Bile acid synthesis precursors in familial combined hyperlipidemia: the oxysterols 24S-hydroxycholesterol and 27-hydroxycholesterol.

Familial combined hyperlipidemia (FCHL), the most common inherited disorder of lipid metabolism is characterized by increasing cholesterol synthesis precursors due to hepatic overproduction of cholesterol. The bile acids synthesis pathway has not been previously studied in FCHL. The aim of this work was to study the oxysterol levels which are involved in the bile acids synthesis from cholesterol in FCHL. Clinical parameters and subclinical atherosclerosis were studied in a total of 107 FCHL patients and 126 normolipidemic controls. Non cholesterol sterols (desmosterol and lanosterol) and oxysterols (27-hydroxycholesterol and 24S-hydroxycholesterol) were measured by high performance liquid chromatography tandem mass spectrometry. Desmosterol and lanosterol, markers of cholesterol synthesis, had a positive correlation with BMI and apo B. However, no correlation was found for 24S-hydroxycholesterol and 27-hydroxycholesterol, precursors of bile acids, with these clinical parameters. Only 27-hydroxycholesterol had a positive correlation with apo B, ρ=0.204 (P=0.037). All oxysterol levels were higher in FHCL as compared to normal controls. A total of 59 FCHL subjects (59%) presented values of 24S-hydroxycholesterol above the 95th percentile of this oxysterol in the control population. All oxysterols showed no association with fat mass in contrast with non-cholesterol sterols. FCHL subjects with oxysterol overproduction had less carotid intima media thickness (cIMT), which suggests less atherosclerosis in these subjects. In summary, our data indicate that high oxysterol levels might be good markers of FCHL, unrelated to fat mass, and may exert a protective mechanism for cholesterol accumulation.

Carotid distension and distensibility impairment in individuals affected by familial combined hyperlipidemia.

OBJECTIVE: To investigate whether individuals affected by familial combined hyperlipidemia, a common lipid disorder increasing the cardiovascular risk, had different carotid ultrasound parameters compared to control subjects without this family disorders. METHODS: 127 cases and 127 controls matched for age and gender were enrolled. Serum glucose, total cholesterol, high-density lipoprotein-cholesterol, triglycerides, ApoB, insulinemia were measured by standard laboratory techniques. All the subjects underwent B-mode ultrasonography to measure the end-diastolic and end-systolic diameter of the common carotid artery and, successively, to calculate distensibility, compliance, Young's elastic modulus and distension. RESULTS: Carotid diameter and Young's elastic modulus were significantly greater among FCH subjects than among controls, and carotid distensibility, compliance, distension and score distension were significantly lower than control, also after analysis of covariance in order to adjust all the carotid indexes for confounding variables. A multiple regression analysis confirmed that familial combined hyperlipidemia status was correlated to carotid indexes. In a model including the lipid parameters, triglycerides was the only lipid variable correlated with distensibility but not with distension. CONCLUSION: This hyperlipidemia, particularly hypertriglyceridemia, could be the direct responsibility of carotid modification leading to the impairment of the distension/distensibility that, in turn, makes the patients prone to atherosclerosis.

Endothelial activation, inflammation and premature atherosclerosis in children with familial dyslipidemia.

OBJECTIVES: Prospective studies demonstrated an increased cardiovascular risk in subjects with high levels of either the endothelial-platelet activation marker P-selectin or high-sensitivity C-reactive protein (hs-CRP). Both children with heterozygous familial hypercholesterolemia (FH) and those with familial combined hyperlipidemia (FCHL) are prone to premature atherosclerosis. Our objective was to investigate in children with either FH or FCHL whether P-selectin and hs-CRP contribute to carotid intima-media thickness (IMT), along with increased plasma lipid levels. METHODS: Carotid IMT, serum lipids and soluble P-selectin and hs-CRP levels were measured in 88 children (mean age 10.5+/-4.3 years) including 44 dyslipidemic children (25 with FH and 19 with FCHL) and 44 non-dyslipidemic controls. RESULTS: Carotid IMT was significantly higher among dyslipidemic than in control children (0.46+/-0.06mm vs 0.43+/-0.06mm, p=0.003) and serum P-selectin levels as well [129(50-254)ng/mL vs 50(24.5-130)ng/mL, p<0.001]. FH but not FCHL children had higher hs-CRP levels than controls [0.7(0.01-6.9)mg/L vs 0.3(0.1-1.2)mg/L, p=0.006]. In the entire sample of dyslipidemic children, carotid IMT was positively associated with soluble P-selectin levels (rho=0.30, p=0.049), but not with hs-CRP. The association between P-selectin and carotid IMT was independent from confounders, including plasma lipid levels. CONCLUSION: Endothelial-platelet activation, more than low-grade systemic inflammation, correlates with premature atherosclerosis among children with familial dyslipidemia, this association being independent from plasma lipid levels.

