Foundation 3
CVS
Arterial Blood Gas (ABG)
A test that measures the levels of oxygen and carbon dioxide in the blood, as
well as the blood's pH, which helps assess lung and kidney function and the
body's overall acid-base balance.
Arterial blood pressure
The pressure exerted by the blood against the walls of arteries, primarily
measured as systolic (pressure during heart contraction) and diastolic (pressure
during heart relaxation) values, typically reported in millimeters of mercury (mm
Hg).
Atrial fibrillation
A common heart rhythm disorder characterized by irregular and often rapid
heartbeat originating in the atria, leading to inefficient pumping of blood into the
ventricles.
Autonomic nervous system
A part of the nervous system responsible for involuntary functions like heart rate,
digestion, and respiratory rate, divided into the sympathetic (fight or flight) and
parasympathetic (rest and digest) branches.
Aorta
The largest artery in the body that originates from the left ventricle of the heart
and carries oxygenated blood to the rest of the body.
Arterio-venous
Relating to the connection or communication between an artery and a vein.
Atrioventricular node
A small cluster of cells in the heart that acts as a natural electrical relay station,
delaying the electrical signal between the atria and ventricles, allowing the
ventricles to fill before contracting.
Atrioventricular valve
Valves located between the atria and ventricles of the heart; the tricuspid valve
separates the right atrium and right ventricle, and the bicuspid (mitral) valve
separates the left atrium and left ventricle.
Blood pressure
The force of blood against the walls of arteries, with systolic pressure (during
heartbeats) and diastolic pressure (between heartbeats); usually expressed as
systolic/diastolic (e.g., 120/80 mm Hg).
Beats per minute
A measure of heart rate, indicating the number of times the heart contracts
(beats) in one minute.
Cerebral blood flow
The rate at which blood is delivered to the brain, crucial for maintaining brain
function and supplying oxygen and nutrients to brain cells.
Capillary hydrostatic pressure
The pressure exerted by blood within capillaries, which forces fluid out of
capillaries and into the surrounding tissues.
Central nervous system
The part of the nervous system that includes the brain and spinal cord,
responsible for processing sensory information, thoughts, and motor commands.
Cardiac output
The volume of blood pumped by the heart in one minute, calculated as the heart
rate multiplied by the stroke volume.
Capillary oncotic pressure
The osmotic pressure generated by proteins (mainly albumin) in the blood, which
helps to draw fluid back into capillaries
Cardiopulmonary pressure
Pressure within the heart and lungs, typically referring to the pressures
measured during medical procedures or tests.
Central venous pressure
The pressure in the vena cava that returns blood to the right atrium of the heart;
it reflects the filling pressure of the right side of the heart.
Diastole
The phase of the cardiac cycle when the heart muscle relaxes and fills with
blood.
Diastolic pressure
The lower number in a blood pressure reading, representing the pressure in
arteries when the heart is at rest (during diastole).
Deep vein thrombosis
A condition where a blood clot forms in a deep vein, most commonly in the legs,
which can be a serious medical condition if the clot breaks free and travels to the
lungs.
Electrocardiogram
A test that records the electrical activity of the heart to evaluate its rhythm and
detect any abnormalities.
Echocardiogram
A diagnostic test that uses ultrasound waves to create images of the heart's
structure and function.
End diastolic pressure
1. The pressure in the ventricles at the end of the diastolic filling phase, just before
the next contraction.
End diastolic volume
The volume of blood in the ventricles at the end of diastole, just before
contraction begins.
Ejection fraction
The volume of blood in the ventricles at the end of diastole, just before
contraction begins.
End systolic volume
The volume of blood remaining in the ventricles at the end of systole (after
contraction).
Heart rate
The number of times the heart beats in one minute, usually expressed as beats
per minute (bpm).
Inferior vena cava
The large vein that carries deoxygenated blood from the lower half of the body
to the right atrium of the heart.
Left atrium
One of the heart's four chambers that receives oxygenated blood from the lungs
and pumps it into the left ventricle.
Left atrial pressure
The pressure in the left atrium of the heart, which reflects the filling pressure of
the left ventricle.
Left ventricle
The heart's main pumping chamber that receives oxygen-rich blood from the left
atrium and pumps it into the aorta to be distributed throughout the body.
Mean artrial pressure
The average pressure in the arteries during one cardiac cycle, calculated as onethird of the systolic pressure plus two-thirds of the diastolic pressure.
Mean arterial blood pressure
Synonymous with mean arterial pressure (MAP), representing the average
pressure in the arteries.
Myocardial infarction
Also known as a heart attack, it occurs when blood flow to a part of the heart
muscle is blocked, leading to tissue damage or cell death.
Pulse pressure
The difference between systolic and diastolic blood pressure, reflecting the force
generated by the heartbeat.
Pulmonary vascular resistance
The resistance or opposition to blood flow in the pulmonary circulation,
important for maintaining blood flow to the lungs.
Right atrium
One of the heart's four chambers that receives deoxygenated blood from the
body and pumps it into the right ventricle.
Right ventricle
The heart's chamber that receives blood from the right atrium and pumps it into
the pulmonary artery, sending it to the lungs for oxygenation.
Sino-atrial node
The natural pacemaker of the heart, located in the right atrium, responsible for
initiating the electrical impulses that regulate the heart's rhythm.
Systole
The phase of the cardiac cycle when the heart muscle contracts and pumps
blood into the arteries.
Systolic pressure
The higher number in a blood pressure reading, representing the pressure in
arteries during heartbeats
What are the three layers of both the heart and
the blood vessels?
1. Tunica Intima - innermost
2. Tunica Media - middle
3. Tunica Externa (adventitia) - outer
What names do we use to refer to the three
layers of the heart instead of the tunica?
1. Endocardium - tunica intima - epithelia lining the heart
2. Myocardium - tunica media - heart muscle
3. Epicardium - tunica adventitia - inner layer of the pericardium (visceral)
What are the layers of pericardium?
1. Fibrous pericardium - outermost
2. Serous pericardium - parietal layer
3. Serous pericardium - visceral layer, epicardium
What is meant by endothelium?
The endothelium is a single layer of squamous endothelial cells that line the
interior surface of blood vessels and lymphatic vessels .
What constitutes the endocardium?
Endothelium and the subepithelial connective tissue
Are endothelial cells the same as epithelial cells
Endothelium cells are a type of epithelial cells that line the bodies vessels lymph and blood
Etymology of myocardium
Ancient greek - mys for muscle become myo and kardia for heart became
cardium
Characteristics of cardiac muscle
• Striated
• Involuntary
• Central nuclei
• Cells are often elongated and branched
• Tightly connected by intercalated discs
• Intercalated dics contains gap junctions, desmosomes, and adhering
junctions
What do the gap junctions, desmosomes, and
adhering junctions of the myocardium create?
A functional syncytium
What is the difference between a true
syncytium and a functional syncytium?
A functional syncytium is a group of individual cells that remain physically
separate but function as a single coordinated unit, typically connected through
gap junctions for the synchronized transmission of electrical or metabolic signals,
whereas, a true syncytium is a single multinucleated cell resulting from the
fusion of individual cells, with continuous cytoplasm and multiple nuclei.
Eg true syncytium
Skeletal muscle cell
Eg functional syncytium
Cardiac muscle cells
What makes up the epicardium?
Mesothelium and connective tissue
Mesothelium
Mesothelium is a type of tissue composed of a layer of flat cells known as
mesothelial cells, which line the body's serous cavities, including the pleural,
pericardial, and peritoneal cavities. These cells secrete a lubricating fluid that
reduces friction between the internal organs and the cavity walls, allowing them
to move smoothly within the body.
What forms the heart valves?
• Formed by thin folds of endocardium
• With dense fibroelastic connective tissue at the core
• Endocarditis - infection of valves that can lead to faulty valves and the
formation of clots that can cause strokes and heart attacks - linked to poor
oral health
What is the fibrous cardiac skeleton?
Four fibrous rings of dense irregular connective tissue that make up the fibrous
core of the heart -> insulates electrically atria from ventricles below and is the
attachment site for myocardium and the heart valves
What are purkinje fibres?
Modified cardiac muscle cells specialised for conduction:
• subendocardial
• stain differently
• they are larger than other cardiac muscle cells
• pale cytoplasm
• contain more glycogen
• few myofibrils and these are mainly located at the cell periphery
• no intercalated discs
The epicardium
What is the tunica media continuous with?
The myocardium
What is the tunica externa or the adventitia
continuous with?
The pericardium
Tunica intima
• Endothelium - simple squamous epithelium
• Basement membrane
• Connective tisue - subendothelial layer
• Sometimes an internal elastic lamina
Tunica media
Mainly concentric layers of smooth muscle and elastin sometimes combined with
an external elastic lamina
Tunica externa/adventitia
• Collagen rich connective tissue
• Simple squamous epithelium
• Larger vessels: lymphatics, nerves, and vasa vasorum - vessel of the vessels
What is different about the tunica media in
arteries and veins?
In arteries, due to them being under higher pressure than veins, the tunica
media is broader.
What are elastic arteries?
Major arteries than come off the heart very quickly, e.g. the aorta, the carotid,
and the pulmonary
What is the specialised histology of elastic
arteries?
• Tunica media - very broad with lots of elastic fibres and collagen
• Elastic arranged in concentric layers
• A few smooth muscle cells
What is the specialised function of elastic
arteries?
• Elastin allows expansion
• Elastic allows recoil and hels maintain arterial pressure during diastole
What does a Van Gieson stain of an elastic
artery show?
The elastin in the elastic of the arteries stains black showing how they are
present in lots and lots of concentric circle layers
What are the distinguishable features of the
elastic arteries?
• Many elastic lamina
• Fenestrations of elastic tissue
• Broad tunica media
What is ageings impact on elastic arteries?
With ageing they lose their elastic tissue which leads to an increase in arterial
resistance and an increase in arterial blood pressure
Muscular arteries eg
Femoral, coronary
Muscular artery lumen size
1-10mm
What is the specialised function of a muscular
artery?
Smooth muscle changes vessel diameter to control blood flow to organs
What is the specialised histology of muscular
arteries?
Tunica media has more smooth muscle cells present than elastic arteries with up
to 40 layers
What is the distinguishable feature of muscular
arteries?
Internal elastic lamina and external elastic lamina present between tunica media
What is the specialised function of arterioles?
Control blood flow to capillaries by vasoconstriction and control blood resistance
and pressure at the periphery
What is the specialised histology of arterioles?
Small artery with small lumen with 1-3 layers of smooth muscle in tunica media.
There is an internal elastic lamina that is present only in large arterioles.
What is the specialised function of capillaries?
Connect arterioles to venules and exchange materials across thin barriers
What is the specialised histology of capillaries?
• Single thin layer of endothelial cells - only part of the tunica intima present no media or adventitia
• supportive pericytes present
What are the three major types of capillaries?
1. Continuous
2. Fenestrated
3. Sinusoid - discontinuous
Features of continuous capillaries
• No pores in endothelial cells
• On complete basement membrane
• Pinocytic vesicles
Features of fenestrated capillaries
• Fenestrae - pores 60-80 mm
• Complete basement membrane
What are the features of sinusoid capillaries?
• Large diameter
• Large fenestrations
• Discontinuous basement membrane permeable to larger macromolecules
• Permeable to larger molecules
What is the specialised function of venules to
medium veins?
• Post-cap venules allow blood return
• WBC usually leave the blood stream here
• Less muscular and elastic content so the lumen is collapsable
• Valves made from fibroelastic tissue prevent backflow
What blood vessel are lymph vessels similar to?
Veins
How are lymph vessels different to veins?
Similar to veins but they have thinner and less distinct layers
What are lymph capillaries?
Thin closed ended vessels - fenestrated endothelium
What is ateriosclerosis?
Arterial stiffening characterised by:
• tunica intima increases in size (intimal proliferation)
• stiffens with age
• can occur in normal ageing
• may be a part of atherosclerotic plaque formation
What is Marfan's syndrome
Genetic disease characterised by:
• mutations in Fibrillin gene
• causes a decrease in functional elastic fibres and therefore a decrease of
recoil
• increased luminal diameter and wall weakening in Marfan's can lead to
aneurysm, aortic dissection/rupture risk
What can replace elastic fibres in blood vessels
in diseases?
Diseases such as ateriosclerosis, atherosclerosis, Marfan's syndrome and EhlersDanlos syndrome can lead to elastic fibres being replaced with collagen.
What are diads in cardiac muscle and how do
they compare with triads in skeletal muscle?
Diads in cardiac muscle and triads in skeletal muscle are structural components
involved in calcium ion regulation for muscle contraction. Diads in cardiac
muscle consist of a T-tubule and a single terminal cisterna of the sarcoplasmic
reticulum, enabling coordinated contractions in the heart. In contrast, triads in
skeletal muscle comprise a T-tubule between two terminal cisternae of the SR,
facilitating powerful and voluntary muscle contractions. While both serve similar
functions, these structures have structural differences that suit the specific
needs of cardiac and skeletal muscle.
What surrounds necrotic cardocytes after a MI?
Three days later after an MI neutrophils surround it
Where is the internal elastic lamina located in
muscular arteries?
Internal Elastic Lamina: The internal elastic lamina is found in the tunica
intima, the innermost layer of the arterial wall. It separates the tunica intima
from the tunica media, which is the middle layer. This layer is primarily
composed of elastic fibers and acts as a boundary between the intima and
media.
Where is the external elastic lamina located in
muscular arteries?
The external elastic lamina is located between the tunica media (middle layer)
and the tunica adventitia (outer layer) of the arterial wall. It is also composed of
elastic fibers and provides structural support to the artery. The external elastic
lamina is not as prominent as the internal elastic lamina but is present in many
muscular arteries
Why does the mitral valve close?
The mitral valve closes during ventricular contraction (systole) to prevent the
backflow of blood from the left ventricle to the left atrium. This closure is driven
by the pressure difference in the cardiovascular system, where the left
ventricular pressure becomes higher than the left atrial pressure. It ensures oneway blood flow, from an area of higher pressure (left ventricle) to an area of
lower pressure (aorta and the rest of the systemic circulation).
Why does the aortic valve open?
The aortic valve opens when the left ventricular pressure becomes higher than
the pressure in the aorta. This pressure difference allows the aortic valve to
open, enabling the ejection of oxygenated blood from the left ventricle into the
aorta, from where it is distributed to the body's systemic circulation.
Why does the aortic valve close and how does
its closing differ from the mitral valve?
The aortic valve closes when the left ventricular pressure falls below the
pressure in the aorta during diastole. This closure prevents the backflow of blood
from the aorta back into the left ventricle. Unlike the mitral valve, which closes
to prevent backflow into the left atrium during ventricular systole when left
ventricular pressure is higher, the aortic valve closes during diastole to prevent
regurgitation into the left ventricle when the aortic pressure exceeds the left
ventricular pressure. This distinction in timing and pressure gradients ensures
the one-way flow of blood in the circulatory system.
Why does the mitral valve open?
The mitral valve opens during ventricular diastole when the left atrial pressure
exceeds the left ventricular pressure. This pressure difference allows the mitral
valve to open, facilitating the flow of oxygenated blood from the left atrium into
the left ventricle, which is a crucial step in the filling of the left ventricle before
the next systolic contraction.
What is end diastolic volume (EDV)?
End-diastolic volume (EDV) is the volume of blood present in the left ventricle at
the end of the diastolic phase of the cardiac cycle, just before the ventricle
contracts (systole). It represents the maximum amount of blood the left ventricle
can hold at the end of its relaxation and filling phase, which occurs during
diastole. EDV is an important parameter in assessing cardiac function and is
often used in calculations to determine measures like stroke volume and ejection
fraction.
What is end systolic volume (ESV)?
End-systolic volume (ESV) is the volume of blood remaining in the left ventricle
at the end of the systolic phase of the cardiac cycle, just after the ventricle has
contracted and ejected blood into the aorta. It represents the minimum amount
of blood left in the ventricle at the end of systole. ESV is an essential parameter
used to calculate stroke volume, which, when combined with the end-diastolic
volume (EDV), helps determine the ejection fraction, a measure of the heart's
pumping efficiency.
Describe the relationship between arterial
blood pressure (ABP), stroke volume (SV), heart
rate (HR), and total peripheral resistance (TPR).
ABP = SV x HR x TPR
What is atrial systole?
The first stage of the two sub-phases of the end of diastole. This sub-phase
occurs towards the end of diastole. It is the period during which the atria
contract to push the remaining blood into the ventricles. Atrial systole
contributes to the filling of the ventricles and ensures that they are maximally
filled before ventricular contraction (systole).
What is isovolumetric contraction?
The second phase of the end of diastole. Immediately following atrial systole,
there is a brief period known as isovolumetric contraction. During this sub-phase,
both the atrioventricular (AV) valves (e.g., the mitral and tricuspid valves) and
the semilunar valves (e.g., the aortic and pulmonic valves) are closed. The
ventricles begin to contract, generating pressure, but no blood is ejected yet.
This phase is called "isovolumetric" because the volume of blood in the
ventricles remains constant.
What is the conduction speed of the atrial
muscle?
0.5 m/s
What is the conduction speed of the AV node?
0.05 m/sec
What is the conduction velocity of the Bundle of
His?
2 m/s
What is the conduction velocity of the left and
right bundle branches?
Both are the same - 2 m/sec
What is the conduction velocity of the
ventricular muscle?
0.5 m/s
What is the conduction velocity of the Purkinje
Fibres?
4 m/sec
Describe the proceedings of the cardiac cycle
1.
2.
3.
4.
Electrical activity
Mechanical activity
Pressure changes
Volume changes
What is the cardiac cycle?
The movement of blood through the heart due to pressure changes generated by
mechanical activity
What is echocardiography used for?
To assess the volume and function of the heart
What happens to the length of the cardiac cycle
when heart rate increases?
It will decrease and vice versa
Which, out of systole and diastole, shortens the
most when heart rate increases?
Diastole
What is the majority of filling?
It is passive - doesn't require atrial contraction to push blood into the ventricles
What is systole?
When the ventricle is contracting resulting in pressure being generated so that
ejection into either the pulmonary artery or aorta can occur
What preportion of the cardiac cycle is systole?
1/3rd
What will contraction of the muscles of a
chamber of the heart do?
It will increase the pressure within that chamber
What happens to the pressure in a chamber of
the heart when that chamber's muscle relaxes?
It drops rapidly
What is the amount of pressure generated in a
chamber of the heart dependent on?
The thickness of the muscle around it, therefore left ventricular pressure is
greater than right ventricular pressure cuz LV muscle is thicker
When will heart valves open?
When there is a pressure/energy gradient across them, e.g. the right
atrioventricular valve will open when the pressure in the right atrium exceeds
that of the pressure in the right ventricle.
What does blood flow down?
A pressure/energy gradient from an area of higher pressure to lower pressure
What happens to the pressure changes in
adjacent chambers of the heart when the
valves are open?
They change together
When valves are closed what can happen to the
pressures in adjacent chambers of the heart?
They are independent of each other and so can be different
What is the average resting heart rate?
70 bpm
What is the average length of a cardiac cycle at
resting heart rate?
850ms
What is the length of diastole at average
resting heart rate?
600 ms
What is the length of systole at average resting
heart rate?
250 ms
What offsets the reduction in passive filling
time seen in diastole when heart rate
increases?
Stimulation of the atrial wall muscle to contract with greater force.
What is cardiac output?
The volume of blood pumped by the heart per minute
Cardiac output equation?
HR (heart rate/bpm) x stroke volume
Stroke volume
Volume of blood ejected from the ventricle with each contraction
Stroke volume calculation
SV = end diastolic volume - end systolic volume
EDV approx value at rest
120ml
ESV approx value at rest
50ml
Stroke volume at rest
70ml
Cardiac output approx at rest
5l/min
EDV
End diastolic volume - volume in the ventricle at the end of diastole
ESV
End systolic volume - volume in the ventricle at the end of systole
How can you increase stroke volume?
By either increasing EDV or decreasing ESV
Why is the fact that the heart doesn't eject all
the blood it contains with each beat?
Because it provides a reserve of blood which allows the stroke volume to be
adjusted on a beat by beat basis depending on the needs of the body
What are textbook values of cardiac function
based on?
21 yr old male
Describe the stages of the cardiac conduction
system
1.
2.
3.
4.
5.
sinoatrial node
Electrical spread through atria
Atrioventricular node delay
Conduction along his bundles and purkinje fibres
Electrical spread from ventricular endocardium out to the epicardium
Which of the areas of the heart have
spontaneous AP generation?
SAN, AVN, and Purkinje fibres
SAN AP/min
80-100
What is the shape of the SAN AP
What ions are responsible for the 1st phase of
the SAN pacemaker potential?
1st phase
What ions are responsible for the second phase
of the SAN AP?
3nd phase of SAN AP
Describe the innervation of the SAN
If the spontaneous AP generation rate is 80-100
AP/min, why is the resting heart rate 60-70
bpm?
Because vagal tone predominates and slows down our heart rate
What is parasympathetic vagal stimulation of
the SAN?
What happens during sympathetic stimulation
of the SAN?
Spontaneous AVN AP/min?
40-60
What does the delay caused by the
atrioventricular node lead to?
ensures atrial depolarisation, contraction & ejection before ventricles
depolarise
Describe the shape of the AV node's action
potential?
What is the hierachy of cardiac pacemakers?
Purkinje fibres spontaneous AP generation - AP/
min?
20-40
Phases of ventricular myocyte action
potentials:
Which ions are responsible for each stage of a
ventricular myocytes action potential?
Refractory periods
Time from initial depolarisation of the first AP to the point at which a second AP
can be stimulated
What determines the refractory period?
The number of available and recovered (re-primed) voltage gated sodium
channels
What is sodium channel recovery dependent
on?
Time and voltage
Does a more negative or more positive
membrane potential cause the sodium channels
to recover faster?
More negative membrane potentials
What causes the cardiac myocytes to be
electrically coupled?
The presence of gap junctions
What do gap junctions between the cardiac
myocytes do?
They electrical couple cardiac myocytes by allowing the passage of positively
charged ions between them if there is a charge gradient
Describe how the electrical stimulation is
conducted across the cardiac myocytes:
1. Before the electrical stimulation reaches the cells (cell 1 and 2) both cells are at
a negative resting membrane potential
2. Therefore, there is no charge gradient
3. So, no movement of ions (sodium ions and chloride ions) between the cells
4. However, when the electrical stimulation reaches cell 1, sodium influx into it
during depolarisation causes the membrane potential to become more positive
(+20mv)
5. This creates a large charge gradient between cell 1 and 2
6. So, there is movement of positive ions from cell 1 to cell 2 through gap junctions
7. This causes cell 2 to become more positive
8. When it reaches threshold (around -60mV) enough voltage gated sodium
channels open that an action potential is triggered in cell 2
What determines conduction velocity?
• The charge gradient between cells
• Set by the magnitude of depolarising current, i.e. the action potential
amplitude
• This varies in disease leading to arrhythmia
How can conduction velocity be modified?
Gap junction expression and function
Where is the sino-atrial node located?
at the junction of the crista terminalis in the upper wall of the right
atrium and the opening of the superior vena cava .
Where is the AV node located?
Posteroinferior interatrial septum wall, within triangle of atrioventricular node
(Koch’s triangle)
What is the cardiac cycle?
The movement of blood through the heart and out the great vessels due to
pressure changes generated by the muscular mechanical activity of heart.
How can the relationship between the arterial
pressure, stroke volume, heart rate, and
resistance be summarised?
