PP of circulatory system – part I: AS-driven
coronary artery disease (CAD) and its
consequences
Coronary artery/coronary heart disease (CAD/CHD) as a
consequence of AS
- summary of AS etiopathogenesis
Myocardial ischemia – compensation
Ischaemic heart disease – clinical forms
- chronic – angina pectoris
- acute coronary syndromes
Ischemic cardiomyopathy as the most prevalent cause of heart
failure
Summary of previous and starting point …
• heart (= pump) needs a lot of energy
• automacy + contraction = ATP demand
• SV  f = CO (5l/min at rest vs. 25L/min during exercise)
• O2 is needed for ATP production
• high O2 extraction (A-V difference) at rest
• during exercise more blood is needed – coronary flow reserve
• other factors (heart rate, contractility, wall tension, myocardial mass)
• vasodilation = normal coronary blood flow
• systole x diastole, heart rate effect on diastole, epi vs. endocardium
• endothelial dysfunction as a trigger of AS
• subsequent progression (fatty streak, fibrous plaque, complicated plaque)
• AS affects arteries in predilection sites
• risk factors are modifiable (screening and treatment) and unmodifiable
• advanced AS leads to myocardial ischemia
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
Coronary vascular anatomy
• Coronary arteries arise
from the sinuses of
Valsalva at the aortic
root
• Left main: divides into
left anterior descending
and left circumflex,
supplies most of the
septum and LV
• Right coronary: supplies
the RV, the sinoatrial
node
• Coronary sinus:
drains into the RA,
venous blood oxygen
saturation here is ~ 30%
capacitance
vessels
resistance vessels
Coronary blood flow
• 5% of cardiac output, or 50-120ml/100g of myocardial mass
• 75% of the left main flow and 50% of RCA flow occurs in diastole
• in systole, LV blood flow is reduced due to the high chamber pressure during contraction
• for the RV, the systolic chamber pressure is lower, and blood flow is less affected
• Thus, diastolic time is more important for LV perfusion, and it can be compromised by
tachycardia
• Coronary blood flow is automatically regulated to meet metabolic demand
• myocardial oxygen extraction ratio is already very high (60-75%).
• thus, the myocardium cannot increase its oxygen extraction efficiency to meet increased metabolic demand
• coronary arterial blood flow has to increase to match myocardial oxygen demand, and the oxygen
extraction ratio remains stable
• with exercise, coronary blood flow can increase several-fold
• Mechanisms of coronary blood flow autoregulation
• myogenic autoregulation (intrinsic arterial smooth muscle property)
• metabolic substrates and by-products are thought to act as vasoactive mediators in the coronary
circulation
• multiple agents are considered important, including adenosine, O2, CO2, lactate, pH, and potassium ions
• ATP-sensitive potassium channels also open in response to decreased ATP, resulting in smooth muscle
membrane hyperpolarisation and thus relaxation
• autonomic nervous system
• α1-adrenergic receptor activation stimulates vasoconstriction
• β-adrenergic receptor activation produces vasodilation
• Muscarinic receptor stimulation produces coronary vasodilation
• various pharmacological agents with coronary vasoactive properties include:
• vasodilators (adenosine, GTN, dipyridamole)
• vasoconstrictors (vasopressin, COX inhibitors
Summary of AS etiopathogenesis – stages
The progression of atherosclerotic lesions: cellular birth and death. During the evolution of the
atherosclerotic plaque, the resident and recruited smooth muscle cells (SMCs) produce extracellular
matrix molecules (such as interstitial collagen and elastin, as well as proteoglycans and
glycosaminoglycans) that contribute to the thickening of the intimal layer. However, T cell mediators
such as IFNγ can impair the ability of the SMC to synthesize interstitial collagen and thereby dampen
the ability of these cells to repair and maintain the fibrous cap that overlies the necrotic core.
