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Despite a similar beneficial effect on blood pressure lowering observed with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor (AT1R) blocker (ARBs), several clinical trials and meta-analyses have reported higher cardiovascular mortality and lower protection against myocardial infarction with ARBs when compared with ACEIs. The European guidelines for the management of coronary syndromes and European guidelines on diabetes recommend using ARBs in patients who are intolerant to ACEIs. We reviewed the main pharmacological differences between ACEIs and ARBs, which could provide insights into the differences in the cardiac protection offered by these 2 drug classes. The effect of ACEIs on the tissue and plasma levels of bradykinin and on nitric oxide production and bioavailability is specific to the mechanism of action of ACEIs; it could account for the different effects of ACEIs and ARBs on endothelial function, atherogenesis, and fibrinolysis. Moreover, chronic blockade of AT1 receptors by ARBs induces a significant and permanent increase in plasma angiotensin II and an overstimulation of its still available receptors. In animal models, AT4 receptors have vasoconstrictive, proliferative, and inflammatory effects. Moreover, in models with kidney damage, atherosclerosis, and/or senescence, activation of AT2 receptors could have deleterious fibrotic, vasoconstrictive, and hypertrophic effects and seems prudent and reasonable to reserve the use of ARBs for patients who have presented intolerance to ACE inhibitors.

Severe acute respiratory syndrome coronavirus 2, which is responsible for the current coronavi-rus disease 2019 pandemic, uses angiotensin-converting enzyme 2 as a gateway into host cells In this review, we summarized the biology of this enzyme which plays a key role in cardiovascular homeostasis and blood pressure control Blockers of the renin-angiotensin-aldosterone system modify the expression and activity of angiotensin-converting enzyme 2, possibly in different ways The effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on the expression and enzyme activity of angiotensin-converting enzyme 2 are reviewed, and the consequences of these treatments for the severity of coronavirus disease 2019 infection are discussed © 2020, John Libbey All rights reserved

Objective Post‐traumatic stress disorder (PTSD) is a chronic, disabling condition. Our main objective is to investigate the association between trait mindfulness and PTSD over a period of 54 months. The secondary objective is to provide an exhaustive description of PTSD trajectories after the Bataclan attack. Methods We designed a prospective cohort study of 133 subjects present in the Bataclan concert hall during the November 2015 terrorist attack in Paris, France. Data were recorded 6, 18, 30, and 54 months after the attack. The primary endpoint was evaluated using the PTSD Check List Scale. Trait mindfulness was measured by the 14‐item Freiburg Mindfulness Inventory. Results FMI scores were consistently, significantly, and negatively associated with PCL‐5 scores. Adjusted odds ratios were at 0.81 (6 months), 0.88 (18 months) 0.82 (30 months), and 0.81 (54 months). PTSD prevalence 6 months after the event was 77%; it remained at 41% after 54 months. PTSD status of subjects is fluctuating. Latent class analysis divided the cohort into 3 groups: 21% of subject who remained below PTSD threshold throughout, 30% who remained above throughout, and 49% who steadily reduced their PTSD scores over time. Conclusion In our cohort, mindfulness is negatively associated with PTSD. Mindfulness programs are designed to improve global resilience and treat anxiety and mood disorders. Further research is needed to investigate if improving trait mindfulness is possible and beneficial for patients suffering from PTSD., PTSD prevalence remains very high for direct victims of terrorism even after 54 months. We found a strong negative association between trait mindfulness and post‐traumatic stress disorder at 6, 18, 30, and 54 months. Mindfulness prevention programs for post‐traumatic stress disorder should be implemented as soon as possible after the trauma.

Aims Hypertension and hypercholesterolemia are independent risk factors for atherosclerotic cardiovascular disease (ASCVD) by acting directly on the endothelium and activating the renin-angiotensin aldosterone system (RAAS) and mevalonate pathways. This review examines how the severity and duration of these risk factors may influence the cardiovascular risk through a reciprocal interplay leading to oxidative stress and pro-inflammatory response. Data synthesis The review highlights the clinical evidence supporting the benefits of statins and angiotensin-converting enzyme (ACE) inhibitors for hypertension, lipid disorders and ASCVD management, both individually and combined, at all stages of the cardiovascular continuum. Conclusion Drug strategies incorporating an ACE-inhibitor and a statin, and in particular perindopril and atorvastatin, have consistently demonstrated reductions in the rate of ASCVD events in patients with hypertension and lipid disorders, cementing their position as first-line therapies for the management of atherosclerosis complications.

A chronic and gradual increase in pulse pressure (PP) is associated with cognitive decline and dementia in older individuals, but the mechanisms remain ill-defined. We hypothesized that a chronic elevation of PP would cause brain microvascular endothelial mechanical stress, damage the neurovascular unit, and ultimately induce cognitive impairment in mice, potentially contributing to the progression of vascular dementia and Alzheimer disease. To test our hypothesis, male control wild-type mice and Alzheimer disease model APP/PS1 (amyloid precursor protein/presenilin 1) mice were exposed to a transverse aortic constriction for 6 weeks, creating a PP overload in the right carotid (ipsilateral). We show that the transverse aortic constriction procedure associated with high PP induces a cascade of vascular damages in the ipsilateral parenchymal microcirculation: in wild-type mice, it impairs endothelial dilatory and blood brain barrier functions and causes microbleeds, a reduction in microvascular density, microvascular cell death by apoptosis, leading to severe hypoperfusion and parenchymal cell senescence. These damages were associated with brain inflammation and a significant reduction in learning and spatial memories. In APP/PS1 mice, that endogenously display severe cerebral vascular dysfunctions, microbleeds, parenchymal inflammation and cognitive dysfunction, transverse aortic constriction–induced high PP further aggravates cerebrovascular damage, Aβ (beta-amyloid) accumulation, and prevents learning. Our study, therefore, demonstrates that brain microvessels are vulnerable to a high PP and mechanical stress associated with transverse aortic constriction, promoting severe vascular dysfunction, disruption of the neurovascular unit, and cognitive decline. Hence, chronic elevated amplitude of the PP could contribute to the development and progression of vascular dementia including Alzheimer disease.

International audience; Since December 2019, the coronavirus 2019 (COVID-19) pandemic has rapidly spread and overwhelmed healthcare systems worldwide, urging physicians to understand how to manage this novel infection. Early in the pandemic, more severe forms of COVID-19 have been observed in patients with cardiovascular comorbidities, who are often treated with renin-angiotensin aldosterone system (RAAS)-blockers, such as angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), but whether these are indeed independent risk factors is unknown. The cellular receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the membrane-bound angiotensin converting enzyme 2 (ACE2), as for SARS-CoV(-1). Experimental data suggest that expression of ACE2 may be increased by RAAS-blockers, raising concerns that these drugs may facilitate viral cell entry. On the other hand, ACE2 is a key counter-regulator of the RAAS, by degrading angiotensin II into angiotensin (1-7), and may thereby mediate beneficial effects in COVID-19. These considerations have raised concerns about the management of these drugs, and early comments shed vivid controversy among physicians. This review will describe the homeostatic balance between ACE-angiotensin II and ACE2-angiotensin (1-7) and summarize the pathophysiological rationale underlying the debated role of the RAAS and its modulators in the context of the pandemic. In addition, we will review available evidence investigating the impact of RAAS blockers on the course and prognosis of COVID-19 and discuss why retrospective observational studies should be interpreted with caution. These considerations highlight the importance of solid evidence-based data in order to guide physicians in the management of RAAS-interfering drugs in the general population as well as in patients with more or less severe forms of SARS-CoV-2 infection.

