Geometric calibration of very large microphone arrays in mismatched free field.

Large microphone arrays are an efficient means for source localization thanks to a wide aperture and a great number of sensors. When such arrays are deployed in situ, accurate geometric calibration becomes essential to obtain the microphone positions. In free field, the classic procedures rely on measured Times of Arrival (TOA) or Time Differences of Arrival (TDOA) between the microphones and several controlled sources. However, free field model mismatches, such as reflectors, generate outliers which severely deteriorate the positioning accuracy. This paper introduces a unified framework for robust calibration using TOA or TDOA by exploiting an outlier-aware noise model. Thanks to the largeness of the array, the existing outliers are sparse and can be identified by a Lasso regression. From this, three iterative robust solvers are proposed: (i) for TOA by Robust Multi Dimensional Unfolding, a particular variation of Robust Multi Dimensional Scaling, (ii) for TDOA by data predenoising based on sparse and low-rank matrix decomposition, and (iii) for TDOA by jointly identifying the outliers and the geometry. The relevance of outlier-aware approaches is asserted by numerical and experimental tests. Compared with the baseline least-square approaches, the proposed robust solvers significantly improve the positioning accuracy in a free field mismatched by reflectors.

Vascular smooth muscle cells are responsible for a prothrombotic phenotype of spontaneously hypertensive rat arteries.

OBJECTIVE: The hypothesis that hypertension induces a hypercoagulable state arises from the complications associated with hypertension: stroke and myocardial infarction. Here, we determine whether hypertension causes changes in the thrombin-generating capacity of the vascular wall. APPROACH AND RESULTS: We used spontaneously hypertensive rats (SHR) compared with Wistar rats. The addition of thoracic aortic rings of SHR to a Wistar or SHR plasma pool resulted in a greater increase in thrombin generation compared with equivalent rings from Wistar. This increase occurred in 12- but not 5-week-old rats and was prevented by an angiotensin II-converting enzyme inhibitor, indicating that established hypertension is required to induce increased thrombin generation within the vessel wall. Whereas no difference was observed for endothelial cells, thrombin formation was higher on aortic smooth muscle cells (SMCs) from SHR than on those from Wistar. Exposure of negatively charged phospholipids was higher on SHR than on Wistar rings, as well as on cultured SMCs. Tissue factor activity was higher in SHR SMCs. Twelve-week-old SHR exhibited accelerated FeCl3-induced thrombus formation in carotid arteries, and the resulting occlusive thrombi were disaggregated by blockade of glycoprotein Ibα-von Willebrand factor interactions. SHR SMCs were more sensitive to thrombin-induced proliferation than Wistar SMCs. This effect was totally abolished by a protease-activated receptor 1 inhibitor. CONCLUSIONS: The prothrombotic phenotype of the SHR vessel wall was due to the ability of SMCs to support greater thrombin generation and resulted in accelerated occlusive thrombus formation after arterial injury, which was sensitive to glycoprotein Ibα-von Willebrand factor inhibitors.

A robust and passive method for geometric calibration of large arrays.

This paper presents a complete strategy for the geometry estimation of large microphone arrays of arbitrary shape. Largeness is intended here in both number of microphones (hundreds) and size (few meters). Such arrays can be used for various applications in open or confined spaces like acoustical imaging, source identification, or speech processing. For so large array systems, measuring the geometry by hand is impractical. Therefore a blind passive method is proposed. It is based on the analysis of the background acoustic noise, supposed to be a diffuse field. The proposed strategy is a two-step process. First the pairwise microphone distances are identified by matching their measured coherence function to the one predicted by the diffuse field theory. Second, a robust multidimensional scaling (MDS) algorithm is adapted and implemented. It takes advantage of local characteristics to reduce the set of distances and infer the geometry of the array. This work is an extension of previous studies, and it overcomes unsolved drawbacks. In particular it deals efficiently with the outliers known to ruin standard MDS algorithms. Experimental proofs of this ability are presented by treating the case of two arrays. They show that the proposed improvements manage large spatial arrays.