Furthermore, activated macrophages show increased production of enzymes of the matrix
metalloproteinases (MMPs) family that degrade the interstitial collagen that lends strength to the
fibrous cap. Thinning and structural weakening of the fibrous cap increases the susceptibility of the
plaque to rupture. SMCs and macrophages in the evolving lesion can divide. SMCs and the
mononuclear phagocytes can also interchange through a process of metaplasia. As the lesion
advances, SMCs and macrophages can undergo cell death including by apoptosis. The debris from
dead and dying cells accumulates, forming the necrotic, lipid-rich core of the atheroma. Impaired
efferocytosis (clearance of dead cells) can contribute to the formation of the necrotic core. LDL, lowdensity
lipoprotein.
Initiation and progression of atherosclerosis. The normal artery wall has a tri- laminar structure. The
outermost layer, the adventitia, contains nerve endings, mast cells, and vasa vasorum, microvessels that
nourish the outer layer of the media. The tunica media consists of quiescent smooth muscle cells and a wellorganized
extracellular matrix comprising elastin, collagen and other macromolecules. The atherosclerotic
plaque forms in the innermost layer, the intima. In the early stage of lesion initiation, low- density lipoprotein
(LDL) particles accumulate in the intima, where protected from plasma antioxidants, they can undergo
oxidative and other modifications that can render them pro- inflammatory and immunogenic. Classic
monocytes that exhibit a pro- inflammatory palette of functions then enter the intima. Monocytes circulate in
the bloodstream and can bind to adhesion molecules expressed by activated endothelial cells.
Chemoattractant cytokines, known as chemokines, can promote the migration of the bound monocytes into
the artery wall. Once in the intima, monocytes can mature into macrophages, and attain characteristics
associated with the reparative or less pro- inflammatory monocyte/ macrophage population. These cells
express scavenger receptors that permit them to bind lipoprotein particles and become foam cells. T
lymphocytes, although numerically less abundant than monocytes, also enter the intima, and regulate
functions of the innate immune cells as well as the endothelial and smooth muscle cells. Smooth muscle cells
in the tunica media can migrate into the intima in response to mediators elaborated by the accumulating
leukocytes. The smooth muscle cell chemoattractant platelet- derived growth factor arising from
macrophages and deposited by activated platelets at sites of endothelial breaches or intraplaque
haemorrhage probably participates in this directed migration of medial smooth muscle cells into the intima.
(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)
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.
Is AS-based CVD important epidemiologically?
The contribution of
cardiovascular diseases to
the global burden of death
in 2016.These data convey
the importance of
atherosclerotic
cardiovascular disease
worldwide. Of note, many
stroke deaths may not
result directly from
atherosclerotic disease but
from hypertension, a highly
prevalent cardiovascular
risk factor. Similarly, not all
cases of cardiomyopathy
result from ischaemic
damage, and some cases of
atrial fibrillation may not be
associated with
atherosclerosis. Data from
the Global Burden of
Disease.
(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)
MYOCARDIAL ISCHEMIA
Myocardial ischemia – symptomatic as a IHD
• a consequence of reduced blood flow in
coronary arteries, due to a combination
of
• fixed vessel narrowing as a result of
atherosclerosis
• length and diameter reduction
• abnormal vascular tone as a result of
endothelial dysfunction
• vasospasm and thrombogenicity
• condition of microvasculature
• systemic factors
• e.g. anemia, hypoxemia in pulmonary
disease, hyperkinetic circulation, blood
pressure etc.
• local cardiac factors
• such as hypertrophy, valvular disease,
tachycardia and other heart rhythm
abnormalities etc.
