Combined Hyperlipidemia Research Articles

Molecular and Metabolic Pathogenesis of Familial Combined Hyperlipidemia and Association with Metabolic Syndrome

Background The objective of this review is to unify the various genetic defects along with elaborating metabolic pathways in Familial Combined Hyperlipidemia(FCHL) and also to differentiate the phenotype of FCHL from metabolic syndrome. Methods PubMed and Cochrane’s library was searched for keyword “Familial combined hyperlipidemia” and latter with “Familial combined hyperlipidemia genes” to finally shortlist 23 articles. Further search with key words “molecular pathogenesis of familial combined hyperlipidemia” and “metabolic syndrome and familial combined hyperlipidemia” was carried out for finding molecular defects in FCHL, non-molecular findings distinguishing FCHL from metabolic syndrome and overlapping features between FCHL and metabolic syndrome. Results Major culprit regions identified included Chromosome-1q21-q24(USF1 and FOXA2) , Ch-11q (APOA5), Ch-16q24, Ch-20q12-q13.1, Ch.4q32.3 (rs6829588), and Ch-19q13.32 containing PVRL-2 gene (Also known as Nectin-2). The genetic and metabolic pathways linked to FCHL may involve: 1-Defective clearance of Apo-B containing lipoproteins, 2-Overproduction of Apo-B containing lipoprotein i.e., VLDL and 3-Adipose tissue dysfunction. FCHL phenotype showed close resemblance with metabolic syndrome clinical and biochemical features with slight differences. Conclusion The reviewed data suggested that FCHL phenotype is the resultant end outcome from multiple molecular defects and thus underlying genetic defect identification in the index case is important for personalized medicine and incoming gene therapy. Further research is warranted to explore specific genetic defects.

Improvement of endothelial dysfunction is mediated through reduction of remnant lipoprotein after statin therapy in patients with coronary artery disease

BackgroundRemnant lipoproteinemia with high levels of low-density lipoprotein cholesterol (LDL-C) is a high risk for endothelial dysfunction. Statins are the first-line lipid-lowering drugs for this combined hyperlipidemia. However, it remains undetermined whether reduction of remnant lipoprotein mediates the relationship between improvement in endothelial dysfunction and reduction of LDL-C level after statin treatment. MethodsA total of 122 coronary artery disease (CAD) patients with impaired flow-mediated dilation (FMD; <5.5%), high levels of LDL-C (≥100 mg/dL), and remnant-like lipoprotein particle cholesterol (RLP-C) (≥5 mg/dL) were examined in this study. The lipid profiles and FMD were measured before and after 6–9 months of statin treatment. The association between changes in LDL-C levels and its relationship with changes in FMD was investigated. Furthermore, mediation analysis was performed to assess the changes in RLP-C level as a mediator of the relationship between the reduction in LDL-C level and improvement of FMD. ResultsTreatment with statins improved FMD in 69 (56.5%) patients. Patients with improved FMD showed lower percent changes of LDL-C, triglyceride (TG), RLP-C, RLP-C/TG, and C-reactive protein (CRP) levels, and higher percent change of HDL-C level, compared to patients who did not show improved FMD. The percent changes in FMD levels had a significant inverse correlation with the percent changes in LDL-C, (r = −0.18, p = 0.03), RLP-C (r = −0.39, p < 0.001), RLP-C/TG (r = −0.34, p < 0.001), and CRP (r = −0.27, p < 0.01). Mediation analysis showed that the relationship between reduction in LDL-C and improvement of FMD was mediated by reduction of RLP-C (34.5%), RLP-C/TG (24.4%), and CRP (24.9%) levels. ConclusionImprovement of remnant lipoproteinemia may be an important mediator for the relationship between improvement of endothelial dysfunction and LDL-lowering after statin treatment in patients with CAD.

Fenofibrate Solid Dispersion Processed by Hot-Melt Extrusion: Elevated Bioavailability and Its Cell Transport Mechanism.

