Principles - advanced editor Flashcards
how do PT and APTT differ?
stimulate different arms of the coagulation cascade
what is the pressure-volume curve?
what does it reflect?
what does it look like in diastole/systole
yaxis = LV pressure
xaxis = LV volume
shows that as volume in the LV increases, the pressure inside increases
in diastole: - hits a limit where to increase volume further, have to massively increase pressure
in systole - get a plateau with a taller curve
annotate
annotate LV pressure loop
which heart sounds are found at which part of the LV pressure-volume loop?
describe how cardiac pacemaker cells set the intrinsic heart rate
3 phases
Phase 0 - upstroke
- depolarisation
- calcium channels open when threshold is released - calcium influx = depolarisation
phase 3
- repolarisation
- K+ flows out to repolarise celll
phase 4
- spontaneous depolarisation - no stable resting membrane potential, due to leaky Na+ hannels
- Na+ and Ca2+ are flowing in
how do parasympathetics slow the heart rate
Ach binds M2 receptors
- these are negatively coupled (inhibit) adenylate cyclase
- ↓cAMP
- inhibits L-type calcium channels from opening
- reduces the Ca2+ current in phase 0 of cardiac contraction
m2 also open K+ channels - this is a hyperpolarising current
- slowss the fluxes of Na and Ca
- slows phase 4 - it takes longer to reach threshold and fire - slows heart rate
how do sympathetics accelerate the sa node
NA -> binds B1 adrenoceptor
- GPCR (stimulatory)
- activates adenylate cyclase -> ↓cAMP
- cAMP -> activates protein kinase A -> phosphorylates sites on Ca2+ channels -> opens Ca2+ channels
- Ca2+ enters
- increased slope of phase 4 in SA and AV nnodes
- ↑rate of firing of SA node
- ↑conduction in AV ode
can trigger dysrhythmias
increase HR too much - can’t cope
dose determines effect
Histology of atheroma (low power)
- Fibrous cap - often exists on top of plaque
- Lumen - 1/4 size of normal; intima is a lot thicker
- Lipid rich core - necrotic tissues (dead foamy cells, extracellular lipid) has formed the white arrow
- see Blood Vessels - can have bleeding within the plaque
- Lymphocytes (dark purple dots) are also seen
Histology of atherosclerotic plaque
- Chronic inflammatory cells - lymphocytes
- dystrophic calcification
- ECM - laid down by infiltrating smooth muscle cells
- Medial smooth muscle cells
- Cholesterol clefts - point ends; deposition of cholesterol crystals
+ necrotic debris
+ lipids
+ foam cells
What is a foam cell?
Macrophage with foamy cytoplasm - lipid rich
Steps in healing of atherothrombus
heals by organisation
- granulation tissue grows in from the intima of the vessel wall
- infiltrates
=> thrombus is replaced by fibrovascular granulation tissue
this turns into scar tissue
in larger vessels - also see recanalisation
- larger vessels develop within the fibrovascular granulation tissue
What are important sites of atherosclerosis? (5)
- abdominal aorta
- carotid arteries - cerebral infarction
- leg vessels - eg femoral artery narrowing - infarction and damage to peripheries
- renal vessels
- mesenteric arteries - occlusion leads to small bowel infarct
Consequence of atherosclerosis in renal artery
renal artery stenosis - causes atrophy of one kidney -> can cause hypertension
renal infarct - embolism in a kidney - necrosis
Risk factors for atherosclerosis
- Age + gender
- Genetics
- Hypertension
- Diabetes mellitus
- Cigarette smoking
- Lipoproteins profile
- Obesity
- Metabolic syndrome
- Physical inactivity
- Proteinuria
- marker of renal disease
- may be overlap of RF’s (same ones lead to renal disease and atherosclerosis)
- ? Type A personality
- ? Role of low grade infection
How do age and gender impact on risk of atherosclerosis?
Age + gender
- Men >45yrs
- Women: post-menopause
Women
- ? protective role of oestrogen?
- relatively higher HDL in premenopausal women
How does hypertension increase risk of atherosclerosis?
shear stress on blood vessels- subtly damages endothelium
What is a genetic RF for atherosclerosis?
genetics= mutlifactorial
familial hypercholesterolaemia - small % of cases (atherosclerosis at young age)
How does diabetes predispose to atherosclerosis?
oxidative stress and endothelial alterations:
- chronic hyperglycaemia -> advanced gycation end products (AGEs) -> oxidative stress and endothelial alterations
Diabetics have altered balance of LDL and HDL - smaller denser LDL = ‘diabetic dyslipidaemia’
How does cigarette smoking predispose to atherosclerosis?
