Skip to main content
SpringerLink
Log in

Concurrent increases in post-pacing action potential duration and contractility predict occurrence of ventricular arrhythmia

  • Signaling and cell physiology
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Excitation-contraction coupling from the integration of action potential duration (APD) and muscle contractility plays an important role in arrhythmogenesis. We aimed to determine whether distinctive excitation-contraction coupling contributes to the genesis of ventricular tachycardias (VTs). Action potential (AP) and mechanical activity were simultaneously recorded under electrical pacing (cycle lengths from 1000 to 100 ms) in the tissue model created from isolated rabbit right ventricular outflow tracts treated with NS 5806 (10 μM, transient outward potassium current enhancer), pinacidil (2 μM, ATP-sensitive potassium channel opener), and pilsicainide (5 μM, sodium channel blocker). There were 15 (9.9%) inducible VT episodes (group 1) and 136 (90.1%) non-inducible VT episodes (group 2) in our tissue model. Group 1 had greater post-pacing increases of the first occurrence of AP at 90% repolarization (ΔAPD90, p < 0.001) and contractility (ΔContractility, p = 0.003) compared with group 2. Triggered VT episodes were common (72.7%) in cases with a ΔAPD90 > 15% and a ΔContractility > 270%, but were undetectable in those with a ΔAPD90 < 15% and a ΔContractility < 270%. In those with pacing-induced VTs, KB-R7943 (10 μM, a Na+–Ca2+ exchanger inhibitor, NCX inhibitor) significantly reduced the occurrence of VTs from 100.0 to 20.0% (15/15 to 3/15 episodes, p < 0.001). Concurrent increases in both post-pacing APD and contractility resulted in the occurrence of ventricular arrhythmias. NCX inhibition may be a potential therapeutic strategy for ventricular arrhythmias.

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
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

AP:

action potential

APA:

action potential amplitude

APD:

action potential duration

DAD:

delayed afterdepolarization

EAD:

early afterdepolarization

E-C:

excitation-contraction

M-E:

mechano-electric

NCX:

Na+–Ca2+ exchanger

NIH:

National Institutes of Health

RV:

right ventricle

RVOT:

right ventricular outflow tract

RyR:

ryanodine receptor

SEM:

standard error of the mean

SPSS:

Statistical Package for the Social Sciences

SR:

sarcoplasm reticulum

VA:

ventricular arrhythmia

VT:

ventricular tachycardia

ΔAPD90 :

first occurrence of post-pacing APD90 prolongation

ΔContractility:

first occurrence of post-pacing contractility enhancement

References

  1. Asakura K, Cha CY, Yamaoka H, Horikawa Y, Memida H, Powell T, Amano A, Noma A (2014) EAD and DAD mechanisms analyzed by developing a new human ventricular cell model. Prog Biophys Mol Biol 116:11–24. https://doi.org/10.1016/j.pbiomolbio.2014.08.008

    Article  CAS  PubMed  Google Scholar 

  2. Bjerregaard P, Gussak I (2013) Short QT Syndrome. In: Gussak I, Antzelevitch C (eds) Electrical diseases of the heart: volume 1: basic foundations and primary electrical diseases. Springer London, London, pp 569–581. https://doi.org/10.1007/978-1-4471-4881-4_33

    Chapter  Google Scholar 

  3. Brugada J, Campuzano O, Arbelo E, Sarquella-Brugada G, Brugada R (2018) Present status of Brugada syndrome: JACC state-of-the-art review. J Am Coll Cardiol 72:1046–1059. https://doi.org/10.1016/j.jacc.2018.06.037

    Article  PubMed  Google Scholar 

  4. Calloe K, Cordeiro JM, Di Diego JM, Hansen RS, Grunnet M, Olesen SP, Antzelevitch C (2009) A transient outward potassium current activator recapitulates the electrocardiographic manifestations of Brugada syndrome. Cardiovasc Res 81:686–694. https://doi.org/10.1093/cvr/cvn339

    Article  CAS  PubMed  Google Scholar 

  5. Chang SL, Chen YC, Chen YJ, Wangcharoen W, Lee SH, Lin CI, Chen SA (2007) Mechanoelectrical feedback regulates the arrhythmogenic activity of pulmonary veins. Heart 93:82–88. https://doi.org/10.1136/hrt.2006.089359

    Article  PubMed  Google Scholar 

  6. Council NR (2011) Guide for the care and use of laboratory animals, 8th edn. The National Academies Press, Washington, DC. https://doi.org/10.17226/12910

    Book  Google Scholar 

  7. Eisner DA, Caldwell JL, Kistamas K, Trafford AW (2017) Calcium and excitation-contraction coupling in the heart. Circ Res 121:181–195. https://doi.org/10.1161/circresaha.117.310230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Fu M, Wu M, Wang J-F, Qiao Y-J, Wang Z (2007) Disruption of the intracellular Ca2+ homeostasis in the cardiac excitation-contraction coupling is a crucial mechanism of arrhythmic toxicity in aconitine-induced cardiomyocytes. Biochem Biophys Res Commun 354:929–936

