Additional prognostic value of physical examination, exercise testing, and arterial ultrasonography for coronary risk assessment in primary prevention.

BACKGROUND: The choice of noninvasive tests used in primary prevention of cardiovascular diseases must be based on medical evidence. The aim of this study was to assess the additional prognostic value, over conventional risk factors, of physical examination, exercise testing, and arterial ultrasonography, in predicting a first coronary event. METHODS: A prospective cohort study was conducted between 1996 and 2004 (n = 2,709), with follow-up in 2006 (response rate 96.6%). Participants had no history or symptoms of cardiovascular disease and had a standardized physical examination, a cardiac exercise testing, and carotid and femoral ultrasonography at baseline. Incident cases of definite coronary events were recorded during follow-up. RESULTS: Over the Framingham risk score, femoral bruit, positive exercise test, intima-media thickness >0.63 mm, and a femoral plaque provided significant additional information to the prediction model. The addition of the exercise test to the traditional risk factors, then the intima-media thickness and lastly the presence of femoral plaques, produces incremental increases in the area under the receiver operating characteristic curve (0.73-0.78, P = .02) and about a 50% increase in the positive predictive value (15.8%-31.4%), with no effect on the negative predictive value (96.4%-96.9%). CONCLUSION: Physical examination, exercise testing, and arterial ultrasonography provide incremental information on the risk of coronary event in asymptomatic adults. Exercise testing and femoral ultrasonography also improve the accuracy of the risk stratification.

Interleukin 6 is associated with subclinical atherosclerosis: a link with soluble intercellular adhesion molecule 1.

BACKGROUND: Among the markers of inflammation, a cytokine, interleukin (IL)-6, promotes the expression of intercellular adhesion molecule 1 (ICAM-1), C-reactive protein (CRP) synthesis, and leads to a series of procoagulant actions with potential major implications on the progression of atherosclerosis. AIM OF THE STUDY: To analyse in a population-based study, the relationship between IL-6 and atherosclerotic lesions and the role of serum ICAM-1 and CRP on this relationship. POPULATION: Among 1015 individuals randomly recruited between 1995 and 1997 in Haute-Garonne, a French region with a low cardiovascular risk, 953 subjects with complete data for all measurements were analysed. Common carotid intima-media thickness (IMT) and the presence of plaques in the carotid and femoral arteries were assessed by ultrasonography. RESULTS: Quartiles of IL-6, serum ICAM-1 and CRP were positively associated with plaques and IMT. After adjustment for traditional risk factors, IL-6 (P < 0.001) and serum ICAM-1 (P < 0.002) remained positively associated with plaques but not CRP (P = 0.20). Neither IL-6, nor serum ICAM-1, nor CRP were independently associated with IMT. When serum ICAM-1 was entered into the model in addition to traditional risk factors and IL-6, the percentage of variance in the number of plaques explained by the model did not increase significantly. CONCLUSION: IL-6 levels are associated with subclinical atherosclerotic lesions independently of traditional risk factors; the influence of IL-6 on ICAM-1 secretion may play a role in this association. These results argue the interest of IL-6 in the stratification of cardiovascular risk.

Soluble intercellular adhesion molecule-1 is associated with carotid and femoral atherosclerosis but not with intima-media thickness in a population-based sample.

