EXAM

Question 1

Describe the pressor and depressor arms of the renin-angiotensin system

Answer 1

Pressor:
- Involves the conversion of angiotensinogen to angiotensin I by renin
- followed by the conversion of angiotensin I to angiotensin II via the angiotensin-converting enzyme (ACE)
- Angiotensin II acts on the angiotensin II type (AT1) receptors, which causes anti-natriuresis, vasoconstriction and pro-inflammatory effects that all contribute to elevated blood pressure.

Depressor:
- Involves the formation of Angiotensin-(1-7) from angiotensin II through ACE2 or from Angiotensin-(1-9) through ACE.
- Angiotensin I can be converted into ang-(1-9) through ACE2
- Ang-(1-7) and angiotensin II act on AT2 and Mas receptors
- This stimulates natriuresis, vasodilation and anti-inflammatory effects that serve as a protective measure against the development of hypertension (high BP)

AT1 receptors are present in the human vasculature, lung, liver, brain, kidney, adrenal gland, skin, and endometrium.

Question 2

Indicate how testosterone and estrogen can alter the balance of these pathways (RAAS)

Answer 2

Testosterone:
- Increases renin and ACE activity
- Increases AT1 receptor expression
- Stimulates the pressor arm of the RAAS
Estrogen:
- Opposes the effects of testosterone
- down-regulates AT1 receptor expression
- Increases ACE2 activity
- Increases AT2 receptor expression
- Favours the depressor arm of the RAAS
The differential expression level of the AT1 and AT2 receptors in the males and females results (due to different sex hormone) in the imbalance of the system as the depressor arm of RAS is more active (dominant) in females and the repressor arm of RAS is dominant in male.

Question 3

In the mid 1990’s females were twice as likely to die of cardiovascular disease as males. Describe four (4) factors that contributed to this poor outcome in women.

Answer 3

1. Yentl Syndrome:
   - This reflects the underrepresentation of women in clinical studies.
   - Most clinical trials excluded women, but applied their findings to both men and women.
   _ As such, there was a lack of evidence-based research for cardiovascular diseases due to the lack of representation of females in clinical trials related to cardiovascular diseases.
   . The presentation of CVD is different in males and females. For example, the Ischemic disease is caused by occlusive artery disease whereases in women it is caused by non-obstructive coronary disease
2. Discrepancy in treatment of CVD
   - Men were more likely to receive medications and procedures for treatment of cardiovascular complications than women.
   - Research has shown that men received significantly more ACE inhibitors than women, and this consequently could have led to greater mortality in women
   - Note: risk of adverse CVD drug effects was also greater in females compared to males due to marked sex differences (e.g. hormonal changes)
3. The research and the healthcare around the women health was more cantered on the breast and reproductive system and complications such as breast cancer, polycystic ovarian cancer and hence there was less research on the women’s risk of CVDs. Also, most women are unaware of their risk of cardiovascular disease. Women perceive they will die due to breast cancer and reproductive diseases.
4. Sex bias in research
   - Historically, most clinical trials exclusively involved males only.
   - In 1993, a law was passed that to ensure that females were included in phase 3 (more severe) of clinical trials
   - However, there was no requirement for translational studies to be conducted in both sexes. was no requirement for Phase 1 where the drug safety, tolerability, pharmacokinetics, and pharmacodynamics is assessed and also phase 2 where the doing and the efficacy is assed
5. Delays in treatment
   - in the case of heart attacks, women often present with atypical symptoms such as dizziness and unusual tiredness. These symptoms were often thought to be reflective of “working too hard”.
   - Hence, most women delay seeking treatment or did not seek treatment at all.
   - When women do seek treatment, the treating physician may not understand or correctly identify symptoms related to CVD.
   - This is also due to treatment medications only being evidence-based treatments for men, and not women.

Question 4

Describe the endothelin (ET) system (including where the receptors are located and their effects)
i) the components of the ET system and (diagram) what is upregulated what is decreased

Answer 4

• A key regulator of vascular tone and kidney function and most potent vasoconstrictor known
• In endothelial cells the precursor of ET-1 (prepro-ET-1) is converted into big ET-1, which is then converted to ET-1 through the endothelin converting enzyme (ECE)
• ET-1 is released and can act on ETA receptors located on smooth muscles, which causes contraction, vasoconstriction , growth, callogen deposition, generation of reactive oxygen species (ROS) and pro-inflammatory responses
• ET-1 can also bind to ETB receptors located on endothelial cells which stimulate the production and release of nitric oxide and prostacyclin (vasodilators)

Question 5

Explain how sex influences the components of ET system and the blood pressure response to ET-1.

Answer 5

• Both estrogen and testosterone influence the synthesis of ET-1 via modulating the transcription of prepro-ET-1 ( precursor)
• Testosterone stimulates prepro-ET-1 in endothelial cells
• estrogen inhibits prepro-ET-1 in endothelial cells and decreases Endothelin converting enzyme activity
• As such, pre-menopausal females will have lower plasma and tissue ET-1 levels than males

Estrogen upregulates expression of ETB receptors in endothelial cells, which stimulates vasodilation through the release of Nitric oxide and prostacyclin

Estrogen downregulates expression of ETA receptors in smooth muscle, which reduces contractions and decreases generation of ROS and has anti-inflammatory responses, which in turn reduces BP.

Testosterone upregulates expression of ETB receptors in smooth muscle, which increases intracellular calcium, inducing greater contractility, increased ROS generation and pro-inflammatory responses, which in turn increases BP.

Males having a greater proportion of smooth muscle ETB receptors whereas females have greater activation and expression of endothelial cell ETB receptors

Loss of the protective effects of Estrogen on the ET system is one of the factors thought to contribute to development of post-menopausal hypertension.

Question 6

ii) the blood pressure response to ET-1.

Answer 6

Endothelin-1 is the most potent vasoconstrictor. The endothelin-1 binding to the ETA (and ETB?) receptor located on the vascular smooth muscle cells will results in vasocontraction, ROS generation and pro-inflammatory response and hence increased blood pressure.
Estrgen increase ETB receptors in endothelial cells, which stimulates vasodilation through the release of Nitric oxide and prostacycline. E also down regulate AT1R and ECE and Pre-pro-E
Testosterone can increase the expression of the ETB receptor smooth muscle in males hence males have greater proportion of ETB receptor and will experience increase in BP after ET-1 administration. On the other hand, in females estrogen increased the ETB expression on endothelial cell and and hence female will experience a reduction in the blood pressure

Question 7

A. List five (5) mechanisms which contribute to the relative cardiovascular protection observed in adult females as compared to age-matched males and post-menopausal (reproductively senescent) females.

Answer 7

Estrogen may serve as a form of cardiovascular protection due to its’ pro-vasodilatory effects in pre-menopausal women.