Fenofibrate (FNB) is an effective drug for the treatment of hypertriglyceridemia, hypercholesterolemia as well as mixed hyperlipidemia. However, due to its poor aqueous solubility, FNB has the problem of poor oral absorption followed by low bioavailability. The aim of this research was to construct FNB amorphous solid dispersion employing PVP VA64 as the carrier by hot-melt extrusion method, in order to improve the oral bioavailability. Additionally, the cell transport experiment was conducted to further investigate the mechanism of promoted osmotic absorption. The physical state of the obtained solid dispersion was characterized using SEM, DSC and XRD. Besides, in vitro Caco-2 cells were used to evaluate the cytotoxicity of the carrier and mimic gastrointestinal drug permeation. At last, in vitro dissolution test and in vivo bioavailability study were also carried out. The prepared FNB solid dispersion was found to be an amorphous state after hot-melt extrusion process. In vitro cytotoxicity test on Caco-2 cells confirmed the excellent biocompatibility of the carrier PVP VA64. Besides, transwell cell transport assay and in vitro dissolution test revealed that FNB released from amorphous solid dispersion was equipped with an improved transmembrane transport and dissolution rate. Moreover, pharmacokinetic study in beagle dogs showed that comparing with commercial micronized product Lipanthyl®, the oral bioavailability of FNB solid dispersion was significantly enhanced (2.45 fold). In conclusion, PVP VA64 can be regarded as a promising polymer to enhance the bioavailability of poorly water-soluble drugs such as FNB processed by hot-melt extrusion. Besides, investigations on the mechanism of the enhanced penetration are expected to lay a foundation on the subsequent development of effective and practical solid dispersion.

Effect Of Lipid-Lowering Treatment In Composition And Functionality Of Lipoproteins In Patients With Familial Combined Hyperlipidemia

Background and Aims: Familial combined hyperlipidemia (FCH) is a hereditary disorder of lipid metabolism associated with atherosclerosis. This study is focused on determining composition and functionality of lipoproteins from these patients before and after lipid-lowering treatment.

Interferensi sampel lipemik pada bayi dengan lipemia retinalis dikarenakan primary mixed hyperlipidemia: laporan kasus

Background: Interference is a condition of which sample components cause an error in the analyte measurement in the analyzer. The most common cause of interference is lipemic sample. Lipemic sample is characterized by turbidity of the serum or plasma caused by an accumulation of lipoprotein particles. Primary mixed hyperlipidemia (PMH) is a cause of primary hypertrigliseridemia with lipemia manifestation.Case report: A three month-old baby boy was admitted to a hospital, having white spots in his black eyes. The spots were seen clearer at light exposure, and ophthalmologic examination indicated lipemia retinalis. Patient’s sample was lipemic and its laboratory analysis resulted in as follow: WBC 13.103/μL, Hb 15.6 gr/dL, RBC 2.99 106/μL, triglyserida 10.435 mg/dL, total cholesterol 631 mg/dL, HDL 12 mg/dL, LDL 195 mg/dL, and apoprotein B 196 mg/dL. Due to a significant interference, SGOT, SGPT, ureum and creatinin were not obtained. Immunologic serum analysis of the patient and his mother showed an increasing of antibody IgG CMV: 28 dan 20 IU/ml, respectively.Conclusion: Lipemic samples could directly affect most of laboratory examination methods. Laboratory results with such lipemia interferences shoud be interpretated critically and accurately to produce precise diagnosis, and in turn, monitoring of patient with lipemia.

The effect of left ventricular remodeling on the longitudinal myocardial kinetics of both heart ventricles in patients with arterial hypertension and cardiovascular risk factors

