Intracranial Atherosclerosis a Major Stroke Risk in Whites

Pauline Anderson

February 17, 2014

Although intracranial carotid artery calcification (ICAC) is a recognized risk factor for stroke in African Americans and Asians, a new study shows that it is also an important cause of strokes among whites.

The association between ICAC and stroke shown in the study was independent of conventional cardiovascular risk factors and of calcification in other vessel beds, the researchers note.

"The results highlight the importance of physicians being aware that even their white patients can have intracranial calcification," study author Arfan Ikram, MD, PhD, Departments of Epidemiology, Radiology, and Neurology, Erasmus Medical Center, Rotterdam, the Netherlands, told Medscape Medical News.

"And if doctors are screening for any patient's cardiovascular risks, they should consider intracranial calcification," he added. "The study also underlines the importance of carrying out more research into treating ICAC or preventing it in the first place."

The study was published online February 17 in JAMA Neurology.

Rotterdam Study

The analysis included 2323 exclusively white participants in the Rotterdam Study, a prospective, population-based study investigating determinants of chronic diseases in the elderly. The mean age of study participants was 69.5 years, and 52.2 % were women.

Red circles indicate ICAC on CT scan.

During examinations at baseline, researchers verified through medical records that study participants did not have a history of stroke. Linkage of the study database with general practice files allowed for continuous monitoring of participants for incident strokes. These were verified by an experienced stroke neurologist and were categorized as ischemic or hemorrhagic.

Also through interviews, as well as physical examinations and blood samples, investigators collected information on cardiovascular risk factors, including obesity, diabetes, hypertension, hypercholesterolemia, and smoking.

Using nonenhanced computerized tomography (CT), researchers scanned the coronary arteries, aortic arch, extra-cranial carotid arteries, and intracranial carotid arteries. To measure atherosclerosis, they calculated calcification volume (expressed in number of cubic millimeters).

The researchers did not collect data on the size, location, or vascular territory of brain infarcts.

Although CT is an ideal tool to visualize calcification, which is a key property of atherosclerosis, and to calculate volume, this technology is limited in that it does not show the entire atherosclerotic process or atherosclerotic plaque. "This means that the true volume of atherosclerosis would likely be higher than the numbers we got," said Dr. Ikram.

And for intracranial arteries, the scans can only be useful when taken at the point where the artery enters the skull. "Ideally, you would visualize the artery further inside the skull, closer to the brain, where the artery is even smaller, but this can't be visualized on nonenhanced CT, as it becomes difficult to distinguish calcification," said Dr. Ikram.

He added that his "gut feeling" is that more calcification would have been picked up in areas closer to the brain, which would make ICAC an even more important stroke risk factor.

Stroke Risk

During a mean follow up of 6.1 years, 91 patients suffered a stroke (71 ischemic, 10 hemorrhagic, and 7 unspecified). The researchers found that larger ICAC volumes were associated with a higher risk for all strokes and for ischemic stroke. Adjustment for cardiovascular risk factors did not change these results.

After additional adjustment for ultrasound carotid plaque score and calcification volumes in other vessel beds, the association remained significant for all strokes (hazard ratio per increase of 1 standard deviation in ICAC volume: 1.43; 95% confidence interval [CI], 1.04 - 1.96), and for ischemic stroke (HR, 1.39; 95% CI, 0.98 - 1.99).

Arfan Ikram

There was no association between coronary artery calcification and stroke, after adjusting for ICAC. This, said Dr. Ikram, indicates that although coronary calcification may be a major risk factor for myocardial infarction, it is atherosclerosis of arteries in the brain that poses the main risk for stroke.

The results show that ICAC played a role in up to 75% of strokes. Dr. Ikram stressed that almost all strokes have more than 1 cause. "That 75% is the upper limit of the number of cases in which ICAC could have played a role; it doesn't mean it was the only cause," he said.

Other research shows that ICAC is involved in up to 50% of strokes in populations of African and Asian descent. But this does not necessarily mean that ICAC is less of a stroke risk factor in these populations, because different methodologies and definitions could have been used, the researchers note.

For aortic arch calcification and calcification in the extracranial carotid artery, ICAC played a role in up to 45% and 25% of all strokes, respectively.

The study measured calcification but not stenosis. Dr. Ikram stressed that he and his colleagues did not use atherosclerosis threshold levels because they were looking at contributing factors, not just a main cause.

"In other studies, researchers assign a stroke to the ICAC category only if the calcification exceeds a certain threshold," explained Dr. Ikram. "It's possible that ICAC in the artery that we studied was contributing to the stroke even though it didn't yet exceed a threshold."

The study could not determine whether the stroke risk centered on the atherosclerosis in a particular location or whether the calcification measurement taken in that location was indicative of the total atherosclerotic burden of the brain. Also, it is possible that it was not only the calcification that caused the stroke but also the combination of calcification and thromboembolism.

To illustrate this, Dr. Ikram used the example of a patient whose carotid artery is narrowed, but not enough to cause a stroke. That patient develops atrial fibrillation that leads to an embolus.

"That embolus gets stuck in that narrowed artery, and at that moment the patient suffers a stroke. The question is, is this stroke due to the embolus from the heart or is it due to narrowing of the arteries? Had that artery not been narrowed, the embolus would not have gotten stuck or would have dissolved or just passed through."

Atherosclerosis, of course, occurs in coronary as well as carotid and other arteries, with hypertension, diabetes, and high cholesterol among the risk factors for all atherosclerosis. It is not known whether some risk factors cause atherosclerosis only in carotid arteries, said Dr. Ikram.

Approaches to prevent ICAC are the same as those to reduce overall cardiovascular burden ― management of diabetes, control of hypertension, smoking cessation, and lowering of cholesterol levels, he said.

Trials investigating aggressive therapy with antithrombotics and surgery "have not shown a clear-cut pattern of what the best treatment is," said Dr. Ikram. Angioplasty in the large carotid artery has been shown to be effective, but it has been difficult to stent the smaller arteries, he said.

Reawakens Interest

This new study "raises important questions" about the role of calcification in the pathophysiology of intracranial atherosclerosis and should "reawaken interest" in intracranial atherosclerosis as a cause of stroke in white individuals, according to an accompanying editorial by Marc I. Chimowitz, MBChB, Medical University of South Carolina, Charleston, and Louis R. Caplan, MD, Beth Israel Deaconess Medical Center, Boston.

Dr. Chimowitz and Dr. Caplan noted, however, that the study does not establish a pathophysiologic, causal relationship between intracranial carotid calcification and stroke.

"Establishing this will require further prospective studies that correlate the association between intracranial arterial calcification and stenosis more clearly, identify atherosclerotic plaque features associated with calcification that may be associated with a high risk for distal embolism, and classify ischemic strokes that occur in patients with intracranial carotid calcification according to size, location (cortical or subcortical), vascular territory, and the coexistence of other potential causes," they conclude.

The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University, Rotterdam, the Netherlands; the Organization for Scientific Research; the Netherlands Organization for Health Research and Development; the Research Institute for Diseases in the Elderly; the Netherlands Genomics Initiative; the Ministry of Education, Culture, and Science; the Ministry of Health, Welfare, and Sports; the European Commission (DG XII); the Municipality of Rotterdam, as well as grants to individual investigators from the Alzheimer's Association, the International Alzheimer Research Foundation, and Erasmus Medical Center. No relevant financial relationships have been disclosed.

JAMA Neurol. Published online February 17, 2014. Abstract, Editorial

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