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Sample records for monocrotaline-induced pulmonary hypertension

  1. Nebivolol has a beneficial effect in monocrotaline-induced pulmonary hypertension.

    PubMed

    Pankey, Edward A; Edward, Justin A; Swan, Kevin W; Bourgeois, Camille R T; Bartow, Matthew J; Yoo, Daniel; Peak, Taylor A; Song, Bryant M; Chan, Ryan A; Murthy, Subramanyam N; Prieto, Minolfa C; Giles, Thomas D; Kadowitz, Philip J

    2016-07-01

    Pulmonary hypertension is a rare disorder that, without treatment, is progressive and fatal within 3-4 years. Current treatment involves a diverse group of drugs that target the pulmonary vascular bed. In addition, strategies that increase nitric oxide (NO) formation have a beneficial effect in rodents and patients. Nebivolol, a selective β1 adrenergic receptor-blocking agent reported to increase NO production and stimulate β3 receptors, has vasodilator properties suggesting that it may be beneficial in the treatment of pulmonary hypertension. The present study was undertaken to determine whether nebivolol has a beneficial effect in monocrotaline-induced (60 mg/kg) pulmonary hypertension in the rat. These results show that nebivolol treatment (10 mg/kg, once or twice daily) attenuates pulmonary hypertension, reduces right ventricular hypertrophy, and improves pulmonary artery remodeling in monocrotaline-induced pulmonary hypertension. This study demonstrates the presence of β3 adrenergic receptor immunoreactivity in pulmonary arteries and airways and that nebivolol has pulmonary vasodilator activity. Studies with β3 receptor agonists (mirabegron, BRL 37344) and antagonists suggest that β3 receptor-mediated decreases in systemic arterial pressure occur independent of NO release. Our results suggest that nebivolol, a selective vasodilating β1 receptor antagonist that stimulates β3 adrenergic receptors and induces vasodilation by increasing NO production, may be beneficial in treating pulmonary hypertensive disorders. PMID:27172427

  2. Role of the TGF-β/Alk5 Signaling Pathway in Monocrotaline-induced Pulmonary Hypertension

    PubMed Central

    Zaiman, Ari L.; Podowski, Megan; Medicherla, Satya; Gordy, Kimberley; Xu, Fang; Zhen, Lijie; Shimoda, Larissa A.; Neptune, Enid; Higgins, Linda; Murphy, Alison; Chakravarty, Sarvajit; Protter, Andrew; Sehgal, Pravin B.; Champion, Hunter C.; Tuder, Rubin M.

    2008-01-01

    Rationale: Pulmonary arterial hypertension is a progressive disease characterized by an elevation in the mean pulmonary artery pressure leading to right heart failure and a significant risk of death. Alterations in two transforming growth factor (TGF) signaling pathways, bone morphogenetic protein receptor II and the TGF-β receptor I, Alk1, have been implicated in the pathogenesis of pulmonary hypertension (PH). However, the role of TGF-β family signaling in PH and pulmonary vascular remodeling remains unclear. Objectives: To determine whether inhibition of TGF-β signaling will attenuate and reverse monocrotaline-induced PH (MCT-PH). Methods: We have used an orally active small-molecule TGF-β receptor I inhibitor, SD-208, to determine the functional role of this pathway in MCT-PH. Measurements and Main Results: The development of MCT-PH was associated with increased vascular cell apoptosis, which paralleled TGF-β signaling as documented by psmad2 expression. Inhibition of TGF-β signaling with SD-208 significantly attenuated the development of the PH and reduced pulmonary vascular remodeling. These effects were associated with decreased early vascular cell apoptosis, adventitial cell proliferation, and matrix metalloproteinase expression. Inhibition of TGF-β signaling with SD-208 in established MCT-PH resulted in a small but significant improvement in hemodynamic parameters and medial remodeling. Conclusions: These findings provide evidence that increased TGF-β signaling participates in the pathogenesis of experimental severe PH. PMID:18202349

  3. The Beneficial Effect of Suramin on Monocrotaline-Induced Pulmonary Hypertension in Rats

    PubMed Central

    Izikki, Mohamed; Mercier, Olaf; Lecerf, Florence; Lubert Guin, Lauriane; Hoang, Eric; Dorfmüller, Peter; Perros, Frédéric; Humbert, Marc; Simonneau, Gerald; Dartevelle, Philippe; Fadel, Elie; Eddahibi, Saadia

    2013-01-01

    Background Pulmonary hypertension (PH) is a progressive disorder characterized by an increase in pulmonary artery pressure and structural changes in the pulmonary vasculature. Several observations indicate that growth factors play a key role in PH by modulating pulmonary artery smooth muscle cell (PA-SMC) function. In rats, established monocrotaline-induced PH (MCT-PH) can be reversed by blocking platelet-derived growth factor receptors (PDGF-R), epidermal growth factor receptors (EGF-R), or fibroblast growth factor receptors (FGF-R). All these receptors belong to the receptor tyrosine kinase (RTK) family. Methods and Results We evaluated whether RTK blockade by the nonspecific growth factor inhibitor, suramin, reversed advanced MCT-PH in rats via its effects on growth-factor signaling pathways. We found that suramin inhibited RTK and ERK1/2 phosphorylation in cultured human PA-SMCs. Suramin inhibited PA-SMC proliferation induced by serum, PDGF, FGF2, or EGF in vitro and ex vivo. Treatment with suramin from day 1 to day 21 after monocrotaline injection attenuated PH development, as shown by lower values for pulmonary artery pressure, right ventricular hypertrophy, and distal vessel muscularization on day 21 compared to control rats. Treatment with suramin from day 21 to day 42 after monocrotaline injection reversed established PH, thereby normalizing the pulmonary artery pressure values and vessel structure. Suramin treatment suppressed PA-SMC proliferation and attenuated both the inflammatory response and the deposition of collagen. Conclusions RTK blockade by suramin can prevent MCT-PH and reverse established MCT-PH in rats. This study suggests that an anti-RTK strategy that targets multiple RTKs could be useful in the treatment of pulmonary hypertension. PMID:24143201

  4. Progesterone inhibits vascular remodeling and attenuates monocrotaline-induced pulmonary hypertension in estrogen-deficient rats.

    PubMed

    Tofovic, P S; Zhang, X; Petrusevska, G

    2009-07-01

    (Full text is available at http://www.manu.edu.mk/prilozi). Pulmonary arterial hypertension (PH) is predominantly a disease of young females. Yet, little is known regarding the effects of female sex hormones in PH. Female rats develop less severe PH compared to male rats, and ovariectomy (OVX) exacerbates PH. Although OVX rats treated with estradiol develop less severe disease, the role of progesterone in OVX-induced exacerbation of disease has not been examined. Progesterone was shown to dilate pulmonary vessels and to inhibit proliferation of endothelial and vascular smooth muscle cells. Therefore, we hypothesized that progesterone may confer protective effects in experimental PH. A total of 30 female rats were ovariectomized and OVX rats were randomly administered either saline (OVX-Control group, n = 7), monocrotaline (60mg/kg i.p.; OVX-MCT group; n = 12), or MCT plus progesterone (30microg/kg/h via osmotic minipumps; OVX-MCT+P group; n = 11). After 32 days animals were instrumented for in situ (open chest) measurements of right ventricle (RV) peak systolic (RVSP) and end diastolic (RVEDP) pressures, and tissue samples were obtained for morphometric and histological analysis. Administration of MCT elevated RVSP (22.2 +/- 1.1 vs. 46.7 +/- 2.4 mmHg) and RVEDP (1.51 +/- 0.86 vs. 11.9+/-2.2 mmHg), increased RV/left ventricle + septum (RV/LV+S) ratio (0.256 +/- 0.010 vs. 0.582 +/- 0.033, OVX vs. OVX-MCT), and induced media hypertrophy of small size pulmonary arteries. In ovariectomized pulmonary hypertensive rats, treatment with progesterone attenuated the severity of disease (OVX-MCT+P group: RVSP = 36.6 +/- 2.3 mmHg; RV/LV+S = 0.468 +/- 0.025; RVEDP = 7.5 +/-1.5 mmHg), attenuated vascular remodeling (media % index: 28.2 +/- 1.1 vs. 34.2 +/- 1.3), and reduced mortality (9% vs. 25%; OVX-MCT+P vs. OVX-MCT). This study provides the first evidence that in estrogen-deficient rats, progesterone has protective effects in MCT-induced PH. Further evaluation of the role of

  5. N-acetylcysteine improves established monocrotaline-induced pulmonary hypertension in rats

    PubMed Central

    2014-01-01

    Background The outcome of patients suffering from pulmonary arterial hypertension (PAH) are predominantly determined by the response of the right ventricle to the increase afterload secondary to high vascular pulmonary resistance. However, little is known about the effects of the current available or experimental PAH treatments on the heart. Recently, inflammation has been implicated in the pathophysiology of PAH. N-acetylcysteine (NAC), a well-known safe anti-oxidant drug, has immuno-modulatory and cardioprotective properties. We therefore hypothesized that NAC could reduce the severity of pulmonary hypertension (PH) in rats exposed to monocrotaline (MCT), lowering inflammation and preserving pulmonary vascular system and right heart function. Methods Saline-treated control, MCT-exposed, MCT-exposed and NAC treated rats (day 14–28) were evaluated at day 28 following MCT for hemodynamic parameters (right ventricular systolic pressure, mean pulmonary arterial pressure and cardiac output), right ventricular hypertrophy, pulmonary vascular morphometry, lung inflammatory cells immunohistochemistry (monocyte/macrophages and dendritic cells), IL-6 expression, cardiomyocyte hypertrophy and cardiac fibrosis. Results The treatment with NAC significantly decreased pulmonary vascular remodeling, lung inflammation, and improved total pulmonary resistance (from 0.71 ± 0.05 for MCT group to 0.50 ± 0.06 for MCT + NAC group, p < 0.05). Right ventricular function was also improved with NAC treatment associated with a significant decrease in cardiomyocyte hypertrophy (625 ± 69 vs. 439 ± 21 μm2 for MCT and MCT + NAC group respectively, p < 0.001) and heart fibrosis (14.1 ± 0.8 vs. 8.8 ± 0.1% for MCT and MCT + NAC group respectively, p < 0.001). Conclusions Through its immuno-modulatory and cardioprotective properties, NAC has beneficial effect on pulmonary vascular and right heart function in experimental PH. PMID:24929652

  6. Calorie Restriction Attenuates Monocrotaline-induced Pulmonary Arterial Hypertension in Rats.

    PubMed

    Ding, Mingge; Lei, Jingyi; Qu, Yinxian; Zhang, Huan; Xin, Weichuan; Ma, Feng; Liu, Shuwen; Li, Zhichao; Jin, Faguang; Fu, Enqing

    2015-06-01

    Calorie restriction (CR) is one of the most effective nonpharmacological interventions protecting against cardiovascular disease, such as hypertension in the systemic circulation. However, whether CR could attenuate pulmonary arterial hypertension (PAH) is largely unknown. The PAH model was developed by subjecting the rats to a single subcutaneous injection of monocrotaline. CR lowered mean pulmonary arterial pressure (mPAP) and reduced vascular remodeling and right ventricular hypertrophy in PAH rats. Meanwhile, CR attenuated endothelial dysfunction as evidenced by increased relaxation in response to acetylcholine. The beneficial effects of CR were associated with restored sirtuin-1 (SIRT1) expression and endothelial nitric oxide synthase (eNOS) phosphorylation and reduced eNOS acetylation in pulmonary arteries of PAH rats. To further clarify the role of SIRT1 in the protective effects of CR, adenoviral vectors for overexpression of SIRT1 were administered intratracheally at 1 day before monocrotaline injection. Overexpression of SIRT1 exhibited similar beneficial effects on mPAP and endothelial function, and increased eNOS phosphorylation and reduced eNOS acetylation in the absence of CR. Moreover, SIRT1 overexpression attenuated the increase in mPAP in hypoxia-induced PAH animals. Overall, the present data demonstrate that CR may serve as an effective treatment of PAH, and targeting the SIRT1/eNOS pathway may improve treatment of PAH. PMID:25636073

  7. Attenuation of the extract from Moringa oleifera on monocrotaline-induced pulmonary hypertension in rats.

    PubMed

    Chen, Kang-Hu; Chen, Yi-Jui; Yang, Chao-Hsun; Liu, Kuo-Wei; Chang, Junn-Liang; Pan, Shwu-Fen; Lin, Tzer-Bin; Chen, Mei-Jung

    2012-02-29

    The purpose of this study was to determine the effects of an extract from Moringa oleifera (MO) on the development of monocrotaline (MCT)-induced pulmonary hypertension (PH) in Wistar rats. An ethanol extraction was performed on dried MO leaves, and HPLC analysis identified niaziridin and niazirin in the extract. PH was induced with a single subcutaneous injection of MCT (60 mg/kg) which resulted in increases in pulmonary arterial blood pressure (Ppa) and in thickening of the pulmonary arterial medial layer in the rats. Three weeks after induction, acute administration of the MO extract to the rats decreased Ppa in a dose-dependent manner that reached statistical significance at a dose of 4.5 mg of freeze-dried extract per kg body weight. The reduction in Ppa suggested that the extract directly relaxed the pulmonary arteries. To assay the effects of chronic administration of the MO extract on PH, control, MCT and MCT+MO groups were designated. Rats in the control group received a saline injection; the MCT and MCT+MO groups received MCT to induce PH. During the third week after MCT treatment, the MCT+MO group received daily i.p. injections of the MO extract (4.5 mg of freeze-dried extract/kg of body weight). Compared to the control group, the MCT group had higher Ppa and thicker medial layers in the pulmonary arteries. Chronic treatments with the MO extract reversed the MCT-induced changes. Additionally, the MCT group had a significant elevation in superoxide dismutase activity when normalized by the MO extract treatments. In conclusion, the MO extract successfully attenuated the development of PH via direct vasodilatation and a potential increase in antioxidant activity. PMID:22242951

  8. Contribution of elastin and collagen to the pathogenesis of monocrotaline induced pulmonary hypertension

    SciTech Connect

    Todorovich, L.; Johnson, D.; Ranger, P.; Keeley, F.; Rabinovitch, M.

    1986-03-01

    Male Sprague-Dawley rats were selected randomly for subcutaneous injections, 24 with monocrotaline (M) (60mg/kg) and 24 with an equivolume of saline, and studied 8, 16 or 28 days later. The right (RV) and left ventricle with septum (LV + S) were separated and weighed. The pulmonary artery (PA) was assessed by light and electron microscopy. Synthesis of elastin collagen and non-collagenous proteins was determined by measuring incorporations of /sup 3/H-valine, /sup 14/C-OH-proline and /sup 14/C-proline respectively. Total content of elastin was determined by weight of residue after CNBr digestion, and of collagen by total OH-proline content in SDS and CNBr extracts. At 16 days, the M injected rats developed a 6-fold increase in PA elastin synthesis and a 2-fold increase in medial wall thickness. Ultrastructural changes included increased microtubules and golgi apparatus in endothelium, decreased proportion of mature elastin in subendothelium and increased ground substance in media. By 28 days, M rats showed a progressive increase in PA elastin and collagen synthesis, greater than 20-fold, and in medial wall thickness, 3-fold. This was associated with a 2-fold increase in total elastin in proportion to the increase in PA weight and the development of RV hypertrophy (RV/LV + S increased more than 2-fold). Progressive irreversible pulmonary hypertension induced by M may be related to continuing stimulation of PA elastin and collagen synthesis.

  9. Therapeutic Benefits of Induced Pluripotent Stem Cells in Monocrotaline-Induced Pulmonary Arterial Hypertension.

    PubMed

    Huang, Wei-Chun; Ke, Meng-Wei; Cheng, Chin-Chang; Chiou, Shih-Hwa; Wann, Shue-Ren; Shu, Chih-Wen; Chiou, Kuan-Rau; Tseng, Ching-Jiunn; Pan, Hung-Wei; Mar, Guang-Yuan; Liu, Chun-Peng

    2016-01-01

    Pulmonary arterial hypertension (PAH) is characterized by progressive increases in vascular resistance and the remodeling of pulmonary arteries. The accumulation of inflammatory cells in the lung and elevated levels of inflammatory cytokines in the bloodstream suggest that inflammation may play a role in PAH. In this study, the benefits of induced pluripotent stem cells (iPSCs) and iPSC-conditioned medium (iPSC CM) were explored in monocrotaline (MCT)-induced PAH rats. We demonstrated that both iPSCs and iPSC CM significantly reduced the right ventricular systolic pressure and ameliorated the hypertrophy of the right ventricle in MCT-induced PAH rats in models of both disease prevention and disease reversal. In the prevention of MCT-induced PAH, iPSC-based therapy led to the decreased accumulation of inflammatory cells and down-regulated the expression of the IL-1β, IL-6, IL-12α, IL-12β, IL-23 and IFNγ genes in lung specimens, which implied that iPSC-based therapy may be involved in the regulation of inflammation. NF-κB signaling is essential to the inflammatory cascade, which is activated via the phosphorylation of the NF-κB molecule. Using the chemical inhibitor specifically blocked the phosphorylation of NF-κB, and in vitro assays of cultured human M1 macrophages implied that the anti-inflammation effect of iPSC-based therapy may contribute to the disturbance of NF-κB activation. Here, we showed that iPSC-based therapy could restore the hemodynamic function of right ventricle with benefits for preventing the ongoing inflammation in the lungs of MCT-induced PAH rats by regulating NF-κB phosphorylation. PMID:26840075

  10. Local and systemic renin-angiotensin system participates in cardiopulmonary-renal interactions in monocrotaline-induced pulmonary hypertension in the rat.

