The aim of the present study was to determine contemporary survival in pulmonary arterial hypertension (PAH), and to investigate whether or not the National Institutes of Health (NIH) equation remains an accurate predictor of survival.In 576 patients with PAH referred during 1991-2007, observed survival was described using the Kaplan-Meier method. In patients with idiopathic, familial and anorexigen-associated PAH (n5247), observed versus NIH equation predicted survival was compared. A new survival prediction equation was developed using exponential regression analysis.The observed 1-, 3-and 5-yr survival in the total cohort were 86, 69 and 61%, respectively. In patients with idiopathic, familial and anorexigen-associated PAH, the observed 1-, 3-and 5-yr survival (92, 75 and 66%, respectively) were significantly higher than the predicted survival (65, 43 and 32%, respectively). The new equation (P(t)5e, where P(t) is probability of survival, t the time interval in years, A(x,y,z)5e(-1.270-0.0148x+0.0402y-0.361z) , x the mean pulmonary artery pressure, y the mean right atrial pressure and z the cardiac index) performed well when applied to published contemporary studies of survival in PAH. Contemporary survival in the PAH cohort was better than that predicted by the NIH registry equation. The NIH equation underestimated survival in idiopathic, familial and anorexigenassociated PAH. Once prospectively validated, the new equation may be used to determine prognosis.KEYWORDS: National Institutes of Health equation, prognosis, pulmonary arterial hypertension, survival P ulmonary arterial hypertension (PAH), a debilitating disease characterised by progressive obstruction and obliteration of the pulmonary arteries, eventually leads to right ventricular failure and death [1]. PAH can be idiopathic, familial or associated with other conditions, including connective tissue disease, congenital heart disease, portal hypertension, HIV and anorexigen exposure [1]. A landmark National Institutes of Health (NIH) registry study, published in 1987, described the clinical characteristics and natural history of patients with primary pulmonary hypertension (PPH), which included idiopathic, familial and anorexigen-associated PAH [2]. The NIH registry proposed an empirically derived equation, based on baseline haemodynamics, for the estimation of survival in patients with PPH [3].Subsequently, many clinical trials in PAH have used the NIH equation to suggest improvements in survival by comparing the observed survival rates on a study drug versus the survival rates predicted by the NIH equation [4][5][6][7][8][9].The NIH registry was initiated during a time when there were no US Food and Drug Administration-approved therapies for PAH. Patients in the NIH registry were treated only with conventional therapy, which included diuretics, digoxin, supplemental nasal oxygen and, in a minority of cases, anticoagulation with warfarin and/or vasodilators, such as calciumchannel blockers and hydralazine [2,3]. Since the mid-1980s, howeve...
These results highlight miR-mediated MCUC dysfunction as a unifying mechanism in PAH that can be therapeutically targeted.
Right ventricular (RV) function determines prognosis in pulmonary arterial hypertension (PAH). We hypothesize that ischemia causes RV dysfunction in PAH by triggering dynamin-related protein 1 (Drp1)-mediated mitochondrial fission. RV function was compared in control rats (n=50) versus rats with monocrotaline-induced PAH (MCT- PAH; n=60) both in vivo (echocardiography) and ex vivo (RV Langendorff). Mitochondrial membrane potential and morphology and RV function were assessed before or after two cycles of ischemia-reperfusion injury challenge (RV-IR). The effects of Mdivi-1 (25 μM), a Drp1 GTPase inhibitor and P110 (1 μM), a peptide inhibitor of Drp1–Fis1 interaction were studied. We found that MCT caused RV hypertrophy, RV vascular rarefaction and RV dysfunction. Prior to IR, the mitochondria in MCT-PAH RV were depolarized and swollen with increased Drp1 content and reduced aconitase activity. RV-IR increased RV end diastolic pressure (RVEDP) and mitochondrial Drp1 expression in both control and MCT-PAH RVs. IR depolarized mitochondria in control RV but did not exacerbate the basally depolarized MCT-PAH RV mitochondria. During RV IR mdivi-1 and P110 reduced Drp1 translocation to mitochondria, improved mitochondrial structure and function, and reduced RVEDP. In conclusion, RV ischemia occurs in PAH and causes Drp1-Fis1-mediated fission leading to diastolic dysfunction. Inhibition of mitochondrial fission preserves RV function in RV-IR.
