Atheromatous Embolization and its Management

Atheromatous embolization is a poorly recognized and underdiagnosed multisystem disorder associated with a high risk of all-cause and cardiovascular mortality. There are a myriad of clinical manifestations that may occur across multiple organ systems, making differential diagnoses broad and diagnosis difficult. Further confounding diagnosis, atheromatous embolization is known by many different names: cholesterol embolization, cholesterol crystal embolization, blue toe syndrome, purple toe syndrome, atheroembolism, and pseudovasculitis. For the purposes of this chapter, these terms will be used interchangeably. After atheroembolism occurs, therapy involves three major strategies: treating the affected end organ, preventing further embolization from occurring, and preventing future cardiovascular morbidity and mortality by risk factor modification. Therefore, it is critical for clinicians to have a high index of suspicion and to recognize the clinical manifestations of this syndrome.

Incidence

The prevalence of atheroembolism ranges from 0.18% to 2.4%, based on series of unselected autopsy studies. However, in older patients with more severe atherosclerosis, the incidence is much higher, from 8.6% to 12.3%. ^, Autopsy studies performed in patients with known advanced atherosclerosis who had undergone cardiac or vascular surgical procedures before their deaths found 22%–27% with evidence of atheroemboli. ^, Postmortem examination of patients who had abdominal aortic aneurysm resection found evidence of atheroembolism in 77% of this population. In general, retrospective autopsy studies may overestimate the frequency of the disease due to detection of subclinical cases and selection bias inherent in obtaining information after necropsy. In contrast, clinically significant atheroembolic disease in clinical studies may be missed because of short-term follow-up. The prevalence of atheroembolic disease in clinical studies has been estimated to be between 1% and 4%. Changing demographics (i.e. an increasingly elderly population accompanied by more advanced atherosclerosis) portend an increased prevalence of atheromatous embolization, while surgical and endovascular technological advancements (i.e. better guide wires, catheters, and techniques) may counter these effects. There have been no recent studies on current prevalence rates.

Pathogenesis

The first description of atheroembolism was published more than a century ago by the German pathologist, Panum. However, Flory is credited for accurately describing the syndrome in 1945. Among 267 consecutive autopsies, he observed that the risk of atheroembolism is directly related to the severity of aortic atherosclerosis. There was no cholesterol crystal embolism when aortic ulceration was absent, 1.4% embolization with moderate aortic plaque erosion, and 12.8% with severe aortic plaque ulceration. The sources of atheroembolism are atherosclerotic plaques in large arteries such as the aorta, iliac, or carotid arteries which consist of a fibrous cap, under which are macrophages, necrotic debris, and cholesterol crystals. The vulnerable plaque, or the plaque at highest risk of rupture, is the one with a thin fibrous cap surrounding a large lipid-rich core. Plaque rupture caused by either spontaneous, traumatic, or iatrogenic maneuvers leads to embolization of cholesterol crystals, platelets, fibrin, and other detritus into arteries or arterioles and results in local mechanical obstruction, as well as an inflammatory reaction that contributes to end-organ ischemia and necrosis.

Cholesterol crystals are white and rhomboidal or rectangular in shape. They can also be elongated, biconvex, and needle shaped, and range in size from 250 μm to less than 10 μm in diameter. Because they are lightweight and hydrophobic, they pass quickly through blood vessels until they are stopped by arterial bifurcations, a narrowing of the vessel lumen, or when reaching the terminal branches of the arterial circulation. Cholesterol crystals that lodge in arterioles immediately incite an inflammatory response characterized by varying degrees of polymorphonuclear and eosinophilic infiltration. ^, ^, ^, By 2–4 weeks, a more chronic inflammatory infiltrate is seen where cholesterol crystals become embedded in multinucleated giant cells and smooth muscle cells. Endothelial proliferation and fibrous tissue can be found surrounding the crystals, ultimately leading to luminal obliteration. ^, At 1–2 months, crystals may extrude out of the vessel lumen and bury in the adventitia, or remain in the lumen, embedded within organized thrombus that may recanalize. The crystals are resistant to breakdown by macrophages and have been shown to persist in tissue for up to 9 months. ^, Arterial lumina are eventually occluded by the accumulation of cells and fibrous material. These pathologic changes result in tissue effects distal to the cholesterol crystal emboli, including ischemia, and rarely, infarction, depending on the extent of organ involvement. This type of foreign body reaction explains the prolonged timeframe (weeks to months) for serum creatinine to rise in patients with atheroembolic renal disease and illustrates why renal function does not usually recover. ^,

