Q J Med 2000; 93: 375-383
© 2000 Association of Physicians
Commentary |
Respiratory infection and coronary heart disease: progression of a paradigm
From the Departments of Medicine and Biochemistry, Blackburn Royal Infirmary & Queens Park Hospital, Blackburn, Lancashire BB2 3LR
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Summary |
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 Top Summary IntroductionDevelopment of a paradigmThe role of recurrent...A putative microbeGeographyAtmospheric pollutionGenderThe influence of splenectomyThe action of statinsThe ‘Northern Ireland...Progression of the paradigmReferences |
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We have developed a previously published paradigm concerning causation of coronary heart disease, based on the probability that the fundamental cause is a microbe, probably Chlamydia pneumoniae, and that the progress of the disease is influenced by number of accelerating and inhibiting factors. We propose that cigarette smoking acts via respiratory infection, this itself being influenced by immunocompetence resulting from sunlight exposure. We also propose an immuno-enhancing effect of oestrogen and an anti-inflammatory effect of statin therapy. In respect of the geographical variation of coronary heart disease, we emphasize that this must be viewed as part of the bigger picture of a high mortality from all causes in countries of North-west Europe that have a particularly low level of sunlight exposure. Finally, we draw attention to the Albanian, French, Italian, Northern Ireland and Scottish paradoxes which should lead to a major review of the conventional wisdom concerning the aetiogenesis of coronary heart disease.
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Introduction |
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TopSummaryIntroductionDevelopment of a paradigmThe role of recurrent...A putative microbeGeographyAtmospheric pollutionGenderThe influence of splenectomyThe action of statinsThe ‘Northern Ireland...Progression of the paradigmReferences |
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Cigarette smoking is well recognized as one of the major risk indicators of myocardial infarction, and it is further recognized that stopping smoking reduces the risk. It is therefore not just a risk indicator but a ‘causative factor’, and it is of importance in the pathogenesis of the disease. It is obviously not the cause, because coronary heart disease occurs in non-smokers. In fact, the lifelong risk of death adjusted for social class is approximately the same in non-smokers, light smokers and heavy smokers.1 However death occurs on average about 10 years earlier in heavy smokers compared to non-smokers and at a given age of 50 years, about twice as many heavy smokers than non-smokers will have died as the result of myocardial infarction.
Yet the mechanism whereby cigarette smoking affects coronary heart disease is unclear. Cigarette smoking produces several metabolic effects which might be of significance,2 but it is perhaps surprising that such a major factor in the pathogenesis of coronary heart disease is not recognised as having a single effect which is fairly obvious. There is therefore no consensus as to the intermediary mechanism, which is perhaps a reflection of the general poor understanding of the causation and fundamental pathological process of coronary heart disease.
This begs the question, what sort of disease is it? Is it ‘degenerative’ (whatever that means)? genetic? a poisoning (too much of something bad for you)? a deficiency state? a metabolic disorder? an infection? or even psychological? Once again there is no consensus and the general impression is that it is ‘multifactorial’, which means that we do not really understand what is going on but that we recognize a lot of clues.
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Development of a paradigm |
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TopSummaryIntroductionDevelopment of a paradigmThe role of recurrent...A putative microbeGeographyAtmospheric pollutionGenderThe influence of splenectomyThe action of statinsThe ‘Northern Ireland...Progression of the paradigmReferences |
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Our poor understanding of the nature of coronary heart disease explains why we lack a clearly expressed paradigm to explain it. All diseases are explained on the basis of a paradigm, or model, which is an expression of present understanding even though it might be incomplete or even wrong. Being able to develop a paradigm, to construct a model, implies a certain level of understanding; the absence of such a paradigm which should include most if not all known risk indicators, implies very little understanding.
