Pulmonary Vasculopathy Research Articles

Hemodynamical Approach to Pulmonary Hypertension

Pulmonary hypertension (PH) is a pathophysiological disorder characterized by a vascular obstruction leading to increased right ventricular overload. It can be caused by multiple conditions that we classify into 5 clinical groups. PH is defined hemodynamically and the role and indications of cardiac catheterization are increasingly important. The subject includes a panoply of pathologies with great complexity at the same time physio-pathological, histo-etiopathogenic, genetic... which are gathered under one chapter: the pulmonary vascular pathology. Right heart catheterization (RHC) is crucial and allows to measure and calculate variables to determine patients hemodynamics that are necessary for positive, etiological and severity diagnosis. It can also have therapeutic purpose: vasoreactivity test (APVT), pre-gesture assessment. Materiel and Methods: retrospective cross-sectional study of 143 patients with suspicion of pulmonary hypertension whom underwent RHC (left heart) performed between January 2017 and December 2021 in cardiology A department within Ibn Sina university hospital center. Results: In terms of the results of our study, we have a very diverse review in which PH is assessed at different levels for all groups and subgroups using a multitude of hemodynamic parameters. Our population is characterized by a clear predominance of women The average age of all 143 cases is 38 years. In terms of hemodynamic classification, isolated pre-capillary PH is the most common (52%). 64% of our cases had PVRs >2 Wu indicating the prevalence of pulmonary vasculopathy. Group 3 represents the population with the most preserved hemodynamical severity parameters. The main vasoreactivity test performed was the NO test.

Usual interstitial pneumonia is the predominant histopathology in patients with systemic sclerosis receiving a lung transplant.

Studies identifying nonspecific interstitial pneumonia (NSIP) as the predominant histopathology in systemic sclerosis-associated interstitial lung disease (SSc-ILD) have primarily utilised surgical lung biopsies in early disease. These case series may only reflect the histopathology of early disease and differ from the histopathology of advanced disease in those with respiratory failure. Patients receiving a lung transplant for a diagnosis of SSc at a single centre from 2000-2021 were included for retrospective analysis. All explanted lungs underwent histopathology review as part of routine care. 127 patients with SSc received a native lung transplant during the study period. Usual interstitial pneumonia (UIP) was identified in 111 explants (87.4%), NSIP in 45 (35.4%) explants, organising pneumonia in 11 explants (8.7%), and lymphocytic bronchitis in 2 explants (1.6%). Areas of both UIP and NSIP were identified in 37 explants (29.1%), with only 9 explants (7.1%) showing neither UIP nor NSIP. Aspiration was identified on histology in 49 (38.6%) explants. Pathology results were available from a prior surgical lung biopsy for 19 patients, with 11 patients maintaining the same primary pathology on biopsy and explant (2 NSIP, 9 UIP) and 8 patients showing different pathology at the timepoints, all of whom had UIP on explant. Most patients (101, 79.5%) had evidence of pulmonary hypertension and vasculopathy on explant. UIP is the predominant histopathology in patients with SSc receiving a lung transplant, with many patients concurrently having both NSIP and UIP or showing progression from NSIP to UIP over time before transplant.

Proline and glucose metabolic reprogramming supports vascular endothelial and medial biomass in pulmonary arterial hypertension.

In pulmonary arterial hypertension (PAH), inflammation promotes a fibroproliferative pulmonary vasculopathy. Reductionist studies emphasizing single biochemical reactions suggest a shift toward glycolytic metabolism in PAH; however, key questions remain regarding the metabolic profile of specific cell types within PAH vascular lesions in vivo. We used RNA-Seq to profile the transcriptome of pulmonary artery endothelial cells (PAECs) freshly isolated from an inflammatory vascular injury model of PAH ex vivo, and these data were integrated with information from human gene ontology pathways. Network medicine was then used to map all aa and glucose pathways to the consolidated human interactome, which includes data on 233,957 physical protein-protein interactions. Glucose and proline pathways were significantly close to the human PAH disease module, suggesting that these pathways are functionally relevant to PAH pathobiology. To test this observation in vivo, we used multi-isotope imaging mass spectrometry to map and quantify utilization of glucose and proline in the PAH pulmonary vasculature at subcellular resolution. Our findings suggest that elevated glucose and proline avidity underlie increased biomass in PAECs and the media of fibrosed PAH pulmonary arterioles. Overall, these data show that anabolic utilization of glucose and proline are fundamental to the vascular pathology of PAH.