• This leads to an imbalance between
myocardial oxygen supply and demand
Hypoxia (O2 in tissue)  ischemia (tissue perfusion = O2 + pH + catabolites)
• hypoxia is a common physiological
situation both pre- and postnatally
driving the tissue homeostasis
• morphogenesis, wound healing, securing
critical organ circulation by collaterals, …
• pathologically involved in many disease
processes such as cancer progression, …
• hypoxia stimulates HIF-1 driven
transcription program
• pathological hypoxia categories
• (1) hypoxic hypoxia (due to hypoxemia)
• lung diseases, blood shunting
• (2) circulatory/ischemic
• heart failure, vessel obstruction, embolism, …
• (3) anaemic
• low Hb or its inability to bind oxygen
• (4) histotoxic
• blockade of the mitochondrial respiratory
chain by poisons such as cyanide or hydrogen
sulphide
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
Coronary artery stenosis – haemodynamic consequences
• change in vessel diameter (i.e. cross-sectional luminal area) produces by
far the most significant effect
• haemodynamically significant stenosis manifests usually after a significant (>50%)
reduction in cross-sectional luminal area
• concomitant factors modify the severity of myocardial ischemia significantly
• condition of microcirculation (endothelial dysfunction)
• heart rate
• hypoxia/anemia, hypovolemia
• aortic stenosis, LV hypertrophy
• dynamic stenosis (thrombus, eccentric plaque, vasospasm)
Metabolic and functional consequences of ischemia
• metabolic changes
•  perfusion  O2   aerobic metabolism  ATP depletion  Na
intracellular retention  swelling  impaired Ca handling  accumulation
of lactate and other catabolites  metabolic acidosis  efflux of potassium
into extracellular space (arrhythmias!)  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
• clinical signs are „tip of the iceberg“
• earlier changes detectable diagnostically
Metabolic and functional consequences of ischaemia
magnitudeofischemia
Consequences of myocardial injury – graded and often co-occurring
• reversible brief / intermittent injury (ischemia) = preconditioning
• due to fixed stenosis and oxygen supply-demand mismatch or
pharmacologically
• molecular mechanisms involve iNOS, COX-2, mitochondrial K-ATP
channels
• prolonged ischemia followed by reperfusion = stunned
myocardium
• depression of myocardial function despite restored flow
• function spontaneously normalises in days – weeks
• chronic reduction of flow (at rest) = hibernating myocardium
• myocyte apoptosis, myofilament autophagy, loss of B-adrenergic
responsiveness and inhomogeneity in sympathetic activity, fibrosis
• clinically: arrhythmia (V tachycardia and fibrillation) risk! and LV
dysfunction
• irreversible injury and myocyte death = myocardial infarction
• after 20 min from occlusion coronary artery in the absence of
significant collaterals
• begins in the subendocardium and spreads as a wavefront towards
epicardium
• transmural death completed after 4 - 6 hrs
• depends on the presence of other factors increasing oxygen consumption, such as
tachycardia, anaemia, hypovolemia, and the degree of preconditioning
Local and systemic parameters modifying severity of
myocardial ischemia on top of AS
• many condition leading to oxygen supply/demand mismatch can cause/aggravate myocardial ischemia
• causes:
• (1) reduction of coronary perfusion due to fixed mechanic obstruction
• (a) coronary AS (with or without superimposed thrombotisation)
• (b) thromboembolism (from distant site – e.g. atrial or ventricular thrombus, bacterial endocarditis etc.)
