Carotid atherosclerosis and lipoprotein particle subclasses in familial hypercholesterolaemia and familial combined hyperlipidaemia

Background and AimsFamilial 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 ResultsRisk 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 (r² = 0.38). The same variables, except cholesterol/HDL ratio, were associated with IMT in FCH (r² = 0.40). Among NMR lipoproteins, only VLDL and chylomicrons increased IMT prediction in FCH by 0.8%.ConclusionFH and FCH subjects show increased carotid atherosclerosis in relation to classical risk factors. Lipoprotein subclasses do not substantially contribute to IMT variability.     

Plasma phospholipid dysregulation in patients with cystathionine-β synthase deficiency

Background & aimsPatients with cystathionine β-synthase deficiency (CBSD) exhibit high circulating levels of homocysteine and enhanced lipid peroxidation. We have characterized the plasma lipidome in CBSD patients and related lipid abnormalities with reactions underlying enhanced homocysteine levels.Methods and resultsUsing an ultra-high-performance liquid chromatography-electrospray ionization-quadrupole-time of flight-mass spectrometry method, plasma lipids were determined with an untargeted lipidomics approach in 11 CBSD patients and 11 matched healthy subjects (CTRL). Compared to CTRL, CBSD patients had a higher medium and long-chain polyunsaturated fatty acids (PUFA) content in phosphatidylethanolamine (PE) and lysophosphatidylethanolamine (LPE) species (p < 0.02), and depletion of phosphatidylcholine (PC; p = 0.02) and of lysophosphatidylcholine (LPC; p = 0.003) species containing docosahexaenoic acid (DHA), suggesting impaired phosphatidylethanolamine-N-methyltransferase (PEMT) activity. PEMT converts PE into PC using methyl group by S-adenosylmethionine (SAM) thus converted in S-adenosylhomocysteine (SAH). Whole blood SAM and SAH concentrations by liquid chromatography tandem mass spectrometry were 1.4-fold (p = 0.015) and 5.3-fold (p = 0.003) higher in CBSD patients than in CTRL. A positive correlation between SAM/SAH and PC/PE ratios (r = 0.520; p = 0.019) was found.ConclusionsA novel biochemical abnormality in CBSD patients consisting in depletion of PC and LPC species containing DHA and accumulation of PUFA in PE and LPE species is revealed by this lipidomic approach. Changes in plasma SAM and SAH concentrations are associated with such phospholipid dysregulation. Given the key role of DHA in thrombosis prevention, depletion of PC species containing DHA in CBSD patients provides a new direction to understand the poor cardiovascular outcome of patients with homocystinuria.     

Arterial endothelial function and wall thickness in familial hypercholesterolemia and familial combined hyperlipidemia and the effect of statins. A systematic review and meta-analysis

BackgroundTo evaluate the impact of familial hypercholesterolemia (FH) and familial combined hyperlipidemia (FCH) on arterial properties and the effects of statins.MethodsWe meta-analyzed 51 studies providing data for 4,057 FH patients and 732 FCH patients with random-effects models, meta-regression analysis and publication bias analysis. The main outcomes of interest were (1) brachial artery flow-mediated dilation (FMD), (2) intima-media thickness (IMT), and (3) change of IMT and FMD after treatment with statins.ResultsCompared to normolipidemic controls, FH patients had lower FMD [pooled mean difference (MD): ?5.31%, 95% CI ?7.09 to ?3.53%, P < 0.001] and higher carotid IMT (pooled MD: 0.12 mm, 95% CI 0.09–0.15 mm, P < 0.001) and femoral IMT (pooled MD: 0.35 mm, 95% CI 0.18–0.51 mm, P < 0.001). FCH patients had lower FMD and increased IMT (pooled MD: ?3.60%, 95% CI ?6.69 to ?0.50%, P = 0.023; and 0.06 mm, 95% CI 0.04–0.08 mm, P < 0.001, respectively). Total and LDL-cholesterol was a significant determinant of FMD and carotid IMT in FCH patients and of FMD and femoral IMT in FH patients. In FH patients, statins improved FMD (pooled MD of change: 5.39%, 95% CI 2.86–7.92%, P < 0.001) and decreased carotid IMT (pooled MD of change: ?0.025 mm, 95% CI ?0.042 to ?0.009 mm, P = 0.003). Changes of both FMD and IMT with statins correlated with the duration × treatment intensity product in FH patients (both P < 0.01). Additionally, statins improved FMD in FCH patients (pooled MD of change: 2.06%, 95% CI 0.43–3.69%, P = 0.013). No significant publication bias was detected.ConclusionArterial properties are impaired in subjects with FH or FCH. Statins improve arterial function and structure in FH patients in a treatment intensity-related manner.     

