As men grow older, circulating testosterone declines while the incidence of cardiovascular disease increases. Thus, the role of sex hormones as biomarkers, and possibly contributing factors to clinical manifestations of cardiovascular disease in the increasing demographic of aging men, has attracted considerable interest. This review focuses on observational studies of endogenous androgens, namely circulating testosterone and dihydrotestosterone, which have examined their associations with cardiovascular events such as myocardial infarction and stroke. Studies which have examined the associations of endogenous estrogens, namely circulating estradiol, with these outcomes are also discussed. In large prospective cohort studies of predominantly middle-aged and older men, lower circulating testosterone consistently predicts higher incidence of cardiovascular events. Of note, both lower circulating testosterone and lower dihydrotestosterone are associated with higher incidence of stroke. These associations are less apparent when myocardial infarction is considered as the outcome. Results for estradiol are inconsistent. Lower circulating testosterone has been shown to predict higher cardiovascular disease-related mortality, as has lower circulating dihydrotestosterone. It is possible that the relationship of circulating androgens to cardiovascular events or mortality outcomes may be U-shaped rather than linear, with an optimal range defining men at lowest risk. Epidemiological studies are observational in nature and do not prove causality. Associations observed in studies of endogenous androgens need not necessarily translate into similar effects of exogenous androgens. Rigorous randomized controlled trials are needed to clarify the effects of testosterone treatment on cardiovascular risk in men.
Cardiovascular Diseases/mortality* ; Dihydrotestosterone/metabolism* ; Estradiol/metabolism* ; Humans ; Incidence ; Male ; Mortality ; Myocardial Infarction/metabolism* ; Stroke/metabolism* ; Testosterone/metabolism*

BACKGROUND: The metabolic syndrome is a cluster of related cardiovascular risk factors and it is the cause of morbidity and mortality in cardiovascular diseases. Recently, new diagnostic criteria of glucose metabolism impairment has been recommended. The purpose of this study was to estimate the difference of cardiovascular risk by investigating the prevalence of metabolic syndrome according to the degree of glucose metabolism impairment. METHODS: A population of 757 subjects was selected from a database of individuals who visited a health promotion center. We classified these subjects into 5 groups [Normal, Isolated impaired glucose tolerance (I-IGT), Isolated impaired fasting glucose (I-IFG), combined IGT with IFG (IGT/IFG) and Diabetes]. We compared the general characteristics, Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and the prevalence of metabolic syndrome in these groups. RESULTS: HOMA-IR and the prevalence of metabolic syndrome in the IGT/IFG and the Diabetes group were significantly greater than the Normal group. HOMA-IR and the prevalence of metabolic syndrome of the I-IGT and the I-IFG group were not significantly different with the Normal group. CONCLUSION: The insulin resistance and the prevalence of metabolic syndrome in the IGT/IFG group was significantly greater than the Normal group, and its presence may increase the risk of cardiovascular diseases. Therefore, it is important to control other combined metabolic disorders to prevent cardiovascular events after effective selection for IGT/ IFG.
Cardiovascular Diseases ; Fasting ; Glucose* ; Health Promotion ; Homeostasis ; Insulin Resistance ; Metabolism* ; Mortality ; Prevalence* ; Risk Factors

OBJECTIVETo review the functional mechanism of apolipoprotein J (apoJ) in the process of atherosclerosis and the feasibility of apoJ as a therapeutic endpoint.

DATA SOURCESRelevant articles published in English from 1983 to present were selected from PubMed. The terms of "atherosclerosis, apolipoprotein J, clusterin (CLU), oxidative stress, and inflammation" were used for searching.

STUDY SELECTIONArticles studying the role of apoJ with atherosclerosis and restenosis after injury were reviewed. Articles focusing on the intrinsic determinants of atherosclerosis were selected. The exclusion criteria of articles were that the studies on immunologic vasculitis.

RESULTSApoJ, involved in numerous physiological process important for lipid transportation and vascular smooth muscle cell differentiation, including apoptotic cell death, cell-cycle regulation, cell adhesion, tissue remodeling, immune system regulation, and oxidative stress, plays a role in the development of clinical atherosclerosis. In the process of relieving atherosclerosis, apoJ can promote cholesterol and phospholipid export from macrophage-foam cells, and exhibit cytoprotective and anti-inflammatory actions by interacting with lots of known inflammatory proteins which may predict the onset of clinical cardiovascular events and may actually play a causal role in mediating atherosclerotic disease such as C-reactive protein, paraoxonase, and leptin. As known as CLU, apoJ has been identified to play central roles in the process of vascular smooth cells migration, adhesion, and proliferation, which can contribute significantly to restenosis after vascular injury.

