Skip to main content
SpringerLink
Log in

Bone morphogenetic protein-4: a novel therapeutic target for pathological cardiac hypertrophy/heart failure

  • Published:
Heart Failure Reviews Aims and scope Submit manuscript

Abstract

Bone morphogenetic protein-4 (BMP4) is a member of the bone morphogenetic protein family which plays a key role in the bone formation and embryonic development. In addition to these predominate and well-studied effects, the growing evidences highlight BMP4 as an important factor in cardiovascular diseases, such as hypertension, pulmonary hypertension and valve disease. Our recent works demonstrated that BMP4 mediated cardiac hypertrophy, apoptosis, fibrosis and ion channel remodeling in pathological cardiac hypertrophy. In this review, we discussed the role of BMP4 in pathological cardiac hypertrophy, as well as the recent advances about BMP4 in cardiovascular diseases closely related to pathological cardiac hypertrophy/heart failure. We put forward that BMP4 is a novel therapeutic target for pathological cardiac hypertrophy/heart failure.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB, Bravata DM, Dai S, Ford ES, Fox CS, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Makuc DM, Marcus GM, Marelli A, Matchar DB, Moy CS, Mozaffarian D, Mussolino ME, Nichol G, Paynter NP, Soliman EZ, Sorlie PD, Sotoodehnia N, Turan TN, Virani SS, Wong ND, Woo D, Turner MB, American Heart Association Statistics Committee and Stroke Statistics Subcommittee (2012) Heart disease and stroke statistics—2012 update a report from the American Heart Association. Circulation 125(1):e2–e220

    Article  PubMed  Google Scholar 

  2. Urist MR (1965) Bone: formation by auto induction. Science 150(3698):893–899

    Article  CAS  PubMed  Google Scholar 

  3. Ducy P, Schinke T, Karsenty G (2000) The osteoblast: a sophisticated fibroblast under central surveillance. Science 289(5484):1501–1504

    Article  CAS  PubMed  Google Scholar 

  4. Wong WT, Tian XY, Huang Y (2013) Endothelial dysfunction in diabetes and hypertension: cross talk in RAS, BMP4, and ROS-dependent COX-2–derived prostanoids. J Cardiovasc Pharmacol 61(3):204–214

    Article  CAS  PubMed  Google Scholar 

  5. Cai J, Pardali E, Sánchez-Duffhues G, ten Dijke P (2012) BMP signaling in vascular diseases. FEBS Lett 586(14):1993–2002

    Article  CAS  PubMed  Google Scholar 

  6. Pachori AS, Custer L, Hansen D, Clapp S, Kemppa E, Klingensmith J (2010) Bone morphogenetic protein 4 mediates myocardial ischemic injury through JNK-dependent signaling pathway. J Mol Cell Cardiol 48(6):1255–1265

    Article  CAS  PubMed  Google Scholar 

  7. Sun B, Huo R, Sheng Y, Li Y, Xie X, Chen C, Liu HB, Li N, Li CB, Guo WT, Zhu JX, Yang BF, Dong DL (2013) Bone morphogenetic protein-4 mediates cardiac hypertrophy, apoptosis, and fibrosis in experimentally pathological cardiac hypertrophy. Hypertension 61(2):352–360

    Article  CAS  PubMed  Google Scholar 

  8. Sun B, Sheng Y, Huo R, Hu CW, Lu J, Li SL, Liu X, Wang YC, Dong DL (2013) Bone morphogenetic protein-4 contributes to the down-regulation of Kv4. 3 K (+) channels in pathological cardiac hypertrophy. Biochem Biophys Res Commun 436:591–594

    Article  CAS  PubMed  Google Scholar 

  9. Kawabata M, Imamura T, Miyazono K (1998) Signal transduction by bone morphogenetic proteins. Cytokine Growth Factor Rev 9(1):49–61

    Article  CAS  PubMed  Google Scholar 

  10. Sato M, Ochi T, Nakase T, Hirota S, Kitamura Y, Nomura S, Yasui N (1999) Mechanical tension-stress induces expression of bone morphogenetic protein (BMP)-2 and BMP-4, but Not BMP-6, BMP-7, and GDF-5 mRNA, during distraction osteogenesis. J Bone Miner Res 14(7):1084–1095

    Article  CAS  PubMed  Google Scholar 

  11. Nelsen SM, Christian JL (2009) Site-specific cleavage of BMP4 by furin, PC6, and PC7. J Biol Chem 284(40):27157–27166

