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

Abstract

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.

Fig 1. (a) Longitudinal section of the biventricular heart geometry; (b) Purkinje structure with terminal Purkinje muscle junctions.

Fig 2. Activation times in a rectangular volume mesh with initial stimulus placed at the bottom left corner for (a) 100 μm and (b) 200 μm mesh sizes.

Results obtained using a mesh with edge length equal to 200 μm are converged within 2% error to the results obtained with a finer 100 μm edge length mesh.

Fig 3. 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.

Fig 4. Homogeneous cable simulations showing increased activation times in the failing cell cables.

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.

Fig 5. Apex-to-Base cable simulations.

At PCL = 400ms, the APD gradient is apparent, especially in the normal cell cable. At PCL = 250ms no 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 concordant alternans whereas the failing cell cable presents complete conduction block.

Fig 6. Transmural cable simulations.

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.

Fig 7. Normal (left) and failing (right) transmural and apex-to-base action potentials.

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

Fig 8. Normal (left) and failing (right) ECG at rest (PCL = 400ms).

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.

Fig 9. ECG traces for representative lead V5 at different PCLs for both the normal and the failing heart models.

From left to right: PCL = 400ms, PCL = 300ms, PCL = 250ms, PCL = 225ms, and PCL = 200ms. From top to bottom: normal and failing heart models. In the normal biventricular model, T-wave alternans increases from PCL≈ 250 to PCL = 200ms. However, no T-wave inversion occurs in the normal biventricular model. In contrast, T-wave alternans appears at PCL = 300ms in the failing biventricular model and progresses to include T-wave inversion and irregular T-waves at faster PCLs.

Fig 10. Delta APD maps generated by computing the difference between the APDs of two subsequent beats measured in milliseconds.

No alternans is evident at PCL = 400ms. At PCL = 250ms, discordant alternans is present in both the normal and the failing biventricular model, although the alternans is very slight in the normal model. At PCL = 200ms, a more marked discordant alternans is evident in the normal biventricular model, whereas full conduction block appears in the basal region of the failing model.

Fig 11. Following the initiation of VF, wavebreak is shown in a time-lapse series of images (left to right, top to bottom) in 10ms intervals.

Images show a curved wave of activation reentering resting tissue causing wavebreak. Images start at 1450ms. See also the corresponding ECG in Fig 12 and S1 Movie.

Fig 12. Normal (left) and failing (right) ECG due to four beats at PCL = 200ms (black arrows) followed by two stimuli at PCL = 180ms (red arrows).

This rapid pacing protocol causes VF in the failing—but not the normal—biventricular heart model.

Fig 13. ECG traces for representative lead V5 due to rapid pacing (PCL = 200ms) followed by two accelerated beats (PCL = 180 ms).

From left to right: complete failing heart model, heart model without the effect of Connexin 43 alteration, heart model with membrane changes only at the cell level, heart model with calcium handling changes only at the cell level.