Smoking-induced long-lasting modifications of human platelet serotonin catabolism through a MAO epigenetic regulation

Postulating that serotonin, secreted from smoking-activated platelets, could be involved in smoking-induced vascular modifications, we studied 115 men distributed in smokers (S), former smokers (FS) and never smokers (NS). The platelet serotonin content was similar in S and NS but lower in FS. This was unexpected because the monoamine oxidase (MAO) activity, which catabolizes serotonin, was inhibited during smoking. However, the amount of platelet MAO was higher in S and FS than in NS. The persistent elevated MAO amount in FS prompted us to study the methylation of its gene promoter in an additional series of patients: it was markedly lower for S and FS vs. NS due to cigarette smoke-induced increase of nucleic acid demethylase activity. This smoking-induced demethylation of the MAO gene promoter, resulting in high MAO amount persisting long after quitting smoking, has cardiovascular consequences and could impact fields such as behavior, mental health, and cancer

Smoking Induces Long-Lasting Effects through a Monoamine-Oxidase Epigenetic Regulation

BACKGROUND: Postulating that serotonin (5-HT), released from smoking-activated platelets could be involved in smoking-induced vascular modifications, we studied its catabolism in a series of 115 men distributed as current smokers (S), never smokers (NS) and former smokers (FS) who had stopped smoking for a mean of 13 years. METHODOLOGY/PRINCIPAL FINDINGS: 5-HT, monoamine oxidase (MAO-B) activities and amounts were measured in platelets, and 5-hydroxyindolacetic acid (5-HIAA)--the 5-HT/MAO catabolite--in plasma samples. Both platelet 5-HT and plasma 5-HIAA levels were correlated with the 10-year cardiovascular Framingham relative risk (P<0.01), but these correlations became non-significant after adjustment for smoking status, underlining that the determining risk factor among those taken into account in the Framingham risk calculation was smoking. Surprisingly, the platelet 5-HT content was similar in S and NS but lower in FS with a parallel higher plasma level of 5-HIAA in FS. This was unforeseen since MAO-B activity was inhibited during smoking (P<0.00001). It was, however, consistent with a higher enzyme protein concentration found in S and FS than in NS (P<0.001). It thus appears that MAO inhibition during smoking was compensated by a higher synthesis. To investigate the persistent increase in MAO-B protein concentration, a study of the methylation of its gene promoter was undertaken in a small supplementary cohort of similar subjects. We found that the methylation frequency of the MAOB gene promoter was markedly lower (P<0.0001) for S and FS vs. NS due to cigarette smoke-induced increase of nucleic acid demethylase activity. CONCLUSIONS/SIGNIFICANCE: This is one of the first reports that smoking induces an epigenetic modification. A better understanding of the epigenome may help to further elucidate the physiopathology and the development of new therapeutic approaches to tobacco addiction. The results could have a larger impact than cardiovascular damage, considering that MAO-dependent 5-HT catabolism is also involved in addiction, predisposition to cancer, behaviour and mental health

Prise en charge ciblée du risque cardio-vasculaire par un réseau ville hôpital (le projet 4P cardio)

PARIS6-Bibl. St Antoine CHU (751122104) / SudocSudocFranceF

Calcifications of the Thoracic Aorta on Extended Non-Contrast-Enhanced Cardiac CT

BACKGROUND: The presence of calcified atherosclerosis in different vascular beds has been associated with a higher risk of mortality. Thoracic aorta calcium (TAC) can be assessed from computed tomography (CT) scans, originally aimed at coronary artery calcium (CAC) assessment. CAC screening improves cardiovascular risk prediction, beyond standard risk assessment, whereas TAC performance remains controversial. However, the curvilinear portion of the thoracic aorta (TA), that includes the aortic arch, is systematically excluded from TAC analysis. We investigated the prevalence and spatial distribution of TAC all along the TA, to see how those segments that remain invisible in standard TA evaluation were affected. METHODS AND RESULTS: A total of 970 patients (77% men) underwent extended non-contrast cardiac CT scans including the aortic arch. An automated algorithm was designed to extract the vessel centerline and to estimate the vessel diameter in perpendicular planes. Then, calcifications were quantified using the Agatston score and associated with the corresponding thoracic aorta segment. The aortic arch and the proximal descending aorta, "invisible" in routine CAC screening, appeared as two vulnerable sites concentrating 60% of almost 11000 calcifications. The aortic arch was the most affected segment per cm length. Using the extended measurement method, TAC prevalence doubled from 31% to 64%, meaning that 52% of patients would escape detection with a standard scan. In a stratified analysis for CAC and/or TAC assessment, 111 subjects (46% women) were exclusively identified with the enlarged scan. CONCLUSIONS: Calcium screening in the TA revealed that the aortic arch and the proximal descending aorta, hidden in standard TA evaluations, concentrated most of the calcifications. Middle-aged women were more prone to have calcifications in those hidden portions and became candidates for reclassification.Fil: Craiem, Damian. Universidad Favaloro. Facultad de Ingeniería y Ciencias Exactas y Naturales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gilles Chironi. Universite de Paris V; Francia. Inserm; Francia. Hopital Europeen Georges Pompidou; FranciaFil: Casciaro, Mariano Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Favaloro. Facultad de Ingeniería y Ciencias Exactas y Naturales; ArgentinaFil: Graf Caride, Diego Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Favaloro. Facultad de Ingeniería y Ciencias Exactas y Naturales; ArgentinaFil: Simon, Alain. Hopital Europeen Georges Pompidou; Francia. Inserm; Francia. Universite de Paris V; Franci

