Claire Bonithon-Kopp

Calcium and fibre supplementation in prevention of colorectal adenoma recurrence: a randomised intervention trial

BACKGROUND Some epidemiological studies have suggested that high dietary intake of calcium and fibre reduces colorectal carcinogenesis. Available data are not sufficient to serve as a basis for firm dietary advice. We undertook a multicentre randomised trial to test the effect of diet supplementation with calcium and fibre on adenoma recurrence. METHODS We randomly assigned 665 patients with a history of colorectal adenomas to three treatment groups, in a parallel design: calcium gluconolactate and carbonate (2 g elemental calcium daily), fibre (3.5 g ispaghula husk), or placebo. Participants had colonoscopy after 3 years of follow-up. The primary endpoint was adenoma recurrence. Analyses were by intention to treat. FINDINGS 23 patients died, 15 were lost to follow-up, 45 refused repeat colonoscopy, and five developed severe contraindications to colonoscopy. Among the 552 participants who completed the follow-up examination, 94 stopped treatment early. At least one adenoma developed in 28 (15.9%) of 176 patients in the calcium group, 58 (29.3%) of 198 in the fibre group, and 36 (20.2%) of 178 in the placebo group. The adjusted odds ratio for recurrence was 0.66 (95% CI 0.38-1.17; p=0.16) for calcium treatment and 1.67 (1.01-2.76, p=0.042) for the fibre treatment. The odds ratio associated with the fibre treatment was significantly higher in participants with baseline dietary calcium intake above the median than in those with intake below the median (interaction test, p=0.028) INTERPRETATION Supplementation with fibre as ispaghula husk may have adverse effects on colorectal adenoma recurrence, especially in patients with high dietary calcium intake. Calcium supplementation was associated with a modest but not significant reduction in the risk of adenoma recurrence.

Effect of Mutation Type and Location on Clinical Outcome in 1,013 Probands with Marfan Syndrome or Related Phenotypes and FBN1 Mutations: An International Study

Mutations in the fibrillin-1 (FBN1) gene cause Marfan syndrome (MFS) and have been associated with a wide range of overlapping phenotypes. Clinical care is complicated by variable age at onset and the wide range of severity of aortic features. The factors that modulate phenotypical severity, both among and within families, remain to be determined. The availability of international FBN1 mutation Universal Mutation Database (UMD-FBN1) has allowed us to perform the largest collaborative study ever reported, to investigate the correlation between the FBN1 genotype and the nature and severity of the clinical phenotype. A range of qualitative and quantitative clinical parameters (skeletal, cardiovascular, ophthalmologic, skin, pulmonary, and dural) was compared for different classes of mutation (types and locations) in 1,013 probands with a pathogenic FBN1 mutation. A higher probability of ectopia lentis was found for patients with a missense mutation substituting or producing a cysteine, when compared with other missense mutations. Patients with an FBN1 premature termination codon had a more severe skeletal and skin phenotype than did patients with an inframe mutation. Mutations in exons 24-32 were associated with a more severe and complete phenotype, including younger age at diagnosis of type I fibrillinopathy and higher probability of developing ectopia lentis, ascending aortic dilatation, aortic surgery, mitral valve abnormalities, scoliosis, and shorter survival; the majority of these results were replicated even when cases of neonatal MFS were excluded. These correlations, found between different mutation types and clinical manifestations, might be explained by different underlying genetic mechanisms (dominant negative versus haploinsufficiency) and by consideration of the two main physiological functions of fibrillin-1 (structural versus mediator of TGF beta signalling). Exon 24-32 mutations define a high-risk group for cardiac manifestations associated with severe prognosis at all ages.

