Drugs used in coronary artery disease

Describe how nitrates are used in management of angina

Angina happens when not enough blood gets through to the cardiac muscle. Nitrates dilate resistance vessels, including the coronary arteries supplying the heart, thus increasing the blood supply to the heart. The two main nitrates are glyceryl trinitrate (GTN) and isosorbide dinitrate. They are converted to nitric oxide via organic nitrate ester reductase, and the nitric oxide produced goes onto cause relaxation of vascular smooth muscle.

GTN and isosorbide mononitrate differ in terms of their pharmacokinetics. GTN has very high first-pass metabolism, meaning that if you try to give it orally, it will be broken down by the liver and you won't get much use out of the drug. Therefore, GTN is usually given by sublingual spray or transcutaneous patch, or by IV in severe cases. Isosorbide mononitrate has a lower first-pass clearance and can be given orally.

Another thing to keep in mind with nitrates is that they can lose their effectiveness quickly. If nitrates are used constantly over 24 hours, they lose their effect- a process called "tachyphylaxis." Therefore, if people are using transcutaneous GTN patches, the patches need to be taken off overnight.

Describe how antiplatelet agents, beta adrenoreceptor blockers, thrombolytics and anticoagulants are used in the context of ischaemic heart disease

This lecture basically covered emergency situations ("acute coronary syndromes"), including unstable angina, non-ST elevation acute myocardial infarction, and ST-elevation acute myocardial infarction (STEMI). (ST-elevation refers to a feature of the ECG tracing.)

Antiplatelet agents

Antiplatelet agents are drugs that block various actions of platelets. I've covered them here. Aspirin and clopidogrel (an ADP receptor antagonist) are good for inhibiting platelet aggregation on coronary plaques.

Beta-adrenoceptor blockers

Beta-blockers, as discussed here, reduce the contractility and rate of the heart. In turn, this reduces the heart's demand for oxygen so that it can make do with less oxygen than before. In acute coronary syndromes, beta-blockers help to limit the size of the infarct and reduce pain.

Thrombolytics

Thrombolytics (a.k.a. profibrinolytics) are good when urgent thrombolysis is needed (i.e. you need to get rid of a blood clot NOW, not prevent them from happening in the future). I have discussed them here.

Anticoagulants

Anticoagulants are good for preventing clots from happening in the future. One of the main ones that is used is low molecular weight heparin, which can prevent thrombotic and embolic complications of heart attacks. I have discussed these here.

Drug Management of Heart Failure

Describe the physiology of Na, K and H2O renal excretion, including the renin-angiotensin-aldosterone system

• Renal Physiology: Reabsorption part 1
• Renal Physiology: Reabsorption part 2

Describe the drug strategies to enhance Na and H2O excretion (ACE inhibitors, aldosterone antagonists)

ACE inhibitors, such as enalapril and captopril, work by inhibiting angiotensin-converting enzyme (ACE), which converts angiotensin I to angiotensin II. Since angiotensin II normally works on the arterioles to cause constriction and on the adrenal cortex to increase the release of aldosterone, inhibiting ACE causes vasodilation (and an increase in blood flow to the kidneys) and an increase in salt and water excretion (via the actions of aldosterone).

Angiotensin II and aldosterone can also be blocked directly. AT1 receptor blockers block the actions of angiotensin II (since AT1 receptors, confusingly enough, are the receptors for angiotensin II). These drugs tend to end with the suffix -sartan, such as irbesartan. Aldosterone antagonists such as spironolactone not only increase salt and water excretion, but also inhibit the myocardial remodelling that occurs during heart failure.

Describe the clinically important beta adrenoreceptor blockers

Beta-1 blockers can also be used to treat heart failure, as they can block cardiac modelling and also decrease the myocardial contractility (which in turn decreases the blood pressure). Furthermore, they can also slow the heart down, allowing more time for the ventricles to fill with blood (which is important in cases of diastolic heart failure). Most beta-blockers end with -olol, and include metoprolol and bisoprolol. Adverse effects of beta-1 blockers are mainly related to off-target activation of beta-2 receptors, and include bronchospasm (which is why beta-blockers tend to be avoided in people with asthma). There are also side-effects from having too much of a good thing, such as excessive slowing of the heart.

Describe the clinically important diuretics

I'll discuss diuretics in a later post, but essentially diuretics act on certain transporters in the tubule to decrease reabsorption and/or increase secretion of salts and water so that you pee more. The main types of diuretics include loop diuretics (e.g. frusemide), thiazides (e.g. hydrochlorothiazide), and aldosterone antagonists (e.g. spironolactone).

Describe how digoxin acts as antiarrhythmic agent and to increase cardiac contractility

Digoxin is an antiarrhythmic that is also used for heart failure. It works by blocking Na+/K+ pumps, thus reducing the gradients of sodium and potassium. Because it blocks the pumping out of sodium, it also has a downstream effect on Na+/Ca2+ exchangers, which bring in sodium to let calcium leave the cell. Because the Na+/Ca2+ exchangers are being affected, there is more intracellular calcium, which leads to more efficient contraction of myocytes and increased cardiac contractility.

Digoxin also has indirect effects on the heart via the vagus nerve. Digoxin stimulates the vagus nerve, causing an increase in parasympathetic stimulation and decreased heart rate. Therefore, digoxin is also good for treating supraventricular tachyarrhythmias (only the supraventricular ones as the ventricles don't get parasympathetic stimulation).

Even though digoxin can reduce heart rate, at toxic doses it can actually increase heart rate. Since digoxin blocks the Na+/K+ pump, there is a smaller potassium gradient and so less potassium leaves the cell during repolarisation. Therefore, the membrane becomes less polarised (i.e. less negative), making it easier to reach threshold during the next heartbeat.

Digoxin toxicity may also present with other symptoms, such as serious arrhythmias, nausea, confusion, and visual problems. Nausea and confusion are most commonly seen in elderly patients. Since digoxin relies a lot on the kidneys for excretion (~70% excretion via the kidneys), it is especially toxic in people with renal impairment. Digoxin is also especially toxic in people who are hypokalaemic, as potassium would ordinarily compete with digoxin for binding to the Na+/K+ ATPase.

Describe how nitrates may be used in heart disease

The actual mechanism of action of nitrates wasn't really discussed in this lecture, other than that they are vasodilators that can help in emergency situations by reducing afterload.

Renal Anatomy

I wasn't sure what to blog about next, so I wrote down all of the fields that we're studying (microbiology, anatomy, physiology, etc.) and let a random number generator pick for me. It picked the number corresponding to Anatomy, so I guess that's what I'll be blogging about now! (Also, I bombed a large proportion of the anatomy questions in the set of formative renal questions that we were given, so I guess I need the extra study...)

Describe the position and functional anatomy of the kidneys and ureters.

The kidneys are located in the abdomen, roughly between T12 and L3. The right kidney is slightly lower than the left kidney because it has been pushed down by the liver. The hilum of each kidney (where the blood vessels etc. join the kidney) is located at around L1-L2. Each kidney is surrounded by a layer of perirenal (or perinephric) fat, which is surrounded by a layer of renal fascia (a.k.a. Gerota's fascia), and then by a layer of pararenal (paranephric) fat.

Demonstrate the topographical relationships of the kidneys and ureters to other abdominal structures.

The kidneys are located laterally to the psoas muscle, and the ureters run along the front of the psoas. As the ureters enter the pelvis, they cross the bifurcation of the iliac arteries.

Describe the blood supply and innervation of the kidneys and ureters.

Blood supply

The kidneys receive blood from the renal arteries. Since both renal arteries arise from the aorta, and the aorta is on the left side of the body, the left renal artery is shorter than the right renal artery. The opposite is true for renal veins: the left renal vein is longer than the right renal vein. The left renal vein also receives blood from the gonads and adrenals (via the left gonadal vein and the left suprarenal vein respectively).

The ureters receive their blood supply from whatever structures are running close to them. The upper part of the ureters tend to receive blood from the renal artery, the middle part of the ureters tend to receive blood from the gonadal arteries and/or the aorta, and the lower part of the ureters tend to receive blood from the vesical arteries.

Innervation

The kidneys receive sympathetic innervation from T10 and T11 nerves (a.k.a. the lesser splanchnic nerves) and parasympathetic innervation from the vagus nerve. Sensory fibres follow the sympathetic fibres back to T10/T11, so kidney pain tends to be felt over those dermatomes. One important point is that nerves are not very important for renal function in general, but for renal blood flow. Aspects of renal function (how much salt and water to absorb, for example) tend to be controlled by hormones.

The ureters receive sympathetic innervation from T12 and L1, and parasympathetic innervation from the vagus and hypogastric (from S234) nerves. Just like with the kidneys, the sensory fibres follow the sympathetic fibres, so pain in the ureters is felt over T12 and L1.

Describe histology (microscopic anatomy) of the renal cortex and medulla including the renal corpuscle, proximal convoluted tubule, Loop of Henle, distal convoluted tubules, and juxtaglomerular apparatus and collecting tubules.

The outer region of the kidney is called the cortex, and is where the renal corpuscles and convoluted tubules are located. (Don't worry, I'll describe what they are and what they do in a bit.) The area deep to the cortex is the medulla, and contains the Loops of Henle and collecting tubules. There is, however, a bit of overlap between these two areas: the columns of the renal medulla contain the structures of the renal cortex, and the medullary rays of the cortex contain structures of the renal medulla.

Renal corpuscle

The renal corpuscle is made out of the glomerulus (a "knot" made out of arteries) and Bowman's space (the first part of the tubular system where urine is formed). Under the microscope, renal corpuscles basically look like a cluster of cells surrounded by a white ring (the Bowman's capsule). The renal corpuscle is the main site where filtration occurs (i.e. the blood gets filtered so that pretty much everything, except for large proteins, is pushed into the Bowman's capsule and the tubular system).

