Angiographic progression of coronary artery disease in patients with end-stage renal disease

Frank Gradaus1,, Katrin Ivens2, Ansgar J. Peters1, Peter Heering2, Frank-Chris Schoebel1, Bernd Grabensee2 and Bodo-Eckehard Strauer1

1 Klinik für Kardiologie, Pneumologie und Angiologie, and 2 Klinik für Nephrologie und Rheumatologie, Heinrich Heine Universität Düsseldorf, Düsseldorf, Germany



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Patients with end-stage renal disease have an increased risk of developing coronary artery disease (CAD). The cardiovascular mortality of dialysis patients is 10–15 times higher compared with the general population. The aim of our study was to evaluate the morphological progression of coronary arteriosclerosis in this cardiovascular high-risk group by visual assessment and quantitative coronary angiography.

Methods and results. In 26 patients with chronic renal failure (age, 47±11 years; 15 male; duration of dialysis, 23±25 months) the severity of CAD and degree of coronary stenoses were assessed in two coronary angiograms after a mean follow-up interval of 30±15 months (12–60). Baseline angiography revealed CAD in 13/22 patients (59%). The second angiography was performed as screening procedure prior to renal transplantation (n=20) and/or as follow-up angiography after coronary angioplasty (n=10). Visual assessment showed a progression defined by the development of haemodynamically relevant stenosis of >50% luminal diameter in 13 patients. Quantitative angiographic evaluation was performed in a total of 45 segments showing >25% narrowing at the second angiogram. A progression (>15% luminal reduction) was found in 17 of 45 segments, a new lesion (initial luminal diameter <20%) was detected in nine segments, resulting in progression or new lesion in 16 patients (62%). Patients with or without progression did not differ in age, duration of dialysis treatment, number of cardiovascular risk factors, or serum total cholesterol and fibrinogen levels. After percutaneous transluminal coronary angioplasty (PTCA) a restenosis was seen in seven of 16 primarily successfully dilated segments. After the second angiography, myocardial revascularization was performed in eight patients (1 PTCA, 7 coronary artery bypass graft).

Conclusions. Patients with end-stage renal disease have a high prevalence of CAD. In line with the clinical course, CAD patients on maintenance dialysis undergo rapid angiographic progression of CAD, which results in a high rate of subsequent myocardial revascularizations.

Keywords: angiography; coronary artery disease; cardiovascular mortality; end-stage renal disease; morphological progression



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Cardiovascular complications are the leading cause of death in patients with end-stage renal disease (ESRD). About 40–50% of deaths are attributed to lethal cardiac events, and cardiac mortality is 10–15 times higher than in the normal population [13]. After acute myocardial infarction, patients on dialysis have a high mortality of 59.3±0.3% at 1 year and 89.9±0.2% after 5 years [4].

The prevalence of coronary artery disease (CAD) in published coronary series, most of them in renal transplant candidates is high, and ranges between 25 and 60% [56]. Due to the high prevalence and rapid clinical progression of CAD, an accelerated atherosclerosis was postulated in patients with ESRD. In this study, we examined the morphological progression of coronary artery disease by means of visual and computer-assisted evaluation of serial coronary angiograms in patients with ESRD.



   Subjects and methods
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patients
In this retrospective study, 26 patients with end-stage renal disease, who had undergone at least two coronary angiographies within a follow-up period of 12–60 months, were included. Apart from suspected CAD coronary investigations and follow-up angiographies were performed either as a screening procedure prior to renal transplantation (n=20) and/or as follow-up after coronary intervention (n=10). All patients had undergone either haemodialysis or peritoneal dialysis for at least 3 months. Post-coronary artery bypass graft patients were not included.

Cardiovascular risk profile
Arterial hypertension was considered present if systolic and diastolic blood pressure ranged above 140 mmHg systolic or 90 mmHg diastolic, or when the patient was on antihypertensive medication. Hyperlipidaemia was defined by concentrations of total cholesterol of >220 mg/dl and triglycerides of >200 mg/dl. Diabetes was defined according to the criteria of the National Diabetes Data Group [7]. Characterization of present or former smoking habits was based on information supplied by the patient.

Laboratory variables
Plasma concentrations of lipids and fibrinogen were routinely determined in patients with CAD or suspected CAD prior to coronary angiography and were taken from the patient record. Total cholesterol and triglycerides were determined with the colorimetric tests (Boehringer Mannheim, Germany)—the CHOD-PAP method and the GPO-PAP method, respectively. High-density lipoprotein (HDL) cholesterol was measured after precipitation with phosphotungstic acid/MgCl2, and low-density lipoprotein (LDL) cholesterol after precipitation with heparin at pH 5.12 (Merck, Darmstadt, Germany). Plasma fibrinogen was measured with a modified version according to Clauss [8] in 9 ml of whole blood added to 1 ml sodium citrate (Multifibrin, Behringwerke AG, Marburg, Germany).