Relation of intima-media thickness to atherosclerotic plaques in carotid arteries : the vascular aging (EVA) study

This study examined the relation between arterial wall thickness and local atherosclerosis in the carotid arteries (CAs) and their specific risk factors. B-mode ultrasonography of the CAs was performed in a cohort of 516 men and 756 women aged 59 to 71 years who had been recruited for the European Vascular Aging Study. Ultrasound examination included measurement of intima-media thickness of the common CA (CCA) and the sites of plaque in the internal CA and bifurcations. Significant associations between increases in CCA intima-media thickness and both the presence and severity of atherosclerotic plaque were found in men and women. Examination of specific risk factors for increases in CCA intima-media thickness in the presence of plaque showed that, after adjustment for sex, both ultrasound measurements were independently related to age, body mass index, hypertension, and ever smoking (versus never smoking). Diabetes and current smoking were associated with intima-media thickness only, whereas hypercholesterolemia was related to plaque only. However, when subjects who were taking lipid-lowering drugs were excluded, lipoproteins and apolipoproteins were more consistently related to intima-media thickness than to plaque. In subjects free from any antihypertensive treatment, both intima-media thickness and plaques were independently associated with systolic blood pressure. After adjustment for sex and other risk factors, the odds ratio for having at least one plaque associated with a 0.10-mm increase in CCA intima-media thickness was 1.18 (95% confidence interval, 1.05 to 1.32). In this relatively aged population, increases in intima-media thickness as measured in the CCAs were clearly related to locally detected atherosclerosis and known risk factors for atherosclerosis. Longitudinal studies are needed to clarify the role of arterial wall thickening in the atherosclerotic process.

Common Carotid Intima-Media Thickness Predicts Occurrence of Carotid Atherosclerotic Plaques Longitudinal Results From the Aging Vascular Study (EVA) Study

The role of the increase in the common carotid artery (CCA) intima-media wall thickness (IMT) in the atherosclerotic process is questionable. This longitudinal study examined the predictive value of CCA-IMT measured at baseline examination (at sites free of plaques) on the occurrence of atherosclerotic plaques in the extracranial carotid arteries during 4 years of follow-up study in a sample of 1010 subjects aged 59 to 71 years. Ultrasound examinations were performed at baseline and 2 years and 4 years later. The occurrence of carotid plaques during follow-up was defined as the appearance of >/=1 plaque in previously normal carotid segments and/or the appearance of new plaques in the carotid segments that previously had plaques. Carotid plaque occurrence was observed in 185 subjects (18.3%). Age- and sex- adjusted odds ratios of carotid plaque occurrence were 2.66 (95% CI 1.58 to 4.46, P<0.001) in subjects having intermediate baseline CCA-IMT values (quartiles 2 and 3) and 3.67 (CI 2.09 to 6.44, P<0.001) in those having the highest baseline CCA-IMT values (quartile 4) compared with those having the lowest baseline CCA-IMT values (quartile 1). Multivariate adjustment for major cardiovascular risk factors did not alter the results. These findings were observed for men and women as well as for subjects with and without carotid plaques at baseline. This 4-year longitudinal study shows that CCA-IMT predicts carotid plaque occurrence in a large sample of relatively old subjects. It extends the findings obtained from cross-sectional studies and suggests that increased intima-media thickness might occur in an earlier phase of the atherosclerotic process.

Risk factors for early carotid atherosclerosis in middle-aged French women.

The prevalence of carotid atherosclerosis and of its risk factors was examined in 517 apparently healthy French women, aged 45-54 years. Early phases of carotid atherosclerosis were assessed by B-mode ultrasonography. An intimal-medial thickening was found in 30.4% of the women and atheromatous plaques in 8.7%. The prevalence rate of carotid atherosclerosis increased with age, smoking, and postmenopausal status. However, after adjustment for the effect of age, postmenopausal women did not have more atherosclerotic lesions than did premenopausal women. No significant associations were found between carotid atherosclerosis and triglyceride, apolipoprotein A-I, body mass index, blood glucose, fibrinogen, plasma viscosity, or hematocrit. The mean age-adjusted levels of total cholesterol, low density lipoprotein cholesterol, apolipoprotein B, and systolic and diastolic blood pressures significantly increased with the severity of carotid atherosclerosis, whereas high density lipoprotein cholesterol significantly decreased. Multiple regression analysis showed that age, smoking, high density lipoprotein cholesterol, low density lipoprotein cholesterol (or apolipoprotein B), and systolic (or diastolic) blood pressure were significantly and independently related to the severity of carotid atherosclerosis. In conclusion, the association of early carotid lesions with major cardiovascular risk factors suggests that carotid atherosclerosis may be used as a marker of the general atherosclerotic process.

