| Action potential duration (APD) alternans can be accompanied by alternans in intracellular calcium, leading to electromechanical alternans. Electromechanical alternans is considered a substrate for ventricular fibrillation, especially during pathophysiological conditions such as ischemia. The work in thesis seeks to elucidate the spatio-temporal evolution of alternans and to investigate the potential pathways through which they occur. High resolution mapping was used to simultaneously map membrane voltage and intracellular calcium in normal rabbit hearts. By mapping both parameters simultaneously in the same region of the heart, we were able to reveal that instability in calcium cycling plays a primary role in the development of EM alternans in the whole heart. Further, we were able to apply a special restitution portrait analysis to predict the onset of both calcium and APD alternans before it occurs. We also wanted to elucidate the mechanisms behind the increased incidences of arrhythmias during ischemia. By simulating ischemic and mitochondrial dysfunction in isolated rabbit hearts, we were able to show that mitochondrial stress caused by uncoupling of the mitochondria is responsible for early occurrence of both APD and calcium alternans in the heart, which in turn creates a substrate to ventricular arrhythmias. Thus, uncoupling of the mitochondrial network that occurs during ischemia might be the primary reason for increased incidences of arrhythmias in the heart during ischemia. Overall, this study improves our knowledge of alternans and their basic underlying mechanism which can be used in the development of better treatment and/or prevention strategies. Development of techniques to predict alternans before it occurs would be a valuable clinical tool, especially for use in implantable pacemakers paving the way for pre-emptive interventions. In addition, elucidating the mechanism or pathways of alternans formation would lead to targeted drug treatments to prevent alternans and thus, VF and sudden cardiac death. |
