Date Published: June 23, 2016
Publisher: Public Library of Science
Author(s): Aditya V. S. Ponnaluri, Luigi E. Perotti, Michael Liu, Zhilin Qu, James N. Weiss, Daniel B. Ennis, William S. Klug, Alan Garfinkel, Andrew D. McCulloch
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.
Partial Text: Heart failure is the leading cause of death and one of the most common causes of hospitalization in the United States. However, the mechanisms that lead to heart failure are still poorly understood. Evaluating the underlying cardiac electrophysiology (EP) can help in the treatment of cardiac arrhythmias and other consequences of heart failure. In this regard, computational biventricular models enable us to investigate the effect of changes in EP parameters and, by comparing the results to empirical clinical evidence, to refine the mechanisms of heart failure.
In order to simulate the electrophysiology of heart failure, we need to develop and validate a single cell failing EP model and the numerical methods necessary to simulate the failing EP in a biventricular model. We present both the EP model and the numerical methods in the following.
Using the models and simulation protocols described earlier, we proceed to validate our single myocyte model, analyze the EP of 1D cables of failing versus healthy myocytes, and investigate VF mechanisms in full biventricular models based on the validated failing myocyte.
The formulation and validation of the heart failure model presented starts at the single cell level, is investigated at the one dimensional level, and culminates with a geometrically and microstructurally accurate biventricular model. In the following, we highlight the advantages and limitations of the presented approach and discuss our findings. Mirroring the formulation of our model, we examine the single cell model, the one dimensional simulations, and the results obtained at the biventricular level.