The effect of cholesterol lowering on carotid and femoral artery wall stiffness and thickness in patients with familial hypercholesterolaemia

BACKGROUND: Early in the process of atherosclerosis, changes in vessel wall stiffness and thickness may occur. The present study evaluates the effect of cholesterol reduction on artery wall stiffness and intima media thickness in patients with familial hypercholesterolaemia (FH). MATERIALS AND METHODS: Forty-five patients with familial hypercholesterolaemia (mean age 46+/-10 years) with untreated LDL cholesterol concentration > 9 mmol L(-1), were studied before and after one year of cholesterol lowering therapy with statins (simvastatin, atorvastatin 40-80 mg day(-1). The distensibility (DC in 10-3 kPa(-1) and compliance (CC in mm2. kPa(-1) of the common carotid artery (CCA) (right and left side) and common femoral artery (CFA) (right side) were determined by a wall track system (Pie Medical). The intima media thickness (IMT) (both right and left) of the CCA, bulb (BUL), internal carotid artery (ICA) and CFA were measured in mm by high-resolution ultrasound (Biosound). RESULTS: The mean concentration of total cholesterol (TC), LDL-cholesterol (LDL-C) and triglycerides (TG) were reduced significantly by 43%, 51% and 25%, respectively, whereas HDL-cholesterol (HDL-C) increased by 13% (P<0.001). In the CFA, the DC and CC increased significantly (DC from 7.9+/-3.0 to 9.1+/-3.7 in 10(-3) kPa(-1); CC 0.5+/-0.2-0.6+/-0.3 in mm2. kPa(-1), whereas the DC and CC did not change in the CCA. In contrast, the IMT of the CCA decreased significantly in both men and women whereas an IMT decrease was also seen in the BUL and ICA in premenopausal women. A LDL-cholesterol reduction of 44.8% and 45.4% was necessary to induce significant decreases in IMT and increases in DC and CC. CONCLUSIONS: One year of cholesterol lowering therapy in FH decreases the wall stiffness in the CFA and the arterial wall thickness in the CCA.     

Low-grade systemic inflammation impairs arterial stiffness in newly diagnosed hypercholesterolaemia

BACKGROUND: Excess of cardiovascular risk among patients with chronic inflammatory diseases has been attributed to increased arterial stiffness. Hypercholesterolaemia has been demonstrated to promote a low-grade inflammatory status. The objective of the present study was to define, in hypercholesterolaemia, the influence of plasma lipids, low-grade inflammation, and indices of adiposity on aortic pulse wave velocity, a measure of arterial stiffness and cardiovascular risk. MATERIALS AND METHODS: Anthropometric characteristics, plasma lipids, C-reactive protein and aortic pulse wave velocity were measured in 85 subjects (60 patients with newly diagnosed never-treated hypercholesterolaemia and 25 age- and sex-matched normocholesterolaemic controls). RESULTS: Plasma C-reactive protein and aortic pulse wave velocity were significantly higher among hypercholesterolaemic patients than in controls (P < 0.05 for both). Aortic pulse wave velocity was associated with age (r = 0.24, P = 0.04), body mass index (r = 0.33, P = 0.006), waist (r = 0.42, P < 0.001) and hip (r = 0.32, P = 0.007) circumferences, as well as with systolic (r = 0.34, P = 0.003) and diastolic (r = 0.30, P = 0.01) blood pressures, plasma C-reactive protein (r = 0.51, P < 0.001), total cholesterol (r = 0.45, P < 0.001), and low-density lipoprotein cholesterol (r = 0.46, P < 0.001). In the multivariate analysis, waist circumference and C-reactive protein levels predicted increased aortic stiffness, independently of traditional cardiovascular risk factors. The degree of independent association between cholesterol, systolic blood pressure and aortic stiffness increased when indices of adiposity and inflammation were excluded from the multivariate analysis. Comparable results were obtained when the analyses were restricted to hypercholesterolaemic patients. CONCLUSIONS: Low-grade systemic inflammation and abdominal fat, more than traditional risk factors, are major determinants of reduced arterial distensibility in hypercholesterolaemia.     

