Presidential address: The carotid bifurcation plaque—a model for the study of atherosclerosis
1986; Elsevier BV; Volume: 3; Issue: 2 Linguagem: Inglês
10.1016/0741-5214(86)90008-x
ISSN1097-6809
Autores Tópico(s)Cerebrovascular and Carotid Artery Diseases
ResumoBeing granted the privilege of delivering a presidential address before a body as distinguished as the Society for Vascular Surgery is a humbling experience, not only because of the professional stature of its members and guests but also because of the brilliance of the presentations of former presidents. In seeking guidance regarding appropriate subject matter and tone from the 38 previous addresses, one can only conclude that there are no limitations as to subject matter and that giving free rein to one's imagination is permissible.1Shumacker Jr, HB. The Society for Vascular Surgery. A history: 1945-1983.in: The Society for Vascular Surgery, Manchester, Mass1984: 343-380Google Scholar The earliest ones, 20 in all, dealt with purely scientific subjects, ranging from authoritative discussions of venous problems to congenital heart disease to extracorporeal circulation, with surprisingly few dealing with arterial surgery. Five were purely historical, four philosophical, whereas seven of the most recent discussed in fairly general terms vascular training and accreditation, emphasizing the need for its recognition and for the maintenance of close affiliation with the general surgical discipline from which we are derived. Two are difficult to classify. Perhaps in making a choice one should be guided by one's own wellsprings of thought and not try to emulate one's predecessors, touching on one's own and the presumed current concerns of the membership of the society. It would be presumptuous for one person to attempt to supply solutions to all or even any problems. More realistic would be the presentation of these problems in a somewhat different perspective, redefining them perhaps and even asking highly specific questions as though from a sense of naiveté, on the premise that the outgoing president has been deeply involved with the affairs of the society, the concerns of its members, and its aims and the reasons for its existence. For those who remember the fable of the emperor's clothes, the innocent vision of the child recognized the emperor's nakedness, whereas the more sophisticated loyal adult subjects felt obliged to perceive him to be clothed in golden garments.2Andersen HC. The emperor's new clothes. Based on Hans Christian Andersen's Tales for Children. D. Appleton & Co, New York1861Google Scholar Much has transpired in recent years that promises to profoundly influence our activities, and indeed we may be at two crossroads. At one are questions regarding the practice of vascular surgery in our communities. At the other are involved decisions regarding the directions to which research into the causation and methods of treatment of atherosclerotic disease should proceed, for it is this pathologic entity that occupies us most and taxes our ingenuity. As a group of experienced vascular surgeons, many privileged to have been involved in the evolution of the surgical vascular discipline to its present state, and all to have seen in living patients the various stages in the development of the pathologic processes that demand our attention, we have become heirs to particular responsibilities demanding the formulation of and answers to highly specific and pertinent questions. Recently the vascular discipline has been accorded well-deserved recognition as one that requires special competence. The introduction of qualifying examinations, certificates of special competence, and accreditation of training programs are all symbolic of this recognition. However, there persists a fear that this will result in the fragmentation of general surgery to the detriment of all. There is the feeling that there exists among us a lack of awareness of the realities of surgical practice in the United States, in that those who have been trained in general surgery are frequently in the position of having to perform urgently needed vascular procedures and that this pattern will continue for the foreseeable future. Therefore, the feeling also exists that the training of every general surgeon should include at least a minimal exposure to vascular surgery as preparation for these exigencies and perhaps also for the performance of some of the "simpler" vascular procedures, which would thus improve the care of patients. The questions that arise are: How much training is required to achieve such competence? Can this training be crowded into the framework of an already crowded 5-year general surgical training program that desirably encompasses the major subspecialties and the complex vascular discipline as well? Which are the "simpler" vascular procedures? What should be the significance of the certificate of special competence? It is for us who have had the most extensive experience in providing vascular services, who have