Primary Pulmonary Arterial Hypertension Research Articles

Novel insights into the pathobiology of pulmonary hypertension in heart failure with preserved ejection fraction.

Heart failure (HF) with preserved ejection fraction (HFpEF) is the most common cause of pulmonary hypertension (PH) worldwide and is strongly associated with adverse clinical outcomes. The American Heart Association recently highlighted a call to action regarding the distinct lack of evidence-based treatments for PH due to poorly understood pathophysiology of PH attributable to HFpEF (PH-HFpEF). Prior studies have described cardiophysiological mechanisms to explain the development of isolated postcapillary PH (ipc-PH); however, the consequent increase in pulmonary vascular (PV) resistance (PVR) may lead to the less understood and more fatal combined pre- and postcapillary PH (cpc-PH). Metabolic disease and inflammatory dysregulation have been suggested to predispose PH, yet the molecular mechanisms are unknown. Although PH-HFpEF has been studied to partly share vasoactive neurohormonal mediators with primary pulmonary arterial hypertension (PAH), clinical trials that have targeted these pathways have been unsuccessful. The increased mortality of patients with PH-HFpEF necessitates further study into viable mechanistic targets involved in disease progression. We aim to summarize the current pathophysiological and clinical understanding of PH-HFpEF, highlight the role of known molecular mechanisms in the progression of PV disease, and introduce a novel concept that lipid metabolism may be attenuating and propagating PH-HFpEF.NEW & NOTEWORTHY Our review addresses pulmonary hypertension (PH) attributable to heart failure (HF) with preserved ejection fraction (HFpEF; PH-HFpEF). Current knowledge gaps in PH-HFpEF pathophysiology have led to a lack of therapeutic targets. Thus, we address identified knowledge gaps in a comprehensive review, focusing on current clinical epidemiology, known pathophysiology, and previously studied molecular mechanisms. We also introduce a comprehensive review of polyunsaturated fatty acid (PUFA) lipid inflammatory mediators in PH-HFpEF.

Lung transplantation in primary pulmonary arterial hypertension and pulmonary venous hypertension.

End-stage lung disease from primary pulmonary hypertension (PPHTN) and pulmonary venous-occlusive disease (PVOD) may require lung transplantation (LT). While medical therapies exist for the palliation of PPHTN, no therapies exist for PVOD. The study's objective is to compare outcomes of LT in these patients. Patients with PPHTN and PVOD who had undergone LT were identified in the UNOS database (2005-2022). Univariable analyses compared differences between groups in demographic, clinical, and post-transplant outcomes. Multivariable logistic regression examined the association between the diagnosis group and survival. Overall survival time between groups was compared using the Kaplan-Meier method. Six hundred and ninety-six PPHTN and 78 PVOD patients underwent LT during the study period. Patients with PVOD had lower pulmonary artery mean pressure (47vs. 53mmHg, p<.001), but higher cardiac output (4.51vs. 4.31 L/min, p=.04). PVOD patients were more likely to receive lungs from donation after cardiac death donors (7.7vs. 2.9%, p=.04). There were no differences in postoperative complications or length of stay. PVOD was associated with superior survival at 30-day (100vs. 93%, p=.02) and 90-day post-transplant (93vs. 83%, p=.03), but not at later time points. In multivariable analyses, PVOD and brain death donor use were associated with better survival up to 90-day mark. Patients undergoing LT for PVOD had better initial survival, which disappeared after 1 year of transplantation. Donation after circulatory death donor use had a short-term survival disadvantage.

A 48-year-old female with chronic, progressive bilateral vision loss and dyspnea.

To describe a unique case of isolated, bilateral serous retinal detachments associated with primary pulmonary arterial hypertension. Case report. A 48-year-old woman with primary pulmonary arterial hypertension presented with bilateral vision loss. She was found to have bilateral serous retinal detachments in the macula with accumulation of the fibrinous material. Optical coherence tomography demonstrated intraretinal and subretinal fluid, hyperreflective material in the subretinal space, and choroidal engorgement. Fluorescein angiography demonstrated pooling in the maculas, an area of blockage corresponding with the area of subretinal exudative material, and a petalloid pattern of leakage in the maculas without evidence of retinal vascular leakage. Her ocular symptoms improved with aggressive medical management of her pulmonary arterial hypertension with the addition of eplerenone. Primary pulmonary arterial hypertension results in chronically elevated systemic venous pressure, leading to both systemic and ocular symptoms. It is important to consider this systemic condition in the differential diagnosis of serous retinal detachments to provide adequate multidisciplinary management.

