Cardiovascular System Flashcards
What is the mediastinum?
Central compartment of thoracic cavity
Surrounded by loose connective tissue
Upper part= vessels to head and neck and limbs
Lower part= anterior, middle, posterior, structures traversing down to abdomen
What is the pericardium?
Membrane (fibroserous sac) enclosing the heart
2 layers= fibrous and serous
Serous has 2 parts (parietal lines fibrous, visceral lines heart)
Why does the serous layer of the pericardium have 2 parts?
Double layer
Lubricating fluid-> mobility
What great vessels enter/leave the RA, RV, LA and LV?
5 great vessels (INTO ATRIA, OUT OF VENTRICLES)
RA= superior and inferior vena cava (return deoxy blood from body circulation into RA) RV= pulmonary artery (splits into L and R, carries deoxy blood from RV to lungs)
LA= pulmonary veins (splits into L and R, carries oxy blood from lungs into LA) LV= aorta (carries oxy blood from LV to systemic circulation)
What are the branches off the aortic arch?
Aortic arch is between ascending and descending aorta (travels backwards)
BRACHIOCEPHALIC TRUNK
Right subclavian artery
Right common carotid artery
LEFT COMMON CAROTID ARTERY
LEFT SUBCLAVIAN ARTERY
What are the subclavian arteries?
Paired major arteries of the upper thorax below the clavicle
Arteries supplies limb (receives blood from aortic arch)
(Vein drains limb)
What are the carotid arteries?
Blood vessels that carry oxygen-rich blood to the head, brain and face
What kind of autonomic control is the vagus nerve under?
Parasympathetic
What are the brachiocephalic arteries?
First branch of the aorta
Supplies blood to tissues of the brain and head (and R arm)
R common carotid
R subclavian
What are the brachiocephalic veins?
Innominate vein
Returns oxygen-depleted blood from upper limbs, neck and head (to heart)
What are the main valves in the heart and where are they/
ATRIOVENTRICULAR VALVES
Mitral (bicuspid)
Tricuspid
SEMILUNAR VALVES (in arteries leaving the heart
Aortic
Pulmonary
What order are the heart valves reached in circulation?
Tricuspid
Pulmonary
Mitral
Aortic
What is the tricuspid valve?
Closes off RA that holds blood coming in from body
Allows blood to flow from RA to RV
Prevents backflow of blood from RV to RA when blood is pumped out of RV
Connected to the papillary muscles but the Chordae tendineae (prevents prolapse or inversion into RA)
What is the pulmonary valve?
Closes off RV
Opens to allow blood to be pumped from the heart to lungs (via pulmonary artery) to receive oxygen
What is the mitral valve?
Closes off LA that collects oxygen-rich blood from lungs
Allows blood to pass from LA to LV
Prevents backflow of blood from LV to LA when blood is pumped out of LV
Anterior cusp
Posterior cusp
What is the aortic valve?
Closes of LV
Opens to allow blood to leave the heart to the body (via aorta)
What cusps are in the tricuspid valve?
Anterior cusp
Septal cusp
Posterior cusp
What cusps are in the pulmonary valve?
Anterior semilunar cusp
Right semilunar cusp
Left semilunar cusp
What are the superior and inferior vena cava?
Bring deoxygenated blood from body to heart
SUPERIOR= from head and upper body-> into RA of heart INFERIOR= from lower body-> into RA of heart
How does blood return from the head and neck to the heart and then back to head?
Blood from head-> enters RA (via superior vena cava)
Blood flows through tricuspid valve into RV
RV pumps blood to lungs (where it absorbs O2) via pulmonary valve
Oxygen-rich blood returns from lungs-> enters LA
Blood flows through mitral valve into LV
LV contract-> blood pumped through aortic valve into aorta
Aorta-> common carotid arteries-> head
What arteries supply oxygen-rich blood to the heart tissue?
Coronary arteries
What veins remove deoxygenated blood from the heart tissue?
Cardiac veins
Describe coronary circulation
Circulation of blood in blood vessels of the heart muscle
Coronary arteries
Cardiac veins
What type of heart damage is the most common cause of UK death?
Damage to coronary arteries
Atheroma and atherosclerosis or MI
What are the coronary arteries?
RIGHT CORONARY ARTERY
Sino-atrial nodal branch of RCA
Right marginal branch of RCA
Posterior interventricular branch of RCA
LEFT CORONARY ARTERY
Circumflex branch of LCA
Left marginal branch of circumflex branch
Anterior interventricular branch of LCA
Diagonal branch of anterior interventricular branch
What are the cardiac veins?
Great cardiac vein
Small cardiac vein
Posterior cardiac vein
Middle cardiac vein
Right marginal vein
Anterior veins of RV
NB. Coronary sinus is where veins come off
What is the cardiac conduction system?
Group of specialised cardiac muscle cells in heart walls that signal to heart muscle causing it to contract
Specialised means the heart independently generates and propagates electrical activity (can beat even without its nerve supply)
Extrinsic nerve supply from ANS to modify and control the intrinsic beating
What are the major components of the cardiac conduction system and what happens to them?
- SAN
- Inter-nodal fibre bundles
- AV node
Ventricular bundles (bundle branches and purkinje fibres)
SA node-> anterior/middle/posterior intermodal tracts-> AV node
AV node-> Bundle of His (into right and left bundle branches)
-> Purkinje fibres in ventricular walls
NB. SA nodes also-> Bachmann’s bundle (LA)
How is calcium involved in contraction of the heart?
Electrical event-> calcium transient-> contractile event
Excitation-contraction coupling
What are T-tubules?
Finger-like invaginations from the cell sruface
Carry surface depolarisation deep into the cell
T tubule lies alongside each Z line of every myofibril (spaced approx 2 um apart)
Outline excitation-contraction coupling (on excitation)
Depolarisation-> influx of Ca into myocyte (via L-type Ca channels)
Ca binds to IC SR-Ca release channels-> conformational change
CICR (Ca induced Ca release) from SR
Ca release-> myocyte contraction
Outline excitation-contraction coupling (on relaxation)
Intracellular Ca taken up into the SR by Ca-ATPase (SERCA)
Ca also removed from myocyte by Na/Ca exchanger
Na/Ca exchanger uses the energy gradient from Na to expel Ca into EC matrix
How can the contraction force be described (graphically)?
Sigmoidal relationship
Between log of cytoplasmic Ca concentration and % of maximum force produced
What is the difference in length-tension relationships for cardiac and skeletal muscle?
Cardiac muscle more resistant to stretch
Less compliant than skeletal muscle
Due to properties of the extracellular matrix and cytoskeleton
Only ascending limb of the relation important for cardiac muscle
What are the two types of contraction?
Isometric (muscle fibres don’t change length, pressures in both ventricles increase)
Isotonic (shortening of fibres and blood is ejected from ventricles)
Define: preload
Weight that stretches muscle before it’s stimulated to contract
Define: afterload
Weight not apparent to muscle in resting state
Only encountered when muscle has started to contract
What is the relationship between afterload and shortening/shortening velocity?
In isotonic contraction
Inverse linear relationship between afterload and shortening
Almost inverse linear relationship between afterload and shortening velocity
What happens if preload increases?
There is an initial enhanced stretch which-> increased ability of the muscle to produce more force (shifts the graph to the right)
I.e. a greater afterload will result in more shortening than before
What are the in-vivo correlates of preload?
As blood fills the ventricles during the relaxation phase (or diastole) of the cardiac cycle it stretches the resting ventricular walls
Stretch or filling determines the preload on the ventricles before ejection
Preload is dependent upon venous return to the heart
Exercise increases pre-load
What are the in-vivo correlates of afterload?
The load against which LV ejects blood after opening of the aortic valve
Any increase in afterload decreases the amount of isotonic shortening that occurs and decreases the velocity of shortening
I.e. small ventricular filling leads to a smaller contraction as the ventricular cardiac muscle responds less effectively to the afterload of the arterial blood pressure
What are the measures of preload?
End-diastolic volume
End diastolic pressure
Right atrial pressure
What is the simple measure of afterload?
Diastolic arterial blood pressure
How can heart contraction be altered?
INTRINSIC MECHANISMS
Frank-Starling relationship
Rate-induced regulation
EXTRINSIC MECHANISMS
Autonomic NS
Endocrine system
Blood gases and pH
What is the Frank-Starling relationship?
Increased diastolic fibre length increases ventricular contraction
Consequence: ventricles pump greater stroke volume so, at equilibrium, cardiac output exactly balances the augmented venous return
What 2 factors is the F-S relationship due to?
Changes in number of myofilament cross bridges that interact
Changes in Ca sensitivity of the myofilaments
Why do changes in number of myofilament cross bridges that interact affect the F-S relationship?
At optimum sarcomere length, there is maximum interdigitation between thick and thin filaments
At shorter lengths than optimal, actin filaments overlap on themselves-> reducing no. of myosin cross bridges that can be made
Why do changes in Ca sensitivity of the myofilaments affect the F-S relationship?
Ca sensitivity changes with changes in sarcomere length
At longer sarcomere lengths, the affinity of Troponin C for Ca is increased
-> less Ca required for the same amount of force produced
OR
With stretch the spacing between myosin and actin filaments (“lattice spacing”) decreases
With decreasing myofilament lattice spacing, the probability of forming strong binding cross- bridges increases
This produces more force for same amount of activating calcium
What is stroke work?
Work done by the heart to eject blood under pressure into the aorta and pulmonary artery
What is stroke volume?
Volume of blood ejected during each stroke by each ventricle
Affected by afterload, preload and contractility
What is pressure (P) in the stroke work equation?
Pressure at which blood is ejected
Greatly influenced by structure
What is the formula for stroke work?
Stroke work= SV x P
What is the Law of Laplace (concept)?
Law states that: when the pressure within a cylinder is held constant, the tension on its walls increases with increasing radius
Therefore, if pressure and tension (wall stress) remain constant, wall thickness must be increased or radius of the cylinder must be decreased
What is the Law of Laplace (formula)?
T = (PR)/h
T= wall tension P= internal pressure R= cylindrical radium h= height/length of cylinder
Why is the Law of Laplace important physiologically?
Radius of curvature of walls of LV is less than that of RV allowing LV to generate higher pressures with similar wall stress (to combat the higher aortic blood pressure than pulmonary BP)
Facilitates late ejection
Wall stress kept low in giraffe by long, narrow, thick-walled ventricle
In frog, where pressures are low the ventricle is almost spherical
Failing hearts often become dilated which decreases pressure generation and ejection of blood and increases wall stress by increasing the radius
Outline the cardiac cycle from atrial systole
DIASTOLE
D3. Late (slow filling)
D4. Atrial systole
SYSTOLE
S1. Isovolumetric ventricular contraction
S2. Ventricular ejection (rapid, reduced)
DIASTOLE
D1. Isovolumetric ventricular relaxation
D2. Late (rapid filling)
What is diastole?
Ventricular relaxation during which ventricles fill with blood
4 sub-phases
What is systole?
Ventricular contraction when blood is pumped into the arteries
2 sub-phases
How can you calculate stroke volume with systolic and diastolic volumes?
End diastolic volume - end systolic volume = stroke volume
What is the ejection fraction and what is the formula to calculate it?
EF = SV/EDV
Percentage of EDV ejected
At peak exercise >80%
In heart failure
What happens in atrial systole? Mechanical events Changes in pressure and volume Electrocardiogram Heart sounds
MECHANICAL EVENTS
Just before, blood flows passively through AV valves (tricuspid and mitral)
Atrial depolarisation-> atrial contraction-> tops up volume of blood in ventricles
CHANGES IN PRESSURE AND VOLUME
As atria contract, ‘a wave’ can be seen (due to increased atrial pressure)
Blood also pushed back into jugular vein-> wave in jugular venous pulse
ELECTROCARDIOGRAM
SAN activation-> atrial depolarisation (P wave)
HEART SOUNDS
No heart sound heard (4th maybe as an abnormality in congestive heart failure, pulmonary embolism or tricuspid incompetence)
What happens in isovolumetric contraction? Mechanical events Changes in pressure and volume Electrocardiogram Heart sounds
MECHANICAL EVENTS
Occurs just as ventricles depolarise
Interval between AV valve closing and semi-lunar valves (aortic/pulmonary) opening
CHANGES IN PRESSURE AND VOLUME
AV valves close as ventricular pressure exceeds the atrial pressure
Since the AV and SL valves are closed-> no blood movement out of ventricles, just increased pressure (approaching aortic pressure)
ELECTROCARDIOGRAM
Ventricular depolarisation marked by QRS complex
HEART SOUNDS
LUB (of lub-dub) due to AV valves closing and associated vibrations
What happens in rapid ejection? Mechanical events Changes in pressure and volume Electrocardiogram Heart sounds
MECHANICAL EVENTS
Ventricular muscle walls undergo isotonic contraction-> push blood out ventricles
SL valves open
CHANGES IN PRESSURE AND VOLUME
As ventricles contract, pressure within them exceeds pressure in aorta and pulmonary arteries
When SL valves open-> volume of ventricles decreases
RV contraction pushes tricuspid valve slightly into atrium (-> small jugular vein wave ‘c wave’)
ELECTROCARDIOGRAM
No changes
HEART SOUNDS
No heart sounds
What happens in reduced ejection? Mechanical events Changes in pressure and volume Electrocardiogram Heart sounds
MECHANICAL EVENTS
Marks end of ventricular systole
Aortic and pulmonary (SL) valves begin to close
CHANGES IN PRESSURE AND VOLUME
Blood flow from ventricles decreases-> ventricular volume decreases more slowly
Pressure in ventricles falls below that in arteries so blood begins to flow back-> SL vales close
ELECTROCARDIOGRAM
Ventricular repolarisation marked by T wave
HEART SOUNDS
No heart sounds
What happens in isovolumetric relaxation? Mechanical events Changes in pressure and volume Electrocardiogram Heart sounds
MECHANICAL EVENTS Beginning of diastole Aortic and pulmonary valves (SL) shut completely AV valves remain closed Atria fill with blood
CHANGES IN PRESSURE AND VOLUME
Atrial pressure rises as blood volume increases
Blood pushing on tricuspid valve gives a second jugular pulse (‘v wave’)
Aortic valve shuts-> rebound pressure wave against the valve (distended aortic wall relaxes)
Recoil reduces the aortic pressure (seen as dichrotic notch)
ELECTROCARDIOGRAM
No changes
HEART SOUNDS 2nd sound (DUB) when aortic and pulmonary valves close
What happens in rapid ventricular filling (late diastole)? Mechanical events Changes in pressure and volume Electrocardiogram Heart sounds
MECHANICAL EVENTS
AV valves open and blood flows rapidly (passively) into ventricles
CHANGES IN PRESSURE AND VOLUME
Ventricular volume increases as atrial pressure falls
ELECTROCARDIOGRAM
No changes
HEART SOUNDS
3rd (abnormal)= can signify turbulent ventricular filling due to sever hypertension or mitral incompetence
What happens in reduced ventricular filling (late diastole)? Mechanical events Changes in pressure and volume Electrocardiogram Heart sounds
MECHANICAL EVENTS
Diastasis
Ventricles fill more slowly as pressure difference between atria and ventricles decreases
CHANGES IN PRESSURE AND VOLUME
Ventricular volume increases more slows
ELECTROCARDIOGRAM
No changes
HEART SOUNDS
No heart sounds
What are the a, c and v waves (in atrial pressure)?
A WAVE (in atrial systole) As atria contract, 'a wave' can be seen (due to increased atrial pressure) Blood also pushed back into jugular vein-> wave in jugular venous pulse
C WAVE (in rapid ejection) RV contraction pushes tricuspid valve slightly into atrium (-> small jugular vein wave 'c wave')
V WAVE (in isovolumetric relaxation)
Blood pushing on tricuspid valve gives a second jugular pulse ('v wave')
What happens on an ECG?
P= Atrial depolarisation QRS= Ventricular depolarisation T= Ventricular repolarisation
When are heart sounds made?
4th (abnormal)
1st (LUB)= AV valves close and associated vibrations
2nd (DUB)= SL valves close
3rd (abnormal)= can signify turbulent ventricular filling due to sever hypertension or mitral incompetence
On a graph showing changes in pressure and volume, what does it mean when pressure lines cross (i.e. atrial and ventricular pressure or ventricular and aortic pressure)?
Valves closing
What is seen as a dichrotic notch in aortic pressure?
Aortic valve shuts-> rebound pressure wave against the valve (distended aortic wall relaxes)
Recoil reduces the aortic pressure
What does the Wiggers diagram show?
RIGHT HEART PRESSURE
Pulmonary artery pressure
Right ventricular pressure
LEFT HEART PRESSURE
Aortic pressure
Left arterial pressure
VENTRICULAR VOLUME
Including EDV and ESV
HEART SOUNDS
S3, S1, S2, S3, S1
MITRAL VALVE
O or C
AORTIC VALVE
O or C
ECG
TIME (sec)
At the top of the Wiggers diagram, the stages of contraction are…
Atrial systole Isovolumetric contraction Ejection (rapid then reduced) Isovolumetric relaxation Rapid filling Reduced filling (diastasis)
What happens to pressures in pulmonary circulation?
