Renal function is associated with arterial stiffness and predicts outcome in patients with coronary artery disease

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1 Q J Med 2009; 102: doi: /qjmed/hcn171 Advance Access publication 7 January 2009 Renal function is associated with arterial stiffness and predicts outcome in patients with coronary artery disease B. ILYAS 1, N. DHAUN 1, D. MARKIE 1, P. STANSELL 1, J. GODDARD 2, D.E. NEWBY 3 and D.J. WEBB 1 From the 1 Clinical Pharmacology Unit, University of Edinburgh, The Queen s Medical Research Institute, 2 Department of Renal Medicine and 3 Department of Cardiology, Royal Infirmary of Edinburgh, Edinburgh EH16 4TJ, UK Received 30 June 2008 and in revised form 4 November 2008 Summary Background: Arterial stiffness (AS) is associated, and a predictor of, outcome in patients with cardiovascular and renal disease. Aim: In this study, we estimated glomerular filtration rate (egfr) and measured indices of AS in patients with suspected coronary artery disease (CAD), and assessed their predictive value on outcome. Design: Prospective cohort study. Methods: AS was measured using pulse wave velocity (PWV) and pulse wave analysis in patients with no known renal disease who had recently undergone coronary angiography. Renal function was assessed using serum creatinine concentration [creat] sr and egfr (Cockcroft & Gault, C&G). The primary endpoint was a combination of hospitalization due to cardiovascular disease and all-cause mortality. Introduction Cardiovascular disease (CVD) is a common cause of morbidity and mortality in patients with renal disease. 1 Arterial stiffness (AS) contributes to cardiovascular events not only in patients with end-stage renal failure, 2 but also in those with hypertension, 3 and coronary artery disease (CAD). 4 AS is associated with renal dysfunction in patients with known renal disease 5 and in patients with hypertension. 6,7 Furthermore, recent data suggest an association Results: Two hundred eighty-four subjects (210 men, 74 women, mean age 62 years) were followed-up for a mean of 1.5 years. PWV was negatively associated with egfr (r 2 = 0.09, P < 0.001), even in patients with an egfr >60 ml/ min/m 2 (r 2 = 0.04, P < 0.01). PWV was determined by age, heart rate, systolic blood pressure, body mass index and [creat] sr (r 2 = 0.38, P < 0.001). A lower egfr (P < 0.01), PWV above the median (P < 0.05) and degree of CAD (P < 0.001) predicted a shorter time to the primary endpoint. egfr and degree of CAD remained independent determinants of outcomes (P < 0.01), even in patients with normal renal function (P < 0.01). Conclusions: This study suggests that even minor reductions in egfr, within the normal range, are an additional independent risk marker in patients with CAD. between AS and renal function within the normal range in patients with hypertension. 7,8 AS 9 and renal dysfunction 10 are both known to be associated with CAD. Renal dysfunction is also an important predictor of acute myocardial infarction (AMI) and mortality in patients with CAD, 11 in patients undergoing coronary artery bypass grafting (CABG), 12 and in patients with acute coronary syndromes (ACS). 13 Renal dysfunction also predicts Address correspondence to Dr N. Dhaun, The Queen s Medical Research Institute, 3rd Floor East, Room E3.23, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK. bean.dhaun@ed.ac.uk! The Author Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please journals.permissions@oxfordjournals.org

2 184 B. Ilyas et al. post-operative complications following coronary angiography 14 or CABG, 15 but information on the association between renal function, AS and outcome in patients with CAD is limited. Indeed, there are no studies examining the relationship between renal function and AS in patients with CAD and normal or near normal renal function. In a cohort of patients with suspected CAD, and without clinically apparent renal disease, we aimed to determine the relationship between AS and renal function, and to identify predictors of the future risk of cardiovascular morbidity and all-cause mortality. Methods We studied 284 patients who had undergone elective coronary angiography at the Western General Hospital and Royal Infirmary, Edinburgh, between October 2002 and March Exclusion