Remnant-like particles cholesterol is higher in diabetic patients with coronary artery disease

Diabetes mellitus (DM) has been well known to be one of the risk factors of coronary artery disease (CAD). Recently, remnant-like particles cholesterol (RLP-C) has been reported to be associated with CAD. However, few studies reported the association of RLP-C level with CAD in subjects with DM. To investigate the effects of presence or absence of DM on the association between RLP-C and CAD, we compared the RLP-C level in 142 male patients with CAD and 123 male subjects without CAD (non-CAD), including 44 and 38 DM patients, respectively. RLP-C was significantly higher in CAD than non-CAD (P <.05). RLP-C and RLP-C/plasma-triglyceride (TG) ratio in CAD with DM were higher than CAD without DM (P <.01, P <.05), and non-CAD with DM (P <.001, P <.05). There was positive correlation between RLP-C and plasma-TG in non-CAD without DM (r =.44, P <.01), non-CAD with DM (r =.56, P <.001), CAD without DM (r =.81, P <.0001), and CAD with DM (r =.75, P <.001). After excluding the hypertriglyceridemic patients (>200mg/dL), RLP-C/plasma-TG ratio was significantly higher in CAD with DM than CAD without DM (P <.001) and non-CAD with DM (P <.05). These results suggest that increased RLP-C to plasma-TG may be associated with CAD in middle-aged diabetic male subjects.     

Apolipoprotein B-100 kinetics in visceral obesity: associations with plasma apolipoprotein C-III concentration

Obesity is strongly associated with dyslipidemia, which may account for the associated increased risk of atherosclerosis and coronary disease. We aimed to test the hypothesis that kinetics of hepatic apolipoprotein B-100 (apoB) metabolism are disturbed in men with visceral obesity and to examine whether these kinetic defects are associated with elevated plasma concentration of apolipoprotein C-III (apoC-III). Very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL) apoB kinetics were measured in 48 viscerally obese men and 10 age-matched normolipidemic lean men using an intravenous bolus injection of d(3)-leucine. ApoB isotopic enrichment was measured using gas chromatography-mass spectrometry (GCMS). Kinetic parameters were derived using a multicompartmental model (Simulation, Analysis, and Modeling Software II [SAAM-II]). Compared with controls, obese subjects had significantly elevated plasma concentrations of plasma triglycerides, cholesterol, LDL-cholesterol, VLDL-apoB, IDL-apoB, LDL-apoB, apoC-III, insulin, and lathosterol (P <.01). VLDL-apoB secretion rate was significantly higher (P =.034) in obese than control subjects; the fractional catabolic rates (FCRs) of IDL-apoB and LDL-apoB (P <.01) and percent conversion of VLDL-apoB to LDL-apoB (P <.02) were also significantly lower in obese subjects. However, the decreased VLDL-apoB FCR was not significantly different from the lean group. In the obese group, plasma concentration of apoC-III was significantly and positively associated with VLDL-apoB secretion rate and inversely with VLDL-apoB FCR and percent conversion of VLDL to LDL. In multiple regression analysis, plasma apoC-III concentration was independently and significantly correlated with the secretion rate of VLDL-apoB (regression coefficient [SE] 0.511 [0.03], P =.001) and with the percent conversion of VLDL-apoB to LDL-apoB (-0.408 [0.01], P =.004). Our findings suggest that plasma lipid and lipoprotein abnormalities in visceral obesity may be due to a combination of overproduction of VLDL-apoB particles and decreased catabolism of apoB containing particles. Elevated plasma apoC-III concentration is also a feature of dyslipidemia in obesity that contributes to the kinetic defects in apoB metabolism.     

Prevalence of diabetic complications in fibrocalculous pancreatic diabetic patients and type 2 diabetic patients: a cross-sectional comparative study