Relation of inflammatory chemokines to insulin resistance and hypoadiponectinemia in coronary artery disease patients

BackgroundAlthough many studies have shown that the metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM) both are associated with chronic inflammatory state and are risk factors for coronary artery disease (CAD), it is still unclear which condition is a more important contributor to the increased production of inflammatory chemokines. The purpose of this study was to assess monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) levels and their association with insulin resistance and adiponectin concentrations in CAD patients, who were categorized as having T2DM, MS, or neither.MethodsCAD male patients were categorized into three groups: 24 non-obese patients with T2DM (D), 24 obese patients with MS (M) and 24 patients without T2DM or MS (W). 20 healthy subjects were selected as controls (C). Insulin resistance was assessed by the HOMA-IR method, but serum MCP-1, IL-8, and adiponectin levels were measured by xMAP technology.ResultsSerum levels of MCP-1 and IL-8 in D and M groups were increased in comparison with W and C groups (p < 0.001, p < 0.01), but the increase in the M group was significantly higher than that in the D group (p < 0.05, p < 0,001), besides MCP-1 and IL-8 concentrations were correlated with HOMA-IR indexes (r = 0.52; r = 0.49, p < 0.0001) and adiponectin levels (r = ? 0.59, p < 0.0001). The M group demonstrated a diminution in the adiponectin level (p < 0.01) and pronounced increase of HOMA-IR in comparison with the other three groups (p < 0.01).ConclusionObese CAD patients with MS have a more pronounced increase of MCP-1, IL-8 and HOMA-IR and more decreased adiponectin levels than non-obese CAD patients without MS.     

Local carotid stiffness and intima-media thickness assessment by a novel ultrasound-based system in essential hypertension

ObjectiveTo evaluate local carotid stiffness (CS) and intima-medial thickness (C-IMT) in hypertensive patients with different cardiovascular risk profile, using a new user-friendly ultrasound-based system, previously validated vs. RF-based echotracking device.MethodsWe investigated a population with different cardiovascular risk: 45 healthy normotensives (NT), 90 non-diabetic hypertensives (HT), and 48 patients with hypertension and type-2 diabetes (DM). Framingham risk factor score (FRS) was calculated. PWV was assessed by applanation tonometry. The relative stroke change in diameter (ΔD) and C-IMT were measured on carotid scans. Distensibility coefficient (DC) was calculated as ΔA/(A*ΔP), where A = diastolic lumen area, ΔA = stroke change in lumen area, and ΔP = carotid pulse pressure. CS (m/s) was calculated as (ρ*DC) ? 1/2 (ρ = blood density).ResultsCS, C-IMT, PWV were significantly increased in HT and DM vs. NT. C-IMT and PWV were significantly higher in DM than HT. ΔD and DC were significantly lower in HT and DM vs. NT. FRS ≥10% group showed increased carotid diameter, C-IMT and CS than the FRS <10%. FRS was (p < 0.001) correlated with CS (r = 0.35); ΔD (r = ?0.36), DC (r = 0.35), C-IMT (r = 0.48), PWV (r = 0.38). CS correlated (p < 0.05) with PWV in the entire population (r = 0.37), in the NT (r = 0.35), in the HT and DM (r = 0.20). PWV (r = 0.50) and CS (r = 0.33) were correlated with age. Determinants of aortic and carotid stiffness were identified by multivariate stepwise analysis.ConclusionsThe proposed B-mode ultrasound-based system is a reliable and user-friendly method that could serve to investigate the predictive value of CS for cardiovascular events in future large clinical studies.     

