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1.
Arch. bronconeumol. (Ed. impr.) ; 56(9): 578-585, sept. 2020. tab, graf
Article En | IBECS | ID: ibc-198502

BACKGROUND AND OBJECTIVE: Ventilatory inefficiency (high V′E/V′CO2) and resting hypocapnia are common in pulmonary vascular disease and are associated with poor prognosis. Low resting PaCO2 suggests increased chemosensitivity or an altered PaCO2 set-point. We aimed to determine the relationships between exercise gas exchange variables reflecting the PaCO2 set-point, exercise capacity, hemodynamics and V′E/V′CO2. METHODS: Pulmonary arterial hypertension (n=34), chronic thromboembolic pulmonary hypertension (CTEPH, n = 19) and pulmonary veno-occlusive disease (PVOD, n = 6) patients underwent rest and peak exercise arterial blood gas measurements during cardiopulmonary exercise testing. Patients were grouped according to resting PaCO2: hypocapnic (PaCO2 ≤ 34 mmHg) or normocapnic (PaCO2 35-45 mmHg). The PaCO2 set-point was estimated by the maximal value of end-tidal PCO2 (maximal PETCO2) between the anaerobic threshold and respiratory compensation point.: Results The hypocapnic group (n=39) had lower resting cardiac index (3.1 ± 0.8 vs. 3.7 ± 0.7L/min/m2, p < 0.01), lower peak V′O2 (15.8 ± 3.5 vs. 20.7 ± 4.3 mL/kg/min, p < 0.01), and higher V′E/V′CO2 slope (60.6 ± 17.6 vs. 38.2 ± 8.0, p < 0.01). At peak exercise, hypocapic patients had lower PaO2, higher VD/VT and higher P(a-ET)CO2. Maximal PETCO2 (r = 0.59) and VD/VT (r = -0.59) were more related to cardiac index than PaO2 or PaCO2 at rest or peak exercise. Maximal PETCO2 was the strongest correlate of V′E/V′CO2 slope (r = -0.86), peak V′O2 (r = 0.64) and peak work rate (r = 0.49). CONCLUSIONS: Resting hypocapnia is associated with worse cardiac function, more ventilatory inefficiency and reduced exercise capacity. This could be explained by elevated chemosensitivity and lower PaCO2 set-point. Maximal PETCO2 may be a useful non-invasive marker of PaCO2 setpoint and disease severity even with submaximal effort


CONTEXTO GENERAL Y OBJETIVO: La ineficiencia ventilatoria (V'E/V'CO2 alta) y la hipocapnia en reposo son comunes en la enfermedad vascular pulmonar y se asocian con un mal pronóstico. La PaCO2 baja en reposo sugiere una mayor quimiosensibilidad o una alteración en el ajuste fisiológico de la PaCO2. Nuestro objetivo fue determinar las relaciones entre las variables de intercambio de gases que reflejan el ajuste de la PaCO2 durante el ejercicio, la capacidad de ejercicio, la hemodinámica y la V'E/V'CO2. MÉTODOS: Se realizaron mediciones de gases en sangre arterial durante las pruebas de ejercicio cardiopulmonar a pacientes con hipertensión arterial pulmonar (n = 34), hipertensión pulmonar tromboembólica crónica (HPTEC, n = 19) y enfermedad venooclusiva pulmonar (EVOP, n = 6). Los pacientes se agruparon de acuerdo con su PaCO2 en reposo: hipocapnia (PaCO2 ≤ 34 mmHg) o normocapnia (PaCO2 35-45 mmHg). El ajuste de la PaCO2 se estimó mediante el valor máximo de PCO2 exhalado (PETCO2 máximo) entre el umbral anaeróbico y el punto de compensación respiratoria. RESULTADOS: El grupo hipocápnico (n = 39) tenía un índice cardíaco en reposo más bajo (3,1 ± 0,8 vs. 3,7 ± 0,7L/min/m2, p < 0,01), un pico de V'O2 más bajo (15,8 ± 3,5 vs 20,7 ± 4,3 mL/kg/min, p < 0,01), y mayor pendiente de V'E/V'CO2 (60,6 ± 17,6 vs. 38,2 ± 8,0, p < 0,01). En el punto de ejercicio máximo, los pacientes hipocápnicos tenían una PaO2 más baja, un VD/VT más alto y una P(a-ET) CO2 más alta. La PETCO2 máxima (r = 0,59) y la VD/VT (r = -0,59) estaban más relacionadas con el índice cardíaco que la PaO2 o la PaCO2 en reposo o en el punto de máximo esfuerzo. La PETCO2 máxima fue la que mayor correlación tuvo con la pendiente V'E/V'CO2 (r = -0,86), la V'O2 máxima (r = 0.64) y la tasa de esfuerzo máximo (r = 0,49). CONCLUSIONES: La hipocapnia en reposo se asocia a una peor función cardíaca, una mayor ineficiencia ventilatoria y una capacidad disminuída de ejercicio. Esto podría explicarse por una quimiosensibilidad elevada y un ajuste fisiológico más bajo de la PaCO2. La PETCO2 máxima puede ser un marcador no invasivo útil del ajuste de PaCO2 y la gravedad de la enfermedad incluso con un esfuerzo submáximo


