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The introduction of singular therapies, such as proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i), to lower high cholesterol levels requires better classification of patients eligible for intensive lipid lowering therapy. According to the European Medicines Administration, PCSK9i are recommended in primary prevention only in familial hypercholesterolemia (FH) patients. Therefore, an FH diagnosis is not simply an academic issue, because it has many clinical implications. The bases of a diagnosis of FH are not entirely clear. The availability of genetic testing, including large genome-wide association analyses and whole genome studies, has shown that some patients with a clinical diagnosis of definite FH have no mutations in the genes associated with the disease. This fact does not exclude the very high cardiovascular risk of these patients, and an early and intensive lipid lowering therapy is recommended in all FH patients. Because an FH diagnosis is a cornerstone for decisions about therapies, a precise definition of FH is urgently required. This is an expert consensus document from the Spanish Atherosclerosis Society. We propose the following classification: familial hypercholesterolemia syndrome integrated by (1) heterozygous familial hypercholesterolemia: patients with clinically definite FH and a functional mutation in one allele of the LDLR, ApoB:100, and PCSK9 genes; (2) homozygous familial hypercholesterolemia: mutations affect both alleles; (3) polygenic familial hypercholesterolemia: patients with clinically definite FH but no mutations associated with FH are found (to be distinguished from non-familial, multifactorial hypercholesterolemia); (4) familial hypercholesterolemia combined with hypertriglyceridemia: a subgroup of familial combined hyperlipidaemia patients fulfilling clinically definite FH with associated hypertriglyceridemia. • There is a mismatch in clinical and genetic familial hypercholesterolemia diagnosis. • Familial hypercholesterolemia is a syndrome including several entities. • Monogenic and polygenic familial hypercholesterolemia determines high vascular risk. • Familial hypercholesterolemia diagnosis has implications to access new therapies. • A new classification including all FH genotypes and phenotypes is warranted. [ABSTRACT FROM AUTHOR]

Background Thioredoxins ( TRX) are major cellular protein disulphide reductases that are critical for redox regulation. Oxidative stress and inflammation play promoting roles in the genesis and progression of atherosclerosis, but until now scarce data are available considering the influence of TRX activity in familial combined hyperlipidaemia ( FCH). Since FCH is associated with high risk of cardiovascular disease, the objective of the present study was to assess oxidative stress status in FCH patients, and evaluate the influence of insulin resistance ( IR). Materials and methods A cohort of 35 control subjects and 35 non-related FCH patients were included, all of them nondiabetic, normotensive and nonsmokers. We measured lipid profile, glucose and insulin levels in plasma, and markers of oxidative stress and inflammation such as oxidized glutathione ( GSSG), reduced glutathione ( GSH) and TRX. Results Familial combined hyperlipidaemia subjects showed significantly higher levels of GSSG, GSSG/ GSH ratio and TRX than controls. In addition, FCH individuals with IR showed the worst profile of oxidative stress status compared to controls and FCH patients without IR ( P < 0·01). TRX levels correlated with higher insulin resistance. Conclusion Familial combined hyperlipidaemia patients showed increased TRX levels. TRX was positively correlated with IR. These data could partially explain the increased risk of cardiovascular events in primary dyslipidemic patients. [ABSTRACT FROM AUTHOR]

Abstract: Background and Aims: Familial hypercholesterolaemia (FH) and familial combined hyperlipidaemia (FCH) are common atherogenic disorders with great variability in cardiovascular disease (CVD). No direct atherosclerosis burden comparisons have been performed between FH and FCH in relation to lipoprotein particle distribution. Methods and Results: Risk factors and three measures of carotid intima-media thickness (IMT) in both sides were determined in 572 FH, 250 FCH and 200 controls. Lipoproteins were assessed by nuclear magnetic resonance (NMR) spectroscopy. Compared with controls, IMT measures were increased in FH and FCH. FCH had the highest adjusted mean–maximum IMT. FH had twice low-density lipoprotein (LDL) particles than controls, but similar LDL subclass size and distribution. FCH subjects also had increased LDL particles and the highest number of small LDL (1519 ± 731 nmol l−1 vs. 887 ± 784 nmol l−1 in FH and 545 ± 409 nmol l−1 in controls). Age, gender, cholesterol/high-density lipoprotein (HDL) ratio, smoking and systolic blood pressure were independently associated with IMT in FH (r 2 = 0.38). The same variables, except cholesterol/HDL ratio, were associated with IMT in FCH (r 2 = 0.40). Among NMR lipoproteins, only VLDL and chylomicrons increased IMT prediction in FCH by 0.8%. Conclusion: FH and FCH subjects show increased carotid atherosclerosis in relation to classical risk factors. Lipoprotein subclasses do not substantially contribute to IMT variability. [Copyright &y& Elsevier]

