Ken-ichi Nakahara

Age-related mitochondrial DNA deletion in human heart: Its relationship with cardiovascular diseases

Background and aims: Accumulation of damage to mitochondrial DNA (mtDNA) occurs in myocardial tissue with advancing age. However, despite higher incidence of cardiac diseases in the elderly, little attempt has been made to detect deletions of mtDNA in the myocardial tissue of aged individuals. The aim of the present study was to clarify the relationship between aging, mtDNA deletion and cardiovascular (CV) diseases. Methods: We examined 163 autopsy cases, aged 60 years or older, using two different kinds of polymerase chain reaction (PCR): highly sensitive PCR to detect a common 4977- bp deletion and long- PCR for multiple deletions, which could be detected in case that deleted mtDNA accounted for more than several percents in total mtDNA. Results: The common 4977- bp deletion was detected in 156 cases (95.7%), showing no significant difference among these age groups and no relation to CV diseases. By long- PCR, multiple deletions in cardiac mtDNA were found in 33 (20.2%) of 163 cases. The proportion of the mtDNA deletion in the nineties (46.2%) was significantly higher than those in the younger (15.3%, p<0.05). Female predominance was significantly found in the group with the mtDNA deletion (p<0.05). Multiple deletions of mtDNA were not significantly related to ischemic change, valvular diseases, left ventricular hypertrophy, congestive heart failure, coronary sclerosis, or heart weight except for right ventricular hypertrophy. Conclusions: These findings suggest that there is a close relationship between aging and deletion of mtDNA, and that the ratio of deleted mtDNA to total mtDNA increases with advancing age. Age-related deletion of mtDNA may have little influence on CV diseases except for right ventricular hypertrophy.

Replication of the association between a chromosome 9p21 polymorphism and coronary artery disease in Japanese and Korean populations

AbstractCoronary artery disease (CAD) has become a major health problem in many countries. Recent genome-wide association studies have identified the association between rs1333049 on chromosome 9p21 and susceptibility to CAD in Caucasoid populations. In this study, we evaluated the associations of rs1333049 with CAD in Japanese (604 patients and 1,151 controls) and Koreans (679 patients and 706 controls). We found a significant association in both Japanese [odds ratio (OR) = 1.30, 95% confidence interval (CI); 1.13–1.49, p = 0.00027, allele count model] and Koreans (OR = 1.19, 95% CI; 1.02–1.38, p = 0.025, allele count model). These observations demonstrated that chromosome 9p21 was the susceptibility locus for CAD also in East Asians.

Insertion/Deletion Polymorphism in the Angiotensin-Converting Enzyme Gene Affects Heart Weight

BACKGROUND Angiotensin (Ang) II, a major regulatory factor for left ventricular mass, is generated from Ang I by ACE. ACE levels are associated with an insertion/deletion (I/D) polymorphism in the ACE gene. The ACE polymorphism should result in varied Ang II concentrations and hence affect left ventricular mass. We therefore investigated whether ACE genotype is a predictor of heart weight. METHODS AND RESULTS From 693 consecutive patients autopsied between 1994 and 1998 in our hospital, patients with valvular disease, myocardial infarction, or cardiomyopathy were excluded. The remaining 443 autopsy patients were the subjects of our study. The heart weight at autopsy was corrected for body surface area. Genomic DNA was purified from the kidney, and ACE genotype was determined by polymerase chain reaction. Heart weight in the DD genotype (249. 9+/-49.9 g/m(2)) was significantly higher than that in the ID (230. 0+/-51.2 g/m(2); P<0.05) and II (226.8+/-49.8 g/m(2); P<0.01) genotypes. Heart weight was also positively related to age (r=0.145, P<0.0001) and coronary stenosis index (r=0.147, P=0.0019). Multiple regression analysis showed that a history of hypertension (P<0.0001), age (P=0.0001), and DD genotype (P=0.0154) were independent predictors of heart weight. CONCLUSIONS ACE genotype predicts cardiac mass; however, it was less effective than epigenetic factors such as hypertension or age.

Developments of geriatric autopsy database and Internet-based database of Japanese single nucleotide polymorphisms for geriatric research (JG-SNP)

To facilitate geriatric research on the roles of genetic polymorphisms of candidate genes, two databases were developed based on data obtained from autopsy examinations of elderly subjects: the geriatric autopsy database (GEAD) and the Japanese single nucleotide polymorphisms (SNP) database for geriatric research (JG-SNP) which is accessible on the Internet (http://www.tmgh.metro.tokyo.jp/jg-snp/english/E_top.html). The data for the GEAD were derived from 1074 consecutive autopsy cases (565 male and 509 female cases) with an average age of 80 years. The GEAD was installed on a stand-alone Windows 2000 server using Oracle 8i as the database application. The GEAD contains clinical diagnoses of 26 geriatric diseases, histories of smoking and alcohol consumption, pathological findings (720 items), severity of atherosclerosis, genetic polymorphism data, etc. On the JG-SNP website, case distribution corresponding to a specified SNP or disease can be searched or downloaded. Although there are several Internet-based SNP databases such as dbSNP, no databases are available at present on the web that contain both SNP data and phenotypic data. As autopsy studies can provide large amounts of accurate medical information, including the presence of undiagnosed diseases such as latent cancers, the GEAD is a unique and excellent database for research on genetic polymorphisms.

