Spontaneous Atheroembolism

Who is at risk?

Spontaneous atheroembolism occurs in older patients with advanced atherosclerosis. In Fine’s review of 221 cases of atheroembolism in the English literature, he noted a predominance of patients with underlying atherosclerotic disease including cardiac, carotid, and kidney disease. In particular, many had significant preexisting chronic kidney disease (CKD) evidenced by elevated serum creatinine (Cr) (CKD stage 3 or 4). There was also a high incidence of aortic aneurysms, present in 25% of these patients.⁵ Many patients with atheroembolic events present with multisystem manifestations. Common presentations of spontaneous atheroembolism included blue toe syndrome, livedo, and progressive renal failure. Stroke/transient ischemic events due to carotid atherosclerosis is one of the best examples of a spontaneous atheroembolic episode. The mechanism of blue toe syndrome has been likened to a brain transient ischemic attack (TIA), but affecting a lower extremity.⁹ Today, many cases of unexplained progressive renal failure may be due to unsuspected atheroembolism.

In most series, males outnumber females, with mean ages ranging from 63 to 69 years.^1,5,10 Skin lesions and renal failure are often the two most common manifestations.^1,5 Skin lesions may be the initial clinical sign of atheroembolization (see Fig. 47-3), of which blue toes and livedo reticularis make up 88% of cutaneous findings.¹ African Americans are less likely to be diagnosed with atheroembolism, perhaps because the faint cutaneous pattern of livedo is more difficult to see in skin that is more deeply pigmented¹¹ (Fig. 47-7).

Figure 47-7 Atheroembolism to left fifth finger. Origin is from subclavian atheromatous plaque.

Procedure-Related Atheroembolism

Anticoagulation/Thrombolysis Issues

The concern that warfarin could precipitate atheroembolism was first raised in 1961 by Fedar and Auerbach, who reported six patients who had developed painful purple toes after initiation of an oral anticoagulant.⁴² Since then, anecdotal reports have linked warfarin with spontaneous atheroembolism. Clinical improvement of atheroembolism manifestations, including livedo reticularis, abdominal pain, and even renal function, has been reported after oral anticoagulants were discontinued.^43,44 Other anecdotal reports have indicated improvement in skin necrosis and livedo when low-molecular-weight heparin (LMWH) was discontinued.^43,45 It is hypothesized that anticoagulation could dissolve or prevent formation of a protective thrombus over an atherosclerotic plaque, leaving it vulnerable to rupture and embolization.

To the contrary, a number of large studies have shown no increased risk of atheroembolism in patients treated with warfarin. Blackshear et al. addressed concerns of warfarin anticoagulation in patients with atrial fibrillation and documented aortic plaque. The SPAF III (Stroke Prevention in Atrial Fibrillation) trial looked at patients with atrial fibrillation and aortic plaque documented by TEE and found that patients assigned to warfarin therapy had an annual cholesterol embolization rate of 0.7 per patient-year, which was lower than those randomized to warfarin plus aspirin. The authors conclude that “elderly patients with AF and aortic plaque can receive adjusted-dose warfarin with a relatively low risk of cholesterol embolism.”⁴⁶ The French Study of Aortic Plaques in Stroke found no difference in recurrent brain infarction in patients receiving warfarin compared to those on aspirin.⁴⁷

Many cardiovascular patients are on anticoagulation, and in most case reports, causation is difficult to prove. Elderly patients are most likely to have advanced atherosclerosis and yet have chronic disorders such as atrial fibrillation requiring long-term anticoagulation. Often these patients had undergone other procedures including angiography, which is more likely an explanation for atheroembolic events. Delayed recognition of an acute event or recurrent showers in patients with shaggy aortas may account for the temporal association of atheroembolism with an oral anticoagulant.⁴⁸

A sensible conclusion is to continue anticoagulation when compelling conditions exist, such as atrial fibrillation and thromboembolism, but consider stopping it if there is a lesser indication.³⁸

Atheroembolism has also been reported to occur after thrombolytic therapy for myocardial infarction.^49–52 In some of these case reports, atheroembolism occurred in the absence of any invasive procedure, therefore implicating thrombolysis as a possible culprit. The mechanism of atheroembolism is thought to be dissolution of thrombus overlying atheromatous plaque, exposing ulcerated plaque to the arterial circulation that can embolize distally. Large trials of thrombolysis for acute myocardial infarction (AMI), including GISSI 2 and GUSTO, did not cite atheroembolism as a complication of thrombolytic therapy, so concern of atheroembolization should not be a reason to withhold thrombolysis.⁵³

Blankenship et al. prospectively followed 60 patients with AMI who later underwent CABG. Half of these patients received thrombolytic therapy and half did not. It was concluded the prevalence of cholesterol embolization was not higher in those who received thrombolytic therapy.⁵⁴

Livedo and Skin Atheroembolism

Skin findings are the earliest and at times the only clinical finding of atheroembolism. Livedo reticularis is the most common manifestation of skin involvement, noted in 49% of patients.^55,56 The incidence of cutaneous manifestations of atheroembolism ranges from 35% to 96%.^1,57,58 Livedo has been labeled an underutilized clue to the diagnosis of atheroembolism because it should be considered an important and common indicator of atheroembolism elsewhere—in particular, to the kidneys or mesenteric organs.^55,59 For example, the suspicion of renal atheroembolism is markedly strengthened by the finding of livedo reticularis affecting the trunk or abdomen.