Patterns essentially identical in L and R heart but pressures in R heart are much lower
Both ventricles eject same amount of blood
What pressure is in the RA, RV, pulmonary artery, LA, LV, aorta?
Pressure (mmHg)
RIGHT SIDE
RA= 0-8
RV= 25/5
Pulmonary artery= 25/12
LEFT SIDE
LA= 8-10
LV= 125/5
Aorta= 120/80
What is the pulmonary artery wedge pressure (PAWP) and what can elevation indicate?
4-13mmHg
Taken from a branch of pulmonary artery when the back pressure has been occluded
Elevation can indicate LV failure, mitral insufficiency, mitral stenosis
Describe the pressure-volume loop
SEE GRAPH
Volume on x axis
Pressure on y axis
4 sided shape (BL= 4, TL=3, TR= 2, BR= 1)
High volume, low pressure= preload (determined by blood filling the ventricle during diastole)
High volume, high pressure= afterload (represented by blood pressures in aorta and pulmonary artery)
On the pressure-volume loop graph, what happens at X1 (bottom right)?
End diastolic volume, i.e. the preload after max ventricular filling
Blood filling the ventricle during diastole determines the preload that stretches the resting ventricle
On the pressure-volume loop graph, what happens at X2 (top right)?
BPs encountered in great vessels (aorta and pulmonary artery) represent the afterload
On the pressure-volume loop graph, what happens between X2 and X3 (top right-> left)?
Between X2 and X3, isotonic contraction of the ventricles occurs
How does the pressure-volume loop relate to the F-S relationship?
The pressure-volume loop can be fitted into the Frank Starling graph
The straight line of the active force is equal to the end-systolic pressure line
What happens to the pressure-volume loop if you increase preload or afterload?
Increasing preload increases stroke volume (increasing X1 increases width of loop)
Increased afterload decreases SV
There is a greater pressure to overcome in order to open the aortic valve, therefore X2 increases and less shortening occurs
What is the contractile capability of the heart?
Simple measure of cardiac contractility is ejection fraction
Contractility is increased by sympathetic stimulation-> Beta-adrenoreceptor activation-> increase cyclic AMP-> phosphorylation of key Ca2+ handling proteins-> Ca2+ channels open for longer-> Ca influx increased-> increased Ca2+ in cytoplasm-> increased force of contraction
During exercise
- Contractility is increased due to increased sympathetic activity
- End diastolic volume is increased due to changes in the peripheral circulation (venoconstriction and muscle pump)
Increasing contractility increases pressure and volume
Decreasing contractility decreases volume and pressure
How long does systole take?
0.3sec
How long does the entire cardiac cycle take?
0.8sec
What is the average heart rate?
72 beats per minute
What is cardiac output?
Amount of blood ejected by each ventricle in one minute
What is the formula for CO and what is a typical value?
CO = HR x SV
CO= 72bpm x 70ml/beat = 5.04L/min
How can you calculate the equilibrium potential?
Nernst equation
What helps maintain the potassium concentration?
Na/K ATPase
What formula can be used to calculate resting membrane potential?
Goldman-Hodgkin-Katz
Takes into account relative permeabilities of ions
What is the duration of a cardiac AP compared to a nerve?
Cardiac action potential is long (several hundred milliseconds)
Duration of AP controls the duration of contraction of the heart
Long, slow contraction is required to produce an effective pump
At rest, membrane potential determined by K
What is a major difference in re-excitability between skeletal and cardiac muscle?
In skeletal muscle repolarization occurs very early in the contraction phase making re-stimulation and summation of contraction possible (can-> tetanus)
In cardiac muscle it is not possible to re-excite the muscle until the process of contraction is well underway hence cardiac muscle cannot be tetanized
Describe the graph of the cardiac AP
Steep vertical AP
Plateau
Gradual decline
Define: absolute refractory period
Time during which no AP can be initiated regardless of stimulus intensity
Relates to Na channel inactivation (Na channels recover from inactivation when the membrane is repolarized)
Define: relative refractory period
Period after absolute refractory where an AP can be initiated but only with stimulus larger than normal
What is full recovery time (regarding refractory period)
The time at which a normal AP can be elicited with normal stimulus
What are the phases of the cardiac AP?
0= upstroke (Na) 1= early repolarisation 2= plateau (Ca) 3= repolarisation (K) 4= resting membrane potential (diastole)
Describe what happens in the plateau phase of a cardiac AP
Calcium influx during early plateau-> trigger Ca release from IC stores
Required for contraction
Activates rapidly (within ms)
What calcium channel antagonists inhibit calcium channel (e.g. in plateau)?
Nifedipine
Nitrendipine
Nisoldipine
Describe what happens during repolarization in a cardiac AP
Gradual activation of K currents
Large K current that is inactive during plateau opens when cells have partially repolarised
What is IK1?
Current responsible for fully repolarising the cell
Large
Flows during diastole
Stabilizes the RMP-> reduced risk of arrhythmias by requiring a large stimulus to excite the cells
Why do different parts of the heart have different AP shapes?
Due to different ionic currently flowing
Different degrees of expression of ionic channels
NB. SAN (more like skeletal AP but with bigger hyperpolarisation) and ventricular (typical cardiac graph)
What is the role of the SAN in initiating the electrical activity of the heart?
Most channels exist in SA node– to some extent
Exception is IK1 – no IK1 in SA node
Very little Na influx – upstroke produced by Ca influx in SAN
Also T-type Ca channels that activate at more –ve potentials than L-type
Ito is very small
Pacemaker current (If) present
What is the natural rhythm of pacemaker cells?
Approx 80 APs (and hence heartbeats) per minute
What is the approximate resting potential of pacemaker cells?
-65mV (but unstable therefore-> more negative)
What is the pre-potential caused by?
Special inward Na+ current into pacemaker cells, along with a decrease in the membrane permeability to K+
I.e. increased Na+ influx, decreased K+ efflux
What influence does the sympathetic nervous system e.g. adrenaline have on pacemaker cells?
Increases Na influx
Seen by increase in pre-potential slope (therefore threshold is reached more rapidly, HR decreased)
What influence does the para sympathetic nervous system e.g. acetylcholine have on pacemaker cells?
Reduces Na influx
Seen by decrease in pre-potential slope ((therefore threshold is reached more slowly, HR increased)
What is the sino-atrial node?
Pacemaker of the heart
A small mass of specialised cardiac muscle situated in the superior aspect of the right atrium
Located in the anterolateral margin between the orifice of the superior vena cava and the atrium
Automatic self-excitation: it initiates each beat of the heart
Since the fibres of the SA node fuse with the surrounding atrial muscle fibres, AP generated in the nodal tissue spreads throughout both atria
At what speed does an AP generated in the nodal tissue spread throughout both atria?
0.3m/s
Produces atrial contraction
Where are inter-nodal fibre fibres and what does it do?
Interspersed among the atrial muscle fibres
Conduct the AP to the AVN with greater velocity than ordinary muscle (1m/s)
Where is the AVN and what does it do?
Located at the border of the RA near the lower part of the interatrial septum
Electrically connects the conduction system between atrial and ventricular chambers.
Produces short delay (approx 0.1s) in transmission
-> Delays fibres in AVN and special junctional fibres that connect the node with ordinary atrial fibres
Why does the AV node produce a short delay?
Allows atria to complete their contraction and empty their blood into the ventricles before the ventricles contract
What is the role of the bundle of His and bundle branches?
As the AV bundle leaves the AV node, it descends in the interventricular septum for a short distance (Bundle of His) and then divides into the right and left bundle branches
These comprise of specialised muscle fibres called Purkinje fibres which terminate in a finger-like fashion on the working myocardial cells
They are very large; conduct the AP at about 6x the velocity of ordinary cardiac muscle (1.5 to 4.0m/s)
What is the role of the Purkinje fibres?
The terminal Purkinje fibres extend beneath the endocardium and penetrate approximately one-third of the distance into the myocardium
They end on ordinary cardiac muscle within the ventricles, and the impulse proceeds through the ventricular muscle at about 0.3 to 0.5 meters per second.
The excitation of the ventricles proceeds upward from the apex of the heart toward its base
What determines the extend of spread of current (in impulse propagation)?
The propagation of AP is due to a combination of passive spread of current and existence of a threshold
Coupling resistance of the cells (gap junction resistance) determines extent of spread of current
What is the purpose of gap junctions in conduction?
Intercellular communication and impulse conduction rely on gap junctions which form at intercalated discs
Describe what deflections are the basis of the ECG
The effects of a wave of depolarisation are detected as the potential difference between two electrodes
When a wave of depolarisation is moving TOWARDS the positive electrode it causes an UPWARD deflection
When a wave of depolarisation is moving AWAY from the positive electrode it causes a DOWNWARD deflection
When a wave of repolarising current is moving TOWARD the positive electrode it causes an DOWNWARD deflection
When a wave of repolarising current is moving AWAY the positive electrode it causes an UPWARD deflection
*Repolarising current is of opposite polarity to depolarising current
If the position of an ECG electrode relative to the heart is known, what can be predicted/
The waveform that it should record assuming a normal process of excitation
Describe chest lead configuration
Use Angle of Louis to find 2nd intercostal space
V1= where the 4th intercostal space meets the sternum (on R)
V2= where the 4th intercostal space meets the sternum (on L)
V4= at the mid-clavicular line in the 5th intercostal space
V3= between V2 and V4
V5= at the anterior axillary line in the 5th intercostal space (immediately below the beginning of the axilla, or under-arm area)
V6= at the mid axillary line in the 5th intercostal space (below the centre point of the axilla)
Where is the neutral ‘zero reference ‘ wire connected?
Right foot/leg= zero reference point
Point of comparison so potentials can be generated
Also removes effect of background electrical noise
Describe limb lead configuration
aVR= R arm aVL= L arm N= R foot aVF= R foot
What cardiac conditions can be detected with an ECG?
Tachyarrhythmias Bradyarrhythmias Myocardial infarction Myocardial ischaemia Cardiomyopathy Assessment of pacing Electrolyte disturbances
What is Einthoven’s triangle?
Equilateral between L arm, L foot and R arm
LEAD 1= R to L arm (L arm considered to be the +ve electrode)
LEAD 2= R arm to L foot (L foot considered to be the +ve electrode)
LEAD 3= L arm to R foot (L foot considered to be the +ve electrode)
What degree are leads 1, 2, and 3 considered to be at?
1= 0 2= +60 3= +120
I.e. The positive pole of Lead 2 is considered to be +60° to the positive pole of Lead I
The positive pole of Lead 3 is considered to be +120° to the positive pole of Lead I
What does it mean if Lead aV is an augmented vector?
Lead aV couples with standard limb leads to form augmented vectors
Describe the 3 augmented leads
aV-R: R arm is considered the positive electrode, and the negative electrode is considered to be half way between the L arm and L foot +ve 0
aV-L: L arm is considered the positive electrode, and the negative electrode is considered to be half way between the R arm and R foot
aV-F: L foot is considered the positive electrode, and the negative electrode is considered to be half way between the R and L arm
What are the standard limb leads and the augmented leads?
Standard= Leads 1, 2 and 3
Augmented= aVR, aVL and aVF
What will the readings of augmented leads be compared to standard limb lead readings?
Bigger
Because they are coupled
Considering Einthoven’s triangle, what are the augmented vectors?
Lead 1 is 0
aV-R is at -150° (150° above the 0° line)
aV-L is at -30° (30° above the 0° line)
aV-F is at +90° (90° below the 0° line, i.e. perpendicular)
How do you achieve a hexagonal reference system?
6 limb leads combined (standard and augmented)
Arranged in 3 pairs of 2 leads which are at right angles to each other:
- Lead I and aVF
- Lead II and aVL
- Lead III and aVR
Are standard or augmented limb leads bipolar?
Standard (limb leads)= bipolar
Augmented (limb leads) and V1-V6 (precordial leads)= unipolar
In leads 1 and 2, are P and QRS positive or negative?
Positive
ECG graph paper has big and small squares, what do they mean?
1 SMALL
1mmx1mm block
Represents 40ms time and 0.1mV amplitude
1 LARGE
5mmx5mm block
Represents 0.2s (200ms) time and 0.5mV amplitude
NB. Amplitude= y
Time= x
What deflection is caused when a wave of depolarisation is moving towards the positive electrode?
Upward (shown by positive waveform)
What deflection is caused when a wave of depolarisation is moving towards the negative electrode?
Downward (shown by negative waveform)
What is the mean vector of wave depolarisation in the ventricles?
Towards the apex of the L ventricle
May be along axis of lead 1 (i.e. at 0 degrees) OR in the direction of aVF (i.e. at +90 degrees)
What is the MFPA?
Mean frontal plane axis of the ventricles
When the waveform is positive (upward deflection), what does this mean about the direction of the wave of depolarisation and the MFPA?
The wave of depolarisation is towards the positive electrode of the MFPA
When the waveform is negative (downward deflection), what does this mean about the direction of the wave of depolarisation and the MFPA?
The wave of depolarisation is away from the positive electrode of the MFPA
Why do waveforms vary in size?
If lead is exactly on MFPA, the signal will be max size (i.e. the angle between the lead and MFPA is 0, and cos0 = 1 = max)
The fraction of the max signal obtained in each lead can be calculated using SOH CAH TO A (if right angled triangles are drawn)
Why are equipotential and negative waves measured?
The value of cos90= 0
Hence the value of (MPFA cos90) is also zero
This explains why a lead with its axis at right angles to the MFPA show no signal (or a small equipotential)
Cosines of angles between 90 and 270 are negative
Thus when a lead is more than 90 to MFPA the ECG will show downward (negative) rather than upward deflections
What is the range of MFPA?
Normal range of the MFPA is between -30° and +90°, and may vary between patients
This depends on the orientation of the heart in the chest
If a patient has an MFPA that is more negative than -30°, they are exhibiting left axis deviation (enlarged left ventricle e.g. aortic stenosis)
If a patient has an MFPA that is more positive than +90°, they are exhibiting right axis deviation (enlarged right ventricle which could be pulmonary disease)
How do you calculate the QRS axis?
Summation of vectors
EXAMPLE 1 QRS axis = Lead 1 + aVF If lead 1= +8 and aVF= +3 Tan(x) = 3/8 x = 21 degrees QRS axis = 21 degrees
EXAMPLE 2 If lead 1= +12 and aVF= -14 Tan(x) = 14/12 x= 49 degrees QRS axis = -49 degrees Left axis deviation (more negative than -30)
EXAMPLE 3 If lead 1= -3 and aVF= 8 Tan(x) = 3/8 x= 21 degrees QRS axis = +111 degrees Right axis deviation (more positive than +90)
Describe how chest (pre-cordial) lead recordings are obtained
6 unipolar leads
Designation as V1 – V6
All electrodes are positive
I.e. for each lead, chest lead is a positive pole
Septum depolarisation occurs first, and is from left to right
MFPA is then in the right to left direction
How is the QRS complex shown by pre-cordial leads?
V6 records small wave of depolarisation AWAY from the electrode, then large wave TOWARDS (qR wave)
V1 records a small wave of depolarisation TOWARDS the electrode, then a large wave AWAY (rS wave seen in diagram)
These combine to form the QRS complex seen on an ECG
V3 records a biphasic (both direction) wave known as the transition zone
The ECG then combines the recordings at the 6 chest electrodes, with the hexagonal reference system for the 6 leads (standard + augmented)
What is the duration and amplitude of the P wave, PR interval, QRS complex, Q wave and QT interval?
P wave= duration
What is normal heart rate?
60-100bpm
How is heart rate calculated from an ECG?
Count number of squares between each QRS complex and divide 300 by this number
Count number of QRS complexes in 10 seconds, and multiply this number by 6
What does the PR interval represent?
Time taken for wave of depolarisation to migrate from one side of the AVN to the other
The AVN acts like a safety valve to separate atrial and ventricular systole
What are the steps for ECG?
- Is it the correct recording?
- Identify the leads
- Check the calibration and speed of the paper (25 mm/s, 1mV = 10mm)
- Identify the rhythm
- Look at the QRS axis
- Look at the P wave
- Look at the PR interval
- Look at the QRS complex
- Determine the position of the ST segment
- Calculate the QT interval
- Look at the T wave
- Check!
What are common abnormalities of cardiac rhythm that can be picked up on the ECG?