Abstract: Background: Familial combined hyperlipidaemia (FCH) is the most common genetic dyslipidaemia associated with coronary artery disease. Single nucleotide polymorphisms (SNPs) and haplotypes in the APOA1/C3/A4/A5 gene cluster are associated with FCH in Caucasians and with elevated triglycerides (TG) in various ethnic groups. We examined these associations with FCH in Hong Kong Chinese. Methods: Fifty-six Chinese FCH patients and 176 unrelated controls were studied. Thirteen SNPs in the APOA1/C3/A4/A5 cluster were genotyped. Results: Four alleles in APOA5 were associated with FCH (P <0.001). The −1131T>C (rs662799) and −3A>G (rs651821) SNPs in APOA5 were in almost complete linkage disequilibrium (LD, r 2 =0.99), and their minor alleles were more frequent (P <0.001) in FCH than controls (0.60 vs. 0.24). The odds ratio (OR) for FCH was 6.2 (95% CI, 2.6–14.8) and 6.1 (2.6–14.6) per copy of −1131C and −3G, respectively, and 24.6 (8.4–72.0) and 24.4 (8.4–70.9) in −1131C and −3G homozygotes, respectively, as compared to wild-type homozygotes. The 1891T>C (rs2266788) SNP was in LD (r 2 =0.68) with −1131T>C and −3A>G, and the minor allele was more frequent in FCH than controls (0.42 vs. 0.19, P <0.001). The 553G>T (rs2075291) nonsynonymous variant was also associated with FCH (0.15 vs. 0.04, P =0.001) and, along with −3A>G (or −1131T>C) and 1891T>C, contributed to haplotypes predicting FCH. The two tightly linked SNPs, −1131T>C and −3A>G polymorphism were significantly associated with lipid traits in all subjects combined, with variant homozygous subjects having higher TG and LDL-C and lower HDL-C levels. Conclusions: Some common polymorphisms and haplotypes in APOA5 are closely associated with FCH in Hong Kong Chinese, and these differ from those found in Caucasians. [Copyright &y& Elsevier]

Aims Low-density lipoprotein cholesterol (LDL-C) levels are often fairly normal in Type 2 diabetes mellitus (DM). We anticipated that a parabolic relation between plasma triglycerides and LDL-C, as previously demonstrated in familial combined hyperlipidaemia (FCHL), might account for this phenomenon. Methods Our hypothesis was tested in 1343 subjects derived from the general population who were studied on two occasions 6 years apart (the Hoorn study). Three groups were constructed depending on plasma triglycerides: group A (individuals with both measurements below 1.5 mmol/l), group B (one measurement below and one above 1.5 mmol/l) and group C (both measurements above 1.5 mmol/l). Diabetes status was ascertained by an oral glucose tolerance test. Results In a mixed linear model, a significant, positive relation between triglycerides and LDL-C was observed for males in group A (βa = 0.5, P < 0.001) and group B (βb = 0.2, P < 0.001), whereas a significant negative relation was found for males in group C (βc = −0.2, P = 0.003). The regression slopes did not differ between diabetic and non-diabetic subjects. Similar results were obtained for women, with the exception that the relation was not significantly negative in group C (βc = −0.1, P = 0.4). Conclusion Plasma triglcyerides and LDL-C are related in a parabolic fashion, not only in FCHL, but also in the general population and Type 2 DM. These findings aid our interpretation of typical dyslipidaemia and the effects of treatment that are frequently observed in hypertriglyceridaemic states. [ABSTRACT FROM AUTHOR]

