Viewpoint: personalizing statin therapy.

Cardiovascular disease (CVD), associated with vascular atherosclerosis, is the major cause of death in Western societies. Current risk estimation tools, such as Framingham Risk Score (FRS), based on evaluation of multiple standard risk factors, are limited in assessment of individual risk. The majority (about 70%) of the general population is classified as low FRS where the individual risk for CVD is often underestimated but, on the other hand, cholesterol lowering with statin is often excessively administered.

The effects of aldosterone on diet-induced fatty liver formation in male C57BL/6 mice: comparison of adrenalectomy and mineralocorticoid receptor blocker.

Objective: Obesity, diabetes, fatty liver, and hypertension are major determinants of the metabolic syndrome. The effects of aldosterone and mineralocorticoid receptor blockers on fatty liver are largely unknown. The aim of the present study was to evaluate the relationships between aldosterone and the development of fatty liver.

Eplerenone reduced lesion size in early but not advanced atherosclerosis in apolipoprotein E-deficient mice.

The beneficial effects of eplerenone, a specific mineralocorticoid receptor blocker, were previously demonstrated in early atherosclerosis (ATS). The aim of the present study was to evaluate the effect of eplerenone in advanced versus early ATS. Apolipoprotein E knockout mice aged 16 or 32 weeks were randomly divided into eplerenone (100 mg·kg·d) or vehicle treatment for 14 weeks.

Mineralocorticoid receptor blockade inhibits accelerated atherosclerosis induced by a low sodium diet in apolipoprotein E-deficient mice.

Introduction: A low-sodium diet (LSD) was shown to increase both angiotensin II (AngII) and aldosterone levels, and to accelerate atherosclerosis in apolipoprotein E-deficient (E0) mice. The aim of the present study was to examine whether accelerated atherosclerosis in E0 mice fed a LSD is mediated by aldosterone, using the mineralocorticoid receptor blocker, eplerenone (Epl).

Methods And Results: Mice were divided into three groups: normal diet (ND), LSD and LSD treated with Epl at 100 mg/kg per day (LSD+Epl) for 10 weeks.

Paraoxonase1 deficiency in mice is associated with hypotension and increased levels of 5,6-epoxyeicosatrienoic acid.

Aim: Serum paraoxonase 1 (PON1) is an HDL-associated lipolactonase and its association with hypertension is controversial. We studied the possible role of PON1 in blood pressure (BP) regulation, by using PON1 knockout (PON1KO) mice.

Methods And Results: Both, systolic and diastolic BPs were lower in PON1KO compared to WT mice.

FAD286, an aldosterone synthase inhibitor, reduced atherosclerosis and inflammation in apolipoprotein E-deficient mice.

Introduction: Aldosterone is known to be involved in atherosclerosis and cardiovascular disease and blockade of its receptor was shown to improve cardiovascular function. It was, therefore, hypothesized that inhibition of aldosterone synthesis would also reduce atherosclerosis development.

Method: To test this hypothesis, we examined the effect of FAD286 (FAD), an aldosterone synthase inhibitor, on the development of atherosclerosis in spontaneous atherosclerotic apolipoprotein E-deficient mice.

Paraoxonase 1 deficiency in mice is associated with reduced steroid biosynthesis: effects on HDL binding, cholesteryl ester accumulation and scavenger receptor type BI expression.

Objective: Selective uptake of high density lipoprotein (HDL) cholesteryl ester (CE) is considered as the major source of cholesterol for production of steroids in the adrenal gland in rodents. As paraoxonase 1 (PON1) is an HDL-associated lipo-lactonase that has been shown to increase binding of HDL to macrophages, we used PON1 knock-out (PON1KO) mice to test the possible role of PON1 in corticosterone (CS) biosynthesis.

Methods And Results: PON1 deficiency was associated with reduced serum CS concentration.

Aspirin promotes low density lipoprotein susceptibility to oxidative modification in healthy volunteers.

Background: Low density lipoprotein oxidation is a major pathogenic pathway in atherosclerosis. Previous studies suggested that aspirin, a commonly prescribed drug in patients with atherosclerosis, when given in a dose of 300 mg/day may decrease LDL susceptibility to oxidative modification. However, the effect of the more common lower dose aspirin on LDL oxidation is not known.

