BACKGROUND Cholesterol is related to improvements in the rate of sustained virological response and a robust immune response against the hepatitis C virus(HCV).APOE gene polymorphisms regulate cholesterol levels modif...BACKGROUND Cholesterol is related to improvements in the rate of sustained virological response and a robust immune response against the hepatitis C virus(HCV).APOE gene polymorphisms regulate cholesterol levels modifying the course of the HCV infection.The relationship between cholesterol,APOE alleles,and the outcome of HCV infection has not been evaluated in the admixed population of Mexico.AIM To investigate the role of APOE-ε2,-ε3,and-ε4 alleles and the metabolic profile in the outcome of HCV infection.METHODS A total of 299 treatment-na?ve HCV patients were included in this retrospective study.Patients were stratified in chronic hepatitis C(CHC)(n=206)and spontaneous clearance(SC)(n=93).A clinical record was registered.Biochemical tests were assessed by dry chemistry assay.APOE genotypes were determined using a Real-Time polymerase chain reaction assay.RESULTS Total cholesterol,low-density lipoprotein cholesterol(LDL-c),triglycerides,and hypercholesterolemia were higher in SC than CHC patients as well as the frequency of the APOEε4 allele(12.4%vs 7.3%).SC patients were overweight(54.8%).Theε4 allele was associated with SC(OR=0.55,95%CI:0.31-0.98,P=0.042)and mild fibrosis(F1-F2)in CHC patients(OR 0.091,95%CI 0.01-0.75,P=0.020).LDL-c≥101.5 mg/dL(OR=0.20,95%CI:0.10-0.41,P<0.001)and BMI≥26.6 kg/m2(OR=0.37,95%CI:0.18-0.76,P<0.001)were associated with SC status;while ALT≥50.5 IU/L was negatively associated(OR=5.67,95%CI:2.69-11.97,P<0.001).CONCLUSION In SC patients,the APOEε4 allele and LDL-c conferred a protective effect in the course of the HCV infection in the context of excess body weight.展开更多
Alzheimer's disease,the primary cause of dementia,is characterized by neuropathologies,such as amyloid plaques,synaptic and neuronal degeneration,and neurofibrillary tangles.Although amyloid plaques are the primar...Alzheimer's disease,the primary cause of dementia,is characterized by neuropathologies,such as amyloid plaques,synaptic and neuronal degeneration,and neurofibrillary tangles.Although amyloid plaques are the primary characteristic of Alzheimer's disease in the central nervous system and peripheral organs,targeting amyloid-beta clearance in the central nervous system has shown limited clinical efficacy in Alzheimer's disease treatment.Metabolic abnormalities are commonly observed in patients with Alzheimer's disease.The liver is the primary peripheral organ involved in amyloid-beta metabolism,playing a crucial role in the pathophysiology of Alzheimer's disease.Notably,impaired cholesterol metabolism in the liver may exacerbate the development of Alzheimer's disease.In this review,we explore the underlying causes of Alzheimer's disease and elucidate the role of the liver in amyloid-beta clearance and cholesterol metabolism.Furthermore,we propose that restoring normal cholesterol metabolism in the liver could represent a promising therapeutic strategy for addressing Alzheimer's disease.展开更多
Background Hypercholesterolemia is a major risk factor for cardiovascular events in patients with established atherosclerotic disease (EAD) and in those with multiple risk factors (MRFs). This study aimed to investiga...Background Hypercholesterolemia is a major risk factor for cardiovascular events in patients with established atherosclerotic disease (EAD) and in those with multiple risk factors (MRFs). This study aimed to investigate the rate of optimal low-density lipoprotein (LDL) cholesterol level in a multicenter registry of patients at high risk for cardiovascular events. Methods A multicenter registry of EAD and MRF patients was conducted. Demographic data,medical history,cardiovascular risk factors,anthropometric data,laboratory data,and medications were recorded and analyzed. We classified patients according to target LDL levels based on recommendation by the European Society of Cardiology (ESC) 2011 into Group 1 which is EAD and diabetes or chronic kidney disease (CKD)–target LDL below 70 mg/dL,and Group 2 which is MRF without diabetes or CKD–target LDL below 100 mg/dL. The rate of optimal LDL level in patients with Group 1 and Group 2 was analyzed and stratified according to the treatment pattern of lipid-lowering medications. Results A total of 3100 patients were included. Of those,51.7% were male. Average age was 65.8 ± 9.7 years. Average LDL level was 96.3 ± 32.6 mg/dL. A vast majority (92.7%) received statin and 9.3% received ezetimibe. Optimal LDL level was achieved in 20.3% of patients in Group 1 (LDL < 70 mg/dL),and in 46.6% in Group 2 (LDL < 100 mg/dL). The overall rate of optimal LDL control was 23% since 89.6% of study population belongs to Group 1. The rate of optimal LDL was not different between high and low potency statin. Factors that were associated with optimal LDL control were older age,the presence of coronary artery disease or peripheral artery disease. Conclusions The rates of optimal LDL level were unacceptably low in this study population. As such,a strategy to improve LDL control in high-risk population should be implemented.展开更多
Statins have been shown to be effective in reducing cardiovascular events.Their magnitude of benefits has been proportionate to the reduction in low-density lipoprotein cholesterol(LDL-c).Intensive lipid-lowering ther...Statins have been shown to be effective in reducing cardiovascular events.Their magnitude of benefits has been proportionate to the reduction in low-density lipoprotein cholesterol(LDL-c).Intensive lipid-lowering therapies using ezetimibe and more recently proprotein convertase subtilisin kexin 9 inhibitors have further improved clinical outcomes.Unselective application of these treatments is undesirable and unaffordable and,therefore,has been guided by LDL-c level.Nonetheless,the residual risk in the post-statin era is markedly heterogeneous,including thrombosis and inflammation risks.Moreover,the lipoprotein related risk is increasingly recognised to be related to other non-LDL-c markers such as Lp(a).Emerging data show that intensive lipid-lowering therapy produce larger absolute risk reduction in patients with polyvascular disease,post coronary artery bypass graft and diabetes.Notably,these clinical entities share similar phenotype of large burden of atherosclerotic plaques.Novel plaque imaging may aid decision making by identifying patients with propensity to develop lipid rich plagues at multi-vascular sites.Those patients may be suitable candidates for intensive lipid lowering treatment.展开更多
Background:The association and its population heterogeneities between low-density lipoprotein cholesterol(LDL-C)and all-cause and cardiovascular mortality remain unknown.We aimed to examine the dose-dependent associat...Background:The association and its population heterogeneities between low-density lipoprotein cholesterol(LDL-C)and all-cause and cardiovascular mortality remain unknown.We aimed to examine the dose-dependent associations of LDL-C levels with specific types of cardiovascular disease(CVD)mortality and heterogeneities in the associations among different population subgroups.Methods:A total of 2,968,462 participants aged 35-75 years from China Health Evaluation And risk Reduction through nationwide Teamwork(ChinaHEART)(2014-2019)were included.Cox proportional hazard models and Fine-Gray subdistribution hazard models were used to estimate associations between LDL-C categories(<70.0,70.0-99.9,100.0-129.9[reference group],130.0-159.9,160.0-189.9,and≥190.0 mg/dL)and all-cause and cause-specific mortality.Results:During a median follow-up of 3.7 years,57,391 and 23,241 deaths from all-cause and overall CVD were documented.We observed J-shaped associations between LDL-C and death from all-cause,overall CVD,coronary heart disease(CHD),and ischemic stroke,and an L-shaped association between LDL-C and hemorrhagic stroke(HS)mortality(P for non-linearity<0.001).Compared with the reference group(100.0-129.9 mg/dL),very low LDL-C levels(<70.0 mg/dL)were significantly associated with increased risk of overall CVD(hazard ratio[HR]:1.10,95%confidence interval[CI]:1.06-1.14)and HS mortality(HR:1.37,95%CI:1.29-1.45).Very high LDL-C levels(≥190.0 mg/dL)were associated with increased risk of overall CVD(HR:1.51,95%CI:1.40-1.62)and CHD mortality(HR:2.08,95%CI:1.92-2.24).The stronger associations of very low LDL-C with risk of CVD mortality were observed in individuals with older age,low or normal body mass index,low or moderate 10-year atherosclerotic CVD risk,and those without diagnosed CVD or taking statins.Stronger associations between very high LDL-C levels and all-cause and CVD mortality were observed in younger people.Conclusions:People with very low LDL-C had a higher risk of all-cause,CVD,and HS mortality;those with very high LDL-C had a higher risk of all-cause,CVD,and CHD mortality.On the basis of our findings,comprehensive health assessment is needed to evaluate cardiovascular risk and implement appropriate lipid-lowering therapy for people with very low LDL-C.展开更多
