Elevated Admission Serum Creatinine Predicts Poor Myocardial Blood Flow (Full title below)
Elevated Admission Serum Creatinine Predicts Poor Myocardial Blood Flow and One-Year Mortality in ST-Segment Elevation Myocardial Infarction Patients undergoing Primary Percutaneous Coronary Intervention
ABSTRACT: Background. Outcomes after percutaneous coronary intervention (PCI) for patients with acute myocardial infarction (AMI) complicated by renal insufficiency have been well described. However, data regarding admission serum creatinine and coronary and myocardial flow are scant. The aims of this study are to evaluate the effects of admission serum creatinine on coronary blood flow and prognosis in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary PCI. Methods. A total of 495 patients undergoing primary PCI for STEMI within 12 hours after symptom onset were studied. Patients were divided into two groups according to admission serum creatinine level: 1) elevated serum creatinine group (elevated group, serum creatinine ≥ 1.3 mg/dl), and 2) normal serum creatinine group (normal group, serum creatinine
J INVASIVE CARDIOL 2009;21:493–498
Key words: STEMI, primary angioplasty, renal insufficiency
Previous studies have shown that patients with renal insufficiency are at increased risk for both cardiovascular disease and adverse cardiovascular outcomes.1–5 Moreover, renal insufficiency, measured as corrected creatinine clearance, blood urea nitrogen or serum creatinine level, has also been investigated in multiple epidemiological studies and clinical trials and found to be an independent predictor of survival in patients with acute coronary syndrome (ACS) or acute myocardial infarction (AMI).6–11
Although prompt restoration of antegrade flow in the infarct-related artery (IRA) is the primary aim of primary percutaneous coronary intervention (PCI), it has been recognized that preservation of the microcirculation is highly critical to clinical outcome.12 Recent attention has shifted from epicardial artery patency to the status of the microvasculature.12,13 Studies have shown that echocontrast “no-reflow,” despite thrombolysis in myocardial infarction (TIMI) grade 3 flow, occurred in one-third of patients after reperfusion therapy, and was associated with a higher incidence of congestive heart failure and left ventricular dysfunction.14,15 Earlier clinical studies have clearly delineated that no-reflow predicts short- and long-term adverse clinical outcomes in patients presenting with AMI.16,17
Accordingly, we aimed to investigate the effects of admission serum creatinine on coronary and myocardial blood flow and short- and long-term prognosis in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary PCI.
Patients and Methods
Study population. Ours was a retrospective observational study. Data on 495 consecutive STEMI patients at Beijing Friendship Hospital who underwent primary coronary intervention within 12 hours of the onset of symptoms were retrospectively collected between October 2004 and November 2007. The diagnosis of STEMI was based on the following: > 30 minutes of continuous chest pain; ST elevation > 2.0 mm in ≥ 2 contiguous electrocardiographic (ECG) leads; creatinine kinase level equivalent to > 2 times the upper limit of normal. Patients with earlier coronary artery bypass graft surgery (CABG), hemodialysis therapy, pain-to-balloon time > 12 hours, presence of any chronic inflammatory-autoimmune disease and known malignancy were excluded from this study. The study protocol was reviewed and approved by the ethical committee at Beijing Friendship Hospital. Informed consent to participate in this study was obtained from all patients.
