A hipertensão arterial pulmonar é uma síndrome caracterizada por vasoconstrição e remodelamento vascular pulmonar, levando a um aumento progressivo na resistência vascular pulmonar, que eleva a pós-carga imposta ao ventrículo direito, gerando consequente hipertrofia e insuficiência cardíaca direita. Essa doença acomete duas vezes mais mulheres do que homens. O estresse oxidativo está envolvido na patogênese da hipertensão arterial pulmonar. O hormônio estrogênio, comportando-se como scavenger de radicais livres, é capaz de modular o estresse oxidativo. O modelo experimental de hipertensão arterial pulmonar induzido por monocrotalina vem sendo utilizado por mimetizar as alterações que decorrem desta patologia em humanos. Dessa maneira, o objetivo desse estudo foi testar a hipótese de que o estrogênio poderia atenuar a hipertrofia do ventrículo direito e sua progressão para insuficiência cardíaca, modulando o estresse oxidativo, nos animais que receberam a monocrotalina. Ratas wistar fêmeas com 60 dias foram ovariectomizadas ou sofreram simulação da mesma. Após sete dias, receberam implantação de pellets subcutâneos com 17β-estradiol ou óleo de girassol. Neste momento, foi também administrada injeção intraperitoneal de monocrotalina ou salina. Os grupos experimentais foram: sham (S) - simulação da cirurgia de ovariectomia, não submetidas ao tratamento com MCT; sham + MCT (SM) - simulação da cirurgia de ovariectomia, e tratadas com MCT; ovariectomia (O) - cirurgia de ovariectomia, não submetidas ao tratamento com MCT; ovariectomia + MCT (OM) - cirurgia de ovariectomia, e tratadas com MCT; ovariectomia + MCT + reposição estrogênio (OMR) - cirurgia de ovariectomia, tratadas com MCT e estrogênio. As medidas hemodinâmicas foram realizadas 21 dias após a administração da monocrotalina ou salina nos animais ovariectomizados e, nos outros grupos, na fase do diestro. Foi verificada a pressão diastólica final do ventrículo direito, pressão sistólica do ventrículo direito e frequência cardíaca. Após a análise, as ratas foram mortas por deslocamento cervical e o coração, pulmão, fígado e útero foram coletados. As análises morfométricas foram realizadas após a retirada dos órgãos para avaliar hipertrofia cardíaca, congestão pulmonar e hepática. Amostras de ventrículo direito foram utilizadas para analisar a concentração de peróxido de hidrogênio, a razão da glutationa reduzida/oxidada, lipoperoxidação e defesas antioxidantes enzimáticas. O imunoconteúdo de ANP (peptídeo natriurético atrial) foi também avaliado em homogeneizado cardíaco. Os dados de pressão sistólica, hipertrofia cardíaca, defesa antioxidante enzimática, concentração de peróxido de hidrogênio e lipoperoxidação não mostraram diferença entre os grupos. Houve congestão pulmonar no grupo OM, sendo esta diminuída no grupo OMR. Isto sugere que o estrogênio esteja atenuando a resistência vascular pulmonar. Também houve aumento da pressão diastólica final do ventrículo direito nos grupos OM e OMR. A razão das glutationas se mostrou diminuída nos grupos O, OM e OMR, assim como a glutationa reduzida nos grupos O e OM, sugerindo a influência do estrogênio na modulação do estado redox celular. Os dados sugerem que o estrogênio possa exercer grande influência no equilíbrio redox celular, podendo este efeito contribuir para evitar o surgimento do edema pulmonar, característico deste modelo de hipertensão arterial pulmonar e insuficiência do ventrículo direito. / Pulmonary arterial hypertension is a syndrome characterized by vasoconstriction and pulmonary vascular remodeling, leading to a progressive increase in pulmonary vascular resistance, which increases the afterload imposed on the right ventricle, causing consequent hypertrophy and heart failure. This disease affects twice as many women as men. The oxidative stress is involved in pulmonary artery hypertension, as well as the estrogen hormone modulating the oxidative stress, behaving like scavenger of free radicals. The experimental model of pulmonary hypertension induced by monocrotaline has been used to mimic the changes from this pathology. Thus, the objective of this study was to test the hypothesis that estrogen could attenuate ventricular hypertrophy law and its progression to heart failure, modulating oxidative stress in animals received monocrotaline. Female Wistar rats aged 60 days were ovariectomized or underwent sham same, 7 days after implantation of pellets were subcutaneous 17β-estradiol or sunflower oil more intraperitoneal injection of monocrotaline or saline. The experimental groups (n = 9-13 per group) were: SHAM (S) – sham surgery, ovariectomy, no treated with MCT, MCT + SHAM - simulation of ovariectomy surgical and treated with MCT; OVARIECTOMY (O) – ovariectomy surgical, no treated with MCT, MCT + OVARIECTOMY (OM) –ovariectomy surgical, and treated with MCT; MCT + + OVARIECTOMY ESTROGEN REPLACEMENT (OMR) - surgery, ovariectomy, and treated with MCT estrogen. Hemodynamic measurements were performed 21 days after administration of saline or monocrotaline in ovariectomized animals and other groups in diestrus phase with anesthetized animals. The