Atherosclerotic Lesions In Coronary Arteries Research Articles

Effects of therapy with diet and simvastatin on atherosclerosis in hypercholesterolemic patients

We evaluated the effect of cholesterol reduction on atherosclerotic coronary artery lesions using diet and simvastatin, a potent HMG CoA reductase inhibitor. Fifteen subjects aged 28-69 years (mean 44), each of whom demonstrated significant (greater than 50%) narrowing of a coronary artery and a baseline cholesterol level greater than 278 mg/dl, were studied. Coronary arteriography was performed prior to and after 20 +/- 2.5 months of therapy. A 42% reduction in total serum cholesterol, a 52% reduction in LDL cholesterol, and an 87% increase in the HDL/LDL cholesterol ratio (p less than 0.01) were achieved. Pretreatment and posttreatment angiograms were reviewed by three experienced angiographers with temporal order masked. Improvement in the overall status of coronary atherosclerotic lesions was demonstrated in two patients (13%), while deterioration occurred in one patient (7%). No overall change was found in the remaining 12 patients (80%). We conclude that a cholesterol-lowering regimen using a nonatherogenic diet and simvastatin therapy may at least stabilize coronary atherosclerosis.

Sustained Arterial Injury and Progression of Atherosclerosisa

In this paper the following findings were described: 1) Murine arteriosclerosis induced by immune challenge was ultrastructurally characterized by intimal monocyte-macrophage recruitment and minor endothelial alterations; 2) Atherosclerotic lesions of human coronary arteries exhibited frequently segmental or patchy neovascularization, probably representing a response to intimal injury as an example of repair process. Newly formed blood vessels in the intima were derived from both adventitial and luminal endothelial growth; 3) Angiogenesis in vitro was related to the activation of fibrinolytic system especially via the autocrine production of u-PA from endothelial cells, and this process was modulated by cytokines and TGF beta. These findings add more evidence for the hypothesis that the chronic inflammation-repair process plays an essential role in the initiation and progression of atherosclerosis.

Flow patterns and spatial distribution of atherosclerotic lesions in human coronary arteries.

To investigate the potential role of fluid mechanical factors in the localized genesis and development of atherosclerotic lesions in humans, the exact anatomic locations of atherosclerotic lesions and the flow patterns at such sites in left and right human coronary arteries were studied in detail by flow visualization and high-speed cinemicrographic techniques using five isolated, transparent human coronary arterial trees prepared postmortem. It was found that atherosclerotic plaques and wall thickenings in left and right coronary arteries were localized almost exclusively on the outer wall of one or both daughter vessels at major bifurcations and T-junctions, which left the flow-divider free of lesions, and along the inner wall of curved segments. When flow patterns in such vessels were studied in detail, it was discovered that these sites were where flow was either slow or disturbed with the formation of slow recirculation and secondary flows and where wall shear stress was low. The results indicate that the major hemodynamic factors directly related to the localization of atherosclerotic plaques and wall thickenings in the human arterial system are the low fluid velocity and the resultant low shear stress that acts on the vessel wall.

The sequence of cell and matrix changes in atherosclerotic lesions of coronary arteries in the first forty years of life