Risk Factors

The major risk factor for atheromatous embolization is atherosclerosis of the thoracic and abdominal aorta. ^, Other risk factors include age (>60 years), coronary artery disease, peripheral arterial disease, and abdominal aortic aneurysms. ^, ^, Elevated serum low-density lipoprotein (LDL) to high-density lipoprotein (HDL) cholesterol ratios >2.23 have been associated with mobile and/or ulcerated aortic plaque in patients with ischemic embolic stroke of unknown source. Patients with protruding mobile atheroma or aortic plaques greater than 4 mm in diameter have increased risk of embolic events. ^, Another feature that increases risk of atheroembolization is lack of plaque calcification. It was hypothesized that non-calcified plaques are probably lipid-laden plaques with thin fibrous caps, which are unstable and prone to ulceration, rupture, and thrombosis. Pedunculated, mobile plaques have also been associated with an increased risk of recurrent embolization ( Table 106.1 ).

TABLE 106.1

Incidence of Events According to Plaque Thickness in the Aortic Arch Proximal to the Ostium of the Left Subclavian Artery

From The French Study of Aortic Plaques in Stroke Group: Atherosclerotic disease of the aortic arch as a risk factor for recurrent ischemic stroke. N Engl J Med . 1996;334:1216–1221.

	Recurrent Brain Infarction			Any Vascular Event ^a
Plaque Thickness (mm)	Person-Years of Follow-Up	Number of Events	Incidence Per 100 Person-Years of Follow-Up	Person-Years of Follow-Up	Number of Events	Incidence Per 100 Person-Years of Follow-Up
<1	359.3	10	2.8	354	21	5.9
1–3.9	312.6	11	3.5	308.2	28	9.1
≥4	92.4	11	11.9	88.4	23	26

a Includes brain infarction, myocardial infarction, peripheral embolism, and death from vascular causes.

Complex thoracic aortic plaques are not only valuable “markers” of severe widespread atherosclerosis ^, but also identify individuals at high-risk for cardiovascular disease such as peripheral arterial occlusive or coronary artery disease. Although atheroembolism could occur spontaneously, it is usually precipitated by plaque dislodgement by mechanical trauma to the arterial wall during endovascular intervention or arterial clamping during cardiac/vascular surgeries. ^,

Endovascular Procedures for Coronary and Peripheral Arterial Occlusive Disease

Endovascular intervention is now the most frequent precipitating cause of the atheromatous embolization syndrome. ^, ^, Manipulation of the aorta with rigid catheters or guide wires and the force of contrast injection can cause mechanical trauma, consequently dislodging atheromatous material from the arterial wall. Nevertheless, the most important risk factor remains the severity of atherosclerotic disease in the aorta. The reported incidence of atheromatous embolization from cardiac catheterization is from 0.15%–2%. ^, Clinically apparent cholesterol embolism, such as livedo pattern on the feet, blue toe syndrome, digital gangrene, or renal failure, was found in 1.4% of patients who underwent left heart catheterization. As with coronary angiography, catheter manipulation of the aorta in endovascular procedures for noncoronary arterial occlusive disease is also a serious concern. Embolic protection devices used in both renal and carotid artery stenting procedures frequently retrieved visible atherosclerotic debris. Piazza et al. analyzed embolic filter debris load in 278 patients undergoing carotid artery stenting for asymptomatic stenosis, and found that embolic debris was present in 74% of patients, with age >75 years, pre-existing ipsilateral cerebral ischemic lesions, hypoechogenic plaque, and plaque length >15 mm as predictors of clinically significant embolic debris burden. In one retrospective autopsy study, spontaneous cholesterol emboli were found in 27% of patients who underwent arteriography in their lifetime versus only 4.3% in those who had not.

Cardiac Surgery

Atheroembolization is a well-recognized complication of cardiac surgery and has profound medical and economic consequences. Doty et al. retrospectively analyzed 18,402 patients who underwent cardiac surgery, finding evidence of atheroembolism in 0.2% of patients at autopsy. The clinical presentation of atheroembolism in this study was broad and included five distinct organ systems: heart, central nervous system, gastrointestinal (GI) tract, kidneys, and the lower extremities. In 21% of these cases, death was directly attributable to atheroembolism. Kolh et al. documented a significant increase in intensive care unit stay, overall hospital stay, and total hospital cost in patients with documented atheroembolism after cardiac surgery.