Abstract: Background: Familial combined hyperlipidaemia (FCH) is an inherited dyslipidaemia that is related to a high risk of coronary artery disease (CAD). We evaluated the prevalence of CAD in a large FCH population and the association of risk factors with CAD according to gender. Methods: In this single-center, observational study, lipid and lipoprotein variables were measured in untreated patients with FCH (565 males and 302 females). CAD was defined as a documented history of myocardial infarction or coronary revascularization, or an abnormal coronary angiogram (stenosis of >50% in an epicardial coronary artery), or angina plus abnormal imaging stress test. Results: Males had higher triglyceride level (P <0.001) but lower total cholesterol (P <0.001) and HDL-cholesterol level (P <0.001) compared to women. The prevalence of CAD was 22.2% in men and 4.6% in women (P <0.001). In logistic regression analysis, male gender was associated with a higher risk of CAD independent of lipid parameters and other risk factors (adjusted ORs for CAD 9.4, P <0.001). In gender-specific analysis, age (OR=1.06 per 1-year increase, P <0.001), diabetes (OR=2.42, P <0.01) and Lp(a) (OR=1.09 per 1-mg/dL increase, P <0.01) were independent predictors of CAD in men. In women, age (OR=1.24, P <0.01), total cholesterol (OR=1.022 per 1-mg/dL increase, P <0.05) and fasting glucose (OR=1.031 per 1-mg/dL increase, P <0.05) were independently associated with CAD. Conclusions: In FCH patients, the prevalence of CAD is higher in males than in females, independent of lipidaemic profile and other risk factors. Among lipid variables, Lp(a) and cholesterol level are predictors of CAD in males and females respectively. [Copyright &y& Elsevier]

Common DNA variants of the transcription factor 7-like 2 gene ( TCF7L2) are associated with type 2 diabetes. Familial combined hyperlipidaemia (FCHL) is characterised by hypertriacylglycerolaemia, hypercholesterolaemia, or both. Additionally, disturbances in glucose metabolism are commonly seen in FCHL. Therefore, we hypothesised that TCF7L2 may contribute to the genetic susceptibility for this common dyslipidaemia. We investigated the effect of the TCF7L2 variants, rs7903146 and rs12255372, on FCHL and its component traits triacylglycerol (TG), total cholesterol (TC) and apolipoprotein B (ApoB) in 759 individuals from 55 Mexican families. As a replication sample, 719 individuals from 60 Finnish FCHL families were analysed. We also used quantitative RT-PCR to evaluate the transcript levels of TCF7L2 in 47 subcutaneous fat biopsies from unrelated Mexican FCHL and normolipidaemic participants. Significant evidence for association was observed for high TG for the T alleles of rs7903146 and rs12255372 ( p = 0.005 and p = 0.01) in Mexican FCHL families. No evidence for association was observed for FCHL, TC, ApoB or glucose in Mexicans. When testing rs7903146 and rs12255372 for replication in Finnish FCHL families, these single nucleotide polymorphisms were associated with TG ( p = 0.01 and p = 0.007). Furthermore, we observed statistically significant decreases in the mRNA levels ( p = 0.0002) of TCF7L2 in FCHL- and TG-affected individuals. TCF7L2 expression was not altered by the SNP genotypes. These data show that rs7903146 and rs12255372 are significantly associated with high TG in FCHL families from two different populations. In addition, significantly decreased expression of TCF7L2 was observed in TG- and FCHL-affected individuals. [ABSTRACT FROM AUTHOR]