OBJECTIVE: To determine the prevalence of diabetes-related complications in subjects with fibrocalculous pancreatic diabetes (FCPD) and compare them with subjects with type 2 diabetes mellitus matched for age, sex, and duration of diabetes. METHODS: The study group comprised of 277 FCPD patients and 277 age, sex, and duration of diabetes-matched type 2 diabetic patients. All the study subjects underwent a detailed clinical examination, and fasting blood samples were obtained for biochemical studies. Peripheral Doppler was used for diagnosis of peripheral vascular disease (PVD). Vibratory perception threshold (VPT) was determined using biothesiometry for diagnosis of neuropathy. Diagnosis of coronary artery disease (CAD) was based on medical history and 12-lead resting ECG. Retinal photographs were used for diagnosis of retinopathy using a modified version of Early Treatment Diabetic Retinopathy Study (ETDRS) grading system. RESULTS: FCPD patients had lower body mass index (BMI) (P<.001), systolic blood pressure (P<.0001), diastolic blood pressure (P<.001), serum cholesterol (P<.001), serum triglyceride (P<.001), and serum creatinine (P<.01) but higher glycosylated hemoglobin (P<.001) levels compared to patients with type 2 diabetes. Prevalence of CAD was significantly higher among type 2 diabetic patients (11.9%) compared to FCPD patients (5.1%), P<.003. There was no significant difference in the prevalence of other diabetic complications between the two study groups (type 2 diabetes vs. FCPD: retinopathy-37.2% vs. 30.1%, PVD-4.3% vs. 4.7%, Neuropathy-25.3% vs. 20.9%, Nephropathy-15.0% vs. 10.1%). Multiple logistic regression analysis revealed the following risk factors for diabetes complications among type 2 diabetic subjects-retinopathy: BMI (P=.028), duration of diabetes (P<.001), and glycosylated hemoglobin (P=.026); nephropathy: diastolic blood pressure (P=.016) and glycosylated hemoglobin (P=.040); neuropathy: age (P<.001), duration of diabetes (P=.003), and glycosylated hemoglobin (P=.001). Among subjects with FCPD, systolic blood pressure (P=.013), glycosylated hemoglobin (P=.021), and duration of diabetes (P<.001) were associated with retinopathy; BMI (P=.057), glycosylated hemoglobin (P=.010), and duration of diabetes (P=.024) with nephropathy and age (P=.011) and BMI (P=.010) with neuropathy. Conclusion: The prevalence of retinopathy, nephropathy, neuropathy, and PVD was similar among FCPD patients and type 2 diabetic patients, but the prevalence of CAD was lower among FCPD patients.     

Adverse psychological and coronary risk profiles in young patients with coronary artery disease and benefits of formal cardiac rehabilitation

BACKGROUND: Recent data indicate that young patients with coronary artery disease (CAD) have a poor long-term prognosis. Although the benefits of formal cardiac rehabilitation and exercise training programs are well established, most of these data come from middle-aged and older patients. METHODS: We assessed baseline behavioral data, quality of life, and risk profiles in 635 consecutive patients with CAD before and after cardiac rehabilitation and exercise training, and specifically assessed data in 104 young patients (mean +/- SD age, 48 +/- 6 years; range, 22-54 years) compared with 260 elderly patients (mean +/- SD age, 75 +/- 3 years; range, 70-85 years). RESULTS: Compared with older patients, young patients had higher body mass indexes (12.2%, P<.001), total cholesterol-high-density lipoprotein ratio (14.6%, P<.01), and triglycerides level (27.2%, P<.01), and a lower high-density lipoprotein cholesterol level (-8.8%, P=.045). Young patients also had higher scores for anxiety and hostility (51.5% and 94.4%, respectively; P<.001 for both), a considerably higher prevalence of anxiety (27.9% vs 13.5%; P<.01) and hostility (12.5% vs 4.6%; P<.01) symptoms, and slightly more depression symptoms (23.1% vs 18.8%) compared with elderly patients. Following cardiac rehabilitation and exercise training, young patients had improvements in body mass index (-1.7%, P<.01), percentage body fat (-4.4%, P<.001), high-density lipoprotein cholesterol level (10.2%, P<.001), high-sensitivity C-reactive protein level (-33.3%, P<.01), peak oxygen consumption (11.3%, P<.001), resting heart rate (-4.5%, P=.01), and resting systolic pressure (-2.3%, P=.049), and marked improvements in scores for depression (-58.5%), anxiety (-46.0%), hostility (-45.7%), somatization (-33.8%), and quality of life (15.8%) (P<.001 for all). Young patients also had greater than 50% to greater than 80% reductions in the prevalence of anxiety (P<.001), hostility (P<.01), and depression (P<.001). CONCLUSION: These data demonstrate the adverse psychological and CAD risk profiles that are present in young patients with CAD following major CAD events, and are consistent with substantial benefit of formal cardiac rehabilitation and exercise training programs in younger adults.     

