A Review of Time Courses and Predictors of Lipid Changes with Fenofibric Acid-Statin Combination

Fibrates activate peroxisome proliferator activated receptor α and exert beneficial effects on triglycerides, high-density lipoprotein cholesterol, and low density lipoprotein subspecies. Fenofibric acid (FA) has been studied in a large number of patients with mixed dyslipidemia, combined with a low- or moderate-dose statin. The combination of FA with simvastatin, atorvastatin and rosuvastatin resulted in greater improvement of the overall lipid profile compared with the corresponding statin dose. The long-term efficacy of FA combined with low- or moderate- dose statin has been demonstrated in a wide range of patients, including patients with type 2 diabetes mellitus, metabolic syndrome, or elderly subjects. The FA and statin combination seems to be a reasonable option to further reduce cardiovascular risk in high-risk populations, although trials examining cardiovascular disease events are missing

Long term hemodialysis aggravates lipolytic activity reduction and very low density, low density lipoproteins composition in chronic renal failure patients

<p>Abstract</p> <p>Background</p> <p>Dyslipidemia, particularly hypertriglyceridemia is common in uremia, and represents an independent risk factor for atherosclerosis.</p> <p>Methods</p> <p>To investigate the effects of hemodialysis (HD) duration on very low density lipoprotein (VLDL) and low density lipoprotein (LDL) compositions and lipopolytic activities, 20 patients on 5 to 7 years hemodialysis were followed-up during 9 years. Blood samples were drawn at T0 (beginning of the study), T1 (3 years after initiating study), T2 (6 years after initiating study) and T3 (9 years after initiating study). T0 was taken as reference.</p> <p>Results</p> <p>Triacylglycerols (TG) values were correlated with HD duration (r = 0.70, P < 0.05). An increase of total cholesterol was noted at T2 and T3. Lowered activity was observed for lipoprotein lipase (LPL) (-44%) at T3 and hepatic lipase (HL) (-29%) at T1, (-64%) at T2 and (-73%) at T3. Inverse relationships were found between HD duration and LPL activity (r = -0.63, P < 0.05), and HL activity (r = -0.71, P < 0.01). At T1, T2 and T3, high VLDL-amounts and VLDL-TG and decreased VLDL-phospholipids values were noted. Increased LDL-cholesteryl esters values were noted at T1 and T2 and in LDL-unesterified cholesterol at T2 and T3.</p> <p>Conclusion</p> <p>Despite hemodialysis duration, VLDL-LDL metabolism alterations are aggravated submitting patients to a greater risk of atherosclerosis.</p

Clinical and Functional Characterization of URAT1 Variants

Idiopathic renal hypouricaemia is an inherited form of hypouricaemia, associated with abnormal renal handling of uric acid. There is excessive urinary wasting of uric acid resulting in hypouricaemia. Patients may be asymptomatic, but the persistent urinary abnormalities may manifest as renal stone disease, and hypouricaemia may manifest as exercise induced acute kidney injury. Here we have identified Macedonian and British patients with hypouricaemia, who presented with a variety of renal symptoms and signs including renal stone disease, hematuria, pyelonephritis and nephrocalcinosis. We have identified heterozygous missense mutations in SLC22A12 encoding the urate transporter protein URAT1 and correlate these genetic findings with functional characterization. Urate handling was determined using uptake experiments in HEK293 cells. This data highlights the importance of the URAT1 renal urate transporter in determining serum urate concentrations and the clinical phenotypes, including nephrolithiasis, that should prompt the clinician to suspect an inherited form of renal hypouricaemia

Effects of Eprosartan on Serum Metabolic Parameters in Patients with Essential Hypertension

The effect of the anti-hypertensive drug eprosartan on metabolic parameters is currently not extensively documented. We evaluated the effect of eprosartan on parameters involved in atherogenesis, oxidative stress and clotting activity. This open-label unblinded intervention study included 40 adult patients with essential hypertension taking eprosartan. Eprosartan significantly reduced by 8% (p<0.001) the systolic and by 13% (p<.001) the diastolic blood pressure, and in-creased by 24% the time needed to produce oxidative by-products (p=0.001), a marker of oxidative stress. In contrast, ep-rosartan did not alter 8-isoprostane (8-epiPGF2a) levels, another marker of oxidative stress. Additionally, eprosartan re-duced by 14% aspartate aminotransferase and by 21% then alanine aminotransferase activity, while it had a neutral effect on the lipid profile and apolipoprotein levels and did not influence glucose homeostasis, creatinine and uric acid levels. Eprosartan did not affect the clotting/fibrinolytic status (estimated by plasminogen activator inhibitor 1, tissue plasmino-gen activator and a2 antiplasmin levels), or the enzymatic activity of the lipoprotein associated phospholipase A2 (Lp-PLA2) and paraoxonase 1 (PON1). In conclusion, eprosartan should be mainly considered as an anti-hypertensive agent with neutral effects on most of the metabolic parameters in hypertensive patients

