C. Frank Starmer (2007), Scholarpedia, 2(11):1847.
Dr. C. Frank Starmer, Duke - NUS Graduate Medical School Singapore
Figure 1: Each propagating excitation wave is trailed by a region of recovering cells.
For example, use-dependent drugs that bind to cardiac sodium channels reduce the density of sodium channels and retard the recovery of excitability (Starmer, C.F., Lastra, A.A., Nesterenko, V.V. and Grant, A.O. 1991; Starmer, C.F., Lancaster, A.R., Lastra, A.A. and Grant.
A.O., 1992)resulting in slowed conduction.
Similarly sodium channel mutations that alter cardiac excitability have an enhanced proarrhythmic potential (Grant, A.O., et. al, 2002; Starmer, C.F., Colatsky, T.J. and Grant, A.O., 2003a).
Clinical trials of antiarrhythmic drugs have uniformly revealed that use-dependent drugs that reduce excitability by binding to cardiac sodium channels display proarrhythmic behavior, i.e. there is an increase in the rate of sudden cardiac death associated with the use of drugs classified as antiarrhythmic (see Cardiac Arrhythmia Suppression Trial (CAST) Investigators, 1989; The Cardiac Arrhythmia Suppression Trial-II Investigators, 1992).
The mechanism of failure of these clinical trials is consistent with the concept of the vulnerable region described above.
Specifically any drug that reduces the excitability will also slow propagation of a wave thereby enlarging the vulnerable region and the probability that spontaneous oscillation of cells within the vulnerable region will trigger a reentrant arrhythmia (Wiener, N. and Rosenblueth, A, 1946; Starmer et. al, 1991, Starmer et. al, 1993, Starobin, J., Zilberter, Y.I. and Starmer, C.F., 1994).
Whitcomb, D.C., Gilliam, F.R., Starmer, C.F. and Grant, A.O. Marked QRS complex abnormalities and sodium channel blockade by propoxyphene reversed with lidocaine.
Journal of Clinical Investigation
Starmer, C.F., Lastra, A.A., Nesterenko, V.V. and Grant, A.O.
A proarrhythmic response to sodium channel blockade: Theoretical model and numerical experiments.
Circulation 1991; 84:1364-1377.
Starmer, C.F., Lancaster, A.R., Lastra, A.A. and Grant.
A.O. Cardiac instability amplified by use-dependent Na channel blockade.
American Journal of Physiology
Nesterenko, V.V., Lastra, A.A., Rosenshtraukh, L.V. and Starmer, C.F.
Gomez-Gesteira, M., Fernandez-Garcia, G., Munuzuri, A.P., Perez-Munuzuri, V., Krinsky, V.I., Starmer, C.F. and Perez-Villar, V. Vulnerability in an excitable Belousov-Zhabotinsky medium: from 1D to 2D.
Physica D 1994; 76:359-368.
Starobin, J., Zilberter, Y.I. and Starmer
, C.F. Vulnerability in one-dimensional excitable media.
Physica D. 1994; 70:321-341.
Starmer, C.F.,Romashko, D.,Reddy, R.S., Zilberter, Y.I., Starobin, J., Grant, A.O. and Krinsky, V.I. Proarrhythmic Response to Potassium Channel Blockade: Numerical Studies of Polymorphic Tachyarrhythmias.
Circulation 1995; 92:595-605.
Grant, A.O., Carboni, M.P., Neplioueva, V., Starmer, C.F., Memmi, M., Napolitano, C. and Priori, S. Long QT, Brugada and conduction system disease linked to a single Na channel mutation.
J. Clin Invest.
Starmer, C.F., Colatsky, T.J. and Grant, A.O.
What happens when cardiac Na channels lose their function?
1: Numerical studies of the vulnerable period in tissue expressing mutant channels.
Cardiovascular Research 2003a; 57:82-91.
Starmer, C.F., Grant, A.O. and Colatsky, T.J.
C. Frank Starmer
(2007) Initiation of excitation waves.
"Vulnerability of cardiac dynamics" by C. Frank Starmer