Familial hypercholesterolemia:Current limitations and future breakthroughs

Familial hypercholesterolemia(FH)is characterized by elevated low-density lipoprotein cholesterol levels due to genetic mutations,presenting with xanthomas,corneal arch,and severe cardiovascular diseases.Early identification,diagnosis,and treatment are crucial to prevent severe complications like acute myocardial infarction.Statins are the primary treatment,supplemented by Ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibitors,though their effectiveness can be limited in severe cases.Over 90%of FH cases remain undiagnosed,and current treatments are often inadequate,underscoring the need for improved diagnostic and management systems.Future strategies include advancements in gene testing,precision medicine,and novel drugs,along with gene therapy approaches like AAV-mediated gene therapy and clustered regularly interspaced short palindromic repeats.Lifestyle modifications,including health education,dietary control,and regular exercise,are essential for managing FH and preventing related diseases.Research into FH-related gene mutations,especially LDLR,is critical for accurate diagnosis and effective treatment.

Dynamic and ultrastructural study of sphincter of Oddi in early-stage cholelithiasis in rabbits with hypercholesterolemia

AIM To study the relationship between pre-formation of gallstone and the kinetics and ultra-structure of sphincter of Oddi.METHODS Adult female rabbits were used anddivided into 3 groups,and fed with either normalor high cholesterol diet for four or eight weeks.Each group contained eight rabbits.Themanometry of sphincter of Oddi,biliarycineradiography,gallbladder volumemeasurement and ultrastructure observationunder electron microscope were performed.RESULTS In groups Ⅰ and Ⅱ,the basalpressure in low-pressure ampulla or highpressure zone of sphincter of Oddi waselevated,the amplitude of phasic contractionwas decreased and the volume of gallbladderwere increased,with a significant difference(P【0.01)from those of control.Gallstones werefound in group Ⅱ rabbits(7/8).Undercineradiography,low-pressure ampulla showeda spasmodic status without apparent peristalticcontraction.Under electron microscope,insidethe muscular cells of sphincter of Oddi,loosening of microfilament and swelling ofplasmosomes which congregated at the top wereobserved.The amount showed no obviouschange under nitric oxide synthase(NOS)stain.CONCLUSION Twisting of the microfilamentand disarrangement of kink macula densa insidethe muscular ceils suggested that the sphincterof Oddi was under spasmodic status.Theimpaired diastolic function caused andaggravated the stasis of cystic bile.Theswelling plasmosome could be one of theimportant factors in elevating the tonic pressureof sphincter of Oddi.

Abdominal Fat Accumulation with Hyperuricemia and Hypercholesterolemia Quail Model Induced by High Fat Diet

Objective To establish abdominal fat accumulation with hyperuricemia and hypercholesterolemia quail model fed with high fat diet. And then to investigate the pathological characteristics of this quail model. Methods Thirty Longcheng quails were randomly divided into two groups： control group and model group （n=15）. The control group quails were fed with normal diet and model group quails were fed with high fat diet for 14 days. After a 12-hour overnight fast, liver and abdominal fat at euthanasia as well as serum were collected. The levels of serum uric acid, total cholesterol, high density lipoprotein cholesterol （HDL-C）, low density lipoprotein cholesterol （LDL-C）, triglyceride, free fatty acid （FFA）, and blood glucose were assayed. The activity changes of adenosine deaminase （ADA）, xanthine oxidase （XOD）, lipoprotein lipase （LPL）, hepatic lipase （HL）, and fatty acid synthetase （FAS） were analyzed. Results Compared with control group, the abdominal fat content （0.74±0.63 vs. 1.36±0.65 g, P〈0.05） and abdominal fat index （0.44%±0.30% vs. 0.85%±0.30%, P〈0.01） as well as live lipid index （3.61%±0.65% vs. 11.33%±2.14%, P〈0.01） in model group significantly increased; the levels of serum uric acid （210.61±94,76 vs. 304.25±141.94 /amol/L, P〈0.05）, total cholesterol （4.20±0.51 vs. 20.10±11.25 mmol/L, P〈0.01）, LDL-C （1.16±0.29 vs. 10.78±6.48 mmol/L, P〈0.01）, and FFA （0.39±0.14 vs. 0.55±0.15 mmol/L, P〈0.01） in model group significantly increased; HDL-C （5.85±0.95 vs. 4.14±2.03 mmol/L, P〈0.05） significantly decreased; the levels of triglyceride and blood glucose had no significant changes （P〉0.05）; the activities of ADA （9.71±3.05 vs. 17.19±5.10 U/ml, P〈0.01） and XOD （10.58±6,88 vs. 19.22＋9.44 U/L, P〈0.01） in model group significantly increased; and FAS, LPL, HL had no significant changes （P〉0.05）. Conclusions High fat diet can induce abdominal fat accumulation with hyperuricemia and hypercholesterolemia quail model. The changes of uric acid and lipid metabolic enzyme activities may he the pathological mechanism of abdominal fat accumulation with hyperuricemia and hypercholesterolemia.

