Monocytes of patients with unstable angina express high levels of chemokine and pattern-recognition receptors.

BACKGROUND AND AIMS: Macrophages derived from monocytes play an important role in atherosclerosis progression. Subpopulations of circulating classical, intermediate, and non-classical monocytes possess distinct functions and phenotypes, and participate in the pathogenesis of disease. The aim of this study was to compare the quantity and phenotypes of circulating monocyte subpopulations in patients with established atherosclerosis and healthy control individuals. Additionally, the study aimed to provide insight into the functional activity of monocytes against a heat shock protein (HSP60). METHODS: Chemokine and pattern recognition receptors in monocyte subsets obtained from peripheral blood of acute and chronic coronary artery disease patients and controls were quantified by flow cytometry. Furthermore, monocytes from healthy controls were stimulated in vitro with HSP60, and the cytokines produced by them were evaluated by flow cytometry. RESULTS: Eighteen controls (C), 34 individuals with risk factors for cardiovascular disease (RF), 32 patients with stable angina (SA), and 16 patients with unstable angina (UA) were enrolled in the study. The absolute count of intermediate monocytes was found to be increased in patients of the UA group; high frequencies of the chemokine receptors CCR2, CCR5, and CX3CR1 were also observed in this subpopulation. Moreover, the pattern recognition receptors TLR2 and TLR4 were more frequent in intermediate monocytes from the UA group. Furthermore, the intermediate monocytes from healthy individuals produced IL-12p70 after stimulation with HSP60. CONCLUSIONS: Our results show that intermediate monocytes of UA patients exhibited an enhanced expression of the receptors involved in the recognition of damage-associated molecular patterns (DAMPs) and enhancement of the migratory function. Hence, they might contribute to the propagation and progression of inflammation observed in atherosclerosis, especially in the acute setting.

Low empowerment and diabetes regimen distress are related to HbA1c in low income type 1 diabetes patients in a Brazilian tertiary public hospital.

BACKGROUND: Adults with type 1 diabetes (T1D) have a high risk of developing depressive symptoms and diabetes-related distress (DD). Low socioeconomic level is associated with increased risk of poor self-management, treatment difficulties and psychological distress. The goals of this study were to document the frequency of major depressive disorder (MDD), high depressive symptoms and high DD, to assess levels of empowerment and to determine the association with each of these measures and glycemic control in a low-income Brazilian sample of adults with T1D. METHODS: In a cross-sectional study, inclusion criteria were age > 18 years and diagnosis of T1D > 6 months. Exclusion criteria were cognitive impairment, history of major psychiatric disorders, severe diabetes-related complications and pregnancy. Diagnoses of MDD were made using interview-based DSM-5 criteria. Depressive symptoms were evaluated by the depression subscale of the Hospital Anxiety and Depression Scale (HAD-D). The Diabetes Distress Scale (DDS) assessed DD. Empowerment levels were evaluated by the Diabetes Empowerment Scale short form (DES-SF). Glycemic control was measured by HbA1c. The latest lipid panel results were recorded. Number of complications was obtained from medical records. RESULTS: Of the 63 T1D patients recruited, 36.5% were male, mean age was 31.5 (± 8.9), mean number of complications was 1 (± 1.1), and mean HbA1c was 10.0% (± 2). Frequency of MDD was 34.9% and 34.9% reported high depressive symptoms. Fifty-seven percent reported clinically meaningful DD. High diabetes regimen distress and low empowerment were associated to HbA1c (p = 0.003; p = 0.01, respectively). In multivariate analyses, lower empowerment levels were associated to higher HbA1c (beta - 1.11; r-partial 0.09; p value 0.0126). MDD and depressive symptoms were not significantly correlated with HbA1c in this expected direction (p = 0.72; p = 0.97, respectively). CONCLUSIONS: This study showed high rates of MDD, high depressive symptoms and high DD and low levels of empowerment in this low income population. Empowerment and diabetes regimen distress were linked to glycemic control. The results emphasize the need to incorporate the psychological and psychosocial side of diabetes into strategies of care and education for T1D patients.

