Prostacyclin for Secondary Pulmonary Hypertension

Kaur, Karamjit; Brown, Bernice; Lombardo, Fred

doi:10.7326/0003-4819-132-2-200001180-00019

Cited by 8 publications

(3 citation statements)

References 3 publications

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“…It is unclear how best to manage elevated pulmonary pressures in children with sickle cell disease. Potential treatment options include reduction of haemolysis by hydroxyurea or chronic transfusions, administration of nitric oxide synthase substrate – L arginine (Morris et al , 2003), inhibition of phosphodiesterase‐5 by sildenaefil (Derchi et al , 2005; Machado et al , 2005) and pulmonary remodelling agents (prostacyclins and endothelin A and B receptor antagonists) (Kaur et al , 2000).…”

Section: Discussionmentioning

confidence: 99%

Longitudinal follow up of elevated pulmonary artery pressures in children with sickle cell disease

et al. 2009

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Summary Elevated pulmonary artery pressures (PAP) occur in approximately 30% of children with sickle cell disease. In adults, pulmonary hypertension is significantly associated with mortality. There are no data on the long term significance in children. Nineteen children with SS/Sß0 thalassaemia had elevated PAP, defined as tricuspid regurgitant jet velocity (TRV) ≥2·5 m/s on screening echocardiograms. They were prospectively followed for 23 months (range 19–31 months). Patients with initial TRV ≥ 3 or TRV ≥ 2·5 m/s on repeat echocardiogram had cardiopulmonary evaluation and were offered treatment with hydroxyurea. Associated conditions like asthma and obstructive sleep apnea were treated. 18/19 patients had follow‐up echocardiograms. These showed normalization of TRV in 8 patients. Risk factors associated with persistent elevation were higher TRV on initial echocardiogram (P = 0·01), lower haemoglobin (P = 0·003) and lower oxygen saturation (P = 0·03). Five patients with persistently elevated PAP were treated with hydroxyurea. Mean right ventricular pressure dropped from 40·16 to 29·26 (P = 0·017) after 3–6 months and to 23·6 mmHg (P = 0·002) after 9–12 months on treatment. In conclusion (i) At borderline elevation of TRV there is intrapatient variability and echocardiograms should be repeated for confirmation. (ii) Elevated PAP are reversible in children with early detection and treatment with hydroxyurea.

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Section: Discussionmentioning

confidence: 99%

Longitudinal follow up of elevated pulmonary artery pressures in children with sickle cell disease

et al. 2009

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“…The oral endothelin receptor blocker bosentan is being tested in patients with SCD and PAH, but no results are available as yet. There are minimal published experiences as yet in SCD with FDA-approved intravenous, subcutaneous, or inhaled prostacyclins [49], although our group has found anecdotal success using intravenous epoprostenol to stabilize two SCD patients with life-threatening right ventricular failure due to PAH. Additional clinical trials are needed to help establish the safety and efficacy of these agents in hemoglobinopathy patients.…”

