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Simulations of Reduced Conduction Reserve in the Diabetic Rat Heart: Response to Uncoupling and Reduced Excitability

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Abstract

Experimental results have shown that action potential (AP) conduction in ventricular tissue from streptozotocin-diabetic (STZ) rats is compromised. This was manifest as increased sensitivity of conduction velocity (CV) to the gap junction uncoupler heptanol, as well as increased sensitivity of CV to reduced cellular excitability due to elevated extracellular K+ concentration, in the STZ hearts. This “reduced conduction reserve” has been suggested to be due to lateralization of connexin43 (Cx43) proteins, rendering them nonfunctional, resulting in compromised intercellular electrical coupling. In this study, we have used computer simulations of one-dimensional AP conduction in a model of rat ventricular myocytes to verify this interpretation. Our results show that compromised intercellular coupling indeed reduces conduction reserve and predict a response to gap junction uncoupling with heptanol that is consistent with experiments. However, our simulations also show that compromised intercellular coupling is insufficient to explain the increased sensitivity to reduced cellular excitability. A thorough investigation of possible underlying mechanisms, suggests that subtle alterations in the voltage-dependence of steady-state gating for the Na+ current (I Na), combined with compromised intercellular coupling, is a likely mechanism for these observations.

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References

  1. Abo, K., Y. Ishida, R. Yoshida, T. Hozumi, H. Ueno, H. Shiotani, K. Matsunaga, and T. Kazumi. Torsade de pointes in NIDDM with long QT intervals. Diabetes Care 19:1010, 1996.

    CAS  PubMed  Google Scholar 

  2. Ashraf, A., and A. Nygren. Cardiac action potential wavefront tracking using optical mapping. In: Proceedings of the 31st Annual International Conference of the IEEE-EMBS, Minneapolis, MN, September 2–6, 2009, pp. 1766–1769.

  3. Bhatnagar, A., S. K. Srivastava, and G. Szabo. Oxidative stress alters specific membrane currents in isolated cardiac myocytes. Circ. Res. 67:535–549, 1990.

    CAS  PubMed  Google Scholar 

  4. Christensen, P. K., M. A. Gall, A. Major-Pedersen, A. Sato, P. Rossing, L. Breum, A. Pietersen, J. Kastrup, and H. H. Parving. QTc interval length and QT dispersion as predictors of mortality in patients with non-insulin-dependent diabetes. Scand. J. Clin. Lab. Invest. 60:323–332, 2000.

    Article  CAS  PubMed  Google Scholar 

  5. de Groot, J. R., and R. Coronel. Acute ischemia-induced gap junctional uncoupling and arrhythmogenesis. Cardiovasc. Res. 62:323–334, 2004.

    Google Scholar 

  6. De Mello, W. C. Impaired cell communication in the diabetic heart. The role of the renin angiotensin system. Mol. Cell Biochem. 296:53–58, 2007.

    Article  PubMed  Google Scholar 

  7. Desplantez, T., E. Dupont, N. J. Severs, and R. Weingart. Gap junction channels and cardiac impulse propagation. J. Membr. Biol. 218:13–28, 2007.

    Article  CAS  PubMed  Google Scholar 

  8. El-Atat, F. A., S. I. McFarlane, J. R. Sowers, and J. T. Bigger. Sudden cardiac death in patients with diabetes. Curr. Diab. Rep. 4:187–193, 2004.

    Article  PubMed  Google Scholar 

  9. Fang, Z. Y., J. B. Prins, and T. H. Marwick. Diabetic cardiomyopathy: evidence, mechanisms, and therapeutic implications. Endocr. Rev. 25:543–567, 2004.

    Article  CAS  PubMed  Google Scholar 

  10. Fonarow, G. C. An approach to heart failure and diabetes mellitus. Am. J. Cardiol. 96:47E–52E, 2005.

    Article  PubMed  Google Scholar 

  11. Ghaly, H., P. Boyle, E. Vigmond, and A. Nygren. Reduced conduction reserve of the propagating cardiac impulse in the diabetic rat heart: a model study. Conf. Proc. IEEE Eng. Med. Biol. Soc. 2008:5926–5929, 2008.

    CAS  PubMed  Google Scholar 

  12. Jongsma, H. J., and R. Wilders. Gap junctions in cardiovascular disease. Circ. Res. 86:1193–1197, 2000.

    CAS  PubMed  Google Scholar 

  13. Kagiyama, Y., J. L. Hill, and L. S. Gettes. Interaction of acidosis and increased extracellular potassium on action potential characteristics and conduction in guinea pig ventricular muscle. Circ. Res. 51:614–623, 1982.

    CAS  PubMed  Google Scholar 

  14. Kanno, S., and J. E. Saffitz. The role of myocardial gap junctions in electrical conduction and arrhythmogenesis. Cardiovasc. Pathol. 10:169–177, 2001.

