Les jonctions communicantes jouent un rôle important dans la prolifération et la réactivité vasculaire systémique. Dans cette étude, nous avons recherché le rôle de ces structures dans la paroi artérielle pulmonaire saine et dans l’hypertension artérielle pulmonaire (HTAP). L’HTAP est une pathologie de la circulation pulmonaire caractérisée par une prolifération cellulaire pathologique et une hyperréactivité à divers agonistes vasoconstricteurs tels que la sérotonine (5-HT). Dans la paroi artérielle pulmonaire de rats sains les protéines constituant les jonctions communicantes vasculaires (les connexines 37, 40 et 43) sont présentes. De plus, la connexine 43 située au niveau de la jonction myoendothéliale (JME) intervient dans la réactivité à la 5-HT. La 5-HT produit par ailleurs, (1) de l’anion superoxyde (O2?) au niveau du muscle lisse et (2) un vasodilatateur (le monoxyde d’azote (NO)) au niveau de l’endothélium. La JME va permettre le passage de l’O2? du muscle lisse vers l’endothélium de façon à piéger le NO et maintenir une contraction physiologique de l’artère pulmonaire. L’étude des jonctions communicantes dans la circulation pulmonaire pathologique a été réalisée sur deux modèles de rats atteints d’HTAP : (1) le modèle de rat atteint d’HTAP suite à une injection de monocrotaline (rat MCT) et (2) le modèle de rat atteint d’HTAP suite à une hypoxie chronique (rat HC). Les connexines 37, 40 et 43 sont également exprimées au niveau de la circulation pulmonaire de ces rats, mais leur distribution au niveau du muscle lisse et l’endothélium est modifiée. La réactivité des artères pulmonaires à divers agents vasoconstricteurs (5-HT, endothéline-1, phényléphrine, solutions dépolarisantes) est modifiée chez les rats MCT et HC. De plus, l’implication des jonctions communicantes dans la réactivité à ces agents est changée chez les rats MCT et HC. Ces données apportent de nouvelles connaissances sur le rôle des jonctions communicantes dans la réponse contractile des artères pulmonaires saines, et de nouveaux éléments permettant de mieux comprendre les altérations de la vasomotricité pulmonaire observée dans l’HTAP. / Gap junction communication plays an important role in proliferation and in the regulation of vascular reactivity. In this study, we investigated the role of gap junctions in physiological pulmonary circulation and in pulmonary arterial hypertension (PAH). PAH is the main pathology of pulmonary circulation and is characterized by cell proliferation and hyperreactivity to several contractile factors such as serotonin (5-HT). In pulmonary circulation from healthy rats, gap junction proteins were observed (connexins 37, 40 and 43). Moreover, connexin 43 located at the myoendothelial junction (MEJ) is involved in the reactivity to 5-HT in pulmonary arteries from healthy rats. Indeed, 5-HT produces (1) superoxyde anion (O2?) from smooth muscle and (2) a vasodilator (nitric oxide (NO)) from endothelium. O2? will pass through MEJ from the smooth muscle to the endothelium in order to scavenge NO and thus maintain contraction in physiological conditions. Gap junctions study in pathological pulmonary arteries has been performed on two animal models of PAH: (1) monocrotaline-induced PAH (MCT rat) and (2) chronic hypoxia-induced PAH (CH rat). Connexins 37, 40 and 43 were observed in pulmonary circulation from these rats, but the localization in smooth muscle and endothelium is modified. Moreover, pulmonary arterial vasoreactivity in response to several contractile agents (5-HT, endothelin-1, phenylephrine, depolarizing solutions) is modified in MCT and CH rats. Finally, the role of gap junctions in the reactivity to these agonists is changed in MCT and CH rats. These data have important implications for understanding physiological vasoreactivity to 5-HT in pulmonary circulation, and to better understand alterations of pulmonary arterial reactivity observed in PAH.