ABP = SV x HR x TPR
What is the resistance that the left side of the
heart has to overcome?
Systemic resistance - total peripheral resistance
What is the resistance the right side of the
heart has to overcome?
Pulmonary vascular resistance
How can the pressure and volume changes in
the aorta and left ventricles be measured
clinically?
Introducing catheters into these structures
What preportion of the cardiac cycle is
diastole?
2/3rds
What are the 5 principles of the cardiac cycle?
1. Pressure will increase in a chamber when muscle around it contracts
2. Valves will open when there is a pressure/energy gradient across them
3. Blood will flow down a pressure/enery gradient from an area of higher pressure/
energy to an area of lower pressure/energy
4. When valves are open, pressures in neighbouring chambers change together
5. When valves are closed, pressures in neighbouring chambers can be different
Why is left ventricular pressure greater than
right ventricular pressure?
Because LV muscle wall is thicker so it can generate a higher pressure to
overcome the larger total peripheral resistance
Energy of blood is:
Pressure x momentum
End diastolic volume
Volume left in heart at the end of diastole
Cardiac cycle phases
1. Ventricular diastole
2. Ventricular systole
Ventricular diastole
1. Isovolumetric relaxation
2. Rapid passive filling
3. Atrial systole
Ventricular systole
1. Isovolumetric contraction
2. Ejection
What is occuring in ventricular diastole?
Ventricles filling with blood
Describe the features of a pressure-volume
loop (for the left ventricle)
What is a Wiggers diagram?
A Wiggers diagram is a graphical representation of a cardiac cycle that illustrates
the key events in the cardiovascular system. It typically shows points for atrial
and ventricular pressure, as well as lines representing electrical activity (ECG),
heart sounds, and major phases like systole and diastole, helping visualize the
sequence of events during one heartbeat.
What happens during atrial systole?
• Atrial Systole :
• Atrial systole is the initial phase of the cardiac cycle.
• During this stage, the atria contract, pushing blood into the relaxed
ventricles.
• Atrioventricular (AV) valves (tricuspid and bicuspid) open, allowing blood to
flow from the atria into the ventricles.
• The semilunar valves (pulmonary and aortic) are closed.
What happens during isovolumetric ventricular
contraction?
• Isovolumetric Ventricular Contraction :
• This phase follows atrial systole.
• The ventricles start to contract, increasing pressure.
• All heart valves are closed, so no blood is ejected yet.
• Pressure builds within the ventricles.
What happens during ventricular ejection?
• Ventricular Ejection :
• As ventricular pressure exceeds the pressure in the pulmonary artery and
aorta, the semilunar valves open.
• Blood is ejected from the ventricles into the pulmonary artery and aorta.
• This is the phase responsible for pumping oxygenated blood to the body (left
ventricle) and deoxygenated blood to the lungs (right ventricle).
What happens during isovolumetric ventricular
relaxation?
• Isovolumetric Ventricular Relaxation :
• After ejection, the ventricles begin to relax.
• All heart valves close briefly to prevent blood backflow into the ventricles.
• This phase marks the end of systole.
What happens during atrial diastole?
• Atrial Diastole :
• During this stage, the atria are relaxed and fill with blood.
• Pressure in the atria exceeds that in the ventricles, causing the AV valves to
open.
• Blood flows from the atria into the ventricles, preparing for the next cycle.
What is the main function of isovolumetric
relaxation?
To reduce ventricular pressure below atrial pressure so the AV valve can open
and ventricular filling can start
What is the small peak in atrial pressure that
occurs during ventricular contraction due to?
AV valve pressing back into atria
What does the wiggers diagram for the left
ventricle look like?
Normal pressure in the aorta
120/80
Normal pressure in the RA
4
Normal pressure in the right heart
25/4
Normal pressure in the PA
25/10
Normal pressure in the LA
8
Normal pressure in the LV
120/8
Flow =
pressure/resistance
Flow =
cardiac output
P-wave
• The P-wave represents atrial depolarization, the electrical activation of the
atria.
• It signifies the initiation of the heartbeat and the contraction of the atria.
QRS Complex
• The QRS complex represents ventricular depolarization, the electrical
activation of the ventricles.
• It is a crucial part of the ECG because it signifies the contraction of the
ventricles, which is responsible for pumping blood to the lungs and the rest
of the body.
• Duration (HR of 60bpm) = 0.08 s (80 ms)
• The amplitude of the QRS complex indicates the amount of ventricular
muscle.
◦ A QRS complex with large amplitudes (>3.5mV) may be explained by
ventricular hypertrophy or enlargement (or both).
T-wave
• The T-wave represents ventricular repolarization, the recovery of the
ventricles to their resting state after depolarization.
• It marks the period when the ventricles are preparing for the next heartbeat.
PR interval
• The PR interval is the time from the beginning of the P-wave to the start of
the QRS complex.
• It indicates the time it takes for the electrical signal to travel from the atria
to the ventricles, including the delay at the atrioventricular (AV) node.
ST segment
• The ST segment is the flat, isoelectric line that follows the QRS complex and
precedes the T-wave.
• It represents the interval between ventricular depolarization and
repolarization.
• Changes in the ST segment can indicate myocardial ischemia or injury.
QT interval
• The QT interval represents the time from the start of the QRS complex to the
end of the T-wave.
• It reflects the total time for ventricular depolarization and repolarization.
• Prolongation of the QT interval can indicate an increased risk of arrhythmias
• Duration (HR 60bpm) = 0.40 s (400 ms)
U-wave
• The U-wave is a small, sometimes observable wave following the T-wave.
• Its exact origin and significance are not entirely understood, but it may be
related to repolarization of Purkinje fibers or electrolyte imbalances.
How many heart sounds are there?
4
What are the 4 heart sounds?
• S1
• S2
• S3
• S4
What is the 1st heart sound?
• S1 (Lub) :
• S1 is the first heart sound and is often described as "lub."
• It is produced by the closure of the atrioventricular (AV) valves (the tricuspid
and bicuspid/mitral valves).
• S1 marks the beginning of ventricular systole, signifying the onset of
ventricular contraction.
• S1 is associated with the start of the ejection of blood from the ventricles
into the pulmonary artery and aorta.
What is the second heart sound?
• S2 (Dub) :
• S2 is the second heart sound and is often described as "dub."
• It is produced by the closure of the semilunar valves (the aortic and
pulmonary valves).
• S2 marks the end of ventricular systole and the beginning of diastole,
signifying the cessation of ventricular contraction and the start of ventricular
relaxation.
• S2 is associated with the closure of the aortic and pulmonary valves as blood
is forced out of the ventricles into the systemic and pulmonary circulations,
respectively.
What is the third heart sound?
• S3 (Third Heart Sound) :
• S3 is an additional heart sound that can sometimes be heard, but it is not
always present.
• It occurs early in diastole and is associated with rapid ventricular filling when
the ventricles relax.
• S3 can be a sign of heart failure or volume overload in the ventricles.
What is the 4th heart sound?
•
S4 (Fourth Heart Sound) :
• S4 is another extra heart sound that is not always present.
• It occurs late in diastole and is associated with atrial contraction just before
ventricular systole.
• S4 can be indicative of conditions like hypertensive heart disease, aortic
stenosis, and ventricular noncompliance.
What is the left atrioventricular valve?
• Otherwise known as the mitral or bicuspid valve
• two cusps - anterior (aortic) and posterior (mural)
• associated with inferior (posterior) and superior (anterolateral) papillary
muscles.
• prevents blood flow from left ventricle into left atrium
What is the right atrioventricular valve?
• tricuspid valve
• three cusps - anterior/superior, septal, and posterior/inferior
• associated with four papillary muscles - anterior, septal (medial), inferior
(posterior), and moderator band (septomarginal trabecular)
• prevents blood from flowing from the right ventricle into the right atrium
What is the pulmonary valve?
• Three semilunar cusps - anterior (non-adjacent), right (right adjacent), and
left (left adjacent)
• No associated papillary muscles
• Prevents backflow of blood from pulmonary circulation into the right ventricle
What is the aortic valve?
• Three semilunar cusps - right coronary (right semilunar), left coronary (left
semilunar), and a non-coronary cusp (posterior semilunar).
• No associated papillary muscles
• Prevents backflow of blood from systemic circulation into the left ventricle
What is the effect of parasympathetic
innervation on the heart?
Vagal stimulation:
• Slowing of heart rate
• Reduced force of contraction
• Decreased atrioventricular node conduction
• Vasodilation
What does the balance between the
sympathetic and parasympathetic inputs to the
heart do?
Maintain heart rate and cardiac function within a range that meets the body's
physiological needs under different circumstances
What is the origin of the parasympathetic
innervation to the heart?
Cranial sacral - mainly vagus but some S2-S4
What is the effect of sympathetic innervation to
the heart?
• Increased heart rate
• Increased force of contraction
• Dilation of coronary arteries
• Enhanced conduction
• Activation of the Beta-1 Adrenergic receptors
What does the activation of Beta-1 Adrenergic
Receptors by the sympathetic nervous system
do on the heart?
This is the pathway that mediates the effects of sympathetic innervation on the
heart. These receptors are found on the surface of cardiac cells and are
responsive to noradrenaline. Activation increases heart rate, contractility, and
conduction speed.
Spinal levels of the sympathetic innervation to
the heart?
T1-T5
What are the two different types of heart
valves?
Atrioventricular valves and semilunar valves
They differ in structure and location
Location:
AV valves - between atria and ventricles
Semilunar valves - between ventricles and arteries (aorta and pulmonary)
Structure:
Semilunar -Semilunar valves have three pocket-like, semilunar-shaped cusps
(hence the name "semilunar"). These cusps are thin and do not contain chordae
tendineae or papillary muscles, unlike the AV valves.
AV - AV valves have two or three cusps, but they are thicker and more muscular
than the cusps of semilunar valves. They also contain chordae tendineae and
papillary muscles, which help prevent valve prolapse during ventricular
contraction.
Which side of the heart is deoxygenated blood
brought too?
Right
Which side of the heart is oxygenated blood
brought too?
Left
At what level does the common carotid artery
bifurcate?
C4/5 - around the level of the superior border of the thyroid cartilage
When does the subclavian artery become the
axillary artery?
When it passes the lateral border of the first rib
When does the axillary artery become the
brachial artery?
At the inferior border of the terres major muscle?
At what point does the brachial artery bifurcate
into the ulnar and radial arteries?
1cm distal to the elbow
What is meant by collatoral blood supply?
Collateral blood supply refers to the alternative or backup pathways through
which blood can flow to a particular tissue or organ when the primary blood
vessels supplying that area become partially or completely blocked.
How many palmer arches are there?
2
What are the two palmer arches?
1. Superficial
2. Deep
What is the superficial palmer arch?
This arch is located closer to the surface of the palm and is formed primarily by
the ulnar artery. The ulnar artery is one of the two main arteries in the forearm,
and it enters the hand from the medial (inner) side. The superficial palmar arch
provides blood supply to the superficial structures of the palm and fingers.
What is the deep palmer arch?
The deep palmar arch is located deeper within the palm and is primarily formed
by the radial artery, the other major artery in the forearm. The radial artery
enters the hand from the lateral (outer) side. The deep palmar arch provides
blood supply to deeper structures of the palm and fingers.
How are the two palmer arches connected and
why is this important?
These two palmar arches are interconnected through a network of smaller
arteries and anastomoses (connections) between them. This interconnected
network allows for a continuous and balanced blood supply to the hand, ensuring
that the hand's muscles, bones, tendons, and other structures receive adequate
oxygen and nutrients.
What is the dorsal venous arch?
The dorsal venous arch, also known as the dorsal venous network or dorsal
venous plexus, is a network of veins located on the dorsal (back) surface of the
hand and the top of the foot. It plays a crucial role in venous return, which is the
process of carrying deoxygenated blood back to the heart after it has circulated
through the body's tissues.
In the hand, what veins feed into the dorsal
venous arch?
In the hand, the dorsal venous arch receives blood from the digital veins of the
fingers and the dorsal metacarpal veins.
What does the dorsal venous arch drain into
(hand)?
The cephalic vein and basilic vein
What does the dorsal venous arch of the foot
drain into?
The great saphenous vein
Origin of the cephalic vein
In the hand, the dorsal venous arch receives blood from the digital veins of the
fingers and the dorsal metacarpal veins.
Course of the cephalic vein
The cephalic vein runs along the lateral (outer) side of the arm, following a
course that is somewhat parallel to the upper arm bone, the humerus. It ascends
along the forearm and into the upper arm. The vein is often visible through the
skin, making it a common choice for venipuncture (inserting a needle into a vein
for various medical procedures).
Termination of the cephalic vein
The cephalic vein typically terminates by draining into the axillary vein. This
convergence of the cephalic vein into the axillary vein usually occurs in the
region of the shoulder, where the axillary vein is formed as the continuation of
the brachial vein. The axillary vein eventually merges with other veins, such as
the subclavian vein, leading to the superior vena cava. The superior vena cava
carries deoxygenated blood back to the heart for circulation to the lungs and the
rest of the body.
Origin of the basillic vein
Arises from the dorsal venous network of the hand and forearm, and it is often a
companion vein to the cephalic vein.
Course of the median vein
Ascends along the medial (inner) aspect of the arm.
Termination of the basilic vein
Typically drains into the brachial vein.
Origin of the brachial vein
Forms from the union of the basilic vein and the profunda brachii vein.
Course of the brachial vein
Courses along the upper arm, paralleling the brachial artery.
Termination of the brachial vein
Drains into the axillary vein.
Origin of the axillary vein
Formed by the union of the brachial vein and the basilic vein.
Course of the axillary vein
Passes through the axilla (armpit) region.
Termination of the axillary vein
The transition from the axillary vein to the subclavian vein typically occurs near
the outer border of the first rib, which is located at the junction of the shoulder
and the upper chest. This region is known as the axillary-subclavian junction.
Course of the subclavian vein
Descends from the shoulder region toward the upper chest.
Termination of the subclavian vein
Drains into the brachiocephalic vein.
What is the median cubital vein?
A bridge or connection between two other important veins in the arm, the
cephalic vein (which travels along the lateral or outer part of the forearm and
arm) and the basilic vein (which runs along the medial or inner aspect of the
forearm and arm).
Why is the median cubital vein often chosen for
venipuncture?
The median cubital vein is often chosen for venipuncture because it is usually
prominent, easy to locate, and less likely to roll or move during the procedure. It
provides good access to the venous system and is commonly used for drawing
blood samples or administering medications through an IV line.
What is the significance of the cubital fossa?
• Common site for venipuncture (blood draw) and IV access.
• Used for blood pressure measurement.
• Contains brachial artery, median nerve, and radial nerve.
• Key anatomical landmark for the elbow's structures.
Cubital fossa location
Triangular depression at the front (anterior aspect) of the elbow.
What are the unpaired branches of the
abdominal aorta?
• Coeliac trunk
• Superior mesenteric artery
• Inferior mesenteric artery
What vertebral level is the coeliac trunk given
off from the abdominal aorta?
T12
What vertebral level is the superior mesenteric
artery given off?
L1
What vertebral level is the inferior mesenteric
artery given off the abdominal aorta?
L3
What is the foregut supplied by arterially?
Coeliac trunk
What is the midgut's arterial supply?
Superior mesenteric artery
What is the arterial supply to the hingut?
Inferior mesenteric artery
What are the paired arteries that come off the
abdominal aorta?
Renal arteries and the gonadal arteries
Midgut boundaries
The midgut begins at the distal part of the duodenum (the point where the bile
duct and main pancreatic duct enter) and extends to the proximal two-thirds of
the transverse colon.
Foregut boundaries
The foregut begins at the oral cavity (mouth) and extends down to the proximal
part of the duodenum.
Hindgut boundaries
1.
• the hindgut encompasses the distal one-third of the transverse colon, the
descending colon, the sigmoid colon, and the upper part of the rectum.
What is the venous drainage from the gi tract?
Portal venous system to the liver
What are the boundaries of the femoral
triangle?
Base - inguinal ligament
Lateral border - sartorius
Medial border - adductor longus
What are the contents of the femoral artery?
• femoral nerve
• femoral artery
• femoral vein
• inguinal lymph nodes
At what anatomical boundary does the external
iliac artery become the femoral artery?
Inguinal ligament
What is the importance of the femoral artery?
It is the principle blood suppy to the lower limb
At what anatomical boundary does the femoral
artery become the popliteal artery?
Adductor hiatus
What are the boundaries of the popliteal fossa?
• Superior Border: Femur's lower end (superiorly)
• Inferior Border: Soleus muscle (inferiorly)
• Medial Border: Semimembranosus and semitendinosus tendons (medially)
• Lateral Border: Biceps femoris muscle (laterally)
What are the contents of the popliteal fossa?
• Popliteal Artery
• Popliteal Vein
• Tibial Nerve
• Common Fibular (Peroneal) Nerve
• Small Saphenous Vein
What is the genicular anastomosis?
A network of arteries that provides collateral circulation around the knee joint.
What are the key arteries of the genicular
anastomosis?
Branches of the femoral, popliteal, and anterior and posterior tibial arteries.
What is the purpose of the genicular
anastomosis?
Crucial for maintaining blood supply to the knee, especially during occlusion or
injury.
What is the clinical significance of the genicular
anastomosis?
Crucial for maintaining blood supply to the knee, especially during occlusion or
injury.
What are the 10 important arteries of the
pelvis?
1. Common iliac
2. Internal iliac/hypogastric
3.
4.
5.
6.
7.
8.
9.
10.
External iliac
Uterine (female)
Superior vesical artery
Inferior vesical artery (male) or vaginal artery (female)
Middle rectal artery
Obturator
Internal pudendal
Common hepatic or gastroduodenal
Common Iliac Arteries
•
• Location: Bifurcation of the abdominal aorta
• Function: Supply blood to the pelvis and lower limbs
Internal Iliac Arteries (Hypogastric Arteries):
•
• Location: Branch from common iliac arteries and enter the pelvis
• Function: Primary supply to pelvic organs, rectum, bladder, and pelvic wall
muscles
External Iliac Arteries:
•
• Location: Continue from common iliac arteries toward the lower limbs
• Function: Supply blood to the lower extremities
Uterine Artery (in females):
•
• Location: Branch from internal iliac artery
• Function: Supplies blood to the uterus
Superior Vesical Artery:
• Location: Arises from the internal iliac artery
• Function: Supplies the superior part of the bladder
Inferior Vesical Artery (in males) or Vaginal
Artery (in females):
• Location: Arises from the internal iliac artery
• Function: Supplies the lower part of the bladder, prostate (in males), or
vaginal structures (in females)
Middle Rectal Artery:
• Location: Branch from the internal iliac artery
• Function: Supplies blood to the rectum
Obturator Artery:
• Location: Travels through the obturator foramen
• Function: Supplies the muscles and structures in the pelvic wall
Internal Pudendal Artery:
• Location: Branch from the internal iliac artery
• Function: Supplies the perineum, external genitalia, and rectum
Femoral arteries
The femoral arteries are the primary arteries of the thigh. They give rise to
various branches, including the deep femoral artery (profunda femoris) and the
descending genicular arteries, which supply the muscles of the thigh and the
knee joint.
Popliteal Artery:
The popliteal artery is located behind the knee joint in the popliteal fossa. It is a
continuation of the femoral artery and provides blood to the muscles, bones, and
other structures in the leg.
Anterior Tibial Artery:
This artery is a branch of the popliteal artery and runs down the front of the leg.
It becomes the dorsalis pedis artery on the dorsum of the foot.
Posterior Tibial Artery:
This artery is also a branch of the popliteal artery and travels down the back of
the leg. It supplies blood to the calf muscles and forms the medial and lateral
plantar arteries in the foot.
Peroneal Artery (Fibular Artery):
The peroneal artery is another branch of the popliteal artery. It runs along the
lateral aspect of the leg and provides blood supply to the lateral compartment of
the leg.
Dorsalis Pedis Artery:
The dorsalis pedis artery is a continuation of the anterior tibial artery and runs
along the dorsum (top) of the foot. It is a key artery supplying the foot and toes.
Medial and Lateral Plantar Arteries:
These arteries originate from the posterior tibial artery and provide blood supply
to the sole of the foot.
Arcuate Artery:
The arcuate artery is a network of smaller arteries that forms between the dorsal
and plantar arteries of the foot, contributing to the overall blood supply of the
entire foot.
Perforating Arteries:
These arteries link the dorsal and plantar arteries, creating a collateral network
that ensures efficient blood distribution throughout the foot and ankle.
Calcaneal Artery:
This artery arises from the posterior tibial artery and supplies blood to the
calcaneus (heel bone).
Tarsal Arteries:
Multiple smaller arteries branch from the major arteries mentioned above to
provide blood supply to the tarsal bones in the ankle region.
What important nervous system structures
surround the axillary artery
along its course through the axilla?
• Surrounding Nerves: Brachial Plexus, Median Nerve, Ulnar Nerve, Radial
Nerve
• Role: Nerves control and provide sensation to the upper limb.
• Significance: Close relationship with axillary artery is vital for arm and hand
function.
As the popliteal vein passes superiorly through
the lower limb, it reaches
the adductor hiatus. From thereon, what is it
referred to as?
The femoral vein
What superficial vein drains into the popliteal
vein at the popliteal fossa?
Small saphenous vein
Where does the small saphenous vein
originate?
the lateral aspect of the foot and runs up the posterior (back) of the leg.
Through which space will the posterior tibial
vein travel to enter the foot?
The posterior tibial vein travels through the tarsal tunnel to enter the foot.
What is the tarsal tunnel?
The tarsal tunnel is a fibro-osseous space on the medial (inner) side of the ankle,
and it contains various structures, including the posterior tibial artery, posterior
tibial vein, tibial nerve, and tendons of several muscles. The posterior tibial vein,
along with the posterior tibial artery, passes through this tunnel to supply blood
to the posterior and plantar regions of the foot.
What neurovascular structures accompany the
posterior tibial vein through the tarsal tunnel?
Posterior tibial artery and the tibial nerve
Give three specific locations where superficial
veins will join deep veins,
naming the vessels involved.
1. Axilla: Cephalic Vein and Basilic Vein join with Axillary Vein.
2. Groin: Great Saphenous Vein and Small Saphenous Vein join with Femoral Vein.
3. Popliteal Fossa: Anterior Tibial Vein and Posterior Tibial Vein join with Popliteal
Vein.
Female vs male pelvic venous drainage
• In females, venous drainage includes ovarian veins, uterine veins, and a
vaginal venous plexus, specific to reproductive structures.
• Ovarian veins drain the ovaries, while the uterine veins drain the uterus.
• Differences in venous drainage patterns due to the presence of femalespecific reproductive organs.
• In males, there are no equivalent structures to the ovarian veins, and the
venous drainage patterns are distinct.
• Recognizing these distinctions is vital for medical diagnosis and treatment,
especially in the context of gynecological and urological conditions.
What common procedures or treatments
involve accessing the superficial
veins of the upper limb?
• Venipuncture for blood tests.
• IV cannulation for medication and fluid administration.
• Phlebotomy for therapeutic blood removal.
• Blood transfusion through superficial veins.
• Chemotherapy via IV lines.
• IV medications in emergency or critical care.
• Intravenous contrast for diagnostic imaging.
• Non-invasive blood pressure measurement.
• Arterial blood gas sampling for blood analysis.
What is the clinical significance of the great
saphenous vein?
• Common site for varicose vein assessment and treatment.