Acquired disorders of mitochondrial metabolism and dynamics in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is an orphan disease of the cardiopulmonary unit that reflects an obstructive pulmonary vasculopathy and presents with hypertrophy, inflammation, fibrosis, and ultimately failure of the right ventricle (RVF). Despite treatment using pulmonary hypertension (PH)-targeted therapies, persistent functional impairment reduces the quality of life for people with PAH and death from RVF occurs in approximately 40% of patients within 5 years of diagnosis. PH-targeted therapeutics are primarily vasodilators and none, alone or in combination, are curative. This highlights a need to therapeutically explore molecular targets in other pathways that are involved in the pathogenesis of PAH. Several candidate pathways in PAH involve acquired mitochondrial dysfunction. These mitochondrial disorders include: 1) a shift in metabolism related to increased expression of pyruvate dehydrogenase kinase and pyruvate kinase, which together increase uncoupled glycolysis (Warburg metabolism); 2) disruption of oxygen-sensing related to increased expression of hypoxia-inducible factor 1α, resulting in a state of pseudohypoxia; 3) altered mitochondrial calcium homeostasis related to impaired function of the mitochondrial calcium uniporter complex, which elevates cytosolic calcium and reduces intramitochondrial calcium; and 4) abnormal mitochondrial dynamics related to increased expression of dynamin-related protein 1 and its binding partners, such as mitochondrial dynamics proteins of 49kDa and 51kDa, and depressed expression of mitofusin 2, resulting in increased mitotic fission. These acquired mitochondrial abnormalities increase proliferation and impair apoptosis in most pulmonary vascular cells (including endothelial cells, smooth muscle cells and fibroblasts). In the RV, Warburg metabolism and induction of glutaminolysis impairs bioenergetics and promotes hypokinesis, hypertrophy, and fibrosis. This review will explore our current knowledge of the causes and consequences of disordered mitochondrial function in PAH.

The outcome of pulmonary function tests and high-resolution computed tomography of chest in post-coronavirus disease 2019-confirmed cases after 3 months of recovery

