Download 2015 department of medicine research day

2015 DEPARTMENT OF MEDICINE RESEARCH DAY
Title of Poster: The Electrophysiology of Heart Failure: Computational Modeling,
Validation, and Application to the Mechanisms Of Fibrillation
Presenter: Luigi E. Perotti and Aditya V. Ponnaluri
Division: Cardiology
☐Faculty ☐Fellow ☐Resident ☒Post-doc Research Fellow ☐Graduate Student ☐Medical Student ☐Other
Principal Investigator/Mentor: Alan Garfinkel
Co-Investigators: Daniel B. Ennis and William S. Klug
Thematic Poster Category: Neurobiology, Smooth, Striated and Cardiac Muscle Function, Cardiac Conduction Systems
and Arrhythmias, Biology of Perception and Pain, Psychoneuroimmunology
Abstract
Relevance: Ventricular fibrillation (VF) is a life-threatening condition, in which the ventricular
myocardium activates chaotically resulting in the inability to pump blood to the rest of the body. VF
can be triggered by external (e.g., an electric stimulus due to a blow to the chest) or internal factors
(e.g., rapid pacing combined with a failing cell electrophysiology). Computational models offer the
unique capability to provide insight to the mechanisms of VF, isolate single causal factors, study their
arrhythmogenic potential, and evaluate new interventional and pharmacological therapies in silico.
Method: We have first constructed, verified, and validated a multiscale biventricular finite element
model [1,2]. Our model includes an anatomically accurate heart geometry obtained from MRI, fiber
directions obtained from DT-MRI, a Purkinje activation network, and experimentally based ionic
cellular models divided in nine transmural and apex-to-base regions to guarantee physiologic
repolarization dispersion. This model reproduced a normal electrocardiogram (ECG), including the
correct QRS and T wave progression and morphology with no fractionation or slurring.
We use our validated model to evaluate cardiac EP and inducibility of VF in hearts with failing
myocardial cells. We model the changes in the failing cell affecting membrane currents, calcium
handling, and tissue microstructure [3-8]. Specifically, we decrease the peak slow and fast potassium
inward currents, decrease the peak potassium delayed rectifier current, and introduce a late sodium
inactivation current. In order to modify the calcium dynamics, we decrease the peak sodium calcium
exchange flux and modify the calcium release from the JSR to the myoplasm. Finally, we consider
changes in the myocardial microstructure by decreasing tissue conductance and its anisotropy. This
change is due to down regulation of Cx43 and consequent gap junction remodeling.
Results: By modeling the aforementioned changes, we were able to obtain the expected
characteristics of a failing cell's EP, i.e., longer action potential, lower and slower calcium transient,
elevated sodium transient, and earlier alternans as detected in the dynamic restitution curve.
Subsequently, we used the validated single failing cell model to study the dynamics of heterogeneous
1D cell cables, observing spatially discordant APD alternans in the failing, but not the normal, model.
Finally we have included the failing cell model in the full biventricular heart geometry, and observed Twave alternans at rapid pacing. T-wave alternans is a known risk factor and potential precursor to VF.
We also observed QRS alternans in the ECG obtained with the failing, but not the normal, cell EP.
Further, we were able to induce VF at rapid pacing with the failing, but not the normal, cell EP.
Conclusions: Using our validated and verified multiscale model we are able to reproduce the changes
observed in the single cell and in the full biventricular model in presence of HF. Most importantly, we
are able to investigate how changes at the cell level lead to VF in HF and we aim to use our model to
provide clinically useful insights and facilitate the understanding and treatment of VF in HF.
[1] Krishnamoorthi et. al., IJNMBE, 29(11):1243–1266, 2013. [2] Krishnamoorthi et. al., PloS ONE,
9(12):e114 494, 2014. [3] Nattel et. al., Physiol Rev, 87(2):425–456, 2007. [4] Hoeker et. al., Am J
Physiol-Heart C, 297(4):H1235–H1242, 2009. [5] Kääb et. al. Circ Res, 78(2):262–273, 1996. [6] Ai
et. al., Circ Res, 96(1):54–63, 2005. [7] Akar et. al. Circ Res, 95(7):717–725, 2004. [8] Dupont et.
al., J Mol Cell Cardiol, 33(2):359–371, 2001.