Normal Low-density Lipoprotein Levels Research Articles

Analysis of Related Factors Influencing Hypertension Classification among Centenarians in Hainan, China.

As a population ages, blood pressure levels gradually increase, leading to a higher incidence of hypertension and increased cardiovascular diseases risk. This study examines factors affecting hypertension grading among centenarians in the Hainan Province. Data from 2014 to 2016 were accessed from the cross-sectional database "Hypertension Levels and Epidemiological Characteristics of the Elderly and Centenarians in Hainan province of China". This study included 690 centenarians with hypertension. Hypertension grading was the dependent variable, analyzed against independent variables including demographic information (sex, age, ethnicity, education level, marital status, cohabitation, and regional distribution), lifestyle factors (smoking, alcohol consumption, and physical activity), body mass index (BMI), and comorbid conditions (diabetes and hyperlipidemia). Logistic regression models, adjusted for these factors, were used to assess the determinants of hypertension grading among the participants. Multivariate regression analysis, after adjusting for other variables, revealed significant associations between BMI, low-density lipoprotein (LDL) levels, and hypertension grades. Individuals with BMI below 18.5 had a 0.614-fold lower risk of developing grade III hypertension (odds ratio [OR]: 0.614, 95% confidence interval [CI]: 0.390-0.966, p = 0.0350) and a 0.586-fold lower risk for grade II hypertension (OR: 0.586, 95% CI: 0.402-0.852, p = 0.0052). Furthermore, individuals with elevated LDL levels had a 6.087-fold greater risk of progressing from grade I to grade III hypertension (OR: 6.087, 95% CI: 1.635-22.660, p = 0.0071) and a 4.356-fold greater risk of progressing from grade II to grade III hypertension (OR: 4.356, 95% CI: 1.052-18.033, p = 0.0423). Additionally, individuals of Li ethnicity had 1.823-fold greater risk of progressing from grade I to grade II hypertension compared to those of Han ethnicity (OR: 1.823, 95% CI: 1.033-3.218, p = 0.0383). A BMI below 18.5 , elevated LDL, and ethnicity emerged the primary factors associated with hypertension grading in centenarians. To reduce the risk of hypertension, it is crucial for centenarians to maintain a healthy weight, normal LDL levels, and adopt dietary habits including a low-cholesterol and low-fat diet.

Self-Association of Von Willebrand Factor (VWF) into Prothrombotic Fibers Is Most Potently Enhanced By the Highly Atherogenic Small, Dense Fraction of Low-Density Lipoprotein (sd-LDL)

