Papers by Pierre Boutouyrie
Current hypertension reviews, Jan 12, 2017
Arterial stiffness has been accumulating evidence as an intermediate cardiovascular endpoint. It ... more Arterial stiffness has been accumulating evidence as an intermediate cardiovascular endpoint. It has been established as an independent risk marker for cardiovascular disease, and reflects the dissociation between chronologic and biologic age of large arteries - attributing earlier the risk that a normal vascular ageing process had installed to occur several years later. The construct of Early Vascular Ageing (EVA) is developed to establish primordial prevention, identifying individuals whose ageing path has been accelerated either by inherent features, interaction with the environment or arterial exposure to several types of insults that evolve to medial layer morphological changes. Understanding the pathophysiology of vascular ageing, its consequences and therapeutic opportunities is therefore an advantage that could be translated in time of prevention and survival free of cardiovascular disease. As the EVA construct is advancing, new features appear as interesting to better trans...
Sang Thrombose Vaisseaux, Oct 1, 2008
Le remodelage arteriel correspond a toute modification de la structure (epaisseur intima-media et... more Le remodelage arteriel correspond a toute modification de la structure (epaisseur intima-media et diametre arteriel) et de la fonction (i.e. rigidite) arterielle au cours de processus physiologiques et pathologiques. Au cours de l’hypertension, l’atteinte des arteres de gros calibre est caracterisee par une atteinte hypertrophique et une augmentation de la rigidite. Cette atteinte differe le long de l’arbre arteriel : elle est importante pour l’aorte, plus moderee pour les arteres elastiques comme l’artere carotide et paradoxalement diminuee pour les arteres musculaires de plus faible calibre. Il est bien demontre que la rigidite aortique est un facteur de risque independant de survenue d’evenements primaires. La valeur pronostique de l’hypertrophie et de l’augmentation de la rigidite pour le risque de survenue d’un evenement cardiovasculaire est maintenant bien etablie et l’hypertrophie parietale est reconnue comme un facteur d’atherosclerose. De meme, les plaques d’atherosclerose carotidienne sont plus frequentes chez les sujets dont l’epaisseur parietale est augmentee. Il s’avere donc que l’exploration fonctionnelle non invasive des gros troncs arteriels s’impose comme une methode d’identification des patients a haut risque cardiovasculaire. Les techniques actuelles d’exploration reposent sur l’echotracking haute definition, la tonometrie d’aplanation et la velocite de l’onde de pouls, permettant l’evaluation du risque a partir de methodes de mesure non invasives, peu contraignantes pour le patient.
Circulation: Cardiovascular Genetics, 2015
Background— We assess the contribution of common and rare putatively functional genetic variants ... more Background— We assess the contribution of common and rare putatively functional genetic variants (most of them coding) present on the Illumina exome Beadchip to the variability of plasma lipids and stiffness of the common carotid artery. Methods and Results— Measurements were obtained from 2283 men and 1398 women, and after filtering and exclusion of monomorphic variants, 32 827 common (minor allele frequency >0.01) and 68 770 rare variants were analyzed. A large fraction of the heritability of plasma lipids is attributable to variants present on the array, especially for triglycerides (fraction of variance attributable to measured genotypes: V (G)/ V p =31.4%, P <3.1×10 –11 ) and high-density lipoprotein cholesterol ( V (G)/ V p =26.4%, P <4.2×10 –12 ). Plasma lipids were associated with common variants located in known candidate genes, but no implication of rare variants could be established. Gene sets for plasma lipids, blood pressure, and coronary artery disease were de...
Atherosclerosis, 2015
While risk scores are invaluable tools for adapted preventive strategies, a significant gap exist... more While risk scores are invaluable tools for adapted preventive strategies, a significant gap exists between predicted and actual event rates. Additional tools to further stratify the risk of patients at an individual level are biomarkers. A surrogate endpoint is a biomarker that is intended as a substitute for a clinical endpoint. In order to be considered as a surrogate endpoint of cardiovascular events, a biomarker should satisfy several criteria, such as proof of concept, prospective validation, incremental value, clinical utility, clinical outcomes, cost-effectiveness, ease of use, methodological consensus, and reference values. We scrutinized the role of peripheral (i.e. not related to coronary circulation) noninvasive vascular biomarkers for primary and secondary cardiovascular disease prevention. Most of the biomarkers examined fit within the concept of early vascular aging. Biomarkers that fulfill most of the criteria and, therefore, are close to being considered a clinical surrogate endpoint are carotid ultrasonography, ankle-brachial index and carotid-femoral pulse wave velocity; biomarkers that fulfill some, but not all of the criteria are brachial ankle pulse wave velocity, central haemodynamics/wave reflections and C-reactive protein; biomarkers that do no not at present fulfill essential criteria are flow-mediated dilation, endothelial peripheral arterial tonometry, oxidized LDL and dysfunctional HDL. Nevertheless, it is still unclear whether a specific vascular biomarker is overly superior. A prospective study in which all vascular biomarkers are measured is still lacking. In selected cases, the combined assessment of more than one biomarker may be required.
