Kuliah Blok 17 Disfungsi Endotel Atherosklerosis Angina Pectoris

KEDOKTERAN DAN
ILMU KESEHATAN
Disfungsi endotel, atherosclerosis

dan angina pektoria
Kuliah Blok 17
Prodi Pendidikan Dokter
7 Desember 2020
IKHLAS MUHAMMAD JENIE

BAGIAN FISIOLOGI FKIK UMY
http://www.fkik.umy.ac.id/
KEDOKTERAN DAN
ILMU KESEHATAN
Regulation of Blood Flow
KEDOKTERAN DAN
ILMU KESEHATAN
Regulation of blood
flow
• Local and humoral control
• Neural control
KEDOKTERAN DAN
ILMU KESEHATAN
Local Control of
Blood Flow
• The rate of blood flow to each tissue of the

body is almost always precisely controlled in
relation to the tissue need.
What are some of the
KEDOKTERAN DAN
ILMU KESEHATAN
specific needs of the
1. Delivery of oxygen to thetissues
tissues for blood flow?
2. Delivery of nutrients, such as glucose, amino acids &
fatty acids
3. Removal of carbon dioxide from the tissues
4. Removal of hydrogen ions from the tissues
5. Maintenance of proper concentrations of other ions
in the tissues
6. Transport of various hormones and other substances
to the different tissues
7. Heat loss (the skin)
8. Delivery of the adequate quantities of blood plasma
to the kidneys to allow the kidneys to excrete the
waste products of the body
KEDOKTERAN DAN
ILMU KESEHATAN
KEDOKTERAN DAN
ILMU KESEHATAN
• Blood flow to the inactive muscle 4

ml/min/100 g for a total 750 ml/min
• Blood flow to the active muscle 80
ml/min/100 g for a total 16,000 ml/min
KEDOKTERAN DAN
ILMU KESEHATAN
Mechanism of blood
flow control
• Acute control
• Long-term control
KEDOKTERAN DAN
ILMU KESEHATAN
Acute control of
blood flow
• Rapid changes in local vasodilation or
vasoconstriction of the arterioles,
metarterioles, and precapillary sphincters.
• Occurring within seconds to minutes to
provide very rapid maintenance of
appropriate local tissue blood flow.
KEDOKTERAN DAN
ILMU KESEHATAN
Long-term control of
blood flow
• Slow changes in flow over a period of days,
weeks, or even months.
• In general, these long-term changes provide
even better control of the flow in proportion
to the needs of the tissues.
• These changes come about as a result of an
increase or decrease in the physical sizes and
numbers of actual blood vessels supplying the
tissues.
KEDOKTERAN DAN
ILMU KESEHATAN
Acute control of
blood flow
• Effect of Tissue Metabolism on Local Blood
Flow
• Acute Local Blood Flow Regulation When
Oxygen Availability Changes
KEDOKTERAN DAN
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Effect of Tissue Metabolism on Local

Blood Flow
• In skeletal muscle, an
increase in metabolism
up to eight times
normal increases the
blood flow acutely
about fourfold.
KEDOKTERAN DAN
ILMU KESEHATAN
Acute Local Blood Flow Regulation When

• One of the most • The blood flow through
necessary of the the tissues increases
metabolic nutrients is markedly at/ in:
oxygen 1. high altitude
2. pneumonia
3. CO poisoning
4. cyanide poisoning
KEDOKTERAN DAN
ILMU KESEHATAN
Acute Local Blood Flow Regulation When

• As the arterial oxygen
saturation decreases to
about 25 per cent of
normal, the blood flow
through an isolated leg
increases about
threefold.
KEDOKTERAN DAN
ILMU KESEHATAN
blood flow:
Theoretical
background
• Vasodilator Theory for Acute Local Blood Flow
Regulation—Possible Special Role of
Adenosine
• Oxygen Lack Theory for Local Blood Flow
Control
KEDOKTERAN DAN
Vasodilator Theory for
ILMU KESEHATAN
Acute Local Blood Flow
Regulation
• The greater the rate of metabolism or the less
the availability of oxygen or some other
nutrients to a tissue, the greater the rate of
formation of vasodilator substances in the
tissue cells.
• The vasodilator substances then diffuse
through the tissues to the precapillary
sphincters, metarterioles, and arterioles to
cause dilation.
KEDOKTERAN DAN
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Vasodilator
substances
• adenosine,
• carbon dioxide,
• adenosine phosphate compounds,
• histamine,
• potassium ions,
• hydrogen ions (including lactic acid).
Vasodilator theory in blood flow
KEDOKTERAN DAN
ILMU KESEHATAN
regulation
• Vasodilators: Adenosine, CO2, lactic acid, ADP, Histamine, ion
Kalium, ion Hydrogen
TISSUE RELEASE OF
METABOLISM VASODILATORS
RESISTANCE IN
ARTERIOLE
BLOOD
FLOW
KEDOKTERAN DAN
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Adenosine
• Minute quantities of adenosine are released

from heart muscle cells when coronary blood
flow becomes too little.
• This causes enough local vasodilation in the
heart to return coronary blood flow back to
normal.
KEDOKTERAN DAN
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Adenosine
• Also, whenever the heart becomes more active
than normal and the heart’s metabolism
increases an extra amount, this, causes increased
utilization of oxygen, and followed by:
1. decreased oxygen concentration in the heart
muscle cells, then
2. consequent degradation of adenosine triphosphate
(ATP), which
3. increases the release of adenosine.
Oxygen Lack Theory
KEDOKTERAN DAN
ILMU KESEHATAN
for Local Blood Flow
Control
• Oxygen (and other nutrients as well) is required as one of
the metabolic nutrients to cause vascular muscle
contraction.
• In the absence of adequate oxygen, the blood vessels
simply would relax and therefore naturally dilate.
• Increased utilization of oxygen in the tissues as a result of
increased metabolism theoretically could decrease the
availability of oxygen to the smooth muscle fibers in the
local blood vessels, and this, too, would cause local
vasodilation.
KEDOKTERAN DAN
ILMU KESEHATAN
Oxygen Lack Theory for Local Blood Flow

Control
• At the origin of the
capillary is a precapillary
sphincter.
• Around the metarteriole
are several other smooth
muscle fibers.
KEDOKTERAN DAN
ILMU KESEHATAN

Control
• The precapillary sphincters
are normally either
completely open or
completely closed.
• The number of precapillary
sphincters open at any
given time is proportional
to the requirements of the
tissue for nutrition
(including oxygen). O
KEDOKTERAN DAN
ILMU KESEHATAN

Control
• The precapillary
sphincters and
metarterioles open and
close cyclically several
times per minute
(vasomotion).
• The duration of the open
phases being proportional
to the metabolic needs of
the tissues for oxygen.
Possible Role of Other
KEDOKTERAN DAN
ILMU KESEHATAN
Nutrients Besides
Oxygen in Control of
Vasodilation occurs when there is:Local Blood Flow
• lack of glucose,
• vitamin deficiency: vitamin B substances (thiamine,
niacin, and riboflavin) -- > beriberi
– The peripheral vascular blood flow everywhere in the body
increases twofold to threefold.
– These vitamins all are needed for oxygen induced
phosphorylation required to produce ATP.
KEDOKTERAN DAN
Oxygen demand theory in blood

ILMU KESEHATAN
flow regulation
TISSUE METABOLISM OXYGEN

or CONCENTRATION IN
OXYGEN DELIVERY TO TISSUES
TISSUES
RESISTANCE
OF ARTERIOL
BLOOD
FLOW
Special examples of
KEDOKTERAN DAN
ILMU KESEHATAN
acute blood flow
control
• Active hyperemia
– Active tissue (exercising muscle, GI gland
during/after meal, brain during mental activity) --
> rate of blood flow increases to those tissues
• Reactive hyperemia
– Blood supply to a tissue is blocked -- > then the
blocking is removed -- > blood flow increases 4-7
fold.
KEDOKTERAN DAN
ILMU KESEHATAN
Auto-regulation of blood flow

• In any tissue of the body, an
acute increase in arterial
pressure causes immediate
rise in blood flow.
• Within less than a minute,
the blood flow in most
tissues returns almost to
the normal level, even
though the arterial pressure
is kept elevated.
KEDOKTERAN DAN
ILMU KESEHATAN
Auto-regulation of blood flow

• Between arterial pressure
of about 70 mm Hg and 175
mm Hg, the blood flow
increases only 30 per cent
even though the arterial
pressure increases 150 per
cent
KEDOKTERAN DAN
ILMU KESEHATAN
Auto-regulation of blood flow:

