Full Text:   <1132>

Summary:  <1131>

CLC number: Q81

On-line Access: 2020-07-07

Received: 2019-11-05

Revision Accepted: 2020-03-11

Crosschecked: 2020-06-05

Cited: 0

Clicked: 2180

Citations:  Bibtex RefMan EndNote GB/T7714

-   Go to

Article info.
Open peer comments

Journal of Zhejiang University SCIENCE B 2020 Vol.21 No.7 P.524-536

http://doi.org/10.1631/jzus.B1900632


Biological pacemaker: from biological experiments to computational simulation


Author(s):  Yacong Li, Kuanquan Wang, Qince Li, Henggui Zhang

Affiliation(s):  School of Computer Science and Technology, Harbin Institute of Technology, Harbin 150001, China; more

Corresponding email(s):   h.zhang-3@manchester.ac.uk

Key Words:  Biological pacemaker, Gene therapy, Cell therapy, Cardiac simulation, Computational modeling


Yacong Li, Kuanquan Wang, Qince Li, Henggui Zhang. Biological pacemaker: from biological experiments to computational simulation[J]. Journal of Zhejiang University Science B, 2020, 21(7): 524-536.

@article{title="Biological pacemaker: from biological experiments to computational simulation",
author="Yacong Li, Kuanquan Wang, Qince Li, Henggui Zhang",
journal="Journal of Zhejiang University Science B",
volume="21",
number="7",
pages="524-536",
year="2020",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.B1900632"
}

%0 Journal Article
%T Biological pacemaker: from biological experiments to computational simulation
%A Yacong Li
%A Kuanquan Wang
%A Qince Li
%A Henggui Zhang
%J Journal of Zhejiang University SCIENCE B
%V 21
%N 7
%P 524-536
%@ 1673-1581
%D 2020
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B1900632

TY - JOUR
T1 - Biological pacemaker: from biological experiments to computational simulation
A1 - Yacong Li
A1 - Kuanquan Wang
A1 - Qince Li
A1 - Henggui Zhang
J0 - Journal of Zhejiang University Science B
VL - 21
IS - 7
SP - 524
EP - 536
%@ 1673-1581
Y1 - 2020
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B1900632


Abstract: 
Pacemaking dysfunction has become a significant disease that may contribute to heart rhythm disorders, syncope, and even death. Up to now, the best way to treat it is to implant electronic pacemakers. However, these have many disadvantages such as limited battery life, infection, and fixed pacing rate. There is an urgent need for a biological pacemaker (bio-pacemaker). This is expected to replace electronic devices because of its low risk of complications and the ability to respond to emotion. Here we survey the contemporary development of the bio-pacemaker by both experimental and computational approaches. The former mainly includes gene therapy and cell therapy, whilst the latter involves the use of multi-scale computer models of the heart, ranging from the single cell to the tissue slice. Up to now, a bio-pacemaker has been successfully applied in big mammals, but it still has a long way from clinical uses for the treatment of human heart diseases. It is hoped that the use of the computational model of a bio-pacemaker may accelerate this process. Finally, we propose potential research directions for generating a bio-pacemaker based on cardiac computational modeling.

生物起搏器:从生物实验到计算机模拟

概要:起搏功能障碍已成为威胁人类健康的一种重大疾病,严重时可能导致心律失常、晕厥,甚至死亡.到目前为止,治疗起搏功能障碍的最佳方案是植入电子起搏器.但是它存在一些缺点,例如电池寿命有限,手术过程具有感染的风险,起搏频率单一等.因此,对生物起搏器的研究显得尤为迫切.生物起搏器不但引起并发症的风险较低,而且能够对生理情绪做出反应,从而有望替 代电子起搏器,进行心脏起搏障碍治疗.本文从生物实验和计算机模拟两方面对生物起搏器的发展进行综述.前者主要包括基因疗法和细胞疗法的实验成果,而后者介绍了多尺度的心脏建模从单个细胞到组织切片进行起搏器研究的进展.迄今为止,生物起搏器已被应用于大型哺乳动物实验,但将其应用于临床心脏病治疗,仍有很长的路要走.利用计算机模型对生物起搏器诱发过程进行建模,有望加速研究进程.在本文中,我们首先回顾了生物起搏器实验研究的发展,然后介绍了生物起搏器计算机模型的目前的相关工作.最后,我们提出了基于心脏计算机模型研究生物起搏器的潜在研究方向.
关键词:生物起搏器;基因治疗;细胞治疗;心脏模拟;计算机模型

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

Reference

[1]Azene EM, Xue T, Marbán E, et al., 2005. Non-equilibrium behavior of HCN channels: insights into the role of HCN channels in native and engineered pacemakers. Cardiovasc Res, 67(2):263-273.

