Matthieu Plichart

Carotid intima-media thickness progression to predict cardiovascular events in the general population (the PROG-IMT collaborative project) : a meta-analysis of individual participant data

BACKGROUND Carotid intima-media thickness (cIMT) is related to the risk of cardiovascular events in the general population. An association between changes in cIMT and cardiovascular risk is frequently assumed but has rarely been reported. Our aim was to test this association. METHODS We identified general population studies that assessed cIMT at least twice and followed up participants for myocardial infarction, stroke, or death. The study teams collaborated in an individual participant data meta-analysis. Excluding individuals with previous myocardial infarction or stroke, we assessed the association between cIMT progression and the risk of cardiovascular events (myocardial infarction, stroke, vascular death, or a combination of these) for each study with Cox regression. The log hazard ratios (HRs) per SD difference were pooled by random effects meta-analysis. FINDINGS Of 21 eligible studies, 16 with 36,984 participants were included. During a mean follow-up of 7·0 years, 1519 myocardial infarctions, 1339 strokes, and 2028 combined endpoints (myocardial infarction, stroke, vascular death) occurred. Yearly cIMT progression was derived from two ultrasound visits 2-7 years (median 4 years) apart. For mean common carotid artery intima-media thickness progression, the overall HR of the combined endpoint was 0·97 (95% CI 0·94-1·00) when adjusted for age, sex, and mean common carotid artery intima-media thickness, and 0·98 (0·95-1·01) when also adjusted for vascular risk factors. Although we detected no associations with cIMT progression in sensitivity analyses, the mean cIMT of the two ultrasound scans was positively and robustly associated with cardiovascular risk (HR for the combined endpoint 1·16, 95% CI 1·10-1·22, adjusted for age, sex, mean common carotid artery intima-media thickness progression, and vascular risk factors). In three studies including 3439 participants who had four ultrasound scans, cIMT progression did not correlate between occassions (reproducibility correlations between r=-0·06 and r=-0·02). INTERPRETATION The association between cIMT progression assessed from two ultrasound scans and cardiovascular risk in the general population remains unproven. No conclusion can be derived for the use of cIMT progression as a surrogate in clinical trials. FUNDING Deutsche Forschungsgemeinschaft.

Carotid intima-media thickness in plaque-free site, carotid plaques and coronary heart disease risk prediction in older adults. The Three-City Study

OBJECTIVES We sought to address the respective association between carotid intima-media thickness (IMT) in plaque-free sites and plaques with coronary heart disease (CHD) and their usefulness for CHD risk prediction in the Three-City Study. METHODS At baseline, 5895 CHD-free adults aged 65-85 years underwent a bilateral ultrasound examination of carotid arteries. Mean IMT was measured in the far wall of the right and left common carotid arteries (CCA) at plaque-free site while the presence of focal plaques was assessed in the near and the far walls of the CCAs, the bifurcations and the origin of the internal carotid arteries. RESULTS After a median follow-up of 5.4 years, 223 subjects had a first ever CHD event. In multivariate analysis, carotid plaques were independent predictors of CHD (Hazard ratio (HR)(plaques at 1 site) = 1.5; 95% confidence interval (CI) = 1.0-2.2; HR(plaques at ≥ 2 sites) = 2.2; 95% CI = 1.6-3.1; p(for trend) < 0.001), contrary to mean CCA-IMT (HR(fifth vs.first quintile) = 0.8; 95% CI = 0.5-1.2; p(for trend) < 0.48). Adding carotid plaques to conventional risk factors significantly improved CHD risk prediction as measured by the area under the ROC curve (from 0.728 to 0.745; p = 0.04), the Harrells c (from 0.748 to 0.762; p < 0.001), and the integrated discrimination improvement (IDI = 0.007; p = 0.002)/net reclassification improvement (NRI = 13.7%; p < 0.001) indices. CONCLUSION Carotid plaques, but not CCA-IMT measured at a plaque-free site, were independent predictors of CHD and improved CHD risk prediction in older adults.