Pulmonary arterial hypertension (PAH) is an obstructive pulmonary vasculopathy, characterized by excess proliferation, apoptosis-resistance, inflammation, fibrosis and vasoconstriction. While PAH therapies target some of these vascular abnormalities (primarily vasoconstriction) most do not directly benefit the right ventricle (RV). This is suboptimal since a patient’s functional state and prognosis are largely determined by the success of the adaptation of the RV to the increased afterload. The RV initially hypertrophies but may ultimately decompensate, becoming dilated, hypokinetic and fibrotic. A number of pathophysiologic abnormalities have been identified in the PAH RV, including: ischemia and hibernation (partially reflecting RV capillary rarefaction), autonomic activation (due to GRK2-mediated down-regulation and desensitization of β-adrenergic receptors), mitochondrial-metabolic abnormalities (notably increased uncoupled glycolysis and glutaminolysis), and fibrosis. Many RV abnormalities are detectable by molecular imaging and may serve as biomarkers. Some molecular pathways, such as those regulating angiogenesis, metabolism and mitochondrial dynamics, are similarly deranged in the RV and pulmonary vasculature, offering the possibility of therapies that treat both the RV and pulmonary circulation. An important paradigm in PAH is that the RV and pulmonary circulation constitute a unified cardiopulmonary unit. Clinical trials of PAH pharmacotherapies should assess both components of the cardiopulmonary unit.
Background: Pulmonary arterial hypertension (PAH) is a lethal vasculopathy. Hereditary cases are associated with germline mutations in BMPR2 and 16 other genes. However, these mutations occur in under 25% of idiopathic PAH patients (IPAH) and are rare in PAH associated with connective tissue diseases (APAH). Preclinical studies suggest epigenetic dysregulation, including altered DNA methylation, promotes PAH. Somatic mutations of Tet-methylcytosine-dioxygenase-2 (TET2), a key enzyme in DNA demethylation, occur in cardiovascular disease and are associated with clonal hematopoiesis, inflammation and adverse vascular remodeling. The role of TET2 in PAH is unknown. Methods: To test for a role of TET2, we utilized a cohort of 2572 cases from the PAH Biobank. Within this cohort, gene-specific rare variant association tests were performed using 1832 unrelated European PAH patients and 7509 non-Finnish European gnomAD subjects as controls. In an independent cohort of 140 patients, we quantified TET2 expression in peripheral blood mononuclear cells. To assess causality, we investigated hemodynamic and histologic evidence of PAH in hematopoietic Tet2-knockout mice. Results: We observed an increased burden of rare, predicted deleterious, germline variants in TET2 in PAH patients of European ancestry (9/1832) compared to controls (6/7509; relative risk=6, p=0.00067). Assessing the whole cohort, 0.39% (10/2572) of patients had 12 TET2 mutations (75% predicted germline and 25% somatic). These patients had no mutations in other PAH-related genes. Patients with TET2 mutations were older (71±7 years versus 48±19 years, p<0.0001) unresponsive to vasodilator challenge (0/7 vs 140/1055 (13.2%)), had lower PVR (5.2±3.1 versus 10.5±7.0 Woods units, p=0.02) and had increased inflammation (including elevation of IL-1β). Circulating TET2 expression did not correlate with age and was decreased in >86% of PAH patients. Tet2-knockout mice spontaneously developed PAH, adverse pulmonary vascular remodeling and inflammation, with elevated levels of cytokines, including IL-1β. Chronic therapy with an antibody targeting IL-1β blockade regressed PAH. Conclusions: PAH is the first human disease related to potential TET2 germline mutations. Inherited and acquired abnormalities of TET2 occur in 0.39% of PAH cases. Decreased TET2 expression is ubiquitous and has potential as a PAH biomarker.
Pulmonary arterial hypertension (PAH) results in right ventricular (RV) dysfunction and failure. Paradoxically, women are more frequently diagnosed with PAH but have better RV systolic function and survival rates than men. The mechanisms by which sex differences alter PAH outcomes remain unknown. Here, we sought to study the role of estrogen in RV functional remodeling in response to PAH. The SU5416-hypoxia (SuHx) mouse model of PAH was used. To study the role of estrogen, female mice were ovariectomized and then treated with estrogen or placebo. SuHx significantly increased RV afterload and resulted in RV hypertrophy. Estrogen treatment attenuated the increase in RV afterload compared with the untreated group (effective arterial elastance: 2.3 ± 0.1 mmHg/μl vs. 3.2 ± 0.3 mmHg/μl), and this was linked to preserved pulmonary arterial compliance (compliance: 0.013 ± 0.001 mm(2)/mmHg vs. 0.010 ± 0.001 mm(2)/mmHg; P < 0.05) and decreased distal muscularization. Despite lower RV afterload in the estrogen-treated SuHx group, RV contractility increased to a similar level as the placebo-treated SuHx group, suggesting an inotropic effect of estrogen on RV myocardium. Consequently, when compared with the placebo-treated SuHx group, estrogen improved RV ejection fraction and cardiac output (ejection fraction: 57 ± 2% vs. 44 ± 2% and cardiac output: 9.7 ± 0.4 ml/min vs. 7.6 ± 0.6 ml/min; P < 0.05). Our study demonstrates for the first time that estrogen protects RV function in the SuHx model of PAH in mice directly by stimulating RV contractility and indirectly by protecting against pulmonary vascular remodeling. These results underscore the therapeutic potential of estrogen in PAH.
