Pathogenesis of coronary heart disease. New ischemic syndromes in cardiology Myocardial stunning
INTRODUCTION
The traditional understanding of myocardial ischemia was previously reduced to such classical conditions as angina (stable and unstable), heart attack or silent myocardial ischemia, which from today’s perspective cannot explain a number of conditions encountered by cardiologists and cardiac surgeons. In turn, the South African scientist L.H. Opie emphasizes that in a patient with coronary artery disease, the disease picture is often characterized by 9-10 clinical syndromes.
Considering the heterogeneity of the causes of the manifestation and course of IHD, the unpredictability of the development and functioning of collateral circulation in the myocardium, it is assumed that it is impossible for even two patients to exist in whom the pathophysiology and clinical course of the disease would be absolutely identical, since in the same patient they can combine and play different roles "new ischemic syndromes".
NEW ISCHEMIC SYNDROMES
In 1996 P.W. Hochachka and colleagues suggested that myocardial viability under ischemic conditions is ensured by adaptation to hypoxia, which can be divided into two stages depending on the duration of the ischemic “attack”: short-term defensive reaction And "survival" phase.
During the period of a short-term protective reaction (short-term period of adaptation), from the point of view of modern understanding of pathophysiological processes, the metabolism of cardiomyocytes switches to anaerobic glycolysis, resulting in depletion of high-energy phosphates (ATP, CrP) in the myocardium. Under conditions of ongoing myocardial ischemia, further adaptation occurs (survival phase, “second window of protection”) through processes such as hibernation, stupor, preconditioning, which are combined into the concept of “new ischemic syndromes”
Thus, “new ischemic syndromes” combine(as suggested by L.H. Opie, 1996): ( 1 ) stupefaction; ( 2 ) hibernation; ( 3 ) metabolic adaptation or preconditioning.
STUPID
Myocardial stupefaction is post-ischemic myocardial dysfunction, that is, a violation of the mechanical function of the myocardium that persists after restoration of perfusion, despite the absence of irreversible damage (necrosis) and complete or almost complete restoration of blood flow.
Postischemic myocardial dysfunction (stupefaction) is observed outside the experiment ( 1 ) with myocardial necrosis in areas adjacent to it; ( 2 ) after a temporary increase in myocardial oxygen demand in areas supplied by a partially stenotic artery; ( 3 ) after an episode of subendocardial ischemia during excessive physical activity in the presence of left ventricular hypertrophy (without stenosis of the heart vessels).
From a pathogenetic point of view, the formation of free oxygen radicals during reperfusion and the loss of sensitivity of myocardial contractile fibers to Ca2+ are important in the development of this condition from a pathogenetic point of view.
Stupefaction of the myocardium is manifested by the fact that local ischemia for 5 minutes (usually the duration of a normal anginal attack) leads to a decrease in left ventricular contractility over the next 3 hours, and local ischemia for 15 minutes leads to a decrease in left ventricular contractility over the next 6 hours or more. A characteristic clinical sign of myocardial “stunning” is left ventricular diastolic dysfunction.
The following options for myocardial stunning are distinguished (G.I. Sidorenko, 2003):
(1 ) atrial stunning– occurs in the period after cardioversion;
(2 ) tachycardiomyopathy is a condition accompanied by a decrease in left ventricular function following restoration of sinus rhythm;
(3 ) microvascular dysfunction– microvascular incompetence, slow recanalization;
(4 ) syndrome of non-resumption of blood flow in the microcirculatory system of the myocardium(“no-reflow”) – microvascular dysfunction accompanying myocardial stunning or hibernation.
Most often, “stunning” of the myocardium is observed when thrombolysis is used in acute myocardial infarction. After a period of sudden cessation of blood supply to a section of the heart muscle and effective thrombolysis, despite the resumption of blood flow in full, the contraction of this segment (or the entire heart at once) is not restored to normal levels, but normalizes over a number of subsequent days and weeks.
Also, “stunning” of the myocardium can occur in acute myocardial infarction complicated by cardiogenic shock, provided that the patient quickly achieves coronary reperfusion.
HIBERNATION
Myocardial hibernation– this is a violation of local contractility of the left ventricle, caused by a decrease in coronary blood flow; contractility is restored when blood flow is restored.
The pathophysiological basis of the “hibernating” (asleep, sleeping) myocardium is a self-regulation mechanism that adapts the functional activity of the myocardium to ischemic conditions, that is, a kind of protective reaction of the “suffering heart” to a decrease in coronary blood flow.
In 1990 V. Dilsizian et al. Using scintigraphic techniques, it was found that from 31 to 49% of the left ventricular myocardium with irreversibly reduced contractility contains viable tissue. That is, in places of reduced local blood flow, normal metabolic activity is maintained, the myocardium is viable, but cannot provide a normal regional ejection fraction, and at the same time there is no myocardial necrosis or manifestations of ischemic symptoms.
Heberation manifests itself in such conditions as stable and unstable angina, silent myocardial ischemia And heart of a patient with heart failure and/or with severe left ventricular dysfunction. According to E.B. Carlson et al., areas of myocardial hibernation are detected in 75% of patients with unstable and in 28% with stable angina.
G.I. Sidorenko (2003) notes that with prolonged and stable ischemia, hibernation worsens and turns into “embalming” and even “heart of stone.” Minimizing metabolic and energy processes in the heart muscle while maintaining the viability of myocytes has allowed some researchers to call this situation a “resourceful heart.”
PRECONDITIONING
Metabolic adaptation (preconditioning)- this is one of the most important natural internal mechanisms of metabolic adaptation of the myocardium, increasing its resistance to ischemic effects as a result of repeated short-term episodes of ischemia.
The phenomenon of metabolic adaptation occurs with a fairly common "warm-up" syndrome(warm-up phenomen), manifested in a gradual decrease in the frequency and intensity of anginal attacks during the day or after moderate physical activity. This phenomenon is based on the rapid adaptation of the myocardium to the load against the background of a decrease in oxygen consumption by the myocardium after the second episode of ischemia.
G.I. Sidorenko (2003) notes that this syndrome is observed in almost 10% of patients with angina pectoris, and the ST segment on the EGC, elevated during an attack, decreases to the isoline, despite continued load. In life, such situations often arise in the morning, when the patient gets out of bed and then becomes more active. In connection with such observations, names such as “primarily hidden angina” or “angina of the first load” appeared.
The mechanisms underlying metabolic adaptation are theoretical in nature, since they have been studied mainly in model experiments, and in different animals.
However, there are two main mechanisms of preconditioning:
(1 ) reduction in tissue accumulation of glycogen breakdown products and adenine nucleotides, such as lactate, H+, NH+ ions and inorganic phosphate;
(2 ) increasing the activity or synthesis of enzyme systems that have a cardioprotective effect against ischemic damage.
When considering issues related to metabolic adaptation, one should also touch upon such concepts as “fast metabolic adaptation” and “slow metabolic adaptation”
Rapid metabolic adaptation manifests itself immediately after the adaptive effects of short-term (within 5 minutes) repeated episodes of ischemia, alternating with periods of reperfusion and helps maintain the intracellular level of high-energy phosphates in the myocardium, and thus provides cardiac protection for a period of time not exceeding 1-2 hours.
Slow metabolic adaptation(“slow phase of adaptive protective reaction”, “second window of preconditioning”) appears 12-24 hours after the adaptive effect, and lasts up to 3 days.
PRINCIPLES OF THERAPY FOR NEW ISCHEMIC SYNDROMES
There are two approaches that can improve the function of affected but viable myocardial segments, which ultimately determine the value of left ventricular ejection fraction, the main predictor of the prognosis of chronic heart failure: this ( 1 ) cytoprotection; ( 2 ) myocardial revascularization.
Nitrates, calcium antagonists, β-blockers, angiotensin-converting enzyme inhibitors have potential cardioprotective properties; Phosphocreatinine, carnitine, mildronate, and antioxidants have cytoprotective properties; Bemethyl, etomerzol, cramisol, tomerzol, etc. have actoprotective properties, the area of use of which requires clarification. Trimetazidine is potentially useful in terms of its impact on the three “new ischemic syndromes,” the mechanism of action of which allows it to have a beneficial effect on the main pathogenetic links in the development of these syndromes.
Numerous studies have proven that the most effective way to have a beneficial effect on the “dormant”, “stunned” myocardium is its revascularization (in the presence of critical stenosis of the coronary arteries), shown not only as a way to eliminate angina pectoris refractory to drug treatment, but also for the treatment of patients with silent myocardial ischemia (especially with multistenoses) and severe left ventricular dysfunction, occurring even without clinically pronounced symptoms of chronic heart failure.
If, after the occurrence of circulatory hypoxia of the heart in its area affected by a lack of oxygen, the ratio of the need of heart cells for oxygen to the delivery of 0 2 to cardiomyocytes continues to remain high, then the pathological changes associated with hypoxia can progress up to cytolysis.
Circulatory hypoxia of the heart induces a protective reaction of the hibernating myocardium (heart hibernation) at the organ level.
Hibernation (Latin: winter, cold) is an artificially induced state of slow vital activity of the body, reminiscent of the hibernation of animals (natural hibernation).
Hibernating myocardium is understood as a condition of the heart that is characterized by inhibition of pumping function under resting conditions without cytolysis of cardiomyocytes, the cause of which is a decrease in the volumetric velocity of blood flow through the coronary arteries. Hibernation sharply limits the ability of the heart to respond by increasing the release of blood into the aorta by the left ventricle per unit of time in response to an increase in the body's need for oxygen (physical activity, fever, hyperthyroidism, etc.). The state of hibernating myocardium is the result of a protective reaction aimed at reducing the high ratio between the force of contractions of the hypoxic region of the heart muscle and its blood supply, that is, the ratio of the need of cardiomyocytes for free energy to the level of capture of free energy by heart cells during aerobic biological oxidation. Thus, hibernation delays the cytolysis of heart cells caused by hypoergosis.
