Thursday, January 12, 2012

Carotid artery disease

Author : Emile R. Mohler, M.D.
Director, Vascular Medicine University of Pennsylvania health system


Carotid disease is a vascular disorder of the arteries in the neck that carry blood to the brain.  The most common problem that develops in the carotid artery is a cholesterol plaque.  Rarely, the carotid arteries can tear, resulting in a carotid dissection.

Carotid artery anatomy 

The carotid arteries are medium sized arteries that originate from the aorta, the main blood vessel that emanates from the left side of the heart (Figure 1).  On the right side, the carotid forms from the innominate artery off the aorta whereas on the left it arises directly from the arch of the aorta.  The vertebral arteries (Figure 1) also carry blood to the brain and arise in the back of the neck from a neck artery called the subclavian.

What is a carotid plaque and how does it develop?

The carotid artery has three layers – the intima, the media, and the adventitia.  The layer closest to blood flow is the intima (Figure 2).  The arterial wall becomes thickened when cholesterol builds up in the intima and may protrude into flowing blood. This thickened area of the artery is called a plaque.  Atherosclerosis is the medical term used to describe the buildup of cholesterol and fibrotic tissue in the arterial wall.  The lining of an artery releases molecules that keep blood moving and inhibit a blood clot from forming.  However, an atherosclerotic plaque may rupture or ulcerate causing development of blood clot in the carotid artery.
 The most frequent cause of a blood clot travelling to the brain from the carotid is an atherosclerotic plaque.  Plaques also contain white cells called macrophages that absorb the cholesterol.  The development of carotid atherosclerotic plaque results from both genetic and environmental influences (see below for causes).  Patients with carotid stenosis (narrowing) are at higher risk for an ischemic stroke.  Other more rare conditions that do not involve cholesterol such as fibromuscular dysplasia and vasculitis may produce carotid blockage.

How does a stroke result from a carotid plaque?

A stroke, also known as a cerebrovascular accident, is a term that describes a problem within the vascular system in the brain that may cause permanent damage.  There are two types of stroke, one where the blood supply is blocked, called an ischemic stroke, and the other is bleeding into the brain, called a hemorrhagic stroke.  There are approximately 750,000 strokes in the United States per year.
 A stroke due to carotid disease results when a blood clot forms on the cholesterol filled plaque. The clot breaks off and then travels from the carotid artery up into the middle cerebral artery, a major supplier of blood to the brain, and blocks blood flow.  The resulting diminished blood flow deprives the brain of oxygen which results in brain cell death. Ischemic stroke may manifest as paralysis, slurred speech, or other neurological problems.

Are some plaques more dangerous than others?

Studies indicate that plaques with high cholesterol and high white cell content are more dangerous than plaques which are highly calcified.  One study examined plaques after surgical removal and reported that the plaques that were filled with sheets of calcium, and even bone, were less likely to cause a stroke.1  It is thought that the heavily calcified plaques are less likely to rupture and develop a blood clot.

How is carotid disease diagnosed?

The initial study to evaluate carotid disease is a carotid ultrasound.  This technique utilizes sound waves to view the carotid artery.  A small amount of saline gel is placed on the neck and an ultrasound probe is used to visualize the carotid arteries (Figure 3).  Ultrasound images may reveal plaque.  The amount of blockage (stenosis in medical terminology) is determined by the velocity of blood flow through the artery; the higher the velocity, the higher the amount of stenosis or narrowing.  One ultrasound-based technique evaluates the thickness of the carotid artery to determine if there is increased risk for stroke or heart attack (Figure 4). carotid artery intimal and medial layer thickness is measured, so called IMT, and a value generated and compared to individuals of similar age.2 carotid IMT value of > 1mm is considered high risk at any age.

What are the risk factors for carotid disease?

The major non-modifiable risk factors for ischemic stroke include: age, inherited pre-disposition, sex, and race (more common in men and in African Americans). The modifiable risk factors include: hypertension, diabetes mellitus, cigarette smoking, elevated homocysteine, and cholesterol (especially in hypertensives).

What is the treatment for carotid disease?