    Article  CAS  Google Scholar 

  9. Gorski PA, Kho C, Oh JG (2018) Measuring cardiomyocyte contractility and calcium handling in vitro. Methods Mol Biol (Clifton, NJ) 1816:93–104. https://doi.org/10.1007/978-1-4939-8597-5_7

    Article  CAS  Google Scholar 

  10. Jafri MS (2012) Models of excitation-contraction coupling in cardiac ventricular myocytes. Methods Mol Biol (Clifton, NJ) 910:309–335. https://doi.org/10.1007/978-1-61779-965-5_14

    Article  CAS  Google Scholar 

  11. Kannankeril P, Roden DM, Darbar D (2010) Drug-induced long QT syndrome. Pharmacol Rev 62:760–781. https://doi.org/10.1124/pr.110.003723

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kohl P, Sachs F, Franz MR (2011) Cardiac mechano-electric coupling and arrhythmias. OUP, Oxford

    Book  Google Scholar 

  13. Lu YY, Chung FP, Chen YC, Tsai CF, Kao YH, Chao TF, Huang JH, Chen SA, Chen YJ (2014) Distinctive electrophysiological characteristics of right ventricular out-flow tract cardiomyocytes. J Cell Mol Med 18:1540–1548. https://doi.org/10.1111/jcmm.12329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Luo CH, Rudy Y (1994) A dynamic model of the cardiac ventricular action potential. II. Afterdepolarizations, triggered activity, and potentiation. Circ Res 74:1097–1113. https://doi.org/10.1161/01.res.74.6.1097

    Article  CAS  PubMed  Google Scholar 

  15. Monasky MM, Pappone C, Piccoli M, Ghiroldi A, Micaglio E, Anastasia L (2018) Calcium in Brugada Syndrome: questions for future research. Front Physiol 9:1088. https://doi.org/10.3389/fphys.2018.01088

    Article  PubMed  PubMed Central  Google Scholar 

  16. Morita H, Morita ST, Nagase S, Banba K, Nishii N, Tani Y, Watanabe A, Nakamura K, Kusano KF, Emori T, Matsubara H, Hina K, Kita T, Ohe T (2003) Ventricular arrhythmia induced by sodium channel blocker in patients with Brugada syndrome. J Am Coll Cardiol 42:1624–1631. https://doi.org/10.1016/j.jacc.2003.06.004

    Article  CAS  PubMed  Google Scholar 

  17. Nademanee K, Veerakul G, Chandanamattha P, Chaothawee L, Ariyachaipanich A, Jirasirirojanakorn K, Likittanasombat K, Bhuripanyo K, Ngarmukos T (2011) Prevention of ventricular fibrillation episodes in Brugada syndrome by catheter ablation over the anterior right ventricular outflow tract epicardium. Circulation 123:1270–1279. https://doi.org/10.1161/circulationaha.110.972612

    Article  PubMed  Google Scholar 

  18. Schober T, Huke S, Venkataraman R, Gryshchenko O, Kryshtal D, Hwang HS, Baudenbacher FJ, Knollmann BC (2012) Myofilament Ca sensitization increases cytosolic Ca binding affinity, alters intracellular Ca homeostasis, and causes pause-dependent Ca-triggered arrhythmia. Circ Res 111:170–179. https://doi.org/10.1161/circresaha.112.270041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Shimizu W, Antzelevitch C (2000) Differential effects of beta-adrenergic agonists and antagonists in LQT1, LQT2 and LQT3 models of the long QT syndrome. J Am Coll Cardiol 35:778–786. https://doi.org/10.1016/s0735-1097(99)00582-3

    Article  CAS  PubMed  Google Scholar 

  20. Sipido KR (2004) Understanding cardiac alternans: the answer lies in the Ca2+ store. Circ Res 94:570–572. https://doi.org/10.1161/01.res.0000124606.14903.6f

    Article  CAS  PubMed  Google Scholar 

  21. Sipido KR, Bito V, Antoons G, Volders PG, Vos MA (2007) Na/Ca exchange and cardiac ventricular arrhythmias. Ann N Y Acad Sci 1099:339–348. https://doi.org/10.1196/annals.1387.066

    Article  CAS  PubMed  Google Scholar 

  22. Tang L, Joung B, Ogawa M, Chen PS, Lin SF (2012) Intracellular calcium dynamics, shortened action potential duration, and late-phase 3 early afterdepolarization in Langendorff-perfused rabbit ventricles. J Cardiovasc Electrophysiol 23:1364–1371. https://doi.org/10.1111/j.1540-8167.2012.02400.x