Toxic damage
May promote thrombosis -> increase risk of complications from atherosclerosis
How does your lipoproteins profile change susceptiblity to atherosclerosis
influenced by genetics, diet
- Elevated low-density lipoproteins (LDL) and very-low-density lipoproteins (VLDL)
- LDL and VLDL are taken up by cells in response to stress and form plaque
- risk is influenced by size and density of LDL
- -> smaller and more dense = more atherogenic
- lipoprotein (a) - elevated levels associated with increased coronary and cerebrovascular disease risk
- Low levels of HDLs
- HDL – prevent oxidation of LDL, and remove cholesterol from circulation
What are some possible complications of atherosclerosis (3)
- Ischaemia
- acute or chornic - depends on the tissue oxygen needs
- due to
- Fixed vessel narrowing +/- endothelial dysfunction leading to impaired release of vasodilators -> relative vasoconstriction of distal smaller vessels = reduces lumen size
- Increased demand for oxygen (other causes)
- Sometimes caused by thrombosis (following acute plaque event) or embolism
- on top of the atherosclerosis
- due to injury, fissuring, ulceration of endothelium
- Infarction
* Not due to the atherosclerosis itself - but something on top (usually thrombus)
* Thrombus may be partially or completely occlusive
* Embolic occlusion: by plaque (athero-embolism) or thrombus (thrombo-embolism)
- Aneurysm
- rupture
- atherosclerosis -> reduced O2 to media -> damage media, weakens, -> dilation
- most common associated wtih atherosclerosis: aorta
How does thrombus occur in atherosclerosis
- Thrombus forms following acute plaque event: ulceration, fissuring, coagulation etc
- Plaques with thin fibrous caps most susceptible to rupture/fissuring - thick caps reduce chance of rupture
- fissure of endothelial wall -> contents of plaque can extrude into blood vessel
- Thrombosis: balance between coagulation and spontaneous fibrinolysis
Aneurysm classifications
Which type does atherosclerosis usually form
True aneurysm (saccular) - focal dilation = berry aneurysm
True aneuryms (fusiform) - entire circumference
atherosclerosis: fusiform
Causes of aneurysms (4)
(1) atherosclerosis
* usually form fusiform aneurysm
(2) congenital weakness in wall
* probably predisposing factor of berry aneurysms around the circle of Willis
(3) systemic hypertension
- arteriolar damage -> form microaneurysms in cerebral arterioles = hyaline arteriosclerosis
- arteriosclerosis -> thickening and hardening of artery -> leads to decreased perfusion of media -> weakening of media -> dilation
(4) infection in artery wall = mycotic aneurysm
other
Complications of aneurysms
rupture - hameorrhage
development of thrombosis + embolism
Vessel dissection
- types
- common sites
- risk factors
- complications
types: A = arises in arch; B = arises further down
sites: aorta, carotids, coronaries
risk factors: hypertension** (+marfan’s)
complications:
- rupture of wall - haemorrhage
- into pleural cavity - death
- into pericardial cavity - tamponade - impair filling - death
- narrow coronary/carotids as they leave aortic arch
- coronary + carotid ischaemia - heart attack, stroke
What are some age-related changes you see in vessels? (age related arteriosclerosis) (3)
- Arteriosclerosis of large arteries
- Intimal thickening of small arteries
- Hyaline arteriolosclerosis - arteriolar hyalinosis
Age related change - arteriosclerosis of large arteries
- pathogenesis
consequences
degeneration of medial elastic tissue and fibrosis (collagen deposition) with age
- leads to loss of elasticity and dilatation
- may increase systolic BP a bit - because not as distensible
see intimal fibrosis - stiffening and thickening of intima
doesn’t cause narrowing of arteries - doesn’t affect blood flow
What is hyaline arteriosclerosis?
RFs
changes in arterial wall
consequences
RF - age, hypertension
Age -> ↑haemodynamic stress on endothelium (aggravated by systemic hypertension)
=> leads to leaky endothelium => deposition of plasma proteins in wall (albumin, fibrinogen, collagen)
Changes in arterial wall
- thickened by hyaline (homogenous eosinophilic glassy materia)
- narrowed lumen
Consequences = narrowed, weakened arteris
- stroke
- chronic ischaemia -> atrophy of supplied tissues
- hypertensive retinopathy (schaemia in retina)
- usually no infarct/acute ischaemia because process is chronic
Ischaemia - definition
causes
Deficiency of O2 blood in a tissue (real or relative) -> shortage of O2, impaired aerobic respiration
(less O2, less waste removal)
Causes
- reduced flow (local vascular narrowing, occlusion)
- increased demand
- systemic hypoperfusion (heart failure, blood loss)
Acute ischaemia
- causes
- effects
- clinical manifestation
Causes- acute narrowing or occlusion, that is not enough for infarct
- often due to increased demand that can’t be met because of atherosclerosis, ventricular hypertrophy (in myocardium)
Effects - depends on the tissue - impaired function, pain; if longer - infarct
Clinical manifestation
- transient ischaemic attacks - eg brain (generally embolic)
- claudication in legs
Chronic ischaemia
- causes
- effects
causes - chronic narrowing of blood vessels - usualyl atherosclerosis
effects - depend on the tissue
- cell, tissue atrophy, often associated fibrosis (macrophages - cytokines)
- impaired healing (requires good blood)
Infarct - definition
- causes
Area of necrosis caused by (acute) ischaemia
Cause: 99% are due to thrombotic/embolic events; almost all arterial
Others - external compression (dissection), vasospasm, systemic hypoperfusion, compartment syndrome
venous causes of infarction
usually thrombotic
otherwise, twisting or compression
how are infarcts classified?
