Assessing the Physiological Effects of Traditional Regional Diets Targeting the Prevention of Cardiovascular Disease: A Systematic Review of Randomized Controlled Trials Implementing Mediterranean, New Nordic, Japanese, Atlantic, Persian and Mexican Dietary Interventions

Traditional regional diets are considered as sustainable dietary patterns, while many have been examined with regard to their health benefits. The aim of the present systematic review was to aggerate all evidence on the physiological effects of regional diets among adults at high risk for cardiovascular disease (CVD). Three databases were searched for randomized controlled trials (RCTs) implementing any regional diet (Mediterranean (MedD), Persian, Southern European Atlantic, Japanese, Chinese, new Nordic, or other) while examining cardiovascular risk factors among adults at increased risk. Primary outcomes included anthropometric indices and secondary outcomes involved blood lipid concentrations, glucose metabolism, inflammation and other markers of CVD progression. Twenty RCTs fulfilled the study’s criteria and were included in the qualitative synthesis, with the majority implementing a MedD. Adherence to most of the regional diets induced a reduction in the BW and anthropometric indices of the participants. The majority of RCTs with blood pressure endpoints failed to note a significant reduction in the intervention compared to the comparator arm, with the exception of some new Nordic and MedD ones. Despite the interventions, inflammation markers remained unchanged except for CRP, which was reduced in the intervention groups of one new Nordic, the older Japanese, and the Atlantic diet RCTs. With regard to blood lipids, regional diet interventions either failed to induce significant differences or improved selective blood lipid markers of the participants adhering to the experimental regional diet arms. Finally, in the majority of RCTs glucose metabolism failed to improve. The body of evidence examining the effect of regional dietary patterns on CVD risk among high-risk populations, while employing an RCT design, appears to be limited, with the exception of the MedD. More research is required to advocate for the efficacy of most regional diets with regard to CVD.


Introduction
Noncommunicable diseases (NCDs), including ischemic heart disease, stroke, cancer, diabetes and chronic lung disease, are collectively responsible for almost 71% of global deaths-over 41 million in total [1]. Among these, 15 million are considered as "premature" deaths, occurring between the ages of 30 and 69 years old [1] and could potentially be avoided. NCDs come also with a large financial burden to both the society, the individual household level and the national healthcare systems [2,3] as well as a substantial disability burden [4].
NCDs are the confluence of genetics, physiological, behavioral and environmental triggers [5]. As per the World Health Organization (WHO), the NCDs include five main categories namely cardiovascular diseases (CVDs), cancers, chronic respiratory diseases, diabetes [5] (Figure 1), and the more recent inclusion of mental health and wellbeing [6]. These five categories often co-occur, sharing intertwined causes. Proximal causes for the development of NCDs include elevated total cholesterol (TC), blood pressure (BP), and fasting plasma glucose (FPG) levels, whereas intermediate causes involve tobacco smoking, unhealthy diets, physical inactivity and excessive alcohol consumption [7]. Among all NCDs, CVDs consist of the leading cause of disease burden globally, demonstrating an alarmingly high rate [8]. Moreover, over the past few years, the global epidemiological CVD landscape has changed dramatically, with unhealthy diet becoming an increasingly important modifiable factor for the development of CVD causes [9].
Nutrition-based lifestyle interventions have been recommended as a primary and secondary prevention strategy for NCDs and for CVD in particular, for all high-risk populations (e.g., those who are obese, physically inactive, smoking, consuming unhealthy diets or excessive amounts of alcohol, etc., [10][11][12]). According to the WHO, globalization has produced a global deviation in dietary patterns, known as nutrition transition [13][14][15], which is responsible for the recorded cumulative increase in NCD burden, regarding the CVD domain in particular [11]. For this, the effect of traditional regional diets (i.e., traditional dietary patterns from different regions of the world) have been extensively examined for the prevention of NCDs. For example, Mediterranean diet (MedD) interventions have been suggested to reduce CVD risk among older adults or post-menopausal populations, both as standalone dietary interventions [16,17] or in conjunction with exercise [18,19], offering both short- [17][18][19] and long-term benefits [20]. Similar findings have been reported in studies assessing the new Nordic [21,22], the Japanese [23], the Southern European Atlantic [24], and the Mexican [25] regional diets.
The aim of the present systematic review was to aggerate all available evidence on the physiologic effects of regional diets among adults at high risk for developing CVD.

