Friday, 14 October 2016

Cholesterol, Statins, and the Council of Nicaea

Cholesterol, Statins, and the Council of Nicaea

The Council of Nicaea, 325AD (Western painting)

A research paper might have a long list of authors, especially in the times of advanced scientific technology and many sites of collaboration. This is expected, and it is important to include the names of all those who contribute to the research. A characteristic of research papers from The Large Hadron Collider at CERN, France and Switzerland, is that there are usually hundreds of authors, and according to New Scientist (September 24th 2016) the first author has always, until very recently, been Georges Aad (by now very famous) as the authors have been listed alphabetically. 

When it comes to review articles, we might expect more than one author, perhaps just two or three. And so it was very surprising to come across a review article in a recent edition of The Lancet that had 28 authors. The first author is Professor Sir Rory Collins from Oxford University. After the first three authors, the next 24 appear to be in alphabetical order, with Professor Sir Richard Peto given the final place on the list.

Why does a review article require so many distinguished authors? 21 are professors and so they are obviously past the stage in their professional careers that requires their names to appear on as many publications as possible. What can be the purpose of a review article that requires so many distinguished authors?

The title of the paper is:

Interpretation of the evidence for the efficacy and safety of statin therapy 
Rory Collins, Christina Reith, Jonathan Emberson, Jane Armitage, Colin Baigent, Lisa Blackwell, Roger Blumenthal, John Danesh, George Davey Smith, David DeMets, Stephen Evans, Malcolm Law, Stephen MacMahon, Seth Martin, Bruce Neal, Neil Poulter, David Preiss, Paul Ridker, Ian Roberts, Anthony Rodgers, Peter Sandercock, Kenneth Schulz, Peter Sever, John Simes, Liam Smeeth, Nicholas Wald, Salim Yusuf, Richard Peto 
The Lancet (September 8th 2016 on line)

It might be thought that we have heard enough of statins being wonder-drugs saving countless thousands of lives. What's new? – Nothing! 

The randomised controlled trials were published several years ago and statins are the most widely prescribed drugs in the world. Why is it necessary for such a review to be published in The Lancet at this stage?

The stated aim at the start of the paper is expressed as follows: "This Review is intended to help clinicians, patients, and the public make informed decisions about statin therapy for the prevention of heart attacks and strokes."

I doubt if many clinicians will read this paper (30 pages) and its references (307). It is tedious and far from an easy read. To expect patients and the general public to read it is ridiculous. 
The statin trials are based on the diet–cholesterol–heart hypothesis, which is far from robust. The statin trials are therefore not objectively simple drugs trials, but are seen by the evangelists of the hypothesis to be strengthening the cholesterol–heart hypothesis itself (the diet component appears to be quietly dropped). 

We usually see in the title “Cholesterol-lowering with statins….”, which links the two variables. Statin medication is carefully controlled in the trials and is randomly allocated to half of the participants. But the cholesterol effect is not controlled: it is just observed in response to the statin medication.
There are many cholesterol sceptics, and I am one. By this I mean that the proposal that cholesterol causes coronary heart disease (CHD) does not stand up to serious scrutiny. Nor does it follow that statins are of benefit because of their undoubted cholesterol-lowering effect.

A paper of mine was published in The Lancet  (Lancet. 2006 Jul 1;368(9529):83-6) a number of years ago, questioning the way in which statins are helpful, the mechanism likely to be other than cholesterol-lowering. I drew an analogy with the treatment of epilepsy a century ago. At that time it was thought that epilepsy was caused by excessive masturbation (no-one defined "excessive"). The logical treatment was therefore bromide, the purpose being to suppress sexual fantasy and arousal. The treatment worked, but for reasons disconnected from the logic (bromide was later replaced by phenobarbitone, a sedative and anticonvulsant). Similarly, the idea that cholesterol causes CHD led to a logical treatment with cholesterol-lowering remedies. Of these only statins have been found to be effective, but this is empirical treatment and its effectiveness cannot be assumed to result from the logical indication.

Scepticism of the diet–cholesterol–heart hypothesis does not please Collins, the current leading exponent of the dogma. By the use of 28 distinguished authors and 30 pages of the prestigious Lancet, the paper is clearly designed to intimidate  and silence sceptics.

This sort of thing has happened before the present time.

The Council of Nicaea

During the first 300 years of Christianity, there were many different churches, many different books about Jesus and the events subsequent to his crucifixion. All were probably contented, that is until Christianity was hijacked by the Roman Empire. In 313AD the emperor Constantine the Great put an end to the persecution of Christians and he himself embraced the religion. It became the official religion of the Roman Empire in 380AD (the Edict of Thessalonica).
Emperor Constantine (statue at York Minster, UK)
However this gave no regard to the fact that different people or churches had different views of Christianity. Constantine declared himself the head of the Christian Church, not just the Emperor of the Roman Empire but also the “Emperor of Christianity”. If his authority was to be respected then the church must be unified.
To achieve this he convened the ecumenical Council of Nicaea in 325AD, with about 300 bishops being present. It was what we would call today a “consensus conference”. The result was the Nicaean Creed (the "consensus statement") which stated the official view of Christianity. The Creed was of course supported by a ruthless treatment of heretics in the western church.

