Acute hyperglycemia and contrast-induced nephropathy in primary percutaneous coronary intervention

Interventional Cardiology

Acute hyperglycemia and contrast-induced nephropathy in primary percutaneous coronary intervention Giancarlo Marenzi, MD, Monica De Metrio, MD, Mara Rubino, MD, Gianfranco Lauri, MD, Annalisa Cavallero, MD, Emilio Assanelli, MD, Marco Grazi, MD, Marco Moltrasio, MD, Ivana Marana, MD, Jeness Campodonico, MD, Andrea Discacciati, MSC, Fabrizio Veglia, PhD, and Antonio L. Bartorelli, MD Milan, Italy

Background Acute hyperglycemia and contrast-induced nephropathy (CIN) are frequently observed in ST-elevation acute myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI), and both are associated with an increased mortality rate. We investigated the possible association between acute hyperglycemia and CIN in patients undergoing primary PCI. Methods

We prospectively enrolled 780 STEMI patients undergoing primary PCI. For each patient, plasma glucose levels were assessed at hospital admission. Acute hyperglycemia was defined as glucose levels N198 mg/dL (11 mmol/L). Contrast-induced nephropathy was defined as an increase in serum creatinine N25% from baseline in the first 72 hours.

Results Overall, 148 (19%) patients had acute hyperglycemia; and 113 (14.5%) patients developed CIN. Patients with acute hyperglycemia had a 2-fold higher incidence of CIN than those without acute hyperglycemia (27% vs 12%, P b .001). Inhospital mortality was higher in patients with acute hyperglycemia than in those without acute hyperglycemia (12% vs 3%, P b .001). Mortality rate was also higher in patients developing CIN than in those without this renal complication (27% vs 0.9%, P b .001). Patients with acute hyperglycemia that developed CIN had the highest mortality rate (38%). Acute hyperglycemia was an independent predictor of CIN and in-hospital mortality. Conclusions In STEMI patients undergoing primary PCI, acute hyperglycemia is associated with an increased risk for CIN and with increased in-hospital mortality. (Am Heart J 2010;160:1170-7.)

In patients presenting with ST-segment elevation myocardial infarction (STEMI), primary percutaneous coronary intervention (PCI) reduces ischemic complications and improves survival, when compared with pharmacologic reperfusion with fibrinolytic agents.1 Patients undergoing primary PCI, however, are at high risk for contrast-induced nephropathy (CIN), a complication that has a serious impact on in-hospital outcome and may partially thwart the overall benefit of primary PCI.2,3 Indeed, in-hospital mortality has been shown to be 20 times higher in patients who experience CIN after primary PCI as compared with those without this complication.3

From the Department of Cardiovascular Sciences, Centro Cardiologico Monzino, I.R.C.C.S, University of Milan, Milan, Italy. Submitted July 26, 2010; accepted September 26, 2010. Reprint requests: Giancarlo Marenzi, MD, Centro Cardiologico Monzino, Via Parea 4, 20138 Milan, Italy. E-mail: [email protected] 0002-8703/$ - see front matter © 2010, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2010.09.022

An increased mortality risk has also been documented in STEMI patients with increased glucose levels at hospital presentation (acute hyperglycemia), even in those without established diabetes mellitus (DM).4-6 Several studies have reported that acute hyperglycemia in STEMI patients is independently associated with acute increase in inflammatory immune markers, lower rate of Thrombolysis In Myocardial Infarction flow grade 3 before primary PCI, impairment of epicardial coronary flow after primary stent implantation, “no-reflow” phenomenon, increased left ventricular dysfunction, larger infarct size, higher risk of congestive heart failure and cardiogenic shock, and hospital mortality.6-11 Noteworthy, glucose normalization after admission in hyperglycemic patients hospitalized with acute myocardial infarction seems to be associated with better survival.12 Although the association between DM and CIN risk has been clearly recognized in patients undergoing elective PCI,13,14 the possible relationship between acute hyperglycemia and CIN in STEMI patients treated with primary PCI has never been established. Potential pathophysiologic mechanisms through which contrast administration may cause renal injury include oxidative