Research Question, PICO and Study Protocol
The research question was "what is the effect of regional diets in ameliorating anthropometric, biochemical, and cardiovascular indices in adults at high risk for developing CVD?" Randomised controlled trials (RCTs) were screened according to the population, intervention, comparison, and outcome (PICO) criteria (Table 1).
The protocol was registered at PROSPERO (CRD42020201200), and the review is presented in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines.

Inclusion and Exclusion Criteria
Inclusion criteria for the synthesis involved (1) publications written in the English language, (2) with a RCT design (parallel or cross-over), (3) with participants having a good general health but who were high risk for the development of CVD according to the WHO (age ≥55 years old, and at least one risk factor including post-menopause, hyperglycemia or prediabetes, hypertension, hyperlipidaemia, overweight or obesity, cigarette smokers, excessive alcohol drinkers, or physically inactive), (4) with one intervention implementing a traditional regional diet only, (5) a comparator arm implementing any other diet, sham diet, or no intervention, and (6) the duration of intervention lasting for at least 4 weeks.
Exclusion criteria involved (1) publications written in languages other than the English, (2) lacking an RCT design, (3) with participants having a confirmed diagnosis of chronic obstructive pulmonary disease, Parkinson's Disease, any form of cancer, or diabetes mellitus diagnosis, (4) incomplete trials, (5) lacking an intervention implementing a traditional territorial diet, (6) implementing a parallel exercise intervention, (7) involving younger participants.

Outcomes of Interest
Primary outcomes included body weight (BW), body mass index (BMI), waist circumference (WC), waist-to-hip ratio and abdominal adiposity.

Data Extraction
An a priori data extraction form was created in Microsoft Excel (version 16.0). Two researchers (A.B. and B.H.) independently extracted all of the data using the form, with two senior researchers (M.K. and M.G.G.) independently checking all of the data for consistency.
Extracted data included bibliographic information, study, and participant characteristics, randomization, wash-out periods (in case of cross-over studies), intervention characteristics, treatment duration, and comparator and outcome data including any relevant parameters named in the primary and secondary outcomes. In the case of any missing or unclear data, two attempts were made to contact the corresponding author by email. If no response was received, the missing data were not included.

Risk of Bias in Individual Studies
The Cochrane Risk of Bias (RoB) 2.0 tool [26] was used to assess the quality at the study level as having a high, low, or unclear risk of bias. The tool evaluates studies based on seven criteria: (1) randomization generation, (2) allocation concealment, (3) blinding of outcome assessors, (4) blinding patients/study personnel, (5) incomplete outcome data (that is, lost to follow-up), (6) selective outcome reporting, and (7) other risks of bias.

Search Results
The initial search of databases identified a combined total of 8173 records. After screening the titles, a total of 20 distinct RCTs fulfilled the predefined criteria and were subsequently included in the qualitative synthesis. A detailed PRISMA flow chart of the RCT selection process is presented in Figure 2.  Table 3 describes the characteristics of the included RCTs. One RCT assessed the effect of the traditional Japanese diet [27,28], another implemented a traditional Chinese diet intervention [29], three RCTs evaluated a new Nordic diet intervention [30][31][32], two RCTs assessed the effect of the Traditional Persian Medicine (TPM) diet [33,34], one trial evaluated adherence to the Mexican diet (MexD) [35], one the Southern European Atlantic Diet (SEAD) [24] and a total of 12 RCTs assessed the results of MedD interventions [36][37][38][39][40][41][42][43][44][45][46][47][48][49].