In practice there is what can be regarded as a flat paradigm for the development of coronary heart disease, in that it is thought to be due to the addition of a wide range of risk indicators (Figure 1
). This is sometimes illustrated in a circular format,3 and it can also be expressed as, for example, the Sheffield Index which indicates a 3% per annum risk of coronary events based on cholesterol concentration, age, gender, the presence or absence of hypertension, diabetes, and ECG evidence of left ventricular hypertrophy.4 The purpose of the index is to predict the future for an individual patient as a guide to treatment, and by no means is it an expression of understanding of the causation of coronary heart disease. The flat paradigm of coronary heart disease means that it might appear to be ‘due to’ genetic influences in one person, cigarette smoking in another, a faulty diet in another, a metabolic abnormality in another, etc. This contravenes traditional pathological teaching that a given disease has a specific cause, although a variety of factors might influence the natural history of the disease. In fact, the flat paradigm is simply a summation of observations and makes no attempt to explain how the various factors might interact.
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We have recently produced a paradigm to explain the pathogenesis of coronary heart disease using as its basis that the disease is fundamentally microbial in origin.5 The model indicates that the progress of the disease can be influenced by a variety of accelerating factors and protective factors which fit in with many observations. The model also acknowledges a major environmental factor, which is proposed to be sunlight and which also influences cholesterol metabolism. The geographic, ethnic and social class variations of coronary heart disease are explained by differential sunlight exposure, which in turn influences immune competence.
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The role of recurrent bronchitis |
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TopSummaryIntroductionDevelopment of a paradigmThe role of recurrent...A putative microbeGeographyAtmospheric pollutionGenderThe influence of splenectomyThe action of statinsThe ‘Northern Ireland...Progression of the paradigmReferences |
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A development of this paradigm (Figure 2
) allows us to give cigarette smoking an important but fundamentally simple role in the pathogenesis of coronary heart disease without the need to create elaborate metabolic theories. In this respect it conforms to Ockham's principle that the simplest explanation for a phenomenon is likely to be the correct one. It has recently been shown that recurrent bronchitis is an important predisposing factor for coronary heart disease.6 We therefore suggest that cigarette smoking, the most obvious effect of which is a chronic cough, might contribute to the development of coronary heart disease by increasing the frequency of respiratory infections, thereby increasing the frequency of microbial invasion of the lungs, circulation and vascular endothelium. Chlamydia pneumoniae is a major respiratory pathogen and it is considered to be a possible, or perhaps the probable, cause of coronary heart disease,7–12 but it might not be the only causative microbe, and cytomegalovirus has also been considered to have such a role.13
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A putative microbe |
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TopSummaryIntroductionDevelopment of a paradigmThe role of recurrent...A putative microbeGeographyAtmospheric pollutionGenderThe influence of splenectomyThe action of statinsThe ‘Northern Ireland...Progression of the paradigmReferences |
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A microbial aetiology of coronary heart disease is by no means ‘proven’ but ‘proof’ is a difficult concept which is relative rather than absolute, being the fulfilment of predetermined criteria. When it is expressed that ‘Chlamydia pneumoniae [as a cause of coronary heart disease] is plausible but not proven’,3 the criteria of proof as applied should be stated. This is however difficult, as medical science has not really moved on from Koch's Postulates as a tool for ‘proving’ a microbial causation of a disease. Koch himself was well aware that although his postulates had a high level of specificity, they had a very low level of sensitivity, and his inability to apply the postulates to cholera was an illustration of this. Polymerase chain reactions and new microbial techniques identifying the presence of microbes which are difficult to culture, have a very high sensitivity but a correspondingly low specificity.