Humans , Male , Female , Adult , Middle Aged , Exercise/physiology , Pulmonary Ventilation/physiology , Pulmonary Gas Exchange/physiology , Hypertension, Pulmonary/physiopathology , Pulmonary Embolism/physiopathology , Pulmonary Veno-Occlusive Disease/physiopathology , Severity of Illness Index , Retrospective Studies , Spirometry , Prognosis
2.
Medicine (Baltimore) ; 99(30): e21517, 2020 Jul 24.
Article En | MEDLINE | ID: mdl-32791767

INTRODUCTION: Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension. It is often underdiagnosed or misdiagnosed as idiopathic pulmonary arterial hypertension (PAH). Inappropriate treatment may cause worsening of symptoms which may lead to fatal outcomes. Anesthetic considerations and management for pulmonary hypertension are well described, but few anesthesiologists are aware of the entity of PVOD and its management. PATIENT CONCERNS: We report a case of PVOD in a 73-year-old female who was on concurrent aspirin and anagrelide, requiring emergent open femoral hernia repair. DIAGNOSIS: PVOD and incarcerated femoral hernia INTERVENTION:: Combined spinal-epidural (CSE) was performed to enable the surgery. OUTCOME: Surgery was completed successfully under central neuraxial anesthesia and the patient remained stable and comfortable throughout, avoiding the need for general anesthesia. Due to the concurrent aspirin and anagrelide therapy, significant bleeding from the CSE puncture site was observed immediately post-operatively. This was resolved with external manual compression and withholding the aspirin and anagrelide. Patient remained well without neurological deficit and was discharged postoperative day seven. LESSONS: It is important to differentiate PVOD from PAH due to the controversial use of pulmonary vasodilators in PVOD. Pulmonary vasodilator is commonly used to treat acute pulmonary hypertension in PAH but its usage may lead to pulmonary edema in patients with PVOD. Hence, with no ideal treatment available, the avoidance of general anesthesia is crucial to prevent acute pulmonary hypertensive crisis in patient with PVOD. However, this needs to be weighed against the elevated risk of central neuraxial bleeding when performing a CSE in a patient on concurrent aspirin and anagrelide therapy. Calculated decision-making considering the risks and benefits of all alternatives should be carried out in such a scenario, and measures should be taken in anticipation of the potential consequences of the eventual decision. CONCLUSION: It is important to differentiate PVOD from PAH. PVOD has unique anesthetic considerations due to the controversial use of pulmonary vasodilators. This case also emphasizes the importance of active anticipation of potential issues and adequate follow up.


