In patients with familial hypercholesterolemia, the use of torcetrapib with atorvastatin, as compared with atorvastatin alone, did not result in further reduction of progression of atherosclerosis, as assessed by a combined measure of carotid arterial-wall thickness, and was associated with progression of disease in the common carotid segment. These effects occurred despite a large increase in HDL cholesterol levels and a substantial decrease in levels of LDL cholesterol and triglycerides. (ClinicalTrials.gov number, NCT00136981 [ClinicalTrials.gov].).
Imaging modalities have been developed to assess atherosclerosis in vivo in the arterial wall because large clinical end-point studies are time-consuming and costly. Historically, in-hospital angiography and Doppler ultrasonography have been used to assess atherosclerosis development. Investigations of the arterial lumen are, however, increasingly being replaced by modalities that can measure changes in the arterial wall itself-intravascular ultrasonography, MRI and multislice CT. The fact that intravascular ultrasonography is invasive, CT involves substantial radiation exposure and requires contrast agents, and that MRI is time-consuming and technically challenging all limit the widespread use of these techniques. Moreover, all modalities have high associated costs. B-mode ultrasonographic imaging of the carotid arterial walls occupies a unique position in atherosclerosis research. This method enables sensitive, reproducible and noninvasive assessment of intima-media thickness (IMT) as a continuous variable. Epidemiological and clinical trial evidence as well as digitization and standardization have made carotid IMT a validated and accepted marker for generalized atherosclerosis burden and vascular disease risk. Here we describe the application of carotid IMT measurements as a tool in risk evaluation of individuals and in studies of atherosclerosis progression and regression.
Several chronic inflammatory disorders, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), and chronic infections that are associated with a chronic inflammatory state, such as human immunodeficiency virus (HIV) infection, are associated with an increased incidence of cardiovascular disease (CVD). Cardiovascular mortality is a major cause of death in patients with these disorders. Direct effects and indirect sequelae of systemic inflammation promote atherothrombotic vascular disease. Pathophysiological processes promoting atherogenesis can initiate years before the diagnosis of a chronic inflammatory disease is made, and since exposure to risk factors in this pre-clinical phase is widespread, early cardiovascular protection in these patients seems warranted.
A chronic inflammatory state is a risk factor for accelerated atherogenesis. The aim of our study was to explore whether Crohn's disease (CD), characterized by recurrent inflammatory episodes, is also associated with accelerated atherogenesis. In 60 CD patients and 122 matched controls, carotid intima media thickness (IMT), a validated marker for the burden and progression of atherosclerosis, was assessed ultrasonographically. Additional subgroup analyses, including plasma levels of acute phase reactants and HDL protein profiling, were performed in 11 consecutive patients with CD in remission, 10 patients with active CD, and 15 healthy controls. Carotid IMT in patients with CD was increased compared with healthy volunteers: 0.71 (0.17) versus 0.59 (0.14) mm (P , 0.0001), respectively. In the subgroup analysis, HDL levels in controls and patients in remission were identical [(1.45 (0.48) and 1.40 (0.46) mmol/l; P 5 0.797], whereas HDL during exacerbation was profoundly reduced: 1.02 (0.33) (P 5 0.022). HDL from patients with active CD and CD patients in remission was characterized by a reduced ability to attenuate oxidation compared with controls (P 5 0.008 and P 5 0.024 respectively). Patients with CD have increased IMT compared with matched controls, indicative of accelerated atherogenesis. The changes during CD exacerbation in terms of HDL concentration and composition imply a role for impaired HDL protection in these patients.-van