Abnormal lipoprotein particles and cholesterol efflux capacity in patients with psoriasis

ObjectivesPsoriasis is a Th-1/17 mediated inflammatory disease associated with increased risk of cardiovascular disease (CVD). Inflammation may modulate lipoprotein particle number and directly impair HDL functions, in particular reverse cholesterol transport (RCT). We sought to study how chronic in vivo inflammation modulates lipoprotein particle composition using nuclear magnetic resonance spectroscopy (NMR) and HDL efflux in psoriasis.Methods and resultsWe prospectively enrolled a consecutive sample of patients with psoriasis (n = 122) and compared lipoprotein and metabolic risk factors to patients without psoriasis (n = 134). Fasting lipids, insulin, glucose were measured by standard assays, and lipoprotein concentration and size were measured by NMR. In a random subset (n = 100 each group), HDL efflux capacity was quantified using a validated ex vivo system involving the incubation of macrophages with apolipoprotein B-depleted serum from patients. Traditional lipid concentrations were similar in both groups except for HDL concentration which was lower in psoriasis (43 mg/dl (36–58) vs 50 (42–62), p < 0.01). However, NMR showed an atherogenic profile in psoriasis similar to that observed in diabetes, with significant increase in LDL particle concentration [1210.5 (1002–1498) vs 1115 (935–1291), p = 0.02] with decrease in LDL size [20.6 (20.3–21.1) vs 21.3 (20.6–21.1), p < 0.001] beyond CV risk factors and HOMA-IR (p = 0.001). Finally, HDL efflux capacity was lower in psoriasis compared to controls in fully adjusted models (beta ?0.14, p = 0.001).ConclusionsThese data support a more atherogenic lipoprotein profile by NMR and decreased HDL efflux capacity in psoriasis patients compared to controls beyond CVD risk factors. The abnormal lipoprotein particle composition and HDL efflux capacity in psoriasis may provide a link between psoriasis and CVD.     

Ezetimibe alone and in combination lowers the concentration of small, dense low-density lipoproteins in type 2 diabetes mellitus

ObjectiveThe effectiveness of the cholesterol absorption inhibitor ezetimibe on LDL subfractions and ultimately on the atherosclerotic risk profile remains controversial. We thus determined the concentration of atherogenic small, dense LDL (sdLDL) in patients with type 2 diabetes and an elevated cardiovascular risk profile.Research design and methodsMulticenter, randomized, open-label 6-week study investigating the effect of ezetimibe 10 mg (E), simvastatin 20 mg (S) and the combination of ezetimibe-/simvastatin 10/20 mg (C) on the concentration of sdLDL separated from fresh plasma by gradient ultracentrifugation in patients with type 2 diabetes (NCT01384058).ResultsFifty-six patients were screened for sdLDL, 41 were randomized, and 40 patients (12 E, 14 S and 14 C) completed the study. Total and LDL cholesterol fell by 14% (p = 0.004) and 15% (p = 0.006) with E, 22% (p < 0.001) and 32% (p < 0.001) with S, and 32% (p < 0.001) and 44% (p < 0.001) with C, respectively. E reduced the concentration of sdLDL by 20% (p = 0.043) whereas S and C reduced sdLDL by 24% (p = 0.020) and 33% (p = 0.003), respectively, and non-sdLDL by 28% (p = 0.004) and 42% (p < 0.001), respectively. However, the further drop in sdLDL by adding E to S was not significant.ConclusionEzetimibe alone and in combination with simvastatin reduced the concentration of atherogenic sdLDL in patients with type 2 diabetes.     