The treatment for carotid atherosclerotic disease includes medical intervention (management of atherosclerotic risk factors, antiplatelet medication) and revascularization (opening the artery) for appropriate candidates.

What medications are available to treat carotid disease?

In the late 1980s to the mid 1990s when most of the carotid surgery studies were being done, the best medical therapy was aspirin.  Since then, new cholesterol lowering drugs and blood pressure control drugs have been developed that favorably impact on the carotid disease process.
High Blood Pressure Medication
High blood pressure is a known risk factor for a stroke, as approximately 60% of strokes are attributed to hypertension.  Blood pressure control is extremely important to prevent strokes.  One study called the Systolic Hypertension in the Elderly Program (SHEP) evaluated blood pressure control in patients over age 60 years.3  When compared with a placebo (inactive pill), there was a 36% reduction in stroke incidence over 4.5 years of follow-up with medication.
Antiplatelet Medication
A blood clot in the carotid artery is formed in part due to an aggregation of platelets on top of the atherosclerotic plaque.  The first-line treatment of stroke prevention in those who have had a stroke is antiplatelet medicine such as aspirin, clopidogrel (Plavix), or the combination of dipyridamole and aspirin (Aggrenox).  The data from an analysis of multiple antiplatelet studies indicate that the risk of a second stroke decreases by approximately 25%.4
These drugs act by blocking platelets from adhering and reduce the risk of a carotid thrombus (clot).  The data regarding treatment with an antiplatelet agent to prevent a stroke from occurring in those who never had a stroke is not as strong.  There are high-risk groups such as those with diabetes mellitus who will likely benefit from antiplatelet drug to prevent stroke.
Cholesterol Lowering Medication
High blood pressure is more of a risk factor for a stroke than high cholesterol, but recent data indicate that lowering high cholesterol reduces progression of carotid plaque and stroke.5  The SPARCL study used an HMG CoA reductase inhibitor (statin drug) to lower cholesterol and compared it with placebo in those with a stroke or mini-stroke (transient ischemic attack).6  After a follow-up of 4.9 years, the statin group had reduced incidence of fatal or nonfatal stroke.  Interestingly, the statin group also had a reduction in heart attacks.

What is the surgical treatment for carotid disease?

The surgical treatment for severe carotid disease is removal of the plaque by a carotid endarterectomy. The surgical removal of an atherosclerotic plaque has been proven safe and effective in numerous randomized clinical studies for symptomatic patients (Table 1). 
Table 1.  Amount of Stenosis and Benefit from Surgery
Percent of Stenosis
Benefit of Endarterectomy
70% Stenosis or greater
50-69% Stenosis
50% Stenosis or less
The North American Symptomatic Carotid Endarterectomy Trial (NASCET) showed that symptomatic patients with more than a 70% diameter carotid artery stenosis had, at two years, a 9% risk of stroke after carotid surgery compared with a 26% risk in patients with the best medical intervention.7  The benefit remained after seven years of follow-up. Patients with a 50-69% stenosis had a marginal improvement from surgery and those with less than 50% stenosis did not benefit from surgery, as determined by a five-year follow up.  Some of the complications associated with carotid endarterectomy in the NASCET trial included: perioperative wound complications, cranial nerve injury, and cardiovascular complications.

Endarterectomy in asymptomatic individuals
Large clinical trials evaluating asymptomatic patients with carotid atherosclerosis and ≥ 60% stenosis, such as the Asymptomatic Carotid Atherosclerotic Study (ACAS), found a risk reduction of 50% over five years with carotid surgery compared with medical therapy with drugs.  The benefit of carotid endarterectomy was realized approximately two years after surgery.  This result was obtained with a very low surgical complication rate of 2.3%, half of which were due to cerebral angiography (contrast dye injection into the arteries of the brain).  A higher surgical complication rate that includes stroke, infection, and reocclusion of the artery, will delay the realized benefit from an endarterectomy.  Asymptomatic patients with ≥80% carotid stenosis are likely to benefit from surgery if their life expectancy is five years and if the operating surgeon has a post-operative complication rate less than 3%.  Of note, current data indicate that the benefit of carotid endarterectomy in asymptomatic patients is lower in woman compared with men.

