Carotid-femoral pulse wave velocity (cfpwv), a measure

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1 Blood Vessels Dissociation of Aortic Pulse Wave Velocity With Risk Factors for Cardiovascular Disease Other Than Hypertension A Systematic Review Marina Cecelja, Philip Chowienczyk Downloaded from by guest on May 8, 2018 Abstract Carotid-femoral pulse wave velocity (cfpwv), a measure of large artery stiffness, is an important predictor of cardiovascular events. This has been attributed to it being an integrative measure of the impact of cardiovascular risk factors on the arterial wall. Pulse wave velocity is strongly associated with age and blood pressure. However, findings with regard to its relation with other risk factors have been inconsistent. We performed a systematic review of cross-sectional published literature reporting independent associations of cfpwv in multivariable regression models. Articles were selected from a PubMed search using a prespecified search strategy. Studies were included if they did the following: (1) measured cfpwv; (2) reported on associations with cfpwv from regression models; and (3) considered age and blood pressure in the model. From 637 retrieved articles, 65 met our inclusion criteria, and 12 studies were included from reference searches. Age and blood pressure were consistently independently associated with cfpwv (91% and 90% of studies, respectively). Diabetes mellitus was associated with cfpwv in 52% studies, but the strength of the association was low. The majority of studies found no independent association between cfpwv and sex, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, smoking, or body mass index. The contribution of risk factors other than age and blood pressure to cfpwv is, thus, small or insignificant. The prognostic value of cfpwv may relate to a process of arterial ageing unrelated to classic risk factors other than hypertension. (Hypertension. 2009;54: ) Key Words: pulse wave velocity aortic stiffness risk factors atherosclerosis arteriosclerosis Carotid-femoral pulse wave velocity (cfpwv), a measure of the intrinsic stiffness of the aortic wall, is highly predictive of cardiovascular events. 1 8 The prognostic importance of cfpwv has been attributed to it being an integrated measure of the impact of cardiovascular risk factors on the arterial wall 9 and to adverse hemodynamic effects of aortic stiffening. 10 The later include an increase in systolic blood pressure and pulse pressure with increased systolic load and decreased myocardial perfusion pressure That cfpwv is closely associated with age and blood pressure is well established. Previous studies have also reported associations between cfpwv and blood pressure independent risk factors, including dyslipidemia, 14 smoking, 15 obesity, 16 sex, 17 heart rate, 18,19 and diabetes mellitus 20 (see review by Benetos et al 9 ). However, findings with respect to risk factors other than age and blood pressure have been inconsistent, and negative findings were not highlighted in many studies. 21,22 The purpose of the present study was, thus, to perform a systematic review of published cross-sectional studies to examine the independent association of cfpwv with cardiovascular risk factors. We included only studies in which cfpwv was used as a measure of arterial stiffness, because there is considerable variability in agreement between other measures of stiffness 23 and a lack of outcome data for measures other than cfpwv. 1 8 cfpwv is, moreover, simple and relatively inexpensive to measure noninvasively with high reproducibility using currently available commercial equipment. 24,25 Methods Search Strategy Studies, published up to December 2008, were searched using 2 strategies: a PubMed search and a manual search of citation lists of relevant publications. In PubMed, key words for the search were PWV, or pulse wave velocity, or arterial stiffness, or aortic stiffness, and these were combined, in turn, with determin* or predict*. Selection Criteria The list of titles and abstracts was initially screened for relevancy. Articles were rejected if they were as follows: (1) did not measure central PWV (between carotid and femoral arteries); (2) included Received June 13, 2009; first decision July 2, 2009; revision accepted October 6, From the King s College London British Heart Foundation Centre, Cardiovascular Division, Department of Clinical Pharmacology, St. Thomas Hospital, London, United Kingdom. Correspondence to Philip Chowienczyk, Department of Clinical Pharmacology, St. Thomas Hospital, Lambeth Palace Rd, London SE1 7EH, UK. phil.chowienczyk@kcl.ac.uk 2009 American Heart Association, Inc. Hypertension is available at DOI: /HYPERTENSIONAHA