Background Coronavirus disease (COVID-19) is a recently prevalent infectious disease that is caused by a virus from the coronavirus family and causes acute respiratory syndrome. It is a pandemic catastrophe that has affected more than 60 million people around the world and has caused about 1.5 million deaths, as reported by the WHO. This disease affects the respiratory system and leads to different forms of symptoms and signs. Pneumonia is a common cause for hospitalization, with most patients treated in hospital wards and others requiring ICU. Although the number of complete recoveries from COVID-19 has increased, there is still concern about complications associated with the disease that appear after recovery. The studies that have looked at past types and other forms of coronavirus epidemics, such as SARS have shown that some cases had respiratory complications from the infection after being full recovered, as 36 and 30% of the entire study population had clinical and high-resolution computed tomography (HRCT) changes at 3 and 6 months after recovery, respectively. Mostly, the abnormalities seen in pulmonary function test (PFT) results are sequelae of diffusion capacity defect. In recovered cases of Middle East respiratory syndrome, 36% of patients showed HRCT sequelae at follow-up of 6 weeks, because of fibrosis. Data on COVID-19 indicate that prolonged disease and persistent symptoms show post-PFT affection and follow-up radiographic changes after recovery from COVID-19 as interstitial pulmonary changes and a degree of pulmonary vasculopathy. In recovered cases of COVID-19, capacity of diffusion is the commonest defect in lung function, followed by the restrictive pattern defects on spirometry; both are related to the degree of severity of pneumonic COVID-19. PFTs (involving spirometry as well as diffusion capacity) are considered as routine follow-up examinations for some of the recovered cases, especially severe cases. Rehabilitation programs of the respiratory system are an option strategy that might be considered. This study aims to show changes in pulmonary function and HRCT of chest in post-COVID-19-infected patients to detect long-term effects on the lungs after 3 months as obstructive or restrictive, or both, lung diseases. Patients and methods The study was conducted on 100 confirmed PCR-positive COVID-19 cases that were admitted to Ain Shams University Isolation Hospitals, and the follow-up was performed in the outpatient clinic. PCR samples (Combined nasopharyngeal and oropharyngeal swab) were taken after 3 months from discharge of patients above the age of 18 years who become negative with clinical improvement. PFT [spirometry and diffusion for carbon monoxide (DLCO)] and chest HRCT were done. All patients’ clinical data were recorded, and CT chest imaging data of these patients were correlated with the clinical data. Results A total of 100 patients were included in this study, where males represented 58% and female represented 42%. The mean±SD age of cases in this study was 45.05 ± 11.80 years and ranged from 20 to 79 years. CT chest severity score (SS) of abnormality in COVID-19-infectedd patients based on HRCT chest findings before and after 3 months from treatment showed a highly significant correlation (P=0.000). The results of PFT in the studied group after 3 months of discharge showed restrictive pattern in 14.9%, obstructive pattern in 17.8%, and both obstructive and restrictive patterns in 5.9% of the total number of cases. There was a significant correlation between DLCO abnormality findings and age of studied group (P=0.032), a significant correlation between abnormality findings on PFT and HRCT chest SS after discharge of the studied group (P<0.001). There was a significant correlation between abnormality findings of DLCO and HRCT chest SS after 3 months of the studied group (P=0.000) and before treatment (P=0.001), whereas there was no significant correlation between other findings of PFT and HRCT chest SS after 3 months and before. There was a significant correlation between HRCT chest SS of the studied group and their age after (P=0.003) and before treatment (P=0.000). This cohort study provided the long-term dynamic sequelae and variations of lung function after hospital discharge. Conclusion DLCO-predicted value detected at 3 months is the most important factor associated with severe respiratory COVID-19, which is identified as the cause of impairment of any ordinary basic activity of patients in the stage of postrecovery from COVID-19. The radiological chest findings must be analyzed in conjunction with other functional parameters to provide accurate assessment of the disease. These findings highlight the significance of a comprehensive follow-up after severe and critical COVID-19 infection, with appropriate management of pulmonary consequences. Patients after discharge and on follow-up in outpatient clinics in the post-COVID-19 stage should be strictly followed up with PFTs. Further studies with longer follow-up periods might be needed.

Elevated VCAM-1, MCP-1 and ADMA serum levels related to pulmonary fibrosis of interstitial lung disease associated with rheumatoid arthritis.

Introduction: Early diagnosis of interstitial lung disease (ILD) associated with rheumatoid arthritis (RA) constitutes a challenge for the clinicians. Pulmonary vasculopathy is relevant in the development of interstitial lung disease. Accordingly, we aimed to explore the role of vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1) and asymmetric dimethylarginine (ADMA), key molecules in the vasculopathy, as potential biomarkers of pulmonary fibrosis in RA-ILD+. Methods: We included 21 RA-ILD+ patients and two comparative groups: 25 RA-ILD- patients and 21 idiopathic pulmonary fibrosis (IPF) patients. Serum levels of the molecules were determined by ELISA, and mRNA expression was quantified by qPCR. Results: VCAM-1, MCP-1 and ADMA serum levels were increased in RA-ILD+ patients in relation to RA-ILD- and IPF patients. Additionally, RA-ILD+ patients exhibited increased CCL2 (gene encoding MCP-1) and decreased PRMT1 (gene related to ADMA synthesis) mRNA expression in relation to RA-ILD- patients. A lower expression of VCAM1, CCL2, and PRMT1 was observed in RA-ILD+ patients when compared with those with IPF. Furthermore, MCP-1 serum levels and PRMT1 mRNA expression were positively correlated with RA duration, and ADMA serum levels were positively associated with C-reactive protein in RA-ILD+ patients. Conclusion: Our study suggests that VCAM-1, MCP-1 and ADMA could be considered as useful biomarkers to identify ILD in RA patients, as well as to discriminate RA-ILD+ from IPF, contributing to the early diagnosis of RA-ILD+.

From acute SARS-CoV-2 infection to pulmonary hypertension.

