Role of gut microbiota and metabolomics in the lipid-lowering efficacy of statins among Chinese patients with coronary heart disease and hypercholesterolemia.

Background: Statins, being the primary pharmacological intervention for hypercholesterolemia, exhibit a notable degree of interpatient variability in their effectiveness, which may be associated with gut microbiota. This study sought to identify the biomarkers for evaluating differences in statin efficacy. Methods: A quasi case-control study was conducted among participants with hypercholesterolemia and coronary heart disease taking rosuvastatin essential. According to the level of low density lipoprotein cholesterol (LDL-C), participants was divided into the "Up to standard" (US) group and the "Below standard" (BS) group. 16S rDNA sequencing and untargeted metabolomics were applied to detected the information of gut microbiota and related metabolites. Results: A total of 8 US and 8 BS group matched by age and sex were included in the final analysis. 16S rDNA sequencing results indicated that the characteristic strains of the US group were f-Eubacterium_coprostanoligenes and g-Papillibacter, while the characteristic flora of the BS group were o-C0119, g-Pseudolabrys, s-Dyella-Marensis and f-Xanthobacaceae. Metabolomic results suggested that the levels of chenodeoxycholic acid-3-ß-D-glucuronide, 1-methylnicotinamide and acetoacetate in stool samples of the US group were significantly higher than those of the BS group. By identifying the differentially abundant bacterial taxa, the gut microbiota could modulate the efficacy of statins through producing enzymes involved in cholesterol metabolism. Conclusions: The findings suggest that the difference in statin efficacy may be related to gut microbiota strains that can produce short-chain fatty acids and secondary bile acids and affect the efficacy of statins by regulating the activities of cholesterol metabolite-related proteins. Metabolites related to short-chain fatty acids and secondary bile acids in the gut are expected to be biomarkers indicating the efficacy of statins.

The Molecular Size of Bioengineered Oxygen Carriers Determines Tissue Oxygenation in a Hypercholesterolemia Guinea Pig Model of Hemorrhagic Shock and Resuscitation.

Polymerized human hemoglobin (PolyhHb) has shown promise in preclinical hemorrhagic shock settings. Different synthetic and purification schemes can control the size of PolyhHbs, yet research is lacking on the impact of polymerized hemoglobin size on tissue oxygenation following hemorrhage and resuscitation in specialized animal models that challenge their resuscitative capabilities. Pre-existing conditions that compromise the vasculature and end organs, such as the liver, may limit the effectiveness of resuscitation and exacerbate the toxicity of these molecules, which is an important but minimally explored therapeutic dimension. In this study, we compared the effective oxygen delivery of intermediate molecular weight PolyhHb (PolyhHb-B3; 500-750 kDa) to high molecular weight PolyhHb (PolyhHb-B4; 750 kDa-0.2 µm) for resuscitative effectiveness in guinea pig models subjected to hemorrhagic shock. We evaluated how the size of PolyhHb impacts hemodynamics and tissue oxygenation in normal guinea pigs and guinea pigs on an atherogenic diet. We observed that while PolyhHb-B3 and -B4 equivalently restore hemodynamic parameters of normal-dieted guinea pigs, high-fat-dieted guinea pigs resuscitated with PolyhHb-B4 have lower mean arterial pressures, impaired tissue oxygenation, and higher plasma lactate levels than those receiving PolyhHb-B3. We characterized the plasma of these animals following resuscitation and found that despite similar oxygen delivery kinetics, circulating PolyhHb-B3 and -B4 demonstrated a size-dependent increase in the plasma viscosity, consistent with impaired perfusion in the PolyhHb-B4 transfusion group. We conclude that intermediate-sized PolyhHbs (such as -B3) are ideal for further research given the effective resuscitation of hemorrhagic shock based on tissue oxygenation in hypercholesterolemic guinea pigs.

Secoisolariciresinol diglucoside and anethole ameliorate lipid abnormalities, oxidative injury, hypercholesterolemia, heart, and liver conditions.

