Combined Hyperlipidemia Research Articles

Longitudinal study of the impact of lipid lowering therapy on carotid atherosclerosis

s / Atherosclerosis 231 (2013) e1–e10 e5 Reassuringly, 72% knew that FH should be considered in adults with a total cholesterol >7.5mmol/l, but just 56% were aware of or had used the Simon Broome criteria. Further, while 61% were aware of the NICE guidelines, just 12% had actually used them. Disappointingly, while 32% had detected FH in a first-degree relative of a patient already diagnosed with FH, 31% were not aware of the indications for cascade testing, Similar numbers believed the diagnosis requires genetic testing. This reflects the finding that only 50% knew the prevalence of FH in the United Kingdom and 54% the pattern of inheritance. 78% underestimated the relative risk of premature death associated with FH. Worryingly, just 8% thought their region managed FH well. 69% believed that better access to specialist lipid clinics would improve care and 74% felt more education would improve the identification and management of FH. These recommendations are in keeping with the results of this survey. We are investigating the effect of targeted education locally. LONGITUDINAL STUDY OF THE IMPACT OF LIPID LOWERING THERAPY ON CAROTID ATHEROSCLEROSIS M. Seed , D. Bond , M. Griffin , A. Nicolaides . 1 Imperial College NHS Trust, London, UK; Vascular U/S Diagnostic Centre, London, UK NICE guidelines for primary prevention of CVD include reduction of LDL-C to 2 mmol/l in high risk patients and by 50% in patients with FH. We wished to see whether such levels might be achieved in a lipid clinic setting, and if so what effect this had on carotid plaque thickness and type. Subjects: 31patients,10with definite FH (mean age 42), the remainder with mixed hyperlipidaemia (MHL), mean age 54, were treated, and followed up with serial carotid ultrasound examinations over a 2-9 year period. No FH patients were hypertensive or diabetic. 10 with MHL had hypertension and 3 type 2 diabetes; 6 were ex-smokers. Methods: B mode ultrasonic assessments of plaque thickness and type were performed in all patients initially and at follow-up (mean 4 years (all); mean 6 years, n1⁄417). Measurements were taken by a single “blinded” operator. Results FH (n1⁄410) MHL (n1⁄421)

Joint Linkage and Association Analysis with Exome Sequence Data Implicates SLC25A40 in Hypertriglyceridemia

Hypertriglyceridemia (HTG) is a heritable risk factor for cardiovascular disease. Investigating the genetics of HTG may identify new drug targets. There are ~35 known single-nucleotide variants (SNVs) that explain only ~10% of variation in triglyceride (TG) level. Because of the genetic heterogeneity of HTG, a family study design is optimal for identification of rare genetic variants with large effect size because the same mutation can be observed in many relatives and cosegregation with TG can be tested. We considered HTG in a five-generation family of European American descent (n = 121), ascertained for familial combined hyperlipidemia. By using Bayesian Markov chain Monte Carlo joint oligogenic linkage and association analysis, we detected linkage to chromosomes 7 and 17. Whole-exome sequence data revealed shared, highly conserved, private missense SNVs in both SLC25A40 on chr7 and PLD2 on chr17. Jointly, these SNVs explained 49% of the genetic variance in TG; however, only the SLC25A40 SNV was significantly associated with TG (p = 0.0001). This SNV, c.374A>G, causes a highly disruptive p.Tyr125Cys substitution just outside the second helical transmembrane region of the SLC25A40 inner mitochondrial membrane transport protein. Whole-gene testing in subjects from the Exome Sequencing Project confirmed the association between TG and SLC25A40 rare, highly conserved, coding variants (p = 0.03). These results suggest a previously undescribed pathway for HTG and illustrate the power of large pedigrees in the search for rare, causal variants.

PS13 - 4. Gender differences in glucose-dependent leukocyte activation in patients with type 2 diabetes mellitus, familial combined hyperlipidemia and healthy controls

Atherosclerosis in type 2 diabetes mellitus (T2DM) and insulin resistance (IR) is characterized by a chronic inflammatory response in which activation of leukocytes is mandatory. Acute and chronic hyperglycemia may be involved in this leukocyte activation. Female T2DM patients have more severe atherosclerosis than male diabetics and differences in inflammation may be responsible for this observation.

