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Coronary Physiology and Pathophysiology
David L. Brown
OUTLINE
Determinants of Myocardial Oxygen Consumption, 60
Metabolic Control, 60
Autoregulation, 60
Vessel Wall and Local Control of Coronary Blood Flow, 61
Coronary Arterial System, 61
Extravascular Compression of Coronary Blood Supply, 62
Neural Control and Reflexes, 62
Pathophysiology, 63
Atherosclerosis, 63
Coronary Microvascular Dysfunction, 63
Collateral Blood Vessels, 63
Myocardial Ischemia, 64
A clear understanding of the physiologic control of coronary
blood flow is essential to considering and treating the underlying
pathophysiology in patients who are acutely ill with an acute
myocardial infarction (MI) in a cardiac intensive care unit (CICU)
or in patients with other severe systemic illnesses and underlying
coronary artery disease (CAD).
DETERMINANTS OF MYOCARDIAL
OXYGEN CONSUMPTION
The working myocardium requires a coronary blood flow of 70
to 90 mL/100 g of myocardium per minute to provide for an
oxygen consumption of 8 to 15 mL/100 g of tissue per minute
at rest for contraction and relaxation. This figure rapidly increases
fivefold to sixfold with exercise or sympathetic arousal. At rest,
the heart consumes most of the oxygen contained in its blood
supply. Therefore any increase in oxygen demand must be met
by an increase in coronary blood flow.
With each beat, developed muscle tension requires oxygen;
total tension developed in unit time is directly proportional to
the oxygen needs of the working myocardium. The frequency
of developed tension (heart rate) is also quantitatively important
with regard to oxygen consumption, whereas stroke volume
(muscle shortening) has a smaller impact on the needs for oxygen
delivery. Excitation–contraction coupling and changes in calcium
flux influence contractility, which impacts the demands for oxygen
delivery and myocardial blood flow.
At the level of the intact heart, myocardial oxygen demand
and myocardial blood flow are determined by developed systolic
wall tension, heart rate, and contractility. In the absence of
coronary vascular disease or dysfunction, myocardial blood supply
is determined by metabolic demands, autoregulation, blood
oxygen-carrying capacity, diastolic time, neurohumoral factors,
and extravascular compressive forces (Fig. 6.1). The following
sections discuss the dominating controlling influences of metabolic regulation and autoregulation.
Metabolic Control
The myocardium generates aerobic energy metabolism; the
prevailing tissue oxygen level provides a powerful signal for the
control of blood flow through the coronary microvasculature
to regulate oxygen supply and maintain physiologic tissue oxygen
tension. With each beat, the myocardial tissue oxygen level exerts
the most powerful effect on coronary vascular resistance within
the microvasculature. Epicardial coronary occlusion causes
instantaneous microvascular dilation to facilitate blood flow.
Similarly, increases in myocardial work increase oxygen consumption and lead to immediate and precisely regulated dilation of
microvascular vessels with increases in regional coronary blood
flow to maintain the oxygen supply to tissues. Tissue oxygen
tension likely signals the coronary microvasculature through
local mechanisms, such as the release of adenosine, tissue levels
of carbon dioxide, pH, nitric oxide, and other substances.
1–3
Autoregulation
The heart provides pressure and blood flow to many organs (i.e.,
perfusion); the vascular resistance in each region of the body varies
from minute to minute. As a result, alterations in pressure and
flow in the ascending aorta can affect coronary circulation, which
must maintain local perfusion to the myocardium (pressure × flow
per unit of tissue) and meet the local needs of the heart. Aortic
pressure can decrease to approximately 50 mm Hg or increase to
approximately 150 mm Hg in health with the microvasculature
adapting to maintain a constant and necessary level of coronary
blood flow. This autoregulation is a protective mechanism and
is probably mediated by the local release of nitric oxide by the
60
CHAPTER 6 Coronary Physiology and Pathophysiology 61
Blood supply
ll tension
Catecholamines vs NO
No adhesion molecules
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Fig. 6.1 Control of myocardial blood flow and oxygen consumption
and demand. (Modified from Ardehali A, Ports TA. Myocardial
oxygen supply and demand. Chest. 1990;98:699.)
endothelium and local constriction of vascular smooth muscle
cells with increasing intraluminal pressure (the myogenic reflex).
The preceding mechanisms are likely transduced via pressuresensitive and flow-sensitive channels on the endothelium and
vascular smooth muscle cells.
narrowing in epicardial coronary arteries alone or in concert with
microvascular dysfunction impairs autoregulation, narrowing
the range of aortic pressure within which changing coronary
resistance can maintain myocardial perfusion at different
aortic pressures. Similarly, hypertension and left ventricular
hypertrophy also can impair the regulation of myocardial
blood flow.
