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BMS 3052 > Vascular Diseases > Flashcards

Vascular Diseases Flashcards

1
Q

How does lipoprotein transport occur?

What are the 4 main types of lipoproteins?

A
  • Lipoproteins are complexes of lipid (hydrophobic core) and apoprotein (hydrophilic coat)
  • Lipids do not dissolve easily in aqueous solutions like blood and therefore must be packaged (by apoproteins)
  • Lipoproteins allow the transport of triglycerides and cholesterol through blood
  • There are 4 main types of lipoproteins (in decreasing size)
    1. Chylomicrons (triglycerides)
    2. Very low density lipoproteins- VLDL (triglycerides)
    3. LDL (cholesterol)
  • can penetrate vascular endothelium
  • form Lp(a) which contains Apo B-100 is similar to and competes with plasminogen
    4. HDL (cholesterol)
  • can penetrate vascular endotheilum
  • contain Apo-1-1 (protective)
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2
Q

Describe lipoprotein transport in the blood:

A
  1. Exogenous pathway:
    - cholesterol/triglycerides derived from GIT
    - move into intestinal lymph
    - are transported as chylomicrons in the plasma
    - are hydrolysed and then used by the muscle for energy or stored in adipose tissue
  2. Endogenous pathway:
    - cholesterol/triglycerides synthesised in the liver
    - transported as VLDL into muscle/adipose tissue
    - hydrolysed
    - lipoprotein particles become LDL (which can morph into HDL)
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3
Q

How do HDLs and LDLs interact with the vascular smooth muscle cells?

A

LDLs:

  • LDL receptors on hepatocytes and VSMCs allow for the receptor mediated endocytosis of LDL via apo-b-100
  • Therefore LDL is strongly correlated with atherosclerosis and CHD: LDL forms plaques and Lp(a) reduces plasminogen activity and favours thrombosis

HDLs:

  • HDLs cause reverse cholesterol transport
  • HDL does not have apo-b-100 so is not incorporated into cells, instead it removes excess cholesterol from cells and incorporates it via the ApoA-1
  • HDL acts as a resevoir to revere and remove cholesterol out of target tissues
  • HDL has a cardioprotective effect and is associated with reduced atherosclerosis and CVD
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4
Q

Describe the mechanism of atherosclerotic plaque formation:

A
  1. Vascular Inflammation:
    - Leukocytes are captured, adhere and migrate into the subendothelial space
    - The infiltration of the leukocytes and the subsequent inflammation triggers the atherosclerotic process
  2. Vascular cholesterol uptake by LDL receptors:
    - Excess LDL infiltrates the artery
    - Oxidised LDL induces adhesion molecule expression on endothelium
    - Oxidised LDL is phagocytosed by vascular macrophages (now called foam cells)
  3. Monocyte recruitment into arterial wall:
    - Adhesion molecules facilitate the entry of monocytes into the vascular tissue
    - The monocytes differentiate into macrophages
    - The macrophages release pro-inflammatory mediators and create a local inflammatory milieu which contributes to CVD
  4. Immune cell surveillance:
    - T cells infiltrate
    - The activated T-cells produce Th1 cytokines (IFNy, IL-1, IL-6, TNF)
    - Results in an amplification of vascular inflammation
  5. There is then the formation of a fibrous cap on the plaque creating a fibrous plaque
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5
Q

What is CRP?

A
  • C-reactive protein (CRP) is an acute phase protein synthesised in the liver
  • It is stimulated by IL-6 from inflammatory cells and binds to the surface of dying cells and promotes phagocytosis
  • It is predictive of inflammation/CVD and informs on statin therapy
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6
Q

Why is outward (non-stenotic) remodeling more likely to be associated with unexpected cardiac failure?

A
  • Non-sentonic lesions are typically more ‘mild’ angiographically as they occlude the arteries to a lesser extent
  • These lesions however have a much thinner fibrous cap is much more prone to rupture which can cause abrupt cardiac failure as plaque rupture will often precede a thromobsis as the plaque contents adhere to the endothelial surface and coagulate cells leading to thrombus formation
  • When there is a break in the endothelial layer e.g. a plaque rupture, platelets readily attach and release mediators leading to further platelet aggregation and coagulation
  • These factors cause the formation of an insoluble fibrin clot
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7
Q

What makes a plaque vulnerable to rupture?

A
  • Decreased collagen synthesis (T cell driven)
  • Increased degradation of the fibrous cap due to MMPs released from macrophages
  • Increased tissue factor released from macrophages
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8
Q

How are acute life-threatening cardiovascular events treated?

