Download Ischemic heart disease

Ischemic heart disease
Jana Plevkova MD, PhD
Associate professor
Department of Patophysiology
JLF UK
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.
Clinical stand point – classification
Chronic forms
Acute forms
Stabile angina pectoris
Non-stabile angina pectoris
Inversive (Prinzmetal) angina
pectoris
Myocardial infarction
IHD with arrhythmias
Sudden cardiac death
Status post MI
Intermediary coronary syndrome
Clinically asymptomatic – silent
ischemia
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
Blood flow through
the coronary arteries
oxygen supply
Perfusion
pressure
Vessel
resistance
Oxygen requirement
Heart rate
Tension in the
ventricular wall
Intraventricular
pressure
Power of
contraction
Ventricular
volume
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
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
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
diastolic
phase
Systolic
phase
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).
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
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
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
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
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
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
Accumulation of lipids
and monocytes adhesion
Smooth muscle
proliferation
Thrombosis
Type I injury
mierna
not present
Type II injury
?
minimal
Type III injury
?
moderate
present
fibromuscular layer
on the plaque surface
strong organization
of the thrombus
I. degree
Endotel
Intima
Media
Adventitia
II. degree
III. degree
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
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
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
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
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
environmental factors
 level of HDL
smoking
 lipoprotein a
hypertension
lack of physical exercise
diabetes mellitus
faty diet
men gender
stress
 level of homocysteine
 level of coagulation factors
obesity
family history
Intravascular ultrasound in case of ATS plaques
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
Progression in the plaque growing
http://www.nature.com/nm/journal/v17/n11/full/nm.2538.html
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
-
http://danilhammoudimd_1.tripod.com/cardio1/id42.htm
http://danilhammoudimd_1.tripod.com/cardio1/id42.htm
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_t
ab/nri1882_F1.html3
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
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
Nonstable plaque
http://www.nature.com/nm/journal/v17/n11/full/nm.2538.html
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
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.
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
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/fig_
tab/nature01323_F1.html
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
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
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)
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
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
• 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
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
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
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
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
1.
Decrease of ATP level – which is necessary for contraction
2.
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
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
Clinical signs of IHD
-
Chest pain
ECG abnormalities
Myocardial enzymes elevation
Systolic/diastolic heart failure
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
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
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
http://www.vetmed.vt.edu/education/Curriculum/VM8304/vet%20pathology/CASES/ISCHEMIA%202006/PAGE1-19.htm
http://cyhsanatomy1.wikispaces.com/What+do+Myosin+and+Actin+do%3F
EKG diagnosis




ST segment elevation
ST segment depression
T wave inversion
Q wave formation
Ischemic Cycle
Ischemia / infarction
Diastolic Dysfunction
Systolic Dysfunction
chest pain
pulmonary
congestion
pO2
LV diastolic pressure
cardiac output
wall tension
catecholamines
(heart rate, BP)
MVO2
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
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
Contractile dysfunction in hypoxic, stunned
and hibernating myocardium
Ca2+ transient
amplitude
Pi / pH i
Myofilament Ca2+
sensitivity
Maximal Ca2+
activated press
Hypoxia

 /


Stunning

=/=


Hibernation

=/=
=
=
Pi - inorganic phosphate; pHi - intracellular pH
- increased relative to control;  - decreased; = - unchanged