cardio Flashcards
6 examples of congenital structural heart diseases?
ventricular / atrial septal defect
coarctation of the aorta
tetralogy of fallot
patent formane ovale / ductus arteriosis
what are the 4 hallmarks of tetralogy of fallot?
vsd
wide aorta (over both ventricles)
right ventricle hypertrophy
pulmonary stenosis
what is coarctation of the aorta?
narrowing of aorta → ventricle has to pump much harder - increased afterload
Risk factors for aortic stenosis?
older age hypertension LDL levels smoking ↑ CRP congenital bicuspid valves CKD radiotherapy
what is aortic stenosis preceded by?
aortic sclerosis (thickening without flow limitation)
how is aortic stenosis suspected?
early-peaking systolic ejection murmur (shrill)
confirmed with echo
3 causes of aortic stenosis?
rheumatic heart disease
calcium build up
congenital heart disease
outline the pathophysiology of aortic stenosis?
abnormal blood flow across valve (eg bicuspid) → damage to valvular endocardium → inflammatory response → leaflet fibrosis and calcium deposition on valve → progresses → ↓ aortic leaflet mobility → stenosis
how does rheumatic heart disease lead to aortic stenosis?
autoimmune inflammatory reaction triggered by streptococcus infection that targeted valvular endothelium → inflammation → calcification → stenosis
what can be the trigger for rheumatic heart disease?
streptococcus infection
what happens to the heart as aortic stenosis progresses?
left ventricular hypertrophy as after load increases
stenosis worsens and wall stress increases → systolic function decreases → systolic heart failure
history and presentation of aortic stenosis?
exertion dyspnoea
fatigue
ejection systolic murmur
h/o rheumatic fever, high LDL, CKD, over 65
what 4 investigations can be carried out for aortic stenosis?
transthoracic echocardiogram
ecg + chest x ray for LVH
catheterisation
mri
what is the primary treatment of symptomatic aortic stenosis?
aortic valve replacement
when is aortic valve replacement the first line treatment for aortic stenosis?
in symptomatic AS
in asymptomatic with severe AS with LVEF < 50%/undergoing cardiac surgery
severe AS but asymptomatic with rapid progression, abnormal exercise test, elevated BNP
management options for aortic stenosis?
AVR
balloon aortic valvuloplasty
antihypertensives
statins
what is aortic regurgitation?
the diastolic leakage of blood from the aorta into the left ventricle
what valve incompetencies are more common than AR?
AS and MR
what can chronic AR culminate in?
congestive heart failure
how can acute AR present?
sudden onset of pulmonary oedema, hypotension/cardiogenic shock
= medical emergency
6 causes of aortic regurgitation?
rheumatic heart disease infective endocarditis aortic stenosis congenital mitral bicuspid valve congenital heart defects aortic root dilation
5 causes of aortic root dilation?”
marfan's syndrome connective tissue/collagen vascular diseases idiopathic ankylosing spondylitis traumatic
how does infective endocarditis lead to AR?
rupture of leaflets , paravalvular leaks, vegetations → inadequate closure of leaflets
pathophysiology of acute AR?
↑ blood volume in LV during systole and ↑ end-diastolic LV pressure → ↑ pulmonary venous pressure → dyspnea and pulmonary oedema → heart failure → cardiogenic shock
pathophysiology of chronic AR?
gradual ↑ in LV volume → LV eccentric hypertrophy (dilates to help maintain normal pressure)
initially EF is normal/slightly raised
eventually falls and ESV ↑
SP rises, DP falls
→ dyspnea, lower coronary perfusion→ ischemia, necrosis. apoptosis
how can acute AR present?
tachycardia cardiogenic shock cyanosis pulmonary oedema Austin flint murmur
what is the Austin flint murmur?
hear at apex of heart in acute AR, caused by blood hitting LV wall
rumbling diastolic murmur
how can chronic AR present?
wide pulse pressure
corrigans pulse
pistol shot pulse - Traube sign
what is Corrigan pulse?
excessive visible pulsations often seen in chronic AR
4 investigations that can be carried out in AR?