Sinus tachycardia Atrial fibrillation Atrial flutter AV nodal reentrant tachycardia (AVNRT/AVRT) Pre-excitation syndrome Heart block Bundle branch block (Right BBB and left BBB) Ventricular tachycardia (monomorphic) Ventricular fibrillation
What abnormalities are seen in sinus tachycardia? Heart rate Rhythm P wave PR interval QRS in seconds
P waves have normal morphology, towards positive electrode of Lead 2 (RA-> LF, similar to axis of heart) and reverse direction of Lead aVR
HEART RATE
>100 bpm
(Atrial 100-200, ventricular 100-200)
RHYTHM
Regular
P WAVE
Before each QRS, identical (normal)
PR INTERVAL
0.12-0.20s
QRS
What abnormalities are seen in atrial fibrillation? Heart rate Rhythm P wave PR interval QRS in seconds
P waves absent, replaced by oscillating baseline fibrillation waves
HEART RATE
Atrial rate= 350-600bpm (all atrial myocytes are firing rapidly, not completely efficient therefore blood pools in the atria-> compromised CO and increased stroke risk)
Ventricular rate= 100-180bpm (irregular rhythm due to atria irregularity, ventricles rapidly depolarise-> narrow QRS complex)
RHYTHM
Irregular
P WAVE
Fibrillatory (fine to course)
PR INTERVAL
n/a
QRS
What abnormalities are seen in AVN reentrant tachycardia? Heart rate Rhythm P wave QRS in seconds
Narrow complex tachycardia
Common in teenagers
Re-entrat circuit within AV node
HEART RATE
Atria and ventricles contract at same time
RHYTHM
Regular or variable
P WAVE
Often buried within QRS or just after QRS
QRS
Regular
What abnormalities are seen in pre-excitation syndrome? P wave PR interval QRS in seconds Characteristics
Accessory pathway (connect atrium to ventricle, which is an abnormal physical pathway)
- 1/3= conduct antegradely (WPW)
- 2/3= conduct retrogradely (concealed pathways)
Depolarisation of the ventricles early (pre-excitation)
- > slurring of the QRS complex and lack of regulation by the AVN
- > electrical activity conducted faster
- > increased HR
P WAVE
Before each QRS, identical (normal)
PR INTERVAL
10s
CHARACTERISTICS
Delta wave distorts QRS
Predisposes to accessory pathway tachycardias (AVRT)
What is a heart block?
AV nodal block
1st degree (prolonged PR interval >20s) 2nd degree (Mobitz type 1 or 2) 3rd degree (complete heart block)
Describe the 2 types of 2nd degree heart blocks
MOBITZ TYPE 1 (Wenckebach)
Disease of AV node
Progressive lengthening of PR interval followed by a blocked P wave (no QRS)
Then PR interval resets and cycle repeats
MOBITZ TYPE 2
Disease of His-Purkinje conduction system
Intermittently non-conducted P waves not preceded by PR interval lengthening and not following by PR interval shortening
Describe 3rd degree heart blocks
Complete Heart Block
1st rhythm= P waves with regular P to P interval
2nd rhythm= QRS complexes with a regular R to R interval
No apparent relationship between P waves and QRS complexes
What 2 ECG changes are seen in the bundle branch block?
- QRS complex widens (>0.12s) – when the conduction pathway is blocked, it takes longer for the electrical signal to pass throughout the ventricles
- QRS morphology changes – depends on lead, and R vs. L BBB
What abnormalities are seen in right bundle branch block? P wave PR interval QRS in seconds Characteristics
Normally left bundle branch depolarizes normally but right bundle has a conduction block
Wide QRS complex in leads overlying right ventricle
Seen as RSR complex instead of a QRS complex (like rabbit ears)
P WAVE
Before each QRS, identical
PR INTERVAL
0.12-0.20s
QRS
>0.12
CHARACTERISTICS
RSR in V1
What abnormalities are seen in left bundle branch block? P wave PR interval QRS in seconds Characteristics
Right ventricle depolarises first
Wide QRS complex in leads opposite the left ventricle
P WAVE
Before each QRS, identical
PR INTERVAL
0.12-0.20s
QRS
>0.12
CHARACTERISTICS
RR in V5
What abnormalities are seen in ventricular tachycardia (monomorphic)?
Medical emergency -> won’t normally see ECGs of it
Irregular rapid contraction of the ventricles, not as a result of depolarisation through the normal AVN and rapid conduction system
This leads to a broad QRS complex
Unstable rhythm disturbance; often occurs in the middle/just after MI
May lead to cardiac ischaemia
What abnormalities are seen in ventricular fibrillation? Heart rate Rhythm P wave PR interval QRS in seconds
Most commonly identified arrhythmia in cardiac arrest patients
Ventricular muscle twitches randomly rather than in a coordinated fashion
HEART RATE
300-600bpm
Severe darangement (usually-> death within mins)
RHYTHM
Extremely irregular
P WAVE
Absent
PR INTERVAL
N/a
QRS
Fibrillatory baseline
What is the role of circulation?
To transport blood around the body
To deliver oxygen, nutrients and signalling molecules
To remove CO2 and metabolites
To regulate temperature
How is blood flow achieved?
By action of a muscular pump (heart)
Generates a pressure gradient that propels blood through a network of tubes (blood vessels)
What role do the ventricles have in circulation?
Left and right ventricles are 2 pumps
Physically coupled and pump through the systemic and pulmonary circulations
Why isn’t diffusion sufficient for transport?
Only for movement of materials through tissues
Only effective over short distances so a capillary needs to be 10um from every cell
Highly branched structure necessary
What is the structure of the circulation?
Highly specialised
Consists of different vessel types (distinct structures which are highly appropriate for their function)
Large elastic arteries- act as conduits and dampening vessels
Small muscular arteries
Arterioles- have extensive smooth muscle in their walls so they can regulate their diameter and resistance to blood flow
Capillaries- very numerous and have thin walls to facilitate transport and diffusion
Venules
Medium sized and large veins- highly compliant vessels which act as a reservoir for blood volume
What would happen in the CO from both ventricles was different?
Blood would pool
CO from RV and LV needs to be same despite differences in pressue
What is the difference in relative areas and volumes within each circulatory system?
Relatively equal
What are capillaries primarily related to?
Exchange function
What are veins and venules primarily related to?
Reservoir function
What happens to the diameter and cross section of blood vessels from the aorta to the capillaries?
The diameter of the blood vessels changes dramatically from the aorta (25mm in man) to the capillaries (5um = 0.005mm)
As a result of the change in diameter and the expansion of components of the vascular system due to branching there are large changes in the cross-sectional area of the vasculature at different levels
Billions of capillaries and this segments represents the largest cross-sectional are of the circulation
This presents a huge surface area for exchange to take place
Although the volume in a single capillary is tiny, the equivalent of the whole cardiac output passes through the capillary bed every minute
Where is the majority of blood volume contained?
Within the venous part of the circulation
Regulation of capacitance of the veins and venules regulates how much blood is stored and influences venous return to the heart and ventricular work via the F-S effect in the heart
Why does blood flow?
Due to pressure difference
Resistance important
Describe Hales horse experiment
Very simple model of the circulation
Assumes the action of the heart (pump) has established a pressure in the tank (the aorta) equivalent to 8 ft of water (as measured by Hales) – this is P1
This drives a steady flow (Q) through the circulation
The branching vessels of the circulation are simplified into a single long rigid pipe for the purposes of this model
Pressure drops along this pipe due to viscous losses of energy (friction), so that the pressure measured at the end (P2) is lower than at P1 – this pressure difference drives the flow (Q)
At the end of the circulation the system empties into the right atrium
What is Ohm’s law?
Electrical circuit
V= I x R
V= voltage difference I= current flow R= resistance
What is Darcy’s law?
Fluid circuit
P = Q x R
P= pressure change Q= volumetric flow R= resistance
What is the formula for MBP and what causes it?
MBP = CO x PVR
Relationship is an approximation since flow in the circulation is not steady
Due to intermittent pumping of the heart
Blood vessels are not rigid
How can you estimate the resistance of circulation?
Relationship between pressure and flow
Regulation of flow is achieved by variation in resistance while blood pressure remains relatively constant
What vessels are the most resistant to flow?
Small arteries and arterioles
What is Poiseuille’s equation?
R= (8Ln/πr^4)
Poiseuille’s equation emphasizes the importance of arterial diameter as a determinant of resistance
Relatively small changes in vascular tone (vasoconstriction/ vasodilation) can produce marked changes in flow
HALVING THE RADIUS DECREASES THE FLOW 16 TIMES
What 3 variables determine resistance?
Fluid viscosity (n, eta) -> not fixed but in most physiological conditions is constant
Length of tube/vessel (L)- > fixed- lengths of blood vessels remain constant
Inner radius of tube/vessel (r)-> variable- main determinant of resistance
What is the difference in blood flow distribution to organs at rest and during exercise?
During exercise, don’t need blood flow to kidneys
What kinds of flow occur in vessels?
Laminar flow
Viscosity
Shear rate
What is laminar flow?
The normal circulation flow is laminar, i.e. the fluid behaves as if it flows in layers or streamlines
shear
Laminar flow can be demonstrated by injecting a dye into fluid
What is viscosity?
Dynamic viscosity (µ) is a measure of the resistance of a fluid to deform under shear stress
Resistance arises as a result of the resistance due to friction between fluid laminae moving at different velocities
What is shear rate?
Shear rate = S = dv/dr
u= velocity of blood flow
r= radial dimension
A force per unit area (the pressure difference) is needed to move the fluid in opposition to viscosity
The flow velocity on the surface of the vessel wall is zero (so called no slip condition) but in a flowing fluid, the velocity of each lamina increases progressively as you move further way from the wall
The spatial velocity gradient is called the shear rate (s)
What is the shear stress (τ)?
Shear rate x dynamic viscosity
τ = (dv/dr) x µ
µ= dynamic viscosity
What happens to the velocity of layers as distance from the wall increases?
Velocity of layers increases
What does it mean to have ‘high shear stress’?
High shear stress, as found in laminar flow, promotes:
- Endothelial cell survival and quiescence
- Cell alignment in the direction of flow
- Secretion of substances that promote vasodilation and anticoagulation
What does it mean to have ‘low shear stress’?
Low shear stress, or changing shear stress direction as found in turbulent flow, promotes:
- Endothelial proliferation and apoptosis
- Shape change, and secretion of substances that promote vasoconstriction
- Coagulation, and platelet aggregation
What is the formula for pulse pressure?
PP = SBP - DBP
Pulse pressure = systolic bp - diastolic bp
What is the formula for mean blood pressure?
MBP = DBP + 1/3PP
How are systolic and diastolic pressure recorded?
SBP/DBP (e.g. 110/70)
When does the aortic valve open?
During systole
Due to the difference in pressure between the ventricles and the aorta
What causes the difference in ventricular and aortic pressure in diastole?
When the aortic valve closes
Ventricular pressure falls rapidly BUT aortic pressure only falls slowly in diastole
(Due to elasticity of the aorta and large arteries which buffer change in pulse pressure)
How is arterial compliance related to pulse pressure?
During ejection, blood enters the aorta and other elastic arteries faster than it leaves them
~40% of the stroke volume is stored by the elastic arteries
When the aortic valve closes, ejection ceases but due to recoil of the elastic arteries, pressure falls slowly and there is diastolic flow in the downstream circulation
This damping effect is sometimes termed the “Windkessel”
How much of the stroke volume is stored by the elastic arteries?
40%
What is ‘Windkessel’?
The damping effect
Reduced by age and when arteries become stiffer (decreased arterial compliance)
NB. PP increases
What is circumferential stress?
σ = tension force (T) / wall thickness (h)
Tension force (according to Law of Laplace= P x r)
σ = (P x r) / h
What does maintained high circumferential stress cause?
Vessel distension
How do aneurysms occur?
Over a prolonged period, vessel walls can weaken causing a balloon-like distension (aneurysm)
As a result of the Law of Laplace, if an aneurysm forms in a blood vessel wall, the radius of the vessel increases
This means that for the same internal pressure, the inward force exerted by the muscular wall must also increase
However, if the muscle fibres have weakened, the force needed can’t be produced and so the aneurysm will continue to expand
Often until it ruptures
(Same way diverticuli form in the gut)
Define: compliance
The relationship between transmural pressure and vessel volume
Depends of vessel elasticity
What is the difference between the compliance of arteries and veins?
Venous compliance is 10-20x greater than arterial compliance at low pressures
What happens to compliance in veins during smooth muscle contraction?
Increasing smooth muscle contraction decreases venous volume and increases venous pressure (so-> lower compliance)
Most blood volume is stored in the veins
How does standing (gravity) affect circulation?
Venous reservoir not always at the same level as heart (in many bipeds)
Standing increases hydrostatic pressure in leg to ~80mmHg as a result of gravity (h·ρ·g)
Height x density x gravitational force
Blood transiently “pools” in the veins due to their compliance and reduces venous return to the heart (affects transmural pressure)
This would reduce cardiac output and blood pressure if there were no compensatory response
BUT the gradient of pressure from large artery to capillary to vein is maintained so flow still occurs in the same way
Major effect of gravity is on the distensible veins in the leg and the volume of blood contained in them
Why don’t people (generally) faint when they stand?
AUTONOMIC RESPONSES
Activate sympathetic NS to:
- Constrict venous smooth muscle and stiffen veins (myogenic venoconstriction)
- Constrict arteries to increase resistance and maintain bp
- Increase HR and force of contraction (and maintain CO)
MECHANICAL RESPONSES
Muscle and ‘respiratory pumps’ improve venous return
BUT cerebral blood flow falls on standing
What happens if muscle and respiratory ‘pumps’ fail (in compliance)?
Incompetent valves cause dilated superficial veins in the leg (varicose)
Prolonged elevation of venous pressure-> oedema in feet
Outline the types of blood vessel and their main function
Arteries- thick muscular walls-> stabilise pulsatile flow
Capillaries– very thin walls-> facilitate gas and solute exchange
Veins– one-way valves-> maintain unidirectional flow
What is the vascular endothelium and what are its functions?
Single cell layer that acts as the blood-vessel interface
Endocrine organ
Different roles including:
- Vascular tone management (secretes and metabolises vasoactive substances)
- Thrombostasis (prevents clots/adhering molecules)
- Absorption and secretion (passive/active transport via diffusion/channels)
- Barrier (prevents atheroma development)
- Growth (mediates cell proliferation)
VTABG (vascular topics are bloody grim)
List vascular endothelium mediators
Nitric oxide (NO) Prostacycline (PGI2) Thromboxane (TXA2) Endothelin-1 (ET-1) Angiotensin II (Ang II)
What are the effects of NO on smooth muscle, myocytes and platelets?
SMOOTH MUSCLE
Relaxation and inhibition of growth
MYOCYTES
Increased blood flow
Enhanced contractility
PLATELETS
Inhibits aggregation
What are the effects of PGI2 on smooth muscle, myocytes and platelets?
SMOOTH MUSCLE
Relaxation and inhibition of growth
MYOCYTES
Increased blood flow
PLATELETS
Inhibits aggregation
What are the effects of TXA2 on smooth muscle, myocytes and platelets?
SMOOTH MUSCLE
Contraction
MYOCYTES
Decreased blood flow
PLATELETS
Stimulates aggregation
What are the effects of ET-1 on smooth muscle, myocytes and platelets?
SMOOTH MUSCLE
Contraction
Weak stimulation of growth
MYOCYTES
Decreased blood flow
Enhanced contractility
PLATELETS
No effect
What are the effects of Ang II on smooth muscle, myocytes and platelets?
SMOOTH MUSCLE
Contraction
Stimulation of growth
MYOCYTES
Decreased blood flow, remodelling and fibrosis
PLATELETS
No effect
What effect do mediators have on vascular tone?
Vasodilation= NO, ET-1, PGI2 Vasoconstriction= TXA2, ET-1, ANGII
Imbalance of mediators-> either vasodilation or vasoconstriction
What is the half life of NO?
Short
How is NO released?
Release is induced by physical force, as well as by acetylcholine or hormones
Precursor is L-arginine, which is cleaved by e-NOS (NO synthase enzyme present in all endothelial cells, whose function is Ca2+ dependent)
ACh binding on endothelial receptors activates the phospholipase C 2nd messenger pathway-> increase in Ca2+ which activates the e-NOS enzyme
The NO then migrates to target (smooth muscle), where is converted to cyclic-GMP by soluble guanylyl cyclase (s-GC)
The cyclic-GMP activates PKG, which causes vasodilation and a decrease in Ca2+
The c-GMP has a short half life, as it is rapidly broken down by phosphoesterases
This is known as flow-induced vasodilation and is a response to increased sheer stress in blood vessels
What is flow-induced vasodilation important in?
Thermoregulation
Penile erection
(NO)
How can endothelium-dependent vasodilatation be measured?
Laser doppler flowmetry (looks at ACh delivery)
Flow-mediated dilatation (with US)
How are prostacyclin and thromboxane released?
Precursor is arachidonic acid
Converted under the influence of cyclo-oxygenase (COX)
2 isoforms of COX:
COX1= healthy CVS
COX2= active in unhealthy CVS
COX1 and 2 act on the arachnidonic acid-> convert to PGC2 and then PGH2
PROSTACYCLIN
Prostacyclin synthase acts on PGH2 to synthesise prostaglandins
Prostacylin acts on IP receptors-> vasodilation and inhibition of platelets (can reduce atherosclerosis)
THROMBOXANE
Thromboxane synthase acts of PGH2 to synthesise thromboxane
TXA2 also converted to TXB2
Thromboxane acts on TP receptors -> vasoconstriction and stimulation of platelets (increases atherosclerosis)
How are ET-1 released?
Derived from nucleus of endothelial cell
At times of pathophysiological insult, transcription of the prepro-ET1 mRNA occurs, which is then translated to form the precursor prepro-ET1
Prepro-ET1 is then converted to pro-ET1, which is then finally converted to ET-1 by ECE-1 (endothelin converting enzyme 1)
What controls transcription of ET-1?
INHIBITION
Prostacyclin
Nitric oxide
ANP, Heparin, HGF & EGF
STIMULATION Adrenaline Ang II Vasopressin Steroids IL-1, TGF-β, Endotoxin, endothelin, VECF, tacrolimus, CsA
Where are ET-1 receptors?
