Total anomalous pulmonary venous connection: Influence of heterotaxy and venous obstruction on outcomes.

BACKGROUND: Previous studies have demonstrated increased early mortality and pulmonary vein reintervention for patients with total anomalous pulmonary venous connection (TAPVC) and heterotaxy syndrome (HTX+) compared with patients with TAPVC without heterotaxy syndrome (HTX-). We aimed to evaluate the longitudinal risk of pulmonary vein reintervention and mortality in HTX + patients. METHODS: A retrospective review was performed to identify longitudinal interventions in patients with TAPVC seen at a single center from 1995 to 2019. The mean cumulative interventions were described for all patients using the Nelson-Aalen estimator. Survival with TAPVC was described using Kaplan-Meier estimates. RESULTS: A total of 336 patients were identified with TAPVC, of whom 118 (35%) had heterotaxy syndrome. Functional single ventricles were identified in 106 of these 118 HTX + patients (90%) and in 14 of 218 HTX- patients (6%) (P < .001). Obstructed TAPVC (OBS+) was present in 49 of 118 HTX + patients (42%) and in 87 of 218 HTX- patients (40%) (P = .89). The median duration of follow-up was 6.5 years. Five-year survival was 69% for HTX+/OBS + patients, 72% for HTX+/OBS- patients, 86% for HTX-/OBS + patients, and 95% for HTX-/OBS- patients (P < .0001, log-rank test). The mean number of pulmonary vein interventions at the median follow-up time was greater in the HTX+/OBS + patients compared with HTX+/OBS- patients (mean, 2.0 vs 1.1; P = .030), HTX-/OBS + patients (mean, 1.3; P = .033), and HTX-/OBS- patients (mean, 1.3; P = .029). CONCLUSIONS: Among the 4 cohorts, HTX+ was associated with a higher rate of mortality, and HTX+/OBS+ was associated with a greater number of pulmonary vein interventions. This may be due in part to the high prevalence of single ventricle physiology in the HTX + cohort.

GCN2 Regulates ATF3-p38 MAPK Signaling Transduction in Pulmonary Veno-Occlusive Disease.

Pulmonary veno-occlusive disease (PVOD) is a fatal disease of pulmonary vascular lesions leading to right heart failure. Heritable PVOD (hPVOD) is related to biallelic mutation of EIF2AK4 (encoding GCN2), but its molecular mechanism remains unclear. In this study, we aimed to investigate the pathogenesis of PVOD and to find potential drug targets for PVOD. GCN2 dysfunction led to an enhanced transcription of collagen I gene (col1a1 and col1a2) through decreasing ATF3-dependent p38 phosphorylation inhibition in PVOD, which promotes the collagen I synthesis in pulmonary arterial smooth muscle cells (PASMCs) and eventually leads to increased collagen deposition in pulmonary artery. Four GCN2 knockout (KO) cell lines (exon 15 or 33 mutation) were successfully constructed by epiCRISPR system. Two induced pluripotent stem cells (iPSCs) were generated by reprogramming peripheral blood mononuclear cells (PBMCs) of PVOD patient. It was also comfirmed that GCN2 dysfunction could lead to increased expression of collagen I in lateral plate mesoderm lineage-smooth muscle cells (LM-SMCs) differentiated from both GCN2 KO cell lines and iPSCs. SB203580 (a specific inhibitor of p38) improved hemodynamics and pulmonary vascular remodeling in mitomycin C (MMC)-induced PVOD rats by right ventricle echocardiography. On the whole, we proposed that GCN2 deficiency decreased ATF3-dependent p38 phosphorylation inhibition in PVOD development and suggested a potential therapeutic reagent of SB203580 for the treatment of the disease.

Pulmonary venous thrombosis in a patient with COVID-19 infection.

