Increase In Pulmonary Blood Pressure Research Articles

In This Issue

HomeCirculation ResearchVol. 127, No. 9In This Issue Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessResearch ArticlePDF/EPUBIn This Issue Ruth Williams Ruth WilliamsRuth Williams Search for more papers by this author Originally published8 Oct 2020https://doi.org/10.1161/RES.0000000000000443Circulation Research. 2020;127:1119is related toEpigenomic and Transcriptomic Dynamics During Human Heart OrganogenesisEnhancement of ALK1 Signaling as a HHT Therapy (p 1122)Boosting activity of kinase ALK1 could be a treatment for hereditary hemorrhagic telangiectasia, say Kim et al.Download figureDownload PowerPointHereditary hemorrhagic telangiectasia (HHT) is a genetic disease characterized by vascular abnormalities called arteriovenous malformations (AVMs) in which arteries are directly connected to veins. Without intervening capillaries, blood pressure in the veins becomes excessive and can cause aneurysms and ruptures. Indeed, HHT patients often endure frequent bleeds and anemia, and sometimes suffer more severe events such as brain or pulmonary hemorrhages. HHT is caused by mutations in one of three genes—ALK1, ENG, or SMAD4—all of which encode components of a TGFβ-related growth factor signaling pathway. Because ninety percent of HHT cases are driven by ALK1 or ENG mutations, Kim et al focused on these two factors, examining how they might interact and compensate for each other. Using mice that conditionally lacked either ALK1 or ENG and had AVMs as a result, the team found that genetically increasing ALK1 production could prevent AVMs in the ENG- and ALK-lacking mice, but that increasing ENG production could only compensate for deficiency of ENG, not ALK1. Together these results suggest that ALK1 acts downstream of ENG in their shared signaling pathway and that augmenting ALK1 production could be a therapeutic approach for treating HHT.Periostin Is a Target to Treat PH (p 1138)Nie et al suggest periostin as a novel therapeutic target for treating pulmonary hypertension.Download figureDownload PowerPointPulmonary hypertension (PH) is a life threatening disease in which excess proliferation of vascular smooth muscle cells (VSMCs) and deposition of extracellular matrix (ECM) thickens the walls of the lung vasculature causing an increase in pulmonary blood pressure. Vasodilatory medications are used to treat the symptoms of the disease, but there are no available treatments that target the underlying pathologic remodeling. Nie and colleagues now suggest that drugs targeting the secreted ECM protein periostin might work. Periostin is unusually abundant in the arteries of PH patients’ lungs and is thought to be involved in cell adhesion and wound healing mechanisms such as proliferation and migration of VSMCs. The team has now confirmed the increased production of periostin in patient lungs and shown the same is true for mice with induced PH. Moreover they showed that genetic deletion of periostin attenuated PH in mice, while suppression of periostin via RNA inhibition could even reverse pathologic vessel thickening and right ventricle hypertrophy. The team went on to identify factors—HIF-1A and TrkB—that mediate periostin’s effects in cultured arterial cells, and suggest that blocking either these factors or periostin itself could be novel strategies for treating PH.Gene Regulatory Dynamics of Developing Human Heart (p e184)VanOudenhove et al examine the epigenomics and transcriptomics of the developing human heart.Download figureDownload PowerPointCongenital heart defects (CHDs) are a common form of birth abnormality. While some genes have been linked to CHDs, the majority—nearly sixty percent—have unknown etiologies. It’s thought that multiple genetic and environmental factors contribute to CHDs, one of which could be variations in regulatory regions of the genome. To find such heart-specific regulatory regions, VanOudenhove and colleagues examined heart tissue from human embryos obtained 4 to 8 weeks after conception. They performed chromatin immunoprecipitation (ChIP) experiments to scour the heart genomes for histone modifications associated with increased or decreased gene transcription. They also performed transcriptome analysis to see whether the genomic regions identified by ChIP corresponded with the activity status of nearby genes. In total, the team found more than 12 thousand previously unknown enhancers that were enriched for binding sites for heart-specific transcription factors (including GATA, MEF2 and NKX) and that tended to be close to genes activated in the heart. Many of the regions also contained sequence variations previously associated with atrial fibrillation. These newly identified sites are potential CHD candidate loci, say the authors, who have made their data freely available for study. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesEpigenomic and Transcriptomic Dynamics During Human Heart OrganogenesisJennifer VanOudenhove, et al. Circulation Research. 2020;127:e184-e209 October 9, 2020Vol 127, Issue 9Article InformationMetrics Download: 270 © 2020 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000443 Originally publishedOctober 8, 2020 PDF download

