CDL3 Flashcards
L side of the heart makes up the ….circulation, R side the..?
Left- systemic (thicker)
Right-pulmonary
Systemic circulation pressure in aorta?
120mmHg (systemic systolic BP) high pressure- to whole body
Pulmonary ciculation pressure in pulmonary artery?
15-30mmHg- lower blood pressure- only to lungs and needs to slow for gaseous exchange and not damage lungs. (check?)
Pulmonary hypertension threshold? Measure?
mPAP greater than 25mmHg. (mean Pulmonary arteriole pressure).
Cathater into to measure.
Pulmonary arterial hypertension also requires:
PAWP / LVEDP ≤ 15 mm Hg
and PVR > 3 Woods Units
(> 240 dyn.sec.cm-5)
Causes of increased mPAP in PH? (4)
- Shunting of systemic blood pressure- if hole in heart higher pressure systemic blood shunted from L-R (increase pressure)
- Thrombus formation ‘pulmonary embolism- lodged blocking pulmonary artery (increases pressure)
- Sustained pulmonary vasconstriction- in lungs, vessels- narrows blood flow, icreasesresistance (afterload) , heart has to work harder, BP increased.
- Pulmonary vascular remodelling- prolonged vasoconstriction can cause vascular remodelling from healthy to proliferative.
Consequences of pulmonary hypertension?
- Right ventricular hypertrophy due to increased of work heart
- Right heart failure- needs more O2 etc,
- Death within 2.8 years average if untreated, arount 7 years with treatment.
Classic case study for a patient with PH?
24year old female. Progressive exertional breathlessness and chest pains. Syncopal episodes after exercise.
After classic case study symptoms seen what tests are done?
ECG- any R heart strain? T wave inversion?
Echocardiogram- High pulomary systemic Pressure?
Chest Xray- R hypertrophy?
Lung function tests- Normal lung volumes?(else could be due to lungs)
R heart catheterisation. Through jugular vein- move down atria into ventricles and into pulmonary artery- measuring pressures.
PVR in PH patients?
Pulmonary vascular resistance
Normal aorund 100dyness but PH can rise to 400-800dyness.
Mean pulmonary arteriole pressure=
Mean pressure 2/3 diastolc +1/3 systolic pressure
Pulmonary Vascular Resistance=
mPAP-PAWP/Cardiac Output
mPAP- mean pulmonary arterial pressure
PAWP- pulmonary wedge pressure (esimate small arteriole pressure- so mPAP-PAWP indicates pressure difference)
How can you measure PAWP?
Pulmonary arterial wedge pressure. Insert a pulmonary cathater with an inflated balloon into pulmonary artery and blood flow pushes it into a small pulmonary arteriole branch to estimate the pressure. Estimation of L atrial/ventricular pressure (preload)
For Pulmonary arterial hypertension thresholds?
mPAP greater than 25mmHg. (mean Pulmonary arteriole pressure).
Pulmonary arterial hypertension also requires:
PAWP / LVEDP ≤ 15 mm Hg (if this is raised likely due to other factors e.g. the L side having to work harder and pushing on the R side.
and PVR > 3 Woods Units
(> 240 dyn.sec.cm-5)
Cost of PH treatment?
£30-100,000 per person per year
PH Threshold debate?
Above 20mmHg mPAP as will go on to develop PH? More research needed
Subgroups of PH? (5- treatable?)
- Pulmonary arterial hypertension- treatment available.
2 PH due to Pulmonary embolism- yes- remove surgery - PH due to lung disease COPD- no treatment
- Multifactorial/unclear- no
- L heart dysfunction - no
Surgery treatment for which type of PH?
Chronic thromboemolic PH- thrombus blocking vessel Can remove unless multiple distal.
Can drain the blood, open the vessel and remove the thrombus.
What is pulmonary arterial hypertension?
The version we learnt about. Remodelling of vessels and vasoconstriction causes the lumen size to reduce, and so the pulmonary vascular resistance to increase.
Pulmonary arterial hypertension causes?
Idiopathic (40%)
Heritated (10%) e.g BMPR2 mutation
x4 times more common in females than males (often 20’s)
40% have PAH mainly due to Connective tissue disease and Chronic heart disease.
1980’s diet pills- 25-50% of incidences due to.
Pathogenesis of PAH (large scale) in lungs?