Background Familial combined hyperlipidaemia (FCH) is characterized by dyslipidaemia, visceral obesity and insulin resistance, and is associated with an increased intima-media thickness (IMT) and an increased risk for cardiovascular disease. In the present study, we investigated whether FCH is associated with early functional vascular wall changes, as represented by endothelial dysfunction, and we determined whether endothelial function in FCH is related to any of the cardiovascular risk factors associated with the FCH phenotype, or to the (increased) IMT. Design In 98 patients with FCH [mean age 51 (48–54) years, 43% male] and 230 unaffected relatives [mean age 44 (42–46) years, 48% male], venous blood was drawn in the fasting state after discontinuation of lipid lowering drugs for at least 4 weeks (if used). IMT was measured by B-mode ultrasound and endothelial function was assessed by determination of flow mediated dilation (FMD) and by measurement of plasma concentrations of various soluble adhesion molecules, including soluble vascular cell adhesion molecule (sVCAM), soluble intercellular adhesion molecule (sICAM) and soluble E-selectin. Results There were no significant differences between FCH patients and their non-affected relatives in FMD [2·9 (2·3–3·6%) vs. 2·8 (2·5–3·2%)] or in the plasma concentrations of the various adhesion molecules. None of the individual clinical and biochemical cardiovascular risk factors was an independent predictor of endothelial function in patients with FCH, nor was IMT. However, subgroup analysis revealed that IMT was an independent and powerful predictor of FMD in subjects with carotid artery plaques (St. β = 4·11, P < 0·004), whereas IMT was no significant predictor in subjects without plaques. Conclusions FCH patients have no impaired endothelial function when compared to their unaffected relatives. IMT is an important predictor of FMD when advanced morphological wall changes are present. Our results question the value of FMD measurements for cardiovascular risk stratification in populations with an anticipated high cardiovascular risk. [ABSTRACT FROM AUTHOR]

Objectives. Familial combined hyperlipidaemia (FCH) is associated with insulin resistance. We hypothesized that pioglitazone treatment of FCH patients might increase insulin sensitivity, but may also improve serum lipid levels, body fat distribution, intramyocellular lipids (IMCL) and endothelial function. Design. Double blind, randomized, cross-over study. Subjects. Seventeen FCH patients. Interventions. Sixteen weeks of pioglitazone treatment (30 mg) compared with 16 weeks of placebo. Main outcome measurements. Insulin sensitivity was measured using the hyperinsulinaemic euglycaemic clamp procedure, body fat distribution and IMCL using magnetic resonance techniques and endothelial function using flow-mediated vasodilatation. Results. Pioglitazone improved insulin sensitivity ( M value 37.7 ± 3.6 μmol min−1 kg−1 vs. 33.0 ± 3.3 μmol min−1 kg−1 during placebo, P < 0.05) and LDL composition by increasing the K value (−0.11 ± 0.06 vs. −0.20 ± 0.06 during placebo, P < 0.05). However, pioglitazone did not affect other serum lipid levels. Endothelial function, body fat distribution and IMCL were also not affected. In addition, pioglitazone was associated with a decrease in liver enzymes (alkaline phosphatase). Conclusion. Pioglitazone treatment of FCH patients without type 2 diabetes mellitus increases insulin sensitivity, decreases liver enzymes and improves LDL composition but has a neutral effect on total serum lipid levels. The change in insulin sensitivity might be too small to induce changes in endothelial function, body fat distribution and IMCL. [ABSTRACT FROM AUTHOR]