Proximal convoluted tubule

The proximal convoluted tubule is the first lot of tubules. The reabsorption of pretty much all glucose and amino acids occurs here, along with reabsorption of many other substances. Proximal convoluted cells are tall, columnar, and have a brush border to increase their surface area for reabsorption. Since the Na+/K+ pump is critically important for maintaining concentration gradients for reabsorption, proximal convoluted tubule cells have plenty of mitochondria to keep them topped up and ready to go.

Loop of Henle

The loops of Henle have two parts: a thin descending limb and a thick descending limb. The thin descending limb is more permeable to water than salt, whereas the ascending limb is impermeable to water but permeable to salt. The appearance of the Loops of Henle depends on whether you have a cross-section or a longitudinal section of the loop: cross-sections look like little circles, whereas the longitudinal sections look like long white stripes that are lined by cells. (I think. Histology isn't my strong point.)

Distal convoluted tubules and collecting duct

The distal convoluted tubule and collecting duct cells are similar to those of the proximal convoluted tubule, except that cells in the distal convoluted tubule and collecting duct tend to be cuboidal and less metabolically active than those in the proximal convoluted tubule. Both the distal convoluted tubule and the collecting duct are under hormonal control to change the amount of salts and/or water reabsorbed.

Another point of interest is the juxtaglomerular apparatus. The juxtaglomerular apparatus of the distal tubule interacts with the afferent arteriole by secreting hormones etc. to maintain filtration rate (see here).

Describe the histology of the ureter.

Ureters, like many other bodily tubes, have a mucosa, muscularis layers, and an adventitia. (However, unlike many other bodily tubes, they likely do not have a submucosa.) There are two muscularis layers: one is circular, and one is longitudinal. Together, the muscularis layers work to propel urine towards the bladder.

Describe the anatomy of the urinary bladder, its base and ureteric openings and its relationship to the overlying peritoneum.

The bladder is shaped kind of like an upside-down triangular pyramid. The urethra connects to the bladder at the inferior "point." The umbilical ligament, which is a remnant of an embryonic structure called the urachus, joins at the apex, which is the anterior superior "point." The ureters join at the posterolateral points and continue to pass through the wall of the bladder.

One point of interest is the bladder trigone, which is formed from the intermediate mesoderm of the urogenital septum. This is in contrast to the rest of the bladder, which is formed from the anterior part of an embryonic structure called the cloaca. The bladder trigone makes up part of the posterior wall of the bladder. The ureters open into the bladder at the upper lateral corners of the bladder trigone.

Describe the blood supply and innervation of the urinary bladder.

The bladder receives its blood supply from the superior and inferior vesical arteries. The superior vesical artery comes from the patent part of the umbilical artery, which in turn comes from the anterior division of the internal iliac artery. The inferior vesical artery comes directly from the internal iliac artery.

Like the ureters, the bladder receives sympathetic stimulation from T12 and L1. However, its parasympathetic innervation is only from the hypogastric plexus (S234). Both sympathetic and parasympathetic nerves activate muscles, but they activate different muscles: sympathetic stimulation causes the external urethral sphincter to tighten (and stop you from peeing), while parasympathetic stimulation causes the detrusor muscle (i.e. the bladder muscle) to contract, thus making you pee. Sensory information is a bit mixed: pain fibres follow the sympathetic nerves back to T12 and L1, whereas stretch fibres follow the parasympathetic nerves back to S234.

An important reflex to discuss here is the micturition reflex. When the bladder wall is stretched, this information is conveyed back to S234, triggering reflex contraction of the detrusor muscle. When this happens, we feel the urge to pee. However, we can override this reflex through various centres in our brain and through contracting the external urethral sphincter.

Discuss the anatomical reasoning behind differences in referred pain from upper and lower urinary tract infections.

As mentioned, different parts of the urinary tract convey sensory fibres to different parts of the spinal cord. In the kidney, sensory fibres go back to T10/T11, in the ureter they go back to T12/L1, and in the bladder the fibres detecting pain (not stretch) go back to T12/L1. When we feel pain in the urinary tract, we tend to feel it over the dermatomes associated with those sensory nerves: e.g. pain in the kidney is felt over the T10/T11 dermatomes. (However, to my understanding, bladder stones might be felt lower down, like in the S1/S2 dermatomes.)

Describe the anatomy of the urethra; explain the anatomy of its different parts in males and females in relation to continence and catheterisation.

The male urethra is quite long and is divided into three parts (prostatic, intermediate / membranous, and spongy), whereas the female urethra is relatively short and isn't divided into parts. (Some textbooks may consider the pre-prostatic, or intramural, part of the urethra to be a fourth part of the urethra.) Because the female urethra is much shorter, it is easier to catheterise than the male urethra. However, the female urethra is more prone to urinary tract infections than the male urethra. Furthermore, women are more prone to incontinence (though this is also partly because they do crazy stuff like give birth).

An important structure within the male urethra is the verumontanum, also known as the seminal colliculus. The verumontanum is a thickening within the prostatic urethra. It has three orifices: one called the prostatic utricle, and two for the openings of the ejaculatory ducts. The verumontanum is an important marker to look for when removing the prostate via the urethra.

Describe the skeletal and ligamentous components of the pelvis.
Discuss the sexual differences in pelvic skeletal anatomy.
Describe the anatomy and functional importance of the pelvic diaphragm.
Describe the topographical arrangement of anatomical structures within the pelvis.

The pelvis wasn't exactly covered in any of the lectures that we just had (despite pelvic stuff being in the learning outcomes), so I guess it's 2nd year undergrad me to the rescue!

• Pelvis part 1
• Pelvis part 2

Tumours of the Bladder and Kidneys

List the major types of neoplasms of the kidney

Kidney tumours can be either benign (e.g. renal papillary adenoma) or malignant (e.g. renal cell carcinoma). In this post, I'll only be covering renal cell carcinoma because it was the only one talked about in depth in the lectures (probably because it's by far and away the most common). Clear cell renal cell carcinomas are the most common type of renal cell carcinomas.

Outline the aetiology, risk factors for development and pathogenesis of kidney neoplasms

Risk factors of renal cell carcinoma are pretty much the same as risk factors for many other illnesses: smoking, hypertension, obesity, genetic factors, and exposure to certain toxic chemicals. It is most commonly seen in men aged 50-70.

One genetic cause of renal cell carcinoma is Von Hippel-Lindau disease, which is a genetic disorder in which the VHL tumour suppressor gene on chromosome 3 is mutated. There are also sporadic forms of the disease in which one of the VHL genes has been lost (due to some kind of deletion of the short arm of chromosome 3), and then the other gene becomes mutated. Inactivation of VHL results in an increase in IGF-1, which is a growth factor that can upregulate hypoxia-inducible factors and ultimately vascular endothelial growth factor (VEGF).

List, in brief, the morphological and histological features of kidney neoplasms

Renal cell carcinoma arises from the epithelial cells of the proximal convoluted tubule. The cells look clear under the microscope and yellow macroscopically (i.e. to the naked eye), as the cells are filled with carbohydrates and lipids.

Outline the clinical presentations of kidney neoplasms

Renal cell carcinoma is usually pretty silent and is often simply picked up when patients are scanned for some other reason. Alternatively, patients might not get noticed at all until their disease has become severe. In patients who do show symptoms, the classic signs include haematuria, abdominal mass, and flank pain, though there may also be other symptoms. For instance, if the carcinoma spreads into the inferior vena cava and obstructs the left gonadal vein, it can result in scrotal varices. There may also be paraneoplastic syndromes from inappropriate secretion of hormones: hypercalcaemia from parathyroid hormone-related protein (PTHrP), erythrocytosis from EPO, hypertension from renin, and even Cushing's syndrome from ectopic ACTH.

Renal cell carcinoma is relatively resistant to traditional chemotherapy and radiotherapy, so surgery is often used as treatment. Immunomodulatory and anti-VEGF treatments may also be tried.

Provide an overview of staging of kidney neoplasms

Staging of renal cell carcinoma is generally done using the TNM system. The T stands for "tumour" and refers to a tumour that has not spread beyond the original site. The N stands for "nodes" and refers to a tumour that has spread to lymph nodes. Finally, the M stands for "metastatic" and refers to a tumour that has spread around the body.

List the major types of lower urinary tract neoplastic disease

The main types of bladder tumours are urothelial carcinoma (a.k.a. transitional cell carcinoma) and squamous cell carcinoma. Urothelial carcinoma is by far the most common in Australia, though squamous cell carcinoma is more common in areas where schistosomiasis (a parasite disease) is endemic.

Outline the aetiology, risk factors for development and pathogenesis of lower urinary tract neoplastic disease
List, in brief, the morphological and histological features of lower urinary tract neoplastic disease

Smoking and certain carcinogenic substances are the main risk factors for bladder cancers. They are most commonly seen in older men.

Urothelial carcinoma may have one of two types of precursor lesions: flat or papillary. Flat precursor lesions include urothelial carcinoma in situ, whereas papillary precursor lesions include papillary urothelial carcinoma. The flat precursors are more often seen in p53-dependent tumours, which tend to be more aggressive than p53-independent tumours, which often have papillary precursors. (p53 is a tumour suppressor gene that is important in the development of many cancers.)

Urothelial carcinoma is multifocal (meaning it can affect multiple sites) and recurrent (meaning that it comes back). There are two main theories as to why this is so: field effect theory and implantation theory. The field effect theory states that whatever caused the first cancer might have affected nearby sites, whereas the implantation theory states that cells from the first tumour could have broken off and implanted somewhere else. In reality, it could be a mixture of the two.

Treatment of urothelial carcinoma is basically a mix of surgery, radiation, and/or chemotherapy, depending on the situation.

Outline the clinical presentations of lower urinary tract neoplastic disease

Bladder cancer often presents with painless haematuria. Remember: painless haematuria is malignancy unless proven otherwise.