VESSEL WALL AND LOCAL CONTROL OF
CORONARY BLOOD FLOW
The coronary vasculature is subject to neural innervation and
the effects of circulating mediators, such as serotonin, adenosine
diphosphate, epinephrine, and vasopressin. These are in addition
to the local mechanisms that respond to the oxygen and metabolic
needs of the heart (discussed earlier). The local microvascular
endothelium transduces many of these physiologic signals,
including local shear force, pulse pressure, sympathetic stimulation, and blood flow itself. It responds by exerting its own local
control on vascular smooth muscle cells by governing constriction
and relaxation. Vascular endothelial cells possess membraneassociated channels sensitive to many circulating and local regulators, such as shear forces, flow, serotonin, and thrombin. The
endothelium is also sensitive to α-adrenergic sympathetic
stimulation and aggregating platelets. These signals can cause
the endothelium to release vasodilators locally, such as nitric
oxide, endothelium-dependent hyperpolarizing factor (EDHF),
and prostacyclin or vasoconstrictors such as endothelin-1 and
thromboxane. The sum total of these local mediators provides
precise control of blood flow in each segment of the coronary
microcirculation.
Healthy coronary arteries maintain the ability to control local
vasomotion, maintain an anticoagulant surface, and present a
biologic barrier that prevents infiltration and proliferation (Fig.
Coronary blood flow
Diastolic phase
Vascular resistance
Metabolic regulation
Autoregulation
Compressive forces
Humoral factors
Neural control
O2-carrying capacity
Myocardial demand
Systolic wa
Contractility
Heart rate
2–4
The presence of atherosclerotic
Vasomotion
Flow vs shear
NO and ET-1
EDHF vs inhibitors
PGI2 and TXA-2
Rho vs NO
Fig. 6.2 Mechanisms present in healthy coronary arteries that
control local vasomotion, maintain an anticoagulant surface,
and sustain a biologic barrier that prevents infiltration and cell
proliferation. EC, Endothelial cells; EDHF, endothelium-derived
hyperpolarizing factor; ET-1, endothelin-1; NO, nitric oxide; PAI-
1, plasminogen activator inhibitor-1; PGI2, prostacyclin; Rho,
Rho proteins; TF, tissue factor; TM, thrombomodulin; TXA-2,
thromboxane A
.
2
Coagulation
TPA vs PA I-1
TM vs inhibitors
TF vs TFI
Thrombin vs TM
Activation vs passivation
Laminar vs turbulent flow
PGI2 vs TXA-2
Negative vs positive charge
Glycoprotein receptors
Sequestration of collagen
Biologic barrier
EC membrane integrity
Cell cycle suppressed
NO production
Negative charge
PGI2
No mediators
Quiescent phenotype
6.2). These key defensive mechanisms are important in maintain-
ing health; a clear understanding of them is important to
understand the effects of diseases such as atherosclerosis.
Coronary Arterial System
The coronary arterial system is composed of three compartments
that have different functions (Fig. 6.3).5 The large epicardial
coronary arteries (diameter ~500 µm to ~5 mm) visualized
on coronary angiography have a capacitance function and
offer little resistance to blood flow. During systole, epicardial
coronary arteries dilate and accumulate elastic energy as they
increase their blood content by about 25%. This elastic energy is
transformed into blood kinetic energy at the beginning of diastole
and contributes to the prompt reopening of intramyocardial
vessels that had been compressed closed by systole.6 Prearterioles
(diameter ~100 to 500 µm) represent the intermediate compartment and are characterized by a measurable pressure drop along
their length. Their specific function is to maintain pressure at
the origin of the next compartment within a narrow range in
response to changes in coronary perfusion pressure and/or flow;
proximal prearterioles are most responsive to changes in flow,
whereas distal prearterioles are most responsive to changes in
pressure. Finally, the distal compartment is composed of arterioles (diameter <
large pressure drop along their length. Arterioles are the site of
metabolic regulation of myocardial blood flow because their
tone is influenced by substances (such as hydrogen peroxide
and adenosine) produced during myocardial metabolism.7 The
specific function of arterioles is the matching of myocardial
blood supply and oxygen demand. Notably, each compartment
is governed by distinct regulatory mechanisms. In contrast to
the epicardial arteries, both prearterioles and arterioles are below
the resolution of current angiographic systems and, therefore,
cannot be visualized using angiography.5 The importance of
coronary microcirculation for the maintenance of appropriate
100 µm), which are characterized by a very
62 PART II Scientific Foundation of Cardiac Intensive Care
Mean pressure
Relative responsiveness
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Aorta
Capillaries
To pressure To flowTo metabolites
Conductive vessels
1
0
1
0
1
Prearteriolar vessels Arteriolar vessels
Fig. 6.3 Coronary arterial circulation. The
coronary arterial system comprises large
conductive vessels and the microcirculation (prearterioles and arterioles). The
drop of pressure relative to that in the
aorta is negligible in conductive vessels.
By contrast, a considerable pressure drop
occurs through prearterioles and, to a
larger extent, through arterioles. Conductive vessels and (to an even greater
extent) proximal prearterioles are most
responsive to flow-dependent dilatation.
Distal prearterioles are most responsive
to changes in intravascular pressure and
are mainly responsible for autoregulation
of coronary blood flow, whereas arterioles are most responsive to changes
in the intramyocardial concentration of
metabolites and are mainly responsible
for the metabolic regulation of coronary
blood flow. (From Crea F, et al. Chronic
ischaemic heart disease. In: Camm AJ,
Lüscher TF, Serruys PW, eds. The ESC
Textbook of Cardiovascular Medicine.