    Article  CAS  PubMed  Google Scholar 

  15. Lerner, D. L., K. A. Yamada, R. B. Schuessler, and J. E. Saffitz. Accelerated onset and increased incidence of ventricular arrhythmias induced by ischemia in Cx43-deficient mice. Circulation 101:547–552, 2000.

    CAS  PubMed  Google Scholar 

  16. Lin, X., M. Crye, and R. D. Veenstra. Regulation of connexin43 gap junctional conductance by ventricular action potentials. Circ. Res. 93:e63–e73, 2003.

    Article  PubMed  Google Scholar 

  17. Lin, H., K. Ogawa, I. Imanaga, and N. Tribulova. Remodeling of connexin 43 in the diabetic rat heart. Mol. Cell. Biochem. 290:69–78, 2006.

    Article  CAS  PubMed  Google Scholar 

  18. Luo, A., J. Ma, P. Zhang, H. Zhou, and W. Wang. Sodium channel gating modes during redox reaction. Cell Physiol. Biochem. 19:9–20, 2007.

    Article  PubMed  Google Scholar 

  19. McHowat, J., M. H. Creer, K. K. Hicks, J. H. Jones, R. McCrory, and R. H. Kennedy. Induction of Ca-independent PLA(2) and conservation of plasmalogen polyunsaturated fatty acids in diabetic heart. Am. J. Physiol. Endocrinol. Metab. 279:E25–E32, 2000.

    CAS  PubMed  Google Scholar 

  20. Miyasaka, Y., M. E. Barnes, B. J. Gersh, S. S. Cha, K. R. Bailey, W. P. Abhayaratna, J. B. Seward, and T. S. Tsang. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation 114:119–125, 2006.

    Article  PubMed  Google Scholar 

  21. Mooradian, A. D. Cardiovascular disease in type 2 diabetes mellitus: current management guidelines. Arch. Intern. Med. 163:33–40, 2003.

    Article  PubMed  Google Scholar 

  22. Morley, G. E., D. Vaidya, F. H. Samie, C. Lo, M. Delmar, and J. Jalife. Characterization of conduction in the ventricles of normal and heterozygous Cx43 knockout mice using optical mapping. J. Cardiovasc. Electrophysiol. 10:1361–1375, 1999.

    Article  CAS  PubMed  Google Scholar 

  23. Nygren, A., and W. R. Giles. Mathematical simulation of slowing of cardiac conduction velocity by elevated extracellular [K+] in a human atrial strand. Ann. Biomed. Eng. 28:951–957, 2000.

    Article  CAS  PubMed  Google Scholar 

  24. Nygren, A., and J. A. Halter. A general approach to modeling conduction and concentration dynamics in excitable cells of concentric cylindrical geometry. J. Theor. Biol. 199:329–358, 1999.

    Article  CAS  PubMed  Google Scholar 

  25. Nygren, A., M. L. Olson, K. Y. Chen, T. Emmett, G. Kargacin, and Y. Shimoni. Propagation of the cardiac impulse in the diabetic rat heart: reduced conduction reserve. J. Physiol. 580:543–560, 2007.

    Article  CAS  PubMed  Google Scholar 

  26. Pandit, S. V., R. B. Clark, W. R. Giles, and S. S. Demir. A mathematical model of action potential heterogeneity in adult rat left ventricular myocytes. Biophys. J. 81:3029–3051, 2001.

    Article  CAS  PubMed  Google Scholar 

  27. Pandit, S. V., W. R. Giles, and S. S. Demir. A mathematical model of the electrophysiological alterations in rat ventricular myocytes in type-I diabetes. Biophys. J. 84:832–841, 2003.

    Article  CAS  PubMed  Google Scholar 

  28. Rossing, P., L. Breum, A. Major-Pedersen, A. Sato, H. Winding, A. Pietersen, J. Kastrup, and H. H. Parving. Prolonged QTc interval predicts mortality in patients with Type 1 diabetes mellitus. Diabet. Med. 18:199–205, 2001.

    Article  CAS  PubMed  Google Scholar 

  29. Rudy, Y., and W. Quan. A model study of the effects of the discrete cellular structure on electrical propagation in cardiac tissue. Circ. Res. 61:815–823, 1987.

    CAS  PubMed  Google Scholar 

  30. Rush, S., and H. Larsen. A practical algorithm for solving dynamic membrane equations. IEEE Trans. Biomed. Eng. 25:389–392, 1978.

    Article  CAS  PubMed  Google Scholar 

  31. Shander, G. S., A. I. Undrovinas, and J. C. Makielski. Rapid onset of lysophosphatidylcholine-induced modification of whole cell cardiac sodium current kinetics. J. Mol. Cell. Cardiol. 28:743–753, 1996.