The Council of Nicaea, Eastern icon
There was also a problem with the many books about Jesus and subsequent events in the first century of the present era. Many were rejected and considered to heretical, and following their destruction or disappearance, heterodox views were suppressed and lost. Aspects of what  must be regarded as the “truth” were hidden from the public domain and only few people know of those that have survived.
The paper by Collins et al in The Lancet is not unlike The Nicaean Creed (but much longer), and the 28 authors are not unlike the Council of Nicaea. The objective is clearly to suppress heterodox views and to bring to an end dissent of the diet-cholesterol-heart hypothesis. And also of course to bring to an end any debate or discord over the extensive and uncritical use of statins (“statins for all by the age of 50” - The Lancet).

The true benefit of statins
As we will see, statin drugs are of undoubted benefit, but there remains concern as to how much benefit. Does everyone benefit or just a few? There are side-effects; these can be troublesome but not dangerous. Do the benefits outweigh the side-effects?
The side-effects are uncommon, as the Lancet paper describes at great lengths. There are those who feel that the side-effects outweigh the benefits, but the paper strongly disagrees with this. The main side-effect is muscle pains, troublesome but not serious. It would be as well to know what the benefits are. 
The thrust of the paper is that all reliable evidence comes from the controlled clinical trials. The first section of the paper was to review the purpose and conduct of clinical trials in general, not really relevant to the alleged purpose of the paper but designed to strengthen authority. 
The paper also warns against using information obtained from observational studies – only the clinical trials are to be regarded as important sources of information. Unfortunately, the original data from the trials are held by the pharmaceutical companies that commissioned them.

CHD risk reduction
A lot of numbers are presented in the paper but the origins of them are far from clear. A 20% reduction in death rate from CHD is mentioned several times and although this is actually correct, it requires a level of understanding that was not presented in the paper. The various clinical trials of statins have shown that this proportional death rate reduction is consistent, at between 20% and 25%. This of course begs the question of “What is the death rate that is being reduced? 25% of what?” 

When it comes to the absolute reduction of death rate, the paper mentions a measure the origin of which is not clear. The absolute effect is assessed indirectly by the mmol/L reduction of LDL cholesterol. 

Remember that cholesterol is attached to protein in the blood and is found in three major forms: low density lipoprotein (LDL, “bad” cholesterol) very low density lipoprotein (VLDL, small in amount and not of major importance), and high density lipoprotein (HDL, the “good” cholesterol). The Lancet paper refers to LDL cholesterol, as is usual in more recent studies.

Cholesterol is in reality a poor indicator of CHD risk, and in the important forty-year Framingham Study (which will never be repeated) it is only applicable to men below the age of fifty. Figure 1 shows that 30 year survival is best (82%) in men aged 31–39 with the lowest blood levels of cholesterol (less than 4.7mmol/L) and worst (67%) in the those with the highest cholesterol (greater than 6.8mmol/L)

Figure 1 Cholesterol and survival, men age 31–39

Although blood level of cholesterol predicts the risk of death in the younger men, in older men there is no difference in 30 year survival based on the blood level of cholesterol. This is shown clearly in Figure 2. 

Figure 2: cholesterol and survival, men age 56–65
It is only to be expected that survival is much less in men aged 56–65 than in those aged 31–39. In the older age group, only 10% survived 30 years, that is to the age of 90. The survival curves are the same in all cholesterol groups.

The Framingham paper states:

The graph in Figure 1 (younger men) is used by cholesterol enthusiasts as a basis to predict a reduction of CHD deaths or events based on the reduction of blood cholesterol by statin therapy. The result in young men is usually extrapolated to older men and to women.

Figure 1 provides the basis for the use of absolute reduction of CHD deaths/events (improved survival) per mmol/L reduction of LDL-cholesterol. However the Framingham study was observational and so predictions based on it should be cautious.

This expression of a reduction of CHD deaths/events by statin therapy based on cholesterol-lowering is indirect and it is far from clear in the statin trials. It is a prediction. Unfortunately, and probably by design, the original data from the various trials are not generally available. The data are held by the pharmaceutical companies that commissioned the trials, and they have not been released despite frequent requests from independent academics led by the British Medical Journal.

West of Scotland


The first published statin trial of the primary prevention of CHD deaths using statin drugs was conducted in the West of Scotland: the West of Scotland Coronary Prevention Study, known as WOSCOPS. It was published  in 1995, but there was an important second paper published in 1998. This contained a great deal of original data, the equivalent of which has not been made available in the publications from the statin trials published later. 

WOCOPS was a randomised controlled trial of pravastatin involving 6595 men aged 45–64 years with an average blood cholesterol level 7 mmol/L (272 mg/deciliter), and followed up for 4.9 years. The men recruited into the trial had no previous clinical features of CHD – it was a primary prevention trial.