A case report on ambrisentan-induced angioedema

Ambrisentan is a selective type A endothelin receptor antagonist used to treat primary pulmonary arterial hypertension (PAH). A 52-year-old female was admitted to the emergency department with presenting symptoms of submandibular swelling and worsening dyspnea. The patient has a history of PAH on treatment. She was previously on sildenafil. All her blood parameters except renal function tests (blood urea, creatinine, potassium, and sodium) were normal during hospitalization for the management of PAH. Some months after treatment with sildenafil, she was switched to Ambrisentan by her consultant. ECG showed severe PAH (80 mmHg), mild right ventricle dysfunction, no regional wall motion abnormalities, and good left ventricle systolic function. She was diagnosed as cor pulmonale. She was dehydrated with reduced skin turgor. USG abdomen revealed bilateral renal parenchymal disease. She also complained of a puffy reddish discoloration of the skin along with angioedema. After ruling out the possibility of other factors contributing to angioedema, Ambrisentan was most likely related and was not excluded. Ambrisentan was, therefore, discontinued and replaced with tadalafil. She was seen on an outpatient basis and was symptomatically better. Health education was provided on the safe use of drugs. Through this report, we bring your attention to the possibility of such events with Ambrisentan, and cannot be neglected.

WITHDRAWN

SESSION TITLE: PAH with Complications SESSION TYPE: Rapid Fire Original Inv PRESENTED ON: 10/17/2022 12:15 pm - 1:15 pm PURPOSE: Congenital heart disease (CHD) serves as the second most commonly associated form of primary pulmonary arterial hypertension (PAH). The prognosis of PAH related to congenital heart disease differ from other types of PAH due to factors such as defect types and sizes. The aim of the study is to compare the outcomes of PAH secondary to CHD (PAH-CHD) and PAH due to other causes. METHODS: We extracted the data from the National Inpatient Sample (NIS) database for the years 2016 to 2019 and analyzed all hospital admissions for PAH-CHD versus primary PAH due to causes other than CHD (Other PAH). We selected CHDs commonly known to be associated with primary pulmonary hypertension: atrial septal defect (ASD), ventricular septal defect (VSD), aortopulmonary window, atrioventricular septal defect, tetralogy of Fallot, patent ductus arteriosus (PDA), truncus arteriosus, double inlet left ventricle and double outlet right ventricle. We compared baseline characteristics, outcomes, and healthcare utilization between the two groups. RESULTS: Of 37,739 patients admitted with PAH, 1,355 patients had concomitant CHD and were compared with 36,384 adult PAH patients without CHD. In the PAH-CHD group, ASD was the most common associated CHD (1,195, 88%) followed by VSD (125, 9.2%) and PDA (39,2, 9%). The PAH-CHD patients were relatively younger (mean age of 53.15 vs 65.7 years), less likely to be of white race (62.36% vs 66%) and had a lower proportion of comorbid coronary artery disease (14.3% vs 28.86%), obesity (15.13% vs 22.66%), dyslipidemia (44% vs 51%), diabetes (18.08% vs 34.48%) and chronic kidney disease (19.93% vs 33.15%) [all p<0.05*]. A total of 115 (8.5%) PAH-CHD patients and 1,844 (5.07%) other PAH patients died during hospitalization. PAH-CHD patients had a higher in-hospital mortality (aOR=1.73 ;95%CI 1.08-2.76, p=0.02*). The PAH-CHD group had higher odds of having chronic respiratory failure (aOR=1.13;95%CI 1.04-1.22, p=0.003*), right ventricular failure (aOR=1.72 ;95%CI 1.12-2.6, p<0.013*), cardiogenic shock (aOR=2.1;95%CI 1.15-3.84, p=0.015*) and acute ischemic stroke (aOR=25.18;95%CI 6.78-93.46, p<0.0001*). compared to the other PAH group. PAH-CHD patients also had longer length of stay (10.6 vs 7.10 days, p=0.0009*) and higher hospitalization costs per admission ($209,507 vs $90,599, p=0.007*). CONCLUSIONS: The PAH-CHD group had higher in-hospital mortality and healthcare resource utilization than the other PAH group. PAH-CHD group were more likely to have chronic respiratory failure, right ventricular failure, cardiogenic shock and ischemic stroke. CLINICAL IMPLICATIONS: PAH-CHD seem to have higher mortality and worse PAH related in-patient complications. The difference between two groups highlights the need for further research and trials to understand the unique natural history and appropriate management of PAH-CHD patients. DISCLOSURES: No relevant relationships by Cyra-Yoonsun Kang No relevant relationships by Sandhya shri Kannayiram No relevant relationships by parnia khamooshi No relevant relationships by Viviana Reyes Pinzon No relevant relationships by Sujitha Velagapudi