Atorvastatin treatment beneficially alters the lipoprotein profile and increases low-density lipoprotein particle diameter in patients with combined dyslipidemia and impaired fasting glucose/type 2 diabetes

Diabetic dyslipidemia is featured by hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol levels, and elevated low-density lipoprotein (LDL) cholesterol commonly in the form of small, dense LDL particles. First-line treatment, fibrates versus statins or both, of dyslipidemia in diabetic patients has been the focus of debate. We investigated the potential hypolipidemic effects of atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor with good triglyceride lowering properties, in patients with combined dyslipidemia and evidence of impaired fasting glucose or type 2 diabetes. Twenty patients were recruited for the study, and after a 60-day wash out period, baseline measurements of lipoprotein parameters, LDL particle diameter, and apolipoprotein B (apoB) degradation fragments were obtained. The group was then randomized, in a double-blinded manner, into 2 subgroups. Group A received atorvastatin (80 mg) and group B received placebo daily for 60 days. After the first treatment period, all patients were reanalyzed for the above parameters. The treatment regime then crossed over for the second treatment period in which group A received placebo and group B received atorvastatin (80 mg) daily for 60 days. All parameters were remeasured at the end of the study. Treatment with atorvastatin resulted in a statistically significant reduction in total cholesterol (41%), LDL cholesterol (55%), triglycerides (TG) (32%), and apoB (40%). Mean LDL particle diameter significantly increased from 25.29 +/- 0.24 nm (small, dense LDL subclass) to 26.51 < 0.18 nm (intermediate LDL subclass) after treatment with atorvastatin (n = 20, P <.005). At baseline, LDL particles were predominantly found in the small, dense subclass; atorvastatin treatment resulted in a shift in the profile to the larger and more buoyant LDL subclass. Atorvastatin treatment did not produce consistent changes in the appearance of apoB degradation fragments in plasma. Our results suggest that atorvastatin beneficially alters the atherogenic lipid profile in these patients and significantly decreases the density of LDL particles produced resulting in a shift from small, dense LDL to more buoyant and less atherogenic particles.     

Kinetics of very-low-density lipoprotein apolipoprotein B-100 in normolipidemic subjects: pooled analysis of stable-isotope studies

To further explore the physiology of very-low-density lipoprotein (VLDL) apolipoprotein B-100 (apoB), we performed a pooled analysis of 21 reports based on the intravenous administration of stable isotope-labeled amino acids in a total of 154 healthy normolipidemic subjects. Prandial status was the most significant independent predictor (P < .001) of the hepatic secretion of apoB, which was higher in the fed state compared with the fasted state (1,819 +/- 188 v 1,046 +/- 61 mg/d, P < .001). In the fed state, apoB secretion increased with age (P = .003) and tended to be higher in men compared with women (P = .0065). The fractional catabolism of VLDL apoB decreased with weight (P = .0038) and was lower in men versus women (8.38 +/- 0.55 v 12.59 +/- 1.65 pools/d, P = .007), as well as patients that were carriers of the E4 allele compared with those who were not carriers of this allele (5.52 +/- 0.49 v 9.58 +/- 0.87 pools/d, P < .001). The VLDL apoB concentration in both the fed and fasted states was dependent on both the rate of hepatic production and fractional clearance of apoB. Plasma cholesterol, triglyceride, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol concentrations in the fasted state were principally determined by the fractional catabolism of VLDL apoB (P< .005). These findings suggest that under physiologic conditions in healthy individuals, the transport of VLDL apoB in plasma is predominantly determined by age, sex, body weight, apoE genotype, and prandial status.     

Atorvastatin improves postprandial lipoprotein metabolism in normolipidemlic subjects

Atorvastatin is a potent HMG-CoA reductase inhibitor that decreases low-density lipoprotein (LDL) cholesterol and fasting triglyceride concentrations. Because of the positive association between elevated postprandial lipoproteins and atherosclerosis, we investigated the effect of atorvastatin on postprandial lipoprotein metabolism. The effect of 4 weeks of atorvastatin therapy (10 mg/day) was evaluated in 10 normolipidemic men (30+/-2 yr; body mass index, 22+/-3 kg/m2; cholesterol, 4.84+/-0.54 mmol/L; triglyceride, 1.47+/-0.50 mmol/L; high-density lipoprotein cholesterol, 1.17+/-0.18 mmol/L; LDL-cholesterol, 3.00+/-0.49 mmol/L). Postprandial lipoprotein metabolism was evaluated with a standardized fat load (1300 kcal, 87% fat, 7% carbohydrates, 6% protein, 80,000 IU vitamin A) given after 12 h fast. Plasma was obtained every 2 h for 14 h. A chylomicron (CM) and a chylomicron-remnant (CR) fraction was isolated by ultracentrifugation, and triglycerides, cholesterol, apolipoprotein B, apoB-48, and retinyl-palmitate were determined in plasma and in each lipoprotein fraction. Atorvastatin therapy significantly (P < 0.001) decreased fasting cholesterol (-28%), triglycerides (-30%), LDL-cholesterol (-41%), and apolipoprotein B (-39%), whereas high-density lipoprotein cholesterol increased (4%, not significant). The area under the curve for plasma triglycerides (-27%) and CR triglycerides (-40%), cholesterol (-49%), and apoB-48 (-43%) decreased significantly (P < 0.05), whereas CR retinyl-palmitate decreased (-34%) with borderline significance (P = 0.08). However, none of the CM parameters changed with atorvastatin therapy. This indicates that, in addition to improving fasting lipoprotein concentrations, atorvastatin improves postprandial lipoprotein metabolism presumably by increasing CR clearance or by decreasing the conversion of CMs to CRs, thus increasing the direct removal of CMs from plasma.     