Increased arterial stiffness in familial combined hyperlipidemia.

OBJECTIVE: The current study was conducted to investigate whether greater arterial stiffening is already present in normolipidemic relatives of patients with familial combined hyperlipidemia (FCHL), as compared with healthy controls, and to establish the factors that are associated with arterial stiffness in comparison with markers of atherosclerosis. METHODS: Seventy-seven FCHL patients, 121 normolipidemic relatives and 72 spouses (controls) underwent ultrasound examination of the common carotid artery to determine the presence of plaques and the degree of arterial stiffness, expressed as stiffness index alpha. RESULTS: Age-adjusted and sex-adjusted analyses revealed that the arterial stiffness index alpha and prevalence of plaques were higher in normolipidemic relatives when compared with spouses, but lower than in FCHL patients (P<0.05). Additional adjustments for visceral obesity, smoking, plasma glucose, insulin, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, pulse frequency and use of lipid-lowering or antihypertensive medication did not affect the results for arterial stiffness, whereas the adjusted prevalence of atherosclerosis was markedly lowered in FCHL patients. Logistic regression analyses demonstrated that age, male sex, pulse frequency and low-density lipoprotein cholesterol were significant independent determinants of atherosclerotic plaques. In contrast, only age and FCHL family status, that is, belonging to an FCHL family or not, contributed to arterial stiffness. CONCLUSION: Arterial stiffening and atherosclerosis appear to be greater in patients who are prone to develop FCHL, that is, normolipidemic FCHL family members, as compared with controls. These findings may add to our understanding of the increased prevalence of cardiovascular complications in not only FCHL patients, but also their siblings and offspring.

Fatty liver--based identification of two distinct hypertriglyceridemic subgroups in familial combined hyperlipidemia.

The present study was conducted to investigate whether the fatty liver phenotype could be helpful in the identification of subgroups with distinct metabolic properties and lipid profiles within familial combined hyperlipidemia (FCHL). One hundred eighty-five FCHL family members participated in the current study; 38 subjects were found to be hypertriglyceridemic, of whom 66% showed evidence of fatty liver as measured with ultrasound. A detailed comparison between the hypertriglyceridemic FCHL subjects with (n = 25) and without (n = 13) fatty liver revealed that, despite very similar plasma triglyceride levels (3.5 vs 3.2 mmol/L in subjects with and without fatty liver, respectively), the fatty liver subgroup presented with significantly higher body mass index, visceral adipose tissue (ultrasound), insulin, and alanine aminotransferase levels. Moreover, very low-density lipoprotein (VLDL) subclass analysis showed that the VLDL2 fraction of the fatty liver subgroup contained significantly less cholesterol and triglycerides (P = .02 for both parameters), which was likely explained by a decreased VLDL2 particle number because VLDL2 apolipoprotein B levels tended to be lower (P = .08). These data indicate that hypertriglyceridemic FCHL subjects may belong to metabolically distinct subgroups and suggest that a refinement of the hypertriglyceridemic FCHL phenotype by adding information on fatty liver will eventually facilitate the elucidation of its complex genetic background.

Fatty liver is an integral feature of familial combined hyperlipidaemia: relationship with fat distribution and plasma lipids.