    Article  PubMed  PubMed Central  Google Scholar 

  23. Tsai WC, Lu YY, Chen YC, Chang CJ, Kao YH, Lin YK, Chen YH, Chen SA, Yang LY, Chen YJ (2015) Ablation of androgen receptor gene triggers right ventricular outflow tract ventricular tachycardia. Int J Cardiol 189:172–181. https://doi.org/10.1016/j.ijcard.2015.04.080

    Article  PubMed  Google Scholar 

  24. Tse G, Chan YW, Keung W, Yan BP (2017) Electrophysiological mechanisms of long and short QT syndromes. Int J Cardiol Heart Vasc 14:8–13. https://doi.org/10.1016/j.ijcha.2016.11.006

    Article  PubMed  Google Scholar 

  25. Venetucci LA, Trafford AW, O’Neill SC, Eisner DA (2008) The sarcoplasmic reticulum and arrhythmogenic calcium release. Cardiovasc Res 77:285–292. https://doi.org/10.1093/cvr/cvm009

    Article  CAS  PubMed  Google Scholar 

  26. Wongcharoen W, Chen YC, Chen YJ, Chang CM, Yeh HI, Lin CI, Chen SA (2006) Effects of a Na+/Ca2+ exchanger inhibitor on pulmonary vein electrical activity and ouabain-induced arrhythmogenicity. Cardiovasc Res 70:497–508. https://doi.org/10.1016/j.cardiores.2006.02.026

    Article  CAS  PubMed  Google Scholar 

  27. Zeng J, Rudy Y (1995) Early afterdepolarizations in cardiac myocytes: mechanism and rate dependence. Biophys J 68:949–964. https://doi.org/10.1016/s0006-3495(95)80271-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zima AV, Bovo E, Mazurek SR, Rochira JA, Li W, Terentyev D (2014) Ca handling during excitation-contraction coupling in heart failure. Pflugers Arch 466:1129–1137. https://doi.org/10.1007/s00424-014-1469-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by grants from the Ministry of Science and Technology (MOST105-2314-B-016-035-MY3, MOST105-2628-B-038-012-MY3, MOST105-2314-B-038-059-MY3, 107-2314-B-281-009, 107-2314-B-038-101-MY3), Taipei Medical University-Wan Fang Hospital (106-eva-02, 106-eva-06, 106-swf-01, 107-wf-swf-01, and 107-wf-eva-01), Cathay General Hospital (107CGH-TMU-05), Chi-Mei Medical Center (107CM-TMU-04), and the Foundation for the Development of Internal Medicine in Okinawa (31-02-003).

Author information

Authors and Affiliations

  1. Heart Rhythm Center, Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

    Chih-Min Liu, Cheng-I Wu & Shih-Ann Chen

  2. Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan

    Chih-Min Liu, Cheng-I Wu & Shih-Ann Chen

  3. Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan

    Feng-Zhi Lin

  4. Department of Biomedical Engineering, National Defense Medical Center, Taipei, Taiwan

    Yao-Chang Chen

  5. Division of Cardiovascular Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, 111 Hsin-Lung Road, Sec. 3, Taipei, Taiwan

    Yung-Kuo Lin & Yi-Jen Chen

  6. Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

    Yung-Kuo Lin

  7. Division of Cardiology, Sijhih Cathay General Hospital, New Taipei City, Taiwan

    Yen-Yu Lu

  8. Cardiac Electrophysiology and Pacing Laboratory, Division of Cardiovascular Medicine, Makiminato Central Hospital, Okinawa, Japan

    Satoshi Higa

  9. Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

    Yi-Jen Chen

  10. Cardiovacular Research Center, Wan Fang Hospital, Taipei Medical University , Taipei, Taiwan

    Yi-Jen Chen

Authors
  1. Chih-Min Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Feng-Zhi Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yao-Chang Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yung-Kuo Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yen-Yu Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Cheng-I Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Satoshi Higa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shih-Ann Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yi-Jen Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

CML and YJC generated the research topic, did the literature search, and prepared the first manuscript. CML and FZL did the electropharmacological experiments and ran the statistical tests. CML, FZL, YCC, and YJC analyzed and interpreted the data. YKL, YYL, CIW, SH, and SAC conceived the study concept and contributed important parts in data interpretation. YJC critically read the manuscript and made vital suggestions in revision. All authors reviewed and approved the final manuscript.

Corresponding author

Correspondence to Yi-Jen Chen.

Ethics declarations

Ethics approval and consent to participate

The investigation was approved by the local ethics review board of Taipei Veterans General Hospital (reference number: IACUC-2019-192).

Competing interests

The authors declare that they have no competing interests.

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

Liu, CM., Lin, FZ., Chen, YC. et al. Concurrent increases in post-pacing action potential duration and contractility predict occurrence of ventricular arrhythmia. Pflugers Arch - Eur J Physiol 472, 1783–1791 (2020). https://doi.org/10.1007/s00424-020-02445-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-020-02445-7

Keywords

Search

Navigation