Cardiovascular System Flashcards

Question

What happens during cardiac looping?

Answer 1

Heart beat begins ~ day 21; beating and blood flow important for structural remodelling occurring. Cardiac looping happens in the middle of the 4th week embryonic development, forms the chambers of the heart. Over the next few days, 2 important events occur 1. Cardiac tube elongation 2. Cardiac looping 2 bulges form; bulbus cordis and primordial ventricle. There is a truncus arteriosus superiorly and sinus venosus leading to an atrium inferiorly. As the heart tube elongates and loops the primitive atria are displaced dorsally and cranially. The primitive ventricles are displaced caudally, with the left ventricle to the left and the right ventricle towards the right.

Answer 2

In the 4th week, blood flow into the sinus venosus of the primitive heart comes from 3 sources; 1. Vitelline Veins (L&R) – returning poorly oxygenated blood from the yolk sac. 2. Umbilical veins (L&R) – carrying oxygenated blood from the chorionic sac. 3. Common cardinal veins (L&R) – returning poorly oxygenated blood from the embryo itself to the heart.

Answer 3

From the end of the 4th week of embryonic development. Dorsal and ventral endocardial cushions (thickenings in walls of the heart) develop into septa by fusing together over the atrioventricular canal. Ventricles: from 5th week, premordial interventricular septum grows upwards to separate right and left ventricles, eventually joining to the endocardial cushions at around week 8. Atria: from 5th week septum primum forms and grows downwards, foramen primum ‘space’ formed. At 32 days, foramen secumdum forms in septum primum, and at 35 days septum secundum begins to form, finishing at around week 8. Septum primum acts as a valve - ‘right to left shunt’ since fetal lungs are not yet functional, so oxygen-rich blood from chorionic sac/placenta enters RA and goes directly into the LA. Foramen Ovale = hole in the atrial septa that permits oxygen-rich blood to move from RA → LA. The timing is very carefully controlled to ensure that there is always a route for blood to flow. After birth the septum primum closes over the oval fossa.

Answer 4

Foramen ovale - Fossa ovalis Ductus arteriosus - Ligamentum arteriosum Ductus venosus - Ligamentum venosum Umbilical vein - Ligamentum teres (hepatis)

Answer 5

Septal defects – ‘hole in the heart’: Most common form is a patent foramen ovale. Abnormal resorption of septum primum during formation of foramen secundum, results in short septum primum and therefore foramen ovale is still open after birth. Some other types of CHDs: Transposition of the great arteries - rare but very serious, pulmonary artery and aorta are swapped over. Truncus arteriosus - rare but very serious, pulmonary artery and aorta don’t develop and remain as single vessel. Patent ductus arteriosus - connection between pulmonary artery and aorta in the fetus remains open after birth.

Answer 6

MAP ~ tissue perfusion pressure (MAP: ABP = COxTPR) PP (pulse pressure) = SBP (systolic BP) - DBP (diastolic BP) MAP=DBP+(PP/3*) (*PP/3 for normal heart rate, in tachycardia PP/2 may be appropriate) 110-70 mmHg is normal ≤60 is ischaemic risk

Answer 7

The difference between diastolic and systolic BP PP=SBP-DBP

Answer 8

Blood Pressure (BP) that is too high. Blood pressure includes systolic (SBP) and diastolic (DBP) quoted as SBP/DBPand measured in mmHg (e.g. 140/90). NICE (2019) Diagnosis of Hypertension requires both conventional BP ≥ 140/90 and ABPM/Home BP ≥ 135/85. BP is not a single invariant pair of figures - not constant during 24 hours, normally lower at night/when asleep, can be affected by how it is measured (clinic > home, ambulatory). BP assessment fit to determine management - needs several (ideally many) careful readings including some assessment for white coat hypertension.

Answer 9

Clinic/surgery BP: ≥80 % upper arm, listen over arterial pulse SBP, DBP (in mmHg). 24 hr ambulatory (device attached for 24hrs and takes constant measurements) and home BP options. For all: relax 5 mins ➔ ≥3 readings over a few mins ➔ BP (Very first assessment - BP both arms) ≥ 3 BPs over several weeks, should include readings away from medical environment (ambulatory/home BP)

Answer 10

Relationship between CV events/stroke and hypertension, especially if diabetic. Big cause of avoidable mortality. Risk factor for: Coronary heart disease - MI, angina, sudden cardiac death, heart failure; Cerebrovascular disease - cerebrovascular accident (CVA, stroke), TIA, multi-infarct dementia Other arterial disease - peripheral vascular disease, renal impairment, renal artery stenosis, abdominal aortic aneurysms (ballooning, rupture risk), retinopathy, papilloedema.

Answer 11

Target people with Highest Sustained BP - Grade II HT +/or Target organ damage And Highest Absolute Risk first - Rather than reduce population’s risk equally by (eg 25%), best to prioritise treatment to high risk groups – as here is where most lives saved, people: already with CVD – previous MI, CVA, with angina; with diabetes, chronic kidney disease (CKD); with 10-yr CVD risk > 10% (age, lipids, smoking, etc.)

Answer 12

Grade; conventional (clinic); daytime average ABMP/at home BP Normal BP; <130/80; <135/85 High normal BP; >130/80-<140/90; <135/85 Hypertension (HT); ≥140/90; ≥135/85 Grade 1 HT (mild); 14/90-<160/100; 135/85-<150/95 Grade 2 HT; ≥160/100-<180/120; ≥150/95 Grade 3 HT (severe); ≥180/120

Answer 13

History & examination: past BP levels, CVD and CVD risk factors. Blood pressure: GP/clinic/hospital and home/ambulatory. Blood tests: U+Es/eGFR, Lipids, HbA1c/glucose, LFTs with yGT, urate. Urinalysis: protein, glucose, blood… ECG (when available). Target organ damage: if BP particularly high (eg new grade II HT) review urinalysis (+eGFR), ECG, fundoscopy, symptoms.

Answer 14

ACE inhibitors: enalapril, lisinopril, ramipril; ANG-II receptor blockers: losartan, candesartan; Calcium channel blockers: nifedipine, amlodipine [+ rate limiting: verapamil, diltiazem]; Diuretics (thiazide/thiazide-like): bendroflumethiazide, [chlortalidone/indapamide]; Beta-blockers:atenolol, metoprolol, bisoprolol; Mineralocorticoid-Blockers (potassium sparing diuretics): spironolactone, eplerenone; Alpha-Blockers: doxazosin.

Answer 15

ACE inhibitors: inhibit ACE, block RAAS, increase bradykinin (BK - a vasodilator), dilate arteries (and veins); AngII receptor blockers: similar to ACEi (no BK effect); Calcium channel blockers: block voltage-operated calcium channels, dilate arteries (± heart rate reduction); Thiazides: inhibit Na+-Cl- symport, distal tubular natriuresis, dilate arteries and veins; Beta-blockers: block beta-adrenoceptors, reduce cardiac rate and output, block RAAS, initial vasoconstriction (ultimately vasodilate); Mineralocorticoid blockers: block mineralocorticoid receptors, distal nephron natriuresis/limit potassium loss; Alpha-blockers: block alpha1-adrenoceptors, dilate arteries and veins.

Answer 16

ACE inhibitors: cough, rise in/high K+, renal dysfunction; Angiotensin receptor blockers: few, rise in/high K+, renal dysfunction; Calcium channel blockers: headaches, flushing, ankle swelling, tachycardia, [different for rate limiting CCBs - eg verapamil: bradycardia, constipation, other GI symptoms]; Diuretics: impotence, rashes, biochemical – low Na+, low K+, raised glucose (risk of diabetes), high urate (risk of gout); Beta-blockers; wheeze [caution with asthma/COPD], cold peripheries, lassitude, exercise intolerance, impotence, bradycardia, heart block, raised glucose; Mineralocorticoid blockers: rise in/high K+, gynaecomastia (just spironolactone); Alpha-blockers: dizziness (especially on standing), urinary symptoms, tachycardia, oedema [caution with heart failure].

Answer 17

Older patients: CCB (amlodipine), thiazides Diabetic nephropathy: ACEi/ARB, MC blocker Heart failure: ACEi/ARB, thiazides, beta-blockers (if stable heart failure), MC blockers (+/- SGLT2)

Answer 18

Pregnancy contraindication: ACEi/ARB Heart block: CCB (amlodipine), beta-blockers Severe renal artery stenosis: ACEi/ARB High K+: ACEi/ARB, MC blocker Low K+: thiazides Heart failure: CCB (verapamil), alpha-blocker

Answer 19

In all cases it’s due to impairment in the kidney regulation of body salt balance. First degree (primary) due to: Genes (30-50% genetic heritability); Environment (obesity, physical inactivity, excess calorie intake, salt – high salt/sodium/low potassium/low magnesium, excess alcohol, stress, diet not rich in grains/vegetables/low saturated fat); Fetal Programming - hypertension in later life. Second degree (secondary ~5%) due to: Endocrine, Renovascular, Renal, Drugs, Coarctation, Others (e.g. Sleep Apnoe).

Answer 20

Primary Aldosteronism: Conn’s tumours,Bilateral adrenal hyperplasia; Phaeochromocytoma/paraganglioma: Thyroid dysfunction, Cushing’s syndrome (incl GC drugs), Hyperparathyroidism, Acromegaly..., Endocrine drugs (oral contraceptive); Rare genetic syndromes: congenital adrenal hyperplasia, apparent mineralocorticoid excess, Liddle’s syndrome.

Answer 21

Oestrogen oral contraceptives, Non-steroidal anti-inflammatory drugs (NSAIDs), Liquorice/carbenoxolone/steroids, Sympathomimetics (including cocaine), Alcohol, Erythropoetin, Cyclosporin A.

Answer 22

Renal artery stenosis (atheroma/fibromuscular), Glomerulonephritis/pyelonephritis/vasculitis, Obstructive uropathy, Polycystic kidney disease. Coarctation of the aorta.

Answer 23

They are organic compounds that are poorly soluble in water but miscible in organic solvents. Important lipids in human physiology: Steroids - cholesterol, steroid hormones (testosterone…); Fat-soluble vitamins - A, D, E, K; Phospholipids, Sphingolipids, Triglycerides. Cholesterol (free and esterified) and triglycerides are important in cardiovascular disease, since these are the components of lipoproteins. Elevated non-HDL cholesterol causes atherosclerosis, in particular coronary artery disease.

