Contents
Introduction
Cardiovascular disease is the leading cause of death in Western Society. About 1 in 6 people suffer from the various forms of the disease, and it accounts for 30-40% of all deaths in developed countries.
Since the 1980s, treatment has greatly improved, and long-term outcomes are far better than they were in previous decades. Medical practitioners have an import role to play in both reducing the incidence of the disease via prevention, and providing treatment for the end results.
This article provides an overview of atherosclerosic cardiovascular disease and its pathology. For more information on the syndromes that result from these cardiovascular diseases, see Acute Coronary Syndromes, Stable Angina, peripheral vascular disease and stroke.
Atherosclerosis
Atherosclerosis is the term used to describe the build of of fatty ‘plaques’ on arterial walls. It is the underlying pathological cause for cardiovascular disease
Epidemiology
- Cardiovascular diseases (i.e. coronary heart disease, ischaemic stroke and peripheral vascular disease) are the leading cause of death in western society
- Cardiovascular disease affects about 1 in 6 people in western countries
- In England and Wales, they account for 40% of all deaths:
- Ischaemic heart disease is 27%
- Cerebral vascular disorders 13%
- Atherosclerosis is by far the most important cause
- In the developed world the incidence has increased massively in the last 50 years
- In the US and some European countries, incidence has actually peaked and in declining
- In the rest of Europe, and in the middle and far east, incidence is rising rapidly
Aetiology
The major risk factors are:
- Age
- Male gender – pre-menopausal women in particular seem to be a very low risk – being pre-menopausal is a preventative factor. After the menopause, gender differences disappear rapidly. HRT also has no role in reducing the risk – infact oestrogen therapy appears to increase the risk.
- Hypertension – anti-hypertensive therapy reduces coronary mortality, stroke and heart failure.
- Smoking – this link is also dose related
- Diabetes
- High levels of LDL
- Low levels of HDL
- Obesity
- Sedentary lifestyle
- Increased levels of blood coagulation factor VII
- Low birth weight – this is thought to be particularly important. Those with a low birth / infant weight are at higher risk of adult obesity. Those with a low birth weight and a subsequent level of obesity in adulthood are 2-3x more likely to die from heart disease than those with a high infant weight. A low infant weight is often (in the past at least) associated with low socio-economic status.
- Low socio-economic status
- Genetic factors – often things like hypertension, hyperlipiedaemia and diabetes run in families, and are multi-genetic. HOWEVER – it is also important to remember than families often share the same environment – and environmental factors may be involved in the apparent family history link.
- Clinically – we say a significant family history is present when first degree relatives have had acute events at <50 years for men and <55 years for women.
However – it is important to note that there are wide variations in the severity of the disease, even within similar populations. These variations are possibly due to genetic factors. For example;
- There is an inherited genetic abnormality whereby an individual has a lack of LDL receptors – familial hyperlipidaemia? – about 1 in 500 caucasians are heterozygous for this abnormality to cope with their reduced number of receptors, they produce increased amount of LDL’s. These people develop coronary heart disease in their 40’s or 50’s.
- Some patients may even be homozygous for this gene – in this case these patients will often die from coronary heart disease in their infancy or teens.
The effect of risk factors is multiplicative, rather than additive. Also remember the difference between relative and absolute risk. For example a man in his 30’s with high cholesterol who smokes, is far more likely to have an acute event in the next 10 years than someone of his age who doesn’t smoke with a normal cholesterol – BUT his absolute risk is still very low.
Pathology
Atherosclerosis can have 3 main types of manifestation:
- Coronary heart disease – angina, MI, sudden death
- Cerebrovascular disease – stroke, TIA
- Peripheral vascular disease – claudication, critical limb disorder
These situations often co-exist, and the pathology is very similar. For example, patients presenting with stroke or claudication will very likely have coronary artery disease – and this co-existing disease is an important cause of mortality.
Normal artery structure:
There are 3 layers of arterial tissue:
- Tunica Intima – this is the innermost layer, and has a single layer of endothelium, with a sparse supportive tissue. This layer is very very thin!
- Tunica Media – this is separated from the intima by the internal elastic lamina. The media is made up of smooth muscle and elastic tissue. In the heart, the elastic tissue is most predominant, but in most arteries, this layer is mostly made up of smooth muscle.
- Tunica Adventitia – this is a fibrous connective tissue. The external elastic lamina separates this from the media. Very small blood vessels can be found in this layer called vasa vasorum and these filter down to supply the media.
- The intima and innermost media receive their nutrients from the arterial lumen via diffusion.
