Atherosclerosis is characterized by inflammatory metabolic change with lipid accumulation in the artery. Atherosclerotic plaque occurs at discrete locations in the arterial system and involves the proliferation of smooth muscle cells (SMCs) together with imbalance of the extracellular matrix elements, elastic fiber in particular. The role of elastin in arterial development and disease was confirmed by generating mice that lack elastin. Thus, elastin is a critical regulatory molecule that regulates the phenotypic modulation, proliferation and migration of SMCs. We estimated that elastin expression and SMC proliferation are coupled inversely: potent stimulators of cell proliferation may potentially inhibit elastin expression and potent inhibitors of cell proliferation can stimulate elastin expression. Moreover, elastin was found to be expressed maximally at the G0 and minimally at the G2/M phase during the cell cycle, suggesting that its expression is regulated by the cell growth state. The elastin peptide VPGVG enhanced SMC proliferation, resulting in the reduction of elastin expression. The inhibition of elastin expression by elastin fragments may be reflected in the negative feedback regulatory mechanism. The relationship between cell proliferation and elastin expression may be changed in atherosclerosis. Areas of atherosclerotic plaque show abnormality of elasticity and permeability from the viewpoint of the physiological function of the arterial wall. The etiology was estimated to be that cholesterol and calcium are deposited on the elastic fiber, resulting in decreased elastin synthesis and cross-linking formation. In addition, these dysfunctions of elastin fiber are also associated, in that the down-regulation of elastin and its related components (fibrillin-1 and lysyl oxidase) are directly related to calcification in SMCs. The denatured arterial elastin by cholesterol and calcium accumulation was also susceptible to proteolytic enzymes such as elastase and matrix metalloproteinase (MMP). Therefore, metabolic change in elastic fiber induces decreased elasticity and is associated with essential hypertension. Vitamin K2 is used in drug therapy against atherosclerosis, or calcification in diabetes mellitus or dialysis, due to its promotion of the carboxylation of the matrix Gla protein.
Epidemiological studies have enhanced the importance of high-density lipoprotein (HDL) as a risk factor for CAD, as well as disability and frailty in the oldest elderly. Therefore, HDL and molecules involved in HDL metabolism seem to be attractive candidates for longevity-promoting factors. A series of observational studies has demonstrated that the predominance of the larger, more lipid-rich HDL2 subclass is a reproducible phenotype among centenarians. This finding was recently evolved by nuclear magnetic resonance technology in quantification of lipoprotein particle size. However, results of investigations into the mechanisms underlying the lipoprotein profiles in the oldest elderly have been conflicting. Genetic variation in cholesteryl ester transfer protein (CETP), which is a carrier protein in reverse cholesterol transport, was demonstrated to have no association with longevity in one study, but to have positive impacts on large HDL particles and longevity in another. Regarding environmental factors, acute phase reactant and nutritional status are frequently associated with HDL-C levels in the oldest elderly, however, the causality of the association remains to be elucidated. Determination of the association between cognitive function and HDL in the oldest elderly is also a future task. To obtain further insight into the mechanistic roles of low HDL in the pathophysiology of geriatric syndrome, a much greater effort should be invested in this research field.
The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or "statins", are used as cholesterol-lowering agents worldwide. Statins inhibit cholesterol biosynthesis, leading to enhanced uptake of low-density lipoprotein (LDL) from the circulation via LDL receptors. This strong cholesterol-lowering action contributes to the beneficial effects of statins. For example, large clinical trials have demonstrated that statins significantly reduce cardiovascular risk. Recent research has shown that statins have other multiple actions involved in endothelial function, cell proliferation, inflammatory response, immunological reactions, platelet function, and lipid oxidation. These "pleiotropic actions" of statins probably provide a significant contribution to the reduction of cardiovascular events. This review summarizes the pleiotropic actions of statins in both basic and clinical studies. It also considers the potential for statin therapy in the treatment of stroke and dementia.