Section: Treatmentmentioning

confidence: 97%

PULMONARY HYPERTENSION IN SICKLE CELL DISEASE: Relevance to Children

Kato

Onyekwere

Gladwin

2007

Pediatric Hematology and Oncology

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Pulmonary arterial hypertension (PAH), once considered a rare complication of sickle cell disease (SCD) and thalassemia, appears to be more common in adults with hemoglobinopathy than previously appreciated. On prospective screening of adults with SCD, approximately one-third of adults are found on echocardiography to have a tricuspid regurgitant jet velocity (TRV) of 2.5 m/s or higher, many of whom are asymptomatic. Dyspnea on exertion is the most common presenting symptom. This TRV abnormality is a marker for approximately 40% 3-year mortality in adults, and it is associated with laboratory values suggestive of more severe intravascular hemolysis. Release of hemoglobin and arginase from lysed red cells causes scavenging of nitric oxide (NO) and catabolism of L-arginine, the obligate substrate for NO synthase. The resulting impairment in NO bioavailability is associated with pulmonary vasoconstriction, endothelial dysfunction, thrombosis, and eventual development of plexogenic arterial lesions, the histological hallmark of all forms of PAH. Undoubtedly, additional pathophysiological mechanisms will also play a role in its multifactorial pathogenesis. Early data from children with SCD indicate a similar prevalence of elevated TRV, but the prognostic implications of this remain to be established. Individual patient diagnosis of PAH requires confirmation by right heart catheterization studies and individualized management. Hemolysis-associated PAH with impairments in NO bioavailability is being identified in thalassemia and other hemolytic disorders, and may be a general consequence of long-standing, severe intravascular hemolytic anemia.Keywords sickle cell; thalassemia; pulmonary hypertension; nitric oxide; arginase Pulmonary hypertension is a complication of sickle cell disease (SCD) and thalassemia gaining considerable attention in the past 4 years. Cor pulmonale, the clinical syndrome of right ventricular failure, has been considered for decades to be a rare, but well-known, terminal complication in adults with both hemoglobinopathies [1,2]. As the survival of patients with hemoglobinopathies has improved dramatically in the last forty years, the prevalence of such chronic complications has increased. Well-documented studies of pulmonary arterial hypertension (PAH) have drawn the attention of the hematology community to its frequent occurrence and poor prognosis [3][4][5][6][7]. This article will review the current understanding of hemoglobinopathy-associated pulmonary hypertension, with special attention to the most recently developing data in children. PREVALENCE AND PROGNOSISIn the last few years, echocardiographic screening studies have suggested that the prevalence of hemoglobinopathy-associated PAH is much higher than previously known. In SCD, approximately one-third of adult patients have an elevated tricuspid regurgitant jet velocity (TRV) of 2.5 m/s or higher, a threshold that correlates in right heart catheterization studies to a pulmonary artery systolic pressure of at least 30 mm Hg [8][9]...

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“…In SCD, pharmacological treatment of pulmonary arterial hypertension is actually limited to the synthetic prostacyclin (26,27) and more recently to the phoshodiesterase-5 (PDE-5) inhibitor, sildenafil (18, 28 -31). Several members of the PDEs superfamily (PDE-1, -2, -3, -4, -5) have been identified in pulmonary vasculature regulating the vascular metabolism of cyclic-guanine-5-monophosphate (cGMP) and cyclic adenine-5-monophosphate (cAMP) (32).…”

mentioning

confidence: 99%

Protective effects of phosphodiesterase‐4 (PDE‐4) inhibition in the early phase of pulmonary arterial hypertension in transgenic sickle cell mice

Franceschi¹,

Platt

Malpeli³

et al. 2008

FASEB j.

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Pulmonary arterial hypertension (PAH) is one of the leading causes of morbidity and mortality in adult patients with sickle cell disease (SCD). Here, we developed a model to study the early stage of PAH in SCD. We exposed wild-type and transgenic sickle cell SAD (Hbb(s)/Hbb(s)) mice to hypoxia (8% O(2)) for 7 days. Prolonged hypoxia in SAD mice only induced 1) increased neutrophil count in both bronchoalveolar lavage (BAL) and peripheral circulation; 2) increased BAL IL1beta, IL10, IL6, and TNF-alpha; and 3) up-regulation of the genes endothelin-1, cyclo-oxygenase-2, angiotensin-converting-enzyme, and IL-1beta, suggesting that amplified inflammatory response and activation of the endothelin-1 system may contribute to the early phase of PAH in SCD. Since phosphodiesterases (PDEs) are involved in pulmonary vascular tone regulation, we evaluated gene expression of phosphodiesterase-4 (PDE-4) isoforms and of PDE-1, -2, -3, -7, -8, which are the main cyclic-adenosine-monophosphate hydrolyzing enzymes. In SAD mouse lungs, prolonged hypoxia significantly increased PDE-4 and -1 gene expressions. The PDE-4 inhibitor, rolipram, prevented the hypoxia-induced PDE-4 and -1 gene up-regulation and interfered with the development of PAH, most likely through modulation of both vascular tone and inflammatory factors. This finding supports a possible therapeutic use of PDEs inhibitors in the earlier phases of PAH in SCD.

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Prostacyclin for Secondary Pulmonary Hypertension

Cited by 8 publications

References 3 publications

Longitudinal follow up of elevated pulmonary artery pressures in children with sickle cell disease

Longitudinal follow up of elevated pulmonary artery pressures in children with sickle cell disease

PULMONARY HYPERTENSION IN SICKLE CELL DISEASE: Relevance to Children

Protective effects of phosphodiesterase‐4 (PDE‐4) inhibition in the early phase of pulmonary arterial hypertension in transgenic sickle cell mice

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