Circulation research, Jan 13, 2015
Pathophysiological studies have extensively investigated the structural factor in hypertension, i... more Pathophysiological studies have extensively investigated the structural factor in hypertension, including large and small artery remodeling and functional changes. Here, we review the recent literature on the alterations in small and large arteries in hypertension. We discuss the possible mechanisms underlying these abnormalities and we explain how they accompany and often precede hypertension. Finally, we propose an integrated pathophysiological approach to better understand how the cross-talk between large and small artery changes interacts in pressure wave transmission, exaggerates cardiac, brain and kidney damage, and lead to cardiovascular and renal complications. We focus on patients with essential hypertension because this is the most prevalent form of hypertension, and describe other forms of hypertension only for contrasting their characteristics with those of uncomplicated essential hypertension.
Arterial Disorders, 2015
Arteries are permanently exposed to mechanical stress. Mechanical stress can be divided according... more Arteries are permanently exposed to mechanical stress. Mechanical stress can be divided according to their nature, either tensile stress or shear stress. Tensile stress corresponds to changes in dimension according to changes in forces applied on the vessel. Shear stress is of a different nature; it corresponds to the friction of viscous fluid (here the blood) on the inner surface of the vessel (here the endothelium). It is to be noted that direct measurement of stress is difficult in vivo and that stress is most of the time deduced from stretch (elongation) and force (derived from pressure). Stress can also be derived from mechanical modelling.
Journal de Radiologie, 2009
Matériels et méthodes : Cinquante deux patients avec F et 52 témoins ont été explorés par IRM 1,5... more Matériels et méthodes : Cinquante deux patients avec F et 52 témoins ont été explorés par IRM 1,5 T en séquences Ciné axiales et obliques. Les mesures de diamètre des différents segments de l'aorte thoracique ont été comparées entre les deux populations. Résultats: Une dilatation significative de l'anneau (22,6 mm ± 2,8 vs 20 mm ± 2,7, P < 0,0001), de la racine aortique (36 mm ± 4 vs 31 mm ± 3,4, P < 0,0001) et de la portion tubulaire (30,1 mm ± 3,7 vs 27,7 mm ± 4, P < 0,0094) est observé chez les F vs contrôle, mais pas sur la crosse et la descendante. Cette dilatation est indépendante de l'âge, de la présence d'une hypertension ou d'une insuffisance rénale. Conclusion: Cette étude montre que la dilatation de la racine aortique est une expression phénotypique de la maladie de Fabry, au même titre que l'atteinte cutanée, cardiaque, rénale et neurologique. Mots clés : Aorte, génétique
Archives of Cardiovascular Diseases Supplements, 2014
Binding mechanism of pharmacological inhibitors and antihypertensive food peptides to human somat... more Binding mechanism of pharmacological inhibitors and antihypertensive food peptides to human somatic angiotensin I-converting enzyme (ACE)
Hypertension, 2014
Whether angiotensin receptor blockers can dose-dependently remodel the arterial wall during long-... more Whether angiotensin receptor blockers can dose-dependently remodel the arterial wall during long-term treatment has been largely debated. In this phase III, multicenter, randomized, double-blind, parallel-group study, 133 subjects with hypertension and metabolic syndrome were assigned to olmesartan, either 20 mg (n=44), 40 mg (n=42), or 80 mg (n=47) once a day, according to a force titration design during a 1-year period. Office blood pressure, 24-hour blood pressure, aortic stiffness (carotid-femoral pulse wave velocity), and carotid parameters were measured at baseline, 24 weeks, and 52 weeks. Pulse wave velocity significantly decreased (P<0.001) with time in each group, with no significant time-dose interaction, despite a tendency (P=0.0685) for a smaller effect of 20 mg, compared with 40 and 80 mg at week 52. When the 40 and 80 mg doses were combined (40/80 mg versus 20 mg), a significant blood pressure-independent reduction in pulse wave velocity (-0.61 m/s) was observed at ...
