Cardiovascular System Flashcards

Question

What are the coronary arteries?

Answer 1

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

Answer 2

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

Answer 3

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

Answer 4

1. SAN 2. Inter-nodal fibre bundles 3. 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)

Answer 5

Electrical event-> calcium transient-> contractile event Excitation-contraction coupling

Answer 6

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)

Answer 7

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

Answer 8

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

Answer 9

Sigmoidal relationship | Between log of cytoplasmic Ca concentration and % of maximum force produced

Answer 10

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

Answer 11

Isometric (muscle fibres don't change length, pressures in both ventricles increase) Isotonic (shortening of fibres and blood is ejected from ventricles)

Answer 12

Weight that stretches muscle before it's stimulated to contract

Answer 13

Weight not apparent to muscle in resting state | Only encountered when muscle has started to contract

Answer 14

In isotonic contraction Inverse linear relationship between afterload and shortening Almost inverse linear relationship between afterload and shortening velocity

Answer 15

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

Answer 16

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

Answer 17

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

Answer 18

End-diastolic volume End diastolic pressure Right atrial pressure

Answer 19

Diastolic arterial blood pressure

Answer 20

INTRINSIC MECHANISMS Frank-Starling relationship Rate-induced regulation EXTRINSIC MECHANISMS Autonomic NS Endocrine system Blood gases and pH

Answer 21

Increased diastolic fibre length increases ventricular contraction Consequence: ventricles pump greater stroke volume so, at equilibrium, cardiac output exactly balances the augmented venous return

Answer 22

Changes in number of myofilament cross bridges that interact Changes in Ca sensitivity of the myofilaments

Answer 23

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

Answer 24

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

Answer 25

Work done by the heart to eject blood under pressure into the aorta and pulmonary artery

Answer 26

Volume of blood ejected during each stroke by each ventricle Affected by afterload, preload and contractility

Answer 27

Pressure at which blood is ejected | Greatly influenced by structure

Answer 28

Stroke work= SV x P

Answer 29

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

Answer 30

T = (PR)/h ``` T= wall tension P= internal pressure R= cylindrical radium h= height/length of cylinder ```

Answer 31

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

Answer 32

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)

Answer 33

Ventricular relaxation during which ventricles fill with blood 4 sub-phases

Answer 34

Ventricular contraction when blood is pumped into the arteries 2 sub-phases

Answer 35

End diastolic volume - end systolic volume = stroke volume

Answer 36

EF = SV/EDV Percentage of EDV ejected At peak exercise >80% In heart failure

Answer 37

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)

Answer 38

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

Answer 39

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

Answer 40

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

Answer 41

``` 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 ```

Answer 42

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

Answer 43

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

Answer 44

``` 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') ```

Answer 45

``` P= Atrial depolarisation QRS= Ventricular depolarisation T= Ventricular repolarisation ```

Answer 46

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

Answer 47

Valves closing

Answer 48

Aortic valve shuts-> rebound pressure wave against the valve (distended aortic wall relaxes) Recoil reduces the aortic pressure

Answer 49

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)

Answer 50

``` Atrial systole Isovolumetric contraction Ejection (rapid then reduced) Isovolumetric relaxation Rapid filling Reduced filling (diastasis) ```

Answer 51

Patterns essentially identical in L and R heart but pressures in R heart are much lower Both ventricles eject same amount of blood

Answer 52

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

Answer 53

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

Answer 54

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)

Answer 55

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

Answer 56

BPs encountered in great vessels (aorta and pulmonary artery) represent the afterload

Answer 57

Between X2 and X3, isotonic contraction of the ventricles occurs

Answer 58

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

Answer 59

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

Answer 60

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

Answer 61

72 beats per minute

Answer 62

Amount of blood ejected by each ventricle in one minute

Answer 63

CO = HR x SV CO= 72bpm x 70ml/beat = 5.04L/min

Answer 64

Nernst equation

Answer 65

Na/K ATPase

Answer 66

Goldman-Hodgkin-Katz Takes into account relative permeabilities of ions

Answer 67

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

Answer 68

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

Answer 69

Steep vertical AP Plateau Gradual decline

Answer 70

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)

