This proposal aims to measure and manipulate in vivo cardiac flux through myocardial creatine kinase (CK) in mice to test the energy starvation hypothesis of heart failure (CHF). The requirement of ATP for normal cardiac contractile function is absolute and the CK reaction is the major energy reservoir of the heart. CK metabolites are reduced in CHF and predict outcomes. The first direct measures of ATP flux through CK in the human heart recently revealed dramatic 50-70% reductions in CK flux in CHF even before global [ATP] loss occurs. Despite this supporting evidence, conventional metabolic interventions have failed to augment CK pools or flux in failing hearts to directly test the energy starvation hypothesis. This application proposes the use of new transfection approaches, just developed by the investigators, to genetically over-express the factors most likely limiting CK flux in CHF and determine, in vivo, the energetic and functional consequences.
The specific aims are: 1.) to implement new clinical MR techniques in mouse studies for assessing in vivo cardiac CK metabolites, flux and function, 2.) to test the hypothesis that increasing CK expression in CHF increases in vivo cardiac CK flux and improves ventricular function, 3.) to test the hypothesis that increasing creatine transport protein expression will increase myocardial creatine, CK flux, and mechanical function in CHF, 4.) to test the hypothesis that conditional CK gene deletion will exacerbate the development of CHF and that CK rescue will provide protection. This proposal uniquely brings together novel non-invasive tools to measure in vivo cardiac CK flux, new technology to perform genetic CK manipulations, relevant animal models that capitulate characteristics of human CHF, and finally, sophisticated means to assess the functional consequences. These mouse studies offer interventions not possible in human CHF and promise new insights for this prevalent, growing disease. Lay summary: Heart failure is an important and growing cause of morbidity and mortality in the United States. Our recent observations in human heart failure guide these studies that currently can only be performed in mice. We will use state-of-the-art techniques to increase energy metabolism in failing mouse hearts and see if that improves the contraction of the heart and reduces heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063030-09
Application #
8048139
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Adhikari, Bishow B
Project Start
2000-04-01
Project End
2014-03-31
Budget Start
2011-04-01
Budget End
2014-03-31
Support Year
9
Fiscal Year
2011
Total Cost
$410,000
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Weiss, Kilian; Schär, Michael; Panjrath, Gurusher S et al. (2017) Fatigability, Exercise Intolerance, and Abnormal Skeletal Muscle Energetics in Heart Failure. Circ Heart Fail 10:
Cannavo, Alessandro; Rengo, Giuseppe; Liccardo, Daniela et al. (2017) ?1-Blockade Prevents Post-Ischemic Myocardial Decompensation Via ?3AR-Dependent Protective Sphingosine-1 Phosphate Signaling. J Am Coll Cardiol 70:182-192
Paolocci, Nazareno; Cannavo, Alessandro; Chelko, Stephen P et al. (2017) Burning Redoxstats in the Brainstem: Lack of Nrf2 and the Rise of Hypertension. Hypertension 69:1019-1021
Chen, Lin; Zeng, Haifeng; Xu, Xiang et al. (2017) Investigation of the contribution of total creatine to the CEST Z-spectrum of brain using a knockout mouse model. NMR Biomed 30:
Weiss, Kilian; Bottomley, Paul A; Weiss, Robert G (2015) On the theoretical limits of detecting cyclic changes in cardiac high-energy phosphates and creatine kinase reaction kinetics using in vivo ³¹P MRS. NMR Biomed 28:694-705
Schär, Michael; Gabr, Refaat E; El-Sharkawy, AbdEl-Monem M et al. (2015) Two repetition time saturation transfer (TwiST) with spill-over correction to measure creatine kinase reaction rates in human hearts. J Cardiovasc Magn Reson 17:70
Ardekani, Siamak; Gunter, Geoffrey; Jain, Saurabh et al. (2014) Estimating dense cardiac 3D motion using sparse 2D tagged MRI cross-sections. Conf Proc IEEE Eng Med Biol Soc 2014:5101-4
Abraham, M Roselle; Bottomley, Paul A; Dimaano, Veronica Lea et al. (2013) Creatine kinase adenosine triphosphate and phosphocreatine energy supply in a single kindred of patients with hypertrophic cardiomyopathy. Am J Cardiol 112:861-6
Gupta, Ashish; Rohlfsen, Cory; Leppo, Michelle K et al. (2013) Creatine kinase-overexpression improves myocardial energetics, contractile dysfunction and survival in murine doxorubicin cardiotoxicity. PLoS One 8:e74675
Akki, Ashwin; Gupta, Ashish; Weiss, Robert G (2013) Magnetic resonance imaging and spectroscopy of the murine cardiovascular system. Am J Physiol Heart Circ Physiol 304:H633-48

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