Atheroslcerosis: usage and misusage

D ear S ir, Wide acknowledgement of specific disease entities based on aetiology and accurate pathology, acceptable definitions and scientific word usage is overdue. All scientific communication necessitates correct word usage. Misusage of terms, the result of which is to misrepresent the pathology, misleads the credulous and unwary and can be perpetuated for generations. Atherosclerosis is frequently used loosely and incorrectly [ 1] particularly in the presence of co-existing diseases ‘Transplantation atherosclerosis’ is commonly used in reference to changes in coronary arteries in cardiac transplants and in vessels associated with chronic rejection of transplanted kidneys and other organs. Atherosclerosis is a specific, chronic degenerative disease of blood vessels, ubiquitous in humans and widespread in lower animals. Its consistent topography, morphology, pathogenesis and complications have been reviewed in the light of new data [ 2, 3]. Early lesions exhibit specific anatomical localization and morphology, with more diffuse, inexorable progression throughout life and eventual development of complications (mural tears, ulceration, ectasia, tortuosity and aneurysms). It continues to affect blood vessel walls even in the presence of concomitant or superimposed diseases which tend to enhance local mural vulnerability to atherogenesis. The aetiology and pathogenesis of immunological graft rejection are distinct from atherogenesis. The former is diffuse, concentric rejection arteritis varying in severity with the immune response and immunosuppression, whilst atherosclerosis varies in severity according to vascular site, anatomy, diameter, blood pressure and function [ 2, 3]. Transplanted arteries continue to be affected by atherogenesis concomitantly with immunological and cell-mediated rejection of vascular and parenchymal tissues. Logically the resulting vascular lesions of the transplant are manifestations of concomitant immune rejection of variable severity to foreign tissue, and atherosclerosis which does not disappear but continues unabated in all the host's vessels. Aetiologically, clinically, morphologically, topographically and pathologically these are distinct diseases and irrespective of which predominates, the combined lesion is not atherosclerosis per se. In rejection arteritis mural cells are likely to be more susceptible to haemodynamic stress, and aggravated by hypertension in 80% of subjects with end-stage kidneys. Nor can chronic rejection phenomena be regarded as variants of atherosclerosis or of arteriosclerosis. The latter is often used generically to encompass chronic degenerative diseases and at times as a synonym of atherosclerosis. When a third disease (e.g. cytomegalovirus infection) complicates the scenario (which is not unexpected in immunosuppressed subjects [ 4]), viral arteritis is superimposed on pre-existing diseases. Again the end result is not atherosclerosis per se. Labelling such combined lesions as atherosclerosis constitutes pathological misdiagnosis and lacks the precision so essential in science. Carried to the extreme, atherosclerosis would encompass all non-atherosclerotic vascular diseases. Koch's postulates, considered the epitome of logic, excluded spurious causes from consideration, thereby emphasizing specificity of cause and effect. The crux of his postulates was that the cause must reproduce the disease, its pathology, pathogenesis and complications under conditions analogous to those prevailing in the human disease [ 5]. It follows that to designate pathological changes as a specific disease entity such as atherosclerosis, the pathology, pathogenesis, complications and extravascular lesions (other than complications) and the causes of the two pathological lesions will of necessity be the same. In the case of an allograft, the vascular pathology does not comply with these criteria and the causes unquestionably differ. Nor does benefit derived from statin drug therapy (with its immunosuppressive effects) support allegations that the combined lesions are atherosclerotic. Therefore the vascular lesions in an allograft are not atherosclerotic and neither are lesions complicated by additional confounding diseases (bacterial, viral or fungal). The term ‘transplant vasculopathy’ is preferable since ‘vasculopathy’ is non-specific and in reality graft rejection constitutes only one manifestation of the arterial changes. High cholesterol/fat diets are widely used to produce hypercholesterolaemia in experimental animals with or without thyroid suppression. Such artificial experiments do not comply with modified Koch's postulates [ 5] nor are vascular lesions of debilitated cholesterol-overladen animals atherosclerotic. The pathology, pathogenesis and complications of their vascular lesions and extravascular xanthomatosis, while dissimilar to atherosclerosis [ 2, 3], exhibit remarkable similarities to metabolic lipid storage disorders such as familial hypercholesterolaemia (FH). Every conceivable type of vascular injury predisposes to lipid deposition in cholesterol-overfed animals. Similar experiments using infectious or immunological agents instead of physical or thermal injuries still result in combined lesions (such as infectious or immune vasculitis and a fat storage disorder) not atherosclerosis. Haemodynamically stressed