The aim – to study the longitudinal kinetics of the left, right ventricles and interventricular septum (IVS), depending on the type of left ventricular (LV) remodeling in patients with arterial hypertension (AH) in combination with additional cardiovascular risk factors with preserved LV contractility, as well as to determine the correlation of changes in the right ventricular systolic and diastolic parameters estimated with the tissue pulsed-wave Doppler imaging (TDI) with the same indices of the LV and IVS.Materials and methods. The study included 71 patients (average age – 54) with essential AH (68 % men) with a normal LV ejection fraction. The patients had the obese stage 1, combined hyperlipidemia, 29.6 % of patients had type II diabetes, 33.8 % were smokers. The patients were distributed into 4 groups depending on the types of remodeling: 1 – normal geometry (12.7 %); 2 – concentric remodeling (47.9 %); 3 – concentric hypertrophy (35.2 %); 4 – eccentric hypertrophy (4.2 %). TDI of the left and right ventricles and IVS was performed, systolic and diastolic TDI indices were determined, and the index of isovolumic myocardial acceleration (IVA) was calculated for the right ventricle (RV).Results and discussion. The type of LV concentric hypertrophy negatively affects the longitudinal myocardial kinetics of LV and IVS in the study group. The early diastolic velocity Em and the systolic velocity Sm were significantly decreased for the LV and IVS, the late diastolic velocity Am was decreased for the IVS and the E/Em for LV ratio was notably increased. Among the diastolic RV TDI indices only the deceleration time DTEm was significantly longer in LV concentric remodeling and concentric hypertrophy, than in its normal geometry. The IVA index was decreased in changing the type of LV geometry from normal to eccentric hypertrophy, indicating worsening of the RV longitudinal myocardial systolic function. There was a close correlation between diastolic and systolic TDI indices of the RV and IVS, which potentially indicated the importance of IVS in the mechanism of interventricular interaction and its effect on the RV function. The reliable dependence of systolic and diastolic RV TDI indices on the LV contractility was established.Conclusions. The type of LV remodeling, especially concentric hypertrophy, negatively affects the longitudinal myocardial kinetics of both ventricles in patients with AH in combination with additional cardiovascular risk factors. IVA can be a sensitive diagnostic criterion in the detection of early myocardial disorders of the RV systolic function with the changes of the LV geometry in this category of patients. Indices of RV longitudinal myocardial kinetics are closely dependent on changes in the function of IVS, which has a leading role in the formation of interventricular interaction.

Hepatic Glycogenoses Among Children—Clinical and Biochemical Characterization: Single-Center Study

Glycogen storage disease (GSD) is typified by early morning seizures. Absence of this results in delayeddiagnosis, especially the non-GSD 1 group. Data are limited to few patients with unclear outcome. 1. Study the common presentation and types of GSD. 2. Study the clinical and biochemical outcome. 3.Review genetic mutations. Observational study from May 2016-April 2019 at metabolic clinic at our center. Total of 30 patients were diagnosed with GSD. Ten were excluded-Fanconi-Bickel (3) and <4 months follow-up (7). Data were analyzed for 20 patients (16 males). Mean age at presentation was4.3yrs. All had hepatomegaly, 90% had short stature, and 40% had early morning seizures. Mean follow-up was 22 months. There was a statistically significant improvement in metabolic parameters on treatment (mean)-fasting glucose from 50.4 to 79.5mg/dl, SGPT from 416 to 199 U/L. Lipid profile showed reduction in triglycerides (318-225mg/dl) but minimal increase in cholesterol (178-188mg/dl). Mean weight centile improved from 14.1 to 20.3 and height centile from 2.3 to 7.9. Genetic testing confirmed types VI(3), III (3), IXa (1), IXc (1), and Ia (1). Liver biopsy confirmed GSD in 15/20. All were managed with uncookedcorn starch. In addition, omega-3 fatty acid was used in 8/20 and high protein diet in 2 with GSD type III. Awareness of GSD needs to improve among pediatricians and hepatologists. Themost common symptoms are asymptomatic hepatomegaly and short stature. Dietary therapy with uncooked corn starch remains mainstay of treatment. Mixed hyperlipidemia is difficult to control despite good metabolic improvement. Role of omega-3 fatty acid needs to be explored further. Genetic mutation analysiscanassist with tailoring treatment and should get precedence over liver biopsy.

Evaluation of Dyslipidaemia Using an Algorithm of Lipid Profile Measures among Newly Diagnosed Type II Diabetes Mellitus Patients: A Cross-Sectional Study at Dormaa Presbyterian Hospital, Ghana