Answer 24

Transport cholesterol & triglycerides aroundthe body in the circulation. Main types: Chylomicrons - biggest, mostly triglycerides; Very Low Density Lipoprotein (VLDL) - quite big, pred. triglycerides; Intermediate Density Lipoprotein (IDL) - medium-sized, very short lived; Low Density Lipoprotein (LDL) - small, cholesterol-rich, long-lived; High Density Lipoprotein (HDL) - smallest, cholesterol-rich, long-lived. Apolipoproteins determine lipoprotein behaviour. ApoB48 - chylomicrons; ApoB100 - VLDL, IDL, LDL; ApoA1 - HDL. Created within: Small intestine - dietary lipids; Liver - endogenous lipids (go to peripheral tissues and then back via reverse cholesterol transport)

Answer 25

Transport & metabolism can be divided up into three main pathways: Intestinal absorption (cholesterol + triglycerides) via exogenous lipid pathways. Hepatic synthesis (cholesterol + triglycerides) via endogenous lipid pathways. These 2 pathways are how it gets to peripheral tissues - from there it goes through ‘reverse cholesterol transport’ - returns to the liver for hepatic excretion (cholesterol + bile acids). Lipoproteins transport cholesterol & triglycerides. Triglycerides = energy: Chylomicrons, created in the gut, deliver triglycerides to muscle & adipose tissue (where converted to NEFA) - post-prandial; VLDLs, synthesized in liver, also deliver triglycerides to muscle & adipose tissue (again converted to NEFA) - fasting state. Cholesterol = essential building block & precursor (steroid hormones, Vitamin D): Liver is the master organ - synthesis, secretion, uptake, excretion; Delivered to peripheral tissues via LDL; Uptake from circulation via remnants, IDL, LDL, HDL; Returned to liver (from peripheral tissues) via HDL

Answer 26

Intestinal absorption from diet: Triglycerides ➔ NEFA ➔ muscle, adipose tissue; Cholesterol & (triglycerides) ➔ liver Carried by chylomicrons, lipoprotein lipase (LPL) degrades endothelial surface, so 3 NEFA (non-esterified fatty acids - free fatty acids) combine with a glycerol to form a triglycerides, stored in muscle/adipose. Chylomicron remnants are returned to liver.

Answer 27

NEFA (non-esterified fatty acids) (albumin bound) and glucose and glycerol go to the liver. Can be carried by VLDL (very low density lipoprotein), which are degraded by LPL (lipoprotein lipase), into glycerol and NEFA, which created triglycerides stored in muscle/adipose. VLDL can also turn into IDL (intermediate density lipoprotein) where it goes back to the liver. Can also be carried by LDL (low density lipoprotein) where LDL receptors in peripheral tissues cause them to store cholesterol. From LDL, can also be transported back to the liver.

Answer 28

HDL picks up cholesterol from the intestine and liver as well as from the peripheral tissue (ABC-A1 transporter converts stored cholesterol in peripheral tissues into free cholesterol which the enzyme LCAT transfers to the HDL). The HDL can then be returned to the liver via SRB-1 or CETP esterifies the cholesterol so it enters VLDL (becomes part of endogenous pathway). So basic HDL returns cholesterol to the liver but CETP can disrupt this. LCAT = lecithin-cholesterol acyl transferase ABC1-A1 = ATP binding cassette A1 transporter SRB-1 = scavenger receptor B type 1 CETP = cholesterol-ester transfer protein

Answer 29

Non-HDL cholesterol elevated levels causes atherosclerosis and CAD. Gut chylomicron remnants and liver VLDL/IDL/LDL are all ApoB-carrying lipoproteins which can be taken into arterial walls if not cleared by liver. LDLs are relatively long-lived (~9x lifetime of a VLDL); LDL accumulation, within arterial wall, maximised by: high concentration of LDL and damage to arterial wall - mechanical (hypertension), chemical (oxidation/glycation); This leads to formation of fatty streaks. Lowering LDL-C by statins decreases CV risk.

Answer 30

1. Formation of fatty streaks: LDL + monocytes + O-free radicals. HTN/glycation/O-free radicals(produced by glycation reactions - diabetes, toxins from cigarette smoke, macrophages) damage endothelium, which attracts monocytes to the damage. LDLs oxidised by O-free radicals are consumed by macrophages ➔ macrophages laden with LDL are foam cells ➔ fatty streak is collection of foam cells within arterial wall. 2. Atheromatous plaque formation. Smooth muscle cells (SMCs) are stimulated by macrophages to migrate, proliferate, differentiate ➔ SMCs differentiate into fibroblasts which produce a fibrous collagen cap ➔ Foam cells undergo necrosis or apoptosis to leave a pool of extra cellular cholesterol ➔ atheroma = cholesterol pool beneath a fibrous cap within the arterial wall. 3. Plaque rupture. Cholesterol rich lesions ➔ plaque rupture + thrombosis ➔ total lumen obstruction ➔ tissue ischaemia (MI). Or. Fibrous lesions (less cholesterol) ➔ less liable to rupture ➔ reduced blood blow (stable angina).

Answer 31

E.g. Familial Hypercholesterolaemia (FH) Autosomal dominant, Mutation in LDL receptor (or ApoB, PCSK9), Common ~1:500 to 1:200 (heterozygotes), High LDL-C levels (typically >4.9 mmol/L), Untreated leads to premature CHD onset: ~50% men by 55 yr, ~33% women by 60 yr, Statin treatment shown to reduce CVD risk to that of general population. Other symptoms: tendon xanthoma, corneal arcus, xanthalasma. Be suspicious if: Family history of hyperlipidaemia/prem CVD, Unusually high LDL-C despite v. healthy lifestyle, History of hyperlipidaemia from young age.

Answer 32

Specialist labs can measure concentrations of: lipoproteins (ultracentrifugation), apolipoproteins (e.g. ApoA1, ApoB100). Routine laboratory measurements of lipids: total cholesterol (TC), HDL cholesterol (HDL-C), triglycerides. LDL cholesterol (LDL-C) is calculated, not measured: LDL-C = TC - (HDL-C + trig/2.2) This is the friedewald equation (assumes fasting sample - no chylomicrons) (Trig/2.2 = VLDL-C)

Answer 33

Re-perfusion via primary PCl, Drug-eluting stents (anti-proliferative agent to prevent re-occlusion). Reduced morbid and mortality but prevention saves more lives.

Answer 34

Secondary prevention (patients with disease) since risk of further CVD or CV-mortality is very high, >20% risk of a CV-event over 10 years: Lifestyle changes - smoking cessation, diet, activity, obesity, alcohol… Drugs: ACE-inhibitor, Beta-blocker – reduce post-MI mortality; Aspirin + Clopidogrel – reduce CVD recurrence & mortality; Statins – reduce CVD recurrence & mortality. Primary prevention (without disease): Lifestyle changes - diet (reduce saturated fat, simple carbs, salt), aerobic exercise, aim for BMI 20-25, reduce alcohol, quit smoking… Drugs - for those at highest absolute risk - extreme risk-factors (very high LDL-C in Familial Hypercholesterolaemia, severe hypertension) and use risk calculator (ASSIGN, QRISK…), deprivation is also a risk-factor. Ultimately individual choice

Answer 35

Statins: Reduce LDL-C, lower risk of coronary heart disease, 1st choice lipid-lowering drug class for CVD prevention; HMG-CoA reductase inhibitors, inhibit rate-limiting step of cholesterol synthesis, intra-cellular cholesterol depletion causes increased LDL uptake Ezetimibe: Reduce LDL-C, lower risk of coronary heart disease, usually an adjunct; Inhibits chol absorption at small intestine. binds to NPC1L1 (Nieman-Pick C1 Like 1) protein - a critical mediator of cholesterol absorption in GI epithelial cells Fibrates: Reduce LDL-C & Trigs, increase HDL-C, only beneficial where low HDL-C & high Trigs e.g. T2DM, usually an adjunct to statin therapy; Stimulates PPAR-a (Peroxisome Proliferator-Activator Receptor-alpha), a nuclear transcription factor, causes increased LPL activity and hepatic fatty acid oxidation, enhanced IDL/LDL uptake, reduced VLDL synthesis Next generation (but expensive): PCSK9-inhibitors; Monoclonal antibodies, delivered by fortnightly s/c injection - Alirocumab, Evolocumab - Capable of ~60% reduction of LDL-C (as adjunct to statin).

Answer 36

Foetus: ~0-2 months yolk sac; ~2-7 months liver & spleen; ~5-9 months bone marrow. Infant: all bone marrow. Adult: central skeleton, proximal ends of femur. ~ 1 billion cells produced each day in healthy adult; 1 haematopoietic stem cell (HSC) can produce ~ 10^6 mature blood cells after 20 divisions; HSCs are rare – only ~ 1 in 10,000 bone marrow cells.

Answer 37

Multipotential haematopoitic stem cell (haemocytoblast) can differentiate into either a common myeloid progenitor or a common lymphoid progenitor. Common myeloid progenitors can differentiate further into a megakaryocyte (makes thrombocytes), erythrocyte, mast cell, or myeloblast. A myeloblast can further differentiate into a basophil, neutrophil, eosinophil, or monocyte (becomes macrophage). Common lymphoid progenitors can become natural killer cells (large granular lymphocyte), or small lymphocyte. Small lymphocyte can become a T lymphocyte or B lymphocyte. B lymphocytes become plasma cells.

Answer 38

Haemocytoblast ➔ Common erythroid/granulocytic precursor ➔ Myeloblast ➔ Promyelocyte ➔ Myelocyte ➔ Metamyelocyte ➔ Band cell ➔ Neutrophil

Answer 39

Haemocytoblast ➔ Common erythroid/granulocytic precursor ➔ Proerythroblast ➔ Early erythroblast ➔ Intermediate erythroblast ➔ Late erythroblast ➔ Polychromatic erythrocyte ➔ Mature erythrocyte

Answer 40

The HSC (haematopoietic stem cell) niche - pairing of haematopoietic and mesenchymal stromal cells to regulate HSC self-renewal, differentiation and proliferation. Contains stromal cells: fibroblasts, adipocytes, macrophages, endothelial cells, osteoblasts/osteoclasts; and microvasculature.

Answer 41

Extrinsic signalling: Growth factors - cell survival/proliferation, differentiation, maturation, activation; Adhesion molecules - interact with extracellular matrix. Intrinsic signalling: Transcription factors. Growth Factor Examples (specific lineages): Erythropoiesis - regulated by renal erythropoietin which is stimulated by tissue oxygen; Myelopoiesis - G-CSF (granulocytes), M-CSF (macrophages), IL-5 (eosinophils); Thrombopoiesis - thrombopoietin from liver, feedback mechanism controls platelet count.