Protocolo terapéutico de las dislipidemias

The reduction in LDL cholesterol (c-LDL) is one of the main objectives in cardiovascular prevention. Multiple clinical studies have demonstrated the benefit of lowering c-LDL. Clinical management of dyslipidemias should be performed in three steps. First, we should know the subject's cardiovascular risk, then establish set goals for c-LDL, or for non c-HDL if triglycerides > 200mg/dl, and finally, schedule an therapeutic strategy which should always include changes in lifestyle, and in many cases the administration of lipid-lowering drugs. Statins alone or in combination with ezetimibe or resins if isolated hypercolesterolesterolemia, or with fenofibrate or n-3 fatty acids in case of mixed hyperlipidemia, are the mainstays of drug treatment.

Inherited lipemic splenomegaly and the spectrum of apolipoprotein E p.Leu167del mutation phenotypic variation

We review disorders associated with splenomegaly and dyslipidemia with an emphasis on the APOE p.Leu167del mutation. Recent studies suggest that this rare mutation may present more often without splenomegaly in patients with familial combined hyperlipidemia or autosomal dominant hypercholesterolemia. We supplement the literature review by reporting a new kindred. We reviewed our 3405-patient lipid clinic database to identify persons with dyslipidemia and splenomegaly. Identified patients were evaluated for relevant disorders, including genetic testing for a 3-base pair deletion in APOE that causes deletion of leucine at position 167 of apolipoprotein E. We identified 4 patients with splenomegaly and dyslipidemia, one of whom had a heterozygous APOE p.Leu167del mutation. This proband is a 76-year-old man with a history of splenomegaly first noted at age 13 and subsequent diagnosis of hypertriglyceridemia, low high-density lipoprotein cholesterol, leukopenia, and thrombocytopenia in his third decade. He never required splenectomy, and his splenic enlargement regressed over time with medical management of his hypertriglyceridemia. The APOE p.Leu167del mutation was also found in the proband's son and granddaughter, neither of whom has splenomegaly or marked dyslipidemia. Splenomegaly in association with dyslipidemia may indicate the presence of an underlying disorder. We discuss possible causes, review the literature relating to the rare APOE p.Leu167del mutation, and present a 3-generation kindred with variable phenotypic expression of this mutation. Severity of expression may depend on genotype, sex, or effective medical management of dyslipidemia or a combination of these factors. Aggressive lipid treatment may improve or prevent splenomegaly among patients with this disorder.

Bergamot polyphenolic fraction enhances rosuvastatin-induced effect on LDL-cholesterol, LOX-1 expression and protein kinase B phosphorylation in patients with hyperlipidemia

BackgroundStatins are the most commonly prescribed drugs to reduce cardiometabolic risk. Besides the well-known efficacy of such compounds in both preventing and treating cardiometabolic disorders, some patients experience statin-induced side effects. We hypothesize that the use of natural bergamot-derived polyphenols may allow patients undergoing statin treatment to reduce effective doses while achieving target lipid values. The aim of the present study is to investigate the occurrence of an enhanced effect of bergamot-derived polyphenolic fraction (BPF) on rosuvastatin-induced hypolipidemic and vasoprotective response in patients with mixed hyperlipidemia. MethodsA prospective, open-label, parallel group, placebo-controlled study on 77 patients with elevated serum LDL-C and triglycerides was designed. Patients were randomly assigned to a control group receiving placebo (n=15), two groups receiving orally administered rosuvastatin (10 and 20mg/daily for 30days; n=16 for each group), a group receiving BPF alone orally (1000mg/daily for 30days; n=15) and a group receiving BPF (1000mg/daily given orally) plus rosuvastatin (10mg/daily for 30days; n=15). ResultsBoth doses of rosuvastatin and BPF reduced total cholesterol, LDL-C, the LDL-C/HDL-C ratio and urinary mevalonate in hyperlipidemic patients, compared to control group. The cholesterol lowering effect was accompanied by reductions of malondialdehyde, oxyLDL receptor LOX-1 and phosphoPKB, which are all biomarkers of oxidative vascular damage, in peripheral polymorphonuclear cells. ConclusionsAddition of BPF to rosuvastatin significantly enhanced rosuvastatin-induced effect on serum lipemic profile compared to rosuvastatin alone. This lipid-lowering effect was associated with significant reductions of biomarkers used for detecting oxidative vascular damage, suggesting a multi-action enhanced potential for BPF in patients on statin therapy.