We have studied the cell and matrix composition of normal intima and of atherosclerotic lesions in the coronary arteries of 691 subjects less than 40 years old. These arteries were obtained at autopsy and fixed by perfusion with glutaraldehyde under physiological pressure. A defined segment of the left coronary artery, known for its susceptibility to develop advanced lesions, was studied by light and electron microscopy. The initial intimal lesion occurred in infants and consisted in an increase in intimal macrophages and presence of isolated lipid-laden macrophages (foam cells). At puberty, more substantial accumulations of foam cells, accompanied now by lipid droplets in smooth muscle cells and by thinly scattered extracellular lipid (fatty streaks), were present. After puberty, an increasing number of subjects had intermediate lesions and atheroma. Intermediate lesions, characterized by greatly increased extracellular lipid, were the link between fatty streaks and atheroma. Atheroma was characterized by a massive core of extracellular lipid that damaged arterial structure by displacing normal intimal cells and matrix. In the third and more often in the fourth decade, some atheroma contained greatly increased collagen and smooth muscle cells above the lipid core (fibroatheroma). Collagenization and thickening were more marked when evidence of thrombotic deposits was present on the surface or within lesions. Smooth muscle cells were present in the intima of all subjects from birth. In early lesions, lipid in the intima was not associated with an increase in the number of smooth muscle cells. Smooth muscle cells were increased in lesions containing massive extracellular lipid, more so in those having, in addition, a thrombotic component; smooth muscle cells with massive basement membranes occurred in advanced lesions. Macrophages and macrophage foam cells were the cells that increased intimal cellularity at the onset of lesions. Other cell types associated with lesions were lymphocytes, mast cells, and plasma cells, but all of these were less numerous than either smooth muscle cells or macrophages. From birth, intima was always thicker opposite the flow divider wall of a bifurcation (eccentric thickening). When atherosclerotic lesions of any type were present in coronary arteries, the amount of lipid and accompanying cell reactions were greatest in eccentric thickening; intermediate lesions and atheroma were present only in eccentric thickening while fibroatheroma often extended beyond eccentric thickening.

Endothelial cell denudation, labelling indices and monocyte attachment in advanced swine coronary artery lesions

This study shows that frank endothelial denudation, as measured by scanning electron microscopy, is associated with coronary artery atherosclerotic lesions in swine fed hyperlipidemic diets for 9 or 18 months. The largest areas of endothelial cell denudation were found to be associated with the most advanced atherosclerotic lesions, and lesser areas of denudation were present in less severely atherosclerotic arteries. Overall, the study suggests that frank endothelial denudation in swine coronaries occurs secondarily to advanced lesion development, and is proportionate to the amount of lesion present. In contrast attachment of monocytes to the endothelial surface was not proportionate to the amount of lesion present. While the number of attached monocytes after 9 or 18 months of a hyperlipidemic diet was much greater than in the mash-fed swine, there was no difference between the two hyperlipidemic groups. In both hyperlipidemic groups, the attached monocytes were concentrated over lesion areas. By scanning electron microscopy, most attached monocytes in these perfused coronary arteries showed a slender foot process extending into a gap between endothelial cells. Endothelial cell turnover, as measured by tritiated thymidine labelling indices, increased with the amount of coronary artery atherosclerosis. However, it did not become significantly greater than in mash-fed swine until advanced lesions developed.

Complex and simple coronary artery stenoses: a new way to interpret coronary angiograms based on morphologic features of lesions.

For many years, atherosclerotic coronary artery lesions have been described by angiographers only in terms of location and degree of narrowing. However, it has become apparent that coronary stenoses generally have distinct morphologic features that can be recognized at angiography and that allow them to be classified as either "simple" or "complex" plaques. Complex plaques are those characterized by ulcerated or ruptured surfaces, subintimal hemorrhage, superimposed partially occluding thrombi, recanalized thrombi, or some combination. Pathologic studies have shown a very high frequency of these lesions at sites of total thrombotic occlusion of coronary arteries. Clinical and angiographic studies have demonstrated a high frequency of such lesions in living patients with both unstable angina and acute myocardial infarction. The presence of complex stenoses has also been found to increase the risk of future myocardial infarction. Plaque morphology thus appears to significantly affect the prognosis of patients with coronary disease and should be carefully evaluated in interpretation of all coronary angiograms.

Atherosclerosis in the hypercholesterolemic hare: Comparison of coronary artery lesions induced by dietary cholesterol in the hare and the rabbit

Atherosclerotic lesions in coronary arteries were compared to 10 hybrid hares and 14 rabbits after induction of hypercholesterolemia, using a cholesterol-enriched diet. All proximal portions of hare coronary arteries contained intimal lesions, often with severe luminal stenosis. These lesions were characterized by the presence of foam cells, smooth muscle cells, and areas of atheronecrosis. Foam cells were also found focally in the media. As part of the intimal changes, iron deposition was present in 65% and calcification was present in 32.5% of proximal segments examined. The proportion of segments with intimal lesions and the intima/media cross-sectional area ratios (I/M ratios) were greatest in proximal segments with stepwise decreases in the mid and distal segments. As area of myocardial infarction was present in one hare. In contrast, 46.5% of proximal segments of rabbit coronary arteries had no intimal lesions and those lesions present had no calcium or iron deposition. No infarction was observed in rabbit hearts. The proportion of segments with lesions and the mean I/M ratios were significantly greater in the hare than the rabbit, with proximal and mid coronary segments showing the most marked differences. The hare appears to develop coronary artery lesions more like those seen in man, with high grade, proximal stenoses occurring uniformly in hypercholesterolemic animals. In contrast, the atherosclerosis developing in rabbit coronary arteries is less uniform and includes involvement of intramyocardial arterioles. The hare offers several advantages as a model of human atherosclerosis.