Theoretical background
The metabolic theory The myogenic theory
• When the arterial pressure • Sudden stretch of small blood vessels
becomes too great, the excess causes the smooth muscle of the
flow provides too much oxygen vessel wall to contract for a few
and too many other nutrients to seconds.
the tissues. • When high arterial pressure stretches
• These nutrients (especially the vessel, this in turn causes reactive
oxygen) cause the blood vessels vascular constriction that reduces
to constrict and the flow to return blood flow nearly back to normal.
nearly to normal despite the • Conversely, at low pressures, the
increased pressure. degree of stretch of the vessel is less,
so that the smooth muscle relaxes
and allows increased flow.
KEDOKTERAN DAN
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blood flow:
Theoretical
• background
The myogenic response is inherent to vascular smooth muscle
and can occur in the absence of neural/hormonal influences.
• It is most pronounced in arterioles but can also be observed
in arteries, venules, veins, lymphatic vessels.
• Myogenic contraction is initiated by stretch-induced vascular
depolarization -- > rapidly increases calcium ion entry from
the extracellular fluid into the cells -- > vascular smooth
muscle to contract.
• Changes in vascular pressure may also open or close other ion
channels that influence vascular contraction.
KEDOKTERAN DAN
ILMU KESEHATAN
blood flow:
Theoretical
• background
The myogenic mechanism is important in preventing excessive
stretch of blood vessel when blood pressure is increased.
• However, the pressure sensing mechanism in the myogenic
mechanism cannot directly detect changes in blood flow in
the tissue.
• Metabolic factors override the myogenic mechanism in
circumstances where the metabolic demands of the tissues
are significantly increased (such as during vigorous muscle
exercise) -- > dramatic increases in skeletal muscle blood flow.
KEDOKTERAN DAN
ILMU KESEHATAN
for acute blood flow
control in specific
1. Kidneys tissue
– Tubuloglomerular feedback
2. Brain
– Concentration of CO2 and hydrogen ion
KEDOKTERAN DAN
ILMU KESEHATAN Tubuloglomerular feedback in the kidneys
• The composition of the fluid in the early distal tubule is

detected by an epithelial structure of the distal tubule itself
called the macula densa.
• This is located where the distal tubule lies adjacent to the
afferent and efferent arterioles at the nephron
juxtaglomerular apparatus.
• When too much fluid filters from the blood through the
glomerulus into the tubular system, appropriate feedback
signals from the macula densa cause constriction of the
afferent arterioles, in this way reducing both renal blood flow
and glomerular filtration rate back to or near to normal.
KEDOKTERAN DAN
ILMU KESEHATAN
Control of blood flow
in the brain
• In the brain, in addition to control of blood flow by tissue
oxygen concentration, [CO2] and [H-] play very prominent
roles.
• An increase of either or both of [CO2] and [H-] -- > dilates the
cerebral vessels -- > rapid washout of the excess CO2 or H-
from the brain tissues.
• This is important because the level of excitability of the brain
itself is highly dependent on exact control of both [CO2] and
[H-].
Mechanism KEDOKTERAN
for DAN
Dilating
ILMU KESEHATAN Upstream Arteries when
Microvascular Blood Flow Increases: The Endothelium-
• The localDerived Relaxing
mechanisms forFactor (Nitric tissue
controlling Oxide)blood
flow (tissue metabolism) can dilate only the very
small arteries and arterioles in each tissue because
tissue cell vasodilator substances/oxygen deficiency
can reach only these vessels, not the intermediate
and larger arteries back upstream.
• When blood flow through a microvascular portion of
the circulation increases, this induces another
mechanism that does dilate the larger arteries as
well.
for DAN
Dilating
Derived Relaxing
• The endothelial cells lining Factor
the (Nitric Oxide)
arterioles and small
arteries synthesize several substances that, when
released, can affect the degree of relaxation or
contraction of the arterial wall.
• The most important of these is a vasodilator
substance called endothelium derived relaxing factor
(EDRF), which is composed principally of nitric oxide,
which has a half-life in the blood of only 6 seconds.
for DAN
Dilating
Derived
• Rapid flow Relaxing
of blood Factor
through the(Nitric Oxide)
arteries and
arterioles causes shear stress on the endothelial cells
because of viscous drag of the blood against the
vascular walls.
• This stress contorts the endothelial cells in the
direction of flow and causes significant increase in
the release of nitric oxide.
• The nitric oxide then relaxes the blood vessels.
for DAN
Dilating
Derived Relaxing
• This is fortunate becauseFactor (Nitric the
it increases Oxide)
diameters
of the upstream arterial blood vessels whenever
microvascular blood flow increases downstream.
• Without such a response, the effectiveness of local
blood flow control would be significantly decreased
because a significant part of the resistance to blood
flow is in the upstream small arteries.
KEDOKTERAN DAN
ILMU KESEHATAN
Long-Term Blood
Flow Regulation
• Besides the rapidity of the acute mechanisms for
local blood flow regulation, but the regulation is still
incomplete because there remains an excess
increase in blood flow.
• Over a period of hours, days, and weeks, a long-term
type of local blood flow regulation develops in
addition to the acute regulation, which gives far
more complete regulation.
KEDOKTERAN DAN
ILMU KESEHATAN
Long-Term Blood
Flow Regulation
• Long-term regulation of blood flow is especially
important when the long-term metabolic demands
of a tissue change.
• If a tissue becomes chronically overactive and
therefore requires chronically increased quantities of
oxygen and other nutrients, the arterioles and
capillary vessels usually increase both in number and
size within a few weeks to match the needs of the
tissue.
Mechanism of Long-
KEDOKTERAN DAN
ILMU KESEHATAN
Term Regulation:
Change in “Tissue
• The mechanism of long-termVascularity”
local blood flow
regulation is principally to change the amount
of vascularity of the tissues.
• For instance, if the metabolism in a given
tissue is increased for a prolonged period,
vascularity increases; if the metabolism is
decreased, vascularity decreases.
Mechanism of Long-
KEDOKTERAN DAN
ILMU KESEHATAN
Term Regulation:
Change in “Tissue
Vascularity”
• The time required for long-term regulation to
take place may be only a few days in the
neonate or as long as months in the elderly
person.
• This reconstruction also occurs rapidly in new
growth tissue, such as in scar tissue and
cancerous tissue but occurs much more slowly
in well-established tissues.
Mechanism of Long-
Term Regulation:
KEDOKTERAN DAN
ILMU KESEHATAN
Change in “Tissue
• The final degree of responseVascularity”
is much better in
younger tissues than in older
– In the neonate, the vascularity will adjust to match
almost exactly the needs of the tissue for blood
flow.
– In older tissues, vascularity frequently lags far
behind the needs of the tissues.
KEDOKTERAN DAN
ILMU KESEHATAN
Long Term Blood
Flow Regulation
• Long-term control means slow, controlled
changes in flow over a period of days, weeks,
or even months.
KEDOKTERAN DAN
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Role of Oxygen in
Long-Term Regulation
• Oxygen is important not only for acute control
of local blood flow but also for long-term
control.
– Increased vascularity in tissues of animals that live
at high altitudes, where the atmospheric oxygen is
low.
– Fetal chicks hatched in low oxygen have up to
twice as much tissue blood vessel.
KEDOKTERAN DAN
ILMU KESEHATAN
Retrolental
Fibroplasia
• Premature human babies put into oxygen tents for
therapeutic purposes.
– The excess oxygen -- > immediate cessation of new
vascular growth in the retina/degeneration of some of the
small vessels that already have formed.
– When the infant is taken out of the oxygen tent -- >
explosive overgrowth of new vessels to make up for the
sudden decrease in available oxygen -- > over-growth that
the retinal vessels grow out from the retina into the eye’s
vitreous humor -- > blindness
Vascular Endothelial
KEDOKTERAN DAN
Growth Factor in
ILMU KESEHATAN
Formation of New Blood

• A dozen or more factors that increase
Vessels growth
of new blood vessels have been found, almost
all of which are small peptides.
• Three of those that have been best
characterized are:
– vascular endothelial growth factor (VEGF),
– fibroblast growth factor, and
– angiogenin
KEDOKTERAN DAN
ILMU KESEHATAN
Growth Factor in
• Essentially all the angiogenic factors promote
Vessels
new vessel growth in the same way.
• They cause new vessels to sprout from other
small vessels.
• The first step is dissolution of the basement
membrane of the endothelial cells at the point
of sprouting.
KEDOKTERAN DAN
ILMU KESEHATAN
Growth Factor in
• This is followed by rapid reproduction
Vessels of new
endothelial cells that stream outward through
the vessel wall in extended cords directed
toward the source of the angiogenic factor.
• The cells in each cord continue to divide and
rapidly fold over into a tube.
KEDOKTERAN DAN
ILMU KESEHATAN
Growth Factor in
• The tube connects with another tube budding
Vessels
from another donor vessel (another arteriole
or venule) and forms a capillary loop through
which blood begins to flow.
• If the flow is great enough, smooth muscle
cells eventually invade the wall, so that some
of the new vessels eventually grow to be new
arterioles or venules or perhaps even larger
vessels.
KEDOKTERAN DAN
ILMU KESEHATAN
KEDOKTERAN DAN
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Growth Factor in
• Blood vessels can also be madeVessels
to disappear
when not needed.
• Certain other substances, such as some
steroid hormones, have exactly the opposite
effect on small blood vessels, occasionally
even causing dissolution of vascular cells and
disappearance of vessels.
KEDOKTERAN DAN
Determined by
Maximum Blood Flow
ILMU KESEHATAN
Need, Not by Average