2nd ed. Oxford: Oxford University Press;
2009.)
myocardial perfusion has been recognized by physiologists since
the 1950s; evidence has accrued over the past 30 years indicating
that functional and structural abnormalities of this section of
the circulation can be responsible for impairment of myocardial
perfusion and ischemia, a condition often referred to as coronary
microvascular dysfunction (CMD).
in both men (51%) and women (54%) with suspected CAD
and is associated with adverse outcomes in both stable CAD
and acute MI.
9
Extravascular Compression of Coronary
Blood Supply
Intracavity pressure and vascular compression achieved by
contracting heart muscle act to obstruct coronary blood flow
during systole, even causing reversed flow in the intramyocardial
microvasculature. In health, diastolic driving pressures overcome
diastolic compressive forces because the aortic diastolic pressure
is higher than the pressure in the coronary sinus or right atrium.
Intracavitary pressures and vascular compression are important
forces influencing flow during systole and diastole. These myocardial or extravascular forces are more prominent in the inner
layer of the left ventricle (i.e., the subendocardium). Flow in the
8
CMD has a high prevalence
epicardium is generally 25% higher than that in the endocardium.
Increases in wall stress in health and disease place greater demands
for oxygen and blood flow in the subendocardial layers. This
layer also exhibits the greatest susceptibility to limitations of
flow (ischemia) in disease states. Increased wall tension from
ventricular hypertrophy and decreased perfusion pressure from
coronary stenoses and shock are more likely to jeopardize
subendocardial coronary flow.
1
Neural Control and Reflexes
α1-Adrenergic and α2-adrenergic innervation can produce coro-
nary constriction. This sympathetic stimulation also produces
increases in heart rate and myocardial work, increasing myocardial
oxygen demand, which leads to the dominating effect of coronary
vasodilation through increased metabolic demand. β2-Adrenergic
stimulation produces coronary dilation; parasympathetic stimulation dilates only the small coronary arteries. The chemoreceptors
can indirectly alter sympathetic stimulation of the heart, affecting
developed tension, heart rate, myocardial oxygen demand, and
coronary resistance. The carotid sinus nerve mediates sympathetic
stimulation and coronary dilation. The sympathetic receptors
seem to cause coronary dilation and there are receptors that can
CHAPTER 6 Coronary Physiology and Pathophysiology 63
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also lead to coronary dilation through muscarinic pathways.
Finally, continuous modulation of α-adrenergic sympathetic
outflow seems to exert a tonic level of constrictor tone on the
coronary circulation, which is opposed by the dilator effect
of the continuous production of nitric oxide by a healthy
endothelium
1–4,10
PATHOPHYSIOLOGY
Common cardiovascular risk factors—including aging, hypertension, diabetes, insulin resistance, dyslipidemia, tobacco smoking,
obesity, and chronic inflammation—impair the production of an
important endothelium-derived relaxing factor, nitric oxide, by
the vascular endothelium in the epicardial arteries and microvasculature. This impaired production of nitric oxide results in the
failure of endothelium-dependent dilation in response to shear
stress, blood flow, and the sympathetic stimulation of exercise.
The lack of reflex dilation is replaced by abnormal constriction.
These risk factors interfere with a wide range of endothelial
functions, including nitric oxide production by uncoupling
the enzymes that produce nitric oxide, oxidant stress, disabling
necessary cofactors, and inhibiting the mRNA that governs the
production of nitric oxide by nitric oxide synthase.
Atherosclerosis
Atherosclerosis leads to local accumulation of matrix, inflammatory cells, debris, cholesterol crystals, and smooth muscle
cells within the coronary arterial wall, which ultimately can lead
to the development of focal stenoses in epicardial arteries. When
a stenosis is sufficiently severe, a pressure gradient develops across
the lesion and, eventually, blood flow decreases as a stenosis
progresses. The effect of luminal plaque and stenosis on coronary
blood flow depends on the minimum cross-sectional area of
narrowing; blood viscosity; vessel wall function; loss of laminar
flow; development of turbulence; the severity, length, and
complexity of the lesion; and the function of the microvasculature.
In the presence of stenoses greater than 70%, small increases in
blood flow greatly increase the pressure gradient across the
stenosis. In the aforementioned circumstances, exercise increases
myocardial oxygen demand, producing resistance vessel dilation,
a decrease in poststenotic pressure, an increase in pressure gradient
across the stenosis, and a further decrease in poststenotic perfusion
pressure to the subendocardium. The minimal cross-sectional
area within the stenosis is the most important measure of the
lesion’s rheologic effect on blood. At this point, small changes
in stenosis severity produce exaggerated increases in the pressure
gradient, which jeopardizes coronary blood supply. Physiologic
increases in coronary blood flow are blunted when the stenosis
exceeds approximately 45%, and they are abolished when the
stenosis exceeds 80%. Resting coronary blood flow declines when
the stenosis exceeds 90% to 95%.
Apart from the structural disease and physical effects of stenosis
on flow as described earlier, atherosclerosis is characterized by
a dysfunctional endothelium that loses its ability to regulate
local microvasculature vasodilation and permits abnormal and
paradoxical constriction, particularly in response to the sympathetic stimulation that occurs during everyday life. This reflex
11,12
constriction also has important consequences at the epicardial
sites of severe stenoses. During physical exercise, exposure to
cold and mental stimulation or sympathetic arousal leads to
abnormal or exaggerated reflex constriction at the site of severe
stenoses, leading to the development of ischemia. In atherosclerosis, the endothelium also loses other healthy functions—the
maintenance of an anticoagulant surface, its antiinflammatory
effect, and the local control of growth and cell proliferation. The
loss of these functions permits platelet aggregation and thrombus
formation locally, infiltration of inflammatory cells, local growth
of smooth muscle cells, and extracellular matrix accumulation,
all of which contribute to lesion progression.