criteria were marked left ventricular impairment (ejection fraction < 25%), significant valvular heart disease, critical aortic stenosis or a history of known renal disease [a pre-existing renal diagnosis, an estimated glomerular filtration rate (egfr) of <60 ml/min/1.73 m 2 or evidence of renal damage as suggested by urinary or structural abnormalities]. Subjects attended for the study 1 week after coronary angiography or at least 3 months after a coronary revascularization procedure [such as percutaneous coronary intervention (PCI) or CABG]. Demographic data, with details of cardiovascular risk factors, were obtained on the day of the study. Hypercholesterolemia was indicated by a previous diagnosis or the use of a cholesterollowering agent. Patients were classified as having diabetes, hypertension, ischemic heart disease (IHD), myocardial infarction or heart failure indicated by a previous clinical diagnosis. All studies were undertaken in accordance with the Declaration of Helsinki (1989) of the World Medical Association. The study protocols were approved by the local research ethics committee and written informed consent obtained from each participant before each study. Outcomes The primary pre-defined outcome of the study was a combination of hospitalization due to a cardiovascular event and all-cause mortality. Follow-up time was calculated as the time between the first study visit and the date of the first cardiovascular event, death or the date of last follow-up for censored subjects. Cardiovascular events were defined as non-fatal AMI, non-fatal stroke, emergency hospitalization for unstable angina or transient ischemic attack, or coronary revascularization. Hospitalization follow-up data were obtained from the Scottish Morbidity Record for all inpatient and daycase discharges (SMR 01). 16 Individual diagnoses were classified according to the 10th revision of the International Classification of Disease (ICD- 10) codes. Operations were coded based on the Office for Populations Census and Surveys Version 4 (OPCS4) codes for the classification of surgical operations and procedures. Revascularization procedures more than 6 months after study participation were included in the analysis, while revascularization procedures within 6 months were presumed to be planned elective procedures. Deaths were confirmed by certificates from the General Register Office, Scotland, and all other subjects were considered to be alive at the end of the follow-up period. Fasting venous blood was obtained on the day of the study and routine clinical biochemistry analyses were performed by the regional clinical reference laboratories using the Vitros Õ 950 Chemistry Products system (Ortho-Clinical Diagnostics Inc., Rochester, New York). Low-density lipoprotein cholesterol (LDL-C) concentration was calculated using the Friedewald equation. 17 Renal function was measured using [creat] sr and GFR estimated on the basis of the creatinine clearance obtained using the C&G equation 18 (egfr) corrected for body surface area. 19 C&G was chosen in preference to GFR estimation using the Modification of Diet in Renal Disease (MDRD) equation because GFR based on C&G is more accurate at higher levels of renal function. 20 Subjects were also divided into three groups according to egfr (>90, and <60 ml/ min/m 2 ). Subjects were studied following an overnight fast and abstained from alcohol for 24 h, and tobacco and caffeine-containing drinks for 12 h before the study. Subjects were asked to omit their morning medications on the day of the study. Subjects rested for 20 min following which baseline blood pressure (BP) and heart rate (HR) measurements were made. Non-invasive BP measurements were carried out on the right arm using a validated oscillometric technique (HEM-705CP, Omron Corporation, Japan). 21 Next, pulse wave velocity (PWV) and pulse wave analysis (PWA) recordings were made sequentially at 5-min intervals with a BP recording before each measurement. Carotid-femoral PWV, the gold standard for measurement of AS in older subjects, 22 was measured using the SphygmoCor Õ system (SphygmoCor Õ Mx, AtCor Medical, Sydney, Australia, version 6.31), in which a high-fidelity micromanometer (SPC-301, Millar Instruments, TX, USA) was used to determine carotid-femoral PWV.