Colour: red (haemorrhage), pale (anaemic)
Presence/abscence of infection - septic or bland
Where do you see haemorrhagic infactrs?
- Venous occlusion
- reperfusion of necrosis
- Loose tissues that allow blood to collect in infarcted zone - lung
- Tissues with dual circulations - lung, small intestine (blood from unobstructed flows to necrotic zone)
pale infacts - where are they found
arterial occlusoin in solid organs with end-arterial circulation
=> solidity limits amount of haemorrhage that can seep into necrotic area
heart, spleen, kidney
what type of infarct seen in brain?
pale + haemorrhagic
what shape are most infarcts?
what might you see in serosal surface?
What do you see at lateral margins
mostly wedge-shaped - occluded vessel at apex, periphery of organ at base
if serosal surface - overlying fibrinous exudate
Lateral margins - follow the blood supply
- start of poorly defined + haemorrhagic
- over time - better defined, with narrow rim of inflammation at edge
Histology of infarct
- features
- when do you see change
- how does it progress over time
Coagulative necrosis - hypereosinophilic, ghost outlines, karyolysis (fading nuclei), loss of detail in cytoplasm
Don’t see any change in first 6-12hrs
OVer time:
- initially acute inflammation (neutrophils)
- healing by organisation= granulation tissue (macrophages, capillaries, fibroblasts, lymphocytes), cells replaced by scar tissue
EXCEPT BRAIN - liquefactive necrosis
-
What are some factors that influence whether ischaemia develops into infarct / affect size of infarct (7)
- Size of the artery occluded
- Duration of occlusion and the vulnerability of the cells to ischaemia (eg neurons vs glial cells; neurons - survive only minutes; cardiac muscle cells - ~20 mins of complete ischaemia requred, where skeletal muscles survive hours)
- Whether the artery is carrying oxygenated or deoxygenated blood
- The nature of the arterial supply -
- end artery
- dual supply (lung, liver)
- natural collateral circulation
- Previous development of a collateral circulation as a result of chronic ischaemia
- The oxygen content of blood
- The state of the systemic circulation
- Rate of development of occlusion
- slowly developing occlusions allow time for collateral vessels to develop/grow
Formation of thrombus - pathogenesis
disturbance of balance between factors that promote thrombogenesis + thrombolysis
= disturbance to virchow’s triad
- endothelial injury (main influence)
- alteration of normal blood flow
- hypercoagulability
how does endothelial injury promote thrombosis
what are some causes of injury
- Endothelial injury - dominant influence
- physical disruption: exposes blood to collagen and tissue factor
- dysfunction: disruption of the normal balance between production of pro- and anti-thrombotic factors
- due to hemodynamic stresses of hypertension, turbulent blood flow over scarred valves, bacterial endotoxins
causes include:
- Direct trauma
- Atherosclerosis
- Immunologic or infective inflammation of endothelium or endocardium e.g. infective endocarditis, vasculitis
- Of endocardium following myocardial infarction
how does alteration to normal blood flow promote thrombosis
what are some causes
- Alternation of normal blood flow = eg stasis, turbulence
normal flow: laminar -> platelets flow centrally, and are separated from endothelium by slower moving, clear zone of plasma
if you disrupt laminar flow
- bring platelets into contact with endothelium
- prevent dilution of active clotting factors by fresh flowing blood
- retard inflow of clotting factor inhibitors and permit the build-up of thrombi
- promote endothelial cell activation
causes include
- Turbulence e.g. in aneurysms
- also causes endothelial injury or dysfunction, forms countercurrents and pockets of stasis
- Slowing e.g.
- In impaired mobility: role of leg muscle pump
- Hyperviscosity of blood
- Atrial fibrillation
How does hypercoagulability promote thrombosis
what are some causes
increase in pro-coagulation factors and decrease in anti-coagulation factors
causes include
- Post operative and post-traumatic states and with severe burns
- Genetic e.g. Factor V Leiden mutation, prothrombin mutation
- Certain malignancies (notably adenocarcinoma of the pancreas), probably via the production of procoagulant substances
- High oestrogen levels: peri-partum, oral contraceptives
- Post myocardial infarction
- Antiphospholipid antibody syndrome
- Obesity
morphology of thrombus (4)
- types of thrombus, what are their defining features
variable size/shape (depends on origin,dev), characteristic - area of attachment to underlying vessel/heart wall
Types
- arterial thrombi
- morphology: grow in retrograde direction from point of attachment
- form due to ulcerated atheroscl plaque/aneurysmal dilation
- tend to be pale = tangled mesh of platelets, fibrin, RBC’s, degenerating leukocytes
- venous thrombi
- morphology: extend in direction of blood flow
- propagating tail not wella ttachmed, prone to fragmentation
- tend to be red = formed in stasis; more RBC
- aneurysms
- thrombi have lines of Zahn (grossly apparent laminations)
- alternating pale layers of platelets + fibrin, darker with more RBC
- thrombosis at site of flow
- thrombi have lines of Zahn (grossly apparent laminations)
- heart = mural thrombi
- form due to abnormal myocardial contraction
Fate of thrombus (4)
- Embolisation
- Fibrinolysis
- usually only in newer thrombi - older thrombi have fibrin polymerisation that renders it more resistant to proteolysis
- Organisation
- may induce inflammation and fibrosis (organisation) and eventually become recanalised - re-establish vascular flow or be incorporated into a thicker vascular wall
- Persistance
- eg thrombi in aortic aneurysms
What are the 3 major cardiovascular causes of death?
