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 #
5R01HL061912-12
Application #
8115199
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
2011-08-01
Budget End
2012-07-31
Support Year
12
Fiscal Year
2011
Total Cost
$569,497
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
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Hays, Allison G; Iantorno, Micaela; Schär, Michael et al. (2017) Local coronary wall eccentricity and endothelial function are closely related in patients with atherosclerotic coronary artery disease. J Cardiovasc Magn Reson 19:51
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Iantorno, Micaela; Hays, Allison G; Schär, Michael et al. (2016) Simultaneous Noninvasive Assessment of Systemic and Coronary Endothelial Function. Circ Cardiovasc Imaging 9:e003954
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
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
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
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Bottomley, Paul A; Panjrath, Gurusher S; Lai, Shenghan et al. (2013) Metabolic rates of ATP transfer through creatine kinase (CK Flux) predict clinical heart failure events and death. Sci Transl Med 5:215re3

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