Anesthesia, Epidural , Anesthesia, Spinal , Intraoperative Complications/prevention & control , Pulmonary Veno-Occlusive Disease/complications , Aged , Female , Hernia, Femoral/surgery , Herniorrhaphy , Humans , Intraoperative Complications/etiology
3.
PLoS One ; 15(4): e0232216, 2020.
Article En | MEDLINE | ID: mdl-32348326

BACKGROUND: The knowledge of hereditary predisposition has changed our understanding of Pulmonary Arterial Hypertension. Genetic testing has been widely extended and the application of Pulmonary Arterial Hypertension specific gene panels has allowed its inclusion in the diagnostic workup and increase the diagnostic ratio compared to the traditional sequencing techniques. This is particularly important in the differential diagnosis between Pulmonary Arterial Hypertension and Pulmonary Venoocclusive Disease. METHODS: Since November 2011, genetic testing is offered to all patients with idiopathic, hereditable and associated forms of Pulmonary Arterial Hypertension or Pulmonary Venoocclusive Disease included in the Spanish Registry of Pulmonary Arterial Hypertension. Herein, we present the clinical phenotype and prognosis of all Pulmonary Arterial Hypertension patients with disease-associated variants in TBX4. RESULTS: Out of 579 adults and 45 children, we found in eight patients from seven families, disease-causing associated variants in TBX4. All adult patients had a moderate-severe reduction in diffusion capacity. However, we observed a wide spectrum of clinical presentations, including Pulmonary Venoocclusive Disease suspicion, interstitial lung disease, pulmonary vascular abnormalities and congenital heart disease. CONCLUSIONS: Genetic testing is now essential for a correct diagnosis work-up in Pulmonary Arterial Hypertension. TBX4-associated Pulmonary Arterial Hypertension has marked clinical heterogeneity. In this regard, a genetic study is extremely useful to obtain an accurate diagnosis and provide appropriate management.


Familial Primary Pulmonary Hypertension/genetics , Genetic Variation , T-Box Domain Proteins/genetics , Adolescent , Adult , Child , Child, Preschool , Codon, Nonsense , Diagnosis, Differential , Familial Primary Pulmonary Hypertension/diagnosis , Familial Primary Pulmonary Hypertension/diagnostic imaging , Female , Gene Deletion , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Mutation, Missense , Pedigree , Phenotype , Polymorphism, Single Nucleotide , Prognosis , Pulmonary Veno-Occlusive Disease/diagnosis , Pulmonary Veno-Occlusive Disease/genetics
4.
Am J Pathol ; 190(7): 1382-1396, 2020 07.
Article En | MEDLINE | ID: mdl-32275906

Pulmonary hypertension and pulmonary vascular remodeling (PVR) are common in many lung diseases leading to right ventricular dysfunction and death. Differences in PVR result in significant prognostic divergences in both the pulmonary arterial and venous compartments, as in pulmonary arterial hypertension (PAH) and pulmonary veno-occlusive disease (PVOD), respectively. Our goal was to identify compartment-specific molecular hallmarks of PVR, considering the risk of life-threatening pulmonary edema in PVOD, if treated by conventional pulmonary hypertension therapy. Formalin-fixed and paraffin-embedded tissues from fresh explanted human lungs of patients with PVOD (n = 19), PAH (n = 20), idiopathic pulmonary fibrosis (n = 13), and chronic obstructive pulmonary disease (n = 15), were analyzed for inflammation and kinome-related gene regulation. The generated neuronal network differentiated PVOD from PAH samples with a sensitivity of 100% and a specificity of 92% in a randomly chosen validation set, a level far superior to established diagnostic algorithms. Further, various alterations were identified regarding the gene expression of explanted lungs with PVR, compared with controls. Specifically, the dysregulation of microtubule-associated serine/threonine kinase 2 and protein-o-mannose kinase SGK196 in all disease groups suggests a key role in pulmonary vasculopathy for the first time. Our findings promise to help develop novel target-specific interventions and innovative approaches to facilitate clinical diagnostics in an elusive group of diseases.


