Skip to main content

Advertisement

Log in

Proliferative Potential of Cardiomyocytes in Hypertrophic Cardiomyopathy: Correlation with Myocardial Remodeling

  • Translated from Kletochnye Tekhnologii v Biologii i Meditsine (Cell Technologies in Biology and Medicine)
  • Published:
Bulletin of Experimental Biology and Medicine Aims and scope

Proliferating Ki-67+ cardiomyocytes were detected in the interventricular septum myocardium of adult patients with hypertrophic cardiomyopathy. In the same patients, the severity of hypertrophy and the degree of cardiomyocyte differentiation were assessed by the content of myofibrils, ultrastructural morphology, and the pattern of connexin 43-containing gap junction distribution. Adult Ki-67+ cardiomyocytes containing sarcomeric α-actin (sarc α-act+) in the sarcoplasm (diameter 23.9±6.9 μ) were detected in the myocardium of patients with hypertrophic cardiomyopathy; their relative content varied from 2 to 3084 cells per 1 million cardiomyocytes. Small early differentiating Ki-67+/sarc α-act+ cardiomyocytes with a thin cytoplasm layer (diameter 5.9±1.7 μ) constituted from 3 to 2262 cells per 1 million cardiomyocytes. These cells were found in the myocardium with the most pronounced structural changes: hypertrophy of cardiomyocytes with signs of their partial dedifferentiation.

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.

Similar content being viewed by others

References

  1. Belenkov YuN, Privalova EV, Kaplunova VYu. Hypertrophic Cardiomyopathy. Moscow, 2011. Russian.

  2. Bokeria LA, Berseneva MI, Malenkov DA. Arrhythmogenic complications of hypertrophic cardiomyopathy. Ann. Aritmol. 2010;7(3):62-69. Russian.

  3. Egorova IF, Serov RA. Hypertrophy of cardiomyocytes: some aspects of morphogenesis. Serd.-Sosud. Zabol. 2005;6(5):5-12. Russian.

  4. Sukhacheva TV, Chudinovskikh YA, Eremeeva MV, Samsonova MV, Chernyaev AL, Serov RA, Bockeria LA. Resident stem cells in the myocardium of patients with obstructive hypertrophic cardiomyopathy. Bull. Exp. Biol. Med. 2012;153(4):535-539.

    Article  CAS  PubMed  Google Scholar 

  5. Sukhacheva TV, Chudinovskikh YA, Eremeeva MV, Serov RA. Age-Related Features of Cardiomyocyte Ploidy in Patients with Hypertrophic Obstructive Cardiomyopathy. Bull. Exp. Biol. Med. 2015;159(1):95-99.

    Article  CAS  PubMed  Google Scholar 

  6. Shlyakhto EV, Rybakova MG, Semernin EN, Gudkova AY, Bokeria LA, Borisov KV, Selivanova GV, Vlasova TD, Parfenov VN. Cell aspects of pathogenesis of hypertrophic cardiomyopathy: the role of cardiomyocyte polyploidy and activation of the proliferating cell nuclear antigen in myocardium. Tsitologiya. 2007;49(10):817-823. Russian.

  7. Akar FG, Spragg DD, Tunin RS, Kass DA, Tomaselli GF. Mechanisms underlying conduction slowing and arrhythmogenesis in nonischemic dilated cardiomyopathy. Circ. Res. 2004;95(7):717-725.

    Article  CAS  PubMed  Google Scholar 

  8. Ausma J, Schaart G, Thoné F, Shivalkar B, Flameng W, Depré C, Vanoverschelde JL, Ramaekers F, Borgers M. Chronic ischemic viable myocardium in man: aspects of dedifferentiation. Cardiovasc. Pathol. 1995;4(1):29-37.

    Article  CAS  PubMed  Google Scholar 

  9. Beltrami AP, Urbanek K, Kajstura J, Yan SM, Finato N, Bussani R, Nadal-Ginard B, Silvestri F, Leri A, Beltrami CA, Anversa P. Evidence that human cardiac myocytes divide after myocardial infarction. N. Engl. J. Med. 2001;344(23):1750-1757.