1. Women are thought to gain weight post-menopause, cardioprotective effects suppressed by estrogen. (low estrogen change in fat distribution to abdomin and insulin resistance) Increased risk of hypertension
2. Sympathetic activation increases post-menopause, which contributes to cardiovascular complications - Sympathetic activation can result in increased release of renin and angiotensin II
3. Shift in estrogen and testosterone balance, as women observe reduced estrogen following menopause (with similar E and T ratio), thereby, reducing anti-vasodilatory effects.
4. Changes in Activation of RAAS, post-menopausal women have reduced depressor arm (natriuresis, vasodilatory and low BP)
5. endothelin (ET) pathway, there is an increase in anti-inflammatory responses , decreased ET-1 ROS, in pre-menopausal women due to increased expression of ETB receptors in endothelial cells. leading to reducing Vasoconstriction

• Renal function - Slower decline in renal function in women compared to men, due to estrogen increasing nitric oxide bioavailability.

Question 8

Why is the cerebral vasculature unique? Include a description of the main blood vessels supplying blood flow to the brain AND two safety mechanisms.

Answer 8

The cerebral vasculature has unique anatomy and physiology. The main blood vessels that supply the blood flow brain are l
Common internal carotid artery and each supplies 40% of the cerebral blood flow. The internal carotid artery branches from the Common crotid artety -> aorta.
-the left and right vertebral arteries, which branch from the Subclavian artery
- These branch into the basilar artery and cerebral arteries (anterior, middle and posterior) which combine to form the circle of Willis.
- The circle of Willis in one of the safety mechanisms of the brain. If there is a blockage or narrowing that slow the BF or prevent BF the BF can be maintained through the other side – the network of vasculature goes around the brain, so the blood supply is uniform across the brain and the most important grey matter has a blood vessel nearby
- The blood brain barrier is another safety mechanism which filters and control what molecules are entering the brain tissue. . It is physical, selective permeability (favors lipophilic), it has specific selective transporters for glucose and proteins. The large arteries leading to the brain are external to the blood brain barrier and smaller arteries penetrate the brain through a large and highly dense capillary network. The BBB is formed by the tight endothelial junctions it is a thick continuous basement membrane and the glial cell and astrocytes project to vessel lining. Neurotransmitters are excluded by their precursor such as choline and dopa are taken up

Question 9

Explain the regulation of cerebral blood flow. In your answer, compare and contrast how mean arterial pressure, arterial PO2 and arterial PCO2 influence cerebral blood flow.

Answer 9

• Cerebral blood flow involves the delivery of oxygen, glucose and nutrients to the brain while removing the build uo of Co2, metabbolites and lactic acid.
• The cerebral blood flow is autoregulated by a balance of intrinsic and extrinsic factors. Intrinsic factors /control has much greater control over the regulation of blood flow to the brain . To maintain the metabolic need of the brain the metabolic factors such as [CO2], [H+] and [O2] are important for autoregulation. (Ordered based on the importance)
  The local distribution of blood in the brain is also controlled by active hyperemia. Increase in Brain activity results in increase cerebral blood flow to that area.
  Through sympathetic influence on cerebral circulation however this is minimal (extrinsic)
• The CO2 in the brain is a by-product of glucose metabolism, thus this process is the major contributor to pCO in the brain. Increase in the arterial [CO2+] results in increased vasodilation in the brain, increase blood flow, increase CO2 removal, and restores [H+]. ( to restore the pH )
  Very slight changes in PCO2 will have a large influence on the cerebral blood flow this is one the most important factor that will lead to either vasodilation or vasoconstriction.
• If the tissue PO2<30 mmHg asodilation will occur. If the PO2 is higher than 30 mmHg cerebral vasoconstriction.
• MAP has some influece over the cerebral blood flow, however not to the same extent as the the intrinsic factor. Between the MAP of 50-150 mmHg the cerebral blood flow is very well regulated, which suggest that brain can cope to some extent with changes in systemic circulation which is due to autoregulation (ensuring brain BF is pioritised) Below 50 mmHg there is a rapid decline n the cerebral blood flow (fainting) and above 150 there’s increase in cerebral blood flow.

Question 10

Explain why someone may choose to hyperventilate before diving and how this may be dangerous.

Answer 10

Hyperventilation is when you breath faster or deeper than it is necessary, and this leads to reduce CO2 concentration in the blood (below the normal).
The deliberate hyperventilation before diving enables the diver to stay down in water for longer as they breath more CO2 then they produce metabolically this inhibit the urge to breath ( as the concentration of CO2 is lower breathing suspended)
Hyperventilation can be dangerous as the increased CO2 levels activate the chemoreceptor to inform the brain the oxygen level is low, so it simulates breathing and Higher CO2 will initiate greater cerebral blood flow (dilation of the vessels)
Slightest changes in CO2 level changes the cerebral blood flow dramatically
When CO2 is low, the stimulus to breathing is low due. also the blood vessels in the brain will constrict and reduce cerebral blood flow leading to light headedness and fainting
The rapid decrease in the blood CO2 without increase in O2 before the dive and during the dive O2 decreases without desire to beath as the CO2 level is low. So decease in cerebral blood flow and decrease in O2 will cause individuals to black out (loss consciousness) before they urge to breath which can be fatal.

Question 11

Describe the three main types of strokes including the major causes of each type.

Answer 11

• Stroke is insufficient blood supply to the brain which makes the brain deprived of glucose and O2 and leads to build up of waste. 6-8 minutes ->cerebral infarction
• The three types of strokes are mini stroke, ischemic stroke and hemorrhagic stroke
• The common lifestyle risk factors of stroke are
  Modifiable: behavior ( smocking, heavy alcohol use, physical inactivity, drug use), hypertension, diabetes mellites cardiac disease, obesity, atrial fibrillation, carotid stenosis, hyperlipidemia, pregnancy.
• The non-modifiable are ag, gender, race and heredity.
• Mini stroke is caused by mini clots blocking the Small capillaries supplying small regions of the brain tissue. That leads to brief episode of confusion, difficulty speaking and understanding, visual problems, dizziness, and loss of balance. It can lead to major ischemic stroke- 30% ( if the clot is caused by asthercotic plaque) and occurs during sleep.
• Ischaemic stroke is caused when a blood vessel supplying the brain is obstructed either
• by blood clot or debris from else where block the flow of the blood to the brain (Embolism)
• Thrombotic - The clot can be from carotid artery disease , dislodged plaque from atherosclerotic plaque in artery which block the blood flow (stenosis) over 80% of stroke are ischaemic.
  If the anti-clotting drugs are administered immediately the chances of survival are greater. (thrombolysis - recombinant plasminogen activator)
• Haemorrhagic stroke is caused by Bleeding in the brain caused by burst blood vessel or aneurysm. The burst of the blood vessel aneurysm can result in damage to the surrounding tissue. The coiled stent is placed at the base of the aneurysm to completely block the blood pocket or blood sac. Effective before the burst.

Question 12

The vascular endothelium plays a major role in matching blood flow to work performance in a tissue. How is this achieved?

