Background —Carriers of the apolipoprotein A-I _Milano (apoA-I _M ) mutant present with very low plasma HDL cholesterol and moderate hypertriglyceridemia, apparently not leading to premature coronary heart disease. The objective of this study was to establish whether this high-risk lipid/lipoprotein profile is associated with structural changes in the carotid arteries and heart, indicative of preclinical atherosclerosis. Methods and Results —Twenty-one A-I _M carriers were compared with age- and sex-matched control subjects from the same kindred and with 2 series of matched subjects with primary hypoalphalipoproteinemia (HA). Structural changes in the carotid arteries were defined as the intima-media thickness (IMT) measured by B-mode ultrasound. HA subjects, both recruited among patients attending our Lipid Clinic and blood donors, showed significant thickening of the carotids (average IMT, 0.86±0.25 and 0.88±0.29 mm, respectively) compared with control subjects (average IMT, 0.64±0.12 mm); the apoA-I _M carriers instead showed normal arterial thickness (average IMT, 0.63±0.10 mm). Moreover, a significantly higher prevalence of atherosclerotic plaques was found in patients and blood donors with HA (both 57%) compared with apoA-I _M carriers (33%) and control subjects (21%). Echocardiographic findings and maximal treadmill ECG did not differ significantly between apoA-I _M carriers and control subjects, apart from a slight increase in left ventricular end-diastolic dimension in the carriers. Conclusions —Despite severe HA, carriers of the apoA-I _M mutant do not show structural changes in the arteries and heart, in contrast to HA subjects, who are characterized by a marked increase in carotid IMT and increased prevalence of atherosclerotic plaques.

Therapeutic approaches to metabolic syndrome (MetS) are numerous and may target lipoproteins, blood pressure or anthropometric indices. Peroxisome proliferator-activated receptors (PPARs) are involved in the metabolic regulation of lipid and lipoprotein levels, i.e., triglycerides (TGs), blood glucose, and abdominal adiposity. PPARs may be classified into the α, β/δ and γ subtypes. The PPAR-α agonists, mainly fibrates (including newer molecules such as pemafibrate) and omega-3 fatty acids, are powerful TG-lowering agents. They mainly affect TG catabolism and, particularly with fibrates, raise the levels of high-density lipoprotein cholesterol (HDL-C). PPAR-γ agonists, mainly glitazones, show a smaller activity on TGs but are powerful glucose-lowering agents. Newer PPAR-α/δ agonists, e.g., elafibranor, have been designed to achieve single drugs with TG-lowering and HDL-C-raising effects, in addition to the insulin-sensitizing and antihyperglycemic effects of glitazones. They also hold promise for the treatment of non-alcoholic fatty liver disease (NAFLD) which is closely associated with the MetS. The PPAR system thus offers an important hope in the management of atherogenic dyslipidemias, although concerns regarding potential adverse events such as the rise of plasma creatinine, gallstone formation, drug–drug interactions (i.e., gemfibrozil) and myopathy should also be acknowledged.

White lupin (Lupinus albus, L.), a widely cultivated crop that has been consumed for many years in Western Europe, may provide a useful alternative for individuals wishing to substitute animal with plant proteins for cardiovascular disease prevention. Lupin seeds have a very low content of isoflavones, and lupin protein isolates are essentially isoflavone free. In rats fed a casein-based cholesterol + cholic acid diet, a relatively low daily intake (50 mg/d by gavage for 2 wk) of total lupin protein extract reduced plasma total and VLDL + LDL cholesterol concentrations by 21 and 30%, respectively (both P < 0.001). In an attempt to elucidate the lipid-lowering mechanism, LDL receptor activity was evaluated in a human hepatoma cell line (HepG2). In this model, the lupin total protein extract was essentially inactive, whereas one purified minor protein component, conglutin γ, had a remarkable upregulatory effect, with maximal increases of 53 and 21% (both P < 0.05) for LDL uptake and degradation, respectively. This initial study indicates that lupin, although isoflavone free, has hypocholesterolemic activity similar to that of other leguminous proteins in an established animal model. Further, the cholesterol reduction appears to be associated with stimulation of LDL receptors by a well-defined protein component of the lupin seeds as demonstrated by in vitro studies.

Phytoestrogens are plant‐derived hormone‐like diphenolic compounds of dietary origin that are present at high levels in plasma of subjects living in areas with low atherosclerosis and cancer incidence. The term phytoestrogen is commonly applied to the soy isoflavones genistein, daidzein and glycitein. As outlined in a previous review article in this journal by Adlercreutz and Mazur , these compounds are weakly estrogenic and appear to influence the cardiovascular system, the production, metabolism and biological activity of sex‐hormones, as well as malignant cell proliferation, differentiation and angiogenesis. Recently skepticism has developed concerning the true potential of phytoestrogens to beneficially modify these processes. A critical analysis of the early findings from supplementing the diet with soy protein has failed to confirm phytoestrogens as the responsible agent for beneficial cardiovascular effects, be it by way of lipid reduction, vasodilation or lipoprotein oxidation. Furthermore, contrasting data have been reported on the potential of phytoestrogens to prevent hormone‐dependent cancers (e.g. breast and prostate) and to successfully treat post‐menopausal complaints, an indication for which they are widely used. These potentially negative findings have led health authorities in several countries to suggest maximum daily intake levels for phytoestrogens. There is now growing interest in the use of soy products containing low levels of phytoestrogens and in research on other phytoestrogen free legumes such as lupin.