Inhalation of hydrogen gas protects against mitomycin-induced pulmonary veno-occlusive disease.

BACKGROUND: As a subtype of pulmonary hypertension (PH), pulmonary veno-occlusive disease (PVOD) is devastating and life-threatening disease without effective therapy. Hydrogen has been reported to exhibits antioxidant and anti-inflammatory effects in a rat model induced by monocrotaline of PH. In this study, we investigated the effects of inhaled hydrogen gas on the prevention and treatment of PVOD induced by mitomycin C (MMC) in rats. METHODS: PVOD was induced in female Sprague-Dawley rats through intraperitoneal injection of MMC at a concentration of 3 mg·kg- 1·wk- 1 for 2 weeks. Inhalation of hydrogen gas (H2) was administered through a designed rat cage concurrently or two weeks after MMC administration. The severity of PVOD was assessed by using hemodynamic measurements and histological analysis. The expression levels of general control nonderepressible 2 (GCN2), nuclear factor erythroid 2-related factor-2 (Nrf2), heme oxygenase-1 (HO-1) and endothelial-to-mesenchymal transition (EndoMT) related proteins in lung tissue were measured. Levels of lipid peroxidation pro-inflammatory cytokines in serum were determined. RESULTS: Inhaled H2 improved hemodynamics and right heart function, reversed right ventricular hypertrophy, and prevented pulmonary vessel reconstitution in both prevention and treatment approaches. It decreased malondialdehyde (MDA) levels in the serum and the expression of NADPH oxidase 1 (NOX-1) in lung tissue. It regulated Nrf2/HO-1 signaling pathway and anti-inflammatory factor GCN2 in lung tissue, accompanied by a decrease in macrophages and pro-inflammatory cytokines. Our data suggested that H2 inhalation effectively countered EndoMT induced by MMC, as evidenced by the detection of endothelial markers (e.g., VE-cadherin and CD31) and mesenchymal markers (e.g., vimentin and fibronectin). Further research revealed that H2 preserved p-Smad3 and induced p-Smad1/5/9. CONCLUSION: Inhalation of H2 effectively inhibits the pathogenesis of PVOD induced by MMC in rats. This inhibitory effect may be attributed to the antioxidant and anti-inflammatory properties of H2.

The chest CT signs for pulmonary veno-occlusive disease correlate with pulmonary haemodynamics in systemic sclerosis.

OBJECTIVE: Pulmonary arterial hypertension associated with systemic sclerosis (PAH-SSc) sometimes accompanies pulmonary veno-occlusive disease (PVOD). We aimed to reveal the relation between clinical signs of PVOD and severing of pulmonary vasculopathy in SSc. METHODS: This study comprised 52 consecutive SSc patients who had pulmonary haemodynamic abnormalities (mPAP > 20 mmHg, PVR > 2 W.U. or PAWP > 15 mmHg). The chest CT scan was evaluated in all patients. Patients were divided into two groups, the 0-1 group and the 2-3 group, according to the number of chest CT signs for PVOD, including 1) mediastinal lymph node enlargement, 2) thickened interlobular septal wall, and 3) ground glass opacity. Pulmonary haemodynamics, echocardiography and MRI-based cardiac function, pulmonary function, and serum biomarkers were compared between the two groups. RESULTS: Mediastinal lymph node enlargement, thickened interlobular septal wall, and ground glass opacity were observed in 11 (21%), 32 (62%), and 11 (21%) patients, respectively. The 2-3 group (n = 15) had higher mPAP (p= 0.02) while lower DLco/VA (p= 0.02) compared with the 0-1 group (n = 37). Other parameters, including PAWP, cardiac output, left ventricular ejection fraction, left atrial diameter, forced vital capacity, brain natriuretic peptide, and Krebs von den Lunge-6 were not different between the two groups. CONCLUSION: The CT signs for PVOD had positive correlation with mPAP but negative correlation with DLco in SSc patients, indicating that PAH-SSc may reflect a spectrum of pulmonary vascular disease that ranges from the pulmonary artery to the vein.

Pulmonary veno-occlusive disease in Sjogren's syndrome: a case report.