Apolipoprotein E and its role in aging and survival.

The study of biological aging has seen spectacular progress in the last decade and markers are increasingly employed for understanding physiological processes that change with age. Recently, it has been demonstrated that apolipoprotein E (apoE) has a major impact on longevity, but its mechanisms are still not fully understood. ApoE-deficient (E(o)) mice have proved to be a very popular model for studying spontaneous hypercholesterolemia and the subsequent development of atherosclerotic lesions, but only limited data are available with regard to aging and aging changes.

Aldosterone up-regulates 12- and 15-lipoxygenase expression and LDL oxidation in human vascular smooth muscle cells.

Several lines of evidence suggest that aldosterone excess may have detrimental effects in the cardiovascular system, independent of its interaction with the renal epithelial cells. Here we examined the possibility that aldosterone modulates 12- and/or 15-lipoxygenase (LO) expression/activity in human vascular smooth muscle cells (VSMC), in vitro, thereby potentially contributing to both vascular reactivity and atherogenesis. Following 24 h treatment of VSMC with aldosterone (1 nmol/L), there was a approximately 2-fold increase in the generation rate of 12 hydroxyeicosatetraenoic acid (12-HETE), 70% increase in platelet type 12-LO mRNA expression (P < 0.

High plasma high-density lipoprotein levels, very low cardiovascular risk profile, and subclinical carotid atherosclerosis in postmenopausal women.

Background: Low plasma concentrations of high-density lipoprotein (HDL) are associated with increased risk of cardiovascular disease. However, recently several studies have questioned the protective role of high plasma HDL levels.

Objective: This study was designed to evaluate HDL functions in women with high plasma HDL cholesterol and very low risk profile with relation to subclinical carotid atherosclerosis (ATS).

Vitamin E supplementation reduces cardiovascular events in a subgroup of middle-aged individuals with both type 2 diabetes mellitus and the haptoglobin 2-2 genotype: a prospective double-blinded clinical trial.

Objective: Clinical trials of vitamin E have failed to demonstrate a decrease in cardiovascular events. However, these studies did not address possible benefit to subgroups with increased oxidative stress. Haptoglobin (Hp), a major antioxidant protein, is a determinant of cardiovascular events in patients with Type 2 diabetes mellitus (DM).

[The importance of ACE2 in regulating the cardiovascular system].

A recently discovered homologue of the angiotensin-converting enzyme, ACE2, insensitive to ACE inhibitors, was found in rodents and humans. ACE2 is expressed mainly in the vasculature, heart and kidney. ACE2 removes a single amino acid of the carboxy terminal of peptides.

High incidence of reduced plasma HDL cholesterol in diabetic patients treated with rosiglitazone and fibrate.

Background: A paradoxical plasma HDL-Cholesterol (HDL-C) reducing effect following combined fibrate and thiazolidinediones (TZDs) therapy was recently reported in occasional cases. As HDL-C level is inversely related to cardiovascular disease (CVD) risk, we have studied the incidence of reduced HDL-C level following mono- and combined therapy with these drugs in a large diabetic population.

Methods: This study was designed as a retrospective 5-year study.

ACE2 activity is increased in monocyte-derived macrophages from prehypertensive subjects.

Background: Hypertension is a major risk factor for cardiovascular disease and the renin-angiotensin-aldosterone system (RAAS) plays a central pathophysiological role in its formation. Angiotensin-converting enzyme (ACE) and its homologue ACE2 control the formation of counteracting effectors, angiotensin II (AngII), a potent vasopressor and Ang-(1-7) which has vasodilatory action. It is therefore hypothesized that the balance of the activities of these two enzymes, ACE and ACE2, could be important for the control of blood pressure (BP).

ACE2 of the heart: From angiotensin I to angiotensin (1-7).

Angiotensin II (Ang II), a bioactive peptide of the renin-angiotensin system (RAAS), plays an important role in the development of cardiovascular diseases (CVD). Pharmacological inhibition of angiotensin-converting enzyme (ACE), the Ang II forming enzyme, or specific blockade of Ang II binding to angiotensin type 1 receptor (AT1R) through which it exerts its deleterious effects, were shown to provide some protection against progression of CVD. The ACE-Ang II-AT1R axis has been challenged over the last few years with RAAS components able to counterbalance the effects of the main axis.