2 Cecelja and Chowienczyk Cardiovascular Risk Factors and Aortic Stiffness 1329 Downloaded from by guest on May 8, 2018 children; (3) were animal studies; (4) were in vitro or model-based studies; or (5) were review articles. Relevant articles were then checked in full to confirm eligibility and extract data. Studies were included if they fulfilled the following criteria: (1) involved performance of multivariable regression models for potential associates of cfpwv; (2) involved inclusion of age and blood pressure in the regression model; and (3) had sufficient detail of variables entered into the regression model and outcomes. Any blood pressure measure (ie, systolic, mean, or diastolic) or combination of measures was accepted. There were no restrictions on sample size or inclusion of mixed populations (but, where separate values were given for different groups, these were included). Articles by the same authors or groups were excluded unless it was clear that different populations were used. Studies were restricted to the English language. Additional studies were identified by a manual search of references from relevant publications. Data Extraction Data extraction was standardized by use of a single form, which included publication date and author, sample size (number and percentage of men), age, method of cfpwv measurement, mean cfpwv, blood pressure, variables included in multivariable regression analysis, outcomes, and R 2 values. When a variable was not included in a regression model because it was not significantly associated with cfpwv on univariate analysis, it was regarded as having no independent association with cfpwv. Results The initial search identified 2275 potential articles. Of these, 1638 were excluded on initial screen of title and abstract. The remaining 637 were retrieved in full, and a further 572 were excluded because of ineligibility or overlapping subject cohorts from a previous publication (see Figure S1 in the online Data Supplement, available at org). A further 12 studies were identified and included in the review from a reference search, giving a total of 77 included publications. Thirteen of these reported on 2 separate groups, giving 97 subject groups in total (including a total of subjects; see online Supplemental Data for further details). Independent Predictors of PWV Age and blood pressure were significantly independently associated with cfpwv in 91% and 90% of studies, respectively. The majority of studies used only systolic blood pressure (n 43; 44%) or mean arterial pressure (n 30; 31%) as the measure of blood pressure, and only 4 (4%) used a combination of these blood pressure measures. The Figure shows the number of studies in which heart rate and other risk factors were included and the proportion of these in which the risk factor was significantly associated with cfpwv. A total of 51 studies evaluated the predictive value of heart rate, of which 26 (51%) found a significant association. The presence of diabetes mellitus and sex was associated with cfpwv in 12 (52%) of 23 and 15 (27%) of 54 studies, respectively. Smoking and body mass index were associated with cfpwv in 6 (14%) of 44 and 7 (13%) of 53 studies, respectively. Inclusion of measures of cholesterol differed: total cholesterol was considered in 41 studies, of which only 2 (5%) found a significant association. Low-density lipoprotein cholesterol and high-density lipoprotein cholesterol were significantly associated in only 1 (5%) of 21 and 4 (11%) of 37 studies, respectively. Only 1 (3%) of 38 reported a significant A No. of studies variable included in regression model B No. of studies variable included in regression model BMI Smoking Sex TG HDL LDL TC DM HR BP Age BMI Smoking Sex TG HDL LDL TC DM HR BP Age No. of studies variable significant in regression model association with triglyceride levels. When only studies including healthy, hypertensive, or population cohorts were considered, associations were similar (Figure). Studies excluded (n 66; including a total of subjects) because of possible replication in the same population or not fully reporting outcomes of regression models are described in the online Data Supplement. Coefficient of Variation (R 2 ) Values Twenty-three studies reported individual R 2 values, representing the amount of variability in cfpwv accounted for by correlates of cfpwv (see Figure S2). Age accounted for 2.0% to 53.0% (mean: 23.5%) and blood pressure 1.8% to 41.0% (mean: 13.8%) of variance in cfpwv. R 2 values for all of the other variables reported were much lower, with heart rate only accounting for 0.6 to 3.4%, sex accounting for 1.0% to 13.0%, diabetes mellitus accounting for 1.0% to 8.0%, and smoking accounting for 0.3 to 2.2%. R 2 values for body mass No. of studies variable significant in regression model Figure. The number of studies in which classic risk factors and heart rate were included (bars) and the proportion of these (solid line) in which the risk factor was significantly independently associated with PWV. A, All studies. B, Studies including only healthy, hypertensive, or population cohorts. BP indicates blood pressure; HR, heart rate; DM, diabetes mellitus; TC, total cholesterol; LDL, low-density lipoprotein cholesterol; HDL, highdensity lipoprotein cholesterol; TG, triglycerides; BMI, body mass index.

