The Role of Plasma Triglyceride/High‐Density Lipoprotein Cholesterol Ratio to Predict New Cardiovascular Events in Essential Hypertensive Patients

Triglyceride (TG) to high‐density lipoprotein cholesterol (HDL‐C) ratio (TG/HDL‐C) has been suggested as a simple method to identify unfavorable cardiovascular outcomes in the general population. The effect of the TG/HDL‐C ratio on essential hypertensive patients is unclear. About 900 consecutive essential hypertensive patients (mean age 52.9±12.6 years, 54.2% male) who visited our outpatient hypertension clinic were analyzed. Participants were divided into quartiles based on baseline TG/HDL‐C ratio and medical records were obtained periodically for the occurrence of fatal events and composite major adverse cardiovascular events (MACEs) including transient ischemic attack, stroke, aortic dissection, acute coronary syndrome, and death. Participants were followed for a median of 40 months (interquartile range, 35–44 months). Overall, a higher quartile of TG/HDL‐C ratio at baseline was significantly linked with higher incidence of fatal and nonfatal cardiovascular events. Using multivariate Cox regression analysis, plasma TG/HDL‐C ratio was independently associated with increased risk of fatal events (hazard ratio [HR], 1.25; 95% confidence interval [CI], 1.13–1.37; P≤.001] and MACEs (HR, 1.13; 95% CI, 1.06–1.21; P≤.001). Increased plasma TG/HDL‐C ratio was associated with more fatal events and MACEs in essential hypertensive patients.     

Paradoxical Decrease in High‐Density Lipoprotein Cholesterol with Fenofibrate: A Quite Rare Phenomenon Indeed

Some recent clinical reports have suggested that paradoxical decreases in high‐density lipoprotein cholesterol (HDL‐C) levels after fenofibrate treatment may be quite common. These appear to occur mainly in patients with combined fibrate/statin therapy and possibly in those with low baseline HDL‐C. Reports on HDL‐C reductions after fenofibrate are possibly supported by the disappointing results in terms of HDL‐C responses from the recent FIELD study. A survey on 581 patients treated for 1 year or longer was carried out in our Clinical Center. This indicated that paradoxical HDL‐C reductions are a relatively uncommon phenomenon. Not more than 15.3% of the present series showed an HDL‐C reduction, mostly of a modest degree. Further, reductions of HDL‐C appear to occur mainly in individuals with significant HDL‐C elevations (>50 mg/dL), almost never in patients with low HDL‐C. Otherwise, there seems to be no impact of a previous diagnosis of diabetes or hypertension on the HDL‐C changes. From a very recent pharmacogenomic study on the apo A1/C3/A4/A5 gene cluster, genetic influences appear only to reduce the positive impact of fenofibrate on HDL‐C, but do not indicate any risk of occurrence of HDL‐C reductions. Also based on our very long experience with this drug, it appears that fenofibrate raises HDL‐C levels in the vast majority of treated patients, with a particularly dramatic effect in individuals with low HDL‐C and hypertriglyceridemia.     

Exercise Training and Plasma C‐Reactive Protein and Interleukin‐6 in Elderly People

OBJECTIVES: To determine the effects of a long‐term exercise intervention on two prominent biomarkers of inflammation (C‐reactive protein (CRP) and interleukin‐6 (IL‐6)) in elderly men and women. DESIGN: Single‐blind, randomized, controlled trial: The Lifestyle Interventions and Independence for Elders (LIFE) Trial. SETTING: The Cooper Institute, Dallas, Texas; Stanford University, Stanford, California; University of Pittsburgh, Pittsburgh, Pennsylvania; and Wake Forest University, Winston‐Salem, North Carolina. PARTICIPANTS: Four hundred twenty‐four elderly (aged 70–89), nondisabled, community‐dwelling men and women at risk for physical disability. INTERVENTION: A 12‐month moderate‐intensity physical activity (PA) intervention and a successful aging (SA) health education intervention. MEASUREMENTS: CRP and IL‐6. RESULTS: After adjustment for baseline IL‐6, sex, clinic site, diabetes mellitus, treatment group, visit, and group‐by‐visit interaction, the PA intervention resulted in a lower (P=.02) IL‐6 concentration than the SA intervention. Adjusted mean IL‐6 at month 12 was 8.5% (0.21 pg/mL) higher in the SA than the PA group. There were no significant differences in CRP between the groups at 12 months (P=.09). Marginally significant interaction effects of the PA intervention according to baseline functional status (P=.05) and IL‐6 (above vs below the median; P=.06) were observed. There was a greater effect of the PA intervention on participants with lower functional status and those with a higher baseline IL‐6. CONCLUSION: Greater PA results in lower systemic concentrations of IL‐6 in elderly individuals, and this benefit is most pronounced in individuals at the greatest risk for disability and subsequent loss of independence.     