AIM: To investigate how hepatitis C virus (HCV) G1b infection influences the particle number of lipoproteins.METHODS: The numbers of lipoprotein particles in fasting sera from 173 Japanese subjects, 82 with active HCV...AIM: To investigate how hepatitis C virus (HCV) G1b infection influences the particle number of lipoproteins.METHODS: The numbers of lipoprotein particles in fasting sera from 173 Japanese subjects, 82 with active HCV G1b infection (active HCV group) and 91 with cleared HCV infection (SVR group), were examined. Serum lipoprotein was fractionated by high-performance liquid chromatography into twenty fractions. The cholesterol and triglyceride concentrations in each fraction were measured using LipoSEARCH. The number of lipoprotein particles in each fraction was calculated using a newly developed algorithm, and the relationship between chronic HCV G1b infection and the lipoprotein particle number was determined by multiple linear regression analysis.RESULTS: The median number of low-density lipoprotein (LDL) particles was significantly lower in the active HCV group [1182 nmol/L, interquartile range (IQR): 444 nmol/L] than in the SVR group (1363 nmol/L, IQR: 472 nmol/L, P < 0.001), as was that of high-density lipoprotein (HDL) particles (14168 nmol/L vs 15054 nmol/L, IQR: 4114 nmol/L vs 3385 nmol/L, P = 0.042). The number of very low-density lipoprotein (VLDL) particles was similar between the two groups. Among the four LDL sub-fractions, the number of large LDL particles was similar between the two groups. However, the numbers of medium (median: 533.0 nmol/L, IQR: 214.7 nmol/L vs median: 633.5 nmol/L, IQR: 229.6 nmol/L, P < 0.001), small (median: 190.9 nmol/L, IQR: 152.4 nmol/L vs median: 263.2 nmol/L, IQR: 159.9 nmol/L; P < 0.001), and very small LDL particles (median: 103.5 nmol/L, IQR: 66.8 nmol/L vs median: 139.3 nmol/L, IQR: 67.3 nmol/L, P < 0.001) were significantly lower in the active HCV group than in the SVR group, respectively. Multiple linear regression analysis indicated an association between HCV G1b infection and the decreased numbers of medium, small, and very small LDL particles. However, active HCV infection did not affect the number of large LDL particles or any sub-fractions of VLDL and HDL particles.CONCLUSION: HCV G1b infection decreases the numbers of medium, small, and very small LDL particles.展开更多
Objective Foreign studies have reported that coronary artery disease(CAD) patients with high baseline low-density lipoprotein cholesterol(LDL-C) may have a good prognosis, which is called the “cholesterol paradox”. ...Objective Foreign studies have reported that coronary artery disease(CAD) patients with high baseline low-density lipoprotein cholesterol(LDL-C) may have a good prognosis, which is called the “cholesterol paradox”. This study aimed to examine whether the “cholesterol paradox” also exists in the Chinese population.Methods A total of 2,056 patients who underwent the first percutaneous coronary intervention(PCI)between 2014 and 2016 were enrolled in this retrospective cohort study and classified into two groups based on baseline LDL-C = 2.6 mmol/L(100 mg/d L). The outcomes of interest included major adverse cardiovascular events(MACE), all-cause mortality, recurrent nonfatal myocardial infarction, unexpected coronary revascularization, or any nonfatal stroke.Results All-cause mortality occurred in 8 patients(0.7%) from the low-LDL-C group and 12 patients(2.4%) in the high-LDL-C group, with a significant difference between the two groups(adjusted hazard ratio: 4.030, 95% confidence interval: 1.088–14.934;P = 0.037). However, no significant differences existed for the risk of MACE or other secondary endpoints, such as unexpected revascularization, nor any nonfatal stroke in the two groups.Conclusion In this study, a high baseline LDL-C was not associated with a low risk of clinical outcomes in CAD patients undergoing first PCI, which suggested that the “cholesterol paradox” may be inapplicable to Chinese populations.展开更多
The American Diabetes Association (ADA) 2013 guidelines state that a reasonable hemoglobin A1c goal for many nonpregnant adults with diabetes is less than 7.0% a hemoglobin A1c level of less than 6.5% may be considere...The American Diabetes Association (ADA) 2013 guidelines state that a reasonable hemoglobin A1c goal for many nonpregnant adults with diabetes is less than 7.0% a hemoglobin A1c level of less than 6.5% may be considered in adults with short duration of diabetes, long life expectancy, and no significant cardiovascular disease if this can be achieved without significant hypoglycemia or other adverse effects of treatment. A hemoglobin A1c level less than 8.0% may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced macrovascular and microvascular complications, extensive comorbidities, and long-standing diabetes in whom the hemoglobin A1c goal is difficult to attain despite multiple glucoselowering drugs including insulin. The ADA 2013 guidelines recommend that the systolic blood pressure in most diabetics with hypertension should be reduced to less than 140 mmHg. These guidelines also recommend use of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in the treatment of hypertension in diabetics unless they are pregnant. Diabetics at high risk for cardiovascular events should have theirserum low-density lipoprotein (LDL) cholesterol lowered to less than 70 mg/dL with statins. Lower-risk diabetics should have their serum LDL cholesterol reduced to less than 100 mg/dL. Combination therapy of a statin with either a fibrate or niacin has not been shown to provide additional cardiovascular benefit above statin therapy alone and is not recommended. Hypertriglyceridemia should be treated with dietary and lifestyle changes. Severe hypertriglyceridemia should be treated with drug therapy to reduce the risk of acute pancreatitis.展开更多
Objective To investigate the effects of rapamycin on cholesterol homeostasis of glomerular mesangial cells and the underlying mechanisms. Methods Intracellular cholesterol accumulation was measured by Oil Red O stain...Objective To investigate the effects of rapamycin on cholesterol homeostasis of glomerular mesangial cells and the underlying mechanisms. Methods Intracellular cholesterol accumulation was measured by Oil Red O staining and high performance liquid chromatography. The effects of rapamycin on interleukin-1β（1L-1β）-induced mRNA and protein changes of low-density lipoprotein receptor （LDLR） and ATP-binding cassette transporter Al （ABCAl） were assayed by quantitative real-time PCR and Western blot. Transient expressions of 3 types of mammalian target of rapamycin （mTOR）, including mTOR-WT （wild type）, mTOR-RR （rapamycin resistant, with kinase activity）, and mTOR-RR-KD （rapamycin resistant, without kinase activity）, were obtained by plasmid transfection. Results Rapamycin had no significant influence on intracellular cholesterol concentration trader normal condition, but it significantly decreased the intracellular cholesterol concentration in the presence of IL-1β. Rapamycin dose-dependently suppressed the increased expression of LDLR induced by IL-1β and up-regulated the suppressed expression of ABCAl caused by IL-1β Transient expression of 3 types of mTOR all reduced ABCAl mRNA expression significantly, which all could be overroded by rapamycin. Conclusions Rapamycin may contribute to the maintaining of glomerular mesangial cell intracellular cholesterol homeostasis under inflammatory state by both reducing cholesterol uptake and increasing cholesterol effiux. And the effect may be not completely mediiated by mTOR.展开更多
Lipoproteins are protein-lipid macromolecular assemblies which are used to transport lipids in circulation and are key targets in cardiovascular disease （CVD）. The highly dynamic lipoprotein molecules are capable of...Lipoproteins are protein-lipid macromolecular assemblies which are used to transport lipids in circulation and are key targets in cardiovascular disease （CVD）. The highly dynamic lipoprotein molecules are capable of adopting an array of conformations that is crucial to lipid transport along the cholesterol transport pathway, among which high-density lipopro- tein （HDL） and low-density lipoprotein （LDL） are major players in plasma cholesterol metabolism. For a more detailed illustration of cholesterol transport process, as well as the development of therapies to prevent CVD, here we review the functional mechanism and structural basis of lipoproteins in cholesterol transport, as well as their structural dynamics in the plasma lipoprotein （HDL and LDL） elevations, in order to obtain better quantitative understandings on structure-function relationship of lipoproteins. Finally, we also provide an approach for further research on the lipoprotein in cholesterol transport.展开更多
Objective There is a large population of patients classified as complex higher-risk and indicated patients(CHIPs)in China with a poor prognosis.The treatment of these patients is complex and challenging,especially whe...Objective There is a large population of patients classified as complex higher-risk and indicated patients(CHIPs)in China with a poor prognosis.The treatment of these patients is complex and challenging,especially when acute cardiac events occur,such as acute coronary syndrome(ACS)or heart failure.Pharmacotherapy and some mechanical circulatory support(MCS)therapeutic devices can provide stable hemodynamic support for CHIPs-percutaneous coronary intervention(PCI).LDL-C is an important pathogenic factor in atherosclerosis,and the target of blood lipid control.Recent studies have revealed that lipoprotein(a)[Lp(a)],which is formed when a covalent bond between apolipoprotein(a)and apolipoprotein B-100 is made,produces an LDL-like particle.This particle is an independent risk factor for the development of atherosclerosis,and is closely correlated to stent thrombosis and restenosis.Furthermore,this requires active intervention.PCSK9 inhibitors have been used in lipid-lowering treatment,and preventing atherosclerosis.The present study explores the efficacy of PCSK9 inhibitors in CHIPs-ACS,and the association between the change in Lp(a)and survival after 2 years of follow-up.Methods The present real-world,prospective control study enrolled 321 CHIPs-ACS who underwent emergency PCI from August 2019 to November 2020,and these patients were followed up for 2 years.These patients were divided into two groups:PCSK9 group(n=161)given the combined PCSK9 inhibitor(140 mg of evolocumab every 2 weeks)and statins-based therapy,and SOC group(n=160)treated with statin-based lipid-lowering therapy alone.Then,the change in lipid index was measured,and the cardiovascular(CV)event recurrence rate was evaluated after one month and 2 years.Afterwards,the contribution of serum lipid parameters,especially the Lp(a)alteration,in patients with earlier initiation of the PCSK9 inhibitor to the CV outcome was analyzed.Results The LDL-C level was significantly reduced in both groups:52.3%in the PCSK9 group and 32.3%(P<0.001)in the SOC group.It is noteworthy that the Lp(a)level decreased by 13.2%in the PCSK9 group,but increased by 30.3%in the SOC group(P<0.001).Furthermore,the number of CV events was not significantly different between the PCSK9 and SOC groups after the 2-year follow-up period.In the PCSK9 group,the Lp(a)reduction was associated with the baseline Lp(a)levels of the patients(r2=−0.315,P<0.001).Moreover,the decrease in Lp(a)contributed to the decline in CV events in patients who received ACS CHIPs-PCI,and the decrease in Lp(a)level was independent of the LDL-C level reduction.Conclusion The early initiation of PCSK9 inhibitors can significantly reduce the LDL-C and Lp(a)levels in ACS CHIPs-PCI.However,further studies are needed to confirm whether PCSK9 inhibitors can reduce the incidence of CV disease in CHIPs.展开更多