• Evaluated for venous reflux and insufficiency.
• Used as a graft in coronary artery bypass surgery.
• Relevant in managing lower limb edema and venous ulcers.
• Considered in cases of deep vein thrombosis (DVT).
• Important in aesthetic sclerotherapy for varicose veins.
• Key vessel in vascular medicine and surgery.
What are varicose veins and how can they be
treated?
• Varicose veins are swollen, twisted, and often painful veins, typically in the
legs.
• Causes include damaged vein walls, aging, hormonal changes, prolonged
sitting/standing, and obesity.
• Symptoms may include visible veins, discomfort, swelling, and skin changes.
• Treatments range from lifestyle changes and compression stockings to
minimally invasive procedures (sclerotherapy, EVLT, radiofrequency ablation)
and, in severe cases, surgical removal.
What is collateral circulation? Give 2 examples,
naming the relevant vessels,
discussing their functional relevance.
• Definition: Alternative blood vessels that provide backup routes when
primary vessels are blocked.
• Example 1 (Coronary): In the heart, collateral vessels from different coronary
arteries help maintain blood supply and reduce heart tissue damage during
artery blockages.
• Example 2 (Cerebral): Collateral circulation in the brain, such as the circle of
Willis, redistributes blood flow, protecting against brain damage during
arterial blockages.
Abdominal aortic aneurysm
• Definition: Abnormal dilation of the abdominal aorta.
• Location: Typically below the renal arteries.
• Risk Factors: Age, smoking, atherosclerosis, hypertension, and family history.
• Symptoms: Often asymptomatic, but can cause abdominal or back pain.
• Complications: Rupture is a major concern, leading to life-threatening
bleeding.
• Diagnosis: Imaging tests (ultrasound, CT, MRI) assess size and condition.
• Management: Treatment varies based on size and symptoms, including
monitoring, surgery, or stent graft placement.
• Prevention: Lifestyle changes can help reduce the risk and prevent AAA
development.
How can the force of contraction of cardiac
tissue be increased?
1. Increasing the calcium sensitivity of the contractile apparatus
2. Increasing the concentration of calcium in the cell
What factors affect venous return to the right
ventricle?
1.
2.
3.
4.
5.
Blood volume
Skeletal muscle pump
Respiratory pump
Venous tone
Gravity
Where is the blood volume distributed?
1.
2.
3.
4.
5.
Systemic veins and venules - 60-70%
Pulmonary circulation - 10-12%
Systemic arteries - 10-12%
Heart - 8-11%
Systemic capillaries - 4-5%
What does an increased blood volume (as seen
in renal failure) lead to?
Increased venous return, increased right ventricular filling, and increased stroke
volume
What does decreased blood volume (as seen in
dehydration) lead to?
Decreased venous return, decreased end diastolic volume, and decreased stroke
volume
Why is the fact that the heart doesn't eject all
the blood important?
Because it provides a reserve of blood
Define excitation-contraction coupling
The process by which an electrical signal (action potential) triggers a mechanical
response (contraction) in cardiac muscle cells.
Calcium-induced calcium release
In order for the myosin heads to interact with the myosin binding site on actin,
the regulatory troponin complex must undergo a conformational change to move
out of the way. This occurs through calcium-induced calcium release:
• calcium enters the cardiac muscle cells during the action potential via L type
calcium channel
• this stimulates the release of calcium from the sarcoplasmic reticulum via
ryanodine receptor which is the calcium release channel on the sarcoplasmic
reticulum
• it is the calcium that is released from the sarcoplasmic reticulum that binds
to troponin C and moves the regulatory complex out of the way allowing
actin and myosin to form cross bridges and for contraction to occur
• as such, it is calcium that regulates the number of actin-myosin crossbridges formed and therefore the force of ventricular contraction
How can the force of contraction be increased?
Increasing force of contraction means increasing the number of actin-myosin
cross-bridges formed, and this can be accomplished by:
1. increasing the calcium sensitivity of the contractile apparatus so you get more
cross-bridges formed for a given contraction of intracellular calcium
2. increasing the concentration of intracellular calcium in the cell
How does cardiac muscle relaxation occur?
When calcium is pumped back into the sarcoplasmic reticulum via SERCA which
is regulated by phospholamban
What is SERCA?
Sacro endoplasmic reticulum calcium ATPase
Define Starling's Law of the Heart
A physiological principle that states that the force of cardiac contraction (stroke
volume) increases as the volume of blood filling the heart (end-diastolic volume)
increases, up to a point.
Explain Starling's Law of the Heart
• Starling's Law of the Heart, also known as the Frank-Starling mechanism,
describes the relationship between the volume of blood entering the heart's
chambers (ventricles) and the force of contraction during systole.
• It suggests that as the volume of blood returning to the heart (preload)
increases, the cardiac muscle fibers are stretched, leading to a more forceful
contraction.
• This increased force of contraction results in a greater stroke volume, which
is the amount of blood ejected from the heart with each beat.
• Starling's Law helps the heart adapt to varying conditions and maintain an
adequate cardiac output to meet the body's demands.
• However, there is an upper limit to this relationship. Beyond a certain point,
excessive stretching of the cardiac muscle fibers can impair contraction,
reducing stroke volume and cardiac efficiency.
How does increased end diastolic volume lead
to increased stroke volume?
• Increased end-diastolic volume (the volume of blood in the heart's ventricles
at the end of diastole, or the relaxation phase) leads to increased stroke
volume (the amount of blood ejected from the heart with each beat).
• When there is more blood in the ventricles at the end of diastole, the cardiac
muscle fibers are stretched, following Starling's Law of the Heart.
• This increased preload (end-diastolic volume) results in a more forceful
contraction during systole (the contraction phase of the cardiac cycle).
• The greater force of contraction leads to a larger volume of blood being
ejected during the next beat, reinforcing the relationship between increased
end-diastolic volume and increased stroke volume.
Why is it important that right stroke volume =
left stroke volume?
Because if RSV was greater than LSV then blood would become congested in the
pulmonary circulation and if LSV was greater than RSV, blood would become
congested in the venous side of the systemic circulation.
How are venous return and central venous
pressure (CVP) involved in regulating enddiastolic volume (EDV) in the heart?
• Venous return refers to blood flow from the body's systemic circulation back
to the heart.
• Venous return directly affects EDV: greater venous return leads to an
increased EDV.
• Central venous pressure (CVP) reflects right atrial filling pressure and is
influenced by venous return.
• An increase in venous return elevates CVP, promoting more effective right
ventricle filling and increasing EDV.
• A greater EDV, according to the Frank-Starling mechanism, results in a more
forceful contraction and contributes to efficient cardiac output.
What is the skeletal muscle pump, and how
does it assist in venous return?
•
◦ The skeletal muscle pump is a mechanism in the legs that aids venous
return.
◦ During muscle contraction, veins are squeezed, and blood is propelled
upward.
◦ Semilunar valves in the veins prevent backflow and ensure one-way
blood flow toward the heart.
◦ Muscle relaxation allows veins to refill, and the process repeats, assisting
in venous return to the heart.
Explain the role of the respiratory pump in
venous return to the right ventricle
• The action of breathing helps to return blood to the heart
• When we breathe in, the diaphragm flattens and presses down on the
abdomen causing an increase in abdominal pressure
• At the same time the chest wall expands which decreases pressure in the
thorax
• This pressure gradient sucks blood from the abdominal vena cava into the
thoracic vena cava
• This will deliv more blood to the right side of the heart and into the right
ventricle
• This increases filling of the heart and so increases EDV and by starling's law
of the heart, the SV as well
How does venous tone affect right ventricular
filling?
• 70% of our blood volume is contained within the venous circulation
• Therefore, venous return can be increased by mobilising some of this stored
blood
• It is mobilised by vasoconstriction so that they cannot store as much blood
• This moves blood back towards the heart and increases venous return.
What mediates venous return?
The sympathetic nervous system
What is the most important factor that
influences venous return?
Gravity
What happens when someone moves from the
supine position to a standing position in terms
of the cardiovascular system?
You get a redistribution of blood due to gravity:
Legs:
- higher venous volume
- higher venous pressure
Thorax:
- lower venous volume
- lower venous pressure
This leads to a fall in venous return and central venous pressure and as such, a
decrease in EDV and SV
Describe the distribution of blood in a supine
position
In the supine position the venous vessels will be approximately at the level of the
heart:
• this allows blood to be evenly distributed between all areas of the body from
the head, down towards the feet
• therefore, venous return is unaffected as central venous pressure can be
maintained
What is meant by preload?
The stretch of myocardium
How come atrial contraction, at rest, does not
contribute much to end diastolic volume?
Because atrial contraction contributes 5ml of blood to the ventricles at rest, with
the majority being from passive filling
How does atrial contraction play an important
role in end diastolic volume during exercise?
Sympathetic stimulation of atrial muscles increases the force of atrial contraction
leading to a greater end diastolic volume and this maintains end diastolic volume
during exercise because at higher heart rates seen in exercise the rapid passive
filling phase of ventricles is shortened so it compensates for this
How does heart rate influence EDV, particularly
during exercise?
• Our EDV is also influenced by our HR.
• However, this is only at a high HR - when atrial contraction can’t
compensate.
• Diastole is approximately 2/3 of the cardiac cycle.
• When HR increases the diastole time decreases.
• But as most of the filling occurs during the rapid filling phase at beginning of
atrial, systole, we can compensate for this shortening with and increased
atrial contraction.
• However, when HR > 180bpm, he passive filling plus the increase in atrial
contraction is not sufficient to maintain EDV and therefore SV won’t be able
to be maintained.
• So, at HR > 180bpm, EDV will be reduced, so as ventricular muscle won’t be
stretched as much, the SV will be reduced and so CO will be compromised.
Where does the sympathetic nervous system
originate?
Thoracolumbar
Where does the parasympathetic nervous
system originate?
Craniosacral
What are the effects of sympathetic stimulation
on the cardiovascular system?
• increased heart rate and contractility (Beta-1 receptors)
• vasoconstriction (alpha-1 and alpha-2 receptors)
• some vasoconstriction (beta-2 receptors)
• regulations of renin release for volume control (beta-1 receptor)
Where are the perivascular nerves located in
the vessels?
The tunica externa/adventitia
What allows for specific targeting of drugs?
Receptor subtypes are located at relatively distinct cellular locations
What adrenoreceptors are present in the
vasculature?
All the alpha subtypes and beta 2
Which adrenoreceptor is present in the heart?
Beta 1
What are the effects of beta-adrenceptor
activation on the heart?
• increased heart rate by the positive chronotropic effect
• increased contractility rate by the positive inotropic effect
• increased automaticity (tendency to produce a spontaneous rhythm)
• fast relaxation and recovery by the lusitropic effect
What is the significance of beta-adrenceptor
activation leading to increased automaticity in
terms of resuss?
Adrenaline administration
When is exogenous adrenaline used in clinical
practice?
• the treatment of asystole, ventricular fibrillation and other severe arrhymias
• anaphylaxis
• commonly used in a mixture with local anesthetic because when it is injected
locally it causes vasoconstriction
What is adrenaline an agonist for?
beta and alpho adrenceptors
What is the difference between agonists and
antagonists in pharmacology?
• Agonists:
◦ Activate receptors when they bind.
◦ Mimic the action of endogenous ligands.
◦ Can be full or partial agonists.
◦ Induce a biological response.
• Antagonists:
◦ Block or inhibit receptor activation.
◦ Compete with agonists for binding.
◦ Can be competitive or non-competitive antagonists.
◦ Prevent a biological response.
What is the difference between competitive and
non-competitive antagonists in pharmacology?
• Competitive Antagonists:
◦ Compete for the same receptor binding site as agonists.
◦ Block receptor activation by directly competing with agonists.
◦ Reversible binding.
• Non-competitive Antagonists:
◦ Bind to a different site on the receptor, causing conformational changes.
◦ Inhibit receptor activation without directly competing with agonists.
◦ May result in irreversible binding.
What is dobutamine and what is it used for?
beta-1 agonist and it is used to treat cardiogeneic shock by providing inotropic
support
What is phenylephrine and what is it used for?
It is a alpha 1 adrenceptor agonist that leads to vasoconstriction and is used to
treat nasal congestion. Because of this it is one of many potential ingredients in
sudafed.
What is midodrine and what is it used for?
It is a prodrug for alpha 1 adrenceptor agonist and it leads to vasoconstriction
with venoconstriction (due to increased capacitance) (this is more important)
and it is used for postural hypotension in autonomic failure. Postural hypotension
is also treated with a mineralocorticoid to increase circulating volume called
fludrocortisone.
What is droxidopa and what is it used for?
It is a prodrug for noradrenaline (by analogy with dopa for dopamine) and is used
for short-term treatment of postural hypotension in autonomic failure.
What is postural hypotension?
• Postural hypotension, or orthostatic hypotension, is a condition characterized by
a significant drop in blood pressure when changing from lying down or sitting to
a standing position.
• Symptoms include dizziness, lightheadedness, and, in severe cases, fainting.
• It can result from various causes, including dehydration, medication side effects,
or underlying medical conditions.
• Treatment depends on the underlying cause and may involve lifestyle changes,
medication adjustments, and support garments
What are the two alpha-2 adenoceptor
agonists?
1. Clonidine - centrally-acting antihypertensive and it works by decreasing
sympathetic drive
2. Brimonidine - direct transcutaneous vasoconstriction used in the treatment of
rosacea
What is doxazosin and what is it used for?
It is an antagonist drug to the alpha-1 adrenceptor that causes vasodilation by
opposing resting tone and it is used to treat hypertension and raynaud's
syndrome.
What is raynaud's syndrome?
• Raynaud's Syndrome, also known as Raynaud's disease or Raynaud's
phenomenon, is a medical condition that affects blood circulation, primarily
in the fingers and toes.
• It is characterized by episodes of vasospasm, where blood vessels in
extremities constrict, causing reduced blood flow and color changes in the
affected areas.
• Common triggers include exposure to cold temperatures or emotional stress.
• Raynaud's episodes can cause fingers or toes to turn white (pallor), then blue
(cyanosis), and finally red (rubor) as blood flow returns.
• While Raynaud's is not usually serious, it can be uncomfortable and may be
associated with underlying medical conditions.
What are beta-blockers and what are they used
for?
• Beta blockers are a class of medications that block the effects of stress
hormones like adrenaline on beta receptors in the body.
• They are commonly used to treat conditions such as high blood pressure
(hypertension), angina, irregular heart rhythms (arrhythmias), and heart
failure.
• Beta blockers can also be prescribed to manage anxiety, migraines, and
certain symptoms of hyperthyroidism.
• By reducing the workload on the heart and blocking the effects of adrenaline,
beta blockers help lower blood pressure, slow the heart rate, and improve
heart function.
What effects do beta blockers do?
• negative chronotropic actions
• negative inotropic actions
• inhibit automaticity
• therefore, decrease the work done by the heart
Name drugs that block both alpha and beta
adrenergic receptors.
• Carvedilol and labetalol are examples of non-selective adrenergic blockers.
• They block both alpha (alpha-1 and alpha-2) and beta (beta-1 and beta-2)
adrenergic receptors.
• Used to treat conditions like high blood pressure and heart-related issues.
What is carvedilol?
• Carvedilol is a non-selective adrenergic receptor blocker used as a
medication.
• It blocks both alpha-1, alpha-2, beta-1, and beta-2 adrenergic receptors.
• Carvedilol is primarily prescribed to treat conditions such as congestive heart
failure and high blood pressure.
• Its action helps reduce heart workload and dilate blood vessels, leading to
improved heart function and lower blood pressure.
Where is the thoracic notch located?
The thoracic inlet is located at the top of the thorax, at the base of the
neck and the upper part of the chest. It is situated between the first
thoracic vertebra (T1) at the back and the upper border of the sternum
(breastbone) at the front.
What are the anatomical boundaries of the
thoracic inlet?
1. Posterior Boundary: The first thoracic vertebra (T1) forms the posterior
boundary.
2. Anterior Boundary: The upper border of the sternum (manubrium) and
the first pair of ribs (the first rib) form the anterior boundary.
3. Lateral Boundaries: The first pair of ribs and the first thoracic vertebrae
on each side create the lateral boundaries.
What structures pass through the thoracic
inlet?
Several important structures pass through or near the thoracic inlet,
including the trachea, esophagus, major blood vessels (such as the
brachiocephalic arteries and veins), and nerves.
What is the clinical significance of the thoracic
inlet?
The thoracic inlet is a significant anatomical landmark for healthcare
providers, especially when assessing and diagnosing conditions related
to the neck, chest, and upper thorax. It is also relevant in
understanding conditions like thoracic outlet syndrome, which can
affect the neurovascular structures passing through this region.
What structures form the costal margin?
The costal margin is formed by the lower edges of the ribs. Specifically,
the structures that contribute to the costal margin include the costal
cartilages of the seventh, eighth, ninth, and tenth ribs, and to a lesser
extent, the costal cartilage of the sixth rib. These cartilaginous
extensions from the lower ribs create a curved, semi-rigid boundary
along the lower edge of the ribcage and are important anatomical
landmarks in clinical examinations and procedures.
What structures can you palpate at the jugular
notch?
Tracheal cartilages
Why do auscultation sites for heart sounds
differ from valve surface projections?
• Auscultation sites are selected for optimal sound transmission through chest
tissues.
• Heart sounds originate internally, not directly beneath the chest surface.
• Healthcare providers place the stethoscope at specific sites to hear and
assess cardiac sounds accurately.
At what vertebral level is the manubriosternal
joint located?
T3
At what vertebral level is the xiphisternal joint?
T9
What structures are you able to palpate at the
jugular notch?
The tracheal cartilages
In which costal cartilage can you palpate the
apex heart?
5th
Why are peripheral pulses important in clinical
assessment?
• Peripheral pulses are essential for assessing cardiovascular health.
• They serve as vital signs, indicating overall well-being.
• Monitoring pulses helps diagnose and manage heart and vascular conditions.
• Changes in pulse quality and symmetry may suggest pathology.
• In emergencies, pulses aid rapid patient assessment.
• They guide medication management and treatment effectiveness.
Where is the axillary pulse located and what
nearby/associated structures are there to it?
• Location: Located in the axilla (armpit), near the shoulder.
• Nearby/Associated Structures: Adjacent to the axillary artery, which supplies
blood to the upper arm and shoulder.
Where is the brachial pulse located and what
nearby/associated structures are there to it?
• Location: Found on the inner aspect of the upper arm, just below the
shoulder and medial to the biceps muscle.
• Nearby/Associated Structures: The brachial artery is located close to this
pulse point. It is a major blood vessel that supplies the arm.
Where is the radial pulse and what nearby/
associated structures are there to it?
• Location: Located on the inner wrist, on the thumb side. It can be felt by
placing fingers on the radial bone (radius).
• Nearby/Associated Structures: The radial artery runs along the same path
and is a major vessel supplying the forearm and hand.
Where is the ulnar pulse located and what
associated/nearby structures are there to it?
• Location: Located on the inner wrist, on the little finger side. It can be felt by
placing fingers on the ulnar bone (ulna).
• Nearby/Associated Structures: The ulnar artery runs alongside the ulnar
pulse point, supplying blood to the forearm and hand.
Where is the femoral pulse located and what
associated/nearby structures are there to it?
• Location: Found in the groin area, near the crease where the thigh meets the
pelvis. It can be located just below the inguinal ligament.
• Nearby/Associated Structures: The femoral artery is located adjacent to the
femoral pulse point and supplies blood to the thigh and lower extremities.
Where is the popliteal pulse located and what
associated/nearby structures are there to it?
• Location: Located at the back of the knee joint, in the popliteal fossa, which
is a small depression in the knee area.
• Nearby/Associated Structures: The popliteal artery runs through the popliteal
fossa, supplying blood to the lower leg.
Where is the posterial tibial pulse located and
what associated/nearby structures are there to
it?
• Location: Found on the inner side of the ankle, just behind and slightly below
the medial malleolus (the prominent bone on the inner side of the ankle).
• Nearby/Associated Structures: The posterior tibial artery runs along the same
path and provides blood to the foot and calf muscles.
Where is the dorsalis pedis located and what
associated/nearby structures are there to it?
• Location: Located on the top of the foot, just below the ankle joint, in line
with the extension of the big toe.
• Nearby/Associated Structures: The dorsalis pedis artery is adjacent to this
pulse point and supplies blood to the toes and the top of the foot.
How does the position of the head affect your
ability to feel the carotid pulse lateral to the
superior aspect of the thyroid cartilage?
1. Neutral Head Position: When the head is in a neutral, upright position, the
carotid artery runs parallel to the neck. You can typically feel the carotid pulse
easily by gently placing your fingers on the neck, just lateral (to the side) to the
superior aspect of the thyroid cartilage.
2. Head Extension: If the head is extended backward, such as when tilting the
head backward or looking up at the ceiling, the carotid artery may be more
exposed and easier to palpate. This head position may provide even better
access to the carotid pulse.
3. Head Flexion: Conversely, when the head is flexed forward, such as when
looking downward or bringing the chin toward the chest, the carotid artery may
be partially obscured by the surrounding structures, including the anterior neck
muscles. In this position, it may be more challenging to feel the carotid pulse.
Which vessel can be seen passing inferiorly
across the sternocleidomastoid muscle and
entering the subclavian vein?
External jugular vein
Where can the facial artery pulse be palpated
and what are the nearby structures to it?
1. Location for Pulse Palpation:
• The facial artery pulse can be palpated in the area of the lower jaw, slightly
anterior to the masseter muscle, which is one of the chewing muscles.
• Specifically, it is often felt at the inferior border of the mandible, near the
angle of the jaw.
2. Nearby/Associated Structures:
• Nearby structures include the mandible (lower jaw), the masseter muscle
(one of the main muscles involved in chewing), and the buccinator muscle (a
muscle of the cheek).
• The facial artery itself, which carries oxygenated blood to the face, originates
from the external carotid artery and runs a course through the face,
supplying blood to various facial structures.
Where can the superficial temporal pulse be
palpated and what are the associated/nearby
structures to it?
1. Location for Pulse Palpation:
• The facial artery pulse can be palpated in the area of the lower jaw, slightly
anterior to the masseter muscle, which is one of the chewing muscles.
• Specifically, it is often felt at the inferior border of the mandible, near the
angle of the jaw.
2. Nearby/Associated Structures:
• Nearby structures include the mandible (lower jaw), the masseter muscle
(one of the main muscles involved in chewing), and the buccinator muscle (a
muscle of the cheek).
• The facial artery itself, which carries oxygenated blood to the face, originates
from the external carotid artery and runs a course through the face,
supplying blood to various facial structures.
Where is the aortic valve sound listened for?
• Aortic Area (Second Right Intercostal Space):
• Located in the second right intercostal space near the sternal border.
• Best for listening to aortic valve sounds.
Where is the pulmonary valve heart sound
listened for?
• Pulmonic Area (Second Left Intercostal Space):
• Located in the second left intercostal space near the sternal border.
• Ideal for auscultating pulmonic valve sounds.
Where is the tricuspid heart sound listened for?
• Tricuspid Area (Lower Left Sternal Border):
• Located along the lower left sternal border.
• Best for hearing tricuspid valve sounds.
Where is the mitral valve sound listened for?
• Located in the fifth left intercostal space at the midclavicular line (between
the left nipple and the left midclavicular line).
• Ideal for listening to mitral valve sounds, which are also known as the apex
beat.
Why do the heart valve sounds listened for in
locations other than their surface projections?