American Heart Journal Volume 160, Number 6

Marenzi et al 1171

stress, endothelial dysfunction, and apoptosis.15 All these processes are also activated in the setting of acute hyperglycemia.16 There is ample evidence, from in vitro and animal studies, that marked fluctuations in glucose levels have consequences that are even more deleterious than those of chronically elevated glucose levels, and that they are mediated by increased rates of cellular apoptosis and increased oxidative stress.16-18 Thus, acute hyperglycemia could exacerbate the toxic effects of contrast exposure, significantly increasing the risk of CIN and negatively impacting hospital morbidity and mortality of STEMI patients. Recognition of the mechanisms associated with increased risk is challenging. However, it may allow for identification of potential targets for intervention. The hope is that pharmacologic control of acute hyperglycemia might reduce CIN risk and consequently improve patient outcome after primary PCI. Accordingly, we sought to prospectively assess the relationship between admission glucose levels and the risk of subsequent CIN and in-hospital major adverse events in patients with STEMI who undergo primary PCI.

defined as an increase in creatinine N25% from the baseline value within the 72-hour period following primary PCI.2,3 Pharmacologic therapy during and after primary PCI was left to the discretion of the interventional and coronary care unit cardiologists, based on current standards of care.21 The primary aim of the study was to determine the possible association between acute hyperglycemia and occurrence of CIN. In-hospital mortality rate and other major adverse events were also evaluated as secondary end points.

Methods

Statistical analysis

Study population This prospective observational study was conducted at the Centro Cardiologico Monzino between January 1, 2003, and December 31, 2008. We enrolled all consecutive patients with STEMI undergoing primary PCI. Patients were included if they presented within 12 hours (18 hours for STEMI complicated by cardiogenic shock) from the onset of symptoms (characteristic pain not responsive to nitrates, with electrocardiographic STsegment elevation or left bundle-branch block). Patients in longterm dialytic treatment were excluded. Patients undergoing cardiac surgery for emergency coronary revascularization and/ or mechanical complications, and those dying during PCI were excluded from the analysis. The study was approved by the Ethics Committee of our Institute, and written informed consent was obtained from all patients. No extramural funding was used to support this work. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper, and its final contents.

Study design In all patients, plasma glucose levels were assessed at hospital admission; and acute hyperglycemia was defined as glucose levels N198 mg/dL (11 mmol/L), regardless of the diabetic status.10,19 Patients were recognized as having DM if they had a history of DM on admission with the use of oral antihyperglycemic agents or any extended-release insulin. Serum creatinine concentration was measured at hospital admission, every day for the following 3 days, at discharge from the coronary care unit, and at hospital discharge. Glomerular filtration rate (eGFR) was estimated using the modified formula of Levey et al,20 and preprocedural renal insufficiency was categorized as an eGFR b60 mL/(min 1.73 m2). Contrast-induced nephropathy was

PCI procedure Primary PCI was performed by a 24-hour on-call interventional team, according to standard clinical practice. Standard guide catheters (6F), guide wires, and balloon catheters were used via the femoral approach. Patients received an intravenous bolus of 5,000 U heparin, followed by additional boluses during the procedure to maintain the activated clotting time N300 seconds (between 200 and 250 seconds when abciximab was used). Coronary stenting was performed with standard technique. A nonionic, low-osmolality contrast agent (iomeprol) was used. After contrast exposure, isotonic (0.9%) saline was given intravenously at a rate of 1 mL/(kg h) (0.5 mL/[kg h] in case of left ventricular ejection fraction [LVEF] b40% or heart failure) for 12 hours. Poststenting antithrombotic treatment consisted of aspirin and clopidogrel at standard dosages.