Characteristics of the Traditional Regional Diets
Characteristics of the traditional regional diets included in the RCTs are presented in Figure 3. The traditional Japanese diet is based on several elements, including a high consumption of soy products, fish and shellfish, vegetables (pickles in particular), seaweed, mushrooms, fruit, and green tea [27,51]. Specific condiments of the dietary pattern include dashi (soup stock) and fermented seasoning (soy sauce, miso, vinegar, mirin, and sake), with rice and soup being consumed as part of the meals. The traditional Chinese diet is similar to the Japanese one, including pickled vegetables, dry-and brine-slated vegetables, jellyfish, fish-balls and salted fish, soups, poultry, tofu and tofu by-products (koji), rice and rice snacks, fermented sauces, and eggs (salted and thousand-year-old) [52].
The new Nordic diet [53] is rich in high-fiber plant foods (fruits, berries, vegetables, whole grains, nuts), rapeseed oil, fish, and low-fat milk products. Salt intake, sugar, and saturated fats are rarely consumed.
Characteristics of the MedD include a high intake of vegetables, legumes and fruit, grains and nuts, olive oil as the main cooking fat, plenty of fish and shellfish as well as regionally grown herbs [54][55][56].
The traditional Persian diet includes a great variety of rice-based dishes (rice with stew, cooked rice, mixed pilaf, rice in a high-protein dish, vegetables stuffed with rice and kofta, or tahchin), soups and pottages, and many desserts, some which are rice-or semolina-based (halva, digcheh, milk-rice pudding, rice cookies, rice flour pudding, or saffron rice pudding) [57].
As for the traditional Mexican diet, it is rich in grains and tubers, maize products (corn tortillas), legumes, vegetables, fruits, meats, herbs and condiments [25]. Typical dishes include a variety of corn-based dishes that are mainly cooked with chilies, onions, garlic, and herbs (e.g., tamales), beans, squash, meats, rice, citrus fruits, full-fat milk, vegetables, Mexican cheeses, and lard [35]. Moreover, the diet is low in refined grains and added sugars [58].
Finally, the Atlantic diet is based on a frequent consumption of bread, cereals (including whole-grain), rice, pasta, potatoes, fruit, vegetables (including vegetable soup) and olive oil, a daily intake of dairy products, frequent consumption of nuts (preferably chestnuts or walnuts), fish (in particular cod) and seafood [59,60]. Eggs, lean meat, and pulses are also consumed on a weekly basis (2-3 times), whereas fatty meats and cured sausages, butter and margarine as well as desserts, sweets, pastries, cakes, and ice cream are sparingly consumed [60]. Table 4 details the CVD outcomes of the individual RCTs favoring the regional diet intervention arms. Table 4. Overview of CVD-specific outcomes (favoring the intervention arm) in RCTs implementing regional dietary patterns among participants with increased CVD risk.

Japanese
Asano [27,28]  Adherence to most of the regional diets induced a reduction in the BW and anthropometric measures of participants.
The majority of trials with BP endpoints failed to note a significant reduction in the intervention compared to the comparator arm, with the exception of some new Nordic [30,31] and MedD [40,43,48,49] interventions.
Despite the interventions, inflammation markers remained unchanged, except for CRP, which was reduced in the intervention groups of one new Nordic [25], the older Japanese [27,28], and the Atlantic diet [24] RCTs.
With regard to blood lipid concentrations, the regional diet interventions either failed to induce significant differences or improved the lipid profile of participants adhering to the experimental regional diets.
Finally, in the majority of the RCTs, glucose metabolism failed to improve in participants with increased CV risk.