Answer 71

Period after absolute refractory where an AP can be initiated but only with stimulus larger than normal

Answer 72

The time at which a normal AP can be elicited with normal stimulus

Answer 73

``` 0= upstroke (Na) 1= early repolarisation 2= plateau (Ca) 3= repolarisation (K) 4= resting membrane potential (diastole) ```

Answer 74

Calcium influx during early plateau-> trigger Ca release from IC stores Required for contraction Activates rapidly (within ms)

Answer 75

Nifedipine Nitrendipine Nisoldipine

Answer 76

Gradual activation of K currents | Large K current that is inactive during plateau opens when cells have partially repolarised

Answer 77

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

Answer 78

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)

Answer 79

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

Answer 80

Approx 80 APs (and hence heartbeats) per minute

Answer 81

-65mV (but unstable therefore-> more negative)

Answer 82

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

Answer 83

Increases Na influx | Seen by increase in pre-potential slope (therefore threshold is reached more rapidly, HR decreased)

Answer 84

Reduces Na influx | Seen by decrease in pre-potential slope ((therefore threshold is reached more slowly, HR increased)

Answer 85

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

Answer 86

0.3m/s Produces atrial contraction

Answer 87

Interspersed among the atrial muscle fibres | Conduct the AP to the AVN with greater velocity than ordinary muscle (1m/s)

Answer 88

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

Answer 89

Allows atria to complete their contraction and empty their blood into the ventricles before the ventricles contract

Answer 90

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)

Answer 91

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

Answer 92

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

Answer 93

Intercellular communication and impulse conduction rely on gap junctions which form at intercalated discs

Answer 94

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

Answer 95

The waveform that it should record assuming a normal process of excitation

Answer 96

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)

Answer 97

Right foot/leg= zero reference point Point of comparison so potentials can be generated Also removes effect of background electrical noise

Answer 98

``` aVR= R arm aVL= L arm N= R foot aVF= R foot ```

Answer 99

``` Tachyarrhythmias Bradyarrhythmias Myocardial infarction Myocardial ischaemia Cardiomyopathy Assessment of pacing Electrolyte disturbances ```

Answer 100

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)

Answer 101

``` 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

Answer 102

Lead aV couples with standard limb leads to form augmented vectors

Answer 103

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

Answer 104

Standard= Leads 1, 2 and 3 Augmented= aVR, aVL and aVF

Answer 105

Bigger | Because they are coupled

Answer 106

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)

Answer 107

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

Answer 108

Standard (limb leads)= bipolar | Augmented (limb leads) and V1-V6 (precordial leads)= unipolar

Answer 109

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

Answer 110

Upward (shown by positive waveform)

Answer 111

Downward (shown by negative waveform)

Answer 112

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)

Answer 113

Mean frontal plane axis of the ventricles

Answer 114

The wave of depolarisation is towards the positive electrode of the MFPA

Answer 115

The wave of depolarisation is away from the positive electrode of the MFPA

Answer 116

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)

Answer 117

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

Answer 118

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)

Answer 119

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) ```

Answer 120

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

Answer 121

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)

Answer 122

P wave= duration

Answer 123

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

Answer 124

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

Answer 125

1. Is it the correct recording? 2. Identify the leads 3. Check the calibration and speed of the paper (25 mm/s, 1mV = 10mm) 4. Identify the rhythm 5. Look at the QRS axis 6. Look at the P wave 7. Look at the PR interval 8. Look at the QRS complex 9. Determine the position of the ST segment 10. Calculate the QT interval 11. Look at the T wave 12. Check!

