Chronic kidney disease increases the risk for developing ischemic heart disease, but it has not been well known whether it also affects the manifestation of painless acute myocardial infarction (AMI), which has important clinical implications. The aim of this study was to identify whether chronic kidney disease is associated with the presentation of painless AMI. A total of 2,656 consecutively hospitalized patients with AMI from January 2008 to February 2012 were enrolled. Estimated glomerular filtration rate (eGFR) was calculated using calibrated serum creatinine and the abbreviated Modification of Diet in Renal Disease (MDRD) equation. Patient clinical characteristics, angiographic findings, and the use of medications were reviewed. Multivariate logistic regression analysis was used to examine the association of reduced eGFR and presentation with painless AMI. A total of 2,176 adults with painful AMI and 480 adults with painless AMI were studied, and baseline eGFR was calculated. Mean eGFR was lower in subjects with painless AMI compared to those with painful AMI. Compared to an eGFR >90 ml/min/1.73 m 2 , a strong, graded, independent association was observed between reduced eGFR and presentation with painless AMI, with adjusted odds ratios of 1.65 (95% confidence interval 1.16 to 2.36) for an eGFR of 60 to 89 ml/min/1.73 m 2 , 2.92 (95% confidence interval 1.89 to 4.52) for an eGFR of 45 to 59 ml/min/1.73 m 2 , and 3.44 (95% confidence interval 2.20 to 5.38) for an eGFR <45 ml/min/1.73 m 2 . In conclusion, lower eGFR was a strong, independent predictor of presentation with painless AMI versus painful AMI.
Typical chest pain is clinically most important in acute myocardial infarction (AMI) because it encourages patients to seek immediately medical attention, leading to early diagnosis and early revascularization and thus improved prognosis. However, AMI without typical chest pain can be unrecognized by patients and discovered only on subsequent routine electrocardiography or cardiac enzyme analysis, and in such cases, patients may delay seeking medical attention, so that AMI is not diagnosed until after admission to the hospital. Painless AMI is often followed by silent myocardial ischemia. Silent myocardial ischemia seems to be an independent predictor of future cardiac morbidity and mortality. Also, patients with painless AMI have been reported to have worse short-term and long-term outcomes than patients with painful AMI. Accordingly, these findings warrant more investigation of the early detection of painless AMI. Chronic kidney disease (CKD) is an independent risk factor for cardiovascular disease. There is a graded, independent association between reduced estimated glomerular filtration rate (eGFR) and the risk for death, cardiovascular events, and hospitalization. Although silent myocardial ischemia is common in patients with end-stage renal disease, the clinical presentation of AMI in the larger population of patients with CKD has not been well defined. CKD is mainly associated with hypertension, diabetes mellitus, and dyslipidemia, all of which are major risk factors for ischemic heart disease (IHD). Although it is well known that the CKD population has an increased burden of IHD, it has not been well known whether CKD is associated with painless AMI. The objective of the present study was to assess the hypothesis that patients presenting with painless AMI are more likely to have CKD than those presenting with painful AMI and that the association is related to the severity of CKD.
Methods
We studied 2,656 consecutive patients who presented with AMI to Chonnam National University Hospital (Gwangju, Korea) from January 2008 to February 2012. The present study was conducted as a retrospective study to examine the influence of reduced kidney function on the likelihood of presenting with either painless AMI or painful AMI as the clinical expression of IHD.
Eligible patients were aged ≥18 years at admission; AMI was defined as the association of ≥1 clinical and ≥1 biologic criteria: acute-onset chest pain and/or typical modification on 12-lead electrocardiography (ST-segment or T-wave modification or new left bundle branch block) and an increase of troponin >99th percentile of the upper reference limit. Painless AMI was defined as AMI without painful symptoms, which included chest pain, upper back pain, shoulder pain, chest tightness, and chest discomfort. Patients were excluded if eGFR could not be calculated. Also, the entire study population underwent diagnostic coronary angiography, and patients with stress-induced cardiomyopathy or myocarditis were excluded. Routine laboratory measurements including cardiac enzymes were done on blood samples drawn as soon as possible after admission, and fasting lipid profiles were obtained <24 hours after admission.
We analyzed baseline demographic and clinical characteristics, relevant laboratory results, and coronary angiographic findings. Body mass index was measured during admission period using standard procedures. Multivessel coronary artery disease was defined as >50% diameter stenosis by quantitative coronary angiography in ≥2 coronary arteries or a left main coronary artery lesion. Coronary artery lesion type was determined according to the American College of Cardiology and American Heart Association classification. The left ventricular ejection fraction was determined using echocardiography during the admission period. Kidney function was assessed using eGFR, calculated using the 4-variable abbreviated Modification of Diet in Renal Disease (MDRD) study equation: eGFR (ml/min/1.73 m 2 ) = 186 × (serum creatinine [mg/dl]) −1.154 × (age) −0.203 × 0.742 (if female). We used the following classification system to define CKD: ≥90, 60 to 89, 45 to 59, and <45 ml/min/1.73 m 2 , on the basis of previous work demonstrating an important eGFR threshold of 45 ml/min/1.73 m 2 for risk for adverse outcomes and the recently published updated Kidney Disease: Improving Global Outcomes guidelines. For estimation of steady-state renal function, eGFR was calculated when patients stabilized after the acute phase passed. However, in patients who died during the in-hospital period, the use of serum creatinine level estimated at admission was unavoidable.
