Cholesterol embolisation syndrome occurs when cholesterol crystals and other contents of an atheroslerotic plaque embolise - traveling from a large proximal artery to smaller distal arteries, lodging in and obstructing circulation, causing end-organ damage, i.e damage occurring to organs fed by the circulatory systems. The only definitive test for diagnosis is biopsy, such that exact incidence and prevalence are unknown. Table 1 summarises incidence in various clinical settings (1). Cholesterol embolisation syndrome has been linked to the general development of atherosclerosis and shares its risk factors, including age, male sex, tobacco use, systemic hypertension, diabetes mellitus, hypercholesterolemia, and family history.
How it develops
Essential steps are as follows: 1) atherosclerotic plaques in a proximal large-caliber artery, within the arterial intima exist 2) these rupture, 3) cholesterol crystals and plaque debris embolise and 4) emboli lodge in small and medium-sized arteries 5) inflammatory response ensues and 6) end-organ damage occurs. (1)
An atheromatous aorta is the primary source of both cholesterol emboli (or atheroemboli) and the more common, thromboemboli. The abdominal aorta and the ileo-femoral arteries are the most common sources of cholesterol emboli - plaques consisting of a necrotic core and a fibrous cap (2). The core contains foam cells (macrophages) and various lipids, including low-density lipoprotein-derived cholesterol crystals which become the source of cholesterol emboli (3). They are deep inside the plaque and indicate advanced atherosclerosis. Atherosclerotic plaque in the aorta and its large branches may be visualised by transesophageal echocardiography, computed tomography, magnetic resonance imaging and aortography (4), also by transthoracic echocardiography or endoscopic ultrasound imaging of the upper gastrointestinal tract (3). Irrespective of the imaging technique, the index plaque - the source of cholesterol embolisation syndrome- can often not be recognised. Nevertheless, the presence of plaques is a sign of generalised atherosclerosis and supports diagnosis.
Plaque ruptures mostly occur spontaneously. Iatrogenic plaque rupture leading to cholesterol embolisation syndrome have been described following cardiac catheterisation (5), cardiovascular surgery (6) and percutaneous carotid interventions (7). It is uncertain, however, whether thrombolytic or anticoagulant therapy is an independent risk of plaque rupture leading to cholesterol embolisation syndrome (3). Embolisation from atherosclerotic plaque in the aorta occurs mainly in antegrade fashion but occasionally in retrograde direction as well. This retrograde flow from the descending thoracic aorta into the aortic arch vessels can be demonstrated by MRI and Doppler echocardiography (8).
After travelling through the arterial circulation, cholesterol crystals obstruct the arterioles and small arteries. In routinely processed biopsy specimens, cholesterol crystals are washed away, leaving characteristic crescent-shaped clefts within the arterial lumen (Fig.1). Cholesterol crystals can only be visualised in specially preserved specimens in which these crystals demonstrate birefringence under polarised light (3).
In addition to mechanically occluding the small arteries, cholesterol crystals also trigger an inflammatory response, which consists of foreign body reaction and intravascular thrombus formation followed by endothelial proliferation and finally, fibrosis. The end result of cholesterol crystal embolisation is partial or complete occlusion of target arteries leading to tissue ischemia (1). Any organ can be affected however the most commonly involved organs are: the brain, kidneys, skin, gastrointestinal tract and skeletal muscles.
Figure 1: Histopathology of cholesterol embolisation. Characteristic empty clefts (arrows) are seen within obliterated lumen of a small artery in the kidney.
Table 1: Risk of cholesterol embolisation in various clinical settings (1)
|Clinical Context||Type of Study||Incidence of atheroembolism|
|Coronary angioplasty||Clinical ||0.6|
|After cardiac surgery||Autopsy||≤22|
|After abdominal aortic resection||Autopsy||≤77|
Clinical presentation of cholesterol embolisation syndrome is a combination of 1) a systemic inflammatory response and signs and 2) symptoms specific to end-organ damage.
The inflammatory response often manifests clinically as fever, anorexia, weight loss, fatigue and myalgias. Laboratory tests may demonstrate anemia, thrombocytopenia, leukocytosis, high erythrocyte sedimentation rate and C-reactive protein in addition to hypocomplementemia. Hypereosinophilia and eosinophiluria are a frequently observed sign of CES. Hypereosinophilia may occur in up to 80% of the patients with CES and is often observed only during the first few days of CES (9).
