Yoichi Ogushi

Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review

Objective It is well known that total cholesterol becomes less of a risk factor or not at all for all-cause and cardiovascular (CV) mortality with increasing age, but as little is known as to whether low-density lipoprotein cholesterol (LDL-C), one component of total cholesterol, is associated with mortality in the elderly, we decided to investigate this issue. Setting, participants and outcome measures We sought PubMed for cohort studies, where LDL-C had been investigated as a risk factor for all-cause and/or CV mortality in individuals ≥60 years from the general population. Results We identified 19 cohort studies including 30 cohorts with a total of 68 094 elderly people, where all-cause mortality was recorded in 28 cohorts and CV mortality in 9 cohorts. Inverse association between all-cause mortality and LDL-C was seen in 16 cohorts (in 14 with statistical significance) representing 92% of the number of participants, where this association was recorded. In the rest, no association was found. In two cohorts, CV mortality was highest in the lowest LDL-C quartile and with statistical significance; in seven cohorts, no association was found. Conclusions High LDL-C is inversely associated with mortality in most people over 60 years. This finding is inconsistent with the cholesterol hypothesis (ie, that cholesterol, particularly LDL-C, is inherently atherogenic). Since elderly people with high LDL-C live as long or longer than those with low LDL-C, our analysis provides reason to question the validity of the cholesterol hypothesis. Moreover, our study provides the rationale for a re-evaluation of guidelines recommending pharmacological reduction of LDL-C in the elderly as a component of cardiovascular disease prevention strategies.

Statins stimulate atherosclerosis and heart failure: pharmacological mechanisms

In contrast to the current belief that cholesterol reduction with statins decreases atherosclerosis, we present a perspective that statins may be causative in coronary artery calcification and can function as mitochondrial toxins that impair muscle function in the heart and blood vessels through the depletion of coenzyme Q10 and ‘heme A’, and thereby ATP generation. Statins inhibit the synthesis of vitamin K2, the cofactor for matrix Gla-protein activation, which in turn protects arteries from calcification. Statins inhibit the biosynthesis of selenium containing proteins, one of which is glutathione peroxidase serving to suppress peroxidative stress. An impairment of selenoprotein biosynthesis may be a factor in congestive heart failure, reminiscent of the dilated cardiomyopathies seen with selenium deficiency. Thus, the epidemic of heart failure and atherosclerosis that plagues the modern world may paradoxically be aggravated by the pervasive use of statin drugs. We propose that current statin treatment guidelines be critically reevaluated.

Application of telepsychiatry: A preliminary study

Telemedicine is the provision of professional medical services from sites removed from the patient. This study was conducted in order to assess the reliability of psychiatric evaluations via video‐consultation. The inter‐rater reliability was determined for each interviewing condition by employing the reliability‐testing paradigm in which the brief psychiatric rating scale (BPRS) and the interclass correlation coefficient (ICC) are used. The inter‐rater reliability scores between face‐to‐face interviews and interviews conducted by video at two different levels of image qualities were compared by the authors. Reliability was found to be in perfect agreement in each of the interviewing conditions. This study verifies that telepsychiatry is a reliable method of assessing patient conditions. It may be used to provide much needed mental health‐care services to patients whose access to them is restricted.

Association of health-related quality of life with health examination including organic functions and lifestyles in Japanese employees

Objective: The objective of this study was to compare the association of each item of a health examination including organic functions and lifestyles with health-related quality of life (HRQoL) by gender. Methods: A cross-sectional survey by a self-administered questionnaire using the 36-Item Short Form Health Survey (SF-36) was conducted for Japanese employees from October 1999 to September 2000. Participants in this study consisted of 458 men and 321 women systematically selected from the health examinees. Main results: The determination of organic functions including ‘body mass index’, ‘blood pressure’, ‘liver functioning’, and ‘blood sugar control’ was hardly associated with HRQoL, except for the body mass index in women. All the lifestyle items including smoking cigarettes, drinking alcohol, eating breakfast, doing exercise, adhering to bedtime, and working overtime were associated with HRQoL in the multiple regression models. In the mental component summary (MCS), the standardized regression coefficient of ‘hours of overtime’ was −0.235 in the men and −0.212 in the women (p < 0.001). In the physical component summary (PCS), that of ‘energy consumed in exercise’ was 0.149 in the women (p < 0.01). Conclusion: This study reveals that the association between lifestyle and HRQoL was stronger than that between organic function and HRQoL.

Comparison of eicosapentaenoic acid concentrations in plasma between patients with ischemic stroke and control subjects.