1,13
Coronary Microvascular Dysfunction
CMD can be sustained by several pathogenic mechanisms (Box
6.1).14 Even though several of these mechanisms can be observed
in the same clinical condition, their relative importance seems
to vary between settings. From a pathophysiologic point of view
and independently of the underlying mechanisms, CMD results
in varying degrees of disruption of normal coronary physiology.
CMD can be sustained by a combination of functional mechanisms that lead either to impaired dilatation or increased constriction of coronary microvessels (see Fig. 6.3 and Box 6.1). Their
abnormalities eventually impair the capacity of myocardial blood
flow to adapt to changes in myocardial oxygen demand.
5
Collateral Blood Vessels
Preexisting but nonfunctioning vascular channels and collateral
blood vessels connect the coronary arteries within the myocardium. If narrowing of large coronary arteries causes a decrease
BOX 6.1 Pathogenic Mechanisms of
Coronary Microvascular Dysfunction
Type 1: In the Absence of Myocardial Diseases and
Obstructive Coronary Artery Disease
•
Microvascular remodeling
• Endothelial dysfunction
• Smooth muscle dysfunction
Type 2: In Myocardial Diseases Without Obstructive
Coronary Artery Disease
•
Microvascular remodeling
• Smooth muscle dysfunction
• Extramural compression
• Reduced diastolic perfusion time (increased intramyocardial pressure or
tissue edema)
•
Vascular wall infiltration
• Vascular rarefaction
• Perivascular fibrosis
Type 3: In Obstructive Coronary Artery Disease
•
Endothelial dysfunction
• Smooth muscle dysfunction
• Luminal obstruction (microembolization)
Type 4: Iatrogenic
•
Luminal obstruction (microembolization by plaque and thrombus debris)
• Autonomic dysfunction
64 PART II Scientific Foundation of Cardiac Intensive Care
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in perfusion pressure, the collateral channels can open immediately
and, over a period of days, can undergo passive widening to
facilitate coronary blood flow between previously unconnected
regions of the ventricles. Over weeks, specific cell growth leads
to formation of new collateral vessels. This process is stimulated
by ischemia, myocardial work, and oxygen demand with growth
factors as mediators. Serotonin from platelets can cause opposite
effects, such as collateral vessel constriction, and can worsen
tissue perfusion. Endothelium-derived relaxing factors, such as
nitric oxide, can dilate collateral vessels and facilitate regional
myocardial blood flow.
Preexisting collateral vessels can partially compensate for
coronary stenoses and occlusions. If the stimulus for collateral
growth is persistent over months and collateral blood vessels
develop, they can become capable of compensating for occlusion
of large proximal epicardial arteries. Nevertheless, collateral vessels
have limited ability to provide sufficient myocardial perfusion
under stress and circumstances of increased demand, such as
exercise or concurrent illness.
Myocardial Ischemia
Ischemia occurs when myocardial blood flow fails to deliver
sufficient oxygen to meet the myocardial demand required for
contraction, relaxation, and cellular metabolism. This failure is
commonly caused by decreased myocardial blood flow or
increased myocardial oxygen demand when blood supply is fixed
by obstructive coronary artery disease and/or preexisting CMD.
During ischemia, tissue oxygen tension decreases and aerobic
metabolism becomes anaerobic; left ventricular relaxation and
then contraction fails within seconds; and there are characteristic
changes on the surface electrocardiogram (ECG) that may or
may not be followed by angina pectoris.
Episodes of transient myocardial ischemia may occur in the
presence of one or more atherosclerotic stenoses in the epicardial
coronary arteries of 70% or greater but also occur in the absence
of a severe epicardial stenosis due to spasm of the epicardial or
microvascular vessels or by fixed microvascular obstruction. In
addition, these atherosclerotic vessels exhibit endothelial dysfunction and, with exercise, mental arousal, or sympathetic stimulation
(e.g., cold), their abnormal constriction increases the resistance
at stenoses and further limits coronary blood supply, often at a
time when there is an increase in myocardial oxygen demand.
While abnormal constriction occurs at atherosclerotic stenoses,
myocardial oxygen demand is increased by any increase in heart
rate, developed tension, and contractility, often in the presence
of some degree of left ventricular hypertrophy or anemia. The
mechanisms that lead to transient ischemia often include
abnormalities of supply and demand, which may coexist and
act in concert. During myocardial ischemia, tissue oxygen tension
decreases, energy stores decline, inorganic phosphate accumulates,
and intracellular calcium can no longer facilitate myocardial
relaxation or contraction by myofilaments. There is temporary
loss of the healthy transmembrane ion gradients while intracellular
pH decreases. Myocardial relaxation fails first, and then contraction fails, followed by characteristic electrocardiogram changes
with ST segment depression when there is patchy endocardial
ischemia and ST elevation with severe transmural ischemia.
