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Prognostic significance of microalbuminuria in non-diabetic patients with acute myocardial infarction
International Journal of Cardiology 106 (2006) 218 – 223 www.elsevier.com/locate/ijcard
Prognostic significance of microalbuminuria in non-diabetic patients with acute myocardial infarction Ioannis Lekatsasa, Spyridon Koulourisa,T, Konstantinos Triantafylloua, Georgia Chrisanthopouloub, Paraskevi Moutsatsou-Ladikouc, Georgios Ioannidisb, Nikolaos Thalassinosb, Anastasios Kalofoutisc, Lambros Anthopoulosa a
1st Department of Cardiology, Evagelismos Hospital, Athens, Greece Department of Endocrinology, Evagelismos Hospital, Athens, Greece c Department of Biological Chemistry, University of Athens Medical School, Athens, Greece b
Received 24 June 2004; received in revised form 5 February 2005; accepted 6 February 2005 Available online 9 April 2005
Abstract Background: The aim of this study was to examine whether the presence of microalbuminuria (20–200 Ag/min) can predict in-hospital morbidity and mortality in non-diabetic patients with acute myocardial infarction. Methods: Two hundred twenty-three (172 men and 51 women) non-diabetic patients with acute myocardial infarction were studied prospectively. The main outcome measures of the study were based on a comparison of in-hospital mortality and major non-fatal in-hospital events (pulmonary edema, post-infarction angina, infarct extension, mechanical complications, conduction disturbances and ventricular arrhythmias) between microalbuminuric and normoalbuminuric patients. Results: A significant proportion of patients (33.6%) had microalbuminuria. Seventy-six patients (34%) developed an in-hospital event (fatal or non-fatal). Six patients (2.7%) with acute myocardial infarction died in the hospital. Patients with microalbuminuria had a higher mortality rate in comparison with normoalbuminuric patients (6.6% vs. 0.68%, p = 0.01). For non-fatal events, the incidence of pulmonary edema and ventricular arrhythmias was significantly higher in patients with microalbuminuria (14.6% vs. 3.4%, p b 0.001 and 12% vs. 3.4%, p = 0.01, respectively). The combined end-point of the total number of fatal and non-fatal events was significantly higher in patients with microalbuminuria (57.3% vs. 22.3%, p b 0.001). In multiple logistic regression analysis, microalbuminuria ( p b 0.001) and ejection fraction ( p = 0.01) were independently related to the occurrence of major in-hospital events. Conclusions: Microalbuminuria is a significant predictor of in-hospital morbidity and mortality in non-diabetic patients with acute myocardial infarction. D 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Microalbuminuria; Acute myocardial infarction; Ventricular arrhythmias; Heart failure; Mortality
1. Introduction A slightly elevated urinary albumin excretion rate, socalled microalbuminuria, has been proposed as an independent prognostic factor of cardiovascular morbidity and mortality in patients with diabetes mellitus [1,2] and in nondiabetic subjects [3,4]. Recent reports, which included both T Corresponding author. 64 Kekropos street, 151 25, Marousi, Athens, Greece. Tel.: +30 210 6148740/36944 914545; fax: +30 210 7218025. E-mail address: [email protected] (S. Koulouris). 0167-5273/$ - see front matter D 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2005.02.004
diabetics and non-diabetics, have shown that increased urinary protein excretion appears to be an early and proportional response to acute myocardial infarction and it yields prognostic information about in-hospital mortality additional to that provided by clinical or echocardiographic evaluation of left ventricular performance [5,6]. However, it is not known whether microalbuminuria is an important predictor of mortality in non-diabetic patients hospitalized with acute myocardial infarction. Since diabetes is a clinical condition that significantly affects both the presence of microalbuminuria [7] and acute myocardial
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infarction in-hospital mortality [8], it is possible that its presence might have been a confounder of the association between microalbuminuria and in-hospital mortality. In addition, little information exist regarding the role of microalbuminuria in morbidity and consequently in risk stratification following acute myocardial infarction. The aim of this study was to examine whether the presence of microalbuminuria can predict in-hospital morbidity and mortality in non-diabetic patients with acute myocardial infarction.
