Skip to main content
Log in

Tissue-level inflammation and ventricular remodeling in hypertrophic cardiomyopathy

  • Published:
Journal of Thrombosis and Thrombolysis Aims and scope Submit manuscript

Abstract

Hypertrophic cardiomyopathy (HCM) is a common cardiac condition caused primarily by sarcomeric protein mutations with several distinct phenotypes, ranging from asymmetric septal hypertrophy, either with or without left ventricular outflow tract obstruction, to moderate left ventricular dilation with or without apical aneurysm formation and marked, end-stage dilation with refractory heart failure. Sudden cardiac death can occur at any stage. The phenotypic variability observed in HCM is the end-result of many factors, including pre-load, after-load, wall stress and myocardial ischemia stemming from microvascular dysfunction and thrombosis; however, tissue level inflammation to include leukocyte-derived extracellular traps consisting of chromatin and histones, apoptosis, proliferation of matrix proteins and impaired or dysfunctional regulatory pathways contribute as well. Our current understanding of the pathobiology, developmental stages, transition from hypertrophy to dilation and natural history of HCM with emphasis on the role of tissue-level inflammation in myocardial fibrosis and ventricular remodeling is summarized.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Nguyen K, Roche S, Donal E, Odent S, Eicher JC, Faivre L, Millat G, Salgado D, Desvignes JP, Lavoute C, Haentjens J, Consolino E, Janin A, Cerino M, Reant P, Rooryck C, Charron P, Richard P, Casalta AC, Michel N, Magdinier F, Beroud C, Levy N, Habib G (2019) Whole exome sequencing reveals a large genetic heterogeneity and revisits the causes of hypertrophic cardiomyopathy. Circ Genomic Precis Med 12:e002500

    Google Scholar 

  2. Maron BJ, Maron MS, Maron BA, Loscalzo J (2019) Moving beyond the sarcomere to explain heterogeneity in hypertrophic cardiomyopathy: JACC review topic of the week. J Am Coll Cardiol 73:1978–1986

    PubMed  PubMed Central  Google Scholar 

  3. Packer M (2019) What causes sudden death in patients with chronic heart failure and a reduced ejection fraction? Eur Heart J. https://doi.org/10.1093/eurheartj/ehz553

    Article  PubMed  PubMed Central  Google Scholar 

  4. Cheng S, Choe YH, Ota H, Cui C, Yin G, Lu M, Li L, Chen X, Prasad SK, Zhao S (2018) CMR assessment and clinical outcomes of hypertrophic cardiomyopathy with or without ventricular remodeling in the end-stage phase. Int J Cardiovasc Imaging 34:597–605

    PubMed  Google Scholar 

  5. Lu DY, Ventoulis I, Liu H, Kudchadkar SM, Greenland GV, Yalcin H, Kontari E, Goyal S, Corona-Villalobos CP, Vakrou S, Zimmerman SL, Abraham TP, Abraham MR (2019) Sex-specific cardiac phenotype and clinical outcomes in patients with hypertrophic cardiomyopathy. Am Heart J 219:58–69

    PubMed  Google Scholar 

  6. Lorenzini M, Anastasiou Z, O’Mahony C, Guttman OP, Gimeno JR, Monserrat L, Anastasakis A, Rapezzi C, Biagini E, Garcia-Pavia P, Limongelli G, Pavlou M, Elliott PM (2019) Mortality among referral patients with hypertrophic cardiomyopathy vs the general European population. JAMA Cardiol. https://doi.org/10.1001/jamacardio.2019.4534

    Article  PubMed Central  Google Scholar 

  7. Gersh BJ, Oh JK, Ong KC, Nishimura RA, Ommen SR, Hebl VB, Geske JB, Ackerman MJ, Siontis KC, Hodge DO, Miller VM, Schaff HV (2017) Women with hypertrophic cardiomyopathy have worse survival. Eur Heart J 38:3434–3440

    PubMed  PubMed Central  Google Scholar 

  8. Kuusisto J, Karja V, Sipola P, Kholova I, Peuhkurinen K, Jaaskelainen P, Naukkarinen A, Yla-Herttuala S, Punnonen K, Laakso M (2012) Low-grade inflammation and the phenotypic expression of myocardial fibrosis in hypertrophic cardiomyopathy. Heart 98:1007–1013