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Hao J, Ho JN, Lewis JA, Karim KA, Daniels RN, Gentry PR, Hopkins CR, Lindsley CW, Hong CC (2010) In vivo structure—activity relationship study of dorsomorphin analogues identifies selective VEGF and BMP inhibitors. ACS Chem Biol 5(2):245–253

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Zimmerman LB, De Jesús-Escobar JM, Harland RM (1996) The Spemann organizer signal noggin binds and inactivates bone morphogenetic protein 4. Cell 86(4):599–606

    Article  CAS  PubMed  Google Scholar 

  14. Piccolo S, Sasai Y, Lu B, De Robertis EM (1996) Dorsoventral patterning in Xenopus: inhibition of ventral signals by direct binding of chordin to BMP-4. Cell 86(4):589–598

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Nakayama N, Chun-ya EH, Cam L, Lee JI, Pretorius J, Fisher S, Rosenfeld R, Scully S, Nishinakamura R, Duryea D, Van G, Bolon B, Yokota T, Zhang K (2004) A novel chordin-like BMP inhibitor, CHL2, expressed preferentially in chondrocytes of developing cartilage and osteoarthritic joint cartilage. Development 131(1):229–240

    Article  CAS  PubMed  Google Scholar 

  16. Moser M, Binder O, Wu Y, Aitsebaomo J, Ren R, Bode C, Bautch VL, Conlon FL, Patterson C (2003) BMPER, a novel endothelial cell precursor-derived protein, antagonizes bone morphogenetic protein signaling and endothelial cell differentiation. Mol Cell Biol 23(16):5664–5679

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Stabile H, Mitola S, Moroni E, Belleri M, Nicoli S, Coltrini D, Peri F, Pessi A, Orsatti L, Talamo F, Castronovo V, Waltregny D, Cotelli F, Ribatti D, Presta M (2007) Bone morphogenic protein antagonist Drm/gremlin is a novel pro angiogenic factor. Blood 109(5):1834–1840

    Article  CAS  PubMed  Google Scholar 

  18. Pi X, Schmitt CE, Xie L, Portbury AL, Wu Y, Lockyer P, Dyer LA, Moser M, Bu G, Flynn EJ, Jin S-W, Patterson C (2012) LRP1-dependent endocytic mechanism governs the signaling output of the bmp system in endothelial cells and in angiogenesis novelty and significance. Circ Res 111(5):564–574

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Spoelgen R, Hammes A, Anzenberger U, Zechner D, Andersen OM, Jerchow B, Willnow TE (2005) LRP2/megalin is required for patterning of the ventral telencephalon. Development 132(2):405–414

    Article  CAS  PubMed  Google Scholar 

  20. Oelgeschläger M, Larraín J, Geissert D, De Robertis EM (2000) The evolutionarily conserved BMP-binding protein twisted gastrulation promotes BMP signalling. Nature 405(6788):757–763

    Article  PubMed Central  PubMed  Google Scholar 

  21. Chang C, Holtzman DA, Chau S, Chickering T, Woolf EA, Holmgren LM, Bodorova J, Gearing DP, Holmes WE, Brivanlou AH (2001) Twisted gastrulation can function as a BMP antagonist. Nature 410(6827):483–487

    Article  CAS  PubMed  Google Scholar 

  22. Oelgeschläger M, Reversade B, Larraín J, Little S, Mullins MC, De Robertis E (2003) The pro-BMP activity of twisted gastrulation is independent of BMP binding. Development 130(17):4047–4056

    Article  PubMed Central  PubMed  Google Scholar 

  23. Zakin L, De Robertis E (2004) Inactivation of mouse twisted gastrulation reveals its role in promoting Bmp4 activity during forebrain development. Development 131(2):413–424

    Article  CAS  PubMed  Google Scholar 

  24. Blitz IL, Cho KW, Chang C (2003) Twisted gastrulation loss-of-function analyses support its role as a BMP inhibitor during early Xenopus embryogenesis. Development 130(20):4975–4988

    Article  CAS  PubMed  Google Scholar 

  25. Miyazono K (1999) Signal transduction by bone morphogenetic protein receptors: functional roles of Smad proteins. Bone 25(1):91–93

    Article  CAS  PubMed  Google Scholar 

  26. Zhu H, Kavsak P, Abdollah S, Wrana JL, Thomsen GH (1999) A Smad ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation. Nature 400(6745):687–693

    Article  CAS  PubMed  Google Scholar 

  27. Zhang Y, Chang C, Gehling DJ, Hemmati-Brivanlou A, Derynck R (2001) Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase. Proc Natl Acad Sci USA 98(3):974–979