Obstructive disease of the epicardial coronary arteries is the main cause of angina. However, a number of patients with anginal symptoms have normal coronaries or non-obstructive coronary artery disease (CAD) despite electrocardiographic evidence of ischaemia during stress testing. In addition to limited microvascular vasodilator capacity, the coronary microcirculation of these patients is particularly sensitive to vasoconstrictor stimuli, in a condition known as microvascular angina. This review briefly summarizes the determinants and control of coronary blood flow (CBF) and myocardial perfusion. It subsequently analyses the mechanisms responsible for transient myocardial ischaemia: obstructive CAD, coronary spasm and coronary microvascular dysfunction in the absence of epicardial coronary lesions, and variable combinations of structural anomalies, impaired endothelium-dependent and/or -independent vasodilation, and enhanced perception of pain. Lastly, we exemplify mechanism of angina during tachycardia. Distal to a coronary stenosis, coronary dilator reserve is already recruited and can be nearly exhausted at rest distal to a severe stenosis. Increased heart rate reduces the duration of diastole and thus CBF when metabolic vasodilation is no longer able to increase CBF. The increase in myocardial oxygen consumption and resulting metabolic vasodilation in adjacent myocardium without stenotic coronary arteries further acts to divert blood flow away from the post-stenotic coronary vascular bed through collaterals.

Summary Severe acute respiratory syndrome coronavirus 2, which is responsible for the current coronavirus disease 2019 pandemic, uses angiotensin-converting enzyme 2 as a gateway into host cells. In this review, we summarize the biology of this enzyme, which plays a key role in cardiovascular homeostasis. Blockers of the renin-angiotensin system modify the expression and activity of angiotensin-converting enzyme 2 in different ways. The effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on the expression and enzyme activity of angiotensin-converting enzyme 2 are reviewed, and the consequences of these treatments for the severity of coronavirus disease 2019 infection are discussed.

Heart rate plays a major role in myocardial ischemia. A high heart rate increases myocardial performance and oxygen demand and reduces diastolic time. Ivabradine reduces heart rate by inhibiting the If current of sinoatrial-node cells. In contrast to beta-blockers, ivabradine has no negative inotropic and lusitropic effect for a comparable heart rate reduction. Consequently, diastolic duration is increased with ivabradine compared to beta-blockers. This has potential consequences on coronary blood flow since compression of the vasculature by the surrounding myocardium during systole impedes flow and coronary blood flow is mainly diastolic. Moreover, ivabradine does not unmask alpha-adrenergic vasoconstriction and, unlike beta-blockers, maintains coronary dilation during exercise. In comparison with beta-blockers, ivabradine increases coronary flow reserve and collateral perfusion promoting the development of coronary collaterals. Ivabradine attenuates myocardial ischemia and its consequences even in the absence of heart rate reduction, possibly through reduced formation of reactive oxygen species. In conclusion, ivabradine differs from other anti-anginal agents by improving coronary blood flow and by additional pleiotropic effects. These properties make ivabradine an effective anti-anginal and anti-ischemic agent for the treatment of patients with coronary artery disease.

To assess the prognostic value of the wall shear stress (WSS) measured in the feeding native arteries upstream from facial superficial arteriovenous malformations (sAVMs). Reliable prognostic criteria are needed to distinguish progressive from stable sAVMs and thus support the indication for an aggressive or a conservative management to avoid severe facial disfigurement. We prospectively included 25 patients with untreated facial sAVMs, 15 patients with surgically resected sAVMs and 15 controls. All had undergone Doppler ultrasound examination (DUS) with measurements of inner diameters, blood flow velocities, computation of blood flow and WSS of the feeding arteries. Based on the absence or presence of progression in clinical and imaging examinations 6 months after, we discriminated untreated patients as stable or progressive. WSS in the ipsilateral external carotid artery was higher in progressive compared to stable sAVMs (15.8 ± 3.3dynes/cm² vs. 9.6 ± 2.0dynes/cm², mean±SD, p 0.0001) with a cut-off of 11.5dynes/cm² (sensitivity: 92 %, specificity: 92 %, AUC: 0.955, [95 %CI: 0.789-0.998], p = 0.0001). WSS in the ipsilateral facial artery was also higher in progressive compared to stable sAVMs (50.7 ± 14.5dynes/cm² vs. 25.2 ± 7.1dynes/cm², p 0.0001) with a cut-off of 34.0dynes/cm² (sensitivity: 100 %, specificity: 92 %, AUC: 0.974, [95 %CI: 0.819-1.000], p = 0.0001). The hemodynamic data of operated patients were not different from those of the control group. WSS measured in the feeding arteries of an sAVM may be a simple reliable criterion to distinguish stable from progressive sAVMs. This value should be considered to guide the therapeutic strategy as well as the long-term follow-up of patients with facial sAVMs.ZIEL: Beurteilung des prognostischen Wertes der Wandschubspannung (WSS), gemessen in den zuführenden nativen Arterien stromaufwärts von oberflächlichen arteriovenösen Fehlbildungen des Gesichts (sAVMs). Um progressive von stabilen sAVMs zu unterscheiden sind verlässliche prognostische Kriterien erforderlich, die bei der Indikation für eine aggressive oder konservative Behandlung hilfreich sind, um schwere Gesichtsdeformierungen zu vermeiden. Prospektiv wurden 25 Patienten mit unbehandelten sAVMs im Gesicht, 15 Patienten mit chirurgisch-resezierten sAVMs und 15 Kontrollpatienten eingeschlossen. Alle hatten eine Doppler-Ultraschalluntersuchung (DUS) mit Bestimmungen der Innendurchmesser, Blutflussgeschwindigkeiten, Berechnung des Blutflusses und der WSS der zuführenden Arterien. Aufgrund des Fehlens oder Auftretens einer Progression bei den klinischen und bildgebenden Untersuchungen nach 6 Monaten unterschieden wir unbehandelte Patienten als stabil oder progressiv. WSS in der ipsilateralen A. carotis externa war bei progressiven sAVMs im Vergleich zu stabilen sAVMs höher (15,8 ± 3,3 dyn/cm² vs. 9,6 ± 2,0 dyn/cm², Mittelwert±SD, p 0,0001) mit einem Cut-off von 11,5 dyn/cm² (Sensitivität: 92 %, Spezifität: 92 %, AUC: 0,955, [95 %CI: 0,789–0,998], p = 0,0001). WSS in der ipsilateralen A. facialis war ebenfalls höher bei den progressiven im Vergleich zu den stabilen sAVMs (50,7 ± 14,5 dyn/cm² vs. 25,2 ± 7,1 dyn/cm², p 0,0001) mit einem Cut-off von 34,0 dyn/cm² (Sensitivität: 100 %, Spezifität: 92 %, AUC: 0,974, [95 %CI: 0,819–1,000], p = 0,0001). Die hämodynamischen Daten operierter Patienten unterschieden sich nicht von denen der Kontrollgruppe. WSS, gemessen in den zuführenden Arterien eines sAVM, kann ein einfache zuverlässiges Kriterium sein, um stabile von progressiven sAVMs zu unterscheiden. Dieser Wert sollte als Richtschnur für die therapeutische Strategie sowie für die langfristige Nachsorge von Patienten mit sAVM im Gesicht angesehen werden.