transthoracic echo
chest xray
cardiac catheterisation
cardiac MRI/CT
first line management for chronic asymptomatic AR?
normal LV function → positive ionotrope and vasodilator drugs
first line management for chronic symptomatic AR?
valve replacement with adjunct vasodilator therapy
main cause of mitral stenosis in developing countries?
rheumatic fever
what does mitral stenosis progress to?
pulmonary hypertension and right heart failure
causes of mitral valve stenosis?
rheumatic fever carcinoid syndrome sertotenergic drugs SLE mitral annular calcification amyloidosis RA Whipple disease congenital valve deformity
when does mitral stenosis often present?
years after rheumatic fever
why does exertion dyspnoea present in mitral stenosis?
increase in left atrial pressure during moderate exercise/tachycardia
how does severe mitral stenosis lead to dyspnoea at rest?
very high left atrial pressure → transudation of fluid into lung interstitium
how can haemoptysis occur as a result of mitral stenosis?
↑ LA pressure → pulmonary hypertension → brachial vein rupture
how can mitral stenosis present?
dyspnoea orthopnea diastolic murmur loud P2 neck vein distention hemoptysis h/o rheumatic fever 40-50 yrs
5 investigations for mitral stenosis?
ECG chest x ray cardiac catheteristation chest CT/MRI transthoracic echo
management for progressive asymptomatic MS?
no therapy
management for severe asymptomatic MS?
no therapy
can offer adjuvant balloon valvotomy
management for severe symptomatic MS?
first line : diuretic + balloon valvotomy, valve replacement or repair
adjuvant : beta blockers
causes of acute mitral regurgitation?
mitral valve prolapse rheumatic heart disease infective endocarditis post valvular surgery prosthetic mitral valave dysfucntion
causes of chronic mitral regurgitation?
rheumatic heart disease scleroderma SLE hypertrophic cardiomyopathy drug related
how does infective endocarditis lead to MR?
accesses form leading to vegetations on the valves → ruptured chordae tendinae → leaflet perforation
in chronic MR what changes are seen in the heart?
eccentric hypertrophy of LHS
increased preload and end diastolic volume
decreased after load and end systolic volume
→ LV dysfunction
presentation of MR?
dyspnoea, orthopnea high pitched, blowing murmur diminished S1 fatigue chest pain atrial fibrilaltion
MR investigations?
ECG chest xray mri/ct echo catheterisation
management for acute MR?
emergency surgery adjunct preoperative diuretics and intra-aortic balloon counterpulsation
management for chronic asymptomatic MR
1st line CE inhibitors + beta blockers
surgery if LV EF < 60%
management for chronic symptomatic MR
surgery + medical treatment if LV EF ≥ 30%
LVEF <30% → medical + intraaortic balloon counterpulsation
3 types of cardiomyoptahies?
dilated
hypertrophic
restrictive
causes of dilated cardiomyopathy? primary and secondary?
primary - familial , idiopathic w/out fhx
secondary - valve disease, post natal, thyroid disease, myocarditis, alcoholism, autoimmune, drug ingestion, mitochondrial disorders
dilated cardiomyopathy pathophysiology?
left ventricle eccentric hypertrophy → ↓ EF and ↑ ESV → ↑ ventricular wall stress
compensation → ↑ HR and ↑ tone of peripheral vascalature, activation of RAAS, ↑ catecholamines, ↑ natriuretic peptides
eventual heart failure
presentation of dilated cardiomyopathy?
dyspnoea
systolic murmur, displaced apex beat, s3
fatigue, angina, pulmonary congestion , ↓ CO
investigations for dilated cardiomyopathy?
genetic testing viral serology ECG CXR catheterisation cardiac mri/ct exercise stress test echo
management for dilated cardiomyopathy?
diet modifications → ↓ fluids and na+
treat underlying cause
acei, b blockers, diuretics, arbs → if ineffective → LVAD/ICD/transplant
anticoags for atrial fibrillation
how could you characterise dilated cardiomyopathy?
enlarged ventricle chamber with systolic dysfunction
normal wall thickness in LV
what is the leading causing of sudden cardiac death in adolescents and preadolescents?