• Vascularity is determined mainlyNeed
by the
maximum level of blood flow need rather than
by average need.
• During heavy exercise the need for whole
body blood flow often increases to six to eight
times the resting blood flow. This great excess
of flow may not be required for more than a
few minutes each day.
KEDOKTERAN DAN
Determined by
Maximum Blood Flow
ILMU KESEHATAN
Need, Not by Average

• Even this short need can cause enough
Need VEGF
to be formed by the muscles to increase their
vascularity as required.
• After extra vascularity does develop, the extra
blood vessels normally remain mainly
vasoconstricted, opening to allow extra flow
only when appropriate local stimuli (oxygen
lack, nerve vasodilatory stimuli) released for
extra flow.
Collateral Circulation: A
KEDOKTERAN DAN
Phenomenon of Long-
ILMU KESEHATAN
Term Local Blood Flow

• When an artery or a vein is blocked in any
Regulation
tissue of the body, a new vascular channel
usually develops around the blockage and
allows at least partial re-supply of blood to the
affected tissue.
• The first stage in this process is dilation of
small vascular loops that already connect the
vessel above the blockage to the vessel below.
KEDOKTERAN DAN
Phenomenon of Long-
ILMU KESEHATAN

• This dilation occurs within the first minute or
Regulation
two, indicating that the dilation is simply a
neurogenic or metabolic relaxation of the
muscle fibers of the small vessels involved.
• After this initial opening of collateral vessels,
the blood flow often is still less than one
quarter that needed to supply all the tissue
needs.
KEDOKTERAN DAN
Phenomenon of Long-
ILMU KESEHATAN

• Further opening occurs within the ensuing
Regulation
hours, so that within 1 day as much as half the
tissue needs may be met, and within a few
days often all the tissue needs.
• The collateral vessels continue to grow for
many months thereafter, almost always
forming multiple small collateral channels
rather than one single large vessel.
KEDOKTERAN DAN
Phenomenon of Long-
ILMU KESEHATAN

• Under resting conditions, theRegulation
blood flow
usually returns very near to normal, but the
new channels seldom become large enough to
supply the blood flow needed during
strenuous tissue activity.
KEDOKTERAN DAN
Phenomenon of Long-
ILMU KESEHATAN

• The development of collateral vessels follows
Regulation
the usual principles of both acute and long-
term local blood flow control, the acute
control being rapid neurogenic and metabolic
dilation, followed chronically by manifold
growth and enlargement of new vessels over a
period of weeks and months.
KEDOKTERAN DAN
Phenomenon of Long-
ILMU KESEHATAN

• The most important exampleRegulation
of the
development of collateral blood vessels occurs
after thrombosis of one of the coronary
arteries.
• Almost all people by the age of 60 years have
had at least one of the smaller branch
coronary vessels close.
KEDOKTERAN DAN
Phenomenon of Long-
ILMU KESEHATAN

• Yet most people do not knowRegulation
that this has
happened because collaterals have developed
rapidly enough to prevent myocardial damage.
• It is in those other instances in which coronary
insufficiency occurs too rapidly or too severely
for collaterals to develop that serious heart
attacks occur.
Humoral Control of
KEDOKTERAN DAN
ILMU KESEHATAN
the
Circulation
• Humoral control of the circulation means
control by substances secreted or absorbed
into the body fluids—such as hormones and
ions.
• Some of these substances are formed by
special glands and transported in the blood
throughout the entire body.
• Others are formed in local tissue areas and
cause only local circulatory effects.
KEDOKTERAN DAN
ILMU KESEHATAN
the
Circulation:
• Norepinefrin Vasocontrictor Agent
• Epinefrin
• Angiotensin II
• Vasopresin
• Endothelin
KEDOKTERAN DAN
ILMU KESEHATAN
Norepinephrine and
Epinephrine
• Norepinephrine is an especially powerful
vasoconstrictor hormone;
• Epinephrine is less so and in some tissues even
causes mild vasodilation
– A special example of vasodilation caused by
epinephrine occurs to dilate the coronary arteries
during increased heart activity.
KEDOKTERAN DAN
ILMU KESEHATAN
Norepinephrine and
Epinephrine
• A dual system of control:
1. Direct nerve stimulation
2. Indirect effects of norepinephrine and/or
epinephrine in the circulating blood
KEDOKTERAN DAN
ILMU KESEHATAN
Direct nerve
stimulation
• During stress or exercise -- > the sympathetic
nervous system in most or all parts of the
body is stimulated -- > the sympathetic nerve
endings release norepinephrine -- > excites
the heart and contracts the veins and
arterioles
Indirect effects of
norepinephrine and/or
KEDOKTERAN DAN
ILMU KESEHATAN
epinephrine in the
• The sympathetic nerves tocirculating blood
the adrenal
medullae -- > the glands secrete both
norepinephrine and epinephrine into the
blood -- > the hormones circulate to all areas
of the body -- > almost the same effects as
direct sympathetic stimulation
KEDOKTERAN DAN
ILMU KESEHATAN
Angiotensin II
• Angiotensin II is another powerful
vasoconstrictor substance.
• The effect of angiotensin II is to constrict
powerfully the small arterioles.
• It acts on many of the arterioles of the body at
the same time to increase the total peripheral
resistance -- > increasing the arterial pressure
-- > regulation of BP
KEDOKTERAN DAN
ILMU KESEHATAN
Vasopressin
• Vasopressin, also called antidiuretic hormone
(ADH), is more powerful than angiotensin II as
a vasoconstrictor.
• It is formed in nerve cells in the hypothalamus
of the brain but is then transported downward
by nerve axons to the posterior pituitary
gland, where it is finally secreted into the
blood.
KEDOKTERAN DAN
ILMU KESEHATAN
Vasopressin
• Normally, only minute amounts of vasopressin
are secreted, so that most physiologists have
thought that vasopressin plays little role in
vascular control.
• But the concentration of circulating blood
vasopressin after severe hemorrhage can rise
high enough to increase BP.
Endothelin: A Powerful
KEDOKTERAN DAN
ILMU KESEHATAN
Vasoconstrictor in
Damaged Blood Vessels
• Endothelin, a peptide of a large 21 amino acid,
ranks along with angiotensin and vasopressin
in its vasoconstrictor capability, which requires
only nanogram quantities to cause powerful
vasoconstriction.
• This substance is present in the endothelial
cells of all or most blood vessels.
Endothelin: A Powerful
KEDOKTERAN DAN
ILMU KESEHATAN
Vasoconstrictor in
Damaged Blood Vessels
• The usual stimulus for release is damage to
the endothelium, such as that caused by
crushing the tissues or injecting a traumatizing
chemical into the blood vessel.
• After severe blood vessel damage, release of
local endothelin and subsequent
vasoconstriction helps to prevent extensive
bleeding from arteries.
KEDOKTERAN DAN
ILMU KESEHATAN
Vasodilator Agents
• Bradykinin
• Histamin
KEDOKTERAN DAN
ILMU KESEHATAN
Bradykinin
• Several substances called kinins cause
powerful vasodilation when formed in the
blood and tissue fluids of some organs.
• The kinins are small polypeptides that are split
away by proteolytic enzymes from alpha2-
globulins in the plasma or tissue fluids.
KEDOKTERAN DAN
ILMU KESEHATAN
Bradykinin
• Kallikrein is one of proteolytic enzyme, which
is present in the blood and tissue fluids in an
inactive form.
• This inactive kallikrein is activated by
maceration of the blood, by tissue
inflammation, or by other similar chemical or
physical effects on the blood or tissues.
KEDOKTERAN DAN
ILMU KESEHATAN
Bradykinin
• As kallikrein becomes activated, it acts
immediately on alpha2-globulin to release a
kinin called kallidin that then is converted by
tissue enzymes into bradykinin.
• Bradykinin persists for only a few minutes
because it is inactivated by the enzyme
carboxypeptidase or by converting enzyme
(the same enzyme that also plays an essential
role in activating angiotensin).
KEDOKTERAN DAN
ILMU KESEHATAN
Bradykinin
• Bradykinin causes both powerful arteriolar
dilation and increased capillary permeability.
• Injection of bradykinin into the brachial artery
of a person increases blood flow through the
arm as much as sixfold and marked local
edema resulting from increase in capillary
pore size.
KEDOKTERAN DAN
ILMU KESEHATAN
Bradykinin
• Kinins may play special roles in regulating
blood flow and capillary leakage of fluids in
inflamed tissues.
• Bradykinin may play a normal role to help
regulate blood flow in the skin as well as in
the salivary and gastrointestinal glands.
KEDOKTERAN DAN
ILMU KESEHATAN
Histamine
• Histamine is released in essentially every
tissue of the body if the tissue becomes
damaged or inflamed or is the subject of an
allergic reaction.
• Most of the histamine is derived from mast
cells in the damaged tissues and from
basophils in the blood.
KEDOKTERAN DAN
ILMU KESEHATAN
Histamine
• Histamine has a powerful vasodilator effect on
the arterioles
• Histamine has the ability to increase greatly
capillary porosity, allowing leakage of both
fluid and plasma protein into the tissues
inducing edema (prominent during allergic
reactions).
KEDOKTERAN DAN
ILMU KESEHATAN
Vascular Control by Ions and Other

