Plaques In Human Coronary Arteries Research Articles

Composition of coronary atherosclerotic plaque in the intima and media affects intravascular ultrasound measurements of intimal thickness

Objectives. The purpose of this study was to evaluate how intravascular ultrasound-determined thickness and reflectivity of the inner echogenic layer of coronary artery plaque is affected by changes in collagen, elastin, proteoglycan, calcium and lipid content in the intima and media.Background. Coronary artery plaque often results in disruption of the internal elastic lamina and in increased collagen in the media as well as increased intimal lipid, calcium and proteoglycan content. How these factors affect intravascular ultrasound-derived measurements of intimal thickness are unknown.Methods. Twenty-one coronary artery segments from 10 patients with varying degrees of coronary artery disease were obtained fresh and unfixed at autopsy. Instravascular ultrasound (30-MHz, 3.5F catheter) was performed at regions in the vessel where a three-layered region was evident. Quantitative measurements of inner echogenic and deeper echolucent layer thickness were determined as well as estimates of ultrasound reflectivity and compared with histologic measurments of intimal and medial thickness and collagen, proteoglycan, lipid and calcium content.Results. In plaque >300 μm thick and equivalent histologic levels of collagen, inner echogenic layer reflectivity was greater in regions with a greater amount of calcium and proteoglycan and lesser amounts of lipid. Inner echogenic layer thickness correlated well with intimal thickness but had the best correlation with intimal and medial thickness when medial collagen content was increased (r = 0.89). The median observed difference between intimal and inner echogenic thickness was 160 (p < 0.05 compared with zero), whereas the median observed difference between inner echogenic thickness and intimal plus medial thickness when medial collagen content was increased was 60 (not significantly different from zero).Conclusions. The inner echogenic layer of human coronary artery plaque may represent both intima and media. The echolucent layer by ultrasound may represent only the basal section of the media that does not contain high collagen contest.

Experimental Vasoprotection by Calcium Antagonists Against Calcium-Mediated Arteriosclerotic Alterations

According to chemical analyses, the development of conventional human coronary artery plaques from "fatty streaks" to "fibrous plaques" and "complicated lesions" is dominated by progressive mural calcium (Ca) incorporation. The atherogenic significance of Ca ions and arterial Ca overload was examined under the influence of nicotine, oxidatively modified low-density lipoproteins, spontaneous hypertension, and an elevated extracellular Ca concentration or vitamin D3. Experiments were carried out either in vitro on cultured medial cells of rats or in vivo on various types of experimental arteriosclerosis of rats. Suitable Ca antagonists (verapamil, diltiazem, nifedipine, or nitrendipine) prevented experimental Ca overload of arterial walls and transmembrane Ca uptake into cultured medial cells produced by risk factors. Thus they protected, in vivo and/or in vitro, against the atherogenic potential of Ca ions, i.e., migration, proliferation, matrix production and intracellular Ca overload of vascular smooth-muscle cells, as well as calcification of elastic fibers. The data indicate that various Ca-consuming processes demand a progressive uptake of Ca into arterial walls if Ca-dominated types of arteriosclerosis develop. Under experimental conditions, specific Ca antagonists inhibit Ca-mediated arteriosclerotic alterations by preventing progressive mural Ca incorporation.

Angiogenic processes in the pathogenesis of human coronary atherosclerosis.

Intimai neovascularization, which represents the newly formed vasa vasorum, has been recognized in atherosclerotic plaques of human coronary arteries for many years (Winternitz et al. 1938; Barger et al. 1984; Kamat et al. 1987). Nevertheless, there are still several unresolved questions regarding the origin and pathogenesis of these newly formed blood vessels as well as their pathophysiologic significance in the progression and/or regression of atherosclerosis, and especially the development of its sequelae such as thrombi and intimal hemorrhage. It is well known that neovascularization is a ubiquitous and vital response in various physiologic and pathologic conditions such as embryonic development, the inflammatory-repair process, and the growth of solid cancer (Folkman 1990).

