PP of circulatory system – part I:
Myocardial blood supply & metabolism
Ethiopathogenesis of atherosclerosis
Myocardial ischemia – compensation
Coronary artery disease (CAD)
Klinical manifestation & outcomes
Heart needs a lot of energy to continually perform as a pump
CO = SV  f
sympathetic
system
parasympathetic
system
venous return
MYOCARDIAL METABOLISM
Myocardial metabolism
• heart is a pump that has to continually perform 2 processes:
• automacy = generation of action potential in order to perform
• contraction
• myocardium thus has a very high demand for ATP even in resting state
• for contraction
• actin/myosin – ATP
• Ca2+ handling (Ca2+-ATP-ase, SERCA)
• for repolarisation
• Na+/K+-ATP-ase
• ATP is produced by oxidation of substrates
• FFA
• glucose (glycogen)
• ketone bodies and lactate
• therefore myocardium requires large amounts of O2 and must be,
therefore, well perfused !!
Excitation-contraction coupling in a ventricular cardiomyocyte
• .Illustrated are the protein complexes, cardiomyocyte
architecture and intracellular organelles involved in cardiac
excitation–contraction coupling. The initial event in the cardiac
cycle is membrane depolarization, which occurs with ion entry
through connexin channels from a neighbouring cardiomyocyte
(right) followed by opening of voltage-gated Na+ channels and
Na+ entry (top). The resultant rapid depolarization of the
membrane inactivates Na+ channels and opens both K+ channels
and Ca2+ channels. Entry of Ca2+ into the cell triggers the release
of Ca2+ from the sarcoplasmic reticulum through the ryanodine
channel. Ca2+ then binds to the troponin complex and activates
the contractile apparatus (the sarcomere, bottom). Cellular
relaxation occurs on removal of Ca2+ from the cytosol by the
Ca2+-uptake pumps of the sarcoplasmic reticulum and by
Na+/Ca2+ exchange with the extracellular fluid. Intracellular Na+
homeostasis is achieved by the Na+/K+ pump. The molecular
components that are required for normal electrophysiological
activity, contractile function and cell–cell adhesion (the latter
mediated by desmosomes) all need to be positioned correctly
within the cell and anchored to each other and the cytoskeleton.
Some cardiomyocyte components are not shown (for example,
stretch-activated channels, and ankyrins that target channels and
other proteins to their correct locations within the cell). Red stars
indicate proteins encoded by genes that are mutated in primary
arrhythmia syndromes; many of these proteins form part of
macromolecular complexes, so mutations in several genes could
be responsible for these syndromes. Green stars indicate protein
complexes in which mutations in multiple genes cause
cardiomyopathies often associated with arrhythmias; these
complexes include the sarcomere (in hypertrophic
cardiomyopathy), the desmosome (in arrhythmic right ventricular
cardiomyopathy), and the cytoskeleton, sarcoglycan complex and
mitochondrion (in dilated cardiomyopathy).
