Int J Cardiol. 2018 Apr 7. pii: S0167-5273(17)36555-5. doi: 10.1016/j.ijcard.2018.04.026. [Epub ahead of print]

National trends and outcomes of hospitalizations for pulmonary hypertension in Spain (2001-2014).

de-Miguel-Díez J¹, López-de-Andrés A², Hernandez-Barrera V³, Jimenez-Trujillo I³, de-Miguel-Yanes JM⁴, Mendez-Bailón M⁵, Jimenez-Garcia R³.

Author information:

1. Respiratory Department, Hospital General Universitario Gregorio Marañón, Facultad de Medicina, Universidad Complutense de Madrid (UCM), Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.
2. Preventive Medicine and Public Health Teaching and Research Unit, Health Sciences Faculty, Universidad Rey Juan Carlos, Alcorcón, Madrid, Spain. Electronic address: ana.lopez@urjc.es.
3. Preventive Medicine and Public Health Teaching and Research Unit, Health Sciences Faculty, Universidad Rey Juan Carlos, Alcorcón, Madrid, Spain.
4. Internal Medicine Department, Hospital General Universitario Gregorio Marañon, Madrid, Spain.
5. Internal Medicine Department, Hospital Universitario Clínico San Carlos, Madrid, Spain.

Abstract

OBJECTIVE:
To assess changes in incidence, diagnostic procedures, comorbidity profiles, length of hospital stay (LOHS), costs, and in-hospital mortality (IHM) for patients hospitalized with pulmonary hypertension (PH).

METHODS:
We included patients hospitalized with PH in Spain from 2001 to 2014. The data were collected from the National Hospital Discharge Database.

RESULTS:
We included 644,436 discharges (43.31% males and 56.09% females) admitted for primary PH (8.34%) or secondary PH (91.66%). The crude incidence rate increased from 58.67 to 148.32 hospitalizations per 100,000 inhabitants between 2001 and 2002 and 2013-2014 (p < 0.001). The percentage of patients with a Charlson comorbidity index ≥2 was 27.87% in 2001-2002, increasing to 47.02% in 2013-2014 (p < 0.001). IHM was 8.77%, with a reduction in the value yielded by the multivariable analysis between 2009 and 2010 and 2013-2014. Median LOHS was 9 ± 9 days in 2001-2002, which decreased to 7 ± 8 days in 2013-2014 (p < 0.001). The mean cost per patient increased from €3352.4 ± €1495 in the period 2001-2002 to €4198.94 ± €1287.96 in 2013-2014 (p < 0.001).

CONCLUSIONS:
Despite the increase over time in hospital admissions for PH, associated comorbidity, and costs, LOHS and IHM decreased, suggesting that the management of PH-related hospitalizations improved in Spain during the study period.

Copyright © 2018 Elsevier B.V. All rights reserved.

PMID: 29673852

AJR Am J Roentgenol. 2018 Apr 18:1-5. doi: 10.2214/AJR.17.19208. [Epub ahead of print]

Egg-and-Banana Sign: A Novel Diagnostic CT Marker for Pulmonary Hypertension.

Scelsi CL¹, Bates WB¹, Melenevsky YV¹, Sharma GK², Thomson NB¹, Keshavamurthy JH¹.

Author information:

1. Department of Radiology, Medical College of Georgia, Augusta University, 1120 15th St, Augusta, GA 30912.
2. Department of Cardiology, Medical College of Georgia, Augusta University, Augusta, GA.

Abstract

OBJECTIVE:
The purpose of this study was to retrospectively determine whether the egg-and-banana sign, defined as the visualization of the main pulmonary artery (PA) at the level of the aortic arch, is a sensitive and specific diagnostic marker for pulmonary hypertension.

MATERIALS AND METHODS:
A total of 186 patients who, between January 2014 and July 2017, received right heart catheterizations and underwent CT studies that included the aortic arch within 140 days of catheterization were evaluated in this retrospective study. Of these patients, 127 had pulmonary hypertension (PH), and 59 who did not have PH served as control subjects. Two blinded radiologists reviewed each study for the egg-and-banana sign. The diameters of the main PA and ascending aorta were also measured. Contingency tables, ROC curves, and a t test were used for statistical analysis.

RESULTS:
The egg-and-banana sign was associated with a higher mean PA pressure, a higher ratio of the diameter of the PA to the diameter of the ascending aorta (Ao) (hereafter referred to as the “PA-to-Ao ratio”), and a larger PA diameter (p < 0.006). It had a specificity of 85% and a positive predictive value of 85%. When the egg-and-banana sign was used in combination with a main PA diameter larger than 29 mm and a PA-to-Ao ratio greater than 1, its specificity increased to 91% and 93%, respectively. When considered as individual markers, the PA diameter had a high sensitivity (80%; AUC value, 0.74) and the PA-to-Ao ratio had a high specificity (81%; AUC value, 0.73) for PH. Moderate correlations were noted between PA pressure and PA diameter (r = 0.37) and between PA pressure and PA-to-Ao ratio (r = 0.43).

CONCLUSION:
The egg-and-banana sign has a high specificity and PPV for PH. Specificity increased when the sign was used in combination with other classic CT markers.

PMID: 29667884

Int J Cardiol. 2018 Apr 7. pii: S0167-5273(17)33890-1. doi: 10.1016/j.ijcard.2018.04.024. [Epub ahead of print]

Strengths and weaknesses of echocardiography for the diagnosis of pulmonary hypertension.

D’Alto M¹, Bossone E², Opotowsky AR³, Ghio S⁴, Rudski LG⁵, Naeije R⁶.

Author information:

1. Department of Cardiology, Second University of Naples – Monaldi Hospital, Naples, Italy. Electronic address: michele.dalto@ospedalideicolli.it.
2. Department of Cardiology, University of Salerno, Salerno, Italy.
3. Department of Cardiology, Boston Children’s Hospital, Boston, MA, USA; Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.
4. Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
5. Azrieli Heart Center, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
6. Department of Pathophysiology, Free University of Brussels, Brussels, Belgium.

Abstract

Doppler echocardiography is extensively used in clinical practice for the screening and detection of pulmonary hypertension (PH). It allows for accurate estimates of pulmonary artery pressures, but with moderate precision, which explains why it is more appropriate for population studies than for definitive diagnosis of PH in individual patients. Moreover, echocardiography allows one to distinguish different patterns of right ventricular remodelling in various forms of PH and enables clinically satisfactory differentiation between pre- and post-capillary PH. This article will review the methods for evaluating PH by echocardiography, while also providing an insight into specific strengths and weaknesses.

PMID: 29655950

Am J Cardiol. 2018 Mar 14. pii: S0002-9149(18)30287-X. doi: 10.1016/j.amjcard.2018.02.051. [Epub ahead of print]

Incidence and Mortality of Adults With Pulmonary Hypertension and Congenital Heart Disease.

Schwartz SS¹, Madsen N², Laursen HB³, Hirsch R², Olsen MS³.

Author information:

1. Department of Clinical Epidemiology, Aarhus University Hospital, Arhus, Denmark. Electronic address: sarasschwartz@gmail.com.
2. Heart Institute, Cincinnati Children’s Hospital Medical Center; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
3. Department of Clinical Epidemiology, Aarhus University Hospital, Arhus, Denmark.