Progressive. Gradually more and more vessels in the lungs become stiff and blocked, use of collateral vessels initially until these become blocked and gradually more and more blocked off vessels, resistance increases and therefore pressure.
Patients can lose 2/3 of pulmonary tree before symptoms.
6 steps of PAH formation?
- Regulated EC lay on an elastic lamina with VSMC’s below.
- Sustained pulmonary constriction due to external factors causes ruffling of ECs ( uncontrolled proliferation and pro-apoptotic), and this damage allows serum leak.
- Serum can leak across the elastic lamina. e.g. SM mitogens from ECM storage sites, GF’s and inflammatory mediators such as ET-1, proteases, elastinases, NO dysfunction, thromboxane A2 etc. CONSTRICTION.
- The elastin breaks down by elastin peptides released by VSMCs in response to serum. LEAKY. Stiff. These peptides stimulate the production of fibronectin which alters SMCs shape from contractile to motile.
- Smooth muscle proliferation (concentric hypertrophy) and then migration (plexiform lesions- remodelled)- lumen v small.
- Occluded small vessels, collaterals used but progressive disease so more and more blocked.
Difference between the two lesion stages of PAH?
Concentric lesions: Highly proliferative EC and VSMCs and gaps in epithelial cells with inflammatory cells in, but all within their layers still. Apoptose and proliferate
Plexiform lesion: VSMCs migrated up into EC layer chaotic, EC apoptotic resistant.
Cost to sequence genome now vs 15 years ago?
$100M to $1000-
Genetic part of PAH? (2)
15 genes have been detected to be involved.
e. g. BMPR2 mutations can cause PAH, which is a TGFB receptor. Binding causes the phosphorylation of smad 8 which activated SMAD 4 and activates TF’s chnaging gene expression.
- 80% of HPAH and 20% IPAH due to.
Or BMP9 another ligand to BMPR2- increases receptor count protects endothelium from apoptosis retaining the impermeability. Decreases R ventricular systolic pressure.
Primary type of drugs for PAH? Examples (6)
Vasodilators.
e.g. Ca channel blockers, nitric oxide donors, Endothelin R antagonists, PDE5 inhibitors,Prostacyclin derivatives
CCBs for PAH?
calcium channel blockers are only effective in patients with acute response to vasodilators (can test in clinic add NO, catheter in heart Right, see if mPAP reduces by 10mmHg- around 10%).
If do respond- good can survive 20+ years on.
Negative impacts of CCBs?
sytemic hypotension, bradycardia, periphery oedema.
3 main pathways targetted by drugs for PAH?
- Endothelin to ETA/B-PLC Gq- IP3- increases Ca- CONSTRICTION (inhibit)
- NO- Soluble GC- cGMP- reduces Ca and activates PKG DILATION (promote)
- Prostaglandin 2- IP- AC- CAMP- reduce Ca and PKA- DILATION (promote)
PDE5 inhibitors for PAH?
E.g. Sildenafil
CAMP and cGMP is broken down by PDE5, so if inhibit this prolong the impacts of cAMP and cGMP which reduce Ca and activate PKG (gmp) and PKA (camp) which causes vasodilation.
First line action with ETA/B antagonists also.
Avoid with nitrates drops systemic pressure too low.
PDE5 inhibitors side effects?
flushing, headaches, colour vision change, nose bleeds, persistant erection, neuropathy.
Endothelin receptor antagonists for PAH?
E.g. Bosentan, Maciltentan, Ambrientan. (oral)
Blocks ET A/B which causes VSMC contraction and proliferation and extravascularisaion and inflammation of EC.
Added to PDE5 inhibitor early.
Endothelin receptor antagonists side effects?
Abnormal liver function, headache, nasopharyngitis, periphery oedema, anaemia.
Macitentan? Trial?
Enothelin R antagonist for PAH:
Has slower R dissociation rate, and greater lipid solubility and therefore increased tissue penetration.
SERAPHIN Trial: delayed clinical worsening measured by walking distance before breathlessness.
But continuous ET-1 stimulation overcomes the receptor blocking.
Nitric oxide donors for PAH? Side effects?
Riociguat- if have low NO, this stimulates GC bypassing NO need. Lincenced but not for use with PDE5 inhibitors- vasodilate too much.
