week 2 Flashcards
1
Q
risk factors for atherosclerosis
A
age male gender family history smoking hypertension hyperlipidaemia diabetes obesity
2
Q
causes of chest pain
A
cardiac respiratory gastrointestinal musculoskeletal other
3
Q
most common cardiac causes of chest pain seen in clinical practice
A
cardiac ischaemia
aortic dissection
pulmonary embolism
4
Q
types of cardiac ischaemia
A
troponin positive and troponin negative
5
Q
causes of troponin positive (cardiac)
A
type I and type II MI
coronary spasm
spontaneous coronary artery dissection (SCAD)
6
Q
causes of troponin negative (cardiac)
A
angina
coronary artery spasm
7
Q
where does cardiac pain typically radiate to
A
left arm, neck and jaw
8
Q
typical cardiac pain
A
site - central
radiation - arm, jaw, other
character - tight pressure
precipitating and relieving factors - exercise/rest
severity - variable but usually severe
duration - prolonged
associated symptoms - breathlessness, pallor, sweating, nausea and vomiting
9
Q
investigation of chest pain
A
layered history observations lab tests ECG serial ECG CXR
10
Q
invasive coronary angiogram
A
insert plastic tube through radial artery (or femoral) and take pictures of coronary arteries
can cause dissections, arhythmic events and can induce an MI
11
Q
tests for cardiac chest pain
A
exercise stress test stress echo myocardial perfusion scan CT coronary angiogram stress perfusion cMR invasive coronary agiogram
12
Q
how can you tell there is significant occlusion in a blood vessel
A
ST depression during exercise
13
Q
anti-anginal drug action
A
reduce cardiac workload: slow heart rate reduce force of contraction reduce pre-load/after-load improve blood supply: coronary artery vasodilation
14
Q
types of drugs for angina
A
beta-blockers calcium antagonists nitrates K+ channel activator If blocker
15
Q
risk factors for atherosclerotic disease
A
age family history sex ethnicity cigarette smoking diabetes mellitus hyperlipidemia hypertension obesity physical inactivity
16
Q
acute coronary syndromes
A
unstable angina (comes on at rest)
NSTEMI - non ST elevation MI
STEMI (more heart muscle damage)
17
Q
unstable angina
A
unstable plaque without myocardial necrosis
critical coronary disease
18
Q
NSTEMI
A
plaque rupture/thrombus without total vessel occlusion
ST depression
19
Q
treatment of type I MI (NSTEMI)
A
dual platelet therapy to stop platelets sticking
statin
ACE inhibitor
Beta-blocker
20
Q
treatment of type I MI (STEMI)
A
primary percutaneous coronary intervention
systemic thrombolysis - dissolving clot
21
Q
STEMI
A
complete vessel occlusion
ST elevation
22
Q
complications of acute MI
A
pericarditis RV infarct mural thrombus heart failure mechanical ventricular septal defect aneurysm ischemia
23
Q
treatment of coronary artery disease
A
no cure primary prevention anti-anginal drugs anti-platlet drugs thrombolytic drugs angioplasty and stents CABG surgery secondary prevention
24
Q
two types of risk factors
A
non-modifiable
modifiable - cannot be changed
25
how can you use risk
```
inform or educate the public and patients
modify behaviour
selection for interventions
measure effectiveness of interventions
deliver health/public health services
```
26
risk measurements
```
absolute risk
relative risk
odds ratio
attributable risk
population attributable risk
```
27
what is absolute risk
the incidence of disease in a population
population could be the general pop, a subgroup of a pop, those with a risk factor
it is the number of new cases per population over specified time - so x new cases per x population per x years
28
what is relative risk
if having a risk factor/exposure is related to the outcome
| compare two populations: one with exposure/RF and one without
29
working out incidence
number with disease/total population
30
working out relative risk
incidence in exposed/incidence in not exposed
31
if RR = 1
risk in exposed = risk in not exposed
| so no association
32
if RR > 1
risk in exposed > risk in not exposed
positive association
risk may be a cause of outcome
33
if RR < 1
risk in exposed < risk in not exposed
negative association
exposure/risk may be protective
34
case control study
compare 2 groups of people defined by their outcome eg. people with disease and people without
compare two groups on whether they report having had the exposure/risk
35
relative risk or odds ratio
