7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) : Muhamed Saric, MD, PhD, FACC, FASE : Catherine M Otto, MD, Jos Biller, MD, FACP, FAAN, FAHA, John F Eidt, MD, Joseph L Mills, Sr, MD : Kathryn A Collins, MD, PhD, FACS All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Mar 31, 2021. INTRODUCTION Aortic atherosclerotic plaques are a manifestation of systemic atherosclerosis. They are associated with general risk factors for atherosclerotic disease, including age, hypertension, and hypercholesterolemia, and are more common in patients with coronary artery disease [1,2]. Aortic atherosclerotic plaques are an important source of emboli, leading to cerebral (eg, transient ischemic attack, stroke), extremity, or visceral embolization ( picture 1) [3-6]. Embolic events can occur spontaneously or can be induced by interventions, including cardiac catheterization, arteriography, peripheral interventions, intraaortic balloon pumping, and cardiac or vascular surgery [7,8]. The general manifestations and treatment of cholesterol crystal embolism, diagnosis, and medical and surgical management will be reviewed. Thromboembolism from unstable aortic plaques is discussed elsewhere. (See "Thromboembolism from aortic plaque".) Specific considerations related to end-organ ischemia (kidney, gut, extremity) that may result from cholesterol crystal embolus are discussed in separate topic reviews. ATHEROEMBOLISM VERSUS THROMBOEMBOLISM https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 1/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate Two types of emboli originate from atherosclerotic plaques: thromboemboli and atheroemboli (cholesterol crystal emboli). Although the underlying risk factors may be similar, the two can often be differentiated based upon associated conditions and clinical manifestations. This is an important distinction, since the prognosis and treatment differ. Thromboembolism from complex aortic plaques is common, particularly from thoracic aortic plaques. In comparison, cholesterol crystal embolism is fairly rare but is probably underrecognized given its diverse presentations. (See 'Epidemiology and risk factors' below and "Thromboembolism from aortic plaque".) Although there is some overlap, these two disorders can be distinguished from each other. Thromboembolism occurs when thrombus, which is usually superimposed on an atherosclerotic plaque, dislodges due to plaque rupture or other forces. The thromboemboli tend to be single and lodge in medium or large arteries. Thromboemboli from aortic atherosclerotic plaque most often result in transient ischemic attack or stroke [3-6]. Acute ischemia of the extremities, intestines, or solid organs (eg, kidney, spleen) can also occur [9]. The term cholesterol crystal embolism is used synonymously with cholesterol embolism or atheroembolism [10]. Cholesterol crystal embolism occurs when atherosclerotic plaque is disrupted and cholesterol crystals within the plaque or portions of the plaque embolize distally. The debris showers into the circulation, partially or totally occluding arterioles that are <200 micrometers in diameter, leading to a myriad of occlusions that typically affect multiple organs. These characteristic sizes of atheroemboli were illustrated in an experimental study using human aortorenal endarterectomy specimens. Following ex vivo "angioplasty" of these specimens, thousands of fragments 20 to 40 micrometers in size, the approximate size of the human afferent arteriole, and hundreds >100 micrometers in size, were collected [11]. EPIDEMIOLOGY AND RISK FACTORS Cholesterol embolization is most likely to occur in the male patient >50 years of age, with risk factors for atherosclerosis following cardiac catheterization or a vascular procedure. Cholesterol crystal embolism is strongly associated with older age, with the average age being 66 years in a review of 221 published cases [12]. Lighter-skinned individuals may be more often affected, but it is more likely that subtle skin manifestations are not recognized in patients with darker skin tones. (See 'Skin' below.) The incidence and prevalence of cholesterol crystal embolism are unknown. The published estimates are limited by suboptimal or unclear diagnostic criteria (such as solely relying on https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 2/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate elevation of serum creatinine concentration after a procedure) and infrequent biopsy data. The full manifestations of the syndrome are probably rare. (See 'Clinical manifestations' below.) Cholesterol crystal embolization may arise spontaneously or as