Cardiovascular disease Flashcards
Cholesterol and hypercholesterolemia
Cholesterol is the primary component of cell membranes and a precursor in the synthesis of bile acids, steroid hormones and vitamin D.
Hypercholesterolemia is a major risk factor for atherosclerosis.
Atherosclerosis is focal lesions in the form of plaques on the inner surface of an artery. It can lead to narrowing of the arteries and eventually a complete blockage, which can cause myocardial infarction (coronary arteries) or stroke (brain).
In the periphery, plaques can become loose and damage organs, known as an embolism.
Hypercholesterolemia is a total plasma cholesterol >6.5 mmol/l. An ideal level is <5.2mmol/l.
25-30% of the middle aged population have hypercholesterolemia. CVD kills 1 person every 33 seconds.
An especially important risk factor is a high LDL-C component or low HDL-C.
Lipoproteins
Cholesterol is transported around the body in lipoproteins including HDL, LDL, VLDL and chylomicrons.
HDL transports cholesterol back to the liver, removing excess cholesterol from tissues.
LDL transports cholesterol around the body, storing it in adipose tissues and the muscles
VLDL normally transports triglycerides around the body, delivering these to adipose tissue and muscles.
Chylomicrons transport fat from the GIT to the liver.
Dietary cholesterol
The liver produces 70-80% of cholesterol in the body. When we consume a lot of cholesterol in the diet, the liver compensates by reducing its cholesterol production.
Dietary cholesterol has a minor impact on the cholesterol levels in the body, but the type of fat consumed also matters. Saturated and trans fats increase LDL-C.
The first line of treatment for hypercholesterolemia is modifying the diet, cutting the ‘bad fat’ out.
Plaque development in Atherosclerosis
The healthy endothelium becomes damaged, causing inflammation in the blood vessel. High BP, smoking (free radicals) and ageing can all contribute to damage.
This triggers the atherosclerosis process.
LDL-C enters the tunica intima by receptor-mediated endocytosis.
The damaged endothelial cells express adhesion proteins. WBCs attach to these and enter the endothelial layer, squeezing between cells.
WBCs, particularly monocytes, release ROS and oxidise LDL-C. The ox-LDL-C attracts more WBCs.
Macrophages engulf the ox-LDL-C and form foam cells.
Foam cells die and release their contents. Accumulating lipids and cell fragments form a plaque.
Dead foam cells attract more WBCs at the site of damage, which sets up a positive feedback loop.
Over time, the plaque hardens up and accumulates calcium, becoming larger and narrowing the blood vessel. This is known as stenosis.
If the endothelial cell becomes ruptured, platelet aggregation can occur, which can cause complete blockage. Downstream organs become ischemic.
Aspirin, antiplatelet drugs or clot-busting drugs can be used to prevent or remove clots.
Angioplasty and stenting can be used to open up the artery and remove the stenosis.
The process can be slowed or reversed with lifestyle measures, BP control, glycaemic control and statins.
Exercise has been found to improve endothelial function.
Cholesterol synthesis
The two starting precursors of cholesterol synthesis are acetyl CoA and acetoacetyl CoA.
HMG-CoA synthase converts the precursors to HMG-CoA (hydroxy-methyl-glutaryl-CoA).
HMG-CoA is further converted to Mevalonic acid by HMG-CoA reductase, an important enzyme in the cholesterol synthesis pathway as this is the first committed step.
Statins
Statins inhibit HMG-CoA reductase to prevent cholesterol synthesis in hepatocytes.
Examples include simvastatin, lovastatin, pravastatin, atorvastatin, fluvastatin.
Statins also increase LDL receptor expression and so increase the uptake of LDL-cholesterol. This is because the liver adapts to the decrease in cholesterol synthesis by taking up more LDL-C for the production of bile and adrenal hormones.
In homozygous familial hypercholesterolaemia, the individual can’t make LDL receptors and so can’t increase receptor number, so statins are ineffective.
Statins are hepatoselective. After first-pass metabolism in the liver, only 5% reaches the systemic circulation.
Statins also reduce the risk of CVD and mortality in people with normal cholesterol levels. This may ne because the cholesterol precursors geranyl pyrophosphate and farnesyl pyrophosphate are involved in post-translational modification of Ras an RhoA, involved in smooth muscle contraction. Statins control this pathway.
- Some precursors are involved in post-translational modification and activation of proteins, so statins inhibit signalling pathways independently of the effects on cholesterol.
There are some side effects associated with the use of statins, including hepatotoxicity and myopathy.