As the world progressively recovers from the acute stages of the coronavirus disease 2019 (COVID-19) pandemic, we may be facing new challenges regarding the long-term consequences of COVID-19. Accumulating evidence suggests that pulmonary vascular thickening may be specifically associated with COVID-19, implying a potential tropism of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) virus for the pulmonary vasculature. Genetic alterations that may influence the severity of COVID-19 are similar to genetic drivers of pulmonary arterial hypertension. The pathobiology of the COVID-19-induced pulmonary vasculopathy shares many features (such as medial hypertrophy and smooth muscle cell proliferation) with that of pulmonary arterial hypertension. In addition, the presence of microthrombi in the lung vessels of individuals with COVID-19 during the acute phase, may predispose these subjects to the development of chronic thromboembolic pulmonary hypertension. These similarities raise the intriguing question of whether pulmonary hypertension (PH) may be a long-term sequela of SARS-COV-2 infection. Accumulating evidence indeed support the notion that SARS-COV-2 infection is indeed a risk factor for persistent pulmonary vascular defects and subsequent PH development, and this could become a major public health issue in the future given the large number of individuals infected by SARS-COV-2 worldwide. Long-term studies assessing the risk of developing chronic pulmonary vascular lesions following COVID-19 infection is of great interest for both basic and clinical research and may inform on the best long-term management of survivors.

888: COMPARISON OF THE PROGNOSTIC VALUE OF PULMONARY DEAD SPACE PROXIES IN COVID-19 ARDS OUTCOMES

Introduction: Mortality and morbidity associated with COVID-19 acute respiratory distress syndrome (ARDS) has been associated with pulmonary vasculopathy, which has been hypothesized to increase pulmonary dead space (VD/VT). However, VD/VT is rarely measured at the bedside. As a result, multiple proxy estimates have been developed. Our hypothesis was proxy estimates for VD/VT would have differing utilities in prognostication of COVID-19 ARDS. Methods: We conducted a retrospective cohort study of patients admitted to an intensive care unit with SARS-CoV-2 ARDS who required invasive mechanical ventilation. Ventilation parameters were collected 2-8 hours after intubation. The VD/Vt proxies examined were 1) ventilatory ratio (VR), 2) estimation of VD/VT using the Harris-Benedict equation for energy expenditure (VD/VT-HB), 3) direct estimation of VD/VT using Beitler et. al.’s formula (VD/VT-Dir), and 4) corrected minute ventilation (VECorr). For each proxy, subjects were dichotomized using the median value. Comparisons were performed using the Wilcoxon rank-sum test with ⍺=0.05. Results: For 139 subjects, mean VR was 2.08 (SD±0.80), mean VD/VT-HB was 0.614 (±0.15), mean VD/VT-Dir was 0.657 (±0.08), and mean VECorr was 12.2 (±4.6) L/min. All four proxies had strong inter-measure correlation (Pearson’s r 0.748-0.881, p< 0.001 for all comparisons). No proxy was predictive of 30-day hospital mortality. High VR and VECorr were associated with increased morbidity using a composite endpoint of death or organ failure (defined as requiring renal dialysis or extracorporeal membrane oxygenation) with both having an odds ratio of 2.20 (95% CI: 1.12-4.33, p=0.022), while VD/VT-HB (p=0.552) and VD/VT-Dir (p=0.554) were not significantly associated. Of all proxies, only VR was significantly associated with increased sequential organ failure assessment (SOFA) score at 10±4 days post-intubation (6.2 vs. 4.8, p=0.024) and more ventilator-free days within the 30 days after intubation (3.2 vs. 1.8, p=0.029). Conclusions: Ventilatory ratio and corrected minute volume appear to have stronger associations with morbidity in COVID-19 ARDS compared to other VD/VT estimates. Ventilatory ratio is also associated with ventilator-free days and delayed SOFA score.

Targeting VEGF-A/VEGFR2 Y949 Signaling-Mediated Vascular Permeability Alleviates Hypoxic Pulmonary Hypertension.

