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Published in: Clinical Research in Cardiology 4/2014

01-04-2014 | Original Paper

The Th17/Treg imbalance in patients with cardiogenic shock

Authors: Maria del Rosario Espinoza Mora, Michael Böhm, Andreas Link

Published in: Clinical Research in Cardiology | Issue 4/2014

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Abstract

Aims

Type 17 helper T (Th17) cells producing the proinflammatory signature cytokine interleukin (IL)-17 are conterregulated by regulatory T cells (Treg) producing anti-inflammatory cytokines like transforming growth factor (TGF)-β and interleukin-(IL)-10. An imbalance of the Th17/Treg-ratio toward Th17 cell subset was shown to be involved in plaque destabilization and acute myocardial infarction (AMI), while no data exist in infarction-related cardiogenic shock (CS). The objective of this study was to evaluate the role of Th17/Treg and their related cytokines in uncomplicated AMI and infarction-related CS.

Methods and results

In an observational monocentric study, blood sample from age-matched healthy controls (HC, n = 20), patients with uncomplicated AMI (n = 20), patients with CS who survived for at least 28 days (CS-survivors, n = 20) and CS-non-survivors (n = 20) were analyzed. Circulating Th17 and Treg cell subsets and their intracellular cytokine expression were measured by flow cytometry and associated with circulating proinflammatory Th17-derived cytokines IL-6, IL-17 and their anti-inflammatory Treg-derived cytokines TGF-β and IL-10 measured by enzyme immunoassay. According to the severity of ACS, CS-non-survivors showed the highest levels of Th17 (p < 0.001) and the lowest levels of Treg cells (p < 0.001) favoring a Th17/Treg imbalance toward the proinflammatory Th17 response (p < 0.001). Changes of T cell subsets were also associated with a proinflammatory cytokine expression measured by increased IL-6 (p < 0.001) and IL-17 levels (p < 0.001) and decreased TGF-β (p < 0.001) and IL-10 levels (p = 0.057). For the Th17/Treg-ratio at admission, a cut-off point of >0.33 had a sensitivity of 90 % and a specificity of 80 % to determine 28-day mortality in CS (confirmed by ROC analysis, area under the curve: 0.88 ± 0.06, p < 0.001). Th17/Treg-ratio >0.33 was observed to be an independent predictor for 1-year mortality in CS confirmed by Cox proportional hazard analysis (hazard ratio (HR): 4.31; 95 % confidence interval (CI) 1.44–12.93; p = 0.009).