Answer 12

The endothelium facilitates vasodilation of arterioles in order to increase blood flow to metabolically active organs and tissues. It does this by releasing factors such as nitric oxide, prostaglandins and endothelial-derived hyperpolarising factor (EDHF), all of which act to induce smooth muscle relaxation, thus reducing vascular resistance and increasing blood flow.
- The working muscle with high metabolic demand such as contracting skeletal muscle or parts of the brain release metabolites such as lactic acid and also Ca+ which cause the opening Ca+ sensitive K channel ( as the Ca+ inside endothelium increase) in the endothelial cell and results in hyperpolarization (-) in the endothelial cells as the potassium leave the Endothelial cells.
- This induces the endothelium derived hyperpolarizing factor (EDHF)
- Endothelial cells are so well connected their neighbouring ET cells via gap junctions promotes rapid hyperpolarisation from the distal arteries to the proximal arteries, and to the underlying smooth muscles via myoendothelial gap junctions and results in vasodilation (This inhibits calcium release in smooth muscle cells, causing them to relax) in arteries that supply blood to the distal arteries and hence the working tissues/muscles.

• In addition, increased blood flow through the microvascular arteries and arterioles can cause sheer stress on ET cells due to viscous drag of blood against the vascular walls. This induces increased release of nitric oxide (vasodilator), which contributes to increased vasodilation and diameter of larger upstream blood vessels.

Question 13

Sustained elevations in blood sugar levels lead to dysregulation of blood flow. Discuss.

Answer 13

Elevated blood sugar levels can be very damaging to endothelial cells thus disrupt their ability to regulate blood flow
ECs have high expression of glut1 receptors, so high bgl causes glucose to be transported into EC where it is metabolized to ATP and superoxide O2- (a ROS) is produced as a by-product which is inactivated by SOD and GPX (antioxidants).
The body needs a healthy amount of ROS to help white blood cells fight off infections and invading antigens through the promotion of inflammation
An increase in glucose increases superoxides (ROS) in the endothelial cells. This eventually reduces the availability of SOD and GPX, and leads to builds of ROS in the mitochondria and cytoplasm.

The Glucose can aggregate on SOD and other proteins through non-enzymatic glycation and causes part of the protein to break off with the glucose, resulting in destruction and inactivation of SOD and formation of Advanced glycation end-products hence there’s oxidative/antioxidant imbalance.

AGE binds to RAGE and results in increased proinflammatory cytokines and chemokines and ROS.
AGE can reduce eNOS expression and eNOS damage results in reduced NO production and vasoconstriction and increased BP. O2- also converts NO into ONOO-, another ROS, reducing NO and increasing oxidative stress.
Under oxidative stress and high plasma sugar levels, the gap junction of the endothelial cells is damaged, leaving inappropriate holes on the ET cell layer, this increases leakage and results in decreased endothelium derived hyperpolarizing factor (EDHF), which limits hyperpolarization of smooth muscles and in turn, prevents vasodilation.
ET cells swell up, block capillaries and tissue hypoxia.

Question 14

Vascular endothelial dysfunction has a major input into the reduced lifespan associated with diabetes. Discuss this statement

Answer 14

• Diabetes is underpinned by high glucose levels, and insulin -resistance → high plasma glucose levels.
  Elevated blood sugar level leads to vascular endothelial dysfunction which exacerbates the reduced life span associated with diabetes.

Glucose is taken up by the endothelial cell, for production of ATP by the mitochondria. Through this process reactive oxygen species (ROS) produced as by product. Body needs healthy amount of ROS to help the white cells fight off infections and invading antigens through promotion of inflammation. The ROS are usually inactivated by the antioxidants SOD, GPX and catalase to avoid them damaging the cells.

In diabetic individuals, due to high blood glucose and insulin resistance the endothelial cells undergo high oxidative stress.
More glucose is transported into EDs via Glut1 while the muscles are starving for glucose (different transporter GLUT4)
The production of ROS by mitochondria increases significantly as result of glucose metabolism. These superoxide damage proteins, lipids, DNA and eNOS

The high blood glucose level leads this will lead to non-enzymatic glycation of proteins, as they continue to be exposed to the elevated plasma sugar levels .This leads to the inactivation and breakdown of protein, including antioxidants such as SODs which are important in the defense against oxidative stress in the body, via advanced glycation end-products (AGEs).
Therefore, there is a significant imbalance in oxidants and antioxidants.
Consequently this buildup of ROS results in endothelial cell stress and cell death and cause vascular endothelial dysfunction.
AGEs receptors also contribute to vascular dysfunction. Individuals with diabetes will therefore have increased oxidative stress (ROS) and proinflammatory response. This results in hypertension.

Therefore, the lack of antioxidants such SODs will lead to high oxidative stress in patients with diabetes, and this will disconnection of endothelial cells, which leaves inappropriate gaps on the layer of the ET cells, and this increases leakage (water can flow in). This result in swelling of the endothelial cells. This causes the blockage of capillaries which is common in the brain → can result in dementia,
This also allow other usually restricted agents that can lead to disturbed tissue function including increased fibrosis in heart, damaged blood brain barrier.

The activation of RAGE and the excessive ROS results in eNOS damage and reduces NO bioavailability. This results in decreased epithelial cell capacity to relax and vasodilated when necessary and leads to hypertension which predisposes to number of cardiovascular complications such as atherosclerosis, stroke, heart failure and nephropathy and kidney failure.

Damages to EDs can reduced the endothelium dependent hyperpolarization factor produced by vascular smooth muscle.

Endothelial damage also increases platelet adhesion and aggregation, as well as transmission of inflammatory cells. This may increase fatty deposits in endothelial cells, leading to atherosclerosis.

Question 15

Discuss the role of nitric oxide in the control of blood flow.

Answer 15

NO is a potent vasodilator and Regulates blood flow through blood vessels (lipid soluble gas)
NO is produced and secreted from endothelial cells in response to an increase in Ca2+. Ca2+ binds to calmodulin, activating eNOS which uses L-Arg to make NO. Due to its lipid solubility, crosses freely from EC into adjacent smooth muscle cells and into the bloodstream
NO acts on Guanyl cyclase enzyme, which increases production of cGMP, which in turn results in vasodilatory effects / caused smooth muscle relaxation.
It also plays a role in preventing smooth muscle proliferation, preventing leukocyte adhesion, and inhibiting endothelial adhesion molecule expression. All these actions help to decrease plaque build-up on artery walls and therefore reduce the risk of atherosclerosis. This maintains a healthy arterial lumen for normal blood flow to occur and allow smooth blood flow. it also prevents smooth muscle proliferation (atherosclerosis)
NO has important role in percise redistribution of blood flow to areas of need.
NO dominates in larger arteries and can move through the thick layer of smooth muscle cells.
Increased blood flow through the microvascular arteries can put a lot of stress on endothelial cells due to the viscous drag of blood against the vascular walls. In response this, release of NO is increased and contributes to the increase in diameter of larger upstream arteries that favour laminar blood flow and reduces Blood pressure.
- Reduced Nitric oxide (in case of diabetes) contribute to to atherosclerosis, high blood pressure and other risk factors for heart disease and predispose to heart failure.