BACKGROUND: Pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD) belongs to Group 1 pulmonary hypertension. Pulmonary veno-occlusive disease (PVOD), which is characterized by venous system aberrations, has been previously reported in CTD-PAH; however, it has rarely been observed in Sjogren's syndrome (SS). CASE PRESENTATION: Our 28-year-old female patient was admitted to the hospital with recurrent shortness of breath even after minimal physical activity. Her chest high-resolution CT scan demonstrated pulmonary artery dilatation and bilateral ground-glass nodules. A subsequent right heart catheterization confirmed pulmonary hypertension because her mean pulmonary arterial pressure was 62 mmHg. Our inquisitive genomic assessment identified a novel EIF2AK4 mutation at c.1021 C > T (p. Gln341*), the dominant causal gene of PVOD. Histological examination demonstrated stenosis and occlusions in the pulmonary veins. Because she presented with features such as dry eyes and Raynaud's phenomenon, we performed a biopsy on the labial salivary gland, which confirmed SS. Her treatment regimen included PAH-targeted therapies (tadalafil and macitentan) in combination with hydroxychloroquine. Although she was hospitalized several times due to acute exacerbation of PAH, her disease progression was under control, and she did not demonstrate any signs of pulmonary edema even after a three-year treatment period. CONCLUSION: Here, we report the case of an SS-PAH patient with PVOD who carried a novel biallelic EIF2AK4 mutation, and PAH-targeted therapies were well tolerated by our patient.

Home-inhaled nitric oxide in a child with pulmonary arterial hypertension associated with post-operative pulmonary venous obstruction.

Home-inhaled nitric oxide therapy was effective and feasible in the patients with intractable pulmonary arterial hypertension. We present the case of a child with severe pulmonary arterial hypertension associated with post-operative pulmonary venous obstruction who was treated with home-inhaled nitric oxide therapy.

Clinical Implications of the Genetic Background in Pediatric Pulmonary Arterial Hypertension: Data from the Spanish REHIPED Registry.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a severe and rare disease with an important genetic background. The influence of genetic testing in the clinical classification of pediatric PAH is not well known and genetics could influence management and prognosis. OBJECTIVES: The aim of this work was to identify the molecular fingerprint of PH children in the REgistro de pacientes con HIpertensión Pulmonar PEDiátrica (REHIPED), and to investigate if genetics could have an impact in clinical reclassification and prognosis. METHODS: We included pediatric patients with a genetic analysis from REHIPED. From 2011 onward, successive genetic techniques have been carried out. Before genetic diagnosis, patients were classified according to their clinical and hemodynamic data in five groups. After genetic analysis, the patients were reclassified. The impact of genetics in survival free of lung transplantation was estimated by Kaplan-Meier curves. RESULTS: Ninety-eight patients were included for the analysis. Before the genetic diagnoses, there were idiopathic PAH forms in 53.1%, PAH associated with congenital heart disease in 30.6%, pulmonary veno-occlusive disease-PVOD-in 6.1%, familial PAH in 5.1%, and associated forms with multisystemic disorders-MSD-in 5.1% of the patients. Pathogenic or likely pathogenic variants were found in 44 patients (44.9%). After a genetic analysis, 28.6% of the cohort was "reclassified", with the groups of heritable PAH, heritable PVOD, TBX4, and MSD increasing up to 18.4%, 8.2%, 4.1%, and 12.2%, respectively. The MSD forms had the worst survival rates, followed by PVOD. CONCLUSIONS: Genetic testing changed the clinical classification of a significant proportion of patients. This reclassification showed relevant prognostic implications.

Comparison of Human and Experimental Pulmonary Veno-Occlusive Disease.

