Cardiovascular System Flashcards
What are the events of the cardiac cycle?
- Flow into atria, continuous except when they contract. Inflow leads to pressure rise.
- Opening of A-V valves - Flow to ventricles.
- Atrial systole - completes filling of ventricles.
- Ventricular systole (atrial diastole). Pressure rise closes A-V valves, opens aortic and pulmonary valves.
- Ventricular diastole – causes closure of aortic and pulmonary valves.
What do ECG waves correspond to?
P = Atrial depolarisation
QRS = L + R ventricular depolarisation
T = Ventricular repolarisation
What are the heart sounds?
Sounds generated in sequence by events during each heart beat:
1st Heart Sound - Closing of AV valves (Lub).
2nd Heart Sound - Closing of semilunar valves (Dub).
3rd Heart Sound - Early diastole of the young and trained athletes, normally absent after middle age, sounds like “Kentu..cky” - termed the ventricular gallop. Re-emergence in later life indicates abnormality (e.g. heart failure).
4th Heart Sound – Caused by turbulent blood flow, due to stiffening of walls of left ventricle, occurs prior to 1st heart sound, atrial gallop.
In Tachycardia, 3 + 4 indistinguishable = Summation Gallop
What happens to stroke volume in the cardiac cycle?
The chambers do not empty completely.
Stroke volume = volume of blood pumped by each ventricle per beat (≏ 75ml) - may double during exercise.
Ejection fraction = % volume pumped out. Ejection fraction = 55-60% (exercise 80%). In heart failure may be 20%.
Systemic arterial pressure remains high throughout cycle due to elasticity of the vessel walls and peripheral resistance.
What is the elastic function of the arterial tree?
Stores pressure energy - helps maintain pressure in arterial system during diastole (pressure drops only about one third from systolic B.P.).
What is cardiac output?
How does it change during exercise?
Cardiac output is the volume blood pumped per minute (by each ventricle).
Cardiac output (~5000ml/min) = Heart rate (~70/min) x Stroke volume (~75ml)
At rest C.O. = 5 l/min
In exercise > 25 l/min as heart rate increases 2-3 fold and stroke volume increases 2 fold.
What is the effect of heart rate on cardiac output?
Normally ↑H.R. is associated with ↑C.O.
But not always: if ↓ filling time then ↓stroke volume.
Venous return determines cardiac output.
During exercise CO increases as HR increases until around 150 beats/min, where CO peaks and CO begins to drop slightly.
What is stroke volume dependent on?
- Contractility (the force of contraction). e.g. adrenaline ↑force, ↑stroke volume.
- End diastolic volume (volume of blood in ventricle at the end of diastole).
Force is stronger the more muscle fibres are stretched (within limits):
Frank - Starling Mechanism or Starling’s Law of the Heart:
Stroke volume (=) Diastolic Filling
What is the Frank-Starling mechanism?
Also known as the Preload.
Important in ensuring the heart can deal with wide variations in venous return and balancing the outputs of the two sides of the heart.
As end diastolic volume increases, SV or CO increases, until a point then begins to decrease slightly.
What is peripheral resistance?
(Afterload)
Resistance to blood flow away from the heart - altered by dilation or constriction of blood vessels (mainly pre-capillary resistance arteries).
Cardiac Output = Blood pressure/Peripheral Resistance
Sum of afterload (back pressure) and end diastolic volume determine force.
Normally small changes of peripheral resistance have little effect on cardiac output.
What are normal cardiac pressures?
(Average level [mm Hg], upper limit of normal [mm Hg])
Right atrium (mean): 3, 6
Right ventricle (sys/diast): 18/4, 30/5
Pulmonary artery (sys/diast): 18/12, 30/15
Left atrium (mean): 8, 12
Left ventricle (sys/diast): 120/8, 140/12
Systemic arterial (sys/diast): 120/70, 140/90
What is the cardiac excitation pathway?
Sinus rhythm = heart rate controlled by S.A. node, rest rate approx. 72 beats/min (wide variation).
Begins at the sinoatrial node.
Action potential then activates atria.
Atrial A.P. activates atria-ventricular node (A.V. node - small cells, slow conduction velocity - introduces delay of 0.1 sec).
A.V. node activates Bundle of His/Purkinje fibres.
Purkinje fibres activate ventricles.
How are cardiac action potentials generated?
Cardiac muscle is ‘myogenic’ – it generates its own action potentials.
Action potentials develop spontaneously at the sino-atrial node.
Action potentials conducted from cell to cell via intercalated
discs which have gap (or nexus) junctions.
What is the sinoatrial node?
The pacemaker of the heart.
Pacemaker potential due to:↑gCa,↑gNa,↓gK
Action potential upstroke due to: ↑gCa
Repolarisation due to: ↑ gK, ↓ gCa
Noradrenaline - ↑gNa ↑gCa
Acetyl choline - ↑ gK, ↓ gCa
(g = conductance)
What are the differences between cardiac and skeletal muscle?