Diarrhoaea, indigestion, loss of vapillaries in the gut
Prostacyclin derivatives for PAH? Examples.
Epoprostenol (Flolan): i.v.
Iloprost (Ventavis): inhaled
Treprostinil (Remodulin): s.c. or i.v.
Beraprost (Japan & Korea only): oral
Prostacyclin derivatives for PAH pharmacology?
Use in advanced stages.
COX converts arachidonic acid into prostaglandin H2 (which is converted into many active prostaglandins. These cause dilation through Ip-AC- CAMP-PKA.
These cause dilation of pulmonary and systemic arteriole vessels. This decreases PAP and PVR, reducing afterload.
Also inhibits pulmonary SMCs proliferation in vitro. (no evidence of in vivo)
Struggle with prostacyclin derivatives timing?
Producing a stable analogue has been difficult as body broken down quickly- half life 2minutes.
iloprost- 20-30mins
Beraprost- 40-60mins
treprostinil 180-270mins. (oral or IV)
So needs continual use- can have a pump deliver but risk of infection, thrombosis, keeping cool and need to make up daily. (£100k patient each year).
or inhaled form 6-9 times a day (30mins a time) compliance problems and therapy stopped overnight.
Struggle with prostacyclin derivatives specificity?
Bind to other receptors also, giving off target effects e.g. diarrhoea, flushing, headache. Tolerance also.
Prostacyclin derivatives PAH option for overcoming short half life? (1-T)
Treprostinil 180-270mins half life.
Subcutaneous patch.
Redness of skin, site pain, irritation- pill under skin, increase in fibrosis of skin here- decrease in elasticity.
Problems with prostacyclin therapy? (6)
Development of tolerance Side effects (diarrhoea, flushing, headache) Cost (close to £100K per yr per patient) Need for continuous delivery system Line related complications (infection, thrombosis, pump failure) Has to be made up daily & kept cold
Prostacyclin derivatives PAH option for overcoming short half life being researched? (2-S)
Selexipag- novel oral non prostanoid IPR agonist in phase III trials. Half life is 8hours.
Problem: there are multiple PG receptors, this only blocks one, which is both good and bad- there are some beneficial impacts of the other receptors (in lung EP2) but some of these also cause constriction ( EP1 gut and EP3 in lungs inhibit AC- may downregulate IP receptors maybe).
PH other treatments? (5)
- Anticoagulants to increase the clotting risks especially for patients on IV or who have chronic thromboembolic pulmonary hypertension.
- Oxygen- when have COPD.
- Duiretics- reduce oedema due to R heart failure.
- sex hormone inhibitors
- Elastase inhibitors
PH sex hormones?
Research into why x4 more likely in females.
Aromatase involved in production of oestrogen. If block this, positive impact on PAH seen. Oestrogen and BMP cross talk- link with this?
Genetic therapy for PAH?
FK506- if transfect a reporter line to express- induced BMPR2 signalling, increases P SMAD.
reduced RVSP and lung pressures in mice.
Elastase inhibitors for PAH?
Elafin is reduced in PAH which is a type of elastin. Elastases actively cleave Elastin- toxic to the cells causing inflammation, apoptosis and compensatory proliferation. Inhibtors to increase elastase- phase 1 clinical trials for, but off target effects.
3 layers of an arterial blood vessel?
Tunica externa/ Adventia: connective tissue and Vaso verosum.
Media: SMC and external elastic.
Intima: Endothelium+internal elastic lamina. 1 cell thick can be thickened.
Is inflammation of the arterial blood vessels good or bad?
Either.
Good inflammation is response to pathogens, parasites, tumour wound healing (scar formation).
Bad: Atherosclerosis, Restenosis, Rheumatoid arthritis etc
What is restenosis?
Can happen after treatment (intervention) for atherosclerosis.
Risks with atherosclerosis?
Principal cause of health attack, stroke, and gangrene of exteemities. Risk of rupturing- thrombus formation and occluding a blood vessel causng death.
What is atherosclerosis?
Hardening stiffening of arteries by plaque formation, due to lipid build up in the walls after initial dysfunction of endothelium causing inflammation.
A nectrotic core, with a fibrous plaque (SMCs and EXC M)
Main risk factors for atherosclerosis?
modifiable/lifestyle: diet, smoke, alcohol, obesity, stress, physical inactivity, hypertension, diabtes, dyslipidaemia
Medical/ NOn modifiable: inflammation, age, gender (male), genetics,family history of CVD.