been trained in and therefore have a basic understanding of general surgery and its problems, who have been involved in training both general surgical and vascular residents, to attempt to formulate a comprehensive program, the primary aim of which must be the delivery of the best possible general vascular surgical services to the community. For is that not the aim of all of our research efforts and of our participation in training programs? Indeed, is that not the basic reason for the existence of this society? To date, we have perhaps responded to the concerns of our general surgical colleagues in fragmented and sometimes negative ways, without full appreciation of the impact of our recommendations on the entire medical and patient community. Were we to formulate a comprehensive plan for the delivery of vascular surgical care to our various communities, the interaction of the general surgeon, the cardiothoracic surgeon, the neurosurgeon, the interventional radiologist, and the general vascular surgeon would be better defined and integrated, for all are now involved, as an example, in the surgical care of patients with extracranial cerebral arterial disease. We, as a group of concerned vascular surgeons must openly discuss and achieve a consensus among ourselves regarding the criteria for competence in particular vascular surgical procedures. We must come to grips with issues such as manpower needs within the context of a comprehensive program. We must find realistic ways of fulfilling those needs. We must evaluate dispassionately the relative values of caseload reports, of extraclinical activities, of participation in laboratory investigations, of attendance at meetings, and of careful record keeping to permit peer review, as prerequisites for admission to the recognition examination in vascular surgery. Should the mere participation in a formal vascular training program beyond the 5-year general surgical program be sufficient reason for admission to the examination? Should the qualifications for the vascular surgical academician be the same as for the full-time practicing vascular surgeon? Is there a role for the occasional vascular surgeon and what realistically should be expected of such a person? How should this level of expertise be achieved? Should the ultimate qualifying factor for accreditation in vascular surgery be merely passing the vascular examinations, both writen and oral, regardless of training? What should be the role of the general surgeon, who may have received minimal training in vascular surgery, in the delivery of both emergency and elective vascular surgical services to the community? Who is to judge what he or she may do in the community and on what factors should these judgments be made? How should the vascular surgeon and general surgeon interact in the delivery of these usually complex services? Should there be innovative techniques for bringing the patients in need of such care to highly trained vascular surgeons? The trauma surgeons have taken advantage of modern travel and communication techniques. Should we as well? Trauma centers are quite successfully used in some countries for the delivery of vascular services. Should there be vascular centers as there are trauma centers? Or should all surgical trainees be trained completely in the vascular discipline adding an additional 1 and perhaps 2 years to the general surgical training programs? Should there be different tracks for physicians with different interests in these extended training programs? Are there not regional geographic factors that require particular considerations in any planning and might not the regional vascular societies be in ideal situations to study and evaluate such factors, which must inevitably influence the evolution of any comprehesive plan of vascular health care delivery? It is for us as a community of surgeons, interested primarily in general vascular surgery, who recognize the complexities and pitfalls involved in the performance of deceivingly "simple" vascular procedures to come to grips with these issues among ourselves, to achieve a consensus by considering the options and their impact not only on the surgical trainees but on the general surgical community and the patients who need these services. Then we must forthrightly present clear-cut comprehensive recommendations as part of such a plan to the appropriate accreditation bodies through meaningful participatory representation without fear of reprisal. Our ultimate goal should continue to be, as it has been, to improve the delivery of vascular services to the patient population in need of them. With such forethought, training programs would then have a direction and a purpose meaningful to the community. Without such comprehensive plans, our combined experience in vascular surgery would be wasted in negativism and negotiations for minor and, in the long range, meaningless issues, inviting intervention from outside our medical community from a federal bureaucracy ever ready to