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Ultrasound imaging versus morphopathology in cardiovascular diseases. Coronary collateral circulation and atherosclerotic plaque
© Baroldi et al; licensee BioMed Central Ltd. 2005
Received: 14 February 2005
Accepted: 01 March 2005
Published: 01 March 2005
This review article is aimed at comparing the results of histopathological and clinical imaging studies to assess coronary collateral circulation in humans. The role of collaterals, as emerging from morphological studies in both normal and atherosclerotic coronary vessels, is described; in addition, present role and future perpectives of echocardiographic techniques in assessing collateral circulation are briefly summarized.
In the past 25 years, the concept of a compensatory function of the coronary collaterals (or anastomoses) – i.e. vessels that join different coronary arteries or branches – has been practically cancelled from the mind of cardiologists since cineangiography shows that the onset of coronary heart disease (CHD) occurs independently of their presence. The assumption, therefore, was and is that they have no compensatory meaning  and coronary obstruction causes ischemia. A crucial and questionable assumption which disregards solid and recognized pathological data and supports invasive therapies, the diagnostic gold standard being the coronary cineangiography. In many cardiological centers, at the first chest discomfort, the latter is the guide for emergency angioplasty + stent or surgical bypass when a coronary ostruction is found; with the belief that a severe coronary stenosis causes angina pectoris, its occlusion an acute myocardial infarct (AMI) or sudden death (SD) and chronic ischemia explains hibernating myocardium.
Both homo-intercoronary and plaque collateral systems are anatomical structures capable to adapt in particular pathological conditions. The question is whether or not they are able to prevent ischemia and compensate an occlusion which by cineangiography appears as a "cut off" of a vessel without imaging of its distal tract. It must be stressed that in postmortem casts with coronary occlusion the latter was always injected through collaterals.
In 87% of AMI patients, within four hours from clinical onset, a cineangiographic occlusion was observed and in 88% of cases undergone emergency bypass surgery, a "layered thrombus" was recovered "proximal to stenosis" ; a thrombus due to plaque rupture [6–8] causing the infarct or sudden death.
In discussing this dogma the first need is to review the function of the collaterals.
Capillary function in presence of normal coronary arteries
In normal hearts and in pathologic hearts with normal coronary arteries, the collaterals, due to their capillary structure, participate to the metabolic exchange as terminal capillary bed. This means a much greater extent of the exchange surface which invalidates any "one myocardial / one capillary" model to study the delivery of any substance from capillary to myocardial cell. The myocardial interstitium is crossed by a myriad of "endothelial" vessels in any direction.
Compensatory function in presence of coronary obstruction
The demonstration of tridimensional collateral enlargement by casts indicates, per se, that there was an increased blood flow. Their adequacy to compensate one or more severe coronary obstructions is documented by the following main facts:
Maximal atherosclerotic lumen diameter reduction and number of main arteries with severe (≥ 70%) stenosis
Acute myocardial infarct
Sudden death unexpected
Non cardiac atherosclerotic Patients
Accidental death in normal people
% Lumen reduction
No. arteries ≥ 70%
Lack of correlation between number of severe (≥ 70%) coronary stenoses and acute infarct size (% left ventricular mass) in 200 consecutive and selected fatal cases.
Acute myocardial infarct
≥ 3 vessels
3. No relation between the total vascular territory of obstructed coronary artery and infarct size which often extended in territories of non stenosed or occluded vessels. In vivo hypokinetic zones expand in well perfused region .
4. The relatively frequent finding of a coronary occlusion without an infarct.
5. In an experiment done in a leading dog lab, a controlled coronary stenosis, maintained for few days and then occluded, did not determine any dysfunction or infarct because a dramatic increase of collateral flow [10–12].
These are the main facts supporting the concept that collaterals shown postmortem succeed in limiting or abolishing ischemia induced by coronary obstruction and question the existence of chronic ischemia due to coronary atherosclerosis since a plaque takes time to develop while collaterals [10, 11] adapt itself quickly as soon a pressure gradient between stenosis and distal vessel is established. On the other hand, there is no demonstration of a possible failure, both acute or chronic, of collaterals; including spasm since they have not tunica media.
The inability of cineangio imaging to visualize collateral systems is explained by its very limited power of resolution of all intramural vessels and by the selective injection of radiopaque labelled blood flow in one coronary artery competing with non labelled flow from the other coronary artery. Only very enlarged intercoronary anastomoses can be seen cineangiographically without any value in relation to cardiac dysfunction. Acute ischemia induced by balloon inflation at angioplasty may depend on sudden occlusion by compression of the collateral plaque system.
