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Ultrasound imaging versus morphopathology in cardiovascular diseases. Coronary atherosclerotic plaque
© Baroldi et al; licensee BioMed Central Ltd. 2004
- Received: 09 August 2004
- Accepted: 14 December 2004
- Published: 14 December 2004
This review article is aimed at comparing the results of histopathological and clinical imaging studies to assess coronary atherosclerotic plaques in humans. In particular, the gap between the two techniques and its effect on the understanding of the pathophysiological basis of coronary artery disease is critically discussed.
- Atherosclerotic Plaque
- Right Coronary Artery
- Coronary Heart Disease Patient
- Familial Hypercholesterolemia
- Fatty Streak
Amongst the clinical approaches ultrasound imaging is one of the more promising technique to understand dysfunction. The need is to compare morphopathological counterpart to have a correct pathophysiological interpretation.
In four reviews, morphopathology of the main cardiovascular disorders, in relation to the status of art of clinical imaging will be presented. The aim is to recall the pathological anatomy to stimulate ultrasound experts to further sharpen their technology till "histological" perfection.
The present first review concerns the coronary atherosclerosis since the current dogma of "unifying theory" assumes that the acute coronary syndromes, namely unstable angina, myocardial infarct and sudden death, are caused by atherosclerotic plaque rupture or "explosion" with occlusive thrombus formation preceded by intramyocardial emboli. An assumption which implies to discover a clinical imaging able to show when a coronary atherosclerotic plaque becomes vulnerable i.e. prone to rupture.
The risk of the latter has been correlated with large lipid core (atheroma in our definition), thin fibrous cap (< 65 μm) covering atheroma. Therefore any imaging should have a 50 μm resolution to identify a fibrous cap prone to rupture, 100 μm or 150 μm thickness being respectively at low or minimal risk. Matrix-digesting enzymes released from inflammatory cells (monocytes, macrophages, T-cells, B-cells, neutrophils, mastcells) may contribute to plaque rupture. An attractive approach since, despite many years of preventive and therapeutical attempts, coronary heart disease (CHD) remains the main cause of death and morbidity in advanced societies and selects people at the top of their work skillness and productivity.
The first question is whether ultrasound imaging may or may not discriminate extent and morphology of plaque variables seen within the intima.
Physiological intimal thickening
The first conclusion is that such intimal thickening is a physiologic structural respons to hemodynamics and not the initial phase of atherosclerosis as claimed by some authors.
Coronary atherosclerotic intimal thickening
In contrast to the uniformely diffuse physiological intimal thickening, the atherosclerotic one is focal and protrudes within the lumen which is progressively reduced. In order to quantitatively study this progression, we sampled systematically in each heart the first tract of the main left trunk (LCA), left descending (LAD) and circumflex (LCX) branches, right coronary artery (RCA), posterior descending branch (PD) and the middle tract of LAD and marginal and posterior tracts of RCA. These selected tracts correspond to the sites where atherosclerotic changes generally occur. The coronary arterial sampling was performed in 100 fatal cases of acute myocardial infarct without other diseases and not undergone invasive techniques; 208 cases of sudden and unexpected coronary death (SUD) which occurred in apparently normal people, acting their usual life, without resuscitation attempts and autopsy findings limited to coronary atherosclerosis of any degree, myocardial necrosis or scar, with or without cardiac hypertrophy: 50 cases with chronic angina pectoris who died within 25 day after coronary by-pass surgery; and 97 normal subjects who died by accident without pathological findings at autopsy but coronary atherosclerosis. In a total of 3,640 coronary sections the following variables were quantified:
1. Lumen reduction calculated in percent of the normal diameter measured in normal coronary arteries and branches injected by plastic substance under pressure. Measurement often referred to the cross-sectional area within the internal elastic membrane may result in severe stenosis despite a normal lumen since the atherosclerotic plaque may enlarge the cross-section.
2. Shape of residual lumen: concentric if encircled by pathological intima or semilunar when an arch of the wall was normal.
3. Length calculated in number of segments involved by the plaque, all extramural coronary arteries being sistematically cross-sectioned at 3 mm interval.
4. Intimal and tunica media thickness measured in microns.
5. Atherosclerotic changes within the intima: fibrosis alone, basophilia i.e. proteoglycan accumulation, atheroma or lipoprotein/cholesterol material, calcification, vascularization, hemorrhage, adventitial and intimal lymphocytic infiltration. All these variables were expressed in percent of the total intima but vascularization calculated in number of vessels found.
Amongst 1,519 sections without lumen reduction with an intimal physiological thickness less of 300 μm we never found subendothelial or internal lipoprotein/cholesterol infiltration or deposit (fatty streaks), monocytes or macrophages or foam cells, platelet aggregates, fibrin-platelet thrombi or inflammatory elements. A similar negative finding was observed in 1,315 coronary sections with a lumen reduction less than 69% and pathological intimal thickness less than 600 μm. In all these sections we were unable to demonstrate an intimal fissuration. We must emphasize that in selecting our material cases of familial hypercholesterolemia were excluded.
In general the atherosclerotic intimal variables increased in frequency and extent in parallel with the lumen reduction and pathological intimal thickeness with the exception of proteoglycan accumulation less found in stenoses >90% and intimal thickness >2000 μm. Of 990 sections with calcification, 488 (49%) had mild stenosis, calcification being severe in 162 (33%). This finding indicates that calcification per se does not necessarily means a severe lumen reduction. The less frequent variable was intimal hemorrhage mainly seen in plaques located in a vessel tributary to an acute infarct.