Provide an overview of staging of lower urinary tract neoplastic disease

Just like renal cell carcinoma, urothelial carcinoma also uses TNM staging. The T stage can be further divided up depending on where the tumour is. At the T1 stage, the tumour is in the lamina propria. T2 means that the tumour is in the muscularis propria, T3 in the perivesical fat, and T4 in adjacent organs. N refers to invasion of nodes, whereas M refers to metastasis.

Urinary tract congnital anomalies, cystic disease, urolithiasis, and obstructive disease

List the major types of congenital malformations affecting the kidney
Describe the anatomical and renal functional defects of the major types of congenital malformations affecting the kidney

The major types of congenital malformations affecting the kidney are agenesis of the kidney, kidney hypoplasia, ectopic kidneys, and horseshoe kidneys.

Agenesis

Agenesis involves the absence of one or both kidneys. Bilateral renal agenesis, also known as Potter's syndrome, is incompatible with life, as not only does it result in oligohydramnios (decreased urine output), it also results in hypoplastic lungs (small lungs that haven't formed properly). Fetuses with Potter's disease tend to have very "squashed" faces. Unilateral agenesis, on the other hand, is usually asymptomatic, partly because the remaining kidney may undergo compensatory hypertrophy. Patients with unilateral renal agenesis may also be other abnormalities of the genitourinary tract.

Hypoplasia

Hypoplastic kidneys have developed normally, but are small. Usually only one kidney is affected.

Ectopic kidneys

Ectopic kidneys are kidneys that aren't where they're supposed to be (between around T12 and L3). Usually ectopic kidneys are found in the pelvis due to failure to ascend, but rarely you might get a kidney that has managed to ascend all the way into the thorax. Most ectopic kidneys are either normal sized or slightly smaller.

Horseshoe kidneys

Horseshoe kidneys are formed from fusion of the upper or lower poles of the kidneys. They are usually located quite low down as their ascension is obstructed by the inferior mesenteric artery. Usually horseshoe kidneys have numerous renal arteries supplying them.

Outline the major types of cystic disease of the kidney in terms of aetiology, pathogenesis, clinical features and complications

Cystic diseases are, well, diseases in which there are cysts. There are a range of cystic kidney diseases, but in this post we will only focus on some of the main ones.

Simple renal cysts

Simple, or localised, renal cysts are incredibly common, especially in patients over the age of 50. However, simple cysts are usually asymptomatic. There is a risk of rupture, causing haematuria, pain, and so on, but usually the biggest problem with simple renal cysts is that a malignant tumour might be mistaken as a simple renal cyst. There are some clues, however, that might help in differentiating a malignancy from a simple cyst: multiple septa, thickened cyst walls, and solid areas within or around cysts are all clues to malignancy.

Cystic renal dysplasia

Cystic renal dysplasia is malformation of the kidney (or kidneys- it can be either unilateral or bilateral) with cysts of various sizes. It is a common cause of abdominal mass in infants. Under the microscope, kidneys look abnormal and have many immature structures.

Polycystic kidney disease

Polycystic kidney disease is characterised by fluid-filled cysts in the kidney. It comes in two flavours: autosomal dominant (ADPKD) and autosomal recessive (ARPKD).

ADPKD is the most common type of polycystic kidney disease. The three main genes identified are PKD-1, PKD-2, and PKD-3. Cyst formation begins in utero but progresses very slowly, so patients usually don't present until they are in their 30s or even in their 50s. Due to the formation of cysts, the kidneys can become quite large and the cysts can compress surrounding renal tissue. The resulting damage can cause symptoms such as pain and haematuria.

ARPKD is rare and involves the PKHD1 gene. The kidneys appear smooth and have small cysts. ARPKD, unlike ADPKD, presents quite early on (in childhood or even in infancy).

Classify the different forms of urinary tract obstruction according to aetiology, pathogenesis, morphology, clinical features and complications.
Explain how urinary tract obstruction can lead to kidney injury

Obstructive uropathy is a fancy term that refers to obstruction anywhere in the urinary tract. There are many causes of obstructive uropathy, but they tend to lead to dilation of the renal pelvis and calyces and eventual enlargement of the kidney. The bladder may also have a thick wall. Hydronephrosis may occur as a result of obstructive uropathy. In hydronephrosis, the urine backs up, causing distension and dilation of the renal pelvis and calyces. Eventually, this can lead to atrophy of the kidney, because while kidneys can dish out urine like it's nobody's business, they can't take it.

Urolithiasis, or kidney stones, is a common cause of obstructive uropathy. There are many types of kidney stones, all formed by various solutes precipitating out of solution. Dehydration, hypercalciuria, and several other conditions can all conspire to increase the risk of kidney stones. Certain bacteria (Proteus and Klebsiella) may even be responsible for stones that are made out of struvite (magnesium ammonium phosphate). Such stones are quite large and are sometimes known as "staghorn calculi" because they are shaped somewhat like the horns of a stag.

Kidney stones might be painless if they are small, but if they are larger, they can cause pain and other symptoms related to obstructive uropathy. If they cause damage, they may also result in haematuria and/or infection. If the kidney stones are large, one type of pain that might be experienced is "renal colic," which is an excruciating pain that radiates from the flank to the groin. Renal colic might also be accompanied with other symptoms, from haematuria to vomiting. I have discussed treatment of kidney stones here.

Vascular and Tubulointerstitial Diseases of the Kidney

This lecture actually did have some more learning outcomes, but I think I might actually just stick to using the diseases as headings.

Vascular Diseases

Vascular diseases of the kidney, as the name implies, are diseases that affect the vasculature of the kidney.

Hypertensive nephrosclerosis

Hypertensive nephrosclerosis is scarring (sclerosis) of the kidney (nephro-) due to hypertension. Hypertensive nephrosclerosis can be either benign or malignant. Benign nephrosclerosis is due to chronic hypertension, defined as a blood pressure greater than 140/90, whereas malignant nephrosclerosis is due to accelerated hypertension (i.e. a rapid spike in blood pressure) or malignant hypertension, defined as a blood pressure greater than 180/110 with acute end-organ damage.

Benign hypertensive nephrosclerosis is the third most common cause of chronic renal failure. Over time, the small arteries and arterioles become thickened and there is damage to the glomeruli and tubules. Benign hypertensive nephrosclerosis may be asymptomatic with proteinuria, but over time it may progress to chronic renal failure. Malignant hypertensive nephrosclerosis is a medical emergency in which the damage is quite severe, and may present as acute renal failure. Under the microscope, there is fibrinoid necrosis of arterioles and hyperplastic arteriolosclerosis.

Renal artery stenosis

Renal artery stenosis is narrowing (stenosis) of the renal artery, which can lead to secondary hypertension. (As you can see, there can be a bit of interplay between the kidneys and hypertension: renal artery stenosis can lead to hypertension, which can lead to hypertensive nephrosclerosis.) Renal artery stenosis is usually due to atherosclerosis in elderly patients, but it can also be due to fibromuscular dysplasia in young women. (Fibromuscular dysplasia involves segmental thickening of arteries, which looks kind of like a string of beads on angiography. So far, the cause of this is unknown.)

One of the problems with renal artery stenosis is that it decreases blood flow to the kidneys, activating the RAAS, which increases vasoconstriction. The vasoconstriction triggered by the RAAS exacerbates the problem, forming a vicious cycle.

Tubulointerstitial Diseases

Tubulointerstitial diseases are diseases that affect the tubules and the interstitium of the kidney. (I love it when names are logical!)

Acute tubular necrosis

Acute tubular necrosis is one of the most common causes of renal failure. Acute tubular necrosis is necrosis of the kidney tubules (again, I'm loving these logical names), which may be due to ischaemia or toxins. There are three main phases of acute tubular necrosis: initiation, maintenance, and recovery. In the initiation phase, there is mild oliguria and a mild increase in serum creatinine. In the maintenance phase, oliguria and the increase in serum creatinine continue. There may also be uraemia. Finally, in the recovery phase, there is a large amount of diuresis (peeing). Because you're losing a lot of fluid pretty rapidly, you're also losing a lot of electrolytes at the same time, which can pose other problems.

Tubulointerstitial nephritis

Tubulointerstitial nephritis is inflammation of the tubules of the kidney. Tubulointerstitial nephritis may be either acute or chronic, with the chronic form being irreversible. There are many causes of tubulointerstitial nephritis but the main one to be aware of is drugs, particularly NSAIDs, proton pump inhibitors, and antibiotics. Unfortunately, drug-related tubulointerstitial nephritis is somewhat hard to predict: we don't really know who will get it and at what dose. It is thought that drugs act as a hapten in order to trigger an immune response (see here for information on what a hapten is).

It is important to distinguish between acute tubulointerstitial nephritis and acute pyelonephritis, as the two conditions may present similarly. (Apparently we will be learning about acute pyelonephritis next week, so stay tuned!) While acute tubulointerstitial nephritis is often drug-related and can be treated by simply removing the drug (and perhaps also giving some steroids), acute pyelonephritis is usually due to an ascending UTI that can be treated with antibiotics.

Chronic pyelonephritis

Chronic pyelonephritis is chronic inflammation of the kidney. It is usually due to either reflex nephropathy (reflux of urine back into the kidney) or obstructive nephropathy (some obstruction to urinary outflow). The kidney surface can have very deep, irregular scars, and under the microscope the inflammation can be so severe that the tubules look almost like the follicles of the thyroid gland. (This is also known as "tubular thyroidisation.")

Myeloma kidney

Myeloma kidney is a result of plasma cell myeloma (a.k.a. multiple myeloma). As the name suggests, plasma cell myeloma is a malignant proliferation of plasma cells (i.e. antibody-producing B cells). Plasma cell myelomas secrete large amounts of the same antibody, and sometimes these antibodies might be abnormal. For instance, the antibodies that are secreted might only consist of light chains. There are a range of complications that can result from myeloma kidney, but for now we'll only focus on two: myeloma cast nephropathy and amyloidosis.