    PubMed

    Malikova, Eva; Galkova, Kristina; Vavrinec, Peter; Vavrincova-Yaghi, Diana; Kmecova, Zuzana; Krenek, Peter; Klimas, Jan

    2016-07-01

    Renin-angiotensin system (RAS) is one of the pathophysiological mechanisms in heart failure. Recently, involvement of the kidney in the disease progression has been proposed in patients with pulmonary arterial hypertension (PAH). We hypothesized that local and systemic RAS could be the central regulators of cardiopulmonary-renal interactions in experimental monocrotaline-induced pulmonary hypertension (PH) in rats. Male 12-week-old Wistar rats were injected subcutaneously with monocrotaline (60 mg/kg). The experiment was terminated 4 weeks after monocrotaline administration. Using RT-PCR, we measured the expression of RAS-related genes in right and left ventricles, lungs and kidneys, together with indicators of renal dysfunction and damage. We observed a significantly elevated expression of angiotensin-converting enzyme (ACE) in both left and right ventricles and kidneys (P < 0.05), but a significantly decreased ACE in the lungs (P < 0.05). Kidneys showed a significant 2.5-fold increase in renin mRNA (P < 0.05) along with erythropoietin, TGFβ1, COX-2, NOS-1 and nephrin. Expression of erythropoietin correlated inversely with hemoglobin oxygen saturation and positively with renin expression. In conclusion, monocrotaline-induced PH exhibited similar alterations of ACE expression in the left and right ventricles, and in the kidney, in contrast to the lungs. Increased renal renin was likely a consequence of renal hypoxia/hypoperfusion, as was increased renal erythropoietin expression. Alterations in RAS in the monocrotaline model are probably a result of hypoxic state, and while they could serve as a compensatory mechanism at a late stage of the disease, they could be viewed also as an indicator of multiorgan failure in PAH. PMID:27344167

  11. Local and systemic renin-angiotensin system participates in cardiopulmonary-renal interactions in monocrotaline-induced pulmonary hypertension in the rat.

    PubMed

    Malikova, Eva; Galkova, Kristina; Vavrinec, Peter; Vavrincova-Yaghi, Diana; Kmecova, Zuzana; Krenek, Peter; Klimas, Jan

    2016-07-01

    Renin-angiotensin system (RAS) is one of the pathophysiological mechanisms in heart failure. Recently, involvement of the kidney in the disease progression has been proposed in patients with pulmonary arterial hypertension (PAH). We hypothesized that local and systemic RAS could be the central regulators of cardiopulmonary-renal interactions in experimental monocrotaline-induced pulmonary hypertension (PH) in rats. Male 12-week-old Wistar rats were injected subcutaneously with monocrotaline (60 mg/kg). The experiment was terminated 4 weeks after monocrotaline administration. Using RT-PCR, we measured the expression of RAS-related genes in right and left ventricles, lungs and kidneys, together with indicators of renal dysfunction and damage. We observed a significantly elevated expression of angiotensin-converting enzyme (ACE) in both left and right ventricles and kidneys (P < 0.05), but a significantly decreased ACE in the lungs (P < 0.05). Kidneys showed a significant 2.5-fold increase in renin mRNA (P < 0.05) along with erythropoietin, TGFβ1, COX-2, NOS-1 and nephrin. Expression of erythropoietin correlated inversely with hemoglobin oxygen saturation and positively with renin expression. In conclusion, monocrotaline-induced PH exhibited similar alterations of ACE expression in the left and right ventricles, and in the kidney, in contrast to the lungs. Increased renal renin was likely a consequence of renal hypoxia/hypoperfusion, as was increased renal erythropoietin expression. Alterations in RAS in the monocrotaline model are probably a result of hypoxic state, and while they could serve as a compensatory mechanism at a late stage of the disease, they could be viewed also as an indicator of multiorgan failure in PAH.

  12. [Effect of chrysin on expression of NOX4 and NF-κB in right ventricle of monocrotaline-induced pulmonary arterial hypertension of rats].

    PubMed

    Li, Xian-wei; Guo, Bo; Shen, Yuan-yuan; Yang, Jie-ren

    2015-09-01

    The aim of the present study is to investigate the protective effect of chrysin (5,7-dihydroxyflavone) on right ventricular remodeling in a rat model of monocrotaline-induced pulmonary arterial hypertension (PAH). PAH rats were induced by a single injection of monocrotaline (60 mg x kg(-1), sc) and were administered with chrysin (50 or 100 mg x kg(-1) x d(-1)) for 4 weeks. At the end of experiment, the right ventricular systolic pressure (RVSP) and mean pulmonary artery pressure (mPAP) were monitored via the right jugular vein catheterization into the right ventricle. Right ventricle (RV) to left ventricle (LV) + septum (S) and RV to tibial length were calculated. Right ventricular morphological change was observed by HE staining. Masson's trichrome stain was used to demonstrate collagen deposition. The total antioxidative capacity (T-AOC) and malondialdehyde (MDA) levels in right ventricle were determined according to the manufacturer's instructions. The expressions of collagen I, collagen III, NADPH oxidase 4 (NOX4) and nuclear factor-kappa B (NF-κB) were analyzed by immunohistochemisty, qPCR and (or) Western blot. The results showed that chrysin treatment for 4 weeks attenuated RVSP, mPAP and right ventricular remodeling index (RV/LV+S and RV/Tibial length) of PAH rats induced by monocrotaline. Furthermore, monocrotaline-induced right ventricular collagen accumulation and collagen I and collagen III expression were both significantly suppressed by chrysin. The expressions of NOX4, NF-κB and MDA contents were obviously decreased, while the T-AOC was significantly increased in right ventricule from PAH rats with chrysin treatment. These results suggest that chrysin ameliorates right ventricular remodeling of PAH induced by monocrotaline in rats through its down-regulating of NOX4 expression and antioxidant activity, and inhibiting NF-κB expression and collagen accumulation.

  13. Rosuvastatin intensifies the beneficial effects of rho-kinase inhibitor in reversal of monocrotaline-induced pulmonary hypertension

    PubMed Central

    Owczarek, Jacek; Sołtysiak, Urszula; Orszulak-Michalak, Daria

    2015-01-01

    Introduction It remains controversial whether statins have a beneficial effect on pulmonary arterial hypertension (PAH). This study is intended to evaluate whether statin, co-administered with Rho-kinase inhibitor, could enhance its efficacy. Although Rho-kinase inhibitors, including fasudil, have been reported to improve pulmonary hypertension in experimental and clinical studies, the combination of these agents has not been tested in the treatment of pulmonary hypertension (PH). Material and methods The effects of such a regimen on hemodynamics, right ventricle hypertrophy, and Rho-associated protein kinase (ROCK) activity in experimental monocrotaline (MCT)-induced pulmonary hypertension were examined. Fourteen days after monocrotaline injection (60 mg/kg), male rats were treated orally for another 14 days with fasudil (15 mg/kg per day), or with a combination of fasudil + rosuvastatin (10 mg/kg per day). Results The drug combination reversed the MCT-induced increase in right ventricle pressure (RVP) and reduced right ventricular hypertrophy (RV/LV + S ratio) more than Rho kinase inhibitor alone. The simultaneous administration of fasudil and rosuvastatin caused a further decrease of RhoA kinase activity in isolated lung tissues as compared to fasudil alone. Conclusions The results indicate that rosuvastatin intensifies the beneficial effects of Rho-kinase inhibitor on the Rho/Rho-kinase pathway and such a combination may represent an option for the treatment of pulmonary arterial hypertension. PMID:27478473

  14. Ruscogenin exerts beneficial effects on monocrotaline-induced pulmonary hypertension by inhibiting NF-κB expression

    PubMed Central

    Zhu, Rong; Bi, Liqing; Kong, Hui; Xie, Weiping; Hong, Yongqing; Wang, Hong

    2015-01-01

    This study aims to examine the effect of ruscogenin on pulmonary arterial hypertension (PAH) and to determine the mechanism underlying this effect. We isolated pulmonary vascular smooth muscle cells (PVSMCs) from the pulmonary artery of the rats; the PVSMCs were cultured in vitro and then were treated with platelet-derived growth factor (PDGF), PDGF + ruscogenin, or PDGF + ruscogenin + parthenolide. We randomized Sprague-Dawley rats into five groups as follows: control group, PAH group, low-dose group, medium-dose group, and high-dose group; the rats in the low-, medium-, and high-dose groups received the vehicle and ruscogenin 0.1, 0.4, and 0.7 mg/kg, respectively, from day 1 to day 21 after injection of monocrotaline (MCT). We measured the mean pulmonary arterial pressure (mPAP), right ventricular systolic pressure (RVSP), and medial wall thickness of the pulmonary artery (PAWT). We examined the levels of the nuclear factor kappa B (NF-κB) protein by using immunohistochemistry and western blot analysis, and the mRNA levels of NF-κB in PVSMCs were evaluated using real-time polymerase chain reaction (PCR). The mPAP, RVSP, and PAWT and the protein and mRNA levels of NF-κB were significantly higher in the PAH model group than in the control group (P < 0.05). Ruscogenin induced a significant dose-dependent decrease in the mPAP, RVSP, and PAWT and in the NF-κB expression in the PAH group (P < 0.05), which suggests that ruscogenin will also exert dose-dependent effects on MCT-induced PAH through the inhibition of NF-κB. PMID:26722401

  15. 1H NMR-Based Analysis of Serum Metabolites in Monocrotaline-Induced Pulmonary Arterial Hypertensive Rats

    PubMed Central

    Lin, Taijie; Gu, Jinping; Huang, Caihua; Zheng, Suli; Lin, Xu; Xie, Liangdi; Lin, Donghai

    2016-01-01

    Aims. To study the changes of the metabolic profile during the pathogenesis in monocrotaline (MCT) induced pulmonary arterial hypertension (PAH). Methods. Forty male Sprague-Dawley (SD) rats were randomly divided into 5 groups (n = 8, each). PAH rats were induced by a single dose intraperitoneal injection of 60 mg/kg MCT, while 8 rats given intraperitoneal injection of 1 ml normal saline and scarified in the same day (W0) served as control. Mean pulmonary arterial pressure (mPAP) was measured through catherization. The degree of right ventricular hypertrophy and pulmonary hyperplasia were determined at the end of first to fourth weeks; nuclear magnetic resonance (NMR) spectra of sera were then acquired for the analysis of metabolites. Principal component analysis (PCA) and orthogonal partial least-squares discriminant analysis (OPLS-DA) were used to discriminate different metabolic profiles. Results. The prominent changes of metabolic profiles were seen during these four weeks. Twenty specific metabolites were identified, which were mainly involved in lipid metabolism, glycolysis, energy metabolism, ketogenesis, and methionine metabolism. Profiles of correlation between these metabolites in each stage changed markedly, especially in the fourth week. Highly activated methionine and betaine metabolism pathways were selected by the pathway enrichment analysis. Conclusions. Metabolic dysfunction is involved in the development and progression of PAH. PMID:27057080

  16. Changes of Gene Expression after Bone Marrow Cell Transfusion in Rats with Monocrotaline-Induced Pulmonary Hypertension

    PubMed Central

    Kim, Kwan Chang; Lee, Hae Ryun; Kim, Sung Jin; Cho, Min-Sun

    2012-01-01

    Pulmonary artery hypertension (PAH) causes right ventricular failure and possibly even death by a progressive increase in pulmonary vascular resistance. Bone marrow-derived mesenchymal stem cell therapy has provided an alternative treatment for ailments of various organs by promoting cell regeneration at the site of pathology. The purpose of this study was to investigate changes of pulmonary haemodynamics, pathology and expressions of various genes, including ET (endothelin)-1, ET receptor A (ERA), endothelial nitric oxide synthase (NOS) 3, matrix metalloproteinase (MMP) 2, tissue inhibitor of matrix metalloproteinase (TIMP), interleukin (IL)-6 and tumor necrosis factor (TNF)-α in monocrotaline (MCT)-induced PAH rat models after bone marrow cell (BMC) transfusion. The rats were grouped as the control (C) group, monocrotaline (M) group, and BMC transfusion (B) group. M and B groups received subcutaneous (sc) injection of MCT (60 mg/kg). BMCs were transfused by intravenous injection at the tail 1 week after MCT injection in B group. Results showed that the average RV pressure significantly decreased in the B group compared with the M group. RV weight and the ratio of RH/LH+septum significantly decreased in the B group compared to the M group. Gene expressions of ET-1, ERA, NOS 3, MMP 2, TIMP, IL-6, and TNF-α significantly decreased in week 4 in the B group compared with the M group. In conclusion, BMC transfusion appears to improve survival rate, RVH, and mean RV pressure, and decreases gene expressions of ET-1, ERA, NOS 3, MMP 2, TIMP, IL-6, and TNF-α. PMID:22690090

  17. Beneficial effects of a novel agonist of the adenosine A2A receptor on monocrotaline-induced pulmonary hypertension in rats

    PubMed Central

    Alencar, Allan K N; Pereira, Sharlene L; Montagnoli, Tadeu L; Maia, Rodolfo C; Kümmerle, Arthur E; Landgraf, Sharon S; Caruso-Neves, Celso; Ferraz, Emanuelle B; Tesch, Roberta; Nascimento, José H M; de Sant'Anna, Carlos M R; Fraga, Carlos A M; Barreiro, Eliezer J; Sudo, Roberto T; Zapata-Sudo, Gisele

    2013-01-01

    Background and Purpose Pulmonary arterial hypertension (PAH) is characterized by enhanced pulmonary vascular resistance, right ventricular hypertrophy and increased right ventricular systolic pressure. Here, we investigated the effects of a N-acylhydrazone derivative, 3,4-dimethoxyphenyl-N-methyl-benzoylhydrazide (LASSBio-1359), on monocrotaline (MCT)-induced pulmonary hypertension in rats. Experimental Approach PAH was induced in male Wistar rats by a single i.p. injection of MCT (60 mg·kg−1) and 2 weeks later, oral LASSBio-1359 (50 mg·kg−1) or vehicle was given once daily for 14 days. Echocardiography was used to measure cardiac function and pulmonary artery dimensions, with histological assay of vascular collagen. Studies of binding to human recombinant adenosine receptors (A1, A2A, A3) and of docking with A2A receptors were also performed. Key Results MCT administration induced changes in vascular and ventricular structure and function, characteristic of PAH. These changes were reversed by treatment with LASSBio-1359. MCT also induced endothelial dysfunction in pulmonary artery, as measured by diminished relaxation of pre-contracted arterial rings, and this dysfunction was reversed by LASSBio-1359. In pulmonary artery rings from normal Wistar rats, LASSBio-1359 induced relaxation, which was decreased by the adenosine A2A receptor antagonist, ZM 241385. In adenosine receptor binding studies, LASSBio-1359 showed most affinity for the A2A receptor and in the docking analyses, binding modes of LASSBio-1359 and the A2A receptor agonist, CGS21680, were very similar. Conclusion and Implications In rats with MCT-induced PAH, structural and functional changes in heart and pulmonary artery were reversed by treatment with oral LASSBio-1359, most probably through the activation of adenosine A2A receptors. PMID:23530610

  18. Effects of Single Drug and Combined Short-term Administration of Sildenafil, Pimobendan, and Nicorandil on Right Ventricular Function in Rats With Monocrotaline-induced Pulmonary Hypertension

    PubMed Central

    Tanaka, Ryou; Yoshiyuki, Rieko; Fukayama, Toshiharu; Goya, Seijiro; Fukushima, Ryuji

    2015-01-01

    Abstract: This study was designed to assess the progression of pulmonary arterial hypertension (PAH) and the effectiveness of therapy using recently investigated echocardiographic parameters. PAH is characterized by the progressive elevation of pulmonary artery pressure and right ventricular hypertrophy and dysfunction, which ultimately results in right-sided heart failure and death. Echocardiography results and invasive measurements of right and left ventricular systolic pressures were compared after 3-week administrations of sildenafil (S group), pimobendan (P group), nicorandil (N group), and their combinations (SP and SPN groups) in male rats with monocrotaline (MCT)-induced pulmonary hypertension (M group) and without this condition (C group). The groups that received pimobendan alone and in combinations (SP and SPN groups) showed improvement in their echocardiographic parameters of systolic function. A significant improvement of diastolic function was achieved in the SPN group. Invasive measurements showed the most significant decreases of right ventricular systolic pressure in the N and SPN groups, and the use of pimobendan resulted in a comparatively low risk of adverse hemodynamic effects (left ventricular systolic pressure). Although our results suggested the attenuation of PAH severity in all treatment groups, PAH could not be reversed. PMID:25806612

  19. Effects of Single Drug and Combined Short-term Administration of Sildenafil, Pimobendan, and Nicorandil on Right Ventricular Function in Rats With Monocrotaline-induced Pulmonary Hypertension.

    PubMed

    Nakata, Telma M; Tanaka, Ryou; Yoshiyuki, Rieko; Fukayama, Toshiharu; Goya, Seijiro; Fukushima, Ryuji

    2015-06-01

    This study was designed to assess the progression of pulmonary arterial hypertension (PAH) and the effectiveness of therapy using recently investigated echocardiographic parameters. PAH is characterized by the progressive elevation of pulmonary artery pressure and right ventricular hypertrophy and dysfunction, which ultimately results in right-sided heart failure and death. Echocardiography results and invasive measurements of right and left ventricular systolic pressures were compared after 3-week administrations of sildenafil (S group), pimobendan (P group), nicorandil (N group), and their combinations (SP and SPN groups) in male rats with monocrotaline (MCT)-induced pulmonary hypertension (M group) and without this condition (C group). The groups that received pimobendan alone and in combinations (SP and SPN groups) showed improvement in their echocardiographic parameters of systolic function. A significant improvement of diastolic function was achieved in the SPN group. Invasive measurements showed the most significant decreases of right ventricular systolic pressure in the N and SPN groups, and the use of pimobendan resulted in a comparatively low risk of adverse hemodynamic effects (left ventricular systolic pressure). Although our results suggested the attenuation of PAH severity in all treatment groups, PAH could not be reversed.

  20. Liraglutide prevents and reverses monocrotaline-induced pulmonary arterial hypertension by suppressing ET-1 and enhancing eNOS/sGC/PKG pathways.

