This investigation looked at the possibility of modulating diverse cardiometabolic risk factors by a diet based on multiple functional food concepts. Although a number of therapy-oriented dietary studies have been reported in dyslipidemic subjects [4, 6, 8, 45, 47], no randomized intervention has examined the potential CMD preventive power of a complex functional food array targeting subclinical inflammation. Present results put forward interesting possibilities for this dietary approach.
One characteristic of this study is the healthy condition of the cohort evaluated. The volunteers had no particular diagnosis, beyond being considered at risk for cardiometabolic alterations due to their age (63.3 ± 0.8 y) and BMI (28.5 ± 0.3 kg/m2). According to mean baseline values for blood lipids, BP and glucose homeostasis parameters (Table 1), the group represents the healthy segment of the Swedish population in the 50-75 year-old range. This judgment is supported by the fact that 59% of the volunteers exhibited none of the MetS features evaluated, which contrasts with data from a recent survey of MetS prevalence among 50-60 year olders living in Gothenburg, showing that only 5% of this population group has no risk factor associated to the syndrome .
The AD evaluated here included a cluster of functional concepts selected for their abilities to influence different CMD-associated factors, with emphasis on anti-inflammatory properties. The efficacy of the individual concepts has been documented at various levels including intervention studies with humans. Furthermore, since the concepts influence different aspects of the pathophysiological processes associated with CMD, synergistic interaction between functional agents may occur and facilitate the overall modulation of multiple risk indicators. Thus, the daily dosage of some functional components was set below the amount required for optimal effect when tested separately (Table 3), improving the general palatability of the diet.
CD exhibited a good nutritional profile, which matched the Nordic Nutritional Recommendations. Although its dietary fiber content was lower, the CD contribution approached the current estimated fiber intake for the Swedish population (Swedish Food Administration, Personal Communication). Also, besides being rich in functional ingredients, AD had an improved fat quality (Table 2) and its long-chain ω-3 fatty acid content was 10 times larger than in CD. Both diets were well accepted and tolerated by the participants. The variety of foods encompassed, the inclusion of meat and other animal products and the minor amount of alcoholic drinks allowed favored the high dietary adherence and completion rates recorded.
A somewhat greater weight loss was observed after AD, which agrees with the marked satiating action reported for this diet by most participants, an effect that may be due to its higher dietary fiber and protein contents. In fact, 50% of the participants were prescribed increased dietary energy after the first 2 weeks on the regime when their weight loss tendency became evident, in contrast to only 25% requiring that intervention during the CD period. In spite of that a 1.8% (1.4 ± 0.2 kg) mean decrease was recorded after AD. Nonetheless, the statistical adjustment made for the impact of weight variation showed that most of the metabolic improvement observed after AD was attributable to the dietary modification per se and not to a mere weight loss effect.
Blood lipid and apolipoprotein profiles were practically unaffected by CD but sharp reductions in triglycerides, total cholesterol, LDL cholesterol as well as in LDL/HDL and apoB/apoA1 ratios were recorded after the AD period. The latter observation is noteworthy, given the strong association between this quotient and the MetS . The beneficial impact of a low glycemic index diet on blood cholesterol  together with the triglyceride-reducing action of polyunsaturated fatty acids from marine origin  and content of other known cholesterol-lowering foods and ingredients (soybeans and soy protein, viscous dietary fibers, plant stanols and almonds) are most probably responsible for the overall effect observed with AD.
None of the diets affected insulin sensitivity as estimated by HOMA-IR, although AD promoted slightly higher fasting glucose values than CD. Such an increased glycemia should not pose a risk for healthy individuals, a presumption supported by the reduction recorded in HbA1c and unchanged values for fasting FFA.
The minor decrease in HbA1-c observed with AD might be the consequence of modulated glycation rate during the AD period. The diet's low glycemic impact and high phenolic content, both with anti-glycative effects [51, 52], may have contributed to this result.