Pulmonary Artery Smooth Muscle Cell Bone Morphogenetic Protein 2 Promotes Pulmonary Endothelial Cell Migration and Angiogenesis

BACKGROUNDPulmonary Arterial Hypertension (PAH) is an incurable disease and remains a significant cause of morbidity and mortality in children and adults. In PAH, pulmonary arteries narrow in diameter which increases blood flow resistance in the lungs. Eventually the increase in pulmonary blood pressure causes irreversible damage to the heart. There are a variety of reasons why the pulmonary arteries become obstructed, known and unknown; yet, the molecular mechanisms driving this disease remain to be elucidated. Approximately 1000 new cases of PAH are diagnosed each year in the U.S. alone. The average survival rate for patients diagnosed with PAH is 7 years. Therefore, any insight into the molecular mechanisms that promote PAH progression may represent new strategies to treat patients with PAH.OBJECTIVEUp to 20% of PAH patients with no family history of PAH carry a bone morphogenetic protein receptor 2 (BMPR2) mutation, whereas in patients with a family history of PAH up to 82% carry a BMPR2 mutation. Therefore, it appears extremely likely that BMPR2 loss of function promotes the dysfunctional angio‐proliferative phenotype of PAH. In fact, it has recently been shown that in endothelial cells (EC) deficient in BMPR2 exposed to exogenous bone morphogenetic protein 2 (BMP2), a ligand for BMPR2, are migratory compared to control cells. To determine if the loss of BMPR2 promotes the PAEC dysfunctional angiogenesis observed in patients with PAH, we used cells from control and PAH patients to determine the role of pulmonary artery smooth muscle cell (PASMC) secreted BMP2 in promoting the migration of pulmonary artery endothelial cells (PAEC) and angiogenesis.METHODSPASMC and PAEC from control and PAH patients were examined for the expression of BMPR2 and BMP2. Cell migration, cell invasion, and angiogenetic assays were performed using PASMC and PAEC from control and PAH patients to assess differences in migration, invasion, and angiogenesis.RESULTSPAEC from PAH patients have a significant reduction in the expression of BMPR2, consistent with published reports. PASMC from PAH secrete BMP2, while BMP2 is undetectable in control cells. Co‐culturing PAH PASMC with PAH PAEC promotes PAEC migration. This migration is further enhanced in the presence of exogenous BMP2. PAH PASMC co‐cultured with PAH PAEC promote the development of PAEC‐derived angiogenetic masses. This dysfunctional angiogenetic response is further amplified in the presence of exogenous BMP2. In contrast, control PAEC exposed to control PASMC respond normally and do not form disorganized masses of vessels. Control PAEC exposed to exogenous BMP2 further promotes a normal angiogenetic response.CONCLUSIONSPASMC from PAH patients secrete BMP2. BMP2 exposure promotes the migration of PAH PAEC and a dysfunctional angiogenetic response. In contrast, BMP2 promotes a normal angiogenetic response when added to co‐cultures of control PASMC and PAEC. These data suggest that in PAH, angiogenesis becomes dysfunctional in part due to PAEC exposure to BMP2; therefore, inhibitors of BMP2 may represent a therapeutic strategy to pursue in the treatment of PAH.