2. Methods 2.1. Patient selection Two hundred ninety-seven patients admitted to the Coronary Unit of Evangelismos Hospital (Athens, Greece) were studied prospectively. The diagnosis of acute myocardial infarction was based on at least two of the three following criteria: substernal chest pain lasting N 30 min at rest, increased plasma levels of cardiac enzymes (MB isoenzyme of creatine kinase) and typical ECG changes with ST-T segment elevation N 1 mm in at least two contiguous leads. Exclusion criteria in addition to diabetes mellitus were: 1) positive urine dipstick for haemoglobin, glucose, leucocytes or nitrites, 2) history of renal or urinary tract disease or overt albuminuria (N 200 Ag/min), 3) history of inflammatory rheumatic disease and 4) major in-hospital event prior to the urine collection for the determination of albumin urine level. This exclusion procedure left 223 patients eligible for the study. 2.2. End-point definition A physician who did not participate in the study and was blinded to patient identity or the urinary albumin excretion value of the patient, independently coded all fatal and nonfatal events. The primary outcome measure of the study was based on a comparison of in-hospital major adverse event rates between microalbuminuric and normoalbuminuric patients. In addition to death, the following major non-fatal in-hospital events after urine collection, that affect the day of discharge and the risk stratification following acute myocardial infarction, were recorded: post-infarction angina, infarct extension, mechanical complications, conduction disturbances, ventricular arrhythmias and pulmonary edema. To assess in-hospital morbidity and mortality, the combined end-point events rate included the total number of deaths and the above-mentioned non-fatal inhospital events. In patients with multiple non-fatal events only the first event was considered. Post-infarction angina was defined as recurrent angina at rest with either new ST-segment depression (z 0.1 mV) or
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T-wave inversion in at least two contiguous leads. Infarct extension was defined as ST-T segment elevation N 1 mm in at least two new contiguous leads associated with new MB isoenzyme of creatine kinase elevation. Mechanical complications were defined as free wall rupture, rupture of the interventricular septum or rupture of a papillary muscle diagnosed by echocardiography and confirmed through surgery or post-mortem examination. Conduction disturbances were defined as second-degree atrioventricular block type II or complete atrioventricular block or new complete bundle branch block. Ventricular arrhythmias were considered the following: non-sustained ventricular tachycardia (three or more consecutive ventricular ectopic beats, at a rate N 100 beats/min and lasting b 30 s), sustained ventricular tachycardia (consecutive ventricular ectopic beats at a rate N 100 beats/min, lasting N 30 s or associated with dizziness, syncope or chest pain) or ventricular fibrillation (presence of irregular undulations of varying contour and amplitude in the electrocardiogram). Pulmonary edema was defined as rales over more than 50% of the lung fields on auscultation (class III according to the Killip classification). 2.3. Study design On the day of admission and in the following 2 days serum enzymes and 12-lead ECGs were recorded every 8 h. After this period these examinations were performed daily. A further standard ECG had to be taken for central evaluation in case of any major in-hospital event. The presence and severity of heart failure were assessed on the two first days after admission, according to Killip classification. The day after admission fasting blood samples were drawn to measure total cholesterol, triglycerides and high density lipoprotein cholesterol (using enzymatic methods: Roche Diagnostics GmbH, Mannheim, Germany), creatinine (using a modified Jaffe reaction-Synchron C 5 Delta Chemistry Analyser; Beckman Instruments, Brea, CA) and complete blood cell count (assessed with an automated instrument). To minimize potential confounding factors present at the onset of acute myocardial infarction, the participants had an 8-hour urine collection on the third day of admission to assess urine levels of albumin. Microalbuminuria was defined as an albumin excretion rate 20–200 Ag/min. Urinary albumin concentration was measured from samples stored at 208 by a radioimmunologic method (double antibody PEG sedimentation-RIA, Diagnostic Products Corporation, Los Angeles, CA). The intra- and inter-assay variations of the method ranged from 3% to 5% and from 7.9% to 10.6% respectively and the threshold of detection was 0.3 Ag/ml. The urine was also screened for leucocytes, nitrites, haemoglobin and glucose. Patients admitted to the study underwent a complete Mmode, two-dimensional and Doppler examination with the use of a Hewlett-Packard, Sonos 2500 echocardiographic
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Table 1 Basic characteristics of the microalbuminuric and normoalbuminuric patients Number of patients (%) Age (years) Men/women Hypertension (yes/no) Smoking (yes/no) Body mass index (kg/m2) Total cholesterol (mg/dl) Triglycerides (mg/dl) HDL cholesterol (mg/dl) WBC (103 cells/ml) Ejection fraction (%) History of CAD (yes/no) Serum creatinine (mg/dl) CK-MB (mg/dl) Killip class N1 (yes/no) Thrombolysis (yes/no) PCI (yes/no)
ML (+)
ML ( )
75 (33.6%)
148 (66.4%)
63.5F 11.4 61 (81%)/14 (19%) 34 (45%)/41 (55%) 52 (69%)/23 (31%) 27F4.6 207.18F 39.7 144.5F 59.8 29.77F 8.4 13.64F 4.2 47.6 F10.2 14 (19%)/61 (81%) 0.98F 0.14 152.8F 134 21 (28%)/54 (72%) 33 (44%)/42 (56%) 26 (34%)/49 (66%)
60.2F 11.7 111 (75)/37 (25%) 49 (33%)/99 (67%) 110 (74%)/38 (26%) 26.8F 3 210.63F 45.3 155.3F 109 32.05F 11.6 11.83F3.6 48.9F 8.5 23 (15%)/125 (85%) 0.93F 0.18 106.2F 95.7 53 (36%)/95 (64%) 86 (58%)/62 (42%) 70 (47%)/78 (53%)
p Value 0.06 0.32 0.08 0.43 0.73 0.61 0.48 0.28 0.00 0.29 0.34 0.25 0.00 0.29 0.04 0.15
Values are expressed as number of patients (%) or meanFS.D. Abbreviations: CAD, coronary artery disease; CK-MB, MB isoenzyme of creatine kinase; HDL, high density lipoprotein; ML, microalbuminuria; PCI, percutaneous coronary intervention during hospitalization; WBC, white blood cells.
machine the third day of admission, to assess the left ventricular ejection fraction. The study was approved by the Regional Ethics Committees and was in accordance with the Helsinki Declaration.
3. Results 3.1. Patients characteristics From the 223 patients enrolled in this study, 172(77.1%) were men (age, 60F 12 years) and 51(22.9%) were women (age, 66 F11 years). The baseline clinical and biochemical characteristics of the patients with and without microalbuminuria are shown in Table 1. A significant proportion of the study patients (33.6%) had microalbuminuria at the time of the urine examination. One hundred eighty-two patients (81.6%) had an ST elevation myocardial infarction and 41 patients (18.4%)had a non-ST elevation myocardial infarction. The use of nitrates ( p =0.48), angiotensin converting enzyme inhibitors ( p =0.15), b-blockers ( p = 0.19), calcium channel blockers ( p =0.55), antiarrhythmic ( p = 0.09) and antiplatelet agents ( p = 0.54) was similar between patients with and without microalbuminuria, respectively. In contrast, diuretics ( p =0.01) and digitalis ( p b0.001) were more frequently used in patients with microalbuminuria. Finally, microalbuminuric patients were less likely to have undergone thrombolysis ( p =0.04). The level of peak MB isoenzyme of creatine kinase was significantly higher in the patients with microalbuminuria (152.8 F 134 vs. 106.2F 95.7 mg/dl, p b 0.001). On the other hand, the ejection fraction was similar in the two groups (47.6 F10.2% vs. 48.9 F8.5%, p = 0.29). Moreover, the number of white blood cells was significantly higher in the patients with microalbuminuria (13.64 F4.22 vs.