A sample size of 750 patients was calculated under the following assumptions: 30% incidence of acute hyperglycemia and 20% incidence of CIN in STEMI patients undergoing primary PCI.2,7,10 This sample size allowed for a N90% statistical power to assess a significantly higher (α error of .05) CIN incidence (relative risk [RR] = 1.7) in the group with acute hyperglycemia. Continuous variables are presented as mean ± SD and were compared using the t test for independent samples. Variables not normally distributed are presented as median and interquartile ranges, and were compared with the Wilcoxon rank sum test. Categorical data were compared using the χ2 test or the Fisher exact test, as appropriate. Linear regression analysis was used to explore the relationship between glucose blood levels at hospital admission and creatinine percentage maximal increase after primary PCI. Multivariable log-binomial regression models were developed to evaluate whether the association between acute hyperglycemia and clinical outcomes (CIN and in-hospital mortality) persisted after adjustment for other patient characteristics and for potential confounders. We chose log-binomial model, instead the logistic regression model, because the former directly estimates the RR that, in contrast with odds ratio, applies also to outcomes with a high prevalence (N10%, as in our case). Results are reported as RR and 95% CIs. At first, we included in the log-binomial model only acute hyperglycemia (model 1). To adjust for potential confounders selected among clinical variables associated with CIN after primary PCI (ie, DM, anterior STEMI, LVEF, time-to-reperfusion, contrast volume, and baseline eGFR b or N60 mL/[min 1.73 m2]) and with development of acute kidney injury (cardiogenic shock, mechanical ventilation, and ventricular fibrillation), we developed 3 multivariable log-binomial regression models: model 2, adjusting for DM and eGFR; model 3, adjusting for

American Heart Journal December 2010

1172 Marenzi et al

Table I. Baseline clinical and procedural characteristics of patients with and without acute hyperglycemia Acute hyperglycemia (n = 148)

No acute hyperglycemia (n = 632)

P value

64 ± 11 115 (78%) 76 ± 13 74 (50%) 74 (50%) 73 (49%) 52 (35%) 31 (21%) 10 (7%) 76 (51%) 3.0 (2.0-4.5)

62 ± 12 518 (82%) 75 ± 12 359 (57%) 35 (6%) 303 (48%) 281 (44%) 105 (17%) 31 (5%) 293 (46%) 2.5 (1.5-4.0)

.05 .23 .60 .14 b.001 .70 .04 .20 .34 .23 .04‡ .45

1 (0.7%) 77 (52%) 50 (34%) 18 (12%) 2 (1.3%) 46 (36-52) 1.16 (0.95-1.34) 65.3 (49.8-86.0) 58 (39%) 235 (120-384) 252 (220-314) 146 (99%) 58 (39%) 237 (174-308)

3 (0.5%) 294 (47%) 208 (33%) 113 (18%) 14 (2%) 51 (45-57) 1.04 (0.93-1.18) 76.3 (59.5-92.0) 160 (25%) 163 (77-297) 129 (113-153) 624 (99%) 277 (44%) 235 (170-321)

Mean age, y Men, n (%) Weight, kg Smokers, n (%) DM, n (%) Hypertension, n (%) Dyslipidemia, n (%) Previous myocardial infarction, n (%) Previous CABG, n (%) Anterior infarction, n (%) Time-to-reperfusion, h† Infarct artery, n (%) Left main Left anterior descending Right coronary artery Left circumflex Bypass graft Mean LVEF, %† Mean serum creatinine level, mg/dL† eGFR, mL/(min 1.73m2)† eGFR b60 mL/(min 1.73m2), n (%) Highest CK-MB, ng/mL† Glucose level at admission, mg/dL⁎,† Coronary stenting, n (%) Abciximab, n (%) Contrast volume, mL†

b.001‡ b.001‡ b.001‡ .001 .001‡ – .93 .30 .93‡

CABG, Coronary artery bypass graft surgery. ⁎ To convert glucose to millimoles per liter, multiply by 0.0555. † Median and interquartile range. ‡ By nonparametric Wilcoxon rank sum test.

the 6 predictors of CIN; and model 4, adjusting for all variables. Given the relatively small number of events, we only considered mortality models with ≤3 covariates (DM, eGFR, and contrast volume). To assess whether the effect of acute hyperglycemia on CIN was different in patients with or without renal insufficiency and in those with or without DM, we included the appropriate interaction terms in log-binomial regression model 2. All tests were 2-sided. All calculations were computed with the aid of the SAS software package (Version 9.13; SAS Institute Inc, Cary, NC).