Since inflammatory mechanisms seem to be involved in different stages of atherosclerosis, we analysed a random population-based sample of 972 subjects to assess the relationships between soluble intercellular adhesion molecule-1 (sICAM-1), subclinical peripheral atherosclerosis and intima-media thickness (IMT). B-mode ultrasonography was used to assess the presence of carotid (common and internal) and femoral atherosclerotic plaques and to measure common carotid IMT (avoiding plaque sites). Mean sICAM-1 level was 287.4 (standard deviation: 102.8) and 255.2 (83.5) ng/ml, respectively, in subjects with and without carotid plaques (P<0.0001). It equalled 286.7 (101.1) and 249.7 (79.7) ng/ml, respectively, in subjects with and without femoral plaques (P<0.0001). Subjects beyond the 90th percentile of common carotid IMT had higher sICAM-1 levels than those below, but this was not significant (P=0.08). Multiple logistic regression analyses adjusted for age, gender and other cardiovascular risk factors showed that sICAM-1 was independently associated with the risk of having at least one carotid plaque (adjusted odds ratio for a 10 ng/ml increase in sICAM-1: OR=1.03, 95% confidence interval: [1.02-1.05]) and with the risk of having at least one femoral plaque (adjusted OR=1.04 [1.02-1.06]). On the other hand, no significant relationship was found in multivariate analysis between sICAM-1 and common carotid IMT.

Relationship between C reactive protein and pulse pressure is not mediated by atherosclerosis or aortic stiffness.

BACKGROUND: Pulse pressure (PP), C reactive protein (CRP) and soluble intercellular adhesion molecule-1 (sICAM-1) levels have been associated with cardiovascular prognosis. Interestingly, previous reports have shown that PP was associated both with CRP and sICAM-1. The mechanisms underlying these associations remain unknown. On the one hand, it has been shown that PP influences, via endothelial function, the expression of various molecules, which in turn may generate inflammation. On the other hand, inflammation-induced changes in the arterial wall, modifying the PP, may be the confounding factor of these relationships. The aim of the present study was to investigate the role played by the arterial structure and the aortic stiffness on these relationships. METHODS: In a cross-sectional population sample of 891 healthy subjects, carotid-femoral pulse wave velocity and blood pressure were measured in the supine position. The common carotid intima-media thickness and the presence of plaques were assessed by ultrasonography. CRP and sICAM-1 levels were measured by an immunonephelemetric method and an immunoenzymatic method, respectively. RESULTS: A positive relationship was found between PP and CRP (P < 0.001). This relationship remained after adjustment for classical cardiovascular risk factors, and successively for mean blood pressure, intima-media thickness, presence of plaques and pulse wave velocity (P < 0.05). No significant association was observed between PP and sICAM-1. CONCLUSIONS: The results of this study demonstrate that changes in arterial structure and in arterial stiffness are not confounding factors in the relationship between PP and CRP.

CD14 C(-260)T gene polymorphism, circulating soluble CD14 levels and arteriosclerosis.

BACKGROUND: CD14 pathway is at the crossroads between infection and inflammation. In human pathology, divergent results have been reported on the relationship between a polymorphism in the promoter of receptor CD14 (C260T), expression of soluble CD14 (sCD14) receptor and atherosclerosis. The aim of the study was to investigate in a cross-sectional population-based sample the relationships between C260T polymorphism in CD14 gene, sCD14 blood levels and arterial wall. METHODS: Among 1015 subjects, randomly recruited by the Toulouse MONICA center between 1995 and 1997, 899 subjects with complete data for all the measurements, were analyzed. sCD14 was measured using an immuno-enzymatic method. Common carotid intima-media thickness (IMT) and the presence of plaques in the carotid and femoral arteries were assessed by ultrasonography. A genotypic examination for the CD14 C260T polymorphism was performed. RESULTS: An increase in sCD14 expression was observed in subjects carrying t allele (P < 0.01). No significant difference in intima-media thickness, number of plaques and pulse wave velocity was noticed according to C260T polymorphism. An interaction (P < 0.05) was observed between C260T polymorphism and current smoking in sCD14 expression: among smokers, no significant change in sCD14 was observed in individuals carrying t allele. CONCLUSION: Although (C260T) polymorphism in CD14 gene in this study is associated with expression of sCD14, no significant association was found between this polymorphism and early markers of atherosclerosis. This polymorphism affects plasma levels of sCD14 in relation to current smoking status. Further studies are needed to determine whether this interaction influences the deleterious effect of smoking on vascular events.

Soluble CD14 and aortic stiffness in a population-based study.