Increased inflammatory markers in children with familial hypercholesterolaemia

BACKGROUND: While data are abundant on increased levels of inflammatory markers in adult patients with hypercholesterolaemia, such data in children are limited. Therefore, we sought to investigate the degree and character of inflammation in children with heterozygous familial hypercholesterolaemia (FH) by measuring levels of neopterin, high-sensitivity C-reactive protein (hsCRP), and soluble CD40 ligand (sCD40L). MATERIALS AND METHODS: In the present study, we compared the concentration of inflammatory markers in children suffering from heterozygous FH (n = 207) with those in unaffected siblings (n = 84). Furthermore, we investigated the effect of 2-year treatment with pravastatin (20-40 mg qd) or placebo on plasma levels of those markers. RESULTS: Our main finding was that serum levels of neopterin and hsCRP were significantly higher in FH children compared with healthy siblings, whereas sCD40L was not. Body mass index and high-density lipoprotein cholesterol levels were significant independent predictors of hsCRP and neopterin. Furthermore, pravastatin therapy decreased neopterin, but not hsCRP and sCD40L, in the FH children, but these changes were not different from the placebo group. CONCLUSION: These findings indicate low-grade monocyte/macrophage hyperactivity in the early stages of atherogenesis, but our findings also suggest that inflammation as well as anti-inflammatory effects of statins are less prominent features of atherosclerosis in FH children than in FH adults.     

Low HDL cholesterol concentration is associated with increased intima-media thickness independent of arterial stiffness in healthy subjects from families with low HDL cholesterol

BACKGROUND: Low high-density lipoprotein cholesterol (HDL-C) is associated with increased risk for developing coronary artery disease. Cardiovascular disease is characterized by increased intima-media thickness (IMT) and arterial stiffness, but the effect of low HDL on these measurements has not been reported. MATERIALS AND METHODS: We studied 18 apparently healthy subjects from families with low HDL-C and 18 control subjects, which were pair-matched to maximize statistical power. Intima-media thickness was assessed using ultrasound examination of the carotid arteries. Arterial stiffness was measured using applanation tonometry on the radial artery and pulse-wave analysis to obtain central aortic pulse-pressure waveform, from which the augmentation index, a measure of global large artery stiffness, was calculated. RESULTS: Low HDL subjects (age 41 +/- 3 years, BMI 26.6 +/- 1.0 kg m(-2) had significantly lower HDL-C than the control subjects (age 41 +/- 3 years, BMI 26.5 +/- 1.0 kg m-2; 1.00 +/- 0.05 vs. 1.49 +/- 0.09 mmol L-1, low HDL vs. control subjects, P < 0.0001). Subjects with low HDL-C had significantly thicker mean IMTs than the control subjects (0.77 +/- 0.03 vs. 0.70 +/- 0.02 mm, low HDL vs. control subjects, P < 0.01). The maximal (0.99 +/- 0.04 vs. 0.89 +/- 0.03 mm, P < 0.01), far wall (0.76 +/- 0.04 vs. 0.69 +/- 0.02 mm, P < 0.05) and carotid bulb (1.11 +/- 0.06 vs. 0.97 +/- 0.04 mm) IMTs were also significantly increased, whereas the mean common carotid and the internal artery IMT were not. The age-related increase in mean IMT was more pronounced in the low HDL subjects than the control subjects (P < 0.01 for difference between elevations of age vs. IMT slopes). There were no differences in central pressure augmentation, the augmentation index, peripheral or central blood pressures between the groups. CONCLUSIONS: A low HDL-C concentration is associated with thickening of carotid IMT independent of other risk factors in healthy affected members of low HDL families.     

Aortic stiffness and carotid intima‐media thickness: two independent markers of subclinical vascular damage in young adults?