ON SMOOTH MUSCLE CELLS
ETA – leads to contraction of the smooth muscle
ETB – leads to contraction of the smooth muscle
ON ENDOTHELIAL CELLS
ETB – binding causes NO to be produced, which then in turn acts on the smooth muscle cells with a vasodilatory effect
Inhibiting ET-1 pathway produces vasodilation (can have therapeutic potential)
What is the structure of ET-1?
Endothelin-1 is a very potent vasoconstrictor
It has a polypeptide chain consisting of 21 amino acids
Specific conformation due to the bods between cysteine molecules
Outline the renin-angiotensin-aldosterone system
Angiotensinogen with renin-> angiotensin I
Angiotensin I with ACE-> angiotensin II
What is renin?
An enzyme from the kidneys produced in response to decreased blood pressure
Converts angiotensinogen (from the liver)-> angiotensin I
Released due to:
- A decrease in the renal perfusion pressure
- A decrease of blood pressure in the pre-glomerular vessels
- A decrease in arterial blood pressure
- Haemorrhage, salt and water loss, hypotension (low blood pressure)
- A change in Cl- (or Na+) ion concentration
- β1-receptor activation in the kidney (sympathetic nervous system)
- NaCl reabsorption at macula densa (a group of cells in the glomerulus)
What is ACE?
Angiotensin converting enzyme
Converts angiotensin I-> II
Simultaneously degrades bradykinin on epithelial cells (acts on beta-1 receptors to release vasodilators)
What does Angiotensin II lead to (regarding BP)?
TO INCREASE WATER RETENTION
ADH secretion
Aldosterone secretion
Tubular sodium reabsorption
TO INCREASE VASCULAR RESISTANCE
Arteriolar vasoconstriction (enhanced peripheral resistance)
Sympathoexcitation
Increased water retention and increased vascular resistance-> increased blood pressure
As well increasing blood pressure, what are the additional effects of the RAAS system?
OXIDATIVE STRESS
NAD(P)H oxidase activity
Reactive oxygen species
LDL peroxidation
INFLAMMATION
Vascular permeability
Activation of signalling pathways
Inflammatory mediators
REMODELLING
Matrix deposition
VSMC proliferation
MMP activation
ENDOTHELIAL DYSFUNCTION
Platelet aggregation
Vasoconstriction
How can NO bioavailability be increased?
Stimulate NO production-> endothelium-dependent-> acetylcholine
Enhance the effects of NO-> prevents counterproductive processes-> viagra
‘Donate’ ready-to-use NO-> endothelium independent-> GTN, nicorandil, ISMN
List types and examples of drugs involved in NO pharmacology
NO- donors e.g. nitroglycerine, nitroprusside
E-NOS activators e.g. endothelium-dependent vasodilators
Phosphodiesterase inhibitors e.g. Viagra, zaprinast
How do NO donors work?
Nitrovasodilators donate NO
Increase NO concentration in smooth muscles cells (where it is converted to cyclic-GMP by soluble guanylyl cyclase s-GC)
cGMP activates pKG-> vasodilation and decreased calcium concentration
How does viagra work?
Phosphodiesterase inhibitor
Stops phosphodiesterase breaking down cGMP so excess cGMP activity-> vasodilation
How does aspirin work?
Works by balancing the effects of thromboxane and prostacyclin
Effects of 75mg of aspirin over 7 days:
- > Prostacyclin production reduction of 10% each day
- > Reduction of thromboxane production 10% more each day (i.e. -10%, -20%, -30% etc)
Aspirin causes irreversible inhibition of COX enzymes
COX-1
Aspirin acetylation inactivates enzyme
COX-2
Aspirin acetylation switches its function (to generating protective lipids)
What is the difference in COX inhibition between aspirin and other NSAIDs?
Aspirin causes irreversible inhibition of COX enzymes
Other non-specific NSAIDs cause reversible inhibition
COX-2-specific inhibitors cause reversible inhibition of COX-2 isoforms only
What are calcium channel blockers?
Drugs that do not act by modifying endogenous receptors or enzymes, but increase or decrease IC Ca by affecting the entry of Ca into the cell
Vasodilation-> reduced afterload and increased Q
Negative ionotropic effects
Prevent coronary artery vasospasm which makes them very useful in the treatment of variant angina
What are voltage-gated calcium channels and why is calcium important?
Mediate calcium influx in response to membrane depolarisation
Calcium acts as an intracellular ‘second messenger’ in transduction pathways
Regulate intracellular processes such as:
- Actin-myosin interaction
- Membrane transport
- Neurotransmission
- Gene expression
Activity is essential to couple electrical signals in the cell surface to physiological events in cells
How do calcium channel blockers know which channel to block?
Their affinity for channel is related to the membrane potential of the target cells
What happens to smooth muscle cells and cardiac myocytes (response, resting Em, -ve potentials) when calcium channels are blocked?
SMOOTH MUSCLE CELL
Response= vasodilation
Resting Em= -50mV
-ve potentials= higher
CARDIAC MYOCYTE
Response= negative inotrope
Resting Em= -80mV
-ve potentials= lower
What are dihydropyridine calcium channel blockers used for?
Often used to reduce systemic blood pressure,
NOT to treat angina because the vasodilation and hypotension can lead to reflex tachycardia
What are the side effects of vasoactive mediation?
Our body often uses the same chemical to regulate multiple processes
Interaction between different systems in the body
Unfortunately, drugs are not always tissue-specific
Receptor expression and distribution varies between tissues
What is the autonomic nervous system comprised of?
Parasympathetic and sympathetic nervous systems
Sympathetic NS is organized around the thoracic and lumbar SC
No sympathetic innervation in the bronchi but practically everywhere else
Outline autonomic cardiovascular control
Hypothalamic autonomic centre receives input from:
- Cardiac baroreceptors
- Arterial baroreceptors
- Carotid sinus baroreceptors
- Aorta baroreceptors
- > Brainstem solitary tract nucleus
- Vagus nerve
- Sympathetic outflow
Outputs->
- Sinus node
- B2 receptor (via vagus nerve)
- a1 receptors (end of pre-ganglionic neurone)
- a2 receptors (in arterioles)
How do baroreceptor responses influence blood pressure?
Baroreceptors in carotid sinus and aortic arch are sensitive to stretch
Increased stretch-> increased frequency of impulses to hypothalamic autonomic centre
Increased frequency of impulses-> reduced inhibition of sympathetic activity from solitary tract nucleus-> increased vasoconstriction-> increased BP
What is the sympathetic outflow of effector nerves?
Paravertebral sympathetic chain ganglion – neurotransmitter is acetylcholine therefore is a cholinergic receptor
Post-ganglionic fibre contains lots of noradrenaline vesicles which are released on depolarisation, binding to the adrenergic receptor on the effect organ
The NA is then either taken up by the neurone and repackaged, or taken up by the effector organ and broken down by COMT
What is the parasympathetic outflow of effector nerves?
Parasympathetic ganglia are in or near effector organ, and involve acetylcholine
Effector organ also has cholinergic receptor, which binds to the acetylcholine released by the postganglionic neurone
This acetylcholine is then recycled
Explain the synthesis, release and removal of noradrenaline
Noradrenaline and adrenaline are synthesised in the terminal variscosity (fusion, exocytosis, biosynthesis replenishes granular criteria)
Tyrosine into variscosity
Tyrosine-> DOPA-> dopamine
Dopamine into vesicle
Dopamine-> NA
How are catecholamines removed from the neuro-effector junctional synapse?
NA and A removed via uptake systems
Neuronal reuptake and recycling, or degradation into deaminated metabolites by MAO
Extraneuronal uptake into effector organ and degradation by COMT or MAO
What types of adrenoceptors are there in the sympathetic nervous system?
EXCITATORY EFFECTS ON SMOOTH MUSCLE
a-adrenoceptor-mediated
-> Increase in IC Ca
RELAXANT EFFECTS ON SMOOTH MUSCLE AND STIMULATORY ON THE HEART
b-adrenoceptor-mediated
-> Increased cAMP-> increased Ca in heart but decreased Ca in smooth muscle
Where are beta-adrenoceptors located?
b1-adrenoceptors located on:
- Cardiac muscle
- Smooth muscle of the gastrointestinal tract
b2-adrenoceptors located on:
- Bronchial, vascular and uterine smooth muscle
Recent addition to classification:
b3-adrenoceptors: found on fat cells (adipocytes) and possibly on smooth muscle of GI tract
Involved in thermogenesis but few B3Rs in humans so unlikely to be that useful in ‘slimming-solver’
Where are alpha-adrenoceptors located?
a1-adrenoceptors:
Located post-synaptically i.e. predominantly on effector cells
Important in mediating constriction of resistance vessels in response to sympathomimetic amines
a2 -adrenoceptors:
Located on presynaptic nerve terminal membrane
Their activation by released transmitter causes negative feedback inhibition of further transmitter release
Some are post-synaptic on vascular smooth muscle
What are adrenoceptors coupled to?
a1 with GPCR which activates the PLC pathway-> increased free calcium and activated protein kinases (IP3/DAG)
a2 and b with GPCR which activates adenylyl cyclase (ATP-> cAMP-> decreased IC Ca)
Which catecholamines act on which adrenoceptors?
NATURAL
Noradrenaline- a1, a2, b1
Adrenaline- a1, a2, b1, b2
Dopamine- weak effects at a1 and b1 (has own Rs)
SYNTHESIC
Isoprenaline- b1, b2 (unselective beta agonist)
Phenylephrine- a1
What do noradrenaline, adrenaline and isoprenaline do to SBP, DBP, MBP and heart rate?
NORADRENALINE SBP= !!! increase DBP= !! increase MBP= !! increase Heart rate= ! decrease
ADRENALINE SBP= !! increase DBP= ! decrease MBP= ! increase Heart rate= ! increase
ISOPRENALINE SBP= ! increase DBP= !! decrease MBP= ! decrease or same Heart rate= !! increase
(!’s to show relative strength)
What effect does adrenaline have on TPR?
Adrenaline tends to reduce TPR
What effect do noradrenaline, adrenaline and isoprenaline have on major vascular bed (skin, visceral, renal, coronary, skeletal)?
SKIN (a Rs)
NA= constriction
A= constriction
ISO= no effect
VISCERAL (a Rs)
NA= constriction
A= constriction
ISO= no effect (slight dilation)
RENAL (a and b Rs)
NA= constriction
A= constriction
ISO= no effect (slight dilation)
CORONARY (a and b1 Rs)
NA= dilation
A= dilation
ISO= dilation
SKELETAL MUSCLE (a and b2 Rs) NA= constriction A= dilation ISO= dilation
What enzymes are involved in angiotensinogen-> angiotensin I-> angiotensin II (-> angiotensin III)?
Renin
ACE
Aminopeptidase
What are angiotensin II type 1 (AT1) receptors ?
Angiotensin II Type 1 (AT1) receptors
G-protein coupled; Gi and Gq
Also couples to phospholipase A2
Located in blood vessels, brain, adrenal, kidney and heart
Activation of AT1 Rs works to increase bp
Ucosuric effect (not all)
No effects of Bradykinin system
What are the effects of angiotensin II?
Peripheral resistance (-> rapid pressor response) Renal function (-> slow pressor response) Cardiovascular structure (-> vascular and cardiac hypertrophy and remodelling)
How does angiotensin II affect peripheral resistance?
Direct vasoconstriction
There is enhanced action of peripheral noradrenaline
- > Increased norandrenaline release
- > Decreased noradrenaline uptake
Increased sympathetic discharge (CNS)
Release of catecholamines from the adrenal glands.
These all act to produce a rapid pressor response
How does angiotensin II affect renal clearance?
Direct effects to increase Na+ reabsorption in the proximal tubule
Synthesis and release of aldosterone from the adrenal cortex
Altered renal haemodynamics
- > Renal vasoconstriction
- > Enhanced noradrenaline effects on the kid
These all act to produce a slow pressor response
How does angiotensin II affect cardiovascular structure?
HAEMODYNAMIC EFFECTS
Increased preload and afterload
Increased vascular wall tension
NON-HAEMODYNAMIC EFFECTS
Increased expression of proto-oncogenes
Increased production of growth factors
Increased synthesis of extracellular matrix proteins
These all act to induce vascular and cardiac hypertrophy and remodelling
What is ACE an enzyme for?
In RAAS= angiotensin I to II (so increased BP)
Breaking down of bradykinin-> inactive so vasodilation can;t happen so BP not decreased
What happens in ACE is inhibited?
Prevents angiotensin II production-> reduces BP
Stops bradykinin from breaking down so bradykinin-> vasodilation-> decreased BP
What does aldosterone do?
PHYSIOLOGICAL EFFECTS
Maintains body content of Na+, K+ (and water)
Increases Na+ (and hence water) retention
Increases K+ (and H+) excretion
Where are aldosterone receptors found?
Previously only knew kidneys, now know brain, heart, vessels
What are the pathophysiological effects in CVD?
Myocardial fibrosis and necrosis
Inflammation, vascular fibrosis and injury
Prothrombotic effects – impaired fibrinolysis
Central hypertensive effects
Endothelial dysfunction
Autonomic dysfunction:
- Catecholamine potentiation
- Decreased heart rate variability
Ventricular arrhythmias
Sodium retention
Potassium and magnesium loss
How do the sympathetic nervous system and renin-angiotensin system modulate the behaviour of the CV system in stress?
Sympathoadrenal systemrenin-angiotensin system
On both the sympathoadrenal system, and the renin-angiotensin system: Increased blood pressure Increased heart rate Increased Na+/water retention Increased coagulation Decreased fibrinolysis Increased platelet activation
What is resistance?
Hindrance to blood flow due to friction between moving and stationary vascular walls
What is blood flow rate?
Volume of blood passing through a vessel per unit time
What types of vessels make up the branching structure of the microvasculature?
1st order arterioles
Terminal arterioles (perpendicular to arterioles and venules)
Capillaries (network between arterioles and veins)
Pericytic venule (post-capillary, perpendicular to venules and arterioles)
Venules
What are arterioles and why is their pressure important?
The major resistance vessels
Pressure= 93mmHg (much higher than in capillaries e.g. 37mmHg)
Without this pressure difference, blood would not reach tissue capillary beds
Arteriolar SM normally displays a state of partial constriction at rest
-> Vascular tone
What functions are radii of arterioles adjusted independently to accomplish?
Match blood flow to the metabolical needs of specific tissues= INTRINSIC
(Chemical e.g. metabolic and physical e.g. stretch)
Help regulate arterial blood pressure= EXTRINSIC
(Neural e.g. symp. output and hormonal e.g. adrenaline, ATII, AVP)
How do arterioles match blood flow to the metabolical needs of specific tissues?
Arteriole radii adjustments depending on body’s momentary needs
Regulated by local (intrinsic) controls (independent of nerves or hormones)
CHEMICAL
Active hyperemia e.g. skeletal muscle in initial exercise
Increased metabolism-> increased oxygen usage and glucose requirement
Sensed by tissue-> reflex vasodilation of arterioles
PHYSICAL
E.g. reduced blood temp on superficial structures e.g. skin
Sensed locally
Rebound vasoconstriction-> divert blood from the tissue-> decrease blood flow
PHYSICAL
E.g. stretch
Autoregulatory response to physical stretch of arterioles
Myogenic vasoconstriction occurs (e.g. gut during exercise)-> increased vascular resistance hence reducing blood flow
How do arterioles help regulate arterial blood pressure?
Controlling resistance in all tissues-> can control the MAP (MAP=CO x TRP)
NEURAL
Cardiovascular control centre (CCC) in medulla-> sends vasoconstriction signal which decreases flood flow to all organs
Can be used after significant blood loss-> preserves MAP but not good long term (-> dysfunction and infarction)
a receptors within periphery and B receptors in heart respond to this neural signal
(B receptors especially important as they can result in an increase in HR)
HORMONAL
Vasoconstrictors
- Vasopressin- posterior pituitary gland
- Angiotensin II- lungs
Hormones which act on a and B receptors to increase sympathetic activity
- Adrenaline and noradrenaline
How is the design of capillaries useful for its function?
Single cell wall (1 micrometer diameter)
Diameter of lumen (7 micrometers)
Extensive branching increases surface area
->
Minimise diffusion distance and time
Maximise surface area
What does the capillary network depend on?
Highly metabolically active tissues – denser capillary networks
E.g. skeletal muscle, myocardium, brain, lung
However not all capillaries dilated at once, e.g. at rest only 10% of capillaries are dilated in skeletal muscle
What are the possible structure types of capillaries?
Continuous
Fenestrated
Discontinuous
How are continuous capillaries arranged?
Most common – continuous flattened endothelial cells with water-filled gap junctions
As blood flows through the capillary:
- Nutrients diffuse across junctions
- Lipo molecules diffuse across cells
- Transport proteins present to transport larger molecules into tissues
E.g. BLOOD BRAIN BARRIER: modified continuous capillary of the brain
- Very tight gap junctions reduce capacity for a large number of small molecules diffusing into the brain tissue
- More selective control of transport than tissues
How are fenestrated capillaries arranged?
Circular fenestrae (circular holes approx. 80 nm large) allow slightly larger molecules to leave the blood and enter the tissues
E.g. GLOMERULUS kidney nephron
How are discontinuous capillaries arranged?