Atherosclerotic lesions in coronary arteries of hyperlipidemic swine: Part 2. Endothelial cell kinetics and leukocyte adherence associated with early lesions

The role of endothelial cells (EC) in the development and progression of early swine intimal cell mass (ICM)-derived coronary artery lesions in 55 swine fed either a mash or hyperlipidemic diet for 14, 49 or 90 days was investigated. Characteristics studied were endothelial cell turnover (using tritiated thymidine autoradiography), adhesion of leukocytes (presumably chiefly monocytes) to endothelium, and the presence or absence of endothelial cell denudation. The major findings were: (a) An increased adherence of leucocytes to endothelial cells over ICM-lesions in the HL-90 day group compared to the corresponding mash value at 90 days as well as to that of each of the other HL and mash groups. (b) Significant positive correlation between the labeling indices (LI) of endothelial cells lying over coronary artery lesion cells and the labeling indices of the underlying ICM-lesion cells; also, a significant positive correlation between the labeling indices of endothelial cells over lesions of the abdominal aorta and those of the coronary arteries. (c) At 90 days the endothelial cell LI over lesions in the HL group was significantly higher than the corresponding values in the mash group. Since the EC increase rates by growth in the two groups are also significantly different, the differences in LIs reflect at least in part EC growth differences and no strong conclusion can be made regarding possible cell turnover differences. (d) No frank endothelial denudation was found. The findings suggest that in swine coronary arteries participation by monocytes from circulating blood is a factor in the early progression of the lesion as well as smooth muscle cell proliferation.

A Pathological Survey of Atherosclerotic Lesions of Coronary Artery and Aorta in China

A pathological survey of atherosclerotic lesions was carried out on 7159 hearts and 2044 aortae from autopsy material. The results showed that: 1. The prevalence of coronary atherosclerosis was 41.65%, while that of coronary stenosis was 9.41%. Lesions of comparable severity occurred about 5-10 years earlier in age in specimens collected after 1949 in this study, as compared with those before 1949 as reported previously by others. 2. Fatty streaks of coronary artery were found in newborns, whereas fibrous plaques were identified in coronary artery in the 10-19 year group. The prevalence of coronary stenosis increased rapidly after 35 years of age by a rate of about 8.6% per year up to 55 years and declined thereafter. 3. The prevalence of coronary atherosclerosis was higher in males than in females, with a significant difference found in the 20-59 year groups. Coronary atherosclerosis was more frequently found in the left anterior descending branch than other branches including the left main trunk. The proximal segments of each branch are the sites of predilection. 4. The prevalence of aortic atherosclerosis was 76.71%. Atherosclerotic lesions appeared about 10 years earlier in the aortae than in the coronary arteries. 5. The prevalence of coronary atherosclerosis and stenosis was higher in the northern part of China than in the south and the occurrence of lesions showed a lag of about 10 years by age in the latter. The difference was statistically significant.

The disease-free wall in coronary atherosclerosis: Its relation to degree of obstruction

Coronary atherosclerotic lesions are more often located eccentrically (70%) than concentrically (30%). In this study, the configuration of eccentric coronary artery atherosclerotic lesions was assessed by means of computerized planimetry in 100 specimens of eccentric arterial lesions. Special attention was given to the relation between the disease-free wall and the severity of obstruction. The mean disease-free wall are length measured between 17 and 23% of the total vessel circumference in eccentric coronary artery lesions that obstructed 50 to 90% of the cross-sectional area. This ratio persisted irrespective of the location of the lesion within the vessel and was not significantly different with vessels of different sizes. The presence of disease-free arcs of coronary artery wall as observed in this pathologic study may relate to three factors in clinical coronary artery disease: The published observations of spasm in segments of arteries harboring structural obstructive lesions may be explained by the frequent presence of uninvolved arcs of coronary artery walls. Multiple views during coronary arteriography are necessary to accurately reflect the degree of obstruction. The results of percutaneous transluminal coronary angioplasty may be influenced by both the disease-free arc and the atheromatous obstruction.