In response to a halving of the volumetric blood flow velocity, the thickening caused by systolic contraction decreases
walls of the corresponding segment by 50%. This is how cardiac hibernation manifests itself as the cause of inhibition of the pumping function of the left ventricle. In addition, hibernation is evidenced by the return to the initial level of the concentration of protons, creatine phosphate and carbon dioxide tension in the venous blood flowing from the heart, 1-3 hours after the onset of circulatory hypoxia, leading to a heart attack.
Hypokinesia and akinesia of segments of the left ventricular wall caused by cardiac hibernation do not yet indicate irreversible changes in cardiomyocytes, in which histopathological examination does not show signs of degeneration characteristic of the initial stages of hypoxic hypoergosis. Hibernation preserves cardiomyocytes in such a way that the resumption of blood flow within a week after the onset of ischemia (coronary artery bypass grafting, percutaneous endovascular coronary artery repair) reverses the development of hypo- and akinesia of segments of the ventricular wall. As hypokinesia and akinesia of the segments disappear, the synchrony of their systolic contraction is restored, the ejection fraction of the left ventricle increases, and the ability of the heart to respond by increasing the release of blood into the aorta in response to the increased needs of organs and tissues is restored.
It can be assumed that at present there are no widely available reliable methods for determining the viability (hibernation) of cardiac cells in asynchronously contracting segments of the left ventricular wall. Only a combination of angiography, echocardiography, scintigraphy and computed tomography of the heart during accumulation in cardiomyocytes and elimination of radionuclides from them allows us to obtain reliable information about the degree of viability of the hibernating myocardium.
Stunning (English stunning - stunning, stunning) of the myocardium is a condition due to a decrease in the pumping function of the heart as a result of its circulatory hypoxia, which does not undergo reverse development, despite the restoration of the volumetric velocity of blood flow in the segments of the walls of the heart chambers that have experienced circulatory hypoxia.
The severity and duration of stunning are directly related to the degree and duration of circulatory hypoxia of a region of the heart muscle. It is still unclear whether stunning is a purely pathological state of the myocardium or a consequence of the protective reaction of hibernation. A significant difference between stunning and hibernation is that restoring the delivery of oxygen and energy-plastic substrates to heart cells does not eliminate the inhibition of the pumping function of the heart. Presumably, the development of stunning is based on the formation of free oxygen radicals, disturbances in the migration of calcium through cell membranes, and the low efficiency of free energy capture by cardiomyocytes during biological oxidation.
Myocardial stunning can develop after thrombolytic therapy, when intravenous administration of streptokinase leads to lysis of a thrombus in the area of coronary artery stenosis, or after coronary artery bypass surgery. The state of myocardial stunning can last for days or months. In these cases, the use of drugs with a positive inotropic effect is justified only if inhibition of the pumping function of the ventricle can become a link in tantogenesis.
In experiments in a number of mammalian species, it was shown that short periods of acute circulatory hypoxia (ischemia) of the heart (ischemic preconditioning of the myocardium) significantly increase its resistance to long-term ischemia with a decrease in the infarction area by 80% of the area of its distribution in animals of the control group.
Ischemic preconditioning is the most effective natural mechanism known in mammals for protecting myocardial cells from ischemia. In the cardioprotective effect of ischemic preconditioning, a special role belongs to Sp proteins localized in the plasma membrane of heart cells. These transmembrane proteins act as mediators of a decrease in adenylate cyclase activity, which decreases due to stimulation of adenosine A1 receptors and muscarinic Mg receptors. Excitation of receptors of these two types through activation of βg proteins leads to activation of ATP-dependent potassium channels of the outer cell membranes of cardiomyocytes, inhibition of their sodium transmembrane channel and blocks the transfer of calcium through the membranes of cardiac cells through its L-type channels. Each of these effects of Orprotein activation leads to a decrease in the utilization of free energy by all heart cells, mainly due to less work of the cells of the working myocardium during contraction. It is assumed that the activation of β-proteins during ischemia occurs due to the release of a large number of adenosine molecules by cardiac cells associated with hypoergosis.
If the heart is not subjected to ischemic preconditioning, then ischemia causes a steady decrease in the level of activation of O1 proteins, that is, their dysfunction associated with hypoergosis. In the heart of experimental animals after ischemic preconditioning, the sensitivity of Orproteins to the activation of the corresponding receptors during ischemia increases. Sustained activation of these transmembrane proteins in the zone of circulatory hypoxia of the heart, which has gone through several periods of short-term ischemia that does not lead to cytolysis, presumably underlies the cardioprotective effect of ischemic preconditioning.
It is believed that the data obtained from studying ischemic preconditioning in experimental animals will make it possible to extrapolate their results to the practice of treating myocardial infarction in patients. This to a certain extent confirms the preliminary report on the effectiveness of the adenosine breakdown blocker acadesine in the prevention of intraoperative myocardial infarction during coronary artery bypass grafting.
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IHD is a discrepancy between coronary blood flow and the metabolic needs of the myocardium, i.e. volume of myocardial oxygen consumption (PMO 2). (Fig. 1).
Rice. 1. Diagram of the balance of energy delivered and consumed and the factors determining their levels
The equivalent of the heart's performance as a pump is the level of PMO 2, the delivery of which is ensured by the coronary blood flow (Qcor). The amount of coronary blood flow is regulated by the tonic state of the coronary vessels and the pressure difference in the ascending aorta and the cavity of the left ventricle, which corresponds to intramyocardial pressure (tension):
P 1 - pressure in the ascending aorta,
P 2 - pressure in the left ventricle (intramyocardial tension),
R core - resistance of the coronary vessels.
The energy supply for the pumping function of the heart in a wide range of its activity - from rest to the level of maximum load - occurs due to the coronary reserve. Coronary reserve is the ability of the coronary vascular bed to increase coronary blood flow many times adequately to the level of PMO 2, due to dilatation of the coronary vessels. (Fig.2).
The magnitude of the coronary reserve (I), depending on the pressure in the coronary vessels, lies between the straight line corresponding to the coronary blood flow with maximally dilated vessels (A, B), and the curve of the magnitude of the coronary blood flow with normal vascular tone (area of autoregulation). Under normal conditions, with intact coronary arteries, the heart is in a “superfusion” situation, i.e. O 2 delivery slightly exceeds the PMO 2 level.
Rice. 2. Diagram of coronary reserve and its dynamics depending on various pathological conditions of the cardiovascular system.
The diagram shows that coronary reserve can change upward or downward depending on physiological conditions or pathology of the coronary vessels, blood, and myocardial mass. In a person at rest, the coronary blood flow in the heart muscle is 80-100 ml/100 g/min and at the same time about 10 ml/100 g/min is absorbed by O2.
When the coronary arteries are damaged by atherosclerosis or as a result of inflammatory changes in the vascular wall, the ability of the latter to maximum dilatation (expansion) is sharply reduced, which entails a decrease in coronary reserve.
Conversely, with an increase in myocardial mass (left ventricular hypertrophy - hypertension, hypertrophic cardiomyopathy) or a decrease in the level of hemoglobin, the O 2 carrier, to adequately provide PMO 2, it is necessary to increase coronary blood flow in the area of autoregulation (upward movement of the autoregulation curve), which leads to a decrease coronary reserve (II), especially with atherosclerotic lesions of the coronary vessels (B - decrease in the direct line, characterizing the dilatation ability). In general terms, the coronary reserve diagram gives an idea of the mechanisms that ensure the correspondence between changing levels of PMO 2 depending on the intensity of cardiac activity and the amount of O 2 delivery.
Acute coronary insufficiency is an acute discrepancy between the delivery of O 2, determined by the magnitude of coronary blood flow, and the level of PMO 2. (Fig. 3).
This discrepancy may be due to various reasons:
1 - a sharp drop in coronary blood flow as a result of thrombus formation, spasm (complete or partial occlusion) of the coronary arteries against the background of a normal PMO value 2;
2 - extreme increase in PMR 2, exceeding the value of the coronary reserve;
3 - limited coronary reserve with a physiological increase in the level of PMO 2;
4 - multidirectional changes in the magnitude of coronary blood flow (decrease) and the level of PMO 2 (increase).
Rice. 3. Diagram of the relationship between the values of myocardial oxygen consumption (PMO 2) and the volume of coronary blood flow (Q)
Based on the onset of development of acute coronary insufficiency, factors influencing the level of PMO 2 and the magnitude of coronary blood flow can be identified; by etiology - coronarogenic, myocardial, extracardiac factors.
Of course, such a division is conditional, since in the conditions of a whole organism, all factors participate to one degree or another.
Animal studies have demonstrated that ischemic or hypertrophied myocardium is more sensitive than healthy myocardium to even small decreases in hemoglobin levels. This negative effect of anemia on heart function has also been noted in patient studies. At the same time, a decrease in hemoglobin levels is accompanied by a decrease in blood oxygenation in the lung, which also contributes to a decrease in oxygen delivery to the myocardium.
Clinical observations indicate that with reduced coronary reserve, ischemic, chronic myocardial dysfunction (systole-diastolic) can form even against the background of a normal volume of coronary blood flow at rest.
More recently, the generally accepted clinical forms of IHD included:
1 - angina at rest and exertion,
2 - unstable angina,
3 - acute coronary syndrome (pre-infarction condition),
4 - myocardial infarction; which, from the standpoint of today’s understanding of pathological processes during an ischemic attack, cannot explain a number of conditions encountered in the clinic by general practitioners, cardiologists and, in particular, cardiac surgeons.
Currently, based on data obtained from pathophysiological studies in experiments and clinical observations, from the standpoint of cellular - subcellular and molecular mechanisms of cardiomyocyte functioning, a modern understanding of “new ischemic syndromes” has been formulated - “stunned myocardium” (“Myocardil Stunning”), “hibernating - sleeping myocardium” (“Muosadil Hybernatin”), “preconditioning” (“Preconditioning”), “preconditioning is the second window of protection” (“Second Window Of Protection - SWOP”).
For the first time, the term “new ischemic syndromes”, combining the above-described conditions of the myocardium after various episodes of ischemia, reflecting adaptive-maladaptive changes in metabolism and the contractile state of cardiomyocytes, was proposed by the South African cardiologist L.H. Opie in 1996 at a working meeting of the International Society of Cardiology in Cape Town, under the auspices of the Council on Molecular and Cellular Cardiology.
