Atherosclerosis

The process of atherosclerosis begins as early as childhood or adolescence, developing slowly over many years. Its effects rarely manifest before the fourth or fifth decade of life. Traditional risk factors for atherosclerosis include hypertension, diabetes, smoking, and elevated serum cholesterol concentration.

Atherosclerosis mainly affects large and medium-sized arteries. Intravascular sites of blood turbulence favor the development of atherosclerotic lesions. Initial changes in arterial wall morphology result in the formation of fatty streaks that consist of lipid-engorged macrophages in the arterial intima. Progression of such precursor lesions occurs secondary to an inflammatory process initiated by endothelial injury and dysfunction.³ Insufficient nitric oxide production results in increased adhesion and aggregation of platelets. Up-regulation in the endothelial expression of adhesion molecules and selectins leads to accumulation of monocytes and T lymphocytes. These cells become activated and produce growth factors, cytokines, and chemokines. Smooth-muscle cells migrate from the media into the intima and proliferate. In time, these lesions develop into raised fibrous plaques consisting of a fibrous cap covering a core containing necrotic material, lipids, and cholesteryl esters. This advanced plaque forms the basis onto which the complicated plaque develops, consisting of fissures, erosions, or ulceration. There has been increased interest in the role of monocytes and macrophages in the pathogenesis of plaque progression and rupture,⁴ which is related to thrombosis and/or embolism and clinical manifestations.

Atheromatous Embolization

Atheromatous embolization is a descriptive term for embolization of any atheromatous material. Atheroembolization refers to the dislodgement of vascular plaque material that contains cholesterol crystals, red blood cells, and fibrin.⁵ This “cholesterol emboli” syndrome consists of renal failure, skin lesions, blue toes, and neurologic manifestations. It may develop spontaneously (due to plaque rupture), follow the use of thrombolytics or anticoagulants,⁶ or result from arterial manipulation (during surgical procedures, cardiac catheterization, or insertion of an intraaortic balloon pump [IABP]).⁷ Disruption of vascular plaque results in the release of cholesterol crystals. These crystals cause downstream vascular obstruction and initiate an inflammatory process leading to lymphocytic and mononuclear cell infiltration. Biopsy specimens of affected organs such as skin or kidneys are usually diagnostic.

Plaque Morphology and Embolic Risk

Severe atherosclerosis of the ascending aorta appears to be the most important morphologic indicator of an increased risk of atheromatous embolization. The French Aortic Plaque in Stroke group identified a plaque thickness of 4 mm or greater as an independent predictor of recurrent embolization,^8,9 with an odds ratio of 13.8. Although ulceration and calcification occurred more frequently in plaques 4 mm or more in thickness, the presence of ulceration did not significantly increase the risk of vascular events. Absence of calcification, however, was associated with a significant increase in risk (relative risk, 10.3 compared with 5.7 for those with calcification). Another study reported an association between the presence of ulceration in aortic plaques and an increased rate of cryptogenic stroke.¹⁰ Ulceration and increased size of aortic plaques seem to be markers of severe generalized atherosclerosis and therefore predict a higher risk for thromboembolic complications.

Macroembolization and Microembolization

Emboli can be generally divided into macroemboli and microemboli. The former occlude arteries larger than 200 µm in diameter, whereas the latter result in occlusion of smaller arteries, arterioles, and capillaries.¹¹ The clinical manifestations of each vary. Whereas macroemboli may cause overt clinical presentations (e.g., stroke or peripheral ischemia), microemboli tend to be more occult in their manifestations of end-organ injury or dysfunction (e.g., renal injury, neuropsychological impairment). Their clinical impact depends on the number and nature of microemboli. Embolization may arise spontaneously or be related to vascular interventions and cardiovascular surgery.