Fluvastatin slow-release lowers platelet-activating factor acetyl hydrolase activity: a placebo-controlled trial in patients with type 2 diabetes

Fluvastatin reduces atherogenic dense low-density lipoprotein (dLDL) in patients with type 2 diabetes mellitus (T2DM). dLDLs are associated with platelet-activating factor acetyl hydrolase (PAF-AH), an enzyme involved in inflammation and related to coronary artery disease (CAD). The association of preexisting CAD and PAF-AH and the effect of fluvastatin on enzyme activity is investigated in a placebo-controlled trial in patients with T2DM. A multicenter, double-blind, randomized comparison of fluvastatin XL (80 mg) (n = 42) and placebo (n = 47), each given once-daily for 8 wk, in 89 patients with T2DM, was conducted. At baseline and on treatment, lipoproteins, including lipoprotein (a) [Lp(a)] and LDL subfractions, and the activity of PAF-AH were measured. Increasing PAF-AH activity was significantly associated with a positive history of CAD (+0.7% per IU/liter PAH-AH; P = 0.010), the odds ratio estimate adjusted for age, gender, and body mass index of the highest quartile being 10.6 (P = 0.036). At baseline and at study end, PAF-AH activity was associated with the apolipoprotein B (apoB) content in dLDL (LDL-5 and LDL-6) (r = 0.447; P < 0.001 and r = 0.651; P < 0.001, respectively) and with non-HDL cholesterol at baseline (r = 0.485; P < 0.001). However, after additional adjustment for apoB in dLDL and non-HDL cholesterol at baseline, the odds ratio increment for CAD across PAF-AH quartiles was 2.09 (95% confidence interval, 1.02-4.29; P = 0.043). Fluvastatin treatment decreased the activity of PAF-AH by 22.8% compared with an increase of 0.4% in the placebo group (P < 0.001). This effect was independent of changes of Lp(a) concentrations. In patients with T2DM, PAF-AH activity is associated with a positive history of CAD. Fluvastatin not only decreases atherogenic dLDL but also PAF-AH activity, emphasizing the significance of fluvastatin treatment in T2DM. The antiatherogenic potential of fluvastatin in T2DM may thus be greater than expected from its effects on LDL-C and triglycerides alone.     

Carriers of the frequent lipoprotein lipase S447X variant exhibit enhanced postprandial apoprotein B-48 clearance

The frequent lipoprotein lipase S447X variant (LPLS447X) is firmly associated with a lower incidence of cardiovascular disease, the mechanisms for which remain to be established. To further unravel these beneficial effects, we studied the consequences of LPLS447X heterozygosity on LPL mass and activity, as well as on the postprandial lipoprotein profile. Fifteen male heterozygous LPLS447X carriers and 15 matched control subjects received an oral fat load (30 g/m(2)). Lipid parameters were evaluated at baseline and 2, 3, 4, and 6 hours after fat loading. LPL concentration and activity were analyzed, and endothelial function was evaluated noninvasively as flow-mediated dilation of the brachial artery. Although baseline apoprotein B-48 (apoB48) levels were similar, the rise in apoB48 was attenuated in LPLS447X carriers with 25% lower peak values compared with controls (P=.04). In conjunction, LPLS447X carriers were characterized by a 2.4-fold increase in pre-heparin LPL mass (P<.0001). The decrease in postprandial flow-mediated dilation was comparable in both groups. LPLS447X carriers exhibit enhanced apoB48 clearance with concomitant increase in pre-heparin LPL mass, without changes in LPL activity. This combination might suggest a role for increased ligand action of LPL in LPLS447X carriers contributing to the cardiovascular protection in carriers of this mutation.     