    PubMed  Google Scholar 

  9. Brill A, Fuchs TA, Savchenko AS, Thomas GM, Martinod K, De Meyer SF, Bhandari AA, Wagner DD (2012) Neutrophil extracellular traps promote deep vein thrombosis in mice. J Thromb Haemost 10:136–144

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Thalin C, Daleskog M, Goransson SP, Schatzberg D, Lasselin J, Laska AC, Kallner A, Helleday T, Wallen H, Demers M (2017) Validation of an enzyme-linked immunosorbent assay for the quantification of citrullinated histone H3 as a marker for neutrophil extracellular traps in human plasma. Immunol Res 65:706–712

    PubMed  PubMed Central  Google Scholar 

  11. Jones JE, Causey CP, Knuckley B, Slack-Noyes JL, Thompson PR (2009) Protein arginine deiminase 4 (PAD4): current understanding and future therapeutic potential. Curr Opin Drug Discov Dev 12:616–627

    CAS  Google Scholar 

  12. Weckbach LT, Grabmaier U, Uhl A, Gess S, Boehm F, Zehrer A, Pick R, Salvermoser M, Czermak T, Pircher J, Sorrelle N, Migliorini M, Strickland DK, Klingel K, Brinkmann V, Abu Abed U, Eriksson U, Massberg S, Brunner S, Walzog B (2019) Midkine drives cardiac inflammation by promoting neutrophil trafficking and NETosis in myocarditis. J Exp Med 216:350–368

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Woulfe KC, Sucharov CC (2017) Midkine's role in cardiac pathology. J Cardiovasc Dev Dis 4:13

    PubMed  PubMed Central  Google Scholar 

  14. Abu-Abed U, Brinkmann V (2019) Immunofluorescent detection of NET components in paraffin-embedded tissue. Methods Mol Biol (Clifton, NJ) 2087:415–424

    Google Scholar 

  15. Mariero LH, Torp MK, Heiestad CM, Baysa A, Li Y, Valen G, Vaage J, Stenslokken KO (2019) Inhibiting nucleolin reduces inflammation induced by mitochondrial DNA in cardiomyocytes exposed to hypoxia and reoxygenation. Br J Pharmacol 176:4360–4372

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Noubouossie DF, Whelihan MF, Yu YB, Sparkenbaugh E, Pawlinski R, Monroe DM, Key NS (2017) In vitro activation of coagulation by human neutrophil DNA and histone proteins but not neutrophil extracellular traps. Blood 129:1021–1029

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Ammollo CT, Semeraro F, Xu J, Esmon NL, Esmon CT (2011) Extracellular histones increase plasma thrombin generation by impairing thrombomodulin-dependent protein C activation. J Thromb Haemost 9:1795–1803

    CAS  PubMed  Google Scholar 

  18. Labberton L, Kenne E, Long AT, Nickel KF, Di Gennaro A, Rigg RA, Hernandez JS, Butler L, Maas C, Stavrou EX, Renne T (2016) Neutralizing blood-borne polyphosphate in vivo provides safe thromboprotection. Nat Commun 7:12616

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Grassle S, Huck V, Pappelbaum KI, Gorzelanny C, Aponte-Santamaria C, Baldauf C, Grater F, Schneppenheim R, Obser T, Schneider SW (2014) von Willebrand factor directly interacts with DNA from neutrophil extracellular traps. Arterioscler Thromb Vasc Biol 34:1382–1389

    PubMed  Google Scholar 

  20. Savchenko AS, Borissoff JI, Martinod K, De Meyer SF, Gallant M, Erpenbeck L, Brill A, Wang Y, Wagner DD (2014) VWF-mediated leukocyte recruitment with chromatin decondensation by PAD4 increases myocardial ischemia/reperfusion injury in mice. Blood 123:141–148

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Oehmcke S, Morgelin M, Herwald H (2009) Activation of the human contact system on neutrophil extracellular traps. J Innate Immunity 1:225–230

    Google Scholar 

  22. Elaskalani O, Abdol Razak NB, Metharom P (2018) Neutrophil extracellular traps induce aggregation of washed human platelets independently of extracellular DNA and histones. Cell Commun Signal 16:24