Cerebral

As the prevalence of aortic atherosclerotic disease increases with age, so does the rate of atheromatous embolization. Postmortem studies indicate that it affects 20% of patients in their fifth decade, increasing to 80% in those in their eighth decade.¹² Emboli from the atherosclerotic aorta may result in stroke or transient ischemic attack, and the clinical manifestations of these conditions vary depending on the cerebrovascular territory affected; the middle cerebral artery is the most frequent site of arterial embolism. Stroke has profound effects; outcomes from acute stroke are measured in terms of survival, functional independence, and financial cost. Survival after stroke is significantly poorer than after myocardial infarction (MI) or most cancers and is the leading cause of disability in developed countries.¹³ When considered separately from other cardiovascular diseases, stroke ranks third among all causes of death, behind diseases of the heart and cancer. Its economic impact is huge, with 2009 estimated direct and indirect costs of stroke in the United States of $68.9 billion.

Cholesterol emboli are an important and frequently unrecognized cause of stroke.¹⁴ Microembolization is a recognized cause of more subtle, sometimes subclinical neurologic injury.^15,16 Most frequently this injury is manifested by subtle changes in cognitive function that may only be evident on detailed neuropsychological testing.^17,18 This more subtle impairment may appear trivial, but its importance has increased over recent years, particularly in patients undergoing cardiac surgery.¹⁹

Cardiac

Atherosclerotic cardiovascular disease is the leading cause of death in developed countries. Every year it results in over 19 million deaths worldwide, and coronary heart disease accounts for the majority of those.²⁰ MI is a consequence of diseased coronary arteries as part of the overall systemic picture of atherosclerosis. Most acute coronary syndromes are due to plaque rupture. Distal embolization of cholesterol and atheromatous material may be important in the pathogenesis of some acute coronary syndromes.²¹ The occurrence of distal coronary embolization in the setting of acute coronary syndromes has been followed using serum levels of cardiac troponins to detect small degrees of myocardial necrosis. The clinical importance of distal coronary embolization, as defined by serum troponins, is its predictive value for future cardiac events. Embolization following percutaneous coronary interventions is well recognized, and elevations in cardiac troponins are seen in up to 44% of patients undergoing intervention.^22,23

Peripheral

Peripheral emboli most frequently lodge in the lower extremities. Cholesterol atheroembolization can be subclinical or can otherwise result in systemic effects. While renal, neurologic, and cutaneous manifestations tend to dominate the clinical picture, involvement of most organs has been previously reported. Atheromatous material can be identified in the pancreas, intestine, and spleen. Symptoms and presentation depend on the site of dislodgement. Embolization into the renal arteries results in renal ischemia and can lead to renal impairment or failure.^24,25 In those cases, renal biopsy is diagnostic.²⁶

Involvement of the cutaneous vessels leads to livedo reticularis and the “blue-toe” syndrome, whereas retinal emboli²⁷ result in visual symptoms. Other reported effects include small-bowel bleeding²⁸ and renal transplant failure.²⁹

X-Ray Angiography

X-ray angiography is an invasive procedure that allows assessment of the vascular lumen by providing a measure of the degree of stenosis and by identifying plaque disruption, thrombosis, and calcification. However, it provides no information about the vessel wall or the components of the atherosclerotic plaque. Despite that, angiography is still regarded as the gold standard for imaging coronary, carotid, and peripheral arterial disease.³⁰

Surface and Transesophageal Ultrasonography

Measurement of carotid and aortic wall thickness as well as qualitative and quantitative assessment of atherosclerotic plaques can be determined using ultrasonography. The North American Symptomatic Carotid Endarterectomy Trial and the Asymptomatic Carotid Artery Stenosis Study have shown that the degree of stenosis and its hemodynamic consequences are important in the development of stroke.^31,32 High-resolution, real-time B-mode ultrasound with Doppler flow imaging is currently considered the modality of choice in imaging the carotid arteries.³³

With respect to screening, carotid intima-medial thickness (CIMT) measured by B-mode ultrasound represents a risk factor and a marker for vascular disease risk that most accurately represents subclinical vascular disease but not plaque formation or atherosclerosis per se. Epidemiologic and clinical trial evidence, digitization, and standardization have made CIMT a validated and accepted marker for generalized atherosclerosis burden and vascular disease risk.³⁴ Numerous studies have linked CIMT and CIMT progression with prevalent symptomatic coronary and cerebrovascular disease. Furthermore, CIMT is a predictor of coronary events and stroke as well as all-cause mortality.^35,36 The American Society of Echocardiography Carotid Intima-Media Thickness Task Force recommends the use of CIMT measurement by ultrasound in intermediate-risk asymptomatic patients, with a goal of predicting future coronary heart disease events.³⁷