At the end of the study period, 4.1% of those in the placebo control group had died, and 3.2% in the pravastatin treated group. Pravastatin appeared therefore to be effective. It is important that there is a reduction of total deaths, as the easiest way to reduce only CHD deaths would be to cause an increase in deaths from something else.

The results show both definite coronary events and definite plus suspected coronary events. For the purpose of this brief analysis I will use the “definite + suspected” data. 

Deaths from definite + suspected CHD were 1.9% in the placebo group and 1.3% in the pravastatin group. Non-fatal MI occurred in 7.8% of the control group and  5.8% in the pravastatin group. Again effectiveness of statin therapy.

The absolute benefit from statins

The absolute reduction of all-cause death was 4.1% - 3.2% = 0.9%, approximately 1%. The absolute reduction in CHD death was 1.9% - 1.3% = 0.6%. The absolute reduction of non-fatal MI was 7.8% - 5.8% = 2%.

This is all simple and straightforward. The data is clearly presented in the WOSCOPS paper and it can followed easily. It logically means that for every 100 men aged between 45 and 64 years in the West of Scotland given pravastatin for five years, just one did not die as a result of the pravastatin (from 1% absolute reduction). It required 170 (from 0.6%, 100/0.6) to be treated to prevent one specific CHD death, and 50 (from 2%, 100/2) to prevent one non-fatal MI. 

These simple calculations can be expressed as the “number needed to be treated” (NNT) to achieve one endpoint, in this case death, CHD death or non-fatal MI. This is the best measure of effectiveness of a medical treatment, favoured by health economists but not by pharmaceutical companies.

This clear and simple approach to assessing effectiveness is not presented in the  paper by Collins and colleagues.

Proportional reduction of deaths

A 0.6% reduction in CHD death does not sound very dramatic, nor does a 2% reduction of non-fatal MI. They would certainly not be good for the marketing of statins. Therefore the pharmaceutical companies, and the research doctors and statisticians who they support or effectively employ, express benefit as the proportional reduction of death or other event rate. This was used in the paper by Collins and colleagues.

The proportional reduction is the proportion of expected deaths that did not occur in the treated group. It is calculated from the absolute death rate reduction in the treated group divided by the death rate in the placebo (control) group:  

1.9% - 1.3% / 1.9% 

and then expressed as a percentage, therefore 

0.6% / 1.9% = 32%

This widely-used calculation involves taking a percentage of a percentage, which is mathematically unsound.

We see a 32% reduction of CHD deaths in WOSCOPS. By a similar calculation we can arrive at 25% reduction in all-cause deaths, slightly higher than the 20% in most subsequent statin trials. 32% and 25% sound to be much more dramatic than 1%. However it begs the question, 32% or 25% of what? 

The answer is a 32% and 25% reduction of the current CHD and all-cause death rates in people not taking statins. If the current death rate is high we can expect a significant population benefit, but if the death rate is low there will be very little benefit.

As the death rate from CHD goes down (a good thing), the NNT goes up (a bad thing). There must be point at which the NNT is so high that statin medication for healthy individuals ceases to be of benefit to the population.

In the West of Scotland in the 1980s (the time of recruitment into WOSCOPS) the total death rate in middle-aged men was 4.1% after five years, as we have seen in the control population. This is 0.8% per year, and it equates to 800 per 100,000 per year. 

The background CHD death rate of these men in the West of Scotland in the 1980s was 1.9% after 5 years, or 0.4% per year (again from the control population). This is 400 per 100,000 per year. We can therefore see that half of all deaths in this age-group and in this location at this time were due to CHD. This was the epidemic at its greatest.

Scotland today - the utility of statins

Here we meet a problem. The calculation of the death rate from the specific group studied in WOSCOPS does not immediately translate into the data that comes from national statistics. In 1970 the peak death rate of 600 per 100,000 in Scotland was age-standardised, whereas WOSCOPS presented raw data that had not been manipulated for the purpose of national and international comparisons.

WOSCOPS, like other trials was snapshot, and we must look elsewhere if we wish to see any change in CHD deaths with time.

Figure 3: Changing CHD mortality in the UK, 1971–2013

We can see in Figure 3 (from the Scottish Office) that the age standardised male death rate from CHD in Scotland has fallen from 500 per 100,000 at the time of recruitment to WOSCOPS in the 1980s to 150 per 100,000 in 2013. This equates in 2013 to 0.15% per year CHD deaths, 0.75% at five years. 

We can expect statins to reduce the 2013 death rate at five years by 25%, from of 0.75% to 0.56%. The absolute reduction is therefore 0.19%. We can round this to 0.2% and the NNT is therefore 500 (0.2 x 500 = 100). This means that in 2013 in Scotland, 500 men aged 45–64 would need to take a statin for five years for one death to be delayed (immortality is not an option).  

The NNT would be about 1000 for women of that age whose death rate from CHD is about one half that of men. It would be much greater for men in their 40s than for men in their 60s. If the annual death rate in men at the age of 40 were 0.015% rather than 0.15%, the NNT would be 5,000 and for women 10,000. 

