Prostaglandin I2 signaling prevents angiotensin II-induced atrial remodeling and vulnerability to atrial fibrillation in mice.

Atrial fibrillation (AF) is the most common arrhythmia, and atrial fibrosis is a pathological hallmark of structural remodeling in AF. Prostaglandin I2 (PGI2) can prevent the process of fibrosis in various tissues via cell surface Prostaglandin I2 receptor (IP). However, the role of PGI2 in AF and atrial fibrosis remains unclear. The present study aimed to clarify the role of PGI2 in angiotensin II (Ang II)-induced AF and the underlying molecular mechanism. PGI2 content was decreased in both plasma and atrial tissue from patients with AF and mice treated with Ang II. Treatment with the PGI2 analog, iloprost, reduced Ang II-induced AF and atrial fibrosis. Iloprost prevented Ang II-induced atrial fibroblast collagen synthesis and differentiation. RNA-sequencing analysis revealed that iloprost significantly attenuated transcriptome changes in Ang II-treated atrial fibroblasts, especially mitogen-activated protein kinase (MAPK)-regulated genes. We demonstrated that iloprost elevated cAMP levels and then activated protein kinase A, resulting in a suppression of extracellular signal-regulated kinase1/2 and P38 activation, and ultimately inhibiting MAPK-dependent interleukin-6 transcription. In contrast, cardiac fibroblast-specific IP-knockdown mice had increased Ang II-induced AF inducibility and aggravated atrial fibrosis. Together, our study suggests that PGI2/IP system protects against atrial fibrosis and that PGI2 is a therapeutic target for treating AF.The prospectively registered trial was approved by the Chinese Clinical Trial Registry. The trial registration number is ChiCTR2200056733. Data of registration was 2022/02/12.

Inhaled iloprost in off-pump coronary artery bypass surgery: a randomized controlled trial.

PURPOSE: Mechanical cardiac constraint during off-pump coronary artery bypass surgery (OPCAB) causes right ventricle (RV) compression and increased pulmonary artery pressure (PAP), which may further compromise RV dysfunction. We aimed to assess the effect of inhaled iloprost, a potent selective pulmonary vasodilator, on the cardiac index (CI) during mechanical constraint. The secondary aim was to determine the resultant changes in the hemodynamic and respiratory parameters. METHODS: A total of 100 adult patients with three-vessel coronary artery disease who had known risk factors for hemodynamic instability (congestive heart failure, mean PAP ≥ 25 mm Hg, RV systolic pressure ≥ 50 mm Hg on preoperative echocardiography, left ventricular ejection fraction < 50%, myocardial infarction within one month of surgery, redo surgery, and left main disease) were enrolled in a randomized controlled trial. The patients were randomly allocated to the control or iloprost groups at a 1:1 ratio, in which saline and iloprost (20 µg) were inhaled for 15 min after internal mammary artery harvesting, respectively. Cardiac index was measured by pulmonary artery catheterization. RESULTS: There were no significant intergroup differences in CI during grafting (P = 0.36). The mean PAP had a significant group-time interaction (P = 0.04) and was significantly lower in the iloprost group at circumflex grafting (mean [standard deviation], 26 [3] mm Hg vs 24 [3] mm Hg; P = 0.01). The remaining hemodynamic parameters were similar between the groups. CONCLUSION: Inhaled iloprost showed a neutral effect on hemodynamic parameters, including the CI and pulmonary vascular resistance index, during OPCAB. TRIAL REGISTRATION: ClinicalTrials.gov (NCT04598191); first submitted 12 October 2020.

RéSUMé: OBJECTIF: La contrainte cardiaque mécanique lors d'un pontage aortocoronarien à cœur battant (OPCAB) provoque une compression du ventricule droit (VD) et une augmentation de la pression artérielle pulmonaire (PAP), ce qui peut compromettre davantage le dysfonctionnement du VD. Notre objectif était d'évaluer l'effet de l'iloprost inhalé, un puissant vasodilatateur pulmonaire sélectif, sur l'index cardiaque (IC) au cours de la contrainte mécanique. L'objectif secondaire était de déterminer les modifications résultantes des paramètres hémodynamiques et respiratoires. MéTHODE: Au total, 100 patient·es adultes atteint·es d'une coronaropathie à trois vaisseaux qui présentaient des facteurs de risque connus d'instabilité hémodynamique (insuffisance cardiaque congestive, PAP moyenne ≥ 25 mm  Hg, pression systolique du VD ≥ 50 mm Hg à l'échocardiographie préopératoire, fraction d'éjection ventriculaire gauche < 50 %, infarctus du myocarde dans le mois précédant la chirurgie, chirurgie de reprise et maladie principale gauche) ont été inclus·es dans une étude randomisée contrôlée. Les patient·es ont été réparti·es au hasard dans les groupes témoin ou iloprost dans un rapport de 1:1, dans lequel la solution saline et l'iloprost (20 µg) ont été inhalés pendant 15 minutes après le prélèvement de l'artère mammaire interne, respectivement. L'indice cardiaque a été mesuré par cathétérisme de l'artère pulmonaire. RéSULTATS: Il n'y a eu aucune différence significative entre les groupes en matière d'IC pendant le pontage (P = 0,36). La PAP moyenne présentait une interaction significative groupe-temps (P = 0,04) et était significativement plus faible dans le groupe iloprost au pontage de l'artère circonflexe (moyenne [écart type], 26 [3] mm Hg vs 24 [3] mm Hg; P = 0,01). Les autres paramètres hémodynamiques étaient similaires entre les groupes. CONCLUSION: L'iloprost inhalé a montré un effet neutre sur les paramètres hémodynamiques, y compris sur l'IC et l'indice de résistance vasculaire pulmonaire, pendant un pontage aortocoronarien à cœur battant. ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov (NCT04598191); soumis pour la première fois le 12 octobre 2020.

