Atrial rhythm disorders are the most common type of sustained arrhythmias and contribute significantly to cardiac related morbidity and mortality. The electrophysiological substrates for many cardiac rhythm disturbances are set in place early in heart development. Although a number of genes and signaling pathways involved in specification and differentiation of the early embryonic heart, major gaps in our understanding of the functional implications of such findings remain. In particular, we know little about the electrophysiologic properties of the major atrial structures during development and how their alteration contributes to an arrhythmogenic substrate. This proposal focuses on the developmental aspects of impulse initiation and the genesis of atrial conduction. The central hypothesis we will test is that impulse initiation in the sinus node and coordinated conduction through the atria to the AV node results from the developmental modulation of ion channels and connexin expression. We will test this hypothesis by pursuing the following 3 specific aims:
SPECIFIC AIM 1. Determine the electrophysiological features that accompany the formation of a mature sinoatrial node with emphasis on the role played by the inward rectifier current (IK1).
SPECIFIC AIM 2. Determine the role of developmental changes of connexin expression in impulse initiation and propagation in the mouse sinus node and atria.
SPECIFIC AIM 3. Determine the relative contributions of cellular excitability and intercellular coupling in impulse initiation and atrial conduction. Our overall goal is to generate information that will directly impact our understanding of the basic electrophysiological events underlying mammalian heart development and their role in the formation of atrial arrhythmias. Our findings are expected to have a major impact on human health, because they will allow us to form new strategies to prevent major frequently occurring cardiac arrhythmias.
| Mahoney, Vanessa M; Mezzano, Valeria; Mirams, Gary R et al. (2016) Connexin43 contributes to electrotonic conduction across scar tissue in the intact heart. Sci Rep 6:26744 |
| Mahoney, Vanessa M; Mezzano, Valeria; Morley, Gregory E (2016) A review of the literature on cardiac electrical activity between fibroblasts and myocytes. Prog Biophys Mol Biol 120:128-33 |
| Mezzano, Valeria; Morley, Gregory E (2015) New insights into the complex effects of KChIP2 on calcium transients. Am J Physiol Heart Circ Physiol 309:H553-4 |
| Park, David S; Cerrone, Marina; Morley, Gregory et al. (2015) Genetically engineered SCN5A mutant pig hearts exhibit conduction defects and arrhythmias. J Clin Invest 125:403-12 |
| Delmar, Mario; Morley, Gregory E (2015) Genetically Encoded Voltage Indicators: Mapping Cardiac Electrical Activity Under a New Light. Circ Res 117:390-1 |
| Park, David S; Morley, Gregory E (2013) The funny and not-so-funny effects of dronedarone. Heart Rhythm 10:1698-9 |
| Benamer, Najate; Vasquez, Carolina; Mahoney, Vanessa M et al. (2013) Fibroblast KATP currents modulate myocyte electrophysiology in infarcted hearts. Am J Physiol Heart Circ Physiol 304:H1231-9 |
| Vasquez, Carolina; Morley, Gregory E (2012) The origin and arrhythmogenic potential of fibroblasts in cardiac disease. J Cardiovasc Transl Res 5:760-7 |
| Bernstein, Scott A; Wong, Brian; Vasquez, Carolina et al. (2012) Spinal cord stimulation protects against atrial fibrillation induced by tachypacing. Heart Rhythm 9:1426-33.e3 |
| Remo, Benjamin F; Qu, Jiaxiang; Volpicelli, Frank M et al. (2011) Phosphatase-resistant gap junctions inhibit pathological remodeling and prevent arrhythmias. Circ Res 108:1459-66 |
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