BACKGROUND: Previous reports have shown that carotid intima-media thickness (CIMT) and arterial stiffness are strong predictors of subsequent cardiovascular disease (CVD) morbidity and mortality, and are well related to an unfavourable cardiovascular risk profile in middle-aged and older subjects. These similarities suggest that arterial stiffness may play a role in the development of atherosclerosis or vice versa. However, studies show conflicting results and are limited to elderly subjects. To study this issue further, we evaluated the relation of arterial stiffness to subclinical atherosclerosis in 524 healthy young adults, aged 27-30 years. METHODS AND RESULTS: Aortic stiffness was assessed using pulse wave velocity (PWV) and CIMT was used as measure of subclinical atherosclerosis. The positive crude correlation between for mean arterial pressure adjusted PWV and CIMT (Pearson's correlation coefficient: 0.11; P=0.016) attenuated after adjustment for common determinants of both measurements like gender and age (partial correlation coefficient: 0.03; P=0.512). Furthermore, multivariate linear regression models showed that male gender, age and blood pressure were independent determinants of both CIMT and PWV while body mass index and LDL-cholesterol were independent determinants of CIMT only. CONCLUSIONS: These observations suggest that in healthy young adults arterial stiffness and CIMT reflect two separate entities of vascular damage.     

大动脉僵硬度与冠脉病变严重性的相关研究

目的：探讨大动脉僵硬度与冠脉病变严重程度的相关性。方法：选择2006年1月一2007年12月疑诊为冠心病人院患者637例，所有入选患者均进行颈股脉搏波传导速度（c—FPwV）检测，评价动脉僵硬度。行冠脉造影评价冠永病变严重程度。根据c—FPwV水平分为三组：I组（C—FPWV0～10．0，220例），Ⅱ组（C—FPWV10．1～13．0，242例），Ⅲ组（C—FPWV≥13．1，175例），观察患者临床特征。结果：各组间比较，Ⅲ组年龄偏大，糖尿病，心肌梗死和高血压病史多，C型病变和三支病变常见，多因素Logistic分析冠脉病变严重程度和C—FPWV呈正相关联，相对危险性（OR）为1．51（95％CI1．017～2．241）。结论：CFPWV是最为经典的评价动脉僵硬度的方法，与冠脉病变的严重程度密切相关，可作为心血管疾病的一个危险信号，指导早期干预，为心血管疾病独立强有力预测因子，对冠心病防治有广泛应用前景。     

Impact of genetic defects on coronary atherosclerosis in patients suspected of having familial hypercholesterolaemia

BACKGROUND: In the present study we assessed whether the presence of genetic mutations typical of familial hypercholesterolaemia (FH) was associated with greater atherosclerosis in the coronary vessels in patients with severe hypercholesterolaemia and a family history of early cardiovascular disease. MATERIALS AND METHODS: Two hundred and thirty-five patients selected for having severe hypercholesterolaemia and a family history of cardiovascular disease were classified as FH (57 men and 38 women) or non-FH (84 men and 56 women) according to a genetic analysis of the LDL-R or ApoB genes. Coronary atherosclerosis was evaluated by performing a thoracic CT scan and exercise stress testing. RESULTS: Familial hypercholesterolaemia individuals had a significantly higher prevalence of coronary calcification than the non-FH patients from among both the men (OR = 3.90; 95% CI 1.86-8.19; P < 0.001) and the women (OR = 2.34; 95% CI 1.01-5.48; P = 0.05). In exercise stress testing, ECG abnormalities suggestive of cardiac ischaemia were found with a higher prevalence in the FH patients than the non-FH patients from among both the men (OR 6.15; 95% CI 2.16-17.5; P < 0.001) and the women (OR 4.76; 95% CI 0.91-24.6; P = 0.06). All differences were statistically significant after adjusting for age and cholesterol and for most classical risk factors that differed between the FH and non-FH groups. CONCLUSION: Among patients with severe hypercholesterolaemia and a family history of early cardiovascular disease, the presence of a genetically ascertained FH is associated with a higher prevalence of coronary artery calcifications and a positive exercise stress test. These results suggest that despite a similar phenotype, patients carrying mutations suggestive of FH may have a greater cardiovascular risk than patients without these mutations.     