Coronary angiography and angioplasty
Selective coronary angiography was performed following the administration of intracoronary glyceryl nitrate. At least six standardized projections of the left coronary artery and two of the right coronary artery were obtained routinely. CAD was defined by the presence of haemodynamically relevant stenosis (>50% of the luminal diameter). The severity of the coronary artery disease was determined visually and was classified as single-, double-, or triple-vessel disease according to manifestations of haemodynamically relevant stenosis in the three major vessels. A progression of CAD was defined by the development of haemodynamically relevant stenoses of >50% luminal diameter.

Coronary balloon angioplasty was performed after administration of 500 mg aspirin and 10 000 IU of heparin before angioplasty, and 5000 IU heparin intravenously after the intervention. Balloon sizes ranging from 2.5 to 3.5 mm were used; none of the patients underwent additional stent implantation.

Quantitative coronary angiography
Quantitative computer-assisted angiographic measurements were performed with the computer assisted contour analysis (Cardio 500, Kontron, Munich, Germany). The reproducibility and accuracy of measurements using this system is described elsewhere [9]. A single observer trained in quantitative angiography performed the analysis. The image of the coronary angiogram showing the most severe narrowing at end diastole was compared with identical projections after coronary angioplasty and/or at the follow-up angiography.

All stenoses of estimated >25% luminal diameter reduction were assessed selectively. A progression was defined as an increase of >15% in percent diameter stenosis. A new lesion was defined when a localized stenosis of >30% at the follow-up angiography was normal (<20% luminal reduction) at the first angiogram. Re-stenosis after angioplasty was defined by the presence of a stenosis >50% luminal diameter at the time of follow-up.

Statistics
The data were analysed with the Statistical Package for Social Sciences (SSPS for Windows, SSPS, Munich, Germany). For comparison of two groups the Mann-Whitney U test was used. A significant difference between groups was assumed at a level of error of <5%. All data are presented as mean±SD.



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patients
Twenty-six patients with ESRD were included in this observational study. Duration of dialysis treatment was at least 3 months and ranged between 3 and 108 months. More than one-half of these patients (54%) had diabetic nephropathy. The mean age of the patients was 47±11 years, ranging from 25 to 73 years. Twenty-two patients were on a pre-transplantation waiting list (age 45±10 years, duration of dialysis 22±25 months).

All patients were characterized by a high number of established cardiovascular risk factors (2.8±0.7 per patient), nearly all of them needed antihypertensive medication, 15 patients were active or former smokers and hyperlipidaemia was found in 66% (Table 1Go). Laboratory assessment of lipids and fibrinogen showed elevated concentrations of triglycerides, total cholesterol with low HDL cholesterol levels, and high plasma concentrations of fibrinogen (Table 1Go).


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Table 1. Patient characteristics

 

Coronary angiography
Baseline coronary angiography demonstrated coronary artery disease in 17 patients and excluded haemodynamically relevant stenoses in nine patients. While CAD was known in four patients, it was diagnosed de novo in 13 of 22 patients (59%). Eleven of 17 patients with CAD had angina pectoris; three of nine patients without relevant stenoses reported chest pain prior to coronary angiography.

After a mean follow-up of 30±15 months, visual quantification of the second angiogram revealed a progression of CAD in 13 patients (50%). Three of nine patients in whom CAD had been excluded at baseline presented with relevant stenoses after a follow-up of 42±12 months, and in two patients triple-vessel disease was now diagnosed. Ten of 17 patients with known CAD (58%) showed progression (follow-up 25±13 months).

Forty-five segments, excluding stenoses which had undergone mechanical alteration by PTCA, were analysed by quantitative coronary angiography (QCA). The mean percent diameter stenosis increased from 33±12 to 49±12%, corresponding to a decrease of the mean minimal luminal diameter from 1.98±0.52 to 1.52±0.59 mm (Table 2Go). Seventeen diseased segments presented a progression, while new lesions were noted in nine coronary segments, altogether, resulting in a progression or new lesion in 16 patients (62%).


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Table 2. Results of coronary angiography and quantitative coronary evaluation

 
Patients with or without progression of coronary artery disease did not differ in age, duration of dialysis treatment, number of cardiovascular risk factors and plasma concentrations of lipids or fibrinogen (Table 3Go).


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Table 3. Age, duration of dialysis, number of risk factors, and laboratory variables in patients with or without progression

 
In patients with diabetic nephropathy (n=14, age 42±11 years, duration of dialysis 20±34 months) CAD was demonstrated in six patients at baseline. Progression was seen in six of 14 patients (43%) after a follow-up of 37±15 months, quantitative assessment of 25 segments in 11 patients showed a progression in nine segments as well as four new lesions. Altogether a progression of CAD was found in nine patients (64%) by additional evaluation of QCA.

After the first angiography 10 patients underwent coronary angioplasty. As a routine procedure in our hospital, a follow-up angiography was performed in all of these patients after 6 months. An angiographic re-stenosis, defined by the presence of haemodynamically relevant stenosis of >50% luminal diameter was found in six patients (7 of 16 primarily successfully dilated coronary stenoses (44%)).