extend its influence. All this can be accomplished within the framework of existing accreditation bodies, once we know our own minds and express our conclusions constructively. The difficult initial steps have been taken, and a recognition has been achieved that unique problems exist in this area. This is recognized not only by the vascular surgical community but by our general surgical colleagues as well. Witness the progress that has been made, which was so admirably summarized by Dr. DeWeese.3DeWeese JA. Presidential address: The vascular societies—How involved should they be?.J Vasc Surg. 1986; 3: 1-9PubMed Scopus (8) Google Scholar Representatives of your vascular society, through the Joint Council, have met and will continue to meet with representatives of the American Board of Surgery and the Residency Review Committee to discuss issues and problems regarding training and accreditation. The second major crossroad at which we find ourselves, which promises to tax our ingenuity and profoundly influence the manner in which our patients will be treated, relates to our need to choose from a number of frequently conflicting concepts, on the true nature of atherosclerosis and the manner in which it produces the ischemia with which we are so familiar. (For as dramatic as the results of our surgical endeavors can be, we do not cure the underlying arterial problem.) What initiates it? Can it be prevented or reversed? Are the factors that promote the atherosclerotic process the same as those that precipitate ischemia? Is our thinking in this area hampered by poor terminology, namely, the term atherosclerosis, literally gruel-like (athere—Gr) hardening (sklerosis—Gr) of the arterial wall, a term coined long before the subtleties of arterial wall physiology and pathology were appreciated.4Stedman's medical dictionary. rev ed 15. Williams & Wilkins, Baltimore1942Google Scholar Should the presence of fat in proliferative lesions of the intima be the hallmark of the lesion that should occupy our major research and therapeutic efforts? In addition, if there is no fat, then what shall we call the nonfatty proliferative lesions? Are they innocuous if fat-free? Of a different nature? Can we contribute to an understanding of these processes from our daily, unique observations of these lesions in situ in living patients in our operating rooms? Are these observations made in vivo not as valid and as valuable as those made in the experimental laboratories under sometimes highly artificial conditions, and should they not therefore be used to help direct the course of basic research and to formulate recommendations regarding treatment and prevention? There is a wealth of information locked up within us, derived from our combined surgical experiences. Let us not permit it to be wasted but rather let us refer to it, at first innocently perhaps, but with increasing sophistication if we will permit it to stimulate our thinking. So-called atherosclerotic plaques encountered at carotid bifurcations are ideal for study. They occur at stereotyped locations with sterotyped distributions, anatomically distant from the end organ in which they cause ischemia so that changes within them cannot be said to be a result of end-organ ischemia as is sometimes said for coronary artery plaques. They can be observed in their entirety in both symptomatic and asymptomatic patients exhibiting distinct similarities and some rather dramatic differences. They are available for study in large numbers; when their gross characteristics in situ and their microscopic appearances are compared, a spectrum of complexity can be created and deductions made regarding their evolution. Let us then examine a series of plaques observed in the operating room in situ and then removed from both symptomatic and asymptomatic patients to see what meaningful questions can be formulated regarding pathogenesis and treatment.5Imparato AM Riles TS Gorstein F. The carotid bifurcation plaque: Pathologic findings associated with cerebral ischemia.Stroke. 1979; 10: 238Crossref PubMed Scopus (204) Google Scholar, 6Lusby RJ Ferrell LD Ehrenfeld WK Stoney RJ Wylie EJ. Carotid plaque hemorrhage. Its role in production of cerebral ischemia.Arch Surg. 1982; 117: 1479-1488Crossref PubMed Scopus (301) Google Scholar The spectrum that emerges from these observations suggests that the simplest of plaques is a smooth-surfaced intimal thickening apparent even on gross observation of such a plaque in situ. It involves the carotid bulb extending a limited distance into the internal carotid as well as into the external carotid artery. Maximal thickening is present at the origin of the internal carotid artery, tapering to an end point distally. At microscopic examination it appears to consist of only fibrous tissue with no fat or foam cells, with a surface lining of flat cells (incidentally, a wonderfully nonthrombogenic surface). The next band in the spectrum is not easily identified. There appear plaques with intimal tears and blood