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Failure to maintain a low ADP concentration impairs diastolic function in hypertrophied rat hearts
R Tian1, L Nascimben, J S Ingwall
1Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass 02115, USA. rong@bustoff.bwh.harvard.edu
Insights
High levels of adenosine diphosphate (ADP) contribute to diastolic dysfunction in hypertrophied hearts by slowing cross-bridge cycling. Impaired creatine kinase function hinders ADP rephosphorylation, exacerbating this condition.
Area of Science:
- Cardiovascular Physiology
- Biochemistry
- Cardiac Metabolism
Background:
- Diastolic dysfunction in hypertrophied hearts may involve mechanisms beyond calcium overload.
- This study investigates the role of adenosine diphosphate (ADP) concentration in diastolic dysfunction.
Purpose of the Study:
- To test the hypothesis that failure to maintain low intracellular free ADP concentration in hypertrophied hearts contributes to diastolic dysfunction.
- To explore the underlying mechanisms, specifically the inhibition of cross-bridge cycling rate.
Main Methods:
- Isolated rat hearts from aortic-banded (left ventricular hypertrophy, LVH) and sham-operated (control) groups were perfused with pyruvate and 2-deoxyglucose (2DG).
- 31P Nuclear Magnetic Resonance (NMR) spectroscopy was used to measure phosphorus-containing compounds, including intracellular free ADP.
- Left ventricular end-diastolic pressure (LVEDP) was measured to assess diastolic function.
Main Results:
- 2DG perfusion induced a threefold increase in LVEDP and intracellular free ADP in LVH hearts, while control hearts maintained stable LVEDP and low ADP.
- A significant linear relationship was observed between increased ADP and LVEDP (r2=.66, P=.001).
- The capacity of the creatine kinase reaction to rephosphorylate ADP was significantly decreased in LVH hearts (P=.0001).
Conclusions:
- Elevated intracellular free ADP levels contribute to diastolic dysfunction in hypertrophied hearts, likely by slowing cross-bridge cycling.
- A diminished capacity of the creatine kinase reaction is a key mechanism leading to the failure in maintaining low ADP levels in LVH.
Background:
Mechanisms in addition to diastolic calcium overload may contribute to diastolic dysfunction in hypertrophied hearts. In this study, we tested the hypothesis that failure to maintain a low ADP concentration in hypertrophied hearts contributes to diastolic dysfunction by inhibiting the rate of cross-bridge cycling.
Methods And Results:
By perfusing isolated rat hearts with pyruvate and 2-deoxyglucose (2DG), we were able to perturb [ADP] with minimal changes in [ATP] and [inorganic phosphate] or the contribution of glycolytic ATP to ATP synthesis. The effects of 2DG were compared in aortic-banded (LVH, n=5) and sham-operated (control, n=5) rat hearts. 31P NMR spectroscopy was used to measure the concentrations of phosphorus-containing compounds. We found a threefold increase of left ventricular end-diastolic pressure (LVEDP) in LVH during 2DG perfusion, and this increase was concomitant with a threefold increase in intracellular free [ADP]. The [ADP] in the control hearts was maintained <40 micromol/L, and no change in LVEDP was observed. A linear relationship between increases in [ADP] and LVEDP was found (r2=.66, P=.001). Furthermore, the capacity of the creatine kinase reaction, a major mechanism for maintaining a low [ADP], was decreased in LVH (P=.0001).
Conclusions:
Increased [ADP] contributes to diastolic dysfunction in LVH, possibly due to slowed cross-bridge cycling. Decreased capacity of the creatine kinase reaction to rephosphorylate ADP is a likely contributing mechanism to the failure to maintain a low [ADP] in LVH.