Normal age-related changes
These will usually be inconsequential by age 40, and very common by age 70. They are often termed arteriosclerosis. the changes affect all blood vessels, right down to the arterioles. They include:
- Progressive fibrous thickening of the intima
- Fibrosis and scarring of the muscular and elastic media
- Accumulation of mucopolyysaccharide ground substance
- Fragmentation of the elastic laminae
Ultimately these changes reduce the strength and elasticity of the vascular wall. Clinically, this will mean there is dilation of the aorta and coronary arteries – and this finding is common.
- In the aorta this can lead to stretching of the aortic ring – resulting in valve incompetence
- Dilation of the aortic arch and thoracic aorta can also lead to ‘unfolding’ of the aorta – which can be seen in chest x-rays as a loss of the aortic notch, and a widened appearance of the central vascular column in the x-ray.
To compensate for these changes, there is often smooth muscle hypertrophy and production of extra layers of collagen in the internal elastic laminae.
Atherosclerosis is a disease of the medium and large sized arteries only. It is very uncommon in arteries of less than 2mm diameter. It is caused by 3 types of lesion:
- Fatty streaks
- Fibrolipid plaques
- Complicated lesions
In atherosclerosis, there is inflammation of the arterial wall, characterised by lipid-rich deposits of atheroma. These deposits do not cause a problem until they become large enough to occlude the artery, or until they ulcerate, or until they become disrupted and a thrombosis forms on their surface.
Signs of atherosclerosis appear early in life, for instance “fatty streaks” in the arteries of children have been noted as young as the age of 7. However, these are asymptomatic.
The disease is basically characterised by:
- Fibrosis
- Lipid deposition
- Chronic inflammation
In the early stages of the disease, there may be many separate streaks and deposits, but in late disease, these all may be confluent.
Progression
Early atherosclerosis
Fatty streaks:
- These will occur at areas of turbulent flow, such as bifurcations, and they are associated with abnormal endothelial function.
- They themselves are of no clinical significance, and occur in all populations
- They are basically a yellow linear elevation of the intimal lining.
Pathogenesis
- Endothelial cells will begin to show unusual adhesion molecules (e.g. ICAM-1 and E-selectin). These may be similar to those seen in acute inflammation.
- This attracts monocytes (macrophages) to the site – and these can be seen both entering and leaving the endothelium.
- At the same time, high levels of LDL in the blood will begin to accumulate in the arterial wall. It may be that these lipid deposition sets off an inflammatory reaction, and the macrophages are attracted like they would be to any type of inflammation.
- The macrophages entering the arterial wall will come into contact with these lipid cores, and will take up the oxidized LDL, becoming foam cells. The macrophages will also be activated by the inflammatory products released by the arterial wall.
- The foam cells can die, and they release their products, causing the formation of a pool of lipid. This pool is called a lipid core.
- The activated macrophages will release lots of their own products. These include cytokines and growth factors, particularly PDGF. These growth factors lead to proliferation of the smooth muscle layer. It will proliferate towards the lipid pool, and in an attempt to repair and stabilise the lesion, it may form a layer around the pool. The smooth muscle cells change their phenotype from contractile, to repair – they now permanently become repair type cells.
- If this process of repair is successful, the plaque will be a stable atherosclerotic plaque and will remain asymptomatic, unless it grows big enough to occlude an artery.
At some point, T lymphocytes will also invade the plaque.
Advanced atherosclerosis
If inflammation dominates over the repair mechanisms of the smooth muscle, then the plaque may become ‘active’ or ‘unstable’, and this could lead to ulceration and thrombosis.
- Many more products are released by the macrophages, including, IL-1, TNF-α, interferon gamma, PDGF and matrix metalloproteinases.
- These can cause the smooth muscle cells overlying the plaque to thin, and thus the protective ‘fibrous cap’ covering the plaque can become weak.
- The macrophages themselves can also digest collagen struts that are holding the cap in place.
- These changes in themselves don’t completely destroy the cap, but make it more vulnerable to external shearing forces
- When the contents of the plaque become exposed to the lumen, this can trigger thrombus formation. This may cause complete occlusion at the site of the plaque, but the thrombus may also break off, and cause a blockage somewhere else.
As the disease progresses, there are:
- More plaques
- A greater number of macrophages and t-lymphocytes within the plaques
- Release of more cytokines and growth factors (including IL-1 and IL-6 that are chemotactic for macrophages
- Elevated levels of antibodies to pathogens, such as Chlamydia pneumoniae. Some people aregue that such organisms (also including cytomegalo virus, herpes and helicobacter) have a causatory role (to initially start the inflammation) although the evidence for this is limited.
- In coronary artery disease – elevated levels of inflammatory markers; such as CRP – this is an indicator of future acute events.
- In transplanted hearts – patients with transplanted hearts may have a particularly quickly progressing form of the disease in the transplanted heart. The pathology of this disease is also slightly different from that of normal atheroma. This further supports the theory that the disease is a result of an immune problem. To minimize the risk all heart transplant patients are given lipid lowering drugs.