Background Left ventricular (LV) torsion plays a key role in cardiac efficiency. In hypertension, aortic stiffening augments cardiac afterload. However, little is known about the links between LV regional contraction and aortic stiffness. We, therefore, investigated these relationships and their contribution to LV diastolic function. Methods and Results The study included normotensive and hypertensive individuals with normal LV ejection. Apical, basal, and global LV rotation rate and LV global longitudinal strain were measured (2‐dimensional speckle tracking echocardiography). Aortic stiffness was calculated from carotid‐femoral pulse wave velocity, and LV relaxation was calculated from early diastolic mitral annulus motion. The ratio of basal or apical untwist/twist rates was calculated to assess relationships between aortic stiffness and LV torsion parameters. LV twist and untwist rates were greater in hypertensive than normotensive individuals because of increased basal twist ( P P P R =0.43; P R =0.41; P =0.001). The ratio of basal untwist/twist rate was positively correlated with carotid‐femoral pulse wave velocity, and in the hypertensive group, was greater than in the control group and positively correlated to carotid‐femoral pulse wave velocity( P Conclusions In hypertensive individuals, greater basal LV torsion was associated with increased aortic stiffness and improved diastolic function. These changes may compensate for the deleterious effects of aortic stiffening on LV relaxation.

International audience; The pathophysiology of sporadic Alzheimer's disease (AD) remains uncertain. Along with brain amyloid-β (Aβ) deposits and neurofibrillary tangles, cerebrovascular dysfunction is increasingly recognized as fundamental to the pathogenesis of AD. Using an experimental model of limb ischemia in transgenic APPPS1 mice, a model of AD (AD mice), we showed that microvascular impairment also extends to the peripheral vasculature in AD. At D70 following femoral ligation, we evidenced a significant decrease in cutaneous blood flow (- 29%, P

Clinical trials of cell therapy in stroke favor autologous cell transplantation. To date, feasibility studies have used bone marrow-derived mononuclear cells, but harvesting bone marrow cells is invasive thus complicating bedside treatment. We investigated the therapeutic potential of peripheral blood-derived mononuclear cells (PB-MNC) harvested from diabetic patients and stimulated by ephrin-B2 (PB-MNC+) (500,000 cells), injected intravenously 18–24 hours after induced cerebral ischemia in mice. Infarct volume, neurological deficit, neurogenesis, angiogenesis, and inflammation were investigated as were the potential mechanisms of PB-MNC+ cells in poststroke neurorepair. At D3, infarct volume was reduced by 60% and 49% compared to unstimulated PB-MNC and PBS-treated mice, respectively. Compared to PBS, injection of PB-MNC+ increased cell proliferation in the peri-infarct area and the subventricular zone, decreased microglia/macrophage cell density, and upregulated TGF-βexpression. At D14, microvessel density was decreased and functional recovery was enhanced compared to PBS-treated mice, whereas plasma levels of BDNF, a major regulator of neuroplasticity, were increased in mice treated with PB-MNC+ compared to the other two groups. Cell transcriptional analysis showed that ephrin-B2 induced phenotype switching of PB-MNC by upregulating genes controlling cell proliferation, inflammation, and angiogenesis, as confirmed by adhesion and Matrigel assays.Conclusions. This feasibility study suggests that PB-MNC+ transplantation poststroke could be a promising approach but warrants further investigation. If confirmed, this rapid, noninvasive bedside cell therapy strategy could be applied to stroke patients at the acute phase.

International audience; CONTEXT:Controversial data exist on cardiovascular damages in patients with congenital adrenal hyperplasia (CAH).OBJECTIVE:To assess blood pressure and early cardiovascular damages on a large cohort of adult CAH patients and control individuals.DESIGN:Case-control study.SETTING:Referral Center for Rare Disease, Pitié Salpêtrière Hospital, Paris, France.PATIENTS OR OTHER PARTICIPANTS:Fifty-eight women and 26 men with CAH diagnosed in childhood and 85 controls matched-paired for sex, age and smoking status were prospectively included.INTERVENTION:Measurement of large arteries and microcirculatory anatomical and functional indices as well as hormonal status and cardiovascular risk factors evaluation.MAIN OUTCOME MEASURE:The primary objective was to compare carotid intima-media thickness (cIMT) in CAH patients and controls. The secondary objectives were to compare blood pressure (BP), radial augmentation index (rAI), central BP, carotid-femoral pulse wave velocity (PWV), skin microcirculation indices and inflammation parameters in CAH patients and controls.RESULTS:Although PWV and cIMT were identical in patients and controls, higher rAI (64.6 ± 1.7 vs. 59.9 ± 1.6%, P = 0.02) and higher central SBP (101.8 ± 1.5 vs. 95.1 ± 1.5 mmHg, P

Neuropathy is the most common complication of the peripheral nervous system during the progression of diabetes. The pathophysiology is unclear but may involve microangiopathy, reduced endoneurial blood flow, and tissue ischemia. We used a mouse model of type 1 diabetes to study parallel alterations of nerves and microvessels following tissue ischemia. We designed an easily reproducible model of ischemic neuropathy induced by irreversible ligation of the femoral artery. We studied the evolution of behavioral function, epineurial and endoneurial vessel impairment, and large nerve myelinated fiber as well as small cutaneous unmyelinated fiber impairment for 1 month following the onset of ischemia. We observed a more severe hindlimb dysfunction and delayed recovery in diabetic animals. This was associated with reduced density of large arteries in the hindlimb and reduced sciatic nerve epineurial blood flow. A reduction in sciatic nerve endoneurial capillary density was also observed, associated with a reduction in small unmyelinated epidermal fiber number and large myelinated sciatic nerve fiber dysfunction. Moreover, vascular recovery was delayed, and nerve dysfunction was still present in diabetic animals at day 28. This easily reproducible model provides clear insight into the evolution over time of the impact of ischemia on nerve and microvessel homeostasis in the setting of diabetes. © 2015 Wiley Periodicals, Inc.

The theory begins with the major premise that mortality is a fundamental factor in population dynamics. At the beginning of time was the age of so-called pestilence and famine. Mortality was high; life expectancy around 20–30 years; and famine, injuries, and infectious diseases were common causes of death. The fi rst transition took place around 10 000 years ago which brought the world into the age of receding pandemics. Life expectancy increased to 40 years and tuberculosis, cholera, typhus, and the plague were responsible for deadly infectious pandemics. Populations shifted from foraging food to primary food production, and swelling populations, domestication of plants and animals, and progressively more sedentary lifestyles increased the prevalence of infectious diseases. The second transition happened in the 20th century when life expectancy reached 50 years. Profound changes in health and disease patterns took place in children and young women, and the primary cause of death shifted from infectious disease to chronic degenerative diseases. 2

In chronic stable angina, elevated heart rate contributes to the development of symptoms and signs of myocardial ischaemia by increasing myocardial oxygen demand and reducing diastolic perfusion time. Accordingly, heart rate reduction is a well-known strategy for improving both symptoms of myocardial ischaemia and quality of life (QOL). The heart rate-reducing agent ivabradine, a direct and selective inhibitor of the I f current, decreases myocardial oxygen consumption while increasing diastolic time, without affecting myocardial contractility or coronary vasomotor tone. Ivabradine is indicated for treatment of stable angina and chronic heart failure (HF). This review examines available evidence regarding the efficacy and safety of ivabradine in stable angina, when used as monotherapy or in combination with beta-blockers, in particular angina subgroups and in patients with stable angina with left ventricular systolic dysfunction (LVSD) or HF. Trials involving more than 45 000 patients receiving treatment with ivabradine have shown that this agent has antianginal and anti-ischaemic effects, regardless of age, sex, severity of angina, revascularisation status or comorbidities. This heart rate-lowering agent might also improve prognosis, reduce hospitalisation rates and improve QOL in angina patients with chronic HF and LVSD.