Oxygen extraction by various tissues/organs
Organ CaO2 - CvO2 (vol %) % extraction
heart 10 – 12 65 – 70
skeletal muscle (resting) 2 – 5 13 – 30
kidney 2 – 3 13 – 20
intestine 4 – 6 25 – 40
skin 1 – 2 7 – 13
whole body 20 – 30 %
• Theoretically, the maximal amount of oxygen that can be extracted is 20 vol % (if CaO2 = 200 ml O2/l )
• In reality, however, the maximal oxygen extraction is around 15 - 16 vol % because of the kinetics of oxygen
dissociation from haemoglobin
• Therefore, the heart is extracting one-half to two-thirds of the physiologically available oxygen under normal
operating conditions
• Meeting increased demands (during exercise) is only possible by increasing coronary perfusion (= coronary flow
reserve, CFR)
Oxygen consumption – quantitative aspects
• amount of oxygen supplied by the coronary blood (VO2): ~45 ml
O2/min
• VO2 = Qm  CaO2
• myocardial perfusion (Qm) = 210 – 240 ml/min in the resting state
• but 1000 – 1200 ml/min during the exercise
• CaO2 = 200 ml O2/l
• for PaO2 = 13.3 kPa and c[Hb] = 150 g/l
• consumption in the resting state: ~30 ml O2/min (~60 - 80%)
• very high O2 extraction (A - VO2 difference) compared to other organs
• therefore, the only mechanism increasing the oxygen supply is an
increase of blood flow
• because aorta has a constant pressure, it has to be done by
vasodilatation in the coronary bed = CFR
• small scale neovascularisation is also possible
• majority of oxygen is consumed by LV (generating the arterial
pressure)
• therefore CBF is a critical determinant of its function (i.e. contractility
mainly)
Blood supply of the heart
• demand for O2 and substrates is met by heart blood
vessels - coronary arteries - branching from the
ascendant aorta
• (1) left coronary artery
• (a) left ant. desc. branch
• supplies front part of the LV and RV and front part of the septum
• (b) circumflex branch
• supplies left and back wall of the LV
• (2) right coronary artery
• supplies RV
Coronary blood flow (CBF) – a temporal and spatial pattern
• marked phasic variations = blood flow is diminished during the systole
due to:
• (1) temporal blocking of coronary ostia by opened aortic valves
• „problematic“ anatomy of coronary arteries
• (2) high flow in aorta during the systole
• which “sucks” the blood out (= Venturi effect)
• (3) compression of vessels (microvasculature) during the systolic contraction
• less blood in through arteries, more blood out through veins
• therefore most of the coronary flow occurs during diastole
• tachycardia has adverse effect since it shortens diastole so there is relatively less
time available for coronary flow during diastole to occur
• moreover, subendocardium is much more susceptible to ischemia
than epicardium due to several reasons:
• coronary arteries penetrates myocardium from surface (epicardium) to the
internal chamber lining (endocardium) direction
• decrease in diameter and oxygen tension
•  perfusion pressures in pathological conditions (e.g. epicardial artery stenosis due to
atherosclerosis)
• systolic compression too is nor evenly distributed
• more at subendocardium
•  intracardial pressure due to congestion in pathological conditions (e.g. heart failure)
• lesser capillary density in subendocardium compared to epicardium
CBF autoregulation - tightly coupled to the oxygen demand
• autoregulation between 60 to 200 mmHg of the perfusion pressure (i.e.
systemic arterial pressure) helps to maintain normal coronary blood flow
whenever coronary perfusion pressure changes due
to changes in aortic pressure
• resistance coronary arteries (100-400 µm diameter) – haemodynamic regulation
• shear-stress (flow-induced) mediated intraluminal control – dilation by endothelial NO
• myogenic regulation as a response to transmural pressure/wall stress mediated by stretchactivated
L-type Ca channels (Ca2+ in influx)
• arterioles - metabolic regulation
• adenosine as the most important mediator of active hyperemia
• a metabolic coupler between oxygen consumption and coronary blood flow = formed from cellular
AMP by 5'-nucleotidase
• AMP is derived from hydrolysis of intracellular
ATP and ADP
• neural regulation – negligible at rest
• during sympathetic activation (mainly -adrenergic) vasodilation
• 1-receptor (more than 1-receptor) activation results in coronary vasodilation (plus
increased heart rate, contractility)
• "functional sympatholysis“: sympathetic activation to the heart results in coronary vasodilation and
increased coronary flow due to increased metabolic activity (increased heart rate, contractility)
despite direct vasoconstrictor effects of sympathetic activation on the coronaries
• + Ach induced vasodilation too (though the role of parasympathetic system is less obvious)
Summary of control mechanisms of coronary microvasculature tone
Factors influencing myocardial O2 consumption (MVO2)
• (1) wall tension
• that’s why O2 demand is  in pressure or volume
overload
• (2) contractility
• (3) heart rate
• that’s why (i.e. 2 & 3) O2 demand is  during
sympathetic activation
• (4) myocardial mass
• that’s why O2 demand is  in cardiac hypertrophy (esp.