the result of instrumentation of the vasculature (eg, cardiac catheterization, arteriography, vascular surgery). The following observations are from some of the studies that have evaluated the incidence or prevalence of cholesterol crystal embolism: In a review of 519 patients with extensive thoracic aortic plaque on transesophageal echocardiography, cholesterol crystal embolism occurred in 1 percent of patients during a follow-up of more than three years [13]. In a series of 1011 patients who underwent infrarenal aortic and infrainguinal vascular surgery or angiographic manipulation, clinical and pathologic evidence of cholesterol crystal embolism was found in 2.9 percent [14]. Lower rates are seen after cardiac surgery (0.2 percent) [15]. In a prospective observational study of 1786 patients undergoing cardiac catheterization, definite cholesterol crystal embolism was observed in 0.8 percent [16]. In a retrospective review of 493 patients who underwent aortoiliac stent placements, 72 bilateral, the incidence of atheroembolism was 1.6 percent [17]. Many cases of cholesterol crystal embolism are not recognized clinically [18]. This issue was addressed in a prospective study of 60 patients with an acute myocardial infarction, one half of whom were treated with thrombolytic therapy [19]. All patients underwent coronary artery bypass graft surgery (CABG) within one month, and two muscle biopsy specimens and one skin biopsy specimen were obtained at the time of surgery. Seven patients (12 percent) had pathologic evidence of cholesterol crystal emboli in the muscle biopsy specimens, only one of whom had clinically evident disease. This finding of asymptomatic disease is consistent with the prevalence of cholesterol crystal embolism in autopsy studies in unselected patients that range from 0.7 to 4 percent [15,20]. Even higher rates of cholesterol embolization (up to 75 percent) are reported in retrospective autopsy studies in patients selected for atherosclerotic risk factors or following surgery or instrumentation, but these studies may overestimate the incidence of cholesterol crystal embolism due to selection bias [21]. In addition to asymptomatic disease, it is probable that clinical manifestations of cholesterol crystal embolism are ascribed to other causes. This may be most likely with acute renal failure, where acute kidney injury is much more common than cholesterol crystal embolism, which will https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 3/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate not be diagnosed unless tissue is available for pathology if there are no other manifestations of this syndrome [22]. (See 'Renal' below.) Risk factors for aortic atherosclerosis Risk factors for developing cholesterol crystal embolism are largely those associated with developing general atherosclerotic disease such as smoking, hypercholesterolemia, hypertension, obesity, and diabetes. The data supporting these associations are discussed in detail separately. (See "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach".) The "classic" risk factors of hypertension, age, and smoking have been correlated with severe atherosclerotic plaque in the thoracic aorta. This relationship was demonstrated with transesophageal echocardiography (TEE) in a population-based study [23]. Among those with aortic plaque, the odds of having complex plaque increased as systolic blood pressure increased (odds ratio [OR] 1.43 for each 10 mmHg increase, 95% CI 1.10-1.87). Complex aortic plaque also correlated with hypertension treatment, controlling for age and history of smoking. Risk factors for embolization The risk of cholesterol crystal embolization is directly related to the severity of atherosclerosis. Any factor that destabilizes atherosclerotic plaque can result in cholesterol crystal embolism. Embolization may be spontaneous or iatrogenic precipitated by vascular manipulation during arteriography or surgery. It was previously estimated that 50 to 60 percent of cases of cholesterol crystal embolization were spontaneous [14,24]. However, the increasing frequency of endovascular manipulations (eg, coronary, aortoiliac, renal) has increased the incidence of iatrogenic embolization [24,25]. In one retrospective review, spontaneous embolism occurred in only 25 percent of patients [26]. Abdominal aortic aneurysms are a known source of cholesterol emboli. In a prospective study of 660 patients with abdominal aortic aneurysm who were followed for 1 to 60 months (mean 15 months), cholesterol crystal embolization was diagnosed in 2.9 percent of the patients [27]. (See "Clinical features and diagnosis