A
  1. Revascularisation:
    - Pericutaneous coronary intervention (PCI)/angioplasty
    - Usually with stents
    - A coronary artery bypas graft is also commonly used to bypass the occluded vessel
  2. Drugs:
    - t-PA (narrow window of effect- 12 hours for a MI and 4 hours for a stroke)
    - activates plasminogen into plasmin which dissolves the clot
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9
Q

How are chronic issues with artherosclerosis treated?

A
  1. Lipid-lowering drugs
    - statins
  2. Anti-platelet drugs
  3. Anti-coagulant drugs
  4. Other drugs to reduce CHD burden
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10
Q

What is hyperlipidaemia?

A

Primary:

  • A combination of high cholesterol (hypercholesterolaemia) and/or high triglycerides (hypertriglyceridaemia)
  • Caused by genetics e.g. FH (defective LDL receptor) or dietary excess

Secondary (to another disease):
e.g. diabetes, alcoholism, obstructive liver disease, drugs

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11
Q

How do statins work?

A
  • Statins are HMG-CoA reductase inhibitors
  • Therefore these drugs stop the endogenous formation of cholesterol in hepatocytes
  • This promotes increased expression of LDL receptors (by feedback regulation) which then increases LDL plasma clearance
  • Therefore they help lower LDL and TG, and increase HDL
  • Statins are extremely effective and used as a primary prevention against CVD and secondary prevention of MI and stroke
  • Has only mild side effects (GI disturbance, insomnia, rash)
  • Reduced CRP levels indicate effective therapy
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12
Q

How do PCSK9 inhibitors work?

A
  • PCSK9 is a circulating serine protease that binds to LDL receptors and facilitates their lysosomal degradation and thus reduces LDL receptor recycling to the surface of cells
  • Inhibiting this enzyme (as a novel therapy) has the potential to prevent PCSK9 from binding LDL receptors and promoting the expression of LDL receptors on the surface of hepatocytes
  • This will help increase plasma clearance of LDL and this LDL can then be converted into HDL by the hepatocyte
  • The current inhibitors are antibodies (biologics) meaning they are not orally active but instead must be administered via intramuscular injections
  • Could be used in patients that do not respond well to statins
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13
Q

What are acute vs. chronic presentations of coronary heart disease?

A

Acute presentation:

  • Acute coronary syndrome
  • Angina with radiating chet pain
  • Acute MI

Chronic disease:

  • Stable angina
  • Heart failure
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14
Q

Why is the sub-endocardial zone so vulnerable to ischaemia?

A
  • The coronary arteries are external to the myocardium and are embedded in a layer of fat- they then branch into the myocardium
  • The sub-endocardial zone oxygen supply is a balance of coronary supply vs diffusion from LV
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15
Q

Describe the acute coronary syndrome continuum:

A
  • The ACS continuum goes from normal -> angina -> ACS (any condition causing sudden, reduced blood flow to the heart) which falls into 2 categories which both show CK elevations:
    1. no ST-segment elevation MI (NSTEMI) which is less severe
    2. ST-segment elevation MI (STEMI): usually more severe infarcts
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16
Q

What is angina pectoris?

A
  • Severe, crushing chest pain and potentially shortness of breath
  • Due to an imbalance in mycardial O2 demand&raquo_space; O2 supply
  • There are 3 main types:
    1. Chronic, stable angina:
  • caused by ‘demand’ e.g. exercise, stress-test etc.
    2. Unstable angina:
  • unpredictable, thrombi formation, may not resolve in a few minutes, classic ACS
    3. Variant angina:
  • spasm of the coronary artery
  • no artherosclerosis
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17
Q

How is angina pectoris treated?

A
  1. Acute relief by rest and/or nitro-vasodilators
  2. Prevention by nitro-vasodilators, B1 adrenoreceptor antagonist, calcium channel antagonists (stable angina)
  • The main aim is to increase coronary artery perfusion to increase oxygen supply and reduce the metabolic demand of the heart muscle
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18
Q

How do nitro-vasodilators treat angina?

A
  • Nitric oxide is produced in endothelial cells and then enters the VSMC and activates the guanylyl cyclase system creating cGML which offsets the contraction of the smooth muscle causing a relaxing and vasodilatory effect
  • Glyceryl trinatrate (GTN) can be used as a treatment for angina by providing an additional exogenous source of NO
  • The venous dilation reduces venous pressure and pre-load which then causes a decrease in cardiac oxygen consumption
  • The arteriolar dilation reduces peripheral vascular resistance and after-load which then causes a decrease in cardiac oxygen consumption
  • Only acts on smooth muscle (no effect on cardiac or skeletal muscle)
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19
Q

What are the limitations of using nitro-vasodilators?

A
  • Can cause hypotension therefore should not be combined with viagra or other drugs (which inhibit PDE and thus prevents breakdown of cGMP)
  • Hypotension can cause fainting, reflex tachycardia, headaches and flushing
  • After continous exposure to nitrates a tolerance may develop (which must be offset by nitrate-free periods between transdermal patches)
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20
Q

What is an acute mycordial infarction?