Myeloma cast nephropathy occurs when abnormal light chains precipitate out of solution, forming casts. These casts can clog up the tubules, resulting in acute renal failure. Under immunofluorescence, these light chains will consist of only kappa chains or only lambda light chains (remember, in myeloma, large amounts of the same antibody are being made).

Amyloidosis is characterised by a build-up of amyloid, which consists of abnormally-folded extracellular proteins that resist degradation. Amyloid can be visualised with the Congo red stain. Under the Congo red stain, they stain salmon-pink, and if seen under polarised light while stained, they appear apple-green. In myeloma kidney, amyloidosis occurs due to the light chains in myeloma, and thus this type of amyloid is called AL-amyloid. Amyloid can deposit in a range of places in the kidney, causing a lot of problems.

Glomerulonephritis

Yes, I'm skipping ahead to another pathology lecture. Yes, I know that I've written more about pathology than about any other field this year. Unfortunately, pathology is the area that I've been struggling with the most, so it's the area I'm writing about the most, and unless anyone comments asking for me to cover a different topic, I'm just going to keep ploughing ahead.

This lecture was long, but it only had one learning outcome: "Classify glomerulonephritis with reference to aetiology, pathogenesis, clinical presentation, key morphological findings and natural history." I will be using my own headings for this post instead.

Clinical Presentations of Renal Disease

There are four (or five, depending on how you count them) main presentations of renal disease: acute renal failure, chronic renal failure, nephritic syndrome, and nephrotic syndrome. There is also rapidly-progressing glomerulonephritis, which is a subset of nephritic syndrome. Renal diseases are very common: around 40% of adults over 75 will have indicators of chronic kidney disease, and this number is even higher in Indigenous populations.

Acute renal failure

Acute renal failure is characterised by azotaemia, which is a rapid rise in serum urea and/or creatinine (a marker of renal function). There may also be uraemia, which is essentially just symptomatic azotaemia (symptoms include lethargy, decreased appetite, shortness of breath, peripheral neuropathy, and oedema). Other symptoms include oliguria (reduced urine output), or maybe even anuria (no urine output). Symptoms arise over days to weeks and may completely resolve (though there is a chance of progressing to chronic renal failure).

Causes of renal failure can be classified into three categories: pre-renal, renal, and post-renal. Pre-renal causes encompass basically anything that affects the blood supply to the kidneys. Renal failure encompasses intrinsic kidney diseases, and post-renal causes encompass anything that affects urine outflow.

Chronic renal failure

Chronic renal failure is basically the same as acute renal failure, but it is over a longer period of time (months to years). Furthermore, chronic renal failure is irreversible and will eventually progress to end-stage renal failure, defined as a glomerular filtration rate of less than 5% of normal. Treatment of chronic renal failure aims to delay progression.

Nephritic syndrome

Nephritic syndrome is a set of symptoms that includes azotaemia/uraemia, oliguria, macroscopic haematuria (blood in the urine that you can see), mild/moderate proteinuria, and hypertension. It is usually caused by glomerulonephritis (disease that affects the glomerulus). Rapidly-progressive glomerulonephritis (RPGN) is a subset of nephritic syndrome in which the rise in serum urea and creatinine is very rapid. RPGN is usually due to a subset of glomerulonephritis called crescentic glomerulonephritis.

Nephrotic syndrome

Nephrotic syndrome is a set of symptoms that includes proteinuria (>3.5g/24h), hypoalbuminaemia, peripheral oedema, hyperlipidaemia, and lipiduria. Nephrotic syndrome, like nephritic syndrome, is usually due to glomerulonephritis. If glomerulonephritis increases the permeability of glomerular capillaries, proteins can leak out into the urine, resulting in proteinuria. Since protein is leaving the body through the urine, there is low protein in the serum, leading to hypoalbuminaemia and a reduced serum oncotic pressure, which in turn can lead to peripheral oedema. At the same time, there is increased hepatic lipid synthesis, leading to hyperlipidaemia and eventually lipiduria.

Glomerulonephritis

I've mentioned glomerulonephritis before, but what is it exactly? Well, glomerulonephritis refers to a range of diseases that affect the glomeruli of the kidneys. Most of these diseases are mediated by the formation of immune complexes or structural issues. Diagnostic tools for glomerulonephritis include light microscopy, immunofluorescence, and electron microscopy. Glomerulonephritis can be iether primary or secondary: primary glomerulonephritis has no identifiable cause, whereas secondary glomerulonephritis is due to a recognisable cause (e.g. drugs, infections, etc.).

Glomerulonephritis can present in different ways, depending on the specific disease. Some types of glomerulonephritis have a presentation resembling nephrotic syndrome, whereas others have a presentation resembling nephritic syndrome. In this post, I'll be starting with the most "nephrotic" types of glomerulonephritis and working my way towards the most "nephritic" types of glomerulonephritis.

Minimal change disease

Minimal change disease is a type of glomerulonephritis that mainly affects children and presents with nephrotic syndrome. It is a disease mediated by structural changes, in particular of the podocytes surrounding glomerular capillaries. As you can guess by the name, there are minimal changes in the diagnostic tests. Light microscopy and immunofluorescence both look normal: you have to use electron microscopy to see the difference. Normal podocytes have "slit diaphragms" between the foot processes, and these "slit diaphragms" have the negative charge that repels proteins and stops them from getting into the urine. In minimal change disease, foot processes are effaced and fused together, meaning that the slit diaphragms and the repulsive negative charge are lost, allowing proteins to leak into the urine, resulting in nephrotic syndrome.

Prognosis of minimal change disease is very good in children, as it responds well to steroids in this population. The response in adults, however, is less predictable.

Membranous nephropathy

Membranous nephropathy mainly affects adults and results in nephrotic syndrome. It is mediated by immune complexes that deposit in the subepithelial space (i.e. under the podocytes but outside the basement membrane... I think). Basement membrane "spikes" (thickening of the basement membrane) appear between the deposits of immune complexes. Immunofluorescence shows granular IgG and C3.

Unlike with other forms of glomerulonephritis, primary membranous nephropathy now has an identifiable cause. Primary membranous nephropathy is due to autoantibodies to the podocyte phospholipase A2 receptor. Secondary membranous nephropathy can be all the usual suspects: drugs, infections, autoimmune diseases, etc.

Prognosis of membranous nephropathy is quite variable. 40% of patients will go into pontaneous remission. However, 40% of patients will progress to chronic renal failure. The remaining 20% of patients will have stable disease.

Focal segmental glomerulosclerosis (FSGS)

Focal segmental glomerulosclerosis (FSGS) is focal, meaning that less than 50% of all glomeruli are affected, and segmental, meaning that less than 50% of an individual glomerulus is affected. (Just for comparison: diffuse means that more than 50% of all glomeruli are affected, whereas global means that more than 50% of individual glomeruli are affected). FSGS is the most common cause of nephrotic syndrome in adults and is due to structural abnormalities in the podocytes.

As the "sclerosis" part of the name suggests, there is scarring involved in FSGS. Scarring can be seen under both light and electron microscopy. FSGS is not immune-mediated, but due to scarring, larger antibodies such as IgM may be trapped and can be identified under immunofluorescence. Sometimes, complement molecules such as C3 may be also be activated by the trapping of IgM.

Prognosis of FSGS is not the worst, but it's not the best either. Around 30% of patients respond to steroids, but the rest progress to chronic renal failure.

IgA nephropathy (a.k.a. Berger's disease)

IgA nephropathy is the most common cause of glomerulonephritis worldwide and usually affects young adults. It is immune-complex mediated and presents with nephritic syndrome (note: this is the first type of glomerulonephritis I've spoken about so far that presents with nephritic, rather than nephrotic, syndrome). Under light microscopy, there is mesangial matrix expansion and hypercellularity, and under electron microscopy, the immune-complexes can be seen. Immunofluorescence reveals granular IgA (hence why this disease is called IgA nephropathy).

Prognosis of IgA nephropathy follows the "Rule of Thirds": around 1/3 resolve spontaneously, 1/3 have stable disease, and 1/3 progress to FSGS and/or chronic renal failure.

Post-infectious glomerulonephritis (a.k.a. acute proliferative glomerulonephritis or post-streptococcal glomerulonephritis)

Post-infectious glomerulonephritis usually affects children around 1-4 weeks after a bout of cellulitis or pharyngitis. It is immune-complex mediated and is often a response to streptococcal pyrogenic exotoxin B, which is why this disease is sometimes called post-streptococcal glomerulonephritis. (Note, however, that Streptococcus species are not the only species that can cause this disease.) Post-infectious glomerulonephritis presents with nephritic syndrome. Microscopy reveals inflammation and immune-complex deposits, whereas immunofluorescence reveals granular IgG and C3.

There is no such thing as primary post-infectious glomerulonephritis: it is always secondary to infection (hence the "post-infectious" in the name). As mentioned before, it is usually due to Streptococcus, but not always. Prognosis is very good in children, with nearly all children recovering with only conservative treatment. However, prognosis is not so good in adults: around 40% of adults with post-infectious glomerulonephritis progress to chronic renal failure.

Crescentic glomerulonephritis

As mentioned earlier, crescentic glomerulonephritis is a subset of glomerulonephritis that can present with rapidly progressive glomerulonephritis (a subset of nephritic syndrome). Crescentic glomerulonephritis is not a diagnosis- it is simply a histological pattern with an underlying cause that needs to be identified.

The "crescents" in crescentic glomerulonephritis are formed by a proliferation of parietal epithelial cells, which are epithelial cells lining Bowman's capsule. The crescents can fill up Bowman's space and block it, leading to chronic renal failure within weeks to months. There are three main categories of crescentic glomerulonephritis. Type I crescentic glomerulonephritis is characterised by anti-glomerular basement membrane (anti-GBM) autoantibodies, type II is immune complex mediated, and type III is "pauci-immune" (which I think means that there is minimal evidence of hypersensitivity).