    Article  CAS  PubMed  Google Scholar 

  10. Bonda TA, Szynaka B, Sokołowska M, Dziemidowicz M, Winnicka MM, Chyczewski L, Kamiński KA. Remodeling of the intercalated disc related to aging in the mouse heart. J. Cardiol. 2015. doi: 10.1016/j.jjcc.2015.10.001.

    PubMed  Google Scholar 

  11. Danon A, Zeevi-Levin N, Pinkovich DY, Michaeli T, Berkovich A, Flugelman M, Eldar YC, Rosen MR, Binah O. Hypoxia causes connexin 43 internalization in neonatal rat ventricular myocytes. Gen. Physiol. Biophys. 2010;29(3):222-233.

    Article  CAS  PubMed  Google Scholar 

  12. Díaz FM, Gilar MB, Saurí AR, Bosh AL, Luna A. Usefulness of DNA quantification in diagnosis of hypertrophic cardiomyopathies. A preliminary study. Forensic Sci. Int. 2006; 157(1):40-45.

    Article  PubMed  Google Scholar 

  13. Fry CH, Gray RP, Dhillon PS, Jabr RI, Dupont E, Patel PM, Peters NS. Architectural correlates of myocardial conduction: changes to the topography of cellular coupling, intracellular conductance, and action potential propagation with hypertrophy in Guinea-pig ventricular myocardium. Circ. Arrhythm. Electrophysiol. 2014;7(6):1198-1204.

    Article  PubMed  Google Scholar 

  14. Kajstura J, Rota M, Cappetta D, Ogórek B, Arranto C, Bai Y, Ferreira-Martins J, Signore S, Sanada F, Matsuda A, Kostyla J, Caballero MV, Fiorini C, D’Alessandro DA, Michler RE, del Monte F, Hosoda T, Perrella MA, Leri A, Buchholz BA, Loscalzo J, Anversa P. Cardiomyogenesis in the aging and failing human heart. Circulation. 2012;126(15):1869-1881.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kaprielian RR, Gunning M, Dupont E, Sheppard MN, Rothery SM, Underwood R, Pennell DJ, Fox K, Pepper J, Poole-Wilson PA, Severs NJ. Downregulation of immunodetectable connexin43 and decreased gap junctions size in the pathogenesis of chronic hibernation in the human left ventricle. Circulation. 1998;97(7):651-660.

    Article  CAS  PubMed  Google Scholar 

  16. Kitamura H, Ohnishi Y, Yoshida A, Okajima K, Azumi H, Ishida A, Galeano EJ, Kubo S, Hayashi Y, Itoh H, Yokoyama M. Heterogeneous loss of connexin43 protein in nonischemic dilated cardiomyopathy with ventricular tachycardia. J. Cardiovasc. Electrophysiol. 2002;13(9):865-870.

    Article  PubMed  Google Scholar 

  17. Kołcz J, Drukała J, Bzowska M, Rajwa B, Korohoda W, Malec E. The expression of connexin 43 in children with Tetralogy of Fallot. Cell Mol. Biol. Lett. 2005;10(2):287-303.

    PubMed  Google Scholar 

  18. Kostin S, Dammer S, Hein S, Klovekorn WP, Bauer EP, Schaper J. Connexin 43 expression and distribution in compensated and decompensated cardiac hypertrophy in patients with aortic stenosis. Cardiovasc. Res. 2004;62(2):426-436.

    Article  CAS  PubMed  Google Scholar 

  19. Kostin S, Rieger M, Dammer S, Hein S, Richter M, Klövekorn WP, Bauer EP, Schaper J. Gap junction remodeling and altered connexin43 expression in the failing human heart. Mol. Cell. Biochem. 2003;242(1-2):135-144.

    Article  CAS  PubMed  Google Scholar 

  20. Maes A, Flameng W, Nuyts J, Borgers M, Shivalkar B, Ausma J, Bormans G, Schiepers C, De Roo M, Mortelmans L. Histological alterations in chronically hypoperfused myocardium. Correlation with PET findings. Circulation. 1994;90(2):735-745.

    Article  CAS  PubMed  Google Scholar 

  21. Martins-Marques T, Catarino S, Zuzarte M, Marques C, Matafome P, Pereira P, Girão H. Ischaemia-induced autophagy leads to degradation of gap junction protein connexin43 in cardiomyocytes. Biochem. J. 2015;467(2):231-245.

