ischemic heart disease n.
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Ischemic heart disease

Ischemic heart disease

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Ischemic heart disease

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  1. Ischemic heart disease Jana Plevkova MD, PhD Associate professor Department of Patophysiology JLF UK

  2. Ischemic heart disease Acute or chronic disorder of myocardial functions developed on the basis of reduced coronary blood flow due to damage of the coronary vessels mostly due to coronary atherosclerosis So this mean that inbalance between oxygen needs and oxygen supply that was discussed earlier is caused by pathological process in the coronary arteries.

  3. Chronic forms Stabile angina pectoris Inversive (Prinzmetal) angina pectoris IHD with arrhythmias Status post MI Clinically asymptomatic – silent ischemia Acute forms Non-stabile angina pectoris Myocardial infarction Sudden cardiac death Intermediary coronary syndrome Clinical stand point – classification

  4. The heart works permanently and this work requires a lot of energy The heart is aerobic organ – this means that energy is provided by metabolizing of substrates and the oxygenis necessary for this process For optimal functions of the heart there should be a precise balance between oxygen supply and the oxygen requirement in the heart cells

  5. Blood flow through the coronary arteries oxygen supply Oxygen requirement Perfusion pressure Vessel resistance Tension in the ventricular wall Power of contraction Heart rate Ventricular volume Intraventricular pressure

  6. Coronary circulation Provides oxygen and substrate supply - Epicardial arteries • Intramyocardial branches • Capillaries Blood flow through the coronary arteries is determined by: • perfusion pressure • extra vascular compression of the myocardium • heart rate (diastolic period) • coronary auto regulation • endothelial functions • neurohumoral regulation • functional condition of the heart and it's metabolic requirements

  7. Regulation of coronary circulation • auto regulation, metabolic, hormonal, neural regulation Coronary perfusion is relatively constant in the ranges of the pressure in aorta between 40 – 160 mmHg – auto regulation The main regulating factor is metabolic rate of the myocardial cells • of the metabolic rate leads to coronary vasodilatation, via factors like adenosine, CO2, H+, K+, NO released from endothelial cells due to accumulation of metabolic products and sudden vasodilatation neural regulation is less important

  8. Extravascular pressure – compression of the vessels by the myocardium during systolic phase could result into complete block of the blood flow in the left ventricle and significant reduction of the blood flow in the right ventricle Intramyocardial branches are perffused only during diastolic phase Increasing of the heart rate facilitates metabolic requirements of the heart cells, but on the other hand leads to reduction of the diastolic phase – therefore limits the coronary blood flow

  9. diastolicphase Systolicphase

  10. Myocardial ischemia Myocardial ischemia is a pathological process developed in condition of reduced coronary blood flow, which does not satisfy energetic requirements of the myocardial cells. Disturbed balance leads to activation of biochemical processes disturbing ionic homeostasis of the heart. Hearse, 1994).

  11. Pathogenesis of the coronary artery damage There is mostly atherosclerotic damage of the vessel wall, but coronary arteries could be affected also by other types of pathological processes – inflammatory response, autoimmune damage, metabolic changes – mediocalcinosis, trauma Pathogenesis of atherosclerosis –„response to injury“ new aspect – ATS is complex inflammatory response

  12. Endothelium – is not only a physical barrier between the blood stream and the vessel wall • high metabolic activity, contribution to vessel reactivity, regulation of thrombogenesis, influence on the circulating cells properties • endothelial surface is about 500 - 1000 m2 thus providing contact between the circulating cells and the vessel wall endothelium is the largest endcrine organ /1500g/ • metabolic and secretoric systems influence mainly vessel tone and therefore blood flow and blood pressure • endothelial cells naturally prefer tendency to vasodilatation

  13. Endothelial vasodilatators • production of NO – from L arginine by NO synthasis, created molecule diffuses into the smooth muscles below the endothelium and activates guanylatcyclase thereby increasing production of cGMP - this leads to relaxation of smooth muscle cells resulting into vasodilatation • production of NO is responsible for permanently maintained vasodilatation in the arterial system • production of NO is stimulated by shear stress, molecules released from thrombocytes (ATP, ADP, serotonine), sudden distension of the vessel lumen – dilatation depending on the blood flow • NO is dominant vasodilating substance in basal condition, but endothelium could also release other molecules PGI2 (prostacycline) PGE2, PGD2able to enlarge vessel lumen