Endothelial nitric oxide synthase gene variant modulates the relationship between serum cholesterol levels and blood pressure in the general population: new evidence for a direct effect of lipids in arterial blood pressure.

BACKGROUND: A causal relationship between plasma cholesterol and blood pressure remains poorly understood. It has been postulated that the decrease in nitric oxide (NO) availability is a potential mechanism by which hypercholesterolemia may stimulate blood pressure elevation. However, evidence supporting the role of the L-arginine-NO pathway on the relationship between hypertension and hypercholesterolemia is still lacking. METHODS AND RESULTS: We tested for an association of the expressed NO synthase (eNOS) Glu298Asp gene variant and plasma levels of lipids and lipoproteins in the determination of systolic blood pressure levels in a 1577 individuals randomly selected from the general population. Significant interactions could be disclosed either between the Glu298Asp gene variant and total-cholesterol (p = 0.02), log-transformed triglycerides (p = 0.004) or non-HDL-cholesterol (p = 0.003) in the determination of systolic blood pressure. In addition, although the presence of the AspAsp genotype did not significantly increase the risk of hypertension in individuals in the 50% lowest percentile of total-cholesterol, presence of this genotype significantly increased the risk of hypertension in individuals in the 50% highest percentile. Finally, in a multiple logistic regression model adjusting for age, sex, diabetes, ethnicity, smoking status and BMI, the AspAsp genotype significantly increased the risk of hypertension only in individuals with total-cholesterol above 209 mg/dL (p = 0.05, odds ratios (OR) = 2.0). CONCLUSION: Taken together, these results provide evidence supporting the role of the eNOS Glu298Asp gene variant in modulating blood pressure through a relationship with lipid levels.

The effects of gemfibrozil upon the metabolism of chylomicron-like emulsions in patients with endogenous hypertriglyceridemia.

OBJECTIVE: To evaluate the effects of gemfibrozil upon the intravascular metabolism of chylomicron-like emulsions in endogenous hypertriglyceridemia. METHODS: We evaluated the plasma kinetics of a chylomicron-like emulsion in 39 subjects: 27 hypertriglyceridemics, total cholesterol (TC) expressed as median (%25; %75) 7.47 (6.1; 8.19) mmol/l and plasma triglycerides (TG) 4.28 (3.6; 18.5) mmol/l and in 12 normolipidemics, TC 4.7 (3.85; 5.37) mmol/l and TG 0.91 (0.64; 1.75) mmol/l. Hypertriglyceridemics were evaluated at baseline and after a 30-day 1200-mg/day gemfibrozil (n=8) or placebo treatment (n=7). The emulsion labelled with 14C-cholesteryl oleate (14C-CO) and 3H-triolein (3H-TO) was injected intravenously after a 12-h fast. The plasma kinetics of 3H-TO and 14C-CO were determined to assess, respectively, lipolysis and clearance of chylomicron and remnants by compartmental analysis. RESULTS: The residence times (in minutes) of 3H-TO and 14C-CO of hypertriglyceridemics were roughly twice the values of normolipidemics, i.e. 8.0 (5.5; 12.0) versus 15.0 (11.0; 24.0) and 21.5 (14.0; 33.0) versus 44.0 (32.0; 72.0), P=0.001. Gemfibrozil treatment of hypertriglyceridemic patients reduced the residence times of 3H-TO and 14C-CO, respectively, by 46% (P=0.003) and 53% (P=0.008). Effects were noted on the slow phase of emulsion plasma removal, which was reduced in hypertriglyceridemics. After treatment, the emulsion residence times determined in hypertriglyceridemics attained the values of the normolipidemic group. CONCLUSIONS: Gemfibrozil treatment normalised the defects in chylomicron-like emulsion catabolism observed in endogenous hypertriglyceridemia patients.

Arterial tissue and plasma concentration of enzymatic-driven oxysterols are associated with severe peripheral atherosclerotic disease and systemic inflammatory activity.