Airway Remodeling/physiology , Hypertension, Pulmonary/physiopathology , Pulmonary Veno-Occlusive Disease/physiopathology , Adolescent , Adult , Aged , Child , Child, Preschool , Female , Humans , Hypertension, Pulmonary/classification , Hypertension, Pulmonary/diagnosis , Idiopathic Pulmonary Fibrosis/classification , Idiopathic Pulmonary Fibrosis/diagnosis , Idiopathic Pulmonary Fibrosis/physiopathology , Male , Middle Aged , Pulmonary Disease, Chronic Obstructive/classification , Pulmonary Disease, Chronic Obstructive/diagnosis , Pulmonary Disease, Chronic Obstructive/physiopathology , Pulmonary Veno-Occlusive Disease/classification , Pulmonary Veno-Occlusive Disease/diagnosis , Transcriptome , Young Adult
5.
Radiology ; 295(1): 240-244, 2020 04.
Article En | MEDLINE | ID: mdl-32176598

HistoryA 34-year-old man presented to the emergency department of our hospital for progressive shortness of breath and worsening productive cough of 2 weeks duration. He reported a 10-kg weight loss over 4 months but denied experiencing fever, chills, night sweats, or gastrointestinal, musculoskeletal, or neurologic symptoms. His medical history was unremarkable. Although he was a native of Morocco, he had lived in Europe for many years and worked as a truck driver. The patient had a smoking history but had quit smoking 5 years prior to presentation. He denied alcohol abuse or recreational drug use. He did not have any allergies. Besides bilateral clubbing, the physical examination findings were normal. At the time of admission, he had an oxygen (O2) saturation of 87% at ambient air, which increased to 100% with 1 L of O2 administered via a nasal cannula. The blood sample revealed a slight increase in his hemoglobin concentration (18.7 g/dL; normal range, 13.6-17.2 g/dL) and hematocrit level (50.8%; normal range, 39%-49%). His inflammatory parameters were normal, as were his hepatic and renal function. The arterial blood gas test showed partially compensated pulmonary alkalosis (pH, 7.43; normal range, 7.35-7.42; PCO2, 26 mmHg; normal range, 38-42 mmHg; PO2, 89 mmHg; normal range, 75-100 mmHg; bicarbonate level, 17 mEq/L [17 mmol/L]; normal range 22-26 mEq/L [22-26 mmol/L]). The results of the pulmonary function tests were expressed as the percentage of predicted values and were 92% for forced vital capacity, 93% for forced expiratory volume in 1 second, 116% for total lung capacity, and 60% for diffusing capacity of carbon monoxide. Anteroposterior chest radiography and enhanced chest CT were also performed at admission.


Hemangioma/complications , Lung Neoplasms/complications , Pulmonary Veno-Occlusive Disease/complications , Adult , Capillaries , Hemangioma/blood supply , Humans , Lung Neoplasms/blood supply , Male
6.
Am J Respir Cell Mol Biol ; 63(1): 118-131, 2020 07.
Article En | MEDLINE | ID: mdl-32209028

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 Veno-Occlusive Disease/metabolism , Pulmonary Veno-Occlusive Disease/pathology , Animals , Disease Models, Animal , Endothelial Cells/metabolism , Endothelial Cells/pathology , Humans , Hypertension, Pulmonary/metabolism , Hypertension, Pulmonary/pathology , Lung/metabolism , Lung/pathology , Mutation/genetics , Pulmonary Artery/metabolism , Pulmonary Artery/pathology , Rats , Signal Transduction/physiology , Transcription Factor CHOP/metabolism
7.
J Thorac Cardiovasc Surg ; 160(3): 777-790.e5, 2020 Sep.
Article En | MEDLINE | ID: mdl-32222412