Livedo reticularis has a classic appearance as a reddish-blue lacy or netlike color pattern of the skin (Fig. 47-8). It is noted when the cutaneous venous plexus becomes visible owing to desaturated venous blood. In the presence of atheroembolism, small arteries are obstructed, reducing flow into the venous plexus and resulting in stasis of deoxygenated blood.⁶⁰ Characteristics of livedo reticularis include blanching with local pressure. It is more prominent when the patient is upright and may not be apparent if the patient is examined in the supine position.⁵⁵ Atheroembolism is less frequently diagnosed in nonwhite individuals because darker skin may disguise visible manifestations.¹¹ Livedo is most commonly seen on the feet and legs, but thighs, buttocks, lower back, abdomen, and upper-extremities can also be affected, depending on the source of the atheroembolism.¹

Figure 47-8 Unusual nonblanching livedo reticularis of thigh in patient with suspected livedo vasculitis.

Less common cutaneous findings in atheroembolism include splinter hemorrhages, petechiae, purpura, and erythematous nodules. Cholesterol embolism to the skin has been called a pseudovasculitic syndrome.⁶¹ Livedo due to atheroembolism has been mistaken for small-vessel vasculitis in 16% of patients.⁶² The diagnosis of atheroembolism can be confirmed by skin biopsy, and is positive in 92% of cases.^57,62

In young women, livedo reticularis may be a common normal finding due to cold-induced vasospasm of skin vessels, and classically disappears with warming. It can also be seen in a number of diseases including collagen vascular disorders, antiphospholipid antibody syndrome, disseminated intravascular coagulation (DIC), vasculitides such as systemic lupus erythematosus (SLE) and polyarteritis nodosa, infective endocarditis, cryoglobulinemia, and hyperviscosity disorders.³⁸

Atheroembolic Renal Disease

About half of all reported cases of atheroembolism involve the kidney.⁷ The kidney receives a major percentage of the cardiac output and is the most common site for atheroembolism, followed by skin and gastrointestinal tract.^1,63 In clinical practice, it has been estimated that up to 10% of all cases of acute renal failure may be due to atheroembolism.⁶⁴

Atheroembolic renal disease is defined as a syndrome of renal failure secondary to obstruction of small kidney arteries, arterioles, and glomerular capillaries by cholesterol crystal atheroembolism dislodged from the aorta or proximal renal arteries.⁶⁵ Renal atheroembolism may occur spontaneously in patients who have advanced atheromatous disease of the abdominal aorta, but more frequently it occurs as a complication of an angiographic or endovascular procedure. As noted earlier, passage of a catheter or guidewire through the aorta or renal arteries may dislodge atheromatous plaque fragments that travel to the kidneys, where they remain in small vessels. Today, approximately three fourths of renal atheroembolization cases are iatrogenic secondary to invasive procedures, in particular angiography. Coronary angiography is the most common angiographic procedure.^7,8

The exact incidence of spontaneous atheroembolic renal disease is difficult to determine because most studies are retrospective. However, approximately 20% of atheroembolic episodes to the kidneys are thought to be unprovoked spontaneous episodes.⁶⁵ In addition, many atheroembolic episodes are subclinical, difficult to diagnose, and may be missed unless specifically looked for.

In renal biopsy studies, the prevalence of renal atheroembolism in all patients and age groups is quite low, ranging from 0.31% to 2.4%.^8,10 Moolenaar and Lamers reviewed the Netherlands experience of 842 cases of cholesterol crystal embolization in the Dutch National Pathology Information System and found an incidence of 6.0 cases per million population. Among autopsy reports, they also found a low incidence of 0.31%.⁶³ In other renal biopsy series, Greenberg et al. found 24/500 had atheroembolic findings.⁶⁶ In another large series of 755 renal biopsies, atheroemboli were discovered in 8 patients (1.1%).⁶⁷ Selection bias may account for the low prevalence; these patients were selected for biopsy because of unexplained recent worsening of renal function.

Atheroembolism to the kidneys can also occur during any vascular surgical procedure, in particular AAA resection, renal revascularization, and aortoiliac or aortofemoral bypass. In those who died after aortic surgery or an angiographic procedure, the finding of atheroembolism at autopsy ranged from 12% to 77%.⁸ Atheromatous emboli to the kidney was documented in 77% of patients following surgical repair of abdominal aortic aneurysms.²

Atheroembolism to the kidneys also occurs as complication of endovascular procedures (Box 47-2). Modi and Rao reports 85% of patients presenting with atheroembolic renal disease underwent an invasive vascular procedure within the prior 3 months (abdominal aorta, coronary, or carotid angiography).⁶⁵ Olin has stated that atheroembolism likely occurs in every patient undergoing an endovascular procedure (renal artery angioplasty and stent) for atherosclerotic renal disease.⁶⁸ A study by Kawarada et al. used intrarenal duplex ultrasound to detect microembolic signals and found that emboli occurred in all 13 patients undergoing renal artery stent implantation, in particular post dilation of the stent.⁶⁹ Underappreciation of this frequent occurrence is because clinicians attribute acute renal failure after a procedure to another cause such as contrast-induced nephropathy.

