Sildenafil as Adjunct Therapy to High-Dose Epoprostenol in a Patient with Pulmonary Veno-Occlusive Disease

doi:10.1016/j.hlc.2005.07.002

Heart, Lung and Circulation

Volume 15, Issue 2, April 2006, Pages 139-142

https://doi.org/10.1016/j.hlc.2005.07.002 Get rights and content

Pulmonary veno-occlusive disease is refractory to medical treatment and is generally associated with a poor prognosis. Treatment with vasodilators, such as prostacyclin, of patients with PVOD is controversial because of concerns regarding hemodynamic deterioration. Although a preferential pulmonary vasodilatory effect of a specific phosphodiesterase-5 inhibitor, sildenafil, has recently been reported in patients with primary pulmonary hypertension, little information is available regarding the effect of sildenafil on patients with pulmonary veno-occlusive disease. In the present case, remarkable improvement of hemodynamics and of clinical course was produced by adjunctive use of oral sildenafil in association with intravenous high-dose epoprostenol. These findings suggest that sildenafil may be a therapeutic option in the medical treatment of pulmonary veno-occlusive disease.

Introduction

Pulmonary veno-occlusive disease (PVOD) is a disease in a subset of patients with pulmonary hypertension histologically characterized by fibrous occlusion of the smaller pulmonary veins. In most cases, PVOD is refractory to medical treatment and is generally associated with a progressively deteriorating clinical course¹. Although occasional and temporary favourable response to some agents has been reported, treatment with vasodilators, such as prostacyclin (PGI₂), in patients with PVOD is controversial because of concerns regarding not only systemic hypotension or increasing intra-pulmonary shunt flow but also precipitation of pulmonary oedema.1, 2

Recently, sildenafil, a specific phosphodiesterase-5 (PDE5) inhibitor widely approved for the treatment of erectile dysfunction, is reported to decrease pulmonary vascular resistance (PVR) in patients with pulmonary hypertension.³ This novel vasodilating agent might, therefore, also be a treatment option for patients with PVOD, and progress in medical treatment of PVOD might be possible with a combination of treatment modalities.

Here we report a patient with PVOD with heart failure, who had been resistant to treatment including continuous intra-venous high-dose PGI₂, but who exhibited marked improvement after the initiation of adjunct oral sildenafil therapy with no major adverse effect.

Section snippets

Case Report

A 39-year-old businessman with New York Heart Association (NYHA) class III functional limitation was emergently hospitalized with a chief complaint of dyspnoea in March 2001. Chest radiography revealed pulmonary congestion and cardiomegaly. Improvement of symptoms and oxygenation were noted over time with no treatment except temporary inhalation of oxygen, but bilateral interstitial infiltrates remained. Bronchoscopy findings and histological analysis of a transbronchial lung biopsy (TBLB)

Discussion

Patients with PVOD exhibit a rapidly progressive course leading to death within 2 years of diagnosis. Medical therapy is ineffective in most cases. The symptom of the present case first appeared in March 2001, followed by second attack of dyspnoea in December 2001, gradually progressed and finally worsened in July 2003. The clinical course also gradually progressed during these 2 years in the present case. Differentiation between PVOD and primary pulmonary hypertension (PPH) is often difficult

References (6)

S.M. Palmer et al.
Massive pulmonary edema and death after prostacyclin infusion in a patient with pulmonary veno-occlusive disease
Chest
(1998)
H. Okumura et al.
Effects of continuous iv prostacyclin in a patient with pulmonary veno-occlusive disease
Chest
(2002)
L.L. Davis et al.
Effect of prostacyclin on microvascular pressures in a patient with pulmonary veno-occlusive disease
Chest
(1995)

There are more references available in the full text version of this article.

Cited by (28)