3 Renal function and arterial stiffness in coronary artery disease 185 PWA was assessed using a probe containing piezoelectric pressure sensors (Colin Õ 7000, Colin Medical Technology Corporation, Japan). PWA was used to derive the central aortic pressure waveforms from the radial pressure waveforms. The central aortic pressure waveform was then used to calculate the central augmentation index (AIx%) and AIx corrected to a HR of 75 beats per minute (AIx75%). 23 Statistical analyses Statistical analyses were performed using Microsoft Excel 2002 and SPSS version 11.5 for Windows program (SPSS, Inc., Chicago, IL, USA). The bivariate associations between variables were examined using Pearson s correlation coefficients. All parametric data were analysed using Student s t-test, ANOVA and ANCOVA where appropriate. The Bonferroni correction was used for all post hoc comparisons. Stepwise multiple linear regression analyses were used to determine which variables were independently associated with pulse wave form measures. Univariate analysis of time to a composite end-point against both demographic and biochemical parameters were assessed. Variables that were found to correlate in univariate analysis were further analysed in multivariate analysis (stepwise linear regression analysis) to determine the interaction of other variables. The multivariate model included conventional risk factors and factors such as CAD burden, PWV and egfr. Cumulative survival and event-free probabilities were determined using the Kaplan Meier product-limit method and compared by the Mantel (log-rank) test. Data are expressed as mean SD, and statistical significance was taken at the 5% level. Results The baseline characteristics of the 284 study participants are given in Table 1. The sample comprised 210 men and 74 women with a mean age of 62 8 years. Thirty-five (12%) of subjects had angiographically normal coronary arteries; 71 (25%), 1-vessel disease; 94 (33%), 2-vessel disease; 84 (30%), 3-vessel disease. Augmentation indices were available in 284 subjects whereas satisfactory PWV recordings were available in only 245 subjects, and [creat] sr in 282 subjects. Subjects with and without CAD had similar demographics (Table 1), except those with CAD had a lower mean HDL-C concentration but no differences in the other lipid measures. There were no differences in [creat] sr or egfr between varying degrees of severity of CAD (data not shown). There were also no differences in PWV, and no consistent relationships between augmentation measures, and severity of CAD. In univariate analysis, PWV and AIx increased with age (r 2 = 0.47, P < 0.01; r 2 = 0.12, P < 0.05, respectively). Women had higher augmentation indices (AIx, 39 9 vs. 33 9, P < and, AIx75, 32 8 vs. 24 8, P < 0.001) than men. No difference in PWV was found between men and women. Body mass index (BMI) correlated positively with PWV but negatively with AIx and AIx75. HR correlated positively with PWV (r 2 = 0.20, P < 0.01), and inversely with AIx (r 2 = 0.39, P < 0.001). Subjects with higher systolic and mean BPs had higher PWV, AIx and AIx75 measures. In addition, subjects with high PWV or AIx75 measures had high diastolic BPs. In respect of renal function, PWV correlated inversely with egfr and positively with [creat] sr (Figure 1). The inverse association between PWV and egfr (r 2 = 0.04, P < 0.01) persisted in subjects with renal function within the normal range (egfr >60 ml/min/m 2 ). When subjects were grouped according to egfr tertiles, those with a lower egfr had a higher PWV (Figure 2). However, augmentation indices did not correlate similarly. In multivariate analysis, PWV correlated positively with age, HR, central systolic BP, BMI and [creat] sr. Together, these variables explained 38% of the variance in PWV (Table 2). Again, augmentation indices were not associated with BP or [creat] sr. There was no association between use of cardiovascular drugs, or presence or absence of the