Diabetes, Low HDL, High Homocysteine Levels Predict Poorer Stroke Recovery

November 29, 2007 — Vascular risk factors associated with metabolic stress, including diabetes, low levels of high-density lipoprotein (HDL) cholesterol, and elevated levels of homocysteine predict slower stroke recovery, new research suggests.
The study found that individuals with diabetes, low levels of HDL cholesterol, and high levels of homocysteine who have had a mild to moderate ischemic stroke were twice as likely as their counterparts without these conditions to have poorer cognitive function and greater disability after a stroke.
The researchers also found that recovery was most difficult in individuals older than age 57 years with high total plasma levels of homocysteine.
"The first thing we realized [from the results] is that the dominant influence in the study is recovery, so that in general patients tend to improve after a stroke. However, there were certain factors that significantly slowed the effects of natural recovery, such that not everyone was recovering at the same rate," the study's lead author George C. Newman, MD, PhD, of the Albert Einstein Healthcare Network in Philadelphia, Pennsylvania, told Medscape Neurology & Neurosurgery.
The study is published in the November 27 issue of Neurology.
Mechanism Unclear
Although the mechanism by which these factors impede recovery is not clear, Dr. Newman speculated that oxidative stress may impair endothelial function in the central nervous system or directly affect neuronal function by a complex interaction of several metabolic and inflammatory pathways.
The study is a post hoc analysis of the Vitamin Intervention for Stroke Prevention (VISP), a randomized controlled trial designed to determine whether lowering total plasma levels of homocysteine with large doses of folic acid, pyridoxine, and vitamin B12 would reduce the incidence of recurrent stroke or myocardial infarction.
The original study showed no impact of moderate reductions of levels of homocysteine with vitamin supplementation on recurrent stroke, myocardial infarction, or death at 2-year follow-up. However, the study did establish elevated levels of homocysteine as a vascular risk factor.
"We know it was possible to lower serum homocysteine through large doses of B12, B6, and folate, so the question was would this reduce the risk of heart attack and stroke. The answer was no. The interpretation of this is that it is not the homocysteine itself that injures the blood vessels but that it is a marker for some other process that increases heart attack and stroke risk," said Dr. Newman.
Using the information from the VISP database, the investigators in the current analysis examined the hypothesis that vascular risk factors associated with oxidative stress were also associated with a slower recovery of cognitive function after a stroke.
Rich Database
To conduct the post hoc analysis, Dr. Newman's team mined the VISP trial data, which includes information on 3680 men and women older than age 35 years who have had a mild to moderate ischemic stroke within 90 days of trial enrollment and a fasting level of homocysteine greater than the 25th percentile for patients with stroke.
Participants were recruited from 56 centers in Canada, the United States, and Scotland between 1996 and 2003.
"We wanted to explore whether oxidative stress, which has been associated with vascular dementia in previous studies, would impede recovery of cognitive function following stroke," said Dr. Newman.
The primary outcome variables for the secondary analysis were changes in cognitive function and physical disability as measured by the Mini-Mental State Examination (MMSE) and modified Rankin Scale (mRS), respectively.
To establish potential risk factors for the 2 outcomes, researchers determined MMSE and mRS scores at baseline and at 1 and 2 years after stroke and compared them with vascular risk factor data collected during the 2-year study period.
The researchers looked at several factors that might have an impact on recovery including medication use, race, and age, among others.
Race Linked to Recovery
Medications that individuals took during the study had no impact on either cognitive or physical recovery. These medications included angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, beta-blockers, statins, antiplatelet medications, warfarin, and treatment with high-dose or low-dose study vitamins. However, said Dr. Newman, age and race did have an effect.
"Not surprisingly, the older people were, the more difficult it was for them to recover from stroke. However, what was a bit of a surprise was that individuals of nonwhite race had a slower return of their cognitive function."
He added that only African-American race was associated with slower recovery of physical function.
The 3 factors most strongly associated with poorer cognitive function and greater disability after a stroke were diabetes, low levels of HDL cholesterol, and high levels of homocysteine. The investigators also found the factors that influenced recovery of physical function.
According to Dr. Newman, it was not surprising that diabetes impaired physical recovery. However, he added, the magnitude of its effect in slowing recovery of cognitive function was somewhat unexpected but consistent with the oxidative stress hypothesis.
"Diabetes had a very strong influence on cognitive function. This is likely due to its damaging impact on the brain's capillaries and microvessels and that this small-vessel damage is slowing recovery," he said.
The study also showed that higher levels of HDL cholesterol were associated with better cognition, with no significant interaction with age.
Age, Homocysteine Interaction
High levels of homocysteine were also associated with slowed cognitive recovery but only in individuals older than age 57 years. This finding, said Dr. Newman, is consistent with those from the Framingham study, which found a negative effect of high levels of homocysteine on MMSE only in patients older than age 60 years.
"If I were to speculate, I would say this effect is due to the impact of the aging process on natural repair mechanisms and that homocysteine probably puts additional stress on these," said Dr. Newman.
According to Dr. Newman, the study's findings have important implications for clinical practice.
"Patients who have suffered a stroke, have diabetes, low HDL and high homocysteine are much less likely to recover and are also at increased risk of a second stroke. This is a high-risk population that justifies much more aggressive management of their risk factors," said Dr. Newman.
Unfortunately, said Dr. Newman, at this point there are no clear answers about how to manage homocysteine levels because the study showed no benefit of lowering them with folate or vitamin B supplementation. On the other hand, he said, it is important that patients are not B12 deficient.
The study was supported by the National Institutes of Health and the National Institute of Neurological Disorders and Stroke. Three of the study authors have received funding for the original VISP trial.
Neurology. 2007;69:2054-2062.