Cardiovascular risk factor control and outcomes in peripheral artery disease patients in the Reduction of Atherothrombosis for Continued Health (REACH) Registry

OBJECTIVES: To examine differences in risk factor (RF) management between peripheral artery disease (PAD) and coronary artery (CAD) or cerebrovascular disease (CVD), as well as the impact of RF control on major 1-year cardiovascular (CV) event rates. METHODS: The REACH Registry recruited >68000 outpatients aged >/=45 years with established atherothrombotic disease or >/=3 RFs for atherothrombosis. The predictors of RF control that were evaluated included: (1) patient demographics, (2) mode of PAD diagnosis, and (3) concomitant CAD and/or CVD. RESULTS: RF control was less frequent in patients with PAD (n=8322), compared with those with CAD or CVD (but no PAD, n=47492) [blood pressure; glycemia; total cholesterol; smoking cessation (each P<0.001)]. Factors independently associated with optimal RF control in patients with PAD were male gender (OR=1.9); residence in North America (OR=3.5), Japan (OR=2.5) or Latin America (OR=1.5); previous coronary revascularization (OR=1.3); and statin use (OR=1.4); whereas prior leg amputation was a negative predictor (OR=0.7) (P<0.001). Optimal RF control was associated with fewer 1-year CV ischemic symptoms or events. CONCLUSIONS: Patients with PAD do not achieve RF control as frequently as individuals with CAD or CVD. Improved RF control is associated with a positive impact on 1-year CV event rates.

Relation of morning serum cortisol to prothrombotic activity in women with stable coronary artery disease

BACKGROUND: Increased circulating cortisol levels have been associated with severity of atherosclerosis. Low-grade systemic thrombogenicity plays a major role in the initiation and progression of coronary disease. We hypothesized a direct relationship between cortisol and hemostasis factors related to a prothrombotic state in coronary artery disease. METHODS: We measured morning serum cortisol and activated clotting factor VII, fibrinogen, von Willebrand factor antigen, and plasminogen activator inhibitor-1 activity in 285 women (56 +/- 7 years) between 3 and 6 months after an acute coronary event. To test whether the relationship between cortisol and hemostasis factors would be independent, statistical adjustment was made for demographic, biomedical, life style, and psychosocial variables. RESULTS: Higher serum cortisol levels predicted higher fibrinogen (beta = .17, P = .001) and higher von Willebrand factor (beta = .16, P = .008), all independently of covariates, including C-reactive protein, which was also an independent predictor of fibrinogen (beta = .20, P = .001) and von Willebrand factor (beta = .16, P = .004). Higher levels of vital exhaustion were associated with higher levels of activated clotting factor VII independently of covariates and depression (beta = .18, P = .045). Cortisol showed crude correlations with vital exhaustion (r = .14, P = .022) and with depression (r = .13, P = .043) but did not mediate the relationship between psychosocial variables and hemostatic factors. CONCLUSIONS: Morning serum cortisol showed a modest but independent association with prothrombotic activity in women with coronary artery disease suggesting that increased cortisol levels might contribute to atherosclerosis via eliciting a hypercoagulable state.

Percutaneous coronary revascularization in patients with formerly "refractory angina pectoris in end-stage coronary artery disease" - not "end-stage" after all