New Therapies Targeting apoB Metabolism for High-Risk Patients with Inherited Dyslipidaemias: What Can the Clinician Expect?

Apolipoprotein B (apoB) has a key role in the assembly and secretion of very low-density lipoprotein (VLDL) from the liver. Plasma apoB concentration affects the number of circulating atherogenic particles, and serves as an independent predictor of the risk of atherosclerotic cardiovascular disease. While statins are the most potent apoB-lowering agents currently prescribed, their efficacy in achieving therapeutic targets for low-density lipoprotein cholesterol (LDL-C) in high-risk patients, such as those with familial hypercholesterolaemia (FH), is limited. Resistance and intolerance to statins also occurs in a significant number of patients, necessitating new types of lipid-lowering therapies. Monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9; AMG 145 and REGN727), a sequence-specific antisense oligonucleotide against apoB mRNA (mipomersen) and a synthetic inhibitor of microsomal triglyceride transfer protein (MTTP; lomitapide) have been tested in phase III clinical trials, particularly in patients with FH. The trials demonstrated the efficacy of these agents in lowering apoB, LDL-C, non-high-density lipoprotein cholesterol and lipoprotein(a) by 32-55%, 37-66%, 38-61% and 22-50% (AMG 145), 21-68%, 29-72%, 16-60% and 8-36% (REGN727), 16-71%, 15-71%, 12-66% and 23-49% (mipomersen) and 24-55%, 25-51%, 27-50% and 15-19% (lomitapide), respectively. Monoclonal antibodies against PCSK9 have an excellent safety profile and may be indicated not only in heterozygous FH, but also in statin-intolerant patients and those with other inherited dyslipidemias, such as familial combined hyperlipidaemia and familial elevation in Lp(a). Mipomersen and lomitapide increase hepatic fat content and are at present indicated for treating adult patients with homozygous FH alone.

In vivo actions of peroxisome proliferator-activated receptors: glycemic control, insulin sensitivity, and insulin secretion.

Peroxisome proliferator–activated receptors (PPARs) form a family of nuclear hormone receptors involved in energy hemostasis and lipid metabolism (1,2) and include three isotypes encoded by different genes: PPARα (chromosome 22q12–13.1), PPARβ/δ (chromosome 6p21.2–21.1), and PPARγ (chromosome 3p25). PPARα was the first discovered and causes cellular peroxisome proliferation in rodent livers (3), giving this receptor family its name. Upon activation, PPARs interact with retinoid X receptor to create heterodimers, which bind to a specific DNA sequence motif termed peroxisome proliferator response element (4). Peroxisome proliferator response element usually appears in promoter regions and is constructed from repeats of nucleotide sequence AGGTCA separated by a single nucleotide. PPARα is widely expressed in tissues with high fatty acid catabolic activity: brown fat, heart, liver, kidney, and intestine (5). Upon activation by endogenous fatty acids and their derivatives, PPARα mediates fatty acid catabolism, gluconeogenesis, and ketone body synthesis, mainly in liver (6–9). In rodents, PPARα activation also influences immune modulation (10,11) and amino acid metabolism (12), reduces plasma triglyceride, reduces muscle and liver steatosis, and ameliorates insulin resistance (IR) (13,14). Pharmacologic PPARα activation is achieved by fibrates (7) and results in reduced (30–50%) triglyceride and VLDL levels by increasing lipid uptake, lipoprotein lipase–mediated lipolysis, and β-oxidation (15). This is accompanied by a modest increase in HDL cholesterol (5–20%), secondary to transcriptional induction of apolipoprotein A-I/A-II synthesis in liver (15). In man, the primary effect of PPARα is to reduce plasma triglyceride concentration; effects on plasma free fatty acid (FFA) concentration/FFA oxidation, muscle/liver fat content, and muscle/hepatic insulin sensitivity have not been demonstrated with current PPARα agonists such as fenofibrate (16,17). Fibrates are used to treat severe hypertriglyceridemia and combined hyperlipidemia (18–20). Clinical trials to establish a role for PPARα agonists (fenofibrate, gemfibrozil) …