Results A total of 780 consecutive patients were included in this study. Of them, 109 (14%) had DM and 218 (28%) had an estimated eGFR b60 mL/(min 1.73 m2) at hospital presentation. Median baseline glucose level was 140 (117-178) mg/dL. It was 236 (179-299) mg/dL and 133 (114-162) mg/dL in patients with and without DM, respectively (P b .001). One hundred forty-eight (19%) patients had acute hyperglycemia. The baseline clinical and procedural characteristics of patients with and without acute hyperglycemia are shown in Table I. Patients with acute hyperglycemia were more likely to have DM, reduced eGFR, longer time-to-reperfusion, lower LVEF, and higher

creatine kinase (CK)–MB peak values than patients without acute hyperglycemia. They also experienced a more complicated in-hospital clinical course (Table II). Contrast-induced nephropathy occurred in 113 (14.5%) patients. The frequency of CIN was 10% (n = 77) when an absolute rise in creatinine (N0.5 mg/dL [N44 μmol/L]) was used as the case definition. Twenty-one patients (17.5% of patients with CIN) required in-hospital hemofiltration. The incidence of CIN was 14% (n = 91) in the subgroup of patients without DM and 20% (n = 22) in those with DM (P = .06), and increased up to 32% in those with DM and renal insufficiency (n = 42). Figure 1 shows the incidence of CIN in patients with and without acute hyperglycemia, when the whole population and patients stratified according to the presence or absence of DM and reduced eGFR were considered. The rate of CIN was significantly higher in patients with acute hyperglycemia in all the considered subgroups, except in that of DM patients. A significant relationship between glucose blood levels at hospital admission and the percentage maximal increase of creatinine after primary PCI was found in the entire population (r = 0.19, P b .001). Overall, in-hospital mortality of the study population was 4.7% (n = 37) and was higher in patients with acute hyperglycemia than in those without it (12% vs 3%, P b

American Heart Journal Volume 160, Number 6

Marenzi et al 1173

Table II. In-hospital complications of patients with and without acute hyperglycemia

Atrial fibrillation, n (%) Ventricular fibrillation, n (%) Acute pulmonary edema, n (%) Cardiogenic shock requiring IABP, n (%) Major bleeding (with blood transfusion), n (%) Mechanical ventilation, n (%) Contrast nephropathy (N25%), n (%) Contrast nephropathy (N0.5 mg/dL), n (%) Contrast nephropathy requiring hemofiltration, n (%) In-hospital death, n (%) Length of hospital stay, d⁎

Acute hyperglycemia (n = 148)

No acute hyperglycemia (n = 632)

P value

17 (11%) 25 (17%) 32 (22%) 32 (22%) 10 (7%) 35 (24%) 40 (27%) 35 (24%) 9 (6%) 18 (12%) 8 (5-11)

47 (7%) 48(8%) 40 (6%) 44 (7%) 32 (5%) 29 (5%) 73 (12%) 42 (7%) 12 (2%) 19 (3%) 7 (5-9)

.11 b.001 b.001 b.001 .41 b.001 b.001 b.001 .005 b.001 .08†

IABP, Intraaortic balloon counterpulsation. ⁎ Median and interquartile ranges. † By nonparametric Wilcoxon rank sum test.

Figure 1

Incidence of CIN in patients with and without acute hyperglycemia.