OUTCOMES OF PRIMARY PULMONARY HYPERTENSION WITH CONNECTIVE TISSUE DISORDERS VS OTHER PRIMARY PULMONARY HYPERTENSION: AN ANALYSIS OF A NATIONAL INPATIENT SAMPLE

SESSION TITLE: Pulmonary Manifestations of Systemic Diseases SESSION TYPE: Original Investigations PRESENTED ON: 10/18/2022 2:45 pm - 3:45 pm PURPOSE: Primary pulmonary arterial hypertension (PAH) serves as one of the serious complications of connective tissues disorders (CTDs). It has a detrimental effect on the CTD patients’ quality of life and mortality. Namely, the prevalence of PAH in systemic sclerosis (SSc) patients is as high as 12% and is associated with a less favorable outcome compared to idiopathic PAH. There has also been growing evidence that suggests an early treatment of PAH in CTDs may prevent irreversible pathologic changes in pulmonary vessels. However, the morbidity and mortality of PAH in non-SSc CTDs remains largely unknown due to the lack of large cohort studies. The aims of this study were to compare the outcomes of patients primarily admitted for primary PAH with and without CTDs. METHODS: We used the National Inpatient Sample (NIS) database for the years 2015 to 2018 to analyze all hospital admissions for primary PAH (ICD-10 CM code I27.0) with versus without CTDs. We selected CTDs most commonly associated with primary pulmonary hypertension: systemic sclerosis, systemic lupus erythematosus, mixed CTD, rheumatoid arthritis, dermatomyositis and sjögren’s syndrome. We compared baseline characteristics, outcomes and healthcare utilization between the two groups. RESULTS: From 2015 - 2018, a total of 3,010,994 patients were included in the study group. 10.9% (5479) of the study population had the CTDs. The cohort with CTDs had slightly older mean age (59.61 vs 56.42, p=0.04), more women (91.2% vs 75.5%, p<0.001), higher number of Charlson comorbidity index of more than 4 (20.2% vs 16.3%, p<0.001), but less diagnosis of diabetes (13.5% vs 31.2%, p<0.001). After adjusting for age, race, hospital regions and other comorbid conditions, the odds ratio (aOR) for mortality in patients with CTDs compared to those without CTDs was slightly increased to 1.09, albeit not significantly (95% CI: 0.46 - 2.59, p=0.838). Similarly, there existed no statistically significant differences in length of stay (LOS) (9.2 vs 8.1 days; p=0.831) or total hospital charges ($137,212 vs $117,221; p= 0.858) between the two groups. CONCLUSIONS: Hospitalizations for primary PAH with CTDs had comparable mortality, LOS, total hospital charges compared to those without CTDs. CLINICAL IMPLICATIONS: The results of the study suggest non-significant mortality differences between primary PAH associated with CTDs and those without CTDs. A large cohort study of CTD-associated PAH would be essential as the management and outcomes may differ from those of other pulmonary hypertension. DISCLOSURES: No relevant relationships by Iriagbonse Asemota No relevant relationships by Cyra-Yoonsun Kang No relevant relationships by Sandhya shri Kannayiram No relevant relationships by parnia khamooshi No relevant relationships by Viviana Reyes Pinzon

Advances in the Study of Inhaled Formulations for the Treatment of Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a serious disease with reduced systemic circulation and low bioavailability associated with conventional and dosed therapy, which inhaled drugs can avoid. A mean pulmonary artery pressure (mPAP) of ≥25 mmHg (1 mmHg = 0.133 kPa) at rest or ≥30 mmHg during exercise and a pulmonary capillary pressure or left atrial pressure (PLA) of ≤15 mmHg can be diagnosed with PAH. Pulmonary hypertension is classified into primary PAH and secondary PAH according to the presence or absence of principles or risk factors. The main symptoms of pulmonary hypertension include dyspnoea, syncope, weakness, chest pain, and the presence of varying degrees of peripheral oedema. It is a highly pathogenic and life-threatening disease and can lead to delays in treatment if not diagnosed in time. In the past few years, the studies related to this progressed slowly, which brought great harm to patients with PAH. Reports showed that patients diagnosed with PAH should receive routine preventative care, such as pneumococcal and influenza vaccinations. Inhalation therapy is mainly used for the treatment of respiratory diseases and is of great interest due to the concentration of the drug in the airways and lung tissues. Therefore, the present situation of pulmonary hypertension and the characteristics of inhalation preparation were reviewed in this paper to provide some related cue for the treatment of pulmonary hypertension. In the future, it is necessary to develop more treatment methods for pulmonary hypertension.