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Wang W, Mariani FV, Harland RM, Luo K (2000) Ski represses bone morphogenic protein signaling in Xenopus and mammalian cells. Proc Natl Acad Sci USA 97(26):14394–14399

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Yoshida Y, Tanaka S, Umemori H, Minowa O, Usui M, Ikematsu N, Hosoda E, Imamura T, Kuno J, Yamashita T, Miyazono K, Noda M, Noda T, Yamamoto T (2000) Negative regulation of BMP/Smad signaling by Tob in osteoblasts. Cell 103(7):1085–1097

    Article  CAS  PubMed  Google Scholar 

  30. Miyazono K, Maeda S, Imamura T (2005) BMP receptor signaling: transcriptional targets, regulation of signals, and signaling cross-talk. Cytokine Growth Factor Rev 16(3):251–263

    Article  CAS  PubMed  Google Scholar 

  31. Kretzschmar M, Doody J, Massagu J (1997) Opposing BMP and EGF signalling pathways converge on the TGF-β family mediator Smad1. Nature 389(6651):618–622

    Article  CAS  PubMed  Google Scholar 

  32. Sapkota G, Alarcón C, Spagnoli FM, Brivanlou AH, Massagué J (2007) Balancing BMP signaling through integrated inputs into the Smad1 linker. Mol Cell 25(3):441–454

    Article  CAS  PubMed  Google Scholar 

  33. Massagué J, Seoane J, Wotton D (2005) Smad transcription factors. Genes Dev 19(23):2783–2810

    Article  PubMed  Google Scholar 

  34. Hilfiker-Kleiner D, Landmesser U, Drexler H (2006) Molecular mechanisms in heart failure focus on cardiac hypertrophy, inflammation, angiogenesis, and apoptosis. J Am Coll Cardiol 48(9s1):A56–A66

    Article  CAS  Google Scholar 

  35. Bernardo BC, Weeks KL, Pretorius L, McMullen JR (2010) Molecular distinction between physiological and pathological cardiac hypertrophy: experimental findings and therapeutic strategies. Pharmacol Ther 128(1):191–227

    Article  CAS  PubMed  Google Scholar 

  36. Jiao K, Kulessa H, Tompkins K, Zhou Y, Batts L, Baldwin HS, Hogan BL (2003) An essential role of Bmp4 in the atrioventricular septation of the mouse heart. Genes Dev 17(19):2362–2367

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Abdelwahid E, Rice D, Pelliniemi LJ, Jokinen E (2001) Overlapping and differential localization of Bmp-2, Bmp-4, Msx-2 and apoptosis in the endocardial cushion and adjacent tissues of the developing mouse heart. Cell Tissue Res 305(1):67–78

    Article  CAS  PubMed  Google Scholar 

  38. Liu W, Selever J, Wang D, Lu M-F, Moses KA, Schwartz RJ, Martin JF (2004) Bmp4 signaling is required for outflow-tract septation and branchial-arch artery remodeling. Proc Natl Acad Sci USA 101(13):4489–4494

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Mungrue IN, Zhao P, Yao Y, Meng H, Rau C, Havel JV, Gorgels TG, Bergen AA, MacLellan WR, Drake TA, Bostrom KI, Lusis AJ (2011) Abcc6 deficiency causes increased infarct size and apoptosis in a mouse cardiac ischemia-reperfusion model. Arterioscler Thromb Vasc Biol 31(12):2806–2812

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Ogura Y, Ouchi N, Ohashi K, Shibata R, Kataoka Y, Kambara T, Kito T, Maruyama S, Yuasa D, Matsuo K, Enomoto T, Uemura Y, Miyabe M, Ishii M, Yamamoto T, Shimizu Y, Walsh K, Murohara T (2012) Therapeutic impact of follistatin-like 1 on myocardial ischemic injury in preclinical models. Circulation 126(14):1728–1738

    Article  PubMed Central  PubMed  Google Scholar 

  41. Jeffery TK, Upton PD, Trembath RC, Morrell NW (2005) BMP4 inhibits proliferation and promotes myocyte differentiation of lung fibroblasts via Smad1 and JNK pathways. Am J Physiol Lung Cell Mol Physiol 288(2):L370–L378

    Article  CAS  PubMed  Google Scholar 

  42. Yi ES, Kim H, Ahn H, Strother J, Morris T, Masliah E, Hansen LA, Park K, Friedman PJ (2000) Distribution of obstructive intimal lesions and their cellular phenotypes in chronic pulmonary hypertension: a morphometric and immunohistochemical study. Am J Respir Crit Care Med 162(4):1577–1586

