1. In the Guideline (2007), diagnostic criteria were proposed in terms of LDL-C instead of total cholesterol (TC). In the Joint Panel Discussion, it was criticized that no available data in Japan support the criteria proposed. Moreover, LDL-C was revealed to be a predictor of longevity in the Koriyama-Isehara Study. 2. The Guideline described that high-LDL-C is a risk factor for CHD even in aged populations, citing several references. However, the cited references do not present LDL-C but TC, and that the association of TC with CHD mortality is weak and not conclusive. An example was reproduced here that a significantly negative association of TC with CHD changed to positive after adjustments for several confounding factors. Thus, the evidence presented so far does not justify hypocholesterolemic medications but it tells us that such medications are inappropriate for aged populations. 3. Those with inborn genetic factors such as familial hypercholesterolemia (FH) and an apo E genotype are different from hypercholesterolemic non-FH subjects in that the supply of LDL-carried lipids to peripheral tissues is restricted from young ages in the former but is fulfilled in the latter. The delegates from the Japan Atherosclerosis Society appeared not to accept this interpretation. As a chairperson, I emphasize that the ω6⁄ω3 balance of dietary and tissue lipids rather than plasma cholesterol is a critical factor for atherosclerotic diseases, and that dietary recommendations in the Guideline (2007) need to be revised.
The targets of lipid lowering therapy in Japan are severer than those in western countries. Two hundred twenty mg⁄dl for total cholesterol (TCH), 140mg⁄dl for LDL-C, 150 mg⁄dl for triglyceride (TG) are used for the target values. In western countries, those values are 270 mg⁄dl, 190 mg⁄dl and 1,000 mg⁄dl respectively for low risk persons. But, a morbidity rate of coronary heart disease in Japan is a third in western countries. Strange to say, the number of women who accepts the therapy is twice of that of men in Japan. We have verified the targets used in Japan by some kinds of studies. We established clinical reference intervals of TCH, LDL-C, TG and HDL-C from the results of health checkup of about 700,000 persons by the method comparable to NCCLS in USA. We performed cohort studies and found cutoff points where mortalities increased significantly. These results are equal to the targets used in western countries. People diagnosed as hyperlipidemia by Japanese standard have less morbidity of strokes. If they develop strokes, their clinical indexes are better than persons in normal lipid level. In conclusion, the guideline for hyperlipidemia in Japan should be revised according to Japanese evidences soon.
In 2007, Japan Atherosclerosis Society published Guidelines for prevention of atherosclerotic cardiovascular diseases. However, the Guidelines had serious flaws with regard to serum cholesterol levels. The followings are the list of those flaws: #1. They started to use LDL-cholesterol (LDL-C) levels instead of serum total cholesterol (TC) levels. In this case they must show at least some basic data on the relationship between LDL-C and mortality or morbidity from coronary heart disease (CHD). In the Guidelines there were no such data at all! #2. They recommended LDL-C be below 140 mg⁄dL or 3.6 mmol⁄L (corresponding to TC of 220 mg⁄dL or 5.7 mmol⁄L). These levels were unreasonable considering that TC levels of 240-260 are the best in terms of all-cause mortality in Japan. They did not show any data on all-cause mortality in the Guidelines. #3. There are big differences in mortality and morbidity from CHD between sexes. However, they discussed the matter without differentiating sexes, just counting being male as one risk factor. #4. Conflict of interest of editors of the Guidelines has never been disclosed as of the end of year 2008. #4. Diets for preventing CHD have never succeeded in Japan yet. #5. The only large-scaled study with a statin in Japan (MEGA Study) had incredible defects; the cholesterol-lowering strategy depended on that extremely unreliable study. #6. The astonishing results of 4S (Simvastatin Scandinavian Survival Study) has hardly been reproduced by any other trials. There are serious doubts about the data from pharmaceutical company-supported trials. In conclusion, familial hypercholesterolemia is probably the only target of statins.
Statins are potent inhibitors of cholesterol biosynthesis and have been used for the reduction of serum cholesterol levels to prevent cardiovascular diseases according to the cholesterol hypothesis of atherosclerosis. However, a wide varieties of beneficial effects of statins are known to rather actually occur earlier than serum cholesterol goes down, indicating cholesterol-independent effects. The effects beyond cholesterol lowering are socalled "pleiotropic effects" of statins, including eNOS expression, anti-oxidative function, anti-inflammatory action, osteomorphogenesis and so on. In addition to those, the effects of statins against carcinogenesis and degenerative processes in the brain leading to Alzheimer's disease and Parkinson's disease are examined in the literature. The pleiotropic effects of statins observed so far might be the reverse of a coin, where serious impairments of physiological functions of the intermediates of cholesterol biosynthesis take place. Adverse effects may happen to be manifested in the course of long-term use of statins. Considering the not much size of the benefits, statins should not be given to a large population to avoid terrible side-effects or demerits. Statin use may rather be better to be confined to patients with familial hypercholesterolemia who definitely obtain merits.
