Cardiovascular Flashcards
What is the normal value for end systolic volume?
75 mL
What is the normal value for stroke volume?
100 mL or less
What is the normal value for end diastolic pressure?
15 mmHg
What is the normal value for early diastolic pressure?
5 mmHg
Why does the gradient of the diastolic left ventricular pressure-volume curve increase more steeply with increase left ventricular volume?
Ventricle gets filled to its physical capacity > exponentially greater increase in pressure
What is the Frank-Starling relationship?
Greater pre-load on cardiac muscle fibres prior to contraction > increase in force of contraction
Within limits, more the heart fills with blood during diastole, the greater the force of contraction during systole
Pre-load is proportional to end diastolic volume
Therefore, the greater the end diastolic volume, the more forceful the contraction
What determines end diastolic volume?
Duration of ventricular diastole
Venous return
Why can the duration of ventricular diastole be short?
Heart rate increase > less filling time
What will happen to contractility if there is acidosis?
Decreases
What will happen to contractility if there is parasympathetic nerve deactivation?
Increases to small extent, as parasympathetic nervous system more important in heart rate and atrioventricular node firing
What will happen to contractility if there is caffeine intake?
Increases to small extent
What will happen to contractility if there is hypercapnia?
Decreases
Why does left ventricular pressure never reach maximal capacity during systole?
Aortic valve releases pressure when left ventricular pressure is greater than in aorta
In effect, aorta acts as release valve
Describe the blood distribution in the circulation
Veins = 65% Arteries = 13% Capillaries = 5% Lungs = 10% Heart = 7%
Why is atrial pressure more sensitive to changes in volume than venous pressure?
Veins more compliant > taking blood out of veins will have less effect on pressure change
What is mean circulatory filling pressure?
Eventual average systemic pressure if heart stopped and blood settled in vessels
What is mean circulatory filling pressure determined by?
Volume of blood
Compliance of vessels
What effect would an increase in cardiac output have on venous pressure?
Decrease venous pressure
What effect would an increase in total peripheral resistance have on the volume of blood in the arterial and venous systems?
No effect
What effect would decreasing venous pressure have on cardiac output?
Decrease cardiac output due to reduced filling pressure
What is central venous pressure?
Pressure in great veins just outside heart
Why might central venous pressure rise?
Systemic venous congestion during right heart failure
Why might central venous pressure fall?
Shock = systemic vasodilation Venous return poor - Blood loss - Upright posture - Inadequate muscle and respiratory pumps
What effect would an increase in contractility have on cardiac output and venous pressure?
Increase cardiac output
Decrease venous pressure
What substances produced by the endothelium alter muscle contraction?
Nitric oxide = vasodilator
Endothelin = vasoconstrictor
Prostacyclin = vasodilator
What is antagonist potency mostly determined by?
Potency
Which antagonists stop binding?
Competitive antagonists
Which antagonists stop activation?
Non-competitive antagonists
What does propranolol do?
Competitive antagonist of beta-adrenoceptors = beta-blocker
What are the factors affecting drug distribution?
Molecular size
Ability to bind plasma proteins
Lipid solubility
What is volume of distribution?
Volume of fluid in which amount of drug in body would need to be uniformly distributed to produced observed concentration in blood
How do you work out the volume of distribution?
Total amount of drug in body/drug blood plasma concentration
What does a small volume of distribution indicate?
Drug binds strongly to plasma proteins
What does a large volume of distribution indicate?
Drug take up by cells and binds to tissues > greater distribution
How does pH affect lipid solubility and thus the passage of drugs?
Drugs more lipid-soluble if uncharged
At which pH are acidic drugs more lipid soluble?
Low pH
At which pH are basic drugs more lipid soluble?
High pH
How is acetylcholine synthesised?
- Choline transported into cell by choline carrier
- Choline + acetyl-CoA > acetylchole
- Acetylcholine loaded into synaptic vessel
How is noradrenaline synthesised?
- Tyrosine transported into cell
- Converted to L-DOPA
- Converted to dopamine
- Transported into synpatic vesicle
- Converted to noradrenaline
How is adrenaline synthesised?
Noradrenaline converted to adrenaline in synpatic vesicle
What is co-transmission?
Autonomic nerves often release more than one neurotransmitter
How is acetylcholine inactivated?
Inactivated and degraded by acetylocholinesterase on effector tissue surface
How is noradrenaline inactivated?
Uptake 1 = reuptake via high affinity receptor
Uptake 2 = taken up via low affinity receptor by post-synaptic tissue > degraded
What is phenylephrine?
Alpha-adrenergic receptor agonist
How does adrenaline increase blood pressure?
Alpha and beta-adrenergic receptor agonist > vasoconstriction and tachycardia
How do anitcholinesterases work?
Decreased breakdown of acetylcholine > increased levels of acetylcholine in synaptic cleft > increased acetylcholine action
What is myasthenia gravis?
Autoimmune condition where Abs produced against nicotinic acetylcholine receptors (on neuromuscular junctions)
Abs bind to receptors
- Receptor internalisation and degradation
- Activation of complement > destruction of neuromuscular junction synapse architecture
How can myasthenia gravis be treated?
Use anticholinesterases
Effective in early stages
Decreased breakdown of acetylcholine > more in synpase > more chance of binding to remaining receptors
What are the effects of muscarinic receptor agonism?
Salivation Lacrimation Urination Defecation Sweating Bradycardia Vasodilation
What are indirectly acting sympathomimetics?
Taken up by neuron > displace noradrenaline from synaptic vesicles > more noradrenaline displaced into synapse
What are some stimuli that induce histamine release?
Ag via IgE Complement fragments C3a and C5a Neuropeptides Cytokines and chemokines Bacterial components Physical trauma
What is the triple response to histamine?
Reddening
Wheal
Flare
What causes reddening in response to histamine?
Vasodilation
What causes a wheal in response to histamine?
Increased vessel permeability > local oedema
What causes a flare in response to histamine?
Spreading response through sensory fibres
What type of histamine receptors do classic antihistamines act on?
H1 receptors
Why do H1 receptor antagonists cause sleepiness?
Antagonise H1 receptors in cerebral cortex > reduce neuronal excitation
Bloch acetylcholine receptors > excess acetylcholine > drowsiness
What was the problem with using terfenadine as a non-sedative H1 receptor antagonist?
Cause rare, sudden ventricular arrhythmia
From which cells in the gastrointestinal tract is histamine released?
Enterochromaffin-like (ECL) cells
What two things does bradykinin mediate?
Pain
Inflammation
What triggers release of bradykining?
Pre-kallikrein cleaved to kallikrein by activated factor XII
Kallikrein becomes kininogen
Kininogen activated to bradykinin
What are the actions of bradykinin?
Potent endothelium-dependent vasodilator Contraction of non-vascular smooth muscle in bronchus and gut Increase of vascular permeability Sensitises pain nerve endings Natriuresis
What are the effects of bradykinin on blood pressure and how?
Decreases blood pressure through
- Vasodilation
- Natriuresis
How do ACE inhibitors cause cough?
ACE normally breaks down bradykinin
ACE blocked > build up of bradykinin > bronchoconstriction > dry cough
What are the physiological roles of nitric oxide?
Flow-dependent vasodilation
Inhibits platelet adhesion and aggregation
Neurotransmitter
How is arachidonic acid stored?
Esterified and stored in membrane phospholipids
How is arachidonic acid liberated from membranes?
Increase in intracellular Ca > hospholipase A2 activated > breaks bond between arachidonic acid and phospholipid
What is the difference in expression between COX1 and COX2?