The Need for Combination Drug Therapies in Patients with Complex Dyslipidemia

Statins are first line therapy for the prevention of cardiovascular disease (CVD). Only 30 %-70 % of high risk patients will attain standard low-density lipoprotein cholesterol targets. Patients with familial hypercholesterolemia and genetic mixed hyperlipidemias do not meet goals with standard therapy. Patients with mixed hyperlipidemia secondary to the metabolic syndrome, diabetes, renal, or HIV infection are at high residual risk due to low HDL-cholesterol or high triglycerides. Newer therapies can be added to statins. The use of ezetimibe has CVD outcomes evidence in chronic renal disease. Adding omega-3 fatty acids, fibrates, or niacin to statins has failed to show any benefit except possibly with fibrates in patients with diabetes and low HDL-C/high triglycerides. Additional benefits on lipid profiles have been shown with pro-protein convertase subtilisin/kexin-9 (PCSK9), mipomersen, lomitapide, and cholesterol ester transfer protein inhibitors (CETPIs). Two CETPIs have failed to show benefit in hard outcomes trials but others remain under investigation. It remains unclear whether additional therapies add to statins for the prevention of CVD in most patients. They may have some added benefit in patients with complex dyslipidemias.

Emerging role of lymphatic vessels in reverse cholesterol transport

As a major constituent of cell membrane, cholesterol is essential for cellular homeostasis through the control of membrane fluidity and permeability. Abnormal levels of cholesterol can have important cellular consequences and may lead to diseases such as atherosclerosis and type II diabetes. Therefore, cells have developed complex mechanisms to regulate the abundance of intracellular cholesterol. Among these mechanisms, the process referred to as reverse cholesterol transport (RCT) has been shown to be critical for the removal of excess cholesterol from peripheral tissues and its transport to the liver via plasma for excretion [1]. RCT is initiated when cells including macrophages efflux out the excess of cholesterol to prevent intracellular over-accumulation. This step is tightly regulated through the action of ATP-binding cassette transporters ABCA1, ABCG1 and scavenger receptor class BI (SR-BI) and high density lipoprotein (HDL) which serves as the major acceptor for cellular cholesterol released in extrahepatic tissues [2]. Following cholesterol efflux, HDL-cholesterol is transported from the tissue back into the blood circulation. In the final step of RCT, the majority of HDL-derived cholesterol is removed from the liver by secretion into the bile [1, 2]. In contrast to the knowledge on the mechanisms by which cholesterol is effluxed out of the cells and its fate after reaching the liver, little information is available on how HDL-cholesterol travels from the peripheral tissues back to the blood circulation. Since one of the major roles of lymphatic vessels is to drain macromolecules from the interstitial space back to the circulation and lymph is rich in cholesterol and HDL [3], the implication of lymphatics in the transport of lipoproteins from interstitium to blood has been suspected. The recent studies by Martel et al., and Lim et al., now provide convincing evidence for a role of lymphatic vessels in RCT [4, 5]. Indeed, impairment of lymphatic drainage induced by surgical excision in wild-type mice [4, 5] or naturally occurring in mice lacking the expression of one allele of vascular endothelial growth factor-C receptor [4] significantly decreased the efficiency of RCT. Furthermore, Lim et al., showed that the transport of effluxed cholesterol from peripheral tissue to the blood circulation via lymphatics is not passive as anticipated but an active process dependent on HDL and SR-BI [5]. Therefore, these new findings establish that lymphatic vessels tightly regulate RCT through the active transport of HDL-cholesterol. Accumulation of cholesterol in tissues including arteries and skin is a hallmark of atherosclerosis and xanthomas, respectively, and these features are recapitulated in mouse models lacking apoE (apoE−/−) or LDL receptor which develop hypercholesterolemia. Interestingly, we showed previously that skin lymphatic vessels in these hypercholesterolemic mice exhibit structural defects which severely compromise their function [6]. These observations suggest that the accumulation of cholesterol in arteries and skin from hyper-cholesterolemic mice may result from poor lymphatic drainage. We now provide definitive evidence that restoring lymphatic function in apoE−/− mice ameliorates the clearance of cholesterol from skin by supporting RCT [5]. In strong agreement with these findings in skin, Martel et al., showed in an elegant surgical model of aorta transplantation that impeding lymphatic vessel growth interferes with the removal of cholesterol from the transplanted aorta [4]. Altogether, these findings reveal the potential atheroprotective role of lymphatic drainage by actively contributing to RCT. The relevance of these findings in humans is supported by clinical studies reporting a possible interconnection between lymphatic function and lipid accumulation in tissues (Figure ​(Figure1).1). Patients with familial combined hyperlipidemia, a genetic dyslipidemia, which share similar clinical and biochemical features with type II diabetes mellitus, obesity and the metabolic syndrome showed decreased expression of FOXC2 and Prox-1 genes in their adipose tissue [7]. Since these two genes regulate the structure and function of lymphatic vessels these findings support the hypothesis that defective lymphatic drainage may contribute to this lipid disorder. Massive lipid deposits are evident in the edematous tissues of patients with lymphedema and poor lymphatic drainage has been associated with the formation of xanthomas in humans [8]. However, it remains to be determined whether RCT is affected in patients with lymphedema. Interestingly, the use of compression garments to resolve lymphedema ameliorate xanthomatous eruptions in patients [8]. Therefore, promoting efficient lymphatic drainage in lipid-related diseases including atherosclerosis and diabetes whose prevalence will continue to augment as a result of increase in aging population may be an attractive therapeutic intervention that deserves future investigations. Figure 1 Lymphatic vessels are important for peripheral lipid clearance. Under normocholesterolemic conditions, functional lymphatic vessels regulate cholesterol transport from extra-hepatic tissues by contributing to RCT. Hypercholesterolemic conditions results ...