A prospective study at a VA medical center looked at renal failure after cardiac catheterization. Atheroembolism was suspected on the basis of a 0.5 mg/dL or more rise in Cr 3 weeks after a coronary angiogram. Although the incidence of renal impairment was low in this group, two of the five died of renal failure. Of note, none of the five had skin signs of livedo, and the diagnosis of atheroembolism would have been missed on examination.³¹

Atheroembolism to the kidneys is underrecognized as a cause of acute and chronic renal disease. In one review of 259 patients who underwent renal biopsy for acute renal failure, cholesterol emboli were found in 6.9% of cases. Of note, 15 of 18 of these patients were clinically unsuspected to have atheroembolism as a cause of renal failure. Another study found 7.5% of patients with acute renal failure had documented atheroembolism on renal biopsy.⁷⁰

In one review, Mayo and Swartz estimated that 4% of all inpatient nephrology consults were due to atheroembolism.⁶⁴ This may be a conservative estimate because older patients with multiple risk factors accounted for a higher proportion of in-hospital nephrology consults. Of those consults seen with acute renal failure, 5% to 10% were felt to be due to atheroembolic renal disease.⁶⁴

Atheromatous emboli and cholesterol crystals tend to lodge in arcuate and interlobar arteries which are 150 to 200 microns in diameter.^8,65 Cholesterol crystal emboli not only cause mechanical vessel obstruction but also set up an endothelial inflammatory reaction that some have labeled microcrystalline angiitis.⁸ This is characterized by polymorphonuclear leukocyte and eosinophil infiltration around the vessel, and subsequently mononuclear cells with giant cell formation in the perivascular tissues. Endothelial distortion, intimal proliferation, perivascular fibrosis, and sometimes extraluminalization of crystals can be seen.⁶⁷ With thrombus formation, there is further microvascular occlusion of renal vessels. Over 2 to 4 weeks, there is a progressive gradual decline in renal function following an acute atheroembolic episode. Renal infarction or necrosis is rare because the process is patchy and does not obstruct the larger feeding arteries to the kidney.

Atheroembolic renal disease presents as acute or subacute renal dysfunction in older patients, rarely younger than age 50, usually affecting those with preexisting renal insufficiency.^5,35,65,71 Patients with atheroembolism have multiple risk factors including smoking, diabetes, hypertension, and hyperlipidemia. A review of 52 cases of atheroembolic renal failure at the Massachusetts General Hospital from 1981 to 1990 found these patients were more likely to have significant hypertension and coronary and peripheral artery disease (PAD).⁷²

The clinical course may be variable. In contrast-induced nephropathy, renal failure occurs immediately after dye infusion, with a peak in Cr within several days and resolving in less than 2 weeks.⁸ Unlike contrast-induced nephropathy, atheroembolic renal failure may slowly worsen over a period of weeks to months, likely because of recurrent spontaneous showers of emboli. The kidney responds to ischemic damage with inflammatory changes that lead to glomerular sclerosis, tubular atrophy, and interstitial fibrosis.^38,65 Sometimes, features of focal segmental necrotizing glomerulonephritis and crescentic glomerulonephritis are seen in renal biopsy specimens.^65,66,73

Atheroembolism to kidneys may be subclinical. Subacute presentation is more common with progressive renal failure over several weeks. In one report, the average time interval between an angiographic procedure and diagnosis of atheroembolic renal disease was 5 weeks.³⁵ Renal function declined over 3 to 8 weeks.⁷²

A chronic form of renal failure may be mild and can be clinically silent. Atheroembolism may present acutely, with onset within 1 week, or be subacute with delayed onset of renal impairment 2 to 6 weeks after an inciting procedure. A step-and-plateau drop in renal function has been described, perhaps owing to intermittent recurrent showers of cholesterol crystals over a period of time. One to two thirds of patients with atheroembolic renal disease will need dialysis. Lye et al. reviewed the English literature in 1993, noting that 40% of patients required dialysis.⁶ Only 20% to 30% will recover sufficient renal function to stop dialysis.^6,8,74

Clinical features are often absent but may include flank pain and gross hematuria due to renal infarction. Abdominal pain, nausea, vomiting, and blood loss can result from embolization to the gastrointestinal tract. In approximately half of these patients, there may be livedo reticularis or purple toe discoloration due to cholesterol embolization to the skin. Fever, malaise, and weight loss may be accompanying systemic symptoms.⁶⁵

Severe or resistant hypertension has been noted in up to half of patients with atheroembolic renal disease.^6,15 Hypertension may result from activation of renin angiotensin system, or be volume mediated secondary to inability of the kidney to excrete excess fluid. Malignant hypertension can occur with atheromatous embolization to the kidneys.⁷⁵

Gastrointestinal Tract Atheroembolism

The gastrointestinal tract is one of the common sites for aortic atheroembolism and ranks as the third most frequently affected organ system after skin and renal involvement.⁶³ Cholesterol embolization should be in the differential diagnosis of all patients with atherosclerosis presenting with gastrointestinal symptoms after a vascular interventional procedure. Symptoms may be nonspecific and difficult to diagnose but include abdominal pain, fever, and diarrhea. Gastrointestinal bleeding due to mucosal infarcts and ulceration caused by bowel ischemia may occur.^57,91,92 In severe cases, intestinal infarction may require urgent surgery for necrotic bowel or bowel perforation. The colon is most commonly involved. Multiple emboli over time may result in stricture formation, bowel obstruction, or polypoid lesions.^93–95 Rarely, atheroembolism to the gut can mimic colon cancer.⁹⁶ Sometimes symptoms may be misdiagnosed for months until a catastrophic event such as small-bowel perforation with peritonitis or bleeding occurs.⁹⁷ The liver, gallbladder, and pancreas are also uncommon sites for atheroembolism, but there are case reports of acute pancreatitis and acute acalculous cholecystitis from aortic atheroembolism.^98–103 Cholesterol embolization has been reported after protracted vomiting.¹⁰⁴ The stomach is rarely involved. An endoscopic biopsy should include submucosa to detect cholesterol clefts in small arterioles.⁹¹ Most patients with atheroembolism to the gastrointestinal tract have advanced atherosclerosis, and atheroembolism affects multiple organs.⁹² When atheroembolism involves the gastrointestinal tract, cholesterol embolization can also be seen as livedo reticularis or associated blue toe syndrome.⁹⁷ At least half of these cases are precipitated by an angiographic procedure and have a high mortality rate.⁹¹