Quantification of intimal cell masses and atherosclerotic lesions in coronary arteries of control and hyperlipidemic swine

In the current study of swine coronary arteries, we have attempted to quantify the coronary intimal cell masses (ICM) with regard to two aspects: (1) percentage of total arterial wall cells (intimal plus medial) that are in the intima, and (2) percentage of arterial wall area occupied by intima. We have studied 4 coronary sites: left main stem (LMS), proximal right (RCA), proximal left circumflex (LCX), and proximal left anterial descending (LAD). In mash-fed (‘normal’) swine we carried out the study at 3 ages: 2, 5 and 12 months. In addition, we have carried out a similar study in swine fed hyperlipidemic (HL) diets for 3 or ∼ 10 months starting at 2 months of age. In the control swine we found approximately 6% of the arterial wall occupied by intima at 2 months of age with no significant increases by 12 months. There were no consistent significant differences among the 4 coronary artery sites with regard to percentage of wall occupied by intima. When the HL diet was fed, there were significant increases in the percentage of the arterial wall occupied by intima (now atherosclerotic lesion) by 3 months on diet and much larger increases by 10 months (up to 87% of wall occupied by intimal lesion) with extensive regions of lipid-rich, calcific, necrotic debris. After 3 months on HL diet the RCA lesions occupied significantly greater percentages of areas than the other 3 sites but this difference had disappeared by 10 months on the HL diet.

Anatomic-ultrasound correlations for intraoperative open chest imaging of coronary artery atherosclerotic lesions in human beings

This study was performed to further validate a method for intraoperative ultrasound imaging of coronary arteries. Ultrasound images of coronary atherosclerotic lesions were compared with anatomic specimens of the coronary arteries obtained from open chest human subjects. The anatomic specimens were derived from four cardiac transplant recipients, accepted as candidates for transplantation because they had severe diffuse atherosclerotic disease, and one patient who died in the early postoperative period after a coronary artery bypass procedure. Twenty-six ultrasonically imaged atherosclerotic areas of the coronary arteries in these patients were compared with formalin-fixed and decalcified anatomic specimens. Specific ultrasound appearances for atherosclerotic lesions were observed, including 1) discrete (focal) stenosing fibrous/atheromatous plaques; 2) diffuse nonobstructive fibrous/atheromatous disease (detectable even in anatomically small vessels); 3) complete occlusion by fibrous/atheromatous lesions or organizing thrombus; and 4) "shadowing," an ultrasound pattern characteristic of significant calcification within atherosclerotic plaques. As part of this study, a new 12 MHz water path probe was evaluated for coronary artery scanning. The new probe allowed improved access to coronary arteries and increased detail of anatomic visualization. Both the performance of the new high resolution probe and the knowledge gained by the anatomic correlations obtained in this study should aid the development of intraoperative coronary artery scanning for surgical localization of atherosclerotic disease during coronary bypass surgery.

Risk factors and raised atherosclerotic lesions in coronary and cerebral arteries. Statistical analysis from the Oslo study.

In 1972-1973, about 16,200 men living in Oslo, aged 40 to 49 years, were examined for cardiovascular disease, and had a number of coronary risk factors measured. This report gives the results of 129 autopsied cases with regard to the association between raised atherosclerotic lesions in coronary and cerebral arteries and various coronary risk factors. For coronary raised lesions, the high density lipoprotein (HDL) cholesterol ratio was the most significant risk factor. Systolic blood pressure and total serum cholesterol were also significantly associated. Physical activity at work and at leisure, nonfasting triglycerides, and cigarette smoking did not show a significant association with coronary artery raised lesions. The association between total serum cholesterol and systolic blood indicates that total serum cholesterol may be more important than systolic pressure in the synergism affecting the development of coronary atherosclerosis. For cerebral artery raised lesions, blood pressure was the most important risk factor, even though serum cholesterol was highly associated with the lesions. The interaction analysis also suggested that blood pressure was more important than serum cholesterol in the synergism.