Postprandial lipoprotein metabolism in familial hypobetalipoproteinemia

OBJECTIVE: Familial hypobetalipoproteinemia (FHBL) is an autosomal codominantly inherited disorder of lipoprotein metabolism characterized by decreased plasma concentrations of low-density lipoprotein-cholesterol and apolipoprotein (apo) B. We examined the effect of truncated apoB variants (相似文献   

A new but frequent mutation of apoB-100-apoB His3543Tyr

ApolipoproteinB 100 (apoB-100) is an important component of atherogenic lipoproteins such as LDL and serves as a ligand for the LDL-receptor. Familial defective apolipoproteinB 100 (FDB) is caused by a R3500Q mutation of the apoB gene and results in decreased binding of LDL to the LDL-receptor. So far FDB is the most frequent and best studied alteration of apoB-100. Apart from this, three other apoB mutations, R3500W, R3531C and R3480W, affecting binding to the LDL-receptor are known to date. We screened the apoB gene segment of codons 3448-3561 by denaturing gradient gel electrophoresis (DGGE) analysis in a total of 853 consecutively sampled German patients undergoing diagnostic coronary angiography for suspected CAD. By this, a new single base mutation was detected and confirmed by DNA sequencing. The mutation, CAC(3543)TAC results in a His3543Tyr substitution in apoB-100 (H3543Y). The prevalence of heterozygotes for H3543Y in the study population was 0.47% compared to 0.12% for the known Arg 3500 Gln (R3500Q) mutation. In conclusion, the new mutation is four times more frequent than "classical" FDB and thus appears to be the most common apoB mutation in Germany.     

Mechanism of action of a 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor on apolipoprotein B-100 kinetics in visceral obesity

We examined the effect of atorvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on the kinetics of apolipoprotein B-100 (apoB) metabolism in 25 viscerally obese men in a placebo-controlled study. Very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL) apoB kinetics were measured using an iv bolus injection of [(2)H(3)]leucine. ApoB isotopic enrichment was measured using gas chromatography-mass spectrometry. Kinetic parameters were derived by using a multicompartmental model (SAAM-II). Compared with the placebo group, atorvastatin treatment resulted in significant (P < 0.001) decreases in total cholesterol (-34%), triglyceride (-19%), LDL cholesterol (-42%), total apoB (-39%), and lathosterol (-86%); VLDL-apoB, IDL-apoB, and LDL-apoB pool sizes also fell significantly (P < 0.002) by -27%, -22%, and -41%, respectively. This was associated with an increase in the fractional catabolic rates of VLDL-apoB (+58%, P = 0.019), IDL-apoB (+40%, P = 0.049), and LDL-apoB (+111%, P = 0.001). However, atorvastatin did not significantly alter the production and conversion rates of apoB in all lipoproteins. We conclude that in obese subjects, atorvastatin decreases the plasma concentration of all apoB-containing lipoproteins chiefly by increasing their catabolism and not by decreasing their production or secretion. This may be owing to up-regulation of hepatic receptors as a consequence of inhibition of cholesterogenesis.     

Effects of atorvastatin on the clearance of triglyceride-rich lipoproteins in familial combined hyperlipidemia

Familial combined hyperlipidemia (FCHL) patients have an impaired catabolism of postprandial triglyceride (TG)-rich lipoproteins (TRLs). We investigated whether atorvastatin corrects the delayed clearance of large TRLs in FCHL by evaluating the acute clearance of Intralipid (10%) and TRLs after oral fat-loading tests. Sixteen matched controls were included. Atorvastatin reduced fasting plasma TG (from 3.6 +/- 0.4 to 2.5 +/- 0.3 mM; mean +/- SEM) without major effects on fasting apolipoprotein B48 (apoB48) and apoB100 in large TRLs. Atorvastatin significantly reduced fasting intermediate density lipoprotein (Svedberg flotation, 12-20)-apoB100 concentrations. After Intralipid, TG in plasma and TRL showed similar kinetics in FCHL before and after atorvastatin treatment, although compared with controls, the clearance of large TRLs was only significantly slower in untreated FCHL, suggesting an improvement by atorvastatin. Investigated with oral fat-loading tests, the clearance of very low density lipoprotein (Sf20-60)-apoB100 improved by 24%, without major changes in the other fractions. The most striking effects of atorvastatin on postprandial lipemia in FCHL were on hepatic TRL, without major improvements on intestinal TRLs. Fasting plasma TG should be reduced more aggressively in FCHL to overcome the lipolytic disturbance causing delayed clearance of postprandial TRLs.     