It is herein discussed what should be measured as predictors of atherosclerosis, to increase the predictive power of coronary risk evaluation in clinical practice. Plasma apolipoprotein (apo)B and apoAI have been reported to be stronger predictors of coronary artery disease (CAD) than plasma low-density lipoprotein (LDL)-cholesterol (C) and high-density lipoprotein (HDL)-C. The estimation of plasma levels of remnants of TG-rich lipoproteins is also important for coronary risk evaluation. An increase in plasma small, dense LDL is a risk factor for CAD. It is not practical to measure plasma small, dense LDL as a routine clinical examination. We should estimate the plasma levels of small, dense LDL by plasma triglyceride (TG), apoB, and HDL-C levels. Oxidized LDL (ox-LDL) plays an important role in atherosclerosis. Further large-scale, prospective studies are necessary to determine whether the measurement of plasma ox-LDL and autoantibodies against ox-LDL is an essential predictor of atherosclerosis. High plasma levels of Lp(a) are a risk factor for atherosclerotic vascular diseases in subjects with high plasma LDL-C levels and multiple coronary risk factors. Metabolic syndrome (MS) has been recognized recently as a predictor of CAD. As a result, it should be elucidated whether MS must be involved in the coronary risk evaluation score because all components of MS are involved in the score. A high plasma level of high-sensitivity C-reactive protein (hs-CRP) is an important predictor of atherosclerotic diseases. Whether it is essential to measure the plasma levels of atherosclerosis surrogate markers in clinical practice remains to be elucidated. It is concluded that plasma levels of apoB, apoAI, remnant-like particle (RLP)-C, lipoprotein (a) [Lp(a)], and hs-CRP in addition to those of lipids should be measured as predictors of atherosclerosis in clinical practice. We need to establish a new atherosclerosis risk evaluation scoring system involving the above factors, based on large-scale, prospective studies, to prevent atherosclerotic vascular diseases. In Japan, plasma levels of Lp(a), RLP-C, and hs-CRP are routinely measured in clinical practice. As a result, it would be rather easy to establish a new atherosclerosis risk evaluation scoring system in Japan.
We studied the coronary risk factors of hospitalized patients with coronary artery disease (CAD) in the Department of Cardiovascular Internal Medicine of Kobe University Hospital in 1993, 1996, 1999 and 2003, and examined trends in the factors over the past decade. The prevalences of diabetes mellitus (DM) (24.7%, 33.6%, 41.1% and 44.7%, respectively) and impaired glucose tolerance (IGT) (5.9%, 8.0%, 9.3% and 11.0%, respectively) steadily increased, whereas dyslipidemia (high total cholesterolemia, high triglyceridemia, or low high-density lipoproteinemia) and hypertension remained unchanged. We also revealed an increase in hemoglobin A1c levels (5.8%, 5.9%, 6.2% and 6.4%, respectively), in contrast to modest improvements in lipid levels and blood pressure levels. Additionally, patients with multi-vessel disease (MVD, stenosis in more than two major coronary vessels) significantly increased from 44.7% in 1993 to 58.8% in 2003 (p < 0.01). In 1993, DM and dyslipidemia were significant predictors for MVD (Odds Ratio: 2.72 and 2.68, respectively). On the other hand, in 2003, the significant predictor for MVD shifted to DM alone (Odds Ratio: 2.38). In conclusion, the prevalence rate of DM among CAD patients significantly increased in this decade, and the consequent increase in the prevalence of MVD should be recognized as the most important problem clinically.
Hypertriglyceridemia is often associated with small dense low density lipoprotein (LDL), elevated remnants, and decreased high density lipoprotein (HDL)-cholesterol (C), which comprise the dyslipidemic triad. The objective of this study was to investigate the effect of fenofibrate on the lipoprotein subfraction profile and inflammation markers in hypertriglyceridemic men. Twenty hypertriglyceridemic men were administered fenofibrate, 200 mg daily, for 8 weeks. Lipoprotein subclasses were measured by nuclear magnetic resonance (NMR) spectroscopy. Inflammation markers including C-reactive protein (CRP), interleukin-6 (IL-6), and monocyte chemotactic protein-1 (MCP-1) were also determined. Fenofibrate lowered triglyceride (TG) by 58% and increased HDL-C by 18%. NMR analysis revealed that very low density lipoprotein (VLDL), particularly large VLDL, intermediate density lipoprotein (IDL), and small LDL, were significantly decreased, and LDL distribution shifted towards the larger particles. HDL distribution was altered; there was an increase in small HDL and a decrease in large HDL, resulting in a significant decrease in HDL particle size, from 9.1 to 8.9 nm, as well as a 27% increase in HDL particle number. Among inflammation markers, CRP was significantly decreased by 42%. In conclusion, fenofibrate effectively improves atherogenic dyslipidemia by reducing remnants and small LDL, as well as by increasing HDL particles. These effects, together with the favorable effect on inflammation, might provide a clinical benefit in hypertriglyceridemic subjects.
