In this issue of the Journal of Hypertension the independent association between dietary cholesterol intake and blood pressure (BP) was tested in the INTERMAP study . The INTERMAP is a large cross-sectional study designed to determine which nutrients independently contribute to BP in ethnically representative adult samples (40–59 years) of men and women from four countries including the USA, China, Japan and the UK . The study has already provided important results on the magnitude and direction of the association between several nutrients and BP and a summary of their effect size is provided in Table 1. This editorial will discuss the relationship of dietary cholesterol intake with BP by comparing the magnitude of the effects to other nutrients as well as in the context of other dietary preventive strategies such as the Dietary Approach to Stop Hypertension (DASH diet) .
Why is it important to identify nutrients associated with blood pressure?
Elevated BP is a well established risk factor for coronary heart disease, end-stage kidney disease and stroke . The disease-risk association is continuous and not limited to hypertensive individuals as the effects of BP on the cardiovascular system are already detectable in nonhypertensive individuals . The high prevalence of hypertension in ageing populations in industrialized countries [6,7], and the high probability of fatal and nonfatal cardiovascular events associated with hypertension  call for immediate and effective interventions at all levels (public health, clinical, research) to minimize disability and prolong life expectancy. The primary prevention of essential hypertension is based on lifestyle modifications (dietary, physical activity, socio-behavioural) at the individual, group or community level . In contrast, pharmacological control of BP is necessary to manage resistant hypertension and is employed for the secondary and tertiary prevention of hypertension-related comorbidities [10,11]. Pharmacological therapies, however, require concomitant nutritional and lifestyle changes to maximize the efficacy of the treatments and minimize disease progression [10,11].
The dualism of dietary prevention of hypertension
The dietary prevention of hypertension has generally followed two separate strategies in the last two decades. The first focuses on the identification of single nutrients or foods associated with significant changes in BP . The second is a more integrated approach based on the simultaneous modification of several dietary elements such as to create distinctive dietary patterns associated with increased/decreased risk of hypertension . The two approaches have advantages and disadvantages. Dietary strategies based on single nutrients/foods can provide information about the size and direction of the effects of particular foods on BP which can be linked to specific physiological mechanisms. The main limitation, however, is that for most nutrients effect sizes are small to moderate (1–5 mmHg), with dietary manipulation of salt intake being notoriously more effective in inducing a larger decrease in BP than any other intervention . The feasibility of these strategies also depends on the direction of the dietary changes. For example, if the objective is a reduction in nutrient intake (i.e. saturated fat, salt) multiple dietary changes may be necessary in order to attain the desired change in intake. If the objective is an increase in nutrient then intake-targeted dietary modifications and/or supplementations could be implemented. However, the simultaneous changes of different food components may interfere with the physiological understanding of the nutrient–BP relationship, which is usually overcome by statistical adjustments.
The DASH diet is the most recognized composite dietary strategy for the prevention of hypertension . The diet is based on an increased consumption of fruit and vegetables, low-fat dairy products and nuts. The cumulative effect of these dietary modifications on nutrient intake include an increase intake in fibre, essential fatty acids, antioxidants, complex carbohydrates, potassium and a reduction in saturated fat, cholesterol, sodium and simple sugars. In addition to these nutritional components, an increase in inorganic nitrate intake has been suggested to contribute to the beneficial effects of the DASH diet .
The efficacy and effectiveness of the DASH diet has been tested in both research and community settings [3,14]. Significant changes in BP have been reported which, in some sub-groups (hypertensive patients), are comparable to pharmacological interventions . The dietary pattern strategy is often associated with more beneficial changes in BP compared to the manipulation of single dietary components . However, the nutrient-specific physiological mechanisms underpinning these changes are more difficult to dissect as BP changes are probably related to small, additive effects of simultaneous changes in individual nutrients.
Where does the INTERMAP study fit in this preventive scheme?
The overall aim of the INTERMAP study was to examine the association between single nutrients and BP , and the results presented by Sakurai et al.  were focused specifically on the effects of dietary cholesterol intake on BP. The authors found that dietary cholesterol was associated with an average increase of 1 mmHg in systolic BP in hypertensive patients whose cholesterol intake was 2 SD above mean intake . A minimal, not significant effect was observed for diastolic BP. The association did not substantially change if the analysis was conducted in nonintervened individuals [not on a special diet, not consuming nutritional supplements, no diagnosed cardiovascular disease (CVD)/diabetes, not taking medication for high BP, high cholesterol, CVD or diabetes) . A greater effect size was instead observed in nonhypertensive individuals , which could be explained by a reduced health awareness of this sub-group, therefore making them more likely to adopt less healthy dietary and lifestyle habits. These could have potentially widened the variability in dietary cholesterol intake and BP levels and increased the strength of the association. The finding may be important for the development and implementation of prevention strategies taking into consideration the prevention paradox model for the prevention of chronic diseases .