Table 2 The incidence proportion of major in-hospital events in patients with and without microalbuminuria Number of patients (%)
2.4. Statistical analysis Pulmonary edema (F)
Statistical analysis was performed with the use of SPSS 10.0 for Windows statistical package (SPSS Inc. 1999, Evanston, IL, USA). Data are presented as mean FS.D. for continuous variables and as a proportion for patients with a characteristic for categorical variables. Comparisons between continuous variables were done with the unpaired Student’s t-test while chi-square test was performed for the comparison of the proportions of each categorical variable between the patients with and without microalbuminuria. Univariate logistic regression analysis was used to relate the incidence of the combined study end-point to the various continuous and categorical variables. The variables with a significant predictive power in the univariate models were subsequently introduced into a multiple logistic regression model with the combined study end-point as the dependent variable. All p’s are two tailed and statistical significance was established as p b0.05.
ML (+)
ML ( )
75 (33.6%)
148 (66.4%)
11 (14.6%)/64 (85.4%) Infarct extension (F) 5 (6.7%)/70 (93.3%) Post-infarction angina (F) 10 (16.7%)/65 (83.3%) Conduction disturbances (F) 2 (4%)/73 (96%) Mechanical complications (F) 1 (2.7%)/74 (97.3%) Ventricular arrhythmia (F) 9 (12%)/66 (88%) Death (F) 5 (6.6%)/70 (93.4%) Combined end-pointa (F) 43 (57.3%)/32 (42.7%)
p value
5 (3.4%)/143 b0.001 (96.6%) 9 (6.1%)/139 0.53 (93.9%) 11 (7.5%)/137 0.22 (92.5%) 1 (0.7%)/147 0.26 (99.3%) 1 (0.7%)/147 0.56 (99.3%) 5 (3.4%)/143 0.01 (96.6%) 1 (0.68%)/147 0.01 (99.32%) 33 (22.3%)/115 b0.001 (77.7%)
Abbreviations: ML, microalbuminuria. +=presence, =absence. Data are expressed as number of patients (%). a Pulmonary edema or infarct extension or post-infarction angina or conduction disturbances or mechanical complications or ventricular arrhythmia or death.
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11.83F 3.6 103 cells/ml, p =0.00). No other differences were found between the two groups. 3.2. Incidence of events During the hospital stay (range, 8 to 26 days), 76 out of 223 patients (34%) developed a major in-hospital event (fatal or non-fatal). The incidence proportion of the major in-hospital events in patients with and without microalbuminuria is shown in Table 2. Six patients (2.7%) with acute myocardial infarction died in the hospital, all from cardiovascular complications (2 from ventricular fibrillation on 4th and 9th hospital day, 2 from reinfarction/cardiogenic shock on 6th and 7th hospital day, 2 from cardiogenic shock on 12th and 21st hospital day, respectively). The small number of deaths precluded any further analysis of the mortality alone. Seventy-four patients (33.2%) of the study had a Killip class N 1. No differences were found between the levels of urinary albumin excretion in patients with Killip class N1 and in patients with Killip class 1 (21.34 F 23.65 vs. 21.48 F23.41Ag/ml, p =0.95, respectively). The incidence of pulmonary edema and of ventricular arrhythmias was significantly higher in patients with microalbuminuria (14.6% vs. 3.4%, p b 0.001 and 12% vs. 3.4%, p =0.01, respectively). In addition, the combined end-point event rate was significantly higher in patients with microalbuminuria (57.3% vs. 22.3%, p b 0.001). The combined end-point event rate remained higher in patients with microalbuminuria, even if those who had Killip class N1 were excluded from the analysis ( p b 0.001). 3.3. Univariate and multiple regression analysis Possible predictors of in-hospital morbidity and mortality were examined in univariate logistic regression models. The continuous variables tested included age, total cholesterol, triglycerides, high density lipoprotein cholesterol, white blood cells, body mass index, ejection fraction, creatinine and MB isoenzyme of creatine kinase. The categorical variables tested included sex, preexisting hypertension, smoking, previous history of coronary artery disease and the use of thrombolysis. Table 3 shows the results of multiple logistic regression analysis, which included all the above variables related to
Table 3 Multiple logistic regression analysis, which included all the variables, related to the combined end-point event rate b Ejection fraction White blood cells Microalbuminuria Age History of CAD
0.05 0.06 0.012 0.03 0.47
Exp(b)
95% CI of Exp(b)
p value
0.94 1.06 1.07 1.02 1.60
0.90–0.98 0.97–1.16 1.02–1.12 0.99–1.05 0.91–2.80
0.01 0.16 b0.001 0.06 0.10
Abbreviations: b, beta coefficient; Exp(b), exponential(b); CI, confidence interval; CAD, coronary artery disease.
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the combined end-point event rate. Only microalbuminuria ( p b0.001) and ejection fraction ( p = 0.01) were independently related to the occurrence of the combined end-point event rate.
