Normal rhythms originate in the sino-atrial node (SAN), a specialized cardiac tissue consisting of only a few thousands pacemaker cells. Malfunction of pacemaker cells due to diseases or aging leads to rhythm generation disorders (e.g., bradycardias) which often necessitate the implantation of electronic pacemakers. Although effective, electronic devices are associated with significant expenses, risks (such as infection, hemorrhage, lung collapse and death) and other disadvantages (e.g., limited battery life, permanent implantation of leads and the lack of autonomic responses). If, encoded by the hyperpolarization-activated cyclic nucleotide-gated or HCN1-4 channel gene family, figures prominently in cardiac pacing. During the last funding period (2004-8), we first obtained insights into the structure-function properties of HCN channels by performing a series of mutagenesis studies. Using the basic knowledge gained and transient adenovirus-mediated gene transfer of the engineered construct HCN1-??? (whose S3-S4 linker has been shortened to favor opening for mimicking the native heteromultimeric If), we subsequently demonstrated that an in vivo HCN-based bioartificial SAN (bio-SAN) can be constructed. To further our effort, here we propose: 1) To test the hypothesis that adeno- associated virus (AAV)-mediated bio-SAN displays a sustained in vivo functional efficacy and safety (24 months) in a swine model of sick sinus syndrome (SSS);2) To test the hypothesis that right atrial (RA)-converted pacemaker-like cardiomyocytes (CMs) that make up the bio-SAN do not undergo undesirable time-dependent cellular electrophysiological changes in vivo;3) To test the hypothesis that the HCN-based bio-SAN does not promote reentrant arrhythmias (by high-resolution ex vivo optical mapping), and undergoes time-dependent adaptation in vivo. Taken collectively, the proposed study will shed insights into the basis of cardiac pacing and may lead to biological alternatives or supplement to electronic pacemakers. .

Public Health Relevance

Malfunction of pacemaker cells due to diseases or aging leads to rhythm generation disorders which often necessitate the implantation of electronic pacemakers. Although effective, electronic devices are associated with significant expenses, risks and other disadvantages (e.g., limited battery life, permanent implantation of leads and the lack of autonomic responses). Built on our previous work in the area, the proposed study aims to obtain a better fundamental understanding of the basis of cardiac automaticity and to further develop biological alternatives or supplements to electronic pacemakers with long-term efficacy and safety.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL072857-08
Application #
8265653
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Lathrop, David A
Project Start
2003-04-01
Project End
2014-04-30
Budget Start
2012-06-12
Budget End
2013-04-30
Support Year
8
Fiscal Year
2012
Total Cost
$419,513
Indirect Cost
$172,013
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Liao, Song-Yan; Tse, Hung-Fat; Chan, Yau-Chi et al. (2013) Overexpression of Kir2.1 channel in embryonic stem cell-derived cardiomyocytes attenuates posttransplantation proarrhythmic risk in myocardial infarction. Heart Rhythm 10:273-82
Lieu, Deborah K; Fu, Ji-Dong; Chiamvimonvat, Nipavan et al. (2013) Mechanism-based facilitated maturation of human pluripotent stem cell-derived cardiomyocytes. Circ Arrhythm Electrophysiol 6:191-201
Sirish, Padmini; Lopez, Javier E; Li, Ning et al. (2012) MicroRNA profiling predicts a variance in the proliferative potential of cardiac progenitor cells derived from neonatal and adult murine hearts. J Mol Cell Cardiol 52:264-72
Fu, Ji-Dong; Rushing, Stephanie N; Lieu, Deborah K et al. (2011) Distinct roles of microRNA-1 and -499 in ventricular specification and functional maturation of human embryonic stem cell-derived cardiomyocytes. PLoS One 6:e27417
Poon, Ellen; Kong, Chi-Wing; Li, Ronald A (2011) Human pluripotent stem cell-based approaches for myocardial repair: from the electrophysiological perspective. Mol Pharm 8:1495-504
Chen, Aaron; Lieu, Deborah K; Freschauf, Lauren et al. (2011) Shrink-film configurable multiscale wrinkles for functional alignment of human embryonic stem cells and their cardiac derivatives. Adv Mater 23:5785-91
Jiang, Peng; Rushing, Stephanie N; Kong, Chi-wing et al. (2010) Electrophysiological properties of human induced pluripotent stem cells. Am J Physiol Cell Physiol 298:C486-95
Kong, Chi-Wing; Akar, Fadi G; Li, Ronald A (2010) Translational potential of human embryonic and induced pluripotent stem cells for myocardial repair: insights from experimental models. Thromb Haemost 104:30-8
Chan, Yau-Chi; Tse, Hung-Fat; Siu, Chung-Wah et al. (2010) Automaticity and conduction properties of bio-artificial pacemakers assessed in an in vitro monolayer model of neonatal rat ventricular myocytes. Europace 12:1178-87
Fu, Ji-Dong; Jiang, Peng; Rushing, Stephanie et al. (2010) Na+/Ca2+ exchanger is a determinant of excitation-contraction coupling in human embryonic stem cell-derived ventricular cardiomyocytes. Stem Cells Dev 19:773-82

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