Ascertainment Bias in the Association Between Elevated Lipoprotein(a) and Familial Hypercholesterolemia

BackgroundLipoprotein(a) is an atherogenic low-density lipoprotein–like particle and circulating levels are largely determined by genetics. Patients with familial hypercholesterolemia (FH) have elevated lipoprotein(a); however, it remains unclear why.ObjectivesThis study compared the levels of lipoprotein(a) and associated genetic factors between individuals that were ascertained for FH clinically versus genetically.MethodsWe investigated causes of elevated lipoprotein(a) in individuals with clinically diagnosed FH (FH cohort, n = 391) and in individuals with genetically diagnosed FH from the general population (UK Biobank; n = 37,486).ResultsPatients in the FH cohort had significantly greater lipoprotein(a) levels than either the general population or non-FH dyslipidemic patients. This was accounted for by increased frequency of the rs10455872-G LPA risk allele (15.1% vs. 8.8%; p < 0.05). However, within the FH cohort, lipoprotein(a) levels did not differ based on the presence or absence of an FH-causing variant (means = 1.43 log mg/dl vs. 1.42 log mg/dl; p = 0.97). Lipoprotein(a) levels were also not statistically different between individuals with and without an FH-causing variant in the UK Biobank cohort, which represents a population sample not biased to cardiovascular ascertainment (n = 221 vs. 37,486). We performed a phenome-wide association study between LPA genotypes and 19,202 phenotypes to demonstrate that elevated lipoprotein(a) is associated with increased low-density lipoprotein cholesterol, a family history of cardiovascular disease, premature coronary artery disease, and a diagnosis of FH.ConclusionsThese results suggest that FH does not cause elevated lipoprotein(a), but that elevated lipoprotein(a) increases the likelihood that an individual with genetic FH will be clinically recognized.     

Phosphatidylcholine and lysophosphatidylcholine in intestinal mucus of ulcerative colitis patients. A quantitative approach by nanoelectrospray‐tandem mass spectrometry

Background: A defective mucus composition represents a key pathogenetic factor for intestinal injury. Phosphatidylcholine (PC) is an essential component contributing to formation of a hydrophobic mucus layer. For evaluation of PC in the pathogenesis of inflammatory bowel disease, the concentration and composition of PC in the rectal mucus of patients with ulcerative colitis was determined. Electrospray ionization (ESI) tandem mass spectrometry (MS/MS) allows quantification of PC species and enables analysis of crude extracts. Methods: Lipid extracts of material obtained by light scrapings of the intestinal lumen were analysed quantitatively by nanoESI MS/MS with synthetic internal PC and lysophosphatidylcholine (LPC) standards. PC and LPC species from rectoscopically acquired mucus aliquots of patients with ulcerative colitis were compared to Crohn disease and control subjects. Results: Patients with inactive ulcerative colitis showed significantly less PC and LPC (median 346 [IQR: 230–405]?pmol total PC/mg dry weight) in rectal mucus compared to Crohn disease (median 1126 [IQR: 465–1941]?pmol total PC/mg dry weight) and control subjects (median 1285 [IQR: 850–1639]?pmol total PC/mg dry weight) (P?Conclusion: NanoESI MS/MS is a suitable tool for analysing and quantifying small amounts of PC in human mucus. Patients with ulcerative colitis have significant less PC in their intestinal mucus despite a comparable PC molecular species composition pattern. This suggests that a low amount of protective mucus PC is a characteristic feature in ulcerative colitis and explains an increased susceptibility to luminal contents.     

The association of fasting plasma sulfur-containing compounds with BMI, serum lipids and apolipoproteins

Background and aimSulfur amino acids are recognized as potent modulators of lipid metabolism. Plasma total cysteine (tCys) is associated with fat mass, obesity and serum LDL-cholesterol and apolipoprotein (Apo)-B in large population studies. It is not known how fasting plasma concentrations of cysteine precursors and products relate to these associations in humans, given that sulfur-containing compounds (SCC) influence rodent weight gain and serum lipids.Methods and resultsWe investigated the cross-sectional associations of fasting plasma SCC (methionine, total homocysteine, cystathionine, tCys, taurine and total glutathione) with BMI and fasting serum lipids and apolipoproteins in 854 men and women with and without cardiovascular disease (CVD).In multiple linear regression analysis adjusted for age, gender, CVD and other SCC, neither methionine, taurine, nor total glutathione was associated with BMI. Plasma taurine was, however, inversely related to HDL-cholesterol (partial r = ?0.12, p = 0.004) and its associated apoA1 (partial r = ?0.18, p < 0.001). Plasma cystathionine correlated positively with triglycerides and BMI, while tCys positively correlated with total cholesterol, LDL-cholesterol (partial r = 0.20, p < 0.001) and its associated apoB. The associations of SCC with serum lipids were independent of BMI. tCys was also independently associated with BMI (partial r = 0.20, p < 0.001) after adjustment for other SCC, glucose, lipids and apolipoproteins.ConclusionsFasting tCys is associated with BMI independently of metabolically related SCC. Elevation of plasma SCC is generally associated with an unfavorable lipid profile. The negative relations of plasma taurine with HDL-C and apoA1 deserve further investigation.     