4. Discussion Our study suggests that microalbuminuria measured on the third day after admission is a strong predictor of inhospital morbidity and mortality in non-diabetic patients with acute myocardial infarction. Previous studies have shown a pattern of urinary excretion after acute myocardial infarction similar to that found following trauma, surgery and acute pancreatitis [9–11]. After an initial high rate of excretion, urine albumin levels fall rapidly towards normal during the week after admission to the hospital [12]. In accordance to these data, a significant proportion of acute myocardial infarction patients (33.6%) in our study, continued to have high levels of protein urinary excretion even on the third post-infarction day. Our results are in agreement to a recent study [6] where in a mixed population of diabetics and non-diabetics with acute myocardial infarction, both first-day albumin excretion rate and third-day albumin excretion rate were the strongest independent predictors of in-hospital mortality compared to other clinical and echocardiographic indexes of left ventricular performance. In the present study after multiple logistic regression analysis microalbuminuria and ejection fraction were the strongest independent predictors of in-hospital morbidity and mortality. In addition, inhospital mortality rate remained higher in patients with microalbuminuria, even if those who had Killip class N 1 were excluded from the analysis. According to our results, the incidence of pulmonary edema was far less common in patients without microalbuminuria. This is in agreement with Ellekilde et al. [13] who found higher levels of albumin excretion rate in acute myocardial infarction patients with heart failure compared with a group of patients without heart failure. Furthermore, Berton et al. [6] showed that a relationship exists between plasma aldosterone levels and albumin excretion rate in Killip class N 1 patients with acute myocardial infarction. It is possible that the elevated glomerular capillary pressure, which is found in patients who develop heart failure, like the acute myocardial infarction patients with pulmonary edema, facilitates the trans-glomerular passage of albumin [14]. The finding that, microalbuminuria remained a powerful prognostic indicator even if we excluded acute myocardial infarction patients with Killip class N 1 from the analysis, may suggest that microalbuminuria is related to the adverse prognosis of acute myocardial infarction with a mechanism different from the development of congestive heart failure. Many hypotheses have been proposed in order to explain the high albumin excretion rate during acute myocardial infarction. It is estimated that during the initial two days
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after acute myocardial infarction, heart failure or haemodynamic alterations [15], seem to be the main determinant of urinary albumin excretion rate, but endothelial dysfunction and inflammation [16] seem to play the key role from the third day. Inflammation is an important feature in patients with acute myocardial infarction [17,18]. Ischaemia produces a systemic increase in vascular permeability, including the vessels in the kidney, as part of the acute inflammatory process, thereby increasing the leak of urinary albumin [19]. Our finding of higher white blood cells in patients with microalbuminuria further supports the association of the severity of inflammation with the degree of microalbuminuria [20,21]. However, the possible pathophysiologic mechanism responsible for an association between microalbuminuria and adverse prognosis after acute myocardial infarction, remains under investigation. Whether the prognostic significance of microalbuminuria in patients with acute myocardial infarction, is based on direct pathogenetic effects [22], on a role as an epiphenomenon to an alternative pathogenetic mechanism [23], or on a role as a marker of hemodynamic compromise [24], remains unresolved. This way, the relationship in our study between microalbuminuria and the presence of ventricular arrhythmias, is of greater importance. In a recent study, Hassanabad et al. [25] showed that coronary endothelial dysfunction increased the severity of ischaemia and induced ventricular arrhythmias in rat isolated perfused hearts. Increased oxidative stress, which is more prevalent in patients with microalbuminuria [26], has also been implicated in the development of reperfusion arrhythmias [27]. In addition, inflammatory markers have been associated with postoperative arrhythmias in patients undergoing myocardial revascularization [28]. Since microalbuminuria may reflect a systemic increase in vascular permeability and a concomitant generalized endothelial dysfunction it is possible that, in patients with microalbuminuria and acute myocardial infarction, coronary endothelial dysfunction and the coexisting inflammatory process may promote the development of ventricular arrhythmias both during ischemia and reperfusion [29,30]. The present study has several limitations. First, the measurement of urinary albumin excretion was based on a single (8 h) urine collection. Three measurements instead of a single one, although difficult to perform in a large number of patients, would have been preferable. However, a single urine sample has been proposed in many studies as an accurate estimate of the presence of microalbuminuria and this procedure has been extensively used in epidemiological studies. In addition, serial urine collections would have been impractical during the short in-hospital follow up period of our study. Feld-Rasmussen reported that serial urine measurements have minor impact upon the validity of classification of patients as micro- or normoalbuminuric [31]. On the other hand, he proposed serial urine collections only as an index of the progression of an already increased urine albumin excretion rate. Thus, misclassification resulting
from our sampling procedure is likely to have weakened the relationship as shown, suggesting that the true relations may be in fact stronger. Second, because of the relatively small number of patients with microalbuminuria, we may have missed significant differences and relationships, especially in the different categories of in-hospital events. Third, we measured urinary albumin excretion on the third day after admission. Thus we excluded all the events that happened in the first two hospital days. However, this way we may have avoided the confounding effect of the acute inflammatory response and haemodynamic alterations, which characterize the early phase of the myocardial infarct development. The blate microalbuminuriaQ found in our patients probably reflects a more permanent endothelial dysfunction rather than a transient acute phase endothelial response.
5. Clinical implications Our study has shown that microalbuminuria is a significant predictor of both morbidity and mortality in non-diabetic patients with acute myocardial infarction and this finding may suggest that patients with microalbuminuria may need a more aggressive medical and interventional therapy before their discharge. However the possible role of microalbuminuria as an index of in-hospital risk stratification in patients with acute myocardial infarction remains unclear. Further studies will be necessary to assess the long-term prognostic significance of microalbuminuria in order to better guide our therapeutic strategies for patients who have sustained an acute myocardial infarction.