Inactivation of serum response factor contributes to decrease vascular muscular tone and arterial stiffness in mice.

RATIONALE: Vascular smooth muscle (SM) cell phenotypic modulation plays an important role in arterial stiffening associated with aging. Serum response factor (SRF) is a major transcription factor regulating SM genes involved in maintenance of the contractile state of vascular SM cells. OBJECTIVE: We investigated whether SRF and its target genes regulate intrinsic SM tone and thereby arterial stiffness. METHODS AND RESULTS: The SRF gene was inactivated SM-specific knockout of SRF (SRF(SMKO)) specifically in vascular SM cells by injection of tamoxifen into adult transgenic mice. Fifteen days later, arterial pressure and carotid thickness were lower in SRF(SMKO) than in control mice. The carotid distensibility/pressure and elastic modulus/wall stress curves showed a greater arterial elasticity in SRF(SMKO) without modification in collagen/elastin ratio. In SRF(SMKO), vasodilation was decreased in aorta and carotid arteries, whereas a decrease in contractile response was found in mesenteric arteries. By contrast, in mice with inducible SRF overexpression, the in vitro contractile response was significantly increased in all arteries. Without endothelium, the contraction was reduced in SRF(SMKO) compared with control aortic rings owing to impairment of the NO pathway. Contractile components (SM-actin and myosin light chain), regulators of the contractile response (myosin light chain kinase, myosin phosphatase target subunit 1, and protein kinase C-potentiated myosin phosphatase inhibitor) and integrins were reduced in SRF(SMKO). CONCLUSIONS: SRF controls vasoconstriction in mesenteric arteries via vascular SM cell phenotypic modulation linked to changes in contractile protein gene expression. SRF-related decreases in vasomotor tone and cell-matrix attachment increase arterial elasticity in large arteries.

Calibration of the axial stiffness of a single-beam acoustic tweezers.

Single-beam acoustic tweezers have recently been demonstrated to be capable of selective three-dimensional trapping. This new contactless manipulation modality has great potential for many scientific applications. Its development as a scientific tool requires precise calibration of its radiation force, specifically its axial component. The lack of calibration for this force is mainly due to its weak magnitude compared to competing effects such as weight. We investigate an experimental method for the calibration of the axial stiffness of the radiation force by observing the axial oscillations of a trapped bead in a microgravity environment. The stiffness exhibits a linear relationship with the acoustic intensity and is of the mN/m order. Then, a predictive model, loaded with the experimental acoustic field, is compared to the measured stiffness with very good agreement, within a single amplitude coefficient. This study paves the way for the development of calibrated acoustic tweezers.

Early MRI termination with major impact on the radiological interpretation: The experience of a large university hospital.

PURPOSE: To report the incidence of early magnetic resonance imaging (MRI) terminations and analyse their risk factors in a large university hospital. METHOD: All consecutive patients aged > 16 years who underwent an MRI over a 14-month period were included. The following parameters were collected: demographics, in- or outpatient, history of claustrophobia, anatomical region investigated, and early MRI termination along with its cause. The potential link between these parameters and early MRI termination was statistically analysed. RESULTS: Overall, 22,566MRIs were performed (10,792 [48%] men and 11,774[52%] women, mean age: 57 [range: 16-103] years). Early MRI termination was reported in 183 (0.8%) patients (99 men and 84 women, mean age: 63 years). Of these early terminations, 103 (56%) were due to claustrophobia and 80 (44%) to other causes. Early terminations were more common in inpatients than outpatients (1.2% vs. 0.6%, p < 0.001), for both claustrophobia- and non-claustrophobia-related reasons. A prior history of claustrophobia was strongly associated with claustrophobia-related early termination (6.6% vs. 0.2%, p = 0.0001). Non-claustrophobia-related early terminations were significantly more common (0.6% vs. 0.2%) in elderly patients (>65 years old) than in younger ones. No other parameter was significantly associated with early termination. CONCLUSIONS: Early MRI termination is currently rare. The main risk factors for claustrophobia-related terminations comprised a prior history of claustrophobia, and examinations in inpatients. Non-claustrophobia-related early terminations were more common in both elderly patients and inpatients.