The age range of recruits into WOSCOPS was between 45 and 64 years. This is a wide age range. At present in the UK the risk of CHD death in men in the 55–64 age group is three times higher than in the 45–54 age group. This would mean a three times greater NNT. In the age group 35–44 the CHD death rate is one-ninth than in 55–64 age group, with a corresponding nine times greater NNT. This would be 18 times greater in women age 35–44, about 10,000. Hopefully not many healthy younger women are taking a statin.

The NNT is the true measure of the benefit of statins (or any other medication), and it is against this that the disadvantage of side effects must be balanced. 

The price of statins and the cost of benefit

There is also the financial cost to be considered. The present cost of 500 men treated for five years must be borne by the one who benefits and does not die during the five years. At the time of WOSCOPS only propriety pravastatin was available, the price being approximately £1 per tablet. For an NNT of 200 to prevent one CHD death the cost would have been £365,000, perhaps judged to be good value for money at that time. For reduction of all-cause death the cost would have been half that, £180,000 (there were slightly fewer trauma deaths in the pravastatin group).

The price of a non-proprietary 40mg pravastatin tablet is now £0.066. With the present CHD death rate and an NNT of 500, the cost of preventing one male CHD death is £60,000 (giving the statin at about the age of 60 years). To prevent a female CHD death, £120,000. Whether or not this is good value for money is a matter of judgement, but it must be balanced against other competing health-care costs and financial pressures.

In the younger women (35–44) with an NNT of 10,000, prevention (delay) of one death would cost £2.4 million! 

The elderly paradox

We have seen that one conclusion of the Framingham Study was that blood level of cholesterol did not determine life expectancy in men (and women) above the age of 50 years.

Other observational studies have shown a lack of positive association between blood levels of cholesterol and survival in the elderly (see previous Post). Some studies, and particular those from Paris, Honolulu and Connecticut, have shown that a high cholesterol level does not provide a survival disadvantage, and perhaps gives a longer survival. If despite this statins give an advantage, it would not be in keeping with the cholesterol hypothesis. Statins are prescribed only on the basis of blood level of cholesterol: in The Lancet, Collins et al make this clear.

The paper discussed this apparent paradox arguing that there is no paradox. It is stated that the elderly with low cholesterol levels had cancer or some other near-fatal condition. This was excluded in the various studies. However the subjects in these studies would have been frail as they had lost their independence and they were living in residential accommodation. 

To refute the suggestion that blood level of cholesterol is not a determinant of survival in the elderly, or even that a high level might be an advantage, Collins and colleagues referred to a British Medical Journal paper from 1994. This paper investigated the possibility that a low blood level of cholesterol might be related to certain disease states and found a weak association only with brain haemorrhage. However the paper (observational) did not stratify the populations or samples according to age and it did not not mention age-groups. Similarly it did not measure life expectancy, which is the measure in the more recent cholesterol–survival observations in the elderly.

This paper was misrepresented by Collins and his 27 colleagues. I wonder how many of the authors had actually read the paper (and its 309 references) to which their names were added.

CHD death reduction and cholesterol lowering.

The Lancet paper did not use the simple direct method of calculating benefit, but the cholesterol-lowering transposition. The second WOSCOPS data gives insight into this. 

The study divided the subjects taking pravastatin into five groups (quintiles) based on the change in the blood level of cholesterol during the study. The observed death rate for each group enabled an assessment of the relationship between death rate and cholesterol-lowering. The results are shown in Figure 4.

Figure 4: WOSCOPS CHD event rate based on change in cholesterol with pravastatin

In the first group (left) there was no change in the blood level of cholesterol (percent change = 0). This was at first puzzling, but it became clear that the men in this group had not actually taken the pravastatin, or at least not reliably. Compliance can be checked in most trials today by detecting randomly the blood level of the drug, but this was not possible in WOSCOPS. We can see that this group, who appeared not to have taken the pravastatin, had the highest death rate of the five groups.

In the other four quintiles there was lowering of cholesterol, by 12%, 24%, 31%, 39%. The tablets had been taken and blood levels of cholesterol had fallen by these amounts. The death rate was reduced in all groups, but unexpectedly by about the same amount. There was clearly no association between the quantity of cholesterol-lowering and reduction of CHD death rate. This is clear from Figure 5, which removes the group in which there was no change in cholesterol (statin not taken). 

Figure 5: lack of association between cholesterol lowering and CHD events

This detail of data has not been made available from the other statin trials. It is ignored in the meta-analysis of Collins and colleagues, the Cholesterol Treatment Trialists’ (CTT) Collaboration. Most publications of CTT appear in The Lancet, perhaps an editorial bias by this journal.


Not only has the truth been hidden from public view in this long and tedious Lancet paper but its highly prestigious multitude  of authors is clearly designed to suppress dissent. 