Sedentary subjects have higher PAI-1 and lipoproteins levels than highly trained athletes

Physical exercise protects against the development of cardiovascular disease, partly by lowering plasmatic total cholesterol, LDL-cholesterol and increased HDL-cholesterol levels. In addition, it is now established that reduction plasmatic adiponectin and increased C-reactive protein (CRP) and plasminogen activator inhibitor-1 (PAI-1) levels play a role in the maintenance of an inflammatory state and in the development of cardiovascular disease. This study aimed to examine plasma lipid profile and inflammatory markers levels in individual with sedentary lifestyle and/or highly trained athletes at rest. Methods: Fourteen male subjects (sedentary lifestyle n = 7 and highly trained athletes n = 7) were recruited. Blood samples were collected after an overnight fast (~12 h). The plasmatic lipid profile (Triglycerides, HDL-cholesterol, LDL-cholesterol, total cholesterol, LDL-oxidized and total cholesterol/HDL-c ratio), glucose, adiponectin, C - reactive protein and PAI-1 levels were determined. Results: Total cholesterol, LDL-cholesterol, TG and PAI-1 levels were lower in highly trained athletes group in relation to sedentary subjects (p < 0.01). In addition, we observed a positive correlation between PAI-1 and total cholesterol (r = 0.78; p < 0.0009), PAI-1 and LDL-c (r = 0.69; p < 0.006) and PAI-1 and TG levels (r = 0.56; p < 0.03). The plasma concentration of adiponectin, CRP, glucose, HDL-cholesterol and total cholesterol/HDL-c ratio levels were not different. These results indicate that lifestyle associated with high intensity and high volume exercise induces changes favourable in the lipid profile and PAI-1 levels and may reduce risk cardiovascular diseases

Fenofibrate Reduces Mortality and Precludes Neurological Deficits in Survivors in Murine Model of Japanese Encephalitis Viral Infection

Background: Japanese encephalitis (JE), the most common form of viral encephalitis occurs periodically in endemic areas leading to high mortality and neurological deficits in survivors. It is caused by a flavivirus, Japanese encephalitis virus (JEV), which is transmitted to humans through mosquitoes. No effective cure exists for reducing mortality and morbidity caused by JEV infection, which is primarily due to excessive inflammatory response. Fenofibrate, a peroxisome proliferator-activated receptor-a (PPARa) agonist is known to resolve inflammation by repressing nuclear factor-kB (NF-kB) and enhancing transcription of anti-oxidant and anti-inflammatory genes. In addition, fenofibrate also up-regulates a class of proteins, cytochrome P4504Fs (Cyp4fs), which are involved in detoxification of the potent pro-inflammatory eicosanoid, leukotriene B4 (LTB4) to 20-hydroxy LTB4. Methodology/Principal Findings: The neuroprotective effect of fenofibrate was examined using in vitro (BV-2 microglial cell line) and in vivo (BALB/c mice) models of JEV infection. Mice were treated with fenofibrate for 2 or 4 days prior to JEV exposure. Pretreatment with fenofibrate for 4 but not 2 days reduced mortality by 80 % and brain LTB4 levels decreased concomitantly with the induction of Cyp4f15 and 4f18, which catalyze detoxification of LTB4 through hydroxylation. Expression of cytokines and chemokine decreased significantly as did microglial activation and replication of the JEV virus. Conclusions/Significance: Fenofibrate confers neuroprotection against Japanese encephalitis, in vivo, in mouse model o

Genome-Wide Association Study of Lp-PLA2 Activity and Mass in the Framingham Heart Study

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an emerging risk factor and therapeutic target for cardiovascular disease. The activity and mass of this enzyme are heritable traits, but major genetic determinants have not been explored in a systematic, genome-wide fashion. We carried out a genome-wide association study of Lp-PLA2 activity and mass in 6,668 Caucasian subjects from the population-based Framingham Heart Study. Clinical data and genotypes from the Affymetrix 550K SNP array were obtained from the open-access Framingham SHARe project. Each polymorphism that passed quality control was tested for associations with Lp-PLA2 activity and mass using linear mixed models implemented in the R statistical package, accounting for familial correlations, and controlling for age, sex, smoking, lipid-lowering-medication use, and cohort. For Lp-PLA2 activity, polymorphisms at four independent loci reached genome-wide significance, including the APOE/APOC1 region on chromosome 19 (p = 6×10−24); CELSR2/PSRC1 on chromosome 1 (p = 3×10−15); SCARB1 on chromosome 12 (p = 1×10−8) and ZNF259/BUD13 in the APOA5/APOA1 gene region on chromosome 11 (p = 4×10−8). All of these remained significant after accounting for associations with LDL cholesterol, HDL cholesterol, or triglycerides. For Lp-PLA2 mass, 12 SNPs achieved genome-wide significance, all clustering in a region on chromosome 6p12.3 near the PLA2G7 gene. Our analyses demonstrate that genetic polymorphisms may contribute to inter-individual variation in Lp-PLA2 activity and mass