O BPP-10c é um decapeptídeo bioativo, rico em resíduos de prolina e é expresso em uma proteína precursora no cérebro e na glândula de veneno da Bothrops jararaca. Recentemente demonstramos que o BPP-10c tem um potente e sustentado efeito anti-hipertensivo em ratos espontaneamente hipertensos (SHR), sem, no entanto, causar qualquer efeito em ratos normotensos, por um mecanismo farmacológico independente da inibição da enzima conversora de angiotensina (ECA), levando à hipótese de que outro mecanismo poderia estar envolvido na atividade do peptídeo. Neste trabalho, usamos cromatografia de afinidade para isolar e identificar as proteínas renais com afinidade pelo BPP-10c e demonstramos que a argininosuccinato sintase (AsS) é a principal proteína a se ligar ao peptídeo. Além disso, mostramos que essa interação promove um aumento na atividade catalítica da enzima, de forma dose-dependente. A AsS é reconhecida como uma peça chave na regulação do ciclo da citrulina-óxido nítrico (NO), e sua ação é passo limitante na síntese de NO. A interação funcional do BPP-10c com a AsS foi evidenciada pelos seguintes efeitos promovidos pelo peptídeo: i) estimulação da produção de NO por células HUVEC e da produção de arginina por células HEK 293, ii) aumento da concentração plasmática de arginina em SHR. Corroborando esses achados, mostramos a reversão dos efeitos do peptídeo, inclusive sobre a pressão arterial em SHR, quando o MDLA, um inibidor específico da AsS, foi co-administrado. Em conjunto, os resultados apresentados neste trabalho sugerem que a AsS é fundamental para o efeito anti-hipertensivo do BPP-10c. Tais resultados nos levaram a propor a AsS como um novo alvo terapêutico, e o BPP-10c como molécula-líder para a geração de medicamentos para tratamento de doenças relacionadas à hipertensão arterial / BPP-10c is a bioactive proline-rich decapeptide, part of the C-type natriuretic peptide precursor, expressed in the brain and in the venom gland of Bothrops jararaca. We recently showed that BPP-10c displays a strong, sustained anti-hypertensive effect in spontaneous hypertensive rats (SHR), without causing any effect in normotensive rats, by a pharmacological mechanism independent of angiotensin converting enzyme inhibition; therefore, we hypothesized that another mechanism should be involved in the peptide activity. Here we used affinity chromatography to search for kidney cytosolic proteins with affinity for BPP-10c and demonstrate that argininosuccinate synthetase (AsS) is the major protein binding to the peptide. More importantly, this interaction activates the catalytic activity of AsS in a dose-dependent manner. AsS is recognized as an important player of the citrulline-nitric oxide (NO) cycle that represents a potential limiting step in NO synthesis. Accordingly, the functional interaction of BPP-10c and AsS was evidenced by the following effects promoted by the peptide: i) increase of NO production in human umbilical vein endothelial cell culture, and of arginine in human embryonic kidney cells; ii) increase of arginine plasma concentration in SHR. Moreover, MDLA, a specific AsS inhibitor, significantly reduced the anti-hypertensive activity of BPP-10c in SHR. These results led us to suggest AsS as a new therapeutically useful target for the development of activators, such as BPP- 10c, useful to treat hypertension related diseases

L’Hypertensions Artérielle Pulmonaire (HTAP) résulte de l’obstruction progressive des artères pulmonaires de petits calibres due à un remodelage de la paroi vasculaire ainsi qu’à une vasoconstriction. Cette thèse repose sur 3 piliers de la physiopathologie de l’HTAP : l’inflammation, l’épigénétique et la susceptibilité génétique de la maladie.Le premier projet démontre que les cellules dendritiques des patients atteints d’HTAP sont moins sensibles à l’action immunomodulatrice des glucocorticoïdes et orientent la réponse des lymphocytes T vers une réponse Th17, souvent impliquée dans les maladies autoimmunes.Le second projet a pour but de comparer le profil de méthylation des cellules endothéliales d’artères pulmonaires (CE-AP) de patients atteints d’HTAP comparé aux CE-AP de patients contrôles. Nous avons mis en évidence des clusters de gènes ayant un profil de méthylation différents entre les CE-HTAP comparé aux CE-CTR. Un gène différentiellement méthylé s’est dégagé durant l’étude bioinformatique : ABCA1 (ATP binding cassette 1). L’altération de son expression prédite par l’étude bioinformatique a été validée chez l’homme et le modèle de rat monocrotaline.Enfin, le dernier projet décrit la caractérisation d’un nouveau modèle animal de susceptibilité génétique à l’HTAP liée à des mutations dans le gène Bmpr2 chez le rat, au niveau hémodynamique, histologique, vasculaire, moléculaire et électrophysiologique. Nous avons démontré que ce modèle reproduit des schémas physiopathologiques pertinents vis-à-vis de la maladie humaine, ces résultats font de ce modèle un nouveau outil d’étude de la physiopathologie de l’HTAP. / Pulmonary arterial hypertension (PAH) is characterized by a progressive pulmonary arterial obstruction due to pulmonary vascular remodeling of distal arterioles as well as abnormal vasoconstriction. This project allowed to study three biological process clearly establish to be implicated in physiopathology of PAH.The first project demonstrated a dendritic cells dysfunction and a Th17 immune polarization of idiopathic PAH patients.The objective of the second project was to study the epigenetic variations in pulmonary endothelial cells (PEC) through a specific pattern of DNA methylation. We identified clusters of probes that discriminates controls and PAH patients. During bioinformatics study, ABCA1 (ATP binding cassette 1) gene was emphasized. Alteration of ABCA1 expression predicted during bioinformatics study has been validated in human and in monocrotaline rat model.The last project described the validation of a new PAH model by a hemodynamic, histological, vascular, molecular and electrophysiological characterization of heterozygous rat mutated to Bmpr2 gene. Whole functional and molecular dysregulation define this animal model like a useful tool in the study of BMPRII signaling alteration in PAH physiopathology.