Smooth muscle αv integrins regulate vascular fibrosis via CD109 downregulation of TGF-ß signalling.

Aims: αv integrins are implicated in fibrosis in a number of organs through their ability to activate TGF-ß. However their role in vascular fibrosis and collagen accumulation is only partially understood. Here we have used αv conditional knockout mice and cell lines to determine how αv contributes to vascular smooth muscle cell (VSMC) function in vascular fibrosis and the role of TGF-ß in that process. Methods and results: Angiotensin II (Ang II) treatment causes upregulation of αv and ß3 expression in the vessel wall, associated with increased collagen deposition. We found that deletion of αv integrin subunit from VSMCs (αv SMKO) protected mice against angiotensin II-induced collagen production and assembly. Transcriptomic analysis of the vessel wall in αv SMKO mice and controls identified a significant reduction in expression of fibrosis and related genes in αv SMKO mice. In contrast, αv SMKO mice showed prolonged expression of CD109, which is known to affect TGF-ß signalling. Using cultured mouse and human VSMCs, we showed that overexpression of CD109 phenocopied knockdown of αv integrin, attenuating collagen expression, TGF-ß activation, and Smad2/3 signalling in response to angiotensin II or TGF-ß stimulation. CD109 and TGF-ß receptor were internalized in early endosomes. Conclusion: We identify a role for VSMC αv integrin in vascular fibrosis and show that αv acts in concert with CD109 to regulate TGF-ß signalling.

Tissue factor pathway inhibitor: a new link among arterial stiffness, pulse pressure, and coagulation in postmenopausal women.

OBJECTIVE: To investigate in women older than 60 whether aortic stiffness or pulse pressure (PP) is associated with selected procoagulant or anticoagulant factors and to examine whether pulsatile stretch influences these factors in human vascular smooth muscle cells (VSMCs) in vitro. METHODS AND RESULTS: Aortic pulse wave velocity (PWV) and carotid PP were studied in 123 apparently healthy postmenopausal women. PWV, PP, von Willebrand factor, and free tissue factor pathway inhibitor (TFPI), but not mean arterial pressure, increased with age. Free TFPI and PWV were positively correlated, even after adjustment for age and PP and other confounding parameters. In vitro, 5% or 10% pulsatile stretch (at 1 Hz) enhanced TFPI synthesis and secretion by VSMCs in a time-independent manner (1 to 48 hours) without changes in protein level of smooth muscle myosin heavy chain. Application of 5% static stretch had no effect. CONCLUSIONS: In postmenopausal women, free TFPI increases as vascular wall function deteriorates and PP increases. These findings are supported by the increase in TFPI synthesized by VSMCs in response to cyclic stress in vitro. They suggest that VSMCs require pulsatility to interfere with the coagulation process and highlight the relevance of plasma free TFPI levels to cardiovascular diseases.

Cell senescence: basic mechanisms and the need for computational networks in vascular ageing.

This review seeks to provide an update of the mechanisms of vascular cell senescence, from newly identified molecules to arterial ageing phenotypes, and finally to present a computational approach to connect these selected proteins in biological networks. We will discuss current key signalling and gene expression pathways by which these focus proteins and networks drive normal and accelerated vascular ageing. We also review the possibility that senolytic drugs, designed to restore normal cell differentiation and function, could effectively treat multiple age-related vascular diseases. Finally, we discuss how cell senescence is both a cause and a consequence of vascular ageing because of the possible feedback controls between identified networks.