Conclusion

The Th17/Treg imbalance toward a Th17 shift might represent a promising candidate as therapeutic target and risk indicator in cardiogenic shock.
Literature
1.
go back to reference Hansson GK (2005) Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 352(16):1685–1695PubMedCrossRef Hansson GK (2005) Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 352(16):1685–1695PubMedCrossRef
2.
go back to reference Caligiuri G, Paulsson G, Nicoletti A, Maseri A, Hansson GK (2000) Evidence for antigen-driven T-cell response in unstable angina. Circulation 102(10):1114–1119PubMedCrossRef Caligiuri G, Paulsson G, Nicoletti A, Maseri A, Hansson GK (2000) Evidence for antigen-driven T-cell response in unstable angina. Circulation 102(10):1114–1119PubMedCrossRef
3.
go back to reference De Palma R, Del Galdo F, Abbate G, Chiariello M, Calabro R, Forte L et al (2006) Patients with acute coronary syndrome show oligoclonal T-cell recruitment within unstable plaque: evidence for a local, intracoronary immunologic mechanism. Circulation 113(5):640–646PubMedCrossRef De Palma R, Del Galdo F, Abbate G, Chiariello M, Calabro R, Forte L et al (2006) Patients with acute coronary syndrome show oligoclonal T-cell recruitment within unstable plaque: evidence for a local, intracoronary immunologic mechanism. Circulation 113(5):640–646PubMedCrossRef
4.
go back to reference Liuzzo G, Biasucci LM, Trotta G, Brugaletta S, Pinnelli M, Digianuario G et al (2007) Unusual CD4+CD28null T lymphocytes and recurrence of acute coronary events. J Am Coll Cardiol 50(15):1450–1458PubMedCrossRef Liuzzo G, Biasucci LM, Trotta G, Brugaletta S, Pinnelli M, Digianuario G et al (2007) Unusual CD4+CD28null T lymphocytes and recurrence of acute coronary events. J Am Coll Cardiol 50(15):1450–1458PubMedCrossRef
5.
go back to reference Mor A, Luboshits G, Planer D, Keren G, George J (2006) Altered status of CD4(+)CD25(+) regulatory T cells in patients with acute coronary syndromes. Eur Heart J 27(21):2530–2537PubMedCrossRef Mor A, Luboshits G, Planer D, Keren G, George J (2006) Altered status of CD4(+)CD25(+) regulatory T cells in patients with acute coronary syndromes. Eur Heart J 27(21):2530–2537PubMedCrossRef
6.
go back to reference Cheng X, Yu X, Ding YJ, Fu QQ, Xie JJ, Tang TT et al (2008) The Th17/Treg imbalance in patients with acute coronary syndrome. Clin Immunol 127(1):89–97PubMedCrossRef Cheng X, Yu X, Ding YJ, Fu QQ, Xie JJ, Tang TT et al (2008) The Th17/Treg imbalance in patients with acute coronary syndrome. Clin Immunol 127(1):89–97PubMedCrossRef
7.
go back to reference Li Q, Wang Y, Chen K, Zhou Q, Wei W (2010) The role of oxidized low-density lipoprotein in breaking peripheral Th17/Treg balance in patients with acute coronary syndrome. Biochem Biophys Res Commun 394(3):836–842PubMedCrossRef Li Q, Wang Y, Chen K, Zhou Q, Wei W (2010) The role of oxidized low-density lipoprotein in breaking peripheral Th17/Treg balance in patients with acute coronary syndrome. Biochem Biophys Res Commun 394(3):836–842PubMedCrossRef
8.
go back to reference Liuzzo G, Trotta F, Pedicino D (2013) Interleukin-17 in atherosclerosis and cardiovascular disease: the good, the bad, and the unknown. Eur Heart J 34(8):556–559PubMedCrossRef Liuzzo G, Trotta F, Pedicino D (2013) Interleukin-17 in atherosclerosis and cardiovascular disease: the good, the bad, and the unknown. Eur Heart J 34(8):556–559PubMedCrossRef
9.
go back to reference Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA (2001) CD4+CD25high regulatory cells in human peripheral blood. J Immunol 167(3):1245–1253PubMed Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA (2001) CD4+CD25high regulatory cells in human peripheral blood. J Immunol 167(3):1245–1253PubMed
10.