The Effects of the Decaffeination of Coffee Samples on Platelet Aggregation in Hyperlipidemic Rats

The effect of coffee on cardiovascular diseases is still controversial. It is known that the process of decaffeination may influence the chemical constitution and, therefore, the biological effects of coffee. This study thus evaluated the effects of decaffeination on the levels of total phenols and chlorogenic acids in Coffea arabica L. samples, as well as the effects of ingesting both integral and decaffeinated coffee on the lipid profile and hemostatic and hematological parameters in normal and hyperlipidemic rats. Samples of integral and decaffeinated lyophilized coffee (Coffea arabica L., planted in Brazil) were used for chemical analysis (total phenols, chlorogenic acid and caffeine contents). For the bioassays, coffee beverages were prepared with non-lyophilized samples (10% w/v) and were filtered and administered to animals by gavage (7.2 mL/kg/day) over 30 days. On the 31st day after beginning the treatment with coffee beverages, hyperlipidemia was induced to the animals by administering Triton WR-1339 (300 mg/kg body weight). On day 32, blood was taken to determine the lipid profile, platelet aggregation, prothrombin time, partially activated thromboplastin time and hemogram. The contents of both phenolic compounds and chlorogenic acid in the integral coffee beverage were significantly lower than those in the decaffeinated coffee beverage. The animals treated with Triton WR-1339 presented a mixed hyperlipidemia. Although the decaffeination process caused a relative increase in total phenols and chlorogenic acids, the coffee drinks were unable to change the lipid profile or the hemostatic and hematological parameters in the studied animals.

Comparison of free serum oxylipin concentrations in hyper- vs. normolipidemic men

Oxylipins, the oxidation products of unsaturated fatty acids (FA), are potent endogenous mediators being involved in the regulation of various biological processes such as inflammation, pain and blood coagulation. Compared to oxylipins derived from arachidonic acid (AA) by cyclooxygenase action, i.e. prostanoides, only limited information is available about the endogenous levels of hydroxy-, epoxy- and dihydroxy-FA of linoleic acid (LA), AA, α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in humans. Particularly, it is unknown how metabolic disorders affect endogenous oxylipin levels in humans. Therefore, in the present study we compared the serum concentrations of 44 oxylipins in 20 normolipidemic with 20 hyperlipidemic (total cholesterol >200mg/dl; LDL-C>130mg/dl; TG>150mg/dl) men (age 29–51y). The serum concentration varied strongly among subjects. For most hydroxy-, epoxy- and dihydroxy-FA the concentrations were comparable to those in plasma reported in earlier studies. Despite the significant change in blood lipid levels the hyperlipidemic group showed only minor differences in oxylipin levels. The hyperlipidemic subjects had a slightly higher serum concentration of 8,9-DiHETrE, 5-HEPE, 10,11-DiHDPE, and a lower concentration of 12,13-DiHOME, 12-HETE, 9,10-DiHODE, and 12,13-DiHODE compared to normolipidemic subjects. Overall the hydroxy-, epoxy- and dihydroxy-FA levels were not changed suggesting that mild combined hyperlipidemia has no apparent effect on the concentration of circulating oxylipins. By contrast, serum levels of several hydroxy-, epoxy-, and dihydroxy-FA are dependent on the individual status of the parent FA. Particularly, a strong correlation between the EPA content in the erythrocyte membrane and the serum concentration of EPA derived oxylipins was observed. Given that the synthesis of EPA from other n-3 FA in humans is low; this suggests that oxylipin levels can be directly influenced by the diet.