clotted within a fibrous matrix. When first encountered our search for an explanation resulted in the overwhelming opinion, which at first appeared to be quite reasonable, that this represented dissection of blood into probably degenerated "atheromatous" plaques. But in 1972 we first recognized a carotid plaque with what appeared to be absolutely fresh intraplaque blood, which had raised the overlying intima to produce marked stenosis in a 45-year-old man who was suffering a stroke in evolution. Yet there was no apparent break in the overlying fibrous cap of the plaque, suggesting that the previously offered explanation that intraplaque hemorrhage was a phenomenon resulting from "atheromatous" degeneration or caused by dissection of blood from the lumen through breaks in the intima might be faulty. Thereafter by recording the appearances of carotid plaques in situ and by their careful dissection it was possible to recognize large, contained collections of intraplaque blood; this finding suggested that hemorrhage occurred as a primary event within fibrous plaques. There appeared to be no need to invoke either dissection from the lumen or "atheromatous" degeneration as initiating factors. Indeed, in some instances there appeared to be contained hemorrhages of various ages,7Imparato AM Riles TS Mintzer R Baumann FG. The importance of hemorrhage in the relationship between gross morphologic characteristics and cerebral symptoms in 376 carotid artery plaques.Ann Surg. 1983; 197: 195Crossref PubMed Scopus (245) Google Scholar deduced from the grossly visible chocolate-colored material in association with more recent hemorrhage. As the spectrum widens, yellow material is found in association with hemorrhage and microscopically there are clefts within these areas of hemorrhage interpreted as representing cholesterol crystals. Subsequently at the very sites at which hemorrhage is usually found, where the fibrous thickening is apt to be greatest (i.e., at the origin of the internal carotid artery and usually on its lateral wall) the so-called cholesterol abscess is encountered, which has the same configuration as hemorrhage, sometimes in association with hemosiderin seen microscopically; this finding suggests that intraplaque hemorrhages degenerate to form cholesterol abscesses. Close to the end of the spectrum there can be found the rare "coral reef" plaque,8Qvarfordt PG Reilly LM Sedwitz MM Ehrenfeld WK Stoney RJ. "Coral reef" atherosclerosis of the suprarenal aorta: A unique clinical entity.J Vasc Surg. 1984; 1: 903-909Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar a calcific mass found in the same location as the intraplaque hemorrhage and the cholesterol abscess, begging the perhaps obvious conclusion that it represents the end stage of evolution of an intraplaque hemorrhage. How then does cerebral ischemia occur, short of by complete occlusion of the carotid arteries? What of the concept of platelet embolization as a major cause of serious cerebral ischemia? Gray particles are sometimes seen in the retina in symptomatic patients and interpreted as representing emboli consisting of platelet clumps. But yellow particles are seen as well9Hollenhorst RW. Significance of bright plaques in the retinal arterioles.JAMA. 1961; 178: 23-29Crossref PubMed Scopus (216) Google Scholar and they are admitted to be "cholesterol" particles whose origin is difficult to conceive as originating from minute ulcerations described from electron microscopic examination of the carotid bifurcation.10Hertzer NE Beven EG Benjamin SP. Ultramicroscopic ulcerations and thrombi of the carotid bifurcation.Arch Surg. 1977; 112: 1394-1402Crossref PubMed Scopus (30) Google Scholar The hemorrhagic plaque with portions of its fibrous cap missing suggests that segments of the arterial wall can also be dislodged and embolize. As much can be said for the cholesterol abscess. In addition, what of the craterlike pits at the sites where hemorrhage and cholesterol abscesses occur? Does it not suggest that the entire contents of a hemorrhage or of a cholesterol abscess has embolized? Highly complex plaques may contain surface thrombus as well but the phenomenon of thrombus formation is variable. Nonstenotic plaques with central pitlike depressions and characteristic flow thrombus are seen, whereas highly stenotic plaques from other patients have none, which suggests that factors related to blood coagulability, although difficult to detect in the laboratory,11Collins Jr, GJ Scialla S Kimball Jr, DB. Enhanced coagulation and inappropriate thrombosis: Hypercoagulability..in: Vascular occlusive disorders. Futura Publishing Co, New York1981: 27-67Google Scholar are begging to be defined and probably differ markedly among patients—some form luminal thrombus more readily than others. The seeming paradox of marked stenosis caused by intraplaque hemorrhage, of flow thrombus at the stenotic area and stasis clot proximally and distally can result in the final stage in our spectrum, which is the totally occluded internal carotid artery. Now there are many questions to ask—What induced the original fibrous intimal thickening? Hemodynamic forces, undoubtedly. But what particular aberration of flow? Diminished lateral pressure?12Texon M Imparato AM Lord J Helpern M. Experimental production of arterial lesions.Arch Intern Med. 1962; 110: 50Crossref PubMed Scopus (13) Google Scholar Shear stress?13Fry DL. Acute vascular endothelial changes associated with increased blood velocity gradients.Circ Res. 1968; 22: 165Crossref PubMed Scopus (1032) Google Scholar Lack of shear stress?14Caro CG Fitzgerald JM Schroter RC. Arterial wall shear and distribution of early atheroma in man.Nature (London). 