Flavanones in Citrus Fruit May Lower Stroke Risk

High intake of flavanones, a subclass of flavonoids found in the greatest concentrations in oranges and grapefruit, is associated with a 19% lower risk for ischemic stroke in women, a new analysis from the Nurses’ Health Study has shown. 

Although oranges are the best source of flavanones, North Americans tend to drink the juices of these fruits, lead author Aedín Cassidy, PhD, professor, nutrition, Norwich Medical School, University of East Anglia, Norwich, United Kingdom, told Medscape Medical News.

However, because commercial juices often contain sugar that may increase diabetes risk, she said, "our advice would be to eat more of the citrus fruits as opposed to product made from the citrus fruits."

Much of the recent evidence has focused on vitamin C, Dr. Cassidy added. "What we’re showing here is that there are other bioactive constituents in citrus fruits that may be responsible for this cardioprotective effect."

The results are published online February 23 in Stroke.

Cumulative Intake

This analysis used data from the Nurses’ Health Study on 69,622 participants who completed food-frequency questionnaires (FFQs) every 4 years. The 1990 FFQ was used as a baseline and included dietary intake data collected over the next 14 years.

Researchers used a state-of-the-art food database to examine 6 commonly consumed flavonoids: flavanones (including eriodictyol, hesperetin, and naringenin), anthocyanins, flavan-3-ols, flavonoid polymers, flavonols, and flavones. To arrive at intakes of individual compounds, they multiplied the sum of the consumption frequency of each food by the content of the specific flavonoid of a specified portion size. They averaged the intake for the current and preceding FFQ to determine the cumulative intakes (energy adjusted) for a given questionnaire cycle.

A diagnosis of stroke was confirmed from medical records. Researchers categorized strokes into ischemic, including embolic or thrombotic; hemorrhagic, including subarachnoid or intraparenchymal stroke; and unknown. Over the course of the study, 1803 strokes occurred; 943 of these were ischemic, 253 were hemorrhagic, and 607 were of unknown type.

The baseline median intake of total flavonoids (quintile 3) was 232 mg/d; the lowest intake (quintile 1) was 96.8 mg/d, and the highest (quintile 5) was 761.2 mg/d.

Tea was the main contributor to total flavonoid intake, with apples and oranges/orange juices also contributing significant amounts. Blueberries were the main source of anthocyanins, and oranges and orange juice were the main contributors to flavanone and flavone intake.

The study found that flavanone intake was inversely related to the risk for ischemic stroke. After adjustment for stroke risk factors, such as age, body mass index, physical activity, alcohol consumption, menopausal status, smoking, and history of type 2 diabetes, women in the top quintile of flavanone intake had a relative risk of 0.81 (95% confidence interval [CI], 0.66 - 0.99; P for trend = .04) compared with women in the bottom quintile. Further adjustment for calcium or magnesium intakes did not greatly alter the results.

Highest intake of citrus fruits/juices, which represent the main dietary source of flavanones, also tended to be associated with a reduced risk for ischemic stroke, with a relative risk of 0.90 (95% CI, 0.77 - 1.05).

Vitamin C

In this analysis, the addition of vitamin C to the statistical model did not substantially change the relationship between flavanones and ischemic stroke risk. "That’s not to say vitamin C isn’t important," stressed Dr. Cassidy. "We know that vitamin C may be one of the constituents responsible for the effect, but here’s some evidence that suggests that perhaps there are other components in citrus fruits that also may be responsible."

Animal and in vitro experiments have shown that the flavanones naringenin and hesperetin have anti-inflammatory and neuroprotective effects. "Some of these compounds can cross the blood-brain barrier so they are actually getting to the brain," said Dr. Cassidy.

There’s growing interest in the protective qualities of flavonoids, and with it progressively more sophisticated food databases that cover the wide range of flavonoids in the diet.

"About 5 years ago, people would have been publishing on flavonoids, but only on 2 or 3 of the subclasses," Dr. Cassidy noted. "Here we have an as-good-as-we-can-get database on 6 different subclasses. If you do large population-based study like this one, this can really help to generate hypotheses."

Using such a database can help further the understanding of possible mechanisms, dose effects, and optimal sources of various flavonoids, she added. The study found only a modest, and nonsignificant, inverse association between a higher intake of flavones and anthocyanins and the risk for total and ischemic stroke. There was no evidence of a link between flavones and stroke risk.

The lack of association between some flavonoids and stroke was somewhat surprising because there is evidence that dark chocolate, which contains these compounds, has positive effects on blood pressure, blood flow, and vascular and heart function, said Dr. Cassidy. "We assumed that they also may well have had effect on stroke risk, but we didn’t find that in these data sets."

The study found no association between any of the flavonoids and hemorrhagic stroke.

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