Gas Chromatography and Flame-Ionization Detection of Non-Cholesterol Sterols as Indicators of Cholesterol Absorption and Synthesis in 158 Chinese Individuals with Normolipidemia, Hyperlipidemia, and Familial Hypercholesterolemia.

BACKGROUND There are limited studies on the effects of cholesterol homeostasis in populations at high risk for cardiovascular disease. We aimed to use gas chromatography and flame-ionization detection (GC-FID) of non-cholesterol sterols as indicators of cholesterol absorption and synthesis. Sterol indicators of cholesterol absorption included campesterol, stigmasterol, and sitosterol. Sterol indicators of cholesterol synthesis included squalene, 7-lathosterol, and desmosterol. MATERIAL AND METHODS A total of 158 participants were enrolled in 3 groups: healthy control (n=64), hyperlipidemia (n=69), and familial hypercholesterolemia (FH, n=25). Age, sex, blood pressure, blood glucose, and lipoprotein were collected, and cholesterol absorption and synthesis markers were determined by GC-FID. RESULTS All 6 cholesterol concentration indicators, except squalene, were significantly different among the 3 groups (all P<0.05); whereas in the ratio to cholesterol (%, sterols/cholesterol), only desmosterol and lathosterol were significantly different (P<0.05). Multifactorial regression analysis showed that triglycerides, total cholesterol, and desmosterol were independent risk factors affecting the development of hyperlipidemia (P<0.05). The efficacy of the ROC curve for the diagnosis of dyslipidemia was also higher for all 3 indices (Model 1, AUC=0.960). Model 1 was superior to Model 2 for the 6 indicators of cholesterol. For the FH and dyslipidemia groups, the 6-indicator model (Model 3) was shown to have a good diagnostic value (AUC=1.000). CONCLUSIONS The 6 sterol indicators of cholesterol absorption and synthesis had a dynamic course in all study participants. Desmosterol was an indicator of dyslipidemia. The combined use of the 6 sterol indicators differentiated between healthy individuals and patients with dyslipidemia and FH.

Speckle-Tracking Echocardiography for Detecting Subclinical Left Ventricular Dysfunction in Patients With Familial Hypercholesterolemia.

Myocardial ischemia and left ventricular dysfunction have been documented in young adults with familial hypercholesterolemia. We investigated whether speckle-tracking echocardiography can be used to detect subclinically impaired global and regional myocardial function in patients with this lipid disorder. This single-center study included 47 patients with familial hypercholesterolemia and 37 healthy control subjects who underwent transthoracic Doppler echocardiography and speckle-tracking echocardiography from January 2003 through December 2016. Conventional echocardiographic and strain parameters in the 2 groups were analyzed and compared. Left ventricular dimensions were significantly larger at end-diastole (P=0.02) and end-systole (P=0.013), left ventricular walls were significantly thicker (P <0.0001), and the early transmitral/early diastolic mitral annular velocity ratio was significantly higher (P=0.006) in the patient group than in the control group. In the patient group, global longitudinal and circumferential strain values were significantly lower (P <0.0001) and global radial strain values significantly higher (P=0.006); all segmental longitudinal strain (P <0.04) and most segmental circumferential strain values (P ≤0.01) were significantly lower; and some segmental radial strains, especially at the apex, were significantly higher (P ≤0.04). However, average longitudinal, circumferential, and radial strains in the different segments of the 3 main coronary artery territories were significantly lower in the patient group (P <0.01). Global longitudinal strain (r=0.561; P=0.001) and global circumferential strain (r=0.565; P <0.0001) were inversely correlated with low-density-lipoprotein cholesterol levels. We conclude that speckle-tracking echocardiography can be used to detect subclinical global and regional systolic abnormalities in patients with familial hypercholesterolemia.

Case Report: Cardiac Surgery and Combined Lipid-Lowering Drug Therapy for Homozygous Familial Hypercholesterolemia.

Homozygous familial hypercholesterolemia (HoFH) is a rare, autosomal dominant, hereditary, metabolic disease. HoFH patients exhibit severe coronary stenosis and valvular disease, which may result in sudden death, even during adolescence. The challenges faced during surgery and the poor curative effect of conventional lipid-lowering therapy create a treatment bottleneck. We report a rare case of HoFH in a 12-years-old boy with acute myocardial infarction, severe mitral insufficiency, and moderate aortic insufficiency. Coronary artery bypass grafting and valvuloplasty resulted in improved heart function. Postoperative combined lipid-lowering drug therapy was able to reduce low-density lipoprotein cholesterol level from 15.37 mm/L to 6.41 mmol/L. Thus, the combination of medical and surgical treatment was considered effective and can be used to inform treatment guidelines for HoFH with severe complications.