Lower Extremities and Blue Toe Syndrome

In 1961, Feder and Auerbach described six patients who presented with painful purple toes and noted findings of dark-tinged discoloration of the plantar surfaces and sides of the first and second toes bilaterally. He noted the toes were painful and tender to touch, and that the blue discoloration of the skin blanched with local pressure, which he felt differentiated this entity from localized hematoma or purpura. These patients were older, with ages ranging from 53 to 69, and had atherosclerotic cardiovascular diseases including diabetes, stroke, or congestive heart failure. Most of these patients had intact peripheral pulses.⁴² Feder and Auerbach associated these skin changes with initiation of warfarin anticoagulation but recognized these features were not due to warfarin-induced skin necrosis.

Fifteen years later in 1976, Karmody et al. established the term blue toe syndrome, recognizing that the sudden onset of pain and cyanosis was the result of a microembolic event to the digital arteries. Angiography in a number of these patients localized the source of embolism to the femoral, popliteal, or aortoiliac arteries.⁹

The typical patient with blue toe syndrome presents with sudden onset of painful cyanotic skin lesions that may involve one or many toes. Cyanosis results from decreased arterial inflow along with impaired venous outflow, leading to stasis of desaturated blood. Initially, the cyanosis blanches with pressure, but with worsening ischemia and tissue damage, the blue discoloration may become nonblanchable. The affected toe is dark blue in color, painful due to ischemia, and exquisitely tender to touch. Digital ischemia can progress to cause skin necrosis, ulceration, and black gangrene. Livedo reticularis of the foot may also be present involving the base of the affected toe, forefoot, plantar surface, or heel (Figs. 47-9 through 47-13). Myalgias due to muscle atheroembolism may occur, with clinical features of local muscle tenderness, sometimes with actual myonecrosis.¹⁰⁵

Figure 47-9 Blue toe syndrome with infarction of fifth toe.

Figure 47-10 Atheroembolic mottling of the big toe.

Figure 47-11 Severe episode of atheroembolism to forefoot.

Figure 47-12 Plantar surface of same patient as in Figure 47-11, showing purple toes and severe atheroembolism to forefoot.

Figure 47-13 Livedo reticularis from atheroembolism involving lateral aspect of foot and heel.

Clinical examination should be the initial step to determine the source of atheroembolism. In 78% of patients, peripheral pulses including pedal pulses are intact.¹ Although distal pulses are palpable in the classic case of blue toe syndrome, occlusive arterial disease is present in up to half of patients, based on ankle- brachial indices (ABIs) less than 0.9.¹⁰⁶ Careful pulse examination with auscultation for bruits may suggest proximal arterial disease. A widened expansile common femoral or popliteal pulse may suggest an aneurysm. Palpation of the abdomen may reveal an aortic aneurysm. The location of livedo, such as the foot, thigh, or abdomen, suggests a more proximal site.

Lower-extremity atheromatous emboli can originate from focal or diffuse atherosclerosis, from stenotic or aneurysmal disease, and from disease above or below the inguinal ligament.¹⁰⁶ If both lower extremities are involved, this suggests the origin of the atheroembolism is proximal to the aortic bifurcation. In unilateral blue toe syndrome, the culprit site is likely at or distal to the iliac artery. Common sites of atherosclerosis are the common or external iliac artery (EIA), the superficial femoral artery (SFA) at the adductor hiatus (due to stenotic disease), and the popliteal artery (arising from a local aneurysm). The aortoiliac segment is the most common origin for atheroembolism, accounting for two thirds of cases.^106–109 One third of cases are found to arise from the femoropopliteal arteries.¹⁰⁶

When no embolic source is readily identifiable, imaging of the thoracic aorta is important and may reveal a coral reef (see later discussion) or mobile plaque as the source of distal atheroemboli. Sometimes a solitary embolic source cannot be isolated, owing to the diffuse nature of atherosclerosis. For example, in one study, arteriograms showed diffuse disease at both aortoiliac and femoropopliteal levels in 40% of patients, making it difficult to discern the likely source of atheroembolism.