Hypercholesterolemia,low density lipoprotein receptor and proprotein convertase subtilisin/kexin-type 9

Atherosclerotic cardiovascular disease is the main cause of mortality and morbidity in the world. Plasma levels of low density lipoprotein cholesterol （LDL-C） are positively correlated with the risk of atherosclerosis. High plasma LDL concentrations in patients with hypercholesterolemia lead to build-up of LDL in the inner walls of the arteries, which becomes oxidized and promotes the formation of foam cells, consequently initiating atherosclerosis. Plasma LDL is mainly cleared through the LDL receptor （LDLR） pathway. Mutations in the LDLR cause familiar hyperch- olesterolemia and increase the risk of premature coronary heart disease. The expression of LDLR is regulated at the transcriptional level via the sterol regulatory element binding protein 2 （SREBP-2） and at the posttranslational levels mainly through proprotein convertase subtilisin/kexin-type 9 （PCSK9） and inducible degrader of the LDLR （IDOL）. In this review, we summarize the latest advances in the studies of PCSK9.

The p53-mediated Apoptosis in Hypercholesterolemia-induced Renal Injury of Rats

Summary： The apoptosis and the expression of tumor suppressor gene p53 in hypercholesterolemia （HC）-induced renal injury were investigated in rats. A high cholesterol diet （HCD）-induced HC rat model was made and serum lipid, urinary protein excretion （UPE） and N-aceto-β-D-glucosidase （NAG） were measured. The levels of malondialdehyde （MDA）, as an index of lipid peroxidation, in renal cortex and serum were compared between the two diet groups. Apoptosis and p53 expression were determined by TUNEL and immunohistochemistry, respectively. In the HCD-induced HC group, serum total cholesterol （TC）, low density lipoprotein cholesterol （LDL-C） as well as triglyceride （TG） were significantly increased, while the level of high density lipoprotein cholesterol （HDL-C） decreased. Meanwhile, increased excretions of UPE and NAG in urine were observed, which were accompanied with a decrease in urinary creatinine clearance （Ccr） and indicated both glomerular and tubular damages. In addition, apoptotic cell death coexisted in the kidney, as revealed by increased TUNEL positive cells. Finally, an increase in p53 expression was observed in tubuli, but not in glomeruli. Both TUNEL positive cells and p53 expression were found to be correlated to the level of renal cortical MDA （r=0. 817, P〈0.01 and r=0.547, P〈0.01, respectively）. The major manifestation of HCD-induced renal injury is apoptosis. The lipid peroxidation is a critical event to induce DNA damage and p53 is involved in the pathogenesis of lipid-induced renal injury.