maladaptive)
• rough estimate of energetic demands of heart:
tension-time index (TTI)
• SBP x heart rate
Wall tension x pressure or volume overload x MVO2
• wall tension () = tension generated by myocytes that
results in a given intraventricular pressure at a particular
ventricular radius
• pressure and volume overload have very various effects
on MVO2
• afterload = pressure
• preload = volume (filling ~ end-diastolic pressure)
• V = 4/3 × r3
• r = 3 V
•  = P × 3 V / d
• 100% increase in ventricular volume (V) increases wall
tension () by only 26%
• in contrast, increasing intraventricular pressure (P) by
100% increases wall tension () by 100%!
for detail
see
previous
slide
Why hypertrophy does not  O2 consumption at the end
• hypertrophy ( d) normalizes wall tension ()
per gram of myocardium in case of pressure
or volume overload
•  = P × r / d
• initially, it does reduces MVO2 when wall tension
increases and heart has to generate higher
pressure to overcome V or P overload
• however, as the total mass of myocardium
increases, consumption of O2 increases as
well
• myocardial hypertrophy is not paralleled by similar
growth of coronary bed
Coronary collaterals & angiogenesis
• enhancement of blood flow to
ischaemic myocardium can result
from
• (1) recruitment of pre-existing coronary
collaterals
• variable density among people?
• (2) true angiogenesis/arteriogenesis
• angiogenesis = budding of capillaries
that leads to the formation of new
microvessels from pre-existing
vascular structures
• due to hypoxia (HIF-1/VEGF)
• failure of concomitant angiogenesis in
hypertrophic myocardium
Hypoxia – HIF-1 driven transcription programme
formation of
collaterals
Consequences of O2/ATP depletion
•  contractility (= systolic dysfunction)
•  EF (ejection fraction),  SV (stroke volume)
•  diastolic relaxation (= diastolic dysfunction)
•  EDP (end-diastolic pressure)
• in summary …  CO (cardiac output)
• in the most serious form = cardiogenic shock
• (auto)regulatory and systemic regulatory mechanisms cause
vasodilation in the intact part of coronary bed - vascular steal
• stenotic arteries do not react to this stimulation and healthy ones further
“steal” the blood from already ischemic region
• accumulation of K+, lactate, serotonin and ADP causes ischemic pain
(angina)
• in the less advanced form above mentioned processes appear only
during the exercise, later also in the rest
Nitrates restore „vascular steal“ by dialation of collaterals
ENDOTHELIAL DYSFUNCTION
Endothelium - physiological role of ECs
• (1) vasodilation
• smooth muscle cells (SMC) in blood vessels - notably
arterioles - work in close association with the overlying ECs
• action of hormones, neurotransmitters (ACh) or deformation
of the ECs by flow of blood (shear stress) trigger reactions
that influence associated SMC, these effects operates via
second messenger systems
• phospholipase A2 (PLA2) which activate cyclooxygenase (COX) /
prostacyclin synthase (PCS) to produce prostaglandins (PGI2) which
diffuse readily through the tissue fluids to act on SMC
• alternatively, nitric oxide synthase (L-arginase) (NOS) produces
highly diffusible gaseous "neurotransmitter„ NO acting on SMC
either through G-protein systems or directly on ion channels
• (2) antiadhesive /anti-inflammatory action
• no VCAM, ICAM, selectins, …
• (3) antithrombotic, antiagregant and fibrinolytic action
• heparansulphate
• thrombomodulin
• tPA
NO-mediated vasodilation
• biosynthesis of the key endogenous vasodilator
NO is principally performed by the calciumdependent
endothelial isoform of nitric oxide
synthase (eNOS)
• this is triggered by the binding of agonists or by
shear stress (1) and facilitated by a variety of
cofactors and the molecular chaperone heatshock
protein 90 (HSP90)
• amino acid L-Arg is converted by eNOS into NO
(2), with L-citrulline as a byproduct. NO diffuses
into adjacent smooth muscle cells (3) where it
activates its effector enzyme, guanylate cyclase
(GC)
• GC (4) converts GTP into the second messenger
cyclic guanosine monophosphate (cGMP), which
activates protein kinase G (PKG) (5), leading to
modulation of myosin light chain kinase and
smooth muscle relaxation.