COX1 expression constitutive
COX2 expression inducible
- Expressed in response to inflammation
Which cells express high levels of lipoxygenase?
Inflammatory cells
What are the stable prostaglandins?
PGE2
PGD2
PGF2
What are the functions of PGE2?
Vasodilation
Pyrogenesis
- In hypothalamus, increases temperature set-point
Angiogenesis
What are the indications for non-steroidal anti-inflammatory drugs (NSAIDs)?
Anti-inflammatory
Analgesia
Antipyretic
Why is paracetamol often preferred over aspirin as an anti-pyretic?
Highly selective for COX2
Won’t cause gastric irritation/ulceration
Describe how bradykinin and PGE2 work in synergy to intensify pain
PGE2 > vasodilation > increased blood flow
Bradykinin > vascular leakiness
PGE2 increases sensitivity to pain caused by bradykinin
How is the set point raised during fever originating from inflammation?
Inflammation > macrophage activation > cytokines > PGE2 synthesis in hypothalamus > increase temperature set point
What are the gastro-protective roles of PGE2?
Promote blood flow
Increase mucus secretion
Reduce gastric acid secretion
How do NSAIDs cause gastric irritation?
Inhibit PGE2
Where is prostacyclin (PGI2) produced?
Endothelial cells
What is the function of PGI2?
Reduce platelet activation
Vasodilation
Where is TXA2 produced?
Platelets
What is the function of TXA2?
Increase platelet activation
Vasoconstriction
How do PGI2 and TXA2 differ in function?
Oppose actions of each other
How does aspirin differ to other NSAIDs?
Irreversibly inactivates COX
What effect can aspirin have on COX in platelets?
Irreversibly inactivate COX in platelets
Since platelets have no nucleus, won’t resynthesise COX for entire lifespan of 8 days
What effect does inactivation of COX in platelets by aspirin have?
TXA2 levels reduced more than PGI2 levels > endothelium-mediated vasodilation and decreased platelet activation
What are aspirin-triggered lipoxins?
Acetylation of COX2 alters its activity > produces aspirin-triggered lipoxins
Active
What is the suggested mechanism for cardio-protection from intake of fish oil?
Fish oil increases synthesis of PGI3
PGI3 has prostacyclin-like activity > suggested that it decreases incidence of coronary artery disease
What types of cells is 5-lipoxygenase activity only seen in?
Inflammatory cells
What is the link between leukotriene activity and asthma?
Leukotrienes potent bronchoconstrictors, also causing bronchospasm
What is the link between leukotriene and hayfever?
Allergic response > leukotriene release > nasal tissue oedema > nasal congestion
How can leukotriene action be blocked?
Leukotriene receptor antagonists
Why do coaguation factors normally not cause thrombosis in vessels?
Circulate as pro-enzymes
What are the three phases of haemostasis?
Primary haemostasis
Secondary hamostasis
Fibrinolysis
What happens in primary haemostasis?
Vasoconstriction
Platelet adhesion
Platelet aggregation
What happens in secondary haemostasis?
Activation of coagulation factors
Formation of fibrin
What happens in fibrinolysis?
Activation of fibrinolysis
Lysis of clot
What makes up Virchow’s triad?
Endothelial injury
Abnormal blood flow
Hypercoagulability
What is required to trigger the coagulation system?
Tissue factor
What molecules can inactivate thrombin?
Protein C
Anti-thrombin
What is the pharmacological mechanism of warfarin?
Inhibits reduction of vitamin K > no activation of vitamin K-dependent factors
What is the pharmacological mechanism of heparin?
Binds antithrombin > doesn’t cleave thrombin
What is the difference between risk and rate?
Risk = probability of disease occurring in a disease-free population during a specified time period Rate = probability of disease occurring in disease-free population during sum of individual follow-up periods
What is risk a measure of?
Incidence
What is person-time?
Makes explicit time population at risk actually spent being at risk
What are the benefits of using person-time?
Adjusts for loss of participants to follow
Risk can potentially underestimate true incidence
What is hazard, in relation to rate?
Type of rate that’s continuously updated as longitudinal study progresses
Rate that applies to an exact point in time = instantaneous rate
If absolute risk is isolated, how is it possible to provide an indication of association between a risk and an outcome?
Generate relative risk = risk ratio
Relative risk = risk among exposed/risk among unexposed
What is attributable risk?
Indicates absolute magnitude of change in risk/rate of outcome
How is attributable risk calculated?
Risk among exposed - risk among unexposed
What does attributable risk percentage represent?
Percentage of incident disease among exposed people that was due to exposure
What is population attributable risk?
Additional/excess risk of outcome in population, due to exposure
How do you calculate population attributable risk?
Risk in whole population - risk among unexposed
What does the population attributable risk percentage represent?
Proportion of incident disease among the whole population due to exposure
What is the population attributable risk percentage also known as?
Preventable fraction
When do chemoreceptors start to act in the context of blood pressure control?
When blood pressure falls below 60 mmHg
Where are baroreceptors located?
Carotid sinus
Aortic arch
Pre-glomerular arterioles
What is the carotid sinus?
Thin spot of wall in internal carotid artery
More compliant
More sensitive to changes in stretch due to change in pressure
Where are chemoreceptors located?
Carotid and aortic bodies outside arteries
What do chemoreceptors respond to?
Low flow
Low O2
High CO2
Low pH
What components of the cardiovascular system are responsive to parasympathetic signals?
Heart rate
Conduction speed at the sinoatrial node
How can a stroke occur from an atrial thrombus?
Atria starts beating at sinus rhythm, may have to pump against higher pressure due to decreased ventricular compliance
Thrombus may dislodge and travel up to brain
Cerebral embolism > stroke
How do systolic and diastolic blood pressures vary with age?
Systolic pressure increases
Diastolic pressure increases until 60, then decreases
Why does pulse pressure increase with age?
Decreasing compliance > increased systolic and decreased diastolic
Why does compliance decrease with age?
In arteries
- More collagen
- Less elastin
How does blood pressure vary with sex?
Males > females
How does blood pressure vary with body size?
Larger body size > higher blood pressure
What is the diurnal variation in blood pressure?
Lower at night
Less variability at night
What is the population paradox?
More deaths occur in people at moderate risk (large group) than in people at high risk (small group)
What are social permissions?
What doctors are allowed to do, that others can’t
Why are explicit ethical principles needed?
To address vulnerability inherent in patient’s position, by affirming particular ethical obligations of doctors to protect and respect patients
Provide counter to negative culture of medicine
What are the basic ethical principles?
Beneficence Non-maleficence Respect for autonomy Respect for privacy Justice
What is the difference between moral confusion and moral distress?
Moral confusion = feeling unsure what’s right thing to do, and not knowing how to resolve it
Moral distress = feeling unable to do what you think is right and feeling compelled to do what you think is wrong
What are the targets for parasymathetic control of heart rate?
Sinoatrial and atrioventricular nodes via acetylcholine action on muscarinic cholinergic receptors
What is the effect of muscarinic receptor blockade on heart rate in healthy young individuals?
Increases it
What are the targets for sympathetic control of heart rate?
Sinoatrial node
Conducting pacemaker tissue
Myocardial cells
What is the effect of sympathetic release of noradrenaline and adrenaline on the heart?
Bind to beta-adrenoceptors > directly increase heart rate and contractility
What are the phases of the sinoatrial node pacemaker action potential?
Phase 0 - Depolarisation - Ca in Phase 3 - Repolarisation - K out Phase 4 - Spontaneous depolarisation - Na and Ca in
Why don’t the pacemaker cells have a stable resting membrane potential?