Background and Objectives: Dyslipidaemia and its associated complications have been reported to increase mortality among type 2 diabetes mellitus (T2DM) patients. However, there is a dearth of data on the incidence of dyslipidemia among Ghanaian patients with T2DM. This study evaluated dyslipidemia among newly diagnosed T2DM patients at Dormaa Presbyterian Hospital, Ghana. Materials and Methods: This cross-sectional study recruited a total of 215 participants at the Presbyterian Hospital, Dormaa-Ghana. A well-structured questionnaire was administered to collect demographic data. Predisposing factors of dyslipidemia such as BMI, hypertension, and family history of diabetes were also obtained. Lipid profile was performed on the serum obtained from each respondent. Dyslipidaemia was defined as total cholesterol (TC) >200 mg/dL, triglyceride (TG) >150 mg/dL, low density lipoprotein cholesterol (LDL-c) >100 mg/dL, and high-density lipoprotein cholesterol (HDL-c) <40 in males and <50 mg/dL in females. Combinations of the individual parameters of dyslipidaemia were further evaluated. Results: Of the total (215) participants, 86 (40%) were males and 129 (60%) were females, representing a ratio of 1:1.5. High total cholesterol was more prevalent in females (69.0%) than males (53.5%). Generally, dyslipidaemia was predominant among those aged >40 years, with the exception of increased LDL-c (25.1%), which was higher among the 20–40 years age group. The male participants exhibited significantly (p < 0.001) higher percentages of all combined measures of dyslipidaemia—such as high TG and reduced HDL-c (77.9%), high TG and elevated LDL-c (75.6%) and high LDL and low HDL (65.1%). BMI was significantly associated with HDL levels (p = 0.02), whereas family history of diabetes was associated with TC (p = 0.004) and TG levels (p = 0.019). Conclusion: Combined dyslipidaemia is relatively high among newly diagnosed T2DM patients in Ghana, and in those >40 years. Gender is significantly associated with combined dyslipidaemia in T2DM, and males may be at a higher risk than females. BMI and family history of diabetes are potential risk factors of dyslipidaemia in T2DM.

Quantitative Prediction of Human Pharmacokinetics and Pharmacodynamics of CKD519, a Potent Inhibitor of Cholesteryl Ester Transfer Protein (CETP).

CKD519, a selective inhibitor of cholesteryl ester transfer protein(CETP), is undergoing development as an oral agent for the treatment of primary hypercholesterolemia and mixed hyperlipidemia. The aim of this study was to predict the appropriate efficacious dose of CKD519 for humans in terms of the inhibition of CETP activity by developing a CKD519 pharmacokinetic/pharmacodynamic (PK/PD) model based on data from preclinical studies. CKD519 was intravenously and orally administered to hamsters, rats, and monkeys for PK assessment. Animal PK models of all dose levels in each species were developed using mixed effect modeling analysis for exploration, and an interspecies model where allometric scaling was applied was developed based on the integrated animal PK data to predict the human PK profile. PD parameters and profile were predicted using in vitro potency and same-in-class drug information. The two-compartment first-order elimination model with Weibull-type absorption and bioavailability following the sigmoid Emax model was selected as the final PK model. The PK/PD model was developed by linking the interspecies PK model with the Emax model of the same-in-class drug. The predicted PK/PD profile and parameters were used to simulate the human PK/PD profiles for different dose levels, and based on the simulation result, the appropriate efficacious dose was estimated as 25 mg in a 60 kg human. However, there were some discrepancies between the predicted and observed human PK/PD profiles compared to the phase I clinical data. The huge difference between the observed and predicted bioavailability suggests that there is a hurdle in predicting the absorption parameter only from animal PK data.

Familial combined hyperlipidemia: An overview of the underlying molecular mechanisms and therapeutic strategies.

Among different types of dyslipidemia, familial combined hyperlipidemia (FCHL) is the most common genetic disorder, which is characterized by at least two different forms of lipid abnormalities: hypercholesterolemia and hypertriglyceridemia. FCHL is an important cause of cardiovascular diseases. FCHL is a heterogeneous condition linked with some metabolic defects that are closely associated with FCHL. These metabolic features include dysfunctional adipose tissue, delayed clearance of triglyceride-rich lipoproteins, overproduction of very low-density lipoprotein and hepatic lipids, and defect in the clearance of low-density lipoprotein particles. There are also some genes associated with FCHL such as those affecting the metabolism and clearance of plasma lipoprotein particles. Due to the high prevalence of FCHL especially in cardiovascular patients, targeted treatment is ideal but this necessitates identification of the genetic background of patients. This review describes the metabolic pathways and associated genes that are implicated in FCHL pathogenesis. We also review existing and novel treatment options for FCHL. © 2019 IUBMB Life, 71(9):1221-1229, 2019.