Answer 126

``` 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 ```

Answer 127

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

Answer 128

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

Answer 129

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

Answer 130

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)

Answer 131

AV nodal block ``` 1st degree (prolonged PR interval >20s) 2nd degree (Mobitz type 1 or 2) 3rd degree (complete heart block) ```

Answer 132

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

Answer 133

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

Answer 134

- 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

Answer 135

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

Answer 136

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

Answer 137

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

Answer 138

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

Answer 139

To transport blood around the body To deliver oxygen, nutrients and signalling molecules To remove CO2 and metabolites To regulate temperature

Answer 140

By action of a muscular pump (heart) | Generates a pressure gradient that propels blood through a network of tubes (blood vessels)

Answer 141

Left and right ventricles are 2 pumps Physically coupled and pump through the systemic and pulmonary circulations

Answer 142

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

Answer 143

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

Answer 144

Blood would pool CO from RV and LV needs to be same despite differences in pressue

Answer 145

Relatively equal

Answer 146

Exchange function

Answer 147

Reservoir function

Answer 148

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

Answer 149

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

Answer 150

Due to pressure difference | Resistance important

Answer 151

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

Answer 152

Electrical circuit V= I x R ``` V= voltage difference I= current flow R= resistance ```

Answer 153

Fluid circuit P = Q x R ``` P= pressure change Q= volumetric flow R= resistance ```

Answer 154

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

Answer 155

Relationship between pressure and flow Regulation of flow is achieved by variation in resistance while blood pressure remains relatively constant

Answer 156

Small arteries and arterioles

Answer 157

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

Answer 158

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

Answer 159

During exercise, don't need blood flow to kidneys

Answer 160

Laminar flow Viscosity Shear rate

Answer 161

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

Answer 162

``` 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

Answer 163

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)

Answer 164

Shear rate x dynamic viscosity τ = (dv/dr) x µ µ= dynamic viscosity

Answer 165

Velocity of layers increases

Answer 166

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

Answer 167

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

Answer 168

PP = SBP - DBP Pulse pressure = systolic bp - diastolic bp

Answer 169

MBP = DBP + 1/3PP

Answer 170

SBP/DBP (e.g. 110/70)

Answer 171

During systole | Due to the difference in pressure between the ventricles and the aorta

Answer 172

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)

Answer 173

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”

Answer 174

The damping effect Reduced by age and when arteries become stiffer (decreased arterial compliance) NB. PP increases

Answer 175

σ = tension force (T) / wall thickness (h) Tension force (according to Law of Laplace= P x r) σ = (P x r) / h

Answer 176

Vessel distension

Answer 177

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)

Answer 178

The relationship between transmural pressure and vessel volume Depends of vessel elasticity

Answer 179

Venous compliance is 10-20x greater than arterial compliance at low pressures

Answer 180

Increasing smooth muscle contraction decreases venous volume and increases venous pressure (so-> lower compliance) Most blood volume is stored in the veins

Answer 181

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

Answer 182

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

Answer 183

Incompetent valves cause dilated superficial veins in the leg (varicose) Prolonged elevation of venous pressure-> oedema in feet

Answer 184

Arteries- thick muscular walls-> stabilise pulsatile flow Capillaries– very thin walls-> facilitate gas and solute exchange Veins– one-way valves-> maintain unidirectional flow

Answer 185

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)

Answer 186

``` Nitric oxide (NO) Prostacycline (PGI2) Thromboxane (TXA2) Endothelin-1 (ET-1) Angiotensin II (Ang II) ```

Answer 187

SMOOTH MUSCLE Relaxation and inhibition of growth MYOCYTES Increased blood flow Enhanced contractility PLATELETS Inhibits aggregation

Answer 188

SMOOTH MUSCLE Relaxation and inhibition of growth MYOCYTES Increased blood flow PLATELETS Inhibits aggregation

Answer 189

SMOOTH MUSCLE Contraction MYOCYTES Decreased blood flow PLATELETS Stimulates aggregation

Answer 190

SMOOTH MUSCLE Contraction Weak stimulation of growth MYOCYTES Decreased blood flow Enhanced contractility PLATELETS No effect

Answer 191

SMOOTH MUSCLE Contraction Stimulation of growth MYOCYTES Decreased blood flow, remodelling and fibrosis PLATELETS No effect

Answer 192

``` Vasodilation= NO, ET-1, PGI2 Vasoconstriction= TXA2, ET-1, ANGII ``` Imbalance of mediators-> either vasodilation or vasoconstriction

Answer 193

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

Answer 194

Thermoregulation Penile erection (NO)

Answer 195

Laser doppler flowmetry (looks at ACh delivery) Flow-mediated dilatation (with US)

Answer 196

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)

Answer 197

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)

