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Recent pathological advances in experimental and iatrogenic atherosclerosis and critical review of the epidemiology of coronary heart disease revealed fallacious data and methodological errors underlying the hypercholesterolaemia/lipid hypothesis. Misuse of risk factors, inappropriate use of surrogates and misinterpretation of data pertaining to cholesterol's role in atherogenesis necessitate greater precision in word usage and terminology, reinstitution of the statistical reference range for cholesterol and closer scientific surveillance of aetiological endeavours in medicine.

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A 41-year-old man with a small perimembranous ventricular septal defect (VSD) developed aneurysms and aortic elongation, tortuosity and dissecting aneurysm. The asymptomatic VSD, without pulmonary circulatory disturbance, was considered hemodynamically benign and too small to warrant surgical closure. However, prolonged strenuous sporting activities could have potentiated premature development of aortic sclerosis and the unusual vascular lesions secondary to the VSD, and an injury may have precipitated mural dissection in the vulnerable aortic wall. Clinicopathological analysis of the unusual complications associated with the VSD suggests that closure of the defect at an early age should be considered to possibly obviate premature degenerative, valvular and vascular changes in adulthood and also secondary endocardial infection.

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Science being the search for truth or factual knowledge pertaining to nature and human health, accurate and precise word usage is prerequisite to avoid unintentional misrepresentation in scientific communication. The increasing frequency of word misusage necessitates review of a number of definitions and frequently misused words in vascular pathology. Correction of such errors is essential to foster accurate, standardized definitions. Otherwise scientific progress is delayed, the unwary are misled and fallacious data and concepts are propagated. Adherence to correct word usage facilitates the development of logic and precision so essential in education and in scientific thinking and literature, whereas consistently misused words ultimately become meaningless and unusable.

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Review of two autopsy cases of progeria confirms severe smooth muscle cell (SMC) depletion in the atherosclerotic aortic media and the presence of collagen types I, III, IV, V, and VI in the aorta and renal vessels as is consistent with atherosclerotic disease.

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Lipid-rich caseous debris of advanced lesions stimulated interest in the role of cholesterol and lipids in atherosclerosis. Lipid-containing arterial lesions in cholesterol-overfed animals (cholesterolosis) and xanthomatous vascular lesions in subjects with familial hypercholesterolemia were then misrepresented as being atherosclerotic and led to the development of the hypercholesterolemic/lipid hypothesis. It is untenable that cholesterol, an essential multifunctional metabolite, is pathogenic at all blood levels and hypercholesterolemia is not prerequisite for human or experimental atherosclerosis. Serum cholesterol levels display a poor correlation with atherosclerosis at autopsy and with unreliable national coronary heart disease (CHD) mortality in each sex. Atherosclerosis topography and its iatrogenic production in humans and experimentally in herbivores by hemodynamic means both support a biomechanical causation and preclude causality by any circulating humoral factor. CHD, not a specific disease, is a nonspecific complication of many diseases including atherosclerosis and cannot be equated with coronary atherosclerosis due to differences in pathology and pathogenesis. Thus, extrapolations from CHD risk factors or correlations with fallacious vital statistics to atherosclerosis are invalid. It follows that the hypercholesterolemic/lipid hypothesis evolving from false premises, misuse of CHD, scientific misrepresentation, and fallacious data has no legitimate basis.

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Early development of the hypercholesterolemic/lipid hypothesis of atherosclerosis was based on false premises including fallacious national mortality rates and misrepresentation of the vascular lesions in cholesterol-overfed animals and monogenic hypercholesterolemias (MH). Nonspecific coronary heart disease (CHD) was inappropriately used as a surrogate of atherosclerosis, unmeasured and unseen. Causality was assumed and implied by classifying statistical correlates of CHD as atherogenic risk factors. These faults were compounded by methodological errors, pooling of all causes of CHD, a large clinical diagnostic error, biased age selection of cohorts leading to confounding by age and MH, and emphasis on population and cohort mean values which conceal heterogeneity within cohorts and are inapplicable to individuals. Overzealous investigators neglected to review the premises and relevant pathology on which the hypothesis was based or to reconcile valid criticisms, inconsistencies, and invalidation of CHD epidemiology by pathological, experimental, and iatrogenic evidence. Statistical data, pertaining to CHD but with no scientific applicability to atherosclerosis, progressively imparted to readers a misleading perception of the relationship of serum cholesterol to CHD. Concurrently the statistical serum cholesterol range was unjustifiably abandoned. The evidence establishes that the lipid hypothesis of atherosclerosis lacks scientific basis.

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A prerequisite of scientific communications is that words should not be misrepresented. Currently, the frequent misuse of adaptation and remodeling derives from faulty analysis and misrepresentation of the pathology of coronary atherosclerotic lesions. This misperception of vascular pathology has misled the uncritical and unwary, and propagates fallacious data and concepts. Unless the misusage ceases, the terms will continue to be meaningless merely furthering promulgation of unscientific data and concepts that effectively obstructs scientific progress.

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This histological study of endocardial thickening in human hearts revealed that as in adult hearts, the proliferation in fetal, neonatal, and infant hearts consisted of collagen, elastin, and smooth muscle cells. Variation in severity from chamber to chamber and site to site indicated that severity is not an aging phenomenon and that predominantly local blood flow conditions determine localization and progression of proliferation. The similarity to endocardial thickening of cardiac valves and to intimal proliferation in blood vessels was remarkable. In old age and in chronic rheumatic heart disease the proliferation exhibited hyalinization, cell depletion, loss and fragmentation of elastin, lipid accumulation, and thrombosis, indicative of a similar pathogenesis to atherosclerotic changes in valvular endocardium and blood vessels. It was concluded that these chronic hemodynamically induced degenerative changes in the endocardium, including cardiac valves, should be classified as endocardial atherosclerosis analogous to that in arteries and veins and that severity is aggravated by high blood pressure, cardiac malformations, and dysfunction or damage caused by other disease processes.