Arterial stiffness in relation to subclinical atherosclerosis

Background Increased arterial stiffness or arteriosclerosis, represents a physiological part of ageing. Atherosclerosis is a process that does not affect the arterial bed uniformly but has a variable local distribution and is frequently superimposed on stiffened vessels. We therefore addressed the question of whether any correlation exists between the general characteristics of arterial stiffness or wave reflection and subclinical atherosclerosis as assessed by carotid intima‐media thickness (IMT) in a sample of healthy subjects. Methods A total of 116 healthy subjects (mean age 55 years, 43 female) were evaluated. Arterial stiffness and wave reflection was assessed with the use of digital volume pulse analysis (DVP) and pulse wave analysis (PWA). Subclinical atherosclerosis was assessed by measurement of IMT. Results Stiffness Index (SI_DVP), the measure of general arterial stiffness correlated significantly with IMT (r = 0·37, P < 0·01). IMT correlated significantly with age (r = 0·5, P < 0·0001), waist to hip ratio (WHR) (r = 0·39, P < 0·0001) and mean blood pressure (BPmean) (r = 0·4, P < 0·0001). IMT did not correlate with measures of wave reflection. SI_DVP correlated significantly with age (r = 0·32, P < 0·005), WHR (r = 0·36, P < 0·0001), BPmean (r = 0·36, P < 0·0001) and measurements of wave reflection. However analysis of a model which included variables that significantly influenced SI_DVP and IMT, such as age, WHR and mean BP showed that arterial stiffness is not independently associated with subclinical atherosclerosis. Conclusions The indices of subclinical atherosclerosis, arterial stiffness and wave reflection, indicate different aspects of vascular status in otherwise healthy subjects     

The regulation of sterol biosynthesis in leucocytes of subjects with familial hypercholesterolaemia

Abstract. The regulation of sterol synthesis and 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoA reductase) activity in leucocytes has been studied in seventy-five subjects of whom thirteen had familial hypercholesterolaemia (heterozygous). The activity of HMG-CoA reductase in leucocytes was closely parallel to the incorporation of ¹⁴C-acetate into sterols over a wide range of activities, suggesting that the enzyme is ratedetermining for the pathway. When six obese subjects were placed on an acaloric diet for 7 days sterol synthesis declined by 75% in adipocytes but was unaffected in leucocytes. A low cholesterol diet (< 250 mg/day) for 7 days did not affect sterol synthesis in either cell type.
In subjects with familial hypercholesterolaemia (heterozygous) the enzyme tended to increase to higher levels than controls when leucocytes were incubated in a lipid-deficient medium; but a more marked abnormality was a failure of suppression of the enzyme when leucocytes from affected subjects were returned for 8 h to a medium containing low-density lipoprotein. In one kindred the index patient with severe heterozygous familial hypercholesterolaemia had a normally regulated enzyme whereas his affected siblings (brother and sister) showed incomplete suppression of the enzyme by low-density lipoprotein.
It is concluded that loss of regulation of HMG-CoA reductase may be phenotypically linked to the origin of familial hypercholesterolaemia and in most cases provides a useful genetic marker for the disease.     

脉搏波传导速度评价动脉僵硬度的应用进展

动脉脉搏波传导速度（PWV）是反映动脉僵硬度的可靠指标,为临床评估动脉硬化提供了重要信息。近年来,随着科学技术的发展,PWV作为能够定量评价动脉僵硬度的指标,其检测效能和应用价值得到不断的提升,已被越来越多的临床工作者所认可。本文就PWV评价动脉僵硬度的研究进展进行综述。     

Elevated apolipoprotein B-48 and remnant-like particle-cholesterol in heterozygous familial hypercholesterolaemia