Fennel seeds and flaxseed have been traditionally used against many medical ailments due to their medicinal characteristics. The aim of the study was to investigate the health properties of secoisolariciresinol diglucoside (SDG) and anethole from flaxseed and fennel seeds in rats fed with high-fat diet. Histopathological changes in the heart and liver were also examined. Sixty rats were divided into two main groups. Group I (10 rats) was used as a negative control group and fed on the basal diet only. Group II (50 rats) was fed a hypercholesterolemic diet but not given any drugs during the trial for 2 weeks. This group was further divided into five subgroups (10 rats each). One of them was fed on the basal diet and used as a positive control group. However, the other four subgroups were fed on basal diets and anethole (20 mg/kg/day, orally), SDG (20 mg/kg/day, orally), a mixture of anethole + SDG (10 + 10 mg/kg/day, orally), and atorvastatin (10 mg/kg/day, orally) for 6 weeks. Compared to control, treatment with a combination of anethole + SDG showed a significant (p ≤ .05) improvement in serum levels of triglyceride (TG) (137.88 ± 1.61 mg/dL), total cholesterol-(TC) (180.12 ± 8.99 mg/dL), LDL-C (46.40 ± 6.67 mg/dL), VLDL-C (11.81 ± 1.07 mg/dL), aspartate aminotransferase (AST) (75.97 ± 6.92 U/L), alanine aminotransferase (ALT) (34.83 ± 2.17 U/L), alkaline phosphatase (ALP) (130.65 ± 1.05 U/L), and malondialdehyde (MDA) (30.12 ± 1.89 mmol/g), and improved activities of catalase (70.99 ± 3.29 U/g) and superoxide dismutase (SOD) (35.13 ± 2.53 U/dL) enzymes while SDG and anethole group had relatively less impact. Atorvastatin also improved serum levels of triglyceride, total cholesterol, LDL-C, and VLDL-C significantly and rose serum high-density lipoprotein cholesterol (HDL-C) levels considerably meanwhile it had a minor but negative impact on AST, ALT, and ALP, and negligible impact on activities of MDA, CAT, and SOD enzymes compared to the positive control group. The study revealed that combining anethole and SDG may improve dyslipidemia, improve lipid profile, decrease risks of chronic heart diseases, increase HDL-C, and enhance antioxidant enzymes' activities.

The Beneficial Effect of Lomitapide on the Cardiovascular System in LDLr-/- Mice with Obesity.

OBJECTIVES: Homozygous familial hypercholesteremia (HoFH) is a rare, life-threatening metabolic disease, mainly caused by a mutation in the LDL receptor. If untreated, HoFH causes premature death from acute coronary syndrome. Lomitapide is approved by the FDA as a therapy to lower lipid levels in adult patients with HoFH. Nevertheless, the beneficial effect of lomitapide in HoFH models remains to be defined. In this study, we investigated the effect of lomitapide on cardiovascular function using LDL receptor-knockout mice (LDLr-/-). METHODS: Six-week-old LDLr-/- mice were fed a standard diet (SD) or a high-fat diet (HFD) for 12 weeks. Lomitapide (1 mg/Kg/Day) was given by oral gavage for the last 2 weeks in the HFD group. Body weight and composition, lipid profile, blood glucose, and atherosclerotic plaques were measured. Vascular reactivity and markers for endothelial function were determined in conductance arteries (thoracic aorta) and resistance arteries (mesenteric resistance arteries (MRA)). Cytokine levels were measured by using the Mesoscale discovery V-Plex assays. RESULTS: Body weight (47.5 ± 1.5 vs. 40.3 ± 1.8 g), % of fat mass (41.6 ± 1.9% vs. 31.8 ± 1.7%), blood glucose (215.5 ± 21.9 vs. 142.3 ± 7.7 mg/dL), and lipid levels (cholesterol: 600.9 ± 23.6 vs. 451.7 ± 33.4 mg/dL; LDL/VLDL: 250.6 ± 28.9 vs. 161.1 ± 12.24 mg/dL; TG: 299.5 ± 24.1 vs. 194.1 ± 28.1 mg/dL) were significantly decreased, and the % of lean mass (56.5 ± 1.8% vs. 65.2 ± 2.1%) was significantly increased in the HFD group after lomitapide treatment. The atherosclerotic plaque area also decreased in the thoracic aorta (7.9 ± 0.5% vs. 5.7 ± 0.1%). After treatment with lomitapide, the endothelium function of the thoracic aorta (47.7 ± 6.3% vs. 80.7 ± 3.1%) and mesenteric resistance artery (66.4 ± 4.3% vs. 79.5 ± 4.6%) was improved in the group of LDLr-/- mice on HFD. This was correlated with diminished vascular endoplasmic (ER) reticulum stress, oxidative stress, and inflammation. CONCLUSIONS: Treatment with lomitapide improves cardiovascular function and lipid profile and reduces body weight and inflammatory markers in LDLr-/- mice on HFD.