Differentiation Between Calcium-and Cholesterol-Dominated Types of Arteriosclerotic Lesions

In a series of animal studies we have clearly demonstrated since 1970 that calcium overload of the arterial wall is crucially involved in the pathogenesis of arteriosclerotic lesions. Following excessive calcium uptake, vascular stretch compliance and distensibility were lost together with structural integrity. Conversely, calcium antagonists that counteract abundant calcium uptake were found to prevent pathogenic mural calcium accumulation and damage. These effects were realized with light and electron microscopy as well as with measurements of calcium accumulation using atomic absorption spectrometry and radiocalcium. The experiments were carried out on rats exposed to various well-known risk factors such as nicotine, alloxan diabetes, high doses of vitamin D3, or dihydrotachysterol. Another particularly vasotoxic factor appeared to be hypertension, which develops in spontaneously hypertensive Okamoto rats (SHRs), in hypertensive NaCl-loaded salt-sensitive Dahl-S rats, and in rats with nephrogenic Goldblatt hypertension. Interestingly, aging arteries in animals and humans also exhibit, as a characteristic phenomenon, a steady increase in arterial calcium content. This natural age-dependent calcium accumulation is further enhanced in severe diabetics, heavy smokers, and hypertensive patients. However, the most excessive degree of toxic calcium overload, correlated with dramatic structural damage, occurred in human coronary artery plaques. Here, in "fatty streaks" (type I plaques according to World Health Organization classification), the mural calcium content exhibited a rise by 13 times above normal; in type II lesions (fibrous plaques), the increase in calcium was 24-fold; and in type III plaques, i.e., in "complicated lesions of stenosing character," calcium overload amounted to a value greater than 80 times above that found in healthy coronary segments.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium — a Neglected Key Factor in Arteriosclerosis. The Pathogenetic Role of Arterial Calcium Overload and Its Prevention by Calcium Antagonists

Using specific calcium antagonists as experimental tools, both the physiological messenger and current carrying function of calcium ions as well as their pathogenetic potencies could be elucidated. Notably, excess intracellular calcium signalling and intra- and extracellular calcium overload turned out to be pathogenetic principles of general importance. In this context, progressive calcium overload of arteriosclerotic vascular walls and the antiarteriosclerotic effects of calcium antagonists, deserve particular interest. In fact, with the help of calcium antagonists, arterial calcium overload as decisive component of various types of experimental arteriosclerosis became accessible to a direct therapeutic intervention. According to their responsiveness to calcium antagonists, two pathophysiologically different types of experimental coronary plaques could be characterized: (1) The calcium type, i.e. coronary calcinosis of vitamin D3-intoxicated rats highly sensitive to calcium antagonist treatment, (2) the cholesterol type, represented by coronary atheromata of cholesterol-intoxicated rabbits; this primary coronary cholesterol accumulation could not be inhibited by calcium antagonists. The formation of conventional human coronary artery plaques is characterized from the very early lesion onwards by a progressive local uptake of calcium, finally leading to lethal consequences. Conversely, the analysis of the mural cholesterol does not allow to discriminate arteriosclerotic from normal coronary artery segments. Thereby, conventional human coronary plaques typically represent a calcium-dominated type of human arteriosclerosis and differ widely from plaques produced in cholesterol-fed rabbits. The results indicate the decisive pathophysiological role of calcium and calcium overload in both calcium-dominated types of experimental arteriosclerosis and conventional human coronary artery plaques. Moreover, the antiarteriosclerotic effects of calcium antagonists are demonstrated to be based--in various types of experimental arteriosclerosis--on the inhibition of intra- and extracellular calcium overload of arterial walls evoked by various risk factors (vitamin D3 intoxication, hypertension, nicotine, diabetes).

Excessive mural calcium overload — A predominant causal factor in the development of stenosing coronary plaques in humans

Healthy human coronary artery walls contain, over their entire lifetime, more free and total cholesterol than calcium. However, as soon as arteriosclerotic alterations set in, the calcium content increases. Thus in coronary fatty streaks (arteriosclerotic plaques of WHO stage I), calcium was increased 13 times, in stage II plaques 25 times, and in fully developed stage III plaques 80 times above normal on average. The most dramatic calcium incrustation was found in coronary stage III plaques that had produced massive fatal coronary infarction. Here, the proportion of calcium salts (particularly hydroxyapatite) may amount to almost 50% of dry weight. Thus the most excessive accumulation of calcium seems to be correlated with the highest fatality. In contrast, there is no correlation between mural coronary free or total cholesterol content, and plaque severity. Accordingly, stenosing coronary stage III plaques contain less cholesterol than do fatty streaks. Moreover, in coronary stage III plaques the proportion of free cholesterol was 1.37%, and of total cholesterol only 2.34% of the whole mass, certainly not enough for directly causing coronary occlusion. Thus the calcium-rich plaques of human coronary arteries considerably differ from the well-known cholesterol-rich plaques (stage I and II) of human aortae. Our findings justify a new prophylactic approach with suitable calcium antagonists to interfere with deleterious calcium uptake in coronary plaque development.