The epidemiological link between hypertension and Alzheimer disease is established. We previously reported that hypertension aggravates the Alzheimer-like pathology in APPPS1 mice (amyloid precursor protein/presenilin-1, mouse model of Alzheimer disease) with angiotensin II–induced hypertension, in relation with hypertension and nitric oxide deficiency. To provide further insights into the role of nitric oxide in the hypertension—Alzheimer disease cross-talk, we studied the effects of nitric oxide blockade in APPPS1 mice using N (ω)-nitro- l -arginine methyl ester ( l -NAME) alone or in combination with hydralazine, to normalize blood pressure. Compared with normotensive APPPS1 mice, those with l -NAME–induced hypertension had greater amyloid burden ( P P P P l -NAME–induced deterioration except for cortical amyloid angiopathy, linked to hypertension-induced arterial wall remodeling. By testing the cerebrovascular response to hypercapnic breathing, we evidenced early functional impairment of cerebral vasomotor activity in APPPS1 mice. Whereas in control wild-type normotensive mice, carbon dioxide breathing resulted in 15±1.3% increase in the mean blood flow velocity ( P P l -NAME–treated hypertensive APPPS1 mice (2.5±1.2%) and partly reversed to mild vasodilation by hydralazine (3.2±1.5%, P l -NAME–induced hypertension. Only cerebral amyloid angiopathy seems to be dependent on hypertension.

In the present review, microvascular remodelling refers to alterations in the structure of resistance vessels contributing to elevated systemic vascular resistance in hypertension. We start with some historical aspects, underscoring the importance of Folkow's contribution made half a century ago. We then move to some basic concepts on the biomechanics of blood vessels, and explicit the definitions proposed by Mulvany for specific forms of remodelling, especially inward eutrophic and inward hypertrophic. The available evidence for the existence of remodelled resistance vessels in hypertension comes next, with relatively more weight given to human, in comparison with animal data. Mechanisms are discussed. The impact of antihypertensive drug treatment on remodelling is described, again with emphasis on human data. Some details are given on the three studies to date which point to remodelling of subcutaneous resistance arteries as an independent predictor of cardiovascular risk in hypertensive patients. We terminate by considering the potential role of remodelling in the pathogenesis of end-organ damage and in the perpetuation of hypertension.

Background Mottling around the knee, reflecting a reduced skin blood flow, is predictive of mortality in patients with septic shock. However, the causative pathophysiology of mottling remains unknown. We hypothesized that the cutaneous hypoperfusion observed in the mottled area is related to regional endothelial dysfunction. Methods This was a prospective, observational study in a medical ICU in a tertiary teaching hospital. Consecutive adult patients with sepsis admitted to ICU were included. After resuscitation, endothelium-dependent vasodilation in the skin circulation was measured before and after iontophoresis of acetylcholine (Ach) in the forearm and the knee area. We analyzed the patterns of induced vasodilatation according to the presence or absence of mottling and vital status at 14 days. Results We evaluated 37 septic patients, including 11 without and 26 with septic shock. Overall 14-day mortality was 22%. Ten patients had mottling around the knee (10/37, 27%). In the knee area, the increased skin blood flow following iontophoresis of Ach was lower in patients with mottled skin as compared to patients without mottled skin (area under curve (AUC) 3280 (2643–6440) vs. 7980 (4233–19,707), both P

International audience; In patients undergoing radiotherapy for cancer, radiation dose to healthy tissue can occur, causing microvascular damage. Monocytes that have been shown to promote tissue revascularization comprise the subsets CD11b+Ly6G-7/4hi/monocyteshi and CD11b+Ly6G-7/4lo/monocyteslo. We hypothesized that monocytes were implicated in postirradiation blood vessel formation. C57Bl6 mice underwent localized colorectal irradiation and were sacrificed at different times after exposure. Bone marrow, spleen, blood and colon were collected. Fourteen days postirradiation, colons expressed proangiogenic actors and adhesion molecules. Monocyteshi, which were the main subset of infiltrating monocytes, mobilized to the blood from spleen and bone marrow, peaking at day 14 postirradiation, and were associated with lymphocyte Th1 polarization. At day 28 postirradiation, angiographic score and capillary density increased by ∼1.8-fold, and then returned to nonirradiated levels at day 60. Clodronate-mediated depletion of circulating monocytes prior to irradiation resulted in a ∼1.4-fold decrease in angiographic score and capillary density compared to the nontreated control. Histological analysis of the colon in clodronate-treated mice revealed a massive decrease of macrophage and lymphocyte infiltration as well as reduced collagen deposition in crypt area at day 21. However, late depletion of monocytes from day 25 postirradiation had no effect on fibrotic process. These findings demonstrate a central role for monocyte/macrophage activation in the orchestration of a neovascularization mechanism after localized colorectal irradiation. © 2017 by Radiation Research Society.

Background Patho-physiological and pharmacological studies have consistently noticed that, with the exception of subjects with end-stage renal disease, total intravascular blood volume is not increased in patients with chronic hypertension. Methods Because the mean circulatory pressure is enhanced in such subjects, it was postulated that the compliance of the cardiovascular system could be abnormally low in this particular population. This simple observation has influenced a great part of our experimental and clinical research directed toward subjects with hypertension and their relationship with the compliance of the vascular system. Results These works started between 1970 and 1980 by methodological investigations and validations followed by analysis of clinical situations that showed that venous and mostly arterial stiffness were significantly increased in hypertensive patients independently of blood pressure level. During the same time, we assessed the role of endothelium on the large arterial wall mechanical properties in normotensive and hypertensive rats. Thereafter more specific directions have been developed, affecting large arteries structure and function and arterial wall remodeling, including their consequences on central and peripheral hemodynamics. In parallel, epidemiological studies identified the pulsatile hemodynamic parameters as major independent predictors of cardiovascular risks. Conclusions The consequences of these alterations on clinical pharmacology and therapeutics in hypertension are analyzed in detail.