Effective control of refractory pulmonary hypertension with iloprost inhalation in an infant with congenital absence of the right pulmonary artery: a case report.

Unilateral absence of the pulmonary artery is a rare congenital cardiovascular anomaly that can lead to pulmonary hypertension and poor outcomes. We report the case of a 1-month-old infant with isolated unilateral absence of the pulmonary artery and severe pulmonary hypertension on the right and left sides, respectively. The patient was unresponsive to multiple medications for pulmonary hypertension, and surgical revascularisation was unfeasible. However, iloprost inhalation was effective.

BK Channels in Tail Artery Vascular Smooth Muscle Cells of Normotensive (WKY) and Hypertensive (SHR) Rats Possess Similar Calcium Sensitivity But Different Responses to the Vasodilator Iloprost.

It has been reported that, in the spontaneously hypertensive rat (SHR) model of hypertension, different components of the G-protein/adenylate cyclase (AC)/Calcium-activated potassium channel of high conductance (BK) channel signaling pathway are altered differently. In the upstream part of the pathway (G-protein/AC), a comparatively low efficacy has been established, whereas downstream BK currents seem to be increased. Thus, the overall performance of this signaling pathway in SHR is elusive. For a better understanding, we focused on one aspect, the direct targeting of the BK channel by the G-protein/AC pathway and tested the hypothesis that the comparatively low AC pathway efficacy in SHR results in a reduced agonist-induced stimulation of BK currents. This hypothesis was investigated using freshly isolated smooth muscle cells from WKY and SHR rat tail artery and the patch-clamp technique. It was observed that: (1) single BK channels have similar current-voltage relationships, voltage-dependence and calcium sensitivity; (2) BK currents in cells with a strong buffering of the BK channel activator calcium have similar current-voltage relationships; (3) the iloprost-induced concentration-dependent increase of the BK current is larger in WKY compared to SHR; (4) the effects of activators of the PKA pathway, the catalytic subunit of PKA and the potent and selective cAMP-analogue Sp-5,6-DCl-cBIMPS on BK currents are similar. Thus, our data suggest that the lower iloprost-induced stimulation of the BK current in freshly isolated rat tail artery smooth muscle cells from SHR compared with WKY is due to the lower efficacy of upstream elements of the G-Protein/AC/BK channel pathway.

Thrombospondin-1 promotes hemostasis through modulation of cAMP signaling in blood platelets.

Thrombospondin-1 (TSP-1) is released by platelets upon activation and can increase platelet activation, but its role in hemostasis in vivo is unclear. We show that TSP-1 is a critical mediator of hemostasis that promotes platelet activation by modulating inhibitory cyclic adenosine monophosphate (cAMP) signaling. Genetic deletion of TSP-1 did not affect platelet activation in vitro, but in vivo models of hemostasis and thrombosis showed that TSP-1-deficient mice had prolonged bleeding, defective thrombosis, and increased sensitivity to the prostacyclin mimetic iloprost. Adoptive transfer of wild-type (WT) but not TSP-1-/- platelets ameliorated the thrombotic phenotype, suggesting a key role for platelet-derived TSP-1. In functional assays, TSP-1-deficient platelets showed an increased sensitivity to cAMP signaling, inhibition of platelet aggregation, and arrest under flow by prostacyclin (PGI2). Plasma swap experiments showed that plasma TSP-1 did not correct PGI2 hypersensitivity in TSP-1-/- platelets. By contrast, incubation of TSP-1-/- platelets with releasates from WT platelets or purified TSP-1, but not releasates from TSP-1-/- platelets, reduced the inhibitory effects of PGI2. Activation of WT platelets resulted in diminished cAMP accumulation and downstream signaling, which was associated with increased activity of the cAMP hydrolyzing enzyme phosphodiesterase 3A (PDE3A). PDE3A activity and cAMP accumulation were unaffected in platelets from TSP-1-/- mice. Platelets deficient in CD36, a TSP-1 receptor, showed increased sensitivity to PGI2/cAMP signaling and diminished PDE3A activity, which was unaffected by platelet-derived or purified TSP-1. This scenario suggests that the release of TSP-1 regulates hemostasis in vivo through modulation of platelet cAMP signaling at sites of vascular injury.