By influencing the mevalonate pathway, statins may have multiple effects besides lipid lowering. This study was designed to evaluate the effect of rosuvastatin on serum lipids and insulin sensitivity in nondiabetic subjects with familial combined hyperlipidaemia (FCH), a population characterized by decreased insulin sensitivity. In a double-blind randomized crossover study, 18 subjects with FCH (without evident cardiovascular disease, mean age 54 ± 7 years) were randomized to rosuvastatin 40 mg day−1 or placebo for 12 weeks. Blood samples were taken at baseline and after 4, 8 and 12 weeks of both treatment periods. Insulin sensitivity was determined with euglycaemic–hyperinsulinaemic clamp after 12 weeks of both treatment periods. Serum lipids and lipoproteins improved significantly. Mean total cholesterol after the rosuvastatin treatment period was 44% lower compared to the placebo treatment period (triglycerides −28%; LDL-c −50%; VLDL-c −56%, VLDL-TG −39%) and both parameters of low-grade inflammation (as measured by hsCRP, −16%) and oxidative stress (as measured by plasma-oxLDL, −55%) decreased markedly after rosuvastatin therapy as compared to placebo. However, the insulin sensitivity index was unchanged (41·7 ± 17·4 vs. 40·6 ± 11·1 L kg−1 min−1, placebo vs. rosuvastatin, P = 0·71). Despite marked improvements in lipid and lipoprotein values, low-grade inflammation and oxidative stress, a relatively high dose of rosuvastatin did not change insulin sensitivity in subjects with FCH. Eur J Clin Invest 2005; 35 (9): 558 –564 [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the effects of rosuvastatin and fenofibrate alone and in combination in type 2 diabetes associated with combined hyperlipidaemia. A total of 216 patients with total cholesterol ≥200 mg/dl (≥5.17 mmol/l) and triglycerides ≥200 and <800 mg/dl (≥2.26 and <9.03 mmol/l) were randomised to one of two placebo groups, rosuvastatin 5 mg or rosuvastatin 10 mg for 6 weeks (fixed-dose phase). During the subsequent 18-week dose-titration phase, one placebo group received titrated rosuvastatin 10, 20 and 40 mg (placebo/rosuvastatin); one placebo group received titrated fenofibrate 67 mg once, twice and three times daily (placebo/fenofibrate); and patients receiving 5 or 10 mg rosuvastatin received titrated fenofibrate as above (rosuvastatin 5 mg/fenofibrate and rosuvastatin 10 mg/fenofibrate groups). Doses were increased at 6-week intervals if low-density lipoprotein (LDL) cholesterol remained >50 mg/dl (>1.3 mmol/l). At 24 weeks, the placebo/rosuvastatin group and placebo per fenofibrate group had triglyceride reductions of 30.3% versus 33.6%, respectively (P=NS), and LDL cholesterol was reduced by 46.7% in the rosuvastatin group and increased by 0.7% in the fenofibrate group (P<0.001). The triglyceride reduction in the rosuvastatin 10 mg/fenofibrate group (47.1%) was significantly greater than in the placebo/rosuvastatin group (P=0.001), with no significant differences in other lipid measures found between these two groups. No significant differences in effect on high-density lipoprotein (HDL) were observed among treatment groups. In the fixed-dose phase, rosuvastatin 5 and 10 mg reduced triglycerides by 24.5 and 29.5%, respectively, and decreased LDL cholesterol by 40.7 and 45.8%, respectively. All treatments were well tolerated. These results indicated that rosuvastatin produces marked reductions in triglycerides and LDL cholesterol when used alone or in combination with fenofibrate in type 2 diabetes patients with elevated cholesterol and triglyceride levels and may constitute a valuable treatment option in the diabetic population. [Copyright &y& Elsevier]

BackgroundThe objective of this study was to examine specific membrane binding of [125I]-acylation stimulating protein (ASP) in cultured human skin fibroblasts obtained from normal subjects and patients with hyperapoB. ASP is a small basic protein isolated from human plasma that stimulates triglyceride synthesis (TGS) and glucose transport (GT) in human skin fibroblasts and adipocytes. DesignIn the present study, three groups were studied: normal (NASP-NB) subjects, hyperapoB subjects with normal plasma ASP (NASP-HB) and hyperapoB subjects with high plasma ASP (HASP-HB). ResultsASP-induced TGS in fibroblasts from HASP-HB subjects was significantly less than in the two control groups with normal plasma ASP (NASP-NB and NASP-HB). Similarly, ASP stimulation of GT was less in HASP-HB fibroblasts than in the NASP-HB fibroblasts or the NASP-NB subjects. Insulin-induced TGS was similar in all three groups as was insulin-stimulated GT. As well, protein kinase C-mediated stimulation was equivalent among the three groups both for GT and for TGS. There was no significant difference in the binding affinity (Kd) of [125I]-ASP to intact cells in any group. By contrast, binding of [125I]-ASP revealed a significantly lower Bmax of the HASP-HB cell lines than the NASP-NB cells and the NASP-HB cells. ConclusionA decrease in the ASP cell-surface receptor concentration is responsible for decreased ASP stimulation of TGS, and GT and may contribute to the inefficient post-prandial triglyceride (TG) clearance in HASP-HB subjects. [ABSTRACT FROM AUTHOR]