BACKGROUND: Patients with refractory angina pectoris in end-stage coronary artery disease represent a severe condition with a higher reduction of life-expectancy and quality of life as compared to patients with stable coronary artery disease. It was the purpose of this study to invasively re-evaluate highly symptomatic patients with formerly diagnosed refractory angina pectoris in end-stage coronary artery disease for feasible options of myocardial revascularization. METHODS: Thirty-four patients formerly characterized as having end stage coronary artery disease with refractory angina pectoris were retrospectively followed for coronary interventions. RESULTS: Of those 34 patients 21 (61.8%) were eventually revascularized with percutaneous interventional revascularization (PCI). Due to complex coronary morphology (angulation, chronic total occlusion) PCI demanded an above-average amount of time (66 +/- 42 minutes, range 25-206 minutes) and materials (contrast media 247 +/- 209 ml, range 50-750 ml; PCI guiding wires 2.0 +/- 1.4, range 1-6 wires). Of PCI patients 7 (33.3%) showed a new lesion as a sign of progression of atherosclerosis. Clinical success rate with a reduction to angina class II or lower was 71.4% at 30 days. Surgery was performed in a total of8 (23.5%) patients with a clinical success rate of 62.5%. Based on an intention-to-treat 2 patients of originally 8 (25%) demonstrated clinical success. Mortality during follow-up (1-18 months) was 4.8% in patients who underwent PCI, 25% in patients treated surgically and 25% in those only treated medically. CONCLUSION: The majority of patients with end-stage coronary artery disease can be treated effectively with conventional invasive treatment modalities. Therefore even though it is challenging and demanding PCI should be considered as a first choice before experimental interventions are considered.

Computer-aided diagnosis of carotid atherosclerosis based on ultrasound image statistics, laws' texture and neural networks

Quantitative characterisation of carotid atherosclerosis and classification into symptomatic or asymptomatic is crucial in planning optimal treatment of atheromatous plaque. The computer-aided diagnosis (CAD) system described in this paper can analyse ultrasound (US) images of carotid artery and classify them into symptomatic or asymptomatic based on their echogenicity characteristics. The CAD system consists of three modules: a) the feature extraction module, where first-order statistical (FOS) features and Laws' texture energy can be estimated, b) the dimensionality reduction module, where the number of features can be reduced using analysis of variance (ANOVA), and c) the classifier module consisting of a neural network (NN) trained by a novel hybrid method based on genetic algorithms (GAs) along with the back propagation algorithm. The hybrid method is able to select the most robust features, to adjust automatically the NN architecture and to optimise the classification performance. The performance is measured by the accuracy, sensitivity, specificity and the area under the receiver-operating characteristic (ROC) curve. The CAD design and development is based on images from 54 symptomatic and 54 asymptomatic plaques. This study demonstrates the ability of a CAD system based on US image analysis and a hybrid trained NN to identify atheromatous plaques at high risk of stroke.

Oral contraceptives and the risk of thrombosis and atherosclerosis.

Oral contraceptives containing synthetic oestrogens have been used successfully as birth control for > 40 years and are currently prescribed to > 100 million women worldwide. Several new progestins have been introduced and the third generation of progestins has now been available for two decades. Oral contraceptives are prescribed over a prolonged period of time and therefore substantially impact on hormonal, metabolic and plasmatic functions. Oral contraceptives increase the risk for venous thrombosis and pulmonary embolism, particularly if associated with confounding factors, such as genetic predisposition, smoking, hypertension or obesity. The risk of developing coronary artery disease is also increased in users with cardiovascular risk factors. This article discusses mechanistic and clinical issues and reviews the need for novel approaches targeting the considerable side effects in order to reduce cardiovascular morbidity in women using oral contraceptives.

Non-coronary atherosclerosis

During the last decades, the clinical and research interest in atherosclerosis has been mostly focused on coronary arteries. After the publications of the European Society Guidelines and AHA/ACC Guidelines on Peripheral artery diseases, and of the Registry REduction in Atherothrombosis for Continued Health Registry, there has been an increased interest in atherosclerosis of the lower extremity arteries and its presence in multifocal disease. However, awareness in the general population and the medical community of non-coronary artery diseases, and of its major prognostic implications remain relatively low. The aim of this general review stemming out of an ESC Working Group on Peripheral Circulation meeting in 2011 is to enhance awareness of this complex disease highlighting the importance of the involvement of atherosclerosis at different levels with respect to clinical presentation, diagnosis, and co-existence of the disease in the distinct arterial territories. We also emphasize the need of an interdisciplinary approach to face the broad and complex spectrum of multifocal disease, and try to propose a series of tentative recommendations and measures to be implemented in non-coronary atherosclerosis.