3 1330 Hypertension December 2009 Downloaded from by guest on May 8, 2018 index and total cholesterol were reported in only 1 study and accounted for only 1.4% and 1.0%, respectively, of variance in cfpwv. Other variables accounting for 5% of cfpwv variance in individual studies included angiotensin II type 1 receptor gene polymorphism (A1166C; R ), 26 although in a separate study a more modest contribution was noted (R ) 27 ;as well as C-reactive protein (R ) 28 ; forced expiratory volume in 1 second (R ) 29 ; HIV status (R ) 30 ; respiratory disturbance index (R ) 31 ; C3 (complement component; R ) 32 ; carotid plaque (R ) 32 ; family history of cardiovascular disease (R ) 32 ; and target organ damage (R ). 32 Several single nucleotide polymorphisms other than A1166C were associated with cfpwv but accounted for 5% of the variance in PWV, including angiotensin-converting enzyme insertion/deletion polymorphism (R ) 26 and matrix metalloproteinase 9 polymorphisms C-1562T (R ) and R279Q (R ). 33 A number of other factors correlated with cfpwv but accounted for 5% of the variance in cfpwv (Table). Discussion As far as we are aware, this is the first systematic review to examine the association of cfpwv with risk factors for atherosclerosis. We included only studies that performed a multiple regression analysis to identify associations independent of age and blood pressure. The systematic nature of the review avoided bias in study selection. Our findings confirm the well-established association of cfpwv with age and blood pressure. 34,35 Only a few studies failed to show such associations, and this could be explained by their relatively small sample size and/or relatively narrow spread of age/ blood pressure. A relatively high proportion of studies also reported an independent association between PWV and heart rate, although the strength of the association was weak. These findings are consistent with studies in which heart rate has been manipulated by pacing, 18,19,36 38 although it should be noted that others have found no effect. 39,40 Heart rate may be a confounding factor that should be incorporated into any analysis relating to cfpwv. Fifty-two percent of studies in which diabetes mellitus was included as a risk factor reported a positive association of cfpwv with the presence of diabetes mellitus. However, even within the studies in which a positive association with diabetes mellitus was seen, the strength of the association between cfpwv and diabetes mellitus was weak, with the presence of diabetes mellitus accounting for a mean of 5% of the variation in cfpwv. One possibility to explain the variable association of cfpwv with diabetes mellitus is that it is sex dependent, with a stronger association in women than in men. 41 The major finding of the present review is that, with the exception of age and hypertension, cfpwv is largely independent of classic risk factors for atherosclerosis, with the vast majority of studies showing no association with sex, smoking, and lipids. The association with diabetes mellitus, although positive in a higher proportion studies, is, as discussed above, weak. These results are mainly in agreement with prospective studies, where risk factors other than hypertension are not associated with the progression of cfpwv. 16,42 In the case of cholesterol, it is interesting to note that trials of statin therapy have shown both positive 43 and negative effects on cfpwv, with 1 study showing a significant increase in cfpwv after treatment. 44 Lack of association of cfpwv with sex, smoking, and lipids, all powerful risk factors for atherosclerosis, is somewhat puzzling in view of the reported association of cfpwv with atherosclerotic plaque However, this could be explained by a lack of effect of risk factors, per se, and early stages of atherosclerosis on stiffness of the arterial wall, but advanced plaque, particularly calcified plaque, increasing stiffness. 