Pulmonary hypertension (PH) is associated with increased expression of VEGF-A (vascular endothelial growth factor A) and its receptor, VEGFR2 (vascular endothelial growth factor 2), but whether and how activation of VEGF-A signal participates in the pathogenesis of PH is unclear. VEGF-A/VEGFR2 signal activation and VEGFR2 Y949-dependent vascular leak were investigated in lung samples from patients with PH and mice exposed to hypoxia. To study their mechanistic roles in hypoxic PH, we examined right ventricle systolic pressure, right ventricular hypertrophy, and pulmonary vasculopathy in mutant mice carrying knock-in of phenylalanine that replaced the tyrosine at residual 949 of VEGFR2 (Vefgr2Y949F) and mice with conditional endothelial deletion of Vegfr2 after chronic hypoxia exposure. We show that PH leads to excessive pulmonary vascular leak in both patients and hypoxic mice, and this is because of an overactivated VEGF-A/VEGFR2 Y949 signaling axis. In the context of hypoxic PH, activation of Yes1 and c-Src and subsequent VE-cadherin phosphorylation in endothelial cells are involved in VEGFR2 Y949-induced vascular permeability. Abolishing VEGFR2 Y949 signaling by Vefgr2Y949F point mutation was sufficient to prevent pulmonary vascular permeability and inhibit macrophage infiltration and Rac1 activation in smooth muscle cells under hypoxia exposure, thereby leading to alleviated PH manifestations, including muscularization of distal pulmonary arterioles, elevated right ventricle systolic pressure, and right ventricular hypertrophy. It is important that we found that VEGFR2 Y949 signaling in myeloid cells including macrophages was trivial and dispensable for hypoxia-induced vascular abnormalities and PH. In contrast with selective blockage of VEGFR2 Y949 signaling, disruption of the entire VEGFR2 signaling by conditional endothelial deletion of Vegfr2 promotes the development of PH. Our results support the notion that VEGF-A/VEGFR2 Y949-dependent vascular permeability is an important determinant in the pathogenesis of PH and might serve as an attractive therapeutic target pathway for this disease.

Abstract 15374: Somatic Mutations of Dnmt3a Contribute to Pulmonary Vascular Remodeling and Right Ventricular Dysfunction in PAH

Background: Pulmonary Arterial Hypertension (PAH) is an obliterative pulmonary vasculopathy in which structural changes are driven by inflammation, fibrosis, mitochondrial dysfunction, and pathological angiogenesis. While ~10% of cases of PAH have germline BMPR2 mutations (or one of 16 other recognized or putative PAH genes), the genetic basis for the majority of PAH patients remains unexplained. Somatic mutations in hematopoietic stem cells (HSC) are related to the disorders of clonal hematopoiesis of indeterminate potential (CHIP). Tet methylcytosine dioxygenase 2 (TET2) and DNA methyltransferase 3a (DNMT3A) are among the primary genes involved in CHIP. We found in a PAH-Biobank that 0.39% of PAH patients had somatic or germline TET2 mutations. Also, TET2-knockout mice can develop PAH spontaneously. Thus TET2 is a new PAH gene. We now hypothesize that CHIP driven by mutations of DNMT3A can also cause pulmonary vascular remodeling and right ventricular failure (RVF), contributing to PAH. Methods: Studies were performed on 9 month old DNMT3A knockout (-/-) mice and their relative controls (f/f) (N=5/group). The right ventricular (RV) function was assessed via cardiac ultrasound. Pulmonary artery medial wall thickness (PAMWT) and radial alveolar count (RAC) were assessed in lung tissue sections using light microscopy. Results: In DNMT3A -/- mice, there was a reduction in pulmonary artery acceleration time (PAAT) compared to controls ( p= 0.0268). There was also a significant reduction in percent RV free wall thickening (RVFWT %) compared to controls (57.44±9.97 DNMT3A-/-, 118.5±14.98 f/f; p= 0.017). Both Tricuspid annular plane systolic excursion (TAPSE) and cardiac output (CO) were also significantly reduced in DNMT3A -/- mice ( p &lt; 0.0001, p = 0.0135). The medial thickness of small pulmonary arteries was significantly higher in DNMT3A -/- mice compared to controls (56.51% ±1.19 DNMT3A-/-, 39.79% ±2.07 f/f; p= 0.002). RAC was significantly reduced in the DNMT3A -/- mice when compared to controls ( p= 0.018). Conclusions: DNMT3A mutations may contribute to the development of pulmonary vascular disease and RVF in PAH.

