Study on the prevalence of eccentric and concentric atherosclerotic plaques in various segments of the coronary arterial tree, in unselected and selected Bucharest population samples.

A study was carried out on the prevalence and distribution of eccentric and concentric atherosclerotic plaques in the coronary arterial tree of 916 unselected apparently healthy subjects who died from accidents and of 150 selected patients who died from coronary heart disease. The results show that the percentages of eccentric and concentric plaques vary with age, sex, anatomical branching pattern and cause of death; there are also differences between major coronary arteries and main branch vessels. In addition to eccentric and concentric plaques, we revealed the existence of mixed (both eccentric and concentric) plaques, mainly located at branch points.

The onset and progression of atherosclerotic plaques as related to arterial wall changes.

The coronary arterial beds from more than 1200 subjects aged 1 to 65 years were investigated by both histopathological, histochemical and morphometric methods. Light microscopic aspects were analysed to reveal if plaque development and progression toward obstructive lesions were associated with arterial wall changes, particularly of the intimal connective tissue adjacent to lesions. Six patterns of plaque development in the coronary arterial tree were delineated, emphasis being placed on the observation that the onset and progression of plaques frequently appeared independent of arterial wall changes, in contrast to fatty streaks, gelatinous lesions, intimal necrotic areas, incorporated microthrombi and intramural thrombi. Our results support the view that plaques develop and progress on their own, superimposed on a preexisting arterial wall microarchitecture.

Influence of coronary heart disease risk factors (CHDRFs) on the natural history of coronary atherosclerosis as revealed by a post-mortem study.

A postmortem study was carried out on the whole coronary arterial bed of 430 selected apparently healthy subjects, aged 38 to 65 years, in an effort to reveal the influence exerted by coronary heart disease risk factors (CHDRFs) on the development of coronary obstructive plaques. A clear positive correlation was found in 31% of cases and in more than 50% of 28 selected topographic sites of the coronary arterial bed. On the other hand, the subgroup without CHDRFs also exhibited severe coronary narrowings. Each major CHDRF seems to exert its particular action on selected regions of the coronary arterial bed: proximal or intermediate segments of the major coronary arteries; branching points; nonbranched areas; vessels supplying the conduction system, etc.

Coronary anatomy and microarchitecture as related to coronary atherosclerotic involvement.

A report is given on the authors' main results concerning the anatomy and microarchitecture of human coronary arteries as related to atherosclerotic involvement and to the clinical manifestations of coronary heart disease. The peculiarities of anatomical branching pattern, of the intimal thickening, muscle columns development, of age-related changes, in the intima/media thickness ratio, as well as the segmental characteristics in susceptibility to plaque development and in the plaque pattern are presented. Our results allow to delineate the coronary arterial bed as an entity in anatomical, histological and pathological sense.

Prevalence of thick intimas and of obstructive lesions in the vessels supplying the conduction system of the heart.

A study of the prevalence of thick intimas and of obstructive lesions in the vessels supplying the conduction system of the heart (first septal artery, sinus node artery, atrioventricular node artery, posterior descending artery) was carried out on both non-hospitalized and hospitalized subjects. A total of 932 cases aged 6 to 55 years were investigated. The age period of the onset of both intimal thickenings and atherosclerotic plaques, the percent of cases with intimal thickenings and atherosclerotic plaques in successive age groups and the highest value of the intima thickness/media thickness ratio, were recorded. Comparative data are presented between apparently healthy subjects who died of accidental causes and patients of similar age and sex, who died of coronary heart disease. Sudden cardiac death cases are presented showing as the most important lesion the obstruction of the sinus node and atrioventricular node arteries. The results point to a need for a more frequent routine examination of the vessels supplying the conduction tissue of the heart.

Anatomoclinical correlations in coronary heart disease: recent advances and unanswered questions.

An attempt is made to summarize the recent available information on anatomoclinical correlations in coronary heart disease. The paper focuses attention on: (a) the role in the pathogenesis of unstable angina pectoris, severe arrhythmias and sudden cardiac death, of repeated cycles of formation, disintegration and peripheral embolization of intramural thrombi or of thrombi developed on preexisting atherosclerotic plaques; (b) a still apparently unsolved problem: which comes first, coronary thrombosis or myocardial infarction? (c) the pathophysiological and clinical significance of the "border zone" of myocardial infarcts; (d) the importance, in the pathogenesis of coronary heart disease and particularly of sudden cardiac death, of obstructive lesions which occur in the vessels supplying the conduction system of the heart.