• Vasodilator Chemical Factors
Vasoconstrictor
– potassium
calcium ionion
– carbon dioxide
magnesium ion(indirect effect through vasomotor center -- >
– vasoconstriction
hydrogen ion in the body)
– anions (acetate, citrate)
– carbon dioxide
KEDOKTERAN DAN
ILMU KESEHATAN
Coronary Circulation
Physiologic Anatomy
KEDOKTERAN DAN
ILMU KESEHATAN
of the Coronary
Blood Supply
• The main coronary arteries lie on the surface of the
heart and smaller arteries then penetrate from the
surface into the cardiac muscle mass.
• It is almost entirely through these arteries that the
heart receives its nutritive blood supply.
• Only the inner 1/10 millimeter of the endocardial
surface obtain significant nutrition directly from
the blood inside the cardiac chambers.
KEDOKTERAN DAN
ILMU KESEHATAN
Physiologic Anatomy of the Coronary

Blood Supply
In 80-90% of people:
• The left coronary artery
supplies mainly the anterior
and left lateral portions of
the left ventricle.
• The right coronary artery
supplies most of the right
ventricle as well as the
posterior part of the left
ventricle.
.
KEDOKTERAN DAN
ILMU KESEHATAN
The coronary venous
blood flow
• Venous blood flow from the left ventricular muscle
returns to the right atrium by the coronary sinus.
• Venous blood from the right ventricular muscle
returns through small anterior cardiac veins that flow
directly into the right atrium.
• A very small amount of coronary venous blood also
flows through very minute thebesian veins, which
empty directly into all chambers of the heart.
KEDOKTERAN DAN
ILMU KESEHATAN
Normal Coronary
Blood Flow
• The resting coronary blood flow in the human
being averages about 225 ml/min, which is
about 4 to 5 per cent of the total cardiac
output.
• During strenuous exercise, the heart in the
young adult increases its cardiac output
fourfold to sevenfold, and it pumps this blood
against a higher than normal arterial pressure.
KEDOKTERAN DAN
ILMU KESEHATAN
Normal Coronary
Blood Flow
• Consequently, the work output of the heart
under severe conditions may increase sixfold
to ninefold.
• At the same time, the coronary blood flow
increases threefold to fourfold to supply the
extra nutrients needed by the heart.
KEDOKTERAN DAN
ILMU KESEHATAN
Normal Coronary
Blood Flow
• This increase is not as much as the increase in
workload, which means that the ratio of
energy expenditure by the heart to coronary
blood flow increases.
• Thus, the “efficiency” of cardiac utilization of
energy increases to make up for the relative
deficiency of coronary blood supply.
KEDOKTERAN DAN
ILMU KESEHATAN
Phasic Changes in Coronary Blood Flow During
Systole and Diastole: Effect of
Cardiac Muscle Compression
• The changes in blood
flow through the
nutrient capillaries of
the left ventricular
coronary system in
milliliters per minute in
the human heart during
systole and diastole
KEDOKTERAN DAN
ILMU KESEHATAN
• The coronary capillary blood
flow in the left ventricle
muscle falls to a low value
during systole, opposite to
flow in vascular beds
elsewhere in the body.
• The reason is strong
compression of the left
ventricular muscle around
the intramuscular vessels
during systolic contraction.
KEDOKTERAN DAN
ILMU KESEHATAN
• During diastole, the
cardiac muscle relaxes
and no longer obstructs
blood flow through the
left ventricular muscle
capillaries, so that blood
flows rapidly during all
of diastole.
Coronary Blood Flow
During Systole and
KEDOKTERAN DAN
ILMU KESEHATAN
Diastole: Effect of
Cardiac Muscle
• Blood flow through the coronary capillaries of
Compression
the right ventricle also undergoes phasic
changes during the cardiac cycle,
• The force of contraction of the right
ventricular muscle is far less than that of the
left ventricular muscle -- > the inverse phasic
changes are only partial in contrast to those in
the left ventricular muscle.
KEDOKTERAN DAN
Epicardial Versus Subendocardial Coronary

ILMU KESEHATAN
Blood Flow: Effect

of Intramyocardial Pressure
• On the outer surface epicardial
coronary arteries supply most
of the muscle.
• Smaller, intra-muscular
arteries derived from the
epicardial arteries penetrate
the muscle, supplying the
needed nutrients.
• Lying immediately beneath the
endocardium is a plexus of
subendocardial arteries.
KEDOKTERAN DAN
Epicardial Versus Subendocardial Coronary

ILMU KESEHATAN
Blood Flow: Effect

of Intramyocardial Pressure
• During systole, blood flow
through the subendocardial
plexus of the left ventricle,
where the intramuscular
coronary vessels are
compressed greatly by
ventricular muscle contraction,
tends to be reduced.
• But the extra vessels of the
subendocardial plexus
normally compensate for this.
KEDOKTERAN DAN
ILMU KESEHATAN
Control of Coronary
Blood Flow
• Local Muscle Metabolism is the Primary
Controller of Coronary Flow
• Nervous Control of Coronary Blood Flow
KEDOKTERAN DAN
Local Muscle Metabolism is the Primary

ILMU KESEHATAN
Controller of Coronary Flow

• Blood flow through the coronary system is
regulated mostly by local arteriolar
vasodilation in response to cardiac muscle
need for nutrition.
– Whenever the vigor of cardiac contraction is
increased, regardless of cause, the rate of
coronary blood flow also increases.
– Conversely, decreased heart activity is
accompanied by decreased coronary flow.
Oxygen Demand as a
KEDOKTERAN DAN
ILMU KESEHATAN
Major Factor in
Local Coronary Blood
• The coronary blood flow doesFlow Regulation
increase almost
in direct proportion to any additional metabolic
consumption of oxygen by the heart.
– Normally, about 70% of the oxygen in the coronary
arterial blood is removed as the blood flows
through the heart muscle.
– Because not much oxygen is left, very little
additional oxygen can be supplied to the heart
musculature unless the coronary blood flow
increases.
Oxygen Demand as a
KEDOKTERAN DAN
ILMU KESEHATAN
Major Factor in
Flow
• A substance with great vasodilator Regulation
propensity is
adenosine.
• In the presence of very low concentrations of oxygen in
the muscle cells, a large proportion of the cell’s ATP
degrades to adenosine monophosphate; then small
portions of this are further degraded and release
adenosine into the tissue fluids of the heart muscle,
with resultant increase in local coronary blood flow.
• After the adenosine causes vasodilation, much of it is
reabsorbed into the cardiac cells to be reused.
Oxygen Demand as a
Major Factor in
KEDOKTERAN DAN
ILMU KESEHATAN