I would recommend the two WOSCOPS papers (1985, 1988) as they are good examples as to how trial data should be presented, and then a deeper understanding of the data processing. It was an objective trial but its example was not followed subsequently.

The conclusion of the authors of WOSCOPS (1998) reads:

“Analysis of the relationship in WOSCOPS between the pravastatin induced fall in LDL cholesterol and reduction in CHD risk did not yield the predicted result…. fall in LDL cholesterol failed to be a significant predictor of risk reduction….the influence of pravastatin on CHD risk could not be completely explained by the reduction in LDL cholesterol….the benefit seen with pravastatin treatment, although obviously linked to a decrease in LDL, cannot be explained by this alone.”

This heresy has now been suppressed, but it must not be forgotten. It is one of the major factors that invalidates the diet–cholesterol–heart hypothesis. 

WOCOPS was transparent but subsequent statin trials made certain that much data remains concealed.

Friday, 23 September 2016

Coronary Heart Disease – yesterday, today and tomorrow

Coronary Heart Disease –  yesterday, today and tomorrow

I have previously described the major epidemic of coronary heart disease (CHD). Strictly speaking it was a pandemic as it was international, occurring in all continents simultaneously. It has been described clearly in the UK and in the USA. There is good similar data appearing from Canada. 

The data have been based on recorded death rates. The reason is that death is very distinct and a very definite end-point to life. In respect of CHD it is preceded by a well-defined clinical picture of sudden collapse followed rapidly by death, perhaps with severe constricting chest pain. Deaths from CHD have been quite clearly defined, with probably little diagnostic error.

Patterns of CHD

CHD is fundamentally a pathological process that develops insidiously, without the knowledge of the “sufferer”, until a clinical event occurs after a latent interval of perhaps several decades. The disease is one of atherosclerosis, a low-grade inflammatory process with consequent obstruction of the coronary arteries, found on the surface of the heart. It is actually a bit more than atherosclerosis. CHD is usually patchy within the coronary arteries, with "plaques" that are unstable with possible surface ulceration. It is on the surface of these ulcerations that blood clotting (thrombosis) can occur, with sudden complete occlusion of a coronary artery.

Figure 1: The right and left coronary arteries and their branches

There are five forms of clinical events:
  • sudden death – the result of myocardial infarction (MI), due to complete blockage of one of the coronary arteries, which supply blood to the heart muscle;
  • typical MI – severe constricting chest pain with characteristic ECG changes and rise in blood levels of muscle enzymes;
  • left ventricular failure – a result of myocardial infarction, causing serious impairment of function of the left ventricle, with life-threatening accumulation of fluid in the lungs;
  • angina –  the result of incomplete but serious (>80%) obstruction of a coronary artery, with chest pain occurring on exercise;
  • congestive heart failure – narrowing of coronary arteries over a long period of time, without chest pain but reducing blood flow to the heart muscle, as a result of which the heart does not function adequately and swelling of the legs occurs. 

Figure 2: Atheromatous disease of the coronary arteries
Incidence and prevalence

When we are investigating death, or sudden onset of an illness, we measure incidence. This is the number of deaths (or new cases) occurring in a given population size each year, or other unit of time. The incidence of deaths from CHD (death rate) in England and Wales in 1970 was more than 500 per 100,000 population per year. These would almost all have been deaths from myocardial infarction. (MI)

The incidence of (MI), fatal or non-fatal, can also be calculated, as the number of new cases (events) occurring per 100,000 population each year. This is usually obtained from hospital statistics which are reasonably reliable. One of the successes of the UK NHS with its centralised bureaucracy is its ability to collect comprehensive national statistics. But not all people who develop MI are admitted to hospital and admission rates might vary between localities or countries. 

A further and serious problem is that the diagnostic criteria of MI have changed in recent years. ECG changes used to be an integral part of the diagnosis of MI, and I spent many hours learning about ECG interpretation. But now it is stated that the ECG shows no abnormality or no change in up to 75% of cases diagnosed as MI (called NSTEMI – Non ST Elevation MI). It has been necessary to develop a new test of “highly sensitive troponin” so as to identify such very minor and not dangerous episodes of MI, which in the recent past would not have been identified. In the past the frequent diagnosis of "Chest pain ?cause" had an excellent prognosis. This means that during the past ten years it has not been reliable to look at the incidence of MI  because of such a major change in diagnostic criteria.

When we try to identify the presence of an underlying disease that might not have symptoms, there is no clear and recognisable event at the onset. This would apply to diabetes and hypertension, as well as CHD before clinical features have emerged. We can take a “snap-shot” of a fairly small sample (but the bigger the better) of the population and determine how many people have the condition at any one time. This is the prevalence.

Disease mongering

Defining diabetes and hypertension is a difficult process as there are no clear cut-off points between the “normal” population and those who are considered to have the “illness”. The concept of illness implies that the “sufferer” is at a biological disadvantage in respect of early death or disability. 

During recent years the diagnostic thresholds of many conditions (MI, diabetes, hypertension, kidney failure) have been reduced so that by definition more people have the "illnesses" and fewer people remain “normal”. This has been been called “disease-mongering”, expanding the range of a disease and thereby creating “ill” people out of the normal population. 