Only a few years ago, angiography was the gold standard to search for a culprit lesion, but now with advances in noninvasive imaging, computed tomographic angiography (CTA), magnetic resonance angiography (MRA), duplex ultrasound, and TEE are all first-line well-established methods to image the aorta.^110,111

Blue toes due to atheroembolism should be differentiated from other skin and systemic disorders (Fig. 47-14). Blue toes can also be caused by benign cold-induced reversible vasospasm, similar to Raynaud’s phenomenon of the fingers. Other vascular diseases that can present with a blue toe include pernio, thromboangiitis obliterans (TAO) (Buerger’s disease), and digital artery thrombosis. Paraproteinemia (e.g., myeloma) or myeloproliferative disorders (e.g., polycythemia vera, essential thrombocytosis) may cause small-vessel thrombosis. Cryofibrinogenemia results from complexes of fibrinogen, fibrin, and proteins that precipitate with cold. Secondary forms are associated with cancers, rheumatological diseases, and infections. Cryoglobulinemia results from immunoglobulins (Igs) that precipitate in the cold. There are three types: type 1 cryoglobulinemia occurs in association with lymphoproliferative disease (e.g., chronic lymphocytic lymphoma); types 2 and 3 may be associated with viral hepatitis infections. Hirschmann and Raugi defines the blue toe syndrome as a “blue or violaceous discoloration of one or more toes in the absence of trauma (fracture or strain), cold-induced injury (pernio or frostbite), or disorders that produce systemic cyanosis (methemoglobinemia or hypoxia)”.⁶⁰

Figure 47-14 Blue toes from unknown cause.

The short- and long-term outcome after an atheroembolic episode is variable depending on the extent of atheroembolism and resulting tissue damage. For many patients, the prognosis for atheroembolism is poor, sometimes requiring limb amputation. Improvement may occur but may take several weeks for pain to slowly subside, and longer for skin color changes to improve. In more severe cases, the affected toe(s) may progress to necrosis with black gangrene. If carefully managed, the gangrene may stay dry and demarcate from healthy tissue, allowing future autoamputation of the distal or entire toe. Wet gangrene may lead to infection and may require surgical amputation. A toe amputation may heal satisfactorily at a demarcation line if large-vessel arterial perfusion is intact.

Although some individuals recover after a single episode of atheroembolism, a recurrent episode can cause further irreparable damage resulting in extensive tissue damage and necrosis. Spontaneous embolic episodes tend to be recurrent. With very extensive atheroembolism, skin necrosis may occur, affecting much of the foot; this has been referred to as trash foot¹⁹ (Fig. 47-15). This is potentially limb threatening and is associated with a high mortality rate, owing to coexistent multisystem disease. In one study where trash foot occurred in 19 of 29 patients (7 bilateral) following abdominal aorta or lower-extremity revascularization, 8 patients underwent major amputations, and 5 minor amputations.¹⁹ The risk of major amputation after extensive atheroembolism varies from 10% to 27% depending on the reported series.^9,106,112 Mortality is also significant in multisystem atheroembolism, as in one recent study where 31% of patients died during a follow-up period of 15 months.¹¹³

Figure 47-15 Postangiographic atheroembolism to foot, resulting in critical irreversible foot ischemia requiring below-knee amputation.

Operative management

Once lower-extremity atheroembolism occurs, management principles are to prevent recurrent embolic episodes and provide local care for the affected extremity. General treatment measures are discussed later under the section on treatment.

Surgical or endovascular intervention has been advocated because of the high likelihood of recurrent atheroembolic events leading to worsening irreversible tissue ischemia with risk of limb amputation.^9,112 Embolic recurrence may be as high as 50% to 80%, with a 40% to 60% risk of tissue loss.^106,107 The goal of surgical intervention is to remove or exclude the source of embolization and prevent recurrent episodes leading to organ and extremity loss. Treatment choice is determined by location and severity of disease. The optimal surgical intervention depends on the individual patient. Arterial bypass, endarterectomy, and angioplasty with stent placement have been reported to be effective in selected patients by preventing recurrent embolization.^107,114

A retrospective study at Washington University Medical Center found 62 patients with renal or cutaneous manifestations of atheroembolism. Angiography was done in almost all patients. The aorta and iliac arteries (80%) were felt to be the most common source of atheroembolism, followed by femoral (13%), popliteal (3%), and subclavian (3%) arteries.¹⁰⁸ Bypass grafting procedures were performed on 42 patients to exclude the native diseased artery. Other patients underwent a combination of endarterectomy and bypass grafts. Limb salvage was accomplished in 98%, although 31% had minor amputations. No further episodes of atheroembolism occurred over a mean follow-up period of 20 months.¹⁰⁸

Keen et al. reviewed his experience of surgical management of atheroembolism in 100 patients with lower-extremity, visceral, and upper-extremity atheroembolism who were followed for 12 years.¹⁰⁹ Aortoiliac occlusive disease was present in 47 patients, and aortic aneurysm was present in 20 patients (average size, 3.5 cm). Operations to exclude the embolic source included aortic bypass or aortoiliac endarterectomy, femoral and popliteal endarterectomy, or bypass graft. Several patients underwent extra-anatomical reconstruction.¹⁰⁹ Despite surgery, 6 of 97 had recurrent events, and 9 required major leg amputations with 10 toe amputations.

Friedman and Krishnasastry reviewed a small group of high-risk surgical patients presenting with rest pain, ulceration, or gangrene due to atheroemboli to both lower extremities. These patients, who were not candidates for direct aortic reconstruction because of preexisting medical comorbidities, underwent ligation of the EIA with axillary-bifemoral bypass. Initial limb salvage was accomplished in all, with no limb loss over the next 52 months.¹¹⁵ Kaufman et al. also reported a small group of high-risk patients in whom limb salvage and healing of foot ulcers was accomplished in the majority with an axillobifemoral bypass with exclusion of the external iliacs.¹¹⁶

Hollier et al. reviewed 88 patients with shaggy aorta syndrome who suffered atheromatous embolization (Fig. 47-16). Surgical correction was performed in 27 patients, including endarterectomy, external iliac ligation, and graft replacement. The best outcome (lowest morbidity and mortality) for those with lower-extremity atheroembolism was with ligation of the distal EIA and extra-anatomical bypass.¹¹⁷ The author noted that surgery was not always successful in preventing visceral infarction or renal failure.¹¹⁷

Figure 47-16 Aortogram demonstrating diffuse atheromatous disease, so-called shaggy aorta, with high atheroembolic potential.