Rarely tested or treated but highly prevalent: Hypercholesterolemia in ED observation unit patients with chest pain.

BACKGROUND: Hypercholesterolemia (HCL) is common among Emergency Department (ED) patients with chest pain but is typically not addressed in this setting. This study aims to determine whether a missed opportunity for Emergency Department Observation Unit (EDOU) HCL testing and treatment exists. METHODS: We conducted a retrospective observational cohort study of patients ≥18 years old evaluated for chest pain in an EDOU from 3/1/2019-2/28/2020. The electronic health record was used to determine demographics and if HCL testing or treatment occurred. HCL was defined by self-report or clinician diagnosis. Proportions of patients receiving HCL testing or treatment at 1-year following their ED visit were calculated. HCL testing and treatment rates at 1-year were compared between white vs. non-white and male vs. female patients using multivariable logistic regression models including age, sex, and race. RESULTS: Among 649 EDOU patients with chest pain, 55.8% (362/649) had known HCL. Among patients without known HCL, 5.9% (17/287, 95% CI 3.5-9.3%) had a lipid panel during their index ED/EDOU visit and 26.5% (76/287, 95% CI 21.5-32.0%) had a lipid panel within 1-year of their initial ED/EDOU visit. Among patients with known or newly diagnosed HCL, 54.0% (229/424, 95% CI 49.1-58.8%) were on treatment within 1-year. After adjustment, testing rates were similar among white vs. non-white patients (aOR 0.71, 95% CI 0.37-1.38) and men vs. women (aOR 1.32, 95% CI 0.69-2.57). Treatment rates were similar among white vs. non-white (aOR 0.74, 95% CI 0.53-1.03) and male vs. female (aOR 1.08, 95% CI 0.77-1.51) patients. CONCLUSIONS: Few patients were evaluated for HCL in the ED/EDOU or outpatient setting after their ED/EDOU encounter and only 54% of patients with HCL were on treatment during the 1-year follow-up period after the index ED/EDOU visit. These findings suggest a missed opportunity to reduce cardiovascular disease risk exists by evaluating and treating HCL in the ED or EDOU.

Associations between education level, blood-lipid measurements and statin treatment in a Danish primary health care population from 2000 to 2018.

OBJECTIVE: To examine whether education level influences screening, monitoring, and treatment of hypercholesterolemia. DESIGN: Epidemiological cohort study. SETTING: Department of Clinical Biochemistry, Copenhagen University Hospital Hvidovre. SUBJECTS: Cholesterol blood test results ordered by general practitioners in Greater Copenhagen were retrieved from 2000-2018. Using the International Standard Classification of Education classification, the population was categorized by length of education in three groups (basic education; up to 10 years, intermediate education; 11-12 years, advanced education; 13 years or more). The database comprised 13,019,486 blood sample results from 653,903 patients. MAIN OUTCOME MEASURES: Frequency of lipid measurement, prevalence of statin treatment, age and comorbidity at treatment initiation, total cholesterol threshold for statin treatment initiation, and achievement of treatment goal. RESULTS: The basic education group was measured more frequently (1.46% absolute percentage difference of total population measured [95% CI 0.86%-2.05%] in 2000 and 9.67% [95% CI 9.20%-10.15%] in 2018) over the period compared to the intermediate education group. The advanced education group was younger when receiving first statin prescription (1.87 years younger [95% CI 1.02-2.72] in 2000 and 1.06 years younger [95% CI 0.54-1.58 in 2018) compared to the intermediate education group. All education groups reached the treatment goals equally well when statin treatment was initiated. CONCLUSION: Higher education was associated with earlier statin prescription, although the higher educated group was monitored less frequently. There was no difference in reaching treatment goal between the three education groups. These findings suggest patients with higher education level achieve an earlier dyslipidemia prevention intervention with an equally satisfying result compared to lower education patients.Key PointsLittle is known about the role of social inequality as a possible barrier for managing hypercholesterolemia in general practice.Increasing education level was associated to less frequent measurement and less frequent statin treatment.Patients with higher education level were younger, and less comorbidity at first statin prescription.Education level had no effect on frequency of statin treatment-initiated patients reaching the treatment goal was found.