.001). As expected, it was also higher in patients developing CIN than in those without this renal complication (27% vs 0.9%, P b .001). Figure 2 reports the incidence of major in-hospital adverse events, including death, according to the presence or absence of acute hyperglycemia and CIN. Major adverse event rates were higher in patients with acute hyperglycemia who developed CIN. Table III shows RRs of CIN and in-hospital mortality, adjusted for major clinical confounders. We found a

significant interaction between acute hyperglycemia and DM (P b .001). Indeed, the RR for CIN was 0.59 (95% CI 0.29-1.20) in patients with DM and 3.40 (95% CI 2.324.98) in those without DM. No significant interaction was found between acute hyperglycemia and renal insufficiency (P = .45). To verify whether the lack of an association between acute hyperglycemia and CIN in patients with DM was due to the chosen glycemic threshold, we computed RRs, adjusted for eGFR b or N60 mL/(min 1.73 m2), associated

American Heart Journal December 2010

1174 Marenzi et al

Figure 2

Percentage of patients developing major in-hospital adverse events, according to the presence or absence of acute hyperglycemia and CIN. AF, Atrial fibrillation; CVVH, continuous venovenous hemofiltration; MV, mechanical ventilation; VF, ventricular fibrillation.

Table III. Contrast-induced nephropathy and mortality RR, adjusted for major clinical confounders Included variables RR

95% CI of acute hyperglycemia (yes vs no)

P value

2.33 (1.66-3.29) 2.18 (1.51-3.14) 1.77 (1.39-2.25)

b.001 b.001 b.001

1.59 (1.35-1.88)

b.001

4.05 (2.18-7.52) 3.29 (1.64-6.62) 3.39 (1.73-6.64)

b.001 b.001 b.001

Outcome: CIN (cases/controls) Model 1 (113/667) Model 2 (113/667) Model 3 (104/607)

Acute hyperglycemia Model 1 + eGFR and DM Model 2 + infarct location, LVEF, contrast volume, and time-to-reperfusion Model 4 (104/607) Model 3 + cardiogenic shock, mechanical ventilation, and ventricular fibrillation Outcome: in-hospital mortality (cases/controls) Model 1 (37/743) Acute hyperglycemia Model 2 (37/743) Model 1 + eGFR and DM Model 3 (37/743) Model 2 + contrast volume

with a wide range of cutoffs in patients with and without DM (Figure 3). In patients without DM, the RR reached the highest value at a threshold of about 200 mg/dL, then leveled off above this. On the other hand, the RR peak was reached at a higher threshold (about 300 mg/dL) in DM patients in whom the RR remained always lower than that of patients without DM. In 35 (5%) of the 743 discharged patients, there was a persistent N25% increase in serum creatinine com-

pared with baseline value. No patient was discharged on dialysis.

Discussion Our study shows that, in STEMI patients undergoing primary PCI, admission acute hyperglycemia is a significant and independent predictor of CIN and of poor inhospital outcome.

American Heart Journal Volume 160, Number 6

Marenzi et al 1175

Figure 3

Relative risks (and 95% CIs) for CIN associated with different glucose blood levels cutoffs in patients with DM (red) and in those without DM (blue). Confidence intervals were computed using Cochran-Mantel-Haenszel estimator.

Acute hyperglycemia is common in patients with STEMI, even in the absence of a history of type 2 DM.4-6 Admission glucose has been identified as a major independent predictor of both in-hospital congestive heart failure and mortality in STEMI.22 For every 18-mg/dL (1-mmol/L) increase in glucose level, there is a 4% increase in mortality in nondiabetic patients.23 For the same increase in glucose level, an adjusted increase in mortality risk of 10% has been reported for STEMI patients undergoing primary PCI.7 Even mild hyperglycemia has adverse prognostic implications in patients with acute myocardial infarction.24 Acute hyperglycemia is associated with several adverse effects that may contribute to poor outcome in STEMI. They include endothelial dysfunction, increased cytokine activation, increased oxidative stress, impaired microcirculatory function as manifested by post-PCI “no-reflow” phenomenon, and impaired ischemic preconditioning.7-11,25 Finally, hyperglycemia has been shown to have several prothrombotic effects (enhanced thrombin formation, platelet activation, and fibrin clot resistance to lysis) that may contribute to an increased risk for thrombotic complications in this clinical setting.26,27 In this study, we found that acute hyperglycemia is also associated with a higher incidence of CIN in STEMI patients undergoing primary PCI and that this association further enhances the morbidity and mortality