Aims: Families with 10−12-year-old schoolchildren were informed about and asked to participate in a study to identify children with hyperlipoproteinemia. We hypothesised that children and families with familial blood lipid abnormalities, specifically those with familial hypercholesterolemia (FH) and familial combined hyperlipidemia (FCHL), could be identified by the child’s apolipoprotein B level exceeding the 95th percentile. Methods: Written information and consent was distributed to the families. Families whose child had an apoB concentration exceeding the 95th percentile were further examined. Children and parents were divided into normal, high and very high low density lipoprotein cholesterol (LDLC) groups. In adults a high LDLC level was defined as > 4.1−4.9, a very high as > 4.9 mmol/l, in children as > 3.4−4.1 and > 4.1 mmol/l, respectively. The triglyceride level was regarded as high when > 3.6 mmol/l. Results: Of 2,855 families, 2,186 agreed to participate. The 95th percentile apoB level was for boys 0.98 and girls 1.07 g/l. Of the 131 children with an apoB level above the 95th percentile, 109 families accepted further examinations. Of 109 hyperapoB children 23 were obese. Normal LDLC was found in 28 hyperapo B children of whom six parents had high/very high LDLC and one high triglyceride concentrations. A high LDLC level was found in 52 children of whom 23 parents had higy/very high LDLC and another five high LDLC and/or high triglyceride concentrations. A very high LDLC level was found in 29 children, in two of them due to hypothyroidism, 17 had a parent with high/very high LDLC and another two parents a high triglyceride concentration. Familial hypercholesterolemia, defined as a LDLC concentration above twice the normal one in the child and a very high level in a parent, was suspected in six families, five having a relative with premature CHD. The families with FCHL should be included in the 20 families with hyperapoB and a child with high—very high LDLC and a parent with very high LDLC or TG levels. Conclusion: Of the 109 children examined due to the child’s increased apoB concentration, about 20% were obese and 75% had an increased LDLC concentration. A familial occurrence of hyperlipoproteinemia was evident in about 50% of the families with an hyperapoB child. Six families probably suffer from familial hypercholesterolemia. The definite number of FCHL families could not be defined since extended pedigrees were not available. A high suspicion of FCHL was evident in 20 families. ApoB is an important marker of hyperlipoproteinemia of familial occurrence identifying families in need of primary CHD prevention.
In 1989, we encountered a 68-year-old male patient with marked hyperlipoprotein(a)emia (hyperLp(a)emia), who was being treated for hypertension and arteriosclerotic obliterans (ASO) at an outpatient clinic of our hospital. He began to develop leg edema in 2002 and was referred to the Department of Internal Medicine. It was determined that he had severe hyperlipidemia (total cholesterol, 362 mg/dl), proteinuria, and hypoalbuminemia, suggesting the presence of nephrotic syndrome. On lipoprotein analysis, he was found to have very high levels of Lp(a) in the plasma (329 mg/dl). Severe atherosclerosis was also found: that is, abdominal aortic aneurysm (AAA) and coronary artery disease (CAD) were detected, in addition to ASO. After remission of the nephrotic syndrome, the plasma Lp(a) level decreased to 204 mg/dl and the total cholesterol concentration decreased to 179 mg/dl, while very high levels of Lp(a) persisted. We estimate that the markedly elevated Lp(a) plasma levels in this patient may have played some role in the progression of atherosclerosis.