Blood Pressure and Arterial Wall Mechanics in Cardiovascular Diseases, 2014
Change in arterial stiffness with drugs is a major end point in clinical trials, although evidenc... more Change in arterial stiffness with drugs is a major end point in clinical trials, although evidence for arterial stiffness as a therapeutic target still needs to be confirmed. Drugs which affect arterial stiffness include antihypertensive drugs, mostly blockers of the renin–angiotensin–aldosterone system. Other drugs will be addressed in Chap. 40. Whether the reduction in arterial stiffness after antihypertensive treatment is only due to the blood pressure (BP) lowering which unloads the stiff components of the arterial wall such as collagen, or additional BP-independent effects are involved, has been largely debated. Currently, an increasing body of evidence, including theoretical aspects of arterial mechanics, long-term observational studies in humans and recent meta-analyses of double-blind, randomized, controlled trials, suggests that only part of aortic stiffness could be reduced through the normalization of BP by pharmacological treatment, and further reduction of aortic stiffness would require arterial structural changes, including reduction in collagen density and rearrangement of the wall materials. Mechanistic pharmacological studies are required to demonstrate that novel pharmacological classes have true “de-stiffening” properties.
American journal of nephrology, 2014
Recently, we reported that small renal arteries, defined by a low reference diameter (RD) or mini... more Recently, we reported that small renal arteries, defined by a low reference diameter (RD) or minimal luminal diameter (MD), are independently associated with a low GFR, resistant hypertension, and onset of contrast-induced nephropathy and suggested a post-hoc analysis of CORAL trial based on RD categories. Here we hypothesized that RD and MD are markers of nontraditional cardiovascular risk factors and tested whether low RD and MD could impact the prognosis of patients with ischemic heart disease. Prospective cohort study. We used proportional hazards models to analyze the first onset of cardiovascular events in relation with RD, MD, or percentage of renal artery stenosis (RAS) in those with low-to-moderate RAS (10-70%) (n = 181). During the median follow-up of 4.5 (range, 0.1-5) years, 27.8% participants (n = 623; mean age, 64 years; 29% women) experienced a cardiovascular event (35.4% in those with RAS 10-70%). The presence of low-to-moderate RAS was associated with cardiovascular...
Journal of Hypertension, 2010
Background: Vascular Ehlers-Danlos syndrome (vEDS) resulting from mutations in the gene encoding ... more Background: Vascular Ehlers-Danlos syndrome (vEDS) resulting from mutations in the gene encoding type III procollagen (COL3A1) is clinically characterized by four major and nine minor criteria. The diagnosis is improved by genetic detection of COL3A1 mutations. We aim to assess the genotype-phenotype relationship in vEDS patients. Methods: 132 vEDS patients, diagnosed from clinical criteria, had carotid measurement. Genetic testing was realized in all patients. 57 patients (43%) presented COL3A1 mutations (COL3A1+). Arterial parameters were determined with high-resolution echo-tracking system coupled with applanation tonometry. Statistical analysis was performed using general linear model ANOVA, logistic regression and receiver-operating characteristic (ROC) curves. Results: Demographic data did not differ between COL3A1+ and COL3A1- patients. Patients with COL3A1+ were significantly leaner than COL3A1- patients (-6 kg, p < 0.05). Heart rate, brachial BP, central PP, carotid diameter, distensibility, and Young's elastic modulus were not significantly different between the two groups. Carotid intima-media thickness (IMT) and carotid wall cross-sectional area (WCSA) were significantly lower (-12%, p < 0.001; and -15%, p < 0.001, respectively) in COL3A1+ than COL3A1- patients. Carotid circumferential wall stress was higher (+17%, p < 0.001) in COL3A1+ than COL3A1- patients. Carotid WCSA and circumferential wall stress independently discriminated between COL3A1+ and COL3A1- patients. They were scored from 1 to 3 depending on their threshold values for sensitivity/specificity, and then combined into a total ultrasound (US) score (from 2 to 6). A total US score ≥5 had a high positive predictive value (>75% certainty of COL3A1+ mutations). The area under the ROC curves for the total US score was 0.73 (95% CI, 0.64 to 0.81). Odds ratio for total US score ≥5 was 7.1 (95% CI, 3 to 16.9). Conclusions: An ultrasound score combining carotid WCSA and circumferential wall stress is highly predictive of a COL3A1 mutation in vEDS patients.