metabolic syndrome and AS measures. Outcomes Follow-up was carried out in 284 subjects and was for a mean of 1.5 years. There were six deaths, three of which were due to a cardiovascular cause and the others were due to cancer. There were 103 admissions related to cardiovascular events: non-fatal AMI (3), non-fatal stroke (1), emergency hospitalization for unstable angina (73) or transient ischemic attack (6), or coronary revascularization (16). Sex, smoking status, BP, serum lipid concentrations were not associated with cardiovascular morbidity or all-cause mortality. Subjects who had an event were older, had a lower egfr and a higher PWV compared with subjects who did not have an event (Table 3). Subjects with IHD had a shorter time to the primary endpoint compared with those without IHD (P < 0.001). Moreover, subjects

4 186 B. Ilyas et al. Table 1 Baseline subject demographics and clinical measures No CAD a (N = 35) CAD (N = 249) Total (N = 284) Age, year (range 41 80) Men/Women 15/20 195/54 210/74 Height (cm) Weight (kg) Body mass index (kg/m 2 ) SBP DBP MBP HR, b.p.m. (40 89) Serum creatinine, mmol/l (52 165) egfr, ml/min/m 2 ( ) Total cholesterol (mmol/l) HDL cholesterol (mmol/l) y LDL cholesterol (mmol/l) Triglycerides (mmol/l) Chol:HDL ratio PWV m/s AIx% AIx75% Current smokers 5 (14) 38 (15) 43 (15) Hypercholesterolaemia 27 (77) 204 (82) 231 (81) Diabetes 1 (3) 30 (12) 31 (11) Hypertension 17 (49) 139 (56) 156 (55) Myocardial infarct 17 (6) 37 (91) 34 (97) Heart failure 0 12 (5) 12 (4) Stroke 3 (8) 14 (6) 97 (34) Diuretics 9 (26) 54 (22) 63 (22) b-blocker 14 (40) 175 (70) 189 (67) Nitrates 14 (40) 184 (73) 198 (70) ACE inhibitors 6 (17) 96 (39) 102 (36) Calcium channel blockers 14 (40) 70 (28) 84 (30) Angiotensin receptor blockers 2 (6) 11 (4) 13 (5) Nicorandil 1 (3) 48 (19) 49 (17) Statin 21 (60) 227 (91) 248 (87) Values are mean SD and number of total subjects in each group (%). P < 0.05, P < 0.01, y P < vs. no CAD. SBP: systolic blood pressure; DBP: diastolic blood pressure; MBP: mean blood pressure; HR: heart rate; egfr: estimated glomerular filtration rate; HDL: high density lipoprotein; LDL: low density lipoprotein; ACE: angiotensin converting enzyme a As indicated by coronary angiography with a higher number of affected coronary vessels had a shorter time to an event (Figure 3B, P < 0.001). Subjects who suffered an event had a higher [creat] sr ( vs mmol/l; P < 0.01) and a lower egfr (69 16 vs ml/min; P < 0.001). Degree of CAD and egfr were related (r 2 = 0.074, P < 0.001), and in multivariate analysis both independently determined a shorter time to the primary endpoint (P < 0.01 for both). This association between CAD severity and egfr remained true in subjects with renal function within the normal range (egfr >60 ml/min/m 2, r 2 = 0.064, P < 0.01), as did their predictive values on outcomes (P < 0.01 for both). When subjects were divided into egfr tertiles, those with a lower egfr had a shorter time to the primary endpoint (P < 0.01) (Figure 3A). Subjects in egfr groups 2 and 3 (egfr and ml/ min/m 2, respectively) were older and had higher peripheral and central systolic BP compared with egfr group 1 (>90 ml/min/m 2 ) (Table 4). However, there was an approximately even distribution of severity of CAD across the three groups. A higher percentage of subjects in egfr group 3 (30 59 ml/ min/m 2 ) were on ACE inhibitors with a roughly even