Pulmonary veno-occlusive disease (PVOD) occurs in humans either as a heritable form (hPVOD) due to biallelic inactivating mutations of EIF2AK4 (encoding GCN2) or as a sporadic form in older age (sPVOD). The chemotherapeutic agent mitomycin C (MMC) is a potent inducer of PVOD in humans and in rats (MMC-PVOD). Here, we compared human hPVOD and sPVOD, and MMC-PVOD pathophysiology at the histological, cellular, and molecular levels to unravel common altered pathomechanisms. MMC exposure in rats was associated primarily with arterial and microvessel remodeling, and secondarily by venous remodeling, when PVOD became symptomatic. In all forms of PVOD tested, there was convergent GCN2-dependent but eIF2α-independent pulmonary protein overexpression of HO-1 (heme oxygenase 1) and CHOP (CCAAT-enhancer-binding protein [C/EBP] homologous protein), two downstream effectors of GCN2 signaling and endoplasmic reticulum stress. In human PVOD samples, CHOP immunohistochemical staining mainly labeled endothelial cells in remodeled veins and arteries. Strong HO-1 staining was observed only within capillary hemangiomatosis foci, where intense microvascular proliferation occurs. HO-1 and CHOP stainings were not observed in control and pulmonary arterial hypertension lung tissues, supporting the specificity for CHOP and HO-1 involvement in PVOD pathobiology. In vivo loss of GCN2 (EIF2AK4 mutations carriers and Eif2ak4-/- rats) or in vitro GCN2 inhibition in cultured pulmonary artery endothelial cells using pharmacological and siRNA approaches demonstrated that GCN2 loss of function negatively regulates BMP (bone morphogenetic protein)-dependent SMAD1/5/9 signaling. Exogenous BMP9 was still able to reverse GCN2 inhibition-induced proliferation of pulmonary artery endothelial cells. In conclusion, we identified CHOP and HO-1 inhibition, and BMP9, as potential therapeutic options for PVOD.

Pulmonary vasodilators can lead to various complications in pulmonary "arterial" hypertension associated with congenital heart disease.

Congenital heart disease-associated pulmonary arterial hypertension (CHD-PAH) is one of the major complications in patients with CHD. A timely closure of the left-to-right shunt will generally result in the normalization of the pulmonary hemodynamics, but a few patients have severe prognosis in their early childhood. We hypothesized that wide-ranging pathological mechanism in PAH could elucidate the clinical state of severe CHD-PAH. Using electronic medical records, we retrospectively analyzed six infants with severe CHD-PAH who had treatment-resistant PH. All patients were born with congenital malformation syndrome. After starting on a pulmonary vasodilator, five of the six patients developed complications including pulmonary edema and interstitial lung disease (ILD), and four patients had alveolar hemorrhage. After steroid therapy, the clinical condition improved in four patients, but two patients died. The autopsy findings in one of the deceased patients indicated the presence of recurrent alveolar hemorrhage, pulmonary venous hypertension, ILD, and PAH. Based on the clinical course of these CHD-PAH in patients and the literature, CHD-PAH can occur with pulmonary vascular obstructive disease (PVOD)/pulmonary capillary hemangiomatosis (PCH), ILD, and/or alveolar hemorrhage. The severity of CHD-PAH may depend on a genetic disorder, respiratory infection, and upper airway stenosis. Additionally, pulmonary vasodilators may be involved in the development of PVOD/PCH and ILD. When patients with CHD-PAH show unexpected deterioration, clinicians should consider complications associated with PVOD/PCH and/or pulmonary disease. In addition, the choice of upfront combination therapy for pediatric patients with CHD-PAH should be selected carefully.

Rapid disease progress in a PVOD patient carrying a novel EIF2AK4 mutation: a case report.

BACKGROUND: Pulmonary veno-occlusive disease (PVOD) and pulmonary arterial hypertension (PAH) share an overlapping disease phenotype. Hence it is necessary to distinguish them. CASE PRESENTATION: Our 14-year-old female patient admitted with progressive shortness of breath, dizziness, and fatigue even after minimal physical activity was clinically suspected for PAH, based on her previous history. Her chest computed tomography artery reported the presence of PVOD triad features - subpleural thickened septal lines, ground-glass nodules/opacities and mediastinal lymphadenopathy. Because of her weak physical stature, a lung biopsy was not performed; however, the genetic testing identified a novel heterozygous EIF2AK4 mutation at c.4833_4836dup (p.Q1613Kfs*10) - the dominant susceptible factor driving PVOD. Combination of genetic testing and computed tomography artery facilitated us to distinguish PVOD from PAH. Her disease symptoms advanced aggressively so that she died even before the lung transplantation, which was less than 6 months from the onset of disease symptoms. CONCLUSION: This case report highlights that novel EIF2AK4 mutation at [c.4833_4836dup (p.Q1613Kfs*10)] would predict an aggressive phenotype of PVOD. Hence, we conclude that a genetic test identifying EIF2AK4 mutation would serve as a tool for the early diagnosis of PVOD, circumventing lung biopsy.