Flow Regulation
• Adenosine is not the only vasodilator product that
has been identified.
• Others include:
– adenosine phosphate compounds,
– potassium ions,
– hydrogen ions,
– carbon dioxide,
– bradykinin, and,
– possibly: prostaglandins and nitric oxide.
KEDOKTERAN DAN
ILMU KESEHATAN
Nervous Control of
Coronary Blood Flow
• Stimulation of the autonomic nerves to the heart can
affect coronary blood flow directly & indirectly.
• The direct effects: action of the nervous transmitter
substances acetylcholine from the vagus nerves, and
norepinephrine and epinephrine from the sympathetic
nerves on the coronary vessels themselves.
• The indirect effects: secondary changes in coronary
blood flow caused by increased or decreased activity
of the heart.
KEDOKTERAN DAN
ILMU KESEHATAN
Nervous Control of
Coronary Blood Flow
• The indirect effects, which are mostly opposite to the
direct effects, play a far more important role in
normal control of coronary blood flow.
• Sympathetic stimulation, which releases
norepinephrine and epinephrine, increases both
heart rate and heart contractility as well as increases
the rate of metabolism of the heart.
KEDOKTERAN DAN
ILMU KESEHATAN
Nervous Control of
Coronary Blood Flow
• In turn, the increased metabolism of the heart sets
off local blood flow regulatory mechanisms for
dilating the coronary vessels, and the blood flow
increases approximately in proportion to the
metabolic needs of the heart muscle.
KEDOKTERAN DAN
ILMU KESEHATAN
Nervous Control of
Coronary Blood Flow
• In contrast, vagal stimulation, with its release of
acetylcholine, slows the heart and has a slight
depressive effect on heart contractility.
• These effects in turn decrease cardiac oxygen
consumption and, therefore, indirectly constrict the
coronary arteries.
Nervous Stimuli on
KEDOKTERAN DAN
ILMU KESEHATAN
the Coronary
Vasculature
• The distribution of parasympathetic (vagal)
nerve fibers to the ventricular coronary
system is not very great.
• However, the acetylcholine released by
parasympathetic stimulation has a direct
effect to dilate the coronary arteries.
Nervous Stimuli on
KEDOKTERAN DAN
ILMU KESEHATAN
the Coronary
Vasculature
• The distribution of parasympathetic (vagal)
nerve fibers to the ventricular coronary
system is not very great.
• However, the acetylcholine released by
parasympathetic stimulation has a direct
effect to dilate the coronary arteries.
Nervous Stimuli on
KEDOKTERAN DAN
ILMU KESEHATAN
the Coronary
Vasculature
• There is much more extensive sympathetic
innervation of the coronary vessels.
• The sympathetic transmitter substances
norepinephrine and epinephrine can have
either vascular constrictor or vascular dilator
effects, depending on the presence or
absence of constrictor or dilator receptors in
the blood vessel walls
Nervous Stimuli on
KEDOKTERAN DAN
ILMU KESEHATAN
the Coronary
Vasculature
• The constrictor receptors are called alpha
receptors and the dilator receptors are called
beta receptors.
• Both alpha and beta receptors exist in the
coronary vessels.
• In general, the epicardial coronary vessels
have a preponderance of alpha receptors,
whereas the intramuscular arteries may have
a preponderance of beta receptors.
Nervous Stimuli on
KEDOKTERAN DAN
ILMU KESEHATAN
the Coronary
Vasculature
• Therefore, sympathetic stimulation can, cause
slight overall coronary constriction or dilation,
but usually constriction.
• In some people, the alpha vasoconstrictor
effects seem to be disproportionately severe,
and these people can have vasospastic
myocardial ischemia during periods of excess
sympathetic drive, often with resultant anginal
pain.
KEDOKTERAN DAN
ILMU KESEHATAN
Nervous Control of
Coronary Blood Flow
• Metabolic factors—especially myocardial
oxygen consumption—are the major
controllers of myocardial blood flow.
• Whenever the direct effects of nervous
stimulation alter the coronary blood flow in
the wrong direction, the metabolic control of
coronary flow usually overrides the direct
coronary nervous effects within seconds.
KEDOKTERAN DAN
ILMU KESEHATAN
Disfungsi Endotel
(Endothelial Dysfunction)
KEDOKTERAN DAN
ILMU KESEHATAN
Endotel
• Sel endotel adalah sel epitel skuamosa,
berbentuk poligonal, berinti sel satu, yang
menyusun lapisan endotel.
• Lapisan endotel merupakan lapisan sel epitel
yang melapisi rongga jantung, pembuluh
darah, pembuluh limfa, dan rongga serosa
pada tubuh.
KEDOKTERAN DAN
ILMU KESEHATAN
Endotel
• Lapisan endotel merupakan organ tubuh yang
paling besar dengan massa total seberat 1 kg,
panjang mencapai 100.000 km, dan area yang
dicakup seluas 5000 m2, meskipun
ketebalannya hanya 0,2-4 µm.
• Secara embriologi, endotel berasal dari
mesoderma.
KEDOKTERAN DAN
ILMU KESEHATAN
Endotel
• Semula sel endotel dianggap bersifat pasif.
• Kemudian diketahui bahwa sel endotel secara
aktif mensintesis, mensekresi, dan
memetabolisme berbagai substansi vasoaktif
berperan menjaga homeostasis vascular yang
secara autokrin, parakrin, dan endokrin.
KEDOKTERAN DAN
ILMU KESEHATAN
Endotel
• Dengan demikian, sel endotel dapat
dipertimbangkan sebagai organ endokrin
(endocrine endothelium).
KEDOKTERAN DAN
ILMU KESEHATAN
Endotel
• Endotel berfungsi antara lain dalam:
• 1) regulasi tonus vaskular,
• 2) regulasi hemostasis,
• 3) regulasi lalu lintas lekosit.
KEDOKTERAN DAN
ILMU KESEHATAN
Endotel
• Pengaturan tonus vaskular oleh sel endotel
ditentukan oleh keseimbangan zat-zat
vasodilator, seperti NO dan PGI2, ataupun zat-
zat vasokontriktor, seperti endotelin dan
platelet activating factor.
• Pengaturan hemostasis oleh sel endotel
meliputi efek endotel terhadap trombosit,
sistem koagulasi, dan sistem fibrinolisis.
KEDOKTERAN DAN
ILMU KESEHATAN
Endotel
• Sel endotel normal menghasilkan NO, PGI2 dan
ecto-ADPase, sehingga mencegah adhesi dan
agregasi trombosit.
• Sel endotel normal menghambat koagulasi
darah dengan menghasilkan heparin-
antitrombin, tissue factor pathway inhibitor
(TFPI), dan trombomodulin-protein C.
KEDOKTERAN DAN
ILMU KESEHATAN
Endotel
• Sel endotel normal menyokong fibrinolisis
dengan mensekresikan tissue-type
plasminogen activator (tPA).
• tPA mengubah plasminogen menjadi plasmin,
yang selanjutnya mendegradasi polimer fibrin.
KEDOKTERAN DAN
ILMU KESEHATAN
Endotel
• Sel endotel yang terstimulasi mensekresikan
plasminogen activator inhibitor-1 (PAI-1).
• PAI-1 menghambat pembentukan plasmin,
yang menghambat fibrinolisis.
• Dengan demikian, endotel normal bersifat
provasodilatasi, antitrombosit, antikoagulasi,
dan profibrinolisis.
KEDOKTERAN DAN
ILMU KESEHATAN
Endotel
• Sel endotel juga menjalankan fungsi
imunologik dengan mengatur lalu lintas lekosit
selama reaksi inflamasi.
• Interaksi sel endotel dengan lekosit
diperantarai molekul adhesi yang
diekspresikan dan sitokin proinflamasi yang
diproduksi oleh sel endotel
KEDOKTERAN DAN
ILMU KESEHATAN
KEDOKTERAN DAN
ILMU KESEHATAN
Disfungsi dan Aktivasi
Endotel
• Dalam keadaan homeostasis yang terganggu
sel endotel dapat mengalami disfungsi dan/
atau aktivasi.
• Disfungsi endotel didefinisikan sebagai
penurunan sintesis, sekresi, dan/ atau
aktivitas NO.
KEDOKTERAN DAN
ILMU KESEHATAN
Endotel
• Disfungsi endotel dapat diperluas sebagai
ketidakseimbangan antara produksi dan
aktivitas vasoaktif NO, PGI2, dan/ atau EDHF
sebagai vasodilator dan antiagregasi trombosit
dengan produksi dan aktivitas endotelin-1,
angiotensin II dan/ atau TXA2 sebagai
vasokonstriktor dan agregator trombosit.
KEDOKTERAN DAN
ILMU KESEHATAN
Endotel
• Aktivasi endotel didefinisikan sebagai
perubahan fenotip endotel berupa
peningkatan ekspresi molekul adhesi, seperti
VCAM-1, ICAM-1, dan selektin-endotel
(selektin-E), pada membran sel endotel, yang
biasanya dipicu oleh sitokin proinflamasi,
seperti TNF-α dan IL-6.
KEDOKTERAN DAN
ILMU KESEHATAN
Endotel
• Aktivasi endotel juga dapat meliputi
penurunan integritas vaskular, perubahan
permukaan endotel menjadi protrombotik dan
proadhesi lekosit, serta diproduksinya sitokin
oleh endotel
KEDOKTERAN DAN
ILMU KESEHATAN
Endotel
• Disfungsi dan aktivasi endotel menyebabkan
konstriksi pembuluh darah, proliferasi sel otot
polos vaskular, adhesi lekosit dan trombosit,
agregasi trombosit, oksidasi LDL, dan aktivasi
matrix metalloproteinase (MMP).
• Sel endotel yang mengalami disfungsi bersifat
provasokonstriksi, protrombotik, dan
prokoagulasi.
KEDOKTERAN DAN
ILMU KESEHATAN
Endotel
• Disfungsi dan aktivasi endotel berperan dalam
pembentukan aterosklerosis dan munculnya
penyakit kardiovaskular dan serebrovaskular.
• Disfungsi dan aktivasi endotel berlangsung
lama sebelum munculnya penyakit
kardiovaskular dan serebrovaskular
KEDOKTERAN DAN
ILMU KESEHATAN
Endotel
• Aktivasi dan disfungsi endotel saling berhubungan
erat.
• Penghambatan produksi NO endotel akan
meningkatkan adhesi lekosit pada dinding pembuluh
darah, berarti disfungsi endotel dapat memicu
aktivasi endotel.
• Sebaliknya, stimulasi endotel oleh sitokin
proinflamasi dapat menurunkan produksi dan
aktivitas NO, berarti aktivasi endotel dapat
mendorong timbulnya disfungsi endotel.
KEDOKTERAN DAN
ILMU KESEHATAN
Endotel
• Pengaruh disfungsi endotel terhadap
timbulnya aktivasi endotel melalui aktivasi NF-
κB, yang memicu transkripsi gen penyandi
molekul adhesi.
• Pengaruh aktivasi endotel terhadap terjadinya
disfungsi endotel melalui peningkatan radikal
bebas, yang menghambat ekspresi NO sintase
(NOS) dan meningkatkan degradasi NO.
KEDOKTERAN DAN
ILMU KESEHATAN
Endotel
• Stimulus aktivasi dan/ atau disfungsi endotel
antara lain sitokin proinflamasi (TNF-α, IL-1),
LPS, hiperglikemia, platelet activating factor
(PAF), shear stress, radikal bebas, lipid yang
teroksidasi, dan hipoksia/ reperfusi.
KEDOKTERAN DAN
ILMU KESEHATAN
Nitric Oxide (NO)
• In 1980 the phenomenon of endothelium
dependent relaxation and the existence of the
endothelium-derived relaxing factor (EDRF)
were described by Furchgott and Zawadzki.
• Seven years later EDRF was identified as an
inorganic gas, NO (Palmer et al., 1987).
KEDOKTERAN DAN
ILMU KESEHATAN
KEDOKTERAN DAN
ILMU KESEHATAN
From left to right, William Martin, 1982 Nobel Laureate John Vane and Bob
Furchgott, on the occasion of Furchgott's receipt of the 1998 Nobel Prize
for Physiology or Medicine.
KEDOKTERAN DAN
ILMU KESEHATAN
Nitric Oxide
• NO is synthesized from amino acid L-arginine
by the action of NO synthase (NOS).
• Three isoforms of NOS:
– Endothelial NOS (eNOS)
– Neuronal NOS (nNOS)
– Inducible NOS (iNOS)
KEDOKTERAN DAN
ILMU KESEHATAN
Nitric Oxide
• The gene encoding NOS:
– Chromosome 7 (eNOS)
– Chromosome 12 (nNOS)
– Chromosome 17 (iNOS)
KEDOKTERAN DAN
ILMU KESEHATAN
Nitric Oxide
• eNOS and nNOS are expressed constitutively
in a variety of cells that play a role in
cardiovascular physiology.
• These isoforms are calcium/calmodulin-
dependent and synthesize relatively low
amounts of NO which acts as an intercellular
messenger.
KEDOKTERAN DAN
ILMU KESEHATAN
Nitric Oxide
eNOS nNOS
Endothelium +
Neurones +
Platelets +
Neutrophils +
Endocardium +
KEDOKTERAN DAN
ILMU KESEHATAN
Nitric Oxide
• In contrast, iNOS isoform binds calmodulin
tightly so that its activity is independent of the
prevailing concentration of calcium.
• Once expressed iNOS generates large
quantities of NO, which may have
physiological as well as cytotoxic.
KEDOKTERAN DAN
ILMU KESEHATAN
Nitric Oxide
Increase iNOS Decrease iNOS
• TNF-α • IL-4
• IL-1β • IL-8
• IFN-γ • IL-10
• TGF-β
KEDOKTERAN DAN
ILMU KESEHATAN
Mechanism of endothelium-dependent
vascular relaxation
• Vascular endothelial cells
synthesize NO in response to a
variety of stimuli, including
shear stress, acetylcholine,
histamine, bradykinin,
sphingosine-1-phosphate,
serotonin, substance P, and
ATP.
• These factors increase
intracellular Ca2+, thereby
stimulating the Ca2+/CaM-
activated endothelial NO
synthase (eNOS).
KEDOKTERAN DAN
ILMU KESEHATAN
Mechanism of endothelium-dependent
vascular relaxation
• Endothelial eNOS produces
NO from arginine, and NO
subsequently diffuses to the
vascular smooth muscle cell
to initiate downstream
signaling events, particularly
activation of sGC in vascular
smooth muscle cells, leading
to cGMP production and
vasorelaxation.
KEDOKTERAN DAN
ILMU KESEHATAN
Atherosclerosis
KEDOKTERAN DAN
ILMU KESEHATAN
• The most common cause of death in Western culture