Myocardial layer-specific analysis in patients with heterozygous familial hypercholesterolemia using speckle tracking echocardiography.

OBJECTIVE: Familial hypercholesterolemia (FH) is the most common and serious monogenic disorder of lipid metabolism, causing premature coronary heart disease (CHD) due to accelerated atherosclerosis from birth, and the study of left ventricular (LV) function of this disease is seldom. The purpose of this study was to explore the value of layer-specific strain on assessing the early damage of LV function in asymptomatic and left ventricular ejection fraction (LVEF) well-preserved patients with heterozygous FH (HeFH). METHODS: A total of 49 patients aged 38.7±8.7 diagnosed with heterozygous familial hypercholesterolemia and who had undergone transthoracic echocardiography from 2010 to 2016 were included in this study. A total 32 healthy volunteers aged 35.6±10.3 were included as control group. Longitudinal and circumferential strains of the endocardium, myocardium, and epicardium (LSendo, LSmyo, and LSepi and CSendo, CSmyo, and CSepi) were obtained by a software enabling the analysis of strains in three myocardial layers. RESULTS: In longitudinal strain (LS), the LS of endocardium (LSendo) and the LS of myocardium (LSmyo) are significantly reduced in patients with HeFH (P<.001 in both). In circumferential strain (CS), only the CS of endocardium (CSendo) is significantly reduced (P<.001). The degree of reduction in strain is positively correlated with the TC and LDLC. CONCLUSIONS: Layer-specific evaluation of the left ventricle has great value in evaluating early impairment of LV in patients with FH. And this relatively novel technique may made it possible to help us understand the process of LV impairment in patients with FH better, thus preventing further damage.

Four-year imaging follow-up of a homozygous familial hypercholesterolaemia patient: atherosclerosis ingravescence and coronary flow velocity reserve reduced gradually. Case report.

Homozygous familial hypercholesterolemia (HoFH) is a rare heredity disease in which severe cardiovascular atherosclerosis develops from birth due to severe low density lipoprotein-receptor (LDL-R) defects inherited from both heterozygouscarriers of FH (HeFH) parents. This case describes a HoFH patient who underwent medical imaging examination for 4 years over a course of treatment. In addition to the imaging techniques which demonstrated the development of cardiovascular atherosclerosis ingravescent, transthoracic Doppler echocardiography noninvasively and accurately detected the position of atherosclerotic calcifications and evaluated the hemodynamicsof the coronary flow. Analysis showed the patient had a significantly lower coronary flow velocity reserve due to plaques compromising coronary artery ostia.

Use of targeted exome sequencing in genetic diagnosis of Chinese familial hypercholesterolemia.

Familial hypercholesterolemia is an autosomal dominant inherited disease characterized by elevated plasma low-density lipoprotein cholesterol (LDL-C). It is mainly caused by mutations of the low-density lipoprotein receptor (LDLR) gene. Currently, the methods of whole genome sequencing or whole exome sequencing for screening mutations in familial hypercholesterolemia are not applicable in China due to high cost. We performed targeted exome sequencing of 167 genes implicated in the homozygous phenotype of a proband pedigree to identify candidate mutations, validated them in the family of the proband, studied the functions of the mutant protein, and followed up serum lipid levels after treatment. We discovered that exon 9 c.1268 T>C and exon 8 c.1129 T>G compound heterozygous mutations in the LDLR gene in the proband derived from the mother and father, respectively, in which the mutation of c.1129 T>G has not been reported previously. The mutant LDL-R protein had 57% and 52% binding and internalization functions, respectively, compared with that of the wild type. After 6 months of therapy, the LDL-C level of the proband decreased by more than 50% and the LDL-C of the other family members with heterozygous mutation also reduced to normal. Targeted exome sequencing is an effective method for screening mutation genes in familial hypercholesterolemia. The exon 8 and 9 mutations of the LDLR gene were pedigree mutations. The functions of the mutant LDL-R protein were decreased significantly compared with that of the wild type. Simvastatin plus ezetimibe was proven safe and effective in this preschool-age child.

Gas chromatography analysis of serum cholesterol synthesis and absorption markers used to predict the efficacy of simvastatin in patients with coronary heart disease.

