Maintenance of sufficient cardiac output to provide the body and the heart itself with nutrients and oxygen is a must to sustain life. To accomplish increase output, heart rate goes up significantly, and the specific force generated by the myocardium increases as well, boosting stroke volume. The latter phenomenon is known as the force-frequency relationship (FFR). In recent studies we observed that in rabbits, which display a similar FFR behavior as humans, not only is calcium handling involved in the FFR but post-translational modification of myofilament proteins occurs too, resulting in a frequency-dependent decrease in myofilament calcium sensitivity. This latter finding can at least partially explain the increased contractile kinetics, and explains how the heart can maintain a low diastolic tension despite significantly elevated intracellular calcium levels that prevail at high pacing rates, and may also play a prominent role in the FFR. In heart failure, the positive FFR is severely blunted or even becomes negative, and relaxation is impaired, these are classic hallmarks of this disease. A further understanding of frequency-dependent myofilament processes and modification is therefore paramount in understanding cardiac pathophysiology. Several central questions remain to be resolved in this emerging field. What is the relative contribution of the calcium transient and myofilament properties on frequency-dependent force and kinetics? What are the kinases involved, and what are the myofilament targets of these kinases regarding the FFR? To what extent are the myofilament-based contributions different in hypertrophy and heart failure? What is the sequence of events that leads to the disease's phenotype? Based on our previous work and current preliminary experiments, we have formulated the hypothesis that myofilament-based frequency-dependent regulation is mediated via kinase-mediated phosphorylation, and that this process is deranged in hypertrophy and heart failure. We will address our hypothesis in two rabbit model that exhibits FFR behavior very close to human in both aspects of calcium handling and myofilament composition and properties, as well as in non-failing and failing human tissue via 4 specific aims: 1) Dissect the temporal resolution of the force-frequency relationship, 2) Mechanistically dissect the myofilament-based protein targets and kinase-dependent process that are involved in the FFR. 3) Assess alterations in frequency- dependent activation in human heart failure tissue, and in a rabbit model of hypertrophy, and 4) Correlate and dissect functional and molecular changes in the FFR during the transition from healthy to failing myocardium in a novel muscle culture system. Combined, the outcome of this study will provide critical new information on a central deficit in function in patients with heart failure, and will allow us to strategize future treatment options.

Public Health Relevance

In a healthy human being when the heart rate increases during activity, the heart does not only beat faster, it also bets stronger and faster. This response is significantly impaired in patients with heart failure;their heart has lost the abilityto beat significantly stronger and faster, and this loss is a hallmark of the disease. In this study, e aim to unravel the molecular processes involved in the regulation of heart-rate-dependent strength and speed. In both rabbits that have a very similar rate-dependent regulation of contraction and relaxation, as well as in muscle tissue obtained from end-stage failing human hearts, we will investigate the contribution of myofilament protein phosphorylation on rate-dependent processes. The completion of this study will go a long way in understanding rate-dependent activation in health and disease, and will provide critical new information that can be used to strategize future treatment options.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL113084-03
Application #
8701132
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Boineau, Robin
Project Start
2012-08-15
Project End
2016-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Ohio State University
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Columbus
State
OH
Country
United States
Zip Code
43210
Csepe, Thomas A; Zhao, Jichao; Hansen, Brian J et al. (2016) Human sinoatrial node structure: 3D microanatomy of sinoatrial conduction pathways. Prog Biophys Mol Biol 120:164-78
Li, Ning; Csepe, Thomas A; Hansen, Brian J et al. (2016) Adenosine-Induced Atrial Fibrillation: Localized Reentrant Drivers in Lateral Right Atria due to Heterogeneous Expression of Adenosine A1 Receptors and GIRK4 Subunits in the Human Heart. Circulation 134:486-98
Milani-Nejad, Nima; Chung, Jae-Hoon; Canan, Benjamin D et al. (2016) Insights into length-dependent regulation of cardiac cross-bridge cycling kinetics in human myocardium. Arch Biochem Biophys 601:48-55
Janssen, Paul M L; Biesiadecki, Brandon J; Ziolo, Mark T et al. (2016) The Need for Speed: Mice, Men, and Myocardial Kinetic Reserve. Circ Res 119:418-21
Swager, Sarah A; Delfín, Dawn A; Rastogi, Neha et al. (2015) Claudin-5 levels are reduced from multiple cell types in human failing hearts and are associated with mislocalization of ephrin-B1. Cardiovasc Pathol 24:160-7
Sturm, Amy C; Kline, Crystal F; Glynn, Patric et al. (2015) Use of whole exome sequencing for the identification of Ito-based arrhythmia mechanism and therapy. J Am Heart Assoc 4:
Milani-Nejad, Nima; Canan, Benjamin D; Elnakish, Mohammad T et al. (2015) The Frank-Starling mechanism involves deceleration of cross-bridge kinetics and is preserved in failing human right ventricular myocardium. Am J Physiol Heart Circ Physiol 309:H2077-86
Haizlip, Kaylan M; Milani-Nejad, Nima; Brunello, Lucia et al. (2015) Dissociation of Calcium Transients and Force Development following a Change in Stimulation Frequency in Isolated Rabbit Myocardium. Biomed Res Int 2015:468548
Hansen, Brian J; Zhao, Jichao; Csepe, Thomas A et al. (2015) Atrial fibrillation driven by micro-anatomic intramural re-entry revealed by simultaneous sub-epicardial and sub-endocardial optical mapping in explanted human hearts. Eur Heart J 36:2390-401
Li, Ning; Csepe, Thomas A; Hansen, Brian J et al. (2015) Molecular Mapping of Sinoatrial Node HCN Channel Expression in the Human Heart. Circ Arrhythm Electrophysiol 8:1219-27

Showing the most recent 10 out of 16 publications