Japanese Diet and CVD Prevention
One trial [27,28] assessed the effect of the older Japanese diet compared against the modern Japanese diet among patients with overweight/obesity. Anthropometric indices (BW, BMI and body fat mass) were improved in the arm adhering to the older Japanese diet, whereas in parallel, HDL, LDL, CRP and HbA1c were also improved. No changes were noted with regard to the FPG, IR evaluated through the homeostatic model assessment for IR (HOMA-IR), alanine transaminase (ALT), or blood pressure.

Chinese Diet and CVD Prevention
Leonetti and associates [29] compared the Chinese diet against the typical Western one, both in a hypo-caloric version, among patients with overweight/obesity. After six weeks of intervention, BMI, lean body mass (LBM), subjective hunger, as well as reported physical and mental health indicators were improved in the arm adhering to the Chinese diet.

New Nordic Diet and CVD Prevention
Among the three RCTs evaluating a new Nordic diet intervention (NorD) [30][31][32], one used the typical Western diet as a comparator [31], and the remaining assessed differences between the new Nordic diet (a healthier version of the diet) compared to the typical/average contemporary Danish diet [30,32].
Adherence to the new Nordic diet for 6 weeks [31] among patients with hypercholesterolaemia induced a significant reduction in the BW and BMI of the participants in the intervention arm compared to those allocated to the Western diet group. SBP, fasting insulin, TC, LDL, HDL, LDL/HDL ratio, apolipoprotein A 1 (ApoA 1 ) and B (ApoB) concentrations as well as their ratio (apoB/apoA 1 ) were also improved. No differences were recorded with regard to the FPG and DBP levels.
When the new Nordic diet was compared against the typical Danish diet among patients with abdominal obesity [30], all of the anthropometric indices were improved in parallel to the SBP, IR, TG, TC, and CRP levels. However, no differences were noted in the FPG and insulin levels between treatment arms. Adhering to a high-fiber Nordic diet for eight weeks [32] improved BW and blood lipid levels (TC TG, LDL and HDL) among participants with elevated TC and high-sensitivity CRP (hs-CRP) at baseline. The intervention failed to induce improvements with regard to blood pressure, FPG, insulin, HbA1c, hs-CRP, interleukin-6 (IL-6), ALT, interferon γ (IFNγ), soluble tumor necrosis factor receptor 1 (sTNFR1), apoB, or apoA 1 levels .

Mediterranean Diet and CVD Prevention
Compared to a Western-style diet, the MedD was ineffective in improving the anthropometric, lipid, and FPG profile of non-diabetic patients with abdominal obesity [47] after 10 weeks of intervention. On the other hand, when participants with overweight or simple obesity were recruited [38], BW, TC, and LDL were significantly improved within 8 weeks in the treatment arm compared to the group retaining their usual diet alone or supplemented with fish oil, walnuts, and grape juice.
When the comparative effectiveness of an isocaloric MedD was compared against the DASH diet for 12 weeks [45] in a similar sample, all of the athropometric indices (BW, WC, BF, and visceral adipose tissue [VAT]) and additionally ALT were improved in the MedD arm. In a 2-month comparative effectiveness trial where one group of women with overweight/obesity adhered to a hypo-caloric MedD and another to the Atkins diet [46], BW and FMD were significantly improved in the MedD arm. When the MedD was compared against an energy-restricted Central European dietary pattern for 6 weeks, BW, BF, FFM, and VAT were all reduced among post-menopausal women with overweight/obesity [36,37]. Nevertheless, no differences were recorded in the ADMA or hs-CRP concentrations of participants.
The Cardiovascular Prevention with Vegetarian Diet (CARDIVEG) [44] trial assessed the effect of a hypo-caloric MedD compared against a low-calorie lacto-ovo vegetarian diet for 3 months, in patients at increased CVD risk. Among a variety of hematological and anthropometric outcomes, only LDL and TG levels were improved.
When older adults were used as a sample, a yearly MedD intervention was effective in improving SBP [40,48,49]. Moreover, the Mediterranean diet for cognitive and cardiovascular health in the elderly (MedLey) trial [48,49] revealed additional improvements regarding the DBP, FMD, TG, and F2-isoprostanes levels at 6 months of intervention.
In the MedDairy [43] and MedPork [42] trials, Wade and associates compared the MedD supplemented with servings dairy or lean pork, respectively, against a low-fat diet for 8 weeks among patients at risk for CVD. In MedDairy [43], reductions in the anthropometric indices were noted (BW and BF), paired with improved SBP, HDL, and TG levels. In MedPork [42], the BW, BMI, and WC of the participants were improved. None of trials managed to improve LDL, DBP, FPG, fasting insulin, or TC levels.
When patients with mildly/moderately elevated TC levels were recruited, adherence to the MedD induced significant improvements in the BW, TC, and LDL levels compared to either a low-fat diet or the usual diet of the participants [39]. Nonetheless, measures of stress, cognitive function, well-being, and depression failed to change despite the intervention.

