Heart and Cardiovascular Disease

Dr Paul Clayton, Medical Pharmacologist, Former President of the Forum on Food and Health at the Royal Society of Medicine

My life in nutritional science

My science

HEART AND CARDIOVASCULAR DISEASE
SUMMARY

The reason why foods are so much more protective than drugs is because the right combination of foods (plus supplements), can, unlike magic bullets, provide a complete ‘pharmaco-nutritional’ support programme – ie. support all the body’s defence mechanisms.

They can be combined to provide a comprehensive range of bio-active compounds to resolve, not just one, but all the known biochemical and physiological problems implicated in the pending heart attack victim.

Once this person’s blood chemistry and cardio-vascular physiology have been normalised, he or she is effectively immune to heart and blood vessel disease. This is a situation that exists naturally in parts of the world where sudden (cardiovascular) death is rare – as in Crete.

Heart and cardiovascular disease

Heart disease – and how to prevent and even reverse it – is a classic example of how the drug companies have oversimplified the problem and attacked the wrong targets with yet another set of ‘magic bullets’.

It’s also an example of how inexpensive and simple lifestyle changes can succeed where multi-billion-pound Big Pharma is failing.

Heart disease is usually the number one cause of death in the UK, although every now and then (as is the case today) cancer nudges ahead. In 1996 coronary artery disease was responsible for 24% of all male deaths in England in the over-65 age group, with strokes and other circulatory disease bringing the total death rate to 33%. Women are slightly less at risk but here too the figures are dispiriting, with heart disease causing 21% of all deaths.

The UK statistics, already the worst in the world, are due to get worse – in line with the increasing figures for obesity and diabetes. For example, Irish and Scots men are three times more likely to die of coronary artery disease than their French counterparts, and their wives are nine times more likely to die in this way than their French sisters. This is the well-known French Paradox.

It certainly does seem unfair that the French, with their full fat cheeses and their pestilential Gauloises and Gitanes, should enjoy such immunity. The reasons for this immunity are becoming progressively clearer, and are everything to do with the French lifestyle – and especially their diet. It’s not any one individual item on the menu but a heart-healthy combination of fresh fruits and vegetables, olive oil, red wine, dark chocolate and black coffee – and the nutrients in them.

Of course, there are always Big Pharma’s drugs – and plenty to choose from! In the pre-heart attack phase there are drugs to lower cholesterol, drugs to lower blood pressure and drugs to make blood platelets less sticky.

As the disease progresses and angina sets in there are drugs to slow the heart and reduce its workload, so that it requires less oxygen. And once the heart attack has occurred, there are drugs to alleviate the pain, drugs to dissolve blood clots and drugs to reduce the risk of a fatal arrhythmia. Sorted?

No. The drugs are expensive and cause many adverse effects. The ACE-inhibitors, for example, have one of the worst track records of any drug category for causing adverse effects. To make matters worse, the impressive array of drugs listed above is lamentably ineffective – they may treat some of the symptoms of heart disease, but they do little to prevent it from worsening, as our national statistics so clearly show.

Why are we getting it so wrong?

MAGIC BULLETS, WRONG TARGET

For one thing, the drugs (which are, like all magic bullets, aimed at very specific targets) are fundamentally misguided. In the incipient heart attack victim many things are going wrong. So any strategy designed to knock out just one single element in the complex array of metabolic imbalances that drive the growth atheroma, is bound to be relatively ineffective.

Atheroma is the term that describes the fatty deposits on the lining of the arteries – ie furring of the arteries. Atheroma narrows the arteries, causing increased blood pressure and can result in angina, heart attacks and strokes.

In addition, the choice of targets involved in the design of most of the drugs in current use is poor, to put it mildly. None of them actually addresses the main problem which is a chronic inflammation of the arteries, known as Endothelial Dysfunction or ED.

When the lining of the arteries is inflamed, several potentially damaging mechanisms come into play. The degree to which arteries become narrowed, for example, is the end result of a balance of ‘dilator’and ‘constrictor’ influences. Dilators encourage the arteries to keep open, dilators encourage them to close.