    Article  CAS  PubMed  Google Scholar 

  43. Liu HB, Yang BF, Dong DL (2010) Calcineurin and electrical remodeling in pathologic cardiac hypertrophy. Trends Cardiovasc Med 20(5):148–153

    Article  CAS  PubMed  Google Scholar 

  44. Miriyala S, Nieto MCG, Mingone C, Smith D, Dikalov S, Harrison DG, Jo H (2006) Bone morphogenic protein-4 induces hypertension in mice. Role of noggin, vascular NADPH oxidases, and impaired vasorelaxation. Circulation 113(24):2818–2825

    Article  CAS  PubMed  Google Scholar 

  45. Wong WT, Tian XY, Chen Y, Leung FP, Liu L, Lee HK, Ng CF, Xu A, Yao X, Vanhoutte PM, Tipoe GL, Huang Y (2010) Bone morphogenic protein-4 impairs endothelial function through oxidative stress-dependent cyclooxygenase-2 upregulation: implications on hypertension. Circ Res 107(8):984–991

    Article  CAS  PubMed  Google Scholar 

  46. Tian XY, Yung LH, Wong WT, Liu J, Leung FP, Liu L, Chen Y, Kong SK, Kwan KM, Ng SM, Lai PBS, Yung LM, Yao XQ, Huang Y (2012) Bone morphogenic protein-4 induces endothelial cell apoptosis through oxidative stress-dependent p38MAPK and JNK pathway. J Mol Cell Cardiol 52(1):237–244

    Article  CAS  PubMed  Google Scholar 

  47. Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, Elliott CG, Gaine SP, Gladwin MT, Jing Z-C, Krowka MJ, Langleben D, Nakanishi N, Souza R (2009) Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 54(1s1):S43–S54

    Article  PubMed  Google Scholar 

  48. Cogan JD, Pauciulo MW, Batchman AP, Prince MA, Robbins IM, Hedges LK, Stanton KC, Wheeler LA, Phillips JA III, Loyd JE, Nichols WC (2006) High frequency of BMPR2 exonic deletions/duplications in familial pulmonary arterial hypertension. Am J Respir Crit Care Med 174(5):590

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Rudarakanchana N, Flanagan JA, Chen H, Upton PD, Machado R, Patel D, Trembath RC, Morrell NW (2002) Functional analysis of bone morphogenetic protein type II receptor mutations underlying primary pulmonary hypertension. Hum Mol Genet 11(13):1517–1525

    Article  CAS  PubMed  Google Scholar 

  50. Han C, Hong K-H, Kim YH, Kim M-J, Song C, Kim MJ, Kim S-J, Raizada MK, Oh SP (2013) SMAD1 deficiency in either endothelial or smooth muscle cells can predispose mice to pulmonary hypertension. Hypertension 61(5):1044–1052

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Csiszar A, Labinskyy N, Jo H, Ballabh P, Ungvari Z (2008) Differential proinflammatory and prooxidant effects of bone morphogenetic protein-4 in coronary and pulmonary arterial endothelial cells. Am J Physiol Heart Circ Physiol 295(2):H569–H577

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Frank DB, Abtahi A, Yamaguchi D, Manning S, Shyr Y, Pozzi A, Baldwin HS, Johnson JE, de Caestecker MP (2005) Bone morphogenetic protein 4 promotes pulmonary vascular remodeling in hypoxic pulmonary hypertension. Circ Res 97(5):496–504

    Article  CAS  PubMed  Google Scholar 

  53. Li X, Lu W, Fu X, Zhang Y, Yang K, Zhong N, Ran P, Wang J (2013) BMP4 increases TRPC protein expression by activating p38MAPK and ERK1/2 signaling pathways in PASMC. Am J Respir Cell Mol Biol 49:212–220

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Chesler E, King R, Edwards J (1983) The myxomatous mitral valve and sudden death. Circulation 67(3):632–639

    Article  CAS  PubMed  Google Scholar 

  55. Conway MA, Bottomley PA, Ouwerkerk R, Radda GK, Rajagopalan B (1998) Mitral regurgitation impaired systolic function, eccentric hypertrophy, and increased severity are linked to lower phosphocreatine/ATP ratios in humans. Circulation 97(17):1716–1723

    Article  CAS  PubMed  Google Scholar 

  56. Sainger R, Grau JB, Branchetti E, Poggio P, Seefried WF, Field BC, Acker MA, Gorman RC, Gorman JH, Hargrove CW, Bavaria JE, Ferrari G (2012) Human myxomatous mitral valve prolapse: role of bone morphogenetic protein 4 in valvular interstitial cell activation. J Cell Physiol 227(6):2595–2604