    PubMed

    Lee, Mei-Yueh; Tsai, Kun-Bow; Hsu, Jong-Hau; Shin, Shyi-Jang; Wu, Jiunn-Ren; Yeh, Jwu-Lai

    2016-01-01

    Liraglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, is widely used to treat diabetes. However, its effect on pulmonary arterial hypertension (PAH) is unknown. In this study, we investigated its effects on rats with monocrotaline (MCT)-induced PAH and mechanisms on rat pulmonary artery smooth muscle cells (PASMCs). Liraglutide was investigated for both prevention and treatment of MCT-induced PAH. The hemodynamic and body weight changes, right heart hypertrophy, lung morphology, immune-reactivity of endothelial nitric oxide synthase (eNOS), endothelin-1 and cyclic guanosine monophosphate (cGMP) levels, protein expressions of eNOS, soluble guanylyl cyclase (sGCα), protein kinase G (PKG) and Rho kinase (ROCK) II pathway were measured in both in vivo and in vitro. Cell migration and cell cycle were also determined. Liraglutide both prevented and reversed MCT-induced PAH, right ventricle hypertrophy and pulmonary vascular wall remodeling. Protein expression of ROCK II was increased while eNOS, sGC and PKG were decreased. Pretreatment with liraglutide inhibited platelet-derived growth factor (PDGF)-BB stimulated PASMCs migration, which were associated with cell-cycle arrest at G0/G1 phase. Liraglutide may have both preventive and therapeutic effects on MCT-induced PAH, through the eNOS/sGC/PKG and Rho kinase pathways. Thus, liraglutide may have a therapeutic role in pulmonary vascular remodelling. PMID:27581840

  1. Liraglutide prevents and reverses monocrotaline-induced pulmonary arterial hypertension by suppressing ET-1 and enhancing eNOS/sGC/PKG pathways

    PubMed Central

    Lee, Mei-Yueh; Tsai, Kun-Bow; Hsu, Jong-Hau; Shin, Shyi-Jang; Wu, Jiunn-Ren; Yeh, Jwu-Lai

    2016-01-01

    Liraglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, is widely used to treat diabetes. However, its effect on pulmonary arterial hypertension (PAH) is unknown. In this study, we investigated its effects on rats with monocrotaline (MCT)-induced PAH and mechanisms on rat pulmonary artery smooth muscle cells (PASMCs). Liraglutide was investigated for both prevention and treatment of MCT-induced PAH. The hemodynamic and body weight changes, right heart hypertrophy, lung morphology, immune-reactivity of endothelial nitric oxide synthase (eNOS), endothelin-1 and cyclic guanosine monophosphate (cGMP) levels, protein expressions of eNOS, soluble guanylyl cyclase (sGCα), protein kinase G (PKG) and Rho kinase (ROCK) II pathway were measured in both in vivo and in vitro. Cell migration and cell cycle were also determined. Liraglutide both prevented and reversed MCT-induced PAH, right ventricle hypertrophy and pulmonary vascular wall remodeling. Protein expression of ROCK II was increased while eNOS, sGC and PKG were decreased. Pretreatment with liraglutide inhibited platelet-derived growth factor (PDGF)-BB stimulated PASMCs migration, which were associated with cell-cycle arrest at G0/G1 phase. Liraglutide may have both preventive and therapeutic effects on MCT-induced PAH, through the eNOS/sGC/PKG and Rho kinase pathways. Thus, liraglutide may have a therapeutic role in pulmonary vascular remodelling. PMID:27581840

  2. Liraglutide prevents and reverses monocrotaline-induced pulmonary arterial hypertension by suppressing ET-1 and enhancing eNOS/sGC/PKG pathways.

    PubMed

    Lee, Mei-Yueh; Tsai, Kun-Bow; Hsu, Jong-Hau; Shin, Shyi-Jang; Wu, Jiunn-Ren; Yeh, Jwu-Lai

    2016-09-01

    Liraglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, is widely used to treat diabetes. However, its effect on pulmonary arterial hypertension (PAH) is unknown. In this study, we investigated its effects on rats with monocrotaline (MCT)-induced PAH and mechanisms on rat pulmonary artery smooth muscle cells (PASMCs). Liraglutide was investigated for both prevention and treatment of MCT-induced PAH. The hemodynamic and body weight changes, right heart hypertrophy, lung morphology, immune-reactivity of endothelial nitric oxide synthase (eNOS), endothelin-1 and cyclic guanosine monophosphate (cGMP) levels, protein expressions of eNOS, soluble guanylyl cyclase (sGCα), protein kinase G (PKG) and Rho kinase (ROCK) II pathway were measured in both in vivo and in vitro. Cell migration and cell cycle were also determined. Liraglutide both prevented and reversed MCT-induced PAH, right ventricle hypertrophy and pulmonary vascular wall remodeling. Protein expression of ROCK II was increased while eNOS, sGC and PKG were decreased. Pretreatment with liraglutide inhibited platelet-derived growth factor (PDGF)-BB stimulated PASMCs migration, which were associated with cell-cycle arrest at G0/G1 phase. Liraglutide may have both preventive and therapeutic effects on MCT-induced PAH, through the eNOS/sGC/PKG and Rho kinase pathways. Thus, liraglutide may have a therapeutic role in pulmonary vascular remodelling.

  3. C-122, a novel antagonist of serotonin receptor 5-HT2B, prevents monocrotaline-induced pulmonary arterial hypertension in rats.

    PubMed

    Zopf, David A; das Neves, Liomar A A; Nikula, Kristen J; Huang, Jinbao; Senese, Peter B; Gralinski, Michael R

    2011-11-16

    Pulmonary arterial hypertension (PAH) is a chronic disease characterized by sustained elevation of pulmonary arterial pressure that leads to right ventricle failure and death. Pulmonary resistance arterioles in PAH undergo progressive narrowing and/or occlusion. Currently approved therapies for PAH are directed primarily at relief of symptoms by interfering with vasoconstrictive signals, but do not halt the microvascular cytoproliferative process. In this study we show that C-122 (2-amino-N-(2-{4-[3-(2-trifluoromethyl-phenothiazin-10-yl)-propyl]-piperazin-1-yl}-ethyl)-acetamide trihydrochloride, a novel antagonist of serotonin receptor 5-HT(2B) (Ki=5.2 nM, IC(50)=6.9 nM), when administered to rats for three weeks in daily oral 10mg/kg doses, prevents not only monocrotaline (MCT)-induced elevations in pressure in the pulmonary arterial circuit (19 ± 0.9 mmHg vs. 28 ± 2 mmHg in MCT-vehicle group, P<0.05) and hypertrophy of the right ventricle (right ventricular wt./body wt. ratio 0.52 ± 0.02 vs. 0.64 ± 0.04 in MCT-vehicle group, P<0.05), but also muscularization of pulmonary arterioles (23% vs. 56% fully muscularized in MCT-vehicle group, P<0.05), and perivascular fibrosis in the lung. C-122 is orally absorbed in the rat, and partitions strongly into multiple tissues, including heart and lung. C-122 has significant off-target antagonist activity for histamine H-1 and several dopamine receptors, but shows no evidence of crossing the blood-brain barrier after a single 10mg/kg oral dose in rats. We conclude that C-122 can prevent microvascular remodeling and associated elevated pressures in the rat MCT model for PAH, and offers promise as a new therapeutic entity to suppress vascular smooth muscle cell proliferation in PAH patients.

  4. Activation of AMPK Prevents Monocrotaline-Induced Extracellular Matrix Remodeling of Pulmonary Artery

    PubMed Central

    Li, Shaojun; Han, Dong; Zhang, Yonghong; Xie, Xinming; Ke, Rui; Zhu, Yanting; Liu, Lu; Song, Yang; Yang, Lan; Li, Manxiang

    2016-01-01

    Background The current study was performed to investigate the effect of adenosine monophosphate (AMP) – activated protein kinase (AMPK) activation on the extracellular matrix (ECM) remodeling of pulmonary arteries in pulmonary arterial hypertension (PAH) and to address its potential mechanisms. Material/Methods PAH was induced by a single intraperitoneal injection of monocrotaline (MCT) into Sprague-Dawley rats. Metformin (MET) was administered to activate AMPK. Immunoblotting was used to determine the phosphorylation and expression of AMPK and expression of tissue inhibitor of metalloproteinase-1 (TIMP-1). Gelatin zymography was performed to determine the activity of matrix metalloproteinase-2 (MMP-2) and MMP-9. Results Activation of AMPK by MET significantly reduced the right ventricle systolic pressure and the right ventricular hypertrophy in MCT-induced rat PAH model, and partially inhibited the ECM remodeling of pulmonary arteries. These effects were coupled with the decrease of MMP-2/9 activity and TIMP-1 expression. Conclusions This study suggests that activation of AMPK benefits PAH by inhibiting ECM remodeling of pulmonary arteries. Enhancing AMPK activity might have potential value in clinical treatment of PAH. PMID:26978596

  5. Pulmonary Hypertension

    PubMed Central

    Newman, John H.

    2005-01-01

    The modern era in cardiopulmonary medicine began in the 1940s, when Cournand and Richards pioneered right-heart catheterization. Until that time, no direct measurement of central vascular pressure had been performed in humans. Right-heart catheterization ignited an explosion of insights into function and dysfunction of the pulmonary circulation, cardiac performance, ventilation–perfusion relationships, lung–heart interactions, valvular function, and congenital heart disease. It marked the beginnings of angiocardiography with its diagnostic implications for diseases of the left heart and peripheral circulation. Pulmonary hypertension was discovered to be the consequence of a large variety of diseases that either raised pressure downstream of the pulmonary capillaries, induced vasoconstriction, increased blood flow to the lung, or obstructed the pulmonary vessels, either by embolism or in situ fibrosis. Hypoxic vasoconstriction was found to be a major cause of acute and chronic pulmonary hypertension, and surprising vasoreactivity of the pulmonary vascular bed was discovered to be present in many cases of severe pulmonary hypertension, initially in mitral stenosis. Diseases as disparate as scleroderma, cystic fibrosis, kyphoscoliosis, sleep apnea, and sickle cell disease were found to have shared consequences in the pulmonary circulation. Some of the achievements of Cournand and Richards and their scientific descendents are discussed in this article, including success in the diagnosis and treatment of idiopathic pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension, and management of hypoxic pulmonary hypertension. PMID:15994464

  6. Pulmonary Hypertension

    MedlinePlus

    Pulmonary hypertension (PH) is high blood pressure in the arteries to your lungs. It is a serious condition. If you have ... and you can develop heart failure. Symptoms of PH include Shortness of breath during routine activity, such ...

  7. Types of Pulmonary Hypertension

    MedlinePlus

    ... from the NHLBI on Twitter. Types of Pulmonary Hypertension The World Health Organization divides pulmonary hypertension (PH) ... are called pulmonary hypertension.) Group 1 Pulmonary Arterial Hypertension Group 1 PAH includes: PAH that has no ...

  8. Pulmonary Arterial Hypertension

    MedlinePlus

    ... What Is Pulmonary Hypertension? To understand pulmonary hypertension (PH) it helps to understand how blood ows throughout ... is too high, it is called pulmonary hypertension (PH). How the pressure in the right side of ...

  9. What Causes Pulmonary Hypertension?

    MedlinePlus

    ... from the NHLBI on Twitter. What Causes Pulmonary Hypertension? Pulmonary hypertension (PH) begins with inflammation and changes in the ... different types of PH. Group 1 pulmonary arterial hypertension (PAH) may have no known cause, or the ...

  10. Calpain mediates pulmonary vascular remodeling in rodent models of pulmonary hypertension, and its inhibition attenuates pathologic features of disease.

    PubMed

    Ma, Wanli; Han, Weihong; Greer, Peter A; Tuder, Rubin M; Toque, Haroldo A; Wang, Kevin K W; Caldwell, R William; Su, Yunchao

    2011-11-01

    Pulmonary hypertension is a severe and progressive disease, a key feature of which is pulmonary vascular remodeling. Several growth factors, including EGF, PDGF, and TGF-β1, are involved in pulmonary vascular remodeling during pulmonary hypertension. However, increased knowledge of the downstream signaling cascades is needed if effective clinical interventions are to be developed. In this context, calpain provides an interesting candidate therapeutic target, since it is activated by EGF and PDGF and has been reported to activate TGF-β1. Thus, in this study, we examined the role of calpain in pulmonary vascular remodeling in two rodent models of pulmonary hypertension. These data showed that attenuated calpain activity in calpain-knockout mice or rats treated with a calpain inhibitor resulted in prevention of increased right ventricular systolic pressure, right ventricular hypertrophy, as well as collagen deposition and thickening of pulmonary arterioles in models of hypoxia- and monocrotaline-induced pulmonary hypertension. Additionally, inhibition of calpain in vitro blocked intracellular activation of TGF-β1, which led to attenuated Smad2/3 phosphorylation and collagen synthesis. Finally, smooth muscle cells of pulmonary arterioles from patients with pulmonary arterial hypertension showed higher levels of calpain activation and intracellular active TGF-β. Our data provide evidence that calpain mediates EGF- and PDGF-induced collagen synthesis and proliferation of pulmonary artery smooth muscle cells via an intracrine TGF-β1 pathway in pulmonary hypertension. PMID:22005303

  11. Protection by oestradiol against the development of cardiovascular changes associated with monocrotaline pulmonary hypertension in rats.

    PubMed Central

    Farhat, M. Y.; Chen, M. F.; Bhatti, T.; Iqbal, A.; Cathapermal, S.; Ramwell, P. W.

    1993-01-01

    1. We studied the effects of oestradiol 17 beta on the development of pulmonary vascular changes and right ventricular (RV) hypertrophy in response to monocrotaline in male Sprague-Dawley rats. 2. Rats were treated with either placebo or oestradiol 17 beta (10 mg) in the form of slow release pellets implanted subcutaneously 48 h before monocrotaline administration. Rats were injected with either saline or a single dose of monocrotaline (60 mg kg-1, i.m.). Pulmonary vascular changes and RV hypertrophy were studied at 4 weeks following monocrotaline administration. 3. Monocrotaline induced a significant increase in the ratio of right ventricle (RV) to left ventricle-plus-septum (LV + S) weights. Monocrotaline-treated rats also showed significant myointimal proliferation in small pulmonary arteries, decrease of arterial numbers and increase in the number of abnormal alveolar macrophages. 4. Oestradiol 17 beta attenuated myointimal hyperplasia in pulmonary vessels, decreased the RV/(LV + S) ratio in monocrotaline-treated rats. Oestradiol 17 beta had no significant effect on control animals. 5. Oestradiol treatment prevented the increase in lung wet to dry weight ratio, observed 7 days post monocrotaline administration. 6. These results suggest that oestradiol 17 beta protects against the pulmonary vascular remodelling and RV hypertrophy associated with monocrotaline-induced pulmonary hypertension in the rat. Oestradiol also protects against microvascular leak observed in the early days of lesion. Images Figure 2 PMID:8242243

  12. Fractal Dimension in Quantifying Experimental-Pulmonary-Hypertension-Induced Cardiac Dysfunction in Rats

    PubMed Central

    Pacagnelli, Francis Lopes; Sabela, Ana Karênina Dias de Almeida; Mariano, Thaoan Bruno; Ozaki, Guilherme Akio Tamura; Castoldi, Robson Chacon; do Carmo, Edna Maria; Carvalho, Robson Francisco; Tomasi, Loreta Casquel; Okoshi, Katashi; Vanderlei, Luiz Carlos Marques

    2016-01-01

    Background Right-sided heart failure has high morbidity and mortality, and may be caused by pulmonary arterial hypertension. Fractal dimension is a differentiated and innovative method used in histological evaluations that allows the characterization of irregular and complex structures and the quantification of structural tissue changes. Objective To assess the use of fractal dimension in cardiomyocytes of rats with monocrotaline-induced pulmonary arterial hypertension, in addition to providing histological and functional analysis. Methods Male Wistar rats were divided into 2 groups: control (C; n = 8) and monocrotaline-induced pulmonary arterial hypertension (M; n = 8). Five weeks after pulmonary arterial hypertension induction with monocrotaline, echocardiography was performed and the animals were euthanized. The heart was dissected, the ventricles weighed to assess anatomical parameters, and histological slides were prepared and stained with hematoxylin/eosin for fractal dimension analysis, performed using box-counting method. Data normality was tested (Shapiro-Wilk test), and the groups were compared with non-paired Student t test or Mann Whitney test (p < 0.05). Results Higher fractal dimension values were observed in group M as compared to group C (1.39 ± 0.05 vs. 1.37 ± 0.04; p < 0.05). Echocardiography showed lower pulmonary artery flow velocity, pulmonary acceleration time and ejection time values in group M, suggesting function worsening in those animals. Conclusion The changes observed confirm pulmonary-arterial-hypertension-induced cardiac dysfunction, and point to fractal dimension as an effective method to evaluate cardiac morphological changes induced by ventricular dysfunction. PMID:27223643

  13. Serotonylated fibronectin is elevated in pulmonary hypertension

    PubMed Central

    Wei, Lin; Warburton, Rod R.; Preston, Ioana R.; Roberts, Kari E.; Comhair, Suzy A. A.; Erzurum, Serpil C.; Hill, Nicholas S.

    2012-01-01

    Serotonin (5-HT) and fibronectin (FN) have been associated with pulmonary hypertension (PH). We previously reported that FN is posttranslationally modified by tissue transglutaminase (TGase) to form serotonylated FN (s-FN) in pulmonary artery smooth muscle cells and that serotonylation stimulates their proliferation and migration, hallmarks of PH. We hypothesized that s-FN and its binding to TGase are elevated in human and experimental PH. To assess this hypothesis, FN isolation and electrophoretic, immunoblotting, and densitometric techniques were used. Mean ratio of serum s-FN to total FN level (s-FN/FN) was elevated in 19 consecutive pulmonary arterial hypertension (PAH) patients compared with 25 controls (0.3 ± 0.18 vs. 0.05 ± 0.07, P < 0.001). s-FN/FN also was increased in lungs of mice and rats with hypoxia-induced PH and in rats with monocrotaline-induced PH. In mice, the increase was detected at 1 wk of hypoxia, preceding the development of PH. Hypoxic rats had elevated serum s-FN/FN. Enhanced binding of TGase to its substrate FN occurred in serum from patients with PAH (mean 0.50 ± 0.51 vs. 0.063 ± 0.11, P = 0.002) and s-FN/FN and TGase-bound FN were highly correlated (R2 = 0.77). TGase-bound FN also was increased in experimental PH. We conclude that increased serotonylation of FN occurs in human and experimental PH and may provide a biomarker for the disease. PMID:22523280

  14. Pulmonary hypertension

    MedlinePlus

    ... that damage the lungs, such as scleroderma and rheumatoid arthritis Birth defects of the heart Blood clots in the lung ( pulmonary embolism ) Heart failure Heart valve disease HIV infection Low oxygen levels in the blood ...