Primary angioplasty for iliac or superficial femoral lesions can also be successful for focal high-grade stenotic lesions of the iliac or superficial femoral artery.^114,118 Although there may be concern of provoking further embolization, some studies show good results. In one series of 10 patients treated with primary angioplasty, none had embolization at the time of the procedure, and 8 of the 10 had no recurrent atheroembolic episodes. The patients in this series were more likely to have single focal high-grade stenotic lesions of an iliac or SFA amenable to angioplasty, as opposed to more diffuse proximal atherosclerotic plaque.^112,114

A self-expanding stent has been used to treat atheroembolism arising from an isolated segment of the iliac artery.¹⁰⁷ For more complex plaques, a covered stent has been successfully deployed and offers the advantage of excluding the diseased segment by trapping the atheroma and thrombus under the covered stent.^107,119 In one case report of three patients with iliac artery disease treated with a self-expanding stent covered with Dacron, no recurrences of microembolism were noted after 16 months, and the toe lesions healed.¹⁰⁷

Aortic stent grafting is now commonly used in the management of abdominal aortic aneurysms. In a retrospective study of 19 patients with symptomatic lower-extremity atheroembolism presenting with ischemic ulcers or toe gangrene and an abdominal aneurysm, an aortic stent graft was deployed to exclude an abdominal aortic aneurysm. At 1-year follow-up, eight of nine patients had resolution of ischemic toe symptoms.¹¹³ The authors note that although stent graft repair of AAA may prevent future embolization, it is important to not miss coexisting thoracic aortic disease.

Arterial filters have also been employed in the superficial femoral artery, carotid, renal, and many other vessels. As filter development continues to advance, this may become an adjunctive procedure in the future.¹²⁰

Upper-Extremity Atheroembolism

In the upper extremity, atheroembolism is said to be uncommon.¹⁰⁸ Atherosclerosis may involve the aortic arch and branch vessels. Two sites in particular are important. The subclavian artery is a common site for atherosclerosis. Unequal upper-extremity blood pressures should raise suspicion of disease at or proximal to the subclavian artery level. Most individuals with subclavian atherosclerotic disease are asymptomatic, but this can be a source of atheroembolism to the arm and the fingers (Fig. 47-17). Thoracic outlet syndrome causes extrinsic compression of the subclavian artery as it passes under the clavicle and over the first rib. This is a site for aneurysm formation and subsequent atheroembolism to the hand and fingers. Finally, at the wrist level, repetitive pounding injury to the hypothenar side of the palm, as occurs in carpenters and car mechanics, can result in ulnar artery aneurysm with atheroembolism to the hand and fingers.

Figure 47-17 Cutaneous infarction of fifth finger due to atheroembolism. Note subtle ischemic mottling of other fingers.

Coral Reef Plaque

A coral reef plaque is an exophytic calcified discrete mass that is prone to distal embolization.¹²¹ These are more commonly located in the posterior wall of the suprarenal aorta.¹²² Although unusual, they occur in patients with generalized atherosclerosis. They can be treated by surgical thromboendarterectomy or bypass.^123,124 Endovascular stent placement has also been successful in patients symptomatic with claudication from aortic lumen compromise by a coral reef.¹²⁵

Ascending Aorta/Arch Atheroma and Stroke

Sixty years ago, cerebral vasospasm was speculated to cause stroke. Today, carotid artery disease and atrial fibrillation are known to be major causes of nonhemorrhagic stroke. With the advent of TEE, aortic arch plaque has been identified as an important potential source of cerebral embolic stroke.^126,127 Case-controlled prospective studies have shown a clear association between atherosclerotic disease of the ascending aorta/aortic arch and risk of ischemic stroke.¹²⁸ Autopsy studies found ulcerated plaque in the aortic arch to be present in 26% of 239 patients with cerebrovascular disease (both stroke and brain hemorrhage) but only 5% of patients with another neurological diagnosis.^128,129 Another large study using TEE to detect aortic atheroma compared 215 consecutive patients with first stroke or TIA to 202 control subjects and confirmed that atheroma in the ascending aorta and arch are a significant risk factor for stroke.¹³⁰

Characterization of aortic plaque morphology (hypoechoic plaque, ulceration, calcification, sessile or mobile thrombus) is important in prediction of stroke.¹³¹ In particular, the thickness of plaque in the ascending aorta and arch correlates with risk of stroke. When patients with acute stroke were compared to consecutive controls, 28% had plaques of 4 mm or more in thickness in those with unexplained stroke, compared to 8% of 172 patients who had a known or suspected cause of brain infarct.¹²⁸ In the French Study of Aortic Plaques in Stroke, TEE was done to quantify aortic arch atheromatous disease in 331 patients aged 60 or older admitted to hospital with an acute stroke. The incidence of recurrent brain infarction was 11.9% per 100 person-years in those with aortic plaque thickness greater than 4 mm, compared to 2.8% for those with minimal plaque (<1 mm). The presence of atherosclerotic arch plaque thickness of 4 mm or greater was found to be an independent predictor of recurrent brain infarction and cardiovascular events.¹³² Even moderate atheromatous disease (defined as intimal thickness of the ascending aorta and arch of > 2 mm) is a significant risk factor for stroke after cardiac surgery.¹³³