The changing landscape of pediatric lung transplantation.

There has been a shift over decades in the diagnostic indications for lung transplantation in children; in particular, there has been a reduction in the proportion of pediatric cystic fibrosis (CF) patients undergoing lung transplantation early in life, and more transplants occurring in other diagnostic groups. Here, we examine trends in pediatric lung transplantation with regards to indications by analyzing data from the United Network of Organ Sharing, the International Society for Heart and Lung Transplantation Thoracic Transplant Registry, and other sources. Over the past two years, there has been a precipitous decline in both the number of transplants due to CF and the proportion of CF cases relative to the total number of transplants, likely not solely due to the COVID-19 pandemic. In 2020, primary pulmonary arterial hypertension for the first-time surpassed CF as main indication for pediatric lung transplantation in the United States, a finding that is also reflected in international data. We discuss the effect of novel CFTR modulator therapies as a major factor leading to this shifting landscape. Based on our trending, pulmonary hypertension-related diagnoses and pediatric interstitial lung diseases are rising indications, for which we suggest adjustments of consensus guidelines around candidate selection criteria.

Is Veno-Arterial ECMO as Safe and Effective as Veno-Venous ECMO for Bridging to Lung Transplantation?

Purpose Veno-venous Extra-corporeal Membrane Oxygenation (VV ECMO) has been used as a bridge to lung transplantation with acceptable outcomes. Patients with primary or secondary pulmonary arterial hypertension and/or right ventricular dysfunction have a higher risk profile and will need Veno-arterial ECMO (VA ECMO) as a bridge to lung transplantation. There is limited information on outcome of lung transplantation after VA ECMO. We hypothesized that VA ECMO, as part of a multidisciplinary ECMO program yields similar outcomes as VV ECMO as a bridge in lung transplantation. Methods Records of all patients who had undergone ECMO with the intention to bridge to lung transplantation from January 1, 2012 to January 1, 2020 were reviewed. VV ECMO was performed via a single site dual lumen cannula or via dual peripheral cannulation sites. VA ECMO was performed via peripheral vessels or central cannulation without sternotomy. Results During this interval, 58 patients were placed on ECMO with the intention to bridge to lung transplantation: 27 on VV ECMO, and 31 on VA ECMO. 84% of patients on ECMO as a bridge were breathing spontaneously and ambulatory. Median duration of VV and VA ECMO were 7 days and 21 days, respectively. Incidence of ECMO-related complications were similar in the two groups. 81% of VV ECMO and 81% of VA ECMO patients underwent lung transplantation. Incidence of Primary Graft Dysfunction III at 72 hours in the VV ECMO and the VA ECMO cohorts were 0% and 4%, respectively. Median Intensive Care Unit and hospital stay of the two groups were similar. 30 days and in-hospital survival of the VV ECMO and VA ECMO groups were 100% and 96%, (p=NS). 1-year and 3-year survival of the two groups were also similar, AND did not differ when compared to the contemporary cohort of lung transplant recipients that were not bridged with ECMO. Conclusion VA ECMO, as part of a multi-disciplinary ECMO team, can be used as a bridge to lung transplantation, with similar outcomes as VV ECMO. Moreover, in this selected cohort, the short and medium term survival of bridged patients is similar to non-bridged patients.

Pulmonary hypertension as a risk factor in JAK2-positive polycythemia rubra vera

Introduction The occurrence of primary pulmonary arterial hypertension (PAH (in primary myeloid proliferation neoplasms seems quite high, up to 22% in polycythemia vera. Polycythemia rubra vera (PRV) is one of the myeloproliferative neoplasms. We aimed to study the incidence of PAH among patients with PRV. Patients and methods A prospective cross-section study was performed on 60 (PRV) patients with PRV confirmed by bone marrow and JAK2 positivity. Abdominal ultrasonography, transthoracic echocardiography, and computed tomography chest were done to estimate the pulmonary hypertension (HTN) and exclude other chest diseases. Results Among the studied 60 patients, we found 14 patients with pulmonary HTN (23.4%) who had significantly increased incidence of comorbidities than patients with normal pulmonary pressure (P=0.009). Moreover, there were statistically significant differences in the size of spleen by ultrasound between the two groups (P=0.008). Patients with pulmonary HTN had a higher hemoglobin level compared with those with normal pulmonary pressure (P=0.006). There was a significant positive correlation between pulmonary pressure and existing comorbidities (diabetes mellitus, HTN, or both) but no correlation with the size of the spleen, hemoglobin level, or white blood cells. Conclusion The prevalence of PAH in JAK2-positive patients with PRV is 76.6%, and there was significant relationship between hematological parameters (hemoglobin, white blood cells, lactate dehydrogenase, and urea level and PAH in JAK2-positive patients with PRV.