• PKG also modulates the activity of potassium
channels (IK; 6), thereby increasing cell membrane
hyperpolarization and causing relaxation
Action of agonists on NO production
Endothelial dysfunction
• given the essential role of endothelial integrity in
maintenance of normal
vessel morphology endothelial dysfunction act as
a pro-atherogenic factor increasing adhesivity,
permeability and impairing vasodilatation
• causative factors:
• increase BP (hypertension)
• mechanical shear stress
• turbulent flow
• bifurcations
• biochemical abnormalities
• glucose
• modified proteins
• incl. LDL
• homocysteine
• oxidative stress
• oxygen radicals
• formed by smoking
• inflammation
• certain infections
• Chlamydia pneumoniae
• Helicobacter pylori
Effect of inflammation on EC
Endothelium - summary
Functional Dysfunctional
constant vasodilation due to mechanical stimuli
(shear stress) and mediators (Ach,
bradykinine) mediated by NO, PGI2 (event.
adenosine)
increased sensitivity to paracrine constrictive
mediators (epinephrine, norepinephrine, AT II,
serotonin) and active formation of
vasoconstrictors (ET-1)
anti-adhezive / anti-inflammatory state (NO,
PGI2), inhibition of expression of adhezive
proteins
expression of adhesive molecules (ICAM,
VCAM, selectins), production of cytokines (e.g.
MCP-1) attracting migration of inflammatory
cells into subendothelial space
constant local anticoagulant production
(heparansulphate, thrombomoduline),
antiagregant and thrombolytic state (tPA)
prothrombotic (vWf, TF), anti-fibrinolytic (PAI-
1) phenotype
CORONARY ATHEROSCLEROSIS
Causes of myocardial ischemia
• myocardial ischemia = imbalance between supply of the oxygen (and other essential myocardial nutrients)
and the myocardial demand for these substances
• causes:
• (1) reduced coronary blood flow due to a fixed mechanical obstruction
• coronary atherosclerosis (with or without thrombus) = coronary artery/heart disease (CAD/CHD)
• thrombembolism
• (2) dynamic obstruction
• vascular spasm
• (3) “small vessel disease”
• diabetic angiopathy
• polyarteritis nodosa
• systemic lupus erythematodes
• (4) decrease of blood oxygenation or concentration of oxygen carrier
• hypoxic hypoxia
• anemic hypoxia
• (5) inadequately high demand for oxygen
•    cardiac output (e.g. thyreotoxicosis)
• myocardial hypertrophy (due to pressure or volume overload)
• (1) and (2) affect larger artery branches (epicardially), (3) to (5) smaller terminal branches and very often
superimpose on the previous two processes
• myocardial ischemia is the most commonly occurs as a result of coronary atherosclerosis (AS)
Vessels affected by AS
CAD due to AS – main facts
• AS is a degenerative process characterised by chronic inflammation of
the vessel wall
• AS represents multifactorial disease due to endogenous (typically
with significant genetic component) and environmental factors
• AS can theoretically affect any vessel, in reality AS is limited only to
arteries (= arteriosclerosis)
• due to the role of blood pressure as a pathogenic factor
• moreover, not all arteries are equally affected, but most often those in
predilections (bifurcations, non-laminar flow)
• coronary and cerebral bed, renal artery, truncus coeliacus, lower extremities
artery bifurcations
• main players in the AS ethiopathogenesis
• (1) modified lipoproteins (LDL)
• (2) monocyte-derived macrophages
• (3) normal cells of vessel wall (smooth muscle cells)
• morphologicaly defined stages (findings) in naturalhistory of AS:
• (1) endothelial dysfunction
• (2) fatty streak
• (3) fibrous plaque
• (4) complicated plaque
Cardiovascular risks
• identification of the main CV risks by
prospective epidemiologic studies
• Framingham study =  TK,  cholesterol, 
triglycerides,  HDL, smoking, obesity, diabetes,
physical inactivity,  age, gender (male) and
psychosocial factors
• original cohort (from 1948)
• 5,209 subjects (aged 32 – 60 yrs) from Framingham,
Massachusetts, USA
• detail examination every 2 years
• II. cohort (from 1971)
• 5,124 adult offspring
• III. cohort
• 3,500 grandchildren of original participants
• identified late clinical manifestation of long-term
untreated / decompensated hypertension as well:
• heart attack, stroke ( atherosclerosis)
• heart failure ( left ventricular hypertrophy)
• renal failure ( hyperfiltration, nephrosclerosis)
• retinopathy
Risk factors of AS
Signif. contribution of genetics
 plasma LDL and VLDL,  HDL
 lipoprotein apo(a)
hypertension
diabetes mellitus
male gender
 plasma homocysteine
 plasma haemostatic factors (e.g. fibrinogen, PAI, ..)