5 Renal function and arterial stiffness in coronary artery disease 187 (a) * * PWV (m/s) [creat] sr (µmol/l) PWV (m/s) (b) PWV (m/s) egfr group Figure 2. PWV for subjects grouped according to tertiles of egfr. Group 1: egfr >90 ml/min/m 2, group 2: egfr ml/min/m 2, group 3: egfr ml/min/m 2. Values are mean SD. P < distribution between groups of other drug classes. Subjects who suffered an event had a higher PWV ( vs m/s; P < 0.05) than those without an event. Subjects with a PWV above the median had a shorter time to an event compared to those with a PWV below the median (P < 0.05) (Figure 4). There was a similar distribution of CAD severity between the two PWV groups. Renal function and PWV were independent determinants of outcome. Discussion In this study, we have investigated the effects on cardiovascular morbidity and all-cause mortality of AS and renal function in patients with CAD but no evidence of chronic kidney disease (CKD). Our main findings are that a higher PWV is associated with a lower level of renal function, even within the 80 egfr (ml/min/m 2 ) Figure 1. Scatterplots of PWV vs (A) serum creatinine concentration [creat] sr (r 2 = 0.05, P < 0.001) and (B) estimated glomerular filtration rate (egfr) (r 2 = 0.09, P < 0.001) for all subjects (n = 242 for both). Table 2 Multiple regression analysis for PWV (m/s, r 2 = 0.380, P < 0.001) PWV Regression coefficients Standard error Age, (years) 0.12y 0.02 Heart rate (b.p.m.) 0.07y 0.01 Central systolic blood 0.03y 0.01 pressure (mmhg) Body mass index (kg/m 2 ) Serum creatinine concentration (mol/l) P < 0.05, P < 0.01, y P < Table 3 Variables for subjects with and without the primary endpoint No events (n = 181) Events (103) Age BMI egfr y Central SBP Central DBP Central MBP PWV P < 0.05, P < 0.01, y P < vs. no events.

6 188 B. Ilyas et al. (a) (b) Cumulative event free probability Cumulative event free probability Duration of follow-up (days) Duration of follow-up (days) egfr 90 ml/min/m egfr ml/min/m 2 egfr ml/min/m 2 No vessel disease 1-vessel disease 2-vessel disease 3-vessel disease Figure 3. Kaplan Meier plots of time to the primary endpoint for all subjects grouped by (A) estimated glomerular filtration rate (egfr) and (B) extent of coronary artery disease. normal reference range, when measured by [creat] sr and egfr. Furthermore, an increasing severity of CAD, a lower egfr and a higher PWV are independently associated with a shorter time to the primary endpoint. Importantly, egfr remained an independent predictor of outcome even within the normal reference range. There may be a number of explanations for the association between AS and renal function. Increased AS may be a cause or an effect of reduced renal function. Increased AS leads to an increase in systolic BP resulting in a high pulse pressure. The high pressure waves generated may cause injury to the renal vasculature and thus result in a lowering of GFR. 24,25 Conversely, impaired renal function may lead to stiffening of the large arteries 26,27 through a number of mechanisms including accumulation of advanced glycosylation end products, increased collagen cross-linking, and activation of the renin angiotensin system. 28 Our data show an association between PWV and egfr but not AIx and egfr. This likely reflects the fact that PWV is a more reliable and gold standard measure of AS than AIx. 29 The majority of subjects in this study had normal Table 4 Demographic variables and blood pressures between estimated glomerular filtration groups Group 1 egfr >90 ml/min/m 2 (n = 41) Group 2 egfr ml/min/m 2 (n = 180) Group 3 egfr ml/min/m 2 (n = 54) Age (years) 52 8 a,b 62 8 a 69 5 b Peripheral SBP (mmhg) a,b Peripheral DBP (mmhg) 72 8 b Peripheral MBP (mmhg) 91 9 b Central SBP (mmhg) a,b Central DBP (mmhg) Central MBP (mmhg) 91 9 b Numbers of diseased coronary vessels 0 5 (12) 25 (14) 3 (6) 1 12 (29) 4 (25) 13 (24) 2 12 (29) 57 (31) 24 (44) 3 12 (29) 55 (30) 14 (26) Drug therapy b-blocker 23 (56) 129 (71) 31 (57) Nitrate 32 (78) 128 (70) 34 (63) Statin 36 (88) 159 (87) 47 (87) ACE inhibitor 12 (29) 64 (35) 24 (44) Angiotensin receptor blocker 1 (2) 10 (6) 2 (4) Calcium channel blocker 1 (39) 46 (25) 19 (35) Nicorandil 7 (17) 29 (16) 10 (19) Diuretics 7 (17) 41 (23) 13 (24) Values are mean SD and number of total subjects in each group (%). a Denotes a significant difference to egfr ml/min/m 2 group. b A significant difference to egfr ml/min/m 2 group. SBP: systolic blood pressure; DBP: diastolic blood pressure; MBP: mean blood pressure; ACE: angiotensin converting enzyme.

