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Myocardial energy metabolism in ischemic preconditioning and cardioplegia: a metabolic control analysis
Achim M Vogt1, Albrecht Elsässer, Anja Pott-Beckert
1Medizinische Universitätsklinik (Ludolf-Krehl-Klinik), Abteilung Innere Medizin III (Schwerpunkt Kardiologie, Angiologie und Pulmologie), Heidelberg, Germany. achim.vogt@urz.uni-heidelberg.de
Insights
Cardioplegia (CP) and ischemic preconditioning (IP) protect the heart by preserving high-energy phosphates (HEP). CP slows phosphocreatine breakdown, while IP reduces ATP depletion. Combining CP and IP offers additive cardioprotection.
Area of Science:
- Cardiology
- Biochemistry
- Physiology
Background:
- Cardioplegia (CP) and ischemic preconditioning (IP) are known to increase ischemic tolerance and reduce infarct size.
- These cardioprotective effects are linked to the limitation of high-energy phosphate (HEP) depletion during ischemia.
- CP and IP are hypothesized to act via distinct mechanisms, potentially leading to different effects on myocardial HEP metabolism.
Purpose of the Study:
- To systematically analyze myocardial HEP metabolism for CP, IP, and their combination.
- To investigate whether CP and IP exert different effects on myocardial HEP metabolism.
- To determine if combining CP and IP results in additive cardioprotective effects.
Main Methods:
- Metabolic control analysis was employed to study the regulation of HEP metabolism.
- Open-chest pigs underwent 45 minutes of LAD occlusion (index ischemia).
- Measurements included myocardial ATP and phosphocreatine (PCr) levels, infarct size, and creatine kinase (CK) and ATPase reaction velocities.
Main Results:
- Both CP and IP preserved myocardial ATP and reduced infarct size compared to controls.
- CP primarily slowed PCr breakdown in early ischemia, leaving later ATP breakdown largely unaffected.
- IP increased PCr breakdown but significantly attenuated ATP depletion. Combining CP and IP showed additive effects, further reducing infarct size and preserving ATP levels.
Conclusions:
- CP and IP exhibit distinct effects on myocardial HEP metabolism, specifically on PCr and ATP breakdown.
- CP slows the CK reaction velocity at high PCr levels, while IP alters the CK equilibrium.
- The combination of CP and IP provides additive cardioprotection, likely due to synergistic effects on myocardial energy metabolism.
Abstract:
For both, cardioplegia (CP) and ischemic preconditioning (IP), increased ischemic tolerance with reduction in infarct size is well documented. These cardioprotective effects are related to a limitation of high energy phosphate (HEP) depletion. As CP and IP have to be assumed to act by different mechanisms, their effects on myocardial HEP metabolism cannot be assumed to be identical. Therefore, a systematic analysis of myocardial HEP metabolism for both procedures and their combination was performed, addressing the question whether there are different effects on myocardial HEP metabolism by IP and CP. In this study, metabolic control analysis was used to analyze the regulation of HEP metabolism. In open chest pigs subjected to 45 min LAD occlusion (index ischemia), CP and IP preserved myocardial ATP (control (C) 0.14 +/- 0.05 micromol/g wwt; CP: 0.95 +/- 0.14, IP: 0.61 +/- 0.12; p<0.05 C vs. CP and IP) and reduced myocardial necrosis (infarct size IA/RA: C: 90.0 +/- 3.0%; CP: 0.0 +/- 0.0% but patchy necroses; IP: 5.05 +/- 2.1%; p<0.05 C vs. CP and IP). The effects on HEP metabolism, however, were different: CP acted predominantly by slowing down the breakdown of phosphocreatine (PCr) during early phases of ischemia (C: DeltaPCr 0-2 min: 5.24 +/- 0.32 micromol/g wwt; CP: DeltaPCr 0-2 min: 3.38 +/- 0.23 micromol/g wwt, p<0.05 vs. C), leaving ATP breakdown during later stages unaffected (C: DeltaATP 5-45 min: 1.77 +/- 0.11 micromol/g wwt CP: DeltaATP 5-45 min: 1.59 +/- 0.28 micromol/g wwt, n.s. vs. C). In contrast to CP, in IP PCr breakdown was even increased (IP: DeltaPCr 0-2 min: 7.06 +/- 0.34 micromol/g wwt, p<0.05 vs. C), but ATP depletion greatly attenuated (IP: DeltaATP 5-45 min: 0.48 +/- 0.10 micromol/g wwt, p<0.05 vs. C and CP). Combining IP and CP yielded an additive effect with slowing down the breakdown of both PCr (IP+CP: DeltaPCr 0-2 min: 5.09+/- 0.35 micromol/g wwt, p<0.05 vs. C and IP) and ATP (IP+CP: DeltaATP 5-45 min: 0.56 +/- 0.48 micromol/g wwt, p<0.05 vs. C and CP), resulting in a higher ATP content at the end of index ischemia (1.86 +/- 0.46 micromol/g wwt, p<0.05 vs. C, CP and IP). Compared to IP, combining IP+CP achieved also a further reduction in infarct size (IA/RA: 0.0 +/- 0.0%, p<0.05 vs IP) and--compared to CP--a disappearance of the patchy necroses. The concept of major differences in myocardial HEP metabolism during CP and IP is further supported at a molecular level by metabolic control analysis. CP but not IP slowed down the CK reaction velocity at high PCr levels. In contrast to CP exerting a continuous decline in vATPase for any given ATP level, in IP myocardium ATPase reaction velocity was even increased at higher ATP contents, whereas a marked decrease in ATPase reaction velocity was found if ATP levels decreased. The equilibrium of the CK-reaction remained unchanged following CP, whereas IP induced a changing CK equilibrium, which was the more shifted towards PCr the more myocardial HEP content decreased. The data demonstrate different effects of CP and IP on myocardial HEP metabolism, i.e. PCr and ATP breakdown as well as the apparent equilibrium of the creatine kinase (CK)-reaction. For these reasons the combination of the two protective interventions has an additive effect.