Prognostic implications of coronary calcification in patients with obstructive coronary artery disease treated by percutaneous coronary intervention: a patient-level pooled analysis of 7 contemporary stent trials

OBJECTIVE To investigate the long-term prognostic implications of coronary calcification in patients undergoing percutaneous coronary intervention for obstructive coronary artery disease. METHODS Patient-level data from 6296 patients enrolled in seven clinical drug-eluting stents trials were analysed to identify in angiographic images the presence of severe coronary calcification by an independent academic research organisation (Cardialysis, Rotterdam, The Netherlands). Clinical outcomes at 3-years follow-up including all-cause mortality, death-myocardial infarction (MI), and the composite end-point of all-cause death-MI-any revascularisation were compared between patients with and without severe calcification. RESULTS Severe calcification was detected in 20% of the studied population. Patients with severe lesion calcification were less likely to have undergone complete revascularisation (48% vs 55.6%, p<0.001) and had an increased mortality compared with those without severely calcified arteries (10.8% vs 4.4%, p<0.001). The event rate was also high in patients with severely calcified lesions for the combined end-point death-MI (22.9% vs 10.9%; p<0.001) and death-MI- any revascularisation (31.8% vs 22.4%; p<0.001). On multivariate Cox regression analysis, including the Syntax score, the presence of severe coronary calcification was an independent predictor of poor prognosis (HR: 1.33 95% CI 1.00 to 1.77, p=0.047 for death; 1.23, 95% CI 1.02 to 1.49, p=0.031 for death-MI, and 1.18, 95% CI 1.01 to 1.39, p=0.042 for death-MI- any revascularisation), but it was not associated with an increased risk of stent thrombosis. CONCLUSIONS Patients with severely calcified lesions have worse clinical outcomes compared to those without severe coronary calcification. Severe coronary calcification appears as an independent predictor of worse prognosis, and should be considered as a marker of advanced atherosclerosis.

Prevalence of type 2 diabetes is higher in peripheral artery disease than in coronary artery disease patients.

Type 2 diabetes mellitus and pre-diabetes are risk factors for atherosclerosis and are highly prevalent in patients with coronary artery disease. However, the prevalence of impaired glucose metabolism in patients with peripheral artery disease is not as well elucidated. We aimed at comparing prevalence rates of type 2 diabetes mellitus and pre-diabetes, which were diagnosed according to the current American Diabetes Association criteria, among 364 patients with peripheral artery disease, 529 patients with coronary artery disease and 383 controls. The prevalence of type 2 diabetes mellitus in peripheral artery disease patients was 49.7%. It was significantly higher in these patients than in coronary artery disease patients (34.4%; p < 0.001) and controls (21.4%; p < 0.001). Adjusted for sex, age and body mass index, odds ratios for type 2 diabetes mellitus were 2.0 (95% confidence interval 1.5-2.6) comparing the peripheral artery disease group with the coronary artery disease group (p < 0.001) and 4.0 (2.8-5.8) comparing the peripheral artery disease group with controls (p < 0.001). The prevalence of pre-diabetes among non-diabetic subjects was high in all three study groups (64.5% in peripheral artery disease patients, 63.4% in coronary artery disease patients and 61.8% in controls), without significant between-group differences. In conclusion, the prevalence of type 2 diabetes mellitus is even higher in peripheral artery disease patients than in coronary artery disease patients. This observation underlines the need to consider impaired glucose regulation in the management of peripheral artery disease.

Systemic inflammation is higher in peripheral artery disease than in stable coronary artery disease.