The role of CYP1A1/2 in cholesterol ester accumulation provides a new perspective for the treatment of hypercholesterolemia.

Cholesterol is an important precursor of many endogenous molecules. Disruption of cholesterol homeostasis can cause many pathological changes, leading to liver and cardiovascular diseases. CYP1A is widely involved in cholesterol metabolic network, but its exact function has not been fully elucidated. Here, we aim to explore how CYP1A regulates cholesterol homeostasis. Our data showed that CYP1A1/2 knockout (KO) rats presented cholesterol deposition in blood and liver. The serum levels of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and total cholesterol were significantly increased in KO rats. Further studies found that the lipogenesis pathway (LXRα-SREBP1-SCD1) of KO rats was activated, and the key protein of cholesterol ester hydrolysis (CES1) was inhibited. Importantly, lansoprazole can significantly alleviate rat hepatic lipid deposition in hypercholesterolemia models by inducing CYP1A. Our findings reveal the role of CYP1A as a potential regulator of cholesterol homeostasis and provide a new perspective for the treatment of hypercholesterolemia.

The role of CYP1A1/2 in cholesterol ester accumulation provides a new perspective for the treatment of hypercholesterolemia

Cholesterol is an important precursor of many endogenous molecules. Disruption of cholesterol homeostasis can cause many pathological changes, leading to liver and cardiovascular diseases. CYP1A is widely involved in cholesterol metabolic network, but its exact function has not been fully elucidated. Here, we aim to explore how CYP1A regulates cholesterol homeostasis. Our data showed that CYP1A1/2 knockout (KO) rats presented cholesterol deposition in blood and liver. The serum levels of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and total cholesterol were significantly increased in KO rats. Further studies found that the lipogenesis pathway (LXRα-SREBP1-SCD1) of KO rats was activated, and the key protein of cholesterol ester hydrolysis (CES1) was inhibited. Importantly, lansoprazole can significantly alleviate rat hepatic lipid deposition in hypercholesterolemia models by inducing CYP1A. Our findings reveal the role of CYP1A as a potential regulator of cholesterol homeostasis and provide a new perspective for the treatment of hypercholesterolemia.

Silibinin Suppresses the Hyperlipidemic Effects of the ALK-Tyrosine Kinase Inhibitor Lorlatinib in Hepatic Cells.

The third-generation anaplastic lymphoma tyrosine kinase inhibitor (ALK-TKI) lorlatinib has a unique side effect profile that includes hypercholesteremia and hypertriglyceridemia in >80% of lung cancer patients. Here, we tested the hypothesis that lorlatinib might directly promote the accumulation of cholesterol and/or triglycerides in human hepatic cells. We investigated the capacity of the hepatoprotectant silibinin to modify the lipid-modifying activity of lorlatinib. To predict clinically relevant drug−drug interactions if silibinin were used to clinically manage lorlatinib-induced hyperlipidemic effects in hepatic cells, we also explored the capacity of silibinin to interact with and block CYP3A4 activity using in silico computational descriptions and in vitro biochemical assays. A semi-targeted ultrahigh pressure liquid chromatography accurate mass quadrupole time-of-flight mass spectrometry with electrospray ionization (UHPLC-ESI-QTOF-MS/MS)-based lipidomic approach revealed that short-term treatment of hepatic cells with lorlatinib promotes the accumulation of numerous molecular species of cholesteryl esters and triglycerides. Silibinin treatment significantly protected the steady-state lipidome of hepatocytes against the hyperlipidemic actions of lorlatinib. Lipid staining confirmed the ability of lorlatinib to promote neutral lipid overload in hepatocytes upon long-term exposure, which was prevented by co-treatment with silibinin. Computational analyses and cell-free biochemical assays predicted a weak to moderate inhibitory activity of clinically relevant concentrations of silibinin against CYP3A4 when compared with recommended (rosuvastatin) and non-recommended (simvastatin) statins for lorlatinib-associated dyslipidemia. The elevated plasma cholesterol and triglyceride levels in lorlatinib-treated lung cancer patients might involve primary alterations in the hepatic accumulation of lipid intermediates. Silibinin could be clinically explored to reduce the undesirable hyperlipidemic activity of lorlatinib in lung cancer patients.