IMPAIRED MICROVASCULAR REACTIVITY IN NON-DIABETIC PRIMARY HYPERTENSION IS INVERSELY RELATED TO LOW HDL CHOLESTEROL AND REDUCED GLUCOSE TOLERANCE

Objective: Type 2 diabetes and the metabolic syndrome is characterized by dyslipidaemia with low HDL-cholesterol and skin microvascular dysfunction. The associations of glucose and lipid abnormalities with microvascular dysfunction in hypertension are not well studied. Design and method: We studied untreated hypertensive patients (n = 71, 55 ± 13 years, 34% women) with no overt cardiovascular disease, dyslipidaemia, or diabetes. Arterial endothelial function was studied by forearm post-ischemic flow mediated vasodilatation (FMD), and glyceryl trinitrate (GTN) for nonspecific dilation; and in smaller resistance arteries by change in reflection index (RI) by pulse wave analysis and terbutaline. Skin microvascular reactivity was assessed by laser Doppler fluxmetry and local iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP), and by maximum reactive hyperaemia by heating. Triglyceride glucose index (TyG), defined as: Ln [fasting plasma glucose x plasma triglycerides], was used as a measure of glucose tolerance. Results: Mean BP was 154/93 mmHg, fasting LDL, HDL, triglycerides and glucose 3.48 ± 0.92, 1.40 ± 0.40, 1.16 ± 0.86 and 5.40 ± 0.55 mmol/L, respectively; and TyG 6.74 ± 0.59. The FMD (mean 5.8 ± 4.3%)-to-GTN (mean 14.7 ± 6.9%) ratio related to HDL (r = 0.30, P = 0.018). The RI change (mean 7.0 ± 3.0%) related inversely to HDL (r = −0.42, P < 0.001). Ach peak flux increase (mean 483 ± 380%) related to HDL (r = 0.28, P = 0.021), whereas SNP (679 ± 395%) and heat mediated (906 ± 491%) peak flux increase did not. Changes in cutaneous vascular conductance (CVC) by Ach related to HDL (r = 0.27, P = 0.025). Changes in CVC by local heating related to the LDL-to-HDL ratio (r = −0.30, P = 0.018). Changes in, FMD, GTN, and RI change did not relate to TyG. However, in skin microcirculation, peak flux increase and the change in CVC to Ach tended to relate inversely to TyG (r = −0.22, P = 0.069 and r = −0.22, P = 0.071), while responses to SNP and heat did not. LDL showed no relations to the vascular function indices studied. Conclusions: In contrast to arterial endothelial function, impaired microvascular reactivity relates inversely to low HDL-cholesterol and reduced glucose tolerance in patients with uncomplicated hypertension. These findings, in consort with observations in type 2 diabetes and in familial combined hyperlipidaemia, suggest that impaired microvascular function is an early finding in dyslipidaemia and with impaired glucose tolerance.

Extracellular lipid loading augments hypoxic paracrine signaling and promotes glioma angiogenesis and macrophage infiltration

BackgroundPrimary brain tumors, in particular glioblastoma (GBM), remain among the most challenging cancers. Like most malignant tumors, GBM is characterized by hypoxic stress that triggers paracrine, adaptive responses, such as angiogenesis and macrophage recruitment, rescuing cancer cells from metabolic catastrophe and conventional oncological treatments. The unmet need of strategies to efficiently target tumor “stressness” represents a strong clinical motivation to better understand the underlying mechanisms of stress adaptation. Here, we have investigated how lipid loading may be involved in the paracrine crosstalk between cancer cells and the stromal compartment of the hypoxic tumor microenvironment.MethodsRegions from patient GBM tumors with or without the lipid loaded phenotype were isolated by laser capture microdissection and subjected to comparative gene expression analysis in parallel with cultured GBM cells with or without lipid loading. The potential involvement of extracellular lipids in the paracrine crosstalk with stromal cells was studied by immunoprofiling of the secretome and functional studies in vitro as well as in various orthotopic GBM mouse models, including hyperlipidemic ApoE−/− mice. Statistical analyses of quantitative experimental methodologies were performed using unpaired Student’s T test. For survival analyses of mouse experiments, log-rank test was used, whereas Kaplan-Meier was performed to analyze patient survival.ResultsWe show that the lipid loaded niche of GBM patient tumors exhibits an amplified hypoxic response and that the acquisition of extracellular lipids by GBM cells can reinforce paracrine activation of stromal cells and immune cells. At the functional level, we show that lipid loading augments the secretion of e.g. VEGF and HGF, and may potentiate the cross-activation of endothelial cells and macrophages. In line with these data, in vivo studies suggest that combined local tumor lipid loading and systemic hyperlipidemia of ApoE−/− mice receiving a high fat diet induces tumor vascularization and macrophage recruitment, and was shown to significantly decrease animal survival.ConclusionsTogether, these data identify extracellular lipid loading as a potentially targetable modulator of the paracrine adaptive response in the hypoxic tumor niche and suggest the contribution of the distinct lipid loaded phenotype in shaping the glioma microenvironment.