Critical appraisal of the instantaneous end-diastolic pulmonary arterial wedge pressures.

AimsA substantial shift in the field of pulmonary hypertension (PH) is ongoing, as the previous practice of mean pulmonary arterial wedge pressure (PAWPM) is no longer supported. Instead, aiming for a better estimate of end‐diastolic pressures (EDP), instantaneous PAWP at mid‐A‐wave (PAWPmid‐A) or, in the absence of an A‐wave, at 130–160 ms following QRS onset has recently been recommended. Electrocardiogram‐gated PAWP (PAWPQRS) has also been proposed. The quantitative differences as well as the diagnostic and prognostic utility of these novel PAWP measurements have not been evaluated. We set out to address these issues.Methods and resultsPressure tracings of 141 patients with PH due to left heart disease (PH‐LHD) and 43 with primary pulmonary arterial hypertension (PAH) were analysed. PAWP was measured as follows: (i) mean pressure (PAWPM); (ii) per the latest consensus approach [PAWPmid‐A, or in atrial fibrillation 130, 140, 150, and 160 ms following QRS onset (PAWP130–160)]; (iii) at QRS onset (PAWPQRS); and (iv) Z‐point (PAWPZ). For each PAWP, the corresponding pulmonary vascular resistance (PVR) and diastolic pressure gradient were calculated. The cohort comprised 45% female. Mean age was 66 ± 15. PAWPmid‐A was in good agreement with PAWPZ (17.3 [14.5 to 21.2] vs. 17.6 [14.2 to 21.6] mmHg, P = 0.63), whereas PAWPQRS provided significantly lower values (15.3 [12.5 to 19.2] mmHg, P < 0.001). In atrial fibrillation, PAWP130 and PAWPQRS yielded the optimal temporal and quantitative analyses of EDPs. The ability to differentiate PAH from PH‐LHD was similar for the various PAWP measurements [PAWPM: area under the curve (AUC) 0.98, confidence interval (CI) 0.96–0.99; PAWPmid‐A/130: AUC 0.94, CI 0.91–0.98; PAWPQRS: AUC 0.96, CI 0.94–0.99, P < 0.001 for all]. PVR based on instantaneous PAWP measurements failed to provide superior prognostic information in PH‐LHD as compared with conventional PVR.ConclusionsAlthough instantaneous PAWP measurement might better represent EDP, they nevertheless fail to yield incremental diagnostic or prognostic information in PH‐LHD as compared with conventional measurements.

Exacerbated inflammatory signaling underlies aberrant response to BMP9 in pulmonary arterial hypertension lung endothelial cells

Imbalanced transforming growth factor beta (TGFβ) and bone morphogenetic protein (BMP) signaling are postulated to favor a pathological pulmonary endothelial cell (EC) phenotype in pulmonary arterial hypertension (PAH). BMP9 is shown to reinstate BMP receptor type-II (BMPR2) levels and thereby mitigate hemodynamic and vascular abnormalities in several animal models of pulmonary hypertension (PH). Yet, responses of the pulmonary endothelium of PAH patients to BMP9 are unknown. Therefore, we treated primary PAH patient-derived and healthy pulmonary ECs with BMP9 and observed that stimulation induces transient transcriptional signaling associated with the process of endothelial-to-mesenchymal transition (EndMT). However, solely PAH pulmonary ECs showed signs of a mesenchymal trans-differentiation characterized by a loss of VE-cadherin, induction of transgelin (SM22α), and reorganization of the cytoskeleton. In the PAH cells, a prolonged EndMT signaling was found accompanied by sustained elevation of pro-inflammatory, pro-hypoxic, and pro-apoptotic signaling. Herein we identified interleukin-6 (IL6)-dependent signaling to be the central mediator required for the BMP9-induced phenotypic change in PAH pulmonary ECs. Furthermore, we were able to target the BMP9-induced EndMT process by an IL6 capturing antibody that normalized autocrine IL6 levels, prevented mesenchymal transformation, and maintained a functional EC phenotype in PAH pulmonary ECs. In conclusion, our results show that the BMP9-induced aberrant EndMT in PAH pulmonary ECs is dependent on exacerbated pro-inflammatory signaling mediated through IL6.