Ezetimibe and Cancer: Is There a Connection?

The high level of serum cholesterol caused by the excessive absorption of cholesterol can lead to hypercholesteremia, thus promoting the occurrence and development of cancer. Ezetimibe is a drug that reduces cholesterol absorption and has been widely used for the treatment of patients with high circulating cholesterol levels for many years. Mechanistically, ezetimibe works by binding to NPC1L1, which is a key mediator of cholesterol absorption. Accumulating data from preclinical models have shown that ezetimibe alone could inhibit the development and progression of cancer through a variety of mechanisms, including anti-angiogenesis, stem cell suppression, anti-inflammation, immune enhancement and anti-proliferation. In the past decade, there has been heated discussion on whether ezetimibe combined with statins will increase the risk of cancer. At present, more and more evidence shows that ezetimibe does not increase the risk of cancers, which supports the role of ezetimibe in anti-cancer. In this review, we discussed the latest progress in the anti-cancer properties of ezetimibe and elucidated its underlying molecular mechanisms. Finally, we highlighted the potential of ezetimibe as a therapeutic agent in future cancer treatment and prevention.

Ursolic acid inhibits the cholesterol biosynthesis and alleviates high fat diet-induced hypercholesterolemia via irreversible inhibition of HMGCS1 in vivo.

BACKGROUND: In hypercholesteremia, the concentrations of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) are enhanced in serum, which is strongly associated with an increased risk of developing atherosclerosis. Ursolic acid (UA), a pentacyclic terpenoid carboxylic acid, was found to alleviate hypercholesterolemia and hypercholesterolemia-induced cardiovascular disease. However, the specific targets and molecular mechanisms related to the effects of UA in reducing cholesterol have not been elucidated. PURPOSE: In this study, we aimed to illustrate the target of UA in the treatment of hypercholesterolemia and to reveal its underlying molecular mechanism. METHODS: Nontargeted metabolomics was conducted to analyze the metabolites and related pathways that UA affected in vivo. The main lipid metabolism targets of UA were analyzed by target fishing and fluorescence colocalization in mouse liver. Molecular docking, in-gel fluorescence scan and thermal shift were assessed to further investigate the binding site of the UA metabolite with HMGCS1. C57BL/6 mice were fed a high-fat diet (HFD) for 12 weeks to induce hypercholesteremia. Liver tissues were used to verify the cholesterol-lowering molecular mechanism of UA by targeted metabolomics, serum was used to detect biochemical indices, and the entire aorta was used to analyze the formation of atherosclerotic lesions. RESULTS: Our results showed that hydroxy­3-methylglutaryl coenzyme A synthetase 1 (HMGCS1) was the primary lipid metabolism target protein of UA. The UA metabolite epoxy-modified UA irreversibly bonds with the thiol of Cys-129 in HMGCS1, which inhibits the catalytic activity of HMGCS1 and reduces the generation of precursors in cholesterol biosynthesis in vivo. The contents of TC and LDL-C in serum and the formation of the atherosclerotic area in the entire aorta were markedly reduced with UA treatment in Diet-induced hypercholesteremia mice. CONCLUSION: UA inhibits the catalytic activity of HMGCS1, reduces the generation of downstream metabolites in the process of cholesterol biosynthesis and alleviates Diet-induced hypercholesteremia via irreversible binding with HMGCS1 in vivo. It is the first time to clarify the irreversible inhibition mechanism of UA against HMGCS1. This paper provides an increased understanding of UA, particularly regarding the molecular mechanism of the cholesterol-lowering effect, and demonstrates the potential of UA as a novel therapeutic for the treatment of hypercholesteremia.

A Pharmacovigilance Study of Adverse Drug Reactions Reported for Cardiovascular Disease Medications Approved Between 2012 and 2017 in the United States Food and Drug Administration Adverse Event Reporting System (FAERS) Database.

