Document Detail


Synergistic effects of inward rectifier (I) and pacemaker (I) currents on the induction of bioengineered cardiac automaticity.
MedLine Citation:
PMID:  19460073     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
INTRODUCTION: Normal heart rhythms originate in the sinoatrial node. HCN-encoded funny current (I(f)) and the Kir2-encoded inward rectifier (I(K1)) counteract each other by respectively oscillating and stabilizing the negative resting membrane potential, and controlling action potential firing. Therefore, I(K1) suppression and I(f) overexpression have been independently exploited to convert cardiomyocytes (CMs) into AP-firing bioartificial pacemakers. Although the 2 strategies have been largely assumed synergistic, their complementarity has not been investigated.
METHODS AND RESULTS: We explored the interrelationships of automaticity, I(f) and I(K1) by transducing single left ventricular (LV) CMs isolated from guinea pig hearts with the recombinant adenoviruses Ad-CMV-GFP-IRES-HCN1-AAA and/or Ad-CGI-Kir2.1 to mediate their current densities via a whole-cell patch clamp technique at 37 degrees C. Results showed that Ad-CGI-HCN1-AAA but not Ad-CGI-Kir2.1 transduction induced automaticity (181.1 +/- 13.1 bpm). Interestingly, Ad-CGI-HCN1-AAA/Ad-CGI-Kir2.1 cotransduction significantly promoted the induced firing frequency (320.0 +/- 15.8 bpm; P < 0.05). Correlation analysis revealed that the firing frequency, phase-4 slope and APD(90) of AP-firing LV CMs were correlated with I(f) (R(2) > 0.7) only when -2 >I(K1) >-4 pA/pF but not with I(K1) over the entire I(f) ranges examined (0.02 < R(2) < 0.4). Unlike I(f), I(K1) displayed correlation with neither the phase-4 slope (R(2)= 0.02) nor phase-4 length (R(2)= 0.04) when -2 > I(f) > -4 pA/pF. As anticipated, however, APD(90) was correlated with I(K1) (R(2)= 0.4).
CONCLUSION: We conclude that an optimal level of I(K1) maintains a voltage range for I(f) to operate most effectively during a dynamic cardiac cycle.
Authors:
Yau-Chi Chan; Chung-Wah Siu; Yee-Man Lau; Chu-Pak Lau; Ronald A Li; Hung-Fat Tse
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of cardiovascular electrophysiology     Volume:  20     ISSN:  1540-8167     ISO Abbreviation:  J. Cardiovasc. Electrophysiol.     Publication Date:  2009 Sep 
Date Detail:
Created Date:  2009-09-07     Completed Date:  2009-11-23     Revised Date:  2013-06-02    
Medline Journal Info:
Nlm Unique ID:  9010756     Medline TA:  J Cardiovasc Electrophysiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1048-54     Citation Subset:  IM    
Affiliation:
Cardiology Division, Department of Medicine, University of Hong Kong, Hong Kong.
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MeSH Terms
Descriptor/Qualifier:
Action Potentials / physiology*
Animals
Cyclic Nucleotide-Gated Cation Channels / genetics*
Female
Genetic Engineering / methods*
Guinea Pigs
Heart Conduction System / physiology*
Ion Channel Gating / physiology*
Membrane Potentials / physiology*
Potassium / metabolism*
Potassium Channels / genetics*
Grant Support
ID/Acronym/Agency:
R01 HL072857-04/HL/NHLBI NIH HHS; R01 HL72857/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Cyclic Nucleotide-Gated Cation Channels; 0/Potassium Channels; 0/hyperpolarization-activated cation channel; 7440-09-7/Potassium
Comments/Corrections

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