Viral hepatitis is an example of a disease accepted as being microbial many years before the causative microbes were identified; a paradigm of causation was accepted, based on transmission studies which would be ethically unacceptable today. In respect of coronary heart disease, we are left without any standard criteria of proof, and we must develop a paradigm to model a putative microbial aetiology, relying on ‘plausibility’ to a large extent. Indeed, it is the combination of strength of association together with plausibility that form the main basis of such a paradigm.14 The association between Helicobacter pylori and coronary heart disease is strong,15 but as this microbe appears to confine itself to the lumen of the stomach, there is no clear and plausible mechanism for it to be considered causal. It could be argued that with inflammatory markers being found in association with coronary artery disease, the arterial lesion is a non-specific consequence of distant inflammation. However this would be expected to produce a systemic effect, as with vasculitis for example, but coronary artery disease is often focal or multifocal, suggesting that the process is local and invasive. The detection of Chlamydia pneumoniae in arteriosclerotic lesions thus leads to a much higher plausibility of it being causative,9 as has the prospective demonstration of an association between IgA antibodies to Chlamydia pneumoniae and subsequent risk of death from coronary heart disease.16
The beneficial effect of antibiotics on the natural history of coronary heart disease is supportive of the microbial hypothesis. It has been demonstrated in a case-control study that patients with a diagnosis of myocardial infarction were less likely to have received tetracycline and quinolone antibiotic therapy in the past, suggesting that these antibiotics (but not erythromycin, sulphonamide, penicillin or cephalosporins) might be protective against the subsequent development of coronary heart disease.16
A further preliminary study has shown that treatment of patients suffering from unstable angina and non-Q wave myocardial infarction with the antibiotic roxithromycin resulted in a significant reduction of the clinical end-points of death, non-fatal myocardial infarction and angina at the end of an 180-day follow-up period.11 It must be emphasized, however, that antibiotics might have effects other than antimicrobial that might be in keeping with protection against heart disease.17
The identification of the precise microbe(s) might take a great deal longer and a great deal of further research, as was the case with the recognition of the hepatitis viruses and Helicobacter pylori in relationship to peptic ulcer. The acceptance of a microbial aetiology is a different process from the identification of a causative microbe, but clearly the former is intellectually easier if the microbe is obvious. This is particularly important in respect of chronic disease, when artificial transmission studies might be necessary to produce the criteria of proof as defined by Koch. In acute microbial diseases, spontaneous transmission is often obvious, and with organisms of higher pathogenicity, animal models might be possible.
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Geography |
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TopSummaryIntroductionDevelopment of a paradigmThe role of recurrent...A putative microbeGeographyAtmospheric pollutionGenderThe influence of splenectomyThe action of statinsThe ‘Northern Ireland...Progression of the paradigmReferences |
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The geography of coronary heart disease is well known, with definite latitude factor, noticeable in the United Kingdom as well as in Europe in general.5,18,19 The observation that deaths from coronary artery disease increase with distance from the equator and decrease with altitude of residence20,21 led us to postulate a protective role of sunlight. The effect of latitude on blood cholesterol, the population mean level increasing with distance from the equator, and its variation throughout the year with levels being higher in the winter, led us to suggest that cholesterol metabolism is influenced by sunlight.5
There is also social geography, with a strong social class gradient, coronary heart disease being much more common in the poorer social groups,22,25and an ethnic variation, with incidence being higher in south Asian immigrants into the UK.24,25 Both features can be explained on the basis of sunlight deprivation or avoidance.5
The geography of recurrent respiratory infection, most commonly chronic bronchitis, is similar to that of coronary heart disease with an increasing mortality rate with distance from the equator, as shown in Table 1 and Figure 3. In these data, asthma and chronic bronchitis are combined.26 FEV1 reduction, a feature of both asthma and chronic bronchitis, has previously been shown to be a predictor for coronary heart disease.27 Severe asthma has been shown to have the same social class distribution as coronary heart disease, more common in social classes 4 and 5.28 Our previous studies have suggested that the immunosuppression of relative vitamin D deficiency is important in the development of coronary heart disease and is expected to be more common in the underprivileged.5 This would also explain the increased frequency of chronic bronchitis and asthma in northern parts of Europe and in those of social classes 4 and 5, which would be the mechanism of entry of the putative microbe Chlamydia pneumoniae.