When ED develops, the arteries become less sensitive to dilators and the constrictors dominate. The arteries narrow, and blood pressure goes up. At the same time, the sites of the inflammation attract immune cells that migrate into the inflamed tissue and break down, forming atheroma. (This is the main reason why high blood pressure is associated with an increased risk of heart attacks. Both have a common cause, namely the inflammation of ED.)

The vital significance of ED has not yet been recognised by the drugs industry. They are still selling products based on the now substantially discredited idea, dating back to the ’50s, that excess cholesterol in the arteries is due to excess cholesterol in the blood, which in turn is largely due to excess cholesterol in the diet.

This rather crude idea was kick-started by a plethora of studies in different countries orchestrated by Ancel Keys, aka ‘Monsieur Cholesterol’ (Keys et al ’71, ’86). This body of research showed that in countries with higher dietary intakes of saturated fats and cholesterol, rates of heart attacks were higher than in countries where less cholesterol was consumed. Further evidence came from studies in which animals such as rabbits were force-fed cholesterol and subsequently developed atheroma.

But there is nothing as powerful as an error of thought whose time has come. Nobody seemed to mind that the cholesterol-fed rabbit was a preposterous idea. Cholesterol only occurs in animal-derived foods (meat, dairy, eggs), and rabbits are, on the whole, vegetarian.

And while one interpretation of the Keys data was that cardiac risk rises as cholesterol intakes increase, everyone forgot there was another, equally plausible explanation. When people eat more animal products, they eat fewer plant foods such as fruits, vegetables and whole grains.

The rise in heart attacks could equally have been because meat-eating folks were losing the protection that a largely vegetarian diet had previously conferred. And in fact we now know that plant foods contain a whole range of protective compounds. As these are removed from the diet, the risk of ED, and a subsequent heart attack, inevitably increases.

The drug companies have not developed this idea commercially. Perhaps this is because the most effective tools to damp down ED are the flavonoids. Flavonoids are naturally occurring anti-inflammatory compounds in fruits and certain spices, which target the blood vessel linings and restore normal vascular function surprisingly rapidly.

These compounds are relatively cheap, they can be extracted from a variety of fruits and spices, and as we have been eating them as part of our normal diet for millennia, they are very safe indeed. Why would anyone in their right mind prefer expensive and potentially toxic synthetic compounds?

But Big Pharma continues to peddle cholesterol-lowering drugs. The statins, for example, are expressly designed to lower levels of LDL cholesterol; but cardiological experts now know that lowering cholesterol levels is not a very effective way of reducing the risk of a heart attack. In fact, around half of all heart attacks occur in people who have apparently normal levels of LDL cholesterol.

Most doctors won’t tell you this, as they are rewarded, under the terms of the new GP contract, for achieving set targets for statin prescriptions. The drug companies won’t tell you this, for obvious reasons. And nor will those food companies who have jumped onto the same cholesterol-lowering bandwagon, with their potentially disastrous cholesterol-lowering spreads and yoghurts.

VASCULAR DISEASE – a condition with multiple causes

Many different factors contribute to the overall risk of a heart attack. Although high levels of LDL cholesterol are implicated, it is far from being the most important factor. There are at least 5 other factors.

1. In the average Western adult LDL levels are admittedly too high; but in most people the LDL cholesterol is also insufficiently protected by anti-oxidants and therefore too prone to oxidation. In this state it forms Cholesterol Oxidation Products (COPs) which damage the lining of the arteries, setting up sites of inflammation and exacerbating ED.

2. Levels of HDL cholesterol (the protective form) are too low.

3. Levels of the toxic amino acid homocysteine, which can also drive ED, are too high.

4. The inflamed artery walls produce molecules which attract immune cells into the arterial tissue. In turn, smooth muscle cells in the inner layer of the arteries begin to proliferate (Picture 2), leading to a narrowing of the artery. This reduces blood flow to the heart and can cause chest pain – angina pectoris.

5. Blood platelets are too sticky and therefore clump together – which makes it easier for blockages to take place.

The five factors listed above also explain why LDL cholesterol levels alone are such a poor indicator of risk. In fact, fully half of all heart attacks occur in people with normal LDL levels. LDL levels are just one element in a complex balance of factors which affect overall risk.

If the person with high LDL levels is also low in antioxidants, high in homocysteine and low in anti-inflammatory agents like the flavonoids – a pattern common in those who eat a Western diet – high LDL levels will indeed increase the risk of a heart attack.