Coronary atherosclerosis in Aligarh district, Uttar Pradesh. A morphological study.

The present communication deals with the observations of the type and extent of atherosclerotic lesions in coronary arteries obtained from 108 heart specimens. In 81.4% cases the lesions were present. The earliest lesion of fatty streak was noticed in 2nd decade whereas all the cases above 4th decade had atherosclerotic lesion. Fatty streaks involved 4.5% of the intimal surface in 2nd decade, reaching a maximum to 26% in 6th decade and later on receding to 12% in 7th decade. Fibrous plaques were seen in later period of 2nd decade involving 2% of the surface area. There was a slow and tardy progression of the lesion with the maximum involvement of 32% in 7th decade. Complicated lesions were seen in 3rd decade but involved only 7% of the surface in 7th decade. Left coronary artery was involved in 79.62% cases and the right in 78 (72.22%). Salient histomorphological changes as well as degenerative changes occurring in the development of the disease process have been discussed. Main differences in the natural history of the disease in Indians were the slow progression of fibrous plaque and a very low incidence of grade IV lesions (complicated lesions). Marked disparity between the lesions observed in coronary arteries and root of aorta was noticed.

Advanced coronary atherosclerosis in swine produced by combination of balloon-catheter injury and cholesterol feeding

There has been a constant demand for an animal model of advanced coronary atherosclerosis produced in a short period. It was known that mild atherosclerosis could be produced in various vascular beds by high cholesterol diets. However, it requires considerable time to produce advanced atherosclerotic lesions by diets alone. The current study was designed to investigate effects of combination of a balloon-denudation procedure and high cholesterol diet in swine. We could produce advanced atherosclerotic lesions in coronary arteries in cholesterol-fed swine within a short period of time by inserting a balloon-catheter via carotid artery into the coronary artery, inflating it so as to distend the lumen, and pulling it back quickly, which resulted in extensive denudation of the endothelium of coronary arteries. An atherosclerosis-like lesion develops at the site with eventual narrowing of the lumen leading to myocardial ischemia, myocardial infarction, and occasionally sudden death, thus resembling in many aspects human coronary artery disease. Among 22 swine studied, 10 had severe atherosclerosis with virtual occlusion of proximal portion of either or both coronary arteries and developed myocardial infarction within 2–3 months. Seven of these died suddenly, probably due to arrhythmia. This model should be appropriate for studies where advanced coronary atherosclerosis with its complications is needed.

Relation of blood pressure and serum total cholesterol to severity of atherosclerotic lesions in aorta, coronary and cerebral arteries.

Macroscopic examinations were made on the aorta, the coronary and cerebral arteries of 132 autopsy cases with long follow-up of blood pressure and total serum cholesterol for more than 10 years.The most outstanding finding in the present study was a significant positive correlation between the average of annual systolic pressure and the severity of atherosclerotic lesions in the aorta, the coronary and cerebral arteries. On the other hand, the average of annual diastolic pressure was related only to the severity of cerebral atherosclerosis.Although a linear correlation was demonstrated between the average of total serum cholesterol and the severity of stenosing atherosclerosis of the coronary arteries, the total serum cholesterol value was found to be unrelated to the severity of the atherosclerotic lesions of the aorta and the cerebral arteries.

Experimental coronary atherosclerosis in rabbits

Intermittent cholesterol feeding of mature rabbits for periods of 6–30 months has produced atherosclerotic lesions of the main coronary arteries apprently similar to those found in man. The advantages of the rabbit as an experimental animal are stressed. Individual variations in response to cholesterol feeding were observed.

