In the present study, our results demonstrated that compared with non-AMI subjects, serum levels of sclerostin and OPG were higher in patients with AMI. Both showed predictive values for identification of AMI among patients with acute chest pain. Meanwhile, it was observed that serum sclerostin and OPG levels were associated with GENSINI score, which could reflect the severity of coronary artery occlusion, independently of conventional clinical parameters. In addition, serum OPG levels remained associated with GRACE score after adjustments, which could reflect the risk of mortality in hospitalization of patients with ACS. Moreover, patients above the median of bone-related proteins were accompanied with high incidence of MACE during 1 year follow-up. Furthermore, serum OPG levels remained associated with incident MACE after adjusting conventional risk factors.

Sclerostin, a soluble glycoprotein, was potent inhibitor of Wnt signaling by binding to the co-receptor composed of low-density lipoprotein receptor-related proteins 5 (LRP5) or LRP6 and the Frizzled family proteins [17]. Since accumulating evidence showed the important roles of the Wnt signaling pathways in pathogenesis of atherosclerosis, serum sclerostin was proposed to exert an endocrine role in atherosclerosis [18]. Although circulating sclerostin was expressed mainly by osteocytes [19], Leto et al. demonstrated the expression of sclerostin in VSMCs of atherosclerotic plaques from patients who underwent carotid endarterectomy [10]. Afterwards, Annelies et al. also provided evidence for the local vascular action of sclerostin both in human and rat calcified aortas, meanwhile sclerostin levels were increased in calcifying VSMCs [20]. As VSMCs were considered as major precursors contributing to osteochondrogenesis and calcification in atherosclerosis [21], it was speculated that serum sclerostin may play an endocrine modulatory role in atherosclerosis development. Indeed, a case control study was conducted to detect the levels of sclerostin in Egyptian female patients with type 2 diabetes with and without atherosclerosis, they found a positive relationship between sclerostin and atherosclerosis in patients with type 2 diabetes [22]. Furthermore, Shalash et al. suggested that elevated serum sclerostin levels were independently associated with subclinical atherosclerosis in subjects with type 2 diabetes [23]. Interestingly, Ghardashi-Afousi et al. indicated 12 weeks of high-intensity interval training decreased serum sclerostin levels in patients with type 2 diabetes, meanwhile improved carotid intima-media thickness, a surrogate marker of atherosclerosis, was observed [24]. However, Krishna et al. assessed the possible role of sclerostin on atherosclerosis progression in AngII-infused ApoE−/− mice, they found elevated sclerostin could suppress intimal plaque formation in the aortic arch, exerting a protective role on atherosclerosis progression [25]. Further studies are required to push forward the role of sclerostin in the pathogenesis of atherosclerosis. Until now, few studies were available for elucidating the impact of serum sclerostin on AMI. In present study, we demonstrated that serum sclerostin levels were significantly higher in patients with AMI, indicating a statistically predictive value for identifying AMI among patients with acute chest pain. However, the predictive efficacy of sclerostin seemed to be inferior to cTNI on admission. Meanwhile, significantly positive association between sclerostin and GENSINI score was observed, which could reflect the severity of coronary artery occlusion. Moreover, patients above the median of serum sclerostin levels presented poor prognosis in 1 year follow-up after discharge. Additionally, we found patients in the cTNI-positive group on admission were associated with high MACE rates, nevertheless, the peak values of cTNI after PCI were not associated with the high incidence of MACE. This was in consistence with what has been found in previous study by Jose, et al. They observed that high-sensitivity cTNT on admission, rather than post-reperfusion, was independently associated with prognosis after an average 53 months follow-up period in patients with AMI undergoing primary PCI [26]. The C-index was performed to preliminarily compare the prognostic value of sclerostin and cTNI on admission, the efficacy of sclerostin appeared to be comparable to cTNI on admission, whereas, further studies are needed to validate this finding. Although the multivariate analysis did not obtain a relationship between serum sclerostin and GRACE score, we assume that serum sclerostin could be used to complement risk stratification for AMI.