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Prognostic significance of microalbuminuria in non-diabetic patients with acute myocardial infarction Ioannis Lekatsasa, Spyridon Koulourisa,T, Konstantinos Triantafylloua, Georgia Chrisanthopouloub, Paraskevi Moutsatsou-Ladikouc, Georgios Ioannidisb, Nikolaos Thalassinosb, Anastasios Kalofoutisc, Lambros Anthopoulosa a
1st Department of Cardiology, Evagelismos Hospital, Athens, Greece Department of Endocrinology, Evagelismos Hospital, Athens, Greece c Department of Biological Chemistry, University of Athens Medical School, Athens, Greece b
Received 24 June 2004; received in revised form 5 February 2005; accepted 6 February 2005 Available online 9 April 2005
Abstract Background: The aim of this study was to examine whether the presence of microalbuminuria (20–200 Ag/min) can predict in-hospital morbidity and mortality in non-diabetic patients with acute myocardial infarction. Methods: Two hundred twenty-three (172 men and 51 women) non-diabetic patients with acute myocardial infarction were studied prospectively. The main outcome measures of the study were based on a comparison of in-hospital mortality and major non-fatal in-hospital events (pulmonary edema, post-infarction angina, infarct extension, mechanical complications, conduction disturbances and ventricular arrhythmias) between microalbuminuric and normoalbuminuric patients. Results: A significant proportion of patients (33.6%) had microalbuminuria. Seventy-six patients (34%) developed an in-hospital event (fatal or non-fatal). Six patients (2.7%) with acute myocardial infarction died in the hospital. Patients with microalbuminuria had a higher mortality rate in comparison with normoalbuminuric patients (6.6% vs. 0.68%, p = 0.01). For non-fatal events, the incidence of pulmonary edema and ventricular arrhythmias was significantly higher in patients with microalbuminuria (14.6% vs. 3.4%, p b 0.001 and 12% vs. 3.4%, p = 0.01, respectively). The combined end-point of the total number of fatal and non-fatal events was significantly higher in patients with microalbuminuria (57.3% vs. 22.3%, p b 0.001). In multiple logistic regression analysis, microalbuminuria ( p b 0.001) and ejection fraction ( p = 0.01) were independently related to the occurrence of major in-hospital events. Conclusions: Microalbuminuria is a significant predictor of in-hospital morbidity and mortality in non-diabetic patients with acute myocardial infarction. D 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Microalbuminuria; Acute myocardial infarction; Ventricular arrhythmias; Heart failure; Mortality
1. Introduction A slightly elevated urinary albumin excretion rate, socalled microalbuminuria, has been proposed as an independent prognostic factor of cardiovascular morbidity and mortality in patients with diabetes mellitus [1,2] and in nondiabetic subjects [3,4]. Recent reports, which included both T Corresponding author. 64 Kekropos street, 151 25, Marousi, Athens, Greece. Tel.: +30 210 6148740/36944 914545; fax: +30 210 7218025. E-mail address: [email protected] (S. Koulouris). 0167-5273/$ - see front matter D 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2005.02.004
diabetics and non-diabetics, have shown that increased urinary protein excretion appears to be an early and proportional response to acute myocardial infarction and it yields prognostic information about in-hospital mortality additional to that provided by clinical or echocardiographic evaluation of left ventricular performance [5,6]. However, it is not known whether microalbuminuria is an important predictor of mortality in non-diabetic patients hospitalized with acute myocardial infarction. Since diabetes is a clinical condition that significantly affects both the presence of microalbuminuria [7] and acute myocardial
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infarction in-hospital mortality [8], it is possible that its presence might have been a confounder of the association between microalbuminuria and in-hospital mortality. In addition, little information exist regarding the role of microalbuminuria in morbidity and consequently in risk stratification following acute myocardial infarction. The aim of this study was to examine whether the presence of microalbuminuria can predict in-hospital morbidity and mortality in non-diabetic patients with acute myocardial infarction.