Question 16

Trastuzumab has a low inherent capacity to cause myocyte death but a far greater potential to modify the natural history of cell damage and repair that follows anthracycline exposure. Explain this statement.

Answer 16

Human and animal studies demonstrate that trastuzumab-induced CV toxicity occurs in less than 1-3% of patients
Patients treated with combination therapy with anthracyclines are more prone to development type 2/Trastuzumab-induced CV toxicity as anthracycline exposure may interfere with growth and repair of anthracycline-induced damage.
Treatment with anthracycline leads to oxidative damage in the myocyte (causing some myocyte apoptosis and necrosis). In response, the (HER2) is activated and upregulated to increase the myocyte survival and repair some of the damage
(The damage caused by anthracycline is irreversible damage and starts with the first dose. There’s also a cumulative dose relationship. It causes type l cytotoxicity and increases cardiac mortality. )

Trastuzumab is a targeted cancer drug , it inhibits the HER2 which inhibits the cell repair mechanism and prevents it from division and growth. Administration of Trastuzumab with anthracycline leads to compounding loss of myocyte (due to decrease of cellular repair and increased apoptosis and necrosis) and results in heart failure.

Question 17

Describe four (4) pieces of evidence that demonstrate that cancer and cardiovascular disease share common factors.

Answer 17

• Hyperlipidaemia: Epidemiological data suggest hyperlipidaemia is a risk factor for estrogen receptor positive breast cancer. This suggests that a statin may mitigate breast cancer pathogenesis.
• Inflammation: CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcome) Study. CANTOS study showed that pharmacological inhibition of IL-1B reduced cardiac events and lung cancer incidence and mortality. Inflammation increases in conditions of HF, atherosclerosis and hypertension. During cancer, there are anti-inflammatory systems that are activated.
• Genetic factors (e.g., clonal hematopoiesis of indeterminate potential) Associated with increased risk of hematologic cancers & also serves as a risk factor for myocardial infarction and stroke
• Involves mutations in 3 genes associated with CVDs and increased risk of hematological cancers
• Tobacco: Experimental studies have shown that tobacco produces benzopyrene, a powerful DNA disruptor that is known to produce mutations that can lead to cancer.
  Observational studies show increased formation in plaque can develop from smoking tobacco

Question 18

Describe four (4) pieces of evidence that demonstrate that cancer and cancer therapies increase cardiovascular disease risk.

Answer 18

• In June 2016, USA has 15.5 million cancer survivors. Out of the 69% survivors >50 years of age, >50% of men and 40% of women will develop cardiovascular disease during their remaining lifespan.
• In 2013, there were 420,000 child cancer survivors. As per the Childhood Cancer Survivor Study (CCSS) cohort, the cardiac mortality of child cancer survivors was 7-fold higher, and they had a 15-fold lifetime risk of developing heart failure as compared to age matched population.
• Baseline risk factors and heart disease being equal, patients treated with chemotherapy have an increased risk of cardiomyopathy, heart failure and myocardial infarction in next 20 years
• In long-term cancer survivors: – Higher incidence of hypertension, dyslipidemia, metabolic syndrome (particularly in breast cancer survivors), myocardial infarction and stroke
• Anthracyclines cumulative dose that correlated with 5% of the patients developing heart failure lower doses 300-500 mg/ml -> induces CV toxicity damaging myocytes – patients with extremes of age, prior
• Vascular endothelial growth factor (VEGF) inhibitors, typically used for cancer therapy has been shown to increase incidence of CVD up to nearly 90%.

Question 19

What are the key differences between Type 1 and Type 2 cardiotoxicity?

Answer 19

Type 1; caused/induced by Doxorubicin, results in myocyte death, has a cumulative dose relationship, irreversible and increased cardiac mortality
Risk factors: combination chemotherapy, prior or concomitant radiation therapy, age, history of CVD, hypertension

Type 2: caused and induced by Trastuzumab, results in myocyte dysfunction, no cumulative dose relationship, predominantly reversible with no increased risk of cardiac mortality.
Risk factors: Prior or concomitant anthracyclines, prior or concomitant paclitaxel, age, history of CVD, obesity

Question 20

An oncologist is proposing to treat a stage IV breast cancer patient with 60 mg/m2 doxorubicin on day 1 every 21 days for 4 cycles in combination with cyclophosphamide. The patient was treated with 150 mg/m2 doxorubicin as a child and currently has hypertension. What is your advice to the oncologist? Your answer should take into consideration the patient’s history and how to manage and monitor their cardiovascular health during treatment.

Answer 20

• Studies have shown that the cumulative dose of 300-500 mg/,m2 of Doxorubicin is correlated with cardiovascular toxicity and leads to cardiac failure. As it causes myocyte death, and the damage is irreversible with the first does.
• The patient with extreme age and prior anthracycline exposure, hypertension, history of CVD and combination chemotherapy showed a more CV type I toxicity
• As the patient was treated with 150 mg/m2 doxorubicin as child and the going to be treated with 60 mg/m2 doxorubicin for 4 cycles the cumulative dose will be 390 ml/m2 which is higher then the upper cumulative dose limit and significantly increase the risk of CV type I toxicity
• The patient has hypertension which are established risk factor for type I toxicity
  The patient is going to receive combination treatment with cyclophosphamide which increases the risk of CV type I toxicity and cardiomyocyte death
• Thus, treatment with Doxorubicin is not recommended,
• The patient’s cardiovascular health should be closely monitored during treatment, such as using biomarkers ( troponin, NT-proBNP, ), undertaking cardiac imaging and ECG, assessing kidney function etc. They may also need to take anti-hypertensive medication prior to and during treatment

Question 21

Define cardiac output. Explain how cardiac output changes during an acute bout of exercise in a healthy individual in comparison to someone with heart failure performing an acute bout of exercise.