Ischemia-modified albumin in patients with hyperthyroidism and hypothyroidism

BackgroundThe relationship between ischemia-modified albumin (IMA) and thyroid dysfunction remains uncertain. This study aimed to investigate the influence of overt hypothyroidism (Oho), overt hyperthyroidism (Ohe), and their treatments on serum IMA levels.MethodsA total of 35 untreated patients with Ohe, 35 untreated patients with Oho, and 35 control subjects were enrolled in the study. C-reactive protein (CRP), homocysteine (Hcy), IMA, and lipid profiles were measured and evaluated before and after treatment.ResultsCRP, Hcy, and IMA levels and lipid profiles were higher in patients with Oho than in euthyroid or Ohe subjects (p < 0.05). Basal IMA levels were reduced after treatments in all patients (p < 0.05). In Ohe patients, serum IMA levels were positively correlated with free triiodothyronine (r = 0.424, p = 0.011) and free thyroxine (r = 0.567, p < 0.001) levels. In Oho patients, serum IMA levels were inversely correlated with free triiodothyronine (r = ? 0.555, p = 0.001) and free thyroxine (r = ? 0.457, p = 0.006) but positively correlated with anti-thyroid peroxidase antibody, C-reactive protein, and homocysteine levels (p < 0.05). Linear regression analyses showed that free triiodothyronine was the most important factor affecting serum IMA levels in Ohe (β = 0.694, p = 0.019) and in Oho (β = ? 0.512, p = 0.025).ConclusionsIMA levels are increased in patients with thyroid dysfunction, particularly in overt hypothyroidism. Thyroid dysfunction has a significant impact on the oxidative stress status.     

Urine α-Glutathione S-transferase, systemic inflammation and arterial function in juvenile type 1 diabetes

BackgroundDespite marked improvement in therapy and monitoring of patients with insulin-dependent (type 1) diabetes, diabetic nephropathy remains a serious complication, with subsequent end-stage renal disease in about 20% of cases.ObjectiveTo investigate in young patients with type 1 diabetes whether urine α-Glutathione S-transferase to creatinine ratio (α-GST:crea) relates to markers of systemic inflammation and subclinical vasculopathy.DesignChildren and adolescents (median age and diabetes duration 14 and 6 years, respectively) with type 1 diabetes screened in a previous study for proximal tubular (urine α-GST:crea ratio) and renal (plasma creatinine, cystatin C glomerular filtration rate (GFR), and timed urine albumin excretion rate (AER)) function were, within the same timeframe, also investigated for vascular (blood pressure, carotid artery intima–media thickness (IMT) and compliance (CAC), brachial artery flow-mediated dilatation (FMD) and plasma cyclic guanosine monophosphate (cGMP) and inflammatory (C-reactive protein (CRP), and tumor necrosis factor-alpha (TNF-α)) profiles. Exposure to environmental tobacco smoke (ETS) was assessed through questionnaire (n = 67 respondents).ResultsNone of the patients (n = 69) had overt renal insufficiency. AER correlated with age (p = 0.01, r = 0.3), diabetes duration (p = 0.02, r = 0.3), FMD (p = 0.04, r = ? 0.3, n = 52), CAC (p = 0.03, r = ? 0.3, n = 62) and cGMP (p = 0.01, r = ? 0.3, n = 59). α-GST:crea was lower (p = 0.03) in patients than in controls. α-GST:crea appeared to be particularly lower in older patients (p = 0.004, r = ? 0.34 vs age), in those with worse diabetic control (p = 0.03, r = ? 0.26 vs HbA1c), and in those with lower carotid artery elasticity (p = 0.017, r = 0.3 vs CAC). Although ETS had no direct significant impact on α-GST:crea, α-GST:crea correlated with FMD only in patients with ETS (r = 0.5, p = 0.009, n = 13). α-GST:crea showed positive association with TNF-α (p = 0.01, r = 0.3).ConclusionIn children and adolescents with type 1 diabetes, lower levels of urine excretion of α-GST:crea appear to be associated with decreasing elasticity and endothelial vasomotor function of peripheral arteries, especially in patients with ETS. In contrast, higher levels of α-GST:crea are more common in patients with elevated markers of systemic inflammation. Large scale prospective studies are needed to clarify the meaning and mechanisms of this association.     