1969; 223: 1159Crossref PubMed Scopus (508) Google Scholar Boundary layer separation?15Fox JS Hugh AE. Static zones in the internal carotid artery: Correlation with boundary layer separation and stasis in model flows.Br J Radiol. 1976; 43: 370Crossref Scopus (25) Google Scholar "Meteorite" phenomenon?16Glagov S. Hemodynamic risk factors: Mechanical stress, mural architecture, medial nutrition, and the vulnerability of arteries to atherosclerosis.in: The Pathogenesis of atherosclerosis. Williams & Wilkins, Baltimore1972: 166Google Scholar Turbulence?17McDonald DA. The occurrence of turbulent flow in the rabbit aorta.J Physiol (London). 1952; 118: 340Google Scholar Direct response of the arterial wall to vibratory forces?18Nathan IM Imparato AM. Vibration analysis in experimental models of atherosclerosis.Bull NY Acad Med. 1977; 53: 849PubMed Google Scholar What is the initial reaction of the arterial wall to these flow disturbances that lead to formation of the plaque? Endothelial separation and platelet adherence to subendothelial layers releasing mitogens?19Ross R Glomsett JA Kariya B. A platelet-dependent serum factor that stimulates the proliferation of smooth muscle cells in vitro.Proc Natl Acad Sci USA. 1974; 71: 1207-1210Crossref PubMed Scopus (1294) Google Scholar Lipid permeation of the arterial wall?20Adams CMW. Tissue changes and lipid entry in developing atheroma. In: Atherogenesis: Initiating factors.in: Elsevier, Excerpta Medica, North Holland Associated Scientific Publishers, Amsterdam1973: 1-30Google Scholar Subendothelial thrombus deposition and its organization?21Duguid JB. Thrombosis as a factor in the pathogenesis of aortic atherosclerosis.J Pathol Bacteriol. 1946; 58: 107Crossref PubMed Scopus (260) Google Scholar Fragmentation of the internal elastic lamella and reaction of smooth muscle cells to physical forces?22Roabard S. Negative feedback in the architecture and function of the connective and cardiovascular tissues.Perspect Biol Med. 1970; 13: 507PubMed Google Scholar Certainly fatty streaks are frequently seen in the thickened intima and microscopically appear as fat-laden cells; however, they occur away from the critical sites of advanced pathologic changes associated with ischemia and are infrequently associated with surface intimal abnormalities, ulceration, or thrombosis. There is no conclusive evidence to support the frequently quoted hypothesis that fatty streaks precede fibrous plaques and, indeed, spawn them. Rather, observations of Nature's experiment at the carotid bifurcation would indicate an entirely different sequence of events, implicating the fibrous intimal plaque as the primary culprit and the fatty streak as relatively innocuous and possibly totally unrelated to the arterial wall changes that can produce such disastrous cerebral ischemia. Can intimal lesions that resemble the initial carotid fibrous intimal plaque be produced experimentally? Indeed, intimal thickening can be produced in a variety of experimental models that result in intimal injuries through mechanisms seemingly unrelated to what occurs in the human situation; these include mechanical as well as immunologic trauma.23Bandjeis G Bjorkerud S. Arterial injury and repair after mechanical injury. IV. Uptake and composition of cholesterol ester in morphologically defined regions of atherosclerotic lesions.Atherosclerosis. 1972; 15: 273Abstract Full Text PDF PubMed Scopus (15) Google Scholar, 24Stemerman MB Ross R. Experimental atherosclerosis. I. Fibrous plaque formation in primates, and electron microscope study.J Exp Med. 1972; 136: 769Crossref PubMed Scopus (190) Google Scholar, 25Ramsay MM Walker LN Bowyer DE. Narrow superficial injury to rabbit aortic endothelium: The healing process as observed by scanning electronmicroscopy.Atherosclerosis. 1982; 43: 233Abstract Full Text PDF PubMed Scopus (42) Google Scholar, 26Bjorkerud S Bondjers G. Arterial repair and atherosclerosis after mechanical injury.Atherosclerosis. 