Purpose Determine the effect of repeated intravitreal injections of ranibizumab (0.5 mg; 0.05 ml) on retrobulbar blood flow velocities (BFVs) using ultrasound imaging quantification in twenty patients with exudative age-related macular degeneration treated for 6 months. Methods Visual acuity (ETDRS), central macular thickness (OCT), peak-systolic, end-diastolic and mean-BFVs in central retinal (CRA), temporal posterior ciliary (TPCA) and ophthalmic (OA) arteries were measured before, 2 days, 3 weeks and 6 months after the first injection. Patients were examined monthly and received 1–5 additional injections depending on ophthalmologic examination results. Results Six months after the first injection, a significant increase in visual acuity 50.9 ± 25.9 versus 44.4 ± 21.7 (p

Hypertension is a multifactorial systemic chronic disorder through functional and structural macrovascular and microvascular alterations. Macrovascular alterations are featured by arterial stiffening, disturbed wave reflection and altered central to peripheral pulse pressure amplification. Microvascular alterations, including altered wall-to-lumen ratio of larger arterioles, vasomotor tone abnormalities and network rarefaction, lead to disturbed tissue perfusion and susceptibility to ischemia. Central arterial stiffness and microvascular alterations are common denominators of organ damages. Vascular alterations are intercorrelated, amplifying the haemodynamic load and causing further damage in the arterial network. A plausible precursor role of vascular alterations in incident hypertension provides new insights for preventive and therapeutic strategies targeting macro and microvasculature. Cumulative metabolic burden and oxidative stress lead to chronic endothelial injury, promoting structural and functional vascular alterations, especially in the microvascular network. Pathophysiology of hypertension may then be revisited, based on both macrovascular and microvascular alterations, with a precursor role of endothelial dysfunction for the latter.

Disruption of cerebral blood flow after stroke induces cerebral tissue injury through multiple mechanisms that are not yet fully understood. Smooth muscle cells (SMCs) in blood vessel walls play a key role in cerebral blood flow control. Cerebral ischemia triggers these cells to switch to a phenotype that will be either detrimental or beneficial to brain repair. Moreover, SMC can be primarily affected genetically or by toxic metabolic molecules. After stroke, this pathological phenotype has an impact on the incidence, pattern, severity, and outcome of the cerebral ischemic disease. Although little research has been conducted on the pathological role and molecular mechanisms of SMC in cerebrovascular ischemic diseases, some therapeutic targets have already been identified and could be considered for further pharmacological development. We examine these different aspects in this review.

After the onset of ischemia, cardiac or skeletal muscle undergoes a continuum of molecular, cellular, and extracellular responses that determine the function and the remodeling of the ischemic tissue. Hypoxia-related pathways, immunoinflammatory balance, circulating or local vascular progenitor cells, as well as changes in hemodynamical forces within vascular wall trigger all the processes regulating vascular homeostasis, including vasculogenesis, angiogenesis, arteriogenesis, and collateral growth, which act in concert to establish a functional vascular network in ischemic zones. In patients with ischemic diseases, most of the cellular (mainly those involving bone marrow-derived cells and local stem/progenitor cells) and molecular mechanisms involved in the activation of vessel growth and vascular remodeling are markedly impaired by the deleterious microenvironment characterized by fibrosis, inflammation, hypoperfusion, and inhibition of endogenous angiogenic and regenerative programs. Furthermore, cardiovascular risk factors, including diabetes, hypercholesterolemia, hypertension, diabetes, and aging, constitute a deleterious macroenvironment that participates to the abrogation of postischemic revascularization and tissue regeneration observed in these patient populations. Thus stimulation of vessel growth and/or remodeling has emerged as a new therapeutic option in patients with ischemic diseases. Many strategies of therapeutic revascularization, based on the administration of growth factors or stem/progenitor cells from diverse sources, have been proposed and are currently tested in patients with peripheral arterial disease or cardiac diseases. This review provides an overview from our current knowledge regarding molecular and cellular mechanisms involved in postischemic revascularization, as well as advances in the clinical application of such strategies of therapeutic revascularization.

Active Crohn's disease affects intestine but may alter other locations as eyes vasculature. Previous studies provide evidence of elevated blood flow velocities (BFv) and volume (BFV) in superior mesenteric artery (SMA). We prospectively studied hemodynamics in feeding arteries of bowel and eyes before and 2 weeks after treatment induction with anti-TNFα.Fifteen patients (5 females, 10 males, 35.4 ± 9.0 years, mean ± SD) with active Crohn's disease for 7.5 ± 7.7 years were enrolled. Ultrasound imaging was performed before and 2 weeks after treatment in SMA and retrobulbar arteries: central retinal (CRA), temporal posterior ciliary (TPCA) and ophthalmic (OA) arteries. Serum markers of inflammation (CRP and fibrinogen), arterial blood pressures (ABP) and skin flow-mediated dilation (sFMD) were measured and patients were compared to 10 control age- and sex-matched subjects.Before treatment, CRP and fibrinogen plasma concentrations, SMA BFV (339 ± 100 mL/min) were higher in patients than in controls by 8.5-fold (p0.001), 1.4-fold (p0.01) and 1.5-fold, respectively (p0.01). BFv in CRA (3.5 ± 0.7 cm/s) and TPCA (4.4 ± 1.0 cm/s), sFMD (371 ± 469%) were significantly lower than in controls by 83%, 73% and 52% respectively (p0.05). Two weeks after treatment, CRP and fibrinogen decreased, SMA BFV was normalized (230 ± 39L/min, p0.01), BFv in CRA, TPCA and OA increased respectively to 4.0 ± 1.1 (p0.05), 5.2 ± 1.4 (p0.001), 8.9 ± 3 cm/s (p0.05). ABP and sFMD remained unchanged.In active Crohn's disease, a first anti-TNFα administration rapidly normalized concomitantly plasma inflammatory markers and blood-flows in the mesenteric and retrobulbar arteries without affecting blood pressure and endothelial function.

Aim We aimed to evaluate changes in venous physiologic parameters with aging in healthy volunteers. Methods Sixty subjects (29 women, 31 men, mean age 63.1 ± 4.4, 24 subjects aged over 75 years) with no history of deep venous thromboembolism, venous insufficiency, deep venous thrombosis, peripheral arteriopathy, lower limb edema, atrial fibrillation or acute medical condition within the last 7 days were enrolled. Subjects remained in the supine position for 15 min before and during data acquisition. Mercury strain gauge was put around the calf and connected to the EC6 plethysmograph. We measured the venous parameters by inflating the collecting cuff up to 50 mmHg pressure for 4 min. The data were implemented in the NIVP3 software to measure compliance, maximum venous outflow (MVO) and half-emptying time (T1/2). Results The venous capacitance, compliance and MVO significantly decreased with age ( P = 0.023, P = 0.01 and P = 0.02, respectively, ANOVA) while T1/2 increased with age ( P = 0.02, ANOVA). There was a negative correlation between age and respectively, compliance (rs = −0.21, P = 0.01) and MVO (rs = −0.25, P = 0.0003), and a positive correlation between T1/2 and age (rs = 0.14, P = 0.0003). Using logistic regression analysis, calf circumference ( P = 0.0001), venous capacitance ( P = 0.012) and MVO ( P = 0.033) were the only variables independently associated to age. Conclusion Using a sensitive, non-invasive, painless, reproducible and easily repeatable computerized method, we successfully forecasted changes of venous physiological parameters over age and provided valuable information in the field of physiological aging.