We recently demonstrated that plasma lipoproteins play a major role in regulating the function of the hemostatic system by either inhibiting or promoting the self-association of von Willebrand factor (VWF) into large fibers and bundles that are hyperadhesive for platelets. Such fibers can form on the surface of activated endothelium such as during thrombotic microangiopathies. We showed that high-density lipoprotein (HDL) attenuates VWF self-association and reduces the formation of VWF-platelet thrombi, both in vitro and in mice (PMID:26552698). By contrast, low-density lipoprotein (LDL) enhances VWF self-association and promotes the formation of VWF-platelet thrombi ( Blood, in press). Consequently, wild-type mice with elevated plasma LDL display intense and prolonged VWF-platelet thrombosis in stimulated mesenteric microvessels, exceeding even the thrombosis observed in ADAMTS13-deficient mice with normal LDL levels. All the lipoproteins of low density carry apolipoprotein (apo) B100 and comprise fractions of very low density (VLDL), intermediate density (IDL), and low density (LDL). The LDL fraction comprises two subfractions: small-dense (sd) LDL and large-buoyant (lb) LDL. Epidemiologic studies suggest that sd-LDL is the most atherogenic subfraction (PMID:33586462). Another atherogenic lipoprotein also carries apoB-100, Lp(a), in which the apoB-100 is complexed with apo(a). Here, we sought to determine the effect of LDL subfraction(s) on VWF self-association. We isolated LDL, sd-LDL and lb-LDL from healthy donor plasma by sequential KBr density centrifugation. Lp(a) was purified from patients with high circulating Lp(a) (>50 mg/dL) as described by Mueller et al. (PMID:35650291). We first tested these lipoproteins in microfluidic devices adapted from the design of Herbig and Diamond (PMID:26178390). In these devices, high shear stress and flow acceleration are generated around a 30-um-wide pillar within a 60-um-wide flow channel and induce the attachment and self-association of VWF into fibers on and around the pillar. We quantified VWF fiber accumulation from differential interference contrast (DIC) images. Of all the lipoprotein fractions, sd-LDL was the most potent in accelerating VWF strand accumulation (see figure). The effect of lipoproteins in this device correlated with their impact on microvascular thrombosis in vivo. We infused apoB100-containing lipoproteins into wild-type mice (3-4 weeks old) before inducing VWF-platelet thrombi deposition in the mesenteric microvasculature with ionophore. All the apoB100 lipoproteins enhanced microvascular thrombosis [we did not test Lp(a), which had no effect in the microfluidic channel], but sd-LDL was by far the most potent; the treated mice had twice the number of large thrombi (>30-um diameter) as the mice treated with an equivalent quantity of lb-LDL. The effect also persisted for much longer before returning to baseline with the sd-LDL. We have explored possible reasons why sd-LDL is so much more potent. Compared to the other apoB-containing lipoproteins, sd-LDL is smaller and denser, with a greater surface curvature. Whether this fact changes accessibility to sites on apoB100 is not known. We also compared the lipidomes and proteomes of sd-LDL and lb-LDL for clues to the difference. Compared to lb-LDL, sd-LDL contained a much higher content of cholesterol and cholesterol esters per particle. The proteomes of the two particles were also different, with several proteins being more abundant in lb-LDL, in particular apoC-III, apoE, apoA-IV, and apoC-II. Only apoF was significantly more abundant in sd-LDL. We are currently testing to determine if any of these difference accounts for the differences between the two LDL subfractions in promoting VWF self-association. In summary, we show that the lipoprotein associated with the greatest atherosclerotic burden and most cardiovascular disease is also the one with the most potent effect in promoting a prothrombotic state by enhancing VWF self-association. These findings have important implications for the development of the atherosclerotic lesion, the formation of the thrombus after the lesion ruptures, and for the microvascular dysfunction often observed after revascularization.

SR-BI (Scavenger Receptor BI), Not LDL (Low-Density Lipoprotein) Receptor, Mediates Adrenal Stress Response-Brief Report.

Adrenal gland secretes stress-induced glucocorticoids (iGCs) to coping with stress. Previous study showed that SR-BI (scavenger receptor BI) null (SR-BI-/-) mice failed to generate iGC in stress conditions, suggesting that SR-BI-mediated cholesterol uptake from HDL (high-density lipoprotein) is a key regulator for iGC production. However, the LDL (low-density lipoprotein)/LDLr (LDL receptor) pathway can also provide cholesterol for iGC synthesis, but rodents have limited LDL levels in circulation. Here, we generated SR-BI-/-ApoBtg (apolipoprotein B transgenic) mice with normal LDL levels in circulation to determine the relative contribution of the HDL/SR-BI and LDL/LDLr pathways to iGC production in stress conditions. Approach and Results: To obtain mouse models with normal LDL levels, SR-BI-/- mice were bred to ApoBtg mice. Then, the F1 SR-BI±ApoBtg mice were backcrossed to SR-BI-/- to obtain SR-BI-/-ApoBtg, SR-BI-/-ApoBwt (apolipoprotein B wild type), and SR-BI+/+ApoBtg mice. We first examined the lipoprotein profile, which shows a 6.5-fold increase in LDL levels in SR-BI-/-ApoBtg mice compared with SR-BI-/-ApoBwt mice. Then, we induced stress with adrenocorticotropic hormone and cecal ligation and puncture. One hour after adrenocorticotropic hormone stimulation, SR-BI+/+ApoBtg control mice produced iGC (14.9-fold), but both SR-BI-/-ApoBwt and SR-BI-/-ApoBtg showed no iGC production (P<0.001). Three hours after cecal ligation and puncture treatment, SR-BI+/+ApoBtg control mice showed iGC production (6.4-fold), but both SR-BI-/-ApoBwt and SR-BI-/-ApoBtg mice showed no iGC production (P<0.001). SR-BI-/-ApoBtg mice fail to produce iGC in stress conditions even though with restored LDL levels in circulation. These findings clarify that the HDL/SR-BI, not LDL/LDLr, pathway is responsible for iGC production in stress conditions.