  15. How Is Pulmonary Hypertension Diagnosed?

    MedlinePlus

    ... from the NHLBI on Twitter. How Is Pulmonary Hypertension Diagnosed? Your doctor will diagnose pulmonary hypertension (PH) ... To Look for the Underlying Cause of Pulmonary Hypertension PH has many causes, so many tests may ...

  16. What Is Pulmonary Hypertension?

    MedlinePlus

    ... Pressure Tools & Resources Stroke More What is Pulmonary Hypertension? Updated:Aug 12,2014 Is pulmonary hypertension different ... content was last reviewed on 08/04/2014. High Blood Pressure • Home • About High Blood Pressure (HBP) Introduction What ...

  17. miR-223 reverses experimental pulmonary arterial hypertension.

    PubMed

    Meloche, Jolyane; Le Guen, Marie; Potus, François; Vinck, Jérôme; Ranchoux, Benoit; Johnson, Ian; Antigny, Fabrice; Tremblay, Eve; Breuils-Bonnet, Sandra; Perros, Frederic; Provencher, Steeve; Bonnet, Sébastien

    2015-09-15

    Pulmonary arterial hypertension (PAH) is a devastating disease affecting lung vasculature. The pulmonary arteries become occluded due to increased proliferation and suppressed apoptosis of the pulmonary artery smooth muscle cells (PASMCs) within the vascular wall. It was recently shown that DNA damage could trigger this phenotype by upregulating poly(ADP-ribose)polymerase 1 (PARP-1) expression, although the exact mechanism remains unclear. In silico analyses and studies in cancer demonstrated that microRNA miR-223 targets PARP-1. We thus hypothesized that miR-223 downregulation triggers PARP-1 overexpression, as well as the proliferation/apoptosis imbalance observed in PAH. We provide evidence that miR-223 is downregulated in human PAH lungs, distal PAs, and isolated PASMCs. Furthermore, using a gain and loss of function approach, we showed that increased hypoxia-inducible factor 1α, which is observed in PAH, triggers this decrease in miR-223 expression and subsequent overexpression of PARP-1 allowing PAH-PASMC proliferation and resistance to apoptosis. Finally, we demonstrated that restoring the expression of miR-223 in lungs of rats with monocrotaline-induced PAH reversed established PAH and provided beneficial effects on vascular remodeling, pulmonary resistance, right ventricle hypertrophy, and survival. We provide evidence that miR-223 downregulation in PAH plays an important role in numerous pathways implicated in the disease and restoring its expression is able to reverse PAH. PMID:26084306

  18. Physiological mechanisms of pulmonary hypertension.

    PubMed

    MacIver, David H; Adeniran, Ismail; MacIver, Iain R; Revell, Alistair; Zhang, Henggui

    2016-10-01

    Pulmonary hypertension is usually related to obstruction of pulmonary blood flow at the level of the pulmonary arteries (eg, pulmonary embolus), pulmonary arterioles (idiopathic pulmonary hypertension), pulmonary veins (pulmonary venoocclusive disease) or mitral valve (mitral stenosis and regurgitation). Pulmonary hypertension is also observed in heart failure due to left ventricle myocardial diseases regardless of the ejection fraction. Pulmonary hypertension is often regarded as a passive response to the obstruction to pulmonary flow. We review established fluid dynamics and physiology and discuss the mechanisms underlying pulmonary hypertension. The important role that the right ventricle plays in the development and maintenance of pulmonary hypertension is discussed. We use principles of thermodynamics and discuss a potential common mechanism for a number of disease states, including pulmonary edema, through adding pressure energy to the pulmonary circulation. PMID:27659877

  19. [Pulmonary hypertension: current aspects].

    PubMed

    Tello de Meneses, R; Gómez Sánchez, M A; Delgado Jiménez, J; Gómez Pajuelo, C; Sáenz de la Calzada, C; Zarco Gutiérrez, P

    1996-08-01

    Primary pulmonary hypertension, although less frequent than secondary forms, represents the true paradigm of this disease. The recent investigations on pulmonary vascular response mechanisms to different stimuli has increased our knowledge about the mechanism of high pulmonary pressure. Molecular biology of the endothelial cell has provided evidence that endothelial injury plus a genetic individual predisposition may be the pathogenic mainstream of this disease. The histologic findings of pulmonary hypertension are still a matter of controversy, although the clinical, epidemiological and prognostic features are better defined. Therapeutically, there has been important advances, specially with various vasodilators, like calciumantagonists, prostacyclin, adenosine and nitric oxide, as well as new routes of administration. In more advance stages of the disease, atrial septostomy (only paliative) and pulmonary or cardio-pulmonary transplantation, are other therapeutic options to consider, after an adequate selection of patients.

  20. Pulmonary hypertension imitating HELLP syndrome

    PubMed Central

    2013-01-01

    A case of undiagnosed pulmonary hypertension in a woman with mixed connective tissue disease presenting with microangiopathic haemolysis, thrombocytopenia and elevated liver enzymes imitating severe preeclampsia (HELLP syndrome) is described. Connective tissue disorders are associated with an increased prevalence of pulmonary hypertension. Maternal mortality rates with pulmonary hypertension in pregnancy are extremely high. All women with connective tissue disorders should have pulmonary hypertension excluded by echocardiography before attempting conception. End-stage pulmonary hypertension may be associated with haemolysis and thrombocytopenia and thus may imitate severe preeclampsia in pregnant women. There may be a role for extracorporeal membrane oxygenation in the peripartum management of women with severe pulmonary hypertension. PMID:27656251

  1. Pulmonary hypertension imitating HELLP syndrome

    PubMed Central

    2013-01-01

    A case of undiagnosed pulmonary hypertension in a woman with mixed connective tissue disease presenting with microangiopathic haemolysis, thrombocytopenia and elevated liver enzymes imitating severe preeclampsia (HELLP syndrome) is described. Connective tissue disorders are associated with an increased prevalence of pulmonary hypertension. Maternal mortality rates with pulmonary hypertension in pregnancy are extremely high. All women with connective tissue disorders should have pulmonary hypertension excluded by echocardiography before attempting conception. End-stage pulmonary hypertension may be associated with haemolysis and thrombocytopenia and thus may imitate severe preeclampsia in pregnant women. There may be a role for extracorporeal membrane oxygenation in the peripartum management of women with severe pulmonary hypertension.

  2. [Chronic thromboembolic pulmonary hypertension].

    PubMed

    Kim, Nick H; Delcroix, Marion; Jenkins, David P; Channick, Richard; Dartevelle, Philippe; Jansa, Pavel; Lang, Irene; Madani, Michael M; Ogino, Hitoshi; Pengo, Vittorio; Mayer, Eckhard

    2014-10-01

    Since the last World Symposium on Pulmonary Hypertension in 2008, we have witnessed numerous and exciting developments in chronic thromboembolic pulmonary hypertension (CTEPH). Emerging clinical data and advances in technology have led to reinforcing and updated guidance on diagnostic approaches to pulmonary hypertension, guidelines that we hope will lead to better recognition and more timely diagnosis of CTEPH. We have new data on treatment practices across international boundaries as well as long-term outcomes for CTEPH patients treated with or without pulmonary endarterectomy. Furthermore, we have expanded data on alternative treatment options for select CTEPH patients, including data from multiple clinical trials of medical therapy, including 1 recent pivotal trial, and compelling case series of percutaneous pulmonary angioplasty. Lastly, we have garnered more experience, and on a larger international scale, with pulmonary endarterectomy, which is the treatment of choice for operable CTEPH. This report overviews and highlights these important interval developments as deliberated among our task force of CTEPH experts and presented at the 2013 World Symposium on Pulmonary Hypertension in Nice, France. (J Am Coil Cardiol 2013;62:D92-9) ©2013 by the American College of Cardiology Foundation.

  3. [Chronic thromboembolic pulmonary hypertension].

    PubMed

    Zonzin, Pietro; Vizza, Carmine Dario; Favretto, Giuseppe

    2003-10-01

    Chronic thromboembolic pulmonary hypertension is due to unresolved or recurrent pulmonary embolism. In the United States the estimated prevalence is 0.1-0.5% among survived patients with pulmonary embolism. The survival rate at 5 years was 30% among patients with a mean pulmonary artery pressure > 40 mmHg at the time of diagnosis and only 10% among those with a value > 50 mmHg. The interval between the onset of disturbances and the diagnosis may be as long as 3 years. Doppler echocardiography permits to establish the diagnosis of pulmonary hypertension. Radionuclide scanning determines whether pulmonary hypertension has a thromboembolic basis. Right heart catheterization and pulmonary angiography are performed in order to establish the extension and the accessibility to surgery of thrombi and to rule out other causes. The surgical treatment is thromboendarterectomy. A dramatic reduction in the pulmonary vascular resistance can be achieved; corresponding improvements in the NYHA class--from class III or IV before surgery to class I-II after surgery--are usually observed. Patients who are not considered candidates for thromboendarterectomy may be considered candidates for lung transplantation. PMID:14664293

  4. Pulmonary hypertension and pulmonary artery dissection

    PubMed Central

    Corrêa, Ricardo de Amorim; Silva, Luciana Cristina dos Santos; Rezende, Cláudia Juliana; Bernardes, Rodrigo Castro; Prata, Tarciane Aline; Silva, Henrique Lima

    2013-01-01

    Pulmonary artery dissection is a fatal complication of long-standing pulmonary hypertension, manifesting as acute, stabbing chest pain, progressive dyspnea, cardiogenic shock, or sudden death. Its incidence has been underestimated, and therapeutic options are still scarce. In patients with pulmonary hypertension, new chest pain, acute chest pain, or cardiogenic shock should raise the suspicion of pulmonary artery dissection, which can result in sudden death. PMID:23670510

  5. Definition and classification of pulmonary hypertension.

    PubMed

    Humbert, Marc; Montani, David; Evgenov, Oleg V; Simonneau, Gérald

    2013-01-01

    Pulmonary hypertension is defined as an increase of mean pulmonary arterial pressure ≥25 mmHg at rest as assessed by right heart catheterization. According to different combinations of values of pulmonary wedge pressure, pulmonary vascular resistance and cardiac output, a hemodynamic classification of pulmonary hypertension has been proposed. Of major importance is the pulmonary wedge pressure which allows to distinguish pre-capillary (pulmonary wedge pressure ≤15 mmHg) and post-capillary (pulmonary wedge pressure >15 mmHg) pulmonary hypertension. Pre-capillary pulmonary hypertension includes the clinical groups 1 (pulmonary arterial hypertension), 3 (pulmonary hypertension due to lung diseases and/or hypoxia), 4 (chronic thrombo-embolic pulmonary hypertension) and 5 (pulmonary hypertension with unclear and/or multifactorial mechanisms). Post-capillary pulmonary hypertension corresponds to the clinical group 2 (pulmonary hypertension due to left heart diseases).

  6. EP3 receptor deficiency attenuates pulmonary hypertension through suppression of Rho/TGF-β1 signaling

    PubMed Central

    Lu, Ankang; Zuo, Caojian; He, Yuhu; Chen, Guilin; Piao, Lingjuan; Zhang, Jian; Xiao, Bing; Shen, Yujun; Tang, Juan; Kong, Deping; Alberti, Sara; Chen, Di; Zuo, Shenkai; Zhang, Qianqian; Yan, Shuai; Fei, Xiaochun; Yuan, Fei; Zhou, Bin; Duan, Shengzhong; Yu, Yu; Lazarus, Michael; Su, Yunchao; Breyer, Richard M.; Funk, Colin D.; Yu, Ying

    2015-01-01

    Pulmonary arterial hypertension (PAH) is commonly associated with chronic hypoxemia in disorders such as chronic obstructive pulmonary disease (COPD). Prostacyclin analogs are widely used in the management of PAH patients; however, clinical efficacy and long-term tolerability of some prostacyclin analogs may be compromised by concomitant activation of the E-prostanoid 3 (EP3) receptor. Here, we found that EP3 expression is upregulated in pulmonary arterial smooth muscle cells (PASMCs) and human distal pulmonary arteries (PAs) in response to hypoxia. Either pharmacological inhibition of EP3 or Ep3 deletion attenuated both hypoxia and monocrotaline-induced pulmonary hypertension and restrained extracellular matrix accumulation in PAs in rodent models. In a murine PAH model, Ep3 deletion in SMCs, but not endothelial cells, retarded PA medial thickness. Knockdown of EP3α and EP3β, but not EP3γ, isoforms diminished hypoxia-induced TGF-β1 activation. Expression of either EP3α or EP3β in EP3-deficient PASMCs restored TGF-β1 activation in response to hypoxia. EP3α/β activation in PASMCs increased RhoA-dependent membrane type 1 extracellular matrix metalloproteinase (MMP) translocation to the cell surface, subsequently activating pro–MMP-2 and promoting TGF-β1 signaling. Activation or disruption of EP3 did not influence PASMC proliferation. Together, our results indicate that EP3 activation facilitates hypoxia-induced vascular remodeling and pulmonary hypertension in mice and suggest EP3 inhibition as a potential therapeutic strategy for pulmonary hypertension. PMID:25664856

  7. Treatment of pulmonary hypertension

    PubMed Central

    Patel, Rajendrakumar; Aronow, Wilbert S.; Patel, Laxeshkumar; Gandhi, Kaushang; Desai, Harit; Kaul, Dhiraj; Sahgal, Sumir P.

    2012-01-01

    Summary Pulmonary arterial hypertension (PAH) is a chronic progressive disease of the pulmonary vasculature characterized by elevated pulmonary arterial pressure and secondary right ventricular failure. PAH is considered a life-threatening condition unless treated. This article provides a comprehensive review of controlled and uncontrolled trials to define the risk-benefit for different therapeutic options of this clinical disorder. Relevant published articles were identified through searches of the National Center for Biotechnology PubMed database. All therapeutic measures for PAH were discussed. Six drugs have been approved in the United States for the treatment of PAH. Extensive medical advancement has been achieved in treatment of PAH. However, none of the approved therapies have shown ability to cure the disease. New research should be performed to develop promising new therapies. PMID:22460104

  8. Genetics Home Reference: pulmonary arterial hypertension

    MedlinePlus

    ... Primary pulmonary hypertension 2 Primary pulmonary hypertension 3 Primary pulmonary hypertension 4 ClinicalTrials.gov (1 link) ClinicalTrials.gov Scientific articles on PubMed (1 link) PubMed OMIM (4 links) ...

  9. Pulmonary hypertension and hepatic cirrhosis.

    PubMed

    Téllez Villajos, L; Martínez González, J; Moreira Vicente, V; Albillos Martínez, A

    2015-01-01

    Pulmonary hypertension is a relatively common phenomenon in patients with hepatic cirrhosis and can appear through various mechanisms. The most characteristic scenario that binds portal and pulmonary hypertension is portopulmonary syndrome. However, hyperdynamic circulation, TIPS placement and heart failure can raise the mean pulmonary artery pressure without increasing the resistances. These conditions are not candidates for treatment with pulmonary vasodilators and require a specific therapy. A correct assessment of hemodynamic, ultrasound and clinical variables enables the differential diagnosis of each situation that produces pulmonary hypertension in patients with cirrhosis.