Changes in aortic stiffness related to elastic fiber network anomalies in the Brown Norway rat during maturation and aging.

Adult Brown Norway (BN) rats exhibit numerous internal elastic lamina (IEL) ruptures in the abdominal aorta (AA) and a lower aortic elastin-to-collagen ratio (E/C) compared with other strains. We studied here AA mechanical properties in BN compared with control strains. AA stiffness (assessed by plotting elastic modulus/wall-stress curves obtained under anesthesia), thoracic aorta elastin and collagen contents, and IEL ruptures in AA were measured in male BN and LOU rats aged 6, 10, and 15 wk. The Long Evans (LE) control strain was compared with BN at more advanced ages (15, 28, and 64 wk). At all ages, aortic E/C was lower in BN than in control strains. At 6 wk, AA stiffness was greater in BN than in LOU. In both strains, AA stiffness decreased between 6 and 10 wk, more so in BN than in LOU, and then increased, reaching similar values at 15 wk. BN AA stiffness was not different from that of LE at 15 and 28 wk, but was significantly lower at 64 wk. The increased stiffness in young BN rat AA may be due to the decreased E/C. IEL rupture onset in the BN around 7-8 wk, which decreases stiffness, as suggested by its pharmacological modulation, abolished such differences by 15 wk. Thereafter, age-related AA stiffness increased less in BN than in LE, likely due to the numerous IEL ruptures. We conclude that, in the BN rat, the lower E/C and the presence of IEL ruptures have opposing effects on arterial stiffness.

Comparison of the effects of semicarbazide and beta-aminopropionitrile on the arterial extracellular matrix in the Brown Norway rat.

To investigate a putative role for semicarbazide-sensitive amine oxidase (SSAO) in arterial extracellular matrix (ECM) organization, we compared arteries of growing Brown Norway (BN) rats after chronic administration of semicarbazide (SCZ) and beta-aminopropionitrile (BAPN), two inhibitors with different properties and relative specificities for SSAO and lysyl oxidase (LOX). The BN model is particularly well adapted to evaluating effects of toxic compounds on the arterial elastic network. We measured aortic LOX and SSAO activities and quantified several ECM parameters. After a pilot study comparing doses previously studied and testing for additivity, we studied low and high equimolar doses of SCZ and BAPN. Both compounds similarly inhibited LOX, whereas SCZ inhibited SSAO far more effectively than BAPN. Both decreased carotid wall rupture pressure, increased tail tendon collagen solubility, decreased aortic insoluble elastin (% dry weight) and dose-dependently increased defects in the internal elastic lamina of abdominal aorta, iliac and renal arteries. Our results suggest that either these effects are mediated by LOX inhibition, SCZ being slightly more effective than BAPN in our conditions, or SSAO acts similarly to and in synergy with LOX on ECM, the greater SCZ effect reflecting the simultaneous inhibition of both enzymes. However, the high SCZ dose increased aortic collagen and ECM proteins other than insoluble elastin markedly more than did equimolar BAPN, possibly revealing a specific effect of SSAO inhibition. To discriminate between the two above possibilities, and to demonstrate unequivocally a specific effect of SSAO inhibition on ECM formation or organization, we must await availability of more specific inhibitors.

Publisher Correction: Vimentin knockout results in increased expression of sub-endothelial basement membrane components and carotid stiffness in mice.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Carotid arterial stiffness, elastic fibre network and vasoreactivity in semicarbazide-sensitive amine-oxidase null mouse.