A
  • Defined as cardiomyocyte necrosis in a clinical setting consistent with acute myocardial ischaemia
  • For there to be the diagnosis of an acute MI there must be:
    1. Symptoms of ischaemia
    2. New/presumed new changes in ST-T wave or left bundle block on ECG
    3. Development of pathological Q waves on ECG
    4. Imagining evidence of new or presumed new loss of viable myocardium
    5. Intracoronary thrombus detected
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21
Q

What cardiac biomarkers indicate an acute myocardial infarction?

A
  1. Elevated cardiac troponin (cTn)
    - Gold standard
    - Detected 4-10 hours after MI (peak at 12-48)
    - Larger window to detect
    - Cardiac specific
  2. Elevated myoglobin:
    - Released into blood after AMI (1-2 hours)
    - Also detected after skeletal muscle injury
  3. Elevated creatine kinase:
    - Detected in blood after an AMI or skeletal muscle injury
    - CK-MB is considered relatively heart specific
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22
Q

What are the causes of acute myocardial infarction?

A
  • Coronary artery occlusion (atheroma)
  • Aortic valve problems
  • Coronary artery aneurysms
  • Arrhythmia
  • Cocaine/methamphetamines
  • Chemotherapy
  • Hypertension
  • Diabetes
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23
Q

What is the time-course of outcomes after an MI?

A
  • There can be sudden death due to electrical/mechanical pump failure (within hours)
  • Arrythmias (first few days)
  • Pain (within days)
  • Angina (immediate or delayed)
  • Cardiac failure (variable to chronic state)
  • Mitral incompetence (variable)
  • Pericarditis (2-4 days)
  • Cardiac rupture (0-5+ days as tissue is the weakest)
  • Mural thrombosis (1+ weeks)
  • Ventricular aneurysm (4+ weeks)
  • Further infarction (variable)
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24
Q

What is acute vs chronic heart failure?

A

Acute heart failure:

  • Precipitated by an event e.g. trauma or AMI
  • Can progress into chronic heart failure

Chronic heart failure:

  • Persistant cardiac injury that occurs over decases
  • There are 2 main kinds:
    1. Systolic dysfunction (impaired contraction, reduced ejection fraction- now called HF with reduced rejection fraction)
    2. Diastolic dysfunction (contraction okay but filling impaired, now called HF with preserved ejection fraction)
  • People with stable chronic heart failure can have an acute heart failure inducing event
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25
Q

How do different forms of ventricular remodelling affect the type of chronic heart failure that develops?

A

Systolic heart failure:

  • Dilated cardiomyopathy (thin ventricular walls)
  • Reduced cardiac output (ejection fraction)
  • Reduced EF

Diastolic heart failure:

  • Thickening of the ventricles
  • Ventricle relaxation and filling reduced
  • CO preserved with rest but reduced with exercise
  • Normal EF
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26
Q

How does a myocardial infarct evolve and change in structure?

A
  • There is a concept of reparative and reactive fibrosis
  • This means that not only does fibrous tissue replace the necrotic region, there is also fibrous spillover into non-infarcted tissue (due to local inflammation and oxidative stress)
  • This fibrous spilloever impairs contraction of the heart
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27
Q

What is congestive heart failure?

A
  • Congestive heart failure is a reduction in the cardiac output to a point where it is unable to meet the metabolic demands of the body
  • It is the result of progressive ventricular dysfunction
  • There are many different causes including: coronary heart disease, atheroscleoris, AMI, ischaemia, angina, hypertension etc.
  • It causes a wide range of symptoms and levels of impairment (how much activity is limited by dyspnea)
  • It is treated with lifestyle changes such as weight loss, reduction in sodium and exercise and well as drugs to decrease cardiac workload such as angiotensin inhibition, B-blockers and diuretics
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28
Q

What are the most common drugs used to treat heart failure and hypertension?

A

A: angiotensin converting enzyme (ACE) inhibitors and angiotensin atagonists

B: beta blockers

C: calcium channel blockers (not for heart failure, only hypertension)

D: diuretics (thiazides, loop, K+ sparing)

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29
Q

What is angiotensin II?

A
  • Angiotensin II is a hormone that is part of the RAAS system that is important in the long-term control of BP
  • It has peripheral effects such as vasoconstriction, aldoesterone release (increased Na+ absorption), increased noradrenaline release and upregulation of fibrosis, hypertrophy and oxidative stress
  • Its central effects include upregulated BP, increased vasopressin release
  • Angiotensin II is upregulated to raise MAP in response to reduced cardiac output, this causes increased vasoconstriction and thus worsens the cardiac state (as the heart must pump harder to overcome the resistance)
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30
Q

What are angiotensin converting enzyme inhibitors and how do they work?