is ischemic heart disease, which results from
insufficient coronary blood flow.
• About 35 per cent of people in the United States die
of this cause.
• Some deaths occur suddenly as a result of acute
coronary occlusion or fibrillation of the heart,
whereas other deaths occur slowly over a period of
weeks to years as a result of progressive weakening
of the heart pumping process.
Atherosclerosis as a
KEDOKTERAN DAN
ILMU KESEHATAN
Cause of Ischemic
Heart Disease
• The most frequent cause of diminished
coronary blood flow is atherosclerosis.
• The atherosclerotic process is discussed in
connection with lipid metabolism.
KEDOKTERAN DAN
ILMU KESEHATAN
Atherosclerosis
• Atherosclerosis is a disease of the large and
intermediate-sized arteries in which fatty
lesions called atheromatous plaques develop
on the inside surfaces of the arterial walls.
• Arteriosclerosis, in contrast, is a general term
that refers to thickened and stiffened blood
vessels of all sizes.
KEDOKTERAN DAN
ILMU KESEHATAN
Atherosclerosis
• One abnormality that can be measured very early
in blood vessels that later become atherosclerotic
is damage to the vascular endothelium.
• This, in turn, increases the expression of
adhesion molecules on endothelial cells and
decreases their ability to release nitric oxide and
other substances that help prevent adhesion of
macromolecules, platelets, and monocytes to the
endothelium.
KEDOKTERAN DAN
ILMU KESEHATAN
Atherosclerosis
• After damage to the vascular endothelium
occurs, circulating monocytes and lipids (mostly
low-density lipoproteins) begin to accumulate at
the site of injury.
• The monocytes cross the endothelium, enter the
intima of the vessel wall, and differentiate to
become macrophages, which then ingest and
oxidize the accumulated lipoproteins, giving the
macrophages a foam like appearance.
KEDOKTERAN DAN
ILMU KESEHATAN
Atherosclerosis
• These macrophage foam cells then aggregate on
the blood vessel and form a visible fatty streak.
• With time, the fatty streaks grow larger and
coalesce, and the surrounding fibrous and
smooth muscle tissues proliferate to form larger
and larger plaques.
KEDOKTERAN DAN
ILMU KESEHATAN
Atherosclerosis
• Also, the macrophages release substances that
cause inflammation and further proliferation of
smooth muscle and fibrous tissue on the inside
surfaces of the arterial wall.
• The lipid deposits plus the cellular proliferation
can become so large that the plaque bulges into
the lumen of the artery and greatly reduces
blood flow, sometimes completely occluding the
vessel.
KEDOKTERAN DAN
ILMU KESEHATAN
Atherosclerosis
• Even without occlusion, the fibroblasts of the plaque
eventually deposit extensive amounts of dense
connective tissue; sclerosis (fibrosis) becomes so
great that the arteries become stiff and unyielding.
• Still later, calcium salts often precipitate with the
cholesterol and other lipids of the plaques, leading to
bony-hard calcifications that can make the arteries
rigid tubes.
• Both of these later stages of the disease are called
“hardening of the arteries.”
KEDOKTERAN DAN
ILMU KESEHATAN
Atherosclerosis
• Atherosclerotic arteries lose most of their
distensibility, and because of the degenerative areas
in their walls, they are easily ruptured. Also, where
the plaques protrude into the flowing blood, their
rough surfaces can cause blood clots to develop, with
resultant thrombus or embolus formation, leading to
a sudden blockage of all blood flow in the artery.
KEDOKTERAN DAN
ILMU KESEHATAN
Atherosclerosis
• Almost half of all deaths in the United States and
Europe are due to vascular disease.
• About two thirds of these deaths are caused by
thrombosis of one or more coronary arteries.
• The remaining one third are caused by thrombosis or
hemorrhage of vessels in other organs of the body,
especially the brain (causing strokes), but also the
kidneys, liver, gastrointestinal tract, limbs, and so
forth.
KEDOKTERAN DAN
ILMU KESEHATAN
Atherosclerosis
Development of atherosclerosis plaque http://www.fkik.umy.ac.id/

Basic Causes of
KEDOKTERAN DAN
ILMU KESEHATAN
Atherosclerosis—The
Roles of Cholesterol and
Lipoproteins
Increased Low-Density Lipoproteins
• An important factor in causing atherosclerosis