Blood was drawn in the emergency room or coronary care unit before primary coronary angiography. The patients were initially divided into two groups based on their admission serum creatinine level. The normal range of serum creatinine was between 0.6–1.3 mg/dl, thus the normal serum creatinine group was defined as
Coronary angiography. All patients received an intravenous (IV) bolus injection of 2,000 U of heparin prior to angiography. Diagnostic coronary angiography was performed via the femoral or radial approach using the Judkins technique. After an additional IV or intra-arterial bolus injection of 6,000 U of heparin, PCI was performed. Primary PCI was done using the conventional technique, and coronary stents were used without restrictions. The IRA was the only target of the procedure. Intra-aortic balloon counterpulsation (IABP) was performed in cases of hemodynamic instability. TIMI grade 3 coronary flow in the treated vessel with a residual stenosis
Angiographic analysis. Angiographic images were acquired using a GE INOVA-2000 single-plane system (GE Healthcare, Wauwatosa, Wisconsin) at a cine rate of 30 frames per second. Basal TIMI flow and collateral circulation to the culprit vessel were evaluated on the first angiogram. TIMI flow grades (TFGs), corrected TIMI frame count (CTFC) and TIMI myocardial perfusion grade (TMPG) were graded on the angiograms taken immediately after PCI. Epicardial blood flow was assessed by use of either TFGs18 or CTFC,19,20 and myocardial perfusion by use of TMPG.21 A latero-lateral view for the left anterior descending (LAD) coronary artery, a left anterior oblique 45° view for the right coronary artery (RCA), and a caudal 45° or right anterior oblique 30° view for the circumflex artery were used in most cases. Ten seconds of cine filming were required to allow some filling of the venous system and to evaluate the washout phase of contrast dye. To facilitate the subjective grading of TMPG, angiograms were digitized and a logarithmic nonmagnified mask-mode background subtraction was applied to the image subset to eliminate non-contrast medium densities. The TMPGs were assessed as previously defined by Gibson et al in 2000.21 In brief, in TMPG 0, there is minimal or no myocardial blush; in TMPG 1, dye stains the myocardium and this stain persists on the next injection; in TMPG 2, dye enters the myocardium but washes out slowly so that dye is strongly persistent at the end of the injection; and in TMPG 3, normal entrance and exit of dye are in the myocardium so that dye is mildly persistent at the end of the injection. Every case was analyzed by the two cardiologists who were blinded to the patients’ identity, ECG and echocardiographic outcome, and a third cardiologist provided the final result if there was disparity in the TFGs and TMPGs between the two cardiologists. CTFC for every case was calculated by the mean value of the two cardiologists’ measurements.
Electrocardiography analysis. An 18-lead ECG was recorded just before and at the end of the procedure. Analysis was performed by one observer who was unaware of the clinical and angiographic data. The sum of ST-segment elevation (ΣSTe) was measured manually 20 ms after the end of QRS complex from leads exploring the infarct area. Resolution of ΣSTe after PCI was quantified as a percentage of the value obtained from the basal ECG. A > 50% reduction of the initial value was considered significant ΣSTe recovery.
Echocardiography analysis. A two-dimensional echocardiogram was performed in-hospital and at 1-year follow up for the evaluation of left ventricular (LV) wall motion and LV ejection fraction (LVEF). The analysis was carried out by two observers blinded to the clinical and angiographic data.
Clinical follow up. Clinical follow-up data were obtained from out-patient examinations or by the investigators who made telephone contact with patients at about 1 year post PCI. In-hospital and 1-year complications included death, heart failure, reinfarction and angina requiring revascularization.
Statistical analysis. Analyses were performed using SPSS software, version 13.0 (SPSS, Inc., Chicago, Illinois). Continuous data are expressed as mean values ± standard deviation. The student’s t-test was used to analyze continuous variables. Categorical variables were analyzed by the chi-square or Fisher’s exact test. Relative risks (RRs) were calculated to investigate the effects on poor myocardial perfusion and 1-year mortality. Logistic regression models were used to identify the clinical and angiographic variables correlated with poor myocardial perfusion and deaths at 1-year follow up. Univariate correlations with p-values of
Baseline clinical characteristics. Baseline clinical characteristics of the patients grouped by admission serum creatinine level are provided in Table 1. Patients with elevated serum creatinine were older, more often male, more likely to have hypertension, previous myocardial infarction (MI), in-hospital worsened creatinine defined as a 25% elevation in serum creatinine or an absolute increase of 0.5 mg/dl during hospitalization compared to the admission level, higher admission and discharge creatinine levels, and were more prone to show symptoms of congestive heart failure on presentation. Differences in concomitant therapy and device use including thrombus aspirator and drug-eluting stents (DES) during PCI between the two groups had no statistical significance. None of the patients underwent thrombolysis prior to their PCI, which may have affected TIMI flow evaluation.
Angiographic and ECG characteristics. Patients in the elevated group were more likely to have multivessel disease. There were no significant differences between the two groups in terms of frequency of TFGs 3 in the IRA after PCI, however CTFCs were higher in the elevated group. There were more frequent TMPGs 0–1 in the elevated group. In addition, significant ΣSTe recovery occurred less frequently in the elevated group (Table 2).