• (2) dynamic obstruction due to vascular spasm
• (3) “small vessel disease”
• diabetic microangiopathy, polyarteritis nodosa, systemic lupus erythematosus, autoimmune vasculitis
• (4) hypoxemia, hypoxia, hypotension
• pulmonary disease, anaemia, abnormal haemoglobin, poisoning, shock, sepsis, …
• (5) exaggerated oxygen demand
•    CO (e.g. thyrotoxicosis, amphetamine or cocaine abuse, …)
• LV hypertrophy as a consequence of pressure (volume) overload
• (6) polycythaemia, hyper-coagulation, DIC
• causes (1) and (2) affect larger arteries and branches (ischemia more epicardially)
• causes (3) to (6) smaller terminal branches and often coincide with (1) or (2)
• note hypoxia  ischemia
by far the most important
factor ( 90%)
ISCHEMIC HEART (IHD) DISEASE AS A CLINICAL
MANIFESTATION OF CAD/CHD
Atherosclerosis: Known and unknown
Clinical manifestation is a relatively late event
• AS is slowly progressing and asymptomatic
for the most part of its progression
• Initial stages present already in the firstsecond
decade of life
• Subclinical AS is present in 63% of the
population (71% of men and 48% of
women) by 40–54 years of age (Spanish
PESA cohort)
• When symptoms do arise, they usually
relate to
• a critical reduction in blood flow caused by
the luminal stenosis (narrowing) =
chronic/stable angina pectoris
• typically exertional
• 50% lumen reduction – symptoms during
exercise
• 75% lumen reduction – symptoms at rest
• but other factors play a role
• plaque length, eccentricity, outward
remodelling, sensitivity to vasodilators
etc.
• or to thrombotic obstruction = acute
coronary syndrome
Fate of advanced AS plaque
• 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
Clinical forms of CAD/CHD/IHD
• CAD/CHD/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
• classification/clinical forms
• stable coronary syndromes = stable angina pectoris
• recurrent, transient episodes of chest pain due to demand-supply mismatch
• causes
• obstructive CAD (angiographically proven)
• INOCA (ischaemia and no obstructive coronary artery disease), formerly „coronary
syndrome X“ (negative coronary angiography) – 10-20%
• 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
• abnormal pain perception
• silent myocardial ischemia (both obstructive and INOCA)
• sometimes mixed – some episodes of ischemia with chest pain, others silent
• acute coronary syndromes
• unstable angina
• myocardial infarction (heart attack) = frank cardiac necrosis
• STEMI / transmural / Q-wave MI
• ECG: ST-segment elevation present
• non-STEMI / subendocardial / non-Q wave MI
• ECG: ST-segment elevation absent
• sudden cardiac death due to MI complications (usually ventricular arrhythmias)
• heart failure due to IHD
Angina pectoris
• diagnosis of angina is largely based on the clinical history
• the chest pain/dyscomfort 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
• typically exertional
• dyspnoea can be a consequence of severe LV dysfunction ( LV filling pressure)
• nocturnal angina in combination with sleep apnoea
• grading systems
• ECG finding tent to be normal at rest, ST segment abnormalities (typically depression) during angina
• additional changes such as LBBB and LAFB associated with impaired LV function and indicate poor prognosis
• 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
ACUTE CORONARY SYNDROMES
Atherothrombosis due to the rupture of vulnerable plaque
• Typical features of vulnerable plaque
• a thin fibrous cap (thin cap fibroatheroma)
• extensive inflammatory infiltration by macrophages and T
lymphocytes
• large lipid core
• small numbers of SMCs
• intra-plaque haemorrhage or angiogenesis
• from vasa vasorum
• tendency to lower extent of calcification
• more often spotty calcification
• inflammation is the most important part of progression
and destabilization of an atherosclerotic plaque
• release of pro-inflammatory cytokines and matrix
metalloproteinases contributes to the 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
Shift from „vulnerable plaque“ to „vulnerable patient concept“
Myocardial infarction (MI) = heart attack
• 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
• timing defines the extent of necrosis
• irreversible changes develop 20-40 min after complete
occlusion of the artery
• initially always subendocardial non-STEMI
• spreads epicardially
• eventually, after >3hrs STEMI develops
• Therefore, the size of the resulting infarction
depends on
• (i) the size of the ischaemic area at risk
• where the stenosis/occlusion happens
• (ii) the duration and intermittency of coronary occlusion
• time of reperfusion (spontaneous or induced)
• (iii) the magnitude of residual collateral blood flow
• (iv) condition of preconditioned x hibernating myocardium
• (v) the extent of coronary microvascular dysfunction
• (vi) intensity of the pain
• event. silent
Clinical features of MI
• severe (crushing) 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
• symptoms are produced directly by MI/ischemia (heart, brain, …)
• chest pain, dizziness,
• or, indirectly, by autonomous nervous system activation
• sympathetic
• sinus tachycardia and the fourth heart sound
• sweating
• restlessness
• parasympathetic
• nausea, vomiting
• pulmonary congestion due to diastolic dysfunction
• dyspnoea/breathlessness
• referred pain (back, jaw, shoulder, …) – important for differential diagnosis!
