The Mediterranean Diet and Cardiovascular Protection: Biochemical Mechanisms with Emphasis on Platelet-Activating Factor

Landmark epidemiological studies and clinical trials, such as the Seven Countries Study, the Lyon Diet Heart Study, the PREDIMED Study and the CORDIOPREV Study, have shown significant reductions in cardiovascular events in those following the Mediterranean diet (MD). The aim of the present work is to summarize the most robust available evidence and the major biological pathways underlying the protective effects of the MD, with particular emphasis on the role of PAF inhibitors. Mechanistically, MD functions through a complex synergy of antioxidant, anti-inflammatory, and antithrombotic effects that collectively improve lipid profiles, enhance endothelial function, optimize postprandial metabolism and cell membrane signaling, making it a functional model for human longevity. The PAF-Implicated Atherosclerosis Theory has emerged as a key unifying framework, proposing that Platelet-Activating Factor (PAF)—a highly potent lipid inflammatory mediator—plays a central role in the initiation and progression of atherosclerosis. Oxidized LDL promotes the production of PAF and PAF-like lipids, leading to endothelial dysfunction, vascular inflammation, and atherosclerotic plaque formation. Traditional Mediterranean foods are rich in natural PAF inhibitors, particularly the polar lipid fractions of extra virgin olive oil, as well as wine, fish, vegetables, onions, and garlic. Animal studies demonstrate that these compounds can reduce or even regress atherosclerotic lesions, independently of serum cholesterol levels. Human dietary interventions have further shown that MD-based meals and functional foods enriched with PAF inhibitors reduce PAF activity and improve thrombosis-related biomarkers. This mechanistic framework helps explain phenomena such as the “French Paradox” and the cardio-protective effects associated with fish consumption. Moreover, the extraction of PAF inhibitors from Mediterranean food by-products, such as olive pomace, offers promising ecological and economic advantages. Collectively, targeting PAF and increasing dietary intake of PAF inhibitors represent promising strategies for the prevention and management of atherosclerosis and other inflammatory diseases, supporting the view that PAF may function as a major, modifiable risk factor in these conditions.