In acute MI, coronary blood supply is decreased further by
thrombus formation superimposed on disrupted atherosclerotic
plaques. If the balance between blood supply and myocardial
demand is sustained and severe beyond 20 minutes (with plaque
rupture, thrombosis, or sustained stimulation), the myocardial
pathology described earlier is accompanied by progressive irreversible changes in myocardial membranes, enzymes, and proteins,
leading to a central area of myocardial necrosis. Myocardial
necrosis may result from a single episode over approximately
6 hours or may be the result of stuttering ischemic insults distributed over days. At this stage, the severity of ischemia and the
development of necrosis depend almost entirely on the rapidity
with which coronary blood flow can be restored.
In acute MI, restoration of coronary blood flow to the myocyte
following successful reperfusion of the epicardial artery is
dependent on the state of the microvasculature. In patients with
ST elevation MI (STEMI), coronary microvascular dysfunction
and obstruction (CMVO) occurs in up to half of patients following
successful primary percutaneous coronary intervention (PCI)
and is associated with a much worse outcome.15 There are four
interacting mechanisms in the pathogenesis of CMVO in STEMI:
ischemia-related injury, reperfusion-related injury, distal embolization, and individual susceptibility of the microcirculation to
injury15 (Fig. 6.4).
Animal models have demonstrated that 90 minutes following a coronary occlusion, severe capillary damage occurs with
endothelial protrusions and blebs that obstruct the capillary
lumen.16 Gaps in the endothelium allow erythrocytes to leave the
vasculature. Interstitial edema compresses capillaries and small
arterioles, further decreasing flow through these dysfunctional
vessels.17 Sodium and calcium overload result in cell swelling.
The most important clinical predictors of ischemia-related injury
are the duration and extent of ischemia.
15
When ischemia lasts more than 3 hours prior to reperfusion,
ischemia-associated injury is compounded by reperfusion injury.18
CMVO is caused by further obliteration of the vessel lumen by
neutrophil-platelet aggregates that release vasoconstrictor and
inflammatory substances.19 Reperfusion stimulates the production
of radical oxygen species by cardiomyocytes that, along with
rapid normalization of pH, leads to opening of mitochondrial
membrane permeability pores, calcium overload, mitochondrial
swelling, and cell disruption.19 Neutrophils—a major source of
oxidants, proteolytic enzymes, and proinflammatory mediators—
may exacerbate CMVO.
19
A third important mechanism of CMVO is distal embolization.
In experimental models, myocardial perfusion starts failing when
microspheres obstruct more than 50% of coronary capillaries.20
In humans, emboli of different sizes can originate from epicardial
coronary thrombus and disrupted atherosclerotic plaques during
primary PCI. Spontaneous embolization prior to PCI probably
occurs as well. Thrombus volume and the presence of lipid-rich
plaque are associated with a greater risk of distal embolization.21
Certain plaque features may also predispose to distal embolization.
In particular, plaque erosion appears to result in more distal
embolization than plaque rupture.
15
Finally, there appears to be variation in individual susceptibility
to microvascular dysfunction possibly related to the function,
CHAPTER 6 Coronary Physiology and Pathophysiology 65
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Genetic variability
Diabetes
Acute hyperglycemia
Hypercholesterolemia
Lack of preconditioning
Individual susceptibility
Thrombus
burden
Distal
embolization
Endothelial gaps with
extravascular erythrocytes
Endothelial
profusion
Platelet-neutrophil
aggregates
Ischemia-related
Ischemia driven
Ischemia extent
Vasoconstrictor
substances
release
Myocardial
cell swelling
injury
Obstructive
emboli
Interstitial
edema
Activated
neutrophils
with oxygen-tree
radical release
Fig. 6.4 There are four interacting mechanisms involved in the pathogenesis of coronary micro-
vascular obstruction in humans: ischemia-related injury, reperfusion-related injury, distal embolization,
and individual susceptibility (both genetic and due to preexisting coronary microvascular dysfunction)
of the microcirculation to injury. Ischemic injury depends on duration and extent of ischemia and
is characterized by severe capillary damage, endothelial protrusions, and blebs that block the
capillary lumen, and endothelial gaps with extravascular erythrocytes (in red). Interstitial myocardial
edema compresses capillaries and small arterioles, further decreasing flow through these dysfunctional vessels, whereas sodium and calcium overload explains myocardial cell swelling.
Reperfusion injury: The principal determinants of this phenomenon are represented by neutrophils
(in green), endothelin-1, thromboxane-A2, and platelets (in yellow). The obliteration of vessel
lumen by neutrophil–platelet aggregates is associated with release of vasoconstrictors and
inflammatory mediators (in brown). Furthermore, in cardiomyocytes, reperfusion stimulates the
production of reactive oxygen species by mitochondria, further aggravating microvascular function.
Finally, reperfusion may increase infarct size due to mitochondria swelling and cell rupture based
on opening of the mitochondrial membrane permeability transition, as well as favor intramyocardial
hemorrhage. Distal embolization (in blue) of plaque and thrombus material may mechanically
obstruct the microcirculation, but it is also a source of vasoconstrictors and procoagulant substances.
Both thrombus and plaque features modulate the effect of distal embolization on coronary
microvascular obstruction. Individual susceptibility of the microcirculation to injury: Factors modulating
individual susceptibility to coronary microvascular obstruction are presented by genetic variability,
diabetes, acute hyperglycemia, hypercholesterolemia, and lack of preconditioning.