of abdominal aortic aneurysm", section on 'Limb ischemia'.) Plaque characteristics and location The risk of cholesterol crystal embolism in patients with aortic atherosclerosis is markedly increased if transesophageal echocardiography reveals protruding plaques, particularly if 4 mm in thickness; ulceration; or superimposed mobile thrombi [5,9,28-33]. A correlation between complex plaque seen on two-dimensional transesophageal echocardiography (2D-TEE) and embolization phenomena was first noted in 1990 [31]. Subsequent 2D-TEE studies found that complex plaques may give rise to either cholesterol crystal emboli or thromboemboli ( image 1 and movie 1). In a few case reports, cholesterol crystal embolism to the skin and kidneys was proven by biopsy in patients with complex plaques https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 4/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate in the descending thoracic aorta on 2D-TEE [32,33]. In another report, transesophageal echocardiography demonstrated mobile particulate matter in transit from a complex plaque in a patient who subsequently died after multisystem involvement from cholesterol crystal embolism ( image 2) [34]. Plaque in the aortic arch is implicated as a risk factor for cerebral embolization. However, data are conflicting. In longitudinal population-based studies in nonselected individuals, complex aortic atherosclerosis does not appear to be associated with an increased risk of primary stroke [35]. However, most reports evaluating secondary stroke risk have found that complex aortic atherosclerosis is a risk factor for recurrent stroke. This may be due to selection bias as the studies linking aortic atheroma and secondary stroke were usually performed in patients referred for TEE to evaluate a cardiac source of emboli rather than in a random population sample. Mechanistically, aortic plaque may be both a source of cerebral emboli and a marker of generalized atherosclerosis. Studies of aortic arch plaque have found a 12 to 14 percent risk of cerebral embolization, particularly when the plaque is ulcerated or mobile. On the other hand, aortic plaque may be a marker of aging, and age is an independent predictor of cerebrovascular events [36]. Atherosclerotic plaque in the thoracic aorta is typically associated with distal embolization (abdominal organs, lower extremities). However, retrograde flow from complex descending thoracic aortic plaques may be a source of cranial or upper extremity embolization. In a study of 94 patients using transesophageal echocardiography, retrograde diastolic flow reached the left subclavian artery in 60 percent, the left common carotid artery in 26 percent, and the brachiocephalic trunk in 14 percent [37]. The abdominal aorta and iliac arteries are commonly identified as a source for lower extremity cholesterol crystal embolization. In one surgical series of 62 patients, the aorta or iliac arteries were identified angiographically as the embolic source in 80 percent of patients [24]. Atherosclerotic plaque in the femoral, popliteal, or subclavian arteries may also be a source of extremity embolization. Instrumentation Iatrogenic embolism is typically related to cardiovascular manipulation during arteriography, stenting, or surgery [38,39]. Surgical procedures may disrupt atherosclerotic plaque as vessels are dissected, cross-clamped, or as an arteriotomy is made. Trauma is an unusual cause [24]. https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 5/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate Arteriography is a more common iatrogenic cause than surgery, accounting for as many as 85 percent of iatrogenic cases [14]. The source of the emboli in a review of 29 patients was the abdominal aorta (16 patients), iliac arteries (7 patients), and femoropopliteal arteries (6 patients) [14]. Patients with atherosclerotic renal artery stenosis often have diffuse atherosclerosis and are at a relatively high risk for cholesterol crystal embolism after renal arteriography, with an overall incidence of approximately 2 percent [40]. The effect of arterial manipulation has been illustrated in several studies [16,41-43]. In a prospective series of 1000 patients who underwent percutaneous coronary interventions, guiding catheter placement was associated with visible scraping of debris from the walls of the aorta in more than one half of the patients [43]. Clinical cholesterol crystal embolism was not seen, however, as ischemic events were not associated with visualization of debris in the catheter. Similarly, in reviews of renal artery angioplasty and stenting, grossly visible material (cholesterol crystals, atheromatous material, and thrombus) was retrieved from the embolic protection filter in 45 to 60 percent of cases [44,45]. (See "Clinical presentation, evaluation, and treatment of renal atheroemboli".) Anticoagulation/thrombolytic therapy Cholesterol crystal embolism has been reported after the use of thrombolytic agents or anticoagulants (eg, heparin, warfarin, direct factor Xa inhibitors, direct oral anticoagulants) [46,47]. However, a causal relationship between the use of these medications and cholesterol crystal embolism has not been established, and, based on available evidence, the overall risk appears to be low. In the 40 years since the introduction of thrombolytic therapy, a total of 30 cases as a complication of thrombolysis have been reported; 28 patients received a thrombolytic agent for acute myocardial infarction and 2 patients for deep venous thrombosis [48,49]. These case reports gave the impression that there might be a causal relationship between thrombolysis and cholesterol crystal embolism. However, there is no evidence to suggest that lysis of thrombus overlying atherosclerotic plaque leads to plaque destabilization and atheroembolism. There are no large-scale clinical trials that specifically addressed the issue of cholesterol crystal embolism in the setting of thrombolytic therapy. One small study of 60 patients found no differences in the rate of cholesterol crystal embolism between the patients who received thrombolysis and those who did not. The presence or absence of cholesterol crystal embolism in this study was based upon skin and muscle biopsies [19]. However, given the low incidence of embolism and the small number of patients in the study, a significant difference may not have been detectable. Cholesterol crystal embolism has also been blamed on therapy with anticoagulant drugs, particularly heparin or warfarin, with plaque hemorrhage as the putative precipitating factor [50,51]. However, it is unclear if cholesterol crystal embolism was caused by anticoagulants or it https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 6/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate simply occurred in patients who happened to be on anticoagulation therapy. Trials that have randomly assigned patients with documented aortic plaque identified by transesophageal echocardiography to anticoagulant therapy have not identified an increased risk for atheroembolism [13,16,52,53]. Thus, the putative risk associated with anticoagulation therapy appears to be low. CLINICAL MANIFESTATIONS The variability in clinical manifestation is related to the location of the embolic source, extent of embolization, whether there is partial or complete occlusion of the affected vessels, and the presence or absence of preexisting disease in the affected vascular bed (eg, peripheral artery disease). Atheroemboli from the aortic arch typically embolize to the brain, eye, or upper extremity while descending thoracic or abdominal aortic plaque causes gastrointestinal or lower extremity symptoms and signs. Retrograde embolization from the thoracic aorta can also occur. (See 'Plaque characteristics and location' above.) The presenting symptoms of cholesterol crystal embolism may be subtle and nonspecific. As an example, 21 percent of patients in a review of 221 cases presented with systemic symptoms of fever, myalgias, headache, and weight loss [12]. Often there is a delay between the embolic event and subsequent symptoms. In a review of histologically proven cholesterol embolization, skin signs developed more than 30 days after a precipitating event in 50 percent of patients [54]. More dramatic clinical presentations are generally due to a diffuse showering of larger, atheromatous debris originating from usually aortic plaque. The emboli may lodge into the renal, mesenteric, pelvic, carotid, coronary, or extremity vascular beds [55]. Classic manifestations include "blue toe syndrome," livedo reticularis, acute or subacute renal failure, and intestinal ischemia. Other manifestations include gastrointestinal bleeding and pancreatitis. Skin Skin findings are the most common clinical sign of cholesterol crystal embolism, occurring in 34 percent of patients in one systematic review [12]. In this study, the most frequent findings included livedo reticularis (16 percent), gangrene (12 percent), cyanosis (10 percent), skin ulcer (6 percent), purpura or petechiae (5 percent), and firm, painful erythematous nodules (3 percent) [12]. Splinter hemorrhages have also been described as a possible cutaneous manifestation of cholesterol crystal embolization [56]. Gangrene