go back to reference Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299(5609):1057–1061PubMedCrossRef Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299(5609):1057–1061PubMedCrossRef
11.
go back to reference Brusko TM, Putnam AL, Bluestone JA (2008) Human regulatory T cells: role in autoimmune disease and therapeutic opportunities. Immunol Rev 223:371–390PubMedCrossRef Brusko TM, Putnam AL, Bluestone JA (2008) Human regulatory T cells: role in autoimmune disease and therapeutic opportunities. Immunol Rev 223:371–390PubMedCrossRef
12.
go back to reference Hansen W, Westendorf AM, Buer J (2008) Regulatory T cells as targets for immunotherapy of autoimmunity and inflammation. Inflamm Allergy Drug Targets 7(4):217–223PubMedCrossRef Hansen W, Westendorf AM, Buer J (2008) Regulatory T cells as targets for immunotherapy of autoimmunity and inflammation. Inflamm Allergy Drug Targets 7(4):217–223PubMedCrossRef
13.
go back to reference Miyara M, Gorochov G, Ehrenstein M, Musset L, Sakaguchi S, Amoura Z (2011) Human FoxP3+ regulatory T cells in systemic autoimmune diseases. Autoimmun Rev 10(12):744–755PubMedCrossRef Miyara M, Gorochov G, Ehrenstein M, Musset L, Sakaguchi S, Amoura Z (2011) Human FoxP3+ regulatory T cells in systemic autoimmune diseases. Autoimmun Rev 10(12):744–755PubMedCrossRef
14.
go back to reference Bettelli E, Oukka M, Kuchroo VK (2007) T(H)-17 cells in the circle of immunity and autoimmunity. Nat Immunol 8(4):345–350PubMedCrossRef Bettelli E, Oukka M, Kuchroo VK (2007) T(H)-17 cells in the circle of immunity and autoimmunity. Nat Immunol 8(4):345–350PubMedCrossRef
15.
go back to reference Kurebayashi Y, Nagai S, Ikejiri A, Koyasu S (2013) Recent advances in understanding the molecular mechanisms of the development and function of Th17 cells. Genes Cells 18(4):247–265PubMedCentralPubMedCrossRef Kurebayashi Y, Nagai S, Ikejiri A, Koyasu S (2013) Recent advances in understanding the molecular mechanisms of the development and function of Th17 cells. Genes Cells 18(4):247–265PubMedCentralPubMedCrossRef
16.
go back to reference Zhao Z, Wu Y, Cheng M, Ji Y, Yang X, Liu P et al (2011) Activation of Th17/Th1 and Th1, but not Th17, is associated with the acute cardiac event in patients with acute coronary syndrome. Atherosclerosis 217(2):518–524PubMedCrossRef Zhao Z, Wu Y, Cheng M, Ji Y, Yang X, Liu P et al (2011) Activation of Th17/Th1 and Th1, but not Th17, is associated with the acute cardiac event in patients with acute coronary syndrome. Atherosclerosis 217(2):518–524PubMedCrossRef
17.
go back to reference Eid RE, Rao DA, Zhou J, Lo SF, Ranjbaran H, Gallo A et al (2009) Interleukin-17 and interferon-gamma are produced concomitantly by human coronary artery-infiltrating T cells and act synergistically on vascular smooth muscle cells. Circulation 119(10):1424–1432PubMedCentralPubMedCrossRef Eid RE, Rao DA, Zhou J, Lo SF, Ranjbaran H, Gallo A et al (2009) Interleukin-17 and interferon-gamma are produced concomitantly by human coronary artery-infiltrating T cells and act synergistically on vascular smooth muscle cells. Circulation 119(10):1424–1432PubMedCentralPubMedCrossRef
18.
go back to reference Simon T, Taleb S, Danchin N, Laurans L, Rousseau B, Cattan S et al (2013) Circulating levels of interleukin-17 and cardiovascular outcomes in patients with acute myocardial infarction. Eur Heart J 34(8):570–577PubMedCrossRef Simon T, Taleb S, Danchin N, Laurans L, Rousseau B, Cattan S et al (2013) Circulating levels of interleukin-17 and cardiovascular outcomes in patients with acute myocardial infarction. Eur Heart J 34(8):570–577PubMedCrossRef
20.
go back to reference (1985) The thrombolysis in myocardial infarction (TIMI) trial. Phase I findings. TIMI study group. N Engl J Med 312(14):932–6 (1985) The thrombolysis in myocardial infarction (TIMI) trial. Phase I findings. TIMI study group. N Engl J Med 312(14):932–6
