The general hypotheses of Project 1 center on remodeling of cardiac repolarization and rate as follows: (1) postnatal electrophysiologic modeling of ventricular myocardium results in evolution of transmural gradients for repolarization and its dispersion which, when excessive may be arrhythmogenic; (2) engineered pacemaker channels expressed in specific regions of the heart will develop regular, autonomic-responsive rhythms. Testing these hypotheses will satisfy the two major goals of Project 1: (1) to understand the evolution of ventricular repolarization in developing hearts, its clinical implications and its linkage to sympathetic innervation and angiotensin II, and (2) to learn whether specific pacemaker constructs expressed in vivo can determine cardiac rhythm. In studies of intact animals, isolated tissues and single myocytes in canine and rat models, our 5 aims are to test the following hypotheses: 1: Evolution of transmural dispersion of repolarization and of rate adaptation depends importantly on evolution of I-to, I-Kr and I-Ks; 2: The distribution of I-to, I-Kr and I-Ks in epi-, endo- and midmyocardium in young hearts predisposes to proarrhythmic actions of I-Kr blocking drugs; 3: In canine ventricle developmental evolution of a transmural gradient for KChlP2 around days 40-60 of age determines the transmural gradient for I-to; 4A: Endogenous angiotensin II modulates developmental evolution of repolarization; 4B: The postnatal changes in I-Ks are modulated by sympathetic innervation, such that denervation will slow the evolution of I-Ks and expression of the transmural gradient; 4C: The general hypotheses of Project 1 center on remodeling of cardiac repolarization and rate as follows: (1) postnatal changes in I-to are modulated by sympathetic innervation and the cardiac angiotensin II pathway; 5: Specific alpha and beta subunit constructs of the pacemaker channel can function as pacemakers in the heart in situ. This research will help us understand the mechanisms underlying postnatal evolution of repolarization and rate, and their modulation. The implications are far-reaching in light of the potential lethality of specific pathophysiologic events inducing arrhythmias in children and adults and the need for better understanding of etiology, prevention and treatment. Moreover, if the engineering of pacemaker current can provide reproducible, consistent impulse initiation for the heart this will suggest important new therapeutic directions for treatment of sinus node dysfunction and of heart block.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Columbia University (N.Y.)
New York
United States
Zip Code
AlmaƧa, Joana; Liang, Tao; Gaisano, Herbert Y et al. (2015) Spatial and temporal coordination of insulin granule exocytosis in intact human pancreatic islets. Diabetologia 58:2810-8
Nawathe, Pooja A; Kryukova, Yelena; Oren, Ronit V et al. (2013) An LQTS6 MiRP1 mutation suppresses pacemaker current and is associated with sinus bradycardia. J Cardiovasc Electrophysiol 24:1021-7
Kryukova, Yelena N; Protas, Lev; Robinson, Richard B (2012) Ca2+-activated adenylyl cyclase 1 introduces Ca2+-dependence to beta-adrenergic stimulation of HCN2 current. J Mol Cell Cardiol 52:1233-9
Yan, Qinghong; Masson, Rajeev; Ren, Yi et al. (2012) Evolution of CpG island promoter function underlies changes in KChIP2 potassium channel subunit gene expression in mammalian heart. Proc Natl Acad Sci U S A 109:1601-6
Guo, Jianfen; Gertsberg, Zoya; Ozgen, Nazira et al. (2011) Protein kinase D isoforms are activated in an agonist-specific manner in cardiomyocytes. J Biol Chem 286:6500-9
Zhang, Hao; Lau, David H; Shlapakova, Iryna N et al. (2011) Implantation of sinoatrial node cells into canine right ventricle: biological pacing appears limited by the substrate. Cell Transplant 20:1907-14
Rosati, Barbara; Yan, Qinghong; Lee, Mi Sun et al. (2011) Robust L-type calcium current expression following heterozygous knockout of the Cav1.2 gene in adult mouse heart. J Physiol 589:3275-88
Kanaporis, G; Brink, P R; Valiunas, V (2011) Gap junction permeability: selectivity for anionic and cationic probes. Am J Physiol Cell Physiol 300:C600-9
Potapova, Irina A; Cohen, Ira S; Doronin, Sergey V (2010) Von willebrand factor increases endothelial cell adhesiveness for human mesenchymal stem cells by activating p38 mitogen-activated protein kinase. Stem Cell Res Ther 1:35
Wang, Wei; Gao, Junyuan; Entcheva, Emilia et al. (2010) A transmural gradient in the cardiac Na/K pump generates a transmural gradient in Na/Ca exchange. J Membr Biol 233:51-62

Showing the most recent 10 out of 303 publications