and ulcerations typically affect the toes but may extend to more proximal portions of the lower extremities. (See "Management of chronic limb-threatening ischemia".) https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 7/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate These classic skin findings in cholesterol crystal embolism commonly occur in areas where the arterial pulse is palpable since the embolization is to smaller arteries [12,54,57]. However, the arterial pulse may not be palpable in patients who also have underlying peripheral artery disease. (See "Noninvasive diagnosis of upper and lower extremity arterial disease" and 'Treatment' below.) Cholesterol crystal embolization to the skin of the genitalia is rare but, when it occurs, can lead to severe scrotal or penile skin loss [58-60]. This devastating complication has been reported following open and, more recently, endovascular repair of abdominal aortic aneurysm [60]. Livedo reticularis Livedo reticularis is a reticulated, mottled, or erythematous skin discoloration that blanches on pressure ( picture 2). It may be red or blue, and even ulcerated, depending on the degree of blood flow compromise and oxygen desaturation through the affected area. Livedo reticularis is not specific for atheroembolism and has an extensive differential diagnosis. In patients with cholesterol crystal embolization, livedo reticularis is usually bilateral and is typically found on the feet and lower legs but may extend toward the thighs, buttocks, and back. Upper extremities are less commonly involved. Atheroembolism involving the breast has also been reported [61]. In patients undergoing abdominal aortic aneurysm repair, livedo reticularis may appear on the back and the buttocks due to cholesterol embolization into the branches of the internal iliac arteries. Blue toe syndrome Although cholesterol crystal embolization is often referred to as the "blue toe syndrome" ( picture 3), blue skin discoloration is less common than other skin findings. In the overall population of patients with cholesterol embolization syndrome, skin manifestations are seen in only approximately one third of such patients, and of these, blue toes are present in 10 to 15 percent [12,18,54]. The blue toe syndrome may be considered as a specific manifestation of retiform purpura ( picture 4 and picture 5). (See "Approach to the patient with retiform (angulated) purpura".) In a retrospective review of 78 patients with cutaneous manifestations of cholesterol crystal embolization, blue toes were noted in 14 percent of the patients. More common skin manifestations were livedo reticularis (49 percent), gangrene (35 percent), cyanosis (28 percent), and ulceration (17 percent) [54]. In another study of 221 patients, skin manifestations were present in 75 patients. Of these 75, blue toes were observed in 11 patients [12]. https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 8/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate Renal Acute kidney injury is a common manifestation of cholesterol crystal embolism [26,62]. Acute kidney injury is present in 25 to 50 percent of cases [12,15,24,63]. Renal disease most often occurs after invasive vascular procedures but can occur spontaneously. In such patients, the diagnosis may be difficult to establish without biopsy unless other manifestations of crystal embolism are present. Because the cholesterol crystal emboli are irregularly shaped and nondistensible and typically do not completely occlude larger vessels, the renal manifestations are those of distal parenchymal ischemia usually manifested as a bland sediment rather than renal infarction as seen with thromboemboli, which present with flank pain, hematuria that may be gross, and markedly elevated serum lactate dehydrogenase ( image 3). The characteristics of renal involvement are discussed in detail separately ( picture 6A-B). (See "Clinical presentation, evaluation, and treatment of renal atheroemboli".) When acute kidney injury occurs after arteriography, the primary differential diagnosis is contrast nephropathy and cholesterol crystal embolism. Unless there are other signs of cholesterol crystal embolism, the two disorders are distinguished by differences in the clinical course. Contrast nephropathy typically begins to recover within three to five days, while cholesterol crystal embolism shows at best an incomplete recovery, and there may be a stuttering course with further showers of cholesterol crystals. (See "Contrast-associated and contrast-induced acute kidney injury: Clinical features, diagnosis, and management".) Although not a common manifestation