Transesophageal echocardiography (TEE) is a quick, safe, and minimally invasive procedure that can be used in different settings ranging from the operating theatre to the bedside.³⁸ It is regarded as the procedure of choice in detection, assessment, and characterization of thoracic aortic atherosclerosis. Imaging using the transthoracic approach is also possible but at the expense of significant loss of resolution when compared to the transesophageal technique. TEE can reliably detect intimal thickening, ulceration, calcification, and the presence of mobile components within the aortic plaque. As outlined earlier, the French Aortic Plaque in Stroke investigators used TEE to assess aortic plaque thickness in patients with stroke and reported that increased plaque thickness imparted a significant increase in stroke risk.^8,9 Katz and colleagues used a 5-grade ranking system for the severity of aortic atherosclerosis, assessed using TEE in 130 patients undergoing cardiac surgery with cardiopulmonary bypass: grade 1, normal aorta; grade 2, flat intimal thickening; grade 3, protruding atheroma in the aortic lumen (<5 mm); grade 4, protruding atheroma (>5 mm); and grade 5, atheroma with a mobile thrombus.³⁹ Patients with grade 5 lesions were at highest risk of stroke. Logistic regression identified aortic arch atheroma as the only variable that was predictive of stroke, with an odds ratio of 5.8. Another study of 315 coronary artery bypass graft (CABG) patients undergoing intraoperative TEE also reported a significant increase in the risk of stroke in patients with aortic arch intimal thickening of greater than 5 mm.⁴⁰

It is no surprise that patients with the highest-risk carotid lesions also have high-risk aortic plaques. Assessment of the carotid arteries as well as the aorta is prudent in the investigation of atherosclerotic patients who have suffered embolic events.

Intraoperative Epiaortic Ultrasound

Epiaortic ultrasonography involves intraoperative imaging of the ascending aorta using a sterile-sheathed transducer. This technique is noninvasive and has been used in the context of cardiac surgery to detect areas of ascending aortic atherosclerosis.⁴¹ It allows modification of the surgical technique in an attempt to reduce potential embolic complications.⁴² The main disadvantage of this technique is suboptimal imaging of the aortic arch. Intraoperative epiaortic ultrasound can therefore be used to complement the information on the aortic arch obtained by TEE.

Transcranial Doppler

Transcranial Doppler (TCD) ultrasonography can be used to detect and quantify cerebral microemboli. Ultrasound probes are placed bilaterally on the temple, overlying the middle cerebral vessels. Emboli cause an increase in the reflected ultrasound, causing high-intensity transient signals (HITS). These HITS are the footprints of microemboli, which may consist of air, fat, atheromatous material, or platelet-fibrin emboli. In addition to detecting cerebral microemboli, TCD can be reliably used to assess cerebral vasomotor reactivity and autoregulation, to document the circle of Willis functional status, and to identify cerebral hypo- and hyperperfusion, recanalization, and re-occlusion.⁴³

TCD can reliably detect HITS intraoperatively and has been used extensively in the context of cardiac and carotid surgery. During cardiac surgery, microemboli can be detected following intraoperative aortic manipulation (aortic cannulation and application and removal of aortic cross-clamp) as well as during cardiopulmonary bypass.⁴⁴ HITS have also been identified in patients with symptomatic carotid artery stenosis,⁴⁵ patients with prosthetic heart valves,⁴⁶ and those with aortic atherosclerosis.⁴⁷ They are a common phenomenon in patients with acute stroke, and their detection may continue for several days after the acute event. Their presence is a significant independent predictor of early recurrence of stroke.⁴⁸

