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Novel Systems Physiology Instrumentation: Addressing Limitations in Heart Failure Reseearch
Date of Award
Doctor of Philosophy (PhD)
Heart disease remains the leading cause of death in the United States, but technology (e.g., pacemakers, defibrillators, and imaging systems) has dramatically lowered mortality associated with heart disease. In basic research science, integrative approaches with different tools have been crucial to understanding the multifactorial nature of heart disease from the individual protein to the organ level. Despite available technology, important limitations still exist in our ability to phenotype heart disease and to characterize failures in therapeutic intervention. One specific area of cardiology with insufficient tools for basic research and clinical applications is heart failure.
Heart failure is one of the most common and costly cardiac diseases in developing and industrialized countries. Despite its important public health implications, no definitive cure exists for heart failure patients. An important reason for this is a wide array of symptoms in heart failure: loss of cardiac contractility, ventricular chamber dilation, increased valvular resistance, impaired fluid homeostasis, and increased incidence of sudden cardiac death due to arrhythmias. This complex pathology makes treating and studying the failing heart particularly difficult. Recently, systems physiology (i.e., understanding interactions between mechanical, electrical, and metabolic systems in the heart) has become a popular meme in heart failure research. If systems physiology is to revolutionize heart failure research, new tools are necessary to address critical limitations in cardiology from bench-top to bedside.
In this dissertation, I introduce and evaluate novel tools for addressing limitations in heart failure research in three specific areas: animal models of heart failure, imaging technology for electromechanical mapping, and treatment of arrhythmias associated with heart failure. First, I present a miniature, implantable pacemaker for mice as a tool for investigating pacing-induced heart failure and cardiac memory. In previous studies, reliable, chronic pacing in mice has been limited to a maximum of one week. Here, I demonstrate 30 days of in vivo pacing in mice with a novel, wirelessly powered and controlled pacemaker. Long-term pacing in genetically-modified mouse models will yield a critical tool for the association of genes/proteins with specific disease mechanisms in heart failure. Second, I show the development and application of a structured light imaging system for description of whole-heart mechanical mapping in the beating heart. The high temporal (&g;667 FPS) and spatial resolution (87 μm in-plane, 10 μm depth) of this structured light imaging system enables dynamic assessment of both rhythmic and arrhythmic contraction without gating to the cardiac cycle, a feature presently impossible with current technology. Additionally, I present a novel method for tracking epicardial displacement on a pixel-by-pixel basis without the use of fiducial markers. By combining structured light with optical mapping of fluorescent dyes, imaging of excitation-contraction-metabolic coupling of healthy and failing hearts can be performed at unprecedented spatio-temporal resolution. In the final chapter of this dissertation, I evaluate potential mechanisms of failure for High Intensity Focused Ultrasound (HIFU) ablation in cardiac tissue. HIFU ablation offers a unique opportunity to develop effective strategies for noninvasive or minimally invasive treatment of atrial fibrillation and other arrhythmias. Despite its promises, current HIFU technology has failed to demonstrate high standards of safety and efficacy. Here, I identify three potential mechanisms that may be responsible for the failure of current HIFU technology: acoustic cavitation, acoustic radiation force, and discontinuous linear lesions. Improving our understanding of these mechanisms and their role in the creation of transmural lesions will facilitate the development of new HIFU technologies that would improve patient outcomes. Specifically, this research underscores the critical need for real time feedback to monitor thermal deposition in 3D space and acoustic pressure.
Igor R Efimov
Tao Ju, Martin Arthur, Philip Bayly