Low Lipoprotein(a) Concentration Is Associated with Cancer and All-Cause Deaths: A Population-Based Cohort Study (The JMS Cohort Study)

Background Experimental studies support the anti-neoplastic effect of apo(a), but several clinical studies have reported contradictory results. The purpose of this study was to determine whether a low lipoprotein(a) [Lp(a)] concentration is related to mortality from major causes of death, especially cancer. Methods The subjects were 10,413 participants (4,005 men and 6,408 women) from a multi-center population-based cohort study in Japan (The Jichi Medical School cohort study). The average age at registration was 55.0 years, and the median observation period was 4,559 days. As the estimated hazard ratio was high for both the low and very high Lp(a) levels, we defined two Lp(a) groups: a low Lp(a) group [Lp(a)<80 mg/L] and an intermediate-to-high Lp(a) group [Lp(a)≥80]. Participants who died from malignant neoplasms (n = 316), cardiovascular disease (202), or other causes (312) during the observation period were examined. Results Cumulative incidence plots showed higher cumulative death rates for the low Lp(a) group than for the intermediate-to-high Lp(a) group for all-cause, cancer, and miscellaneous-cause deaths (p<0.001, p = 0.03, and p = 0.03, respectively). Cox proportional hazards analyses with the sex and age of the participants, body mass index, and smoking and drinking histories as covariates showed that a low Lp(a) level was a significant risk for all-cause, cancer, and miscellaneous-cause deaths (p<0.001, p = 0.003, and p = 0.01, respectively). The hazard ratio (95% CI) [1.48, 1.15–1.92] of a low Lp(a) level for cancer deaths was almost the same as that for a male sex (1.46, 1.00–2.13). Conclusions This is the first report to describe the association between a low Lp(a) level and all-cause or cancer death, supporting the anti-neoplastic effect of Lp(a). Further epidemiological studies are needed to confirm the present results.

High lipoprotein(a) level promotes both coronary atherosclerosis and myocardial infarction: a path analysis using a large number of autopsy cases

Objective: To investigate whether hyper-lipoproteinaemia(a) (Lp(a)) promotes coronary atherosclerosis, acute thrombosis resulting in myocardial infarction (MI), or both. Design: Retrospective chart review. Setting: A community-based general geriatric hospital. Patients: 1062 consecutive autopsy cases (609 men, 453 women). The mean age at the time of death was 80 years. Main outcome measures: A semiquantitative evaluation of the coronary stenosis on cut sections and pathological definition of MI. Lp(a) levels of fresh serum taken antemortem, measured by a latex-enhanced turbidimetric immunoassay. Results: The prevalence of severe coronary stenosis and pathological MI increased linearly with increasing Lp(a) levels with no apparent threshold. The odds ratios (95% CI) of hyper-Lp(a) (2.99 (1.70 to 5.28) for 200–299 mg/l and 3.25 (1.90 to 5.54) for >300 mg/l) for severe coronary stenosis were larger than those of hypertension (2.61 (1.88 to 3.63)), diabetes mellitus (2.09 (1.41 to 3.11)) and hypercholesterolaemia (2.05 (1.31 to 3.21)). The severe coronary sclerosis was much stronger risk of MI (6.28 (4.33 to 9.11)) than hyper-Lp(a), hypertension and diabetes mellitus. A path analysis showed that the Lp(a) levels affected both coronary sclerosis and MI, with path coefficients of 0.15 and 0.07 (direct effect), respectively. In cases with severe coronary sclerosis Lp(a) affected only MI (0.15). Conclusions: Lp(a) levels have distinct effects on coronary sclerosis and MI, with about half of the overall effect on MI being via coronary sclerosis. This result supports the prothrombotic and a probable proinflammatory role of Lp(a) in coronary events.

Association of Estrogen Receptor α Gene Polymorphisms with Neurofibrillary Tangles