Answer 42

Red cells, Platelets, White cells - Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils

Answer 43

95% range (ref interval) = mean +/- 2sd Haemoglobin (g/l): M 130-180, F 115-165 RBC (x10^12/l): M 4.5-6.5, F 3.8-5.8 Haematocrit: M 0.4-0.54, F 0.37-0.47 MCV (fl): 78-98 Reticulocyte (x10^9/l): 25-85 or 0.5-2.5% WCC x10^9/l: 4-11 Neutrophils: 2.0-7.5 Lymphocytes: 1.5-4.0 Monocytes: 0.2-0.8 Eosinophils: 0.04-0.4 Basophils: 0.01-0.1 Platelets x10^9/l: 150-450

Answer 44

Too much (-cytosis): Erythrocytosis (or ‘polycythaemia’), Leucocytosis, Thrombocytosis (or ‘thrombocythaemia) Too little (-cytopenia): Anaemia (red), Leucopenia (white), Thrombocytopenia (platelets), Pancytopenia (red, white & platelets) Malignant Vs Non-malignant

Answer 45

Red cell disorder. Symptoms: Lethargy, Breathlessness, Chest pain, Headache, dizziness, Pallor. Symptoms depend on degree of anaemia, speed and comorbidities. Examples: Blood loss; Reduced RBC production - Deficiency (Iron, B12/folate), Malignancy, Chronic disease, kidney disease, Thalassaemia, Bone marrow failure; Increase RBC destruction - Haemolysis (e.g. autoimmune), Sickle cell disease…

Answer 46

Causes: Chronic blood loss - menstruation, GI bleeding ; Dietary - vegetarian, vegan, toddlers; Malabsorption - coeliac disease, gastric surgery; Increased requirements - pregnancy, growth. Perform iron studies on peripheral blood, Microcytic hypochromic anaemia = MCV < 80fl, MCH <27 pg; Pencil cells/target cells (microscopy)

Answer 47

Defective DNA synthesis during RBC production causing cell growth without division. Macrocytic anaemia (increased MCV): Anisocytosis, oval macrocytes, Neutropaenia with hyper-segmented neutrophils, Thrombocytopenia, Reduced reticulocytes, Non haematological effects. Usually due to B12/folate deficiency: Test levels of B12/folate in blood & replace (+ remove cause of deficiency). Folate dietary sources are green vegetables (folate free diet causes deficiency in weeks). Deficiency can be due to inadequate intake, malabsorption (coeliac…), excess consumption (pregnancy), drugs (anticonvulsants…). Vitamin B12 dietary sources are meat, dairy, fish. Deficiency due to vegan diet, autoimmune (pernicious anaemia), malabsorption (gastric/ileal surgery).

Answer 48

Normal: Old RBC (120 day life span) - RES removal and recycling. Haemolytic anaemia is excessive/premature RBC breakdown: Spherocytes or fragments, Anaemia and reticulocytosis, Raised bilirubin and LDH. Extravascular or intravascular. Causes – many: Inherited (E.g. Hereditary spherocytosis), Acquired (E.g. Autoimmune haemolytic anaemia).

Answer 49

Increased haematocrit (HCT) and/or haemoglobin. Absolute (increased red cell mass): Primary – Polycythaemia Rubra Vera (myeloproliferative conditon) - Associated with thrombosis and risk of progression to malignancy; Secondary – Increased EPO – Chronic hypoxia (COPD, altitude), renal tumours. Relative/apparent (reduced plasma volume): Acute dehydration, alcohol, diuretics.

Answer 50

Leucocytes (WBCs) can be many types: monocyte, lymphocytes, neutrophil, eosinophil, basophil. Leucocytosis is too many. Leucopenia is too few. Can be one cell type or a combination. Can be benign or malignant. Malignant cause of leucocytosis: Lymphoid – lymphoma/leukaemia, Myeloid – myeloproliferative disorders/leukaemia. Benign physiological responses: Neutrophilia – Infection, inflammation, malignancy, bone marrow infiltration, steroids, pregnancy, g-csf; Monocytosis – Acute or chronic infection, connective tissue disease; Eosinophilia – Allergy, parasites, skin disease, drugs. Leucopaenia is mainly neutropenia. Infections - recurrent bacterial skin infections, mouth ulcers, overwhelming sepsis, unusual infections. Neutropenia (NR 2-7.5 x10^9/l) - but ethnic variation <0.5 x 10^9/l - significantly increased risk of infection, Causes: Viral infections, Autoimmune, Drug induced (chemotherapy agents to treat various cancers, nadir for neutrophils at 7-10 days after chemotherapy), B12/folate deficiency, Liverdisease/hypersplenism, Myelodysplasia/leukaemia/marrow infiltration.

Answer 51

Leucopaenia (too few WBCs) is mainly neutropenia. Infections - recurrent bacterial skin infections, mouth ulcers, overwhelming sepsis, unusual infections. Neutropenia (NR 2-7.5 x10^9/l) - but ethnic variation <0.5 x 10^9/l - significantly increased risk of infection, Causes: Viral infections, Autoimmune, Drug induced (chemotherapy agents to treat various cancers, nadir for neutrophils at 7-10 days after chemotherapy), B12/folate deficiency, Liverdisease/hypersplenism, Myelodysplasia/leukaemia/marrow infiltration.

Answer 52

Thrombocytosis: Platelets > 450 x 10^9/L, Primary - Essential thrombocytosis (ET) or another myeloproliferative disorder (MPD); Secondary - Infection/inflammation/surgery, Post-splenectomy, Iron deficiency, malignancy Thrombocytopenia: Platelets <150 x 10^9/l, Symptoms <20x10^9/l - Bruising, Gum bleeding, nose bleeds, Petechiae, Prolonged bleeding from cuts; Increased destruction/consumption - Immune (immune thrombocytopenia purpura, drugs {e.g.heparin}, autoimmune, infection); Non-immune (Hypersplenism, MAHA {e.g. DIC/TTP/HUS}); Decreased production due to - Bone marrow failure, B12/folate deficiency, Drugs/ alcohol, infection, Liver disease. Pancytopenia 🚩: Severe infection, Hypersplenism, Megaloblastic anaemia, Myelosuppressive drugs, Bone marrow failure - Infiltration (e.g. with metastatic solid organ cancer, TB), or, Aplastic anaemia, leukaemia, myelodysplasia, myelofibrosis… Likely need blood film reviewed.

Answer 53

How blood cells are made.

Answer 54

How bloods clot.

Answer 55

Need platelets (normal number, normal function), functional coagulation cascade and normal vascular endothelium.

Answer 56

Size of 0.5x3.0 micrometers, anucleated, discoid shape, mean volume of 7-11 fL, ~150-400x10^9/L, lifespan of 9-12 days. Contains membrane glycoproteins, alpha-granules, mitochondria, metabolites, lysosomal granules, receptors for primary agonists, dense granules.

Answer 57

3 distinct stages involved in the formation of aplatelet rich thrombus: Platelet adhesion, Platelet activation/secretion, Platelet aggregation. The conversion of fibrinogen to fibrin by thrombin, and polymerisation of fibrin stabilises the platelet thrombus, resulting in a platelet-fibrin (“white”) clot. Primary aggregation: Normal platelets in flowing blood adhere to damages endothelium and other platelets undergoing activation. They then undergo aggregation into a thrombus. Secondary coagulation: Thrombin makes fibrin. The primary aggregation and secondary coagulation combine to form the haemostatic clot. Early haemostatic response to injury is triggered by exposure of sub endothelial collagen and the release of tissue factor.

Answer 58

Platelet/Vessel Wall defects all give rise to ‘prolonged bleeding time’. Reduced number of platelets - thrombocytopenia (TP) - many causes like bone marrow failure, peripheral consumption (e.g.immune TP, disseminated intravascular coagulation (DIC), drug-induced)… Abnormal platelet function: Most commonly drugs such as aspirin, clopidogrel…; or Renal failure - uraemia causes platelet dysfunction. Abnormal vessel wall: Scurvy (classical findings of peri-follicular haemorrhage), Ehlers Danlos syndrome, Henoch Schӧnlein purpura, Hereditary Haemorrhagic Telangiectasia (Telangiectasia in skin, gut, lungs can bleed causing anaemia, blood loss) Abnormal interaction between platelets and vessel wall: Von Willebrand disease.

Answer 59

Extrinsic tenase and intrinsic tenase. Prothrombinase.

Answer 60

Prevent the over-activity of the coagulation cascade. TF-VIIa complex/fXa inhibited by TFPI, tissue factor pathway inhibitor. Thrombin and fXa activity inhibited by Antithrombin. Protein C pathway inhibits fVa and fVIIIa.

Answer 61

Prothrombin time (PT): Measured in seconds, reflects the ‘extrinsic pathway’ and the ‘common pathway’. Activated Partial Thromboplastin Time (APTT): Measured in seconds, reflects the ‘intrinsic pathway’ and the ‘common pathway’. Fibrinogen: Measured in grams/L, reflects the functional activity of the fibrinogen protein.

Answer 62

Defect in XII (note - doesn’t cause bleeding): autosomal inheritance, relatively common incidence; XI defect: autosomal inheritance, rare incidence; IX defect - haemophilia B: X-Linked recessive inheritance, 1:30,000 live male births; VIII defect - haemophilia A: X-Linked recessive inheritance, 1:5000-8000 live male births; Von Willerbrand Disease: Autosomal dominant inheritance, common incidence; VII defect: Autosomal recessive inheritance, very rare incidence; X, V, II, XIII: Autosomal recessive inheritance, very rare incidence.