Genetically confirmed familial hypercholesterolemia in outpatients with hypercholesterolemia

Background Familial hypercholesterolemia （FH） is an autosomal dominant disorder of lipoprotein metabolism which can lead to premature coronary heart disease （pCHD）. There are about 3.8 million potential FH patients in China, whereas the clinical and genetic data of FH are limited. Methods Dutch Lipid Clinic Network （DLCN） criteria was used to diagnose FH in outpatients with hypercholesterolemia. Resequencing chip analysis combined with Sanger sequencing validation were used to identify mutations in the definite FH patients according to DLCN criteria. In silico analysis was conducted in mutations with previously unknown pathogenicity. Then, the novel mutant receptors were transfected into human embryo kidney 293 （HEK-293） cells. The binding and the internalization activities of the mu- tant receptors were analyzed by flow cytometry. Results The prevalence of definite FH in outpatients with hypercholesterolemia in this study is 3.2%. Using genetic testing, one homozygous FH （HoFH）, one heterozygous FH （HeFH） and three compound heterozygous FH patients were confirmed. Eight mutations in low-density lipoprotein receptor （LDLR） gene were identified, in which c.357delG was a novel mutation and co-segregated with the FH phenotype. Bioinformatic analysis confirmed that c.357delG was a pathogenic mutation. Furthermore, when compared with the wild-type LDLRs by flow eytometry analysis, the binding and internalization activities of c.357delG mutant LDLRs were reduced by 35% and 49%, respectively. Conclusions This study identified eight LDLR gene mutations in five patients with definite FH, in which c.357delG is a novel pathogenic mutation. These findings increase our understanding of the genetic spectrum of FH in China.

Severe hypercholesterolemia associated with primary biliary cirrhosis in a 44-year-old Japanese woman

A 44-year-old woman developed jaundice and was diagnosed as stage Ⅱ of primary biliary cirrhosis(PBC).She showed a severely high total cholesterol level.This article focuses on atypical presentations of PBC and the need to test the total cholesterol level of PBC patients.

Antihypercholesterolemic effect of Bacopa monniera linn,on high cholesterol diet induced hypercholesterolemia in rats

Objective:To explore the effect of alcoholic extract of Bacopa monniera(AEBM) on high cholesterol diet-induced rats.Methods:The shade-dried and coarsely powdered whole plant material(Bacopa monniera) was extracted with 90%ethanol,finally filtered and dried in vacuum pump.The experimental rats were divided into 4 groups:control(group-Ⅰ),Rats fed with hvpercholesterolemic diet(HCD) for 45 days[4%cholesterol(w/w) and 1%cholic acid].Rats fed with HCD for 45 days+AEBM(40mg/kg,body weight/day orally) for last 30 days(group-Ⅲ) and AEBM alone(group-IV).Blood and tissues(Aorta) were removed to ice cold containers for various biochemical and histological analysis.Results:AEBM treatment significantly decreased the levels of TC,TG,PL,LDL,VLDL,atherogenic index,LDL/HDL ratio,and TC/HDL ratio but significantly increased the level of HDL when compared to HCD induced rats.Activities on liver antioxidant status(SOD,CAT,CPx,CR,GST) were significantly raised with concomitant reduction in the level of LPO were obtained in AEBM treated rats when compared to HCD rats.Treatment with AEBM significantly lowered the activity of SCOT,LDH and CPK.Histopathology of aorta of cholesterol fed rat showed intimal thickening and foam cell deposition were noted.Conclusions: These results suggests that AEBM extended protection against various biochemical changes and aortic pathology in hypercholesterolemic rats.Thus the plant may therefore be useful for therapeutic treatment of clinical conditions associated hypercholesterolemia.

Citrus peel extract and powder attenuate hypercholesterolemia and hyperglycemia using rodent experimental modeling

Objective: To investigate hypocholesterolemic and hypoglycemic potential of citrus peel extract and powder using rodent experimental modeling.Methods: Considering the fact, rat feeding trial was carried out for a period of 56 d to access the prophylaxis of citrus peel flavonoids by employing normal(study Ⅰ),hyperglycemic(study Ⅱ) and hypercholesterolemic(study Ⅲ) rats. Each study was further divided into three groups to ensure the provision of selected diets, i.e.,control, functional and nutraceutical diets. Each study was further divided into three groups to ensure the provision of selected diets, i.e., control, functional and nutraceutical diets.Results: Declining trend for total cholesterol was observed in all studies with maximum reduction(8.55%) in rat group fed on nutraceutical diet in study Ⅲ. Likewise, levels of low density lipoproteins and triglycerides reduced 11.39% and 7.89% respectively in hypercholesterolemic rats. Moreover, nutraceutical diet alleviated the sera glucose level by 8.96% in study Ⅱ.Conclusions: Conclusively, inclusion of citrus peel bioflavonoids in dietary therapies is a promising strategy to modulate lipidemic and glycemic attributes without imparting any deleterious effect on hematological parameters.