1971; 14: 259-276Abstract Full Text PDF PubMed Scopus (56) Google Scholar In these situations, extensive platelet adhesion to subintimal denuded vessel wall occurs, smooth muscle cells migrate to the intima, and a fibrous intimal plaque results, which within months appears to subside if the initial injury is not repeated. Since mitogenic substances can be shown to be liberated by platelets and to be active in vitro, a primary role for platelets in the development of these lesions has been postulated.19Ross R Glomsett JA Kariya B. A platelet-dependent serum factor that stimulates the proliferation of smooth muscle cells in vitro.Proc Natl Acad Sci USA. 1974; 71: 1207-1210Crossref PubMed Scopus (1294) Google Scholar, 27Moore S. Endothelial injury and atherosclerosis.Exp Mol Pathol. 1979; 31: 182-190Crossref PubMed Scopus (45) Google Scholar Other experimental models have been studied, however, that rely on altered blood flow to produce intimal injury.28Imparato AM Texon M Helpern M Lord Jr, J. Experimental production of atherosclerosis by alteration of blood vessel configuration.Surg Forum. 1961; 12: 245Google Scholar, 29Imparato AM Baumann FG. Consequences of hemodynamic alterations of the arterial wall after revascularization.in: Complications in vascular surgery. Grune & Stratton, Inc, New York1980: 107Google Scholar In these models one attempts to mimic more closely the hemodynamic conditions deduced to exist at sites of atherosclerotic plaque formation in human beings. Accentuated curvatures, bifurcations, branchings, and areas of taper can be reproduced in experimental animals. Some of these models include creation of accentuated curvatures by interposing free carotid artery grafts between cut ends of the femoral arteries, by interposing carotid artery grafts between the aorta and the inferior vena cava, and by anastomosing the distal transected end of the right renal artery or the right iliac artery into the side of the vena cava. Fibrous intimal plaques develop in each model and, because these occur at stereotyped locations that are determined by the geometry of the model, prospective serial study by both light and electron microscopy is possible. These serial observations, which have spanned periods of longer than 1 year, start 0 to 15 minutes after flow is restored following completion of the surgical procedure used to create the model. There occurs almost simultaneously loosening of interendothelial bridges, widening of the basement membrane, fragmentation of the interal elastic lamella, and reorientation of smooth muscle cells of the media, which then migrate through the internal elastic lamella to reach the intima, apparently transforming into fibroblasts as they migrate, without the extensive deposition of platelets characteristic of some other models in which intimal injury is mechanically produced.30Imparato AM Baumann FG Pearson J Kim GE Davidson T Ibrahim I Nathan I. Electron microscopic studies of experimentally produced fibromuscular lesions.Surg Gynecol Obstet. 1974; 139: 497-504PubMed Google Scholar, 31Baumann FG Imparato AM Kim GE. The evolution of early fibromuscular lesions hemodynamically induced in the dog renal artery. II. Scanning and correlative transmission electron microscopy.Artery. 1978; 4: 67Google Scholar These hemodynamically induced lesions continue to enlarge long after the luminal surface has been restored within days, apparently by transformed smooth muscle cells or by transformed leukocytes. The lesions are eccentric and closely resemble the fibrous intimal plaques found at the carotid bifurcations, in coronary arteries, and at sites of intimal or neointimal hyperplasia found in late failed arterial reconstructions. Equally remarkable, endarterectomized arteries in experimental animals can heal without the formation of surface thrombus or lamination of the endarterectomized surface with platelets. The endarterectomized artery in which thrombus formation is prevented either by heparin administration or by liberal irrigation of the arterial lumen with saline solution during closure of arteriotomies, becomes layered with leukocytes. The leukocytes appear to convert to flattened cells after undergoing division, whereas the remaining smooth muscle cells of the media develop mitotic figures and appear to proliferate to restore a near normal thickness of the arterial wall, incidentally, also wonderfully nonthrombogenic (unpublished data). The endarterectomized human carotid artery has the ability to develop the fibrous intimal plaque similar to the original fibrous plaque, to develop subneointimal hemorrhage, and finally to progress to lesions that resemble the full-blown atherosclerotic plaque, a spectrum observed in reoperation of patients 1 to 20 years after the initial carotid endarterectomy. One can deduce, then, that what we are observing at the carotid bifurcation is the reaction of the arterial wall to hemodynamic injury,32Ross R Glomsett JA. The pathogenesis of atherosclerosis.N Engl J Med. 1976; 295: 369-420Crossref PubMed Scopus (1470) Google Scholar and intimal fibrous thickening is a reparative process that continues to occur if the trauma persists. Progressive narrowing of the lumen results as the fibrous plaque thickens, without the further disruption of the intima observed after its i
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