Vascular Surgery

The effect of atheroembolism after major vascular surgery was first recognized by Thurlbeck and Castleman in 1957. In their series, atheroembolism was present at autopsy in more than 75% of patients who died after aortic aneurysm surgery. Atheromatous embolization was either the cause of death or significantly contributed to nearly half of the mortalities in this series. Vessel manipulation, cross-clamping, or incision may disrupt plaque during vascular surgeries including aortoiliac and aortofemoral bypass, carotid endarterectomy, and renal artery revascularization. In a retrospective series of 1011 patients who underwent infrarenal aortic surgery or infrainguinal surgery, the diagnosis of cholesterol embolization was 2.9%. In a study of 202 patients undergoing carotid endarterectomy or stenting evaluated with magnetic resonance imaging with diffusion weighted sequences preoperatively and within 24 hours postoperatively, procedure-related new embolic lesions were seen in 78% of stenting patients and 27% of endarterectomy patients. Shorter (<2 cm) and calcified lesions were associated with increased risk of microembolization with stenting, but not endarterectomy. Due to the advent of better surgical techniques and mitigation of atheromatous embolization risk, this complication has become much less common than reported in older literature.

Anticoagulation

An increased risk of cholesterol embolization with anticoagulation and clinical improvement when anticoagulation was removed has been reported in case reports for nearly half a century. ^, One hypothesis is that anticoagulation may prevent thrombus formation over unstable atherosclerotic plaque, thus allowing exposed cholesterol crystals to embolize. Another hypothesis is that these agents may initiate disruption of complex plaques by causing intraplaque hemorrhage. Based on these small case series and case reports, some investigators have recommended that warfarin be discontinued, when feasible, in patients with cholesterol embolization for which no other precipitant can be identified.

However, the data are not entirely clear in assessing anticoagulation safety in patients with a large aortic plaque burden. The assumption that anticoagulation precipitates cholesterol emboli syndrome was not confirmed by the SPAF-3 trial, in which patients with documented aortic plaque assigned to warfarin therapy had low annual rates of cholesterol embolization (0.7% per patient-year; 95% confidence interval, 0.1% to 5.3%). Likewise, there was no report of cholesterol embolization in warfarin-treated patients with aortic arch plaque in The French Study of Aortic Plaques in Stroke Group. Additionally, Dressler et al. found that patients with mobile aortic atheroma not receiving warfarin had a higher incidence of vascular events than those who received warfarin treatment (27% had strokes vs. 0%). Whether anticoagulation is associated with a higher incidence of atheroemboli remains controversial, but anticoagulation has been advocated for patients with crescendo transient ischemic attacks (TIAs), a syndrome caused by atheromatous embolization to the eye or brain. Current literature suggests it is safe to continue anticoagulation therapy in patients with a compelling reason to do so, such as those with atrial fibrillation or venous thromboembolism.

Thrombolysis

Atheromatous emboli have also been associated with thrombolytic therapy in case reports and small series, ^, but again this is controversial. Thrombolytic agents act by converting plasminogen to plasmin; plasmin directly degrades fibrin. Theoretically, any therapy that causes the thrombus to undergo lysis may leave atherosclerotic plaque uncovered, placing the patient at risk for embolization. In one small prospective study, no relationship between the administration of thrombolytic therapy and cholesterol emboli syndrome was found.

Clinical Features

Atheroembolism may not produce clinical symptoms or can present with a myriad of symptoms, including cardiovascular catastrophes such as myocardial infarction, stroke, acute renal failure, mesenteric ischemia, or peripheral arterial occlusive disease ( Box 106.1 ). In general, the organs affected by cholesterol embolism depend on the location of the embolic source. Atheroemboli from the ascending aorta and proximal aortic arch usually manifest with central nervous system or retinal pathology, whereas cholesterol crystal emboli originating from the descending thoracic or abdominal aortas affect the visceral organs and extremities. In general, bilateral lower extremity atheroembolism signifies a source proximal to the aortic bifurcation, whereas unilateral emboli may originate either proximally or in any artery distal to the aortic bifurcation. Patients with one or more large atheromatous plaques in the aorta may present with a catastrophic event, such as an acutely ischemic limb, or renal or mesenteric infarction. ^, Conversely, patients with microemboli may have milder localized signs or a clinical picture that suggests a systemic illness. There may be a temporal delay in clinical findings (especially for renal failure) after the inciting event of up to 8 weeks.

BOX 106.1

Clinical Manifestations of Atheromatous Embolization

Modified from Bartholomew JR, et al. Atheromatous embolization. In: Young JR, et al., eds. Peripheral Vascular Diseases. 2nd ed. St. Louis: C.V. Mosby; 1996.

Skin

Purple or blue toes
Gangrenous digits
Ischemic ulcerations
Livedo reticularis
Nodules

Renal

Acute, subacute, and chronic renal failure
Severe uncontrolled hypertension
Renal infarction (rare)

Neurologic

Transient ischemic attack
Amaurosis fugax
Stroke
Altered mental status

Eye

Hollenhorst plaque

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