BackgroundFamilial combined hyperlipidaemia (FCHL) is a common hereditary disorder. Hypertriglyceridaemia is associated with glucose intolerance and insulin resistance. MethodsTo study glucose tolerance in FCHL patients with different lipid phenotypes [hypercholesterolaemia (IIA), mixed hyperlipidaemia (IIB), hypertriglyceridaemia (IV)], we investigated 253 family members and 92 spouses arising from 33 well-defined Finnish FCHL pedigrees. ResultsIn oral glucose tolerance tests. the affected family members had higher values for glucose area under the curve than did non-affected family members (673 ± 127 min mmol L-1, 754 ± 145 min mmol L-1, 846 ± 180 min mmol L-1 and 838 ± 183 min mmol L-1 for phenotypes normal, IIA, IIB and IV respectively; P < 0.001 after adjustment for body mass index, waist circumference and age). Impaired glucose tolerance and diabetes were more common among affected than non-affected family members (prevalences of normal glucose tolerance 94.0%, 80.0%, 54.3% and 58.5% for phenotypes normal, IIA, IIB and IV). ConclusionAffected FCHL family members were more glucose intolerant than non-affected family members. In men, this disturbance was not related to lipid phenotype nor was it explained by obesity. [ABSTRACT FROM AUTHOR]

The aetiology of familial combined hyperlipidaemia remains obscure, with both genetic and environmental factors contributing to the phenotype, which is frequently associated with premature coronary heart disease. We have studied lipoprotein lipase (LPL) activity and hepatic lipase (HL) activity in patients with coronary heart disease to determine whether variation in lipase activities contributes to this phenotype. Forty-one patients (mean age 50 years; 30 male) were selected on the basis of cholesterol levels above 6.5 mmol/l and triglyceride levels above 2.2 mmol/1, with apoprotein B values over the 90th percentile. There was a family history of premature coronary heart disease in 78% and a personal history in 64%, at mean age 44, the patient group therefore predominantly corresponded to the common definition of familial combined hyperlipidaemia, appropriate in the absence of molecular markers. None of the patients was diabetic; hypertension and smoking were not over represented. Blood samples were taken following intravenous administration of heparin (100IU/kg body wt), and LPL and HL activities were measured. Mean post-heparin LPL was significantly lower in patients than controls 10 min after heparin administration (2.98 ± 1.04 and 3.86 ± 0.93 μmol ml h, respectively, P = 0.001), and 37% patients had values below the 10th percentile of controls. Both male and female patients had significantly higher HL activities than their respective controls at 5, 10, 20 and 30 minutes postheparin. As expected, both female patients and controls had lower HL activities than males, although this sex difference did not reach statistical significance in the patient group. Mean lipid and lipoprotein results were: cholesterol 8.2 mmol/1; triglycerides 4.2 mmol/l; high-density lipoprotein cholesterol 0.90 mmol/1; apoprotein Al 122 mg/dl; apoprotein B 171 mg/dl; lipoprotein (a) 23 mg/dl (median 10 mg/dl). High-density lipoprotein cholesterol and triglycerides were negatively correlated ( r = -0.26, P = 0.05). HL was significantly related to body mass index at all time points whereas the negative correlation between post-heparin LPL and body mass index was significant only 30 min after heparin administration. Post-heparin LPL was only weakly correlated with triglycerides 10 and 20 min after heparin administration. These lipid and lipoprotein results are clearly potentially atherogenic as indicated by the extent of premature coronary heart disease in the group described. A decrease in LPL activity may contribute to this pattern. [ABSTRACT FROM AUTHOR]

Lovastatin, a competitive inhibitor of the rate limiting enzyme in cholesterol biosynthesis, has been shown to be an effective hypocholesterolaemic agent when given in relatively short term studies to normal human subjects and patients with primary hypercholesterolaemia. The present report reviews the author's experience with lovastatin in the treatment of patients with hypercholesterolaemia (predominantly attributable to heterozygous familial hypercholesterolaemia) over a four year period. Lovastatin has been well tolerated and patients maintained on this drug as a single agent have shown sustained reductions in the plasma concentrations of total and low density lipoprotein cholesterol. The hypocholesterolaemic effects of lovastatin can be potentiated by combination therapy with other currently approved lip id lowering medications including bile acidsequestrants and nicotinic acid. Side effects have been uncommon and no consistent pattern of adverse effects of lovastatin has developed with more prolonged use. Lovastatin and related drugs represent a major advance in the therapy of hypercholesterolaemia. [ABSTRACT FROM PUBLISHER]