CABG from zero to hero Physiology introduction.

CORONARY ARTERY
BYPASS GRAFTING
From Zero To Hero
Mahmoud Alhussaini

PHYSIOLOGY OF
CORONARY
CIRCULATION

Regulation of coronary flow
• The coronary circulation is unique among regional
vascular beds in that its perfusion is impeded during the
systolic phase of the cardiac cycle by the surrounding
contracting cardiac muscle.
• Systolic contraction increases LV wall tension and
compresses the intramyocardial micro vessels, thereby
impeding coronary arterial inflow.
• This compression is not uniformly distributed across the
LV wall, resulting in a redistribution of blood flow from the
subendocardium to subepicardium

• LV myocardial oxygen extraction averages 60– 80% of
arterially supplied oxygen at rest.
• Increases in myocardial oxygen consumption (e.g., during
exercise) are predominantly met by proportional increases
in CBF.
• The increase in CBF is principally the result of a reduction
in coronary vascular resistance, due to dilation of coronary
small arteries and arterioles, the so-called resistance
vessels.

• local coronary blood flow is precisely controlled by a
balance of vasodilator and vasoconstrictor mechanisms,
including:
• (1) a metabolic vasodilator system;
• (2) a neurogenic control system
• (3) the vascular endothelium.

• The metabolic vasodilator mechanism responds rapidly
when local blood flow is insufficient to meet metabolic
demand.
• The primary mediator is adenosine generated within the
myocyte and released into the interstitial compartment.
Adenosine relaxes arteriolar smooth muscle cells by
activation of A2 receptors.
• Adenosine is formed when the oxygen supply cannot
sustain the rapid rephosphorylation of ADP to ATP.

• The sympathetic nervous system acts through alpha
receptors (vasoconstriction) and beta receptors
(vasodilation).
• There are direct innervations of the large conductance
vessels and lesser direct innervations of the smaller
resistance vessels.
• Sympathetic receptors on the smooth muscle cells of the
resistance vessels respond to humoral catecholamines.
• Alpha receptors predominate over beta receptors such that

• CBF remains fairly constant over a wide range of coronary
perfusion pressures, owing to adjustments in the diameter
of coronary resistance vessels mediated by both myogenic
and metabolic mechanisms.
• This autoregulation of blood flow is particularly important
to maintain CBF when coronary perfusion pressure is
decreased by an upstream coronary artery stenosis.
• The pressure at which the coronary resistance vessels
become maximally dilated is the lowest pressure at which
normal myocardial blood flow can be maintained and is

• Below this coronary pressure, CBF decreases in a
pressure- dependent manner, leading to myocardial
ischaemia.
• Under normal haemodynamic conditions, resting LV
myocardial blood flow averages 0.7– 1.0 mL/ min/ g of
myocardium and can increase four- to fivefold during
maximal vasodilation.
• The ability to increase CBF above resting levels in
response to pharmacological vasodilation is termed
coronary flow reserve.

CORONARY ENDOTHELIAL FUNCTION
• The vascular endothelial cell layer functions under basal
conditions to maintain the vessel tone, while mitigating
inflammation, oxidative stress, and thrombogenicity.
• The coronary endothelium regulates blood flow to meet the
demands of myocardial oxygen consumption (VO2) by
favoring a relatively neutral state in the balance between
dilatation and constriction mainly through the action of:
• nitric oxide (NO) (guanylate cyclase → cyclic guanosine
monophosphate)
• prostacyclin (PGI2, cyclic adenosine monophosphate, platelet

• The principal vasoconstrictor is the endothelially derived
constricting peptide endothelin-1.
• Other vasoconstrictors include angiotensin II and
superoxide free radical.
• NO is released by the coronary vascular endothelium by
both soluble factors (acetylcholine, adenosine, and ATP)
and mechanical signals (shear stress and pulsatile stress
secondary to increased intraluminal blood flow).

• If the endothelium is intact, acetylcholine from the
sympathetic nerves causes vasodilation through
generation of NO.
• If the endothelium is not functionally intact, acetylcholine
causes vasoconstriction by direct stimulation of the
vascular smooth muscle.
• NO is a potent inhibitor of platelet aggregation and
neutrophil function (superoxide generation, adherence, and
migration), which has implications in the anti-inflammatory
response to ischemia-reperfusion and cardiopulmonary

• Endothelin-1 interacts principally with specific endothelin
receptors, ETA, on vascular smooth muscle, and causes
smooth muscle vasoconstriction.
• Endothelin-1 counteracts the vasodilator effects of
endogenous adenosine, NO, and prostacyclin (PGI2).
• Endothelin-1 is rapidly synthesized in the vascular
endothelium, particularly during ischemia, hypoxia, and
other stress conditions, where it acts in a paracrine
fashion.
• Human coronary arteries demonstrate abundant

• Under ordinary circumstances the metabolic vasodilator
system is the dominant force acting on the resistance
vessels. For example, the increased metabolic activity
caused by sympathetic stimulation leads to vasodilation of
the coronary arterioles through the metabolic system,
despite a direct vasoconstriction effect of norepinephrine.