Venous thrombo-embolism
ischaemic heart disease
stroke
Risk factors for venous thrombosis vs arterial thrombosis
Venous thrombosis
- More important:
- slowing of blood
- hypercoagulability
- Less important:
- endothelial dysfunction
Arterial thrombosis
- endothelial injury (atherosclerosis, endothelial inflammation, vasculitis)
- turbulence - over plaque, aneurysm
Risk factors for venous thromboembolism
Changes in blood flow
- slowing of blood flow
- impaired mobility (no leg pump)
- cardiac failure (venous pooling)
- dehydration
- hyperviscosity of blood - more RBC
Hypercoagulability
- excessive procoagulability factors, inadequate/non-functional anticoagulative factors
- non-congenital, or genetic
Enothelial injury - direct trauma, surgery, catheters
What are some non-congenital causes of hypercoagulability?
Changes in blood flow
Slowing of flow
impaired mobility (↓ leg muscle pump)
hyperviscosity of blood (↑ RBC)
cardiac failure (↑ P in venous system, venous pooling)
dehydration
Hypercoagulability
Excessive procoagulability factors, inadequate/non-functional anticoagulative factors
Non-congenital
Post operative and post-traumatic states and with severe burns
Post myocardial infarction
activation of reactants, imbalance between pro/anti-coag factors by liver
Malignancy (notably adenocarcinoma of the pancreas)
probably via the release of procoagulant substances by tumour; also chemotherapy
High oestrogens
peri-partum, oral contraceptive use, HRT
Anti-phospholipid antibody syndrome (autoimmune)
Nephrotic syndrome
lose protein in urine
Obesity
imbalance of pro/anti-coag factors by liver; adipose tissue -> cytokines -> change liver function
Certain inflammatory diseases
inflammatory bowel disease, certain acute infectious diseases
? Cigarette smoking
Why is post-MI a hypercoagulable state?
activation of reactants
imbalance between pro and anto-coag factors by liver
Why do some malignancies cause a hypercoagulable state?
probably via the release of procoagulant substances by tumour; also chemotherapy
why is obesity a hypercoagulable state?
imbalance of pro/anti-coag factors by liver; adipose tissue -> cytokines -> change liver function
what are some genetic/inherited conditions that cause hypercoagulability? (4)
- Factor V Leiden mutation (APC doesn’t work)
- Prothrombin mutation -> increase in circulating plasma level of prothrombin
- Deficiencies of anti-thrombin, protein C, protein S
- High factor VIII
What is a Factor V Leiden mutation
Mutation in factor V - involved in coagulation
is normally neutralised by activated protein C (APC) - but the mutation means that APC can’t bind to the cleavage site
=> can’t be neutralised -> hypercoagulability
What is thrombophilia?
group of inherited or acquired disorders that increase a person’s risk of developing arterial/venous thromboses
- thromboses may be recurrent, present at unusual site, or present at young age
- hypercoagulable state
Causes
- genetic/inherited
- malignancy
- antiphospholipid syndrome
- pregnancy, high oestrogens
- other
-> doesn’t include more transient states (post-surgery, transient immobility etc).
Thrombosis - why more common in deep veins than superficial?
What is the most common site of DVT?
What is the most clinically significant site?
Superficial veins drain into deep system via perforating veins (with valves) => blood pools in deep veins, not superficial
Calf veins - most common
proximal veins - more clinically significant - more likely to embolise
Prevention of DVT?
Pharmacological prophylaxis - heparin etc
Mobilisation
Exercises
Compression stockings
Lifestyle - diet etc
Symptoms of DVT
50% asymptomatic
otherwise
If symptoms are present - often very subtle
swelling
redness
warmth
discomfort
pain
tenderness
=> increased blood in superficial veins
long term outcomes for DVT
Fibrinolysis, organisation, complete or partial recanalisation of thrombus
Damaged incompetent valves
- varicose veins (dilations of superficial leg veins (deep veins can’t drain blood because of thrombus -> backup in superficial) )
- chronic venous insufficiency (post-phlebitic syndrome)
- venous stasis
- chronic oedema
- pigmentation - RBC - haemosiderin -> legs: brown
- chronic ulceration - oedematous tissue doesn’t heal well
Embolus - definition
Complications
Embolus - detached intravascular solid, liquid, gaseous mass that is carried by the blood to a site distant from its point of origin (thromboemboli, Tumour emboli, Air emboli, Gaseous nitrogen bubbles in ‘the ‘bends’, Fat and marrow emboli, Amniotic fluid )
Complications
- Infarction at site distal to origin = necrosis of distal tissue - inc gangrene
- Transient ischaemia
- Pulmonary thromboembolism: usually source is DVT above the level of the knee
- if >60% of pulmonary circulation is obstructed - sudden death, right heart failure, or cardiovascular collapse
What is ischaemic heart disease?
eneric designation for a group of closely related syndromes that result from myocardial ischaemia
IHD = coronary artery disease (CAD) = coronary heart disease (CHD)
There is an imbalance between perfusion and demand of the heart for oxygenated blood
Which is worse - ischaemia or hypoxia?