Are routine autopsy protocols adequate for accurate appraisal of coronary atherosclerosis?

Atherosclerotic involvement of 1,106 coronary arterial trees was investigated by means of gross inspection, light microscopy, and the method of successive observations of similar topographic sites placed in sequence according to age, sex, cause of death, and anatomic branching pattern. The results obtained, based on strict adherence to routine autopsy protocols, were compared with control studies, which demonstrated that such strict adherence had constrained us to overlook the following aspects: a) existence of particular anatomic branching patterns, such as those of atherogenic character and/or involved in onset of myocardial ischemia; b) development of obstructive plaques in coronary branch vessels; c) presence of obstructive lesions in vessels which supply the conduction system; d) the obstructive character of platelet and fibrin microemboli and thrombi which showered the intramyocardial vessels; e) accurate identification, classification, and grading of atherosclerotic lesions with the aid of routine autopsy protocols, which was not possible in our material.

Role of thrombosis in the onset, progression and obstructive character of coronary atherosclerotic plaques.

A study was carried out on the role of successive microthrombi incorporation and intramural thrombi formation in the onset, progression and obstructive character of coronary atherosclerotic plaques. The coronary arterial tree of 836 apparently healthy subjects 1 to 50 years old who died of accidental causes was investigated. The onset of coronary atherosclerotic plaques having as precursors thrombi could be detected in 10% of advanced lesions. The left anterior descending artery appeared as the vessel of the coronary arterial tree the most susceptible to plaque development induced by thrombi and to the occurrence of thrombi on preexisting plaques. This occurrence of thrombi on preexisting plaques was recorded in 48% of subjects aged 46 to 50 years and was followed by a severe luminal narrowing in the major coronary arteries.

A further study on the influence exerted by vascular geometry on coronary atherosclerotic involvement.

A further study was carried out on the relationship between coronary artery geometry and atherosclerotic involvement. The results show that: a) the coronary artery geometry may expose an individual at an early age to an increased risk for developing atherosclerotic lesions; b) the presence, in the coronary arterial bed of vessels with large diameters (greater than 2 mm) and the succession of numerous branching points also appeared as atherogenic conditions; c) the type of atherosclerotic lesion (proliferative, insudative, necrotic, lipid-rich) was, in our material strongly influenced by the geometry of branch sites.

The relationship between intimal necrosis and lipid accumulation during the onset and progression of atherosclerotic lesions.

In human coronary arteries, aorta and intracranial arteries, the first areas of intimal necrosis preceded the onset of the first lipid accumulation related to atherosclerotic involvement. Both intra- and extracellular lipid accumulations developed only in preexisting areas of intimal necrosis. Intimal necrosis not only caused an abnormal intraarterial retention of fat, but also caused fat to be deposited preferentially in specific forms and particular locations. The areas with mucoid necrosis appeared as adequate sites for the onset of fatty streaks; the areas with swelling necrosis appeared as adequate sites for a diffuse extracellular retention of tiny lipid droplets; the areas with dissecting necrosis appeared as adequate sites for large fatty deposits rich in cholesterol clefts. The results of this paper demonstrate that human atherosclerosis has many attributes of a necrotizing arteriopathy and that lipid accumulation is a secondary phenomenon. These results add support to the insudative theory of atherogenesis built up by German pathologists at the middle of this century and disagree with the often repeated view that human atherosclerosis is a reaction of the arterial wall to lipid that invade it.

Coronary atherosclerosis: where are we now?

An attempt is made to present and summarize recent results in atherosclerosis research which may aid to a better understanding of atherogenesis, progression of atherosclerotic lesions and occurrence of myocardial ischemia. Based on selected data from the available literature and the authors' experience, the review focuses the attention on: the atherogenic role of hemodynamic stresses; the onset and fate of early coronary atherosclerotic lesions; the development of lesions of possible clinical significance; the concept of "critical stenosis"; the view that atherosclerosis is a hyperplastic and/or neoplastic disease.