47 Indeed, this is supported by animal studies, where PWV appears to decrease during early stages of cholesterol-rich diets and increase as atherosclerotic plaques develop in cynomolgus monkeys. 49 It is possible that, in subjects with advanced plaque, where plaque volume might relate to risk factors, the relationship of PWV to risk factors may differ. 50 The dissociation of cfpwv with classic risk factors other than blood pressure for atherosclerosis and cardiovascular events in the majority of studies in this review suggests that, at least in its early stages, aortic stiffening is not driven by an atherosclerotic process but by an alternative pathology in which blood pressure is one of the most important factors. It is well recognized that arterial stiffness depends on mechanical stretch of the arterial wall and, hence, on blood pressure at the time of the measurement. 51 Stretch is thought to transfer loading to stiffer elements within the wall that are of greater tensile strength (eg, from elastin to collagen) and, hence, result in an overall stiffening of the wall. It is difficult to separate effects of a sustained elevation of blood pressure (ie, hypertension) from the level of blood pressure at the time of study. It is possible that hypertension results in structural alterations within the wall, possibly by accelerating agerelated changes, such as decreased elastin content, increased collagen content, change in type of collagen, and collagen cross-links from advanced glycation end products. 52,53 That an acute reduction of blood pressure does not normalize elevated cfpwv in hypertension 54 supports this hypothesis. However, other studies using mathematical techniques to compare hypertensive and controls groups at a common pressure do not show a difference in isobaric PWV between hypertensive and normotensive groups. 55,56 Similarly, other studies have demonstrated no difference in PWV between hypertensive and normotensive groups when blood pressure is adjusted pharmacologically at the time of the study. 57 The present review cannot determine whether cfpwv is associated with hypertension or merely the blood pressure at the time of study. However, given the predictive power of cfpwv for cardiovascular events over and above conventional measures of blood pressure (including ambulatory blood pressure), 8 it is important to identify factors responsible for increased stiffening. It is possible that cfpwv relates more closely to the duration of hypertension and its severity (ie, integration of blood pressure over time) that is not captured by a simple measure of chronological age and blood pressure at the time of study. In this regard, cfpwv could be a better measure of blood pressure than the conventional office measurement. Alternatively or additionally, there may

4 Cecelja and Chowienczyk Cardiovascular Risk Factors and Aortic Stiffness 1331 Table. Characteristics of Studies Included in Systematic Review Reference s Sample, n Men, % Age, y PWV, Method PWV, m/s BP, mm Hg R 2 Variable Significantly Associated With PWV Age BP HR TC LDL HDL TG Sex DM Smoking BMI Other Significant Variables Taquet et al 1993 S1 Healthy, n /82 31 NSu NSu NSu NSu Leucocyte count, family history of DM Asmar et al NT, c NS NS... NS NS S2 HT, c NS NS... NS NS... Tanokuchi et al 1995 S3 T2DM, h /82... *... NS... NS NS NS... NS... Downloaded from by guest on May 8, 2018 Chinese Dart et al u : 6.6; NS NS Migrant status 1995 S4 migrants, 83 : 6.1 Benetos et al 1996 S5 Untreated HT, n /95 37 * NS ACE (I/D) and AGTR1 (A1166C) polymorphism Healthy, n /76 22 * NS Lehmann et PVD, 110, and u / NS NS NS NS NS