  14. Endothelial vasconstrictors Endothelines, thromboxan A2, nonstabile endoperoxides and molecules of RAA system Endothelines (1, 2, 3) – group of peptides with 21 AMA, originates from molecule of proendotheline, which is fragmented by enzymes and converted into active molecules ETA a ETB receptors – vasoconstrictive response, long lasting increased concentration of the endothelines provides also proliferating effect on the smooth muscles in the media

  15. ETB receptors – after binding of endothelin1 molecule  production of NO a prostacycline – backward regulation - decrease of vasoconstrictive effect of endothelines Production of endothelines is stimulated by: hypoxia, thrombin, cytokines, ATII, epinephrine Local system of RAA – endothelial cells in the whole body are able to produce molecules of RAA system, but its role is not entirely understood Adhesion of the cells Intact endothelium does not allow adhesion of circulating cells, but allows rolling of some cells on the endothelial surface CAM – expression of cell adhesion molecules on the endothelial surface and on the surface of circulating cells regulates their rolling, then adhesion onto surface and transmigration through the intima, this process is facilitated during inflammation of endothelial dysfunction

  16. Pathophysiologic classificatin of vascular injury leading to atherosclerosis Type I injury:functional alteration of endothelial cells without morphologic changes Type II injury: endothelial denudation and intimal damage with intact internal elastic lamina Type III injury: endothelial denudation with the damage of both intima and media

  17. Smooth muscle proliferation Accumulation of lipids and monocytes adhesion Thrombosis Type I injury mierna not present present Type II injury ? minimal fibromuscular layer on the plaque surface Type III injury ? moderate strong organization of the thrombus I. degree Endotel II. degree Intima III. degree Media Adventitia

  18. A new insight into atherosclerosis Chronic inflammatory process with participation of lipoproteins, macrophages, T – lymphocytes, endothelial cells and smooth muscle cells. The consequence of this complex process is formation of lesions inside the vessel wall – atherosclerotic plaques The plaques consist of the core - containing pulpy cellular debris and fibromuscular cap Although ATS is generalized problem in all arteries of the human body, clinical manifestation of the ATS is usually restricted to cerebral and coronary circulation and to circulation of the lower extremities

  19. The basic point of ATS process is damage of the endothelium Endothelium could by damaged by: • sudden changes of the blood flow direction (in the sites of the vessel branching) • oxidative stress (overproduction of oxygen reactive species) •  concentration of pro inflammatory cytokines • some infectious agents and their products •  level of homocysteine (is toxic for the endothelium) • Increased blood pressure • Long lasting hyperglycaemia – diabetes mellitus

  20. Endothelial injury could result into endothelial dysfunction and its consequences  endothelial permeability for blood plasma proteins and lipoproteins • Adhesion of monocytes and their transformation into macrophages • Shifting of the balance in the vessel tone regulation into proconstrictive preparedness Particles of the LDL cholesterol are now able to enter the vessel wall LOX 1 receptors – highafinity receptors for oxidative forms of the lipoproteins which are responsible for disposing of the lipids penetrated into the vessel wall

  21. Lipids penetrating the vessel wall (lipids lesions) are phagocyted by macrophages (via LOX1 receptors)  they are after lipid ingestion converted into the foam cells Endothelial cells, thrombocytes and activated macrophages produce growth factors responsible for proliferation and migration of smooth muscle cells towards the lumen of the vessel. This process is responsible for creation of fibromuscular layer on the surface of the plaque. This cap is like an envelope of the plaque, above the accumulated lipids. Stable – fibromuscular plaques – strong fibromuscular cap, less lipids  plaque is growing progressively disturbing the hemodynamic properties of the vessel, complications are not frequent Nonstable – lipid plaques - thin fibromuscular cap, plenty of lipids, they are predisposed to complications

  22. Early lesions in the wall + risk factors of ATS  growing of the ATS plaques genetic participation level of LDL a VLDL level of HDL lipoprotein a hypertension diabetes mellitus men gender level of homocysteine level of coagulation factors obesity family history Progression of ATS process environmental factors smoking lack of physical exercise faty diet stress

  23. Intravascularultrasound in caseof ATS plaques

  24. slow progression in the growing process of the plaque ~ chronic forms of IHD Growing of the plaque is caused by increase of the lipid content inside the core and by the fibromuscular proliferation The surface of the plaque is usually covered by endothelium with impaired functions, which allows creation of small thrombi on the endothelial surface These small thrombi are then organized by conversion into the fibroid structure. Accumulation of such kind of material on the plaque surface leads to its enlargement Creation of small thrombi is usually asymptomatic growing of the plaques  clinical manifestation

