Abstract

128 ALBUQUERQUE, LC ET AL -Vulnerability of atherosclerotic carotid disease: from laboratory to operating room -Part 1 Braz J Cardiovasc Surg 2006; 21(2): 127-135 INTRODUCTION Cerebrovascular obstructive disease (COD) is currently a priority for public healthcare in developed countries, due to its significant prevalence in the adult population, the severity of ischemic events and the high potential to negatively affect productive life [l,2]. Almost 30% of all cases of strokes may be attributed to atherosclerotic disease of the carotid bifurcation, acute thrombotic mechanisms or more commonly to distal embolization In spite of significant advances that occurred in the medicinal treatment of COD, carotid endarterectomy (CE) remains an important measure in the prophylaxis of strokes and the elective treatment in severe obstructive lesions, even when ipsilateral hemispherical symptoms are not present However, the concept of vulnerability of atherosclerotic plaque, initially introduced for coronary artery obstructive disease, reveals that susceptible injuries are characterized by the presence of necrosis in the nucleus of the plaque, by locations with great lipid concentrations but little cellularized, by areas of intraplaque hemorrhage and by eccentric growth, a phenomenon denominated as positive remodeling Evidence on the involvement of inflammatory mechanisms in atherosclerosis have contributed to changing of etiopathogenic paradigms, substituting the traditional model of progressive and concentric accumulation of lipids on the arterial wall for the concept that the inflammation plays a central role in the formation and progression of the atheroma. Part I of this review aims at analyzing recent studies and relevance related to the vulnerability of atherosclerotic disease of carotid arteries, expressed by its epidemiological, clinical and inflammatory aspects. In Part II currently used serum markers are discussed, as are histological aspects and diagnosis by imaging, related to the instability of carotid artery disease, together with possible therapeutic implications or possible changes of criteria related to the current indications for intervention. Epidemiological aspects In developed countries, strokes constitute the third commonest cause of death in the adult population and the greatest determinant of permanent invalidity Among survivors, the reported recurrence of strokes is as high as 9% per year, and the survival over 5 years is not greater than 50% Atheromatosis of the carotid bifurcation is the cause of 25% of the cases of brain infarction and an important factor in primary and secondary prevention of strokes [18]. Furthermore, the reported prevalence of asymptomatic stenosis of 50% or more in over 65-year-olds is between 7% and 10% in men and between 5% and 7% in women CE has been chosen as the first-line surgical procedure in the prevention of recurrent strokes, specifically in high risk subgroups [23] studied the long-term evolution of 5,123 patients treated for cerebrovascular disease and demonstrated that, in the patients who were submitted to CE, the mortality rate over 5 years was 38%, significantly lower than the observed mortality rate in cases of stroke patients who did not operate (60%). The impact on hospital costs due to cerebrovascular events has been the target of worldwide concern as, for example, hospitalizations for strokes use 4% of the healthcare budget in the USA, 5.5% in . In England, although only 55% of patients with cerebral 129 ischemia in effect stay in hospital, strokes involve 2% of all patients released from hospital, 7% of beds available for adults and are responsible for 6% of hospital costs In an epidemiological context, the measures already accepted that aim to reduce the impact of cerebrovascular diseases include: optimized treatment of acute strokes; the control of risk factors for atherosclerosis; effective medicinal or surgical primary prevention of high risk subgroups and prevention of recurrent events. However, studies testing laboratorial or imaging methods that are potentially able to detect instability of the carotid plaque and its susceptibility to clinical events prior to established infarction, may also contribute to an improvement in the current state of affairs. Clinical aspects and indications for intervention In carotid obstructive diseases, the symptoms are generally related to the occurrence of macro-or microembolizations, which indicate resulting regional ischemia. The size of ischemic states will depend on compensatory mechanisms, related to the general hemodynamical state of the patient and on the collateral branches of the Willis polygon. The event may be abrupt and catastrophic or tenuous and subtle, which makes recognition of the symptoms difficult even for the patient. Characteristically, the thromboembolic phenomena deriving from carotid bifurcation occlusion cause focal hemispherical deficits, emerging with ipsilateral amaurosis, hemiparesis or contralateral hemiplegia, predominantly brachial, or by difficulties of expression, such as aphasia, dysphasia or dysarthria, when the dominant cerebral hemisphere is accessed. Although rare, symptoms such as giddiness, vertigo, postural alterations or syncope may occur which generally suggests concomitant compromise of the basilar-vertebral region. At the extremes of the wide clinical range of cerebrovascular disease it is possible to have complaints such as slight and relapsing pins and needles in the hand, to sudden and irreversible hemiplegia states Classically, the nomenclature of cerebral ischemic syndromes takes into account the reversibility and the time of evolution of the neurological deficit. When the clinical syndrome presents total reversal within 24 hours without leaving sequels, it is named a transient ischemic attack (TIA), with a risk of recurrence or evolution to a stroke of 30%. If there is no reversal within this period, it may be characterized as a brain infarction, independently of future recovery or of the degree of neurological sequels. However, nowadays, this division has been made less rigid because of the possibility of identifying small regions of injured tissue. In the USA, it is estimated that the use of magnetic nuclear resonance in the initial investigation of cerebrovascular events, should result in a reduction in the annual rate of TIA of about 33%, and an increase of 7% in the recognition of cerebral infarctions The efficacy of CE to prevent new cerebral events in patients with symptomatic or asymptomatic stenosis has been confirmed in several clinical trials, with current indications for interventions being well-defined and mainly based on the percentage of stenosis. A. Symptomatic patients In symptomatic patients, CE may be performed with the aim of impeding strokes when the clinical