of cholesterol crystal embolism, rhabdomyolysis has been reported in association with massive cholesterol crystal embolism and can lead to heme-pigment-associated acute kidney injury [64]. Rhabdomyolysis presents with elevated serum muscle enzymes (including creatine kinase), red to brown urine due to myoglobinuria if there is persistent renal function, and electrolyte abnormalities. Peak serum creatine kinase levels depend upon the volume of muscle breakdown and the muscle mass of the patient. (See "Clinical features and diagnosis of heme pigment-induced acute kidney injury".) Gastrointestinal Atheroembolism to the mesenteric circulation most commonly involves the colon, small bowel, and stomach [65-68]. The pancreas, liver, and gallbladder also may be affected [69]. (See "Overview of intestinal ischemia in adults" and "Colonic ischemia".) Gastrointestinal manifestations include abdominal pain, diarrhea, and, in approximately 10 percent of patients, bleeding [12,68,70]. Bleeding may originate from any site in the gastrointestinal tract, including the stomach [71]. Other manifestations of cholesterol crystal embolism include necrotizing pancreatitis, focal hepatic cell necrosis, and acalculous necrotizing https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 9/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate cholecystitis. Intestinal infarction has a poor prognosis, with reported mortality rates ranging from 38 to 81 percent [12,72]. Upper endoscopic findings of nonspecific entities such as gastritis may be erroneously diagnosed [71]. A definitive diagnosis can only be established by examination of a biopsy specimen. Central nervous system Central nervous system manifestations of atheroembolism may include amaurosis fugax, transient ischemic attack (TIA), stroke, confusional state, headache, dizziness, or organic brain syndrome. Embolization to the spinal cord is rare but can lead to lower extremity paralysis Transient ischemic attack/stroke Transient ischemic attack due to atheroembolic debris is more commonly associated with carotid atherosclerotic disease, and carotid thrombosis or thromboembolism can lead to hemispheric stroke. (See "Stroke: Etiology, classification, and epidemiology", section on 'Embolism'.) There are conflicting data regarding the stroke risk associated with aortic atherosclerosis [4,5,35,73-78]. Large protruding plaques in the aortic arch, particularly mobile plaques, in our opinion, are an important cause of brain pathology. In one retrospective review of 29 patients with cholesterol emboli in the brain identified on autopsy, encephalopathy presumably due to ischemia was the predominant clinical finding and was most likely due to bilateral diffuse embolization from the identified aortic plaque disease [79]. In clinical longitudinal population studies in unselected patients, complex aortic atherosclerosis does not appear to be associated with an increased risk for primary ischemic stroke [35,75,76]. However, most studies have found that complex aortic atherosclerosis is a risk factor for recurrent stroke [4,5,77,78]. The range of findings is illustrated by the following studies: A prospective study examined the frequency and thickness of atherosclerotic plaques in the ascending aorta and proximal arch in 250 patients admitted to the hospital with ischemic stroke and 250 consecutive controls, all over the age of 60 years [5]. Atherosclerotic plaques 4 mm in thickness were found in 14 percent of patients compared with 2 percent of controls, and the odds ratio for ischemic stroke among patients with such plaques was 9.1 after adjustment for atherosclerotic risk factors. In addition, aortic atherosclerotic plaques 4 mm were much more common in patients with brain infarcts of unknown cause (relative risk 4.7). https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 10/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate In contrast, a population-based study of 1135 subjects who had transesophageal echocardiography (TEE) found that complex atherosclerotic plaque (>4 mm with or without mobile debris) in the ascending and transverse aortic arch was not a significant risk factor for cryptogenic ischemic stroke or TIA after adjusting for age, sex, and other clinical risk factors [75]. However, there was an association between complex aortic plaque and non- cryptogenic stroke. The investigators concluded that complex aortic arch debris is a marker for the presence of generalized atherosclerosis. Methodologic differences are a potential explanation for the discrepant results of these reports assessing the risk of ischemic stroke related to aortic