Unique wreath-like smooth muscle proliferation of the pulmonary vasculature in pulmonary veno-occlusive disease versus pulmonary arterial hypertension.

BACKGROUND/PURPOSE: Pulmonary veno-occlusive disease (PVOD) is a rare but fatal cause of pulmonary hypertension reported to be linked to mutations of eukaryotic initiation factor 2 alpha kinase 4 (EIF2AK4), also known as general control nonderepressible 2 kinase (GCN2). PVOD is difficult to diagnose and often initially misdiagnosed as other types of idiopathic pulmonary arterial hypertension (IPAH). To rapidly and correctly identify PVOD patients and explore the possible pathogenesis, we thoroughly investigated histopathological features and GCN2 protein levels in non-PAH, PVOD and PAH patients. METHODS: Lung specimens were examined for histopathological changes, including those of pulmonary arteries and veins, by Masson's trichrome, modified Verhoeff's and α-SMA staining in the PVOD, IPAH, and non-PAH groups. GCN2 and α-SMA expression in lung tissue was examined by immunohistochemistry and western blotting. RESULTS: PVOD and IPAH patients showed significant intimal and medial thickening of muscular pulmonary arteries compared with non-PAH patients. PVOD patients had more prominent intimal and medial thickening of muscular pulmonary veins than the other two groups. Interestingly, specialized muscle bundles surrounding the tunica adventitia of the pulmonary artery and vein were observed in PVOD patients. A significant decrease in GCN2 expression in the PVOD group was confirmed by immunohistochemistry and western blotting. CONCLUSION: Our study is the first to show remarkable histological structures, including the wreath-like arrangement of a hyperplastic muscle bundle in the adventitia of pulmonary arteries, in PVOD patients as a diagnostic clue and to disclose the biological difference between PAH and PVOD in a Taiwanese population.

Targeted therapy in pulmonary veno-occlusive disease: time for a rethink?

BACKGROUND: Pulmonary veno-occlusive disease (PVOD) is a rare condition with poor prognosis, and lung transplantation is recommended as the only curative therapy. The role of pulmonary arterial hypertension targeted therapy in PVOD remains controversial, and long-term effects of targeted therapy have been rarely reported. This study aims to retrospectively evaluate the role of targeted therapy in PVOD patients and the long-term outcome. METHODS: PVOD patients with good responses to targeted therapies were analyzed, and data pre- and post- targeted therapies were compared. An overview of the effects of targeted therapies on PVOD patients was also conducted. RESULTS: Five genetically or histologically confirmed PVOD patients received targeted therapies and showed good responses. Their mean pulmonary arterial pressure by right heart catheterization was 62.0 ± 11.7 mmHg. Two receiving monotherapy got stabilized, and three receiving sequential combination therapy got improved, cardiac function and exercise capacity significantly improved after treatments. No pulmonary edema occurred. The mean time from the first targeted therapy to the last follow up was 39.3 months, and the longest was 9 years. A systematic review regarding the effects of targeted therapies on PVOD patients indicated majorities of patients got hemodynamics or 6-min walk distance improved, and 26.7% patients developed pulmonary edema. The interval from targeted drugs use to death ranged from 71 min to over 4 years. CONCLUSIONS: Cautious use of targeted therapy could safely and effectively improve or stabilize hemodynamics and exercise capacity of some patients without any complications. PVOD patients could live longer than expected.

Idiopathic, heritable and veno-occlusive pulmonary arterial hypertension in childhood: computed tomography angiography features in the initial assessment of the disease.

