Cardiovascular Disease II (CVD II) Flashcards
What are the layers that make up arteries? What are its properties?
Arteries
3 layers - Intima, media, adventia
Strong, smooth, flexible - required to resist larger pressures
High pressure system
How do arteries change as you move away from the heart?
Changes in thickness as you move away from the heart
- Near the heart – elastic
- Further away – increased muscularity
- Even further away (small arteries & arterioles) – fewer muscle cells, softer, thinner
What are examples of large, medium and small arteries?
Medium vessels – all the arteries that have a name but aren’t considered to be large
Small vessels - end of circulation
Why is this important?
- Vascular pathology is categorized based on vessel size
Why does a blockage in a larger artery have more implications than blockages in smaller arteries?
The main arteries are key routes for perfusion with limited collaterals - no alternative routes
Smaller arteries have many anastomoses - Blood can reach target organs by several routes
Note - Collateral circulation can compensate for occlusion of the main system in some circumstances
What vessel is largely responsible for change the perfusion of organs/tissues?
Arterioles - acts like a sphincter that changes the level of tissue perfusion
How can arterial diseases be divided?
Arterial disease is common
- Can be divided according to vessel diameter (small, medium, large)
- Can be divided according to pathology
- Can be congenital or acquired
What do the following terms means (related to arterial disease):
1. aneurysm
2. stenosis
3. occluded
4. dissection
5. vasospasm
6. vasculitis
What are aneurysms? What are typical causes? Why do we care about them?
Definition = 1.5 x the normal diameter
Can compare the diameters between left and right arteries – is one significantly bigger than the other
Degenerative aneurysms are the most common - breakdown of the wall
Other causes
- Inflammatory, mycotic (infective), traumatic aneurysms
- Connective tissue disease – Marfans, Loeys-Dietz, Elhers Danlos IV
Important
Dilatation/Larger in size results in a thinner wall – eventually leads to a rupture - leading to a haemorrhage
How can an anuerysm be treated?
- Replace the section of blood vessel with a new artificial polyester tubbing
- Endovascular repair - stent introduced – lines the inside of the blood vessel
What is the most common site of a aneurysm?
Aneurysms can present anywhere in the body
Abdominal most common
Second most common – popliteal artery aneurysm
What is the most common cause of artery stenosis?
Atherosclerosis
- Lipid deposits
- Cholesterol rich plaque
- Calcification
- Plaque rupture (very thrombogenic) = occlusion
What is claudication?
Claudication - ANGINA of the leg! - Most common presentation for peripheral vascular stenosis
- Pain on walking a fixed distance
- Worse uphill
- Eases rapidly when you stop
- Can progress to pain at rest/when sleeping
Noctural pain – heart rate drops/blood pressure drops resulting in pain/numbness - patients will start sleeping with the leg hanging from the bed/sleeping in a chair
What is the treatment of claudication?
Treatment for claudication
- Stop smoking
- Physical activity – walking – the more you walk – the more you develop the collateral supply
- Anti-platelet agent – blood flow around clot improves
- Statins – good at vascular remodeling/smooths out vessels and prevent rupturing
What are the acute presentations of peripheral artery occlusion?
Acute
1. Pain (sudden onset)
2. Palor
3. Perishingly cold
4. Parasthesia
5. Pulselessness
6. Paralysis - loss of movement
The SIX P’s
What are the chronic presentations of peripheral artery occlusion?
Chronic
1. Short distance claudication
2. Nocturnal pain
3. Pain at rest
4. Numbness
5. Tissue necrosis
6. Gangrene
Things falling off
What are the treatments for peripheral artery stenosis?
- Stretch open the existing artery - balloon system
- Bypass graft using veins
- Unable to return the blood supply – amputation - related to significant morbidity and mortality
What happens during a arterial dissection? How is it treated?
Intima layer breaks open resulting in blood entering between the layers of the artery – creating a true and false lumen
Bigger lumen (false lumen) – higher pressure and squeezes the true lumen
Treatment - introduce a stent
What happens during arterial vasopasm?
Over sensitive = vasospasm
- Over active vasoconstriction
- Capillary beds shut down
- Triggers – cold, stress
- Possible underlying connective tissue disease
What happens in arterial vasculitis? What are the three types?
