1444
SUETA D et al.
EDITORIAL
Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp
Could Circulatory Syndecan-1 Be a Predictable Biomarker for Acute Kidney Injury in Patients With Acute Decompensated Heart Failure? Daisuke Sueta, MD, PhD; Seiji Hokimoto, MD, PhD
S
yndecans are transmembrane proteoglycans (PGs) that consist of a core protein to which growth factor binding glycosaminoglycan side chains are attached.1 Syndecans affect a wide range of physiological processes, and their contribution is most apparent during wound repair.2 The
Syndecan family, transmembrane heparan sulfate PGs, consists of 4 members: Syndecan-1 (Syndecan=the major syndecan of epithelial cells), Syndecan-2 (Fibroglycan=present primarily on cells of mesenchymal origin), Syndecan-3 (N-Syndecan= primarily observed in neuronal tissue and cartilage), and
Figure. Major heparan sulfate proteoglycans core protein families. Schematic illustration of structurally related Syndecan genes, showing the 2 subfamilies of syndecans: Syndecan-1 and -3, and Syndecans -2 and -4, respectively. The extracellular domain is highly variable, with the exception of the glycosaminoglycan (GAG) attachment sites, and the proteolytic cleavage site near the plasma membrane. In contrast, the endo- and transmembrane domains are well-preserved. MW, molecular weight; kD, kilodalton. (Modified with permission from Szatmari T, et al1 and Rosenberg RD, et al.4)
The opinions expressed in this article are not necessarily those of the editors or of the Japanese Circulation Society. Received May 19, 2015; accepted May 19, 2015; released online June 1, 2015 Department of Cardiovascular Medicine, Kumamoto University Hospital, Kumamoto, Japan Mailing address: Seiji Hokimoto, MD, PhD, Department of Cardiovascular Medicine, Kumamoto University Hospital, 1-1-1 Honjo, Kumamoto 860-8556, Japan. E-mail: [email protected] ISSN-1346-9843 doi: 10.1253/circj.CJ-15-0552 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected] Circulation Journal Vol.79, July 2015
Potent Biomarker for AKI in Patients With ADHF Syndecan-4 (Ryudocan/Amphyglycan=ubiquitously expressed)3,4 (Figure).
Article p 1511 Heart failure (HF) is a common problem with increasingly high rates of mortality and morbidity, and worsening of HF results in multiple re-hospitalizations and excessive healthcare costs. The coexistence of acute kidney injury (AKI) in HF patients leads to poor prognosis, and certain biomarkers that are able to predict AKI onset in the early stage of HF have been identified worldwide. Furthermore, endothelial dysfunction is associated with the development of AKI, and nitric oxide, vascular trophic support, and/or endothelial progenitor cells may be important in ameliorating the acute and/or chronic effects of ischemic AKI.5 It is important to predict and prevent renal worsening because cardiovascular mortality is high in patients with end-stage renal dysfunction.6 A recent report showed an association between plasma noradrenaline/adrenaline levels and plasma Syndecan-1 levels in patients with ST-segment elevation myocardial infarction.7 That study demonstrated that Syndecan-1 is a biomarker of endothelial glycocalyx damage, and circulating Syndecan-1 levels are elevated in patients with acute myocardial infarction. Previous studies have revealed that independent predictors for AKI (worsening renal function: WRF) include a history of HF or diabetes mellitus, and admission to hospital of renal dysfunction or hypertension, and a point score based on these characteristics and their relative risk ratios can also identify patients who are at risk for AKI (WRF).8 Tromp et al9 showed that plasma Syndecan-1 levels correlated with fibrosis markers relating to cardiac remodeling in HF with a reduced ejection fraction, and these levels were associated with clinical outcomes in patients with HF with a preserved ejection fraction.9 In this issue of the Journal, Neves et al10 evaluate the relationship between plasma Syndecan-1 levels and renal dysfunction or mortality in patients with acute decompensated HF (ADHF). These researchers determined that plasma Syndecan-1 levels are predictive for an increased risk of developing AKI, in-hospital death, and mortality in the 6-month follow-up. They describes the usefulness of measuring plasma Syndecan-1 levels in ADHF patients and that it is notably valuable in daily clinical practice. It is important to diagnose