OBJECTIVES: Pulmonary vein obstruction (PVO) frequently occurs after repair of total anomalous pulmonary vein connection with progression of intimal hyperplasia from the anastomotic site toward upstream pulmonary veins (PVs). However, the understanding of mechanism in PVO progression is constrained by lack of data derived from a physiological model of the disease, and no prophylaxis has been established. We developed a new PVO animal model, investigated the mechanisms of PVO progression, and examined a new prophylactic strategy. METHODS: We developed a chronic PVO model using infant domestic pigs by cutting and resuturing the left lower PV followed by weekly hemodynamic parameter measurement and angiographic assessment of the anastomosed PV. Subsequently, we tested a novel therapeutic strategy with external application of rapamycin-eluting film to the anastomotic site. RESULTS: We found the pig PVO model mimicked human PVO hemodynamically and histopathologically. This model exhibited increased expression levels of Ki-67 and phospho-mammalian target of rapamycin in smooth muscle-like cells at the anastomotic neointima. In addition, contractile to synthetic phenotypic transition; that is, dedifferentiation of smooth muscle cells and mammalian target of rapamycin pathway activation in the neointima of upstream PVs were observed. Rapamycin-eluting films externally applied around the anastomotic site inhibited the activation of mammalian target of rapamycin in the smooth muscle-like cells of neointima, and delayed PV anastomotic stenosis. CONCLUSIONS: We demonstrate the evidence on dedifferentiation of smooth muscle-like cells and mammalian target of rapamycin pathway activation in the pathogenesis of PVO progression. Delivery of rapamycin to the anastomotic site from the external side delayed PV anastomotic stenosis, implicating a new therapeutic strategy to prevent PVO progression.


Pulmonary Veins , Pulmonary Veno-Occlusive Disease/prevention & control , Pulmonary Veno-Occlusive Disease/physiopathology , Sirolimus/pharmacology , Vascular Remodeling , Angiography , Animals , Biomarkers/metabolism , Disease Models, Animal , Disease Progression , Muscle, Smooth/cytology , Neointima , Pulmonary Veno-Occlusive Disease/metabolism , Swine , TOR Serine-Threonine Kinases/metabolism
9.
Ann Thorac Surg ; 110(2): 654-659, 2020 08.
Article En | MEDLINE | ID: mdl-31794738

BACKGROUND: We sought to determine the long-term quality of life after repair of anomalous pulmonary venous drainage using the Short Form (SF)-36 questionnaire in adult survivors. METHODS: All patients who underwent repair of partial or total anomalous pulmonary venous drainage (PAPVD or TAPVD) and were 18 years of age or older with a current contact number were identified from the hospital database. The mean age of the 101 patients was 26 ± 7 years (range, 18-49) old. Patients completed the SF-36 quality of life questionnaire via telephone. The results of the 8 domains of the SF-36 questionnaire and the derived health state summary score (SF-6-Dimension) were compared against an age-matched Australian population data. RESULTS: Compared with Australian population age-matched data, the 18- to 24-year-old TAPVD/PAPVD patients ranked their health higher in 1 of 8 domains; however the SF-6-Dimension scores were similar (0.75 for TAPVD and PAPVD patients vs 0.77 for the Australian population, P = .2). In the 25-50 age group TAPVD/PAPVD patients ranked their health higher in 3 of 8 domains. However the SF-6-Dimension scores were similar to Australian age-matched population (0.78 for TAPVD and PAPVD patients vs 0.77 for the Australian population, P = .51). CONCLUSIONS: Young adult survivors after anomalous pulmonary venous drainage repair have similar quality of life outcomes as age-matched Australian control subjects as measured by SF-6-Dimension.


