Download Cardiovascular System

Sybghat Rahim
Cardiovascular System
Heart and Circulation
by Dr Mary Sheppard
Galen Theory
The ancient model of the blood system was accepted until 1600. Two types of blood, the venous and the
arterial with distinct pathways and functions, relating to the three chief body centres: the liver (responsible for
nutrition and growth), the heart (vitality), and the brain (sensation and reason). The heart did not drive blood
through the arteries. Blood’s movement through the arteries was explained by an innate “pulsative faculty” in
the arteries themselves.
This was until William Harvey’s demonstration of the circulation of the blood, building on Vesalian anatomy.
So much blood left the heart in a minute that it could not conceivably be absorbed by the body and be
continually replaced by blood made in the liver. Harvey noted that the amount of blood forced out of the heart
in an hour far exceeded its volume in the whole animal. This quantitative evidence established that the blood
must constantly move in a circuit, otherwise the arteries and body would explode under the pressure.
The Circulation
The circulation comprises the heart, arteries, veins and capillaries. These components function together with
the purpose of supplying nutrients such as oxygen and glucose to organs and removing waste products such as
carbon dioxide and urea.
The heart is located in the middle of the chest behind the sternum, between the lungs. It lies between the 1
th
and the 4 intercostal space.
st
The heart rests in a moistened chamber called the pericardial cavity which is
surrounded by the ribcage. The diaphragm, a tough layer of muscle, lies below.
The heart is very well protected.
A human being’s heart is about the size of a clenched fist. The average adult heart
weighs about 300 - 400 grams.
The heart consists of four chambers, atria and ventricles in one way
communication. The body’s circulation has two parts, with the heart acting as a
double pump. The body has 5 litres of blood continually travelling through it in
the circulatory system. The heart, the lungs, and the blood vessels work together
to form the circulatory system.
There are two circulations. One circulates blood from the body
to the lungs (the pulmonary circulation), which is small with little
peripheral resistance, so low pressures are needed and the walls
of the right ventricle are thin. The other circulation circulates
blood from the lungs around the body (the systemic circulation).
The left side pumps the same volume against greater peripheral
resistance, so the cardiac left ventricular walls are more
muscular and thicker.
The pulmonary artery connects the right ventricle of the heart
with the lungs as part of the pulmonary circulation system. The
two veins that carry blood into the heart (into the right atrium)
are the superior and the inferior vena cavae. The superior vena
cava brings blood from the head, neck and upper limbs. The
inferior vena brings blood from the abdomen and lower limbs.
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Blood Flow through the Heart
The right atrium receives deoxygenated blood from the superior and inferior vena cavae. During contraction
of the atrium, blood moves into the right ventricle through the tricuspid valve. Once the right ventricle is filled
with blood, this chamber contracts, pumping blood via the pulmonary arteries to the lungs.
Blood from the right side pump is dark red (bluish) and low in oxygen. The main
pulmonary artery divides into right and left arteries to enter the lungs at the hilum.
Blood travels in the pulmonary arteries and branches within the lungs where it
receives fresh supplies of oxygen and becomes bright red in the capillary bed. Blood
leaves the lungs in the pulmonary veins (two from each lung) back to the heart’s left
side pump.
The oxygenated blood enters the left atrium through the pulmonary veins. Once this chamber is filled, the left
atrial wall contracts, pushing blood through the mitral valve. After the left ventricle is filled, this chamber
contracts, forcing blood out of the ventricle and into the aorta.
The left ventricle is stronger in order to pump oxygenated blood through the entire body (left ventricle =
15mm; right = 3mm thick). In a cardiac cycle there are about 60 - 100 beats per minute, with each cycle lasting
0.8 seconds. In an average lifetime, the heart beats more than two and a half billion times, without ever
pausing to rest.
Heart Rate
The heart’s rate of pumping oxygen-rich blood is fastest in infancy (about 120 beats per minute). As the child
grows, the heart rate slows. A seven year old child’s heart beats about 90 times per minute. By the age of 18,
the heart rate has stabilised to about 70 beats per minute.
Heart Chambers
The human heart is primarily a muscle shell. There are four cavities inside the heart that fill with blood. Upper
two of these cavities are called atria. The lower two are called ventricles. The two atria form the top of the
heart, and the ventricles meet at the bottom of the heart to form a pointed base which points towards the left
of your chest. The left ventricle contracts most forcefully, so you can best feel your heart pumping on the left
side of your chest.
A wall called the septum separates the right and left sides of the heart. An atrioventricular valve connects
each atrium to the ventricle below it. The mitral valve connects the left atrium with the left ventricle. The
tricuspid valve connects the right atrium with the right ventricle.
Heart Muscle Tissue
Epicardium is the fibrous and adipose connective tissue forming the adventitia of the heart, with autonomic
nerves and vessels present. The myocardium is the muscle layer. Individual myocytes are seen with a pink
stain with pale connective tissue in between containing capillaries.
The Systemic Circulation
The human heart beats 100,000 times a day, propelling 5.5 litres of blood through 60,000 miles of vessels. The
blood is pumped from a 300 gram heart so forcefully that large arteries, when severed, can send a jet of blood
several feet into the air.
The forceful contraction of the heart’s left ventricle forces the oxygenated blood into the aorta which then
branches into many smaller arteries which run throughout the body. The inside layer of an artery is very
smooth, allowing the blood to flow quickly. The outside layer of an artery is very strong muscle, allowing the
blood to flow forcefully. The oxygen-rich blood eventually enters capillaries within organs where the oxygen
and nutrients are released.
In the systemic circulation, the blood leaves the left side of the heart and travels through arteries which
gradually divide into capillaries. In the capillaries, food and oxygen are released to the body cells, and carbon
dioxide and other waste products are returned to the bloodstream. The blood then travels in veins back to the
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right side of the heart. Blood passes through the kidneys. This phase of systemic circulation is known as renal
circulation. Kidneys filter much of the waste from blood and excrete it as urine.
Classification of Blood Vessels
Elastic arteries e.g. the aorta have a wide lumen and elastic wall. They have damp
pressure variations.
Muscular arteries have wide lumen, strong non-elastic walls and have low resistance
conduit.
Arterioles are resistance vessels with narrow lumen and thick contractile walls. They
control resistance and flow, allowing regional redirection of blood
Capillaries are exchange vessels with narrow lumen and thin walls.
Venules and veins are capacitance vessels with wide lumen and distendable walls.
They have low resistance conduit and reservoir. They allow frictional distribution of
blood.
The Coronary Circulation
The heart needs large amounts of oxygen. This is delivered by the coronary
circulation.
Heart damage occurs when it does not receive a normal supply of food and
oxygen.
Damage to the coronary arteries and the heart is the commonest cause of
death in the UK - atheroma and atherosclerosis or myocardial infarction.
Blood Flow to the Limbs
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Exchange vessels
Capillaries are composed of a single endothelial
cell. Across their walls occurs exchange between
blood and tissue fluids, oxygen, CO2, nutrients,
water, inorganic ions, vitamins, hormones,
metabolic products, immune substances, even
immune competent cells. Capillaries may be
plain, fenestrated or sinusoidal - to slow blood
flow.
Capillaries are concentrated into capillary beds.
Some capillaries have small pores between the
cells of the capillary wall, allowing materials to
flow in and out of capillaries as well as the passage of white blood cells. Capillaries are microscopic in size.
Blushing is one manifestation of blood flow into capillaries. Control of blood flow into capillary beds is done by
nerve-controlled sphincters.
Veins
After capillary beds blood is collected in venules
which are tributaries of veins. These vessels provide
a low pressure blood reservoir through which blood
returns to the heart. Veins have the same basic
histological structure as arteries, but are greater in
cross-sectional area, because of slower flow rate.
Arteries are often accompanied by veins.
Because only a little external pressure can stop flow,
veins are confined to the dorsum of the foot and
back of the hand, and often run on the flexor
aspects of joints.
The waste products are collected and the waste-rich blood flows into the veins and return in the venous
circulation back to the right side of the heart via inferior and superior caval veins.
Blood Vessel Structure
Adventitia - outermost layer which is composed of connective tissue and nerve fibres with a small network of
vessels called the vasa vasorum.
Elastic lamina - layers of elastic fibres which provide elasticity to the vessel wall. Two layers, an internal elastic
lamina just below the intima, and an external elastic lamina, sandwiched between the adventitia and media.
Media - the layer of smooth muscle and elastic fibres which provide much of the strength and elasticity of the
vessel.
Intima - inner lining of the blood vessel formed by the endothelial cells and a small amount of connective
tissue.
Endothelial cells - form the lining of the blood vessels. They maintain the permeability, helping to regulate
inflammation, and playing a critical role in blood coagulation and clotting.
Pulse and Blood Pressure
Besides circulating blood, the blood vessels provide two important means of measuring vital health statistics:
pulse and blood pressure. We measure heart rate, or pulse, by touching an artery. The rhythmic contraction of
the artery keeps pace with the beat of the heart. Since the radial artery is near the surface of the skin at the
wrist, we can easily touch the artery here and get an accurate measure of the heart’s pulse.
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The blood flowing through the arteries has a higher pressure than the blood in the veins. Your blood pressure
is measured using two numbers. The first number, which is higher, is taken when the heart beats during the
systole phase. The second number is taken when the heart relaxes during the diastole phase. Those two
numbers stand for millimetres. Normal blood pressure ranges from 110 to 150 millimetres (as the heart beats)
over 60 to 80 millimetres (as the heart relaxes). It is normal for your blood pressure to increase when you are
exercising and to decrease when you are sleeping. Increased blood pressure is called hypertension which is
very common in older people.
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Mechanical Properties of the Heart
by Dr Ken MacLeod
The contraction of the whole heart can be viewed by nuclear
resonance spectroscopy - in a normal heart powerful left and
right sided contractions are visible. It can also be seen that
each contraction in a cell is accompanied by a flash increase
and decrease in calcium ions (calcium ion transient).
In a contraction, an electrical event (cardiac action potential)
2+
causes this Ca transient which gives rise to the contractile
event.
Single Cell Structure
Ventricular cells are 100μm long and 15 μm wide.
T-tubules (transverse tubules) are finger-like invaginations from the cell
surface. T-tubule openings are up to 200nm in diameter. They carry the
surface depolarisation deep into the cell. They are spaced approximately
2μm apart so that a T-tubule lies alongside each Z line of every myofibril.
The T-tubules are closely opposed to the junctional
sarcoplasmic reticulum (muscle cell equivalent of
endoplasmic reticulum in other cells).
The sarcoplasmic reticulum is the store of calcium in
the cells. Morphologically, the SR is a lace-like structure
that overruns and covers up the myofibrils. The store of
calcium therefore lies very close to where it is to be
used.
Myofibrils make up about 46% of the cell, and
mitochondria make up about 36% of the cardiac cell,
and the SR is important but only makes up about 4% of
the cardiac cell.
Excitation-Contraction Coupling in the Heart
When an action potential is produced at the extracellular surface, the wave of depolarisation is pushed down
the T-tubules into the middle of the cell. This is sensed by the L-type calcium channels present in the Ttubules, and they open up. Calcium from outside the cell is then allowed to influx into the cell. Some of this
influx activates the myofibrils directly, but most of it binds to the SR-Calcium release channel in the SR
membrane. The release channel is activated, and allows stored calcium to be released from the SR into the
cytoplasm and activate contraction. This is a calcium-induced calcium release process that happens in the
heart. Skeletal muscle does not need this influx of calcium to release the calcium store. In heart muscle, it
must have this external calcium trigger. Calcium is pumped back into the store by Calcium-ATPase (uses ATP to
take calcium up against the concentration gradient, keeping it in storage, ready to be released in the next
beat). The calcium that comes into the cell is effluxed by the sodium-calcium exchanger during relaxation. It
uses a downhill energy gradient, as there is a low concentration of sodium inside the cell.
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2+
The Relationship between Force Production and Intracellular Ca concentration
Cardiac muscle has a length-tension relationship, i.e. if it is stretched it will change its force.
Cardiac muscle is very resistant to stretch, as it is less compliant than skeletal muscle. This is due to the
properties of the extracellular matrix and the cytoskeleton. Only ascending limb is important for cardiac
muscle.
Preload and afterload
Preload is the weight that stretches muscle before it is stimulated to contract. Afterload is the weight not
apparent to muscle in the resting state - it is only encountered when muscle has started to contract.
Isometric contraction - muscle doesn’t shorten when the force is produced.
Isotonic contraction - muscle shortens when the force is produced.
As blood fills the ventricles during the relaxation phase (or diastole) of the cardiac cycle it stretches the resting
ventricular walls. The stretch or filling determines the preload on the ventricles before ejection. Preload is
dependent upon venous return to the heart. Measures of preload include end-diastolic volume, end diastolic
pressure and right atrial pressure. Afterload is the load against which the left ventricle ejects blood after
opening of the aortic valve. A simple measure of afterload is the diastolic arterial blood pressure. Any increase
in afterload decreases the amount of isotonic shortening that occurs and decreases the velocity of shortening.
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Frank-Starling relationship
From observations by Otto Frank
(1895) and EH Starling (1914) that as
the filling of the heart increased
there was a more forceful
contraction, i.e. increased diastolic
fibre length increases ventricular
contraction. As a consequence, the
ventricles pump greater stroke
volume so that, at equilibrium,
cardiac output exactly balances the
augmented venous return.
This is due to two factors. Firstly,
there are changes in the number of
myofilament cross bridges that
interact. Secondly, there are changes
in the calcium sensitivity of the
myofilaments.
At shorter lengths than optimal the actin filaments overlap on themselves so reducing the number of myosin
cross bridges that can be made.
Calcium is required for myofilament activation. Troponin C is a thin filament protein that binds calcium. TnC
regulates the formation of cross-bridges between actin and myosin. At longer sarcomere lengths the affinity of
troponin C for calcium is increased. Less calcium is required for the same amount of force.
The amount of work done by the heart to eject blood under pressure into the aorta and pulmonary artery is
called the stroke work. Stroke work is the volume of blood ejected during each stoke (SV) times the pressure
at which the blood is ejected (P).
Stroke Work = SV x P
Law of Laplace
The law of Laplace states that when the pressure within a
cylinder is held constant, the tension on its walls increases
with increasing radius.
In order to increase P whilst keeping wall stress (T)
constant, either decrease radius (R) or increase wall
thickness (h).
The radius of curvature of the walls of the left ventricle are
less than that of the right ventricle allowing the left
ventricle to generate higher pressures with similar wall
stress. This facilitates late ejection.
Wall stress is kept low in e.g. a giraffe by a long, narrow, thick-walled ventricle. In a frog, where pressures are
low, the ventricle is almost spherical. Failing hearts often become dilated which decreases pressure generation
and ejection of blood and increases wall stress.
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Electrical Activity of the Heart
by Dr Frank Harrison
Human cardiac myocytes are small cells and are attached to adjacent ones. They join at intercalated discs
(end-to-end junctions) and have gap junctions with very low electrical resistance. Because of this, they have
action potentials that easily spread between cells, which means that the cells act together (syncytium). Cardiac
muscle contains actin and myosin as contractile proteins.
Sino-Atrial
Node
Left Atrium
Atrio-Ventricular
Node
Right
Atrium
Left
Ventricle
Bundle of His
Right
Ventricle
Bundle
Branches
Purkinje Fibres
There are five important components. Firstly the Sino-Atrial Node is a strip of modified muscle tissue located
on the posterial wall of the right atrium, near the vena cava. The second component is the Atrio-Ventricular
Node. The two atria and the two ventricles are separated from one another by a non-conductive fibrous ring
of tissue. The AVN provides an electrical bridge between the atria and the ventricles. The third component is
the Bundle of His, which is a group of rapidly conducting muscle fibres. The Bundle of His conveys the
electrical depolarisation from the AVN towards the septum (wall that divides ventricles). The Bundle of His
divides into two bundle branches running down the right and left sides of the septum. These too are
conducting muscle fibres. The final structure is that the bundle branches give rise to the Purkinje fibres,
located on the inner surface of the ventricular muscle (the endocardium).
The purpose of this specialised conducting fibre system ensures that the muscle mass contracts as near
simultaneously as possible. Because this contraction is quite short, it enables the ventricles to develop
substantial force in a short time which generates systolic blood pressure.
Cardiac muscle is perfectly capable of beating without any outside influence at all. If the heart is taken from an
animal and put in a suitable warm salty solution with appropriate solutes at the right pH, oxygenated, with
glucose etc, the heart will keep beating more many hours! This is in contrast to skeletal muscle, which needs a
stimulus to contract.
A Heart Beat
The wave of depolarisation is initiated at the SAN. It spreads from the SAN across the right and left atria,
causing them to contract. The wave of depolarisation reaches the AVN, and it does so after a brief delay. The
AVN depolarises, and this spreads down into the Bundle of His, down the branches and into the Purkinje fibres,
initiating ventricular contraction.
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The Electrical Activity
Action potentials can be recorded from the SAN. The
resting membrane potential is about -65mV, but it is not
stable. It doesn’t stay level, it shows some spontaneous
depolarisation, known as the pre-potential. When the prepotential takes the cell membrane to a particular value (e.g.
about -50mV), it reaches the threshold, at which point
there is an influx of sodium ions and the cell depolarises.
The cause of that slowly decaying pre-potential has two main factors contributing to it. Firstly, there is a
special current that is innate to pacemaker cells in so far as there is a slow inward sodium current. The
positive sodium ions make the inside of the cells less negative (depolarise). Secondly, the membrane
permeability of potassium ions falls, which inhibits the outward movement of positively charged potassium
ions. The combined effect is therefore that the cell slowly depolarises.
The slope of the pre-potential determines how quickly the cell returns to the threshold and therefore how
quickly the next beat is produced, i.e. the heart rate. Under the influence of the sympathetic nervous system,
the slope of the pre-potential increases, which means the threshold is reached more quickly and the heart rate
increases. On the other hand, under the influence of the parasympathetic nervous system (supply down the
Vegas nerve), the slope of the pre-potential is reduced, and consequently the heart rate goes down. The
reason for these two parts of the autonomous nervous system controlling heart rate is because of their
transmitters - noradrenaline in the sympathetic pathway increases the inward sodium current, and
acetylcholine in the parasympathetic (Vegas) pathway decreases the sodium current.
The action potential of an atrial cell lacks the pre-potential, i.e. the
resting membrane potential is stable and is also a bit more negative than
the resting membrane potential of the pacemaker cells at around -90mV.
The duration of the action potential is about 90ms. The shape is vaguely
triangular, except where it starts to repolarise.
In a ventricular cell, the resting membrane potential is again around -90mV.
However, the duration is much longer, at around 250 to 300ms. The obvious
feature that can be seen is known as the “plateau phase”, which is caused by
an inward calcium ion current. As the membrane depolarises, passing around 35mV, there are voltage sensitive calcium ion channels that open and allow
calcium to move into the cell down its electrochemical gradient. Calcium ions
carry two positive charges and hence delay the process of repolarisation. The
calcium ion current is very important. The action potential of AVN cells
resembles that of ventricular cells as it has a plateau phase, however is also has
a pre-potential.
One problem of the structures of the conducting system described is that it relies upon the current spread
from the atria to the ventricles across that fibrous ring at the AVN. Potentially if the AVN goes wrong, then
there is in principle a loss in mechanism for the atrial depolarisation to spread to the ventricles. This is called
“heart block”. If there was no back-up system for ventricular depolarisation, the consequences would be dire.
There is a back-up mechanism, in which the AVN cells take over the function of pacemaker activity for the
ventricles. There is a difference, however, as the resting heart rate is generated by the depolarisation rate in
the SAN. The equivalent rhythm of the AVN is a bit slower.
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Timing of Venctricular Action Potential and Isometric Force
The diagram illustrates that the electrical activity of the ventricle
occurs before the mechanical events. What is obvious from this
is that the duration of the two events are not that much
different. This is in great contrast to skeletal muscle in which the
action potential has a much shorter duration than the mechanical
response. The refractory period of ventricular tissue is shown in
the diagram, showing that the muscle is still refractory while it
has started to relax, so the force is declining during the
membrane potential’s refractory period. Consequently, a fused
tetanus cannot be produced in cardiac muscle, again in contrast
to skeletal muscle. Cardiac muscle functions rhythmically.