BACKGROUND: In children, idiopathic and heritable pulmonary arterial hypertension present echocardiographic and heart catheterization findings similar to findings in pulmonary veno-occlusive disease. OBJECTIVE: To provide a systematic analysis of CT angiography anomalies in children with idiopathic or heritable pulmonary arterial hypertension, or pulmonary veno-occlusive disease. We also sought to identify correlations between CT findings and patients' baseline characteristics. MATERIALS AND METHODS: We retrospectively analyzed CT features of children with idiopathic and heritable pulmonary arterial hypertension or pulmonary veno-occlusive disease and 30 age-matched controls between 2008 and 2014. We compared CT findings and patient characteristics, including gene mutation type, and disease outcome until 2017. RESULTS: The pulmonary arterial hypertension group included idiopathic (n=15) and heritable pulmonary arterial hypertension (n=11) and pulmonary veno-occlusive disease (n=4). Median age was 6.5 years. Children with pulmonary arterial hypertension showed enlargement of pulmonary artery and right cardiac chambers. A threshold for the ratio between the pulmonary artery and the ascending aorta of ≥1.2 had a sensitivity of 90% and a specificity of 100% for pulmonary arterial hypertension. All children with pulmonary veno-occlusive disease had thickened interlobular septa, centrilobular ground-glass opacities, and lymphadenopathy. In children with idiopathic and heritable pulmonary arterial hypertension, presence of intrapulmonary neovessels and enlargement of the right atrium were correlated with higher mean pulmonary artery pressure (P=0.011) and pulmonary vascular resistance (P=0.038), respectively. Mediastinal lymphadenopathy was associated with disease worsening within the first 2 years of follow-up (P=0.024). CONCLUSION: CT angiography could contribute to early diagnosis and prediction of severity in children with pulmonary arterial hypertension.

Beneficial Effects of Imatinib in a Patient with Suspected Pulmonary Veno-Occlusive Disease.

Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension (PH). The prognosis of PVOD patients remains poor, since no effective medical therapy is yet available. Imatinib is a tyrosine kinase inhibitor specific for platelet-derived growth factor receptor and is expected as a treatment option for pulmonary arterial hypertension (PAH). Recently, it has been reported that imatinib improved functional capacity of a patient with PVOD. We here report a patient with suspected PVOD who has been successfully treated with imatinib and is alive for 6 years after diagnosis. A 57-year-old woman was admitted to a hospital for severe dyspnea. Echocardiography suggested the presence of PH, because tricuspid regurgitation pressure gradient was elevated. The patient was then transferred to our hospital by an ambulance ahead of schedule due to fever and worsening dyspnea. Because the patient had no left heart disease, we diagnosed that she had PAH associated with severe right heart failure. We immediately started treatment with nitric oxide (NO) for her severe hypoxia; however, it caused pulmonary edema. We suspected PVOD from CT characteristics and pulmonary edema after PAH-targeted vasodilator therapy, and then started oral imatinib treatment. In response to imatinib, her pulmonary edema gradually improved. Since then, the patient has been alive for 6 years with imatinib and pulmonary vasodilators. At present, lung transplantation is the only effective therapy for PVOD with limited availability. We therefore propose that imatinib may be a treatment option for PVOD and a bridge to lung transplantation.

Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. METHODS: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource-Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. RESULTS: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%-35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23-38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. CONCLUSIONS: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation.

[Clinical and imaging features of pulmonary veno-occlusive disease and pulmonary capillary hemangioma].

Objective: To improve the diagnosis and treatment of the pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangioma (PCH). Methods: The clinical features, radiological findings, laboratory testing and treatment in 8 cases of PVOD/PCH which was diagnosed from 2013 to 2017 were described. Results: PVOD/PCH was rare. The clinical symptoms were easily confused with IPAH, but the decrease of hypoxemia, clubbing, D(L)CO were more obvious, and the imaging features of HRCT were helpful for PVOD/PCH diagnosis. Combined with gene testing, it was helpful to diagnose PVOD/PCH and avoid the risk of surgical biopsy. Conclusion: PVOD and PCH are rare type of pulmonary vascular diseases. According to clinical manifestations, physical examination, pulmonary function test results, HRCT imaging, CPET and gene detection results, PVOD or PCH can be diagnosed.

Prognostic significance of computed tomography criteria for pulmonary veno-occlusive disease in systemic sclerosis-pulmonary arterial hypertension.