Postoperative Complications/psychology , Pulmonary Veins/abnormalities , Pulmonary Veno-Occlusive Disease/surgery , Quality of Life , Surveys and Questionnaires , Vascular Surgical Procedures/methods , Adolescent , Adult , Australia/epidemiology , Child , Child, Preschool , Female , Follow-Up Studies , Humans , Incidence , Infant , Male , Postoperative Complications/epidemiology , Pulmonary Veins/surgery , Pulmonary Veno-Occlusive Disease/psychology , Retrospective Studies , Survivors , Time Factors , Young Adult
10.
Catheter Cardiovasc Interv ; 95(3): 389-397, 2020 02 15.
Article En | MEDLINE | ID: mdl-31778024

OBJECTIVES: Report long-term outcomes of percutaneous intervention in patients with pulmonary vein stenosis (PVS) after pulmonary vein isolation (PVI) from a single center over 16 years. BACKGROUND: Outcome reports of percutaneous intervention for PVS resulting from PVI are limited. METHODS: Retrospective review of all patients with PVS after PVI who underwent percutaneous intervention at the Cleveland Clinic Foundation between January 2000 and December 2016. RESULTS: A total of 205 patients underwent cardiac catheterization for PVS during the study period. Completely occluded veins which could not be recanalized occurred in six patients. Of the remaining 199 patients, 27 (14%) were lost to follow-up, leaving 172 patients with 276 veins for analysis. Balloon angioplasty was performed in 62 veins and stent implantation in 250 (primary in 214, to treat postdilation restenosis in 36). Re-intervention occurred in 45/62 (73%) balloon-dilated veins and 45/250 (18%) stented veins. Freedom from re-intervention at 1 and 5 years was 90 and 73% following stenting versus 40 and 23% following balloon dilation (p < .001, Hazard ratio (HR) = 5.7). Veins with stent diameter ≥7 mm (n = 231) had greater freedom from re-intervention (95% at 1 year, 79% at 5 years) than veins with stents <7 mm (43% at 1 year, 9% at 5 years), p < .001. There was clear symptomatic improvement after intervention and no procedural mortality. CONCLUSIONS: Stent implantation at ≥7 mm for PVS after PVI is associated with low rates of re-intervention, in contrast to balloon dilation and stenting with small conventional stents.


Angioplasty, Balloon , Atrial Fibrillation/surgery , Catheter Ablation/adverse effects , Pulmonary Veins/surgery , Pulmonary Veno-Occlusive Disease/therapy , Adult , Aged , Angioplasty, Balloon/adverse effects , Angioplasty, Balloon/instrumentation , Atrial Fibrillation/diagnosis , Atrial Fibrillation/physiopathology , Female , Humans , Male , Middle Aged , Ohio , Pulmonary Veins/diagnostic imaging , Pulmonary Veins/physiopathology , Pulmonary Veno-Occlusive Disease/diagnostic imaging , Pulmonary Veno-Occlusive Disease/etiology , Pulmonary Veno-Occlusive Disease/physiopathology , Retrospective Studies , Risk Factors , Stents , Time Factors , Treatment Outcome , Vascular Patency
13.
Ann Thorac Surg ; 109(5): e331-e334, 2020 05.
Article En | MEDLINE | ID: mdl-31586617

Cadaveric lobar lung transplantation is an alternative for patients whose chest cavities have small dimensions. We present here a case where 1 donor was used for bilateral lobar transplantations in 2 high-risk patients. Coordination between the graft preparation at the back table and the 2 concomitant lung transplant teams was necessary to minimize the ischemic injury of the grafts and to plan for adequate vascular and bronchial cuffs for both implantations.


Body Size , Lung Transplantation/methods , Lung/anatomy & histology , Tissue Donors , Adult , Blood Vessels , Bronchi/blood supply , Bronchi/surgery , Female , Humans , Hypertension, Pulmonary/surgery , Interdisciplinary Communication , Intersectoral Collaboration , Lung/blood supply , Male , Microsurgery/methods , Middle Aged , Organ Size , Patient Care Team , Pulmonary Fibrosis/surgery , Pulmonary Veno-Occlusive Disease/surgery , Tissue and Organ Harvesting/methods , Transplant Recipients
14.
J Formos Med Assoc ; 119(1 Pt 2): 300-309, 2020 Jan.
Article En | MEDLINE | ID: mdl-31202500

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.