Six-week improvements in muscle mass and strength during androgen therapy in older men

BACKGROUND: The purpose of our study was to assess the early effects of a potent anabolic androgen on muscle mass and strength, lower extremity power, and functional performance in older men. METHODS: Thirty-two men 72 +/- 6 years of age were randomized to receive oxandrolone (10 mg twice daily) or matching placebo in a 2:1 manner for 12 weeks. Total and appendicular lean body mass (LBM) were assessed by dual-energy x-ray absorptiometry (DEXA). Lower extremity muscle volume was determined by magnetic resonance imaging to validate DEXA changes. RESULTS: Total LBM increased by 2.7 +/- 1.6 kg after 6 weeks with oxandrolone (p <.001), which was greater (p <.001) than the decline in LBM (-0.5 +/- 0.9 kg) with placebo. Appendicular LBM increased by 1.2 +/- 0.9 kg after just 6 weeks with oxandrolone (p <.001), which was greater (p <.001) than the decline in LBM (-0.4 +/- 0.5 kg) with placebo. These changes were >90% of the gains in total and appendicular LBM (3.0 +/- 1.5 kg and 1.3 +/- 0.9 kg, respectively) after 12 weeks. Total thigh and hamstring muscle volume increased by 111 +/- 29 mm(3) (p =.001) and 75 +/- 18 mm(3) (p =.001), respectively, after 12 weeks. Maximal strength increased for the leg press 6.3 +/- 5.6% (p =.003), leg curl 6.7 +/- 8.6% (p =.01), chest press 6.9 +/- 6.5% (p =.001), and latissimus pull-down 4.8 +/- 6.3% (p =.009) with oxandrolone after 6 weeks; these increases were different than those with placebo (p <.001) and were 93%, 96%, 74%, and 94% of the respective gains at week 12. There were no improvements in functional measures. CONCLUSION: Treatment with a potent anabolic androgen may produce significant increases in muscle mass and strength after only 6 weeks in healthy older men. However, such treatment did not improve leg muscle power or walking speed.     

Sodium-lithium countertransport activity in healthy, dyslipidemic, and hypertensive individuals

The aim of our study was to investigate the role of dyslipidemia on red blood cell sodium-lithium countertransport activity in healthy and hypertensive individuals. A total of 128 Caucasian individuals, aged 20 to 60 years old, were divided into 4 groups: dyslipidemic/ hypertensive, dyslipidemic/normotensive, normolipidemic/hypertensive, and normolipidemic/ normotensive (controls). Sodium-lithium countertransport activity was determined based on the Canessa et al method. Sodium-lithium countertransport activity was significantly higher in all patient groups compared with controls (P < .001) and similar in the 3 patient groups. Sodium-lithium countertransport activity was significantly and positively associated with triglyceride levels (P < .001), body mass index (P < .001), total cholesterol levels (P = .001), and systolic (P = .001) and diastolic blood pressure (P = .001). In multivariate regression analysis, triglycerides made the largest contribution to sodium-lithium countertransport variation among the variables tested (R(2) = 0.273). Our results suggest that dyslipidemia affects sodium-lithium countertransport activity independently of essential hypertension and even to a greater extent than hypertension.     

Effect of amlodipine-atorvastatin combination on fibrinolysis in hypertensive hypercholesterolemic patients with insulin resistance

BACKGROUND: The aim of this study was to evaluate the effect of the amlodipine-atorvastatin combination on plasma tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) activity in hypercholesterolemic, hypertensive patients with insulin resistance. METHODS: The study population included 45 patients, aged 41 to 70 years, with mild to moderate essential hypertension (diastolic blood pressure [BP] > or = 95 and < or = 105 mm Hg), hypercholesterolemia (total cholesterol > 200 and < 350 mg/dL), and insulin resistance (HOMA index > 2.5) After a 4-week wash-out period, they were randomized to amlodipine (5 mg) or atorvastatin (20 mg) or their combination at the same oral dosage for 12 weeks in three cross-over periods each separated by a 4-week placebo period (3 by 3 latin square design). At the end of the placebo wash-out and of each treatment period, office BP, total cholesterol, PAI-1, and t-PA activity were evaluated. RESULTS: The amlodipine-atorvastatin combination, in addition to the expected hypocholesterolemic effect, produced: 1) a greater decrease in PAI-1 activity (-10.2 U/mL, P <.01 v placebo) and an even greater increase in t-PA activity (+0.26 U/mL, P <.01 v placebo) than amlodipine (-0.5 U/mL for PAI-1, P = not significant; +0.17 U/mL for t-PA, P <.01 v placebo) and atorvastatin alone (respectively, -9.9 U/mL, P <.01 v placebo and +0.08 U/mL, P <.05 v placebo); and 2) a greater systolic BP/diastolic BP mean reduction (-22/17 mm Hg, P <.005 v placebo) than amlodipine (-18/14 mm Hg, P <.01 v placebo) and atorvastatin alone (-2.8/3.8 mm Hg, P <.05 v placebo only for diastolic BP). CONCLUSIONS: The positive effect on fibrinolytic balance and BP control observed suggests that in hypertensive, hypercholesterolemic patients with impaired fibrinolysis, the combination of amlodipine and atorvastatin could be the treatment of choice.     