Answer 198

INHIBITION Prostacyclin Nitric oxide ANP, Heparin, HGF & EGF ``` STIMULATION Adrenaline Ang II Vasopressin Steroids IL-1, TGF-β, Endotoxin, endothelin, VECF, tacrolimus, CsA ```

Answer 199

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)

Answer 200

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

Answer 201

Angiotensinogen with renin-> angiotensin I Angiotensin I with ACE-> angiotensin II

Answer 202

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)

Answer 203

Angiotensin converting enzyme Converts angiotensin I-> II Simultaneously degrades bradykinin on epithelial cells (acts on beta-1 receptors to release vasodilators)

Answer 204

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

Answer 205

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

Answer 206

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

Answer 207

NO- donors e.g. nitroglycerine, nitroprusside E-NOS activators e.g. endothelium-dependent vasodilators Phosphodiesterase inhibitors e.g. Viagra, zaprinast

Answer 208

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

Answer 209

Phosphodiesterase inhibitor | Stops phosphodiesterase breaking down cGMP so excess cGMP activity-> vasodilation

Answer 210

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)

Answer 211

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

Answer 212

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

Answer 213

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

Answer 214

Their affinity for channel is related to the membrane potential of the target cells

Answer 215

SMOOTH MUSCLE CELL Response= vasodilation Resting Em= -50mV -ve potentials= higher CARDIAC MYOCYTE Response= negative inotrope Resting Em= -80mV -ve potentials= lower

Answer 216

Often used to reduce systemic blood pressure, NOT to treat angina because the vasodilation and hypotension can lead to reflex tachycardia

Answer 217

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

Answer 218

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

Answer 219

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)

Answer 220

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

Answer 221

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

Answer 222

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

Answer 223

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

Answer 224

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

Answer 225

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

Answer 226

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’

Answer 227

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

Answer 228

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)

Answer 229

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

Answer 230

``` 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)

Answer 231

Adrenaline tends to reduce TPR

Answer 232

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 ```

Answer 233

Renin ACE Aminopeptidase

Answer 234

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

Answer 235

``` Peripheral resistance (-> rapid pressor response) Renal function (-> slow pressor response) Cardiovascular structure (-> vascular and cardiac hypertrophy and remodelling) ```

Answer 236

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

Answer 237

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

Answer 238

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

Answer 239

In RAAS= angiotensin I to II (so increased BP) Breaking down of bradykinin-> inactive so vasodilation can;t happen so BP not decreased

Answer 240

Prevents angiotensin II production-> reduces BP Stops bradykinin from breaking down so bradykinin-> vasodilation-> decreased BP

Answer 241

PHYSIOLOGICAL EFFECTS Maintains body content of Na+, K+ (and water) Increases Na+ (and hence water) retention Increases K+ (and H+) excretion

Answer 242

Previously only knew kidneys, now know brain, heart, vessels

Answer 243

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

Answer 244

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 ```

Answer 245

Hindrance to blood flow due to friction between moving and stationary vascular walls

Answer 246

Volume of blood passing through a vessel per unit time

Answer 247

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

Answer 248

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

Answer 249

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)

Answer 250

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

Answer 251

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

Answer 252

Single cell wall (1 micrometer diameter) Diameter of lumen (7 micrometers) Extensive branching increases surface area -> Minimise diffusion distance and time Maximise surface area

Answer 253

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

Answer 254

Continuous Fenestrated Discontinuous

Answer 255

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

Answer 256

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

Answer 257

Very large gap junctions, therefore large molecules i.e. WBCs can leave blood and enter tissues (and vice versa) E.g. BONE MARROW

Answer 258

Hydrostatic pressure (heart, outward flow into surrounding tissues) Oncotic pressure (protein, inward into capillaries)-> generates osmotic force

Answer 259

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

Answer 260

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

Answer 261

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

Answer 262

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

Answer 263

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

Answer 264

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

Answer 265

No heart to induce flow R lymphatic duct, thoracic duct R and L subclavian veins

Answer 266

3L/day returned from lymphatic system into blood

Answer 267

Lymphatic failure-> fluid accumulation-> oedema

Answer 268

Compliance | Venous return

Answer 269

Blood flow to organs they serve MABP Pattern of distribution of blood to organs

Answer 270

The intrinsic capacity to compensate for changes in perfusion pressure by changing vascular resistance