Lung/pathology , Muscle, Smooth/pathology , Pulmonary Arterial Hypertension/pathology , Pulmonary Veno-Occlusive Disease/pathology , Actins/genetics , Actins/physiology , Adult , Aged , Cell Proliferation , Female , Humans , Immunohistochemistry , Male , Middle Aged , Mutation , Protein-Serine-Threonine Kinases/genetics , Protein-Serine-Threonine Kinases/physiology , Pulmonary Arterial Hypertension/genetics , Pulmonary Artery/pathology , Pulmonary Veins/pathology , Pulmonary Veno-Occlusive Disease/genetics , Vascular Remodeling
15.
Catheter Cardiovasc Interv ; 95(5): 954-958, 2020 04 01.
Article En | MEDLINE | ID: mdl-31854110

OBJECTIVES: The aim of this study was to describe management of recurrent pulmonary vein stenosis (PVS) and determine if stenting is superior to balloon angioplasty (BA) in preventing subsequent restenosis. BACKGROUND: PVS is a serious complication of atrial fibrillation ablation. BA and stenting are effective therapies; however, restenosis frequently occurs. Here we report management of recurrent stenosis. METHODS: This was a prospective observational study performed from 2000 to 2014. RESULTS: One hundred and thirteen patients with severe PVS underwent intervention in 88 veins treated with BA and 81 treated with stenting. Forty-two patients experienced restenosis. Restenosis was more common in veins treated with BA (RRR 53% [95% CI 32-70%, p = .008]). A second intervention was performed in 41 patients. In the 34 vessels treated with initial BA, 24 were treated for restenosis with a stent and 10 were treated with a second BA. The recurrence rate was 46% in those treated with BA followed by stenting and 50% in those treated with two BA procedures. In the 22 veins treated with initial stenting, 9 were treated with another stent and 13 were treated with BA. The recurrence rate was 44% in those treated with a second stent and 46% for those treated with a stent followed by BA. The risk of a third stenosis was the same among all groups (Analysis of variance [ANOVA] p = .99). Limited sample size precluded analysis of outcome by stent size. CONCLUSIONS: Restenosis occurred in 44% of patients overall. Management is challenging; stenting does not appear to be superior to BA.


Angioplasty, Balloon/instrumentation , Pulmonary Veno-Occlusive Disease/therapy , Stents , Adult , Angioplasty, Balloon/adverse effects , Female , Humans , Male , Middle Aged , Prospective Studies , Pulmonary Veno-Occlusive Disease/diagnostic imaging , Pulmonary Veno-Occlusive Disease/physiopathology , Recurrence , Risk Factors , Severity of Illness Index , Time Factors , Treatment Outcome
16.
BMC Pulm Med ; 19(1): 257, 2019 Dec 19.
Article En | MEDLINE | ID: mdl-31856792

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.


Endothelin Receptor Antagonists/therapeutic use , Exercise Tolerance , Phosphodiesterase 5 Inhibitors/therapeutic use , Prostaglandins/therapeutic use , Pulmonary Arterial Hypertension/drug therapy , Pulmonary Veno-Occlusive Disease/drug therapy , Acetamides/therapeutic use , Adult , Anticoagulants/therapeutic use , Antihypertensive Agents/therapeutic use , Cardiac Catheterization , Disease Progression , Diuretics/therapeutic use , Drug Therapy, Combination , Echocardiography, Doppler , Enzyme Activators/therapeutic use , Female , Humans , Male , Natriuretic Peptide, Brain/metabolism , Peptide Fragments/metabolism , Pulmonary Arterial Hypertension/etiology , Pulmonary Arterial Hypertension/metabolism , Pulmonary Arterial Hypertension/physiopathology , Pulmonary Diffusing Capacity , Pulmonary Edema/chemically induced , Pulmonary Veno-Occlusive Disease/complications , Pulmonary Veno-Occlusive Disease/metabolism , Pulmonary Veno-Occlusive Disease/physiopathology , Pyrazines/therapeutic use , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Retrospective Studies , Walk Test
17.
Am J Case Rep ; 20: 1551-1557, 2019 Oct 22.
Article En | MEDLINE | ID: mdl-31636247

