Sustained progression and loss of the gender-related difference in atherosclerosis in the very old: a pathological study of 1074 consecutive autopsy cases.

INTRODUCTION: Epidemiological surveys show decrease or reversal of male predominance in cardiovascular mortality in the very old, but the actual condition of atherosclerosis in the very old is largely unknown. The objective of this paper is to reveal whether the atherosclerosis continues to progress, or the gender-related difference exists in the very old. METHODS: The subjects were 1074 consecutive autopsy cases of in-hospital death. The male:female ratio was 1.1:1 and the average age was 80 years. Macroscopic evaluation was performed on the degree of atherosclerosis in 10 arteries including the intracranial arteries, carotid artery, aorta, coronary artery, and femoral artery. RESULTS: The severity of atherosclerosis differed greatly among arteries. The age-related increase of the atherosclerotic degree was evident, even after 80 years of age. The atherosclerosis was more severe in males than in females in their 60s, but this male predominance decreased with ageing and finally disappeared in their 90s. CONCLUSION: The sustained progression of atherosclerosis and loss of the gender-related difference probably account for the increase of cardiovascular mortality in very old females. They also suggest that the prevention of the atherosclerotic progression is still important in the seventh and eighth decade of life.

Aortic pulse wave velocity and the degree of atherosclerosis in the elderly: a pathological study based on 304 autopsy cases.

INTRODUCTION: Studies examining the correlation between aortic pulse wave velocity (PWV) and atherosclerosis have reported conflicting results. The present paper verifies this correlation by conducting autopsy examination of elderly subjects. METHODS: A total of 3456 PWV examinations had been performed on 1538 elderly people, as a part of routine physical check-up. During long-term follow-up, many of these subjects died, and autopsy study could be conducted on 304 of these subjects. The average age at death of the subjects was 83 years and the male: female ratio was 6:5. The pathological atherosclerotic index (PAI) was defined as the average pathological degree of atherosclerosis in eight large arteries, including aorta. RESULTS: Significant positive correlations were observed between the age and PWV (gamma=0.273, P<0.001), and between the systolic blood pressure and PWV (gamma=0.478, P<0.001). There was a significantly positive correlation between the aortic atherosclerotic degree and mean PWV (rho=0.239, P<0.005), and between the PAI and mean PWV (gamma=0.323, P<0.001). The partial regression coefficient between the PAI and mean PWV was 0.209, after adjusting for the mean systolic blood pressure and age at death. CONCLUSION: The present study proved a weak correlation between the PWV and the pathologically verified degree of the aortic and systemic atherosclerosis.

Early pathogenesis of cardiac amyloid deposition in senile systemic amyloidosis: close relationship between amyloid deposits and the basement membranes of myocardial cells.

Despite a number of in vitro studies of transthyretin (TTR) amyloidogenesis the early stage of in vivo amyloidogenesis in the human heart is largely unknown. A heart with a mild degree of cardiac amyloidosis removed from a 90-year old woman at autopsy was selected for analysis. The genotype of the TTR was the wild type. An immunohistochemical study with anti-TTR antibody was performed on serial paraffin sections, and 17 TTR-positive lesions less than 50 micro m in diameter consisting of 13 interstitial and 4 vascular lesions were identified. The early interstitial lesions start as thick membranous deposits between interfacing myocardial cells. They are Congophilic with green birefringence and positive for apolipoprotein E but negative for amyloid P component. The TTR-positive amyloid extends along intercellular spaces and becomes larger, involving several myocardial fibers. The media is the initial site of arteriolar involvement. According to the in vitro studies of amyloid fibrillogenesis, the most critical step is formation of the nucleus under supersaturated conditions. The supersaturated conditions are speculated to be achieved by binding to proteoglycans or lipid membranes. Our results indicate that the basement membrane of myocardial cells is the initial site of amyloid deposition, providing a suitable place for concentration of TTR.