CONCLUSIONSIntense effort and substantial progress have been made to identify the apoJ that relieves atherosclerosis and vascular restenosis after percutaneous coronary intervention. More work is needed to elucidate the exact mechanisms of and the interrelationship between the actions of apoJ and to successfully achieve regression of atherosclerosis by regarding it as a therapeutic endpoint.

Cardiovascular Diseases ; genetics ; mortality ; Clusterin ; genetics ; metabolism ; Coronary Artery Disease ; genetics ; metabolism ; Coronary Restenosis ; genetics ; metabolism ; Humans

In men, obesity and metabolic complications are associated with lower serum testosterone (T) and dihydrotestosterone (DHT) and an increased risk of, and mortality from, multiple chronic diseases in addition to cardiovascular disease (CVD). The causal interrelationships between these factors remain a matter of debate. In men with untreated congenital and lifelong forms of hypogonadotropic hypogonadism, there appears to be no increased risk. Men with Klinefelter's syndrome have an increased risk of various types of cancers, as well as CVD, which persist despite T therapy. In the absence of pathology of the hypothalamic-pituitary-gonadal axis, the effect of modest reductions in serum T in aging men is unclear. The prevalence of low serum T concentrations is high in men with cancer, renal disease, and respiratory disease and is likely to be an indicator of severity of systemic disease, not hypogonadism. Some population-based studies have found low serum T to be associated with a higher risk of deaths attributed to cancer, renal disease, and respiratory disease, while others have not. Although a meta-analysis of longitudinal studies has shown an association between low serum T and all-cause mortality, marked heterogeneity between studies limited a firm conclusion. Therefore, while a decrease in T particularly occurring later in life may be associated with an increase in all-cause and specific types of mortality in men, the differential effects, if any, of T and other sex steroids as compared to health and lifestyle factors are unknown at the current time.
Age Factors ; Cardiovascular Diseases/metabolism* ; Cause of Death ; Dihydrotestosterone/metabolism* ; Humans ; Hypogonadism/metabolism* ; Klinefelter Syndrome/metabolism* ; Male ; Mortality ; Obesity/metabolism* ; Testosterone/metabolism*

Objective: To estimate the association between high-sensitivity C-reactive protein (hs-CRP) and cardiovascular events as well as all-cause mortality events. Methods: During 2009- 2010, out of the 11 623 individuals, 1 000 participants aged 35-64 years, were recruited and divided into 12 age-groups, to have received a study on CVD risk factors. Information on the risk factors of cardiovascular diseases was also collected. Fasting blood sample was gathered for all the participants, with hs-CRP tested. Participants in 7 out of the 12 sites were followed, with 6.21 years (36 075 person-years) as the median follow-up period. Cardiovascular and all-cause mortality events were collected. A total of 6 177 participants had been followed after excluding participants who had baseline infections, or did not take hs-CRP test/physical examination at the baseline. Finally, 5 984 participants were included for analysis. Participants were categorized into three groups based on the hs-CRP (mg/L) values: <1, 1-3 and >3, respectively. Cox proportional hazards regression model was used to analyze the relationships between hs-CRP with cardiovascular events or all-cause mortality events, after adjusting for confounding factors. Results: Mean age of the participants was 50.2 years. The incidence rates of cardiovascular disease events were 3.6/1 000 person-years, 7.1/1 000 person-years,and 10.4/1 000 person-years among three groups and 3.0/1 000 person-years, 5.7/1 000 person-years, 9.1/1 000 person-years for all-cause mortality events, respectively. After adjusting for confounding factors, the hazard risks (HR) for cardiovascular events were 1.33 (95%CI: 0.95-1.84) in the hs-CRP 1-3 mg/L group and 1.76 (95%CI: 1.20-2.60) in the hs-CRP>3 mg/L group when comparing with the hs-CRP<1 mg/L group (trend test P=0.003). The HRs for all-cause mortality events were 1.76 (95%CI: 1.23-2.54) and 2.64 (95%CI: 1.74-4.01) (trend test P<0.001), respectively. Conclusion: Hs-CRP appeared an independent predictor for cardiovascular events and all-cause mortality events.
Adult ; Asian People ; C-Reactive Protein/metabolism* ; Cardiovascular Diseases/mortality* ; China/epidemiology* ; Female ; Hospital Mortality ; Humans ; Incidence ; Male ; Middle Aged ; Proportional Hazards Models ; Risk Factors