Clinical Cardiac Calcium
It is the calcium ion inward current that extends the refractory period, and influences the force of the
contractions of the heart. This has significant clinical implications, as some patients have conditions in which
the heart is failing (not beating forcefully enough). This can be treated with a drug that increases the
intracellular calcium ion concentration. Patients with angina can be treated by reducing the amount of work
that the heart is doing (whilst simultaneously treating the hypoxia) with a calcium ion “hooking drug” (e.g.
Verapamil) to reduce the amount of calcium ions that enter cardiac muscle.
Introduction to ECG
The effects of a wave of depolarisation are detected as the potential difference between two electrodes.
When a wave of depolarisation is moving towards the positive electrode, it causes an upward deflection.
When it is moving away from the positive electrode it produces a downward deflection. In practice, the
equipment used to record ECG has to have high amplification as the signal being looked for is small.
The characteristic shape of the ECG is caused by the wave of depolarisation that occurs in the heart. The wave
of activity travels in several directions as it spreads across, but overall it has a net direction towards the left.
This cumulative sum effect of depolarisation is recorded as a little upward hump at the beginning called the P
wave (depolarisation of atria). The wave of depolarisation reaches the AVN, which has small junctional fibres
of low conduction. They delay the spread into the ventricular system. During this delay, the atria contract,
pumping the blood into the ventricles. Most of the
filling of the ventricles happens during diastole, as the
valves are open and filling occurs passively, but the
last bit of blood is propelled by atrial contraction. The
wave passes through the Bundle of His, with a net
effect being to the left side. The wave then passes
through the Purkinje cells, causing the ventricles to
contract. The sequence of depolarisation of the
ventricles is that the endocardium depolarises before
the epicardium, and the apex depolarises before the
base. The effect of this is that there is a powerful,
short-lasting contraction of the ventricles, which gives
rise to the QRS complex on the ECG. It represents
ventricular depolarisation, followed by repolarisation
of the ventricles seen on the ECG as the T wave.
The net direction of the wave is to the left for good reason. The wall of the left ventricle is thicker than the
wall of the right ventricle. Broadly speaking, both sides of the heart pump out the same volume of blood. The
pressure in the systemic circulation (left) is much higher than that in the pulmonary circulation (right). This
mean direction to the left is known as the Mean Frontal Plane Axis of the ventricle.
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The Microcirculation
by Dr Chris John
The Branching Structure of the Microvasculature:
1st Order Arterioles
Terminal Arterioles
Capillary
Pericytic (post-capillary) Venule
Venule
The overall aim of the cardiovascular system is to provide adequate blood flow through the capillaries. This is
the only way the tissues can function - if blood is supplied to them by the capillaries. A measure of this is
known as blood flow rate, which is the volume of blood passing through a vessel per unit time.
F = ΔP
R
Where:
F is the blood flow rate
P is the pressure, so ΔP is the pressure gradient
R is the vascular resistance.
The pressure gradient is the pressure at the beginning of the arteriole (the pressure as the blood exits the
major artery) compared to the pressure as the blood leaves the arteriole. This is determined by the heart
contraction force vs. the frictional loss.
Resistance is the hindrance to blood flow due to friction between moving fluid and stationary vascular walls.
There are a number of factors that influence this, such as the blood viscosity, the vessel length and the vessel
radius. Blood viscosity as a general rule remains fairly constant, and the vessel length doesn’t change. So the
vessel radius is the main factor that influences resistance. Resistance has a proportional relationship with
vessel radius described by:
R 1
4
r
According to this equation, if the radium is halved, then the resistance in the vessel will increase 16 fold.
The arterioles are the major resistance vessels in the cardiovascular system. They have the greatest influence
on blood pressure. The pressure as blood enters the arterioles is on average 93mmHg (mean arterial pressure),
and the pressure as it leaves the arterioles is on average 37mmHg. The blood is slowed sufficiently so that as it
passes through the capillaries it is passing at a rate suitable for exchange of materials.
The principle of blood flow rate can be applied to whole tissues or organs. F organ = ΔP / Rorgan, where the
pressure gradient is pretty much the same as the mean arterial pressure. Without this pressure difference
blood would not reach tissue capillary beds.
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Blood flow across any given tissue is driven by
the extent to which arterioles are either
constricted or dilated. With powerful
vasoconstriction the muscle in the arterioles
contracts, the radius decreases massively, the
resistance increases massively and the blood
flow decreases. This is how blood flow can be restricted to particular tissues. With vasodilation, the arteriole
muscles relax and the radius increases, the resistance decreases as the flow rate increases as the arterioles
open up. Arteriolar smooth muscle normally displays a state of partial constriction - this is known as vascular
tone.
The radii of arterioles are adjusted independently to accomplish two functions:
1) Match blood flow to the metabolic needs of specific tissues (depending on the body’s momentary
needs). This is regulated by local (intrinsic) controls - independent of nerves or hormones.
2) Help regulate arterial blood pressure - regulated by extrinsic controls.
Chemical alterations mean that if a tissue becomes more metabolically active, the blood flow through that
tissue increases. For example in skeletal muscle, at rest about 10% of the capillaries are open. During exercise
there is a massive increase in blood flow to the skeletal muscles, as more oxygen and more glucose is used.
This is detected locally within the tissue (oxygen concentration changes) and so vasodilation would occur. This
process is termed active hyperaemia.
Physical manipulations are mainly due to heat loss - the need to prevent it or cause it. If the blood
temperature starts to rise, there is a massive dilation of the peripheral arteriolar beds to try to dissipate that
temperature. If the blood temperature starts to fall, then blood is diverted away from the periphery to try to
maintain the blood pressure. For example applying cold compress like frozen peas diverts blood away from
that area of the body which reduces swelling.
Other physical alterations include myogenic vasoconstriction, which is a response to increased stretch of the
arterioles. E.g. during exercise, the tissues that are massively metabolically active have increased blood flow,
but this needs to be compensated for by constriction in other tissues. Commonly, in tissues such as the gut
tissue, there is a rebound vasoconstriction to conserve the blood pressure. If the blood pressure is increased in
one part of the body, it has to be decreased in another part of the body - autoregulation.
In terms of extrinsic controls, arterial blood pressure control can be described by the basic equation F = ΔP / R
as applied to the entire circulation. In this case: blood flow is equivalent to cardiac output (flow per unit time),
pressure gradient is the mean arterial pressure, and the resistance is the total peripheral resistance. Therefore
the resultant equation is:
CO = MAP / TPR, and so MAP = CO x TPR
Therefore, the body can preserve blood pressure when it has to by massive vasoconstriction of arterioles.
Particular tissues are targeted more than others - no vasoconstriction in important tissues. E.g. at times of
haemorrhage the cardiovascular control centre in the brain stem (medulla) sends neural signals to large
numbers of tissue beds to cause profound vasoconstriction. This preserves blood pressure, but can also have
disastrous circulatory failure effects. The receptors mediating the sympathetic nervous system effects are α
receptors (α1) which cause vasoconstriction. β receptors are found on the heart.
There are a number of hormonal mediators that can help to preserve blood pressure by their effects on the
microcirculation. For example: vasopressin (vasoconstrictor), angiotensin II (vasoconstrictor), adrenaline /
noradrenaline (effects on vasculature and heart - sympathetic output).
Capillaries are arguably the most important vessels in the
microcirculation. Capillary exchange is the ultimate function of
the cardiovascular system where there is movement of metabolic
substrates and removal of waste products - it allows tissues to
function normally and in a coordinated fashion. Capillaries are
well designed to facilitate this process. They are incredibly narrow
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(7μm in diameter), have very thin walls (1μm) and form extensive and dense networks. This means that
diffusion distances are very small, and the surface area for it is very large - the tissue is never far away from
the capillary.
Highly metabolically active tissues require a denser capillary network. Different tissues therefore have
different densities of capillary network. Skeletal muscle has dense capillary network of 100cm²/g, the
myocardium and also the brain have denser capillary networks of 500cm²/g. The lungs have the densest
capillary network, but that is because of their role in gas exchange - 3500cm²/g.
Just because there is a dense capillary network doesn’t mean all the capillaries are open at all times. The
precapillary sphincters control the opening and closing of the capillaries. For example in the skeletal muscle at
rest, only about 10% of the capillaries are open and 90% of the blood bypasses the other capillaries in the
system. They open up (active hyperaemia) when exercise begins to allow blood to flow into the tissues.
There are three major forms of capillary structure. The large majority
of capillaries are made up of continuous endothelium. The capillaries
are endothelial cells lined up in a row, with water-filled gap junctions
which allows movement of certain electrolytes and water, but
protein cannot get out of the capillaries into the tissues. In certain
tissues, there are incredibly tight gap-junctions, for example in the
brain (the blood-brain barrier).
The next structure is the fenestrated capillary. There are small
windows within the capillary structure. A lot of the endocrine
glands have this capillary structure to allow small protein
hormones to diffuse into or out of the endocrine tissue. The
kidney is also a good example - Glomerulus filtration is through
a capillary structure such as this.
In some tissues there are discontinuous capillaries where there are
large gaps in the capillary structure. For example in the bone
marrow, where white blood cells that have been generated pass out
of the tissue and into the blood stream.
Capillary structure depends on what the needs and function of the tissue is.
Fluid movement across capillary - a volume of
protein free plasma filters out of the capillary,
mixes with the surrounding interstitial fluid and
is reabsorbed. This is process known as bulk
flow.
Bulk flow is driven by two factors. The first that
drives fluid out of the capillaries and into the
tissues is hydrostatic pressure - the pressure
generated by the heart, by the cardiac output.
The second pressure that draws fluid back in
again is the oncotic pressure. A strong osmotic
pull is generated pulling fluid back into the capillaries from the tissues as proteins don’t leave the blood
stream. These forces are termed Starling’s Forces.
Starling’s hypothesis of 1896 was that there must be a balance between the hydrostatic pressure of the blood
in the capillaries and the osmotic attraction of the blood for the surrounding fluids…and whereas capillary
pressure determines transudation, the osmotic pressure of the proteins of the serum determines absorption.
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Sybghat Rahim
If the pressure inside the capillary is greater than in the interstitial fluid, the result is ultrafiltration. This occurs
early in the capillary. If the inward driving pressure is greater than the outward pressures across the capillary,
the result is reabsorption. This occurs later in the capillary. There is always a net movement of fluid that takes
the fluid overall in and out of the capillary system, but there is also always a small net loss.
The role of the lymphatic system is to make sure that the net loss of fluid
that occurs over the course of the day is eventually returned back into the
bloodstream. Rather like the microcirculation, there is a lymphatic
circulation that runs in parallel to the microcirculation. The lymphatics feed
into all the tissues much like the microcirculation. As the lymphatics enter
the tissues, they become “blind-ended” - it is not a circular system, they end
in the tissues. Lymphatic capillaries are designed in such a way that fluid can
flow into the lymph vessels, but cannot flow back out. So the interstitial fluid
is taken away into the rest of the lymphatic system.
The lymphatic capillaries drain into larger and
larger lymphatic vessels, and eventually have
entry points (e.g. in the thoracic area / lower
neck) back into the venous system to ensure
that blood pressure is preserved.
Lymph nodes found in the lymphatic system are part of the immune system. They
are filled with lymphocytes, and any sort of infection that passes through the
lymphatic system will be detected in the lymph nodes and the various
lymphocytes will attack that infection, whether it be through the generation of
antibodies or otherwise. During an infection the lymph nodes tend to get larger,
and this can be heard as a common complaint of “swollen glands”.
There is no heart to drive lymphatic flow, and so lymphatic fluid gets from the tissues to the thoracic duct by
skeletal muscle contractions and also by negative pressures exerted within the thoracic cavity - e.g. the
contracting diaphragm. Around 3 litres of lymph are returned to the blood stream every day.
Oedema refers to tissue swelling due to fluid accumulation, which occurs when the rate of production of the
fluid is greater than the capacity of the lymphatic system to remove it (lymphatic failure). An unpleasant
disease is the parasitic blockage of the lymph nodes - Elephantiasis. There is massive oedema throughout the
body, primarily because the lymphatic system is blocked and cannot drain properly.
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Sybghat Rahim
Understanding the ECG
by Dr Frank Harrison
Electrocardiography is a transthoracic interpretation of the electrical activity of the heart over time captured
and externally recorded by skin electrodes. The ECG is based around the concept of an equilateral triangle
(Einthoven’s triangle) with the heart at the centre. The points of the triangle are approximated by the limb
leads, connected to the right arm, left arm and left foot. The potential difference between two leads will
depend upon the amplitude of the current, related to the muscle mass and direction of current flow.
Attachment of Electrodes: the right foot is always used as a
zero volt reference point. This leaves two arms and the left
foot for recording signals.
Lead I is LA  RA
Lead II is LF  RA
Lead III is LF  LA
where LA is +
where LF is +
where LF is +
These standard limb leads are bipolar electrodes formed by connecting together two limb leads. In each case it
is necessary to designate one electrode as positive and one negative. By convention, the apparatus is
connected so that as a wave of depolarisation moves towards the positive electrode, an upward deflection is
recorded.
Another 3 limb leads can be connected up which use
one single limb lead as one electrode (+) and another
two leads connected together to make the indifferent
negative electrode.
aVR
aVL
aVF
RA  LA+LF
LA  RA+LF
LF  RA+LA
where RA is +
where LA is +
where LF is +
These are the augmented limb leads. The negative electrode may be assumed to be halfway between the two
points of the triangle that are connected together. The advantage of this arrangement is that it provides three
more angles from which the electrical activity of the heart may be recorded. The three angles are still in the
same frontal plane as the standard limb leads.
The augmented limb leads and the standard limb leads,
together give rise to the hexagonal reference system.
The 6 limb leads therefore give a view of the electrical
activity of the heart every 30 degrees.
The magnitude of the ECG results may vary due to the fact
that the leads assess the heart from different angles,
therefore some leads will be more parallel to the direction
of the electrical impulse and therefore give large ECG
readings (normally lead II), whereas others may be more
perpendicular to the direction of
depolarisation/repolarisation and therefore five a smaller
ECG reading.
The Mean Frontal Plane Axis is the mean direction of the wave of depolarisation, which is usually towards the
left ventricle as it is respective of tissue mass. Generally the mean frontal plane axis is between -30 and +90
because of the large muscle mass of the left ventricle. It does however depend on the way in which the heart
lies as well as the amount of muscle in the left ventricle.
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Sybghat Rahim
If the mean frontal plane axis lies beyond -30° then it is called left axis deviation. This occurs in left ventricular
hypertrophy. If the mean frontal plane axis lies beyond +90° then it is right axis deviation. This occurs in right
ventricle hypertrophy, associated with pulmonary conditions.
o
MFPA 0
o
MFPA 90
Lead I
++
0
Lead
II
+
+
Lead III
+
Lead avL
+
-
Lead avR
-
Lead aVF
0
++
The value of cos90 is zero, hence the value of
MFPAcos90 is also zero. This explains why a lead
with its axis at right angles to the MFPA shows
no signal (or a small equipotential).
Cosines of angles between 90 and 270 are
negative, thus when a lead is more than 90° to
the MFPA the ECG will show downward rather
than upward deflections.
Whereas the limb leads measure depolarisation in the frontal plane, the 6 chest leads measure depolarisation
in different horizontal planes. They are labelled V1 to V6 respectively. They are all positive electrodes.
th
V1 = right 4 intercostal space - parasternal
th
V2 = left 4 intercostal space - parasternal
V3 = left midway between V2 and V4
th
V4 = left 5 intercostal space - mid-clavicular line
V5 = left anterior axillary line - in line with V4
V6 = left mid axillary line
(right ventricle)
(right ventricle)
(septum and anterior wall of left ventricle)
(septum and anterior left ventricle)
(anterior and lateral left ventricle)
(anterior and lateral left ventricle)
The first part of the heart to depolarise is the septum, then the general direction of depolarisation is towards
the left ventricle. Therefore, V1 will have a small upward deflection followed by a large downward one as the
small septal depolarisation is toward the electrode and the large left ventricle depolarisation is away from the
electrode.
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Sybghat Rahim
The ECG - Identifying Some Basic Disturbances of Rhythm
by Dr Sanjay Prasad
The baseline (isoelectric line) is represented as a straight line on the ECG paper where there are no positive or
negative charges of electricity to create deflections.
The above grid shows the small and large squares that an ECG is commonly recorded on. A small square is
1mm by 1mm and a large square is 5mm by 5mm. Above is a normal 12 lead ECG with three additional rhythm
strips at the bottom.
Waveforms are representations of electrical activity created by
depolarisation and repolarisation of the atria and ventricles. If
the electrical current is flowing towards the lead then a positive
deflection will be seen. If the electrical current is flowing away
from the lead then a negative deflection will be seen.
Waveforms that are above and below the isoelectric line are
called biphasic.
Electrical impulses originating in the SA node trigger atrial depolarisation. The normal P wave is no more than
0.1 seconds in duration and 2.5mm high. The direction of electrical activity is from the SA to the AV node. The
P wave is a representation of the time it takes for atrial depolarisation. It is viewed normally as small and
curved with a positive deflection, seen at it’s tallest on lead II.
The QRS complex represents ventricular depolarisation. It consists of three waveforms. The normal complex
begins with a downward deflection known as the Q wave, followed by an upward deflection called the R wave.
The next downward deflection will be the S wave. All ventricular complexes are known as QRS complexes even
if every wave is not present in all complexes. The normal QRS complex is 0.04 to 0.12 seconds.
Ventricular repolarisation (which follows ventricular depolarisation) is represented by the T wave. Its shape is
rounded and taller and wider than the P wave. It is also more sensitive to physiological and hormonal changes
in shape but usually presents as a positive deflection: 5 - 10mm in height.
After T wave an ECG can sometimes show a U wave. It is of the same deflection as the T wave and similar to
the shape of P wave. The U wave is thought to represent late repolarisation of the Purkinje fibres in the
ventricles and is more often not shown on a rhythm strip.
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Sybghat Rahim
Interval refers to the length of a wave
plus the isoelectric line that follows it.
The length of an interval ends when
another wave begins. They are named
by using the letters of both waves on
either side. Intervals contain waves.
Segments refers to the baseline
between the end of one wave and the
beginning of the next wave. Segments
are the lines between waves.
The PR interval is the length along the
baseline from the beginning of the P
wave to the beginning of the QRS
complex. This is normally 0.12 to 0.20
seconds in duration (3 to 5 small
squares).
The QT interval is the beginning of the
QRS complex to the end of the T wave.
In the presence of a U wave the
measure should be from the beginning
of the QRS complex to the end of the U
wave.
The ST segment is the length between the end of the S wave of the QRS complex and the beginning of the T
wave. It is electrically neutral. The PR segment represents the delay in conduction from atrial depolarisation to
the beginning of ventricular depolarisation. It is also electrically neutral.
Estimating rates and rhythm
Graph ECG paper is divided into vertical and horizontal lines, whereby small squares are 1mm sq. and the
larger squares are 5mm sq. The time or rate is estimated by measuring the number of square blocks along the
horizontal line. The distance across one small square is 0.04 seconds. The distance across one large square is
0.2 seconds.
Vertical lines measure amplitude or voltage and is measured in millivolts. Each small square along the vertical
line equates to 0.1mV. One large square equals 0.5mV.
Horizontal lines measure time. Vertical lines measure voltage. A one second strip consists of 5 large blocks,
three seconds equates to 15, six seconds equates to 30 and ten seconds equates to 50.
You begin by counting the R waves in a ten second strip. Multiply that number by 6 to determine the heart
rate in one minute. For example, if there were 16 R waves in a ten second strip this would equate to 16 x 6 =
96 beats/min. A normal 12 lead ECG page (A4 landscape) is just over 10 seconds (25cm).
Count the large blocks that fall between two R waves.
Start by finding an R wave that falls on or close to a dark
line.
To determine a rhythm or pattern, you must measure
the distances between complexes and compare this
against the next grouping of complexes. This is done by
measuring the distance between one P wave and the
next P wave or from one R wave to the next. Consistent
intervals = normal rhythm.
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Sybghat Rahim
Common cardiac arrhythmias:
Bradycardia - resting heart rate of under 60 beats per minute.
Tachycardia - heart rate that exceeds the normal range for a resting heart rate (varies with age). Over
100 beats per minute for adults.