Leaky funny current Na channel
Uses Ca for depolarisation
Describe the mechanism for parasymathetic slowing of the sinoatrial node
Acetylcholine acts on muscarinic receptors on sinoatrial node > decrease in cAMP > K channels open > K efflux > slows Na and Ca fluxes > slower phase 4 > takes longer to reach threshold potential > slows rate of conduction of atrioventricular node
Describe the mechanism of sympathetic acceleration of the sinoatrial node
Noradrenaline and adrenaline act on beta1-adrenoceptors on sinoatrial node > increase in cAMP > opening of Ca channels > increased slope of phase 4 at sinoatrial and atrioventricular nodes > increased rate of firing from sinoatrial node and more rapid conduction to atrioventricular node
What are the phases of the ventricular pacemaker action potential?
Phase 0 - Depolarisation - Na in Phase 1 - Rapid repolarisation - K out Phase 2 - Plateau - Ca in - K out Phase 3 - Repolarisation - K out Phase 4 - Stable membrane potential
What are the mechanisms underlying dysrhythmias?
Altered impulse formation
Altered impulse conduction
Triggered activity
What is altered impulse formation?
Abnormal generation of action potentials at sites other than sinoatrial node
What is altered impulse conduction?
Conduction block
Re-entry > extra beats
What triggers activity in dysrhythmias?
Early/late after-depolarisations due to excess sympathetic activation
What is the molecular mechanism of class 1 anti-dysrhythmics?
Na channel block > reduces phase 0 slope and peak of ventricular action potential
- 1a = moderate block
- 1b = weak block
- 1c = strong block
What is the molecular mechanism of class 2 anti-dysrhythmics?
Beta-adrenoceptor antagonism > decrease rate and conduction
What is the molecular mechanism of class 3 anti-dysrhythmics?
K channel blockade > delay phase 3 of ventricular action potential
What is the molecular mechanism of class 4 anti-dysrhythmics?
Ca channel blockade > reduces rate and conduction
What effects do beta-adrenoceptor antagonists have on Purkinje fibres?
Membrane stabilising effects - local anaesthetic-type action
What are patients on K channel inhibitors at an increased risk of experiencing and why?
K channel inhibition > K takes longer to leave cells > prolonged repolarisation time > prolonged action potential > more chance of triggered events
What is the drug class of lignocaine?
Class 1b
What do the side effects of lignocaine depend on?
Concentration of drug
What are the side effects of lignocaine, with increasing concentrations?
Lip and tongue numbness Light headedness Visual disturbance Muscular twitching Convulsions Coma Respiratory arrest Cardiovascular depression
Other than as an anti-dysrhythmic, what else is lignocaine used as?
Anti-dysrhthmic
What are the adverse effects of beta-adrenoceptor antagonists?
Bradycardia Reduced exercise capacity Hypotension Atrioventricular conduction block Bronchoconstriction Hypoglycaemia
Other than as an anti-dysrhythmic, what else are beta-adrenoceptor antagonists used in?
Hypertension
Heart failure
Angina
Anxiety
What is the drug class of amiodarone?
K channel inhibitor
What are the side effects of amiodarone?
Reversible photosensitisation
Skin discolouration
Hypothyroidism
Pulmonary fibrosis with long term use
What is the dug class of verapamil?
Ca channel blocker
What are the side effects of calcium channel blockers?
Facial flushing Peripheral oedema Dizziness Bradycardia Headache Nausea
Other than as an anti-dysrhythmic, where else are calcium channel blockers used?
Hypertension
Angina
What are the goals for the treatment of hypertension?
Reduce blood pressure to <140/85 mmHg
If diabetes/renal disease present, reduce blood pressure to <130/80 mmHg
What are the controlled variables contributing to blood pressure?
Heart rate
Stroke volume
Total peripheral resistance
What are the effects of angiotensin II?
Vasoconstriction
Aldosterone > salt and water retention
Cell growth
Increased sympathetic activity
What is the mechanism of action of ACE inhibitors?
Block angiotensin I and angiotensin II conversion - Reduce vascular tone > vasodilation - Reduce aldosterone productionn - Reduce cardiac hypertrophy Prevent breakdown of bradykinin - Increase action of bradykinin - Vasodilation - Cardioprotection
What are the adverse effects associated with ACE inhibitors?
1st dose hypotension Dry cough Loss of taste Hyperkalaemia Acute renal failure Pruritis Foetal malformations
What are the types of angiotensin receptor antagonists?
AT1 antagonists - clinically useful
AT2 antagonists - not clinically useful
What do AT1 antagonists do?
Reduce vasoconstriction
Reduce aldosterone release
Reduce cardiac hypertrophy
Reduce sympathetic activity
What are the adverse effects of angiotensin receptor antagonists?
Hyperkalaemia
Headache
Dizziness
How do beta-adrenoceptor antagonists decrease blood pressure?
Reduce cardiac output
- Reduce heart rate
- Reduce contractility
Reduce renin release
How do different beta-adrenoceptor antagonists vary?
Selectivity
Intrinsic sympathomimetic activity
Lipid solubility
What are the adverse effects of using beta-adrenoceptor antagonists?
Cold extremities
Fatigue
Dreams, insomnia
Bronchoconstriction
When is the use of beta-adrenoceptor antagonists contraindicated?
Diabetes Asthma Take care with - Heart failure - Metabolic syndrome
What type of calcium channels to calcium channel blockers block?
Voltage-gated L-type Ca channels in
- Vasculature
- Myocardium
What are the adverse effects of calcium channel blockers?
Oedema
Flushing
Headache
Bradycardia
How do thiuzide diuretics act to lower blood pressure?
Inhibit Na/Cl co-transporter in distal tubule > decrease Na and Cl reabsorption > increases Na and water excretion from kidney and K from collecting ducts > lower blood volume and reduced blood pressure
What are the adverse effects of thiuzide diuretics?
Hypokalaemia
Gout
Hyperglycaemia
Allergic reaction
What is the suffix of ACE inhibitors?
-pril
What is the suffix of angiotensin receptor antagonists?
-sartan
What is the suffix for beta-adrenoceptor antagonists?
-olol
What is the disadvantage of tetracycline use?
Short-half life
Must administer 4 times/day
How is the disadvantage of tetracycline overcome?
Semi-synthetics; eg: doxycycline
Why was penicillin-G replaced by penicillin-V?
Penicillin-G acid labile
- Must be given IV
Penicillin-V acid stable
- Available orally
What are the advantages of dicloxacillin and flucloxacillin over methicillin?
Less toxic
Capable of oral administration
What are the principles of selective toxicity?
Antibiotics should target organism but not damage host
What antibiotic class targets the bacterial cell wall?
Beta-lactams
Glycopeptides
What antibiotic class targets bacterial ribosomes?
Aminoglycosides
Chloramphenicol
What antibiotic class targets bacterial nucleic acids?
Rifamycins
Quinolones
What antibiotic class targets bacterial cell membranes?
Polymyxins
Polyenes - for fungi
What antibiotic class targets bacterial folic acid synthesis?
Sulphonamides
Trimethoprims
What is a cross-sectional study?
Examines sample of population selected and information obtained at 1 point/period in time
No follow up of subjects
Each subject contributes data only once
How is data collected in cross-sectional studies?
Questionnaires
Examinations
Investigations
Prevalence is especially looked at
What are the advantages of cross-sectional studies?
Relatively cheap
Easy
What are the disadvantages of cross-sectional studies?
Often need for representative sample, as study mainly descriptive
Weak evidence of causality because no explicit data on temporal relationships
What is a case-control study?
Comparison of previous exposure status between cases and controls
Looks at effect of exposure on outcome of interest
What is the purpose of matching during a case-control study?
