In this large prospective study, the strongest associations between diet and stroke risk were observed for the Western and Prudent patterns. The Western, Prudent patterns, and a high content of anti-oxidants in the diet all showed consistent associations after adjustment for confounding factors. The prudent and TAC showed high positive correlation, and a similar magnitude of negative association with stroke. When considering splines, the Western, Prudent and TAC showed dose responses which agreed with the quintile-based models.
Many studies have shown that a traditional, or prudent diet, is associated with lower rates of chronic and non-communicable diseases. The traditional Mediterranean diet is perhaps the best known diet associated with lower rates of chronic disease, and is defined by high consumptions of olive oil, nuts, fruit and vegetables, similar to the Prudent pattern identified in the E3N cohort. Recently, a large American study identified inverse associations between an alternate Mediterannean diet and a healthy plant diet, with cardiovascular disease (including stroke) and mortality35. In this study of E3N women, the prudent diet score showed positive correlations with TAC, and negative correlations with DII, suggesting that it is both rich in anti-oxidants, and anti-inflammatory, which may explain the strong observations. Anti-oxidants are associated with lower rates of high blood-pressure 23, a main risk factor for stroke. Dietary TAC has been previously inversely associated with stroke36,37, and other diseases such as coronary disease38, cancer28,39, and mortality40. In this population, a diet high in anti-oxidants was associated with a 29 % lower risk of stroke than a diet low in anti-oxidants, a similar magnitude to the prudent diet score. TAC has also been associated with outcome after stroke41. A systematic review 42 of cross-sectional and prospective studies concluded that intakes of carotenoids (an anti-oxidant common in yellow and red fruits and vegetables) are associated with a reduced risk of stroke, but that the mechanism was yet to be determined. Interestingly, TAC from coffee was not associated with the risk of stroke in this population. It is possible that this is due to residual confounding from other lifestyle factors associated with coffee consumption in the French population, such as smoking. Previously, coffee-TAC also showed null associations with hypertension in this cohort. Other prospective studies and meta-analyses have identified weak protective associations between coffee and stroke.
Western dietary patterns have been linked to higher risk of chronic and non-communicable diseases in many other studies. Consistent associations have been observed between western diets and stroke, coronary disease, and cardio-metabolic risk factors. The strong observations presented in this work add to the plethora of studies that support the idea that a western diet, with a high consumption of processed foods, and refined carbohydrates, is positively associated with stroke risk and should be considered a major risk-factor. The western diet is recognised as being highly inflammatory, and is associated with increased levels of inflammatory markers in human studies26,43. Similarly, the DII has been shown to be associated increased concentrations of inflammatory markers19, and a show positive associations with a number of diseases such as stroke, coronary disease and CVD mortality22,44, hypertension20,23, and cancer45,46. Only weak associations were observed between DII and stroke in our study of E3N women. Previously, we have observed only weak associations between DII and hypertension in this cohort20, suggesting a pro-inflammatory diet may not be a strong stroke risk-factor in this population.
Mechanisms
Ischaemic stroke is a heterogeneous entity for which one of the leading mechanisms is atherosclerosis of the arteries supplying blood to the brain, which can cause reduced lumen diameter, and eventually becoming blocked by thrombus. Reactive oxygen species (ROS) are implicated in the atherogenic pathway, and can cause the oxidation of low-density lipoprotein in the vascular wall. All cardiovascular risk-factors including dyslipidaemia, hypertension and diabetes are known to increase ROS production. Vascular cells contain various anti-oxidising enzymes in order to reduce the oxidative burden, but a diet rich in anti-oxidant molecules could independently reduce the availability of ROS through free radical scavenging47, and their negative effects. Flavonoids (a type of anti-oxidant) in particular have been shown to have blood pressure lowering effects, and can improve endothelial function48. Oxidative stress is also potentially implicated in the high-morbidity and mortality rate attributed to haemorrhagic stroke. For example iron deposited after haemorrhagic stroke can lead to the production of free radicals and oxidative stress, leading to nerve damage in the brain49. A diet high in anti-oxidants may enhance the antioxidant defence capacity following haemorrhagic stroke, and studies in animals have suggested that pre-treatment with certain antioxidants may reduce neurological deficit after haemorrhagic stroke50. Similarly, oxidative stress may be implicated another leading cause of stroke, cerebral small vessel disease51, and a diet high in anti-oxidants may reduce the risk of its development.
Chronic inflammation is a feature of aging, and is implemented in the route leading to ischaemic stroke through atherosclerosis and endothelial damage. Pro-inflammatory mediators can cause endothelial cells lining the blood vessels to adhere to white blood cells, eventually leading to the formation of plaques through the migration of smooth muscle cells from the media to the intima layer of the blood vessel 52,53. It has been demonstrated that certain foods, such as saturated fats 54,55, can increase the presence of inflammatory markers and endotoxins in the blood. Oxidised LDL can also trigger vascular inflammation56, leading to a cascading effect. If a diet with a high inflammatory potential was to raise levels of inflammatory mediators, this could potentially increase the rate of atherogenesis and lead to an increased risk of stroke. Local brain inflammation also increases following both ischaemic and haemorrhagic stroke 57, which can last for weeks following the stroke, and can lead to secondary damage of the brain. It is unclear if a diet leading to a high level of chronic inflammation may exacerbate this, or if a diet with a high anti-inflammatory potential may reduce the risk of secondary damage.
Strengths and Limitations
The main strengths of this study are the large cohort, long follow-up, detailed dietary assessment, and the use of only validated stroke cases according to a standardized procedure by trained stroke physicians. The main limitation is a relatively small number of stroke cases. The E3N cohort is at relatively low risk of diseases such as stroke, and other studies in low risk populations have also reported low incidence rates58. Moreover, as the ascertainment of incident stroke events is initially based self-reporting in questionnaires, we cannot exclude that minor strokes that have not led to a hospitalization may have been underreported, why may explain the relatively high proportion of fatal strokes. Data on fatal strokes was also available for a slightly longer period, until December 2010, which explains partly the relatively high fatal stroke incidence. Dietary data was self-reported, and could be subject to recall error, or bias. Since the study is observational, it cannot claim causality. One limitation with regards to considering dietary scores is that they cannot be used to give specific dietary advice, and are difficult to consider as a well-defined exposure. There is a possibility that the results are due to unmeasurable confounding, but this would be unlikely to explain the strong associations observed.
One potential reason for the slightly stronger associations from the prudent and western pattern could be that they are developed using data specific to the cohort (post-priori), whereas the DII and TAC are scored depending on specific food items (a-priori). For the TAC, we chose values based on an Italian database, as opposed to a Norwegian database, assuming that the Italian diet would be closer to the French. For DII, we made use of the majority of the foods used to calculate the score; however a small number had to be omitted as they were not present in our questionnaire. A-priori scores may benefit from corrections or calibrations depending on variations on the regional diet.