GDF-15, soluble ST2 and Troponin-I: Biomarkers of Subclinical Vascular Disease?
2016; Elsevier BV; Volume: 248; Linguagem: Inglês
10.1016/j.atherosclerosis.2016.02.008
ISSN1879-1484
AutoresAndreas Tomaschitz, Stefan Pilz, Winfried März,
Tópico(s)Nutrition and Health in Aging
ResumoResearch increasingly focuses on biomarkers as reliable early screening tools for primary cardiovascular disease prevention beyond under- and over-predicting risk scores, which do not fully explain inter-individual variations of cardiovascular risk. In particular, the measurement of easy obtainable and generally reproducible soluble biomarkers is an upcoming promising strategy for an accurate and cost-effective cardiovascular risk screening. In a scientific statement, the AHA recommended six criteria for the evaluation of novel markers of cardiovascular risk [[1]Hlatky M.A. Greenland P. Arnett D.K. Ballantyne C.M. Criqui M.H. Elkind M.S. et al.Criteria for evaluation of novel markers of cardiovascular risk: a scientific statement from the American Heart Association.Circulation. 2009; 119: 2408-2416Crossref PubMed Scopus (918) Google Scholar]: proof of concept (difference of biomarker concentrations between subjects with and without outcome) [[2]Vlachopoulos C. Xaplanteris P. Aboyans V. Brodmann M. Cifkova R. Cosentino F. et al.The role of vascular biomarkers for primary and secondary prevention. A position paper from the European Society of Cardiology Working Group on peripheral circulation: endorsed by the Association for Research into Arterial Structure and Physiology (ARTERY) Society.Atherosclerosis. 2015; 241: 507-532Abstract Full Text Full Text PDF PubMed Scopus (491) Google Scholar]; prospective validation [[3]Wang T.J. Wollert K.C. Larson M.G. Coglianese E. McCabe E.L. Cheng S. et al.Prognostic utility of novel biomarkers of cardiovascular stress: the Framingham heart study.Circulation. 2012; 126: 1596-1604Crossref PubMed Scopus (363) Google Scholar]; incremental value in addition to standard risk markers [[4]Gaggin H.K. Szymonifka J. Bhardwaj A. Belcher A. De Berardinis B. Motiwala S. et al.Head-to-head comparison of serial soluble ST2, growth differentiation factor-15, and highly-sensitive troponin T measurements in patients with chronic heart failure.JACC Heart Fail. 2014; 2: 65-72Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar]; clinical utility (impact on clinical management) [[5]Andersson C. Preis S.R. Beiser A. DeCarli C. Wollert K.C. Wang T.J. et al.Associations of circulating growth differentiation factor-15 and ST2 concentrations with subclinical vascular brain injury and incident stroke.Stroke. 2015; 46: 2568-2575Crossref PubMed Scopus (42) Google Scholar]; improvement of clinical outcomes; and [[6]Andersson C. Enserro D. Sullivan L. Wang T.J. Januzzi Jr., J.L. Benjamin E.J. et al.Relations of circulating GDF-15, soluble ST2, and troponin-I concentrations with, vascular function in the community: the Framingham heart study.Atherosclerosis. 2016; https://doi.org/10.1016/j.atherosclerosis.2016.02.013Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar] cost-effectiveness [[1]Hlatky M.A. Greenland P. Arnett D.K. Ballantyne C.M. Criqui M.H. Elkind M.S. et al.Criteria for evaluation of novel markers of cardiovascular risk: a scientific statement from the American Heart Association.Circulation. 2009; 119: 2408-2416Crossref PubMed Scopus (918) Google Scholar]. In 2015, the thorough position paper from the European Society of Cardiology Working Group on peripheral circulation extended these criteria by adding [[7]Baum C. Johannsen S.S. Zeller T. Atzler D. Ojeda F.M. Wild P.S. et al.ADMA and arginine derivatives in relation to non-invasive vascular function in the general population.Atherosclerosis. 2016; 244: 149-156Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar]: ease of use for facilitating widespread application [[8]Zachariah J.P. Hwang S. Hamburg N.M. Benjamin E.J. Larson M.G. Levy D. et al.Circulating adipokines and vascular function: cross-sectional associations in a community-based cohort.Hypertension. 2016; 67: 294-300Crossref PubMed Scopus (29) Google Scholar]; methodological consensus to allow comparisons between studies; and [[9]Hagstrom E. Ahlstrom T. Arnlov J. Larsson A. Melhus H. Hellman P. et al.Parathyroid hormone and calcium are independently associated with subclinical vascular disease in a community-based cohort.Atherosclerosis. 