2. Methods 2.1. Patient selection Two hundred ninety-seven patients admitted to the Coronary Unit of Evangelismos Hospital (Athens, Greece) were studied prospectively. The diagnosis of acute myocardial infarction was based on at least two of the three following criteria: substernal chest pain lasting N 30 min at rest, increased plasma levels of cardiac enzymes (MB isoenzyme of creatine kinase) and typical ECG changes with ST-T segment elevation N 1 mm in at least two contiguous leads. Exclusion criteria in addition to diabetes mellitus were: 1) positive urine dipstick for haemoglobin, glucose, leucocytes or nitrites, 2) history of renal or urinary tract disease or overt albuminuria (N 200 Ag/min), 3) history of inflammatory rheumatic disease and 4) major in-hospital event prior to the urine collection for the determination of albumin urine level. This exclusion procedure left 223 patients eligible for the study. 2.2. End-point definition A physician who did not participate in the study and was blinded to patient identity or the urinary albumin excretion value of the patient, independently coded all fatal and nonfatal events. The primary outcome measure of the study was based on a comparison of in-hospital major adverse event rates between microalbuminuric and normoalbuminuric patients. In addition to death, the following major non-fatal in-hospital events after urine collection, that affect the day of discharge and the risk stratification following acute myocardial infarction, were recorded: post-infarction angina, infarct extension, mechanical complications, conduction disturbances, ventricular arrhythmias and pulmonary edema. To assess in-hospital morbidity and mortality, the combined end-point events rate included the total number of deaths and the above-mentioned non-fatal inhospital events. In patients with multiple non-fatal events only the first event was considered. Post-infarction angina was defined as recurrent angina at rest with either new ST-segment depression (z 0.1 mV) or
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T-wave inversion in at least two contiguous leads. Infarct extension was defined as ST-T segment elevation N 1 mm in at least two new contiguous leads associated with new MB isoenzyme of creatine kinase elevation. Mechanical complications were defined as free wall rupture, rupture of the interventricular septum or rupture of a papillary muscle diagnosed by echocardiography and confirmed through surgery or post-mortem examination. Conduction disturbances were defined as second-degree atrioventricular block type II or complete atrioventricular block or new complete bundle branch block. Ventricular arrhythmias were considered the following: non-sustained ventricular tachycardia (three or more consecutive ventricular ectopic beats, at a rate N 100 beats/min and lasting b 30 s), sustained ventricular tachycardia (consecutive ventricular ectopic beats at a rate N 100 beats/min, lasting N 30 s or associated with dizziness, syncope or chest pain) or ventricular fibrillation (presence of irregular undulations of varying contour and amplitude in the electrocardiogram). Pulmonary edema was defined as rales over more than 50% of the lung fields on auscultation (class III according to the Killip classification). 2.3. Study design On the day of admission and in the following 2 days serum enzymes and 12-lead ECGs were recorded every 8 h. After this period these examinations were performed daily. A further standard ECG had to be taken for central evaluation in case of any major in-hospital event. The presence and severity of heart failure were assessed on the two first days after admission, according to Killip classification. The day after admission fasting blood samples were drawn to measure total cholesterol, triglycerides and high density lipoprotein cholesterol (using enzymatic methods: Roche Diagnostics GmbH, Mannheim, Germany), creatinine (using a modified Jaffe reaction-Synchron C 5 Delta Chemistry Analyser; Beckman Instruments, Brea, CA) and complete blood cell count (assessed with an automated instrument). To minimize potential confounding factors present at the onset of acute myocardial infarction, the participants had an 8-hour urine collection on the third day of admission to assess urine levels of albumin. Microalbuminuria was defined as an albumin excretion rate 20–200 Ag/min. Urinary albumin concentration was measured from samples stored at 208 by a radioimmunologic method (double antibody PEG sedimentation-RIA, Diagnostic Products Corporation, Los Angeles, CA). The intra- and inter-assay variations of the method ranged from 3% to 5% and from 7.9% to 10.6% respectively and the threshold of detection was 0.3 Ag/ml. The urine was also screened for leucocytes, nitrites, haemoglobin and glucose. Patients admitted to the study underwent a complete Mmode, two-dimensional and Doppler examination with the use of a Hewlett-Packard, Sonos 2500 echocardiographic
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Table 1 Basic characteristics of the microalbuminuric and normoalbuminuric patients Number of patients (%) Age (years) Men/women Hypertension (yes/no) Smoking (yes/no) Body mass index (kg/m2) Total cholesterol (mg/dl) Triglycerides (mg/dl) HDL cholesterol (mg/dl) WBC (103 cells/ml) Ejection fraction (%) History of CAD (yes/no) Serum creatinine (mg/dl) CK-MB (mg/dl) Killip class N1 (yes/no) Thrombolysis (yes/no) PCI (yes/no)
ML (+)
ML ( )
75 (33.6%)
148 (66.4%)
63.5F 11.4 61 (81%)/14 (19%) 34 (45%)/41 (55%) 52 (69%)/23 (31%) 27F4.6 207.18F 39.7 144.5F 59.8 29.77F 8.4 13.64F 4.2 47.6 F10.2 14 (19%)/61 (81%) 0.98F 0.14 152.8F 134 21 (28%)/54 (72%) 33 (44%)/42 (56%) 26 (34%)/49 (66%)
60.2F 11.7 111 (75)/37 (25%) 49 (33%)/99 (67%) 110 (74%)/38 (26%) 26.8F 3 210.63F 45.3 155.3F 109 32.05F 11.6 11.83F3.6 48.9F 8.5 23 (15%)/125 (85%) 0.93F 0.18 106.2F 95.7 53 (36%)/95 (64%) 86 (58%)/62 (42%) 70 (47%)/78 (53%)
p Value 0.06 0.32 0.08 0.43 0.73 0.61 0.48 0.28 0.00 0.29 0.34 0.25 0.00 0.29 0.04 0.15
Values are expressed as number of patients (%) or meanFS.D. Abbreviations: CAD, coronary artery disease; CK-MB, MB isoenzyme of creatine kinase; HDL, high density lipoprotein; ML, microalbuminuria; PCI, percutaneous coronary intervention during hospitalization; WBC, white blood cells.
machine the third day of admission, to assess the left ventricular ejection fraction. The study was approved by the Regional Ethics Committees and was in accordance with the Helsinki Declaration.
3. Results 3.1. Patients characteristics From the 223 patients enrolled in this study, 172(77.1%) were men (age, 60F 12 years) and 51(22.9%) were women (age, 66 F11 years). The baseline clinical and biochemical characteristics of the patients with and without microalbuminuria are shown in Table 1. A significant proportion of the study patients (33.6%) had microalbuminuria at the time of the urine examination. One hundred eighty-two patients (81.6%) had an ST elevation myocardial infarction and 41 patients (18.4%)had a non-ST elevation myocardial infarction. The use of nitrates ( p =0.48), angiotensin converting enzyme inhibitors ( p =0.15), b-blockers ( p = 0.19), calcium channel blockers ( p =0.55), antiarrhythmic ( p = 0.09) and antiplatelet agents ( p = 0.54) was similar between patients with and without microalbuminuria, respectively. In contrast, diuretics ( p =0.01) and digitalis ( p b0.001) were more frequently used in patients with microalbuminuria. Finally, microalbuminuric patients were less likely to have undergone thrombolysis ( p =0.04). The level of peak MB isoenzyme of creatine kinase was significantly higher in the patients with microalbuminuria (152.8 F 134 vs. 106.2F 95.7 mg/dl, p b 0.001). On the other hand, the ejection fraction was similar in the two groups (47.6 F10.2% vs. 48.9 F8.5%, p = 0.29). Moreover, the number of white blood cells was significantly higher in the patients with microalbuminuria (13.64 F4.22 vs.