Skeletal muscle is ‘neurogenic’. It needs a nervous impulse to initiate a contraction. Cardiac muscle is ‘myogenic’. The muscle generates action potentials spontaneously.
Cardiac action potential is much longer than in skeletal muscle (500 msec vs 50msec). Plateau rather than spike.
Action potential controls duration of contraction in heart. Acts only as a trigger in skeletal muscle.
Ion currents during action potential in skeletal are ‘simple’, cardiac complex. In skeletal depolarisation due to influx of Na+ then repolarisation during to efflux of K+. In cardiac depolarisation due to large increase in Na+, plateau due to increase in Ca2+, but decrease in K+, then repolarisation due to decrease in Ca2+ and K+.
Source of Ca for contraction: in skeletal [Ca] at rest = 10^-7 M, contraction = 10^-5 M; whereas in cardiac [Ca] at rest = 10^-7 M, contraction = 10^-6 to 10^-5M.
What are the ion currents responsible for cardiac action potential?
g=conductance
Depolarisation - large gNa
Plateau - small gNa, increase gCa, decrease gK
Repolarisation - decrease gCa, increase gK
What is the structure of the cardiac sarcomere?
A sarcomere is a contractile unit in muscle. Sarcolemma surrounds it
Myofibrils are surrounded by sarcoplasmic reticulum (network of membranes) which has terminal region lying next to T-tubules or sarcolemma. The t-tubules come from invaginations of the sarcolemma and are positioned at the Z line in cardiac muscle (at the ends of I bands in skeletal muscle).
There are many mitochondria.
How is Ca sourced for contraction in cardiac cells?
At rest [Ca] = 10^-7M, for contraction, [Ca] between 10^-6 and 10^-5 M in cardiac muscle. (In skeletal, at rest [Ca] = 10^-7M, for contraction, [Ca] = 10^-5 M).
Ca is released from the sarcoplasmic reticulum but for heart cells Ca entry from outside is needed (‘Ca induced Ca release’).
How does Skeletal Excitation-Contraction Coupling work?
Action potential travels along sarcolemma and down t-tubules.
Plasma membrane potential changes are detected by dihydropyridine (DHPR) receptors, which interact allosterically with sarcoplasmic reticulum (SR) ryanodine receptors subtype 1 (RyR1).
Ca2+ is released from the SR, so increased Ca2+ in the myoplasm (intracellular).
Myoplasmic Ca2+ buffering system and the contractile apparatus are activated by 4 Ca2+ binding to troponin (inhibits it so myosin binding sites are revealed), leading to muscle contraction.
Ca2+ is removed from the myoplasm, mainly by reuptake by SR through SR Ca2+ ATPase (SERCA), so muscles relax.
How does Cardiac Excitation-Contraction Coupling work?
Calcium-induced calcium release involving the voltage-gated calcium channels and ryanodine receptor subtype 2 (RyR2). Similar to skeletal striated muscle but Ca2+ influx is slow (through L-type voltage gated Ca channel in sarcolemma), creating a substantially longer action potential (5msec skeletal vs 150-300msec cardiac).
Action potential travels along sarcolemma and down t-tubules.
Plasma membrane potential changes are detected by dihydropyridine (DHPR) receptors, which interact allosterically with sarcoplasmic reticulum (SR) ryanodine receptors subtype 2 (RyR2). It also causes the L-type voltage-gated calcium channels to open.
Ca2+ is released from the SR (intracellular) and inflows through now open ion channels (extracellular), so increased Ca2+ in the myoplasm (intracellular).
Contractile apparatus are activated by 4 Ca2+ binding to troponin (inhibits it so myosin binding sites are revealed), leading to muscle contraction.
Ca2+ is removed from the myoplasm by reuptake by SR through SR Ca2+ ATPase (SERCA), and exits the cell via an ATP driven Ca pump (weak) and a Na-Ca exchange protein (energy driven from Na entry gradient), so muscles relax.
What is the first major system to function in the embryo?
Cardiovascular system.
Embryo is rapidly growing and needs to form a system to help with nutritional and oxygen demands. This accompanies a reduction in nutritional support provided by the yolk sac.
What are key dates for cardiovascular development?
3rd week of gestation - Primordial heart & vascular system begin to develop.
Day 21-23 – ‘heart’ starts to beat.
4th week of gestation – blood flow begins in the embryo.
What happens during cardiac lineage establishment?
Before week 3 gestation.
The blastocyst forms and gastrulation occurs (single layered blastocyst turns into a multi-layered structure).
The trilaminar disc formed by gastrulation contains an ectoderm (becomes epidermis, CNS/PNS, eyes/ears), endoderm (becomes epithelial linings of digestive/respiratory tracts), and the mesoderm (becomes skeletal muscles, blood cells, most of CV system).
From the mesoderm the heart fields form. From cardiac progenitors that appear in the primitive streak, cardiac precursors are in the mesoderm which form a crescent-shaped heart field.
How is the primary heart tube formed?
At the beginning of the 4th week gestation.