OBJECTIVE: We examined the arterial phenotype of semicarbazide-sensitive amine-oxidase null mouse (SSAO -/-) using various techniques including high resolution echotracking. METHODS AND RESULTS: SSAO -/- mice showed no change in arterial pressure under anesthesia. The in vivo arterial diameter, only measured in the carotid artery (CA), was higher in SSAO -/- than in SSAO +/+ animals. Elastic modulus-wall stress curves and CA rupture pressure were similar between SSAO -/- and +/+ mice, indicating no change in arterial wall stiffness or mechanical strength. There was no significant difference in insoluble elastin, total collagen content and elastic lamellar morphology between the two genotypes. No alteration in vascular reactivity was observed in aortic rings and mesenteric arteries from SSAO -/- mice. Aortic lysyl oxidase (LO) activity remained unaltered, indicating that SSAO invalidation is not accompanied by a compensatory increase in LO activity. CONCLUSION: This is the first functional study of arteries lacking SSAO. Our results indicate that SSAO -/- mice present an increased arterial diameter associated with normal arterial mechanical properties, suggesting that SSAO deficiency might contribute to arterial wall remodeling. However, these results argue against the hypothesis that SSAO intervenes in elastic fibre organization, elastin cross-linking processes and vasoreactivity.

Implication of Free Fatty Acids in Thrombin Generation and Fibrinolysis in Vascular Inflammation in Zucker Rats and Evolution with Aging.

Background: The metabolic syndrome (MetS) and aging are associated with modifications in blood coagulation factors, vascular inflammation, and increased risk of thrombosis. Objectives: Our aim was to determine concomitant changes in thrombin generation in the blood compartment and at the surface of vascular smooth muscle cells (VSMCs) and its interplay with adipokines, free fatty acids (FFA), and metalloproteinases (MMPs) in obese Zucker rats that share features of the human MetS. Methods: Obese and age-matched lean Zucker rats were compared at 25 and 80 weeks of age. Thrombin generation was assessed by calibrated automated thrombography (CAT). Results: Endogenous thrombin potential (ETP) was increased in obese rats independent of platelets and age. Clot half-lysis time was delayed with obesity and age. Interleukin (IL)-1ß and IL-13 were increased with obesity and age respectively. Addition of exogenous fibrinogen, leptin, linoleic, or palmitic acid increased thrombin generation in plasma whereas adiponectin had an opposite effect. ETP was increased at the surface of VSMCs from obese rats and addition of exogenous palmitic acid further enhanced ETP values. Gelatinase activity was increased in aorta at both ages in obese rats and MMP-2 activity was increased in VSMCs from obese rats. Conclusions: Our study demonstrated in MetS an early prothrombotic phenotype of the blood compartment reinforced by procoagulant properties of dedifferentiated and inflammatory VSMCs. Mechanisms involved (1) increased fibrinogen and impaired fibrinolysis and (2) increased saturated fatty acids responsible for additive procoagulant effects. Whether specifically targeting this hypercoagulability using direct thrombin inhibitors would improve outcome in MetS is worth investigating.

Vimentin knockout results in increased expression of sub-endothelial basement membrane components and carotid stiffness in mice.

Intermediate filaments are involved in stress-related cell mechanical properties and in plasticity via the regulation of focal adhesions (FAs) and the actomyosin network. We investigated whether vimentin regulates endothelial cells (ECs) and vascular smooth muscle cells (SMCs) and thereby influences vasomotor tone and arterial stiffness. Vimentin knockout mice (Vim-/-) exhibited increased expression of laminin, fibronectin, perlecan, collagen IV and VE-cadherin as well as von Willebrand factor deposition in the subendothelial basement membrane. Smooth muscle (SM) myosin heavy chain, α-SM actin and smoothelin were decreased in Vim-/- mice. Electron microscopy revealed a denser endothelial basement membrane and increased SM cell-matrix interactions. Integrin αv, talin and vinculin present in FAs were increased in Vim-/- mice. Phosphorylated FA kinase and its targets Src and ERK1/2 were elevated in Vim-/- mice. Knockout of vimentin, but not of synemin, resulted in increased carotid stiffness and contractility and endothelial dysfunction, independently of blood pressure and the collagen/elastin ratio. The increase in arterial stiffness in Vim-/- mice likely involves vasomotor tone and endothelial basement membrane organization changes. At the tissue level, the results show the implication of FAs both in ECs and vascular SMCs in the role of vimentin in arterial stiffening.