Apolipoprotein B-48 (apoB-48) is a marker of triglyceride-rich lipoprotein (TRL) remnants of intestinal origin. Chylomicron remnants are causally related to atherosclerosis. We have shown previously that fasting plasma apoB-48 may predict postprandial lipaemia. Remnant-like particle-cholesterol (RLP-C) may also reflect TRL remnants. We aimed to determine whether subjects with heterozygous familial hypercholesterolaemia (FH) had an accumulation of remnants of intestinal origin, as reflected by fasting plasma apoB-48 and RLP-C levels. The fasting plasma concentrations of apoB-48 and RLP-C were measured in 15 subjects with heterozygous FH and 15 age- and sex-matched, normolipidaemic subjects. ApoB-48 was determined using SDS-PAGE and a western blotting/enhanced chemi-luminescence technique. RLP-C was measured using an immuno-separation assay. Serum apolipoprotein B-100 (apoB-100) levels were measured using immunonephelometry; lipids were assayed enzymatically. Compared with controls, FH subjects had significantly elevated plasma concentrations of apoB-48 (29.3 median, 16.7-45.1 mg L-1 range vs. 12.8, 7.3-28.6; P < 0.001) and RLP-C (16.2, 1.5-114.3 mg dL-1 vs. 8.5, 5.0-13.5; P = 0.003), as well as serum total apoB-100 (1.9, 1.3-2.6 g L-1 vs. 1.0, 0.3-1.3; P < 0.001), LDL-cholesterol (8.1, 4.6-10.4 mmol L-1 vs. 3.5, 2.4-4.4; P < 0.001) and triglyceride (1.5, 0.6-5.6 mmol L-1 vs. 1.0, 0.4-1.8; P = 0.018). There was no significant difference in HDL cholesterol. The findings suggest that patients with heterozygous FH have elevated plasma concentrations of TRL remnants, including those of intestinal origin. This may be a consequence of decreased clearance of these particles by the LDL-receptor.     

腹膜透析患者血尿酸与动脉僵硬度的相关性研究

目的动脉僵硬是心血管疾病的重要危险因素。本研究探讨腹膜透析患者血尿酸和动脉僵硬度的关系。方法采集158名稳定腹膜透析患者的临床和生化数据,测定其颈-股动脉脉搏波速度(CF-PWV)作为动脉僵硬度的指标。结果根据血尿酸浓度,患者被分为4组。在组间有显著性差异的指标有C反应蛋白(CRP)(P<0.05)和CF-PWV(P<0.01)。Pearson相关分析显示,和CF-PWV明显相关的因素包括收缩压(P<0.05)和尿酸浓度(P<0.01)。多元逐步回归分析显示,血尿酸浓度(β=-0.300,P=0.001)和钙磷乘积(β=0.179,P=0.027)是CF-PWV的独立影响因素。结论血尿酸水平和动脉僵硬度有独立的相关关系。血尿酸浓度升高和动脉僵硬度增加有关,可能参与了心血管事件的发生。     

Inflammation and oxidative stress are associated differently with endothelial function and arterial stiffness in healthy subjects and in patients with atherosclerosis

Inflammation and oxidative stress (OxS) play key roles in atherogenesis; however, their causal relationship is not yet completely understood. Much attention has been given to the possibility that inflammation is a primary process of atherosclerosis and that OxS may be a by‐product of the inflammatory process. We hypothesized, accordingly, that chronic systemic inflammation affects endothelial vasomotor function in the subclinical condition, whereas oxidative modifications are more involved in the structural stiffening of the arteries in atherosclerosis. The aim of our study was to test this hypothesis. Endothelial function and arterial stiffness were assessed non‐invasively by pulse wave analysis, and blood/urinary samples were taken in 39 patients with peripheral arterial disease as well as in 34 controls. The patients showed significantly reduced endothelial function index (EFI) and increased augmentation index (AIx), as well as higher estimated aortic pulse wave velocity (PWV) and elevated values of the intercellular adhesion molecule‐1 (ICAM‐1), high sensitivity C‐reactive protein, myeloperoxidase and urinary 8‐iso‐prostaglandin F_2a (F₂‐IsoPs). There was an inverse association between EFI and ICAM‐1 (R = ?0.44, p = 0.009) in the controls, but not in the patients. Augmentation index and estimated aortic PWV correlated with F₂‐IsoPs only in the patients (R = 0.5, p = 0.001; R = ?0.43, p = 0.006, respectively). After controlling for potential confounders, these associations remained significant. The study demonstrates that impairment of endothelial vasomotor capacity is affected by degree of inflammation in the subclinical condition, whereas arterial stiffening is determined by level of oxidative modifications in atherosclerosis.     

