Energy crisis of cardiomyocytes
The pathogenesis is based on acute coronary insufficiency encompassing the period of ischemia itself and the initial stage of reperfusion. The main problem is a total disruption of cellular energy supply, which develops via two main pathways.
The first pathway is associated with a direct oxygen deficit. Hypoxia leads to the inhibition of tissue respiration. Trying to compensate for the energy shortage, cells activate anaerobic glycolysis. However, this results in massive lactate accumulation and the development of intracellular acidosis. The acidic environment, in turn, secondarily blocks glycolysis, depriving the cell of its final energy sources.
The second pathway is neurohumoral. Against the background of prevailing cholinergic influences, the activity of the enzyme phosphorylase drops sharply (it even begins to leak out of cells). This further inhibits glycolysis. The ultimate result of both pathways is a catastrophic drop in ATP levels.
Chronology of cell death
Pathological changes in the heart muscle progress rapidly. Counting from the moment of vessel occlusion, the picture looks as follows:
- First seconds: a steady decline in ATP concentration begins.
- 1–2 minutes: contractile function ceases entirely; akinesia of the ischemic area sets in.
- About 10 minutes: ATP reserves drop to approximately 50% of the initial baseline.
- About 20 minutes: critical energy deficit occurs — ATP levels drop by 90%.
- 20–40 minutes: the point of no return. Irreversible structural damage develops, ending in cardiomyocyte death (necrosis).
Mechanisms of cell damage
Cell destruction during ischemia is not limited to energy shortage alone. Five main damage mechanisms are triggered:
- Intoxication via LPO: a sharp surge in free-radical lipid peroxidation occurs.
- Activation of hydrolases: dissolved, membrane-bound, and lysosomal enzymes are activated, destroying the cell from within.
- Conformational changes: the spatial structure of key macromolecules—proteins, phospholipids, and lipoproteins—is disrupted.
- Blockade of repair: de novo synthesis of components and resynthesis of damaged membranes are completely suppressed.
- Mechanical ruptures: due to cellular edema (hyperhydration), membranes stretch and rupture.
These processes trigger a secondary biochemical cascade. Degradation products (free fatty acids, lysophospholipids) accumulate in huge quantities and exert a powerful toxic, detergent effect on surviving structures.
Autonomic "seesaw"
Myocardial ischemia is accompanied by pronounced changes in the autonomic nervous system, which are divided into two phases.
The initial stage is characterized by the dominance of the sympathoadrenal system. The concentration of noradrenaline and, in particular, adrenaline increases sharply in the myocardium. Clinically, this manifests as tachycardia. Cardiac output increases briefly, although it usually begins to fall immediately after the onset of coronary insufficiency. Parasympathetic influences (acetylcholine) also rise but are significantly inferior to sympathetic ones.
Late stages (tens of minutes or hours later) proceed differently. Sympathetic activity fades, and noradrenaline levels drop. The parasympathetic system comes to the forefront as acetylcholine concentrations remain high. During this period, the patient exhibits bradycardia, decreased cardiac output, and a reduced rate of heart muscle contraction and relaxation.
Briefly: answers to topical questions
Which biochemical markers of cardiomyocyte necrosis are determined in the blood during irreversible ischemia?
During irreversible ischemia and the destruction of cardiomyocytes, intracellular enzymes and proteins enter the bloodstream. Biochemical markers of myocardial necrosis include:
- Troponins I and T.
- Creatine kinase isoenzymes, specifically the MB fraction of CK / CK-MB.
- Mitochondrial form of aspartate aminotransferase (m-AST): an increase in its blood activity indicates tissue necrosis and destruction of cell membranes, including in myocardial infarction.
What are the mechanisms of myocardial reperfusion injury?
The mechanisms of myocardial reperfusion injury are associated with increasing damage to membranes and enzymes following ischemia and at the initial stage of reperfusion. The main mechanisms include:
- Reperfusion oxygen-dependent activation of lipid peroxidation: intensification of lipid peroxidation.
- Calcium activation of hydrolases: activation of proteases, lipases, and phospholipases under the action of excess Ca²⁺ ions.
- Osmotic damage: swelling and rupture of cardiomyocyte membranes and their organelles.
- Potentiation of ion and water imbalance: intracellular accumulation of Na⁺, Ca²⁺, and fluid, leading to cellular edema.
- Impairment of energy processes: mitochondrial damage, uncoupling action of excess Ca²⁺, washout of purine compounds, and impaired intracellular ATP transport.
What factors contribute to the development of acute coronary insufficiency leading to ischemia?
The development of acute coronary insufficiency and myocardial ischemia is facilitated by factors that reduce the delivery of oxygen and substrates to the myocardium or increase its demand for them. Immediate causes include:
- Thrombosis or prolonged spasm of a sclerosed coronary artery.
- Thromboembolism (sources: thrombi on the endocardium or within an aneurysm cavity).
- Atherosclerotic changes in coronary vessels.
- Vasculitis of various etiologies.
- Functional myocardial overstrain against the background of stenosing coronary sclerosis.
- General hemodynamic disorders (decreased blood inflow, systemic hypotension).
- Severe general hypoxia and anemia.
To memorize the main factors of membrane destruction, use the rule "LIC": LPO (lipid peroxidation), Ihydrolases (enzymatic cleavage), Conformation (change in macromolecular structure).
Class and exam questions
Why does intracellular acidosis occur during ischemia?
Due to a lack of oxygen, cells are forced to switch to anaerobic glycolysis. A side effect of this compensatory mechanism is the accumulation of lactate, which shifts the pH toward the acidic side.
How quickly does myocardial necrosis develop after vessel occlusion?
Irreversible damage and cardiomyocyte death develop within 20 to 40 minutes from the moment blood flow ceases.
Why does tachycardia give way to bradycardia in later stages of ischemia?
After tens of minutes, the activity of the sympathoadrenal system becomes exhausted. Parasympathetic influence begins to predominate due to the maintenance of a stably high level of acetylcholine in the tissues.
What else to study on this topic
- The role of free fatty acids and lysophospholipids in detergent damage to cell membranes
- Mechanisms of hyperhydration and mechanical rupture of cardiomyocytes
- Pathogenesis of the initial stage of reperfusion in coronary insufficiency
- The effect of the cholinergic system on phosphorylase activity in the myocardium
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