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Whereas the incidence of coronary heart disease is low in Italy, the incidence of carcinoma lung is high. Figure 4
shows the relationship between cigarette smoking and lung cancer. Figure 5 shows the corresponding relationship with coronary heart disease, in both the data being social-class-adjusted in that it relates only to doctors.1 The difference in the relationships between the two diseases with cigarette smoking is striking. The relationship with lung carcinoma shows a clear dose relationship, and conforms to cigarette smoking being a direct cause. The relationship between cigarette smoking and coronary heart disease is entirely different, indicating an accelerating process and thus an indirect relationship with coronary heart disease. This explains the ‘Italian Paradox’, that a nation with a high prevalence of cigarette smoking has a low incidence of deaths from coronary heart disease. This observation indicates that cigarette smoking is unlikely to have a direct toxic effect on the vascular endothelium and can only be an indirect cause of coronary heart disease. We suggest that recurrent respiratory infection is the intermediary mechanism.
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), light smokers (•), moderate smokers (
) and heavy smokers (
).
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Atmospheric pollution |
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TopSummaryIntroductionDevelopment of a paradigmThe role of recurrent...A putative microbeGeographyAtmospheric pollutionGenderThe influence of splenectomyThe action of statinsThe ‘Northern Ireland...Progression of the paradigmReferences |
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Several studies have demonstrated an increased rate of deaths from all causes29 and from coronary heart disease30 in particular in cities with a high level of atmospheric pollution, mainly particulate. Mechanisms for this are provided by the paradigm presented: firstly, atmospheric pollution (like cigarette smoking) gives rise to recurrent respiratory infections and hence the entry of Chlamydia pneumoniae into the body. Secondly, especially when particulate, it reduces the sunlight penetration to ground level and thus leads to immune suppression. The two factors can of course be synergistic, but could be of great importance in the new industrial cities of the developing world.
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Gender |
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TopSummaryIntroductionDevelopment of a paradigmThe role of recurrent...A putative microbeGeographyAtmospheric pollutionGenderThe influence of splenectomyThe action of statinsThe ‘Northern Ireland...Progression of the paradigmReferences |
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Men are more susceptible to coronary heart disease than are women, but following the menopause the incidence in women rises towards that of men. Although this phenomenon might reflect behavioural gender differences, it is generally though to be biological, hence a justification for hormone replacement therapy in post-menopausal women.
The phenomenon is likely to be biological as there are significant gender variations in the incidence of several diseases which are not related to specific anatomical or physiological differences. Generally speaking, men have a higher incidence of disease than women and, in the presence of safe childbirth and the absence of war, a reduced life expectancy. The underlying mechanisms are not known.
A recent review has shown that males of many arthropod species have a higher prevalence of parasitic infestations than females, in the adult but not in the juvenile when sexual development has not fully taken place.31 It is suggested that this gender effect is the result of an immune-enhancing effect of oestrogen and a corresponding immune-suppressing effect of androgens.32 Applying this principle to the human species, it might explain some gender variations of disease incidence. The principle can be applied to the paradigm of the pathogenesis of coronary heart disease presented above, recurrent respiratory infections and consequent arteriopathic infection being inhibited by the immune-enhancing effects of oestrogen in women and promoted by the absence of this and the presence of testosterone in men.
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The influence of splenectomy |
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TopSummaryIntroductionDevelopment of a paradigmThe role of recurrent...A putative microbeGeographyAtmospheric pollutionGenderThe influence of splenectomyThe action of statinsThe ‘Northern Ireland...Progression of the paradigmReferences |
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An excess of deaths from coronary heart disease in ex-servicemen who had splenectomy for trauma33 was recently reviewed and confirmed by a further study of patients who had splenectomy for spherocytosis.34 They were shown to have a relative risk of 5.6 for arteriosclerotic events. The cause of the interesting phenomenon can only be conjectural, but it conforms with the paradigm presented in that splenectomy results in a degree of immune suppression and a known increased susceptibility to infection.