INTRODUCTION: Cholesterol undergoes oxidation via both enzymatic stress- and free radical-mediated mechanisms, generating a wide range of oxysterols. In contrast to oxidative stress-driven metabolites, enzymatic stress-derived oxysterols are scarcely studied in their association with atherosclerotic disease in humans. METHODS: 24S-hydroxycholesterol (24S-HC), 25-hydroxycholesterol (25-HC), and 27-hydroxycholesterol (27-HC) were assessed in plasma and arteries with atherosclerotic plaques from 10 patients (54-84 years) with severe peripheral artery disease (PAD) as well as arteries free of atherosclerotic plaques from 13 individuals (45-78 years, controls). RESULTS: Plasma 25-HC was higher in PAD individuals than in controls (6.3[2] vs. 3.9[1.9] ng/mgCol; p = 0.004). 24S-HC and 27-HC levels were, respectively, five- and 20-fold higher in the arterial tissue of PAD individuals than in those of the controls (p = 0.016 and p = 0.001). Plasma C-reactive protein correlated with plasma 24-HC (r = 0.51; p = 0.010), 25-HC (r = 0.75; p < 0.001), 27-HC (r = 0.48; p = 0.015), and with tissue 24S-HC (r = 0.4; p = 0.041) and 27-HC (r = 0.46; p = 0.023). CONCLUSION: Arterial intima accumulation of 27-HC and 24S-HC is associated with advanced atherosclerotic disease and systemic inflammatory activity in individuals with severe PAD.

Effects of etofibrate upon the metabolism of chylomicron-like emulsions in patients with coronary artery disease.

Slow chylomicron intravascular catabolism has been associated with coronary artery disease and screening for drugs that can speed-up this process can be important. In this study, the effects of etofibrate upon chylomicron metabolism was tested by determination of the plasma kinetics of a chylomicron-like emulsion model in 12 patients with coronary artery disease, aged 59+/-11 years, (total cholesterol: 240+/-41 mg/dl; triglycerides: 188+/-42 mg/dl) submitted to a randomized, crossover, double-blind, placebo-controlled study with administration of 1 g per day etofibrate or placebo for 1-month. A 1-month washout period was inserted between the treatment periods. Patients were intravenously injected a chylomicron-like emulsion doubly labeled with 14C-cholesteryl oleate and 3H-triolein at baseline and after treatments. After etofibrate treatment, there was decrease of total cholesterol and triglyceride plasma levels and a trend to increase high-density lipoprotein cholesterol plasma levels. Etofibrate elicited 62% enhancement of post-heparin lipolytic activity and 100% increase of 3H-triglyceride fractional clearance rate compared with placebo treatment. 14C-cholesterol ester fractional clearance rate was 260% greater after etofibrate than after placebo. Therefore, a potent effect of etofibrate on both chylomicron lipolysis and remnant removal was achieved, indicating that this drug can be used to improve this metabolism in future prospective studies.

Effect of niacin and etofibrate association on subjects with coronary artery disease and serum high-density lipoprotein cholesterol <35 mg/dl.

Niacin treatment (alone) was compared with etofibrate and niacin combination to treat patients with high-density lipoprotein <35 mg/dl and without hypertriglyceridemia. The niacin and etofibrate combination proved to be safe and increased high-density lipoprotein cholesterol levels to 48%, which was 3 times higher than that obtained with niacin alone.

Additional reduction in blood pressure after cholesterol-lowering treatment by statins (lovastatin or pravastatin) in hypercholesterolemic patients using angiotensin-converting enzyme inhibitors (enalapril or lisinopril).

Blood pressure (BP) reduction was compared between patients receiving angiotensin-converting enzyme inhibitors alone and patients receiving these medications plus statins after 3 months of dietary intervention. Although BP was similarly reduced at week 4, the statin-treated group had a greater reduction in BP and total cholesterol levels at week 16, suggesting a synergistic effect between cholesterol lowering with statins and angiotensin-converting enzyme inhibitor treatment for hypertensive patients.