Answer 271

Myogenic theory Metabolic theory Injury (serotonin release from platelets-> constriction)

Answer 272

Smooth muscle fibres respond to tension in the vessel wall | E.g. as pressure rises, muscle fibres contract and stretch-sensitive channels are involved

Answer 273

As blood flow decreases, 'metabolites' accumulate and vessels dilate When flow increases, 'metabolites' are washed away E.g. CO2, H, adenosine, K

Answer 274

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)

Answer 275

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

Answer 276

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

Answer 277

More innervating the vessels supplying kidneys, gut, spleen and skin Fewer innervating skeletal muscle and the brain

Answer 278

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

Answer 279

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

Answer 280

Sympathetic vasoconstrictor nerves Local controls- O2, K+, CO2, H+, osmolarity, metabolites Circulating hormones e.g. NA

Answer 281

Increasing activity of sympathetic nerves to heart Decreasing activity of parasympathetic nerves to heart Increasing plasma adrenaline

Answer 282

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

Answer 283

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)

Answer 284

Increased respiratory movements-> decrease in intrathoracic pressure Increased venous return Increased atrial pressure (also increased by increased venous return)

Answer 285

Increased plasma adrenaline Increased activity of sympathetic nerves to the heart Decreased activity of parasympathetic nerves to the heart

Answer 286

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

Answer 287

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

Answer 288

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

Answer 289

Baroreceptors reflex most sensitive around 90 – 100 mmHg Carotid sinus baroreceptors respond to pressures between 60 and 180 mmHg

Answer 290

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

Answer 291

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

Answer 292

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

Answer 293

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

Answer 294

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)

Answer 295

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

Answer 296

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)

Answer 297

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

Answer 298

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

Answer 299

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

Answer 300

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)

Answer 301

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

Answer 302

Afferent input to medullary CV centre - Preprogrammed pattern - Muscle chemoreceptors Efferent output to heart, veins and arterioles - Via ANS

Answer 303

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

Answer 304

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

Answer 305

Prevention of blood loos for intact vessels | Arrest of bleeding from injured vessels

Answer 306

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)

Answer 307

Constrict= local contractile response Vascular smooth muscle cells contract locally-> limits blood flow to the injured vessels Particularly important in small blood vessels

Answer 308

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

Answer 309

GAGs – glycosaminoglycan TFPI - tissue factor pathway inhibitor TM – thrombomodulin EPCR - endothelial protein C receptor

Answer 310

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

Answer 311

Unstable platelet plug formed 1. PLATELET ADHESION Recruitment of platelets from flowing blood to site of injury 2. PLATELET ACTIVATION Conversion from a passive to an interactive functional cell 3. PLATELET AGGREGATION Formation of the plug

Answer 312

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

Answer 313

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

Answer 314

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

Answer 315

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)

Answer 316

These clotting factors circulate as inactive precursors (zymogens) Then activated by specific proteolysis (to form either as serine protease zymogens or cofactors)

Answer 317

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

Answer 318

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

Answer 319

Tissue factor | Although FXII can be activated to FXIIa this is mainly in vitro (useful diagnostically)

Answer 320

Activated platelets (PI) which localize and accelerate the reactions Pl= platelet membrane phospholipid

Answer 321

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

Answer 322

tPA and streptokinase (a bacterial activator) Used in therapeutical thrombolysis for Myocardial Infarction

Answer 323

A small amount of factor VIIa produces a large amount of thrombin

Answer 324

Because of coagulation inhibitory mechanisms

Answer 325

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)

Answer 326

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)

Answer 327

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

Answer 328

``` Antithrombin deficiency Protein C deficiency Protein S deficiency Factor V Leiden ALL risk factors for thrombosis ```

Answer 329

1. Fibrinolytic factors, anticoagulant proteins 2. Coagulation factors, platelets Normal 1=2 Bleeding less 2, more 1 Thrombosis less 1, more 2

Answer 330

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

Answer 331

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

Answer 332

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

Answer 333

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)

Answer 334

