Diet and Cardiovascular Disease: The Mediterranean Diet

The Mediterranean Diet in Cardiovascular Disease Prevention

To introduce the effect the traditional Mediterranean lifestyle has had on health we will start anecdotally and historically. The best way to introduce the effect the traditional Mediterranean lifestyle has had on health is to start anecdotally and historically. Ikaria, the “Greek island of old age,” has been characterized as one of the world’s Blue Zones, so-named because many of its inhabitants live to celebrate their 100th birthdays. This was highlighted by Stamatis Moraitis, who returned there after being diagnosed with lung cancer in the United States and given 6 months to live (Murphy and Parletta, 2018). Forty-five years later, he was celebrating his 98th birthday. In a BBC interview, he attributed his longevity to the wine, which he makes himself and shares with his friends. He also has his own olive and fruit trees, like other Ikarians who grow and cook their own food and make tea from the wild herbs that grow on the island. Although Blue Zone inhabitants enjoy other health-promoting qualities such as fresh air and a relaxing lifestyle, another feature they share is their dietary patterns and habits (Murphy and Parletta, 2018). What does the scientific evidence say about its health benefits?

As discussed in Chapter 5, the Mediterranean diet is predominantly plant-based, rich in vegetables, fruit, nuts, legumes, unrefined cereals, and seeds. Liberal use of olive oil is the main source of added fat, which occupies a central position in the diet dating back to 5000 BCE and was considered a “gift of the Gods.” The diet also includes a moderate intake of fish and dairy products; low red meat and poultry consumption; and little or no packaged and highly processed foods, refined carbohydrates, or unhealthy fats (Trichopoulou et al., 2003). The Mediterranean diet encourages moderate consumption of alcohol, mainly red wine, to be consumed with meals, and acknowledges conviviality, frugality, and the importance of physical activity  (Trichopoulou et al., 2003; Murphy and Parletta, 2018). Its fertile history has earned the Mediterranean diet an inscription on the list of the intangible cultural heritage of humanity with the United Nations Educational, Scientific, and Cultural Organization (UNESCO) (Murphy and Parletta, 2018).

The Seven Countries Study, established in 1958 by Ancel Keys, as discussed in Chapter 4, was the first study to suggest a link between the local diet and a reduction in CVD prevalence and death in Mediterranean populations. In this pioneering study, CHD mortality was positively associated with saturated fat and inversely associated with monounsaturated fat (MUFA) (Keys et al., 1986). However, this led to the dissemination of a low-fat message and the protective effects of the high MUFA diet were lost, a message that Ancel Keys never intended to promote. In 1995, Trichopoulou and colleagues showed that adherence to a Mediterranean diet was associated with an increase in overall survival in an elderly Greek population (Trichopoulou et al., 1995). And in a recent systematic review and meta-analysis, the Mediterranean diet, without a restriction on fat intake, was associated with a reduction in the incidence of cardiovascular events, breast cancer, and type II diabetes mellitus (Bloomfield et al., 2016). A cumulative meta-analysis of prospective studies (observational cohorts and trials) showed that a two-point increment in a 0–9 score of Mediterranean diet adherence was associated with an 11% relative reduction in the risk of CVD (risk ratio 0:89; 0.86–0.91) (Martı´nezGonza´lez et al., 2017).

Potential Mechanisms Implicated in CVD Prevention

Over the last few decades, several studies have tried to identify potential mechanisms explaining the benefits of the Mediterranean diet on CVD (Salas-Salvado et al., 2018). Its high fiber content, the specific lipid profile (rich in MUFA acids and PUFA), and its richness in other microconstituents with recognized antioxidant and anti-inflammatory properties have been proposed as the main protagonists in the protection against CVD (Tsoupras et al., 2018b) through the modulation of its surrogates such as blood pressure, lipid profile, body weight, and fasting blood glucose (Salas-Salvado´ et al., 2018). For example, plant-based foods of the Mediterranean diet such as legumes, nuts, fruits, and vegetables are high sources of fiber, which promote cardiovascular health through the control of body weight and the long-term weight loss maintenance by lowering energy intake and triggering satiety cues (Wanders et al., 2011), but also through lowering LDL-C (Brown et al., 1999). The abundance of plant-based foods and the moderate presence of animal products favors beneficial effects in glycemic control, weight loss, and cardiometabolic risk factors by lowering LDL-C levels and ameliorating the oxidative stress and inflammation, which has also been attributed to specific constituents of this dietary pattern (Annuzzi et al., 2014; Huo et al., 2014; Kim
et al., 2017).

In addition, because of its richness in legumes, nuts, fruits, and vegetables, the Mediterranean diet could modulate gut microbiota and influence the production of metabolites thereof, affecting CVD risk (De Filippis et al., 2015; Salas-Salvado´ et al., 2018). For instance, it has been reported that adherence to the Mediterranean diet is associated with a favorable reduction of the urinary trimethylamine-N-oxide (TMAO), a metabolite that is associated with
the transformation of macrophages to foam cells and also contributes to modifying cholesterol and sterol metabolism. Furthermore, the Mediterranean diet is associated with an increase of the fecal short-chain fatty acid (SCFA) levels, which increases fatty acid oxidation and decreases de novo fatty acid synthesis as well as plasma glucose and cholesterol levels in the liver (den Besten et al., 2013).

The Mediterranean Diet: PAF-Related Inflammatory Pathways and Metabolism

As presented in Chapter 3, common junctions in the mechanistic crosstalk of inflammatory mediators, signaling pathways, and cellular interactions that occur during chronic and unresolved inflammatory manifestations seem to be a promising therapeutic target for the prevention and treatment of inflammation-related chronic diseases. Drug-based therapeutic interventions targeting inflammatory mediators such as cytokines and eicosanoids have been proposed and relative trials such as CANTOS are still in progress. However, such approaches can sometimes provide undesirable effects and may leave the individual immunocompromised and at a greater risk of infections because disruption of the physiological balance seems to be a risky strategy (Capra et al., 2013; Moss and Ramji, 2016).

On the other hand, because PAF and its related inflammatory cascades are implicated in the most vital joint mechanistic pathways of inflammation-related chronic disorders (Tsoupras et al., 2018b), the exploration of possible therapeutic approaches targeting PAF and its related pathways may provide positive outcomes. Focus initially was given to the PAF/PAF-R interaction and thus inhibiting the exacerbation of the complex PAF inflammatory pathways (Koltai et al., 1991a,b; Negro Alvarez et al., 1997; Singh et al., 2013; Palur Ramakrishnan et al., 2017). There are several agonists of synthetic and natural origin (Koltai et al., 1991a,b; Negro Alvarez et al., 1997; Tsoupras et al., 2009; Singh et al., 2013; Palur Ramakrishnan et al., 2017), which can competitively or noncompetitively displace PAF from its binding sites on PAF-R and thus (Feige et al., 2010; Papakonstantinou et al., 2017) directly inhibit the PAF/PAF-R related pathways and PAF activities. Furthermore, other similar molecules can indirectly affect the PAF/PAF-R pathways by affecting the up-stream and/or downstream microenvironment of the PAF-R, lipid rafts, and other related cellular receptors (Tsoupras et al., 2018b).

Author: Audrey Tierney, Ronan Lordan, Alexandros Tsoupras, Ioannis Zabetakis