Type I crescentic glomerulonephritis

Type I crescentic glomerulonephritis, or anti-GBM disease, involves autoantibodies against the α3 chain of the Type IV collagen in the glomerular basement membrane. These autoantibodies may cross-react with the basement membranes of other tissues, notably in the lung, resulting in a syndrome called pulmonary-renal syndrome. Pulmonary-renal syndrome is also known as Goodpasture syndrome.

Type II crescentic glomerulonephritis

Type II crescentic glomerulonephritis is immune-complex mediated and includes several types of glomerulonephritis that I've already written about above, including post-infectious glomerulonephritis and IgA nephropathy.

Type III crescentic glomerulonephritis

Type III crescentic glomerulonephritis, or pauci-immune glomerulonephritis, involves an antibody called ANCA. ANCA stands for anti-neutrophil cytoplasmic antibody, and as the name suggests, it acts against cytoplasmic enzymes in neutrophils. Type III crescentic glomerulonephritis is associated with small-vessel vasculitis, including Wegener's granulomatosis (a.k.a. granulomatosis with polyangiitis, or GPA), and Churg-Strauss syndrome (a.k.a. eosinophilic granulomatosis with polyangiitis, or EGPA). GPA involves necrotising granulomatous inflammation of the respiratory tract and kidney. EGPA is similar, but there may also be asthma and eosinophil-rich granulomas.

Cardiovascular Anatomy 1 and 2

A lot of the content in this lecture was basic stuff I've covered many times before. Half the reason I'm writing this post is because I want to productively procrastinate over having to write anything more difficult. Yay.

Identify the major anatomical features of each chamber of the heart and explain their functional significance.
Describe the position of the atrioventricular, pulmonary and aortic valves and describe their function in the prevention of reflux of blood during the cardiac cycle.
Describe the origin, course and main branches of the left and right coronary arteries and discuss the functional consequences of their obstruction in conditions such as ischaemic heart disease.

• Heart and Mediastinum
• Coronary Artery Disease

Outline the embryological development of the heart.

(NOTE: I don't think this was actually covered in the lecture, so this post is going to have wayyyyyyyy more detail than you actually need for this course.)

• Development of the Heart

List cardiac structures that are susceptible to congenital defects.

I'm not sure if this was even covered in lecture either, but this post has a bit about congenital defects:

• Dysrhythmias and Congenital Heart Defects

Describe the differences between foetal and neonatal circulation.

• Development of the Heart

Describe the histology of the heart wall and myocardium.

• Muscles I and II (tl;dr cardiac muscle is stripy and branched- I think that's literally all we need to know for this lecture)
• Tubes (relevant for blood vessels)

Lipid-lowering therapies

This post is one of my first in a while to not be about pathology! This one is about pharmacology instead :)

Know basic principles of lipid metabolism and how this can lead to biochemical derangement and disease

• Lipid and Lipoproteins: Structure, Function, and Metabolism

Understand the relationship between cholesterol level and cardiovascular disease risk

Pretty much the main takeaway from this lecture is that levels of LDL cholesterol is positively associated with increased cardiovascular disease risk. Therefore, it is important to try and manage cholesterol levels so that levels of "good" cholesterol (HDL) prevail over levels of all the "bad" cholesterol (pretty much all of the other types of cholesterol).

Understand the options of drug and non-drug treatments for hyperlipidaemia

Drug treatments

There are various drugs that can lower lipid levels. I will discuss this a bit further down in this post.

Non-drug treatments

There are several non-drug lifestyle treatments that can help with hyperlipidaemia. In short: cessation of smoking, exercise, and a healthy diet are all factors that can help in treating hyperlipidaemia. The Mediterranean diet (see here) is generally considered to be one of the best for overall cardiovascular health. For patients who specifically need to lower cholesterol, a low saturated fat diet may be helpful, and for patients who specifically need to lower triglycerides, simply losing weight may be helpful. (However, please note that I am not a dietician, so do take my words with a pinch of salt ;) )

Know the main classes of lipid lowering drugs

Statins

Statins are the first-line therapy for lowering LDL and reducing the risk of cardiovascular disease. They decrease the synthesis of cholesterol by inhibiting the enzyme HMG-CoA reductase. They can also increase SREBPs (transcription factors that regulate LDL receptors), increasing LDL receptor production, which in turn increases removal of cholesterol from the blood. Common side effects of statins include an increase in diabetes risk and some hepatic side effects (0.5-3% of patients have an increase in an enzyme called transaminase, which to my understanding is a marker of liver damage). Myositis is another side-effect of statins. There has also been concern about memory loss associated with statin use, but only 60 cases of this have been reported since 1997.

Another important thing to know about statins is that while a small dose of statins can reduce LDL levels by a decent amount, increasing the dose has a much smaller effect. Therefore, in some cases, it might be better to add a second drug (e.g. ezetimibe, which I'll talk about next) rather than increase the dose of the statin.

Ezetimibe

Ezetimibe is the second-line therapy for lowering LDL and reducing cardiovascular disease risk. Ezetimibe inhibits NPC1L1 receptors on enterocytes, preventing uptake of cholesterol. It is generally well-tolerated but may have some side-effects such as diarrhoea and fatigue. It is sometimes used as a good alternative to statins in patients with myositis, or used in addition to statins to reach the target LDL level.

PCSK9 inhibitors

PCSK9 inhibitors are relatively new. PCSK9 can bind to LDL particles that have bound to LDL receptors, triggering breakdown of the receptor as well as the LDL. What this means is that the LDL receptor is not recycled and taken to the surface, meaning that the cell cannot remove as much LDL from the circulation. Patients with gain-of-function mutations in the PCSK9 gene may be at a greater risk of familial hypercholesterolaemia (high levels of cholesterol in the blood). Currently-approved PCSK9 inhibitors include alirocumab and evolocumab, which are antibodies against PCSK9. Since they are antibodies, they need to be given by injection every few weeks. Side effects from PCSK9 inhibitors appear to be relatively mild, such as nasopharyngitis and reactions at the injection site.

Mipomersen

Mipomersen is an antisense oligonucleotide against the mRNA of apoB. Therefore, it can stop production of apoB. However, it seems to have a high rate of injection site reactions (~90%) and may increase hepatic fat and transaminase levels.

Lomitapide

Lomitapide is an inhibitor of microsomal transfer protein (MTP) (an enzyme that packages cholesteryl ester and triglycerides together to form chylomicrons). Hence, lomitapide prevents the formation of lipoproteins that contain apoB. Unfortunately, it seems to have a high rate of GI side effects (~93%).

Fibrates

Fibrates activate PPARα, increase beta-oxidation of fatty acids, and down-regulates ApoCIII. As ApoCIII inhibits lipoprotein lipase (contrast with ApoCII which activates lipoprotein lipase), downregulation of ApoCIII allows lipoprotein lipase to become more active and break down lipoproteins.

n3 Polyunsaturated Fatty Acids

n3 polyunsaturated fatty acids (a.k.a. omega-3 fatty acids), such as those found in fish, may help to reduce cardiovascular disease. The actual mechanism is quite complex, but it may help reduce synthesis of lipoproteins. In particular, they seem to reduce levels of basically all non-HDL cholesterols, with the exception of LDL, which they increase.

Niacin

Niacin downregulates hepatic DGAT, reducing the synthesis of triglycerides. However, it has not been seen to improve outcomes in people with cardiovascular disease, and has very limited indications now.

GLP1
DPP-4 inhibitors

• Pathophysiology of Glucose Metabolism and its Treatment

While these drugs can be used to manage glucose levels, they are also being trialled to see if they will help with cardiovascular disease as they appear to also affect lipid levels.

Thiazolidinediones

Thiazolidinediones are PPARγ agonists that act on adipose tissue, muscle, and liver. They can stimulate uptake of lipids and reduce fatty acid supply to the liver and muscles. They can also increase glucose uptake and decrease glucose production, so they are often used to treat diabetes. (Cardiovascular disease outcomes, however, are still uncertain.)

Cardiomyopathy, myocarditis, and diseases of the pericardium

Aaaaaaand yes it's another pathology lecture! Believe it or not, we still have another sneaky cardiac pathology lecture coming up in the middle of the renal block for some reason...

Cardiomyopathy

Cardiomyopathy is defined as heart disease that results from an abnormality in the myocardium.

Classification

Cardiomyopathy, which is often diagnosed via biopsy, is usually classified into four broad categories: dilated, hypertrophic, restrictive, and arrhythmogenic. I will discuss them in more detail later.

Aetiology

Cardiomyopathy may be primary, meaning that it only affects the heart (often idiopathic or due to some genetic cause), or secondary, meaning that it is secondary to some other cause (such as a neuromuscular disease or connective tissue disorder).

Pathogenesis, morphological changes, clinical features, and clinical sequelae

Dilated cardiomyopathy is the most common type of cardiomyopathy, making up around 90% of cardiomyopathies. As you may guess from the name, in dilated cardiomyopathy, all of the chambers are dilated (the heart can be up to 3x the size of normal), resulting in progressive cardiac dilation and systolic dysfunction. Patients with dilated cardiomyopathy often present between 20-50 years of age with shortness of breath and fatigue. Roughly 20-50% of dilated cardiomyopathies are thought to be genetic.

Hypertrophic cardiomyopathy involves left ventricular hypertrophy without an obvious external cause. It is pretty much always due to an autosomal dominant mutation, often in the beta-myosin heavy chain. Since the left ventricle is hypertrophied, diastolic filling is impaired and there may be blocking of the outflow tract (which is why this type of cardiomyopathy is sometimes called HOCM- Hypertrophic Obstructive Cardiomyopathy). The septum is particularly thickened (this is in contrast to hypertensive heart disease, which has an evenly thickened wall), resulting in a ventricular lumen that looks like a banana. Under a microscope, the myocytes look bigger and the fibres are disorganised.