Background: Fingolimod is the first oral immunomodulatory therapy approved for highly active relapsing remitting multiple sclerosis. Based on the distribution pattern of fingolimod interacting sphingosine-1-phosphat receptors in organism including immune system and cardiovascular system clinical monitoring of patients and evaluation of adverse events are recommended. Despite extensive data on cardiovascular safety, experience with fingolimod in patients with concomitant cardiological disease, especially within the pulmonary circulation, is rare. Case presentation: We report the case of a 46-year-old woman presented with relapsing remitting multiple sclerosis and severe idiopathic pulmonary arterial hypertension. Fingolimod was initiated because of disease activity of multiple sclerosis with two relapses and gadolinium-enhancing lesions in MRI. The patient demonstrated stable disease course of idiopathic pulmonary arterial hypertension when fingolimod was started. Fingolimod therapy did not alter or even worsen the pulmonary or cardiovascular conditions during first dose application as well as follow up of nine months. Conclusion: In this report, we present the first case of fingolimod treatment in a patient with highly active multiple sclerosis and severe idiopathic pulmonary arterial hypertension. We suggest an interdisciplinary approach with detailed cardiopulmonary monitoring for safety in such patients.

No description available.

EINLEITUNG: Die „Hypertension and Diabetes Risk Screening and Awareness (HYDRA-)-Studie“ beschrieb und quantifizierte erstmals umfassend und bundesweit in einer Reihe von Publikationen1- 10 (siehe auch www.hydra-studie.de) die hausärztliche Versorgungssituation von Patienten mit arterieller Hypertonie und Diabetes mellitus. Mit Hilfe dieser Studie konnten neue Erkenntnisse zur Häufigkeit und Schwere, zu häufigen Begleit- oder Folgeerkrankungen, sowie zur Therapie dieser beiden Erkrankungen gewonnen werden. Insgesamt wurden im September 2001 in einer bundesrepräsentativen Stichprobe von 1.912 zufällig ausgewählten primärärztlichen Praxen (auf der Grundlage des IMS-Registers, Instituts für Medizinische Statistik, Frankfurt) eine Stichtagsbefragung von 45125 nicht-selektierter, konsekutiver Patienten ab dem 16. Lebensjahr durchgeführt (60,0 Prozent Frauen; Altersgruppen: 12,7 Prozent 16 bis 29 Jahre, 21,9 Prozent 30 bis 44 Jahre, 23,2 Prozent: 45 bis 59 Jahre, 42,2 Prozent: = 60 Jahre) und ihre Erkrankungen und Interventionen dokumentiert. Im folgenden Beitrag sollen die Ergebnisse für Sachsen gesondert berichtet und den bundesdeutschen Ergebnissen gegenübergestellt werden. In Sachsen nahmen an der HYDRA-Studie n=126 Ärzte teil, die an zwei aufeinander folgenden Studientagen insgesamt 2.407 Patienten dokumentierten. Die Datenerhebung erfolgte im Rahmen eines klinischepidemiologischen Stufendesigns: (i) Zunächst wurden die teilnehmenden Ärzte in einer Voruntersuchung hinsichtlich ihrer Ausbildungsund Praxismerkmale, ihren Erfahrungen und Problemen mit Hypertonikern und Diabetikern sowie ihren Einstellungen zu diesen Patientengruppen befragt. (ii) Am Erhebungstag wurden alle Patienten, die die teilnehmenden Praxen aufsuchten, ausführlich zu ihren Beschwerden, Krankheiten sowie zu ihrem Gesundheitsverhalten befragt (Patientenfragebogen). (iii) Die Ärzte dokumentierten dann für jeden Patienten die von ihnen vergebenen klinischen Diagnosen sowie die Therapie (Arztbogen); zudem wurden ausgewählte Messwerte am Studientag erfasst (Blutdruck, Mikroalbuminurie mit Micral-Teststreifen) und weitere Laborwerte aus der Akte entnommen. Für die ärztlichen Diagnosen wurden keine Vorgaben (zum Beispiel Nennung von Grenzwerten) gemacht. Die Methodik der Studie und wesentliche Ergebnisse wurden in einer Reihe von Originalarbeiten detailliert beschrieben.5

