title: The cardiac vulnerable period and reentrant arrhythmias: targets of anti- and proarrhythmic processes.
abstract: Because sudden cardiac death is usually preceded by a reentrant arrhythmia, the precipitating arrhythmia must be multicellular in origin. Therefore clinicians seeking to reduce the incidence of reentrant arrhythmias in their patients with antiarrhythmic drugs that alter propagation may reasonably question the applicability of drug classification schemes (e.g. Sicilian Gambit) that are based on measurements in single cells. This raises a major question: are measures of a drug's anti- and proarrhythmic potential in single cells predictive of its anti- and proarrhythmic properties in tissue? The problem is as follows. From single cell measurements, one expects Class I drugs to reduce excitability, thereby attenuating the occurrence of PVCs. Similarly, one expects Class III drugs to prolong refractoriness and reduce the occurrence of PVCs. We have found in simple models of cardiac tissue that sodium channel blockade (the target of Class I drugs) extends the vulnerable period of a propagating excitation wave, whereas potassium channel blockade (the target of Class III drugs) destabilizes the reentrant path in a manner that amplifies the likelihood of polymorphic tachyarrhythmias. Using analytical, numerical, and experimental studies, we determined that sodium channel blockade was proarrhythmic. In fact, we found that any intervention that slowed conduction was proarrhythmic because slowed conduction increases the vulnerable period and reduces the spatial requirements for sustained reentry. We also found that when obstacles were placed in the path of a propagating wave, reentry occurred when the conduction velocity was less than a critical value. Once reentry was established, we observed that the ECG displayed monomorphic QRS complexes when the reentrant path did not vary from cycle to cycle. Moreover, when the reentry path did vary from cycle to cycle, the ECG displayed polymorphic QRS complexes. The cycle-to-cycle variation in QRS morphology was caused by the spatial variability of the reentry path. The variability of reentry paths (and hence the degree of polymorphic variation in QRS complexes) was amplified by Class III agents. The results presented here show that multicellular proarrhythmic effects are derived from the same mechanisms that exhibit antiarrhythmic properties in single cells.
authors.affiliation: Department of Medicine (Cardiology), Duke University Medical Center, Durham, North Carolina 27710, USA. cfs@rodney.mc.duke.edu
authors.forename: C F
authors.initials: CF
authors.lastname: Starmer
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000503:physiopathology*; D009202:Cardiomyopathies / Q000503:physiopathology; D006329:Heart Conduction System / Q000187:drug effects / Q000503:physiopathology; D008133:Long QT Syndrome / Q000188:drug therapy; D008955:Models, Cardiovascular; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism; D013610:Tachycardia / Q000188:drug therapy / Q000503:physiopathology; D013997:Time Factors
chemical_list: D015221:Potassium Channels; D015222:Sodium Channels