L.H. Opie emphasizes that “in patients with coronary artery disease, the clinical picture of the disease is often characterized by 9-10 clinical syndromes, which are due to the heterogeneity of causes and the diversity of adaptation mechanisms.
Considering the heterogeneity of the manifestation of an ischemic episode, the unpredictability of the development and functioning of collateral circulation in the myocardium, as the first stage of myocardial protection, during circulatory arrest in the coronary region, it can be assumed that it is impossible for even two identical patients to exist in whom the pathophysiology and clinical course of the disease would be absolutely the same. In the same patient, various adaptive mechanisms of “new ischemic syndromes” can be combined and formed.
In 1996 RW. Hochachka and colleagues suggested that the viability of the myocardium under conditions of ischemia is ensured by adaptation to hypoxia, which can be divided into two stages depending on the duration of the ischemic “attack” - a short-term protective reaction and the “survival” phase.
From the point of view of modern understanding of pathophysiological processes, this looks like this. When switching to anaerobic glycolysis, at the stage of a short-term period of adaptation, the reserves of macroergic phosphates (ATP, CrP) in the myocardium are depleted, which are always not large. This is accompanied primarily by a violation of the diastolic phase of cardiomyocyte relaxation and, as a consequence, a decrease in the contractile function of the myocardium in the area of ischemia.
Under physiological conditions, 10% of ATP is formed by oxidative phosphorylation in mitochondria due to aerobic glycolysis (breakdown of glucose to pyruvate). This amount of ATP, produced as a result of aerobic glycolysis, is not enough to ensure the functioning of calcium, sodium and potassium ion channels of the sarcolemma and, in particular, the calcium pump of the sarcoplasmic reticulum (SRR).
Replenishment of the remaining amount of energy for the functioning of the cardiomyocyte with normal oxygen supply occurs due to the oxidation of free fatty acids (FFA), the breakdown of which during oxidative phosphorylation provides up to 80% of ATP. However, compared to glucose, FFAs are a less efficient source of ATP, the “fuel” for the heart pump, since their oxidation requires approximately 10% more oxygen to produce the same amount of ATP. A pronounced imbalance between the oxygen demand during the oxidation of glucose and FFAs towards the latter leads to the fact that during ischemia (a sharp drop in oxygen delivery) a large number of under-oxidized active forms of FAs accumulate in the mitochondria of cardiomyocytes, which further aggravates the uncoupling of oxidative phosphorylation. (Fig.4).
Under-oxidized active forms of FA, in particular acylcarnitine, acylCoA, as metabolites block the transport of ATP from the site of synthesis in mitochondria to the site of their consumption inside the cell. In addition, the increased concentration of these two metabolites in mitochondria has a destructive effect on the membrane of the latter, which further leads to a deficiency of energy necessary for the life of the cardiomyocyte. In parallel, in the cell against the background of anaerobic metabolism, an excess amount of protons (Na +, H +) accumulates, i.e. its “acidification” occurs.
Next, Na +, H + are exchanged for other cations (mainly Ca ++), resulting in an overload of myocytes with Ca ++, which is involved in the formation of contracture contraction. Excessive amounts of Ca ++ and a decrease in the functional capacity of the calcium pump SPR (energy deficiency) lead to impaired diastolic relaxation of the cardiomyocyte and the development of myocardial contracture.
Thus, the transition to an anaerobic oxidative process is accompanied by activation of FAs (long-chain cetylcarnitine and acylCoA), which contribute to the uncoupling of oxidative phosphorylation, the accumulation of excess amounts of Ca ++ in the cytosol, a decrease in myocardial contractility and the development of contracture with “adiastole”. (Fig.5).
Rice. 4. Scheme of energy balance distribution in a cardiomyocyte during anaerobic metabolism
Rice. 5. Scheme of cardiomyocyte Ca overload during restoration of coronary blood flow.
The survival phase is the stage of self-preservation of the myocardium under conditions of prolonged ischemia. The most significant adaptive reactions of the myocardium in response to ischemia include the so-called “new ischemic syndromes”: hibernation, stupor, preconditioning, preconditioning - the second window of protection.
The term “stunning” of the myocardium was first introduced by G.R. Heidricx et al in 1975; concept " hibernation"in 1985 described S.H. Rahimatoola; " preconditioning" - SE. Murry and his collaborators proposed in 1986, and " preconditioning - second window" - simultaneously M.S. Marber et al. and T. Kuzuya et al. in 1993.
Stunned(Stunning) of the myocardium is a phenomenon of post-ischemic myocardial dysfunction in the form of disruption of relaxation-contraction processes, clinically expressed as inhibition of the pumping activity of the heart, and persisting after restoration of coronary blood flow for several minutes or days.
In animal experiments, a short period of time of an ischemic attack (stopping blood flow) from 5 to 15 minutes does not lead to the development of myocardial necrosis, however, ischemia lasting at least 5 minutes (a typical anginal attack) leads to a decrease in contractile function over the next 3 hours , and an ischemic attack within 15 minutes (without necrosis of the heart muscle) prolongs the period of recovery of contractile function to 6 hours or more (Fig. 6).
A similar state of the myocardium in response to ischemic episodes occurs in 4 situations:
1 - in the boundary layers with necrosis of the heart muscle;
2 - after a temporary increase in PMO 2 in areas supplied by a partially stenotic coronary artery;
3 - after episodes of subendocardial ischemia during excessive physical activity in the presence of left ventricular myocardial hypertrophy (normal coronary arteries);
4 - situation - “ischemia-reperfusion” (hypoxia of the heart muscle with subsequent reoxygenation).
Rice. 6. Graph of recovery of myocardial contractility depending on the duration of ischemia.
The duration of coronary artery occlusion of at least 1 hour is accompanied by “ severe damage(maimed) myocardium" or " chronic stupefaction", which is manifested by the restoration of the pumping function of the heart after 3-4 weeks.
A typical clinical manifestation of myocardial stupor is a feeling of a “heavy, stony heart”, which is based on a violation of the diastole of the left ventricle - “ineffective diastole”.
Currently, two theories of pathophysiological processes dominate in the formation of this phenomenon: A - the formation of an excess amount of free oxygen radicals during reperfusion, with the activation of lipid peroxidation; B - uncontrolled entry of Ca ++ and its excessive accumulation in the cardiomyocyte, as a result of damage to the sarcolemma by lipid peroxidation after reperfusion.
G.I. Sidorenko, summarizing the results of clinical observations, identifies 4 clinical variants of myocardial stupefaction, depending on the root cause of the violation of the correspondence of PM0 2 to the value of coronary blood flow (Q co p No. PM0 2): atrial - post-tachycardiomyopathic, microvascular and syndrome of unrestored blood flow - “reflow” .
Atrial stunning occurs in the period after cardioversion, posttachycardiomyopathy is a condition accompanied by a decrease in the pumping function of the heart after restoration of normosystole; microvascular dysfunction is reduced competence of microcirculation due to ineffective (incomplete) coronary recanalization; “by-reflow” syndrome - non-restoration of blood flow at the level of microcirculation (stage I of DIC - thrombotic).
The mechanism of development of myocardial “stunning” is not fully understood: at least three factors are leading in the pathogenesis of “Stunning”: the formation of an excessive amount of ROS, post-perfusion calcium overload of cardiomyocytes, and a decrease in the sensitivity of myofibrils to calcium.
It has been shown that in approximately 80% of cases the formation of the phenomenon of “myocardial hibernation” is caused by the action of ROS, in 20% - by calcium overload, which is realized through the sequential inclusion of Na + /H + and Na + /Ca ++ exchangers. It is possible that ROS may participate in the formation of calcium overload through damage to proteins involved in the intracellular kinetics (transport) of Ca++. In turn, calcium overload of the myoplasm can activate calpins, enzymes that cause proteolysis of myofibrils. The need for resynthesis of new myofilaments is one of the factors determining the duration of restoration of the contractile function of cardiomyocytes.
Reversible myocardial damage caused by the accumulation of free radicals in the myocardium, in a state of myocardial stunning, manifests itself either in the form of a direct effect of free radicals on myofibrils with their damage, or indirectly through the activation of proteases, followed by degradation of myofibril proteins.
Another mechanism of disturbances in the contractile function of cardiomyocytes in stunned myocardium is the accumulation of an excess amount of cytosolic Ca - an increase in the intracellular concentration of ionized calcium (Ca ++).
After blood flow is restored, excessive calcium influx occurs through the damaged sarcolemma, not regulated by calcium channels. A deficiency of macrophosphate energy does not ensure the functioning of the calcium pump of the sarcoplasmic reticulum (SRR), which regulates the cytoplasmic concentration of Ca. The lack of ATP in myofibrils manifests itself in two ways: the remaining unopened connecting bridges between actin and mosin (incomplete diastole) reduce the number of possible interaction sites, which further limits the mutual movement of myofilaments in the sarcomere (contraction).
Thus, an excess amount of cytosolic calcium contributes to the development of incomplete diastole and the development of myocardial contracture.
Cell survival during a certain period of ischemia is possible due to the existence of a number of protective mechanisms aimed primarily at limiting the consumption of ATP in myofibrils. These mechanisms are realized through a decrease in the entry of Ca ++ into the cardiomyocyte and a decrease in the sensitivity of the contractile apparatus to it.
Microvascular disorders, in most cases of a secondary nature, due to aggregation of blood cells (platelets, erythrocytes, leukocytes) against the background of myocardial contracture, also take part in maintaining myocardial stupor.
"Myocardial hibernation"- adaptive decrease in intracellular energy metabolism, by inhibiting the contractile state of the cardiomyocyte, in response to a decrease in coronary blood flow.
