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Pulmonary hypertension in hemolytic disorders: pulmonary vascular disease: the global perspective.

ABSTRACT: The inherited hemoglobin disorders sickle cell disease and thalassemia are the most common monogenetic disorders worldwide. Pulmonary hypertension is one of the leading causes of morbidity and mortality in adult patients with sickle cell disease and thalassemia, and hemolytic disorders are potentially among the most common causes of pulmonary hypertension. The pathogenesis of pulmonary hypertension in hemolytic disorders is likely multifactorial, including hemolysis, impaired nitric oxide (NO) bioavailability, chronic hypoxemia, chronic thromboembolic disease, chronic liver disease, and asplenia. In contrast to patients with traditional forms of pulmonary arterial hypertension, patients with hemolytic disorders have a mild-to-moderate degree of elevation in mean pulmonary pressures, with mild elevations in pulmonary vascular resistance. The hemodynamic etiology of pulmonary hypertension in these patients is multifactorial and includes pulmonary arterial hypertension, pulmonary venous hypertension, and pulmonary hypertension secondary to a hyperdynamic state. Currently, there are limited data on the effects of any specific treatment modality for pulmonary hypertension in patients with hemolytic disorders. It is likely that maximization of treatment of the primary hemoglobinopathy in all patients and treatment with selective pulmonary vasodilators and antiproliferative agents in patients with pulmonary arterial hypertension would be beneficial. However, there is still a major need for large multinational trials of novel therapies for this patient population.

SUBMITTER: Machado RF

PROVIDER: S-EPMC2882115 | biostudies-other | 2010 Jun

REPOSITORIES: biostudies-other

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Project description:BACKGROUND:We hypothesized that pulmonary venous hypertension in heart failure (HF) leads to predominate remodeling of pulmonary veins and that the severity of venous remodeling is associated with the severity of pulmonary hypertension (PH) in HF. METHODS:Patients with HF (n=108; 53 preserved and 55 reduced ejection fraction) with PH (HF-PH; pulmonary artery systolic pressure [PASP] ?40 mm?Hg) were compared to normal controls (n=12) and patients with primary pulmonary veno-occlusive disease (PVOD; n=17). In lung specimens from autopsy (control, HF-PH, and 7 PVOD) or surgery (10 PVOD), quantitative histomorphometry was performed in all analyzable arteries (n=4949), veins (n=7630), and small indeterminate vessels (IV; n=2168) to define percent medial thickness (arteries) and percent intimal thickness (%IT) (arteries, veins, and IV) relative to external diameter. RESULTS:The average arterial percent medial thickness (control, 6.9; HF-PH, 11.0; PVOD, 15.0), arterial %IT (control, 4.9; HF-PH, 14.9; PVOD, 31.1), venous %IT (control, 14.0; HF-PH, 24.9; PVOD, 43.9), and IV %IT (control, 10.6; HF-PH, 25.8; PVOD, 50.0) in HF-PH were higher than controls (P<0.0001 for all) but lower than PVOD (P?0.005 for all). PASP (mm?Hg) was lower in HF-PH (median, 59 [interquartile range, 50-70]) than in PVOD (median, 91 [interquartile range, 82-103]). PASP correlated with arterial percent medial thickness (r=0.41) and arterial %IT (r=0.35) but more strongly with venous %IT (r=0.49) and IV %IT (r=0.55) (P<0.0001 for all). Associations between PASP and venous or IV %IT remained significant after adjusting for arterial percent medial thickness and %IT and did not vary by HF type. In patients with right heart catheterization (30 HF-PH, 14 PVOD), similar associations between the transpulmonary gradient and pulmonary vascular remodeling existed, with numerically stronger associations for venous and IV %IT. Although the PASP was slightly higher in patients with HF-PH with right ventricular dysfunction, pulmonary vascular remodeling was not more severe. Pulmonary vascular remodeling severity was associated with reductions in the diffusing capacity of the lungs. CONCLUSIONS:In HF, PH is associated with global pulmonary vascular remodeling, but the severity of PH correlates most strongly with venous and small IV intimal thickening, similar to the pattern observed in PVOD. These findings expand our understanding of the pathobiology of PH in HF.

Project description:ObjectiveConnective tissue disease (CTD)-associated pulmonary arterial hypertension (PAH) is the second most common etiology of PAH and carries a poor prognosis. Recently, it has been shown that female human tumor necrosis factor (TNF)-transgenic (Tg) mice die of cardiopulmonary disease by 6 months of age. This study was undertaken to characterize this pathophysiology and assess its potential as a novel model of CTD-PAH.MethodsHistologic analysis was performed on TNF-Tg and wild-type (WT) mice to characterize pulmonary vascular and right ventricular (RV) pathology (n = 40 [4-5 mice per group per time point]). Mice underwent right-sided heart catheterization (n = 29) and micro-computed tomographic angiography (n = 8) to assess vascular disease. Bone marrow chimeric mice (n = 12), and anti-TNF-treated mice versus placebo-treated mice (n = 12), were assessed. RNA sequencing was performed on mouse lung tissue (n = 6).ResultsTNF-Tg mice displayed a pulmonary vasculopathy marked by collagen deposition (P < 0.001) and vascular occlusion (P < 0.001) with associated RV hypertrophy (P < 0.001) and severely increased RV systolic pressure (mean ± SD 75.1 ± 19.3 mm Hg versus 26.7 ± 1.7 mm Hg in WT animals; P < 0.0001). TNF-Tg mice had increased α-smooth muscle actin (α-SMA) staining, which corresponded to proliferation and loss of von Willebrand factor (vWF)-positive endothelial cells (P < 0.01). There was an increase in α-SMA-positive, vWF-positive cells (P < 0.01), implicating endothelial-mesenchymal transition. Bone marrow chimera experiments revealed that mesenchymal but not bone marrow-derived cells are necessary to drive this process. Treatment with anti-TNF therapy halted the progression of disease. This pathology closely mimics human CTD-PAH, in which patient lungs demonstrate increased TNF signaling and significant similarities in genomic pathway dysregulation.ConclusionThe TNF-Tg mouse represents a novel model of CTD-PAH, recapitulates key disease features, and can serve as a valuable tool for discovery and assessment of therapeutics.

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Pulmonary hypertension in hemolytic disorders: pulmonary vascular disease: the global perspective.

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