An updated review of lipid-modifying therapy.

Statin drugs reduce low-density lipoprotein (LDL)-cholesterol (LDL-C) and cardiovascular risk. Ezetimibe may be used to supplement statin therapy, or used alone in cases of statin intolerance. Statin-associated side effects do occur, especially muscle symptoms and new onset diabetes, but they do not detract from the benefits of statin therapy. Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce LDL-C and cardiovascular risk. Evolocumab is subsidised in Australia for patients with familial hypercholesterolaemia when LDL-C is not adequately controlled with maximum doses of statin or ezetimibe or when statin therapy is contraindicated. Fenofibrate reduces triglycerides and cardiovascular risk in patients with type 2 diabetes when triglycerides are elevated and high-density lipoprotein (HDL) is low. A role for dietary omega-3 fatty acids and esters in reducing cardiovascular risk remains controversial. All cases of secondary cardiovascular disease prevention merit intensive lipid therapy, unless a contraindication exists. Lipid therapy is justified in cases of primary prevention when absolute risk is high, especially when lipids are highly elevated or when multiple risk factors are present. Clinical management requires a focus on the predominant lipid disorder present, namely hypercholesterolaemia, hypertriglyceridaemia or combined hyperlipidaemia. There is an ongoing problem of poor long term persistence on lipid therapy, as well as reduced awareness by practitioners of poor risk factor control.

Adverse effects of statin therapy: real evidence

Aim. To provide a current view on the tolerability and safety of statin therapy. Materials and methods. The data of 73 scientific sources from Russian and foreign literature published within 1996-2018 are considered. Results. It is generally accepted that statins are first-line therapeutic agents for hypercholesterolemia and combined hyperlipidemia. Today there in growing evidence that lowering of low-density lipoprotein cholesterol levels prevents atherosclerotic diseases and reduces a risk of cardiovascular and overall mortality. Main issues of current statin therapy include a use of inadequate dosage for atherosclerotic diseases prevention, low treatment compliance and drug intolerance. In recent years the issue of statin intolerance has become of great importance. Criteria were proposed for determining an inability to tolerate statins, some experts suggest replacing definition of “statin intolerance” with the term “statin-associated side-effects”. Most discussed adverse effects due to statins include muscle-related symptoms (myalgia/myopathy), hepatotoxicity (hepatic hyperenzymemia) new-onset diabetes, dementia and cognitive impairment. Mechanisms of development of these adverse effects are still unclear. Certain factors and conditions capable of triggering some adverse effects as well as absolute contraindications to statin therapy were established. Some factors and conditions capable of triggering some adverse effects as well as absolute contraindications to statin therapy were identified. Occurrence of statin-associated side-effects depends on statin dose, a patient's age, gender, comorbidity and concomitant therapy. Many adverse effects of statins are drug class effect. At the same time each of statins has specific features of its structure, metabolism, drug interactions and pharmacokinetics. Pitavastatin belongs to the last generation of statins and it has distinct pharmacological features and neutral diabetogenic effects, etc. Risk of adverse effects due to statins is often exaggerated while benefit from the use of statins for preventing atherosclerotic diseases outweighs potential risks. Real occurrence of some adverse effects due to statin therapy requires additional evidence. Conclusion. Overall, statins have a good tolerability profile and are approved for use in the vast majority of patients who required lipid-lowering therapy.

Prevalence of heterozygous familial hypercholesterolemia and combined hyperlipidemia phenotype in very young survivors of myocardial infarction and their association with the severity of atheromatous burden