Hibernation(Hybernatin) myocardium, as defined by Professor S.N. Rahimatoola (1999) - a rapidly occurring disorder of local contractility of the left ventricle in response to a moderate decrease in coronary blood flow. Hibernating myocardium is characterized by a chronic decrease in the contractility of cardiomyocytes while their viability is preserved. From the point of view of pathophysiological processes of adaptation to stressful situations, “hibernating myocardium” is “a self-regulation mechanism that adapts the functional activity of the myocardium to ischemic conditions,” i.e. a kind of protective reaction of the “suffering heart” to an inadequate decrease in coronary blood flow to the level of PMO 2. This term, “hibernating (asleep) myocardium” S.H. Rahimatoola was first proposed in 1984 at the CHD Treatment Workshop at the US National Heart, Lung, and Blood Institute.
The authors, using thallium scintigraphic technique, identified from 31 to 49% of viable tissue in areas with irreversibly reduced contractile function of the left ventricular myocardium. That is, in places of reduced local blood flow, relatively normal metabolic activity is maintained - the myocardium is viable, but it cannot provide a normal regional ejection fraction. In this case, there are clinical symptoms of ischemia, but which do not end with the development of myocyte necrosis. In the clinic, such situations can occur with stable and unstable angina, in patients with CHF.
According to E.V. Carlson and colleagues, published in 1989, in patients who underwent effective coronary angioplasty, areas of myocardial hibernation were detected in 75% of cases among patients with unstable angina and in 28% of cases with stable angina. Minimizing metabolic and energy processes in the heart muscle while maintaining the viability of myocytes has allowed some researchers to call this situation either a “resourceful heart” (Smart Heart), or a “self-preserving heart” (Self-preservation Heart) or a “playing heart” (Playing Heart) . Italian researchers defined this condition of the heart muscle as “myocardial lethargy.”
The mechanisms of hibernation are poorly understood. In clinical practice, against the background of a reduced coronary reserve, the gradual development of destructive changes in the hibernating myocardium is a consequence of cumulative shifts in energy metabolism in response to periodic inotropic stimulation.
Under conditions of limited blood flow, a positive inotropic response is achieved by depleting the metabolic status of the cardiomyocyte. Thus, gradually accumulating metabolic changes can cause disorganization of the intracellular structures of the heart muscle.
Preconditioning(Preconditioning) - metabolic adaptation to ischemia, after repeated short-term episodes of decreased coronary blood flow, manifested by increased resistance of the heart muscle to a subsequent, longer ischemic attack.
Preconditioning is a beneficial change in the myocardium caused by rapid adaptive processes during a short-term episode of ischemic attack on the myocardium followed by rapid restoration of blood flow (reperfusion), which protect the myocardium from ischemic changes until the next episode of ischemia/reperfusion. This phenomenon is phylogenetically determined and is typical for all organs of the mammalian body.
In 1986, under experimental conditions on dogs, SE. Murry and co-workers convincingly demonstrated that repeated short episodes of regional myocardial ischemia adapt the heart muscle to subsequent episodes of ischemic attacks, as documented by the preservation of intracellular ATP at sufficient levels for cardiomyocyte function, with the absence of necrotic cell damage.
Other experiments have shown that pre-intermittent 5-minute episodes of coronary artery occlusion followed by 5-minute intervals of reperfusion (ischemia/reperfusion) lead to a 75% reduction in the size of ischemic necrosis of the heart muscle (compared to a control group of dogs that received a unique 5-minute training (ischemia/reperfusion) was not carried out in response to circulatory arrest for 40 minutes.
A similar caprdioprotective effect of short-term episodes of ischemia/reperfusion was defined as “ischemic preconditioning”, while the absence of the development of the phenomenon of “reperfusion syndrome” was noted. This protective phenomenon was later identified by R.A. Kloner and D. Yellon (1994) in clinical practice.
Previously, it was believed that the cardioprotective effect of ischemic preconditioning appears immediately after short-term episodes of ischemia/reperfusion, and then loses its protective properties after 1-2 hours. In 1994, D. Yellon, in collaboration with G.F. Baxter showed that the phenomenon of “post-ischemic preconditioning” can develop again after 12-24 hours with a duration of up to 72 hours, but in a weakened form. A similar, long-term phase of tolerance to ischemic myocardial damage was defined by the authors as "second protection window" (« S second W indow O f P protection - SWOP"), in contrast to the early "classical ischemic preconditioning".
Clinical situations of “classical ischemic preconditioning” are the “Warm-up Phenomen” or “Walk-Through-Angina” syndrome, which manifest themselves in a gradual decrease in the frequency and intensity of anginal attacks during ongoing moderate physical or household activity.
The “pacing” phenomenon is based on the rapid adaptation of the myocardium to the load against the background of a decrease in the ratio - Qcor/PMR 2 after the second episode of ischemia. G.I. Sidorenko notes that this syndrome is observed in almost 10% of patients with angina pectoris, and the ST segment on a standard ECG, elevated during the first attack, decreases to the isoline, despite the ongoing load. (Fig.7).
A similar picture is observed in a number of cases during stress testing, when angina pain and/or ST segment displacement appear at the height of the load, and they disappear as it continues. Such situations made it possible to formulate such concepts as “primarily hidden angina” (First Holeangina) or “first-effort angina” (First - Effort-Angina).
Rice. 7.“Preconditioning” effect - initial ECG (a), coronary artery spasm against the background of moderate load with ST elevation on the ECG (b) and ECG recovery (c) against the background of ongoing moderate load
It is possible that ischemic preconditioning underlies the fact that patients with pre-infarction angina tend to have a more favorable prognosis compared with those patients in whom MI developed against the background of previous complete well-being.
It has been shown that angina attacks preceding the development of myocardial infarction (pre-infarction angina) can have a protective effect on the myocardium (reduction of the affected area) if they occurred within 24-48 hours before the development of myocardial infarction. Such observations in clinical practice are reminiscent of the cardioprotective effect of long-term ischemic preconditioning (“second window of protection”) in animal experiments.
Phenomenon “lack of restoration of blood flow in the intramural to subendocardial coronary arteries”(no-reflow) - a significant decrease in coronary blood flow in patients with coronary artery disease against the background of vascular damage and reperfusion, despite the complete restoration of patency (recanalization) in the epicardial coronary arteries.
There is evidence that in clinical practice, pre-infarction angina can reduce the “no-reflow” phenomenon, thereby protecting the myocardium from ischemia and reperfusion caused by microvascular damage in the heart. This reduces the risk of developing myocardial infarction or its size, improves the restoration of the pumping function of the left ventricle in cases of damage, and also significantly reduces the risk of in-hospital mortality.
The cardioprotective role of pre-infarction angina may be explained by a number of mechanisms:
1 - protection of late post-ischemic preconditioning;
2 - opening of collateral circulation;
3 - increased sensitivity to thrombolysis.
The effect of ischemic preconditioning on the size of myocardial infarction and on the degree of preservation of its functional state (pumping function of the heart) after myocardial infarction depends on many factors, including the severity of collateral coronary blood flow, and the duration of the time interval between the onset of ischemia and treatment.
When performing myocardial revascularization using coronary artery bypass grafting using activation of post-ischemic preconditioning (two cycles of 3-minute total cardiac ischemia using temporary clamping of the ascending aorta under artificial circulation, followed by 2-minute periods of reperfusion, 10 minutes before global myocardial ischemia), a decrease in the severity of necrotic myocardial damage was noted.
In another study, when activated, post-ischemic preconditioning (aortic cross-clamping for 1 minute followed by reperfusion for 5 minutes before cardiac arrest) resulted in a significant increase in cardiac output (CO) after CABG and a decrease in the need for inotropic drugs.
The formation of post-ischemic preconditioning is due to the inclusion of many complex adaptation mechanisms, of which two are currently the most studied: A - reduction in the accumulation of glycogen breakdown products and adenine nucleotides by cardiomyocytes, such as H+ ions, NH3, lactate, inorganic phosphates, adenosine; B - increased activity or synthesis of enzyme systems that have a cardioprotective effect against ischemic damage.
Table 1 presents the most studied endogenous and exogenous mediators and mechanisms for implementing the action of ischemic preconditioning. In 2002, Y.R. Wang and colleagues presented convincing data indicating a cardioprotective effect in the late preconditioning phase of increasing NO production by stimulating the production of NO synthase ( I nducible S yntase NO- iNOS).
It is known that the induced isoform of NO synthase is found in many cells of the body, in particular, in cardiomyocytes, vascular smooth muscle cells, and macrophages. They are instantly activated under the influence of a number of pro-inflammatory factors such as cytokines IL-1B, IL-2, IFN-g, TNF-b and others. Adenosine, acetylcholine, bradykinin, lipopolysaccharides, opioids, free radicals, and serotonin can participate as endogenous mediators that trigger the activation and synthesis of iNOS.
Restoration of coronary blood flow (reperfusion) is accompanied by “washing out” from the ischemic area of the myocardium of products of anaerobic energy metabolism that inhibit the contractile activity of cardiomyocytes, and the “surging” supply of oxygen causes a kind of “explosion” inside the cell in the formation of reactive oxygen species - secondary free radicals (hydroxyl - BUT - , lipoxyl - LO ‑).
Reperfusion removal of inhibition of contraction activation by “washing out” adenosine, K + , H + is accompanied by rapid restoration of myocardial contractile function, using the existing reserves of CrP and ATP. The degree of further reduction depends on the state of mitochondria, which ensure the synthesis of phosphate macroergs through oxidative phosphorylation. The resumption of aerobic resynthesis of ATP and its rate are determined by the degree of preservation of the electron transport chain and enzymes of the cycle
Table 1. Endogenous mediators of ischemic preconditioning mechanisms
|
Endogenous mediators of preconditioning |
|
|
Mediators |
Mechanisms of action |
|
Adenosine |
Through adenosine A and tyrosine kinase |
|
Acetylcholine |
Protein kinase activation |
|
Opioids (Morphine) |
S-opioid receptor activation |
|
Norepinephrine |
Activation - a - adrenergic receptor |
|
Serotonin |
Vasodilating effect? |
|
Activation of K-ATP-sensitive channels |
|
|
Cytokines IL-1B, IL-2 | |
|
By expressing iNOS stimulation |
|
|
Antioxidants - influence on reactive O2 species |
By expressing iNOS stimulation |
|
External incentives |
|
|
Lipopolysaccharides (bacterial endotoxin) |
Promotes the production of Heat Shok Protein 70i (hsp 70i) affecting the myocardium. |
|
Monophospholipid (MLA) |
iNOS gene induction |
|
Pharmacological substances |
Increased expression of C-jun c-tos mRNA catalase and mn-containing dismutase |
|
K+ channel activators: dimakaine, cromacaline, nicorandil |
They are direct “openers of ATP-sensitive K + channels |
Krebs in mitochondria. In the presence of damage to mitochondria, and consequently to part of the oxidative phosphorylation chain, the rate of ATP synthesis may lag behind the needs of the contractile apparatus and the restoration of contractile function will be incomplete.
