PP of circulatory system – part I:
Heart is a pump in need of energy!
Myocardial blood supply & metabolism
Etiopathogenesis of atherosclerosis
Myocardial ischemia – compensation
Coronary artery/heart disease (CAD/CHD)
Heart needs a lot of energy (= ATP) to continually
perform as a pump (7,500 L/day,  40 mil beats/year)
SV  f = CO  70mL  70 bpm =  5 L/min
sympathetic
nervous
system
parasympathetic
nervous
system
venous return (i.e. circulating volume)
synergistic LV contraction
wall integrity
valvular competence
systemic vascular resistance (i.e. blood pressure or valve obstruction)
• quantitatively
• heart rate 70/min
• SV 70ml
• CO 70  70 = 4,900 ml/min  5 L/min at rest
• CO  20 - 25L/min during
exercise!!!!
• influenced by
• autonomic nervous system activity
• hormones
• age
• gender
• genetics
• drugs
• fitness
• anatomy/size of the heart
MYOCARDIAL METABOLISM
Myocardial metabolism – a lot of ATP is needed
• heart is a pump that has to continually perform 2 processes:
• (1) automacy = generation of action potential in order to perform
• (2) contraction
• myocardium thus has a very high demand for ATP even in the 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 - preferentially
• glucose (glycogen)
• ketone bodies and lactate
• since myocardium requires large amounts of O2 it must be, therefore,
well perfused !!
Excitation-contraction coupling in a ventricular cardiomyocyte
• 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
coronary 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 much larger arterial
pressure compared to right heart supplying pulmonary circulation)
• 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 hyperaemia
• 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) heart rate
• more cardiac cycles = more ATP consumption
• (2) contractility
• that’s why (i.e. 1 & 2) O2 demand is  during
sympathetic activation
• positive chrono- and inotropic effect
• (3) wall tension (see La Place law)
• that’s why O2 demand is  in pressure or volume
overload, but the extent is not the same!
• effect of  afterload is much greater than that of  preload
• (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
Hypoxia  ischemia
• hypoxia is a common situation
both pre- and postnataly
driving the tissue homeostasis
• morphogenesis, wound healing,
cancer progression, …
• stimulates HIF-1 driven
transcription programme
formation of
collaterals
Coronary collaterals & angiogenesis
• enhancement of blood flow to
ischaemic myocardium can result
from
• (1) recruitment of pre-existing
coronary collaterals (= arteriogenesis)
• variable density among people?
• (2) de novo angiogenesis
• angiogenesis = budding of capillaries that
leads to the formation of new
microvessels from pre-existing vascular
structures
• orchestrated by hypoxia (HIF-
1/VEGF)
• prominent interinidividual variability
• failure of concomitant angiogenesis
in hypertrophic myocardium
Metabolic and functional consequences of ischemia
• metabolic changes
•  perfusion  O2   aerobic metabolism  ATP depletion   creatine
phosphate  accumulation of lactate and other catabolites  metabolic
acidosis  efflux of potassium into extracellular space  loss of membrane
function and cellular integrity  cardiomyocyte death
• accumulation of K+, lactate, serotonin and ADP causes ischemic pain (angina)
• functional changes
•  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
• the extent of perfusion limitation decides whether the above
mentioned processes appear only during the exercise, also in the
rest or whether myocardial necrosis develops and what is its
extent
ENDOTHELIAL DYSFUNCTION AS A TRIGGER OF
ATHEROSCLEROSIS
Vessels – types and function
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 by-product. 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
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??
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
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, carotids, renal artery, 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 (AS) 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
significantgeneticcontribution
Major
dyslipidaemia ( LDL and VLDL,  HDL)
hypertension
diabetes mellitus
male gender
Minor (20% of CV events occur in subjects without major risks)
 plasma homocysteine
 plasma haemostatic factors (e.g. fibrinogen, PAI, ..)