PURPOSE: Between 2012 and 2017, the FDA approved 29 therapies for a cardiovascular disease (CVD) indication. Due to the limited literature on patient safety outcomes for recently approved CVD medications, this study investigated adverse drug reports (ADRs) reported in the FDA Adverse Event Reporting System (FAERS). METHODS: A disproportionality analysis of spontaneously reported ADR was conducted. Reports in FAERS from Quarter 1, 2012, through Quarter 1, 2019, were compiled, allowing a 2-year buffer following drug approval in 2017. Top 10 reported ADRs and reporting odds ratios (ROR; confidence interval (CI)), a measure of disproportionality, were analyzed and compared to drugs available prior to 2012 as appropriate. RESULTS: Of 7,952,147 ADR reports, 95,016 (1.19%) consisted of reports for newly approved CVD medications. For oral anticoagulants, apixaban had significantly lower reports for anemia and renal failure compared to dabigatran and rivaroxaban but greater reports for neurological signs/symptoms, and arrhythmias. Evaluating heart failure drugs, sacubitril/valsartan had greater reports for acute kidney injury, coughing, potassium imbalances, and renal impairment but notably, lower for angioedema compared to lisinopril. Assessing familial hypercholesterolemia drugs, alirocumab had greater reports for joint-related-signs/symptoms compared to other agents in this category. A newer pulmonary arterial hypertension treatment, selexipag, had greater reports of reporting for bone/joint-related-signs/symptoms but riociguat had greater reports for hemorrhages and vascular hypotension. CONCLUSION: Pharmacovigilance studies allow an essential opportunity to evaluate the safety profile of CVD medications in clinical practice. Additional research is needed to evaluate these reported safety concerns for recently approved CVD medications.

Abordaje de la hipercolesterolemia en planes y estrategias de saluden España: estado actual y propuestas de futuro / The approach to hypercholesterolemia in health strategies and plans in Spain: present situation and future proposals

Fundamento: Las enfermedades cardiovasculares (ECV)son la principal causa de muerte a nivel mundial y la hipercolesterolemia (HC) es un importante factor de riesgo cardiovascular (FRCV). En España, aproximadamente un25% de los adultos de mediana edad presentan hipercolesterolemia. Nuestro objetivo fue analizar las estrategias y planes de salud existentes en España respecto a las ECVy a la HC, y definir líneas de actuación para su controldesde la gestión y política sanitaria. Material y métodos: Estudio observacional, descriptivo.En la primera fase se revisó la literatura y se realizaronseis entrevistas semiestructuradas; en una segunda fase,12 expertos identificaron las barreras existentes y propusieron estrategias para reducir la mortalidad prematura por las ECV.Resultados: Se identificaron 51 documentos de planificación, el 43% hacían referencia a la HC. Se detectó una altavariabilidad en la implementación de iniciativas a nivel autonómico para el control de la HC. Las barreras identificadas para explicar estos resultados fueron: banalización de la HC, falta de participación activa de agentes clave, desconocimiento del impacto de la HC, el modelo de atención y los circuitos asistenciales existentes, y las políticas sanitarias a corto plazo y con escasa dedicación de recursos a la HC.Conclusiones: A pesar del impacto en salud y socioeconómico de las ECV y de la HC en España, el peso de la HC en las políticas de salud no parece corresponderse con esa relevancia. Faltan medidas para su abordaje, pese a la evidencia de su efectividad. Este estudio propone medidas concretas para avanzar en su control.(AU)

Background: Cardiovascular diseases (CVD) are a major cause of death worldwide and Hypercholesterolemia (HC) is an important cardiovascular risk factor. In Spain,approximately 25% of middle-aged adults suffer from HC.Our objective was to analyse current health strategiesand plans in Spain related to CVD and HC in order todefine possible future courses of action to bring aboutbetter control from a health management and policy perspective.Methods: The study was observational and descriptive.In the first step, a literature review was carried out, followed by six semi structured interviews. In the second step, a group of 12 experts in the field identified existing barriers to HC control and suggested ways to reduce premature mortality due to CVD. Results: A total of 51 documents were identified, of which 43% referred to HC. There was a high variability at the regional level in the implementation of measures and initiatives for the control of HC. Barriers that were identified were : trivialization of HC, lack of active participation bykey stakeholders, lack of understanding of the impact ofHC, existing care models and pathways, and short-termhealth policies that limit the provision of resources forHC care and control. Conclusion: Despite the considerable medical and socioeconomic burden of CVD and HC in Spain, the importance of HC is not reflected in health policies. There is a lack of HC control measures, even when they are shown to be highly feasible and beneficial. This article proposes specific measures to improve control of this issue.(AU)

APOE Gene Associated with Cholesterol-Related Traits in the Hispanic Population.