C-reactive protein is directly related to plasminogen activator inhibitor type 1 (PAI-1) levels in diabetic subjects with the 4G allele at position -675 of the PAI-1 gene

Background and aimsC-reactive protein (CRP) has been identified as a possible factor able to promote atherosclerosis. “In vitro” studies have demonstrated that CRP induces plasminogen activator inhibitor type 1 (PAI-1) expression, suggesting a hypofibrinolytic role for CRP. As CRP and PAI-1 levels increase in type 2 diabetic subjects, we decided to study the relationship between CRP and PAI-1, and the role of the 4G/5G polymorphism of the PAI-1 gene on this relationship in a diabetic population without complications.Methods and resultsTwo hundred and ninety-five type 2 diabetic patients (age 60.9 ± 10.5 years) and 290 healthy controls (age 59.2 ± 11.5 years) were enrolled. A significant correlation between PAI-1 and CRP in diabetic subjects was found (r = 0.45, p < 0.001), whereas no relationship was evident in the control subjects between these inflammatory markers. Multiple regression analysis highlighted that CRP is the only one significant variable of PAI-1 antigen in diabetic subjects (partial r = 0.31, p < 0.01). Stratifying by genotype, a positive correlation between PAI-1 and CRP in 4G/4G (partial r = 0.64 p < 0.001) and 4G/5G (partial r = 0.47, p < 0.001) subjects was found, whereas no correlation in 5G/5G was present. Multiple regression analysis confirmed the presence of this correlation in 4G/4G (partial r = 0.45, p < 0.001) and in 4G/5G (partial r = 0.34, p = 0.007) diabetic patients.ConclusionsThese findings demonstrate that CRP plays an important role in the complex mechanism regulating PAI-1 antigen in 4G diabetic carriers.     

Impact of low-density lipoprotein receptor mutational class on carotid atherosclerosis in patients with familial hypercholesterolemia

Background and objectivesDefects in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolemia (FH), a highly atherogenic condition. The effect of different LDLR mutations on coronary heart disease (CHD) risk is insufficiently defined. We assessed carotid intima-media thickness (IMT), a surrogate marker of CHD, in relation to LDLR mutational class in FH.MethodsIn 436 Spanish FH patients (223 men and 213 women, age 44 ± 14 years) with known LDLR mutations, alleles were classified by standard criteria as null (n = 269), defective (n = 162), or undetermined (n = 5). LDLR defects were detected using a microarray (Lipochip^®) designed to uncover prevalent mutations in Spain and gene sequencing when no mutations were detected. Carotid IMT and plaque were assessed in FH patients and 268 healthy subjects.ResultsAll carotid measurements were increased in FH patients versus controls (p < 0.05), irrespective of genotype. After adjustment for gender and age, patients with null alleles compared with defective alleles had similar mean and maximum common carotid artery (CCA) IMT, but higher maximum IMT at any carotid segment, with median values (95% confidence interval) of 1.25 mm (1.19–1.31) and 1.11 mm (1.05–1.18), respectively. Multivariate analysis showed that null alleles were independently associated with maximum CCA-IMT (β = 0.09, p = 0.033) with an impact similar to that of gender (β = 0.10, p = 0.035).ConclusionsFH patients show advanced carotid atherosclerosis in relation to LDLR mutational class. The findings support the utility of genetic testing in FH beyond providing a secure diagnosis.     

