Electrophysiological and Structural Remodeling in Heart Failure Modulate Arrhythmogenesis. 1D Simulation Study

Background: Heart failure is a final common pathway or descriptor for various cardiac pathologies. It is associated with sudden cardiac death, which is frequently caused by ventricular arrhythmias. Electrophysiological remodeling, intercellular uncoupling, fibrosis and autonomic imbalance have been identified as major arrhythmogenic factors in heart failure etiology and progression. Objective: In this study we investigate in silico the role of electrophysiological and structural heart failure remodeling on the modulation of key elements of the arrhythmogenic substrate, i.e., electrophysiological gradients and abnormal impulse propagation. Methods: Two different mathematical models of the human ventricular action potential were used to formulate models of the failing ventricular myocyte. This provided the basis for simulations of the electrical activity within a transmural ventricular strand. Our main goal was to elucidate the roles of electrophysiological and structural remodeling in setting the stage for malignant life-threatening arrhythmias. Results: 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 and repolarization time. Specifically, selective heterogeneous remodeling of expression levels for the Na+ /Ca2+ exchanger and SERCA pump decrease these heterogeneities. In contrast, fibroblast proliferation and cellular uncoupling both strongly increase repolarization heterogeneities. Conduction velocity and the safety factor for conduction are also reduced by the progressive structural remodeling during heart failure. Conclusion: An extensive literature now establishes that in human ventricle, as heart failure progresses, gradients for repolarization are changed significantly by protein specific electrophysiological remodeling (either homogeneous or heterogeneous). Our simulations illustrate and provide new insights into this. Furthermore, enhanced fibrosis in failing hearts, as well as reduced intercellular coupling, combine to increase electrophysiological gradients and reduce electrical propagation. In combination these changes set the stage for arrhythmias.This work was partially supported by (i) the "VI Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica" from the Ministerio de Economia y Competitividad of Spain (grant number TIN2012-37546-C03-01) and the European Commission (European Regional Development Funds - ERDF - FEDER), (ii) the Direccion General de Politica Cientifica de la Generalitat Valenciana (grant number GV/2013/119), and (iii) Programa Prometeo (PROMETEO/2012/030) de la Conselleria d'Educacio Formacio I Ocupacio, Generalitat Valenciana. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Gómez García, JF.; Cardona, K.; Romero Pérez, L.; Ferrero De Loma-Osorio, JM.; Trénor Gomis, BA. (2014). Electrophysiological and Structural Remodeling in Heart Failure Modulate Arrhythmogenesis. 1D Simulation Study. PLoS ONE. 9(9). https://doi.org/10.1371/journal.pone.0106602S9

The formation and properties of helium-degenerate dwarfs

We have systematically analyzed the evolution of a wide variety of binary systems that ultimately lead to the formation of detached or semi-detached helium degenerate dwarfs (HeDD's). Specifically, we have explored some of the more important dimensions of parameter space including various: (i) metallicities; (ii) mass-transfer rates; and, (iii) states of evolution of the donor at the onset of mass transfer (equivalent to choosing different initial orbital separations). As has been shown in other papers, there is a sharp bifurcation in the evolutionary phenomena that lead to the formation of HeDD's. If the donor star is sufficiently evolved at the onset of mass transfer, then the binary will ultimately evolve to long orbital periods and the HeDD will detach from its Roche Lobe and cool indefinitely. In the other case, the donor continuously loses mass as the binary evolves to very short orbital periods. By examining the evolutionary results for a comprehensive range of starting conditions, the initial properties of HeDD's that undergo cooling can be determined. This is especially important since HeDD's initially cool very quickly and are most likely to be detected when they are relatively luminous. Moreover, many HeDD's are observed as companions in binary millisecond pulsar (BMSP) systems, and thus an accurate evaluation of their initial properties (e.g., surface temperature and luminosity) is central to the estimation of the ages of these systems

Mathematical simulations of sphingosine-1-phosphate actions on mammalian ventricular myofibroblasts and myocytes