    Article  CAS  PubMed  Google Scholar 

  22. Matturri L, Biondo B, Grosso E, Lavezzi AM, Rossi L. Morphometric and densitometric approach in hypertrophic cardiomyopathy (HCM). Eur. J. Histochem. 1995;39(3):237-244.

    CAS  PubMed  Google Scholar 

  23. Meckert PC, Rivello HG, Vigliano C, González P, Favaloro R, Laguens R. Endomitosis and polyploidization of myocardial cells in the periphery of human acute myocardial infarction. Cardiovasc. Res. 2005;67(1):116-123.

    Article  CAS  PubMed  Google Scholar 

  24. Müller P, Kazakov A, Semenov A, Böhm M, Laufs U. Pressure-induced cardiac overload induces upregulation of endothelial and myocardial progenitor cells. Cardiovasc. Res. 2008;77(1):151-159.

    Article  PubMed  Google Scholar 

  25. Noorman M, Hakim S, Kessler E, Groeneweg JA, Cox MG, Asimaki A, van Rijen HV, van Stuijvenberg L, Chkourko H, van der Heyden MA, Vos MA, de Jonge N, van der Smagt JJ, Dooijes D, Vink A, de Weger RA, Varro A, de Bakker JM, Saffitz JE, Hund TJ, Mohler PJ, Delmar M, Hauer RN, van Veen TA. Remodeling of the cardiac sodium channel, connexin43, and plakoglobin at the intercalated disk in patients with arrhythmogenic cardiomyopathy. Heart Rhythm. 2013;10(3):412-419.

    Article  PubMed  Google Scholar 

  26. Peters NS, Green CR, Poole-Wilson PA, Severs NJ. Reduced content of connexin43 gap junctions in ventricular myocardium from hypertrophied and ischemic human hearts. Circulation. 1993;88(3):864-875.

    Article  CAS  PubMed  Google Scholar 

  27. Peters NS, Wit AL. Myocardial architecture and ventricular arrhythmogenesis. Circulation. 1998;97(17):1746-1754.

    Article  CAS  PubMed  Google Scholar 

  28. Ripplinger CM, Li W, Hadley J, Chen J, Rothenberg F, Lombardi R, Wickline SA, Marian AJ, Efimov IR. Enhanced transmural fiber rotation and connexin 43 heterogeneity are associated with an increased upper limit of vulnerability in a transgenic rabbit model of human hypertrophic cardiomyopathy. Circ. Res. 2007;101(10):1049-1057.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Rücker-Martin C, Pecker F, Godreau D, Hatem SN. Dedifferentiation of atrial myocytes during atrial fibrillation: role of fibroblast proliferation in vitro. Cardiovasc. Res. 2002;55(1): 38-52.

    Article  PubMed  Google Scholar 

  30. Salameh A, Haunschild J, Bräuchle P, Peim O, Seidel T, Reitmann M, Kostelka M, Bakhtiary F, Dhein S, Dähnert I. On the role of the gap junction protein Cx43 (GJA1) in human cardiac malformations with Fallot-pathology. A study on paediatric cardiac specimen. PLoS One. 2014;9(4):e95344.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Salameh A, Krautblatter S, Karl S, Blanke K, Gomez DR, Dhein S, Pfeiffer D, Janousek J. The signal transduction cascade regulating the expression of the gap junction protein connexin43 by beta-adrenoceptors. Br. J. Pharmacol. 2009;158(1):198-208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Sanbe A, James J, Tuzcu V, Nas S, Martin L, Gulick J, Osinska H, Sakthivel S, Klevitsky R, Ginsburg KS, Bers DM, Zinman B, Lakatta EG, Robbins J. Transgenic rabbit model for human troponin I-based hypertrophic cardiomyopathy. Circulation. 2005;111(18):2330-2338.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sasano C, Honjo H, Takagishi Y, Uzzaman M, Emdad L, Shimizu A, Murata Y, Kamiya K, Kodama I. Internalization and dephosphorylation of connexin43 in hypertrophied right ventricles of rats with pulmonary hypertension. Circ. J. 2007;71(3):382-389.