  10. Pulmonary arterial hypertension

    PubMed Central

    2013-01-01

    Pulmonary arterial hypertension (PAH) is a chronic and progressive disease leading to right heart failure and ultimately death if untreated. The first classification of PH was proposed in 1973. In 2008, the fourth World Symposium on PH held in Dana Point (California, USA) revised previous classifications. Currently, PH is devided into five subgroups. Group 1 includes patients suffering from idiopathic or familial PAH with or without germline mutations. Patients with a diagnosis of PAH should systematically been screened regarding to underlying mutations of BMPR2 gene (bone morphogenetic protein receptor type 2) or more rarely of ACVRL1 (activine receptor-like kinase type 1), ENG (endogline) or Smad8 genes. Pulmonary veno occusive disease and pulmonary capillary hemagiomatosis are individualized and designated as clinical group 1'. Group 2 'Pulmonary hypertension due to left heart diseases' is divided into three sub-groups: systolic dysfonction, diastolic dysfonction and valvular dysfonction. Group 3 'Pulmonary hypertension due to respiratory diseases' includes a heterogenous subgroup of respiratory diseases like PH due to pulmonary fibrosis, COPD, lung emphysema or interstitial lung disease for exemple. Group 4 includes chronic thromboembolic pulmonary hypertension without any distinction of proximal or distal forms. Group 5 regroup PH patients with unclear multifactorial mechanisms. Invasive hemodynamic assessment with right heart catheterization is requested to confirm the definite diagnosis of PH showing a resting mean pulmonary artery pressure (mPAP) of ≥ 25 mmHg and a normal pulmonary capillary wedge pressure (PCWP) of ≤ 15 mmHg. The assessment of PCWP may allow the distinction between pre-capillary and post-capillary PH (PCWP > 15 mmHg). Echocardiography is an important tool in the management of patients with underlying suspicion of PH. The European Society of Cardiology and the European Respiratory Society (ESC-ERS) guidelines specify its role

  11. Pulmonary arterial hypertension.

    PubMed

    Montani, David; Günther, Sven; Dorfmüller, Peter; Perros, Frédéric; Girerd, Barbara; Garcia, Gilles; Jaïs, Xavier; Savale, Laurent; Artaud-Macari, Elise; Price, Laura C; Humbert, Marc; Simonneau, Gérald; Sitbon, Olivier

    2013-01-01

    Pulmonary arterial hypertension (PAH) is a chronic and progressive disease leading to right heart failure and ultimately death if untreated. The first classification of PH was proposed in 1973. In 2008, the fourth World Symposium on PH held in Dana Point (California, USA) revised previous classifications. Currently, PH is devided into five subgroups. Group 1 includes patients suffering from idiopathic or familial PAH with or without germline mutations. Patients with a diagnosis of PAH should systematically been screened regarding to underlying mutations of BMPR2 gene (bone morphogenetic protein receptor type 2) or more rarely of ACVRL1 (activine receptor-like kinase type 1), ENG (endogline) or Smad8 genes. Pulmonary veno occusive disease and pulmonary capillary hemagiomatosis are individualized and designated as clinical group 1'. Group 2 'Pulmonary hypertension due to left heart diseases' is divided into three sub-groups: systolic dysfonction, diastolic dysfonction and valvular dysfonction. Group 3 'Pulmonary hypertension due to respiratory diseases' includes a heterogenous subgroup of respiratory diseases like PH due to pulmonary fibrosis, COPD, lung emphysema or interstitial lung disease for exemple. Group 4 includes chronic thromboembolic pulmonary hypertension without any distinction of proximal or distal forms. Group 5 regroup PH patients with unclear multifactorial mechanisms. Invasive hemodynamic assessment with right heart catheterization is requested to confirm the definite diagnosis of PH showing a resting mean pulmonary artery pressure (mPAP) of ≥ 25 mmHg and a normal pulmonary capillary wedge pressure (PCWP) of ≤ 15 mmHg. The assessment of PCWP may allow the distinction between pre-capillary and post-capillary PH (PCWP > 15 mmHg). Echocardiography is an important tool in the management of patients with underlying suspicion of PH. The European Society of Cardiology and the European Respiratory Society (ESC-ERS) guidelines specify its role

  12. Reduced immunoreactivities of B-type natriuretic peptide in pulmonary arterial hypertension rats after ranolazine treatment.

    PubMed

    Lee, Jae Chul; Kim, Kwan Chang; Choe, Soo Young; Hong, Young Mi

    2016-03-01

    Pulmonary arterial hypertension (PAH) is a severe pulmonary vascular disease characterized by sustained increase in the pulmonary arterial pressure and excessive thickening and remodeling of the distal small pulmonary arteries. During disease progression, structural remodeling of the right ventricular (RV) impairs pump function, creates pro-arrhythmic substrates and triggers for arrhythmias. Notably, RV failure and lethal arrhythmias are major contributors to cardiac death in PAH that are not directly addressed by currently available therapies. Ranolazine (RAN) is an anti-anginal, anti-ischemic drug that has cardioprotective effects of heart dysfunction. RAN also has anti-arrhythmic effects due to inhibition of the late sodium current in cardiomyocytes. Therefore, we hypothesized that RAN could reduce the mal-adaptive structural remodeling of the RV, and prevent triggered ventricular arrhythmias in the monocrotaline-induced rat model of PAH. RAN reduced ventricular hypertrophy, reduced levels of B-type natriuretic peptide, and decreased the expression of fibrosis. In addition, RAN prevented cardiovascular death in rat model of PAH. These results support the notion that RAN can improve the functional properties of the RV, highlighting its potential benefits in the setting of heart impairment. PMID:27051563

  13. Reduced immunoreactivities of B-type natriuretic peptide in pulmonary arterial hypertension rats after ranolazine treatment

    PubMed Central

    Lee, Jae Chul; Kim, Kwan Chang

    2016-01-01

    Pulmonary arterial hypertension (PAH) is a severe pulmonary vascular disease characterized by sustained increase in the pulmonary arterial pressure and excessive thickening and remodeling of the distal small pulmonary arteries. During disease progression, structural remodeling of the right ventricular (RV) impairs pump function, creates pro-arrhythmic substrates and triggers for arrhythmias. Notably, RV failure and lethal arrhythmias are major contributors to cardiac death in PAH that are not directly addressed by currently available therapies. Ranolazine (RAN) is an anti-anginal, anti-ischemic drug that has cardioprotective effects of heart dysfunction. RAN also has anti-arrhythmic effects due to inhibition of the late sodium current in cardiomyocytes. Therefore, we hypothesized that RAN could reduce the mal-adaptive structural remodeling of the RV, and prevent triggered ventricular arrhythmias in the monocrotaline-induced rat model of PAH. RAN reduced ventricular hypertrophy, reduced levels of B-type natriuretic peptide, and decreased the expression of fibrosis. In addition, RAN prevented cardiovascular death in rat model of PAH. These results support the notion that RAN can improve the functional properties of the RV, highlighting its potential benefits in the setting of heart impairment. PMID:27051563

  14. Vascular Remodeling in Pulmonary Hypertension

    PubMed Central

    Shimoda, Larissa A; Laurie, Steven S.

    2013-01-01

    Pulmonary hypertension is a complex, progressive condition arising from a variety of genetic and pathogenic causes. Patients present with a spectrum of histologic and pathophysiological features, likely reflecting the diversity in underlying pathogenesis. It is widely recognized that structural alterations in the vascular wall contribute to all forms of pulmonary hypertension. Features characteristic of the remodeled vasculature in patients with pulmonary hypertension include increased stiffening of the elastic proximal pulmonary arteries, thickening of the intimal and/or medial layer of muscular arteries, development of vaso-occlusive lesions and the appearance of cells expressing smooth muscle specific markers in normally non-muscular small diameter vessels, resulting from proliferation and migration of pulmonary arterial smooth muscle cells and cellular trans-differentiation. The development of several animal models of pulmonary hypertension has provided the means to explore the mechanistic underpinnings of pulmonary vascular remodeling, although none of the experimental models currently used entirely replicates the pulmonary arterial hypertension observed in patients. Herein, we provide an overview of the histological abnormalities observed in humans with pulmonary hypertension and in preclinical models and discuss insights gained regarding several key signaling pathways contributing to the remodeling process. In particular, we will focus on the roles of ion homeostasis, endothelin-1, serotonin, bone morphogenetic proteins, Rho kinase and hypoxia-inducible factor 1 in pulmonary arterial smooth muscle and endothelial cells, highlighting areas of cross-talk between these pathways and potentials for therapeutic targeting. PMID:23334338

  15. Distal vessel stiffening is an early and pivotal mechanobiological regulator of vascular remodeling and pulmonary hypertension

    PubMed Central

    Liu, Fei; Haeger, Christina Mallarino; Dieffenbach, Paul B.; Sicard, Delphine; Chrobak, Izabela; Coronata, Anna Maria F.; Velandia, Margarita M. Suárez; Vitali, Sally; Colas, Romain A.; Norris, Paul C.; Marinković, Aleksandar; Liu, Xiaoli; Ma, Jun; Rose, Chase D.; Lee, Seon-Jin; Comhair, Suzy A.A.; Erzurum, Serpil C.; McDonald, Jacob D.; Serhan, Charles N.; Walsh, Stephen R.; Tschumperlin, Daniel J.; Fredenburgh, Laura E.

    2016-01-01

    Pulmonary arterial (PA) stiffness is associated with increased mortality in patients with pulmonary hypertension (PH); however, the role of PA stiffening in the pathogenesis of PH remains elusive. Here, we show that distal vascular matrix stiffening is an early mechanobiological regulator of experimental PH. We identify cyclooxygenase-2 (COX-2) suppression and corresponding reduction in prostaglandin production as pivotal regulators of stiffness-dependent vascular cell activation. Atomic force microscopy microindentation demonstrated early PA stiffening in experimental PH and human lung tissue. Pulmonary artery smooth muscle cells (PASMC) grown on substrates with the stiffness of remodeled PAs showed increased proliferation, decreased apoptosis, exaggerated contraction, enhanced matrix deposition, and reduced COX-2–derived prostanoid production compared with cells grown on substrates approximating normal PA stiffness. Treatment with a prostaglandin I2 analog abrogated monocrotaline-induced PA stiffening and attenuated stiffness-dependent increases in proliferation, matrix deposition, and contraction in PASMC. Our results suggest a pivotal role for early PA stiffening in PH and demonstrate the therapeutic potential of interrupting mechanobiological feedback amplification of vascular remodeling in experimental PH. PMID:27347562

  16. Pulmonary Hypertension: Diagnosis and Treatment.

    PubMed

    Dunlap, Beth; Weyer, George

    2016-09-15

    Pulmonary hypertension is a common, complex group of disorders that result from different pathophysiologic mechanisms but are all defined by a mean pulmonary arterial pressure of 25 mm Hg or greater. Patients often initially present to family physicians; however, because the symptoms are typically nonspecific or easily attributable to comorbid conditions, diagnosis can be challenging and requires a stepwise evaluation. There is limited evidence to support screening of asymptomatic individuals. Echocardiography is recommended as the initial step in the evaluation of patients with suspected pulmonary hypertension. A definitive diagnosis cannot be made on echocardiographic abnormalities alone, and some patients require invasive evaluation by right heart catheterization. For certain categories of pulmonary hypertension, particularly pulmonary arterial hypertension, treatment options are rapidly evolving, and early diagnosis and prompt referral to an expert center are critical to ensure the best prognosis. There are no directed therapies for many other categories of pulmonary hypertension; therefore, family physicians have a central role in managing contributing comorbidities. Other important considerations for patients with pulmonary hypertension include influenza and pneumonia immunizations, contraception counseling, preoperative assessment, and mental health. PMID:27637122

  17. Microarray analysis in pulmonary hypertension.

    PubMed

    Hoffmann, Julia; Wilhelm, Jochen; Olschewski, Andrea; Kwapiszewska, Grazyna

    2016-07-01

    Microarrays are a powerful and effective tool that allows the detection of genome-wide gene expression differences between controls and disease conditions. They have been broadly applied to investigate the pathobiology of diverse forms of pulmonary hypertension, namely group 1, including patients with idiopathic pulmonary arterial hypertension, and group 3, including pulmonary hypertension associated with chronic lung diseases such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. To date, numerous human microarray studies have been conducted to analyse global (lung homogenate samples), compartment-specific (laser capture microdissection), cell type-specific (isolated primary cells) and circulating cell (peripheral blood) expression profiles. Combined, they provide important information on development, progression and the end-stage disease. In the future, system biology approaches, expression of noncoding RNAs that regulate coding RNAs, and direct comparison between animal models and human disease might be of importance. PMID:27076594

  18. Microarray analysis in pulmonary hypertension

    PubMed Central

    Hoffmann, Julia; Wilhelm, Jochen; Olschewski, Andrea

    2016-01-01

    Microarrays are a powerful and effective tool that allows the detection of genome-wide gene expression differences between controls and disease conditions. They have been broadly applied to investigate the pathobiology of diverse forms of pulmonary hypertension, namely group 1, including patients with idiopathic pulmonary arterial hypertension, and group 3, including pulmonary hypertension associated with chronic lung diseases such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. To date, numerous human microarray studies have been conducted to analyse global (lung homogenate samples), compartment-specific (laser capture microdissection), cell type-specific (isolated primary cells) and circulating cell (peripheral blood) expression profiles. Combined, they provide important information on development, progression and the end-stage disease. In the future, system biology approaches, expression of noncoding RNAs that regulate coding RNAs, and direct comparison between animal models and human disease might be of importance. PMID:27076594

  19. Purinergic dysregulation in pulmonary hypertension.

    PubMed

    Visovatti, Scott H; Hyman, Matthew C; Goonewardena, Sascha N; Anyanwu, Anuli C; Kanthi, Yogendra; Robichaud, Patrick; Wang, Jintao; Petrovic-Djergovic, Danica; Rattan, Rahul; Burant, Charles F; Pinsky, David J

    2016-07-01

    Despite the fact that nucleotides and adenosine help regulate vascular tone through purinergic signaling pathways, little is known regarding their contributions to the pathobiology of pulmonary arterial hypertension, a condition characterized by elevated pulmonary vascular resistance and remodeling. Even less is known about the potential role that alterations in CD39 (ENTPD1), the ectonucleotidase responsible for the conversion of the nucleotides ATP and ADP to AMP, may play in pulmonary arterial hypertension. In this study we identified decreased CD39 expression on the pulmonary endothelium of patients with idiopathic pulmonary arterial hypertension. We next determined the effects of CD39 gene deletion in mice exposed to normoxia or normobaric hypoxia (10% oxygen). Compared with controls, hypoxic CD39(-/-) mice were found to have a markedly elevated ATP-to-adenosine ratio, higher pulmonary arterial pressures, more right ventricular hypertrophy, more arterial medial hypertrophy, and a pro-thrombotic phenotype. In addition, hypoxic CD39(-/-) mice exhibited a marked increase in lung P2X1 receptors. Systemic reconstitution of ATPase and ADPase enzymatic activities through continuous administration of apyrase decreased pulmonary arterial pressures in hypoxic CD39(-/-) mice to levels found in hypoxic CD39(+/+) controls. Treatment with NF279, a potent and selective P2X1 receptor antagonist, lowered pulmonary arterial pressures even further. Our study is the first to implicate decreased CD39 and resultant alterations in circulating purinergic signaling ligands and cognate receptors in the pathobiology of pulmonary arterial hypertension. Reconstitution and receptor blocking experiments suggest that phosphohydrolysis of purinergic nucleotide tri- and diphosphates, or blocking of the P2X1 receptor could serve as treatment for pulmonary arterial hypertension. PMID:27208163

  20. Post splenectomy related pulmonary hypertension

    PubMed Central

    Palkar, Atul V; Agrawal, Abhinav; Verma, Sameer; Iftikhar, Asma; Miller, Edmund J; Talwar, Arunabh

    2015-01-01

    Splenectomy predisposes patients to a slew of infectious and non-infectious complications including pulmonary vascular disease. Patients are at increased risk for venous thromboembolic events due to various mechanisms that may lead to chronic thromboembolic pulmonary hypertension (CTEPH). The development of CTEPH and pulmonary vasculopathy after splenectomy involves complex pathophysiologic mechanisms, some of which remain unclear. This review attempts congregate the current evidence behind our understanding about the etio-pathogenesis of pulmonary vascular disease related to splenectomy and highlight the controversies that surround its management. PMID:26949600

  1. “Denervation” of autonomous nervous system in idiopathic pulmonary arterial hypertension by low-dose radiation: a case report with an unexpected outcome

    PubMed Central

    Hohenforst-Schmidt, Wolfgang; Zarogoulidis, Paul; Oezkan, Filiz; Mahnkopf, Christian; Grabenbauer, Gerhard; Kreczy, Alfons; Bartunek, Rudolf; Darwiche, Kaid; Freitag, Lutz; Li, Qiang; Huang, Haidong; Vogl, Thomas; LePilvert, Patrick; Tsiouda, Theodora; Tsakiridis, Kosmas; Zarogoulidis, Konstantinos; Brachmann, Johannes

    2014-01-01

    Vasointestinal peptide metabolism plays a key physiological role in multimodular levels of vasodilatory, smooth muscle cell proliferative, parenchymal, and inflammatory lung reactions. In animal studies, vasointestinal peptide relaxes isolated pulmonary arterial segments from several mammalian species in vitro and neutralizes the pulmonary vasoconstrictor effect of endothelin. In some animal models, it reduces pulmonary vascular resistance in vivo and in monocrotaline-induced pulmonary hypertension. A 58-year-old woman presented with dyspnea and mild edema of the lower extremities. A bronchoscopy was performed without any suspicious findings suggesting a central tumor or other infiltrative disease. Endobronchial ultrasound revealed enlarged pulmonary arteries containing thrombi, a few enlarged lymph nodes, and enlarged mediastinal tissue anatomy with suspicion for mediastinal infiltration of a malignant process. We estimated that less than 10% of the peripheral vascular bed of the lung was involved in direct consolidated fibrosis as demonstrated in the left upper lobe apex. Further, direct involvement of fibrosis around the main stems of the pulmonary arteries was assumed to be low from positron emission tomography and magnetic resonance imaging scans. Assuming a positive influence of low-dose radiation, it was not expected that this could have reduced pulmonary vascular resistance by over two thirds of the initial result. However; it was noted that this patient had idiopathic pulmonary arterial hypertension mixed with “acute” (mediastinal) fibrosis which could have contributed to the unexpected success of reduction of pulmonary vascular resistance. To the best of our knowledge, this is the first report of successful treatment of idiopathic pulmonary arterial hypertension, probably as a result of low-dose radiation to the pulmonary arterial main stems. The patient continues to have no specific complaints concerning her idiopathic pulmonary arterial hypertension

  2. Who Is at Risk for Pulmonary Hypertension?

    MedlinePlus

    ... exact number of people who have pulmonary hypertension (PH) isn't known. Group 1 pulmonary arterial hypertension ( ... have group 1 PAH tend to be overweight . PH that occurs with another disease or condition is ...