Cross-Sectional and 4-Year Longitudinal Associations Between Brachial Pulse Pressure and Common Carotid Intima-Media Thickness in a General Population: The EVA Study

BACKGROUND AND PURPOSE The cross-sectional and 4-year longitudinal associations between brachial pulse pressure (PP) and ultrasound measurements of common carotid intima-media thickness (CCA-IMT) were assessed. METHODS A population of 957 volunteers aged 59 to 71 years was recruited from the electoral rolls of the city of Nantes (western France) and reexamined 4 years later. Longitudinal changes in PP and CCA-IMT were computed as the difference between 4-year follow-up and baseline values. RESULTS Baseline CCA-IMT and PP were positively associated in both age- and sex-adjusted analysis (partial correlation coefficient=0.20, P<0.001) and in multivariate analysis adjusted for traditional cardiovascular risk factors and mean blood pressure (partial correlation coefficient=0.18, P<0.001). In longitudinal analysis, baseline PP was associated with the change in 4-year CCA-IMT (partial correlation coefficient=0.11, P<0.001), and baseline CCA-IMT was a predictor of the 4-year change in PP (partial correlation coefficient=0.10, 0.001<P<0.01). No association between mean blood pressure and CCA-IMT was observed once PP was taken into account, in either cross-sectional or longitudinal analyses (partial correlation coefficients ranged from 0.00 to 0.03). Similar patterns of results were observed in hypertensive, nonhypertensive, and antihypertensive-treated and -nontreated subjects. CONCLUSIONS This longitudinal study of a large population of relatively aged subjects suggests that elevated levels of PP are associated with the progression of CCA-IMT, and increased CCA-IMT is associated with PP widening. The nature of these relationships and whether atherosclerosis progression over time is involved or not in these associations merit further investigations.

Factors of Carotid Arterial Enlargement in a Population Aged 59 to 71 Years: The EVA Study

BACKGROUND AND PURPOSE Factors of carotid arterial enlargement are not well known in general populations. The purpose of this study was to assess the cross-sectional associations of arterial wall lesions and cardiovascular risk factors with carotid lumen diameter in elderly subjects. METHODS B-mode ultrasound examinations of the carotid arteries and risk factor assessment were made in 1272 participants in the EVA (Etude sur le vieillissement artériel) Study, a longitudinal study designed to evaluate vascular and cognitive aging in men and women aged 59 to 71 years. Ultrasound examinations included measurements of intima-media thickness (IMT) and interadventitial and lumen diameters of the common carotid arteries and quantification of atherosclerotic plaques in extracranial carotid arteries. RESULTS Men showed greater IMT interadventitial and lumen diameters of the common carotid arteries than did women. In both sexes, common IMT and plaque score were positively associated with common interadventitial and lumen diameters. Stepwise multiple regression analysis showed that male sex, body height and weight, common IMT, plaque score, systolic blood pressure, and alcohol consumption were positively and independently related to lumen diameter. On the other hand, an independent negative association was observed between low density lipoprotein cholesterol and lumen diameter. CONCLUSIONS In 59- to 71-year-old subjects, increased IMT and atherosclerotic plaques were accompanied by an increase in lumen diameter of the common carotid arteries, indicating an overcompensation. Luminal enlargement observed with several risk factors and with high blood pressure in particular might be partially counteracted by high lipid levels.

Plasma angiotensin-converting enzyme activity and carotid wall thickening.