Background：Comprehensive management of diabetes should include management of its comorbid conditions,especially cardiovascular complications,which are the leading cause of morbidity and mortality among patients with ...Background：Comprehensive management of diabetes should include management of its comorbid conditions,especially cardiovascular complications,which are the leading cause of morbidity and mortality among patients with diabetes.Dyslipidemia is a comorbid condition of diabetes and a risk factor for cardiovascular complications.Therefore,lipid level management is a key of managing patients with diabetes successfully.However,it is not clear that how well dyslipidemia is managed in patients with diabetes in local Chinese health-care communities.This study aimed to assess how well low-density lipoprotein cholesterol （LDL-C） was managed in Nanjing community hospitals,China.Methods：We reviewed clinical records of 7364 diabetic patients who were treated in eleven community hospitals in Nanjing from October 2005 to October 2014.Information regarding LDL-C level,cardiovascular risk factors,and use of lipid-lowering agents were collected.Results：In patients without history of cardiovascular disease （CVD）,92.1% had one or more CVD risk factors,and the most common CVD risk factor was dyslipidemia.The overall average LDL-C level was 2.80 ± 0.88 mmol/L,which was 2.62 ± 0.90 mmol/L and 2.82 ± 0.87 mmol/L in patients with and without CVD history respectively.Only 38% of all patients met the target goal and 37.3% of patients who took lipid-lowering agents met target goal.Overall,24.5% of all patients were on lipid-lowering medication,and 36.3% of patients with a CVD history and 20.9% of patients without CVD history took statins for LDL-C management.The mean statin dosage was 13.9 ± 8.9 mg.Conclusions：Only a small portion of patients achieved target LDL-C level,and the rate of using statins to control LDL-C was low.Managing LDL-C with statins in patients with diabetes should be promoted,especially in patients without a CVD history and with one or more CVD risk factors.展开更多
The relationship between low levels of serum low-density lipoprotein cholesterol(LDL-C)and subsequent cognitive decline remains unclear.The present study aimed to evaluate the longitudinal association between low LDL-...The relationship between low levels of serum low-density lipoprotein cholesterol(LDL-C)and subsequent cognitive decline remains unclear.The present study aimed to evaluate the longitudinal association between low LDL-C levels and cognition decline in the context of the current aggressive guideline-recommended targets(LDL-C levels less than 55 mg/dL for individuals at very high risk of cardiovascular events,and less than 70 mg/dL for high risk individuals).Data from wave 13(2016)to wave 14(2018)of the Health and Retirement Study(HRS)were utilized.LDL-C concentrations measured at wave 13 were categorized into 5 levels,reflecting currently recommended values for lipid lowering treatment.Of 7129 included participants(mean age:69.0±9.9 years,60.3%female),we found that compared to participants with LDL-C levels of 70.0-99.9 mg/dL,those with LDL-C levels of<55 mg/dL had significantly slower 2-year decline rates in global cognitive function(0.244 point/year;95%confidence interval(CI):0.065-0.422;P=0.008),working memory(0.068 point/year;95%CI:0.004-0.133;P=0.038),and borderline significantly in episodic memory(0.155 point/year;95%CI:-0.004-0.315;P=0.057).Similarly,significantly slower decline rates were observed in those with LDL-C levels of 55.0-69.9 mg/dL.The present study demonstrated that compared with LDL-C levels 70.0-99.9 mg/dL,low LDL-C levels(<70 mg/dL,especially<55 mg/dL)were associated with significantly slower cognitive decline in population-based setting.Future randomized controlled trials are warranted to ascertain the safety and benefit of current aggressive guideline-recommended targets on cognitive function.展开更多
Background Genetic factors account for approximately 50% of the individual variation in plasma low-density lipoprotein cholesterol (LDL-C) concentrations in the general population. Several candidate genes have been pr...Background Genetic factors account for approximately 50% of the individual variation in plasma low-density lipoprotein cholesterol (LDL-C) concentrations in the general population. Several candidate genes have been proposed but their relative contributions to the variance in LDL-C are not known, except for apolipoprotein E (apoE). We report here an investigation of the relationship between LDL-C and cholesterol 7α-hydroxylase (CYP7), as well as apoE and low-density lipoprotein receptor (LDLR), three pivotal genes in LDL metabolism. Methods Our study population included more than 200 nuclear families with increased coronary heart disease (CHD) risk from the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study. Variance-component linkage methods, a measured genotype approach, and a variance-component linkage analysis conditional on a measured genotype association were used. Results The results showed significant linkage between a genetic determinant of plasma LDL-C concentrations and a polymorphism near CYP7 with its allelic variation accounting for 27% of the total LDL-C variation. There is significant association between plasma LDL-C concentrations and apoE genotypes. Conditional on the apoE association, the total LDL-C variation accounted by allelic variation of a polymorphism near CYP7 was increased significantly.Conclusion Our results suggest the apoE and CYP7 may be two important genes accounting for the genetic variation of plasma LDL-C concentrations in a population with cardiovascular diseases.展开更多
Low-density lipoprotein(LDL)is the main carrier of cholesterol and cholesteryl ester in circulation.High plasma levels of LDL cholesterol(LDL-C)are a major risk factor of atherosclerotic cardiovascular disease(ASCVD)....Low-density lipoprotein(LDL)is the main carrier of cholesterol and cholesteryl ester in circulation.High plasma levels of LDL cholesterol(LDL-C)are a major risk factor of atherosclerotic cardiovascular disease(ASCVD).LDL-C lowering is recommended by many guidelines for the prevention and treatment of ASCVD.Statins,ezetimibe,and proprotein convertase subtilisin/kexin type 9 inhibitors are the mainstay of LDL-C-lowering therapy.Novel therapies are also emerging for patients who are intolerant to statins or respond poorly to standard treatments.Here,we review the most recent advances on LDL-C-lowering drugs,focusing on the mechanisms by which they act to reduce LDL-C levels.The article starts with the cornerstone therapies applicable to most patients at risk for ASCVD.Special treatments for those with little or no LDL receptor function then follow.The inhibitors of ATP-citrate lyase and cholesteryl ester transfer protein,which are recently approved and still under investigation for LDL-C lowering,respectively,are also included.Strategies targeting the stability of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and cholesterol catabolism can be novel regimens to reduce LDL-C levels and cardiovascular risk.展开更多
Atorvastatin decreases inflammation and thrombogenesis in patients with carotid artery plaque. Atorvastatin is administered to lower lipid levels, but its anti-inflammatory and anti-thrombogenic effects remain unclear...Atorvastatin decreases inflammation and thrombogenesis in patients with carotid artery plaque. Atorvastatin is administered to lower lipid levels, but its anti-inflammatory and anti-thrombogenic effects remain unclear. Eighty-nine patients from northeastern China with acute ischemic stroke caused by large-artery atherosclerosis were randomly divided into the study and control groups. All patients received routine treatment, including antiplatelet therapy, circulatory support, and symp- tomatic treatment. The study group （n = 43） also received daily atorvastatin 20 mg/d, and the control group （n = 46） received daily placebo pills containing glucose. After 4 weeks, the levels of C-reactive protein, fibrinogen, and D-dimer were significantly lower in the study group than in the control group. Decreases in the levels of C-reactive protein, fibrinogen, and D-dimer were not associated with de- creases in the levels of triacylglycerol and low-density lipoprotein cholesterol. These results suggest that atorvastatin reduces inflammation and thrombogenesis independent of its lipid-lowering effects in patients with acute ischemic stroke caused by large-artery atherosclerosis.展开更多
