Cardiovascular Disease II (CVD II) Flashcards

Question

Do veins have a lot of different anastomoses? If yes, what implications does this have?

Answer 1

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

Answer 2

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

Answer 3

Venous system relies on... 1. Muscle pumps - veins located in muscles 2. Thoracic pump action during respiration 3. Gravity – lying down, elevating leg to help venous return 4. Proper functioning of the right heart 5. Requires functioning competent valves

Answer 4

Venous disease is very common - 1/3 of the adult population will run into venous disease at one point 1. Can be divided according to pathology 2. Can be congenital or acquired

Answer 5

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

Answer 6

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

Answer 7

1. Emollient to stop skin cracks 2. Compression Bandages Wraps Graduated Stockings - gradient of tightness 3. Elevate and mobilise

Answer 8

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

Answer 9

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?

Answer 10

Virchow’s triad – highlights three factors that increase the risk of thrombosis

Answer 11

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

Answer 12

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

Answer 13

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

Answer 14

Blood is diverted into the systemic venous system via anastamoses between portal vein and systemic circulation - short circuit the liver

Answer 15

1. Three layers – adventia, media, intima 2. Capillary structure 3. Valves like veins 4. Rhythmic contraction of smooth muscle cell pump 5. Many, many anastomoses 6. Drain to lymph nodes 7. Ultimate drain to thoracic duct 8. Thoracic duct empties to left subclavian vein Role - drain interstitial fluid

Answer 16

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

Answer 17

Worldwide – most common cause is filariasis – parasitic worm that destroys your lymphatic channel and lymph nodes UK most common cause due to medical procedures

Answer 18

Missing treatments – mainly compression therapy and raising leg - surgery is limited 1. Compression 2. Skin care 3. Exercise 4. Manual lymphatic drainage - Specialised massage technique 5. Rarely surgery to debulk, liposuction or connecting lymph channel to veins

Answer 19

Venous hypertension – higher pressure in venules Lymphoedema – failure to clear interstitial fluid

Answer 20

Underlying theme of IHD - narrowing of the coronary artery Causes 1. Atheroma - stable (angine) or unstable/thrombus formation (MI) 2. Coronary artery spasm

Answer 21

Non-pharmacological Reduce modifiable risk factors e.g. diet, smoking, blood pressure Pharmacological - Reduce development: lipid-lowering interventions: statin, PCSK9 inhibitors, fibrates, ezetemibe - Treat symptoms: stable angina - Prevent thrombosis Surgical intervention Stent placement, balloon angioplasty for plaque removal; coronary artery bypass grafting

Answer 22

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

Answer 23

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

Answer 24

Fibrates e.g. gemfibrozil, fenofibrate 1. Decrease circulating LDL and triglyceride, only small effect on LDL 2. Increase ‘protective’ high density lipoprotein (HDL) How? 1. Activate peroxisome proliferator-activated receptors (PPARα) - increase lipid metabolism 2. Increase expression of genes associated with lipid clearance, e.g. lipoprotein lipase, apoA1(component of HDL)

Answer 25

Ezetimibe - Blocks active transport of cholesterol from the gut wall to the liver, without affecting absorption of fat soluble vitamins, triglycerides or bile acids Blocks 1. Blocks NPC1L1 protein on the gastrointestinal tract epithelial cells and in hepatocytes 2. Blocks aminopeptidase N and interrupts a caveolin 1–annexin A2 complex involved in trafficking cholesterol Note on how it is used: Added to statin where response is inadequate alone

Answer 26

Reduce demand - most effective way of treating angina (relative to increasing supply) Either by... - Reduce heart rate or force of contraction - Reduce preload (blood volume and venous tone - increased constriction more return) or afterload (tone of arterioles) Acute during the attack 1. Rest 2. Rapid acting organic nitrate e.g.Glyceryl Trinitrate Prophylactic - reduce likelihood of attack 1.Targets blood vessels a) longer lasting nitrate b) KATP channel opener 2. Targets heart a) β adrenoreceptor antagonist b) Calcium ‘antagonist’ c) ‘funny’ channel blocker

Answer 27

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

Answer 28

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

Answer 29

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

Answer 30

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

Answer 31

Less side effects than β-blockers, used as alternative or as adjunct to β blocker therapy

Answer 32

Block entry of calcium into cardiac muscle cells – reduce contractility – reduce O2 demand

Answer 33

Blood vessel wall damage – platelets activate and stick – drives coagulation cascade to form fibrin mesh - creates plug

Answer 34

Anti-thrombotic drugs - taken prophylactically to reduce the risk of thrombus if atherosclerotic plaque ruptures, in patients at high risk, or those who have already had an MI. Usually anti-platelet (aspirin, clopidogrel, voripaxar) But also anti-coagulant (warfarin, rivaroxaban)