Comparison of various treatment modalities for the management of bone marrow edema syndrome/transient osteoporosis in men and non-pregnant women: a systematic review.

Transient osteoporosis (TO) or bone marrow edema syndrome (BMES) is a self-limited clinical condition, which affects middle-aged men and women. It can be treated with miscellaneous conservative and surgical measures, which are analyzed in this systematic review. INTRODUCTION: BMES/TO is a transient clinical entity, which can be treated with various therapeutic modalities. The aim of our study was to assess the efficacy of different therapeutic options for the alleviation of pain and reduction of bone marrow edema (BME) in patients with BMES/TO, as well as to propose a therapeutic algorithm. METHODS: PubMed, Scopus, Cochrane, and Google Scholar were searched. Eligibility and extraction of studies were conducted by two authors. Methodological quality assessment was carried out with the modified Delphi technique, Methodological Index for Non-Randomized Studies (MINORS) criteria, and Cochrane Collaboration's risk of bias tool. Outcomes that were compared were time of pain resolution, VAS pain scores, and BME regression on magnetic resonance imaging (MRI). RESULTS: A total of 36 articles (880 patients) were included. Bisphosphonates had higher efficiency in less than 1-month outcomes on pain resolution compared with core decompression (CD), while iloprost was more efficient at 1-3 months compared with bisphosphonates and CD. At 3-6 months, all three of the aforementioned showed equal results on pain resolution, and at a period of 6-12 months, CD and extracorporeal shockwave therapy (ESWT) showed excellent results followed by bisphosphonates and the conservative group (CG) consisting of non-steroidal anti-inflammatory drugs (NSAIDs) and/or analgesics and/or restricted weight bearing. On MRI at 1-3 months, bisphosphonates, iloprost, and CD had relatively the same outcomes on BME resolution, with the least promising being the CG. At 3-6 months, CD seemed to have achieved the best results on the resolution of BME, followed by ESWT, CG, and bisphosphonates group. At 6-12 months, ESWT had the best outcomes compared with the conservative, bisphosphonates, and iloprost groups. CONCLUSION: BMES/TO has been treated with many non-standardized measures due to the low number of highly reliable studies. Current literature shows promising results with regard to the reduction of the clinical course of BMES/TO, but further large multicenter randomized controlled trials, as well as standardized radiological and clinical scores, are warranted to acquire evidence-based recommendations on the therapeutic algorithm.

A review of the development of gangrene in patients with systemic lupus erythematosus - A 44-year follow-up study.

OBJECTIVES: This review addresses the question of what happens long-term to those systemic lupus erythematosus (SLE) patients who develop gangrene. It also seeks to find common clinical and serological features, risk factors and triggers and how best to manage this challenging complication. METHODS: We reviewed 850 patients with SLE attending a UK tertiary referral center, followed up over 44 years, assessing their demographics, clinical and serological features, treatment in the acute phase, their long-term outcome and long-term management. RESULTS: Ten out of 850 patients (1.2%) developed gangrene; the mean age of onset was 17 years (range 12-26 years) Eight out of 10 patients had a single episode of gangrene. One of the other two was not willing to have anticoagulation. The first episode of gangrene ranged from presentation to 32 years after SLE onset, mean duration of SLE at the onset of the gangrene was 18.5 years SD 11.5 years. Anti-phospholipid (PL) antibodies were over-represented in the patients with gangrene. All had active SLE at the time the gangrene developed. All patients were treated with intravenous (IV) iloprost infusions, and the antiphospholipid-antibody positive patients were anti-coagulated, most staying on long term anticoagulation. Underlying possible triggers were treated appropriately. Two patients who did not respond to the initial treatment needed further immunosuppression. All patients suffered digit loss. CONCLUSION: Although rare, gangrene is a sinister, potentially late developing complication of SLE, it rarely recurs. It is associated with anti-phospholipid antibodies, active disease, and other possible triggers such as infection and cancer. Anticoagulation therapy, steroids and iloprost, and further immunosuppression may be needed to stop the evolution of gangrene.

Kinetics of response to iloprost evaluated by laser speckle contrast analysis in systemic sclerosis.

OBJECTIVE: Iloprost (ILO) is recommended for the treatment of systemic sclerosis (SSc) microangiopathy, but there is no common consensus on its optimal dosage. The aim of this study is to evaluate the kinetics of response to ILO administered in a daily outpatient scheme in SSc subjects using laser speckle contrast analysis (LASCA). METHOD: Adult SSc patients in stable therapy with ILO administered for 6 h for 2 consecutive days every 4 weeks were enrolled. Peripheral finger perfusion was assessed by LASCA. Each patient underwent five LASCA evaluations: before and after each day of ILO (D1pre, D1post, D2pre, and D2post) and after 4 weeks (D30). RESULTS: Twenty-seven SSc patients (77.8% female, mean age 61.5 years) were enrolled. LASCA showed an increase in perfusion at the end of each ILO course, but on the second day (both D1pre vs D2pre and D2pre vs D2post) the increase was no longer significant in half of the fingers. Moreover, compared to D1post, at the beginning of the second ILO day most of the fingers had already shown a significant reduction in perfusion. After 1 month, there were no statistically significant differences between the perfusion values of D1pre and D30. CONCLUSION: This LASCA study highlights the transience of the vasoactive effect of ILO, with a perfusion benefit that is completely lost after 1 month. The brevity of the perfusion effect of ILO and the use of LASCA are elements to consider in the design of future SSc trials to determine the optimal ILO dosage.