What are the complications of carotid surgery?
Potential complications associated with vascular surgery include stroke, nerve damage, and infection.  Symptomatic patients have a higher post-operative complication rate than asymptomatic patients.  Some patients may re-occlude the artery due to scar tissue, so called recurrent carotid artery disease.  The rate of repeat surgery for recurrent carotid artery stenosis after endarterectomy has been under 10%.  For patients who underwent a repair of the carotid artery with a vein or patch graft, the recurrent stroke rate is under 2% for individuals with greater than 70% stenosis.  In one study, asymptomatic patients did not benefit from endarterectomy if they had a completely occluded carotid artery on the opposite side of the neck.

Percutaneous carotid revascularization (Angioplasty & Stenting)
There are two types of operations, the traditional one using a scalpel, and a relatively more recent technique where a puncture is done through the skin with a needle called a percutaneous approach.  In this latter method, a catheter (plastic tube) is inserted through the needle and into the artery being treated.  Percutaneous carotid artery revascularization has emerged as an alternative therapy to surgical carotid endarterectomy for the treatment of carotid stenosis.8  The percutaneous approach is attractive given that it is a less-invasive approach that may not have the complications associated with surgical treatment.
The first percutaneous method developed to treat artery blockages involves passing a catheter with a balloon attached into the artery and inflating the balloon to squeeze the plaque against the wall and open the vessel.  Carotid artery balloon angioplasty was first performed in 1979 and a clinical study of carotid angioplasty (CAVATAS) showed, at three years, there was no difference in the rate of stroke compared with surgery.9  However, percutaneous procedures are not without risk.  Catheter manipulation is associated with death and complications which include the potential for dislodging a plaque during the procedure resulting in embolic stroke.
The early studies of percutaneous carotid angioplasty were directed at lesions with lower risk of embolic complications, such as early carotid restenosis and fibromuscular dysplasia.  The stroke rates attributed to the procedure range from 1.4 to 12%.  During long-term follow-up, restenosis of the internal carotid artery is reported to occur in up to 15% of patients and dissection in 5% of patients.
A second percutaneous method involves placing a metallic stent in the artery after the balloon angioplasty, in order to keep the artery open.  A carotid stent is preferred to angioplasty, as it can reduce the risk of threatened vessel closure due to a dissection and, over the long-term, restenosis.  Newer stents are coated with medication to further reduce the risk of carotid restenosis.  Of note, there are ongoing clinical trials to evaluate if the benefit of a lower restenosis rate is not offset by later clotting in the artery.

Comparison of percutaneous versus surgical carotid revascularization
Clinical trials comparing angioplasty and stenting with carotid endarterectomy have yielded insight into both the success rate and complication rate of both procedures.  There is conflicting data on the efficacy of angioplasty and stenting compared with endarterectomy.  Two initial trials that did not use embolic protection (see below) indicated a worse outcome with the percutaneous technique.  One such study, the WALLSTENT Study, showed a one-year, ipsilateral stroke rate higher in the percutaneous group compared with surgery (12.2% versus 3.6%).  Other trials, such as the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS) and a separate randomized trial in a community hospital found that both treatments had similar major risks and effectiveness.

Carotid protection devices against stroke
In order to reduce complication rates from carotid angioplasty and stenting, protection devices were developed to reduce embolic debris traveling to the brain.  The complication that is trying to be avoided is dislodging of small bits of plaque lining the blood vessel during the procedure which could travel in the blood stream and lodge in a brain artery causing a stroke. Filtering devices or “damming” devices are temporarily inserted either immediately at the procedure site, or somewhat upstream to catch the debris and filter it out of the body- Each of these approaches had some disadvantages but these protection devices clearly reduce complication rates.