OBJECTIVES: Infection with the SARS-COV2 virus (COVID-19) may be complicated by thrombotic diathesis. This complication often involves the pulmonary microcirculation. While macrovascular thrombotic complications of the lung may include pulmonary artery embolism, pulmonary artery thrombus in situ has also been hypothesized. Pulmonary vein thrombosis has not been described in this context. METHODS/RESULTS: Herein, we provide a case of an otherwise healthy male who developed an ischemic stroke with left internal carotid thrombus. Further imaging revealed pulmonary emboli with propagation through the pulmonary veins into the left atrium. This left atrial thrombus provides a source of atypical "paradoxic arterial embolism". CONCLUSIONS: Thrombotic outcomes in the setting of severe COVID 19 pneumonia may include macrovascular venous thromboembolism, microvascular pulmonary vascular thrombosis and arterial thromboembolism. Pulmonary vein, herein described, provides further mechanistic pathway for potential arterial embolic phenomenon.

Characteristics and Long-term Outcomes of Pulmonary Venoocclusive Disease Induced by Mitomycin C.

BACKGROUND: Pulmonary venoocclusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) predominantly characterized by pulmonary vein and capillary involvement. An association between chemotherapy, in particular mitomycin C (MMC), and PVOD has been reported. RESEARCH QUESTION: What are the characteristics of MMC-induced PVOD, and what is the prognosis for patients with MMC-induced PVOD? STUDY DESIGN AND METHODS: We report the clinical, functional, radiologic, and hemodynamic characteristics at diagnosis and outcomes of patients with PVOD from the French PH Registry after exposure to MMC. The results are expressed as the median (minimum-maximum). RESULTS: From June 2011 to December 2018, 17 incident cases of MMC-induced PVOD were identified. At diagnosis, these patients had severe clinical and functional impairment, with 12 patients having a New York Heart Association (NYHA) functional class of III or IV and a 6-min walk distance of 220 (0-465) m. Right heart catheterization confirmed severe precapillary PH with a mean pulmonary artery pressure of 38 (30-52) mm Hg, a cardiac index of 2.2 (1.5-4) L/(min × m2), and pulmonary vascular resistance of 8.3 (5.1-14.5) Wood units. The diffusing capacity of the lungs for carbon monoxide was markedly decreased at 31% (20%-51%) of the theoretical values associated with severe hypoxemia. MMC was withdrawn for all patients, and 14 patients received specific pulmonary arterial hypertension (PAH) therapies. Among these patients, mild but statistically insignificant improvements were observed in NYHA functional class (P = .10), 6-min walk distance (P = .09), and pulmonary vascular resistance (-4.7 Wood units; P = .052) at reassessment (median delay of 4.8 months). Three patients experienced pulmonary edema requiring the cessation or reduction of PAH treatment. The median overall survival was 20 months, and the 6-, 12-, and 24-month survival rates were 76%, 58%, and 18%, respectively. INTERPRETATION: PVOD after MMC treatment is a rare but life-threatening complication associated with a poor prognosis despite MMC withdrawal and PAH-specific therapy.

Gas Exchange and Ventilatory Efficiency During Exercise in Pulmonary Vascular Diseases / Intercambio de gases y eficiencia de ventilación durante el ejercicio en enfermedades vasculares pulmonares

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

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.

Venoocclusive Disease With Both Hepatic and Pulmonary Involvement.

Pulmonary venoocclusive disease (PVOD) is a rare form of pulmonary vascular disease with pulmonary hypertension characterized by preferential involvement of the pulmonary venous system. Hepatic venoocclusive disease (HVOD), also known as sinusoidal obstruction syndrome, is a condition that occurs in 13% to 15% of patients after hematopoietic stem cell transplantation (HSCT). Although hepatic and pulmonary venoocclusive diseases may share some pathologic features as well as some etiologies such as HSCT, these two disorders have never been described together in a single adult patient. We report the case of a patient who received HSCT and developed HVOD and PVOD within 9 months. Despite their differences, PVOD and HVOD share common risk factors and associated conditions, suggesting that in the context of HSCT, the two diseases share common pathophysiological mechanisms. Optimal treatment for HSCT-related PVOD remains to be determined.