Low‐Density Lipoprotein Apheresis and Changes in Plasma Components

Abstract: Several different techniques of low‐density lipoprotein (LDL) apheresis are available for management of severe hypercholesterolemia. Among them, the adsorption system with a dextran‐sulfate cellulose (DSC) column is most widely used. In addition to adsorption of LDL, DSC adsorbs plasma constituents that have the following characteristics: proteins containing apolipoprotein B (Lp[a]); proteins involved in the initial contact phase of the intrinsic coagulation pathway (coagulation factor XII, high‐molecular‐weight kininogen and prekallikrein); factors with lipophilic characteristics (coagulation factor VII, coagulation factor VIII, and vitamin E); and proteins with adhesive or other characteristics (von Willebrand factor, fibronectin, serum amyloid P component, hepatocyte growth factor). The adsorption of these proteins seems to ameliorate prevention or regression of atherosclerosis. Moreover, plasma treatment by the DSC column may be useful for treatment of inexorable diseases, such as amyloidosis. On the other hand, the DSC column generates bradykinin by activation of the initial contact phase of the intrinsic coagulation pathway. Bradykinin generation may explain the functional improvement in the circulatory system, as well as hypotension during LDL apheresis, which is observed in patients taking ACE inhibitors.     

磷脂转运蛋白在高密度脂蛋白代谢和胆固醇逆向转运中的生物学作用

磷脂转运蛋白(PLTP)活性与糖尿病、肥胖、动脉粥样硬化等疾病明显相关的作用机制主要与其参与脂蛋白代谢有关。其中最引人注目的是PLTP在高密度脂蛋白(HDL)代谢和胆固醇逆向转运(RCT)中发挥的复杂生物学作用。PLTP可否通过影响HDL和RCT而发挥对动脉粥样硬化的作用?本文通过近年的文献复习并结合我们的相关工作与读者一同寻找答案和线索。     

Chronic Alcohol Consumption Disrupted Cholesterol Homeostasis in Rats: Down‐Regulation of Low‐Density Lipoprotein Receptor and Enhancement of Cholesterol Biosynthesis Pathway in the Liver

Background: Chronic alcohol consumption causes alcoholic liver disease, which is associated, or initiated, with dysregulated lipid metabolism. Very recent evidence suggested that dysregulated cholesterol metabolism plays an important role in the pathogenesis of alcoholic fatty liver diseases, however, the effects of chronic alcohol exposure on cholesterol homeostasis have not been well studied and underlying mechanisms behind are still elusive. Methods: Male Sprague–Dawley rats weighing 250 ± 5.5 g (mean ± SEM) divided into 2 groups (8 rats per group) and pair‐fed with liquid diets containing (in percent of energy intake) 18% protein, 35% fat, 12% carbohydrate, and 35% either ethanol (ethanol diet) or an isocaloric maltose‐dextrin mixture (control diet), according to Lieber and De Carli, for 4 weeks. Results: Long‐term excessive alcohol feeding to rats caused fatty liver and liver injury, which was associated with disrupted cholesterol homeostasis, characterized by increased hepatic cholesterol levels and hypercholesterolemia. Hepatic cholesterol increases were concomitant with constantly activated sterol regulatory element‐binding protein‐2 (SREBP‐2) in the liver and increased expression of 3‐hydroxy‐3‐methyl‐glutaryl‐CoA (HMG‐CoA) reductase, a rate‐limiting enzyme for cholesterol de novo synthesis, indicating enhanced cholesterol biosynthesis. Alcohol‐induced hypercholesterolemia was accompanied by decreased LDL receptor (LDLr) levels in the liver. Further investigations revealed that chronic alcohol exposure increased hepatic proprotein convertase subtilisin/kexin type 9 (PCSK9) contents to down‐regulate LDLr via a post‐translational mechanism. Moreover, alcohol feeding suppressed extracellular signal‐regulated kinase (ERK) activation in the liver. In vitro studies showed that inhibition of ERK activation was associated with decreased LDLr expression in HepG2 cells. Conclusions: Our study provides the first evidence that both increased PCSK9 expression and suppressed ERK activation in the liver contributes to alcohol‐induced hypercholesterolemia in rats.     

Plasma Lipoprotein Composition and Cholesteryl Ester Transfer from High Density Lipoproteins to Very Low Density and Low Density Lipoproteins in Patients with Non-insulin-dependent Diabetes Mellitus

We have examined cholesteryl ester transfer (CET) from HDL to low density and very low density lipoproteins (LDL and VLDL) and lecithin:cholesterol acyl transferase (LCAT) activity in plasma from 28 men with non-insulin-dependent diabetes mellitus (NIDDM) treated with diet alone or diet and sulphonylurea drugs and in 27 healthy non-diabetic controls. Patients and healthy subjects had similar LCAT activity, but CET was significantly higher in NIDDM 26.1 ± 11.5 μmol l⁻¹ h⁻¹) than in healthy men (17.8 ± 6.5 μmol l⁻¹ h⁻¹) (p = 0.001). Diabetic men also had higher CET compared to 15 healthy non-diabetic men (18.7 ± 5.6 μmol l⁻¹ h⁻¹) (p = 0.001) with similar serum lipids. CET activity was similar in patients treated with diet alone (24.8 ± μmol l⁻¹ h⁻¹) or with sulphonylureas (27.7 ± 15.8 μmol l⁻¹ h⁻¹). The Sf 0–12 fraction was significantly enriched with total cholesterol (p = 0.0001) and free cholesterol (p = 0.006) in diabetic subjects whether treated with diet alone or on sulphonylureas compared to the 15 non-diabetic controls matched for serum triglycerides. The free cholesterol/phospholipid, the free cholesterol/total protein and the free cholesterol/mass ratios were increased in the Sf 0–12 fraction in diabetic subjects (p < 0.01). These findings indicate that CET is accelerated in patients with NIDDM and that this may be due to the altered composition of acceptor lipoproteins.