Contribution of Rare and Common Genetic Variants to Plasma Lipid Levels and Carotid Stiffness and Geometry: A Substudy of the Paris Prospective Study 3.

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 defined on the basis of recent meta-analyses of genome-wide association studies. We observed a strong association between the plasma lipids gene set and plasma lipid variables, but none of the 3 genome-wide association studies gene sets was associated with the carotid parameters. Significant V(G)/V(p) ratios were observed for external (14.5%, P<2.7×10(-5)) and internal diameter (13.4%, P<4.3×10(-4)), stiffness (12.5%, P<8.0×10(-4)), intima-media thickness (10.6%, P<7.9×10(-4)), and wall cross-sectional area (13.2%, P<2.4×10(-5)). A significant association was observed between the common rs2903692 polymorphism of the CLEC16A gene and the internal diameter (P<4.3×10(-7)). CONCLUSIONS: These results suggest an involvement of CLEC16A, a gene that has been reported to be associated with immune disorders, in the modulation of carotid vasodilatation.

Selective reduction of heart rate by ivabradine: effect on the visco-elastic arterial properties in rats.

BACKGROUND: The heart rate (HR) reduction obtained by ivabradine is associated in rats with a decrease in diastolic blood pressure (DBP) and mean blood pressure (MBP), and with an increased pulsatile carotid arterial diameter. OBJECTIVE: To determine, in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats, whether acute reductions of the HR in response to ivabradine induced changes in the carotid visco-elastic behavior, as assessed by echo-tracking techniques. METHODS: The hysteresis of the carotid diameter/pressure curve was used to determine the dissipated energy per cardiac cycle, a classical index of arterial viscosity. Four doses of 1 mg/kg intravenous ivabradine were repeated in anesthetized rats to obtain subsequent HR reductions. RESULTS: In WKY, repeated administration of ivabradine produced reduction of MBP, DBP and HR, without change of systolic blood pressure (SBP). In SHR, ivabradine produced a higher reduction in DBP, SBP and HR than in WKY rats, but the increase in pulse pressure was similar in both strains. In SHR and WKY rats, ivabradine did not modify the incremental elastic modulus-stress curves, and shifted the distensibility-pressure curves through changes in blood pressure, indicating no modification in isobaric carotid stiffness. In both strains, ivabradine produced an identical increase of the energy dissipated per cardiac cycle. CONCLUSION: In WKY rats and SHR, acute ivabradine reduces MBP and DBP and increases pulse pressure, but without change in arterial stiffness. In both strains, the HR reduction due to ivabradine induces an identical increase of the energy dissipation of the arterial wall.

Increased stiffness and cell-matrix interactions of abdominal aorta in two experimental nonhypertensive models: long-term chemically sympathectomized and sinoaortic denervated rats.

RATIONALE: Sinoaortic denervated (SAD) and chemically sympathectomized (SNX) rats are characterized by a decrease in arterial distensibility without hypertension and would, thus, be relevant for analyzing arterial wall stiffening independently of blood pressure level. The fibronectin network, which plays a pivotal role in cell-matrix interactions, is a major determinant of arterial stiffness. We hypothesized that in SAD and SNX rats, arterial stiffness is increased, due to alterations of cell-matrix anchoring leading to spatial reorganization of the extracellular matrix. METHODS: The intrinsic elastic properties of the arterial wall were evaluated in vivo by the relationship between incremental elastic modulus determined by echotracking and circumferential wall stress. The changes of cell-extracellular matrix links in the abdominal aorta were evaluated by studying fibronectin, vascular integrin receptors, and ultrastructural features of the aorta by immunochemistry. RESULTS: In both experimental conditions, wall stiffness increased, associated with different modifications of cell-extracellular matrix adhesion. In SAD rats, increased media cross-sectional area was coupled with an increase of muscle cell attachments to its extracellular matrix via fibronectin and its α5-ß1 integrin. In SNX rats, reduced media cross-sectional area was associated with upregulation of αv-ß3 integrin and more extensive connections between dense bands and elastic fibers despite the disruption of the elastic lamellae. CONCLUSION: In aorta of SNX and SAD rats, a similar arterial stiffness is associated to different structural alterations. An increase in αvß3 or α5ß1 integrins together with the already reported increase in the proportion of less distensible (collagen) to more distensible (elastin) components in both models contributes to remodeling and stiffening of the abdominal aorta.