Parental smoking, maternal alcohol, coffee and tea consumption during pregnancy and childhood malignant central nervous system tumours: the ESCALE study (SFCE)

Parental smoking and maternal alcohol and caffeinated beverage consumption are prevalent exposures which may play a role, either directly or through their influence on metabolism, in the aetiology of childhood malignant central nervous system (CNS) tumours. The hypothesis was investigated in the Epidemiological Study on childhood Cancer and Leukemia ESCALE study, a national population-based case–control study carried out in France in 2003–2004. The study included 209 incident cases of CNS tumours and 1681 population-based controls, frequency matched with the cases by age and sex. The data were collected through a standardized telephone interview of the biological mothers. No association between maternal smoking during pregnancy and CNS tumours [odds ratio (OR): 1.1 (0.8–1.6)] was observed. Paternal smoking during the year before birth was associated with CNS tumours (P for trend=0.04), particularly astrocytomas [OR: 3.1 (1.3–7.6)]. Maternal alcohol consumption during pregnancy was not associated with CNS tumours. Associations between ependymomas and the highest consumption of coffee [OR: 2.7 (0.9–8.1)] and tea [OR: 2.5 (1.1–5.9)] were observed. A strong association between CNS tumours and the highest maternal consumption of both coffee and tea during pregnancy was observed [OR: 4.4 (1.5–13)]. The results constitute additional evidence for a role of paternal smoking and suggest that maternal coffee and tea consumption during pregnancy may also increase the risk of CNS tumours. The study does not suggest an increased risk of CNS tumours related to alcohol consumption during pregnancy.

Inflammatory markers and extent and progression of early atherosclerosis: Meta-analysis of individual-participant-data from 20 prospective studies of the PROG-IMT collaboration

Background Large-scale epidemiological evidence on the role of inflammation in early atherosclerosis, assessed by carotid ultrasound, is lacking. We aimed to quantify cross-sectional and longitudinal associations of inflammatory markers with common-carotid-artery intima-media thickness (CCA-IMT) in the general population. Methods Information on high-sensitivity C-reactive protein, fibrinogen, leucocyte count and CCA-IMT was available in 20 prospective cohort studies of the PROG-IMT collaboration involving 49,097 participants free of pre-existing cardiovascular disease. Estimates of associations were calculated within each study and then combined using random-effects meta-analyses. Results Mean baseline CCA-IMT amounted to 0.74 mm (SD = 0.18) and mean CCA-IMT progression over a mean of 3.9 years to 0.011 mm/year (SD = 0.039). Cross-sectional analyses showed positive linear associations between inflammatory markers and baseline CCA-IMT. After adjustment for traditional cardiovascular risk factors, mean differences in baseline CCA-IMT per one-SD higher inflammatory marker were: 0.0082 mm for high-sensitivity C-reactive protein (p < 0.001); 0.0072 mm for fibrinogen (p < 0.001); and 0.0025 mm for leucocyte count (p = 0.033). ‘Inflammatory load’, defined as the number of elevated inflammatory markers (i.e. in upper two quintiles), showed a positive linear association with baseline CCA-IMT (p < 0.001). Longitudinal associations of baseline inflammatory markers and changes therein with CCA-IMT progression were null or at most weak. Participants with the highest ‘inflammatory load’ had a greater CCA-IMT progression (p = 0.015). Conclusion Inflammation was independently associated with CCA-IMT cross-sectionally. The lack of clear associations with CCA-IMT progression may be explained by imprecision in its assessment within a limited time period. Our findings for ‘inflammatory load’ suggest important combined effects of the three inflammatory markers on early atherosclerosis.