• modest fever (up to 38°C) due to myocardial necrosis often occurs over the
course of the first 5 days
Localisation of MI depends on obstructed artery
• Majority of stenoses and subsequent ruptures or erosions of
an AS plaque develop in proximal parts of epicardial arteries
(or 1st order branches)
• thus can be assessed by coronarography
• stenoses in intramyocardial (penetrating) branches are rare
• LV much more commonly affected
• 40-50% cases LAD
• 15-20 % cases LCX
• RV and atria rarely
• 30-40% cases RCA
Pathology of MI
• irreversible changes develop 20-40 min after
complete occlusion of the artery
• swelling, electrolyte abnormalities
• 6 hours after the onset of infarction, the
myocardium is swollen and pale
• coagulation necrosis
• in 24 hours the necrotic tissue appears deep red
owing to haemorrhage
• LV wall in infarct zone weakened and dilated
• 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 viable myocardium
Cardiac markers of myocardial damage / 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
• possibility to detect re-infarcion
• 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)
• 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 – 6 hrs 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 for confirming myocardial infarction in patients
presenting several days after an episode of chest pain
ECG changes evolve in parallel with tissue changes
Temporal 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 or may disappear
Evolution of STEMI (and to some extent of non-STEMI)
• STEMI is a dynamic process that does not occur in instant
• changing ECG and echocardiography pattern parallels the
evolution
• substantial area at risk (30–50%) is still viable and
therefore salvageable by reperfusion after some time
from the onset of angina symptoms
• early and late complication of MI are function of its size
• recent meta-analyses emphasized the pivotal importance of
infarct size within 1 month after MI as a determinant of allcause
mortality and hospitalization for heart failure at 1 year
• spontaneous reperfusion begins after 12-24 hrs
• to salvage at risk and stunned myocardium reperfusion
therapy should be initiated as soon as possible
• first line therapy nowadays together with strategies decreasing
myocardial oxygen demands
• pharmacological = thrombolysis / fibrinolysis
• time! decreased efficacy as coronary thrombi mature
• administration of t-PA
• mechanical = PCI (percutaneous coronary intervention)
• balloon angioplasty
• stent deployment
Differential dg. of ACS
Unstable angina
(UA)
Non-ST-elevation
myocardial infarction
(NSTEMI)
ST-elevation
myocardial infarction
(STEMI)
Thrombus size partially occlusive partially occlusive completely occlusive
Myocardial
necrosis
absent
present in small
amount
present in large
amount
Serum
biomarkers
(cTnT, cTnI, CK-
MB)
absent present present
Complications of STEMI (and to some extent of non-STEMI)
• Early changes in infarction (minutes to days)
•  tissue O2 levels  rapid conversion from aerobic
to anaerobic metabolism 
• impaired ATP production
•  impaired contractile protein function = systolic dysfunction
• loss of synchronous myocyte contraction → compromised
cardiac output
•  reduced ventricular compliance (i.e. impaired relaxation due
to Ca cytoplasmic retention) and elevation of ventricular filling
pressures = diastolic dysfunction
•  impairment of transmembrane Na-K-ATPase  increased
intracellular Na  intracellular edema and increased
extracellular K  alteration in transmembrane potential 
electrical instability and susceptibility to arrhythmias
•  increased intracellular Ca  activation of degradative lipases
and proteases  tissue necrosis
• Intermediate changes in infarction (days)
• resorption of irreversibly injured/dead myocytes by
macrophages  structural weakness of ventricular
wall and susceptibility to myocardial wall rupture
Sudden cardiac death
• cardiogenic shock
• due to single massive MI or MI superimposed on multiple prior MIs
• area of abnormal contraction > 25% results in HF
• area of abnormal contraction > 40% results in cardiogenic shock
• arrhythmias
• leading mechanism in acute phase is re-entry
• 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
• LV wall rupture
• death from hemopericardium and cardiac tamponade
• occasionally pseudoaneurysm
• rupture of the papillary muscle
• from inferior wall MI
• massive regurgitation
• The three mechanisms, automaticity (A), triggered activity (B), and reentry (C) can play a role in
arrhythmogenesis during ischemia.