Overproduction of VLDL (very-low-density lipoprotein) particles is an important cause of FCHL (familial combined hyperlipidaemia). It has been shown recently that VLDL production is driven by the amount of hepatic fat. The present study was conducted to determine the prevalence of fatty liver in relation to the different fat compartments and lipid parameters in FCHL. A total of 68 FCHL patients, 110 normolipidaemic relatives and 66 spouses underwent ultrasound of the abdominal region to estimate the amount of subcutaneous, visceral and hepatic fat. Skinfold callipers were used to measure subcutaneous fat of the biceps, triceps, subscapular and supra-iliacal regions. Fatty liver was observed in 18% of the spouses, 25% of the normolipidaemic relatives and 49% of the FCHL patients. After adjustment for age, gender and body mass index, the prevalence of fatty liver was significantly higher in FCHL patients compared with spouses [OR (odds ratio), 3.1; P=0.03], and also in the normolipidaemic relatives compared with spouses (OR, 4.0; P=0.02), whereas no differences were observed between FCHL patients and normolipidaemic relatives (OR, 0.8; P=0.58). In the normolipidaemic relatives and FCHL patients combined, both visceral fat mass and subcutaneous abdominal fat were independent predictors of fatty liver (P<0.001 for both fat compartments; FCHL status corrected). Of interest, fatty liver stages were correlated with both VLDL-apoB (apolipoprotein B) and VLDL-triacylglycerols (triglycerides) in a representative subset (n=69) of patients and relatives (r(2)=0.12, P=0.006; and r(2)=0.18, P=0.001 respectively). These results show that fatty liver is a central aspect of FCHL, i.e. patients and normolipidaemic relatives. Both visceral and subcutaneous adiposity contribute to its 3-4-fold higher risk in FCHL.

The use of Achilles tendon sonography to distinguish familial hypercholesterolemia from other genetic dyslipidemias.

OBJECTIVE: Achilles tendon (AT) xanthomas, specific for familial hypercholesterolemia (FH), may be clinically undetectable. We assessed the usefulness of AT sonography in the diagnosis of FH. METHODS AND RESULTS: Sonographic AT characteristics were evaluated in 127 subjects with FH (81 genetically ascertained), 84 familial combined hyperlipidemia, 79 polygenic hypercholesterolemia, and 88 normolipidemic controls. Abnormal echostructure (sonographic xanthoma) was noted only in FH. AT thickness was higher (P<0.001) in FH men and women compared with all of the other groups and, in FH mutation carriers but not in others, correlated positively with low-density lipoprotein cholesterol (r=0.345; P<0.001) and negatively with high-density lipoprotein cholesterol (r=-0.265, P=0.015). Thickness thresholds for the diagnosis of FH with specificity >80%, as were derived from receiver operating curves, were 5.3 and 5.7 mm in men < and >45 years, and 4.8 and 4.9 mm in women < and >50 years, respectively. In FH mutation carriers, sonographic findings increased the clinical diagnosis of xanthomas from 35 (43%) to 55 (68%). Using thresholds in validation sets of 70 genetically identified FH and 54 dyslipidemic non-FH correctly classified 80% and 88%, respectively. CONCLUSIONS: Sonographic AT characteristics are normal in non-FH dyslipidemias. Identification of suspected FH by ultrasound using sex- and age-specific AT thickness thresholds is recommended.

Additive beneficial effects of fenofibrate combined with atorvastatin in the treatment of combined hyperlipidemia.

OBJECTIVES: We compared vascular and metabolic responses (and adverse responses) to statin and fibrate therapies alone or in combination in patients with combined hyperlipidemia. BACKGROUND: The mechanisms of action for statins and fibrates are distinct. METHODS: Fifty-six patients were given atorvastatin 10 mg and placebo, atorvastatin 10 mg and fenofibrate 200 mg, or fenofibrate 200 mg and placebo daily during each two-month treatment period of a randomized, double-blind, placebo-controlled crossover trial with two washout periods of two months' each. RESULTS: Lipoproteins were changed to a greater extent with combined therapy when compared with atorvastatin or fenofibrate alone. Flow-mediated dilator response to hyperemia and plasma high-sensitivity C-reactive protein and fibrinogen levels were changed to a greater extent with combined therapy when compared with atorvastatin or fenofibrate alone (p < 0.001, p = 0.182, and p = 0.015 by analysis of variance [ANOVA], respectively). The effects of combined therapy or fenofibrate alone on plasma adiponectin levels and insulin sensitivity (determined by the Quantitative Insulin-Sensitivity Check Index [QUICKI]) were significantly greater than those of atorvastatin alone (p = 0.022 for adiponectin and p = 0.049 for QUICKI by ANOVA). No patients were withdrawn from the study as the result of serious adverse effects. CONCLUSIONS: Combination therapy is safe and has beneficial additive effects on endothelial function in patients with combined hyperlipidemia.