[2]Bakker ML, Boink GJJ, Boukens BJ, et al., 2012. T-box transcription factor TBX3 reprogrammes mature cardiac myocytes into pacemaker-like cells. Cardiovasc Res, 94(3):439-449.

[3]Boink GJJ, Duan L, Nearing BD, et al., 2013. HCN2/SkM1 gene transfer into canine left bundle branch induces stable, autonomically responsive biological pacing at physiological heart rates. J Am Coll Cardiol, 61(11):1192-1201.

[4]Bruzauskaite I, Bironaite D, Bagdonas E, et al., 2016. Relevance of HCN2-expressing human mesenchymal stem cells for the generation of biological pacemakers. Stem Cell Res Ther, 7:67.

[5]Burridge PW, Matsa E, Shukla P, et al., 2014. Chemically defined generation of human cardiomyocytes. Nat Methods, 11(8):855-860.

[6]Chauveau S, Anyukhovsky EP, Ben-Ari M, et al., 2017. Induced pluripotent stem cell-derived cardiomyocytes provide in vivo biological pacemaker function. Circ Arrhythm Electrophysiol, 10(5):e004508.

[7]Chen L, Deng ZJ, Zhou JS, et al., 2017. Tbx18-dependent differentiation of brown adipose tissue-derived stem cells toward cardiac pacemaker cells. Mol Cell Biochem, 433(1-2):61-77.

[8]Chen WQ, Gao RL, Liu LS, et al., 2018. Chinese cardiovascular disease report essentials. Chin Circ J, 33(1):1-8 (in Chinese).

[9]Cho HC, Kashiwakura Y, Marban E, 2007. Creation of a biological pacemaker by cell fusion. Circ Res, 100(8):1112-1115.

[10]Choi YS, Dusting GJ, Stubbs S, et al., 2010. Differentiation of human adipose-derived stem cells into beating cardiomyocytes. J Cell Mol Med, 14(4):878-889.

[11]Choudhury M, Black N, Alghamdi A, et al., 2018. TBX18 overexpression enhances pacemaker function in a rat subsidiary atrial pacemaker model of sick sinus syndrome. J Physiol, 596(24):6141-6155.

[12]Cohen IS, Brink PR, Robinson RB, et al., 2005. The why, what, how and when of biological pacemakers. Nat Clin Pract Cardiovasc Med, 2(8):374-375.

[13]Freudenberger RS, Wilson AC, Lawrence-Nelson J, et al., 2005. Permanent pacing is a risk factor for the development of heart failure. Am J Cardiol, 95(5):671-674.

[14]Germanguz I, Sedan O, Zeevi-Levin N, et al., 2011. Molecular characterization and functional properties of cardiomyocytes derived from human inducible pluripotent stem cells. J Cell Mol Med, 15(1):38-51.

[15]Gorabi AM, Hajighasemi S, Khori V, et al., 2019a. Functional biological pacemaker generation by T-Box18 protein expression via stem cell and viral delivery approaches in a murine model of complete heart block. Pharmacol Res, 141:443-450.

[16]Gorabi AM, Hajighasemi S, Tafti HA, et al., 2019b. TBX18 transcription factor overexpression in human-induced pluripotent stem cells increases their differentiation into pacemaker-like cells. J Cell Physiol, 234(2):1534-1546.

[17]Hoffmann S, Schmitteckert S, Griesbeck A, et al., 2017. Comparative expression analysis of Shox2-deficient embryonic stem cell-derived sinoatrial node-like cells. Stem Cell Res, 21:51-57.