• Auscultation points provide optimal access to hear specific heart sounds.
• Heart sounds are transmitted through complex pathways within the chest.
• Sound waves travel through cardiac tissues, structures, and chest wall.
• Clinical relevance guides the choice of auscultation points for accurate
assessment.
What is the effect of parasympathetic
stimulation on blood vessels?
• Limited vasodilation, because of limited innervation, despite widespread
endothelial mAChrRs
• Complicated by muscarinic receptor-induced release of NO from endothelial
cells
What is the effect of parasympathetic
stimulation on the heart?
• negative chronotropic action through action at the sinoatrial node
• Slow AV node conduction
• Little effect on myocardial contractility, but evidence for vagal modulation of
ventricular rhythm
How is acetylcholine released and modulated at
nerve terminals?
• Acetylcholine (ACh) is synthesized and stored in synaptic vesicles within the
nerve terminal.
• When an action potential reaches the nerve terminal, it depolarizes the
membrane, opening voltage-gated calcium channels.
• Calcium ions enter the nerve terminal, triggering fusion of ACh-containing
vesicles with the presynaptic membrane and releasing ACh into the synaptic
cleft.
• ACh binds to postsynaptic receptors, leading to a depolarization of the
postsynaptic membrane.
• Acetylcholinesterase (AChE) in the synaptic cleft breaks down ACh to
terminate the signal.
• Modulation can occur through various mechanisms, such as autoreceptors,
reuptake, or enzymatic degradation.
What does modulation mean in
neurotransmission, specifically at cholinergic
synapses?
• Modulation involves the regulation of neurotransmitter effects.
• It influences the strength and duration of synaptic transmission.
• At cholinergic synapses, modulation can occur through factors like receptor
sensitivity, autoreceptors, reuptake, enzymatic degradation, and
neuromodulators.
What does cholinergic mean?
It is a term used to describe anything related to or influenced by acetylcholine.
Cholinergic neurones
Cholinergic neurons are nerve cells that use acetylcholine as their primary
neurotransmitter. These neurons release ACh to transmit signals to other
neurons, muscles, or glands
Cholinergic receptors
Cholinergic receptors are specialized proteins on the surfaces of target cells
(such as muscle cells or other neurons) that bind to acetylcholine. There are two
main types of cholinergic receptors: nicotinic and muscarinic receptors.
Nicotinic receptors
One of the two main types of cholinergic receptor (the other being muscarinic).
These are found at neuromuscular junctions and in the central and peripheral
nervous system and they mediate fast excitatory responses.
Muscarinic receptors
One of the two main types of cholinergic receptors (the other being nicotinic
receptors) that are found in various tissues, including smooth muscle, cardiac
muscle, and certain glands. They mediate more varied responses compared to
nicotinic receptors and can be excitaroy or inhibitory.
Cholinergic efffects
The effects of acetylcholine at cholinergic synapses vary depending on the
specific receptor type, the location of the synapse, and the context. For example,
cholinergic transmission is involved in muscle contractions, regulating heart rate,
controlling secretions, and modulating neural circuits in the central nervous
system.
Cholinergic drugs
Medications that affect the cholinergic system can be used for various purposes.
For example, cholinergic agonists mimic the effects of acetylcholine and are used
to treat conditions like myasthenia gravis, while cholinergic antagonists block the
effects of ACh and can be used to treat conditions like overactive bladder.
What are prodrugs and predrugs (precursor
drugs) in pharmacology?
• Prodrugs are inactive or less active compounds administered in an inactive
form, converted to active drugs in the body.
• Precursor drugs (pre-drugs) may refer to intermediate compounds in the
synthesis of active pharmaceutical drugs but lack pharmacological activity.
What does sympathetic drive refer to in
physiology?
• Sympathetic drive is the activation of the sympathetic nervous system.
• It prepares the body for a "fight or flight" response to stress or challenges.
• Involves physiological responses like increased heart rate, alertness, and
redirection of blood flow.
• Operates in balance with the parasympathetic nervous system.
What does resting tone refer to in the context
of neuroscience?
• Resting tone in neuroscience describes the baseline level of muscle tension
in skeletal muscles when the body is at rest.
• It is important for maintaining posture, stability, and rapid responses to
changes in body position.
• Resting tone is regulated by the nervous system and plays a role in overall
muscle function.
What are the two main M2-mediated signalling
pathways in the heart?
1. Direct G-protein mediated activation of K ACh
2. Inhibition of adenylate cyclase (ADC) - opposing PKA-mediated actions on a
range of channels
What is atropine and what are its
cardiovascular uses?
It is a muscarinic antagonist:
• cardiac effects - block cardiac M
2
receptors
• other effects (against all muscarinic receptors) - decreased secretions
(mouth, airways, gut), bronchodilation, constipation, urinary retension,
pupillary dilation, confusion/hallucinations
What are the BNF approved uses of atropine?
brachycardia following MI with hypotension, excessive bradycardia with betablocker use, intra-operative bradycardia
What is the Uptake 1 block of noradrenaline?
• Neuronal uptake of NAd
• Mediated by NAT - noradrenaline transporter
• is a secondary active transporter (requiring sodium and calcium)
• blocked by cocaine and the tricyclic antidepressants
• causes pro-arrhythmic effects of drugs such as cocaine
How does cocaine's inhibition of norepinephrine
reuptake lead to proarrhymic effects in the
heart?
• Cocaine inhibits the reuptake of norepinephrine.
• This leads to excess norepinephrine at adrenergic receptors in the heart.
• Excessive activation of adrenergic receptors disrupts normal cardiac rhythm.
• Proarrhythmic effects, including ventricular tachycardia, can result,
increasing the risk of life-threatening arrhythmias.
How do monoamine oxidase inhibitors (MAOIs)
interact with the cardiovascular system?
• MAOIs can increase blood pressure by inhibiting the breakdown of
norepinephrine.
• They can lead to a hypertensive crisis when combined with tyramine-rich
foods.
• MAOIs may cause tachycardia, irregular heartbeats, and mydriasis.
• They have the potential for serious cardiovascular side effects and drug
interactions.
What is a hypertensive crisis?
• A hypertensive crisis is a severe, life-threatening increase in blood pressure.
• It can lead to symptoms such as severe headache, chest pain, shortness of
breath, and neurological symptoms.
• Hypertensive crises can result from various causes, including uncontrolled
high blood pressure or interactions with certain medications.
• Immediate medical attention is necessary to prevent complications.
What is the mechanism of action of
methyldopa?
• Methyldopa is converted to methylnorepinephrine.
• Methylnorepinephrine stimulates central alpha-2 receptors in the brain.
• This leads to reduced sympathetic nervous system activity.
• Decreased norepinephrine release results in vasodilation and lowered blood
pressure.
Why is methyldopa used to treat hypertension
in pregnancy?
Because most of the other anti-hypertensives are contraindicated in pregnancy.
What are the two ways that drugs can affect
the heart?
1. Directly
2. Indirectly - by affecting the vasculature and changing blood volume,
composition, and renal function and through this affect heart function
What are arrhythmias?
Disorders of heart rate or rhytm and they occur when there is abnormal
generation or conduction of the electrical activity of the heart
What are the three causes of arrythmia?
• Pathological
• Drug induced
• Congenital
What are the names of the different types of
arrhythmias based on?
Their origin and their effect
How do arrhythmic drugs work?
By altering the cardiac action potentials and/or ion currents which in turn affect
heart rate/rhythm
How do class 1 antiarrhythmic drugs work?
By blocking sodium channels in cardiac cells
What is the mechanism of action of Class 1a
antiarrhythmic drugs?
Class Ia drugs block sodium channels during depolarization, slowing the rate at
which sodium enters cardiac cells and delaying repolarization.
What is the mechanism of action of class 1b
antiarrythmic drugs?
Class Ib drugs block sodium channels, but they are particularly effective in
damaged or ischemic cardiac tissue. They reduce the rate of sodium influx and
can stabilize the cardiac membrane.
What are the 9 protected characteristics as
outlined in the equality act of 2010?
1.
2.
3.
4.
5.
6.
7.
8.
9.
Age
Disability
Gender reassignment
Pregnancy and maternity
Race including colour, nationality, ethnic, or national origin
Religion, belief, or lack of religion/belief
Sex
Sexual orientation
Marriage and civil partnership
What are human rights?
Human rights are the basic rights and freedoms that belong to every person in
the world from when they are born till they die. These rights are based on shared
values like dignity, fairness, respect, and independence. The human rights act of
1988 is a British act that protects these human rights for its citizens.
Why might we need drugs that affect rate/
rhythm?
To treat disorders of rate and rhythm due to abnormal generation and conduction
What is the most popular classification system
for antiarrhythmic drugs?
Vaughan Williams system
Eg class 1 antiarrhytmic drugs
Lidocaine, flecainide
What is the target for lidocaine?
Voltage gated sodium channels
General mechanism of class 1 antiarrhythmic
drugs
Increasing refractory period of cardiac myocytes - decreased excitability
Class 2 antiarrhythmic drug mechanism
opposing sympathetic affect - these are beta blockers
Metabolic/endocrine functions of the kidney
• synthesis of hormones
• vit d
• erythropoietin
• renin
Homeostatic functions of the kidney
• water/fluid
• electrolytes
• acid-base
• blood pressure
• elimination of waste
• excretion of drugs and drug metabolities
eg exogenous filtration markers
inulin, 51Cr-EDTA
What are the issues with using exogenous
filtration markers?
• require injection or infusion
• require multiple sample collection
• cumbersome and intrusive
Problems with endogenous filtration markers
• urinary clearance of creatinine
• requires accurate timed urine collection and matched serum sample
• cumbersome and error-prone
When are techniques to measure glomerular
filtration rate only used?
Specific purposes when clinical decisions depend on accurate knowledge of GFR
What is the first limitation of using serum
creatine to measure GFR?
there is a non-linear relationship between serum creatine and GFR, i.e. small
changes in serum creatine value can mean large changes in GFR
What is the second limitation of using serum
creatine to measure GFR?
• creatinine is an end product of muscle turnover so its production is
preportional to muscle mass
• it can also be derived from dietary meat or creatine supplements
How do we quantify proteinuria?
• Measure total amount - protein excretion in 24hr urine sample
• Measure ratio to reference analyte, e.g. protein-creatinine ratio or albumincreatinine ratio
How is CKD defined?
Any abnormalities of kidney structure or function present for more than 3
months with implication for health
Two features of CKD
• irreversible loss of renal function (loss of nephrons)
• progressive loss of renal failure if untreated
Features of stage 5 CKD - end stage renal
failure
• insufficient renal function to sustain life or health
• haemodialysis
• kidney transplantation
• death
What GFR would be an indication of CKD?
GFR < 60ml/min/1.73 m 2
What are the markers of kidney damage?
• albuminuria
• urine sediment abnormalities
• electrolyte and other abnormalities due to tubular disorders
• abnormalities detected by histology
• structural abnormalities detected by imaging
• history of kidney transplantation
What albuminuria levels would suggest kidney
disease?
• AER - > or equal to 30mg/24 hrs
• ACR > or equal to 30mg/g 0r 3mg/mmol
Class II antiarrhythmic drug eg
Metoprolol and other beta blockers
How do class II antiarrhythmic drugs work?
They decrease the sympathetic activity to the SAN
Class 3 antiarrhythmic drug eg
Amiodarone and sotalol
What is the mechanism of action of class 3
antiarrhythmic drugs?
These drugs are able to prolong action potentials by delaying repolarisation by
blocking sodium channels
Why can amiodarone lead to complications in
individuals who have a thyroid function
problem?
Because iodine is part of its structure
What is the mechanism of action of class 4
antiarrhythmic drugs?
They decrease the rate of depolarisation, particularly at the AVN, slowing down
conduction between the atria and ventricles by blocking L type calcium
channels.
eg class 4 antiarrhythmic drug
Verapamil
Why is verapamil described as being relatively
cardio-selective?
Because it principally has its action on cardiac myocytes and has no action in the
vasculature
What is the mechanism of action of adenosine?
It acts on adenosine receptors on the SA/AV cells causing the potassium
channels to open leading to hyperpolarisation meaning that the cell's action
potential is further away from the threshold point at which an AP can be
generated. This results in an increase in the refractory period thus slowing
conduction through the SA and AV nodes
What is adenosine, and what are its key
functions?
• Adenosine is a purine nucleoside composed of adenine and ribose.
• Key Functions:
◦ Energy currency (ATP breakdown).
◦ Neuromodulator and neurotransmitter.
◦ Vasodilatory effect in cardiovascular regulation.
◦ Immunomodulation and anti-inflammatory properties.
◦ Role in cyclic adenosine monophosphate (cAMP) signaling.
◦ Medication use for cardiac testing and arrhythmia treatment.
Why does caffeine have its effect on the heart?
BECAUSE IT IS AN ANTAGONIST FOR ADENOSINE RECEPTORS. If you have too
much caffiene you feel your heart is elevated leading to heart palpitations
because the nodal cells are closer to threshold and are more likely to fire and so
heart rate increases.
What class of antiarrhythmic drugs is digoxin
part of?
It is non-classified
What is digoxin's mechanism of action?
Increases vagal activity increasing parasympathetic activity and as a
consequence of this we get a decrease in the conduction rate in the AV node and
a decrease in ventricular rate as well.
What factors must be considered when deciding
what antiarrhythmic drug to use?
• Cause of arrhythmia (i.e. pathological, drug induced, congenital)
• comorbidities - drug interactions - pharmacokinetics
What are the general side effects of
antiarrhythmic drugs?
• All antiarrhythmic drugs affect ion balance across the cell membrane of
cardiac myocytes.
• Therefore, if we get drug doses wrong or use the wrong drug for a specific
type of arrythmia, we could get to a situation where the drug actually causes
an arrythmia.
• In addition, as well as the drug interacting with ion channels that affect
electrical activity they may affect other aspects of cardiomyocyte function
that are dependent on ion action.
• E.g. drugs can have a negative inotropy (force of contraction) action.
Why do we need drugs that affect the force of
contraction?
Because there are some conditions where force of contraction is insufficient:
• Anaphylaxis
• Heart failure
How is the force of contraction of cardiac
myocytes normally determined?
• Ca2+ is released from the SR.
• This release is induced by calcium entry that occurs following depolarisation
of cardiac myocyte membrane which allows for the opening of calcium
selective channels.
• The calcium in the cell can then promote the actin myosin interaction
for contraction.
• We can use this to understand how drugs affect influence force of
contraction.
What are the 3 classes of inotropic drugs?
Sympathomimetics, cardic glycosides, phosphodiesterase inhibitors
Positive inotropic drugs...
... increase intracellular calcium and therefore increase force of contraction
allow
Negative inotropic drugs...
... decrease intracellular calcium and decrease the force of contraction
Is digoxin still extracted from plants?
Yes as we cant relaibly synthesise it
What is the mechanism of action of digoxin as a
positive inotropic drug?
Digoxin binds to and results in partial inhibition of Na + /K + ATPase (this is the
protein responsible for maintaining the ion concentration gradient inside and
outside cells). This leads to an accumulation of sodium inside the cell and an
increase in intracellular sodium concentration:
• if intracellular sodium levels rose the gradient for sodium between the
outside and inside of the cell would diminish
• therefore, this transporter would be less efficient at allowing sodium to enter
and removing calcium (calcium extrusion is coupled with sodium import)
• so calcium concentration increases intracellularly and an increase force of
contraction
Side effects of digoxin due to ionic disturbances
• Side effects can occur due to ionic disturbances (changes in actions of Na/K
ATPase & Na+/Ca2+ exchanger)
◦ The Membrane potential becomes more positive cells become closer to
threshold value increase excitability more likely to fire AP lead to
arrhythmia.
◦ Digoxin can cross the BBB and therefore impact neurones in CNS in a
similar way. At a high toxic level, Digoxin can cause neurological
disturbance
◦ Na/K ATPase is also found in the smooth muscle of GIT. So disturbing its
function will disturb ion balance negatively impact SM function
problem GIT function.
Why can digoxin cause gyneacomastia?
• Due to the structure of digoxin – it is very large.
• When Digoxin is broken down you get a steroid ring that is similar to that
found in oestrogen.
• This molecule is able to fool oestrogen receptors
breast growth
• (This is quite rare)
What subset of heart failure patients is digoxin
used for?
Those who have both contraction problems and an arrhythma
Why do patients taking both diurects and
digoxin need to be monitered closely?
• Diuretics can be used in heart failure patients as well.
• An individual who has indications that they should have both diuretic and
Digoxin have to be monitored closely.
• This is because Diuretics promote the loss of K+ from the body
(hypokalaemia).
• This decrease in K+ in the body promotes the relative Digoxin effect:
◦ This is because Digoxin usually binds to Na+/K+ ATPase at the same site
as K+.
◦ I.e. they compete with each other.
◦ So, if there are fewer K+ ions in the cell, we have less competition
easier for Digoxin molecules to bind to ATPase so we get an apparent
increase in Digoxin effect despite having the same dose more likely to
get adverse side effects mentioned earlier.
What are phosphodiesterase?
They're a group of enzymes that breakdown cAMP/cGMP (the secondary
messenger molecules)
Broadly how do phosphodiesterase inhibitors
work?
They inhibit the breakdown of phosphodiesterase enzymes and therefore
increase the concentration of cAMP/cGMP within the cel of the drug targets.
What is the specificity of phosphodiesterase
inhibitors?
• PDE enzymes are not uniformly found through the body.
• There is a high distribution of PDE Type 3 found at the heart.
• This means using specific PDE type 3 inhibitor, like Milrinone, means we can
particularly adjust levels of cAMP within the cardiac myocyte.
What are some adverse effects of PDE
inhibitors?
We may get increased excitability as PDE type 3 inhibition adjusts calcium levels
in the cardiac myocytes resulting in arrhythmias.
When would we use PDE type 3 inhibitors?
• PDE type 3 inhibitors has very short heart life the amount of time drug is
active for is short so patient has to be dosed regularly.
• Some research has suggested chronic use actually decreases survival of
patients with heart failure.
• Therefore, these drugs are mainly used for patient going into acute heart
failure (acute emergencies only)
If inotropes are not very promising we can use
ajust the other factros related to cardiac
function?
• We can decrease HR in order to adjust cardiac function.
• This can allow everything to become balanced again
of fluid in the lungs.
fix congestive effect
• Examples:
◦ Beta blockers can be used to reduce HR.
◦ Ivabradine:
▪ The IF channel in cardiac myocytes is important in determining the
pace maker potential.
▪ Ivabradine blocks the IF channel – slows down HR by increasing time
between beats.
• Some drugs are used for heart failure that do not have a direct
effect on heart cells
◦ Diuretics – decrease blood volume
◦ Vasodilators – increase systemic volume
◦ ACE inhibitors: Angiotensin converting enzyme inhibitors
What does an ECG provide?
A visual representation of the spread of electrical events through the heart
P wave
• Represents atrial depolarization
• Duration (HR of 60bpm) = 0.10 s (100 ms)
P-R interval
• Begins at the start of the P wave and ends at the start of the QRS complex
• It represents the time taken for the electrical activity to move between the
atria and the ventricles.
◦ I.e. it reflects conduction through AV node.
• Duration (HR 60bpm) = 0.12 - 0.20 s (120 - 200 ms)
• A change in the P-R interval indicates delayed conduction through the AV
node.
• This can occur in isolation or co-exist with other blocks (e.g. second-degree
AV block).
T wave
• Represents ventricular repolarisation
• Duration (HR 60bpm) = 0.16 s (160 ms)
R-R interval
• Begins at the peak of one R wave and ends at the peak of the next R wave
• You can use it to calculate HR
What are the 12 standard ECG leads?
• 3 standard limb leads
• 3 augmented limb leads
• 6 unipolar chest leads
What do the 6 limb leads of the heart do?
They look at the heart in a coronal plane
How are the limb electrodes of an ECG
arranged?
Three electrodes, one each, to the right and left arm and left leg.
What is the electrode attached to the right leg
on an ECG?
It is an earth electrode
What are limb leads 1, 2, and 3?
They are bipolar - they measure the voltage between 2 of the three limb
electrodes
What does limb lead 1 of an ECG represent?
The voltage btween the right arm (negative pole) and the left arm (positive pole)
and thus looks at the heart from the left
What does limb lead 2 measure on an ECG?
The voltage between the right arm (negative pole) and the left leg (positive pole)
forming the inferior left view
What does limb lead 3 of an ECG measure?
The voltage between the left arm (negative pole) and the left leg (positive pole)
looking at the heart from an inferior right angle
What are the augmented limb leads on an ECG?
aVR, aVL, and aVF and they are unipolar
How do the augmented limb leads work?
They use one limb electrode as the positive pole, and take the average of inputs
from the other two as the zero reference
How do augmented limb lead work on an ECG?
They use one limb electrode as the positive pole, and take the average of inputs
from the other two as the zero reference from the other two as the zero
reference.
ECG Chest leads key facts
• The chest leads, view the heart in a transverse (HORIZONTAL) plane.
• These are unipolar leads.
• The corresponding chest electrodes serve as the positive poles.
• The reference negative value is the same for all chest leads and is calculated
as the average of inputs from the three limb electrodes.
Describe the general mechanism of an ECG
• The isoelectric line is the 'resting line'.
• If a wave of electrical depolarization, moving through the heart, moves
TOWARDS a lead it produces a POSITIVE deflection on the ECG (above the
isoelectric line)
• If a wave of electrical depolarization, moving through the heart, moves
TOWARDS AWAY from a lead gives a NEGATIVE deflection on the ECG (below
the isoelectric line)
• The REVERSE is true for repolarization.
• The magnitude of these deflections is greatest when the vector is moving
directly toward the electrode (i.e. following the axis of the lead).
• A vector that moves at right angles to the axis of a lead produces little
deflection on the trace.
What is Einthoven's Triangle
It is an imaginary triangular formation of the three limb leads in a triangle used
in electrocardiogram, formed by the two shoulders and the pubis. The shape
forms an inverted equilateral triangle with the heart at the centre.
What does constriction of arterioles to one
organ do?
Decreases flow to that organ, e.g. skin in cold conditions
What does constriction of arterioles to multiple
organs do?
Increase total peripheral resistance and therefore increase arterial blood
pressure. This is useful in situations where vasculure integrity is compromised,
e.g. in haemorrhage or upon standing, because it helps maintain blood pressure.
What is arteriole normal tone?
The normal position of arterioles being slightly constricted at rest
What results in the release of vasoactive
substances by the endothelium that effect
vascular muscle cells?
Circulating hormones, paracrine hormones, shear stress, and hypoxia
What is the most important vasoactive
substance?
Nitrous Oxide:
• synthesised continuously by the enzyme NOS
• It has a half life of less than 10s in vivo so its effects are very localised
• its release leads to a fall in calcium levels in smooth muscle cells and thus
causes vasodilation due to the relaxation of arteriole smooth muscle
Describe the impact of nitrous oxide for
coronary circulation
• helps to increase coronary blood flow in exercise when cardiac activity and
metabolism are increased
• in coronary artery disease NO synthesis is reduced and this limits the ability
of coronary flow to increase during exercise
What is the most important endothelium
derived vasoconstrictor?
Endothelin
Endothelin and pulmonary hypertension
Treated with endothelin blockers
What prostaglandin is a endothelium derived
vasodilator?
Prostacyclin
What are many of the local factors responsible
for regulation of blood flow?
Metabolic by-products, e.g.:
• adenosine - vasodilator
• potassium - vasodilator
• CO2 - vasodilator
• Hydrogen ions - vasodilator
How do local factors have an effect on
regulating flow in tissues?