Thymoquinone attenuates monocrotaline-induced pulmonary artery hypertension via inhibiting pulmonary arterial remodeling in rats

BackgroundPulmonary artery remodeling induced by excess proliferation, migration and apoptosis resistance of pulmonary arterial smooth muscle cells (PASMCs) is a key component in pulmonary artery hypertension (PAH). Thymoquinone (TQ) triggers cancer cells apoptosis through multiple mechanisms. In addition, TQ inhibits migration of human nonsmall-cell lung cancer cells and human glioblastoma cells. ObjectivesIn the current study, we investigated effects of TQ on MCT-induced PAH in rats and its underlying mechanisms. MethodsAfter 2weeks of monocrotaline injection (MCT, 60mg/kg), Male Sprague–Dawley rats received TQ (8mg/kg, 12mg/kg, 16mg/kg) or olive oil per day for 2weeks. Hemodynamic changes, right ventricular hypertrophy, and lung morphological features were examined 4weeks later. In addition, TUNEL, PCNA, α-SMA, Bax and Bcl-2 were detected by immunohistochemistry staining. Bax, Bcl-2, cleaved caspase-3, cleaved poly (ADP-ribose) polymerase (PARP) MMP2, MMP9 and activation of p38MAPK and NF-κB were assessed by Western blot. ResultsMCT-induced an increase in pulmonary blood pressure and right ventricular hypertrophy, which were attenuated by TQ treatment. TQ also blocked MCT-induced pulmonary arterial remodeling, proliferation of PASMCs, elevation of MMP2 and downregulation of ratio of Bax/Bcl-2, cleaved caspase-3 and cleaved PARP. Furthermore, TQ inhibited MCT-induced activation of p38MAPK and NF-κB. ConclusionsTQ ameliorates MCT-induced pulmonary artery hypertension by inhibiting pulmonary arterial remodeling partially via p38MAPK/NF-κB signaling pathway in rats.

Altitude et système cardiovasculaire

A stay at high altitude exposes an individual to various environmental changes (cold, exercise, isolation) but the most stressful for the body is hypoxia. However, the cardiovascular system yields some efficient mechanisms of acclimatization to oxygen lack. Hypoxia activates the adrenergic system and induces a tachycardia that decreases during a prolonged stay at altitude. The desensitization of the adrenergic system leads to a decrease in maximal heart rate and a protection of the myocardium against an energy disequilibrium that could be potentially harmful for the heart. Hypoxia induces a peripheral vasodilation and a pulmonary vasoconstriction, leading to few changes in systemic blood pressure and an increase in pulmonary blood pressure (PHT) that can contribute to a high altitude pulmonary edema. Advice to a cardiac patient who plans to go to high altitude should take into account that all diseases aggravated by increased adrenergic activity or associated with a PHT or a hypoxemia (right-to-left shunt) will be aggravated at high altitude. As altitude increases, a patient with a coronary disease will present an ischemic threshold for a lower power output during an EKG exercise test. The only test allowing predicting the tolerance to high altitude is the hypoxia exercise test realized at 30% of maxVO(2)and at an equivalent altitude of 4,800m.

Uncommon Causes of Hemodynamic Instability During Myocardial Revascularization without Cardiopulmonary Bypass

