Dr Diana R Holdright MD, FRCP, FESC, FACC, MBBS, DA, BSc. Consultant Cardiologist CARDIOVASCULAR DISEASE AND CHOLESTEROL.

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1 Dr Diana R Holdright MD, FRCP, FESC, FACC, MBBS, DA, BSc. Consultant Cardiologist CARDIOVASCULAR DISEASE AND CHOLESTEROL

2 Cardiovascular disease Cardiovascular disease is the umbrella term given to soft fatty deposits or hard calcified plaques within one or more arteries in the body. Arteries become diseased through the process of atherosclerosis, where fatty deposits begin to line the walls of the arteries, causing them to fur up, such that the normally smooth inner lining of the vessels becomes irregular and narrower: Normal coronary artery Narrowed artery Plaque Furring up in the coronary arteries, the arteries that supply the heart, is known as coronary artery disease. With stress (typically in the form of exercise) the body has a greater demand for oxygen, and the heart has to beat faster in order to pump the oxygenated blood around the body. At these times the heart itself too has a greater demand for blood and oxygen, but if an artery supplying the heart muscle has become narrowed with fatty deposits or plaque, the blood supply will be inadequate, causing the symptoms of angina. Another manifestation of the same disease process is a myocardial infarction, more commonly known as a heart attack. This typically occurs when an area of plaque suddenly ruptures, exposing the undersurface of the artery lining and provoking an injury response. Anyone who has ever had so much as a papercut will have noticed that the body is quick to create a clot over the wound to halt blood loss and prevent infection. The injury response in arteries is similar, however in this instance the clot formation can block the blood flow through the artery, completely starving the muscle it supplies of oxygen.

3 In most cases this is unheralded and is often the first indication that a patient has a heart problem, highlighting the importance of screening in medium and high risk populations (more on this later). A heart attack is a medical emergency and needs immediate treatment to restore the blood supply to the heart and minimise damage to the heart muscle; during a heart attack the heart muscle that received its blood supply from the affected artery will die, leaving behind a scar. The larger the scar, the greater the effect on the remaining healthy heart muscle, and the less effectively the heart will work in the future. 999 Cholesterol Doctors tend to test a patient s cholesterol level from time to time because there is a documented link between high cholesterol levels and the risk of cardiovascular disease. There are several components that together make up the blood cholesterol level, the two major components being LDL (low density lipoprotein) and HDL (high density lipoprotein). High levels of LDL cholesterol increase the risk of cardiovascular disease, whereas high levels of HDL cholesterol are protective, and as such people often refer to LDL as the bad cholesterol, and to HDL as the good. These days doctors also talk about non-hdl cholesterol, a measure of LDL plus the other unhealthy components in the blood. Cholesterol is one of the components of the fatty deposits which begin the atherosclerotic process, and so it stands to reason that people at risk of developing cardiovascular disease, or those who have already been proven to have it, should keep their levels as low as possible to prevent development or progression of the disease. For patients with coronary artery disease guidelines generally recommend a non-hdl cholesterol of less than 2.5 mmol/l and an LDL cholesterol of less than 2 mmol/l. HDL cholesterol is protective, and so the higher the value, the better. An adverse cholesterol profile is just one risk factor for cardiovascular disease, and so doctors use various scoring systems to estimate an individual s future risk. Examples include the JBS3 Cardiovascular Risk Assessment and QRISK calculators, which factor in variables particular to each patient in order to generate their unique risk of sustaining a heart attack or stroke over the next ten years:

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5 Some cardiovascular risk factors, such as age and family history, are clearly fixed and cannot be modified, whilst modifiable risk factors include: Current guidelines recommend that anyone with more than a 10% risk of a cardiovascular event in the next ten years should look at aspects of their lifestyle to see if there are any changes they can make themselves to lower their risk. Patients who are not able to bring their risk down to less than 10% are offered statin therapy to chemically lower their cholesterol. This is known as primary prevention. Before starting medication many patients are understandably keen to stratify their individual risk further still, and advances in technology have allowed us to develop methods of scanning which can look at a patient s coronary and carotid arteries in detail and determine whether or not they have any early or established changes indicative of disease. Imaging of the coronary and carotid arteries CT scanning uses a series of two-dimensional X-ray images to build a 3D picture of an area of the body. A CT coronary angiogram takes about 30 minutes and involves an injection of a contrast agent into a vein in the arm to visualise the coronary arteries. As part of a CT coronary angiogram a coronary artery calcium score is undertaken, and this detects calcified plaque in the artery walls. A calcium score of zero equates with a low risk of coronary artery disease, but it takes many years for early disease in the arteries to form calcium, and so a zero score does not mean zero risk.

6 The advantage of a CT coronary angiogram is that it is able to detect not only calcified lesions but also any early changes, known as soft plaque, in the lining of the arteries. This is enormously helpful to doctors who are then able to offer a patient a statin to stabilise the disease and thereby reduce the future risk of a heart attack or stroke by up to 50%. There is a small radiation dose attached to the scan, but this is equivalent to the natural background radiation we are exposed to over the course of two months just going about our daily lives. The vascular changes that take place in the coronary arteries can also occur in the carotid arteries, which supply the brain, and rupture of a plaque in these vessels may lead to a stroke. Thankfully there are also scans that can detect changes in these arteries, for example, a carotid Doppler ultrasound. This test uses a probe and ultrasound waves (no radiation) to look at the arteries and determine whether or not there are any narrowings which might predispose to future problems. These tests are particularly useful in seemingly low risk populations such as those where there is no family history of vascular disease. Patients with high cholesterol should also consider screening in this way, since the presence of disease would advocate the need for statin therapy to lower cholesterol, stabilise the disease and markedly reduce the future risk of a heart attack or stroke. Familial hypercholesterolaemia Some patients have a purely genetically determined cholesterol level, familial hypercholesterolaemia, which can cause exceptionally high cholesterol levels and is known to cause premature atherosclerosis and heart disease, greatly increasing a person s risk of sustaining a heart attack at a young age. Anyone with a first degree relative (parent, sibling or child) with the condition should be tested; the advent of genetic testing and developments in screening tools have improved our ability to detect carriers of the gene at a young age and begin treatment early to reduce their risk of future heart problems. Green = not affected Red = affected

7 Statins Statins are one of the most commonly prescribed drug classes worldwide, given to hundreds of millions of patients across the globe. Statins have three mechanisms of action: firstly they stabilise plaques, making them less likely to rupture and thereby reducing the likelihood of a heart attack; secondly they reduce the level of cholesterol in the blood by inhibiting the enzyme in the liver that produces it. Less cholesterol in the blood stream means that there is less that can be deposited in the artery walls and create new plaques. Statins have also been shown to have anti-inflammatory properties within the arteries, further reducing the risk of plaque rupture. Cholesterol is measured in mmol/l in the UK (mg/dl in other countries), and a large meta-analysis (a combination of results from multiple studies) was conducted in 2012 and concluded that for every 1 mmol/l drop in LDL (the bad ) cholesterol, there was a reduction of 24% in the risk of heart attack, 15% in the risk of stroke, and 19% in the risk of death from coronary artery disease. The average patient on an appropriate statin at the correct dose might therefore expect their future cardiovascular risk to be halved. LDL cholesterol by 1 mmol/l = 24% in risk of heart attack 15% in risk of stroke 19% in risk of death from coronary artery disease With any medication there is always a trade-off between the potential benefit the drug may have in an individual, and the risk of it causing side-effects. The most publicised side-effect associated with statins is muscle pain, with particular concern about a link between statins and a potentially fatal muscle condition called rhabdomyolosis, however many papers have examined the prevalence of this and have found it to be very rare. In terms of general muscle aches and statin usage, and also potential side-effects such as nausea, insomnia and fatigue, a 2014 review of statin studies looked at the experiences of 83,000 people and concluded that almost all reported symptoms occurred just as frequently when patients were administered placebo - in other words the statin was not responsible.