This study induced the recognition of two types of coronary atherosclerotic plaque: one, which belongs to the general population, (including CHD patients) and starts as nodular intraluminal proliferation of smooth muscle cells followed by elastic tissue hyperplasia and final substitution by fibrous tissue. Subsequently, a deep proteoglycan pool forms and becomes a deposit of lipoprotein/cholesterol and/or calcium salts. The recurrence of these phenomena explains the radial, circumferential, longitudinal progression of the coronary plaque resulting in increasing lumen reduction. This type of myohyperplastic plaque is totally different from the hypercholesterol plaque obtained experimentally by hypercholesterol diet in animals free of atherosclerosis or observed in a small group of patients with familial hypercholesterolemia. In literature too often the hypercholesterol plaque is taken as a model of an atherosclerotic plaque in man . In timing the sequence of the events is important to stress that the inflammatory lymphocytic-plasmacellular process (autoimmune phenomenon?) starts after the proteoglycan insudation, being a relatively late complication.
Natural History of Human Coronary Atherosclerotic Plaque
Transendothelial lipoprotein/cholesterol infiltration
Nodular smooth myocell-elastic hyperplasia protruding in lumen
Proteoglycan accumulation below fibrous cap between media/intima
Necrotic core-atheroma under fibrous cap
Interstitial/macrofagic (foam cells) storage of lipoprotein-cholesterol and/or calcium salts in proteoglycan pool
Rupture fibrous cap
Plaque tridimensional growth by recurrence of previous phenomena
Late vascularization of atherosclerotic intima
Echocardiographic approach to coronary arteries.
Anatomic information (plaque)
Functional information (flow)
ICUS image analysis has been extensively used for determining plaque composition [10–13]. However, there are some limitations to this approach: 1) digitizing videotapes is time-consuming and therefore not suitable for real-time analysis; (2) image resolution is reduced to that of videotape, approximately 330 μm; (3) parameters such as gain, including time gain compensation and intensity, can be adjusted by the operator, thereby adding variability to the data set; (4) the dynamic range, pre- and postprocessing of the images depend on the analog-to-digital converters used in the ICUS consoles; (5) finally, due to the small dimension of the transducer, the transmitted acustic energy is low. Thus, some concerns still exist on whether this technique is ready to go for clinical use. In particular, definition of plaque composition seems not enough reproducible to provide an alternative independent standard to quantitative histology .
New technical development based on noninvasive molecular imaging [15, 16], such as the use of novel targeted contrast agents able to identify fibrin deposited within plaque microfissures , adhesion or thrombogenic molecules expressed on endothelium of vulnerable plaques [18–22], matrix metalloproteinases in the cores of progressing lesions , or even early angiogenic expansion of the vasa vasorum that supports plaque development , will contribute to fill the gap between information derived from direct, quantitative histology and ultrasound imaging. Moreover, spectral analysis of the radiofrequency signal allows a more detailed analysis of various vessel components than does image analysis of digitized videotape images and can be potentially employed in real-time. This approach is expected to improve tissue characterization .
The working hypothesis is to stabilize the atherosclerotic plaque by increasing the thickness of the fibrous cap or by regression of atheroma burden (1). However, present imaging techniques (coronary cineangiography, angioscopy, contrast magnetic resonance, contrast echocardiography, nuclear scintigraphy, etc.) cannot provide adequate clinical evaluation of plaque vulnerability. In particular, ICUS is unable to provide discrimination between physiological and pathological intimal thickening and to define the shape of plaque, i.e. concentric or semilunar. In fact, amongst 2121 coronary sections at the site of maximal lumen-diameter reduction the stenosis was concentric in 70% of the cases (99% in supplying vessels of an acute myocardial infarct). Furthermore, in 408 CHD patients the maximal stenosis in each single case was less than 69% in 68, 70%, in 67, 80% in 109 and >90% in 164. These data mean that the residual lumen ranged from 900 to less than 50 μm and catheter of 1500 μm in most instances must break the plaque, being the residual lumen too small. Therefore, shape and contour of a plaque can be altered with a misleading higher frequency of semilunar stenosis giving an erroneous support to the questionable concept of vessel wall remodelling following an atherosclerotic plaque formation.
According to the previous data the main conclusions are: 1. The natural history of coronary atherosclerotic plaque in the general population, inclusive of CHD patients, is different from plaques obtained by experimental hypercholesterol diet or found in familial hypercholesterolemia. Most data refer to the latter as a valid model for the human plaque. In particular, fatty streaks is not the starting change of the myohyperplastic atherosclerotic plaque; 2. Emphasis is given to a "macrophagic inflammation" as source of proteolytic and/or thrombogenic moleculae causing plaque rupture. However, macrophagic reaction belongs to a repair process to digest necrotic or extraneous material rather than typical elements of an inflammatory process, as lymphocytes, neutrophils. The assumption that on increased number of labelled macrophages may indicate a risk of rupture is questionable in human coronary myohyperplastic plaque.
In the present review we have discussed the behaviour and meaning of components of the human coronary atherosclerotic plaque to emphasize the inconsistency of the current myths:
1. Experimental hypercholesterol model and correspondent human conditions do not represent the natural history of atherosclerosis in coronary arteries in the general population.
2. Physiological intimal thickening can not be interpreted as starting point of the atherosclerotic process.
3. Fatty streak does not represent the early atherosclerotic lesion.
4. Calcification is not synonymous of severe stenosis.
5. Hemorrhage is not consequent to endothelial fissuration.
6. Prevention of macrophage "inflammation" as source of substances able to disrupt the fibrous cap allowing rupture and thrombosis as well as identification of the thickness of fibrous cap to diagnose a vulnerable plaque may have little, if any, sense. Rupture and thrombosis may be secondary phenomena and not the cause of an acute coronary syndrome.
7. Degree and number of severe coronary plaques do not predict onset, course, complications and death in CHD.
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