Table 2 The incidence proportion of major in-hospital events in patients with and without microalbuminuria Number of patients (%)
2.4. Statistical analysis Pulmonary edema (F)
Statistical analysis was performed with the use of SPSS 10.0 for Windows statistical package (SPSS Inc. 1999, Evanston, IL, USA). Data are presented as mean FS.D. for continuous variables and as a proportion for patients with a characteristic for categorical variables. Comparisons between continuous variables were done with the unpaired Student’s t-test while chi-square test was performed for the comparison of the proportions of each categorical variable between the patients with and without microalbuminuria. Univariate logistic regression analysis was used to relate the incidence of the combined study end-point to the various continuous and categorical variables. The variables with a significant predictive power in the univariate models were subsequently introduced into a multiple logistic regression model with the combined study end-point as the dependent variable. All p’s are two tailed and statistical significance was established as p b0.05.
ML (+)
ML ( )
75 (33.6%)
148 (66.4%)
11 (14.6%)/64 (85.4%) Infarct extension (F) 5 (6.7%)/70 (93.3%) Post-infarction angina (F) 10 (16.7%)/65 (83.3%) Conduction disturbances (F) 2 (4%)/73 (96%) Mechanical complications (F) 1 (2.7%)/74 (97.3%) Ventricular arrhythmia (F) 9 (12%)/66 (88%) Death (F) 5 (6.6%)/70 (93.4%) Combined end-pointa (F) 43 (57.3%)/32 (42.7%)
p value
5 (3.4%)/143 b0.001 (96.6%) 9 (6.1%)/139 0.53 (93.9%) 11 (7.5%)/137 0.22 (92.5%) 1 (0.7%)/147 0.26 (99.3%) 1 (0.7%)/147 0.56 (99.3%) 5 (3.4%)/143 0.01 (96.6%) 1 (0.68%)/147 0.01 (99.32%) 33 (22.3%)/115 b0.001 (77.7%)
Abbreviations: ML, microalbuminuria. +=presence, =absence. Data are expressed as number of patients (%). a Pulmonary edema or infarct extension or post-infarction angina or conduction disturbances or mechanical complications or ventricular arrhythmia or death.
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11.83F 3.6 103 cells/ml, p =0.00). No other differences were found between the two groups. 3.2. Incidence of events During the hospital stay (range, 8 to 26 days), 76 out of 223 patients (34%) developed a major in-hospital event (fatal or non-fatal). The incidence proportion of the major in-hospital events in patients with and without microalbuminuria is shown in Table 2. Six patients (2.7%) with acute myocardial infarction died in the hospital, all from cardiovascular complications (2 from ventricular fibrillation on 4th and 9th hospital day, 2 from reinfarction/cardiogenic shock on 6th and 7th hospital day, 2 from cardiogenic shock on 12th and 21st hospital day, respectively). The small number of deaths precluded any further analysis of the mortality alone. Seventy-four patients (33.2%) of the study had a Killip class N 1. No differences were found between the levels of urinary albumin excretion in patients with Killip class N1 and in patients with Killip class 1 (21.34 F 23.65 vs. 21.48 F23.41Ag/ml, p =0.95, respectively). The incidence of pulmonary edema and of ventricular arrhythmias was significantly higher in patients with microalbuminuria (14.6% vs. 3.4%, p b 0.001 and 12% vs. 3.4%, p =0.01, respectively). In addition, the combined end-point event rate was significantly higher in patients with microalbuminuria (57.3% vs. 22.3%, p b 0.001). The combined end-point event rate remained higher in patients with microalbuminuria, even if those who had Killip class N1 were excluded from the analysis ( p b 0.001). 3.3. Univariate and multiple regression analysis Possible predictors of in-hospital morbidity and mortality were examined in univariate logistic regression models. The continuous variables tested included age, total cholesterol, triglycerides, high density lipoprotein cholesterol, white blood cells, body mass index, ejection fraction, creatinine and MB isoenzyme of creatine kinase. The categorical variables tested included sex, preexisting hypertension, smoking, previous history of coronary artery disease and the use of thrombolysis. Table 3 shows the results of multiple logistic regression analysis, which included all the above variables related to
Table 3 Multiple logistic regression analysis, which included all the variables, related to the combined end-point event rate b Ejection fraction White blood cells Microalbuminuria Age History of CAD
0.05 0.06 0.012 0.03 0.47
Exp(b)
95% CI of Exp(b)
p value
0.94 1.06 1.07 1.02 1.60
0.90–0.98 0.97–1.16 1.02–1.12 0.99–1.05 0.91–2.80
0.01 0.16 b0.001 0.06 0.10
Abbreviations: b, beta coefficient; Exp(b), exponential(b); CI, confidence interval; CAD, coronary artery disease.
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the combined end-point event rate. Only microalbuminuria ( p b0.001) and ejection fraction ( p = 0.01) were independently related to the occurrence of the combined end-point event rate.