Other: turbulent blood flow bifications haemodynamics.
What can cause high cholesterol levels?
Mainly bad diet etc, but can have familial hypercholesteraemia, which is inherited and can occur at birth.
Atherosclerosis age?
Can come on in childhood with people with FH, else mainly an aging disease, builds up with age. Mostly asymptomatic until late stages.
Atherosclerosis where and haemodynamics?
MOST COMMON PERIPHERY/CORONARY ARTERIES- bifications.
Constant high stress blood on the endothelium will activate eNOS and increase Nitric Oxide release in endothelial cells. This will act upon SMCs and vasodilate, and activate atheroprotective factors. Whereas turbulent flow activated atherogenic impacts e.g. upregulating adhesion molecules on EC, ROS, Cytokine upregulation- chemokine gradient promotes WBC migration, promotion of LDL infiltration.
Virchow suggested?
Suggested that atherosclerosis was initiated by injury to endothelial cells- endothelial dysfunction and inflammation. Russell Ross built upon this idea also. Whereas Leonardo Da Vinci saw it as only a lipid storage disease where the plaque ‘absorbing increased nourishment from the blood’
How do Activated endothelial cells leak WBCs?
Activated endothelial cells upregulate V-CAM1 and I-CAM1 adhesion molecules. Monocytes/ WBCs bind and roll along the endothelial wall untilt the have firm adhesion. The inflammatory mediators create a chemoattractive gradient (cytokines, GFs)to promote internalisation of monocytes (transmigration). (under inflammation e.g. IL-1 differentiates into macrophages).
ATHEROSCLEROSIS here.
Cholesterol is carried around in the blood in what?
liposomes carry cholesterol around in the bloodstream as it is hydrophobic in nature.
LDL migration into the vessel wall?
Accumulation of LDL-C causes the migration into the vessel wall. EC’s and macrophages generate ROS. By ROS these are oxidated Ox-LDL.
This is engulfed by macrophages to form foam cells. Foam cells are lipid filled cells which release more inflammatory cytokines, attracting more macrophages etc.
atherosclerosis cytokine examples?
IL-1, 6, 8 IFN-Y, TGFB.
Atherosclerosis fibrous plaque?
SMCs proliferate and make up the fibrous plaque. This can pertrude and occlude the blood vessel. This is weakened by SMCs and foam cells which degrade the collagen and make the plaque more susceptable to rupture.
After plaque rupture what can happen?
In the event of rupture, coagulants are released and this increases the likelihood of thrombus formation here. This can detatch and occlude a blood vessel- MI or stroke/ death
What are the stages of atherosclerosis?
Edothelial dysfunction-progressive fatty streak-intermediate lesion- fibrous plaque/advanced lesion-plaque rupture
What is a fatty streak?
Earliest lesion in atherosclerosis, appear at very early stages less than 10years. Accumulation of lipid laden macrophages (foam cells) and T lymphocytes within the intimal layer of the vessel.
What is an intimediate lesion?
In intima layers of foam cells, vascular smooth muscle cells, pools of extracellular lipid/cholesterol (foam cells apoptose and release cholesterol crystals).
T-lymphocytes. Adhesion and aggregation of platelets to the vessel.
Still small asymptomatic lesion- most atherosclerosis stops here.
Why does most atherosclerosis stop at an intimediate lesion?
Protective mechanism.
Reverse cholesterol transport. HDLs contain apo-A1 particles to interact with foam cells to sequest cholesterol from them. Mature HDL then travels back to the liver to release the cholesterol (processed fro excretion). HDL particle then recirculate back to the heart and repeat the process.
ATHEROPROTECTIVE.
What are fibrous plaques/advanced lesions?
Thought to need another risk factor e.g. area of distubed flow etc to overcome the protective HDL mechanism.
Cytokine release by cells cause SMC proliferation and depositio of connective tissue. This leads to dense fibrous cap overlying a lipid-rich core (collagen=strength) (elastin=flexibility).
Lipid core beneath contains necrotic and apoptotic debris, SMCs, foam cells, T lymphocytes, macrophages.
This impedes blood flow as the plaque pushes out into the vessel lumen.