SPSS for Windows version 17.0 (SPSS, Inc., Chicago, Illinois) was used for all analysis. All continuous variables are expressed as mean ± SD and evaluated using Student’s t tests. Categorical variables are expressed as counts and percentages and were analyzed using chi-square tests. We performed a series of multivariate logistic regression models to examine the association between level of kidney function and the odds of presenting with painless AMI versus painful AMI after adjustment for potential confounders. Covariates included in models were based on variables that were significantly different between painless AMI and painful AMI on bivariate analysis or have previously been shown to be associated with painless AMI. Variables were grouped into 3 categories: (1) demographics and social habits, (2) history and co-morbidities, and (3) body mass index, blood pressure, ST-segment elevation myocardial infarction, Killip class, the left ventricular ejection fraction, laboratory findings, and coronary angiographic findings. A series of nested models were conducted that additionally adjusted for each category of covariates. The entry method was used to select the predictive variables. Model fit for the final models was assessed using Hosmer-Lemeshow goodness-of-fit methods. Statistical significance was assumed at a p value <0.05.
Results
We retrospectively enrolled 2,176 adults with painful AMI and 480 adults with painless AMI. Patient characteristics divided by the 2 study groups are listed in Table 1 . Subjects with painless AMI were older and more likely to be women. The mean eGFR was lower in subjects with painless AMI compared to those with painful AMI, with a higher proportion of subjects with eGFRs <60 ml/min/1.73 m 2 . Subjects presenting with painless AMI were more likely to be current smokers or ex-smokers compared to those with painful AMI. Subjects with painless AMI were more likely than those with painful AMI to have hypertension, diabetes mellitus, previous stroke, or previous heart failure, but hyperlipidemia was more prevalent in subjects with painless AMI. Subjects with painless AMI were less likely than those with painful AMI to have familial histories of IHD, and body mass indexes were lower in subjects with painless AMI. Subjects with painless AMI were less likely than those with painful AMI to present with ST-segment elevation myocardial infarction, and symptom-to-door time was longer in subjects with painless AMI. Mean systolic and diastolic blood pressures were higher in subjects with painful AMI. In contrast, systolic, but not diastolic, blood pressure was more likely to be lower in subjects with painless AMI when the range of blood pressure was categorized. High Killip class was common in subjects with painless AMI, and this population showed lower left ventricular ejection fractions.
| Variable | Painful AMI | Painless AMI | p Value |
|---|---|---|---|
| (n = 2,176) | (n = 480) | ||
| Age (years) | 63.3 ± 12.6 | 69.9 ± 12.3 | <0.001 |
| Women | 587 (27.0%) | 221 (46.0%) | <0.001 |
| eGFR (ml/min/1.73 m 2 ) | 86.2 ± 32.1 | 64.6 ± 35.5 | <0.001 |
| Category of eGFR (ml/min/1.73 m 2 ) | |||
| >90 | 925 (42.6%) | 92 (19.2%) | <0.001 |
| 60–89 | 869 (40.0%) | 152 (31.8%) | 0.001 |
| 45–59 | 204 (9.4%) | 107 (22.4%) | <0.001 |
| <45 | 173 (8.0%) | 127 (26.6%) | <0.001 |
| Smoking status | |||
| Current | 891 (40.9%) | 124 (25.8%) | <0.001 |
| Former | 437 (20.1%) | 84 (17.5%) | 0.205 |
| Nonsmokers | 848 (39.0%) | 272 (56.7%) | <0.001 |
| Hypertension | 1,040 (47.9%) | 291 (61.1%) | <0.001 |
| Diabetes mellitus | 581 (26.7%) | 174 (36.6%) | <0.001 |
| Hyperlipidemia | 711 (32.7%) | 103 (21.5%) | <0.001 |
| Stroke | 129 (5.9%) | 60 (12.5%) | <0.001 |
| Peripheral artery disease | 21 (1.0%) | 10 (2.1%) | 0.056 |
| Heart failure | 5 (0.2%) | 8 (1.7%) | 0.001 |