Answer 21

• Cardiac output is the amount of blood ejected from the LV entering aorta each minute (CO= SV x HR) . Stroke volume is the amount of blood heart pumps/beat and hear rate is the number of times heart beats/minute
• During exercise there is more metabolic demand in the tissues and CO increases 3-4x in a healthy individual by:
• Exercise activates the sympathetic nervous system (baroreceptor) and decrease the activity of the parasympathetic nervous system which results in increased sympathetic output in the sinoatrial node and increased heart rate. The increased sympathetic nervous system stimulates the increased released of norepinephrine (NE) and epinephrine (E) which increased the heart rate by acting on SA node. And also, results act on the myocytes to increased cardiac contractility.
• The NE results in increased venous return by vasodilation. The skeletal muscle pumps also increased the venous return which leads to increased end diastolic volume and hence increased stroke volume as the increased EDV results in increased stretching of ventricle and increased the ventricle contractility (franks starling) and hence increased Stroke volume and hence CO.
• In comparison with someone who has heart failure the heart is unable to produce adequate cardiac output to fulfill the oxygen requirement of the tissues or it takes a lot more afford and increased filling pressure to do so.
• As a result of heart failure, the there is an increase in afterload due to increased heart size, stiffness of the heart tissue (loss of compliance of aorta) and elevated blood pressure which decreased the stroke volume and the cardiac output hence they the HF individuals cannot meet the metabolic demand.
• In phase 1, compensatory mechanisms allow the heart to maintain CO at rest (increase in sympathetic activity, RAAS and myocyte growth/hypertrophy), but the heart is unable to increase its function further during exercise
  In decompensated HF, due to heart cell death and reduced contractility, CO declines to be inadequate even at rest.

Question 22

Define cardiac hypertrophy and list key features of physiological and pathological cardiac hypertrophy including stimuli, heart size, heart function, presence or absence of features including fibrosis and apoptosis.

Answer 22

• Cardiac hypertrophy is increase in heart muscle mass (or enlargement of heart muscle) which occurs as compensatory mechanism to decrease the ventricular wall stress (thickening the ventricular wall) as stress is an inverse function of thickness.(caused by prolonged increased workload)
• Cardiac hypetrophy can be both physiological and pathological.
• In the physiological cardiac hypertrophy, the stimulus is chronic exercise which results in increased heart size, while maintaining the normal organisation and cardiac structure. This is because in chronic excecise the heart need to supply the body with CO it requires dueing physical activity. (Also known as athelet’s heart) The physiological cardiac hypertrophy results in normal or enhanced function of the heart.
  This is what normally occurs post-natal development of baby’s heart in size.
• As compared to the pathological cardiac hypertrophy, the stimulus is pressure overload (High blood pressure) , volume overload, myocardial infarction and cardiomyopathy which results in increased heart size, fibrosis ( increased fibroblast deposition)/ increased wall thickness and myocyte apoptosis that leads to depressed/reduced heart function. Pathological cardiac hypertrophy significantly increases the risk of complications such as stroke and heart failure which leads to increased mortality.

Question 23

Describe factors which influence cardiac output. Explain what happens to cardiac output in a setting of heart failure.

Answer 23

• SV and HR influence CO
• Cardiac output is the amount of blood ejected from the LV entering aorta each minute (CO= SV x HR) . It is determined by heart rate, the number of beats per minute, and stroke volume, the amount of blood that the heart pumps per beat.
• Stroke volume equals end-diastolic volume minus end-systolic volume
• The factors that influence CO are the factors that effect HR and SV. SV is determined by 3 factors preload, afterload, and contractility.
• Preload is the volume of the blood that the ventricle has available to pump (EDV). Afterload is the arterial pressure against which the muscle will contract, and contractility is the force that the heart muscle can generate.
• In heart failure the cardiac output decreased which is due to increase in afterload due to hypertension and loss of compliance of aorta (increase aortic pressure) and aortic valve stenosis all resulting in heart’s ability to pump blood .The increase in afterload shifts the frank-starling curve to the right, decreases the Stroke volume and decreased Cardiac output.
• Low cardiac output means the blood pumped around the body may not be sufficient enough for the tissues and their metabolic demand.
• Increase in HR maybe a compensatory mechanism, however this is temporary or only sufficient for CO maintance during rest.
• Compensatory mechanisms such as increased sympathetic activity, increased fluid retention (RAAS) and cardiac hypertrophy may initially allow the heart to maintain cardiac output at rest.
  Increase RAAS activity, results in increased BP through vasoconstriction by hypretensive action of Ang II, increasing pre-load and maintaining CO.
• This also increases the afterload (ventricle have to work harder to pumpl blood out ) Eventually, this leads to cardiomyocyte death and thinning of the ventricle wall.This is known as decompensated hypertrophy and leads to reduced cardiac function and a decrease in cardiac output.
• Increase in preload and inotropy leads to increase in SV which increases the stroke volume and hence CO. The increase in afterload can lead to decreased stroke volume and decreased CO.

Question 24

Describe the key differences between pathological and physiological cardiac hypertrophy. Include structural, functional and molecular differences.

Answer 24

• The pathological cardiac hypertrophy is caused by stimulus such as increased blood pressure, pressure overload, volume overload, cardiomyopathy and myocardial infarction and results in increased heart size, fibrosis and myocyte apoptosis which results in depressed cardiac function. ( initial increase in cardiomyocyte growth and heart size, which eventually leads to cardiomyocyte death and ventricular dilation.)
• On the other hand, physiological cardiac hypertrophy is stimulated by chronic exercise training which results in increased heart size, enhances or normal heart function and maintains the structural organisation of the heart.
• In pathological hypertrophy the stimulus results in increased release of angiotensin II, epinephrine and endothelin-1 which activate the Gaq receptor and activate the calmodulin and MAPK. Calmodulin activates calcineurin and MAPK activates protein kinase C. This results in activation of the subsequent transcription factors and second messenger molecules which increase gene expression, protein synthesis, stimulate fibroblast to increase ECM production leading to fibrosis, increase in cell size and can lead to cell death (fetal gene expression).
• In comparison the exercise increases the growth factor (IGF-1) binding to the receptor tyrosine kinase which activates the PI3K and AKT signalling pathways. This leads to increased gene expression, increased protein synthesis and cell size that results in enhanced or normal heart function. PI3K is the master regulator of good heart growth while Gaq/Ga11 is responsible for pathological heart growth

Question 25

For the two different plaques below, define (name) them and discuss their likely fate i.e. what symptoms/ disease would they likely cause if lodged in a patient’s coronary arteries. Also, include details of a possible treatment plan (inclusive of reasons why that strategy is taken) for both patients and discuss whether there may be any long-term consequences.

Fibroatheroma with a fibrous cap of ~40 micrometres, with a large lipid pool, low smooth muscle cell content and high degree of inflammation.