21.
go back to reference Idanpaan-Heikkila JE (1994) WHO guidelines for good clinical practice (GCP) for trials on pharmaceutical products: responsibilities of the investigator. Ann Med 26(2):89–94PubMedCrossRef Idanpaan-Heikkila JE (1994) WHO guidelines for good clinical practice (GCP) for trials on pharmaceutical products: responsibilities of the investigator. Ann Med 26(2):89–94PubMedCrossRef
22.
go back to reference Le Gall JR, Lemeshow S, Saulnier F (1993) A new simplified acute physiology score (SAPS II) based on a European/North American multicenter study. JAMA 270(24):2957–2963PubMedCrossRef Le Gall JR, Lemeshow S, Saulnier F (1993) A new simplified acute physiology score (SAPS II) based on a European/North American multicenter study. JAMA 270(24):2957–2963PubMedCrossRef
23.
go back to reference Hochman JS, Sleeper LA, Webb JG, Sanborn TA, White HD, Talley JD et al (1999) Early revascularization in acute myocardial infarction complicated by cardiogenic shock. Shock investigators. Should we emergently revascularize occluded coronaries for cardiogenic shock. N Engl J Med 341(9):625–634PubMedCrossRef Hochman JS, Sleeper LA, Webb JG, Sanborn TA, White HD, Talley JD et al (1999) Early revascularization in acute myocardial infarction complicated by cardiogenic shock. Shock investigators. Should we emergently revascularize occluded coronaries for cardiogenic shock. N Engl J Med 341(9):625–634PubMedCrossRef
24.
go back to reference Werdan K, Russ M, Buerke M, Delle-Karth G, Geppert A, Schondube FA (2012) Cardiogenic shock due to myocardial infarction: diagnosis, monitoring and treatment: a German–Austrian S3 Guideline. Dtsch Arztebl Int 109(19):343–351PubMedCentralPubMed Werdan K, Russ M, Buerke M, Delle-Karth G, Geppert A, Schondube FA (2012) Cardiogenic shock due to myocardial infarction: diagnosis, monitoring and treatment: a German–Austrian S3 Guideline. Dtsch Arztebl Int 109(19):343–351PubMedCentralPubMed
25.
go back to reference Selejan SR, Poss J, Hewera L, Kazakov A, Bohm M, Link A (2012) Role of receptor for advanced glycation end products in cardiogenic shock. Crit Care Med 40(5):1513–1522PubMedCrossRef Selejan SR, Poss J, Hewera L, Kazakov A, Bohm M, Link A (2012) Role of receptor for advanced glycation end products in cardiogenic shock. Crit Care Med 40(5):1513–1522PubMedCrossRef
26.
go back to reference Link A, Poss J, Rbah R, Barth C, Feth L, Selejan S et al (2013) Circulating angiopoietins and cardiovascular mortality in cardiogenic shock. Eur Heart J 34(22):1651–1662PubMedCrossRef Link A, Poss J, Rbah R, Barth C, Feth L, Selejan S et al (2013) Circulating angiopoietins and cardiovascular mortality in cardiogenic shock. Eur Heart J 34(22):1651–1662PubMedCrossRef
27.
go back to reference Sakaguchi S, Ono M, Setoguchi R, Yagi H, Hori S, Fehervari Z et al (2006) Foxp3+CD25+CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev 212:8–27PubMedCrossRef Sakaguchi S, Ono M, Setoguchi R, Yagi H, Hori S, Fehervari Z et al (2006) Foxp3+CD25+CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev 212:8–27PubMedCrossRef
28.
go back to reference Han SF, Liu P, Zhang W, Bu L, Shen M, Li H et al (2007) The opposite-direction modulation of CD4+CD25+Tregs and T helper 1 cells in acute coronary syndromes. Clin Immunol 124(1):90–97PubMedCrossRef Han SF, Liu P, Zhang W, Bu L, Shen M, Li H et al (2007) The opposite-direction modulation of CD4+CD25+Tregs and T helper 1 cells in acute coronary syndromes. Clin Immunol 124(1):90–97PubMedCrossRef
29.
go back to reference Ghoreschi K, Laurence A, Yang XP, Hirahara K, O’Shea JJ (2011) T helper 17 cell heterogeneity and pathogenicity in autoimmune disease. Trends Immunol 32(9):395–401PubMedCentralPubMedCrossRef Ghoreschi K, Laurence A, Yang XP, Hirahara K, O’Shea JJ (2011) T helper 17 cell heterogeneity and pathogenicity in autoimmune disease. Trends Immunol 32(9):395–401PubMedCentralPubMedCrossRef