4. Discussion Our study suggests that microalbuminuria measured on the third day after admission is a strong predictor of inhospital morbidity and mortality in non-diabetic patients with acute myocardial infarction. Previous studies have shown a pattern of urinary excretion after acute myocardial infarction similar to that found following trauma, surgery and acute pancreatitis [9–11]. After an initial high rate of excretion, urine albumin levels fall rapidly towards normal during the week after admission to the hospital [12]. In accordance to these data, a significant proportion of acute myocardial infarction patients (33.6%) in our study, continued to have high levels of protein urinary excretion even on the third post-infarction day. Our results are in agreement to a recent study [6] where in a mixed population of diabetics and non-diabetics with acute myocardial infarction, both first-day albumin excretion rate and third-day albumin excretion rate were the strongest independent predictors of in-hospital mortality compared to other clinical and echocardiographic indexes of left ventricular performance. In the present study after multiple logistic regression analysis microalbuminuria and ejection fraction were the strongest independent predictors of in-hospital morbidity and mortality. In addition, inhospital mortality rate remained higher in patients with microalbuminuria, even if those who had Killip class N 1 were excluded from the analysis. According to our results, the incidence of pulmonary edema was far less common in patients without microalbuminuria. This is in agreement with Ellekilde et al. [13] who found higher levels of albumin excretion rate in acute myocardial infarction patients with heart failure compared with a group of patients without heart failure. Furthermore, Berton et al. [6] showed that a relationship exists between plasma aldosterone levels and albumin excretion rate in Killip class N 1 patients with acute myocardial infarction. It is possible that the elevated glomerular capillary pressure, which is found in patients who develop heart failure, like the acute myocardial infarction patients with pulmonary edema, facilitates the trans-glomerular passage of albumin [14]. The finding that, microalbuminuria remained a powerful prognostic indicator even if we excluded acute myocardial infarction patients with Killip class N 1 from the analysis, may suggest that microalbuminuria is related to the adverse prognosis of acute myocardial infarction with a mechanism different from the development of congestive heart failure. Many hypotheses have been proposed in order to explain the high albumin excretion rate during acute myocardial infarction. It is estimated that during the initial two days
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after acute myocardial infarction, heart failure or haemodynamic alterations [15], seem to be the main determinant of urinary albumin excretion rate, but endothelial dysfunction and inflammation [16] seem to play the key role from the third day. Inflammation is an important feature in patients with acute myocardial infarction [17,18]. Ischaemia produces a systemic increase in vascular permeability, including the vessels in the kidney, as part of the acute inflammatory process, thereby increasing the leak of urinary albumin [19]. Our finding of higher white blood cells in patients with microalbuminuria further supports the association of the severity of inflammation with the degree of microalbuminuria [20,21]. However, the possible pathophysiologic mechanism responsible for an association between microalbuminuria and adverse prognosis after acute myocardial infarction, remains under investigation. Whether the prognostic significance of microalbuminuria in patients with acute myocardial infarction, is based on direct pathogenetic effects [22], on a role as an epiphenomenon to an alternative pathogenetic mechanism [23], or on a role as a marker of hemodynamic compromise [24], remains unresolved. This way, the relationship in our study between microalbuminuria and the presence of ventricular arrhythmias, is of greater importance. In a recent study, Hassanabad et al. [25] showed that coronary endothelial dysfunction increased the severity of ischaemia and induced ventricular arrhythmias in rat isolated perfused hearts. Increased oxidative stress, which is more prevalent in patients with microalbuminuria [26], has also been implicated in the development of reperfusion arrhythmias [27]. In addition, inflammatory markers have been associated with postoperative arrhythmias in patients undergoing myocardial revascularization [28]. Since microalbuminuria may reflect a systemic increase in vascular permeability and a concomitant generalized endothelial dysfunction it is possible that, in patients with microalbuminuria and acute myocardial infarction, coronary endothelial dysfunction and the coexisting inflammatory process may promote the development of ventricular arrhythmias both during ischemia and reperfusion [29,30]. The present study has several limitations. First, the measurement of urinary albumin excretion was based on a single (8 h) urine collection. Three measurements instead of a single one, although difficult to perform in a large number of patients, would have been preferable. However, a single urine sample has been proposed in many studies as an accurate estimate of the presence of microalbuminuria and this procedure has been extensively used in epidemiological studies. In addition, serial urine collections would have been impractical during the short in-hospital follow up period of our study. Feld-Rasmussen reported that serial urine measurements have minor impact upon the validity of classification of patients as micro- or normoalbuminuric [31]. On the other hand, he proposed serial urine collections only as an index of the progression of an already increased urine albumin excretion rate. Thus, misclassification resulting
from our sampling procedure is likely to have weakened the relationship as shown, suggesting that the true relations may be in fact stronger. Second, because of the relatively small number of patients with microalbuminuria, we may have missed significant differences and relationships, especially in the different categories of in-hospital events. Third, we measured urinary albumin excretion on the third day after admission. Thus we excluded all the events that happened in the first two hospital days. However, this way we may have avoided the confounding effect of the acute inflammatory response and haemodynamic alterations, which characterize the early phase of the myocardial infarct development. The blate microalbuminuriaQ found in our patients probably reflects a more permanent endothelial dysfunction rather than a transient acute phase endothelial response.
5. Clinical implications Our study has shown that microalbuminuria is a significant predictor of both morbidity and mortality in non-diabetic patients with acute myocardial infarction and this finding may suggest that patients with microalbuminuria may need a more aggressive medical and interventional therapy before their discharge. However the possible role of microalbuminuria as an index of in-hospital risk stratification in patients with acute myocardial infarction remains unclear. Further studies will be necessary to assess the long-term prognostic significance of microalbuminuria in order to better guide our therapeutic strategies for patients who have sustained an acute myocardial infarction.
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