Myocardial revascularization (MR) in patients with ventricular hypertrophy and/or dysfunction is frequently performed without cardiopulmonary bypass (CB), since it can be difficult to wean those patients off CB. Intraoperative control demands strict hemodynamic adjustment, as well as partial clamping of the aorta to minimize hemodynamic changes. The objective of this study was to report two cases of hemodynamic instability during MR without CB after partial clamping of the aorta. The first case is a female patient, whose aortic diameter was slightly reduced (2.8 cm); the second case refers to a patient with left ventricular ejection fraction (LVEF) of 24% on the echocardiogram. In both cases, significant hypotension and increase in pulmonary blood pressure were observed immediately after clamping of the aorta. The surgical teams were informed of the problem, and in both cases the hemodynamic instability was reverted after unclamping of the aorta. Afterwards, smaller areas of the aorta were clamped and proximal anastomoses were performed without intercurrence. Although cardiac manipulation and changes in ventricular preload represent the most common causes of hemodynamic instability during MR without CB, in the cases presented here, hypotension and pulmonary hypertension were most likely secondary to a reduction in cardiac output due to the increase in afterload in patients with a relatively small aortic diameter or ventricular dysfunction even with partial clamping. Adequate intraoperative monitoring and immediate correction of the hemodynamic changes can minimize surgical morbidity and mortality.

Function of the serotonin 5-hydroxytryptamine 2B receptor in pulmonary hypertension.

Primary pulmonary hypertension is a progressive and often fatal disorder in humans that results from an increase in pulmonary blood pressure associated with abnormal vascular proliferation. Dexfenfluramine increases the risk of pulmonary hypertension in humans, and its active metabolite is a selective serotonin 5-hydroxytryptamine 2B (5-HT(2B)) receptor agonist. Thus, we investigated the contribution of the 5-HT(2B)receptor to the pathogenesis of pulmonary hypertension. Using the chronic-hypoxic-mouse model of pulmonary hypertension, we found that the hypoxia-dependent increase in pulmonary blood pressure and lung remodeling are associated with an increase in vascular proliferation, elastase activity and transforming growth factor-beta levels, and that these parameters are potentiated by dexfenfluramine treatment. In contrast, hypoxic mice with genetically or pharmacologically inactive 5-HT(2B)receptors manifested no change in any of these parameters. In both humans and mice, pulmonary hypertension is associated with a substantial increase in 5-HT(2B) receptor expression in pulmonary arteries. These data show that activation of 5-HT(2B) receptors is a limiting step in the development of pulmonary hypertension.

Reversal of chronic hypoxia-induced alterations in pulmonary artery smooth muscle electromechanical coupling upon air breathing.

Chronic hypoxia (CH) induces selective pulmonary hypertension which is accompanied by structural and functional alterations in the pulmonary vasculature. Little information is available on the regression of CH-induced functional alterations of pulmonary wall. In the present work, we investigated the reversal of CH-induced pulmonary hypertension with a special focus on alterations in the electrophysiological properties of pulmonary artery smooth muscle cells (PAMCs) after normoxia recovery. Rats were exposed to a hypobaric environment for 3 weeks (CH rats) and then subjected to a normoxic environment for 3 weeks (normoxia-recovery group) and compared with rats maintained in a normoxic environment (control rats). Electrophysiological properties of PAMCs were studied using conventional microelectrodes and patch-clamp technique. CH rats exhibited a threefold increase in pulmonary blood pressure compared to control rats and this increase was fully reversed following 3 weeks of normoxia. PAMCs from CH rats were depolarised (about 20 mV), had an elevated calcium concentration and exhibited a hypersensitivity to 4-aminopyridine (4-AP) of membrane potential as well as the tone of arterial rings compared with tissues from control rats. Whole cell patch-clamp recordings indicated that voltage gated potassium channel currents I(Kv) and I(K(N)) were decreased in PAMCs from CH rats with a hyper sensitivity of I(K(N)) to 4-AP. CH-induced alterations in electrophysiological properties of PAMCs were also fully reversed after 3 weeks of normoxia recovery. Both the increase in the pulmonary blood pressure and alterations in electrophysiological properties of PASMCs simultaneously reverse after normoxia recovery. This complete reversibility of all of the CH-induced pulmonary vascular alterations suggests that curative treatments for PAHT may now be designed aimed at targeting the very limited key factors implicated in hypoxia sensing.