ventricular end diastolic pressure right ventricular systolic pressure and right heart rate was verified. After analyzing, the rats were killed by cervical dislocation and the heart, lung, liver and uterus were collected. Analyses morphometry were performed after withdrawal of agencies to evaluate cardiac hypertrophy, congestion lung and liver. The right ventricular mass was used to analyze the redox status (hydrogen peroxide and glutathione ratio) antioxidant enzymatic defenses and protein expression of ANP. The Data for systolic blood pressure, cardiac hypertrophy, antioxidant defense enzyme concentration hydrogen peroxide and lipid peroxidation showed no difference between the groups, which may be related with normal distribution. There was congestion pulmonary CO group and decreased in group OMR, suggesting that estrogen is attenuating the pulmonary vascular resistance, as well as increased end-diastolic pressure in the right ventricle OMR and OM groups. The glutathione ratio was shown decreased in groups O, CO and OMR, as well as reduced glutathione in groups O and CO, suggesting the influence of estrogen on modulation of cellular redox state. The data suggest that estrogen can exert great influence on the cellular redox balance and this effect may help to avoid the appearance of pulmonary edema, a characteristic of pulmonary hypertension and right ventricular failure.

Contexte: Le syndrome de détresse respiratoire aigüe (SDRA) est associé à une dysfonction vasculaire pulmonaire. Objectifs: Préciser le retentissement cardiaque de cette dysfonction vasculaire pulmonaire en recherchant la fréquence et le pronostic du foramen ovale perméable, du passage transpulmonaire de bulles en échographie de contraste, du cœur pulmonaire aigu (CPA), de la dysfonction systolique ventriculaire droite ainsi que de la déformation ventriculaire gauche au cours du SDRA. Nous avons aussi évalué la tolérance hémodynamique de la ventilation en Pression Expiratoire Positive (PEP) élevée. Méthodes: Les explorations étaient menées par échographie trans-œsophagienne (ETO) traditionnelle et en signature acoustique. Résultats: La faisabilité de l'ETO en décubitus ventral est bonne. Le foramen ovale perméable, détecté chez 19% des patients, est associé à une moins bonne réponse à l'augmentation de la PEP et à un recours aux thérapeutiques de sauvetage plus fréquent. Le passage de bulles transpulmonaire ne rend pas compte du seul shunt intra-pulmonaire anatomique, et dépend plus des conditions hémodynamiques (augmentation du débit cardiaque associée au sepsis) que de la ventilation. Le CPA, retrouvé chez 22% des patients, est associé à une pression motrice plus élevée, et au sepsis ; il est fréquemment associé à une insuffisance circulatoire, avec une mortalité plus élevée à J28. La quantification de la déformation ventriculaire gauche systolique par l'index d'excentricité est un bon marqueur de CPA, mais pas la dysfonction contractile ventriculaire droite évaluée en signature acoustique. Enfin, nous n'avons pas retrouvé de lien robuste entre la tolérance hémodynamique et l'efficacité respiratoire (recrutement alvéolaire) des niveaux de PEP élevés, sous réserve d'un nombre limité de patients. Conclusion: Les conséquences cardiaques de la dysfonction vasculaire pulmonaire restent fréquentes et associées à un pronostic péjoratif, avec des implications respiratoires et circulatoires. / Context: Acute respiratory distress syndrome (ARDS) leads to pulmonary vascular dysfunction Aims: We assessed cardiac consequences of pulmonary vascular dysfunction by detecting patent foramen ovale and transpulmonary bubbles transit using contrast echocardiography, acute cor pulmonale, right ventricle systolic dysfunction and left ventricle deformation during ARDS. We also assessed hemodynamic tolerance of high positive end expiratory pressure (PEEP). Methods: Transesophageal echocardiography (TEE) was performed with standard measurements and speckle tracking. Results: TEE could be safely performed in prone position. Patent foramen ovale was detected in 19% of patients, and was associated with a poor oxygenation response to PEEP, and greater use of adjunctive interventions. Transpulmonary bubbles transit was not solely related to anatomical intrapulmonary shunt, but was merely influenced by hemodynamic status (increased cardiac output associated with sepsis). Acute cor pulmonale occurred in 22% of patients, and was associated with a higher driving pressure and with sepsis; it was often associated with circulatory failure, with higher day-28 mortality. Left ventricle systolic deformation (evaluated by eccentricity index) but not right ventricle contractile impairment (evaluated with speckle tracking) was associated with acute cor pulmonale. Finally, we did not find a robust relation between hemodynamic tolerance and alveolar recruitment with higher PEEP levels, but the limited number of patients restricted the power of the analysis. Conclusion: Cardiac consequences of pulmonary vascular dysfunction remain frequent and associated with a poorer prognosis, with respiratory and circulatory implications.