Answer 35

1. Stimulus - damage 2. Arachidonic acid release - using PLA2 3. Cyclic endoperoxidases formation via COX 4. Converted to TxA2 (thromboxane) 5. TxA2 binds to the receptor on platlets leading to increase intracellulaer Ca2+ 6. Results in platlet activation Site of intervention - thrombin and COX

Answer 36

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

Answer 37

Target P2Y12 receptor - breaking positive feedback loop Target gpIIb/IIIa - to prevent platelet-fibrin interaction

Answer 38

Anti-platelet drugs - taken prophylactically to reduce the risk of thrombus **Cyclooxygenase inhibitor** e.g. aspirin -Irreversible inhibition of COX = prevents formation of TxA2 & platelet activation **P2Y12 inhibitor** e.g. clopidogrel, ticagrelor blocks effect of ADP and prevents platelet activation **Thrombin-receptor antagonist** e.g. voripaxar - prevent activation of PAR-1 receptors on platelets - more reading Risk: bleeding, newer drugs are shorter acting or reversible

Answer 39

Prevent the formation of fibrin to stabilise platelet plug 1. Intravenous e.g. heparin 2. Orally active e.g. warfarin, rivaroxaban

Answer 40

Body produces antithrombin 3 – neutralizes the serine proteases Hence, heparin binds to antithrombin 3 and potentiates/activates this system - block coagulation cascade

Answer 41

Warfarin – inhibits Vitamin K cycle which is required for clotting factor production Reduced clotting factors in circulation = reduce clotting Factors II, VII, IX, X

Answer 42

1. Narrow optimal range – high risk of bleeding 2. Metabolized in liver – prone to be modified by other drugs and environmental influences 3. Blood levels need to be checked regularly

Answer 43

Orally active anti-coagulant: direct inhibitor of factor Xa

Answer 44

Heart Failure - failure of the heart to meet the demand of the body Leading to... impaired tissue perfusion: fluid retention, breathlessness, muscle weakness etc also arrythmia Types: 1. HF with reduced ejection fraction (HFrEF) or systolic HF - impaired contractility and emptying of ventricle - most common and drugs directed here 2. HF with preserved ejection fraction (HFpEF) or diastolic HF - impaired relaxation and filling of ventricle - growing recognition, more common in women, diabetes, mechanisms less understood Note - MI's can lead to heart failure - leads to damage/necrosis of heart tissue leading to impaired function - some replacement of cardiomyocytes occurs but not enough.

Answer 45

Inotropic agents to increase contractility Example - Digoxin Digoxin - cardiac glycosides that increase the force of contraction (+ve inotrope - increase contractility) therefore increases kidney perfusion and fluid loss

Answer 46

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

Answer 47

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.... 1. Cardiac glycosides block Na+/K+ ATPase 2. Increase intra-[Na] 3. Results in less movement of Ca2+ outwards 4. Results in an accumulation of Ca2+ in the cell – increase contractility Note - acute solution but too much calcium accumulation is toxic for cardiomyocyte

Answer 48

Inotropes to increase contractility - acutely 1. digoxin 2. dobutamine (ß1 adrenoreceptor agonist iv for rapid response), increases heart rate and contractility Provide support in acute heart failure, but results in increased oxygen and energy demand so **NOT** helpful in the long term for chronic heart failure

Answer 49

1. Reduce Preload 2. Reduce Afterload Reduce load on the heart – reduction in heart failure exacerbation

Answer 50

Determined by... 1. Blood volume - RAAS & SNS 2. Venous ‘tone’ - capacity of the venous circulation to hold blood - SNS Increased preload... 1. Sympathetic NS activation 2. Renal failure 3. Heart failure

Answer 51

ANGII - Constricts blood vessels increasing after-load + increase blood volume by increasing levels of aldosterone resulting in increased pre-load

Answer 52

Sympathetic nervous system (SNS) response to decreasing blood pressure

Answer 53

Main goal for many of drugs is to break vicious cycle

Answer 54

1. Renin inhibitor e.g. aliskiren 2. ACE inhibitor e.g. enalapril, lisinopril 3. AT receptor antagonists e.g. losartan, valsartan

Answer 55

ß adrenoreceptor antagonists: e.g. atenolol, metoprolol (ß1 selective) 1. Reduce sympathetic drive to the heart (reduced O2 demand) - decrease HR 2. Block renin release from the kidney, therefore decrease RAAS activation, decrease pre-load & after-load Few side-effects, but not useful in asthmatics (especially non-selective) - high doses can activate B2 receptors – drive bronchoconstriction

