In Memoriam: Wolfgang Kiowski, M.D. (1949–2012) - Pioneer in clinical endothelin research

AbstractWolfgang Kiowski, M.D. (1949–2012) was a German physician-scientist who made exemplary contributions to clinical research in human physiology, heart failure, arterial hypertension, and endothelin science. His academic career took him from Heinz Losse, M.D. at the University of Münster, Germany, to the University of Michigan, U.S.A., to work with Stevo Julius, M.D. In 1979, Kiowski was recruited to the University of Basel in Switzerland and ultimately moved to the Hospital of the University of Zürich in Switzerland. Twenty years ago, Kiowski published a landmark study pioneering the use of endothelin receptor antagonists (ERAs) in patients (Lancet 1995; 346: 732–736), which introduced a new therapeutic principle to human medicine. During his career, he published numerous studies in the area of pathophysiology, clinical pharmacology (particularly calcium channel blockers, ERAs, and PDE5 inhibitors), heart failure, cardiac transplantation, coronary artery disease, and many case reports from his clinical work. Kiowski was an active mentor and trained many young physicians and physician-scientists. He died unexpectedly in Zürich during the planning stages of the Thirteenth International Conference on Endothelin to be held in Tokyo in 2013. This article summarizes Kiowski's achievements, his role as a mentor and as the human being he was. He will be remembered as a role model of an outstanding, curious clinician who was highly successful as a physician, scientist, and teacher, and at the same time managed to enjoy many hobbies and life with his family. Referring to Wolfgang Kiowski, the article closes with a “It can be done!”—message to young physician-scientists by Dr. Stevo Julius

Reduction of C-reactive protein and the use of anti-hypertensives

Inflammatory processes are increasingly recognized as important participants in the pathophysiology of hypertension and cardiovascular disease. Angiotensin II may be to a large degree responsible for triggering vascular inflammation by inducing oxidative stress, resulting in up-regulation of inflammatory mediators. Inflammatory markers such as C-reactive protein are increased in the blood of patients with hypertension and predict the development of cardiovascular disease. Moreover, C-reactive protein may be a pro-inflammatory molecule under certain circumstances. C-reactive protein and high blood pressure in combination have additional predictive value for cardiovascular outcomes, as they contribute as independent determinants of cardiovascular risk. Therapeutic intervention aimed to reduce vascular inflammation in hypertensive patients has been proposed. Recent lines of evidence suggest that lifestyle modification and pharmacological approaches may reduce blood pressure and inflammation in patients with hypertension. Antagonism of the renin-angiotensin system with the selective angiotensin receptor blockers may improve cardiovascular outcome beyond blood pressure control, by reducing vascular inflammation and remodeling

Angiotensin II, Aldosterone, and Anti-Inflammatory Lymphocytes: Interplay and Therapeutic Opportunities

Inflammation is recognized as an important factor in the pathophysiology of hypertension, with the renin-angiotensin-aldosterone system (RAAS) playing a key role in the disease. Initially described because of its contribution to extracellular fluid and electrolyte homeostasis, the RAAS has been implicated in endothelial dysfunction, vascular remodeling, oxidative stress, proinflammatory cytokine production, and adhesion molecule synthesis by the vascular wall. Both angiotensin II and aldosterone are involved in these systemic effects, activating innate and adaptive immune responses. This paper highlights some aspects connecting RAAS to the hypertensive phenotype, based on experimental and clinical studies, with emphasis on new findings regarding the contribution of an increasingly studied population of T lymphocytes: the T-regulatory lymphocytes. These cells can suppress inflammation and may exert beneficial vascular effects in animal models of hypertension

Angiotensin II, Aldosterone, and Anti-Inflammatory Lymphocytes: Interplay and Therapeutic Opportunities