Hemodynamic
Effect of Coronary
Artery Stenosis
• Surgically treatable
atherosclerotic
disease primarily
affects the large
conductance
vessels of the heart.
• The hemodynamic
effect of a stenosis
is determined by
Poiseuille’s law,

Hemodynamic Effect of
Coronary Artery Stenosis
• Resistance (pressure
change/flow) is inversely
proportional to the fourth
power of the radius and
directly proportional to
the length of the
narrowing.
• Therefore, a small change

Hemodynamic Effect of Coronary Artery
Stenosis
• Conductance vessels are sufficiently large that a 50%
reduction in the diameter of the vessel has minimal
hemodynamic effect. A 60% reduction in the diameter of
the vessel has only a very small hemodynamic effect.
• As the stenosis progresses beyond 60%, small decreases
in diameter have significant effects on blood flow. For a
given segment length, an 80% stenosis has a resistance
that is 16 times greater a 60% stenosis. For a 90% stenosis,
the resistance is 256 times greater than for a 60% stenosis.
• Furthermore, for successive stenoses in the same vessel

Stenosis
• lesions can cause conversion from laminar to turbulent
flow. With laminar flow the pressure drop is proportional to
flow rate Q; with turbulent flow pressure drop is
proportional to Q2.
• For all these reasons, patients who have had a small
progression in the degree of coronary stenosis may
experience a rapid acceleration of symptoms.
• Atherosclerosis also alters normal vascular regulatory
mechanisms. The endothelium is often destroyed or
damaged, so vasoconstrictor mechanisms are relatively

Stenosis
• As noted, when a stenosis is less than 60%, little change is
flow is noted. This is due to compensation by the coronary
flow reserve of the resistance vessels distal to the stenotic
conductance vessel.
• As resistance to flow is additive, a decrease in distal
resistance will balance an increase in proximal resistance
and flow will be unchanged. As flow reserve decreases, any
stimulus that increases myocardial oxygen demand (such a
tachycardia, hypertension, or exercise) cannot be met by
dilation of the distal vasculature, and myocardial ischemia

Stenosis
• With sudden coronary occlusion, although there is usually
modest collateral flow through very small vessels (20 to
200 μm in size), this flow is generally insufficient to
maintain cellular viability. Collateral flow gradually begins
to increase over the next 8 to 24 hours, doubling by about
the third day after total occlusion. Collateral blood flow
development appears to be nearly complete after 1 month,
restoring normal or nearly normal resting flow to the
surviving myocardium in the ischemic region.
• Previous ischemic events or gradually developing

Endothelial Dysfunction
• Ischemia- reperfusion, hypertension, diabetes, and
hypercholesterolemia can impair generation of NO and
vasoconstriction may predominate, mediated by the
relative overexpression of endothelin-1.
• Reperfusion after temporary myocardial ischemia is one
situation in which NO production may be impaired, leading
to a vicious cycle in which the vasodilator reserve of the
resistance vessels is reduced with a consequent and
progressive “low-flow” or “no-flow” phenomenon.
• The coronary vascular NO system may also be impaired in

• The endothelium helps prevent cell-cell interactions
between blood-borne inflammatory cells (ie, leukocytes
and platelets) that initiate a local or systemic inflammatory
reaction. Inflammatory cascades occur with sepsis,
ischemia-reperfusion, and cardiopulmonary bypass.
• Under normal conditions, the vascular endothelium resists
interaction with neutrophils and platelets by tonically
releasing adenosine and NO, which have potent
antineutrophil and platelet inhibitory effects.