hypertrophic cardiomyopathy
how is hypertrophic cardiomyopathy characterised?
increased left ventricle wall thickness not explained by abnormal stresses
abnormal diastolic function
which area of the lv is most often involved in hypertrophic cardiomyopathy?
inter ventricular septum → obstructs outflow from LV
what valve disorders can dcm lead to?
mitral and tricuspid valve regurgitation as valves don’t fully close when walls are stretched
how is diastolic function affected in hcm?
smaller ventricular chamber and less compliant walls → less filling in diastole →↓ stroke volume → diastolic heart failure
what is the Venturi effect?
outflow of lv is obstructed by enlarged interventricular septum → increased blood flow velocity → pulls mitral valve leaflet towards septum → further obstruction
what is often the first clinical manifestation of hcm?
death due ventricular tachycardia or arrhythmia - increased muscle requires more oxygen but theres reduced blood flow so tissue becomes ischaemic
commonest cause of hcm?
genetic mutation
how can hcm present?
sudden cardiac death
syncope
s3 gallop
congestive heart failure
dizziness, palpitations, angina, dyspnea
ejection systolic murmur (crescendo, descendo)
investigations for hcm?
Hb levels bnp and troponin t levels echo cxr cardiac mri
management for hcm?
1st : b blockers, verapamil
2nd : disopyramide
3rd : mechanical therapy , septal myectomy, ablation §
how is restricted cardiomyopathy characterised?
diastolic dysfunction
enlarged atrium
ventricles are less complaint but have normal wall thickness and volume
pathophysiology of rcm?
depositions in heart tissue → stiffer ventricles → less compliant → cannot stretch as much → less diastolic filling → less stroke volume → diastolic heart failure
causes of rcm?
genetic
idiopathic
secondary : amyloidosis, sarcoidosis, fabry’s disease, haemochromatosis, radiation → depositions in heart tissue
how can rcm present?
patient prefers sitting ascites pitting oedema hepatomegaly , ± painful weight loss cardiac cachexia
how can amyloidosis present as in rcm?
macroglossia
carpal tunnel syndrome
easy bruising
periorbital purpura
investigations for rcm?
fbc, serology, amylodois check
cxr, ecg, echo, catherisation, mri
management for rcm?
heart failure → ACEi, ARBs, diuretics, aldosterone inhibitors antiarrhythmic therapies immunosuppression pacemaker transplant
EF =
EDV /SV x 100
CO =
HR x SV
MAP =
DP + 1/3 (PP)
= DP + 1/3 (SP-DP)
what is infective endocarditis?
infection of endocardium or vascular endothelium of heart
what heart structure is most often affected in endocarditis?
the valves
what bacteria is most common cause for infective endocarditis?
streptococcus
pathophysiology of infective endocarditis?
bacteria adhere to damaged endothelium and microthrombi → proliferate → macrophage, neutrophil infiltration → platelets fibrin → vegetation
how can infective endocarditis present?
fever, malaise, swetas, unexplained weight loss
heart murmur
anemia, raised infection markers
investigations for infective endocarditis?
fbc, cultures
echo → vegetation , abscess , valve perforation , regurgitation
what type of echo is more sensitive over another in infective endocarditis?
transoesophageal better than transthoracic
what criteria are used to assess possible infective endocarditis ?
Dukes
what are dukes criteria?
Major :
postive blood culture for typical organisms ≥2 times
echo : vegetation, prosthetic valve dishedence , abscess
new regurgitation murmur
coxiella burnetti infection
Minor:
predisposing heart condition or IV drug use
fever ≥ 38C
vascular - emboli, janeway lesions
immunological - glomerulonephritis, roths spots, oslers nodes, janeway lesions
other +ve blood culture
what is required for +ve IE diagnosis?
2 major
1 major + 3 minor dukes criteria
5 minor
what is required for possible IE diagnosis?
1 major + ≥2 minor dukes
3 minor
signs and symptoms of cardiac decompensation?