OBJECTIVES: We investigated the changes in cholesterol absorption and synthesis markers before and after simvastatin therapy in Chinese patients with coronary heart disease. DESIGN AND METHOD: We developed a gas chromatography method to identify cholesterol synthesis and absorption markers and measured them in patients with coronary heart disease. We then tested their use in predicting the efficacy of simvastatin in lowering cholesterol. Serum samples from 45 patients and 38 healthy humans (controls) were analyzed in a gas chromatography-flame ionization detector. RESULTS: Squalene and five non-cholesterol sterols--desmosterol and lathosterol (synthesis markers) and campesterol, stigmasterol, and sitosterol (absorption markers)--were detected. The recovery rates of the markers were 95-102%. After simvastatin treatment for four weeks, the total cholesterol and low-density lipoprotein cholesterol levels had significantly decreased from the baseline values (p<0.05). The baseline lathosterol level was significantly higher in good responders than in poor responders (p<0.05), and the stigmasterol level was significantly lower in good responders than in poor responders (p<0.05). CONCLUSIONS: This method should be suitable for the detection of serum squalene and non-cholesterol markers and can be used to predict the efficacy of simvastatin in patients with coronary heart disease.

Analysis of coronary flow haemodynamics in homozygous familial hypercholesterolaemic adolescents with aortic supravalvular stenosis.

OBJECTIVE: To study coronary artery haemodynamics in adolescents with homozygous familial hypercholesterolaemia and aortic supravalvular stenosis. METHODS: Patients diagnosed with familial hypercholesterolaemia who were younger than 16 years and who had undergone transthoracic echocardiography from 2007 to 2010 were included in this study. We included patients with homozygous familial hypercholesterolaemia and aortic supravalvular stenosis and those with heterozygous familial hypercholesterolaemia. All patients underwent stress echocardiography, and left anterior descending coronary artery flow was successfully detected. Coronary flow velocity reserve was calculated as the ratio of hyperaemic mean diastolic flow velocity after injection of adenosine to basal mean diastolic flow velocity. Changes in coronary haemodynamics and the relationship between lipid concentrations were determined. RESULTS: A total of 11 patients with homozygous familial hypercholesterolaemia were enrolled in this study. Lipid concentrations were measured, and the mean coronary flow velocity reserve was 1.97 plus or minus 0.51. Seven children were included in the group of patients with heterozygous familial hypercholesterolaemia. In these children, the mean coronary flow velocity reserve was 3.08 plus or minus 0.84. CONCLUSION: The coronary flow velocity reserve of homozygous familial hypercholesterolaemic patients is lower than that of heterozygous familial hypercholesterolaemic patients, and it is associated with a high concentration of low-density lipoprotein cholesterol. Aortic stenosis and plaques compromised the ostia of the coronary artery and caused increased basal mean diastolic coronary velocity with blunted increase in peak velocity, which decreased the coronary flow velocity reserve.

Noninvasive evaluation of coronary flow velocity reserve in homozygous familial hypercholesterolemia by transthoracic Doppler echocardiography.

OBJECTIVE: To evaluate the value of transthoracic Doppler echocardiography (TTDE) of the left anterior descending coronary for the detection of early abnormalities of coronary arteries in asymptomatic patients with homozygous familial hypercholesterolemia (HoFH). METHODS: Seventeen asymptomatic patients with HoFH and 10 controls had plasma total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides measured and underwent TTDE of their left coronary descending artery to determine peak and mean flow velocities under basal conditions and under hyperemia induced by adenosine infusion. Coronary flow velocity reserve (CFVR) was calculated from the mean flow velocities. The presence of aortic supravalvular stenosis was also determined from supravalvular flow velocity and aortic valve thickening values. RESULTS: HoFH patients had similar basal but significantly lower hyperemic flow velocities and CFVR than control patients. Eight of the 17 HoFH patients had supravalvular aortic stenosis, and these patients had significantly higher LDL cholesterol and lower CFVR than those without this stenosis. Treatment with lipid-lowering drugs lowered lipid levels and increased CFVR values, but neither of these parameters reached normal values. CONCLUSIONS: TTDE is a suitable noninvasive technique to detect early abnormalities of coronary arteries and to monitor the clinical efficacy of lipid-lowering treatment in asymptomatic HoFH patients.

[Research progress on the association between genetic variations in lipid metabolism and premature coronary artery disease].

Recent research has demonstrated a strong genetic linkage between premature coronary artery disease (pCAD) and dyslipidemia. Genetic variation in lipid metabolism can lead to impediment of lipid anabolism and catabolism, which promotes vascular arterosclerogenesis. Currently, related studies were focused on: (1) Gene mutations related to low density lipoprotein metabolism, such as low density lipoprotein receptor, apolipoprotein B, apolipoprotein E; (2) Gene mutations related to high density lipoprotein metabolism-related genes, such as ATP binding cassette transporter, apolipoprotein A1, lipoprotein lipase; (3) low density lipoprotein receptor-related genes: Adiponectin. These genes had been proved to be cor-related with pCAD. Mutations of these genes can lead to series of genetic disease characterized by pCAD. This review gives a brief summary of the roles of these genes played in the initiation and development of pCAD, providing valuable information to primer prevention and individualized treatment of CAD.