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The action of statins |
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TopSummaryIntroductionDevelopment of a paradigmThe role of recurrent...A putative microbeGeographyAtmospheric pollutionGenderThe influence of splenectomyThe action of statinsThe ‘Northern Ireland...Progression of the paradigmReferences |
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It is now clear that statin drugs reduce coronary deaths, coronary events and need for coronary revascularization procedures.35,36 The rationale for administering this class of drugs is to lower blood cholesterol and thereby reduce coronary events, on the basis of conventional wisdom that cholesterol is arteriopathic. However this mechanism of action cannot be assumed to be true, and it is necessary to take into account the fact that other ways of lowering blood cholesterol, by diet and by other classes of drugs such as fibrates, have not been demonstrated as reducing coronary events. The conclusion to be drawn from this is that statin drugs might act in a different specific way on the development of coronary heart disease, and that the cholesterol-lowering effect might not be the important action.
Statins have several effects which have a potential role in the inhibition of coronary heart disease.37 They cannot be regarded as being simply cardioprotective, as statin therapy results in a reduced risk of stroke38 and therefore must have a role in the arteriosclerotic process. An anti-inflammatory mechanism can be postulated in addition to the lipid-lowering effect as, for example, pravastatin inhibits pro-inflammatory cytokine production,39 and statin therapy reduces the level of C-reactive protein in patients with coronary artery disease.40
The WOSCOPS Study36 showed clearly that pravastatin therapy (which should not be regarded as synonymous with cholesterol reduction) reduced coronary events, but there were several enigmas which indicated that cholesterol reduction might be only part of the effect:41 there was no clear relationship between the fall in LDL cholesterol and the reduction in deaths from coronary heart disease; risk reduction was maximal in subjects with a mean fall in LDL cholesterol of 24%, and further fall of LDL was not associated with a greater reduction in coronary heart disease risk; in the quintile analysis, the fall in LDL cholesterol failed to be a significant predictor of risk reduction (the lowest quintile in which there was no reduction of either LDL cholesterol or risk was assumed to result from subjects who were not compliant with medication); the benefit of therapy was independent of baseline LDL cholesterol level; comparison with the Framingham Risk Equation, giving coincidence between predicted and observed coronary heart disease event rates in the placebo group, underestimated the benefit of pravastatin therapy by about 31%; and the beneficial effect of pravastatin on coronary heart disease could not be completely explained by reduction in LDL cholesterol.
As a result of these observations, we have given statin drugs two positions in our paradigm, corresponding to their known major actions. Firstly, the inhibition of synthesis of cholesterol precursors and secondly, an inhibitory effect on the inflammatory process which leads to coronary heart disease, and which we feel is most likely to be initiated by a microbe. We do not believe that cholesterol has an initiating role in coronary heart disease, as firstly, coronary heart disease can occur in people with normal or low levels of cholesterol in the blood and secondly, it has been observed that although cholesterol is a powerful predictor of coronary events in people with coronary heart disease, it is a very weak predictor in people with no clinical manifestations.42 This conforms with cholesterol having an accelerating role, but this itself must remain unclear as long as cholesterol-lowering interventions other than statin drugs are not observed to have an effect in reducing coronary events. Primary prevention studies with statin drugs do show clinical benefit, but undoubtedly some subjects would have coronary heart disease without clinical manifestations of it at the time of recruitment (in practice, the only indicator of arteriosclerotic disease). We have not included in the paradigm the possibility that aspirin might reduce coronary events by inhibition of the inflammatory process leading to coronary heart disease and not just by its known role of the inhibition of thrombotic events.
It is important in respect of scientific objectivity that the term ‘statin drugs’ should be used in preference to ‘lipid-lowering drugs’ when only statin drugs are used in a clinical experiment. In fact statin drugs should not be viewed just as preventing coronary and cerebrovascular events but as a treatment of arteriosclerotic disease.