DAD-6: A 6-ltem Version of the Disability Assessment for Dementia Scale Which May Differentiate Alzheimer’s Disease and Mild Cognitive Impairment from Controls

Background: The need to detect early changes in instrumental activities of daily life led us to modify the Disability Assessment for Dementia Scale (DAD) by focusing on executive components of 6 instrumental items (DAD-6). Aim: To evaluate the relevance of the DAD-6 for detecting early impairment in a nondemented population. Methods: The DAD-6 was administered to informants of 84 patients: 31 with mild dementia (MD), 53 with mild cognitive impairment (MCI) and 55 healthy controls. Results: DAD-6 scores gradually decreased with increasing severity of the cognitive status [18 in healthy controls vs. 15.1 ± 3.2 in MCI versus 9.6 ± 3.5 in MD, p < 0.0001). Receiver-operating characteristic curve analyses yielded an optimal cut score of 14 to distinguish MCI from MD with a sensitivity of 0.83 (95% confidence interval 0.74–0.92) and a specificity of 0.84 (0.71–0.94), and a cut score of 15 to distinguish single-domain MCI from multi-domain MCI with a sensitivity of 0.96 (0.90–0.99) and a specificity of 0.54 (0.33–0.75). Conclusion: The DAD-6 reliably detects early loss of autonomy due to cognitive impairment.

Carotid Intima Media Thickness Progression and Risk of Vascular Events in People With Diabetes: Results From the PROG-IMT Collaboration

OBJECTIVE Carotid intima-media thickness (CIMT) is a marker of subclinical organ damage and predicts cardiovascular disease (CVD) events in the general population. It has also been associated with vascular risk in people with diabetes. However, the association of CIMT change in repeated examinations with subsequent CVD events is uncertain, and its use as a surrogate end point in clinical trials is controversial. We aimed at determining the relation of CIMT change to CVD events in people with diabetes. RESEARCH DESIGN AND METHODS In a comprehensive meta-analysis of individual participant data, we collated data from 3,902 adults (age 33–92 years) with type 2 diabetes from 21 population-based cohorts. We calculated the hazard ratio (HR) per standard deviation (SD) difference in mean common carotid artery intima-media thickness (CCA-IMT) or in CCA-IMT progression, both calculated from two examinations on average 3.6 years apart, for each cohort, and combined the estimates with random-effects meta-analysis. RESULTS Average mean CCA-IMT ranged from 0.72 to 0.97 mm across cohorts in people with diabetes. The HR of CVD events was 1.22 (95% CI 1.12–1.33) per SD difference in mean CCA-IMT, after adjustment for age, sex, and cardiometabolic risk factors. Average mean CCA-IMT progression in people with diabetes ranged between −0.09 and 0.04 mm/year. The HR per SD difference in mean CCA-IMT progression was 0.99 (0.91–1.08). CONCLUSIONS Despite reproducing the association between CIMT level and vascular risk in subjects with diabetes, we did not find an association between CIMT change and vascular risk. These results do not support the use of CIMT progression as a surrogate end point in clinical trials in people with diabetes.

A novel device for measuring arterial stiffness using finger-toe pulse wave velocity: Validation study of the pOpmètre®

BACKGROUND The finger-toe pathway could be a good alternative for assessing arterial stiffness conveniently. AIM To evaluate the accuracy of the pOpmètre®--a new device that measures finger-toe pulse wave velocity (ft-PWV). METHODS The pOpmètre has two photodiode sensors, positioned on the finger and the toe. Pulse waves are recorded continuously for 20 seconds, and the difference in pulse wave transit time between toe and finger (ft-TT) is calculated. The travelled distance is estimated using subject height. Study 1 compared ft-PWV with carotid-femoral PWV (cf-PWV) obtained by the reference method (SphygmoCor®) in 86 subjects (mean age 53±20 years), including 69 patients with various pathologies and 17 healthy normotensives. Study 2 compared changes in ft-PWV and cf-PWV during a cold pressor test in 10 healthy subjects. Study 3 assessed repeatability in 45 patients. RESULTS ft-PWV correlated significantly with cf-PWV (R2=0.43; P<0.0001). A better correlation was found in terms of transit time (R2=0.61; P<0.0001). The discrepancy between transit times was related to age. The cold pressor test induced parallel changes in cf-PWV and ft-PWV, with increased aortic stiffness that was reversible during recovery. Intra-session repeatability was very good, with a coefficient of variation of 4.52%. CONCLUSION The pOpmètre® allows measurement of arterial stiffness in routine clinical practice. The greatest advantages of ft-PWV are simplicity, rapidity, feasibility, acceptability by patients and correct agreement with the reference technique. Further studies are needed to adjust for bias and to validate the pOpmètre in larger populations.