Intraoperative Implications of the Recipients' Disease for Double-Lung Transplantation

To compare intraoperative patterns among patients based on their primary pulmonary disease (cystic fibrosis [CF], chronic obstructive pulmonary disease [COPD]/emphysema [CE], and pulmonary fibrosis [PF]) during double- lung transplantation. The following 3 major outcomes were reported: blood transfusion, extracorporeal membrane oxygenation (ECMO) management, and the possibility of immediate extubation at the end of surgery. Retrospective analysis of a prospectively maintained database, including donor and recipient characteristics and intraoperative variables. Foch Hospital, Suresnes, France (academic center performing60-80 lung transplantations per year). Patients who underwent double- lung transplantation from 2012-2019. Patients with retransplantation, multiorgan transplantation, or surgery performed with cardiopulmonary bypass were excluded. None. Two hundred forty-six patients had CF, 117 had CE, and 66 had PF. No patient had primary pulmonary arterial hypertension. Blood transfusion was higher in the CF group than in the other 2 groups (red blood cells [p < 0.001], fresh frozen plasma [p = 0.004]). The CF and CE groups were characterized by a lower intraoperative requirement of ECMO (p = 0.002), and the PF group more frequently required postoperative ECMO (p < 0.001). CF and CE patients were more frequently extubated in the operating room than were PF patients (37.4%, 50.4%, and 13.6%, respectively; p < 0.001). Intraoperative outcomes differed depending on the initial pathology. Such differences should be taken into account in specific clinical studies and in intraoperative management protocols.

Pulmonary Hypertension in Adults with Congenital Heart Disease: Real-World Data from the International COMPERA-CHD Registry.

Introduction: Pulmonary hypertension (PH) is a common complication in patients with congenital heart disease (CHD), aggravating the natural, post-operative, or post-interventional course of the underlying anomaly. The various CHDs differ substantially in characteristics, functionality, and clinical outcomes among each other and compared with other diseases with pulmonary hypertension. Objective: To describe current management strategies and outcomes for adults with PH in relation to different types of CHD based on real-world data. Methods and results: COMPERA (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension) is a prospective, international PH registry comprising, at the time of data analysis, >8200 patients with various forms of PH. Here, we analyzed a subgroup of 680 patients with PH due to CHD, who were included between 2007 and 2018 in 49 specialized centers for PH and/or CHD located in 11 European countries. At enrollment, the patients’ median age was 44 years (67% female), and patients had either pre-tricuspid shunts, post-tricuspid shunts, complex CHD, congenital left heart or aortic disease, or miscellaneous other types of CHD. Upon inclusion, targeted therapies for pulmonary arterial hypertension (PAH) included endothelin receptor antagonists, PDE-5 inhibitors, prostacyclin analogues, and soluble guanylate cyclase stimulators. Eighty patients with Eisenmenger syndrome were treatment-naïve. While at inclusion the primary PAH treatment for the cohort was monotherapy (70% of patients), with 30% of the patients on combination therapy, after a median observation time of 45.3 months, the number of patients on combination therapy had increased significantly, to 50%. The use of oral anticoagulants or antiplatelets was dependent on the underlying diagnosis or comorbidities. In the entire COMPERA-CHD cohort, after follow-up and receiving targeted PAH therapy (n = 511), 91 patients died over the course of a 5-year follow up. The 5-year Kaplan–Meier survival estimate for CHD associated PH was significantly better than that for idiopathic PAH (76% vs. 54%; p < 0.001). Within the CHD associated PH group, survival estimates differed particularly depending on the underlying diagnosis and treatment status. Conclusions: In COMPERA-CHD, the overall survival of patients with CHD associated PH was dependent on the underlying diagnosis and treatment status, but was significantly better as than that for idiopathic PAH. Nevertheless, overall survival of patients with PAH due to CHD was still markedly reduced compared with survival of patients with other types of CHD, despite an increasing number of patients on PAH-targeted combination therapy.

Primary pulmonary arterial hypertension: Protocol to assess comprehensively in the rat the response to pharmacologic treatments

The identification of new treatments for primary pulmonary arterial hypertension (PAH) is a critical unmet need since there is no a definitive cure for this disease yet. Due to the complexity of PAH, a wide set of methods are necessary to assess the response to a pharmacological intervention. Thus, a rigorous protocol is crucial when experimental studies are designed. In the present experimental protocol, a stepwise approach was followed in a monocrotaline-induced PAH model in the rat, moving from the dose finding study of treatment compounds to the recognition of the onset of disease manifestation, in order to identify when to start a curative treatment. A complete multidimensional evaluation of treatment effects represented the last step. The primary study endpoint was the change in right ventricular systolic pressure after 14 days of treatment; echocardiographic and biohumoral markers together with heart and pulmonary arterial morphometric parameters were considered as secondary efficacy and/or safety endpoints and for the evaluation of the biologic coherence in the different results.