BACKGROUND Mechanisms underlying the previously reported association between a deletion polymorphism in the gene encoding for angiotensin-converting enzyme (ACE) and the risk of myocardial infarction in low-risk subjects are unclear. The purpose of this case-control study was to examine the relation of plasma ACE activity to intimal-medial thickness of the carotid wall measured ultrasonographically in an apparently healthy population. METHODS AND RESULTS We determined plasma ACE activity in 80 pairs of subjects without any history of ischemic heart disease or any treatment of hypertension and diabetes. Cases and control subjects were defined on the basis of intimal-medial thickness measured in the common carotid arteries by B-mode ultrasound and were matched for sex, sonographer, and the presence of atheromatous plaques. Subjects were selected from a sample of 434 men and 602 women between 60 and 69 years old participating in an ongoing study on vascular aging (EVA). Subjects with intimal-medial thickening (cases) showed a slight but not significant increase in plasma ACE activity in comparison with control subjects (P < .16). However, after exclusion of subjects receiving lipid-lowering drugs, the mean plasma ACE activity became significantly higher in cases than in control subjects (29.9 +/- 7.7 U/L versus 27.5 +/- 8.0 U/L; n = 54 pairs, P < .03). The mean case-control difference in plasma ACE activity was further increased when analysis was restricted to pairs without carotid atheromatous plaques (n = 42 pairs). After adjustment for body mass index, smoking, and systolic blood pressure, the odds ratio for having carotid wall thickening based on 1 SD difference in log ACE was 2.29 (95% confidence interval, 1.16 to 4.52; P < .02). CONCLUSIONS The results of the study suggest that chronic exposure to high levels of plasma ACE could be involved in structural changes of the arterial wall.

Relations of cardiovascular risk factors to aortic pulse wave velocity in asymptomatic middle-aged women

Cross-sectional associations between aortic elasticity assessed by carotid to femoral pulse wave velocity (PWV) and cardiovascular risk factors were examined in 429 apparently healthy middle-aged women. PWV was strongly and positively related to blood pressure and hypertension. Weak but significant positive associations were also found between PWV and age, heart rate, some lipids and lipoproteins, blood glucose (either as a continuous or dichotomous variable), body mass index, haematocrit, leucocyte count and family history of diabetes. No associations were observed between PWV and high density lipoprotein cholesterol, apolipoprotein Al, fibrinogen, cigarette smoking, menopausal status and a family history of hypertension or myocardial infarction. After adjustment for systolic blood pressure, PWV remained significantly related to heart rate, leucocyte count, blood glucose (as a dichotomous variable) and a family history of diabetes. Multiple regression analysis showed that systolic blood pressure and, to a lesser extent, heart rate, leucocyte count and a family history of diabetes were all independent determinants of PWV. This pattern of associations suggests that arterial stiffness measured by PWV reflects the sclerotic rather than the atherotic component of atherosclerosis. The potential influence of a family history of diabetes on the elastic properties of the aorta needs to be ascertained in further studies.

Colorectal Adenoma Characteristics as Predictors of Recurrence

PURPOSEThe identification of groups with a high risk of colorectal adenoma recurrence remains a controversial issue for clinicians. This study was designed to assess the predictive value of initial patient and adenoma characteristics of the three-year recurrence.METHODSThe study population was composed of 552 patients with resected colorectal adenomas who completed the European Fiber-Calcium Intervention trial. At both baseline and three-year examinations, the characteristics of adenomas were recorded according to a standardized protocol. The main outcomes measured were the three-year overall recurrence, recurrence of multiple adenomas, recurrence of advanced adenomas (size ≥ 1 cm or tubulovillous/villous architecture or moderate/severe dysplasia), and proximal and distal recurrence.RESULTSA three-year recurrence was observed in 122 patients (22.1 percent), and more than one-half of them had recurrent adenomas on the proximal colon. After adjustment for patient characteristics and treatment allocation, the number of adenomas and their proximal location at baseline were the main predictors of recurrence. In comparison with patients who had one or two adenomas on the distal colon, patients with three or more adenomas with at least one of them located on the proximal colon had a much higher risk of overall recurrence (5.3; 95 percent confidence interval, 2.7–10.3), proximal recurrence (8.5; 95 percent confidence interval, 4.1–18), and advanced adenoma recurrence (5.5; 95 percent confidence interval, 2.4–12.6).CONCLUSIONSFollow-up colonoscopies in patients with adenomas should include careful examination of the proximal colon. The time interval between follow-up examinations could probably be extended beyond three years in patients who have only one or two distal adenomas.