Lateral folding of the embryo in the midline (from cranial to caudal) brings the heart fields together. So the 2 endocardial tubes go from being on opposite sides of the crescent-shaped heart field, to coming together and fusing.
At this point, there is an arterial end of the heart, fused heart tubes, infused heart tubes and the venous end of the heart. Within it there is:
Myocardium: walls of the heart – formed from mesoderm containing myocardial progenitor cells.
Cardiac jelly: separates the myocardium from the cardiac tube.
Endocardium - inner lining of the heart.
Heart beat begins ~ day 21, beating and blood flow important for structural remodelling occurring.
What happens during cardiac looping?
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.
When and how des blood flow into the heart tube?
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.
When and how does cardiac septation occur?
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.
What are some fetal cardiac structures and their corresponding adult structures?
Foramen ovale - Fossa ovalis
Ductus arteriosus - Ligamentum arteriosum
Ductus venosus - Ligamentum venosum
Umbilical vein - Ligamentum teres (hepatis)
What are some congenital heart defects?
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.
What is mean arterial BP (MAP)?
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
What is pulse pressure?
The difference between diastolic and systolic BP
PP=SBP-DBP
What is hypertension?
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.
How is hypertension measured?
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)
Why is hypertension important?
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.
Who would you treat with hypertension?
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.)
What are the grades of hypertension?
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
What are the initial investigations for someone with raised BP/hypertension?
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.
What are common anti-hypertensive drugs?
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.
What is the mechanism of action of common antihypertensive drugs?
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.
What are side effects of common antihypertensive drugs?
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].
What are situations where specific antihypertensives are indicated?
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)
What are situations where specific antihypertensives are cautioned?
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
What causes hypertension?
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).
What are endocrine causes of (secondary) hypertension?
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.
What are medicinal causes of (secondary) hypertension?
Oestrogen oral contraceptives,
Non-steroidal anti-inflammatory drugs (NSAIDs),
Liquorice/carbenoxolone/steroids,
Sympathomimetics (including cocaine),
Alcohol,
Erythropoetin,
Cyclosporin A.
What are renal/vascular causes of (secondary) hypertension?
Renal artery stenosis (atheroma/fibromuscular),
Glomerulonephritis/pyelonephritis/vasculitis,
Obstructive uropathy,
Polycystic kidney disease.
Coarctation of the aorta.
What are lipids and why are they important?
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.
What are lipoproteins?
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)
Describe lipoproteins metabolism.
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
What is the exogenous lipid pathway (of lipoprotein metabolism)?
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.
What is the endogenous lipid pathway (of lipoprotein metabolism)?
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.
What is reverse cholesterol transport (via HDL)?
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
How is CVD driven by lipids?
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.
What is the mechanism of atherosclerosis?
- 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. - 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. - 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).
What are inherited disorders of lipoprotein metabolism?
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.
What is the relationship between lipoproteins and cholesterol measurement?
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)
What is the acute treatment of an MI?
Re-perfusion via primary PCl,
Drug-eluting stents (anti-proliferative agent to prevent re-occlusion).
Reduced morbid and mortality but prevention saves more lives.
What is prevention of CVD.
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
What are some lipid lowering drugs?
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).
What are the sites of haematopoiesis?
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.
Describe what can be made in adult haematopoiesis.
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.
How is a neutrophil formed?
Haemocytoblast ➔ Common erythroid/granulocytic precursor ➔ Myeloblast ➔ Promyelocyte ➔ Myelocyte ➔ Metamyelocyte ➔ Band cell ➔ Neutrophil
How is a mature erythrocyte formed?
Haemocytoblast ➔ Common erythroid/granulocytic precursor ➔ Proerythroblast ➔ Early erythroblast ➔ Intermediate erythroblast ➔ Late erythroblast ➔ Polychromatic erythrocyte ➔ Mature erythrocyte
What is in bone marrow?
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.
How is adult haematopoiesis controlled?
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.
What is the adult blood cell repertoire?
Red cells,
Platelets,
White cells - Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils
What is normal peripheral blood ‘Full blood count’?
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
What can go wrong with haematopoiesis?
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
What is anaemia?
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…
What is iron deficiency anaemia and its causes?
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)
What is megaloblasic anaemia?
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).
What is haemolytic anaemia?
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).
What is Polycythaemia/Erythrocytosis?
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.
What are some issues with white blood cells?
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.
What is leucopaenia?
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.
What are some issues with platelets?
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.
What is haematopoiesis?
How blood cells are made.
What is haemostasis?
How bloods clot.
What is needed for the normal mechanism for coagulation?
Need platelets (normal number, normal function), functional coagulation cascade and normal vascular endothelium.
What is the structure of platelets?
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.
How is the haemostatic plug generated?
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.
What can go wrong with Platelet/Vessel Wall Interactions?
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.
What enzyme complexes are involved in the coagulation cascade?
Extrinsic tenase and intrinsic tenase.
Prothrombinase.
What are natural inhibitors of the coagulation cascade?
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.
How is haemostasis measured in the lab?
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.
What are some hereditary coagulation factor deficiencies?
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.
