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Figure 2. Schematic of metabolic changes in myocardial ischemia. Lack of oxygen slows mitochondrial activity (-). Consequently, slowing and then cessation of both TCA and FAO cyclcs occurs (•). Cytosolic glticosc metabolism is enhanced (+). Glucose increases due to the enhanced glucose uptake and glycogen breakdown (+). The regulatory enzyme PDH is inhibited (-) so (hat less pyruvate enters the TCA cycle. Enhanced glycolysis provides the ATP required for maintaining cell membrane integrity. Intermediates of fatty acid metabolism accumulate and damage heart cell membranes. Breakdown of ATP to AMI' results in AMPK activation. AMPK stimulates glycolysis while inhibits the malonyl-CoA synthesis and removes its negative regulatory effect on FFAs transport to mitochondria. FFAs use the residual oxygen instead of the energy friendly glucose substrate. See text for a more detailed explanation.

Figure 2. Schematic of metabolic changes in myocardial ischemia. Lack of oxygen slows mitochondrial activity (-). Consequently, slowing and then cessation of both TCA and FAO cyclcs occurs (•). Cytosolic glticosc metabolism is enhanced (+). Glucose increases due to the enhanced glucose uptake and glycogen breakdown (+). The regulatory enzyme PDH is inhibited (-) so (hat less pyruvate enters the TCA cycle. Enhanced glycolysis provides the ATP required for maintaining cell membrane integrity. Intermediates of fatty acid metabolism accumulate and damage heart cell membranes. Breakdown of ATP to AMI' results in AMPK activation. AMPK stimulates glycolysis while inhibits the malonyl-CoA synthesis and removes its negative regulatory effect on FFAs transport to mitochondria. FFAs use the residual oxygen instead of the energy friendly glucose substrate. See text for a more detailed explanation.

"C -Glucose

Intracellular sodium excess results in enhanced osmotic pressure and swelling as well as in calcium overload. In fact, sodium leaves the cell in exchange with calcium due to the activated sodium-calcium exchanger (in the reverse direction). Figure 3. Calcium reuptake by the sarcoplasmic reticulum is reduced (due to energy depletion) and further contributes to calcium overload. Figure 3. Calcium overload leads to cell damage by activating membrane phospholipases, depresing mitochondrial respiration and increasing mitochondrial permeability, reviewed by Carmeliet.55

Loss of intracellular potassium occurs early during ischemia. Depletion of the cy-tosolic ATP and ADP and adenosine, breakdown products of ATP, leads to opening of the membrane potassium channel with subsequent potassium loss. Figure 3. These channels serve as metabolic sensors and respond to the decreased sub-sarcolemmal ATP. Furthermore, potassium moves out the cell together with negatively charged lactate and phosphate ions while inhibition of the Na+/K+-ATPase also contributes to potassium leakage. Potassium loss causes membrane action potential shortening and may prevent excessive calcium entry into the cell, reviewed by Carmeliet.55 Cytosolic potassium also decreases due to the opening of mitochondrial ATP depended potasium channels (KATP). Mitochondrial KATp channels are activated during ischemia and may serve an important role in the adaptive response of the cell to ischemic stress.56

Magnesium increases in cytosol due to the hydrolysis of ATP to which magnesium is bound and from inadequate removal of magnesium via the magnesium-ATPase and sodium-magnesium exchanger. Magnesium exerts stabilizing effects but can also cause (via effects on phosphorylation) changes in sodium and calcium channels (blocking the pores) and inward rectification in the case of potassium channels, reviewed by Carmeliet.55

Several changes in ion membrane homeostasis also occur from fatty acid and long chain acylcarnitines (LCAC) accumulation or from the formation of lysophosphadyl-choline (LPC) and arachidonic acid (AA) due to phospholipid breakdown by lipases. In fact, fatty acids and AA favor activation of K+ outward current while LCAC and LPC favor inward over outward current, reviewed by Carmeliet.55

1.5. Contractile dysfunction

1.5.1 Ischemic contracture

Under normoxic conditions, the interaction between actin-myosin starts when intracellular calcium increases and removes the inhibitory action of troponin I. Myosin heads are attached to actin and flex at the expense of the energy produced by ATP hydrolysis. This results in myocardial contraction. ATP then binds to myosin heads and detaches them from actin filaments resulting in myocardial relaxation.57 Figure 4. During severe and prolonged ischemia, the strong interaction between the myosin heads and actin is maintained due to ATP depletion and ischemic contracture develops. Increased ADP levels seem to be the early trigger of rigor contracture development. Interestingly, ADP further increases myosin ATPase activity leading to ATP depletion.58 Rigor bridges exert a cooperative effect on the thin filament and calcium sensitivity is increased. However, calcium sensitivity can be reduced when hydrogen ions and phosphate are accumulated. Ischemic contracture is moderate in its extent and does not actually cause major structural damage but it leads to cytoskeletal defects and cardiomyocytes become more fragile and susceptible to mechanical damage. In perfused heart models, the development of contracture has been correlated to pre-ischemic myocardial glycogen content

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