Inflammation is recognized as an important factor in the pathophysiology of hypertension, with the renin-angiotensin-aldosterone system (RAAS) playing a key role in the disease. Initially described because of its contribution to extracellular fluid and electrolyte homeostasis, the RAAS has been implicated in endothelial dysfunction, vascular remodeling, oxidative stress, proinflammatory cytokine production, and adhesion molecule synthesis by the vascular wall. Both angiotensin II and aldosterone are involved in these systemic effects, activating innate and adaptive immune responses. This paper highlights some aspects connecting RAAS to the hypertensive phenotype, based on experimental and clinical studies, with emphasis on new findings regarding the contribution of an increasingly studied population of T lymphocytes: the T-regulatory lymphocytes. These cells can suppress inflammation and may exert beneficial vascular effects in animal models of hypertension

L'hypertension artérielle et les désordres vasculaires induits par l'érythropoïétine recombinante humaine et le système rénine-angiotensine-aldostérone (Effet de l'exercice et des cellules T régulatrices)

L hypertension artérielle (HTA) est l une des pathologies les plus fréquentes et les plus préoccupantes des pays occidentaux. Elle est souvent associée au surpoids, à des maladies rénales, cardiaques et aussi à un dysfonctionnement du système endocrinien. Les désordres vasculaires compliquant l HTA induite par le traitement par l érythropoïétine recombinante (r-HuEPO) chez les patients ayant une maladie rénale chronique ou en lien avec une perturbation du système rénine-angiotensine-aldostérone (SRAA), associent une augmentation de la rigidité artérielle, une dysfonction endothéliale, un déséquilibre endothéline-1/monoxyde d azote (ET-1/NO) et un état inflammatoire. L'inflammation vasculaire contribue à la physiopathologie de l'HTA par l augmentation du stress oxydatif et l'activation des cellules immunitaires. Plusieurs études ont suggéré que le système immunitaire est impliqué dans le développement des maladies cardiovasculaires. Cependant le rôle des lymphocytes T régulatrices (Treg) dans l'HTA ou d'autres formes de maladies cardio-vasculaires, reste encore largement inconnu. Bien que la majorité des études ont montré que l HTA induite par l r-HuEPO est associée à une dysfunction endothéliale et à un déséquilibre du rapport (ET-1/NO), les mécanismes exacts restent à être identifier.Plusieurs études ont montré que l exercice physique d endurance prévient l HTA chez les patients ou les modèles animaux. L objectif de la première partie du travail est d étudier l impact du shear stress et de l exercice sur les désordres vasculaires et l HTA induits par l r-HuEPO, en présence d un déséquilibre endothélial (ET-1/NO). Pour ce faire, trois environnements ont été utilisés (in vitro (cellules en culture), in vitro (artères mésentériques (AM)) et in vivo (souris transgéniques sur-exprimant l ET-1 au niveau de l endothélium). Nos résultats montrent que l'association L-NAME/r-HuEPO est responsable d'une vasoconstriction flux-dépendante et une augmentation accrue du shear stress correspondant (plus de 25 dyn/cm2). Le Bosentan, inhibiteur non sélectif des récepteurs de l ET-1, empêche la vasoconstriction flux-dépendante engendrée par la combinaison L-NAME/rHu-EPO, sans pour autant corriger la vasodilatation; Le traitement des souris transgéniques eET-1 avec l r-HuEPO augmente la pression artérielle systolique, la concentration plasmatique en ET-1, le stress oxydatif, l infiltration des monocytes et des macrophages aortiques (MOMA-2), le taux des cytokines pro-inflammatoire INF-g, TNF-a et IL-6 et exacerbe la dysfonction endothéliale. L exercice physique prévient tous les effets délétères engendrés par l administration de l r-HuEPO. Il est à noter aussi que l exercice augmente le taux du Foxp3 dans la rate et le cortex rénal. Quant à la deuxième partie, il s'agissait de tester l effet du transfert adoptif des Treg sur l HTA et les désordres vasculaires induits par l administration d angiotensine II ou d aldostérone à des souris. Nos résultats montrent que le transfert adoptif des Treg prévient l HTA induite par l Ang II, l altération de la vasodilatation endothélium-dépendante, prévient l augmentation de la rigidité des AM, diminue le stress oxydatif et les