Answer 63

X-linked recessive disorder. Typically expressed in males and carried in females. 1 : 5-8000 males; 30% cases are sporadic mutations. Deficiency of fVIII (or dysfunction). Severity of haemophilia same within different generations. Clinical severity of haemophilia correlates to fVIII level. <1% : SEVERE : frequent haemarthroses, 2 - 10% : MODERATE : bleeding after minor trauma, 11 - 30% : MILD : bleeding after surgical challenge A “normal” FVIII level ranges from 50-150%. Causes traumatic bleeding in soft tissue, spontaneous bleeding (spontaneous acute haemartherosis), chronic arthrophathy (narrowing of joint space). Traditional Management of Haemophilia: Supportive Measures - Ice, immobilisation, rest; Replacement of missing clotting protein by - Coagulation factor concentrates (plasma-derived, recombinant, extended half-life products), Desmopressin (DDAVP) (used to increase factor VIII levels in mild/moderate haemophilia A), Novel therapies (monoclonal antibodies, knock-out AT now becoming reality); Antifibrinolytic Agents - Tranexamic acid. Management: Specialised Centres (Comprehensive Care Haemophilia Centre), Multidisciplinary Approach, Home treatment, Patient Education and Social Support, Physiotherapy/Psychology, Orthopaedic Advice & Treatment, Treatment & Diagnosis of Liver Disease, Specialised Management for HIV Positive Patients, Genetic Counselling. Can be congenital or acquired. Congenital: Haemarthroses, Muscle bleeds, Soft tissue bleeds. Acquired: Large haematomas, Gross haematuria, Retropharyngeal & retroperitoneal haematomas, Cerebral haemorrhages, Compartment syndromes.

Answer 64

Roles of Von Willebrand Factor: promote platelet adhesion to subendothelium at high shear rates, and carrier molecule for FVIII. Most common heritable bleeding disorder. Mainly autosomal dominant inheritance. Men and women affected. Associated with defective primary haemostasis. Variable reduction in Factor VIII levels - mucocutaneous bleeding including menorrhagia, post-operative and post partum bleeding. Variable penetrance for mild types. Diagnosis of mild vWD difficult due to confounding factors (e.g. blood group O lowers VWF levels). Management: Antifibrinolytics (tranexamic acid), DDAVP (for type 1 vWD), Factor concentrates containing vWD - plasma-derived (recombinant concentrates are just coming into the market), Vaccination against hepatitis A and B, Contraceptive pill for menorrhagia.

Answer 65

Underproduction of coagulation factors: Liver failure, Vitamin K deficiency (e.g haemorrhagic disease of the newborn – deficiency of vit K at birth due to liver immaturity, lack of gut bacterial synthesis of vit K2, and fall in coagulation factors if breast fed – leads to haemorrhage in baby at days 2-4 or at 2 months; all newborn babies offered 1mg vit K intramuscular at birth). Anticoagulants: warfarin, direct oral anticoagulants. Immune: Acquired haemophilia, acquired VW Syndrome. Consumption of coagulation factors: DIC

Answer 66

Reduced hepatic synthesis of clotting factors. Thrombocytopenia secondary to hypersplenism. Reduced vitamin K absorption due to cholestatic jaundice causing deficiencies of factors II, VII, IX & X. Treat with plasma products and platelets to cover procedures, and vitamin K.

Answer 67

A humanised bi-specific antibody that binds to and bridges fIXa and fX. Acts as a FVIII-mimetic agent. Now being used in patients with severe haemophilia A with and without inhibitors, but may have side effects of microvascular thrombosis if concurrently treated with other factor concentrates (such as “FEIBA”).

Answer 68

An acquired syndrome of systemic intravascular activation of coagulation – “thrombin explosion”. Widespread deposition of fibrin in circulation. Tissue ischaemia and multi-organ failure. Consumption of platelets and coagulation factors to generate thrombin, may induce severe bleeding. To maintain vascular patency, plasmin generated in excess, leads to fibrinogenolysis. Aetiology: Sepsis – G+ or –ve sepsis, fungal infection, parasitic infection; Tumour – solid, haematological (Acute Promyelocytic Leukaemia); Trauma – fat embolism, head injury, burns, lightning strikes; Pancreatitis; Obstetric – amniotic fluid embolism, abruptio placentae, Pre-eclampsia/eclampsia syndrome; Vascular – Kasabach Merritt syndrome (haemangioma)(incidence of DIC is 25%), aortic aneurysm (incidence of DIC is 0.5 to 1%); Toxic – recreational drugs, snake bites, bugs, bats, caterpillars, (“creepy crawlies”); Transfusion of ABO incompatible cells. Can cause multi-organ failure: acute renal injury due to fibrin deposition. Examination of the peripheral blood film may show red cell fragments. Markers of consumption of coagulation factors: Prolonged prothrombin time (PT), Prolonged activated partial thromboplastin time (APTT), Low fibrinogen. Marker of increased fibrinolysis: Raised D-dimmers.

Answer 69

The three factors contributing to thrombosis: Stasis, Hypercoagulability, Vascular injury

Answer 70

Natural inhibitors prevent over-activity of the coagulation cascade: TF-VIIa complex/fXa inhibited by TFPI, tissue - factor pathway inhibitor; Thrombin and fXa activity inhibited by Antithrombin; Protein C pathway inhibits fVa and fVIIIa.

Answer 71

Age (older), obesity, varicose veins (lower after surgery), previous VTE, family history of VTE, thrombophilia, active cancer, hormone therapy, immobility, hospitalisation, travel, central venous catheters, pregnancy/puerperium, other thrombotic states (heart failure/recent MI/stroke…)

Answer 72

Pain, swelling, increased temperature of limb, dilatation of superficial veins; usually unilateral, may be bilateral if thrombosis sited in inferiorvena cava; Differential diagnosis: calf haematoma, ruptured Baker’s cyst, cellulitis; Clinical probability score = Well’s score

Answer 73

Clinical Model to Standardise Clinical Assessment. Pre-test probability (clinical likelihood) of DVT. Stratify patients into low-, intermediate-or high-probability categories.

Answer 74

Well’s score pre-test for probability. Use of D-dimer as a negative predictor of venous thromboembolism, Gold standard test is contrast venography (very rarely performed), Venous ultrasonography (USS) - Non-compressibility of the common femoral vein or popliteal vein are diagnostic of DVT, sensitivity 95%, specificity 96% for diagnosis of symptomatic proximal DVT, but sensitivity and specificity of only 60-70% for isolated calf vein thrombosis.

Answer 75

Depends on number, size and distribution of emboli: Collapse, faintness, crushing central chest pain, Pleuritic chest pain, Difficulty breathing, Haemoptysis, Exertional dyspnoea

Answer 76

Chest X-ray (to exclude other pathology), Electrocardiogram (ECG), Arterial blood gases, D-dimer, Ventilation Perfusion (V/Q) scan, CT-pulmonary angiogram, Echocardiogram

Answer 77

1. Rapid initial anticoagulation: Parenteral anticoagulant - heparin, low molecular weight heparin, fondaparinux, or Direct oral anticoagulant; Aim to reduce the risk of thrombus extension and fatal pulmonary embolism. 2. Extended therapy: Orally active anticoagulant - vitamin K antagonist, or Direct oral anticoagulant; Aim to prevent recurrent thrombosis and chronic complications such as post-phlebitic syndrome.

Answer 78

Used for VTE over past few years; Dabigatran, Rivaroxaban, Edoxaban & Apixaban licensed in UK for treatment of acute DVT; Enables rapid initial anticoagulation orally; Then continue a maintenance dose for 6 months, or longer for secondary prevention of VTE; Apixaban and Rivaroxaban do not need any overlap with heparin – big advantage in outpatient setting

Answer 79

Full Blood Count; Antithrombin, Protein C, Free protein S, Antiphospholipid antibodies and lupus anticoagulant; Thrombin time/reptilase time (to investigate fibrinogen function); Factor V Leiden, Prothrombin 20210A (genetic tests); JAK-2 mutation (to investigate myeloproliferative conditions); PNH screen (if patient has cytopenia, for splanchnic bed thrombosis).

Answer 80

Venous thrombosis <45yrs, Recurrent venous thrombosis, Family history of unprovoked thrombosis, Combined arterial and venous thrombosis, Venous thrombosis at an unusual site (e.g. cerebral vein thrombosis, Budd-Chiari syndrome, portal vein and splanchnic vein thromboses)

Answer 81

Unfractionated heparin (UFH) - heterogeneous group of molecules with a range in MW from 3000 to 30,000 D (unpredictable anticoagulant response due to binding to plasma proteins - monitoring required by activated partial thromboplastin time (APTT)), continuous IV infusion/twice daily sc administration, risk of osteoporosis/heparin-inducedthrombocytopenia (HIT) - use when high bleeding risk - reverse by d/c infusion or protamine; Low-molecular weight heparin (LMWH) - nearly 100% bioavailability means reliable dose dependent anticoagulant effect and dose-dependent renal clearance, no monitoring required (unless renal impairment/extremes of body weight/pregnancy - measure LMWH-antiXa level), once daily dosing reduced risk of osteoporosis and HIT, cannot be reversed. Sulphated glycosaminoglycan, biological product derived from porcine intestine. Binds to unique pentasaccharide on antithrombin and potentiates its inhibitory action towards factor Xa and thrombin.

Answer 82

E.g. warfarin Inhibit vit K dependent carboxylation of factors II, VII, IX and X in the liver, Causes a relative deficiency of these coagulation factors, Monitored by the International Normalised Ratio (INR), derived from the prothrombin time (PT), Takes around 5 days to establish maintenance dosing, Loading regimens assist early dosing, Individual dose for each patient - racial differences reflect natural occurring polymorphisms in CYP2C9 and VKORC1 genes, Dietary intake of vit K also affects warfarin dose. Many drug interactions - requires monitoring at least monthly. Most common serious side-effect is bleeding - major bleeding occurs in 1% of patients each year, risk of fatal intracranial haemorrhage 0.25% per annum. Reversal: vit K (oral/IV), or by administering deficient clotting factors (tendency to use factor concentrate - factor II,VII, IX and X - in place of fresh frozen plasma (4-factor prothrombin complex concentrate, “PCC”))

Answer 83

Treatment of deep vein thrombosis and pulmonary embolism, Prevention of cardioembolic events in patients with atrial fibrillation. Benefits over warfarin: more predictable anticoagulation profile, fewer drug/food interactions, wider therapeutic window, oral administration, no need for monitoring, simple dosing.

Answer 84

New antidote now in use for reversing dabigatran (Idarucizumab - Humanised Fab fragment, binding affinity ~350 times higher than dabigatran to thrombin, binds to free and thrombin-bound dabigatran to neutralise activity - no intrinsic procoagulant/anticoagulant activity, IV dosing by bolus or rapid infusion, immediate onset of action), New antidote now starting in use for reversing Apixaban and Rivaroxaban in NHS Scotland (Andexanet alfa - recombinant human factor Xa “decoy protein”, reverses the inhibition of fXa). For all DOACs - basic measures: Determine how long since last dose, Start standard resuscitation measures, Moderate to severe bleeding - Local measures, Fluid replacement, Consider fresh frozen plasma or platelets, Antifibrinolytic inhibitors.