OBJECTIVE ω-3 fatty acids, including eicosapentaenoic acid (EPA), prevent ischemic stroke. However, the clinical importance of EPA for ischemic stroke and its subtype has not been fully elucidated. METHODS In a cross-sectional study, we determined whether ω-3 fatty acids were predictive factors for ischemic stroke. We compared common clinical parameters among 65 patients with ischemic stroke and 65 control subjects. The parameters included blood chemistry data; concentrations of EPA, docosahexaenoic acid, and arachidonic acid (AA); EPA/AA ratio; smoking; alcohol intake; fish consumption more than four times per week; and the incidence of underlying diseases. The comparisons were performed using the Mann-Whitney U test, and multiple logistic regression analysis was applied to the significant factors in the non-parametric test. We also applied the same approach to the ischemic stroke subtypes, cardioembolism and large-artery atherosclerosis. RESULTS In the multiple logistic regression analysis after the Mann-Whitney U test, a lower EPA concentration was one of the significant risk factors for ischemic stroke, as were a lower body mass index, lower high-density lipoprotein cholesterol, and smoking (sensitivity 0.846, specificity 0.831, positive predictive value 0.833). In the analysis of subtypes, a lower EPA/AA ratio and a lower body mass index were the significant risk factors for cardioembolism (sensitivity 0.800, specificity 0.733, positive predictive value 0.750). However, large-artery atherosclerosis was not related to the EPA concentration or the EPA/AA ratio. CONCLUSIONS In this study, the plasma EPA concentration and the EPA/AA ratio were potential predictive risk factors for ischemic stroke, especially for cardioembolism. Further prospective studies are necessary.

The current status of medicolegal issues surrounding telepathology and telecytology in Japan.

The medicolegal issues surrounding telepathology and telecytology in Japan have been partly resolved since the government declared that telediagnosis in these fields using a microscope is essentially a medical practice between doctors. Thus it does not contravene article 20 of the law pertaining to medical practice in Japan, which states that there must be an actual face-to-face encounter between the doctor performing any diagnostic or treatment episode and the patient. It is, however, only beginning to be recognized that the medicolegal issues surrounding telepathology and telecytology depend on factors such as the type of system used (e.g. active versus passive). In an active diagnostic system, the telepathologist or telecytopathologist can control a robotic microscope at the remote site, while in a passive diagnostic system the telepathologist or telecytopathologist makes the diagnosis based on the microscope images that have been selected, and transmitted, by someone in the remote hospital. In the former case the interpreting telepathologist or telecytopathologist must assume most of the responsibility for the diagnostic process, while in the latter more responsibility must be assumed by those at the remote site. The duties and responsibilities of all participants in the telediagnostic process, whatever the system employed, must be determined. We have established working guidelines for telepathological and telecytological diagnoses to help achieve this and hence ensure safe and effective clinical practice.

Lifestyle and colorectal cancer: A case-control study

A case-control study has been conducted to investigate the relationship between lifestyle and risk of colorectal cancer. Cases are one hundred patients diagnosed with colon and rectal cancer in Tokai University Hospital between 1986 and 1994. Three controls per case were individually matched by age, sex, local areas and date of health checkups at the Automated Multi-phasic Health Testing and Services (AMHTS ) Center of the hospital. The results were analyzed by multi-factorial logistic regression models. Positive history of maternal cancer, large consumption of alcohol, frequent consumption of potato products and white-collar job were predominant risk factors while frequent intake of seaweed was a protective factor. Frequent intakes of dairy foods and lack of exercise showed no significant tendency to increase risk of colorectal cancer. Smoking habits, intakes of meat and egg were shown not to be related to this disease. These findings suggest that family history of cancer and dietary factors play a key role in causation and prevention of colorectal cancer.