Previous MI al 1998 S6 controls, 51 Ferreira et Healthy, c /85... NSu NSu NS al 1999 S7 Taniwaki et DM, h 9 138/76 33 NS... NS... NS NS Duration of DM al 1999 S8 Healthy, h /74 41 NS... NS NS NS Sytton-Tyrell et al 2001 S9 Population, u NS Hemoglobin A1c, HT, visceral fat Selzer et al 2001 S10 Premenopausal SLE, u /74 26 NS NS Carotid plaque, C3, hydroxychloroquine use Postmenopausal SLE, u / NS Family history of CVD glucose, creatinine, WBC organ damage score Havlik et al Healthy u /79 22 NS NS NS... NS 2001 S11 sedentary, 530 Amar et al Healthy, c /79 27 NS NS NSu NS... NSu NS 2001 S12 Treated HT, DM, c / NS Apolipoprotein B HC, 247 Asmar et al HT, c / NS Creatinine, glucose 2001 S13 Boutouyrie HT, c /92... NS NS NS... HC et al 2002 S14 Benetos et Treated HT, n /88... NS... NS NS... al 2002 S15 NT, n / NS... NS NS Lebrun et al Postmenopausal 0 66 s / NS 2002 S16, 385 Achimastos et al HT, c /97 43 NS... NS NS NS... Country (Greek vs French) 2002 S17 Lantelme et HT, c/n /92... NS NS NS... NS... HT treatment, glucose al 2002 S18 Mackey et Men, u /73 32 NS al 2002 S19 Women, u /70 21 NS NS Waist circumference, HT treatment Oren et al Young adults, s 6 125/ NS NS 2003 S Nurnberger et al Healthy, n /73... NS Left ventricular ejection time 2003 S21 Blacher et al ESRD, u NS NS... NS NS NS Heart period 2003 S22 Healthy, u NS NS... NS NS NS Heart period Stompór et al 2003 S23 ESRD, u / Basic fibroblast growth factor Kimoto et al T2DM, 161 and n / NS NS... NS NS S24 controls, 129 Mitchell et al 2004 S25 Healthy, n / NS NS Walk test (Continued)

5 1332 Hypertension December 2009 Table. Continued Downloaded from by guest on May 8, 2018 Reference s Sample, n Men, % Age, y PWV, Method PWV, m/s BP, mm Hg R 2 Variable Significantly Associated With PWV Age BP HR TC LDL HDL TG Sex DM Smoking BMI Other Significant Gardier et al 2004 S26 HT, c / NS NS AGTR1 (A1166C) polymorphism Bahous et al Kidney c / Acute rejection 2004 S27 transplant, 106 Lacy et al DM and s /79 73 * NS NS NS NS... Previous CVD 2004 S28 controls, 132 Hansen et al Healthy, n / NS NS NS ll NS NS NS Log insulin 2004 S29 Booth et al Vasculitis and s NS NS NS LogCRP 2004 S30 controls, 63 Silva et al NT 132, c / NSu NSu NS Waist circumference 2004 S31 White-coat NT, c / NSu NSu NSu 39 White-coat HT, c / NSu NSu NS Waist circumference 87 Untreated HT, c / NSu NSu NSu 154 Treated HT, c / NSu NSu NSu DM, c / NSu NSu NSu Pirro et al 2004 S32 Untreated HC, s /78... NS NS NS NS NS NS NS NS NS Waist circumference CRP Shinohara et ESRD, h / NS... NS... NS NS Hemodialysis, HOMA-IR al 2004 S33 McEniery et Young adults, s / al 2005 S Mahmud et Untreated HT, n /92 57 NS... NS NS... NS... NS NS Adiponectin al 2005 S35 76 Kullo et al Community, s /73 41 NS NS NS NS NS 2005 S36 Filipovski et Population, s 7.8; 128/82; 14 NS NS... NS NS Glucose al 2005 S /78 Smith et al 2005 S38 T2DM, s / Duration of DM, HT drugs, ACEI/ARB use Wang et al CKD, s /78... NS NSu NS NSu NS GFR 2005 S39 Briet et al CKD, 95; CKD / GFR 2006 S40 and HT 121; HT, 57 Mäki-Petäjä Rheumatoid s /82 71 NS NS NS NS CRP et al 2006 S41 arthritis, 77 Schillaci et Untreated HT, s /95 34 NS NS NS... NS NS GFR al 2006 S Yasmin et al 2006 S43 Population, s /79 57 NS NS NS MMP-9 (C-1562T and R279Q) polymorphism McEniery et al 2006 S44 Healthy, s /72 81 NS NS NS NS NS NS Endothelial function, glucose Bonapace et Dilated u /81... NSu NS NSu... Type III collagen al 2006 S45 cardiomyopathy, 89 van Trijp et Healthy, s / NS NS... al 2006 S46 Alecu et al Population, p / NS 2006 S47 Paini et al NT, c / NS NS 2006 S48 HT, c / NS T2DM, c / NS... NS Otsuki et al Athletes, 22 and n /65 61 NS NS NS NS NS Endothelin S49 controls, 12 Perkins et al 2006 S50 Healthy, c /81 31 NS NS Variables (Continued)