RR can only be obtained from cohort studies
| OR used for case control and cross sectional studies
36
what is attributable risk
incidence of cases among those exposed that are due to the exposure/risk factor
= incidence of disease in exposed - incidence of disease in un-exposed
37
attributable risk percent
percentage of cases among those exposed that are due to the exposure/risk factor
= AR x 100 / incidence of disease in exposed
38
population attributable risk (PAR)
incidence of cases among whole population that are due to exposure
= AR x prevalence of exposure
39
prevalence of exposure
= total exposed/total population
40
population attributable rise percent
percentage of cases in the whole population that are due to the exposure/RF
= PAR x 100 / incidence of disease in population
41
modifiable risk factors for acute MI risk
```
smoking
hypertension
lipids
abdominal obesity
diabetes
fruit and veg
alcohol
exercise
psychosocial
```
42
primary prevention strategies for MI
single risk factor strategy eg treat bp in individuals with hypertension
population health strategy eg lower bp in whole population
high baseline risk strategy eg treat bp and other risk factors in individuals with high overall risk
43
primary prevention
reducing risk of getting the disease
44
secondary prevention
reducing the risks associated with having the disease
45
haemostasis
functions to limit blood loss following vascular damage
| does not compromise the fluidity of blood
46
thrombosis
occlusion of blood vessel by an intravascular blood clot or platelet clump
47
describe platelets
cell fragments produced from megakaryocytes in bone marrow
no nucleus so cannot produce new proteins
danger of haemorrhage if there is a deficiency
48
how is intravascular blood coagulation and platelet activation normally supressed
non-thrombrogenic surface of endothelium
production by endothelium of prostacyclin (PGI2) and nitric oxide which inhibit platelet aggregation - nitric oxide also inhibits adhesion of platelets to vascular wall
presence of natural anticoagulants in plasma
NO increases cGMP which has an anti-platelet effect
49
how are platelets and the coagulation cascade activated
platelets adhere to exposed sub-endothelial collagen and become activated
coagulation initiated by exposure of blood to tissue factor (f3) and is facilitated by exposure of pro-coagulant phospholipid on platelet surface
50
role of platelets in coagulation
platelets release agents which promote vasoconstriction and aggregation ie. thromboxane A2, 5-HT and ADP
51
stages in platelet activation
vessel is cut or atherosclerotic plaque ruptures leading to activation of platelets by sub-endothelial collagen
platelet surface integrin (glycoprotein (GPIb) permits adhesion to collagen in vessel wall via von Willebrand factor bridge
platelets change shape from discoid to spherical with development of pseudopodia
activated platelets expose another cell-surface integrin (GPIIb/IIIa)
platelets aggregate - fibrinogen cross-links GPIIb/IIIa receptors on adjacent platelets
arachidonic acid metabolism initiated forming thromboxane A2 - activates adjacent platelets and promotes vasoconstriction
platelets degranulate releasing stored ADP and 5-HT to activate adjacent platelets and promote vasoconstriction
exposure of pro-coagulant phospholipid on platelet surface activates the coagulation cascade (intrinsic pathway)
52
which factor catalyses the formation of thrombin
10a
53
von willebrand disease
deficiency of von willebrand factor
| binds to and stabilises factor VII and binds platelets to collagen
54
blood clotting disorders
von willebrand disease
| haemophilia A, B and C
55
haemophilia A
deficiency of factor VIII
56
haemophilia B
deficiency of factor IX
57
haemophilia C
deficiency of factor XI
58
fibrinolytic system
physiological repair system for removing blood clots
| plasminogen bound to fibrin is converted to plasmin by tissue plasminogen activator
59
venous thrombosis
intravascular blood clot forms in deep veins, particularly of the legs when flow is sluggish
fragment may bud off (embolus) and block blood vessel, often pulmonary artery
anticoagulant drugs such as warfarin and heparin used to treat
60
arterial thrombosis
platelets aggregate usually at the site of a ruptured atherosclerotic plaque, then encapsulated by clot