Clinical and echocardiographic outcomes. In-hospital and 1-year deaths were significantly higher in patients with elevated serum creatinine (4.7% vs. 1.2%, p 0.05), however there were statistical differences in MACE at 1-year follow up (14.0% vs. 7.3%, p
Admission serum creatinine ≥ 1.3 mg/dl (relative risk [RR] = 1.41, 95% confidence interval [CI]: 1.24–2.69), TMPGs 0–2 (RR = 1.54, 95% CI: 1.27–2.09), age ≥ 70 years (RR = 1.09, 95% CI: 1.04–1.19), previous MI (RR = 1.24, 95% CI: 1.05–1.84), in-hospital worsened creatinine (RR = 1.40, 95% CI: 0.96–1.74), Killip Class II–IV (RR = 1.96, 95% CI: 1.56–2.38), number of narrowed coronary arteries (RR = 1.32, 95% CI: 1.05–1.79), TFGs 0–2 (RR = 1.17, 95% CI: 1.01–1.54), and significant ΣSTe recovery (RR = 2.35, 95% CI: 1.24–4.23) were independent predictors of a higher rate of 1-year mortality in STEMI patients undergoing primary PCI (Table 4).
Admission serum creatinine ≥ 1.3 mg/dl (RR = 3.93, 95% CI: 1.13–6.84), discharge serum creatinine ≥ 1.3 mg/dl (RR = 2.01, 95% CI: 1.59–4.32), in-hospital worsened creatinine (RR = 2.84, 95% CI: 1.65–5.32), and number of narrowed coronary arteries (RR = 1.41, 95% CI: 1.07–1.68) were also independent predictors of poor myocardial perfusion detected by TMPG in STEMI patients undergoing primary PCI (Table 5).
In our study, interactive relationships of admission serum creatinine and myocardial blood flow and long-term mortality in STEMI patients undergoing primary PCI were investigated, and were not systematically observed previously.1–11 The results demonstrated that in the setting of STEMI, patients with elevated admission creatinine levels had less complete ST-segment resolution, greater impairment of myocardial blood flow and more short- and long-term MACE and death after primary PCI. Elevated admission serum creatinine predicted poor myocardial flow independently, which predicted 1-year mortality in STEMI patients undergoing primary PCI despite age, admission creatinine level, Killip’s grades at presentation and number of narrowed coronary arteries.
Previous studies have shown that patients with baseline renal dysfunction have increased cardiovascular risk.22–26 In addition, they showed the existence of significant differences in baseline patient characteristics between those with and those without renal insufficiency, and suggested that poor outcomes in the renal insufficiency patients could be explained by the multitude of comorbid conditions and worse preprocedural cardiac status.
Our result expands on previous analyses demonstrating that impaired renal function is associated with an increased risk of death in patients with STEMI. These results were in agreement with previous studies of patients undergoing PCI.22–26 In our study population, patients with elevated serum creatinine levels were older, more likely to present with symptoms of heart failure (Killip Class ≥ II), systemic hypertension, multivessel disease, were more prone to have in-hospital worsened creatinine levels, and have a history of MI than patients without renal decline. Nevertheless, the effect of an elevation of serum creatinine concentration on long-term mortality was independent of these risk factors when evaluated in a multivariate model. In our opinion, three factors may have contributed to these results. First, the higher level of serum creatinine also reflects clinical pathophysiological mechanisms such as low cardiac output, resulting in decreased renal blood flow, decreased myocardial flow, chronic volume overload and diastolic LV dysfunction. Second, the elevated serum creatinine group had a greater prevalence of multivessel coronary disease and a history of MI. Although the precise mechanisms of the interaction between impaired renal function and coronary artery disease are not clear, the serum creatinine concentration may be a marker for concomitant cardiovascular risk factors such as diabetes mellitus, systemic hypertension and advanced age. Third, patients with elevated serum creatinine are easier to show worsening serum creatinine levels during hospitalization, which has been proven to correlate with higher short- and long-term mortality.27–29 In our study, in-hospital worsened creatinine level, defined as a 25% elevation in serum creatinine during hospitalization or an absolute increase of 0.5 mg/dl compared to the admission level, was an independent predictor of 1-year mortality, which is consistent with previous studies.27–29
Several investigators have documented that the no-reflow phenomenon was observed in > 30% of the patients after thrombolysis or catheter-based PCI for AMI.14,30 In addition, it has been demonstrated that no-reflow predicts short- and long-term adverse clinical outcomes in the clinical setting of AMI.14,16,17,30 The severity of the no-reflow phenomenon correlates well with the severity of myocardial damage.12 The angiographic no-reflow phenomenon strongly predicts cardiac complications independent of other well-known early predictors of long-term outcome after AMI such as age, Killip Class and LVEF.31 Recently, Kazuyoshi et al found that lesion length and blood glucose level on admission could be used to stratify AMI patients into a lower or higher risk for angiographic slow- or no-flow before optimal coronary intervention. Moreover, angiographic slow- or no-flow predicts an adverse outcome in AMI patients.32
However, the divergence in mortality rates among patients with TIMI grade 3 flow is also associated with a degree of microvascular dysfunction and subsequent impairment of tissue perfusion. More specifically, the restoration of blood flow in the IRA may not be a reliable predictor of restoration of tissue reperfusion supplied by the IRA, hence the creation of TMPG.13 In our study, there was no difference in epicardial coronary flow evaluated by TFGs between the elevated and normal creatinine groups, but a significant difference was found when evaluated by CTFC and TMPG, which are much more sensitive and useful than TFGs and are associated with impaired microvascular flow. At the same time, TMPG was an independent risk predictor of 1-year mortality in our study. We therefore concluded that abnormal myocardial flow may contribute to poorer outcomes.