Objectives: SSc-pulmonary arterial hypertension (SSc-PAH) is associated with worse response to therapy and survival when compared with idiopathic PAH. It is suggested that the vasculopathy in SSc may involve postcapillary pulmonary venules resulting in pulmonary veno-occlusive disease (PVOD). This may underlie the lower gas transfer and worse outcome on therapy. We sought to test whether CT signs of PVOD (CTS-PVOD) were frequent in SSc-PAH and whether they were associated with pulmonary oedema on therapy and worse survival. Methods: CT thorax of 66 SSc patients with precapillary pulmonary hypertension (PH) were blindly scored by two radiologists for CTS-PVOD (⩽1 or ⩾ 2). Case note and radiograph review determined the presence of pulmonary oedema on therapy. Results: Fifty-nine patients (89%) had ⩽1 CTS-PVOD and only 7 (11%) had ⩾2 CTS-PVOD. Pulmonary oedema on therapy was relatively common in those with ⩾2 CTS-PVOD. On univariate analysis ⩾2 CTS-PVOD were associated with a trend towards worse survival. Conclusion: CTS-PVOD were less frequent in this SSc-PAH cohort than in previous reports but the presence of at least two of these signs is associated with pulmonary oedema on therapy and a trend towards worse survival on univariate analysis.

Sorafenib as a potential strategy for refractory pulmonary arterial hypertension.

Sorafenib is an inhibitor of multi-kinases including tyrosine and serine/threonine kinases. We investigated the efficacy and safety of sorafenib for the treatment of patients with refractory pulmonary arterial hypertension (PAH). Sorafenib was started in 9 patients (7 with idiopathic PAH, 2 with pulmonary veno-occlusive disease) who had severe PAH and right heart failure, in spite of treatment with vasodilators specific for PAH. Sorafenib was started as an add-on therapy at a dose of 50 or 100 mg/day, and increased to 100-400 mg/day. New York Heart Association functional class improved in 8 patients and did not change in 1. Mean pulmonary arterial pressure improved in 6 patients (14-28% decrease) and did not apparently change in 2 (follow-up catheterization was not performed in 1 patient). The main adverse effects of sorafenib were skin reactions on the hands and feet, which appeared in 5 patients. They were tolerable in 4 patients, but discontinuation of sorafenib was needed in only 1 patient. In conclusion, sorafenib had favorable effects to improve symptoms and objective variables in patients with refractory PAH, with tolerable adverse events. Sorafenib is an alternative strategy for patients with refractory PAH.

Vasoproliferative process resembling pulmonary capillary hemangiomatosis in a cat.

BACKGROUND: Pulmonary capillary hemangiomatosis is a rare, vascular obstructive disorder that uniformly causes pulmonary arterial hypertension. Clinically, pulmonary capillary hemangiomatosis is indistinguishable from primary pulmonary arterial hypertension and histology is required for definitive diagnosis. The distinctive histologic feature of pulmonary capillary hemangiomatosis is non-malignant extensive proliferation of capillaries in the alveolar septae. Vasodilator treatment of humans with primary arterial hypertension due to pulmonary capillary hemangiomatosis can result in fatal acute pulmonary edema. Computed tomography is thus critical to discern pulmonary capillary hemangiomatosis from other causes of pulmonary arterial hypertension prior to vasodilator therapy. This is the first report of a vasoproliferative process resembling pulmonary capillary hemangiomatosis in the feline species. CASE PRESENTATION: A 15-year-old, male castrated, domestic shorthair cat presented for persistent labored breathing presumptively due to congestive heart failure despite treatment with diuretics for 7 days. Echocardiography showed evidence of hypertrophic cardiomyopathy with severe pulmonary hypertension; however, a normal sized left atrium was not consistent with congestive heart failure. Thoracic computed tomography was performed and showed evidence of diffuse ill-defined nodular ground glass opacities, enlarged pulmonary arteries, and filling defects consistent with pulmonary thromboembolism. The cat acutely decompensated after a single dose of sildenafil and was euthanized. Histopathology of the lungs showed severe multifocal alveolar capillary proliferation with respiratory bronchiolar infiltration, marked type II pneumocyte hyperplasia and multifocal pulmonary arterial thrombosis. CONCLUSION: This is the first description in a cat of a vasoproliferative disorder resembling pulmonary capillary hemangiomatosis complicated by multifocal pulmonary arterial thrombosis. Inspiratory and expiratory ventilator-driven breath holds with angiography revealed lesions predominantly characterized by ground glass opacification and vascular filling defects with absence of air trapping. The results from this report suggest that, as in humans, the cat can develop a pulmonary capillary hemangiomatosis-like disease in which vasodilator therapy to address pulmonary hypertension may lead to fatal pulmonary edema.