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The ‘Northern Ireland paradox’ |
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TopSummaryIntroductionDevelopment of a paradigmThe role of recurrent...A putative microbeGeographyAtmospheric pollutionGenderThe influence of splenectomyThe action of statinsThe ‘Northern Ireland...Progression of the paradigmReferences |
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As part of the important MONICA project, mortality rates have been compared for Belfast in Northern Ireland and Toulouse in the south of France. The differences are striking. During the period of study, the death rate for all causes per 100 000 men aged 55 to 64 was 2112 in Belfast compared to 1197 in Toulouse and the comparable numbers for coronary heart disease were 761 and 175.43 There was no obvious explanation for this, and the diets were remarkably similar considering major differences in climate and agriculture. The difference in death rates from all causes indicates a need to look beyond coronary heart disease and its possible causes and at an overall susceptibility factor to disease, related to geography.
A further development of this study has come from the Prospective Epidemiological Study of Myocardial Infarction (PRIME). On the basis of known major risk factors (age, cigarette smoking, blood pressure, total cholesterol and BMI) the prediction of an individual man's chance of developing a major coronary heart event was at the most, only 2% higher in Belfast than in Lille. This fell far short of the observed difference of incidence of 250% excess of events in Belfast over Lille, with an even greater excess compared with Strasbourg or Toulouse.44 In other words, the conventional paradigm of coronary heart disease does not provide explanations for the geographical variations and perhaps we need to look at geography and associated climatic factors.
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Progression of the paradigm |
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TopSummaryIntroductionDevelopment of a paradigmThe role of recurrent...A putative microbeGeographyAtmospheric pollutionGenderThe influence of splenectomyThe action of statinsThe ‘Northern Ireland...Progression of the paradigmReferences |
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We have thus taken the paradigm which we have presented previously5 and adjusted it to take into account newly published data in respect of respiratory infection, atmospheric pollution, gender and the wider than expected range of effects of statin drugs. The paradigm as presented in Figure 2
might be incomplete, but it attempts to provide a dynamic understanding of many factors involved in the pathogenesis of coronary heart disease. It attempts to take an overall view, providing a bridge between the ‘cholesterol hypothesis’ and the increasingly persuasive microbial theory of aetiology. It also provides a link with social, ethnic and climatic factors. Finally, it explains why dietary factors look to be such promising targets for manipulation but so disappointing in their application: diet is a reflection of local agriculture which in turn is a reflection of prevailing climate and sunshine energy at ground level. It is important that we look beyond coronary heart disease and understand that there is a much larger burden of illness within the north-western parts of Europe.5,43 Within ethnicity, gender, social class and physical geography, it is necessary to look for factors which will explain these aspects of epidemiology, and we suggest that these are female gender and sunlight, both of which enhance immune competence. When it comes to specific diseases, then we must look for specific causes: with coronary heart disease it looks increasingly as though this is a microbe.
The ‘Albanian paradox’ that a population of low socio-economic status,45 the ‘French paradox’ that a population which eats the ‘wrong food’,46 and the ‘Italian paradox’ that a population with a high prevalence of cigarette smoking, all have a low adult mortality rate, especially from coronary heart disease, together with the ‘Northern Ireland paradox’ that a population with a very high incidence of coronary heart disease does not have the expected risk indicators and the ‘Scottish paradox’ that treatment with pravastatin has much greater than expected benefit not clearly related to cholesterol lowering, are not paradoxes at all if we view climate as having a direct effect on the susceptibility of the human adult to a variety of microbial diseases including arteriosclerotic disease.
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Notes |
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Address correspondence to Dr D.S. Grimes, Department of Medicine, Blackburn Royal Infirmary, Blackburn, Lancashire BB2 3LR
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References |
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TopSummaryIntroductionDevelopment of a paradigmThe role of recurrent...A putative microbeGeographyAtmospheric pollutionGenderThe influence of splenectomyThe action of statinsThe ‘Northern Ireland...Progression of the paradigmReferences |
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