31.
go back to reference Gao Q, Jiang Y, Ma T, Zhu F, Gao F, Zhang P et al (2010) A critical function of Th17 proinflammatory cells in the development of atherosclerotic plaque in mice. J Immunol 185(10):5820–5827PubMedCrossRef Gao Q, Jiang Y, Ma T, Zhu F, Gao F, Zhang P et al (2010) A critical function of Th17 proinflammatory cells in the development of atherosclerotic plaque in mice. J Immunol 185(10):5820–5827PubMedCrossRef
32.
go back to reference Liao YH, Xia N, Zhou SF, Tang TT, Yan XX, Lv BJ et al (2012) Interleukin-17A contributes to myocardial ischemia/reperfusion injury by regulating cardiomyocyte apoptosis and neutrophil infiltration. J Am Coll Cardiol 59(4):420–429PubMedCentralPubMedCrossRef Liao YH, Xia N, Zhou SF, Tang TT, Yan XX, Lv BJ et al (2012) Interleukin-17A contributes to myocardial ischemia/reperfusion injury by regulating cardiomyocyte apoptosis and neutrophil infiltration. J Am Coll Cardiol 59(4):420–429PubMedCentralPubMedCrossRef
33.
go back to reference Zhu F, Wang Q, Guo C, Wang X, Cao X, Shi Y et al (2011) IL-17 induces apoptosis of vascular endothelial cells: a potential mechanism for human acute coronary syndrome. Clin Immunol 141(2):152–160PubMedCrossRef Zhu F, Wang Q, Guo C, Wang X, Cao X, Shi Y et al (2011) IL-17 induces apoptosis of vascular endothelial cells: a potential mechanism for human acute coronary syndrome. Clin Immunol 141(2):152–160PubMedCrossRef
34.
go back to reference Danzaki K, Matsui Y, Ikesue M, Ohta D, Ito K, Kanayama M et al (2012) Interleukin-17A deficiency accelerates unstable atherosclerotic plaque formation in apolipoprotein E-deficient mice. Arter Thromb Vasc Biol 32(2):273–280CrossRef Danzaki K, Matsui Y, Ikesue M, Ohta D, Ito K, Kanayama M et al (2012) Interleukin-17A deficiency accelerates unstable atherosclerotic plaque formation in apolipoprotein E-deficient mice. Arter Thromb Vasc Biol 32(2):273–280CrossRef
35.
go back to reference Taleb S, Romain M, Ramkhelawon B, Uyttenhove C, Pasterkamp G, Herbin O et al (2009) Loss of SOCS3 expression in T cells reveals a regulatory role for interleukin-17 in atherosclerosis. J Exp Med 206(10):2067–2077PubMedCentralPubMedCrossRef Taleb S, Romain M, Ramkhelawon B, Uyttenhove C, Pasterkamp G, Herbin O et al (2009) Loss of SOCS3 expression in T cells reveals a regulatory role for interleukin-17 in atherosclerosis. J Exp Med 206(10):2067–2077PubMedCentralPubMedCrossRef
36.
go back to reference Hein F, Massin F, Cravoisy-Popovic A, Barraud D, Levy B, Bollaert PE et al (2010) The relationship between CD4+CD25+CD127− regulatory T cells and inflammatory response and outcome during shock states. Crit Care 14(1):R19PubMedCentralPubMedCrossRef Hein F, Massin F, Cravoisy-Popovic A, Barraud D, Levy B, Bollaert PE et al (2010) The relationship between CD4+CD25+CD127− regulatory T cells and inflammatory response and outcome during shock states. Crit Care 14(1):R19PubMedCentralPubMedCrossRef
37.
go back to reference Hashmi S, Zeng QT (2006) Role of interleukin-17 and interleukin-17-induced cytokines interleukin-6 and interleukin-8 in unstable coronary artery disease. Coron Artery Dis 17(8):699–706PubMedCrossRef Hashmi S, Zeng QT (2006) Role of interleukin-17 and interleukin-17-induced cytokines interleukin-6 and interleukin-8 in unstable coronary artery disease. Coron Artery Dis 17(8):699–706PubMedCrossRef
38.