tissue associated with proliferative atherosclerotic lesions is also a site of predilection for lipid storage in rabbit cholesterolosis [ 2]. Such lesions do not potentiate atherogenesis but are mixed lesions. Haemodynamics governs spontaneous and dietary induced lipid deposition in the vessel wall and it is still uncertain whether FH and other inherited lipid storage diseases preferentially affect regions severely stressed haemodynamically. Ubiquitous, atherosclerosis at times co-exists with inherited metabolic diseases often with no discernible effect on the vessels. Several nonlipid metabolic disorders affect vessels and exhibit tissue storage of a metabolite, sometimes with widespread cellular and connective tissue dysfunction. A generalized metabolic disorder affecting every cell in the body (e.g. diabetes mellitus) can aggravate the severity of atherosclerosis just as it predisposes to bacterial and fungal infections. Some disorders result in defective or deficient connective tissue proteins or other mural constituents secondarily predisposing to premature vascular fragility and vessel wall failure (mural tears, aneurysms, dissections and arteriovenous shunts) [ 2, 3]. In each instance the relationship to atherosclerosis requires careful analysis and classification as predisposing, aggravating or potentiating atherogenetic factors [ 3]. Some metabolic disorders affect certain viscera or tissues more than others depending on the metabolic pathways involved. others are prone to affect naturally occurring degenerative diseases involving blood vessels, cardiac valves and joints such as lipid storage disorders like FH which is a specific genetically determined disease entity. Its clinical manifestations, aetiology, topography, pathogenesis, complications and extravascular manifestations differ substantially from atherosclerosis [ 2, 6]. The xanthomatous nature of the vascular lesions is re�ected in the early titles (aortic xanthomatosis or xanthelasma) and Goldstein and Brown's description ‘xanthomatous plaquing of arteries’ [ 7]. Familial defective apolipoprotein B-1OO and type III hyperlipoproteinaemia are also similar pathologically since they too are fat storage disorders and arterial lesions comprise lipid storage superimposed on atherosclerosis. It follows that these disorders should be excluded from clinical/epidemiological studies concerned with atherosclerotic heart disease and it is invalid to extrapolate from these lipid dystrophies to normocholesterolaemic subjects [ 6]. Some non-lipid heritable storage disorders (Fabry's disease, homocystinuria, mucopolysaccharidoses, alkaptonuria etc.) also affect blood vessels, often aggravating wear-and-tear degenerative diseases of cardiac valves and joints and may exhibit widespread cellular and connective tissue dysfunction and tissue storage. They are considered as separate diseases and the vascular lesions are not purely atherosclerotic. They affirm the nonspecificity of metabolic storage in blood vessels of subjects with lipid dystrophies [ 6]. A working group of the National Institutes of Health [ 8] defined coronary heart disease (CHD) as coronary atherosclerosis (of unspecified severity). Since CHD) is a nonspecific, collective term incorporating all cases of myocardial ischaemia, atherosclerotic or otherwise, the terms are not synonymous. Even medical students should know the pathological differences between these terms which regrettably in CHD epidemiology are currently used synonymously and interchangeably. Serious consequences involved in this misrepresentation [ 6] are yet to be realized. Misusage of atherosclerosis has been carried a step further by referring to the ‘process of angioplasty stenosis, vein graft failure and transplant atherosclerosis’ as ‘syndromes of accelerated atherosclerosis’ [ 9]. ‘Syndrome’ is misused and the pathology and pathogenesis of the lesions are misrepresented. Because vascular tissues are not plastic, angioplasty is accompanied by mural disruption since the diameter of the stenosis is forcibly enlarged by a factor of two to five times and conceivably injury to mural thombi and ulcerations takes place along the arterial tree traversed by the catheter. Superadded thromboembolism ensues as with any traumatic injury followed by repair of tissue, and some regression and remodelling of the surface over the scar [ 2]. The damaged wall and compensatory repair tissue are continuously subjected to haemodynamic stresses, the deleterious effects of which are being recognized only in recent years [ 2, 3]. Referring to iatrogenic trauma to an atherosclerotic artery and transplantation vasculopathy as atherosclerotic syndromes [ 9] is erroneous. Of the three ‘syndromes’ cited only venous bypass grafts develop true accelerated severe atherosclerosis, and this despite the fact that if left intact, the vein, like those elsewhere, would develop minimal changes for the remaining years of life, a phenomenon that can be explained by haemodynamics but not by the lipid hypothesis [ 2, 3]. Atherosclerosis is a specific disease and correct usage of the term depends on precise pathological analysis. Distinguishing between combined lesions and atherosclerosis is not a pedantic exercise but a matter of scientific exactitude. Incorrect and loose usage of ‘atheroclerosis’ misrepresents the pathology and thereby impedes scientific progress.