Cholesterol embolism syndrome should be suspected in a patient who develops worsening renal function, hypertension, distal ischemia, or acute multisystem dysfunction after an invasive arterial procedure. Atheroemboli may also occur spontaneously. The protean manifestations of this syndrome make the diagnosis challenging. As the population ages, the incidence of cholesterol embolism syndrome will increase.
Key components of cholesterol embolism syndrome include the following:
Any organ system, with the exception of the lungs, may be directly affected. Cholesterol embolism syndrome has two mechanisms of action.
With the first mechanism, cholesterol crystals spontaneously break off from severely atherosclerotic plaques and shower into downstream organs, occluding arterioles 100-200 μm in diameter. The crystals induce an inflammatory foreign-body reaction and adventitial fibrosis, which eventually obliterate the vessel lumen. Local vasospastic mediators compound tissue ischemia and produce progressive, irreversible organ damage.
With the second mechanism, larger cholesterol plaques break off and occlude larger arteries, causing tissue infarction with acute organ dysfunction. This can occur after local trauma to the atherosclerotic plaque, such as that caused by angiography or aortic trauma, or it can occur after destabilization of the protective clot overlying the plaque, which can occur as a result of anticoagulation.
Cholesterol crystal embolization (see the image below) occurs from the arterial system, and crystals are trapped in the arterioles, where they either immediately occlude the vessels or induce an intense inflammatory response that leads to tissue ischemia. Crystals do not travel to the lungs; however, inflammatory mediators released by ischemic tissue may result in acute lung injury.
Cholesterol crystal embolization from upstream coronary artery plaque after percutaneous transluminal coronary angioplasty.
Any risk factor for atherosclerotic disease is a risk factor for cholesterol embolism.
Preoperative risk factors for cholesterol embolism syndrome after coronary artery bypass surgery (CABG) include the following:
Although the other factors have been well known for some time, it was only comparatively recently that the association between mitral annular calcification and aortic atherosclerosis was identified.
Identifying patients at risk and making efforts to minimize aortic wall trauma help reduce the chance of cholesterol embolism. The risk that cholesterol embolism will develop may be reduced by using a brachial or axillary approach in patients known to have severely ulcerated aortic plaque, using soft flexible catheters, and avoiding high-pressure jets of contrast material.
Estimates of the incidence of cholesterol embolic disease are usually based on autopsy data. Tissue sections from patients with the following diseases or procedures indicate the incidence of atheroembolic events:
Of patients undergoing angiography, 25-30% may have atheroembolic events, whereas 2.5-3% of patients who receive percutaneous transluminal coronary angioplasty (PTCA) vein grafts and 1.4-3% of patients undergoing renal artery angioplasty or cardiac catheterization have been reported to have clinical signs of atheroemboli. Cholesterol embolism syndrome has been reported as occurring months after thrombolytic therapy for stroke, but the true incidence is unknown.[1, 2]
Cholesterol embolism is a disease of persons ranging from middle-aged to elderly, with a minimum age of 50 years. The risk is greater for men than it is for women.
Patients with multisystem cholesterol embolism syndrome have a poor prognosis. The mortality of acute multisystem organ failure resulting from cholesterol embolism syndrome is 58-90%. Jucgla found an overall incidence of 58% at 15 months, increasing to 65% if visceral organs were involved. Preexisting chronic renal insufficiency had a relative risk of death of 4.54.
The mortality of severe cholesterol embolism is 90% at 3 months. Mild cases with renal dysfunction, with or without skin findings, have a mortality of 16%.
Cholesterol crystal showers can become stabilized, leaving patients with varying degrees of organ dysfunction. Renal function can recover if no further insults occur, even to the degree that dialysis can be discontinued. However, patients remain at risk for recurrence of emboli.
Patients should be educated to watch for ulcerations and infections in chronically ischemic areas, particularly feet and toes. Ischemic neuropathy may exacerbate injury and tissue loss, predisposing the patient to gangrene.
For patient education resources, see the Cholesterol Center, as well as High Cholesterol, Cholesterol Charts (What the Numbers Mean), Lifestyle Cholesterol Management, and Cholesterol Lowering Medications.
The diagnosis of cholesterol embolism must be considered in patients older than 50 years who have atherosclerotic disease and who present with multisystem dysfunction after undergoing an invasive vascular procedure or receiving an anticoagulant or thrombolytic agent within the past several months. All patients with the classic triad of livedo reticularis, acute renal failure, and eosinophilia should undergo evaluation for cholesterol embolism, including a funduscopic examination.
Clinicians should be aware that the syndrome may not manifest until chronic crystal embolization and inflammatory changes have occluded enough vessels to create detectable organ damage. Patients may have unexplained fever, weight loss, myalgias, or anorexia for weeks or months after a procedure before presenting with acute renal failure, hyperkalemia, gastrointestinal (GI) bleeding, or stroke.