    Article  CAS  PubMed  Google Scholar 

  32. Shang, L. L., S. Sanyal, A. E. Pfahnl, Z. Jiao, J. Allen, H. Liu, and S. C. Dudley, Jr. NF-kappaB-dependent transcriptional regulation of the cardiac scn5a sodium channel by angiotensin II. Am. J. Physiol. Cell Physiol. 294:C372–C379, 2008.

    Article  CAS  PubMed  Google Scholar 

  33. Shaw, R. M., and Y. Rudy. Electrophysiologic effects of acute myocardial ischemia: a mechanistic investigation of action potential conduction and conduction failure. Circ. Res. 80:124–138, 1997.

    CAS  PubMed  Google Scholar 

  34. Shimoni, Y., T. Emmett, R. Schmidt, A. Nygren, and G. Kargacin. Sex-dependent impairment of cardiac action potential conduction in type 1 diabetic rats. Am. J. Physiol. Heart Circ. Physiol. 296:H1442–H1450, 2009.

    Article  CAS  PubMed  Google Scholar 

  35. Shimoni, Y., H. S. Ewart, and D. L. Severson. Type I and II models of diabetes produce different modifications of K+ currents in rat heart: role of insulin. J. Physiol. 507:485–496, 1998.

    Article  CAS  PubMed  Google Scholar 

  36. Shimoni, Y., L. Firek, D. L. Severson, and W. Giles. Short-term diabetes alters K+ currents in rat ventricular myocytes. Circ. Res. 74:620–628, 1994.

    CAS  PubMed  Google Scholar 

  37. Shimoni, Y., D. Hunt, K. Chen, T. Emmett, and G. Kargacin. Differential autocrine modulation of atrial and ventricular potassium currents and of oxidative stress in diabetic rats. Am. J. Physiol. Heart Circ. Physiol. 290:H1879–H1888, 2006.

    Article  CAS  PubMed  Google Scholar 

  38. Shimoni, Y., D. Hunt, M. Chuang, K. Y. Chen, G. Kargacin, and D. L. Severson. Modulation of potassium currents by angiotensin and oxidative stress in cardiac cells from the diabetic rat. J. Physiol. 567:177–190, 2005.

    Article  CAS  PubMed  Google Scholar 

  39. Spach, M. S., J. F. Heidlage, R. C. Barr, and P. C. Dolber. Cell size and communication: role in structural and electrical development and remodeling of the heart. Heart Rhythm. 1:500–515, 2004.

    Article  PubMed  Google Scholar 

  40. Vigmond, E. J., and C. Clements. Construction of a computer model to investigate sawtooth effects in the Purkinje system. IEEE Trans. Biomed. Eng. 54:389–399, 2007.

    Article  PubMed  Google Scholar 

  41. Weingart, R., and F. F. Bukauskas. Long-chain n-alkanols and arachidonic acid interfere with the Vm-sensitive gating mechanism of gap junction channels. Pflugers Arch. 435:310–319, 1998.

    Article  CAS  PubMed  Google Scholar 

  42. Xu, Z., K. P. Patel, M. F. Lou, and G. J. Rozanski. Up-regulation of K(+) channels in diabetic rat ventricular myocytes by insulin and glutathione. Cardiovasc. Res. 53:80–88, 2002.

    Article  CAS  PubMed  Google Scholar 

  43. Zimmet, P., K. G. Alberti, and J. Shaw. Global and societal implications of the diabetes epidemic. Nature 414:782–787, 2001.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Operating funding from the Natural Sciences and Engineering Research Council (NSERC) and the Heart & Stroke Foundation of Canada is gratefully acknowledged. Patrick Boyle was supported by scholarships from NSERC and the Alberta Ingenuity Fund.

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Authors and Affiliations

  1. Department of Electrical & Computer Engineering, University of Calgary, 2500 University Dr. NW, Calgary, AB, T2N 1N4, Canada

    Haisam A. Ghaly, Patrick M. Boyle, Edward J. Vigmond & Anders Nygren

  2. Centre for Bioengineering Research & Education, University of Calgary, Calgary, AB, Canada

    Edward J. Vigmond & Anders Nygren

  3. Department of Physiology & Pharmacology, University of Calgary, Calgary, AB, Canada

    Yakhin Shimoni

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  1. Haisam A. Ghaly
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Correspondence to Anders Nygren.

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Ghaly, H.A., Boyle, P.M., Vigmond, E.J. et al. Simulations of Reduced Conduction Reserve in the Diabetic Rat Heart: Response to Uncoupling and Reduced Excitability. Ann Biomed Eng 38, 1415–1425 (2010). https://doi.org/10.1007/s10439-009-9855-2

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  • DOI: https://doi.org/10.1007/s10439-009-9855-2

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