From cells to ventricles: understanding the mechanisms of ventricular fibrillation through multiscale modeling

by Shankarjee Krishnamoorthi et al.

Electrophysiology of Heart Failure Using a Rabbit Model: From the Failing Myocyte to Ventricular Fibrillation.

Heart failure is a leading cause of death, yet its underlying electrophysiological (EP) mechanisms are not well understood. In this study, we use a multiscale approach to analyze a model of heart failure and connect its results to features of the electrocardiogram (ECG). The heart failure model is derived by modifying a previously validated electrophysiology model for a healthy rabbit heart. Specifically, in accordance with the heart failure literature, we modified the cell EP by changing both membrane currents and calcium handling. At the tissue level, we modeled the increased gap junction lateralization and lower conduction velocity due to downregulation of Connexin 43. At the biventricular level, we reduced the apex-to-base and transmural gradients of action potential duration (APD). The failing cell model was first validated by reproducing the longer action potential, slower and lower calcium transient, and earlier alternans characteristic of heart failure EP. Subsequently, we compared the electrical wave propagation in one dimensional cables of healthy and failing cells. The validated cell model was then used to simulate the EP of heart failure in an anatomically accurate biventricular rabbit model. As pacing cycle length decreases, both the normal and failing heart develop T-wave alternans, but only the failing heart shows QRS alternans (although moderate) at rapid pacing. Moreover, T-wave alternans is significantly more pronounced in the failing heart. At rapid pacing, APD maps show areas of conduction block in the failing heart. Finally, accelerated pacing initiated wave reentry and breakup in the failing heart. Further, the onset of VF was not observed with an upregulation of SERCA, a potential drug therapy, using the same protocol. The changes introduced at the cell and tissue level have increased the failing heart's susceptibility to dynamic instabilities and arrhythmias under rapid pacing. However, the observed increase in arrhythmogenic potential is not due to a steepening of the restitution curve (not present in our model), but rather to a novel blocking mechanism

Simulation Methods and Validation Criteria for Modeling Cardiac Ventricular Electrophysiology.

We describe a sequence of methods to produce a partial differential equation model of the electrical activation of the ventricles. In our framework, we incorporate the anatomy and cardiac microstructure obtained from magnetic resonance imaging and diffusion tensor imaging of a New Zealand White rabbit, the Purkinje structure and the Purkinje-muscle junctions, and an electrophysiologically accurate model of the ventricular myocytes and tissue, which includes transmural and apex-to-base gradients of action potential characteristics. We solve the electrophysiology governing equations using the finite element method and compute both a 6-lead precordial electrocardiogram (ECG) and the activation wavefronts over time. We are particularly concerned with the validation of the various methods used in our model and, in this regard, propose a series of validation criteria that we consider essential. These include producing a physiologically accurate ECG, a correct ventricular activation sequence, and the inducibility of ventricular fibrillation. Among other components, we conclude that a Purkinje geometry with a high density of Purkinje muscle junctions covering the right and left ventricular endocardial surfaces as well as transmural and apex-to-base gradients in action potential characteristics are necessary to produce ECGs and time activation plots that agree with physiological observations

Transmural cable simulations.

<p>At PCL = 400ms, the APD gradient is apparent, especially in the normal cell cable. At PCL = 250ms a slight concordant alternans is visible in the normal cell cable, whereas discordant alternans is visible in the failing cell cable. At PCL = 200ms, the normal cell cable shows discordant alternans whereas the failing cell cable presents complete conduction block.</p

Membrane current changes from normal to failing cell model.

<p>Membrane current changes from normal to failing cell model.</p

Normal (left) and failing (right) transmural and apex-to-base action potentials.

<p>In the failing heart, we notice the longer action potential and the reduced transmural and apex-to-base gradients.</p

Normal (left) and failing (right) ECG at rest (PCL = 400ms).

<p>The failing heart ECG shows slight widening of QRS waves, lower T-wave peaks in all leads, and marked ST-segment depression in leads V5 and V6.</p

Calcium handling changes from normal to failing cell model.

<p>Calcium handling changes from normal to failing cell model.</p

Homogeneous cable simulations showing increased activation times in the failing cell cables.

<p>Discordant alternans is visible at PCL = 250ms and PCL = 200ms in the failing cell cable. In contrast, in the normal cell cable, moderate concordant alternans is visible at PCL = 250ms and discordant alternans appears at PCL = 200ms.</p

Comparison between normal and failing basal-epicardial myocyte models showing the characteristic EP of a failing myocyte: (a) longer action potential (as seen in Fig. 1 of [2]) (top); lower, slower, and longer calcium transient (as seen in Fig. 1 of [3]) (bottom); (b) elevated intracellular sodium; and (c) early onset of alternans.

<p>Comparison between normal and failing basal-epicardial myocyte models showing the characteristic EP of a failing myocyte: (a) longer action potential (as seen in Fig. 1 of [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004968#pcbi.1004968.ref002" target="_blank">2</a>]) (top); lower, slower, and longer calcium transient (as seen in Fig. 1 of [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004968#pcbi.1004968.ref003" target="_blank">3</a>]) (bottom); (b) elevated intracellular sodium; and (c) early onset of alternans.</p