Mexican Diet and CVD Prevention
Santiago-Torres and colleagues [35] evaluated a traditional Mexican diet intervention compared against the US diet in women with overweight/obesity for a total of 24 days in a cross-sectional manner. Among the plethora of evaluated outcomes only fasting insulin levels were improved post-intervention, with FPG, CRP, insulin-growth factor 1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3), adiponectin, IL-6, and IR failing to be improved.

Traditional Persian Medicine Diet and CVD Prevention
Two RCTs compared the TPM against hypo-caloric diets [33,34] in patients with NAFLD [33] and women who were overweight [34], respectively. In the first RCY [33], BMI, NAFLD grade, ALT, and aspartate aminotransferase (AST) levels were significantly improved in the TPM arm, as compared to the low-fat hypo-caloric diet group. In the second trial, no improvements were noted, either when compared against the typical hypo-caloric diet (1200-1600 kcal/day) plus orlistat, or when compared to the typical hypo-caloric diet plus Majoon Davaye Balgham (MDB) ONS.

Traditional Southern European Atlantic Diet and CVD Prevention
The GALIAT study [24] assessed the results of a traditional Atlantic diet intervention in in 250 families (irrespective of their health status), compared to their habitual diet. The intervention induced a reduction in anthropometric indices (BW, BMI, BF), as well as in the TC and LDL concentrations. No differences were reported with regard to inflammation markers.

Risk of Bias
A summary risk of the bias of the included RCTs is presented in Figure 4. The majority of RCTs had an unclear overall risk of bias, three had a low overall bias, and five were classified as having a high overall risk of bias.

Synthesis of the Outcomes
Although the number of studies and the total patient population were adequate, the high clinical and methodological heterogeneity did not allow for a synthesis of the outcomes.

Discussion
The present study revealed that research applying regional dietary interventions while examining CVD outcomes is very limited. From the examined dietary patterns, the MedD appears to be the most researched diet using an RCT design. Although individual RCTs indicate selective improvements in CVD outcomes following adherence to regional dietary interventions, any extrapolation of the findings for the formulation of recommendations would be rather premature and hasty.