But if the person with high LDL is eating a diet replete in antioxidants, B vitamins and anti-inflammatory compounds, high LDL will have little effect.

It is because there is a complex, combined sequence of events that leads to a heart attack, that magic pharmaceutical bullets targeting only one element are doomed to ineffectiveness.

In addition heart disease does not, of course, develop overnight. When its symptoms become overt – tingling in the arms and hands, high blood pressure, angina, chest pain etc – the disease has already been progressing for years. Fortunately the state can be halted and reversed in months.

HOW THE DRUGS WORK

Statins
For some time it was thought that the rather slight degree of protection against heart attacks conferred by the statins was due to their ability to lower LDL cholesterol.

Recently, however, a series of chance findings showed that some of the drugs in the statin group have slight anti-oxidant and anti-inflammatory effects. It is now thought that these effects, rather than the cholesterol-lowering effect, lie behind their modest cardio-protection. In other words, they are behaving like synthetic flavonoids.

As could have been predicted, they are less effective than real flavonoids and significantly more toxic, to the point where experts no longer recommend them for use in the elderly. They are associated with some reduction in the risk of heart attacks but, unexpectedly, do not prolong life This could be due to the fact that they have conflicting effects on cancer risk (Lam & Cao ’05); they may increase the risk of breast cancer (Duncan et al ’05), while possibly lowering the risk of prostate cancer (Shannon et al ’05).

ACE-inhibitors lower blood pressure and thereby reduce the risk of strokes, as do other anti-hypertensive drugs such as the thiazides and the beta blockers.

None of these, however, prevent the accumulation of atheroma in blood vessel walls; none of them reduce the risk of a heart attack significantly; and two of the three, the ACE-inhibitors and beta blockers, are among the medication classes most likely to cause adverse drug effects.

As for the aspirin-type drugs which reduce the tendency of platelets to form clots – one of the last links in the chain that leads to a heart attack – they also have no effect on atheroma formation at all.

The Mediterranean Diet – a common-sense solution

A groundbreaking French study published in Circulation had already compared the effectiveness of the Mediterranean diet versus drugs in preventing heart attacks, and had shown that dietary change was about 3 times more protective than statins (de Lorgeril et al ’99).

In the same edition of the same journal, scientists at the University of Naples showed that the Mediterranean diet had an array of beneficial effects in people with the metabolic syndrome, a condition characterised by obesity, high blood pressure, increased blood sugar and a very high risk of cardiovascular disease (Esposito et al ’04).

In this group, the diet decreased blood pressure, body weight, levels of glucose, insulin, total cholesterol and triglycerides (blood fats) and increased levels of HDL (high-density lipoprotein) cholesterol – to the point where half the Mediterranean group were effectively cured, and fell out of the high risk category altogether.

A parallel Greek study demonstrated significant reductions in blood pressure and in Spain the traditional diet was strongly linked to lower body weight.

Features of the Mediterranean Diet

A Mediterranean diet is generally defined as one rich in plant foods and fish, low in meat and dairy products, and with a high ratio of monounsaturated fatty acids (like olive oil) to polyunsaturated fatty acids. But there is not just one Mediterranean diet, but several – and the differences between them are significant.

The Keys ’86 study had found that although Italians and Cretans both eat variants of the Mediterranean Diet, death rates from heart disease in Crete were half those in Italy, while the heart disease rate in Italy was a tenth of that in the USA. (The Cretan heart disease rate is just 5% of the USA!!)

This was why the diet used in the French trial, which proved to be so much more effective at protecting people against heart attacks than statins, was a modified version of the Cretan diet.

Why food is better than drugs

The reason why foods are so much more protective than drugs is because the right combination of foods (plus supplements), can, unlike magic bullets, provide a complete ‘pharmaco-nutritional’ support programme – ie. support all the body’s defence mechanisms.

They can be combined to provide a comprehensive range of bio-active compounds to resolve, not just one, but all the known biochemical and physiological problems implicated in the pending heart attack victim.

Once this person’s blood chemistry and cardio-vascular physiology have been normalised, he or she is effectively immune to heart and blood vessel disease. This is a situation that exists naturally in parts of the world where sudden (cardiovascular) death is rare – as in Crete.