The likelihood that no-reflow will occur correlates with the severity of myocardial damage incurred during infarction and the resulting TIMI flow. No-reflow in the IRA after reperfusion therapy is mainly ascribed to the dysfunction of distal microcirculation. Reperfusion injury and free-radical release,33 as well as microvascular endothelial dysfunction and microvascular constriction,34 may play a significant role in the development of no-reflow. Although the exact pathophysiologic mechanisms by which baseline renal dysfunction increase the risk of poor myocardial perfusion development after primary PCI are not clearly elucidated, one could propose that anemia, oxidative stress, inflammation, elevation of proinflammatory cytokines, more unfavorable lipid profile, derangements in calciumphosphate homeostasis and conditions promoting coagulation — all of which are associated with accelerated atherosclerosis and endothelial dysfunction — play an essential role in this pathophysiology.35 Serum creatinine concentration is considered to correlate with oxidative stress, endothelial dysfunction, inflammation and more progressive atherosclerosis.36–41 From that point of view, one can conclude that microvascular endothelial dysfunction, conditions promoting coagulation and increased free-radical release may be responsible for poor myocardial perfusion after primary PCI in patients with renal impairment.
In our study, renal impairment in the STEMI patients who underwent primary PCI, measured by an easily-acquired admission creatinine ≥ 1.3 mg/dl, signified poor myocardial flow compared with STEMI patients who had normal serum creatinine, which was observed by TMPGs and significant ΣSTe recovery. In the multivariable regression analyses, admission creatinine level was an independent predictor of poor myocardial perfusion after primary PCI in patients with STEMI.
Study limitations. First, the number of study participants was limited. The statistical power thus might not be adequate for any negative data. Secondly, because the level of serum creatinine is of limited value in the early detection of renal insufficiency and is influenced by factors such as age, gender, race and lean muscle mass, there may be a claim that the serum creatinine level is an unreliable estimate of renal insufficiency, which limits our study, but these findings warrant further investigation regarding the role of renal insufficiency measured by direct GFR in STEMI patients. Thirdly, pathophysiological mechanisms of admission serum creatinine, increasing the risk of poor myocardial flow and adverse events in this study are not well studied, which could be explained by confounding variables that were not accounted for in the multivariable analysis, except for poor myocardial blood flow.
In conclusion, the elevated admission serum creatinine levels, acquired easily and directly, are associated with impaired coronary flow in STEMI patients undergoing primary PCI, which may contribute at least in part to worse cardiac function and poor short- and long-term prognosis. Therefore, we believe that baseline renal impairment detection by the use of simple serum creatinine test might be helpful in identifying patients with a greater risk of poor coronary blood flow and worse short- and long-term prognosis.
From the Department of Cardiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
The authors report no conflicts of interest regarding the content herein.
Manuscript submitted March 27, 2009, provisional acceptance given May 7, 2009, final version accepted May 28, 2009.
Address for correspondence: Lin Zhao, MD, Department of Cardiology, Beijing Friendship Hospital, Capital Medical University, No.95 Yong’an Road, Xuanwu District, Beijing, 100050, China. E-mail: firstname.lastname@example.org
1. Muntner P, He J, Hamm L, et al. Renal insufficiency and subsequent death resulting from cardiovascular disease in the United States. J Am Soc Nephrol 2002;13:745–753.
2. Nakamura K, Okamura T, Hayakawa T, et al. Chronic kidney disease is a risk factor for cardiovascular death in a community-based population in Japan: NIPPON DATA90. Circ J 2006;70:954–959.