OBJECTIVE: Soluble CD14 (sCD14), an effective mediator for the activation of monocytes by bacterial endotoxin is involved in the release of substances able to modify the characteristics of the arterial wall. The aim of this study was to investigate, in humans, the relationship of sCD14 with aortic stiffness and to analyse the influence of arterial structure and endothelial function on this relationship. DESIGN: Cross-sectional population-based study. PARTICIPANTS: One thousand and fifteen subjects randomly selected from the polling lists, were recruited by the Toulouse MONICA centre between 1995 and 1997. METHODS: Carotid-femoral pulse wave velocity (PWV) and blood pressure (BP) were measured in the supine position. Common carotid intima-media thickness (IMT) and the presence of plaques were assessed by ultrasonography. sCD14 was measured using an immunoenzymatic method. RESULTS: The results concern the 891 subjects with complete data for all the variables. In the bivariate analyses, PWV (P < 0.001), systolic BP (P < 0.05), pulse pressure (PP) (P < 0.01), IMT (P < 0.001), the number of plaques (P < 0.05) and von Willebrand factor activity (vWFa) (P < 0.001) were positively associated with sCD14, whereas no significant relationship was observed between sCD14 and diastolic BP. After adjustment for age and sex, no significant relationship remained between IMT, the number of plaques, SBP, PP and sCD14. A significant and positive relationship was observed between sCD14 and PWV (trend P < 0.05) after adjustment for numerous confounders. CONCLUSION: This population-based study yields first evidence that sCD14 is associated with aortic stiffness independently of age, BP and atherosclerosis in humans.

A single complete ultrasound investigation of the venous network for the diagnostic management of patients with a clinically suspected first episode of deep venous thrombosis of the lower limbs.

In patients clinically suspected of deep-vein thrombosis (DVT) of the lower limbs, it is safe to withhold anticoagulant therapy after a negative ultrasound (US) limited to the popliteal and the femoral veins, provided that this can either be repeated or combined with other diagnostic procedures. To assess the safety of withholding anticoagulants after a single negative complete US, we performed a multicenter, prospective, cohort study including consecutive ambulatory outpatients from institutional and private practice settings, with a clinically suspected first episode of DVT. Patients fulfilling the inclusion criteria were enrolled after careful clinical assessment. A complete US examination of the proximal and the distal veins was performed according to a standardized and detailed protocol. Anticoagulant therapy was administered in patients with proximal or isolated distal DVT and withheld in those with negative results. The main outcome measure was the occurrence of objectively documented clinical thromboembolic events during a three-month follow-up after a negative US. Out of 623 patients, 401 (64.4%) had a baseline negative US, were not anticoagulated and could be followed-up for three months. Two patients presented a calf DVT within three months. The incidence of venous thromboembolic events, including distal DVT, was 0.5% [95% confidence interval: 0.1-1.8]. No proximal DVT, or non-fatal or fatal pulmonary embolism occurred (incidence: 0.0% [95% confidence interval: 0.0-0.9]). In conclusion, it is safe to withhold anticoagulant therapy in patients with clinically suspected DVT after a single, negative, complete US. Integrating this method within diagnostic strategies for DVT could improve management and be more acceptable for patients and physicians.

The Multidomain Intervention to preveNt disability in ElDers (MINDED) project: rationale and study design of a pilot study.