Do Health Benefits Lie in the Constituents/Nutrients of Regional Diets?
According to Cena and Calder [61], healthy dietary patterns are apparent in certain regions of the world and are rooted in the local tradition while making use of the naturally available food sources in a sustainable manner [62]. Thus, to evaluate the potential beneficial effects of regional diets on CVD risk factors, it seems appropriate to consider the food sources, and quantities thereof, provided in the pre-scribed dietary interventions that might consist of the driving forces behind the improved health outcomes. Common denominators in the healthier, regional dietary interventions include a high fruit and vegetable intake, the consumption of fish and plant oils as well as the low intake of fat, sugar, sweets, and desserts ( Figure 5). For each one of these diet components, a great body of evidence is backing the health benefits associated with its consumption. Figure 5. Shared food-group components of regional diets included in the present analysis.
Collectively, the dietary interventions implemented herein suggest an increased consumption of fruits and vegetables. This pattern has been shown to reduce serum TC in healthy men and women [6] and has been inversely related to LDL concentrations in healthy individuals and individuals with T2DM or coronary artery disease (CAD) [63]. Fruits and vegetables have a high fiber content, which, in turn, may reduce the glycemic index of foods, conferring benefits against CVD or its precursors (glycemic control, BW, etc.) [64].
Moreover, a high fruit and vegetables intake usually coincides with a reduced intake of sweets and sugar, indicating the adoption of a "healthier" dietary pattern. Literature is unanimous on the beneficial effects of low sugar intake on CV health [65,66], with benefits spanning from low subclinical inflammation [67], improved gut microbiota [68], and the attainment of a "healthy" body weight [69].
With regard to the fat intake, several studies have associated a higher fats intake, particularly SFA, to greater LDL concentrations, and the development of inflammation, T2DM and dyslipidemia [70]. Indeed, for many years, even the smallest intake of fat was "demonized" and a high-fat diet was a synonym to a higher CVD-risk diet [71]. Recently however, evidence from studies of higher hierarchy, including dose-response meta-analyses, has contradicted this narrative, suggesting that SFA intake has either a null effect, or even a positive one on the CV health according to the results of dose-response analyses [71][72][73]. Moreover, according to a recent Cochrane systematic review [74], cutting down on SFA for a period of four years has little or no effect on non-fatal myocardial infarction, coronary heart disease (CHD) and cancer mortality/incidence, diabetes diagnosis, HDL and serum TG concentrations, or blood pressure, and unclear effects on total myocardial infarction (MI), stroke and CHD events. Moreover, the number-needed-to-treat (NNT) for an additional beneficial outcome based on the primary prevention trials was 56, translating to 56 people needed to reduce their SFA intake for four years, in order for one person to avoid a CVD event [74]. When secondary prevention trials were accounted for, the NNT was calculated at 32 [74]. Accordingly, some researchers claim that the absolute intake of macronutrients appears to be less relevant to health than the selected food sources [75].
A high fish intake is an indisputable component of most of the regional diets included herein, and interestingly, all regional diets included in the present analysis involved countries with direct access to the sea. Research has showed that fishing is an important contributor to food security in water surrounding regions [76], and seafoods form both a traditional component of the regional diets, as well as an important effector of diet quality [77]. Moreover, according to meta-analyses of observational studies, greater fish intake is associated with a lower CHD incidence and mortality [78], as well as stroke risk [79].
Despite the health effects demonstrated by the consumption of individual foods and food-groups, as Schoenfeld and Ioannides promptly noted, it is risky to associate individual foods and nutrients with distinct health outcomes, as nutritional epidemiology is often biased by its limited reproducibility [54,80].