Mobile Atheroma

Atheromatous plaque that is protruding and pedunculated has been correlated with an increased risk of stroke. The presence of mobile components, however, denotes the highest risk for stroke.^{109,132,134–141} In a study of 118 elderly patients studied with intraoperative TEE, 3 of 12 patients (25%) with a mobile aortic arch atheroma had suffered a perioperative stroke, compared to 2 of 118 (2%) patients without a mobile atheroma.¹³⁴ A mobile mass overlying an atheromatous plaque is likely adherent thrombus and therefore is more likely to respond to anticoagulation than the underlying plaque itself. Whether to use anticoagulation for mobile thrombus in the aorta, however, remains controversial.

Warfarin anticoagulation has been advocated for the management of mobile aortic atheroma. A study by Dressler et al. documented effectiveness of warfarin in preventing recurrent embolic events in those with symptomatic thoracic aorta mobile atheroma compared to those not receiving anticoagulation.¹⁴² He reviewed 31 patients with mobile aortic atheroma who presented with a systemic embolic event. At follow-up, those patients not receiving warfarin had a much higher incidence of vascular events (45% vs. 5%). Recurrent strokes occurred in 38% of patients. There were no strokes in those on warfarin.¹⁴² Of note, those with small mobile atheroma were not treated with warfarin, and recurrent strokes occurred in 37% of these patients.¹⁴²

Warfarin was noted to be more effective than antiplatelet medications in another study of patients with severe ascending aortic atheromatous disease.¹⁴⁰ Further randomized controlled trials would be needed to address anticoagulation vs. antiplatelet therapy for this important issue.

In case examples, peripheral embolization from plaque-related mobile thrombus in the thoracic aorta has been successfully treated with warfarin. In one case report, a 71-year-old man had atheroembolism to the toes after vomiting. A large mobile mass in the descending thoracic aorta was identified by TEE. After 3 months of warfarin anticoagulation, there was virtual resolution of the aortic mass, suggesting it was thrombus covering atheromatous plaque. The toe pain and discoloration from atheroembolism also resolved completely.¹⁰⁴

Stroke due to atheroembolism can occur during carotid surgery. Microemboli occurs during carotid endarterectomy and can be detected by TCD ultrasound. Ackerstaff et al. found a positive correlation with the occurrence of microembolism during carotid endarterectomy and perioperative TIA and stroke. Magnetic resonance imaging also documented new ischemic brain lesions in these patients.¹⁴³

Carotid sinus massage may reproduce syncope in patients with carotid sinus hypersensitivity but also cause inadvertent atheroembolic stroke in patients with carotid atherosclerosis.¹⁴⁴

Embolic stroke should be suspected in the proper clinical setting. In young patients with unexplained embolism, TEE has identified unsuspected mobile aortic arch thrombus on atherosclerotic plaque.¹²⁷ Brain imaging characteristically shows multiple small ischemic lesions. Brain pathology has also documented multiple cholesterol emboli.¹⁴⁵ Lacunar infarcts are generally thought to be due to small brain infarcts from hypertension. It is possible some lacunar infarcts may be due to cholesterol emboli.¹⁴⁶

Preventive

It has been said many times that the best treatment for many diseases is prevention.¹⁴⁷ Angiography is the most common iatrogenic cause of atheroembolism, responsible for up to 80% of cases, so safer angiographic techniques and newer technologies may decrease the incidence of catheter-induced atheroembolism.⁸ For example a “no touch technique” has been advocated to reduce potential for intimal disruption during renal artery stenting. A second guide is placed within the guide catheter to minimize contact between the guide catheter and aorta.¹⁴⁸ Arterial filters have also been successfully employed in the superficial artery.¹²⁰ Distal protection devices are available for renal and cerebral angioplasty.^149–151 Cerebral protection devices may reduce stroke during carotid artery stenting, but device-related complications can occur.^147,152

Reduction of atherosclerotic burden and plaque stabilization has been a major focus for preventing coronary events and should also be a focus for preventing atheroembolism. Reducing lipid content in the plaque core, decreasing inflammation and inflammatory cells, and reducing vasa vasorum neovascularization are future strategies.

Control of lifestyle-related risk factors includes cessation of cigarette smoking and avoidance of all tobacco products, avoiding obesity, adult-onset diabetes, and elevated triglycerides, with recognition and management of the metabolic syndrome and decreasing salt in the diet. Avoiding physical inactivity by pursuing an aerobic exercise program is an important step to preventing progression of atheromatous disease and therefore lessening the risk of atheroembolism.¹⁵³

Pharmacological therapy consists of statin medications, antiplatelet agents, ACE inhibitors, often in combination, as well as medications to control hyperglycemia and hypertension.

