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SCIENTIFIC LETTER
Clinical and echocardiographic correlates of plasma osteopontin in the community: the Framingham Heart Study ¨ rnlo¨v, J C Evans, E J Benjamin, M G Larson, D Levy, P Sutherland, D A Siwik, T J Wang, JA W S Colucci, R S Vasan ............................................................................................................................... Heart 2006;92:1514–1515. doi: 10.1136/hrt.2005.081406
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ecent investigations have highlighted the importance of the matricellular protein osteopontin as a key mediator in the cardiovascular system, specifically in the processes of vascular remodelling, vascular and valvular calcification and left ventricular (LV) remodelling.1 To our knowledge, no prior study has investigated whether plasma osteopontin concentrations are related to cardiovascular disease risk factors, valve calcification, and LV dilatation and hypertrophy in a community-based sample. Accordingly, we investigated the clinical and echocardiographic correlates of plasma osteopontin in a community-based sample.
METHODS The design and selection criteria of the Framingham Offspring study have been described previously.2 On the basis of the sex-specific distributions of echocardiographic LV measurements, we sampled participants from the sixth examination cycle (1995–8) with both LV end diastolic dimension (LVEDD) and wall thickness (LVWT) below the sex-specific median (referent, n = 129), with increased LVEDD (> 90th sex-specific centile, n = 134) and increased LVWT (> 90th sex-specific centile, n = 128) in a 1:1:1 ratio. Eighteen participants were included in both LV dilatation and increased LVWT groups, so the study sample consisted of 373 participants. Participants underwent a standardised medical history and physical examination. Fasting blood samples were drawn and frozen at 270˚C without any freeze–thaw cycles until assay. Plasma osteopontin was measured in duplicate by using an enzyme-linked immunosorbent assay (Calbiochem, Inc) with an intra-assay coefficient of variation of 4.6%. All participants underwent routine transthoracic echocardiographic examination. M-mode LV measurements were obtained by using a leading-edge to leading-edge technique. The interventricular septum thickness, posterior LVWT and LVEDD were measured at end diastole. LVWT was calculated as the sum of interventricular septum thickness and posterior LVWT. Moderate or greater mitral annular calcification was considered present if an echo-dense band was visualised in the mitral annulus that was . 0.3 cm thick on the M-mode, or if more than one third of the circumference of the annulus was calcified in the two-dimensional parasternal short axis view. Moderate or greater aortic annular calcification was considered present if more than one half of the aortic annulus had increased echogenicity and appeared thickened. Multiple linear regression was used to relate plasma osteopontin (dependent variable) to cardiovascular risk factors and prevalent cardiovascular disease. Multiple logistic regression was used to examine the associations of plasma osteopontin with the presence of increased LVEDD, increased LVWT and prevalence of mitral annular calcification, aortic annular calcification and either mitral or aortic annular calcification (separate models for each). Sex-specific quartiles
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of plasma osteopontin were used as the predictor variables (see table 1 for range).
RESULTS Our sample consisted of middle-aged individuals (mean (SD) age 58 (10) years; 49% women). The mean (SD) plasma osteopontin concentration was 695 (180) ng/ml. The prevalence of diabetes mellitus was 13% and of hypertension 42%; 14% had prevalent cardiovascular disease (coronary heart disease, cerebrovascular disease, peripheral arterial disease and heart failure). Plasma osteopontin concentrations were higher in men than in women (age-adjusted means 729 ng/ml v 658 ng/ml, respectively, p ,0.001) and increased with age (28 ng/ml increase/decade (sex-adjusted), p = 0.002). Osteopontin concentration was not associated with blood pressure, the ratio of total to high density lipoprotein cholesterol, smoking, diabetes, body mass index, heart rate or prevalent cardiovascular disease (all p . 0.10). In our sample the mean LVEDD was 5.2 (0.7) cm in men and 4.7 (0.5) cm in women. Mean LVWT was 2.1 (0.4) cm in men and 1.9 (0.3) cm in women. In multivariable-adjusted models, relative to the lowest quartile, the top quartile of plasma osteopontin was associated with a borderline significant 2.48-fold odds of increased LVEDD (p , 0.07) (table 1). When analyses were repeated after exclusion of the 35 participants with prevalent myocardial infarction or heart failure, the borderline relationship of osteopontin with increased LVEDD was maintained (odds ratio for top quartile relative to the lowest of 2.58, 95% confidence interval 0.89 to 7.50, p = 0.08). Plasma osteopontin was not related to increased LVWT (table 1) or to mitral or aortic annular calcification (p . 0.4). At a type I error (a) of 0.05, statistical power to detect an odds ratio of 1.5 for tests of trend across osteopontin quartiles was 49% for any annular calcification, 73% for increased LVEDD and 64% for increased LVWT.