Answer 56

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

Answer 57

Currently.... Markers for increased risk: Total Cholesterol (TC) Low Density Lipoprotein (LDL) Markers for decreases risk: High Density Lipoprotein (HDL) How can risk stratification be improved? Add in additional biochemical markers - CRP – marker of inflammation - Other atherogenic lipoproteins e.g. Lipoprotein a - Troponin Improve risk score calculations - ASSIGN to be updated - Other scores – QRISK3 - ?role for machine learning algorithms in the future - ?role for Imaging

Answer 58

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

Answer 59

1. Very Sensitive - illustrated by image - low amounts of cardiac muscle damage to produce signal 2. Tissue Specific (cardiac trop) 3. Useful for early and late presentations - levels stay raised 4. Predicts Future Cardiac Events (Risk stratification) Note - Trop I or T seem to be equally effective - Trop C normally measured

Answer 60

Used as a part of the diagnosis criteria 1. Based on clinical syndrome 2. ECG changes 3. Increased markers - troponin >99th percentile of the reference population (top 1% of measurments) Note - Increasing sensitivity of troponin assays has resulted in progressively lower thresholds being used to define MI Current NHS Lothian Trop T cut offs: 9 ng/L (women) and 16 ng/L (men) - variation in heart size between men and women

Answer 61

Results in increased numbers of patients diagnosed with AMI Important - as at the low tropnin concentrations (0-25ng/L) - there is a linear relationship between troponin concentration and death from MI/recurrent MI Having information at this low concentration range is valuable - helped to save lives

Answer 62

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

Answer 63

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!

Answer 64

Used as a rule-out test - negative = heart failure unlikely.

Answer 65

Point of contact testing for biomarkers - more relevant for us in the future - bedside tool Chest Pain - TROPONIN Breathless – BNP, D-dimer

Answer 66

Exercise physiology – looking at the interaction between all these systems

Answer 67

↑EXERCISE → ↑OXYGEN DEMAND V̇O2 (oxygen uptake) is dependent upon: 1. Ventilatory capacity to provide oxygen 2. Circulation to deliver O2 to exercising muscle 3. Muscle ability to utilise O2 for energy conversion Maximal oxygen uptake (V̇O2 max) – Used as a global measure of fitness

Answer 68

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

Answer 69

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

Answer 70

Maximal exercise ventilation (VĖ max) - expected maximal exercise ventilation VEmax - can be estimated from maximal voluntary ventilation (MVV) using FEV1 MVV = FEV1 x 40

Answer 71

Breathing not usually an exercise-limiting factor Maximal exercise is achieved with gas left in the tank Other factors – cardiac, physical fitness and motivation

Answer 72

1. Five-fold increase in cardiac output during exercise - Increases in HR - Increases in stroke volume 2. Improved oxygen transfer during exercise - Increased blood volume within pulmonary capillaries - Re-distribution of blood flow to muscle 3. Re-distribution of blood flow to peripheries - Increased blood flow to exercising muscles - Less blood flow to splanchnic circulation (gut)

Answer 73

YES! CARDIAC PHYSIOLOGY = Rate-limiting factor to maximal exercise in health Maximal Heart Rate (HRmax) = Ceiling of Exercise Along with efficiency of exercise performance in reaching HRmax

Answer 74

How our muscles take up oxygen and convert it to ATP (muscle metabolism) - dependent on... Muscular capillaries for oxygen transfer Mitochondria for oxygen utilisation Oxidative enzymes for energy transformation The efficiency of these mechanisms define our level of physical conditioning

Answer 75

Point at which ventilation increases at a faster rate than oxygen uptake (VO2) and... Reflects the point at which **anaerobic metabolism begins to predominate** with exponentially **increasing carbon dioxide** production and **accumulation of fatigue-related metabolites** including lactate. Measuring anaerobic threshold: 1. Lactate Threshold - invasive 2. Gas Exchange Threshold -invasive 3. Ventilatory threshold - non-invasive

Answer 76

Training results in... 1. Improvements in cardiac stroke volume 2. Increases in the size of the muscle capillary network 3. Increased mitochondrial density 4. Increased oxidative enzyme concentrations By improving fitness, AT is reached later in exercise = later switch from aerobic to anaerobic metabolism = able to exercise more efficiently Capable of reaching greater exercise capacity

Answer 77

Exercise-limiting factors - Limited by maximum heart rate and by level of fitness/conditioning Training can improve adaptation to exercise - Improve our level of physical conditioning and exercise performance

Answer 78

1. Exercise may exacerbate an underlying disease a) Asthma b) Arrhythmia 2. Understanding exercise limitation may be important in disease - By impacting exercise performance, one may impact prognosis 3. Exercise testing can inform surgical risk Poor exercise performance and early AT may be deal-breakers to major surgery - can yield negative health outcomes During surgery... - Inability to meet needs for CO2 elimination (VCO2) - Adverse myocardial effects of Lactate accumulation

Answer 79

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