  3. Increased oxidative stress and severe arterial remodeling induced by permanent high-flow challenge in experimental pulmonary hypertension

    PubMed Central

    2011-01-01

    Background Involvement of inflammation in pulmonary hypertension (PH) has previously been demonstrated and recently, immune-modulating dendritic cells (DCs) infiltrating arterial lesions in patients suffering from idiopathic pulmonary arterial hypertension (IPAH) and in experimental monocrotaline-induced PH have been reported. Occurrence of perivascular inflammatory cells could be linked to local increase of oxidative stress (OS), as it has been shown for systemic atherosclerosis. The impact of OS on vascular remodeling in PH is still to be determined. We hypothesized, that augmented blood-flow could increase OS and might thereby contribute to DC/inflammatory cell-recruitment and smooth-muscle-cell-proliferation. Methods We applied a monocrotaline-induced PH-model and combined it with permanent flow-challenge. Thirty Sprague-Dawley rats were assigned to following groups: control, monocrotaline-exposure (MCT), monocrotaline-exposure/pneumonectomy (MCT/PE). Results Hemodynamic exploration demonstrated most severe effects in MCT/PE, corresponding in histology to exuberant medial and adventitial remodeling of pulmonary muscular arteries, and intimal remodeling of smaller arterioles; lung-tissue PCR evidenced increased expression of DCs-specific fascin, CD68, proinflammatory cytokines (IL-6, RANTES, fractalkine) in MCT/PE and to a lesser extent in MCT. Major OS enzyme NOX-4 was maximal in MCT/PE. Antioxidative stress enzymes Mn-SOD and glutathion-peroxidase-1 were significantly elevated, while HO-1 showed maximal expression in MCT with significant decrease in MCT/PE. Catalase was decreased in MCT and MCT/PE. Expression of NOX-4, but also of MN-SOD in MCT/PE was mainly attributed to a highly increased number of interstitial and perivascular CXCR4/SDF1 pathway-recruited mast-cells. Stress markers malonedialdehyde and nitrotyrosine were produced in endothelial cells, medial smooth muscle and perivascular leucocytes of hypertensive vasculature. Immunolabeling for OX62, CD68

  4. Pulmonary Hypertension: Types and Treatments

    PubMed Central

    Rose-Jones, Lisa J; Mclaughlin, Vallerie V

    2015-01-01

    Pulmonary arterial hypertension (PAH) is a panvasculopathy that affects the distal pulmonary arteries and leads to restricted blood flow. This increased afterload leads to adaptive mechanisms of the right ventricle, with eventual failure once it can no longer compensate. Pulmonary hypertension from associated conditions, most importantly left heart disease, i.e. heart failure, can also lead to the same sequela. Patients often experience early vague symptoms of dyspnea and exercise intolerance, and thus PH can elude clinicians until right heart failure symptoms predominate. Evidence-based treatment options with pulmo-nary vasodilators are available for those with PAH and should be employed early. It is essential that patients be accurately categorized by their etiology of PH, as treatment strategies differ, and can potentially be dangerous if employed in the wrong clinical scenario. PMID:24251459

  5. Pulmonary Hypertension Secondary to COPD.

    PubMed

    Shujaat, Adil; Bajwa, Abubakr A; Cury, James D

    2012-01-01

    The development of pulmonary hypertension in COPD adversely affects survival and exercise capacity and is associated with an increased risk of severe acute exacerbations. Unfortunately not all patients with COPD who meet criteria for long term oxygen therapy benefit from it. Even in those who benefit from long term oxygen therapy, such therapy may reverse the elevated pulmonary artery pressure but cannot normalize it. Moreover, the recent discovery of the key roles of endothelial dysfunction and inflammation in the pathogenesis of PH provides the rationale for considering specific pulmonary vasodilators that also possess antiproliferative properties and statins.

  6. A global view of pulmonary hypertension.

    PubMed

    Hoeper, Marius M; Humbert, Marc; Souza, Rogerio; Idrees, Majdy; Kawut, Steven M; Sliwa-Hahnle, Karen; Jing, Zhi-Cheng; Gibbs, J Simon R

    2016-04-01

    Pulmonary hypertension is a substantial global health issue. All age groups are affected with rapidly growing importance in elderly people, particularly in countries with ageing populations. Present estimates suggest a pulmonary hypertension prevalence of about 1% of the global population, which increases up to 10% in individuals aged more than 65 years. In almost all parts of the world, left-sided heart and lung diseases have become the most frequent causes of pulmonary hypertension. About 80% of affected patients live in developing countries, where pulmonary hypertension is frequently associated with congenital heart disease and various infectious disorders, including schistosomiasis, HIV, and rheumatic heart disease. These forms of pulmonary hypertension occur predominantly in those younger than 65 years. Independently of the underlying disease, the development of pulmonary hypertension is associated with clinical deterioration and a substantially increased mortality risk. Global research efforts are needed to establish preventive strategies and treatments for the various types of pulmonary hypertension. PMID:26975810

  7. DNA Damage and Pulmonary Hypertension

    PubMed Central

    Ranchoux, Benoît; Meloche, Jolyane; Paulin, Roxane; Boucherat, Olivier; Provencher, Steeve; Bonnet, Sébastien

    2016-01-01

    Pulmonary hypertension (PH) is defined by a mean pulmonary arterial pressure over 25 mmHg at rest and is diagnosed by right heart catheterization. Among the different groups of PH, pulmonary arterial hypertension (PAH) is characterized by a progressive obstruction of distal pulmonary arteries, related to endothelial cell dysfunction and vascular cell proliferation, which leads to an increased pulmonary vascular resistance, right ventricular hypertrophy, and right heart failure. Although the primary trigger of PAH remains unknown, oxidative stress and inflammation have been shown to play a key role in the development and progression of vascular remodeling. These factors are known to increase DNA damage that might favor the emergence of the proliferative and apoptosis-resistant phenotype observed in PAH vascular cells. High levels of DNA damage were reported to occur in PAH lungs and remodeled arteries as well as in animal models of PH. Moreover, recent studies have demonstrated that impaired DNA-response mechanisms may lead to an increased mutagen sensitivity in PAH patients. Finally, PAH was linked with decreased breast cancer 1 protein (BRCA1) and DNA topoisomerase 2-binding protein 1 (TopBP1) expression, both involved in maintaining genome integrity. This review aims to provide an overview of recent evidence of DNA damage and DNA repair deficiency and their implication in PAH pathogenesis. PMID:27338373

  8. Isolated pulmonary hypertension secondary to rheumatoid arthritis.

    PubMed

    Castro, Glaucio W R; Appenzeller, Simone; Bertolo, Manoel B; Costallat, Lilian T L

    2006-11-01

    The authors report a case of a woman with pulmonary hypertension secondary to rheumatoid arthritis, whose treatment with azathioprine resulted in normalization of pulmonary artery pressure and resolution of clinical symptoms. Different etiologies for pulmonary hypertension are discussed and literature review is presented.

  9. [Radiographic assessment of pulmonary hypertension: Methodical aspects].

    PubMed

    Korobkova, I Z; Lazutkina, V K; Nizovtsova, L A; Riden, T V

    2015-01-01

    Pulmonary hypertension is a menacing complication of a number of diseases, which is responsible for high mortality rates and considerably poorer quality of life in a patient. The timely detection for pulmonary hypertension allows timely initiation of treatment, thus improvement in prognosis in the patient. Chest X-ray is the most commonly used radiographic technique for various causes. Physicians' awareness about the radiographic manifestations of pulmonary hypertension may contribute to the earlier detection of this severe disease. Owing to the natural contrast of reflected structures, a chest X-ray film gives a unique opportunity to assess pulmonary circulation vessels, to reveal the signs of pulmonary hypertension, and to estimate trends in the course of the disease. The paper details a procedure for analysis and the normal radiographic anatomy of pulmonary circulation vessels, gives the present classification of pulmonary hypertension, and sets forth its X-ray semiotics. PMID:26552229

  10. [Radiographic assessment of pulmonary hypertension: Methodical aspects].

    PubMed

    Korobkova, I Z; Lazutkina, V K; Nizovtsova, L A; Riden, T V

    2015-01-01

    Pulmonary hypertension is a menacing complication of a number of diseases, which is responsible for high mortality rates and considerably poorer quality of life in a patient. The timely detection for pulmonary hypertension allows timely initiation of treatment, thus improvement in prognosis in the patient. Chest X-ray is the most commonly used radiographic technique for various causes. Physicians' awareness about the radiographic manifestations of pulmonary hypertension may contribute to the earlier detection of this severe disease. Owing to the natural contrast of reflected structures, a chest X-ray film gives a unique opportunity to assess pulmonary circulation vessels, to reveal the signs of pulmonary hypertension, and to estimate trends in the course of the disease. The paper details a procedure for analysis and the normal radiographic anatomy of pulmonary circulation vessels, gives the present classification of pulmonary hypertension, and sets forth its X-ray semiotics.

  11. Pulmonary arterial hypertension and pregnancy

    PubMed Central

    Terek, Demet; Kayikcioglu, Meral; Kultursay, Hakan; Ergenoglu, Mete; Yalaz, Mehmet; Musayev, Oktay; Mogulkoc, Nesrin; Gunusen, Ilkben; Akisu, Mete; Kultursay, Nilgun

    2013-01-01

    This is the case report of a pregnant woman who refused pregnancy termination when diagnosed with pulmonary arterial hypertension (PAH) functional class 2–3 at the 24th week of gestation and of her newborn. A pregnant woman with PAH functional class 2–3 was treated with inhaled prostacyclin analog (iloprost), oral sildenafil, oxygen, and low molecular weight heparin. She delivered at 32nd week by Cesarean section. The infant required oxygen up to 36th week postconceptional age and had a short steroid treatment. The mother needed close cardiovascular monitorization, intensive oxygen and pulmonary vasodilator therapy for 2 months and was discharged with oxygen and oral iloprost treatment. A multidisciplinary approach together with pulmonary vasodilator therapy may be succesful in such a high-risk pregnant woman. PMID:23900530

  12. Pulmonary arterial hypertension in primary amyloidosis

    PubMed Central

    Emerson, Lyska L.; Bull, David A.; Hatton, Nathan; Nativi-Nicolai, Jose; Hildebrandt, Gerhard C.; Ryan, John J.

    2016-01-01

    Abstract Amyloidosis involves extravascular deposition of fibrillar proteins within tissues and organs. Primary light chain amyloidosis represents the most common form of systemic amyloidosis involving deposition of monoclonal immunoglobulin light chains. Although pulmonary amyloid deposition is common in primary amyloidosis, clinically significant pulmonary amyloidosis is uncommon, and elevated pulmonary artery pressures are rarely observed in the absence of other underlying etiologies for pulmonary hypertension, such as elevated filling pressures secondary to cardiac amyloid. In this case report, we present a patient with primary light chain amyloidosis and pulmonary arterial hypertension in the setting of pulmonary vascular and right ventricular myocardial amyloid deposition. PMID:27252852

  13. Splenectomy and chronic thromboembolic pulmonary hypertension

    PubMed Central

    Jais, X; Ioos, V; Jardim, C; Sitbon, O; Parent, F; Hamid, A; Fadel, E; Dartevelle, P; Simonneau, G; Humbert, M

    2005-01-01

    Background: An increased prevalence of splenectomy has been reported in patients with idiopathic pulmonary arterial hypertension. Examination of small pulmonary arteries from these subjects has revealed multiple thrombotic lesions, suggesting that thrombosis may contribute to this condition. Based on these findings, we hypothesised that splenectomy could be a risk factor for chronic thromboembolic pulmonary hypertension (CTEPH), a condition defined by the absence of thrombus resolution after acute pulmonary embolism that causes sustained obstruction of the pulmonary arteries and subsequent pulmonary hypertension. Methods: The medical history, clinical characteristics, thrombotic risk factors and haemodynamics of 257 patients referred for CTEPH between 1989 and 1999 were reviewed. In a case-control study the prevalence of splenectomy in patients with CTEPH was compared with that of patients evaluated during the same period for idiopathic pulmonary hypertension (n = 276) or for lung transplantation in other chronic pulmonary conditions (n = 180). Results: In patients with CTEPH, 8.6% (95% CI 5.2 to 12.0) had a history of splenectomy compared with 2.5% (95% CI 0.7 to 4.4) and 0.56% (95% CI 0 to 1.6) in cases of idiopathic pulmonary arterial hypertension and other chronic pulmonary conditions, respectively (p<0.01). Conclusion: Splenectomy may be a risk factor for chronic thromboembolic pulmonary hypertension. PMID:16085731

  14. Drugs induced pulmonary arterial hypertension.

    PubMed

    Seferian, Andrei; Chaumais, Marie-Camille; Savale, Laurent; Günther, Sven; Tubert-Bitter, Pascale; Humbert, Marc; Montani, David

    2013-09-01

    Pulmonary arterial hypertension (PAH) is a rare disorder characterized by progressive obliteration of the pulmonary microvasculature, resulting in elevated pulmonary vascular resistance and premature death. According to the current classification, PAH can be associated with exposure to certain drugs or toxins, particularly appetite suppressant drugs, such as aminorex, fenfluramine derivatives and benfluorex. These drugs have been confirmed to be risk factors for PAH and were withdrawn from the market. The supposed mechanism is an increase in serotonin levels, which was demonstrated to act as a growth factor for the pulmonary arterial smooth muscle cells. Amphetamines, phentermine and mazindol were less frequently used but are also considered as possible risk factors for PAH. Dasatinib, a dual Src/Abl kinase inhibitor, used in the treatment of chronic myelogenous leukaemia was associated with cases of severe PAH, in part reversible after its withdrawal. Recently several studies raised the potential endothelial dysfunction that could be induced by interferon, and few cases of PAH have been reported with interferon therapy. Other possible risk factors for PAH include: nasal decongestants, like phenylpropanolamine, dietary supplement - L-Tryptophan, selective serotonin reuptake inhibitors, pergolide and other drugs that could act on 5HT2B receptors. Interestingly, PAH remains a rare complication of these drugs, suggesting possible individual susceptibility and further studies are needed to identify patients at risk of drugs induced PAH. PMID:23972547

  15. [Pulmonary hypertension: definition, classification and treatments].

    PubMed

    Jutant, Etienne-Marie; Humbert, Marc

    2016-01-01

    Pulmonary hypertension (PH) is a cardio-pulmonary disorder that may involve multiple clinical conditions and can complicate the majority of cardiovascular and respiratory diseases. Its definition is an increase in mean pulmonary artery pressure (mPAP) \\hbox{$\\geqslant $} ⩾ 25 mmHg at rest, leading to right heart failure and ultimately death. The clinical classification of pulmonary hypertension (PH) categorizes PH into groups which share similar pathophysiological and hemodynamic characteristics and treatments. Five groups of disorders that cause PH are identified: pulmonary arterial hypertension (Group 1) which is a pre-capillary PH, defined by a normal pulmonary artery wedge pressure (PAWP) \\hbox{$\\leqslant $} ⩽ 15 mmH, due to remodelling of the small pulmonary arteries (<500 μm); pulmonary hypertension due to left heart disease (Group 2) which is a post-capillary PH, defined by an increased pulmonary artery wedge pressure (PAWP) >15 mmHg; pulmonary hypertension due to chronic lung disease and/or hypoxia (Group 3); chronic thrombo-embolic pulmonary hypertension (Group 4); and pulmonary hypertension due to unclear and/or multifactorial mechanisms (Group 5). PAH (PH group 1) can be treated with agents targeting three dysfunctional endothelial pathways of PAH: nitric oxide (NO) pathway, endothelin-1 pathway and prostacyclin pathway. Patients at low or intermediate risk can be treated with either initial monotherapy or initial oral combination therapy. In patients at high risk initial combination therapy including intravenous prostacyclin analogues should be considered. Patients with inadequate clinical response to maximum treatment (triple therapy with an intravenous prostacyclin) should be assessed for lung transplantation. Despite progresses, PAH remains a fatal disease with a 3-year survival rate of 58%. Treatment of group 2, group 3 and group 5 PH is the treatment of the causal disease and PAH therapeutics are not recommended. Treatment of group 4 PH is

  16. [Pulmonary hypertension: definition, classification and treatments].

    PubMed

    Jutant, Etienne-Marie; Humbert, Marc

    2016-01-01

    Pulmonary hypertension (PH) is a cardio-pulmonary disorder that may involve multiple clinical conditions and can complicate the majority of cardiovascular and respiratory diseases. Its definition is an increase in mean pulmonary artery pressure (mPAP) \\hbox{$\\geqslant $} ⩾ 25 mmHg at rest, leading to right heart failure and ultimately death. The clinical classification of pulmonary hypertension (PH) categorizes PH into groups which share similar pathophysiological and hemodynamic characteristics and treatments. Five groups of disorders that cause PH are identified: pulmonary arterial hypertension (Group 1) which is a pre-capillary PH, defined by a normal pulmonary artery wedge pressure (PAWP) \\hbox{$\\leqslant $} ⩽ 15 mmH, due to remodelling of the small pulmonary arteries (<500 μm); pulmonary hypertension due to left heart disease (Group 2) which is a post-capillary PH, defined by an increased pulmonary artery wedge pressure (PAWP) >15 mmHg; pulmonary hypertension due to chronic lung disease and/or hypoxia (Group 3); chronic thrombo-embolic pulmonary hypertension (Group 4); and pulmonary hypertension due to unclear and/or multifactorial mechanisms (Group 5). PAH (PH group 1) can be treated with agents targeting three dysfunctional endothelial pathways of PAH: nitric oxide (NO) pathway, endothelin-1 pathway and prostacyclin pathway. Patients at low or intermediate risk can be treated with either initial monotherapy or initial oral combination therapy. In patients at high risk initial combination therapy including intravenous prostacyclin analogues should be considered. Patients with inadequate clinical response to maximum treatment (triple therapy with an intravenous prostacyclin) should be assessed for lung transplantation. Despite progresses, PAH remains a fatal disease with a 3-year survival rate of 58%. Treatment of group 2, group 3 and group 5 PH is the treatment of the causal disease and PAH therapeutics are not recommended. Treatment of group 4 PH is

  17. Propylthiouracil Attenuates Experimental Pulmonary Hypertension via Suppression of Pen-2, a Key Component of Gamma-Secretase.