Estrogen receptor α (ERα) may be implicated in the pathogenesis of Alzheimer’s disease (AD). The aim of this study was to clarify the association between ERα gene polymorphisms and AD-related pathologic changes. The staging of neurofibrillary tangles (NFT) and senile plaques (SP) was performed according to the method by Braak and Braak and two polymorphisms, PvuII (P or p) and XbaI (X or x), of the ERα gene were typed in 551 Japanese cadavers (294 men and 257 women; mean age, 80.8 years). Distributions of the NFT and SP stages significantly correlated with age (NFT: r = 0.306, p < 0.0001; SP: r = 0.237, p < 0.0001) and were significantly higher in patients with the apolipoprotein E Ε4 allele (p < 0.0001). Possession of the P allele showed a trend to be associated with a more serious NFT stage, but had no relationship with the SP stage. In men, a significant association between PvuII polymorphism and the NFT stage (p = 0.002) was found, revealing a gene- dose effect of the P allele. Similar results were obtained in the men without the Ε4 allele (p = 0.011). Multiple regression analyses demonstrated that age was the strongest determinant of the NFT stage, possession of the Ε4 allele was the next strongest, and PvuII polymorphism was the third strongest (p < 0.0001, R2 = 0.144). The XbaI polymorphism did affect neither the NFT stage nor the SP stage. In conclusion, the PvuII polymorphism of the ERα gene is associated with Braak NFT stages and possession of the P allele may act as a risk factor for AD in Japanese men, especially in those without the Ε4 allele.

Evaluation of electrocardiographic criteria for left ventricular hypertrophy based on anatomical comparison

The reliability of precordial electrocardiographic criteria for left ventricular hypertrophy (LVH) was evaluated by comparing it with the anatomical findings of 421 postmortem hearts examined by the chamber dissection technique. Of these 421 postmortem hearts, 136 without cardiovascular disease served as normal controls. The weights of the left ventricular free wall with interventricular septum (LV + S) and of the whole heart in normal controls were 153 +/- 36 grams (mean +/- SD) and 289 +/- 67 grams, respectively. Correlation coefficients between LV + S and whole heart were 0.89 for men and 0.90 for women. Anatomical LVH was defined as the weight of LV + S exceeding the average plus one standard deviation of that of a normal control heart. Anatomically established LVH was found in 99 (28%) of 353 cases having precordial electrocardiograms available for evaluation. The sensitivity, specificity, and predictive accuracy of electrocardiographic criteria for LVH were as follows: SV1 + RV5 greater than 3.5 mV, 56.6%, 76.0% and 47.9%; SV1 + RV5 greater than 4.0 mV, 45.5%, 87.4% and 58.4%; SV1 + RV5 greater than 5.0 mV, 21.2%, 94.5% and 60.0%; SV1 + RV5 greater than 3.5 mV with strain type ST-T, 35.4%, 93.3% and 67.3%; SV1 + RV5 greater than 4.0 mV with strain type ST-T, 29.3%, 94.9% and 69.0%; SV1 + RV5 greater than 5.0 mV with strain type ST-T, 14.1%, 98.0% and 73.7%; strain type ST-T, 36.4%, 92.5% and 65.5%; nonspecific ST-T, 26.3%, 76.4% and 30.2%; SV1 + RV5 greater than 3.5 mV with nonspecific ST-T, 12.1%, 93.3% and 41.4%; and right anteriorly directed T vector, 39.4%, 89.4% and 59.1%.(ABSTRACT TRUNCATED AT 250 WORDS)

Association between a promoter polymorphism of the paraoxonase PON1 gene and pathologically verified idiopathic Parkinson’s disease

Background:  Exposure to pesticide is associated with an elevated risk of Parkinson’s disease (PD). Oxidative stress is also implicated in the etiology of PD. Paraoxonase (PON1) detoxifies organophosphates and exhibits antioxidant properties. It was postulated that polymorphisms of the PON1 gene lead to increased risk of PD.

高齢者糖尿病患者における動脈硬化性血管障害とLp (a) の関係について

Lipoprotein(a) (Lp(a)) is an independent risk factor for cardiovascular diseases in non-diabetic people, but few studies have been done in diabetic patients. To investigate whether Lp(a) is a risk factor for cardiovascular disease in elderly people with diabetes, we examined the association of Lp(a) and serum lipid levels (total cholesterol: TC; triglycerides: TG; and high-density lipoprotein cholesterol: HDL-c) with the incidence of coronary artery disease and cerebrovascular disease. We studied 354 outpatients(131 men and 223 women, 60-97 years of age) with non-insulin-dependent diabetes mellitus. The mean concentration of Lp(a) was 21.1 +/- 19.6 mg/dl and the median was 14.0 mg/dl. The Lp(a) concentration did not correlate significantly with age or with sex, but it did correlate significantly with TC (r = 0.152, p < 0.05) and with the level of apoprotein B (r = 0.168, p < 0.05). The incidence of cerebrovascular disease was significantly higher in patients with high concentrations of Lp(a) (> or = 30 mg/ dl) than in those with low concentrations (< 30 mg/ dl). Multivariate logistic regression analysis revealed that male sex, hypertension, a high level of HbA1c, a low level of HDL, and a high level of Lp(a) were independent risk factors for cerebrovascular disease. The incidence of coronary artery disease tended to the higher in those with high concentrations of Lp(a) (> or = 30 mg/dl). However, multivariate logistic regression analysis revealed no significant correlation between Lp(a) concentration and the incidence of coronary artery disease. We conclude that a high concentration of Lp(a) is an independent risk factor for cerebrovascular disease in elderly patients with diabetes.