Background: To study the influence of blood lipid levels on hemorrhagic transformation(HT) and prognosis after acute cerebral infarction(ACI).Methods: Patients with ACI within 72 h of symptoms onset between January 1 ...Background: To study the influence of blood lipid levels on hemorrhagic transformation(HT) and prognosis after acute cerebral infarction(ACI).Methods: Patients with ACI within 72 h of symptoms onset between January 1 st, 2015, and December 31 st, 2016, were retrospectively analyzed. Patients were divided into group A(without HT) and group B(HT). The outcomes were assessed after 3 months of disease onset using the modified Rankin Scale(m RS). An m RS score of 0–2 points indicated excellent prognosis, and an m RS score of 3–6 points indicated poor prognosis.Results: A total of 732 patients conformed to the inclusion criteria, including 628 in group A and 104 in group B. The incidence of HT was 14.2%, and the median onset time was 2 d(interquartile range, 1–7 d). The percentages of patients with large infarct size and cortex involvement in group B were 80.8% and 79.8%, respectively, which were both significantly higher than those in group A(28.7 and 33.4%, respectively). The incidence rate of atrial fibrillation(AF) in group B was significantly higher than that in group A(39.4% vs. 13.9%, P<0.001). The adjusted multivariate analysis results showed that large infarct size, cortex involvement and AF were independent risk factors of HT, while total cholesterol(TC) was a protective factor of HT(OR=0.359, 95% CI 0.136–0.944, P=0.038). With every 1 mmol/L reduction in normal TC levels, the risk of HT increased by 64.1%. The mortality and morbidity at 3 months in group B(21.2% and 76.7%, respectively) were both significantly higher than those in group A(8.0% and 42.8%, respectively). The adjusted multivariate analysis results showed that large infarct size(OR=12.178, 95% CI 5.390–27.516, P<0.001) was an independent risk factor of long-term unfavorable outcomes, whereas low-density lipoprotein cholesterol(LDL-C) was a protective factor(OR=0.538, 95% CI 0.300–0.964, P=0.037). With every 1 mmol/L reduction in normal LDL-C levels, the risk of an unfavorable outcome increased by 46.2%. Major therapies, including intravenous recombinant human tissue plasminogen activator(r TPA), intensive lipid-lowering statins and anti-platelets, were not significantly related to either HT or long-term, post-ACI poor prognosis.Conclusions: For patients with large infarct sizes, especially those with cortex involvement, AF, or lower levels of TC, the risk of HT might increase after ACI. The risk of a long-term unfavorable outcome in these patients might increase with a reduction in LDL-C.展开更多
Objective To examine target attainment of lipid-lowering, antihypenensive and antidiabetic treatment in the elderly in a specialist set- ting of a University Hospital in Greece. Methods This was a retrospective study ...Objective To examine target attainment of lipid-lowering, antihypenensive and antidiabetic treatment in the elderly in a specialist set- ting of a University Hospital in Greece. Methods This was a retrospective study including consecutive subjects 〉 65 years old （n = 465） with a follow-up 〉 3 years. Low-density lipoprotein cholesterol （LDL-C）, blood pressure （BP） and glycated hemoglobin （HbAlc） goal achievement were recorded according to European Society of Cardiology/European Atherosclerosis Society （ESC/EAS）, European Society of Hypertension （ESH）/ESC and European Association for the Study of Diabetes （EASD） guidelines. Results The LDL-C targets were attained by 27~,4, 48% and 62% of very high, high and moderate risk patients, respectively. Those receiving statin ＋ ezetimibe achieved higher rates of LDL-C goal achievement compared with those receiving statin monotherapy （48% vs. 33%, P 〈 0.05）. Of the diabetic sub- jects, 71% had BP 〈 140/85 mmHg, while 78% of those without diabetes had BP 〈 140/90 mmHg. A higher proportion of the non-diabetic individuals （86%） had BP 〈 150/90 mmHg. Also, a higher proportion of those with diabetes had HbAlc 〈 8% rather than 〈 7% （88% and 47%, respectively）. Of note, almost one out of three non-diabetic individuals and one out of ten diabetic individuals had achieved all three treatment targets. Conclusions Even in a specialist setting of a University Hospital, a high proportion of the elderly remain at suboptimal LDL-C, BP and HbAlc levels. The use of drug combinations could improve multifactorial treatment target attainment, while less strict tar- gets could be more easily achieved in this population.展开更多
Objective： To observe the effect of Gengnianchun Recipe （更年春方, GNC） on bone mineral density （BMD）, bone biomechanical parameters and serum lipid level in the bilaterally ovariectomized （OVX） rats and to exp...Objective： To observe the effect of Gengnianchun Recipe （更年春方, GNC） on bone mineral density （BMD）, bone biomechanical parameters and serum lipid level in the bilaterally ovariectomized （OVX） rats and to explore the prophylactic and therapeutic action of GNC on ovariectomy induced osteoporosis and hyperlipidemia. Methods： OVX SD rats, 10- 12 months old, were divided into different groups and fed with GNC 2 g/d, GNC 1 g/d and Nilestriol 0. 125 mg/week, respectively for 4 months to observe the change of BMD and bone biomechanical parameters of the lumbar vertebrae, and the serum levels of total cholesterol （TO）, triglyceride（TG）, high-density lipoprotein cholesterol （HDL-C） and low-density lipoprotein cholesterol （LDL-C）, and to compare the effect of the two drugs on the morphology of the uterus. Results： There was marked reduction in BMD and biomechanical parameters in lumbar vertebrae （ P〈0. 01 ） and increase of serum TO and LDL-C levels （ P〈0. 01 ） in rats after OVX. GNC or Nilestriol significantly improved the decreased BMD and biomechanical parameters of the lumbar vertebrae （ P〈0.05 or P〈0. 01 ）, and reduced the serum TO and LDL-C levels （ P〈0. 01 ）. In the Nilestriol group, the wet weight of uterus got increased obviously （ P〈0.01 ）, the number of uterine glands increased, uterine columnar epithelium thickened, and the mitotic figures in the epithelial stroma and myointimal cells augmented. But no such effect in wet weight and morphology of uterus was found in the GNC group. Conclusion： GNC could increase the BMD and biomechanical parameters of the lumbar vertebrae, reduce the serum TO and LDL-C levels, yet produce no adverse reaction in stimulating proliferation and hypertrophy of uterus.展开更多
Background Low-density lipoprotein （LDL） receptor is normally regulated via a feedback system that is dependent on intracellular cholesterol levels. We have demonstrated that cytokines disrupt cholesterol-mediated L...Background Low-density lipoprotein （LDL） receptor is normally regulated via a feedback system that is dependent on intracellular cholesterol levels. We have demonstrated that cytokines disrupt cholesterol-mediated LDL receptor feedback regulation causing intracellular accumulation of unmodified LDL in peripheral cells. Liver is the central organ for lipid homeostasis. The aim of this study was to investigate the regulation of cholesterol exogenous uptake via LDL receptor and its underlying mechanisms in human hepatic cell line （HepG2） cells under physiological and inflammatory conditions. Methods Intracellular total cholesterol （TC）, free cholesterol （FC） and cholesterol ester （CE） were measured by an enzymic assay. Oil Red O staining was used to visualize lipid droplet accumulation in cells. Total cellular RNA was isolated from cells for detecting LDL receptor, sterol regulatory element binding protein （SREBP）-2 and SREBP cleavage-activating protein （SCAP） mRNA levels using real-time quantitative PCR. LDL receptor and SREBP-2 protein expression were examined by Western blotting. Confocal microscopy was used to investigate the translocation of SCAP-SREBP complex from the endoplasmic reticulum （ER） to the Golgi by dual staining with anti-human SCAP and anti-Golgin antibodies. Results LDL loading increased intracellular cholesterol level, thereby reduced LDL receptor mRNA and protein expression in HepG2 cells under physiological conditions. However, interleukin 1β （IL-1β） further increased intracellular cholesterol level in the presence of LDL by increasing both LDL receptor mRNA and protein expression in HepG2. LDL also reduced the SREBP and SCAP mRNA level under physiological conditions. Exposure to IL-1β caused over-expression of SREBP-2 and also disrupted normal distribution of SCAP-SREBP complex in HepG2 by enhancing translocation of SCAP-SREBP from the ER to the Golgi despite a high concentration of LDL in the culture medium. Conclusions IL-1β disrupts cholesterol-mediated LDL receptor feedback regulation by enhancing SCAP-SREBP complex translocation from the ER to the Golgi, thereby increasing SREBP-2 mediated LDL receptor expression even in the presence of high concentration of LDL. This results in LDL cholesterol accumulation in hepatic cells via LDL receptor pathway under inflammatory stress.展开更多
基金Supported by Programa para el Desarrollo Profesional Docente(PRODEP)to Gonzalez-Aldaco K,No.UDG-PTC-1422Consejo Nacional de Ciencia y Tecnología(CONACYT)to Panduro A,No.2017-01-5254
文摘BACKGROUND Cholesterol is related to improvements in the rate of sustained virological response and a robust immune response against the hepatitis C virus(HCV).APOE gene polymorphisms regulate cholesterol levels modifying the course of the HCV infection.The relationship between cholesterol,APOE alleles,and the outcome of HCV infection has not been evaluated in the admixed population of Mexico.AIM To investigate the role of APOE-ε2,-ε3,and-ε4 alleles and the metabolic profile in the outcome of HCV infection.METHODS A total of 299 treatment-na?ve HCV patients were included in this retrospective study.Patients were stratified in chronic hepatitis C(CHC)(n=206)and spontaneous clearance(SC)(n=93).A clinical record was registered.Biochemical tests were assessed by dry chemistry assay.APOE genotypes were determined using a Real-Time polymerase chain reaction assay.RESULTS Total cholesterol,low-density lipoprotein cholesterol(LDL-c),triglycerides,and hypercholesterolemia were higher in SC than CHC patients as well as the frequency of the APOEε4 allele(12.4%vs 7.3%).SC patients were overweight(54.8%).Theε4 allele was associated with SC(OR=0.55,95%CI:0.31-0.98,P=0.042)and mild fibrosis(F1-F2)in CHC patients(OR 0.091,95%CI 0.01-0.75,P=0.020).LDL-c≥101.5 mg/dL(OR=0.20,95%CI:0.10-0.41,P<0.001)and BMI≥26.6 kg/m2(OR=0.37,95%CI:0.18-0.76,P<0.001)were associated with SC status;while ALT≥50.5 IU/L was negatively associated(OR=5.67,95%CI:2.69-11.97,P<0.001).CONCLUSION In SC patients,the APOEε4 allele and LDL-c conferred a protective effect in the course of the HCV infection in the context of excess body weight.