TCD is a simple, user-friendly technique that can be used at the patient bedside as well as in the operating room. It can provide valuable information intraoperatively on cerebral blood velocity, which is closely related to flow, and microembolic load, allowing for intraoperative technical modifications. A major limitation is an inadequate acoustic window in 5% to 20% of individuals.⁴⁹ Another limitation is the ability to reliably reject artifacts (closely resembling microembolic signals and generated by movement) and/or to distinguish between gaseous and particulate microemboli. With multirange, multifrequency Doppler systems, automatic artifact rejection and differentiation between solid and gaseous microemboli has become possible with high sensitivity and specificity.^50,51 We have reported a significant reduction in intraoperative cerebral microembolism as well as a reduction in the proportion of solid microemboli, with avoidance of cardiopulmonary bypass and minimizing manipulation of the ascending aorta during cardiac surgery.^44,52

An exciting recent development with TCD ultrasonography is its use therapeutically in the treatment of stroke. This involves the use of TCD ultrasound to augment the effect of fibrinolysis and has been shown to at least double the chance of early complete arterial recanalization.⁵³

Computed Tomography

Computed tomography (CT) can be used in imaging the aorta and quantifying aortic wall calcification. Contrast-enhanced CT has been proposed as a valuable method for following the progression and regression of atherosclerotic disease.⁵⁴ The main advantage over TEE is the ability to completely image the thoracic and abdominal aorta. Other advantages of CT include its minimally invasive nature, its wide availability, and its provision of images of lumens of arteries and of calcium. Disadvantages include radiation and contrast exposure with potential for renal damage, limiting its use in asymptomatic populations.

Coronary multidetector CT angiography (MDCTA) can be used in identifying patients at a particularly high risk of dying suddenly or suffering a nonfatal MI. It provides information on coronary artery stenosis as well as an estimate of calcification, coronary artery calcium (CAC). The latter is related to multiple risk factors of coronary artery disease. The importance of CAC screening lies in its potential ability to increase predictive power for future events.^36,55

Magnetic Resonance Imaging Techniques

Magnetic resonance imaging (MRI) has emerged as a leading noninvasive imaging modality for atherosclerotic disease. It can be used to image atherosclerotic plaques in aortic, carotid, peripheral, and coronary arterial disease.^56,57 Its major strengths rest in its ability to determine plaque morphology. Using a range of techniques, MRI can provide valuable information on the composition of the atherosclerotic plaque by identifying the three main factors that determine plaque stability: (1) presence of a lipid core, (2) thickness of the fibrous cap, and (3) inflammation within the cap. MRI allows identification of high-risk unstable plaques and thus guides intervention and therapy.⁵⁸ Some studies have documented regression of atherosclerotic lesions on MRI in patients treated with statins.⁵⁹ Magnetic resonance angiography has a high sensitivity and specificity and can be used to image the aorta, carotid, renal, and other peripheral vessels. Evolving magnetic resonance techniques include intravascular⁶⁰ and transesophageal⁶¹ MRI. MRI is therefore a noninvasive, powerful tool with high spatial resolution that can be used clinically without exposing the patient to the risks of ionizing radiation.

Cardiac Surgery

Stroke, transient ischemic attack, and peripheral embolization are potential complications following cardiac surgery. Atheroembolism results in a variety of clinical manifestations and can be fatal in about 20% of patients.⁶² Stroke affects less than 2% of CABG patients, and this is further increased in those undergoing open-heart procedures.⁶³ The risk of perioperative stroke increases with advancing age, and those with concomitant cardiovascular risk factors are at highest risk.⁶⁴ In addition, it has been shown that the female gender is independently associated with a significantly higher risk of perioperative stroke.⁶⁵ Embolization from the atheromatous aorta is the single most important etiologic factor for stroke. This risk arises during intraoperative manipulation of the aorta, including cannulation for cardiopulmonary bypass, application and removal of aortic cross-clamp for administration of cardioplegia, and the use of side-clamps for anastomosis of the proximal end of the graft to the aorta.⁶⁶ Roach et al. showed that atherosclerosis of the ascending aorta is the strongest independent predictor of perioperative stroke, with an odds ratio of 4.5.⁶⁷

The functional impact of stroke is enormous; adverse overt cerebral outcomes after cardiac surgery are associated with a 10-fold increase in mortality and substantial increases in the length of hospitalization and the use of intermediate- or long-term care facilities. New diagnostic and therapeutic strategies must be developed to lessen such injury.