Inflammation plays a key role in ischemic stroke pathophysiology: microglial/macrophage cells and type-1 helper cells (Th1) seem deleterious, while type-2 helper cells (Th2) and regulatory T cells (Treg) seem protective. CD4 Th0 differentiation is modulated by microglial cytokine secretion. Glatiramer Acetate (GA) is an immunomodulatory drug that has been approved for the treatment of human multiple sclerosis by means of a number of mechanisms: reduced microglial activation and pro-inflammatory cytokine production, Th0 differentiation shifting from Th2 to Th2 and Treg with anti-inflammatory cytokine production and increased neurogenesis. We induced permanent (pMCAo) or transient middle cerebral artery occlusion (tMCAo) and GA (2 mg) or vehicle was injected subcutaneously immediately after cerebral ischemia. Mice were sacrificed at D3 to measure neurological deficit, infarct volume, microglial cell density and qPCR of TNFα and IL-1β (pro-inflammatory microglial cytokines), IFNγ (Th2 cytokine), IL-4 (Th2 cytokine), TGFβ and IL-10 (Treg cytokines), and at D7 to evaluate neurological deficit, infarct volume and neurogenesis assessment. We showed that in GA-treated pMCAo mice, infarct volume, microglial cell density and cytokine secretion were not significantly modified at D3, while neurogenesis was enhanced at D7 without significant infarct volume reduction. In GA-treated tMCAo mice, microglial pro-inflammatory cytokines IL-1β and TNFα were significantly decreased without modification of microglial/macrophage cell density, cytokine secretion, neurological deficit or infarct volume at D3, or modification of neurological deficit, neurogenesis or infarct volume at D7. In conclusion, Glatiramer Acetate administered after cerebral ischemia does not reduce infarct volume or improve neurological deficit in mice despite a significant increase in neurogenesis in pMCAo and a microglial pro-inflammatory cytokine reduction in tMCAo.

Metabolic syndrome (MetS), an important component of insulin resistance and cardiovascular (CV) risk, is defined by 3 or more of the following characteristics: abdominal obesity, hyperglycemia, hypertension, hypertriglyceridemia, and hypo-high-density lipoprotein cholesterolemia. Based on the previously published age- and sex-mediated DESIR (Data from an Epidemiological Study on the Insulin Resistance Syndrome) cohort and parallel central hemodynamic measurements, our goal was to evaluate the effects of MetS on brachial central pulse pressure (PP), PP amplification, aortic stiffness, and wave reflections. These data were then compared with those of patients with essential hypertension but without MetS for the same mean arterial pressure. Increased aortic stiffness, a major mechanical factor predicting CV risk, has been well identified as playing a role in MetS. Its age progression is proportional to the number of risk factors involved in MetS and is responsible for increased systolic blood pressure and decreased diastolic blood pressure with increasing age, the principal hallmarks of hypertension in the elderly. Beyond brachial pressure measurements, central hemodynamic parameters involve increased aortic stiffness, reduced wave reflections, and increased PP amplification, a parameter commonly associated with increased heart rate. With the exception of arterial stiffness, all these findings are opposite in direction to those observed in essential hypertension, in which MetS is absent. A divergent behavior of wave reflections and PP amplification, but not of arterial stiffness, is observed when hypertension is studied alone or when compared with MetS for the same mean arterial pressure. This pulsatile hemodynamic abnormality contributes independently to increase age- and sex-mediated CV risk, justifying new research regarding Framingham scores and drug treatment.

We hypothesized that in vitro treatment of peripheral blood mononuclear cells (PB-MNCs) from diabetic patients with ephrin-B2/Fc (EFNB2) improves their proangiogenic therapeutic potential in diabetic ischemic experimental models. Diabetes was induced in nude athymic mice by streptozotocin injections. At 9 weeks after hyperglycemia, 105 PB-MNCs from diabetic patients, pretreated by EFNB2, were intravenously injected in diabetic mice with hindlimb ischemia. Two weeks later, the postischemic neovascularization was evaluated. The mechanisms involved were investigated by flow cytometry analysis and in vitro cell biological assays. Paw skin blood flow, angiographic score, and capillary density were significantly increased in ischemic leg of diabetic mice receiving EFNB2-activated diabetic PB-MNCs versus those receiving nontreated diabetic PB-MNCs. EFNB2 bound to PB-MNCs and increased the adhesion and transmigration of PB-MNCs. Finally, EFNB2-activated PB-MNCs raised the number of circulating vascular progenitor cells in diabetic nude mice and increased the ability of endogenous bone marrow MNCs to differentiate into cells with endothelial phenotype and enhanced their proangiogenic potential. Therefore, EFNB2 treatment of PB-MNCs abrogates the diabetes-induced stem/progenitor cell dysfunction and opens a new avenue for the clinical development of an innovative and accessible strategy in diabetic patients with critical ischemic diseases.

Objective— Leukocyte infiltration in ischemic areas is a hallmark of myocardial infarction, and overwhelming infiltration of innate immune cells has been shown to promote adverse remodeling and cardiac rupture. Recruitment of inflammatory cells in the ischemic heart depends highly on the family of CC-chemokines and their receptors. Here, we hypothesized that the chemokine decoy receptor D6, which specifically binds and scavenges inflammatory CC-chemokines, might limit inflammation and adverse cardiac remodeling after infarction. Methods and Results— D6 was expressed in human and murine infarcted myocardium. In a murine model of myocardial infarction, D6 deficiency led to increased chemokine (C-C motif) ligand 2 and chemokine (C-C motif) ligand 3 levels in the ischemic heart. D6-deficient (D6 −/−) infarcts displayed increased infiltration of pathogenic neutrophils and Ly6Chi monocytes, associated with strong matrix metalloproteinase-9 and matrix metalloproteinase-2 activities in the ischemic heart. D6 −/− mice were cardiac rupture prone after myocardial infarction, and functional analysis revealed that D6 −/− hearts had features of adverse remodeling with left ventricle dilation and reduced ejection fraction. Bone marrow chimera experiments showed that leukocyte-borne D6 had no role in this setting, and that leukocyte-specific chemokine (C-C motif) receptor 2 deficiency rescued the adverse phenotype observed in D6 −/− mice. Conclusion— We show for the first time that the chemokine decoy receptor D6 limits CC-chemokine–dependent pathogenic inflammation and is required for adequate cardiac remodeling after myocardial infarction.

We tested the effect of acetazolamide on blood mechanical properties and pulmonary vascular resistance (PVR) during chronic hypoxia. Six groups of rats were either treated or not treated with acetazolamide (curative: treated after 10 days of hypoxic exposure; preventive: treated before hypoxic exposure with 40 mg · kg(-1) · day(-1)) and either exposed or not exposed to 3 weeks of hypoxia (at altitude5,500 m). They were then used to assess the role of acetazolamide on pulmonary artery pressure, cardiac output, blood volume, haematological and haemorheological parameters. Chronic hypoxia increased haematocrit, blood viscosity and PVR, and decreased cardiac output. Acetazolamide treatment in hypoxic rats decreased haematocrit (curative by -10% and preventive by -11%), PVR (curative by -36% and preventive by -49%) and right ventricular hypertrophy (preventive -20%), and increased cardiac output (curative by +60% and preventive by +115%). Blood viscosity was significantly decreased after curative acetazolamide treatment (-16%) and was correlated with PVR (r=0.87, p0.05), suggesting that blood viscosity could influence pulmonary haemodynamics. The fall in pulmonary vascular hindrance (curative by -27% and preventive by -45%) after treatment suggests that acetazolamide could decrease pulmonary vessels remodelling under chronic hypoxia. The effect of acetazolamide is multifactorial by acting on erythropoiesis, pulmonary circulation, haemorheological properties and cardiac output, and could represent a pertinent treatment of chronic mountain sickness.