Very large gap junctions, therefore large molecules i.e. WBCs can leave blood and enter tissues (and vice versa)
E.g. BONE MARROW
What are Starling’s forces?
Hydrostatic pressure (heart, outward flow into surrounding tissues)
Oncotic pressure (protein, inward into capillaries)-> generates osmotic force
What is bulk flow?
Volume of protein free plasma that filters out of the capillary, mixes with the surrounding interstitial fluid (IF) and is reabsorbed
Affected by HP and COP
Describe Starling’s hypothesis
Needs to be a balance between the hydrostatic pressure of the blood in the capillaries and the oncotic attraction of the blood for the surrounding fluids
HP pressure determines transudation
COP determines absorption
Oncotic pressure remains relatively constant but there are changes in the hydrostatic pressure
What happens when there are changes in the hydrostatic pressure?
Hydrostatic pressure at venous end of capillary is in the IF, there is a net loss of fluid into the surrounding tissues (Hydrostatic pressure > Oncotic pressure)
VENOUS END
Reabsorption- when the oncotic pressure > hydrostatic pressure, there is a net reabsorption of fluid back into the capillary
There is a net loss of fluid from the capillaries, as the oncotic pressure is never great enough to reabsorb all the fluid lost by ultrafiltration
Therefore a mechanism is required for the return of this loss of fluid to the capillaries – this is the role of the lymphatic system
What is the role of the lymphatic system?
To return the loss of fluid to the capillaries
Loss of fluid as the oncotic pressure is never enough to reabsorb all the fluid lost by ultrafiltration
Describe the structure and function of lymphatic capillaries
Permeate every tissue
Blind ended
Large, permeable water filled channels surrounded by a single layer of endothelial cells
Blind ended means they can’t form complete loop so fluid which enters can’t leave
Excess fluid in capillaries is drained back into blood
What is the purpose of lymph nodes?
Important for immune surveillance (defence mechanism)
Filled with immune cells (excess fluid passes through the lymph nodes before draining into the blood)
Spleen organ acts as giant lymph node
Where does the lymph flow drain?
No heart to induce flow
R lymphatic duct, thoracic duct
R and L subclavian veins
How much is returned per day from the lymphatic system into the blood?
3L/day returned from lymphatic system into blood
What happens in the lymphatic system fails?
Lymphatic failure-> fluid accumulation-> oedema
What does vein constriction determine?
Compliance
Venous return
What does arteriole constriction determine?
Blood flow to organs they serve
MABP
Pattern of distribution of blood to organs
Define: autoregulation (regarding blood flow)
The intrinsic capacity to compensate for changes in perfusion pressure by changing vascular resistance
What are the 3 main reasons for autoregulation?
Myogenic theory
Metabolic theory
Injury (serotonin release from platelets-> constriction)
What is myogenic theory?
Smooth muscle fibres respond to tension in the vessel wall
E.g. as pressure rises, muscle fibres contract and stretch-sensitive channels are involved
What is metabolic theory?
As blood flow decreases, ‘metabolites’ accumulate and vessels dilate
When flow increases, ‘metabolites’ are washed away
E.g. CO2, H, adenosine, K
What substances are released from the endothelium?
Nitric oxide (endothelium-derived relaxing factor, synthesised from arginine, plays key role in vasodilation)
Prostacyclin and thromboxane A2 (vasodilator and vasoconstrictor, relative amounts important for clotting)
Endothelins (potent vasocontrictors)
What extrinsic circulating hormones are involved in systemic regulation of blood flow by hormones?
KININS (e.g. bradykinin)
Complex interaction with RAAS
Relax vascular smooth muscle
ANP (atrial natriuretic peptide)
Secreted from the cardiac atria
Visodilatory
CIRCULATING VASOCONSTRICTORS
ADH (VP) secreted from posterior pituitary
NA released from adrenal medulla
Angiotensin II formed by increased renin secretion from kidney
How does the autonomic nervous system controls blood vessel diameter and heart rate?
SYMPATHETIC
The sympathetic nervous system is important in controlling the circulation (innervate all vessels except capillaries, precapillary sphincters and some metarterioles)
- Noradrenaline and adrenaline
- Fibres originate in thoracic and lumbar nerves
- Short pre-ganglionic fibres with long post-ganglionic fibres that release noradrenaline
PARASYMPATHETIC
Parasympathetic NS is important in regulating HR, but has no effect on vessel radius
- Fibres originate in cranial and sacral nerves
- Long pre-ganglionic fibres with short post-ganglionic fibres that release acetylcholine
At all pre-ganglionic fibres, acetylcholine is released
Describe the distribution of sympathetic fibres
More innervating the vessels supplying kidneys, gut, spleen and skin
Fewer innervating skeletal muscle and the brain
What is the vasomotor centre (VMC) in the brain?
VMC is located bilaterally in the reticular substance of the medulla and the lower third of the pons
Composed of a vasoconstrictor (pressor) area, a vasodilator (depressor) area and a cardio-regulatory inhibitory area
VMC transmits impulses distally through SC to almost all blood vessels
Many higher centres of the brain such as the hypothalamus can exert powerful excitatory or inhibitory effects on the VMC
Lateral portions of VMC controls heart activity by influencing HR and contractility
Medial portion of VMC transmits signals via vagus nerve to heart that tend to decrease HR
How is blood vessel diameter controlled by nervous system?
Blood vessels receive sympathetic post-ganglionic innervation
NT= noradrenaline
Always some level of tonic activity
Control of nerve activity can accomplish dilation or constriction
Generally no parasympathetic innervation to vascular system
What contributes to vessel radius?
Sympathetic vasoconstrictor nerves
Local controls- O2, K+, CO2, H+, osmolarity, metabolites
Circulating hormones e.g. NA
What autonomic features increase HR?
Increasing activity of sympathetic nerves to heart
Decreasing activity of parasympathetic nerves to heart
Increasing plasma adrenaline
How does contractility rely on extrinsic mechanisms?
Noradrenaline binds to the beta1- adrenoreceptor present on the membrane of myocytes
Binding causes the increase in cyclic AMP which activates PKA (protein kinase A)
This activation leads to the phosphorylation of Ca2+ handling proteins and channels, e.g. the L type Ca channel
The channel is then open for longer, which leads to a greater delivery of Ca2+ to myofilaments, increasing force of contraction
How is stroke volume controlled?
EXTRINSIC (to increase SV)
Increase activity of sympathetic nerves to heart
Increase plasma adrenaline
INTRINSIC (to increase SV)
Increased end diastolic ventricular volume (due to Starling’s law- increased venous return-> increased stretch and preload-> increased force)
What increases end diastolic volume?
Increased respiratory movements-> decrease in intrathoracic pressure
Increased venous return
Increased atrial pressure (also increased by increased venous return)
What increases heart rate?
Increased plasma adrenaline
Increased activity of sympathetic nerves to the heart
Decreased activity of parasympathetic nerves to the heart
What does the fight or flight response affect?
Leads to:
Increased circulating catecholamines (plasma adrenaline)
-> affects SV and HR-> affects CO
Increased respiratory movements -> affects SV-> affects CO
Increased sympathetic activity
-> affects SV and HR-> affects CO
How does feedback work with a controlled variable?
Set point (determined within CNS)
Comparator (within CNS)
Output (SNS, PNS, Ang II, ADH)
Controlled variable (arterial bp)
DISTURBANCE-> affects controlled variable
Sensory (baroreceptors)
Back to comparator
What are baroreceptors?
Afferent neurone cell bodies from the internal carotid arteries to the brain via the glossopharyngeal
Afferent neurone cell bodies from aortic arch to brain via vagus nerve
Both the glossopharyngeal and vagus nerve input lead to increased activity in the VMC
Increased blood pressure -> increased afferent activity to brain (although increase is sigmoidal)
Baroreceptors respond to changes in arterial pressure
Where are baroreceptors reflexes more sensitive?
Baroreceptors reflex most sensitive around 90 – 100 mmHg
Carotid sinus baroreceptors respond to pressures between 60 and 180 mmHg
Describe how reciprocal innervation allows control of the heart?
PARASYMPATHETIC
Afferent input stimulates parasympathetic nerves to heart
Increased parasympathetic stimulation of the heart decreases HR
SYMPATHETIC
Simultaneously inhibits sympathetic innervation to heart, arterioles and veins
Decreased sympathetic stimulation of the heart decreases HR and SV
Decreased sympathetic stimulation to blood vessels -> vasodilation
How do baroreceptors control blood pressure?
Increased afferent input via vagus nerve to VMC in medulla oblongata
- > Increased parasympathetic stimulation of the heart via vagus nerve
- > Decreased heart rate
- > Decreased blood pressure
- > Decreased sympathetic stimulation of the heart
- > Decreased heart rate and stroke volume
- > Decreased cardiac output
- > Decreased blood pressure
Also via sympathetic chain, there is decreased sympathetic stimulation to the blood vessels, which produces vasodilation (may cause blood supply redistribution to different organs)
Opposite if blood pressure faths
How does impulse activity change in the carotid sinus nerve when BP in increased or decreased?
Decreased blood pressure
- > Reduced stretch of baroreceptors
- > Decreased afferent activity to VMC via carotid sinus nerve
- > Decreased efferent activity via vagus nerve to SAN (parasympathetic)
- > Increased heart rate
- > Increased sympathetic activity via cardiac nerve to ventricle
- > Increased heart rate and increased contractility
- > Increased sympathetic activity via vasoconstrictor nerves to resistance vessels (arterioles) and capacitance vessels (veins)
- > Increased constriction
Increased blood pressure (reverse occurs)
Sympathetic vasoconstrictor nerves allow the control of venous return
What baroreceptor response is triggered by a haemorrhage?
Reduced blood volume
- > Reduced venous pressure and return to heart
- > Reduced atrial pressure
- > Reduced end diastolic volume
- > Reduced stroke volume and cardiac output
- > Decreased blood pressure
Describe arterial and venous pressures (heart, head and feet) when lying flat and when standing
LYING FLAT
Arterial heart= 100
Arterial head= 95
Arterial feet= 95
Venous heart= 1
Venous head= 5
Venous feet= 5
STANDING
Arterial heart= 100
Arterial head= 55
Arterial feet= 195
Venous heart= 1
Venous head= -35
Venous feet= 105
All pressures (mmHg)
With vertical posture, how is pressure in the body affected?
Below heart, working against gravity
In a foot capillary, usual bp= resulting from cardiac contraction= 25mmHg
On standing, additional effect of gravity on a column of blood-> increase to 105mmHg
Standing also increases hydrostatic pressure in blood vessels in the legs
(Particularly extensive in venous system-> blood pools in veins which are easily distended due to expandable thin muscular wall)
If hydrostatic pressure > oncotic pressure
- > Fluid forced into surrounding tissue beds
- > Reduces effective circulating blood volume
- > Decreased bp
More blood in veins= less in arteries= lower blood pressure
End result= reduced venous return-> decreased end-diastrolic volume
-> Decreased stroke volume
Transient hypotension
What compensatory mechanisms are present when standing?
Decrease in blood pressure is detected by arterial baroreceptors in the carotid sinus and aortic arch -> decreased firing to VMC
Max baroreceptor sensitivity occurs near normal mean arterial blood pressure
Effects of decreased blood pressure -> reduced afferent input via vagus nerve to VMC in medulla oblongata
Reduced parasympathetic stimulation of the heart via vagus nerve
Reduced inhibition of sympathetic stimulation of the heart
Increased heart rate and stroke volume
- > Increased cardiac output
- > Increased blood pressure
Also via sympathetic chain, there is reduced inhibition of sympathetic stimulation to the blood vessels, which produce vasoconstriction (redistribution of blood supply to the different organs)
How does a haemorrhage lead to cardiovascular problems?
Reduced actual circulating blood volume
Reduced baroreceptor firing
-> Increased HR
-> Increased heart contractility (helps to maintain CO)
-> Increased TPR (via organ specific vasoconstriction)
Same as with change of posture
Additional mechanisms:
- Autotransfusion
- Decreased urinary output
Why is autotransfusion used after a haemorrhage?
Reduces the hydrostatic pressure, while oncotic pressure remains same:
- > Reduced ultrafiltration from blood
- > Increased reabsorption of fluid from interstitial fluid
This bulks up blood volume using extracellular fluid and no erythrocytes
Why is urinary output decreased after a haemorrhage?
ADH/VP release from pituitary -> water retention in collecting duct
Angiotensin II synthesis -> decreased renal blood flow
Aldosterone production -> increased Na+ and therefore water retention
What volumes of haemorrhage affect blood pressure and how are they treated ?
constant BP (compensation via bp variation)
20-30% (1-1.5l)-> decreased BP (hypotension with maintained tissue perfusion)
30-40% (1.5-2l)- shock (tissue perfusion not maintained)
Tissue resuscitation can be used initially as treatment but then a blood transfusion should be performed
Major problem= increased blood flow and decreased TPR (BP=CO X TPR)
How is exercise associated with cardiovascular problems?
Significantly increased blood flow is required to certain tissues (heart, lungs and skeletal muscle), but TPR decreases, which may reduce mean arterial blood pressure (MABP = CO x TPR)
Exercise increases blood flow, metabolism and oxygen usage within tissues, leading to vasodilation -> active hyperaemia
COMPENSATION
CO increases because of increased HR, contractility and venous return
TPR decreases because of increased vasodilation
CO increase > TPR decrease so overall bp increases
What control mechanisms are used when exercising?
Afferent input to medullary CV centre
- Preprogrammed pattern
- Muscle chemoreceptors
Efferent output to heart, veins and arterioles
- Via ANS
How does control of TPR contribute to compensation when exercising?
Increases sympathetic activity in GI tract and kidney -> profound vasoconstriction
Decreased sympathetic activity in heart, lungs, skeletal muscle and skin -> vasodilation
Net result:
- Reduced TPR
- Increased CO
- Increased blood flow to muscles, heart, lungs
- Reduced blood flow to GI tract and kidneys
How does control of CO contribute to compensation when exercising?
Reduced parasympathetic activity and increased sympathetic activity -> increased SV and increased HR
If stroke volume increases, venous return must increase
Due to increased force of contraction by skeletal muscle pump, and increased breathing (which reduces pressure in thoracic cavity)
There are also negative effect:
- Reduced plasma volume opposes increased venous return
- There is increased capillary pressure across muscle walls
- Loss of salt and water due to sweat
Net result:
- Increased heart rate
- Increased contractility
- Increased venous return ->increased SV
- Increased cardiac output
What is the purpose of haemostasis?
Prevention of blood loos for intact vessels
Arrest of bleeding from injured vessels
Outline haemostatic plug formation
Response to injury-> vessel constriction
Formation of an unstable platelet plug
- Platelet adhesion
- Platelet aggregation
(Disease= primary haemostasis)
Stabilisation of the plug with fibrin
- Blood coagulation
(Disease= secondary haemostasis)
What do vessels do in response to injury?
Constrict= local contractile response
Vascular smooth muscle cells contract locally-> limits blood flow to the injured vessels
Particularly important in small blood vessels
What does a normal cell wall consist of?
Layers of endothelial cell
- Anticoagulant barrier
- Consists of anticoagulant proteins (GAGs, TFPI, TM, EPCR)
Subendothelium
- Procoagulant
- Consists of elastin, collagen VSMC (tissue factor, vascular smooth muscle cells), fibroblasts (tissue factor)
Other
- Platelets
- Clotting factors
- Plasma proteins
AFTER INJURY (few secs)-> minimise blood loss via local constriction
What anticoagulant proteins are present in the endothelial cells?
GAGs – glycosaminoglycan
TFPI - tissue factor pathway inhibitor
TM – thrombomodulin
EPCR - endothelial protein C receptor
What are platelets?
Circulate in blood
Derived from megakaryocytes in the bone marrow
Each megakaryocyte produces a large number of platelets
Have a granulated cytoplasm, and are highly specialised anuclear plasma cells
Many different ultrastructural features
Can become activated in a number of ways, including:
- When coagulation process takes place, thrombin important
- Thrombin cleaves R and further activates platelet
Platelet releases ADP and thromboxane
What happens during formation of unstable platelet plug?
Unstable platelet plug formed
- PLATELET ADHESION
Recruitment of platelets from flowing blood to site of injury - PLATELET ACTIVATION
Conversion from a passive to an interactive functional cell - PLATELET AGGREGATION
Formation of the plug
How does platelet adhesion happen in formation of unstable plug?
Within the blood, there are circulating platelets and VWF (von Willebrand factor – a glycoprotein)
These do not interact, as the VWF are in a globular conformation therefore their binding sites are hidden from the platelets
(Binding sites are called Gp1b=membrane glycoprotein Ib)
Vascular injury damages the endothelium and exposes the sub-endothelial matrix which consists of collagen
-> sub-endothelial collagen then binds to VWF, recruiting them to the endothelial surface
The shear forces of flowing blood through vessel then unravels the VWF on the endothelial surface
Unravelled VWF has exposed binding site (Gp1b) therefore platelets bind
(Platelets can also bind directly to the exposed collaged via Gp1a, but this is only under low shear forces)
This binding recruits the platelets to the site of vessel damage
How does platelet activation happen in formation of unstable plug?