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. Freeman RV, Otto CM (2005) Spectrum of calcific aortic valve disease pathogenesis, disease progression, and treatment strategies. Circulation 111(24):3316–3326

    Article  PubMed  Google Scholar 

  58. Otto CM, Lind BK, Kitzman DW, Gersh BJ, Siscovick DS (1999) Association of aortic-valve sclerosis with cardiovascular mortality and morbidity in the elderly. N Engl J Med 341(3):142–147

    Article  CAS  PubMed  Google Scholar 

  59. Rabkin E, Aikawa M, Stone JR, Fukumoto Y, Libby P, Schoen FJ (2001) Activated interstitial myofibroblasts express catabolic enzymes and mediate matrix remodeling in myxomatous heart valves. Circulation 104(21):2525–2532

    Article  CAS  PubMed  Google Scholar 

  60. Mohler ER, Gannon F, Reynolds C, Zimmerman R, Keane MG, Kaplan FS (2001) Bone formation and inflammation in cardiac valves. Circulation 103(11):1522–1528

    Article  PubMed  Google Scholar 

  61. Osman L, Yacoub MH, Latif N, Amrani M, Chester AH (2006) Role of human valve interstitial cells in valve calcification and their response to atorvastatin. Circulation 114(1 suppl):I547–I552

    PubMed  Google Scholar 

  62. Poggio P, Sainger R, Branchetti E, Grau JB, Lai EK, Gorman RC, Sacks MS, Parolari A, Bavaria JE, Ferrari G (2013) Noggin attenuates the osteogenic activation of human valve interstitial cells in aortic valve sclerosis. Cardiovasc Res 98(3):402–410

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  63. Goldman DC, Donley N, Christian JL (2009) Genetic interaction between Bmp2 and Bmp4 reveals shared functions during multiple aspects of mouse organogenesis. Mech Dev 126(3):117–127

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  64. Lavery K, Swain P, Falb D, Alaoui-Ismaili MH (2008) BMP-2/4 and BMP-6/7 differentially utilize cell surface receptors to induce osteoblastic differentiation of human bone marrow-derived mesenchymal stem cells. J Biol Chem 283(30):20948–20958

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  65. Izumi M, Fujio Y, Kunisada K, Negoro S, Tone E, Funamoto M, Osugi T, Oshima Y, Nakaoka Y, Kishimoto T, Yamauchi-Takihara K, Hirota H (2001) Bone morphogenetic protein-2 inhibits serum deprivation-induced apoptosis of neonatal cardiac myocytes through activation of the Smad1 pathway. J Biol Chem 276(33):31133–31141

    Article  CAS  PubMed  Google Scholar 

  66. Rosenkranz S (2004) TGF-β1 and angiotensin networking in cardiac remodeling. Cardiovasc Res 63(3):423–432

    Article  CAS  PubMed  Google Scholar 

  67. Schultz JEJ, Witt SA, Glascock BJ, Nieman ML, Reiser PJ, Nix SL, Kimball TR, Doetschman T (2002) TGF-β1 mediates the hypertrophic cardiomyocyte growth induced by angiotensin II. J Clin Invest 109(6):787–796

    Article  CAS  PubMed Central  Google Scholar 

  68. Miyazono K, Kusanagi K, Inoue H (2001) Divergence and convergence of TGF-β/BMP signaling. J Cell Physiol 187(3):265–276

    Article  CAS  PubMed  Google Scholar 

  69. Abreu JG, Ketpura NI, Reversade B, De Robertis E (2002) Connective-tissue growth factor (CTGF) modulates cell signalling by BMP and TGF-β. Nat Cell Biol 4(8):599–604

    CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Basic Research Program of China (Grant Number 2012CB517803), the National Natural Science Foundation of China (81173049, 81121003) and the Chang Jiang Scholar Candidates Program for Provincial Universities in Heilongjiang [Grant Number 2011CJHB002].

Conflict of interest

None.

Ethical standard

All human and animal studies have been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Author information

Authors and Affiliations

  1. Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Baojian Road 157, Harbin, 150086, Heilongjiang Province, People’s Republic of China

    Wen-Ting Guo & De-Li Dong

Authors
  1. Wen-Ting Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. De-Li Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to De-Li Dong.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guo, WT., Dong, DL. Bone morphogenetic protein-4: a novel therapeutic target for pathological cardiac hypertrophy/heart failure. Heart Fail Rev 19, 781–788 (2014). https://doi.org/10.1007/s10741-014-9429-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10741-014-9429-8

Keywords

Search

Navigation