Genetic variants in the apolipoprotein E (APOE) gene are associated with lipid metabolism and lipid-related traits in the non-Hispanic population. There have been limited studies regarding the association between the APOE gene and hypercholesterolemia in the Hispanic population; therefore, our aim for this study is to examine the APOE gene's associations with cholesterol level and its related phenotypes. The APOE gene consists of three different alleles, ε2, ε3, and ε4, with ε4 being associated with dementia and cardiovascular diseases. A total of 1,382 subjects were collected from the Texas Alzheimer's Research and Care Consortium (TARCC, N = 1320) and the Initial Study of Longevity and Dementia from the Rio Grande Valley (ISLD-RGV, N = 62). Questionnaires on demographics, medical history, and blood/saliva samples were collected and APOE genotypes were performed. We observed allele frequencies of the APOE ε3 (96.7%), ε4 (22.6%) and ε2 (6.8%) alleles, respectively. Multivariable logistic regression revealed a significant association between the APOE ε4 allele and hypercholesteremia (p = 1.8 × 10-4) in our studied Hispanic population. We prove for the first time, that the APOE ε4 allele increases the risk for hypercholesterol in Hispanics. Further research is needed to confirm and supports our current findings.

Current Practices and Gaps in Management of Dyslipidemia in Type 2 Diabetes Mellitus (T2DM) in Accordance with American Diabetes Association (ADA) Guidelines: A Subset Analysis from a Real-World, Cross-Sectional Observational Study (LEADD Study).

BACKGROUND: Diabetic dyslipidemia is a risk factor for coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM). American Diabetes Association (ADA) provides internationally accepted guidelines to manage dyslipidemia in T2DM. OBJECTIVE: To assess if ADA guidelines are followed for managing dyslipidemia in patients with T2DM in India. METHODS: This was a subset analysis of a prospective, cross sectional, observational study (LEADD Study) conducted at 199 sites across India to evaluate dyslipidemia management practices in T2DM patients (N=4002), in a real-world setting. The data was stratified based on age and atherosclerotic cardiovascular disease (ASCVD) and ASCVD risk factors to record the percentages of T2DM patients achieving LDL-C target and treated optimally with the Guideline directed intensity of statin. Analysis was conducted using descriptive statistics. RESULTS: As per ADA 2018 targets: LDL-C levels (<100mg/dL) were seen in 30.6% of participants. High intensity statins were prescribed to 13.4% of the participants with LDL levels ≥100 mg/dL. ASCVD risk assessment details were available for 89.2% of participants. Data was not available for smoking and albuminuria. In participants <40 years of age, 80% and 64.2% with ASCVD and ASCVD risk factors, respectively, did not achieve target LDL-C levels. In this age group, 15.6% and 83.3% of participants with ASCVD risk factors and ASCVD group, respectively, were not receiving statins in the recommended dose. In participants ≥40 years of age, 88.0% and 91.5% with ASCVD and ASCVD risk factors, respectively, did not have LDL-C levels as per ADA 2018 targets. In this age group, 87.2% and 77.9% of participants with ASCVD risk factors and ASCVD, respectively, were not receiving statins in the recommended dose. CONCLUSION: The sub-analysis of LEADD study shows sub-optimal adherence to ADA 2018 guidelines for management of diabetic dyslipidemia.

Outcomes of Acute Myocardial Infarction in Patients with Familial Hypercholesteremia.