Objective-Low high-density lipoprotein (HDL) cholesterol is a strong independent cardiovascular risk factor, which has been attributed to its role in reverse cholesterol transport. Whereas HDL also has potent antiinflammatory effects, the relevance of this property remains to be established in humans. In the present study, we evaluated whether there is a relation between HDL and sensitivity toward a low-dose endotoxin challenge. Methods and Results-Thirteen healthy men with genetically determined isolated low HDL cholesterol (averaging 0.7Ϯ0.1 mmol/L) and 14 age-and body weight-matched healthy men with normal/high HDL cholesterol levels (1.9Ϯ0.4 mmol/L) were challenged with low-dose endotoxin intravenously (1 ng/kg body weight). The incidence and severity of endotoxin-associated clinical symptoms was increased in the low HDL group. Accordingly, both the inflammatory response (tumor necrosis factor-␣, IL-1, IL-6, IL-8, and monocyte chemoattractant protein-1) as well as thrombin generation (prothrombin activation fragments F 1ϩ2 ) were significantly increased in the low HDL group on endotoxin challenge. A fter the first report on the potential antiatherogenic effect of high-density lipoprotein (HDL) almost 60 years ago, HDL is now generally acknowledged as a potent antiatherogenic mediator. 1 The impact of isolated low HDL cholesterol on atherogenesis was recently underscored by the finding that carotid intima-media thickness in patients with genetically determined low apolipoprotein (apo) A-I was comparable to that in patients with familial hypercholesterolemia. 2 In line, HDL increasing drugs now are prime candidates for combined use with statins in high-risk subjects. Conclusions-LowTraditionally, the protective effect of HDL was considered to be confined to its role in the reverse cholesterol transport pathway. However, recent evidence supports a wide array of antiatherogenic effects by HDL, comprising antioxidative, antithrombotic, and antiinflammatory effects. 3 The latter has attracted special interest, because inflammation has been acknowledged to underlie atherosclerotic lesion formation. At the same time, HDL cholesterol consistently shows an inverse relation with systemic markers of inflammation. 4 Interestingly, HDL-increasing compounds (eg, reconstituted HDL) have recently been shown to attenuate systemic inflammation in humans, 5 as well as vessel wall inflammation in experimental animal models. 6 However, it remains to be established whether HDL also exerts antiinflammatory effects in the human setting. In the present study, we evaluated the impact of plasma HDL cholesterol level on the sensitivity toward a low-dose endotoxin challenge in subjects with genetically determined low versus normal/high HDL cholesterol levels. Patients and Methods Study ParticipantsStudy subjects were recruited from a study designed to identify genes that control HDL cholesterol levels. 2 Healthy male subjects with plasma HDL cholesterol levels Ͻ10 th percentile (low HDL group, nϭ13) and healthy male subjects with plasma...
Background:Macrophage migration inhibitory factor (MIF) has recently emerged as an important cytokine possibly linking rheumatoid arthritis (RA) and atherogenesis. Because atherogenesis is accelerated in RA this study was conducted to investigate whether anti-tumour necrosis factor (TNF) therapy could lead to sustained downregulation of systemic MIF levels and improvement in lipid profiles.Methods:Fifty RA patients with active disease (disease activity score in 28 joints (DAS28) ⩾3.2), who started adalimumab therapy at 40 mg every other week, were included. At baseline, weeks 16 and 52 serum levels of MIF and lipids were assessed. In addition, the DAS28 and serum C-reactive protein (CRP) levels and erythrocyte sedimentation rate (ESR) were determined.Results:After 16 weeks of adalimumab therapy, both DAS28 and MIF levels were significantly decreased (p<0.001 and p = 0.020, respectively). This was sustained up to week 52 (p<0.001 and p = 0.012, respectively). CRP levels and ESR were significantly reduced after 16 and 52 weeks of adalimumab therapy (p<0.001). High-density lipoprotein cholesterol levels increased at week 16 (p<0.001), but returned to baseline at week 52. Apolipoprotein (apo) A-I levels increased at week 16 (p<0.001) and remained stable (p = 0.005). This resulted in an improved apo B/A-I ratio.Conclusions:The results underline the sustained downregulation of MIF as a potential new mechanism by which anti-TNF therapy might reduce vascular inflammation, and as such perhaps cardiovascular morbidity in RA patients. This hypothesis is supported by an improved apo B/A-I ratio as well as reduced CRP levels in these patients.
Objective-To determine the association between serum levels of mannose-binding lectin (MBL) and the risk of future coronary artery disease (CAD) in apparently healthy men and women. Methods and Results-We performed a prospective case-control study among apparently healthy men and women nested in the EPIC-Norfolk cohort.
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