IHD = worse than hypoxaemia -> it results in reduced availability of nutrients and inadequate removal of metabolites
Causes of ischaemic heart disease?
In 90% of cases - the cause of myocardial ischaemia is a reduction in coronary blood flow due to **atherosclerotic coronary arterial obstruction **
Other less common causes of coronary artery occlusion
- thromboemboli from the heart - eg through AF (normally go up carotids)
- vasculitis leading to thrombosis
- aortic dissection
- LV hypertrophy
- Rapid tachycardias (decrease time for perfusion of myocardium - can only occur in diastole)
- Hypoxaemia
- Shock - decrease blood pressure, decrease perfusion pressure in coronary arteries
Territory of the Left anterior descending (LAD)
supplies most of apex of heart, anterior wall of LV and anterior 2/3 of ventricular septum
Left anterior descending coronary artery (40% to 50%): infarcts involving
- anterior wall of left ventricle near the apex
- the anterior portion of ventricular septum
- the apex circumferentially
Territory of Right coronary artery
supplies posterobasal wall of LV, posterior portion of ventricular septum, posterior 1/3 of ventricular septum
if left-dominant circulation (20%) - LCX perfuses posterior 1/3 of IV septum; if ight dominang circulation (80%) - RCA perfuses this
Right coronary artery (30% to 40%): infarcts involving the:
- inferior/posterior wall of left ventricle
- posterior portion of ventricular septum
- inferior/posterior right ventricular free wall in some cases
Territory of left circumflex artery
lateral LV wall
in left-dominant circulation, also perfuses posterior 1/3 of IV septum
Left circumflex coronary artery (15% to 20%):
- infarcts involving the lateral wall of left ventricle except at the apex
Which part of coronary circulation is usually affected by atherosclerosis?
atherosclerosis primarily affects epicardial parts of coronary arteries
- the medium arteries seen on surface of the heart (not intramural branches inside myocardium)
the arteries initially run in endocardium -> then branch of into myocardium
usually in the first several cm of LAD and LCX, and along entire RCA.
What 4 syndromes are encompassed by ischaemic heart disease?
Myocardial Infarction
Angina pectoris (stable, unstable)
Chronic IHD with heart failure
Sudden cardiac death
ischaemic heart disease - the balance of which factors is important?
Imbalance betwen demand of O2 in the heart + supply of O2 in the heart
Demand depends on cardiac workload
- ventricular wall stress (increased stress with myocardial pressure - eg aortic stenosis, hypertension)
- cardiac output - HR, SV
- preload
- afterload
Supply depends on coronary artery flow
- O2 of blood
- blood flow in the myocardium (perfusion pressure is affected by external pressure, vascular resistance)
Anything that increases demand or reduces supply can cause ischaemic heart disease
example:
- fixed atherosclerotic narrowing
- acute plaque event
What has to happen when O2 demand in the myocardium increases?
The blood flow must increase - as the myocardium normally removes all the O2 from the blood
What factors can increase vasodilation in coronary arteries (3)
local metabolites - adenosine, lactate, H+ (produced in ischaemia)
endothelial substances (vasodilators - prostacyclin, NO; vasoconstrictors - endothelin)
innervation - SNS
How does an acute plaque event lead to ischaemic heart disease?
- atherosclerosis with unstable plaque
- if there is rupture/fissure ->blood is exposed to subendothelial tissues -> thrombus formation
- platelets are activated by exposed collagen -> adhesion, secretion, aggregation
- tissue factor activates coagulation cascade -> fibrin formed from fibrinogen
- thrombosis is a dynamic process - may have ischaemia and it just goes away (lysed)
- natural inhibitors of coagulation and promoters of fibrinolysis are present in the blood and on endothelium
- thrombosis here is an acute event -> really quick occlusion/narrowing of artery
- if narrows enough - angina at rest
- increases the narrowing compared to just a plaque
What is the role of inflammation in ischaemic heart disease?