Because resistance vessels, i.e. arterioles, are sensitive to these products and
dilate when exposed to them
What is reactive hyperaemia?
Transient increase in flow seen after period of ischemia (no flow) usually due to
arterial occulsion, e.g. the reactive hyperaemia seen in muscles after isotonic
contraction during weight lifting.
Why is reactive hyperaemia thought to occur?
Due to the build up of metabolites during occlusion which are then washed out in
the hyperaemia causing vasodilation allowing CO2 removal to increase - the
longer the ischemia, the greater the hyperaemia
What is active hyperaemia?
Increase in flow due to increase in metabolic activity
What is the increase in flow seen in active
hyperaemia proportional to?
The increase in metabolic activity
What does active hyperaemia allow for?
The increase in oxygen delivery when there is a increased oxygen demand
Active hyperaemia potency example
flow to skeletal muscle can increase 20-50 times dye to active hyperaemia
during exercise
What part of the nervous system innervates
resistance arterioles?
Sympathetic
What are the exceptions to the fact there is
little parasympathetic innervation to the blood
vessels?
Exocrine glands of the head and genitalia
What is responsible for the vascular smooth
muscle tonic vasomotor tone?
Ongoing sympathetic nerve activity
How does the sympathetic nervous system
cause vasoconstriction?
NA release from sympathetic fibres binding to alpha 1 adenoceptors on arterioles
How does the sympathetic nervous system
cause vasodilation?
NA release from sympathetic nerve fibres binding to beta adenoceptors weakly
and cause vasodilation. However, this is usually masked by alpha 1 stimulation
What is the primary effect of circulating
adrenaline?
Increase HR and contractility
The presence of what indicates circulating
adrenaline is able to change the radius of
arterioles?
Alpha and beta adrenoceptors
What is circulating adrenaline's vasoactive
function?
Vasodilation by having a higher affinity for B2 adrenoceptors on on the vessels.
What is the vasoactive role of ADH?
• major role in regulation of water retention when osmolality changes
• helps maintain BP during haemorrhage
• very high levels it causes vasoconstriction
Vasoactive role of angiotension 2
Produced when the renal artery pressure falls and is a potent vasoconstrictor
What happens during exercise in terms of
changes in resistance?
1. During exercise sympathetic activity to blood vessels increases
2. Results in a reduction in blood flow to reproductive system, GIT, and kidneys
3. But, blood flow to muscles increases because locally produced metabolities are
able to override the SNA and all for vasodilation, decreasing resistance, and
increasing flow into the muscles
How does the flow in an organ change due to
the perfusion pressure?
It will change preportionally to the perfusion pressure
Myogenic mechanism of autoregulation of
vascular radius
• myogenic mechanisms are present in vascular smooth muscle such that
when there is an increased intravascular pressure, smooth muscle will
respond by contracting to restore the original diameter by vasoconstriction
• this is due to vascular smooth muscle cells depolarising due to calcium entry
• this is shown to varying degrees in different organs depending on how well
said organs can tolerate a drop in blood flow in the face of a fall in pressure,
e.g. coronary is very good at this but skin is not
Autoregulation question - if the pressure was to
fall you would get what in order to keep flow
the same?
Vasodilation
What is meant by the autoregulatory range?
This is the pressure range over which resistance vessels can constrict or dilate to
compensate for a drop or increase in blood pressure to maintain the same blood
flow.
What happens as blood pressure drops below
the autoregulatory range?
Maximal vasodilation has been reached and so flow will start to fall
What happens when blood pressure exceeds
the autoregulatory range?
Beyond this point any change in pressure will directly affect the blood flow and
will lead to an increase in blood flow which could potentially be damaging.
Compare the blood flow to the heart and brain
to resting muscle and skin
Heart and brain recieve more
How does the level of oxygen consumption vary
between tissues?
Cardiac tissue has the highest compared to low in the skin
What does a-VO2 mean?
The max amount of oxygen that can be extracted by a tissue out of the oxygen
delivered to it
What is the max amount of oxygen that can be
extracted from 100ml?
15ml
How are vascular beds arranged?
In parallel so that they all recieve the same arterial po2
What does the level of pO2 in the blood leaving
a vascular bed depend on?
The demands of that tissue, e.g. high demand means low pO2 leaving
Where are the coronary arteries derived from?
The aorta just distal to the aortic valve
What do the coronary arteries lie on?
The epicardic surfaces
Broad course of the coronary veins
Lie adjacent to the arteries and drain into the coronary sinus which then empties
into the right atrium
What are thebasian veins?
Small, valve-less, veins that drain venous blood from the myocardium directly
into any of the heart chambers, being most abundant in the right atrium, and
least abundant in the left ventricle. They are also known as the smallest cardiac
veins.
What will thebasian veins cause in the systemic
blood?
Their presence causes a slight drop in oxygen content in the system blood
Why is it that in the coronary circulation it is
the regulation of flow that is responsible for
matching oxygen supply to metabolic demand?
Because the heart has a low capacity for anaerobic metabolism, with it recieving
5% of CO and extracting almost the maximum amount of oxygen possible at rest
(very large a-VO2). Therefore, an increased demand for oxygen due to an
increased heart rate must be met by a large flow increase that is roughly
preportional to the increase in oxygen consumption.
What are the two mechanisms that facilitate
oxygen supply to cardiac cells?
1. The capillary density of myocardial tissue is very high with there being 1
capillary per myocyte
2. The transport of oxygen to cardiac cells is helped by the presence of myoglobin
in cardiac myocytes
Why does the high capillary density of
myocardial tissue help oxygen transport?
Because it crreates a large endothelium surface area for exchange and reduces
diffusion distance - both facilitating delivery of oxygen and nutrients from
capillaries to tissues as well as removal of metabolic by products
How does the presence of myoglobin in cardiac
myocytes facilitate oxygen transport?
• While myoglobin can only bind 1 oxygen molecule, it has a higher affinity for
oxygen compared to Hb
• Therefore, in the capillaries of the coronary circulation Hb hands oxygen to
myoglobin inside cardiac muscle cells
• Myoglobin molecules inside the myocytes transfer the oxygen from one
myoglobin molecule to the next speeding up the diffusion of oxygen through
the muscle cell to the mitochondria
What is coronary flow reserve?
The difference between the resting level of flow and the max flow that can be
obtained by dilating vessels
By how much does the coronary flow reserve
alow for flow to increase above resting levels?
5x
What is the dominant form of regulation of the
coronary flow?
Metabolic/functional/active hyperaemia because it overrides autonomic control
Describe how active hyperaemia of coronary
flow works?
1. An increase in metabolic activity, a fall in coronary blood flow, or a fall
in myocardial pO2 will all result in adenosine release
2. Adenosine is a potent vasodilator that acts by reducing intracellular
calcium levels in the vascular smooth muscle cells
3. Extracellular potassium also rises as cardiac work increases and this may
contribute to an intial increase in coronary perfusion but it is unlikely to mediate
a sustained rise in coronary flow
4. When O2 demand exceeds O2 supply a rise in CO2 and acidosis may also lower
vascular resistance to increase local oxygen supply
5. Endothelial derived vasodilators like nitrous oxide and prostacyclin also have a
role.
By how much does stenosis need to exceed to
have a significant effect on flow?
60-70%
Where does stenosis usually occur?
In the large epicardiac arteries
What does coronary artery disease cause that
affects arteriole's ability to vasodilate?
Atherosclerotic built up damages endothelial cells leading to a fall in nitrous
oxide and prostacyclin production which are two important local factor
vasodilators
What type of angina is life threatening and
why?
Unstable angina because it indicates the danger of vessels becoming completely
occluded and so often intervention including balloon angioplasty or implanting
stents to open stenotic arteries or coronary bypass graft surgery is required
What is angina?
It is chest pain or discomfort caused by an imbalance between oxygen supply
(decreased coronary blood flow) and oxygen demand (increased myocardial
oxygen consumption), which leads to a decrease in the oxygen supply/demand
ratio and myocardial hypoxia.
What can the decreased blood flow in the
coronary circulation seen in angina be caused
by?
Coronary artery vasospasm, fixed stenotic lesions (chronic vessel narrowing), or
from a blood clot (thrombus) that incompletely (non-occlusive thrombus) or
completely occludes a coronary artery (occlusive thrombus).
Calcium-Channel Blockers (CCBs) and
Vasospasm:
• Mechanism: Inhibit entry of calcium ions into smooth muscle cells.
• Effect: Prevent excessive smooth muscle contraction.
• Result: Induce vasodilation of blood vessels.
• Clinical Use:
◦ Treat conditions with vasospasm.
◦ Example: Used in coronary artery vasospasm.
• Application: Alleviate vasospasm, improve blood flow to tissues.
• Examples: Nifedipine, diltiazem.
Vasospasm
• Definition: Sudden, involuntary constriction or narrowing of a blood vessel.
• Causes:
◦ Hypoxia/ischemia.
◦ Cold exposure.
◦ Emotional stress.
◦ Underlying medical conditions.
◦ Drug reactions.
• Example: Coronary artery vasospasm can cause chest pain (angina).
• Clinical Significance: Reduces blood flow to tissues.
• Treatment: Address underlying causes; use medications like calciumchannel blockers to induce vasodilation.
• Common Medications: Calcium-channel blockers (e.g., nifedipine) are used
to prevent or relieve vasospasms.
Nitrodilators and Vasospasm:
• Mechanism: Nitrodilators release nitric oxide (NO).
• NO Effects:
◦ Increases cGMP in smooth muscle cells.
◦ Induces vasodilation.
• Prevents Vasospasm:
◦ Counters excessive smooth muscle contraction.
• Clinical Use:
◦ Treatment of angina.
◦ Dilates coronary arteries in coronary artery vasospasm.
• Common Medications:
◦ Nitroglycerin, isosorbide dinitrate.
• Monitoring:
◦ Careful dosage and administration under healthcare supervision.
How does vascular steal lead to angina?
V ascular steal is a hemodynamic condition where multiple stenotic lesions can
lead to a redistribution of flow within the major supply arteries of the heart under
conditions of exercise or vasodilator therapy. Therefore, as blood flow increases
in one region of the coronary vascular network, blood flow will reciprocally
decrease in another region, leading to angina.
What are the three types of angina?
1. Variant
2. Stable
3. Unstable
Compare the three types of angina
What is stable angina?
The most common type of angina, caused by a narrowing of the coronary
arteries that reduces blood flow to the heart. It typically occurs during physical
activity or emotional stress and goes away with rest or medication.
How does the narrowing of the coronary
arteries cause angina in stable angina?
When a coronary artery narrows beyond a critical value known as critical
stenosis, the myocardial tissue perfused by the artery will not recieve adequate
blood flow because the coronary flow reserve decreases resulting in the tissue
becoming ischaemic and hypoxic, particularly during times of increased oxygen
demand like physical exertion.
How is stable angina treated?
Lifestyle changes, such as diet and exercise, and medications, such as
nitroglycerin (nitrodilators), beta-blockers, and calcium-channel blockers, are
used to treat stable angina
What is unstable angina?
A more serious type of angina that can occur at rest or with less exertion than
stable angina. It is a sign that the coronary arteries are narrowing or becoming
blocked, which can lead to a heart attack.
How is unstable angina treated?
With drugs that reduce oxygen demand (i.e. beta blockers, calcium channel
blockers, and nitrodilators) and, most importantly, drugs that inhibit thrombus
formation (e.g. anti-platelet drugs and aspirin)
How does unstable angina work?
It is caused by the transient formation and dissolution of thrombosis within a
coronary artery. These clots often form in response to plaque rupture in
atherosclerotic coronary arteries, but it may also form because diseased
coronary endothelium is unable to produce NO and prostacyclin that inhibits
platelet aggregation and clot formation. When the clot forms, coronary flow is
reduced, leading to supply ischaemia.
How can unstable angina lead to acute
myocardial infarction?
Unstable angina is characterised by the transient formation and dissolution of
thrombosis and if one of these thrombosis completely occludes the coronary
artery for a sufficient amount of time, the myocardium supplied by the vessel will
become infarcted - aka a acute myocardial infaction has occured.
How is an acute myocardial infarction different
from a myocardial infarction?
An acute myocardial infarction is one that comes on suddenly due a sudden
blockage of a coronary artery that causes damage to the myocardium, whereas
a myocardial infarction is a broader term that encompasses both an AMI and
other more slower onset forms. In effect, myocardial infarction is an umbrella
term and AMI is a sub-type.
What is variant angina?
A type of angina that is caused by spasms in the coronary arteries, which
temporarily reduce blood flow to the heart. It typically occurs at rest and is often
associated with emotional stress, exposure to cold temperatures, or smoking.
How is variant angina treated?
Nitrodilators and calcium-channel blockers
How does vasospasm cause variant angina?
Because it temporarily reduces coronary blood flow, producing ischaemia by
reducing blood supply, thereby decreasing the oxygen/demand ratio.
How does enhanced sympathetic activity
precipitate vasospastic angina (variant
angina)?
Enhanced sympathetic activity, especially when coupled with with a
dysfunctional coronary vascular endothelium (i.e. reduced endothelial production
of the vasodilators nitric oxide and prostacyclin) can precipitate vasospastic
angina.
What is demand ischaemia?
A type of ischaemia that occurs when the heart's demand for oxygen exceeds its
supply.
Critical stenosis
• Definition: Critical stenosis refers to a severe narrowing or constriction of a
blood vessel, often due to atherosclerosis or other pathological processes.
• Significance: This level of stenosis significantly reduces blood flow through
the affected vessel, compromising oxygen and nutrient delivery to
downstream tissues.
• Clinical Implications: Critical stenosis is a key factor in conditions like
coronary artery disease, where reduced blood flow to the heart muscle can
lead to ischemia and potentially trigger heart-related events.
• Diagnostic Tools: Detected through imaging studies (e.g., angiography)
that visualize and assess the degree of narrowing.
• Treatment: Interventions, such as angioplasty or stent placement, may be
necessary to restore proper blood flow and prevent complications.
• Monitoring: Regular assessment is crucial to manage and prevent
complications associated with critical stenosis.
What is stenosis?
The narrowing of an artery or other passage in the body
Neuronal hypoxia longer than ... leads to
neuronal damage
4 mins
How quickly does syncope (fainting) occur after
cerebral ischaemia?
seconds
How does local cerebral blood flow alter?
Metabolic/functional hyperaemia
Grey matter vs white matter - which recieves
the majority of blood flow to the brain?
Grey matter as it contains the neuronal cell bodies
What is the blood flow to the brain through?
2 internal carotid and 2 vertebral arteries
What anastomoses to form the circle of willis?
The 2 internal carotid and 2 vertebral arteries
What is the significance of the circle of willis
being an anastomosis?
If one of the source arteries (i.e. the internal carotid or vertebral) develops a
stenosis or is obstructed the other source arteries can provide alternative flow it is protective of the brain blood flow
What are the pial arteries
Definition: Arteries associated with the pia mater, the innermost layer of the
meninges covering the brain and spinal cord. Pial arteries play a crucial role in
supplying oxygenated blood to the nervous tissue.
1. Location: Found within the pia mater, the innermost layer of the meninges.
2. Function: Responsible for supplying oxygenated blood to the brain and spinal
cord.
3. Anatomy: Pial arteries branch out into smaller vessels, forming an intricate
network to ensure proper blood supply to different regions of the nervous
system.
4. Clinical Significance: Disruptions in blood supply to the brain through pial
arteries can lead to serious conditions such as strokes or other vascular
disorders.
Do the capillary networks of the brain have
high or low resistance?
Relatively high resistance
What is different about the brain capillaries
compared to the systemic circulation?
In the systemic circulation capillaries are leaky due to the presence of
fenestrations which allow for substances to cross the capillary wall. However,
these fenestrations are not present in the capillary walls present in the brain
because of the blood brain barrier - instead the edges of adjacent endothelial
cells are joined together and completely sealed via tight junctions, preventing
bulk flow and diffusion of water and ions that is seen in systemic circulation.
What is the blood brain barrier?
Definition: A selective semipermeable membrane barrier that separates the
bloodstream from the brain's extracellular fluid, formed by tight junctions
between endothelial cells in brain capillaries.
Key Points:
1. Function: Protects the brain by restricting the passage of potentially harmful
substances from the bloodstream.
2. Structure: Tight junctions between endothelial cells create a physical barrier,
selectively allowing essential nutrients while blocking larger or hydrophilic
molecules.
3. Role of Astrocytes: Astrocytes contribute to BBB regulation, releasing chemical
signals that influence barrier permeability.
4. Significance: Essential for maintaining the optimal neural environment; poses
challenges for drug delivery to the brain, prompting ongoing research for
improved methods.
What is the significance of the blood brain
barrier for substance transport?
All substances entering or leaving the brain must pass through the 2 plasma
membranes and the cytoplasm of the endothelial cells rather than moving
between cells:
• Like all capillaries, the cerebral capillariers are permeable to lypophilic
solutes like oxygen, carbon dioxide, alcohol, nicotine, and caffeine.
• Glucose and plasma proteins move through cells via plasma proteins
• Carrier proteins move surplus molecules out preventing a build-up of
anything that could interfere with brain function:
- when potassium in the interstitium increases due to neuronal activity it is
pumped out via the sodium/potassium ATPase pump, helping to regulate
cerebral interstitium potassium concentration
- this is the reason why cerebral endothelium cells have 5-6x as many
mitochondria than muscle cells
How many more mitochondria do do cerebral
capillary endothelium have compared to muscle
endothelium?
5-6 times more
How is the blood flow to the brain safeguarded?
Through the regulation of peripheral resistance to other vascular beds - when
neccessary, the perfusion of peripheral organs (except the heart) is sacrificed
through vasoconstriction to maintain arterial pressure and therefore cerebral
flow.
How does autoregulation safeguard cerebral
blood flow?
If the blood pressure falls, cerebral resistance vessels dilate to maintain cerebral
flow due to the release of local factors like NO and prostacyclin. They are able to
compensate for pressure changes between 60-150 mmHg. Hypotension below
50-60 mmHg leads to the failure of autoregulation and decreased blood flow, and
so decreased oxygen perfusion, and so mental confusion and syncope.
How are cerebral vessels responsive to CO2?
Very:
1. Hypercapnia induces vasodilating of cerebral vessels which is useful during
suffocation to maintain oxygen delivery:
• small pial arteries dilate more than larger cerebral arteries in response to
CO2
• the vasodilation is partly mediated by endothelial NO and is perhaps aided
by a fall in myocyte pH
2. Hypocapnia invokes vasoconstriction of cerebral vessels:
• an arterial CO2 level of 2pka will half total cerebral flow
• this is responsible for the dizziness experienced in hypocapnia
Hypercapnia
High CO2 levels in the blood (PaCO2 >5kpa)
Hypocapnia
Low CO2 levels in the blood (PaCO2 <5kpa)
In comparison to their responsiveness to CO2,
how does the responsiveness of cerebral
vessels compare for O2?
Less responsive:
- a halving of normal PO2 is unlikely to affect cerebral flow
- severe hypoxia will lead to vasodilation in cerebral circulation via adenosine,
potassium, and NO
Why does severe hypoxia often lead to a
masking of the expected vasodilation in
cerebral vessels?
Because severe hypoxia invokes hyperventilation, which will, in turn, lead to a
fall in PCO2, and therefore cerebral vasoconstriction will occur and will
counteract the vasodilation seen from the severe hypoxic response. This is
because cerebral vessels are far more responsive to PCO2 than PO2.
What is meant by neuronal activity-evoked
functional hyperaemia?
While total cerebral blood flow is relatively constant due to autoregulation,
regional changes in blood distribution occur in response to changing patterns of
neuronal activity with flow shifting towards areas of increased neuronal activity,
i.e. blood distribution will be different in a person sleeping to a person studying.
What factors are important in coupling tissue
metabolism to local cerebral flow?
• Increased interstitial potassium ion concentration
• adenosine
• neuronal NO
• metabolites released from astrocytes during increased neuronal activity
• CO2 level
How does increased interstitial [K+] aid in
coupling cerebral tissue metabolism to local
flow?
• neuronal activity increases potassium ion permeability of the membranes
• the extracellular potassium concentration can increase 3x the basal level
• potassium ions are a potent vasodilator so you see increased flow
How does adenosine aid in coupling cerebral
tissue metabolism to local flow?
Because it is released when metabolism increases and is a vasodilator
How does neuronal nitric oxide aid in coupling
cerebral tissue metabolism to local flow?
Neuronal activity causes the release of neuronally derived nitric oxide and it is a
vasodilator so leads to vasodilation which leads to increased blood flow by
decreased resistance
How do metabolites released by astrocytes
during increased neuronal activity aid in
coupling cerebral tissue metabolism to local
flow?
The astrocyte end foot processes envelope blood vessels in the brain and they
send signals to the arterial/arteriole smooth muscle cells which allows for them
to control vessel diameter
How does PCO2 aid in coupling cerebral tissue
metabolism to local flow?
Increased metabolism increases CO2 production which will cause vasodilation - >
minimal effect
How is it that the intracellular space is a K+
reserve?
Becasue it exists in the intracellular space at a higher concentration than the
extracellular space (140mM vs 4mM) combined with the much larger volume of
the intracellular space compared to the extracellular space (14l vs 28l)
Where will any additional potassium in the
extracellular space go?
It will be taken up into the cell - any potassium we ingest is moved into cells
quickly by an active process
What is the maximal increase to cerebral
resistance vessels resistance that sympathetic
stimulation can exert, and how does this
compare to the skeletal muscle?
20-30% - compared to 500%
Baroreceptors have little influence on cerebral
flow, otherwse every time you stood up or
exercised...
we would compromise cerebral blood flow by increasing sympathetic stimulation
What are baroreceptors?
Baroreceptors are pressure-sensitive receptors located in blood vessels,
particularly in the carotid sinus and aortic arch. They monitor changes in blood
pressure by detecting the stretch of arterial walls. When blood pressure
increases, baroreceptors signal the brain's cardiovascular center, leading to
adjustments such as decreased heart rate and vasodilation to lower pressure.
Conversely, if blood pressure drops, the response includes increased heart rate
and vasoconstriction. Baroreceptors play a vital role in maintaining blood
pressure within a normal range and are part of the autonomic nervous system.
What is the carotid body?
The carotid body is a cluster of chemoreceptor cells located near the common
carotid arteries. It monitors blood oxygen, carbon dioxide, and pH levels. When
hypoxia, hypercapnia, or acidosis occurs, the carotid body stimulates respiratory
centers in the brainstem to adjust breathing. This helps maintain proper blood
gas levels and supports overall respiratory regulation.
What are the three intracranial constituents?
Tissue, blood, and CSF
An increase in intracranial pressure comes
about by what?
Either one of the three constituents of the intracranium increasing in volume
An increase in the volume of one of the three
constituents of the intracranium means that?
If tissue increases, then blood and CSF would need to decrease and vice versa
What is raised ICP commonly caused by?
Intracranial bleeding, cerebral oedema, and tumour growth
What does high ICP result in?
Collapsed veins and a decrease in the effective cerebral perfusion pressure
leading to a reduced blood flow
How do you calculate cerebral perfusion
pressure?
ABP-ICP
What is the normal range of ICP?
5-15 mmHg
When there is an increase in ICP past ...
combined with ... then cerebral blood flow can
be significantly reduced
20 mmHg and systemc hypotension
What is a transient ischaemic attack?