| Previous angina pectoris | 83 (3.8%) | 26 (5.4%) | 0.126 |
| Previous myocardial infarction | 125 (5.7%) | 27 (5.6%) | 1.0 |
| Previous coronary revascularization | 126 (5.8%) | 24 (5.0%) | 0.585 |
| Familial history of coronary heart disease | 117 (5.4%) | 12 (2.5%) | 0.007 |
| Body mass index (kg/m 2 ) | 24.3 ± 3.1 | 23.2 ± 3.2 | <0.001 |
| Category of body mass index (kg/m 2 ) | |||
| <23 | 731 (33.6%) | 241 (50.1%) | <0.001 |
| 23–24.9 | 587 (27.0%) | 104 (21.7%) | 0.033 |
| ≥25 | 858 (39.5%) | 135 (28.1%) | <0.001 |
| ST-segment elevation myocardial infarction | 1,120 (51.5%) | 190 (39.6%) | <0.001 |
| Symptom-to-door time (minutes) | 478.5 ± 1,234.9 | 720.2 ± 1,553.3 | 0.001 |
| Systolic blood pressure (mm Hg) | 126.1 ± 25.4 | 112.9 ± 27.5 | <0.001 |
| Category of systolic blood pressure (mm Hg) | 0.042 | ||
| ≤120 | 1,049 (48.2%) | 57.9 (57.9%) | |
| 121–139 | 388 (17.8%) | 57 (11.9%) | |
| 140–159 | 503 (23.1%) | 87 (18.1%) | |
| 160–179 | 179 (8.2%) | 43 (9.0%) | |
| ≥180 | 57 (2.6%) | 15 (3.1%) | |
| Diastolic blood pressure (mm Hg) | 78.3 ± 15.7 | 69.8 ± 27.5 | <0.001 |
| Category of diastolic blood pressure (mm Hg) | 0.256 | ||
| ≤80 | 1,446 (66.5%) | 338 (70.4%) | |
| 81–90 | 464 (21.3%) | 88 (18.3%) | |
| 91–100 | 241 (11.1%) | 45 (9.4%) | |
| ≥101 | 25 (1.1%) | 9 (1.9%) | |
| Heart rate (beats/min) | 75.9 ± 16.8 | 78.3 ± 32.0 | 0.114 |
| Killip class ≥III on presentation | 218 (10.0%) | 237 (49.4%) | <0.001 |
| Left ventricular ejection fraction (%) | 56.0 ± 11.8 | 50.2 ± 18.9 | <0.001 |
| Left ventricular ejection fraction ≤40% | 239 (11.0%) | 123 (25.6%) | <0.001 |
Laboratory findings had a varied distribution across groups ( Table 2 ). Low-density lipoprotein cholesterol and triglyceride levels were lower in subjects with painless AMI, but peak troponin I, high-sensitivity C-reactive protein, and N-terminal pro–brain natriuretic peptide levels were higher in the same population. Coronary angiographic findings are listed in Table 2 as well. The left main stem as the location of the culprit lesion was more frequently observed in subjects with painless AMI, and multivessel disease was also more common in the same population. Preprocedural Thrombolysis In Myocardial Infarction (TIMI) flow grades were worse in subjects with painful AMI, but there was no significant difference in lesion complexity.
| Variable | Painful AMI | Painless AMI | p value |
|---|---|---|---|
| (n = 2,176) | (n = 480) | ||
| Total cholesterol (mg/dl) | 183.8 ± 43.8 | 172.2 ± 45.1 | <0.001 |
| Low-density lipoprotein cholesterol (mg/dl) | 117.9 ± 38.7 | 106.7 ± 38.5 | <0.001 |
| High-density lipoprotein cholesterol (mg/dl) | 42.4 ± 11.6 | 42.1 ± 13.3 | 0.716 |
| Triglyceride (mg/dl) | 131.6 ± 95.4 | 117.2 ± 92.3 | 0.004 |
| Peak creatine kinase-MB (U/L) | 75.8 ± 154.8 | 61.0 ± 110.8 | 0.051 |
| Peak troponin I (ng/ml) | 47.2 ± 93.0 | 34.0 ± 73.3 | 0.001 |
| High-sensitivity C-reactive protein (mg/dl) | 1.68 ± 5.66 | 3.72 ± 5.25 | <0.001 |
| N-terminal pro–brain natriuretic peptide (pg/ml) | 2,295.2 ± 5,195.4 | 7,899.1 ± 10,173.3 | <0.001 |
| Glycosylated hemoglobin (%) | 6.6 ± 1.5 | 6.6 ± 1.4 | 0.840 |
| Location of culprit coronary lesion | |||
| Left main | 59 (2.9%) | 21 (5.2%) | 0.031 |
| Left anterior descending | 940 (46.6%) | 185 (46.0%) | 0.870 |
| Left circumflex | 356 (17.6%) | 60 (14.9%) | 0.193 |
| Right | 662 (32.8%) | 136 (33.8%) | 0.727 |
| American College of Cardiology/American Heart Association lesion type B2/C | 1,850 (91.7%) | 369 (91.8%) | 1.0 |
| Multivessel disease | 955 (47.3%) | 240 (59.7%) | <0.001 |
| Preprocedural TIMI flow grade | |||
| 0 | 932 (46.2%) | 157 (39.1%) | 0.008 |
| I | 97 (4.8%) | 14 (3.5%) | 0.296 |
| II | 536 (26.6%) | 120 (29.9%) | 0.177 |
| III | 452 (22.4%) | 111 (27.6%) | 0.028 |
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