BACKGROUND Pulmonary capillary hemangiomatosis (PCH) and pulmonary veno-occlusive disease (PVOD) are rare diseases that share clinical, X-ray, and histological features. Most patients have poor prognosis due to severe respiratory impairment. Recently, EIF2AK4 mutations were found in some patients with PCH and PVOD, but the role of this mutation is still unknown. We report an autopsy case of PCH and discuss a mechanism of respiratory dysfunction based on an electron microscopy study. CASE REPORT The patient was a Japanese man in his sixties. He suffered from acute exacerbation of dyspnea during treatment of COPD. Respiratory function testing revealed DLCO' 32.1% and DLCO'/VA 23.6%. Echocardiography demonstrated findings consistent with pulmonary hypertension. A CT scan showed mild emphysema and small ground-glass opacity in the lungs. However, we could not find the exact cause of his respiratory failure and he died 28 days after admission. At autopsy, the histology showed multilayering capillary proliferation within the alveolar walls. Electron microscopy examination revealed prominent widening of the air-blood barrier, scarce fusion of the epithelial and capillary basement membranes, and frequent narrowing of the capillary lumen. CONCLUSIONS We reported an autopsy case with PCH with no histological findings of PVOD. Whether PCH and PVOD are 2 different histological patterns of the same disease remains to be verified. The changes in the air-blood barrier detected by electron microscopy may explain the respiratory impairment and pulmonary arterial hypertension.


Autopsy , Hemangioma, Capillary/diagnosis , Microscopy, Electron , Aged , Asian Continental Ancestry Group , Blood-Air Barrier/pathology , Fatal Outcome , Hemangioma, Capillary/ultrastructure , Humans , Male , Middle Aged , Pulmonary Veno-Occlusive Disease , Respiratory Function Tests , Respiratory Insufficiency
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Autops. Case Rep ; 9(3): e2019111, July-Sept. 2019. ilus
Article En | LILACS | ID: biblio-1016910

Pulmonary capillary hemangiomatosis (PCH) is a rare and controversial entity that is known to be a cause of pulmonary hypertension and is microscopically characterized by proliferation of dilated capillary-sized channels along and in the alveolar walls. Clinically, it is mostly seen in adults. Clinical features are characterized by nonspecific findings such as shortness of breath, cough, chest pain, and fatigue. It can be clinically indistinguishable from pre-capillary pulmonary arterial hypertension disorders such as primary pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension. However, the diagnostic distinction, which usually requires a multidisciplinary approach, is crucial in order to avoid inappropriate treatment with vasodilator medications usually used for PAH treatment. Prognosis of PCH remains poor with lung transplant being the only definitive treatment. We report an autopsy case of pulmonary capillary hemangiomatosis unmasked at autopsy that was treated with a prostacyclin analog, usually contraindicated in such patients. We emphasize that this entity should always be on the differential diagnosis in a patient with pulmonary hypertension and requires great vigilance on the part of the clinician, radiologist and pathologist to make the diagnosis and guide appropriate management.


Humans , Female , Aged , Hemangioma, Capillary/diagnosis , Hemangioma, Capillary/pathology , Pulmonary Heart Disease , Autopsy , Pulmonary Veno-Occlusive Disease , Fatal Outcome , Diagnosis, Differential , Hypertension, Pulmonary
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