Abstract

Reports on pulmonary hypertension (PH) in the aging congenital heart disease (CHD) population are few and focused on arterial PH and patients with systemic-to-pulmonary shunts. Our objective was to estimate incidence and mortality of adult-onset PH in the CHD population. Using Danish nationwide registries, we identified all patients diagnosed with CHD from 1963 to 1974 and 1977 to 2012. Patients were matched 1:10 by birth year and gender with general population subjects. Between 1977 and 2013 adults >18 years of age were followed up until PH diagnosis, death, or emigration, whichever came first, using data from the Danish National Registry of Patients. We computed cumulative incidences of PH. Using Cox regression, we compared the mortality rate between CHD subjects with and without PH matched by gender and birth year. We identified 14,860 patients with CHD. At 70 years of age, their overall cumulative incidence of PH was 7.2% (8.3% in those with systemic-to-pulmonary shunts and 5.3% in those without) compared with 0.4% in the general population. The 1-, 5-, and 10-year mortality for adults with CHD and PH was 24%, 44%, and 52%, respectively. This represented a 4-fold (95% confidence interval 3.3 to 5.6) increase in mortality compared with adults with CHD without PH after adjusting for gender, birth year, CHD severity, and presence of extracardiac defects. In conclusion the incidence of PH was substantially increased in adults with CHD relative to the general population. Of note, the increased incidence was not limited to those with a history of systemic-to-pulmonary shunts. PH was associated with increased mortality.

PMID: 29655882

Am J Respir Crit Care Med. 2018 Apr 17. doi: 10.1164/rccm.201709-1835OC. [Epub ahead of print]

Endothelial and Smooth Muscle Cell Interaction via FoxM1 Signaling Mediates Vascular Remodeling and Pulmonary Hypertension.

Dai Z¹, Zhu MM¹, Peng Y¹, Jin H¹, Machireddy N¹, Qian Z², Zhang X¹, Zhao YY³.

Author information:

1. Northwestern University, Chicago, Illinois, United States.
2. University of Illinois at Chicago College of Medicine, 12247, Chicago, Illinois, United States.
3. Northwestern University, Pediatrics, Chicago, Illinois, United States ; youyang.zhao@northwestern.edu.

Abstract

RATIONALE:
Angioproliferative vasculopathy is a hallmark of pulmonary arterial hypertension (PAH). However, little is known how endothelial cell (EC) and smooth muscle cell (SMC) crosstalk regulates the angioproliferative vascular remodeling.

OBJECTIVES:
We aimed to investigate the role of EC and SMC interaction and underlying signaling pathways in PH development.

METHODS:
SMC-specific Foxm1 or Cxcr4 knockout mice, EC-specific Foxm1 or Egln1 knockout mice, as well as EC-specific Egln1/Cxcl12 double knockout mice were used to assess the role of FoxM1 on SMC proliferation and PH. Lung tissues and cells from PAH patients were employed to validate clinical relevance. FoxM1 inhibitor Thiostrepton was used in Sugen 5416/hypoxia- and monocrotaline-challenged rats.

MEASUREMENTS AND MAIN RESULTS:
FoxM1 expression was markedly upregulated in lungs and pulmonary arterial SMCs of idiopathic PAH patients and 4 discrete PH rodent models. Mice with SMC- (but not EC-) specific deletion of Foxm1 were protected from hypoxia- or Sugen 5416/hypoxia-induced PH. The upregulation of FoxM1 in SMCs induced by multiple EC-derived factors (PDGF-B, CXCL12, ET-1 and MIF) mediated SMC proliferation. Genetic deletion of endothelial Cxcl12 in Egln1Tie2Cre mice or loss of its cognate receptor Cxcr4 in SMCs in hypoxia-treated mice inhibited FoxM1 expression, SMC proliferation and PH. Accordingly, pharmacological inhibition of FoxM1 inhibited severe PH in both Sugen 5416/hypoxia and monocrotaline-challenged rats.

CONCLUSIONS:
Multiple factors derived from dysfunctional ECs induced FoxM1 expression in SMCs and activated FoxM1-dependent SMC proliferation which contributes to pulmonary vascular remodeling and PH. Thus, targeting FoxM1 signaling represents a novel strategy for treatment of IPAH.

PMID: 29664678

PLoS One. 2018 Apr 20;13(4):e0195047. doi: 10.1371/journal.pone.0195047. eCollection 2018.

Synergistic interaction between a PDE5 inhibitor (sildenafil) and a new adenosine A2A receptor agonist (LASSBio-1359) improves pulmonary hypertension in rats.

Alencar AK¹, Carvalho FI¹, Silva AM¹, Martinez ST², Calasans-Maia JA³, Fraga CM¹, Barreiro EJ¹, Zapata-Sudo G¹, Sudo RT¹.

Author information:

1. Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil.
2. Instituto de Química, Universidade Federal Fluminense, Rio de Janeiro, Rio de Janeiro, Brazil.
3. Serviço de Anestesiologia, Hospital Universitário, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil.

Abstract

INTRODUCTION:
Pulmonary hypertension (PH) is characterized by enhanced pulmonary vascular resistance, which causes right ventricle (RV) pressure overload and results in right sided heart failure and death. This work investigated the effectiveness of a combined therapy with PDE5 inhibitor (PDE5i) and a new adenosine A2A receptor (A2AR) agonist in mitigating monocrotaline (MCT) induced PH in rats.

METHODS:
An in vitro isobolographic analysis was performed to identify possible synergistic relaxation effect between sildenafil and LASSBio 1359 in rat pulmonary arteries (PAs). In the in vivo experiments, PH was induced in male Wistar rats by a single intraperitoneal injection of 60 mg/kg MCT. Rats were divided into the following groups: control (saline injection only), MCT + vehicle, MCT + sildenafil, MCT + LASSBio 1359 and MCT + combination of sildenafil and LASSBio 1359. Fourteen days after the MCT injection, rats were treated daily with oral administration of the regimen therapies or vehicle for 14 days. Cardiopulmonary system function and structure were evaluated by echocardiography. RV systolic pressure and PA endothelial function were measured.

RESULTS:
Isobolographic analysis showed a synergistic interaction between sildenafil and LASSBio 1359 in rat PAs. Combined therapy with sildenafil and LASSBio 1359 but not monotreatment with low dosages of either sildenafil or LASSBio 1359 ameliorated all of PH related abnormalities in cardiopulmonary function and structure in MCT challenged rats.

CONCLUSIONS:
The combination of sildenafil and LASSBio 1359 has a synergistic interaction, suggesting that combined use of these pharmacological targets may be an alternative to improve quality of life and outcomes for PH patients.

PMID: 29677206

J Thromb Haemost. 2018 Apr 2. doi: 10.1111/jth.14016. [Epub ahead of print]

Chronic thromboembolic pulmonary hypertension from the perspective of patients with pulmonary embolism.

Klok FA^1,2, Delcroix M³, Bogaard HJ⁴.