``` Immediate Easy bruising Nosebleeds (prolonged: >20 mins) Gum bleeding (prolonged) Menorrhagia (anaemia) Bleeding after trauma/surgery Petechiae (specific for thrombocytopenia) ```

Answer 335

Failure to generate fibrin to stabilise platelet plug | Defect= secondary haemostasis (coagulation)

Answer 336

Not enough thrombin generated | Deficiency or defect of coagulation factors I-XIII

Answer 337

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)

Answer 338

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

Answer 339

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

Answer 340

Spontaneous bleeding into joints Hallmark of haemophilia Increases pressure in joints Very painful and damaging

Answer 341

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

Answer 342

Can be used in therapy to break down clots after MI Must be done carefully as can lead to haemorrhage

Answer 343

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

Answer 344

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

Answer 345

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

Answer 346

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

Answer 347

Genetic constitution Effect of age and previous events, illnesses, medication Acute stimulus

Answer 348

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

Answer 349

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)

Answer 350

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

Answer 351

Reduced flow (stasis) increases the risk of venous thrombosis Possibly after surgery, fracture, long haul flight, bed rest

Answer 352

``` 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

Answer 353

Pregnancy Malignancy Surgery Inflammatory response

Answer 354

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)

Answer 355

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)

Answer 356

Heparin= increased anticoagulant activity Warfarin= lower procoagulant factors

Answer 357

Stasis inflammation-> increased coagulation factors, platelets

Answer 358

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

Answer 359

The level of BP above which investigation and treatment do more good than harm

Answer 360

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

Answer 361

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

Answer 362

``` Coronary heart disease Stroke Peripheral vascular disease/atheromatous disease Heart failure Atrial fibrillation Dementia /cognitive impairment Retinopathy ```

Answer 363

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?

Answer 364

Identifiable causes

Answer 365

Twin and other studies suggest 30-50% of variation in blood pressure is attributable to genetic variation but identified SNPs only account for

Answer 366

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

Answer 367

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?)

Answer 368

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

Answer 369

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

Answer 370

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

Answer 371

Hypertension is commonly associated with increase in left ventricular wall mass (LVMI) and changes in chamber size

Answer 372

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

Answer 373

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)

Answer 374

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

Answer 375

Reduction in capillary density-> impaired perfusion and increased PVR Elevated capillary pressure-> damage and leakage

Answer 376

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

Answer 377

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

Answer 378

``` 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

Answer 379

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 1. 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) 2. 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 3. 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 4. 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

Answer 380

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

Answer 381

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

Answer 382

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

Answer 383

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

Answer 384

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

Answer 385

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)

Answer 386

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

Answer 387

``` 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 ```

Answer 388

Homeostasis Safe clearance, reverse cholesterol transport Inflammation Activation of 'bug detector' pathways

Answer 389

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

Answer 390

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

Answer 391

Macrophages accumulate modified LDL to become enlarged foam cells

Answer 392

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

Answer 393

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

Answer 394

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

Answer 395

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

Answer 396

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

Answer 397

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

Answer 398

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

Answer 399

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

Answer 400

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

Answer 401

Angina | Intermittent claudication

Answer 402

Activity of proteases expressed by macrophages fragmenting the matrix of the fibrous cap Can also be caused by intra-plaque haemorrhage

Answer 403

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)

Answer 404

Clearing debris (modified lipoproteins, dead cells) Stimulating “wound healing” response involving VSMCs

Answer 405

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

Answer 406

Protect plaque integrity Contrasting role to macrophages in plaque instability

Answer 407

Stimulate it

Answer 408

``` 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] ```

Answer 409

``` Macrophage accumulation Formation of necrotic core Fibrous-cap formation Angiogenesis Senescence ```

Answer 410

Tunica intima – endothelium Tunica media – smooth muscle cells Tunica adventitia – vasa vasorum, nerves

Answer 411

Endothelial cells surrounded by basement membrane and pericapillary cells (pericytes)