taux plasmatiques des cytokines proinflammatoires (INF-g, TNF-a et IL-6), ainsi que l infiltration aortique et rénale des macrophages. Le transfert adoptif des Treg prévient partiellement l augmentation de la pression artérielle systolique induite par l Aldo, prévient l altération de la vasodilatation endothelium dépendante et le remodelage hypertrophique des AM, diminue le stress oxydatif et l infiltration des cellules immunitaires inflammatoires. Le transfert adoptif des cellules T effectrices (Teff) exacerbe la majorité des effets de l Aldo. Nos résultats justifient, d une part, l importance de l exercice comme outil préventif de l HTA induite par l r-HuEPO, et d autre part, présentent les Treg comme élément essential dans la modulation de l HTA et des désordres cardiovasculaires.Hypertension (HTN) is one of the most frequent disease and is of greatest concern in Western countries.HTN is often associated with overweight, kidney, heart and endocrine system disease. Vasculardisorders, associated with HTN induced by erythropoietin (r-HuEPO) treatment in chronic kidneydisease or in case of disruption of the renin-angiotensin-aldosterone system (RAAS), associated increasein arterial stiffness, endothelial dysfunction, unbalanced endothelin-1/nitric oxide ratio (ET-1/NO) andinflammation. Vascular inflammation contributes to the pathophysiology of hypertension by increasingoxidative stress and activation of immune cells. Several studies have suggested that the immune systemis involved in the development of cardiovascular disease. However, the role of regulatory T cells (Treg)in HTN and other forms of cardiovascular diseases remains largely unknown. In addition, most of thestudies have shown that hypertension induced by r-HuEPO is related to endothelial dysfunction and theratio (ET-1/NO). The exact mechanisms remain to be identified. Several studies have shown thatphysical exercise prevents HTN in patients or animal models. The aim of the first part of this work is tostudy the impact of shear stress and exercise on HTN and vascular disorders induced by r-HuEPO, in thepresence of an endothelial imbalance (ET-1/NO). This was carried out in three settings: in vitro (culturecells), ex vivo (mesenteric arteries) and in vivo (transgenic mice overexpressing ET-1 in endothelialcells). Our results show that the association L-NAME/r-HuEPO is responsible for a significant decreasein intravascular diameter, in response to elevated intravascular flow resulting in a flow-dependentvasoconstriction and increased corresponding shear stress (more than 25 dyn/cm2). Bosentan (a nonselectiveantagonist of ET-1 receptors) inhibits flow-dependent vasoconstriction induced by thecombination L-NAME/rHu-EPO without correcting vasodilation. Treatment of ET-1 transgenic micewith r-HuEPO increases systolic blood pressure, ET-1 plasma concentration, oxidative stress, infiltrationof aortic monocytes and macrophages (MOMA-2), pro-inflammatory cytokines levels INF-g, TNF-a andIL-6 and exacerbate endothelial dysfunction. Exercise prevents all the deleterious effects of r-HuEPO. Itis also noteworthy that exercise increases the number of Foxp3-positive cells in the spleen and renalcortex. Then, the second aim of our study was to test the effect of adoptive transfer of Treg cells on HTNand vascular disorders induced in mice treated with angiotensin II (Ang II) or aldosterone (Aldo). Ourresults show that adoptive transfer of Treg prevents Ang II induced hypertension, endothelialdysfunction, prevents stiffness of mesenteric arteries, decreases oxidative stress and plasma levels ofpro-inflammatory cytokines (IFN-g, TNF-a and IL-6) and the aortic and renal infiltration ofmacrophages. Adoptive transfer of Treg prevents the increase in systolic blood pressure induced byAldo, prevents impaired endothelium-dependent vasodilatation and hypertrophic remodelling ofmesenteric arteries, decreases oxidative stress and infiltration of inflammatory immune cells. Theadoptive transfer of T effectors cells (Teff) exacerbates the majority of the Aldo effects. Our resultsjustify, on one hand, the importance of exercise as a preventive tool for hypertension induced by r-HuEPO, and on the other hand, highlight the role of Treg as an essential component in the modulation ofhypertension and cardiovascular disorders.AVIGNON-Bib. numérique (840079901) / SudocSudocFranceF

