Mechanisms of Ventricular Fibrillation : The role of mechano-electrical feedback and tissue heterogeneity

The heart is a muscular organ that pumps blood throughout the body. The human heart contracts approximately once per second, adding up to more than 2.5 billion contractions over 80 years. Failure in cardiac contraction leads to sudden cardiac death, which is one of the most common causes of death in the industrialized world. In most cases this is caused by ventricular fibrillation (VF). During VF turbulent excitation patterns occur, causing uncoordinated contraction of the ventricles. If VF is not halted by means of defibrillation, blood circulation will cease, causing cardiac death within minutes. One important tool to study the mechanisms underlying cardiac physiology, is mathematical modeling. Over the last decades mathematical models ranging from single cell dynamics to complex three-dimensional whole organ models have been used to study cardiac arrhythmias. The focus of this thesis is to gain more insight in the underlying mechanisms of VF using electrophysiological and mechanical models of the human heart. We are especially interested in mechano-electrical feedback and in the role of tissue heterogeneity in the onset of cardiac arrhythmias. In the first part of this thesis we investigated the basic effects of mechano-electrical feedback in two-dimensional systems using simple low dimensional models to describe cardiac excitable behavior. In the second part of this thesis we used anatomically based models of the human ventricles to study the mechanisms and dynamics of VF and investigated the effects of tissue heterogeneity and mechano-electrical feedback. The most important conclusions regarding mechano-electrical feedback is that local tissue deformations can lead to automatic pacemaker activity via the stretch-activated channels, and that local stretch of fibers can cause an otherwise stable spiral wave to break up. The most important conclusions regarding tissue heterogeneity is that action potential duration restitution heterogeneity is not only important for the initiation of wavebreaks and re-entry, but also affects the dynamics of ventricular fibrillation. Furthermore, different initial conditions can lead to different mechanisms of ventricular fibrillation: either mother rotor or multiple wavelet ventricular fibrillation. These results indicate that mechano-electrical feedback and tissue heterogeneity may play an important role in the initiation and dynamics of ventricular fibrillation. Hence, reducing electrophysiological heterogeneity may be a fruitful target for therapeutic intervention

Self-organized pacemakers in a coupled reaction-diffusion-mechanics system

Using a computational model of a coupled reaction-diffusion-mechanics system, we find that mechanical deformation can induce automatic pacemaking activity. Pacemaking is shown to occur after a single electrical or mechanical stimulus in an otherwise nonoscillatory medium. We study the mechanisms underpinning this effect and conditions for its existence. We show that self-organized pacemakers drift throughout the medium to approach attractors with locations that depend on the size of the medium, and on the location of the initial stimulus

Computer simulations of successful defibrillation in decoupled and non-uniform cardiac tissue

AIM: The aim of the present study is to investigate the origin and effect of virtual electrode polarization in uniform, decoupled and non-uniform cardiac tissue during field stimulation. METHODS: A discrete bidomain model with active membrane behaviour was used to simulate normal cardiac tissue as well as cardiac tissue that is decoupled due to fibrosis and gap junction remodelling. Various uniform and non-uniform electric fields were applied to the external domain of uniform, decoupled and non-uniform resting cardiac tissue as well as cardiac tissue in which spiral waves were induced. RESULTS: Field stimulation applied on non-uniform tissue results in more virtual electrodes compared with uniform tissue. The spiral waves were terminated in decoupled tissue, but not in uniform, homogeneous tissue. By gradually increasing local differences in intracellular conductivities, the amount and spread of virtual electrodes increased and the spiral waves were terminated. CONCLUSION: Fast depolarization of the tissue after field stimulation may be explained by intracellular decoupling and spatial heterogeneity present in normal and pathological cardiac tissue. We demonstrated that termination of spiral waves by means of field stimulation can be achieved when the tissue is modelled as a non-uniform, anisotropic bidomain with active membrane behaviour

The role of the hyperpolarization-activated inward current I_f in arrhythmogenesis : a computer model study

Atrial fibrillation is the most common cardiac arrhythmia. Structural cardiac defects such as fibrosis and gap junction remodeling lead to a reduced cellular electrical coupling and are known to promote atrial fibrillation. It has been observed that the expression of the hyperpolarization-activated current I_ f is increased under pathological conditions. Recent experimental data indicate a possible contribution of I_ f to arrhythmogenesis. In this paper, the role of I_ f in action potential propagation in normal and in pathological tissue is investigated by means of computer simulations. The effect of diffuse fibrosis and gap junction remodeling is simulated by reducing cellular coupling nonuniformly. As expected, the conduction velocity decreases when cellular coupling is reduced. In the presence of I_ f the conduction velocity increases both in normal and in pathological tissue. In our simulations, ectopic activity is present in regions with high expression of I_ fand is facilitated by cellular uncoupling. We conclude that an increased I_ f may facilitate propagation of the action potential. Hence, I_ f may prevent conduction slowing and block. Overexpression of I_ f may lead to ectopic activity, especially when cellular coupling is reduced under pathological conditions