Gender-specific trends in heart rate in the general population from 1992-2007: a study of 226,288 French adults.

Objectives: Heart rate (HR) has been associated with cardiovascular (CV) risk factors and with CV mortality. Trends in CV risk factors have been described in recent decades, but HR changes over time have been less studied. We thus aimed to examine the secular trends in HR and interrelationships between HR and traditional CV risk factors and mortality. Methods: We studied 226,288 consecutive participants (141,533 men and 84,755 women) aged 44.7 ± 12.7 years who had a free standard health check up, between 1992 and 2007. Each had resting HR measured systematically on a 10-cycle electrocardiogram, and assessment of lipoproteins, blood pressure, smoking, glyacemic status, body mass index, and physical activity. Sex-specific trends in mean HR were estimated by a general linear model adjusted for traditional CV risk factors and CV treatment. In that model, year was considered as a continuous variable. Results: Crude mean HR decreased over the study period (from 68.9 ± 10.4 to 63.7 ± 9.0 beats/min in men; from 72.2 ± 10.3 to 65.2 ± 9.0 beats/min in women; p < 0.001 for both). The amplitude of the HR decrease was similar after full adjustment and across the pre-cited risk factors categories. On multivariate analysis, higher HR (≥80 beats/min vs. <60 beats/min) was associated with higher mortality rate over 5 years in men (hazard ratio 2.11, 95% CI 1.79⊟2.49) and women (hazard ratio 1.58, 95% CI 1.16⊟2.15). Conclusion: In this large population-based study of 226,288 middle-aged participants, heart rate declined over 16 years independently of traditional CV risk factors.

Normative values for carotid intima media thickness and its progression: Are they transferrable outside of their cohort of origin?

Background The clinical use of carotid intima media thickness (cIMT) requires normal values, which may be subject to variation of geographical factors, ethnicity or measurement details. The influence of these factors has rarely been studied. The aim of this study was to determine whether normative cIMT values and their association with event risk are generalizable across populations. Design Meta-analysis of individual participant data. Method From 22 general population cohorts from Europe, North America and Asia we selected subjects free of cardiovascular disease. Percentiles of cIMT and cIMT progression were assessed separately for every cohort. Cox proportional hazards models for vascular events were used to estimate hazard ratios for cIMT in each cohort. The estimates were pooled across Europe, North America and Asia, with random effects meta-analysis. The influence of geography, ethnicity and ultrasound protocols on cIMT values and on the hazard ratios was examined by meta-regression. Results Geographical factors, ethnicity and the ultrasound protocol had influence neither on the percentiles of cIMT and its progression, nor on the hazard ratios of cIMT for vascular events. Heterogeneity for percentiles of cIMT and cIMT progression was too large to create meaningful normative values. Conclusions The distribution of cIMT values is too heterogeneous to define universal or regional population reference values. CIMT values vary widely between different studies regardless of ethnicity, geographic location and ultrasound protocol. Prediction of vascular events with cIMT values was more consistent across all cohorts, ethnicities and regions.

Disability and incident coronary heart disease in older community-dwelling adults: the three-city study.

OBJECTIVES: To prospectively assess the association between disability and incident fatal and nonfatal coronary heart disease (CHD) in older adults free of cardiovascular disease (CVD).