Hypertensive eye disease

Hypertensive eye disease includes a spectrum of pathological changes, the most well known being hypertensive retinopathy. Other commonly involved parts of the eye in hypertension include the choroid and optic nerve, sometimes referred to as hypertensive choroidopathy and hypertensive optic neuropathy. Together, hypertensive eye disease develops in response to acute and/or chronic elevation of blood pressure. Major advances in research over the past three decades have greatly enhanced our understanding of the epidemiology, systemic associations and clinical implications of hypertensive eye disease, particularly hypertensive retinopathy. Traditionally diagnosed via a clinical funduscopic examination, but increasingly documented on digital retinal fundus photographs, hypertensive retinopathy has long been considered a marker of systemic target organ damage (for example, kidney disease) elsewhere in the body. Epidemiological studies indicate that hypertensive retinopathy signs are commonly seen in the general adult population, are associated with subclinical measures of vascular disease and predict risk of incident clinical cardiovascular events. New technologies, including development of non-invasive optical coherence tomography angiography, artificial intelligence and mobile ocular imaging instruments, have allowed further assessment and understanding of the ocular manifestations of hypertension and increase the potential that ocular imaging could be used for hypertension management and cardiovascular risk stratification

Is it time to reappraise blood pressure thresholds and targets? Statement from the international society of hypertension - a global perspective

No abstract available

Vascular smooth muscle cell NAD(P)H oxidase activity during the development of hypertension: Effect of angiotensin II and role of insulinlike growth factor-1 receptor transactivation

We investigated whether angiotensin II (Ang II)-induced reactive oxygen species (ROS) generation is altered in vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHR) during the phases of prehypertension, developing hypertension, and established hypertension and assessed the putative role of insulinlike growth factor-1 receptor (IGF-1R) in Ang II-mediated actions. The VSMCs from SHR and Wistar-Kyoto rats (WKY) aged 4 (prehypertensive), 9 (developing hypertension), and 16 (established hypertension) weeks were studied. The ROS production and NAD(P)H oxidase activation were determined by fluorescence and chemiluminescence, respectively. The role of IGF-1R was assessed with the selective inhibitor AG1024. The ROS bioavailability was manipulated with Tiron (10-5 mol/L) and diphenylene iodonium (DPI) (10-6 mol/L). Angiotensin II dose dependently increased ROS production in WKY and SHR at all ages. The Ang II-induced responses were greater in SHR versus WKY at 9 and 16 weeks (P < .05). The Ang II-stimulated ROS increase was greater in 9- and 16-week-old SHR versus 4-week SHR (P < .05). These effects were reduced by AG 1024. Basal NAD(P)H oxidase activity was higher in VSMCs from 9-week-old SHR versus 4-week-old rats (P < .05). Angiotensin II induced a significant increase in oxidase activity in VSMCs from 9- and 16-week-old SHR (P < .001), without influencing responses in cells from 4-week-old SHR. Pretreatment of 9- and 16-week-old SHR cells with AG1024 reduced Ang II-mediated NAD(P)H oxidase activation (P < .05). Basal and Ang II-induced NAD(P)H-driven ROS generation are enhanced in VSMCs from SHR during development of hypertension, but not in cells from prehypertensive rats. Transactivation of IGF-1R by Ang II may be important in vascular oxidative excess in the development of hypertension in SHR.Fil: Cruzado, Montserrat Cecilia. Universidad Nacional de Cuyo; Argentina. Universidad de Mendoza; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Risler, Norma Raquel. Universidad Nacional de Cuyo; ArgentinaFil: Miatello, Roberto Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Yao, Guoying. Institut de Recherches Cliniques de Montréal; CanadáFil: Schiffrin, Ernesto L.. Institut de Recherches Cliniques de Montréal; CanadáFil: Touyz, Rhian M.. Institut de Recherches Cliniques de Montréal; Canad

A new look at the mosaic theory of hypertension

No abstract available