Prevalence of the "normal" aspect of the coronary arteries in an unselected population sample of Bucharest aged 1-60 years.

The coronary arterial trees obtained from 640 subjects 1-60 years old were studied grossly and by light microscopy, including morphometric methods. The highest values of of the ratio intima/media thickness were recorded in successive age groups, with special reference to those topographic sites where this ratio acquired an abnormal value. The percent of children, adolescents, young and mature adults free of atherosclerotic plaques, gelatinous lesions and intima necrotic areas, fatty streaks and intramural thrombi was also evaluated. An association was revealed between the number of subjects with anatomically normal coronary arteries and the presence of the common type of distribution of the coronary arteries in these subjects.

Method-dependent number and topography of coronary narrowings.

A comparative gross and light microscopic study of the coronary arterial bed carried out on 95 selected male subjects aged 51-55 years, revealed that the number and topography of narrowings (more than 50% luminal insufficiency) showed wide method-dependent variations. If only routine gross inspection of the major coronary arteries was performed (method 1) 52% of the subjects exhibited narrowings; if gross inspection was extended to the proximal segment of the first diagonal, first septal, left marginal, right marginal and posterior descending vessels, the proportion of subjects with coronary narrowings augmented to 61% (method 2); finally the use of the light microscopy to investigate vessels supplying the conduction system and terminal vessels (method 3) augmented this proportion to 73%. Conversely, we recorded the absence of narrowings encroaching more than 50% in 48% of the subjects with method 1, in 39% with method 2 and in only 27% with method 3. Using the second method we revealed in coronary branches 29 narrowings and with the third method 52 narrowings. From the 95 cases investigated 46 (48%) did not show narrowings in the major coronary arteries. Of these 46 cases, 17 (37%) exhibited narrowings in coronary branches. This would indicate that more than 1/3 of the subjects without greater than 50% narrowings in the major coronary arteries showed such lesions in the branches of these major coronary arteries. The results of this study demonstrated the necessity of gross and light microscopic examination of the whole coronary arterial bed in all attempts to offer a realistic anatomo-clinical correlation in ischemic heart disease: they also demonstrated that the atherosclerotic involvement of the coronary arterial bed is not limited to the segments grossly examined by each pathologist.

Atherosclerotic involvement of coronary branch vessels.

The atherosclerotic involvement of coronary branch vessels (first diagonal, first septal, posterior descending, left and right marginals, conus and the vessels supplying the conduction system) was investigated in 450 apparently healthy subjects aged 11-55 years who died of accidental causes. In subjects 35-55 years old, 1 out of every 3 persons with atherosclerotic plaques in the major coronary arteries also had atherosclerotic plaques in coronary branch vessels; the respective relation for fatty streaks was 1 out of every 12 subjects, for intimal necrotic areas 1 out of every 7 subjects and for incorporated microthrombi 1 out of every 9 subjects. One out of every 3 subjects 51-55 years old had more than 50% lumen reduction in the undistended major coronary arteries, compared to 1 out of every 6 subjects in undistended coronary branch vessels. A small subgroup (8.2%) showed more severe stenotic lesions in coronary branch vessels than in coronary major arteries. The atherosclerotic plaques of coronary branch vessels appeared as 'underdeveloped', lacking a thick fibrohyaline cap, a large detritus cavity, abundant lipid deposition, cholesterol crystals, basal vascularization, intraplaque hemorrhage, ulceration, calcification, occlusive thrombosis. On the other hand the stenotic character of these plaques was often severe (more than 75% lumen reduction). The questionable value of the estimation of the ischemic significance of a coronary stenosis in the absence of available data on the development of a compensatory collateral circulation is discussed.

Centrifugal extension of coronary intimal necrotic areas.