2015; 238: 420-426Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar] reference values/cut-off values [[2]Vlachopoulos C. Xaplanteris P. Aboyans V. Brodmann M. Cifkova R. Cosentino F. et al.The role of vascular biomarkers for primary and secondary prevention. A position paper from the European Society of Cardiology Working Group on peripheral circulation: endorsed by the Association for Research into Arterial Structure and Physiology (ARTERY) Society.Atherosclerosis. 2015; 241: 507-532Abstract Full Text Full Text PDF PubMed Scopus (491) Google Scholar]. In recent years, a row of soluble biomarkers were related to cardiovascular morbidity and mortality. The risk prediction of these markers, however, might be limited by its different behavior in various medical conditions. Growth differentiation factor-15 (GDF-15), soluble ST2 (sST2) and high sensitivity troponin-I (hs-TnI) represent three promising markers of cardiovascular stress. GDF-15 belongs to the transforming growth factor beta cytokine superfamily and is increasingly expressed by cardiomyocytes in response to i.e. metabolic stress or mechanical stretch, thereby regulating inflammatory and apoptotic pathways in the setting of tissue damage. sST2 is the soluble truncated from of the membrane-bound ST2, a member of the Toll-interleukin-1 receptor family, which binds interleukin-33. ST2/interleukin-33 signaling participates in the immune response following tissue damage. The soluble form of ST2 originates from the myocardium in the course of pressure or volume overload. The sarcomeric protein cardiac troponin is measured by highly sensitive troponin assays (hs-TnI) and reflects myocardial damage due to myocardial infarction or heart failure. In the majority of prospective cohort studies in different populations GDF-15, sST2 and hs-TnI have provided incremental values to established markers (i.e. natriuretic peptides) for risk stratification of subjects affected across a broad spectrum of cardiovascular diseases, including heart failure and stroke [3Wang T.J. Wollert K.C. Larson M.G. Coglianese E. McCabe E.L. Cheng S. et al.Prognostic utility of novel biomarkers of cardiovascular stress: the Framingham heart study.Circulation. 2012; 126: 1596-1604Crossref PubMed Scopus (363) Google Scholar, 4Gaggin H.K. Szymonifka J. Bhardwaj A. Belcher A. De Berardinis B. Motiwala S. et al.Head-to-head comparison of serial soluble ST2, growth differentiation factor-15, and highly-sensitive troponin T measurements in patients with chronic heart failure.JACC Heart Fail. 2014; 2: 65-72Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar, 5Andersson C. Preis S.R. Beiser A. DeCarli C. Wollert K.C. Wang T.J. et al.Associations of circulating growth differentiation factor-15 and ST2 concentrations with subclinical vascular brain injury and incident stroke.Stroke. 2015; 46: 2568-2575Crossref PubMed Scopus (42) Google Scholar]. Arterial stiffness and endothelial dysfunction are well described surrogate endpoints of cardiovascular events. In view of these associations, Andersson et al. examined the cross-sectional relationship between GDF-15, sST2 and hs-TnI and measures of subclinical vascular dysfunction in the Framingham Offspring cohort [[6]Andersson C. Enserro D. Sullivan L. Wang T.J. Januzzi Jr., J.L. Benjamin E.J. et al.Relations of circulating GDF-15, soluble ST2, and troponin-I concentrations with, vascular function in the community: the Framingham heart study.Atherosclerosis. 2016; https://doi.org/10.1016/j.atherosclerosis.2016.02.013Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar]. Participants with impaired kidney function were excluded from the analyses. Determinations of circulating biomarkers and vascular function measurement were thoroughly performed by use of applanation tonometry and ultrasound in 1823 subjects (mean age: 61 years; 54% women). In linear regression models adjusted for a panel of confounders, the authors show that higher levels of GDF-15 are related to greater aortic and medium-sized artery stiffness (reflected by carotid-femoral pulse-wave velocity [CFPWV] and forward pressure wave amplitude) and endothelial dysfunction (reflected by flow-mediated dilatation). In addition, higher sST2 concentrations were associated with greater CFPWV. Finally, inverse associations were documented between levels of hs-TnI and hyperemic flow velocity. These associations corresponded to an increment, in age of 0.5–2 years, on vascular function and were independent of several factors, i.e. natriuretic peptides, renin, hs-CRP, known to impact on vascular function. The investigations of Andersson et al. for the first time indicated a complex interplay between biomarkers of cardiac stress and measures of vascular stiffness and function. Limitations of the study comprise the cross-sectional design, and a suggested residual confounding. Indeed, previous studies reported several parameters (i.e. arginine derivatives, adipokines and parathyroid hormone) that might interact with vascular dysfunction, but have not been considered in the present multivariate analyses [7Baum C. Johannsen S.S. Zeller T. Atzler D. Ojeda F.M. Wild P.S. et al.ADMA and arginine derivatives in relation to non-invasive vascular function in the general population.Atherosclerosis. 