A
  • ACE inhibitors block the conversion of angiotensin I into angiotensin II
  • This helps reduce BP as angiotensin raises BP via a number of mechanisms (vasoconstriction, sodium reaborption, noradrenaline release)
  • ACE inhibitors also inhibit bradykinin breakdown (ACE = kininase II): bradykinin is a local inflammatory mediator that has a marked local vasodilatory effect (but is also an irritant)
  • The overall effects of this are: reduced peripheral resistance (due to vasodilation) and increased sodium and water excretion (reduces BP)
  • The drug is therefore used to treat hypertension, heart failure (and to prevent diabetic vascular complications)
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31
Q

What are the adverse effects of ACE inhibitors?

A

Common:

  • Cough (due to increased bradykinin)
  • Marked hypotension
  • Hyperkalaemia

Infrequent:

  • Rash/itch
  • Angioedema

Contraindication:

  • Less effective in patients of African origin (as they have low renin)
  • Should be avoided in pregnancy and in people with bilateral renal artery stenosis
32
Q

What are angiotensin receptor blockers?

A
  • Angiotensin receptor blockers (ARBs/sartans) inhibit angiotensin-induced vasoconstriction and aldosterone ouput
  • This results in decreases peripheral vascular resistance and increased sodium and water excretion
  • Used to treat hypertension, heart failure and diabetic nephropathy
  • Ideal for patients intolerant to ACE inhibitors
  • Adverse effects include hypotension (although less than ACE inhibitors), hyperkalaemia and should not be used in pregnancy of with bilateral renal artery stenosis
33
Q

What is hypertension?

A
  • Hypertension is higher resting BP than normal
  • BP > 140/90
  • Results in organ damage (heart, brain, retina, kidney, aortic aneurysm)
  • Decreasing BP prevents vessel damage and reduces morbidity and mortality rates
  • It is classified as:
    1. Primary (90%)
  • Aetiology unknown but risk factors include genetics, smoking, stress, environment, diet
    2. Secondary (10%)
  • High BP that is secondary to an abnormality or drug e.g. renal and renal vascular disease, coarctation of aorta (aortic narrowing), primary aldoesteronism, glucocorticoid exces, drugs e.g. cocaine, ketamine, nicotine, NSAIDS etc.
34
Q

What physiologically determines BP?

A
  • Pulse pressure = systolic pressure - diastolic pressure

Mean arterial blood pressure: MAP = cardiac output x TPR (afterload aka total peripheral resistance)

  • Most drugs that lower BP reduce TPR
  • In younger people hypertension is mediated via increased CO, but in elderly people it is mediated by increased TPR
35
Q

How is renin release controlled?

A
  • The rate of renin release is regulated by pressure within the afferent arteriole of the kidney
  • A fall in pressure activates the release of renin (via innervation of juxtaglomerular cells)
  • A decrease in sodium delivery to the macula densa triggers the release of renin
  • Upregulation of renin causes the conversion of angiotensin to angiotensin I
36
Q

Why are ACE inhibitors not routinely combined with angiotensin antagonists?

A
  • Whilst combining ACE inhibitors with AT1 blockers is very good at reducing BP, dual therapy is associated with an increase in adverse events such as hyperkalaemia, hypotension and renal failure compared to monotherapy alone
37
Q

What is the role of AT2R during AT1R blockade?

A
  • There are 2 types of angiotensin receptors: AT1 (promotes vasoconstriction, growth and fibrosis) and AT2 (promotes vasodilation, prevents growth and prevents fibrosis)
  • The inhibition of AT1 by sartans (angiotensin antaganonists) leads to increased levels of angiotensin II which can stimulate AT2R
  • There is research into potential therapeutics that can directly stimulate AT2R
38
Q

What are natiriuretic peptides?

A
  • These peptides (NPs) stimulate Na+ and water loss
  • They are also vasodilators
  • They are natural endogenous inhibitors of Angiotensin II
  • They are released in response to atrial distension and LV stretch
39
Q

What are neutral endopeptidase inhibitors?

A
  • These drugs inhibit the breakdown of NPs by inhibiting neutral endopeptidases
  • This allows an increase in the levels of natriuretic peptides and thus an increase in their effects (increasing Na+ and water excretion and inhibition of AngII)
  • These blockers have been used in large scale trials but have been shown to cause angioedema
  • Combination of NEP blockers with AT1R blockers (ARNI) is being developed as an anti-hypertensive and a treatment for heart failure
40
Q

How do beta-adrenoreceptor antagonists help treat hypertension and heart failure?