Reperfusion-related injury
Neutrophil
count
ET-1 levels
TXA-2 levels
Mean platelet
volume
or reactivity
66 PART II Scientific Foundation of Cardiac Intensive Care
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structure, and density of the microcirculation in individual
patients prior to the development of acute coronary syndrome.
There are a number of invasive and non-invasive techniques
for diagnosing CMVO, including direct invasive measurement
of coronary blood flow velocity with an intracoronary Doppler
Fig. 6.5 The diagnostic indexes for coronary microvascular obstruction detection, classified as
invasive (green circle) or noninvasive tools (blue circle) (B). Invasive indexes: The gold standard method for coronary microvascular dysfunction and obstruction assessment is the direct
measurement of coronary flow reserve using intracoronary Doppler wire; the typical coronary
microvascular dysfunction and obstruction pattern is characterized by systolic retrograde flow,
diminished systolic anterograde flow, and rapid deceleration of diastolic flow. The figure at
bottom left shows the systolic retrograde flow (white arrows) during intracoronary Doppler. The
index of microvascular resistance provides a more reproducible assessment of microcirculation,
independent of hemodynamic perturbations; hyperemic microvascular resistance is associated
with ventricular recovery and clinical outcome after ST segment elevation myocardial infarction.
The image at bottom right shows the typical pattern of coronary microvascular dysfunction and
obstruction: reduced coronary flow reserve and increased index of microvascular resistance/
hyperemic microvascular resistance. Angiographic parameters of coronary microvascular dysfunction and obstruction are represented by Thrombolysis in Myocardial Infarction (TIMI) flow score,
myocardial blush grade, and TIMI myocardial perfusion grade. Of note, it is becoming common
practice to define angiographic coronary microvascular dysfunction and obstruction as follows:
TIMI flow grade less than 3 or 3 with a myocardial blush grade or TIMI myocardial perfusion grade
0 to 1. The image at the top shows a case of angiographic coronary microvascular dysfunction
and obstruction (white arrow) in the posterior descending branch of the right coronary artery.
Noninvasive indexes: ST segment resolution represents a useful tool of coronary microvascular
dysfunction and obstruction, also considering its prognostic value (see the top left image for the
ST segment before opening infarct-related artery; see the top right image for the ST segment
after opening infarct-related artery during coronary microvascular dysfunction and obstruction).
Myocardial contrast echocardiography can be employed for coronary microvascular dysfunction
and obstruction diagnosis. The typical pattern is represented by lack of intramyocardial contrast
opacification (white arrows, center left image). Cardiac magnetic resonance allows multislice imaging
with high tissue contrast and high spatial resolution, enabling accurate quantification and localization
of coronary microvascular dysfunction and obstruction and infarct size relative to the entire left
ventricle. Typical signs of coronary microvascular dysfunction and obstruction are represented by
lack of gadolinium enhancement during the first pass (white arrow, bottom left image) and lack
of gadolinium enhancement within a necrotic region (late gadolinium hyper-enhancement) (white
arrow, bottom right image). Finally, the hybrid positron emission tomography/cardiac computed
tomography allows monitoring of inflammatory reactions after reperfusion (white arrows, center
right image). CFR, coronary flow reserve; CMR, cardiac magnetic resonance; HMR, hyperemic
microvascular resistance; IMR, index of myocardial resistance; MBG, myocardial blush grade;
MCE, myocardial contrast echocardiography; MVO, microvascular obstruction; PET, positron
emission tomography; STR, ST segment resolution; TMPG, TIMI myocardial perfusion grade.
wire, Thrombolysis in Myocardial Infarction (TIMI) frame count,
22
myocardial blush grade, TIMI perfusion grade, ST segment
resolution, myocardial contrast echo, cardiac magnetic resonance,
and hybrid positron emission tomography/cardiac computed
tomography (PET/CT) scanning (Fig. 6.5).15 Regardless of the
Invasive indexes Noninvasive indexes
TIMI
MBG
TMPG
CFR
IMR
HMR
IMR/HMR
O
MV
CRF
MCE PET
STR
Before After
Ear Lately
CMR
CHAPTER 6 Coronary Physiology and Pathophysiology 67
Cumulative (%)
Months Months
Event-free survival (%)
mortality
ST-segment recovery and
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Angiographic TIMI flow
100
75
50
25
P < .0001
0
020406080 100
Myocardial contrast echo
100
90
80
70
60
50
P < .0001
40
02040
Reflow group
No reflow group
(TIMI ×2)
No microvascular
dysfunction
Microvascular
dysfunction
60 80 100
15
10
5
Cumulative (%)
0
036912
100
75
50
25
Event-free survival (%)
0
0510 15 20 25
myocardial blush grade
P = .01
<70%, blush 0/1 (a)
<70%, blush 2/3 (b)
>70%, blush 0/1 (c)
>70%, blush 2/3 (d)
Magnetic resonance imaging
No microvascular
obstruction
Microvascular
obstruction
P < .01
Fig. 6.6 The prognostic role of coronary microvascular obstruction. Top left: Kaplan-Meier survival
curve showing, at long-term follow-up (100 months), that patients in the coronary microvascular
obstruction group, evaluated by angiographic thrombolysis in myocardial infarction flow, had a
significantly higher incidence of cardiac death (%) compared with those without coronary microvascular obstruction (log-rank P < .0001).
