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Dr. Carl Sims Assistant Professor Anatomy and Physiology 330-941-2895 csims01@ysu.edu WBSH 4021 B.A.   Youngstown State University, 1982 M.S.   Kent State University, 1992 Ph.D.   Case Western Reserve University, 2004

Research Interests

My research interests are focused on studying the regulation of cardiac L-type calcium channel and its role in cellular mechanisms of arrhythmia. Sudden death from cardiac arrhythmia claims over 300,000 lives in the United States alone each year. Sex is a risk factor for sudden death from arrhythmia in Long QT Syndrome type 2 (LQT2), with women considerably more vulnerable than men to life-threatening arrhythmias. Women are also more susceptible to drugs that inhibit delayed rectifier potassium currents, making them at higher risk for prolonged action potential duration, which is implicated as an underlying mechanism of Long QT Syndrome-related arrhythmias. Remarkably, sex differences in arrhythmia phenotype are reversed in children with the congenital disease, and in pre-pubertal rabbit models of drug-induced LQT2. Male children with congenital Long QT Syndrome type 2 have a significantly greater risk than their female counterparts of having a lethal arrhythmia.

My research attempts to shed light on understanding the cellular mechanisms responsible for the sex and age gap in the vulnerability to cardiac arrhythmia. It is clear that factors other than repolarizing potassium channels, action potential duration and hormones modulate arrhythmia vulnerability. Candidates include the L-type calcium and sodium/calcium exchange currents, which are key determinants of intracellular calcium homeostasis, and have been implicated as triggers of arrhythmia. We are investigating novel ways in which these currents alter normal electrical and biochemical signaling pathways to produce arrhythmias. To study this question we utilize multidimensional experimental approaches. Animal models are employed that utilize individual cells or tissue from the hearts of rabbits or guinea pigs. To study the function of ion channels in isolated myocytes, a biophysical method, the patch clamp technique is employed. Also, biochemical and molecular biology techniques are used to study the expression of calcium cycling proteins that regulate cardiac excitation-contraction coupling in normal and diseased hearts. Mathematical modeling is another powerful technique we have used to investigate differences in ion current responses on action potentials in specific regions of the heart. This research is both exciting and promising, yielding a new understanding of heart function in ways that will foster information that leads to longer and healthier lives.

Selected Publications

Zhou, J., Sims, C., Berti-Mattera, L., Hopfer, U., and J. G. Douglas "Proximal Tubular Epithelial Cells Possess a Novel 42-Kilodalton Guanine Nucleotide-Binding Protein" (1990) Proc. Natl. Acad. Sci. USA 87: 7532-7535

Sims, C., Ashby, K., and J.G. Douglas "Angiotensin II Induced Changes in Guanine Nucleotide-Binding and Regulatory Proteins" (1992), Hypertension 19: 146-152

Sims, C., Chiu, J., and R.D. Harvey "Tyrosine Phosphatase Inhibitors Selectively Antagonize ß-Adrenergic Receptor-Dependent Regulation of Cardiac Ion Channels" (2000) Molecular Pharmacology 58: 1213-1221

Belevych, A.E., Sims, C. and R.D. Harvey "Acetylcholine-Induced Rebound Stimulation of the Ventricular L-Type Ca²⁺ Current is mediated by Gßg-dependent Activation of Adenylyl Cyclase" , (2001) Journal of Physiology 536.3: 667-692.

Belevych, A.E., Nulton-Persson, A., Sims, C. and R.D. Harvey "Role of Tyrosine Kinase Activity in Inhibition of the a-Adrenergically Regulated L-type Ca²⁺ Current in Guinea Pig Ventricular Myocytes", (2001) Journal of Physiology 537.3: 779-92

Sims, C. and R.D. Harvey "Redox Modulation of Basal and ß-Adrenergically Stimulated Cardiac L-type Ca²⁺ Channel Activity by Phenylarsine Oxide", (2004) British Journal of Pharmacology 142(4): 797-807

Sims, C., Reisenweber, S., Viswanathan, P., Choi, BR., Walker, W., and G. Salama "Sex, Age and Regional Differences in L-type Calcium Current are determinants of Arrhythmia Phenotype in Rabbit Hearts with Drug Induced Long QT Type 2", (2008) Circulation Research, 102:e86-e100 ⁺²