A
  • End in the suffix ‘olol’
  • There are B1-adrenoreceptors in the heart and kidneys
  • Inhibiting the binding of NA to them and their activation in the heart results in a decreased sympathetic drive to the heart and thus decreased cardiac output, heart rate and total peripheral resistance
  • Decreased NA B-adrenoreceptor activation in the kidneys causes a reduction in renin release (and thus a decrease in angiotensin II)
  • May be effective in treating hypertension, angina, post MI, arrythymias and clinically stable heart failure
41
Q

Why should beta-adrenoreceptor blockers only be used for stable heart failure?

A
  • As beta-adrenoreceptor antagonists decrease the sympathetic drive the heart they may remove critical sympathetic compensation (which may be needed if a heart is failing)
  • These drugs may worsen heart failure in the short term so they should only be added when the patient is stable in low doses that increase slowly
42
Q

What are the adverse effects of beta-blockers?

A
  1. Respiratory: can cause bronchorestriction
  2. Cardiovascular: decreased heart contractility, bradycardia, exercise intolerence, impotence
  3. Brain (if lipid soluble): depression, sedation, sleep problems
  4. Diabetes: can exacerbate and mask hypoglycaemia
43
Q

How are calcium channel antagonists/blockers used to treat hypertension?

A
  • These cause a blockade of L-type (voltage) Ca2+ channels
  • This reduces the entry of Ca2+ into vascular and cardiac myocytes (not skeletal muscle cells)
  • This causes a reduction in intracellular calcium in these cells and thus reduced contraction
  • This results in reduced BP, reduced HR (especially veraprimil and diltiazem) and reduced TPR (especially nifedipine and amlodipine)
  • The end result of calcium channel blockers is vasodilation and reduced cardiac contractility (esp. verapamil)
  • It is therefore used to treat hypertension, angina and tachychardias
  • It should not be used to treat heart failure (as they comprimise cardiac function), and verapamil and dilitazem should not be combined with a B blocker (as this reduces cardiac function)
44
Q

How do diuretics work to treat hypertension and heart failure?

A
  • Diuretics e.g. thiazide types and loops, increase Na+ excretion in the renal tubules, which increases water excretion which decreases blood volume and thus decreases CO and BP
  • Loop diuretics e.g. frusemide, act at the ascending limb of the loop of Henle to block Na+/K+/2Cl- symporters
  • Most efficacious
  • Used as frontline treatment for heart failure
  • Thiazide diuretics e.g. hydrochlorothiazide: acts at the distal convoluted tubule to block Na+/Cl- cosymporter and causes a modest increase in sodium excretion
  • used for mild/moderate hypertension
45
Q

What are the adverse effects of diuretics?

A
  • Can cause an electrolyte imbalance (hypokalaemia)

- Can cause hyperuricermia (gout), hypercholesteraemia and hyperglycaemia

46
Q

How do aldoesterone receptor antagonists work?

A
  • Acts as a weak diuretic that acts at the late distal tubule/collecting duct
  • Binds and inhibits aldoesterone receptors and reduces Na+ reabsorption
  • A potassium sparing diuretic
  • Thought to reduce collagen formation and fibrosis in the heart (good for heart failure)
  • Can be used to help limit diuretic induced hypokalaemia
  • An adverse effect can be hyperkalaemia
47
Q

What is pulmonary hypertension?

A
  • Pulmonary hypertension is characterised by high blood pressure that affects the arteries in your lungs and right side of the heart
  • It is the result of the constriction of blood vessels in the lungs
  • Causes hypertrophy of the right heart
  • Pulmonary hypertension >25mmHg
48
Q

Why does pulmonary blood pressure need to be lower than systemic blood pressure?

A
  • The BP can be lower in the pulmonary circuit as the blood is pumped a much shorter distance
  • The pulmonary vasculature is only designed to deal with a lower pressure (they have a much thinner smooth muscle layer than systemic vessels)
  • High pulmonary pressure therefore would damage the architecture of the pulmonary vasculature
49
Q

What are the symptoms of pulmonary hypertension?

A
  1. Shortness of breath
  2. Difficulty breathing with exertion
  3. Dizziness
  4. Rapid breathing
  5. Rapid heart rate
50
Q

What are the risk factors for the development of pulmonary hypertension?

A
  1. Family history:
    - 2 or more family members with PH or a PH causing gene mutation, the risk is increased
  2. Obesity and obstructive sleep apnea:
    - Obesity is not a risk factor in isolation, however if obesity is combined with sleep apnea (oxygen levels fall whilst a person is sleeping) mild PH may occur
  3. Gender:
    - Idiopathic PH and heritable PH are over 2.5x more common in women that men (especially women of childbearing age)
  4. Pregnancy:
    - Possible risk factor
    - Women with PH that become pregnant have a much greater risk of mortality
  5. Altitude:
    - Living at high altitude for many years predisposes a person to PH
    - PH symptoms may be aggravated by high altitude
  6. Other diseases:
    - Congenital heart disease, lung disease, liver diseases and connective tissue disorders such as scleroderma and lupus can lead to the development of PH
  7. Drugs and toxins:
    - Methamphetamines are known to cause PH
51
Q

What are the types of pulmonary hypertension?