8 Statins can, however, be incriminated in two areas: firstly in about 3% of patients the drugs are associated with a rise in liver enzymes, and secondly the rate of developing diabetes is slightly higher in statin takers than those taking placebo (3% and 2.4% respectively). In asymptomatic patients it is unclear as to whether the rise in liver enzymes is harmful, but many people naturally have raised liver enzymes as a result of obesity or alcohol intake in any case, and in most instances the findings are dose-dependent such that lowering the statin dose results in normalisation of the liver enzymes. In terms of diabetes, the study found that only 1 in 5 new diagnoses of diabetes could be directly attributed to taking a statin. Although diabetes itself is a major risk factor for cardiovascular disease, the beneficial effect of the statin on the cardiovascular system outweighs the risk posed by it potentially triggering diabetes. - Statins and dementia There have been many headlines over the years citing confusion, memory loss and dementia as possible consequences of statin therapy but the literature has been very variable, making it difficult for a clear consensus to be reached. Most recently (2013) a team of researchers from Johns Hopkins University in the US undertook a systematic review and meta-analysis of the short and long term cognitive effects of statins. They found that short term use of statins did not have any consistent adverse effects in terms of confusion or memory loss. Long term studies, which encompassed 23,443 patients with an average exposure to statin therapy from 3 to 24.9 years, found no association between statin use and increased risk of dementia. Pooling the trial results actually revealed a 29% reduction in the risk of dementia in statin-treated patients.

9 Ezetimibe Ezetimibe is a different type of drug, which works by reducing absorption of cholesterol from the small intestine. Ezetimibe can be used in isolation in patients who are intolerant of statins, but it is more often used in addition to a statin in patients who have not been able to achieve a low enough LDL cholesterol level (less than 2 mmol/l) on a statin alone. A study in 2015 showed that the addition of ezetimibe to simvastatin resulted in a drop in LDL cholesterol of 24%, which in turn resulted in a lower risk of heart attack, stroke and death in these patients. The outcome of this study further supports the already well established fact that the lower the LDL cholesterol, the lower the cardiovascular risk. PCSK9 inhibitors Statins were first introduced in the late 1980s and became established as the most effective way to lower LDL cholesterol and so reduce cardiovascular risk. Despite their success, a small proportion of patients cannot take statins due to side-effects, and some patients with particularly high levels of cholesterol, such as those with familial hypercholesterolaemia, cannot achieve adequate cholesterol lowering with statins alone. Research in recent years has found that people who have greater levels of an enzyme called PCSK9 have higher cholesterol levels and a greater incidence of early heart disease, whilst people with less of the enzyme have lower cholesterol and a lower risk of cardiovascular disease. PCSK9 inhibitors are very effective at lowering LDL cholesterol, but at the moment they are also incredibly expensive, with treatment costing in the region of 4,000 per year. As such they are only funded on the NHS on a case by case basis and there are naturally very specific conditions in which they are prescribed. At present the drug has to be given by injection subcutaneously every 2 to 4 weeks but future innovations may lead to alternative modes of delivery.