Impact of pharmacological interventions on intrapulmonary shunt during one-lung ventilation in adult thoracic surgery: a systematic review and component network meta-analysis.

BACKGROUND: Intrapulmonary shunt is a major determinant of oxygenation in thoracic surgery under one-lung ventilation. We reviewed the effects of available treatments on shunt, Pao2/FiO2 and haemodynamics through systematic review and network meta-analysis. METHODS: Online databases were searched for RCTs comparing pharmacological interventions and intrapulmonary shunt in thoracic surgery under one-lung ventilation up to March 30, 2022. Random-effects (component) network meta-analysis compared 24 treatments and 19 treatment components. The Confidence in Network Meta-Analysis (CINeMA) framework assessed evidence certainty. The primary outcome was intrapulmonary shunt fraction during one-lung ventilation. RESULTS: A total of 55 RCTs were eligible for systematic review (2788 participants). The addition of N2O (mean difference [MD]=-15%; 95% confidence interval [CI], -25 to -5; P=0.003) or almitrine (MD=-13%; 95% CI, -20 to -6; P<0.001) to propofol anaesthesia were efficient at decreasing shunt. Combined epidural anaesthesia (MD=3%; 95% CI, 1-5; P=0.005), sevoflurane (MD=5%; 95% CI, 2-8; P<0.001), isoflurane (MD=6%; 95% CI, 4-9; P<0.001), and desflurane (MD=9%; 95% CI, 4-14; P=0.001) increased shunt vs propofol. Almitrine (MD=147 mm Hg; 95% CI, 58-236; P=0.001), dopexamine (MD=88 mm Hg; 95% CI, 4-171; P=0.039), and iloprost (MD=81 mm Hg; 95% CI, 4-158; P=0.038) improved Pao2/FiO2. Certainty of evidence ranged from very low to moderate. CONCLUSIONS: Adding N2O or almitrine to propofol anaesthesia reduced intrapulmonary shunt during one-lung ventilation. Halogenated anaesthetics increased shunt in comparison with propofol. The effects of N2O, iloprost, and dexmedetomidine should be investigated in future research. N2O results constitute a research hypothesis currently not backed by any direct evidence. The clinical availability of almitrine is limited. SYSTEMATIC REVIEW PROTOCOL: PROSPERO CRD42022310313.

The perioperative use of inhaled prostacyclins in cardiac surgery: a systematic review and meta-analysis.

PURPOSE: Perioperative pulmonary hypertension (PH) is an independent risk factor for morbidity and mortality in cardiac surgery. While inhaled prostacyclins (iPGI2s) are an established treatment of chronic PH, data on the efficacy of iPGI2s in perioperative PH are scarce. METHODS: We searched PubMed, Embase, the Web of Science, CENTRAL, and the grey literature from inception until April 2021. We included randomized controlled trials investigating the use of iPGI2s in adult and pediatric patients undergoing cardiac surgery with an increased risk of perioperative right ventricle failure. We assessed the efficacy and safety of iPGI2s compared with placebo and other inhaled or intravenous vasodilators with random-effect meta-analyses. The primary outcome was mean pulmonary artery pressure (MPAP). Secondary outcomes included other hemodynamic parameters and mortality. RESULTS: Thirteen studies were included, comprising 734 patients. Inhaled prostacyclins significantly decreased MPAP compared with placebo (standardized effect size, 0.46; 95% confidence interval [CI], 0.11 to 0.87; P = 0.01) and to intravenous vasodilators (1.26; 95% CI, 0.03 to 2.49; P = 0.045). Inhaled prostacyclins significantly improved the cardiac index compared with intravenous vasodilators (1.53; 95% CI, 0.50 to 2.57; P = 0.004). In contrast, mean arterial pressure was significantly lower in patients treated with iPGI2s vs placebo (-0.39; 95% CI, -0.62 to 0.16; P = 0.001), but higher than in patients treated with intravenous vasodilators (0.81; 95% CI, 0.29 to 1.33; P = 0.002). With respect to hemodynamics, iPGI2s had similar effects as other inhaled vasodilators. Mortality was not affected by iPGI2s. CONCLUSION: The results of this systematic review and meta-analysis show that iPGI2s improved pulmonary hemodynamics with similar efficacy as other inhaled vasodilators, but caused a significant small decrease in arterial pressure when compared with placebo, indicating spill-over into the systemic circulation. These effects did not affect clinical outcomes. STUDY REGISTRATION DATE: PROSPERO (CRD42021237991); registered 26 May 2021.