7 Renal function and arterial stiffness in coronary artery disease 189 Cumulative event free probability PWV >9.13m/s PWV >9.13m/s Duration of follow-up (days) 1000 Figure 4. Kaplan Meier plots of time to the primary endpoint for subjects grouped according to PWV above and below the median. [creat] sr. However, this is a relatively insensitive measure of renal function. C&G egfr is a better measure as it takes into account the age, gender and weight of individual subjects. Using this, the majority of patients (221/276) still had egfrs of >60 ml/min/m 2 which, in the absence of structural or urinary abnormalities, is regarded as normal renal function. 30 Thus, these data suggest that the increase in AS observed as renal function declines, begins early in the trajectory of renal dysfunction in patients with CAD. Our data show a positive association between the presence and severity of CAD and adverse outcomes, in keeping with previous findings. 31,32 A novel and important finding of our study is that in patients with CAD, a lower egfr was predictive of a shorter time to the primary endpoint. Furthermore, this remained true even in those subjects who had an egfr within the normal reference range. This continuous interaction between GFR and cardiovascular outcomes has previously been shown in patients following AMI. 33 The current data suggest the importance of surrogate measures of renal function as potential prognostic indicators in patients with CAD in the absence of known renal disease. The fact that there was a fairly equal distribution of subjects according to severity of CAD and use of CVD drugs across the egfr tertiles reinforces the observation that egfr is potentially an additional measure of risk in these subjects. Our findings extend two previous studies carried out in patients with CAD. 11,34 In the first, egfr was found to be a predictor of death, AMI or a composite of both. This association was most apparent in those subjects with poorest renal function (mean GFR 41 ml/min). 11 Furthermore, this study comprised of patients who had stable or unstable angina as well as subjects who had suffered AMI. As renal dysfunction is a recognized long-term predictor of mortality in patients after AMI, this may affect interpretation of the data although the association remained when AMI was removed as an endpoint. 35,36 The present study has built on these findings by assessing the association between normal renal function and cardiovascular morbidity and all-cause mortality in subjects with predominantly stable CAD. The second study in CAD patients, by van Domburg and colleagues. 34 is supportive of our outcome data. However, the authors included subjects with a diagnosis of CAD based on history alone and many subjects had not undergone coronary angiography. In the current study, a diagnosis of CAD was based on the gold standard of coronary angiography. Furthermore, estimation of GFR in both these studies was based on the MDRD equation. This was developed for patients with moderate to severe renal dysfunction and performs less well at the higher levels of renal function 20 seen in some of the cohorts incorporated into both of these studies. Study limitations We recognize a number of limitations to our study. First, GFR estimated by the C&G equation may not be the most accurate measure of actual GFR. However, it correlates strongly with measured GFR 20 and was chosen in preference to GFR estimation using the MDRD equation because of the higher levels of renal function expected in this study. Second, the pre-specified censor date for the data did not allow the number of deaths, AMIs and strokes to be assessed as separate endpoints and we recognize that the small number of these events in our study limit data interpretation. However, we feel that the use of a composite measure of cardiovascular morbidity and all-cause mortality represents the most appropriate measure of cardiovascular outcome. Conclusions Our data suggest that even minor reductions in egfr, within the normal reference range, are an additional independent risk marker in patients with CAD but no known renal disease. Funding This work was supported by the British Heart Foundation (PG/2001/128) and was carried out in

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