Cholesterol Issues in Japan – Why Are the Goals of Cholesterol Levels Set So Low

cholesterol levels and that low cholesterol levels were not the cause of death [5] . Without liver disease death, this would be no longer all-cause mortality. Besides, hepatitis C virus (HCV) enters hepatic cells via LDL receptors [7] , and low cholesterol levels are one of the major risk factors of HCV infection and chronic hepatitis. Hence, death from liver disease could be the result of low cholesterol levels [8] . Third, NIPPON DATA 80 apparently included a higher percentage of participants with familial hypercholesterolemia (FH) than the general Japanese population [9] , which exaggerated the risk of TC. With regard to Japanese women, no study has ever shown that TC or LDL-C is a risk factor of mortality from coronary heart disease (CHD) except for that flawed NIPPON DATA 80 [5] . Consequently, it is hard to understand why women for primary intervention comprise nearly two thirds of statin users in Japan [Ogushi, unpubl. data]. JASG 2012 has many flaws. It omitted many important pieces of information that the readers have to know. The strangest point is that the committee members of JASG 2012 did not disclose COI at all. How can one assess the reliability of medical guidelines without COI disclosure? In fact, most of the committee members are known to be recipients of huge amounts of research grants from the related industries. The following are some other unacceptable points of JASG 2012: This summary aims to elucidate the relationship between serum total cholesterol (TC) or LDL-cholesterol (LDL-C) levels and mortality from all and cardiovascular causes in Japan, and to criticize the recently revised ‘Japan Atherosclerosis Society (JAS) Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases, 2012’ [1] (JASG 2012). The hypothesis ‘the lower the cholesterol levels are, the better’ is absolutely wrong. The epidemiological studies in Japan with 1 10,000 participants over follow-ups of 1 10 years showed that allcause mortality in the groups of the highest TC or LDL-C levels was lower than most of the other groups [2–4] . The only exceptional study (NIPPON DATA 80, on which JASG 2012 depends almost exclusively) claimed that the group of the highest TC levels had the highest all-cause mortality [5] . However, this study had several important flaws. First, results were adjusted for sex and albumin levels. Without adjustment for sex, all-cause mortality in the groups of the highest TC levels ( 1 259 mg/dl) was not significantly higher than control groups (160–179 mg/dl) either in men or women. Serum albumin levels are positively associated with TC levels, especially in elderly people [6] . Thus, the adjustment for albumin (a negative risk factor for all-cause mortality) cancelled good aspects of TC. Second, the authors excluded liver disease deaths from all-cause mortality in one of their analyses claiming that liver disease caused both death and depression of Published online: December 4, 2012

Health and welfare data on optical memory cards in Isehara city

An off-line network system of health and welfare for elderly people using optical memory cards has been established in Isehara city (Japan) since 1991. 2775 citizens have the cards and 24 offices have the terminals. It covers almost one third of people aged over 65 in Isehara city and almost all of the offices concerned with their health and welfare. About a half of holders use optical memory cards every time they visit these offices. The optical memory card holds data including basic data for health and welfare, health check data over 5 years, medical images with scripts and history of welfare services. All the data are used for medical care, health consultation and management of health and welfare services. A card can hold health and welfare data for a lifetime, and it is easy to expand the system. It has been a good experience for us, because the optical memory card system needs co-operation among citizens, medical association and local government, and the experience will help us to expand the system in the future.

A Critical Review of the Consensus Statement from the European Atherosclerosis Society Consensus Panel 2017

Background: The Consensus Statement from the European Atherosclerosis Society (EAS) Consensus Panel 2017 concludes on the basis of 3 different types of clinical studies that low-density lipoprotein (LDL) causes atherosclerotic cardiovascular disease (ASCVD). In Mendelian randomization studies, rare genetic mutations affecting LDL receptor function were found to cause higher or lower LDL-C levels, which are associated with correspondingly altered ASCVD risk. In prospective cohort studies and randomized controlled trials (RCTs) of statins, a remarkably consistent log-linear association was demonstrated between the absolute magnitude of LDL-C exposure and ASCVD risk. The EAS Statement proposes that any mechanism of lowering plasma LDL concentration should reduce the risk of ASCVD events proportional to the absolute reduction in LDL-C and the cumulative duration of exposure to lower LDL-C. However, as we explain, we do not find this conclusion acceptable. Summary: Our review points out that different interpretations are possible for the results of Mendelian randomization studies. As for prospective cohort studies, many inconsistent reports on the association of LDL-C and ASCVD were disregarded when drafting the Statement, reports with and without genetic factors related to LDL receptor function should be analyzed separately, and the term ASCVD in the Statement is used inappropriately because myocardial infarction and cerebral infarction differ in their association with LDL-C. As for RCTs, clinical reports on statins published before and after the implementation of new regulations affecting clinical trials (2004/2005) should not both be included in meta-analyses because the evaluated efficacy of statins changed markedly, and the irreversible adverse effects of statins need to be evaluated more rigorously now that their mechanisms have been elucidated. Key Messages: Apart from the EAS hypothesis that LDL causes ASCVD, recent pharmacological/biochemical studies, as summarized in this review and elsewhere, have revealed that atherosclerosis is caused by statins taken to lower LDL-C, as well as by warfarin and some types of vegetable fats and oils, in the absence of significantly elevated LDL-C levels. Thus, the promotion of statin treatment by the Statement is rather risky and we do not feel that the conclusions are justified for the prevention of ASCVD.