Satoki Homma

Carotid Plaque and Intima-Media Thickness Assessed by B-Mode Ultrasonography in Subjects Ranging From Young Adults to Centenarians

UNLABELLED BACKGROUND AND PURPOSE-To investigate relationships among plaque formation, increasing intima-media thickness, and age, we examined ultrasonographically carotid arteries of subjects who had no major atherosclerotic risk factors and who ranged in age from young adults to centenarians. METHODS We studied 319 healthy subjects (154 men, 165 women; age range, 21 to 105 years) with no history of hypertension, diabetes mellitus, or atherosclerotic disease. Mean intima-media wall thickness (IMT) of common carotid arteries at plaque-free sites and prevalence of plaques were evaluated by B-mode ultrasound. RESULTS Mean common carotid IMT increased in a linear manner with age for all decades of life, including centenarians [IMT=(0.009xAge)+0.116] (r=0.83). In centenarians (n=30), intima-media complexes were diffusely thickened (mean IMT, 1.01 mm). Plaque prevalence increased up to the tenth decade of life (83.3%, n=30) but decreased in centenarians (60.0%). IMT and plaque prevalence were closely associated in the seventh and eighth decades of life but not at older ages. CONCLUSIONS The present study indicates that increased IMT is a physiological effect of aging that corresponds to diffuse intimal thickening, especially in very elderly persons, and that IMT is distinct from pathological plaque formation.

C-Peptide Colocalizes with Macrophages in Early Arteriosclerotic Lesions of Diabetic Subjects and Induces Monocyte Chemotaxis In Vitro

Objective—Increased levels of C-peptide, a cleavage product of proinsulin, circulate in patients with insulin resistance and early type 2 diabetes, a high-risk population for the development of a diffuse and extensive pattern of arteriosclerosis. This study tested the hypothesis that C-peptide might participate in atherogenesis in these patients. Method and Results—We demonstrate significantly higher intimal C-peptide deposition in thoracic artery specimens from young diabetic subjects compared with matched nondiabetic controls as determined by immunohistochemical staining. C-peptide colocalized with monocytes/macrophages in the arterial intima of artery specimen from diabetic subjects. In vitro, C-peptide stimulated monocyte chemotaxis in a concentration-dependent manner with a maximal 2.3±0.4-fold increase at 1 nmol/L C-peptide. Pertussis toxin, wortmannin, and LY294002 inhibited C-peptide–induced monocyte chemotaxis, suggesting the involvement of pertussis toxin-sensitive G-proteins as well as a phosphoinositide 3-kinase (PI3K)-dependent mechanism. In addition, C-peptide treatment activated PI3K in human monocytes, as demonstrated by PI3K activity assays. Conclusion—C-peptide accumulated in the vessel wall in early atherogenesis in diabetic subjects and may promote monocyte migration into developing lesions. These data support the hypothesis that C-peptide may play an active role in atherogenesis in diabetic patients and suggest a new mechanism for accelerated arterial disease in diabetes.

Elevated Serum C-Reactive Protein Levels and Advanced Atherosclerosis in Youth

Objective—To determine the associations among serum C-reactive protein (CRP) concentration, age, sex, risk factors for coronary heart disease (CHD), and atherosclerosis in young people. Methods and Results—In 1244 subjects 15 to 34 years of age, we measured gross atherosclerotic lesions in the right coronary artery (RCA) and abdominal aorta (AA) and American Heart Association (AHA) lesion grade in the left anterior descending (LAD) coronary artery; serum CRP, lipoprotein cholesterol, and thiocyanate (for smoking) concentrations; intimal thickness of renal arteries (for hypertension); glycohemoglobin (for hyperglycemia); and body mass index (for obesity). Serum CRP levels increased with age, were higher in women than in men, and were positively related to obesity and hyperglycemia. Serum CRP ≥10 mg/L was associated with more extensive gross raised lesions in the RCA after age 25 and in the AA after age 30. Serum CRP ≥3 was associated with a greater prevalence of AHA grade 5 lesions in the proximal LAD coronary artery after age 25. The associations of CRP with lesions were independent of the traditional CHD risk factors. Conclusion—Serum CRP level is independently associated with advanced atherosclerosis in young persons.

Deficiency of choresteryl ester transfer protein and gene polymorphisms of lipoprotein lipase and hepatic lipase are not associated with longevity

Cholesteryl ester transfer protein (CETP) is one of the key proteins in reverse cholesterol transport (RCT). The role of CETP in atherosclerosis remains controversial. In this study we investigated the associations between polymorphisms of CETP (mutations in intron 14 and exon 15, and Taq1B), hepatic lipase (C-514T), lipoprotein lipase (PvuII and HindIII), and ATP-binding cassette transporter 1 (R219K) loci and longevity in 256 centenarians and 190 healthy younger controls. Although heterozygous CETP deficiency and the B2 allele of the Taq1B polymorphism was consistently associated with higher HDL-C concentrations both in centenarians and controls, the allelic frequencies of those polymorphisms did not differ between the two groups. The allelic frequencies of other gene polymorphisms in RCT were not different between the two groups. Centenarians with lipoprotein lipase P(−/−) genotype had significantly higher HDL-C concentration than those with P(−/+) or with P(+/+), in contrast, there was no such a relationship among controls. In stepwise multiple regression analysis, serum albumin, CETP deficiency and lipoprotein lipase PvuII genotype were independently associated with HDL-C in centenarians. Sex, CETP deficiency, and the Taq1B genotype were also independently associated with HDL-C; however, lipoprotein lipase PvuII genotype had no significant effect on their HDL-C in controls. In conclusion, we observed that CETP deficiency and other gene polymorphisms in RCT have no impact on longevity for Japanese centenarians.

