Nearly 1 in 8 (12.5%) of Americans are older than 65 years and the number of individuals 65 and over is expected to increase to ~20% over the next 2 decades. Cardiac disease is prevalent in the aged population and therefore represents a major public health concern in America. The heart remodels with advancing age and these remodeling events often result in the impaired ability of the heart to relax between each beat. This period of relaxation is the cardiac diastole, during which time the heart fills with blood and prepares for the next contraction during systole. With aging, diastolic dysfunction is characterized by increased """"""""stiffness"""""""". Given that greater stiffness makes it harder to fill, the heart is less effective as a pump and operates at elevated filling pressures and volumes with a greater propensity for arrhythmia. Because the mechanism(s) underlying cardiac dysfunction with advancing age are poorly understood, developing new therapeutic treatments for affected individuals requires new mechanistic insight. The rise and fall of calcium concentration within cardiac cells controls their contraction and relaxation, respectively, and is regulated by the sarcoplasmic reticulum (""""""""SR""""""""). Therefore, this project is focused on understanding how aging alters the relationship between diastolic filling (i.e., passive stretching of cardiac myocytes) an calcium release from the SR. To directly observe well-defined functional elements (e.g., calcium """"""""sparks"""""""" and """"""""waves"""""""") of calcium release, high resolution confocal imaging will be used with fluorescent calcium indicators (Fluo-4) with reference to the well-defined spacing of contractile proteins (i.e., sarcomere length). More specifically, this research project will compare intact perfused hearts and enzymatically dissociated intact ventricular cardiomyocytes from young (3 month), middle-aged (14 month), and senescent (24 month) C57BL/6 mice to test the central hypothesis that with advancing age cardiomyocytes have increased passive stiffness with highly sensitive coupling between stretch and SR calcium release.
Aim 1 will determine the actual changes that occur in cell and sarcomere lengths of young, middle-aged, and senescent hearts in response to defined changes in left ventricular filling pressure.
In Aim 2, the length of individual isolated cardiomyocytes will be controlled to determine how passive stretch of the cell alters calcium release in order to identify key age-associated differences in cell stiffness and calcium regulation.
In Aim 3, findings from Aims 1 and 2 will be integrated by investigating calcium release and pressure development within the intact, working heart. Overall, this project utilizes innovative methods to study the function of individual cardiomyocytes under highly controlled experimental conditions as well as in their native environment within the intact heart. This mentored award will also provide important technical training in a highly integrative environment at the University of Missouri, which will give the applicant unique experimental skills and valuable perspective into cardiac physiology as it relates to aging populations. It is anticipated that results from this project will yield insight into the mechanisms of cardiac diseas during aging, with the ultimate goal of translating these findings into treatments for the aging population.

Public Health Relevance

The healthy heart exhibits highly coordinated intracellular calcium release in order to function as an effective pump. Alterations in calcium release during diastolic filling (i.e., passive stretch) predispose the heart to impaired filling and arrhythmia, which are commonly associated with aging. This research proposal investigates how aging affects stretch-induced intracellular calcium release with the goal of translating our findings int the development of therapies to improve cardiac function in the aging population.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Scientist Development Award - Research & Training (K01)
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National Institute on Aging Initial Review Group (NIA)
Program Officer
Kohanski, Ronald A
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University of Missouri-Columbia
Schools of Medicine
United States
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Peana, Deborah; Domeier, Timothy L (2017) Cardiomyocyte Ca2+ homeostasis as a therapeutic target in heart failure with reduced and preserved ejection fraction. Curr Opin Pharmacol 33:17-26
Hiemstra, Jessica A; Lee, Dong I; Chakir, Khalid et al. (2016) Saxagliptin and Tadalafil Differentially Alter Cyclic Guanosine Monophosphate (cGMP) Signaling and Left Ventricular Function in Aortic-Banded Mini-Swine. J Am Heart Assoc 5:e003277
Yue, Yongping; Binalsheikh, Ibrahim M; Leach, Stacey B et al. (2016) Prospect of gene therapy for cardiomyopathy in hereditary muscular dystrophy. Expert Opin Orphan Drugs 4:169-183
Bostick, Brian; Habibi, Javad; DeMarco, Vincent G et al. (2015) Mineralocorticoid receptor blockade prevents Western diet-induced diastolic dysfunction in female mice. Am J Physiol Heart Circ Physiol 308:H1126-35
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
Clay, Sarah A; Domeier, Timothy L; Hanft, Laurin M et al. (2015) Elevated Ca2+ transients and increased myofibrillar power generation cause cardiac hypercontractility in a model of Noonan syndrome with multiple lentigines. Am J Physiol Heart Circ Physiol 308:H1086-95
Socha, Matthew J; Boerman, Erika M; Behringer, Erik J et al. (2015) Advanced age protects microvascular endothelium from aberrant Ca(2+) influx and cell death induced by hydrogen peroxide. J Physiol 593:2155-69
Jia, Guanghong; Habibi, Javad; DeMarco, Vincent G et al. (2015) Endothelial Mineralocorticoid Receptor Deletion Prevents Diet-Induced Cardiac Diastolic Dysfunction in Females. Hypertension 66:1159-1167
Hiemstra, Jessica A; GutiƩrrez-Aguilar, Manuel; Marshall, Kurt D et al. (2014) A new twist on an old idea part 2: cyclosporine preserves normal mitochondrial but not cardiomyocyte function in mini-swine with compensated heart failure. Physiol Rep 2:
GutiƩrrez-Aguilar, Manuel; Douglas, Diana L; Gibson, Anne K et al. (2014) Genetic manipulation of the cardiac mitochondrial phosphate carrier does not affect permeability transition. J Mol Cell Cardiol 72:316-25

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