Vasculitis = Inflamed arteries - divided up by size
Large vessel – Takayasu’s disease – “the pulseless disease” - arteries loss their elasticity
Medium vessel – Giant Cell Arteritis / Polymyalgia Rheumatica
Small vessel – lots of polyangiitis conditions usually involving the kidneys
What are the treatments for vasculitis?
Steroids and other immunosuppressive agents
Avoid operating or endovascular treatment if possible
Approach
1. Rheumatologist
2. Nephrologist
What are the different causes of ‘broken arteries’?
- Trauma
- Self-inflicted
- Iatrogenic - medical exmination/treatment cause
What is the link between diabetes and arterial disease?
Diabetes and Arterial Disease
Diabetic patients are 20 times more likely to have an amputation
The diabetic foot is almost a speciality in its own right!
Diabetic foot - Small vessel arterial disease
- observe calcified vessels - it is Neuropathic (no pain), Ischaemic (tissue hypoperfusion), and infected
- Charcot Foot – end stage diabetic foot changes - Neuropathic, warm (Due to AV shunting - connection between artery and vein) and multiple fractures (don’t bare weight properly)
Plus patients can sometimes not see their feet due to retinopathy
What are the characteristics/properties of veins?
- Three layers – adventia, media, intima
- Thin walled
- Large expandable lumen - possible due to low smooth muscle content in walls
- Not so circular
- Low pressure
- VALVES
How can veins be organised in accordance with size?
Veins have tributaries (not branches) and increase in size
Small vessels
Blood veins in the hand and foot, the kidneys, the brain, the eye
Medium vessels
mesenteric, renal, femoral, popliteal, tibial, subclavian, brachial
Large vessels
Vena cava, great veins in chest, iliacs
Do veins have a lot of different anastomoses? If yes, what implications does this have?
Veins have many, many anastomoses
Blood can drain from organs by many routes
Collateral circulation can compensate for occlusion of the main system in almost all circumstances
Do veins hold a large proportion of the blood in the body?
Yes, there is a large venous reservoir - high capacitance system
64% of the total systemic circulation is within the veins
- 18% in the large veins
- 21% in large venous networks such as liver, bone marrow
- 25% in venules and medium sized veins
How do veins solve the problem of gravity and return blood to the heart?
Venous system relies on…
- Muscle pumps - veins located in muscles
- Thoracic pump action during respiration
- Gravity – lying down, elevating leg to help venous return
- Proper functioning of the right heart
- Requires functioning competent valves
How can venous disease be categorised?
Venous disease is very common - 1/3 of the adult population will run into venous disease at one point
- Can be divided according to pathology
- Can be congenital or acquired
What is venous insufficiency? Causes?
Venous insufficiency - blood pooling in the legs
Can be caused by…
Failure of the calf muscle pump to pump venous blood back up the body
1. Immobility
2. Dependency
3. Fixed ankle
4. Loss of muscle mass
Failure of the valves
Results in…
Hemosiderin staining – brown discoloration of the skin – heme pigment is left behind in the skin
What is venous hypertension? What does it result in? Clinical features?
Venous hypertension - elevated blood pressure in the venous system - result in increased hydrostatic pressure (moving blood/fluid out) - resulting in fluid retention and swelling
Clinical features
1. Haemosiderin staining
2. Swollen legs
3. Itchy, fragile skin
4. “Gaiter” distribution(shinpad)
5. Risk of ulceration
What are the treatments for venous hypertension?
- Emollient to stop skin cracks
- Compression
Bandages
Wraps
Graduated Stockings - gradient of tightness - Elevate and mobilise
What are the two types of valve failure (think location)?
Superficial veins = Varicose veins
Increase blood pooling in varicose veins - sign that venous pressure is going up – very few people actually get complications
Deep veins = venous hypertension
How can valve failure be treated?
Superficial veins
1. Endothermal ablation (heat treat to remove)
2. Surgical removal
3. Foam sclerotherapy
4. Adhesive occlusion
5. Compression
- If no complications and purely cosmetic can be left alone
Deep veins
1. Compression
2. Only?
What is Virchow’s Triad?