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Emphysema is a slowly progressive degenerative lung disease involving fragmentation and depletion of elastic fibers, loss of lung elastance, and architectural destruction with ectasia, tortuosity, and loss of bronchioles irrespective of localization or morphological type. Occurring under physiological conditions, predominantly in geriatrics, matrix laxity and destructive parenchymal lesions are indicative of a pathological loss of tissue tensile strength attributable to bioengineering or structural fatigue in repetitively stressed tissues. The occurrence of severe premature emphysema in inherited connective tissue diseases and under some experimental and iatrogenic conditions is supportive evidence. Experiments advocating unrestrained proteolysis as a cause or pathogenic factor are invalid, being based on a false premise and assumed causality.

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Logic dictates that for scientific progress in atherogenesis "cause" must be the sole prequisite without which the disease cannot occur. Nor can it be assumed that statistical associations (risk factors) with coronary heart disease (CHD) are causal for atherosclerosis and extrapolations from correlations with CHD incidence to atherosclerosis are invalid. Any factor considered to play a role in atherogenesis requires pathological and experimental evidence consistent with the logic of Koch's specificity of cause and effect. Current epidemiological misuse and manipulation of cause and risk factors are contrary to the basic precepts of scientific logic and the fundamental need for precision in word usage. The term "risk factor", because of the current deeply entrenched false concept of causality has retarded medical progress and should be abandoned. Its adherents, guilty of a disservice to the tenets of their discipline, have also sullied the scientific integrity of medicine as a whole.

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Programmed cell death or its current synonym, apoptosis, is considered a genetically controlled biological process of cell deletion complementary to cell replication. Apoptosis is most likely a self-regulatory mechanism whereby a genetically determined biochemical pathway to death is initiated in cells sustaining irreparable damage particularly of DNA. Initiating factors in each instance need to be established. Identified in arteries, apoptosis correlates with the localization and severity of atherosclerosis. Granulovesicular disintegration of vascular smooth muscle cells leads to abundant vesicular debris mostly in the intima and increasing with age and hypertension and such matrix vesicle production is a major pathogenetic feature of atherosclerosis. The abundant debris produced accumulates lipid and minerals as usually occurs in non-phagocytosed cell debris. Similar vesiculation in erythrocytes under haemodynamic stress supports the contention that vascular cells under haemodynamic biomechanical stresses in spontaneous and experimental atherosclerosis degenerate due to depletion of cytoplasm, DNA fragmentation and oxidative damage with some cells inevitably undergoing terminal apoptosis. Evaluation of apoptosis must take into account the concomitant changes in the whole vessel wall and its matrix. Currently generalizations about therapeutic or pathogenetic roles for apoptosis in any disease are speculative and unwarranted.

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It has been suggested that progeria, a congenital disorder associated with clinical features that resemble premature aging, may be the result of a connective tissue abnormality. Although to date the clinical and pathologic features for 14 autopsied cases of progeria have been reported, details as to the renal changes in progeria are scanty. We investigated the histological features from a male and female with progeria who died aged 11 years and 20 years respectively. In our young male subject there was no glomerulosclerosis, while the kidney from the older subject showed focal renal scarring with focal glomerulosclerosis and associated tubular atrophy. Two small papillary adenomas were present within the renal cortex of the latter subject. In both cases non-sclerotic glomeruli were moderately enlarged with expansion of mesangial matrix. Immunohistochemical detection of collagens showed absence of collagen I and III within the mesangium of non-sclerotic glomeruli, while there was moderate to marked expression of collagen IV, V and VI. Collagen V is thought to be involved in matrix assembly while collagen VI probably has a regulatory role in extracellular matrix development and these are either not seen or are very weakly expressed in normal renal mesangium. The distribution of collagen within the mesangium of progeria kidney is evidence in support of the concept that progeria is a primary connective tissue disorder.

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Irrespective of their intended use, the best models of spontaneous aneurysms in humans are produced under conditions analogous to those occurring in humans and specific for the site. Even if appropriate for other purposes, models dependent on artificial conditions (physical and thermal trauma, chemical and enzymatic degradative processes), not in compliance with the above, bear no relationship to the etiology or pathology of the lesion or disease under investigation. Surgical models of poststenotic dilatation and aneurysm, arteriovenous shunts, and venous graft aneurysms are suitable for study of the prevailing hemodynamics and pathological effects of the associated stresses on the vessel wall which have bearing on degenerative aneurysms at other sites. The protracted course of atherosclerosis and constraints of time and research funds when reproducing the pathology and conditions prevailing in the human situation legitimize the use of models which accelerate development and complications. The limitations of any model are of paramount consideration. The value of some current models of aortic and cerebral aneurysms is discussed.

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The caterpillar chromatin pattern of the nucleus in longitudinal section and owl-eye appearance in transverse section characterize the Anitschkow cell of Aschoff bodies in rheumatic heart disease. Determining whether it is of muscle origin or cardiac histiocyte has been a source of controversy for many years. In a study of fetal and neonatal hearts from humans, vesicular nuclei often displaying the Anitschkow chromatin pattern were the predominant cell type in the myocardium. Because a similar pattern was also observed in two cell types related to laryngeal cartilage and the neighbouring fibrous tissue in a six week old neonate, it was concluded that the Anitschkow chromatin pattern probably indicates cellular immaturity rather than any specific cell type.

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