Abstract 336: Overrepresentation of Familial Hypercholesterolemia-causing Mutations in Patients with Familial Combined Hyperlipidemia

Background_ Elevated plasma low-density lipoprotein (LDL) cholesterol is a feature of both familial hypercholesterolemia (FH) and familial combined hyperlipidemia (FCH). FH is predominantly a monogenic _autosomal dominant_ condition that results from mutations in the genes coding for low density lipoprotein receptor (LDLR), apolipoprotein B-100 (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9). In contrast, the genetic basis of FCH, a very common dyslipidemia in the human population, is less well understood, but is considered to be polygenic. Investigations in other polygenic lipid disorders indicate that genetic susceptibility is comprised of both common polymorphisms and rare heterozygous mutations. Re-sequencing technologies have identified greater accumulation of missense rare variants in candidate genes of diseased cohorts relative to healthy controls, thus indicating a potential role of candidate genes in disease etiology. Objective_ Our aim was to understand the genetic etiology of FCH. We hypothesized missense rare variants in the 3 known autosomal dominant FH-causing genes and the newly characterized inducible degrader of the low density lipoprotein receptor (IDOL), would accumulate in FCH patients (n=138) (cases) relative to controls (n=94). We tested this hypothesis using Sanger sequencing of coding sequences, intron-exon boundaries and some regulatory regions of the 4 candidate genes. Results & Discussion_ For cases vs controls, the total missense rare variant carrier counts were 7/138 vs 4/94 in LDLR and 14/138 vs 9/94 in APOB. Of all these missense rare variants found in our entire cohort, we found functionally verified FH-causing variants only in our cases and not in our controls (P =0.09), namely LDLR G314S, D333V, V806I and APOB R3500W variants. These variants likely explain hypercholesterolemia in those particular FCH patients. Conclusions_ This preliminary analysis of FCH candidate gene sequences supports the idea that rare FH-causing mutations are over-represented in FCH. The findings also support future expanded case-control and family studies to identify possible monogenic causes of FCH using various next-generation sequencing technologies.

Dyslipidämie – Wann ist der Einsatz von Lipidsenkern in der Praxis sinnvoll?

Dyslipidemia is one of the main modifiable cardiovascular risk factors. There is strong evidence for the efficacy of lipid-lowering drugs in secondary prevention, as well as in primary prevention for patients at high cardiovascular risk. In primary prevention, indication for lipid-lowering interventions should be based on an individual assessment of the cardiovascular risk and on the LDL cholesterol level, despite less strong evidence for the efficacy of drug-based interventions in low risk patients. Treatment consists of statins, as well as lifestyle modifications such as body weight control and increased physical exercise. The latter constitute the primary intervention in patients at low cardiovascular risk. Secondary dyslipidemias due to an underlying medical condition and familial dyslipidemias such as Familial Hypercholesterolemia and Familial Combined Hyperlipidemia should be identified and treated accordingly, taking into account that the risk scoring systems are not appropriate in these situations.

Mitochondrial Triglyceride Transfer Protein Inhibition: New Achievements in the Treatment of Dyslipidemias

