Spiral waves and reentry dynamics in an in vitro model of the healed infarct border zone

Circ Res. 2009 Nov 20;105(11):1062-71. doi: 10.1161/CIRCRESAHA.108.176248. Epub 2009 Oct 8.

Abstract

Rationale: Reentry underlies most ventricular tachycardias (VTs) seen postmyocardial infarction (MI). Mapping studies reveal that the majority of VTs late post-MI arise from the infarct border zone (IBZ).

Objective: To investigate reentry dynamics and the role of individual ion channels on reentry in in vitro models of the "healed" IBZ.

Methods and results: We designed in vitro models of the healed IBZ by coculturing skeletal myotubes with neonatal rat ventricular myocytes and performed optical mapping at high temporal and spatial resolution. In culture, neonatal rat ventricular myocytes mature to form striated myocytes and electrically uncoupled skeletal myotubes simulate fibrosis seen in the healed IBZ. High resolution mapping revealed that skeletal myotubes produced localized slowing of conduction velocity (CV), increased dispersion of CV and directional-dependence of activation delay without affecting myocyte excitability. Reentry was easily induced by rapid pacing in cocultures; treatment with lidocaine, a Na(+) channel blocker, significantly decreased reentry rate and CV, increased reentry path length and terminated 30% of reentrant arrhythmias (n=18). In contrast, nitrendipine, an L-type Ca(2+) channel blocker terminated 100% of reentry episodes while increasing reentry cycle length and path length and decreasing reentry CV (n=16). K(+) channel blockers increased reentry action potential duration but infrequently terminated reentry (n=12).

Conclusions: Cocultures reproduce several architectural and electrophysiological features of the healed IBZ. Reentry termination by L-type Ca(2+) channel, but not Na(+) channel, blockers suggests a greater Ca(2+)-dependence of propagation. These results may help explain the low efficacy of pure Na(+) channel blockers in preventing and terminating clinical VTs late after MI.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Channel Blockers / pharmacology
  • Calcium Channels, L-Type / physiology
  • Heart Conduction System / drug effects
  • Heart Conduction System / pathology
  • Heart Conduction System / physiopathology
  • Muscle Fibers, Skeletal / cytology
  • Muscle Fibers, Skeletal / physiology
  • Myocardial Infarction / pathology*
  • Myocardial Infarction / physiopathology*
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / physiology
  • Organ Culture Techniques
  • Potassium Channel Blockers / pharmacology
  • Rats
  • Sodium Channel Blockers / pharmacology
  • Sodium Channels / physiology
  • Tachycardia, Ventricular / pathology*
  • Tachycardia, Ventricular / physiopathology*
  • Voltage-Sensitive Dye Imaging
  • Wound Healing / physiology*

Substances

  • Calcium Channel Blockers
  • Calcium Channels, L-Type
  • Potassium Channel Blockers
  • Sodium Channel Blockers
  • Sodium Channels