From Bill Lands:
A likely candidate for a very early step in atherogenesis is the repeated postprandial reversible loss of endothelial function  and  which could occasionally convert into a chronic inflammatory locus. Endothelium-dependent dilation is lower with higher postprandial triacylglycerolemia (a marker for high food energy density). An often-neglected postprandial process when excess food energy forms the much-discussed circulating blood biomarker low-density lipoprotein (LDL) is the hydrolytic release of large amounts of non-esterified fatty acid (NEFA) into the plasma . The biological impact of the much-neglected NEFA and its resultant oxidant stress (indicated in Fig. 3B) may be greater than the effect of the co-produced LDL (with its adherent cholesterol). However, daily messages about LDL cholesterol from marketing and research groups greatly exceed information on the simultaneously released NEFA, and they divert attention away from harmful NEFA actions.
8.1 Actions of non-esterified fatty acids (NEFA) amplified by n-6 mediators
Meal-induced vascular dysfunction and oxidative inflammatory conditions (measured by hydrogen peroxide and isoprostane levels) as well as released monocyte chemoattractant protein-1 were less when diets included fish oil n-3 HUFA . Lipemia-induced loss of endothelial function involves impaired nitric oxide actions, and it can be alleviated in part by supplements of arginine . However, arginine did not prevent an accompanying pro-thrombotic expression of P-selectin and vonWillebrand factor on platelets. Impaired endothelial function monitored as flow-mediated dilation after an oral fat challenge was related to the extent of hypertriacylglycerolemia and oxygen-derived free radicals . Postprandial lipemia was accompanied by increased plasma hydroperoxides and a neutrophil chemotactic agent, IL-8 .
Importantly, leukocyte chemotaxis and adhesion are much greater when the mediator is n-6 LTB4 rather than n-3 LTB5 . A significant increase in adhesion of monocytes to the endothelial monolayer occurred in the presence 20:4n-6, and it was decreased with 20:5n-3 . Pro-inflammatory mediators (intercellular adhesion molecule 1, vascular cell adhesion molecule 1, E-Selectin, IL-6, and TNFα) were all significantly increased in endothelial cells incubated with 20:4n-6. Thus, the n-3 and n-6 HUFA proportions in tissues shown in Fig. 3A must be considered when interpreting the impact of food energy density upon risk for CVD shown in Fig. 3B.
Important arithmetic in managing food energy is in balancing intake with expenditure during the course of a day. The on-going societal shift toward a sedentary lifestyle puts a premium on awareness of energy intake and expenditure. During 3 h of typical modern lifestyle activities, a 150 lb person may expend approximately: 225 Cal riding in a car; 202 Cal using computer/internet; 216 Cal watching television; 202 Cal reading book/newspaper; 202 Cal sleeping. Physical activity like walking for 1 h may expend about 270 Cal, and one hour of bicycling, about 500 Cal.
In contrast to low energy expenditure, an average restaurant meal may have 1327 Cal , which is 1100 in excess of that likely to be burned in the next 3 h. As a result, much remains for the liver to convert to plasma VLDL and begin the transient process of postprandial endothelial dysfunction. An important, simple tactic to distribute food energy intake more evenly is to eat fewer calories per meal and use small snacks to lower the burden of food energy per hour upon the liver.
With three meals per day and 365 days per year, people may have a thousand postprandial situations per year. If only one per hundred (1%) of these transient postprandial insults converted to a chronic inflammatory site, there might be 10 new sites each year leading to 200 sites in 20 year-old individuals, 400 in 40-year olds and 600 in 60-year olds. Such a low frequency for initiation fits the slow age-dependent histological evidence in the PDAY Study (see Fig. 14 in ). While food energy can give reversible pathologies, a more serious process may be the n-6 mediated amplification of transient dysfunction into chronic inflammatory plaques.
The propensity for recruiting macrophages that convert a vascular area into a chronic inflammatory site is much greater when the tissue HUFA balance has a high %n-6 in HUFA. In this way, the higher risk of mortality associated with higher levels of the food energy biomarker, cholesterol (Fig. 1), is seen in populations that have a higher HRA value for the %n-6 in HUFA. A high prevalence of CVD for Americans has remained for decades near 40% for 40-year olds, 60% for 60-year olds and 80% for 80-year olds  indicating a failure to prevent the continual disease progression that the PDAY Study showed to begin youth.
Fig. 3A shows how n-3 and n-6 mediators act in CVD, and Fig. 3B shows how food energy intake leads to a high body mass index (BMI) or obesity, which is a predictive associated risk factor for CVD. While factors that cause obesity may also cause CVD, a high BMI per se is not a certain cause of vascular damage, CVD or death. A very large expensive effort to lower CVD by lowering BMI with intensive lifestyle intervention of 5145 overweight or obese patients in 16 study centers  gave weight loss through decreased caloric intake and increased physical activity. However, the trial was stopped after millions of dollars and 9.6 years of follow-up showed no lowering of observed risk of cardiovascular morbidity or mortality compared with controls. While many people believe that obesity (high BMI) causes death, the fatal mechanisms and mediators will need to be better identified and prevented if we are to design cost-effective interventions that prevent harm from food energy.