BACKGROUND: There is a paucity of contemporary data regarding the outcomes of acute myocardial infarction among patients with familial hypercholesteremia. METHODS: We queried the Nationwide Readmissions Database (2016-2018) for hospitalizations with acute myocardial infarction. Multivariable regression analysis was used to compare in-hospital outcomes and 30-day readmissions among patients with and without familial hypercholesteremia. RESULTS: The analysis included 1,363,488 hospitalizations with acute myocardial infarction. The prevalence of familial hypercholesteremia was 0.07% among acute myocardial infarction admissions. Compared with those without familial hypercholesteremia, admissions with familial hypercholesteremia were younger and had less comorbidities but were more likely to have had prior infarct and revascularization. Admissions with familial hypercholesteremia were more likely to present with ST-elevation myocardial infarction and undergo revascularization. After multivariable adjustment, there was no difference in in-hospital case fatality among patients with hypercholesteremia compared with those without it (adjusted odds ratio [aOR] = 0.76; 95% confidence interval [CI] 0.41-1.39). Admissions with acute myocardial infarction and familial hypercholesteremia had higher adjusted rates of cardiac arrest and utilization of mechanical support. There were no group differences in overall 30-day readmission (aOR 0.75; 95% CI 0.51-1.10) or 30-day readmission for acute myocardial infarction. However, a nonsignificant trend toward higher readmission for percutaneous coronary intervention was observed among patients with familial hypercholesteremia (aOR 1.89; 95% CI 0.98-3.64). CONCLUSION: In this contemporary nationwide observational analysis, patients with familial hypercholesteremia represent a small proportion of the overall population with acute myocardial infarction and have a distinctive clinical profile but do not appear to have worse in-hospital case fatality compared with those without familial hypercholesteremia.

One-step modification to identify dual-inhibitors targeting both pancreatic triglyceride lipase and Niemann-Pick C1-like 1.

Pancreatic triglyceride lipase (PTL) and Niemann-Pick C1-like 1 (NPC1L1) have been identified as attractive therapeutic targets for obesity and hypercholesteremia, respectively. Obesity and hypercholesteremia usually co-exist, however no dual-inhibitors against PTL and NPC1L1 were reported for the treatment of obesity patients with hypercholesteremia so far. In this work, molecular hybridization-based one-step modification screening identified a potent dual-inhibitor against PTL and NPC1L1. Compound P1-11 has IC50 values of 2.1 µM against PTL through covalent binding, as well as significantly reduces cholesterol absorption in a non-competitive inhibitory manner. Molecule docking and molecular dynamics studies revealed the reason of its activity to both PTL and NPC1L1. Moreover, the gene and protein expression levels of PTL and NPC1L1 were also determined respectively after the treatment of P1-11. Development of dual-inhibitors against PTL and NPC1L1 could provide novel treatment options for obesity patients with hypercholesteremia. The results of current research would great support the development of dual-inhibitors against PTL and NPC1L1.

Bempedoic Acid: A New Tool in the Battle Against Hyperlipidemia.

PURPOSE: This article discusses the pharmacology of bempedoic acid, the trials that led to United States Food and Drug Administration (FDA) approval of its use, and the overall safety and efficacy of this therapy in heterozygous familial hypercholesterolemia, established atherosclerotic cardiovascular disease (ASCVD), and hyperlipidemia. METHODS: A database search of PubMed and ClinicalTrials.gov was conducted for articles published between January 2012 to September 2020 and containing the key words bempedoic acid, ezetimibe, Nexletol and Nexlizet. Trials from the CLEAR series were selected, as they played a pivotal role in the establishment of FDA approval, along with additional trials published after FDA approval, which provided novel evidence on the use of bempedoic acid in the treatment of hypercholesterolemia. Publications that were not randomized, controlled trials were not included in this review. Only randomized controlled trials in which ezetimibe was used in conjunction with bempedoic acid were included in this review as they were relevant to the new FDA approval of bempedoic acid. FINDINGS: The findings of the present review show that bempedoic acid is both an effective and well-tolerated option for the treatment of hypercholesterolemia when used without ezetimibe in addition to standard therapy. It also appears that the combination with ezetimibe increases the cholesterol-lowering effect more than either agent alone when added to standard therapy. IMPLICATIONS: Hypercholesteremia continues to be a major contributing factor leading to ASCVD. Bempedoic acid is an additional treatment option, along with both statins and diet and exercise, for reducing cholesterol levels and ASCVD events. With the new FDA approval, bempedoic acid may offer an effective therapy for reducing low-density lipoprotein cholesterol in patients at high risk for cardiovascular events due to established ASCVD or heterozygous familial hypercholesterolemia.