This is of very important commercial advantage in many countries to doctors and other health care providers, and also to pharmaceutical companies. There is a significant cost to those who pay, but from the viewpoint of the providers this is someone else’s problem, and of course it is "in the best interests of the general population"!

“Monger” is an old English term for someone who creates or sells things, such as an iron-monger or a fish-monger. It is also used in the expression “war-monger”, someone who creates wars. Disease-monger is thus someone who creates disease by simple change in definition. 

A good example is the new “disease” of female sexual dysfunction, created by medical “experts”. The introductory conference was funded by the pharmaceutical company that was developing the “treatment”. Pre-diabetes, pre-hypertension, and even “high cholesterol” are also non-diseases. They create significant detrimental effects on the innocent “sufferers”, such as increased insurance premiums, increased medical assessments and pharmaceutical interventions, unnecessary dietary restrictions, and of course great anxiety. These activities give no benefit to the great majority.

Identification of sub-clinical CHD

With many conditions the process of testing is easy – a blood test for diabetes or kidney failure, blood pressure check for hypertension. When it comes to the recognition of sub-clinical CHD the process is more difficult. 

Ideally coronary angiograms are necessary for the identification of CHD, being highly specific (very few false positives – when the test is positive it is strong confirmation of the presence of disease) and also sensitive (very few false negatives – if negative the disease can be confidently excluded). But coronary angiograms are invasive, potentially but only rarely dangerous, expensive, and not acceptable as a means of case-finding. It is only when clinical disease has occurred that coronary angiograms are performed. 

Figure 3: Coronary angiogram

CHD is based on an inflammatory process within the coronary arteries, and  as with chronic inflammation anywhere in the body, after many years there can be deposition of calcium in the inflamed tissues. The calcification can be identified on a CT scan and this can be used as a method of detection of CHD. However CT scanning is also an expensive procedure and it gives a high level of radiation. It is therefore not applicable for population screening, especially as the detection of calcium in an asymptomatic person would not lead to any useful intervention. It might result in higher insurance premiums.

Figure 4: Transverse thoracic CT image of the heart showing calcification of coronary artery

Finally, autopsy studies can be used to identify CHD and assess its frequency (prevalence) within the population. This is not very useful at present as many fewer people die young and autopsy rates have diminished considerably.

Early features of atherosclerosis

Those who do die young and on whom autopsy rates are high are soldiers. It was noted during the Korean War (1950–1953) that autopsies performed on soldiers killed in conflict (and also young  civilians killed in road accidents) frequently showed atherosclerotic change and evidence of CHD. This led to the realisation that the disease commenced as early as childhood. It appeared that there were several decades between the onset of the disease process and the occurrence of clinical illness. 

During the war in Korea, (1951–55) almost 80% of young soldiers killed in action were shown at autospy to have evidence of CHD, and almost 20% to have it in a severe form. This in itself is remarkable and at the time was rather frightening. It was evidence of the long latent period between pathological evidence of asymptomatic disease and its clinical expression in future years.

In both rheumatic heart disease and syphilitic heart disease there also is a long interval between the onset of the disease process (an infection) and the onset of the clinical illness. It has been possible to assess the prevalence of both as the conditions could be diagnosed by clinical examination. Auscultation of the heart would lead to the identification of damaged heart valves, characteristic of both rheumatic and syphilitic heart diseases, and a blood test (Wassermann reaction – WR) has long been very useful in the recognition of the late effects of syphilis.

We have seen in previous posts details of the epidemic nature of deaths from CHD (= MI). Evidence from US soldiers killed in action are available not just from the Korean War, but also from the Vietnam War  (1968–1975) and the Iraq and Afghanistan Wars (2000–2011). The results show a major reduction in the prevalence of atherosclerosis and CHD during the time of these three wars, from 1968 until very recently. This can be seen in Figure 5, and I find it to be the strongest evidence of all that we are experiencing the end of a very serious epidemic. 

The important thing is that early evidence of CHD had become quite uncommon (less than 10%) by the early 21st century. The soldiers killed would have been born during the 1980s, a time when exposure to the causative micro-organism had almost passed and when herd immunity within the population was high.
Figure 5: CHD and severe disease found at autopsy in US servicemen killed in action.

Such data are not available from the early stages of the epidemic, from the First and Second World Wars. During WW1 the clinical epidemic had not started and in WW2 there was no major interest in CHD as it was not at the time appreciated as being an epidemic or a major public health problem. 

One thing is clear – that in the early years of the 20th century pathologists conducting autopsies were not aware of a significant prevalence of CHD. It was clearly not a significant cause of fatal disease.  But there is historical evidence of atherosclerosis, the pathological process that underlies CHD.

Atherosclerosis in history

Egyptian mummies, about 3,500 years old, have been shown to have evidence of atherosclerosis. One was the Pharaoh Merenptah, who died in the year 1203 BCE.