- atherosclerosis begins with inflammation
- inflammation plays role in stages from inception to plaque rupture
- destabilisation of atherosclerotic plaque occurs thru macrophage metalloproteinase secretion
what can induce vasoconstriction (in relation to ischaemic heart disease)
- circulating adrenergic antagonists
- locally released platelet contents
- imbalance between endothelial cell-relaxing factors (NO) and contractive (endothelin) due to endothelial dysfunction
- mediators released from perivascular inflammatory cells
Management of ischaemic heart disease
Lifestyle modifications - reduce risk factors
- smoking
- physical activity
- weight
Treatment of underlying
- hypertesion
- dyslipedaemia
- diabetes
Treat symptoms - Pharmacological interventions
- nitrites
- beta-blockers
- calcium channel blockers
- angiotensin converting enzyme inhibitors, anti-platelet agents, fibrinolytics, anticoagulants, lipid lowering drugs
Ivabradine - reduces HR -> reduces risk of MI
- only pharmacological intervention that reduces risk, others only treat symptoms
Revascularisation
- PCI - percutaneous coronary intervetion
CABG - Coronary artery bypass graft
Stable angina
- cause
- symptoms
consequences
Cause = stable plaque that narrows artery by at least 70%
- acute ischaemia on exertion: demand > supply
Pathogenesis
- stable plaque - reduce supply of blood (fixed narrowing)
- initially have remodelling of vessel wall to prevent stenosis, later fixed narrowing
- vasodilation impaired because of plaque
- also have endothelial dysfunction - impaired release of vasodilators
- when demand > supply - not enough O2
- ATP depletion -> acidosis
- accumulation of local metabolic products - lactic acid, adenosine -> act on nerve endings -> pain
- dyspnoea:
- relaxation of myocardium is energy dependent - can’t dilate LV -> ↑LA P -> pulmonary congestion
Signs and symptoms
- predictable, episodic chest pain
- associated with exertion or other types of increased demand (eg tachycardia)
- crushing, squeezing
- substernal
- radiation of pain: left arm, left jaw
- relieved: by rest (reduce demand)
- or nitroglycerin (vasodilator - increases coronary perfusion)
- ECG findings - ST depression
In long run, chronic narrowing can lead to heart failure
What is variant angina?
vasospastic - coronary vasospast at rest
unpredictable
unknown mediator
Classifications of gangrene
Primary: gas gangrene
Secondary = tissue is already dead (eg of ischaemia/infarct)
- black colour is from altered haemoglobin
- Types:
- Wet gangrene: e.g. complicating acute appendicitis or cholecystitis or infarction of small bowel; usually secondary to a bacterial infection, not infarct
- Dry gangrene: with infarction of toes/ foot/ leg – usually there is mummification and saprophytic organisms are few
- usually secondary to ischaemia - eg PVD
- may have small amount of bacteria
Most common valve disease
Aortic stenosis
what is the ejection fraction?
how much of the end diastolic volume is ejected during systole
is normally ~50%
What are the 2 broad categories of valve pathologies?
What do effect do they have on the heart
Valve stenosis + incompetence
Valve stenosis = narrowing
- pressure gradient is created across the valve - need to generate pressure to push blood through
- pressure overload on the ventricle/atrium
Valve incompetence = regurgitation = leak
- heart needs to pump a greater stroke volume to maintain forward CO
- have ↑EDV in atrium/ventricle -> try to ↑ejection fraction to compensate
what compensations do you see in atrium/ventricle with
-stenosis (of aortic valve/mitral valve)
incompetence (of aortic valve, mitral valve)
Stenosis
- artic stenosis = LV concentric hypertrophy
- mitral stenosis = LA dilatation + increased P -> pulmonary hypertension
Regurgitation
- aortic regurgitation- LV dilatation
- mitral regurgitation - LA dilatation. LV dilatation
what are the most common causes of defective valves?
primary cause used to be rheumatic fever - now uncommon, except for in NT
now: generally due to degenerative conditions - acquired defects
- myxomatous mitral valve (genetic or acquired) - 2% population
- degenerative: calcification
- inflammation - rheumatic fever, infective endocarditis, immune mediated
occasionally congenital
- bicuspid aortic vale (should be tricuspid) - 1% population
- can function normally, but more susceptive to endocarditis + calcification
consequences of defective valves
cardiac compensation is very effective - even severe lesions can be asymptomatic for many years
eventually compensation fails
- ventricular enlargement and irreversible failure
- regurgitation: irreversible LV changes occur about the same time that symptoms develop
- have to intervene early - acc to echo
- stenosis - symptoms indicate the time to intervene
- LVH changes usually regress
in which valvular disorders must you intervene before symptoms?
in which can you wait?