Peroxisome proliferator-activated receptor (PPAR)-alpha belongs to the nuclear family of ligand-activated transcriptional factors. The main role of PPAR-alpha is to activate the expression of the genes that are involved in fatty acid oxidation to achieve energy homeostasis. Fibrates are a known class of PPAR-alpha agonists, and they been used clinically for their effects of lowering triglycerides and elevating high-density lipoprotein-cholesterol (HDL-C). Further, recent experimental studies have demonstrated the anti-inflammatory and anti-atherosclerotic actions of PPAR-alpha agonists directly on the vascular wall. PPAR agonists are currently emerging as a promising therapeutic option to control systemic and vascular atherogenic factors. Regardless of their strong anti-atherosclerotic properties, large clinical studies have demonstrated inconsistent results for the cardioprotective effect of PPAR-alpha agonists; moreover, it has been observed that they did not decrease the total mortality, which stands in contrast to the statin trials. This review summarizes the current knowledge regarding the PPAR biology and the mechanisms of the effects of PPAR-alpha on lipid metabolism, the vessel wall and the cardiac metabolism. We also describe the results and lessons learned from the important clinical trials of PPAR-alpha agonists and we discuss these drugs' efficacy and safety.
Biology ; Cardiovascular Diseases* ; Fibric Acids ; Homeostasis ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Lipid Metabolism ; Metabolism ; Mortality ; Nuclear Family ; Peroxisome Proliferator-Activated Receptors ; Peroxisomes* ; Triglycerides

PURPOSE: Systemic inflammatory reaction (SIR) is an important determinant of cardiovascular (CV) mortality in CRF patients. UA is an end-product of purine metabolism, and recent studies have demonstrated that an elevated serum UA level is associated with an increased level of inflammatory mediators. Since hyperuricemia is one of the most prevalent complications in CRF and is linked to CV disease, we hypothesized hyperuricemia in CRF may play an important role in the development of CV disease by inducing SIR. METHODS: PBMCs were isolated by density gradient centrifugation in 21 CRF patients and age and sex-matched 20 healthy adults. CRP expression was evaluated by real time PCR and ELISA in PBMC stimulated with UA (0.3-12 mg/dL). RESULTS: There was no difference in constitutional CRP expression in PBMC from control and CRF patients. UA induced CRP mRNA (RT-PCR) and protein (ELISA) expression in PBMC, which was blocked by the organic anion transport inhibitor, probenecid (1 mM), suggesting entry of uric acid into cells was responsible for CRP expression. PBMC from CRF patients showed a significantly higher CRP production by UA compared to healthy control. There was no correlation between serum UA level and % increase in CRP production by UA. CONCLUSION: The exaggerated CRP expression by UA can be another mechanism of SIR and increased CV morbidity in CRF patients. Prospective studies with uric acid-lowering therapy are necessary to confirm clinical significance of these interesting in-vitro findings.
Adult ; C-Reactive Protein* ; Cardiovascular Diseases ; Centrifugation, Density Gradient ; Enzyme-Linked Immunosorbent Assay ; Humans ; Hyperuricemia ; Inflammation ; Metabolism ; Mortality ; Probenecid ; Real-Time Polymerase Chain Reaction ; RNA, Messenger ; Uric Acid*

The incidence of obesity has increased dramatically during recent decades. Obesity increases the risk for metabolic and cardiovascular diseases and may therefore contribute to premature death. With increasing fat mass, secretion of adipose tissue derived bioactive molecules (adipokines) changes towards a pro-inflammatory, diabetogenic and atherogenic pattern. Adipokines are involved in the regulation of appetite and satiety, energy expenditure, activity, endothelial function, hemostasis, blood pressure, insulin sensitivity, energy metabolism in insulin sensitive tissues, adipogenesis, fat distribution and insulin secretion in pancreatic beta-cells. Therefore, adipokines are clinically relevant as biomarkers for fat distribution, adipose tissue function, liver fat content, insulin sensitivity, chronic inflammation and have the potential for future pharmacological treatment strategies for obesity and its related diseases. This review focuses on the clinical relevance of selected adipokines as markers or predictors of obesity related diseases and as potential therapeutic tools or targets in metabolic and cardiovascular diseases.
Adipogenesis ; Adipokines ; Adipose Tissue ; Appetite ; Biomarkers ; Blood Pressure ; Cardiovascular Diseases ; Diabetes Mellitus, Type 2 ; Energy Metabolism ; Hemostasis ; Incidence ; Inflammation ; Insulin ; Insulin Resistance ; Liver ; Mortality, Premature ; Obesity