Children with familial hypercholesterolemia are characterized by an inflammatory imbalance between the tumor necrosis factor α system and interleukin-10

ObjectiveFamilial hypercholesterolemia (FH) is associated with increased risk of premature atherosclerosis. Increasing evidence supports involvement of inflammation in atherogenesis. The inflammatory cytokine tumor necrosis factor (TNF)α has been regarded as a key mediator in the development of atherosclerosis due to its involvement in several stages in this process. We hypothesized that children with FH, as a model of early atherosclerosis, have different serum levels of inflammation markers than healthy control children.MethodsWe measured serum levels of TNFα, as well as its endogenous inhibitors (i.e., soluble TNF receptors [sTNFR] 1 and 2) and the anti-inflammatory cytokine interleukin (IL)-10 in healthy children (7–20 years) with (n = 102) and without (n = 48) heterozygote FH as well as adult FH subjects (n = 20) and healthy adult controls (n = 16).ResultsThe main findings were: Compared to control children, FH children had higher serum levels of TNFα, accompanied by lower sTNFRs levels, resulting in an increased TNFα/sTNFRs ratio (P < 0.05), potentially reflecting enhanced TNFα activity. In contrast to the increased TNFα levels, FH children had decreased serum levels of IL-10 (P < 0.01) resulting in an increased TNFα/IL-10 ratio (P < 0.01). We did not observe any difference in the same parameters between adult subjects with and without FH.ConclusionsFH children are characterized by an inflammatory imbalance between TNFα and IL-10, potentially contributing to the accelerated atherosclerotic process in these individuals.     

Relationship between n-3 and n-6 plasma fatty acid levels and insulin resistance in coronary patients with and without metabolic syndrome

Background and aimsAnimal studies show that ecosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are effective for the prevention and treatment of insulin resistance (IR). Data from human studies are contradictory. We sought to determine whether the relationships between plasma n-3 and n-6 polyunsaturated fatty acid (FA) levels and IR differ according to the presence or absence of metabolic syndrome (MS) in a coronary heart disease sample.Method and resultsClinical, metabolic parameters, plasma phospholipid FA profiles and indirect measurement of IR (homeostatic model assessment-HOMA) were measured in 734 subjects, 8 weeks following acute coronary syndrome. FA levels and their correlations with IR were compared in subjects with and without MS. MS patients had higher saturated (16:0, 18:0) and n-6 (18:3n-6, 20:3n-6, 22:4n-6, 22:5n-6) FA levels, and lower EPA and DHA levels. HOMA-IR correlated positively with total saturated (r = 0.13, P = 0.017) and n-6 (r = 0.17, P = 0.001) FA levels and negatively with total n-3 FA levels (r = −0.13, P = 0.012), in MS subjects only. Total n-3 and n-6 FAs and n-6/n-3 ratio were associated with HOMA-IR levels in MS subjects independent of total saturated FA levels, age, sex, sedentary behaviour, smoking, waist circumference, triglycerides, HDL-cholesterol, and systolic blood pressure.ConclusionsRelationships between polyunsaturated FA type and IR vary according to the presence or absence of MS. N-3 FAs including EPA and DHA are associated with lower HOMA-IR, while the opposite is true for n-6 FAs. Prospective studies are required to address the potential effects of intermediate dose EPA and DHA on glucose handling in MS patients.     

The Homeostasis Model Assessment-adiponectin (HOMA-AD) is the most sensitive predictor of insulin resistance in obese children