The task - the initial restoration of myocardial energy reserves - has been the subject of study over the past two decades, which have shown that not ATP, but CrP is the main energy substrate that determines the level of contractile function, the consumption and restoration of which take place primarily after reperfusion.
For example, in the “hibernating myocardium” (against the background of a reduced functional state), the level of ATP is moderately reduced. Unlike ATP, the level of CrP can be restored much faster, because creatine, necessary for its synthesis, leaves the cell more slowly than adenosine, which forms the basis of ATP. However, restoration of the contractile function of the cardiomyocyte as a result of a rapid increase in the intracellular concentration of CrF is limited by ATP molecules involved in the regulation of ion transport of cardiomyocytes.
Currently, based on data from various levels of research, a hypothesis has been formulated about the mechanisms of the protective effect of classical ischemic preconditioning, the essence of which is associated with modifications of intracellular metabolism - maintaining a sufficiently high level of ATP by limiting the utilization of high-energy phosphates.
Ischemic preconditioning is triggered by the interaction of endogenous factors (triggers) with their specific receptors.
Triggers are biological active substances released from cardiomyocytes during ischemic episodes and reperfusion (adenosine, bradykinin, prostanoids, catecholamines, endorphins, NO, ROS, etc.) and realize their effects through different intracellular signaling pathways (Fig. 8, 9).
Rice. 8. Energy exchange during a short attack of ischemia (A) and intracellular signaling pathways activated by adenosine during ischemic preconditioning (B): FlS - phospholipase, DAG - diacylglycerol, F - phosphate, PkS - protein kinase, IPG - inositol triphosphate
Rice. 9. Intracellular signaling pathways activated by bradykinin during ischemic preconditioning: NO - nitrous oxide, PDE - phosphodiesterase, GTP - guanesine triphosphate, cGMP - cyclic guanesine monophosphate, cAMP - cyclic adenosine monophosphate
The hypothesis of the participation of the trigger system in the initiation of ischemic preconditioning is based on the following facts revealed in experiments:
- The intracellular concentration of triggers increases during ischemia;
- Its administration into the coronary bed or non-ischemic myocardium causes a protective effect similar to ischemic preconditioning;
- Administration of trigger inhibitors blocks the cardioprotective effects of ischemic preconditioning.
Based on the essence of the action of factors - natural limiters of myocardial contractile function during stopped coronary blood flow, it can be assumed that the preservation of their influence after reperfusion should be accompanied by a more complete restoration of the pumping activity of the heart.
The above shows that to reduce myocardial damage during post-ischemic reperfusion, it is necessary to ensure the restoration of energy reserves to the initial level and prevent excessive formation of ROS.
Various modifications of reperfusion solutions with calcium antagonists (Magnesium preparations), increased potassium concentrations, and the addition of metabolites that promote accelerated synthesis of adenine nucleotides can improve the restoration of the pumping function of the heart after ischemia.
To solve another problem - to reduce the excessive formation of ROS - it is possible to use reperfusion solutions with antihypoxants and antioxidants (Actovegin).
Finally, the third approach consists of mobilizing one’s own protective mechanisms that are activated during ischemic episodes (the basis of the “preconditioning” effect), when a series of periods of short-term ischemia (pain for no more than 5 minutes) is combined with periods of restoration of blood flow - relief of pain with organic nitrates sublingually.
Recent studies have revealed the existence of a “second window of protection” or late ischemic preconditioning.
Unlike classical ischemic preconditioning, the protective effects of which appear immediately after short-term episodes of ischemia/reperfusion, late ischemic preconditioning is detected after a day or more with a prolonged and less intense response. The mechanisms of this form of ischemic preconditioning are due to the inclusion of the expression of genes for the synthesis of “heat shock” proteins and cellular iNO synthase.
There are opinions that the protective effect of the “second window” of preconditioning is mediated precisely through an increase in the formation of primary ROS, in particular NO, during prolonged ischemia, which is blocked by macrophage oxygen radical scavengers (scavenger receptors) and iNO synthase inhibitors.
Many different factors are involved in the mechanisms of development of the protective effect of ischemic preconditioning, but, according to the latest information, the leading role is played by mitochondrial Ca ++ - activated K + - channels, realized through their influence on changes in the electron transport chains of mitochondria. There is ample evidence that the pharmacological opening of AFT-dependent K + channels fully reproduces the protective effect of ischemic preconditioning.
Mitochondrial ATP-dependent K + channels are more sensitive than similar sarcolemmal channels to opening and closing signals
It is believed that the energy-saving effect of ischemic preconditioning is due to a decrease in the activity of proton mitochondrial F0 F1 ATPase, which dephosphorylates the bulk of ATP during ischemia. The activity of this enzyme is inhibited by the IF1 protein, which is synthesized in response to ischemia with an increase in its affinity for ATPase during acidosis. Other reasons may be a decrease in the activity of enzymes that catalyze ATP-dependent metabolic reactions, less use of ATP by myofibrillar ATPase as a result of “Stunning”, a decrease in the activity of sarcolemmal Na +, K + - ATPase, Ca ++ - ATPase of the sarcoplasmic reticulum.
The consequence of less utilization and degradation of high-energy phosphates (CrP, ATP) during prolonged ischemia is a decrease in intracellular acidosis, since the main source of H + is the breakdown of ATP. During ischemic preconditioning, less accumulation of under-oxidized glycolytic products (pyruvates, phosphoglycerates, lactates, etc.) is recorded, which helps maintain plasma osmolarity at an acceptable level and prevents intracellular edema of cardiomyocytes.
It has been shown that during a short time of classical preconditioning there is no activation of genes responsible for the resynthesis of intracellular proteins of cardiomyocytes. At the same time, the formation of “Heat shock” proteins, iNO synthase, superoxide dismutase and some key enzymes of energy metabolism serve as essential conditions for the manifestation of the cardioprotective effects of the “second window”.
It is assumed that, in addition to the formation of proteins, the mechanisms of action of the “second window” of preconditioning also include the generation of free radicals of oxygen and peroxynitrite - a product of the interaction of NO and O 2 - (ONOO -). This is supported by the fact that pre-administration of free radical scavengers before episodes of brief ischemia blocks the protective effects of delayed preconditioning.
A new strategy in the pharmacological protection of the heart from ischemia and reperfusion injury is the use of Na + /H + transporter inhibitors in the sarcolemma. Under normal conditions, the sarcolemmal Na + /H + exchanger is not activated. During ischemia, in response to rapidly developing intracellular acidosis and, possibly, to other stimulating factors, its activity increases.
This leads to an increase in the intracellular concentration of Na + ions, which is also facilitated by inhibition of Na + /K + - ATPase, the main mechanism for removing Na + from the myocyte. In turn, with the accumulation of Na + ions, the entry of Ca ++ ions into the cell through the Na + /Ca ++ exchanger increases, which contributes to “Ca ++ overload”. (Fig. 5).
Na + /H + - exchange inhibitors exert their cardioprotective effect during ischemia by partially blocking this sequence of ion exchange during ischemia. Ischemic preconditioning can block the Na + /H + exchanger for a long period of ischemia, reducing the overload of ischemic cardiomyocytes with Na + and Ca ++ ions at the stage of early reperfusion. To date, several groups of inhibitors have been synthesized with exceptionally high affinity for the Na + /H + transporter and low affinity for the Na + /Ca ++ exchanger and Na + /HCO 3 ? - simporter.
Using nuclear magnetic resonance and fluorescent dyes, it was shown that blocking the Na + /H + transporter is accompanied by a decrease in the frequency of reperfusion arrhythmias and support of ionic hemostasis in the ischemic myocardium. At the same time, a decrease in the formation and release of inorganic phosphates into the interstitium - products of ATP degradation, better preservation of the intracellular fund of high-energy phosphates, less accumulation of Ca ++ in the mitochondrial matrix and a decrease in damage to the ultrastructure of cardiomyocytes was recorded.
Currently, inhibition of the Na + /H + - transporter has become a method of protecting the heart, which is increasingly used in the clinic, these include 4-isopropyl-3-methylsulfonyl-benzoylguanidine-methanesulfonate(Kriporida, HO 642).
In clinical practice, the protective effect of ischemic preconditioning is documented by non-pharmacological reduction of ST segment elevation on the ECG during continued exercise testing.
Thus, myocardial ischemia is a discrepancy between the delivery of blood oxygen to the myocardium and the needs of aerobic synthesis of adenosine triphosphate in mitochondria to ensure normal cardiac function at a given heart rate, preload, afterload and contractile state of the heart muscle. With oxygen deficiency, the anaerobic pathway of ATP synthesis is activated through the breakdown of glycogen reserves with the accumulation of lactate, a decrease in the intracellular pH level and an overload of cardiomyocytes with calcium ions, manifested by diastolic-systolic dysfunction.
Periods of ischemic episodes are accompanied sequentially by stages of metabolic adaptation - the implementation of various pathways of intracellular metabolism (“ischemic preconditioning”), functional adaptation - a decrease in the contractile function of the myocardium according to the level of energy phosphates (“myocardial hibernation”), followed by biological rehabilitation - restoration of contractile function (“myocardial stupefaction” ) or death of myocardial cells (apoptosis) (Fig. 10).
Rice. 10.