[Marked decrease of intracranial atherosclerosis in contrast with unchanged coronary artery stenosis in Japan].

We conducted comparative studies on intracranial atherosclerosis and coronary artery stenosis over the past 28 years. Two-year consecutive autopsy case studies from an urban geriatric hospital between 1974-1975 (Group I. 484 cases). 1986-1987 (Group II, 504 cases) and 2000-2001 (Group III, 273 cases) were employed. Atherosclerotic changes of the bilateral middle cerebral arteries and basilar artery were semiquantitatively evaluated as none (0), mild (1), moderate (2) and severe (3) and values of the 3 arteries were totalled to give a value of 0-9 which was taken as the intracranial atherosclerotic index (ICAI). The coronary stenotic index was calculated as previously reported (Sugiura et al 1969). ICAI and CSI were directly compared with each other, together with risk factors for each, including mean blood pressure (BP), serum level of total cholesterol (Tch) and the history of diabetes mellitus (DM+). Chronologically ICAI decreased dramatically but CSI did not change at all. There was continuous lowering of BP, elevation of Tch and increased incidence of DM+. There was a significant positive correlation in BP in relation to both ICAI and CSI (p < 0.01). DM+ vs. CSI (p < 0.01) and ICAI (p < 0.05), and Tch vs. CSI (p < 0.01) but not ICAI. Regression analysis highlighted age and BP as major risk factors for ICAI. Our study provides the first morphological confirmation of marked decrease of the intracranial atherosclerosis in the recent 28 years, in contrast with unchanged coronary stenosis in Japanese elderly subjects.

[An autopsied case with a bicuspid aortic valve who had progressive angina pectoris and heart failure during follow-up of 27 years].

A Japanese man who died at age 85 had been followed since the age of 59, when he first presented. He had hypertension of 162/102 mmHg and a loud systolic murmur on his first visit. He had had an active daily life without any medication for the next 10 years. At the age of 72 he complained of mild chest discomfort on exercise. Although electrocardiography showed no abnormalities, echocardiogram showed calcified bicuspid aortic valve with mild stenosis. At the age of 81 the dyspnea and chest oppression were exacerbated, associated with marked ST depression on exercise electrocardiogram and restriction of aortic valve opening on echocardiograms. In the following years a gradual increase in QRS voltage and ST depression with T wave inversion were recorded on resting electrocardiograms and sharp increases in both left ventricular end-diastolic diameter and flow velocity at the aortic root were observed on echocardiograms. At the age of 85 he died of intractable heart failure with massive pleural effusion. Autopsy revealed marked hypertrophy and moderate dilatation of the heart (weight: 580 g). The bicuspid aortic valve had anterior-posterior cusps with a raphe on the anterior cusp. The mobility of the cusps was almost lost because of severe calcification and thickening. Severe stenosis was found near the orifice of the right coronary artery, but there were no significant ischemic myocardial lesions.

Significant association between hypolipoproteinemia(a) and lifetime risk of cancer: an autopsy study from a community-based Geriatric Hospital.

BACKGROUND: Our recent study showed that a low lipoproteinemia(a) [Lp(a)] level was a risk factor for cancer and all-cause deaths. The purpose of this study was to verify the role of the Lp(a) level on cancer among consecutive autopsy cases. METHODS: The subjects consisted of 1354 cases (775 men and 579 women). The average age at death was 79.9 years. Hypolipoproteinemia(a) was defined as an Lp(a) level of below 80 mg/L. Overall, 62.3% of the subjects had suffered from at least one to a maximum of five malignancies throughout their lives. The most frequent type of malignancy was gastric cancer, followed by leukemia, lung cancer, and colon cancer. RESULTS: The cancer-bearing status decreased linearly according to the Lp(a) level in both men and women (P=0.01 and P<0.001, respectively). The median Lp(a) level was significantly lower among the cases with hepato-biliary-pancreatic cancers or hematopoietic malignancy, but was higher among cases with lung cancer, especially lung adenocarcinoma. Hypolipoproteinemia(a) was a significant risk factor for any origins of cancer, with an odds ratio of 1.94 (95% CI, 1.45-2.60; P<0.001). It was also a risk factor for hepato-biliary cancers and leukemia, but it was a protective factor for lung cancer. CONCLUSIONS: Our findings suggested hypolipoproteinemia(a) would be a significant risk factor for cancer except lung cancer. This study complements our previous study showing that hypolipoproteinemia(a) would increase the lifetime risk of cancer other than lung cancer.