Low-grade Albuminuria Associated with Subclinical Left Ventricular Diastolic Dysfunction and Left Ventricular Remodeling.

Low-grade albuminuria (LGA) has been shown to be associated with increased risk for cardiovascular disease. Our study investigated the relationship between normal urinary albumin-to-creatinine ratios (UACRs) and subclinical left ventricular (LV) diastolic dysfunction and remodeling in diabetics and non-diabetics. A total of 888 diabetic and 208 non-diabetic patients with normal UACRs (< 30 mg/g) from Fuzhou, Fujian Province, China were examined. The subjects were stratified into quartiles based on their respective UACR levels. LV diastolic function was defined by early diastolic transmitral velocities (E)/average early diastolic annular velocities (average e), accompanied by average e. LV remodeling was defined by LV mass indexed to body surface area and relative wall thickness based on 2-dimensional and Doppler echocardiography. UACR was independently associated with cardiac diastolic function as defined by E/e and average e (OR=1.042, P=0.001) and LV remodeling (OR=1.037, P=0.001) in all participants. Diabetic patients in the highest quartile of UACR demonstrated a greater risk of developing LV diastolic dysfunction by a magnitude of 1.625 (OR=1.625, P=0.037) than patients in the lowest quartile; those in the third and highest quartiles demonstrated a greater risk of LV remodeling by a magnitude of 1.729-1.994 compared to the lowest quartile (OR=1.729, P=0.027 and OR=1.994, P=0.005, respectively). The association between UACR and subclinical diastolic dysfunction was most prevalent in younger, non-obese, non-hypertensive females or patients who had experienced diabetes for fewer than 10 years. The association between UACR and LV remodeling was most prevalent in non-obese, older males, in patients with normal low-density lipoprotein levels, in patients who had experienced diabetes for fewer than 10 years, and in patients without hypertension. UACR was associated with subclinical LV diastolic dysfunction and remodeling in both patients with and without Type 2 diabetes. We conclude that LGA may also be a marker for subclinical cardiovascular damage in Type 2 diabetics.

Statin use and risk of diabetes mellitus

The 3-hydroxy-methylglutaryl coenzyme A reductase inhibitors, statins, are widely used in the primary and secondary prevention of cardiovascular diseases to lower serum cholesterol levels. As type 2 diabetes mellitus is accompanied by dyslipidemia, statins have a major role in preventing the long term complications in diabetes and are recommended for diabetics with normal low density lipoprotein levels as well. In 2012, United States Food and Drug Administration released changes to statin safety label to include that statins have been found to increase glycosylated haemoglobin and fasting serum glucose levels. Many studies done on patients with cardiovascular risk factors have shown that statins have diabetogenic potential and the effect varies as per the dosage and type used. The various mechanisms for this effect have been proposed and one of them is downregulation of glucose transporters by the statins. The recommendations by the investigators are that though statins can have diabetogenic risk, they have more long term benefits which can outweigh the risk. In elderly patients and those with metabolic syndrome, as the risk of diabetes increase, the statins should be used cautiously. Other than a subset of population with risk for diabetes; statins still have long term survival benefits in most of the patients.