Rapidly progressive pulmonary veno-occlusive disease in an infant with Down syndrome.

A 4-month-old girl with Down syndrome showed unexpected deterioration of pulmonary hypertension. Despite aggressive pulmonary vasodilation therapy, the patient died at 5 months of age. Lung autopsy showed that the pulmonary veins were obliterated by intimal fibrous thickening, and the media of the veins was arterialised with an increase in elastic fibres. Pulmonary veno-occlusive disease should be considered in the management of individuals with Down syndrome.

Mitomycin-Induced Pulmonary Veno-Occlusive Disease: Evidence From Human Disease and Animal Models.

BACKGROUND: Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension characterized by the obstruction of small pulmonary veins and a dismal prognosis. PVOD may be sporadic or heritable because of biallelic mutations of the EIF2AK4 gene coding for GCN2. Isolated case reports suggest that chemotherapy may be a risk factor for PVOD. METHODS AND RESULTS: We reported on the clinical, functional, and hemodynamic characteristics and outcomes of 7 cases of PVOD induced by mitomycin-C (MMC) therapy from the French Pulmonary Hypertension Registry. All patients displayed squamous anal cancer and were treated with MMC alone or MMC plus 5-fluoruracil. The estimated annual incidence of PVOD in the French population that have anal cancer is 3.9 of 1000 patients, which is much higher than the incidence of PVOD in the general population (0.5/million per year). In rats, intraperitoneal administration of MMC induced PVOD, as demonstrated by pulmonary hypertension at right-heart catheterization at days 21 to 35 and major remodeling of small pulmonary veins associated with foci of intense microvascular endothelial-cell proliferation of the capillary bed. In rats, MMC administration was associated with dose-dependent depletion of pulmonary GCN2 content and decreased smad1/5/8 signaling. Amifostine prevented the development of MMC-induced PVOD in rats. CONCLUSIONS: MMC therapy is a potent inducer of PVOD in humans and rats. Amifostine prevents MMC-induced PVOD in rats and should be tested as a preventive therapy for MMC-induced PVOD in humans. MMC-induced PVOD in rats represents a unique model to test novel therapies in this devastating orphan disease.

EIF2AK4 mutation as "second hit" in hereditary pulmonary arterial hypertension.

BACKGROUND: Mutations in the eukaryotic translation initiation factor 2α kinase 4 (EIF2AK4) gene have recently been identified in recessively inherited veno-occlusive disease. In this study we assessed if EIF2AK4 mutations occur also in a family with autosomal dominantly inherited pulmonary arterial hypertension (HPAH) and incomplete penetrance of bone morphogenic protein receptor 2 (BMPR2) mutations. METHODS: Clinical examinations in a family with 10 members included physical examination, electrocardiogram, (stress)-echocardiography and lung function. Manifest PAH was confirmed by right heart catheterisation in three affected subjects. Genetic analysis was performed using a new PAH-specific gene panel analysis with next generation sequencing of all known PAH and further candidate genes. Identified variants were confirmed by Sanger sequencing. RESULTS: All living family members with manifest HPAH carried two pathogenic heterozygous mutations: a frame shift mutation in the BMPR2 gene and a novel splice site mutation in the EIF2AK4 gene. Two family members who carried the BMPR2 mutation only did not develop manifest HPAH. CONCLUSIONS: This is the first study suggesting that EIF2AK4 can also contribute to autosomal dominantly inherited HPAH. Up to now it has only been identified in a recessive form of HPAH. Only those family members with a co-occurrence of two mutations developed manifest HPAH. Thus, the EIF2AK4 and BMRPR2 mutations support the "second hit" hypothesis explaining the variable penetrance of HPAH in this family. Hence, the assessment of all known PAH genes in families with a known mutation might assist in predictions about the clinical manifestation in so far non-affected mutation carriers.