维持性血液透析患者脉压及相关因素分析

目的探讨维持性血液透析（MHD）患者的脉压水平及其相关因素。方法对北京大学人民医院血液净化中心90例MHD患者采用WelchAllyn血压计测定非内瘘侧上肢肱动脉血压并记录。脉压（PP）和平均动脉压（MAP）分别根据收缩压（SBP）-舒张压（DBP）和（SBP＋2DBP）/3计算得出。检测患者血生化指标和全段甲状旁腺素（iPTH）水平。采用Complior SP脉搏波速度（PWV）测定仪测定其单次透析前颈动脉-股动脉脉搏波速度（CFPWV）。对MHD患者PP与相关因素进行多元逐步回归。对糖尿病透析患者和非糖尿病透析患者进行独立样本t检验。36例性别、年龄匹配的健康成人作为对照。结果MHD患者PP（59.8±16.8）mmHg（1mmHg=0.133kpa）,SBP（140.9±20.4）mmHg,MAP（101.1±14.7）mmHg,CFPWV（13.22±3.23）m/s,均高于正常对照（P〈0.05）。多元逐步回归发现,年龄、糖尿病和CFPWV是MHD患者PP的独立影响因素。糖尿病患者SBP、PP及CFPWV明显高于非糖尿病患者（P〈0.05）,DBP低于非糖尿病患者,但差异无统计学意义。结论维持性血液透析患者脉压明显增加,SBP增高是其主要原因。年龄、糖尿病和CFPWV是脉压的独立影响因素。     

中国福建畲族自然人群血管结构功能及其影响因素

目的 探讨中国福建畲族自然人群血管结构功能及其影响因素。方法 选取358名福建畲族志愿者,根据颈-股动脉脉搏波传导速度（cf-PWV）不同分为动脉弹性正常组（cf-PWV≤9 m/s,144名）和动脉弹性降低组（cf-PWV>9 m/s,214名）。应用多普勒超声诊断仪测定左侧颈动脉内膜-中层厚度（L-CIMT）、右侧颈动脉内膜-中层厚度（R-CIMT）,并进行实验室检查测定总胆固醇（TC）、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）、甘油三酯（TG）、空腹血糖（FPG）、尿酸（UA）、尿素氮（BUN）、肌酐（Cr）、超敏C反应蛋白。并进行统计学分析。结果 动脉弹性降低组的L-CIMT、R-CIMT、年龄、心率、收缩压、舒张压、脉压、BUN、Cr、FPG、TG、TC、cf-PWV、LDL-C水平均显著高于动脉弹性正常组（P均<0.05）。动脉硬化的危险因素包括年龄、心率、收缩压、BUN、TC,而LDL-C是动脉硬化的保护因素。动脉弹性降低组和动脉弹性正常组cf-PWV与L-CIMT、R-CIMT均呈正相关（r=0.369、0.316,0.223、0.171,P均<0.05）。L-CIMT的独立影响因素为年龄和收缩压（P均<0.05）,R-CIMT的独立影响因素为年龄和脉压（P均<0.05）。结论 中国福建畲族自然人群的年龄、心率、收缩压、BUN、TC是动脉硬化的危险因素,cf-PWV与双侧CIMT均呈正相关。     

老年高血压患者血浆同型半胱氨酸浓度与动脉壁僵硬度的相关性研究

目的：探讨老年高血压患者动脉脉搏波速率与血管危险因子同型半胱氨酸浓度的关系。方法选取2012年2月-2013年2月在本院老年科住院的老年高血压患者52例,在空腹状态下测定血浆同型半胱氨酸浓度及动脉脉搏波速率。结果血浆同型半胱氨酸浓度与脉搏波速率具有显著相关性（r＝0．8854,P＜0．001）。结论在血压控制的情况下,老年高血压患者血浆同型半胱氨酸浓度与脉搏波速率呈正相关。