Morphology of the endothelium over atherosclerotic plaques in human coronary arteries.

The right coronary arteries of six hearts removed from patients with atherosclerosis, who were undergoing cardiac transplantation, were perfused with 2% buffered glutaraldehyde for 20 minutes before preparation for scanning electron microscopy. Perfusion was started within five minutes of explanation. In two patients the artery was angiographically normal, in one it was irregular in outline, and three had focal segments with significant stenosis. None of the patients had concentrations of plasma lipids above 5.5 mmol/l. The endothelial surface showed widespread focal abnormalities ranging from adhesion and migration of monocytes to loss of individual endothelial cells. Larger areas of endothelial denudation with exposure of underlying collagen were also seen consistently. Loss of endothelial cells was associated with accumulation of monocytes, on and deep to the surface, as well as adhesion of platelets to the exposed subendothelial tissue. These results accord with the endothelial damage and platelet adhesion seen in hyperlipidaemic animals fed a high lipid diet.

Morphology of the endothelium over atherosclerotic plaques in human coronary arteries

Morphology of the endothelium over atherosclerotic plaques in human coronary arteries

Transforming gene in human atherosclerotic plaque DNA.

The monoclonal hypothesis equates atherosclerotic plaques with benign smooth muscle cell tumors and proposes that plaques can arise via mutational or viral events. Here, we provide direct evidence that molecular events, heretofore associated only with tumor cells, are common to plaque cells as well. Three distinct groups of human coronary artery plaque (hCAP) DNA samples transfected into NIH 3T3 cells gave rise to transformed foci. DNA samples from a panel of normal noncancerous human tissues, including coronary artery, were negative in the assay. Southern-blotted focus DNA yielded positive signals when hybridized to the 32P-labeled nick-translated repetitive human "Alu" DNA sequence. The DNA from cloned foci was used successfully in a second round of transfection. Focus DNA hybridized to nick-translated v-Ki-ras, v-Ha-ras, or N-ras probes failed to detect human fragments of these genes. Primary focus cells from each of five clones elicited tumors after injection into nude mice (6/42). Several distinct high molecular weight (greater than 6.6 kilobases) bands were detected after BamHI-digested tumor DNA was hybridized to Alu. Preliminary characterization of these hCAP DNA-associated tumors indicates that they are similar to the fibrosarcomas that arise after injection of ras-transformed cells into nude mice. We propose that transforming genes in plaque cells behave in a manner analogous to the way in which oncogenes behave in cancer cells.

Distribution of fatty and fibrous plaques in young human coronary arteries

We have correlated atheromatous plaque distribution with vessel geometry in coronary arteries from subjects dying of non-cardiovascular causes under 40 years of age. After standardised preparation, the area, and circumferential and longitudinal position of each plaque, were measured in the major coronary arteries. Of 41 sets of vessels, two were free of disease. In the remainder, total plaque area varied from 8 to 586 mm 2. Half the cases showed fatty plaques only, and half showed both fatty and fibrous plaques. We analysed the distribution of plaques in those vessels affected only by very early fatty disease. In all vessels, plaques were concentrated proximally, but in the left anterior descending and circumflex branches the wall close to the flow-divider was spared. Circumferential distribution was also not random. In the right coronary artery, lesions were concentrated on the inner wall of the major curvature. In the left anterior descending branch, lesions spiralled anticlockwise from the orifice. We suggest that local mechanical factors may determine these patterns.

CONTRIBUTION OF ATHEROMATOUS GRUEL TO THROMBUS FORMATION.

SummaryGruel obtained from experimental thromboatherosclerotic plaques and from human coronary artery plaques was tested in in vitro studies for its possible thromboplastic potency. Gruel from experimental thromboatherosclerotic plaques was moderately thrombogenic, but that obtained from the human plaque appeared to be non-thrombogenic. The lipid extract of the experimental gruel failed to exhibit any thrombogenic propensity.