Matched on bases of confounders to reduce potential for bias
What are the advantages of case-control studies?
Gives explicit knowledge about temporal relationship between exposure and outcome
Useful for studying rare outcomes
Why is relative risk unmeasurable in case-control studies?
Relative risk = measure of incidence
Case-control studies retrospective > no data on incidence
What is used as an approximation of relative risk in case-control studies?
Odds ratio
What are cohort studies?
Longitudinal studies done with follow-up of subjects to collect incidence data
Compares outcomes between exposed and not exposed to risk factor > relative risks derived
What are the advantages of cohort studies?
Explicit and detailed knowledge about temporal relationship between exposure and outcome
Can include multiple exposures and outcomes
Cohorts can be established as part of routine clinical care
What are the disadvantages of cohort studies?
Difficult to study rare outcomes
Not cheap nor easy
Why is a retrospective cohort study still considered a longitudinal study?
Researchers begin study at time where cohort has already been established and data available bout exposure in past
What is bias?
Unintentional error, due to systematic difference between/among groups > under-/overestimation of true results
What are the two main types of bias?
Selection
Information (measurement)
What is selection bias?
Systematic difference in characteristics of people selected for study and those not selected
How is selection bias minimised?
Representative sample
Cases and controls from same source
Maximise response
Minimise subjects lost to follow-up
What is information bias?
Systematic differences in way information collected between/among groups being compared
What is recall bias?
Information bias where cases more likely to recall presence of exposure due to already established prejudice about association between risk factor and outcome
How is information bias minimised?
Ensuring methods for collecting information uniform between/among groups being compared
What is confounding?
Influences relationship between exposure and outcome
3rd variable that
- Independently affects outcome
- Related to exposure
What are the two universal confounders?
Age
Sex
How is confounding minimised?
In design and execution of stages of study - Matching by confounder - Restriction In analysis - Stratification - Multivariate analyses
What are the three layers of the heart?
Epicardium
Myocardium
Endocardium
What are the sub-layers of the epicardium?
Squamous epithelium Sub-epicardial connective tissue - Blood vessels - Fat - Nervous tissue
What makes up the myocardium?
Muscle cells
Capillaries
What are the sub-layers of the endocardium?
Endothelial layer
Subendocardial connective tisse
Conducting tissue
Describe the cell size, location of nucleus, and fibre structure of cardiac muscle cells
Small cells
Central nucleus
Branching fibres
- Joined to each other by intercalated discs
Richly vascularised
WBCs between myocardial cells and capillaries
What is the role of intercalated discs?
Anchors actin filaments in 1 cell’s sarcomere to sarcomere in another cells via fascia adherens
How can intercalated discs come apart?
Removing Ca supply
What are Purkinje fibres?
Larger, modified cardiac muscle cells with limited contractile machinery
Where are Purkinje fibres found?
Bundles in subendocardium
What is the role of the endothelium?
Inhibits clotting by secreting inhibitors
Secretes clotting factor into subendothelial tissue
Releases vasoactive substances
Apart from constriction and relaxation, what is the role of smooth muscle in the tunica media of vessels?
Secretes connective tissue
- Extracellular matrix
- Collagen
- Elastin
- Ground substance
Which layer is the vasa vasorum located in?
Adventitia
Where are the elastic arteries generally found?
Closest to heat, where there’s highest blood pressure fluctations
- Aorta
- Carotid arteries
What is the purpose of the many layers of elastin in elastic arteries?
Can stretch due to higher blood pressure
When heart relaxes, layers of elastin in media store energy > compress blood > restores energy to blood during diastole > blood pressure never drops to 0
Allows blood flow to be continuous
What is the diastolic blood pressure due to?
Elastic energy applied to blood
What is the primary role of muscular arteries?
Distribute blood to tissue
Regulate blood pressure through contractions of media
How is capillary flow regulated?
Single smooth muscle cell sphincters
What is the structure of capillaries?
Single endothelial cells rolled into tubed Sealed to each other by tight junctions Basal lamina = thick connective tissue Sometimes media = pericyte Adventitia = few collagen fibres
How do the layers of veins differ from those of arteries?
Same layers
Media thinner
Adventitia thicker
have 1-way valves
What type of vessel is the preferred site of diapedesis of leukocytes?
Venules
- Affected by histamines and other cytokines
Where are the lymphatic vessels located in relation to the blood vessels?
On venous side
How are lymphatics distinguished from veins?
Absence of RBCs
Presence of WBCs
What are the risk factors for developing atherosclerosis?
Hyperlipidaemia Hypertension Smoking Toxins Haemodynamic factors Immune reactions Viruses
What is the pathophysiology of atherosclerosis?
Endothelial injury/dysfunction > LDL entry and oxidation via ROS > cytokine production > recruitment of monocytes > phagocytosis of lipics and formation of foam cells > recruitment of lymphocytes > recruitment of smooth muscle cells from tunica media and formation of ECM > degeneration of components of plaque > lipid-rich necrotic core > initial remodelling of vessel wall preserves lumen diameter > continued endothelial dysfunction > vessel stenosis, impaired vasodilation, plaques vulnerable to rupture, local pro-thrombotic environment
What is the definition of the metabolic syndrome?
Central obesity + any 2 of following
- Raised triglycerides
- Reduced HDL
- Raised blood pressure
- Raised fasting plasma glucose
What are the complications of atherosclerosis?
Ischaemia
Infarction
Aneurysm
Why can ischaemia follow atherosclerosis?
Fixed vessel narrowing
Acute plaque event
Why can infarction follow atherosclerosis?
Occlusion by plaque/thrombus
What are the types of aneurysms?
True
- Saccular
- Fusiform
False = extravasation into extravascular connective tissue
What causes aneurysms?
Atherosclerosis
Congenital weakness in wall
Systemic hypertension
Infection in artery wall
Describe the mechanism of hyaline arteriolosclerosis?
Age-related change caused by endothelial stress > deposition of plasma proteins and increased collage in vessel wall > arteriole wall thickens with homogenous eosinophilic hyaline > lumen narrows
What can cause cardiac remodelling and hypertrophy?
Myocardial infarction
Cardiac damage
Volume overload
Pressure overload
What effect on left ventricular mass and left ventricular wall thickness does concentric hypertrophy have?
Increased left ventricular mass
Increased left ventricular wall thickness
What effect on left ventricular mass and left ventricular wall thickness does remodelling have?
Normal left ventricular mass
Increased left ventricular wall thickness
What effect on left ventricular mass and left ventricular wall thickness does eccentric hypertrophy have?
Increased left ventricular mass
Normal relative wall thickness
What is concentric hypertrophy?
Increased wall thickness without left ventricular enlargement
Often due to pressure overload
More sarcomeres in parallel
What is eccentric hypertrophy?
Increased chamber size and normal relative wall thickness
Often due to volume overload
Myocyte stretching - more sarcomeres in series
Describe LaPlace’s law
Wall stress = pressure pulling heart apart
- Stress counteracted by desmosomes joining myocytes
- Increasing wall thickness reduces wall stress because it increases number of desmosomes
Pressure greater determinant of wall stress than volume
What is decompensation
Occurs in long-term following hypertrophy
Characterised by
- Reduced systolic function and cardiac output
- Increased left ventricular end diastolic pressure
- Eventual cardiac failure
What are some environmental causes of concentric and eccentric hypertrophy?
Concentric: pressure overload due to high afterload
- Hypertension
- Aortic stenosis
Eccentric: volume overload due to high preload
- Mitral and aortic regurgitation
- Ventricular septal defect
What are two genetic causes of ventricular hypertrophy?