    Article  CAS  PubMed  Google Scholar 

  34. Sato T, Ohkusa T, Honjo H, Suzuki S, Yoshida M.A, Ishiguro YS, Nakagawa H, Yamazaki M, Yano M, Kodama I, Matsuzaki M. Altered expression of connexin43 contributes to the arrhythmogenic substrate during the development of heart failure in cardiomyopathic hamster. Am. J. Physiol. Heart Circ. Physiol. 2008;294(3):H1164-H1173.

    Article  CAS  PubMed  Google Scholar 

  35. Sepp R, Severs NJ, Gourdie RG. Altered patterns of cardiac intercellular junction distribution in hypertrophic cardiomyopathy. Heart. 1996;76(5):412-417.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Smith JH, Green CR, Peters NS, Rothery S, Severs NJ. Altered patterns of gap junction distribution in ischemic heart disease. An immunohistochemical study of human myocardium using laser scanning confocal microscopy. Am. J. Pathol. 1991;139(4):801-821.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Suzuki G, Iyer V, Lee TC, Canty JM Jr. Autologous mesenchymal stem cells mobilize cKit+ and CD133+ bone marrow progenitor cells and improve regional function in hibernating myocardium. Circ. Res. 2011;109(9):1044-1054.

    Article  CAS  PubMed  Google Scholar 

  38. Teunissen BE, Jongsma HJ, Bierhuizen MF. Regulation of myocardial connexins during hypertrophic remodelling. Eur. Heart J. 2004;25(22):1979-1989.

    Article  CAS  PubMed  Google Scholar 

  39. Thijssen VL, Ausma J, Liu GS, Allessie MA, van Eys GJ, Borgers M. Structural changes of atrial myocardium during chronic atrial fibrillation. Cardiovasc. Pathol. 2000;9(1):17-28.

    Article  CAS  PubMed  Google Scholar 

  40. Urbanek K, Quaini F, Tasca G, Torella D, Castaldo C, Nadal-Ginard B, Leri A, Kajstura J, Quaini E, Anversa P. Intense myocyte fomation from cardiac stem cells in human cardiac hypertrophy. Proc. Natl Acad. Sci. 2003;100(18):10 440-10 445.

  41. Uzzaman M, Honjo H, Takagishi Y, Emdad L, Magee AI, Severs NJ, Kodama I. Remodeling of gap junctional coupling in hypertrophied right ventricles of rats with monocrotaline-induced pulmonary hypertension. Circ. Res. 2000;86(8):871-878.

    Article  CAS  PubMed  Google Scholar 

  42. Vetter C, Zweifel M, Zuppinger C, Carrel T, Martin D, Haefliger J.A, Delacrétaz E. Connexin 43 expression in human hypertrophied heart due to pressure and volume overload. Physiol. Res. 2010;59(1):35-42.

    CAS  PubMed  Google Scholar 

  43. Waring CD, Henning BJ, Smith AJ, Nadal-Ginard B, Torella D, Ellison GM. Cardiac adaptations from 4 weeks of intensity-controlled vigorous exercise are lost after a similar period of detraining. Physiol. Rep. 2015;3(2):e12302. doi: 10.14814/phy2.12302.

  44. Waring CD, Vicinanza C, Papalamprou A, Smith AJ, Purushothaman S, Goldspink DF, Nadal-Ginard B, Torella D, Ellison GM. The adult heart responds to increased workload with physiologic hypertrophy, cardiac stem cell activation, and new myocyte formation. Eur. Heart J. 2014;35(39):2722-2731.

    Article  PubMed  Google Scholar 

  45. Zhang Y, Li TS, Lee ST, Wawrowsky KA, Cheng K, Galang G, Malliaras K, Abraham MR, Wang C, Marbán E. Dedifferentiation and proliferation of mammalian cardiomyocytes. PLoS One. 2010;5(9):e12559.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to T. V. Sukhacheva.

Additional information

Translated from Kletochnye Tekhnologii v Biologii i Meditsine, No. 3, pp. 196-207, July, 2016

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sukhacheva, T.V., Chudinovskikh, Y.A., Eremeeva, M.V. et al. Proliferative Potential of Cardiomyocytes in Hypertrophic Cardiomyopathy: Correlation with Myocardial Remodeling. Bull Exp Biol Med 162, 160–169 (2016). https://doi.org/10.1007/s10517-016-3566-0

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10517-016-3566-0

Key Words

Navigation