6 Cecelja and Chowienczyk Cardiovascular Risk Factors and Aortic Stiffness 1333 Table. Continued Downloaded from by guest on May 8, 2018 Reference s Sample, n Kimoto et al T2DM with and 2006 S51 without CKD, 434; and controls, 192 Variable Significantly Associated With PWV Men, % Age, y PWV, Method PWV, m/s BP, mm Hg R 2 Age BP HR TC LDL HDL TG Sex DM Smoking BMI Other Significant Variables h / NS... NS... Non-HDL cholesterol, GFR Strain et al 2006 S52 European, c /79... NS NS NS Weight, waist:hip ratio, waist circumference European T2DM, c / NS NS Waist:hip ratio 51 African c /83... NS NS NS Weight Caribbean, 88 African c /87... NS NS NS Caribbean T2DM, 66 Podolec et Angina c / NS NS NS... al 2007 S53 undergoing angiography, 107 Ng et al Takayasu s 0 40 c /72... NS Takayasu s arteritis 2006 S54 arteritis, 10 and controls, 11 Lemos et al CKD, c NS NS S55 Noma et al Healthy male, n /66 79 NS... NS NS... Rho-associated kinases 2007 S56 51 Zhou et al 2007 S57 Untreated HT, c /90 48 NS... NS NS NS... NS NS MMP-9 (C-1562T) polymorphism Park et al HT, h / NS NS NS Log aldosterone 2007 S58 Karakitsos et al ESRD, u / Body surface area, HT, plasma endothelin 2007 S59 Kim et al HT and NT, i / S60 Ronnback et Healthy, s / NS NS NS NS al 2007 S61 Weber et al Cardiomyopathy, i /75 73 NS NS NS NS S62 21 and controls, 42 Sabit et al 2007 S63 COPD, 75 and control, s /82 39 NS... NS NS... NS NS Forced expiratory volume, interleukin 6 Tan et al 2007 S64 HT, c / NS Tissue inhibitor of metalloproteinase 1 Martinez et Familial HC, c /77 37 NS... NSu NSu... NS NSu al 2008 S65 Matsumae et al Hemodialysis with DM, h /89 32 NSu NSu NSu NSu NSu NSu NSu NSu HemoglobinA1c, duration of DM 2008 S66 Hemodialysis without DM, h /89 44 NSu NSu NS NSu NSu NSu Hemodialysis duration, hemoglobin A1c 148 Frost et al 2008 S67 Postmenopausal, s NS NS NS NS Bone mineral density at the hip Schillaci et HIV, 39; healthy s 120/79 46 NS NS... NS NS NS... NS NS HIV infection al 2008 S68 controls, 78 Saez et al Renal transplant s /83... NSu NSu NS 2008 S69 with and without DM, 318 Zhe et al CAPD, c /83 24 NS... NSu... NSu... NS NSu Metabolic syndrome 2008 S70 Lee et al HT, h /80... NS NSu NSu NSu NSu NSu Atrial fibrillation 2008 S71 Papaioannou et al 2008 S72 HT and NT, c /81 49 NS Tr (Continued)

7 1334 Hypertension December 2009 Table. Continued Downloaded from by guest on May 8, 2018 Reference s Sample, n Men, % Age, y PWV, Method PWV, m/s BP, mm Hg R 2 be other factors independent of classic risk factors and blood pressure or interacting with blood pressure that lead to arterial stiffening. PWV has been noted to be of high heritability independent of blood pressure, and several studies within this review demonstrated an association of PWV with genetic polymorphisms. 21,26,27,33 A genetic component to arterial stiffening is, thus, likely. 62 This review is subject to a number of important limitations. First, all of the studies were cross-sectional, and, as such, they highlight associations, and they do not necessarily imply causality. Second, only studies reporting cfpwv as a measure of arterial stiffness were included. However, this measure is clinically the most relevant, because it has been shown to be predictive of cardiovascular morbidity and mortality. The diversity in the description of statistical procedures and results limits the retrieval of publications to the search terms used. We cannot entirely exclude the possibility of publication bias in this systematic review. However, by using a prespecified search strategy and including studies that were not specifically designed to test associations with particular risk factors, bias should be minimized. It is notable that, when we performed the same analysis on excluded studies, we reached similar conclusions. Reported R 2 values for individual contributions of variables