Virchow’s triad – highlights three factors that increase the risk of thrombosis
Where do DVTs normally orginate? What are the risk factors for a DVT?
Typically pelvic/leg veins but can be axillary/subclavian upper limb DVT
Risk factors
1. Over 60
2. Smoker
3. Previous DVT
4. Right heart failure
5. Overweight
6. Cancer
7. Contraceptive Pill
What is Phlegmasia? How is it treated?
Phlegmasia is a term that has been used to describe extreme cases of lower extremity DVT, which may progress to critical limb ischemia (Venous Gangrene) and potentially limb loss.
Often with because of an underlying cancer!
Treatment – thrombolysis – break up the clot
How is DVT managed?
Standard management - anticoagulation - stops more clots from forming to allow the body to break the clot down normally
Thrombolysis (direct breakdown) also possible - using a mechanical method (shown in image) - this procedure is followed by introducing a stent.
DVT can lead to valve problems (blockage)– valves doesn’t function optimally – leading to reflux - not as problematic in calf vein DVT but more so in iliac vein
What happens to venous return from the gut, when there is liver disease/portal hypertension?
Blood is diverted into the systemic venous system via anastamoses between portal vein and systemic circulation - short circuit the liver
Outline the characterisitics of the lymphatic system.
- Three layers – adventia, media, intima
- Capillary structure
- Valves like veins
- Rhythmic contraction of smooth muscle cell pump
- Many, many anastomoses
- Drain to lymph nodes
- Ultimate drain to thoracic duct
- Thoracic duct empties to left subclavian vein
Role - drain interstitial fluid
What is lymphoedema and what is its aetiology?
Lymphoedema - lymphatic channels are blocked leading interstitial fluid accumulating - swelling
Aetiology - Congenital or acquired
a) Congenital – presents at birth, puberty (Praecox) or adulthood (tarda)
b) Acquired – most common
- Post-surgery especially lymph node surgery for cancer
- Post-radiotherapy damage
Worldwide what is the most common cause of lymphoedema?
Worldwide – most common cause is filariasis – parasitic worm that destroys your lymphatic channel and lymph nodes
UK most common cause due to medical procedures
What is the treatment for Lymphoedema?
Missing treatments – mainly compression therapy and raising leg - surgery is limited
- Compression
- Skin care
- Exercise
- Manual lymphatic drainage - Specialised massage technique
- Rarely surgery to debulk, liposuction or connecting lymph channel to veins
Summary - two vascular causes of a swollen limb?
Venous hypertension – higher pressure in venules
Lymphoedema – failure to clear interstitial fluid
What are the two primary causes of IHD?
Underlying theme of IHD - narrowing of the coronary artery
Causes
1. Atheroma - stable (angine) or unstable/thrombus formation (MI)
2. Coronary artery spasm
What are statins? What are they used for?
Statins - Inhibitors of HMG-CoA (3-hydroxy-3- methylglutaryl-CoA) reductase in the liver
e.g. lovastatin, simvastatin, atorvastatin
HMG-CoA - rate limiting enzyme in LDL cholesterol biosynthetic pathway - blocking it prevents further production by liver + leads to upregulation of LDL receptors on hepatocytes = increasing clearance from circulation
What are the side effects associated with statin use?
What are PCSK9 inhibitors? How do they work?
Normally, PCSK9 promotes degradation of LDL bound receptors inside the cell - i.e. after binding and uptake of LDL by receptor, receptor is degraded (PCSK9 drives this)
PCSK9 inhibitor blocks PCSK9 binding to the LDL receptor – results in the LDL receptor not being degraded – means that cholesterol is taking up but the receptors are recycled and brought to the surface – increasing LDL uptake from circulation
Monoclonal antibody (Evolocumab) first used
Nowadays small interfering RNAs (Inclisiran) are also used - 2x injection per year
What is angina pectoris?
How do nitrates work to relax blood vessels?
Nitrates - glyceryl trinitrate (sub-lingual, rapid action), isosorbide dinitrite (oral, longer lasting)
Nitrates - stimulate guanylate cyclase – increase cGMP - reduces amount of Ca2+ available - cause relaxation
Nitrates mimicking the effect of the NO that your endothelial cell is releasing
How do nitrates help in the instance of angina pectoris?