metabolic syndrome/ins. resistance
obesity
chronic inflammation
Environment / non-genetic
smoking
physical inactivity
high fat intake in diet
certain infections
(1) Initiation – formation of fatty streak
• LDLs can exist in native or modified forms
• native LDL is recognised and bound by LDL-R
• modified LDL is uptaken by scavenger receptors
• in vivo LDL is modified by oxidation (acetylation or
glycation) in circulation and in subendothelial space
• minimally at first (mmLDL), extensively later (oxLDL)
• mmLDL and oxLDL are cytotoxic and pro-inflammatory,
they increase expression of adhesive molecules (VCAM,
ICAM, selectins) by EC
• monocytes and T lymphocytes adhere to endothelium
and migrates to subendothelial space, here monocytes
transform to macrophages
• interestingly, neutrophils that are constant cell type
present in inflammatory lessions are completely absent in
AS, finding not entirely understood; it might be because of
the particular cytokine spectrum – expression of MCP-1
(monocyte chemotactic protein) by EC
• macrophages ingest oxLDL via their scavenger receptors
(SR-A and CD36) and form this was so called “foam
cells” (= lipid-laden macropghges)
• macroscopically seen as a yellowish dots or streaks in
subendothelium, hence “fatty streaks”
• free cholesterol from oxLDL in macrophages is again
esterified by ACAT-1 (acyl-CoA cholesterol acyltransferase)
and stored together with lipids, inversely, it
can be transform into soluble form by hormonesensitive
lipase, inbuilt into plasma membrane and
exported from the cell (by transporter ABCA1 and HDL)
• reverse CH transport via HDL is crucial anti-atherogenic
mechanism
Role of macrophages in AS initiation
• scavenger receptors of macrophages for modified
macromolecules play physiologically important role in
cellular defence against cytotoxic agents, but at the
same time they can act as pathogenic mechanisms
under the:
• high CH levels
• its increased modification
• oxidation, glycation
• defective reverse CH transport
• Tangier disease (mutation in ABCA1)
• abnormal stimulation of monocytes
• scavenger receptors are part of the innate immunity
• both natural antibodies and scavenger receptors developed
during evolution under the frequent stimulation by certain
pathogens
• (1) natural antibodies (IgM)
• against bacterial pathogen-associated molecular patterns
[PAMPs]
• (2) pattern-recognition receptors (PPRs)
• SR-A, CD36, TLR (Toll-like receptor)
• oxidised molecules (i.e. particular epitopes) are very
often similar to PAMP !!