Evaluation of some biochemical changes in the serum of phensedyl addicts of Gaibandha District, Bangladesh

Context: Abuse of the drug, Phensedyl like any other drug might exert adverse effects on vital organs of th e h u m an body like liver, kidney and heart. Objectives: To determine the effects of Phensedyl intake on the serum biochemical parameters of the addicts in order to access for damages of vital human organs like liver, kidney and heart. Materials and Methods: Study population consisted of 127 male Phensedyl addicts within the ages of 18–55 years of defined criteria from Gaibandha district, a Northern part of Bangladesh, during July 2009 to December 2011. Fifty (50) non-drug dependent healthy men of matched age, height, and socioeconomic status were included as controls from the same community. Biochemical parameters analyzed were – Serum creatinine, SGOT, SGPT and Lipid profiles (total serum cholesterol (TC), Serum triglyceride (TG), serum high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol determined by semiautomatic biochemistry analyzer using commercially available kits Results: Abuse of Phensedyl appears not to hamper the normal renal and liver function in most of the addicts even after 8 years of Phensedyl intake irrespective of age except in case of 4 abusers. Serum total cholesterol (TC) remained almost unchanged among the addicts abusing Phensedyl for less than 8 years. But very strikingly, addicts taking Phensedyl for more than 8 years had higher trends in serum cholesterol i.e. more than 200 ml/dl. Of the addict’s, 44.36% abusing Phensedyl for less than 8 years had normal triglyceride (TG) values whereas, in 45.66% addicts abusing the drug for more than 8 years had clinically very significantly elevated triglyceride levels, which was also found to be statistically very significant (p value =0.0001), indicating the risk of developing cardiac diseases. Of the total addicts 53.53% had low levels of HDL cholesterol, which is clinically and statistically found to be very significant (p value =0.002). Of the addict’s 43% taking the drug for less than 8 years had normal LDL levels but significantly elevated values were recorded in 34% of the abusers who had been taking the drug for more than 8 years. Conclusion: Long time (&gt; 8 years) Phensedyl abusers are at the high risk of developing Brain stroke, Coronary Heart Disease (CHD), Ischemic stroke or transient ischemic attack (TIA) as there is the triad of: Elevated LDL cholesterol, Low HDL cholesterol and elevated Triglyceride. DOI: http://dx.doi.org/10.3329/jbs.v20i0.17656 J. bio-sci. 20: 57-65, 2012

Recent advances in management of cerebrovascular diseases.

A comprehensive approach to managing the vascular risk factors in both primary and secondary stroke prevention settings can lower the risk of first and recurrent stroke. Recent studies highlight the benefits of blood pressure treatment in the elderly, use of statins in healthy subjects with normal low-density lipoprotein levels, and comparison of various anti-platelet agents. For acute stroke the efficacy of thrombolysis beyond 3 hours has recently been shown.

Rosuvastatin Reduces Primary Cardiovascular Events in Apparently Healthy Individuals with Elevated C-Reactive Protein Levels

This large prospective study is the first to show that statin therapy can prevent cardiovascular (CV) events among individuals who do not have elevated lipid levels. The Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin [JUPITER; NCT00239681] trial demonstrated that rosuvastatin 20 mg significantly reduced the rate of primary CV events in an apparently healthy population that had normal low-density lipoprotein levels but elevated high-sensitivity C-reactive protein levels.

Implications of cardiovascular risk in patients with type 2 diabetes who have abnormal lipid profiles: is lower enough?

Patients with type 2 diabetes are at high risk for coronary heart disease (CHD); frequently, these patients have abnormal lipid profiles, placing them at even greater risk. A syndrome of insulin resistance, hyperinsulinaemia, hypertension, and high levels of fibrinogen and plasminogen activator inhibitor contributes to cardiovascular risk, which is not sufficiently decreased by glycaemic control alone. In several large interventional trials, CHD risk in patients with diabetes was substantially reduced by aggressive lipid-lowering therapy. In patients with diabetes, CHD, low high-density lipoprotein levels, and normal low-density lipoprotein levels, gemfibrozil reduced fatal and non-fatal CHD events. For lipid-lowering in patients with diabetes and CHD, pravastatin and simvastatin are the only HMG-CoA reductase inhibitors shown to reduce fatal and non-fatal CHD events. Of these, pravastatin has less potential for drug-drug interactions and may be safer to use, particularly for combination therapy with fibric acid derivatives, as may now be important for CHD prevention in mixed dyslipidaemias.