Reduce venous circulation – decrease preload, reduce afterload and relaxes coronary arteries (spasm)
Main effect is on venous circulation
Glyceryl trinitrate - given acutely – not long term as it results in tolerance
What is Nicorandi? How does it help with angina pectoris?
Nicorandil - Main drug use to target blood vessels
Drives hyperpolarisation of smooth muscle (opening of ATP-sensitive K+ channel) and acts as a nitrate (stimulates guanylate cyclase)
Relax preload and afterload + dilates coronary arteries – similar mode of action to nitrates but less likely to develop tolerance
How do β-adrenoreceptor antagonists help with alleviating angina pectoris?
Short term - Block the effects of noradrenaline (B1 adrenoreceptor) on the heart – reduce the heart rate and therefore oxygen demand
Long term - Block Renal B1 adrenoreceptor – blocking the RAAS system – reduce volume of blood – long term
How does Ivabradine work and how does this help with angina pectoris?
Less side effects than β-blockers, used as alternative or as adjunct to β blocker therapy
How do Calcium antagonist work? How does it help with angina pectoris?
Block entry of calcium into cardiac muscle cells – reduce contractility – reduce O2 demand
Recap - how is thrombus formed?
Blood vessel wall damage – platelets activate and stick – drives coagulation cascade to form fibrin mesh - creates plug
What are the steps that lead to platelet activation?
- Stimulus - damage
- Arachidonic acid release - using PLA2
- Cyclic endoperoxidases formation via COX
- Converted to TxA2 (thromboxane)
- TxA2 binds to the receptor on platlets leading to increase intracellulaer Ca2+
- Results in platlet activation
Site of intervention - thrombin and COX
What happens to platelets when they start becoming activated and clump together?
When activated platelets change shape and release contents of granules to further increase activation e.g. adenosine diphosphate (ADP)
Furthemore, platelets express glycoprotein IIb/IIIa receptors for attachment of fibrin, from coagulation cascade to stabilise thrombus
How can we intervene with ADP mediated platelet activation and platelet-fibrin interaction?
Target P2Y12 receptor - breaking positive feedback loop
Target gpIIb/IIIa - to prevent platelet-fibrin interaction
How does heparin work as an anti-coagulant?
Body produces antithrombin 3 – neutralizes the serine proteases
Hence, heparin binds to antithrombin 3 and potentiates/activates this system - block coagulation cascade
How does warfarin work as an anti-coagulant?
Warfarin – inhibits Vitamin K cycle which is required for clotting factor production
Reduced clotting factors in circulation = reduce clotting
Factors II, VII, IX, X
How does the anti-coagulant rivaroxaban work?
Orally active anti-coagulant: direct inhibitor of factor Xa
What are 5 common causes of heart failure?
Outline the different phases of the cardiomyocte action potential.
Cardiomyocyte resting membrane potential = –80 mV to –90 mV
Maintained by the balance of K+, Na+, Cl- and Ca2+ ions across the cell membrane
Action Potential
Phase 0 – sodium going into the cell
Phase 1 – transient efflux of K+ - depolarization
Phase 2 – Influx of Ca2+ and Na+ drives contraction
Phase 3 – K+ efflux – repolarization
Phase 4 – re-establishment of the correct ion levels in and outside the cell
How do cardiac glycosides work (thinking about cardiomyoctes and action potentials)?
Na+/K+ ATPase is an unequal exchanger that ensures that Na levels are low within the cell - creating a concentration gradient - which can then be used to drive movement of Ca2+ out of the cell using a Na+/Ca2+ exchanger – ensures Ca2+ localises outside – ready for another contraction
Hence….
- Cardiac glycosides block Na+/K+ ATPase
- Increase intra-[Na]
- Results in less movement of Ca2+ outwards
- Results in an accumulation of Ca2+ in the cell – increase contractility
Note - acute solution but too much calcium accumulation is toxic for cardiomyocyte
Physiology - what two ways can we ‘unload’ the heart?
- Reduce Preload
- Reduce Afterload
Reduce load on the heart – reduction in heart failure exacerbation
Outline how the RAAS effects pre-load and afterload.