common at CAs leading to an MI or cerebral arteries leading to a thrombotic stroke
immediate therapy - dissolve existing clots with fibrinolytics
long term therapy - anti-platelet drugs (antithrombotics) such as aspirin
61
anticoagulants used in vitro (when blood is being stored)
heparin - sulphated glycosaminoglycans of variable chain length - polyanionic meaning multiple negative charges on chain
calcium chelators - remove calcium which is required in coagulation cascade - would not use in vivo
62
anticoagulants used in vivo
heparin or low molecular weight heparin (LMWH)
| oral anticoagulants - vitamin K antagonists and newer agents such as thrombin inhibitors and factor Xa inhibitors
63
mechanism of action of heparin
heparin binds to and enhances the action of endogenous anticoagulant, antithrombin III
the heparin-antithrombrin III complex binds to and inhibits the action of clotting factors IIa, IXa, Xa, XIa, XIIa
immediate inhibition of clotting
low MW heparins inhibit factor Xa predominantly
64
difference between aspirin and heparin
heparin is an anticoagulant so prevents blood clot formation
| aspirin is an anti-inflammatory drug that reduces platelet aggregation and so reduces blood clotting
65
differences between un-fractionated (standard) heparin and LMWH
both can inhibit action of Xa by binding to antithrombin
in order to inactivate thrombin (IIa), heparin molecule must be long enough to bind to both antithrombin and thrombin - < half od chains of LMWH are long enough
66
advantages of LMWH
high bioavailability of subcutaneous route
lower incidence of HIT (heparin induced thrombocytopenia - abnormally low levels of platelets)
no need to monitor PTT
ideal during pregnancy (SC route)
67
disadvantages of LMWH
requires dosage adjustment in renal sufficiency - renal function monitoring required
cannot be used in patients with HIT once it develops
longer half life may prolong risk of bleeding
only partially reversed with protamine
expensive
bruising at injection site
68
administering heparin and LMWH
not orally active
IV or subcutaneously
does not cross placenta or blood-brain barrier
69
uses of heparin and LMWH
deep venous thrombosis
safe for pre-eclampsia of pregnancy - warfarin not safe
in vitro anticoagulant
70
side effects of heparin
allergic reactions
haemorrhage - heparin causes more bleeding if already bleeding
heparin induced thrombocytopaenia (HIT)
71
how to reverse side effects of heparin
protamine is a heparin antagonist
| a polycationic protein that binds and inactivates heparin
72
oral anticoagulant
warfarin
| blocks synthesis of coagulation factors
73
mechanism of action of warfarin
reduced vitamin K is essential for post ribosomal gamma-carboxylation of glutamic acid residues at N-terminals of factors II, VII, IX and X
warfarin blocks vit.K reductase so blocking carboxylation
no gamma-carboxyglutamate therefore no Ca2+ binding therefore no coagulation
74
uses of warfarin
venous thrombosis
prevention of pulmonary embolism
prevention of embolism in patients with atrial fibrillation
prophylaxis of thrombosis after insertion of prosthetic heart valves etc
75
activity of warfarin
active in vivo not vitro
| effect delayed 1-3 days - existing pool of functional clotting factors need to be replaced by the dysfunctional ones)
76
administration of warfarin
oral
99% bound to plasma albumin
aspirin displaces warfarin from binding sites on albumin, increasing plasma [warfarin] - aspirin also inhibits platelet function
77
side effects of warfarin
haemorrhage
| crosses placenta and blood brain barrier - haemorrhage in foetus
78
reversal of side effects
transfuse with plasma or coagulation factor concentrates
| oral vitamin K - slow
79
what is INR
INR stands for international normalized ratio and is measured with a blood test called PT-INR. PT stands for prothrombin time. The test measures how much time it takes for your blood to clot and will determine if you're receiving the right dose of warfarin
80
how is INR derived
from the ratio of a patients prothrombin time to a control sample
INR target range on warfarin is 2-3
high INR increases risk of haemorrhage
low INR decreases risk of thrombosis
81
newly introduced oral anticoagulants
potential to replace warfarin but expense restricts
dabigatran exilate - direct thrombin (factor IIa) inhibitor
rivaroxaban - direct Xa inhibitor