Face a la prevalence importante des accidents vasculaires cerebraux (AVC) dans les pays industrialises et la fenetre therapeutique etroite (< 4,5 h) d’administration du fibrinolytique, la comprehension des phenomenes de plasticite cerebrale survenant dans les jours suivant l’AVC ont permis le developpement de nouvelles strategies therapeutiques. C’est dans ce contexte que la therapie cellulaire basee sur l’administration de cellules souches a emerge. Les nombreuses etudes experimentales realisees sur des modeles animaux d’ischemie cerebrale ont montre la recuperation du deficit neurologique par differentes approches : l’immunomodulation et la neuroprotection, la stimulation de l’angiogenese et de la neurogenese endogene. Cependant, si les essais cliniques de phase I ou de phase II ont debute, les mecanismes d’action des therapies cellulaires restent encore mal compris. L’acces a de nouvelles sources de cellules souches aux potentialites superieures, les induced plutipotent stems cells ou iPS, et a la bioingenierie avec la transplantation de cellules souches dans une matrice synthetique contenant des facteurs de croissance, ouvre le champ des perspectives dans le traitement des AVC.

Objective— Catecholamines have been shown to control bone marrow (BM)–derived cell egress, yet the cellular and molecular mechanisms involved in this effect and their subsequent participation to postischemic vessel growth are poorly understood. Methods and Results— Tyrosine hydroxylase mRNA levels, as well as dopamine (DA) and norepinephrine (NE) contents, were increased in the ischemic BM of mice with right femoral artery ligation. Angiographic score, capillary density, and arteriole number were markedly increased by treatments with DA (IP, 50 mg/kg, 5 days) or NE (IP, 2.5 mg/kg, 5 days). Using chimeric mice lethally irradiated and transplanted with BM-derived cells from green fluorescent protein mice, we showed that DA and NE enhanced by 70% ( P P N ω -nitro- l -arginine methyl ester. DA and NE also upregulated the number of CD45-positive cells in blood 3 days after ischemia and that of macrophages in ischemic tissue 21 days after ischemia. Of interest, DA and NE increased BM endothelial nitric oxide synthase (eNOS) mRNA levels and were unable to promote BM-derived cell mobilization in chimeric eNOS-deficient mice lethally irradiated and transplanted with BM-derived cells from wild-type animals. Furthermore, administration of a β2 adrenergic agonist (clenbuterol, IP, 2 mg/kg, 5 days) and that of a dopaminergic D1/D5 receptor agonist (SKF-38393, IP, 2.5 mg/kg, 5 days) also enhanced BM-derived cell mobilization and subsequently postischemic vessel growth. Conclusion— These results unravel, for the first time, a major role for the sympathetic nervous system in BM-derived cell egress through stromal eNOS activation.

This adventure in dermatology took place between 1960 and 1962. An immigration ruling forced Dr Bernard Gordon, a Canadian, to spend 2 years abroad before he could legally live and practice in the United States. Dr Gordon had just completed a 3-year residency at the New York University Skin and Cancer Unit. Dr Gordon met with his mentor, Dr Marion Sulzberger, for advice. This world-famous dermatologist took an interest in his situation and was able to arrive at an extraordinary solution. Dr Sulzberger consulted with his many dermatology colleagues and made arrangements for Dr Gordon to work abroad. He would spend 1 year in Caracas, Venezuela, teaching and conducting research in tropical skin diseases. The second year would be spent in Europe, beginning with 3 months in Madrid, Spain, followed by 3 months in Geneva, Switzerland, and concluding with 6 months at the Hopital Saint Louis in Paris, France. Dr Gordon worked with the leading dermatologists at each hospital. These 2 years abroad led to a deeper understanding of world dermatology and lasting friendships.

A close relationship between tumor angiogenesis, growth, and carcinomatosis has been observed. Netrin-4 (NT-4) has been shown to regulate angiogenic responses. We aimed to examine the effects of NT-4 on colon tumor angiogenesis, growth, and carcinomatosis. We showed that NT-4 was expressed in human colon cancer cells (LS174). A 20-fold increase in NT-4 expression was stably induced by NT-4 pcDNA in LS174 cells. In vivo, a Matrigel angiogenesis assay showed that NT-4 overexpression altered vascular endothelial growth factor (VEGF)/basic fibroblast growth factor-induced angiogenesis. In nude mice with LS174 xenografts, NT-4 overexpression inhibited tumor angiogenesis and growth. In addition, these NT-4-involved inhibitory effects were associated with decreased tumor cell proliferation and increased tumor cell apoptosis. Using an orthotopic peritoneal carcinomatosis model, we demonstrated that NT-4 overexpression decreased colorectal cancer carcinomatosis. Moreover, carcinomatosis-related ascites formation was significantly decreased in mice transplanted with NT-4 LS174 cells versus control LS174 cells. The antiangiogenic activity of NT-4 was probably mediated by binding to its receptor neogenin. Netrin-4 had a direct effect on neither in vitro apoptosis and proliferation of cultured LS174 cells nor the VEGF-induced acute increase in vascular permeability in vivo. We propose that NT-4 overexpression decreases tumor growth and carcinomatosis, probably via an antiangiogenic effect, underlying the potential therapeutic interest in NT-4 in the treatment of colorectal cancer growth and carcinomatosis.

BACKGROUND Microvascular rarefaction and endothelium dysfunction are hallmarks of hypertension. We assessed whether antihypertensive treatments affect the microcirculation and whether the fixed-dose combination perindopril/indapamide (per/ind) modifies the microcirculation of hypertensive patients independently of blood pressure reduction. METHODS One hundred ninety-three consecutive patients were enrolled into one of four groups depending on their blood pressure and existing treatment: (i) controlled hypertensive patients treated with per/ind (controlled-per/ind), (ii) controlled hypertensive patients treated with agents other than angiotensin-converting enzyme (ACE) inhibitors or diuretics (controlled-other), (iii) uncontrolled hypertensive patients treated with agents other than ACE inhibitors or diuretics (uncontrolled-other), (iv) untreated normotensive subjects. Macro- and microcirculation parameters were evaluated once in every patient. We used intravital video microscopy to measure dermal capillary density in the dorsum of the fingers. Microvascular endothelial function was assessed by measuring the perfusion increases after pilocarpine iontophoresis and central hemodynamic parameters by tonometry. RESULTS Capillary density was significantly higher in controlled-per/ind patients (99 ± 12 capillaries/mm(2)) than in all other groups (P < 0.05). Controlled-per/ind patients had a significantly greater endothelial response to pilocarpine than patients from all other groups (P < 0.05). Central hemodynamic parameters were similarly improved in both controlled groups compared with the uncontrolled-other group (P < 0.05). CONCLUSIONS Thus, hypertensive patients with blood pressure controlled with the combination per/ind had normalized capillary density and endothelial function, whereas other antihypertensive treatments, excluding ACE inhibitors or diuretics, had less effect despite similar blood pressure control.

Given known correlations between vascular health and cognitive impairment, the development of tools to image microvasculature in the whole brain could help investigate these correlations. We explore the feasibility of using an automated serial two-photon microscope to image fluorescent gelatin-filled whole rodent brains in three-dimensions (3-D) with the goal of carrying group studies. Vascular density (VD) was computed using automatic segmentation combined with coregistration techniques to build a group-level vascular metric in the whole brain. Focusing on the medial prefrontal cortex, cerebral cortex, the olfactory bulb, and the hippocampal formation, we compared the VD of three age groups (2-, 4.5-, and 8-months-old), for both wild type mice and a transgenic model (APP/PS1) with pathology resembling Alzheimer's disease (AD). We report a general loss of VD caused by the aging process with a small VD increase in the diseased animals in the somatomotor and somatosensory cortical regions and the olfactory bulb, partly supported by MRI perfusion data. This study supports previous observations that AD transgenic mice show a higher VD in specific regions compared with WT mice during the early and late stages of the disease (4.5 to 8 months), extending results to whole brain mapping.

