Multiscale Modeling and Simulation of Human Heart Failure

Resumen

Heart failure (HF) constitutes a major public health problem worldwide. Operationally it is defined as a clinical syndrome characterized by the marked and progressive inability of the ventricles to fill and generate adequate cardiac output to meet the demands of cellular metabolism. HF may have significant variability in its etiology and it is the final common pathway of various cardiac pathologies. Susceptibility to cardiac arrhythmias is increased in account of failing phenotype. Much attention has been paid to the understanding of the arrhythmogenic mechanisms induced by the structural, electrical, and metabolic remodeling of the failing heart. Due to the complexity of the electrophysiological changes that may occur during heart failure, the scientific literature is complex and sometimes equivocal. Nevertheless, a number of common features of failing hearts have been documented. At the cellular level, prolongation of the action potential (AP) involving ion channel remodeling and alterations in calcium handling have been established as the hallmark characteristics of myocytes isolated from failing hearts. At the tissue level, intercellular uncoupling and fibrosis are identified as major arrhythmogenic factors. The rapid development of biophysically detailed computer models of single myocytes and cardiac tissues have contributed greatly to our understanding of processes underlying excitation and repolarization in the heart. In that sense, a model of the failing human ventricular myocyte was proposed, based on modifications to the Grandi et al. and O¿Hara et al. human ventricular AP models, to study the mechanisms of HF-associated arrhythmias. Multiscale simulations to characterize the arrhythmia phenotype associated to this pathology were performed. At the single cell level, we specifically looked at the role of the late sodium current (INaL), including the formulation of this current. Experimental data from several sources were used to validate the model. Due to variability in literature a sensitivity analysis was performed to assess the influence of main ionic currents and parameters upon most related biomarkers. The role of electrophysiological and structural heart failure remodeling in setting the stage for malignant arrhythmias was assessed through several configurations of transmural ventricular strands and the presence of controversial M cells was evaluated as well. Furthermore, the effect of fibrotic content and intercellular uncoupling on vulnerability to reentry was tested in transmural heterogeneous failing tissues. The proposed model for the human INaL and the electrophysiological remodeling of myocytes from failing hearts accurately reproduce experimental observations. An enhanced INaL appears to be an important contributor to the electrophysiological phenotype and to the dysregulation of calcium homeostasis of failing myocytes. Our strand simulation results illustrate how the presence of M cells and heterogeneous electrophysiological remodeling in the human failing ventricle modulate the dispersion of action potential duration (APD) and repolarization time (RT). Conduction velocity (CV) and the safety factor for conduction (SF) were also reduced by the progressive structural remodeling during heart failure. In our transmural ventricular tissue simulations, no reentry was observed in normal conditions or in the presence of HF ionic remodeling. However, defined amount of fibrosis and/or cellular uncoupling were sufficient to elicit reentrant activity. Under conditions where reentry was generated, HF electrophysiological remodeling did not alter the width of the vulnerable window (VW). However, intermediate fibrosis and cellular uncoupling significantly widened the VW. In addition, biphasic behavior was observed, as very high fibrotic content or very low tissue conductivity hampered the development of reentry. Detailed phase analysis of reentry dynamics revealed an increase of phase singularities with progressive fibrotic components. In conclusion, enhanced fibrosis in failing hearts, as well as reduced intercellular coupling, combine to increase electrophysiological gradients and reduce electrical propagation. In that sense, structural remodeling is a key factor in the genesis of vulnerability to reentry, mainly at intermediates levels of fibrosis and intercellular uncoupling. Electrophysiological remodeling promotes arrhythmogenesis and could be altered by the stage of HF.