The primary goal of our research is to identify the underlying cellular mechanisms for lethal heart rhythm disorders. Our approach to this problem involves both computer modeling and experimental studies. Simple dynamical models and more complex ionic models are used to study cellular electrical dynamics in single cardiac myocytes and in one-, two- and three-dimensional recreations of cardiac tissue. The models have been developed using data generated by voltage clamp studies of single canine ventricular myocytes and by experiments conducted in isolated Purkinje fibers, arterially perfused canine ventricle and intact dogs. Predictions made by the computer models are tested experimentally and the resulting data are used to further refine the models. Currently, we are testing the idea that the most lethal of heart rhythm disorders, ventricular fibrillation, is caused by the nucleation of a spiral wave of reentrant excitation, which subsequently disintegrates into multiple, self-perpetuating spiral waves. This process is facilitated by the dynamical heterogeneity of cellular electrical properties that arises from a steeply sloped electrical restitution relation (the relation between the duration of the cardiac action potential and the interval between action potentials). Recent experiments indicate that reducing the slope of the restitution relation, either pharmacologically or by overexpression of selected ionic currents, may prevent the induction and maintenance of ventricular fibrillation. We are now in the process of evaluating various methods of reducing dynamical heterogeneity, with the expectation that such an approach might provide an effective means of preventing sudden cardiac death, the leading cause of death in the US.

SELECT PUBLICATIONS

1. Gelzer ARM, Koller ML, Otani NO, Fox JJ, Enyeart M, Bartoli CR, Riccio ML, Moïse NS, Gilmour RF Jr: Dynamic mechanism for initiation of ventricular fibrillation in vivo – antifibrillatory effects through modulation of restitution parameters. Circulation (in press)
2. Pumir A, Nikolski V, Hörning M, Isomura A, Agladze K, Yoshikawa K, Gilmour R, Bodenschatz E, Krinsky V: Wave emission from heterogeneities opens a way to controlling chaos in the heart. Phys Rev Lett 99:208101, 2007.
3. Freeman LC, Narvaez DF, McCoy A, von Stein FB, Young S, Silver K, Ganta S, Koch D, Hunter R, Gilmour RF, Lillich JD: Depolarization and decreased surface expression of K+ channels contribute to NSAID-inhibition of intestinal restitution. Biochem Pharmacol 74:74-85, 2007.
4. Karma A, Gilmour RF Jr. Nonlinear dynamics of heart rhythm disorders. Phys Today 60:51-57, 2007.
5. Chen X, Lal A, Riccio ML, Gilmour RF Jr. Ultrasonically activated silicon microprobes for cardiac signal recording. IEEE Trans Biomed Eng 53:1665-1671, 2006.
6. Christini DJ, Karma A, Riccio ML, Culianu CA, Fox JJ, Gilmour RF Jr. Control of electrical alternans in canine cardiac Purkinje fibers. Phys Rev Lett 96:104101-4, 2006.
7. Koller ML, Maier SKG, Gelzer AR, Bauer WR, Meesmann, M, Gilmour RF Jr. Altered dynamics of action potential restitution and alternans in humans with structural heart disease. Circulation 112:1542-1548, 2005.
8. Hua F, Gilmour RF Jr: Contribution of IKr to rate-dependent action potential dynamics in canine endocardium. Circ Res 94:810-819, 2004.
9. Hua F, Johns DC, Gilmour RF Jr: Suppression of electrical alternans by overexpression of HERG in canine ventricular myocytes. Am J Physiol 286: H2342-H2351, 2004.
10. Tyner KM, Roberson MS, Berghorn KA, Li L, Gilmour RF Jr, Giannelis EP: Intercalation, delivery and expression of the gene encoding green fluorescence protein utilizing nanobiohybrids. J Control Release 100:399-409, 2004.
11. Fox JJ, Riccio ML, Drury P, Werthman A, Gilmour RF Jr: Dynamic mechanism for conduction block in heart tissue. New J Phys 5:101.1-101.14, 2003.
12. Fox JJ, McHarg JL, and Gilmour RF Jr: Ionic mechanism of cardiac alternans. Am J Physiol 282:H516-H530, 2002.
13. Finley MR, Li Y, Hua F, Lillich J, Mitchell KE, Gilmour RF Jr, and Freeman LC: Expression and co-association of ERG1, KCNQ1 and KCNE1 potassium channel proteins in horse heart. Am J Physiol 283:H126-H138, 2002.
14. Fox JJ, Riccio ML, Hua F, Bodenschatz E, and Gilmour RF Jr: Spatiotemporal transition to conduction block in cardiac tissue. Circ Res 90:297-304, 2002.
15. Stubna MD, Rand RH, and Gilmour RF Jr: Analysis of a nonlinear partial difference equation and its application to cardiac dynamics. J Diff Eqns Appl 8:1147-1169, 2002.
16. Fox JJ, Gilmour RF Jr and Bodenschatz E: Conduction block in one dimensional heart fibers. Phys Rev Lett 89:198101-4, 2002.
17. Fox JJ, Bodenschatz E, and Gilmour RF Jr. (2002) Period-doubling instability and memory in cardiac tissue. Phys Rev Lett 89:138101-5, 2002.