23
Top right: Kaplan-Meier survival curve showing cumulative
adverse event rates (%), according to myocardial blush grade, among patients with and without
ST segment resolution, during 1-year follow-up (log-rank, P = .01). In particular, among patients
with ST segment resolution <70%, the cumulative adverse event rate was 10.1% for myocardial
blush grade 0/1 and 6.3% for myocardial blush grade 2/3. Among patients with ST segment
resolution greater than 70%, the cumulative event rate was 5.1% for myocardial blush grade
0/1 and 1.2% for myocardial blush grade 2/3.
combined event-free survival (%) in patients with and without microvascular reperfusion, after
24
Bottom left: Kaplan-Meier survival curve showing
perfused acute myocardial infarction, evaluated by myocardial contrast echocardiography. In
particular, patients without microvascular reperfusion exhibit a higher cumulative 5-year combined
event rate (log-rank test, P < .0001), than those without microvascular dysfunction.
right: Kaplan-Meier survival curve showing combined event-free survival (%) in patients with and
25
Bottom
without microvascular obstruction, after perfused acute myocardial infarction, evaluated by magnetic
resonance imaging. In particular, patients with microvascular obstruction exhibit a higher cumulative
2-year combined event rate (log-rank test, P = .001) than those without microvascular obstruction.
TIMI, Thrombolysis in Myocardial Infarction.
1-year
10.1%
6.3%
5.1%
1.2%
26
modality used, the diagnosis of coronary microvascular obstruction is associated with increased mortality and reduced event-free
survival (Fig. 6.6). New therapies directed at preservation and
restoration of microvascular function are urgently needed to
reduce morbidity and mortality from acute MI and to continue
the progress achieved by revascularization of the epicardial
lesion.
Acknowledgment
I acknowledge the contributions of Andrew Selwyn, MD, to this
chapter in previous editions of this text.
The full reference list for this chapter is available at
ExpertConsult.com.
CHAPTER 6 Coronary Physiology and Pathophysiology 67.e1
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REFERENCES
1. Braunwald E, Ganz P. Coronary blood flow and myocardial
ischemia. In: Braunwald E, ed. Heart Disease: A Textbook of
Cardiovascular Medicine. 4th ed. Philadelphia: Saunders; 1992.
2. Austin RE Jr, Smedira NG, Squiers TM, Hoffman JI. Influence of
cardiac contraction and coronary vasomotor tone on regional
myocardial blood flow. Am J Physiol. 1994;266:H2542–H2553.
3. Duncker DJ, Van Zon NS, Crampton M, et al. Coronary
pressure-flow relationship and exercise: contributions of heart
rate, contractility and alpha1 adrenergic tone. Am J Physiol.
1994;266:H795–H810.
4. DeFily DV, Chilian WM. Coronary microcirculation:
autoregulation and metabolic control. Basic Res Cardiol.
1995;90:381–396.
5. Camici PG, d’Amati G, Rimoldi O. Coronary microvascular
dysfunction: mechanisms and functional assessment. Nat Rev
Cardiol. 2015;12:48–62.
6. Crea F, Lanza GA, Camici PG. Coronary Microvascular
Dysfunction. Springer Verlag; 2014.
7. Camici PG, Olivotto I, Rimoldi OE. The coronary circulation
and blood flow in left ventricular hypertrophy. J ol Cell Cardiol.
2012;52:857–864.
8. Camici PG, Crea F. Coronary microvascular dysfunction. N Engl
J Med. 2007;356:830–840.
9. Murthy VL, et al. Effects of sex on coronary microvascular
dysfunction and cardiac outcomes. Circulation.
2014;129:2518–2527.
10. Indolfi C, Rapacciuolo A, Condorelli M, Chiariello M. Alphaadrenergic control of coronary circulation in man. Basic Res
Cardiol. 1994;89:381–396.
11. Uren NG, Melin JA, De Bruyne B, et al. Relation between
myocardial blood flow and the severity of coronary-artery
stenosis. N Engl J Med. 1994;330:1782–1788.
12. Wilson RF. Assessing the severity of coronary-artery stenoses
[Editorial]. N Engl J Med. 1996;334:1735–1737.
13. Sheridan FM, Cole PG, Ramage D. Leukocyte adhesion to the
coronary microvasculature during ischemia and reperfusion in
an in vivo canine model. Circulation. 1996;93:1784–1787.
14. Crea F, Camici PG, Bairey Merz CN. Coronary microvascular
dysfunction; an update. Eur Heart J. 2013;35:1101–1111.
15. Niccoli G, Scalone G, Lerman A, Crea F. Coronary microvascular
obstruction in acute myocardial infarction. Eur Heart J.
2016;37:1024–1033.
16. Reffelman T, Kloner R. The no-reflow phenomenon: a basic
mechanism of myocardial ischemia and reperfusion. Basic Res
Cardiol. 2016;101:359–372.
17. Kloner RA, Ganote CE, Jennings RB. The ‘no reflow’
phenomenon after temporary occlusion in the dog. J Clin Invest.
1972;54:1496–1508.
18. Frohlich GM, Meier P, White SK, Yellon DM, Hausenloy DJ.
Myocardial reperfusion injury: looking beyond primary PCI. Eur
Heart J. 2013;34:1714–1722.