RéSUMé: OBJECTIF: L'hypertension pulmonaire (HTAP) périopératoire est un facteur de risque indépendant de morbidité et de mortalité en chirurgie cardiaque. Bien que l'inhalation de prostacyclines (iPGI2) constitue un traitement établi de l'HTAP chronique, les données sur l'efficacité de ce traitement en cas d'HTAP périopératoire sont rares. MéTHODE: Nous avons effectué des recherches dans les bases de données PubMed, Embase, Web of Science, CENTRAL et dans la littérature grise depuis leur création jusqu'en avril 2021. Nous avons inclus des études randomisées contrôlées portant sur l'utilisation de l'iPGI2 chez la patientèle adulte et pédiatrique bénéficiant d'une chirurgie cardiaque avec un risque accru d'insuffisance ventriculaire droite périopératoire. Nous avons évalué l'efficacité et l'innocuité des iPGI2 par rapport à un placebo et à d'autres vasodilatateurs inhalés ou intraveineux avec des méta-analyses à effets aléatoires. Le critère d'évaluation principal était la pression artérielle pulmonaire moyenne (PAPm). Les critères d'évaluation secondaires incluaient d'autres paramètres hémodynamiques et la mortalité. RéSULTATS: Treize études portant sur 734 patient·es ont été incluses. Les prostacyclines inhalées ont diminué de manière significative la PAPm par rapport au placebo (taille d'effet standardisée, 0,46; intervalle de confiance [IC] à 95 %, 0,11 à 0,87; P = 0,01) et aux vasodilatateurs intraveineux (1,26; IC 95 %, 0,03 à 2,49; P = 0,045). Les prostacyclines inhalées ont significativement amélioré l'index cardiaque par rapport aux vasodilatateurs intraveineux (1,53; IC 95 %, 0,50 à 2,57; P = 0,004). En revanche, la pression artérielle moyenne était significativement plus faible chez les patient·es traité·es par iPGI2 vs placebo (−0,39; IC 95 %, −0,62 à 0,16; P = 0,001), mais plus élevée que chez les personnes traitées par vasodilatateurs intraveineux (0,81; IC 95 %, 0,29 à 1,33; P = 0,002). En ce qui concerne l'hémodynamie, les iPGI2 ont eu des effets similaires à ceux des autres vasodilatateurs inhalés. La mortalité n'a pas été affectée par les iPGI2. CONCLUSION: Les résultats de cette revue systématique et méta-analyse montrent que les iPGI2 ont amélioré l'hémodynamie pulmonaire avec une efficacité similaire à celle des autres vasodilatateurs inhalés, mais ont entraîné une diminution légère mais significative de la pression artérielle par rapport au placebo, indiquant un débordement dans la circulation systémique. Ces effets n'ont pas affecté les résultats cliniques. ENREGISTREMENT DE L'éTUDE: PROSPERO (CRD42021237991); enregistrée le 26 mai 2021.

Incidence of Bloodstream Infection in Patients with Pulmonary Hypertension under Intravenous Epoprostenol or Iloprost-A Multicentre, Retrospective Study.

Intravenous synthetic prostacyclin analogs (iPCAs), such as epoprostenol, treprostinil and iloprost have been widely used for the treatment of pulmonary arterial hypertension (PAH). Despite having good outcomes, continuous infusion of iPCAs has been associated with some adverse effects. Bloodstream infection (BSI) is one of the most severe complications, although poorly recognized, especially under iloprost administration, which few studies have addressed. This study aimed to compare the BSI incidence rates between intravenous iloprost and epoprostenol administration. Patients with pulmonary hypertension (PH) functional class III or IV receiving intravenous iloprost or epoprostenol through Hickman catheter, between 2004 and 2019, were retrospectively selected from two PH treatment centers. From a total of 36 patients (13 for iloprost and 23 for epoprostenol), 75% (n = 27) fulfilled the PAH criteria, mainly belonging to the idiopathic group. Overall BSI rate was 1.5/1000 days of treatment (3.38 and 0.09/1000 days for iloprost and epoprostenol, respectively). Patients receiving iloprost were at a higher risk of developing BSI than those receiving epoprostenol (HR: 12.5; 95% CI: 1.569-99.092). A higher mortality rate from BSI was also identified in the iloprost group (p = 0.04). Twenty-seven patients developed BSI, with 92% of them requiring hospitalization. A total of 29 agents were found, 10 Gram-positive (mainly Staphylococcus aureus; n = 5) and 19 Gram-negative (mainly Pseudomonas aeruginosa; n = 6) bacteria. Iloprost administration was linked to a significantly higher incidence of BSI, worse prognosis, and more BSI-related deaths than epoprostenol. BSI due to Gram-negative, commensal, low-virulence bacteria was also higher in the iloprost group. In short, physicians should be aware when prescribing iPCA to guarantee their patients' safety and best medical care.

Congenital Isolated Unilateral Agenesis of Pulmonary Arteries with 3-Year Follow-Up after Initiation of Treatment.