It is a temporary reduction in flow to a cerebral tissue that can last a few minutes
to hours.
What is an ischaemic stroke?
An ischaemic stroke occurs when there is a total interruption in cerebral flow due
to atherosclerosis or blood clot in an extracerebral artery
What is a haemorrhagic stroke?
• Definition: A type of stroke caused by bleeding in or around the brain.
• Types:
◦ Intracerebral Hemorrhage (ICH): Bleeding within the brain tissue.
◦ Subarachnoid Hemorrhage (SAH): Bleeding into the space between the
brain and its covering.
• Symptoms: Sudden severe headaches, weakness, numbness, difficulty
speaking, and visual disturbances.
• Causes: High blood pressure, cerebral aneurysms, arteriovenous
malformations.
• Treatment: May involve surgery to repair bleeding vessels or other
interventions.
• Importance of Prompt Medical Attention: Critical for minimizing damage and
improving outcomes.
What is a thrombus?
A thrombus is a blood clot that forms and remains attached to the vascular wall
at the site of its formation. It can partially or completely block blood flow,
depending on its size and location. Thrombi are often associated with conditions
such as atherosclerosis or damage to blood vessel walls.
What is an embolus?
An embolus is a detached, moving blood clot or other foreign material that
travels through the bloodstream. It can potentially lodge in a smaller blood
vessel and cause an obstruction, leading to conditions such as pulmonary
embolism (if it lodges in the lungs) or stroke (if it reaches the brain).
What is an embolism?
An embolism is the blockage of a blood vessel by an embolus. This blockage can
impede blood flow and cause damage to tissues supplied by the affected vessel.
Depending on where the embolism lodges, it can lead to various medical
emergencies.
What is a DVT?
Deep vein thrombosis refers to the formation of a blood clot (thrombus) within a
deep vein, typically in the legs. If a clot from a DVT breaks loose and travels to
the lungs, it can cause a pulmonary embolism.
What is pulmonary embolism?
A pulmonary embolism occurs when an embolus, usually from a deep vein
thrombosis, travels to the pulmonary arteries in the lungs and blocks blood flow.
This condition can be life-threatening and requires prompt medical attention.
What is thrombophlebitis?
Thrombophlebitis is the inflammation of a vein accompanied by the formation of
a thrombus. It often occurs in the legs and can cause pain, swelling, and redness
at the affected site.
Infarction
obstruction of the blood supply to an organ or region of tissue, typically by a
thrombus or embolus , causing local death of the tissue.
What is the main function of cutaneous
circulation?
Maintanance of constant body temperatrue - thermoregulation
Describe the range in blood flow to the
cutaneous circulation
• When ambient temperature falls below thermoneutral zone, cutaneous blood
flow can fall as low as 1ml per minute per 100g of tissue.
• A rise in core temperature can increase flow to skin to 200x that level.
What important feature of the cutaneous
circulation is responsible for its
thermoregulatory ability?
The arterio-venous anastomoses - blood can bypass the capillaries in the
epidermis and flow straight into venous plexi (allowing for a rapid expansion in
cutaneous blood volume - remember veins are storage vessels because they can
dilate so much).
Where are A-V anastomoses particularly
prominent?
The skin of the nose, lips, ears, toes, and especially fingertips - why these go red
when hot
Describe the cutaneous thermoregulatory
response to increased body temperature
Increased body temperature causes the arterioles of the skin to vasodilate due to
the withdrawal of sympathetic tone, including the arterioles of the arterio-venous
anastomoses. Therefore, blood flow into the cutaneous circulation increases
massively, accomodated by the arterio-venous plexi vasodilation increasing flow
into the venous plexi, which are able to stretch to hold this increased blood
volume (veins are the compliance vessels).
This massive increase in cutaneous flow accomodated by the A-V anastomoses
and the venous plexi provide a large surface area for heat exchange between the
body (blood) and the environment, lowering body temperature.
This affect is combined with an increase in sweat production stimulated by the
hypothalamus through cholinergic fibres innervating sweat glands. This is
significant for two reasons:
1. Sweat evaporation speeds up energy (heat) exchange with the environment
2. Sweat enhanced vasodilation of the vessels because it contains an enzyme that
acts on tissues to stimulate bradykinin release. This bradykinin acts locally on
through paracrine signalling to relax smooth muscle cells and enhance
vasodilation, possibly through the formation of NO
How is blood pressure maintained in response
to the vasodilation seen in the cutaneous
circulation after an increase in body
temperature?
• The vasodilation seen in response to increase temperature has
consequences for whole CVS:
◦ Vasodilation results in fall in TPR and this leads to fall in Blood pressure if
there is no accompanying increase in CO.
◦ Via the baroreceptor reflex, CO is increased predominantly by increasing
HR.
◦ Increasing HR is brought about by increase in SNS activity and decrease
in vagal activity to SA node and by the direct effect of increase
temperature on cells of SA node.
◦ Therefore, a tachycardia of 10bpm per degrees increase in temperature,
ensure BP is maintained.
How can an increase in body temperature result
in syncope?
Because increases in temperature lead to vasodilation of the resistance vessels
of the cutaneous circulation due to a withdrawal in sympathetic tone to these
vessels in the cutaneous circulation. This happens because of the
thermoregulatory role of the skin - increasing blood flow to the skin, and
therefore the blood volume in the skin (A-V anastomoses) enhances heat
exchange and lowers temperature. However, due to this vasodilation, there is a
fall in total peripheral resistance, and therefore a fall in blood pressure unless
there is an increase in cardiac output. Therefore, an inability to increase cardiac
output sufficiently can result in falls in BP being too great to maintain adequate
cerebral perfusion and therefore syncope occurs to restore cerebral blood flow.
Why does syncope occur when there is a
decreased blood flow to the brain?
Because syncope, a sudden temporary loss of consciousness, results in the
person falling down into a horizontal position. Being in a horizontal position
means that cerebral perfusion can be restored because the circulatory system no
longer has to work against gravity and allows for the blood pooled in the legs
due to gravity to return. Therefore, venous return is increased, preload is
increased, and cardiac output is increased which ensures adequate cerebral
perfusion.
How does the cutaneous circulation respond to
decreased body temperature?
• If temperature drops there is an increase in sympathetic activity to the
cutaneous vessels and an increase NA release, leading to vasoconstriction of
cutaneous arterioles.
• There is also an increase in sympathetic activity to A-V anastomosis, this
results in their constriction prevent blood flow through to vein.
• These changes increase resistance to blood flow and divert blood to low
resistance vessels in the interior of body.
• This minimises heat loss by keeping blood away from surface, blood diverted
to deep veins that lie beneath insulating fat.
What and why does paradoxical cold
vasodilation occur?
• With prolonged exposure to cold the vasoconstriction in the cutaneous
circulation changes to a paradoxical cold vasodilation.
• This gives the skin a red appearance.
• The example shown here is taken form human studies where blood flow to
calve is measured by a laser Doppler flux metre.
• The dilation is thought to be due to paralysis of noradrenergic
neurotransmission is response to cold and the release of vasodilators such as
prostacyclin
• The redness of the blood is largely due to the increase in affinity of Hb for O2
as reflected by leftward shift of o2 dissociation curve when temperature is
reduced.
• Cold induced vasodilation is thought to prevent cold weather injury to
tissues.
Describe the action of vasodilators
Vasodilators have an indirect action on the heart function by having a direct
action on the smooth muscle cells of the vasculature
What are the two different ways that disease
states can involve the vasculature?
• Systemically
• Locally
What are the three ways vascular tone is
maintained?
• Autonomic innervation - systemic factor
• Circulating hormones - systemic factor
• Local factors - affect vasculature in their immediate area
What are the two processes that can be
targeted by pharmocological vasodilators?
• Indirectly by targeting circulating vasoconstrictors
• Directly by targeting the processes going on in the smooth muscle cell
Two divisions of vasodilator drugs
Direct and indirect
Three ways that vasodilator drugs have an
indirect action?
1. Blocking the autonomic nervous system - sympathetic blockage via alpha-1
adrenoceptor antagonists -> block the vasoconstricting action of noradrenaline
and will result in vasodilation
2. Renin-angiotension-aldosterone system (RAAS) - angiotension 2 is a potent
vasoconstrictor, therefore, blocking its action using antagonists will cause
vasodilation
3. Enothelins - circulating factors that cause vasoconstriction -> targeting these is
an active area of research
What are the two sources of calcium in vascular
smooth muscle cells?
• Intracellular store release
• Entry from extracellular sources via voltage gated calcium channels
What are the three main targets for indirect
vasodilator drugs?
• VC calcium channesl
• Membrane potential - because calcium ion channels are voltage gated,
anything that impacts membrane potential will impact these channels and so
impact intracellular calcium levels
• cGMP - intracellular messenger that is an important determinant of smooth
muscle action that affects how long calcium channels are opne and, through
intermediates, affect myosin acting interaction
What are the three classes of drugs that treat
angina?
1. Class A - not vasodilators, includes beta-blockers and ivadradine
2. Class B - Organic Nitrates - Vasodilators
3. Class C - Calcium channel blockers - Vasodilators
What are the two main class A drugs used to
treat angina?
Beta-blockers and ivabradine
How do beta-blockers treat angina?
beta-blockers alleviate angina symptoms by decreasing the heart rate, reducing
the force of cardiac contraction, lowering blood pressure, and improving the
balance between oxygen supply and demand in the heart muscle
What is ivabradine and what is it used for?
It inhibits IF ion channel which is responsible for the pacemaker potential that
sets heart rate. Its inhibition will reduce heart rate and decrease the cardiac
work. It is used to treat angina.
How do nitrate drugs like GTN sprays work?
These drugs are a class of vasodilators and they work by:
• they contain nitrogen atoms and so when broken down in the body they
create NO
• NO is a physiological signalling molecule involved in smooth muscle control
• NO through its actions on the enzyme guanylate cyclase will result in an
increase in cGMP
• Increasing cGMP promotes relaxation of the smooth muscle cells =
vasodilation
• this occurs due interference with myosin-actin interaction and the
enhancement of calcium efflux
How does increasing cGMP levels affect calcium
levels in vascular smooth muscle cells, and
what does this result in?
• Increased cGMP activates PKG.
• PKG phosphorylates proteins, inhibiting calcium entry.
• Calcium efflux is enhanced.
• Result: Smooth muscle relaxation due to decreased intracellular calcium levels.
• Important in vasodilation and used in medications like nitroglycerin and PDE5
inhibitors
Therefore intracellular levels decrease and vasodilation occurs due to
smooth muscle cell relaxation
What is cGMP?
Prominent second messenger molecule
What are second messengers, and what is their
role in cellular signaling?
• Definition: Second messengers are molecules that relay signals from cell
surface receptors to the cell interior.
• Examples:
◦ Cyclic AMP (cAMP) activates protein kinase A (PKA).
◦ Cyclic GMP (cGMP) regulates smooth muscle relaxation.
◦ Inositol trisphosphate (IP3) releases calcium; diacylglycerol (DAG)
activates protein kinase C (PKC).
◦ Calcium (Ca2+) influences various cellular processes.
◦ Nitric oxide (NO) activates guanylate cyclase, producing cGMP.
• Role: Essential for signal transduction, allowing cells to respond to external
stimuli and regulate physiological processes.
What is shear stress in the cardiovascular
system?
• Definition: Shear stress is the force per unit area parallel to the vessel wall
generated by blood flow.
• Endothelial Response:
◦ Influences endothelial function and integrity.
◦ Important for the release of nitric oxide and signaling molecules.
• Effects:
◦ Beneficial in moderate and regular patterns.
◦ Altered patterns, like low shear stress, can contribute to atherosclerosis.
• Measurement: Typically measured in units of force per unit area (e.g., dyn/
cm² or pascal, Pa).
Define physiological
Refers to anything related to the normal functioning of living organisms
and their parts
What is afterload?
• Definition: Afterload is the resistance the left ventricle must overcome
during systole to eject blood into the aorta.
• Determinants:
◦ Influenced by arterial tone and systemic resistance.
◦ Arterial blood pressure is a major factor.
• Clinical Implications:
◦ High afterload increases the heart's workload.
◦ Conditions like hypertension contribute to elevated afterload.
• Impact:
◦ Affects cardiac output and can lead to left ventricular hypertrophy with
chronic elevation.
What is the mechanism of action that explains
how GTN relieves angina?
• GTN affects the systemic vessels and the venous vesses are affected more
than the arterial vessels
• Due to it affecting venous vessels and venous vessels being the storage
vessels of the CVS, we increase blood storage in veins, and thus decrease
venous return greatly
• This in turn reduces cardiac work via starling's law and therefore the oxygen
demand of the coronary tissue is greatly reduced
• There is a significant enough reduction in cardiac work and thus oxygen
demand for the coronary blood supply to maintain sufficient oxygenation of
cardiac myocytes
Is hypotension an unwanted effect of GTN
sprays?
Yes, due to its systemic effects GTN can cause excessive vasodilation which can
lead to hypotension leading to syncope -> one of the responses to this
hypotension is reflex tachycardia via the baroreceptor reflex -> this is bad
becaue patients who require GTN have compromised coronary blood flow, and
GTN sprays are meant to decrease cardiac work and therefore cardiac myocyte
oxygen demand but here it is having the opposite effect
How can GTN cause a headache?
By causing excessive vasodilation of the blood vessels supplying the head
How does GTN affect the GIT?
By relaxing smooth muscle in the GIT it can cause a reduction of motility
Why can't GTN be administered orally?
Because upon being absorbed from the GIT, it is completely metabolised through
first pass metabolism in the liver - so this way it is removed before it can even
have its effect.
What are the two ways that GTN is
administered?
Sublingually and transdermally
Why is GTN often administered sublingually?
Because it cannot be administered orally due to it being removed completely in
first pass metabolism and so must be administered in a way that allows it to
exerts its effect before being metabolised in the liver, and the highly
vascularised underside of the tongue provides the perfect place for this.
Why do people with angina often only use GTN
sublingually for immediate and short-term
symptomatic relief but not long term relief?
Because it is metabolised by the body so quickly do to it not surviving first pass
metabolism
Why is the option of transdermal
administration of GTN important?
Because GTN does not survive first pass metabolism it cannot be administered
orally and nor does it stick around long enough to have long acting effects when
administered sublingually. Transdermal administration allows the drug to be
constantly diffused into the body at low levels to prevent angina attack.
What organic nitrate medication can be
administered orally?
Isosorbide mono/dinitrate - works in the same way as GTN but with different
pharmacokinetics that mean it can be given orally and have a longer duration of
action
How is the development of tolerance a problem
for GTN treatment?
• Physiological tolerance - the blood vessels have multiple factors that control
their state and GTN only acts on one of these pathways so over time the
other factors can adapt to counteract GTN action
• Pharmacological tolerance - there is a fundemental change in the way the
drug interacts with the target with constant exposure of the target to the
drug that can mean the system stops responding to the drug
What is the mechanism of action of vasodilators
that target calcium blockers (class 3 for angina
treatment)?
• Blocking voltage gated calcium channels reduces the efflux of calcium into
the smooth muscle cells and so reduces the intracellular concentration of
calcium and therefore the level of contraction (remember that calcium can
also be sourced intracellularly from intracellular calcium stores)
What is an example of a family of drugs that
are VG calcium channel blocking vasodilators?
DHPs (dihydropyridines) which act on the vasculature, e.g. amlodipine
Why is selectivity important for VG calcium
channel blocking drugs?
VG calcium channels are instrumental in determing contractility of all smoot
muscle cells and as such are found throughout the CVS. However, blocking VG
calcium channels in the SM of the vessels and then blocking them in cardiac
myocytes exerts different affects. Therefore, drugs that selectively target either
VG calcium channels on cardiac myocytes or SM of blood vessels is important for
targeting treatment, e.g. verapamil is selective for cardiac myocyte VG calcium
channels and therefore is used to treat arrythmia, whereas DHPs are selective for
those found in the vasculature and therefore are vasodilators.
How is diltiazem unique?
Because it isn't selective for either VG calcium channels on cardiac myocytes or
those on SM of the vasculature and so can exert both anti-arrythmic affects and
vasodilation.
How do Class 3 vasodilators treat angina?
Mechanism of action:
• systemic
• act more on the arterial system than the venous system and so reduce total
peripheral resistance
• this therefore decreases cardiac work and so decreases the oxygen demand
of cardiac myocytes
• so there will be a significant enough reduction in cardiac work so that
coronary circulation is able to maintain sufficient oxygenation of cardiac
myocytes.
• they also have a minor action - increasing coronary flow
What is coronary flow?
The movement of blood through the coronary circulation
What are some unwanted side effects of VG
calcium channel blocking vasodilators?
• flushing of any part of the body due to vasodilation
• effect of sm of GIT - reduction in motility
Why don't calcium channel blockers used in the
treatment of CVS conditions cause significant
weakness in the skeletal muscle?
Because these drugs target the particular isoform of L-type calcium channels
found within the CVS and skeletal muscles express a different isoform.
What does isoform mean in the context of cell
receptors?
An isoform in this context refers to a different molecular form or variation of a
receptor protein that is dervied from the same gene.
What are some other conditions that
vasodilators are useful for?
1.
2.
3.
4.
Raynaud's syndrome
Erectile dysfunction (impotence)
Male pattern baldness
Improved cerebral function - treatment of haemorrhagic stroke and vascular
dementia (only improve cerebral function if there is a preexisting reduction in
cerebral function due to reduction in cerebral perfusion and so they are not
useful as study drugs)
How are vasodilators useful for the treatment
of Raynaud's syndrome?
Raynaud's syndrome is characterised by extreme vascular spasm within the
extremities (most often in the distal parts of the fingers), usually in response to
cold weather. This results in the fingers going white due to reduced blood flow
and is often accompanied by extreme pain.
Nifedipine, which is a DHP, is used to vasodilate and restore blood flow.
Not always helpful - this suggests there are different mechanisms causing
Raynaud's, i.e. different subtypes.
Why are locally acting vasodilators useful in the
treatment of erectile dysfunction?
1. To establish an erection the corpora cavernosa in the penis must fill with blood this is a specialised form of vasodilation
2. Under normal physiological circumstances this process is controlled by the
release of NO and its subsequent action on cGMP
3. Interfering with this process allows us to affect the state of the smooth muscle of
the vessels of the corpora cavernosa
4. Phosphodiesterase enzymes degrade cGMP found in smooth muscle cells
5. Therefore, inhibiting these leads to an increase in cGMP leading to vasodilation
so more blood can flow allowing for an erection
6. It is important for this to be local as systemic vasodilation wouldn't counteract
the problem
What is a major example of a
phosphodiesterase inhibitor?
Sildenafil, otherwise known as Viagra:
• PDE inhibitor that is selective for type 4 PDE (the type mainly found in
genital tissue)
• Therefore, localised action in male genital tissue
• Vasodilates blood vessels of the corpora cavernosa facilitating an erection
(when the individual is aroused - no arousal no erection)
What is a severe side effect of sildenafil/viagra?
The major drug interaction it has with nitrates, either pharmaceuticals like GNT
or recreational drugs like poppers. This interaction can cause a fatal drop in
blood pressure.
What vasodilator is useful in the treatment of
male pattern baldness?
Minoxidil
What is the mechanism of action for minoxidils
treatment of male pattern baldness?
Minoxidil is a vasodilator:
• opens up potassium channels allowing potassium to leave cells
• efflux of potassium from cells causes membrane hyperpolarisation
• the calcium channels required to allow calcium to enter the cells of smooth
muscle are voltage gated
• therefore, membrane hyperpolarisation leads to the voltage gated calcium
channels being less likely to be open
• so less intracellular calcium and reduces contractility
This treats hairloss because:
- it is believed that the vasodilatory effect of minoxidil leading to improved scalp
perfusion when applied topically could contribute to it causing hypertrichosis
(increased hair growth) all though its action for this isn't fully understood.
How does using vasodilators help with the
management of a haemorrhagic stroke?
• haemorrhage causes the blood vessels to go into vasospasm by contraction
of smooth muscle
• whilst this is helpful to reduce blood loss it lasts a long time
• this presents a problem because all of the territory downstream of the blood
vessels are not being supplied by blood and so the neurones there are under
hypoxic conditions
• at best this will cause them to dysfunctional and worst it will cause them to
die
• so it has been proposed it would be useful to have something to treat this
and so research into using calcium channel blockers have been investigated
for this
How might using vasodilators be useful for the
treatment of vascular dementia?
Vasular dementia is due to changes in the vasculature of the brain and it has
been suggested that maintaining cerebral blood flow by using vasodilators could
hold off symptoms
Which cells activate T cells?
Dendritic cells
What state do T cells enter the circulation after
having matured in the thymus?
As naive T cells (this means they have not encountered a pathogen). At this time
the frequency of T cells for any given peptide/MHC complex is very low. When
they leave they are either CD4, CD8, or T-Regulatory Cells.
Why don't immature T cells produced in the
bone marrow cause problems during their
migration to the thymus?
• Maturation Status:
◦ Immature T cells leaving the bone marrow are not fully mature and lack
the ability to initiate immune responses.
• Lack of Antigen Recognition:
◦ They have not undergone antigen recognition and selection processes,
preventing them from recognizing specific antigens.
• Controlled Migration:
◦ Migration to the thymus is tightly regulated, guided by homing receptors
and specific molecules.
• Immune Privilege of Thymus:
◦ The thymus is an immune-privileged site with mechanisms to create an
environment conducive to T cell development without inducing immune
responses.
• Regulation of Immature T Cells:
◦ The immune system has checkpoints and control points to ensure proper
maturation and selection before T cells become fully functional.
• Microenvironment of the Thymus:
◦ The thymus provides specific signals for maturation, and its unique
microenvironment minimizes the potential for inappropriate immune
responses during T cell migration.
What must naive T cells must do before they
are useful?
T hey must undergo:
1. Proliferation of antigen-specific cells
2. Differentiate to provide effector function
What is needed to initiate proliferation and
differentiation of naive T cells?
Present antigens, via the MHC complex located on the surface of the antigen
presenting cell the dendritic cell to the T cell
What are the similarities between the different
antigen presenting cells?
• all very efficient at taking up antigens and processing them
• they then are able to upregulate the level of MHC expression (on B cells it is
already high), and also upregulate co-stimulation molecule activity.
For the CVS, the efferent nerves come from...
... the ANS
Given that reflex responses are superimposed
on local influences, what are the local
influences of the heart?
• The local influences on the heart are its intrinsic beating (originates in SAN)
and Starling’s Law.
• These influence the HR and SV.
Given that reflex reponses are superimposed on
local influences, what are the local influences of
the arterioles (resistance vessels)?
The local influences on the arterioles are the substances released from the
endothelial lining, metabolic influences (metabolites released from surrounding
cells), the vascular smooth muscle response to myogenic stimuli.
Given that reflex reponses are superimposed on
local influences, what are the local influences of
the capillaries?
• The local influences on the capillaries are the forces across the capillaries
e.g. osmotic and hydrostatic pressure.
• These influence diffusion, filtration and exchange
What are the local influences on veins
(capacitance vessels)?
Gravity, the respiratory pump, and the skeletal muscle pump
When can the CNS initiate its own
cardiovascular and respiratoru responses?
Under certain conditions like emotional thoughts, previous experience, and
volition or the willingness to engage in activities
What are the two types of afferent pathways
that affect the CVS?
Cranial nerves and spinal nerves
What are the two forms of efferent pathways
that affect the CVS?