Cardiac conduction abnormalities
Supraventricular arrhythmias
o Atrial fibrillation, atrial flutter, AVNRT
Ventricular arrhythmias
o Ventricular tachycardia, fibrillation
Normal ECG values:
P wave
Duration < 0.11s; Amplitude < 2.5mm in lead II
PR interval
0.12 - 0.20s
QRS complex
Duration < 0.12s; Amplitude: R wave in V6 < 25mm; Axis -30 to +90 degrees
Q wave
Duration < 0.04s; Amplitude < 25% of total QRS complex amplitude
QT interval
0.38 - 0.42s
ST segment
Should be isoelectric
T wave
May be inverted in lead III, aVR, V1 and V2 without being abnormal.
Checking an ECG:
1. Is it the correct recording?
2. Identify the leads
3. Check the calibration and speed of the paper
4. Identify the rhythm
5. Look at the QRS axis
6. Look at the P wave
7. Look at the PR interval
8. Look at the QRS complex
9. Determine the position of the ST segment
10. Calculate the QT interval
11. Look at the T wave
12. Check again
Sinus Tachycardia
P waves have normal morphology, but there is an atrial rate of 100 - 200 beats per minute. There is a regular
ventricular rhythm, but a ventricular rate of 100 - 200 beats per minute. One P wave precedes every QRS
complex.
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Sybghat Rahim
Atrial Fibrillation
P waves absent; oscillating baseline f (fibrillation) waves. Atrial rate 350 - 600 beats per minute, and irregular
ventricular rhythm. Ventricular rate 100 - 180 beats per minute.
Atrial Flutter
Undulating saw-toothed baseline F (flutter) waves. Atrial rate 250 - 350 beats per minute. Regular ventricular
rhythm. Ventricular rate typically 150 beats per minute (with 2:1 atrioventricular block). 4:1 is also common
(3:1 and 1:1 block uncommon).
Preexcitation Syndrome
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Sybghat Rahim
Heart Block
This is also known as AV nodal block.
st
1 Degree AV nodal block shows a prolonged PR interval.
nd
2 Degree AV nodal block is Mobitz Type I (Wenckebach) or Mobitz Type II.
rd
3 Degree AV nodal block is complete heart block.
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Sybghat Rahim
Bundle Branch Blocks
In a normal impulse conduction, the impulse moves from the sinoatrial node, to
the AV node, through the bundle of His, through the bundle branches, on to the
Purkinje fibres. So depolarisation of the bundle branches and Purkinje fibres are
seen on an ECG as the QRS complex. Therefore, a conduction block of the
bundle branches would be reflected as a change in the QRS complex.
With bundle branch blocks there are usually two changes:
1) the QRS complex widens (>0.12 seconds)
2) the QRS morphology changes (varies depending on the ECG lead, and
if it is a right or left bundle branch block)
The QRS complex widens because when the conduction pathway is blocked, it will take longer for the electrical
signal to pass throughout the ventricles.
For right bundle branch block, the wide QRS assumes a unique, virtually diagnostic
shape in those leads overlying the right ventricle (V1 and V2): “rabbit ears”.
For left bundle branch block, the wide QRS complex assumes a characteristic change in
shape in those leads opposite the left ventricle (right ventricular leads - V1 and V2). They
show broad, deep S waves.
Ventricular Fibrillation
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Sybghat Rahim
Blood Vessel Order, Function and Specialisation
by Dr Adrian H Chester
The cardiovascular system comprises the heart, blood vessels and the blood. The functions of the
cardiovascular system are mainly associated with the rapid convective transport of nutrients (such as oxygen,
glucose, amino acids, fatty acids, vitamins and water) as well as wastes (such as carbon dioxide, urea,
creatine). The cardiovascular system is also responsible homeostatic components such as hormone transport,
temperature regulation, etc.
Endothelial cells generate and release a whole range of mediators. For
example:
Nitric oxide: a smooth muscle relaxant. It increases the size of
blood vessels. It can also influence the growth of the smooth
muscle cells with an inhibitory effect. It can increase the blood flow
to myocytes, and can inhibit platelet aggregation.
Prostacyclin: can also cause smooth muscle cell relaxation,
inhibition of growth and also platelet aggregation. Acts
synergistically with nitric oxide.
Thromboxane: contracts smooth muscle cells, reduces blood flow
and stimulates platelet aggregation. Directly opposes nitric oxide
and prostacyclin.
Endothelin-1: very powerful contractile agent to vascular smooth
muscle cells and so reduces blood flow. Also has a weak ability to
stimulate growth of the cells.
Angiotensin II: similar to endothelin, increases contraction and
stimulates growth (production of extracellular matrix) and
therefore reduces blood flow. The matrix production can cause
remodelling and fibrosis in the heart.
All of these are produced at the same time, and so there is a
balancing mechanism so that vasodilation and vasoconstriction can
be controlled by tipping the scale to one side or another as
appropriate.
Nitric oxide
The endothelium has a key role in vascular tone. Nitric oxide, known as the “endothelium-derived relaxing
factor”, is one of the few gaseous signalling molecules known, playing a role in a variety of biological
processes. The endothelium of blood vessels uses nitric oxide to signal the surrounding smooth muscle to
relax, thus resulting in vasodilation and increasing blood flow. It is highly reactive but diffuses freely across
membranes. A signalling molecule that causes the release of NO is acetylcholine in endothelium-dependent
vasodilation. It stimulates L-arginine to be cleaved by endothelial nitric oxide synthase to release nitric oxide,
which then stimulates guanate cyclase, which then stimulates the formation of cGMP, which causes a
2+
decrease in Ca concentration = relaxation.
In blood vessels, there is flow induced vasodilation, as NO is released in response to increased sheer stress.
Vasodilation in the skin is usually due to thermoregulation (temperature change). Penile erection involved
flow mediated dilation of the corpus cavernosus.
Prostacyclin
Both prostacyclin and thromboxane are made by the family of enzymes called cyclo-oxygenase (COX). There
are two cyclo-oxygenase isoforms. COX-1 is associated with healthy maintenance of the cardiovascular system.
COX-2 mediates inflammation and pain. These enzymes act on Arachidonic Acid to synthesise membrane
phospholipids, and via a cascade of intermediates produce prostaglandins and thromboxane.
Although produced by the same enzymes, the molecular structures and the receptor binding of prostacyclin
and thromboxane differ. Prostacyclin receptors are IP receptors, whereas thromboxane receptors are TP
receptors. Prostacyclin activates the cAMP signalling pathway, and thromboxane activates the IP3 signalling
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Sybghat Rahim
pathway. Prostacyclin is a vasodilator, anti-atherogenic and anti-platelet molecule. Thromboxane is a
vasoconstrictor, pro-atherogenic and pro-platelet molecule.
Endothelin
Endothelin is a 21 amino acid polypeptide. It can be stimulated by
a whole range of different inflammatory mediators or
compounds that control vascular tone (adrenaline, angiotensin II,
vasopressin, steroids, IL-1, etc) and can be counter-acted by a
range of molecules (prostacyclin, nitric oxide, heparin, etc).
When stimulated it relies on synthesis within the endothelial cell by stimulation of the prepro-endothelin-1
mRNA gene. Prepro-endothelin-1 goes through a series of steps to form endothelin-1, which is released by the
cell and acts on the underlying smooth muscle cells. There are ETA and ETB receptors. The ETA receptor
mediates smooth muscle cell contraction, and the ETB receptor is present on endothelial cells, and promotes
the release of nitric oxide in a self-limiting mechanism (negative feedback) and also mediates smooth muscle
cell contraction. It is a potent vasoconstrictor, and so inhibiting the ET-1 pathway should produce vasodilation.
ACE and Angiotensin II
Angiotensin II is made from angiotensin I by
the action of angiotensin converting enzyme
(ACE), which is found predominantly in the
lung capillaries. Angiotensin I is formed by
the action of renin from a longer polypeptide
angiotensinogen. Bradykinin is also broken
down by ACE, which can mediate the release
of nitric oxide.
Angiotensin II has a whole range of effects as
an endocrine, autocrine and paracrine
hormone throughout the body:
Cardiovascular effects
o vasoconstrictor
Neural effects
o thirst sensation
o decrease baroreflex
o secretion of vasopressin
o secretion of ACTH
Adrenal effects
o aldosterone release
Renal effects
+
o increase Na reabsorption
o increase glomerular capillary hydrostatic pressure
Adrenergic Hormones
Noradrenaline and adrenaline can come from sympathetic nerve
endings or the adrenal glands, contributing to circulating and locally
released levels of catecholamines.
Adrenaline stimulates a whole range of adrenergic receptors - α1 and 2, and also β1 and 2 in vascular smooth
muscle cells. These receptors have differing effects on different tissues. Adrenaline can cause an increase in
the systolic blood pressure, contractility of the heart, and heart rate. It also causes vasoconstriction in the
arterioles of the skin, mucosa and intestinal blood vessels (splanchnic areas). In the skeletal muscles, it causes
dilatation as a first-line response to stress. It does this because it acts on different receptors in these different
locations of the body. There are well characterised chronotropic and inotropic effects on the heart.
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Sybghat Rahim
Noradrenaline is an agonist of α and β1 adrenergic receptors. It principally causes vasoconstriction. Circulating
levels come from spill-over from sympathetic nerve terminals and from adrenal medullary cells. Noradrenaline
exerts direct positive inotropic and chronotropic effects in the heart. Hypertension is caused by increasing
peripheral vascular resistance.
Aspirin
Inhibits the COX system, and therefore blocks the synthesis of prostacyclin and thromboxane. With low dose
aspirin daily over a period of time, prostacyclin levels drop but then remain constant. Thromboxane levels
drop until 70% inhibited, and so the balance is tipped in favour of prostacyclin. The endothelial cell that
releases prostacyclin is nucleated and so can make new proteins as and when needed. If a little bit of COX is
inhibited each day, the cell can make a bit more and maintain the level of prostacyclin release. Platelets
(principle source of thromboxane) don’t have a nucleus, so once the enzyme is inhibited, that’s it!
Nitric oxide drugs
Drugs that are classified as NO donors (such as nitroglycerine and nitroprusside) supply nitric oxide. eNOS
activators (such as endothelium-dependent vasodilators) stimulate nitric oxide. Phosphodiesterase inhibitors
(such as Viagra and Zaprinast) prevent nitric oxide breakdown by preventing the breakdown of cGMP.
β-Blockers
Beta-blockers are able to inhibit the binding of adrenaline and noradrenaline to β-receptors. They prevent
the normal ligand from binding to the beta-adrenoreceptor by competing for the binding site. The heart has
both β1 (predominant) and β2 receptors, and so cardiac effects are blocked. Vascular smooth muscle has β2
receptors (normally activated by noradrenaline released by sympathetic adrenergic nerves or by circulating
noradrenaline), and so vascular effects are blocked.
β1-blockers are “cardioselective”. They can decrease contractility (negative inotropy), decrease relaxation
rate, decrease heart rate (negative chronotropy), and decrease conduction velocity. Therapeutic use of βblockers can therefore be for hypertension, angina, myocardial infarction, arrhythmias and heart failure, as
these drugs lack the vascular effects of β2 receptor blockade.
All of the mentioned compounds ultimately regulate the release of calcium from a cell to induce relaxation or
contraction. Calcium entry into cells is regulated by calcium channels in the plasma membrane. Therefore,
compounds that block the calcium channels (such as dihydropyridines like Nifedipine or phenylalkylamines
like Verapamil) can also be of use in the regulation of vascular tone (non-specific). The vasodilation reduces
afterload (cardiac output increases). Negative inotropic effects occur (decreased work done by the heart), and
oxygen demand is also reduced. They prevent coronary artery vasospasm, which makes them very useful in
the treatment of variant angina.
Drugs that have ability to block β2 receptors as well may cause vasoconstriction and/or bronchoconstriction.
Voltage-gated calcium channels mediate calcium influx in response to membrane depolarisation. They
regulate intracellular processes such as contraction, secretion, neurotransmission and gene expression.
Activity is essential to couple electrical signals in the cell surface to physiological events in cells. Their affinity
for the channel is directly related to the membrane potential of the target cells. By blocking calcium entry into
a smooth muscle cell, vasodilatation can be caused and this reduces the afterload on the heart and cardiac
output will increase (higher negative potentials). There can also be a negative inotropic effect on myocytes to
decrease the work done by the heart and decrease the oxygen demand (lower negative potentials).
Dihydropyridine calcium channel blockers are often used to reduce systemic vascular resistance and arterial
pressure, but are not used to treat angina because the vasodilation and hypotension can lead to reflex
tachycardia.
Why do Drugs have Side Effects?
Our body often uses the same chemical to regulate more than one process, and there is always interaction
between different systems in the body. Unfortunately, drugs are not always as selective. There is just tissue
specific distribution of receptors. It is also a fact that two people taking the same medicine can have very
different experiences.
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Sybghat Rahim
Viagra was originally developed as an anti-hypertensive, but there were some interesting side effects. Viagra
was much more selective for inducing penile erection rather than lowering blood pressure. This is because
Phosphodiesterase enzymes aren’t all the same - there are 5 types of the enzyme and expression varies
between tissues. In the corpus cavernosum, there is phosphodiesterase 5, and Viagra is selective for that
particular enzyme.
Patients prone to asthma may get attacks when they take aspirin. This is because if COX-1 and COX-2 are
blocked, then the metabolism of arachidonic acid is shunted towards an alternative pathway to produce
leukotrienes which causes asthma in 3 to 5% of patients.
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Sybghat Rahim
Mechanical Properties of the Heart 2
by Dr Ken MacLeod
In the cardiac cycle, the heart beat is divided into two main phases: diastole and systole. Diastole is ventricular
relaxation during which the ventricles fill with blood. This is split into four sub-phases. Systole is ventricular
contraction when blood is pumped into the arteries. This is split into two sub-phases.
The cardiac cycle is a description of mechanical and electrical events, volume changes and sounds associated
with the heart beat.
Atrial systole
Just prior to atrial systole blood flows passively through the open atrioventricular valves. The atria contract,
“topping off” the volume of blood in the ventricles. Atrial contraction is complete before the ventricle starts.
As the atria contract, there is increased pressure in the atria and blood is pushed back up the jugular vein
causing the first discernable wave in a jugular venous pulse.
It is the sino-atrial node activation which depolarises the atria. On an ECG, the P wave is atrial depolarisation.
th
Sometimes a 4 heart sound can be heard during this time. It is an abnormal sound, and occurs with
congestive heart failure, pulmonary embolism or tricuspid valve incompetence.
Isovolumic contraction
This is the interval between the atrioventricular valves closing and the semi-lunar valves opening. During this
time, the ventricles are isolated from the rest of the circulation. There is then contraction of the ventricles with
no change in volume. The atrioventricular valves close as ventricular pressure exceeds the atrial pressure.
Pressure in the ventricles increases without a volume change and approaches aortic pressure.
st
On an ECG, the QRS complex marks ventricular depolarisation. The 1 heart sound (lub) can be heard due to
closure of the atrioventricular valves and associated vibrations.
Rapid ejection
Aortic and pulmonary valves open and mark the start of this phase. As the ventricles contract, pressure within
them exceeds the pressure in the aorta and pulmonary arteries. The semi-lunar valves open and blood is
pumped out and volumes in the ventricles decrease. Right ventricular contraction pushes the tricuspid valve
into the atrium and creates a small pressure into the jugular vein.
Reduced ejection
This phase marks the end of systole. Aortic and pulmonary valves begin to close. Blood flow from the
ventricles decreases and the ventricular volume decreases more slowly. As pressures in the ventricles fall
below that in the arteries, blood begins to flow back causing the semi-lunar valves to close.
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Sybghat Rahim
On an ECG, the T wave is due to
ventricular repolarisation marking the
end of ventricular systole.
Isovolumic relaxation
This is the beginning of diastole. The
aortic and pulmonary valves have now
just shut. The atrioventricular valves
remain closed until the end of this
phase. The atria have now filled with
blood, but the atrioventricular valves
have shut, so the atrial pressure rises.
Blood pushing the tricuspid valve gives
a second jugular pulse. There is also a
rebound pressure against the aortic
valve as the distended aortic wall
relaxes.
nd
The 2 heart sound is heard (dubb)
when the aortic and pulmonary valves
close.
Rapid ventricular filling
Once the atrioventricular valves open,
blood in the atria flows rapidly into the
ventricles. The ventricular volume
increases and atrial pressures fall. The
rd
presence of a 3 heart sound is usually
abnormal and can signify turbulent
ventricular filling. This “gallop” can be
due to severe hypertension or mitral
valve incompetence.
Reduced ventricular filling
This phase can be called diastasis.
Ventricular volume increases more
slowly.
The diagram on the right is the Wiggers
Diagram.
Pulmonary Circulation Pressures
The patterns of pressure changes in the right heart are essentially identical to those of the left. Quantitatively,
the pressures in the right heart and pulmonary circulation are much lower (peak of systole - 25mmHg in
pulmonary artery). Despite the lower pressures, the right ventricle ejects the same amount of blood as the left.
Systemic and pulmonary circulations have different pressures - 120/80 vs 25/5 mmHg.
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Sybghat Rahim
The Pressure-Volume Loop in the Heart
Left ventricular pressure and left ventricular volume can be
represented graphically.
Starting at point 1 (end diastolic volume), there is a low ventricular
pressure. At point 2, there is the period of isovolumic contraction
where the pressure rises, but there is no change in volume. As the
aortic pressure is reached and exceeded, blood is ejected and point
3 is reached (end systolic volume). Pressure in the ventricle drops
again with no volume change, and this takes the line to point 4. The
heart is then filled with blood again with little change in pressure,
back to the end diastolic volume.
Blood filling the ventricle during the diastolic period determines the preload (the
stretch on the resting ventricle). The blood pressures seen at point 2 determine
the afterload, as these are the pressures in the great vessels.
Increasing preload increase the stroke volume, and increasing afterload
decreases stroke volume. This is because as afterload increases, the amount of
shortening that occurs decreases.
Cardiac output = heart rate x stroke volume
↘
preload, afterload, contractility
Contractility is the contractile capacity (strength of contraction) of the heart. A
simple measure of cardiac contractility is ejection fraction. Contractility is
increased by sympathetic stimulation. There is a family of different FrankStarling relations as cardiac contractility changes.
During exercise, contractility is increased due to increased sympathetic activity.
During exercise end diastolic volume is increased due to changes in peripheral
circulation (venoconstriction and muscle pump).
30
Sybghat Rahim
Blood Vessels and Flow
by Professor Alun Hughes
The primary role of the circulation is to deliver oxygen and nutrients and to remove metabolites and carbon
dioxide. This achieved by the simple device of connecting a pump to a system of branching pipes which
converge at the pump to complete the circuit. The pump (heart) generates a pressure gradient that drives bulk
flow of blood through the network of blood vessels. At the capillary level, gas and nutrient exchange is
accomplished by diffusion. This means that for exchange to work effectively no cell should be further than
10m from a capillary. These considerations impose a number of limitations on circulatory design and from a
fluid dynamics perspective the circulation is extremely complex.
In reality the circulatory system consists of two such circuits both
originating and terminating in the heart. Blood is pumped by the
right heart through the low resistance pulmonary circulation to
the left heart. En route the blood is oxygenated. The left heart
then pumps blood through the systemic circulation which
supplies the tissues and returns blood to the right heart.
The structure of vessels is highly appropriate for their function
e.g. large elastic arteries act as conduits and dampening vessels,
while muscular arteries and arterioles have extensive smooth
muscle in their walls so they can regulate their diameter and the
resistance to blood flow. While capillaries are very numerous
and have very thin walls to facilitate transport and diffusion and
veins are highly compliant and act as a reservoir for blood
volume.
The circulation has exchange function as well as reservoir
function. The diameter of the blood vessels changes dramatically
from the aorta (25mm in man) to the capillaries (5m =
0.005mm). As a result of the change in diameter and the
expansion of components of the vascular system due to branching there are large changes in the crosssectional area of the vasculature at different levels. There are billions of capillaries and this resents by far the
largest cross-sectional area of the circulation. Capillary beds present a huge surface area for exchange to take
place. Although the volume in a single capillary is tiny, the equivalent of the whole cardiac output passes
through the capillary bed every minute. The majority of blood volume is contained within the venous part of
the circulation. Regulation of the capacitance of the veins and venules regulates how much blood is stored
and influences venous return to the heart and ventricular work via the Frank-Starling effect in the heart.