1 Univerzita Karlova v Praze 1. lékařská fakulta Některé aspekty patofyziologie plicní arteriální hypertenze a její výskyt v České republice Some aspects of pathophysiology of pulmonary arterial hypertension and its epidemiology in the Czech Republic MUDr. Pavel Jansa Praha 2011 2 Abstract Pulmonary arterial hypertension (PAH) is a group of diseases characterized by a progressive increase of resistance and pressure in pulmonary vascular bed. In all types of PAH the same four pathological processes are reported: vasoconstriction, inflammation, thrombosis and remodelling. The genetic background is essential for the development of PAH. We aimed to investigate the role of polymorphisms of endothelial nitric oxide synthase (eNOS) genes in PAH. We studied 142 PAH patients and 189 healthy subjects. We examined 3 polymorphisms of the eNOS gene, including the Glu298Asp polymorphism, 27-base pair (bp) variable numbers of tandem repeats (VNTR) and -786 T/C promoter gene polymorphism. Prevalence of 27-bp VNTR allele A was higher in patients with PAH compared with healthy controls. Patients with PAH associated with connective tissue diseases had higher prevalence of AA genotype compared with other PAH subgroups. The Glu298Asp polymorphism and -786 T/C polymorphism are not associated with PAH. Thrombotic arteriopathy is...

Pulmonell hypertension (PH) är en sjukdom med flera olika etiologier som bidrar till ett förhöjt tryck i lungkretsloppet. PH definieras som ett medelartärtryck i lungpulsådern   25mm Hg i vila uppmätt vid högersidig hjärtkateterisering (RHC). De olika orsakerna till PH delas in i fem grupper. Denna studie fokuserar på grupp I, som utgörs av pulmonell arteriell hypertension (PAH). PAH bidrar till en tryckbelastning av högerkammaren där högerkammaren måste arbeta mot ett högre tryck. Detta leder till en nedsatt högerkammarfunktion. I nuläget används right ventricular stroke work index (RVSWI) inom RHC, för att mäta högerkammarens arbete. Syftet med studien var att jämföra RVSWI beräknat med ekokardiografi och RHC. Detta för att finna ytterligare ett mått vid bedömning av högerkammarfunktion med ekokardiografi hos patienter med PAH. RVSWI beräknades med två ekokardiografiska metoder (RVSWIEKO1= 90 - (0,62 x pulmonalisflödets accelerationstid (PAT) x slagvolymindex (SVIEKO)), RVSWIEKO2= ((0,61 x maximala gradienten över tricuspidalisinsufficiensen (TRmaxPG)) + medeltrycket i höger förmak (mRAP) + 2) x SVIEKO). Båda metoderna påvisade statistisk signifikant skillnad (p <0,001) i absoluta värden mot RVSWI erhållet med RHC.  En av metoderna (RVSWI EKO2) påvisade en måttlig korrelation mot RHC, medan RVSWI EKO1 hade en försumbar korrelation mot RHC. Studien visade att ekokardiografiskt beräknat RVSWI kan användas, som ett ytterligare mått vid bedömning av högerkammarens funktion. Det krävs dock fler studier för att parametern ska kunna användas kliniskt. / Pulmonary hypertension (PH) is a disease with many different etiologies contributing to an increased pressure in the pulmonary circulation. PH is defined as a mean arterial pressure in the pulmonary artery ≥ 25mm Hg at rest measured by right heart catheterization (RHC). The different causes of PH are divided into five groups. This study focuses on group I, which consists of pulmonary arterial hypertension (PAH). PAH contributes to a pressure overload of the right ventricle. The right ventricle must work at a higher pressure, which leads to a reduced right ventricular function. Currently, right ventricular stroke work index (RVSWI) by right heart catheterization (RHC) is a measure of right ventricular workload. The purpose of the study was to compare RVSWI calculated with echocardiography to RVSWI by RHC. And to find an additional measure for assessing right ventricular function by echocardiography in patients with PAH.  RVSWI was evaluated with two echocardiographic methods (RVSWIEKO1= 90 - (0,62 x pulmonary acceleration time (PAT) x stroke volume index (SVIEKO)), RVSWIEKO2= ((0,61 x tricuspid regurgitant maximum pressure gradient (TRmaxPG)) + mean right atrial pressure (mRAP) + 2) x SVIEKO). Both the echocardiographic methods showed a statistically significant difference (p <0.001) in absolute values ​​compared to RVSWI by RHC. One of the echocardiographic methods (RVSWI EKO2) showed a moderate correlation with RHC, while RVSWIEKO1 showed a negligible with RHC. The study has shown that RVSWI evaluated with echocardiography can be used as an additional measure, when assessing right ventricular function. However, more studies are needed until the parameter can be used clinically.