Molecular Profiling of Vascular Remodeling in Chronic Pulmonary Disease.

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.

Peculiarities of Histological Structure of Pulmonary Veins in Patients with Total Anomalous Pulmonary Venous Drainage as Morphological Substrates Relating to Formation of Postoperative Pulmonary Venous Obstruction.

The histological and immunohistochemical methods were employed to examine the peculiarities of histological structure of pulmonary veins and left atrium of the heart in norm and in various types of total anomalous drainage of pulmonary veins. In contrast to normal pulmonary vein covered with external multiple muscle layers (myocardial sleeve), such sleeve is absent in veins that have no connection with the left atrium irrespective of the type of the defect. In patients with total anomalous pulmonary venous drainage, the structure of left atrium was heterogeneous featuring either the presence or absence of inner angiomural lining in this atrium. The structural peculiarities are important for insight into etiology of the development of postoperative pulmonary venous obstruction in patients with total anomalous pulmonary venous drainage.

Progression of vascular remodeling in pulmonary vein obstruction.

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 venous obstruction after extracardiac total cavopulmonary connection in right atrial isomerism.

BACKGROUND: Patients with functional single ventricle and right atrial isomerism (RAI) often have multiform cardiac pulmonary venous (PV) connection, which could be a risk factor for pulmonary venous obstruction (PVO) after extracardiac total cavopulmonary connection (EC-TCPC) owing to compression of the conduit. OBJECTIVE: To investigate the anatomical risk factors for PVO after EC-TCPC in RAI. METHODS: Twenty-nine patients with RAI without extracardiac total anomalous pulmonary venous connection were enrolled. No patients had PVO before EC-TCPC. A total of 14 and 15 patients had PV orifices ipsilateral and contralateral to the extracardiac conduit, respectively. The former 14 patients were assigned to two groups based on development of PVO after EC-TCPC (groups O and N). The pre- and post-operative cardiac morphologies and their relationship with the conduit were compared. RESULTS: After the EC-TCPC, the pressure gradients between the atrium and the PV were 5.0 ± 2.5 and 0.44 ± 0.2 mmHg in groups O and N, respectively (p < 0.01); however, the pressure gradients in the left and right PVs were not significantly different, suggesting stenosis of the common PV orifice. The ratio of the horizontal distance from the vertebrae to the PV orifice and to the lateral edge of the atrium was significantly higher (0.38 ± 0.2 vs. 0.17 ± 0.1; p = 0.04) and the orifice was smaller (8.9 ± 2.0 vs. 15 ± 4.7 mm; p < 0.01) in group O than in group N. CONCLUSION: In cases with ipsilateral locations of the conduit and PV orifice, small size and more lateral location of the PV orifice may be preoperative risk factors for development of PVO.

Long-term outcome of percutaneous intervention for pulmonary vein stenosis after pulmonary vein isolation procedure.

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.

Recurrent pulmonary vein stenosis after successful intervention: Prognosis and management of restenosis.

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.

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.

Use of vasodilators for the treatment of pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis: A systematic review.

BACKGROUND: There are several medications available to treat pulmonary arterial hypertension (PAH): PAH-targeted drugs. However, in patients with pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis (PVOD/PCH), rare diseases that cause pulmonary hypertension, the effectiveness and safety of vasodilators, including PAH-targeted drugs, are unclear. METHODS: We searched English-language publications listed in three electronic databases (PubMed, Cochrane Library, and the Japan Medical Abstracts Society). Reports with efficacy outcomes (survival, improvement in 6-minute walk distance, and pulmonary vascular resistance) and data on development of pulmonary edema after administration of vasodilators to patients with PVOD/PCH were selected (1966 to August 2015). RESULTS: We identified 20 reports that met our criteria. No randomized controlled or prospective controlled studies were reported. The survival time ranged from 71 minutes to 4 years or more after initiation of vasodilators. Most of the reported cases showed an improvement in the 6-minute walk distance and pulmonary vascular resistance. Pulmonary edema was reported in 15 articles, some cases of which were lethal. CONCLUSIONS: The present study demonstrates the potential efficacy and difficulties in the use of vasodilators in patients with PVOD/PCH; however, drawing a firm conclusion was difficult because of the lack of randomized controlled trials. Further research is needed to ascertain if vasodilator use is beneficial and safe in patients with PVOD/PCH.