Active coronary atherosclerotic plaque according to cineangio imaging
Active plaque means an impending infarct expressed by a variety of angiographic signs as irregular lumen, haziness with ill-defined margins, smudge appearance, inhomogeneity, opacification, luciencies, persistence of radiopaque material, etc. Signs difficult to correlate with postmortem findings since terminal changes can not be excluded. They may represent the irregular vascularization of the atherosclerotic plaque opacified by the injected radiopaque material. Worthy of note is that cineangio defects can persist unchanged per years .
Cineangio coronary occlusion
The very high frequency of coronary occlusion seen angiographically in AMI patients (see above) does not correspond to that observed in pathological studies in which the mean figure is 50% for AMI and 29% for SUD patients. Nevertheless, different selection of material, divergent definition and an absence of a correct correlation of all pertinent variables give reason of dissimilar conclusions. In 200 selected AMIs and 208 SUD cases the unique cause of occlusion was a thrombus found in 41% and 29% respectively. In AMI group it correlated significantly with a lumen reduction greater than 70% (93%), length of plaque more than 6 millimeters (95%), its concentric shape (100%), prevailing atheroma (84%), medial neuritis (92%) infarct size greater than 50% (86%). SUD cases showed a similar behavior.
One case is only one case but when for the first time shows how the events developed, it becomes a precious mile stone for our knowledge demonstrating that the cineangio occlusion was a pseudocclusion namely a blood flow stasis in LAD secondary to an increased intramyocardial resistance. The first main question is how many of the 87% cineangio occlusion are pseudocclusion and whether the "layered" thrombus recovered at bypass surgery was a true thrombus or a coagulum which frequently show a layering of blood elements not seen in thrombus formation.
"Red" thrombus, namely a coagulum, is frequently and erroneously considered as thrombus. The second question concerns the nature of increased intramyocardial resistance: spasm of intramural arterial vessels or their extravascular compression by an asynergic myocardium? The first sign of CHD is hypokinesis of a myocardial zone which particularly in systole may compress vessels. Any time there is an increase of the intraventricular pressure with bulging of hypokinetic myocardium such a compression may abolish blood flow with subsequent infarction. In the reported patient location and infarct size corresponded to the hypokinetic area observed before the infarct onset.
A last comment deserves the supposition that small atherosclerotic plaques undetectable at cineangio, may rupture causing an infarct. A supposition based on the cineangio finding of a non critical stenosis observed in a vessel tributary of a territory in which an infarct will develop. Since, when the latter occurred, stenoses in other non supplying vessels did not show a further lumen reduction, the conclusion was that even the plaque related to infarction had a non critical lumen reduction . A conclusion that ignores the following two main facts. First that no one pathological study demonstrated the rupture of a small plaque associated with a thrombus occluding a normal or mild stenotic lumen. Second, myocardial asynergy by increasing intramyocardial resistance, promotes plaque progression by an increased dynamic stress on wall of the supplying extramural artery. For instance, in the previous case both LAD and vein graft with a normal lumen at surgery, in 12 months became critically stenotic (90% and 80% respectively). Regional myocardial dysfunction is an important cofactor in accelerating atherosclerosis lesion in related artery.
Target of ultrasound diagnosis: the present and the future
In the past years, clinical methods available to measure collateral flow have been too crude and showed major limitations, thus contributing to debate and confusion about the functional relevance of collateral circulation in the human myocardium. Coronary angiography allows visualization of collateral vessels having a diameter ≥100 μm, that actually prevents the majority of them from being detectable with this technique [16, 17]. On the other hand, scintigraphic perfusion imaging techniques have limited spatial resolution . Intracoronary wedge pressure and Doppler flow velocity measurements clearly demonstrated the presence of considerable collateral flow even in patients without angiographic evidence of collaterals [19, 20], but they are invasive and not suitable for routine clinical use. With the introduction of new generation echo contrast agents and advanced ultrasound techniques, myocardial contrast echocardiography (MCE), an ultrasound imaging technique that utilizes physiologically inert gas-filled microbubbles as red blood cell tracers, has gained importance for the non-invasive assessment of blood flow at the level of myocardial perfusion [21, 22]. Although evaluation of viability is the main clinical application of MCE , indirect assessment of collateral derived myocardial perfusion has been described in different clinical and experimental settings. In patients with severe left coronary artery disease, the placement of a graft to the posterior descending coronary artery was found to improve the collateral derived peak contrast effect within the anterior left ventricular wall . In a series of subjects with healed myocardial infarction and total occlusion of the culprit vessel, a correlation was found between angiographic collateral grade and peak contrast effect after contralateral intracoronary contrast injection . Collateral perfusion detected by MCE paralleled changes detected by radiolabeled microspheres during thrombosis and vasodilator administration in a canine model . The usefulness of MCE has been confirmed in subjects without coronary occlusion where it was able to map the myocardial territory perfused by coronary collateral flow and to evidence immediate reduction of perfusion when collateral flow was abolished by angioplasty . In patients with no prior myocardial infarction undergoing coronary angiography, intracoronary MCE effectively quantified coronary collateral flow, as demonstrated by the linear correlation existing between peak echo contrast effect and collateral flow index determined by intracoronary wedge pressure . On the other hand, a strong correlation was reported between collateral receiving area at MCE and regional wall motion score index in patients with coronary occlusion, thus providing evidence that collateral derived perfusion is a good indicator of preserved regional function . Likely, the grade of collateral flow on MCE was inversely correlated to the infarct size and was able to predict functional improvement following coronary revascularization . Using an experimental model of chronic ischemia, it was found that not only the presence of collaterals can be identified by MCE, but also that temporal and spatial development of collateral circulation can be tracked serially .