Hypertrophic cardiomyopathy > thickened septum
Fabry’s disease
How is left ventricular hypertrophy clinically identified?
Forceful apex beat S3 and S4 heart sounds ECG Chest x-ray Echocardiogram MRI
What are the causes of left ventricular remodelling?
Renin-angiotensin-aldosterone Adrenergic nervous system Endothelin Cytokines Local factors
What are the causes of right ventricular hypertrophy?
Congenital
Pulmonary hypertension
Right heart valves
Describe the pathology of hypertrophic cardiomyopathy?
Increased left ventricular wall thickness, especially of septum > left ventricle outflow tract obstruction > cellular hypertrophy > myocyte disarray
What is athlete’s heart?
Eccentric hypertrophy with normal cardiac function
Usually regresses with deconditioning but may not regress > ventricular arrhythmia and sudden cardiac death
What are the four determinants of cardiac output?
Contractility
Preload
Afterload
Heart rate
Describe the length-tension relationship in muscle fibres
Increased sarcomere length > increased force of contraction
How is left ventricular end diastolic pressure measured?
Measure pulmonary wedge pressure = ventricular pressure = atrial pressure
How is right ventricular end diastolic pressure measured?
Non-invasive = JVP Invasive = across tricuspid valve
How do pulmonary artery wedge pressure and JVP reflect preload?
Pulmonary artery wedge pressure = left ventricular end diastolic pressure
JVP = right ventricular end diastolic pressure
Why does cardiac failure happen?
Usually due to decreased cardiac output arising from systolic failure = loss of contractility
How does cardiac failure happen?
Loss of myocardial muscle - Ischaemic heart disease - Cardiomyopathy Pressure overload - Aortic stenosis - Hypertension Volume overload - Valve regurgitation - Shunts
How may cardiac failure worse by inappropriate homeostatic adaptations?
Increased end diastolic pressure and thus end diastolic volume to maintain same cardiac output
However, increased end diastolic volume > more fluid in left ventricle > more fluid in left atrium > more pressure in left atrium > pulmonary hypertension > pulmonary oedema
What are the homeostatic mechanisms to combat cardiac failure?
RAAS stimulation > Na and water retention > peripheral/pulmonary oedema
Corresponding K loss and vasoconstriction
Why is long term sympathetic stimulation of the heart unfavourable?
Vasoconstriction
Ventricular arrhythmias
Direct toxic effect
What is the pathophysiology of diastolic heart failure?
Normal systolic function
Reduced left ventricular compliance due to
- Infarct
- Chronic hypertension
- Hypertrophy
Increased left ventricular end diastolic pressure required to fill left ventricle > increase in pulmonary venous pressure > pulmonary congestion/oedema
Why is overdosing of diuretics unfavourable for cardiac function in patients with heart failure?
Drop in blood pressure to do compromised systolic function > cardiogenic shock
How is peptidoglycan synthesised?
Synthesised from intermediates in cytoplasm on inner aspect of plasma membrane
Building block transported to exterior membrane and linked to growing peptidoglycan chain
How does vancomycin work?
Binds to terminal D-Ala-D-Ala in peptidoglycan building block
Prevents cell wall synthesis
What types of bacteria is vancomycin effective against?
Gram positive bacteria only, because can’t cross Gram negative outer membrane
What is the basis of vancomycin resistance in enterococci?
Enterococci change terminal D-Ala to D-Lac > vancomycin can’t bind
What is the mechanism of action of penicillin?
Has similar structure to D-Ala-D-Ala
Binds to and deactivates penicillin-binding proteins > no cross-linking
Defective synthesis of cell wall
Bacteria starts to break down its own cell wall
What do beta-lactamases do?
Have similar structures to penicillin binding proteins
Beta-lactam antibiotic binds to beta-lactamase > hydrolysed
Unstable antibiotic > can’t fulfill role in disrupting cell wall synthesis
What are the two mechanisms of resistance to beta-lactams?
Beta-lactamases
Altered penicillin-binding proteins
What are the two types of beta-lactamase expression?
Expressed on plasmids
- Susceptible to clavulanic acid
Chromosomal expression
- Susceptible to ticarcillin
Which beta-lactam is Pseudomonas aeruginosa susceptible to?
Ticarcillin
What is the mechanism of beta-lactam resistance in methicillin-resistant Staphylococcus aureus (MRSA)?
Altered penicillin binding proteins
Why is the combination of clavulanic acid and amoxycillin effective?
Clavulanic acid binds to beta-lactamase > inhibits it
Amoxycillin can now act
How do aminoglycosides work?
Bind to 30S ribosomal subunit
Distort reading frame > altered proteins > early termination
How does chloramphenicol work?
Binds to 50S ribosomal subunit
Interferes with peptidyl transfer
How do macrolides work?
Bind to 50S ribosomal subunit
Interfere with translocation
What are the mechanisms of resistance to aminoglycosides?
Efflux = drug pumped out of cell
Gram negative bacteria may modify outer membrane to reduce drug entry
Enzymatic modification > reduced entry
Ribosomal mutation > reduced drug binding
Why is metronidazole only effective against strict anaerobes?
Strict anaerobes produce nitro-reductase > needed for activation of metronidazole into active form
What is intrinsic resistance?
Resistant to antibiotic naturally
What is acquired resistance?
Mutation
Horizontal gene transfer
How does transfer of genes between bacteria occur?
Transformation
Phage-mediated transduction
Plasmid- mediated conjugation
Why are multiresistance plasmids a major problem?
Potential for transfer between completely unrelated bacteria
Can lead to simultaneous acquisition of resistance to multiple antibiotics in 1 genetic event
What is a benefit and risk of using digoxin?
Increases contractility but increases risk of dysrhythmias
How does digoxin work?
Inhibits Na/K ATPase
Increased intracellular Na > decreased Ca exit
Increase Ca in sarcoplasmic reticulum
Increase Ca release with each action potential
What is the drug class of digoxin?
Glycosides
What are the adverse effects of using glycosides in heart failure?
Low therapeutic index Affect all excitable tissues - Gut: anorexia, nausea, diarrhoea - CNS: drowsiness, confusin, psychosis - Cardiac: ventricular dysrhythmias Increased toxicity - Hypokalaemia - Hypercalcaemia - Renal impairment
How do beta1 agonists increase contractility?
Agonist binds beta1-adrenoceptor > in creased cAMP > phosphorylation of Ca channel > increased Ca entry
What is dobutamine?
Selective beta1-adrenoceptor agonist
What are the adverse effects associated with beta-adrenoceptor agonists?
Increased cardiac work
Risk of arrhythmias
How do phosphodiesterase inhibitors work?
Block action of phosphodiesterase > increased cAMP > increased protein kinase activity > more open Ca channels > increased intracellular Ca > increased contractility
What is the effect on adrenoceptors during chronic heart failure?
Chronic overactivation of beta1-adrenoceptors with sympathetic compensation for reduced cardiac output > reduced beta1-adrenoceptor expression and impaired beta1-adrenoceptor coupling > reduced sensitivity to beta1- adrenoceptor agonists/sympathetic drive
What are the three main mechanisms leading to heart failure?
Decreased contractility due to loss of functional myocardial muscle
Pressure overload (afterload too high) due to
- Aortic stenosis
- Hypertension
Volume overload (preload too high) due to
- Valve regurgitation
- Shunts
What are the compensatory responses to a fall in cardiac output?
