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The Role of Transient Outward Current in Regulating Cardiomyocytes Electrical and Mechanical Functions

Dong, Min
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1273521671

Abstract Details

2010, PhD, University of Cincinnati, Medicine : Molecular, Cellular and Biochemical Pharmacology.
The transient outward current (Ito) is a major repolarizing current in the heart and is heterogeneously expressed across the ventricular wall. Marked reduction of Ito density is consistently observed in human heart failure (HF) and animal HF models. It was proposed that this Ito reduction contributes to a significant action potential duration (APD) prolongation and to the impaired contractility in failing heart. In addition, a high density of Ito in the right ventricular (RV) epicardial myocytes has been suggested to play a critical role in the arrhythmogenesis for the Brugada syndrome, an arrhythmia that is responsible for up to 12% of sudden cardiac deaths. Due to the lack of a specific Ito blocker, however, whether above suggestions are true is still under question. This dissertation, use the dynamic clamp to specifically simulate Ito in ventricular myocytes, delineates the role of Ito in regulating cardiomyocytes electrical and mechanical functions. Firstly, to understand the role of Ito in regulating the AP morphology and duration, we introduced simulated Ito conductance in guinea pig and canine endocardial ventricular myocytes using the dynamic clamp technique. The effects of simulated Ito in both types of cells were complex and bi-phasic, separated by a clear density threshold of about 40 pA/pF. Below this threshold, simulated Ito resulted in a distinct phase 1 notch, and had little effect on or moderately prolonged the APD. Ito above the threshold resulted in all-or-none repolarization and precipitously reduced the APD. We conclude that, in animals such as dogs and guinea pigs that have a broad cardiac AP, Ito does not play a major role in setting the APD. We next examined the influence of Ito on the mechanical properties of canine ventricular myocytes. In endocardial myocytes, where the native Ito is small, simulation of an epicardial-level Ito by the dynamic clamp significantly suppressed cell shortening by 19%. The peak amplitude of Ca2+ transient was also reduced in the presence of simulated Ito. Conversely, subtraction, or “blockade” of the native Ito enhanced contractility in epicardial cells. These results agree with the inverse correlation between Ito levels and myocyte contractility and Ca2+ transient amplitude in epicardial and endocardial myocytes. Our results show that Ito acts as a negative, rather than positive regulator of myocyte mechanical properties in large animals. In the third study, the cellular mechanism of the electrical abnormality in Brugada syndrome and the potential basis of the RV contractile abnormality observed in the syndrome were addressed. Tetrodotoxin was used to reduce cardiac Na+ current (INa) to mimic a Brugada syndrome-like setting in canine ventricular myocytes. INa reduction resulted in prolongation of APD or all-or-none repolarization in RV epicardial myocytes, and marked attenuation of myocyte contraction and Ca2+ transient. Dynamic clamp and computational modeling were used to examine the interplay between INa and the Ito and its influence on AP morphology. Both reduction of INa and increase of Ito have similar bi-phasic effects on APD, and reduction of INa shifts the APD-Ito density curve to the left. As a result, in the presence of a large Ito, INa reduction either prolongs or collapses the AP, depending on the exact density of Ito. Computational modeling showed that these repolarization changes alter myocyte Ca2+ dynamics by reducing Ca2+ influx and sarcoplasmic reticulum load. As such, the contractile abnormality of the RV wall in Brugada syndrome may be secondary to the electrical abnormalities. Together, this dissertation demonstrated the dynamic clamp as a powerful tool for studying the cardiac electrophysiology. More importantly, it quantitatively addressed the role of Ito in terms of its physiological functions and its potential contributions to arrhythmic diseases.
Hongsheng Wang, PhD (Committee Chair)
Scott Belcher, PhD (Committee Member)
Evangelia Kranias, PhD (Committee Member)
Walter Jones, PhD (Committee Member)
Steven Kleene, PhD (Committee Member)
217 p.
Biophysics
transient outward current; Brugada syndrome; dynamic clamp; ventricular myocytes; contraction; calcium transient

Recommended Citations

Citations

  • Dong, M. (2010). The Role of Transient Outward Current in Regulating Cardiomyocytes Electrical and Mechanical Functions [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1273521671

    APA Style (7th edition)

  • Dong, Min. The Role of Transient Outward Current in Regulating Cardiomyocytes Electrical and Mechanical Functions. 2010. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1273521671.

    MLA Style (8th edition)

  • Dong, Min. "The Role of Transient Outward Current in Regulating Cardiomyocytes Electrical and Mechanical Functions." Doctoral dissertation, University of Cincinnati, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1273521671

    Chicago Manual of Style (17th edition)

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This open access ETD is published by University of Cincinnati and OhioLINK.