(2) Progression – formation of plaque
• immunologic interaction between
macrophages and T lymphocytes (Th1 and
Th2 sub-population) locally maintains the
chronic inflammation
• production of both pro-atherogenic Th1 cytokines
(MCP-1, IL-6, TNF-α, …) and anti-atherogenic Th2
(IL-4)
• mutual balance between Th1 and Th2 is topically
modified by many factors
• macrophages as antigen-presenting cells help
to activate B lymphocytes to wards
production of auto-antibodies against oxLDL
 formation of immune complexes 
inflammation
• cytokines stimulate other cells, mainly SMCs
to migrate from media into intima, proliferate
( intima thickening) and secrete proteins of
extracelullular matrix (collagen)  fibrose
plaque
• pathologic calcification of atherosclerotic
vessel wall is not a passive consequence but
result of changed gene expression in
macrophages (osteopontin)
Macrophages in advanced AS – role in AS
progression• M in early lesions
• majority of Ch in the form of
esters (enzyme ACAT)
• non-thrombogenic
• HDL reverse transport works
• M in advanced lesion
• accumulation of free Ch (FCH)
• highly thrombogenic
• FCH in membranes of
endoplasmic reticulum changes
its permeability and Ca
concentration inside →
ER stress → apoptosis of
macrophages → more of FCH
extracellularly → increased
thrombogenicity of atheroma
• production of MMPs
(3) Complication – rupture and thrombosis
• plaque can grow and slowly obstruct lumen or it
can become unstable and lead to
rupture/fissuration and thrombosis and acute
complete obstruction  “complicated plaque”
• intimal macrophages and SMC die (necrosis and
cytokine-induced apoptosis) and establish necrotic
core of the plaque with accumulated extracellular
CH
• stimulated and hypoxic macrophages produce
proteolytic enzymes degrading extracellular
matrix proteins (matrix metaloproteinases, MMPs)
which further weaken the plaque
• plaque rupture (often eccentric and CH-rich),
typically in the plaque “shoulder” lead to exposure
of accumulated lipids and tissue factors to platelets
and coagulation factors and cause thrombosis
• this can be manifested as a complete vessel
occlusion and thus lead to tissue necrosis (e.g.
myocardial infarction or stroke) or incomplete
occlusion as a consequence of repeated cycles of
rupture  microthrombotisation  fibrinolysis 
healing = “unstable plaque” or angina
• vulnerable plaque (i.e. rupture-prone) vs.
vulnerable patient
• see further
Thrombosis of the plaque
• Two different mechanisms are
responsible for a thrombosis on the
plaque:
• (1) denudation of endothelium covering
the plaque
• subendothelial connective tissue is exposed
- platelet adhesion occurs - thrombus is
adherent to the surface of the plaque
• (2) deep endothelial fissuring of the
advanced plaque with a lipid core
• plaque cap tears (ulcerates, fissures or
ruptures), allowing blood from the lumen to
enter the inside of the plaque itself (the core
with lamellar lipid surfaces, tissue factor
(triggering platelet adhesion) produced by
macrophages and exposed collagen, is highly
thrombogenic
• thrombus forms within the plaque,
expanding its volume and distorting its shape
Animal models of AS - mouse
• generally, it is extremely difficult to simulate AS in
animals, even those kept in captivity
• in this aspect Homo sapiens is quite unique in their
susceptibility to damage of vessel wall
• although mice is the most studied model, exp. induced
AS is not entirely similar to man
• exp. model of AS
• induced
• high CH diet + endothelial denudation + hypertension
(ligation of a. renalis)
• spontaneous (knock-out)
• ApoE -/- mouse
• LDL-R -/- mouse
• exp. model spontaneous IM
• induced
• ligation of coronaries
• spontaneous
• comb. apoE/LDL-R -/+
mental stress + hypoxia
Coronary artery stenosis – haemodynamic consequences
• change in vessel diameter (cross-sectional area) produces by
far the most significant effect
• haemodynamically significant stenosis manifests usually after a
significant (>50%) reduction in luminal diameter
• concomitant factors modify the severity significantly
• condition of microcirculation (endothelial dysfunction)
• hypoxia/anemia
• aortic stenosis, LV hypertrophy
• dynamic stenosis (thrombus, excentric plaque)
ISCHEMIC HEART DISEASE (IHD) AS A CLINICAL
MANIFESTATION OF CAD
Clinical manifestation of CAD/myocardial ischemia
• Ischaemic heart disease (IHD) is the leading global cause of
death and lost life years in adults