The effect of rapid lipid lowering with atorvastatin on autonomic parameters in patients with coronary artery disease

Many cardiovascular disease states are associated with autonomic dysfunction, specifically sympathetic activation and parasympathetic withdrawal. Both these autonomic derangements are independently associated with adverse prognostic outcomes. HMG CoA reductase inhibitors (statins) reduce cardiovascular mortality and morbidity when compared to placebo in subjects with proven coronary artery disease (CAD), including sudden presumed arrhythmic death. As autonomic dysfunction is associated with arrhythmogenesis, statins may be having a beneficial effect on autonomic function in these subjects. We conducted a randomised, double-blind, placebo-controlled, cross-over study examining the effect of rapid short-term lipid lowering with a statin on autonomic function in CAD patients. Ten subjects with proven CAD (8 male, 2 female; mean age 63.4 years) were randomised to receive either 80 mg atorvastatin or placebo over a 4 week period followed by a 4 week washout, then the alternative treatment for a further 4 weeks. Autonomic parameters assessed were plasma noradrenaline levels on recumbency and 80 degrees head-up tilt, cold pressor testing, and heart rate variability (HRV) analysis. Plasma noradrenaline levels were significantly reduced (p=0.050) after 20 min rest in the recumbent position, with atorvastatin compared to placebo. A nonsignificant reduction in plasma noradrenaline with atorvastatin compared to placebo was observed in the prolonged 80 degrees head-up position (p=0.207). In addition, sympathovagal balance was shifted to greater vagal predominance with atorvastatin (low-frequency/high-frequency ratio in the HRV frequency domain) when compared to placebo, p=0.06. We found that rapid lipid lowering with atorvastatin reduces sympathetic nervous system in this pilot study of CAD patients. Larger trials are required to definitively address the effects of statins on autonomic activity in these patients.     

A comparison of the effects of raloxifene and conjugated equine estrogen on bone and lipids in healthy postmenopausal women

BACKGROUND: Although many studies have assessed the effects of estrogen and raloxifene hydrochloride on bone mineral density and serum lipid concentrations, there are few direct comparative data. METHODS: Randomized placebo-controlled trial for 3 years, intention-to-treat analysis. Six hundred nineteen postmenopausal women with prior hysterectomy (mean age, 53.0 years) were studied in 38 centers in Europe, North America, Australasia, and South Africa. They were randomized to 60 mg/d or 150 mg/d of raloxifene, 0.625 mg/d of conjugated equine estrogen (CEE), or placebo. Bone density of the lumbar spine and proximal femur, biochemical markers of bone turnover, and fasting serum lipid concentrations were assessed for 3 years. RESULTS: Compared with baseline, bone density in the lumbar spine progressively declined by 2.0% in the placebo group (P <.05), was stable in the 2 raloxifene groups, and increased 4.6% in the subjects receiving CEE (P <.001). Effects in both raloxifene groups were different from those observed in the CEE and placebo groups (P <.001). Bone density in the total hip showed similar results. Conjugated equine estrogen produced significantly greater depression of serum osteocalcin, bone-specific alkaline phosphatase, and urine C-telopeptide, compared with raloxifene. Each of the active treatments caused comparable depression of low-density lipoprotein cholesterol below placebo levels (P <.001 at most time points). Raloxifene did not affect high-density lipoprotein cholesterol, whereas CEE increased it by 13.4% compared with placebo at 3 years (P <.001). Triglyceride concentrations increased 24.6% in the CEE group at 3 years (P <.003), a significantly greater change than in the raloxifene groups, which were 4.9% and 8.0% above baseline (P < or =.002) but not different from placebo. Urinary incontinence was reported in 11 women receiving CEE, but in only 1 or 2 in each of the other groups (P < or =.01 compared with the other groups). Hernias occurred less frequently in those receiving 150 mg/d of raloxifene or CEE (P =.03 vs placebo). CONCLUSIONS: Raloxifene and CEE have beneficial effects on bone density and bone turnover, although effects of CEE are more marked. Raloxifene and CEE produce different patterns of lipid responses and have distinct adverse effect profiles.     