Restrictive cardiomyopathy involves a rigid left ventricular wall which results in impaired diastolic filling. It is often idiopathic but may be due to diseases that affect the myocardium. Up close, there may be patchy or diffuse fibrosis. The ventricles are usually normal size or slightly enlarged. Restrictive cardiomyopathy may be confused with other conditions in which there is fibrosis of the endocardium, such as endocardial fibroelastosis, endomyocardial fibrosis, and Loeffler's endomyocarditis.

Myocarditis

Myocarditis is inflammation of the myocardium.

Aetiology

Myocarditis may be due to infections or immune-mediated reactions. There are also other miscellaneous causes of myocarditis, such as radiation therapy. Myocarditis can even affect generally healthy people.

Clinical features and everything else

In the active phase of myocarditis, the heart may be either normal or dilated. As the disease advances, the ventricular myocardium may become flabby and mottled. Myocarditis may be patchy, i.e. not affecting everywhere in the heart, so biopsies may turn up with false negatives, which might be problematic as myocarditis can result in cardiac failure or even sudden death.

Pericarditis

Pericarditis is inflammation of the pericardium (outer covering of the heart).

Aetiology

Pericarditis may be due to infections, or due to a variety of non-infectious causes ranging from aortic dissection to uraemia (high levels of urea in the blood). There are also some autoimmune conditions that might result in pericarditis, such as rheumatic fever and rheumatoid arthritis.

Pathogenesis

One type of pericarditis is effusive pericarditis, in which there is effusion of fluid into the pericardium. The more rapid the effusion occurs, the worse the outcome. Slowly-accumulating effusions generally do not interfere greatly with heart function, but rapid accumulation of fluid may lead to a condition called cardiac tamponade, in which the fluid presses against the heart and restricts its filling, which may result in death from restrictive heart failure.

Classification etc.

Pericarditis can be classified according to the length of time that it lasts. Acute pericarditis lasts for less than 6 weeks, chronic pericarditis lasts for longer than 6 months, and subacute pericarditis is in between. Chronic pericarditis can be further divided into several subtypes. Adhesive pericarditis rarely interferes with cardiac function. Adhesive mediastinopericarditis, on the other hand, can cause issues as the heart is tethered to surrounding structures and it may pull on the structures that it is tethered to. In constrictive pericarditis, there is dense fibrosis and possibly calcification as well, reducing filling. Some of the pericardium may have to be removed in constrictive pericarditis.

Valvular Heart Disease

Yet another pathology lecture because, once again, that's the part I've been struggling with most. Do comment below if there's anything else you want me to cover though!

This post is all about valvular heart disease, which is about diseases that affect the heart valves (!). The heart valves have three main layers. The fibrosa, made up of a dense layer of collagen, is located close to the outflow surface. Below that is the spongiosa, which is made up of loose connective tissue. Finally, close to the inflow surface is an elastic layer called the atrialis (in the case of the mitral/tricuspid valves) or the ventricularis (in the case of the aortic/pulmonary valves).

Classification

Valvular heart disease can be classified as stenosis (in which the heart valves can't open properly) or stenosis (in which the heart valves can't close properly). It is possible to get stenosis and incompetence simultaneously- sometimes the changes that prevent a valve from closing fully also prevent the valve from opening fully. Sometimes valves can be affected by surrounding structures- for instance, abnormalities in supporting structures may lead to functional regurgitation (regurgitation due to an abnormality in a supporting structure rather than due to abnormality in the valve itself). Valvular heart disease can also be classified according to which valve is affected.

Aetiology and predisposing factors

Major aetiologies are slightly different between the types of valvular heart disease, but the common ones include post-inflammatory scarring from rheumatic heart disease, infectious endocarditis, and damage to supporting structures (e.g. rupture of papillary muscles can lead to mitral regurgitation). Rheumatic heart disease is common to pretty much all types of valvular heart disease and occurs as a result of previous damage to heart valves from rheumatic fever (see here for more information on rheumatic fever, as well as more information on infective endocarditis). I will discuss other common causes of particular types of valvular heart disease later.

Different causes of valvular heart disease may lead to growth of different kinds of vegetations on the cusps. Rheumatic fever may lead to small, warty vegetations. Infective endocarditis may lead to large, irregular masses that may extend onto the chordae tendinae. Nonbacterial thrombotic endocarditis may lead to small, bland vegetations. Libman-Sacks endocarditis, which is sometimes seen in systemic lupus erythematosus (see here), may lead to small- or medium-sized vegetations on either or both sides of the leaflets.

Pathogenesis and pathophysiology
Morphological changes, complications, clinical features and clinical sequelae of valvular heart disease

I'm going to break this up into types of valvular heart disease, because that might be easier.

Mitral stenosis

Mitral stenosis, which is more common in females and is usually caused by rheumatic fever, is where the mitral valve fails to open properly. It is associated with a rumbling diastolic murmur. Since blood fails to get through to the left ventricle, blood can back up into the pulmonary system, leading to haemoptysis (coughing up blood), pulmonary congestion, pulmonary hypertension, and right ventricular hypertrophy.

Mitral incompetence

Mitral incompetence, which is more common in males, is where the mitral valve fails to close properly. The main causes are myxoid degeneration ("floppy valve"), rheumatic fever, dilation of the valve ring, and damage to papillary muscles. It is associated with a mid-systolic click.

Another common cause of mitral incompetence is mitral valve prolapse, where the valves bulge back into the left atrium. The valves tend to be thickened with elongated, thinned, or ruptured chordae tendinae. Mitral valve prolapse is associated with a mid- or late systolic click.

Aortic stenosis

Aortic stenosis is where the aortic valve fails to open properly. It is usually caused by degenerative calcification of the valve, which in turn is more common in patients with a congenital bicuspid valve (an aortic valve in which two of the leaflets remain fused together so that the aortic valve has two cusps). It may also be a result of rheumatic heart disease. Aortic stenosis is associated with an ejection systolic murmur.

Aortic incompetence

Aortic incompetence is where the aortic valve fails to close properly. It is often caused by severe hypertension, rheumatic heart disease, dilation of the aortic root, or rheumatoid arthritis. Patients with aortic incompetence may have a wide pulse pressure. Aortic incompetence is associated with a mid-diastolic murmur with an opening snap as well as a third heart sound.

Clinical sequelae

Valvular heart disease might be treated using a prosthetic valve. Valves may be mechanical or tissue-based, and they can be implemented via TAVI (transcatheter aortic valve implantation- essentially where a catheter is used to insert the new valve). Unfortunately, serious complications are very common, with around 60% of recipients suffering from a serious complication within 10 years of implementation.

Bacteraemia, Septicaemia, and Endocarditis

I know I've been doing a lot of pathology, but it's the pathology lectures I've been struggling with most, so here we are. Of course, if there's anything that you want me to cover, let me know in the comments and I'll get to it when I have time (ha!). In the meantime, some of the other topics that we've covered this year (such as physiology and some of the micro stuff) are also covered in some of my earlier blog posts, so you can use the search bar to (hopefully) find what you need :)

Define sepsis and bacteraemia

Sepsis is when a dysregulated immune response to an infection (e.g. inability of the immune system to contain the infection) results in life-threatening organ dysfunction. Bacteraemia, on the other hand, is simply the presence of bacteria in the blood.

Understand the key clinical issues around sepsis and bacteraemia

Sepsis

Sepsis, as you are probably well aware, is not a good state to be in. Patients who are in sepsis may have rigors (extreme shivering), fever, delirium, dyspnea, and many other fun symptoms. Even after the illness is over, patients may be immunosuppresed for some time afterwards, increasing their susceptibility to other infections.

The severity of sepsis can be measured using assessment tools such as the qSOFA. The qSOFA simply looks at 3 different criteria: a systolic blood pressure lower than 100mmHg, an altered mental status, and a respiratory rate faster than 22 per minute. The more criteria a patient meets, the worse their outcome. The actual cause of infection can be detected in the usual ways (blood/urine culture, imaging, and so on).

To treat sepsis, you need to provide supportive care to the host (fluids, ventilation if required, etc.), and give antimicrobial therapy to treat the causative agent. Also, any infected catheters etc. should be removed.

To prevent sepsis, you basically just have to use the same infection control measures that you'd use for anything. This includes handwashing and being mindful of catheters and other devices that are being inserted into patients. Keeping up-to-date with immunisations helps too.

Bacteraemia

Bacteraemia can be classified according to how frequently and how persistent the bacteraemia is. If bacteraemia is only transient, like what happens when you brush your teeth, it is transient bacteraemia. If the bacteraemia repeatedly comes and goes for short bursts at a time, it is likely from a focus of infection, such as an abscess. If the bacteraemia persists for a while, the source of infection is likely in the bloodstream.

Bacteraemia can be tested for by using blood culture bottles (see here). When collecting specimens, care must be taken to avoid contamination of the sample. Blood is often taken from 2-3 sites to make it easier to tell what is a contaminant and what is the causative agent. After bacteria have been cultured, they can be identified. Since sepsis is pretty life-threatening, rapid methods such as MALDI-TOF (see here) are preferred.

Define endocarditis

Endocarditis is infection of the endocardial surfaces of the heart, such as the valves. It is mostly left-sided but can also be right-sided (IV drug users are most likely to have right-sided infectious endocarditis). Endocarditis can be classified into acute, subacute, and chronic endocarditis. Acute endocarditis can kill within 6 weeks, chronic endocarditis takes longer than 3 months to kill, and subacute is somewhere in between.

Understand and discuss the aetiology, pathogenesis and pathophysiology, clinical features and treatment principles for infective endocarditis

Aetiology

The main causative agents of acute endocarditis include S. aureus, S. pneumoniae, and N. gonorrhoeae. The main causative agents of chronic endocarditis include Viridians streptococci, the "HACEK" group of bacteria (Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, Kingella), and Enterococcus.

People who have some kind of heart disease or history of previous infectious endocarditis are most likely to get endocarditis.