Reflex circulatory collapse following intrapulmonary entrapment of activated platelets: mediation via 5‐HT3 receptor stimulation

1. The role of 5-HT2 and 5-HT3 receptors in the mediation of direct and reflex vascular responses to intrapulmonary platelet activation was investigated. 2. Anaesthetized rabbits were challenged intravenously with an emulsion of autologous bone marrow that produced a sharp increase in pulmonary blood pressure, a fall in systemic blood pressure, platelet consumption and death. 3. Platelet depletion before the challenge nearly abolished all the cardiovascular effects and prevented death. Bilateral vagotomy prevented the fall in systemic blood pressure and death but did no prevent the increase in pulmonary pressure. The intravenous administration of the 5-HT2 antagonist, ketanserin, only reduced the increase in pulmonary pressure without affecting the systemic response or mortality. 4. The effects of intravenous 5-HT and of electrical stimulation of the cephalic ends of the cut vagi nerves were also explored. 5-HT injection increased the pulmonary vascular pressure but its effects on systemic blood pressure were variable. These response were modified by the 5-HT antagonists in a manner that resembles their effects on bone marrow embolism. Afferent vagal stimulation produced a fall in systemic blood pressure that was not prevented by MDL-7222. 5. This study indicates that a centrally mediated reduction of peripheral vascular tone is the cause of the potentially lethal circulatory collapse that follows the intrapulmonary entrapment of activated platelets. This reflex is initiated by the action of 5-HT on 5-HT3 receptors in the lung.

Contribution a l'étude du type et de la répartition des apnées au cours du syndrome de Pickwick

The authors report a polygraphic study of apneic episodes and nocturnal sleep in 12 patients presenting a Joe or Burwell type of Pickwickian syndrome. The parameters studied were : electrical and behavioural concomitants of sleep, thoracic and abdominal movements, pressure of expired O 2 and CO 2 , mean and systolic-diastolic pulmonary arterial pressures (PAP), systemic blood pressures and blood gas levels. Apneic episodes which occur from the onset of sleep are a determining feature in the diagnosis and evolution of the disease. The episodes were identified as central or peripheral and if the latter their obstructive nature was confirmed. The presence or absence of alveolar hypoventilation does not dictate the occurrence of sleep onset or apneic episodes. For each patient respiratory arrest always occurs at the same point of either inspiration or expiration of the tidal volume ; the haemodynamic effects of the two types differ fundamentally. Expiratory apnoea is accompanied by a sudden increase in pulmonary and systemic blood pressure which is rapidly corrected when respiration resumes ; inspiratory apnoea causes a post-apneic increase in pulmonary blood pressure which is still completely corrected when a further apneic episode follows : hence there is a progressive increase in PAP during sleep. The development towards cardio-respiratory insufficiency seems to occur particularly early in patients with inspiratory apnoea. The comparative study of the various stages in development of these disorders reveals the existence of unmanifested (undeclared/covert) Pickwick syndromes. Die Autoren berichten über eine polygraphische Studie der Apnoepausen und des Nachtschalfs bei 12 Kranken mit einem Pickwick-Syndrom vom Typ Joe oder Burwell unter Registrierung folgender Parameter : Elektrische und Verhaltenskomponenten im Schlaf, Thorakogramm, abdominale Atemex kursionen, exspiratorischer O 2 und CO 2 -Druck, systolisch-diastolische Drucke der Arteria pulmonalis sowie Mitteldruck (PAP), arterieller Blutdruck und Blutgaswerte. Die bereits zu Beginn des Einschlafvorgangs auftretenden Apnoepausen geben entscheidende diagnostische und prognostiche Hinweise. Die zentrale oder periphere Natur der Apnoe wurde erneut festgestellt und bei letzterem Typ ihre obstruktive Natur bestätigt. Die Schlafneigung sowie das Auftreten von Apnoepausen hängen nicht davon ab, ob eine alveoläre Hypoventilation vorliegt oder nicht. Beim gleichen Kranken tritt der Atemstillstand immer in der gleichen inspiratorischen oder exspiratorischen Position ein ; dabei sind die hämodynamischen Folgen grundlegend verschieden. Die exspiratorische Apnoe wird von einem raschen Anstieg des Pulmonalis-und arteriellen Blucdrucks begleitet, der rasch nach Wiederaufnahme der Atemtätigkeit korrigiert wird ; die inspiratorische Apnoe führt zu einem post-apnoischen Anstieg des Pulmonalisdrucks, der noch nicht vollständig korrigiert ist, wenn eine erneute Apnoepause eintritt ; daher findet sich eine fortschreitende Zunahme des PAP im Schlaf. Die Entwicklung einer kardio-respiratorichen Insuffizienz scheint bei Patienten mit inspiratorischen Apnoepausen besonders früh einzutreten. Die vergleichende Untersuchung verschiedener Entwicklungsstadien bezieht die Existenz frustraner Formen des Pickwick-Syndroms ein.