Increased intima-media thickness in familial combined hyperlipidemia associated with apolipoprotein B.

The aim of the present study was to quantify intima-media thickness (IMT) in familial combined hyperlipidemia (FCHL) and to evaluate the relationship of IMT in FCHL-affected subjects with lipids and apolipoproteins, blood pressure values, and surrogate markers of insulin resistance. IMT was measured by ultrasound at the left and right common carotid arteries in 46 FCHL-affected subjects who were free of clinical manifestations of atherosclerosis and in 55 age- and sex-matched healthy control subjects. FCHL-affected subjects had significantly increased IMT compared with healthy control subjects, with a difference of 57 microm (age- and sex-corrected P<0.01). In the FCHL group, significantly positive age- and sex-corrected univariate correlations were observed between IMT and total cholesterol, non-high density lipoprotein cholesterol, and apolipoprotein B. Multivariate regression analyses revealed that age, sex, and apolipoprotein B were significant and independent predictors of IMT, whereas body mass index was of borderline significance. Combined, these factors explained almost 50% of the observed IMT variation (P<0.001). The increased IMT observed in FCHL corresponds with approximately 7 years of physiological IMT increase in excess of the average IMT in age- and sex-matched control subjects. These novel findings show the important relationship between lipoprotein particles, marked by increased apolipoprotein B concentrations, and an increased IMT in FCHL. The increased IMT in FCHL-affected subjects is in agreement with the known high risk of cardiovascular disease in FCHL.

Coronary flow reserve in young men with familial combined hyperlipidemia.

BACKGROUND: Familial combined hyperlipidemia (FCHL) is a common hereditary disorder of lipoprotein metabolism estimated to cause 10% to 20% of premature coronary heart disease. We investigated whether functional abnormalities exist in coronary reactivity in asymptomatic patients with FCHL. METHODS AND RESULTS: We studied 21 male FCHL patients (age, 34.8+/-5.4 years) and a matched group of 21 healthy control subjects. Myocardial blood flow (MBF) was measured at baseline and during dipyridamole-induced hyperemia with PET and 15O-labeled water. The baseline MBF was similar in patients and control subjects (0.79+/-0.19 versus 0.88+/-0.20 mL. g-1. min-1, P=NS). An increase in MBF was seen in both groups after dipyridamole infusion, but MBF at maximal vasodilation was lower in FCHL patients (3.54+/-1.59 versus 4.54+/-1.17 mL. g-1. min-1, P=0.025). The difference in coronary flow reserve (CFR) was not statistically significant (4.7+/-2.2 versus 5.3+/-1.6, P=NS, patients versus control subjects). Considerable variability in CFR values was detected within the FCHL group. Patients with phenotype IIB (n=8) had lower flow during hyperemia (2.5+/-1.2 versus 4.2+/-1.5 mL. g-1. min-1, P<0.05) and lower CFR (3.4+/-2.1 versus 5.4+/-2.0, P<0.05) compared with phenotype IIA (n=13). CONCLUSIONS: Abnormalities in coronary flow regulation exist in young asymptomatic FCHL patients expressing phenotype IIB (characterized by abnormalities in both serum cholesterol and triglyceride concentrations). This is in line with previous observations suggesting that the metabolic abnormalities related to the pathophysiology of FCHL are associated with the phenotype IIB.

Decreasing common carotid artery intimal thickness during hypolipidemic therapy.