Patient-specific and gene-corrected induced pluripotent stem cell-derived endothelial cells elucidate single-cell phenotype of pulmonary veno-occlusive disease
2022, Stem Cell Reports
Citation Excerpt :
Another frequently used drug for PAH patients is sildenafil, which is a type 5 phosphodiesterase inhibitor that reduces pulmonary arterial pressure by increasing the levels of cGMP and nitric oxide in the pulmonary vasculature (Dhariwal and Bavdekar, 2015; Galiè et al., 2005). In a previous study, the patient developed acute pulmonary edema after the introduction of sildenafil (Duarte et al., 2020; Kuroda et al., 2006). We treated the PVOD-iPSC-ECs at 5, 10, and 20 μM concentrations, and the results revealed that sildenafil exhibited a slight upregulation on PVOD-iPSC-EC proliferation capacity (Figures 6A and 6F).
Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension characterized by the preferential remodeling of the pulmonary venules. Hereditary PVOD is caused by biallelic variants of the EIF2AK4 gene. Three PVOD patients who carried the compound heterozygous variants of EIF2AK4 and two healthy controls were recruited and induced pluripotent stem cells (iPSCs) were generated from human peripheral blood mononuclear cells (PBMCs). The EIF2AK4 c.2965C>T variant (PVOD#1), c.3460A>T variant (PVOD#2), and c.4832_4833insAAAG variant (PVOD#3) were corrected by CRISPR-Cas9 in PVOD-iPSCs to generate isogenic controls and gene-corrected-iPSCs (GC-iPSCs). PVOD-iPSC-endothelial cells (ECs) exhibited a decrease in GCN2 protein and mRNA expression when compared with control and GC-ECs. PVOD-ECs exhibited an abnormal EC phenotype featured by excessive proliferation and angiogenesis. The abnormal phenotype of PVOD-ECs was normalized by protein kinase B inhibitors AZD5363 and MK2206. These findings help elucidate the underlying molecular mechanism of PVOD in humans and to identify promising therapeutic drugs for treating the disease.
Use of vasodilators for the treatment of pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis: A systematic review
2019, Respiratory Investigation
Citation Excerpt :
As a result, 23 full-text articles were assessed for eligibility and three full-text articles were excluded due to only reporting acute vasodilator testing results. Finally, 20 studies with 64 patients who received vasodilator therapy were included in qualitative synthesis (Fig. 1, Table 1) [7,8,10–14,19,21–32], and there were no studies were included in quantitative synthesis (meta-analysis) because all articles were case reports or case series. In the quality assessment of selected articles, serious limitations related to non-randomized controlled trials were observed including serious inconsistency, indirectness, and imprecision (Table 2).
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.
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).
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.
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.
Pulmonary veno-occlusive disease
2018, Revue des Maladies Respiratoires
La maladie veino-occlusive pulmonaire (MVO) est une forme rare d’hypertension pulmonaire (HTP) se caractérisant par une atteinte veinulaire pulmonaire et capillaire prédominante. On distingue au sein des MVO les formes idiopathiques, héritables (mutations bialléliques du gène EIF2AK4), secondaires à une exposition à un toxique (chimiothérapies, solvants organiques) et les MVO associées à une connectivite, en particulier la sclérodermie. La présentation clinique de la MVO est proche de celle de l’hypertension artérielle pulmonaire (HTAP). Les biopsies pulmonaires sont contre-indiquées dans l’HTP et le diagnostic repose donc sur un faisceau d’argument. Le diagnostic de MVO est généralement évoqué devant la présence d’anomalies scannographiques (lignes septales, nodules flous, adénopathies médiastinales), d’une DLCO effondrée associée à une hypoxémie profonde. Le pronostic des patients atteints de MVO est sombre. Les traitements spécifiques de l’HTAP n’ont pas prouvé leur efficacité dans la MVO et peuvent entraîner des œdèmes pulmonaires sévères. La transplantation pulmonaire constitue aujourd’hui le seul traitement curatif de cette maladie.
Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension (PH) characterized by preferential remodelling of pulmonary venules and angioproliferation. PVOD term includes idiopathic, heritable (biallelic mutations of EIF2AK4 gene), drugs and toxins induced (alkylating agents, organic solvents) and connectivite-associated forms (especially systemic-sclerosis associated form). PVOD and pulmonary arterial hypertension (PAH) share a similar clinical presentation. Lung biopsy is contraindicated in PVOD due to high risk of life-threatening bleeding. A noninvasive diagnostic approach, including oxygen parameters, low diffusing capacity for carbon monoxide and characteristic signs on high-resolution computed tomography of the chest, is used to support a diagnosis of PVOD. PVOD prognosis is worse than other forms of PAH. There is no evidence-based medical therapy for PVOD and life-threatening pulmonary edema may occur following PAH targeted therapy in PVOD. Lung transplantation remains the preferred definitive therapy for eligible patients.
Early Onset Noninfectious Pulmonary Syndromes after Hematopoietic Cell Transplantation
2017, Clinics in Chest Medicine
Citation Excerpt :
Additional potential therapies include diuretics, inotropes, and pulmonary vasodilators (eg, calcium channel blockers, phosphodiesterase-5 inhibitors, endothelin receptor antagonists, prostanoids).126,128 In contrast to PAH, historical experience with pulmonary vasodilators in PVOD demonstrates mixed results.137–139 Vasodilators may cause harm and even death in patients with predominantly postcapillary vascular constriction.
The First Experience of Pulmonary Veno-occlusive Disease Treatment With Macitentan and Sildenafil
2017, Revista Espanola de Cardiologia
Pulmonary Capillary Hemangiomatosis and Pulmonary Veno-occlusive Disease
2016, Clinics in Chest Medicine
Citation Excerpt :
Initiation of these therapies frequently leads to increased transcapillary pressures and pulmonary edema following pulmonary arterial vasodilation and can result in rapid clinical deterioration or death. Nonetheless, there are case reports of clinical improvement with intravenous and inhaled prostacyclins,10,38–41 phosphodiesterase type-5 inhibitors (PDE5-I),42–44 and endothelin receptor antagonists.45 For this reason, experts have recommended cautious consideration of these therapies in patients with PVOD.38

View all citing articles on Scopus

View full text

Copyright © 2005 Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand. Published by Elsevier Ltd. on behalf of The Australasian Society of Cardiac and Thoracic Surgeons and The Cardiac Society of Australia and New Zealand All rights reserved.

Case ReportSildenafil as Adjunct Therapy to High-Dose Epoprostenol in a Patient with Pulmonary Veno-Occlusive Disease

Introduction

Section snippets

Case Report

Discussion

Chest

Chest

Chest

Case Report
Sildenafil as Adjunct Therapy to High-Dose Epoprostenol in a Patient with Pulmonary Veno-Occlusive Disease