A
  1. Type 1: Pulmonary arterial hypertension, includes idiopathic PAH, inherited PAH and PAH caused by congenital heart disease, thyroid disease, HIV, autoimmune disease or certain drugs
  2. Type 2: caused by diseases that affect the left side of the heart e.g. mitral valve prolapse
  3. Type 3. Results from breathing conditions such as COPD, intersistial lung disease and obstructive sleep apnea
  4. Type 4. PH caused by blood disorders such as clotting disorders or sickle cell anaemia
  5. PH caused by other medical conditions e.g. sarcoidosis, or by a tumour pressing on pulmonary arteries
52
Q

How is pulmonary hypertension treated?

A
  1. Oxygen
    - to replace low oxygen in the blood
  2. Anticoagulants
    - decreases blood clot formation so blood flows more freely through vessels
  3. Diuretics:
    - removes extra fluids from tissues and blood stream which reduces swelling and makes breathing easier
  4. Intropic agents:
    - e.g. digoxin, improves the hearts pumping ability
  5. Vasodilators:
    - lowers pulmonary BP and may improve pumping capacity of right side of heart
  6. Endothelin-1 antagonists:
    - help block the action of endothelin which causes narrowing of lung blood vessels
    - endothelin is a vasoconstrictor via Ca2+ and Ca2+ independent mechanisms and also leads to increases smooth muscle thickness
  7. Sildenafil:
    - relaxes pulmonary smooth muscle cells which leads to dilation of the pulmonary arteries
  8. Pulmonary thromboendarterctomy:
    - Surgical removal of blood clots in the pulmonary artery
  9. Lung transplantation:
    - Most effective treatment option for PH
    - Reserved for PH that does not respond to therapy
53
Q

What are the mechanisms underlying the development of type 3 pulmonary hypertension (caused by breathing conditions e.g. COPD)

A
  1. Hypoxic pulmonary vasoconstriction:
    - In a normal lung breathing air at sea level, ventilation and perfusion are matched (V/Q=1)
  2. V/Q mismatch without HPV:
    - If ventilation to one compartment were completely obstructed without changing perfusion, V/Q would decrease to 0 in the obstructed compartment and then the non-obstructed compartment would increase to 2
  3. V/Q mismatch with HPV (hypoxic pulmonary vasocontriction):
    - The body then constricts the blood flow towards the obstructed alveolus (thereby reducing bloodflow) so that more blood is shunted to the alveoli that can reoxygenate the blood
    - In the short term this can compensate for the blockage/obstruction, but in the long term is leads to an increase in pulmonary arterial hypertension
54
Q

What are the different consequences of short term vs long term hypoxic pulmonary vasoconstriction:

A
  1. Short term HPV:
    - Results in factors such as endothelin-1 (ET-1) being released in blood vessels around the obstructed alveolus
    - This causes vasocontriction and thus a reduced luminal radius of the vessel
    - This causes increased vascular resistance and increases pulmonary arterial pressure in the short-term
  2. Chronic HPV:
    - Has more detrimental consequences
    - Over a long period of time upregulated endothelin-1 not only causes vasoconstriction but also leads to smooth muscle proliferation
    - The increases smooth muscle layer in the vessel decreases luminal radius and also makes it more difficult for the vessel to dilate
    - This means that pulmonary arterial pressure must increase to maintain blood flow
55
Q

What are the mechanisms underlying chronic hypoxia induced pulmonary hypertenion (pulmonary vasoconstriction)

A
  • The mechanisms underlying chronic hypoxia induced pulmonary hypertension is hypoxic vasoconstriction (polycythemia has a minor effect on increasing PAP and vascular remodelling is not a driving force)
  • The factors driving vasoconstriction (the cause of CH induced PH) are:
    1. Hypoxic vasoconstriction
    2. Vasoactive fctors e.g. ET-1 causing vasoconstriction by disrupting endothelium and reducing NO
    3. Increased basal vascular smooth muscle (VSM) tone: e.g. Ca2+ causing contraction of smooth muscle in vessels- increased sensitivity due to relative decrease in MLCP activity and activation of RhoA-Rho kinase activity
56
Q

What is a stroke? What are the two main kinds?