HMG-CoA reductase inhibitors, or statins, are well-established medications for lowering cholesterol and reducing cardiovascular mortality. Statin medications likely have multiple effects that include antiinflammatory properties, improvement in endothelial function, and reducing blood thrombogenicity. They may also have immunomodulatory effects, decreasing recruitment of monocytes and T cells into the arterial wall and stabilizing arterial plaque, thus decreasing the risk of plaque rupture.¹⁵⁴

Many large trials have confirmed the benefits of statin agents in secondary prevention of cardiovascular events.^153,155 Slowing atherosclerosis progression is a laudable goal. Recently, regression of atheroma volume (of almost 7%) has been documented in the ASTEROID trial, which achieved an average low-density lipoprotein (LDL) decline from 130.4 to 60.8 mg/dL and increase in high-density lipoprotein (HDL) by 14.7%.¹⁵⁶ Cholesterol education program guidelines for lipid management suggest an initial treatment goal of LDL less than 100 mg/dL, except in those at highest risk with established atheromatous disease, who should have an LDL goal of less than 70 mg/dL.¹⁵³

There are no large randomized trials of statin medications in atheroembolism, but there are a number of observational case reports. Tunick et al. looked at the rate of cholesterol embolism in 519 patients with complex aortic plaque seen during TEE in a retrospective study in which atheroembolism occurred in 21%. Although treatment was not randomized, multivariate analysis showed a benefit of statin medication, with absolute risk reduction of 17%. No protective effect was found for warfarin or antiplatelet drugs.¹⁵⁷

Antiplatelet agents prevent platelet activation and thrombosis. Commonly used oral antiplatelet agents include aspirin (75-365 mg/day), dipyridamole plus aspirin, and clopidogrel 75 mg daily. Many clinical trials have documented the effectiveness of combined antiplatelet therapy in coronary disease. Aspirin blocks the enzyme cyclooxygenase (COX)-1 to prevent synthesis of thromboxane A₂ (TxA₂), thus inhibiting platelet aggregation. Thienopyridines act by blocking adenosine diphosphate (ADP)-mediated platelet aggregation via the glycoprotein (GP)-IIb/IIIa receptor. Dipyridamole is a phosphodiesterase (PDE) inhibitor that reduces the breakdown of cyclic adenosine and guanine monophosphate (cAMP and cGMP) and increases activity of prostacyclin(PGI₂), which inhibits platelet aggregation.¹⁵⁸ It is not known whether antiplatelet agents prevent recurrent atheroembolism.

Cilostazol has antiplatelet and vasodilatory effects. One small study of five patients reported healing of distal limb ulcers and improved large- and small-vessel perfusion, but there was no control group and therefore no compelling evidence that ulcer healing was related to this drug.¹⁵⁹ Iloprost therapy has been used for cholesterol emboli syndrome.¹⁶⁰ Anecdotal treatment of blue toe syndrome has included nifedipine and pentoxifylline.¹⁶¹ With fixed microvascular disease, there is no clear benefit of vasodilator therapy in the majority of patients with atheroembolism.

Although anticoagulation may be of benefit for mobile thrombus overlying atheromatous plaque, it is not routinely used in asymptomatic patients with nonmobile atheroma.¹⁶²

Supportive

Organ failure has to be treated. Kidney disease has to be monitored, with correction of electrolyte abnormalities, volume excess, and uremia. Renal replacement therapy with dialysis may be temporary or permanent. Heart failure and hypertension should be managed with diuretics, renin-angiotensin-aldosterone system (RAAS) antagonists, β-blockers, and vasodilators. The HOPE trial showed benefit for ACE inhibitors in patients with vascular disease or diabetes, with reduced rates of stroke, myocardial infarction, and overall death.¹⁶³ The efficacy of renin-angiotensin system inhibition in preventing recurrent atheroembolism is not known.

Wound care may be needed for management of lower-extremity skin necrosis, using surgical wound débridement and application of topical agents and dressings. Limited amputation of toes or forefoot is necessary in some patients, and limb amputations may be necessary for patients with irreversible ischemia with gangrene. Antibiotics may be necessary for infection. A fluffy, soft vascular boot can protect the ischemic foot from trauma. Pneumatic arterial pumps can improve arterial perfusion in some patients.

Effective pain control is very important; ischemic pain can be severe and persist for weeks after lower-extremity atheroembolism.¹⁶⁴ The degree of pain from blue toe syndrome may seem to be out of proportion to the extent of tissue involvement but reflects microvascular necrosis. Besides narcotic and neurotransmitter pharmaceutical agents, several other modalities have been used for pain associated with lower-extremity ischemia.

Lumbar sympathectomy was popular 50 years ago when surgical options for PAD were more limited. There has always been controversy regarding actual benefit in patients with atherosclerotic disease.^165–168 Lumbar sympathectomy historically has been done for critical leg ischemia with gangrene, ischemic ulcerations, and rest pain. A 60% improvement rate has been reported, although not all respond. In one retrospective review of 45 patients (50 limbs) with toe gangrene treated with lumbar sympathectomy, amputation rate remained high at 40%.^169,170 More recently, some surgeons continue to advocate lumbar sympathectomy for selected patients in situations of threatened tissue loss.¹⁶² The hope is that this may improve collateral blood flow and open arteriovenous connections by relieving smooth muscle constriction.¹⁶² Some studies do show improved tissue perfusion and enhanced healing in addition to surgical reconstruction.

Today, a lumbar sympathetic block may be done by local injection, with the goal of improving skin warmth and pain. A spinal cord stimulator has been of benefit in a few selected patients.¹⁶⁴

Other treatment options may include hyperbaric oxygen or pneumatic leg compression to improve distal perfusion in selected cases of extremity atheroembolism.¹⁷¹