基金financially supported by the Science and Technology Innovation Program of Hunan Province,No.2022RC1220(to WP)China Postdoctoral Science Foundation,No.2022M711733(to ZZ)+2 种基金the National Natural Science Foundation of China,No.82160920(to ZZ)Hebei Postdoctoral Scientific Research Project,No.B2022003040(to ZZ)Hunan Flagship Department of Integrated Traditional Chinese and Western Medicine(to WP)。
文摘Alzheimer's disease,the primary cause of dementia,is characterized by neuropathologies,such as amyloid plaques,synaptic and neuronal degeneration,and neurofibrillary tangles.Although amyloid plaques are the primary characteristic of Alzheimer's disease in the central nervous system and peripheral organs,targeting amyloid-beta clearance in the central nervous system has shown limited clinical efficacy in Alzheimer's disease treatment.Metabolic abnormalities are commonly observed in patients with Alzheimer's disease.The liver is the primary peripheral organ involved in amyloid-beta metabolism,playing a crucial role in the pathophysiology of Alzheimer's disease.Notably,impaired cholesterol metabolism in the liver may exacerbate the development of Alzheimer's disease.In this review,we explore the underlying causes of Alzheimer's disease and elucidate the role of the liver in amyloid-beta clearance and cholesterol metabolism.Furthermore,we propose that restoring normal cholesterol metabolism in the liver could represent a promising therapeutic strategy for addressing Alzheimer's disease.
基金supported by the Heart Association of Thailand under the Royal Patronage of H.M. the Kingthe National Research Council of Thailand
文摘Background Hypercholesterolemia is a major risk factor for cardiovascular events in patients with established atherosclerotic disease (EAD) and in those with multiple risk factors (MRFs). This study aimed to investigate the rate of optimal low-density lipoprotein (LDL) cholesterol level in a multicenter registry of patients at high risk for cardiovascular events. Methods A multicenter registry of EAD and MRF patients was conducted. Demographic data,medical history,cardiovascular risk factors,anthropometric data,laboratory data,and medications were recorded and analyzed. We classified patients according to target LDL levels based on recommendation by the European Society of Cardiology (ESC) 2011 into Group 1 which is EAD and diabetes or chronic kidney disease (CKD)–target LDL below 70 mg/dL,and Group 2 which is MRF without diabetes or CKD–target LDL below 100 mg/dL. The rate of optimal LDL level in patients with Group 1 and Group 2 was analyzed and stratified according to the treatment pattern of lipid-lowering medications. Results A total of 3100 patients were included. Of those,51.7% were male. Average age was 65.8 ± 9.7 years. Average LDL level was 96.3 ± 32.6 mg/dL. A vast majority (92.7%) received statin and 9.3% received ezetimibe. Optimal LDL level was achieved in 20.3% of patients in Group 1 (LDL < 70 mg/dL),and in 46.6% in Group 2 (LDL < 100 mg/dL). The overall rate of optimal LDL control was 23% since 89.6% of study population belongs to Group 1. The rate of optimal LDL was not different between high and low potency statin. Factors that were associated with optimal LDL control were older age,the presence of coronary artery disease or peripheral artery disease. Conclusions The rates of optimal LDL level were unacceptably low in this study population. As such,a strategy to improve LDL control in high-risk population should be implemented.
文摘Statins have been shown to be effective in reducing cardiovascular events.Their magnitude of benefits has been proportionate to the reduction in low-density lipoprotein cholesterol(LDL-c).Intensive lipid-lowering therapies using ezetimibe and more recently proprotein convertase subtilisin kexin 9 inhibitors have further improved clinical outcomes.Unselective application of these treatments is undesirable and unaffordable and,therefore,has been guided by LDL-c level.Nonetheless,the residual risk in the post-statin era is markedly heterogeneous,including thrombosis and inflammation risks.Moreover,the lipoprotein related risk is increasingly recognised to be related to other non-LDL-c markers such as Lp(a).Emerging data show that intensive lipid-lowering therapy produce larger absolute risk reduction in patients with polyvascular disease,post coronary artery bypass graft and diabetes.Notably,these clinical entities share similar phenotype of large burden of atherosclerotic plaques.Novel plaque imaging may aid decision making by identifying patients with propensity to develop lipid rich plagues at multi-vascular sites.Those patients may be suitable candidates for intensive lipid lowering treatment.
基金supported by the Chinese Academy of Medical Sciences Innovation Fund for Medical Science(No.2021-I2M-1-011)the National High Level Hospital Clinical Research Funding(Nos.2022-GSP-GG-4,2023-GSP-RC-20)the Ministry of Finance of China and National Health Commission of China,and the 111 Project from the Ministry of Education of China(No.B16005).
文摘Background:The association and its population heterogeneities between low-density lipoprotein cholesterol(LDL-C)and all-cause and cardiovascular mortality remain unknown.We aimed to examine the dose-dependent associations of LDL-C levels with specific types of cardiovascular disease(CVD)mortality and heterogeneities in the associations among different population subgroups.Methods:A total of 2,968,462 participants aged 35-75 years from China Health Evaluation And risk Reduction through nationwide Teamwork(ChinaHEART)(2014-2019)were included.Cox proportional hazard models and Fine-Gray subdistribution hazard models were used to estimate associations between LDL-C categories(<70.0,70.0-99.9,100.0-129.9[reference group],130.0-159.9,160.0-189.9,and≥190.0 mg/dL)and all-cause and cause-specific mortality.Results:During a median follow-up of 3.7 years,57,391 and 23,241 deaths from all-cause and overall CVD were documented.We observed J-shaped associations between LDL-C and death from all-cause,overall CVD,coronary heart disease(CHD),and ischemic stroke,and an L-shaped association between LDL-C and hemorrhagic stroke(HS)mortality(P for non-linearity<0.001).Compared with the reference group(100.0-129.9 mg/dL),very low LDL-C levels(<70.0 mg/dL)were significantly associated with increased risk of overall CVD(hazard ratio[HR]:1.10,95%confidence interval[CI]:1.06-1.14)and HS mortality(HR:1.37,95%CI:1.29-1.45).Very high LDL-C levels(≥190.0 mg/dL)were associated with increased risk of overall CVD(HR:1.51,95%CI:1.40-1.62)and CHD mortality(HR:2.08,95%CI:1.92-2.24).The stronger associations of very low LDL-C with risk of CVD mortality were observed in individuals with older age,low or normal body mass index,low or moderate 10-year atherosclerotic CVD risk,and those without diagnosed CVD or taking statins.Stronger associations between very high LDL-C levels and all-cause and CVD mortality were observed in younger people.Conclusions:People with very low LDL-C had a higher risk of all-cause,CVD,and HS mortality;those with very high LDL-C had a higher risk of all-cause,CVD,and CHD mortality.On the basis of our findings,comprehensive health assessment is needed to evaluate cardiovascular risk and implement appropriate lipid-lowering therapy for people with very low LDL-C.