Augmentation index (AIx), a marker of the number of aortic wave reflections (AWRs), is influenced not only by the magnitude of incident and reflected pressure waves but also by the time of return. A new triangulation method has been developed, enabling us to better quantify AWRs and to determine their sex differences, which may relate to body size or pulse pressure (PP) amplification, measured from the brachial PP-to-carotid PP (B/C) ratio. With the use of pulse wave analysis, AWRs were evaluated in 51 women and 72 men treated for hypertension and studied in relationship to age, blood pressure, and pulse wave velocity. When women were compared with men, AIx (expressed in %PP and adjusted to heart rate) was significantly higher, together with a significant decrease of the B/C ratio and an increase of the reflection magnitude and of the amplitude (but not the timing) of the backward pressure wave. The significance of the amplitude difference between men and women was enhanced after an adjustment to heart rate or pulse wave velocity but was abolished after an adjustment to body height or the B/C ratio. In the overall population, AIx and the reflection magnitude index were positively ( r2 = 0.39) and independently associated, after excluding confounding factors such as drug treatment. In conclusion, when compared with men, women treated for hypertension have increased AIx, related to the increased amplitude, and not timing, of backward pressure waves. This finding relates to sex differences in body size and mostly brachial-carotid PP amplification, a parameter highly related to the sex difference of cardiovascular risk.

BACKGROUND Obesity is associated with increased cardiovascular morbidity. The skin is a unique site allowing simple, noninvasive assessment of capillary density and endothelial function. In the present study, we measured skin capillary density and endothelial function in a group of normotensive overweight/obese nondiabetic individuals and healthy lean controls. METHODS AND RESULTS We examined 120 relatively insulin-sensitive overweight individuals (BMI 27.9 +/- 2.7 kg/m, mean +/- SD) with normal blood pressure and fasting plasma glucose and 130 lean (BMI 22.4 +/- 1.7 kg/m) controls. We used video microscopy to measure skin capillary density in the resting state and during venous occlusion. Laser Doppler flowmetry, combined with iontophoresis of acetylcholine (endothelial-dependent vasodilation) and following skin heating (endothelial-independent dilation), was performed. Resting capillary density was negatively correlated with BMI (r = -0.130, P < 0.05). Resting capillary density (mean +/- SE) was lower, however nonsignificantly, in overweight as compared with the lean individuals (88.6 +/- 1.5 vs. 91.8 +/- 1.4, P = 0.117). Capillary recruitment, defined as the percentage increase in capillary density during venous congestion, was higher in overweight (9.5 +/- 1.0%) than in controls (5.4 +/- 0.9%, P = 0.003), which remained significant after adjustment for age, sex, mean arterial pressure and fasting glucose. As a consequence, capillary density during venous occlusion was similar between the groups. Endothelial-dependent and independent cutaneous vasodilation was also similar between groups. No correlations were found between capillary density and plasma markers of adiposity, inflammation or endothelial dysfunction. CONCLUSION BMI was inversely correlated with resting capillary density. This suggests a lower baseline tissue perfusion associated with higher vasomotor tone. Despite this, capillary recruitment was higher in overweight as compared with lean individuals, resulting in similar capillary density during venous congestion. Our results suggest that skin microcirculation abnormalities, in the absence of endothelial dysfunction, may be one of the earliest detectable alterations in vascular function in overweight individuals.

The metabolic syndrome (MetS) is associated with increased risk of type-2 diabetes and cardiovascular disease (CVD). We hypothesized that both small and large arteries may be impaired in subjects with the MetS, even in the absence of known CVD or diabetes. We compared both skin capillary density (CD) and pulse-wave velocity (PWV) in 36 cases with the MetS with those from 108 age- and gender-matched controls from the SU.VIM.AX-2 cohort. Compared with controls, MetS subjects demonstrated increased PWV (12.2+/-2.8 vs. 10.7+/-1.9 m s(-1), P=0.005) and lower functional CD (83.1+/-15.7 vs. 89.4+/-14.2 capillaries per mm(2), P=0.03). Functional CD was inversely related to fasting glucose, triglycerides (TGs) and HOMA-IR (all P0.05). On the other hand, no association was found between CD and BP or with PWV. In multivariate models, the odds ratios (95% confidence interval) for one standard deviation change, for having an impaired PWV (or=12 m s(-1), n=44), were: 1.65 (1.11-2.45) for systolic BP and 1.93 (1.25-2.99) for TG only. For impaired CD (or=80 capillaries per mm(2)), the odds ratios (95% confidence interval) were 1.45 (1.00-2.08) for TG and 1.65 (1.13-2.43) for fasting glucose, only. In conclusion, MetS subjects exhibited evidence of macro- and microcirculatory dysfunction, even in the absence of diabetes and CVD. The common mechanism linking MetS components to CVD risk through small- and large-artery dysfunctions may be mediated through metabolic factors related to insulin resistance, not to increased BP.

Les medicaments anti-angiogeniques (medicaments anti-VEGF sur le marche: bevacizumab (Avastin®), sunitinib (Sutent®), sorafenib (Nexavar®) sont de plus en plus utilises dans le traitement de certains cancers (colon, sein, poumon, foie et rein). Leurs effets secondaires sont mal connus des medecins. L’hypertension arterielle (HTA) est l’effet indesirable le plus frequent. Son incidence depend de la definition de la molecule et de la dose. Elle est generalement controlable par les traitements antihypertenseurs et compromet rarement la poursuite du traitement. Plus rarement, elle peut avoir des consequences graves (HTA maligne, leucoencephalopathie posterieure reversible, accident vasculaire cerebral, etc.). Des atteintes renales sont moins frequentes: proteinurie moderee le plus souvent, reversible, et plus rarement, syndrome nephrotique, insuffisance renale aigue, glomerulopathie proliferative, nephrite interstitielle et microangiopathie thrombotique. Allongement de l’espace QT et insuffisance cardiaque ont ete observes avec des tinibs. Sur le plan therapeutique: 1) avant l’administration d’une premiere dose d’un traitement anti-angiogenique, il ne faut pas retarder l’administration d’une premiere dose ou administrer un traitement antihypertenseur en raison d’une pression arterielle (PA) elevee; 2) le bilan initial comporte unemesure de la PA realisee avec un appareil de mesure valide soit par le medecin traitant, soit au mieux en automesure tensionnelle (« regle des 3 », http://www.has-sante.fr), soit en mesure ambulatoire de la PA (appareil de mesure humeral valide (liste: http://afssaps.sante.fr); 3) la bandelette urinaire (et le cas echeant, quantification de la proteinurie), l’estimation de la fonction renale (formule de MDRD simplifiee plutot que Cockcroft et Gault) doivent etre faites avant traitement et au cours du suivi; 4) la prise en charge therapeutique se fait conformement aux recommandations (HAS HTA 2005: http://www.has-sante.fr); 5) la surveillance et la prise en charge therapeutique se feront au mieux dans le cadre d’un travail en reseau comprenant medecin generaliste, oncologue, cardiologue et nephrologue.