Predictors of In-Hospital Events for Patients with Nonischemic Acute Heart Failure

Abstract Aim The main purpose of this article is to evaluate the clinical profile and in-hospital outcome among heart failure (HF) patients due to different diseases other than acute coronary syndromes (ACS) admitted in intensive coronary care unit (ICCU) at a tertiary center in South India. Materials and Methods This is an observational study of HF patients who were admitted to ICCU for a period of 6 months from January 2019 to June 2019. ACS patients were excluded. All the demographic data, clinical history, examination details, electrocardiographic (ECG), two-dimensional echocardiography (ECHO), baseline routine, and special investigations were collected. In-hospital progress of the patient was monitored along with events (recurrence of HF, arrhythmias, acute kidney injury, cardiogenic shock, and death). Results The total number of patients included in the study was 130. The male:female ratio was 2.09:1(88/42) with a mean age of 53.61 years. Hypertension and diabetes were present in 52.3% (68 patients). The etiology of HF was either ischemic (51 patients—39.2%) or dilated (24 patients—18.4%) cardiomyopathy in the majority of the patients (75 patients—57.6%). Rest of the diagnosis for HF were hypertrophic cardiomyopathy in 6 (4.6%) patients, chronic rheumatic heart disease in 18 (13.8%) patients, primary pulmonary arterial hypertension in 6 (4.6%) patients, severe valvular pulmonary restenosis in 3 (2.3%) patients, Cor-pulmonale in 6 (4.6%) patients, and others in 16 (12.3%) patients. Events occurred in 17 patients (13.1%). Mortality occurred in 6 patients (4.62%). Patients with events had more severe dyspnea with pedal edema with low systolic blood pressure clinically; all patients had ECG abnormalities with more severe left ventricular (LV) dilatation with right and LV dysfunction with significant functional mitral regurgitation (MR) with more laboratory abnormalities including grossly elevated N-terminal pro B-type natriuretic peptide (NT pro-BNP) levels when compared with patients without events. All the above said parameters were statistically significant (p &lt; 0.05). Conclusion The common cause of HF admissions in ICCU was predominantly due to ischemic cardiomyopathy. Still, valvular heart diseases were accounting for 13.8% of admissions. High incidence of event rate (13.1%) despite the improvement in treatment strategies of ICCU patients in this new era, also the all-cause in-hospital mortality, was 4.62%. There were multiple clinical (degree of dyspnea, pedal edema, low systolic blood pressure), ECHO (LV dilatation with dysfunction, right ventricle dysfunction, significant MR), and laboratory parameters (pre-azotemia, anemia, thrombocytopenia, grossly elevated NT pro-BNP levels) to predict the in-hospital events.

Primary Pulmonary Arterial Hypertension in children: A Hospital Based study

Primary Pulmonary Arterial Hypertension in children: A Hospital Based study

Progression of Mitral Valve Regurgitation after Lung Transplantation

Purpose Development of early post-operative mitral valve regurgitation (MR) after lung transplantation is associated with substantial morbidity and may be an under-recognised phenomenon. Data is limited to single case reports only. We sought to review our centre's experience. Methods From 1990 to 2018, 1330 patients underwent lung transplantation at our centre (1032 bilateral, 298 single). We identified patients in whom significant MR developed post-operatively. Clinical and investigative data were evaluated. Results We identified 7 patients who developed severe MR post-lung transplantation. Five patients had undergone bilateral sequential lung transplantation while 2 underwent single right lung transplant Indications for transplantation were interstitial lung disease (ILD) in 4, chronic obstructive airways disease (COAD) in 2 and primary pulmonary arterial hypertension (PAH) in 1. Pre-operatively, 2 had trivial MR, 4 patients had mild, and 1 had moderate.. Three patients (2 ILD, 1 PAH) had pre-operative pulmonary hypertension with right ventricular dilatation and systolic dysfunction. Post-transplant MR was discovered intra-operatively in 2 patients, 4 were diagnosed within 6 months and one was diagnosed at 9 months post-transplant. Five patients underwent mitral valve surgery (2 repair, 3 replacement) between 1 day to 1.2 years post-transplant. One patient underwent transcatheter mitral valve repair at 3 months. Indications for mitral procedures were cardiogenic shock in 1, and progressive symptoms in the other 5. One patient had non-operative management of the mitral valve but required right pneumonectomy for graft necrosis. There were two mortalities at 5 and 13 years due to cancer and stroke respectively. Conclusion Development of significant mitral valve regurgitation is a rare but morbid complication after lung transplantation. We postulate that this phenomenon may be related to changes in left ventricular geometry due to RV unloading after lung transplantation coupled with unmasking of mild degenerative mitral valve disease. As an increasing number of patients with PAH and ILD with RV dysfunction undergo lung transplantation, post-transplant MR should be recognised as a rare but hemodynamically important complication that may require intervention.