Effect of pravastatin on plasma removal of a chylomicron-like emulsion in men with coronary artery disease.

The speed of the plasma removal of chylomicrons, the lipoproteins that carry dietary lipids absorbed in the intestine, may influence atherogenesis. Thus, the effects of a 30-day pravastatin or placebo treatment on the plasma kinetics of chylomicron-like emulsions were evaluated in 25 patients with coronary artery disease who were not hypertriglyceridemic in a randomized, single-blinded study. Eleven patients (53 +/- 4 years, 10 men) received pravastatin 40 mg/day and 14 received placebo (52 +/- 3 years, 13 men). Emulsions labeled with triolein ((3)H-TO) and cholesteryl oleate ((14)C-CO) to assess lipolysis and clearance of chylomicron and remnants, respectively, were injected intravenously in a bolus after a 12-hour fast. Blood samples were collected during 60 minutes to determine radio isotope decaying curves and fractional catabolic rates. Subjects were studied at baseline and after the treatment period. Compared with placebo (data expressed as mean +/- SEM), pravastatin treatment increased the (14)C-CO fractional catabolic rates (70 +/- 45% vs 18 +/- 10%, p = 0.01), reduced total cholesterol (-21 +/- 3% vs -3 +/- 2% p = 0.0001), low-density lipoprotein (LDL) cholesterol (-25 +/- 5% vs 4 +/- 6%, p = 0.0001), and apolipoprotein B levels (-22 +/- 3% vs -7 +/- 3% p = 0.01). (3)H-TO fractional catabolic rates, plasma triglycerides, very-low-density lipoprotein (VLDL) cholesterol and high-density lipoprotein (HDL) cholesterol variations did not differ between the groups. The fractional catabolic rate of (14)C-CO was inversely correlated with plasma apolipoprotein B levels (r = -0.7, p = 0.04). This suggests that besides reducing LDL cholesterol, pravastatin also increases chylomicron remnant clearance, with possible antiatherogenic implications.

Cholesterol lowering with statins reduces exercise-induced myocardial ischemia in hypercholesterolemic patients with coronary artery disease.

Coronary flow reserve is mainly influenced by the combination of luminal stenosis and vascular dilation capacity. Thus, after statin treatment, the reduction of ischemic threshold in patients submitted to exercise testing could be intensely influenced by angiographic severity. In this study, we verify the effect of statin treatment on exercise-induced myocardial ischemia in hypercholesterolemic patients with a broad range of coronary angiographic severities. Patients with 2 consecutive positive exercise tests, coronary stenosis > or =70%, total cholesterol > or =300 mg/dl, and triglycerides < or =200 mg/dl were randomly assigned to a 16-week treatment period with either diet alone (n = 39) or diet plus statins (simavastatin, n = 31 and pravastatin, n = 10). Statin-treated patients had a significant variation in total cholesterol (-46% vs -2.7%; p <0.01), low-density lipoprotein cholesterol (-58% vs 0.8%; p <0.01), and high-density cholesterol (+28% vs -6%; p <0.05) in comparison with the diet-only group. After 16 weeks of treatment, 36 patients (92%) in the diet group still had positive exercise tests, whereas only 7 patients (15%) of the statin group had a positive test (p <0.01). The proportion of positive tests was significantly reduced in subgroups of patients with 1-, 2-, or 3-vessel disease. Regarding the severity of coronary stenosis, the proportion of positive tests was significantly reduced in patients with stenosis between 70% and 90% and in patients with stenosis > or =90%. Moreover, the proportion of positive tests tended to decrease to a greater extent in patients with mild coronary disease. In conclusion, cholesterol-lowering treatment with statins reduces exercise-induced myocardial ischemia in hypercholesterolemic patients with mild or severe epicardial coronary stenosis.

Triglyceride and lipoprotein (a) are markers of coronary artery disease severity among postmenopausal women.