Decreased CO > decreased BP > baroreflex > increased sympathetic outflow
- Beta-adrenoceptor activation > increased renin > increased angiotensin II > increased aldosterone > Na retention > volume expansion > increased preload
- Alpha-adrenoceptor activation + angiotensin II > vasoconstriction > increased afterload
Increased preload + afterload > increased oxygen demand > worsening function > myocardial remodelling
Which drugs can reduce preload during congestion?
Venodilators
Diuretics
Aldosterone receptor antagonists
ADH receptor antagonists
What is the drug class of nitrates?
Venodilators
What is the drug class of frusemide?
Loop diuretics
What is the drug class of spironolactone?
Aldosterone receptor antagonists
What does spironolactone do?
Inhibit aldosterone action on cortical and distal tubules
Spares K
Shows increase in long term survival
Which drugs can reduce afterload?
Arterial vasodilators - Prone to reflex tachycardia ACE inhibitors and ARBs AT1 antagonists Beta-adrenoceptor antagonists
Which drugs are first line therapy for heart failure?
ACE inhibitors and ARBs
In which grades of heart failure are ACE inhibitors and ARBs effective?
All
What effect do ACE inhibitors and ARBs have on heart failure?
Improve symptoms
Delay progression of remodelling
Decrease constriction and fluid retention
Slows progression of hypertrophy
What are the side effects of using beta-adrenoceptor antagonists for heart failure?
Hypotension Fatigue Bronchoconstriction - Contraindication for asthma Cold extremities - Contraindicated in peripheral vascular disease May cause/mask signs of hypoglycaemia - Contraindicated for diabetes
What is the difference between a clot and a thrombus?
Clot forms in static blood in vitro
Thrombus forms in vivo
What is thrombosis?
Pathological formation of haemostatic plug in blood vessel in absence of blood loss
What are the three main stages of physiological haemostasis?
- Vasoconstriction: exposed collagen on damaged vessel wall > platelets stick to collagen > become activated > release ADP and serotonin > serotonin powerful vasoconstrictor
- Platelet adhesion and activation: granule contents secreted > mediators synthesised > platelets aggregate and adhere
- Fibrin formation: thrombin cleaves fibrinogen
What are some stimuli for platelet activation?
Collagen
Thrombin
Thromboxane
ADP
How is blood coagulation controlled?
Enzyme inhibitors > cascade inhibition
Fibrinolysis by plasmin
Which drugs can affect fibrin formation?
Procoagulant drugs
Injectable anticoagulants
Oral anticoagulants
How does heparin work?
Injected
Enhances activity of antithrombin > inhibits and inactivated factor Xa and thrombin
What version of heparin has a longer half life?
Low molecular weight heparin
How does warfarin work?
Oral administration Inhibits reduction of vitamin K > prevents activation of clotting factors - II - VII - IX - X Delayed onset of action
How is the anti-coagulant effect of heparin monitored?
APTT = activated partial thromboplastin time
Measure of intrinsic pathway
Which drugs may lead to increased warfarin activity?
Aspirin - Impaired platelet aggregation NSAIDs - Competition for plasma protein binding Alcohol - Competition for cytochrome p450 pathway
How is the anti-coagulant effect of warfarin monitored?
PT = prothrombin time
Time for clot formation after addition of Ca and tissue factor
Measure of extrinsic pathway
What is the INR?
Ratio of patient PT to normal PT
Which drugs can affect platelet activation and adhesion?
ADP receptor antagonists
Thromboxane synthesis inhibitors
Glycoprotein IIb/IIIa receptor antagonists
What is the drug class of clopidogrel?
ADP receptor antagonists
How is streptokinase used?
Activates plasminogen
Used IV
Single use - antigenic and can activate immune system upon re-exposure because derived from bacteria
How is alteplase used?
Human recombinant tPA
Not antigenic
IV infusion because has short half life
How does aortic stenosis arise?
Progressive narrowing of aortic valve due to fibrosis and calcification
How does the left ventricle respond to aortic stenosis?
Pressure overload of left ventricle > concentric hypetrophy > walls thicken > less compliance > diastolic dysfunction > increased left ventricular end diastolic pressure required to fill left ventricle > cardiac failure
What are the two main types of causes of aortic regurgitation?
Damage of aortic leaflets - Endocarditis - Rheumatic fever Dilatation of aortic root - Marfan's syndrome - Aortic dissection - Collagen vascular disorders - Syphilis
Describe the progression of acute severe aortic regurgitation>
Sudden increase in left ventricular end diastolic pressure and left atrial pressure > acute pulmonary oedema > cardiogenic shock > early surgery needed to prevent death
What are the causes of mitral regurgitation?
Myxomatous degeneration > mitral valve prolapse
Ruptured chordae tendineae > flail leaflet
Infective endocarditis
Myocardial infarct > ruptured papillary muscle
Rheumatic fever
Collagen vascular disease
Cardiomyopathy
What is usually the cause of acute ischaemia?
Increased demand for oxygen that isn’t met
What are the causes of infarction?
Arterial occlusion - Thrombotic - External compression in dissection Venous occlusion Systemic reduction in tissue perfusion
What does the size of an infarction depend on?
Size of artery occluded Duration of occlusion Vulnerability of cells to ischaemia Whether artery carrying oxygenated/deoxygenated blood Nature of arterial supply Oxygen content of blood State of systemic circulation
What are usually the causes of haemorrhagic infarcts?
Dual circulation/natural collateral circulation
Reperfusion
Venous occlusion
What can cause endothelial dysfunction/injury?
Direct trauma
Atherosclerosis
Immunological/infective inflammation of endothelium/endocardim
Endocardium after MI
What can cause hypercoagulability?
Post operative and post traumatic states Genetic Certain malignancies; eg: adenocarcinoma of pancreas High oestrogen levels - Peri-partum - Oral contraceptives Post myocardial infarction Antiphospholipid Ab syndrome Obesity
What can cause changes in blood flow?
Turbulence; eg: aneurysm
Slowing
What is gangrene?
Necrosis complicated by bacterial infection that eats dead organic matter = saprophytic
What is primary gangrene?
Gas gangrene
What is secondary gangrene?
Wet gangrene > complicating acute appendicitis/cholecystitis/infarction of small bowel
Dry gangrene > infarction of toes/foot/leg
How does randomisation help to deal with confounding?
Aims to make treatment groups identical in all aspects other than intervention
How is information bias dealt with?
Blinding - reduces preconceived ideas relating to intervention being undertaken
- Single blind
- Double blind
What is intention to treat analysis?
Deals with selection bias
Assumes subjects remained in their randomised group, regardless of what they did in real life
Always underestimates any treatment effect
What is survival analysis?
During follow up
Explicit capture of outcomes and their time of occurrence
Measures time to event
Usually plotted on the Kaplan-Meier curve
What is the number needed to treat?
Number of people needed to undergo intervention in order to prevent outcome in one
Marker of efficiency of intervention
How is the number needed to treat calculated?
1/absolute risk or rate reduction
What is the number needed to treat affected by?
Relative effect
Underlying likelihood of outcome
How does social gradient affect health?
Life expectancy shorter and disease more common down social ladder
How does stress affect health?
Stressful circumstances and inability to cope damaging to health > can lead to premature death
How does work affect health?
More control over work > better health
How does unemployment affect health?
Job security increases health
How does social support affect health?
Social support improves health
How does food affect health?
Good diet and adequate food supply improve health
What are the four stages of health transition?
- Age of pestilence and famine
- Age of receding pandemics
- Age of degenerative and man-made diseases
- Age of delayed degenerative diseases
What are the most powerful class of diuretics?
Loop diuretics
What is the mechanism of action of loop diuretics?