ANGII - Constricts blood vessels increasing after-load + increase blood volume by increasing levels of aldosterone resulting in increased pre-load
Outline how the SNS effects pre-load and afterload.
Sympathetic nervous system (SNS) response to decreasing blood pressure
Outline how the SNS and RAAS feedback systems create the viscious cycle seen in chronic heart failure patients.
Main goal for many of drugs is to break vicious cycle
What drugs are used to block the RAAS system?
- Renin inhibitor e.g. aliskiren
- ACE inhibitor e.g. enalapril, lisinopril
- AT receptor antagonists e.g. losartan, valsartan
What two types of drugs are used to reduce blood volume/preload in CHF patients?
What two types of drugs are used to reduce vasoconstriction in CHF patients?
How are biochemical markers used for Heart Disease risk stratification?
Biochemical markers are used to identify individuals who may benefit from preventative treatments i.e. Before a heart attack or stroke occurs – “primary prevention”
These markers are then combined into a risk assessment tool that indicates the liklihood that an individual will suffer from a cardiac event - e.g. Assign risk score
Biomarkers for diagnosis - What are the properties of an ideal biomarker?
What is the current gold standard biomarker that is used for MI?
Troponin - The troponin complex (3 sub-unit) is a component of the thin filaments in striated muscle complexed to actin
Cardiac specific forms – measured using Immunoassay with monoclonal antibodies
Why is cardiac troponin useful as a tool for diagnosing MI’s?
- Very Sensitive - illustrated by image - low amounts of cardiac muscle damage to produce signal
- Tissue Specific (cardiac trop)
- Useful for early and late presentations - levels stay raised
- Predicts Future Cardiac Events (Risk stratification)
Note - Trop I or T seem to be equally effective - Trop C normally measured
What are other causes of raised troponin to keep in mind?
What are the two main types of MI?
Type 1 and type 2 (up to 6 types)
Type 1 – classic acute thrombus MI
Type 2 MI – supply-demand imbalance – fixed Atherosclerosis, vasospasm or endothelial dysfunction
What investigations are performed to diagnose heart failure?
Imaging – Measure cardiac
pressures/ejection fraction - gold standard but long waiting list
1. Echocardiography
2. MRI
Biochemical correlates of diagnosis, prognosis,treatment: Natriuretic peptides - can be measured!
What are the different types natriuretic peptide?
How are naturetic peptides used in the diagnosis of heart failure?
Used as a rule-out test - negative = heart failure unlikely.
What is the future of using biomarkers in healthcare - particularly in heart disease?
Point of contact testing for biomarkers - more relevant for us in the future - bedside tool
Chest Pain - TROPONIN
Breathless – BNP, D-dimer
When thinking about exercise physiology, what three systems are we interested in?
Exercise physiology – looking at the interaction between all these systems
What are the two primary functions of ventilation? What is the respiratory quotient?
Ventilation
1. Uptake of oxygen
2. Clearance of CO2 produced
Respiratory quotient (RQ) or Respiratory Exchange Ratio (RER):
RQ = CO2/ V̇O2
CO2 produced / O2 consumed
RQ increases with exercise - CO2 clearnace increase more than O2 uptake
How does ventilation change with increasing exercise difficulty? What is ventilation per minute?
Increased ventilation needed as O2 demands (V̇O2) and need to clear CO2 (V̇CO2) increase
Increased ventilation achieved by:
1. Increases in respiratory rate (RR)
2. Increased size (tidal volume - VT) of each breath
Ventilation per minute (VE)=̇ RR x VT
Minute ventilation (V̇E) may increase up to 25-fold on exercise
Is breathing normally a limting factor in exercise?
Breathing not usually an exercise-limiting factor
Maximal exercise is achieved with gas left in the tank
Other factors – cardiac, physical fitness and motivation
How are angiotensin receptor & neprilysin inhibitors (ARNI) use in patients with heart failure?
Combination of a neprilysin inhibitor (blocks break down of natriuretic peptides) and angiotensin receptor inhibitor (Block activation of RAAS system)
ARB is required as neprilysin inhibitor also block AngII break down - hence, we need to counter that
Result
1. Reduced preload
2. Reduced afterload