    PubMed

    Lai, Ying-Ju; Chang, Gwo-Jyh; Yeh, Yung-Hsin; Pang, Jong-Hwei S; Huang, Chung-Chi; Chen, Wei-Jan

    2015-01-01

    Gamma-secretase-mediated Notch3 signaling is involved in smooth muscle cell (SMC) hyper-activity and proliferation leading to pulmonary arterial hypertension (PAH). In addition, Propylthiouracil (PTU), beyond its anti-thyroid action, has suppressive effects on atherosclerosis and PAH. Here, we investigated the possible involvement of gamma-secretase-mediated Notch3 signaling in PTU-inhibited PAH. In rats with monocrotaline-induced PAH, PTU therapy improved pulmonary arterial hypertrophy and hemodynamics. In vitro, treatment of PASMCs from monocrotaline-treated rats with PTU inhibited their proliferation and migration. Immunocyto, histochemistry, and western blot showed that PTU treatment attenuated the activation of Notch3 signaling in PASMCs from monocrotaline-treated rats, which was mediated via inhibition of gamma-secretase expression especially its presenilin enhancer 2 (Pen-2) subunit. Furthermore, over-expression of Pen-2 in PASMCs from control rats increased the capacity of migration, whereas knockdown of Pen-2 with its respective siRNA in PASMCs from monocrotaline-treated rats had an opposite effect. Transfection of PASMCs from monocrotaline-treated rats with Pen-2 siRNA blocked the inhibitory effect of PTU on PASMC proliferation and migration, reflecting the crucial role of Pen-2 in PTU effect. We present a novel cell-signaling paradigm in which overexpression of Pen-2 is essential for experimental pulmonary arterial hypertension to promote motility and growth of smooth muscle cells. Propylthiouracil attenuates experimental PAH via suppression of the gamma-secretase-mediated Notch3 signaling especially its presenilin enhancer 2 (Pen-2) subunit. These findings provide a deep insight into the pathogenesis of PAH and a novel therapeutic strategy.

  18. The serotonin transporter promotes a pathological estrogen metabolic pathway in pulmonary hypertension via cytochrome P450 1B1

    PubMed Central

    2016-01-01

    Abstract Pulmonary arterial hypertension (PAH) is a devastating vasculopathy that predominates in women and has been associated with dysregulated estrogen and serotonin signaling. Overexpression of the serotonin transporter (SERT+) in mice results in an estrogen-dependent development of pulmonary hypertension (PH). Estrogen metabolism by cytochrome P450 1B1 (CYP1B1) contributes to the pathogenesis of PAH, and serotonin can increase CYP1B1 expression in human pulmonary arterial smooth muscle cells (hPASMCs). We hypothesized that an increase in intracellular serotonin via increased SERT expression may dysregulate estrogen metabolism via CYP1B1 to facilitate PAH. Consistent with this hypothesis, we found elevated lung CYP1B1 protein expression in female SERT+ mice accompanied by PH, which was attenuated by the CYP1B1 inhibitor 2,3′,4,5′-tetramethoxystilbene (TMS). Lungs from female SERT+ mice demonstrated an increase in oxidative stress that was marked by the expression of 8-hydroxyguanosine; however, this was unaffected by CYP1B1 inhibition. SERT expression was increased in monocrotaline-induced PH in female rats; however, TMS did not reverse PH in monocrotaline-treated rats but prolonged survival. Stimulation of hPASMCs with the CYP1B1 metabolite 16α-hydroxyestrone increased cellular proliferation, which was attenuated by an inhibitor (MPP) of estrogen receptor alpha (ERα) and a specific ERα antibody. Thus, increased intracellular serotonin caused by increased SERT expression may contribute to PAH pathobiology by dysregulation of estrogen metabolic pathways via increased CYP1B1 activity. This promotes PASMC proliferation by the formation of pathogenic metabolites of estrogen that mediate their effects via ERα. Our studies indicate that targeting this pathway in PAH may provide a promising antiproliferative therapeutic strategy. PMID:27162617

  19. Therapeutic Strategies in Pulmonary Hypertension

    PubMed Central

    Fuso, Leonello; Baldi, Fabiana; Perna, Alessandra Di

    2011-01-01

    Pulmonary hypertension (PH) is a life-threatening condition characterized by elevated pulmonary arterial pressure. It is clinically classified into five groups: patients in the first group are considered to have pulmonary arterial hypertension (PAH) whereas patients of the other groups have PH that is due to cardiopulmonary or other systemic diseases. The management of patients with PH has advanced rapidly over the last decade and the introduction of specific treatments especially for PAH has lead to an improved outcome. However, despite the progress in the treatment, the functional limitation and the survival of these patients remain unsatisfactory and there is no cure for PAH. Therefore the search for an “ideal” therapy still goes on. At present, two levels of treatment can be identified: primary and specific therapy. Primary therapy is directed at the underlying cause of the PH. It also includes a supportive therapy consisting in oxygen supplementation, diuretics, and anticoagulation which should be considered in all patients with PH. Specific therapy is directed at the PH itself and includes treatment with vasodilatators such as calcium channel blockers and with vasodilatator and pathogenetic drugs such as prostanoids, endothelin receptor antagonists and phosphodiesterase type-5 inhibitors. These drugs act in several pathogenetic mechanisms of the PH and are specific for PAH although they might be used also in the other groups of PH. Finally, atrial septostomy and lung transplantation are reserved for patients refractory to medical therapy. Different therapeutic approaches can be considered in the management of patients with PH. Therapy can be established on the basis of both the clinical classification and the functional class. It is also possible to adopt a goal-oriented therapy in which the timing of treatment escalation is determined by inadequate response to known prognostic indicators. PMID:21687513

  20. Inflammation in pulmonary arterial hypertension.

    PubMed

    Price, Laura C; Wort, S John; Perros, Frédéric; Dorfmüller, Peter; Huertas, Alice; Montani, David; Cohen-Kaminsky, Sylvia; Humbert, Marc

    2012-01-01

    Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling of the precapillary pulmonary arteries, with excessive proliferation of vascular cells. Although the exact pathophysiology remains unknown, there is increasing evidence to suggest an important role for inflammation. Firstly, pathologic specimens from patients with PAH reveal an accumulation of perivascular inflammatory cells, including macrophages, dendritic cells, T and B lymphocytes, and mast cells. Secondly, circulating levels of certain cytokines and chemokines are elevated, and these may correlate with a worse clinical outcome. Thirdly, certain inflammatory conditions such as connective tissue diseases are associated with an increased incidence of PAH. Finally, treatment of the underlying inflammatory condition may alleviate the associated PAH. Underlying pathologic mechanisms are likely to be "multihit" and complex. For instance, the inflammatory response may be regulated by bone morphogenetic protein receptor type 2 (BMPR II) status, and, in turn, BMPR II expression can be altered by certain cytokines. Although antiinflammatory therapies have been effective in certain connective-tissue-disease-associated PAH, this approach is untested in idiopathic PAH (iPAH). The potential benefit of antiinflammatory therapies in iPAH is of importance and requires further study. PMID:22215829

  1. [Treatment of pulmonary arterial hypertension].

    PubMed

    Roman, Antonio; López-Meseguer, Manuel; Domingo, Enric

    2015-06-22

    Treatment of pulmonary arterial hypertension has achieved significant progress over the past 20 years. Currently, 3 groups of drugs have proven useful for the treatment of this disease: endothelin receptor antagonist, phosphodiesterase inhibitors and prostacyclin and its analogues. It is recommended to initiate treatment with one of these drugs, the choice depending on the initial severity of patient disease and the preferences of the treating physician. When the patient does not have a satisfactory response, new drugs acting at a different pathway are most commonly added. At this time, considering referral for lung transplantation could be an alternative. Most experts recommend grouping maximum experience in what is known as expert centers. Treatment has led to better survival in these patients, but there is still a long way to cure this life-threatening disease.

  2. Pathophysiology of Pulmonary Hypertension in Chronic Parenchymal Lung Disease.

    PubMed

    Singh, Inderjit; Ma, Kevin Cong; Berlin, David Adam

    2016-04-01

    Pulmonary hypertension commonly complicates chronic obstructive pulmonary disease and interstitial lung disease. The association of chronic lung disease and pulmonary hypertension portends a worse prognosis. The pathophysiology of pulmonary hypertension differs in the presence or absence of lung disease. We describe the physiological determinants of the normal pulmonary circulation to better understand the pathophysiological factors implicated in chronic parenchymal lung disease-associated pulmonary hypertension. This review will focus on the pathophysiology of 3 forms of chronic lung disease-associated pulmonary hypertension: idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and sarcoidosis.

  3. [Surgical treatment of chronic thromboembolic pulmonary hypertension].

    PubMed

    Mercier, Olaf; Fadel, Elie; Mussot, Sacha; Fabre, Dominique; Ladurie, François-Leroy; Angel, Claude; Brenot, Philippe; Riou, Jean-Yves; Bourkaib, Riad; Lehouerou, Daniel; Musat, Andy; Stephan, François; Rohnean, Adéla; Jaïs, Xavier; Humbert, Marc; Sitbon, Olivier; Simonneau, Gérald; Dartevelle, Philippe

    2014-09-01

    Chronic thromboembolic pulmonary hypertension is a rare but underdiagnosed disease. The development of imaging played a crucial role for the screening and the decision of operability over the past few years. Indeed, chronic thromboembolic pulmonary hypertension is the only type of pulmonary hypertension with a potential curative treatment: pulmonary endarterectomy. It is a complexe surgical procedure performed under cardiopulmonary bypass with deep hypothermia and circulatory arrest. The aim of the procedure is to completely remove the scar tissue inside the pulmonary arteries down to the segmental and sub-segmental levels. Compared to lung transplantation, which carries a postoperative mortality of 15-20% and a 5-year survival of 50%, pulmonary endarterectomy is a curative treatment with a postoperative mortality of less than 3%. However, lung transplantation remains an option for young patients with inoperable distal disease or after pulmonary endarterectomy failure. Considering that medical history of deep venous thrombosis or pulmonary embolism is lacking in 25 to 50%, the diagnosis of chronic thromboembolic pulmonary hypertension remains challenging. The lung V/Q scan is useful for the diagnosis showing ventilation and perfusion mismatches. Lesions located at the level of the pulmonary artery, the lobar or segmental arteries may be accessible to surgical removal. The pulmonary angiogram with the lateral view and the pulmonary CT scan help to determine the level of the intravascular lesions. If there is a correlation between the vascular obstruction assessed by imaging and the pulmonary resistance, pulmonary endarterectomy carries a postoperative mortality of less than 3% and has a high rate of success. If the surgery is performed at a later stage of the disease, pulmonary arteriolitis developed mainly in unobstructed territories and participated in the elevated vascular resistance. At this stage, postoperative risk is higher. PMID:25154908

  4. Advances in Neonatal Pulmonary Hypertension.

    PubMed

    Steinhorn, Robin H

    2016-01-01

    Persistent pulmonary hypertension of the newborn (PPHN) is a surprisingly common event in the neonatal intensive care unit, and affects both term and preterm infants. Recent studies have begun to elucidate the maternal, fetal and genetic risk factors that trigger PPHN. There have been numerous therapeutic advances over the last decade. It is now appreciated that oxygen supplementation, particularly for the goal of pulmonary vasodilation, needs to be approached as a therapy that has risks and benefits. Administration of surfactant or inhaled nitric oxide (iNO) therapy at a lower acuity of illness can decrease the risk of extracorporeal membrane oxygenation/death, progression of disease and duration of hospital stay. Milrinone may have specific benefits as an 'inodilator', as prolonged exposure to iNO plus oxygen may activate phosphodiesterase (PDE) 3A. Additionally, sildenafil and hydrocortisone may benefit infants exposed to hyperoxia and oxidative stress. Continued investigation is likely to reveal new therapies such as citrulline and cinaciguat that will enhance NO synthase and soluble guanylate cyclase function. Continued laboratory and clinical investigation will be needed to optimize treatment and improve outcomes. PMID:27251312

  5. Pulmonary Hypertension Complicating Fibrosing Mediastinitis

    PubMed Central

    Seferian, Andrei; Steriade, Alexandru; Jaïs, Xavier; Planché, Olivier; Savale, Laurent; Parent, Florence; Amar, David; Jovan, Roland; Fadel, Elie; Sitbon, Olivier; Simonneau, Gérald; Humbert, Marc; Montani, David

    2015-01-01

    Abstract Fibrosing mediastinitis is caused by a proliferation of fibrous tissue in the mediastinum with encasement of mediastinal viscera and compression of mediastinal bronchovascular structures. Pulmonary hypertension (PH) is a severe complication of fibrosing mediastinitis caused by extrinsic compression of the pulmonary arteries and/or veins. We have conducted a retrospective observational study reviewing clinical, functional, hemodynamic, radiological characteristics, and outcome of 27 consecutive cases of PH associated with fibrosing mediastinitis diagnosed between 2003 and 2014 at the French Referral Centre for PH. Fourteen men and 13 women with a median age of 60 years (range 18–84) had PH confirmed on right heart catheterization. The causes of fibrosing mediastinitis were sarcoidosis (n = 13), tuberculosis-infection confirmed or suspected (n = 9), mediastinal irradiation (n = 2), and idiopathic (n = 3). Sixteen patients (59%) were in NYHA functional class III and IV. Right heart catheterization confirmed moderate to severe PH with a median mean pulmonary artery pressure of 42 mm Hg (range 27–90) and a median cardiac index of 2.8 L/min/m2 (range 1.6–4.3). Precapillary PH was found in 22 patients, postcapillary PH in 2, and combined postcapillary and precapillary PH in 3. Severe extrinsic compression of pulmonary arteries (>60% reduction in diameter) was evidenced in 2, 8, and 12 patients at the main, lobar, or segmental levels, respectively. Fourteen patients had at least one severe pulmonary venous compression with associated pleural effusion in 6 of them. PAH therapy was initiated in 7 patients and corticosteroid therapy (0.5–1 mg/kg/day) was initiated in 3 patients with sarcoidosis, with 9 other being already on low-dose corticosteroids. At 1-year follow-up, 3 patients had died and among the 21 patients evaluated, 3 deteriorated, 14 were stable, and only 4 patients with sarcoidosis improved (4 receiving corticosteroids and 1

  6. Medical Therapy in Chronic Thromboembolic Pulmonary Hypertension.

    PubMed

    Pepke-Zaba, Joanna; Jais, Xavier; Channick, Richard

    2016-07-01

    Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare but life-threatening condition resulting from unresolved thromboembolic obstructions. Pulmonary endarterectomy surgery is currently the standard of treatment, as it is potentially curative; however, not all cases are amenable to surgical intervention due to distal distribution of the organized thromboembolic material or the presence of comorbidities. Up to one-third of patients have persistent or recurrent pulmonary hypertension after pulmonary endarterectomy. In addition to the occlusive organized thromboembolic material, there is a small-vessel vasculopathy in nonoccluded parts of the pulmonary circulation that is histologically similar to that described in pulmonary arterial hypertension. This observation has led to frequent off-license use of approved pulmonary arterial hypertension therapies in CTEPH. Small uncontrolled trials have investigated prostacyclin analogs, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors in CTEPH with mixed results. A phase III study of the endothelin receptor antagonist bosentan met only one of its two coprimary end points. The first large randomized controlled trial showing a positive treatment effect was the Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase Stimulator Trial (CHEST). This study led to the licensing of riociguat for use in inoperable or persistent recurrent CTEPH. Rigorous randomized controlled trials of medical therapy for CTEPH are needed, and several are underway or planned. In the future, outcomes research may be facilitated by identification of novel end points specific to CTEPH. PMID:27571006

  7. Hyperthyroidism and pulmonary hypertension: an important association.

    PubMed

    Vallabhajosula, Sailaja; Radhi, Saba; Cevik, Cihan; Alalawi, Raed; Raj, Rishi; Nugent, Kenneth

    2011-12-01

    Pulmonary hypertension is a complex disorder with multiple etiologies. The World Health Organization Group 5 (unclear multifactorial mechanisms) includes patients with thyroid disorders. The authors reviewed the literature on the association between hyperthyroidism and pulmonary hypertension and identified 20 publications reporting 164 patients with treatment outcomes. The systolic pulmonary artery (PA) pressures in these patients ranged from 28 to 78 mm Hg. They were treated with antithyroid medications, radioactive iodine and surgery. The mean pretherapy PA systolic pressure was 39 mm Hg; the mean posttreatment pressure was 30 mm Hg. Pulmonary hypertension should be considered in hyperthyroid patients with dyspnea. All patients with pulmonary hypertension should be screened for hyperthyroidism, because the treatment of hyperthyroidism can reduce PA pressures, potentially avoid the side-effects and costs with current therapies for pulmonary hypertension and limit the consequences of untreated hyperthyroidism. However, the long-term outcome in these patients is uncertain, and this issue needs more study. Changes in the pulmonary circulation and molecular regulators of vascular remodeling likely explain this association.

