The association of uncarboxylated matrix Gla protein with mitral annular calcification differs by diabetes status: The Heart and Soul study
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.
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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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Vascular and valvular calcification biomarkers
2020, Advances in Clinical ChemistryCitation Excerpt :Accordingly, decreased ucMGP, associated with hypovitaminosis K, have been proposed as additive biomarker to assess CV risk and valvular calcification progression [67–69]. Interestingly, the association of ucMGP with MAC seems modulated by T2D status: higher ucMGP associated with lower odds of MAC in no-T2D subjects, and higher odds of MAC in T2D patients [70]. In this context, it is possible that insulin resistance/T2D induces greater ucMGP bioavailability (more production or lowered clearance), and that the association of higher ucMGP with valve calcification in the T2D subset may reflect longer exposure to or greater severity of T2D.
Serum total matrix Gla protein: Reference interval in healthy adults and variations in patients with vascular and osteoarticular diseases
2019, Clinica Chimica ActaCitation Excerpt :Several cross-sectional studies conducted on patients with VD have reported mounting evidence about the influence of hs-CRP [12–15], age [12,13,16] and blood pressure [12] on the circulating MGP species. For instance hs-CRP, a confirmed biomarker of inflammation, was reported as being positively correlated with dp-ucMGP [13] and tMGP [12], negatively associated with t-dpMGP [14] or uncorrelated with t-ucMGP [15]. On the other hand, age was found positively associated with both dp-ucMGP and dp-cMGP in patients with aortic stenosis [13] or tMGP in postmenopausal women [12], but was also associated with circulating dp-ucMGP levels in patients with DM [16].
Association of matrix γ-carboxyglutamic acid protein levels with insulin resistance and Lp(a) in diabetes: A cross-sectional study
2017, Diabetes Research and Clinical PracticeCitation Excerpt :The pathogenesis of vascular calcification in diabetes is not completely understood, though high glucose and other potential factors may play an important role by transforming VSMCs into osteoblast-like cells [47]. Our findings are consistent with Parker’s et al. who found significantly higher levels of uncarboxylated MGP (the precursor of MGP) associated with mitral annular calcification and aortic stenosis in patients with diabetes compared to those without diabetes [48]. This finding supports the hypothesis that MGP plays a key role in the increased vascular calcification process observed in patients with diabetes.
Relation Between Epicardial Adipose and Aortic Valve and Mitral Annular Calcium Determined by Computed Tomography in Subjects Aged ≥65 Years
2016, American Journal of CardiologyThe matrix-gla protein awakening may lead to the demise of vascular calcification
2015, Nephrologie et Therapeutique