SoB, coughing, ascites and ankle swelling , fatigue
↑ JVP , lung crackles, oedema
vascular/embolic phenomena : stroke, janeway lesions, splinter/conjunctival haemorrhages
immunological phenomena : osler nodes , Roth spots
what valve is most commonly affected in IE?
aortic ≥ mitral ≥ right sided
advantages if ecg?
cheap and easy
reproducible between people and centres
quick turnaround
what cells make up the SAN?
autorhythmic myocytes
what is seen on ecg when the avn is depolarised?
isoelectric line - slows signal transduction
why are no deflections seen on ecg when the bundle of his is depolarised?
well insulated
what is the placement of each limb lead? and direction?
aVr - right arm (210/-150) aVl - left arm (-30) avF - left leg (90) N - right leg lead I - (RA → LA) (0) lead II - (RA → LL) (60) lead III - (LA→LL) (120)
where are the chest leads placed?
V1 - right sternal border, 4th intercostal space
V2 - left sternal border, 4th intercostal space
V3 - between v2 and v4
V4 - mid clavicular line in 5th intercostal space
V5 - ant axillary line at v4 level
V6 - mid axillary line at v4 level
what planes do the limb and chest leads look at?
limb - coronal
chest - axial
which leads are associated with the left circumflex artery?
I
aVL
V5
V6
which leads are associated with the right coronary artery?
II
III
aVF
which leads are associated with the left anterior descending artery?
V1 - V4
5 little squares = how many seconds on ecg?
2s
what is sinus rhythm?
P waves followed by QRS in 1:1
regular rate
normal bpm
what can cause sinus bradycardia?
can be normal
vagal stimulation
meds
what is sinus arrhythmia?
each p wave followed by qrs
irregular rate but normal bpm
R-R interval varies with breathing (shortens on inspiration and HR increases)
what counteracts the SAN to maintain heart rate?
vagus nerve
how is atrial fibrillation seen on ecg?
oscillating baseline - no isoelectric as atria are contraction asynchronously
irregular rhythm , slow rate
atrial fibrillation increases risk of?
clotting due turbulent flow
how is atrial flutter seen on ecg?
regular saw tooth pattern in baseline in leads II, III, aVF
atrial : ventricular beats → 2 : 1 / 3 : 1
how is first degree heart block seen on ecg?
prolonger P-R interval → slower AV conduction
regular rhythm 1:1 P:QRS
progressive disease of aging
how is mobitz I seen on ecg?
gradual prolongation of P-R interval until beat skipped - no QRS after p wave
regular irregular rhythm
what causes mobitz I?
diseased AVN
another name for mobitz I?
wenckebach
how is mobitz II seen on ecg?
regular p waves but only some followed by qrs
no p-r elongation
regularly irregular
can rapidly deteriorate into third degree
how is third degree heart block seen on ecg?
regular p waves and qrs complexes but no relationship
p waves can be hidden in bigger vectors
non-sinus rhythm
how is ventricular tachycardia seen on ecg?
hidden p waves
regular rate but fast (100-200bpm)
dissociated atrial rhythm
give 2 examples of a shockable rhythm?
ventricular tachycardia
ventricular fibrillation
how is ventricular fibrillation seen on ecg?
irregular hr
fast (≥250bpm)
filling and ejection uncoordinated
what causes ST elevation?
infarction of tissue by hypo perfusion eg obstructed vessel
ST elevation is seen in leads II, III and aVF. what does this indicate?
obstruction in RCA
what causes ST depression?
myocardial ischaemia due to coronary insufficiency
what is the normal axis range?
-30 to 90
what can cause an axis change?
hypertrophy - deviation to side of hypertrophy
infection/ischaemia - deviation away
what happens immediately after damage to endothelial vessel lining?
vascular smooth muscle contract → constrict vessel → limit blood flow to vessel
outline primary haemostasis?
platelets bind to collagen (adhesion)
- indirectly : VWF via GIpIb receptor
-directly : via GIpIa receptor
ADP and thromboxane (from arachidonic acid) released
platelets aggregate using fibrinogen and calcium to connect in GIpIa/b receptors
what can cause thrombocytopenia?