Why does blood flow?
The diagram on the right is a very simple model of the circulation
but it is useful in understanding how the system works. It assumes
that the action of the heart (pump) has established a pressure in
the tank (the aorta) equivalent to 8 ft of water (as measured by
Hales in 1733). This drives a steady flow (Q) through the
circulation. The branching vessels of the circulation are simplified
into a single long rigid pipe for the purposes of this model.
Pressure drops along this pipe due to viscous losses of energy
(friction), so that the pressure measured at the end (P2) is lower
than at P1 – this pressure difference drives the flow (Q). At the end
of the circulation the system empties into the right atrium of the heart which is almost at atmospheric
pressure.
In its simplest form the circulation can be equated to an electrical circuit. The pressure difference (P) is
equivalent to the potential difference (V); the fluid flow (Q) is equivalent to current flow (I) and the fluid
resistance (R) equates to the electrical resistance (R). Ohm’s law can be used to describe the relationship
between V, I and R or P, Q and R.
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Sybghat Rahim
The haemodynamic determinants of mean blood pressure
In the circulation (systemic & pulmonary) Ohm’s relationship between pressure, flow and resistance can be
restated in physiological terms as:
Mean Blood Pressure = Cardiac Output x Peripheral Vascular Resistance
This relationship is an approximation since flow in the circulation is not steady (due to the intermittent
pumping of the heart) and blood vessels are not rigid. Nevertheless it is a simple and useful relationship which
is applicable in many situations. The relationship between pressure and flow can be used to estimate the
resistance of the circulation using estimates of cardiac output as bulk flow/unit time and the difference
between mean arterial and venous pressure as the pressure drop across the circulation. It is pressure drop not
absolute pressure itself that drives flow. If this is done for the systemic and pulmonary circulation then it is
clear that the resistance of the pulmonary circulation is substantially less than the systemic. Physiologically,
regulation of flow is achieved by variation in resistance while blood pressure remains relatively constant.
Pressure is not constant in the circulation. It falls due to
the resistance to blood flow provided by the blood
vessels.
The magnitude of oscillation in pressure (pulse pressure)
is damped in the smaller arteries and arterioles. The
major site of resistance (i.e. major region of pressure
drop) is in small muscular arteries (<0.5mm internal
diameter) and arterioles.
The pulmonary circulation operates at lower pressures
but shows a broadly similar distribution of pressure
across the difference components of the circulation.
Why is there resistance to blood flow?
In the normal circulation flow is laminar, i.e. the fluid behaves as if it flows in layers or streamlines. Laminar
flow can be demonstrated by injecting a dye into fluid, showing the existence of a clearly defined streamline.
Dynamic viscosity (μ) is a measure of the resistance of a fluid to deform under shear stress. Resistance arises
as a result of the resistance due to friction between fluid laminae moving at different velocities.
A force per unit area (the pressure difference) is needed to move the fluid in opposition to viscosity. The flow
velocity on the surface of the vessel wall is zero (so called no slip condition) but in a flowing fluid, the velocity
of each lamina increases progressively as you move further way from the wall. The spatial velocity gradient is
called the shear rate and the shear rate multiplied by the dynamic viscosity is the shear stress. The shear stress
near the wall is believed to be an important influence on endothelial function in health and disease (e.g. the
development of atherosclerosis).
What accounts for resistance is Poiseuille’s Law and vessel calibre. Experiments performed by Jean Poiseuille
(1797-1869) in long glass tubes began to show the relationship between pressure and laminar flow (i.e.
resistance) in long straight tubes. Subsequently the theoretical basis of this relationship was derived by
Wiedman, and Neumann and Hagenbach. The resistance to flow in a long straight rigid tube depends on the
viscosity of the fluid (μ), the length of the tube (L) and the radius of the tube (r) and is described by
Poiseuille’s equation:
Resistance = 8 L/  r
4
This equation emphasises the importance of arterial diameter as a determinant of resistance. Consequently
relatively small changes in vascular tone (vasoconstriction/vasodilatation) can achieve marked changes in
flow. A striking example of this is during exercise where dilation of the arteries and arterioles feeding skeletal
muscle results in a 30fold increase in muscle blood flow.
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What is the effect of blood pressure on the vessel wall?
Pressure difference between two locations in the circulation is
important for flow, but the pressure inside the vessel (transmural
pressure) determines the distension of the vessel wall. The
relationship between transmural pressure and wall tension is
determined by Laplace’s law. This and the wall thickness
determine the circumferential stress. In extreme cases over a
prolonged period in a weakened vessel high circumferential
stress can cause a balloon like distension (aneurysm) or even
rupture.
Compliance properties of arteries and veins
The elastic properties of blood vessels depend mainly on
structural proteins, elastin and collagen. Elastin is much more
distensible than collagen. The combination of elastin and
collagen in vessels results in a non-linear relationship between
vessel pressure and volume (i.e. non-linear compliance).
The elastic properties of arteries and veins differ and this is
important for their function. Veins are highly compliant at low
pressures while arteries are compliant over a wider pressure
range. This means that relatively small changes in venous
pressure distend veins and increase the volume of blood stored
in them. This is important when the pressure in veins changes
for example on standing.
In man the venous reservoir is not always at the same level as the heart. On standing gravity increases
pressure in the lower limbs (80mmHg). Since veins are compliant this increases the volume of blood in these
vessels and (transiently) reduces the venous volume returning to the heart. This would reduce cardiac output
and blood pressure if there were no compensatory response.
The effect of gravity and posture affects the transmural pressure in all vessels, but at any particular location
the gradient of pressure from large artery to capillary to vein is maintained so flow still occurs in the same way.
The major effect of gravity is on the distensible veins in the leg and the volume of blood contained in them.
A number of mechanisms act to limit the effect of blood pooling in the lower limb veins on the circulation.
Veins act as an important reservoir for blood. This is because despite the low pressures, vein walls are
relatively thin and compliant therefore they accommodate large volumes of blood (2/3 total blood volume) at
low pressures. This reservoir/compliance function is physiologically regulated. Vein walls, although thin, do
contain smooth muscle. The role of this muscle is not to narrow venous diameter and affect resistance (as it
does in small arteries), but to stiffen the wall i.e. reduce compliance. Stimulation of the sympathetic nervous
system which innervates this smooth muscle (noradrenaline acting via α adrenoceptors) therefore reduces
venous compliance and hence increases venous return to the heart. This is an important site of action of the
sympathetic nervous system and contributes to reflex responses to standing and haemorrhage.
Return of blood to the heart during upright posture is assisted by the contraction of skeletal muscle in the
lower limb which compresses veins within the muscle and forces blood back to the heart. This is called the
muscle pump.
Another mechanism called the respiratory pump also assists venous return. During respiration expansion of
the chest and diaphragm causes a negative pressure within the thorax which effectively sucks blood into the
central veins by reducing the extra-vascular pressure in the thorax and increasing it in the abdominal cavity.
Both the skeletal and respiratory pumps depend on the presence of valves in the veins outside the chest to
prevent retrograde flow.
Incompetent calves cause dilated superficial veins in the leg (varicose veins). Prolonged elevation of venous
pressure causes oedema in the feet.
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Sybghat Rahim
Pulsatility and arterial compliance
Conventionally blood pressure measurements are made in the
arm. Blood pressure varies over the cardiac cycle with a peak in
systole and a minimum in diastole. The systolic (SBP) and diastolic
pressure (DBP) are usually recorded in clinic as SBP/DBP (e.g.
110/70). Values of blood pressure vary widely in a community.
High levels of blood pressure are termed hypertension.
The ability of the aorta and the elastic arteries to buffer or damp the oscillation in blood pressure is often
termed a Windkessel (German for air chamber) after the device used in early fire-engines.
In systole more blood is ejected into the aorta and large elastic
arteries than leaves them. This distends these vessels. In effect
some of the pressure energy generated in systole is converted to
elastic energy in the artery wall which is stored during systole.
Once the heart ceases ejection and the aortic valve closes, pressure
starts to fall. Consequently the walls of the aorta and elastic
arteries recoil and the elastic energy is reconverted into pressure
and the stored volume is discharged. This process damps the
magnitude of pressure change and accounts (to a large extent) for
the diastolic component of arterial pressure. It also accounts for
the maintenance of flow in the microcirculation during diastole. If
arterial compliance is reduced (i.e. arteries get stiffer e.g. with age)
then this mechanism is less able to damp the fluctuation in
pressure and pulse pressure increases.
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Sybghat Rahim
Sympathetic Nervous System and Renin-Angiotensin System
by Dr Mike Schachter
Most of the sympathetic outflow to the rest of the body comes from the spinal cord - particularly from the
thoracic spinal cord and some from the upper lumbar part. This is all ultimately controlled and influenced by
factors much higher up in the central nervous system, e.g. in the medulla of the brain and to some extent
beyond that (conscious response to stress).
One important aspect of autonomic cardiovascular control is focussed on baroreceptors. Arterial
baroreceptors respond to changes in pressure, and changes in distension of the blood vessels (particularly the
carotid sinus and aortic arch). Increasing stretch of the vessels corresponds to increasing blood pressure. The
purpose of the receptors is to respond to changes in blood pressure so that a decrease in blood pressure
causes an increase in sympathetic nervous activity. On the other hand if the blood pressure goes too high,
there is activation of the parasympathetic system to lower blood pressure. The overall purpose is to maintain
blood pressure and cardiac output.
Autonomic effector nerves control and regulate effector organs such as vascular
smooth muscle. Adrenergic receptors are present on the effector organs, where the
sympathetic nerve endings release noradrenaline. Adrenaline is a hormone that is
not produced by nerves, but the adrenal medulla is technically a sort of modified
sympathetic ganglion (producing adrenaline in preference to noradrenaline).
Noradrenaline is generated from dopamine, and there is a system for inactivating
the transmitter by uptake into the neurone and the effector organ. Any transmitter
that is released is indeed limited by inactivation both pre-synaptically and postsynaptically - a very carefully regulated process.
Synthesis of adrenaline and noradrenaline occurs in the terminal varicosity
of a sympathetic nerve. A vesicle which contains the transmitter fuses with
the plasma membrane, and there is a channel opening from the vesicle into
the outside world so the neurotransmitter is released. It is actively
expelled, and it requires ATP to release the transmitter. The process of
reuptake ensures the neurotransmitter that is not destroyed is recycled.
There is a constant process of synthesis, recycling and reuptake, which
maintains (under normal circumstances) the quantity of noradrenaline in
the sympathetic nerves.
There are two main ways to remove the noradrenaline from
the synapse. Neuronal uptake is called uptake 1. Extraneuronal
uptake is called uptake 2, usually into the effector organ.
Uptake 1 tends to be a recycling process, whereas uptake 2 is
an inactivation process where the transmitter is broken down.
Two enzymes are responsible for this: catetechol-O-methyltransferase (COMT) and monoamine-oxidase (MAO).
Adrenoceptors is the name given to all receptors which interact with adrenergic transmitters such as
adrenaline or noradrenaline. There are two groups of effects. Excitatory effects on smooth muscle (αadrenoreceptor mediated), and relaxant effects on smooth muscle but stimulatory effects on the heart (βadrenoreceptor mediated).
β1-adrenoceptors are located on cardiac muscle and the smooth muscle of the gastrointestinal tract. β2adrenoceptors are located on bronchial, vascular and uterine smooth muscle. β3-adrenoceptors are found on
fat cells and possibly on smooth muscle of gastrointestinal tract.
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Sybghat Rahim
α1-adrenoceptors are located post-synaptically i.e. predominantly on effector cells. This is important in
mediating constriction of resistance vessels in response to sympathetic vasoconstriction. α2-adrenoceptors are
located on pre-synaptic nerve terminal membranes. Their activation by released transmitter causes negative
feedback inhibition of further transmitter release. Some are post-synaptic on vascular smooth muscle, and
also mediate vasoconstriction.
The α1 receptor is a classical calcium-dependent receptor. It is linked to G proteins, which are in turn linked to
phospho-lipase C, which in turn release phosphate, which release calcium. Calcium is the lead mediator for
muscle constriction.
β receptors and α2 receptors are different, as they are linked to cyclic AMP. β receptors increase levels of
cAMP, and in smooth muscle this leads to relaxation, as cAMP is an antagonist of calcium. In the heart, cAMP
actually increases calcium and therefore increases heart rate and contractility. In most cases however, cAMP is
considered a relaxant, as an inhibitor transmitter. α2 receptor activation inhibits cAMP synthesis, and this
directly increases calcium levels.
Cardiovascular effects of catecholamines in man:
Isoprenaline is a synthetic compound - a pure β agonist.
Noradrenaline is predominantly an α agonist and
adrenaline is a bit of both. Noradrenaline decrease heart
rate due to a reflex effect from vasoconstriction, which
activates baroreceptors to slow the heart.
Adrenaline lowers diastolic pressure because it causes
peripheral dilatation in some muscle beds. There is a rise in
heart rate due to the direct effect of adrenaline via β
receptors.
So noradrenaline and adrenaline have opposing effects on heart rate but similar effects on mean blood
pressure.
Isoprenaline causes no vasoconstriction; it causes vasodilatation which leads to decreased diastolic blood
pressure. It causes some increase in systolic pressure because of its direct effect on the heart, activating
contractility. This is why the heart rate goes up quite strongly. The effects of all three of these can be
measured with blood pressure.
Noradrenaline: α1, α2, β1
Adrenaline: α1, α2, β1, β2
Dopamine: α1, β1 (weak effects, has its own receptors)
Isoprenaline: β1, β2
Phenylephrine: α1
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Sybghat Rahim
Regulation of the Cardiovascular System
by Dr Ken MacLeod
Stroke volume = end diastolic volume - end systolic volume
Cardiac output = heart rate x stroke volume
Mean systemic arterial pressure = cardiac output x total peripheral
resistance
The design of the cardiovascular system is such that there are systemic
and pulmonary circulations. Blood is pumped from the right heart to the
lungs back to the left heart.
Veins are vessels that have capacitance. Venous volume distribution is
affected by peripheral venous tone, gravity, skeletal muscle pump and
respiratory pump (breathing). Central venous pressure (mean pressure
in the right atrium) determines the amount of blood flowing back to the
heart. The amount of blood flowing back to the heart determines stroke
volume (using Starling’s Law of the heart).
Flow Control
In veins, constriction determines compliance and venous return. In arterioles, constriction determines blood
flow to organs they serve, mean arterial blood pressure and the pattern of distribution of blood to organs.
Flow is changed primarily by altering vessel radius.
F = ΔP
R
R=1
4
r
There are various ways in which blood flow is regulated. There are local mechanisms, intrinsic to the smooth
muscle itself or closely associated. There is systemic regulation in the form of hormones, and there is also the
influence of the autonomic nervous system.
Local Mechanisms Regulating Blood Flow
Autoregulation is the intrinsic capacity to compensate for changes in perfusion pressure by changing vascular
resistance.
Myogenic theory is that smooth muscle fibres respond to tension in the
vessel wall - as pressure rises muscle fibres contract. Stretch sensitive
channels are involved.
Metabolic theory is that as blood flow decreases, “metabolites”
accumulate and vessels dilate. When flow increases, “metabolites” are
+
+
washed away, e.g. CO2, H , adenosine, K .
Substances released from the endothelium:
Nitric oxide (endothelium derived relaxing factor) synthesised
from arginine and plays a key role in vasodilation.
Prostacyclin and thromboxane (vasodilator and vasoconstrictor)
relative amounts are important for clotting.
Endothelins (potent vasoconstrictors).
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Sybghat Rahim
Systemic Regulation of Blood Flow by Hormones
Circulating hormones affecting the vascular system:
Kinins: e.g. bradykinin, have complex interactions with renin-angiotensin system to relax vascular
smooth muscle.
ANP: atrial natriuretic peptide, secreted from the cardiac atria is a vasodilator.
Circulating vasoconstrictors: ADH (vasopressin) secreted from posterior pituitary, noradrenaline
released from adrenal medulla, angiotensin II formed by increased renin secretion from kidney.
The Autonomic Nervous System
Sympathetic nerve fibres innervate all vessels except capillaries and precapillary sphincters and some
metarterioles. Large veins and the heart are also sympathetically innervated. Distribution of sympathetic fibres
is variable. There are more innervating vessels supplying the kidneys, gut, spleen and skin and fewer
innervating the skeletal muscle and brain.
The vasomotor centre (VMC) in the brain is located bilaterally in
the reticular substance of the medulla and the lower third of the
pons. The VMC is composed of a vasoconstrictor area, a
vasodilator area and a cardioregulatory inhibitory area.
The VMC transmits impulses distally through the spinal cord to
almost all blood vessels. Many higher centres of the brain such as
the hypothalamus can exert powerful excitatory or inhibitory
effects on the VMC.
Lateral portions of the VMC controls heart activity by influencing
heart rate and contractility.
The medial portion of the VMC transmits signals via the vagus
nerve to the heart that tend to decrease heart rate.
All blood vessels receive sympathetic post-ganglionic innervation.
The transmitter is noradrenaline. There is always some level of
tonic activity. Control of nerve activity can accomplish dilation or
constriction. Generally, there is no parasympathetic innervation
to the vascular system.
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Sybghat Rahim
Cardiac innervation has a number of different mechanisms. For example, increased activity of sympathetic
nerves to the heart, increased plasma adrenaline, or decreased parasympathetic activity to the heart will all
cause a rise in heart rate.
The force of contraction is ultimately
controlled by calcium ions.
In both cardiac and skeletal muscle, the
force-generating molecular motors
(crossbridges) are turned on by increasing
the intracellular free calcium level that
regulates the troponin-tropomyosin system.
The force of contraction can be controlled
2+
2+
by increasing Ca influx or Ca uptake into
intracellular stores increased.
Stroke volume can be increased in a
number of ways, for example, by
increasing sympathetic innervation of the
heart and by increasing plasma
adrenaline. These are extrinsic controls.
Intrinsic controls involve increasing end
diastolic ventricular volume. This can be
done by increasing atrial pressure,
increasing venous return or increasing
respiratory movements to create a low
intrathoracic pressure.
Feedback
Baroreceptors detect changes in stretch in arteries such as the aortic arch and the carotid sinus. The
baroreceptors fire signals to the vasomotor centre in the medulla oblongata via the vagus nerve and the
glossopharyngeal nerve.
Carotid sinus baroreceptors respond to pressures between 60 and 180mmHg. Baroreceptors respond to
changes in arterial pressure. Baroreceptor reflex is most sensitive at pressures around 90 to 100mmHg.
Reciprocal innervation involves an afferent input which stimulates parasympathetic nerves to the heart and
simultaneously inhibits sympathetic innervation to the heart, arterioles and veins. Increased parasympathetic
stimulation of the heart decreases the heart rate. Decreased sympathetic stimulation of the heart decreases
the heart rate and stroke volume.
Venous Return
The regulation of venous return can be achieved by controlling venous pressure.
Venous pressure can be increased in a number of ways, e.g. increasing blood
volume, respiratory movements, sympathetic activity and by using the skeletal
muscle pump. Increasing venous pressure increases venous return and this in
turn has an effect on atrial pressure and end-diastolic volume.
39
Sybghat Rahim
40
Sybghat Rahim
Cardiovascular Stress
by Dr Chris John
Cardiovascular stress is applicable in change of posture, haemorrhage and exercise.
Change of posture
The problem for the cardiovascular system going from a sitting or lying (supine) to standing position is a severe
challenge to human circulation. The problem is the addition of gravity to the situation.
Going from a supine position to a vertical position, the standard mean arterial pressure (95-100mmHg) in the
body is altered by gravity as you go away from the heart. Gravity pushes down on the column of blood, and
therefore the pressure in the head is reduced, and the pressure in the feet is increased. The blood pressure in
the arteries supplying the feet is considerably greater than the pressure generated by the heart itself. This is
then a problem when this blood is to return to the heart.
The pressure in the feet is less when it enters the veins. The venous pressure in the head is negative, as gravity
simply forces the blood back down to the heart. Venous pressure in the lower limbs is going to take a lot of
effort to get the blood back to the heart. For example, in a foot capillary, the usual pressure resulting from
cardiac contraction is 25mmHg, but the added effect of gravity on the column of blood is 80mmHg.
