Abstract
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
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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.
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