Effects of simvastatin on lipid levels and platelet activation in elderly patients with hypercholesterolemia

Background and Objective To investigate the effects of simvastatin on lipid lowering therapy and platelet activation in elderly patients with hypercholesterolemia. Methods Fasting serum lipids, CD63, CD41a, serum glucose, hepatic and renal function, routine urine analysis (UA) were measured in 50 healthy subjects, and in 50 elderly patients with hypercholesterolemia before and after 4 weeks treatment with simvastatin (20mg daily for 4 weeks). Results 1. After simvastatin treatment for 4 weeks, the fasting serum level of lipids in elderly patients with hypercholesterolemia was significantly lower than before treatment (P<0.01). 2. CD63 and CD41a were decreased after treatment compared with before, respectively (1.36 0.34) vs (4.26 1.06), (P<0.01) and (123.54 19.73) vs (253.78 16.75), (P<0.01). 3. Changes in serum lipid level tended to be positively correlated with the declines in CD63 and CD41a, but there was no statistical significance (P>0.05). Conclusions The results suggested that lipid lowering therapy with simvastatin inhibit platelet activity.(J Geriatr Cardiol 2007;4:215-217.)

Effect of hypercholesterolemia on experimental colonic anastomotic wound healing in rats

AIM： To evaluate the mechanical and biochemical parameters of colonic anastomotic healing in hypercholesterolemic rats. METHODS： Sixty rats were divided into two groups of 30 each according to their dietary regimens. The test group was fed with a high cholesterol-containing diet for two months while the control group had standard diet. These two groups were further divided into three subgroups consisting of ten rats each. After hypercholesterolemia was established, left colon resection and anastomosis were performed in both groups and samples from liver and abdominal aorta were taken to evaluate the systemic effects of hypercholesterolemia. Anastomotic wound healing, blow-out pressures and tissue hydroxyproline levels were evaluated. RESULTS： The test group had a significant weight gain in two months. Microscopic examination of the abdominal aorta revealed no atherosderotic change in none of the groups, but liver tissue specimens showed significant steatosis in the test group. Tissue hydroxyproline levels and anastomotic blow-out pressures were significantly lower in the test group than in the controls. CONCLUSION： Hypercholesterolemia not only increases hydroxyproline levels and blow-out pressures but also worsens anastomotic wound healing.

Ezetimibe Completely Replaced LDL-Apheresis for the Treatment of Familial Hypercholesterolemia and Coronary Artery Disease after CABG—A Case Report

Intensive treatment of hyperlipidemia is an important factor in the prevention of cardiovascular disease. Among several therapies, statins are well recognized as playing a central role, although low density lipoprotein bound cholesterol-apheresis can be used to treat very severe cases of familial hypercholesterolemia. However, statins are not always effective on their own and, recently, ezetimibe has emerged as a unique anti- hypercholesterolemic drug that acts as a cholesterol transporter inhibitor;its role is only partially understood. I experienced rare case that appeared to benefit from ezetimibe therapy, and report them as they help increase our knowledge of this novel drug.