Answer 85

Mechanical - mechanical foot pumps, graduated compression stockings; Pharmacological - LMWH/UFH, Fondaparinux, Dabigatran, Rivaroxaban, Warfarin

Answer 86

Oral: TTP889 - acts at IX, Rivaroxaban, Apixaban, Edoxaban, Batrixaban - acts at Xa, Dabigatra - acts at IIa Parenteral: TFPI (tifacogin) - acts at TF/VIIa, APC (drotrecogin alfa), sTM (ART-123) - acts at VIIIa and Va, Fondaparinux, Idraparinux, Idrabiotaparinux - acts at AT (which acts at Xa), DX-9065a, Otamixaban - acts at Xa.

Answer 87

Arteriosclerosis: ‘Hardening of the arteries’ – a generic term for the thickening and loss of elasticity of arterial walls, Multiple causes (including atheroma, age-related sclerosis and calcification). Atherosclerosis: A specific form of arteriosclerosis (athere = porridge-like; sclerosis = hardness) due to atheroma, Worldwide, may contribute to up to 50% of all deaths. Atheroma (fibro-fatty plaques): Athere – ‘porridge-like’; oma – ‘tumour’; Refers to plaques found particularly in elastic and medium-to-large muscular arteries, These can protrude into and variably-obstruct the lumen and also weaken the underlying media.

Answer 88

Increasing age, sex hormone influences (M>F but this equalises by 8th decade), Genetics (‘Family History’ – probably polygenic), Hyperlipidaemia (esp. LDL-cholesterol), Hypertension (both systolic and diastolic levels are important), cigarette smoking, Diabetes mellitus.

Answer 89

Chronic or repetitive endothelial injury/dysfunction - unclear what initiates this but it seems to lead to increased endothelial permeability, enhanced leukocyte adhesion and thrombotic potential; Accumulation of intimal lipid - in ‘attracted’ cells (foamy macrophages) as well as extra-cellularly; Smooth muscle cell migration to, and proliferation, in the intima (and elaboration of extra-cellular matrix with accumulation of collagenand proteoglycans); Fibrosis forming a fibro-lipid plaque. The evolving atheroma consists of a chronic inflammatory reaction associated with macrophages, lymphocytes, endothelial cells and smooth muscle cells all expressing, or contributing to, a cocktail of factors that influence the behaviour of other cells. Plaque injury – thrombosis and haemorrhage (can be associated with catastrophic clinical events depending on the site).

Answer 90

Calcification; Ulceration and plaque rupture [with the possible exposure of highly thrombogenic substances and the induction of thrombus formation or the discharge of micro-embolic debris (‘cholesterol emboli’)]; Haemorrhage (into a plaque, may be initiated by rupture of fibrous cap or of thin-walled capillaries that vascularise the plaque; a contained haematoma may expand the plaque or induce plaque rupture); Super-imposed thrombosis (which may partially occlude or fully occlude the lumen); Aneurysmal dilatation. These can lead to vessel obstruction and downstream ischaemia. External vessel rupture may also occur, particularly with abdominal aortic aneurysms.

Answer 91

Abdominal mass (pulsatile), Impingement on adjacent structure (eg. ureter), Embolisation (atheroma or mural thrombus), Vessel ostia obstruction, Rupture into the peritoneal cavity or retro-peritoneum with potentially massive (fatal) haemorrhage.

Answer 92

Cerebral infarction, Carotid atheroma - emboli causing TIA/cerebral infarcts, MI, cardiac failure, Aortic Aneurysms - rupture causes sudden death, Peripheral vascular disease with intermittent calcification, Gabgreen.

Answer 93

A thrombus is a solidification of blood constituents that forms within the vascular system during life. Thrombosis is a pathological process. It denotes the formation of thrombus within the uninterrupted vascular system. Solidification of blood constituents outside the vascular system or after death is termed blood clot or haematoma (particularly if formed within tissues).

Answer 94

Endothelial integrity is the single most important, factor especially in high-flow arterial scenarios but the endothelium need not necessarily be physically disrupted to contribute to thrombosis; any perturbation in the dynamic balance of pro- and anti- thrombotic effects of endothelium can influence local clotting. Ulcerated atheromatous plaques (Aorta, Carotid arteries, Iliac and femoral arteries, Coronary arteries); Left ventricular endocardium after myocardial infarction; Vasculitis; SARS Co-V2; Abnormal cardiac valves (Rheumatic fever, Infective endocarditis, Prosthetic valves)

Answer 95

Disrupts laminar flow (may be more likely for platelets to contact endothelium); Prevents the dilution of clotting factors; Retards the inflow of inhibitors of clotting factors; Causes endothelial injury - promoting endothelial cell activation. Turbulence - contributes to the development of arterial and cardiac thrombi. Stasis - important in the formation of venous thrombi.

Answer 96

Alteration of the blood coagulation mechanism (particularly platelets and the clotting cascade) that in some way predisposes to thrombosis. May be a genetic predisposition - e.g. Mutations in the Factor V gene or the prothrombin gene; 5-20% of Caucasians have the Leiden mutation (R506Q) rendering it resistant to cleavage by protein C; resistance to protein C-mediated inactivation of Factor Va promotes coagulation. There are also other rare inherited deficiencies associated with the anti-coagulant proteins: protein S and protein C. May be acquired – e.g. in immobility, post-trauma or surgery, stasis and vascular injury may also be more important while in lower-risks cenarios such as pregnancy or OCP-use (due to altered hepatic synthesis of various coagulation factors).

Answer 97

Mural thrombi: Applied to one wall of the underlying structure, Occur in the capacious cavities of the cardiac chambers and the aorta. Arterial thrombi: Usually occlusive, May be mural, Occur anywhere butmore frequent in Coronary/Carotid/Cerebral/Femoral arteries. Venous thrombosis: Also termed phlebothrombosis, Not to be confused with thrombophlebitis, Occurs typically in pelvic and leg veins in association with stasis.

Answer 98

Occlusion of artery or vein. Arterial occlusion: Loss of pulses distal to the thrombus, Area becomes cold, pale, painful, Eventually tissue dies and gangrene results. Embolism: Arterial – away from the heart (distal), Venous – towards the heart (proximal). Venous thrombosis: Superficial (saphenous system) – Congestion, swelling, pain, tenderness (rarely embolise), Deep – foot and ankle oedema, may be asymptomatic and recognised only when they have embolised (eg via IVC and right side of heart to the lung).

Answer 99

An embolus is a detached intravascular solid, liquid, or gaseous mass that is carried by the blood to a site distant from its point of origin. 99% of all emboli arise from thrombi (thromboembolism); Unless otherwise qualified, the term embolus implies thromboembolism. Less common/rare forms of emboli include fragments of: Bone/bone marrow, Atheromatous debris, Droplets of fat, Tumour cells, Foreign bodies (such as bullets), Bubbles of air/nitrogen.

Answer 100

Pulmonary embolism, Systemic embolism, Amniotic fluid embolism, Air embolism, Fat embolism.

Answer 101

Embolism, usually thrombo-embolism, to the pulmonary arteries. Occlusion of a large or medium-sized pulmonary artery is almost always embolic in origin until proved otherwise (large vessel in situ thrombosis of the pulmonary arteries is rare and only develops in the presence of pulmonary hypertension, pulmonary atherosclerosis and heart failure). Most (95%) of pulmonary emboli arise in thrombi within the large deep veins of the lower leg (the next most common origin is in the pelvic veins, in association with pelvic masses). Large emboli may impactin the main pulmonary artery or lodge at the bifurcation as a ‘saddle’ embolus; These are associated with collapse and sudden death; Their effect is to cause circulatory obstruction. Smaller emboli can travel out into the more peripheral pulmonary arteries and if these are of intermediate size, they may cause pulmonary infarction - particularly inpatients with cardiac failure; however in patients with adequate cardiovascular function, the bronchial artery supply can often sustain the lung parenchyma despite the local obstruction to the pulmonary arterialsystem. If very small and recurrent, they may lead to pulmonary hypertension. In the presence of an inter-atrial or inter-ventricular defect, they may gain access to the systemic circulation - paradoxical embolism.

Answer 102

Large embolus: Circulatory obstruction, Collapse, Incompatible with life. Medium-sized embolus: Pulmonary infarction, Haemoptysis, Pleuritic chest pain. Small emboli (usually multiple): Asymptomatic until heart failure develops, Pulmonary hypertension, Right ventricular failure.

Answer 103

Systemic Embolism refers to emboli that travel through the systemic arterial circulation; 80-85% arise from thrombi within the heart; Less common sources include thrombi developing in relation to: Ulcerated atherosclerotic plaques, Aortic aneurysms, Infective endocarditis, Artificial heart valves/aortic grafts. Arterial emboli almost always cause infarction; Major sites for systemic emboli to lodge are: Lower extremities (commonest), The brain, Viscera (mesenteric, renal, splenic arteries), Upper limbs (much less common).

Answer 104

Infarct (Latin: infarcire = to stuff): Is an area of ischaemic necrosis caused by occlusion of arterial supply or venous drainage in a particular tissue. Necrosis (Greek: nekroζ = dead): Refers to a spectrum of morphological changes that follow cell death in living tissue, largely resulting from the progressive action of enzymes on the lethally injured cells.

Answer 105

Thrombosis and thromboembolism accountfor the vast majority; Other causes include: Vasospasm, Expansion of atheroma, Compression of a vessel, Twisting of the vessels through torsion (eg testis or bowel), Traumatic rupture. Factors That Influence Development of an Infarct: Nature of the vascular supply - Single (e.g. spleen) or dual (e.g. lung, small bowel); Rate of development of occlusion - Rapid occlusion more likely to cause infarction; Vulnerability of affected tissue to hypoxia - More metabolically active tissues more vulnerable e.g. heart; Oxygen content of blood - Hypoxia increases risk.

Answer 106

Ischaemic coagulative necrosis [minutes - days] (Liquefactive necrosis in the central nervous system); Inflammatory response [hours - 7 days]; Reparative response [1 - 2 weeks]; Scarring [2 weeks - 2 months].