Mitochondrial alterations in human and experimental atherosclerosis

Electron microscopic observations of the lesions seen in the enzymatic induction of atherosclerosis in rabbits, the repair of surgically injured arteries in dogs, and the human atherosclerotic lesions in coronary arteries have lead to an hypothesis of atherogenesis. Injury to mitochondria characterized by disruption of the cristae appears to precede accumulation of lipid vesicles in the smooth muscle cells. Accumulation of lipid within injured mitochondria is noted. These processes are seen in injury-altered smooth muscle cells, and injury-altered reparative type cells. It is concluded that injury at the level of the mitochondria causes a metabolic blockade which results in the accumulation of lipids. This process is analogous to that seen in the liver in fatty metamorphosis. Since the accumulation of lipid in cells where it is not normally present is by definition fatty metamorphosis, it is postulated that this may be the basic underlying process in atherosclerosis.

The synergism of x-irradiation and cholesterol-fat feeding on the development of coronary artery lesions

Summary (1)High cholesterol diet produced xanthomatoses limited to the origins of the major coronary arteries and intramyocardial branches of rabbits. (2)Fractionated X-ray to the hearts of otherwise normal rabbits in the amounts and intervals we employed was apparently responsible for rare areas of medial degeneration and intimal proliferation of major epicardial arteries. (3)Exposure of hearts of rabbits on high cholesterol diets to fractionated doses of X-ray produced diffuse severe arteriosclerotic and atherosclerotic lesions of major epicardial coronary arteries. (4)Synergism between a physical agent (X-ray) and a chemical substance (cholesterol) were apparently necessary to evoke this effect. Deposition of lipid in portions of vessels damaged by X-irradiation was probably one of the prime mechanisms in the genesis of these lesions. (5)In the elderly patient in whom frank or incipient vessel damage was already present, the tissue damaging effect of the X-irradiation may have accelerated the development of the coronary arteriosclerosis.

The Natural History of aortic and coronary atherosclerosis in colombia evaluated by necropsy examination

Summary A total of 626 aortas and 379 coronary artery sets were collected from consecutive autopsies of persons aged 1-79 years in a large charity hospital and the medico-legal office in Cali, Colombia. Atherosclerotic lesions were estimated visually in terms of the percentage of the intimal surface of each arterial segment involved by the various types of atherosclerotic lesions. Fatty streaks develop in the aorta of Colombian males and females to a greater extent than the New Orleans white males and females, and in lesser degree than in New Orleans Negro males and females. In spite of this initial change the formation of fibrous plaques is observed in lesser extent in the Colombian population than in the New Orleans group, but at slightly larger proportion than the Guatemalans and the Bantu. The differences with the New Orleans cases are more striking when the more severe atherosclerotic lesions are considered (fibrous plaques, complicated and calcified lesions). When the "severity index" of the abdominal aorta in the Colombian group is compared with the New Orleans cases, a clear stratification of the groups is observed with New Orleans white males and females showing the highest values and the Colombian cases exhibiting the least severe involvement. Atherosclerotic lesions in the coronary arteries are also present in the Colombian cases but the extent and severity of such lesions is lesser in degree than for the aortas when the same age groups and sex are considered. Coronary artery lesions were compared between Colombian and New Orleans white and negro males and again the same pattern as with the aortic atherosclerotic lesions was observed. Aortic and coronary artery atherosclerotic lesions were less severe in Colombian females than in males at any age group studied. These results show also that the cause of death should be taken into consideration for the purpose of geographic comparisons of pathological observations of necropsy material for the purpose of the study of atherosclerotic lesions. Cases dying of "atherosclerotic heart disease" or because of other diseases considered to aggravate atherosclerosis should be excluded for this comparison. The product-moment correlation coefficient was calculated for aortic with coronary atherosclerotic lesions in 427 cases, where both the aorta and coronary arteries were studied. A weak but positive correlation was found between most of the lesion measures compared. The highest values were for aortic total surface with coronary total surface ( r 0.52), aortic and coronary fibrous plaques ( r 0.51) and aortic severity index with coronary total surface (r 0.59) and with coronary fibrous plaques ( r 0.54). These data on aortic and coronary atherosclerosis are inconsistent with the extremely low rate of arteriosclerotic heart disease attributed to Colombia on the basis of vital statistics data, and suggest that this rate, at least for Cali, should be higher than presently reported, but lower than for the North American whites.