Answer 25

characteristic of an unstable plaque which is more predominate in male (High LDL)
- The unstable plaque is formed when the smooth muscle cell undergoes apoptosis and hence less collagen and ECM is produced leading to thinning of the cap.- Impaired SMC collagen synthesis – interferon (IFN𝛄) - inhibit it
There are also increased macrophages leading to increased inflammation. The inflammatory cytokine results in elevated level of proteas, including metalloproteinases which degrade ECM contributing to thinning of the cap

• The unstable plaque is prone to rupture as the thin fibrous cap cannot stand the pressure exerted by the blood flow and hence will rupture. The rupture can result in increased thrombosis.
• Following the rupture, the healing can occur which will result in SMCs proliferation, increased extracellular matrix production, and LDL accumulation which will results in stenosis where in coronary artery can cause angina.
• The rupture of the thin Fibroatheroma and the thrombosis in the coronary artery can also cause Myocardial infarction. The symptoms of myocardial infarction are increase pressure, tightness, pain in the chest, back, jaw, cold sweats, heart burn, fatigue, and dizziness.
• The immediate treatment for MI can be administration of Nitro-glycerine to cause vasodilation and increase the blood flow to the region of the heart that is blood/oxygen deprived, anticoagulant such as aspirin to decrease the platelet aggregation and relieve the thrombosis/ decrease clot formation.
• The follow up treatment can be Beta blockers to decrease heart rate and hence blood pressure, ACE inhibitors to decrease blood pressure and statin to reduce the plasma LDL. There is also surgical treatment available such as the coronary angioplasty and stenting ( metal and drug eluting).
  Long-term consequences:
• Blockages in coronary arteries may cause necrosis in the tissue, leading to cardiac complications (e.g. arrhythmias)

Question 26

Calcified plaque with high collagen content and small lipid pool that has contributed to outward expansion of the blood vessel and a narrowed lumen.
Treatment plan ( one for angina and one for MI)

Answer 26

• These are the characteristic of a stable plaque. A stable plaque is lipid poor, proteoglycan rich, has few inflammatory cells and is more predominant female with high triglyceride level .
• Low risk of plaque rupture but the narrowed lumen and leads to stenosis may still impede blood flow to the heart muscle. This may cause angina (ischemia) and chronic chest pain.
• As per Glagov’s coronary remodelling hypothesis, there will be compensatory enlargement or positive remodelling of blood vessels. This can lead to a large buildup of plaque with no visible symptoms present until more severe complications occur. If stenosis of coronary arteries is present, this can lead to demand ischemia.
• The stable plaque can result in plaque erosion ( the programmed cell death of ECs) . The plaque erosion is a common cause of acute MI and is triggered by the oxidative stress, Neutrophil extracellular traps (NETs) and vascular spasm.
• The patient might take nitrates (e.g. nitroglycerine) to increase vasodilation of coronary arteries, or anticoagulants (e.g. aspirin) to reduce the viscosity of the blood. LDL-lowering treatment using statins may be useful in the long-term to reduce plasma lipids and prevent development of future plaques
  Long term consequences:
• If condition continues to worsen, this can increase the risk of severe CV-related events including heart failure and myocardial infraction.
  Triggers of erosion = oxidative stress (hypochlorous acid which is product of myeloperoxidase), binding to TLR2 by hyaluronan and Gm positive bacterial component, Neutrophil extracellular traps (NETs), vascular spasm

Question 27

What is dyslipidemia and how does it lead to atherosclerosis?

Answer 27

• Dyslipidemia, defined as elevated total or LDL cholesterol levels (total cholesterol <5 mmol/L or LDL <3 mmol/L), or low levels of high-density lipoprotein (HDL) cholesterol (HDL >1 mmol/L) and high level of triglyceride which is an important risk factor for atherosclerosis and hence increased risk of CVD.
• Lipoproteins are complex plasma particles responsible for transport of cholesterol. LDLs promote the cholesterol transport to the peripheral tissues from the liver and hence atherogenic while HLD is responsible for peripheral cholesterol uptake and transport it to the liver and hence and is anti-atherogenic
  • Increased plasma lipids cause LDL to become trapped in endothelial cells lining blood vessels. Here they are oxidised to form oxLDL, which promotes endothelial inflammation, monocyte migration and adhesion, and reduced nitric oxide production.
  • Monocytes infiltrate the intima and differentiate into macrophages which absorb ox-LDL to form foam cells. These aggregate in the blood vessel wall, forming a fatty streak
  • Further accumulation of lipids and apoptosis of foam cells leads to formation of a lipid core. Smooth muscle cells produce ECM proteins that from a fibrous cap, completing the atherosclerotic plaque.
• (familial hypercholesterolemia ) Mutations cause defective LDL metabolism and result in reduced cellular uptake of LDL and increased plasma LDL concentration; the heterozygotes for this mulation develop CHF by 55-60 and the homozygous develop CHD if untreated by 20 years of age. LDL lowering treatment is very successful in reducing death
• Mutation in genes encoding key proteins in LDL receptor endocytosis and recycling causes LDL receptor loss of function mutation, apolipoprotein B mutation and PCSK9 gain of function mutation
• Mutation of those 3 results in liver with only 50% functional LDL receptor – elevated cholesterol-> atherosclerosis – coronary heart disease- MI, ANGIOGENESIS
• The LDL can undergo oxidation and other molecular modifications that are responsible for endothelial damage, macrophage chemoattraction, and pathologic arterial changes leading to atherosclerosis

Question 28

Treatment of dislypidimia

Answer 28

PCSK9 therapeutic - PCSK9 facilitates LDL-LDLR interaction, Inhibition of PCSK9 results in LDL lysosomal degradation and LDLR recycling, PCSK9 also stimulates inflammatory cytokines, PCSK9 inhibitors reduce inflammation in arterial wall
HDL -Based therapies - HDL-C thought to be anti-atherogenic, H DL promotes reverse cholesterol transport, Cholesterol taken up into liver, out of circulation (LCAT promoters- increase cholesterol esterification (reduce free cholesterol), CETP inhibitors – prevents transfer of cholesterol esters to other lipoproteins (such as ‘bad’ LDL))
statin – inhibit the HMG-CoA reductase activity, reduction of hepatic cholesterol, increased LDL receptor expression and increase clearance of LDL-C
LDL-lowering- ezetimibe : Decreases intestinal cholesterol absorption, Anti-inflammatory/ antioxidant, Increases plaque stabilisation

Question 29

Describe the process by which an atherosclerotic plaque can lead to a myocardial infarction.

Answer 29

Atherosclerotic plaque can lead to MI if it ruptures and thrombus forms that block the blood vessle supplying the heart such as cornory artery.
The plaque are prevented from rupture by their collagen rich fiberous cap.
A decrease in smooth muscle cell (SMC) collagen synthesis (caused by interferon (IFN𝛄) , increased SMC apoptosis or an increase in infiltrating macrophages which degrade the collagen rich cap matric through matrix metalloproteinases (MMPs) and Plasminogen activators and cathepsins can all contribute to thinning of the fibrous cap over time and result in an unstable plaque.
If the factors that degrade collagen outweigh the factors that produce it, this may cause the plaque to rupture. Also the imbalance between the mechanical strength of fibrous cap and forces that impinge on it can cause the plaque to rupture.
Apoptotic macrophages and SMCs may generate a tissue factor that promotes the formation of a microvascular thrombosis after plaque disruption.
Red blood cells and platelets may coagulate to increase the blockage. As the thrombus continues to grow, it may impede the flow of blood through the artery and may form blood clots, where blood flow is blocked completely.
If the blockage occurs in the coronary arteries and a section of heart muscle is starved of oxygen, this may cause a myocardial infarction and possibly permanent cardiac damage to occur.
Success of lipid-lowering therapy in reducing the incidence of acute myocardial infarction ⇒ may result from a reduced accumulation of lipid and a decrease in inflammation and plaque thrombogenicity

Question 30

Name four (4) risk factors for cardiovascular disease. Briefly, comment on how each of these risk factors are thought to contribute to the development or progression of cardiovascular disease.