Skin: Skin findings have been reported in CES ranging from 35 to 96% in different reports. They include livedo reticularis (figure 2(B)) (49% of patients with skin manifestations), gangrene (35%), cyanosis (28%), ulceration (17%), nodules (10%) and purpura (9%). These findings are most often seen on the lower extremities, and none of them is considered pathognomonic for CES. For example, livedo reticularis can also be seen in polyarteritis nodosa, systemic lupus erythematosus or following the use of potent vasoconstriction agents. In the lower extremities, CES can lead to sudden development of purple or blue discoloration of toes and/or other regions of the foot. Although the term ‘blue-toe syndrome’, - see previous e-journal article on blue-toe syndrome, was first described in the context of CES, it may also be seen in vasculitis, antiphospholipid syndrome, hyperviscosity states and endocarditis (1,3). These skin changes are merely a reflection of microvascular ischemia, which may result in tissue necrosis, ulcerations and gangrene.
Renal: Cholesterol emboli to the kidneys – also referred to as atheroembolic kidney disease – chiefly affect the arcuate and interlobar renal arteries. Because cholesterol crystal embolisation has a patchy distribution, renal biopsies may be negative for CES (10). Renal CES can lead to acute, subacute and chronic kidney failure. Acute and subacute forms are typically caused by a sudden massive shower of cholesterol emboli (e.g. after a vascular procedure), whereas chronic forms often result from spontaneous low-level cholesterol crystal embolisation over extended periods of time (3).
Neurologic: Typically, CES results in diffuse brain injury (characterised by confusion and memory loss) rather than focal neurologic deficits. Neurologic manifestations of CES are predominantly due to small ischemic lesions and border zone infarcts (11). Microemboli in cerebral arteries can be detected by transcranial Doppler ultrasonography as high-intensity transient signals superimposed on standard spectral Doppler flow velocity recordings. High-intensity transient signals are, however, not pathognomonic for cholesterol crystal emboli, as they may also be seen with microembolisation of fat, air and calcium particles (3).
Gastrointestinal: The reported incidence of gastrointestinal manifestations ranges from one-fifth to about one-half of all patients with CES. gut ischemia, which may lead to intestinal blood loss, pseudopolyp formation, ulceration and intestinal perforation (1, 3) can cause cholesterol embolisation syndrome. Less frequent gastrointestinal manifestations of CES may include acalculous necrotising cholecystitis and acute pancreatitis.
Ocular : Cholesterol crystal emboli may lead to retinal artery occlusion, presenting clinically as amaurosis fugax. These emboli are seen on fundoscopy as highly refractive yellow particles at branching points of retinal arteries and are termed Hollenhorst plaques (1,3).
Diagnosis and Treatment
Cholesterol embolisation syndrome should be suspected in any patient (oftentimes, an elderly man) with any of the previous clinical and laboratory manifestations, especially after cardiovascular interventions. However histopathologic diagnosis is the only test for confirming diagnosis. Skin, skeletal muscles or the kidneys are the usual biopsy locations. Since poor healing at the sampling site has been observed, biopsies in CES should be performed with caution.
Since CES is a manifestation of atherosclerosis, risk factor modification should be an essential part of CES treatment, including cessation of tobacco use, lowering of serum cholesterol, and control of hypertension and diabetes mellitus.
There is still no specific therapy for CES. Treatment consists of supportive care and secondary prophylaxis against further episodes of CES (12). There is no evidence that anti-inflammatory treatments are beneficial in CES. Although there is also no direct evidence that antiplatelet agents and angiotensin converting enzyme inhibitors directly prevent the recurrence of CES, their use appear reasonable as they have been shown to prevent other adverse cardiovascular events, including myocardial infarction, the leading cause of death in patients with atherosclerosis.
It is not advised to initiate thrombolytic or anticoagulant therapy in patients with CES, given the unresolved controversy over whether such agents precipitate CES or not. However, if there is a different indication for anticoagulation, such as atrial fibrillation, anticoagulation should be continued (1,3).
Surgical therapy such as endarterectomy, vessel ligation or bypass or percutaneous interventions (e.g. endoluminally placed stent grafts) may decrease the rate of further embolism (13).
Cholesterol embolisation syndrome is a form of arterio-arterial embolism in which components of a ruptured plaque in the aorta or a large proximal artery embolise to distal small to medium sized arteries. This leads to ischemic end-organ damage through a combination of mechanical plugging and inflammation in the target arteries. There are no clinical or laboratory findings that are specific to CES, such that a high degree of clinical suspicion is necessary in establishing the diagnosis and biopsy is the only means of antemortem confirmation of the diagnosis of CES. Treatment is directed toward general management of atherosclerosis and arterial ischemia.
Notes to editor
Dr Adel Shabana, Heart Hospital, Hamad Medical Corporation, Doha, Qatar.
Authors' disclosures: None declared.