WHO projects that approximately 2.3 billion adults will be overweight in 2015. The fundamental cause of overweight is an energy imbalance between calories consumed and calories expended. Overweight is a risk factor for a cardiovascular disease. In experimental animals, numerous studies have found that dietary restriction without malnutrition prolongs the lifespans. Preliminary data indicate that this is true in monkeys, and could be true in humans as well. Fasting is a type of dietary restriction, representing the complete restriction of nutrients. It has been reported that intermittent fasting and short-term repeated fasting, in which fasting is repeatedly alternated with ad libitum feeding, is effective in increasing animal lifespans. Dietary restriction and fasting have been documented to have a preventative effect on various diseases, such as malignancy, autoimmune diseases and Parkinson's disease. Recently, we applied dietary restriction to allergy diseases in animal models, and found that atopic dermatitis and contact dermatitis were suppressed. Furthermore, in a clinical study, we offered a low-energy diet to 19 adults with atopic dermatitis during 8 weeks, and reported remarkable improvement of atopic dermatitis, which was associated with weight loss by a low-energy diet. With regard to rheumatoid arthritis, the effect of fasting followed by one year of vegetarian diet was assessed in a randomized, single-blind controlled trial. However, clinical evidence for allergic disease and autoimmune disease is still limited. Therefore, an accurate and large-scale study is necessary in the future so that dietary restriction may establish it as a treatment of atopic dermatitis and rheumatoid arthritis.
Deficits in prepulse inhibition (PPI) are a biological marker for schizophrenia. To unravel the mechanisms that control PPI, we performed quantitative trait loci (QTL) analysis, on 1010 F2 mice derived by crossing C57BL/6 (B6) animals that show high PPI with C3H/He (C3) animals that show low PPI. We detected 6 major loci for PPI. A promising candidate on the chromosome 10-QTL was Fabp7 (fatty acid binding protein 7, brain), a gene with functional links to the NMDA receptor and expression in neural stem/progenitor cells in developmental stage. Fabp7-deficient mice indeed showed decreased PPI. A quantitative complementation test supported Fabp7 as a potential PPI-QTL gene. Disruption of Fabp7 attenuated neurogenesis in vivo. Human Fabp7 showed genetic association with schizophrenia. FABP7 is known to have high affinity for polyunsaturated fatty acids, in particular docosahexaenoic acid. These results suggest that FABP7 plays a novel and crucial role, linking the NMDA, neurodevelopmental and nutritional issues of schizophrenia pathology.
Fish oil is a commercial source of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and it plays important roles in human health and wellness. Nippon Suisan Kaisha has been researching on the use of fish oil for human health since 1979. For medical use, we have developed industrial method to concentrate EPA from fish oil by using distillation and urea adduct separation. Purified EPA is now used in the treatment of arteriosclerosis and hyperlipemia in Japan. For food use, we have developed "IMARK" which is a liquid FOSHU (Food for Specified Health Uses) containing 600 mg of EPA and 260 mg of DHA per one serving (100 ml). Numbers of 53 volunteers were participated in randomized, double-blind controlled study of IMARK and received a daily amount of 100 ml for 12 weeks. The average blood triglyceride level of participants was 170 mg/dl before treatment, and it decreased significantly to 145, 132, and 134 mg/dl after 4, 8, and 12 weeks of treatment, respectively. We have also examined the clinical effect of a liquid supplement containing 1260 mg of EPA and 540 mg of DHA on atopic dermatitis. The liquid supplement was taken by 21 patients, once per day for 12 weeks. Following this treatment for the remained 18 patients, led to significant clinical improvement on the skin symptoms of 13 patients. These results suggested that the liquid supplement containing dietary EPA and DHA might have a beneficial impact on health maintenance and as an alimentary therapy for hyperlipemia and atopic dermatitis.
心疾患予防を目指した二種類の大規模な介入試験が米国でなされた。一つはコレステロール仮説に基づくものであり(MRFIT研究)、他は“総脂肪摂取エネルギー比率を下げ、穀類、野菜類、果物を増やす”もの(Women's Health Initiative Study)であった。しかしこれらはともに、心疾患、痛予防などに効果が無かった。これらに欠けている視点は脂肪酸のn-6/n-3(ω6/ω3)バランスである。将来、介入試験を企画する場合は、次の視点を考慮することが望まれる。 (1)リノール酸(ω6)系の摂取を、現在の米国の7 en % からISSFALワークショップの提案している上限、3 en %に向けて減らすこと10)、 (2) ω3系脂肪酸の摂取を日本人の摂取量1.5 en %（鎖長18と≧20の脂肪酸をほぼ同量）に増やすこと、 (3)水添植物油と動物に有害な作用を示す数種の植物油の摂取を最小限にすること。これらの植物油脂より動物性脂肪のほうが安全である。