Background and objective: Unilateral agenesis of pulmonary arteries (UAPA) is a rare disease, with approximately 400 cases reported to date. UAPA is often associated with congenital heart disease, and the uncomplicated form is isolated UAPA, which accounts for approximately 30% of all cases of UAPA. The incidence of pulmonary hypertension due to UAPA has been reported to range from 19 to 44%. There is no consensus treatment for pulmonary hypertension associated with UAPA. We present the first reported case in which a three-drug combination, comprising of iloprost inhalation, riociguat, and ambrisentan, was administered to a patient with UAPA, and was followed-up for 3 years post-diagnosis. Case presentation: A 68-year-old Japanese woman presented to our hospital with dyspnea and chest discomfort. She underwent chest radiography, blood tests, and echocardiography; however, the cause of the patient's symptoms could not be identified. During regular follow-up, an echocardiography 21 months after the initial visit revealed elevated right ventricular pressure (peak tricuspid regurgitation velocity: 5.2 m/s and right ventricular systolic pressure: 120 mmHg) and a diagnosis of pulmonary hypertension was made. Contrast-enhanced computed tomography (CT) of the chest and a pulmonary blood flow scintigram were performed to investigate the cause of pulmonary hypertension, and isolated UAPA was diagnosed. The patient was treated with a three-drug combination of iloprost inhalation, riociguat, and ambrisentan and followed up for 3 years with good therapeutic outcomes. Conclusions: We present a case of pulmonary hypertension caused by isolated UAPA. Although rare, this disease can lead to pulmonary hypertension and should be treated cautiously. While there is no consensus regarding the treatment of this disease, a three-drug combination of iloprost inhalation, riociguat, and oral ambrisentan proved effective.

Combinatory lung tumor inhibition by myo-inositol and iloprost/rapamycin: association with immunomodulation.

Although both preclinical and clinical studies have suggested that myo-inositol (MI) may be a safe and effective lung cancer chemopreventive agent, its efficacy is moderate. To test whether the chemopreventive agents iloprost (IL) or rapamycin enhance the lung tumor inhibitory effects of MI, A/J mice were treated with the tobacco smoke carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and, beginning one week after the end of NNK treatment, given MI, IL, rapamycin, MI + IL or MI + rapamycin for 17 weeks. Analyses of the number and size of tumors on the surface of the lung have indicated that MI, IL, rapamycin, MI + IL and MI + rapamycin reduced the multiplicity of NNK-induced lung tumors by 41, 34, 46, 79 and 67%, respectively, and larger tumors (lung tumors with a diameter of 1-2 or >2 mm) were absent in the MI + IL and MI + rapamycin groups. These results clearly indicated that MI + IL and MI + rapamycin are more effective than MI alone in inhibiting the formation and growth of lung tumors. Assessment of the immunomodulatory effects of the drugs showed that whereas MI + rapamycin and MI + IL increased the infiltration of lung tumors by CD4+ and CD8+ T cells, MI + rapamycin reduced the expression of the immune checkpoint protein programmed-death ligand-1 (PD-L1). Moreover, all treatments, except IL, increased apoptosis, whereas cell proliferation was markedly suppressed in all treated groups. In summary, these results suggest that IL and rapamycin could enhance the efficacy of MI in lung cancer chemoprevention trials.

The impact of nebulized epoprostenol and iloprost on hemoglobin oxygen affinity: an ex vivo experiment.

Inhalational prostacyclins act as strong vasodilators, potentially improving oxygenation by reducing shunt fraction and ventilation-perfusion mismatch. As prostacyclin receptors are known to be present on human erythrocytes, possible direct effects on hemoglobin oxygen transport were further explored by examining the sole in vitro influence of prostacyclins on hemoglobin oxygen (Hb-O2) affinity. Venous blood samples from 20 healthy volunteers were exposed in vitro to supramaximal doses of epoprostenol, iloprost, and compared with control. By high-throughput measurements, hemoglobin oxygen dissociation curves (ODCs) were derived. Hb-O2 affinity, expressed by P50 and Hill coefficient, was determined and analyzed for three subgroups: males (n = 10), females not taking oral contraceptives (n = 4), and females taking oral contraceptives (n = 6). Epoprostenol significantly decreased P50 in all (males, females without contraceptives, and females taking oral contraceptives) [27.5 (26.4-28.6) mmHg (control) vs. 24.2 (22.7-25.3) mmHg; P < 0.001. median (interquartile range, IQR)] thereby increasing Hb-O2 affinity. Inversely, iloprost only showed significant effects in females taking oral contraceptives where P50 was markedly increased and therefore Hb-O2 affinity decreased [28.4 (27.9-28.9) mmHg (control) vs. 34.4 (32.2-36.0) mmHg; P < 0.001]. Prostacyclin-receptor stimulation and subsequent cAMP-mediated ATP release from erythrocytes are discussed as a possible underlying mechanism for the effect of epoprostenol on Hb-O2 affinity. The reason for the sex hormone-modified iloprost effect remains unclear. Being aware of potentially differing effects on Hb-O2 affinity might help select the right prostacyclin (epoprostenol vs. iloprost) depending on the patient and the underlying disease (e.g., acute respiratory distress syndrome vs. peripheral arterial disease).

Sudden winter iloprost withdrawal in scleroderma patients during COVID-19 pandemic.