Myocardial infarction. A.M. Shilov
For quotation: Shilov A.M. Some features of the pathogenesis of coronary heart disease // RMZh. 2007. No. 9. P. 686
Coronary heart disease (CHD) is a discrepancy between the volume of coronary blood flow and the amount of myocardial oxygen consumption (PMO2) (Fig. 1).
The equivalent of the heart's performance as a pump is the level of PMO2, the delivery of which is ensured by the coronary blood flow (Qcor). The amount of coronary blood flow is regulated by the tonic state of the coronary vessels and the pressure difference in the ascending aorta (the mouth of the coronary arteries) and the cavity of the left ventricle, which corresponds to intramyocardial pressure (tension):
P1-P2
Qcor = (ml), where
Rcore
P1 - pressure in the ascending aorta,
P2 - pressure in the left ventricle (intramyocardial tension),
Rcor is the resistance of the coronary vessels.
The energy supply for the pumping function of the heart in a wide range of its activity - from rest to the level of maximum load - occurs due to the coronary reserve. Coronary reserve is the ability of the coronary vascular bed to increase coronary blood flow many times adequately to the level of PMO2 due to dilatation of the coronary vessels (Fig. 2). The magnitude of the coronary reserve (I), depending on the pressure in the coronary vessels, lies between the straight line corresponding to the coronary blood flow with maximally dilated vessels (A, B), and the curve of the magnitude of the coronary blood flow with normal vascular tone (area of autoregulation). Under normal conditions, with intact coronary arteries, the heart is in a “superfusion” situation, i.e. O2 delivery slightly exceeds the PMO2 level. .
Coronary reserve can change upward or downward depending on physiological conditions or pathology of the coronary vessels, physiological blood parameters, and myocardial mass. In a person at rest, coronary blood flow in the heart muscle is 80-100 ml/100 g/min. and at the same time about 10 ml/100 g/min is absorbed by O2. When the coronary arteries are damaged by atherosclerosis or as a result of inflammatory changes in the vascular wall, the ability of the latter to maximum dilatation (expansion) is significantly reduced, which entails a decrease in coronary reserve. Conversely, with an increase in myocardial mass (left ventricular hypertrophy - hypertension, hypertrophic cardiomyopathy) or a decrease in the level of hemoglobin, the O2 carrier, to adequately provide PMO2, an increase in coronary blood flow in the area of autoregulation is necessary (upward movement of the autoregulation curve), which leads to a decrease in coronary reserve ( II), especially with atherosclerotic lesions of the coronary vessels (B - decrease in direct line, characterizing the dilatation ability of the coronary arteries).
Acute coronary syndrome (ACS) is an acute discrepancy between O2 delivery, determined by the magnitude of coronary blood flow, and the level of PMO2. This discrepancy may be a consequence of various reasons: 1 - a sharp drop in coronary blood flow as a result of thrombus formation, spasm (complete or partial occlusion) of the coronary arteries against the background of a normal PMO2 value; 2 - extreme increase in PMO2, exceeding the value of the coronary reserve; 3 - limited coronary reserve with a physiological increase in the level of PMO2; 4 - multidirectional changes in the magnitude of coronary blood flow (decrease) and PMO2 level (increase).
Animal studies have demonstrated that ischemic or hypertrophied myocardium is more sensitive than healthy myocardium to even small decreases in hemoglobin levels. At the same time, a decrease in hemoglobin levels is accompanied by a decrease in blood oxygenation in the lung, which also contributes to a decrease in oxygen delivery to the myocardium.
Clinical observations indicate that with limited coronary reserve, ischemic, chronic myocardial dysfunction (systole-diastolic) can form even against the background of a normal volume of coronary blood flow at rest.
More recently, the generally accepted clinical forms of IHD included: 1 - angina at rest and exertion, 2 - unstable angina, 3 - acute coronary syndrome (pre-infarction state), 4 - myocardial infarction - which, from the standpoint of today's understanding of pathological processes during an ischemic attack, cannot explain a number of conditions that therapists, cardiologists, and especially cardiac surgeons encounter in clinical practice.
Currently, based on data obtained from pathophysiological studies in experiments and clinical observations from the standpoint of cellular - subcellular and molecular mechanisms of cardiomyocyte functioning, a modern understanding of “new ischemic syndromes” - “myocardil stunning”, “hibernating - sleeping myocardium” (“Myocardil Hybernatin”), “preconditioning”, “preconditioning - second window of protection” (“Second Window Of Protection - SWOP”). .
For the first time, the term “new ischemic syndromes”, combining the above-described conditions of the myocardium after various episodes of ischemia, reflecting adaptive and maladaptive changes in metabolism and the contractile state of cardiomyocytes, was proposed by the South African cardiologist L.H. Opie in 1996 at a working meeting of the International Society of Cardiology in Cape Town under the auspices of the Council on Molecular and Cellular Cardiology.
L.H. Opie emphasizes that in patients with coronary artery disease, the clinical picture of the disease is characterized by 9-10 clinical manifestations, which are due to the heterogeneity of causes and the diversity of adaptation mechanisms. Considering the diversity of manifestations of ischemic syndrome, the unpredictability of the development and functioning of collateral circulation in the myocardium, as the first stage of myocardial protection during circulatory arrest in the coronary region, it can be assumed that it is impossible for even two identical patients to exist in whom the pathophysiology and clinical course of the disease would be absolutely the same. Even in the same patient, various adaptive mechanisms of “ischemic syndromes” can be combined and formed.
In 1996, P.W. Hochachka and colleagues suggested that myocardial viability under ischemic conditions is ensured by adaptation to hypoxia, which can be divided into two stages depending on the duration of the ischemic “attack”: a short-term protective reaction and a “survival” phase. From the point of view of modern understanding of pathophysiological processes, this may look like this. When switching to anaerobic glycolysis, at the stage of a short-term adaptation period, the reserves of macroergic phosphates (ATP, CrP) in the myocardium are depleted, which is accompanied primarily by a violation of the diastolic phase of cardiomyocyte relaxation and, as a consequence, a decrease in the contractile function of the myocardium in the area of ischemia.
Under physiological conditions, 10% of ATP is formed by oxidative phosphorylation in mitochondria due to aerobic glycolysis (breakdown of glucose to pyruvate). This amount of ATP produced as a result of aerobic glycolysis is not enough to ensure the functioning of the calcium, sodium and potassium ion channels of the sarcolemma, and in particular the calcium pump of the sarcoplasmic reticulum (SRR). Replenishment of the remaining amount of energy for the functioning of the cardiomyocyte with normal oxygen supply occurs due to the oxidation of free fatty acids (FFA), the breakdown of which during oxidative phosphorylation ensures the synthesis of ATP up to 80%. However, compared to glucose, FFA is a less efficient source of ATP - “fuel” for the heart pump, since during their oxidation, 10% more O2 is required to produce the same amount of ATP. A pronounced imbalance between the oxygen demand during the oxidation of glucose and FFA towards the latter leads to the fact that during ischemia (a sharp drop in oxygen delivery) a large number of under-oxidized active forms of FA accumulate in the mitochondria of cardiomyocytes, which further aggravates the uncoupling of oxidative phosphorylation. Under-oxidized active forms of FA block the transport of ATP from the site of synthesis in mitochondria to the site of their consumption inside the cell. In addition, the increased concentration of FA metabolites in mitochondria has a destructive effect on the membrane of the latter, which further leads to a deficiency of energy necessary for the life of the cardiomyocyte. In parallel, an excess amount of protons (Na+, H+) accumulates in the cell against the background of anaerobic metabolism, i.e. its “acidification” occurs. Next, Na+, H+ are exchanged for other cations (mainly Ca++), as a result of which the myocytes are overloaded with Ca++. Excessive amounts of Ca++ and a decrease in the functional capacity of the calcium pump SPR (energy deficiency) lead to impaired diastolic relaxation of the cardiomyocyte and the development of myocardial contracture. Thus, the transition to an anaerobic oxidative process is accompanied by activation of FAs (long-chain cetylcarnitine and acylCoA), which contribute to the uncoupling of oxidative phosphorylation, the accumulation of excess Ca++ in the cytosol, a decrease in myocardial contractility and the development of contracture with “adiastole” (Fig. 3).
The survival phase is the stage of self-preservation of the myocardium under conditions of prolonged ischemia. The most significant adaptive reactions of the myocardium in response to ischemia include the so-called “new ischemic syndromes”: hibernation, stupor, preconditioning, preconditioning - the second window of protection.
The term “stunning” of the myocardium was first introduced by G.R. Heidricx et al. in 1975; The concept of “hibernation” was described in 1985 by S.H. Rahimatoola; "preconditioning" C.E. Murry and co-workers were proposed in 1986, and “preconditioning - second window” was simultaneously proposed by M.S. Marber et al. and T. Kuzuya et al. in 1993.
Stunning of the myocardium is post-ischemic dysfunction of the myocardium in the form of disruption of relaxation-contraction processes, clinically expressed by inhibition of the pumping activity of the heart and persisting after restoration of coronary blood flow for several minutes or days.
In animal experiments, a short period of time of an ischemic attack (stopping blood flow) from 5 to 15 minutes does not lead to the development of myocardial necrosis, but ischemia lasting at least 5 minutes (a typical anginal attack) leads to a decrease in contractile function over the next 3 hours, and an ischemic attack within 15 minutes (without necrosis of the heart muscle) prolongs the period of recovery of contractile function to 6 hours or more. When the coronary artery is occluded for up to 1 hour, restoration of the pumping function of the heart occurs within 3-4 weeks - “chronic stupor” (Fig. 4).
A typical clinical manifestation of myocardial stupor is the feeling of a “heavy, stony heart”, which is based on a violation of the left ventricular diastole - “ineffective diastole”. Currently, two theories of pathophysiological processes dominate in the formation of this phenomenon: A - the formation of an excess amount of free oxygen radicals after restoration of coronary blood flow (reperfusion) with activation of lipid peroxidation; B - uncontrolled entry of Ca++ and its excessive accumulation in the cardiomyocyte as a result of damage to the sarcolemma by lipid peroxidation after reperfusion.
