Sudden cardiac death kills as many as 300,000 Americans every year, and in most cases the ultimate demise of the individual is due to the abrupt onset of abnormal electrical activity or cardiac arrhythmia. Even though the incidence of sudden cardiac death is often associated with some sort of preexisting condition, a significant number of victims have no apparent underlying cardiovascular disease. The critical, yet unanswered, question is what triggers fatal arrhythmias in these individuals? Although the mechanisms responsible remain largely unknown, there is substantial evidence that heart-brain interactions involving the autonomic nervous system play a critical role in many cases. Our working hypothesis is that dynamic interactions between the sympathetic and parasympathetic branches of the autonomic nervous system trigger abnormal electrical responses that can lead to the generation of life threatening ventricular arrhythmias. We believe that these abnormal responses are due to complex subcellular signaling mechanisms that affect the activity of a number of different ion channels in the heart. To test our hypothesis, we are using a systems biology approach that combines computational modeling with a variety of powerful experimental techniques. These include single cell recording of membrane currents and action potentials as well as live cell imaging of subcellular signaling responses using fluorescence resonance energy transfer (FRET) based biosensors. The ultimate goal is to identify the conditions under which imbalances in autonomic tone are likely to trigger ventricular arrhythmias in order that they might be prevented.
- Harvey, R.D. and J. Hell. CaV1.2 Signaling Complexes in the Heart. Journal of Molecular and Cellular Cardiology 58:143-152, 2013.
- Harvey, R.D. and S.C. Callaghan. Caveolae create local signaling domains through their distinct protein content, lipid profile and morphology. Journal of Molecular and Cellular Cardiology 52:366-375, 2012.
- Agarwal, S.R., MacDougall, D.A., Tyser, R., Calaghan, S.C., and Harvey R.D. Effects of cholesterol depletion on compartmentalized cAMP responses in adult cardiac myocytes. Journal of Molecular and Cellular Cardiology 50:500-509, 2011.
- Iancu, R.V., S.W. Jones, and R.D. Harvey. Compartmentation of cAMP signaling in cardiac myocytes: a computational study. Biophysical Journal 92:3317-3331, 2007.
- Warrier, S., G. Ramamurthy, R.L. Eckert, V.O. Nikolaev, M.J. Lohse, and R.D. Harvey. cAMP microdomains and Ca2+ channel regulation in cardiac ventricular myocytes. Journal of Physiology 580:765-776, 2007.
- Lehnart, S.E., X.H. Wehrens, S. Reiken. S. Warrier, A.E. Belevych, R.D. Harvey, W. Richter, S.-L. Jin, M. Conti, and A.R. Marks. Phosphodiesterase 4D deficiency in the ryanodine receptor complex promotes heart failure and arrhythmias. Cell 123:1-11, 2005.
- Harvey, R.D. and A.E. Belevych. Muscarinic regulation of cardiac ion channels. British Journal of Pharmacology. 139:1074-1084, 2003.
- Belevych, A. and R.D. Harvey. Muscarinic inhibitory and stimulatory regulation of the L type Ca2+ current is not altered in cardiac myocytes from mice lacking endothelial nitric oxide synthase. Journal of Physiology 528:279-289, 2000.
- Zakharov, S.I., S. Pieramici, G.K. Kumar, N.R. Prabhakar and R.D. Harvey. Nitric oxide synthase activity in guinea pig ventricular myocytes is not involved in muscarinic inhibition of cyclic AMP regulated ion channels. Circulation Research 78:925-935, 1996.
- Overholt, J.L., M.E. Hobert and R.D. Harvey. On the mechanism of rectification of the cAMP-dependent chloride current in cardiac ventricular myocytes. Journal of General Physiology 102:1-26, 1993.
- Harvey, R.D. and J.R. Hume. Autonomic regulation of a chloride current in heart. Science 244:983 985, 1989.
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