• despite reductions in morbidity and mortality in general, these
are not consistent across subgroups
• IHD classification
• stable coronary syndromes = angina pectoris
• recurrent, transient episodes of chest pain reflecting demand-supply
mismatch
• causes
• obstructive CAD (angiographically proven)
• INOCA (ischaemia and no obstructive coronary artery disease), formerly
‘coronary syndrome X’ (negative coronary angiography)
• due to coronary microvascular dysfunction (i.e. functional and/or
structural abnormalities in the coronary microcirculation,
• due to coronary vasospasm (Prinzmetal variant angina)
• due to other local or systemic causes
• silent myocardial ischemia
• acute coronary syndromes
• unstable angina
• myocardial infarction
• subendocardial (non-Q)
• ECG: ST-segment elevation absent (non-STEMI)
• transmural (Q)
• ECG: ST-segment elevation present (= STEMI)
Angina pectoris
• diagnosis of angina is largely based on the clinical history
• the chest pain is generally described as 'heavy', 'tight' or 'gripping‘
• typically, the pain is central/retrosternal and may radiate to the jaw
and/or arms
• it can range from a mild ache to a most severe pain that provokes
sweating and fear, there may be associated breathlessness
• types:
• manifestation
• stable
• provoked by physical exertion, especially after meals and in cold
• aggravated by anger or excitement
• pain occurs predictably at a certain level of exertion and fades with rest (the threshold
for developing pain is variable depending on the extent of the stenosis)
• unstable
• angina of recent onset (less than 1 month)
• worsening angina (previously stable for certain time)
• angina at rest
• causes
• obstructive CAD
• INOCA
• cardiac syndrome X
• personal history of angina + positive exercise test + angiographically normal
coronary arteries
• heterogeneous group (more common in women)
• due to microvascular abnormalities
• variant (Prinzmetal) angina
• occurs without provocation, usually at rest or night, as a result of coronary
artery spasm
• more frequently in women
STEMI vs. non-STEMI
Myocardial infarction (MI)
• Results from the rupture or erosion of an AS plaque with
thrombotic occlusion of an epicardial coronary artery and
subsequent ischemia
• occlusive thrombus consists of a platelet-rich core ('white clot') and a
surrounding fibrin-rich ('red') clot
• The infarct develops in a typical wave front manner, starting in the
subendocardial layers in the centre of the area at risk and
progressing into subepicardial layers and to the border zones of
area at risk with ongoing duration of coronary occlusion
• irreversible changes develop 20-40 min after complete occlusion of the
artery
• 6 hours after the onset of infarction, the myocardium is swollen and pale
• in 24 hours the necrotic tissue appears deep red owing to haemorrhage
• during the next few weeks, an inflammatory reaction develops and the
infarcted tissue turns grey and gradually forms a thin, fibrous scar
• late remodelling
• alteration in size, shape and thickness of both the infarcted myocardium (which
thins and expands) and the compensatory hypertrophy that occurs in other areas
of the myocardium
• However, the size of the resulting infarction depends on
• (i) the size of the ischaemic area at risk,
• (ii) the duration and intermittency of coronary occlusion
• (iii) the magnitude of residual collateral blood flow
• (iv) the extent of coronary microvascular dysfunction
Vulnerable plaque vs. vulnerable patient
MI and reperfusion
• Substantial area at risk (30–50%) is still viable and therefore salvageable by reperfusion after
some time from the onset of angina symptoms
• Therefore, reperfusion is a first line therapy nowadays
• mechanical = PTCA or stenting
• pharmacological = thrombolysis
• BUT reperfusion also inflicts additional injury!
• reversible = stunning
• irreversible = increase of infarction size or coronary microvascular dysfunction
• no-reflow phenomenon as an extreme reperfusion injury
• Ongoing modification of reperfusion techniques in order to perform ‘safe’ gentle reperfusion
• Recent meta-analyses emphasized the pivotal importance of infarct size within 1 month after
MI as a determinant of all-cause mortality and hospitalization for heart failure at 1 year
• Additional strategies for cardio-protection
• ischemic pre-conditioning
• the pathophysiological impact of pre-infarction angina!
