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Low HDL, High Homocysteine Predicts Poor Stroke Recovery For Diabetics

Dec 4, 2007

Patients with diabetes and 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.

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 researchers also found that recovery was most difficult in individuals older than age 57 years with high total plasma levels of homocysteine.

Lead author George C. Newman, MD, PhD, of the Albert Einstein Healthcare Network in Philadelphia, Pennsylvania, states that,  “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."

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. "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 researchers looked at several factors that might have an impact on recovery including medication use, race, and age, among others.

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.

High levels of homocysteine were also associated with slowed cognitive recovery but only in individuals older than age 57 years. 

Dr. Newman stated that, ."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." 

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.

Practice Pearls

  • Both MMSE and mRS scores improve within 2 years after a stroke in adults.
  • Predictors of poorer cognitive recovery after a stroke in adults include increased age, nonwhite race, recurrent stroke, diabetes mellitus, cortical lesions in the left hemisphere, lower levels of HDL cholesterol, and higher levels of homocysteine.

Neurology. Nov. 27,2007;69:2054-2062.

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