Calcium (Ca2+) oscillations underlie many important cellular processes that enable organ function, including contraction in the heart. Abnormalities in Ca2+ handling accompany most types of cardiac pathology, and may contribute to both ventricular dysfunction and arrhythmias. This proposal is aimed at developing a novel imaging technology to study spatial and temporal heterogeneities in Ca2+ transients in living animals. We will use adeno-associated virus serotype 9 (AAV-9) to stably deliver GCaMP2, a recently developed genetically encoded Ca2+-sensing molecule, into the hearts of living animals. Fiber optical probes (optrodes) will then be used to serially assess Ca2+ concentration at multiple transmural sites in both open- and closed-chest animals. We will test the hypothesis that transmural variation in Ca2+ transients during pathological states contributes to the development of cardiac dysfunction and arrhythmias.
In Specific Aim 1, acute changes in Ca2+ transients will be studied in an open-chest rabbit model of ischemia-reperfusion during ligation of the left anterior descending coronary artery.
In Specific Aim 2, chronic changes in Ca2+ transients will be studied in dogs with pacing-induced heart failure. These temporal and spatial measurements of in-situ Ca2+ transients at multiple sites in the heart will provide insights into the mechanisms by which abnormal Ca2+ handling contributes to cardiac dysfunction and arrhythmias in the setting of ischemia and heart failure.
Heart attacks and heart failure remain leading causes of illness and premature death in the United States. Calcium triggers the contraction during each heart beat, and calcium regulation is abnormal after a heart attack and in heart failure. In this proposal, we will develop a method to measure calcium concentrations in the heart cells of living animals and use this technology to better understand how abnormalities in calcium contribute to heart failure and sudden death.