The result is an increased hydrostatic pressure in the blood vessels of
the legs. As the blood enters the venous system at high pressure, there
is venous distension. This means blood effectively pools in the legs as
the veins stretch to maintain the blood at high pressure, but this makes
it more difficult to get it back up to the heart.
Another problem of increased hydrostatic pressure (forcing fluid out of
the capillaries into the interstitium) with added gravity is that there is a
lot more fluid leaving the capillaries further away from the heart
downwards. In the feet, a fair amount of fluid is lost from the capillaries into the interstitium. The end result is
a reduction in the effective circulating blood volume as a lot of the volume is lost into the interstitium, as the
oncotic pressure normally drawing the fluid back into the blood is not sufficient.
Starling’s Law states that ventricular filling during diastole (end diastolic volume) determines the volume of
blood ejected during systolic contraction (stroke volume). If a large amount of blood is being maintained
within the distended veins in the legs and if fluid is also lost via the capillaries in those regions, then the
amount of blood that can be returned to the heart is reduced. If this is the case, then there is a lower end
diastolic volume and hence a reduced stroke volume. This leads to a drop in blood pressure - transient
hypotension.
Feelings of dizziness during transient hypotension quickly pass as there are compensatory mechanisms that
deal with the problems. The first mechanism relates to arterial baroreceptors (mainly in the carotid sinus and
within the aortic arch). These are nerve endings that protrude out into the blood flow. They are predominantly
stretch receptors, responding to the stretch of the arteries. The higher the pressure, the more the
baroreceptors fire; and the lower the pressure, the less they fire. The baroreceptors are exceptionally sensitive
around the mean arterial pressure, so any increase or decrease here will be detected and responded to
accordingly with an increase in firing rate (to raise BP) or fall in firing rate (to lower BP).
Arterial baroreceptors send afferent nerves to the medulla in the brain, innervating the cardiovascular control
centre. The cardiovascular control centre takes that information and passes it on to the autonomic nervous
system. Baroreceptor firing mechanisms preserve blood pressure by influencing sympathetic or
parasympathetic discharge.
The secondary compensatory mechanism to transient hypotension is an increased sympathetic discharge. The
firing rate of the baroreceptors decreases, which causes the loss of the parasympathetic drive. An increased
sympathetic discharge increases the heart rate, increased contractility, increased splanchnic/renal
vasoconstriction, and veno constriction in the legs to try to return the blood to the heart.
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Sybghat Rahim
Haemorrhage
The problem here is a reduction in the actual circulating blood volume. Again, the body tries to compensate for
the loss of blood to preserve blood pressure, particularly in the brain and heart. The mechanisms are very
similar for change of posture. Baroreceptor rate falls massively, which leads to increased heart rate and
increased contractility. There is massive organ specific vasoconstriction, e.g. in the skin, to centralise the blood
to preserve the pressure.
There are extra compensatory mechanisms with regards to haemorrhage. If there is significant blood loss, then
the hydrostatic pressure in the capillaries falls, so the amount of fluid going into the interstitium is reduced. On
average the pressure difference at the arteriolar end is about 34mmHg and about 17mmHg at the venular end.
After haemorrhage, these values fall markedly and the hydrostatic pressure falls massively. But there is still the
colloid osmotic pressure that draws fluid out of the interstitium back into the blood. In a normal individual the
balance between ultrafiltration and reabsorption is tipped more towards ultrafiltration. In someone who has
undergone haemorrhage, reabsorption is the predominant force in the capillaries, which is known as
autotransfusion. The blood bulks up using the fluid from the interstitium. Although the erythrocytes are not
replaced, increasing blood volume will help to preserve pressure.
Other compensatory mechanisms include hormone-driven decrease in urinary output (activation of the reninangiotensin system). As blood pressure falls, the reduced renal blood flow stimulates the production of renin,
and so eventually the production of angiotensin II, which is a powerful vasoconstrictor, particularly in the
kidney. Increased aldosterone production will promote sodium and water retention, and also the stimulation
of ADH secretion will lead to water retention in the kidneys. All these factors act to prevent fluid loss and
preserve blood pressure.
The body can cope with less than 10% of blood loss (about 500ml), and there will be no noticeable change in
blood pressure. If the body loses up to 30% of blood, there will be a fall in blood pressure but survival is highly
likely. Above 30% blood loss, blood has to be redirected away from certain organs which results in shock,
where certain tissues aren’t receiving adequate blood supply. Fluid resuscitation is the best course of action
when dealing with haemorrhage.
Exercise
The problem here is that it is necessary to increase blood flow to the heart and skeletal muscles. By increasing
blood flow, there is going to be a massive fall in total peripheral resistance. In theory, exercise should be
associated with a fall in blood pressure, but clearly it is not. This is the challenge for the cardiovascular system increasing blood flow to tissues whilst preserving and maintaining blood pressure.
As the skeletal muscle and the heart start to work harder, they use up more oxygen and generate more waste
products, which is detected locally and causes profound vasodilation within the arterioles of that tissue. This is
the process of active hyperaemia.
There are control mechanisms by which the cardiovascular system maintains the blood pressure. The “preprogrammed pattern” is a system whereby the medullary cardiovascular centre starts to adapt to the exercise
even before exercise has started - an anticipatory pre-programmed effect. This signal increases sympathetic
outflow. On top of this, once the exercise starts, the muscle chemoreceptors pick up increasing metabolites
being produced and this sends afferent signals to the medullary cardiovascular centre, which again causes it to
act to preserve blood pressure.
Local effects are in the heart and lungs and in the skeletal muscle to increase blood flow. The pre-programmed
pattern decreases sympathetic drive to the skin and increased sympathetic drive to the GI tract and the
kidneys. The net result is that there is profound vasoconstriction in the gut and kidneys, and this increases
total peripheral resistance. With regards to the skin (an exception to the pre-programmed pattern), there is
increased blood flow (reduced sympathetic activity) to dissipate the heat that is generated.
There is a 10 fold increase in blood flow to skeletal muscle during exercise, and a 4 fold increase in blood flow
to the heart. This decreases total peripheral resistance. But it is the vasoconstriction in other organs that
increases total peripheral resistance. The overall result, however, is a decrease in total peripheral resistance,
so it is clear that the skeletal muscle predominates.
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By the pre-programmed pattern as well as input from muscle chemoreceptors, there is increased sympathetic
innervation to the heart. This causes increased heart rate, increased force of contraction, and also increased
venoconstriction to increase stroke volume. All these factors will increase cardiac output. Contracting skeletal
muscles will also cause an increase in venous return, which again will increase stroke volume.
Cardiac Output = Stroke Volume x Heart Rate
There are negative effects of this. A slight decrease in plasma volume opposes increasing venous return.
Increased capillary pressure across the muscle walls - by dilating the capillaries of the skeletal muscle, there is
more blood flowing through this muscle and so more fluid is lost into the interstitium. This reduces the
effective blood volume to a certain degree, and is added to by the loss of salt and water due to sweat. The net
result, however, is an increase in cardiac output due to the sympathetic drive predominating.
Cardiac output increases massively due to sympathetic effects, and peripheral resistance reduces due to
vasodilation in the skeletal muscle and the heart (although it is mitigated by vasoconstriction elsewhere).
Overall the increased cardiac output is more important than the reduction in total peripheral resistance, which
is why blood pressure increases during exercise.
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Chambers, Valves, Conduction System & Coronary Circulation
by Professor Yen Ho
The heart is a hollow muscular organ that comprises of two pumps in parallel. One pump, the right heart,
receives systemic venous return and pumps it to the lungs for oxygenation. The second pump, the left heart,
receives oxygenated blood from the lungs and sends it around the body. The two pumps are separated by a
partition – the cardiac septum. Each pump is made up of an atrium and a ventricle. Each ventricle has an inlet
valve that stops back flow to the atrium and an outlet valve that stops reflux from the conduits (the great
arteries) leaving the heart. Thus, the heart has four chambers and four main valves.
[Deoxygenated blood from body and heart]
[Oxygenated blood from lungs]
Right atrium
Left atrium
(tricuspid valve)
(mitral valve)
Right ventricle
Left ventricle
(pulmonary valve)
(aortic valve)
Pulmonary trunk
Aorta
Lungs
Body
Arrangement of chambers – understanding the cardiac silhouette
Although the two pumps are designated right heart and left heart, the chambers are not strictly to the right
nor to the left. Indeed, the arrangement of the cardiac chambers to one another is complex. When viewed
from the front, the right heart chambers are anterior and to the right of the left heart chambers. Very little of
the left heart is visible. This is the strip of left ventricle forming the left heart border (Figure 1). The atrial
chambers are to the right of their respective ventricular chambers. The left atrium is the most posterior
cardiac chamber. The cardiac valves are arranged at an angle to one another with the pulmonary valve being
sited most superiorly.
Figure 1. Arrangement of
the cardiac chambers and
valves. Left heart chambers
are pale (stippled), right
heart chambers are dark
grey.
P= pulmonary,
A= aortic,
M= mitral,
T= tricuspid valve.
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The Cardiac Chambers
Right atrium
This chamber comprises of an appendage and a venous component.
1. The appendage is large and lined by parallel ridges, the pectinate muscles.
2. The venous component receives the openings of the systemic veins: the superior caval vein, the inferior
caval vein and the coronary sinus.
The right atrium shares the septum with the left atrium. The oval fossa is an oval depression where the
septum is thin. The muscular rim around the oval fossa is distinctive of the right atrium. The smooth vestibule
of the right atrium leads to the opening of the tricuspid valve.
Left atrium
This chamber comprises of an appendage and a venous component.
1. The appendage is small and finger-like.
2. The venous component receives the pulmonary veins from the lungs.
The septal surface is not marked by an oval depression. The left atrium leads to the mitral valve.
Right ventricle
The right ventricle is elliptical in shape. There are three components to a normal ventricle.
1. Inlet: This contains the tricuspid valve and its tensor apparatus.
2. Outlet: This is the infundibulum that supports the pulmonary valve. The tricuspid and pulmonary valves
are widely separated from one another by an expanse of muscle, the supraventricular crest.
3. The trabecular portion is at the apex comprises of irregular bundles of muscle that project into the cavity.
The trabeculations in the right ventricle are coarse relative to that in the left ventricle. A prominent
bundle crossing the ventricular cavity near the apex is termed the moderator band.
The ventricular septum is curved and runs obliquely. The major part of the septum is muscular. A tiny part near
the atrium is membranous.
Left ventricle
This chamber is more conical in shape and has a rounded cross-section. It is also thicker walled than the right
ventricle in the normal heart.
1. Inlet: This contains the mitral valve. Unlike the right heart, the aortic and mitral valves are adjacent to
each other. There is an extensive area of fibrous continuity between these two valves. The thicker areas at
each end of the area of fibrous continuity are termed the right and left fibrous trigones. Together with the
membranous septum, the right fibrous trigone forms the central fibrous body.
2. Outlet: Owing to the central position of the aortic valve in the heart, the aortic outlet lies between the
ventricular septum and the mitral valve.
3. The trabecular portion comprises of thin criss-crossing muscle bundles that mainly line the apical third of
the ventricular cavity.
The upper part of the ventricular septum is smooth. There is no equivalent of the moderator band although
occasionally thin tendons stretch across the cavity.
The valves of the heart
Atrioventricular (or inlet) valves
These valves guard the junctions between atrial and ventricular chambers and prevent backflow to the atria
when the ventricles contract in systole. They are characterised by having a hinge-like attachment of leaflets to
the atrioventricular junction and tendinous cords that attach the leaflets to papillary muscles. The papillary
muscles attach to the septum or ventricular wall. The attachments of the cords prevent the leaflets from
billowing into the atrial chambers when the valves are closed during systole.
Tricuspid valve As its name suggests, this valve comprises of three leaflets. Named according to their
locations, these are the antero-superior, mural(or inferior) and septal leaflets. Tendinous cords attach to the
underside (ventricular aspect) toward the free margins of the leaflets. The septal leaflet of the tricuspid valve
is distinctive in having direct cordal attachments to the ventricular septum.
Mitral valve This valve has two leaflets – the anterior (or aortic) and mural (or posterior). The aortic leaflet
interposes between left ventricular inlet and outlet. The mural leaflet is often scalloped in appearance. Two
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groups of papillary muscles in antero-lateral and postero-medial positions support the mitral valve. Tendinous
cords from both leaflets are attached to each group of muscles. The attachment of the mitral valve is
strengthened by strut cords and basal cords.
Arterial valves (or outlet valves)
The arterial valve guards the junction between the ventricular chamber and a great artery, preventing reflux.
They open when the ventricles contract in systole and close when the ventricles are filled in diastole. Unlike
the atrioventricular valves, arterial valves are not attached to cords or papillary muscles. Each valve has three
semilunar shaped leaflets. Their hingelines mark crescents that cross the ventriculo-arterial junctions. At the
valvar insertions, the arterial walls are dilated to form the arterial sinuses corresponding to the leaflets. In the
middle of each free margin is a thickened area termed the nodule. Each leaflet forms a pocket that fills with
blood and closes the valve in diastole but are pushed apart in systole allowing flow to escape from the
ventricle.
Pulmonary valve Guarding the end of the right ventricular infundibulum, the pulmonary valve is hinged in
part to the musculature of the infundibulum and in part to the wall of the pulmonary trunk.
Aortic valve Similar in structure to the pulmonary valve, the nodules are slightly thicker. The coronary orifices
are located in two of the aortic sinuses. Half of the circumference of the aortic valve is in fibrous continuity
with the mitral valve.
Coronary Circulation
The muscle of the heart is nourished by the coronary arteries. The deoxygenated blood from the myocardium
drains back to the heart mainly by the coronary veins, with a small portion draining directly to the cardiac
chambers via thebesian orifices.
Coronary arteries
The coronary arteries arise from the sinuses of the aorta. In the normal heart there are usually two coronary
orifices, the left and right coronary orifices (ostia). The major coronary arteries are the right coronary, the
anterior descending, the circumflex and the posterior descending coronary arteries (Figure 2). Smaller
arteries arise from the major arteries to supply the atrial and ventricular musculature including the septum. In
90% of individuals, the right coronary artery continues into the posterior descending (interventricular)
coronary artery that supplies the ventricular septum, and, in many of these cases, the right coronary artery
continues to run into the inferior sector of the left atrioventricular groove to supply also the postero-medial
wall and the papillary muscle of the mitral valve. The arrangement whereby the right coronary artery supplies
the posterior descending coronary artery is termed ‘right coronary dominance’ (Figure 3). Similarly, ‘left
coronary dominance’ is the term used in cases where the left system continues into the posterior descending
coronary artery.
Figure 2. The major
coronary arteries. The
posterior descending
(interventricular artery is
represented by the
broken line)
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Figure 3. The concept
of coronary
dominance
Coronary veins
Coronary veins convey the major portion of coronary venous return back to the heart. The main cardiac veins
are the known as the great, middle, and small cardiac veins. These veins drain into the coronary sinus that, in
turn, drains into the right atrium. Smaller veins, known as thebesian veins, drain directly into the cardiac
chambers.
The cardiac conduction system
In addition to the contractile or working myocardium, the heart possesses histologically ‘specialised’
myocardium that forms the cardiac conduction system (Figure 4). The initiation and conduction of impulses for
the contraction of the heart occurs with the specialized myocytes of this system. The cardiac conduction
system consists of:
1) The sinus node (the pacemaker of the heart)
2) The atrioventricular conduction system which comprises of
 The atrioventricular node
 The penetrating atrioventricular bundle of His
 The atrioventricular bundle which branches into the right bundle branch and the left bundle branch
 The peripheral ramifications of the bundle branches (so-called Purkinje network)
Figure 4. The components of the cardiac conduction system
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Haemostasis and Thrombosis
by Professor David Lane and Professor Mike Laffan
Knowledge of haemostatic mechanisms is important for diagnosis and treatment of bleeding disorders, as well
as identification of risks and treatment for thrombotic disease. It is also important for monitoring
anticoagulant drugs.
The functions of haemostasis:
Prevention of blood loss from intact vessels
Arrest of bleeding from injured vessels
The haemostatic plug formation is a sequential response to injury. The first step is vessel constriction, which
happens primarily in the small blood vessels to stop local blood loss. The second step involves the blood
platelets - the formation of an unstable platelet plug. There are two mechanisms to this, which are platelet
adhesion and platelet aggregation. Next is the stabilisation of the plug with fibrin, which involves blood
coagulation. The last step is the break down (dissolution) of the clot and the initiation of vessel repair, which
involves fibrinolysis (an enzyme cascade system).
There is a very rapid response to vessel injury, initiated by platelets recognising a site of injury…
Platelet adhesion:
Disruption in endothelial cells exposes subendothelial structures
such as collagen, which is particularly important in the haemostatic
response. One mechanism by which platelets adhere to the site of
injury is through a protein called Von Willebrand factor. Von
Willebrand factor recognises the exposed collagen, and forms a
bridge that links the platelet to the site of vessel injury. The platelet
has a glycoprotein 1b receptor which binds to the Von Willebrand
factor. Platelets can also directly bind to the site of injury via a
second receptor - glycoprotein 1a, which directly binds to collagen
at the site of injury.
Platelet aggregation:
The glycoprotein bound platelets become activated and release ADP
(stored within the platelet) and generate prostaglandins, which
cause the platelets to aggregate. Platelet aggregation is the
clumping of the platelets, mediated by glycoprotein 2b / 3a
and fibrinogen forming bridges.
Blood Coagulation:
The main sites of synthesis of clotting factors, fibrinolytic
factors and inhibitors are the liver, endothelial cells and
megakaryocytes. Most synthesis is in the liver but some
proteins are produced in high local concentration in the
endothelium (e.g. Von Willebrand factor) and in
megakaryocytes (e.g. factor V).
Factor XII is an inactive protein which can be activated to
factor XIIa, which activates XI to XIa, etc as a cascade
amplification mechanism. This is called the intrinsic
pathway. There are co-factors that help these reactions work
effectively, efficiently and help to localise them. The first of
these co-factors is factor VIII. Activated factor VIII interacts
with platelet membrane phospholipid (Pl) and calcium ions to accelerate and localise the reaction on the
surface of the platelet. The activation of coagulation occurs on the activated platelets of the haemostatic plug.
The second mechanism by which coagulation is activated is where tissue factor (protein exposed on damaged
vessel) becomes activated and interacts with factor VII or factor VIIa to activate the cascade for X to Xa. This
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leads to the common pathway, whereby factor Xa activates thrombin from prothrombin on the surface of the
platelet.
Throughout the cascade, zymogens (inactive) are activated to protease enzymes. Prothrombin is activated to
thrombin, which activates platelets and also activates factor VIII to VIIIa and factor V to Va.
Fibrinogen is a normal plasma protein circulating in high concentrations, which is converted by thrombin into
fibrin to stabilise the platelet plug. Thrombin also stabilises the fibrin by activating factor XIII to XIIIa to form
cross-linked fibrin.
Simply viewed, the coagulation system is a cascade or amplification system. There are zymogens which are
converted to proteases, as well as co-factors which need to be activated on surfaces. The surface might be
platelets, which localise and accelerate the reactions. The trigger to initiate coagulation in vivo is tissue factor.
Although factor XII can be activated to factor XIIa, this is mainly an in vitro reaction, useful for some diagnostic
tests.
Fibrinolysis
This involves plasminogen (a zymogen). Tissue plasminogen activator (tPA) activates plasminogen into plasmin.
It is activated when a fibrin clot forms. The formation of the fibrin clot is the trigger for the activation of
plasminogen into plasmin. Plasmin is a proteolytic enzyme which breaks down the clot, producing fibrin
degradation products, which can be used in diagnostic tests. tPA and a bacterial activator (streptokinase) are
used in therapeutical thrombolysis for myocardial infarction (clot busters).
The clotting cascade is an amplification system where a small amount of factor VIIa produces a large amount
of thrombin. However, blood does not clot completely whenever clotting is initiated by vessel injury because
there are inhibitory mechanisms to prevent this. There are two general mechanisms:
1) Direct inhibition: e.g. antithrombin, this is an
inhibitor of thrombin and other clotting
proteinases.