    PubMed  PubMed Central  Google Scholar 

  23. Grasso S, Neumann A, Lang IM, Etscheid M, von Kockritz-Blickwede M, Kanse SM (2018) Interaction of factor VII activating protease (FSAP) with neutrophil extracellular traps (NETs). Thromb Res 161:36–42

    CAS  PubMed  Google Scholar 

  24. Seif K, Alidzanovic L, Tischler B, Ibrahim N, Zagrapan B, Rauscher S, Salzmann M, Hell L, Mauracher LM, Budde U, Schmid JA, Jilma B, Pabinger I, Assinger A, Starlinger P, Brostjan C (2018) Neutrophil-mediated proteolysis of thrombospondin-1 promotes platelet adhesion and string formation. Thromb Haemost 118:2074–2085

    PubMed  PubMed Central  Google Scholar 

  25. Grechowa I, Horke S, Wallrath A, Vahl CF, Dorweiler B (2017) Human neutrophil elastase induces endothelial cell apoptosis by activating the PERK-CHOP branch of the unfolded protein response. FASEB J 31:3868–3881

    CAS  PubMed  Google Scholar 

  26. Ruf W, Ruggeri ZM (2010) Neutrophils release brakes of coagulation. Nat Med 16:851–852

    CAS  PubMed  Google Scholar 

  27. Higuchi DA, Wun TC, Likert KM, Broze GJ Jr (1992) The effect of leukocyte elastase on tissue factor pathway inhibitor. Blood 79:1712–1719

    CAS  PubMed  Google Scholar 

  28. Goel MS, Diamond SL (2003) Neutrophil cathepsin G promotes prothrombinase and fibrin formation under flow conditions by activating fibrinogen-adherent platelets. J Biol Chem 278:9458–9463

    CAS  PubMed  Google Scholar 

  29. Kolpakov V, D'Adamo MC, Salvatore L, Amore C, Mironov A, Iacoviello L, Donati MB (1994) Neutrophil derived cathepsin G induces potentially thrombogenic changes in human endothelial cells: a scanning electron microscopy study in static and dynamic conditions. Thromb Haemost 72:140–145

    CAS  PubMed  Google Scholar 

  30. Gould TJ, Vu TT, Swystun LL, Dwivedi DJ, Mai SH, Weitz JI, Liaw PC (2014) Neutrophil extracellular traps promote thrombin generation through platelet-dependent and platelet-independent mechanisms. Arterioscler Thromb Vasc Biol 34:1977–1984

    CAS  PubMed  Google Scholar 

  31. Carestia A, Rivadeneyra L, Romaniuk MA, Fondevila C, Negrotto S, Schattner M (2013) Functional responses and molecular mechanisms involved in histone-mediated platelet activation. Thromb Haemost 110:1035–1045

    CAS  PubMed  Google Scholar 

  32. Semeraro F, Ammollo CT, Morrissey JH, Dale GL, Friese P, Esmon NL, Esmon CT (2011) Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4. Blood 118:1952–1961

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Bravo PE, Zimmerman SL, Luo HC, Pozios I, Rajaram M, Pinheiro A, Steenbergen C, Kamel IR, Wahl RL, Bluemke DA, Bengel FM, Abraham MR, Abraham TP (2013) Relationship of delayed enhancement by magnetic resonance to myocardial perfusion by positron emission tomography in hypertrophic cardiomyopathy. Circ Cardiovasc Imaging 6:210–217

    PubMed  PubMed Central  Google Scholar 

  34. Zhang YD, Li M, Qi L, Wu CJ, Wang X (2015) Hypertrophic cardiomyopathy: cardiac structural and microvascular abnormalities as evaluated with multi-parametric MRI. Eur J Radiol 84:1480–1486

    PubMed  Google Scholar 

  35. Ge L, Zhou X, Ji WJ, Lu RY, Zhang Y, Zhang YD, Ma YQ, Zhao JH, Li YM (2015) Neutrophil extracellular traps in ischemia-reperfusion injury-induced myocardial no-reflow: therapeutic potential of DNase-based reperfusion strategy. Am J Physiol Heart Circ Physiol 308:H500–H509

    CAS  PubMed  Google Scholar 

  36. Witsch T, Martinod K, Sorvillo N, Portier I, De Meyer SF, Wagner DD (2018) Recombinant human ADAMTS13 treatment improves myocardial remodeling and functionality after pressure overload injury in mice. J Am Heart Assoc 7:e007004