Pathogenesis and Pathophysiology

Bacteria adhere to and colonise the endocardium, something something something. There's not very much in the lecture slides on this so I'm just going to leave it there and move on :)

Clinical Features

There are a range of complications associated with infective endocarditis. The complications that are most likely to lead to death are cardiac complications, which include valve destruction and abscesses. Emboli may also occur, as may metastatic abscesses and immunological complications such as deposition of immune complexes. There may also be sepsis.

Treatment Principles

To diagnose endocarditis, you can use bacterial cultures and echocardiogram. Imaging may also help to detect complications. Treatment is primarily through antibiotics and surgery. The exact antibiotic regimen depends on the causative agent, but usually around six weeks of intravenous antibiotics are required. Most surgery is valve replacement surgery.

As for prevention, it is common practice to give prophylaxis prior to dental procedures in patients considered to be at high risk of endocarditis. Prophylaxis generally takes the form of amoxycillin, but there are alternatives that can be used if the patient is allergic to penicillin.

Cardiovascular Tumours and Tumour-Like Lesions

Understand the basic terminology applying to benign and malignant tumours
Understand the principles of morphological tumour diagnosis, grading and staging

• Growth Disorders

Note that while neoplasm and tumour do have subtly different meanings (as described in the above post), many people use them interchangeably. I will try and stick to the definitions I gave in the above linked post.

Discuss the common neoplasms of the heart

Neoplasms in the heart are rare, and malignant neoplasms are even rarer. The most common heart neoplasm is a myxoma, which is a benign neoplasm. Myxomas are usually located in the atrium, particularly in the left atrium, near the fossa ovalis. They may be sessile, meaning that they basically look like a lump coming out of the wall of the heart, or they may be pedunculated, meaning that they are joined to the side of the wall via a stalk. Pedunculated myxomas look a little bit like a wrecking ball. Roughly 10% of people with myxomas have a genetic syndrome called Carney's complex.

Discuss the common neoplasms of the blood vessels

Neoplasms of the blood vessels are much more common than neoplasms of the heart. Most benign neoplasms are haemangiomas (from blood vessels), but there are also glomus tumours (from cells surrounding endothelial cells and lymphangiomas (from lymph vessels). Malignant neoplasms of blood vessels tend to be sarcomas, rather than carcinomas. In this post, I will discuss haemangiomas, Kaposi Sarcoma, and angiosarcoma.

Juvenile haemangiomas are haemangiomas acquired before or around the time of birth. Haemangiomas that are present at birth are called congenital haemangiomas and usually disappear over the first year of life. Haemangiomas that arise a few weeks after birth (usually due to changes induced by switching from prenatal to postnatal circulation) are called infantile haemangiomas. Infantile haemangiomas, which are usually found on the head and neck, tend to grow rapidly before fading and usually disappear by age 10.

There are three main types of acquired haemangiomas (i.e. haemangiomas acquired later in life). The three main types are capillary haemangiomas, cavernous haemangiomas, and lobular capillary haemangiomas (also known as pyogenic granulomas). Capillary haemangiomas, as the name suggests, primarily affect capillaries and are found in the skin and subcutaneous tissues. Cavernous haemangiomas primarily affect veins and can be large enough to compress surrounding structures. Lobular capillary haemangiomas are often found on the skin, gums, and oral mucosa. Also, despite the fact that lobular capillary haemangiomas are also called pyogenic granulomas, they do not form pus, nor do they form granulomas.

Kaposi Sarcoma is an intermediate-grade neoplasm, meaning that it is only locally aggressive and/or has a low risk of metastasis. There are four main forms of Kaposi Sarcoma: classic, endemic African, transplant-associated, and HIV-associated. All four forms are due to Human Herpes Virus 8 (HHV8) and progress from the patch stage through to the plaque stage and finally through to the nodule stage.

Angiosarcoma is a malignant neoplasm, meaning that it is locally aggressive and has a high risk of metastasis. They can occur nearly anywhere, but usually in the skin, soft tissue, breast, and liver. Liver angiosarcomas are often associated with environmental exposure to carcinogens, such as arsenic, and can take a long time to form. Angiosarcomas are quite aggressive and the five-year survival rate is fairly low, at only around 30%.

Discuss the common non-neoplastic tumour-like lesions and malformations of the CVS

There are many lesions that look like neoplasms but aren't, and since it's important to know what you're dealing with when patients present with something lumpy, I'll discuss them here.

Several vascular malformations can look like tumours. Tumour-like vascular malformations in slow-flowing vessels include naevus flammeus, also known as a "firemark" or "Port Wine stain," and congenital lymphangioma, which may be associated with chromosomal abnormalities. Tumour-like vascular malformations in fast-flowing blood vessels include cerebrovascular arteriovenous malformation.

Varicose veins are dilated and tortuous veins that have incompetent venous valves, resulting in pooling of blood and veins that stick out. Varicose veins usually occur in superficial veins of the leg and thigh, but can also occur in other vessels such as oesophageal veins and anorectal veins. In fact, haemorrhoids are essentially just varicose veins in the anus. If veins in the scrotum or spermatic cord are dilated, this is called varicocoele.

Aneurysms and Vasculitides

Just like our lecture on atherosclerosis and hypertension, the learning outcomes are a bit broad so I'll be using a different style of headings for this post (rather than simply using learning outcomes as headings).

Aneurysms

Aetiology and predisposing factors

The main causes of aneurysms are congenital, mycotic (the name suggests fungal infections, but in this case the term actually refers to any kind of infection, including bacterial), inflammatory, and traumatic.

Pathogenesis and pathophysiology

Aneuryms are abnormal dilations of the blood vessel or heart wall that may be due to some kind of weakness in the tunica media (or myocardium, if the aneurysm is in the heart). Aneurysms are most common in arteries and the left ventricle.

Classification scheme

Aneurysms can be classified as true or false aneurysms. True aneurysms are bounded by components of the arterial wall. False aneurysms are formed due to leakage of blood through a breach in the vascular wall, forming a haematoma.

Aneurysms can also be classified by morphology. Bubble-like aneurysms that only affect part of the artery wall are known as saccular aneurysms. Swelling that involves the whole wall is called a fusiform aneurysm.

Aneurysms can also be classified by cause and/or location.

Morphological changes and clinical features

One common type of aneurysm is the berry aneurysm, or cerebral saccular aneurysm. Berry aneurysms are usually found at branch points in the Circle of Willis (a circle of arteries in the brain). They usually form where there are some congenital defects in the tunica media. Note that the aneurysm itself is not congenital; however, it is the conditions that allow the aneurysm to form that are congenital. (In fact, the aneurysm itself normally doesn't form until around 30-60 years of age) Berry aneurysms may compress cranial nerves and may affect vision if they press on the optic nerve. If berry aneurysms rupture, patients may experience a sudden headache that feels like a "thunderclap." The resulting subarachnoid haemorrhage can be highly fatal if untreated and of the survivors, around 50% have permanent neurological damage. Berry aneurysms may be diagnosed by imaging and subarachnoid haemorrhage may be detected by looking at cerebrospinal fluid.

Aortic aneurysms similarly occur due to some kind of abnormality in the tunica media. However, in aortic aneurysm, the most common cause of such abnormalities are atherosclerosis. Abdominal aortic aneurysms are fairly common (2-4% of Caucasians) but is usually not the cause of death in these patients. Rupture is rapidly fatal due to the size of the aorta. Another consequence of abdominal aortic aneurysm is the formation of blood clots due to disturbance of blood. Clots may break off and occlude downstream arteries.

Thoracic aortic aneurysms are mainly associated with hypertension. They may press on airways or the oesophagus. If the aortic root is dilated, aortic regurgitation may result.

Complications and clinical sequelae

Aneurysms may rupture, leading to haemorrhage that can be rapidly fatal. They may also cause disturbance of blood within the arteries, resulting in thrombus formation. Aneurysms may also push against surrounding structures and compress them.

Aortic Dissection

Aortic dissection is not an aneurysm, but since it was covered in this slide, I'll talk about it anyway. In aortic dissection, there is a tear in the intima of the aorta, allowing blood to enter and separate the intima and media. Many patients with aortic dissection experience a sudden excruciating pain in the chest or back between the shoulder blades. Aortic dissection usually occurs due to weakening of the tunica media (just like most aneurysms, even though aortic dissection isn't an aneurysm). In hypertension or some genetic conditions, like Marfan syndrome, there are fewer elastic fibres and excess polysaccharides in the tunica media: a change known as cystic medial necrosis. Cystic medial necrosis can, in turn, lead to aortic dissection (as well as aortic aneurysms).

Vasculitides

Aetiology and predisposing factors

Vasculitis just refers to inflammation of the blood vessels, which can be due to a range of factors. Some types of vasculitis, such as temporal giant cell arteritis, have no known cause. Others may be due to infection, malignancy, medications, etc.

Pathogenesis and pathophysiology

Often, vasculitis starts off by the deposition of immune complexes in the blood vessels. These immune complexes can activate the complement cascade and cause propagation of the inflammatory response. Antibodies may also directly attack the blood vessel wall.

Classification scheme

Vasculitis is mainly classified by the size of the vessels affected. Large-vessel vasculitis includes takayasu arteritis and temporal giant cell arteritis. Medium-vessel vasculitis includes polyarteritis nodosa and Kawasaki's disease. Small-vessel vasculitis includes granulomatosis with polyangiitis (a.k.a. Wegener's granulomatosis), Churg-Strauss Syndrome, and Henoch-Schonlein purpura. (Note that this is not an exhaustive list of all of the types of vasculitis.) In this post, we will be focusing on temporal giant cell arteritis, polyarteritis nodosa, and granulomatosis with polyangiitis.

Morphological changes and clinical features

Temporal giant cell arteritis involves inflammation of large- and medium-sized arteries, especially the carotid and temporal arteries. It is usually diagnosed by a biopsy of the temporal artery, though an issue with this is that you could just as easily remove a part of the temporal artery that is unaffected.