19. Bekkers SC, Yazdani SK, Virmani R, Walternberger J.
Microvascular dysfunction: underlying pathophysiology and
clinical diagnosis. J Am Coll Cardiol. 2010;55:1649–1660.
20. Heusch G, Kleinbongard P, Bose D, et al. Coronary
microembolization: from bedside to bench and back to bedise.
Circulation. 2009;120:1822–1836.
21. Choi BJ, Prasad A, Gulati R, et al. Coronary endothelial
dysfunction in patients with early coronary artery disease is
associated with the increase in intravascular lipid core plaque.
Eur Heart J. 2013;34:2047–2054.
22. Niccoli G, Burzotta F, Galiuto L, Crea F. Myocardial no-reflow in
humans. J Am Coll Cardiol. 2009;54:281–292.
23. Morishima I, Sone T, Okumura K, et al. Angiographic no-reflow
phenomenon as a predictor of adverse long-term outcome in
patients treated with percutaneous transluminal coronary
angioplasty for first acute myocardial infarction. J Am Coll
Cardiol. 2000;36:1202–1209.
24. Sorajja P, Gersh BJ, Costantini C, et al. Combined prognostic
utility of ST-segment recovery and myocardial blush after
primary percutaneous coronary intervention in acute myocardial
infarction. Eur Heart J. 2005;26:667–674.
25. Bolognese L, Carrabba N, Parodi G, et al. Impact of
microvascular dysfunction on left ventricular remodeling and
long-term clinical outcome after primary coronary angioplasty
for acute myocardial infarction. Circulation. 2004;109:1121–1126.
26. Wu KC, Zerhouni EA, Judd RM, et al. Prognostic significance of
microvascular obstruction by magnetic resonance imaging in
patients with acute myocardial infarction. Circulation.
1998;97:765–772.
7
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Pathophysiology of Acute
Coronary Syndromes: Plaque
Rupture and Atherothrombosis
Nishtha Sodhi, David L. Brown
OUTLINE
Atherogenesis, 68
Development, 68
Fatty Streak, 68
Plaque Formation, 69
Progression of Atherosclerosis, 73
Chronic Endothelial Injury, 73
Recurrent Thrombosis, 74
Plaque Disruption, 74
Vulnerability, 74
Core Size and Content, 74
Cap Thickness and Content, 75
Inflammation, 75
Rupture Triggers, 75
Cap Tension, 75
Cap and Plaque Compression, 76
Thrombosis, 76
Platelet Biology, 76
Coagulation Cascade, 77
Fibrinolysis, 78
Factors That Influence Thrombus Formation, 79
Integrated Pathogenesis of Acute Coronary
Syndromes, 79
Conclusion, 80
Circumferential Bending, 76
Longitudinal Flexion, 76
Hemodynamic Factors, 76
Platelet Adherence, 77
Platelet Activation and Aggregation, 77
Local Factors, 79
Systemic Factors, 79
The acute coronary syndromes (unstable angina, myocardial
infarction [MI], sudden cardiac death) are a major cause of
morbidity and mortality in developed countries. MI alone is the
major cause of death in most Western countries.1 The rapidly
increasing prevalence in developing countries, specifically South
Asia and Eastern Europe—coupled with an increasing incidence
of tobacco abuse, obesity, and diabetes—is predicted to make
cardiovascular disease the major global cause of death by 2020.2
Although MI in patients with normal coronary arteries (MINOCA)
is being increasingly recognized, atherosclerotic plaque formation
within the coronary arteries with subsequent lesion disruption,
platelet aggregation, and thrombus formation remains the leading
cause of acute coronary syndromes in humans.
During the early 1900s, the first description of the clinical
presentation of acute MI was published by Obstrastzow and
Straschesko.
presentation of acute MI with thrombotic occlusion of the
coronary arteries. Much has been learned since these early
observations concerning the pathophysiology of coronary artery
disease and the acute coronary syndromes. This chapter reviews
the pathogenesis of atherosclerosis and explores the mechanisms
responsible for the sudden conversion of stable atherosclerotic
plaques into unstable life-threatening atherothrombotic lesions.
68
3
Shortly thereafter, Herrick4 associated the clinical
ATHEROGENESIS
Development
Atherogenesis, or the development of plaques within the walls
of blood vessels, is the result of complex interactions involving
blood elements, vessel wall abnormalities, and alterations in blood
flow. Several pathologic mechanisms play an important role,
including inflammation with activation of endothelial cells and
monocyte recruitment,
proliferation and matrix synthesis,
accumulation,
thrombosis.16 These diverse processes result in the formation of
atheromatous plaques that form the substrate for future acute
coronary syndromes.
Fatty Streak. Vascular injury and thrombus formation are
key events in the formation and progression of atherosclerotic
plaques. Fuster and colleagues17 proposed a pathophysiologic
classification of vascular injury that divides the damage into three
types (Fig. 7.1). Type I injury consists of functional deviations
from normal endothelial function without obvious morphologic
changes. Type II injury involves a deeper form of vascular damage
that includes denudation of endothelial cells and intimal damage
12,13
5–9
growth with smooth muscle cell
necrosis, calcification and ossification,
10,11
degeneration with lipid
14,15
and
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