Heart failure (HF) is the final common pathway for most cardiovascular diseases and is associated with high mortality and morbidity. Because ATP is required for normal myocardial contractile function, it has been hypothesized that impaired ATP synthesis and/or delivery contribute to contractile dysfunction in HF patients. Our focus is on the creatine kinase (CK) reaction which generates ATP at the contractile elements, is the major cardiac energy reserve responsible for buffering ATP, and which is particularly critical because of the temporally varying energy demands of the beating heart and the spatial heterogeneity of the ATP generating and utilizing reactions within myocytes. We developed the first non-invasive means to measure the rate of ATP synthesis through myocardial CK in the human heart and observed significant reductions in human HF of sufficient magnitude to theoretically limit ATP delivery during the cardiac cycle. In other patients, the kinetics of ATP turnover through CK distinguished failing and non-failing hearts. This body of clinical evidence demonstrates a critical role for reduced CK capacity in human HF and is now supported by causal evidence that reduced CK contributes to dysfunction and remodeling in a murine model of HF. These recent, novel clinical and basic results from our laboratory provide the justification and rationale for studies to address important mechanistic and clinically-relevant issues concerning the prognostic and causal roles of reduced CK capacity in human HF as outlined in these specific aims. The first three aims examine the hypothesis that reduced CK capacity is a causal factor in progressive contractile dysfunction. They do so by testing whether it is an independent predictor of important clinical HF outcomes, including mortality, cardiac transplantation and HF hospitalization (first aim), that HF medications known to improve survival and clinical outcomes improve cardiac CK flux and energetics (second aim) and that reduced CK flux occurs when contractile dysfunction is first recognized in patients with malignant disease receiving cardiotoxic but also lifesaving chemotherapy (third aim). We will also examine two more mechanistic questions that can only now be tested in HF patients due, in part, to new higher field 3T MR scanners. These are whether spatial heterogeneity in CK flux and energetics across the myocardial wall contributes to dysfunction in HF patients and whether the temporal heterogeneity in ATP demand during the cardiac cycle is an important factor related to reduced CK buffering capacity on impaired function (fourth aim). The latter would have direct clinical relevance in terms of the importance of heart rate interventions in this patient population. We believe these proposed, truly translational studies address critical and timely questions of mechanistic and clinically-relevant importance. Our group is uniquely qualified and the timing is ideal to exploit recent observations and new technology to advance our understanding of the role of impaired ATP delivery through CK in human HF.

Public Health Relevance

The pumping action of the heart, like an engine, requires chemical fuel and the failing heart has been hypothesized to be low on fuel. The chemical fuel used by the heart is ATP and we recently developed the first means to measure the rate of ATP turnover in the human heart and find it is significantly reduced in heart failure. The proposed studies are important because they will determine whether that reduction in ATP rate predicts heart failure progression in death, and what the underlying mechanisms are that could be targeted for future heart failure therapy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL061912-13
Application #
8311018
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Evans, Frank
Project Start
1999-07-19
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
13
Fiscal Year
2012
Total Cost
$569,497
Indirect Cost
$115,057
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Zhang, Yi; Zhou, Jinyuan; Bottomley, Paul A (2015) Minimizing lipid signal bleed in brain (1) H chemical shift imaging by post-acquisition grid shifting. Magn Reson Med 74:320-9
Soleimanifard, Sahar; Stuber, Matthias; Hays, Allison G et al. (2014) Robust volume-targeted balanced steady-state free-precession coronary magnetic resonance angiography in a breathhold at 3.0 Tesla: a reproducibility study. J Cardiovasc Magn Reson 16:27
Loring, Zak; Strauss, David G; Gerstenblith, Gary et al. (2013) Cardiac MRI scar patterns differ by sex in an implantable cardioverter-defibrillator and cardiac resynchronization therapy cohort. Heart Rhythm 10:659-65
Zhang, Yi; Gabr, Refaat E; Zhou, Jinyuan et al. (2013) Highly-accelerated quantitative 2D and 3D localized spectroscopy with linear algebraic modeling (SLAM) and sensitivity encoding. J Magn Reson 237:125-38
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
Hays, Allison G; Stuber, Matthias; Hirsch, Glenn A et al. (2013) Non-invasive detection of coronary endothelial response to sequential handgrip exercise in coronary artery disease patients and healthy adults. PLoS One 8:e58047
El-Sharkawy, Abdel-Monem M; Gabr, Refaat E; Schar, Michael et al. (2013) Quantification of human high-energy phosphate metabolite concentrations at 3 T with partial volume and sensitivity corrections. NMR Biomed 26:1363-71
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
Wieslander, Bjorn; Wu, Katherine C; Loring, Zak et al. (2013) Localization of myocardial scar in patients with cardiomyopathy and left bundle branch block using electrocardiographic Selvester QRS scoring. J Electrocardiol 46:249-55
Andersson, Linus G; Wu, Katherine C; Wieslander, Bjorn et al. (2013) Left ventricular mechanical dyssynchrony by cardiac magnetic resonance is greater in patients with strict vs nonstrict electrocardiogram criteria for left bundle-branch block. Am Heart J 165:956-63

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