OBJECTIVE The knowledge on the level of systemic inflammation in peripheral artery disease (PAD) is less well established than that in coronary artery disease (CAD). Systemic inflammation frequently coincides with atherosclerosis, but also with various traits of the metabolic syndrome (MetS). The individual contribution of CAD, PAD, and the MetS to inflammation is not known. METHODS We enrolled a total of 1396 patients, 460 patients with PAD Fontaine stages IIa-IV verified by duplex ultrasound (PAD group) and 936 patients free of limb claudication undergoing coronary angiography, of whom 507 had significant CAD with coronary stenoses ≥50% (CAD group), and 429 did not have significant CAD at angiography (control group). RESULTS C-reactive protein (CRP) was significantly higher in the PAD than in the CAD or in the control group (0.86 ± 1.85 mg/dl versus 0.44 ± 0.87 mg/dl and 0.39 ± 0.52 mg/dl, respectively, p < 0.001 for both comparisons). These significant differences were confirmed when patients with and subjects without the MetS were analyzed separately. In particular, within the PAD group, CRP was significantly higher in patients with the MetS than in subjects without the MetS (1.04 ± 2.01 vs. 0.67 ± 1.64 mg/dl; p = 0.001) and both, the presence of PAD and the MetS proved to be independently associated with CRP in analysis of covariance (F = 31.84; p < 0.001 and F = 10.52; p = 0.001, respectively). CONCLUSION Inflammatory activity in PAD patients is higher than in CAD patients and is particularly high in PAD patients affected by the MetS. Low grade systemic inflammation is independently associated with both the MetS and PAD.

Hemoglobin, iron metabolism and angiographic coronary artery disease (The Ludwigshafen Risk and Cardiovascular Health Study).

BACKGROUND Anemia has been shown to be a risk factor for coronary artery disease and mortality. The involvement of body iron stores in the development of CAD remains controversial. So far, studies that examined hemoglobin and parameters of iron metabolism simultaneously do not exist. METHODS AND RESULTS Hemoglobin and iron status were determined in 1480 patients with stable angiographic coronary artery disease (CAD) and in 682 individuals in whom CAD had been ruled out by angiography. The multivariate adjusted odds ratios (OR) for CAD in the lowest quartiles of hemoglobin and iron were 1.62 (95%CI: 1.22-2.16), and 2.05 (95%CI: 1.51-2.78), respectively compared to their highest gender-specific quartiles. The fully adjusted ORs for CAD in the lowest quartiles of transferrin saturation, ferritin (F) and soluble transferrin receptor (sTfR)/log10F index were 1.69 (95%CI: 1.25-2.27), 1.98 (95%CI: 1.48-2.65), and 1.64 (95%CI: 1.23-2.18), respectively compared to their highest gender-specific quartiles. When adjusting in addition for iron and ferritin the OR for CAD in the lowest quartiles of hemoglobin was still 1.40 (95%CI: 1.04-1.90) compared to the highest gender-specific quartiles. Thus, the associations between either iron status or low hemoglobin and CAD appeared independent from each other. The sTfR was only marginally associated with angiographic CAD. CONCLUSIONS Both low hemoglobin and iron depletion are independently associated with angiographic CAD.

Biological variation of established and novel biomarkers for atherosclerosis: Results from a prospective, parallel-group cohort study.

BACKGROUND Biomarkers are a promising tool for the management of patients with atherosclerosis, but their variation is largely unknown. We assessed within-subject and between-subject biological variation of biomarkers in peripheral artery disease (PAD) patients and healthy controls, and defined which biomarkers have a favorable variation profile for future studies. METHODS Prospective, parallel-group cohort study, including 62 patients with stable PAD (79% men, 65±7years) and 18 healthy control subjects (44% men, 57±7years). Blood samples were taken at baseline, and after 3-, 6-, and 12-months. We calculated within-subject (CVI) and between-subject (CVG) coefficients of variation and intra-class correlation coefficient (ICC). RESULTS Mean levels of D-dimer, hs-CRP, IL-6, IL-8, MMP-9, MMP-3, S100A8/A9, PAI-1, sICAM-1, and sP-selectin levels were higher in PAD patients than in healthy controls (P≤.05 for all). CVI and CVG of the different biomarkers varied considerably in both groups. An ICC≥0.5 (indicating moderate-to-good reliability) was found for hs-CRP, D-Dimer, E-selectin, IL-10, MCP-1, MMP-3, oxLDL, sICAM-1 and sP-selectin in both groups, for sVCAM in healthy controls and for MMP-9, PAI-1 and sCD40L in PAD patients. CONCLUSIONS Single biomarker measurements are of limited utility due to large within-subject variation, both in PAD patients and healthy subjects. D-dimer, hs-CRP, MMP-9, MMP-3, PAI-1, sP-selectin and sICAM-1 are biomarkers with both higher mean levels in PAD patients and a favorable variation profile making them most suitable for future studies.