Triglycerides and coronary risk.

Despite extensive research, it has not yet been determined whether triglycerides represent an independent risk factor for coronary heart disease (CHD). The association has been obscured by imprecision in triglyceride measurements, individual variability, and complex interactions between triglycerides and other lipid-nonlipid parameters. Recent large-scale epidemiologic data indicate that elevated fasting triglycerides represent a useful marker for risk of coronary heart disease. The strong interrelationships of triglyceride level, high-density lipoprotein (HDL) level, and low-density lipoprotein (LDL) particle size with CHD risk suggest a metabolic interaction between the triglyceride-rich and cholesterol ester-rich lipoproteins in increasing risk of myocardial infarction. Limited data from clinical trials suggest that intervention with agents that lower triglycerides and raise HDL tend to reduce event rates among those with elevated and normal LDL levels. Many important issues defining the role of triglycerides in the primary and secondary prevention of CHD need further evaluation. These issues include the degree of risk associated with high triglyceride levels in various age, gender, racial, and ethnic subgroups, and the prognostic significance of postprandial versus fasting triglyceride levels. Further, primary and secondary intervention trials that more specifically address the clinical benefit of reducing triglyceride levels are warranted. Ultimately, screening and treatment guidelines may have to be modified to allow greater focus on fasting-triglyceride levels. Although current guidelines do not mandate screening for elevated triglyceride levels in the general population, obtaining triglyceride levels in those with known CHD or with other risk factors can provide valuable prognostic information and therefore be of aid in therapeutic decisions.

Atherogenic levels of low density lipoprotein alter the permeability and composition of the endothelial barrier

In the present study we investigated the influence of elevated low density lipoprotein (LDL) concentration on endothelial permeability. Endothelial cells were cultured on microporous membranes until confluence and albumin, dextran and LDL transfer across endothelial monolayers was determined to assess macromolecular permeability. Exposure of proliferating aortic endothelial cells to LDL levels of more than 1 mg/ml LDL-cholesterol induced a concentration-dependent exponential increase in the permeability of confluent endothelial monolayers. Acute addition of high LDL concentration did not alter macromolecular permeability. Once elevated permeability was induced, it persisted. It was not readily reversible after addition of normal LDL levels. Change in permeability was accompanied by a selective decrease in basement membrane associated heparan sulfate proteoglycan (HSPG) content. The apparent parallel between the loss in endothelial barrier function and HSPG decrease implicates a connection between the two events. Prolonged, but not acute, incubation with antiserum directed against the core-protein of HSPG also led to increased permeability, suggesting a causal role of HSPG for the proper function of endothelium. The fact that non-atherogenic LDL-cholesterol levels had no effect indicates that a ‘threshold’ concentration for LDL-cholesterol may exist, leading to nondenuding injury in the endothelial barrier as an early event in development of atherosclerosis.

Variable expression of the mutation in familial defective apolipoprotein B-100.

Although most subjects with familial defective apolipoprotein B-100 (FDB) have raised plasma low-density lipoprotein (LDL) levels, a few have LDL levels within the normal range. We have previously identified two normocholesterolemic FDB heterozygotes in an affected family. Results obtained from a study of this family are compatible with a major genetic contribution to the normocholesterolemia in the two heterozygotes. However, our findings are not compatible with inheritance of a variant normal allele at the apolipoprotein B locus in this family that neutralizes the effect of an FDB allele on the plasma LDL level. Polymorphic variations at the apolipoprotein E and LDL receptor loci did not explain the presence of normal LDL levels in the two heterozygous FDB subjects.

Alcohol produces dose-dependent antiatherogenic and atherogenic plasma lipoprotein responses.