Pulmonary Hypertension in Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a common medical condition associated with increased morbidity and mortality. Through different mechanisms, including passive left-sided congestion and/or vasculopathy, patients with HFpEF can develop pulmonary hypertension (PH). This association -PH-HFpEF- is linked with worsening symptomatology and long-term outcomes. Although pulmonary vasodilators have been effective in treating patients with a pulmonary vasculopathy, such as pulmonary arterial hypertension (PAH), these results have not been replicated in those with PH-HFpEF. There is an unmet need to develop effective medical therapy for this challenging population. In this article, we focus on understanding the definition, epidemiology, diagnosis, clinical implications, and treatment for PH in the setting of HFpEF.

An integrated proteomic and transcriptomic signature of the failing right ventricle in monocrotaline induced pulmonary arterial hypertension in male rats

Aim: Pulmonary arterial hypertension (PAH) is an obstructive pulmonary vasculopathy that results in death from right ventricular failure (RVF). There is limited understanding of the molecular mechanisms of RVF in PAH. Methods: In a PAH-RVF model induced by injection of adult male rats with monocrotaline (MCT; 60mg/kg), we performed mass spectrometry to identify proteins that change in the RV as a consequence of PAH induced RVF. Bioinformatic analysis was used to integrate our previously published RNA sequencing data from an independent cohort of PAH rats. Results: We identified 1,277 differentially regulated proteins in the RV of MCT rats compared to controls. Integration of MCT RV transcriptome and proteome data sets identified 410 targets that are concordantly regulated at the mRNA and protein levels. Functional analysis of these data revealed enriched functions, including mitochondrial metabolism, cellular respiration, and purine metabolism. We also prioritized 15 highly enriched protein:transcript pairs and confirmed their biological plausibility as contributors to RVF. We demonstrated an overlap of these differentially expressed pairs with data published by independent investigators using multiple PAH models, including the male SU5416-hypoxia model and several male rat strains. Conclusion: Multiomic integration provides a novel view of the molecular phenotype of RVF in PAH which includes dysregulation of pathways involving purine metabolism, mitochondrial function, inflammation, and fibrosis.

Hemodynamic markers of pulmonary vasculopathy for prediction of early right heart failure and mortality after heart transplantation

Elevated pulmonary vascular resistance (PVR) is broadly accepted as an imminent risk factor for mortality after heart transplantation (HTx). However, no current HTx recipient risk score includes PVR or other hemodynamic parameters. This study examined the utility of various hemodynamic parameters for risk stratification in a contemporary HTx population. Patients from seven German HTx centers undergoing HTx between 2011 and 2015 were included retrospectively. Established risk factors and complete hemodynamic datasets before HTx were analyzed. Outcome measures were overall all-cause mortality, 12-month mortality, and right heart failure (RHF) after HTx. The final analysis included 333 patients (28% female) with a median age of 54 (IQR 46-60) years. The median mean pulmonary artery pressure was 30 (IQR 23-38) mm Hg, transpulmonary gradient 8 (IQR 5-10) mm Hg, and PVR 2.1 (IQR 1.5-2.9) Wood units. Overall mortality was 35.7%, 12-month mortality was 23.7%, and the incidence of early RHF was 22.8%, which was significantly associated with overall mortality (log-rank HR 4.11, 95% CI 2.47-6.84; log-rank p < .0001). Pulmonary arterial elastance (Ea) was associated with overall mortality (HR 1.74, 95% CI 1.25-2.30; p < .001) independent of other non-hemodynamic risk factors. Ea values below a calculated cutoff represented a significantly reduced mortality risk (HR 0.38, 95% CI 0.19-0.76; p < .0001). PVR with the established cutoff of 3.0 WU was not significant. Ea was also significantly associated with 12-month mortality and RHF. Ea showed a strong impact on post-transplant mortality and RHF and should become part of the routine hemodynamic evaluation in HTx candidates.