INTRODUCTION: Intravenous iloprost is currently recommended in the treatment of Raynaud's phenomenon (RP) refractory to oral therapy and of digital ulcers (DUs) related to systemic sclerosis (SSc). In real-life practice there is a huge heterogeneity about the Iloprost regimens used. METHODS: A survey was carried out on SSc patients that interrupted Iloprost infusion to compare acral vascular symptoms just before Iloprost withdrawal and just after the missed infusion. Severity, and frequency of RP, new DUs onset or aggravation of those pre-existing were reported. Last available capillaroscopic images were also evaluated. RESULTS: The analysis includes 50 patients. After iloprost withdrawal, 11 patients reported a RP worsening because of enhanced intensity (p = 0.007). Only 8 patients of them also complained of an increased frequency (p = 0.07). None of the patients experienced digital ulcers for the first-time during quarantine. Among the 27 patients with a history of digital ulcers, 9 reported worsening and 7 recurrence of DUs. Overall, 17 patients (34.0 %) complained of a worsening of SSc vascular acral manifestations, namely RP or DUs. Reduced capillary density was associated with RP worsening, in particular, each unit increase of capillary density corresponds to an average 44 % decrease in the odds of RP worsening (OR 0.56, CI 95 % 0.36-0.97, p = 0.037). As for RP worsening, the aggravation of DU was associated with a lower capillary density. CONCLUSIONS: Low capillary density can predict a worsening of both RP and DUs in controlled quarantine conditions within a month after iloprost discontinuation in SSc patients.

Prostacyclin is an endosteal bone marrow niche component and its clinical analog iloprost protects hematopoietic stem cell potential during stress.

Hematopoietic stem cells (HSCs) with superior reconstitution potential are reported to be enriched in the endosteal compared to central bone marrow (BM) region. To investigate whether specific factors at the endosteum may contribute to HSC potency, we screened for candidate HSC niche factors enriched in the endosteal compared to central BM regions. Together with key known HSC supporting factors Kitl and Cxcl12, we report that prostacyclin/prostaglandin I2 (PGI2 ) synthase (Ptgis) was one of the most highly enriched mRNAs (>10-fold) in endosteal compared to central BM. As PGI2 signals through receptors distinct from prostaglandin E2 (PGE2 ), we investigated functional roles for PGI2 at the endosteal niche using therapeutic PGI2 analogs, iloprost, and cicaprost. We found PGI2 analogs strongly reduced HSC differentiation in vitro. Ex vivo iloprost pulse treatment also significantly boosted long-term competitive repopulation (LT-CR) potential of HSCs upon transplantation. This was associated with increased tyrosine-phosphorylation of transducer and activator of transcription-3 (STAT3) signaling in HSCs but not altered cell cycling. In vivo, iloprost administration protected BM HSC potential from radiation or granulocyte colony-stimulating factor-induced exhaustion, and restored HSC homing potential with increased Kitl and Cxcl12 transcription in the BM. In conclusion, we propose that PGI2 is a novel HSC regulator enriched in the endosteum that promotes HSC regenerative potential following stress.

The Efficacy of Conservative Treatment of Bone Marrow Edema Syndrome: A Scoping Review of the Last Ten Years of Literature.

PURPOSE: The purpose of this review was to conduct a literature search assessing the efficacy of various conservative treatments of BMES. METHODS: According to the PRISMA guidelines, a literature search was conducted in April 2021 in MEDLINE database via PubMed and Embase to identify original articles describing the results of conservative treatments for BMES of hip and knee published in the last ten years. For each study, information regarding study characteristics, description of the treatment, patient's demographic and clinical data, length of follow-up, clinical outcome measure, disability, adverse events, classification, and extent and of edema on MRI, were extracted. RESULTS: A total of 12 studies were identified. Two studies described treatment with iloprost, three with hyperbaric oxygen (HBO), two with bisphosphonates, five with extracorporeal shockwave therapy (ESWT). The total number of patients was 351: 34 treated with iloprost, 64 with hyperbaric oxygen, 37 with bisphosphonates, 216 with ESWT. In ESWT studies, treatment with a higher flux density and a higher number of therapy sessions lead to better clinical and radiological scores. In iloprost studies, a more remarkable improvement in the VAS scale was observed in the study on hip patients. CONCLUSIONS: The treatment of idiopathic bone marrow edema is currently not standardized, making it difficult to find data that can be compared in a highly reliable way. The studies available in the literature show promising results as for the possibility to cure bone marrow edema efficiently. Standardized radiological scores for evaluating bone marrow edema area are needed in future studies.