Mathematical modeling has been used to explore the consequences of the actions of sphingosine-1-phosphate (S-1-P) within the ventricular myocardium. Electrophysiological data obtained from rabbit cultured myofibroblasts (Chilton et al. 2007) provided the basis for modifications of our model of electrotonic coupling between ventricular myocytes and fibroblasts (MacCannell et al. 2007). Specifically, an in silico fibroblast/myocyte hybrid model was modified to account for the electrophysiological properties that are characteristic of the myofibroblast (the wound healing phenotype of the fibroblast). In addition, equations describing an S-1-P-induced current that can be activated in the myofibroblast were added. \ud \ud The sets of simulations that constitute this paper demonstrate that S-1-P can cause a significant depolarization of the resting membrane potential in both the myofibroblast and myocyte. When the myocyte to fibroblast coupling ratio is 1:1, this concentration-dependent effect is due to ligand-gated current in the myofibroblast depolrizing the myocyte through heterotypic connexin-mediated intercellular junctions. In addition to changing the resting potential in the myocyte, the S-1-P induced current resulted in significant changes in action potential waveform.\ud \ud A second set of simulations was done for the purpose of exploring the effects of S-1-P on myocytes that have some of the main electrophysiological properties of those from the failing heart. In these computations, the ten Tusscher model of the human ventricular myocyte was modified by reducing parameters as follows: cell capacitance, inward rectifier K+ current, delayed-rectifier K+ currents (IKs and IKr), and transient outward K+ current. In combination, these changes (each of which is associated with heart failure), resulted in prolongation of action potential duration. Simulations of electrotonic coupling between this 'failing' myocyte and myofibroblasts demonstrated that the resting potential and APD in the failing myocyte is more susceptible to modulation by electrotonic influences from S-1-P-stimulated myofibroblasts when a 'failing' electrophysiological phenotype is mimicked.\ud \ud In summary, our simulations draw attention to important effects of S-1-P on the ventricular myocardium even when this paracrine substance actos only on the fibroblast cell population. These cell-specific S-1-P effects alter the myocyte action potential via electrotonic coupling with myocytes. It is apparent that myofibroblasts can have significant effects on myocyte action potentials; and these effects would be expected to be more pronounced in the presence of ligand-gated effects on the myofibroblast. The general setting that we have attempted to replicate with this first order model has some similarities to acute or sterile inflammation in the myocardium wherein S-1-P concentrations in the interstitium are relatively high

Genesis of Atrial Fibrillation Under Different Diffuse Fibrosis Density Related with Atmospheric Pollution. In-Silico Study

Atrial remodeling is a widely acknowledged process that accelerates the susceptibility to and progression of atrial fibrillation. An increasingly recognized structural component is atrial fibrosis. Recent studies have shown that air pollution increases the risk of heart arrhythmias, where the exposure to particulate matter (PM) contributes to the generation of myocardial fibrosis, increasing the cardiovascular risk. The density and patterns of fibrosis (interstitial, compact and diffuse) are relevant in abnormal conduction and vulnerability to cardiac arrhythmias. Taking into account that fibrosis has been widely reported as one of the consequences of PM exposure, in this work, we evaluated the effects of low and high diffuse fibrosis density on conduction velocity and arrhythmic propagation patterns. For this purpose, cellular models of atrial myocyte and fibroblast were implemented in a 3D model of the human atria. Low (6.25%) and high (25%) fibrosis densities were simulated in the left atrium and its effect on conduction velocity and fibrillatory dynamics was evaluated. Results showed a conduction velocity reduction of 71% associated with a high fibrosis density. At low fibrosis density, few reentries were observed. On the other hand, at high fibrosis density, irregular propagation patterns, characterized by multiple wavelets and rotors, were observed. Our results suggest that high diffuse fibrosis density is associated with a significant conduction velocity reduction and with chaotic propagation patterns during atrial fibrillation. © 2020, Springer Nature Switzerland AG