A CASE OF PULMONARY HYPERTENSION AS A POSSIBLE EXTRACRANIAL MANIFESTATION OF MOYAMOYA DISEASE

A CASE OF PULMONARY HYPERTENSION AS A POSSIBLE EXTRACRANIAL MANIFESTATION OF MOYAMOYA DISEASE

INHALED IMATINIB FOR PULMONARY ARTERIAL HYPERTENSION CLINICAL TRIAL: DESIGN OF THE IMPACT PHASE 2B/3 STUDY DESIGN

INHALED IMATINIB FOR PULMONARY ARTERIAL HYPERTENSION CLINICAL TRIAL: DESIGN OF THE IMPACT PHASE 2B/3 STUDY DESIGN

Maladaptation of Right Ventricle to High Pulmonary Hypertension in an Adult Patient with Patent Ductus Arteriosus

Pulmonary arterial hypertension is an obstructive pulmonary vasculopathy and the RV is considered a major determinant of survival in patients with precapillary pulmonary hypertension. The transition from adaptive to maladaptive phenotype remains poorly understood and clinically unpredictable. Several mechanisms having been suggested in right heart disease but the causes of maladaptive cardiac remodeling remain unknown and require further research. We report the case of PAH in the context of an overlooked patent ductus arteriosus in adulthood with RV consequences.

Update on balloon pulmonary angioplasty for treatment of chronic thromboembolic pulmonary hypertension

To provide an update on balloon pulmonary angioplasty (BPA) for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH), a pulmonary vascular disease that is characterized by fibro-thrombotic material mechanically obliterating major pulmonary arteries, resulting in increased pulmonary vascular resistance (PVR), progressive pulmonary hypertension (PH) combined with a microscopic pulmonary vasculopathy [1▪▪], right ventricular (RV) failure [2] and premature death. Data from a most recent CTEPH European registry (2015 and 2016) suggest significantly improved survival [3▪] of CTEPH patients compared with survival in the eighties [4], or with data from 2007 and 2009 [5]. Pulmonary endarterectomy (PEA) is still the gold-standard therapy for CTEPH [6,7]. However, only around two thirds of all CTEPH patients are amenable to surgery [3▪,5]. Patients not suitable for PEA and treated conservatively have a poor prognosis [8]. BPA may have a role for this particular group of patients. [9-11]. Currently, BPA programs are available in many countries, with excellent results at expert centers [12-15,16▪,17,18▪▪]. Based on recent data, BPA seems to have a greater impact on symptomatic and hemodynamic improvement than medical therapy with riociguat alone [15]. The evidence favoring BPA is growing, but there is still a lack of published controlled trials. In addition, treatment concepts including indication, technical performance, use of PH-targeted medication, and the concept of follow-up vary between centers. In addition, there is a significant learning curve impacting outcomes [13]. The data from the International BPA registry will provide answers for some of the open questions.

Immunohistochemical profile of the pulmonary vasculature in subjects with cirrhosis and histopathologic evidence of pulmonary vascular disease: An autopsy study

Portopulmonary hypertension (POPH) is a complication of cirrhosis that results in right ventricular failure and death. The objective of this autopsy investigation was to compare pulmonary arterial receptors in subjects with cirrhosis and histopathologic evidence of pulmonary vascular disease (PVD) and control group subjects with cirrhosis lacking evidence of PVD. Autopsy records of 824 subjects with cirrhosis were reviewed to identify pulmonary arterial vasculopathy. Lung sections from paraffin embedded blocks were immunostained for endothelin A (ET-A), endothelin B (ET- B), estrogen α (ER-α), estrogen β (ER-β), and vascular endothelial growth factor (VEGF). Subjects with cirrhosis and histopathologic evidence of PVD included 27 individuals with intimal hyperplasia (93%), medial hypertrophy (96%), and plexiform lesions (78%). Immunohistochemical staining for ET-A revealed positive reactivity in 40% of the group with cirrhosis and histopathologic evidence of PVD and 13% of the control group (NS). ET-B reactivity in the pulmonary endothelium and smooth muscle was identified in all subjects with cirrhosis and histopathologic evidence of PVD and control group. VEGF reactivity was identified in the endothelium in all subjects with cirrhosis and histopathologic evidence of PVD compared with 33% of the control group (p = 0.0002). ER-β reactivity was observed in four subjects (26.6%) with cirrhosis and histopathologic evidence of PVD while none in the control group (NS). Cirrhosis and histopathologic evidence of PVD was found in 3.3% of autopsies with the pulmonary vasculature immunohistochemical profile demonstrating endothelial and smooth muscle reactivity for endothelin, VEGF and ER-β.