leukaemia , B12 deficiency (bone marrow failure)
Immune thrombocytopenic purpura , disseminated intravascular coagulation (accelerated clearance)
pooling and destruction in spleen
what can cause impaired platelet function?
hereditary absence of glycoproteins or granules
drugs such as aspirin, clopidogrel, NSAIDS
3 examples of hereditary platelet defects?
glanzmanns thrombasthenia
Bernard soulier syndrdome
storage pool disease
what does arachidonic acid produce and via what?
thromboxane a2 prostaglandin and prostacyclin PGI2 via cyclo-oxygenase
how does aspirin work in inhibiting primary haemostasis?
irreversibly blocks cyclo-oxygenase so less thromboxane a2 is produced from arachidonic acid → ↓ platelet aggregation
what is the function of prostacyclin pgi2?
inhibits platelet aggregation
where else is prostacyclin pgi2 produced? why is this useful
from endothelial cells
even when aspirin blocks COX pgi2 can still be produced and help inhibit platelet aggregation
how long do the effects of aspirin last?
about 7 days
how does clopidogrel work in inhibiting primary haemostasis?
irreversibly blocks ADP receptor on platelets
what are the functions of VWF?
bind to collagen and capture platelets
stabilise f VIII
what is the cause of von willebrand disease? types?
hereditary - autosomal
type 1 and 3 - deficiency of vwf
type 2 - vwf w abnormal function
what disorders cause vessel wall defects that inhibit primary haemostasis?
inherited - haemorrhage telangiectasia , Ehlers- Danlos syndrome
acquired - steroids, ageing, vasculitis, scurvy
how do disorders of primary haemostasis present?
immediate, prolonged bleeding nose bleeds ≥ 20 mins gum bleeding menorrhagia easy/spontaneous bruising (ecchymosis) petechiae purpura (bigger) , non-blanching
what tests are done for disorders of primary haemostasis?
platelet count and morphology
vwf assays
clinical observation
APPT and PT in disorders of primary haemostasis?
normal
except in severe VWD when fVIII is low
how can disorders disorders of primary haemostasis be treated?
replace vwf or platelets stop drugs like apsirin immunosuppressuin splenectomy for ITP desmopressin to increase VWF and fVIII
what are the causes of coagulation factor deficiency?
genetic - haemophilia A/B (f8 & 9)
acquired - liver disease, anticoagulant drugs like warfarin and doacs
how can a blood transfusion lead to a coagulation disorder?
if there is insufficient plasma in the transfusion then the blood become diluted and there are less coagulation factors
what can cause an increased consumption of coagulation factors?
disseminated intravascular coagulation
autoantibodies
what happens in haemophilia?
failure to produce fibrin to stabilise the platelet plug → breaks up → bleeding
what is the hallmark of haemophilia?
haemarthrosis → spontaneous joint bleeding
what should not be given to haemophilia patients?
intramuscular injections
what coagulation factor deficiency is lethal?
factor II (prothrombin)
what are the symptoms of a factor XI deficiency?
bleeding after trauma
not spontaneous
what are the symptoms of a factor XII deficiency?
none - no bleeding
why does liver failure lead to coagulation dysfunction?
most coagulation factors are made in the liver
which factors are not synthesised in the liver? where?
vWF - endothelial cells
fV - platelets , megakaryocytes
outline disseminated intravascular coagulation
can be caused by sepsis, major tissue damage, inflammation
generalised coagulation activation via tissue factor → ↑ clots around body → ↓ platelets (thrombocytopenia) and clotting factors , ↓ fibrinogen & ↑ D - dimer → spontaneous bleeding and organ failure as clots interrupt blood supply leading to ischaemia
what are the clinical features of 2* haemostasis coagulation disorders?
superficial cuts don't bleed brushing is common nosebleeds rare deep spontaneous bleeding - joints and muscles trauma bleeding prolonged, delayed bleeding restarts after stopping
how can you distinguish between bleeding due to platelets and coagulation disorders?
platelets
- superficial bleeding - skin and mucosal membranes
- bleeding immediately after injury
factors
- deep bleeding - joints and muscles
- trauma bleeding delayed but severe and prolonged
what are the screening tests for coagulation disorders?
full blood count for platelets
prothrombin time
activated partial thromboplastin time
differences between PT and APTT?