- Liver function should be monitored in liver disease patients
- Myopathy rarely leads to rhabdomyolysis. The released myoglobin can cause kidney damage. Cerivastatin was withdrawn because of reports of fatal rhabdomyolysis, possibly due to inhibition of mitochondrial function.
- Simvastatin is metabolised by CYP3A4. CYP3A4 is inhibited by the calcium-channel blocker amlodipine, increasing the plasma concentration of simvastatin and causing a risk of toxicity.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) and statins
PCSK9 is a serine protease.
Mice overexpressing PCSK9 have decreased LDL receptors and higher LDL- cholesterol levels.
Mice with PCSK9 knockout have increased LDL receptors and lower LDL- cholesterol levels.
Statins increase PCSK9 activity, which reduces their effectiveness.
- Statins cause the synthesis of more LDL receptors, but it also increases PCSK9 activity.
- PCSK9 binds to newly synthesised receptors and it causes them to become internalised.
LDL signalling and PCSK9
LDL-cholesterol binds to the LDL receptor.
The LDL-C/receptor complex is internalised.
LDL-C is removed from the LDL receptor, and the receptor is returned to the plasma membrane.
PCSK9 binds to the LDL receptor which leads to its internalisation.
The LDL receptor is targeted to the lysosome where it is degraded.
Inhibiting PCSK9 results in less LDL receptor degradation and so more LDL-C being taken up.
PCSK9 inhibitors
Inhibitors of PCSK9 lead to reduced breakdown of LDL receptor, therefore more LDL-C taken up into hepatocytes
These therapeutics are antibodies with long-term effects, so they can be given by monthly injection.
Alirocumab and Evolocumab are monoclonal antibodies against PCSK9. They bind the enzyme and reduce its activity.
Inclisiran is a siRNA that inhibits synthesis of PCSK9.
AZD0708 is a small molecule oral inhibitor of PCSK9 in phase II trials, developed by AstraZeneca. Oral inhibitors achieved 52% inhibition in LDL cholesterol in phase I trials, which is a very promising result.
siRNA
siRNA causes post-transcriptional gene silencing. This is a short, double-stranded RNA fragment that reduces the translation of mRNA into the target protein.
Longer siRNAs (>30 nucleotides) lose their selectivity and can lead to immune reactions and global silencing of genes, resulting in cell death.
A carrier is required to get the siRNA around the body and into cells. This is because circulating siRNA will just be degraded in the plasma.
Carriers can be nanocarriers, aptamers, antibodies, peptides/proteins or sugars/amine sugars. Nanoparticles are the most commonly used.
Carriers are translocated into the cell, and siRNA is then released by endosomal escape.
Inside the cell the siRNA binds to an RNA-induced silencing complex (RISC).
The siRNA is then unwound into a single strand, the antisense strand, which can bind mRNA.
The RISC degrades the mRNA strand, leading to decreased protein production.
Inclisiran is a siRNA that targets the mRNA sequence encoding the PCSK9 enzyme.
Numerous chemical modifications have been applied to siRNA to enhance its PK and PD properties, increase half-life, improve stability in the blood, modulate the body’s immunity and reduce off-target effects. These include sugar moieties, phosphate backbone linkage, base pair stabilisation, modification of overhangs/termini, modifications to the duplex structure.
Olpasiran
Olpasiran lowers lipoprotein expression in the treatment of atherosclerosis.
It is a siRNA that interferes with the production of apolipoprotein(a), a component of LDL.
Phase II data reports positive results and phase III trials began in 2022.
Cholesteryl ester transfer protein (CETP) inhibitors
Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein produced in the liver and adipose tissue.
It circulates in the blood bound to HDL.
It is involved in transfer of cholesterol esters from HDL to VLDL and LDL.
Inhibiting CETP therefore increases levels of HDL-C. Greater inhibition leads to lowering of LDL-C as well.
Obicetrapib is a CETP inhibitor in clinical trials.
However, previous clinical trials involving CETP inhibitors have failed.
Torcetrapib caused an increase in mortality in clinical trials. It increased BP and the increase in HDL-C was small.
Dalcetrapib trials were halted due to a lack of “meaningful clinical efficacy” → HDL-C levels were decreased but the change was not large enough to have an effect on atherosclerosis.
Evacetrapib trials were also halted due to a lack of efficacy.
Anacetrapib trials were abandoned.
However, the REVEAL study found that combining Anacetrapib with a statin led to a reduction in cardiovascular risk.
Combination therapy of Obicetrapib plus a statin was evaluated in phase 3 trial, which achieved its primary endpoint, demonstrating a statistically significant reduction in LDL-C compared to placebo. There was a 21% reduction in major adverse cardiovascular events after 1 year. Obicetrapib was observed to be well-tolerated, with safety results comparable to placebo.