may have been underestimated, because some variability may be explained by interactions with age and blood pressure. Finally, the majority of studies did not include a measure of atherosclerotic plaque burden or calcification, so we were unable to distinguish between effects of risk factors, per se, and plaque burden/calcification. Perspectives The present systematic review reinforces age and blood pressure as being strongly associated with cfpwv. The contribution of other cardiovascular risk factors is small or nonsignificant. The prognostic value of cfpwv is likely to relate to a process of arterial ageing unrelated to classic risk factors other than hypertension. As well as seeking novel environmental/genetic factors that determine arterial stiffness, future studies should include prospective studies in sufficiently large cohorts to elucidate the contribution of hypertension over time to arterial stiffening. Sources of Funding This work was supported by British Heart Foundation Project grant PG/06/032. We also acknowledge financial support from the Department of Health via the National Institute for Health Research comprehensive Biomedical Research Centre award to Guy s and St. Thomas National Health Service Foundation Trust in partnership with King s College London and King s College Hospital National Health Service Foundation Trust. None. Variable Significantly Associated With PWV Age BP HR TC LDL HDL TG Sex DM Smoking BMI Disclosures Other Significant Variables CAD and Delles et al s / NS NS... NS CAD 2008 S73 controls, 103 Nguyen et al White, u / NS NS NS NS S74 Black, u / NS NS NS NS Adiponectin Protogerou et al Obstructive sleep apnea, s /85 50 NS NS NS NS NS... Respiratory disturbance index 2008 S75 Tsioufis et HT, c / NS... NS NS al 2008 S76 Bellasi 2008 S77 Black/white hemodialysis, s / NS # NS NS ACEI/ARBs, vitamin D3 and analogs R 2 indicates coefficient of determination; BP, blood pressure; HR, heart rate; TC, total cholesterol; LDL, low-density lipoprotein cholesterol; HDL, high-density lipoprotein cholesterol; TG, triglycerides; DM, diabetes mellitus; BMI, body mass index;, significant;, significant positive association;, significant negative association; NS, nonsignificant; NSu, nonsignificant in univariate analysis.... denotes that variable was not included in model. Sample characteristics: HT indicates hypertensive; NT, normotensive; HC, hypercholesterolemia; MI, myocardial infarction; SLE, systemic lupus erythematosus; CVD, cardiovascular disease; WBC, white blood cells; ESRD, end-stage renal disease; CRP, C-reactive protein; HOMA-IR, homeostasis model assessment for insulin resistance; ACE, angiotensin-converting enzyme; ACEI, ACE inhibitor; ARB, angiotensin receptor blocker; AGTR1, angiotensin II type 1 receptor; CKD, chronic kidney disease; MMP, metalloproteinase; GFR, glomerular filtration rate; Tr, travel time of the pressure wave from the heart to the reflection site and back to the aorta; C3, complement component; T2DM, type 2 diabetes mellitus; PVD, peripheral vascular disease; COPD, chronic obstructive pulmonary disease; CAPD, continuous ambulatory peritoneal dialysis; CAD, coronary artery disease. Methods: n indicates noninvasive pressure recordings; i, invasive pressure recordings; c, complier; s, SphygmoCor; p, pulse pen; u, ultrasound; h, Hasegawa method. *Data show a positive association with systolic BP and negative association with diastolic BP. Data show a negative association for women vs men. Data show a negative association where 1 is assigned to men and 2 is for women. Data show a negative association for women. lldata show a positive association for men vs women. Data show a positive association with men. #Data show a negative association with absence of diabetes mellitus. s Reference in online data supplement, available at References 1. Blacher J, Guerin AP, Pannier B, Marchais SJ, Safar ME, London GM. Impact of aortic stiffness on survival in end-stage renal disease. Circulation. 1999;99:

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10 Dissociation of Aortic Pulse Wave Velocity With Risk Factors for Cardiovascular Disease Other Than Hypertension: A Systematic Review Marina Cecelja and Philip Chowienczyk Downloaded from by guest on May 8, 2018 Hypertension. 2009;54: ; originally published online November 2, 2009; doi: /HYPERTENSIONAHA Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX Copyright 2009 American Heart Association, Inc. All rights reserved. Print ISSN: X. Online ISSN: The online version of this article, along with updated information and services, is located on the World Wide Web at: Data Supplement (unedited) at: Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Hypertension can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: Subscriptions: Information about subscribing to Hypertension is online at:

11 ONLINE SUPPLEMENT HYPERTENSION/2009/ R1 DISSOCIATION OF AORTIC PULSE WAVE VELOCITY WITH RISK FACTORS FOR CARDIOVASCULAR DISEASE OTHER THAN HYPERTENSION: A SYSTEMATIC REVIEW Marina Cecelja, BSc Philip Chowienczyk, FRCP Short Title: Cardiovascular risk factors and aortic stiffness King s College London British Heart Foundation Centre, Cardiovascular Division, Department of Clinical Pharmacology, St Thomas Hospital, London UK Correspondence to: Prof PJ Chowienczyk Department of Clinical Pharmacology St Thomas Hospital Lambeth Palace Road London SE1 7EH UK Tel: Fax: phil.chowienczyk@kcl.ac.uk 1

12 Study Characteristics Table 1 provides an overview of subject groups in terms of study population, sample size, demographic details, method used for PWV measurement and independent correlates of PWV in multivariable regression analysis. These studies included a total of 26,970 subjects. Of these 9918 were healthy subjects, 6071 were hypertensive subjects, 5412 subjects were from population or community cohorts, 1505 were patients with chronic kidney disease (CKD), 1018 were subjects with diabetes and 149 were hypercholesterolemic subjects. Mixed groups of subjects with hypertension, diabetes, hypercholesterolemia, coronary artery disease, chronic kidney disease (CKD) and controls made up 2069 subjects. The remaining 828 subjects included groups with vascular disease, rheumatoid arthritis, dilated cardiomyopathy, angina, Takayasu s Arteritis, chronic obstructive pulmonary disease, human immunodeficiency virus (HIV) and obstructive sleep apnoea syndrome. PWV Measurements The majority of studies utilised commercially available devices for non-invasive measurement of PWV. Twenty-three studies used the SphygmoCor system (Atcor Medical, Australia); twenty-one used the Complior (Artech Medical, France) and one used the Pulse Pen (DiaTecne s.r.l, Italy). Eleven used ultrasound techniques to record flow waves. The remaining studies manually calculated PWV from invasive (n=2) or non-invasive (n=10) pressure recordings and 7 studies used the method introduced by Hasegawa et al. S144 which also utilises pressure recordings at the carotid and femoral artery. One study used both Complior and non-invasive pressure recordings. Excluded Studies Of these 100% found an association between PWV and age, 96% with blood pressure, 50% with HR, 50% with diabetes, 20% with gender, 17% with smoking and 25% with BMI. Total cholesterol was reported in 11 excluded studies of which only 1 (9%) found a significant association. Low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol were significant predictors in only 1 of 7 and 3 of 16 excluded studies respectively. 2

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