Journal of Hypertension, 2011
Journal of Hypertension, 2004
Objective To determine whether carotid artery stiffness was increased in patients with untreated ... more Objective To determine whether carotid artery stiffness was increased in patients with untreated essential hypertension who are homozygous for the T allele of the M235T polymorphism of the angiotensinogen (AGT) gene and in mutant mice carrying three copies of the angiotensinogen (Agt) gene. Methods Using echotracking systems, we studied carotid mechanical properties in 98 never-treated hypertensive patients according to their AGT genotype, and in Agt mutant mice. Results Patients homozygous for the T allele had a reduced carotid distensibility and an increased stiffness of the carotid wall material (Young's elastic modulus), independent of blood pressure, compared with patients homozygous for the M allele. In Agt1/2 mice, carotid distensibility was not significantly different from that of Agt1/1 (wild-type). Moreover, the stiffness of the arterial wall material was lower in Agt1/2 mice than in wild-type mice. In Agt1/2 mice, the greater blood pressure was not associated with arterial hypertrophy, resulting in a greater circumferential wall stress. The in-vivo and in-vitro pressor responses to angiotensin II were reduced in Agt1/2 mice, whereas the contractile response to phenylephrine was not significantly different between Agt1/1 and Agt1/2 mice, indicating the integrity of the contractile apparatus and suggesting a dysfunction of the angiotensin II type 1 receptor signalling pathways in Agt1/2 mice. Conclusion These data suggest that the angiotensinogen TT genotype at position 235 could be a genetic marker for arterial stiffness in patients with never-treated hypertension, whereas in Agt1/2 mice the dysfunction of the angiotensin II type 1 receptor signalling pathways could explain the lack of arterial wall hypertrophy and stiffness.
Journal of Hypertension, 2012
Atherosclerotic renovascular disease is associated with resistant hypertension and chronic kidney... more Atherosclerotic renovascular disease is associated with resistant hypertension and chronic kidney disease, although the causal relationship is discussed. To date, the role of renal artery diameter on these pathological conditions was not clearly studied. We aimed to identify the association of reference diameter and minimal luminal renal artery diameter with glomerular filtration rate (GFR) and resistant hypertension in a high cardiovascular risk population. In this cross-sectional, single-center study, we enrolled 734 patients who underwent a renal angiography immediately after a coronary angiography indicated for a diagnosis of ischemic heart disease. Mean age was 64 ± 10 years (men 72%). GFR was 79 ± 22 ml/min per 1.73 m(2). Five hundred and eighteen patients had no luminal narrowing and 216 patients had low-to-moderate luminal narrowing (10-70%, mean 36%). A positive significant association between reference diameter and GFR was detected in patients without luminal narrowing [beta 2.2 ml/min per 1.73 m(2) for 1 mm increase, 95% confidence interval (CI) 0.3-4.0, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05] and in those with low-to-moderate luminal narrowing (beta 7.7 ml/min per 1.73 m(2) for 1 mm increase, 95% CI 4.2-11.1, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001). The lowest quartile of reference diameter (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;5.2 mm) was associated with GFR less than 60 ml/min per 1.73 m(2) [odds ratio (OR) 3.18, 95% CI 1.61-6.29, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001]. Patients with resistant hypertension had low minimal diameter and reference diameter. Reference diameter less than 5.2 mm was associated with an increased risk of resistant hypertension (OR 2.63, 95% CI 1.02-6.77, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05). Small renal arteries, defined by a low reference diameter or minimal luminal diameter, are independently associated with low GFR and resistant hypertension, independent of the degree of stenosis and major confounders.
Journal of Clinical Investigation, 2005
Tissue kallikrein (TK), the major kinin-forming enzyme, is synthesized in several organs, includi... more Tissue kallikrein (TK), the major kinin-forming enzyme, is synthesized in several organs, including the kidney and arteries. A loss-of-function polymorphism of the human TK gene (R53H) induces a substantial decrease in enzyme activity. As inactivation of the TK gene in the mouse induces endothelial dysfunction, we investigated the vascular, hormonal, and renal phenotypes of carriers of the 53H allele. In a crossover study, 30 R53Rhomozygous and 10 R53H-heterozygous young normotensive white males were randomly assigned to receive both a low sodium-high potassium diet to stimulate TK synthesis and a high sodium-low potassium diet to suppress TK synthesis, each for 1 week. Urinary kallikrein activity was 50-60% lower in R53H subjects than in R53R subjects. Acute flow-dependent vasodilatation and endothelium-independent vasodilatation of the brachial artery were both unaffected in R53H subjects. In contrast, R53H subjects consistently exhibited an increase in wall shear stress and a paradoxical reduction in artery diameter and lumen compared with R53R subjects. Renal and hormonal adaptation to diets was unaffected in R53H subjects. The partial genetic deficiency in TK activity is associated with an inward remodeling of the brachial artery, which is not adapted to a chronic increase in wall shear stress, indicating a new form of arterial dysfunction affecting 5-7% of white people.