1. Parasympathetic vagal supply to the heart that affects the SAN and AVN
2. Sympathetic supply to the heart (SAN and AVN) and blood vessles
What are the three hormones that are involved
in CVS reflex responses?
• Catecholamines - NAd and Ad
• ADH - posterior pituitary
• Renin-angiotensin system
Sympathetic supply to the heart and blood
vessels
• SAN and AVN and blood vessels
• Sympathetic preganglionic neurones originate in the spinal cord between T1L2
• They then synapse in sympathetic chain or in the prevertebral ganglia
• Post ganglionic neurones then go to the heart, arterioles or venous vessels.
• In order for the brain to influence sympathetic outflow, there are descending
pathways in the spinal cord that influence sympathetic pre-ganglionic
neurones.
What would happen to the CVS in a spinal
transection?
• Lose the ability to reflex control the sympathetic nerve fibres that supply
heart and BV
• You would also lose tonic excitatory influence on sympathetic preganglionic
neurones so your BP would be low.
What level do simle reflexes in the CVS occur?
The medulla
What is tonic referring to in the nervous
system?
Continuos and baseline nervous impulses - either excitatory or inhibitory
Nucleus Ambiguus in Cardiovascular Regulation
Anki Card Summary:
Topic: Nucleus Ambiguus in Cardiovascular Regulation
Key Points:
1. Location: Nucleus ambiguus is located in the medulla oblongata, part of the
brainstem.
2. Function: It is crucial for parasympathetic control of the heart.
3. Parasympathetic Output: Nucleus ambiguus provides parasympathetic
efferent fibers to the heart via the vagus nerve (cranial nerve X).
4. Vagal Tone: Maintains vagal tone, influencing baseline heart rate during rest.
5. Baroreflex Control: Involved in baroreflex mechanisms, helping regulate blood
pressure.
6. Coordination: Works in coordination with other cardiovascular centers in the
brainstem.
7. Clinical Relevance: Imbalances in nucleus ambiguus activity may contribute to
cardiovascular disorders.
Rostral Ventrolateral Medulla (RVLM) in
Cardiovascular Regulation
1. Location: RVLM is located in the rostral part of the medulla oblongata.
2. Function: It plays a crucial role in the sympathetic control of the cardiovascular
system.
3. Sympathetic Output: RVLM contains sympathetic pre-ganglionic neurons that
project to the sympathetic ganglia.
4. Blood Pressure Control: Influences blood pressure by regulating peripheral
vascular resistance.
5. Baroreceptor Input: Receives input from baroreceptors, helping modulate
sympathetic outflow in response to blood pressure changes.
6. Coordination: Works in conjunction with other brainstem centers, including the
nucleus ambiguus, to maintain cardiovascular homeostasis.
7. Clinical Relevance: Dysregulation of RVLM activity may contribute to
conditions such as hypertension.
What level do the more complex reflexes of the
cardiovascular system occur?
At the level of the hypothalamus there are discrete integrating areas which
are responsible for reflex patterns of response that we show under different
circumstances:
• Exercise pattern of response
• Feeding/satiety pattern of response
• Alerting/Defensive pattern of response
• Thermoregulation pattern of response
• Reproductive type behaviour
These all have to communicate with nucleus ambiguus and the RVLM in order to
affect vagal (parasympathetic) and sympathetic outflow to the heart and blood
vessels.
What does the baroreceptor reflex do?
Homeostatically and autonomously regulates arterial blood pressure
What are the two types of baroreceptors?
Carotid baroreceptors and aortic baroreceptors
The carotid baroreceptors
• Located in the carotid sinus of the internal carotid artery, close to the
bifurcation of the common carotid artery.
• These receptors are supplied by the afferent sinus nerves, which then join
the Glossopharyngeal nerve CNIX.
Where are the carotid baroreceptors?
The carotid sinus of the internal carotid artery, close to the bifurcation of the
common carotid artery
What nerve synapses with the carotid
baroreceptors?
Glossopharyngeal nerve (CN IX)
The aortic baroreceptors?
• Located in 2 patches in the aortic arch.
• These receptors are supplied by the afferent aortic nerve fibres, which then
runs in vagus nerve CNX.
Where are the aortic baroreceptors located
In two patches in the aortic arch
What nerve recieves input from the aortic
baroreceptors?
Vagus nerve - CN X
How do the baroreceptors work?
They're stretch receptors:
• They sense changes in the stretch of arterial walls caused by changes in
pressure inside of artery.
• When arterial blood pressure rises it leads to a stretch in the arteries, this
cause an increase in afferent activity
• The afferent activity carries information to the Nucleus Tractus Solitarius
(NTS) (located in medulla)
• This nucleus collects afferent information from lots of afferent nerve fibres
and receptors that serve the CV, respiratory and GI system.
How does the baroreceptor nerve impulses
change according to arterial blood pressure?
As arterial blood pressure increases, more impulses are sent. This is due to the
fact that each baroreceptor is made up of multiple constituent neurones that
each have a different threshold pressure before they start firing. Therefore, the
higher the pressure, the greater the number of neurones reaching threshold, and
so the greater the number of impulses.
How do baroreceptors respond to the pulsatile
nature of blood pressure?
ABP is pulsatile due to systole and diastole - blood pressure is higher when the
ventricles contract in systole and lower when they relax during diastole.
Therefore, the baroreceptors increase their activity during systole and decrease
during diastole - peaks and troughs in activity - but as long as ABP remains the
same, the average number of impulses will remain the same.
What is the brains autoregulatory range?
60-180 mmHg
What is the autoregulatory range of the
kidneys?
70-120 mmHg
Why is the baroreceptor reflux important?
Because it tonically keeps ABP down and continuosly buffers against changes in
ABP that would otherwise be dangerously big
Respiratory Pump in Cardiovascular Physiology
Function: The respiratory pump aids blood flow within the thoracic cavity.
1. Inhalation: During inhalation, the diaphragm contracts, lowering intrathoracic
pressure.
2. Venous Return: Lower intrathoracic pressure enhances venous return, aiding
3.
4.
5.
6.
blood flow to the heart.
Cardiac Filling: Increased venous return optimizes cardiac filling, crucial for
maintaining preload.
Exhalation: During exhalation, the diaphragm relaxes, raising intrathoracic
pressure.
Pulmonary Circulation: Increased intrathoracic pressure during exhalation
assists blood flow in the pulmonary vessels.
Cardiovascular Coordination: The respiratory pump complements the cardiac
cycle, optimizing blood flow and cardiac function.
What is sinus arrythmia?
The interaction between inspiration and heart rate:
• inspiration - heart rate goes up
• expiration - HR goes down
What are the two mechanisms of sinus
arrythmia?
1. Cardiac vagal motor neurone activity
2. Involve the nucleus ambiguus
Describe the central nervous mechanism of
sinus arrythmia
• There are central inspiratory neurones which are active during inspiration.
• They are able to increase activity of inspiratory motor neurones (phrenic &
intercostal nerves) that supply the inspiratory muscles (diaphragm and
intercostal muscles)
• Inspiratory neurones are also able send inhibitory influences to the Nucleus
ambiguus (NA)
• The NA is the nucleus that supplies vagus nerves to heart.
• So, every time you breathe in there is an inhibitory influence to NA, which
reduces vagal tone to heart ↑ HR.
Describe how the reflex initiated by the
pulmonary stretch receptors in respiratory
airways leads to sinus arrythmia
• The stretch receptors have vagal afferents.
• The act of inspiration causes widening of the airways and therefore
stimulation of the pulmonary stretch receptors.
• The Pulmonary stretch receptors send impulses, via vagal afferents, to the
Nucleus Tractus Solitarius (NTS).
• From the NTS the impulses, that originated in pulmonary stretch receptors,
are sent to NA and have an inhibitor effect on this nucleus.
• Vagal tone is reduced and therefore heart rate increases
At what arterial concentration of oxygen is the
body considered to be under systemic hypoxia?
8.1kPa or 60mmHg
What are the two groups of peripheral
chemoreceptors?
Coratid body and aortic body
Where to the afferents from the carotid and
aortic bodies run up to?
The nucleus tractus sollitarius
What are the peripheral chemoreceptors
stimulated by?
Fall in PaO2, increase in PaCO2, and a decrease in arterial blood pH
Carotid body
• Located at the bifurcation of the common carotid artery
• Innervated by afferent fibres that joint the glossopharyngeal nerve (CNIX).
• These afferents run up to NTS.
Aortic body
• Located in in the wall of the arch of aorta.
• Innervated by afferent fibres that join the vagus nerve (CNX).
• These afferents also run up to NTS.
What do the peripheral chemoreceptors do
when there is a fall in PaO2?
Increase afferent stimulation to the nucleus tractus sollitarius
Describe the reflex that occurs when
respiration cannot increase but there is hypoxia
• you get a primary cardiovascular reflex in response to peripheral
chemoreceptor simulation.
• The result of this reflex is bradycardia and vasoconstriction occurring via
vagus nerve and sympathetic nerve activity to all major BV in body, except
the brain (it has a weak sympathetic nerve supply).
1.
2.
3.
4.
5.
6.
Mechanism:
Peripheral chemoreceptors are stimulated, impulses sent to NTS.
Pathways from Nucleus Tractus Sollitarius go to and stimulate the Nucleus
ambiguus.
This stimulates vagal activity which produces a reflex bradycardia (↓HR)
Pathways from NTS also go and stimulate the Rostral Ventrolateral Medulla
This produces an excitatory drive to sympathetic neurones that preferentially
innervate the blood vessels (not heart) and causes vasoconstriction.
Hence bradycardia and vasoconstriction.
This is an oxygen conserving reflex:
• Reducing O2 consumption of the heart by causing bradycardia
• Vasoconstriction reduces the blood flow to various tissue reduces O2
Describe the action of the peripheral
chemoreceptors when respiration can increase
in response to hypoxia
• In this scenario when peripheral chemoreceptors stimulate central
inspiratory neurones which then increase inspiratory motor neurone activity
respiration does increase.
• Increase in respiration widens airways stimulates pulmonary stretch
receptors.
• This allows input from pulmonary stretch receptor afferent nerve fibres into
NTS inhibit NA.
• So now you have 2 inhibitory influences on NA and 1 excitatory influence.
• The end result is HR goes up rather than down.
• So in response to increase in respiration when chemoreceptors are
stimulated there is an increase in HR but still there is vasoconstriction
exerted via sympathetic fibres and RVLM.
In what circumstances can systemic hypoxia
occur despite the patient being able to increase
respiration
• If in Hypoxic atmosphere
• If at High altitude
• In you have a less severe respiratory disease – still have ability to increase
respiration.
What are 5 examples of when systemic hypoxia
would occur due to respiration not able to
match demand?
• Patient given muscle relaxant when in surgery and so is paralysed - patient
needs to be pump ventilated at a constant rate and depth
• After high spinal transection - pt can no longer use phrenic nerves to control
respiration and therefore cannot breathe unaided
• Long dive under water
• Fetus in utero if umbilical cord gets twisted
• Patient with severe respiratory disease
What are the local effects of hypoxia?
• Decreased heart rate and contractility - local hypoxia to the SAN and
myocardium
• Cerebral vasodilation
• Muscle vasodilation
• Pulmonary vasoconstriction
In respiratory disease a person who has
hypoxia and is able to increase their respiration
is known as...
a pink puffer
In respiratory disease a person with systemic
hypoxia who is not able to increase their
respiration is known as...
a blue bloater
Describe what happens when there is systemic
hypoxia and respiration can be increased
• The reflex effects of peripheral chemoreceptor stimulation on the heart are
overcome by the effects of ↑ respiration on HR
• Thus, you see an ↑ respiration + ↑ HR + generalised vasoconstriction (as a
result of increase of sympathetic nerve activity):
◦ ↑ respiration helps to restore PaO2 (homeostatic part of reflex)
◦ ↑ HR and ↑ cardiac output that preferentially goes to brain (local
vasodilation in response to hypoxia)
• Because PaO2 better controlled when respiration can increase tissues do not
become as hypoxic and pulmonary vasoconstriction less severe
Hypoxic Pulmonary Vasoconstriction (HPV)
• Definition: HPV is a physiological response to systemic hypoxia in the lungs.
• Mechanism:
◦ Pulmonary arterioles in poorly ventilated areas sense low oxygen levels.
◦ Smooth muscle in arteriole walls contracts, causing vasoconstriction.
• Purpose:
◦ Redirects blood flow to well-ventilated lung regions.
◦ Optimizes ventilation-perfusion (V/Q) matching for efficient gas
exchange.
• Outcome:
◦ Conserves oxygen by improving oxygenation of blood.
• Clinical Relevance:
◦ Normal response but can contribute to pulmonary hypertension if
excessive or prolonged.
What is decreased respiration associated with?
Bradycardia
What are the three zones of trigeminal afferent
innervation?
Opthalamic, maxillary, and mandibular
What zone of trigeminal afferent innervation is
the most sensitive to the diving reflex?
Maxillary
How does the diving reflex work?
• Trigeminal receptors are stimulated by Cold water on face/nose - evokes
Diving Reflex
• Stimulation of trigeminal afferents feeds into nucleus tractus sollitarius. This
results in:
◦ Inhibition of central inspiratory neurones. This results in:
▪ Expiratory apnoea (breath out and stay in expired position).
▪ This also removes influences that increase HR (discussed previously).
▪ This cause by a pathway from nucelus tractus sollitarius to central
inspiratory neurons.
◦ ↓ HR (↑ vagal activity)
▪ This is caused by a pathway from nucleus tractus sollitarius having
an excitatory effect on cardiac vagal motor neurones.
◦ Vasoconstriction in tissues (GIT, Muscles, Skin, X Brain) due to ↑
sympathetic.
▪ This is caused by a pathway from nucelus tractus sollitarius having
an excitatory effect to rostral ventrolateral medulla.
• The sum total of this reflex is another O2 conserving reflex
• If you are using this response e.g. when your face hits cold water that would
be an advantage as you are conserving O2 at a time when you cannot
breathe anymore O2 in.
• Children have very strong diving reflex.
◦ Some children fallen under ice in Canada and rescued 30 mins later.
This is due reduced O2 consumption.
Expiratory apnoea
• Definition: Expiratory apnea refers to the temporary cessation of breathing
during expiration.
• Characteristic: Breathing pauses after exhalation, leading to a brief period
without airflow.
• Physiology:
◦ Occurs during forced expiration.
◦ Results from decreased lung volume triggering reflexive apnea.
• Clinical Relevance:
◦ Seen in conditions like asthma or chronic obstructive pulmonary disease
(COPD).
◦ Can contribute to dynamic hyperinflation and respiratory distress.
• Management:
◦ Address underlying respiratory conditions.
◦ Consider bronchodilators or other appropriate therapies.
What are the two reflexes that cause
bradycardia when there is decreased
respiration?
Diving reflex (trigeminal nerve stimulation by cold water) and a similar
reflex triggered from receptors in the facial sinuses, larynx, and
pharynx
What occutions can trigger bradycardia upon
decreased respiration other than the diving
reflex?
• sinus washing
• irritant vapours
• intubatin, bronchoscopy, laryngoscopy
• when lumps of food get caught in pharynx or touch larynx
• quadriplegic patients - occurs when mucous aspirated
What is a way that supraventricular tachycardia
can be stopped?
Ice bag on the face - stimulates the diving trigeminal nerve reflex casuing apnea
and bradycardia, which triggers heart rate to go back to normal. Alternatively:
defib, carotid sinus massage, infusing adenosine
What is steak house death?
Some people are very sensitive to the two reflexes that cause bradycardia on
decreased respiration and as such experience such a strong response they get
complete expiratory apnoea and cardiac arrest resulting in death. Mouth to
mouth ventilation can terminate apnoea and so reverse the reflex due to
inspiratory input which restored breathing and heart rhythm. Steak house death
is not due to food occluding airways but because of profound bradycardia and
apnoea due to the bradycardia upon decreased respiration reflex being
stimulated by food in touching the larynx or getting caught in the pharynx
What are the two main effector arms of the
baroreceptor reflex?
• Autonomic nervous system - fast
• Renin-aldosterone-angiotensin system: aldosterone has its action at the
kidneys to alter blood volume (slow) and RAAS system acts on the vessels,
e.g. angiotension 2 acts as a vasoconstrictor (fast)
What factors need to be considered when
beginning treatment for a newly diagnosed
patient with hypertension?
• Age of individual
• Genetic heritage of individual
• Comorbidities
What are the drug classes for the treatment for
hypertension?
• Drug class A - RAAS system
• Drug class C - calcium-channel blockers
• Drug class D - diuretics
What is the mechanism of action of ACE
inhibitors?
ACE inhibitors are Angiotensin Converting Enzyme Inhibitors so:
• inhibit angiotensin converting enzyme (ACE)
• ACE is needed to covert angiotensin 1 to angiotensin 2
• So decreased production of angiotensin 2 leads to a fall in both TPR and CO:
1. Angiotensin 2 is a vasoconstrictor so by reducing the concentration you get
vasodilation and so decreased TPR - decreased ABP
2. Reduces aldosterone so less salt and water retension leading to a decreased
venous return and therefore decreased cardiac output and therefore decreased
ABP
• additionally, they inhibit the degradation of vasodilator kinins such as
bradykinin leading to vasodilation although this is minor
What causes the dry cough side effect of ACE
inhibitors?
Dry cough:
• Due to reduced degradation of Kinins.
• This means Kinins are in the blood for longer periods and so enter the lungs.
• The sensory nerve endings are irritated due to the presence of kinins which
causes the dry cough
• Some evidence suggests not all individuals are equally susceptible to
developing drug cough – women> men, older>younger, east Asian> others.
This may influence drug choice
What is a significant drug interaction seen
when using ACE inhibitors?
Sudden severe hypotension on first dose of ACE inhibitor if individual is also
taking a diuretic. This is very short lived so does not precluded combination
being used.
When are ACE inhibitors used?
First line treatment for uncomplicated, mild hypertension in younger patients
(under 55)
What is the hydrostatic pressure at the
arteriolar end of the capillary?
35 mmHg
What is the hydrostatic pressure at the venular
end of the capillary?
15mgHg
What is the hydrostatic pressure of the
interstitial fluid?
Negligible - 0 mmHg
What is the oncotic pressure of the capillaries?
25 mmHg
What is the interstitial oncotic pressure?
negligible - 0 mmHg
Alterting/defence response extreme
fight/flight/fright
What does a typical alerting response consist
of/
• Increase in respiration
• An increase in CO, increase in BP due to decreased parasympathetic activity
and increased sympathetic activity to the heart (reinforced by increased
respiration stimulating vagal activity)
• Reduction in skin temperature due to vasoconstriction
• Increase in renal vascular resistance (vasoconstriction) (increased
sympathetic activity)
• GIT and splenic circulation reduced due to vasoconstriction (both due to
increased sympathetic activity)
• Reduction in limb muscle resistance (vasodilation) which is accompanied by
an increase in muscle blood flow due to decreased sympathetic
noradrenaline to the muscles and increased circulating adrenaline
What is the alerting response often
accompanied by?
Facial expressions - apprehension, startled, suprised, acutely concerned, fear,
aggression, defensive
What can the alerting response be evoked by?
Emotion, mental stress, visual, sound, pain, and novel environmental stimuli
Is there always the same magnitude of
response in the alerting response?
No - it is graded with stimulus strength
What is the alerting response accompanied by?
Pupillary dilation, sweating, piloerection and, in extreme circumstances, urination
and defaecation
if a stimulus that previously caused an alerting
response what can it show?
• habituation - decrease reponse pattern with repeated exposure (type B)
• sensitisation - response pattern gets bigger and bigger (type A)
Can the alerting response be conditioned?
Yes - typical pavlovian conditioning
Why can the arterial blood pressure become
very high during a strong alerting response?
Because the baroreceptor reflex is suppressed
What are the regions of the brain from which
the whole alerting/defense response can be
evoked by electrical stimulation via electrode
activation?
• the ventral hypothalamus
• peri-aquaductal grey matter
• the dorsal medulla
What part of the thymus does V(D)J
recombination occur?
subcapsular cortex
How is vasovagal syncope treated?
• avoid fainting triggers
• avoid hot crowded places
• avoid alcohol
• foot exercises, compression stockings, tensing leg muscles
• adequate salt in diet
• fludrocortisone acetate - expand blood volume
• pacemaker - triggers when HR falls below predetermined level
What is heart failure?
Inability of the heart to supply adequate blood flow and therefore oxygen
delivery to peripheral tissues and organs
How common is heart failure in the UK?
900,000
What preportion of patients diagnosed with
heart failure die within a year?
30-40%
What are the symptoms of heart failure?
• rapid weight gain
• shortness of breath
• increased swelling in the lower body
• trouble sleeping
• frequent dry, hacking cough
• loss of appetite
What is the most common caue of heart failure?
Post MI development
What happens in myocardial ischaemia?
Tissue becomes:
• hypoxic - low O2
• hypercapnic - high CO2
• glycolytic and acidotic - low pH
• nutrient depleted (no substrate supply so reliant on glycogen and fat store
metabolism)
• tissue at risk of necrosis
What are the causes of hypertension?
Most common - post MI damage
Others:
Pressure overload - hypertension and aortic stenosis
Contractile dysfunction - ischaemic heart disease, congenital cardiomyopathies
What is the significance of a reverberating
circuit found in the alerting/defence response?
There is a reverberating circuit which goes from the amygdala, to the
hypothalamus, and up round the stria terminalis, before going back to the
amygdala. This helps us understand why and when a stimulus evokes an alerting
response it doesn't just happen and then stop:
• you tend to remain aroused for a period of time, and CV changes are
prolonged for as long as you are showing the behaviour changes and
experiencing the feeling of arousal
• this is because the response reactivates itself through this reverberating
circuit
What is the amygdala?
Part of the brain that is part of the limbic system and is concerned with
emotional behaviour and how we deal with it
What are the regions of the brain where the
alerting/defence response can be evoked by
exogenous electrical stimulation?
• the ventral hypothalamus
• peri-aquaductal grey matter
• the dorsal medulla
What regions of the brain can modulate the
response patterns that are evoked in the main
part of the defence area?
Pre-frontal cortex and orbitofrontal cortex:
• either inhibitory or excitatory
• involved in sensitisation, habituation and conditioning
Sensory input for the alerting/defense response
goes to?
Thalamus
Dopamine output seen in the alerting/defense
response comes from?
Ventral tegmental area
Top-down processing in the alerting/defense
response happens where?
• medial prefrontal cortex
• orbital frontal cortex
• anterior cingulate cortex
Motor output seen in the alerting/defense
response comes from?
Peri aquaductal grey
Central alerting ciruit in the alerting/defense
response is?
Amygdala and hypothalamus
What is the clinical significance of the alerting/
defense response?
It will:
• increase arousal or apprehension in the individual
• increased cardiac output which is preferentially redistributed to skeletal
muscle allowing for a split second advantage before fight/flight before any
exercise begun reinforces and increased muscle vasodilation
Generally no benefit in everyday life:
• increased ABP seen from this response in stress produces an acute risk for
those with coronary artery disease (could cause MI or angina attack) and
fragile cerebral blood vessels (stroke or burst aneurysm
• chronically - repeated stress activitation of this response in individuals who
do not habituate leads to the development of essential hypertension
• however, those chronically stressed do show habituation of muscle
vasodilation which then becomes vasoconstriction which contributes to the
pressor response
• large population studies show the pressor response to environmental and/or
mental stressors increases the risk of developing chronic hypertension by 3-4
times over a 10-yr period
What is the difference between the pressor
response and the alerting/defense response?