Acute effects of inhaled iloprost on intracardiac conduction in patients with pulmonary arterial hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a severe, life-threatening disorder despite the availability of specific drug therapy. A lack of endogenous prostacyclin secondary to downregulation of prostacyclin synthase in PAH may contribute to vascular pathologies. Therefore, prostacyclin and its analogs including inhaled iloprost may decrease pulmonary arterial pressure and ventricular pressure. METHODS: Here, we studied that acute effects of iloprost used in pulmonary vasoreactivity testing on the intracardiac conduction system in patients with PAH. A total of 35 (15 idiopathic PAH, 20 congenital heart disease) patients with PAH were included in this prospective study. Patients were divided into two groups: 22 patients with negative pulmonary vasoreactivity in group 1 and 13 with positive pulmonary vasoreactivity in group 2. Electrophysiological parameters including basic cycle length, atrium-His (AH) interval, His-ventricle (HV) interval, PR interval, QT interval, QRS duration, Wenckebach period, and sinus node recovery time (SNRT) were evaluated before and after pulmonary vasoreactivity testing in both groups. RESULTS: The AH interval (81 [74-93]; 80 [65.5-88], p = 0.019) and SNRT (907.7 ± 263.4; 854.0 ± 288.04, p = 0.027) was significantly decreased after pulmonary vasoreactivity testing. Mean right atrium pressure was found to be correlated with baseline AH (r = 0.371, p = 0.031) and SNRT (r = 0.353, p = 0.037). CONCLUSION: Inhaled iloprost can improve cardiovascular performance in the presence of PAH, primarily through a reduction in right ventricular afterload and interventricular pressure. Decreased pressure on the interventricular septum and ventricles leads to conduction system normalization including of the AH interval and SNRT due to resolution of inflammation and edema.

Effects of Inhaled Iloprost for the Management of Persistent Pulmonary Hypertension of the Newborn.

OBJECTIVE: The study aimed to evaluate the effects of inhaled iloprost on oxygenation indices in neonates with persistent pulmonary hypertension of the newborn (PPHN). STUDY DESIGN: We conducted a retrospective chart review of 30 patients with PPHN from January 2014 to November 2018, who did not respond to inhaled nitric oxide (iNO) alone and received inhaled iloprost. Twenty-two patients met the inclusion criteria and eight patients were excluded from the study (complex cardiac disease and extreme prematurity). Patients were categorized as responders or nonresponders (patients who required extracorporeal membrane oxygenation or died). Oxygenation index, mean airway pressure (MAP), and arterial partial pressure of oxygen (PaO2) were recorded. RESULTS: Among a total of 22 patients who were included in the study, 10 were classified as nonresponders as they required either extracorporeal membrane oxygenation or died. Gestational age and gender did not differ between responders and nonresponders. The median PaO2 was lower (37 vs. 42 mm Hg; p < 0.05) and median MAP was higher (20 vs. 17 cm H2O; p < 0.02) in nonresponders compared with responders just prior to initiating iloprost. Iloprost responders had a significant increase in median PaO2 and decrease in median oxygenation index in the 24 hours after initiating treatment (p < 0.05), with no significant change in required mean airway pressure over that same period. There was no change in vasopressor use or clinically significant worsening of platelets count, liver, and kidney functions after initiating iloprost. CONCLUSION: Inhaled iloprost is well tolerated and seems to have beneficial effects in improving oxygenation indices in neonates with PPHN who do not respond to iNO. There is a need of well-designed prospective trials to further ascertain the benefits of using inhaled iloprost as an adjunct treatment in neonates with PPHN who do not respond to iNO alone. KEY POINTS: · Inhaled iloprost seems to have beneficial effects in improving oxygenation indices in PPHN.. · Inhaled iloprost is generally well tolerated in newborns with PPHN.. · There is a need for prospective randomized controlled trials to further ascertain the benefits of using inhaled iloprost..

Efficacy and safety of endotracheal instillation of iloprost for persistent pulmonary hypertension of the newborn.

OBJECTIVE: To determine the efficacy and safety of endotracheal instillation of iloprost as a rescue therapy for persistent pulmonary hypertension of the newborn. METHODS: Neonates diagnosed with persistent pulmonary hypertension who were unresponsive to standard treatment protocol applied for persistent pulmonary hypertension in our unit, and who were being followed up with mechanical ventilation, were included in the study. Iloprost was instilled endotracheally as a rescue treatment. Systolic pulmonary artery pressure, oxygen saturation index, mean airway pressure, fraction of inspired oxygen, preductal and postductal venous oxygen saturation, heart rate, and blood pressure were recorded before and after 30 minutes of endotracheal iloprost instillation. Adverse events after endotracheal iloprost were recorded. RESULTS: Twenty neonates were included. The median gestational age and birth weight were found to be 37 (30.5-38) weeks and 2975 (2125-3437.5) grams, respectively. When compared to the period before endotracheal iloprost instillation, systolic pulmonary artery pressure, oxygen saturation index, mean airway pressure, and fraction of inspired oxygen values significantly decreased (p < 0.001, p < 0.001, p = 0.021, p = 0.001, respectively), whereas preductal and postductal oxygen saturation values significantly increased 30 minutes after the endotracheal iloprost instillation (p = 0.002, p < 0.001, respectively). There were no significant differences in heart rate and blood pressure values before and after the iloprost administration. No adverse events were observed. CONCLUSION: Endotracheal instillation of iloprost was found to be an effective and safe therapy for persistent pulmonary hypertension unresponsive to conventional treatment.