Electrophysiological Instabilities and Arrhythmia Onset

Our laboratory utilizes a hybrid approach of computational modeling and experiments to investigate biophysical mechanisms of electrophysiological instabilities and arrhythmia onset from the subcellular to organ level. Such instabilities are a main trigger of lethal cardiac arrhythmias.

Alternans

One example of such an instability is ”alternans”, which at the cellular level, is characterized by a beat-to-beat alternation in membrane potential and intracellular calcium dynamics. Alternans, which manifests on the surface electrocardiogram as T-wave alternans, is a putative trigger of some types of reentrant arrhythmias. Two possible mechanisms have been proposed for alternans – either transmembrane ionic currents or intracellular calcium dynamics fail to cycle completely during one beat, due to insufficient time, leading to the beat-to-beat alternations characteristic of alternans. Importantly, because the voltage and intracellular calcium dynamics are bidirectionally coupled, alternans in one system will lead to secondary alternans in the other. Because of this coupling it is difficult to determine which mechanism is the main source of the instability. In our laboratory, we attempt to disentangle the contributions of voltage and calcium dynamics leading to cellular alternans via a hybrid approach combining a physiologically relevant spatially extended cell model combined with patch clamp and calcium fluorescence-imaging experiments in in vitro guinea pig left ventricular myocytes.

On the subcellular level, intracellular calcium dynamics can alternate out of phase. Using isolated guinea pig ventricular myocytes, we have been able to characterize the occurrence of subcellular alternans; i.e., alternans in calcium concentration alternating out of phase in adjacent regions of a myocyte. Our experimental data and the analysis with a computational model strongly suggest that the underlying mechanism is a dynamical pattern-forming instability. A movie showing this phenomenon is available here, and shown below. This movie shows 3-region (regions are notated by colored boxes in the movie and by the corresponding traces at left) subcellular alternans in one myocyte; towards the end of the movie, the subcellular alternans is replaced by whole-cell alternans.

  1. “Characterizing the contribution of voltage- and calcium-dependent coupling to action potential stability: implications for repolarization alternans,” American Journal of Physiology293.4: H2109-H2118 (2007).
  2. “Feedback-control induced pattern formation in cardiac myocytes: a mathematical modeling study,” Journal of Theoretical Biology266: 408-418 (2010).
  3. “Dynamical mechanism for subcellular alternans in cardiac myocytes,” Circulation Research105: 335-342 (2009).

Phase-2 Reentry

Another instability example is “phase-2 reentry.” Phase 2 reentry occurs when electrotonic current propagates from sites of normal “notch-and-dome” cardiac action potentials (APs) to loss-of-dome abbreviated AP sites, causing abnormal reexcitation. The existence of two neighboring regions exhibiting these two different AP morphologies is believed to be sufficient for local reexcitation and development of phase-2 reentry. If sufficiently large and ill timed, the secondary activation associated with phase 2 reentry may initiate ventricular fibrillation and cause sudden cardiac death. We use a computational modeling approach to study this instability. One notable finding is that a main factor underlying phase 2 reentry is not the presence of two different stable morphologies in adjacent regions but rather unstable switching AP morphology within a significant subset of cells. Such work could help illuminate this unstable dynamic and point towards potential antiarrhthymia approaches.

  1. “Instability in action potential morphology underlies phase 2 reentry: A mathematical modeling study,” Heart Rhythm, 6.8: 1255