Dysregulation of miR-135a-5p promotes the development of rat pulmonary arterial hypertension in vivo and in vitro.

Pulmonary arterial hypertension (PAH) is the most common form of pulmonary hypertension. Pulmonary arterial remodeling is closely related to the abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs), which leads to the thickening of the medial layer of muscular arteries and then results in the narrowing or occlusion of the precapillary arterioles and PAH. However, the mechanisms underlying the abnormal proliferation of PASMCs remain unclear. In this study, we established rat primary PAH models using monocrotaline (MCT) injection or hypoxic exposure, then investigated the expression patterns of seven miRNAs associated with multiple pathogenic pathways central to pulmonary hypertension, and further explored the roles and the possible mechanisms of miR-135a during the development of PAH. In the rat primary PAH models, we observed that the expression of miR-135a-5p in lungs was drastically decreased at the initial stage of PAH development after MCT administration or hypoxic exposure, but it increased by 12-fold or 10-fold at the later stage. In vitro study in PASMCs showed a similar pattern of miR-135a-5p expression, with downregulation at 6 h but upregulation at 18, 24, and 48 h after hypoxic exposure. Early, but not late, administration of a miR-135a-5p mimic inhibited hypoxia-induced proliferation of PASMCs. The protective role of early miR-135a-5p agomir in the PAH rat model further supported the hypothesis that the early decrease in the expression of miR-135a-5p contributes to the proliferation of PASMCs and development of PAH, as early administration of miR-135a-5p agomir (10 nM, i.v.) reversed the elevated mean pulmonary arterial pressure and pulmonary vascular remodeling in MCT-treated rats. We revealed that miR-135a-5p directly bound to the 3'-UTR sequence of rat transient receptor potential channel 1 (TRPC1) mRNA and decreased TRPC1 protein expression, thus inhibiting PASMC proliferation. Collectively, our data suggest that dysregulation of miR-135a-5p in PASMCs contributes to the abnormal proliferation of PASMCs and the pathogenesis of PAH. Increasing miR-135a-5p expression at the early stage of PAH is a potential new avenue to prevent PAH development.

Principles of pharmacological correction of pulmonary arterial hypertension

Definition and classification: Pulmonary hypertension (PH) is a group of life-threatening progressive diseases of various genesis, characterized by a progressive increase in arterial pressure (AP) in the pulmonary artery (PA), the remodeling of pulmonary vessels, which leads to an increase in pulmonary vascular resistance and pulmonary arterial pressure and more often leads to right ventricular heart failure and premature death. Pulmonary hypertension is clinically divided into five groups: patients in the first group have idiopathic pulmonary arterial hypertension (IPAH), whereas in patients of other groups secondary PH associated with cardiopulmonary or other systemic diseases is observed. The development of secondary LH is caused by congenital heart defects, collagenoses, presence of thrombus in the pulmonary artery, prolonged high pressure in the left atrium, hypoxemia, chronic obstructive pulmonary diseases (COPDs). In case of secondary PH, thrombosis and other changes in the pulmonary veins occur.&#x0D; Ways of pharmacological correction of pulmonary hypertension: Over the last decade pharmacotherapy of PH has been developing rapidly, and the introduction of modern methods of treatment, especially for primary PAH, has led to positive results. However, despite the progress in treatment, the functional limitations and survival of patients remain unsatisfactory. Currently, there are two levels of treatment for pulmonary hypertension: primary and specific pathogenetic therapies. Primary therapy is aimed at the main cause of PH. It also includes supportive therapy. Pathogenetic therapy includes prostanoids, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors. Tactics of therapy can be established on the basis of either clinical classification, or functional class. Prostanoids are a promising group of drugs for the treatment of pulmonary arterial hypertension (PAH), since they possess not only vasodilating, but also antiplatelet and antiproliferative actions. Therefore, it seems logical to use prostacyclin and its analogs to treat patients with various forms of PAH.