OBJECTIVE: After menopause, some women manifest coronary artery disease (CAD) with highly variable angiographic severity. For these women, postmenopausal appearing of some CAD risk factors may have differently influenced the CAD risk and severity. In this study, we attempt to unravel differences in the frequency or intensity of CAD risk factors among postmenopausal women with different angiographic severity. METHODS: We studied 182 postmenopausal women (64+/-6 years) who underwent coronary angiography to investigate thoracic pain. Subjects with no detectable coronary lesions at angiography were recruited to the non-obstructive group and patients with CAD were grouped in one-vessel or multi-vessel groups. We compared clinical variables as the body mass index (BMI), age at menopause, age, hypertension, diabetes and cigarette smoking, and lipid measurements as plasma levels of total cholesterol, triglyceride, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, apolipoprotein (apo) A1, apo B and lipoprotein(a) (Lp(a)). RESULTS: Comparing to the non-obstructive group, Lp(a) was twofold higher in the one-vessel group and threefold higher in the multi-vessel group and triglycerides were 34% higher in the one-vessel group and 50% higher in the multi-vessel group. No further difference was found among the three groups. After multivariate logistic regression analysis, triglyceride (odds ratio: 1.01; P=0.0013) and Lp(a) (odds ratio: 1.006; P<0.0001) were independently indicative of the presence of obstructive CAD. CONCLUSIONS: We found that both Lp(a) and triglycerides constitute useful markers of CAD severity among postmenopausal women.

Apolipoprotein and lipid abnormalities in chronic liver failure.

Total serum lipids, as well as apolipoproteins A-I (apo A-I) and B (apo B), were determined in 74 patients with chronic liver failure without cholestasis and in 82 normal subjects. The VLDL, LDL and HDL lipid fractions were reduced in the liver failure group by 36%, 24% and 46%, respectively (P < 0.001). Apolipoproteins A-I and B were also reduced by 26% and 25%, respectively (P < 0.001). However, the reduction of HDL cholesterol (HDLc) was more pronounced than that of apo A-I and the HDLc:apo A-I ratio was significantly lower in the liver failure group. After separating these patients into groups with plasma albumin lower than 3.0, between 3.0 and 3.5, and higher than 3.5 g/dl, the HDLc:apo A-I ratio was proportional to plasma albumin, but the correlation was not statistically significant. When these patients were separated by the Child classification of liver function, there was a correlation between the HDLc:apo A-I ratio and liver function. The differences in the HDLc:apo A-I ratio between the Child groups B and C, and A and C were statistically significant (P < 0.05). We conclude that there is a more pronounced reduction in HDL cholesterol than in apo A-I in liver failure patients. Therefore, the HDLc:apo A-I ratio is a marker of liver function, probably because there is a decreased lecithin-cholesterol acyltransferase production by the diseased liver.

Etofibrate but not controlled-release niacin decreases LDL cholesterol and lipoprotein (a) in type IIb dyslipidemic subjects.

Etofibrate is a hybrid drug which combines niacin with clofibrate. After contact with plasma hydrolases, both constituents are gradually released in a controlled-release manner. In this study, we compared the effects of etofibrate and controlled-release niacin on lipid profile and plasma lipoprotein (a) (Lp(a)) levels of patients with triglyceride levels of 200 to 400 mg/dl, total cholesterol above 240 mg/dl and Lp(a) above 40 mg/dl. These patients were randomly assigned to a double-blind 16-week treatment period with etofibrate (500 mg twice daily, N = 14) or niacin (500 mg twice daily, N = 11). In both treatment groups total cholesterol, VLDL cholesterol and triglycerides were equally reduced and high-density lipoprotein cholesterol was increased. Etofibrate, but not niacin, reduced Lp(a) by 26% and low-density lipoprotein (LDL) cholesterol by 23%. The hybrid compound etofibrate produced a more effective reduction in plasma LDL cholesterol and Lp(a) levels than controlled-release niacin in type IIb dyslipidemic subjects.