PT - extrinsic pathway -2, 7
APTT - intrinsic pathway - 1, 2, 9, 10, 11, 12
prolonged APTT can indicate what?
haemophilia A/B
factor XI or XII deficiency
prolonged PT can indicate what?
factor VII deficiency
prolonged APTT and PT can indicate what?
liver disease warfarin / doacs DIC dilution following rbc transfusion vit k deficiency
what are the factor replacement therapy options? (5)
fresh frozen plasma - all factors
cryoprecipitate - fibrinogen , 8, vwf, 13
factor concentrates - all except 5
prothrombin complex concentrates - 2, 7, 9, 10
recombinant forms of 8 and 9 - prophylactic or treatment
what is the current approved treatment for haemophilia?
recombinant clotting factors
what are novel treatment options for haemophilia?
gene therapy (A and B) bispecific antibodies (A) - mimics procaogulant function of fVIII RNA silencing (A and B) - targets antithrombin
additional treatment options for abnormal haemostasis?
transexamic acid - antifibrinolytic
desmopressin - vasopressin analogue → increase vwf and fVIII
fibrin glu/spray
what can cause increased bleeding via increased fibrinolysis?
↑ tissue plasminogen activator - stroke
what can cause increased bleeding via increased anticoagulation?
heparin
how can a pulmonary embolism present?
tachycardia hypoxia , sob chest pain haemoptysis sudden death
how can a dvt present?
painful leg
swelling, red, warm
can embolise to lungs
what is virchows triad?
the 3 contributing factors to thrombosis
- blood (venous)
- vessel wall (arterial)
- blood flow (both)
what is thrombophilia? presentation?
increased venous thrombosis risk
- thrombosis at young age, spontaenous
- multiple thromboses
- thrombosis while anti coagulated
what can cause venous thrombosis? think blood
↓ antithrombin , protein c & s
↑ coagulation factors - 2 , 5 leiden , 8
myeloprolifrtaive disorders
how do antithrombin and protein c&s deficiencies lead to thrombosis
antithrombin normally inactivates fXa and IIa
c and s normally inactivate Va and VIIIa
↓ → ↑ clotting factors
how is the vessel wall thought to be involved in thrombosis?
coagulation proteins expressed in vessel endothelial cells - altered during inflammation
when does blood flow contribute to thrombosis?
stasis increases risk
surgery, long flights, pregnancy (compression from foetus)
treatment options for venous thrombosis?
assess and prevent risks
prophylaxis - anticoagulant therapy, heparin
lower procoagulant factors - warfarin, doacs to reduce risk of recurrence
three layers of blood vessels?
tunica adventitia - vasa vasorum, nerves
tunica media - smooth muscle
tunica intima - endothelium
(all except venues and capillaries)
structures of capillaries and venues?
endothelium supportert by mural cells/pericytes and a basement membrane
function of microvascular endothelium?
promotes tissue homeostasis and organ regeneration via angiocrine release
what can dysfunctional endothelium contribute to?
cancer
diabetes
ischaemia
chronic inflammatory diseases
what kind of properties do endothelial cells have?
organ-typic - continuous (fenestrated or non-fensprated) or discontinuous
what is contact inhibition?
endothelial cells form a monolayer with cdll-cell junctions
what blood vessel functions do endothelial cells regulates?
tissue homeostasis and regeneration
vascular tone - vasoconstrictors/dilators
angiogenesis - growth factors & matrix products
haemostasis and thrombosis - procoagulant factors/antithrombotic
permeability
inflammation - adhesion molecules
what can lead to an activated endothelium?
smoking oxidised LDL mechanical stress viruses inflammation high bp high glucose
risk factors for atherogenesis?
hypercholstrolaemia DM hypertension sex hormone imbalance ageing
difference between a capillary and a post capillary senile?