is a high blood plasma concentration of
cholesterol in the form of low-density
lipoproteins (LDL).
KEDOKTERAN DAN
ILMU KESEHATAN
Increased Low-Density
Lipoproteins
• The plasma concentration of these high
cholesterol low-density lipoproteins is
increased by several factors, including eating
highly saturated fat in the daily diet, obesity,
and physical inactivity.
• To a lesser extent, eating excess cholesterol
may also raise plasma levels of low-density
lipoproteins.
KEDOKTERAN DAN
ILMU KESEHATAN
Increased Low-Density
Lipoproteins
• An interesting example occurs in rabbits,
which normally have low plasma cholesterol
concentrations because of their vegetarian
diet.
• Simply feeding these animals large quantities
of cholesterol as part of their daily diet leads
to serious atherosclerotic plaques throughout
their arterial systems.
Familial
KEDOKTERAN DAN
ILMU KESEHATAN
Hypercholesterolemi
a
• This is a disease in which the person inherits
defective genes for the formation of low-
density lipoprotein receptors on the
membrane surfaces of the body’s cells.
• In the absence of these receptors, the liver
cannot absorb either intermediate-density or
low-density lipoproteins.
Familial
KEDOKTERAN DAN
ILMU KESEHATAN
Hypercholesterolemi
a
• Without this absorption, the cholesterol
machinery of the liver cells goes on a
rampage, producing new cholesterol;
• It is no longer responsive to the feedback
inhibition of too much plasma cholesterol. As
a result, the number of very low density
lipoproteins released by the liver into the
plasma increases immensely.
Familial
KEDOKTERAN DAN
ILMU KESEHATAN
Hypercholesterolemi
a
• Patients with full-blown familial
hypercholesterolemia have blood cholesterol
concentrations of 600 to 1000 mg/dl, levels
that are four to six times normal.
• Many of these people die before age 20
because of myocardial infarction or other
sequelae of atherosclerotic blockage of blood
vessels throughout the body.
KEDOKTERAN DAN
ILMU KESEHATAN
Lipoproteins in
Preventing
• High-density lipoproteins Atherosclerosis
do help protect
against the development of atherosclerosis.
• When a person has a high ratio of high-density
to low-density lipoproteins, the likelihood of
developing atherosclerosis is greatly reduced.
KEDOKTERAN DAN
ILMU KESEHATAN
Hypotheses of
Atherogenesis
• 1) The response-to-injury,
• 2) The response-to-retention,
• 3) Oxidative modification.
KEDOKTERAN DAN
ILMU KESEHATAN
The response-to-
injury hypotheses
• In this hypothesis, the proposed initial step in
atherogenesis is endothelial denudation
leading to a number of compensatory
responses that alter the normal vascular
homeostatic properties.
• Injury enhances endothelial adhesiveness for
leukocytes and platelets and alters the local
vascular anticoagulant milieu to a
procoagulant one.
KEDOKTERAN DAN
ILMU KESEHATAN
The response-to-
injury hypotheses
• Recruited leukocytes and platelets then
release cytokines, vasoactive agents, and
growth factors that promote an inflammatory
response that is characterized by migration of
smooth muscle cells into the intima and their
proliferation to form an intermediate lesion.
KEDOKTERAN DAN
ILMU KESEHATAN
The response-to-
injury hypotheses
• Another component of the inflammatory
response is the recruitment of macrophages
into the arterial wall. These macrophages take
up deposited LDL lipid to form lipid-laden “foam
cells,” the hallmark of an early atherosclerotic
lesion.
• The process of lipid accumulation and foam cell
formation perpetuates an inflammatory
response that perpetuates macrophage and
lymphocyte recruitment.
KEDOKTERAN DAN
ILMU KESEHATAN
The response-to-
injury hypotheses
• Continued inflammation allows for cellular
necrosis, with a concomitant release of cytokines,
growth factors, and proteolytic enzymes that sets
the stage for autocatalytic expansion of the lesion
to form a space-occupying collection in the
intima not unlike an abscess that would form in
other tissues. As the lesion enlarges it begins to
encroach upon the lumen and, ultimately, blood
flow is impaired.
KEDOKTERAN DAN
ILMU KESEHATAN
The response-to-
injury hypotheses
• This response-to-injury hypothesis was originally based
on the notion of endothelium desquamation as a
principal event initiating atherosclerosis. More recently,
it has become clear that endothelial desquamation is not
common and that an intact endothelial cell layer covers
developing atherosclerotic lesions. These facts, among
others, promoted refinement of the initial hypothesis
such that endothelial dysfunction is sufficient to initiate
atherogenesis through increased endothelial
permeability to atherogenic lipoproteins.
KEDOKTERAN DAN
ILMU KESEHATAN
The response-to-
injury hypotheses
KEDOKTERAN DAN
ILMU KESEHATAN
The response-to-
retention hypothesis
• This hypothesis submits that the lipoprotein
retention is the inciting event for atherosclerosis.
• According to the original hypothesis mild to
moderate hyperlipidemia causes lesion development
in specific sites within the arterial tree characterized
by local synthesis of apolipoprotein B-retentive
molecules.
KEDOKTERAN DAN
ILMU KESEHATAN
The response-to-
• Accumulation is thought to result from both
apolipoprotein B-100 motifs that mediate
proteoglycan binding and arterial factors such as
secretory sphingomyelinase that facilitate lipoprotein
aggregation.
• The accumulation of apolipoprotein B-100-containing
lipoproteins within the arterial wall is thought to
further trigger a proinflammatory cascade.
KEDOKTERAN DAN
ILMU KESEHATAN
The response-to-
• Lipoprotein oxidation may or may not be part of
these responses.
• Similar to LDL, apolipoprotein B-48-containing
chylomicron remnants may also bind to
proteoglycans via residues of the apolipoprotein and
hence be retained within the arterial wall.
KEDOKTERAN DAN
ILMU KESEHATAN
The response-to-
The oxidative
KEDOKTERAN DAN
ILMU KESEHATAN
modification
hypothesis
• The oxidative modification hypothesis focuses
on the concept that LDL in its native state is
not atherogenic.
• LDL modified chemically is readily internalized
by macrophages through a “scavenger
receptor” pathway.
The oxidative
KEDOKTERAN DAN
ILMU KESEHATAN
modification
hypothesis
• It is now clear that one mechanism whereby
cells in vitro render LDL a substrate for the
scavenger receptor pathway is via oxidation of
LDL lipids and the resulting modification of
apolipoprotein B-100.
The oxidative
KEDOKTERAN DAN
ILMU KESEHATAN
modification
hypothesis
• This modification of apolipoprotein B-100
renders LDL susceptible to macrophage
uptake via a number of scavenger receptor
pathways producing cholesterol ester-laden
foam cells. It is this accumulation of foam cells
that forms the nidus of a developing
atherosclerotic lesion.
The oxidative
KEDOKTERAN DAN
ILMU KESEHATAN
modification
hypothesis
MORPHOLOGY OF
KEDOKTERAN DAN
ILMU KESEHATAN
ATHEROSCLEROTIC
LESIONS
• Atherosclerosis manifests itself histological as
arterial lesions known as plaques that have
been extensively characterized into six major
types of lesions that reflect the early,
developing, and mature stages of the disease.
MORPHOLOGY OF
KEDOKTERAN DAN
ILMU KESEHATAN
ATHEROSCLEROTIC
LESIONS
• In lesion-prone arterial sites, adaptive
thickening of the intima is among the earliest
histological changes.
• As macrophages accumulate lipid, type II
lesions form as nodular areas of lipid
deposition that are also known as “fatty
streaks,” and these represent lipid-filled
macrophages (i.e., foam cells).
MORPHOLOGY OF
KEDOKTERAN DAN
ILMU KESEHATAN
ATHEROSCLEROTIC
LESIONS
• Continued foam cell formation and
macrophage necrosis can produce type III
lesions that contain small extracellular pools
of lipid.
• Types II and III lesions are readily apparent
through the use of fat-soluble dyes that stain
cholesterol esters accumulated in
macrophages and the extracellular space.
MORPHOLOGY OF
KEDOKTERAN DAN
ILMU KESEHATAN
ATHEROSCLEROTIC
LESIONS
• These early lesions are often evident by age
10 and can occupy as much as one-third of the
aortic surface by the third decade.
• Developing lesions represent the next two
types of lesions and are characterized by
significant areas of extracellular lipid that
represents the “core” of the atherosclerotic
lesion.
MORPHOLOGY OF
KEDOKTERAN DAN
ILMU KESEHATAN
ATHEROSCLEROTIC
• Type IV lesions are defined by aLESIONS
relatively thin
tissue separation of the lipid core from the
arterial lumen, whereas type V lesions exhibit
fibrous thickening of this structure, also known
as the lesion “cap.”
• These type IV and V lesions can be found
initially in areas of the coronary arteries,
abdominal aorta, and some aspects of the
carotid arteries in the third to fourth decade of
life.
MORPHOLOGY OF
KEDOKTERAN DAN
ILMU KESEHATAN
ATHEROSCLEROTIC
• Mature type VI lesions exhibitLESIONS
architecture
that is more complicated and characterized by
calcified fibrous areas with visible ulceration.
• These types of lesions are often associated
with symptoms or arterial embolization.
MORPHOLOGY OF
KEDOKTERAN DAN
ILMU KESEHATAN
ATHEROSCLEROTIC
LESIONS
• It was once thought that end-organ damage
and infarction were due to gradual
advancement of these lesions, but we now
know the processes involved in precipitating
heart attack and stroke are considerably more
complex.
KEDOKTERAN DAN
ILMU KESEHATAN
Varying stages of atherosclerosis from the earliest stages (top left) to the most advanced
(bottom right) culminating in plaque rupture and associated thrombosis.
KEDOKTERAN DAN
ILMU KESEHATAN
Other Major Risk Factors