Polymorphisms of LTA, LGALS2, and PSMA6 genes and coronary atherosclerosis: a pathological study of 1503 consecutive autopsy cases.

OBJECTIVE: Recent genome-wide association studies have identified polymorphisms of lymphotoxin-α (LTA), galectin-2 (LGALS2), and proteasome subunit a type 6 (PSMA6) genes as genetic risk factors for myocardial infarction (MI). However, their effects on coronary atherosclerosis, an intermediate phenotype of MI, remain largely unknown. METHODS: We investigated the correlation between polymorphisms of the LTA, LGALS2, and PSMA6 genes and the severity of pathological coronary stenosis index (CSI) and MI in 1503 consecutive autopsy cases of Japanese elderly patients. RESULTS: The polymorphisms LTA rs1041981 and LGALS2 rs7291467 were associated with CSI with odds ratios of 1.54 (95% CI, 1.17-2.01; AA+CA over CC) and 1.62 (95% CI, 1.11-2.37; TT over CC+CT), respectively. PSMA6 rs1048990 was not associated with CSI. None of the SNPs was associated with MI in our sample. CONCLUSION: Our findings indicate that the LTA and LGALS2 polymorphisms affect the subclinical phenotype of the coronary artery, which predisposes to the incidence of MI.

Age is a major pathobiological determinant of aortic dilatation: a large autopsy study of community deaths.

AIM: Aortic dilatation is a well-known phenomenon in the elderly. We therefore aimed to study the pathobiological determinants of aortic dilatation. METHODS: Retrospective chart review. The subjects were 833 consecutive autopsy cases (616 men and 217 women) of community deaths. The age at death ranged from 20 to 94 years, with an average of 59.2 years. We measured the internal circumference of the aortic root, arch, descending portion, abdominal portion, and bifurcation in unfixed opened aorta at the time of autopsy. RESULTS: The simple correlation between age and aortic circumference was strongest for the descending portion, followed by the arch, abdominal portion, root, and bifurcation. The simple correlation coefficient reached 0.836 for the descending portion (p < 0.001). The circumference of the descending portion increased significantly as the severity of aortic atherosclerosis increased (p for trend < 0.001). Multiple regression analysis showed that age, sex, and body height were significantly correlated with the aortic circumference at all five measurement sites, while severe atherosclerosis was correlated with the aortic circumference at the root, and descending and abdominal portions. Six contributing factors (age, sex, body height, smoking history, hypertension, and severe atherosclerosis) explained 68.5% of the variance in circumference in the descending portion; age explained 57.5%; sex 8.4%; body height 1%; and severe atherosclerosis 0.8%. CONCLUSION: The contribution of atherosclerosis to aortic dilation was very weak, representing less than one seventieth of the contribution of age. The aortic circumference, especially in the descending portion, serves as an excellent age-related marker.

Mitochondrial haplogroups A and M7a confer a genetic risk for coronary atherosclerosis in the Japanese elderly: an autopsy study of 1,536 patients.