Nevertheless, He et al. investigated the relationship between serum sclerostin levels and adverse outcomes in elderly patients with stable CAD who were undergoing PCI [27]. After a 3-year follow-up, they observed the higher serum sclerostin levels were associated with better outcomes after PCI. Age ≥ 65 years and eGFR ≥ 45 mL/min.1.73m2 met the inclusion criteria. The SYNTAX score was used to assess severity of CAD, however, the direct correlation analysis between sclerostin levels and SYNTAX score was not available. Another observational study was also performed to assess the relation of serum sclerostin with atherosclerosis severity by SYNTAX score in patients with stable coronary artery disease or ACS, but the results failed to support direct relationship between sclerostin and CAD severity [28]. Recently, Kern et al. investigated the impact of baseline sclerostin levels on 9-years outcomes in patients without significant renal function impairment and undergoing coronary angiography [29]. 205 patients with a mean age of 62.9 ± 0.6 years were enrolled. They showed that the high sclerostin (above median) group presented statistically significant higher rates of MACE and death, implying subjects with above median sclerostin levels might have a worse prognosis. Afterwards, in subgroup analysis, the chronic coronary syndrome subgroup, rather than the ACS subgroup showed statistically significant impact of sclerostin levels on MACE and death. Possible explanations for the discrepancy were the feature of subjects enrolled, evaluation tools, baseline kidney function, and follow-up times. In our study, follow-up subjects comprised of ST-elevated (64.1%) and non-ST-elevated (35.9%) myocardial infarction undergoing PCI with average age 56.8 ± 10.7 years and eGFR ≥ 60 mL/min.1.73 m2. The severity of CAD was evaluated by traditional GENSINI score rather than SYNTAX score. Notably, AMI may occur when an atherosclerotic plaque erosions or ruptures, which was different from stable CAD condition [12]. We assumed that the more severe the atherosclerotic plaque ruptured, the more sclerostin was released from the calcified VSMCs, which might be related to the extent of vulnerability of plaque in acute phase. Moreover, due to the heterogeneity in enrolled subject cohorts, the impact of serum sclerostin on clinical outcome in chronic kidney disease remains controversial. However, Zou et al. found that low serum sclerostin was related with better overall survival in patients with peritoneal dialysis, which was consistent with ours [30]. Furthermore, only first 1-year follow-up after discharge was observed in present study, which itself was the high prevalence period of MACE. As the real contribution of sclerostin to the development of atherosclerosis is still uncertain, further mechanistic and clinical studies are needed to confirm our speculation.

Increasing evidence indicated that OPG levels were associated with CAD [6, 31]. In present study, we confirmed that serum OPG levels had predictive value of AMI, which was comparable to cTNI on admission. Meanwhile, serum OPG levels were positively associated with GENSINI score and GRACE score, indicating the predictive value of severity of AMI, which was consistent with previous studies [8]. Moreover, Fuernau et al. suggested serum OPG levels collected 24 h after infarction were independent predictors of MACE in acute STEMI patients [11]. In our study, we also validated that serum OPG was associated with incident MACE in patients with AMI after discharge by adjusting conventional risk factors. The C-index was applied to preliminarily compare the prognostic value of serum OPG and cTNI on admission, the efficacy of OPG seemed to be superior to cTNI on admission. Conversely, insights from the PLATO (Platelet Inhibition and Patient Outcomes) trial showed plasma OPG was not an independent marker of ischemic cardiovascular events in patients with ACS [32]. Explanation for the discrepancy may be different reagent test kit. Subsequent studies warranted to understand the complex interrelations between OPG and atherosclerosis.

Nevertheless, there are several limitations in present study. First, we are not able to obtain a direct cause-and-effect relationship between bone-related proteins and clinical events due to the observation study design. Second, residual confounders are hard to avoid. For example, diet, excise, medication compliance, and osteoporosis were not monitored during the study. Third, since serum sclerostin and OPG were measured only once within first 24 h after MI diagnosis, changes in these proteins in response of treatment and disease progression could not be assessed. Fourth, we noticed the impact of age, postmenopausal women, and history of diabetes on the serum levels of sclerostin [18, 19]. In present study, there were no significant differences in age and history of diabetes between AMI and non-AMI groups. Women commonly suffered from AMI after postmenopausal period due to possibly estrogen protection. In our study, all of them were postmenopausal women. Fifth, the study population was relatively small, further large prospective studies with well-characterized population are required to confirm the role played by serum sclerostin and OPG in the development and progression of AMI.

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