Conversion from a passive to an interactive functional cell
Due to:
- Changed shape (spreads and flattens)
- Changed membrane composition
- New proteins present on their surface (GpIIb/GpIIIa)
The platelets bound to collagen or VWF release ADP and thromboxane – these activate the platelets
Collagen and thrombin also activate platelets
How does platelet aggregation happen in formation of unstable plug?
Activated platelets bind more tightly to the collagen and VWF via GpIIb/IIIa
GpIIb/IIIa also binds fibrinogen, which develops the platelet plug
The platelet plug helps slow bleeding and provides a surface for coagulation
What happens during coagulation?
Stabilisation of the plug with fibrin (and clotting factors)
Blood coagulation= complex biochemical process-> stops blood loss
Components involved from liver (plasma haemostatic proteins), endothelial cells (VWF, TM, TFPI) and megakaryotes (VWF, FV)
Where are clotting factors before use in coagulation?
These clotting factors circulate as inactive precursors (zymogens)
Then activated by specific proteolysis (to form either as serine protease zymogens or cofactors)
How is coagulation regulated by the tissue factor pathway?
INTRINSIC
Initiated when FXII is activated (not biologically as important)
FVIIIa is the only cofactor, all other activated clotting factors are serine proteases
Coagulation not triggered down intrinsic pathway
EXTRINSIC (separate notecard)
Primary driver of clotting cascade
COMMON
Prothrombin-> thrombin
How does the extrinsic tissue factor pathway affect clotting?
Initiated when TF on surface of cells (which normally do not come into contact with blood) are exposed to plasma clotting factors
TF + FVII -> TF-FVIIa complex
TF-FVIIa then activates FIX and FX
FXa activates prothrombin (ProT) inefficiently leading to the generation of trace amounts of thrombin
Thrombin can then activate FVIII and FV, which function as non-enzymatic cofactors for FIXa and FXa, respectively
FIXa-FVIIIa catalyses the conversion of increased quantities of FXa
FXa-FVa catalyse enhanced generation of thrombin (more efficient by bypassing initial step)
Thrombin at the site of vessel damage converts fibrinogen (Fbg) to fibrin (Fbn), which is the molecular scaffold of a clot
What is the trigger to initiate coagulation in vivo?
Tissue factor
Although FXII can be activated to FXIIa this is mainly in vitro (useful diagnostically)
What is the surface in the coagulation system made up of?
Activated platelets (PI) which localize and accelerate the reactions
Pl= platelet membrane phospholipid
What does fibrinolysis do?
Breaks down the plug
Normally no interaction between plasminogen (plasma protein, zymogen) and tissue plasminogen activator (tPA) (plasma protein, proteinase)
Plasminogen -> (tPA) -> plasmin
Plasmin starts to break down the clot
What are examples of ‘clot busters’?
tPA and streptokinase (a bacterial activator)
Used in therapeutical thrombolysis for Myocardial Infarction
Why can the clotting cascade be described as an amplification system?
A small amount of factor VIIa produces a large amount of thrombin
Why does blood not clot complete whenever clotting is initiated by vessel injury?
Because of coagulation inhibitory mechanisms
Describe coagulation inhibitory mechanisms
DIRECT INHIBITION
E.g. Anti-thrombin (sometimes known as antithrombin III), which is an inhibitor of thrombin and other clotting proteinases
INDIRECT INHIBITION
E.g. inhibition of thrombin generation by the protein C anticoagulant pathway
(Factors VIII and V are activated by trace amounts of thrombin and become cofactors so need to inactivate them)
What is heparin used for and how does it affect thrombin?
Heparin is used for immediate anticoagulation in venous thrombosis and pulmonary embolism
Accelerates the action of antithrombin
Antithrombin affects XIa, IXa, Xa, mostly thrombin (IIa)
How does the protein C anticoagulant pathway down-regulate thrombin generation?
Coagulation activation-> thrombin binds to thrombomodulin-> activates protein C (zymogen)
Works with cofactor protein S which inactivate Factors Va and VIIIa
Downregulates the amount of thrombin that is produced
Factor V Leiden= not so easily inactivated
What happens when coagulation inhibitory mechanisms fail?
Antithrombin deficiency Protein C deficiency Protein S deficiency Factor V Leiden ALL risk factors for thrombosis
What happens if haemostasis and thrombosis aren’t balanced?
- Fibrinolytic factors, anticoagulant proteins
- Coagulation factors, platelets
Normal 1=2
Bleeding less 2, more 1
Thrombosis less 1, more 2
Define: abnormal bleeding
The result of an increase in fibrinolytic factors and anticoagulant proteins, and a decrease in coagulation factors and platelets
Bleeding is
- Spontaneous
- Out of proportion to the trauma/injury
- Unduly prolonged
- Restarts after appearing to stop
What % of the population have easy bruising?
12%
What are examples of significant bleeding history?
Epistaxis not stopped by 10 mins compression or requiring medical attention/transfusion
Cutaneous haemorrhage or bruising without apparent trauma (especially multiple/large)
Prolonged (>15 mins) bleeding from trivial wounds, or in oral cavity or recurring spontaneously in 7 days after wound
e.g. Spontaneous GI bleeding leading to anaemia
Menorrhagia (abnormally heavy menstrual bleeding) requiring treatment or leading to anaemia, not due to structural lesions of the uterus
Heavy, prolonged or recurrent bleeding after surgery or dental extractions
In the normal response to injured endothelial cell lining, how does each stage attempt to reduce blood loss?
Vessel constriction= limits blood flow to injured vessel
Formation of an unstable platelet plug= limits blood loss and provides surface for coagulation
Stabilisation of the plug with fibrin= stops blood loss
Vessel repair and dissolution of clot= restores vessel integrity
In haemostatic disorders, what are deficient or defective in primary haemostasis?
COLLAGEN- vessel wall
- Due to steroid therapy, age, scurvy
VON WILLEBRAND FACTOR
- Genetic deficiency
- Can’t initiate the coagulation process
PLATELETS
- Aspirin and other drugs, thrombocytopenia (decreased platelets-> small blood spots)
What patterns of bleeding usually occur in primary haemostasis?
Immediate Easy bruising Nosebleeds (prolonged: >20 mins) Gum bleeding (prolonged) Menorrhagia (anaemia) Bleeding after trauma/surgery Petechiae (specific for thrombocytopenia)
What is haemophilia?
Failure to generate fibrin to stabilise platelet plug
Defect= secondary haemostasis (coagulation)
In haemostatic disorders, what are deficient or defective in secondary haemostasis?
Not enough thrombin generated
Deficiency or defect of coagulation factors I-XIII
What causes secondary haemostasis?
Genetic eg: Haemophilia: FVIII or FIX deficiency
Liver disease (acquired) - Most coagulation factors are made in the liver)
Drugs (warfarin – inhibits synthesis, other block function)
Dilution (results from volume replacement)
Consumption (DIC*) (acquired)
What is DIC and how does it lead to secondary haemostasis?
DIC= disseminated intravascular coagulation
Generalised activation of coagulation – tissue factor
Associated with sepsis, major tissue damage, inflammation
Consumes and depletes coagulation factors and platelets
Activation of fibrinolysis which depletes fibrinogen
- > Widespread bleeding, from iv lines, bruising, internal
- > Deposition of fibrin in vessels which causes organ failure
What patterns of bleeding usually occur in disorders of secondary haemostasis?
Often delayed (after primary haemostasis)
Prolonged
Deeper: joints and muscles
Not from small cuts (primary haemostasis ok)
Nosebleeds rare
Bleeding after trauma/surgery
After i/m injections
Ecchymosis- easy bruising (virtually all bleeding disorders)
Haemarthrosis- spontaneous bleeding into joints
What is haemarthrosis?
Spontaneous bleeding into joints
Hallmark of haemophilia
Increases pressure in joints
Very painful and damaging
How can a haemostatic disorder be caused from fibrinolysis?
Due to either:
- Excess fibrinolytic components – plasma, tPA
(Can occur with some tumours or therapeutic administration)
- Deficient antifibrinolytic components – antiplasmin
(Can have a genetic antiplasmin deficiency)
NB. anticoagulant excess is usually only due to therapeutic administration, e.g. Heparin or hirudin
How can fibrinolysis be used therapeutically?
Can be used in therapy to break down clots after MI
Must be done carefully as can lead to haemorrhage
Define: thrombosis
Result of a decrease in fibrinolytic factors and anticoagulant proteins, with an increase in coagulation factors and platelets
E.g.
Intravascular coagulation
Inappropriate coagulation (inside a blood vessel or not preceeded by bleeding)
Thrombi may be venous or arterial
What does thrombosis cause?
OBSTRUCTED FLOW OF BLOOD
Artery – myocardial infarction, stroke, limb ischaemia
Vein – pain and swelling
EMBOLISM
Arterial emboli, usually from heart, may-> stroke/limb ischaemia
Venous emboli, to lungs (pulmonary embolus) or deep vein thrombosis
What are the 2 main types of venous thrombo-embolism?
Deep vein thrombosis
- Symptomes= venous return of blood is obstructed (painful, swollen leg)
- Causes= trauma, surgery, immobility, malignancy, autoimmune disease
- Diagnosis= clinical (Wells Score), D-dimer, duplex ultrasound, CT, MRI, venography
- Complications= PE, post-thrombotic syndrome, venous ulcer
- Treatment= anticoagulation, fibrinolgysis, thrombectomy
Pulmonary embolism
- Symptoms= shortness of breath (dyspnoea), chest pain, may lead to sudden death
- Diagnosis= clinical, ECG, D-dimer, echo, MRI, CTPA, VQ scan, pulmonary arteriogram
- Complications= death, shock, pulmonary hypertension, RV failure
- Treatment= anticoagulation, fibrinolysis, mechanolysis, IVC filter
What do venous thrombo-embolisms lead to (over time)?
Death- VT mortality 5%
Recurrence - 20% in first 2 years and 4% pa thereafter
Thrombophlebitic syndrome
Severe TPS in 23% at 2 years (11% with stockings)
Pulmonary hypertension - 4% at 2 years
What are the risk factors for venous thrombosis?
Genetic constitution
Effect of age and previous events, illnesses, medication
Acute stimulus
How does Virchow’s triad relate to thrombosis?
Contributory factors to thrombosis
May be inherited or acquired
Abnormal blood constitutents (endothelial dysfunction, hypercoagulability, abnormal platelet function, altered fibrinolysis, metabolic, hormonal factors)
- Dominant in venous thrombosis
Abnormal vessel wall (endothelial dysfunction, inflammation, atherosclerosis)
- Dominant in arterial thrombosis
Abnormal blood flow (endothelial dysfunction, turbulent flow at bifurcations and stenoses, stasis)
- Contributes to both
How does blood relate to increased risk of thrombosis?
Deficiency of anticoagulant proteins
E.g. Antithrombin, Protein C, Protein S
Increased coagulant proteins/activity
E.g. Factor VIII, Factor II and others, Factor V Leiden (increased activity due to activated protein C resistance)
How do vessel walls relate to increased risk of thrombosis?
Relatively little known
Many proteins active in coagulation are expressed on the surface of endothelial cells
E.g. Thrombomodulin, tissue factor, tissue factor pathway inhibitor
Expression altered in inflammation
E.g. due to malignancy, infection, immune disorders
How does flow relate to increased risk of thrombosis?
Reduced flow (stasis) increases the risk of venous thrombosis
Possibly after surgery, fracture, long haul flight, bed rest
How does thrombophilia relate to increased risk of thrombosis?
CLINICAL Thrombosis at young age ‘Idiopathic thrombosis’ Multiple thromboses Thrombosis whilst anticoagulated
LAB
Identifiable cause of increased risk
AT deficiency, Factor V Leiden, global measures of coagulation activity
What conditions make thrombosis more likely?
Pregnancy
Malignancy
Surgery
Inflammatory response
What is the prevalence of venous thrombo-embolism?
Overall 1 in 1000 - 10 000 per annum
Incidence doubles with each decade
PE is cause of 10% hospital deaths
Estimated 25,000 preventable deaths per year
(Overall, not many get thrombosis but in hospital it is a major and preventable cause of death)
How is venous thrombosis treated?
TO LYSE CLOT
E.g. tPA (high risk of bleeding)
TO LIMIT RECURRENCE/ EXTENSION/ EMBOLI Increase anticoagulant activity
- E.g: heparin (immediate acting, parenteral)
Lower procoagulant factors
- E.g.: warfarin (oral, slow acting for long term therapy)
Inhibit procoagulant factors– direct inhibitors
- Rivaroxaban (Xa), Apixaban (Xa), Dabigatran (IIa)
What’s the difference between the actions of heparin and warfarin?
Heparin= increased anticoagulant activity
Warfarin= lower procoagulant factors
What does stasis inflammation lead to?
Stasis inflammation-> increased coagulation factors, platelets
How can thrombosis be prevented?
Assess individual risk and circumstantial risk
All patients admitted should have VTE risk assessment
- Hospital target >90%
Give prophylactic anti-thrombotic therapy
E.g heparin for in-patients
+/ TED stockings
Define: hypertension
The level of BP above which investigation and treatment do more good than harm
Describe the distribution of blood pressure
Unimodal distribution
Arbitrary distinction between normal and abnormal
AGE
Mean bp rises with age
PP rises with age
Number of people with hypertension increases with age
How can the relationship between BP and risk be described?
Exponential (log linear)
No threshold for risk
Every 20mmHg increase in bp-> 2x risk of stroke (similar with CHD)
High bp causes more deaths than any other single cause
What does increased bp lead to an increased risk of?
Coronary heart disease Stroke Peripheral vascular disease/atheromatous disease Heart failure Atrial fibrillation Dementia /cognitive impairment Retinopathy
What causes primary/essential hypertension?
Unidentifiable cause
90-95% of cases
GENETIC
Monogenic (rare)
Complex polygenic (common)
ENVIRONMENTAL
Dietary salt (sodium)- major factor in the rise in BP with age
Obesity / overweight, lack of exercise
Alcohol
Pre-natal environment (~birthweight)
Pregnancy (pre-eclampsia)
Other dietary factors and environmental exposures?
What causes secondary hypertension?
Identifiable causes
What evidence is there for genes being related to blood pressure?
Twin and other studies suggest 30-50% of variation in blood pressure is attributable to genetic variation but identified SNPs only account for
What is hypertension associated with (haemodynamic factors)?
BP = CO x PVR
Typically, established hypertension is associated with:
- Increased TPR
- Reduced arterial compliance (higher PP)
- Normal CO
- Normal blood volume/extracellular volume
- Central shift in blood volume secondary to reduced venous compliance
Why is PVR elevated in hypertension?
Evidence supporting increased active vasoconstriction in hypertension is equivocal
Active narrowing of arteries
-> Vasoconstriction (probably short-term)
Structural narrowing of arteries
-> Growth and remodelling (adaptive?)
Loss of capillaries
-> Rarefaction (adaptive/damage?)
What is isolated systolic hypertension?
Systolic BP ≥ 140, diastolic BP ≤ 90
Condition of people >60y
Due to increasing stiffness of medium/large arteries
Pulse wave reflected and is greater by the time it reaches brachial artery
There are no specific treatments for ISH as against “standard” hypertension
What are the main possible causes of primary hypertension?
KIDNEY
Key role in BP regulation (Guyton)
Best evidence especially in relation to salt intake
Impaired renal function or blood flow is the commonest 2º cause of hypertension (e.g. renal parenchymal disease, renal artery stenosis)
SYMPATHETIC NERVOUS SYSTEM
Evidence linking high sympathetic activity to the development of hypertension
ENDOCRINE/PARACRINE FACTORS
Inconsistent evidence
Why does the kidney affect blood pressure?
The kidney exerts a major influence on BP through regulation of sodium/ water/ extracellular fluid volume
Almost all monogenic causes of hypertension affect renal Na+ excretion
Salt intake is strongly linked with blood pressures (populations with low salt have low population blood pressures and no rise in BP with age)
Animals with reduced renal Na+ handling (genetic or experimental) develop hypertension
BP FOLLOWS THE KIDNEY
Retting et al rat study
What is the relationship between hypertension and the heart?
Hypertension is commonly associated with increase in left ventricular wall mass (LVMI) and changes in chamber size
What is the relationship between hypertension and congestive heart failure (CHF)?
The prevalence of heart failure (CHF) is increasing (unlike other CVD)
Hypertension increases the risk of CHF 2 -3 fold
Hypertension probably accounts for about 25% of all cases of CHF
Hypertension precedes CHF in 90% of cases
The majority of CHF in the elderly is attributable to hypertension
What is the relationship between hypertension and large arteries?
High BP -> changes in large arteries
Typically associated with thickened walls (hypertrophy) of large arteries and acceleration of atherosclerosis
Hypertension may causes arterial rupture or dilations (aneurysms)
This can lead to thrombosis or haemorrhage (e.g. strokes)
What is the relationship between hypertension and the retina?
Hypertension adversely affects the microcirculation
E.g. in the retina (microvascular damage)
Thickening of the wall of small arteries-> arteriolar narrowing-> vasospasm-> impaired perfusion and increased leakage into the surrounding tissue
What is the relationship between hypertension and the microvasculature?