Heterozygous familial hypercholesterolemia (HeFH) and combined hyperlipidemia (CHL) phenotype are associated with premature myocardial infarction (MI). To assess the prevalence of HeFH and CHL phenotype among young survivors of MI and compare patients' characteristics with these 2 lipid disorders. We recruited 382 young survivors of MI (≤40years). Fasting lipids, lipoprotein(a) [Lp(a)], apolipoprotein A-1, and apolipoprotein B (apoB) levels were determined. Using the Dutch Lipid Clinic Network (DLCN) algorithm, patients having definite or probable HeFH were identified. Patients with apoB levels >120mg/dL and triglyceride levels >170mg/dL (1.92mmol/L) [>90th percentile of 326 age and sex-matched healthy controls] were classified as having CHL phenotype. Common carotid artery intima-media thickness (CCA-IMT) was measured by B-mode ultrasonography. Eighty-one patients (21.2%) had definite/probable HeFH and 62 (16.2%) had CHL phenotype. Twenty-three patients fulfilled the criteria for both HeFH and CHL phenotype and were removed from further comparisons. Patients with HeFH (n=58) had higher levels of total cholesterol, low-density lipoprotein (LDL)-cholesterol, Lp(a), and apoB, whereas patients with CHL phenotype (n=39) had higher levels of triglycerides and lower high-density lipoprotein (HDL)-cholesterol levels. The prevalence of metabolic syndrome was higher in patients with CHL phenotype compared to those with HeFH (67.0% vs 16.4%, P<.001). Patients with HeFH had more extensive coronary artery disease (3-vessel disease: 36.2% vs 12.8%, P=.011) and greater right CCA-IMT (0.67±0.11mm vs 0.56±0.09mm, P<.001) and left CCA-IMT (0.68±0.10mm vs 0.56±0.08mm, P<.001) compared to CHL phenotype patients. Both HeFH and CHL phenotype are common among patients with premature MI. CHL phenotype compared to HeFH is associated with less atheromatous burden in coronary and carotid arteries at the time of first MI.

Treatment of a high cardiovascular risk patient with McArdle's disease with PCSK9 inhibitors

A 60-year-old male with familial combined hyperlipidemia, ischaemic heart disease and type 2 diabetes. Since childhood, intolerance to intense exercise. The patient was diagnosed of McArdle's disease after an episode of rhabdomyolysis associated with statins as treatment after a myocardial infarction. Since then, he had been treated with diet, fibrates and ezetimibe with good tolerance, despite this, LDL cholesterol (cLDL) remained >180mg/dl. He started to be treated with alirocumab 150mg/sc every 14 days, with excellent clinical response and a decrease in cLDL to 15mg/dl. Our case shows that PCSK9 inhibitors are effective and safe in patients with muscle diseases who have statin contraindication, and they are a good therapeutic tool for these patients.

Association of serum calprotectin (S100A8/A9) concentrations and idiopathic hyperlipidemia in Miniature Schnauzers.

BackgroundIdiopathic hyperlipidemia (IH) is a common condition in Miniature Schnauzers (MS). Studies in people have linked IH to low‐grade inflammation, which plays an important role in the pathogenesis of IH complications. The role of inflammation in MS with IH is unknown.ObjectiveEvaluation of the inflammatory markers serum calprotectin and S100A12 in MS with IH and in response to dietary intervention for IH management.AnimalsOne‐hundred fifty clinically healthy MS.MethodsSerum triglyceride, cholesterol, calprotectin, and S100A12 concentrations were measured before and after placing the dogs on an ultra‐low fat diet.ResultsHypertriglyceridemia (HTGL, P < .001) and hypercholesterolemia (HCHOL, P = .01) were independently associated with increased serum calprotectin but not S100A12 concentrations. Compared to normolipidemic MS, serum calprotectin concentrations were significantly higher in MS with HTGL (P < .001) or combined hyperlipidemia (P = .02), but not those with isolated HCHOL (P = 1.0000). Presence (P = .005) and severity (P = .003) of HTGL and serum cholesterol concentrations (P = .04) decreased in MS with IH within 14‐26 weeks after being placed on the ultra‐low fat diet, but neither serum calprotectin nor S100A12 concentrations changed significantly with this dietary intervention.Conclusions and clinical importanceSubclinical (low‐grade) inflammation appears to be present in some MS with IH, and an ultra‐low fat diet does not decrease serum concentrations of inflammatory proteins in those dogs. Whether this presumed inflammatory phenotype in MS with IH is associated with the development of IH complications (eg, insulin resistance) requires further research.

Hypoglycemic and Hypolipemic Effects of a New Lecithin Formulation of Bergamot Polyphenolic Fraction: A Double Blind, Randomized, Placebo- Controlled Study.