 Lipoprotein (a) – Lp(a)
chronic inflammation (CRP as a surrogate)
non-genetic
Environmental
smoking (major risk!)
physical inactivity
diet
certain infections
metabolic
syndrome
driven by
obesity
Lipoprotein metabolism / lipid transport overview
(1) Initiation – formation of fatty streak
• LDLs can exist in a native or modified forms
• native LDL is recognised and bound by LDL-R
• modified LDL is up-taken 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 a 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) Advanced AS plaque
• 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
Fate of advanced AS plaque - rupture an thrombosis
• Pathophysiological scenarios
• (1) progressive growth of the plaque
• asymptomatic until >50% of diameter reduction (= >75% crosssectional
area reduction)
• typical cause of stable angina
• (2) superficial erosion
• denudation/apoptosis od ECs – mural platelet thrombi – healing –
further lumen reduction
• (3) plaque rupture and thrombosis
• clinically leads to acute coronary event (MI or sudden death) in case
of total occlusion of the vessel or unstable angina or no symptoms
in case of a healing
• very often happens in haemodynamically insignificant stenosis
• plaque composition rather than plaques size matters
• can happen due to the fracture of the fibrous cap or in the
„shoulder“
• imbalance between forces/mechanical strength
Vulnerable plaque - thin cap fibroatheroma
• Typical features
• a thin fibrous cap
• extensive inflammatory infiltration by macrophages and
T lymphocytes
• large lipid core
• small numbers of SMCs
• intra-plaque haemorrhage
• inflammation is the most important part of progression
and destabilization of an atherosclerotic plaque
• release of proinflammatory cytokines and matrix
metalloproteinases contributes to degradation of
collagenous components in the fibrous cap of the
atheroma
• apoptosis of collagen synthesizing SMCs
• tissue factor produced by intra-plaque inflammatory cells
• identification of vulnerable plaque (= prone to rupture)
is clinically extremely important
Summary of AS etiopathogenesis – stages
Atheroma complication: disruption and healing.The
fracture of the fibrous cap of the atherosclerotic plaque
permits blood coagulation components to access to the
core of the plaque. Pro-coagulant substances such as tissue
factor can trigger thrombosis, which can cause occlusion of
the vessel and lead to an acute ischaemic event. Many
mural thrombi may not totally occlude the vessel or may
undergo lysis due to endogenous fibrinolytic defences. The
resorbing thrombus, a source of transforming growth
factor-β (TGFβ) and platelet-derived growth factor
elaborated by activated platelets, can stimulate smooth
muscle cell migration and extracellular matrix production.
These processes lead to increased lesion volume and
eventual encroachment upon the arterial lumen.
Pathological studies of advanced human atherosclerotic
plaques showed ‘buried caps’ that provide evidence for
prior rupture and healing. Plaques that lack a well-defined
lipid core and have abundant rather than sparse
extracellular matrix can provoke coronary thrombi due to a
process known as superficial erosion. The clots associated
with superficial erosion have characteristics of platelet-rich
‘white’ thrombi; by contrast, ‘red’ thrombi are rich in fibrin
and trapped erythrocytes and associate with plaque
rupture
(cit. Libby, P., Buring, J.E., Badimon, L. et al. Atherosclerosis. Nat Rev Dis Primers 5, 56 (2019). https://doi.org/10.1038/s41572-019-0106-z)
Clinical manifestations of AS in different predilection sites
• AS is a systemic disease that may
involve multiple vessels
• Consequently, the clinical
manifestations vary widely
according to the vascular territory
involved
• Despite the systemic nature of
many risk factors such as
hypercholesterolaemia,
hypertension, diabetes mellitus
and smoking, AS tends to involve
primarily specific regions of the
arterial tree
• Arterial areas subjected to either
disturbed flow or low shear stress
have particular susceptibility to
atheroma formation
• These conditions prevail at branch
points in the arterial tree.
Shift from „vulnerable plaque“ to „vulnerable patient concept“
Essential PP questions:
• How?
• Why???
Thank you for your attention