2) Indirect inhibition: e.g. inhibition of thrombin
generation by the protein C anticoagulant
pathway.
1)
Antithrombin can inhibit most of the coagulation
proteinases highlighted in red.
The enzymes are released, but are inhibited and
controlled by a natural inhibitor.
Heparin is used for the immediate anticoagulation
in venous thrombosis and in pulmonary embolism.
Heparin accelerates the action of antithrombin.
2)
Involves co-factors VIIIa and Va, which are
activated by trace amounts of thrombin and
become co-factors. Indirect inhibition inactivates
the generation of thrombin.
Thrombin binds to a receptor on the endothelium
called thrombomodulin, which activates protein C.
Activated protein C is an anticoagulant, which
inactivates the two co-factors VIIIa and Va. This is
the mechanism of control.
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These mechanisms are important in thrombosis, as 5% of the population have a variant of factor V, which is
the polymorphism called Factor V Leiden, which is not easily inactivated by activated protein C, and so is a risk
factor for thrombosis. Coagulation inhibitory mechanisms can fail if there is antithrombin deficiency, protein C
deficiency, protein S deficiency, or due to Factor V Leiden - all these are risk factors for thrombosis.
Normal haemostasis is a state of equilibrium. It is a balance between fibrinolytic factors and anticoagulant
proteins against coagulation factors and platelets.
Bleeding is when the balance tips towards fibrinolytic
factors and anticoagulant proteins. Abnormal bleeding
doesn’t stop. For example with disorders such as
haemophilia, the bleeding is not necessarily severe, but
it will not stop. Abnormal bleeding is usually
spontaneous, out of proportion to the trauma, unduly
prolonged and restarts after appearing to stop. For
example, many people get nose bleeds.
Significant Bleeding History: Examples
Epistaxis not stopped by 10 minutes compression or requiring medical attention/transfusion.
Cutaneous haemorrhage or bruising without apparent trauma (especially multiple/large).
Prolonged (>15 minutes) bleeding from trivial wounds, or in oral cavity or recurring spontaneously in
7 days after wound.
Spontaneous GI bleeding leading to anaemia.
Menorrhagia requiring treatment or leading to anaemia, not due to structural lesions of the uterus.
Heavy, prolonged or recurrent bleeding after surgery or dental extractions.
Defects in Primary Haemostasis
Abnormal bleeding is mainly as a result of problems with primary haemostasis - forming the platelet plug. This
requires collagen, Von Willebrand factor and platelets. Patients can have problems with all of these, most
commonly Von Willebrand factor deficiency or low platelet numbers.
Defective collagen in the vessel wall is a rare disorder, but could be due to steroid therapy or age. Deficient
Von Willebrand factor can be as a result of Von Willebrand disease (genetic), and platelets may be
compromised by use of aspirin and other drugs, or by thrombocytopenia.
There is usually a pattern of bleeding in defects of primary haemostasis. Typically: easy bruising, nosebleeds,
gum bleeding, Menorrhagia, bleeding after trauma/surgery, petechaie (specific for thrombocytopenia).
Defects in Secondary Haemostasis
Defects of secondary haemostasis are to do with stabilisation of the plug with fibrin (blood coagulation). Fibrin
mesh formation will be affected if there is deficiency or defect of coagulation factors (I-XIII). Common
examples are haemophilia (factor VIII or IX; genetic), drugs (warfarin), liver disease (acquired), consumption
(e.g. Disseminated Intravascular Coagulation; acquired).
Disseminated intravascular coagulation is where there is generalised activation of coagulation (tissue factor). It
is associated with sepsis, major tissue damage and inflammation. Coagulation factors and platelets are
consumed and depleted, and the activation of fibrinolysis depletes fibrinogen. The consequences are
widespread bleeding and bruising, and deposition of fibrin in vessels causing organ failure.
The patterns of bleeding in secondary haemostatic defects are typically: delayed bleeding, deeper bleeding
from joints and muscles, not from small cuts, nosebleeds are rare, bleeding after trauma/surgery, bleeding
after intramuscular injections.
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Defects in Fibrinolysis
Defects of clot stability usually involve fibrinolysis. Clot stability is affected if there is excess fibrinolytic factors
(e.g. plasmin, tPA), with common examples being therapeutic administration and some tumours. Alternatively
there may be deficient antifibrinolytic factors (e.g. antiplasmin), as in antiplasmin deficiency (genetic).
Unbalanced haemostasis may be due to anticoagulant excess, which is only due to therapeutic administration
e.g. heparin or hirudin.
If the balance is tipped in favour of coagulation factors and platelets, the result may be thrombosis.
Thrombosis is inappropriate intravascular coagulation, not preceded by bleeding. Thrombi may be venous or
arterial.
Effects of thrombosis vary. Obstructed flow of blood in an artery could lead to myocardial infarction, stroke of
limb ischaemia. In a vein, obstruction will lead to pain and swelling. An embolus from veins may go to the lungs
and cause pulmonary embolus, and arterial emboli (usually from the heart) may cause stroke or limb
ischaemia. Deep vein thrombosis is where venous return is obstructed, and the patient will typically present
with a painful and swollen leg. Pulmonary embolism will cause shortness of breath, chest pain and potentially
sudden death.
The prevalence of venous thromboembolism is overall 1 in 1,000 to 10,000 per year. The incidence doubles
with each decade. Pulmonary embolism is present in 13% of hospital deaths, and is the cause of 5 to 10% of
hospital deaths.
Thromboembolism has a mortality rate of about 5%, with 20% recurrence in the first 2 years and 4% per year
thereafter. Severe thrombophlebitic syndrome is seen in 23% of patients at 2 years (11% with stockings).
Pulmonary hypertension is seen in 4% at 2 years.
People may get thrombosis due to genetic constitution and
risks, the effects of age and previous events, illnesses or due
to acute stimulus.
Genetic and acquired factors cause an increased risk of
thrombosis. Virchow’s triad shows there are three main
contributory factors to thrombosis:
1) Endothelial injury (vessel wall is dominant cause in
arterial thrombosis).
2) Abnormal blood flow (complex, contributes to both
arterial and venous).
3) Hypercoagulability (blood is the dominant cause in
venous thrombosis).
Venous thrombosis is usually due to the balance being tipped in favour of too much coagulative activity and
too little fibrinolytic activity. There is increased risk of thrombosis if there is a deficiency of anticoagulant
proteins (e.g. antithrombin, protein C, protein S). On the other hand the risk also increases if there are
increased coagulant proteins and activity (e.g. factor VIII, factor II, factor V Leiden, thrombocytosis).
Increased risk of thrombosis due to the vessel wall involves endothelial cell proteins. Many proteins active in
coagulation are expressed on the surface of endothelial cells and their expression, which is altered in
inflammation (e.g. thrombomodulin, tissue factor, tissue factor pathway inhibitor). Changes in the
endothelium make it more pro-coagulate.
Increased risk of thrombosis due to blood flow can be due to reduced flow (stasis). This can occur after
surgery, fracture, during a long haul flight, or in prolonged bed rest.
“Thrombophilia” is a term used for anyone with an increased risk of thrombosis. Thrombosis can occur at a
young age, or spontaneously. There can be multiple thromboses, even whilst anti-coagulated. The laboratory
tests will measure anti-thrombin, Factor V Leiden, protein C, etc.
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There are of course acquired risks for thrombosis. Numerous conditions will alter blood coagulation, the vessel
wall and blood flow to precipitate thrombosis or make it more likely. For example: oral contraceptive pill,
pregnancy, malignancy, surgery, inflammatory response.
The prevention of thrombosis is based on the assessment of individual risk and circumstantial risk. The
potential risk factors should be avoided or prophylactic anticoagulant therapy should be given. Treatment is to
limit recurrence, for example by increasing anticoagulant activity (heparin) or by lowering pro-coagulant
factors (warfarin). Clots can be lysed by using tPA.
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Hypertension
by Professor Alun Hughes
Hypertension is a major cause of mortality and morbidity, as currently it
affects nearly a billion individuals worldwide. It accounts for approximately
one in eight of all deaths globally. But blood pressure shows a continuous
relationship with cardiovascular risk. Most disease that is attributable to
increased blood pressure occurs in individuals that are not labelled as
hypertensive.
Blood pressure distribution is unimodal and any distinction between normal
and abnormal is arbitrary.
Hypertension is the level of blood pressure above which
investigation and treatment do more good than harm.
An important factor to bear in mind is that an individual’s blood
pressure does not remain constant with age. Mean pressure
difference between systolic and diastolic pressures rises with age,
but particularly after the age of about 50 there is a significant
change. The majority of people over the age of 60 are
hypertensive by current definitions. The pulse pressure also rises
with age.
Blood pressure is continuously distributed in a population and there is no threshold for blood pressure risk.
The major risks attributable to elevated blood pressure are the risks of coronary heart disease, stroke, heart
failure and peripheral vascular disease / atheromatous disease. The risks are increased between 3 to 6 fold in
hypertensives.
95% of cases of hypertension have an unidentifiable cause, and this is called primary or essential
hypertension. 5% of cases have an identifiable cause, and this is called secondary hypertension. Secondary
causes of hypertension may include:
Renal disease, including renal artery stenosis
Tumours secreting aldosterone (Conn’s syndrome)
Tumours secreting catecholamines (pheochromocytoma)
Oral contraceptive pill
Pre-eclampsia / pregnancy associated hypertension
Rare genetic causes (e.g. Liddle’s syndrome)
Pathophysiology of primary hypertension
The haemodynamics of hypertension can be expressed by the equation:
Blood pressure = Cardiac Output x Peripheral Vascular Resistance
Typically, established hypertension is associated with several
factors. For example: uniformly increased peripheral resistance,
reduced arterial compliance, normal cardiac output, normal blood
volume / extracellular volume, and central shift in blood volume.
Established primary hypertension is characterised by elevated
total peripheral resistance and normal or reduced carbon dioxide.
Elevated peripheral vascular resistance is caused by the active
narrowing of arteries (vasoconstriction) and the structural
narrowing of arteries by growth and remodelling (possibly
adaptive?).
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In a genetic sense, hypertension is unlikely to have a monogenic cause. Commonly hypertension is a complex
polygenic. Environmental factors include dietary salt, obesity, alcohol, pre-natal environment and others.
Twins and other studies suggest 30 to 50% of variation in blood pressure is attributable to genetic variation.
Monogenic causes (under 1% of hypertension) include Liddle’s syndrome, which is a mutation in amiloride+
sensitive tubular epithelial Na channel. Complex polygenic causes are due to multiple genes with small
effects, interactions with sex, other genes and the environment.
There is strong evidence that the kidneys (in relation to salt intake) affect hypertension. Impaired renal
function or blood flow is the commonest secondary cause of hypertension (e.g. renal parenchymal disease,
+
renal artery stenosis). Most monogenic causes of hypertension affect renal Na excretion. Salt intake is
strongly linked with blood pressures of human populations. Populations with low salt have low population
blood pressures and no rise in blood pressure with age. Animals with reduced renal sodium handling develop
hypertension. Excess salt intake in many animals results in elevated blood pressure. In rats, hypertension can
be “transplanted” with the kidney, and there is similar (though incomplete) data in man. Also high
sympathetic activity in children may contribute to hypertension. There is inconsistent evidence for endocrine /
paracrine factors.
Effects of Hypertension
High blood pressure has adverse effects on numerous organs, such as the
brain (strokes and dementia), eyes (microvascular disease and
retinopathy), the entire circulation (peripheral vascular disease), the heart
(myocardial infarction, heart failure, atrial fibrillation) and kidneys (renal
disease and failure).
The increased peripheral resistance places an excessive load on the heart,
and one of the immediate consequences of this is that the heart has to
work harder. It adapts structurally to this - there is often marked
thickening of the heart wall. Hypertension is commonly associated with an
increase in left ventricular wall mass and changes in chamber size.
Thickening of the wall is also a feature of large arteries in hypertension.
This is attributable both to a structural remodelling of the wall (hypertrophy to help artery to resist higher
pressures) and also to an increased acceleration of atherosclerosis.
Hypertension may cause arterial rupture or dilations (aneurysms). This can lead to thrombosis or
haemorrhage (e.g. strokes). In smaller arteries, hypertension is associated with hypertrophy and/or narrowing
of the lumen of small arteries. This normalises wall stress but increases resistance. In the microvasculature,
high blood pressure is associated with vessel loss. There is a reduction in capillary density, which leads to
impaired perfusion and increased peripheral vascular resistance. There is also elevated capillary pressure,
which leads to damage and leakage.
The retina illustrates microvascular damage in
hypertension. There is thickening of the wall of
small arteries, vasospasm, rarefaction,
impaired perfusion and increased leakage into
the surrounding tissue. In a Grade III
retinopathy, silver wiring can be seen (wall
thickening), haemorrhages (wall rupture), AV
nipping (wall thickening) and hard exudates
(plasma leaks).
Renal dysfunction is common in hypertension. Extreme (accelerated/malignant hypertension) is now rare but
leads to progressive renal failure. In primary hypertension the kidney degenerates to a granular capsular
surface, with cortical thinning and renal atrophy. With accelerated hypertension there are subcapsular
haemorrhages. Increased blood pressure is associated with increased albumin loss in the urine, which is
indicative of renal microvascular damage.
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Introduction to Atherosclerosis
by Professor Dorian O Haskard
Ischaemic heart disease and cerebrovascular disease have become
very significant world disease burdens in the last few decades, and
it is estimated that by 2020 ischaemic heart disease will be the top
burden.
Atherosclerosis is an unavoidable disease in medicine. It affects
general practice, acute medicine, metabolic medicine,
endocrinology, vascular surgery, cardiac surgery, cardiology and
neurology.
Atherosclerosis was noted by Virchow is 1852 - the deposition of
lipids in arteries, although he considered the condition an arteritis.
The condition doesn’t necessarily involve the full circumference of
the artery, it usually only occurs on one side. There is accumulation
of lipid deposited in the arterial wall in relation to macrophages.
These depositions become more numerous, and there ends up
being lipid, dead cell and necrotic material covered by a hard
fibrous cap. This will lead to the gradual narrowing of the lumen
which will lead to ischaemic manifestations. Or it could fracture or
rupture, and this will lead to the exposure of the clotting cascade to
tissue factor and other thrombogenic stimuli in the necrotic core.
This will lead to thrombotic occlusion of the artery and infarction.
The risk factors for atherosclerosis are modifiable and non-modifiable.
The potentially modifiable risks include smoking, lipids, blood pressure, diabetes,
obesity and lack or exercise.
The non-modifiable risk factors include age, sex, and genetic background.
Paradigms of atherosclerosis pathogenesis
1. Inevitable consequence of aging, which is true to some extent.
2. The cholesterol hypothesis - this is probably the main driver to atherosclerosis.
3. Inflammation and immunity - is linked to the cholesterol.
The cholesterol hypothesis was devised by N. N. Anitschkow, who fed cholesterol to rabbits and showed that
they did indeed develop very human looking atherosclerosis, with necrotic cores, the fibrous plaque and foam
cells. When he took the rabbits off the cholesterol diet, the problems largely went away.
Today there is overwhelming evidence that cholesterol is the major aetiological factor in atherosclerosis. There
is experimental evidence, clinical genetic evidence (familial hypercholesterolaemia), epidemiological evidence
(Framlingham), and interventional evidence (randomised controlled trials of statins).
Cholesterol is deposited in the form of LDLs that penetrate the endothelial barrier into the subintimal space of
the arterial wall. The LDL gets physically trapped in to the matrix proteoglycans in the intima. The LDL particles
become susceptible to various forms of modification which denature them and render them recognisable by
macrophages.
An LDL particle has a core of cholesterol and tricglycerides, encased by a layer of phospholipids and held
together by a large protein. When this particle is trapped in the wall, free radicals and enzymes such as
phospholipases modify the particle. Normally the LDL particle is taken up into cells such as macrophages by a
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molecule called the LDL receptor. This takes the LDL
particle into the cell and provides the cell with as
much cholesterol as it needs for the membrane etc.
If the cell has enough cholesterol, it shuts down
expression of the LDL receptor. When the LDL
particle is modified by free radicals or enzymatic
action, the recognition element of the LDL receptor
is damaged, and so the LDL receptor is no longer
recognised. Instead, the macrophage recognises
the modified particle as denatured material by its
scavenger receptors.
Unlike the homeostatic process of taking in the LDL
through the LDL receptor, the scavenger receptor
mediated mechanism is not regulated and the cell
can’t have enough - it goes on consuming until it
becomes a foam cell with lots of lipid within the
cell.
This is a mechanism that essentially is protective, as it is for removing debris. Monocytes are recruited to take
up LDL and dispose of it. When there are risk factors such as high cholesterol, this homeostatic process
becomes pro-inflammatory leading to lesions. The macrophages die when they have too much cholesterol,
which contributes to the junk in the necrotic core. They may also make or recruit angiogenic factors, VSMC
growth factors, proteases and free radicals to cause further damage.
Manifestations of Atherosclerosis
Atherosclerosis doesn’t affect the entire circumference of arteries and it doesn’t affect all arteries. Generally,
atherosclerosis occurs at branch points of arteries and at curvatures. For example, at the carotid bifurcation
where the laminar arterial flow becomes a complex flow pattern with reversals and oscillations - the
endothelium is exposed to different mechanical forces.
Atherosclerosis leads to gradual narrowing of arteries. Stenosis refers to gradual loss
of luminal diameter leading to critical reduction in blood flow. This can be visualised
by angiography where there is little blood flowing through the artery. The effect of
stenosis is ischaemia.
Ischaemia is insufficient blood supply to meet metabolic demands of the tissues, which leads to hypoxic
cellular dysfunction. It is typically experienced as pain on exertion, for example in the heart as angina pectoris
or in the legs as intermittent claudication.
Ischaemia causes discomfort, though it is not necessarily life threatening. A more serious manifestation is
when the plaque ruptures or erodes.
The localised area of fat deposition and tissue breakdown (necrosis) within the arterial wall is referred to as
atherosclerotic plaque. Plaque erosion is the breakdown of the endothelial lining of the lesion without the full
rupture of the fibrous cap. Plaque rupture is the breakdown of the fibrous cap of tissue separating the plaque
from the blood. The effects of plaque erosion or rupture vary.
Platelet recruitment and blood coagulation at the site of erosion or minor rupture may lead to silent nonocclusive thrombus and plaque growth. However, blood coagulation at the site of rupture may lead to an
occlusive thrombus and cessation of blood flow - infarction.
Embolism is the dislodgement of solid material (e.g. platelet plug, thrombus, cholesterol-rich plaque contents)
into the arterial circulation leading to occlusion at distant sites. The consequences depend on the size of the
embolus and the target organ (e.g. brain, eye, bowel, limbs).
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The effects of arterial occlusion from thrombosis or embolism also vary:
Transient occlusion: short ischaemia from an occlusion that spontaneously resolves, e.g. in the brain
“Transient Ischaemic Attack” or in the eye “amaurosis fugax”.
Infarction: death of tissue due to unresolved ischaemia, e.g. in the heart (myocardial infarction) or in
the brain (cerebrovascular accident).
Timeline of Atherosclerosis
Evidence has shown that lifestyles associated with a ‘western’ culture such as a diet rich in saturated fats and
high in calories, smoking and physical inactivity, are some of the modifiable risk factors leading to an increase
in the prevalence of CV events. Of these, three are considered to be of prime importance:
Smoking is responsible for 50% of all avoidable deaths, of which half are due to CVD.
Raised blood pressure has been found to be an important risk factor for the development of CHD, cardiac
failure and cerebrovascular disease. The greater the increase in blood pressure the higher the risk. Greatest
benefit of blood pressure lowering is seen in those at higher risk. Even modest reductions produce substantial
benefits in those with multiple risk factors.
Dyslipidaemia, in particular, raised low-density lipoprotein (LDL) cholesterol and triglyceride levels, and low
high-density lipoprotein (HDL) cholesterol are associated with increased risk of CVD. However, raised LDL
cholesterol has been shown to be most strongly associated with the development of atherosclerosis and the
risk of CV events.
Between the ages of 40 and 50 is
a period of time known as the
window of opportunity for
primary prevention. This
depends on lifestyle and risk
factor management.