Pulmonary arterial hypertension (PAH) is an uncommon but serious disease that causes increased pressure in the pulmonary vessels and increased pulmonary vascular resistance (PVR), which in turn leads to right heart failure. At diagnosis, mean pulmonary artery pressure (mPAP) must be >20 mmHg, pulmonary artery wedge pressure (PAWP) ≤15 mmHg and PVR >2 Wood units (WU). Calculation of cardiac output (CO) is an important hemodynamic parameter to be measured and assessed in these patients during a right heart catheterization (RHC). Prevailing ESC guidelines recommend using direct Fick's principle (dFp), which is considered the gold standard, or thermodilution when calculating CO. The aim of this study was to compare these two methods to see if there is a significant difference in the calculation of CO in patients with PAH. The aim was also to see if calculated cardiac index (CI) and PVR differ significantly depending on which of the methods for calculating CO is used. A retrospective study was conducted in which 34 patients who underwent RHC at the University Hospital in Örebro were included. The result showed a significant difference between dFp and thermodilution (p<0,05), where dFp on average measures higher volumes compared to thermodilution. It also showed a low agreement between the two methods. A significant difference was seen between CI and PVR (p<0,05) depending on which of the methods is used. Therefore, dFp and thermodilution cannot be said to have a good agreement in this patient group. It is important to use the same method for follow-up examinations as the assessment of PVR and CI is used as a predictor of whether the disease progresses or remains stable.

Background: Renal denervation (RDN) can reduce cardiac sympathetic activity maintained by arterial hypertension (aHT). Its potential antiarrhythmic effect on rhythm outcome in patients with multi-drug resistant aHT undergoing catheter ablation for atrial fibrillation (AF) is unclear. Methods: The RDN+AF study was a prospective, randomized, two-center trial. Patients with paroxysmal or persistent AF and uncontrolled aHT (mean systolic 24-h ambulatory BP > 135 mmHg) despite taking at least three antihypertensive drugs were enrolled. Patients were 1:2 randomized to either RDN+AF ablation or AF-only ablation. Primary endpoint was freedom from any AF episode > 2 min at 12 months assessed by implantable loop recorder (ILR) or 7d-holter electrocardiogram. Secondary endpoints included rhythm outcome at 24 months, blood pressure control, periprocedural complications, and renovascular safety. Results: The study randomized 61 patients (mean age 65 ± 9 years, 53% men). At 12 months, RDN+AF patients tended to have a greater decrease in ambulatory BPs but did not reach statistical significance. No differences in rhythm outcome were observed. Freedom from AF recurrence in the RDN+AF and AF-only group measured 61% versus 53% p = .622 at 12 months and 39% versus 47% p = .927 at 24 months, respectively. Periprocedural complications occurred in 9/61 patients (15%). No patient died. Conclusion: Among patients with multidrug-resistant aHT and paroxysmal or persistent AF, concomitant RDN+AF ablation was not associated with better blood pressure control or rhythm outcome in comparison to AF-only ablation and medical therapy.