Disability is hardly reversible at old age, negatively impacts on the elders' quality of life, and significantly threatens the sustainability of public health services. Therefore, preventive interventions become necessary for successfully avoiding its onset. The translation of the successful clinical approach represented by the geriatric comprehensive assessment at the community-level and the specific targeting of frailty (a well-established geriatric syndrome) might represent a promising possibility. This approach may allow the implementation of preventive interventions before the irreversible features of disability onset. Unfortunately, there is a lack of evidence on the effectiveness of primary prevention programs against disability in community-dwelling elders. Moreover, the novelty of the topic makes it difficult for the immediate design and conduction of a full-scale trial. For these reasons, a pilot project aimed at obtaining the preliminary information for the design of a subsequent definitive trial is required. In the present article, we describe the objectives, design, and methods of the Multidomain Intervention to preveNt Disability in ElDers (MINDED) project. MINDED is articulated into three sequential phases. First, a screening tool for indentifying non-disabled frail older persons in the community (ideal target population for preventive interventions against disability) will be validated. Then, the organization of a multidisciplinary team in the development and design of a multidomain preventive plan against disability will be verified/optimized. Finally, a randomized controlled trial measuring the effect size of a multicomponent intervention (based on physical exercise, nutrition, and cognitive training) against incident mobility disability versus usual care in community-dwelling frail elders will be conducted.

A self-reported screening tool for detecting community-dwelling older persons with frailty syndrome in the absence of mobility disability: the FiND questionnaire.

BACKGROUND: The "frailty syndrome" (a geriatric multidimensional condition characterized by decreased reserve and diminished resistance to stressors) represents a promising target of preventive interventions against disability in elders. Available screening tools for the identification of frailty in the absence of disability present major limitations. In particular, they have to be administered by a trained assessor, require special equipment, and/or do not discriminate between frail and disabled individuals. Aim of this study is to verify the agreement of a novel self-reported questionnaire (the "Frail Non-Disabled" [FiND] instrument) designed for detecting non-mobility disabled frail older persons with results from reference tools. METHODOLOGY/PRINCIPAL FINDINGS: Data are from 45 community-dwelling individuals aged ≥60 years. Participants were asked to complete the FiND questionnaire separately exploring the frailty and disability domains. Then, a blinded assessor objectively measured the frailty status (using the phenotype proposed by Fried and colleagues) and mobility disability (using the 400-meter walk test). Cohen's kappa coefficients were calculated to determine the agreement between the FiND questionnaire with the reference instruments. Mean age of participants (women 62.2%) was 72.5 (standard deviation 8.2) years. Seven (15.6%) participants presented mobility disability as being unable to complete the 400-meter walk test. According to the frailty phenotype criteria, 25 (55.6%) participants were pre-frail or frail, and 13 (28.9%) were robust. Overall, a substantial agreement of the instrument with the reference tools (kappa = 0.748, quadratic weighted kappa = 0.836, both p values<0.001) was reported with only 7 (15.6%) participants incorrectly categorized. The agreement between results of the FiND disability domain and the 400-meter walk test was excellent (kappa = 0.920, p<0.001). CONCLUSIONS/SIGNIFICANCE: The FiND questionnaire presents a very good capacity to correctly identify frail older persons without mobility disability living in the community. This screening tool may represent an opportunity for diffusing awareness about frailty and disability and supporting specific preventive campaigns.

Long-term therapy with low-molecular-weight heparin in cancer patients with venous thromboembolism.

Long-term therapy with low-molecular-weight heparin (LMWH) is the treatment of choice for cancer patients with venous thromboembolism (VTE). However, the ideal doses of LMWH have not been thoroughly studied. We used the RIETE Registry data to assess the influence of the daily LMWH dosage on outcome during the first three months after VTE. We used propensity score-matching to compare patients who received <150 vs. those receiving ≥150 UI/kg/day LMWH. Up to July 2010, 3,222 cancer patients with VTE received long-term therapy with fixed doses of LMWH. Of these, 1,472 (46%) received <150 IU/kg/day (mean, 112 ± 28), and 1,750 received ≥150 IU/kg/day (mean, 184 ± 32). Results of the propensity score matching involved 1269 matched pairs. During follow-up, the incidence of pulmonary embolism (PE) recurrences was similar (1.2% vs. 1.9%), but patients receiving <150 IU/kg/day LMWH had a lower incidence of fatal PE than those treated with ≥150 IU/kg/day (0.2% vs. 1.0%; p=0.004). Multivariate analysis confirmed that patients receiving <150 IU/kg/day LMWH had a lower risk for fatal PE (odds ratio [OR]: 0.2; 95% confidence interval [CI]: 0.06-0.8) and for major bleeding (OR: 0.6; 95% CI: 0.3-1.0) than those treated with ≥150 IU/kg/day. In real life, one in every two cancer patients with VTE received lower doses of LMWH than those used in randomised trials, with large variations from patient to patient. Unexpectedly, patients treated with <150 IU/kg/day LMWH had fewer fatal PE cases and fewer major bleeding events than those receiving ≥150 IU/kg/day LMWH. This finding, however, should be validated in prospective clinical trials.