A
  • A stroke is a sudden disruption of the blood supply to a part of the brain leading to hypoxia and ischaemia
  • There are 2 kinds:
    1. Ischaemic stroke: occlusion of a blood vessel (most commonly the middle cerebral artery) by thrombus (grows in vessel in brain) or embolism (travels from body to brain)
    2. Haemorrhagic stroke: rupture of a blood vessel, can be subarachnoid (bleeding in space around brain) or intracerebral (bleeding in brain tissue itself)
57
Q

What are the risk factors for stroke?

A
  1. Hypertension
  2. Atrial fibrillation (irregular heart beat)
  3. Smoking
  4. Diabetes
  5. Age
  6. High cholesterol
  7. Gender (increased risk in men (estrogen is neuroprotective in younger women and older women with hormone replaement), but worse outcomes in women)
  8. Obesity
  9. Birth control pills
58
Q

What are the symptoms of a stroke?

A
  1. Vision: blurred or decreased
  2. Language: difficulty speaking or understanding
  3. Numbness, weakness or paralysis: of face, arm or leg
  4. Dizziness
  5. Swallowing: difficulty
  6. Headache: usually severe and of abrupt onset
Acronym: 
F- facial drooping 
A- arm weakness 
S- speech difficulties (understanding or producing) 
T- time is off the essence!
59
Q

What is the treatment for stroke?

A
  1. Diagnosis of stroke type- MRI, CT scan
  2. If stroke is ischaemic and occurred <4 hours previously, t-PA will be injected (strict time limit as if given after 4 hours can cause intracerebral bleeding)
  3. High BP treated
  4. If stroke is ischaemic anticoagulants and antiplatelet drugs ar administered
  5. Osmotic agents and elevation of the head is haemorrhagic stroke
  6. Mechanical thrombectomy: stent is inserted to remove clot, most occur after t-PA and must be within 6 hours)
  7. Physiotherapy, speech therapy- as soon as possible
60
Q

What are the cell death mechanisms following stroke?

A

Short term:

  • Excitotoxicity
  • Oxygen derived free radicals
  1. 2-3 days later:
    - Neuroinflammation
    - Oxygen derived free radicals
61
Q

What evidence is there to support the use of stem cells to treat damage following a stroke?

A

Human amnion epithelial cells (hAECs):

  • Low immunomodulatory properties (suppress immune cells)
  • Low immunogenicity (can evade host immune cells)
  • Lack tumorigenicity (as they lack telomerase)
  • Readily available
  • Has shown positive results in animal studies with reduced infarcts, limited apoptosis and improved functional outcomes
  • The mechanism most well studies is the immunomodulatory properties
62
Q

What are the benefits of stem cell-derived exosomes?

A
  • Exosomes are nano-sized vesicles secreted by stem cells
  • Contain varying substances that regulate reparative functions including miRNAs and siRNAs, lipids and proteins
  • Fewer limitation tthat stem cells: able to pass through lungs and BBB, can inject higher dose, ready to inject in minutes
63
Q

What are the main animal stroke models?

A
  1. Middle cerebral artery occlusion
  2. Photothrombotic stroke
  3. Endothelin-1 stroke model
  4. Embolic stroke: injecting particles that will clot and form and embolism in cerebral blood vessels
  5. Craniectomy
64
Q

Describe the middle cerebral artery occlusion model or stroke:

A
  • Surgery is performed on anaethetised mouse and middle cerebral artery occlusion is caused and monitored using a silicon coated filament
  • Retraction of the filament allows reperfusion

Pros:

  • Mimics human stroke (middle cerebral artery occlusion)
  • Duration and reperfusion controlled
  • Less invasive than other models
  • Most common

Cons:
- Variable infarct damage

65
Q

Describe the photochrombic model of stroke:

A
  • Involves administering a compound known as rose bengal intra-peritoneally into an anaethetised animal
  • The scalp is then opened and a light is shone on the brain
  • The rose bengal causes endothelial cell damage, free radical formation and subsequent platelet aggregation
  • Results in the formation of multiple thrombi in the brain

Pros:

  • Induces a thrombus
  • Minimal surgical intervention
  • Highly reproducible infarct damage

Cons:

  • Little or no ischemic pneumbra
  • Unaabe to measure blood flow
66
Q

Describe the endothelin-1 model of stroke:

A
  • The skull is opened, and a small catheter is placed over a particular blood vessel
  • Endothelin-1 is added which causes constriction of the vessel (for an unknown period of time)

Pros:

  • Conscious model of stroke (anaesthesia in other models could have neuroprotective effects)
  • Reproducible infarct damage
  • Low mortality rate (enables study of animals for longer periods of time)

Cons:

  • Induces astrocytosis and facilitates axonal sprouting (induced by endothelin and does not occur in humans
  • Unable to measure blood flow changes
67
Q

How do most people that survive after 24 hours post-stroke die?