Die Wirkung von Aminorex (Menocil�) auf die H�modynamik des kleinen und gro�en Kreislaufs bei i.v. Darreichung am Hund

The effects of a single i.v. injection or infusion of Aminorex (2-amino-5-phenyl-2-oxazoline-fumarate) on blood pressure, blood flow, and haemodynamic resistance of the pulmonary and femoral arteries were investigated in anaesthetized dogs and compared with those of Norepinephrine. The following results were obtained: 1. Aminorex (dose-range between 10 and 160 μg/kg i.v.) caused a transient increase in the mean blood pressure of the pulmonary artery and in the mean pulmonary perfusion pressure (Part. pulm. - Pleft atrium). At the same time the pulmonary blood flow fell by 10–20%. A dose-dependent increase in the vascular resistance of the pulmonary vessels was observed in all experiments. The effects lasted for 20 to 60 min, according to the dose. Isoproterenol (1,0 μg/kg i.v.) led to a fall in the pulmonary vascular resistance and abolished the resistance increase following the Aminorex-administration. 2. An i.v. infusion of Aminorex (dose-range between 5 and 50 μg/kg/min) led to an increase in pulmonary blood pressure and vascular resistance. At the same time a slight decrease in heart rate and pulmonary blood flow was obtained. These pulmonary haemodynamic changes reached their maximum 15 min after the onset of the infusion and remained constant during the whole period of an infusion lasting 40 min. After discontinuing the infusion the pressure and resistance values returned only partially to the preinfusion values. 3. An infusion of 10 μg/kg/min Aminorex led to an increase in the blood pressure of the systemic circulation and in the total peripheral vascular resistance. Both changes were less marked when compared with the simultaneously occurring effects on the pulmonary haemodynamics. At the same time the blood flow in the femoral artery was diminished to a greater degree than in the pulmonary artery. As a result of the observed flow- and pressure changes in the pulmonary and femoral arteries the influence of an Aminorex-infusion on the haemodynamic resistance of both vessels was identical with regard to the time course and the intensity of the observed effects. 4. Pretreatment with Phentolamine abolished the effects of an infusion of 10 μg/kg/min Aminorex on pulmonary blood pressure and vascular resistance, whereas pretreatment with Propranolol enhanced these effects. 5. Following an i.v. infusion of 0.5 μg/kg/mm Norepinephrine pulmonary blood pressure and vascular resistance rose only transiently, whereas the pulmonary blood flow decreased at the same time, due to an initial fall in heart rate. These initial changes did not last in spite of a continued Norepinephrine infusion. 6. The effects of Norepinephrine on the systemic blood pressure were more pronounced than those on the pulmonary blood pressure. As a consequence, the increase in the work done by the left ventricle was greater than the increase in the work done by the right ventricle. In contrast, the increase in blood pressure and vascular resistance caused by Aminorex was more pronounced in the pulmonary circulation and therefore the right ventricular work increased more than the left ventricular work.