BIOMEDICAL SCIENCES GRADUATE PROGRAM SPRING 2018

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1 THE OHIO STATE UNIVERSITY BIOMEDICAL SCIENCES GRADUATE PROGRAM SPRING 2018 Jae-Hoon Chung PhD Candidate Regulation of Human Cardiac Muscle Contraction and Relaxation in Health and Disease February 26, 2018 Hamilton 302C 10:00 am

2 VITA July 25, Born Pupyeong, South Korea B.A. Chemistry, Northwestern University 2012-Present.... MD/PhD Candidate, The Ohio State University COMMITTEE MEMBERS Paul M.L. Janssen, PhD, Advisor Jonathan Davis, PhD Noah Weisleder, PhD Bryan Whitson, MD/PhD

3 ABSTRACT Heart disease is the leading cause of death in the United States. Heart failure is a disease in which the heart fails to pump sufficient amount of blood to the body. It is a serious health burden that claims the lives of 58,000 Americans per year with a grim 5- year mortality rate of 50%. Over the years, the field of cardiovascular medicine has produced improved treatment options for patients with heart failure, such as beta blockers and angiotensin converting enzyme (ACE) inhibitors. However, the field has not yet been able to produce treatments to reverse the pathophysiology of heart failure, as the mechanism of disease has not been fully elucidated. We have obtained human non-failing and failing hearts and isolated intact trabeculae from left and right ventricle. We first utilized right ventricular intact trabeculae to characterize baseline twitch force and kinetics and found that non-failing and failing trabeculae do not have different developed force or contraction kinetics. However, failing trabeculae had slower relaxation kinetics. In addition, we found evidence that suggests trabeculae from males trend towards having greater developed force compared to trabeculae from females. After baseline twitch characterization, we investigated changes in their contractile and relaxation capacities at different lengths, stimulation frequencies, and beta-adrenergic activation levels. We found that lengthdependent activation is present in both non-failing and failing trabeculae. Moreover, the slowing of contraction and relaxation kinetics at longer lengths was observed in both non-failing and failing trabeculae. Non-failing trabeculae exhibited positive forcefrequency relationship, meaning that their developed force increases as stimulation frequency is increased. On the other hand, failing trabeculae displayed negative force-freqeuncy. Upon maximal beta-adrenergic stimulation, developed force was increased by ~ 5 fold in non-failing trabeculae and ~3 fold in failing trabeculae. Kinetics of contraction and relaxation were

4 accelerated in both non-failing and failing trabeculae upon betaadrenergic stimulation, but these kinetics were slower in failing trabeculae compared to non-failing trabeculae. We further investigated the mechanism of force-frequency relationship by inhibiting the sarcoplasmic reticulum (SR) in human right ventricular trabeculae via cyclopiazonic acid (CPA) and ryanodine. Upon SR blockade, force-frequency relationship was preserved and contraction kinetics slowed down. In addition, early relaxation kinetics was not affected by SR blockade, but total twitch time was slower at low frequencies after SR blockade. We also studied the role of cross-bridge cycling kinetics in forcefrequency relationship. We measured ktr, an index of rate of crossbridge cycling, in non-failing and failing left ventricular trabeculae and found that ktr does not change at different frequencies but failing trabeculae had slower ktr and lower potassium contracture at 3 Hz stimulation frequency. Across the frequencies we tested, contraction kinetics was not different between non-failing and failing trabeculae, but relaxation kinetics were slower. The maximal rate of force decay was significantly slower in failing trabeculae at 3 Hz stimulation frequency.

5 RECENT ABSTRACTS AND PRESENTATION Chung JH., Milani-Nejad N., Karaze T., Kilic A., Mohler PJ., and Janssen PML. Effect of Frequency Modification on Kinetic Parameters of Explanted Human Myocardium with Non-ischemic and Ischemic Cardiomyopathy. Biophysics Society Meeting, Los Angeles, California. (February 2016). Chung JH., Milani-Nejad N., Karaze T., Kilic A., Mohler PJ., and Janssen PML. Effect of Frequency Modification on Kinetic Parameters of Explanted Human Myocardium with Non-ischemic and Ischemic Cardiomyopathy. Myofilament Meeting: Local and Global Regulatory Networks in Muscle, Madison, Wisconsin. (June 2016). Chung JH., Milani-Nejad N., Karaze T., Kilic A., Mohler PJ., and Janssen PML. Effect of Frequency Modification on Kinetic Parameters of Explanted Human Myocardium. Ohio Physiological Society Meeting, Columbus, Ohio. (November 2016). Chung JH., Milani-Nejad N., Karaze T., Whitson BA., Kilic A., Mohler PJ., and Janssen PML. Effect of Stimulation Frequency on Kinetic Parameters of Explanted Human Myocardium. Biophysics Society Meeting, New Orleans, Louisiana. (February 2017). Chung JH, Cross-bridge Cycling Kinetics in Intact Cardiac Muscle. The Ohio State University and University of Pittsburgh MSTP Joint Retreat. July Chung JH, Effect of Frequency Modification on Kinetic Parameters of Explanted Human Myocardium. Nishikawara Scholar Award Lecture at The Ohio State University Physiology and Cell Biology Research Day. March 2017.

6 RECENT PUBLICATIONS Milani-Nejad N.*, Chung JH.*, Canan BD., Fedorov VV., Whitson BA., Kilic A., Mohler PJ., Janssen PML. Increased crossbridge recruitment contributes to transient increase in force generation beyond maximal capacity in human myocardium. Journal of Molecular Cellular Cardiology Chung JH., Biesiadecki BJ., Ziolo MT., Davis JP., Janssen PML. Myofilament Calcium Sensitivity: Role in Regulation of In vivo Cardiac Contraction and Relaxation. Review. Frontiers in Physiology Milani-Nejad N., Chung JH., Canan BD., Davis JP., Fedorov VV., Higgins RSD., Kilic A., Mohler PJ., Janssen PML. Insights into Length-Dependent Regulation of Cardiac Cross-Bridge Cycling kinetics in Human Myocardium. Archives of Biochemistry and Biophysics Milani-Nejad N., Canan, BD., Elnakish MT., Davis JP., Chung JH., Fedorov VV., Binkley PF., Higgins RSD., Kilic A., Mohler PJ., Janssen PML. The Frank-Starling Mechanism Involves Deceleration of Cross-Bridge Kinetics and is Preserved in Failing Human Right Ventricular Myocardium. American Journal of Physiology - Heart and Circulatory Physiology (* denotes equal contribution to the project)

7 AWARDS AND HONORS University Fellowship: Ohio Physiological Society Research Award: 2016 Margaret T. Nishikawara Scholarship: 2017 American Heart Association Predoctoral Fellowship: FUTURE PLANS I am returning to medical school to complete the last two years of my medical training. My current goal is to pursue residency in internal medicine followed by a fellowship. I would like to become an expert and leader in my chosen medical field to make significant contribution to patient care and solve medical problems through translational research.

8 Biomedical Sciences Graduate Program 1170 Graves Hall 333 W. 10 th Avenue Columbus, Ohio 43210