;94:237–245. [DOI] [PubMed] [Google Scholar]
- 42. Heusch G, Kleinbongard P, Skyschally A. Myocardial infarction and coronary microvascular obstruction: an intimate, but complicated relationship. Basic Res Cardiol. 2013;108:380. [DOI] [PubMed] [Google Scholar]