Over 60 years of age is a time
called the window of clinical
prevention, which refers to
secondary prevention. For
example catheter based
interventions, revascularisation
surgery or treatment of heart
failure.
Pathogenesis of Atherosclerosis
Atherosclerosis is a chronic inflammatory response in the walls of arteries, in large part in reaction to the
deposition of lipoproteins (plasma proteins that carry cholesterol and triglycerides).
The main cell types involved in atherosclerosis are:
vascular endothelial cells
white blood cells (leukocytes), particularly monocytes recruited to macrophages
platelets
vascular smooth muscle cells
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Vascular Endothelium in Atherosclerosis
by Dr Anna M. Randi
To understand the effects of atherosclerosis on the vascular
endothelium, it is important to have knowledge of the structure of
arteries and veins.
There are generally three layers (except for capillaries and venules):
Tunica intima
o Endothelium
Tunica media
o Smooth muscle cells
Tunica adventitia
o Vasa vasorum, nerves
The endothelium is the surface separating blood from other tissues. This is very extensive, with a surface area
of over 1000m² and a weight of over 100g. The vascular endothelium acts as a vital barrier separating blood
from tissues, formed by a monolayer of endothelial cells (contact inhibition). Endothelial cells are very flat,
about 1 to 2μm thick and 10 to 20μm in diameter.
Endothelial cells regulate a variety of factors, such as:
Leukocyte transmigration
Permeability
Angiogenesis
Mechano transduction
Inflammation
Thrombosis and haemostasis
Vascular tone
However, not all endothelial cells in the body are the same. There are structural, functional and genetic
differences according to the position in the cardiovascular tree. There is no universal endothelial cell marker,
as different vascular beds express different proteins. The intact endothelium displays ultrastructural diversity
and molecular heterogeneity.
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Regulation of endothelial homeostasis is a balance.
There are anti and pro factors for inflammation,
thrombosis, and proliferation and angiogenesis.
Usually, the balance is tipped to the anti side.
Endothelial activation can lead to a chronic increase
in thrombosis, angiogenesis, leukocyte recruitment,
permeability and ultimately the risk factors
contributing to atherosclerosis.
Permeability
The endothelium regulates the flux of fluids and molecules from blood to tissues and vice versa. Increased
vascular permeability results in leakage of plasma proteins into the subendothelial space (below the
endothelium). The subendothelial space is composed of extracellular matrix and separates the endothelium
from the internal elastic lamina and the media (vascular smooth muscle cells). Activation of the endothelium
causes the endothelial junctions to come apart, and lipoproteins can get modified (oxidative) and trapped in
proteoglycans in the subendothelial space. Macrophages
then become foam cells when they phagocytose too
much lipid, which causes chronic inflammation.
Leukocyte Recruitment
Leukocyte recruitment involves the endothelial
junctions. Between the endothelial junctions, there are
many proteins present that bind to form a “zipper”. If a
leukocyte wants to go through, it squeezes past the
proteins. Leukocytes will normally flow in the blood
circulation. If, however, there is inflammation and
activation of the endothelium, the endothelial cells
express proteins that can bind to proteins on the
leukocytes. The leukocytes roll, change shape, stick and
go through the endothelial junction.
The problem with atherosclerosis is that the leukocyte goes through in the wrong type of vessel. It goes
through a blood vessel that has a thick vessel wall, and so when it goes through the wall and chews up the
basement membrane, it finds a thick vessel wall where it gets stuck. It finds lipids there, it starts gobbling them
up and this begins the atherosclerotic problem.
In capillaries, the endothelial cells are surrounded by basement membrane and pericapillary cells (pericytes).
The post-capillary venule is a structure similar to capillaries but has more pericytes. In an artery there are
three thick layers, rich in cells and extracellular matrix.
Recruitment of blood leukocytes into tissues takes place normally during inflammation. Leukocytes adhere to
the endothelium of post-capillary venules and transmigrate into tissues. In atherosclerosis, leukocytes adhere
to the activated endothelium of large arteries and get stuck in the subendothelial space. Newly formed postcapillary venules at the base of developing lesions provide a further portal for leukocyte entry.
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Plaque macrophages express inflammatory factors involved in monocytes recruitment. Cytokines capable of
activating endothelial cell adhesion molecules (e.g. E-selectin, ICAM-1, VCAM-1) include interleukin-1 and
tumour necrosis factor α. Proteins with direct chemoattractant (chemokine) properties on monocytes include
interleukin-8 and monocytes chemotactic protein-1 (MCP-1).
Blood Flow
Laminar flow is streamlined flow, with the outermost layer moving
slowest and the centre moving fastest. Laminar blood flow
promotes nitric oxide production, and factors that inhibit
coagulation, leukocyte adhesion, and smooth muscle cell
proliferation. Laminar blood flow promotes endothelial survival.
Disturbed flow is interrupted, and the rate of flow exceeds the
critical velocity. This can occur when the fluid passes a constriction,
a sharp turn, or a rough surface. Disturbed flow promotes
coagulation, leukocyte adhesion, smooth muscle cell proliferation
and endothelial apoptosis.
Nitric oxide is a gas identified in 1980 as the endothelium derived relaxing factor (EDRF). NO is lipophilic, and
passes easily through cell membranes. Nitric oxide is synthesised by the reaction of oxygen with L-arginine to
produce NO and L-citrulline under the catalytic activity of NO synthase. There are 3 isoforms of NO synthase.
Endothelial NO synthase = eNOS. The main function of nitric oxide in endothelial cells is the regulation of
vascular tone (blood supply to organs).
Nitric oxide is reduced by risk factors. Loss of nitric oxide bioactivity is mainly due to quenching by superoxide,
released in response to risk factors such as diabetes and smoking. The superoxide reacts with nitric oxide to
form peroxynitrite, which causes tissue injury.
Angiogenesis
Angiogenesis is the formation of new blood vessels by sprouting from pre-existing vessels.
Atherosclerosis lesions can be vascularised by a network of capillaries that arise from the
adventitial vasa vasorum. These capillaries may be important regulators of plaque growth
and instability.
Macrophages within the plaque release growth factors that stimulate angiogenesis:
Platelet derived growth factor
Fibroblast growth factor
Transforming growth factor beta
Vascular endothelial growth factor
The new capillaries are immature, fragile and prone to rupture. Consequences of neovascularisation can
therefore include haemorrhage leading to debris addition in the necrotic core, increase in plaque size and
plaque rupture, as well as being a further portal of entry for leukocyte recruitment.
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Lipids, Macrophages and Vascular Smooth Muscle Cells in Atherosclerosis
by Dr Joseph J Boyle
Atherosclerosis is a stereotypic arterial response to injury, the exact pathology of which is determined by the
nature and duration of the stimulus.
Risk factors have been identified to predispose an individual to the development or progression of coronary
heart disease and the occurrence of cardiovascular events. Evidence has shown that lifestyles associated with
a ‘western’ culture such as a diet rich in saturated fats and high in calories, smoking and physical inactivity,
are some of the modifiable risk factors leading to an increase in the prevalence of cardiovascular events.
Of these, three are considered to be of prime importance:
Smoking is responsible for 50% of all avoidable deaths, of which half are cardiovascular problems.
Raised blood pressure has been found to be an important risk factor for the development of CHD,
cardiac failure and cerebrovascular disease. The greater the increase in blood pressure the higher the
risk. Greatest benefit of blood pressure lowering is seen in those at higher risk. Even modest
reductions produce substantial benefits in those with multiple risk factors.
Dyslipidaemia, in particular, raised low-density lipoprotein (LDL) cholesterol and triglyceride levels,
and low high-density lipoprotein (HDL) cholesterol are associated with increased risk of CVD.
However, raised LDL cholesterol has been shown to be most strongly associated with the
development of atherosclerosis and the risk of CV events.
Monocytes
Monocytes are a type of white blood cell. White blood cells are defence cells, which normally kill
microorganisms (germs) by a number of mechanisms. White blood cells can sometimes injure host tissue if
they are activated excessively or inappropriately.
Low density lipoproteins (LDLs) leak through the endothelial
barrier and become trapped in the sub-endothelium. Trapped
LDLs become oxidatively modified by free radicals, and then
they are phagocytosed by macrophages. This stimulates
chronic inflammation.
Lipoproteins
Low density lipoproteins are the bad cholesterol, synthesised in the liver. LDLs
carry cholesterol from the liver to the rest of the body, including the arteries
themselves.
High density lipoproteins are the good cholesterol. They carry cholesterol from
peripheral tissues including arteries back to the liver. This is known as “reverse
cholesterol transport”.
Oxidised LDLs or “modified” LDLs are created by the action of free radicals.
These are not one single substance. There are whole families of highly
inflammatory and toxic forms of LDL found in vessel walls.
Familial hyperlipidaemia is due to a failure to clear LDL particles from the blood. This results in xanthomas,
which are small collections of fat visible on the skin as lumps, and early atherosclerosis. Brown and Goldstein
received the Nobel Prize for medicine in 1985, when they hunted for the gene responsible for familial
hypercholesterolaemia (high LDL and severe atherosclerosis). They discovered the LDL receptor (expression of
which is negatively regulated by intracellular cholesterol). This led to the discovery of HMG-CoA Reductase
inhibitors (statins) for lowering plasma cholesterol. They also proposed a second LDL receptor (this time not
under feedback control) involved in atherosclerotic lesions. These were called the scavenger receptors since
they hoovered up chemically modified (oxidised) LDLs. Today there are known to be a family of scavenger
receptors expressed by macrophages.
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Macrophages within Plaques
Monocyte-macrophage differentiation occurs after transendothelial migration. Macrophage scavenger
receptors mediate the clearance of microorganism, apoptotic cells and oxidised lipoproteins. Macrophages
1
within atherosclerotic plaques generate free radicals that modify (oxidise) lipoproteins . The macrophages
phagocytose modified lipoproteins and become foam cells. On activation, they express and secrete:
2
Cytokine mediators that recruit more monocytes (e.g. TNFα, IL-1, MCP-1)
3
Chemoattractants and growth factors for vascular smooth muscle cells
4
Proteinases that degrade tissue (e.g. the fibrous cap)
5
Tissue factor that stimulates coagulation upon contact with blood
Macrophages die by apoptosis, which further contributes to the lipid-rich core of the plaque.
1.
Macrophages have oxidative enzymes that can modify native LDLs.
NADPH oxidase is found in the membrane of the macrophages and generates superoxide by
transferring electrons from NAPDH inside the cell across the membrane and coupling these to
molecular oxygen to produce the free radical. In the macrophage, superoxide can spontaneously form
hydrogen peroxide that will undergo further reactions to generate reactive oxygen species (ROS).
Another enzyme called superoxide dismutase converts superoxide into hydrogen peroxide.
Myeloperoxidase produces hypochlorous acid (HOCl) from reactive oxygen species and chloride. It
can also produce peroxynitrite, which is an oxidant and nitrating agent.
2.
Plaque macrophages express inflammatory factors involved in monocyte recruitment. Cytokines are capable
of activating endothelial cell adhesion molecules (e.g. E-selectin, ICAM-1, VCAM-1). For example, interleukin1 and tumour necrosis factor α.
Proteins with direct chemoattractant (chemokine) properties on monocytes include interleukin-8 and
monocyte chemotactic protein-1 (MCL-1).
3.
This is to do with the “wound healing” role of macrophages in atherosclerosis. Macrophages release protein
growth factors that recruit vascular smooth muscle cells and stimulate them to proliferate and deposit
extracellular matrix. Platelet derived growth factor causes
vascular smooth muscle cell chemotaxis and cell division.
Fibroblast growth factor promotes smooth muscle cell survival
and cell division. Transforming growth factor beta is key in
increasing collagen synthesis.
Vascular smooth muscle cells are non-striated, elongated cells.
They are normally specialised for contraction, which constricts
the vessel lumen and regulates blood flow. Under injury or free
radical stress, vascular smooth muscle cells may switch to a
“synthetic” phenotype, specialised for synthesis of extracellular
matrix.
4.
Macrophages proteolyse extracellular matrix. Metalloproteinases
are a family of about 28 homologous enzymes. They activate each
other by proteolysis and degrade collagen by a catalytic
mechanism based on zinc.
Vulnerable and stable plaques are large soft eccentric lipid-rich
necrotic cores with a thin fibrous cap. They have reduced vascular
smooth muscle cells and collagen content, and there is increased
vascular smooth muscle cell apoptosis. There is an infiltrate of
activated macrophages expressing metalloproteinases.
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5.
Plaque macrophages express tissue factor. Tissue factor is a 263 amino acid membrane protein expressed on
activated macrophages. It initiates the coagulation cascade by interacting with Factor VII. It can be readily
detected on macrophages in atherosclerotic plaques. Erosion or rupture of the fibrous cap leads to access of
the plasma coagulation cascade to macrophage tissue factor with consequent thrombosis.
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Coronary Heart Disease, Angina and Myocardial Infarction
by Professor Peter Collins
The commonest cause of death in this country in both men and women is coronary heart disease. The risk of
chronic disease and death in relation to coronary heart disease increases exponentially with age.
Most risk factors of coronary heart disease are modifiable. For example: hypertension, diabetes, cigarette
smoking, lipids, sedentary lifestyle, obesity and oestrogen status (oestrogen is cardio-protective). Nonmodifiable risk factors include gender (women are more protected), age, menopause, family history and
ethnicity. The risk factors don’t just add to each other, they can actually synergise together, which causes
immensely increased chances of coronary heart disease. 90% of cardiovascular disease is preventable, as long
as the risk factors are identified and managed.
Coronary heart disease is to do with the coronary arteries which supply the heart itself with oxygenated blood.
If they are blocked for whatever reason, it will lead to the death of the muscle being supplied. The disease
process that causes heart disease is atherosclerosis. Atherosclerosis is largely due to the aforementioned risk
factors. Narrowing of the vessel due to atheromatous plaque can cause angina pectoris or a thrombotic
occlusion of the coronary artery. A developing clot can become very large within minutes, and chest pain
worsens as the vessel closes.
Coronary heart disease starts after birth, according to data from heart transplant donations. 17% of 13 to 19
year olds often have significant narrowing or deposits in the coronary arteries. The process starts in the teen
years, and can worsen over time.
Diet and lifestyle are the most important factors that will influence the cause of coronary heart disease.
Weight loss can have very profound effects on blood pressure, cholesterol and blood triglycerides, and so
patients are often encouraged to change their lifestyle. It can make a huge difference to important risk factors
such as blood sugar, blood lipids and blood pressure.
Chest Pain
“Strangling in the chest” is angina. Obstructive narrowing in the coronary arteries reduces blood flow into the
myocardium, and lack of oxygen produces ischaemia, and therefore produces chest pain. Atheroma is the
obvious cause of angina pectoris, and is also the setting for coronary thrombosis which leads to myocardial
infarction. Only about 60% of people suffering heart attack reach hospital in time, in particular young men
don’t get angina, they go straight to thrombosis and infarction - sudden death.
Angina pectoris: chest discomfort or pain on exertion due to myocardial ischaemia typically associated with
coronary artery disease (other causes may be aortic stenosis or hypertrophic obstructive cardiomyopathy).
Stable angina: angina occurring over several weeks without major destruction, although symptoms may vary
considerably over time e.g. with exertion or stress. In cold weather angina can get worse as sympathetic drive
is increased to cause peripheral vasoconstriction, so the heart has to do more work.
Unstable angina: abruptly worsening (crescendo) angina or new angina at low work load. The frequency and
severity of chest pain will change and exercise tolerance will decrease. This means there could be critical
narrowing or the dynamic process of the ruptured plaque.
Variant (Prinzmetal) angina: rarer spontaneous (i.e. no precipitating cause) angina with ST segment elevation
on an ECG. Classically this is patients describing chest pain at night (nocturnal angina) - spasm of the coronary
arteries (less than 1% of all patients).
Syndrome X angina: angina with objective evidence of myocardial ischaemia (e.g. ST depression) in the
absence of evident coronary atherosclerosis or epicardial (large vessel) disease.
Decubitus angina: angina when lying flat due to slight increase in venous return - signifies critical coronary
disease.
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A diagnosis of cardiac chest pain is often made from a patient history, and an examination can make the
confirmation. In the past medical history, previous illness should be taken into account, as well as diabetes,
hypertension, medication and allergies. Angina investigations include taking a blood pressure, lipids, ECG,
stress test and angiography. A coronary angiogram is where a tube is inserted into an artery at the groin and
directed towards the coronary arteries. A dye is injected and X-rays of the heart and coronary arteries are
taken.
The site of chest pain is usually in the centre of the chest, with a characteristic feeling of dull pressure that gets
worse with exercise. The mode of onset is usually progressive but can sometimes have a sudden onset. The
pain radiates up into the neck and left arm. If the pain is positional, then it is unlikely to be a cardiac problem,
with the exception of pericarditis in young people where the lining of the pericardium is infected by a virus,
and the pain can be worse depending on body position. The patient should be asked of precipitating or
relieving factors for the pain. Glyceryl-trinitrate (GTN) tablets can often bring relief.
Myocardial infarction is “crushing” pain which is sudden and severe and causes sweating. There are other
structures in the chest which can mimic cardiac chest pain. For example, a “tearing” pain going into the back
can be aortic dissection. Pericarditis is a sharp, sudden onset associated with posture and breathing. Only 20%
of myocardial infarction are preceded by angina. 50% of myocardial infarction are followed by angina.
Treatment
The aims of therapy are to reduce morbidity and mortality and to eliminate angina with minimal adverse
effect allowing the patient to return to normal activities. Cardio-protective medication usually doesn’t treat
angina, e.g. statins and aspirin. The overview of management is to treat the angina with drugs, for example
with beta-blockers (such as atenolol, metoprolol, bisoprolol) which decrease exercise induced heart rate.
Calcium antagonists like dihydropyridines block calcium channels in vascular smooth muscle to open up the
coronary arteries. Nitrates such as GTN act like nitric oxide to open up blood vessels (smooth muscle
relaxation). Nicorandil is another calcium channel opener to cause vasodilation. All these methods decrease
myocardial work to decrease the chance of angina. Education and risk factor management is important, as well
as anti-platelet therapy or revascularisation therapy.
Beta-blockers are first line therapy because of the prognostic benefit. All are equally effective at symptom
relief, and the dose is adjusted to achieve a resting heart rate of 55 to 60. There are contraindications of betablockers, for example absolute beta-blockers can induce severe Bradycardia, high-grade AV block or sick sinus
syndrome. Relative beta-blockers can induce asthma, depression or peripheral vascular disease. Side-effects of
beta-blockers can include fatigue and lethargy, insomnia and nightmares, claudication or asthma, impotence
and erectile dysfunction.
Calcium antagonists are added to or are used instead of beta-blockers. All are negative inotropic and cause
variable peripheral vasodilation. Amlodipine is more vasoselective than nifedipine and so is preferred. Shortacting dihydropyridines may increase adverse cardiac events. Contraindications and side effects of calcium
antagonists include decompensated heart failure, Bradycardia and high-grade AV block, sick sinus syndrome,
hypotension, peripheral oedema, cardiac decompensation, constipation, headache, flushing and dizziness.
Nitrates reduce the preload and dilate coronary arteries. GTN is used for immediate relief or prophylaxis
before exercise. Long-lasting nitrates are added to or are used instead of beta-blockers or calcium antagonists.
However, nitrate-free intervals are required of usually 8 to 12 hours per day. Contraindications and sideeffects of nitrates include outflow tract obstruction, headache, hypotension, presyncope and syncope.
Nicorandil is a potassium channel activator with a nitrate component. It is a veno and arteriodilator, and is as
effective as the other anti-anginals. It should, however, be avoided in situations of low cardiac output and/or
hypovolaemia. Its side-effects include headaches and flushing.
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Thrombosis and Embolism
by Dr Mary Sheppard
Normal haemostasis is the result of well regulated processes that:
1) Maintains blood in a fluid, clot-free state in normal vessels,
2) Induces a rapid and localised haemostatic plug at the site of vascular injury.
Thrombosis is a pathologic opposite of haemostasis and is an inappropriate activation of the normal
haemostatic processes. It is the formation of a blood clot in uninjured vasculature or a thrombotic occlusion of
a blood vessel after a minor injury.
Virchow’s triad was endothelial injury, stasis or turbulence of blood flow, and blood hypercoagulability. If any
of these are triggered, thrombosis is the result.