AKI/WRF in the early stages of HF, and these researchers observed a potent biomarker that could predict an increased risk of AKI in ADHF patients. Importantly, these researchers investigated an endothelial functional marker and assessed not only inhospital mortality rates but also long-term mortality rates. Moreover, with regard to other endothelial markers, there were no significant relationships between AKI in ADHF and intercellular adhesion molecule-1 or nitrogen oxides. These data are highly valuable, and plasma Syndecan-1 may be a potent useful biomarker in clinical practise. A further detailed and comparative discussion may be required for the following reasons: if increased plasma Syndecan-1 levels reflect endothelial dysfunction, there may be a relation-
1445 ship among plasma Syndecan-1 level, AKI/WRF onset, and certain endothelial function markers, such as the flow-mediated dilation11 test or reactive hyperemia peripheral arterial tonometry.12 Moreover, an assessment of the amelioration in endothelial function, which clarifies medications, including vasodilators, may also be required. Although these researchers demonstrated the relationships between plasma syndecan-1 levels and hospital or long-term mortality rates in their study, the mechanism remains unclear. Thus, further pathophysiological discussions, including animal experiments, are warranted. The usefulness of plasma Syndecan-1 levels is expected clinically; thus, verification using large-scale clinical studies is needed. Finally, Neves et al provide clinically useful and important information for the risk stratification of ADHF patients who might develop AKI/WRF. The authors demonstrated that Syndecan-1 may be a potent useful biomarker in clinical situations, and their study cannot be highly evaluated until it has been published and read widely. References 1. Szatmari T, Dobra K. The role of syndecan-1 in cellular signaling and its effects on heparan sulfate biosynthesis in mesenchymal tumors. Front Oncol 2013; 3: 310. 2. Bass MD, Morgan MR, Humphries MJ. Syndecans shed their reputation as inert molecules. Sci Signal 2009; 2: pe18. 3. Bernfield M, Kokenyesi R, Kato M, Hinkes MT, Spring J, Gallo RL, et al. Biology of the syndecans: A family of transmembrane heparan sulfate proteoglycans. Annu Rev Cell Biol 1992; 8: 365 – 393. 4. Rosenberg RD, Shworak NW, Liu J, Schwartz JJ, Zhang L. Heparan sulfate proteoglycans of the cardiovascular system: Specific structures emerge but how is synthesis regulated? J Clin Invest 1997; 99: 2062 – 2070. 5. Basile DP. The endothelial cell in ischemic acute kidney injury: Implications for acute and chronic function. Kidney Int 2007; 72: 151 – 156. 6. Hokimoto S, Sakamoto K, Akasaka T, Kaikita K, Honda O, Naruse M, et al. High mortality rate in hemodialysis patients who undergo invasive cardiovascular procedures related to peripheral artery disease: Community-based observational study in Kumamoto Prefecture. Circ J 2015; 79: 1269 – 1276. 7. Ostrowski SR, Pedersen SH, Jensen JS, Mogelvang R, Johansson PI. Acute myocardial infarction is associated with endothelial glycocalyx and cell damage and a parallel increase in circulating catecholamines. Crit Care 2013; 17: R32. 8. Forman DE, Butler J, Wang Y, Abraham WT, O’Connor CM, Gottlieb SS, et al. Incidence, predictors at admission, and impact of worsening renal function among patients hospitalized with heart failure. J Am Coll Cardiol 2004; 43: 61 – 67. 9. Tromp J, van der Pol A, Klip IT, de Boer RA, Jaarsma T, van Gilst WH, et al. Fibrosis marker syndecan-1 and outcome in patients with heart failure with reduced and preserved ejection fraction. Circ Heart Fail 2014; 7: 457 – 462. 10. Neves FMdeO, Meneses GC, Sousa NEA, Pessoa Bezerra de Menezes RR, Parahyba MC, Martins AMC, et al. Syndecan-1 in acute decompensated heart failure: Association with renal function and mortality. Circ J 2015; 79: 1511 – 1519. 11. Kajikawa M, Maruhashi T, Iwamoto Y, Iwamoto A, Matsumoto T, Hidaka T, et al. Borderline ankle-brachial index value of 0.91–0.99 is associated with endothelial dysfunction. Circ J 2014; 78: 1740 – 1745. 12. Matsuzawa Y, Sugiyama S, Sugamura K, Sumida H, Kurokawa H, Fujisue K, et al. Successful diet and exercise therapy as evaluated on self-assessment score significantly improves endothelial function in metabolic syndrome patients. Circ J 2013; 77: 2807 – 2815.
Circulation Journal Vol.79, July 2015
SUETA D et al.