Relationship of regional adiposity to insulin resistance and serum triglyceride levels in nonobese Japanese type 2 diabetic patients

The aim of this study was to investigate the relationships between insulin resistance and regional abdominal fat area, body mass index (BMI), and serum lipid profile in nonobese Japanese type 2 diabetic patients. A total of 63 nonobese Japanese type 2 diabetic patients aged 45 to 83 years were examined. The duration of diabetes was 8.4 +/- 0.8 years. BMI, glycosylated hemoglobin (HbA(1c)) levels, and fasting concentrations of plasma glucose, serum lipids (total cholesterol, high-density lipoprotein [HDL] cholesterol, and triglycerides), and serum insulin were measured. The low-density lipoprotein (LDL) cholesterol level was calculated using the Friedewald formula (LDL cholesterol = total cholesterol - HDL cholesterol - 1/5 triglycerides). Insulin resistance was estimated by the homeostasis model assessment (HOMA-IR). Computed tomography (CT) was used to measure cross-sectional abdominal subcutaneous and visceral fat areas in all the patients. Adipose tissue areas were determined at the umbilical level. Subcutaneous and visceral abdominal fat areas were 136.5 +/- 6.0 and 86.0 +/- 4.1 cm(2), respectively. Univariate regression analysis showed that insulin resistance was positively correlated with subcutaneous (r =.544, P <.001) and visceral (r =.408, P =.001) fat areas, BMI (r =.324, P =.009), HbA(1c) (r =.254, P =.001), serum triglycerides (r =.419, P <.001), and serum LDL cholesterol (r =.290, P =.019) levels and was negatively correlated with serum HDL cholesterol level (r =.254, P =.041). Multiple regression analyses showed that insulin resistance was independently predicted by the areas of subcutaneous (F = 6.76, P <.001) and visceral (F = 4.61, P <.001) abdominal fat and serum triglycerides (F = 8.88, P <.001) level, which explained 36.9% of the variability of insulin resistance. Moreover, the present study demonstrated that whereas BMI was positively correlated with visceral (r =.510, P <.001) and subcutaneous (r =.553, P <.001) fat areas, serum triglyceride level was positively associated with visceral (r =.302, P =.015), but not with subcutaneous (r =.222, P =.074) fat area. From these results, it can be suggested that (1) both subcutaneous and visceral abdominal fat areas are independently associated with insulin resistance and (2) visceral fat area, but not the subcutaneous one, is associated with serum triglyceride levels in our nonobese Japanese type 2 diabetic patients.     

Effects of increasing doses of simvastatin on fasting lipoprotein subfractions, and the effect of high-dose simvastatin on postprandial chylomicron remnant clearance in normotriglyceridemic patients with premature coronary sclerosis

Postprandial hyperlipidemia has been linked to premature coronary artery disease (CAD) in fasting normotriglyceridemic patients. We investigated the effects of increasing doses of simvastatin up to 80 mg/day on fasting and postprandial lipoprotein metabolism in 18 normotriglyceridemic patients with premature CAD. Fasting lipoprotein subfractions and cholesteryl ester transfer protein (CETP) activity were determined after each 5-week dose titration (0, 20, 40 and 80 mg/day). At baseline and after treatment with simvastatin 80 mg/day, standardised Vitamin A oral fat loading tests (50 g/m2; 10 h) were carried out. Ten normolipidemic healthy control subjects matched for gender, age and BMI underwent tests without medication. Treatment with simvastatin resulted in dose-dependent reductions of fasting LDL-cholesterol, without changing cholesterol levels in the VLDL-1, VLDL-2 and IDL fractions. In addition, simvastatin decreased CETP activity dose-dependently, although HDL-cholesterol remained unchanged. Simvastatin 80 mg/day decreased fasting plasma triglycerides (TG) by 26% (P < 0.05), but did not decrease significantly TG levels in any of the subfractions. The TG/cholesterol ratio increased in all subfractions. The plasma TG response to the oral fat loading test, estimated as area under the curve (TG-AUC), improved by 30% (from 21.5 +/- 2.5 to 15.1 +/- 1.9 mmol h/L; P < 0.01). Treatment with simvastatin 80 mg/day improved chylomicron remnant clearance (RE-AUC) by 36% from 30.0 +/- 2.6 to 19.2 +/- 3.3 mg h/L (P < 0.01). After therapy, remnant clearance in patients was similar to controls (19.2 +/- 3.3 and 20.3 +/- 2.7 mg h/L, respectively), suggesting a normalization of this potentially atherogenic process. In conclusion, high-dose simvastatin has beneficial effects in normotriglyceridemic patients with premature CAD, due to improved chylomicron remnant clearance, besides effective lowering of LDL-cholesterol. In addition, the lipoprotein subfractions became more cholesterol-poor, as reflected by the increased TG/cholesterol ratio, which potentially makes them less atherogenic.