Endothelial Injury
Atherosclerosis occurs throughout the vasculature, only on the
arterial side. Veins do not get atheromas as they are too wide and
the pressure is much lower - the endothelium is not easily
damaged. The most vulnerable arteries are the coronary arteries.
Atheroma can be seen on angiograms in the coronary arteries,
and the patient will present with angina, which is pain on
exertion. Angiography is where radio-opaque die is injected into
the arteries to look for areas of narrowing.
Atheroma in the iliac or femoral vessels would present as
claudication (limping), and atheroma in the vascular of the head
and neck would present as transient ischaemic attacks, with loss
of ability to speak etc.
Atheroma lipid deposition in the vessel wall is like a nuclear bomb in the circulation as it activates many
clotting factors and sets up a huge thrombus. If the vessel is blocked abruptly, there is no time for collateral
development of other vessels to compensate, there is just loss of blood supply, oxygen deprivation and
infarction. CD34 is found in endothelium, which if lost can be a marker for endothelial erosion.
Abnormal Blood Flow
Thrombosis can also result from alterations in blood flow. Normal blood flow is
laminar, and cellular elements flow centrally. There is a slower moving clear zone
of plasma which separates cellular elements from the endothelium. Turbulence
contributes to thrombosis by causing endothelial injury/dysfunction, forming
countercurrents and local stasis, which is a major factor in the development of
venous thrombosis.
Turbulence and stasis disrupt laminar flow and bring platelets into contact with
the endothelium. They prevent the dilution of activated clotting factors, and
retard the inflow of clotting factor inhibitors. In this way, abnormal blood flow
permits the build-up of thrombi.
Slow moving blood is common in the deep veins of the calf - deep vein thrombosis is still a big killer in
hospitals, particularly in the elderly. Patients lying in bed for prolonged times can be a ticking time bomb for
pulmonary embolism, which can lead to sudden death or infarction of the lung.
Hypercoagulability
Activated platelets send out pseudopodia and interact with each other. There are several receptors that can
activate and aggregate platelets, (glycoprotein 2B3a is a major one). Anti-platelet therapy can block receptors
to prevent platelet aggregation and deposition of fibres around those platelets.
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The coagulation cascade involves conversion of fibrinogen to fibrin. Hypercoagulability states do occur,
although they contribute less frequently to thrombotic states. Primary hypercoagulability states are genetic
and inherited, whereas secondary states are acquired.
Inherited hypercoagulability commonly involves a factor V gene mutation (2 to 15% of the Caucasian
population), which is known as Factor V Leiden or Leiden mutation. The carrier frequency may be as high as
60% of patients with recurrent deep venous thrombosis. There can also be a lack of “natural” anticoagulants,
such as antithrombin III, protein C, or protein S. Inherited elevated levels of homocysteine may also contribute
to arterial or venous thromboses.
Acquired hypercoagulability states include post surgery, as many clotting factors are activated, and also post
childbirth as DVT can occur (common cause of maternal mortality). Anti-coagulation is therefore very
important in childbirth. Heparin-induced thrombocytopenia and antiphospholipid antibody syndrome are
common in the elderly.
Hypercoagulability can also be as a result of congestive heart failure, trauma, surgery, burns, vessel injury and
release of procoagulant substances. Advanced age, bed rest and immobilisation are all factors that increase
the risks.
Ante-mortem thrombi show laminations called lines of Zahn produced by alternating pale layers of platelets
and fibrin and dark layers of red cells. This means there was thrombosis at the site of blood flow while the
person was alive. A post mortem clotting is common after death, but this will be a dark jelly making up the
shape of the vessel - no lines of Zahn.
Types of Arterial Thrombi
Mural thrombi are adherent to the wall of an underlying structure (such as heart chamber) and
indicate abnormal cardiac contraction or damage.
Aortic thrombi are usually associated with ulcerated atherosclerotic plaque and/or aneurysmal
dilation.
Arterial thrombi are usually occlusive, involving coronary, cerebral and femoral arteries most commonly. They
are usually superimposed on atherosclerotic plaque (other forms of vascular injury may be involved, such as
vasculitis or trauma). Arterial thrombi are typically grey-white, friable, firmly adherent and composed of
platelets, fibrin, erythrocytes and degenerating leukocytes (which is why they are also known as “white
thrombi”).
Risk factors for arterial thrombosis:
Atherosclerotic occlusive disease
Aortic and peripheral aneurysms (especially popliteal)
Hypercoagulable states
Vasculitis
Catheterisation procedures
Thrombi development can be seen in heart failure. The importance of thrombi in general is that they are an
obstruction of arteries and veins that are a source of emboli. Arterial thrombi cause obstruction and infarction
(e.g. myocardial infarction). Infarction can be seen as destruction of the tissue. In cardiac tissue, there can be
pale areas of infarction. Thrombosis in a middle cerebral vessel can cause cerebral infarct. Cerebral infarct
heals by forming a cyst.
Venous Thrombi
Phlebothrombosis is also frequently occlusive (red or stasis thrombi). They usually involve the veins of the
lower extremities (in 90% of cases), occurring in the superficial saphenous system or the deep veins of the legs.
The risk factors for venous thrombosis are similar, with stasis in bed rest, obesity, congestive cardiac failure,
trauma, surgery, hypercoagulable states and drug abuse. Venous thrombi can cause life-threatening
pulmonary embolism. The superficial venous thrombi rarely embolise, but cause local congestion with
swelling, pain, tenderness and may lead to varicose ulcers. The deep thrombi are more serious as they can
embolise. Obstruction can be bypassed by collateral channels. 50% of cases are entirely asymptomatic.
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1% of venous thromboses cause complications. As a clot develops in size, pieces can break off - these are
emboli. The emboli float through the blood system and travel through the heart to the pulmonary arteries in
the lungs, causing sudden death if they are very large. Blocks in the pulmonary vessels will cause pulmonary
infarction.
Fate of a Thrombus:
Propagation: accumulation of additional platelets and fibrin.
Embolisation: dislodging of all or part of the thrombus and travelling to other sites in the vasculature.
Dissolution: activation of fibrinolytic pathways may cause rapid shrinkage or total lysis.
Big thrombi with extensive fibrin cannot be lysed completely.
Organisation and recanalisation.
A thrombus that breaks off and circulates through the bloodstream is called an embolus. The source of an
embolus can be veins, arteries or even the heart. The rate of fatal pulmonary embolism has declined, but is still
responsible for up to 200,000 U.S. deaths yearly. Most are clinically silent because of their small size. Sudden
death, cardiovascular collapse, or right heart failure may occur when 60% or more of pulmonary circulation is
occluded by emboli.
Organisation refers to ingrowth of endothelial and smooth muscle cells and fibroblasts, with formation of
capillary channels. Recanalisation may allow re-establishment of blood flow and thrombus is incorporated as
subendothelial swelling.
Embolism
An embolus is a detached intravascular solid, liquid or gaseous mass that is carried by the blood to a site
distant from its point of origin. An embolus will circulate freely through vessels until it reaches one so small
that it cannot go further. Most emboli are part of a dislodged thrombus (thromboembolism). Rare forms
include fat droplets, air or nitrogen bubbles, atherosclerotic debris (cholesterol emboli), tumour, foreign
bodies, etc. The potential consequence of embolism is ischaemic necrosis of distal tissue (infarction).
Emboli from the heart cause atrial flutter, valve disease, myocardial infarction, cardiomyopathy, cardiac
tumours and endocarditis.
Systemic thromboembolism is when emboli are travelling within the arterial circulation. Most arise from
intracardiac mural thrombi (80%) from left ventricular wall infarction, and a quarter from dilated left atria. The
remainder are from aortic aneurysms, thrombi on atherosclerotic plaques, and fragmentation of valvular
vegetation. A small fraction is paradoxical emboli which pass through atrial septic defects to the systemic
circulation.
Air embolism is made up of three main types of gases - oxygen, carbon dioxide and nitrogen. An air embolism
is when bubbles of air are in the circulating blood. In the “bends”, associated with diving, the air embolism is a
bubble of nitrogen. In other air embolisms, not caused by diving, the bubble contains a normal mix of air gases.
Fat embolism syndrome follows long bone fractures. Vascular occlusion in fat embolism is often temporary or
incomplete since fat globules do not completely obstruct blood flow.
Infarction
An infarct is an area of ischaemic necrosis caused by the occlusion of either the arterial supply or the venous
drainage in a particular tissue. Infarction is often as a result of blockage of blood circulation to a localised area
or organ of the body resulting in tissue death. Infarctions commonly occur in the spleen, kidney, lungs, brain
and heart.
Factors that influence the development of an infarct include the nature of the vascular supply, the rate of
development of an occlusion, the vulnerability of tissue to hypoxia, and the oxygen content of the blood.
Types of infarcts are based on the colour and presence/absence of microbial infection. Red infarcts occur with
venous occlusions where loose tissues allow blood to collect or in previously congested tissues with dual
circulation. They often occur following re-establishment of blood flow.
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White infarcts occur with arterial occlusions. They occur in solid organs where solidity of tissue limits the
amount of haemorrhage. The infarcts tend to be wedge shaped, and tend to show ischaemic coagulative
necrosis, except in the brain, where cell death results in liquefactive necrosis.
Septic infarctions can sometimes develop, with bacterial vegetation fragments. The microbes seed necrotic
tissue, and the infarct can convert into an abscess. E.g. renal abscess due to septic embolus in bacterial
endocarditis (embolus from valve in heart).
Gangrene is the death of tissue in part of the body, usually the limbs. Gangrene occurs when a body part loses
its blood supply, due to blocking of a vessel, injury or infarction. Risk of gangrene increases with diabetes,
blood vessel diseases, serious injuries, surgery, immunosuppression and meningococcal septicaemia.
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Pathophysiology of Heart Failure
by Professor Peter Collins
Heart failure can be defined as a syndrome when the heart is unable to maintain an appropriate blood
pressure without support. This is a good definition as it is not a single entity, and the main feature of the heart
is that it maintains blood pressure. It is a clinical syndrome caused by abnormality of the heart, recognised by
characteristic pattern of haemodynamic, vascular, kidney, neural and hormonal responses.
In evolutionary terms, heart failure is the body’s response to haemorrhage. When the heart fails, it perceives
that it the body is bleeding, and so it tries to conserve the intravascular volume, and these are the changes
that can be seen in chronic heart failure. There are a number of responses that bring about the changes we see
- baroreflexes, chemoreflexes, ergoreflexes and perfusion of organs.
In some ways, heart failure is hypoperfusion of the kidneys. As the heart fails to maintain a cardiac output,
this is seen by the kidneys, which in turn switch on all sorts of different reflexes to facilitate salt and water
retention (this is seen in heart failure).
Acute heart failure is quite synonymous with pulmonary oedema, which is fluid in the lungs. Circulatory
collapse is quite synonymous with cardiogenic shock (poor peripheral perfusion, oliguria, hypotension). The
oliguria is a result of the kidneys trying desperately to conserve fluid.
Chronic heart failure is termed congestive cardiac failure. These patients will find it difficult to exercise, will
feel tired and lethargic and will develop fluid retention (swelling at the ankles, sacral oedema and pulmonary
oedema).
Causes
There are many causes of heart failure, for example arrhythmias - a persistence tachycardia or atrial
fibrillation, ventricular tachycardia. Valve diseases such as leaking mitral or aortic valves or tight aortic valves
can cause left ventricular failure because the heart will have to work harder. Pericardial disease due to
infection or inflammation will cause problems of diastole (heart can’t relax) as the heart will be encased in
such a way that it can’t beat properly. Congenital heart disease, transposition of great arteries, single
ventricles, patent ductus arteriosus can all result in the heart failing.
The most common cause is myocardial disease. Cardiomyopathy can be specific or idiopathic, and can also be
due to genetics (e.g. hypertrophic obstructive cardiomyopathy), can be restrictive or can rarely be due to
rhythm disturbances. High blood pressure (hypertension) is a common cause of cardiomyopathy due to
hypertrophy of the heart walls. Drugs can impair heart function, for example beta-blockers, calcium
antagonists and anti-arrhythmics.
Terms in relation to heart failure
“Forward and backward” heart failure is terminology used to describe back pressure in the lungs causing a rise
in pressure which causes fluid to settle in the lungs.
“Right and left ventricular” heart failure are related, as the commonest cause of right sided heart failure is left
sided heart failure. This is also termed congestive heart failure.
“Systolic” heart failure means the heart is impaired or damaged by an infarct so there is only a partial amount
of the myocardium to cause systole. “Diastolic” heart failure means the heart doesn’t fill properly, e.g. if the
heart muscle is very stiff.
“High and low” heart failure is in relation to cardiac output.
High output states can have a number of different causes:
- In anaemic patients the heart will have to pump more to deliver blood to the tissues.
- Extreme thyrotoxicosis will over-stimulate the heart.
- Pregnancy-associated cardiomyopathy can be fatal.
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-
Arterio-venous shunts will increase cardiac output.
Beriberi is a rare cause in parts of Africa.
The increased blood supply to the bones in Paget’s disease.
Kidney diseases associated with inflammation e.g. Nephritis can cause high output.
Heart Failure and Cardiomyopathy
“Cardiomyopathy” is heart disease in the absence of a known cause - particularly coronary artery disease,
valve disease and hypertension. Cardiomyopathy is the cause of approximately 5% of heart failure in the
population:
Hypertrophic cardiomyopathy can sometimes lead to the sudden death of athletes due to
hypertrophic obstruction - this is a 1 in 500 chance, and so there is now screening in schools.
Idiopathic Dilated cardiomyopathy has a 1 in 5,000 prevalence in this 5%, and is an idiopathic disease
where the heart balloons.
Restrictive cardiomyopathy has a prevalence of 1 in 10,000.
Arrhythmic right ventricular cardiomyopathy has 1 in 5,000 prevalence and can be picked up by
echocardiogram.
People die from heart failure with progression as the heart becomes more dysfunctional. There is increased
myocardial wall stress and increased retention of sodium and water. Sudden death results from opportunistic
arrhythmia or an acute coronary event (often undiagnosed). Of course a cardiac event such as a myocardial
infarction can result in death, and also other cardiovascular events such as strokes or peripheral vascular
disease. There are also non-cardiovascular diseases such as pneumonia which can result in death by heart
failure.
Rarer causes
Causes associated with fibrosis can lead to diastolic dysfunction. This is sometimes seen in the elderly
with hypertrophy, ischaemia and scleroderma.
Infiltrative disorders (e.g. amyloidosis, sarcoid disease, inborn errors of metabolism, neoplasia) can
also cause cardiomyopathy.
Storage disorders like haemochromatosis and haemosiderosis are iron deposits in the heart (common
in Mediterranean) which can cause cardiomyopathy.
Endomyocardial disorders such as endomyocardial fibrosis (common in sub-Saharan Africa),
hypereosinophilic syndrome, carcinoid, metastases, and radiation damage can all cause
cardiomyopathy.
Heart Disease and Heart Failure
Coronary heart disease is the leading cause of death in Europe. Modern treatment causes an increase in
survival, and the death rate from coronary heart disease is dropping every year. Survivors, however, are left
with a damaged heart, and 50% of all heart attack survivors develop some form of heart failure or myocardial
dysfunction. Deaths due to heart attacks are declining but deaths due to heart failure are increasing. The
population is ageing and heart failure is commoner in old age. Only a minority of patients with heart failure are
receiving the latest drugs.
Epidemiology of Heart Failure
Heart failure has a prevalence of 1 to 3% in the general population, and 10% in those over 75 years of age. The
incidence (new cases) ranges from 0.5 to 1.5% per year. The prognosis of heart failure is often worse than
cancer, and 50% of patients are dead within 3 years. In the community the mean age is 76 years old, and is
50/50 in men and women.
Heart failure results in 5% of acute hospital admissions and 10% of bed occupancy, and accounts for 40% of
readmissions in one year. 40% of hospital admissions are dead within one year, and heart failure takes
approximately 2% of the total health budget, and is particularly a burden because there are often comorbidities in the elderly.
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Hormonal Mediators in Heart Failure
There are all sorts of activated systems in heart failure, and treatment is aimed at interaction with these
systems. The mediators stimulated in heart failure are the mediators released if, for example, your femoral
artery was cut and a litre of blood was lost.
The body releases adrenaline and noradrenaline (vasoconstriction), turns on renin-angiotensin to shut down
the kidneys for water retention, and vasopressin is released. There are also dilators that are released, which
are in some ways disadvantageous. For example, ANP, prostaglandin E2, nitric oxide, dopamine, etc. In the
long term, growth factors such as insulin, TNF alpha, growth hormone, angiotensin II, catecholamines, etc are
released and can cause detriment to the cardiovascular system.
There are some organ-specific inflammatory markers and cytokines. Troponin is released from the heart, ICAM
and VCAM are released from the vessel walls, and lipoprotein associated macrophages are released. From all
cell types there are interleukins and TNF alpha released, which stimulate the liver to release C-reactive protein,
fibrinogen and serum amyloid A. All these factors produce a chronic inflammatory response.
One of the systems that has been prominent over the last 10 years is the angiotensin converting enzyme
system which is activated in heart failure. It has allowed a very effective form of therapy called ACE inhibition
by drugs (the prils). They block the production of angiotensin II (potent vasoconstrictor) and bradykinin. ACE
inhibition improves symptoms of patients with heart failure and improves longevity. As ACE inhibitors block
bradykinin, however, a cough is a common symptom of patients being treated. There can also be risks of
endothelial dysfunction such as plaque rupture, fissure, instability or activation which has significant clinical
sequelae.
NYHA Classification of Functional Capacity
Class I:
Patients with cardiac disease but without resulting limitation of physical activity. Ordinary
physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain.
Class II:
Patients with cardiac disease resulting in slight limitation of physical activity. They are
comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or
anginal pain.
Class III:
Patients with cardiac disease resulting in marked limitation of physical activity. They are
comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea, or
anginal pain.
Class IV:
Patients with cardiac disease resulting in inability to carry on any physical activity without
discomfort. Symptoms of heart failure or the anginal syndrome any be present even at rest.
If any physical activity is undertaken, discomfort is increased.
The Criteria Committee of the New York Heart Association (NYHA) (revision) Circulation 1994;90:644-645
Signs and symptoms of heart failure
Pitting oedema - pressing for a few seconds causes the oedema to pit, causing indentation. This can be gross if
there is serious heart failure. Increased jugular venous pressure is the only way to assess intracardiac pressure
clinically (pressure in the right atrium). This measurement can be used to assess whether the patient is getting
better or not. Sometimes patients can develop serious ascites, with litres of fluid build-up in the abdomen.
Cardiac enlargement shown on an x-ray can also be indicative of heart failure if the heart has enlarged to over
50% of the thoracic diameter. Chest x-rays will also show signs of pulmonary oedema. Magnetic resonance
imaging can be used to assess the condition of a patient with heart failure, measuring wall thicknesses etc.
Objectives of treatment in chronic heart failure:
1) Prevention: identify the causes of myocardial damage (occurrence, progression) and reoccurrence
(symptoms, fluid accumulation, hospitalisation).
2) Relief of symptoms and signs: eliminate oedema and fluid retention and increase exercise capacity.
Reduce fatigue and breathlessness.
3) Prognosis: reduce mortality.
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Management of heart failure:
The causes and predisposing factors need to be eliminated (e.g. limit/avoid alcohol).
Prevent myocardial ischaemia and treat hypertension.
Prevent paroxysmal arrhythmias and reduce salt intake.
Check drugs prescribed and taken and assess lipids.
Encourage exercise and give advice on lifestyle - flu immunisation and discourage smoking.
Options in the treatment of heart failure:
1.
Drugs Diuretics
2.
3.
4.
5.
+
Loop, thiazide, K sparing, metolazone
spironolactone or combination
ACE inhibitors
Beta-blockers
Digoxin
Aspirin, statins, anticoagulants
Angiotensin II receptor inhibitors, nitrates, hydralazine
antiarrhythmics, IV inotropes
Surgery, CABG or valve surgery
Implantable cardioverter-defibrillator - ICD, pacing
Haemofiltration, peritoneal dialysis or haemodialysis
Aortic balloon pump, ventricular assist devices
cardiomyoplasty, volume reduction, transplantation
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