PCV has more pericytes
outline normal leukocyte recruitment
during inflammation leukocytes adhere to endothelium of post capillary venules and transmigrate into tissues
outline leukocyte recruitment in atherosclerosis
leukocytes adhere to endothelium of large arteries and get stuck in sub endothelial space
monocytes then migrate in and differentiate into macrophages and foam cells
how does vascular permeability contribute to atherogenesis?
endothelial dysfunction leads to ↑ permeability → lipoproteins can move into subendothelial space and bind to matrix proteoglycans → oxidised LDLs → bind ti macrophages → foam cells
where are atherosclerotic plaques most likely to form? why?
at bifurcations and curvatures
due to turbulent, nonuniform flow → low wall shear stress → endothelial cell activation
benefits of laminar flow?
promote antithrombotic and anti-inflammatory factors
endothelial survival, inhibits smc proliferation
NO production
disadvantages of disturbed blood flow?
thrombosis, inflammation - leukocyte adhesion
endothelial apoptosis and smc proliferation → shape chnage
loss of NO production
protective effects of NO on vascular endothelium?
dilates blood vessels reduces LDL oxidation reduces release of superoxide radicals reduces SMC proliferation inhibits monocyte adhesion reduces platelet activation
what can promote angiogenesis?
hypoxia as in advanced atherosclerosis
modifiable risk factors for CHD?
smoking, lipids intake, blood pressure, diabetes, obesity, sedentary lifestyle
nonmodifiable risk factors for CHD?
age, sex, genetics
outline the progression of atherosclerosis
hypertrophy of smooth muscle in lesion-prone coronary artery (eg at bifurcation) → lesion occurs → macrophages enter and engulfs oxLDLs → foam cells → pools of extracellular lipid → core of extracellular lipid → fibrous thickening (SMC hypertrophy) → fissure , hepatoma & thrombus
type II lesion → preatheroma → atheroma → fibroatheroma → complicated lesion
two types of macrophages?
inflammatory - kill microorgansisms
resident - homeostatic, suppress inflammation
outline how LDLs lead to inflammation in blood vessels?
damaged endothelium → LDLs can leak through into sub endothelial space → trapped by proteoglycans → modified bu mechanisms like oxidation (free radicals) → phagocytosed by macrophages → die and become foam cells → chronic inflammation
what is familial hypercholestrolaemia?
autosomal disease
↑↑↑cholsetrol due to failure to clear LDL from blood
xanthomas
early atherosclerosis
statins inhibit ethic enzyme?
HMG-CoA reductase
what allows macrophages to bind to OxLDLs?
macrophage scavenger receptor A and B
how do macrophages further oxidise LDLs?
NADPH oxidase
myeloperoxidase
= ↑ oxidation = ↑ endothelial damage
how do plaque macrophages recruit more monocytes?
cytokines - eg IL-1 → ↑ VCAM-1
chemokine MCP-1 → CCR2
explain the positive feedback loop in atheroscelrosis
oxidised LDLs become phagocytosed by macrophages → macrophages release free radicals to oxidise more LDLs → macrophages phagocytose more → die and become foam cells → release cytokines and chemokine → more monocyte recruitment
outline the ‘wound-healing’ role of macrophages in atherosclerosis
macrophages release :
-platelet derived growth factor → ↑ VSMC
-transforming growth factor beta → ↑ collagen and matrix deposition
forms fibrous cap around necrotic core
VSMC becomes less contractile and more synthetic
outline the role of proteinases released by macrophages
release metalloproteinases which activate each other to degrade collagen (w Zn) → plaque erosion → rupture → blood coagulation → occlusive thrombus
what are the characteristics of a vulnerable plaque?
thin fibrous cap large soft eccentric lipid-rich core increased vsmc apoptosis reduced collagen content activated macrophages expressing mmps
outline macrophage apoptosis
macrophages are overloaded by oxLDLs → die via apoptosis → release macrophage tissue factors and toxic lipids → into necrotic core (central death zone) containing thrombogenic material → walled off by fibrous cap
rupture → thrombosis
what is the master regulator of inflammation?
nuclear factor kappa b (activates macrophages)
how is NFkB activated? what does it do?
scavenger receptors, toll-like receptors, IL-1
switches on inflammatory genes (MMPs, inducible nitric oxide synthase, IL-1)
