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J Mol Cell Cardiol. 2015 Feb;79:256-63. doi: 10.1016/j.yjmcc.2014.12.002. Epub 2014 Dec 10.

2-Deoxy adenosine triphosphate improves contraction in human end-stage heart failure.

Author information

1
Division of Cardiology, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
2
Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.
3
Division of Cardiology, Department of Medicine, University of Washington, Seattle, WA 98195, USA; Center for Cardiovascular Biology, University of Washington, Seattle, WA 98195, USA.
4
Department of Bioengineering, University of Washington, Seattle, WA 98195, USA; Center for Cardiovascular Biology, University of Washington, Seattle, WA 98195, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98195, USA. Electronic address: mregnier@uw.edu.

Abstract

We are developing a novel treatment for heart failure by increasing myocardial 2 deoxy-ATP (dATP). Our studies in rodent models have shown that substitution of dATP for adenosine triphosphate (ATP) as the energy substrate in vitro or elevation of dATP in vivo increases myocardial contraction and that small increases in the native dATP pool of heart muscle are sufficient to improve cardiac function. Here we report, for the first time, the effect of dATP on human adult cardiac muscle contraction. We measured the contractile properties of chemically-demembranated multicellular ventricular wall preparations and isolated myofibrils from human subjects with end-stage heart failure. Isometric force was increased at both saturating and physiologic Ca(2+) concentrations with dATP compared to ATP. This resulted in an increase in the Ca(2+) sensitivity of force (pCa50) by 0.06 pCa units. The rate of force redevelopment (ktr) in demembranated wall muscle was also increased, as was the rate of contractile activation (kACT) in isolated myofibrils, indicating increased cross-bridge binding and cycling compared with ATP in failing human myocardium. These data suggest that dATP could increase dP/dT and end systolic pressure in failing human myocardium. Importantly, even though the magnitude and rate of force development were increased, there was no increase in the time to 50% and 90% myofibril relaxation. These data, along with our previous studies in rodent models, show the promise of elevating myocardial dATP to enhance contraction and restore cardiac pump function. These data also support further pre-clinical evaluation of this new approach for treating heart failure.

KEYWORDS:

Ca(2+) sensitivity; Contraction; Heart failure; Myofibrils; Treatment

PMID:
25498214
PMCID:
PMC4301986
DOI:
10.1016/j.yjmcc.2014.12.002
[Indexed for MEDLINE]
Free PMC Article

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