CRP is an indicator of the inflammatory status of recognized importance in relation to cardiometabolic alterations [42, 53], with independent predictive value for incident diabetes and cardiovascular diseases [7, 54]. The biomarker decreased markedly after AD, with significant difference between diets after adjustment for weight change. It is tempting to speculate that the improved CRP levels may be due to the antinflammatory properties of AD. The CRP-lowering effectivity of a diet enriched in oily fish, blueberries and wholegrain products was recently shown in patients with impaired glucose tolerance .
In addition to improving metabolic risk indicators, AD promoted a significant drop in systolic BP. Such a change may be related, for instance, to the high supply of long chain ω-3 fatty acids, ingredients with suggested BP-modulating activity . Although the present cohort was normotensive (Table 1), the observed pressure reduction resembles that observed with a composite drug treatment in hypertensive volunteers .
Besides modulating individual markers associated to CMD, AD also decreased cardiovascular risk as estimated by two different models. The Reynolds algorithm resulted in larger variation from baseline (-34%) than the Framingham score (-30%), stressing the importance of the CRP reduction promoted by this diet.
The improvement achieved for different biomarkers after AD in this relatively low risk group, compares favorably with other dietary interventions. Most of the investigations on the effect of diet CMD-related parameters have been carried out in patients that have metabolic alterations, such as dyslipidemia. A portfolio of cholesterol-lowering foods reduced LDL cholesterol values by 33% in a 4-week trial with hypercholesterolemics , which is alike the variation recorded here with a normocholesterolemic group. Furthermore, the presently reported impact of AD on the apoB/Apo A1 ratio, CRP concentration and Framinghams CVD risk is comparable to those previously attained in hypercholesterolemics following the cholesterol-lowering portfolio regime [5, 6].
Also, the effect of AD on total (-26%) and LDL cholesterol levels (-34%) exceeds those reported for the "Nordic" diet in hypercholesterolemic individuals (-16% and -21%, respectively) a regime that, in contrast to ours, did not affect triglycerides or systolic BP beyond weight-loss effects . The AD also promoted greater LDL-cholesterol, triglyceride and CRP reductions than Mediterranean-style regimes administered to individuals at high cardiovascular risk .
Compared to other dietary interventions performed in healthy volunteers, the action of the AD on different CMD-related variables is also remarkable. Its effects on systolic BP are similar to those of reduced sodium/DASH  or whole-grain  regimes. Moreover, in terms of LDL cholesterol reduction AD appears impressively more effective than vegetarian  or low GI  regimes. The larger effectiveness of AD reflects the power of its multifunctional character.
It is relevant noting that the AD effects were observed under conditions aiming to prevent weight changes. In view of the perceived high satiating ability of the diet, larger weight reductions could be expected if it was consumed ad libitum. This potential deserves further investigation, since dietary interventions promoting weight losses of 5% or more generally result in additional metabolic improvement [9, 62, 63].
The present study had limitations. An evident constraint is the unbalanced gender participation, since 80% of the participants were women. Nevertheless, the lower responsiveness of women to treatments targeting metabolic alterations, such as hyperlipidemias [64, 65], stresses the relevance of our results. The relative heterogeneity of the cohort regarding metabolic characteristics may also be seen as limiting. However, the group reflects the healthy mature segment of the local population. The study length represents another limitation. Prolonged open interventions often yield inferior results, a pattern influenced by reduced dietary compliance. Nonetheless, the good acceptability recorded for the AD allows expectations for reasonable treatment adherence in longer term trials. An increased availability of active food items and ingredients in the near future may ease the achievement of this goal.
The possible impact of AD on body composition and fat distribution was not evaluated here. Since these factors are importantly associated with cardiometabolic risk [46, 54], it would be interesting to include them in future studies on the role of functional diets in the prevention of cardiometabolic alterations. At last, the experimental design envisaged sufficient statistical power regarding changes in LDL cholesterol and CRP but the greater statistical dispersion associated to other biomarkers, such as insulin, PAI-1 and TNF-α, may have left the study underpowered to confirm their modification. This should be born in mind when interpreting the non-significant changes recorded in these parameters.