Answer 107

Renal disease: Chronic renal failure, Renal artery stenosis, Polycystic kidneys; Endocrine causes: Pituitary - ACTH, Adrenal cortex - glucocorticoid excess (Cushing syndrome) or mineralocorticoid excess (primary hyperaldosteronism), Adrenal medulla - catecholamines (e.g phaeochromocytoma); Drug treatment e.g. steroids; Others e.g. co-arctation of the aorta Potentially treatable - Careful clinical assessment - Test the urine

Answer 108

Heart: Hypertension, in part, as a risk factor for atherosclerosis, is one of the most important risk factors for coronary artery disease, peripheral vascular disease and cerebro-vascular disease; hypertension can also lead to cardiac hypertrophy and, potentially, cardiac failure (hypertensive heart disease); Kidney (with possible renal failure); Brain (e.g. Intra-cerebral haemorrhage causing stroke); Other blood vessels (including retina - hypertensive retinopathy, and aorta)

Answer 109

Left ventricular hypertrophy (an increase in individual cell size); this is an adaptive response to the pressure load. This is clinically-important as an increased heart mass predicts excess cardiac mortality: it predisposes to chronic heart failure but left ventricular hypertrophy is also an independent risk factorfor sudden death (in part due to a predisposition to develop arrhythmias). Fibrosis. Coronary artery atheroma and ischaemic heart disease. Therefore, hypertension has both a primary and a secondary role (in the potentiation of multiple interacting aetiologies) to reduce heart function.

Answer 110

Nephrosclerosis: ‘Drop-out’ (loss) of nephrons secondary to vascular/arteriolar narrowing (hyaline arteriolosclerosis)-related focal ischaemia. [nephrosclerosis can cause renal insufficiency but this is more pronounced and occurs at a younger age in the presence of systemic hypertension or other vascular pathology e.g. secondary to diabetes] Proteinuria, Chronic renal failure. Rapid rises in blood pressure can be associated with acute renal failure (‘malignant’ hypertension).

Answer 111

The pulmonary circulation is low resistance and pulmonary BP is about 1/8th of systemic BP (pulmonary hypertension is considered to be present if the mean pulmonary pressure reaches ¼ of systemic BP). Primary (or idiopathic) pulmonary hypertension is rare. PH is usually secondary to cardio-pulmonary conditions that increase pulmonary blood flow and/or vascular resistance or increase left-sided heart resistance to blood flow. This includes: Some diseases of the pulmonary parenchyma - COPD, interstitial lung disease… - associated with destruction of the lung parenchyma (there are fewer alveolar capillaries and this leads to an increase in pulmonary arterial resistance and pressure); Congenital or acquired heart disease – e.g. mitral stenosis (this increases left atrial pressure causing an increase in pulmonary venous pressure and consequently pulmonary arterial pressure); Recurrent thrombo-emboli (the reduction in the area of the pulmonary vascular bed leads to an increase in pulmonary vascular resistance); Autoimmune disorders – e.g. systemic sclerosis. Pulmonary hypertension can result in right ventricular hypertrophy, right ventricular dilatation, and right ventricular failure secondary to the prolonged elevated pressure (pure RVF is termed cor pulmonale).

Answer 112

The blood supply to the myocardium is insufficient to meet its metabolic demands - i.e. there is an imbalance between supply (perfusion) and the metabolic/functional requirements; this results in ischaemia. Deficient supply: Coronary artery disease (commonest; 90% of cases and due to atherosclerosis), Reduced coronary artery perfusion (shock/severe aortic valve stenosis) Excessive demand: Pressure overload - e.g. hypertension, valve disease; Volume overload - e.g. valve disease

Answer 113

Coronary blood flow is normally independent of aortic pressure. The initial response to luminal narrowing of the artery is auto-regulatory compensatory vasodilatation but >75% fixed luminal occlusion generally causes symptomatic ischaemia (initially e.g. on exercise) while a 90% occlusion can lead to such inadequate blood flow that there may be symptoms at rest. Ischaemia can, however, stimulate the development of collateral circulation. Types of CAD include: Atheroma-related coronary artery disease (by far the most common) - Progressive stenosis, Haemorrhage into a plaque, Thrombosis - These may cause ‘acute coronary syndromes’ (angina, acute MI and sudden death); Emboli e.g. from inflamed aortic valve (endocarditis); Vasculitis

Answer 114

Myocardial Infarction: An area of necrosis of heart muscle resulting from reduction (usually sudden) in the coronary artery blood supply (primarily an ‘end-artery’). Due to: Coronary artery thrombosis, Haemorrhage into a coronary plaque, Increase in demand in the presence of ischaemia. Clinical features: Central ‘crushing’ chest pain, Features of heart failure (not always). Diagnosis: Clinical history, ECG changes, Blood markers (enzymes e.g. creatine kinase, other proteins e.g. troponin).

Answer 115

Right coronary artery: Inferior infarction, ECG changes in leads II, III, and aVF, Can involve posterior septum, 30% of cases Circumflex artery obstruction: Lateral infarction, ECG changes in leads I and aVL and lateral chest leads (V4-6), 20% of cases Left anterior descending artery obstruction: Artery of ‘sudden death’, Anterior infarction, ECG changes in anterior chest leads, 50% of cases

Answer 116

Sudden death: Within hours, often caused by ventricular fibrillation; Dysrhythmias: First few days, caused by abnormal electrical activity; Persistent pain: 12 hours - few days, caused by progressive necrosis (extension); Angina: Immediate or delayed (weeks), caused by ischaemia of non-infarcted cardiac muscle; Cardiac failure: Variable time interval, caused by ventricular dysfunction Dysrhythmias; Mitral incompetence: First few days, caused by papillary muscle dysfunction, necrosis; Pericarditis: 2 - 4 days, caused by inflammation of the pericardium, produces sharp chest pain; Cardiac rupture: 3 - 7 days, caused by weakening of wall by necrosis; Mural thrombosis: 1 week or more, caused by abnormal endothelial surface; Ventricular aneurysm (may rupture): 4 weeks or more, caused by stretching of newly formed scar tissue

Answer 117

Chronic angina - Exercise-induced chest pain, Heart failure - Related to reduced myocardial function. Usually widespread coronary artery atheroma, areas of fibrosis often present in the myocardium.

Answer 118

Failure of the heart to pump sufficient blood to satisfy metabolic demands (hypoperfusion) and/or accommodate systemic venous return. Leads to under-perfusion, fluid retention and increased blood volume. Two different, but linked, circulations (systemic and pulmonary). Acute heart failure: Rapid onset of symptoms, often with definable cause e.g. myocardial infarction; Chronic heart failure: Slow onset of symptoms, associated with ischaemic heart disease/valvular heart disease/etc.; Acute-on-chronic heart failure: Chronic failure becomes decompensated by an acute event Can be: Left ventricular failure, Right ventricular failure, Congestive cardiac failure - failure of both ventricles; Systolic failure - impaired ventricular contraction and ejection (this is seen in 70% but most patients systolic failure will also have some diastolic dysfunction), Diastolic failure - impaired relaxation and ventricular filling.

Answer 119

Pressure overload: Hypertension (pulmonary or systemic), Valve disease e.g. aortic stenosis. Volume overload: Valve disease e.g. aortic incompetence. Intrinsic cardiac disease: Ischaemic heart disease, Primary heart muscle disease, Myocarditis, Pericardial disease, Conducting system disorders

Answer 120

Usually this is caused by ischaemic heart disease, hypertension, aortic or mitral valve disease. The clinical effects primarily result from progressive damming of blood in the pulmonary circulation and reduced peripheral blood flow (hypoperfusion due to reduced cardiac output). The LV dysfunction results in an increase in the amount of blood in the ventricle and an increase in both the end-systolic and end-diastolic volumes; this leads to an increase in left ventricular end-diastolic pressure with a consequential increase in left atrial pressure and the capillaries in the lungs (pulmonary congestion). When this pressure exceeds plasma oncotic pressure, fluid leaks from the pulmonary capillaries into the tissue (oedema); eventually, the sustained back-pressure can cause right ventricular failure. Combined left and right ventricular failure is often called ‘congestive’ cardiac failure. Multiple compensatory mechanisms occur in an attempt to maintain adequate function. These include increasing the cardiac output via the Frank-Starling mechanism (as preload (LVEDV) increases, there is an increase in LVEDP, which causes an increase in myocardial stretch and a subsequent increase in stroke volume and cardiac output), increasing ventricular volume and wall thickness through ventricular remodeling while mean arterial pressure is augmented through hormones. Although initially beneficial in the early stages of heart failure, if untreated, a cycle of progressive functional decline ensues.

Answer 121

Common causes: Secondary to left ventricular failure, Related to intrinsic lung disease – ‘cor’ pulmonale e.g. chronic obstructive pulmonary disease (COPD)

Answer 122

Forward failure: Reduced perfusion of tissues. Tends to be more associated with advanced failure. Backward failure: Due to increased venous pressures Dominated by fluid retention and tissue congestion - Pulmonary oedema (left ventricular failure)/Hepatic congestion and ankle oedema (right ventricular failure). Left ventricular failure: Hypotension, Pulmonary oedema - Paroxysmal nocturnal dyspnoea, Orthopnoea, Breathlessness on exertion, Acute pulmonary oedema with production of frothy fluid. Right ventricular failure: Ankle swelling, Hepatic congestion (may be painful and/or tender)

Answer 123

From left internal carotid artery (ICA), an embolus could travel to: Left anterior cerebral artery (ACA) - cause right hemiplegia (lower limb - LL); Left middle cerebral artery (MCA) - cause right hemiplegia (upper limb - UL, face) and aphasia (Broca’s area); Left ophthalmic artery - can travel to left central artery of retina (end artery) and cause left amaurosis fugax From circle of Willis (posterior circulation), an embolus could travel to: Left posterior cerebral artery (PCA) - cause right homonymous hemianopia

Answer 124

Aorto-iliac (in pelvic region); Fem-pop (thigh); Crural (leg). Intermittent claudication - when 1 segment is affected; Critical ischaemia - when 2+ segments are affected

Answer 125

3 layers: Intima, media, adventia. They are strong, smooth, flexible; under high pressure. They are more elastic near heart, more muscular further away from it. Arterioles have only a few smooth muscle cells.

Answer 126

The main arteries are key routes for perfusion with limited collaterals; Smaller arteries have many anastomoses; Blood can reach target organs by several routes; Collateral circulation can compensate for occlusion of the main system in some circumstances. Between arterioles and venules are capillary beds, with sphincters separating the bed from the vessels.