10 Natural ways of lowering cholesterol Patients often ask what they themselves can do to lower their cholesterol rather than relying on medication alone. In addition to the standard advice which recommends weight loss, regular exercise and a sensible diet (fish, fruit and vegetables, fewer dairy products, less red and more lean meat), there are some products, available without prescription, that are marketed as cholesterol-lowering substances. Products which claim to be natural are not regulated in the same way as conventional medicines and their full effects have not necessarily been rigorously tested, and so it is important to use these with caution - Plant stanols and sterols Plant stanols and sterols have a similar molecular structure to cholesterol, and so they compete for absorption within the gut; this means that the plant stanols and sterols take the place of some of the cholesterol being absorbed into the bloodstream, the cholesterol being excreted as waste instead. Plant stanols and sterols are found in small quantities in plant-based foods such as cereals, vegetable oils, seeds and nuts, meaning that the average diet probably contains around 300 mg of these per day. Research has shown that an intake of 1.5 to 2.4 g per day could reduce cholesterol by 7 to 10%. Although vegetarian diets are much higher in plant stanols and sterols, it would still be difficult to achieve an intake of 2 g daily with diet alone. They are available in tablet form from health food shops, but there is also a range of fortified milk, spreads, yoghurts and yoghurt drinks on the market (e.g. Benecol, Flora Pro Active) which allow people to work plant stanols and sterols into their diet more easily. Guidelines generally support the intake of 2 to 2.5 g of plant stanols and sterols per day as part of a healthy balanced diet. Most studies have shown that there is no benefit to consuming higher quantities, and that in fact larger amounts may interfere with the absorption of fat soluble vitamins, so it is important to limit intake of these to within the recommended guidelines. It is safe to take plant stanols and sterols alongside statins, but they are not recommended for people taking ezetimibe, or for pregnant or breastfeeding women.

11 - Red yeast rice As the name might suggest, red yeast rice is a bright red/purple fermented rice, frequently used in Chinese cooking, and also in Chinese medicine. Back in 2008 red yeast rice hit the headlines following a study in China, which showed a correlation between intake of red yeast rice and lower cholesterol levels, which in turn led to fewer deaths from cardiovascular disease within the group that had been taking it. 4,870 people were used in the trial, and they were all individuals who had experienced a heart attack in the five years leading up to the trial start date. The participants were put on a controlled diet and taken off any medication that might reduce their cholesterol levels, and were then given either tablets containing red yeast rice extract or inactive (placebo) tablets. The results of the study showed that 10.4% of people in the placebo group had suffered either a heart attack or stroke, or had died during the follow-up period, compared with only 5.7% of people in the red yeast rice group. In some respects this result was not surprising, as one of the first ever statins, lovastatin, was extracted from red yeast rice, and countless studies over the years have demonstrated that lower cholesterol equates with a lower cardiovascular risk. Red yeast rice should not be taken in addition to a statin, since the mechanism of action is the same and the combination may therefore cause toxicity to the liver. Most manufacturers recommend a dose of 1,200 mg daily (typically in the form of two 600 mg tablets), which is estimated to contain around 7 to 8 mg of lovastatin. It is interesting to note that the Food and Drug Administration (FDA) in the US actually considers any red yeast rice product containing lovastatin to be an unlicensed drug, highlighting the importance of caution when taking these supplements. - Almonds Almonds have been shown to reduce LDL cholesterol, in some individual cases by as much as 10 to 15%. Replacing a packet of crisps or other high carbohydrate snack for a handful of almonds might prove to be a swap that could help to reduce cardiovascular risk, but since nuts are very high in calories, patients are advised to limit their intake to around 35 g (approximately a handful) per day.

12 - Oats Oats contain a type of fibre called beta glucan, which binds with cholesterol in the intestine, thereby preventing it from being absorbed. Studies have shown that around 3 g of beta glucan per day can reduce cholesterol by around 10%. 1 g is roughly equivalent to a bowl of porridge, 1 oat breakfast biscuit, 3 oatcakes or a serving of an oat-based breakfast cereal, so three of those would need to be consumed each day in order to confer a cholesterol-lowering benefit. Further information For further information relating to cardiovascular disease and cholesterol, you might find the following resources of interest: The British Heart Foundation The nation s heart charity Heart UK The UK s cholesterol charity JBS3 Risk Calculator Heart age calculator QRISK Calculator Cardiovascular risk calculator Dr. Diana Holdright Ltd t/a Dr. Diana Holdright Registered in England: Company Number , Registered Address: 7 Lindum Terrace, Lincoln LN2 5RP