[18]Hu YF, Dawkins JF, Cho HC, et al., 2014. Biological pacemaker created by minimally invasive somatic reprogramming in pigs with complete heart block. Sci Transl Med, 6(245):245ra94.

[19]Huang Y, Jia XL, Bai K, et al., 2010. Effect of fluid shear stress on cardiomyogenic differentiation of rat bone marrow mesenchymal stem cells. Arch Med Res, 41(7):497-505.

[20]Huang Y, Zheng LS, Gong XH, et al., 2012. Effect of cyclic strain on cardiomyogenic differentiation of rat bone marrow derived mesenchymal stem cells. PLoS ONE, 7(4):e34960.

[21]Ionta V, Liang WB, Kim EH, et al., 2015. SHOX2 overexpression favors differentiation of embryonic stem cells into cardiac pacemaker cells, improving biological pacing ability. Stem Cell Rep, 4(1):129-142.

[22]Kapoor N, Liang WB, Marbán E, et al., 2013. Direct conversion of quiescent cardiomyocytes to pacemaker cells by expression of Tbx18. Nat Biotechnol, 31(1):54-62.

[23]Kehat I, Kenyagin-Karsenti D, Snir M, et al., 2001. Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes. J Clin Invest, 108(3):407-414.

[24]Kehat I, Khimovich L, Caspi O, et al., 2004. Electromechanical integration of cardiomyocytes derived from human embryonic stem cells. Nat Biotechnol, 22(10):1282-1289.

[25]Kurata Y, Hisatome I, Matsuda H, et al., 2005. Dynamical mechanisms of pacemaker generation in IK1-downregulated human ventricular myocytes: insights from bifurcation analyses of a mathematical model. Biophys J, 89(4):2865-2887.

[26]Kuwabara Y, Kuwahara K, Takano M, et al., 2013. Increased expression of HCN channels in the ventricular myocardium contributes to enhanced arrhythmicity in mouse failing hearts. J Am Heart Assoc, 2(3):e000150.

[27]Li YJ, Yang M, Zhang GG, et al., 2018. Transcription factor TBX18 promotes adult rat bone mesenchymal stem cell differentiation to biological pacemaker cells. Int J Mol Med, 41(2):845-851.

[28]Lieu DK, Chan YC, Lau CP, et al., 2008. Overexpression of HCN-encoded pacemaker current silences bioartificial pacemakers. Heart Rhythm, 5(9):1310-1317.

[29]Luo CH, Rudy Y, 1991. A model of the ventricular cardiac action potential. Depolarization, repolarization, and their interaction. Circ Res, 68(6):1501-1526.

[30]Mayer JH 3rd, Almond CH, Anido H, et al., 1967. Complete heart block. Treatment by pedicle grafting of the sinoauricular node to the right ventricle. Arch Surg, 94(1):90-95.

[31]Miake J, Marban E, Nuss HB, 2002. Biological pacemaker created by gene transfer. Nature, 419(6903):132-133.

[32]Miake J, Marban E, Nuss HB, 2003. Functional role of inward rectifier current in heart probed by Kir2.1 overexpression and dominant-negative suppression. J Clin Invest, 111(10):1529-1536.

[33]Morishita Y, Poirier RA, Rohner RF, 1981. Sino-atrial node transplantation in the dog. Vasc Surg, 15(6):388-393.

[34]Munshi NV, Olson EN, 2014. Improving cardiac rhythm with a biological pacemaker. Science, 345(6194):268-269.

[35]Novak A, Shtrichman R, Germanguz I, et al., 2010. Enhanced reprogramming and cardiac differentiation of human keratinocytes derived from plucked hair follicles, using a single excisable lentivirus. Cell Reprogram, 12(6):665-678.

[36]Planat-Benard V, Menard C, André M, et al., 2004. Spontaneous cardiomyocyte differentiation from adipose tissue stroma cells. Circ Res, 94(2):223-229.

[37]Plotnikov AN, Sosunov EA, Qu JH, et al., 2004. Biological pacemaker implanted in canine left bundle branch provides ventricular escape rhythms that have physiologically acceptable rates. Circulation, 109(4):506-512.