• remote conditioning
• e.g. by limb ischaemia or by peripheral artery disease
• ischemic post-conditioning
• alternating cycles of reperfusion and coronary re‐occlusion
• pharmacological
• Risks associated with both MI and reperfusion injury
• increase of infarction size or coronary microvascular dysfunction
• myocardial dysfunction
• stunned myocardium = viable myocardium salvaged by coronary reperfusion that exhibits prolonged postischemic
dysfunction after reperfusion
• hibernating myocardium = is ischemic myocardium supplied by a narrowed coronary artery in which
ischemic cells remain viable but contraction is chronically depressed
• arrhythmias
Clinical features of MI
• severe chest pain
• onset is usually sudden, often occurring at rest, and persists
fairly constantly for some hours
• however, as many as 20% of patients with MI have no pain
• so-called 'silent' myocardial infarctions are more common in
diabetics and the elderly
• MI is often accompanied by sweating, breathlessness,
nausea, vomiting and restlessness
• differential diagnosis!
• sinus tachycardia and the fourth heart sound are
common
• modest fever (up to 38°C) due to myocardial necrosis
often occurs over the course of the first 5 days
• branch of coronary arteries
• LCA
• ascendant
• circumflex
• RCA
• stenosis/occlusion
• epicardial - STEMI
• subendocardial – non-STEMI
Localisation, dynamics and extent of MI on ECG
MI diagnosis
• requires at least two of the following:
• a history of chest pain
• evolving ECG changes in respective leads
• a rise in cardiac enzymes or troponins
ECG changes during STEMI
• first few minutes – tall spiked T waves
• during first hours - ST segment elevation develops
(Parde waves)
• after the first few hours - the T wave inverts
• during days after onset - the R wave voltage is
decreased and Q waves develop
• after a few days - the ST segment returns to normal
• after weeks or months - the T wave may return to
normal
• deep Q wave remains forever
Cardiac markers of acute MI
• necrotic cardiac tissue releases several enzymes and proteins into the serum:
• CK - creatinkinase
• peaks within 24hrs and is usually back to normal by 48hrs (also produced by damaged skeletal muscle and brain)
• cardiac-specific isoforms (CK-MB) allows greater diagnostic accuracy
• the size of the enzyme rise is broadly proportional to the infarction size
• Troponins I and T
• consists of three subunits, troponin I (TnI), troponin T (TnT) and troponin C (TnC), each subunit is responsible for part of troponin complex
function
• TnI inhibits ATP-ase activity of acto-myosin. TnT and TnI are presented in cardiac muscles in different forms than in skeletal muscles
• only one tissue-specific isoform of TnI is described for cardiac muscle tissue (cTnI)
• it is considered to be more sensitive and significantly more specific in diagnosis of MI than the CK-MB and LDH isoenzymes
• cTnI can be detected in blood 3–6hrs after onset of the chest pain, reaching peak level within 16–30hrs
• Myoglobin
• historically AST - aspartate aminotransferase and LDH - lactate dehydrogenase
• AST and LDH rarely used now for the diagnosis of MI
• LDH peaks at 3-4 days and remains elevated for up to 10 days and can be useful
confirming myocardial infarction in patients presenting several days after
an episode of chest pain
Complications of MI
• early phase (days after MI)
• arrhythmias
• ventricular extrasystoles
• ventricular tachycardia (may degenerate into ventricular fibrillation)
• atrial fibrillation (in about 10% of patients with MI)
• sinus bradycardia (associated with acute inferior wall MI)
• escape rhythm such as idioventricular rhythm (wide QRS complexes with a
regular rhythm at 50-100 b.p.m.) or idiojunctional rhythm (narrow QRS
complexes) may occur
• sinus tachycardia
• AV nodal delay (first-degree AV block) or higher degrees of block
• may occur during acute MI, especially of the inferior wall (the right coronary
artery usually supplies the SA and AV nodes)
• acute anterior wall MI may also produce damage to the distal conduction
system (the His bundle or bundle branches)
• development of complete heart block usually implies a large MI and a poor
prognosis
• cardiac failure
• pericarditis
• later
• recurrent infarction
• unstable angina
• thromboembolism
• mitral valve regurgitation
• ventricular septal or free wall rupture
• late complications
• post-MI syndrome (Dressler's syndrome)
• chronic v.s. autoimmune pericarditis
• ventricular aneurysm
• recurrent cardiac arrhythmias
Acute interventions – stenting & angioplasty
(PTCA)
Follow-up interventions – by-pass surgery &
transplantation