intervene: aortic and mitral regurgitation
wait: mitral or aortic stenosis
murmurs - which ones are systolic, whcih are diastolic
Systolic murmurs
- aortic stenosis
- mitral regurgitation
Diastolic murmurs
- aortic regurgitation
- mitral stenosis
possible interventions for dodgy valves
valve replacement
- mechanical prosthetic: metal, plastic
- thrombogenic - lifelong anticoagulant treatment, due to no normal anti-thrombotic properties of endothelium
- also susceptible to infective endocarditis
- last a lifetime
- bioprostheses - pig valves, calf pericardium, human
- not thrombogenic
- last only 10-15 years
valve repair
especially mitral valve
balloon valvotomy
stretch out valve
stent valves
deliver percutaneously
struts hold valve into aorta - can be applied using balloon
valve prostheses - mechanical vs bio
mechanical prosthetic: metal, plastic
- thrombogenic - lifelong anticoagulant treatment, due to no normal anti-thrombotic properties of endothelium
- also susceptible to infective endocarditis
- last a lifetime
bioprostheses - pig valves, calf pericardium, human
- not thrombogenic
- last only 10-15 years
Aortic stenosis
- common cause
- consequence on left ventricle
- clinical sign
- when do you intervene
- older patients: usually calcific, fibrosis; otherwise congenital/rheumatic
- reduces valve area -> creates a pressure gradient across valve -> puts pressure overload on LV
- LV compensates through concentric hypertrophy -> less compliant - diastolic dysfunction and requires atrial contraction (need ↑LVEDP to fill the LV)
- sign - systolic murmor, crescendo-decrescendo
- intervention: trigger is development of symptoms, surgery to replace or repair valve
(once you get rid of pressure gradient, changes to LV reverse)
aortic regurgitation
- cause
- consequences of regurgitation on left ventricle
- clinical sign
- intervention
sign of acute severe aortic regurgitation
- cause:
- damage to aortic leaflets (rheumatic fever, endocarditis)
- dilation of aortic root (marfan’s, aortic dissection)
- consequeces: part of SV leaks back with each contraction - have volume overload on LV -> increased EDV -> LV dilation
- see: increased EDV, increased ejection fraction, decreased aortic diastolic pressure
- no pressure gradient
- clinical sign: early diastolic murmur, 2nd heart sound is lost - valve not closing, bounding pulse (increased ejection pressure) or collapsing pulse (↓aortic diastolic pressure)
- intervention: valve replacement, repair - track with echo, must do it before decompensation
decompensation
- ↑LV diastolic volume
- ↓LV function
- ↑LV systolic volume
acute aortic regurgitation
- sudden ↑LVEDP and LAP
- acute pulmonary oedema
- cardiogenic shock
Mitral regurgitation
- causes
- consequences on left ventricle
- clinical signs
- management/intervention
causes:
- myxomatous degeneration (mitral valve prolapse) - enlarged chordae tendanae etc
- infective endocarditis
- MI - ruptured papillary
- rheumatic fever
- marfan’s, cardiomyopathy (change ventricle shape)
- consequeces:
- part of SV ejected into LA from LV -> have volume overload -> to pump out same CO, the LV must pump a greater SV with each beat
- see: increased EDV, increased ejection fraction to maintain same ESV
- consequences: dilated LA (risk of AF), may see right sided heart failure (pulmonary congestion, oedema, hypoxia)
- decompensation: ↑LV diastolic volume, ↓ejection fraction, ↑LV systolic volume
clinical signs
- pansystolic murmur
management: watch development of echo, once symptoms occur - too late, has decompensated
Mitral stenosis
- causes
- consequences on heart chambers
- what risks are associated with mitral valve
- management + interventions
- almost always due to rheumatic fever
consequence:
- pressure gradient across valve - need left atrial contraction; LV systolic function is unaffected ( not a cause of LV heart failure)
- LA is dilated -> increased LA vlume and pressure
- can cause right sided failure (pulmonary congestion, oedema, hypoxia etc)
risks
- dilated LA -> atrial fibrillation
- risk of thrombus in LA
management - trigger for intervention: symptoms, or pulmonary hypertension on echo
then valvotomy, valve replacement
Definitions for murmus
- pansystolic
- ejection systolic
Pansystolic - same intensity through systole
Ejection systolic = crescendo-decrescendo
increasing and decreasing intensity through systole; gets louder and then softer
Type of murmur
- aortic stenosis
- mitral regurgitation
AS - systolic, crescend-decresendo
- during systole - the gradient between the LV and aorta increases -> increasing sound
MR - systolic, pansystolic
- the gradient during systole is very high thoughout - doesn’t change too much
In what ways does the body inappropriately try to compensate for heart failure?
- Hypertrophy of cardiac myocytes
- try to grow so that can increase CO and make up for heart failure - Na+ and water retention - Starling effect -> want to increase venous return to increase CO
- reduced blood pressure -> increased sympathetic outflow -> increased renin production by kidneys -> increased angiotensin II
- angII -> vasoconstriction -> reduced blood flow to kidneys -> inc. Na+ and water retention
- angII -> aldosterone -> Na+ retention - Activation of nervous system
- increase noradrenaline -> increases contractility
What is hypertrophy (LV)
increase in LV mass relative to body size
- increase in myocardial cell size (not number)
- more mitochondria, myofibrils, sarcoplasmic reticulum
- increased fibroendothelial cell numbers
- increased interstitial matrix
Causes of LV hypertrophy
Injury to cardiac muscle:
Environmental
- Concentric pressure overload - high afterload
- hypertension
- aortic stenosis
- Eccentric pressure overload - high preload
- mitral regurgitation
- aortic regurgitation
- ventricular septal defect (shunt)
- myocardial infarction
- cardiac injury - eg myocarditis
- systemic disease
- obesity
- diabetes
- renal failure
- infiltration
- proteins - eg amyloid -> amyloidosis
Genetic
- Hypertrophic cardiomyopathy
- Fabry’s disease
- enzyme deficiency - we can now treat (manufacture enzyme)
Mechanisms of LV hypertrophy
not well understood
- Angiotensin
- Aldosterone
- Catecholamines
- Local factors
- Cellular and molecular mechanisms
- ?stem cells
for each of concentric, eccentric hypertrophy and remodelling:
- does LV mass change?
- does relative wall thickness change?
- does heart size change?