DISCUSSION The positive relationship between age and plasma osteopontin may be due to age-associated changes in the cardiovascular and other organ systems. For instance, osteopontin has been positively associated with conditions such as vascular calcification and osteoporosis that increase with age.1 The reasons for the higher osteopontin concentrations in men are less clear. Experimental data indicate that oestrogen inhibits the production of osteopontin by vascular smooth muscle cells.3 It is unclear whether such oestrogen-mediated antagonism of osteopontin underlies the lower plasma values in women. Abbreviations: LV, left ventricular; LVEDD, left ventricular end diastolic dimension; LVWT, left ventricular wall thickness
Scientific letter
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Table 1 Multiple logistic regression models of plasma osteopontin concentrations, increased left ventricular diastolic dimensions and increased wall thickness Osteopontin quartile 1
Plasma osteopontin mean (range) (ng/ml)
Men: 520 (345–606) Women: 477 (284–552) 2 Men: 647 (609–704) Women: 589 (554–634) 3 Men: 760 (704–825) Women: 680 (635–754) 4 Men: 992 (829–1330) Women: 881 (754–1081) Trend across quartiles
OR for LVD (95% CI)
OR for increased LVWT p Value (95% CI) p Value
Referent
Referent
1.37 (0.51 to 3.65)
0.53
1.36 (0.46 to 4.04)
0.58
1.53 (0.59 to 4.02)
0.38
1.18 (0.40 to 3.48)
0.76
2.48 (0.93 to 6.63)
0.07
1.86 (0.62 to 5.56)
0.27
1.33 (0.98 to 1.81)
0.07
1.18 (0.84 to 1.66)
0.33
Values >90th centiles defined left ventricular dilatation (LVD) and increased left ventricular wall thickness (LVWT) and were for left ventricular end diastolic dimension (LVEDD), 5.1 cm in women and 5.3 cm in men; and for LVWT, 2.1 cm in women and 2.3 cm in men. All models are adjusted for age, sex, height, weight, heart rate, systolic and diastolic blood pressure, hypertension treatment, ratio of total to high density lipoprotein cholesterol, smoking, valve disease and diabetes. Participants who had both increased LVEDD and increased LVWT were included in both groups. OR, odds ratio.
We also observed a borderline significant association between higher osteopontin concentration and increased LVEDD but no such association was evident for increased LVWT. This may seem paradoxical, as experimental data suggest that increased myocardial osteopontin reflects heightened angiotensin II/aldosterone activity,1 and would be accompanied by greater LVWT. However, whereas myocardial osteopontin primarily increases collagen synthesis and decreases LV dilatation, higher osteopontin concentrations may indicate a compensatory response to haemodynamic stimuli. Higher plasma osteopontin may therefore be a marker of LV dilatation rather than being causally related to LV dilatation. Such a thesis is consistent with the observation that circulating osteopontin is positively related to LV dimensions and inversely to LVEF in postmyocardial infarction patients.4 An alternative explanation for our observation may be that osteopontin has been reported to activate matrix metalloproteinases,5 and such activation would favour LV dilatation. However, the substantial overlap in plasma concentrations between people with and without increased LVEDD or LVWT indicates that osteopontin is not a suitable biomarker for screening for LV dilatation or hypertrophy in the community. We did not find any association of plasma osteopontin with the presence of mitral or aortic annular calcification. One explanation for the absence of an association may be that we had limited statistical power to detect modest associations. An alternative explanation may be that osteopontin is expressed in tissues at sites of calcification, but such expression is not reflected in circulating concentrations of osteopontin. .....................
Authors’ affiliations
¨ rnlo¨v, J C Evans, E J Benjamin, M G Larson, D Levy, P Sutherland, JA T J Wang, R S Vasan, National Heart, Lung and Blood Institute’s Framingham Heart Study, Framingham, Massachusetts, USA
D A Siwik, W S Colucci, Myocardial Biology Unit, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA Sources of support: Bergmarks travel grant, Viking Bjo¨ rks ¨ ) and through research Hedersledamotstipendium, Capio travel grant (JA grants (NHLBI/NIH Contract N01-HC-25195, 1R01HL67288, 1K23 HL074077-01 (TJW) and 2K24HL04334 (RSV)) from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA. Conflict of interest: None of the authors have a conflict of interest to report as related to this manuscript. Ethics approval: the study was approved by the Institutional Review Board at Boston Medical Center and all subjects gave written informed consent. Correspondence to: Dr Ramachandran S Vasan, Framingham Heart Study, 73 Mt Wayte Avenue, Framingham, MA 01702-5827, USA;
[email protected] Accepted 3 March 2006
REFERENCES 1 Giachelli CM, Liaw L, Murry CE, et al. Osteopontin expression in cardiovascular diseases. Ann N Y Acad Sci 1995;760:109–26. 2 Kannel WB, Feinleib M, McNamara PM, et al. An investigation of coronary heart disease in families. The Framingham offspring study. Am J Epidemiol 1979;110:281–90. 3 Li G, Chen YF, Kelpke SS, et al. Estrogen attenuates integrin-beta(3)dependent adventitial fibroblast migration after inhibition of osteopontin production in vascular smooth muscle cells. Circulation 2000;101:2949–55. 4 Suezawa C, Kusachi S, Murakami T, et al. Time-dependent changes in plasma osteopontin levels in patients with anterior-wall acute myocardial infarction after successful reperfusion: correlation with left-ventricular volume and function. J Lab Clin Med 2005;145:33–40. 5 Rangaswami H, Bulbule A, Kundu GC. Nuclear factor-inducing kinase plays a crucial role in osteopontin-induced MAPK/IkappaBalpha kinase-dependent nuclear factor kappaB-mediated promatrix metalloproteinase-9 activation. J Biol Chem 2004;279:38921–35.
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