atherosclerosis, as the earlier case-control studies may have been skewed by selection and referral bias. However, many patients with aortic atherosclerosis also have cardiac or large artery lesions, a problem that may confound purely epidemiologic studies. Ocular signs Hollenhorst plaques are bright, refractile lesions in the retina indicative of cholesterol crystal embolization from a proximal atherosclerotic source ( picture 7) [80,81]. The most common proximal source is the carotid artery [82,83]. In a review of 130 patents with Hollenhorst plaque or retinal artery occlusion (amaurosis excluded), 61 percent complained of ocular symptoms, including eye pain, blurred vision, or other atypical visual symptoms [84]. Of the 98 patients who underwent carotid duplex, all had some evidence of carotid stenosis ipsilateral to the ocular findings, but the degree of stenosis was less than 60 percent in 90 of the 130 patients. Over a mean of 22 months, no patient suffered from a transient ischemic attack (including amaurosis fugax) or stroke. Evaluation of the more central vasculature was performed in approximately 20 percent of the patients, and, although some minor valvular problems were found, a cardiac or aortic source for the retinal findings was not found. Cholesterol embolization resulting in Hollenhorst plaques can occur following arteriography or cardiac catheterization, vascular surgery, or trauma. The mere finding of Hollenhorst plaques in a patient presenting with suspected cholesterol embolization syndrome should not be used to confirm that the acute clinical presentation is due to cholesterol emboli. A finding of Hollenhorst plaque may represent a prior event [85,86]. In one study, serial funduscopic examination found persistence of Hollenhorst plaques for over one year [83]. Moreover, approximately one third of patients who have Hollenhorst plaques are asymptomatic. Thus, additional evaluation may be needed to confirm the diagnosis of acute cholesterol embolization syndrome. (See 'Diagnosis' below.) Other Other vascular beds including coronary, pulmonary, prostate, thyroid, and adrenal glands may rarely be affected with diagnosis often established at autopsy [87]. https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 11/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate DIAGNOSIS A diagnosis of cholesterol crystal embolization should be highly suspected in a patient with known atherosclerotic disease and a classic history: the development of renal failure, abdominal pain or diarrhea, typical skin findings or a finding of Hollenhorst plaques of the retina following arteriography, cardiac catheterization, vascular surgery, or trauma to the abdomen. (See 'Clinical manifestations' above.) Laboratory testing is generally nonspecific and may show elevations in the white blood cell count, decreased red blood cell count, or thrombocytopenia. Inflammation markers including elevated erythrocyte sedimentation rate, C-reactive protein and fibrinogen have been associated with atheroembolism [16]. Other abnormalities may include transient hypocomplementemia and eosinophilia. Because there is an association between occlusive diseases in large peripheral arteries and cholesterol crystal embolization to smaller arteries, patients with extremity embolism should undergo noninvasive vascular testing to identify the presence of hemodynamically significant proximal peripheral artery disease. Even when a stenotic peripheral artery may not be the source of cholesterol crystal embolism, arterial revascularization may improve clinical outcomes. (See 'Revascularization' below.) Specific abnormalities may indicate end-organ dysfunction such as increased creatinine or eosinophiluria if the kidneys are involved [88-91], increased amylase with pancreatic (and possibly bowel) involvement, elevated transaminases with hepatic involvement, or elevated creatine kinase and myoglobinuria with sufficient muscle involvement. Imaging Plaques in the aorta can be visualized, characterized, and quantified by a variety of imaging techniques; however, the index plaque that is the cause of the cholesterol crystal embolization is rarely determined. The diagnosis is more difficult in patients without typical clinical features, particularly if cholesterol crystal embolism has occurred spontaneously. However, the identification of complex aortic plaque or multiple ischemic strokes on imaging studies may permit a presumptive diagnosis to be made [5,29,30]. Plaques can be simple or complex ( image 4). Simple plaques are characterized by wall thickness <4 mm and the absence of mobile components. Complex plaques are 4 mm in