EDITORIAL
Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp
Could Circulatory Syndecan-1 Be a Predictable Biomarker for Acute Kidney Injury in Patients With Acute Decompensated Heart Failure? Daisuke Sueta, MD, PhD; Seiji Hokimoto, MD, PhD
S
yndecans are transmembrane proteoglycans (PGs) that consist of a core protein to which growth factor binding glycosaminoglycan side chains are attached.1 Syndecans affect a wide range of physiological processes, and their contribution is most apparent during wound repair.2 The
Syndecan family, transmembrane heparan sulfate PGs, consists of 4 members: Syndecan-1 (Syndecan=the major syndecan of epithelial cells), Syndecan-2 (Fibroglycan=present primarily on cells of mesenchymal origin), Syndecan-3 (N-Syndecan= primarily observed in neuronal tissue and cartilage), and
Figure. Major heparan sulfate proteoglycans core protein families. Schematic illustration of structurally related Syndecan genes, showing the 2 subfamilies of syndecans: Syndecan-1 and -3, and Syndecans -2 and -4, respectively. The extracellular domain is highly variable, with the exception of the glycosaminoglycan (GAG) attachment sites, and the proteolytic cleavage site near the plasma membrane. In contrast, the endo- and transmembrane domains are well-preserved. MW, molecular weight; kD, kilodalton. (Modified with permission from Szatmari T, et al1 and Rosenberg RD, et al.4)
The opinions expressed in this article are not necessarily those of the editors or of the Japanese Circulation Society. Received May 19, 2015; accepted May 19, 2015; released online June 1, 2015 Department of Cardiovascular Medicine, Kumamoto University Hospital, Kumamoto, Japan Mailing address: Seiji Hokimoto, MD, PhD, Department of Cardiovascular Medicine, Kumamoto University Hospital, 1-1-1 Honjo, Kumamoto 860-8556, Japan. E-mail: [email protected] ISSN-1346-9843 doi: 10.1253/circj.CJ-15-0552 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected] Circulation Journal Vol.79, July 2015
Potent Biomarker for AKI in Patients With ADHF Syndecan-4 (Ryudocan/Amphyglycan=ubiquitously expressed)3,4 (Figure).
Article p 1511 Heart failure (HF) is a common problem with increasingly high rates of mortality and morbidity, and worsening of HF results in multiple re-hospitalizations and excessive healthcare costs. The coexistence of acute kidney injury (AKI) in HF patients leads to poor prognosis, and certain biomarkers that are able to predict AKI onset in the early stage of HF have been identified worldwide. Furthermore, endothelial dysfunction is associated with the development of AKI, and nitric oxide, vascular trophic support, and/or endothelial progenitor cells may be important in ameliorating the acute and/or chronic effects of ischemic AKI.5 It is important to predict and prevent renal worsening because cardiovascular mortality is high in patients with end-stage renal dysfunction.6 A recent report showed an association between plasma noradrenaline/adrenaline levels and plasma Syndecan-1 levels in patients with ST-segment elevation myocardial infarction.7 That study demonstrated that Syndecan-1 is a biomarker of endothelial glycocalyx damage, and circulating Syndecan-1 levels are elevated in patients with acute myocardial infarction. Previous studies have revealed that independent predictors for AKI (worsening renal function: WRF) include a history of HF or diabetes mellitus, and admission to hospital of renal dysfunction or hypertension, and a point score based on these characteristics and their relative risk ratios can also identify patients who are at risk for AKI (WRF).8 Tromp et al9 showed that plasma Syndecan-1 levels correlated with fibrosis markers relating to cardiac remodeling in HF with a reduced ejection fraction, and these levels were associated with clinical outcomes in patients with HF with a preserved ejection fraction.9 In this issue of the Journal, Neves et al10 evaluate the relationship between plasma Syndecan-1 levels and renal dysfunction or mortality in patients with acute decompensated HF (ADHF). These researchers determined that plasma Syndecan-1 levels are predictive for an increased risk of developing AKI, in-hospital death, and mortality in the 6-month follow-up. They describes the usefulness of measuring plasma Syndecan-1 levels in ADHF patients and that it is notably valuable in daily clinical practice. It is important to diagnose AKI/WRF