Answer 127

Dilated = aneurysm Narrowed = stenosis Blocked = occluded Split = dissection Over sensitive = vasospasm Inflamed = vasculitis Broken = a problem

Answer 128

Definition = 1.5 x the normal diameter; Degenerative aneurysms are the most common; Inflammatory, mycotic (infective), traumatic can also occur; Connective tissue disease – Marfans, Loeys-Dietz, Elhers Danlos IV. Require open surgery or endovascular repair.

Answer 129

Narrowing of arteries - atherosclerosis (Lipid deposits, Cholesterol rich plaque, Calcification, Plaque rupture = occlusion), 20% of the UK population aged 55-75 have peripheral arterial disease, 5% have symptoms, their cardiovascular risk is high. Symptoms: Claudication - Pain on walking a fixed distance, Worse uphill, Eases rapidly when you stop (angina of the leg). Short distance Claudication, Nocturnal pain/rest pain is bad.

Answer 130

Symptoms: Pain on walking a fixed distance, Worse uphill, Eases rapidly when you stop (angina of the leg). Short distance Claudication, Nocturnal pain/rest pain is bad. Treatment: Smoking cessation, exercise, aspirin, statins.

Answer 131

Acute: the 6 Ps: Pain (sudden onset), Palor, Perishingly cold, Parasthesia, Pulselessness, Paralysis Chronic: Short distance claudication, Nocturnal pain, Pain at rest, Numbness, Tissue necrosis, Gangrene, Things falling off

Answer 132

Over active vasoconstriction, causes capillary beds to shut down, triggered by cold/stress/etc., can be due to underlying connective tissue disease

Answer 133

Inflamed arteries. Large vessel – Takayasu’s disease – “the pulseless disease”, Medium vessel – Giant Cell Arteritis/Polymyalgia Rheumatica, Small vessel – lots of polyangiitis conditions usually involving the kidneys. Treatment (rheumatologist/nephrologist referral): Steroids and other immunosuppressive agents, Avoid operating or endovascular treatment if possible

Answer 134

Neuropathic, Ischaemic, Infected, Calcified vessels, Small vessel arterial disease, Patients can’t see their feet (retinopathy). Charcot Foot – end stage diabetic foot changes: Neuropathic, Warm (>2°C than normal), AV shunting, Multiple fractures, “Rocker bottom” sole.

Answer 135

Three layers – adventia, media, intima; Thin walled; Large expandable lumen - not so circular; Low pressure - have valves. Veins have tributaries 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. Blood can drain by many different routes. 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. 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 136

Muscle pumps, Thoracic pump action during respiration, Gravity – lying down/elevating leg, Right heart function. Requires functioning competent valves.

Answer 137

Starlings forces of hydrostatic pressure on the venule side of the capillary bed increase so harder for osmotic pressure to overcome it and return blood. Haemosiderin staining, Swollen legs, Itchy/fragile skin, “Gaiter” distribution (shinpad), Risk of ulceration. Treatment: Emollient to stop skin cracks, Compression - Bandages/Wraps/Graduated Stockings, Elevate and mobilise.

Answer 138

Superficial veins = Varicose veins, Deep veins = venous hypertension. Treatment: Varicose veins are common - if no complications and purely cosmetic can be left alone, for symptom relief graduated compression stockings - not the same as TED stockings. For in Superficial veins: Endothermal ablation, Surgical removal, Foam sclerotherapy, Adhesive occlusion, Compression. For in deep veins: Compression.

Answer 139

Post thrombolysis/recannalisation stenting.

Answer 140

Mesenteric or ‘portal venous’ drainage is via the liver before the heart. Systemic circulation is returns to the heart directly. In liver disease the portal system fails to drain and portal hypertension develops. Blood is therefore diverted into the systemic venous system.

Answer 141

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. Under normal circumstances the lymphatic system collects interstitialfluid and ultimately returns this to the circulation. If the lymphatic channels are blocked interstitial fluid accumulates this leads to Lymphoedema.

Answer 142

Under normal circumstances the lymphatic system collects interstitialfluid and ultimately returns this to the circulation. If the lymphatic channels are blocked interstitial fluid accumulates this leads to Lymphoedema. Can be: Congenital – presents at birth, puberty (Praecox) or adulthood (tarda), or Acquired – most common – Post-surgery especially lymph node surgery for cancer, Post-radiotherapy damage. Worldwide most common cause is Filariasis. Treatment: Compression, Skin care, Exercise, Manual lymphatic drainage (specialised massage technique), Rarely surgery to debulk/liposuction/connecting lymph channel to veins.

Answer 143

Reduced oncotic pressure: oncotic pressure is the colloid osmotic pressure induced by protein in the blood plasma; Low protein (albumin) states lead to limb swelling and oedema. Caused by: Liver failure, Renal disease (Low protein/Too much water), Malnutrition - kwashiorkor.

Answer 144

Vasodilation at arteriole level, Opening pre-capillary sphincter, More permeable capillaries. All lead to swollen, hot tissue. Lower limb cellulitis presents as hot swollen leg, tissue oedema. Unfortunately chronic cellulitis can lead to lymphatic obstruction.

Answer 145

Central venous pressure rises, Peripheral venous pressure rises, Increased interstitial fluid, Oedema.

Answer 146

Ischaemic heart disease: Ischaemia results in cardiacmuscle pain and damage –> angina, myocardial infarction. Heart failure: Impairment of muscle function.

Answer 147

Plaque formation, progression and endothelial dysfunction. Plaque destabilisation - erosion/rupture with exposure of lipid core, can promote thrombogenesis. Platelet activation and aggregation (white thrombus). Progression to thrombotic occlusion (red thrombus).

Answer 148

Aim is to identify individuals who may benefit from preventative treatments (before a heart attack or stroke occurs – primary prevention).

Answer 149

Increases Risk: Total Cholesterol (TC), Low Density Lipoprotein (LDL). Decreases Risk: High Density Lipoprotein (HDL). To improve risk stratification, add in additional biochemical markers: Other atherogenic lipoproteins (e.g. Lipoprotein a), Troponin, CRP – marker of inflammation.

Answer 150

Troponin: The troponin complex is a component of the thin filaments in striated muscle complexed to actin; regulates muscle contraction. Troponin is a 3 subunit complex with Troponin T (Tropomyosin binding), Troponin I (inhibitory protein), Troponin C (Calcium Binding). Cardiac specific forms – measured using immunoassay with monoclonal antibodies. It is very sensitive, tissue specific (cardiac trop), useful for early and late presentations, predicts future cardiac events (risk stratification). Trop I or T seem to be equally effective. Older markers of myocardial damage: AST (Aspartate Aminotransferase), LDH (Lactate Dehydrogenase), CK Activity (Total Creatine Kinase), CK-MB (Creatine Kinase MB isoenzyme). In general not cardiac specific, slow to rise.

Answer 151

Cardiovascular – MI, aortic dissection, arrhythmias, cardiac inflammation, Myocardial injury, Respiratory – acute pulmonary embolus, Infectious/immune - sepsis, Gastrointestinal – severe GI bleed, Renal – Chronic kidney disease, Endocrine – severe hypothyroidism, Artefactual – assay related, Others – endurance exercise, inherited disorders – Duchenne musculodystrophy, rhabdomyolysis.

Answer 152

Type 1 MI is acute - plaque rupture with thrombosis. Type 2 MI could be vasospasm/endothelial dilation, fixed atherosclerosis and supply-demand imbalance, or supply-demand imbalance alone.

Answer 153

Still indicates myocardial damage, some may benefit from intervention, predicts major adverse cardiac events (death, further MI).

Answer 154

Clinical syndrome with typical symptoms (breathlessness, ankle swelling, fatigue) and signs (↑ JVP, lung creps, peripheral oedema). Caused by structural and/or functional abnormality leading to raised intracardiac pressures and/or inadequate cardiac output at rest or exercise.

Answer 155

Clinical diagnosis often inaccurate but important to get right as there are proven effective drugs: ACE inhibitiors, Betablockers, Entresto, SGLT2 inhibitors. Symptoms - breathlessness, ankle swelling, fatigue; Signs -↑ JVP, lung creps, peripheral oedema. Imaging can be used (echocardiography, MRI) but expensive and long wait list. Biochemical marker correlates of diagnosis, prognosis, and treatment: Natriuretic peptides.

Answer 156

Myocyte stretch and vasoconstriction leads to ANP and BNP release; This is beneficial as it counters vasoconstriction, and opposes renal salt and H2O retention (Promotes natriuresis). ANP = 28 amino acids, released by atria of heart, BNP = 32 amino acids, released by ventricles of heart, C-type NP = 53 or 22 amino acids, released by vascular endothelium. Can Measure BNP or Nt-proBNP, but Nt-proBNP more stable in blood. (PreproBNP cleaved into ProBNP, split into Nt-proBNP and BNP). They are sensitive but not specific (levels rise with age, hypertension, MI, AF, valvular heart disease, severe COPD, pneumonia, PE, renal impairment, sepsis, cirrhosis) so used to ‘rule out’ or for monitoring treatment response.

Answer 157

Efficient: At rest - 1 molecule of fatty acids (substrate) used to generate 44 ATP, using 23 O2, producing 16 CO2; In aerobic exercise - 1 molecule of glucose used to generate 38 ATP, using 6 O2, producing 6 CO2. Inefficient: In anaerobic exercise - 1 molecule of glucose used to generate 2 ATP (+ 2 lactate), not using any O2, producing 2 CO2.

Answer 158

↑exercise → ↑oxygen demand Oxygen demand known as oxygen uptake (V̇O2). V̇O2 is dependent upon: Ventilatory capacity to provide oxygen, Circulation to deliver O2 to exercising muscle, Muscle ability to utilise O2 for energy conversion, Maximal oxygen uptake (V̇O2 max – Used as a global measure of fitness).

Answer 159

Ventilation adapts to meet needs for uptake of oxygen and clearance of CO2 produced. RER also known as Respiratory quotient (RQ): V̇CO2/ V̇O2, CO2 produced/O2 consumed, RQ (RER) increases with exercise. At rest RER = 0.7 since both O2 consumption and CO2 produced is low; During aerobic exercise RER = 1.0 since both O2 consumption and CO2 produced is slightly increased; During anaerobic exercise RER >>1.0 since is O2 consumption has increased again slightly compared to aerobic but CO2 produced has increased a lot.

Answer 160

Increased ventilation needed as O2 demands (V̇O2) and need to clear CO2 (V̇CO2) increase. Increased ventilation achieved by: Increases in respiratory rate (RR), Increased size (tidal volume - VT) of each breath; Ventilation per minute (V̇E) = RR x VT Minute ventilation (V̇E) may increase up to 25-fold on exercise.