active immediately
do not require monitoring
82
mechanism of action of low dose aspirin
irreversibly inhibits cyclooxygenase (COX) - acetylation of terminal serine530
inhibits synthesis of platelet TXA2 - this cannot recover since platelets have no nucleus
also inhibits endothelial production of prostacyclin but this recovers through synthesis of new COX
LDA prevents re-infarction
83
mechanism of dipyridamole
inhibits cyclic nucleotide phosphodiesterases
increases cAMP and increases cGMP
so inhibits platelet activation
84
epoprostenol
must be given IV
short duration of action
used during haemodialysis - prevents extra activation of platelets
85
clopidogrel
blocks platelet ADP receptors preventing GPIIb/IIIa receptor exposure
widely used to prevent re-infarction
used in combination with aspirin
86
abciximab
blocks GPIIa/IIIa receptors exposed by any pathway
used during surgical exploration/clearing of intravascular blockage
antigenic - can only be used once
87
fibrinolytic agents
tPA and streptokinase
88
tPA
enzyme produced by vascular endothelium
| activates only plasmin bound to fibrin
89
streptokinase
isolated from group c haemolytic streptococci
activates plasminogen systemically - high incidence of haemorrhage
not an enzyme - binds to plasminogen and activates it by conformational change
antigenic and so ineffective after recent streptococcal infection - antibodies present
90
uses of fibrinolytics
venous thrombosis
MI or thrombotic stroke to re-open occluded arteries (given with aspirin to inhibit platelets)
never in haemorrhagic stroke
haemorrhage treated with tranexamic acid an inhibitor of plasminogen activation
91
side effects of fibrinolytics
allergy and haemorrhage
92
what are lipids
a group of substances soluble in organic solvent and virtually insoluble in water
93
3 main classes of lipids
cholesterol
triglycerides
phospholipids
94
cholesterol uses
component of all cell membranes
synthesis of bile acids - allows absorption of fat soluble vitamins
precursor for endogenous vit d production
precursor for steroid hormones
95
uses of triglycerides
used as an energy source in tissues
| used for energy storage in adipose tissue
96
function of lipoprotein system
transports fats in the aqueous environment of plasma
97
structure of a lipoprotein
complex spherical structure
central core of hydrophobic lipids (triglycerides and cholesterol esters)
surface layer of polar components - phospholipids, free cholesterol, proteins, apoliopoproteins
98
main lipoproteins in order of density (least to most dense)
chylomicron
very low density lipoprotein
low density lipoprotein
high density lipoprotein
99
chylomicron function
synthesised in gut after a meal
| main carrier of dietary triglyceride
100
very low density lipoprotein function
synthesised in the liver
| main carrier of endogenously produced triglyceride
101
low density lipoprotein function
generated from VLDL in the circulation
| main carrier of cholesterol
102
high density lipoprotein function
returns cholesterol from extrahepatic tissues to the liver for excretion
103
structure of apolipoproteins
they are amphiphilic compounds
hydrophobic region interacting with lipid core which provides structure to the lipoprotein
hydrophilic region interacting with the aqueous environment
104
functions of apolipoproteins in lipid metabolism
guiding the formation of lipoproteins
acting as ligands for lipoprotein receptors
serving as activators or inhibitors of enzymes involved in the metabolism of lipoproteins
105
exogenous cycle of lipoprotein metabolism
Dietary cholesterol and fatty acids are absorbed.
Triglycerides are formed in the intestinal cell from free fatty acids and glycerol and cholesterol is esterified.
Triglycerides and cholesterol combine to form chylomicrons.
Chylomicrons enter the circulation and travel to peripheral sites.
In peripheral tissues, chylomicrons are metabolised by lipoprotein lipase, releasing free fatty acids from the chylomicrons to be used as energy, converted to triglyceride or stored in adipose.
Remnants are used in the formation of HDL.
106
endogenous cycle of lipoprotein metabolism
VLDL is formed in the liver from triglycerides and cholesterol esters.
These can be hydrolysed by lipoprotein lipase to form IDL or VLDL remnants.
VLDL remnants are cleared from the circulation or incorporated into LDL.