in the early stages of HF, and these researchers observed a potent biomarker that could predict an increased risk of AKI in ADHF patients. Importantly, these researchers investigated an endothelial functional marker and assessed not only inhospital mortality rates but also long-term mortality rates. Moreover, with regard to other endothelial markers, there were no significant relationships between AKI in ADHF and intercellular adhesion molecule-1 or nitrogen oxides. These data are highly valuable, and plasma Syndecan-1 may be a potent useful biomarker in clinical practise. A further detailed and comparative discussion may be required for the following reasons: if increased plasma Syndecan-1 levels reflect endothelial dysfunction, there may be a relation-
1445 ship among plasma Syndecan-1 level, AKI/WRF onset, and certain endothelial function markers, such as the flow-mediated dilation11 test or reactive hyperemia peripheral arterial tonometry.12 Moreover, an assessment of the amelioration in endothelial function, which clarifies medications, including vasodilators, may also be required. Although these researchers demonstrated the relationships between plasma syndecan-1 levels and hospital or long-term mortality rates in their study, the mechanism remains unclear. Thus, further pathophysiological discussions, including animal experiments, are warranted. The usefulness of plasma Syndecan-1 levels is expected clinically; thus, verification using large-scale clinical studies is needed. Finally, Neves et al provide clinically useful and important information for the risk stratification of ADHF patients who might develop AKI/WRF. The authors demonstrated that Syndecan-1 may be a potent useful biomarker in clinical situations, and their study cannot be highly evaluated until it has been published and read widely. References 1. Szatmari T, Dobra K. The role of syndecan-1 in cellular signaling and its effects on heparan sulfate biosynthesis in mesenchymal tumors. Front Oncol 2013; 3: 310. 2. Bass MD, Morgan MR, Humphries MJ. Syndecans shed their reputation as inert molecules. Sci Signal 2009; 2: pe18. 3. Bernfield M, Kokenyesi R, Kato M, Hinkes MT, Spring J, Gallo RL, et al. Biology of the syndecans: A family of transmembrane heparan sulfate proteoglycans. Annu Rev Cell Biol 1992; 8: 365 – 393. 4. Rosenberg RD, Shworak NW, Liu J, Schwartz JJ, Zhang L. Heparan sulfate proteoglycans of the cardiovascular system: Specific structures emerge but how is synthesis regulated? J Clin Invest 1997; 99: 2062 – 2070. 5. Basile DP. The endothelial cell in ischemic acute kidney injury: Implications for acute and chronic function. Kidney Int 2007; 72: 151 – 156. 6. Hokimoto S, Sakamoto K, Akasaka T, Kaikita K, Honda O, Naruse M, et al. High mortality rate in hemodialysis patients who undergo invasive cardiovascular procedures related to peripheral artery disease: Community-based observational study in Kumamoto Prefecture. Circ J 2015; 79: 1269 – 1276. 7. Ostrowski SR, Pedersen SH, Jensen JS, Mogelvang R, Johansson PI. Acute myocardial infarction is associated with endothelial glycocalyx and cell damage and a parallel increase in circulating catecholamines. Crit Care 2013; 17: R32. 8. Forman DE, Butler J, Wang Y, Abraham WT, O’Connor CM, Gottlieb SS, et al. Incidence, predictors at admission, and impact of worsening renal function among patients hospitalized with heart failure. J Am Coll Cardiol 2004; 43: 61 – 67. 9. Tromp J, van der Pol A, Klip IT, de Boer RA, Jaarsma T, van Gilst WH, et al. Fibrosis marker syndecan-1 and outcome in patients with heart failure with reduced and preserved ejection fraction. Circ Heart Fail 2014; 7: 457 – 462. 10. Neves FMdeO, Meneses GC, Sousa NEA, Pessoa Bezerra de Menezes RR, Parahyba MC, Martins AMC, et al. Syndecan-1 in acute decompensated heart failure: Association with renal function and mortality. Circ J 2015; 79: 1511 – 1519. 11. Kajikawa M, Maruhashi T, Iwamoto Y, Iwamoto A, Matsumoto T, Hidaka T, et al. Borderline ankle-brachial index value of 0.91–0.99 is associated with endothelial dysfunction. Circ J 2014; 78: 1740 – 1745. 12. Matsuzawa Y, Sugiyama S, Sugamura K, Sumida H, Kurokawa H, Fujisue K, et al. Successful diet and exercise therapy as evaluated on self-assessment score significantly improves endothelial function in metabolic syndrome patients. Circ J 2013; 77: 2807 – 2815.
Circulation Journal Vol.79, July 2015