Complex cases of acquired pulmonary vein stenosis after radiofrequency ablation: is surgical repair an option?

AIMS: Results of catheter based interventional treatment for pulmonary vein stenosis (PVS) following radiofrequency ablation (RFA) for atrial fibrillation remain suboptimal. Surgical repair may represent an alternative therapy, though long-term results have not been thoroughly investigated. METHODS AND RESULTS: We retrospectively assessed all patients in our centre undergoing surgical repair for radiofrequency-induced PVS. Data regarding surgical technique, clinical outcome, and rate of pulmonary vein (PV) restenosis were collected and analysed. Between 2004 and 2016, the rate for PVS resulting from RFA for atrial fibrillation in our institution was 0.79% (76/9633). During this period, five male patients with multiple PVS (3 ± 1) underwent surgical repair of a total of 13 symptomatic PVS. Surgery was performed in a standard setting under cardiopulmonary bypass. Stenotic veins were incised longitudinally followed by a patch augmentation plasty using either bovine pericard (n = 7) or polytetrafluoroethylene (PTFE) patches (n = 5). Localization of incision was on the anterior side of the PV only (n = 8) or on both the anterior and posterior sides (n = 4). In one PVS lesion, mechanical dilatation was sufficient. Long-term follow-up after 60 ± 69 months revealed an average restenosis rate of 38%. Restenosis was defined as narrowing >70%. All patients reported clinical improvement of symptoms at follow-up. CONCLUSION: Even in the era of wide circumferential lesions, PVS still occurs. While surgical PV patch plasty represents a valuable treatment option, restenosis remains an issue during follow-up. Nevertheless, surgical repair achieves highly acceptable long-term results for RFA-acquired PVS. Hence, it should be routinely discussed as a therapeutic option in cases with multiple PVS.

Lung transplantation as a viable option of treatment for pulmonary veno-occlusive disease.

Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension caused by alteration of pulmonary veins. Many clinical and hemodynamic similarities to idiopathic pulmonary arterial hypertension (IPAH) may cause diagnostic and therapeutic difficulties. This case report is about a patient with PVOD, whose first symptoms of the disease occurred after infectious mononucleosis. Patient was administered with prostacycline (PGI2) mimetic (Treprostinil), what made qualification process and lung transplantation possible. Despite more and more knowledge about causes, ethiopathogenesis and changes in pulmonary veins on molecular level, lung transplantation is the only successful therapeutic option for patients suffering from PVOD.

Pharmacovigilance in a rare disease: example of the VIGIAPATH program in pulmonary arterial hypertension.

Spontaneous reporting is the primary method used in pharmacovigilance (PV) to detect drug safety signal. Specific criteria used in pharmacovigilance to prove accountability of a drug are rarely present in rare disease. The low number of alerts also makes it challenging. The aim of this commentary is to raise awareness among pharmacists on issues and opportunities for pharmacovigilance in rare diseases, taking pulmonary arterial hypertension (PAH) as example, from which a subset of cases are drug-induced. It is demonstrated how a dedicated program named VIGIAPATH created to reinforce pharmacovigilance of drug-induced pulmonary arterial hypertension at a national level, led to increase self-reporting and confirm safety signals. Thanks to a specific program such as VIGIAPATH, pharmacists can play an important role in communication with clinicians, patients and regulatory agencies, facilitating the detection of potential safety signals at an early stage in rare disease.