Current lipid-lowering drugs are often unable to achieve low density lipoprotein cholesterol (LDL-C) goals. Moreover, despite LDL-C lowering mostly by statins, a considerable residual vascular risk remains. This is partly associated with atherogenic dyslipidemia where apolipoprotein (apo) B-containing lipoproteins predominate. Mitochondrial Triglyceride (TG) transfer protein (MTP) is a key enzyme for apoB-containing lipoprotein assembly and secretion. This is mostly attributed to its capacity to transfer lipid components (TGs, cholesterol esters and phospholipids) to the endoplasmic reticulum lumen, where these lipoproteins are assembled. Several agents were developed to inhibit MTP wherever it is expressed, namely the liver and/or the intestine. Liver-specific MTP inhibitors reduce secretion of very low density lipoproteins (VLDL) mostly containing apoB100, while the intestine-specific ones reduce secretion of chylomicrons containing apoB48. These drugs can significantly reduce total cholesterol, LDL-C, TGs, VLDL cholesterol, as well as apoB levels in vivo. They may also exert anti-atherosclerotic and insulin-sensitizing effects. Limited clinical data suggest that these compounds can also improve the serum lipid profile in patients with homozygous familial hypercholesterolemia (HoFH). The accumulation of unsecreted fat in the liver and intestinal lumen is associated with elevation of aminotransferases and steatorrhea. Liver steatosis can be avoided by the use of intestine-specific MTP inhibitors, while steatorrhea by low-fat diet. Future indications for these developing drugs may include dyslipidemia associated with insulin resistant states, familial combined hyperlipidemia and HoFH. Future clinical trials are warranted to assess the efficacy and safety of MTP inhibitors in various clinical states.

Lipid and lipoprotein responses of dyslipidemic patients to exclusive nutritional counseling by gender and age

OBJECTIVE: The aim of the present study was to evaluate the plasma lipid responses of dyslipidemic patients to nutritional counseling according to gender and age. METHODS: One-hundred and twenty nine dyslipidemic subjects comprised the study, 56 men and 73 women, aged 20 to 73 years, treated at the Dyslipidemia Outpatient Clinic of the Universidade Estadual de Campinas Clinic Hospital. The inclusion criteria established that no lipid-lowering medication had been used in the 30 days prior to and during the nutritional counseling. Blood samples were collected in the morning after a 12 hour fast. The participants were divided into groups according to gender and age (age <60 and > 60 years). The hypercholesterolemic patients were instructed to restrict saturated fats (<7%) and cholesterol (<200mg/day). Those presenting with high triglyceride levels (>300mg/dL) were asked to consume a low fat diet. Those with mixed hyperlipidemia were instructed to do both. Statistical analyses included the Wilcoxon, Mann-Whitney, Chi-square and Fisher's exact tests and Analysis of Covariance. RESULTS: After nutritional counseling, total cholesterol and triglycerides decreased by 16% and 36% in males, and by 12% and 26% in females, respectively, and Low Density Lipoprotein-cholesterol decreased by 12% in females. Only triglycerides decrease significantly. In the mixed hyperlipidemia group, the male and female triglyceride (-44% and -29%), Low Density Lipoprotein-cholesterol (+12% and -15%) and High Density Lipoprotein-cholesterol (+7% and -3%) levels differed significantly. Between the age groups, only triglyceride levels differed significantly, with adults experiencing the highest reductions (33%). CONCLUSION: Nutritional counseling effectively lowered plasma lipid and lipoprotein levels, reinforcing the benefits of dietary interventions for the treatment of dyslipidemia.

Combined Dyslipidemia: Should the Focus be LDL Cholesterol or Atherogenic Dyslipidemia?

As the population becomes more obese and the prevalence of diabetes and the metabolic syndrome increases, low-density lipoprotein-cholesterol (LDL-C) may lose its value as a sole predictor for cardiovascular risk among lipids. Combined dyslipidemia is typically characterized by elevations in LDL-C and triglyceride levels, often accompanied by decreased high-density lipoproteincholesterol (HDL-C) concentrations and increased levels of small, dense LDL. This common disorder results from overproduction of hepatically synthesized apolipoprotein B in very low-density lipoproteins. In the last few years most of the international scientific guidelines as well as several expert panels have confirmed that LDL-C represents the primary or even the only target of treatment. Yet, increasing evidence suggests moving away from a LDL-C target-based approach to a more tailored treatment approach. For example, non- HDL-C has been introduced in the last few years as a target of treatment.