*Other hypercholeserolemia drugs
Cholesterol absorption inhibitors inhibit cholesterol uptake from the diet and also enterohepatic recycling. An example from this class is ezetimibe, which inhibits the intestinal steroid transporter Niemann–Pick C1-Like 1 (NPC1L1).
Bile acid binding resins bind bile salts in the intestine and prevent reabsorption and recycling of cholesterol. An example from this class is cholestyramine, which is used in addition to a statin.
Fibrates activate α-peroxisome proliferator-activated receptors (α-PPARs), which alter lipoprotein metabolism through gene transcription. This increases peripheral lipoprotein lipases, which promotes the breakdown of VLDL, with small reductions in LDL-C and increase in HDL. Examples include bezafibrate, clofibrate and gemfibrozil.
Heart failure
Heart failure is the failure of the heart as a pump to meet the circulatory needs. This may be due to a failure of the heart muscle or valves.
Breathlessness with physical exertion is seen.
Heart failure may be chronic/congestive or acute (post myocardial infarction).
Congestive describes the resulting congestion in the vasculature due to a reduction in pressure on the venous side of the system, resulting in oedema, and pulmonary congestion affecting breathing.
Heart failure is often secondary to hypertension, ischemic heart disease (IHD) or cardiomyopathies (alcohol-induced or viral). These lead to adaptation of the heart muscle, seen as left ventricular hypertrophy (LVH), or damage to the muscle.
Heart failure can also be precipitated by pregnancy, anaemia, hyper or hypothyroidism and fluid-retaining drugs, such as glucocorticoids or NSDAIs.
- In anaemia there is less Hb so the heart needs to work harder to get oxygen around the body.
- Hyperthyroidism increases force of contraction and HR and hypothyroidism has the opposite effect
- Fluid retention can increase pressure in the system and so precipitate heart failure
Neurohormonal adaptation in HF
During heart failure, there is a reduced cardiac output.
The body attempts to compensate through activation of the sympathetic system and RAAS, increasing sodium and water retention and causing vasoconstriction.
This however leads to a vicious circle which further impairs the pump action of the heart due to increased pre and after load.
The heart has to work harder against the increased system pressure, but it is unable to do so when in failure, so there is a further decrease in CO.
Neurohormonal activation therefore leads to myocyte dysfunction.
This results in maladaptation of the heart. Fibrosis occurs due to increased aldosterone, which impairs contraction.
Increased water retention also results in oedema in the lower extremities and congestion in the lungs.
Congestive heart failure
Congestive heart failure (CHF) is a chronic condition that occurs when the heart can’t pump enough blood to meet the body’s needs. This causes fluid to build up in the organs.
Left-sided CHF is the most common type. This is associated with pulmonary oedema due to a build-up of blood, so there is congestion in the pulmonary circulation. Left ventricular hypertrophy (LVH) occurs.
We can also get right-sided failure or HF that affects both sides.
Signs and symptoms:
- Fatigue, listless - due to a lack of oxygen into the brain and skeletal muscle
- Poor exercise tolerance (determines grade)
- Cold peripheries - due to vasoconstriction
- Low blood pressure - high blood pressure can cause HF, but this then reduced BP due to reduced cardiac output
- Reduced urine flow - due to reduced GFR
- Weight loss - due to reduced GIT blood flow and malabsorption
- Breathlessness due to pulmonary oedema
Diagnosis is done on the basis of symptoms and an echocardiogram indicating an ejection fraction of <45%.
A chest X-ray would also reveal cardiomegaly (enlarged heart) and pulmonary oedema.
Prognosis is poor. Median survival in mid to moderate CHF is 5 years.
However, there is an improvement in prognosis as treatments have improved over the years. Survival increases from baseline with the (cumulative) addition of different drugs.
ACEIs
Angiotensin converting enzyme inhibitors (ACEIs) prevent the formation of Angiotensin II, which normally acts to increase BP.
Examples include captopril, enalapril, lisinopril, perindopril and ramipril.
ACEIs reduce arterial and venous vasoconstriction, therefore reducing afterload and preload, respectively.
They also reduce salt/water retention and hence reduce circulating volume by inhibiting aldosterone production.
Aldosterone causes fibrosis and stiffening of the heart. ACEIs inhibit aldosterone production, preventing cardiac remodelling.
ACEIs also potentiate bradykinin, a vasodilator. However, bradykinin also sensitises sensory nerves in the airways and therefore causes a cough as a side effect.