Monoclonal cells – some people have likened the plaques to small benign tumours – because the smooth muscle proliferation that is part of plaque formation occurs from the proliferation of one cell; the cell clones itself many times. In this way, the growth factors can be thought of as ‘mutagens’, although efforts to localise and identify a single mutagen have been unsuccessful.
Disease progression
Individual plaques even within the same patient will progress at different rates. This rate is strongly linked to mechanical stress – the greater the stress, the greater the proliferation.
Vulnerable plaques are those in a place of high mechanical stress, with a lipid-rich core and a thin fibrous cap.
Stable plaques have a thick fibrous cap, possibly with calcification, and they have a small lipid pool, and many collagenous cross-struts.
- It is thought that lipid lowering therapy helps to stabilise vulnerable plaques.
Thrombus formation on plaques
There are two different mechanisms. Either the fibrous cap of the plaque itself gets a superficial injury, and a thrombus forms on it, or, in more advanced, unstable plaques, the fibrous cap completely ruptures, and not only can some of the contents escape, but blood can also enter the plaques, forming a thrombus within the remaining cap of the plaque.
The platelets then release serotonin and thromboxane A2 and this causes vasoconstriction in the area resulting in reduced bloodflow to the myocardium, and ischaemic injury.
A bit about lipids
Lipoproteins
These are the form in which most lipids are transported in the blood. They contain large insoluble glycerides as well as cholesterol. They have a superficial coating of phospholipids and protein, which make the lipoproteins soluble. The proteins coating these molecules will often bind to specific cell membrane receptors, signalling the uptake of that particular phospholipid.
There are four main types of lipoprotein:
- Chylomicrons – these consist of 95% triglyceride. These carry absorbed lipids from the gut to the liver.
- VLDL’s – very low density lipoproteins – these carry triglycerides manufactured by the liver, as well as small amounts of phospholipid and cholesterol. The primary function of these is to transport triglycerides to peripheral tissues. These are the largest of the ‘-DLs’.
- LDL’s – low density lipoproteins – these contain very few triglycerides, a few more lipoproteins, and lots and lots of cholesterol! These are the ‘bad cholesterol’. Their primary role is to deliver cholesterol to peripheral tissue.
- HDL’s – high density lipoproteins – these are the smallest of the ‘-DLs’. They have roughly equal amounts of lipid and protein. The lipids are mainly phospholipid and cholesterol. These will transport excess cholesterol back from peripheral tissue to the liver to excretion in the bile! They are ‘good cholesterol’.
Lifecycle
The liver will synthesise VLDL’s. These will then be released into the blood to deliver triglycerides to the peripheral tissues. Lipoprotein Lipase will remove lots of triglycerides from these lipoproteins, creating intermediate density lipoproteins. These will then go back to the liver, where they will have more of their triglycerides removed, and lots of cholesterol added to them. They will then be released as LDL’s to deliver cholesterol to peripheral tissue.
LDL’s are absorbed by receptor mediated endocytosis into peripheral cells. The amino acids and cholesterol will be released into the cytoplasm.
Cholesterol not used by the cell will diffuse back out of it. It will diffuse back into the blood, where it will be taken up by HDL’s and then taken back to the liver. They will have their cholesterol removed for excretion, and the HDL’s will then continue in the blood stream to pick up more cholesterol.
Prevention of atherosclerosis
Primary prevention aims to prevent the disease in the first place, and involves:
- Cessation of smoking
- Control of BP
- Weight reduction
- Regular exercise
- Dietary modifications
- Diets that are low in saturated fat are particularly associated with a reduced risk of disease
- Fatty acids found in fish also have cardio-protective effects – thus it is recommended you eat at least 2 portions of oily fish per week.
Secondary prevention aims to reduce the risk of acute events in the presence of atheroma. It basically involves the use of drugs, but you should remember these drugs are intended for long term use after an MI and are not involved in the acute treatment of a recent MI.
Generally patients should be offered a combination of the following 4 drugs:
- ACE inhibitor
- Aspirin
- Β-blocker
- Statin
COBRA-A mnemonic for Secondary Prevention in ACS
- C – Clopidogrel – anti-platelet agent
- O – Omacar – Omega 3
- B – Bisoprolol – β-blocker
- R – Ramipril – ACE-i
- A – Aspirin
- A – Atorvastatin – very potent statin!
For information on the mechanisms and side-effects of these drugs, please see the Cardiovascular Drugs Article
References
- Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
- Oxford Handbook of General Practice. 3rd Ed. (2010) Simon, C., Everitt, H., van Drop, F.
- Beers, MH., Porter RS., Jones, TV., Kaplan JL., Berkwits, M. The Merck Manual of Diagnosis and Therapy