  25. Progression in the plaque growing

  26. Sudden enlargement of the plaque – acute coronary syndromes – mainly due to complications of nonstable plaques • Disruption of the plaque surface  uncovering of underlying collagen  collagen stimulates creation of the thrombus • Fragmentation of the thrombus with subsequent embolization of smaller particles forward into the periphery of coronary circulation • Fissuring or disruption of the plaque with subsequent disjunction of some part of the plaque toward the bloodstream • Disruption with bleeding inside the plaque • Coronary spasm in the arteries with endothelial dysfunction



  29. Small parietal thrombi, as well as, healing of the fissuring of the plaque surface – this means fibroproduction, could contribute to development of more serious ATS changes. Thrombogenesis and organization of the thrombi are simultaneous processes Fibrotization of the parietal thrombus is regulated by molecules released mainly from thrombocytes - PGF, TGF - these molecules are growth factors supporting fibroproduction

  30. Mechanisms leading to ischemia • stabile fibromuscular plaques in the CA – usually large plaques, poor of lipids, without tendency to complications • presence of the plaque inside the lumen influence the blood flow resulting into stenosis of the lumen • size of the stenosis limits the blood supply in the distal parts of the coronary circulation • limitation of more than 75% of the lumen could be considered as a serious stenosis Consecutive limitation of the blood flow provide condition for collateral circulation

  31. Stable fibromuscular plaques Their presence inside the lumen could limit the blood flow thus limit oxygen supply addressed for working myocardial cells Long lasting tight stenosis (possibility for opening of collateral circulation) used to result into small infarction due to collateral blood supply Stable plaque ~ stable angina pectoris – Chest pain occurs usually after the same (stabile, constant) dose of physical exercise or emotional event, but important is that this pain lasts less than 15 min and disappears after stopping of the physical activity or due to nitrate therapy

  32. Nonstable plaque

  33. Nonstable angina pectoris Chest pain occurs after different doses of physical exercise or emotional event (once intensive, another day mild activity could provoke the pain). This pain lasts more than 15 min and does not respond to rest condition or nitrate therapy Progress of the stenosis in time without appropriate intervention leads to myocardial infarction Myocardial infarction is necrosis of myocardial cells due to ischemia – clinical symptoms are the same like in nonstable angina, but to make a diagnose of MI we should confirm presence of necrosis by ECG and enzyme analysis – CK – MB, AST, Troponine T

  34. Mechanisms responsible for nonstable AP and MI The main role in this process plays creation of the thrombus on the basis of ATS damage in coronary arteries, usually on the basis of disrupture of the plaque surface Disrupture of the plaque could lead to creation of the labile thrombus (not fixed strongly to base) and our endogenous systems are able to destroy the thrombus partially – nonstable angina If the damage of the plaque surface is too deep to uncover collagen – thrombosis is more intensive, as well as the thrombus is strongly fixed to basis, and endogenous mechanisms are not strong enough to destroy it – MI The most common cause of myocardial infarction is thrombosis of coronary arteries due to dysruption of the plaque surface.

  35. Small plaques are usually rich in lipids and the tendency to complications These plaques also show tendency to disruption in comparison to plaques with fibromuscular envelope In general – plaques with high risk of disruption are small, rich in lipids with increased activity of the macrophages inside the plaque. Disruption of the plaque is usually caused by mechanical events acting on the plaque surface – pressure, shearing or traction • internal pressure on the plaque surface - hypertension • changes of the vessel lumen - spasm of CA • moving of the arteries due to systolic/diastolic phase

  36. Activity of the macrophages inside the plaque MAC - uptake and metabolism of lipids  formation of the plaque MAC enhance transport and oxidation of LDL MAC enhance production of mitogenic factors  proliferation of smoth muscle cells and neovascularisation of the plaque MAC can release proteases  digestion of extracellular matrix risk for disruption MAC release radicals MAC can enhance local thrombogenesis

  37. Thrombosis inside the CA Degree of thrombosis and duration of thrombus deposition are influenced by local and systemic factors present in the affected vessel during plaque disruption These factors are necessary as triggers of different pathological processes in CA and their clinical manifestation

  38. Local factors Degree of plague disruption Superficial damage of the plaque – thrombogenic stimulus is relatively limited, resulting either in small mural thrombosis, or transient thrombotic occlusion similar to nonstable angina pectoris Deeper damage or ulceration exposes collagen, tissue factor and other factors resulting to relatively persistent thrombotic occlusion – MI Degree of stenosis - platelet deposition increases with increased degree of stenosis, indicating shear-induced platelet activation Residual thrombus – predisposed to recurrent thrombotic occlusion