After the follow-up angiography nine of 17 patients with CAD were treated medically, seven patients underwent a CABG, and in one patient coronary angioplasty was repeated. Two patients died respectively 2 days and 3 weeks after the second angiogram. One patient suffered anterior myocardial infarction and developed a cardiogenic shock. The other patient had a two-vessel disease and mitral regurgitation; after simultaneous bypass grafting and mitral valve replacement he died of left ventricular heart failure.



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
This retrospective study is the first to examine the morphological progression of CAD by visual and quantitative assessment of serial coronary angiograms in patients with ESRD. In 17 of 26 dialysis patients, baseline angiography revealed coronary artery disease. During a follow-up of 12–60 months, 50% of the patients showed a relevant progression of CAD, and with the additional use of QCA, progression or new lesions were documented in as many as 62%. A considerable percentage of patients progressed to multi-vessel disease that resulted in a large number of patients requiring coronary artery bypass grafting.

Comparison of our data with studies on the progression of coronary atherosclerosis in patients with normal kidney function is to be undertaken with caution because of the bias of patient selection. Most of these studies only include patients with CAD who do not undergo cardiac intervention during a defined interval between the catheterizations. Because of the small patient group we did include patients who were treated by coronary angioplasty (n=10) as well as patients without CAD at baseline angiography (n=9). The interval between the angiographic investigations ranged between 12 and 60 months, with a mean of about 2 years (25±13 months) for patients with initially documented CAD and 42±12 months for patients without CAD at baseline. Nevertheless our results suggest a more rapid progression of CAD in patients with ESRD compared to patients with normal renal function. Using the same definition of progression Vos et al. [10] studied 129 medically treated patients with mild CAD by serial quantitative coronary angiography after 2 and 4 years. Their rate of progression was 30.2% after 2 years and 36.4% after 4 years. Further investigations using QCA reported a rate of progression of 41% after an interval of 2 years in respectively 335 and 299 patients [11,12]. Bruschke et al. [13] observed a progression of CAD by visual assessment in 168 patients including 38 patients initially without CAD. Ten of those patients (26%) developed CAD, whereas 56 (43%) of patients with CAD showed a progression after a mean follow-up of 33±26 months.

In this study, coronary angioplasty was performed in 10 patients, follow-up angiographies were carried out in all patients as a routine procedure in our hospital and were therefore not dependent on clinical symptoms. In six patients, respectively seven of 16 primarily successfully dilated segments (44%) a restenosis was documented. In patients with ESRD an increased risk of procedural complications, an adverse long-term clinical outcome as well as a high rate of angiographic restenosis after balloon angioplasty have been described [15,16]. Compared with age- and sex-matched controls with normal kidney function, we have previously described an increased rate of restenosis (60%) in dialysis patients compared with the controls (35%) [9].

The rapid morphological progression of CAD as well as the increased rate of restenosis after mechanical alterations due to coronary angioplasty indicate an accelerated form of atherosclerosis in patients with ESRD. This was first concluded by Lindner et al. [17] in 1974 and may be attributed to the high number of established cardiovascular risk factors including arterial hypertension in nearly all patients, and a rising number of patients with diabetic nephropathy and lipoprotein abnormalities. Patients with ESRD are characterized by hypertriglyceridaemia and low HDL cholesterol plasma levels [18,19]. Furthermore, elevated concentration of Lp(a) and homocysteine have also been demonstrated in patients with ESRD and were independent predictors of cardiovascular events in this patient group [20,21]. Plasma levels of C-reactive protein, the prototypical acute-phase protein and a predictor of cardiovascular mortality in the general population, is elevated in chronic dialysis patients, and could also be identified as a prominent risk factor for cardiovascular events and mortality in patients on chronic dialysis [22]. High plasma concentrations of the acute-phase reactant fibrinogen suggest a marked procoagulant state in dialysis patients; an imbalance of the concentrations of plasminogen activator inhibitor (PAI-Ag) and tissue plasminogen acivator (tPA-Ag) indicate disturbances of fibrinolytic activity [2325]. It is therefore conceivable that these haemostatic disorders promote coronary thrombosis as a major role in the pathogenesis of acute coronary syndromes and of progression of coronary atherosclerosis.

Clinical implications
The low sensitivity of clinical symptoms and non-invasive diagnostic procedures for the detection of CAD in dialysis patients implies that the threshold for indication of coronary angiography has to be low [6,26,27]. For renal transplant candidates a baseline coronary angiography may be useful for perioperative risk stratification. Furthermore, our results suggest that, depending on the waiting period prior to transplantation, a follow-up angiography may be necessary to identify progression of CAD or even first manifestations of relevant coronary stenoses.



   Notes
 
Correspondence and offprint requests to: Frank Gradaus MD, Klinik für Kardiologie, Pneumologie und Angiologie, Moorenstrasse 5, D-40225 Düsseldorf, Germany. Back



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 22. 7.00
Revision received 24. 1.01.