Hyperlipidemia related to the use of HIV-protease inhibitors: natural history and results of treatment with fenofibrate.

Hyperlipidemia has been frequently recorded as a side effect of treating HIV patients with protease inhibitors (PI). This study was initiated to analyze the modifications on blood lipids in HIV-patients receiving PI and the safety and efficacy of the treatment with fenofibrate. Total (TC) and HDL-cholesterol, triglycerides (TG), and CD(4)(+) T-cell counts were measured in 30 HAART-naive patients (Group I) before and after PI introduction. In a second phase of the study, the effects of fenofibrate on lipids, CPK, CD(4)(+), and viral load were determined in 13 patients (Group II) with elevated TC or TG. In Group I, 60% of the patients showed TC or TG elevations. Average increments of 31% and 146% in TC and TG respectively (p<0.0006 and p<0.0001) were observed. In Group II, fenofibrate treatment was associated with decrements of 6.6% (TC) and 45.7% (TG) (p=0.07 and 0.0002) and no modifications on CPK, CD(4)(+), and viral load. In conclusion, hyperlipidemia is common during the treatment of HIV with protease inhibitors, and fenofibrate appears to be an effective and safe choice for its treatment.

[Gemfibrozil reduces elevated lipoprotein (a) levels in hypercholesterolemic patients]. / O gemfibrozil reduz níveis elevados de lipoproteína (a) em pacientes hipercolesterolêmicos.

PURPOSE: To compare the effects of gemfibrozil and lovastatin in patients with hypercholesterolemia and increased lipoprotein(a) [Lp(a)] levels. METHODS: Twenty-seven subjects with total cholesterol (TC) > 240 mg/dL, LDL-C > 160 mg/dL and Lp(a) > 25 mg/dL were studied. Patients were randomized to receive gemfibrozil 1200 mg/day, (n = 14, 54 +/- 7 years) or lovastatin 40-80 mg at night (n = 13, 55 +/- 9 years) for 12 weeks. Lipid profile and Lp(a) were determined at 4 and 12 weeks of treatment. RESULTS: Gemfibrozil reduced TC (-21%), LDL-C (-26%), triglycerides (TG)(-48%) and Lp(a) (-25%), increased HDL-C (+48%)(p < 0.001). Lovastatin reduced TC (-29%), LDL-C (-37%) and TG (-25%) (p < 0.001) however, it did not affect Lp(a). CONCLUSION: Besides reducing plasma LDL-C, TG and increasing HDL-C, gemfibrozil effectively lowers Lp(a) levels. Lovastatin did not affect Lp(a) levels.

PANDORA - Survey of Brazilian cardiologists about cholesterol reduction.

OBJECTIVE: To report about a group of physicians' understanding of the recommendations of the II Brazilian Guidelines Conference on Dyslipidemias, and about the state of the art of primary and secondary prevention of atherosclerosis. METHODS: Through the use of a questionnaire on dyslipidemia, atherosclerosis prevention, and recommendations for lipid targets established by the II Brazilian Guidelines Conference on Dyslipidemias, 746 physicians, 98% cardiologists, were evaluated. RESULTS: Eighty-seven percent of the respondents stated that the treatment of dyslipidemia changes the natural history of coronary disease. Although most of the participants followed the total cholesterol recommendations (<200mg/dL for atherosclerosis prevention), only 55.8% would adopt the target of LDL-C <100 mg/dL for secondary prevention. Between 30.5 and 36.7% answered, in different questions, that the recommended level for HDL-C should be <35mg/dL. Only 32.7% would treat their patients indefinitely with lipid- lowering drugs. If the drug treatment did not reach the proposed target, only 35.5% would increase the dosage, and 29.4% would change the medication. Participants did not know the targets proposed for diabetics. CONCLUSION: Although the participating physicians valued the role played by lipids in the prevention of atherosclerosis, serious deficiencies exist in their knowledge of the recommendations given during the II Brazilian Guidelines Conference on Dyslipidemias.