The use of serial cross-sections, camera lucida drawings and photographic reconstruction of longitudinally cut samples, revealed that about half of intimal necrotic areas present in the coronary arteries of subjects aged 41-50 years exhibited a longitudinal diameter greater than 1.0 cm, occurring as very long lesions. In the 16 intimal necrotic areas included in a tridimensional study the longitudinal diameter was 7.8 times greater than the transverse one and 11.3 times greater than the luminal-medial diameter. The important centrifugal extension of coronary intimal necrotic areas during the fifth decade of life, particularly in male subjects, could not be detected grossly; it required a meticulous light microscopic examination of stained tissue section. This centrifugal extension was sometimes associated with the presence of a "border zone" of intermediate injury developed at the point where the intimal necrotic area irradiated in the direction of blood flow. This distal side of the lesion appeared as a highly irregular boundary with numerous peninsulas of interdigitating necrotic and apparently normal connective tissue. The present results, associated with those of our previous reports, support the view that human atherosclerosis has many attributes of a necrotizing arteriopathy.

Atherogenic anatomical patterns of coronary arteries branching related to cardiac and non-cardiac causes of death.

A gross and light microscopic study carried out on 102 selected male subjects aged 51-70 who died of ischemic heart disease and on 102 selected, male subjects of similar age, who died of noncardiac causes revealed that: in subjects who died of ischemic heart disease the prevalence of atherogenic deviations from the common type of distribution of the coronary arteries was 2-4 times greater than in subjects who died of non-cardiac causes; subjects who died of ischemic heart disease, with the atherogenic deviations from the common tape of distribution of the coronary arteries showed an increased number of stenotic atherosclerotic plaques and a particular propensity to "clustering" of these lesions, predominantly around branch mouths.

Presence of atherosclerotic lesions connected with the coronary artery lumen.

Starting from five accidental observations made on isolated tissue sections on the existence of "anchored" lesions in the coronary arteries of adolescents and young adults, 47 selected coronary artery samples removed from subjects 16-40 years old were submitted to a three-dimensional investigation. Based on serial sections and sequential camera lucida drawings, the geometry, diameters and spatial connections of 42 intimal necrotic areas were recorded. All these lesions appeared in a three-dimensional plane connected with the coronary artery lumen by one or several necrotic bands which seemed to communicate freely with the luminal cavity. The role of "anchored" lesions of young subjects as precursors of lipid-rich centers of fibronecrotic plaques of mature adults and elderly people is stressed.

Study of coronary intimal thickening.

A light microscopic study on intimal thickening carried out on 932 subjects 1-50 years old and on 22 selected topographic sites of the coronary arterial bed, revealed: (a) In similar topographic sites intimal thickening developed 5-15 years earlier in subjects with than in subjects without minor deviations from the common type of distribution of the coronary arteries. (b) The most rapid development of the intimal layer was detected in children aged 11-15 years. (c) 6% of children who died of acute diseases (mainly acute peritonitis) showed intimal thickening in both major coronary arteries and branch vessels; in children who died of accidents thickening developed only in the major coronary arteries. (d) More than 50% of subjects 46-50 years old (considered to be in the preclinical stage of ischemic heart disease) exhibited intimal thickening in the branch vessels usually non-opened during routine autopsy and non-removed for light-microscopic examination. (e) An intima/media ratio between 2.0 and 3.0 was associated with a 50% reduction in the luminal diameter; this reduction increased up to 75% when the intima/media ratio surpassed 3.0, the very thick intima acquiring the feature of a 'fixed stenotic lesion' in spite of its apparent normal aspect on light-microscopic examination.

A method which improves anatomo-clinical correlations in ischemic heart disease.

A study carried out on 595 unselected subjects aged 21-55 years who had died of accidental causes and on 56 selected patients who had died of myocardial infarction showed that the light microscopic examination of coronary branch vessels led to an obvious improvement of anatomo-clinical correlations in ischemic heart disease. These branch vessels included atherosclerotic plaques in 51% of unselected subjects 51-55 years old, dead of accidents and in 73% of selected patients dead of myocardial infarction. Severe stenotic plaques of possible clinical significance were found in 14% of subjects dead of accidents and in 48% of patients dead of myocardial infarction. In these cases the atherosclerotic involvement in the major coronary arteries (left anterior descending, circumflex and right coronary arteries) did not reach the level of possible clinical significance (greater than or equal to 75% reduction of the vessel diameter). Several examples emphasize the importance of stenotic lesions in the first diagonal, first septal, posterior descending, left marginal and right marginal vessels, as well as in the vessels supplying the sinoatrial and atrioventricular nodes for an adequate anatomo-clinical correlation in ischemic heart disease.