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.

Advances in Preclinical Research Models of Radiation-Induced Cardiac Toxicity

“…The researchers concluded that the cardiac lesions developed in rabbit hearts after single dose x-ray exposure resembled the lesions seen in humans [40]. Rabbits have since only been used by a few researchers to study RIHD [41,[114][115][116][117][118], although this species is commonly used to study cardiovascular disease from other causes [119][120][121][122][123][124][125]. There might be unique benefits to studying electrophysiological changes caused by radiation in rabbit models over rat models, as the rabbits' Ca2+ transport, action potential duration, and main ionic currents underlying repolarization are similar to humans [113,126,127].…”

“…Even among the larger animals, different species offer differing benefits. For example, models need to be selected carefully to address radiation-induced coronary alterations, an important component of human RIHD that needs additional study [6,[122][123][124][125][126][127]. The coronary circulation of pigs is similar to young human hearts (e.g., no anastomoses between branches of the vasculature), while the coronary circulation in dogs is more similar to older human hearts with ischemic heart disease (highly collateralized circulation) [129][130][131].…”

Microstructural Infarct Border Zone Remodeling in the Post-infarct Swine Heart Measured by Diffusion Tensor MRI

“…Computational modeling of cardiac electromechanics (Krishnamoorthi et al, 2014 ) can provide mechanistic insight to normal and abnormal cardiac function and electrical wave propagation (Ponnaluri et al, 2016 ). Chronic myocardial infarction remains a substantial risk factor for both mechanical heart failure and fatal electric rhythm abnormalities.…”

Semi-implicit Non-conforming Finite-Element Schemes for Cardiac Electrophysiology: A Framework for Mesh-Coarsening Heart Simulations

“…We note here that this study considered an idealized and smooth geometrical representation of the ventricles of the human heart, useful for numerical verification purposes. It is important to note that such idealized domain does not include important anatomical structures such as the intricate endocardial surface, papillary muscles, and Purkinje network, that are currently included in advanced heart models (Ponnaluri et al, 2016 ; Sahli Costabal et al, 2016 ). Future work should focus in understanding how non-conforming formulations can handle such fine-scale anatomical details and structures.…”