Elsevier

Atherosclerosis

Volume 210, Issue 1, May 2010, Pages 320-325
Atherosclerosis

The association of uncarboxylated matrix Gla protein with mitral annular calcification differs by diabetes status: The Heart and Soul study

https://doi.org/10.1016/j.atherosclerosis.2009.11.023Get rights and content

Abstract

Objective

Mitral annular calcification (MAC) and aortic stenosis (AS) are associated with systemic calcification and cardiovascular disease (CVD) events. Matrix Gla protein (MGP) is an inhibitor of vascular calcification and lower levels of its precursor – uncarboxylated MGP (ucMGP) – are associated with vascular calcification in pilot studies.

Methods and results

In this cross-sectional study of 839 outpatients with stable CVD, we measured serum ucMGP, and evaluated MAC and AS by echocardiography. The association of ucMGP with MAC differed by diabetes status (interaction P < 0.001). Among participants without diabetes (n = 615), higher ucMGP (per standard deviation [1178 nM] increase) was associated with lower odds of MAC (odds ratio [OR] 0.73; 95% confidence interval [CI] 0.55–0.97) in models adjusted for traditional CVD risk factors, C-reactive protein, and kidney function. Among persons with diabetes (n = 221), higher ucMGP was associated with higher odds of MAC (OR 1.89; 95% CI 1.29–2.78). Results were qualitatively similar for the association of ucMGP with AS although not statistically significant.

Conclusions

Among outpatients with stable CVD, higher ucMGP is associated with lower odds of MAC in persons without diabetes, and higher odds of MAC in persons with diabetes. Future studies should determine whether ucMGP levels are associated with CVD events, and whether such associations differ by diabetes status.

Introduction

Mitral annular calcification (MAC) and aortic stenosis (AS) are associated with calcification of the aorta and other vascular beds, and may be focal manifestations of a systemic calcific condition [1]. While both are associated with cardiovascular disease (CVD) risk factors [2], the presence of either MAC or AS is associated with incident CVD events, CVD mortality, and all-cause mortality independent of traditional CVD risk factors in community-living populations [3], [4]. Previously thought to reflect a passive process, recent research has demonstrated that cardiac valve calcification is actively regulated and potentially modifiable [5]. Thus, understanding mechanisms of valvular calcification may provide novel insights into CVD.

Matrix Gla protein (MGP) inhibits vascular calcification [6]. MGP knock-out mice are characterized by severe vascular calcification and prematurely die due to spontaneous aortic rupture [7]. Recently, an assay specific for its precursor – uncarboxylated MGP (ucMGP) – has been developed [8]. In a pilot study, persons with coronary atherosclerosis, aortic stenosis, and calcific uremic arteriolopathy had lower ucMPG levels compared to healthy controls [9]. However, the number of participants was small and associations were not adjusted for age or kidney function, two important confounders [10]. The goal of the present manuscript was to determine the independent association of serum ucMGP with cardiac valve calcification in a relatively large cohort of outpatients with stable CVD.

Our secondary objective was to determine whether the association of ucMGP with cardiac valvular calcification differs by diabetes status. MGP complexes with fetuin-A (another inhibitor of vascular calcification) in blood, working in concert to limit calcium crystal growth and precipitation [11]. In a prior study, we demonstrated that in persons with CVD, lower fetuin-A levels were strongly associated with cardiac valve calcification only in persons without diabetes [12]. Since MGP and fetuin-A work in concert, herein we investigate whether the association of ucMGP with valve calcification might also differ by diabetes status. We hypothesized that lower serum ucMGP levels would be associated with both MAC and AS, with stronger relationships in persons without diabetes.

Section snippets

Study participants

The Heart and Soul study is an observational study designed to investigate the influence of psychosocial factors on CVD progression, with methods described previously [13]. Briefly, participants were recruited from outpatient clinics around San Francisco if they had a: (i) history of myocardial infarction (MI); (ii) angiographic evidence of >50% stenosis in one or more coronary vessels; (iii) exercise-induced ischemia by treadmill or nuclear testing; (iv) history of coronary revascularization

Results

Among the 839 study participants, the mean age was 68 ± 11 years, 81% were male, 40% were non-white, and 26% had diabetes mellitus. The mean ± SD ucMGP level was 3287 ± 1178 nM, and its distribution was approximately normal in the study sample. MAC was present in 155 participants (19%) while aortic stenosis was present in 68 (9%). Differences in baseline characteristics according to ucMGP tertile are shown in Table 1. Persons with higher ucMGP were had higher prevalence of diabetes and individual

Discussion

Serum ucMGP levels are strongly associated with MAC in outpatients with stable CVD, but that the direction of association differs by diabetes status. Higher serum ucMGP levels are associated with lower odds for MAC in persons without diabetes, and higher odds for MAC in those with diabetes. These associations were independent of age, kidney function, traditional CVD risk factors, albumin, and CRP and were not materially altered with adjusting for calcium, phosphorus or fetuin-A levels. While

Sources of funding

This study was supported by a Hypertension Training Grant (T32 HL007261) through the National Heart Lung and Blood Institute (BDP) and an American Heart Association Fellow-to-Faculty transition grant (JHI). The Heart and Soul study was supported by the Department of Veterans Epidemiology Merit Review Program; the Department of Veterans Affairs Health Services Research and Development service; the National Heart Lung and Blood Institute (R01 HL079235); the American Federation for Aging Research

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