LDL particles contain a core of cholesterol esters and a smaller amount of triglyceride.
LDL is internalised by hepatic and non-hepatic tissues.
In the liver, LDL is converted into bile acids and secreted into the intestines.
In non hepatic tissues, LDL is used in hormone production, cell membrane synthesis, or stored.
LDL is also taken up by macrophages and other cells which can lead to excess accumulation and the formation of foam cells which are important in plaque formation.
107
cardiovascular disease due to circulation problems
ischaemic heart disease and MIs
108
non-modifiable risk factors for CVD
```
sex - male
age - advancing
family history of premature CVD
ethnicity
comorbidites
```
109
modifiable risk factors for CVD
```
hypertension
high blood triglycerides
high LDL
low HDL
psychosocial issues
smoking
alcohol
high body weight
bad diet
lack of exercise
hypercholesterolaemia/dyslipidaemia
```
110
individuals known to be at high risk of CVD
those diagnosed with CVD
chronic kidney disease (stage 3+)
diabetics aged >40 years or with >20 years of disease or with evidence of diabetes-related organ damage (ie. eyes - retinopathy)
those with familial hypercholesterolaemia
111
risk calculators for CVD
ASSIGN risk calculator
| Qrisk3
112
the reverse cholesterol transport pathway
HDL particles act as cholesterol ester shuttles which help remove the sterol from peripheral tissues and return it to the liver, either directly or via other lipoproteins
this is thought to be anti-atherogenic, with an elevated HDL conferring a decreased risk of CHD
113
if cholesterol levels fall..
LDL receptors are upregulated and more cholesterol is taken up by the cell
leads to lower blood concentrations
114
where are the four main lipoproteins synthesised
chylomicron - gut after eating
HDL - mainly liver
LDL - generated from VLDL in circulation
VLDL - liver
115
what happens if the fatty acids attached to the cholesterol in LDL become oxidised
LDL particles are not taken up by the normal LDL receptor on the liver
they are taken up by scavenger receptors on macrophages at a faster uncontrolled rate and amount
leads to the formation of cholesterol-laden foam cells which can develop into fatty streaks and athermatous plaques which cause narrowing of the arteries
116
why is HDL important
it carries cholesterol from tissues back to the liver where it is excreted
it clears cholesterol from the blood stream
117
how does saturated fat alter blood cholesterol levels
increases total cholesterol, LDL cholesterol and HDL cholesterol
increase in chylomicrons and triglycerides which are thought to be harmful to the arteries
118
how does monounsaturated fat alter blood cholesterol levels
decreases total cholesterol and LDL cholesterol
increases HDL cholesterol
increase in chylomicrons and triglycerides which are thought to be harmful to the arteries but these levels fall quicker than in saturated fats
119
how does polyunsaturated fat alter blood cholesterol levels
decreases total cholesterol and LDL cholesterol
| varied effect on HDL
120
how do fats influence formation of LDL
saturated fats increase LDL formation in plasma by decreasing turnover as they decrease LDLR activity and protein
unsaturated fats increase hepatic LDLR number and LDL turnover
121
target levels of cholesterol for primary prevention of CVD (no prior CVD)
<5mmol/L for total cholesterol
>1 for men, >1.2 for women - HDL
<3 for LDL
122
target levels of cholesterol for secondary prevention of CVD (established CVD)
<3mmol/L for total cholesterol
>1 for men, >1.2 for women - HDL
<1.8 - LDL
123
normal lipid profile
Total Cholesterol - Below 5.2 mmol/L
LDL - less than 2.6 mmol/L
HDL - Above 1.5 mmol/L
Triglycerides - Below 1.7 mmol/L
124
effects of exercise on heart
increased CO
heart rate can increase to 190-200 bpm
increase in SV
filling time decreased ~33%
125
how does dynamic exercise effect BP
increase in systolic pressure
decrease in diastolic pressure - dilated arteries in skeletal muscles and lungs
mean BP stays roughly the same
126
bruce test/protocol
test is based on step increases in intensity of exercise on a treadmill
7 stages of 3 minutes each
completion of 9-12 minutes of exercise or reaching 85% of the maximum predicted heart rate is usually satisfactory
used to diagnose CVD
127
effects of static exercise eg wall sit