3. Marenzi G, Moltrasio M, Assanelli E, et al. Impact of cardiac and renal dysfunction on inhospital morbidity and mortality of patients with acute myocardial infarction undergoing primary angioplasty. Am Heart J 2007;153:755–762.
4. Zhang Q, Zhang RY, Shen J, et al. Impact of admission creatinine level on clinical outcomes of patients with acute ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention with drug-eluting stent implantation. Chin Med J (Engl) 2008;121:2379–2383.
5. Walsh CR, O'Donnell CJ, Camargo CA Jr, et al. Elevated serum creatinine is associated with 1-year mortality after acute myocardial infarction. Am Heart J 2002;144:1003–1011.
6. Sørensen CR, Brendorp B, Rask-Madsen C, et al. The prognostic importance of creatinine clearance after acute myocardial infarction. Eur Heart J 2002;23:948–952.
7. Dixon SR, O'Neill WW, Sadeghi HM, et al. Usefulness of creatinine clearance in predicting early and late death after primary angioplasty for acute myocardial infarction. Am J Cardiol 2003;91:1454–1457.
8. Yamaguchi J, Kasanuki H, Ishii Y, et al. Prognostic significance of serum creatinine concentration for in-hospital mortality in patients with acute myocardial infarction who underwent successful primary percutaneous coronary intervention (from the Heart Institute of Japan Acute Myocardial Infarction [HIJAMI] Registry). Am J Cardiol 2004;93:1526–1528.
9. McCullough PA, Soman SS, Shah SS, et al. Risks associated with renal dysfunction in patients in the coronary care unit. J Am Coll Cardiol 2000;36:679–684.
10. Pitsavos C, Kurlaba G, Panagiotakos DB, et al. Association of creatinine clearance and inhospital mortality in patients with acute coronary syndromes: The GREECS study. Circ J 2007;71:9–14.
11. Yamaguchi J, Kasanuki H, Ishii Y, et al. Serum creatinine on admission predicts long-term mortality in acute myocardial infarction patients undergoing successful primary angioplasty: Data from the Heart Institute of Japan Acute Myocardial Infarction (HIJAMI) Registry. Circ J 2007;71:1354–1359.
12. King SB, Smith SCJ, Hirshfeld JWJ, et al. 2007 focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: A report of the American College of Cardiology/American Heart Association Task Force on Practice guidelines. J Am Coll Cardiol 2008;51:172–209.
13. Gibson CM, Cannon CP, Murphy SA, et al. Relationship of TIMI myocardial perfusion grade to mortality after administration of thrombolytic drugs. Circulation 2000;101:125–130.
14. Ito H, Maruyama A, Iwakura K, et al. Clinical implications of the “no reflow” phenomenon. A predictor of complications and left ventricular remodeling in reperfused anterior wall myocardial infarction. Circulation 1996;93:223–228.
15. Iliceto S, Galiuto L, Marchese A, et al. Functional role of microvascular integrity in patients with infarct-related artery patency after acute myocardial infarction. Eur Heart J 1997;18:618–624.
16. Morishima I, Sone T, Mokuno S, et al. Clinical significance of no-reflow phenomenon observed on angiography after successful treatment of acute myocardial infarction with percutaneous transluminal coronary angioplasty. Am Heart J 1995;130:239–243.
17. Morishima I, Sone T, Okumura K, et al. Angiographic no-reflow phenomenon as a predictor of adverse long-term outcome in patients treated with percutaneous transluminal coronary angioplasty for first acute myocardial infarction. J Am Coll Cardiol 2000; 36:1202–1209.
18. Anderson JL, Karagounis LA, Becker LC, et al. TIMI perfusion grade 3 but not grade 2 results in improved outcome after thrombolysis for myocardial infarction. Ventriculographic, enzymatic, and electrocardiographic evidence from the TEAM-3 study. Circulation 1993;87:1829–1839.
19. Gibson CM, Cannon CP, Daley WL, et al. The TIMI frame count: A quantitative method of assessing coronary artery flow. Circulation 1996;93:879–888.
20. Gibson CM, Murphy SA, Rizzo MJ, et al. Relationship between TIMI frame count and clinical outcomes after thrombolytic administration. Thrombolysis in Myocardial Infarction (TIMI) Study Group. Circulation 1999;99:1945–1950.
21. Gibson CM, Cannon CP, Murphy SA, et al. Relationship of TIMI myocardial perfusion grade to mortality after administration of thrombolytic drugs. Circulation 2000;101:125–130.