The Cretan Diet

1. Use olive oil as the principal oil, replacing other fats and oils.
2. Moderate consumption of wine, normally with meals; one to two glasses per day.
3. Eat fresh fruit as a daily dessert; limit sweets with significant amounts of sugar and saturated fat.
4. Eat plenty of plant-derived foods including fruits and vegetables, wholegrain breads and cereals, beans, nuts, and seeds.
5. Eat minimally processed and seasonally fresh, locally grown foods.
6. Total dietary fat should not exceed 35 percent of energy, with saturated fat no more than 8 percent of total calories.
7. Eat low to moderate amounts of cheese and yoghurt daily.
8. Consume moderate amounts of fish, esp oily fish and poultry weekly; limit eggs to four per week.
9. Red meat no more than once a week.

And add Supplements

One can take the pharmaco-nutritional strategy a step further by focusing on those food supplements whose pharmacological effects have been shown as having a positive effect on the several origins of the disease. The key ones are:

1. Curcuminoids (1-2g/day in divided doses)
The curcuminoids (derived from turmeric) have an extensive range of cardio-protective properties. Curcumin reduces LDL cholesterol in human subjects, slows cholesterol oxidation and raises HDL cholesterol.

Curcumin also lowers (improves) the ratio between what is known as apo-A and apo-B. These are two compounds in the blood which are strongly correlated with the risk of a heart attack. Improving the ratio is considered to be very cardio-protective.

Curcumin also inhibits excessive blood platelet activity, damps down ED by suppressing the formation of inflammation in the lining of the artery walls, and prevents the excessive growth of smooth muscle cells in the artery wall. This is a highly protective series of effects, which add up to a greater degree of cardio-protection than provided by the statins.

It is quite likely that curcumin also blocks ACE, but this has not been studied. Related flavonoid compounds inhibit this enzyme, and reduce blood pressure as a result.

2. Antioxidants
Trials have shown that the classical antioxidants (Vitamins C and E and beta carotene) are ineffective in reducing the risk of vascular disease when used on their own (Heart Protection SCG ‘02), but it makes sense to use them as ingredients in a more comprehensive cardio-protective programme.

A combination of mixed tocopherols (from the Vitamin E family), beta carotene, lutein and lycopene and Vitamin C is the best way to stabilise LDL cholesterol particles, preventing the formation of toxic cholesterol peroxides, which would otherwise increase inflammation in the arterial walls, driving endothelial dysfunction (ED).

3. Omega 3 fatty acids

These are worth adding to the list of ingredients. At low levels of intake (ie 0.9 g/day), they reduce mortality among patients who have already suffered a heart attack. Omega 3 is incorporated into the membranes of heart muscle cells and make the heart less likely to develop a fatal arrhythmia after a heart attack has happened (which I regard as a very late form of protection indeed).

There is considerable debate as to how the omega 3s do this, but in any case this kind of protection is overshadowed by the more substantial benefits conferred by the improvements in triglyceride (blood fat) levels, blood pressure and inflammatory tendencies which can be achieved at intakes of around 2 g / day and above.

Unfortunately, relatively few in the UK are able or willing to eat sufficient amounts of oily fish, calculated at 5 portions per week (SACN ‘04) to achieve these benefits. The answer is a supplement.

4. Resistant starch – or fermentable fibre

This has a variety of effects on blood fats. A recent review suggested that its main impact is to lower LDL cholesterol levels in people with raised cholesterol, and to lower triglycerides in people with normal cholesterol. But it has a more important benefit.

As resistant starch has a low or zero glycemic index (see below), it is a particularly useful dietary substitute for ordinary starch, and in this role is highly cardio-protective. Moreover there is good evidence that it reduces colorectal cancer risk. The following link takes you to an good explanation of how fermentable fibre confers many health benefits. http://smoothie.fs-server.com/user/ArichSource.aspx .

5. Reduced dietary glycemic load

There is a rapidly growing body of evidence that diets with a high glycemic load (ie containing large amounts of starches and sugars) increase the risk of cardiovascular disease. Blood glucose control, as measured by glycosylated haemoglobin (the ‘marker’ HbA1c) is a strong risk factor for heart attacks and strokes, and diabetic complications such as blindness.