Congenital analbuminemia in a patient affected by hypercholesterolemia:A case report

BACKGROUND Congenital analbuminemia(CAA) is a very rare disorder. Our data describes the clinical features and laboratory results of a new case established by mutation analysis of the albumin gene in a 39-year-old woman presenting with hypercholesterolemia. Our findings contribute to shed light on the molecular genetics of the disorder and confirm that safe and well tolerated hypocholesterolemic treatment with atorvastatin may be administered in dislipidemic patient with CAA in order to reduce their cardiovascular risk.CASE SUMMARY Our patient presented with a history of hypercholesterolemia and referred asthenia and heaviness in both legs. She was born from healthy and nonconsanguineous parents and her development was normal. She had not familiarity for early cardiovascular disease, and did not report personal history of hypertension, chronic kidney or liver diseases. Clinical laboratories results showed critically reduced value of albumin whereas other serum proteins were elevated. Main causes of hypoalbuminemia(proteinuria, inflammatory state and insufficient hepatic synthesis) were ruled out by normal procedures and laboratory tests. So the hypothesis of a CAA was tested through mutation analysis of the albumin gene that revealed a homozygous CA deletion in exon 12,at nucleotide positions c1614-1615. This finding brought to the diagnosis of CAA.Currently the patient receives Atorvastatin 20 mg od and undergoes clinical and laboratory follow-up every six months. She never needed albumin infusions.CONCLUSION Our experience shows how treatment with atorvastatin may be safely administered and well tolerated in patients affected by CAA.

Characterization of coronary atherosclerotic plaques in a homozygous familial hypercholesterolemia visualized by optical coherence tomography

Familial hypercholesterolemia(FH)is an autosomal dominant genetic disorder,which resulted in severe elevations in low-density lipoprotein cholesterol(LDL-C)and a markedly increased risk of early-onset coronary disease.[1]t is most frequently caused by loss-of-function mutations in genes affecting the LDL receptor,which clears LDL particles from plasma.

Clinical,biochemical and genetic characteristics of familial hypercholesterolemia with and without type 2 diabetes

Background Though type 2 diabetes mellitus(T2DM)is an important and independent risk factor for coronary artery disease(CAD)in general population,whether this feature also exists in patients with familial hypercholesterolemia(FH)is less determined.The current study aims to characterize the clinical,laboratory,coronary and genetic characteristics of the FH patients with T2DM compared with FH alone.

Prognostic implication of early posttransplant hypercholesterolemia in liver transplantation for patients with hepatocellular carcinoma

Background: Hyperlipidemia is a common complication after liver transplantation(LT) and develops mostly in the early posttransplant period. Recently, some studies have reported a positive correlation between hyperlipidemia and favorable prognosis in patients with hepatocellular carcinoma(HCC) undergoing hepatectomy. This study aimed to evaluate the possibility of predicting prognosis in HCC patients receiving LT by early posttransplant dyslipidemia. Methods: From January 2015 to December 2017, a total of 806 HCC patients from China Liver Transplant Registry database were retrospectively enrolled. The prognostic relevance of early posttransplant hypertriglyceridemia or hypercholesterolemia was examined using survival analysis, and subgroup analysis was implemented based on LT criteria. Results: Early posttransplant hypercholesterolemia(EPHC) was independently inversely associated with the risk of recurrence [hazard ratio(HR) = 0.630;P = 0.022], but was not significantly correlated with the mortality. However, early posttransplant hypertriglyceridemia was not related to prognosis. Intriguingly, with further classification, we found that borderline EPHC(B-EPHC), instead of significant EPHC, was a predictor of lower risk for both recurrence(HR = 0.504;P = 0.006) and mortality(HR = 0.511;P = 0.023). Compared with non-EPHC patients, B-EPHC patients achieved significantly superior 1-year and 3-year tumor-free survival(89.6% and 83.7% vs. 83.8% and 72.7% respectively;P = 0.023), and 1-year and 3-year overall survival(95.8% and 84.8% vs. 94.6% and 77.6% respectively;P = 0.039). In the subgroup analysis, BEPHC remained an independent predictor of better prognosis in patients beyond Milan criteria and those within Hangzhou criteria;whereas there was no significant relationship between B-EPHC and prognosis in patients within Milan criteria and those beyond Hangzhou criteria. More interestingly, patients beyond Milan criteria but within Hangzhou criteria were identified as the crucial subpopulation who benefited from B-EPHC(recurrence HR = 0.306, P = 0.011;mortality HR = 0.325, P = 0.031).Conclusions: B-EPHC could assist transplant teams in dynamically evaluating prognosis after LT for HCC as a postoperative non-oncological biomarker, especially in patients beyond Milan criteria but within Hangzhou criteria.