2016; 244: 149-156Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar, 8Zachariah J.P. Hwang S. Hamburg N.M. Benjamin E.J. Larson M.G. Levy D. et al.Circulating adipokines and vascular function: cross-sectional associations in a community-based cohort.Hypertension. 2016; 67: 294-300Crossref PubMed Scopus (29) Google Scholar, 9Hagstrom E. Ahlstrom T. Arnlov J. Larsson A. Melhus H. Hellman P. et al.Parathyroid hormone and calcium are independently associated with subclinical vascular disease in a community-based cohort.Atherosclerosis. 2015; 238: 420-426Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar]. Even the intensity of physical activity and dietary pattern, such as salt intake, were suggested to impact on vascular function [10Ramos J.S. Dalleck L.C. Tjonna A.E. Beetham K.S. Coombes J.S. The impact of high-intensity interval training versus moderate-intensity continuous training on vascular function: a systematic review and meta-analysis.Sports Med. 2015; 45: 679-692Crossref PubMed Scopus (380) Google Scholar, 11Dickinson K.M. Clifton P.M. Keogh J.B. A reduction of 3 g/day from a usual 9 g/day salt diet improves endothelial function and decreases endothelin-1 in a randomised cross_over study in normotensive overweight and obese subjects.Atherosclerosis. 2014; 233: 32-38Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar]. Finally, the time period of three years between vascular measures and the blood draw for soluble biomarker measurements might have obscured the observed associations. Despite these limitations, the present analysis encourages further and prospective studies to examine the predictive value of GDF-15, sST2, and hs-TnI, in detecting subclinical vascular dysfunction at an early point and independent of co-morbidities such as heart failure. Women have a lower incidence of cardiovascular diseases and the associations between biomarkers (i.e. troponin) and cardiovascular risk might differ compared to men [[12]Paynter N.P. Everett B.M. Cook N.R. Cardiovascular disease risk prediction in women: is there a role for novel biomarkers?.Clin. Chem. 2014; 60: 88-97Crossref PubMed Scopus (19) Google Scholar]. Thus, gender differences in the relationship between these soluble markers and vascular measures should be explored. In addition, studies are needed to examine non-specific variations of GDF-15, sST2 and hs-TnI concentrations in i.e. infectious or pulmonary diseases [[13]Mueller T. Leitner I. Egger M. Haltmayer M. Dieplinger B. Association of the biomarkers soluble ST2, galectin-3 and growth-differentiation factor-15 with heart failure and other non-cardiac diseases.Clin. Chim. Acta. 2015; 445: 155-160Crossref PubMed Scopus (81) Google Scholar]. Furthermore, the incremental prognostic information over time and beyond one-time baseline measurements should be clarified. The prediction of subclinical vascular dysfunction in patients at CVD risk, by use of novel soluble biomarkers, is a promising and clinically relevant field, which was considerably enriched by the investigation of Andersson et al. There is, however, a long way for GDF-15, sST2 and hs-TnI to accomplish the 9-step criteria for vascular biomarkers and to explore the mechanistic pathways beyond the reported observations. We declare there is no conflict of interest. We have nothing to acknowledge. Relations of circulating GDF-15, soluble ST2, and troponin-I concentrations with vascular function in the community: The Framingham Heart StudyAtherosclerosisVol. 248PreviewGrowth differentiation factor-15 (GDF-15), soluble (s)ST2, and high-sensitivity troponin-I (hs-TnI) are associated with incident cardiovascular disease (CVD) including heart failure, yet the underlying mechanisms are not fully understood. We investigated if GDF-15, sST2, and hs-TnI are related to subclinical vascular dysfunction in the community, which may explain the relations of these biomarkers with CVD. Full-Text PDF
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