- intracellular changes
concentric
- increase LV mass
- increase relative wall thickness
- constant heart size
- due to pressure overload
- more sarcomeres in parallel
eccentric
- increase LV mass
- normal wall thickness
- greater heart size
- due to volume overload
- myocyte stretching - more sarcomeres in series
remodelling
- smaller heart with increased wall thickness but constant mass
Why does concentric LV hypertrophy occur?
How does it compensate
what are the consequences
compensation for pressure load - high afterload
thicker wall - reduce wall stress and maintain pumping ability
- maintain systolic function
- diastolic dysfunction - thick wall, doesnt fill as well. need increast EDP to get the same EDV (causing back pressure)
consequences:
- contraction from left atrium becomes important to fill LV - can lead to atrial fibrillation
how does eccentric hypertrophy compensate for increased preload?
increases EDV to maintain the same SV (increases ejection fraction)
What are the consequences of hypertrophy?
_Diastolyc dysfunction _
- heart can work well in systole (grew to compensate) - but doesn’t fill well -> stiff ventricle
- increased LVEDP required to acheive the same EVEDV -> higher P req for same vol
- causes back pressure - increased LA and pulmonary vein pressure
- increase chance of pulmonary congestion - SOB
- more sensitive to fluid loading (inc preload) -> which can lead to heart failure; more sensitive to dehydration (decrease preload - by decreasing BP) - ventricle is stiff and can’t recalibrate
- CO falls
Atrial fibrillation can occur - the contraction from the atrium is more important (because of inc EDV) - can lead to fibrillation
Decompensation
in the long term
LV dilates - eventually to the extent that it cannot increase SV anymore
reduced systolic function and cardiac output
decrease in ejection fraction
increase LVEDV
increase in LVESV
increased LVEDP
eventually have heart failure
Risk factor for: cardiac events
Ischaemic Heart Disease
Increased mortality risk following an MI
worst: concentric -> eccentric -> concentric remodelling -> normal
Cardiac failure
Atrial Fibrillation
because of increased EDV - need harder contraction from atrium
Stroke
Which type of hypertrophy is the worst work increasing risk of ischaemic heart disease?
eccentric -> concentric remodelling -> normal
What is decompenation (regarding LV hypertrophy)
what happens to CO, LVEDP, LVESV, LVEDP, ejection fraction
LV dilates - eventually to the extent that it cannot increase SV anymore
- reduced systolic function and cardiac output
- decrease in ejection fraction
- increase LVEDV
- increase in LVESV
- increased LVEDP
eventually have heart failure
when does left ventricular remodelling occur?
why? what processes are involved?
what changes are seen?
how can you block the process pharmacologically?
following MI - infarct scar thins out, whole heart dilates and you see gradual failure of whole LV
(patient survives MI, and then goes into HF a year later)
involves myocyte hypertrophy and apoptosis, and interstitial fibrosis
changes: ↑LV volume, more spherical shape
block with angiotensin blockers and beta blockers
Causes of right ventricular hypertrophy
- Congenital
- eg. Transposition of Great Arteries (right ventricle pumps into systolic system )
- Pulmonary Hypertensio
- RV has to pump harder
- causes : lung disease, pulmonary embolus, chronic L heart failure,
- Right heart valves
- less common than L valve disease
- pulmonary stenosis/regurgitation
- tricuspid regurgitation
- What is hypertrophic cardiomyopathy?
Genetic disorder - mutation in sarcomere proteins
Mechanism unclear, but ↑LV wall thickness -> much thicker hypertrophy than hypertension-related
- cellular hypertrophy + myocyte disarray
Hypertension - what are the different drugs you can use to treat?
AABCD, other
A= angiotensin converting enzyme inhibitors
A = angiotensin receptor antagonists
B = beta blockers
C = calcium channel blockers
D = diuretics
Other
How do ACE inhibitors work in treatment of hypertension?
what is their suffix
Side effects
“-prils”
Block AngI -> AngII
-> stop effects of AngII
Also prevent breakdown of bradykinin -> vasodilation
Normal activity of AngII
- increase sympathetic activity
- increase aldosterone = salt + water retention
- increased vasoconstriction, increased BP
Side effects
- first-dose hypotension (Start low)
- dry cough
- hyperkalaemia
- acute renal failure
Pathophysiology of rheumatic fever
Molecular mimicry
Streptococcal infection
Tcells are activated by binding of streptococcal antigens. Streptococcal M-protein shares epitopes wtih proteins found in the synovium, heart muscle and heart valve. The ant-M T cells infiltrate heartl, valves, skin
=> nonspecific infalmmation in joints, carditis (valves -> endocardium -> myocardium -> pericardium)
Pathogenesis of MI
- Myocardial infarct => also leads to cessation of blood flow to cardiac tissue =>also leads to autonomic nerve death
- contratile dysfunction
- Necrosis
- inflammation + migration of neutrophils
- phagocytosis of dead myocytes (also leads to loss of functional tissue)
- infiltration of myofibroblasts
- deposition of collagen 3
- scarring process begins
- loss of functional tissue
- contractale dysfunction
- decrease compliance
- decrease CO