Hypertriglyceridemia

Hypertriglyceridemia (HTG) is commonly encountered in lipid and cardiology clinics. Severe HTG warrants treatment because of the associated increased risk of acute pancreatitis. However, the need to treat, and the correct treatment approach for patients with mild to moderate HTG are issues for ongoing evaluation. In the past, it was felt that triglyceride does not directly contribute to development of atherosclerotic plaques. However, this view is evolving, especially for triglyceride-related fractions and variables measured in the non-fasting state. Our understanding of the etiology, genetics and classification of HTG states is also evolving. Previously, HTG was considered to be a dominant disorder associated with variation within a single gene. The old nomenclature includes the term “familial” in the names of several hyperlipoproteinemia (HLP) phenotypes that included HTG as part of their profile, including combined hyperlipidemia (HLP type 2B), dysbetalipoproteinemia (HLP type 3), simple HTG (HLP type 4) and mixed hyperlipidemia (HLP type 5). This old thinking has given way to the idea that genetic susceptibility to HTG results from cumulative effects of multiple genetic variants acting in concert. HTG most is often a “polygenic” or “multigenic” trait. However, a few rare autosomal recessive forms of severe HTG have been defined. Treatment depends on the overall clinical context, including severity of HTG, concomitant presence of other lipid disturbances, and the patient's global risk of cardiovascular disease. Therapeutic strategies include dietary counselling, lifestyle management, control of secondary factors, use of omega-3 preparations and selective use of pharmaceutical agents.

PRINCIPLES AND TREATMENT APPROACHES OF DYSLIPIDAEMIAS: A REVIEW

Dyslipidaemia is a common clinical problem globally. It includes abnormality in LDL cholesterol, HDL cholesterol and triglyceride levels. The prevalence of dyslipidaemia observed higher in males than females among urban Indian adults.(1) Hypertension and dyslipidaemia are well established risk factor for various cardiovascular diseases. There is frequent coexistence of hypertension and hypercholesterolemia.(2) This prevalence varies globally. Causes of dyslipidaemia are either primary disorders of lipoproteins or secondary to metabolic causes. In addition to metabolic syndrome, other causes of combined dyslipidaemia are lack of physical activity, hypothyroidism, diabetes mellitus etc. Clinical conditions such as metabolic syndromes, dyslipidaemia, hypertension, early atherosclerosis and type 2 diabetes results due to Overweight and obesity in childhood and adolescents. Familial hypercholesterolemia is predominant during childhood with elevated Low Density Lipoprotein cholesterol (LDL-C). Hypertriglyceridemia are elevations of either chylomicron, intermediate density lipoproteins (IDL) or very low density lipoproteins (VLDL). Combined dyslipidaemia include abnormalities of severe lipoproteins, usually elevated LDL-C and triglyceride (TG) with low high density lipoprotein cholesterol (LDL-C). Non pharmacologic management of several dyslipidaemias include lifestyle modification, regular exercise, weight management and nutritional approach. Pharmacologic management with statin is individualised based on overall risk, pattern of dyslipidaemia and associated medical conditions. Combination medication to treat cholesterol may be effective when a single agent is ineffective or there is a need to reduce the dosage of medication.

Avances en el conocimiento y manejo de las dislipoproteinemias

Se efectúa una revisión de los factores lipídicos y no lipìdicos de riesgo cardiovascular. Los factores lípídicos más importantes son el incremento del colesterol LDL, VLDL, IDL triglicéridos, lipoproteína(a) y colesterol no HDL, así como disminución del colesterol HDL, los cuales constituyen factores independientes de riesgo cardiovascular. Se clasifica las dislipoproteinemias en primarias y secundarias. Las dislipoproteinemias primarias son alteraciones innatas de carácter familiar o no familiar, dentro de las cuales destacan la hipercolesterolemia común, hiperlipidemia familiar combinada, hipercolesterolemia familiar, hipertrigliceridemia familiar, hiperlipidemia de remanentes de VLDL y la quilomicronemia primaria. Las dislipoproteinemias secundarias se producen como consecuencia de diversas enfermedades; entre las más comunes están el hipotiroidismo, diabetes mellitus, síndrome nefrótico, obstrucción biliar crónica, insuficiencia renal. Asimismo, existen algunos medicamentos o drogas que modifican el metabolismo lipídico, como el alcohol, beta-bloqueadores, diuréticos, progestágenos, corticosteroides, etc. Se enfatiza que la determinación del perfil lípido en ayunas no es suficiente para evaluar el metabolismo lipídico y se sugiere la conveniencia de realizar estudios posprandiales. El manejo terapéutico de estos trastornos debe considerar al régimen alimenticio, el ejercicio y la utilización de medicamentos, como los inhibidores de la hidroxi-metil-glutaril coenzima A y los derivados de los ácidos fíbricos. Se demuestra a través de megaestudios, multicéntricos, internacionales, que las intervenciones terapéuticas disminuyen la prevalencia de eventos cardiovasculares y la morbimortalidad respectiva.