Atherosclerosis and the protective role played by different proteins in apolipoprotein E-deficient mice.

The aim of the present study was to analyze the early events in atherogenesis and the role of pro- or anti-atherosclerotic proteins in the development of atherosclerotic lesions. We used apolipoprotein E-deficient (E(0)) mice that spontaneously develop hypercholesterolemia and atherosclerotic lesions in the aorta in a time-dependent manner. Aortas of mice aged 6, 8, 10 and 12 weeks were examined to determine histopathological changes.

A mouse model for human atherosclerosis: long-term histopathological study of lesion development in the aortic arch of apolipoprotein E-deficient (E0) mice.

Apolipoprotein E-deficient mice, since their introduction in the early 1990s, have proved to be a very popular model for studying spontaneous hypercholesterolemia and the subsequent development of atherosclerotic lesions. The pathogenesis of atherosclerotic lesions in these mice mimics that found in humans on a very short time-scale. Atherosclerotic lesion development is especially prominent in the aortic arch.

Measurement of carotid artery intima-media thickness in dyslipidemic patients increases the power of traditional risk factors to predict cardiovascular events.

A longitudinal observational study investigated whether the measurement, in clinical practice, of carotid maximum intima-media thickness (Max-IMT) could be combined with the Framingham risk score (FRS) to improve the predictability of cardiovascular events in dyslipidemic patients who are at low or intermediate risk. Max-IMT was measured by ultrasound in 1969 patients attending a lipid clinic. The "best threshold values" (BTVs) above which we considered the Max-IMT to be abnormally high were calculated for our dyslipdemic population for each 10-year age interval in men and women.

Macrophage foam-cell formation in streptozotocin-induced diabetic mice: stimulatory effect of glucose.

Background: Diabetes is associated with an increased risk for atherosclerosis. We investigated the effect of diabetes induction on atherogenesis and on macrophage-foam cell formation.

Methods And Results: Atherosclerotic apolipoprotein-E-deficient mice were converted into diabetic mice by streptozotocin injection.

Mineralocorticoid receptor blocker increases angiotensin-converting enzyme 2 activity in congestive heart failure patients.

Aldosterone plays an important role in the pathophysiology of congestive heart failure (CHF), and spironolactone improves cardiovascular function and survival rates in patients with CHF. We hypothesized that the mineralocorticoid receptor blockade (MRB) exerted its beneficial effects by reducing oxidative stress and changing the balance between the counter-acting enzymes angiotensin-converting enzyme (ACE) and ACE2. Monocyte-derived macrophages were obtained from 10 patients with CHF before and after 1 month of treatment with spironolactone (25 mg/d).

Effects of spironolactone and eprosartan on cardiac remodeling and angiotensin-converting enzyme isoforms in rats with experimental heart failure.

Angiotensin-converting enzyme (ACE)-2 is a newly described enzyme with antagonistic effects to those of the classical ACE (ACE-1). Both ANG II and aldosterone play an important role in the pathophysiology of congestive heart failure (CHF) and in the adverse cardiac remodeling during its development. In this study, we examined the effects of experimental CHF induced by an aortocaval fistula (ACF) and of its treatment with ANG II and aldosterone inhibitors on the relative levels of ACE-1 and ACE-2.

Angiotensin II increases the expression of lectin-like oxidized low-density lipoprotein receptor-1 in human vascular smooth muscle cells via a lipoxygenase-dependent pathway.

Background: Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a membrane protein that can act as a surface endocytosis receptor for oxidized LDL (ox-LDL). As increased cellular uptake of ox-LDL by macrophages and activated smooth muscle cells may transform these cells into foam cells, potential interactions among LDL oxidation, ox-LDL uptake, and regulators of vascular smooth muscle cell function are of obvious interest. The objective of this study was to examine the effect of angiotensin II (AII) on the expression of LOX-1 and ox-LDL degradation in human vascular smooth muscle cells (VSMC) METHODS: We performed in vitro experiments in a human VSMC line (T/G HA-VSMC) derived from normal aortic VSMC, using standards methods.