Reduction in capillary density-> impaired perfusion and increased PVR
Elevated capillary pressure-> damage and leakage
What is the relationship between hypertension and the kidney?
Renal dysfunction is common in hypertension (e.g. increased (micro)albumin excretion in urine)
Extreme (accelerated/malignant hypertension) is now rare but leads to progressive renal failure
MICROALBUMINURIA
More subtle evidence of kidney disease evident in may people with high BP
Hypertension causes:
-> Increased albumin loss in the urine
-> Decline in GFR with age
Both indicative of renal damage
What is atherosclerosis?
Disease of medium and large arteries
Changes in arteries from early life (plenty of time for prevention)-> clinical manifestations in middle/old age
Majority of CV deaths
One of the most common diseases in the UK
What are risk factors?
POTENTIALLY MODIFIABLE Smoking Lipids BP Diabetes Obesity Lack of exercise
NOT MODIFIABLE
Age
Sex
Genetic background
Combined risk factors-> higher risk
Hypertension x2, high cholesterol x4, smoking x1.6
All together x16
What is the connection between cholesterol and the development of atherosclerosis?
Thickening on one side of the artery -> develops into an atherosclerotic “plaque”
Plaque consists of a necrotic core of dead tissue covered and separated from the blood by a fibrous cap
DEVELOPMENT OF ATHEROSCLEORIS
- Trapping within the arterial wall of LDL rich in cholesterol
- Because of LDL binding to proteoglycans in the arterial intima, such as biglycan and versican (-> CHRONIC INFLAM) - Once trapped in arterial wall, LDL becomes chemically denatured by reactive oxygen free radicals and/or tissue enzymes (e.g. phospholipases)
- > Phagocytosis of LDL by macrophages, via scavenger receptors such as Scavenger Receptor A and CD36
PROGRESSION OF ATHEROSCLEROSIS
- Over time, thickening response-> increase in smooth muscle cells and macrophages (which -> minor chronic inflam)
- Take up lipid-> too much fat-> cells die-> small pools of EC fat which grow as disease progresses - This leads to abcess-like response
- > Generates occlusive clot or haemorrage OR repair response
RECURRENT EPISODES OF DAMAGE
Each vessel destabilizes and then heals-> step-wise not continuous progression of vascular disease
What are the main cell types and their roles
Vascular endothelial cells
- > Keep blood components in blood (non-blood out)
- Very active cells-> regulate and direct transport across their surface
- Barrier function (e.g. to lipoproteins)
- Leukocyte recruitment
Platelets
- Thrombus generation
- Cytokine and growth factor release
Monocyte-macrophages
- Foam cell formation
- Cytokine and growth factor release
- Major source of free radicals
- Metalloproteinases
Vascular smooth muscle cells
- Migration and proliferation
- Collagen synthesis
- Remodelling and fibrous cap formation
T lymphocytes
-Macrophage activation
How do macrophages contribute to the development of lesions?
WBCs can injure host tissue if they are activated excessively or inappropriately
In atherosclerosis, the main inflammatory cells are macrophages
Macrophages are derived from blood monocytes
- Macrophages that have taken up an excess of lipid are known as “foam cell”
MACROPHAGE SUBTYPES
- Macrophage subtypes are regulated by combinations of transcription factors binding to regulatory sequences on DNA
- Two main classes - resident or inflammatory macrophages
INFLAMMATORY MACROPHAGES
Inflammatory macrophages adapted to kill microorganisms (germs)
RESIDENT MACROPHAGES (normally homeostatic)
- Suppressed inflammatory activity
- Alveolar resident macrophages (surfactant lipid homeostasis)
- Osteoclasts (calcium and phosphate homeostasis)
- Spleen (iron homeostasis)
Release of inflammatory mediators by macrophages and other cells ->
- Activation of vascular endothelial cells with expression of adhesion molecules and chemo-attractants for monocytes
- Recruitment of more monocytes from the blood
- Differentiation within the arterial wall of monocytes into macrophages
Hence the process is self-perpetuating
How do lipoproteins contribute to the development of lesions?
Low density lipoprotein (LDL)
- ‘Bad’cholesterol
- Synthesised indirectly in liver
- Carries cholesterol from liver to rest of body including arteries
High density lipoprotein (HDL)
- ‘Good cholesterol’
- Higher level of HDL cholesterol, the lower the risk of a cardiovascular effect
- Carries cholesterol from ‘peripheral tissues’ including arteries back to liver (=“reverse cholesterol transport”)
Oxidised LDL(s), modified LDL(s)
- Due to action of free radicals on LDL
- Other modifications can also occur
Families of highly inflammatory and toxic forms of LDL found in vessel walls
What is sub-endothelial trapping of LDL?
LDL leak through the endothelial barrier by uncertain mechanisms
LDL is trapped by binding to sticky matrix carbohydrates (proteoglycans) in the sub-endothelial layer
Trapped LDL is susceptible to modification
How are trapped LDL modified?
Best studied modification is oxidation
Chemically represents partial burning
LDL becomes oxidatively modified by free radicals
Oxidised LDL is phagocytosed by macrophages and stimulates chronic inflammation
What is familial hyperlipidemia (FH)?
Autosomal genetic disease
Massively elevated cholesterol (20mmol/L)
Failure to clear LDL from blood
Xanthomas and early atherosclerosis; if untreated fatal myocardial infarction before age 20
Gene affected= LDL receptor, negatively regulated by IC cholesterol (so accumulate cholesterol)
How do macrophages accumulate cholesterol?
In LDLR-negative patients, macrophages accumulate cholesterol
Deduced a second LDL receptor (not under feedback control) is in atherosclerotic lesions
Called the ‘scavenger receptor’ since it hoovers up chemically modified LDL (now known to be oxidised)
Now known that scavenger receptors are a family of pathogen receptors that ‘accidentally’ bind OxLDL
What are the types of macrophage scavenger receptors?
MACROPHAGE SCAVENGER RECEPTOR A CD204 Binds to oxidised LDL Binds to Gram-positive bacteria like Staphylococci and Streptococci Binds to dead cells
MACROPHAGE SCAVENGER RECEPTOR B CD36 Binds to oxidised LDL Binds to malaria parasites Binds to dead cells
How do inflammation and homeostasis affect arterial ox-LDL deposits?
Homeostasis
Safe clearance, reverse cholesterol transport
Inflammation
Activation of ‘bug detector’ pathways
What happens to macrophages within plaques?
Generate free radicals that further oxidise lipoproteins
Phagocytose/scavenge modified lipoproteins and become foam cells
Become activated by modified lipoproteins/free intracellular cholesterol to express/secrete
Macrophages within plaques: how do they generate free radicals?
Macrophages have oxidative enzymes that can modify native LDL
NADPH Oxidase
E.g. Superoxide O2
Myeloperoxidase
E.g. HOCl hypochlorous acid (bleach) from ROS + Cl-
E.g. HONOO Peroxynitrite
-> Generate free radicals that further oxidise lipoproteins
Macrophages within plaques: how do the phagocytose/ scavenge modified lipoproteins, and become foam cells?
Macrophages accumulate modified LDL to become enlarged foam cells
Macrophages within plaques: How do foam cells become activated by modified lipoproteins/free intracellular cholesterol to express/secrete (5)?
Cytokine mediators (eg TNFa, IL-1, MCP-1) that recruit more monocytes (+ve feedback loop)
Chemoattractants and growth factors for VSMC
Proteinases that degrade tissue (e.g. the fibrous cap)
Tissue factor that stimulates coagulation upon contact with blood
Die by apoptosis – contributing to the lipid-rich core of the plaque
Macrophages within plaques (stage 3): outline how cytokine mediators recruit more monocytes
CYTOKINES
Protein immune hormones that activate endothelial cell adhesion molecules
Interleukin-1 upregulates vascular cell adhesion molecule 1 (VCAM-1)
VCAM-1 mediates tight monocyte binding
Atherosclerosis is reduced in mice w/o IL-1 or VCAM-1
CHEMOKINES
Small proteins chemoattractant to monocytes
Monocyte chemotactic protein 1 (MCP-1)
MCP-1 binds to a monocyte GPCR CCR2
Atherosclerosis reduced in MCP-1 or CCR2 deficient mice
Macrophages within plaques (stage 3): outline how chemoattractants and growths factors act on VSMCs
Wound healing role of the macrophage
Macrophages release complementary protein GFs that recruit VSMC and stimulate them to proliferate and deposit EC matrix
Platelet derived growth factor
- > Vascular smooth muscle cell chemotaxis
- > Vascular smooth muscle cell survival
- > Vascular smooth muscle cell division (mitosis)
Transforming growth factor beta
- > Increased collagen synthesis
- > Matrix deposition
Macrophages within plaques (stage 3): outline how proteinases degrade tissue (e.g. the fibrous cap)
Metalloproteinases (=MMPs) = family of ~28 homologous enzymes
- Activate each other by proteolysis
- Degrade collagen
- Catalytic mechanism based on Zn
Effect of plaque erosion
- Blood coagulation at rupture site may lead to occlusive thrombus and cessation of blood flow
Macrophages within plaques (stage 3): outline how foam cells die by apoptosis
OxLDL derived metabolites are toxic e.g. 7-keto-cholesterol
Macrophage foam cells have protective systems that maintain survival in face of toxic lipid loading
Once overwhelmed, macrophages die via apoptosis
Releases macrophage tissue factor and toxic lipids into the ‘central death zone’ called lipid necrotic core
Thrombogenic and toxic material accumulates, walled off, until plaque rupture causes it to meet blood
What is nuclear factor kappa B (NFkB)?
Transcription Factor
Master regulator of inflammation
Activated by numerous inflammatory stimuli
- Scavenger receptors
- Toll-like receptors
- Cytokine receptors
Switches on numerous inflammatory genes
- Matrix metalloproteinases
- Inducible nitric oxide synthase
Where are atherosclerotic lesions normally distributed?
Not random
Branch points and curvatures are ‘hot spots’
Probably due to non-laminar blood flow at these sites
- May suppress inflammatory activation of endothelial cells
- Non-uniform blood flow at hots spots may enhance it
How do plaques contribute to the growth of the necrotic core?
As the plaque grows it is invaded by small blood vessels that develop from the vasa vasorum in the adventitia
These vessels tend to bleed-> contribute to growth of the necrotic core through the supply of erythrocyte-derived cell membranes
What are the characteristics of vulnerable plaques?
Large soft eccentric lipid-rich necrotic core
Thin fibrous cap (collagens synthesised by VSMC)
Reduced VSMC and collagen content
Increased VSMC apoptosis
Infiltrate of activated
Macrophages expressing MMPs
What are the chronic symptoms of atherosclerotic narrowing (stenosis) of the arterial lumen?
Angina
Intermittent claudication
What usually causes plaque rupture?
Activity of proteases expressed by macrophages fragmenting the matrix of the fibrous cap
Can also be caused by intra-plaque haemorrhage
What are the acute symptoms of atherosclerosis usually calused by?
Due to occlusive thrombosis at the site of plaque rupture or to the distant effects of dislodged thrombus
OR
Plaque contents on down-stream smaller blood vessels (embolism)
What are the protective functions of macrophages in the plaque?
Clearing debris (modified lipoproteins, dead cells)
Stimulating “wound healing” response involving VSMCs
What are the deleterious functions of macrophages in the plaque?
Release of free radicals that modify LDL
Recruitment of further monocytes via cytokines and chemokines
Expression of MMPs that may destabilise the fibrous cap
Expression of tissue factor that can stimulate thrombosis
Do macrophages promote or limit plaque rupture?
Promote
What effect do vascular smooth muscle cells (VSMC) have on plaques?
Protect plaque integrity
Contrasting role to macrophages in plaque instability
What effect do lipoproteins deposited in the arterial wall have on macrophage functions?
Stimulate it
What is the pathogenesis of atherosclerosis: inflammation model?
ENDOTHELIAL DYSFUNCTION IN ATHEROSCLEROSIS Endothelial permeability Leukocyte migration Endothelial adhesion Leukocyte adhesion
FATTY-STREAK FORMATION IN ATHEROSCLEROSIS Smooth muscle migration Foam-cell formation T cell activation Adherence and aggregation of platelets Adherence and entry of leukocytes
(Response to injury model) [FORMATION OF ADVANCED, COMPLICATED LESION OF ATHEROSCLEROSIS Macrophage accumulation Formation of necrotic core Fibrous-cap formation Angiogenesis Senescence]
What is the pathogenesis of atherosclerosis: response to injury model?
Macrophage accumulation Formation of necrotic core Fibrous-cap formation Angiogenesis Senescence
What are the layers of blood vessels (except for capillaries and venules)?
Tunica intima – endothelium
Tunica media – smooth muscle cells
Tunica adventitia – vasa vasorum, nerves
Describe the anatomical structure of a capillary
Endothelial cells surrounded by basement membrane and pericapillary cells (pericytes)
Describe the anatomical structure of a post-capillary venule
Structure similar to capillaries but more pericytes
Describe the anatomical structure of an artery
Three thick layers, rich in cells and extracellular matrix
What is the vascular endothelium?
Endothelium is the surface separating blood from other tissues
Very extensive:
- Surface area > 1000 m2
- Weight >100 g
Acts as a vital barrier separating blood from tissues
Formed by monolayer of endothelial cells, 1 cell deep (contact inhibition)
Endothelial cells are flat, about 1-2 µm thick and 10-20 µm in diameter
Not all endothelial cells are the same (heterogeneity)
In vivo, endothelial cells live a long life and have a low proliferation rate (unless new vessels are required: angiogenesis)
Endothelial cells regulate essential functions of blood vessels
What functions do endothelial cells regulate?
ANGIOGENESIS
Matrix proteins
Growth factors
THROMBOSIS AND HAEMOSTASIS
Anti-thrombotic factors
Procoagulant factors
INFLAMMATION
Adhesion molecules
Inflammatory mediators
VASCULAR TONE and PERMEABILITY
Vasodilator factors
Vasoconstrictor factors
What activates endothelium cells?
Inflammation Mechanical stress Viruses Smoking High blood pressure OxLDL High glucose
How does the endothelium normally regulate leukocyte recruitment and inflammation?
Recruitment of blood leukocytes into tissues takes place normally during inflammation
Leukocytes adhere to the endothelium of post-capillary venules and transmigrate into tissues
How is the endothelial dysfunction in atherosclerosis affected by leukocyte recruitment and inflammation?
In atherosclerosis, leukocytes adhere to activated endothelium of large arteries and get stuck in the subendothelial space
Newly formed post-capillary venules at the base of developing lesions provide a further portal for leukocyte entry
How can leukocyte recruitment and adhesion be seen?
Intra-vital microscopy
Capture-> rolling-> slow rolling-> arrest-> adhesion, strenghtening, spreading-> intravascular crawling-> paracellular and transcellular transmigration
NB. rolling-> arrest= activation
So… rolling-> activation-> firm adhesion
How is the endothelial dysfunction in atherosclerosis affected by permeability?
The endothelium regulates the flux of fluids and molecules from blood to tissues and vice versa
Increased permeability results in leakage of plasma proteins through the junctions into the subendothelial space
Causes lipoprotein trapping and oxidative modification
Modified LDLs may then be taken up by macrophages forming foam cells-> chronic inflammation
How is the endothelial dysfunction in atherosclerosis affected by blood flow?
LAMINAR FLOW Normal Streamlined Outermost layer moving slowest, centre moving fastests -> High shear stress
Antithrombotic
Antimigration
Antigrowth
Promotes:
- NO production
- Factors that inhibit coagulation, leukocyte adhesion, smooth muscle cell proliferation
- Endothelial survival
DISTURBED FLOW Branch points Interrupted blood flow Fluid passes a constriction etc. -> Low shear stress
Prothrombotic
Promigration
Progrowth
Promotes:
- Coagulation, leukocyte adhesion, smooth muscle cell proliferation
- Endothelial apoptosis
How is the endothelial dysfunction in atherosclerosis affected by angiogenesis?
Angiogenic factor production -> Release of factor -> Extracellular receptor binding (-> Intracellular signalling occurs) -> Extracellular activation (-> Endothelial matrix degradation) -> Extracellular proliferation -> Directional migration -> Extracellular matrix remodelling
Tube formation
Loop formation
Vascular stabilization
Occurs in 3
- Endothelial dysfunction in atherosclerosis
- Fatty-streak formation in atherosclerosis
- Formation of an advanced, complicated lesion of atherosclerosis
Define: angiogenesis
• formation of new blood vessels by sprouting from pre-existing vessels
o Initiated by pro-angiogenic stimulation of a pre-existing mature blood vessel
What is the Janus paradox
Angiogenesis promotes plaque growth, but can be used therapeutically to induce new formation in ischaemic tissues
Delivers growth factors and stem cells to the ischaemic region to induce new vessel growth
What is cellular senescence?
Growth arrest that halts the proliferation of ageing and/or damaged cells
Why is cellular senescence good/not-so-good?
GOOD
Prevents the transmission of damage to daughter cells
Replicative senescence: the limited proliferative capacity of human cells in culture
Senescence as response to stress and damage
NOT-SO-GOOD
Senescent ells are pro-inflammatory and contribute to many diseases
Senescent cells have distinctive morphology and acquire specific markers, e.g. B-gal
How is the endothelial dysfunction in atherosclerosis affected by cellular senescence?