Answer 412

Structure similar to capillaries but more pericytes

Answer 413

Three thick layers, rich in cells and extracellular matrix

Answer 414

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

Answer 415

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

Answer 416

``` Inflammation Mechanical stress Viruses Smoking High blood pressure OxLDL High glucose ```

Answer 417

Recruitment of blood leukocytes into tissues takes place normally during inflammation Leukocytes adhere to the endothelium of post-capillary venules and transmigrate into tissues

Answer 418

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

Answer 419

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

Answer 420

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

Answer 421

``` 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

Answer 422

``` 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 1. Endothelial dysfunction in atherosclerosis 2. Fatty-streak formation in atherosclerosis 3. Formation of an advanced, complicated lesion of atherosclerosis

Answer 423

• formation of new blood vessels by sprouting from pre-existing vessels o Initiated by pro-angiogenic stimulation of a pre-existing mature blood vessel

Answer 424

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

Answer 425

Growth arrest that halts the proliferation of ageing and/or damaged cells

Answer 426

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

Answer 427

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

Answer 428

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

Answer 429

``` 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

Answer 430

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

Answer 431

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

Answer 432

Sudden cardiac death Acute coronary syndrome - Acute myocardial infarction - Unstable angina Stable angina pectoris Heart failure Arrhythmia

Answer 433

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

Answer 434

Like weight on chest radiating to throat and towards arms

Answer 435

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

Answer 436

Decreased normal resting coronary flow

Answer 437

Less stenosis - > More coronary vasodilator reserve - > Higher hyperemic response (mean hyperemic flow/mean resting flow)

Answer 438

Clinical diagnosis Discomfort in chest, jaw, shoulders, arms or back Provoked by exertion of emotional stress Relived by rest

Answer 439

``` 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

Answer 440

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)

Answer 441

Inflammation - Systemic - Local Plaque - Rupture - Erosion Thrombosis

Answer 442

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

Answer 443

Tissue necrosis due to ischaemia

Answer 444

Detached intravascular solid, liquid or gaseous mass that is carried by the blood to a site distant from its point of origin

Answer 445

Formation of a solid mass of blood constituents within the circulatory system Virchow's triad= predisposition

Answer 446

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

Answer 447

People with hypercoagulable states have an increased risk for blood clots Hypercoagulable states are usually genetic (inherited) or acquired conditions

Answer 448

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)

Answer 449

``` Cancer Some medications used to treat cancer, such as tamoxifen, bevacizumab, thalidomide and lenalidomide Recent trauma or surgery Central venous catheter placement Obesity Pregnancy ```

Answer 450

Thrombosis TF/VIIa with co factors-> Xa -> (II) -> IIa-> FIBRINOGEN TO FIBRIN

Answer 451

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

Answer 452

Most patients with ischaemic incidents suffer them

Answer 453

Coronary artery becomes obstructed | Zone of perfusion is area at risk on endocardium-> zone of necrosis

Answer 454

Reduces infarct size (by 40% from 70->30) Cardioprotection reduces infarct size by a further 25%

Answer 455

Acute infraction= hours Infarct expansion= hours to days Global remodelling= days to months

Answer 456

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

Answer 457

``` 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 ```

Answer 458

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

Answer 459

Mechanical e.g. stent Drugs e.g. statins (high dose) and ACE inhibitors

Answer 460

Non-drug e.g. CRT-P/D, progenitor cells Drugs e.g. B blockers, ACE inhibitors, angiotensin R blockers, aldosterone R antagonists

Answer 461

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

Answer 462

``` Thrombus [ACS, TIA, stroke] Air Fat Amniotic Foreign body/material ```

Answer 463

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

Answer 464

A clinical syndrome caused by an abnormality of the heart and recognised by a characteristic pattern of haemodynamic, renal, neural and hormonal responses

Answer 465

50% dead in 3 years

Answer 466

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

Answer 467

``` 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

Answer 468

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

Answer 469

Heart disease in the absence of a known cause and particularly coronary artery disease, valve disease, and hypertension

Answer 470

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

Answer 471

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

Answer 472

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

Answer 473

``` 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

Answer 474

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 ```

Answer 475

``` 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 ```

Answer 476

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

Answer 477

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 ```

Answer 478

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

Answer 479

``` 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

Answer 480

``` 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)

Answer 481

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 ```

Cardiovascular System Flashcards

(514 cards)