The association between in-stent neoatherosclerosis and native coronary artery disease progression: a long-term angiographic and optical coherence tomography cohort study.

AIMS The purpose of the present study was to investigate the relationship between in-stent neoatherosclerosis (NA) and native atherosclerosis progression of untreated coronary segments. METHODS AND RESULTS In-stent NA was assessed by optical coherence tomography (OCT) among patients included in the SIRTAX-LATE OCT study 5 years after drug-eluting stent (DES) (sirolimus-eluting and paclitaxel-eluting stents) implantation. Neoatherosclerosis was defined as the presence of fibroatheroma or fibrocalcific plaque within the neointima of stented segments with a longitudinal extension >1.0 mm. Atherosclerosis progression in untreated native coronary segments was evaluated by serial quantitative coronary angiography (QCA). The change in minimal lumen diameter (MLD) was serially assessed within matched segments at baseline and 5-year angiographic follow-up. The key clinical endpoint was non-target lesion (non-TL) revascularization throughout 5 years. A total of 88 patients with 88 lesions were available for OCT analysis 5 years after DES implantation. In-stent NA was observed in 16% of lesions with the majority of plaques being fibroatheromas (11.4%) followed by fibrocalcific plaques (5.7%). A total of 704 non-TL segments were serially evaluated by QCA. Between baseline and 5-year follow-up, the reduction in MLD was significantly more pronounced in patients with NA (-0.25 mm, 95% CI -0.36 to -0.17 mm) when compared with patients without NA (-0.13 mm, 95% CI -0.17 to -0.10 mm, P = 0.002). Similarly, non-TL revascularization was more frequent in patients with NA (78.6%) when compared with patients without NA (44.6%, P = 0.028) throughout 5 years. CONCLUSIONS In-stent NA is more common among patients with angiographic and clinical evidence of native atherosclerosis progression suggesting similar pathophysiological mechanisms.SIRTAX trial is registered at http://www.clinicaltrials.gov/ct2/show/NCT00617084.

Impact of cardiovascular risk factors on severity of peripheral artery disease

OBJECTIVE The development of peripheral artery disease is affected by the presence of cardiovascular risk factors. It is unclear, whether particular risk factors are leading to different clinical stages of peripheral artery disease. The aim of this retrospective cross-sectional study was to assess the association of cardiovascular risk factors with the presence of critical limb ischaemia. METHODS The study cohort was derived from a consecutive registry of patients undergoing endovascular therapy in a tertiary referral centre between January 2000 and April 2014. Patients undergoing first-time endovascular intervention for chronic peripheral artery disease of the lower extremities were included. Univariate and multivariate logistic regression models were used to assess the association of age, sex, diabetes mellitus, hypertension, dyslipidaemia, smoking, and renal insufficiency with critical limb ischaemia vs. intermittent claudication. RESULTS A total of 3406 patients were included in the study (mean age 71.7 ± 11.8 years, 2075 [61%] male). There was a significant association of age (OR 1.67, 95%-CI 1.53-1.82, p < 0.001), male gender (OR 1.23, 95%-CI 1.04-1.47, p = 0.016), diabetes (OR 1.99, 95%-CI 1.68-2.36, p < 0.001) and renal insufficiency (OR 1.62, 95%-CI 1.35-1.96, p < 0.001) with the likelihood of critical limb ischaemia. Smoking was associated with intermittent claudication rather than critical limb ischaemia (OR 0.78, 95%-CI 0.65-0.94, p = 0.010), while hypertension and dyslipidaemia did not show an association with critical limb ischaemia. CONCLUSIONS In peripheral artery disease patients undergoing first-time endovascular treatment, age, male gender, diabetes, and renal insufficiency were the strongest predictors for the presence of critical limb ischaemia.