The mechanism of development of myocardial “stunning” is not fully understood: at least three factors are leading in the pathogenesis of “Stunning”: the formation of an excessive amount of ROS, post-perfusion calcium overload of cardiomyocytes, and a decrease in the sensitivity of myofibrils to calcium. In turn, calcium overload of the myoplasm can activate calpins, enzymes that cause proteolysis of myofibrils. The need for resynthesis of new myofilaments is one of the factors determining the duration of restoration of the contractile function of cardiomyocytes.
Thus, disturbances in the contractile function of cardiomyocytes in stunned myocardium are a consequence of the accumulation of excess amounts of cytosolic Ca. After restoration of blood flow, Ca flows through the damaged sarcolemma, which is not regulated by calcium channels. A deficiency of macrophosphate energy does not ensure the functioning of the calcium pump of the sarcoplasmic reticulum (SRR), which regulates the cytoplasmic concentration of Ca.
Cell survival during a certain period of ischemia is possible due to the existence of a number of protective mechanisms aimed primarily at limiting the consumption of ATP in myofibrils, which are realized through a decrease in the sensitivity of the contractile apparatus to Ca.
Microvascular disorders, in most cases of a secondary nature, due to the aggregation of blood cells (platelets, erythrocytes, leukocytes) against the background of myocardial “contracture,” also take part in maintaining myocardial stupor.
“Myocardial hibernation” is a functional adaptation (inhibition of the contractile state) of the cardiomyocyte in response to a decrease in the intracellular energy balance.
Hibernation (Hybernatin) of the myocardium, as defined by Professor S.H. Rahimatoola (1999) - a rapidly occurring disorder of local contractility of the left ventricle in response to a moderate decrease in coronary blood flow. Hibernating myocardium is characterized by a chronic decrease in the contractility of cardiomyocytes while their viability is preserved. From the point of view of pathophysiological processes of adaptation to stressful situations, “hibernating myocardium” is “a self-regulation mechanism that adapts the functional activity of the myocardium to ischemic conditions,” i.e. a kind of protective reaction of the “suffering heart” to an inadequate decrease in coronary blood flow to the level of PMO2. This term, “hibernating (asleep) myocardium”, S.H. Rahimatoola was first proposed in 1984 at a working meeting on the treatment of coronary artery disease at the US National Heart, Lung, and Blood Institute.
In 1990, V. Dilsizian and colleagues published the results of a scintigraphic study of the heart in patients with coronary artery disease after stress. The authors, using thallium scintigraphic technique, identified from 31 to 49% of viable tissue in areas with irreversibly reduced contractile function of the left ventricular myocardium. That is, in places of reduced local blood flow, relatively normal metabolic activity is maintained - the myocardium is viable, but it cannot provide a normal regional ejection fraction. In this case, there are clinical symptoms of ischemia, but which do not end with the development of myocyte necrosis. In the clinic, such situations can occur with stable and unstable angina, in patients with CHF. According to E.B. Carlson and colleagues, published in 1989, in patients who underwent effective coronary angioplasty, areas of myocardial hibernation were detected in 75% of cases among patients with unstable angina and in 28% of cases with stable angina.
Minimizing metabolic and energy processes in the heart muscle in order to preserve the viability of myocytes has allowed some researchers to call this situation either a “resourceful heart” (Smart Heart), or a “self-preserving heart”, or a “playing heart”. . Italian researchers defined this condition of the heart muscle as “myocardial lethargy.”
The mechanisms of hibernation are poorly understood. In clinical practice, against the background of a reduced coronary reserve, the gradual development of destructive changes in the hibernating myocardium is a consequence of cumulative shifts in energy metabolism in response to periodic inotropic stimulation. Under conditions of limited blood flow, a positive inotropic response is achieved by depleting the metabolic status of the cardiomyocyte. Thus, gradually accumulating metabolic changes can cause disorganization of the intracellular structures of the heart muscle.
Preconditioning is a metabolic adaptation to ischemia after repeated short-term episodes of decreased coronary blood flow, manifested by increased resistance of the heart muscle to a subsequent, longer-lasting ischemic attack. Preconditioning is a beneficial change in the myocardium caused by rapid adaptive processes during a short-term episode of ischemic attack on the myocardium followed by rapid restoration of blood flow (reperfusion), which protect the myocardium from ischemic changes until the next episode of ischemia-reperfusion. This phenomenon is phylogenetically determined and typical for all organs of the mammalian body.
In 1986, under experimental conditions on dogs, C.E. Murry and co-workers convincingly demonstrated that repeated short episodes of regional myocardial ischemia adapt the heart muscle to subsequent episodes of ischemic attacks, as documented by the preservation of intracellular ATP at sufficient levels for cardiomyocyte function with the absence of necrotic cell damage.
Other experiments have shown that preliminary intermittent 5-minute episodes of coronary artery occlusion followed by 5-minute intervals of reperfusion (ischemia reperfusion) lead to a 75% reduction in the size of ischemic necrosis of the heart muscle (compared to a control group of dogs that did not undergo a peculiar 5-minute period). minute training - ischemia reperfusion) in response to circulatory arrest for 40 minutes. This cardioprotective effect of short-term episodes of ischemia-reperfusion has been defined as “ischemic preconditioning.” At the same time, the absence of development of the phenomenon of “reperfusion syndrome” was noted. This protective phenomenon was later identified by R.A. Kloner and D. Yellon (1994) in clinical practice.
Previously, it was believed that the cardioprotective effect of ischemic preconditioning appears immediately after short-term episodes of ischemia-reperfusion, and then loses its protective properties after 1-2 hours. In 1994, D. Yellon, in collaboration with G.F. Baxter showed that the phenomenon of “post-ischemic preconditioning” can develop again after 12-24 hours with a duration of up to 72 hours, but in a weakened form. A similar, delayed phase of tolerance to ischemic myocardial damage was defined by the authors as the “second window of protection” (“Second Window Of Protection - SWOP”), in contrast to the early “classical ischemic preconditioning”.
Clinical situations of “classical ischemic preconditioning” are the “Warm-up Phenomen” or “Walk-Through-Angina” syndrome, which manifest themselves in a gradual decrease in the frequency and intensity of anginal attacks during ongoing moderate physical or household activity. The basis of the “pacing” phenomenon is the rapid adaptation of the myocardium to the load against the background of a decrease in the Qcor/PMO2 ratio after the second episode of ischemia. G.I. Sidorenko notes that this syndrome is observed in almost 10% of patients with angina pectoris, and the ST segment on a standard ECG, elevated during the first attack, decreases to the isoline, despite the ongoing load. A similar picture is observed in a number of cases during stress testing, when angina pain or ST segment displacement appears at the height of the load, and when it continues, they disappear. Such situations made it possible to formulate such concepts as “primarily hidden angina” (First Holeangina) or “first-effort angina” (First - Effort - Angina).
It is possible that ischemic preconditioning underlies the fact that patients with pre-infarction angina tend to have a more favorable prognosis compared with those patients in whom MI developed against the background of previous complete well-being.
It has been shown that angina attacks preceding the development of myocardial infarction (pre-infarction angina) can have a protective effect on the myocardium (reduction of the affected area) if they occurred within 24-48 hours before the development of myocardial infarction. Such observations in clinical practice are reminiscent of the cardioprotective effect of long-term ischemic preconditioning (“second window of protection”) in animal experiments.
There is evidence that in clinical practice, pre-infarction angina can reduce the “no-reflow” phenomenon, thereby protecting the myocardium from ischemia and reperfusion caused by microvascular damage in the heart. This reduces the risk of developing myocardial infarction or its size, improves the restoration of the pumping function of the left ventricle in cases of damage, and also significantly reduces the risk of in-hospital mortality.
The cardioprotective role of pre-infarction angina can be explained by a number of mechanisms: 1 - protection of late post-ischemic preconditioning; 2 - opening of collateral circulation; 3 - increased sensitivity to thrombolysis.
The effect of ischemic preconditioning on the size of myocardial infarction and on the degree of preservation of its functional state (pumping function of the heart) after myocardial infarction depends on many factors, including the severity of collateral coronary blood flow, and the duration of the time interval between the onset of ischemia and treatment.
The formation of post-ischemic preconditioning is due to the inclusion of many complex adaptation mechanisms, of which two are currently the most studied: A - reduction in the accumulation of glycogen breakdown products and adenine nucleotides by cardiomyocytes, such as H+ ions, NH3, lactate, inorganic phosphates, adenosine; B - increased activity or synthesis of enzyme systems that have a cardioprotective effect against ischemic damage.
Table 1 presents the most studied endogenous and exogenous mediators and mechanisms for implementing the action of ischemic preconditioning. In 2002, Y.P. Wang and colleagues presented convincing data indicating a cardioprotective effect in the late preconditioning phase of increased NO production by stimulating the production of its synthase (Inducible NO Synthase - iNOS). It is known that the induced isoform of NO synthase is found in many cells of the body, in particular, in cardiomyocytes, vascular smooth muscle cells, and macrophages. They are instantly activated under the influence of a number of pro-inflammatory factors, such as the cytokines IL-1B, IL-2, IFN-a, TNF-a and others. Endogenous mediators that trigger the activation and synthesis of iNOS may include adenosine, acetylcholine, bradykinin, lipopolysaccharides, opioids, free radicals, and serotonin.
Restoration of coronary blood flow (reperfusion) is accompanied by “washing out” from the ischemic area of the myocardium the products of anaerobic energy metabolism that inhibit the contractile activity of cardiomyocytes, and the “surging” supply of oxygen causes a kind of “explosion” inside the cell in the formation of reactive oxygen species - secondary free radicals (hydroxyl - HO- , lipoxyl - LO-) .
Reperfusion removal of inhibition of contraction activation by “washing out” adenosine, K+, H+ is accompanied by rapid restoration of myocardial contractile function using the existing reserves of CrP and ATP. The degree of further reduction depends on the state of mitochondria, which ensure the synthesis of phosphate macroergs through oxidative phosphorylation. In the presence of mitochondrial damage, the rate of ATP synthesis may lag behind the needs of the contractile apparatus, and the restoration of contractile function will be incomplete.