A comprehensive assessment of lipoprotein compositional/metabolic response to incremental caloric ethanol (EtOH) doses ranging from low to moderate to high was undertaken using male squirrel monkeys. Control monkeys were maintained on a chemically defined, isocaloric liquid diet, while experimental primates wee fed increasing doses of alcohol (6, 12, 18, 24, 30, and 36% of energy) substituted isocalorically for carbohydrate at 3-month intervals. Liver function tests and plasma triglyceride were normal for all animals. Plasma cholesterol showed a transient increase at the 12% caloric dose that was attributed solely to an increase in high density lipoprotein (HDL). A more pronounced increase in plasma sterol, beginning at 24% and continuing to 36% EtOH, was the result of increments in both HDL and low density lipoprotein (LDL) cholesterol, although the contribution by the latter was substantial primarily at the 36% dose. Plasma apolipoprotein elevations (HDL apolipoprotein A-I, LDL apolipoprotein B) generally accompanied the lipoprotein lipid increases, although the first atherogenic response for LDL became manifest as a significant increase in apolipoprotein B at 18% EtOH calories. Postheparin plasma lipoprotein lipase was not affected by dietary alcohol, whereas hepatic triglyceride lipase activity showed significant increases at higher (24 and 36%) EtOH doses. Plasma lecithin-cholesterol acyltransferase activity was normal at the 6 and 12% EtOH doses, but exhibited a significant reduction beginning at 18% and continuing to 36% EtOH. Alterations in these key lipoprotein regulatory enzymes may represent the underlying metabolic basis for the observed changes in lipoprotein levels and our earlier findings of HDL2/HDL3 subfraction modifications. Results from our study indicate that in squirrel monkeys, moderate (12%) EtOH caloric intake favors an antiatherogenic lipoprotein profile (increases HDL, normal LDL levels, and lecithin-cholesterol acyltransferase activity), whereas higher doses (24-36%) produce both coronary-protective (increases HDL) and atherogenic (increases LDL) responses. Moreover, the 18% EtOH level represents an important transition dose which signals early adverse alterations in lipoprotein composition (increases apolipoprotein B) and metabolism (decreases lecithin-cholesterol acyltransferase).

Plasma low density lipoprotein transport kinetics in noninsulin-dependent diabetes mellitus.

Plasma low density lipoprotein (LDL) transport kinetics were determined from the disappearance of 125I-LDL injected into age- and weight-matched groups of 13 normal subjects, 20 mild diabetics, and 8 moderately severe diabetic patients (fasting plasma glucose less than 150 and greater than 150 mg/100 ml, respectively). In mild diabetics, LDL apo-lipoprotein-B (apo-B) synthetic rate (SR) was significantly greater than normal. The fractional catabolic rate (FCR), however, was also increased so that plasma LDL concentration remained normal. In moderately severe diabetics, LDL SR was normal but FCR was reduced resulting in increased plasma LDL cholesterol and apo-B concentrations. In normal subjects, moderate obesity was associated with increased LDL secretion. In diabetic subjects, however, changes in LDL turnover were of equal magnitude in obese and nonobese patients. In normolipemic and hyperlipemic mild diabetic subjects with equal degrees of glucose intolerance, both LDL apo-B SR and FCR were greater than normal. The magnitude of these increases, however, was lower in the hyperlipemic individuals. Stepwise regression analysis revealed that both LDL SR and FCR correlated positively and linearly with insulin response to glucose loading, but negatively and curvilinearly with fasting plasma glucose and glucose response. We propose that in noninsulin-dependent diabetes, mild hyperglycemia is accompanied by increased LDL turnover, despite normal plasma LDL levels, whereas moderately severe hyperglycemia is associated with decreased LDL catabolism, resulting in increased plasma LDL levels. These changes cannot be attributed to the presence of obesity or hypertriglyceridemia, and may relate to varying degrees of insulin resistance and decreased insulin secretion affecting plasma very low density lipoprotein (VLDL) secretion, VLDL conversion to LDL, and LDL catabolism. Both increased LDL turnover in mild diabetes and delayed removal of LDL in moderately severe diabetes could increase cholesterol ester availability to peripheral tissues, and may result in an increased risk of atherosclerosis.