Hypertension, 2007
Exposure to urban air pollution, ultrafine particles or gases, is associated with acute cardiovas... more Exposure to urban air pollution, ultrafine particles or gases, is associated with acute cardiovascular mortality and morbidity. We investigated the effect of ambient air pollution on endothelial function in 40 healthy white male nonsmokers spontaneously breathing ambient air in Paris, France. Air pollutant levels (nitrogen, sulfur and carbon oxides, and particulate matter) were averaged during the 5 days preceding arterial measurements. Brachial artery endothelium-dependent flow-mediated dilatation and reactive hyperemia induced by hand ischemia and endothelium-independent glyceryl trinitrate dilatation were measured using a radiofrequency-based echo-tracking device at 2-week intervals. Flow-mediated dilatation was independently and negatively correlated with the average levels of sulfur dioxide ( P <0.001) and nitrogen monoxide ( P <0.01). Sulfur dioxide levels explained 19% of the variance of flow-mediated dilatation. An increase in gaseous pollutants, 2 weeks apart, was sig...
Hypertension, 2012
Chronic kidney disease, even at moderate stages, is characterized by a high incidence of cardiova... more Chronic kidney disease, even at moderate stages, is characterized by a high incidence of cardiovascular events. Subclinical damage to large arteries, such as increased arterial stiffness and outward remodeling, is a classical hallmark of patients with chronic kidney disease. Whether large artery stiffness and remodeling influence the occurrence of cardiovascular events and the mortality of patients with chronic kidney disease (stages 2–5) is still debated. This prospective study included 439 patients with chronic kidney disease (mean age, 59.8±14.5 years) with a mean measured glomerular filtration rate of 37 mL/min per 1.73 m 2 . Baseline aortic stiffness was estimated through carotid-femoral pulse wave velocity measurements; carotid stiffness, diameter, and intima-media thickness were measured with a high-resolution echotracking system. For the overall group of patients, the 5-year estimated survival and cumulative incidence of cardiovascular events were 87% and 16%, respectively. ...
European Journal of Preventive Cardiology, 2011
Aims: Fabry disease is a lysosomal storage disorder due to deficient alpha-galactosidase A activi... more Aims: Fabry disease is a lysosomal storage disorder due to deficient alpha-galactosidase A activity, characterised by glycosphingolipids deposition in tissues. Patients have a common arterial involvement and contract progressive renal and cardiac disease. Although short-term effects of enzyme replacement therapy (ERT) on target organs have been established, no data are available on the long-term outcome. Methods and results: We studied the effects of ERT (agalsidase beta, 1 mg/kg/14 days) on arterial and cardiac structure and function during a longitudinal study beginning in 1999, with 4.5 AE 0.4 years follow-up (four visits) in 30 patients (age: 33 AE 12 years). In addition, we studied 16 untreated Fabry patients during 2.6 AE 1.6 years (two visits). Aortic stiffness was determined by carotid-femoral pulse wave velocity, central pulse pressure by aplanation tonometry, and carotid and radial intima-media thickness and diameter by high definition echotracking device. Left ventricular mass was determined by MRI. A significant decrease in aortic stiffness (À0.56 AE 0.13 m/s/yr, p ¼ 0.0002) was observed after ERT whereas central pulse pressure did not change. Carotid intima-media thickness (IMT) increased (þ18 AE 6 mm/yr; p < 0.005) whereas radial IMT remained stable. Radial artery diameter decreased (À50 AE 20 mm/years, p < 0.05) whereas carotid diameter did not change. Carotid circumferential wall stress was reduced (À1.7 AE 0.6 kPa/yrs, p < 0.01). Left ventricular mass index significantly decreased (À7.8 AE 2.3 g/m 2 /yr, p < 0.005). Conclusion: A sustained reduction in aortic stiffness and left ventricular hypertrophy, and a limited radial artery wall thickening were observed after long-term enzyme replacement therapy. There was no significant benefit of treatment on carotid hypertrophy.
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Papers by Pierre Boutouyrie