The mechanism of initial restoration of myocardial energy reserves has been the subject of study over the past two decades, which have shown that not ATP, but CrP is the main energy substrate that determines the level of contractile function, the consumption and restoration of which take place primarily after reperfusion. For example, in the “hibernating myocardium” (against the background of a reduced functional state), the level of ATP is moderately reduced. Unlike ATP, the level of CrP can be restored much faster, because creatine, necessary for its synthesis, leaves the cell more slowly than adenosine, which forms the basis of ATP. However, restoration of the contractile function of the cardiomyocyte as a result of a rapid increase in the intracellular concentration of CrF is limited by ATP molecules involved in the regulation of ion transport of cardiomyocytes.
Ischemic preconditioning is triggered by the interaction of endogenous factors (triggers) with their specific receptors. Triggers are biological active substances released from cardiomyocytes during ischemic episodes and reperfusion (adenosine, bradykinin, prostanoids, catecholamines, endorphins, NO, ROS, etc.) and realize their effects through different intracellular signaling pathways (Fig. 5).
The hypothesis of the participation of the trigger system in the initiation of ischemic preconditioning is based on the following facts revealed in experiments:
. The intracellular concentration of triggers increases during ischemia;
. Its administration into the coronary bed or non-ischemic myocardium causes a protective effect similar to ischemic preconditioning;
. Administration of trigger inhibitors blocks the cardioprotective effects of ischemic preconditioning.
The above shows that to reduce myocardial damage during post-ischemic reperfusion, it is necessary to ensure the restoration of energy reserves to the initial level and prevent excessive formation of ROS.
Various modifications of reperfusion solutions with calcium antagonists (magnesium preparations), increased potassium concentrations with the addition of metabolites that promote accelerated synthesis of adenine nucleotides can improve the restoration of the pumping function of the heart after ischemia.
To solve another problem - reducing the excessive formation of ROS - it is possible to use reperfusion solutions with antihypoxants and antioxidants.
The mechanisms of late ischemic preconditioning are also due to the inclusion of the expression of genes for the synthesis of “heat shock” proteins and cellular iNO synthase.
Many different factors are involved in the mechanisms of development of the protective effect of ischemic preconditioning, but, according to recent information, mitochondrial Ca++-activated K+ channels play a leading role. There is ample evidence that pharmacological opening of ATP-dependent K+ channels fully reproduces the protective effect of ischemic preconditioning.
Mitochondrial ATP-dependent K+ channels are more sensitive than similar sarcolemmal channels to opening and closing signals.
Other reasons for the energy-saving effect of ischemic preconditioning may be a decrease in the activity of enzymes that catalyze ATP-dependent metabolic reactions, less use of ATP by myofibrillar ATPase as a result of “Stunning”, and a decrease in the activity of sarcolemmal Na+, K+-ATPase, Ca++-ATPase of the sarcoplasmic reticulum.
The consequence of less utilization and degradation of high-energy phosphates (CrP, ATP) during prolonged ischemia is a decrease in intracellular acidosis, since the main source of H+ is the breakdown of ATP. During ischemic preconditioning, less accumulation of under-oxidized glycolytic products (pyruvates, phosphoglycerates, lactates, etc.) is recorded, which helps maintain plasma osmolarity at an acceptable level and prevents intracellular edema of cardiomyocytes.
A new strategy in the pharmacological protection of the heart from ischemia and reperfusion injury is the use of inhibitors of the Na+/H+ exchanger in the sarcolemma. Under normal conditions, the sarcolemmal Na+/H+ exchanger is not activated. During ischemia, in response to rapidly developing intracellular acidosis and, possibly, to other stimulating factors, its activity increases. This leads to an increase in the intracellular concentration of Na+ ions, which is also facilitated by inhibition of Na+/K+-ATPase, the main mechanism for removing Na+ from the myocyte. In turn, with the accumulation of Na+ ions, the entry of Ca++ ions into the cell through the Na+/Ca++ exchanger increases, which contributes to “Ca++ overload” (Fig. 3). Na+/H+ exchange inhibitors exert their cardioprotective effect during ischemia by partially blocking this sequence of ion exchange during ischemia. Ischemic preconditioning can block the Na+/H+ exchanger for a long period of ischemia, reducing the overload of ischemic cardiomyocytes with Na+ and Ca++ ions at the stage of early reperfusion. To date, several groups of inhibitors have been synthesized with exceptionally high affinity for the Na+/H+ transporter and low affinity for the Na+/Ca++ exchanger and Na+/HCO3- symporter.
Using nuclear magnetic resonance and fluorescent dyes, it was shown that blocking the Na+/H+ exchanger is accompanied by a decrease in the frequency of reperfusion arrhythmias and less accumulation of Ca++ in the mitochondrial matrix. At the same time, a decrease in the formation and release of inorganic phosphates, products of ATP degradation, into the interstitium was noted, which indirectly indicates the preservation of the intracellular fund of high-energy phosphates and a decrease in damage to the ultrastructure of cardiomyocytes.
Currently, inhibition of the Na+/H+ transporter has become a method of protecting the heart, which is increasingly used in the clinic, these include 4-isopropyl-3-methylsulfonyl-benzoylguanidine-methanesulfonate.
Thus, myocardial ischemia is a discrepancy between the delivery of oxygen by the coronary bloodstream and the needs of aerobic ATP synthesis in mitochondria, which is necessary to supply energy to the pumping activity of the heart at a given heart rate, preload, afterload and contractile state of the heart muscle. With oxygen deficiency, the anaerobic pathway of ATP synthesis is activated through the breakdown of glycogen reserves with the accumulation of lactate, a decrease in the intracellular pH level and an overload of cardiomyocytes with calcium ions, manifested by diastolic-systolic dysfunction.
Periods of ischemic episodes are accompanied by sequentially combined or time-spaced adaptation-disadaptation stages: metabolic adaptation - “ischemic preconditioning” (implementation of various pathways of intracellular metabolism), functional adaptation - “myocardial hibernation” (decrease in myocardial contractile function according to the level of energy phosphates), biological rehabilitation - “myocardial stunning” (restoration of contractile function) or death of myocardial cells (apoptosis).
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An important pathogenetic method of treating stunned myocardium is use of antioxidants.
Use of calcium channel blockers, which not only reduce afterload, but also limit the entry of Ca 2+ into cardiomyocytes that have retained viability during the period of reperfusion.
Usage Na blockers + /Ca 2+ counter exchanger to reduce Ca 2+ overload of cardiomyocytes.
Usage calcium "sensitizers"(levosimendan), which bind to troponin, which stimulates the interaction of actomyosin complexes, and thereby increases the force of contraction.
The use of drugs with a positive inotropic effect(dobugamine, dopamine), increasing the sensitivity of myofilaments to Ca 2+.
In clinical practice, in the absence of pronounced disturbances in global LV contractility, special measures that accelerate recovery from stanning are, as a rule, not used. Restoration of regional contractility occurs spontaneously within a few days, less often - weeks. Meanwhile, even if stanning does not require treatment, the fact of its detection in patients with coronary artery disease prompts an assessment of the cause of its occurrence and can be considered as an indicator of “coronary trouble” requiring more active medical tactics.
Hibernating (sleeping) myocardium
Myocardial hibernation is a persistent, potentially reversible inhibition of the contractility of viable LV myocardium, resulting from its hypoperfusion as an adaptive reaction.
The biological meaning of this adaptive reaction is to harmonize the myocardial oxygen demand and the level of coronary blood flow. Restoring full blood supply to the myocardial area in a state of hibernation leads to the complete restoration of its contractility. It is important that this should happen in a timely manner, i.e. before the onset of irreversible changes in the ultrastructure of the contractile apparatus of cardiomyocytes, which naturally occur during prolonged hibernation.
Mechanisms of short-term and chronic hibernation
If during ischemia the level of coronary blood supply to the heart remains at least 25% of the initial blood volume, cardiomyocytes can remain viable and not die for a sufficiently long time, provided that their metabolic needs are reduced, primarily due to a decrease in myocardial contractility in the area with limited coronary perfusion.
The most probable mechanisms of acute myocardial hibernation in conditions of its hypoperfusion are:
impaired Ca 2+ uptake by the sarcoplasmic reticulum;
decreased sensitivity of myofibrils to Ca 2+;
accumulation of inorganic phosphate.
In conditions of ongoing myocardial hypoperfusion, its chronic hibernation develops. This variant of hibernation is most often observed in patients with chronic ischemic heart disease. In cardiomyocytes of chronically hibernating myocardium, characteristic changes are revealed:
Reduction in the number of cytoskeletal proteins and contractile apparatus;
Activation of the genetic program for the survival of cardiomyocytes (increased expression of heat shock protein 70 genes; increased production of apoptosis inhibitor, hypoxia-inducible factor (HIF-la) and vascular endothelial growth factor). All of these proteins contribute to increasing the resistance of the myocardium to insufficient coronary blood supply, therefore their activation in the hibernating myocardium explains its resistance to ischemia.
Metabolic adaptation of the myocardium, manifested by increased glucose uptake and increased glycogen content.
Increased expression of enzymes of the glycolytic pathway and inhibition of the expression of enzymes involved in β-oxidation of FAs and oxidative phosphorylation → glucose becomes the main source of energy. This route is most appropriate in conditions of significant hypoperfusion, since it provides more efficient energy production in conditions of oxygen deficiency.
The appearance of signs of cardiomyocyte dedifferentiation (embryonic cell phenotype).
An increase in the number of mitochondria with a change in their shape and ultrastructure.
Decreased local sympathetic innervation of the hibernating area.
Microautophagy of cardiomyocytes and apoptosis of individual cardiomyocytes.
The myocardium in a state of hibernation is sometimes figuratively called the “smart heart,” thereby emphasizing the important adaptive significance of this phenomenon. However, structural and functional changes in the myocardium during hibernation, especially in conditions of prolonged severe hypoperfusion, do not allow us to unambiguously attribute this phenomenon to adaptation mechanisms, since a decrease in cell contractility occurs in parallel with their damage and only timely revascularization can stop the process of cardiomyocyte death.