risk associated with this renal complication. The mechanisms underlying the association between acute hyperglycemia and increased risk for CIN cannot be fully elucidated by our study. We cannot exclude that both conditions are markers of a large infarct size and epiphenomena of the stress response, mediated by cortisol and catecholamines whose release is elicited by the hemodynamic compromise. Our data support, at least in part, this concept, showing higher CK-MB peak and lower LVEF values, both expression of a larger infarct size, in patients with acute hyperglycemia. On the other hand, several effects of acute hyperglycemia may have direct negative impact on kidney function and increase renal toxicity of contrast agents. Indeed, acute hyperglycemia suppresses flow-mediated vasodilatation, likely through increased production of oxygen-derived free radicals, and increases oxidative stress.28,29 Oxidant stress-mediated injury and renal medullary hypoxia and ischemia, due to vasoconstriction in response to contrast medium administration, have been implicated as causative factors for CIN.15 Thus, acute hyperglycemia may exacerbate the deleterious effects of contrast agents on the kidney. Moreover, acute hyperglycemia may induce osmotic diuresis, resulting in volume depletion and dehydration and further increasing CIN risk and severity. Notably, in our study, patients with acute hyperglycemia had a 2-fold higher incidence of CIN

American Heart Journal December 2010

1176 Marenzi et al

than those without it; and a significant relationship between blood glucose levels and maximal serum creatinine increase was found. Furthermore, in-hospital mortality in patients with acute hyperglycemia who developed CIN was almost 40%, a rate that was 2-fold higher than that observed in patients with CIN, but without acute hyperglycemia. The possible association between high glucose levels and acute kidney injury is further supported by previous studies. Van den Berghe et al30 showed that, in 1,548 surgical ICU patients, those rendered relatively euglycemic with insulin infusion had a 41% reduction of renal failure requiring a renal replacement therapy (4.8% vs 8.2%, P = .007) and a lower incidence of acute kidney injury (9% vs 12.3%, P = .04). Similarly, in a medical ICU population, insulin therapy reduced the incidence of acute kidney injury, compared with control subjects (5.9% vs 8.9%, P = .04).31 Overall, these data strongly support a causative relationship between high glucose levels and risk of acute renal dysfunction. The importance of a tight control of hyperglycemia as a strategy for improving prognosis in STEMI patients and, in general, in all critically ill patients is still under debate. Growing evidence, however, suggests that control of hyperglycemia during acute illness among diabetic and nondiabetic patients may be associated with improved outcome. Indeed, in a previous study, glycemic control with insulin in patients with a first acute myocardial infarction who underwent coronary bypass surgery was associated with reduced oxidative stress, inflammation, apoptotic cell death in the periinfarct area, and remodeling.32 Recently, Kosiborod et al12 have shown that glucose normalization after admission is associated with better survival in hyperglycemic patients hospitalized with acute myocardial infarction, whether or not they received insulin therapy. These findings underline the importance of control of acute hyperglycemia as a possible prophylactic strategy for prevention of CIN in STEMI patients undergoing primary PCI. To date, the effect of glucose level normalization on CIN incidence and severity in patients with acute hyperglycemia is unknown and should be a matter for future investigation. In our study, we found that the relationship between acute hyperglycemia and CIN risk was markedly different among patients with and without established DM. Acute hyperglycemia was associated with a significant increase of CIN risk among patients who did not have known DM. In contrast, no such association was observed among patients with established DM who experienced a high CIN rate (20%), regardless of admission glucose levels. Surprisingly, among patients with acute hyperglycemia, CIN rate was higher in nondiabetic than in diabetic patients (38% vs 16%, P = .003). This observation emphasizes the importance of acute glucose level rise, as compared with its chronic elevation, as a predisposing factor for CIN. It also suggests that a higher glucose