Accuracy of the screening physical examination to identify subclinical atherosclerosis and peripheral arterial disease in asymptomatic subjects.

OBJECTIVES: This study assessed the accuracy of the screening vascular physical examination for predicting asymptomatic peripheral arterial disease (PAD) or subclinical atherosclerosis in asymptomatic and apparently healthy subjects. METHODS: A standardized physical examination and a carotid and femoral ultrasonography were administered to 2736 men and women aged 20 to 90 years old, with no personal history of cardiovascular disease (CVD) and no complaint of neurologic, coronary, or lower limb symptom. We assessed the accuracy of auscultation for bruits and pulse palpation for identifying the presence of significant carotid stenosis, carotid plaque, femoral plaque, and ankle-brachial index (ABI) <0.9 at ultrasonography. RESULTS: The presence of a femoral bruit provided information on the presence of both an ABI <0.9 (positive likelihood ratio [+LR], 2.90; 95% confidence interval [CI], 1.63 to 5.16) and a femoral plaque (+LR, 3.23; 95% CI, 2.22 to 4.71), and this information was independent from the cardiovascular risk factors. The absence of both pedal pulses also provided additional information, beyond risk factors, on the presence of an ABI <0.9 (+LR, 3.57; 95% CI, 1.93 to 6.60). The presence of a carotid bruit did not affect the likelihood of carotid stenosis, plaque, or intima-media thickness above the median. CONCLUSION: Unlike carotid auscultation, pulse palpation and auscultation for femoral bruits provided valuable information on the presence of asymptomatic PAD and underlying atherosclerosis in apparently healthy subjects.

Is exercise testing useful to improve the prediction of coronary events in asymptomatic subjects?

OBJECTIVE: The value of exercise testing (ET) in asymptomatic subjects remains controversial and is unknown in countries with a low coronary heart disease (CHD) incidence. The aim of this study was to investigate the ability of ET to improve the prediction of a first coronary event in such a population. METHODS: Using a prospective cohort study, 1051 consecutive healthy asymptomatic adults were enrolled in a cardiovascular screening program including ET. The pre-test risk of CHD was evaluated by the 10-year Framingham risk function. Positive ET was defined as a horizontal or downsloping ST-segment depression >/=1.0 mm. The primary outcome was total coronary events (CE) occurrence, including cardiac deaths, acute myocardial infarction and stable or unstable angina. The mean follow-up period was 6 years. RESULTS: Subjects were aged 18-79 years and 36% were women. A total of 89 subjects (8.5%) had a positive ET. Positive exercise testing was associated with CE occurrence in a univariate analysis only in subjects with higher pre-test risk, defined by a 10-year Framingham risk >10.4% [hazards ratio (HR)=2.61; 95% confidence interval (CI) (1.07-6.40)]. In this risk category, ET was able to provide incremental information over the major risk factors in both men and women [risk factor-adjusted HR for positive ET=2.86; 95% CI (1.14-7.20)]. This risk excess in subjects with positive ET persisted even when a coronary revascularization was performed. Subjects with intermediate pre-test probability (10-15%) and positive ET had a post-test probability of CE largely equivalent to the probability in subjects with known CHD. CONCLUSION: Additional information provided by ET in subjects with a pre-test risk at 10-years >10% should lead to a more efficient use of risk-reducing therapies than it would be the case in this risk category with the analysis of traditional risk factors only.