for Atherosclerosis
• In some people with • Some of the factors are:
perfectly normal levels • (1) physical inactivity
of cholesterol and and obesity,
lipoproteins, • (2) diabetes mellitus,
atherosclerosis still
• (3) hypertension,
develops.
• (4) hyperlipidemia,
• (5) cigarette smoking.
Other Major Risk
KEDOKTERAN DAN
ILMU KESEHATAN
Factors
for Atherosclerosis
• Some of these factors cause atherosclerosis by
increasing the concentration of low-density
lipoproteins in the plasma.
• Others, such as hypertension, lead to
atherosclerosis by causing damage to the
vascular endothelium and other changes in
the vascular tissues that predispose to
cholesterol deposition.
Other Major Risk
KEDOKTERAN DAN
ILMU KESEHATAN
Factors
for Atherosclerosis
• In early and middle adulthood, men are more
likely to develop atherosclerosis than are
women of comparable age, suggesting that
male sex hormones might be atherogenic or,
conversely, that female sex hormones might
be protective.
KEDOKTERAN DAN
ILMU KESEHATAN
Other Risk Factors
for Atherosclerosis
• To add to the complexity of atherosclerosis,
experimental studies suggest that excess blood levels
of iron can lead to atherosclerosis, perhaps by
forming free radicals in the blood that damage the
vessel walls.
• About one quarter of all people have a special type
of low density lipoprotein called lipoprotein(a),
containing an additional protein, apoprotein(a), that
almost doubles the incidence of atherosclerosis.
KEDOKTERAN DAN
ILMU KESEHATAN
Prevention of
Atherosclerosis
• (1) Maintaining a healthy weight, being physically active,
and eating a diet that contains mainly unsaturated fat
with a low cholesterol content.
• (2) Preventing hypertension by maintaining a healthy
diet and being physically active/ effectively controlling
blood pressure with antihypertensive drugs if
hypertension does develop.
• (3) Effectively controlling blood glucose with insulin
treatment or other drugs if diabetes develops.
• (4) Avoiding cigarette smoking.
KEDOKTERAN DAN
ILMU KESEHATAN
Prevention of
Atherosclerosis
• Several types of drugs that lower plasma lipids
and cholesterol have proved to be valuable in
preventing atherosclerosis.
• Most of the cholesterol formed in the liver is
converted into bile acids and secreted in this
form into the duodenum; then, more than
90% of these same bile acids is reabsorbed in
the terminal ileum and used over and over
again in the bile.
KEDOKTERAN DAN
ILMU KESEHATAN
Prevention of
Atherosclerosis
• Any agent that combines with the bile acids in
the gastrointestinal tract and prevents their
reabsorption into the circulation can decrease
the total bile acid pool in the circulating
cholesterol. This causes far more of the liver
cholesterol to be converted into new bile
acids.
KEDOKTERAN DAN
ILMU KESEHATAN
Prevention of
Atherosclerosis
• Eating oat bran, which binds bile acids and is a
constituent of many breakfast cereals, increases the
proportion of liver cholesterol that forms new bile
acids rather than forming new low-density
lipoproteins and atherogenic plaques.
• Resin agents can also be used to bind bile acids in the
gut and increase their fecal excretion, thereby
reducing cholesterol synthesis by the liver.
KEDOKTERAN DAN
ILMU KESEHATAN
Prevention of
Atherosclerosis
• A group of drugs called statins competitively
inhibits hydroxymethylglutaryl-coenzyme A
(HMGCoA) reductase, a rate-limiting enzyme in the
synthesis of cholesterol -- > decreases cholesterol
synthesis and increases low-density lipoprotein
receptors in the liver, usually causing a 25%-50%
reduction in plasma levels of low-density
lipoproteins.
KEDOKTERAN DAN
ILMU KESEHATAN
Prevention of
Atherosclerosis
• The statins may also have other beneficial effects
that help prevent atherosclerosis, such as
attenuating vascular inflammation.
• In general, for each 1 mg/dl decrease in low-
density lipoprotein cholesterol in the plasma, there
is about a 2% decrease in mortality from
atherosclerotic heart disease.
KEDOKTERAN DAN
ILMU KESEHATAN
Acute Coronary
Occlusion
• Acute occlusion of a coronary artery most
frequently occurs in a person who already has
underlying atherosclerotic coronary heart
disease but almost never in a person with a
normal coronary circulation.
• A common site for development of
atherosclerotic plaques is the first few
centimeters of the major coronary arteries.
Causes of
KEDOKTERAN DAN
ILMU KESEHATAN
Acute Coronary
Occlusion
• The atherosclerotic plaque can cause a local
blood clot called a thrombus, which in turn
occludes the artery.
• The thrombus usually occurs where the
arteriosclerotic plaque has broken through the
endothelium, thus coming in direct contact
with the flowing blood.
Causes of
KEDOKTERAN DAN
ILMU KESEHATAN
Acute Coronary
Occlusion
• Because the plaque presents an unsmooth surface,
blood platelets adhere to it, fibrin is deposited, and
red blood cells become entrapped to form a blood
clot that grows until it occludes the vessel.
• The clot can break away from its attachment on
the atherosclerotic plaque and flows to a more
peripheral branch of the coronary arterial tree,
where it blocks the artery at that point (embolus).
Causes of
KEDOKTERAN DAN
ILMU KESEHATAN
Acute Coronary
Occlusion
• Local muscular spasm of a coronary artery also can
occur; the spasm might result from:
– Direct irritation of the smooth muscle of the arterial wall by
the edges of an arteriosclerotic plaque.
– Local nervous reflexes that cause excess coronary vascular
wall contraction.
• The spasm may then lead to secondary thrombosis of
the vessel.
Lifesaving Value of
KEDOKTERAN DAN
ILMU KESEHATAN
Collateral Circulation
in the Heart
• The degree of damage to the heart muscle
caused either by slowly developing
atherosclerotic constriction of the coronary
arteries or by sudden coronary occlusion is
determined to a great extent by the degree of
collateral circulation that has already
developed or that can open within minutes
after the occlusion.
KEDOKTERAN DAN
ILMU KESEHATAN
Lifesaving Value of Collateral Circulation

in the Heart
• In a normal heart, almost
no large communications
exist among the larger
coronary arteries.
• But many anastomoses
do exist among the
smaller arteries sized 20-
250 micrometers in
diameter
Lifesaving Value of
KEDOKTERAN DAN
ILMU KESEHATAN
in the Heart
• When a sudden occlusion occurs in one of the larger
coronary arteries, the small anastomoses begin to
dilate within seconds.
• But the blood flow through these minute collaterals
is usually less than one half that needed to keep alive
most of the cardiac muscle that they now supply.
• The diameters of the collateral vessels do not
enlarge much more for the next 8 to 24 hours.
Lifesaving Value of
KEDOKTERAN DAN
ILMU KESEHATAN
in the Heart
• But then collateral flow does begin to increase,
doubling by the second or third day and often
reaching normal or almost normal coronary flow
within about 1 month.
• Because of these developing collateral channels,
many patients recover almost completely from
various degrees of coronary occlusion when the area
of muscle involved is not too great.
Lifesaving Value of
KEDOKTERAN DAN
ILMU KESEHATAN
in the Heart
• When atherosclerosis constricts the coronary arteries
slowly over a period of many years rather than
suddenly, collateral vessels can develop at the same
time while the atherosclerosis becomes more and
more severe.
• Therefore, the person may never experience an
acute episode of cardiac dysfunction.
Lifesaving Value of
KEDOKTERAN DAN
ILMU KESEHATAN
in the Heart
• But, eventually, the sclerotic process develops
beyond the limits of even the collateral blood supply
to provide the needed blood flow, and sometimes
the collateral blood vessels themselves develop
atherosclerosis.
• When this occurs, the heart muscle becomes
severely limited in its work output, often so much so
that the heart cannot pump even normally required
amounts of blood flow.
Lifesaving Value of
KEDOKTERAN DAN
ILMU KESEHATAN
in the Heart
• But, eventually, the sclerotic process develops
beyond the limits of even the collateral blood supply
to provide the needed blood flow, and sometimes
the collateral blood vessels themselves develop
atherosclerosis.
• When this occurs, the heart muscle becomes
severely limited in its work output, often so much so
that the heart cannot pump even normally required
amounts of blood flow.
KEDOKTERAN DAN
ILMU KESEHATAN
TERIMA KASIH
&
WASSALAMU’ALAIKUM WR.WB

Kuliah Blok 17 Disfungsi Endotel Atherosklerosis Angina Pectoris

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KEDOKTERAN DAN

Disfungsi endotel, atherosclerosis

IKHLAS MUHAMMAD JENIE

Regulation of Blood Flow

• The rate of blood flow to each tissue of the

• Blood flow to the inactive muscle 4

Effect of Tissue Metabolism on Local

Acute Local Blood Flow Regulation When

Acute Local Blood Flow Regulation When

• Minute quantities of adenosine are released

Oxygen Lack Theory for Local Blood Flow

Oxygen Lack Theory for Local Blood Flow

Oxygen Lack Theory for Local Blood Flow

Oxygen demand theory in blood

TISSUE METABOLISM OXYGEN

Auto-regulation of blood flow

Auto-regulation of blood flow

Auto-regulation of blood flow:

• The composition of the fluid in the early distal tubule is

Formation of New Blood

Need, Not by Average

Need, Not by Average

Term Local Blood Flow

Term Local Blood Flow

Term Local Blood Flow

Term Local Blood Flow

Term Local Blood Flow

Term Local Blood Flow

Term Local Blood Flow

Vascular Control by Ions and Other

Physiologic Anatomy of the Coronary

Epicardial Versus Subendocardial Coronary

Blood Flow: Effect

Epicardial Versus Subendocardial Coronary

Blood Flow: Effect

Local Muscle Metabolism is the Primary

Controller of Coronary Flow

Local Coronary Blood

• The most common cause of death in Western culture

Development of atherosclerosis plaque http://www.fkik.umy.ac.id/

• An important factor in causing atherosclerosis

Other Major Risk Factors

Lifesaving Value of Collateral Circulation

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