threshold should be used to define acute hyperglycemia in patients with DM than should be used for patients without DM. This concept is supported by the fact that, in our study population, the RR for CIN was lower in patients with DM than in those without it at each given blood glucose level (Figure 3). In patients with DM, an increase in the RR for CIN was observed only when a glycemic value of about 300 mg/dL was reached. The most reliable glycemic threshold for DM patients, in terms of prognostic relevance, however, should be estimated and validated in large trials. The present study has some limitations. First, we included a population admitted to a single center. Second, causal relationship between acute hyperglycemia and CIN remains uncertain. Whether this association is the effect of direct acute hyperglycemia or simply reflects the severity of the clinical status of these patients cannot be fully elucidated by our study. At multivariate analysis, however, acute hyperglycemia remained an independent predictor of CIN even after adjustment for major clinical variables associated with infarct size and with development of acute kidney injury. Third, we did not serially evaluate blood glucose levels in our patients. Therefore, we do not know whether early spontaneous or pharmacologic normalization of glycemic values is associated with a lower incidence of CIN and a better clinical outcome. This stimulating question should be addressed in future studies. Finally, the lack of screening for patients with newly detected diabetes and with impaired glucose tolerance, and of measurement of glycated hemoglobin A1c, which would have provided some insights into the possible relationship of acute versus chronic hyperglycemia and CIN risk, represents further limitations of our study.

Conclusion In STEMI patients treated with primary PCI, acute hyperglycemia is closely associated with CIN risk and inhospital morbidity and mortality. Future research should focus on whether or not prophylactic strategies based on tight glycemic control will prevent CIN and will improve the clinical outcome of patients with STEMI.

References 1. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet 2003;361:13-20. 2. Marenzi G, Lauri G, Assanelli E, et al. Contrast-induced nephropathy in patients undergoing primary angioplasty for acute myocardial infarction. J Am Coll Cardiol 2004;44:1780-5. 3. Marenzi G, Assanelli E, Campodonico J, et al. Contrast volume during primary percutaneous coronary intervention and subsequent contrast-induced nephropathy and mortality. Ann Intern Med 2009; 150:170-7.

American Heart Journal Volume 160, Number 6

4. Oswald GA, Smith CC, Betteridge DJ, et al. Determinants and importance of stress hyperglycaemia in non-diabetic patients with myocardial infarction. BMJ 1986;293:917-22. 5. Oswald GA, Yudkin JS. Hyperglycaemia following acute myocardial infarction: the contribution of undiagnosed diabetes. Diabet Med 1987;4:68-70. 6. Capes SE, Hunt D, Malmberg K, et al. Stress hyperglycemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic overview. Lancet 2000;355: 773-8. 7. Ishihara M, Kojima S, Sakamoto T, et al. Acute hyperglycemia is associated with adverse outcome after acute myocardial infarction in the coronary intervention era. Am Heart J 2005;150:814-20. 8. Iwakura K, Ito H, Ikushima M, et al. Association between hyperglycemia and the no-reflow phenomenon in patients with acute myocardial infarction. J Am Coll Cardiol 2003;41:1-7. 9. Ishihara M, Inoue I, Kawagoe T, et al. Impact of acute hyperglycemia on left ventricular function after reperfusion therapy in patients with a first anterior wall acute myocardial infarction. Am Heart J 2003;146: 674-8. 10. Nakamura T, Ako J, Kadowaki T, et al. Impact of acute hyperglycemia during primary stent implantation in patients with STelevation myocardial infarction. J Cardiol 2009;53:272-7. 11. Timmer JR, Ottervanger JP, de Boer MJ, et al. Hyperglycemia is an important predictor of impaired coronary flow before reperfusion therapy in ST-segment elevation myocardial infarction. J Am Coll Cardiol 2005;45:999-1002. 12. Kosiborod M, Inzucchi SE, Krumholz HM, et al. Glucose normalization and outcomes in patients with acute myocardial infarction. Arch Intern Med 2009;169:438-46. 13. Parfrey PS, Griffiths SM, Barrett BJ, et al. Contrast material-induced renal failure in patients with diabetes mellitus, renal insufficiency, or both: a prospective controlled study. N Engl J Med 1989;320:143-9. 14. Mccullough PA, Adam A, Becker CR, et al. Risk prediction of contrastinduced nephropathy. Am J Cardiol 2006;98:27K-36K. 15. Persson PB, Tepel M. Contrast medium-induced nephropathy: the pathophysiology. Kidney Int 2006;69(Suppl 100):S8-S10. 16. Ceriello A. Cardiovascular effects of acute hyperglycaemia: pathophysiological underpinnings. Diabetes Vasc Dis Res 2008;5:260-8. 17. Piconi L, Quagliaro L, Assaloni R, et al. Constant and intermittent high glucose enhances endothelial cell apoptosis through mitochondrial superoxide overproduction. Diabetes Metab Res Rev 2006;22: 198-203. 18. Quagliaro L, Piconi L, Assaloni R, et al. Intermittent high glucose enhances apoptosis related to oxidative stress in human umbilical vein endothelial cells: the role of protein kinase C and NAD(P)Hoxidase activation. Diabetes 2003;52:2795-804. 19. Malmberg K, Ryde L, Wedel H, et al. Intense metabolic control by means of insulin in patients with diabetes mellitus and acute