Concerns Regarding the Methodology of the Included RCTs
In the Japanese diet trials, the intervention arm (traditional diet) contained an increased quantity of soy products, seafood, fruits and vegetables, seaweed, and mushrooms compared to the comparator [27]. The 1975 Japanese diet servings contained approximately 4 g less fat per 100 g, 1 g more protein and 1 g extra carbohydrate compared to the modern diet. Differences in the macronutrient content of the two arms appear neglectable or nondifferent between arms; thus, it is the actual foods and their constituents that may have propelled the changes in the metabolic profile of participants, although this is difficult to discern when only one RCT was included.
In the Chinese diet RCT, the reported dietary information of the two arms was poor. Although there were positive significant outcomes reported for the intervention group, the precise nutritional content of the intervention/control diet that was consumed by the participants was not reported, so potential mechanisms could not be explored. Both diets provided approximately 1200 kcal/day, with participants given a variety of different food choices per meal, with set portion sizes. Caloric restriction, whereby the calorie intake is well below what would be consumed ad libitum (>10%), has been shown to have a positive effect on CV health [81]. The effects of caloric restriction in humans include beneficial changes in blood pressure, lipid profile, CV function and inflammatory response [82][83][84]. It seems possible that a contributing factor towards the positive changes in the Chinese diet intervention arm was the result of the caloric restriction. Moreover, since the comparator arm was also energy restricted, the reported results might be attributed to the specific nutrients in the prescribed diets. However, without knowing which nutrients were consumed by the participants, it is difficult to draw conclusions.
Three studies investigating the Nordic diet were included in this review. The new Nordic diet was shown to have positive effects on anthropometric indices and the lipid profile among obese participants and individuals with elevated TC, respectively [30,32].
The key features of the new Nordic diet, as reported by the authors, include replacing the SFA content of the diet with MUFA and PUFA sources, reducing the consumption of processed and refined grains, and increasing the intake of organically grown fruits and vegetables. In Ulven's study, the SFA content was 19.2 g/day in the control arm and as low as 5.7 g/day in the intervention group [32]. The respective PUFA content reached 5.1 g/day and 14.4 g/day in the control diet and intervention diet, respectively. With regard to the fat content, as previously mentioned, recent research of a higher hierarchy disputes the efficacy of SFA replacement in improving CV risk [74]. Thus, the induced changes in the new Nordic diet arms rely on other factors. Thus, more research is required to explore the efficacy of the new Nordic diet and its applicability to populations with different CVD risk factors.
In the present review, there were more studies included that investigated the MedD that any other regional diet. In all but one of the included studies, the MedD was shown to have significant positive effects on most outcomes of interest. Key features of the MedD typically include multiple daily servings of olive oil, tree nuts, fruits and vegetables and fresh fish, white meat and whole grains, while processed foods, grains, and red meat are advised to be consumed less than once daily ( Figure 3) [54,85,86]. A plethora of metaanalyses have shown that adherence to the MedD reduces CV risk factors including hard endpoints [85,86]. Moreover, research also suggests that the MedD can be an effective remedy for precursors of CVD, including hypertension or obesity [87][88][89]. Nevertheless, great heterogeneity is observed with respect to the trials implementing MedD interventions, their design, fragility index, and intervention characteristics, as well as regarding what is considered as a MedD by definition [54].
The only study included that investigated the Mexican diet showed positive changes to Ins and reported no significant positive results for any other biochemical indices of CVD risk [35]. The nutritional information of the planned interventions showed that the Mexican diet and the US diet comparator contained approximately the same amount of calories, with participants prescribed a eucaloric diet depending on their own expenditure. The Mexican diet contained 32.3 g less sugar daily (18.6 g less fructose), which may explain why insulin concentrations were significantly reduced in the intervention arm.
Of the two included studies that investigated the TPM, one showed some significant positive improvements in the anthropometric and biochemical indices [33], and one showed none [34]. The nutritional intervention of Razmgah's study [33] was poorly reported, and potential causal mechanisms cannot be explored. Hamidnia's study [34] failed to reveal any significant positive changes between treatment arms. Thus, based on the available evidence, the effect of the TPM on CVD risk factors in patients at increased risk appears poor.
With regard to the Southern European Atlantic diet, the overall studies backing the "healthy diet" narrative are limited, and more research is required to identify the specific characteristics of this pattern and to associate its adherence with health outcomes.

Health Benefits of Regional Diets beyond CVD Risk
Apart from CVD, which was the main aim of the present systematic review, high quality research has revealed that regional dietary patterns may also be effective in other NCD categories. For instance, meta-analyses of RCTs reveal that the MedD can be an effective complementary therapy in patients with cancers [90], mental health problems [91], or diabetes [86,92,93] diagnoses. Similarly, the aggregation of RCTs implementing the new Nordic diet [94] also revealed improvements in the metabolic control of patients at risk for diabetes. With regard to the adoption of the traditional Chinese diet and medicine, meta-analyses of RCTs have showed selective improvements in patients with a cancer [95] or obesity diagnoses [96]. On the other hand, results from observational studies suggest that adherence to the traditional Japanese diet reduces the risk for developing specific cancers, and in parallel lower all-cause, CVD and cancer mortality [97,98].