Heart Failure with Preserved Ejection Fraction and Pulmonary Hypertension: Focus on Phosphodiesterase Inhibitors.

Pulmonary hypertension (PH) is common in patients with heart failure with preserved ejection fraction (HFpEF). A chronic increase in mean left atrial pressure leads to passive remodeling in pulmonary veins and capillaries and modest PH (isolated postcapillary PH, Ipc-PH) and is not associated with significant right ventricular dysfunction. In approximately 20% of patients with HFpEF, “precapillary” alterations of pulmonary vasculature occur with the development of the combined pre- and post-capillary PH (Cpc-PH), pertaining to a poor prognosis. Current data indicate that pulmonary vasculopathy may be at least partially reversible and thus serves as a therapeutic target in HFpEF. Pulmonary vascular targeted therapies, including phosphodiesterase (PDE) inhibitors, may have a valuable role in the management of patients with PH-HFpEF. In studies of Cpc-PH and HFpEF, PDE type 5 inhibitors were effective in long-term follow-up, decreasing pulmonary artery pressure and improving RV contractility, whereas studies of Ipc-PH did not show any benefit. Randomized trials are essential to elucidate the actual value of PDE inhibition in selected patients with PH-HFpEF, especially in those with invasively confirmed Cpc-PH who are most likely to benefit from such treatment.

Peripheral Microangiopathy Changes in Pulmonary Arterial Hypertension Related to Systemic Sclerosis: Data From a Multicenter Observational Study

Systemic sclerosis (SSc) is a connective tissue disease characterized by immune-system alterations, fibrosis involving the skin and internal organs and diffuse microangiopathy. Pulmonary arterial hypertension (PAH) is a severe complication of SSc affecting about 10–15% of the patients and it is a leading cause of mortality. Due to the devastating nature of SSc-PAH, there is a clear need to systematically adopt appropriate screening programs. Nail fold videocapillaroscopy (NVC) studies have shown a more severe peripheral microvascular dysfunction in SSc patients with PAH suggesting that abnormalities in peripheral microcirculation may correlate with pulmonary microangiopathy. This is a cross-sectional study involving four tertiary University Rheumatology Units in the Center-North of Italy. Seventy patients, 35 adults with SSc and PAH confirmed by RHC (F/M 34/1; median age 65.2 ± 8.9 SD yrs), and 35 SSc patients without PAH were enrolled (F/M 3471; median age 63.3 ± 10.3 SD yrs). Clinical, laboratoristic and instrumental data were collected and NVC was performed in all patient. Specific NVC parameters were evaluated and a semi-quantitative rating scale was adopted to score these changes. Finally, patients were distributed into the suitable NVC pattern belonging to the scleroderma pattern. Our aim was to compare the peripheral microangiopathy changes in SSc patients with and without PAH, and to investigate the relationship between NVC findings and the main hemodynamic parameters of pulmonary vasculopathy. Patients with SSc-PAH+ showed a significant higher frequency of interstitial lung disease (ILD). No significant differences regarding clinical and laboratoristic parameters were observed. NVC abnormalities, avascular areas were more frequent in SSc patients with PAH, respect to those without (p = 0.03), and capillary density was significantly lower when considering grade 3 (p = 0.02). A higher NVC semiquantitative mean was found in SSc-PAH+ patients and a greater rate of the “late” pattern was detected in SSc-PAH+ subjects in respect to PAH- (57.1% vs. 25.7%) (p = 0.03). A significant correlations between pulmonary pressure values (sPAP by TTE and mPAP by RHC) and the capillary density (Spearman's rho 0.35, p = 0.04 for both). Our findings provide additional evidence to the literature data, confirming that a higher degree of peripheral nailfold microangiopathy is more common in SSc-PAH patients, and further strengthening the concept that NVC changes may run parallel with similar abnormalities inside pulmonary microcirculation.