Senescent endothelial cells found in atherosclerotic lesions
Endothelial cell senescence can be induced by CV risk factors e.g. ox stress
Senescent cells have a pro-inflammatory and prothrombotic phenotype and may contribute to atherosclerosis plaque progression/complications
What potential benefits does red wine have?
IN VITRO AND ANIMAL STUDIES
- Resveratrol promotes endothelail protective pathways (eNOS)
- Resveratrol acts as an anti-aging compound and reduces vascular cell senescence
HUMANS
Red wine prevents pro-inflammatory changes induced by a high fat meal in leukocytes
Red wine consumption increases circulating endothelial progenitor cells and improves endothelial function in obese people with T2D
Resveratrol, like other toxins, has an hormetic (i.e. dose-response) action:
- Beneficial effects at lower doses
- Cytotoxic effects at higher doses
BUT alcohol is damaging to users and others
What are the major determinants of CHD risk?
Coronary heart disease determinants of risk: Tobacco use Physical inactivity Harmful use of alcohol Unhealthy diet -> Hypertension Obesity Diabetes mellitus Hyperlipidaemia
Responsible for 80% of CHD
Outline the global and UK burden of CHD
GLOBAL
17million deaths per year= cardiovascular disease
Leading cause of death in age
Leading cause of death in developed and low/medium income countries
UK
88,000 CHD deaths per year, commonest cause of death
CHD accounts for 18% deaths in men and 10% deaths in women
Describe the epidemiology of stable angina
Incidence increasing
~2M cases in UK
Age 55-64y
Affects 8% males and 3% females
Age 65-74y
Affects 14% males and 8% females
Over 300,000 angina patients attended cardiac outpatient clinics in 2009-10
How does coronary artery disease present clinically?
Sudden cardiac death
Acute coronary syndrome
- Acute myocardial infarction
- Unstable angina
Stable angina pectoris
Heart failure
Arrhythmia
What causes myocardial ischaemia?
Mismatch between myocardial oxygen supply and demand
Primary reduction in blood flow
Inability to increase blood flow to match increased metabolic demand
Coronary artery lumen must be reduced by >75% to significantly affect myocardial blood supply
How does MI feel to the patient?
Like weight on chest radiating to throat and towards arms
What factors affect coronary blood flow?
Aortic blood pressure
- Decreased blood pressure reduces coronary flow
Myocardial work
- Exercise increases coronary flow
Coronary artery narrowing
- Fixed narrowing (such as a “fatty plaque”)
- An acute plaque change (due to rupture or haemorrhage)
- A blood clot in the vessel (thrombus)
- Vasoconstriction
Aortic valve dysfunction
Increased right atrial pressure
What does epicardial stenosis cause (on resting coronary resistance and flow)?
Decreased normal resting coronary flow
What happens to the effect of cardiac stenosis (on resting coronary resistance and flow) with vasodilators?
Less stenosis
- > More coronary vasodilator reserve
- > Higher hyperemic response (mean hyperemic flow/mean resting flow)
What is angina pectoris?
Clinical diagnosis
Discomfort in chest, jaw, shoulders, arms or back
Provoked by exertion of emotional stress
Relived by rest
What invasive and non-invasive, functional and anatomical tests can be done to help diagnose angina?
FUNCTIONAL NON-INVASIVE Exercise ECG Stress echo Stress cardiac MRI *PET/CT *Stress nuclear MPS *FFRct (CT subscript)
FUNCTIONAL INVASIVE
- CFR
- Pressure wire (FFR)
- iFR
- IVUS
- OCT
ANATOMICAL NON-INVASIVE
- CT coronary calcium score
- CT coronary angiogram
ANATOMICAL INVASIVE
*Coronary angiogram
*= exposed to ionising radiation
What are the treatment strategies for angina?
PREVENT ATHEROSCLEROSIS PROGRESSION AND RISK OF DEATH/MI
- Education
- Lifestyle modification
- Aspirin, statins, ACE inhibitors
REDUCE MYOCARDIAL OXYGEN DEMAND
- HR (b blockers, Ca antagonists, If blockers)
- Wall stress (ACE inhibitors, Ca antagonists)
- Metabolic modifiers
IMPROVE BLOOD SUPPLY
- Vasodilators (nitrates, nicorandil, Ca antagonists)
- Revascularisation (PCI, CABG)
What are acute coronary syndromes?
Inflammation
- Systemic
- Local
Plaque
- Rupture
- Erosion
Thrombosis
What are the mechanisms underlying MI?
Myocardial cell death arising from interrupted blood flow to the heart
- Coronary plaque rupture
- Coronary plaque erosion
- Coronary dissection
Mechanisms of myocardial cell death
- Oncosis
- Apoptosis
Define: infarction
Tissue necrosis due to ischaemia
Define: embolus
Detached intravascular solid, liquid or gaseous mass that is carried by the blood to a site distant from its point of origin
Define: thrombosis
Formation of a solid mass of blood constituents within the circulatory system
Virchow’s triad= predisposition
What is the difference between white and red thrombi?
WHITE THROMBUS
Platelet rich
Common in arterial thrombosis (high pressure/turbulent circulation)
Benefit from antiplatelet therapy
RED THROMBUS
Fibrin rich, with trapped erythrocytes
Common in venous or low pressure situations (stasis)
Benefit from anticoagulant or antifibrinolytic therapy
What do hypercoagulable conditions cause?
People with hypercoagulable states have an increased risk for blood clots
Hypercoagulable states are usually genetic (inherited) or acquired conditions
List some inherited hypercoagulable conditions
Factor V Leiden (the most common)
Prothrombin gene mutation
Deficiencies of natural proteins that prevent clotting (such as antithrombin, protein C and protein S)
Elevated levels of homocysteine
Elevated levels of fibrinogen or dysfunctional fibrinogen (dysfibrinogenemia)
List some acquired hypercoagulable conditions
Cancer Some medications used to treat cancer, such as tamoxifen, bevacizumab, thalidomide and lenalidomide Recent trauma or surgery Central venous catheter placement Obesity Pregnancy
What does tissue factor determine?
Thrombosis
TF/VIIa with co factors-> Xa -> (II) -> IIa-> FIBRINOGEN TO FIBRIN
What is cardiac troponin useful for?
cTnI and cTnT are very sensitive and specific indicators of damage to the heart muscle (myocardium)
Measured in the blood to differentiate between unstable angina and myocardial infarction (heart attack) in people with chest pain or acute coronary syndrome
cTn complex – thin filament of striated muscle
3 components, coded by separate genes
Proteolytic cleavage during myocardial ischaemia
Circulating cTn: posttranslational modified, degraded and truncated forms
cTn can be released transiently without cardiomyocyte death
Why are thrombi clinically important?
Most patients with ischaemic incidents suffer them
How does an infarction form?
Coronary artery becomes obstructed
Zone of perfusion is area at risk on endocardium-> zone of necrosis
What effect does reperfusion have on myoscardial ischaemia?
Reduces infarct size (by 40% from 70->30)
Cardioprotection reduces infarct size by a further 25%
How long does post-MI LV remodelling take?
Acute infraction= hours
Infarct expansion= hours to days
Global remodelling= days to months
What mechanisms underly LV remodelling?
Infarct thinning, elongation, expansion
LV dilatation
- Reduce wall tension
- Maintains cardiac output
Non-infarcted myocardium
- LVH and myofilament dysfunction
- Altered electromechanical coupling
- Myocardial fibrosis
- Apoptosis
- Inflammation
What are the consequences of adverse LV remodellingLV remodelling?
Increased systolic wall tension/stress Increased MVO2 Reduced myocyte shortening Increased diastolic wall tension/stress Reduced subendocardial perfusion Dysynchronous depolarization/contraction Mitral regurgitation Ventricular arrhythmias Ventricular fibrillation
How can thrombotic burden/risk be managed?
ACUTE
Thrombectomy
Drugs – Oral antiplatelets: Aspirin, clopidogrel, prasugrel, ticagrelor
SC anticoagulants: LMWH, fondaparinux
IV antiplatelets: GpIIb/IIIa inhibitors
IV anticaogulants: Bivalirudin,, fibrinolytics, Factor Xa inhibitors
RECURRENT
Oral antiplatelet drugs
Anticoagulants
Direct thrombin inhibition – Factor Xa inhibitors
How can plaques be stabilised?
Mechanical e.g. stent
Drugs e.g. statins (high dose) and ACE inhibitors
How can LV remodelling be managed?
Non-drug e.g. CRT-P/D, progenitor cells
Drugs e.g. B blockers, ACE inhibitors, angiotensin R blockers, aldosterone R antagonists
What are the types of TIA/stroke?
EMBOLIC
ICA plaque rupture
Intracardiac (e.g. AF, old MI, valve disease)
Intracardiac communication
TREATMENT Fibrinolysis Clot extraction Antiplatelet drugs Modify atherosclerotic risk factors Endarterectomy, stent Hole closure
HAEMORRHAGIC Vascular malformation Hypertension Tumor Iatrogenic
TREATMENT
Coil/clip aneurysm
Withdraw pro-haemorrhagic medication
Control hypertension
What embolisms can be found in arterial vessels?
Thrombus [ACS, TIA, stroke] Air Fat Amniotic Foreign body/material
What are the consequences of a gas, fat, amniotic fluid and cholesterol embolism?
GAS/AIR EMBOLISM
Iatrogenic
Decompression sickness
Trauma
FAT EMBOLISM
Trauma
AMNIOTIC FLUID EMBOLISM Pulmonary vasoconstriction, inflammation Sudden CV collapse Pulmonary HTN + RV failure -> LV failure DIC Rx: pulmonary vasodilators, FVIIa, ITU support
CHOLESTEROL EMBOLISM
Showers of microemboli from within plaque of large calibre artery
Plaque rupture (spontaneous, traumatic, iatrogenic)
Embolization of plaque debris (cholesterol crystals, platelets, fibrin)
Lodging of emboli in arterioles 100-200mm diam.
Foreign body inflammatory response
End-organ damage due to microvascular plugging and inflammation
Define: heart failure
A clinical syndrome caused by an abnormality of the heart and recognised by a characteristic pattern of haemodynamic, renal, neural and hormonal responses
What is the prognosis of heart failure (3 years)?
50% dead in 3 years
What is the incidence and prevalence of heart failure?
Prevalence= 1 - 3 %; 10% in those over 75 years
Worldwide 22 million
Incidence= 0.5 - 1.5 % per annum
2 million
Men:women 1:1
What causes heart failure?
GENERAL Arrhythmias Valve disease Pericardial disease Congenital heart disease Myocardial disease
MYOCARDIAL DISEASE
Coronary artery disease
Cardiomyopathy
- Dilated (DCM) - specific or idiopathic (IDCM)
- Hypertrophic (HCM or HOCM or ASH)
- Restrictive
- Arrhythmic right ventricular cardiomyopathy(ARVC)
Hypertension
Drugs
- Beta-blockers
- Calcium antagonists
- Anti-arrhythmics
Other or unknown
How does heart disease relate to heart failure?
Coronary heart disease is the leading cause of death in Europe
Modern treatment increases survival
Survivors are left with a damaged heart
-> 50% of all survivors develop heart failure
Deaths due to heart attacks are declining but due to heart failure are increasing
Define: cardiomyopathy
Heart disease in the absence of a known cause and particularly coronary artery disease, valve disease, and hypertension
What percentage of heart failure is caused by cardiomyopathy?
5%
What causes dilated cardiomyopathy?
Idiopathic dilated cardiomyopathy
Genetic and/or Familial cardiomyopathies
Infectious causes E.g. Viruses & HIV Mycobacteria Rickettsia Fungus Bacteria Parasites
Toxins and poisons E.g. Ethanol Metals Cocaine Carbon dioxide or hypoxia
Drugs
E.g. Chemotherapeutic agents
Antiviral agents
Metabolic disorders
E.g. Nutritional deficiencies and endocrine diseases
Collagen disorders, autoimmune cardiomyopathies
Peri-partum cardiomyopathy, neuromuscular disorders
What causes restrictivecardiomyopathy?
Associated with fibrosis
E.g. Diastolic dysfunction
(elderly, hypertrophy, ischaemia, scleroderma(
Infiltrative disorders E.g. Amyloidosis Sarcoid disease Inborn errors of metabolism Neoplasia
Storage disorders
E.g. Haemochromatosis and haemosiderosis
Fabry disease, glycogen storage disease
Endomyocardial disorders
E.g. Endomyocardial fibrosis
Hypereosinophilic syndrome carcinoid metastases
Radiation damage
What causes death in heart failure?
Progression of heart failure
- Increased myocardial wall stress
- Increased retention of sodium and water
Sudden death
- Opportunistic arrhythmia
- Acute coronary event (often undiagnosed)
Cardiac event e.g. myocardial infarction
Other cardiovascular event e.g. stroke, PVD
Non cardiovascular cause
What hormonal mediators are involved in heart failure?
CONSTRICTORS Noradrenaline Renin/angiotensin II Endothelin Vasopressin NPY
DILATORS ANP Prostaglandin E2 and metabolites EDRF Dopamine CGRP
GROWTH FACTORS Insulin TNF alpha Growth hormone Angiotensin II Catecholamines NO
CYTOKINES
OXYGEN RADICALS
What inflammatory markers are cytokines are there? (Organ specific and all cells)
ORGAN SPECIFIC
Heart
- Troponin T
- Troponin I
Vessel wall
- ICAM-1
- VCAM-1
- E-selectin
- P-selectin
Macrophages
- Lipoprotein-associated phospholipase A2
- Secretory phospholipase A2
Adipose tissue
ALL CELLS Interleukin-1b Interleukin-6 Tissue necrosis factor a (ABOVE) -> Liver-> (BELOW) C-reactive protein Fibrinogen Serum amyloid A
What are the symptoms and signs of heart failure?
PATIENT SYMPTOMS Ankle swelling Exertional breathlessness Fatigue Orthopnoea PND Nocturia Anorexia Weight loss
CLINICAL SIGNS Tachycardia Decreased pulse volume Pulsus alternans Increased JVP Oedema Rales Hepatomegaly Ascites
INVESTIGATION (SIGNS) X-ray Echocardiogram Radionuclide ventriculogrpahy Ambulatory ECG monitoring Exercise test (VO2) Cardiac catheter
How is functional capacity of patients with heart failure determines?
NYHA classification
Quality of life decreases
Class 1-4
CLASS 1
Patients with cardiac disease but without resulting limitation of physical activity
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain
CLASS 2
Patients with cardiac disease resulting in slight limitation of physical activity
They are comfortable at rest
Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain
CLASS 3
Patients with cardiac disease resulting in marked limitation of physical activity
They are comfortable at rest
Less than ordinary activity causes fatigue, palpitation, dyspnea, or anginal pain.
CLASS 4
Patients with cardiac disease resulting in inability to carry on any physical activity without discomfort
Symptoms of heart failure or anginal syndrome may be present even at rest
If any physical activity is undertaken, discomfort is increased
From onset, how does heart failure progress?
Onset of heart failure
-> Sudden death OR coronary events
Progression-> mild, moderate, severe
1ST STAGE
Loss of myocardium
Fall of bp- baroreceptors ergoreflexes and chemoreflexes activated
Maintains hormone activation
2ND STAGE Bacterial invasion Immune and inflammatory response Onset of cachexia Hastens demise-> rapid decrease in quality of life
What are the syndromes of heart failure?
ENTITY
Synonym or variant
ACUTE HEART FAILURE Pulmonary oedema (large white patch on X ray)
CIRCULATORY COLLAPSE
Cardiogenic “shock” (poor peripheral perfusion, oliguria, hypotension)
CHRONIC HEART FAILURE
Untreated, congestive, undulating, treated, compensated
What are the objectives when treating chronic heart failure?
PREVENTION Myocardial damage - Occurrence - Progression of damage - Further damaging episodes
Reoccurrence
- Symptoms
- Fluid accumulation
- Hospitalisation
RELIEF OF SYMPTOMS AND SIGNS
Eliminate oedema and fluid retention
Increase exercise capacity
Reduce fatigue and breathlessness
PROGNOSIS
Reduce mortality
What management measures are helpful to prevent heart failure?
LIFESTYLE Weight reduction Discontinue smoking Avoid alcohol excess Exercise
MEDICAL Treat HTN, diabetes, arrhythmias Anticoagulation Immunization Sodium / fluid restriction
Diuretics
- Relieve fluid retention
- Decrease symptoms e.g. pulmonary congestion and peripheral oedema
- Can lead to electrolyte depletion
ACE Inhibitors / ARAs Beta-Blockers Aldosterone Antagonists (Spironolactone) Digoxin Devices (cardiac resynchronization, ICD)
(Drugs in order of when to give, generalist-> specialist)
What treatments can be given for severe heart failure?
INTRAVENOUS DRUGS
Diuretics or combination of diuretics
Nitrates
Positive inotropes - dopamine/dobutamine
FLUID CONTROL
Haemofiltration
Peritoneal dialysis or haemodialysis
DEVICES
ICD or pacing
Intraaortic balloon pump
Ventricular assist device, total artificial heart
SURGERY CABG for "hibernation" Valve surgery Cardiomyoplasty, volume reduction/restriction Transplantation