AIM: We previously reported significant associations between mitochondrial single nucleotide polymorphisms (mtSNPs) and myocardial infarction, atherothrombotic cerebral infarction, metabolic syndrome and type 2 diabetes. Here, we assessed the hypothesis that mtSNPs may confer a risk for atherosclerosis, the most important intermediate phenotype of ischemic cardiovascular events. METHODS: The subjects were 1,536 consecutive autopsy cases (827 men and 709 women). The average age at death was 80 years. The severity of coronary atherosclerosis was semi-quantitatively examined on cut sections. We examined 149 mtSNPs using the PCR-Luminex method, with a success rate of 97%. Phylogenetic tree analysis yielded 36 haplogroups. Multiple logistic regression analysis was performed after adjustments for sex, age, and conventional cardiovascular risk factors. RESULTS: Among the 45 mtSNPs with minor genotype frequencies >0.05, 6 mtSNPs were associated with coronary atherosclerosis. Among 10 haplogroups with frequencies >0.04, haplogroups A and M7a were significantly associated with coronary atherosclerosis, with odds ratios (95% confidence intervals) of 1.80 (1.09-2.97; p=0.023) and 1.92 (1.23-3.01; p=0.004), respectively. Haplogroup D4a, which was previously reported to be associated with extreme longevity in a Japanese population, was associated with pathological myocardial infarction in men with an odds ratio of 2.05 (1.01-4.14; p=0.046). CONCLUSIONS: The mitochondrial haplogroups A and M7a confer a significant risk for coronary atherosclerosis in the Japanese. The mitochondrial haplogroup may contribute some genetic risk for coronary heart disease.

Elderly patients with minimal common carotid atherosclerosis not infrequently have severe coronary atherosclerosis and myocardial infarction.

BACKGROUND: The presence of discordances between common carotid and coronary atherosclerosis in the same individual has not been previously reported. METHODS AND RESULTS: The subjects of the present study were 1,518 consecutive autopsy cases at a general geriatric hospital. All were aged 60 years or older (821 men, 697 women) with an average age of 80 years. The atherosclerotic index of the common carotid artery (CC-AI) and coronary stenotic index (CSI) were semi-quantitatively evaluated. The simple correlation coefficient between the CC-AI and CSI was 0.456 (p<0.0001). Among 689 cases with minimal common carotid atherosclerosis (CC-AI < or =2), 74 (11%) had severe coronary atherosclerosis (CSI > or =12), 68 (10%) had coronary heart disease, and 80 (12%) had pathologically-verified myocardial infarction (MI). Among those with minimal common carotid atherosclerosis, the serum total cholesterol level, diabetes mellitus, and history of smoking were significantly higher or more frequent in cases with a CSI > or =12 than in the patients with a CSI <12. CONCLUSIONS: A considerable proportion of cases with minimal common carotid atherosclerosis had severe coronary atherosclerosis and MI. This discordance can potentially lead to an underestimation of coronary risks if normal common carotid morphology is obtained by ultrasound.

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

Coronary 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.

Interaction of BMP10 with Tcap may modulate the course of hypertensive cardiac hypertrophy.

Elevated wall stress by hypertension induces an adaptive myocardial hypertrophy via releasing prohypertrophic hormones such as angiotensin II. In this study, we investigated the involvement of bone morphogenetic protein-10 (BMP10) in hypertension-induced cardiac hypertrophy. Expression of BMP10 was increased in the hypertrophied ventricles from hypertensive rats. BMP10 localized on cell surface and at stretch-sensing Z disc of cardiomyocytes, where BMP10 interacted with a protein called titin-cap (Tcap). A rare variant of the human BMP10 gene, Thr326Ile, was found to be associated with hypertensive dilated cardiomyopathy. The variant BMP10 demonstrated decreased binding to Tcap and increased extracellular secretion. Conditioned medium from cells transfected with wild-type or variant BMP10 induced hypertrophy in rat neonatal cardiomyocytes, except that medium from variant BMP10-carrying cells showed an enhanced effect reflecting the increased secretion. These observations suggested that hypertension induced expression of prohypertrophic BMP10, and the hypertrophic effect of BMP10 was modulated, at least in part, by its binding to Tcap at the Z disc.