increase in HR
| increase in systolic and diastolic BP so mean BP increases
128
what is angina pectoris
chest pain due to myocardial ischemia - ischaemia due to an increase in myocardial O2 demand which is not met
when demand is not met there is a build up of metabolites eg adenosine, CO2, lactate, K+ ions which activate sensory nerves - pain signals to brain
can be due to atherosclerosis
129
3 types of angina
stable
unstable
variant
130
stable angina
narrowing of one or more CAs
attacks are predictable - exercise, stress
myocardial demand not met
involvement of chronic occlusive coronary artery disease - atherosclerosis
131
unstable angina
attacks unpredictable
| coronary artery occlusion due to platelet adhesion to ruptured atherosclerotic plaque
132
varient angina
attacks unpredictable
| coronary artery occlusion due to vasospasm - reduces artery diameter
133
coronary steal
dilates areas that do not need to be dilated
sends more blood to already perfused areas and where dilation cannot occur, less blood is delivered because of the fall in input pressure
134
coronary vasodilators in angina
problematic as blood flow increased to areas that do not need it
135
reducing myocardial O2 demand
B1-adrenoceptor blockers - competitive reversible antagonists of adrenaline and noradrenaline at cardiac B1-adrenoceptor
this decreases HR and force which decrease myocardial O2 demand
used in all forms of angina
136
adverse effects of b-adrenoceptor blockers in angina
exacerbates asthma
intolerance to exercise
hypoglycaemia
may uncover a1-mediated constriction in coronaries
137
ivabradine
recently introduced to treat angina
blocks Na+ current that contributes to SA node depolarisation towards threshold
decreases HR but not force
decreases O2 demand
138
vasodilator drugs in angina
dilation of arteries:
decrease in afterload which decrease myocardial work and O2 demand
dilation of veins:
decreases preload
venous dilation:
decreases venous return, decreases preload, decreases stretch of ventricle and atria, decreases strength of contraction which decreases myocardial work and O2 demand
139
bainbridge reflex
a sympathetic reflex initiated by increased blood in the atria
causes stimulation of the SA node
stimulated baroreceptors in the atria causing increased SNS stimulation
140
nitrovasodilators
GTN - taken as sub-lingual tablet or spray - would be destroyed if taken orally
amyl nitrate - vials opened and inhaled - not used now -- these are poppers
both have rapid onset but short lived
uses:
prophylaxis in stable angina
rapid relief of ongoing anginal attack
141
mechanism of nitrovasodilators
lipophilic so readily enter SMCs and are reduced to NO
mimic action of endothelium-derived NO:
NO activates soluble guanylate cyclase
sGC is a cytoplasmic soluble enzyme
receptor on sGC contains and ferrous (Fe2+) haem moiety
NO binds to haem receptor causing enzyme activation, GTP converted to cGMP, increase in cGMP leads to vasodilation
142
problems with nitrovasodilators
headache - dilation of cerebral arteries
| tolerance on prolonged use
143
locations of voltage gated Ca2+ channels
Smooth muscle, cardiac muscle, pacemakers, neurons
| different types in different locations
144
function of voltage gated Ca2+ channels
open upon membrane depolarisation
| reduced Ca2+ entry results in coronary and peripheral arterial vasodilation
145
classes of voltage gated Ca2+ channels
L = long lasting current
T = transient current
N
P/Q = positive potentials
146
mechanism of l-type channel block
allosteric modulators bind at allosteric site and reduce probability of channel opening at a given voltage
also dilate arteries which decreases TPR
147
uses of L-type blockers
anti-hypertensives
anti-anginals
anti-dysrhythmic agents
148
nicorandil
K+ channel activator
only drug in this class approved for angina
no tolerance
hybrid compound - nicotinamide vitamin group with an organic nitrate
nitrate like action - increased level of cyclic guanosine monophosphate, decrease in cytosolic calcium (opening of K+ channels), vascular smooth muscle relaxation
149
initial anti-anginal drug treatment for stable angina
offer beta blocker or calcium channel blocker
then consider switching to the other option or using both
consider adding a third anti-anginal drug if these options have not worked