Answer 30

• Smoking: Cigarette smoke contains toxic chemicals that damage blood vessels through promoting inflammation and atherosclerosis, raising blood pressure, and disrupting endothelial function
• Hypertension: High blood pressure leads to increased afterload, placing strain on the heart to pump harder and faster. This may lead to ventricular hypertrophy and heart failure. It also promotes atherosclerosis, the narrowing of artery walls which may reduce blood supply to the heart and brain.
• Obesity: Obesity is associated with high levels of leptin, which increases sympathetic activity. This increases cardiac output, vasoconstriction, and fluid retention, all of which may raise blood pressure
• Dyslipidemia: High levels of LDL cholesterol, and low HDL cholesterol may contribute to the build-up of fatty deposits within blood vessels (atherosclerosis), which is the precursor of CVD.
  Diabetes:

Question 31

Briefly describe primary and secondary approaches to prevent disease, highlighting the benefits and limitations of each approach.

Answer 31

Primary prevention is targeted at people who do not have established disease hence the total population, selected groups and healthy individuals
It aims to limit disease incidence by controlling causes and risk factors through two approaches: the high risk approach and the mass approach
The high-risk approach is targeted at those who have established risk factors to prevent disease, whereas the mass approach is targeted at shifting the mean level of risk factor within a population to a lower level.
The advantages of the high risk strategy is that it is appropriate to individuals, there’s subject motivation, physician motivation and favourable benefit-risk ratio. The disadvantages are difficult identifying individuals, temporary and limited effect.
The benefits of mass approach is that it is radical, large potential for the whole population and behaviorally appropriate and the limitations is that the may have poor individual benefit, poor motivation for subject and physician to follow and may requires legislation to implement.
High risk benefit is appropriate for individuals, subject motivation, physician motivation, favourable benefit risk ratio.
limitations are limited and temporary effects, difficulities identifying individuals.

• Secondary prevention focuses on patients with early stages of the disease or to prevent disease recurrence. It is easy to identify who is in need and involves more targeted and personalised care, thus leading to more direct, tangible health outcomes as it can prevent the recurrence. However, it may only have a temporary effect, and does not have as widespread of an impact as it only targets people with known disease.
detecting early stages of CVD can be problematic as patient may notice symptoms when its is too late.

Question 32

Describe the mechanism of anaphylactic shock and effects on cardiovascular physiology, including an agent that could be used to manage this.

Answer 32

Anaphylactic shock is a type of distributive and multi-system shock which is triggered by certain foods, insects and medications.
The pathophysiology of Anaphylaxis involves immunoglobulin (IgE) binding to the foreign antigen and the antigen-bound IgE then activates the high-affinity IgE receptors (FCER1) found on mast cells and basophils. This leads to the release of large amounts of inflammatory mediators, including histamine in the blood stream.

These mediators act to increase the contraction/constriction of bronchial smooth muscles, trigger vasodilation and increase the leakage of fluid from blood vessels ( increase permeability), resulting in a decrease in TPR and thus reduced arterial pressure and cause depressed cardiac function.
Vasdilation and increased vascular permeability can change the distribution of blood towards the smaller blood vessles ( increase local blood flow ) and cause edema. This also results in decreased venous return and SV and CO and hence due to reduce TPR, decreased MAP.
This may cause poor perfusion of tissues such as the brain, leading to dizziness, and increase in blood flow to the skin, causing redness, swelling, and warm peripheries.

Adrenaline is commonly used to treat anaphylaxis. It is a B1 agonist, it binds to B1 receptors in the heart, leading to increased heart rate and (intrope (SV and CO) and contractility (chronotrope), and therefore an increase in SV and cardiac output and consequnetly MAP. This is designed to counteract the fall in MAP but may lead to arrhythmias or hypertension.

Question 33

A 20-year-old female presents to the emergency department with tongue swelling, shortness of breath and an unrecordable blood pressure after trying a friend’s peanut butter sandwich. Identify and describe the most likely physiological mechanisms of shock in this patient, as well as identifying and describing the mechanism of a pharmacological agent that could improve her shock.

Answer 33

Mechanism of shock: Anaphylaxis which is most likley caused by peanut in her sandwhich
It is a Multisystem allergic reaction in response to food, insects, and drugs. The antigen (substance in peanut butter) binds to IgE on mast cells and basophils releasing large amounts of histamine and other inflammatory mediators. It is a distributive or vasodilatory shock.
The inflammatory mediators can cause bronchial smooth muscle contrcation and hence she struggles to breath ( shortness of breath)
The histamine cause vasodilation and increased vascular permeability and dsitribute blood towards the tissue / smaller vessles. This results in reduced venous return, reduced stroke volume and hence reduced Cardiac Output.
The decreased TPR and reduced CO results in decrease Mean arterial pressure and hence hypotension ( unrecordable blood pressure).
The heart rate will increase to compensate for low CO and hence low MAP, however it will not be sufficient.
The other inflammatory mediators can result in cardiac arrhythmias, reduced cornry, blood flow and hypovolemia.

Adrenaline is a pharmacological agent used to treat anaphylaxis. It is a potent β1 agonist (β1 is located on the heart) and acts more selectively on the heart to increase heart rate (chronotrope), contractility (inotrope).
It is also a β2 agonist which results in vasodilation and bronchodilation and also ⍺1 agonist that leads to vasoconstriction and increased peripheral vascular resistance.
The Vasodilation and constriction from β2/ ⍺1 cancelled out. Hence overall it heart rate, cardiac output and MAP.
The adverse effects are : Arrhythmias ◦ Severe hypertension leading cerebral hemorrhage ◦ Cardiac ischemia

Question 34

Describe the circulation of blood through the heart including key structures.

Answer 34

During diastole, the superior and inferior vena cava deliver deoxygenated blood to the right atrium. The blood flows, both passively and actively, through the tricuspid valve and into the right ventricle. At the same time, the pulmonary vein delivers oxygenated blood from the lungs into the left atrium, which travels through the mitral valve into the left ventricle.

During systole, deoxygenated blood in the right ventricle is pumped through the pulmonary valve along the pulmonary artery towards the lungs, while oxygenated blood in the left ventricle is pumped through the aortic valve along the aorta to the rest of the body. Blood from the lungs is pumped into the left atrium, and blood from the body into the right atrium, and the cycle starts over.