Atherosclerosis is a major cause of morbidity and mortality due to cardiovascular diseases, such as coronary artery disease, stroke, and peripheral vascular disease, that are associated with thrombosis-induced organ infarction. In Westernized countries, the high prevalence of obesity-induced insulin resistance is predicted to be a major factor leading to atherosclerotic vascular disease. Both genetic and environmental factors interfere with immune responses in atherosclerosis development with chronic and non-resolving states. The most known autoimmune disease therapy is cytokine-targeted therapy, which targets tumor necrosis factor-α and interleukin (IL)-17 antagonists. Recently, a clinical trial with the anti-IL-1β antibody (canakinumab) had shown that the anti-inflammatory effects in canakinumab-treated subjects play a critical role in reducing cardiovascular disease prevalence. Recent emerging data have suggested effective therapeutics involving anti-obesity and anti-diabetic agents, as well as statin and anti-platelet drugs, for atherothrombosis prevention. It is well-known that specialized immune differentiation and activation completely depends on metabolic reprogramming mediated by mitochondrial dynamics in distinct immune cells. Therefore, there is a strong mechanistic link between metabolism and immune function mediated by mitochondrial function. In this review, we describe that cellular metabolism in immune cells is strongly interconnected with systemic metabolism in terms of diverse phenotypes and activation.
Atherosclerosis ; Autoimmune Diseases ; Autoimmunity ; Cardiovascular Diseases ; Coronary Artery Disease ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Hypercholesterolemia ; Infarction ; Insulin Resistance ; Interleukins ; Metabolism ; Mitochondrial Dynamics ; Mortality ; Necrosis ; Peripheral Vascular Diseases ; Phenotype ; Prevalence ; Stroke ; Vascular Diseases

Although elevated serum low-density lipoprotein-cholesterol (LDL-C) is without any doubts accepted as an important risk factor for cardiovascular disease (CVD), the role of elevated triglycerides (TGs)-rich lipoproteins as an independent risk factor has until recently been quite controversial. Recent data strongly suggest that elevated TG-rich lipoproteins are an independent risk factor for CVD and that therapeutic targeting of them could possibly provide further benefit in reducing CVD morbidity, events and mortality, apart from LDL-C lowering. Today elevated TGs are treated with lifestyle interventions, and with fibrates which could be combined with omega-3 fatty acids. There are also some new drugs. Volanesorsen, is an antisense oligonucleotid that inhibits the production of the Apo C-III which is crucial in regulating TGs metabolism because it inhibits lipoprotein lipase (LPL) and hepatic lipase activity but also hepatic uptake of TGs-rich particles. Evinacumab is a monoclonal antibody against angiopoietin-like protein 3 (ANGPTL3) and it seems that it can substantially lower elevated TGs levels because ANGPTL3 also regulates TGs metabolism. Pemafibrate is a selective peroxisome proliferator-activated receptor alpha modulator which also decreases TGs, and improves other lipid parameters. It seems that it also has some other possible antiatherogenic effects. Alipogene tiparvovec is a nonreplicating adeno-associated viral vector that delivers copies of the LPL gene to muscle tissue which accelerates the clearance of TG-rich lipoproteins thus decreasing extremely high TGs levels. Pradigastat is a novel diacylglycerol acyltransferase 1 inhibitor which substantially reduces extremely high TGs levels and appears to be promising in treatment of the rare familial chylomicronemia syndrome.
Apolipoprotein C-III ; Cardiovascular Diseases ; Diacylglycerol O-Acyltransferase ; Fatty Acids, Omega-3 ; Fibric Acids ; Hyperlipoproteinemia Type I ; Life Style ; Lipase ; Lipoprotein Lipase ; Lipoproteins ; Metabolism ; Mortality ; PPAR alpha ; Risk Factors ; Triglycerides