Figure 6: Egyptian mummy case (Louvre, Lens)

Soft tissues of the unpreserved body do not survive, and there is serious loss of detail even in mummified bodies. However in chronic inflammatory diseases there is often deposition of calcium in the diseased tissues, and this will remain in mummified bodies. The calcium deposits can be detected by X-ray techniques, especially CT scanning. Although not in general use as a method of screening, it has been used in the scientific investigation of mummies. This has resulted in the detection of arterial disease in Egypt 3,500 years ago.

Figure 7: CT scan to be performed on a mummy

The investigators were of course experts in Egyptology and no doubt had only very basic knowledge of CHD. They speculated that these important Egyptians whose bodies were preserved for posterity must have had “atherogenic diets”. Of course we now know that CHD is not a dietary disease and that an "atherogenic diet" is just a popular myth.

But what does the finding from the mummies mean? Was there an epidemic of CHD in Egypt 3,500 years ago? This is possible but it cannot be concluded from a sample of just a few mummies, especially as the hearts had been removed at death and were not available for examination. 

Have atherosclerosis and CHD been present continuously since that time? There is no way of knowing as there are insufficient bodies from the past with preserved soft tissues that can be investigated. 

It is distinctly possible that low-grade atherosclerosis has been present in some individuals during many centuries, in a way that has not had a significant clinical impact. "Hardening of the arteries" has been viewed as a degenerative condition. This might be reasonably correct when applied to the very elderly, but the epidemic of CHD was most certainly not degenerative. It was something very different.

Figure 8: CT reconstruction of remaining internal tissues of an Egyptian mummy

Atherosclerosis and the inflammatory process

We have seen the prevalence of atherosclerosis in young US soldiers killed in action, that it was high in the years of the CHD epidemic, but only minimal in more recent times. It is the persistence of low-grade atherosclerosis in a mild form that suggests that although it might be present as a background disease, the epidemic of CHD during the 20th century was something different and something very special. 

A previous Post has explained that the only sustainable cause of CHD must be a micro-organism. But why one? Is is possible that several micro-organisms can cause arterial inflammation and the development of atherosclerosis? This is suggested as the “dirty chicken hypothesis”, that several micro-organisms might be causative. 

Figure 9: Chickens, probably taking antibiotics

The suggestion is that especially in poor people, who have the highest incidence of CHD death, a number of childhood illnesses create an illness burden that suppresses growth. This can be viewed as similar with chickens and other domesticated animals. Growth of these animals destined for human consumption can be stimulated in a very significant way by giving them large amounts of "routine" antibiotics, presumably supressing low-grade infections. 

It is suggested that in humankind, the inflammatory burden leads to atherosclerosis and CHD. Although a large number of micro-organisms might and probably do cause low-grade atherosclerosis, this is not the same as causing a world-wide pandemic that became the most important cause of death during the 20th century. This would require a very specific micro-organism.

It is well-known that micro-organisms are continuously present in the blood (bacteraemia). Although they are not visible on microscopy or even on culture, they can now be recognised (but not yet clearly identified) by DNA testing. The micro-organisms must have invaded initial body defences - the skin, the respiratory tract, the gums, and the intestinal tract – in order to enter the blood. 

The body has a secondary line of defence processes in the tissues. Bacteria in the blood can invade the walls of the arteries through tiny blood vessels called vasa vasorum, the “vessels of the vessels”. This is well established as the way in which syphilis causes vascular disease, “syphilitic aortitis”. It could and almost certainly will occur with a variety of micro-organisms, but the invasion is halted by immune mechanisms in the arterial wall. 

The immune reaction involves inflammation, a defensive process that is within the experience of all of us. This will ideally eradicate the microbial invasion. If the process is incomplete then it will contain the invasion with continuing low-grade inflammation. The initial part of the defence process is low density lipoprotein (LDL-cholesterol), which is known to have important antibacterial effects. 

The inflammatory process is traditionally characterised by "calor, dolor, rubor, tumor", meaning high temperature, pain, redness, swelling. Although these features are obvious when inflammation is in the skin, they might not always be obvious when in internal tissues. The important feature  of inflammation in the coronary arteries is "tumor", the swelling that is recognised as a "plaque". It is rich in cholesterol as cholesterol is an integral part of the gradual inflammatory process. The greater the expression of cholesterol by an individual, the greater the swelling, and thus the degree of stenosis, narrowing, of the coronary artery. This is what happens with familial hypercholesterolaemia.

Low-grade inflammation of some arteries is likely to be common, just part of life in the elderly and only rarely causing clinical problems. However  if the immune processes are defective, or more importantly if a highly virulent micro-organism is encountered, the defence mechanisms will be overwhelmed, with clinical effects at a younger age. 

Although a background of low-grade atherosclerosis might have been due to a variety of micro-organisms, the epidemic of CHD deaths in the 20th century was clearly due to a new and highly virulent micro-organism. Deaths have been much more likely when immunity has been sub-optimal. The micro-organism concerned has not yet been identified with confidence, but there has not been a major effort to do so. 