    PubMed  PubMed Central  Google Scholar 

  37. Lynch TLT, Ismahil MA, Jegga AG, Zilliox MJ, Troidl C, Prabhu SD, Sadayappan S (2017) Cardiac inflammation in genetic dilated cardiomyopathy caused by MYBPC3 mutation. J Mol Cell Cardiol 102:83–93

    CAS  PubMed  Google Scholar 

  38. Korkmaz HI, Ulrich MMW, Vogels S, de Wit T, van Zuijlen PPM, Krijnen PAJ, Niessen HWM (2017) Neutrophil extracellular traps coincide with a pro-coagulant status of microcirculatory endothelium in burn wounds. Wound Repair Regener 25:609–617

    Google Scholar 

  39. Thalin C, Demers M, Blomgren B, Wong SL, von Arbin M, von Heijne A, Laska AC, Wallen H, Wagner DD, Aspberg S (2016) NETosis promotes cancer-associated arterial microthrombosis presenting as ischemic stroke with troponin elevation. Thromb Res 139:56–64

    PubMed  PubMed Central  Google Scholar 

  40. Jimenez-Alcazar M, Napirei M, Panda R, Kohler EC, Kremer Hovinga JA, Mannherz HG, Peine S, Renne T, Lammle B, Fuchs TA (2015) Impaired DNase1-mediated degradation of neutrophil extracellular traps is associated with acute thrombotic microangiopathies. J Thromb Haemost 13:732–742

    CAS  PubMed  Google Scholar 

  41. Li T, Wang C, Liu Y, Li B, Zhang W, Wang L, Yu M, Zhao X, Du J, Zhang J, Dong Z, Jiang T, Xie R, Ma R, Fang S, Zhou J, Shi J (2019) Neutrophil extracellular traps induce intestinal damage and thrombotic tendency in inflammatory bowel disease. J Crohn's Colitis. https://doi.org/10.1093/ecco-jcc/jjz132

    Article  Google Scholar 

  42. Martinod K, Witsch T, Erpenbeck L, Savchenko A, Hayashi H, Cherpokova D, Gallant M, Mauler M, Cifuni SM, Wagner DD (2017) Peptidylarginine deiminase 4 promotes age-related organ fibrosis. J Exp Med 214:439–458

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Alemán OR, Mora N, Cortes-Vieyra R, Uribe-Querol E, Rosales C (2016) Transforming growth factor-β-activated kinase 1 is required for human FcγRIIIb-induced neutrophil extracellular trap formation. Front Immunol 7:277

    PubMed  PubMed Central  Google Scholar 

  44. Dinh W, Futh R, Nickl W, Krahn T, Ellinghaus P, Scheffold T, Bansemir L, Bufe A, Barroso MC, Lankisch M (2009) Elevated plasma levels of TNF-alpha and interleukin-6 in patients with diastolic dysfunction and glucose metabolism disorders. Cardiovasc Diabetol 8:58

    PubMed  PubMed Central  Google Scholar 

  45. Masters SL, Latz E, O'Neill LA (2011) The inflammasome in atherosclerosis and type 2 diabetes. Sci Transl Med 3:81

    Google Scholar 

  46. Liu S, Yue Y, Pan P, Zhang L, Su X, Li H, Li H, Li Y, Dai M, Li Q, Mao Z (2019) IRF-1 Intervention in the classical ROS-dependent release of NETs during LPS-induced acute lung injury in mice. Inflammation 42:387–403

    CAS  PubMed  Google Scholar 

  47. Chrysanthopoulou A, Mitroulis I, Apostolidou E, Arelaki S, Mikroulis D, Konstantinidis T, Sivridis E, Koffa M, Giatromanolaki A, Boumpas DT, Ritis K, Kambas K (2014) Neutrophil extracellular traps promote differentiation and function of fibroblasts. J Pathol 233:294–307

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Richard C. Becker.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Becker, R.C., Owens, A.P. & Sadayappan, S. Tissue-level inflammation and ventricular remodeling in hypertrophic cardiomyopathy. J Thromb Thrombolysis 49, 177–183 (2020). https://doi.org/10.1007/s11239-019-02026-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11239-019-02026-1

Keywords

Navigation