Describe chronic stresses impact on the pressor
response
Chronic stress can lead to a sustained activation of the alerting/defense
response, which may not fully habituate in some cases. This lack of habituation
can result in changes to the pressor response, particularly in muscle
vasodilation. While other aspects of the alerting/defense response may not show
habituation, muscle vasodilation does, leading to vasoconstriction and an overall
increase in the pressor response. This increase is due to the increased total
peripheral resistance, which elevates blood pressure.
What type of response is seen from the rostral
ventrolateral medulla during the alerting/
defense response?
A very differentiated pattern of repsonse:
• sympathetic activity to all tissues except muscle is increased
• so there must have been an excitatory influence on those pre-motor
neurones going to the gut and kidney and skin and an inhibitory effect of
premotor neurones going to the skeletal muscle
How does chronic stress lead to essential
hypertension?
Environmental stressors activate the defence areas in the brain (i.e.
hypothalamus, amygdala), while multi-sensory cues are modulated by the higher
centres. Genetic and other environmental influences module the response which
will result in an increase in ABP. The increase in shear stress causees
hypertrophy of vascular smooth muscle, narrowing the lumen of these vessels,
increasing TPR. This causes a further increase in ABP, and the cycle continues,
leading to chronic hypertension.
How can essential hypertension be prevented
in those experiencing chronic stress?
Any activites that aid in relaxation and therefore reduce blood pressure such as
exercise, relaxation therapy, music, yoga can help break the vicious cycle of
chronic stress causing essential hypertension.
What is essential hypertension?
Essential hypertension, also known as primary hypertension, is the most
common type of high blood pressure. It is characterised by abnormally high
blood pressure that has no identifiable underlying cause and accounts for 85% of
people with hypertension.
What is secondary hypertension?
Hypertension due to an underlying illness such as renal disease, sleep apnea, or
thyroid problems - 15% of hypertension cases
Vasovagal syncope
Profound bradycardia and vasodilation leading to a massive drop in ABP that falls
below the autoregulatory range of the brain tissue leading to the individual
fainting (fainting aids in restoring blood flow to the brain).
Causes:
• sudden increase in vagal activity to the heart
• a decrease in sympathetic activity to all blood vessels in all major vascular
beds (causes vasodilation)
Preceded by:
• typically preceded by the alerting/defence response
LBNP
Lower body negative pressure
HUT/LBNP test
Head-up-tilt and lowe body negative pressure test. This test is used to assess the
cause of a patients syncope, i.e. orthostatic hypotension, vasovagal syncope, or
cardiac syncope.
Procedure:
1. Patient is strapped to a tilt table
2. ECG attached to chest to monitor heart rhythm
3. Blood pressure cuffs attached to monitor blood pressure
4. Lower body negative pressure system attached to legs
5. Test has three phases
6. (1) Supine - pt lies on back for 20 mins while baseline vitals are recorded
7. (2) Upright - pt tilted to a 60 degree angle for 20 mins to simulate the upright
position
8. (3) LBNP - pt reamins tilted upright while LBNP system gradually decreases the
pressure experienced in their legs (-20mmHg, -40 mmHg, -60 mmHg for 10 mins
each. Further challenges the patients bodies ability to maintain blood pressure in
the upright position.
If the patient has vasovagal syncope they would experience a faint at the point
of the test where negative pressure is being applied as this causes greater
venous pooling. This would cause a faint due to the baroreceptor reflex
decreasing heart rate to conserve blood, central hypovolemia, and
vasoconstriction all leading to reduced perfusion of the brain.
Emotional fainting
Vasovagal syncope can be evoked by strong emotion, e.g. fear or loss. Cortical
influences facilitate the ventricular response, with an initial increase in heart rate
and contractility followed by a vagal reflex, with a profound bradycardia and
vasodilation. This occurs in extreme emotional stress, which may even cause
cardiac arrest in profound fear/shock.
Vasovagal reflex response
1.
2.
3.
4.
5.
Stong defence response leads to increase in HR and contractility
Reduced ventricular filling decreases EDV
Torsion of ventricles stimulates high-threshold mechanoreceptors
Increased vagal afferent activity to the medulla then to the lateral hypothalamus
Reflex increase in vagal (PSNS) activity to the heart decreases HR, decrease in
SNS activity to all blood vessels causes vasodilation
6. This evokes vasovagal syncope with a fall in ABP and cerebral blood flow, so the
patient faints
Adaptive processes in response to heart
failure?
Adaptive processes in response to heart failure, e.g. sympathetic stimulation,
volume loading, and hypertrophy, can help the heart initially to mainting the CO,
but can be deleterious in the long-term
MI
Myocardial infarction - happens when one or more of the coronary arteries
suddenly becomes blocked, and a section of the heart muscle can't get enough
oxygen
Mechanism of MI
Thrombus forms in one of the coronary vessels blocking a coronary vessel
meaning an entire area of the myocardium usually supplied by the artery is at
risk of necrosis. Coronary arteries are end arteries meaning that one part of the
myocardium is only perfused by one artery.
Ischaemia to an area of myocardium results in:
• hypoxia
• hypercapnia
• glycolytic and acidotic (due to lactic acid build up) leading to a low pH
• Nutrient depletion (no substrate supply, so reliant on glycogen and fat store
metabolism - runs out)
• Tissue at risk of necrosis - so speedy treatment vital
How is a MI treated?
Percutaneous Coronary Intervention:
• catheter inserted into the arterial system (usually the femoral artery) and
then threaded through the occluded coronary vessel
• catheter punches through the thrombus physically breaking it up
• once catheter has broken through a balloon is inflated so the coronary vessel
is reopened
• to ensure long term stability of this part of the vessel a stent is fitted
• this allows for the reintroduction of blood flow to this part of the myocardium
• the faster this procedure is done the better the outome for the patient
(ideally done within 2 hrs of ischemic episode)
• introduction of this procedure has meant that mortality due to acute MI has
reduced but this means that more people are living with damaged hearts heart failure
Describe the changes a thrombus causing MI
would effect on an ECG
We see changes to the S-T segment of an ECG:
How can the return of oxygen facilitated by PCI
treatment be damaging to the heart?
• It can result in a massive burst in reaction oxygen species that can cause
further cardiac myocyte death
• if we protect those cardiac myocytes during the re-perfusion phase, we can
then reduce infarct size down further to 5% area of the risk
• this is what the research is focusing on now - providing this protection from
re-perfusion injury
What changes are seen to the starling
ventricular function curve in heart failure?
In a normal starling curve an increase in left ventricular end diastolic volume will
lead to an increased stroke volume. However, in heart failure, an increase in LV
EDV cannot lead to the same magnitude of SV increase for the same EDV,
therefore the maximum SV is greately reduced. This is due to:
• we have lost a proportion of cardiac myocytes
• or they cannot contract as well
In the early stages of heart failure, the SV and
EF can sometimes by preserved, why?
Due to a number of mechanism including the baroreceptor and blood volume
loading (kidney and baroreceptor)
How does baroreceptor reflex stimulation
preserve SV and EF in early heart failure?
Due to the partial loss of ventricular function leading to a decreased stroke
volume and therefore cardiac output leading to a fall in arterial blood pressure.
This causes baroreceptor unloading - the baroreceptor are not as activated so
decrease the baroreceptor afferent activity input into the CNS. This triggers a
number of reflexes:
• reduction in vagal activity to SAN
• increase in sympathetic activity to SAN - collectively these will increase heart
rate and so increase cardiac output
• Increase in sympathetic activity to ventricular cardiac myocytes (via B1
receptors) -> This leads to an increase in contractility increase SV
Increase CO.
Why is it that the autonomic action seen in the
early stages of heart failure that maintains SV
and EF and so CO eventually becomes
deleterious?
Because the autonomic action seen here leads to an increase in heart rate due
to autonomic activity changes to the SAN. And autonomic (specifically
sympathetic here) to the ventricular myocytes leading to increased contractility
of cardiac myocytes - it leads to an increased cardiac workload and metabolic
demand. This promotes pathological hypertrophy:
• cardiac myocytes enlarge and lose shape
• distance between capillaries and cardiac myocytes increases so they
become more at risk due to reduced oxygen delivery
However, recent studies suggest that beta-blocker treatment may attenuate
cardiac hypertrophy
Describe the hormonal action that combats
heart failure?
Fall in ABP -> decrease in baroreceptor afferent activity to the CNS -> reflex
increase in symathetic activity to adrenal gland -> release of adrenaline (95%),
NAd (5%) into the blood stream -> adrenaline acts on cardiac myocytes to
increase contractility and also on SA nodal cells to increase heart rate -> pts with
HF often have chronically high plasma catecholamine levels -> this increase in
workload just to maintain SV and CO at rest promotes pathological hypertrophy.
What are the consequences of persistent
adrenergic stimulation of the heart that occurs
during heart failure?
Initially - increase in cardiac contractility and stroke volume
Later - hyperphosphorylation of Ca2+ handling proteins can lead to dysfunctional
calcium ion homeostasis, contractile dysfunction and arrhythmia
Later - pathological hypertrophy
Later - beta adrenoceptor internalisation -> loss of adrenergic sensitivity (this
partially explains exercise intolerance in HF patients as they have no way to
increase contractility during exercise).
Describe the mechanism of delayed after
depolarisation in heart failure leading to
ventricular arrhythmia
1. Persistent sympathetic stimulation to cardiac myocytes causes an elevation in
sarcoplasmic reticulum calcium lead. Therefore, sarcoplasmic reticulum calcium
overload develops. This is when there is too much calcium stored in the
sarcoplasmic reticulum.
2. This is dangerous because in normal physiology, calcium is only released during
systole following the action potential and the opening of L-type calcium channels
in the process of calcium induced calcium release. However, with pathologically
high levels of SR calcium we can get spontaneous calcium release during
diastole into the myocyte cytosol.
3. This calcium released spontaneously is extruded by the Na/Ca exchanger - this
extrudes 1 calcium ion for three sodium ions leading to an increase in cellular
net charge by one. This is a small depolarising current.
4. Therefore, a delayed after depolarisation starts - this is a small depolarisation
during the diastolic interval
5. If the depolarisation is of significant magnitude, i.e. it causes the cellular charge
to increase to threshold for voltage gated sodium channels, it triggers an AP this is called an ectopic action potential.
6. This pathological spontaneous activity that has developed can be transmitted to
the rest of the myocardium
7. As HR worsens, more of these ectopic action potentials can generate in multiple
myocytes across the ventricles leading to ventricular arrhythmia.
How can the ventricular arrhythmia caused by
ectopic action potential development be made
worse?
• When we have persistaent stimulation of beta-1 adrenoceptors we persistant
action of PKA
• This can result in hyper-phosphorylation of L-type calcium channels, RYR2
and PLB
• RYR2 hyperphosphorylation results in RYR2 becoming very leaky so we are
much more at risk of spontaneous caclium release during diastole which
greately increases the risk of developing DADs and therefore ectopic activity.
How is DADs and ectopic AP activity treated?
Beta-blockers and calcium channel blockers should act to reduce the SR Ca2+
load, reducing the risk of DADs, ectopic activity and arrhythmia
Combatting heart failure mechanism - blood
volume loading - kidney and baroreceptor
The decrease in SV, CO, and ABP in HF leads to:
• baroreceptor unloading increasing sympathetic activity to the kidneys
• reduction in wall tension in renal afferent arterioles
• decrease in sodium delivery to macula densa in the kidneys
Collectively these three mechanisms lead to an increase in renin release from
granula cells in the juxtaglomerular apparatus resulting in an increase in the
conversion of angiotensinogen (synthesised in the liver) into angiotension 1.
Angiotension 1 is then converted by ACE into angiotension 2 -> pt with HR have
chronically high plasma angiotension 2 -> increased angiotensin 2 goes to
adrenal cortex increasing aldosterone secretion:
• aldosterone acts in the pituitary to elevate ADH release
• aldosterone and ADH will both act to increase water reabsorption
Angiotensin 2 acts on hypothalamus to increase feeling of thirst and therefore pt
will increase water uptake
Blood volume increases -> increase in central venous pressure -> increase rate
of cardiac filling -> increase in EDV -> increase in SV
What is the consequence of blood volume
loading in heart failure?
Initial increase in blood volume leads to an increase in EDV -> acts to drive up
SV to maintain SV at rest and preserve CO. However, as we keep increasing
blood volume and so increasing EDV, we get to a point where we get beyond the
plateau of the starling curve and we start to pull the myofilaments so far apart
from each other we get a reduction in SV leading to SV not being maintained at
rest. Therefore, we only want to increase our blood volume a little bit in HF.
Oedema in heart failure
• When there is a mismatch in left ventricular and right ventricular CO due to
failing heart blood can start to accumulate in the systemic or pulmonary
vascular system.
• This leads to an increase in capillary hydrostatic pressure and an elevated
capillary filtration leading to fluid accumulating in the interstitium -> oedema
• this is worsened by the progressive increase in total blood volume seen in HF
• oedema can be in the lungs and/or the periphery
• accumilation of fluid in the lungs makes it harder to breath
• as heart failure progresses this fluid not only accumulates in the interstitium
but also alveoli and reduces the area for gas exchange
Capillary filtration in the Pulmonary Circulation
• Hydrostatic pressure in the capillary is truing to drive fluid out of the
capillary
• Hydrostatic pressure drops as we move from arterial to venous end
• We also have oncotic pressure (colloidal osmotic pressure) which tries to pull
fluid back into the capillary which remains constant along the length of the
capillary
• Under normal circumstances, in the pulmonary capillary, this is greater than
capillary hydrostatic pressure
• So there is a net movement of fluid from the interstitium back into the
capillary
• This is beneficial as we are constantly breathing in humidified air but
because we are taking up fluid from the interstitium back into the capillaires
we don't get a buildup of fluid in the lungs
Pulmonary circulation in left sided HF
• Left sided HF results in a mismatch between L CO and R CO (L CO < R CO) ->
so we get an increase in blood volume in the pulmonary circulation
• Hydrostatic pressure becomes raised in the pulmonary circulation and
becomes higher than the oncotic pressure on the arterial side of the capillary
bed
• Leads to a net gain of fluid out of the capillaries and into the interstitium
• Leads to pulmonary oedema developing - this is a major problem in HF
What are the consequences of pulmonary
oedema?
• diffusion is impaired due to their being an increased distance for gas
exchange -> if severe enough arterial hypoxia develops
• arterial hypoxia results in shortness of breath - the feeling of oxygen
starvation (primal emotion)
• peripheral chemoreceptor activation on the fall of oxygen leads to increased
ventilation, increased cardiac output, and decreased peripheral blood flow
• hypoxia in the lungs leads to hypoxia pulmonary vasoconstriction and
pulmonary hypertension leading to: increased workload of the heart (has to
pump harder to overcome resistance), reduced blood flow to the lungs,
damage to lung tissue (increased pressure damages alveoli), increased risk
of blood clot
How is pulmonary oedma treated?
• 100% Oxygen administered to increase diffusion by increasing the
concentration gradient
• Longer term therapy includes loop diuretics, ACE inhibitors, and AT1R
antagonists
Mechanism of action of loop diuretics, ACE
inibitors, and AT1R antagonists (ARBs) in the
treatment of pulmonary oedema
All work by modifying capillary hydrostatic pressure:
1. Loop diuretics - increase excretion of sodium and water leading to a decrease in
blood volume and therefore CHP
2. ACE inhibitors - block the ACE enzyme, preventing the conversion of
angiotension 1 to angiotensin 2, which reduces CHP
3. AT1R (ARBs) antagonists - block angiotensin 2 type 1 receptors, prevening
vasoconstrictor effects of angiotensin 2, reducing CHP
What are the consequences of cardiac
hypertrophy?
• Increases suceptibility to ischaemia (increase in the diffusion distance
between cardiac myocytes and capillaries)
• Increases incidence of arrythmias (decrease in ion channel density of cardiac
myocytes)
• increases incidence of sudden death
How can the risk of cardiac hypertrophy
developing be reduced?
Reducing afterload with vasodilators, surgical valve replacement, and betablocker therapy (to reduce cardiac work).
What happens to elastic arteries and the pulse
with ageing?
• Ateriosclerosis occurs with ageing leading to an increase in arterial stiffness
and pulse pressure due to changes in vessel media (elastin becomes thin,
broken, and/or disordered, and more collagen is laid down in its stead)
• Mean ABP increases moderately with age due to increased TPR - systolic
pressure increases to a greater extent than mABP due to increased stiffness
and diastolic pressure begins to decline after 60 years
Impaired baroreceptor sensitivity with ageing
• Blunted baroreflex-mediated HR response to low BP means there is less
increase in HR for a given fall in BP
How does autonomic control of heart rate
change with ageing?
• There is age-related reduction in heart rate variability (HRV) in reesponse to
breathing (RSA), cough, and valsalva
• Reduction in baroreflex and vagal modulation of HR
• Relatively greater loss of high frequency vagal parasympathetic component
Ventricular diastolic function change with
ageing
• despite reduced early diastolic filling, stroke volume and cardiac output is
usually preserved by atrial contraction in late diastole
• consequences with disease - loss of atrial contraction with atrial fibrillation
can reduce cardiac output by greater than 50%, tachycardia can threaten CO
by shortening diastole so the ventricle is not adequately filled, risk of
hypotension/syncope at onset of atrial fibrillation and other tachyarrhythmias
Cerebral perfusion with ageing
• Cerebral perfusion reduces with ageing, resting CBF lowers close to the
threshold for ischaemia and therefore small changes in CBF can lead to
symptoms
• Cerebral autoregulation normally maintains CBF despite changes in BP reduced BP results in cerebral dilation, this is preserved with ageing although
reset at higher levels with hypertension - BUT in some patients with
hypotension paradoxical cerebral arteriolar vasoconstriction occurs with
systemic hypotension
The heart and ageing
• Reduced pacemaker cells and altered sympathetic and parasympathetic
activity leads to a decline in heart rate, reduced heart rate variability, and
reduced maximum heart rate with exercise.
• reduced ventricular compliance - hypertrophy of LV in response to arterial
stiffness, drop out of myocytes, cross-linking of proteins
• longer filling time and less tolerant of tachycardia and atrial fibrillation
• less able to respond to changed in demand
CVS - changes in sympathetic nervous system
with age
• increased secretion and decreased clearance of NA, therefore increased
resting NA
• Greater and prolonged NA response to upright posture BUT
• Decreased responsiveness to sympathetic stimulation
- no change in number of cardiac beta-receptors
- reduced affinity for agonists at cardiac beta-receptors
• impaired increase in heart rate localised at level of cardiac beta receptors
Peripheral vascular resistance and ageing
• blunted beta-adrenergic mediated skeletal muscle vasodilation
• most older people do not have orthostatic hypotension despite reduced HR
responses
• BP on standing maintained by increased peripheral vascular resistance - but
particularly vulnerable to vasodilator mediation
Intravascular volume regulation with ageing
Ageing predisposes to intravascular volume reduction - decline in plasma renin
and aldosterone and increase in atrial naturetic peptide promotes renal sodium
excretion; do not experience same sense of thirst as younger subjects - leads to
dehydration and hypotension developing rapidly, e.g. during acute illness,
fasting for procedures, and higher ambient temperatures.
What changes are seen in the CVS with ageing?
• heart changes
• elastic arteries and pulse
• baroreflex sensitivity
• sympathetic nervous system
• autonomic control of the heart rate
• peripheral vascular resistance
• ventricular diastolic function
• intravascular volume regulation
• cerebral perfusion
What happens to large proximal elastic arteries
and distal medium sized arteries with normal
ageing?
Large proximal elastic arteries like the thoracic and carotid arteries undergo
outward hypertrophic remodelling:
• lumen diameter increases
• wall thickness increases
• distensibility decreases
Distal medium sized arteries like the brachial and radial artery undergo
hypertrophic remodelling:
• lumen diameter stays the same
• wall thickness increases
• distensibility stays the same
Arterial wall distensibility
The ability of an artery to stretch or expand in response to an increase in blood
pressure. It is a measure of how much an artery can deform when it is stretched
Artery wall elasticity
The ability of an artery to recoil or contract after it has been stretched. it is a
measue of how quickly an artery can return to its original size after it has been
stretched
Arterial wall compliance
Broad term that includes both distensibility and elasticity. It is a measre of how
easily an artery can be stretched and return to its orginal size. A compliant artery
is one that is easily stretched and returns to its orginal size while an incompliant
artery is one that is diffuclt to stretch and does not return to its orginal size
Haematological changes in pregnancy
1. Plasma volume increases progressively preportional to the birthweight of the
baby and the majority occurs prior to 34 weeks
2. Fall in haemoglobin, haematocrit, and erythrocyte count due to plasma volume
increase being greater than erythrocyte increase
3. Despite haemodilation there is no change to MCV and MCHC
4. Platelet concentrations decrease but remain within normal limits for most women
- a pregnant women is not considered to be thrombocytopenic until platelet
count is less than 100x10 to the 9 cells/L
5. 2-3x increase in iron requirement
6. 10-20x increase in folate requirement
7. 2x B12 requirement
8. Balance in the coagulation system during pregnancy changes producing a
hypercoagulable state in preparation for haemostasis following delivery.
Cardiac changes in pregnancy
1. By 8 wks CO increased by 20%
2. Peripheral vasodilation occurs mediated by endothelium-dependent factors,
including NO synthesis, upregulated by oestrodiol and vasodilatory
prostaglandins
3. Peripheral vasodilation leads to a 25-30 fall in total peripheral resistance and to
compromise a cardiac output increase of 40% occurs
4. Increased CO predominantly due to increased stroke volume
5. Max CO at 20-28 wks
6. Increased stroke volume due to early ventricular wall muscle mass increases and
increased end diastolic volume
7. CO is maintained towards term despite decreased stroke volume and in late
pregnancy due to increased heart rate
8. BP decreases in 1st and 2nd trimester but returns to prior levels by 3rd
9. Maternal position has a significant impact on the haemodynamic profile of
mother and foetus
10. CVP remains the same
11. PVR decreases
12. Serum colloidal pressure (oncotic pressure) decreases by 10-15%
13. Susceptibility to pulmonary oedema increases
14. Pulmonary oedema is associated with increased preload and increased
pulmonary capillary permeability
15. During labour there is a 15% increase in 1st stage and 50% in 2nd stage in CO
16. Post-delivery there is a 60-80% increase in CO due to relief of IVC obstruction
and uterus contraction causing blood to empty into right atrium
What normal physiological changes seen in
pregnancy could be mistaken as being
pathological by one not versed in CVS changes
in pregnancy?
• Bounding or collapsing pulse
• Ejection systolic murmur
• ECG changes:
- Atrial and ventricular ectopics
- Q wave smaller and inverted T wave in lead 3
- ST segment depression and T-wave inversion in the inferior and lateral leads
- left-axis shift of QRS
Why should pregnant women by nursed in the
left or right lateral position?
Because in the supine position, pressure of the gravid uterus on the IVC causes a
reduction in venous return to the heart and a consequent fall in SV and CO. More
haemodynamically stable in lateral position
The precarious balance of the early immune
system
• By birth :
◦ The baby needs to have an immune system developed enough to fight
infection
◦ The Mother can help – maternal antibodies can cross placenta
• In utero :
◦ The mother’s immune system needs to be suppressed enough to prevent
rejection of foetus.
◦ This is because the child is a mixture of their mother and father and so
usually the mother’s immune system will recognise the baby as non-self.