It has been demonstrated in recent years that ultrasound can be used to measure common carotid artery intimal thickness; an increase in intimal thickness is regarded as an early stage of atherosclerosis. This study was designed to establish whether or not intimal thickness can be modulated by therapy. Twenty-nine patients with familial hyperlipoproteinemias had follow-up ultrasound of the common carotid artery after twenty-nine months of comprehensive therapy. In 21 patients with familial hypercholesterolemia, intimal thickness decreased from 0.83 to 0.68 mm (P < 0.01), in 9 with familial combined hyperlipoproteinemia, the decrease was from 0.77 to 0.74 mm (a decrease was seen in only 50% of patients). With the group taken as a whole, the larger decrease was observed in patients treated with statins while the reduction was less marked in those administered fibrates. The authors found a decrease in common carotid artery intimal thickness following hypolipidemic therapy in patients with hyperlipoproteinemias. Their impression is that this was a manifestation of atherosclerosis regression.

[Favorable effect of treatment with statins on the intima of the common carotid artery in patients with familial hyperlipoproteinemia]. / Príznivý vliv lécby statiny na intimu arteria carotis communis u nemocných s familiárními hyperlipoproteinémiemi.

BACKGROUND: In recent years evidence was provided that by measuring the width of the intima of the carotid artery, evaluated by sonography, it is possible to assess the development of arteriosclerosis. The authors used this method to evaluate hypolipidaemic treatment. METHODS AND RESULTS: The authors followed-up by clinical and laboratory methods and treated for a period of 47 months 63 patients with familial hyperlipoproteinaemia. At the beginning and at the end of the follow-up period they made sonographic examinations of the common carotid artery. In 31 patients treated by statins they observed statistically significant changes: cholesterol declined by 23%, LDL cholesterol by 25.3%. The maximal rate in the common carotid artery (ACC) declined from 93 +/- 22 to 73 +/- 13 cm/s. The diameters of the ACC increased from 6.0 +/- 0.8 to 6.5 +/- 0.8 mm. The intima of the ACC diminished from 0.84 +/- 0.26 to 0.75 +/- 0.20 mm. In 22 patients treated with fibrates the anticipated lipid changes occurred. The diameter of ACC did not change, the decline in the width of the intima of the ACC was not statistically significant. In 10 patients who decided that they wanted only dietary treatment the changes in the investigated parameters were small. CONCLUSIONS: In patients with familial hyperlipidaemia who were treated with statins for almost four years the authors observed a diminution of the width of the intima of the common carotid artery which is considered a sign of regressing atherosclerosis.

Utility of transesophageal echocardiography in the diagnosis of disease of the thoracic aorta.

PURPOSE: Transesophageal echocardiography (TEE) offers a rapid, minimally invasive method for diagnosing thoracic aortic disease. High-resolution images are possible because of the close proximity of the esophagus and vascular structures within the chest. Lung and chest wall components have little influence on the image quality and a virtually unobstructed view of the heart, thoracic aorta, and pulmonary vasculature is seen. The role of TEE in diagnosing diseases of the thoracic aorta is rapidly developing. The purpose of this study is to define the role of TEE in the diagnosis of thoracic aortic disease. METHODS: Between July 1, 1989 and December 31, 1992, 1005 TEEs were performed at our center. Of these, 199 (125 men, 74 women) were entered into our aortic disease registry. Indications for the studies included 37 referrals to rule out aortic dissection, 18 to assess aortic aneurysm, 55 to assess for an intraaortic source of embolus, 9 to rule out intraaortic thrombus, and 13 with familial hyperlipidemia being followed to mark response to low-density lipoprotein apheresis. In 67 cases, subclinical aortic plaquing was found incidentally. No complications from the TEE procedure were encountered. RESULTS: In cases of suspected aortic dissection, TEE was equal to computed tomography (CT) scanning in identifying the type (DeBakey) and extent of thoracic aortic dissection. In addition, TEE provided information regarding functional status of the aortic valve, identified interluminal communications, and assessed blood flow and thrombus burden in the false lumen. TEE correctly identified true aneurysms, intraluminal thrombus, and plaques as possible sources of emboli. One false-positive CT scan result for aortic dissection was seen and was ruled out both by TEE and angiography. CONCLUSION: Biplane TEE can be considered the method of choice in diagnosing disease of the thoracic aorta. Information from TEE can be obtained at the patient's bedside or in the operating suite, to assess surgical results before procedure termination and afterward for follow-up. Adjunctive magnetic resonance imaging, CT scanning, or aortography may be needed to assess extension of the disease process into the abdomen or pelvis or to plan surgical intervention.