Clinical Trials using embolic protection devices
A large trial employing distal protection to evaluate against complicating stroke was the Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE).10  High-risk patients were defined as having at least one of the following:
·         Contralateral carotid artery occlusion
·         Radiation therapy to the neck
·         Previous carotid endarterectomy with recurrent stenosis
·         Difficult surgical access, contralateral laryngeal nerve palsy
·         Severe multiple lesions in the carotid artery
·         Heart failure
·         Coronary artery bypass grafting or open heart surgery within 6 months
·         Myocardial infarction (heart attack) 1 day to 4 weeks prior
·         Angina (chest pain from blocked heart artery) at low work load or unstable angina
·         Severe pulmonary disease
·         Age greater than eighty years
A total of 334 patients who had either a symptomatic carotid-artery stenosis of ≥ 50 % or an asymptomatic stenosis of at least 80 % were treated with carotid-artery stenting or surgical endarterectomy.11  The primary end-point of the study was death, stroke, or heart attack after the intervention, which occurred in 20 patients randomly assigned to undergo carotid artery stenting and in 32 patients randomly assigned to undergo endarterectomy.  Both of the groups in the SAPPHIRE Study had a relatively high risk of complications at 30 days, which exceeded the ≤ 3% recommended as the maximum rate according the American Heart Association guidelines.12  Other trials are underway to further define the benefit and risk of percutaneous versus surgical carotid revascularizationThe Food and Drug Administration has approved a coronary stent for use in carotid arteries.

What are the Complications From a Carotid Stent?

Potential complications due to carotid stenting include: bradycardia (slowed heart rate), hypotension (low blood pressure), and minor or major stroke. Hyperperfusion syndrome is a relatively uncommon secondary result of carotid endarterectomy, which manifests as headache on the same side as the revascularized artery and may be accompanied by focal seizures and intracerebral hemorrhage. There are few data regarding prevalence of hyperperfusion syndrome after carotid stenting.

Who Should Have a Carotid Stent?
Clinical trial data continues to accumulate regarding the efficacy and safety of carotid stenting.  The current data indicates that the following conditions favor carotid stenting with embolic protection over surgical endarterectomy:
  • High-risk patients where anesthesia and surgical repair would pose excess risk such as with congestive heart failure, uncontrolled angina pectoris, and severe obstructive pulmonary disease.
  • Anatomic characteristics that increase risk of carotid endarterectomy such as previous radiation therapy to the neck, previous radial neck dissection, restenosis after endarterectomy, and contralateral laryngeal palsy.


     (1)   Hunt JL, Fairman R, Mitchell ME et al. Bone formation in carotid plaques: a clinicopathological study. Stroke 2002 May; 33(5):1214-9.
     (2)   Roman MJ, Naqvi TZ, Gardin JM, Gerhard-Herman M, Jaff M, Mohler E. Clinical application of noninvasive vascular ultrasound in cardiovascular risk stratification: a report from the American Society of Echocardiography and the Society of Vascular Medicine and Biology. J Am Soc Echocardiogr 2006 August; 19(8):943-54.
     (3)   Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group. JAMA 1991 June 26;265(24):3255-64.
     (4)   Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy--I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994 January 8;308:81-106.
     (5)   Mohler ER, III, Delanty N, Rader DJ, Raps EC. Statins and cerebrovascular disease: plaque attack to prevent brain attack. Vasc Med 1999;4(4):269-72.
     (6)   The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-Dose Atorvastatin after Stroke or Transient Ischemic Attack. The New England Journal of Medicine 2006 August 10;355:549-59.
     (7)   Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med 1991 August 15;325(7):445-53.
     (8)   Mohler ER, III. Carotid stenting for atherothrombosis. Heart 2007 September;93(9):1147-51.
     (9)   Endovascular versus surgical treatment in patients with carotid stenosis in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS): a randomised trial. Lancet 2001 June 2;357(9270):1729-37.
   (10)   Yadav JS. Carotid stenting in high-risk patients: design and rationale of the SAPPHIRE trial. Cleve Clin J Med 2004 January;71 Suppl 1:S45-S46.
   (11)   Yadav JS, Wholey MH, Kuntz RE et al. Protected carotid-artery stenting versus endarterectomy in high-risk patients. N Engl J Med 2004 October 7;351(15):1493-501.
   (12)   Sacco RL, Adams R, Albers G et al. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke: co-sponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of this guideline. Circ 2006 March 14;113(10):e409-e449.