Environmental Benefits of Regional Diets
In 1986, Gussow and Clancy [99] were the first to suggest the term "sustainable diet" to describe a diet composed of foods contributing to health and nutrient adequacy, while also contributing to the sustainability of food sources (agricultural system, or fishing). Thus, sustainable diets make use of human and natural resources to produce and consume foods "in a manner that is not wasteful of finite resources as topsoil, water, and fossil energy" [99]. Therefore, it appears that sustainability is multidimensional, with environmental, economic and social impacts, aiming to achieve multiple sustainable development goals (SDGs) in synergy. In this manner, changes in food availability, the industrialization of food systems, technological advances, globalization of the market and food policies and lobbies have all induced a nutrition transition deviating from the traditional regional diets. A return to the traditional regional patterns would not only improve population health, but also contribute to the sustainability of the environment, while taking into account the identity and diversity of food systems and cultures of each region [100].

Limitations of the Present Study
Limitations of the present systematic review include the relatively narrow spectrum traditional regional diets included in the analysis. It appears that several dietary patterns have not been examined yet, with respect to their effect on CVD risk. In the present search, no RCTs were found implementing other traditionally healthy diets with regard to CVD outcomes, including the Inuit (arctic) diet or the South Asian diet. Moreover, the present review also highlighted the great heterogeneity in the regional diets RCTs, not allowing for a synthesis of the evidence.
It should also be noted that an additional limitation of the studies included in the present systematic review involves the lack of biomarker use for assessing treatment adherence. A variety of biomarkers are available today and can confer greater validity when assessing dietary treatment adherence, as compared to the usual tools for dietary assessment. Some are food specific, evaluating fish, meat, or olive oil intake (including urine hydroxytysosol or serum γ-tocopherol concentrations) [101][102][103][104][105][106], whereas others are nutrient-specific. The use of such biomarkers might have resulted in different findings with regard to CVD endpoints. Moreover, metabolic health often stems from the perfect balance of nutrients, with BP for example being affected by many micronutrients apart from sodium intake, including potassium, magnesium, calcium, fish taurine, or soy phytoestrogens. These interacting micronutrients were not assessed in the included studies and this might have reduced the efficacy of regional diets on participants' BP health.
On a side note, in all of the research included herein, specific aspects of the traditional lifestyle beyond regional diets, including the siesta, reduced stress, improved quality of life, and social capital, cannot be transferred to an RCT design, although they might induce improved benefits [54].
Moreover, future research can also aggregate data from the RCTs implementing regional diets for the prevention of other NCD categories, in order to help us attain a better picture on the effects of traditional diets on NCD prevention.

Conclusions
Regional diets are sustainable dietary patterns that make use of locally sourced goods to nurture the surrounding populations. With regard to their CVD benefits, we cannot draw conclusions on whether one specific pattern is superior to another, although the majority of research involves the MedD. Selective CV outcomes (anthropometry, BP, inflammation markers) are improved following regional dietary interventions, although aggregation of data for the recommendation of specific territorial diets for the reduction of CVD risk is not yet feasible, with the possible exception of the MedD.
Although strengths and areas that benefit differ between the distinct target populations of the included RCTs, the reviewed body of evidence suggests that adherence to regional diets may reduce specific CV risk factors, with MedD appearing to offer a wider range of CV-related benefits. Nevertheless, the evidence is still limited for most of the examined regional diets and a great heterogeneity is observed. Thus, more research examining the effects of regional dietary interventions on CVD parameters is required to increase the body of existing evidence. Institutional Review Board Statement: Ethical review and approval were waived for this study, as this involves meta-research.

Informed Consent Statement: Not applicable.
Data Availability Statement: All data are presented within the manuscript text.