Other side effects include hypotension with the first dose, hyperkalaemia and angioedema.
AT1 receptor antagonists
AT1 receptor antagonists oppose the actions of angiotensin II at the AT1 receptor.
These are also called ATRAs, ARBs or sartans and examples include candesartan, losartan and valsartan.
These are equally as effective as ACEIs, but they do not cause a cough.
Diuretics
Diuretics prevent water retention, counteracting the effects of aldosterone.
Thiazides, such as bendroflumethiazide, are used in mild heart failure or in the elderly. These inhibit the reabsorption of Na+ and Cl- in the distal convoluted tubule, leading to diuresis. Circulating volume and so BP decrease, as do afterload and preload, reducing work on the heart.
Loop diuretics like furosemide are especially used when pulmonary oedema is occurring. These are powerful ‘high ceiling’ diuretics that block the Na+/2Cl-/K+ symporter.
One issue with diuretics is hypokalaemia.
They also cause vasodilation, although this mechanism is not fully understood. However, this can cause postural hypotension.
Spironolactone and Eplerenone
Spironolactone and Eplerenone are aldosterone receptor antagonists.
Aldosterone affects the heart, as it is involved in remodelling and causes fibrosis, which causes stiffness of the heart and arrhythmias.
These reverse the left ventricular hypertrophy (LVH).
There is also a reduction of fluid retention as Na+ reabsorption is prevented, similar to the effects caused by diuretics.
β-Adrenoceptor Antagonists
There are a lot of β-adrenoceptor antagonists, but not all of them seem to be effective in heart failure. The beta-blockers licensed in the UK for the treatment of heart failure are bisoprolol, carvedilol, and nebivolol.
Stimulation of the receptors increases CO, so inhibition reduces it.
Decreased CO is already occurring in CHF, so utilising these seems counterintuitive.
However, there are some drugs which initially cause a worsening of HF but this is followed by a rebound, where cardiac function improves.
This may be because antagonism actually leads to increased receptor expression or because this reduces workload on the heart. Alternatively, these particular antagonists may have another unidentified effect.
β-adrenoceptor antagonists reduce disease progression, symptoms and mortality.
They are used in stable or moderate heart failure.
Beta blockers reduce sympathetic stimulation of the heart, reducing heart rate and oxygen consumption.
They have antiarrhythmic activity, which reduces sudden death.
Atrial fibrillation
Atrial fibrillation is a common consequence of CHF. It is an impaired rhythm of contraction of the atria.
Stasis of blood in the atria occurs, resulting in the formation of thrombi.
This can occur in MI, stroke or pulmonary embolism.
There is a need for prophylaxis with warfarin or aspirin.
Aspirin is an irreversible COX inhibitor. It inhibits conversion of arachidonic acid into thromboxane (TXA2), but also the vasodilator PGI2 (prostacyclin). Thromboxane (TXA2) is released from platelets and stimulates aggregation. However, at low doses, aspirin favours PGI2 production over TXA2 because in the endothelial cell the nucleus can respond by upregulating transcription of the COX gene, overcoming the inhibition. Platelets do not have a nucleus, so they cannot produce more enzymes.
Warfarin is a vitamin K reductase inhibitor. Reduced vitamin K is essential for the production of prothrombin and clotting factors VII, IX and X. It acts as a cofactor.
Digoxin
Digoxin is a positive inotrope, strengthening heart contractions and allowing it to pump more blood.
Used for atrial fibrillation and HF.
It inhibits the Na+/K+ ATPase, causing Na+ to accumulate in myocytes, which promotes Ca2+ entry leading to increased contractility.
However, digoxin also impairs atrioventricular conduction at the AV node, which leads to:
- Heart block and bradycardia
- Reduced rate at which contraction passes from atria to ventricles.
This may however be beneficial in atrial fibrillation as it controls ventricular rate, allowing the atria enough time to contract.
Dioxin has a narrow TI and can be toxic, so it is not commonly used.
SGLT2 inhibitors
Sodium-glucose cotransporter 2 (SGLT2) inhibitors, such as dapagliflozin and canagliflozin, inhibit glucose reabsorption in the kidney.
SGLT2 causes cotransport and reuptake of sodium and glucose. Inhibiting these increases excretion in urine, which also pulls water in so blood volume is reduced.
These were developed for the treatment of type 2 diabetes but may be effective in heart failure.
SGLT2 inhibitors offer cardio-renal protection and reduce mortality in patients with heart failure.
They decrease blood pressure without affecting the heart rate due to inhibition of the sympathetic system. This is probably due to prevention of renal damage which would normally increase sympathetic activity.