Opposite predictive value of pulse pressure and aortic pulse wave velocity on heart failure with reduced left ventricular ejection fraction: insights from an Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) substudy.

Although hypertension contributes significantly to worsen cardiovascular risk, blood pressure increment in subjects with heart failure is paradoxically associated with lower risk. The objective was to determine whether pulse pressure and pulse wave velocity (PWV) remain prognostic markers, independent of treatment in heart failure with reduced left ventricular function. The investigation involved 6632 patients of the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study. All subjects had acute myocardial infarction with left ventricular ejection fraction <40% and signs/symptoms of heart failure. Carotid-femoral PWV was measured in a subpopulation of 306 subjects. In the overall population, baseline mean arterial pressure <90 mm Hg was associated with higher all-cause death (hazard ratio, 1.14 [95% confidence interval, 1.00-1.30]; P<0.05), whereas higher left ventricular ejection fraction or pulse pressure was associated with lower rates of all-cause death, cardiovascular death/hospitalization, and cardiovascular death. In the subpopulation, increased baseline PWV was associated with worse outcomes (all-cause death: 1.16 [1.03-1.30]; P<0.05 and cardiovascular deaths: 1.16 [1.03-1.31]; P<0.05), independent of age and left ventricular ejection fraction. Using multiple regression analysis, systolic blood pressure and age were the main independent factors positively associated with pulse pressure or PWV, both in the entire population or in the PWV substudy. In heart failure and low ejection fraction, our results suggest that pulse pressure, being negatively associated with outcome, is more dependent on left ventricular function and thereby no longer a marker of aortic elasticity. In contrast, increased aortic stiffness, assessed by PWV, contributes significantly to cardiovascular death.

Smooth muscle cell mineralocorticoid receptors are mandatory for aldosterone-salt to induce vascular stiffness.

Arterial stiffness is recognized as a risk factor for many cardiovascular diseases. Aldosterone via its binding to and activation of the mineralocorticoid receptors (MRs) is a main regulator of blood pressure by controlling renal sodium reabsorption. Although both clinical and experimental data indicate that MR activation by aldosterone is involved in arterial stiffening, the molecular mechanism is not known. In addition to the kidney, MR is expressed in both endothelial and vascular smooth muscle cells (VSMCs), but the specific contribution of the VSMC MR to aldosterone-induced vascular stiffness remains to be explored. To address this question, we generated a mouse model with conditional inactivation of the MR in VSMC (MR(SMKO)). MR(SMKO) mice show no alteration in renal sodium handling or vascular structure, but they have decreased blood pressure when compared with control littermate mice. In vivo at baseline, large vessels of mutant mice presented with normal elastic properties, whereas carotids displayed a smaller diameter when compared with those of the control group. As expected after aldosterone/salt challenge, the arterial stiffness increased in control mice; however, it remained unchanged in MR(SMKO) mice, without significant modification in vascular collagen/elastin ratio. Instead, we found that the fibronectin/α5-subunit integrin ratio is profoundly altered in MR(SMKO) mice because the induction of α5 expression by aldosterone/salt challenge is prevented in mice lacking VSMC MR. Altogether, our data reveal in the aldosterone/salt hypertension model that MR activation specifically in VSMC leads to the arterial stiffening by modulation of cell-matrix attachment proteins independent of major vascular structural changes.