The contribution of dietary cholesterol to BP levels is largely unexplored as recently highlighted in the American Society of Hypertension report on Dietary Prevention of Hypertension . Only two studies (one cross-sectional , one longitudinal ) have attempted to address this question and both found a statistically significant association of dietary cholesterol with BP. The INTERMAP study has provided unique and more accurate information on the potential effect size of dietary cholesterol intake on BP . However, a major drawback of the INTERMAP study has been the inability to ascertain the direction of the causality of the association and therefore the link between dietary cholesterol intake and BP remains to be tested in prospective, controlled investigations.
How does cholesterol intake compare to other nutrients?
Dietary cholesterol, animal protein and total protein intake (in women only) [1,20] are the only dietary factors in the INTERMAP study to be associated with an increase in BP. Other nutrients investigated including starch , iron , glutamic acid , polyunsaturated fatty acids [24,25], phosphorous  were all associated with a decrease. The magnitude of the effect of dietary cholesterol on systolic BP is lower than dietary iron, glutamic acid and phosphorous and comparable to vegetable protein intake. The results, together with the direction of the association, are described in Table 1.
The effect size of dietary cholesterol on BP is modest and unlikely to have a significant impact on BP control at individual level. The authors rightly argued in their conclusions that simultaneous changes in several nutrient intake may impact on cardiovascular risk at population level by shifting the distribution of BP towards lower levels . However, effects on BP of simultaneous changes in nutrients are sub-additive and not cumulative and the magnitude of these simultaneous nutrient changes remains to be tested. Importantly the INTERMAP study can be considered as the benchmark for these future studies by providing experimental data on which research protocols can be powered to confirm the magnitude and direction of individual and additive nutrients' effects on BP.
Could fructose and inorganic nitrate intake be potential confounders?
The nitric oxide pathway was identified by the authors as the most plausible physiological mechanism behind the relationship between dietary cholesterol intake and BP . The plausibility is confirmed by the repeated and consistent findings in animal and human studies describing a causative link of high cholesterol levels with impaired endothelial-dependent vasodilation and nitric oxide production [27,28]. Indeed, increased oxidative stress and the formation of oxidized low-density lipoprotein could impair endothelial function and destabilize the normal control of vascular tone by heightening resistance over dilation forces [29,30].
The role of two emerging dietary factors (inorganic nitrate and fructose) needs to be discussed in the context of potential modifying or confounding effects on the association between cholesterol and BP. Inorganic nitrate and fructose have been shown to have opposite effects on vascular homeostasis mediated by a nonenzymatic nitric oxide production (nitrate)  and increased inhibition of endothelial nitric oxide synthase via an increased oxidative stress (fructose) [32,33].
The oral supplementation of inorganic nitrate for 1 week reduced diastolic BP by 3 mmHg in normal healthy individuals . In another study dietary nitrate, given to healthy individuals either as an oral supplement (capsules) or as vegetable juice (beetroot), induced an acute, significant reduction in systolic BP (∼6 mmHg) . These findings, however, need to be confirmed in studies with longer duration and patients with chronic metabolic disorders (hypertension, obesity, metabolic syndrome). Hord et al. has recently reviewed the contribution of inorganic nitrate in the DASH diet and advanced the hypothesis that nitrate intake could be contributing to the lowering effects on BP in patients adhering to the DASH dietary regimen. The analysis conducted by Sakurai et al., however, did not account for differences in dietary nitrate intake and it could be speculated that individuals with higher dietary cholesterol intake could have a lower consumption of fruit and vegetables, and therefore a lower nitrate intake contributing to the increase in BP. This is only a hypothesis that remains to be tested.
The same speculation could be applied to added sugars intake as they could negatively affect BP control [33,36]. In particular, high fructose intake has been associated with increased insulin resistance, visceral adiposity and triglycerides as well as with an elevation of BP in human and animal studies [37,38]. It is plausible that individuals following a diet with a high saturated fat and cholesterol content could also have a higher content in added sugars, hence contributing to the increase in BP. The analysis conducted by Sakurai et al. controlled for estimated total sugars intake which represents the sum of natural and added sugars. However, the presence of natural sugars (derived mostly from fruit and natural fruit juice intake) in the term added to the model (estimated total sugars) could have potentially diluted the size of the effect of added sugars on BP. Again this remains to be tested.
The results presented by Sakurai et al. described a modest, direct association of dietary cholesterol with BP. The relevance of the findings has to be critically evaluated in the context of the epidemiology of the outcome (hypertension) and exposure (hypercholesterolemia) as well as assess the advantages of implementing dietary preventive strategies for the reduction of dietary cholesterol intake at population level. A pragmatic analysis points towards potential benefits of a decrease in dietary cholesterol intake for the prevention of hypertension in the general population as part of established recommendations for the prevention of CVDs. However, the magnitude of the changes in BP attributable to a decrease in dietary cholesterol intake is largely unidentified and remains to be evaluated in more controlled, prospective investigations.
The author is very grateful to Dr Blossom Stephan and Dr Les Bluck for their insightful comments on drafts of this article.
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