A
  • 65% die of pneumonia
  • Stroke causes a huge increase in leukocytes in the brain and the body will then attempt to suppress the immune system to limit this
  • Immunosuppressed people may contract pneumonia in a hospital setting
  • After a stroke GI leakage occurs which may allow gut microbiota to spread and cause infections in the lung
68
Q

What is an aneurysm?

A
  • An aneurysm is a bulging, weak area in the wall of an artery
  • Aneurysms can occur anywhere throughout the vascular system, but most commonly occur along the aorta and in the blood vessels of the brain
  • Aneurysms are potentially fatal if they rupture and death can occur in minutes
69
Q

What are the causes and risk factors of aneurysms?

A
  1. Weakness in blood vessel wall that is present from birth (congenital aneurysm)
  2. High blood pressure over many years resulting in damage and weakening of the blood vessels
  3. Previous aneurysm
  4. Race- African Americans at higher risk
  5. Atherosclerosis: fatty plaques weaken vessel walls
  6. Inherited diseases that result in weaker than normal vessel walls
  7. Gender: women are more likely to have brain aneurysms or to suffer a subarachnoid haemorrhage
  8. Trauma: e.g. crush injury to the chest can cause abdominal aneurysm
  9. Polycytsic kidney disease: increases risk of cerebral aneurysm
  10. Syphilis: can target the aorta and weaken its walls
  11. Infections targeting a weakened section of blood vessel
70
Q

What are the 3 main locations where aneurysms occur?

A
  • In the brain (cerebral aneurysm)
  • In the thoracic aorta
  • In the abdominal aorta
71
Q

What is a cerebral aneurysm?

A
  • A ruptured cerebral aneurysm is the cause of 10-15% of all strokes
  • A ruptured aneurysm is fatal in 40% of cases, of those that survive, 66% have a permanent neurological deficit
  • Symptoms include severe headache with rapid onset, neck pain and stiffness, increasing drowsiness, paralysis, seizures
  • Saccular aneurysms are the most common type and account for 80-90% of all intracranial aneurysms
  • There are two types of haemorrhagic strokes: intracerebral 10% of strokes (bleeding in brain tissue) and subarachnoid 5% of strokes (bleeding between arachnoid and pia mater)
  • Brain aneurysms are most prevalent in people aged 35-60
72
Q

What are the 4 types of cerebral aneurysm?

A
  1. Saccular:
    - Known as a berry aneurysm
    - Rounded lobulated outpouching which are usually at arterial bifurcations
    - Most common type
  2. Fusiform:
    - Less common type
    - Outpouching on both sides of the artery
    - No neck/stem
    - Less likely to rupture
  3. Giant:
    - Larger than 2.5cm
    - High risk of rupture and difficult to treat
  4. Dissecting:
    - Artery wall rips (dissects) longitudinarry
    - Bleeding into the weakened wall splits the wall and creates a false lumen
    - Most damaging type of anerurysm
73
Q

What are the statistics for aortic aneuysm?

A
  • The prevalence of aortic aneurysm sharply increases with age
  • Rupture is associated with 80% mortality
  • Surgical repair of a ruptured AA has a mortality of around 50%
  • Screening of men aged over 65 years reduces aneurysm related mortality
  • Patients diagnosed with a small AA should have ongoing surveillance with ultrasound and cardiovascular risk factor modification
74
Q

How are aneurysms treated?

A

Considerations:

  • Risk of haemorrhage
  • Type of haemorrhage (saccular needs treatment before fusiform usually)
  • Size and location
  • Family history
  • Surgical risks

Treatments:

Pharmacological treatment:

  1. Mannitol: osmotic agent that increases osmolarity of plasma and causes the movement of water from tissue into blood
    - Used to reduce edema and intracranial pressure following haemorrhagic stroke
  2. Calcium channel blockers:
    - Prevents vessels from undergoing vasospasms

Surgical treatment:

  1. Surgical clipping:
    - Procedure to close off aneurysm
    - A metal clip is placed on the neck of the aneurysm to stop blood flow into it
  2. Open surgery
  3. Endovascular coiling:
    - coil is placed in aneurysm to reduce the likelihood of rupture
75
Q

Acute coronary syndrome may be diagnosed if the patient exhibits any of the following signs except:

  1. Persistant ECG changes
  2. Elevated BP
  3. Chest pressure at rest
  4. Pain without ST-segment elevation of ECG
A

Elevated BP

76
Q

Which of the following drugs are matched with a major adverse side effect except:

  1. Captopril and angioedema
  2. Frusemide and hyperkalaemia
  3. Spironolactone and hyperkalaemia
  4. Losartan and hyperkalaemia
A
  1. Frusemide and hyperkalaemia:

- Thiazide diuretcs such as frusemide cause HYPO kalaemia

BMS 3052 (8 decks)

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