Author information:

1. Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands.
2. Center for Thrombosis and Hemostasis, University Hospital of the Johannes Gutenberg University Mainz, Mainz, Germany.
3. Department of Pneumology, University Hospitals Leuven and Department CHROMETA, Division Pneumology, KU Leuven, Leuven, Belgium.
4. Department of Pulmonary Diseases, Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center, Amsterdam, The Netherlands.

Abstract

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare but feared long-term complication of acute pulmonary embolism (PE), although CTEPH may occur in patients with no history of symptomatic venous thromboembolism. It represents the most severe presentation of the so-called ‘post-PE syndrome’, a phenomenon of permanent functional limitations after PE caused by deconditioning after PE or ventilatory or circulatory impairment due to unresolved pulmonary artery thrombi. Because the post-PE syndrome may occur in up to 50% of PE survivors, and CTEPH tends to have an insidious and non-specific clinical presentation, CTEPH is often not diagnosed or diagnosed after very long delay. Once the diagnosis is confirmed, the treatment of choice is pulmonary endarterectomy, effectively lowering the pulmonary vascular resistance and normalizing resting pulmonary artery pressures leading to recovery of the right ventricle. When pulmonary endarterectomy is not technically feasible, balloon pulmonary angioplasty may be a potential acceptable alternative. Also, medical treatment may help to improve patient’s symptoms and hemodynamics. Current studies are focussing on strategies for earlier CTEPH diagnosis after acute PE, as well as the most optimal treatment of inoperable patients. This review will focus on the epidemiology, risk factors, diagnosis and treatment of CTEPH from the perspective of the PE patient. This article is protected by copyright. All rights reserved.

PMID: 29608809

Int Heart J. 2018 Mar 30;59(2):443-447. doi: 10.1536/ihj.17-249. Epub 2018 Mar 5.

Pulmonary Tumor Thrombotic Microangiopathy due to Advanced Gastric Cancer with Virchow’s Node Metastasis.

Sato T¹, Mori M², Aoki J¹, Tanabe K¹.

Author information:

1. Division of Cardiology, Mitsui Memorial Hospital.
2. Division of Pathology, Mitsui Memorial Hospital.

Abstract

Pulmonary tumor thrombotic microangiopathy (PTTM) is a fatal cancer-related complication characterized by severe progressive pulmonary hypertension. Antemortem diagnosis is difficult owing to the rapid progression of the condition, especially when the patient has no known malignancies and initially presents with pulmonary hypertension. Here we report a case of PTTM due to occult gastric cancer with metastasis in the left supraclavicular lymph node, also known as Virchow’s node. Enlarged Virchow’s node is an important indicator of advanced gastric cancer. In patients with progressive pulmonary hypertension of unknown origin, enlarged Virchow’s node can be an important indicator for the diagnosis of PTTM.

Free Article
PMID: 29503403 [Indexed for MEDLINE]

Eur J Pharmacol. 2017 Sep 5;810:44-50. doi: 10.1016/j.ejphar.2017.06.010. Epub 2017 Jun 8.

Tadalafil induces antiproliferation, apoptosis, and phosphodiesterase type 5 downregulation in idiopathic pulmonary arterial hypertension in vitro.

Yamamura A¹, Fujitomi E², Ohara N², Tsukamoto K², Sato M³, Yamamura H⁴.

Author information:

1. Department of Physiology, Aichi Medical University, 1-1 Yazakokarimata Nagakute, Aichi 480-1195, Japan; Department of Pharmacy, College of Pharmacy, Kinjo Gakuin University, 2-1723 Omori Moriyamaku, Nagoya 463-8521, Japan.
2. Department of Pharmacy, College of Pharmacy, Kinjo Gakuin University, 2-1723 Omori Moriyamaku, Nagoya 463-8521, Japan.
3. Department of Physiology, Aichi Medical University, 1-1 Yazakokarimata Nagakute, Aichi 480-1195, Japan.
4. Department of Molecular & Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabedori Mizuhoku, Nagoya 467-8603, Japan. Electronic address: yamamura@phar.nagoya-cu.ac.jp.

Abstract

Idiopathic pulmonary arterial hypertension (IPAH) is a fatal disease of the pulmonary artery resulting from a currently unidentified etiology. IPAH is pathologically characterized as sustained vasoconstriction and vascular remodeling of the pulmonary artery. Vascular remodeling is mediated by enhanced proliferation and reduced apoptosis in pulmonary arterial smooth muscle cells (PASMCs). Based on its pathological mechanism, specific phosphodiesterase type 5 (PDE5) inhibitors have been used in the treatment of IPAH. In addition to sildenafil, tadalafil has been approved for the treatment of IPAH. However, the effects of tadalafil on excessive proliferation of IPAH-PASMCs currently remain unknown. In the present study, the in vitro pharmacological profiles of tadalafil for cell proliferation and apoptosis were assessed in IPAH-PASMCs using MTT, BrdU incorporation, and caspase 3/7 assays. Expression analyses revealed that PDE5 mRNA and protein expression levels were markedly higher in IPAH-PASMCs than in normal-PASMCs. The treatment with tadalafil inhibited the excessive proliferation of IPAH-PASMCs in a concentration-dependent manner with an IC50 value of 4.5μM. On the other hand, tadalafil (0.03-100μM) did not affect cell growth of PASMCs from normal subjects and patients with chronic thromboembolic pulmonary hypertension (CTEPH). In addition, tadalafil induced apoptosis in IPAH-PASMCs. The antiproliferative and apoptotic effects of tadalafil were markedly stronger than those of sildenafil and vardenafil. The upregulated expression of PDE5 in IPAH-PASMCs was significantly attenuated by a long-term treatment with tadalafil. Taken together, these results indicate that tadalafil attenuates vascular remodeling by inhibiting cell proliferation, promoting apoptosis, and downregulating PDE5 in IPAH-PASMCs, thereby ameliorating IPAH.

PMID: 28603047 [Indexed for MEDLINE]

Eur J Pharmacol. 2017 Sep 5;810:92-99. doi: 10.1016/j.ejphar.2017.05.048. Epub 2017 May 31.

RP5063, a novel, multimodal, serotonin receptor modulator, prevents monocrotaline-induced pulmonary arterial hypertension in rats.

Bhat L¹, Hawkinson J², Cantillon M³, Reddy DG³, Bhat SR³, Laurent CE⁴, Bouchard A⁴, Biernat M⁴, Salvail D⁴.

Author information:

1. Reviva Pharmaceuticals, Inc., Santa Clara, CA, USA. Electronic address: lbhat@revivapharma.com.
2. Institute for Therapeutics Discovery & Development and Department of Medicinal Chemistry, University of Minnesota, USA.
3. Reviva Pharmaceuticals, Inc., Santa Clara, CA, USA.
4. IPS Therapeutique Inc., Sherbrooke, Quebec, Canada.

Abstract

Pulmonary arterial hypertension (PAH), a condition characterized by pulmonary vasculature constriction and remodeling, involves dysregulation of the serotonin (5-HT) receptors 5-HT2A and 5-HT2B. A rat model of monocrotaline (MCT)-induced PAH was used to examine the potential beneficial effects of RP5063, a 5-HT receptor modulator. After a single 60mg/kg dose of MCT, rats were gavaged twice-daily (b.i.d.) with vehicle, RP5063 (1, 3, or 10mg/kg), or sildenafil (50mg/kg) for 28 days. RP5063 at a dose as low as 1mg/kg, b.i.d. reduced pulmonary resistance and increased systemic blood oxygen saturation. The highest dose of RP5063 (10mg/kg, b.i.d.) reduced diastolic, systolic, and mean pulmonary pressure, right systolic ventricular pressure, ventilatory pressure, and Fulton’s index (ratio of right to left ventricular weight). Doses as low as 3mg/kg RP5063, b.i.d. also increased weight gain and body temperature, suggesting an improvement in overall health of MCT-treated animals. Similar reductions in pulmonary, right ventricular, and ventilatory pressure, pulmonary resistance, and Fulton’s index as well as increased systemic blood oxygen saturation were observed in animals treated with the reference agent sildenafil at a higher dose (50mg/kg, b.i.d.). Histological examination revealed that RP5063 produced dose-dependent reductions in pulmonary blood vessel wall thickness and proportion of muscular vessels, similar to sildenafil. RP5063 completely blocked MCT-induced increases in the plasma cytokines TNFα, IL-1β, and IL-6 at all doses. In summary, RP5063 improved pulmonary vascular pathology and hemodynamics, right ventricular pressure and hypertrophy, systemic oxygen saturation, and overall health of rats treated with MCT.

Free Article
PMID: 28577964 [Indexed for MEDLINE]

Eur J Pharmacol. 2017 Sep 5;810:83-91. doi: 10.1016/j.ejphar.2017.05.052. Epub 2017 May 31.

RP5063, a novel, multimodal, serotonin receptor modulator, prevents Sugen 5416-hypoxia-induced pulmonary arterial hypertension in rats.

Bhat L¹, Hawkinson J², Cantillon M³, Reddy DG³, Bhat SR³, Laurent CE⁴, Bouchard A⁴, Biernat M⁴, Salvail D⁴.

Author information:

1. Reviva Pharmaceuticals, Inc., Santa Clara, CA, USA. Electronic address: lbhat@revivapharma.com.
2. Institute for Therapeutics Discovery & Development and Department of Medicinal Chemistry, University of Minnesota, USA.
3. Reviva Pharmaceuticals, Inc., Santa Clara, CA, USA.
4. IPS Therapeutique Inc., Sherbrooke, Quebec, Canada.

Abstract

RP5063, a multimodal dopamine (DA) and serotonin (5-HT) modulator with high affinity for DA2/3/4 and 5-HT2A/2B/7 receptors and moderate affinity for SERT, is a novel therapeutic of special interest in the treatment of pulmonary arterial hypertension (PAH). Evidence indicates that therapeutics targeting the 5-HT2A/2B receptors can influence the pathogenesis of PAH. However, the therapeutic effect of RP5063 in humans has yet to be investigated. A Sugen 5416-hypoxia (SuHx)-induced PAH model was used to evaluate twice-daily (b.i.d.) RP5063 at 10mg/kg (RP-10) and 20mg/kg (RP-20), as compared with positive (sildenafil 50mg/kg b.i.d.; Sil-50) and negative controls (SuHx+vehicle; SuHx+veh), in 24 adult male Wistar-Kyoto rats. RP5063 showed significantly lower systolic pulmonary arterial (both doses) and systolic right ventricular (RP-10) pressures, and improvement in oxygen saturation (RP-20). It significantly reduced small-vessel wall thickness (RP-20), lowered the percentage of muscular vessels (both doses). Both doses limited arterial obliteration due to endothelial cell proliferation, prevented plexiform lesion formation, and stemmed the release of leukotriene B4. Sildenafil showed statistically greater effects on vessel structure than that seen in both RP5063 groups and improved oxygen saturation. Additionally, Sildenafil did not demonstrate any significant effect on arterial obliteration, plexiform lesion development, or pulmonary arterial or right ventricular pressure. As PAH gains in severity, the impact of RP5063 inhibition of 5HT2B increases, preventing arterial constriction and improving pulmonary hemodynamics. Due to its functional, structural, and chemokine effects, RP5063 represents a promising candidate for investigation in late-phase PAH.

Free Article
PMID: 28576407 [Indexed for MEDLINE]

J Heart Valve Dis. 2016 Mar;25(2):195-197.

An Unusual Case of Persistent Severe Pulmonary Artery Hypertension Following Balloon Mitral Valvuloplasty.

Gopalakrishnan A¹, Kumar Mohanan Nair K¹, Harikrishnan S¹, Valaparambil A¹.

Author information:

1. Department of Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala, India.

Abstract

Persistent pulmonary artery hypertension (PAH) after balloon mitral valvuloplasty (BMV) is not uncommon, and is generally associated with established pulmonary vascular disease, an inadequate result, or the development of mitral regurgitation. An unfavorable mitral valve morphology with a smaller post-procedural mitral valve area is among the most common causes of the condition. While routine cardiac catheterization is no longer recommended prior to intervention in valvular heart disease, patients with persistent PAH after BMV should undergo a thorough evaluation before they are considered for repeat BMV. Here, a rare case is reported of symptomatic persistent PAH in a patient referred for a third BMV, less than one year after the previous intervention, where a hypertensive patent ductus arteriosus was identified, the closure of which led to a regression of the PAH.

PMID: 27989066 [Indexed for MEDLINE]

Medicine (Baltimore). 2018 Mar;97(11):e0122. doi: 10.1097/MD.0000000000010122.

The safety of endothelin receptor antagonists in the treatment of pulmonary arterial hypertension: Protocol for a systemic review and network meta-analysis.

Gu ZC¹, Zhang YJ², Pan MM¹, Zhang C¹, Liu XY¹, Wei AH³, Su YJ¹.

Author information:

1. Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiaotong University.
2. Department of Pharmacy, Third Affiliated Hospital of Second Military Medical University, Shanghai.
3. Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Abstract

BACKGROUND:
Pulmonary arterial hypertension (PAH) is a progressive disease and ultimately leads to right heart failure. Endothelin receptor antagonists (ERAs) have been demonstrated to significantly improve prognosis in PAH. However, ERAs-induced side effects can result in poor patient tolerance. Thus, we aim to evaluate current safety evidence of ERAs in PAH.

METHODS:
An electronic search will be performed for randomized controlled trials (RCTs) that reported the interested safety data (abnormal liver function, peripheral edema, and anemia) of ERAs in PAH. Risk ratios (RRs) with their confidence intervals (CIs) and the surface under the cumulative ranking curve (SUCRA) will be calculated using a network analysis.

RESULTS:
This study will provide the safety evidence of ERAs in PAH by combining the results of individual studies based on direct- and network comparison, and to rank ERAs in the evidence network.

CONCLUSIONS:
The results will supplement missing evidence of head-to-head comparisons between different ERAs and guide both clinical decision-making and future research.

Free PMC Article
PMCID: PMC5882387
PMID: 29538209 [Indexed for MEDLINE]

Eur Respir J. 2018 Apr 4;51(4). pii: 1701197. doi: 10.1183/13993003.01197-2017. Print 2018 Apr.

Incidence of pulmonary hypertension and determining factors in patients with systemic sclerosis.

Coghlan JG^1,2, Wolf M^3,2, Distler O⁴, Denton CP⁵, Doelberg M⁶, Harutyunova S³, Marra AM⁷, Benjamin N³, Fischer C⁸, Grünig E^3,9.

Author information:

1. Cardiology Dept, Royal Free Hospital, London, UK.
2. Both authors contributed equally.
3. Centre for Pulmonary Hypertension, Thorax Clinic at the University Hospital Heidelberg, Heidelberg, Germany.
4. Dept of Rheumatology, Faculty of Medicine, University of Zurich, Zurich, Switzerland.
5. Centre of Rheumatology, Royal Free Hospital, London, UK.
6. Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.
7. IRRC S.D.N., Naples, Italy.
8. Dept of Human Genetics, University of Heidelberg, Heidelberg, Germany.
9. Translational Lung Research Center (TLRC) of the German Center for Lung Research (DZL), Heidelberg, Germany.

Abstract

The objective of this study was to evaluate the incidence of pulmonary hypertension (PH) and determining factors in patients with systemic sclerosis (SSc) and a diffusing capacity of the lung for carbon monoxide (DLCO) <60% predicted.In this bicentric, prospective cohort study, patients with SSc were clinically assessed at baseline and after 3 years, including right heart catheterisation (RHC). Analysis of determining factors for the development of PH was performed using univariate and multivariate analyses.96 patients with a mean pulmonary arterial pressure (mPAP) <25 mmHg at baseline were followed for 2.95±0.7 years (median 3 years). Of these, 71 had a second RHC; 18 of these 71 patients (25.3%) developed PH, and five (7%) developed SSc-associated pulmonary arterial hypertension. For patients with an mPAP of 21-24 mmHg at baseline, the likelihood of presenting with PH as opposed to normal pressures on follow-up was significantly higher (p=0.026). Pulmonary vascular resistance, tricuspid regurgitation velocity, diffusion capacity and the size of the inferior vena cava at baseline were independent predictors for the development of PH during follow-up.In a selected cohort of SSc patients with a DLCO <60%, pulmonary pressures appeared to rise progressively during follow-up. In this population, it was possible to identify manifest PH in almost 25% of patients using prospective RHC during follow-up. Therefore, regular clinical assessment including RHC might be useful in patients with SSc.

PMID: 29563168

JAMA Cardiol. 2018 Mar 14. doi: 10.1001/jamacardio.2018.0128. [Epub ahead of print]

Association Between Hemodynamic Markers of Pulmonary Hypertension and Outcomes in Heart Failure With Preserved Ejection Fraction.

Vanderpool RR^1,2, Saul M³, Nouraie M^1,4, Gladwin MT^1,4, Simon MA^1,2,5,6.

Author information:

1. Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, Pittsburgh, Pennsylvania.
2. Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania.
3. Analytics Center, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
4. Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
5. Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
6. University of Pittsburgh Medical Center Heart and Vascular Institute, Pittsburgh, Pennsylvania.

Abstract

Importance:
Heart failure with preserved ejection fraction (HFpEF) is highly prevalent, yet there are no specific therapies, possibly due to phenotypic heterogeneity. The development of pulmonary hypertension (PH) in patients with HFpEF is considered a high-risk phenotype in need of targeted therapies, but there have been limited hemodynamic and outcomes data.

Objective:
To identify the hemodynamic characteristics and outcomes of PH-HFpEF.

Design, Setting, and Participants:
Cohort study of participants who had a right heart catheterization from January 2005 to September 2012 (median [interquartile range] follow-up time, 1578 [554-2513] days) were analyzed. Hemodynamic catheterization data was linked to the clinical data repository of all inpatient and outpatient encounters across a health system. Single tertiary referral center for heart failure and PH within a large health care network using a common clinical data repository was studied. There were 19 262 procedures in 10 023 participants.

Exposures:
Participants were classified as having no PH, precapillary PH, or PH in the setting of left heart disease (reduced or preserved ejection fraction). Pulmonary hypertension associated with HFpEF was defined as mean pulmonary artery pressure of 25 mm Hg or more, pulmonary artery wedge pressure of 15 mm Hg or more, and left ventricular ejection fraction of 45% or more. Pulmonary hypertension severity was quantified by the hemodynamic parameters transpulmonary gradient, pulmonary vascular resistance, and diastolic pulmonary gradient.

Main Outcomes and Measures:
The primary outcome was time to all-cause mortality. Secondary outcomes were time to acute hospitalization and cardiovascular hospitalization.

Results:
The mean (SD) of all study individuals was 65 (38) years. Of 10 023 individuals, 2587 (25.8%) had PH-HFpEF. Mortality was 23.6% at 1 year and 48.2% at 5 years. Cardiac hospitalizations occurred in 28.1% at 1 year and 47.4% at 5 years. The frequency of precapillary PH using clinically defined cut-offs for transpulmonary gradient (>12 mm Hg), pulmonary vascular resistance (3 Woods units), and diastolic pulmonary gradient (≥7 mm Hg) were 12.6%, 8.8%, and 3.5%, respectively. Transpulmonary gradient, pulmonary vascular resistance, and diastolic pressure gradient were predictive of mortality and cardiac hospitalizations.

Conclusions and Relevance:
In a large cohort referred for invasive hemodynamic assessment, PH-HFpEF was common. Transpulmonary gradient, pulmonary vascular resistance, and diastolic pulmonary gradient are all associated with mortality and cardiac hospitalizations.

PMCID: PMC5875307 [Available on 2019-03-14]
PMID: 29541759

Circ J. 2018 Mar 13. doi: 10.1253/circj.CJ-17-1242. [Epub ahead of print]

Long-Term Outcome of Chronic Thromboembolic Pulmonary Hypertension at a Single Japanese Pulmonary Endarterectomy Center.

Miwa H¹, Tanabe N^1,2, Jujo T^1,2, Kato F¹, Anazawa R¹, Yamamoto K¹, Naito A^1,3, Kasai H¹, Nishimura R¹, Suda R¹, Sugiura T¹, Sakao S¹, Ishida K^4,5, Masuda M^5,6, Tatsumi K¹.

Author information:

1. Department of Respirology, Graduate School of Medicine, Chiba University.
2. Department of Advanced Medicine in Pulmonary Hypertension, Graduate School of Medicine, Chiba University.
3. Department of Advancing Research on Treatment Strategies for Respiratory, Graduate School of Medicine, Chiba University.
4. Department of Cardiovascular Surgery, Graduate School of Medicine, Chiba University.
5. Department of Cardiovascular Surgery, Eastern Chiba Medical Center.
6. Department of Cardiovascular Surgery, National Hospital Organization, Chiba Medical Center.

Abstract

BACKGROUND:
Several new treatments for chronic thromboembolic pulmonary hypertension (CTEPH) have appeared in recent years, which have led to changes in the treatment algorithm. Changes in survival rates and prognostic factors, however, have not been estimated so far.Methods and Results:Two hundred and eighty patients were diagnosed with CTEPH at Chiba University Hospital between June 1986 and June 2016. Survival rate was investigated by date of treatment initiation (group 1, 1986-1998; group 2, 1999-2008; group 3, 2009-2016). Survival rates were also evaluated by treatment strategy: balloon pulmonary angioplasty (BPA), pulmonary endarterectomy (PEA), and medical treatment. Group 3 had significantly better disease-specific survival than groups 1 and 2 (5-year survival: 91.9% vs. 67.1%, 77.0%, respectively). For the non-PEA (BPA+medication) strategy, group 3 had better disease-specific survival than groups 1 and 2 (5-year survival: 94.9% vs. 54.6%, 74.2%, respectively). The PEA strategy had significantly better survival than the medication strategy in groups 1 and 2, whereas no difference was observed between the BPA, PEA, and medication strategies in group 3.

CONCLUSIONS:
Survival in CTEPH in the recent era has significantly improved, especially in non-PEA patients. BPA and selective pulmonary vasodilators could improve survival in the non-PEA group. In the present study, no difference in survival was found between PEA and non-PEA.

Free Article
PMID: 29540628

Open Heart. 2018 Feb 23;5(1):e000736. doi: 10.1136/openhrt-2017-000736. eCollection 2018.

Rationale and design of the ranolazine PH-RV study: a multicentred randomised and placebo-controlled study of ranolazine to improve RV function in patients with non-group 2 pulmonary hypertension.

Han Y¹, Forfia PR², Vaidya A², Mazurek JA¹, Park MH³, Ramani G⁴, Chan SY⁵, Waxman AB⁶.

Author information:

1. Cardiovascular Division, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
2. Cardiovascular Division, Temple University, Philadelphia, Pennsylvania, USA.
3. Department of Cardiology, Houston Methodist DeBakey Heart and Vascular Center, Houston Methodist Hospital, Houston, Texas, USA.
4. Cardiovascular Division, University of Maryland, Baltimore, Maryland, USA.
5. Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
6. Center for Pulmonary Heart Disease, Heart and Vascular and Lung Centers, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

Abstract

Introduction:
A major determining factor on outcomes in patients with pulmonary arterial hypertension (PAH) is right ventricular (RV) function. Ranolazine, which is currently approved for chronic stable angina, has been shown to improve RV function in an animal model and has been shown to be safe in small human studies with PAH. We aim to study the effect of ranolazine on RV function using cardiovascular magnetic resonance (CMR) in patients with pulmonary hypertension (non-group 2 patients) and monitor the effect of ranolazine on metabolism using metabolic profiling and changes of microRNA.

Methods and analysis:
This study is a longitudinal, randomised, double-blind, placebo-controlled, multicentre proof-of-concept study in 24 subjects with pulmonary hypertension and RV dysfunction treated with ranolazine over 6 months. Subjects who meet the protocol definition of RV dysfunction (CMR RV ejection fraction (EF) <45%) will be randomised to ranolazine or placebo with a ratio of 2:1. Enrolled subjects will be assessed for functional class, 6 min walk test and health outcome based on SF-36 tool. Peripheral blood will be obtained for N-terminal-pro brain natriuretic peptide, metabolic profiling, and microRNA at baseline and the conclusion of the treatment period. CMR will be performed at baseline and the conclusion of the treatment period. The primary outcome is change in RVEF. The exploratory outcomes include clinical, other CMR parameters, metabolic and microRNA changes.

Ethics and dissemination:
The trial protocol was approved by Institutional Review Boards. The trial findings will be disseminated in scientific journals and meetings.

Trial registration numbers:
NCT01839110 and NCT02829034; Pre-results.

Free PMC Article
PMCID: PMC5845423
PMID: 29531764

BMJ Open Respir Res. 2018 Mar 1;5(1):e000263. doi: 10.1136/bmjresp-2017-000263. eCollection 2018.

Symptom severity and its effect on health-related quality of life over time in patients with pulmonary hypertension: a multisite longitudinal cohort study.

Yorke J¹, Deaton C², Campbell M¹, McGowen L³, Sephton P⁴, Kiely DG^4,5, Armstrong I⁴.

Author information:

1. Division of Nursing, Midwifery and Social Work, School of Health Sciences, University of Manchester, Manchester, UK.
2. Cambridge Institute of Public Health, University of Cambridge School of Clinical Medicine, Cambridge, UK.
3. School of Healthcare, University of Leeds, Leeds, UK.
4. Sheffield Pulmonary Vascular Disease Unit, Royal Hallamshire Hospital, Sheffield, UK.
5. Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK.

Abstract

Introduction:
The aim of this cohort study was to examine health-related quality of life (HRQoL) and symptomatology in patients with pulmonary hypertension (PH) and explore factors that influence its evolution over time.

Methods:
A prospective longitudinal multisite cohort study. Participants were recruited from specialist UK PH centres and completed a questionnaire pack at baseline, 6, 12 and 18 months to assess HRQoL (emPHasis-10), dyspnoea, fatigue, sleep, anxiety and depression.

Results:
185 patients entered the study at baseline and 126 (68%) completed month 18. At baseline, patients had significant impairment of HRQoL, anxiety, depression, dyspnoea and severe fatigue. No significant changes, apart from a reduction in the Hospital Anxiety and Depression Scale-Anxiety score (P=0.04), were observed over 18 months. Depression and dyspnoea were predictors of HRQoL (P=0.002 and P=0.03, respectively). Oxygen use was also associated with diminished HRQoL and increased symptom severity.

Conclusion:
Patients with PH experience high levels of symptom severity and the negative impact on HRQoL was unchanged over time. The use of oxygen therapy, in particular, was associated with a significant impact on HRQoL. Further study of factors impacting HRQoL and interventions that target a combination of physiological and psychosocial consequences of living with PH are needed.

Free PMC Article
PMCID: PMC5844371
PMID: 29531745

Int J Cardiol. 2018 Jun 1;260:172-177. doi: 10.1016/j.ijcard.2018.02.114. Epub 2018 Mar 4.

CT derived left atrial size identifies left heart disease in suspected pulmonary hypertension: Derivation and validation of predictive thresholds.

Currie BJ¹, Johns C¹, Chin M¹, Charalampopolous T², Elliot CA², Garg P¹, Rajaram S³, Hill C³, Wild JW⁴, Condliffe RA², Kiely DG⁵, Swift AJ⁶.

Author information:

1. Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK.
2. Sheffield Pulmonary Vascular Disease Unit, Royal Hallamshire Hospital, Sheffield, UK.
3. Radiology Department, Royal Hallamshire Hospital, Sheffield, UK.
4. Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK; INSIGNEO, Institute for in silico medicine, University of Sheffield, UK.
5. Sheffield Pulmonary Vascular Disease Unit, Royal Hallamshire Hospital, Sheffield, UK; INSIGNEO, Institute for in silico medicine, University of Sheffield, UK.
6. Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK; INSIGNEO, Institute for in silico medicine, University of Sheffield, UK. Electronic address: a.j.swift@sheffield.ac.uk.

Abstract

BACKGROUND:
Patients with pulmonary hypertension due to left heart disease (PH-LHD) have overlapping clinical features with pulmonary arterial hypertension making diagnosis reliant on right heart catheterization (RHC). This study aimed to investigate computed tomography pulmonary angiography (CTPA) derived cardiopulmonary structural metrics, in comparison to magnetic resonance imaging (MRI) for the diagnosis of left heart disease in patients with suspected pulmonary hypertension.

METHODS:
Patients with suspected pulmonary hypertension who underwent CTPA, MRI and RHC were identified. Measurements of the cardiac chambers and vessels were recorded from CTPA and MRI. The diagnostic thresholds of individual measurements to detect elevated pulmonary arterial wedge pressure (PAWP) were identified in a derivation cohort (n = 235). Individual CT and MRI derived metrics were tested in validation cohort (n = 211).

RESULTS:
446 patients, of which 88 had left heart disease. Left atrial area was a strong predictor of elevated PAWP>15 mm Hg and PAWP>18 mm Hg, area under curve (AUC) 0.854, and AUC 0.873 respectively. Similar accuracy was also identified for MRI derived LA volume, AUC 0.852 and AUC 0.878 for PAWP > 15 and 18 mm Hg, respectively. Left atrial area of 26.8 cm2 and 30.0 cm2 were optimal specific thresholds for identification of PAWP > 15 and 18 mm Hg, had sensitivity of 60%/53% and specificity 89%/94%, respectively in a validation cohort.

CONCLUSIONS:
CTPA and MRI derived left atrial size identifies left heart disease in suspected pulmonary hypertension with high specificity. The proposed diagnostic thresholds for elevated left atrial area on routine CTPA may be a useful to indicate the diagnosis of left heart disease in suspected pulmonary hypertension.

Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Free Article
PMCID: PMC5899969 [Available on 2018-06-01]
PMID: 29530618

Cardiol Res Cardiovasc Med. 2017;2017(1). pii: CRCM-111. Epub 2017 Jan 11.

Does Late Gadolinium Enhancement still have Value? Right Ventricular Internal Mechanical Work, Ea/Emax and Late Gadolinium Enhancement as Prognostic Markers in Patients with Advanced Pulmonary Hypertension via Cardiac MRI.

Abouelnour AE¹, Doyle M¹, Thompson DV¹, Yamrozik J¹, Williams RB¹, Shah MB¹, Soma SK¹, Murali S¹, Benza RL¹, Biederman RW¹.

Author information:

1. Department of Cardiovascular MRI Clinical and Research Program, Allegheny General Hospital, Pittsburgh, Pennsylvania, USA.

Abstract

Objectives:
Investigate the impact of Right Ventricular (RV) Internal Work (IW), ratio of arterial to ventricular end-systolic elastance (Ea/Emax), and RV Insertion Point (IP) Late Gadolinium Enhancement (LGE) on outcome in Pulmonary Hypertension (PH) patients.

Background:
LGE is well known to be present within the RVIPs and Inter Ventricular Septum (IVS) in PH patients, but its prognostic role remains complex and potentially overestimated via 2D qualitative relative to the 3D quantitative measures now available. However, Ea/Emax, a measure of ventricular-arterial coupling and IW, when added to external cardiac work i.e. the P-V loop area as correlates to the heart’s energy demands, might fundamentally improve measures of prognosis as they interrogate physiology beyond just the RV.

Methods:
Cardiac Magnetic Resonance Imaging (CMR) of 124 PH patients (age = 60±13, 85F) referred to a large tertiary PH center, was retrospectively examined for RV volumetric and functional indices and RVIP LGE%. Right Heart Catheterizations (RHC) performed within 1±2 months of the CMR were reviewed. Ea/Emax was derived as RV End-Systolic Volume (ESV/RVSV). IW was estimated as RVESV ×(RV end-systolic pressure-RV diastolic pressure). Patients were followed from date of CMR for up to 5 years for MACE (death, hospitalized RV failure, initiation of parenteral prostacyclin, sustained ventricular arrhythmia or referral for lung transplantation).

Results:
MACE was high; 48/124 (39%) patients had MACE by 1.6±1.3 years. Neither RVIP nor IVS LGE using visual assessment or even 3D quantization predicted MACE. The strongest predictor of MACE was RVIW (OR=1.00013, p<0.002), vs. mPAP, RV mass, RV EF and IP LGE.

Conclusions:
Surprisingly, neither a single time-point RVIP nor whole IVS LGE% can predict outcome in the largest cohort of PH patients studied to date when compared with conventional or contemporary metrics of disease progression. CMR-LGE appears to lose its’ prognostic value in PH patients in stark contradistinction to all other left and right-sided human myocardial pathologies.

Free PMC Article
PMCID: PMC5843365
PMID: 29528042

J Med Chem. 2018 Apr 12;61(7):2725-2736. doi: 10.1021/acs.jmedchem.7b01312. Epub 2018 Mar 19.

Design, Synthesis, and Biological Activity of New N-(Phenylmethyl)-benzoxazol-2-thiones as Macrophage Migration Inhibitory Factor (MIF) Antagonists: Efficacies in Experimental Pulmonary Hypertension.

Le Hiress M^1,2, Akagah B³, Bernadat G⁴, Tu L^1,2, Thuillet R^1,2, Huertas A^1,2,5, Phan C^1,2, Fadel E^1,2, Simonneau G^1,2,5, Humbert M^1,2,5, Jalce G³, Guignabert C^1,2.

Author information:

1. INSERM UMR_S 999, Hôpital Marie Lannelongue, 92350 Le Plessis-Robinson , France.
2. Université Paris-Sud et Université Paris-Saclay , 94270 Le Kremlin-Bicêtre , France.
3. MIFCARE , 24 rue du Faubourg Saint-Jacques , 75014 Paris , France.
4. BioCIS , Université Paris-Sud, CNRS, Université Paris-Saclay , 92290 Châtenay-Malabry , France.
5. AP-HP, Service de Pneumologie, Centre de Référence de l’Hypertension Pulmonaire Sévère, DHU Thorax Innovation, Hôpital Bicêtre, 94270 Le Kremlin-Bicêtre , France.

Abstract

Macrophage migration inhibitory factor (MIF) is a key pleiotropic mediator and a promising therapeutic target in cancer as well as in several inflammatory and cardiovascular diseases including pulmonary arterial hypertension (PAH). Here, a novel series of N-(phenylmethyl)-benzoxazol-2-thiones 5-32 designed to target the MIF tautomerase active site was synthesized and evaluated for its effects on cell survival. Investigation of structure-activity relationship (SAR) particularly at the 5-position of the benzoxazole core led to the identification of 31 that potently inhibits cell survival in DU-145 prostate cancer cells and pulmonary endothelial cells derived from patients with idiopathic PAH (iPAH-ECs), two cell lines for which survival is MIF-dependent. Molecular docking studies helped to interpret initial SAR related to MIF tautomerase inhibition and propose preferred binding mode for 31 within the MIF tautomerase active site. Interestingly, daily treatment with 31 started 2 weeks after a subcutaneous monocrotaline injection regressed established pulmonary hypertension in rats.

PMID: 29526099

Lancet Respir Med. 2016 Apr;4(4):247-9. doi: 10.1016/S2213-2600(16)00058-8. Epub 2016 Feb 27.

Combination or monotherapy for pulmonary arterial hypertension?

Hoeper MM¹.

Author information:

1. Department of Respiratory Medicine, Hannover Medical School and German Centre for Lung Research, 30623 Hannover, Germany. Electronic address: hoeper.marius@mh-hannover.de.

Comment on
Combination therapy versus monotherapy for pulmonary arterial hypertension: a meta-analysis. [Lancet Respir Med. 2016]

PMID: 26935845 [Indexed for MEDLINE]

Curr Opin Pulm Med. 2017 Sep;23(5):398-403. doi: 10.1097/MCP.0000000000000406.

Pediatric pulmonary arterial hypertension: on the eve of growing up.

Douwes JM¹, Berger RMF.

Author information:

1. Department of Pediatric Cardiology, Center for Congenital Heart Diseases, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Abstract

PURPOSE OF REVIEW:
Current recommendations for diagnosis and treatment of pulmonary arterial hypertension (PAH) during childhood are expert opinion based, because of lacking pediatric data. In recent years, however, important pediatric data have emerged on PAH.

RECENT FINDINGS:
PAH in children shows similarities as well as differences compared to adults. Neonates and children know specific clinical presentations and a hemodynamic profile that differs from adults with PAH. Children identified as acute vasodilator responders according to the criteria proposed for adults rather than the pediatric criteria have better outcome when treated with calcium channel blockers. For nonresponders, combination PAH-targeted therapy leads to improved outcome compared to monotherapy. In pediatric PAH, WHO functional class, N-terminal pro-brain natriuretic peptide and tricuspid annular plane systolic excursion were identified as surrogates for survival and therefore qualify to be treatment goals in a goal-oriented treatment strategy.

SUMMARY:
In order to refine current pediatric treatment guidelines, data on efficacy of specific treatment regiments and strategies are needed. The recently validated composite endpoint of clinical worsening allows for trials that will provide these data. For the first time, evidence-based treatment goals have been identified that will allow for a goal-oriented treatment strategy. Furthermore, various prognostic predictors have been identified that may prove treatment goals in future.

PMID: 28590293 [Indexed for MEDLINE]

Eur J Cardiothorac Surg. 2018 Mar 12. doi: 10.1093/ejcts/ezy092. [Epub ahead of print]

Lung volume reduction surgery in selected patients with emphysema and pulmonary hypertension.

Caviezel C¹, Aruldas C¹, Franzen D², Ulrich S², Inci I¹, Schneiter D¹, Weder W¹, Opitz I¹.

Author information:

1. Department of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland.
2. Department of Respiratory Diseases, University Hospital Zurich, Zurich, Switzerland.

Abstract

OBJECTIVES:
Pulmonary hypertension (PH) is considered a contraindication for lung volume reduction surgery (LVRS). Because, it has been reported that endobronchial lung volume reduction may have a beneficial effect without increased mortality in patients with emphysema and PH, we evaluated its effect on PH in patients undergoing LVRS.

METHODS:
From January 2014 until June 2016, 119 LVRSs were performed at Zurich University Hospital. PH was a contraindication for patients with homogeneous emphysema but was acceptable for those with heterogeneous emphysema. Thirty patients underwent echocardiography before and after LVRS, 10 of whom had preoperative systolic pulmonary artery pressures >35 mmHg and 20 of whom had normal systolic pulmonary artery pressure. The effect of LVRS on pulmonary artery pressure, lung function and survival was analysed.

RESULTS:
Ninety-day mortality for all 30 patients was 0, and the postoperative course did not differ significantly between the 2 groups. In patients with PH, the median systolic pulmonary artery pressure decreased from 41 mmHg [interquartile range (IQR) 39-47] to 37 mmHg (IQR 36-38, P = 0.04). These patients had an improvement of forced expiratory volume in 1 s from the median 27% predicted (IQR 23-34) to 33% (IQR 28-40, P = 0.007) 3 months postoperatively.

CONCLUSIONS:
If further confirmed in other cohorts, mild to moderate PH may no longer be considered a contraindication for LVRS in patients with heterogeneous emphysema.

PMID: 29538689

Eur J Cardiothorac Surg. 2018 Mar 8. doi: 10.1093/ejcts/ezy089. [Epub ahead of print]

Central versus peripheral cannulation of extracorporeal membrane oxygenation support during double lung transplant for pulmonary hypertension.

Glorion M^1,2, Mercier O^1,2, Mitilian D^1,2, De Lemos A², Lamrani L², Feuillet S¹, Pradere P¹, Lepavec J^1,2, Lehouerou D³, Stephan F⁴, Savale L^2,5, Fabre D^1,2, Mussot S^1,2, Fadel E^1,2.

Author information:

1. Department of Thoracic and Vascular Surgery and Heart-Lung Transplantation, Marie-Lannelongue Hospital, Paris-Sud University, Le Plessis Robinson, France.
2. Research and Innovation Unit, INSERM U999, DHU TORINO, Paris-Sud University, Marie Lannelongue Hospital, Le Plessis Robinson, France.
3. Department of Anesthesiology, Marie-Lannelongue Hospital, Paris-Sud University, Le Plessis Robinson, France.
4. Intensive Care Unit, Marie-Lannelongue Hospital, Paris-Sud University, Le Plessis Robinson, France.
5. Department of Pulmonary Diseases, Kremlin Bicêtre Hospital-APHP, Paris-Sud University, Kremlin Bicêtre, France.

Abstract

OBJECTIVES:
Extracorporeal membrane oxygenation (ECMO) has become the standard of cardiopulmonary support during a sequential double lung transplant for pulmonary hypertension. Whether central or peripheral cannulation is the best strategy for these patients remains unknown. Our goal was to determine which is the best strategy by comparing 2 populations of patients.

METHODS:
We performed a single-centre retrospective study based on an institutional prospective lung transplant database.

RESULTS:
Between January 2011 and November 2016, 103 patients underwent double lung transplant for pulmonary hypertension. We compared 54 patients who had central ECMO (cECMO group) to 49 patients who had peripheral ECMO (pECMO group). The pECMO group had significantly more bridged patients who received emergency transplants (31% vs 6%, P = 0.001). The incidence of Grade 3 primary graft dysfunction requiring ECMO (14% vs 11%, P = not significant) and of in-hospital mortality (11% vs 14%, P = not significant) was similar between the groups. Groin infections (16% vs 4%, P = 0.031), deep vein thrombosis (27% vs 11%, P = 0.044) and lower limb ischaemia (12% vs 2%, P = 0.031) occurred significantly more often in the pECMO group. The number of chest reopenings for bleeding or infection was similar between the groups. The 3-month, 1-year and 5-year survival rates did not differ between the groups (P = 0.94).

CONCLUSIONS:
Central or peripheral ECMO produced similar results during double lung transplant for pulmonary hypertension in terms of in-hospital deaths and long-term survival rates. Central ECMO provided satisfactory results without major bleeding provided the patient was weaned from ECMO at the end of the procedure. Despite the rate of groin and lower limb complications, peripheral cannulation remained the preferred solution to bridge the patient to transplant or for postoperative support.

PMID: 29528384