Polyarteritis nodosa primarily affects medium-sized vessels, usually the renal and mesenteric arteries. However, it does not involve pulmonary arteries. In polyarteritis nodosa, there is infiltration of the arterial wall by neutrophils, lymphocytes, and plasma cells, and fibrinoid necrosis of the arterial wall.

Granulomatosis with polyangiitis, also known as Wegener's granulomatosis, is a small-vessel vasculitis that primarily affects the respiratory and renal systems. It can affect people of any age and it affects males and females equally.

Complications and clinical sequelae

The inflammation in vasculitis may lead to narrowing of the lumen or disrupted blood flow leading to thrombosis. In both cases, there may be ischaemia to tissues supplied by the blood vessel.

Cardiovascular Dysfunction, Hypertensive Heart Disease, and Ischaemic Heart Disease

Causes of cardiac dysfunction

The cardiovascular system can fail for many different reasons. Firstly, there might be an issue with the heart pump itself: it might not contract enough or relax enough. Secondly, there may be issues with flow: flow may be obstructed (due to a plaque etc.), regurgitant (due to a leaky heart valve), or shunted (diverted due to a congenital or acquired heart defect). Thirdly, there may be issues with conduction of the electrical signal, leading to problems with contraction of the heart.

Causes, consequences and pathological findings of cardiac hypertrophy

The heart may hypertrophy due to an overload in pressure or an overload in volume. An overload in pressure will result in addition of new myofibrils, leading to thickening of the heart wall. This is known as concentric hypertrophy. On the other hand, increased volume will lead to the addition of new sarcomeres, causing the heart chambers to become larger. This is known as eccentric hypertrophy. Cardiac hypertrophy may also be accompanied by synthesis of abnormal protein and DNA, fibrosis (due to the blood supply being insufficient for  a larger heart), or other molecular changes.

Causes and clinical manifestations of heart failure

Heart failure, as discussed here, is when the cardiac output fails to meet the needs of the body. Heart failure can be classified in many different ways.

• Forward vs. backward: In forward heart failure, not enough blood leaves the heart. In backward heart failure, heart backs up into the venous system.
• Left vs. right: Kind of self-explanatory- simply refers to the side of the heart affected.
• Systolic vs. diastolic: In systolic heart failure, there is inability to contract normally. In diastolic failure, there is inability to relax and fill properly. (Note: systolic heart failure is sometimes also known as heart failure with reduced ejection fraction, or HFrEF, and diastolic heart failure is also known as heart failure with preserved ejection fraction, or HFpEF.)
• High vs. low output: In high output heart failure, the heart is pumping out a lot of blood, but due to increased demand by the body, this is still insufficient to supply the body. In low output heart failure, there is insufficient output of blood.
• Acute vs. chronic: Acute onset is sudden (perhaps due to a sudden myocardial infarction), and chronic occurs over time.

There are a range of different clinical manifestations that may accompany heart failure. I have discussed them here.

Pathological findings of hypertensive heart disease, including pulmonary hypertension

Hypertensive heart disease is characterised by left ventricular hypertrophy (thickness of over 15mm and heart weight greater than 500g) with a history of hypertension, but no other cardiovascular pathology. Since the ventricle wall is thick, diastolic filling is impaired. The atria may also hypertrophy in order to try and force blood into the ventricle. Sudden death may result from hypertensive heart disease.

Pulmonary hypertension is essentially the right-sided heart's answer to systemic hypertensive heart disease. It is defined by a pulmonary arterial pressure greater than 30mmHg or greater than 25% of systolic pressure. Pulmonary hypertension can cause right ventricular enlargement, or cor pulmonale.

Aetiology, pathogenesis, classification, morphological changes, clinical features and clinical sequelae of ischaemic heart disease

Aetiology and Pathogenesis

Ischaemic heart disease usually results from atherosclerosis. Therefore, aetiological factors of ischaemic heart disease are basically the same as those for atherosclerosis: see here.

Classification

The four main types of ischaemic heart disease are angina pectoris, myocardial infarction, chronic ischaemic heart disease with heart failure, and sudden cardiac death.

Morphological changes, clinical features, and clinical sequelae

Angina pectoris can be further broken down into three types: stable, Prinzmetal (or variant), and unstable. I have discussed them here.

Myocardial infarctions can be transmural, meaning that they affect the whole thickness of the wall, or subendocardial, meaning that they only affect part of the wall. The damage in myocardial infarction usually starts from the subendocardial area and extends outwards. I have discussed myocardial infarction here.

Chronic ischaemic heart disease with heart failure is progressive and involves a widespread narrowing of coronary arteries. There may be widespread fibrosis and endocardial thickening.

Sudden cardiac death is basically what it says on the box. In this case, "sudden" is defined as being death within 1-24 hours of the onset of symptoms. It is thought to be due to some kind of arrhythmia.

Atherosclerosis and Hypertension

The learning outcomes for this lecture are basically a paragraph, so I'm going to divide this post into talking about atherosclerosis and hypertension separately, and then divide those sections into various different components.

Atherosclerosis

Aetiology and predisposing factors

There are many different predisposing factors for atherosclerosis. Non-modifiable factors include age (older people are more at risk), sex (males are more at risk), and a family history of atherosclerosis. Modifiable risk factors include high lipid levels, high blood pressure, smoking, and uncontrolled diabetes. There may also be many other risk factors other than those that I just listed. Having multiple risk factors can increase your risk of atherosclerosis even further.

Pathogenesis and pathophysiology

In atherosclerosis, artery walls thicken and harden as a result of the formation of atheromas or plaques. The formation of a plaque is also known as atherogenesis. Atherosclerosis is a sub-type of arteriosclerosis, which refers to basically anything that can cause the arteries to harden. (Arteriosclerosis is not to be confused with arteriolosclerosis, which is where arterioles- not arteries- become thickened and hardened. Arteriolosclerosis is generally not the result of atherosclerosis.)

The onset of atherosclerosis can be slow or sudden, and the extent of blockage by the atheroma can be partial or complete. Blockage of the blood vessel reduces the blood supply to the tissues. Formation of atheromas causes the artery wall to weaken and increases the risk of thrombus (clot) formation.

One hypothesis for the formation of atheromas is the response to injury hypothesis. This hypothesis states that damage to the endothelium, as may occur due to high blood pressure, smoking, or some other aetiological factor, may cause the endothelium to become dysfunctional. Over time, lipoproteins can accumulate in the vessel wall. Other changes may happen as well, such as the invasion of monocytes (which turn into macrophages and then into foam cells as they consume lipids), adhesion of platelets, recruitment of smooth muscle cells from the tunica media, and so on.

It is also important to note that atherosclerosis only affects arteries and not veins. However, a vein used a bypass grant can become "arterialised" and develop atheromas. Atheromas are also unlikely to affect arteries that are not under much pressure, such as the pulmonary arteries and upper limb arteries.

Classification scheme

Atherosclerotic lesions can be assigned a class from Type I to Type VI, depending on severity. Type I is the initial lesion and as the lesion progresses, it can move up through to Type VI. Only type IV onwards are considered to be atheromas (though type III is considered an intermediate, or pre-atheroma stage).

Morphological changes and clinical features

A Type II lesion is also known as a fatty streak. Many people can get fatty streaks, even children, but they can regress and do not all progress to the atheroma stage.

A Type V lesion is a fibroatheroma. It is made up of a soft lipid core with a fibrous cap and usually only involves part of the circumference of the wall.

Complications and clinical sequelae

There are many different complications of atheromas. Some atheromas become calcified, increasing the risk of myocardial infarction (heart attack) and death. Atheromas may also release atheroemboli (basically pellets of cholesterol) that may go on to occlude smaller downstream vessels. Another complication is that they might rupture, resulting in formation of a thrombus that may embolise and occlude a downstream artery. Bleeding may also occur into the atheroma, causing the atheroma to expand and block the artery. Finally, atheromas may lead to formation of an aneurysm as the artery wall has weakened.

Atherosclerosis has consequences in many organs in the body. In the heart, atherosclerosis can lead to angina, myocardial infarction, and even sudden death. In the brain, atherosclerosis can lead to transient ischaemic attacks (TIAs) and stroke. In the peripheral arteries, atherosclerosis can lead to pain, ulcers that won't go away, and gangrene. Depending on which arteries are blocked, it may also have other consequences such as impotence. Atherosclerosis, as mentioned before, can also cause aneurysms, particularly in the abdominal aorta.

Systemic hypertension

Aetiology and predisposing factors

Most cases of hypertension are idiopathic, meaning that we don't know what caused the hypertension. However, hypertension can also be a result of a problem elsewhere in the body, such as an endocrine disorder or renal failure. Hypertension may also be due to pregnancy or certain medications.

Pathogenesis and pathophysiology

Some patients with hypertension may develop hypertensive emergency, in which there is a severe rise in blood pressure. The high blood pressure can damage organs, particularly those with small vessels, such as the kidneys and retina.

Classification scheme

Hypertension can lead to arteriolosclerosis (hardening and thickening of arterioles). There are two main types of arteriolosclerosis: hyaline arteriolosclerosis and hyperplastic arteriolosclerosis.

Morphological changes and clinical features

In hyaline arteriolosclerosis, the tunica media is thickened because the high pressure causes eosinophilic hyaline material to leak into the arteriolar wall. There may also be smooth muscle hypertrophy and fibrosis. The lumen of the arterioles is narrowed, resulting in ischaemia (reduced blood flow) to organs.

Hyperplastic arteriolosclerosis pretty much only happens in severe hypertension. It is a proliferation of smooth muscle cells that looks like an onion skin under the microscope. In hyperplastic arteriolosclerosis, the lumen is severely narrowed.

Complications and clinical sequelae

The complications of hypertension and the resulting arteriolosclerosis are similar to that of atherosclerosis: less blood reaches organs, causing ischaemia and damage to those organs. Also, since the blood pressure is higher, the heart has to pump harder, resulting in hypertrophy of the heart. This might sound good, but eventually the heart might grow to the point that the coronary arteries can't adequately supply it any more, resulting in tissue death.