In apparently healthy individuals HbA1c is about 4.5% of total haemoglobin. Typical ‘at risk’ levels are 8 – 10% and above.

Each additional 1% increase in HbA1c correlates with an additional 20% risk of a heart attack or a stroke, which makes it one of the most heavily weighted risk factors known. HbA1c does not itself do the damage, but is merely a marker of blood glucose. When blood glucose is too high, the trouble starts.

High blood glucose levels cause excessive formation of free radicals in the linings of blood vessels, leading to inflammation and ED (endothelial dysfunction). High blood glucose levels also form Advanced Glycation End products (AGE), which also cause inflammation.

Finally, excessive levels of glucose also damage (‘glycate’) proteins in the blood vessel walls, cross-linking them together in a way that makes arteries less elastic. This is another very significant risk factor that denotes early heart disease.

Reducing the glycemic load of the diet would seem to be a healthy option, and has been shown to reduce both the risk of developing diabetes and a range of risk factors including HbA1c.

In diabetics, a 15% reduction in dietary GL over 12 weeks reduced HbA1c by 2%. This translates into a 40% reduction of risk of heart attack and stroke (2), and a 50% reduction in the risk of diabetic induced damage to the eye.

To put this into context, cutting 30g of carbs (eg. one potato) out of your daily diet could lower your risk of developing diabetes and diabetic complications by almost a third!

An ideal complement to the low-GL diet would be a high intake of flavonoids such as the curcuminoids, listed above. These valuable compounds are not only anti-oxidants and anti-inflammatory agents but also have the ability to prevent the protein damage that causes cross-links, inflammation, constriction of arteries and increased arterial stiffness.

The main structural proteins in your arteries are collagen and elastin. Once these proteins have cross-linked and your arteries have stiffened, the flavonoids will still work. However, they will need to be taken for at least 6 months, because that is how long it takes for the body to lay down new, undamaged proteins.

6. B vitamins: B4 (aka folate), B6, B12 and B10 (aka betaine)

Excessive levels of homocysteine in the blood are common in the developed nations, and are associated with an inflammatory state. In the USA, folic acid fortification has been shown to improve homocysteine status, and heart attack mortality figures show a fall in deaths since fortification started in 1998 (Pfeiffer et al ’05).

Homocysteine reduction via B vitamin supplementation alone is insufficient to achieve the desired protective effect (Bonaa et al ’05), and is not recommended.

In fact, I do not recommend any form of nutritional mono-therapy ie using one nutrient on its own. Foods naturally contain a combination of nutrients for health. Indeed the objective in designing a supplement is to supply an ideal mix of the most protective nutrients – but without the calorie load that inevitably comes with food.

7. L-arginine

Another supplement worth considering is the amino acid L-arginine. This amino acid is broken down by the enzyme Nitrous Oxide Synthase (NOS) to form nitrous oxide, a potent vasodilator (ie. artery dilator), and it improves arterial function in a variety of disease states from endothelial dysfunction through to advanced atheroma (Dhawan et al ’05, Parnell et al ’05).

L-arginine has been successfully used to improve arterial elasticity (Hawes ’05), and may do so in part by countering the tissue-damaging effects of a molecule called ADMA (Boger ’04, Boger & Ron ’05). ADMA appears to be far more toxic than homocysteine, and is deeply implicated in a variety of diseases including atherosclerosis, hypertension, chronic renal failure, chronic heart failure and liver disease, where it is an extremely strong predictor of death (Hodges ’05).

8. Lifestyle

The careful reader will have spotted that the pharmaco-nutritional programme described above coincides to a large extent with the Mediterranean diet, and especially with its superior variant, the Cretan diet.

This combines low GI with high levels of flavonoids and other antioxidants, B vitamins and resistant starch/fermentable fibre. If you add to that oily fish (which the Cretans do not eat much of), and L-arginine, available in supplements, the evidence points to decades of extra life expectancy.

You could also assume the recommended lifestyle elements of physical activity and no smoking, although these virtuous habits are not always easy to maintain. Drinking moderate amounts of alcohol might be an easier target for some!

A public health programme that integrated the above lifestyle changes with a Mediterranean diet and nutritional supplement support would, I believe, make heart disease, diabetes and stroke disappear.