Introduction: Right ventricular (RV) fibrosis contributes to RV failure in pulmonary arterial hypertension (PAH). The mechanisms underlying RV fibrosis in PAH and the role of RV fibroblasts (RVfib) are unknown. Activation of the mitochondrial fission mediator dynamin-related protein 1 (Drp1) contributes to dysfunction of RV myocytes in PAH through interaction with its binding partner, fission protein 1 (Fis1). However, the role of mitochondrial fission in RVfib and RV fibrosis in PAH is unknown.Objective: We hypothesize that mitochondrial fission is increased in RVfib of rats with monocrotaline (MCT)-induced PAH. We evaluated the contribution of Drp1 and Drp1–Fis1 interaction to RVfib proliferation and collagen production in culture and to RV fibrosis in vivo.Methods: Vimentin (+) RVfib were enzymatically isolated and cultured from the RVs of male Sprague–Dawley rats that received MCT (60 mg/kg) or saline. Mitochondrial morphology, proliferation, collagen production, and expression of Drp1, Drp1 binding partners and mitochondrial fusion mediators were measured. The Drp1 inhibitor mitochondrial division inhibitor 1 (Mdivi-1), P110, a competitive peptide inhibitor of Drp1–Fis1 interaction, and siRNA targeting Drp1 were assessed. Subsequently, prevention and regression studies tested the antifibrotic effects of P110 (0.5 mg/kg) in vivo. At week 4 post MCT, echocardiography and right heart catheterization were performed. The RV was stained for collagen.Results: Mitochondrial fragmentation, proliferation rates and collagen production were increased in MCT-RVfib versus control-RVfib. MCT-RVfib had increased expression of activated Drp1 protein and a trend to decreased mitofusin-2 expression. Mdivi-1 and P110 inhibited mitochondrial fission, proliferation and collagen III expression in MCT-RVfib. However, P110 was only effective at high doses (1 mM). siDrp1 also reduced fission in MCT-RVfib. Despite promising results in cell therapy, in vivo therapy with P110 failed to prevent or regress RV fibrosis in MCT rats, perhaps due to failure to achieve adequate P110 levels or to the greater importance of interaction of Drp1 with other binding partners.Conclusion: PAH RVfib have increased Drp1-mediated mitochondrial fission. Inhibiting Drp1 prevents mitochondrial fission and reduces RVfib proliferation and collagen production. This is the first description of disordered mitochondrial dynamics in RVfib and suggests that Drp1 is a potential new antifibrotic target.
BackgroundPulmonary arterial hypertension (PAH) is a lethal disease characterized by obstructive pulmonary vascular remodeling and right ventricular (RV) dysfunction. Although RV function predicts outcomes in PAH, mechanisms of RV dysfunction are poorly understood, and RV‐targeted therapies are lacking. We hypothesized that in PAH, abnormal microtubular structure in RV cardiomyocytes impairs RV function by reducing junctophilin‐2 (JPH2) expression, resulting in t‐tubule derangements. Conversely, we assessed whether colchicine, a microtubule‐depolymerizing agent, could increase JPH2 expression and enhance RV function in monocrotaline‐induced PAH.Methods and ResultsImmunoblots, confocal microscopy, echocardiography, cardiac catheterization, and treadmill testing were used to examine colchicine's (0.5 mg/kg 3 times/week) effects on pulmonary hemodynamics, RV function, and functional capacity. Rats were treated with saline (n=28) or colchicine (n=24) for 3 weeks, beginning 1 week after monocrotaline (60 mg/kg, subcutaneous). In the monocrotaline RV, but not the left ventricle, microtubule density is increased, and JPH2 expression is reduced, with loss of t‐tubule localization and t‐tubule disarray. Colchicine reduces microtubule density, increases JPH2 expression, and improves t‐tubule morphology in RV cardiomyocytes. Colchicine therapy diminishes RV hypertrophy, improves RV function, and enhances RV–pulmonary artery coupling. Colchicine reduces small pulmonary arteriolar thickness and improves pulmonary hemodynamics. Finally, colchicine increases exercise capacity.ConclusionsMonocrotaline‐induced PAH causes RV‐specific derangement of microtubules marked by reduction in JPH2 and t‐tubule disarray. Colchicine reduces microtubule density, increases JPH2 expression, and improves both t‐tubule architecture and RV function. Colchicine also reduces adverse pulmonary vascular remodeling. These results provide biological plausibility for a clinical trial to repurpose colchicine as a RV‐directed therapy for PAH.
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