文摘AIM: To investigate how hepatitis C virus (HCV) G1b infection influences the particle number of lipoproteins.METHODS: The numbers of lipoprotein particles in fasting sera from 173 Japanese subjects, 82 with active HCV G1b infection (active HCV group) and 91 with cleared HCV infection (SVR group), were examined. Serum lipoprotein was fractionated by high-performance liquid chromatography into twenty fractions. The cholesterol and triglyceride concentrations in each fraction were measured using LipoSEARCH. The number of lipoprotein particles in each fraction was calculated using a newly developed algorithm, and the relationship between chronic HCV G1b infection and the lipoprotein particle number was determined by multiple linear regression analysis.RESULTS: The median number of low-density lipoprotein (LDL) particles was significantly lower in the active HCV group [1182 nmol/L, interquartile range (IQR): 444 nmol/L] than in the SVR group (1363 nmol/L, IQR: 472 nmol/L, P < 0.001), as was that of high-density lipoprotein (HDL) particles (14168 nmol/L vs 15054 nmol/L, IQR: 4114 nmol/L vs 3385 nmol/L, P = 0.042). The number of very low-density lipoprotein (VLDL) particles was similar between the two groups. Among the four LDL sub-fractions, the number of large LDL particles was similar between the two groups. However, the numbers of medium (median: 533.0 nmol/L, IQR: 214.7 nmol/L vs median: 633.5 nmol/L, IQR: 229.6 nmol/L, P < 0.001), small (median: 190.9 nmol/L, IQR: 152.4 nmol/L vs median: 263.2 nmol/L, IQR: 159.9 nmol/L; P < 0.001), and very small LDL particles (median: 103.5 nmol/L, IQR: 66.8 nmol/L vs median: 139.3 nmol/L, IQR: 67.3 nmol/L, P < 0.001) were significantly lower in the active HCV group than in the SVR group, respectively. Multiple linear regression analysis indicated an association between HCV G1b infection and the decreased numbers of medium, small, and very small LDL particles. However, active HCV infection did not affect the number of large LDL particles or any sub-fractions of VLDL and HDL particles.CONCLUSION: HCV G1b infection decreases the numbers of medium, small, and very small LDL particles.
基金supported by the Ethics Committee of Sir Run Run Shaw Hospital of Zhejiang University [NO.20200224-33]Key Project of Medical and Health Science and Technology of Zhejiang Province [NO. WKJ-ZJ-1715]+7 种基金Zhejiang Province Traditional Chinese Medicine Science and Technology Project [NO. 2017ZA006]Natural Science Foundation of Zhejiang Province [NO. LQ17H020006]Medical health Science and Technology project of Zhejiang Province [NO. 2017KY207]National Natural Science Foundation of China [82070408]Medical and health project [2021RC014]Hangzhou Medical Health Science and Technology Project [B20200116]“Pioneer” and “Leading Goose” R&D Program of Zhejiang[2023C04013]Administration of Traditional Chinese Medicine of Zhejiang Province [GZY-ZJ-KJ-23001]。
文摘Objective Foreign studies have reported that coronary artery disease(CAD) patients with high baseline low-density lipoprotein cholesterol(LDL-C) may have a good prognosis, which is called the “cholesterol paradox”. This study aimed to examine whether the “cholesterol paradox” also exists in the Chinese population.Methods A total of 2,056 patients who underwent the first percutaneous coronary intervention(PCI)between 2014 and 2016 were enrolled in this retrospective cohort study and classified into two groups based on baseline LDL-C = 2.6 mmol/L(100 mg/d L). The outcomes of interest included major adverse cardiovascular events(MACE), all-cause mortality, recurrent nonfatal myocardial infarction, unexpected coronary revascularization, or any nonfatal stroke.Results All-cause mortality occurred in 8 patients(0.7%) from the low-LDL-C group and 12 patients(2.4%) in the high-LDL-C group, with a significant difference between the two groups(adjusted hazard ratio: 4.030, 95% confidence interval: 1.088–14.934;P = 0.037). However, no significant differences existed for the risk of MACE or other secondary endpoints, such as unexpected revascularization, nor any nonfatal stroke in the two groups.Conclusion In this study, a high baseline LDL-C was not associated with a low risk of clinical outcomes in CAD patients undergoing first PCI, which suggested that the “cholesterol paradox” may be inapplicable to Chinese populations.
文摘The American Diabetes Association (ADA) 2013 guidelines state that a reasonable hemoglobin A1c goal for many nonpregnant adults with diabetes is less than 7.0% a hemoglobin A1c level of less than 6.5% may be considered in adults with short duration of diabetes, long life expectancy, and no significant cardiovascular disease if this can be achieved without significant hypoglycemia or other adverse effects of treatment. A hemoglobin A1c level less than 8.0% may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced macrovascular and microvascular complications, extensive comorbidities, and long-standing diabetes in whom the hemoglobin A1c goal is difficult to attain despite multiple glucoselowering drugs including insulin. The ADA 2013 guidelines recommend that the systolic blood pressure in most diabetics with hypertension should be reduced to less than 140 mmHg. These guidelines also recommend use of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in the treatment of hypertension in diabetics unless they are pregnant. Diabetics at high risk for cardiovascular events should have theirserum low-density lipoprotein (LDL) cholesterol lowered to less than 70 mg/dL with statins. Lower-risk diabetics should have their serum LDL cholesterol reduced to less than 100 mg/dL. Combination therapy of a statin with either a fibrate or niacin has not been shown to provide additional cardiovascular benefit above statin therapy alone and is not recommended. Hypertriglyceridemia should be treated with dietary and lifestyle changes. Severe hypertriglyceridemia should be treated with drug therapy to reduce the risk of acute pancreatitis.
文摘Objective To investigate the effects of rapamycin on cholesterol homeostasis of glomerular mesangial cells and the underlying mechanisms. Methods Intracellular cholesterol accumulation was measured by Oil Red O staining and high performance liquid chromatography. The effects of rapamycin on interleukin-1β（1L-1β）-induced mRNA and protein changes of low-density lipoprotein receptor （LDLR） and ATP-binding cassette transporter Al （ABCAl） were assayed by quantitative real-time PCR and Western blot. Transient expressions of 3 types of mammalian target of rapamycin （mTOR）, including mTOR-WT （wild type）, mTOR-RR （rapamycin resistant, with kinase activity）, and mTOR-RR-KD （rapamycin resistant, without kinase activity）, were obtained by plasmid transfection. Results Rapamycin had no significant influence on intracellular cholesterol concentration trader normal condition, but it significantly decreased the intracellular cholesterol concentration in the presence of IL-1β. Rapamycin dose-dependently suppressed the increased expression of LDLR induced by IL-1β and up-regulated the suppressed expression of ABCAl caused by IL-1β Transient expression of 3 types of mTOR all reduced ABCAl mRNA expression significantly, which all could be overroded by rapamycin. Conclusions Rapamycin may contribute to the maintaining of glomerular mesangial cell intracellular cholesterol homeostasis under inflammatory state by both reducing cholesterol uptake and increasing cholesterol effiux. And the effect may be not completely mediiated by mTOR.
基金Project supported by the National Natural Science Foundation of China(Grant Nos.11504287 and 11774279)
文摘Lipoproteins are protein-lipid macromolecular assemblies which are used to transport lipids in circulation and are key targets in cardiovascular disease （CVD）. The highly dynamic lipoprotein molecules are capable of adopting an array of conformations that is crucial to lipid transport along the cholesterol transport pathway, among which high-density lipopro- tein （HDL） and low-density lipoprotein （LDL） are major players in plasma cholesterol metabolism. For a more detailed illustration of cholesterol transport process, as well as the development of therapies to prevent CVD, here we review the functional mechanism and structural basis of lipoproteins in cholesterol transport, as well as their structural dynamics in the plasma lipoprotein （HDL and LDL） elevations, in order to obtain better quantitative understandings on structure-function relationship of lipoproteins. Finally, we also provide an approach for further research on the lipoprotein in cholesterol transport.
基金the Translational Medicine and Interdisciplinary Research Joint Fund of Zhongnan Hospital of Wuhan University(No.ZNLH-201907)the Hubei Province Health and Family Planning Scientific Research Project(No.WJ2019Q041)the Chinese Academy of Medical Science Innovation Fund for Medical Sciences(No.2021-I2M-1-009).