ObjectivesThe aim of this study was to examine the efficacy of three indices i.e. adiponectin/leptin ratio, HOMA-IR and HOMA-AD in assessing insulin resistance among obese children.Patients and methodsOne hundred and twenty-two obese children (57 girls, 65 boys): mean age 13.7 ± 1.3 years, BMI 30.1 ± 4.5 kg/m², eight tanner stage I, 48 tanner stage II-III, 66 tanner stage IV-V, participated in this study. They were classified into four groups according to sex and the presence of metabolic syndrome characteristics: with metabolic syndrome (MS; 21 girls and 36 boys) and controls without metabolic syndrome (CON, 36 girls and 29 boys). The correlations between these three indices of insulin resistance and the MS criteria were analyzed using linear and multiple regressions and receiver operating characteristics (ROC) curves analysis.ResultsThe majority of anthropometric and biological parameters as well as adiponectin/leptin ratio, HOMA-IR and HOMA-AD were significantly different between MS and CON in both sexes. Both HOMA-AD and HOMA-IR were significantly correlated with the majority of metabolic syndrome components than was the adiponectin/leptin ratio in MS of both sexes. In boys and girls with and without MS, multiple regression analyses highlighted that both HOMA-AD and adiponectin/leptin ratio (r = ?0.99 and r = ?0.54 for MS girls and boys respectively, 0.05 < P < 0.001), and HOMA-AD and HOMA-IR (r = 0.66 and r = 0.31 for MS girls and boys respectively, 0.05 < P < 0.01) affected each other but did not adiponectin/leptin ratio and HOMA-IR. Additionally, the area under the ROC curves for predicting insulin resistance were 0.69 (CI 95%, 0.60–0.77), 0.68 (CI 95%, 0.59–0.76) and 0.71 (CI 95%, 0.62–0.79) for adiponectin/leptin ratio, HOMA-IR and HOMA-AD, respectively.ConclusionThe current study strengthens the validity of the HOMA-AD as an adequate tool for determining insulin resistance among obese children with MS.     

Relationship between tissue characterization with 40 MHz intravascular ultrasound imaging and 64-slice computed tomography

BackgroundIdentification of coronary plaque composition is important for selecting the treatment strategy, and 64-slice computed tomography (CT) is a noninvasive method of characterizing atherosclerotic plaques. However, the correlation between plaque characteristics detected by CT and intravascular ultrasound (IVUS) is not clear. A 40 MHz IVUS imaging system (iMap-IVUS) has recently been developed to evaluate plaque composition. The aim of this study was to compare iMap-IVUS with 64-slice CT angiography for the characterization of non-calcified coronary plaques.Methods and resultsBoth 64-slice CT angiography and iMap-IVUS were performed in 19 patients (38 plaques). CT values were measured as Hounsfield units (HU) in circular regions of interest (ROI) drawn on the plaques. The iMap-IVUS system analyzed coronary plaques as fibrotic, lipidic, necrotic, or calcified tissue based on the radiofrequency spectrum.A positive correlation was found between CT values and the percentage of fibrotic plaque (r = 0.34, p = 0.036) or calcified plaque (r = 0.40, p = 0.011). Conversely, a negative correlation was found between CT values and the percentage of lipidic plaque (r = ?0.41, p = 0.01), or necrotic plaque (r = ?0.41, p = 0.01).ConclusionsGood correlations were observed between the characteristics of non-calcified plaque determined by iMap-IVUS and the CT values of plaque detected by 64-slice CT scanning.     

Impact of electronegative low-density lipoprotein on angiographic coronary atherosclerotic burden

ObjectiveLow density lipoproteins (LDL) with an electronegative charge [LDL(?)] may cause endothelial injury. We assessed the association between serum LDL(?) levels and coronary artery disease (CAD) severity.MethodsWe prospectively enrolled patients with CAD angiographic evidence [stable angina (SA) or non-ST-elevation-acute coronary syndrome (NSTE-ACS)], or with normal coronary arteries (NCA). Baseline LDL(?) serum levels were measured in all patients. Angiographic CAD extent was assessed by using the Bogaty extent index, while CAD severity by evaluating the presence of multi-vessel disease.ResultsForty-seven patients (age 61 ± 9 years, male sex 60%) were enrolled (17 SA, 15 NSTE-ACS and 15 NCA patients). LDL(?) levels were significantly higher in SA [21% (18–34) p = 0.0001] and NSTE-ACS [22% (18–28), p = 0.0001] as compared to NCA [6% (5–8)], without significant differences between SA and NSTE-ACS (p = 0.92). Multi-vessel disease patients had higher LDL(?) levels as compared to single-vessel disease patients (p = 0.002) but similar total LDL levels (p = 0.66). LDL(?) significantly correlated with extent index (r = 0.38, p = 0.03), while total LDL did not (p = 0.24).ConclusionLDL(?) serum levels are associated with CAD angiographic severity and extent. This exploratory analysis should prime further larger studies in order to assess LDL(?) proatherogenic role.