Hyperlipemia represents an independent risk factor in the development of atherosclerosis in patients undergoing type 2 diabetes mellitus (DM). Moreover, the pharmacological treatment of dyslipemia in patients undergoing type 2 DM (e.g. by means of statins), is accompanied by relevant side effects and oral supplementation with natural antioxidants, such as Citrus polyphenols, has recently been suggested to improve cardioprotection in such patients. However, due to the poor gastrointestinal absorption of polyphenols, novel formulations have recently been developed for getting a better bioavailability of polyphenolic rich fractions of citrus species extract rich in polyphenols. Here, we investigated the effect of standard bergamot polyphenolic fraction (BPF®) as well as of its phytosomal formulation (BPF Phyto), in patients with type 2 DM and hyperlipemia. A randomized, double blind, placebo-controlled study was carried out in 60 patients suffering from type 2 DM and mixed hyperlipemia. Patients were divided into three groups: one receiving placebo, the second receiving standard BPF and the third BPF Phyto. In the groups receiving BPF and BPF Phyto, a significant reduction of fasting plasma glucose, serum LDL cholesterol and triglycerides accompanied by increased HDL cholesterol was observed. This effect was associated with significant reduction of small dense atherogenic LDL particles, as detected by means of proton NMR Spectroscopy, thus confirming the hypolipemic and hypoglycemic effect of bergamot extract both when using standard formulation as well as BPF Phyto. No differences were seen in the therapeutic response among groups receiving BPF and BPF Phyto, thus suggesting a substantial bioequivalence in their hypoglycemic and hypolipemic profile. However, when comparing the pharmacokinetic profile of naringin (the major component of BPF) and its metabolites, in patients treated with BPF Phyto, an at least 2,5 fold increase in its absorption was found, confirming in human studies the better profile of BPF Phyto compared to standard BPF. These data suggest that better absorption and tissue distribution of BPF Phyto formulation represents an innovative approach in supplementation treatments of cardiometabolic disorders.

Tratamiento de un varón con enfermedad de McArdle y muy alto riesgo cardiovascular con inhibidores de PCSK9

A 60-year-old male with familial combined hyperlipidemia, ischemic heart disease and type 2 diabetes. Since childhood, intolerance to intense exercise. The patient was diagnosed of McArdle's disease after an episode of rhabdomyolysis associated with statins as treatment after a myocardial infarction. Since then, he had been treated with diet, fibrates and ezetimibe with good tolerance, despite this, LDL cholesterol (cLDL) remained >180mg/dl. He started to be treated with alirocumab 150mg/sc every 14 days, with excellent clinical response and a decrease in cLDL to 15mg/dl. Our case shows that PCSK9 inhibitors are effective and safe in patients with muscle diseases who have statin contraindication, and they are a good therapeutic tool for these patients

Type III Hyperlipoproteinemia: The Forgotten, Disregarded, Neglected, Overlooked, Ignored but Highly Atherogenic, and Highly Treatable Dyslipoproteinemia

Cardiovascular risk is so high in type III hyperlipoproteinemia that type III, just like heterozygous familial hypercholesterolemia (FH)2, is a treat-on-diagnosis disorder (1–3). Tragically, although severe hypercholesterolemia is easy to recognize, type III hyperlipoproteinemia cannot be diagnosed using a conventional lipid panel (4) and the original diagnostic tools—electrophoresis and ultracentrifugation—are available in only a miniscule number of clinics (1). Thus, type III cannot be diagnosed in regular clinical care using regular diagnostic tools. Moreover, while the importance of FH is recognized by all the major lipid guidelines, even the existence of type III hyperlipoproteinemia is barely acknowledged, if at all, by the same groups. Consequently, those patients with type III are lumped and dumped with all the others with mixed hyperlipidemia and the result, tragically, can be no treatment when treatment is indicated. In a wonderful paper (3), Paul Hopkins and his colleagues referred to type III hyperlipoproteinemia as the “forgotten phenotype.” Nothing has changed and so the extended title of this editorial. In this issue of Clinical Chemistry , Boot et al. (5) present the advantages of the non-HDL cholesterol (non-HDL-C)/apoB ratio as a diagnostic tool for type III hyperlipoproteinemia. I congratulate them on their work, notwithstanding that their results and conclusions, using their approach, differ at the margins from our results and conclusions using our approach (4). On reflection, it may be that we were too rigid in one direction, while they may be too rigid in another. Nevertheless, what is most important is that the work is powerfully confirmatory of that of David Marais and his colleagues from South Africa, who diagnosed type III based on the total cholesterol (TC)/apoB ratio (6). I met Dr. Marais only once, and then only briefly, but his multiple contributions to the understanding of this disorder, while …