Ischemic heart disease

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Ischemic heart disease

• Jana Plevkova MD, PhD
• Associate professor
• Department of Patophysiology
• JLF UK

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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.

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Clinical stand point classification

• 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

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• 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 oxygen is 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

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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
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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

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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

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• 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

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diastolic phase
Systolic phase
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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).

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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

http//www.kellykite.com/205/heart-disease.html
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• 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

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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, PGD2
  able to enlarge vessel lumen

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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

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• 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

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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
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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
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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

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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

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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 high afinity receptors for
  oxidative forms of the lipoproteins which are
  responsible for disposing of the lipids
  penetrated into the vessel wall

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• 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

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Progression of ATS process

• 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

environmental factors smoking lack of physical
exercise faty diet stress
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Intravascular ultrasound in case of ATS plaques
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growing of the plaques ? clinical manifestation

• 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

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Progression in the plaque growing
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• 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

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• 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

http//www.nature.com/nri/journal/v6/n7/fig_tab/nr
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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

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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

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Nonstable plaque
http//www.nature.com/nm/journal/v17/n11/full/nm.2
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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

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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.

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• 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

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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

http//www.nature.com/nature/journal/v420/n6917/fi
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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

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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

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• 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)

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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

http//www.invasivecardiology.com/article/1156
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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

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• 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

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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

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• 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

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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

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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

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Intensity of contractile dysfunction depends on
intensity and duration of occlusion

• Hypokinesis ischemic part of the ventricular
  wall moves during systolic and diastolic phase
  less than normal nonischemic myocardium
• Akinesis ischemic wall does not move
• Dyskinesis ischemic wall moves paradoxically
  during systolic and diastolic phase
• Nonischemic myocardium has increased
  contractility as a compensatory reaction to
  improve cardiac output (sympathetic system, Frank
  Starling mechanism)
• Contractile dysfunction is usually accompanied
  by diastolic dysfunction relaxation is also
  active process, decreasing ventricular compliance

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Clinical signs of IHD

• Chest pain
• ECG abnormalities
• Myocardial enzymes elevation
• Systolic/diastolic heart failure

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Symptoms and signs of IHD and mechanisms of their
onset
Chest pain stenocardia, is related to the
accumulation of some molecules within the
myocardium, which are able to stimulate afferent
nociceptive vagal fibers to induce pain these
molecules are lactic acid, potassium, proton,
adenosine... They may be ascribed as a products
or consequences of anaerobic metabolic
pathway Angina stable, nonstable This pain is
usually described as sharp, burning, pressure,
very intensive, the pain is spreading into the
left arm, carotid region, or into the
epigastrium, or interscapular region, is
accompanied with vegetative symptoms Silent
ischemia - Short lasting episodes of ischemie, no
affecting IVP, or distribution of vagal
nociceptive afferents, senile or diabetic
neuropathy
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Symptoms and signs of IHD and mechanisms of their
onset

• Nausea, vomiting general symptom, mostly in
  patients with diaphragmatic localization of MI
• Fear, sweating, pallor, sudden diarrhea
  activation of vegetative NS
• Dysrythmias premature beats, ventricular
  tachycardia, or flutter, different types of AV
  blocks electrophysiological changes
• Signs of heart failure, or cardiogenic shock
  according to extent of MI

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Myocardial enzymes
Legend A. Early CPK-MB isoforms after acute
MI B. Cardiac troponin after acute MI C.
CPK-MB after acute MI D. Cardiac troponin
after unstable angina
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EKG diagnosis

• ST segment elevation
• ST segment depression
• T wave inversion
• Q wave formation

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Ischemic Cycle
Ischemia / infarction
Diastolic Dysfunction
Systolic Dysfunction
chest pain
cardiac output
LV diastolic pressure
pulmonary congestion pO2
catecholamines
wall tension
(heart rate, BP)
MVO2
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Reperfusion of ischemic myocardium
spontaneous or therapeutical
reperfusion after short lasting myocardial
ischemia could recover the cardiomyocytes and
restitute their function ad integrum
Stunned myocardium Total non flow ischemia does
not last to long to cause irreversible damage of
the cells necrosis But these cells lack the
ability to contract or their contractility is
significantly reduced it is a phenomenon of
stunned myocardium Decreased contractility could
be improved but this improvement requires time
(sometimes several days or weeks) Prolonged
depression of myocardial function present after
recovery of non flow ischemia is caused by
insensitivity of myofilaments to calcium
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Hibernating myocardium

• reversible reduction of power of contraction
  present during mild degree of coronary
  insufficiency
• typical for chronic forms of coronary flow
  reduction and the myocardium could reduce
  contractility appropriately to reduced blood
  supply (down - regulation)

• there is prolonged depression of contractility
  with simultaneous reduction of energy
  consumption, adequately to decreased blood flow
• Just after the improvement of coronary blood flow
  the contractility becomes improved too
• Contractile dysfunction is caused by reduced
  entrance of Ca into the cardiomyocytes

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Contractile dysfunction in hypoxic, stunned and
hibernating myocardium
Ca2 transient amplitude
Myofilament Ca2 sensitivity
Maximal Ca2 activated press
Pi / pH i
Hypoxia
? ? /? ?
?
Stunning
? / ?
?
Hibernation
?? /

Pi - inorganic phosphate pHi - intracellular
pH ?- increased relative to control ? -
decreased - unchanged