Acts on thick ascending limb of loop of Henle
Inhibits Na/K/2Cl carrier
Reduction in hypertonicity of blood > reduced water absorption into blood
Increased Na in distal tubule > increase osmotic pressure in tubule > reduced water reabsorption from tubule > torrential urine flow
What are the pharmacokinetics of loop diuretics?
Well absorbed from gut
Plasma protein bound
Reaches site of action via secretion from blood into nephron
Duration = 3-6 hrs
What are the adverse effects of loop diuretics?
K loss from distal tubule
H excretion > metabolic alkalosis
What are the clinical uses of loop diuretics?
Ion/water overload in - Acute pulmonary oedema - Chronic heart failure - Ascites - Renal failure Hypertension
What is the mechanism of action of thiazide diuretics?
Acts on distal tubules to inhibit Na/Cl co-transporter
What are the adverse effects of thiazide diuretics?
K loss from collecting ducts
Increased plasma uric acid > gout
What are the clinical uses of thiazide diuretics?
Hypertension
Severe resistant oedema - in combination with loop diuretic
When are potassium sparing diuretics used?
In combination with K losing diuretics to prevent K loss in patients with heart failure
How does spironolactone work?
K sparing diuretic
Competitive antagonist of aldosterone receptor > reduced activation of Na channels and reduced stimulation of Na pump synthesis
How do amiloride and triamterene work?
K sparing diuretics
Block luminal Na channels in collecting tubules and ducts > inhibition of Na reabsorption and inhibition of K secretion
What are osmotic diuretics?
Pharmacologically inert
Filtered but not reabsorbed
Exert osmotic pressure
Where do osmotic diuretics work?
Water permeable part of nephron
- Proximal tubules
- Descending loop of Henle
- Collecting tubules
When are osmotic diuretics used?
Raised intracranial pressure
Raised intraocular pressure
Prevention of acute renal failure
How does gentamicin cause renal toxicity?
In apical membrane of proximal tubule
Alters generation of 2nd messengers > altered intracellular Ca > impaired mitochondrial respiration > cell injury
Nephrotoxicity can impair excretion > further renal damage
What are the three fates of cholesterol made in the liver?
Ester formation and storage in liver for export in VLDL
Bile acid formation
Incorporation into membranes
Which lipoproteins contain the most cholesterol?
LDL then VLDL
What is familial hypercholesterolaemia?
Inherited dominant disorder
Mutation in LDL receptor gene
Failure of LDL receptors to take LDL from circulation
Elevated circulatory LDL
Describe the different areas supplied by the coronary arteries
Anterior and anterior 2/3 septum = left anterior descending territory
Lateral = lateral circumflex territory
Posterior/inferior and 1/3 septum = posterior descending artery/right coronary artery territory
What does oxygen supply to the myocardium depend on?
Oxygen content of blood
Myocardial blood flow
Which section of muscle is most susceptible to ischaemia, and why?
Subendocardial muscle because subjected to greatest pressure, potentiallly impairing blood flow
How is oxygen supply increased during periods of exertion?
In normal state, myocardium removes almost as much oxygen from blood as possible
So vasodilation to increase blood flow to meet increased oxygen demand
Define ischaemic heart disease
Group of conditions in which there’s an imbalance between myocardial oxygen supply and demand > myocardial hypoxia and accumulation of waste products
Which conditions are included under the umbrella of ischaemic heart disease?
Chronic coronary syndromes - Stable angina - Chronic cardiac failure - Some arrhythmias Acute coronary syndromes - Unstable angina - Sudden cardiac death - Myocardial infarction
Which part of coronary arteries does atherosclerosis primarily affect?
Epicardial parts
How does atherosclerosis with stable plaque cause stable angina?
Chronic remodelling of vessel wall > fixed vessel stenosis and endothelial dysfunction > impaired release of vasodilators > inadequate vasodilation of smaller vessels > inability to increase flow during times of increased demand > stable angina
What is an acute plaque event?
Ruptured plaque > blood exposed to subendothelial tissues > platelets activated by exposed collagen > vasoconstriction, primary haemostasis, secondary haemostasis > thrombus formation > acute narrowing of vessel lumen > acute ischaemia > acute coronary syndromes
What is sudden cardiac death?
Unexpected fatal even occurring within 1 hour of beginning of symptoms/without symptoms in apparently healthy subjects/whose disease was not so severe as to predict such an outcome
Desribe the progression of a myocardial infarction
ATP depletion > generation of ROS > altered Ca homeostasis > irreversible cell injury if continuing ischaemia
What are the potential complications of a myocardial infarct after minutes to hours?
Damaged myocytes unstable > arrhythmia
Damaged myocytes can’t contract properly > cardiac failure
What are the potential complications of a myocardial infarct after days?
Damaged myocytes unstable > arrhythmias
Damaged myocytes being destroyed > cardiac failure
Damaged wall isn’t moving normally > mural thrombus
Wall necrotic and weakened > rupture
Inflammatory mediators abound > fibrinous pericarditis
How can the myocardial wall rupture?
Rupture of free ventricular wall > blood into pericardium = haemopericardium > compresses heart until it stops = cardiac tamponade
Rupture of papillary muscle > new onset murmur > mitral regurgitation > cardiac failure > acute severe cardiac failure = cardiogenic shock
Rupture of interventricular septum > new onset murmur > ventricular septal defect > cardiac failure > cardiogenic shock
What are the potential complications of a myocardial infarct after weeks?
Damaged myocytes cleared, leaving islands of viable myocytes in healing tissue > arrhythmia
Damaged myocytes won’t be replaced > cardiac failure
Damged wall not moving normally > mural thrombus
Collagen deposition > wall strong again > flexible to wall stress > stretch > thin > bulge out > aneurysm > mural thrombus
What are the potential complications of a myocardial infarct after months?
Arrhythmia
Cardiac failure
Aneurysm formed won’t regress - unlikely to rupture > mural thrombus
What cellular changes occur in a myocardial infarct within 30 minutes?
Reversible ischaemia
What cellular changes occur in a myocardial infarct within 12 hours?
Cell death and release of troponin
What cellular changes occur in a myocardial infarct within 12-24 hours?
Necrosis
Start of acute inflammation
What cellular changes occur in a myocardial infarct within 1-3 days?
Peak of acute inflammation
What cellular changes occur in a myocardial infarct within 3-7 days?
End of acute inflammation
Start of repair by granulation tissue
Collage at 7 days
What cellular changes occur in a myocardial infarct within 1-8 weeks?
Vascular granulation tissue > fibrous granulation tissue
What cellular changes occur in a myocardial infarct after eight weeks?
Established fibrosis
Outline the general treatment regime for dyslipidaemia
Establish fasting plasma lipid profile for diagnosis
Consider cardiovascular disease status and risk factors
Treat secondary causes
Manage modifiable risk factors
What is the rate limiting step in cholesterol synthesis?
HMG-CoA > mevalonic acid by HMG-CoA reductase
How does high cholesterol in the body lead to decreased endogenous cholesterol synthesis?
Negative feedback inhibits action of HMG-CoA reductase
How does the body compensate in response to a decrease in endogenous cholesterol synthesis due to statin use?
Compensatory increase in hepatic LDL receptors > increased clearance of LDL from blood > decreased plasma total cholesterol and LDL > increased plasma HDL
What is poor compliance to statins attributed to?
Perceived lack of efficacy due to no short term feeling of efficacy
Why do serumu aminotransferases need to be measured every two to four months whillst on statins?
In case toxicity cause by drug-drug interactions
Why might a patient on statins experience muscle pain?
Statin use can lead to minor increases in creatine kinase > breaks down muscle
What are the adverse effects of statin use?