Question 35

Describe the circulation of blood through the heart including key structures - steps

Answer 35

1. Deoxygenated blood flows through the superior and inferior vena cava veins and first enters into the right atrium. (diastole)
2. Blood then flows into the right ventricle via the tricuspid valve. (diastole)
3. Activation of the SA node causes the contraction of the heart, which then pushes the deoxygenated blood from the right ventricle into the pulmonary artery via the pulmonary valve.
4. Deoxygenated blood then travels to the lungs where it undergoes pulmonary circulation and becomes oxygenated and then leaves the lungs and travels back to the heart via the pulmonary veins.
5. The oxygenated blood then enters the left atrium and then flows into the left ventricle via the mitral valve.
6. The left ventricle then pumps the oxygenated blood into the aorta via the aortic valve and undergoes systemic circulation.
7. Finally, the now deoxygenated blood returns into the superior and inferior vena cava and the process is repeated.

Question 36

A 60-year-old man presents to the hospital with a fever and cough and he is found to have pneumonia. Subsequently his blood pressure decreases to 80/50mmHg, he becomes confused and stops making urine, his peripheries are warm. Describe the mechanism of shock, occurring in this man, and an agent that could be used to improve his condition.

Answer 36

Septic shock, a type of distributive shock that is caused by a dysregulated response to infection, in this case pneumonia. The body’s response to fight the infection cause damages to tissues as it causes systemic inflammation, fever, vasodilation and reduced TPR, which results in the low MAP seen in the patient.
Due to systemic inflmammation the the blood is distributed towards tissue and the smaller blood vessles and away from the major blood vessles. This and reduced MAP results in reduced venous return, reduced SV, hence reduced CP and MAP.
Decreased MAP and CO also reduces perfusion pressure in the kidney, leading to low urine output, and reduces blood supply to the brain, causing confusion as the brain does not revcieve sufficent amount of blood.

To counteract this, we must use the following agent:

Noradrenaline is used most to treat septic shock (A1 receptor agonist) It binds to A1 receptors on the surface of blood vessels, stimulating vasoconstriction. This causes an increase in TPR and an increase in MAP, thus counteracting the fall in arterial pressure brought on by sepsis. However, severe vasoconstriction may cause hypertension, decreased end-organ perfusion or peripheral ischemia.

Other agent we can use:

Phenylephrine:
- Used in septic shock as second line treatment, but can be a first line treatment for patients with underlying heart disease or rhythm disturbances.
- Does not increase risk of arrythmias. This is because it is a pure alpha-1 agonist and causes vasoconstriction, thereby increasing TPR and MAP. Furthermore, it has no beta agonist effect, thus, will not impact CO and HR

Question 37

Describe the six stages of atherosclerosis.

Answer 37

Grade 1: Foam cell formation : the endothelial cell is in direct contact with blood and hence it is substile to injury. ( Risk factors of endothelial injury are hypertension, turbulent blood flow, reactive oxygen species, dyslipidaemia (High cholesterol), high blood glucose level). The Low-density lipoprotein trap inside the intima. They can pass through the endothelial cell by endocytosis or damage to the endothelial junction and as the plasma LDL is increased the LDL trapping inside the intima increases. The LDL oxidizes by the enzymes such as lipoxygenase myeloperoxidase and nitric oxide synthase). The oxidized LDL and the cytokines ( by damaged endothelial cell) lead to activation of the endothelial cells which results in increased permeability and expression of adhesion molecule such as VCAM 1 and ICAM 1 and also selectin on the endothelial surface. This increases the leukocytes and monocytes binding, rolling, activation and eventually their migration to the vascular intima. (MCP-1 bindings to CCR2 activate monocyte). The monocyte in the intima differentiates into macrophages (M1). The cytokines OX-LDL and macrophage colony stimulating factor increases the expression of scavenger receptor on macrophages hence as the result the macrophages increase their uptake and accumulation of ox-LDL and leas to formation of foam cells.

Grade 2: Fatty acid streak : The foam cells aggregate in the blood vessel wall forming the fatty streak.

Grade 3: Extracellular fatty acid streak: The macrophages foam cells and the T cell secret pro-inflammatory cytokines such as interleukin-1 and tumour necrosis factor which will attract the smooth muscle cells. With damages internal elastic lamina, the smooth muscle cells in the tunica media travel to the luminal surface, proliferate and synthesize extracellular matrix protein:
Grade 4: Lipid core : The lipid continues to accumulate, and the foam cells die through apoptosis. The aggregation of the ox -LDL, foam cell and apoptotic foam cells and smooth muscle cells lead to formation of a lipid rich necrotic core in the intima.

Garde 5: atherosclerotic plaque lipid core embedded in fibrotic cap: The extracellular matrix proteins produced by the Smooth muscle cells lead to formation of a fibrous cap over the lipid core. The smooth muscle cells produce, interstitial collagen ( type I and III ), elastin fibres and proteoglycans. ( The necrotic lipid core can calcify as well)

Grade 6: Complicated atherosclerotic plaque rupture, erosion, thrombosis : The plaque can rupture, erode of thrombose depending on the type of the plaque formed. If there is a thinning of the fibrous cap as a result of reduction in smooth muscle leading to impaired collagen synthesis (IFN𝛄) or macrophages degrading the collagen rich cap by Matrix metalloproteinases (MMPs), Plasminogen activators and cathepsins the plaque will rupture. There is an Imbalance between mechanical strength of fibrous cap and the forces that impinge on it hence the plaque will rupture . The Apoptotic macrophages and SMCs can generate particulate tissue factor which is a potential instigator (initiator) of microvascular thrombosis after spontaneous plaque disruption

Question 38

Answer 38

Looking at the WT mice, males had a greater change of MAP compared to females (significance denoted by **) upon angiotensin II infusion. Angiotensin II can either act on AT1R and promote vasoconstriction (increase MAP) or AT2R and induce vasodilation (decease MAP). AT1R expression is increased due to testosterone therefore enhancing AngII’s vasoconstriction effect. On the other hand, estrogen in females increases AT2R expression, thus, while AngII acts on AT1R to vasoconstrict, AngII is also acting on the AT2R at a higher level compared to men to help maintain a relatively stable MAP. Despite this, the both sexes of WT mice experienced a significant change in MAP compared to baseline.
In regards to female mice, those with AT2R KO experience a significantly greater change in MAP compared to WT females (P<0.01). These results confirm that the increased expression of AT2R plays a critical role in maintaining stable blood pressure as its absence caused a change in MAP similar to WT males during the early days of infusion.
The data for male mice show that WT and AT2R KO results in a relatively similar change in MAP. This suggests that the AT2R activity in male mice is almost undetectable and has little effect in modulating blood pressure as its absence does not change much compared to WT.
Focusing on the KO mice, both males and females followed a similar pattern in change in MAP. This suggests that WHAT
Overall, the figure demonstrates that upon AngII infusion, females are better at maintaining a relatively stable MAP compared to males. This may be due to the increased expression and activity of AT2R, induced by estrogen, with the AT2R KO producing a noticeable change. This suggests that AT2R is key in inducing the depressor arm of the RAS. However, this is not the case with males as WT and AT2R KO mice exhibiting similar results