Answer 161

Maximal exercise ventilation (V̇E max) can be estimated as maximal voluntary ventilation (MVV). MVV can be calculated from spirometry using FEV1 (forced expiratory volume in 1 second). MVV = FEV1 x 40 is equation favoured by ERS Task Force. MVV can also be directly measured - period of rapid deep breathing over 12 second period.

Answer 162

Five-fold increase in cardiac output during exercise: Increases in HR, Increases in stroke volume. Improved oxygen transfer during exercise: increase in blood volume within pulmonary capillaries, re-distribution of blood flow to muscle (less blood flow to splanchnic circulation - gut hypoperfusion and dysfunction can arise with extremes of exercise - runners diarrhoea).

Answer 163

Cardiac physiology. Cardiac output = HR x SV. Maximal Heart Rate (HRmax) = Ceiling of Exercise (along with efficiency of exercise performance in reaching HRmax) All of us have a maximal heart rate - HRmax can be estimated as 220-age - Useful for identifying training intensity zones.

Answer 164

Energy conversion to ATP is occurring in exercising muscle - relies on ongoing oxygen delivery to exercising muscle for oxidative energy generation: 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. When oxygen demand outstrips the rate of oxygen delivery, energy must be generated by non-oxidative metabolism. The point at which this begins to occur is the ‘Anaerobic Threshold’.

Answer 165

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.

Answer 166

Impaired ability for exercising muscle to extract and utilise oxygen from blood. Causes exercise limitation. Effects: Reduced muscular capillary numbers (reduced O2 transfer at muscular level), Reduced mitochondrial density (reduced O2 utilisation at muscular level), Reduced oxidative enzyme concentrations (reduced energy transformation in muscles). The deconditioned subject will have: Less capacity for oxidative energy generation, Earlier switch to anaerobic metabolism (earlier onset of anaerobic threshold).

Answer 167

“Fitness gaining needs exercise training”. Training is the anti-thesis of deconditioning: Improvements in cardiac stroke volume, Increases in the size of the muscle capillary network, Increased mitochondrial density, Increased oxidative enzyme concentrations. Improvements in O2 delivery to exercising muscles, Improved O2 utilisation by exercising muscles, More efficient energy transformation in exercising muscles. By improving fitness, Anaerobic Threshold is reached later in exercise = later switch from aerobic to anaerobic metabolism = able to exercise more efficiently. Capable of reaching greater exercise capacity.

Answer 168

Reduced all-cause mortality - Delayed by regular physical activity and works if changing from sedentary by increasing physical activity; Cardiometabolic benefit - e.g. reduction in coronary heart disease, stroke, Type II diabetes; Reduction in some cancers - e.g. colon and breast cancer; Improvements in mental health - Reduces rates of depression, anxiety; Protective against cognitive decline and dementia.

Answer 169

>150–300 minutes of moderate-intensity aerobic physical activity (PA) per week, or >75–150 minutes of vigorous-intensity aerobic PA/week, or Equivalent combination of moderate- and vigorous-intensity activity throughout the week. Muscle-strengthening activities at moderate or greater intensity that involve all major muscle groups on 2 or more days a week. Limit time spent sedentary.

Answer 170

Ventilation not a limiting factor in health. HRmax determines ceiling of exercise capacity for us all. Conditioning determines efficiency of exercise performance in reaching HRmax. This is the only one of these factors that is amenable to change (with training).

Answer 171

Disease states have many similarities in exercise approach. Deconditioning common cause of exercise limitation in those with disease. By impacting exercise performance, one may impact prognosis. Exercise capacity can aid stratification of surgical risk - Timing of onset of switch to anaerobic metabolism important in risk assessment for major surgery. May be disease-specific considerations around exercise. Barriers to exercise after surgery (pain, immobility) so lung function often dips. So important to be in best shape possible pre-op.

Answer 172

Oxygen pulse = VO2/HR (oxygen extraction/heart rate). When stroke volume is limited, cardiac output is limited, so, O2 pulse is reduced; There is less ability to meet oxygen demand so VO2 vs HR graph is shifted left (VO2 max occurs at lower HR); Peak VO2 achieved is reduced. In cardiac disease VO2 fails to rise normally in response to increasing work rate, so less oxygen per heart beat delivered to exercising muscle, and earlier switch to anaerobic metabolism.

Answer 173

FEV1 is low but reasonable exercise tolerance - peak VO2 and peak HR achieved, but not ventilatory reserve at end of exercise. Anaerobic threshold occurs late - indicative of fitness and adaptation. i.e. Gets there with no gas left in the tank. Due to increased dead space in lung. However severe CF with more dead space will have much lower max exercise capacity but with no ventilatory reserve.

Answer 174

If reasonable peak VO2 and anaerobic threshold, then better surgical risk. Timing of onset of switch to anaerobic metabolism important in riskassessment for major surgery.

Answer 175

Normal variation in HR - sinus node fires at a variable rate: Speeds up during inspiration, Slows down during expiration, Effect caused by variations in vagus nerve activity (parasympathetic nervous system).

Answer 176

Sinus node fires > 100 per minute. Physiological causes: anxiety, exercise; Pathological causes: fever, anemia, hyperthyroidism, heart failure, shock (sepsis, bleeding, anaphylaxis), almost any acute medical emergency

Answer 177

Sinus node fires < 60 per minute. Physiological causes: sleep, athletic training; Pathological causes: hypothyroidism, hypothermia, sinus node disease, raised intracranial pressure, many others.

Answer 178

Permanent pacemaker to prevent slow rhythms. Antiarrhythmic drugs to prevent or moderate rapid rhythms: beta blocker, digoxin, amiodarone.

Answer 179

A degenerative condition affecting the atria, including the sinoatrial (SA) and atrioventricular (AV) nodes; Characterised by patchy atrial fibrosis, atrial dilatation and altered conduction; Common in individuals age > 70 years; Can lead to sinus tachycardia, sinus bradycardia, atrial ‘ectopic’ beats, and atrial fibrillation. Treatment: Permanent pacemaker to prevent slow rhythms; Antiarrhythmic drugs to prevent or moderate rapid rhythms - beta blocker, digoxin, amiodarone.

Answer 180

QRS complex is ‘dropped’ on ECG. Can cause recurrent dizziness and blackouts. Causes of AV nodal block: sino-atrial disease, coronary heart disease, aortic valve disease, damage during heart surgery, drugs (beta-blockers, digoxin, calcium channel blockers). Treatment: Remove any triggering cause (e.g. drugs), IV atropine or isoprenaline (acute treatment), permanent pacemaker.

Answer 181

Sino-atrial disease, Coronary heart disease, Aortic valve disease, Damage during heart surgery, Drugs (beta-blockers, digoxin, calcium channel blockers).

Answer 182

Remove any triggering cause (e.g. drugs - beta-blockers, digoxin, calcium channel blockers), IV atropine or isoprenaline (acute treatment), Permanent pacemaker.

Answer 183

Episodes of fast, irregular palpitations; Often a history of prolonged childhood illness with arthritis, and heart murmur. Causes: sino-atrial disease, coronary heart disease, valve disease (esp. mitral valve), hypertension, cardiomyopathy, hyperthyroidism, pneumonia/lung pathology. Treatment: drugs to block AV node and therefore limit heart rate (digoxin, beta blocker, calcium channel blocker), electrical cardioversion, catheter ablation.

Answer 184

Sino-atrial disease, Coronary heart disease, Valve disease (esp. mitral valve), Hypertension, Cardiomyopathy, Hyperthyroidism, Pneumonia/lung pathology.

Answer 185

Drugs to block AV node and therefore limit heart rate (digoxin, beta blocker, calcium channel blocker), Electrical cardioversion, Catheter ablation.

Answer 186

May present with episodes of fast, regular palpitation and near collapse, chest pains; history of heart attack; build up of exertional chest discomfort over preceding week. Can lead to cardiac arrest. Treatment: Acute - defibrillation, IV antiarrhythmic drugs, remove any triggering cause; Long term - oral antiarrhythmic drugs, treat underlying heart conditions, implantable defibrillator for some patients.

Answer 187

Antiplatelet medications can be classified by their route of administration and their mechanism of action. Aspirin was the first antiplatelet medication and is a cyclooxygenase (COX) inhibitor. Other oral antiplatelet agents include clopidogrel, ticagrelor, prasugrel and dipyridamole. Glycoprotein IIb/Illa inhibitors such as abciximab and eptifibatide are only available as parenteral agents and are used in acute coronary syndrome (ACS).

Answer 188

Aspirin is the most commonly prescribed oral antiplatelet drug and works by irreversibly inhibiting the cyclooxygenase enzyme (COX) activity in the prostaglandin synthesis pathway (PGH2); This prostaglandin is a precursor of thromboxane A2 (TXA2) and prostacyclin (PGI2); Thromboxane A2 induces platelet aggregation and vasoconstriction while PGI2 works by inhibiting platelet aggregation and induces vasodilation (the latter is mediated mainly by COX-2); Low-dose aspirin (75 mg) can induce complete or near-complete inhibition of COX-1, thus inhibiting the production of TXA2, but larger doses are required to inhibit COX-2.

Answer 189

Oral thienopyridines (clopidogrel and prasugrel) selectively inhibit adenosine diphosphate-induced (ADP-induced) platelet aggregation; These drugs are converted into the active drug with the help of the hepatic CYP450 system (CYP2C19 and CYP3A4) that can irreversibly inhibit the platelet P2Y12 receptor; Prasugrel is the most potent, has a rapid onset of action and is superior to clopidogrel in patients undergoing coronary stenting. Ticagrelor is an ADP analogue that also blocks P2Y12 receptors.

Answer 190

Glycoprotein platelet inhibitors (abciximab and eptifibatide) work by inhibiting glycoprotein IIb/Illa (GplIb-Illa) receptors on platelets, thus decreasing platelet aggregation; Only available in an intravenous form and are therefore used as short-term therapy in ACS.

Answer 191

Dipyridamole has antiplatelet and vasodilating properties and inhibits platelet cyclic nucleotide phosphodiesterase; This enzyme is responsible for the degradation of adenosine monophosphate (AMP) to 5’AMP, which increases intra-platelet cyclic AMP accumulation and inhibits platelet aggregation; It also blocks the uptake of adenosine by the platelets, which also increases cyclic AMP; Dipyridamole is used in the secondary prevention of stroke but not for ACS.

Cardiovascular System Flashcards

(216 cards)