Lipoprotein Metabolism in Japanese Centenarians: Effects of Apolipoprotein E Polymorphism and Nutritional Status

OBJECTIVES: To assess the complex interaction of apolipoprotein (apo) E polymorphisms and environmental factors on lipoprotein profile in centenarians.

Histopathological modifications of early atherosclerotic lesions by risk factors—findings in PDAY subjects

To investigate whether histopathological modifications on early atherosclerotic lesions differ according to risk factors, we compared the histological findings of arteries obtained from a multicenter study in the USA (Pathobiological Determinants of Atherosclerosis in Youth, PDAY) with the antemortem risk factors. The materials comprised aortas and left anterior descending (LAD) coronary arteries of 140 male subjects. Measurements of intimal thickness, classification of intimal lesions, and density of foam cells and intimal fibrosis at the determined sites of LAD and aorta were evaluated. In both arteries, intimal thickness of hypertensives was greater than the normotensives with no definite proliferation of foam cells. In aortas, hypercholesterolemia was associated with an increase in foam cells, but not with an increase in intimal thickness. HDL-C value correlated inversely with number of foam cells in both the arteries, and the degree of intimal thickness in LADs, where early appearance of advanced lesion such as preatheroma and atheroma, was also indicated in the low HDL-C group. Smokers had less number of foam cells in both the arteries and more intensive intimal fibrosis in LAD than non-smokers. Our study suggests that there are several ways to advanced atherosclerotic lesions by risk factors.

Different effects of hypertension and hypercholesterolemia on the natural history of aortic atherosclerosis by the stage of intimal lesions

To investigate the histopathologic modes of the effect of hypertension and hypercholesterolemia on atherosclerosis progression, a total of 573 male autopsied aortas, ranging from 0 to 97 years-old, were histomorphometrically compared by the status based on antemortem risk factors. Specimens were classified into four categories according to the criteria reported by the American Heart Association after histometric measurement at defined sites of the aortas. Intimal lesions progressed in the same fashion in all the risk factor groups examined; normal intima converted to fatty streak, preatheroma (characterized by microscopic extracellular lipid deposition) and then atheroma. This progression of intimal lesions correlated with age-related increases in intimal thickness independent of risk factors. Although the frequency of fatty streaks and the population of foam cells were greater in the hypercholesterolemics than in the non-risk patients, the frequencies of preatheroma and atheroma were not different between these two patient groups until patients reached the fifth decade. In contrast, the frequencies of preatheroma and atheroma were consistently greater in the hypertensives than in the other groups by the fifth decade. Hypertension was also related to intimal thickness in the younger groups. Our findings suggest that hypertension and hypercholesterolemia affect the progression of atherosclerosis differently by histopathologic stages.

High adiponectin concentration and its role for longevity in female centenarians

Background:  Evidence from experimental models of longevity indicates that maintenance of energy homeostasis could be indispensable for longevity across various species. In humans, it has been reported that maintenance of glucose homeostasis and vascular stability is one biomedical feature of centenarians, who have reached the maximum life‐span. We hypothesized that adiponectin, a novel anti‐inflammatory adipocytokine, could be a protective factor against age‐related metabolic alteration and atherogeneity in centenarians.

Histological changes and risk factor associations in type 2 atherosclerotic lesions (fatty streaks) in young adults

OBJECTIVES The purpose of this study was to investigate which histological changes associated with risk factors could contribute to the progression from the initial atherosclerotic lesions including fatty streaks to the advanced lesions. METHODS We examined the associations of histomorphometric findings in the determined anatomical sites of mid-thoracic aortas (TAs) and left anterior descending coronary arteries (LADs) with major risk factors for atherosclerosis, using a young autopsied series from the the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study. The histological classification by the American Heart Association was graded for 1013 TAs and 1009 LADs. Histometric study, including immunohistochemistry, was performed in type 2 lesions (fatty streaks) of TAs from 59 subjects and LADs from 45 ones. RESULTS For the progression from the initial lesions into the advanced atherosclerotic lesions, the most effective lipid profiles were low plasma HDL-C in TA and elevated serum non-HDL-C in LAD. This lipid profile of each artery correlated with number or density of intimal smooth muscle cell-derived foam cells, respectively. The serum concentration of non-HDL-C correlated with macrophage foam cells in TAs. Hypertension and hyperglycemia were associated with increase of intimal area and/or collagen content in both arteries, but not with either types of foam cell proliferation. Smoking correlated with increased collagen content in TAs. CONCLUSION There were histologically different ways of progressing from fatty streaks to advanced atherosclerotic lesions depending on the risk factors. For the atherosclerosis progression from type 2 lesions to advanced lesions, increase in number of smooth muscle cell-derived foam cells could be an important indicator.

The effect of age and other atherosclerotic risk factors on carotid artery blood velocity in individuals ranging from young adults to centenarians.

To evaluate the effect of age and other risk factors for atherosclerosis on arterial blood velocity, carotid arteries in 179 healthy individuals ranging from 21 to 102 years old were examined using color Doppler ultrasonography. Velocity in common and internal carotid arteries decreased consecutively from young adults to very elderly people except for peak internal carotid artery velocity. Peak common carotid artery velocity in the elderly (≥ 65 years old) people was inversely associated with age and diastolic blood pressure and directly associated with pulse pressure. Minimum velocity of common carotid artery was inversely correlated with age and diastolic blood pressure in the elderly people. In elderly group, peak internal carotid artery velocity correlated only with serum high-density lipoprotein cholesterol. Minimum internal carotid artery velocity correlated inversely with systolic blood pressure in adults and diastolic blood pressure in elderly people. Blood velocity in the very elderly population approaches the critical level for thrombogenesis.