Finally, intravenous MCE has been recently reported to provide qualitative and quantitative evaluation of collateral blood flow in the presence of an occluded infarct-related artery, and to emerge as the only predictor of true collateral blood flow among other markers .
All these reports as a whole support the concept that MCE provides important information on collateral flow and represents a promising mean for evaluating the status of coronary collateral circulation in clinical practice. Some important caveat, however, have to be taken into account. First, although the peak contrast pixel intensity has been reported as the most accurate of the variables obtained to measure collateral flow, there is a remarkable scatter in the correlation between peak pixel intensity and true collateral flow . Second, it is known that regional contrast heterogeneity is common, resulting in frequent false positive perfusion defects . Finally, coronary collateral vessels may cause additional dilution of contrast affecting the transit rate calculation. Further technical improvements may contribute in the near future to ensure standardization of the acoustic window and provide a quantitative evaluation of collateral flow. These issues appear to be of crucial importance to turn the echocardiographic assessment of coronary collateral flow into a ready-to-go clinical tool.
Besides the attempt to obtain direct echocardiographic assessment, coronary collateral circulation can indirectly affect the result of diagnostic stress testing with the use of echocardiographic technique. Increased vulnerability to myocardial ischemia induced by pharmacological coronary vasodilation was reported consistently with the hypothesis of a facilitated steal phenomenon in the presence of good collateral circulation . On the other hand, the role of collaterals against echocardiographically-assessed stress-induced myocardial ischemia is controversial, some Authors reporting a protective  and others a neutral  effect. However, dobutamine-induced wall motion worsening in myocardial territories supplied by occluded epicardial vessels has been reported in case of evident collateral circulation , thus emphasizing the importance of a preserved, though reduced, blood flow to distinguish jeopardized myocardium from necrotic tissue. Differently, the ability of low-dose dobutamine stimulation to identify myocardial regions with a high probability of functional improvement after revascularization seems to be independent of both severity of underlying coronary stenosis and degree of collateralization of the involved coronary vessel .
The application of low-frequency ultrasound to intravascular microbubble contrast agents has been receiving attention in the last few years due to its potential therapeutic application, primarily as targeted gene delivery systems . Further evidence from experimental studies has shown small capillary ruptures in exteriorized rat skeletal muscle , intact mouse muscle  and rabbit myocardium  to follow the application of ultrasound power. However, capillary rupturing via microbubble destruction with ultrasound is able to enhance arterioles per muscle fiber, arteriole diameters, and maximum nutrient blood flow in skeletal muscle ; thus, it may be tailored to stimulate an arteriogenesis response that restores hyperemia blood flow following arterial occlusion . The potential of this method to become a clinical tool for stimulating blood flow to organs affected by occlusive vascular disease and, in particular, to the myocardium represents an interesting track for future research involving the application of ultrasound technology in the ischemic heart disease.
Final consideration on coronary atherosclerotic plaque
Any hypothesis on the pathogenic role of a plaque and its activity and vulnerability should consider all interrelated variables for a correct interpretation of findings. When only one or few variables are investigated erroneous conclusions can be reached. An atherosclerotic plaque is always an active structure since its progression depends on a sequence of events due to a variety of correlated phenomena; while vulnerability is just an hypothesis which believe that some findings indicate a risk of plaque rupture.
Occlusive coronary thrombus versus significantly main correlated variables. Percentage distribution
Acute myocardial infarct
Sudden unexpected death
Length stenosis mm
Infarct size %
Most studies analized few variables mainly observed in animals after hypercholesterol diet or in familial hypercholesterolemia. A pattern [46, 47] totally different from that seen in general population and CHD. Furthermore, myocardial infarction is not synonymous of sudden/unexpected death, thrombus is a totally divergent structure from coagulum, collaterals can not be ignored and meaning of the coronary atherosclerotic plaque can be interpreted in another way.
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