thickness and may exhibit irregular borders, ulceration, and mobile components that represent superimposed thrombus. Complex plaques are associated with an increased propensity for embolization. (See 'Plaque characteristics and location' above.) https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 12/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate Transesophageal echocardiography, primarily two-dimensional (2D) transesophageal echocardiography (TEE), is the first-line diagnostic modality to identify a thoracic aortic source of atheroembolism. Real-time three-dimensional transesophageal echocardiography (3D-TEE) provides very detailed information on aortic plaque location and morphology ( picture 8 and movie 2). Transthoracic echocardiography, abdominal ultrasound, and endoscopic ultrasound ( image 5) of the upper gastrointestinal tract have occasionally incidentally identified atherosclerotic plaques in the thoracic or abdominal aorta. Compared with TEE, computed tomography (CT) ( image 6 and movie 3) and magnetic resonance imaging (MRI) ( image 7) are less invasive and more complete evaluations of the extent of atherosclerosis in the aorta. CT and MRI have several advantages over TEE [92,93]. These radiologic techniques are better than TEE for imaging aortic branches. In addition, they can image the entire abdominal aorta. In comparison, only the very proximal abdominal aorta between the diaphragm and the ostium of the superior mesenteric artery can be seen with TEE. Conventional arteriography has low sensitivity for detection of plaques and often fails to identify plaques detected by other imaging techniques and should be avoided given the potential disruption of atherosclerotic debris with instrumentation [94]. (See 'Instrumentation' above.) Radiologic studies of the brain may help suggest the diagnosis in demonstrating multiple small ischemic lesions. (See "Neuroimaging of acute stroke".) Biopsy and pathologic findings Biopsy is the only definitive means of confirming the diagnosis of cholesterol embolization syndrome. Thus, biopsy should be performed whenever the diagnosis is in doubt and when the specimen can safely be obtained from the patient. Histopathologic examination of amputated body parts or embolectomy specimens for cholesterol emboli pose no additional risk to the patient and should be performed if the diagnosis is suspected. Skin and skeletal biopsies are less invasive than renal and gastrointestinal biopsies. The histologic hallmark of cholesterol crystal embolism is the presence of "ghosts" of cholesterol crystals or cholesterol clefts within arterioles, since the cholesterol crystals are dissolved during tissue fixation ( picture 6A-B). The cholesterol clefts are crescentic (with pointed ends) or elongated ovoid spaces present in small or medium-sized arteries or arterioles. Inflammatory or fibrous intimal proliferation develops rapidly and may be the cause for vascular occlusion and resultant ischemic tissue damage [95]. Cholesterol clefts have also been demonstrated in the pulmonary arteries of patients with cholesterol crystal embolism. Since pulmonary arterial atherosclerosis is rare (eg, in end-stage Eisenmenger syndrome), the crystals presumably pass through the systemic capillary bed into https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 13/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate the venous system and lungs. In a case report, cholesterol crystal emboli were seen in 25 percent of the small pulmonary arteries in a patient with atheroembolic disease [96]. Differential diagnosis The diagnosis is often difficult to establish when the presenting symptoms and signs of cholesterol crystal embolism are subtle and nonspecific. Cholesterol crystal embolism needs to be distinguished from thromboembolism given differences in treatment. (See "Thromboembolism from aortic plaque", section on 'Clinical manifestations'.) Because of its many differing effects, cholesterol crystal embolism may be included as one of the "great imitators," (such as tuberculosis, brucellosis) given its often nonspecific symptoms, leading it to be confused with a number of other diseases, including vascular diseases such aortic dissection, and tumors such as left atrial myxoma, lymphoma, and renal cell carcinoma [55]. The differential diagnosis includes many systemic illnesses, including cyanotic congenital heart disease, secondary syphilis, and pheochromocytoma [72]. There is also an extensive differential diagnosis of livedo reticularis that includes Raynaud's phenomenon, vasculitis (polyarteritis nodosa, systemic lupus, dermatomyositis, leukocytoclastic