Review of the Mechanisms of Action of the Statins and Their Pleiotropic Effects in the Treatment of Hypercholesterolemia and Atherosclerosis

Statins are lipid-lowering agents widely used in the treatment of hypercholesterolemia and atherosclerosis. They act by inhibiting of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, an enzyme responsible for the conversion of HMG-CoA to mevalonate in cholesterol biosynthesis. Due to their ability to reduce low-density lipoproteins (LDL) levels more than other cholesterol-lowering drugs, they have become the drugs most often prescribed in the treatment of atherosclerosis.

Familial Hypercholesterolemia with Two Mutations in LDLR Gene: A Case Report and Literature Review

We report a case of Familial hypercholesterolemia (FH) with two mutations in low density lipoprotein receptor (LDLR) gene and speculate the correlation between the newly discovered mutation type of LDLR gene and FH. We collected and analyzed the clinical data of the proband in the case and her immediate family members, and detected the LDLR, Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK-9) and Apolipoprotein B (Apo B) gene in the peripheral blood of all the participants. We found that the curative effect of the patient is limited, but no obvious complication was detected. Genetic testing results pointed out that there were two mutations in the patient’s LDLR gene. One was p.W483* mutation in exon 10 (c. 1448 G > A), another was p.T534I mutation in exon 11 (c. 1601 C > T). The p. W483* mutation in exon 10 was detected in the father and sister, additionally p. T534I mutation in exon 11 was detected in the mother. Both the two LDLR gene mutations are inherited from her parents. We hypothesize that the patient in this case was a complex heterozygote. The newly discovered mutation gene (T534I) may be one of the important causes of dyslipidemia in patients, and its adverse effects are more serious than W483* which have been reported. Also, we predict that the T534I mutation will not cause serious early onset of cardiovascular complications.

Accelerated Atherosclerosis in a Young Female with Familial Hypercholesterolemia

Familial hypercholesterolemia is an autosomal dominant genetic disease due to mutation in low-density lipoprotein-cholesterol receptor gene. It is characterized by elevated plasma low-density lipoprotein-cholesterol and the consequence of which leads to premature cardiovascular disease. The mainstay in the management of familial hypercholesterolemia patient is the treatment with high potency statin. However, current research shows influence of the type of low-density lipoprotein-cholesterol receptor mutations on severity of the cardiovascular disease, lipid profile, and response to statin treatment. We are here presenting a case of young Indian female patient who was diagnosed with familial hypercholesterolemia and treated with percutaneous transluminal coronary angioplasty in view of double vessel disease in the third decade of her life. She was prescribed with statin therapy for elevated low-density lipoprotein cholesterol. After 3 years, she presented once again with a triple vessel disease along with patent stented segments and abnormal lipid profile.

Living Environment and Hypercholesterolemia: Case of Mono and Couffo Departments, Benin, in 2015

Introduction: Studies conducted in Benin have often not emphasized the living environment underlying hypercholesterolemia. The objective was to study the prevalence and factors associated with hypercholesterolemia in the Mono and Couffo departments in 2015 with consideration of the living environment. Methods: Descriptive cross-sectional study with an analytical aim that involved 2490 subjects aged 18 - 69 years, selected using a three-stage randomized sampling technique. Data were collected using the Personal Digital Assistant (WHO STEPS instrument) and analyzed according to STEPS recommendations using Epi-Info7.1.5.0 and SPSS20 software. The Chi-square test was used to compare proportions and the difference was considered significant for p < 0.05. Results: Out of 2490 respondents, 60.20% were women. The mean age was 36.14 ± 12.82 years. The prevalence of hypercholesterolemia was 4.7% (95% CI: [3.88 - 5.54]) and lower in the Couffo. Factors associated with hypercholesterolemia after multivariate analysis were harmful alcohol consumption, high blood pressure, type 2 diabetes, obesity and overweight. Conclusions: Living environment was found to be one of the important factors to consider in strategies to control hypercholesterolemia in the Mono and Couffo departments.