Association of thoracic aorta calcium and non cardiac vascular events in cardiac disease-free individuals

ObjectiveThoracic aorta calcium (TAC) is measurable on the same computed tomography (CT) scan as coronary artery calcium (CAC) but has still unclear clinical value. We assessed TAC and CAC relations with non-cardiac vascular events history in a cohort of subjects at risk for cardiovascular disease.MethodsWe analyzed retrospectively 1000 consecutive subjects having undergone CAC detection by non-contrast multi-slice CT with measurement field longer than usual in order to measure total TAC including aortic arch calcium. We also determined partial TAC restricted to ascending and descending thoracic aorta sites by removing arch calcium from total TAC. Calcium deposits were measured with a custom made software using Agatston score.ResultsCompared with the rest of the cohort, the 30 subjects with non-cardiac vascular event history had higher median values [95% CI] of total TAC (282 [28?1809] vs 39 [0?333], p < 0.01) and partial TAC (4 [0?284] vs 0 [0?5], p < 0.01) but no different value of CAC (73 [0?284] vs 16 [0?148]). Odds ratio [95% CI] of having non-cardiac vascular event per 1-SD increase in log-transformed calcium value was significant for total TAC but not for CAC, if total TAC and CAC were entered separately (1.56 [1.12?2.24], p < 0.01 and 1.13 [0.86?1.50], respectively) or together (1.57 [1.10?2.32], p < 0.01 and 0.98 [0.73?1.32], respectively) in the logistic adjusted model.ConclusionTAC assessment simultaneous with CAC detection provides complementary information on the extra coronary component of cardiovascular risk beyond CAC´s coronary risk prediction. Further studies are required to prospectively confirm this result.Fil: Craiem, Damian. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Favaloro; Argentina. Université Paris-Descartes; FranciaFil: Chironi, Gilles. Université Paris-Descartes; FranciaFil: Casciaro, Mariano Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Favaloro; ArgentinaFil: Sirieix, Marie Emmanuelle. Université Paris-Descartes; FranciaFil: Mousseaux, Elie. Université Paris-Descartes; FranciaFil: Simon, Alain. Université Paris-Descartes; Franci

Microparticles, Vascular Function, and Atherothrombosis

International audienceMembrane-shed submicron microparticles (MPs) are released after cell activation or apoptosis. High levels of MPs circulate in the blood of patients with atherothrombotic diseases, where they could serve as a useful biomarker of vascular injury and a potential predictor of cardiovascular mortality and major adverse cardiovascular events. Atherosclerotic lesions also accumulate large numbers of MPs of leukocyte, smooth muscle cell, endothelial, and erythrocyte origin. A large body of evidence supports the role of MPs at different steps of atherosclerosis development, progression, and complications. Circulating MPs impair the atheroprotective function of the vascular endothelium, at least partly, by decreased nitric oxide synthesis. Plaque MPs favor local inflammation by augmenting the expression of adhesion molecule, such as intercellular adhesion molecule -1 at the surface of endothelial cell, and monocyte recruitment within the lesion. In addition, plaque MPs stimulate angiogenesis, a key event in the transition from stable to unstable lesions. MPs also may promote local cell apoptosis, leading to the release and accumulation of new MPs, and thus creating a vicious circle. Furthermore, highly thrombogenic plaque MPs could increase thrombus formation at the time of rupture, together with circulating MPs released in this context by activated platelets and leukocytes. Finally, MPs also could participate in repairing the consequences of arterial occlusion and tissue ischemia by promoting postischemic neovascularization

Calcifications of the thoracic aorta on extended non-contrast-enhanced cardiac CT

<p>This spreadsheet contains measurements of thoracic aorta calcification (TAC) in 970 asymptomatic patients from an article titled "Calcifications of the thoracic aorta on extended non-contrast-enhanced cardiac CT" and published in PlusONE. Calcifications were quantified using the Agatston method. The thoracic aorta was divided into 5 segments as describes in the publication. The scan covered the aortic arch.The number of calcifications and the cumulative Agatston score are informed per segment. The length of each segment is informed in cm. Risk factors as hypertension (HTA), hypercholesterolemia (HCT), smoking status, diabetes and the presence of coronary artery calcium (CAC) and are also included for each patient.</p

Population description. Continuous variables are expressed as mean±SD.

<p>Population description. Continuous variables are expressed as mean±SD.</p

Spatial distribution of 10831 calcifications found in 618 patients across thoracic aorta segments.

<p><b>A</b>. Number of calcifications by segment and % of total number of calcifications. <b>B</b>. Number of calcifications by average segment length in cm.</p