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Pulmonary hypertension associated with HIV infection: pulmonary vascular disease: the global perspective.

ABSTRACT: The success of antiretroviral therapies in improving the survival of patients infected with HIV and reducing HIV-associated opportunistic infections is undisputed. Nevertheless, long-term outcomes such as noninfectious cardiovascular complications, including cardiomegaly, pericarditis, myocarditis, and pulmonary arterial hypertension, are now serious concerns. The lung is a frequent target organ for disorders associated with HIV infection. HIV-related pulmonary arterial hypertension (HRPAH) affects more individuals who are infected with HIV than individuals who are uninfected. Moreover, the long-standing estimated prevalence of HRPAH in developed countries (calculated at 0.5%) is increasing as more clinician-scientists unify their efforts to screen patients who are pulmonary asymptomatic for pulmonary arterial hypertension. In order to decrease mortality, efforts are directed at early detection, diagnosis, and therapeutic interventions before the disease compromises patients' quality of life. This article reviews the logistics of screening approaches for HRPAH and discusses the substantial disease burden currently faced by developing countries, where the prevalence of HIV infection is higher and complicated by hyperendemic risk factors, limited access to antiretrovirals, and lack of screening tools. We also present mechanistic insights into HRPAH, including the role of HIV proteins and their potential use as screening tools, and, finally, areas that still need intense research.

SUBMITTER: Almodovar S

PROVIDER: S-EPMC2882114 | biostudies-other | 2010 Jun

REPOSITORIES: biostudies-other

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Project description:BackgroundPulmonary hypertension (PH) represents an important complication of idiopathic pulmonary fibrosis (IPF) with a negative impact on patient survival. Herpes viruses are thought to play an etiological role in the development and/or progression of IPF. The influence of viruses on PH associated with IPF is unknown. We aimed to investigate the influence of viruses in IPF patients focusing on aspects related to PH. A laboratory mouse model of gamma-herpesvirus (MHV-68) induced pulmonary fibrosis was also assessed.MethodsLung tissue samples from 55 IPF patients and 41 controls were studied by molecular analysis to detect various viral genomes. Viral molecular data obtained were correlated with mean pulmonary arterial pressure (mPAP) and arterial remodelling. Different clinical and morphological variables were studied by univariate and multivariate analyses at time of transplant and in the early post-transplant period. The same lung tissue analyses were performed in MHV-68 infected mice.ResultsA higher frequency of virus positive cases was found in IPF patients than in controls (p?=?0.0003) and only herpes virus genomes were detected. Viral cases showed higher mPAP (p?=?0.01), poorer performance in the six minute walking test (6MWT; p?=?0.002) and higher frequency of primary graft (PGD) dysfunction after lung transplant (p?=?0.02). Increased arterial thickening, particularly of the intimal layer (p?=?0.002 and p?=?0.004) and higher TGF-? expression (p?=?0.002) were demonstrated in viral cases. The remodelled vessels showed increased vessel cell proliferation (Ki-67 positive cells) in the proximity to metaplastic epithelial cells and macrophages. Viral infection was associated with higher mPAP (p?=?0.03), poorer performance in the 6MWT (p?=?0.008) and PGD (p?=?0.02) after adjusting for other covariates/intermediate factors. In MHV-68 infected mice, morphological features were similar to those of patients.ConclusionHerpesviral infections may contribute to the development of PH in IPF patients.

Project description:BackgroundWe 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.MethodsPatients 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.ResultsThe 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.ConclusionsIn 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 associated with HIV infection: pulmonary vascular disease: the global perspective.

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