文摘Objective There is a large population of patients classified as complex higher-risk and indicated patients(CHIPs)in China with a poor prognosis.The treatment of these patients is complex and challenging,especially when acute cardiac events occur,such as acute coronary syndrome(ACS)or heart failure.Pharmacotherapy and some mechanical circulatory support(MCS)therapeutic devices can provide stable hemodynamic support for CHIPs-percutaneous coronary intervention(PCI).LDL-C is an important pathogenic factor in atherosclerosis,and the target of blood lipid control.Recent studies have revealed that lipoprotein(a)[Lp(a)],which is formed when a covalent bond between apolipoprotein(a)and apolipoprotein B-100 is made,produces an LDL-like particle.This particle is an independent risk factor for the development of atherosclerosis,and is closely correlated to stent thrombosis and restenosis.Furthermore,this requires active intervention.PCSK9 inhibitors have been used in lipid-lowering treatment,and preventing atherosclerosis.The present study explores the efficacy of PCSK9 inhibitors in CHIPs-ACS,and the association between the change in Lp(a)and survival after 2 years of follow-up.Methods The present real-world,prospective control study enrolled 321 CHIPs-ACS who underwent emergency PCI from August 2019 to November 2020,and these patients were followed up for 2 years.These patients were divided into two groups:PCSK9 group(n=161)given the combined PCSK9 inhibitor(140 mg of evolocumab every 2 weeks)and statins-based therapy,and SOC group(n=160)treated with statin-based lipid-lowering therapy alone.Then,the change in lipid index was measured,and the cardiovascular(CV)event recurrence rate was evaluated after one month and 2 years.Afterwards,the contribution of serum lipid parameters,especially the Lp(a)alteration,in patients with earlier initiation of the PCSK9 inhibitor to the CV outcome was analyzed.Results The LDL-C level was significantly reduced in both groups:52.3%in the PCSK9 group and 32.3%(P<0.001)in the SOC group.It is noteworthy that the Lp(a)level decreased by 13.2%in the PCSK9 group,but increased by 30.3%in the SOC group(P<0.001).Furthermore,the number of CV events was not significantly different between the PCSK9 and SOC groups after the 2-year follow-up period.In the PCSK9 group,the Lp(a)reduction was associated with the baseline Lp(a)levels of the patients(r2=−0.315,P<0.001).Moreover,the decrease in Lp(a)contributed to the decline in CV events in patients who received ACS CHIPs-PCI,and the decrease in Lp(a)level was independent of the LDL-C level reduction.Conclusion The early initiation of PCSK9 inhibitors can significantly reduce the LDL-C and Lp(a)levels in ACS CHIPs-PCI.However,further studies are needed to confirm whether PCSK9 inhibitors can reduce the incidence of CV disease in CHIPs.
文摘Background：Comprehensive management of diabetes should include management of its comorbid conditions,especially cardiovascular complications,which are the leading cause of morbidity and mortality among patients with diabetes.Dyslipidemia is a comorbid condition of diabetes and a risk factor for cardiovascular complications.Therefore,lipid level management is a key of managing patients with diabetes successfully.However,it is not clear that how well dyslipidemia is managed in patients with diabetes in local Chinese health-care communities.This study aimed to assess how well low-density lipoprotein cholesterol （LDL-C） was managed in Nanjing community hospitals,China.Methods：We reviewed clinical records of 7364 diabetic patients who were treated in eleven community hospitals in Nanjing from October 2005 to October 2014.Information regarding LDL-C level,cardiovascular risk factors,and use of lipid-lowering agents were collected.Results：In patients without history of cardiovascular disease （CVD）,92.1% had one or more CVD risk factors,and the most common CVD risk factor was dyslipidemia.The overall average LDL-C level was 2.80 ± 0.88 mmol/L,which was 2.62 ± 0.90 mmol/L and 2.82 ± 0.87 mmol/L in patients with and without CVD history respectively.Only 38% of all patients met the target goal and 37.3% of patients who took lipid-lowering agents met target goal.Overall,24.5% of all patients were on lipid-lowering medication,and 36.3% of patients with a CVD history and 20.9% of patients without CVD history took statins for LDL-C management.The mean statin dosage was 13.9 ± 8.9 mg.Conclusions：Only a small portion of patients achieved target LDL-C level,and the rate of using statins to control LDL-C was low.Managing LDL-C with statins in patients with diabetes should be promoted,especially in patients without a CVD history and with one or more CVD risk factors.
基金supported by the National Natural Science Foundation of China (81974490)the 2019 Irma and Paul MilsteinProgram for Senior Health Research Project Award。
文摘The relationship between low levels of serum low-density lipoprotein cholesterol(LDL-C)and subsequent cognitive decline remains unclear.The present study aimed to evaluate the longitudinal association between low LDL-C levels and cognition decline in the context of the current aggressive guideline-recommended targets(LDL-C levels less than 55 mg/dL for individuals at very high risk of cardiovascular events,and less than 70 mg/dL for high risk individuals).Data from wave 13(2016)to wave 14(2018)of the Health and Retirement Study(HRS)were utilized.LDL-C concentrations measured at wave 13 were categorized into 5 levels,reflecting currently recommended values for lipid lowering treatment.Of 7129 included participants(mean age:69.0±9.9 years,60.3%female),we found that compared to participants with LDL-C levels of 70.0-99.9 mg/dL,those with LDL-C levels of<55 mg/dL had significantly slower 2-year decline rates in global cognitive function(0.244 point/year;95%confidence interval(CI):0.065-0.422;P=0.008),working memory(0.068 point/year;95%CI:0.004-0.133;P=0.038),and borderline significantly in episodic memory(0.155 point/year;95%CI:-0.004-0.315;P=0.057).Similarly,significantly slower decline rates were observed in those with LDL-C levels of 55.0-69.9 mg/dL.The present study demonstrated that compared with LDL-C levels 70.0-99.9 mg/dL,low LDL-C levels(<70 mg/dL,especially<55 mg/dL)were associated with significantly slower cognitive decline in population-based setting.Future randomized controlled trials are warranted to ascertain the safety and benefit of current aggressive guideline-recommended targets on cognitive function.
文摘Background Genetic factors account for approximately 50% of the individual variation in plasma low-density lipoprotein cholesterol (LDL-C) concentrations in the general population. Several candidate genes have been proposed but their relative contributions to the variance in LDL-C are not known, except for apolipoprotein E (apoE). We report here an investigation of the relationship between LDL-C and cholesterol 7α-hydroxylase (CYP7), as well as apoE and low-density lipoprotein receptor (LDLR), three pivotal genes in LDL metabolism. Methods Our study population included more than 200 nuclear families with increased coronary heart disease (CHD) risk from the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study. Variance-component linkage methods, a measured genotype approach, and a variance-component linkage analysis conditional on a measured genotype association were used. Results The results showed significant linkage between a genetic determinant of plasma LDL-C concentrations and a polymorphism near CYP7 with its allelic variation accounting for 27% of the total LDL-C variation. There is significant association between plasma LDL-C concentrations and apoE genotypes. Conditional on the apoE association, the total LDL-C variation accounted by allelic variation of a polymorphism near CYP7 was increased significantly.Conclusion Our results suggest the apoE and CYP7 may be two important genes accounting for the genetic variation of plasma LDL-C concentrations in a population with cardiovascular diseases.
基金This work was supported by grants from the Ministry of Science and Technology(2018YFA0800703)the National Natural Science Foundation(91957103,31690102,32021003,and 91957208).B.-L.Song acknowledges the support from the Tencent Foundation through the XPLORER PRIZE.
文摘Low-density lipoprotein(LDL)is the main carrier of cholesterol and cholesteryl ester in circulation.High plasma levels of LDL cholesterol(LDL-C)are a major risk factor of atherosclerotic cardiovascular disease(ASCVD).LDL-C lowering is recommended by many guidelines for the prevention and treatment of ASCVD.Statins,ezetimibe,and proprotein convertase subtilisin/kexin type 9 inhibitors are the mainstay of LDL-C-lowering therapy.Novel therapies are also emerging for patients who are intolerant to statins or respond poorly to standard treatments.Here,we review the most recent advances on LDL-C-lowering drugs,focusing on the mechanisms by which they act to reduce LDL-C levels.The article starts with the cornerstone therapies applicable to most patients at risk for ASCVD.Special treatments for those with little or no LDL receptor function then follow.The inhibitors of ATP-citrate lyase and cholesteryl ester transfer protein,which are recently approved and still under investigation for LDL-C lowering,respectively,are also included.Strategies targeting the stability of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and cholesterol catabolism can be novel regimens to reduce LDL-C levels and cardiovascular risk.