Mild GI symptoms Headache Insomnia Dizziness Myopathy - rare Hepatitis, liver failure - rare Renal failure - rare
What are the contraindications for statin use and why?
Pregnancy - impair foetal myelination
Infection, pre-surgery, post-trauma - drug-drug interactions
What is the mechanism of action of bile acid sequestrants?
Bind bile acid > prevent gut reabsorption of cholesterol > increase in bile excretion > increased demand for cholesterol for bile acid synthesis > upregulation of hepatic LDL receptors > removal of LDL from plasma > more cholesterol metabolism
What are the adverse effect of bile acid resins?
Abdominal discomfort Bloating Constipation Flatulence Steatorrhoea Decreases absorption of other drugs as not very specific
What is the mechanism of action of ezetimibe?
Acts as sterol transporter to intestine > inhibit cholesterol absorption from intestine
Why does ezetimibe not affect absorption of bile acids and fat soluble vitamins?
Extremely specific
What is the mechanism of action of niacin?
Unclear
Normally used in combinations, usually after other combinations have been ineffective
How does hiacin decrease the effects of atherosclerosis?
Decreases secretion of VLDL from liver
Reduces plasma LDL and triglycerides
Increases HDL
Lowers potentially atherogenic lipoprotein A
What are the adverse effects of niacin use?
Vasodilation - Flushing Hypotension Nausea Vomiting
What is the mechanism of action of fibrates?
Agonist at nuclear receptors > regulates gene expression to increase synthesis of lipoprotein lipase > increased breakdwon of triglycerides
What precautions must be taken when administering fibrates?
Mild elevation of serum aminotransferases
Monitor at 3 month intervals
What are the common adverse effects of fibrate use?
Nausea
Dry mouth
Headache
Rash
How does orlistat act to reduce blood triglyceride levels?
Lipase inhibitor > triglycerides excreted undigested
Why does most of coronary perfusion occur in diastole?
During systole coronary arteries compressed
What are the aims of stable angina treatment?
Prevent attacks
Relieve symptoms
Prevent progression to myocardial infarct
What is the mechanism of action of nitrates?
Biotransformation > releases nitric oxide > vascular relaxation
Where do nitrates act?
Mainly in veins to decrease preload
Also in large arteries to decrease afterload
What is glyceryl trinitrate (GTN)?
Short acting nitrate
Given sublingually
- IV for emergency
What is isosorbide dinitrate?
Longer accting nitrate Given orally For - Anticipation of effort - Prophylaxis
What are the adverse effects of nitrate use?
Postural hypotension
Headache
Flushing
Reflex tachycardia
What is the selectivity of verapamil?
1:1 vascular:cardiac selectivity
Can’t be used during heart failure
Can be used for angina and hypertension
What is the selectivity of diltiazem and nifedipine?
Vascular selective
Used in angina and hypertension
Can also be used during heart failure
What is the mechanism of action of calcium channel blockers in the use of ischaemic heart disease?
Blocks Ca entry into heart through L-type channels > decreased HR > increased filling time > increased preload > decreased contractility > decreased cardiac output > reduced oxygen demand
Vascular selective: blocks Ca entry into muscle cells of vessels > arterial dilation > reducd afterload
What are the adverse effects of calcium channel blockers in angina?
Flushing Headache Oedema Nifedipine: hypotension Verapimil: bradycardia, atrioventricular block
How do atenolol and propanolol differ?
Atenolol cardio-selective beta1-adrenoceptor antagonist
Propanolol non-selective beta-blocker
How does ivabradine work?
Blocks If > inhibits Na into cell > decreased velocity of diastolic depolarisation
What are the indications for ivabradine use?
Patients with
- Ischaemic heart disease
- Left ventricular dysfunction, and
- Heart rate of >70 bpm
What are the adverse effects of ivabradine?
Brightness in visula field
Conduction abnormalities
How is variant angina treated?
Relieve coronary spasm with short acting nitrate
Prophylaxis with vascular selective Ca channel blocker
How is unstable angina treated?
Same as with stable angina
Aspiring to prevent thrombosis
What are the methods of antimicrobial testing?
Dilution methods - Minimum inhibitory concentration Diffusion methods - Disc susceptibility test E-test strips combine disc susceptibility test and minimum inhibitory concentration
What is the rationale for using antibiotic combinations?
Temporary measure in ill patient
Delay emergence of resistance
Treat mixed infections
Achieve synergistic effect
What are the mechanisms of synergy?
Block sequential steps of metabolic pathway
Inhibits enzymatic degradation
Enhance antimicrobial uptake by bacterial cell
What are Jawetz’s laws of antibiotic synergy?
Bacteriostatic bacteriostatic = additive/indifferent
Bacteriostatic + bactericidal = antagonistic
Bactericidal + bactericidal = synergistic
What did the Whitehall study show in relation to employment and increased risk of death from cardiovascular disease?
Lower employment grde associated with increased risk of death from cardiovascular disease
What was attributed to the higher risk of mortality with a lower employment grade being because of?
60% - chronic stress related to lack of control within job
Lower income > decreased access to healthcare
Poorer diet
Less education
Smoking
Obesity
Less leisure time
What are the two determinants of the psycho-biological stress response?
Stressors
Resistance/vulnerability factors
Describe the formation of an X-ray image
Image = shadown on detector
X-ray hits detector > converts sliver-halide crystals to silver
More x-rays hit detector > blacker image
Describe the concept of e-densities
How many x-rays get through an object dependent on electron density of object
List the order of e-densities of different objects, from lowest (black) to highest (white)
Air Fat Soft tissue Bone Contrast agents Metal
What is a silhouette sign?
Interface only seen if tissues of differing e-densities next to each other
Will produce silhouette sign
Why is an erect P-A chest x-ray performed under full inspiration?
Lung fulll of air > good silhouette for other structures
Why are chest x-rays usually perfromed in the P-A direction?
Heart closer to fil and less magnified - edges of heart less blurred
Patient instructed to hug x-ray cassette so scapulae moved away from chest wall
Why are chest x-rays usually performed with the patient in the erect position?
Blood flow distribution in lungs can be assessed
Vessels nearer lung base larger than vessels more superior
Easier to see pleural effusions
In left heart failure, how do the vessels in a chest x-ray look different than normal?
Pulmonary vascular redistribution
- Pulmonary vessels near hilum and apex become larger and more dilated due to congestion
Why does hypertrophy occur?
Increased functional demand/stimulation by hormonal or growth factors
What happens to cellular components during atrophy?
Cells decrease in size and activity
Removed by autophagy
Apoptosis
When does atrophy become irreversible?
Cell loss and associated fibrosis
What is involution?
Physiological atrophy involving apoptosis
Define metaplasia
Change from one fully differentiated mature cell type to another - better able to withstand new environmental conditions
What is the mechanism underlying cell metaplasia?
Cytokine/growth factor driven reprogramming of line of differentiation
What are the causes of disturbed valve function?
Congenital abnormalities Myxomatous mitral valve Degenerative changes due to calcifcation Inflammatory - Infection - Immune mediated
What are the possible complications of valve replacements?
Porcine valves susceptible to infective endocarditis
Prosthetic mechanical valves predispose to thrmobosis of valve
- Need to take anticoagulant drugs to prevent thrombosis
Why does concentric hypertrophy develop?
Increased afterlad
Preserves systolic function temporarily
Ultimately thickened myocardium > impaired perfusion > ischaemia
Why does eccentric hypertrophy develop?
Volume loads
Aids function up to a point
Predisposes myocardium to ischaemia
What happens as myocardial hypertrophy worsens?
Decompensation Microscopically - Fibrosis - Apoptosis Dilates > increased end diastolic volume
