Diastolic heart failure is a major cause of illness and death. The condition is nearly always associated with increased ventricular stiffness and is more common in elderly and/or obese populations. There are no effective clinical treatments. The central hypothesis underlying this research is that diastolic myocardial stiffness is the sum of an 'active'stiffness component (due to myosin heads that continue to cycle during diastole) and a 'passive'stiffness component (attributed to titin, collagen, elastin and intermediate filaments). The proposed research determines the relative contributions from these components in preparations ranging from single myocytes to whole hearts and uses these results to create a predictive computational model of diastolic stiffness.
Specific Aim 1 will identify the molecular components responsible for the increased stiffness of myocardium from aged rats. The working hypothesis is that the increased stiffness reflects slowed acto-myosin kinetics. Experiments will measure the mechanical properties of myocardium from 6, 18, 22 and 26-month-old Fischer 344 rats by subjecting chemically permeabilized single myocytes and multicellular preparations to repeated stretches at different levels of calcium activation. Additional experiments will measure ventricular stiffness in the different aged animals by rapidly inflating balloons placed inside the left ventricles of Langendorff-perfused hearts. Titin and myosin isoform content will be measured by gel electrophoresis. Collagen and elastin content and collagen cross-linking will be determined using histological and biochemical techniques.
Specific Aim 2 will use identical methods to identify the molecular components responsible for the increased myocardial stiffness evident in a rat model of diet-induced obesity. The working hypothesis for this aim is that the elevated myocardial stiffness observed in obese Sprague-Dawley rats reflects increased collagen content and/or collagen cross-linking.
Specific Aim 3 uses the experimental results from Aims 1 and 2 to create a predictive computational model of diastolic stiffness. The model framework will consist of elastic and visco-elastic elements (representing titin, collagen, elastin and intermediate filaments) arranged in parallel with a spatially-explicit simulation of acto-myosin interactions. Model parameters will be determined by multi-dimensional optimization. The final model will be used to test predictions about the cross-bridge component of myocardial stiffness and should prove useful for assessing the likely effects of potential new treatments for diastolic heart failure. NARRATIVE This research is relevant to public health because it seeks to identify why hearts become excessively stiff in a common cardiovascular disease called Diastolic Heart Failure. The experimental results should help scientists to develop better treatments for the disease in overweight and elderly patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL090749-05
Application #
8267690
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Schwartz, Lisa
Project Start
2008-09-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$326,329
Indirect Cost
$103,579
Name
University of Kentucky
Department
Physiology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Campbell, Kenneth S (2016) Compliance Accelerates Relaxation in Muscle by Allowing Myosin Heads to Move Relative to Actin. Biophys J 110:661-8
Chung, Charles S; Mechas, Charles; Campbell, Kenneth S (2015) Myocyte contractility can be maintained by storing cells with the myosin ATPase inhibitor 2,3 butanedione monoxime. Physiol Rep 3:
Zhang, Xiaoyan; Haynes, Premi; Campbell, Kenneth S et al. (2015) Numerical evaluation of myofiber orientation and transmural contractile strength on left ventricular function. J Biomech Eng 137:044502
Nance, Michael E; Whitfield, Justin T; Zhu, Yi et al. (2015) Attenuated sarcomere lengthening of the aged murine left ventricle observed using two-photon fluorescence microscopy. Am J Physiol Heart Circ Physiol 309:H918-25
Campbell, Kenneth S; Sorrell, Vincent L (2015) Cell- and molecular-level mechanisms contributing to diastolic dysfunction in HFpEF. J Appl Physiol (1985) 119:1228-32
Haynes, Premi; Nava, Kristofer E; Lawson, Benjamin A et al. (2014) Transmural heterogeneity of cellular level power output is reduced in human heart failure. J Mol Cell Cardiol 72:1-8
Chung, Charles S; Mitov, Mihail I; Callahan, Leigh Ann et al. (2014) Increased myocardial short-range forces in a rodent model of diabetes reflect elevated content of β myosin heavy chain. Arch Biochem Biophys 552-553:92-9
Haynes, Premi; Campbell, Kenneth S (2014) Myocardial hypertrophy reduces transmural variation in mitochondrial function. Front Physiol 5:178
Campbell, Kenneth S (2014) Dynamic coupling of regulated binding sites and cycling myosin heads in striated muscle. J Gen Physiol 143:387-99
Chung, Charles S; Campbell, Kenneth S (2013) Temperature and transmural region influence functional measurements in unloaded left ventricular cardiomyocytes. Physiol Rep 1:e00158

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