22. McCullough PA, Soman SS, Shah SS, et al. Risks associated with renal dysfunction in patients in the coronary care unit. J Am Coll Cardiol 2000;36:679–684.
23. Ferrer HJJ, Dominguez RA, Garcia GMJ, Abreu GP. Renal dysfunction is an independent predictor of in-hospital mortality in patients with ST-segment elevation myocardial infarction treated with primary angioplasty. Int J Cardiol 2007;118:243–245.
24. Schiele F, Legalery P, Didier K, et al. Impact of renal dysfunction on 1-year mortality after acute myocardial infarction. Am Heart J 2006;151:661–667.
25. Reinecke H, Trey T, Matzkies F, et al. Grade of chronic renal failure, and acute and long-term outcome after percutaneous coronary interventions. Kidney Int 2003;63:696–701.
26. Pinkau T, Mann JF, Ndrepepa G, et al. Coronary revascularization in patients with renal insufficiency: Restenosis rate and cardiovascular outcomes. Am J Kidney Dis 2004;44:627–635.
27. Dangas G, Iakovou I, Nikolsky E, et al. Contrast-induced nephropathy after percutaneous coronary interventions in relation to chronic kidney disease and hemodynamic variables. Am J Cardiol 2005;95:13–19.
28. Navaneethan SD, Singh S, Appasamy S, et al. Sodium bicarbonate therapy for prevention of contrast-induced nephropathy: A systematic review and meta-analysis. Am J Kidney Dis 2009;53:617–627.
29. Mehran R, Aymong ED, Nikolsky E, et al. A simple risk score for prediction of contrast-induced nephropathy after percutaneous coronary intervention: Development and initial validation. J Am Coll Cardiol 2004;44:1393–1399.
30. Ito H, Tomooka T, Sakai N, et al. Lack of myocardial perfusion immediately after successful thrombolysis. A predictor of poor recovery of left ventricular function in anterior myocardial infarction. Circulation 1992;85:1699–1705.
31. Halkin A, Singh M, Nikolsky E, et al. Prediction of mortality after primary percutaneous coronary intervention for acute myocardial infarction: The CADILLAC risk score. J Am Coll Cardiol 2005;45:1397–1405.
32. Kazuyoshi S, Nobuo S, Kinya S, et al. Predictors and long-term prognostic implications of angiographic slow/no-flow during percutaneous coronary intervention for acute myocardial infarction. Inter Med 2008;47:899–906.
33. Ma XL, Tsao PS, Viehman GE, Lefer AM. Neutrophil-mediated vasoconstriction and endothelial dysfunction in low-flow perfusion reperfused cat coronary artery. Circ Res 1991;69:95–106.
34. Gibson CM, Murphy SA, Kirtane AJ, et al. Association of duration of symptoms at presentation with angiographic and clinical outcomes after fibrinolytic therapy in patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol 2004;44:980–987.
35. Anavekar NS, McMurray JJ, Velazquez EJ, et al. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med 2004;351:1285–1295.
36. Becker BN, Himmelfarb J, Henrich WL, Hakim RM. Reassessing the cardiac risk profile in chronic hemodialysis patients: A hypothesis on the role of oxidant stress and other non-traditional cardiac risk factors. J Am Soc Nephrol 1997;8:475–486.
37. Fleck C, Schweitzer F, Karge E, et al. Serum concentrations of asymmetric (ADMA) and symmetric (SDMA) dimethylarginine in patients with chronic kidney diseases. Clin Chim Acta 2003;336:1–12.
38. Cauza E, Kletzmaier J, Bodlaj G, et al. Relationship of non-LDL-bound apo(a), urinary apo(a) fragments and plasma Lp(a) in patients with impaired renal function. Nephrol Dial Transplant 2003;18:1568–1572.
39. Dohi Y, Ohashi M, Sugiyama M, et al. Circulating thrombomodulin levels are related to latent progression of atherosclerosis in hypertensive patients. Hypertens Res 2003;26:479–483.
40. Kotaro N, Toshihisa A, Tsutomu Y, et al. Impact of chronic kidney disease on postinfarction inflammation, oxidative stress, and left ventricular remodeling. J Cardiac Fail 2008;14:831–838.
41. Turgay C, Atila I, Cagdas UY, et al. Impact of admission glomerular filtration rate on the development of poor myocardial perfusion after primary percutaneous intervention in patients with acute myocardial infarction. Coron Artery Dis 2008;19:543–549.