  39. Residual thrombus After organization and spontaneous lysis of the thrombi, there are small remnants – residual thrombi These residual thrombi predisposed patients with unstable angina or AMI to residual stenosis and to repeated thrombotic occlusion – rethrombosis could by caused by - residual mural thrombus encroaches into the vessel lumen • residual thrombus is one of the strongest thrombogenic surface probably due to increased thrombin activity • there is also increased activity of platelets and thrombin in the site of surrounding thrombolysis Systemic thrombogenic factors • Primary hypercoagulative or thrombogenic states can favor local thrombosis (level of circ. catecholamine, cigarette smoke, hypercholesterolemia) • Other metabolic abnormalities ( homocysteine level, impaired fybrinolysis,  level of fibrinogene, factor VII)

  40. Spasm of CA Inversive angina – Prinzmetal AP – chest pain occures in rest condition, mainly in bed Spasm of CA can result into acute myocardial infarction – typical clinical signs, positive ECG, positive enzymes, but autopsy does not reveal the thrombus Endothelial dysfunction is a consequence of ATS process As we mentioned before – normal endothelium reveal tendency to produce vasodilating molecules, but endothelium with impaired functions preffer production of pro constrictive substances After provoking stimulus (catecholamine, pressure, emotive event) endothelium could produce vasconstrictvie molecules resulting into coronary artery occlusion due to spasm

  41. Summary of basic mechanisms responsible for myocardial ischemia • Myocardial ischemia is the consequence of inappropriate blood • supply that leads to inbalance between oxygen supply • and real oxygen requirements Inbalance is caused by reduction or complete block of coronary blood flow, or by increased requirement of oxygen for working cardiomyocytes, these mechanisms are usually combined • Lumen of the coronary artery can be reduced to 30-20% of • normal lumen without ischemia in subject in rest condition. But if this • patient will start the physical activity thus increasing oxygen • requirements, myocardial ischemia with chest pain can occur

  42. Extension of myocardial ischemia depends on the level (site) • of arterial occlusion, size of the occluded vessel, presence and • quality of collateral circulation. Ischemic area could be small – • microischemia or extremely large affecting more than 40 % of • left ventricle mass • Intensity of myocardial ischemia may form mild forms to • strong and serious ischemia is depending on the tight of stenosis, • duration of vessel occlusion, collateral circulation and on the preload • and afterload of cardiomyocytes • Duration of myocardial ischemia can be transient short lasting, • can occur repeatedly or can be long lasting (permanent), if the • occlusion is permanent

  43. Development of ischemic injury of myocardium Myocardial cells become ischemic within 10 sec of coronary occlusion, no-flow ischemia Early consequences: • ATP production,  contractility, enhanced glycogenolysis, intracellular acidosis, extracellular hyperkalemia, other ionic and metabolic disturbances After several minutes of ischemia the cells lack the ability to contract, anaerobic processes take over, lactic acid is accumulated inside the cells, myocytes are edematous, content of glycogene is decreased and ultrastructural changes can be seen

  44. Cardiac cells remain viable 20 min under these condition of non-flow ischemia, during this time they can be recovered if blood flow is restored to 20 min from the beginning of the heart attack – there is only functional impairment of the cells After this time irreversible changes (morphological changes) of the cells can be seen – damage of intracellular organelles, more than 20 min non flow status results into necrosis - MI Consequences of myocardial ischemia include changes of electrophysiological properties of the cells and changes of mechanical properties – the pump function

  45. Electrophysiological changes - Due to lack of ATP, ionic inbalance, accumulation of metabolic products, formation of free radicals and neurotransmitter release - decrease of rest membrane potential due to increased extracellular level of K+, decrease of RMP means that this value is nearer to 0 point /absolute value is decreased/ normal is -90 mV, after ischemia can be -70, - 60 mV • decrease of maximal speed of the action potential upstroke • changes of action potential duration • changes of excitability, refractoriness • onset of abnormal automacy • cell to cell electrical uncoupling • changes in conduction speed These mechanisms could be responsible for arrhythmias

  46. Mechanical properties Decreased contractility of myocardial cells can be seen after several seconds of non flow status Absolute contractile dysfunction is developed after 3-5 minutes of non flow status After 10-15 min – ischemic contracture There are two mechanisms probably responsible for this phenomenon • Decrease of ATP level – which is necessary for contraction • Rapidly developing intracellular acidosis Intracellular acidosis leads to ionic inbalance and influence binding of Ca++ onto contractive elements – myofibriles  abnormality of excitatory and contractile cycle  contractile dysfunction For the same reasons myocardial relaxation is impaired