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.

Background: Chronic myeloproliferative disorders (CMPD) seem to be associated with an increased risk for pulmonary hypertension (PH). Case Report: A patient with history of chronic idiopathic myelofibrosis (CIMF) presented with progressive dyspnea (New York Heart Association class III). Until this time he had not received specific treatment for CIMF. Echocardiography and rightheart catheterization confirmed PH. Further diagnostic procedures excluded a specific cause of PH. Therefore, primary PH was assumed. 2 years later he presented again with progressive dyspnea due to a progress of PH. A few days later the patient died from acute posterior myocardial infarction. Pathologic examination of the lung showed an obstruction of the small vessels by conglomerates of megakaryocytes. Discussion: We conclude that PH developed secondarily due to CMPD. PH should be suspected in patients with CMPD and should influence the decision for treatment of CMPD. / Hintergrund: Chronische myeloproliferative Erkrankungen (CMPD) scheinen mit einem erhöhten Risiko für pulmonale Hypertonie (PH) assoziiert zu sein. Kasuistik: Ein Patient mit chronisch idiopathischer Myelofibrose (CIMF) wurde aufgrund einer progressiven Belastungsdyspnoe (New York Heart Association Stadium III) überwiesen. Bis zu diesem Zeitpunkt erhielt er keine spezifische Behandlung seiner CIMF. Echokardiographie und Rechtsherzkatheter ergaben das Vorliegen einer PH. Eine spezifische Ursache der PH konnte zunächst ausgeschlossen werden. Somit wurde das Vorliegen einer primären PH vermutet. 2 Jahre später wurde der Patient mit erneut verschlechterter Belastungsdyspnoe vorgestellt, wobei ein Progress der PH feststellbar war. Einige Tage später verstarb der Patient an einem Hinterwandinfarkt. Die Autopsie des Lungengewebes zeigte einen Verschluss der kleinen Lungengefäße durch Konglomerate von Megakaryozyten. Diskussion: Die Entwicklung der PH ist bei diesem Patienten als Folge der CMPD einzuschätzen. Das Vorliegen einer PH bei Patienten mit CMPD sollte die Entscheidung zu spezifischen therapeutischen Maßnahmen hinsichtlich der CMPD beeinflussen. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Background: N-terminal pro-brain natriuretic peptide (NT-proBNP) is secreted by cardiac ventricular myocytes upon pressure and volume overload and is a prognostic marker to monitor the severity of precapillary pulmonary hypertension and the extent of right heart failure. Objectives: The impact of physical exercise on NT-proBNP levels in patients with left heart disease was demonstrated previously. No data regarding patients with isolated right heart failure and the influence of acute exercise on NT-proBNP serum levels exist. Methods: Twenty patients with precapillary pulmonary hypertension were examined. Hemodynamic parameters were measured during right heart catheterization. Serum NT-proBNP of patients was measured at rest, after a 6-min walking test, during ergospirometry and during recovery, all within 7 h. Significant differences in sequential NT-proBNP values, relative changes compared to values at rest and the correlation between NT-proBNP and obtained parameters were assessed. Results: At rest, the mean serum level of NT-proBNP was 1,278 ± 998 pg/ml. The mean level of NT-proBNP at maximal exercise was increased (1,592 ± 1,219 pg/ml), whereas serum levels decreased slightly during recovery (1,518 ± 1,170 pg/ml). The relative increase of serum NT-proBNP during exercise correlated with pulmonary vascular resistance (r = 0.45; p = 0.026) and cardiac output (r = –0.5; p = 0.015). Conclusions: In this study, we demonstrated acute changes in NT-proBNP levels due to physical exercise in a small group of patients with precapillary pulmonary hypertension. Our results also confirm the predominant usefulness of NT-proBNP as an intraindividual parameter of right heart load. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Background: Even though specific agents for the treatment of patients with pulmonary hypertension (PH) are available, in PH patients, physical capacity and quality of life (QoL) are often restricted and survival is reduced. Objectives: This study prospectively investigated the long-term effects of respiratory and exercise training in patients with severe chronic PH regarding safety, time to clinical worsening and survival. Methods: Fifty-eight consecutive patients with severe PH on stable disease-targeted medication received exercise and respiratory training in hospital for 3 weeks and continued at home. They were prospectively followed for 24 ± 12 months. Primary endpoints were time to clinical worsening and survival. Adverse events and changes in the 6-min walking test, QoL, WHO functional class and gas exchange were secondary endpoints and were evaluated at baseline and at weeks 3 and 15. Results: All patients tolerated the exercise training well without severe adverse events. In week 15, 6-min walking test results were significantly improved compared to baseline (by 84 ± 49 m, p < 0.001), as well as QoL scores, WHO functional class (from 2.9 ± 0.5 to 2.6 ± 0.6, p < 0.01), peak oxygen consumption (from 12.5 ± 3.0 to 14.6 ± 3.9 ml/min/kg, p < 0.001), heart rate at rest (from 75 ± 12 to 61 ± 18 beats/min, p < 0.001) and maximal workload (from 65 ± 21 to 80 ± 25 W, p < 0.001). Survival at 1 and 2 years was 100 and 95%, respectively. Fifteen events occurred during the follow-up. Conclusion: This study indicates that exercise and respiratory training as add-on to medical treatment may improve exercise capacity and QoL, and that they have a good long-term safety in the described setting. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

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Eine Melanomerkrankung im metastasierten Stadium ist heute noch eine nicht heilbare und in den meisten Fällen tödlich verlaufende Erkrankung. Über 50% der Patienten mit metastasierendem malignen Melanom entwickeln Lungenmetastasen. Nach dem Auftreten von Lungenmetastasen beträgt die durchschnittliche Überlebenszeit noch 7,3 Monate. Demnach ist die Entwicklung von Therapiestrategien notwendig, um das Fortschreiten von Tumormetastasen oder sogar deren Entstehung zu verhindern. Die lokale Stimulation der angeborenen Immunabwehr durch Behandlung mit Toll-like-Rezeptor-Agonisten käme hierfür in Frage. Inhalative Behandlungen mit Immunmodulatoren, wie sie für IL-2 beschrieben wurden, könnten insbesondere für die Behandlung pulmonaler Metastasen genutzt werden. In der vorliegenden Arbeit wurde das pulmonale angeborene Immunsystem im Mausmodell durch den TLR2/6-Agonisten MALP-2 stimuliert und die Auswirkung dieser Immunstimulation auf experimentell induzierte pulmonale Melanommetastasen untersucht. Intratracheale Instillationen von 0,5 µg MALP-2 führten zu starker Einwanderung neutrophiler Granulozyten (6-fach) und Makrophagen (3,4-fach) in die Lunge von C57/BL6-Mäusen. Innerhalb von 24 h war das Maximum der Immunzelleinwanderung erreicht. Der Leukozyteneinstrom fiel dann innerhalb von 72 h wieder auf das Ursprungsniveau zurück. Weitere Untersuchungen konnten zeigen, dass MALP-2 auch zu einer deutlichen Steigerung der Expression von VCAM-1 in pulmonalen Blutgefäßen führt. In vitro Experimente zeigten, dass dieses Adhäsionsmolekül die Bindung von B16-F10-Melanomzellen vermitteln kann.  Außerdem führte die MALP-2-Behandlung weder in vitro noch in vivo zu einer signifikanten Steigerung der Fähigkeit von Immunzellen, B16-F10-Melanomzellen zu lysieren.  So konnte, im Gegensatz zu Rückschlüssen aus früheren Publikationen, trotz der ausgeprägten Stimulation des pulmonalen Immunsystems und unabhängig vom Applikationsregime durch MALP-2 vor oder nach Tumorinokulation im Mausmodell keine signifikante Änderung der pulmonalen Metastasen erreicht werden. Durch Markierung von Melanomzellen, die stabil mit Green fluorescent Protein transfiziert waren, war es möglich, Melanomzellen kurz nach Tumorzellaussaat zu untersuchen. Eine lokale TLR2/6-Aktivierung durch MALP-2-Instillation 24 h vor Tumorinokulation führte aber in vivo zu keiner Beeinflussung des pulmonalen Melanomzellarrests im Mausmodell. Außerdem konnte gezeigt werden, dass auch das „Boostern“ des Immunsystems durch wiederholte intratracheale MALP-2-Applikation an bereits etablierten pulmonalen Metastasen zu keiner Änderung des klinischen Gesamtresultates führt. Zusammenfassend kann festgestellt werden, dass diese teilweise unerwarteten Ergebnisse deutlich machen, dass klinische Vorhersagen bezüglich immunmodulierender Therapien mit Vorsicht zu stellen sind, insbesondere, da multiple, sich wechselseitig beeinflussende Effekte durch die Immunstimulantien selbst das Gesamtergebnis einer Tumortherapie beeinflussen können.