基金supported by the Natural Science Foundation of Liaoning Province in China,No.20092192the National Natural Science Foundation of China,No.81071058
文摘Atorvastatin decreases inflammation and thrombogenesis in patients with carotid artery plaque. Atorvastatin is administered to lower lipid levels, but its anti-inflammatory and anti-thrombogenic effects remain unclear. Eighty-nine patients from northeastern China with acute ischemic stroke caused by large-artery atherosclerosis were randomly divided into the study and control groups. All patients received routine treatment, including antiplatelet therapy, circulatory support, and symp- tomatic treatment. The study group （n = 43） also received daily atorvastatin 20 mg/d, and the control group （n = 46） received daily placebo pills containing glucose. After 4 weeks, the levels of C-reactive protein, fibrinogen, and D-dimer were significantly lower in the study group than in the control group. Decreases in the levels of C-reactive protein, fibrinogen, and D-dimer were not associated with de- creases in the levels of triacylglycerol and low-density lipoprotein cholesterol. These results suggest that atorvastatin reduces inflammation and thrombogenesis independent of its lipid-lowering effects in patients with acute ischemic stroke caused by large-artery atherosclerosis.
文摘Background: To study the influence of blood lipid levels on hemorrhagic transformation(HT) and prognosis after acute cerebral infarction(ACI).Methods: Patients with ACI within 72 h of symptoms onset between January 1 st, 2015, and December 31 st, 2016, were retrospectively analyzed. Patients were divided into group A(without HT) and group B(HT). The outcomes were assessed after 3 months of disease onset using the modified Rankin Scale(m RS). An m RS score of 0–2 points indicated excellent prognosis, and an m RS score of 3–6 points indicated poor prognosis.Results: A total of 732 patients conformed to the inclusion criteria, including 628 in group A and 104 in group B. The incidence of HT was 14.2%, and the median onset time was 2 d(interquartile range, 1–7 d). The percentages of patients with large infarct size and cortex involvement in group B were 80.8% and 79.8%, respectively, which were both significantly higher than those in group A(28.7 and 33.4%, respectively). The incidence rate of atrial fibrillation(AF) in group B was significantly higher than that in group A(39.4% vs. 13.9%, P<0.001). The adjusted multivariate analysis results showed that large infarct size, cortex involvement and AF were independent risk factors of HT, while total cholesterol(TC) was a protective factor of HT(OR=0.359, 95% CI 0.136–0.944, P=0.038). With every 1 mmol/L reduction in normal TC levels, the risk of HT increased by 64.1%. The mortality and morbidity at 3 months in group B(21.2% and 76.7%, respectively) were both significantly higher than those in group A(8.0% and 42.8%, respectively). The adjusted multivariate analysis results showed that large infarct size(OR=12.178, 95% CI 5.390–27.516, P<0.001) was an independent risk factor of long-term unfavorable outcomes, whereas low-density lipoprotein cholesterol(LDL-C) was a protective factor(OR=0.538, 95% CI 0.300–0.964, P=0.037). With every 1 mmol/L reduction in normal LDL-C levels, the risk of an unfavorable outcome increased by 46.2%. Major therapies, including intravenous recombinant human tissue plasminogen activator(r TPA), intensive lipid-lowering statins and anti-platelets, were not significantly related to either HT or long-term, post-ACI poor prognosis.Conclusions: For patients with large infarct sizes, especially those with cortex involvement, AF, or lower levels of TC, the risk of HT might increase after ACI. The risk of a long-term unfavorable outcome in these patients might increase with a reduction in LDL-C.
文摘Objective To examine target attainment of lipid-lowering, antihypenensive and antidiabetic treatment in the elderly in a specialist set- ting of a University Hospital in Greece. Methods This was a retrospective study including consecutive subjects 〉 65 years old （n = 465） with a follow-up 〉 3 years. Low-density lipoprotein cholesterol （LDL-C）, blood pressure （BP） and glycated hemoglobin （HbAlc） goal achievement were recorded according to European Society of Cardiology/European Atherosclerosis Society （ESC/EAS）, European Society of Hypertension （ESH）/ESC and European Association for the Study of Diabetes （EASD） guidelines. Results The LDL-C targets were attained by 27~,4, 48% and 62% of very high, high and moderate risk patients, respectively. Those receiving statin ＋ ezetimibe achieved higher rates of LDL-C goal achievement compared with those receiving statin monotherapy （48% vs. 33%, P 〈 0.05）. Of the diabetic sub- jects, 71% had BP 〈 140/85 mmHg, while 78% of those without diabetes had BP 〈 140/90 mmHg. A higher proportion of the non-diabetic individuals （86%） had BP 〈 150/90 mmHg. Also, a higher proportion of those with diabetes had HbAlc 〈 8% rather than 〈 7% （88% and 47%, respectively）. Of note, almost one out of three non-diabetic individuals and one out of ten diabetic individuals had achieved all three treatment targets. Conclusions Even in a specialist setting of a University Hospital, a high proportion of the elderly remain at suboptimal LDL-C, BP and HbAlc levels. The use of drug combinations could improve multifactorial treatment target attainment, while less strict tar- gets could be more easily achieved in this population.
文摘Objective： To observe the effect of Gengnianchun Recipe （更年春方, GNC） on bone mineral density （BMD）, bone biomechanical parameters and serum lipid level in the bilaterally ovariectomized （OVX） rats and to explore the prophylactic and therapeutic action of GNC on ovariectomy induced osteoporosis and hyperlipidemia. Methods： OVX SD rats, 10- 12 months old, were divided into different groups and fed with GNC 2 g/d, GNC 1 g/d and Nilestriol 0. 125 mg/week, respectively for 4 months to observe the change of BMD and bone biomechanical parameters of the lumbar vertebrae, and the serum levels of total cholesterol （TO）, triglyceride（TG）, high-density lipoprotein cholesterol （HDL-C） and low-density lipoprotein cholesterol （LDL-C）, and to compare the effect of the two drugs on the morphology of the uterus. Results： There was marked reduction in BMD and biomechanical parameters in lumbar vertebrae （ P〈0. 01 ） and increase of serum TO and LDL-C levels （ P〈0. 01 ） in rats after OVX. GNC or Nilestriol significantly improved the decreased BMD and biomechanical parameters of the lumbar vertebrae （ P〈0.05 or P〈0. 01 ）, and reduced the serum TO and LDL-C levels （ P〈0. 01 ）. In the Nilestriol group, the wet weight of uterus got increased obviously （ P〈0.01 ）, the number of uterine glands increased, uterine columnar epithelium thickened, and the mitotic figures in the epithelial stroma and myointimal cells augmented. But no such effect in wet weight and morphology of uterus was found in the GNC group. Conclusion： GNC could increase the BMD and biomechanical parameters of the lumbar vertebrae, reduce the serum TO and LDL-C levels, yet produce no adverse reaction in stimulating proliferation and hypertrophy of uterus.
基金This study was supported by grants from the National Natural Science Foundation of China(Key Program,No.30530360)the National Basic Research Program of China(No.2006CB503907)Royal Free Hospital Special Trustees grant
文摘Background Low-density lipoprotein （LDL） receptor is normally regulated via a feedback system that is dependent on intracellular cholesterol levels. We have demonstrated that cytokines disrupt cholesterol-mediated LDL receptor feedback regulation causing intracellular accumulation of unmodified LDL in peripheral cells. Liver is the central organ for lipid homeostasis. The aim of this study was to investigate the regulation of cholesterol exogenous uptake via LDL receptor and its underlying mechanisms in human hepatic cell line （HepG2） cells under physiological and inflammatory conditions. Methods Intracellular total cholesterol （TC）, free cholesterol （FC） and cholesterol ester （CE） were measured by an enzymic assay. Oil Red O staining was used to visualize lipid droplet accumulation in cells. Total cellular RNA was isolated from cells for detecting LDL receptor, sterol regulatory element binding protein （SREBP）-2 and SREBP cleavage-activating protein （SCAP） mRNA levels using real-time quantitative PCR. LDL receptor and SREBP-2 protein expression were examined by Western blotting. Confocal microscopy was used to investigate the translocation of SCAP-SREBP complex from the endoplasmic reticulum （ER） to the Golgi by dual staining with anti-human SCAP and anti-Golgin antibodies. Results LDL loading increased intracellular cholesterol level, thereby reduced LDL receptor mRNA and protein expression in HepG2 cells under physiological conditions. However, interleukin 1β （IL-1β） further increased intracellular cholesterol level in the presence of LDL by increasing both LDL receptor mRNA and protein expression in HepG2. LDL also reduced the SREBP and SCAP mRNA level under physiological conditions. Exposure to IL-1β caused over-expression of SREBP-2 and also disrupted normal distribution of SCAP-SREBP complex in HepG2 by enhancing translocation of SCAP-SREBP from the ER to the Golgi despite a high concentration of LDL in the culture medium. Conclusions IL-1β disrupts cholesterol-mediated LDL receptor feedback regulation by enhancing SCAP-SREBP complex translocation from the ER to the Golgi, thereby increasing SREBP-2 mediated LDL receptor expression even in the presence of high concentration of LDL. This results in LDL cholesterol accumulation in hepatic cells via LDL receptor pathway under inflammatory stress.