[38]Plotnikov AN, Shlapakova I, Szabolcs MJ, et al., 2007. Xenografted adult human mesenchymal stem cells provide a platform for sustained biological pacemaker function in canine heart. Circulation, 116(7):706-713.

[39]Potapova I, Plotnikov A, Lu ZJ, et al., 2004. Human mesenchymal stem cells as a gene delivery system to create cardiac pacemakers. Circu Res, 94(7):952-959.

[40]Priebe L, Beuckelmann D, 1998. Simulation study of cellular electric properties in heart failure. Circu Res, 82(11):1206-1223.

[41]Qu JH, Barbuti A, Protas L, et al., 2001. HCN2 overexpression in newborn and adult ventricular myocytes: distinct effects on gating and excitability. Circu Res, 89(1):e8-e14.

[42]Qu JH, Plotnikov AN, Danilo P Jr, et al., 2003. Expression and function of a biological pacemaker in canine heart. Circulation, 107(8):1106-1109.

[43]Rangappa S, Fen C, Lee EH, et al., 2003. Transformation of adult mesenchymal stem cells isolated from the fatty tissue into cardiomyocytes. Ann Thorac Surg, 75(3):775-779.

[44]Ravagli E, Bucchi A, Bartolucci C, et al., 2016. Cell-specific dynamic clamp analysis of the role of funny If current in cardiac pacemaking. Prog Biophys Mol Biol, 120(1-3):50-66.

[45]Rosen MR, 2014. Gene therapy and biological pacing. N Engl J Med, 371(12):1158-1159.

[46]Rosen MR, Robinson RB, Brink PR, et al., 2011. The road to biological pacing. Nat Rev Cardiol, 8(11):656-666.

[47]Ruhparwar A, Tebbenjohanns J, Niehaus M, et al., 2002. Transplanted fetal cardiomyocytes as cardiac pacemaker. Eur J Cardio-Thorac Surg, 21(5):853-857.

[48]Saito Y, Nakamura K, Yoshida M, et al., 2015. Enhancement of spontaneous activity by HCN4 overexpression in mouse embryonic stem cell-derived cardiomyocytes—a possible biological pacemaker. PLoS ONE, 10(9):e0138193.

[49]Santoro B, Tibbs GR, 1999. The HCN gene family: molecular basis of the hyperpolarization-activated pacemaker channels. Ann N Y Acad Sci, 868:741-764.

[50]Shlapakova IN, Nearing BD, Lau DH, et al., 2010. Biological pacemakers in canines exhibit positive chronotropic response to emotional arousal. Heart Rhythm, 7(12):1835-1840.

[51]Silva J, Rudy Y, 2003. Mechanism of pacemaking in IK1-downregulated myocytes. Circu Res, 92(3):261-263.

[52]Starzl TE, Hermann G, Axtell HK, et al., 1963. Failure of sino-atrial nodal transplantation for the treatment of experimental complete heart block in dogs. J Thorac Cardiovasc Surg, 46:201-205.

[53]Sun Y, Timofeyev V, Dennis A, et al., 2017. A singular role of IK1 promoting the development of cardiac automaticity during cardiomyocyte differentiation by IK1-induced activation of pacemaker current. Stem Cell Rev Rep, 13(5):631-643.

[54]ten Tusscher KHWJ, Noble D, Noble PJ, et al., 2004. A model for human ventricular tissue. Am J Physiol-Heart Circ Physiol, 286(4):H1573-H1589.

[55]Tong WC, Holden AV, 2005. Induced pacemaker activity in virtual mammalian ventricular cells. In: Frangi AF, Radeva PI, Santos A, et al. (Eds.), Functional Imaging and Modeling of the Heart. FIMH 2005, Lecture Notes in Computer Science, Vol. 3504. Springer, Berlin, Heidelberg, p.226-235.

[56]Valiunas V, Kanaporis G, Valiuniene L, et al., 2009. Coupling an HCN2-expressing cell to a myocyte creates a two-cell pacing unit. J Physiol, 587(21):5211-5226.

[57]Végh AMD, den Haan AD, Cócera Ortega L, et al., 2019. Cardiomyocyte progenitor cells as a functional gene delivery vehicle for long-term biological pacing. Molecules, 24(1):181.