diagnosis is transient ischemic attack (TIA) or with the aim of saving cerebral parenchyma at risk of new infarctions and improving the quality of life in pre-established cases of strokes. Of the clinical trials that have attempted to compare the results of surgical interventions with pharmacological treatment, two currently consolidate the international consensus, the North American Symptomatic Carotid Endarterectomy Trial (NASCET) and the European Carotid Surgery Trial (ECST). In the NASCET study, published in 1991, patients with carotid stenosis = 70% by angiography, who had suffered transient ischemia or non-disabling strokes in the previous 120 days, were randomized to receive platelet antiaggregation therapy associated or not to carotid endarterectomy. In the 659 cases analyzed, the incidence over two years of disabling ipsilateral strokes was significantly greater in the clinically treated group (26%) than in the surgically treated group (9%), with a reduction in the relative risk of 65% Braz In the ECST study, which also included symptomatic patients with stenosis = 70%, 1811 cases referred to surgical treatment presented with a reduction of 84% in the relative risk for major strokes compared to 1213 clinically treated patients (p-value <0.001), with greater benefits for patients with stenosis of more than 80% and in men compared to women. However, the method of measuring the percentage of stenosis was different to that utilized in the NASCET trial, overestimating the severity of the lesions. Obstructions of 80% by ECST criteria were approximately equal to 60% according to NASCET [34]. In addition, the final analysis of the ECST study also demonstrated the benefit of CE in the group of patients with stenosis estimated by angiography of between 50% and 69% and results, in truth worse than antiplatelet therapy in lesions of less than 30%, and thus it should not be indicated for these cases Interestingly, the results of the NASCET and ECST trials confirmed the findings of the Veterans Affairs Cooperative Study, which, studying 189 symptomatic cases with stenosis equal to or greater than 50%, observed an absolute reduction in risk of about 11% in patients who were submitted to CE. This benefit was increased to 17% when only the subgroup with stenosis = 70% was analyzed (p-value = 0.004) B. Asymptomatic patients In cases of asymptomatic carotid obstructive disease, it is difficult to specify the exact number of strokes that may be avoided by CE in the general population. It is estimated that approximately 4% of the American population between 50 and 75 years old has carotid stenosis of from 60% to 99% without symptoms of ischemia. If these individuals could be identified and submitted to CE, the rate of strokes could potentially be reduced from 11% to 5% over 5 years, preventing around 120 cases of strokes for each 10,000 of the population every year, a beneficial prevention measure even though a higher number of patients would undergo surgery to prevent one stroke The most important clinical trials testing the results of CE in asymptomatic patients are the Asymptomatic Carotid Atherosclerosis Study (ACAS) and the Asymptomatic Carotid Surgery Trial (ACST). In the ACAS study, 1662 patients with stenosis of at least 60% demonstrated by ultrasound or arteriography (with similar stenosis measurement criterion to NASCET), were randomized to receive antithrombotic therapy with or without CE and were followed-up over 5 years. In the clinical group, the ipsilateral stroke rate was 11%, a little higher than two times the rate in operated patients (5%), indicating an annual incidence of 2.2% strokes. The reduction in absolute risk was 5.9% and the reduction in relative risk was 55% (p-value < 0.004) with this benefit being more significant for men because of the high rate of complications observed in women (3.6% versus 1.2%) Recently concluded, the ACST European trial enrolled more than 3000 asymptomatic cases with carotid stenosis = 70% by ultrasound or angiography using magnetic nuclear resonance. With more liberal criteria of eligibility than the criteria utilized in the ACAS study so as to increase the applicability of their conclusions, the authors observed that there was reduction of 50% in the relative risk of ipsilateral strokes or death in the group referred to surgical treatment during a 5-year follow-up period (p-value < 0.001). These results already include hospital morbidity and mortality Before the ACAS and ACST studies, other trials had demonstrated conflicting results. The Mayo Asymptomatic Carotid Endarterectomy Study, which randomized 158 patients in two groups for therapy with AAS or CE, was interrupted because of the high occurrence of acute myocardial infarction in the surgical group Recently, the Asymptomatic Carotid Stenosis and Risk of Ipsilateral Hemispheric Ischaemic Events (ACSRS) study ET AL -Vulnerability of atherosclerotic carotid disease: from laboratory to operating room -Part 1 Braz J In the current model of atherogenesis, the alteration of the endothelial homeostasis due to antagonists with local or systemic action, such as the accumulation of lipoprotein, mechanical stress (arterial hypertension, percutaneous interventions), toxins from smoking or oxidant substances, infectious agents, autoimmune diseases, homocysteinemia, constituted the initial event of the formation and progression of the plaque With the continuation of proinflammatory stimuli, the proliferative phase is initiated, at first with marked synthesis of collagen, starting with activation of fibroblasts, thus forming the fibrotic cover Atherosclerosis and Inflammation Faced with the frightening number of more than 19 millions de deaths due to cardiovascular events annually, the early detection of so-called vulnerable or high-risk plaque using local or systemic markers has been a worldwide priority of scientific investigation Historically atherosclerosis was considered a condition resulting from the progressive accumulation of lipoproteins of cholesterol, but nowadays it is known that it is a chronic inflammatory disease of the arterial system. The fact that only 50% of atherosclerotic patients have dyslipidemia Rothwell et al. Braz The development of atheroma plaque also progressively compromises the anticoagulant property of the endothelial surface. Local inflammatory activity stimulating platelet aggregation, increases in the A2 phospholipase, vasoconstriction mediated by angiotensin II, endothelins and serotonin, thrombogenic action of thromboxane and leukotrienes, as well as toxin from tobacco, and the action of extracellular matrix metalloproteinases, are the main factors that cause prothrombotic states, which, in advanced or vulnerable lesions, are associated to intraplaque hemorrhage, fibrous cover rupture, thrombosis and embolization