• Damage to the endothelium lowers the resistance to
neutrophil adhesion. Neutrophils can damage the
endothelium by adhesion to its surface, and subsequent
release of oxygen radicals and proteases. This amplifies
the inflammatory response and decreases the tonic
generation and release of adenosine and NO, which then
permits further interaction with activated inflammatory
cells.
• The products released by activated neutrophils have
downstream physiologic consequences on other tissues,

• The release of cytokines and complement fragments during
cardiopulmonary bypass activates the vascular
endothelium on a systemic basis, which contributes to the
inflammatory response to cardiopulmonary bypass.
• Both adenosine and NO have been used therapeutically to
reduce the inflammatory responses to cardiopulmonary
bypass, and to reduce ischemic-reperfusion injury and
endothelial damage

Biology of the Bypass Vessels
• First, the endothelium activates, thanks to the expression
of angiotensin- converting enzyme on its surface,
angiotensin I into angiotensin II and breaks down
bradykinin, a process that is more pronounced in the
saphenous vein than it is in the internal mammary artery.
• Inhibition of angiotensin- converting enzyme, therefore,
increases endothelium- dependent relaxation to bradykinin
in the saphenous vein, but not in the mammary artery.

• The endothelial l- arginine pathway is an important local
regulator of platelet vessel wall interactions as well as of
vascular tone
• The end product of the pathway, NO, is formed from l-
arginine, and activates soluble guanylyl cyclase (leading to
increased cyclic guanosine monophosphate (cGMP)) and
eventually reduces intracellular calcium concentration and
in turn induces vasodilation and platelet inhibition,
respectively.

• The saphenous vein, when used as a coronary bypass
graft, is prone to bypass graft disease and eventual
occlusion; indeed, intimal hyperplasia and plaque
formation develops continuously over time in venous
bypass vessels after implantation and after 10 years most
venous bypass grafts are occluded.
• In contrast, the internal mammary artery shows the highest
patency rate, while the radial artery and the gastroepiploic
artery give less satisfactory results, due to their propensity
towards spasm especially when patients require

• Of note, the release of NO in response to receptor-
operated agonists such as bradykinin, acetylcholine,
adenosine diphosphate (ADP), or thrombin is much less
pronounced or absent in the saphenous vein than it is in
the internal mammary artery.
• The gastroepiploic artery, however, has an endothelial
function that is similar to that of the internal mammary
artery.

• Importantly, all bypass vessels respond with vasodilation
when exposed to nitrovasodilators indicating that the
vascular smooth muscle cells are capable of forming
cGMP.
• In the gastroepiploic artery, the accumulation of cGMP after
stimulation with nitrovasodilators is even more
pronounced than with other bypass vessels, as are
contractions to vasoconstrictor substances such as
norepinephrine.
• .

• Regulation of platelet/ vessel wall interactions is of
particular importance in graft functioning and may prevent
graft occlusion. In this context, it is of interest that the
platelet- derived mediator ADP binds specific receptors on
endothelial cells and induces NO release, thereby inhibiting
platelet function via accumulation of cGMP and induction
of vasodilation in the mammary artery, a response that is
conversely weak or absent in the saphenous vein

• Thus, the internal mammary artery exhibits endothelium-
dependent relaxation and inhibition of platelet function at
sites where platelets are activated and thereby is protected
from thrombus formation.
• Interestingly, the gastroepiploic artery also exhibits marked
contractions to aggregating platelets similar to the
saphenous vein. This, together with its marked contractile
responses to catecholamines, may explain the less
favourable results seen when it is used as a bypass graft.

• Shear stress exerted by the circulating blood also induces
the release of NO which is an important mechanism of
flow- mediated vasodilation during exercise or under other
conditions of increased demand.
• This response is crucial for the function of mammary artery
grafts when they are implanted into the coronary
circulation and exposed to marked increases in flow.
• When arterial grafts are implanted into coronary segments
with haemodynamically insignificant stenoses, they tend to
shrink or even occlude (angiographically described as the

Biology of the
Bypass Vessels
• Histological analysis
shows that the internal
mammary artery exhibits
little structural changes
and in particular rarely
develops plaques.
• This is obviously in sharp
contrast to the

Biology of the
Bypass Vessels
• The remarkable clinical
differences of mammary
artery and venous grafts
can be explained by their
different biological
properties. Besides
endothelial cells, vascular
smooth muscle cells of
both blood vessels
markedly differ.

• Furthermore, when stimulated with platelet- derived growth
factor (PDGF), saphenous vein vascular smooth muscle
cells rapidly and markedly grow, while this is again hardly
the case with mammary artery cells.
• Finally, and this might be of utmost importance for venous
bypass graft disease, saphenous vein smooth muscle cells
grow rapidly when exposed to pulsatile stretch, while
mammary cells are protected from this physical stimulus.
• Thus, when implanted into the coronary circulation, the
saphenous vein, which physiologically is exposed to

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