• (A) Injury current across the border zone leading to ST elevation in the electrocardiogram,
• (B) Triggered activity mainly caused by Ca 2+ overload in cardiomyocytes or Purkinje fibers.
• (C) Reentry.
• Electrical activation wave front (1) is deflected at the border zone due to unidirectional block (T) into two
wave fronts (2), eventually passing the border zone (3) and exciting the infarct zone (4) and finally passing
the unidirectional block re-exciting the area in front of the block (5). I to , transient outward potassium
current; [K + ] o , extracellular potassium concentration; [Na + ] i , intracellular sodium concentration.
Complications of STEMI (and to some extent of non-STEMI)
• Late changes in infarction (days to weeks)
• fibrous tissue deposition and scarring
• ventricular remodeling
• thinning and dilatation of necrotic tissue without additional
necrosis
• increased ventricular wall stress
• further impairment in systolic contractile function
• increased likelihood of ventricular aneurysm formation
• remodeling of non-infarcted ventricle
• dilatation of overworked non-infarcted segments subjected to
increased wall stress
• enlargement initially compensatory to increase cardiac output via
Frank-Starling mechanism, but can eventually predispose to
ventricular arrhythmias and lead to heart failure
• pericarditis
• thromboembolism
• intra-ventricular thrombus formation can arise from stasis of blood
flow in regions of impaired LV contraction, especially when the
infarction involves the apex or when an aneurysm has formed
• mitral valve regurgitation
• post-MI syndrome (Dressler's syndrome)
• chronic v.s. autoimmune pericarditis
• recurrent cardiac arrhythmias
• recurrent infarction
Percutaneous coronary interventions (PCI) –
stenting & angioplasty (PTCA) • balloon catheters only
• rarely used – risk of re-
stenosis
• bare metal stents
• plus anti-platelet therapy
• ASA + P2Y-receptor
antagonists (i.e.
ticlopidine, clopidogrel)
• drug-eluting stents
• sirolimus-eluting stents
• paclitaxel-eluting stents
Limitation of infarct size - reperfusion
• BUT reperfusion also inflicts additional damage!
• reperfusion injury – damage due to restoration of
blood flow
• mechanisms
• reversible
• stunned myocardium
• prolonged period of contractile dysfunction in salvaged
myocytes
• reperfusion arrhythmias
• microvascular damage
• irreversible = increase of infarction size
• no-reflow phenomenon as an extreme reperfusion injury
• ongoing modification of reperfusion techniques in
order to perform ‘safe’ gentle reperfusion
• ischemic post-conditioning
• alternating cycles of reperfusion and coronary re‐occlusion
• pharmacological
Ischemic cardiomyopathy / heart failure
• the most common aetiology of HF
• accounts for more than 60% of cases of
congestive heart failure
• results from
• myocardial ischemia – hibernating
myocardium
• the larger the contribution the better the
effect od revascularisation
• diffuse fibrosis and LV remodelling
• event. plus multiple scaring due to MI
• event. mitral regurgitation due to
papillary muscle dysfunction
• event. LV aneurysm
• angina might or may not be present
• silent ischemia and confusion with dilated
cardiomyopathy
Follow-up interventions – by-pass surgery &
transplantation
• ‘wellness maintenance’ and not just ‘disease treatment’.