Circulating matrix metalloproteinase 9 levels in relation to sampling methods, femoral and carotid atherosclerosis.

OBJECTIVES To examine whether circulating levels of matrix metalloproteinase 9 (MMP-9) were associated with ultrasound-assessed intima-media thickness (IMT) and echolucent plaques in the carotid and femoral arteries. To examine preanalytical sources of variability in MMP-9 concentrations related to sampling procedures. SUBJECTS AND DESIGN Plasma and serum MMP-9 levels were compared with ultrasound assessed measures of femoral and carotid atherosclerosis, in a cross-sectional study of 61-year-old men (n = 473). Preanalytical sources of variability in MMP-9 levels were examined in 10 healthy subjects. Main outcome measures were circulating levels of MMP-9 in serum and plasma, IMT of the carotid and femoral arteries, and plaque status based on size and echolucency. SETTING Research unit at university hospital. RESULTS Plasma concentrations of total and active MMP-9 were associated with femoral artery IMT independently of traditional cardiovascular risk factors, and were higher in subjects with moderate to large femoral plaques. Plasma MMP-9 concentration was higher in men with echolucent femoral plaques (P = 0.006) compared with subjects without femoral plaques. No similar associations were found for carotid plaques. MMP-9 concentrations were higher in serum than in plasma, and higher when sampling was performed with Vacutainer than with syringe. MMP-9 levels in serum were more strongly associated with peripheral neutrophil count compared with MMP-9 levels in plasma. CONCLUSIONS Plasma MMP-9 levels were associated with atherosclerosis in the femoral artery, and total MMP-9 concentration was higher in men with echolucent femoral plaques. The choice of sample material and sampling method affect the measurements of circulating MMP-9 levels.

Preclinical atherosclerosis and inflammation in 61-year-old men with newly diagnosed diabetes and established diabetes.

OBJECTIVE The aim of this study was to investigate the occurrence of subclinical atherosclerosis and underlying mechanisms in men with newly diagnosed diabetes and established diabetes compared with healthy control subjects. RESEARCH DESIGN AND METHODS In a population-based study of 61-year-old Caucasian men (n = 271) with established diabetes (n = 50) and newly diagnosed diabetes (n = 24) and healthy control subjects (n = 197), standard risk factors and highly sensitive (hs) C-reactive protein (CRP) were measured. Ultrasound measurements of intima-media thickness (IMT) were performed bilaterally in the common carotid artery, and a composite measure was calculated from common carotid and carotid bulb IMT (composite IMT). The plaque status was assessed. RESULTS Composite IMT and carotid plaque size increased gradually among the healthy control subjects, newly diagnosed diabetic patients, and established diabetic patients (P for trend < or =0.001, respectively). CRP was higher in newly and established diabetes (NS between diabetes groups) compared with healthy control subjects (P < 0.001). Total cholesterol levels were lower in newly diagnosed diabetes (5.51 +/- 1.13 mmol/l, P < 0.05) and established diabetes (5.45 +/- 1.15 mmol/l, P < 0.01) compared with those of healthy control subjects (5.77 +/- 1.03 mmol/l). In men with diabetes (n = 74), diabetes onset status (newly diagnosed versus established), waist-to-hip ratio (WHR), and serum triglycerides, but not CRP, explained 16% of the variance in composite IMT. CONCLUSIONS This is the first study to show increased preclinical atherosclerotic changes (IMT and plaque size) and increased inflammation (hs-CRP) in men with newly diagnosed diabetes as well as in patients with established diabetes compared with healthy control subjects. WHR, diabetes onset status (newly diagnosed versus established), and triglycerides, but not CRP, were independent correlates of carotid artery IMT in men with diabetes.