Marenzi et al 1177

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30. 31. 32.

myocardial infarction (DIGAMI 2): effects on mortality and morbidity. Eur Heart J 2005;26:650-61. Levey AS, Beto JA, Coronado BE, et al. National Kidney Foundation Task Force on Cardiovascular Disease. Controlling the epidemic of cardiovascular disease in chronic renal disease. What do we know? What do we need to learn? Where do we go from here? Am J Kidney Dis 1998;32:853-906. Van de Werf F, Ardissino D, Betriu A, et al. Management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2003;24:28-66. Zeller M, Steg PG, Ravisy J, et al. Prevalence and impact of metabolic syndrome on hospital outcomes in acute myocardial infarction. Arch Intern Med 2005;165:1192-8. Stranders I, Diamant M, van Gelder RE, et al. Admission blood glucose level as risk indicator of death after myocardial infarction in patients with and without diabetes mellitus. Arch Intern Med 2004; 164:982-8. Otten R, Kline-Rogers E, Meier DJ, et al. Impact of pre-diabetic state on clinical outcomes in patients with acute coronary syndrome. Heart 2005;91:1466-8. Yang Z, Laubach VE, French BA, et al. Acute hyperglycemia enhances oxidative stress and exacerbates myocardial infarction by activating nicotinamide adenine dinucleotide phosphate oxidase during reperfusion. J Thorac Cardiovasc Surg 2009;137: 723-9. Undas A, Wiek I, Stepien E, et al. Hyperglycemia is associated with enhanced thrombin formation, platelet activation, and fibrin clot resistance to lysis in patients with acute coronary syndrome. Diabetes Care 2008;31:1590-5. Worthley MI, Holmes AS, Willoughby SR, et al. The deleterious effects of hyperglycemia on platelet function in diabetic patients with acute coronary syndromes. Mediation by superoxide production, resolution with intensive insulin administration. J Am Coll Cardiol 2007;49: 304-10. Kawano H, Motoyama T, Hirashima O, et al. Hyperglycemia rapidly suppresses flow-mediated endothelium-dependent vasodilation of brachial artery. J Am Coll Cardiol 1999;34:146-54. Monnier L, Mas E, Ginet C, et al. Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA 2006;295: 1681-7. Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001;345:1359-67. Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med 2006;354:449-61. Marfella R, Di Filippo C, Portoghese M, et al. Tight glycemic control reduces heart inflammation and remodeling during acute myocardial infarction in hyperglycemic patients. J Am Coll Cardiol 2009;53: 1425-36.