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

Moussavi-Harami, Farid, Razumova, Maria V., Ward Racca, Alice, Cheng, Yuanhua, Stempien-Otero, April, Regnier, Michael (2015) 2-Deoxy adenosine triphosphate improves contraction in human end-stage heart failure. Journal of Molecular and Cellular Cardiology, 79 . pp. 256-263. ISSN 0022-2828. E-ISSN 1095-8584. (doi:10.1016/j.yjmcc.2014.12.002) (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided)

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Official URL
http://doi.org/10.1016/j.yjmcc.2014.12.002

Abstract

We are developing a novel treatment for heart failure by increasingmyocardial 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 increasesmyocardial 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 chemicallydemembranated multicellular ventricular wall preparations and isolated myofibrils from human subjects with end-stage heart failure. Isometric force was increased at both saturating and physiologic Ca2+ concentrations with dATP compared to ATP. This resulted in an increase in the Ca2+ 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.

Item Type: Article
DOI/Identification number: 10.1016/j.yjmcc.2014.12.002
Uncontrolled keywords: Heart failure; Contraction; Myofibrils; Ca2+ sensitivity; Treatment;
Subjects: Q Science > QP Physiology (Living systems)
R Medicine
R Medicine > RC Internal medicine > RC667 Diseases of the circulatory (cardiovascular) system
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: A.W. Racca
Date Deposited: 11 Jan 2016 14:49 UTC
Last Modified: 29 May 2019 16:52 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/53685 (The current URI for this page, for reference purposes)
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