[58]Xue T, Cho HC, Akar FG, et al., 2005. Functional integration of electrically active cardiac derivatives from genetically engineered human embryonic stem cells with quiescent recipient ventricular cardiomyocytes: insights into the development of cell-based pacemakers. Circulation, 111(1):11-20.

[59]Yang J, Song T, Wu P, et al., 2012. Differentiation potential of human mesenchymal stem cells derived from adipose tissue and bone marrow to sinus node-like cells. Mol Med Rep, 5(1):108-113.

[60]Yang M, Zhang GG, Wang T, et al., 2016. TBX18 gene induces adipose-derived stem cells to differentiate into pacemaker-like cells in the myocardial microenvironment. Int J Mol Med, 38(5):1403-1410.

[61]Yu H, Chang F, Cohen IS, 1993. Pacemaker current exists in ventricular myocytes. Circ Res, 72(1):232-236.

[62]Zaritsky JJ, Redell JB, Tempel BL, et al., 2001. The consequences of disrupting cardiac inwardly rectifying K+ current (IK1) as revealed by the targeted deletion of the murine Kir2.1 and Kir2.2 genes. J Physiol, 533(3):697-710.

[63]Zhang H, Shlapakova IN, Zhao X, et al., 2008. Biological pacing by implantation of autologous sinoatrial node cells into the canine right ventricle. Circulation, 118:S427-S428.

[64]Zhang H, Lau DH, Shlapakova IN, et al., 2011. Implantation of sinoatrial node cells into canine right ventricle: biological pacing appears limited by the substrate. Cell Transplant, 20(11-12):1907-1914.

[65]Zhang H, Li SC, Qu D, et al., 2013. Autologous biological pacing function with adrenergic-responsiveness in porcine of complete heart block. Int J Cardiol, 168(4):3747-3751.

[66]Zhang J, Huang CX, 2019. A new combination of transcription factors increases the harvesting efficiency of pacemaker-like cells. Mol Med Rep, 19(5):3584-3592.

[67]Zhang JH, Wilson GF, Soerens AG, et al., 2009. Functional cardiomyocytes derived from human induced pluripotent stem cells. Circ Res, 104(4):e30-e41.

[68]Zhang Y, Wang KQ, Zhang HG, et al., 2014. Simulation of ventricular automaticity induced by reducing inward-rectifier K+ current. 2014 IEEE International Conference on Bioinformatics and Biomedicine (BIBM), Belfast, UK. IEEE, p.458-462.

[69]Zhang Y, Wang KQ, Zhang HG, et al., 2015. Simulation of effects of TBX18 on the pacemaker activity of human ventricular cells. 2015 IEEE International Conference on Bioinformatics and Biomedicine (BIBM), Washington, DC, USA. IEEE, p.1548-1551.

[70]Zhang Y, Wang KQ, Li QC, et al., 2016. Pacemaker created in human ventricle by depressing inward-rectifier K+ current: a simulation study. Biomed Res Int, 2016:3830682.

[71]Zhao LL, Ju DP, Gao Q, et al., 2012. Over-expression of Nkx2.5 and/or cardiac α-actin inhibit the contraction ability of ADSCs-derived cardiomyocytes. Mol Biol Rep, 39(3):2585-2595.

[72]Zhou YF, Yang XJ, Li HX, et al., 2007. Mesenchymal stem cells transfected with HCN2 genes by LentiV can be modified to be cardiac pacemaker cells. Med Hypotheses, 69(5):1093-1097.

[73]Zhou YF, Yang XJ, Li HX, et al., 2013. Genetically-engineered mesenchymal stem cells transfected with human HCN1 gene to create cardiac pacemaker cells. J Int Med Res, 41(5):1570-1576.

Open peer comments: Debate/Discuss/Question/Opinion

<1>

Please provide your name, email address and a comment





Journal of Zhejiang University-SCIENCE, 38 Zheda Road, Hangzhou 310027, China
Tel: +86-571-87952783; E-mail: cjzhang@zju.edu.cn
Copyright © 2000 - 2022 Journal of Zhejiang University-SCIENCE