go back to reference Danesh J, Kaptoge S, Mann AG, Sarwar N, Wood A, Angleman SB et al (2008) Long-term interleukin-6 levels and subsequent risk of coronary heart disease: two new prospective studies and a systematic review. PLoS Med 5(4):e78PubMedCentralPubMedCrossRef Danesh J, Kaptoge S, Mann AG, Sarwar N, Wood A, Angleman SB et al (2008) Long-term interleukin-6 levels and subsequent risk of coronary heart disease: two new prospective studies and a systematic review. PLoS Med 5(4):e78PubMedCentralPubMedCrossRef
39.
go back to reference Empana JP, Jouven X, Canoui-Poitrine F, Luc G, Tafflet M, Haas B et al (2010) C-reactive protein, interleukin 6, fibrinogen and risk of sudden death in European middle-aged men: the Prime study. Arter Thromb Vasc Biol 30(10):2047–2052CrossRef Empana JP, Jouven X, Canoui-Poitrine F, Luc G, Tafflet M, Haas B et al (2010) C-reactive protein, interleukin 6, fibrinogen and risk of sudden death in European middle-aged men: the Prime study. Arter Thromb Vasc Biol 30(10):2047–2052CrossRef
40.
go back to reference Ridker PM, Rifai N, Stampfer MJ, Hennekens CH (2000) Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 101(15):1767–1772PubMedCrossRef Ridker PM, Rifai N, Stampfer MJ, Hennekens CH (2000) Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 101(15):1767–1772PubMedCrossRef
41.
go back to reference Prondzinsky R, Lemm H, Swyter M, Wegener N, Unverzagt S, Carter JM et al (2010) Intra-aortic balloon counterpulsation in patients with acute myocardial infarction complicated by cardiogenic shock: the prospective, randomized IABP SHOCK Trial for attenuation of multiorgan dysfunction syndrome. Crit Care Med 38(1):152–160PubMedCrossRef Prondzinsky R, Lemm H, Swyter M, Wegener N, Unverzagt S, Carter JM et al (2010) Intra-aortic balloon counterpulsation in patients with acute myocardial infarction complicated by cardiogenic shock: the prospective, randomized IABP SHOCK Trial for attenuation of multiorgan dysfunction syndrome. Crit Care Med 38(1):152–160PubMedCrossRef
42.
go back to reference Prondzinsky R, Unverzagt S, Lemm H, Wegener N, Heinroth K, Buerke U et al (2012) Acute myocardial infarction and cardiogenic shock: prognostic impact of cytokines: INF-gamma, TNF-alpha, MIP-1beta, G-CSF, and MCP-1beta. Med Klin Intensivmed Notfmed 107(6):476–484PubMedCrossRef Prondzinsky R, Unverzagt S, Lemm H, Wegener N, Heinroth K, Buerke U et al (2012) Acute myocardial infarction and cardiogenic shock: prognostic impact of cytokines: INF-gamma, TNF-alpha, MIP-1beta, G-CSF, and MCP-1beta. Med Klin Intensivmed Notfmed 107(6):476–484PubMedCrossRef
43.
go back to reference Prondzinsky R, Unverzagt S, Lemm H, Wegener NA, Schlitt A, Heinroth KM et al (2012) Interleukin-6, -7, -8 and -10 predict outcome in acute myocardial infarction complicated by cardiogenic shock. Clin Res Cardiol 101(5):375–384PubMedCrossRef Prondzinsky R, Unverzagt S, Lemm H, Wegener NA, Schlitt A, Heinroth KM et al (2012) Interleukin-6, -7, -8 and -10 predict outcome in acute myocardial infarction complicated by cardiogenic shock. Clin Res Cardiol 101(5):375–384PubMedCrossRef
44.
go back to reference Fincke R, Hochman JS, Lowe AM, Menon V, Slater JN, Webb JG et al (2004) Cardiac power is the strongest hemodynamic correlate of mortality in cardiogenic shock: a report from the SHOCK trial registry. J Am Coll Cardiol 44(2):340–348PubMedCrossRef Fincke R, Hochman JS, Lowe AM, Menon V, Slater JN, Webb JG et al (2004) Cardiac power is the strongest hemodynamic correlate of mortality in cardiogenic shock: a report from the SHOCK trial registry. J Am Coll Cardiol 44(2):340–348PubMedCrossRef
Metadata
Title
The Th17/Treg imbalance in patients with cardiogenic shock
Authors
Maria del Rosario Espinoza Mora
Michael Böhm
Andreas Link
Publication date
01-04-2014
Publisher
Springer Berlin Heidelberg
Published in
Clinical Research in Cardiology / Issue 4/2014
Print ISSN: 1861-0684
Electronic ISSN: 1861-0692
DOI
https://doi.org/10.1007/s00392-013-0656-0

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