Constitutional manifestations of cholesterol embolism include the following:
Cardiovascular manifestations include the following:
Neurologic manifestations include the following:
Renal manifestations include the following:
Dermatologic manifestations include the following:
GI manifestations include the following:
Other manifestations are as follows:
Cholesterol embolism can directly affect all organs except the lungs, resulting in complications that range from mild dysfunction to complete organ failure. Supportive care of organ dysfunction may be necessary and may include hemodialysis, bowel resection, cholecystectomy, and pancreatitis management.
Laboratory studies to be considered in the workup for cholesterol embolism include the following:
Contrast angiography of involved organs may be performed to rule out more treatable causes of tissue ischemia, such as polyarteritis nodosa. Angiography may induce atheroembolism.
Transesophageal echocardiography (TEE) is gaining acceptance as an imaging tool for detecting atheromatous lesions in the ascending and thoracic aorta.[6, 7, 8, 9] Protruding mobile atheromatous masses have been associated with a higher incidence of stroke or cholesterol embolism in patients who undergo cardiac bypass or patients who receive anticoagulants. TEE may eventually be performed in all patients undergoing bypass before aortic cannulation. It also may be performed in all patients with ischemic stroke with an unclear etiology.
Thin sections viewed on nonenhanced dual helical (spiral) computed tomography (CT) may be useful for rapid and noninvasive detection of protruding aortic atheroma. This test can help visualize areas that are poorly imaged on TEE, such as the distal ascending aorta and arch. One study suggests 87% sensitivity, 82% specificity, and 84% overall accuracy.
Data on magnetic resonance imaging (MRI) and atheromatous plaque are relatively sparse, but a reasonable expectation is that MRI should exhibit good sensitivity in this setting.
Demonstration of cholesterol crystals in occluded arterioles is the only definitive test for cholesterol embolism. Skin, renal, muscle, or gastrointestinal tract biopsy may reveal crystal ghosts inside vessels. Often, multiple samples may be necessary to demonstrate the crystals.
The actual cholesterol crystals are dissolved during fixation, leaving intra-arterial biconvex ghosts. Often, the crystals are missed because the depth of the tissue sample is inadequate. If these ghosts are absent, the diagnosis still may be inferred from the presence of fibrinoid necrosis (see the image below) and a foreign-body reaction in tissues commonly involved by atheromatous emboli in a patient with consistent clinical findings. Exuberant adventitial fibrosis contributes to vessel lumen occlusion.
Necrosis of the abdominal wall in a patient with cholesterol embolism syndrome who received anticoagulation.
Medical management is supportive. Hemodynamic monitoring, including pulmonary artery catheterization, may be helpful for fluid and vasopressor adjustments. If acute respiratory distress syndrome (ARDS) occurs, mechanical ventilation may be required for a prolonged period. Dialysis should be started when indicated because patients can recover limited renal function. Aggressive nutritional and metabolic support is essential because these patients often lose considerable lean body mass to ongoing catabolism.
Pharmacologic therapy has not been particularly successful in patients with cholesterol embolism syndrome. Vasodilator therapy with calcium channel blockers may help relieve the local ischemia resulting from vasospasm, but angiotensin-converting enzyme (ACE) inhibitors should not be used, because of their negative effects on renal afferent arterioles and the glomerular filtration rate.
Patients presumed to have vasculitis have been treated with high-dose steroids and anti-inflammatory agents, with anecdotal reports of recovery. However, steroids may predispose patients to infectious, metabolic, and nutritional complications and difficulties with wound healing. In a report of four cases of cholesterol embolism after cardiac catherization that were associated with deteriorating renal function, low-dose (0.3 mg/kg/day) corticosteroid therapy yielded improved renal function in three of the four patients.
The use of anticoagulants is controversial because anticoagulants and thrombolytics have been shown to induce atheroemboli. Anecdotal reports of treatment with apheresis, iloprost, statin, colchicine, or combinations of these drugs with steroids report improvement in some cases.[14, 15, 16, 17, 18]
Further invasive vascular procedures and anticoagulant or thrombolytic therapies should be avoided. If such treatments are unavoidable, downstream protection devices to trap atheromatous debris after stenting or angioplasty are suggested.
Surgical therapy (eg, aortic aneurysm resection) may be necessary to remove the source of atheroembolic material. Stent-grafting may be a less invasive method to reduce risk of embolization.
Damaged tissue should be protected and allowed to demarcate for several months. Surprisingly, a majority of the damaged area may recover. Necrotic tissue should be debrided, and establishing vascular access for dialysis also may be necessary.
In severe cases, lumbar sympathetic block (rarely, surgical sympathectomy) has been used to avoid impending lower-extremity tissue loss resulting from intense vasoconstriction.
If an invasive radiologic procedure is necessary, the risk of inducing cholesterol embolism must be considered. If the patient is at high risk, with known or suspected severe aortic atherosclerosis or aortic aneurysm, the Judkins (ie, brachial) approach or a radial artery approach may be used for introducing the catheter into the aorta. However, some investigators found that the approach made no difference, leading them to suspect the ascending aorta as a major source of atheroemboli.
Gentle handling of the severely diseased aorta during cardiac or aortic surgery can reduce the risk of cholesterol embolism. Careful clamping techniques and careful selection of aortotomy sites may minimize disruption of the atherosclerotic plaque.
The following consultations should be considered as indicated: