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Resumen Objetivo Este estudio fue disenado para determinar los predictores de la hipertension pulmonar y los signos de disfuncion cardiaca derecha causados por la embolia pulmonar (EP) que pueden conducir a la deteccion temprana de los pacientes de alto riesgo. Por lo tanto, se evaluo el valor predictivo del indice de obstruccion de la arteria pulmonar (IOAP), medido mediante angiografia pulmonar por TC (APTC) en el contexto agudo, para predecir los pacientes susceptibles de sufrir complicaciones cardiacas por EP. Tambien se investigaron otros dos indices de APTC, el diametro de la arteria pulmonar (DAP) y el strain del ventriculo derecho (VD), en estos pacientes y se demostro su valor predictivo de las complicaciones cardiacas en la ecocardiografia de seguimiento. Materiales y metodos En el estudio fueron incluidos 120 pacientes con diagnostico definitivo de EP. El IOAP, el DAP y el strain del VD se midieron mediante APTC en el momento del diagnostico inicial. Se realizo una ecocardiografia transtoracica 6 meses despues del diagnostico de EP y se midieron los indices ecocardiograficos del VD. Se utilizo la correlacion de Pearson para investigar la correlacion entre IOAP, DAP, strain del VD y los signos de disfuncion del hemicardio derecho. Resultados El IOAP estaba fuertemente correlacionado con la presion arterial pulmonar sistolica (PAPS) (r = 0,83), la presion sistolica del VD (r = 0,78) y el grosor de la pared del VD (r = 0,61) en la ecocardiografia de seguimiento a largo plazo. Se detecto una mayor tasa de disfuncion del VD y de dilatacion del VD entre los pacientes con mayor IOAP (p Conclusiones El IOAP, el DAP y el strain del VD son indices de APTC sensibles y especificos que pueden predecir el desarrollo de complicaciones a largo plazo, como la hipertension pulmonar y la disfuncion cardiaca derecha, en el momento del diagnostico inicial de la EP.

Right ventricular (RV) failure has a significant adverse impact on pulmonary hypertension (PH) prognosis. None of the currently used parameters directly assess whether RV fails to provide enough energy output to propel the blood through diseased pulmonary vascular system. Furthermore, most of the current parameters are affected by the volume status of the patient. We aimed to explore whether RV energy failure has a predictive power for mortality on top of the established prognostic risk parameters in patients with PH. We screened 723 cases from our database. A total of 3 sets of binary regression analyses were executed to determine the hazard ratios (HRs) of RV energy failure for 5-year mortality in clinical, echocardiographic, and hemodynamic context, using adjustment variables chosen according to previous studies. The final study population encompassed 549 cases. A total of 77 patients died during the 5-year follow-up (14%). RV energy failure was observed in 146 of 549 patients (26.6%). In the univariate model, RV energy failure strongly associated with increased long-term mortality (HR 4.25, 95% confidence interval [CI] 2.58 to 7.00, p

Objective: The aim of the study was to evaluate the oxygen saturation index (OSI) as an early predictor of clinical deterioration in infants with congenital diaphragmatic hernia (CDH). Methods: A single-center retrospective cohort study was conducted in consecutive infants with isolated CDH with continuous OSI measurements collected in the first 24 h after birth between June 2017 and July 2021. Outcomes of interest were pulmonary hypertension, extracorporeal membrane oxygenation (ECMO)-therapy, and mortality. We evaluated the discriminative values of the maximum OSI value and of mean OSI values with receiver operator characteristic (ROC) analysis and the area under the ROC curve. Results: In 42 infants with 49,473 OSI measurements, the median OSI was 5.0 (interquartile range 3.1–10.6). Twenty-seven infants developed pulmonary hypertension on a median of day 1 (1-1), of which 15 infants had an indication for ECMO-therapy, and 6 infants died. Maximum OSI values were associated with pulmonary hypertension, ECMO-therapy, and mortality. Mean OSI values had an acceptable discriminative ability for pulmonary hypertension and an excellent discriminative ability for ECMO-therapy and mortality. Although OSI measurements were not always present in the first hours after birth, we determined discriminative cut-offs for mean OSI values already in these first hours for pulmonary hypertension, the need for ECMO-therapy, and mortality. Conclusions: Continuous OSI evaluation is a promising modality to identify those infants at highest risk for clinical deterioration already in the first hours after birth. This provides an opportunity to tailor postnatal management based on the individual patient’s needs.

We present the case of a 35-year-old Asiatic man, with no medical relevant history, who debuted in October 2018 with nocturnal cough and orthopnoea. He was diagnosed by transthoracic echocardiogram of severe acute aortic regurgitation due to aortic root dilatation, with normal left and right

Hepatopulmonary syndrome (HPS) is a serious complication of chronic liver disease, characterised by portal hypertension and arterial hypoxaemia due to intrapulmonary vascular dilatation. We report an unusual case in which a 27-year-old man had a first presentation of portal hypertension and cirrhosis complicated by HPS. This patient presented with progressive dyspnoea on exertion and deterioration in mobility, with a type 1 respiratory failure and increased oxygen demand. A bubble echocardiogram showed a possible right-to-left shunt, CT aortogram displayed evidence of portal hypertension and cirrhosis, and liver biopsy findings were consistent with alpha-1 antitrypsin deficiency. The patient’s increased oxygen demand was subsequently treated with continuous positive airway pressure before he was discharged with 8 L home oxygen. With no current established medical therapy for HPS, the patient was assessed for liver transplantation and a decision was made in favour of this.

Wogonin is one of the main active components of Scutellaria baicalensis, which has anti-inflammatory, anti-angiogenesis, and anti-fibrosis effects. Nevertheless, the effect of wogonin on pulmonary hypertension (PH) still lacks systematic research. This study aims to elucidate the potential mechanism of wogonin against PH through network pharmacology and further verify it through biological experiments in pulmonary arterial smooth muscle cells (PASMCs). The potential targets and pathways of wogonin against PH were predicted and analyzed by network pharmacology methods and molecular docking technology. Subsequently, the proliferation of PASMCs was induced by platelet-derived growth factor-BB (PDGF-BB). Cell viability and migration ability were examined. The method of Western blot was adopted to analyze the changes in related signaling pathways. Forty potential targets related to the effect of wogonin against PH were obtained. Based on the protein–protein interaction (PPI) network, gene-ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment, and molecular docking, it was shown that the effect of wogonin against PH is closely related to the proliferation of PASMCs and the hypoxia-inducible factor-1α (HIF-1α) pathway. A variety of results from biological experiments verified that wogonin can effectively inhibit the proliferation, migration, and phenotypic transformation of PDGF-BB-mediated PASMCs. In addition, the anti-proliferation effect of wogonin may be achieved by regulating HIF-1/ NADPH oxidase 4 (NOX4) pathway.

Introduction: Acute pulmonary embolism (PE) is a disease with a broad spectrum of clinical presentations. While some patients can be treated at home or may even be left untreated, other patients require an aggressive approach with reperfusion treatment. Areas covered: (1) Advanced reperfusion treatment in hemodynamically stable acute PE patients considered to be at high risk of decompensation and death, (2) the treatment of subsegmental pulmonary embolism, (3) outpatient treatment for hemodynamically stable PE patients with signs of right ventricle (RV) dysfunction, and (4) the optimal approach to identify and treatpost-PE syndrome. Expert opinion: Outside clinical trials, hemodynamically stable acute PE patients should not be treated with primary reperfusion therapy. Thrombolysis and/or catheter-directed therapy are only to be considered as rescue treatment. Subsegmental PE can be left untreated in selected low-risk patients, after proximal deep vein thrombosis has been ruled out. Patients with an sPESI or Hestia score of 0 criteria can be treated at home, independent of the presence of RV overload. Finally, health-care providers should be aware of post-PE syndrome and diagnose chronic thromboembolic pulmonary disease (CTEPD) as early as possible. Persistently symptomatic patients without CTEPD benefit from exercise training and cardiopulmonary rehabilitation.

Sarcoidosis is a heterogeneous disease, which can affect virtually every body organ, even though lungs and intra thoracic lymph nodes are almost universally affected. The presence of noncaseating granulomas is the histopathological hallmark of the disease, and clinical picture depends on the organs affected. Data about interaction between sarcoidosis and comorbidities, such as cardiovascular and pulmonary diseases, autoimmune disorders, malignancy and drug-related adverse events are limited. Several lung conditions can be associated with sarcoidosis, such as pulmonary hypertension and fibrosis, making it difficult sometimes the differentiation between complications and distinctive pathologies. Their coexistence may complicate the diagnosis of sarcoidosis and contribute to the highly variable and unpredictable natural history, particularly if several diseases are recognised. A thorough assessment of specific disorders that can be associated with sarcoidosis should always be carried out, and future studies will need to evaluate sarcoidosis not only as a single disorder, but also in the light of possible concomitant conditions.Key messagesComorbidities in sarcoidosis are common, especially cardiovascular and pulmonary diseases.In the diagnostic workup, a distinction must be made between sarcoidosis-related complaints and complaints caused by other separate disorders. It can be very difficult to distinguish between complications of sarcoidosis and other concomitant conditions.The coexistence of multiple conditions may complicate the diagnosis of sarcoidosis, affect its natural course and response to treatment.

Background: Pulmonary hypertension (PH) is a complex disease caused by a wide range of underlying conditions, Tanshinone IIA (Tan IIA) has been widely used in PH patients. The study aimed to explore the possible molecular mechanism of Tan IIA against PH by network pharmacology and molecular docking. Methods: Tan IIA and PH-related targets were retrieved from public databases. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and protein–protein interaction (PPI) network were used to investigate the protein targets and mechanism. The binding activity of core targets and Tan IIA were verified by molecular docking. Results: A total of 26 overlapping target proteins between Tan IIA and PH were screened. PPI network identified HSP90AA1, PTPN11, ATM, CA2, TERT, PRKDC, and APEX1 as key pharmacological targets. The results of GO function enrichment analysis included regulation of smooth muscle cell proliferation and migration, regulation of mitotic cell cycle, and regulation of G1/S transition of mitotic cell cycle. KEGG pathway analysis showed that nitrogen metabolism, NF-kappa B signaling pathway, cell cycle, necroptosis, apoptosis, and JAK-STAT signaling pathway were associated with Tan IIA in PH. The molecular docking results showed that Tan IIA can closely bind three core targets (HSP90AA1, PTPN11, and CA2). Conclusions: The present work initially clarified the effective therapeutic targets, biological processes, and signaling pathways of Tan IIA treatment of PH, which lay a foundation for further research on the pharmacological effects of Tan IIA.

Pulmonary hypertension (PH) is a risk factor for morbidity and mortality in patients undergoing surgery and anesthesia. This document represents the first international consensus statement for the perioperative management of patients with pulmonary hypertension and right heart failure. It includes recommendations for managing patients with PH being considered for surgery, including preoperative risk assessment, planning, intra- and postoperative monitoring and management strategies that can improve outcomes in this vulnerable population. This is a comprehensive document that includes common perioperative patient populations and surgical procedures with unique considerations.

In recent years, magnetic resonance imaging (MRI) has largely increased our knowledge and predictive accuracy of congenital diaphragmatic hernia (CDH) in the fetus. Thanks to its technical advantages, better anatomical definition, and superiority in fetal lung volume estimation, fetal MRI has been demonstrated to be superior to 2D and 3D ultrasound alone in CDH diagnosis and outcome prediction. This is of crucial importance for prenatal counseling, risk stratification, and decision-making approach. Furthermore, several quantitative and qualitative parameters can be evaluated simultaneously, which have been associated with survival, postnatal course severity, and long-term morbidity.Conclusion: Fetal MRI will further strengthen its role in the near future, but it is necessary to reach a consensus on indications, methodology, and data interpretation. In addition, it is required data integration from different imaging modalities and clinical courses, especially for predicting postnatal pulmonary hypertension. This would lead to a comprehensive prognostic assessment. What is Known:• MRI plays a key role in evaluating the fetal lung in patients with CDH.• Prognostic assessment of CDH is challenging, and advanced imaging is crucial for a complete prenatal assessment and counseling. What is New:• Fetal MRI has strengthened its role over ultrasound due to its technical advantages, better anatomical definition, superior fetal lung volume estimation, and outcome prediction.• Imaging and clinical data integration is the most desirable strategy and may provide new MRI applications and future research opportunities.

In recent years, magnetic resonance imaging (MRI) has largely increased our knowledge and predictive accuracy of congenital diaphragmatic hernia (CDH) in the fetus. Thanks to its technical advantages, better anatomical definition, and superiority in fetal lung volume estimation, fetal MRI has been demonstrated to be superior to 2D and 3D ultrasound alone in CDH diagnosis and outcome prediction. This is of crucial importance for prenatal counseling, risk stratification, and decision-making approach. Furthermore, several quantitative and qualitative parameters can be evaluated simultaneously, which have been associated with survival, postnatal course severity, and long-term morbidity.CONCLUSION: Fetal MRI will further strengthen its role in the near future, but it is necessary to reach a consensus on indications, methodology, and data interpretation. In addition, it is required data integration from different imaging modalities and clinical courses, especially for predicting postnatal pulmonary hypertension. This would lead to a comprehensive prognostic assessment.WHAT IS KNOWN: • MRI plays a key role in evaluating the fetal lung in patients with CDH. • Prognostic assessment of CDH is challenging, and advanced imaging is crucial for a complete prenatal assessment and counseling.WHAT IS NEW: • Fetal MRI has strengthened its role over ultrasound due to its technical advantages, better anatomical definition, superior fetal lung volume estimation, and outcome prediction. • Imaging and clinical data integration is the most desirable strategy and may provide new MRI applications and future research opportunities.

PH se definira kao povišenje tlaka u plućnoj cirkulaciji. Prema SZO PH dijeli se u pet skupina. U prvu skupinu pripada plućna arterijska hipertenzija, koja je najčešće idiopatska, no može biti i nasljedna, uzrokovana drugim bolestima i čimbenicima iz okoliša. Glavni patogenetski mehanizmi bolesti su hemodinamske promjene, upalni i imunološki procesi te endotelna disfunkcija. U uznapredovalim stadijima česta je pojava disfunkcije DV-a koja u konačnici može uzrokovati zatajenje DV-a. Ostale četiri skupine PH nastaju sekundarno, kao posljedica drugih bolesti, a tu pripadaju PH uslijed bolesti lijevog srca, PH uslijed plućne bolesti i/ili hipoksije, PH uslijed opstrukcije plućne arterije i PH s nejasnim i/ili multifaktorskim mehanizmima. Simptomi su većinom zajednički pojedinim skupinama PH, a tipično uključuju dispneju, nepodnošenje tjelesnog napora te simptome zatajenja DV-a u uznapredovalim stadijima bolesti., PH is defined as an increased pressure in the pulmonary circulation. According to the WHO, PH is divided into five groups. The first group includes pulmonary arterial hypertension, which is usually idiopathic, but can also be hereditary, caused by other diseases and environmental factors. The main pathogenetic mechanisms of the disease are hemodynamic changes, inflammatory and immune processes, and endothelial dysfunction. In advanced stages, RV dysfunction is common, which can ultimately cause RV failure. The other four groups of PH arise secondarily, as a result of other diseases, and include PH due to left heart disease, PH due to lung disease and/or hypoxia, PH due to pulmonary artery obstruction and PH with unclear and/or multifactorial mechanisms. The symptoms are mostly common in all groups of PH, and typically include dyspnea, inability to bear physical exertion and symptoms of RV failure in advanced stages of the disease.

Introduction: In stable patients with pulmonary arterial hypertension (PAH), pulmonary rehabilitation (PR) is an effective, safe and cost-effective non-pharmacological treatment. However, the effects of PR on vascular function have been poorly explored. This study aimed to compare the amounts of circulating progenitor cells (PCs) and endothelial microvesicles (EMVs) in patients with PAH before and after 8 weeks of endurance exercise training as markers of vascular competence. Methods: A prospective study of 10 consecutive patients with PAH that successfully finished a PR program (8 weeks) was carried out before and after this intervention. Levels of circulating PCs defined as CD34+CD45low progenitor cells and levels of EMVs (CD31+ CD42b-) were measured by flow cytometry. The ratio of PCs to EMVs was taken as a measure of the balance between endothelial damage and repair capacity. Results: All patients showed training-induced increases in endurance time (mean change 287 s). After PR, the number of PCs (CD34+CD45low/total lymphocytes) was increased (p < 0.05). In contrast, after training, the level of EMVs (CD31+ CD42b-/total EMVs) was reduced. The ratio of PCs to EMVs was significantly higher after training (p < 0.05). Conclusion: Our study shows, for the first time, that endurance exercise training in patients with stable PAH has a positive effect, promoting potential mechanisms of damage/repair in favor of repair. This effect could contribute to a positive hemodynamic and clinical response.

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) may lead to typical electrocardiographic changes that can be reversed by balloon pulmonary angioplasty (BPA). The aim of this study was to investigate the significance of rarely used electrocardiogram (ECG) parameters, possible electrocardiographic differences between residual and significantly improved CTEPH and the role of electrocardiographic parameters in low mPAP (mean pulmonary arterial pressure) ranges since the mPAP threshold for the definition of pulmonary hypertension has recently been adjusted (≥25 mmHg to >20 mmHg). Material and Methods: Between March 2014 and October 2020, 140 patients with CTEPH and 10 with CTEPD (chronic thromboembolic pulmonary disease) without pulmonary hypertension (PH) were retrospectively enrolled (12-lead ECG and right heart catheterization before and 6 months after BPA). The ECG parameters of right heart strain validated by studies and clinical experience were evaluated. Special attention was paid to six specific ECG parameters. After BPA, the cohort was divided into subgroups to investigate possible electrocardiographic differences with regard to the haemodynamic result. Results: The present study confirmed that the typical electrocardiographic signs of CTEPH can be found on an ECG, can regress after BPA and partially correlate well with haemodynamic parameters. “R V1, V2 + S I, aVL − S V1” was a parameter of particular note. BPA reduced its frequency (47% vs. 29%) statistically significantly after Bonferroni correction (p < 0.001). Moreover, it showed a good correlation with mPAP and PVR (r-values: 0.372–0.519, p-values: < 0.001). Exceeding its cut-off value before therapy was associated with more severe CTEPH before therapy (higher mPAP, PVR, NT-pro-BNP and troponin and lower TAPSE) and an increased risk of death. Exceeding its cut-off value before and after therapy was associated with more severe CTEPH after therapy (higher RAP, mPAP, PVR, NT-pro-BNP and NYHA class) and an increased risk of death. Men tend to be affected more frequently. After subgrouping, it was observed that a higher median mPAP was associated with a higher right atrial pressure (RAP), a higher pulmonary vascular resistance (PVR) and a lower cardiac output (CO) before and after BPA. In addition, under these conditions, more and more severe electrocardiographic pathologies were detected before and after BPA. Some patients with low mPAP also continued to show mild ECG changes after BPA. In some cases, very few to no pathological ECG changes were detected, and the ECG could present as mostly normal in some patients (5% before BPA and 13% after BPA). Conclusion: “R V1, V2 + S I, aVL − S V1” seems to be able to support the diagnosis of CTEPH, indicate therapeutic improvement and estimate haemodynamics. It also seems capable of predicting a (persistent) severe disease with probably increased need for therapy and increased mortality. Mild PH has been observed to have either no or few mild ECG changes. This might complicate the (early) detection of PH.

Background: Hypersensitivity pneumonitis (HP) is an interstitial lung disease (ILD) that occurs in susceptible individuals in response to various inhaled antigens. The fibrotic phenotype of HP is characterized by disease progression and can lead to pulmonary hypertension (PH). The aim of this study was to estimate the prevalence of PH and to identify predictors of PH in patients with chronic HP. Methods: We conducted an observational longitudinal study that included 85 patients with an established diagnosis of HP. Clinical examination, quality of life questionnaires, high-resolution computed tomography (HRCT) of the chest, arterial blood gases analyses, six-minute walking test (6-MWT), pulmonary function tests, and echocardiography were performed. Results: Patients were divided into groups with fibrotic (71.8%) and nonfibrotic phenotype (28.2%). PH was detected in 41 (48.2%) patients. Patients with PH had the predominant fibrotic phenotype of HP, were older, more symptomatic, and had a higher FVC/DLco ratio. The most significant predictors of PH were CT signs of fibrosis, finger clubbing, FVC/DLco, decreased distance, and SpO2 at the end of 6-MWT, as well as the presence of cardiovascular diseases. Conclusions: PH is a common condition in patients with chronic HP, especially with the fibrotic phenotype. Early detection of the PH predictors is necessary for the timely diagnosis of this complication of HP.

Background and Objectives: Pulmonary hypertension (PH) secondary to left-sided valvular heart disease is associated with poor cardiac surgical outcome compared with patients without PH. Our objective was to investigate the prognostic factors of surgical outcome in patients with PH undergoing mitral valve (MV) and tricuspid valve (TV) surgery, in order to risk stratify their management. Materials and Methods: This is a retrospective observational study on patients with PH who underwent MV and TV surgery from 2011 to 2019. The primary outcome was all-cause mortality. The secondary outcomes were post-op respiratory and renal complications, length of intensive care unit stay and length of hospital stay. Results: Seventy-six patients were included in this study. The all-cause mortality was 13% (n = 10), with mean survival of 92.6 months. Among the patients, 9.2% (n = 7) had post-op renal failure requiring renal replacement therapy and 6.6% (n = 5) had post-op respiratory failure requiring intubation. Univariate analysis demonstrated that pre-operative left ventricular ejection fraction (LVEF), peak systolic tissue velocity at the tricuspid annulus (S’) and etiology of MV disease were associated with respiratory and renal failure. Tricuspid annular plane systolic excursion (TAPSE) was associated with respiratory failure only. S’, type of operation, LVEF, urgency of surgery, and etiology of MV disease were found to be predictive of mortality. After excluding redo mitral surgery, all statistically significant findings remain unchanged, with the addition of right ventricular (RV) size being associated with respiratory failure. In the subgroup analysis of routine cases (n = 56), patients with primary mitral regurgitation who underwent mitral valve repair had better survival outcome. Conclusions: Urgency of surgery, etiology of MV disease, type of operation (replacement or repair), S’ and pre-op LVEF are prognostic indicators in this small cohort of patients with PH undergoing MV and TV surgery. A larger prospective study is warranted to validate our findings.

Objectives: To determine the main clinical and demographic outcomes related to Pulmonary Hypertension (PH) and adverse obstetric and fetal/neonatal outcomes. Methods: This study retrospectively analyzed the medical record data of 154 patients with PH who were admitted to the Third Affiliated Hospital of Guangzhou Medical University between January 2011 and December 2020. Results: According to the severity of elevated Pulmonary Artery Systolic Pressure (PASP), 82 women (53.2%) were included in the mild PH group, 34 (22.1%) were included in the moderate PH group, and 38 (24.7%) were included in the severe PH group. There were significant differences in the incidence of heart failure, premature delivery, Very-Low-Birth-Weight (VLBW) infants, and Small-for-Gestational-Age (SGA) infants among the three PH groups (p < 0.05). Five (3.2%) women died within 7-days after delivery, 7 (4.5%) fetuses died in utero, and 3 (1.9%) neonates died. The authors found that PASP was an independent risk factor for maternal mortality. After adjustment for age, gestational weeks, systolic blood pressure, Body Mass Index (BMI), mode of delivery, and anesthesia, the risk of maternal mortality in the severe PH group was 20.21 times higher than that in the mildmoderate PH group (OR = 21.21 [95% CI 1.7~264.17]), p < 0.05. All 131 (85.1%) patients were followed up for 12 months postpartum. Conclusions: The authors found that the risk of maternal mortality in the severe PH group was significantly higher than that in the mild-moderate group, highlighting the importance of pulmonary artery pressure screening before pregnancy, early advice on contraception, and multidisciplinary care.

Pulmonary artery aneurysms (PAAs) are rare with non-specific clinical presentation but may lead to serious complications such as pulmonary artery dissection, rupture and compression of the left main coronary artery (LMCA). Their complications and PAA association with pulmonary hypertension lead to significant morbidity and mortality. The standard treatment strategy is surgical correction of the aneurysm, however percutaneous coronary intervention in patients with clinically significant compression of the LMCA, due to PAA should be considered as a possible treatment approach. In this article, we present a case report of a 73-year-old with polymorbidity, presenting with an acute coronary syndrome, caused by extrinsic compression of the LMCA by PAA. Due to the high surgical risk, we adopted an endovascular approach with stenting of the compressed LMCA with successful restorationof the blood flow and clinical stabilization. In this case, a percutaneous coronary intervention proved to be a safe and effective treatment option for selected patients, who are at high operative risk.&nbsp

International audience; Pulmonary arterial hypertension (PAH) is a progressive and fatal disease characterized by the dysfunction of pulmonary endothelial cells (ECs) and obstructive vascular remodeling. The non-receptor tyrosine kinase c-Abelson (cAbl) plays central roles in regulating cell-cycle arrest, apoptosis, and senescence after cellular stress. We hypothesized that cAbl is down-activated in experimental and human PAH, thus leading to reduced DNA integrity and angiogenic capacity of pulmonary ECs from PAH patients (PAH-ECs). We found cAbl and phosphorylated cAbl levels to be lower in the endothelium of remodeled pulmonary vessels in the lungs of PAH patients than controls. Similar observations were obtained for the lungs of sugen+hypoxia (SuHx) and monocrotaline (MCT) rats with established pulmonary hypertension. These in situ abnormalities were also replicated in vitro, with cultured PAH-ECs displaying lower cAbl expression and activity and an altered DNA damage response and capacity of tube formation. Downregulation of cAbl by RNA-interference in Control-ECs or its inhibition with dasatinib resulted in genomic instability and the failure to form tubes, whereas upregulation of cAbl with DPH reduced DNA damage and apoptosis in PAH-ECs. Finally, we establish the existence of crosstalk between cAbl and bone morphogenetic protein receptor type II (BMPRII). This work identifies the loss of cAbl signaling as a novel contributor to pulmonary EC dysfunction associated with PAH.

Aims Repeated risk assessments and treatment patterns over long time are sparsely studied in chronic thromboembolic pulmonary hypertension (CTEPH); thus, we aimed to investigate changes in risk status and treatment patterns in incident patients with CTEPH over a 5 year period. Methods and results Descriptive and explorative study including 311 patients diagnosed with CTEPH 2008-2019 from the Swedish pulmonary hypertension registry, stratified by pulmonary endarterectomy surgery (PEA). Risk and PH-specific treatment were assessed in surgically treated (PEA) and medically treated (non-PEA) patients at diagnosis and up to 5 years follow-up. Data are presented as median (Q1-Q3), count or per cent. Prior to surgery, 63% in the PEA-group [n = 98, age 64 (51-71) years, 37% female] used PH-specific treatment and 20,69, and 10% were assessed as low, intermediate or high risk, respectively. After 1 year post-surgery, 34% had no PH-specific treatment or follow-up visit registered despite being alive at 5 years. Of patients with a 5 year visit (n = 23), 46% were at low and 54% at intermediate risk, while 91% used PH-specific treatment. In the non-PEA group [n = 213, age 72 (65-77) years, 56% female], 28% were assessed as low, 61% as intermediate and 11% as high risk. All patients at high risk versus 50% at low risk used PH-specific treatment. The 1 year mortality was 6%, while the risk was unchanged in 57% of the patients; 14% improved from intermediate to low risk, and 1% from high to low risk. At 5 years, 27% had a registered visit and 28% had died. Of patients with a 5 year visit (n = 58), 38% were at low, 59% at intermediate and 1% at high risk, and 86% used PH-specific treatment. Conclusions Risk status assessed pre-surgery did not foresee long-term post-PEA risk and pre-surgery PH-specific treatment did not foresee long-term post-PEA treatment. Medically treated CTEPH patients tend to remain at the same risk over time, suggesting a need for improved treatment strategies in this group. Funding Agencies|Swedish Association of Local Authorities and Regions; Actelion Pharmaceuticals; Janssen Pharmaceutical Company of Johnson & Johnson, Allschwil, Switzerland

Lung transplantation is the definitive surgical treatment for end-stage lung disease. However, infants comprise less than 5% of pediatric cases. This study sought to provide an overview of infant lung transplantation outcomes over the past 3 decades by using linked United Network for Organ Sharing (UNOS) and Pediatric Health Information System (PHIS) data.Infants undergoing lung transplantation from 1989 to 2020 in UNOS were reviewed. UNOS and PHIS records for patients who underwent lung transplantation from 1995 to 2020 were linked using date of birth, sex, and date of surgery ± 3 days. The study assessed underlying diagnoses, pretransplant and posttransplant extracorporeal membrane oxygenation support, retransplant-free survival to discharge, hospital experience (≥1 annual transplant for ≥4 years in a 5-year period), operative decade, bronchiolitis obliterans syndrome, long-term survival, and functional status at latest follow-up.A total of 112 lung transplants were performed in 109 infants over 31 years. Of these, 21 patients died before discharge, and 2 underwent repeat transplantation during the same admission. The study linked 80.6% (83 of 103) of UNOS and PHIS records. Hospital survival was lower for infants with idiopathic pulmonary hypertension and those who underwent transplant procedures at less experienced centers. All 7 infants requiring postoperative extracorporeal membrane oxygenation support died. Median freedom from bronchiolitis obliterans syndrome was 8.1 years (interquartile range, 4.6 to 11.6 years). After discharge, median survival was 10.3 years (interquartile range, 6.3 to 14.4 years), with improved 10-year survival for those patients who underwent transplantation from 2010 to 2020 (87.3%) vs 2000 to 2009 (52.4%; P = .098) and 1989 to 1999 (34.1%; P = .004). A total of 84.6% (33 of 39) of survivors had minor or no restrictions at latest follow-up.Carefully selected infants experience promising short- and long-term outcomes after lung transplantation.

Several tricuspid annuloplasty (TA) techniques are used for concomitant repair of functional tricuspid regurgitation (TR). This study compared the midterm clinical and valvular outcome among 3 annuloplasty techniques.TA was performed in 307 patients (aged 75.9 ± 10.4 years) with a rigid ring (RA) in 184, a flexible band (FA) in 80, or a suture annuloplasty (SA) in 43. Study end points were survival and recurrence of TRgrade 2 at 5 years.TA was performed concomitantly to mitral valve surgery in 136 patients (44.3%), aortic valve surgery in 18 (5.9%), coronary artery bypass grafting in 13 (4.2%), or a combined procedure in 140 (45.6%). Most had TRgrade 2 (78.5%), without significant differences between the TA groups (P = .878). Within a median follow-up of 3.4 years (interquartile range, 2.2-5.0 years), the 5-year survival was 80.1% ± 3.4% for RA, 83.5% ± 4.7% for FA, and 85.1% ± 6.5% for SA (P = .471). Independent risk factors for late mortality were renal impairment (hazard ratio [HR], 2.83; 95% CI, 1.16-6.89; P = .022), diabetes (HR, 2.10; 95% CI, 1.07-4.11; P = .030), and severe right ventricular dysfunction by tricuspid annulus plane systolic excursion10 mm (HR, 11.52; 95% CI, 4.98-26.66; P.001). Pulmonary hypertension was nearly significant (HR, 1.92; 95% CI, 0.98-3.74; P = .057). The cumulative incidence of TR recurrence at 5 years was 15.9%, 19.4%, and 21.1% for RA, FA, and SA, respectively (P = .342). Severe pulmonary hypertension (HR, 2.64; 95% CI, 1.38-5.07; P = .003), preoperative TR grade (HR, 1.82; 95% CI, 1.01-3.27; P = .046), and residual TRgrade 2 at discharge (HR, 3.38; 95% CI, 1.64-6.96; P = .001) were predictive for later TR recurrence, regardless of the annuloplasty technique.This study demonstrates that advanced pathophysiological right circulatory impairment, such as severe pulmonary hypertension and right ventricular dysfunction, affects the midterm survival and TR recurrence rate more than the annuloplasty technique used for concomitant repair of functional TR.

Background: Pulmonary hypertension (PH), a disease with a wide range of etiology, refers to the presence of elevated pressure in the pulmonary vasculature. Red cell distribution width (RDW), a measure of anisocytosis of red cells, has gained interest as a biomarker in various disease conditions. This study aimed to review published studies assessing the clinical utility of RDW in PH. Methods: Restricting ourselves to publications between 2000 and 2019, we systematically searched PubMed, Medline, and Embase using pre-defined search criteria. Studies that evaluated the clinical utility of RDW including prognosis, diagnosis, response to treatment, and correlation to disease severity, in the setting of PH were included in the study. Results: A total of 88 abstracts were found, of which 43 were reviewed, 25 full texts retrieved, and 16 studies included in the final analysis after applying exclusion criteria. There was a broad range of study designs, study types, and study populations. There was evidence supporting the use of RDW in diagnosing PH, predicting survival in PH, predicting vasodilator reactivity in PH, and measuring disease severity. Conclusion: RDW appears to correlate with various parameters in PH. Larger studies are needed to elucidate the possible applicability of RDW in the clinical setting.

The World Symposium on Pulmonary Hypertension (WSPH) was organized by the World Health Organization in 1973 in response to an increase in pulmonary arterial hypertension in Europe caused by aminorex, an appetite suppressant. The mandate of this meeting was to review the latest clinical and scientific research and to formulate recommendations to improve the diagnosis and management of pulmonary hypertension (PH).1 Since 1998, the WSPH has met every five years and in 2018, the sixth annual WSPH revised the hemodynamic definition of PH. This two-part series will review the updated definition, classification, pathophysiology, presentation, diagnosis, management, and perioperative management of patients with PH. In the first part of this series, the definition, classification, pathophysiology, and presentation will be reviewed.

The efficacy of early immunosuppressive therapy without invasive therapy, such as endovascular or surgical revascularization, for pulmonary hypertension due to Takayasu arteritis (TAK-PH) remains to be elucidated. We herein report two cases of TAK-PH due to pulmonary arteritis successfully treated with early immunosuppressive therapy. A literature review of 42 cases of TAK-PH with pulmonary artery involvement showed that the cases treated with immunosuppressive therapy early after the onset (within 12 months) had a higher erythrocyte sedimentation rate and better outcome without invasive therapy than those treated later. TAK-PH may be successfully treated with immunosuppressive therapy without invasive therapy when diagnosed early with high disease activity.

Introduction: The perioperative management of patients with pulmonary hypertension (PH) undergoing cardiac surgery represents one of the most challenging clinical scenarios. This fact mainly depends on the relationship existing between PH and right ventricular failure (RVF). Levosimendan (LS) is an inodilator that might be an effective agent in the treatment of PH and RVF. The aim of this study was to examine the impact of the duration of cardiopulmonary bypass (CPB) on the therapeutic drug monitoring of LS and to evaluate the effect of preemptive administration of LS on perioperative hemodynamic and echocardiographic parameters in cardiac surgical patients with preexisting PH. Materials and Methods: In this study, LS was administered in adult patients undergoing cardiac surgery before CPB in order to prevent exacerbation of preexisting PH and subsequent right ventricular dysfunction. Thirty cardiac surgical patients with preoperatively confirmed PH were randomized to receive either 6 μg/kg or 12 μg/kg of LS after the induction of anesthesia. The plasma concentration of LS was measured after CPB. In this study, a low sample volume was used combined with a simple sample preparation protocol. The plasma sample was extracted by protein precipitation and evaporated; then, the analyte was reconstituted and detected using specific and sensitive bioanalytical liquid chromatography with mass spectrometry (LC-MS/MS) methodology. The clinical, hemodynamic, and echocardiographic parameters were registered and evaluated before and after the administration of the drug. Results: A fast bioanalytical LC-MS/MS methodology (a run time of 5.5 min) was developed for the simultaneous determination of LS and OR-1896, its main metabolite in human plasma. The LC-MS/MS method was linear over a range of 0.1–50 ng/mL for LS and 1–50 ng/mL for its metabolite OR-1896. Measured plasma concentrations of LS were inversely related to the duration of CPB. LS administration before CPB during cardiac surgery was effective in reducing pulmonary artery pressure and improving hemodynamic parameters after CPB, with a more pronounced and durable effect of the drug at the dose of 12 μg/kg. Additionally, administration of LS at a dose of 12 μg/kg in cardiac surgical patients with PH before CPB improved right ventricular function. Conclusion: LS administration decreases pulmonary artery pressure and may improve right ventricular function in patients with PH undergoing cardiac surgery.

First the VG-RVPO as a monitoring for PAH in SSc patients was evaluated, here serial measurements of the VG-RVPO, can be used as a follow-up instrument to detect early changes in RV pressure over time. Then we investigated the role of the VG-RVPO in improving the efficiency of the YEARS algorithm. Neither as a stand-alone diagnostic test nor when combined with the YEARS algorithm, it had any diagnostic value. Then the role of VG-RVPO in estimating the presence of PH, and the prognostic value of an abnormal VG-RVPO in PE patients was evaluated. There was an association between VG-RVPO and RV overload as measured by CTPA. In Chapter 5, the outcome of AAOCA patients is described and linked to pre-and postoperative symptoms. Overall, surgical correction significantly reduces symptoms. The CTOA on pre-and post-operative CTAs of patients with AAOCA was compared and related to anatomy and post-operative outcome. It suggests that CTA can be used to look at the anatomy of AAOCA patients before and after surgery. The last study re-evaluates the late clinical outcome and hemodynamics in patients with TOF. The findings shows, after 17.1 years there was a stabilization of RV function and an impressive durability of the homograft.

IPAVA su krvne žile velikog promjera 15-500 μm (čak i do 1000 μm), prisutne u >95% zdravih osoba, dok je PFO prisutan u ~ 1/3 opće populacije i oboje predstavljaju mogući izvor desno-lijevog šanta. U Studiji I smo istražili učinak nitroglicerina, noradrenalina i aminofilina na otvaranje i novačenje intrapulmonalnih arteriovenskih anastomoza u zdravih ispitanika u mirovanju. Ovi lijekovi primijenjeni u ranije navednim dozama nisu imali učinka na filtrirajuću sposobnost pluća u zdravih ljudi u mirovanju. Čini se da ovi lijekovi nemaju utjecaja na otvaranje i novačenje IPAVA, krvnih žila velikog promjera, kako direktnim (putem receptora) tako niti indirektnim (putem povećanja tlaka ili protoka) učinkom. Unatoč njihovim različitim vazoaktivnim i hemodinamskim učincima, nijedan od lijekova nije uzrokovao značajan porast srčanog minutnog volumena i/ili sistoličkog tlaka u plućnoj arteriji stimulusa ranije dokazanih da pasivno otvaraju i novače IPAVA. Naposljetku valja naglasiti da primjena ovih lijekova, u navedenim dozama, ne otvara mogući put za sistemsku embolizaciju vitalnih organa. U Studiji II smo istražili mogući doprinos protoka krvi kroz IPAVA-e i PFO na arterijsku hipoksemiju u CHF bolesnika sa i bez plućne hipertenzije. Otkrili smo da je arterijska hipoksemija u mirovanju bila prisutna samo kod CHF PH+ bolesnika s PFO-om. S obzirom da protok krvi kroz IPAVA-e nije bio prisutan ili je bio beznačajan, čak i kod onih s plućnom hipertenzijom, zaključujemo da protok krvi kroz IPAVA-e nije pod utjecajem povećanog tlaka u plućnoj arteriji te da isti ne pridonosi arterijskoj hipoksemiji kod ovih bolesnika. Pridonosi li PFO vježbanjem induciranoj arterijskoj hipoksemiji u CHF bolesnika ostaje nepoznato. Podatci dobiveni u ovoj studiji, kao i prethodno publicirani, dokazuju da starenje negativno utječe na IPAVA-e, što podrazumijeva da se sa povećanjem životne dobi protok krvi kroz IPAVA-e značajno smanjuje. Potrebno je istražiti kakve su posljedice, ako ih ima, povezane s tim smanjenjem. Također, u ovoj studiji smo dokazali izvrsnu podudarnost detekcije i kvantificiranja desno-lijevog šanta (protok krvi kroz IPAVA-e i/ili PFO) transtorakalnom kontrastnom ehokardiografijom i transkranijskim doplerom. Dakle, obje metode mogu poslužiti za istu svrhu, što je osobito značajno kada izvođenje jedne od njih nije podobno ili nije moguće. Kirurško/intervencijsko zatvaranje PFO-a može se uraditi zbog različitih indikacija, kao što su, npr. preboljeni ishemijski moždani udar ili tranzitorna ishemijska ataka. Međutim, s obzirom da PFO pridonosi arterijskoj hipoksemiji u CHF bolesnika s plućnom hipertenzijom, ova grupa bolesnika mogla bi profitirati od zatvaranja PFO-a s ciljem da se poboljša i oksigenacija, osobito u onih s težim stupnjem hipoksemije. Postojanje IPAVA je poznato najmanje posljednjih 50 godina, međutim, njihova fiziološka i klinička značajnost nije do kraja istražena. Iako, trenutno predložene uloge uključuju mogućnost alternativnog puta embolima iz venskog sustava da dosegnu sistemsku cirkulaciju, zatim da služe kao paralelna vaskularna mreža, koja se u određenim uvjetima otvara za preusmjeravanje potencijalno štetne hidrodinamske energije od krhkih plućnih kapilara čime čine desno-lijevi šant, zbog čega mogu negativno utjecati na plućnu izmjenu plinova. Proučavanje protoka krvi kroz IPAVA-e i PFO predstavlja značajno istraživačko područje s ciljem da se predložene uloge bolje odrede, zbog čega detektiranje i kvantificiranje protoka kroz IPAVA-e i PFO može postati mnogo važnije i u kliničkoj praksi., IPAVA are large diameter 15-500 μm (up to 1000 μm) vascular conduits, present in >95% of healthy humans, while PFO is present in ~ 1/3 of general population and both represent possible source of right to left shunt. In Study I we investigated the effects of nitroglicerine, norepinephrine and aminophylline on opening and recruitment of intrapulmonary arteriovenous anastomoses in healty humans at rest. We found that these drugs applied in above named doses did not seem to modify the filtering capability of the lung in healthy humans at rest which speakes in fovour that drugs are not affecting the large-diameter inducible intrapulmonary arteriovenous anastomoses by direct effect on opening and recruitment of the IPAVA (via receptors) nor indirect (via increase in pressure and flow). Despite their various vasoactive and hemodynamic effects, none of the drugs caused a substantial increase in QT and/or PASP, stimuli previously shown to passively open IPAVA. Finally, application of these drugs, in named doses, does not open the pathway for systemic micro/embolization of vital organs. However, further research is needed to examine their effect on IPAVA during physical activity intensities required for ordinary daily activities or in moderate and strenuous exercise as well as in others than healthy subjects. In Study II we examined the potential contributions of blood flow through IPAVA and PFO to arterial hypoxaemia in subjects with CHF with and without pulmonary hypertension. We found that arterial hypoxaemia at rest was present in CHF PH+ subjects with PFO. Given that blood flow through IPAVA was absent or insignificant, even in those subjects with pulmonary hypertension, we conclude that blood flow through IPAVA is not influenced by increased pulmonary pressures and does not contribute to arterial hypoxaemia in these subjects. Whether or not PFO contributes to exercise-induced arterial hypoxaemia in subjects with CHF remains unknown. Data from our study and previous data indicate that aging process may negatively affect IPAVA, assuming that blood flow through IPAVA is reduced with increasing age. We still need to investigate what consequences, if any, are associated with this decline. Also, in this study we have shown excellent correlation between detection and quantification of right to left shunt (blood flow through IPAVA and /or PFO) using transthoracic contrast echocardiography and transcranial Doppler. Thus, both methods can be used for the same purpose which is especially important when performing one of them is not suitable or possible. Surgical closure of the PFO may be undertaken for various reasons, such as history of stroke or transient ischaemic attack, yet PFO closure for this purpose remains controversial. However, because PFO contributes to arterial hypoxaemia in subjects with CHF and pulmonary hypertension, these specific subjects may also benefit from PFO closure as an intervention to improve oxygenation, particularly in those subjects with more severe levels of hypoxaemia. IPAVA have been known to exist for over 50 years, but their physiological and clinical significance are still being established; although, currently suggested roles for IPAVA include allowing emboli to reach the systemic circulation, also serve as a parallel vascular network that under certain conditions open to divert potentially damaging hydrodynamic energy from fragile pulmonary capillaries thus creating the right to left shunt which could adversely affect the pulmonary gas exchange. Studying blood flow through IPAVA, as well as through PFO, is an important area of research and as the suggested roles become better established, detecting and quantifying flow throug IPAVA and PFO may become significantly more important in the clinic.

Pulmonary hypertension (PH) is a rare but serious complication of sarcoidosis, with a prevalence between 3-20%, dependent on the ethnicity and severity of sarcoidosis. This thesis showed a PH prevalence around 3% in a mainly Caucasian cohort of sarcoidosis patients newly referred to a tertiary centre (PULSAR cohort). The cause sarcoidosis associated pulmonary hypertension (SAPH) is heterogenic and sometimes multifactorial. Most patients fit a parenchymal phenotype with hypoxemia as main mechanism for the development of PH. Other mechanisms in sarcoidosis, often with a worse hemodynamic profile, include compression of the pulmonary vasculature, chronic thromboembolic disease, left heart disease and suspected vasculopathy. A study assessing the pulmonary vasculature by intravascular ultrasound showed changes in wall thickness and vascular properties predominantly in the upper lobes, similar to sarcoidosis related abnormalities, suggesting a vascular component. Phenotyping is valuable in order to evaluate possible treatment options. The diagnosis of PH is established by measuring the mean pulmonary artery pressure during right heart catheterisation. Since symptoms and signs of sarcoidosis and PH overlap, it can be challenging to identify patients with suspected PH. Besides thorough history taking and patterns in pulmonary function tests, measurement of the pulmonary artery diameter on chest-CT can be helpful. As shown in this thesis, the diameter corrected for the body surface area gives the most accurate prediction. Echocardiography is used as a screening tool to assess the likelihood of PH before performing a right heart catheterisation. The ESC/ERS PH guideline classifies patients into a low, intermediate or high PH probability based on echocardiographic measurements. This thesis shows that in patients with a low PH probability and high PH probability, PH can be ruled out or diagnosed accurately. However in patients with intermediate PH probability, discrimination for the presence of PH is difficult. Furthermore, echocardiographic measurement of the right ventricular systolic pressure has a strong correlation with invasively measured systolic pulmonary artery pressure, however it tends to overestimate the actual pressures in mild PH and underestimates in severe PH. New echocardiographic imaging techniques are arising to assess right ventricular dimension and function. In this thesis knowledge based reconstruction, using three-dimensional coordinates, was investigated but showed no additional value to determine right ventricular dimensions in sarcoidosis patients. Treatment of SAPH consist of supportive heart failure and/or oxygen treatment and, if possible, treating the underlying cause. In carefully selected patients the use of PH targeted therapy can be considered. This thesis investigated a case series of macitentan in SAPH, and showed it was safe and mostly well tolerated with improvement in functional capacity. Survival of the PULSAR cohort was relatively good with a 1, 2, 3 and 4-year survival of 100%, 99.0%, 98.2% and 94.6%. Predictors for mortality were elevated right ventricular systolic pressure, presence of PH on echocardiography and progressive fibrotic disease. The thesis concludes with recommendations based on expert opinion of a task force established by the World Association of Sarcoidosis and Other Granulomatous disease (WASOG) to provide guidance for the diagnosis and management of S

The aim of this study is to investigate the impact of body composition on the risk of portopulmonary hypertension using computed tomography (CT) in patients with liver cirrhosis. We retrospectively included 148 patients with cirrhosis treated at our hospital between March 2012 and December 2020. POPH high-risk was defined as main pulmonary artery diameter (mPA-D) ≥ 29 mm or mPA-D to ascending aorta diameter ratio ≥ 1.0, based on chest CT. Body composition was assessed using CT images of the third lumbar vertebra. The factors associated with POPH high-risk were evaluated using logistic regression and decision tree analyses, respectively. Among the 148 patients, 50% were females, and 31% were found to be high-risk cases on evaluation of chest CT images. Patients with a body mass index (BMI) of ≥25 mg/m2 had a significantly higher prevalence of POPH high-risk than those with a BMI < 25 mg/m2 (47% vs. 25%, p = 0.019). After adjusting for confounding factors, BMI (odds ratio [OR], 1.21; 95% confidence interval [CI], 1.10–1.33), subcutaneous adipose tissue index (OR, 1.02; 95% CI, 1.01–1.03), and visceral adipose tissue index (OR, 1.03; 95% CI, 1.01–1.04) were associated with POPH high-risk, respectively. In the decision tree analysis, the strongest classifier of POPH high-risk was BMI, followed by the skeletal muscle index. Body composition may affect the risk of POPH based on chest CT assessment in patients with cirrhosis. Since the present study lacked data on right heart catheterization, further studies are required to confirm the results of our study.

Au Canada, on estime que 30 000 chirurgies cardiaques sont effectuées chaque année (1). L'insuffisance ventriculaire droite demeure une complication courante chez les patients subissant une chirurgie cardiaque. L'incidence de l’insuffisance ventriculaire droite périopératoire aiguë sévère peut aller de 0,1 % après une cardiotomie à 20 à 30 % après l'implantation d'un dispositif d'assistance ventriculaire gauche (2). La survenue d'une défaillance ventriculaire droite est encore plus fréquente en présence d'hypertension pulmonaire. Les conséquences de l'insuffisance ventriculaire droite en chirurgie cardiaque comprennent une détérioration périopératoire et des effets indésirables tels qu'un sevrage difficile de la circulation extracorporelle, une utilisation accrue d'agents vasoactifs intraveineux, et un risque accru de mortalité. Par conséquent, le diagnostic et le traitement de l’hypertension pulmonaire et de la dysfonction ventriculaire droite sont essentiels dans la période périopératoire pour éviter les complications. La surveillance simultanée et en continue des courbes de pression de l’artère pulmonaire et du ventricule droit à l'aide du cathétérisme de l'artère pulmonaire est un outil de surveillance important chez les patients en chirurgie cardiaque pour la détection précoce d'un dysfonctionnement du ventricule droit et pour évaluer la réponse au traitement. Les stratégies thérapeutiques dans ce contexte devraient se concentrer sur la réduction de la postcharge du ventricule droit et l'amélioration de la fonction du ventricule droit tout en évitant l'hypotension systémique. Les hypothèses de cette thèse sont les suivantes : 1) les vasodilatateurs inhalés sont supérieurs aux agents administrés par voie intraveineuse pour le traitement et la gestion de l’hypertension pulmonaire en chirurgie cardiaque, 2) la combinaison d'époprosténol inhalé et de la milrinone inhalée (iE&iM) est une stratégie efficace pour faciliter le sevrage de la circulation extracorporelle et pour réduire les besoins en inotropes intraveineux, 3) tous les patients n'ont pas une réponse vasodilatatrice positive à la combinaison de l’iE&iM, 4) la réponse à l’iE&iM est associée à des changements des courbes de pression du ventricule droit et de l’artère pulmonaire, et 5) le gradient de la chambre de chasse du ventricule droit et la vitesse d’augmentation de la pression intraventriculaire droite (dP/dt) ont le potentiel d'être des marqueurs pharmacodynamiques de la réponse au traitement. Le travail compris dans cette thèse consiste en 3 études. La première est une revue systématique et méta-analyse d'essais contrôlés randomisés démontrant que l'administration de vasodilatateurs inhalés pour le traitement de l’hypertension pulmonaire pendant la chirurgie cardiaque est associée à une amélioration de la performance du ventricule droit comparé aux agents administrés par voie intraveineuse. La deuxième étude est une analyse de cohorte rétrospective de 128 patients recevant l’iE&iM avant la circulation extracorporelle. Cette étude a démontré une réponse vasodilatatrice au traitement par l’iE&iM chez 77% des patients. Une réponse favorable était associée à un sevrage facile de la circulation extracorporelle plus fréquent et à une utilisation plus faible d'inotropes intraveineux. De plus, cette étude a également démontré qu'une hypertension pulmonaire plus sévère est prédictive d'une réponse vasodilatatrice pulmonaire positive, tandis qu'un European System for Cardiac Operative Risk Evaluation score (EuroSCORE) II élevé est un prédicteur de non-réponse au traitement. La dernière étude de cette thèse est une étude de cohorte prospective incluant 26 patients recevant iE&iM avec surveillance continue de la courbe de pression du ventricule droit démontrant l'innocuité et l'efficacité de cette approche thérapeutique dans l'amélioration de la fonction ventriculaire droite., In Canada there is an estimated 30,000 cardiac surgeries that are performed each year (1). Right ventricular failure (RVF) remains a common complication in patients undergoing cardiac surgery. The incidence of severe acute perioperative RVF can range from 0.1% after cardiotomy to 20-30% after left ventricular assist device implantation (2). The occurrence of RVF is even more frequent in the presence of pulmonary hypertension (PH). Consequences of RVF in cardiac surgery include perioperative deterioration and adverse outcomes such as difficult separation from cardiopulmonary bypass (CPB), increased use of intravenous (IV) vasoactive agents and an increased risk of mortality. Therefore, the diagnosis and treatment of PH and right ventricular (RV) dysfunction is essential in the perioperative period to circumvent complications. Continuous and simultaneous monitoring of both pulmonary artery pressure (Ppa) and RV pressure (Prv) waveforms using pulmonary artery catheterization is an important monitoring tool in cardiac surgery patients for early detection of RV dysfunction and for evaluating response to treatment. Therapeutic strategies in this context should focus on reducing RV afterload and improving RV function while avoiding systemic hypotension. The hypotheses of this thesis are the following: 1) inhaled aerosolized vasodilators are superior to IV administered agents for the treatment and management of PH in cardiac surgery, 2) the combination of inhaled epoprostenol and inhaled milrinone (iE&iM) is an effective strategy to facilitate separation from CPB and reduce the requirements for IV inotropes, 3) not all patients have a positive vasodilator response to iE&iM, 4) response to iE&iM is associated with changes in RV and PA pressure waveforms, and 5) RV outflow tract (RVOT) gradient and RV maximal rate of pressure rise during early systole (dP/dt) have the potential to be pharmacodynamic markers of response to treatment. The work comprised in this thesis consist of 3 studies. The first is a systematic review and meta-analysis of randomized controlled trials showing that administration of inhaled vasodilators for the treatment of PH during cardiac surgery is associated with improved RV performance compared to IV administered agents. The second study is a retrospective cohort analysis of 128 patients receiving iE&iM before CPB. This study showed that 77% of patients have a vasodilator response to iE&iM treatment. A favorable vasodilator response was associated with more frequent easy separation from CPB and lower use of IV inotropes post-CPB. In addition, more severe PH at baseline is shown to be predictive of a positive pulmonary vasodilator response while high European System for Cardiac Operative Risk Evaluation score (EuroSCORE) II is a predictor of non-response to treatment. The last study of this thesis is a prospective cohort study including 26 patients receiving iE&iM with continuous monitoring of Prv waveform demonstrating the safety and efficacy of this treatment approach in improving RV function.

Pulmonary hypertension (PH)-associated with interstitial lung disease (ILD) develops as a consequence of progressive underlying lung disease or disproportionately to the underlying disease. The PH investigation by right heart catheterization (RHC) for defining PH severity is recommended in patients with ILD who show more severe symptoms than expected from lung disease, appearance of right heart failure, and clinical deterioration not matched by the declining lung function. In patient with progressive ILD, RHC is only considered if it affects the future treatment such as lung transplantation or enrollment in clinical trial/registry. The decision to undertake the RHC in progressive ILD was still fraught with doubts. Here we reported a young adult male patient with ILD whom developed progressive signs and symptoms. By RHC, he had severe precapillary PH with hemodynamic parameters indicated the presence of pulmonary vascular disease. A PH-specific treatment, sildenafil citrate, was administered, and patient responded well and was clinically stable during the addition of sildenafil citrate. This case highlights the clinical implication of performing RHC in progressive ILD, which can change the treatment decision by PH-specific drugs. Therefore, the RHC decision making in patient with progressive ILD need reconsideration.

Background: Right heart failure (RHF) is associated with a dismal prognosis in patients with pulmonary hypertension (PH). Exercise right heart catheterization may unmask right heart maladaptation as a sign of RHF. We sought to (1) define the normal limits of right atrial pressure (RAP) increase during exercise; (2) describe the right heart adaptation to exercise in PH owing to heart failure with preserved ejection fraction (PH-HFpEF) and in pulmonary arterial hypertension (PAH); and (3) identify the factors associated with right heart maladaptation during exercise. Methods and results: We analyzed rest and exercise right heart catheterization from patients with PH-HFpEF and PAH. Right heart adaptation was described by absolute or cardiac output (CO)-normalized changes of RAP during exercise. Individuals with noncardiac dyspnea (NCD) served to define abnormal RAP responses (>97.5th percentile). Thirty patients with PH-HFpEF, 30 patients with PAH, and 21 patients with NCD were included. PH-HFpEF were older than PAH, with more cardiovascular comorbidities, and a higher prevalence of severe tricuspid regurgitation (P < .05). The upper limit of normal for peak RAP and RAP/CO slope in NCD were >12 mmHg and ≥1.30 mmHg/L/min, respectively. PH-HFpEF had higher peak RAP and RAP/CO slope than PAH (20 mmHg [16-24 mmHg] vs 12 mmHg [9-19 mmHg] and 3.47 mmHg/L/min [2.02-6.19 mmHg/L/min] vs 1.90 mmHg/L/min [1.01-4.29 mmHg/L/min], P < .05). A higher proportion of PH-HFpEF had RAP/CO slope and peak RAP above normal (P < .001). Estimated stressed blood volume at peak exercise was higher in PH-HFpEF than PAH (P < .05). In the whole PH cohort, the RAP/CO slope was associated with age, the rate of increase in estimated stressed blood volume during exercise, severe tricuspid regurgitation, and right atrial dilation. Conclusions: Patients with PH-HFpEF display a steeper increase of RAP during exercise than those with PAH. Preload-mediated mechanisms may play a role in the development of exercise-induced RHF.

We present the case of a 50-year-old woman with stage IV invasive ER+/PR-/HER2-ductal breast carcinoma who was admitted to the intensive care unit (ICU) with obstructive shock and hypoxic respiratory failure due to pulmonary tumor thrombotic microangiopathy (PTTM), which significantly improved with chemotherapy. Upon presentation, her heart rate was 145 beats/min, her blood pressure was 86/47 mmHg, her respiratory rate was 25 breaths/min, and her oxygen saturation was 80% in room air. She underwent a broad non-diagnostic infectious evaluation,received fluid resuscitation, and was placed on broad-spectrum antibiotics. Transthoracic echocardiography showed evidence of severe pulmonary hypertension with a pulmonary arterial systolic pressure (PASP) of 77 mmHg. She initially requiredoxygen via a high-flow nasal cannula (HFNC) at 40 liters/minute and 80% FiO2 and was subsequently placed on inhaled nitric oxide (iNO) at 40 parts per million (PPM) as well asnorepinephrine and vasopressin drips for acute decompensated right heart failure. Despite her poor performance status, she was started on chemotherapy with carboplatin and gemcitabine. Over the ensuing week, she was weaned off supplemental oxygen, vasoactive agents, and iNO and discharged home. Repeat echocardiography performed 10 days after the initiation of chemotherapy demonstrated marked improvement in her pulmonary hypertension with a PASP of 34 mmHg. This case highlights the potential role of chemotherapy in altering the course of PTTM in select patients with metastatic breast cancer.

Background: About 5–10% of adults with congenital heart disease (ACHD) will develop pulmonary arterial hypertension (PAH), which is associated with significant mortality. Studies on risk factors for poor outcome in a contemporary cohort of these patients with PAH associated with CHD (PAH-CHD) are rare. Methods: In this retrospective, single-center study, adult patients with the diagnosis PAH-CHD who had at least one contact as an outpatient or inpatient at the German Heart Centre Munich during the period January 2010–September 2019 were included. Patients with PAH without a CHD were excluded. The primary endpoint was all-cause mortality. Results: Altogether, 158 patients (mean age 39.9 ± 15.4 years, female 64.6%) were included in the study. A pre-tricuspid shunt was present in 17.7%, other shunts in 51.3%, PAH associated with complex CHD in 22.8%, and segmental PAH in 8.2%. An NT-proBNP measurement at baseline was available in 95 patients (60.1%). During a median follow-up of 5.37 years [IQR 1.76–8.63], the primary endpoint occurred in 10 patients (6.7%). On univariate analysis, CRP (log) (HR 3.35, 95% CI (1.07–10.48), p = 0.037), NT-proBNP (log) (HR: 7.10, 95% CI: 1.57–32.23, p = 0.011), and uric acid (HR: 1.37, 95% CI: 1.05–1.79, p = 0.020) were predictors of the primary endpoint. On multivariate analysis, only NT-proBNP (log) (HR: 6.91, 95% CI: 1.36–35.02, p = 0.0196) remained as an independent predictor. Conclusion: NT-proBNP is an independent predictor of all-cause mortality in a contemporary cohort of PAH-CHD patients. The role of CRP and uric acid should be further assessed in future studies.

Substantial evidence supports the involvement of the renin-angiotensin system in pulmonary hypertension (PH), and the angiotensin II type 2 receptor (AT2R) is known to exert tissue protective actions. The effect of the selective AT2R agonist C21 (also known as Compound 21 or buloxibutid) was evaluated in the rat Sugen-hypoxia PH model. After a single injection of Sugen 5416 and hypoxia for 21 days, C21 (2 or 20 mg/kg) or vehicle was administered perorally twice daily from Day 21 to Day 55. On Day 56, hemodynamic assessments were performed, and lung and heart tissue were prepared for quantification of cardiac and vascular remodeling and fibrosis. Treatment with C21 20 mg/kg improved cardiac output and stroke volume and decreased right ventricular hypertrophy (all p < 0.05). Treatment with C21 2 mg/kg significantly decreased vessel wall and muscular layer thickness and increased the luminal opening in vessels >100 μm (all p < 0.05). There were no significant differences between the two C21 doses on any parameter, and post hoc analyses comparing the merged C21 groups with the vehicle group showed that C21 treatment reduced vascular remodeling (reduced endothelial proliferation and thickening of the vascular wall) in vessels of all sizes; moreover, the diastolic pulmonary artery pressure and right ventricular pressure were reduced along with reduction of right ventricular hypertrophy. Sugen 5416 and hypoxia increased pulmonary collagen deposition, which was counteracted by C21 20 mg/kg. In conclusion, the effects of C21 on vascular remodeling, hemodynamic alterations, and fibrosis suggest that AT2R agonists may have a role in Group 1 and 3 PH treatment.

A 30-year-old COVID-19 recovered pregnant lady presented to us for severe pulmonary hypertension. An emergency caesarean section was performed in view of severe pulmonary hypertension under combined spinal epidural anaesthesia with special precautions including inhaled nitric oxide and extracorporeal membrane oxygenation standby. The surgery was uneventful, and the patient was diagnosed with idiopathic pulmonary hypertension and managed with medical treatment subsequently. This report describes the anaesthetic management of caesarean section in this high-risk patient and reviews the latest evidence regarding the association between COVID -19 infection and pulmonary hypertension.

An inborn term neonate weighing 2600 g developed meconium aspiration syndrome at birth. Baby had respiratory failure requiring high-frequency oscillatory ventilation support at 15 hours of life. He additionally developed hypotension with left ventricular dysfunction noted on point-of-care echocardiography (POCE), which required dopamine and epinephrine infusions. At 28 hours of life, he was started on inhaled nitric oxide (iNO), followed by milrinone due to hypoxaemic respiratory failure and the POCE revealed severe pulmonary artery hypertension (PAH). As PAH was refractory to iNO and milrinone, vasopressin was added which resulted in rapid improvement in oxygenation and normalisation of pulmonary artery pressures. Baby was weaned off from vasoactive support in the next 120 hours. Vasopressin proved to be the rescue agent in this case of iNO refractory PAH without any side effects during therapy. Baby was successfully extubated on day 18 and was discharged with a normal neurological examination finding.

BackgroundPulmonary hypertension (PH) can occur as a complication of schistosomiasis. In humans, schistosomiasis-PH persists despite antihelminthic therapy and parasite eradication. We hypothesized that persistent disease arises as a consequence of exposure repetition.MethodsFollowing intraperitoneal sensitization, mice were experimentally exposed to Schistosoma eggs by intravenous injection, either once or three times repeatedly. The phenotype was characterized by right heart catheterization and tissue analysis.ResultsFollowing intraperitoneal sensitization, a single intravenous Schistosoma egg exposure resulted in a PH phenotype that peaked at 7-14 days, followed by spontaneous resolution. Three sequential exposures resulted in a persistent PH phenotype. Inflammatory cytokines were not significantly different between mice exposed to one or three egg doses, but there was an increase in perivascular fibrosis in those who received three egg doses. Significant perivascular fibrosis was also observed in autopsy specimens from patients who died of this condition.ConclusionsRepeatedly exposing mice to schistosomiasis causes a persistent PH phenotype, accompanied by perivascular fibrosis. Perivascular fibrosis may contribute to the persistent schistosomiasis-PH observed in humans with this disease.

Ventricular interdependence plays an important role in pulmonary arterial hypertension (PAH). It can decrease left ventricular (LV) longitudinal strain (LVLS) and lead to a leftward displacement ("transverse shortening") of the interventricular septum (sTS). For this study, we hypothesized the ratio of LVLS/sTS would be a sensitive marker of systolic ventricular interactions in PAH. In a cross-sectional cohort of patients with PAH (n = 57) and matched controls (n = 57), we quantified LVLS and septal TS in the amplitude and time domain. We then characterized LV phenotypes using upset plots, ventricular interactions using network analysis, and longitudinal analysis in a representative cohort of 45 patients. We also measured LV metrics in mice subjected to pulmonary arterial banding (PAB) using a 7 T magnetic resonance imaging at baseline, Week 1, and Week 7 post-PAB (N = 9). Patients with PAH had significantly reduced absolute LVLS (15.4 ± 3.4 vs. 20.1 ± 2.3%, p

Atrial fibrillation complicated by a fast ventricular response rate can cause a significant physiological burden. This is characterised by systolic pump failure, decreased diastolic filling time and hypotension leading to impaired organ perfusion. Considering that most anaesthetic agents are cardiac suppressants, the additive effects of this condition together with anaesthesia may lead to increased perioperative morbidity and mortality. A 79-year-old male patient who presented with atrial fibrillation, caused by chronic obstructive pulmonary disease and pulmonary hypertension, and a fast ventricular response rate was booked for emergency ligation of the sphenopalatine artery for posterior epistaxis, complicated by significant blood loss. Both electrical and pharmacological alternatives exist to address this conundrum, but here we would like to present this case where digoxin was used successfully to rate control this patient perioperatively. Digoxin has recently fallen into disfavour for the chronic management of atrial fibrillation, and even in select cases of acute atrial fibrillation with a fast ventricular response rate, and the purpose of this case study is to highlight a potentially useful indication for this antiquated drug.

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Native T1, extracellular volume fraction (ECV), and late gadolinium enhancement (LGE) characterize myocardial tissue and relate to patient prognosis in a variety of diseases, including pulmonary hypertension. The purpose of this study was to evaluate if left ventricle (LV) fibrosis measurements have prognostic value for cardiac outcomes in pulmonary hypertension subgroups. 54 patients with suspected pulmonary hypertension underwent right-heart catheterization and were classified into pulmonary hypertension subgroups: pre-capillary component (PreCompPH) and isolated post-capillary (IpcPH). Cardiac magnetic resonance imaging (MRI) scans were performed with the acquisition of balanced cine steady-state free precession, native T1, and LGE pulse sequences to measure cardiac volumes and myocardial fibrosis. Associations between cardiac events and cardiac MRI measurements were analyzed within PreCompPH and IpcPH patients. IpcPH: LV native T1 was higher in patients who experienced a cardiac event within two years vs. those who did not. In patients with LV native T1 > 1050 ms, the rate of cardiac events was higher. ECV and quantitative LGE did not differ between groups. PreCompPH: native T1, ECV, and quantitative/qualitative LGE did not differ between patients who experienced a cardiac event within two years vs. those who did not. LV native T1 may have potential value for forecasting cardiac events in IpcPH, but not in PreCompPH, patients.

Background: Emergent endotracheal intubations (ETI) in pulmonary hypertension (PH) patients are associated with increased mortality. Post-intubation interventions that could increase survivability in this population have not been explored. We evaluate early clinical characteristics and complications following emergent endotracheal intubation and seek predictors of adverse outcomes during this post-intubation period. Methods: Retrospective cohort analysis of adult patients with groups 1 and 3 PH who underwent emergent intubation between 2005-2021 in medical and liver transplant ICUs at a tertiary medical center. PH patients were compared to non-PH patients, matched by Charlson Comorbidity Index. Primary outcomes were 24-h post-intubation and inpatient mortalities. Various 24-h post-intubation secondary outcomes were compared between PH and control cohorts. Results: We identified 48 PH and 110 non-PH patients. Pulmonary hypertension was not associated with increased 24-h mortality (OR 1.32, 95%CI 0.35-4.94, P = .18), but was associated with inpatient mortality (OR 4.03, 95%CI 1.29-12.5, P = .016) after intubation. Within 24 h post-intubation, PH patients experienced more frequent acute kidney injury (43.5% vs. 19.8%, P = .006) and required higher norepinephrine dosing equivalents (6.90 [0.13-10.6] mcg/kg/min, vs. 0.20 [0.10-2.03] mcg/kg/min, P = .037). Additionally, the median P/F ratio (PaO2/FiO2) was lower in PH patients (96.3 [58.9-201] vs. 233 [146-346] in non-PH, P = .001). Finally, a post-intubation increase in PaCO2 was associated with mortality in the PH cohort (post-intubation change in PaCO2 +5.14 ± 16.1 in non-survivors vs. −18.7 ± 28.0 in survivors, P = .007). Conclusions: Pulmonary hypertension was associated with worse outcomes after emergent endotracheal intubation than similar patients without PH. More importantly, our data suggest that the first 24 hours following intubation in the PH group represent a particularly vulnerable period that may determine long-term outcomes. Early post-intubation interventions may be key to improving survival in this population.