The 21st century

What is likely to happen in the future? The epidemic is virtually at an end and we are already in the future. The situation now is that CHD continues but in a very much milder form than previously, and in much older people. There are episodes of MI and these can be fatal, but almost entirely in the very elderly. The great majority of events are not dangerous and there is no abnormality on the  ECG. They would not have been recognised a few years ago, before the re-definition of MI and the introduction of very highly sensitive blood tests.

It is likely that the pattern of CHD deaths has been a cohort effect. People alive between an indeterminate year early in the 20th century and about 1970 would have been exposed to the causative micro-organism, and they started dying from CHD/MI in 1924. The lead time for CHD, what might be called the latent or incubation period, can be several decades. 

We have no idea what this latent period was at the onset of the epidemic, as the acquisition of the micro-organism did not appear to be associated with a clear illness. The initial infections of syphilis (genital sore) and rheumatic fever  (sore throat and joint pains) were usually obvious, followed by a long latent interval before the recognition of heart disease. The latent interval between the acquisition of the causative micro-organism and the development of CHD could initially have been just a few years, with initial exposure immediately after World War One. 

The 1918 influenza epidemic

Could the causative organism possibly have been the one which caused the 1918 influenza pandemic (Spanish flu)? This caused between 20 million and 50 million deaths in the 500 million people affected. As a later effect after a latent interval it is thought to have been responsible for a subsequent 5 million cases of Encephalitis Lethargica, a very serious sleeping sickness (a disease of the brain).

The peak of the epidemic was reached in 1970. If the peak age at death was 70 years, then those dying in 1970 would have been born in 1900. We know from Korean war deaths that the disease process was established in early adult life. Remember that cigarette smoking brings forward death from CHD by 10 years. My father and mother (non-smokers) had both led extremely healthy lives but died as the result of CHD/MI in 1994 and 1997. They were born in 1910 and 1913 and so the time sequence fits into this pattern.

CHD / MI is now a different disease from what we experienced in the years around 1970. It now has a very much lower mortality rate than twenty years ago. This is clear from USA data, in Figure 10. Remember that there were very few effective treatment opportunities between 1970 and 1990.

Figure 10: Mortality rates following MI (USA)
It now affects an older age-group, but as mentioned, this is likely to be a cohort effect. Most of those dying now could have acquired the initial infection in the 1920s or 1930s. They are now the frail very elderly, who have little physiological reserve, and are at risk of death from any minor illness. The main cause of death would be "old age" but there is reluctance for this to be put on a death certificate.

Figures 11 and 12 show a dramatic change in age at death since the peak of CHD deaths, comparing 1968 with 2010. It is much more obvious in men (Figure 11) than women (Figure 12), as CHD death rates were much higher in men.
Figure 11: Shifting pattern of age at death (UK, men)

Figure 12: Shifting pattern of age at death (UK, women)
The dramatic clinical features of MI with a very obvious diagnosis, high complication rate and high early death rate (such as I described was the scene in 1970) are now seen only very rarely. Treatment is better today, but as shown in the long-term international MONICA study, the much reduced death rate from CHD is much more due to a reduced incidence rate of events rather improved survival from them. 

Access to coronary angiography and stent insertion was very restricted in the final years of the 20th century. This has changed in the 21st century and availability of the service is now excellent. Although it would have been wonderful had it been available in 1970, it is of much less therapeutic value today. Minor degrees of coronary artery atheroma are readily identified, but the problem is whether these are of any clinical importance. The 20% narrowing of a coronary artery will not lead to any reduction of blood flow. If discovered in a 70 year-old, it can be expected to progress very little during the remainder of life.

There is now concern that too many stents are being placed in very low risk individuals for no clinical benefit. This is of particular concern in countries in which the cardiologist is paid for each procedure. It is of less financial concern with a salaried service as in the UK. However it all is part of the over-medicalisation of society. Doctors generally do what they have been trained to do,(encouraged by the medical manufacturing industry), and so a cardiologist highly skilled in placing stents will place stents, even though the indications were not as strong as in the past.

The question of immunity

There has been an epidemic / pandemic of deaths from CHD during the 20th century. The decline since 1970 has been a combination of decline of deaths, a much-reduced frequency of events, the change to a much milder form of the disease, and a much-improved survival following an event. What has brought about these remarkable improvements?

A decline of the cause is the obvious first thought. As discussed in a previous Post, the only possible cause that fits in with the facts is a micro-organism, the precise identification of which is not yet established. We can ignore dietary (chemical) factors, as despite a great deal of media attention, diet shows no consistent relationship to CHD. 

A micro-organism does not “go away”, and trillions of micro-organisms cannot all simultaneously mutate into a less virulent form. The end of an epidemic is brought about by the population developing immunity.  And so it is with CHD. There is now widespread immunity, and hence the epidemic is effectively at an end.

There is great deal of information demonstrating the importance of immunity, or lack it, in CHD, and this will be the subject of a further Posts.