  8. cAMP-PKA-CaMKII signaling pathway is involved in aggravated cardiotoxicity during Fuzi and Beimu Combination Treatment of Experimental Pulmonary Hypertension

    PubMed Central

    Zhuang, Pengwei; Huang, Yingying; Lu, Zhiqiang; Yang, Zhen; Xu, Liman; Sun, Fengjiao; Zhang, Yanjun; Duan, Jinao

    2016-01-01

    Aconiti Lateralis Radix Praeparata (Fuzi) and Fritillariae Thunbergii bulbus (Beimu) have been widely used clinically to treat cardiopulmonary related diseases in China. However, according to the classic rules of traditional Chinese medicine, Fuzi and Beimu should be prohibited to use as a combination for their incompatibility. Therefore, it is critical to elucidate the paradox on the use of Fuzi and Beimu combination therapy. Monocrotaline-induced pulmonary hypertension rats were treated with either Fuzi, Beimu, or their combination at different stages of PH. We demonstrated that at the early stage of PH, Fuzi and Beimu combination significantly improved lung function and reduced pulmonary histopathology. However, as the disease progressed, when Fuzi and Beimu combination were used at the late stage of PH, right ventricular chamber dilation was histologically apparent and myocardial apoptosis was significantly increased compared with each drug alone. Western-blotting results indicated that the main chemical ingredient of Beimu could down-regulate the protein phosphorylation levels of Akt and PDE4D, whereas the combination of Fuzi and Beimu could up-regulate PKA and CaMKII signaling pathways. Therefore, we concluded that Fuzi and Beimu combination potentially aggravated the heart injury due to the inhibition of PDK1/Akt/PDE4D axis and subsequent synergistic activation of βAR-Gs-PKA/CaMKII signaling pathway. PMID:27739450

  9. Diagnostic Evaluation of Chronic Thromboembolic Pulmonary Hypertension.

    PubMed

    Gopalan, Deepa; Blanchard, Daniel; Auger, William R

    2016-07-01

    Pulmonary hypertension is defined by a mean pulmonary artery pressure greater than 25 mm Hg. Chronic thromboembolic pulmonary hypertension (CTEPH) is defined as pulmonary hypertension in the presence of an organized thrombus within the pulmonary vascular bed that persists at least 3 months after the onset of anticoagulant therapy. Because CTEPH is potentially curable by surgical endarterectomy, correct identification of patients with this form of pulmonary hypertension and an accurate assessment of surgical candidacy are essential to provide optimal care. Patients most commonly present with symptoms of exertional dyspnea and otherwise unexplained decline in exercise capacity. Atypical chest pain, a nonproductive cough, and episodic hemoptysis are observed less frequently. With more advanced disease, patients often develop symptoms suggestive of right ventricular compromise. Physical examination findings are minimal early in the course of this disease, but as pulmonary hypertension progresses, may include nonspecific finding of right ventricular failure, such as a tricuspid regurgitation murmur, pedal edema, and jugular venous distention. Chest radiographs may suggest pulmonary hypertension, but are neither sensitive nor specific for the diagnosis. Radioisotopic ventilation-perfusion scanning is sensitive for detecting CTEPH, making it a valuable screening study. Conventional catheter-based pulmonary angiography retains an important role in establishing the presence and extent of chronic thromboembolic disease. However, computed tomographic and magnetic resonance imaging are playing a growing diagnostic role. Innovative technologies such as dual-energy computed tomography, dynamic contrast-enhanced magnetic resonance imaging, and optical coherence tomography show promise for contributing diagnostic information and assisting in the preoperative characterization of patients with CTEPH. PMID:27571004

  10. Medical treatment update on pulmonary arterial hypertension.

    PubMed

    Enderby, Cher Y; Burger, Charles

    2015-09-01

    Pulmonary arterial hypertension is a chronic, progressive disease of the pulmonary vasculature resulting in poor outcomes if left untreated. The management of group 1 pulmonary arterial hypertension has included the use of prostanoids, phosphodiesterase-5 inhibitors, and endothelin receptor antagonists targeting the prostacyclin, endothelin-1, and nitric oxide pathways. Three new medications have been approved by the US Food and Drug Administration over the past couple of years. Macitentan is the newest endothelin receptor antagonist, riociguat is a soluble guanylate cyclase stimulator, and treprostinil diolamine is the first oral prostanoid. This review will focus on the key trials leading to their approval, special considerations for each medication, and their potential place in therapy. The use of combination therapy as initial therapy in pulmonary arterial hypertension will also be discussed.

  11. Medical treatment update on pulmonary arterial hypertension

    PubMed Central

    Burger, Charles

    2015-01-01

    Pulmonary arterial hypertension is a chronic, progressive disease of the pulmonary vasculature resulting in poor outcomes if left untreated. The management of group 1 pulmonary arterial hypertension has included the use of prostanoids, phosphodiesterase-5 inhibitors, and endothelin receptor antagonists targeting the prostacyclin, endothelin-1, and nitric oxide pathways. Three new medications have been approved by the US Food and Drug Administration over the past couple of years. Macitentan is the newest endothelin receptor antagonist, riociguat is a soluble guanylate cyclase stimulator, and treprostinil diolamine is the first oral prostanoid. This review will focus on the key trials leading to their approval, special considerations for each medication, and their potential place in therapy. The use of combination therapy as initial therapy in pulmonary arterial hypertension will also be discussed. PMID:26336595

  12. An Update on Pulmonary Arterial Hypertension

    PubMed Central

    Wapner, Joanna; Matura, Lea Ann

    2015-01-01

    Pulmonary arterial hypertension (PAH) is a progressive disease that ultimately leads to right heart failure and death. PAH is defined as a mean pulmonary arterial pressure ≥ 25 mm Hg with a pulmonary capillary wedge pressure ≤ 15 mm Hg at rest. The diagnosis of PAH is one of exclusion; diagnostics include an extensive history, serology, chest radiograph, pulmonary function tests, ventilation/perfusion scan, transthoracic echocardiogram, and right heart catheterization. Treatment and care of patients with PAH can be complex. Therefore, the nurse practitioner is an integral member of the healthcare team caring for PAH patients, helping to ensure seamless care and support. PMID:25954140

  13. Treatment goals of pulmonary hypertension.

    PubMed

    McLaughlin, Vallerie V; Gaine, Sean Patrick; Howard, Luke S; Leuchte, Hanno H; Mathier, Michael A; Mehta, Sanjay; Palazzini, Massimillano; Park, Myung H; Tapson, Victor F; Sitbon, Olivier

    2013-12-24

    With significant therapeutic advances in the field of pulmonary arterial hypertension, the need to identify clinically relevant treatment goals that correlate with long-term outcome has emerged as 1 of the most critical tasks. Current goals include achieving modified New York Heart Association functional class I or II, 6-min walk distance >380 m, normalization of right ventricular size and function on echocardiograph, a decreasing or normalization of B-type natriuretic peptide (BNP), and hemodynamics with right atrial pressure <8 mm Hg and cardiac index >2.5 mg/kg/min(2). However, to more effectively prognosticate in the current era of complex treatments, it is becoming clear that the "bar" needs to be set higher, with more robust and clearer delineations aimed at parameters that correlate with long-term outcome; namely, exercise capacity and right heart function. Specifically, tests that accurately and noninvasively determine right ventricular function, such as cardiac magnetic resonance imaging and BNP/N-terminal pro-B-type natriuretic peptide, are emerging as promising indicators to serve as baseline predictors and treatment targets. Furthermore, studies focusing on outcomes have shown that no single test can reliably serve as a long-term prognostic marker and that composite treatment goals are more predictive of long-term outcome. It has been proposed that treatment goals be revised to include the following: modified New York Heart Association functional class I or II, 6-min walk distance ≥ 380 to 440 m, cardiopulmonary exercise test-measured peak oxygen consumption >15 ml/min/kg and ventilatory equivalent for carbon dioxide <45 l/min/l/min, BNP level toward "normal," echocardiograph and/or cardiac magnetic resonance imaging demonstrating normal/near-normal right ventricular size and function, and hemodynamics showing normalization of right ventricular function with right atrial pressure <8 mm Hg and cardiac index >2.5 to 3.0 l/min/m(2).

  14. Exercise physiology and pulmonary arterial hypertension.

    PubMed

    Waxman, Aaron B

    2012-01-01

    The lungs are the only organ that receives the entire cardiac output with every stroke. The pulmonary circulation is normally a high-flow, low-resistance, low-pressure system that carries blood into the pulmonary microcirculation. In pulmonary artery hypertension (PAH)vascular remodeling contributes to a sustained elevation of pulmonary vascular resistance (PVR) and pulmonary artery pressure (PAP) as a result of vascular remodeling characterized largely by vascular smooth muscle cell proliferation and medial hypertrophy, and endothelial cell proliferation resulting in lumen obliteration. The loss of pulmonary arterial compliance and development of elevated PVR puts an excessive burden on the right ventricle due to the increased workload necessary to overcome the downstream pressure, ultimately leading to right-sided heart failure. The functional status of the pulmonary circulation and the levels of PVR and PAP ultimately determine the outcome of patients with PAH. Study of the pressure-flow relationships in the pulmonary vascular bed will provide an improved appreciation of the pathophysiology of pulmonary hypertension.

  15. The Pathobiology of Chronic Thromboembolic Pulmonary Hypertension.

    PubMed

    Lang, Irene M; Dorfmüller, Peter; Vonk Noordegraaf, Anton

    2016-07-01

    Chronic thromboembolic pulmonary hypertension (CTEPH) is a late sequel of venous thromboembolism that cannot be completely reproduced in animal models. The prevalence of CTEPH in humans is estimated at roughly 17-20 per million; however, partly because up to 50% of patients with CTEPH never experience symptomatic pulmonary embolism, precise numbers on the incidence and prevalence are not known. Because CTEPH is diagnosed at a median age of 63 years in patients who often have other concomitant cardiovascular disease or lung disease, assessment of pathophysiology in patients can be challenging, We do know that CTEPH is a dual vascular disorder. Stenoses, webs, and occlusions predominate in large and medium-sized pulmonary arteries at the sites of previous pulmonary emboli. A "secondary vasculopathy" resembling the pulmonary arteriopathy encountered in other forms of pulmonary hypertension predominates in low-resistance vessels. Anastomoses between bronchial artery branches and precapillary pulmonary arterioles appear during evolution of the disease. Other acquired vascular connections between bronchial arteries and pulmonary veins may trigger venous remodeling. Current concepts regarding the pathophysiology of CTEPH include contributions of hyperactive coagulation (e.g., high coagulation factor VIII, combined coagulation defects, dysfibrinogenemias), insufficient anticoagulation, non-O blood groups, and misguided thrombus resolution (e.g., infection, inflammation, dysfunctional innate immunity, abnormal circulating phospholipids). Current research focuses on the question as to whether a genetic predisposition leads to misguided vascular healing after pulmonary thromboembolism in susceptible individuals. PMID:27571003

  16. Diagnosis and management of primary pulmonary hypertension.

    PubMed

    Krishnan, U

    2000-03-01

    Pulmonary arterial hypertension in children can occur secondary to shunt lesion like ventricular septal defect, patent ductus arteriosus or it may be idiopathic, the so called primary pulmonary hypertension (PPH). The progression of PPH is usually rapid in children as compared to adults and the mean survival is 2-3 years after the diagnosis is made. Histological changes in the form of medical muscular hypertrophy, intinal hyperplasia and later angiomatous, plexiform lesions occur in pulmonary vasculature. The pulmonary vasculature normally is a high flow, low resistance circuit and allows large blood flow without marked increase in pulmonary arterial pressure. However, with prolonged increased flow or any other vasoconstrictor stimulus, histological changes start occurring in the pulmonary bed resulting in increasing pressure in pulmonary artery. Right ventricular hypertension follows resulting in right ventricular hyypertrophy and later dysfunction. Life threatening arrhythmias may result in sudden death in some of these patients. Clinical presentation is in the form of exertional dyspnoea with syncope at times. Over 50% of children with PPH are helped by vasodilators. They may be treated with calcium channel blockers (e.g. nifedipine, dose titrated to blood pressure) orally. Those not responding to oral vasodilators can be put on chronic inhaled nitric oxide or continuous intravenous prostacyclin infusion. Chronic anticoagulation therapy may also increase survival. In symptomatic cases, blade/balloon atrial septostomy may increase survival in patients of PPH with intact atrial sptum. For children not responding to medical therapy, lung transplantation may be the answer in near future.

  17. Developments in pulmonary arterial hypertension-targeted therapy for chronic thromboembolic pulmonary hypertension.

    PubMed

    Hadinnapola, Charaka; Pepke-Zaba, Joanna

    2015-10-01

    Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare disease characterised by the presence of organised chronic thromboembolic material occluding the proximal pulmonary arteries and a vasculopathy in the distal pulmonary arterial tree. Pulmonary endarterectomy (PEA) is a potential cure for many patients with CTEPH. However, PEA is not suitable for patients with a significant distal distribution of chronic thromboembolic material or with significant comorbidities. Also, a proportion of patients are left with residual CTEPH post PEA. Until recently, pulmonary arterial hypertension-targeted therapies have been used off licence to treat patients with inoperable or residual CTEPH. The CHEST1 study investigated the use of riociguat and was the first randomised controlled trial to show efficacy in inoperable or residual CTEPH. In this review, we explore the pathophysiology of CTEPH and review the current trial evidence for pulmonary arterial hypertension-targeted therapies. We also include a discussion of physiological considerations that require further investigation.

  18. Management of pulmonary arterial hypertension.

    PubMed

    McLaughlin, Vallerie V; Shah, Sanjiv J; Souza, Rogerio; Humbert, Marc

    2015-05-12

    Pulmonary hypertension (PH) is common and may result from a number of disorders, including left heart disease, lung disease, and chronic thromboembolic disease. Pulmonary arterial hypertension (PAH) is an uncommon disease characterized by progressive remodeling of the distal pulmonary arteries, resulting in elevated pulmonary vascular resistance and, eventually, in right ventricular failure. Over the past decades, knowledge of the basic pathobiology of PAH and its natural history, prognostic indicators, and therapeutic options has exploded. A thorough evaluation of a patient is critical to correctly characterize the PH. Cardiac studies, including echocardiography and right heart catheterization, are key elements in the assessment. Given the multitude of treatment options currently available for PAH, assessment of risk and response to therapy is critical in long-term management. This review also underscores unique situations, including perioperative management, intensive care unit management, and pregnancy, and highlights the importance of collaborative care of the PAH patient through a multidisciplinary approach.

  19. Role of Vasodilator Testing in Pulmonary Hypertension.

    PubMed

    Sharma, Abhishek; Obiagwu, Chukwudi; Mezue, Kenechukwu; Garg, Aakash; Mukherjee, Debabrata; Haythe, Jennifer; Shetty, Vijay; Einstein, Andrew J

    2016-01-01

    Pulmonary hypertension is clinically defined by a mean pulmonary artery (PA) pressure of 25mm Hg or more at rest, as measured by right heart catheterization. To identify patients who are likely to have a beneficial response to calcium channel blockers (CCBs) and therefore a better prognosis, acute vasodilator testing should be performed in patients in certain subsets of pulmonary arterial hypertension (PAH). A near normalization of pulmonary hemodynamics is needed before patients can be considered for therapy with CCBs. Intravenous adenosine, intravenous epoprostenol, inhaled nitric oxide, or inhaled iloprost are the standard agents used for vasoreactivity testing in patients with idiopathic PAH. In this review we describe the various aspects of vasodilator testing including the rationale, pathophysiology and agents used in the procedure.

  20. Pulmonary arterial hypertension: a clot in question.

    PubMed

    Patel, Bhavin; Pakala, Aneesh; Aronson, Willard; Magharyous, Hany; Brown, Brent

    2014-07-01

    Pulmonary arterial hypertension (PAH) is a group of disorders characterized by a progressive increase in pulmonary vascular resistance leading to right heart failure and premature death. We present an unusual case of PAH diagnosed initially as Idiopathic PAH (IPAH) after secondary causes were excluded which was successfully managed for a number of years with vasodilators and anticoagulation. Over the months after stopping anticoagulation (because of recurring small bowel hemorrhaging) patient developed progressive findings of right heart failure, which failed to respond to escalating doses of prostacyclin. The patient died and an autopsy revealed the surprising finding of extensive organized central pulmonary artery thrombi as is seen in patients with chronic thromboembolic pulmonary hypertension (CTEPH). We discuss the question of whether these thrombi are generally embolic or develop in situ and recommend that clinicians have a high index of suspicion for central thrombi in patients with IPAH were anticoagulation is contraindicated. PMID:25223151

  1. Methylphenidate: pulmonary hypertension and heart valve disease.

    PubMed

    2015-06-01

    Several amphetamine-like appetite suppressants are known to have cardiovascular adverse effects, in particular pulmonary arterial hypertension and cardiac valve disease. Is this also the case with methylphenidate, an amphetamine-like psychostimulant used in attention-deficit hyperactivity disorder (especially in children) and also in narcolepsy? Cases of pulmonary hypertension and heart valve disease have been reported with methylphenidate, including in children. The risk appears to be low, but epidemiological studies are needed to estimate the incidence. This risk should be minimised by only using methylphenidate to treat serious disorders, at the lowest effective dose. Attention should be paid to warning signs such as dyspnoea. PMID:26436168

  2. Pulmonary vascular resistance and compliance relationship in pulmonary hypertension.

    PubMed

    Chemla, Denis; Lau, Edmund M T; Papelier, Yves; Attal, Pierre; Hervé, Philippe

    2015-10-01

    Right ventricular adaptation to the increased pulmonary arterial load is a key determinant of outcomes in pulmonary hypertension (PH). Pulmonary vascular resistance (PVR) and total arterial compliance (C) quantify resistive and elastic properties of pulmonary arteries that modulate the steady and pulsatile components of pulmonary arterial load, respectively. PVR is commonly calculated as transpulmonary pressure gradient over pulmonary flow and total arterial compliance as stroke volume over pulmonary arterial pulse pressure (SV/PApp). Assuming that there is an inverse, hyperbolic relationship between PVR and C, recent studies have popularised the concept that their product (RC-time of the pulmonary circulation, in seconds) is "constant" in health and diseases. However, emerging evidence suggests that this concept should be challenged, with shortened RC-times documented in post-capillary PH and normotensive subjects. Furthermore, reported RC-times in the literature have consistently demonstrated significant scatter around the mean. In precapillary PH, the true PVR can be overestimated if one uses the standard PVR equation because the zero-flow pressure may be significantly higher than pulmonary arterial wedge pressure. Furthermore, SV/PApp may also overestimate true C. Further studies are needed to clarify some of the inconsistencies of pulmonary RC-time, as this has major implications for our understanding of the arterial load in diseases of the pulmonary circulation.

  3. [Treatment goals of pulmonary hypertension].

    PubMed

    McLaughlin, Vallerie V; Gaine, Sean Patrick; Howard, Luke S; Leuchte, Hanno H; Mathier, Michael A; Mehta, Sanjay; Palazzini, Massimillano; Park, Myung H; Tapson, Victor F; Sitbon, Olivier

    2014-10-01

    With significant therapeutic advances in the field of pulmonary arterial hypertension, the need to identify clinically relevant treatment goals that correlate with long-term outcome has emerged as 1 of the most critical tasks. Current goals include achieving modified New York Heart Association functional class I or II, 6-min walk distance >380 m, normalization of right ventricular size and function on echocardiograph, a decreasing or normalization of B-type natriuretic peptide (BNP), and hemodynamics with right atrial pressure <8 mm Hg and cardiac index >2.5 L/dk/m2. However, to more effectively prognosticate in the current era of complex treatments, it is becoming clear that the "bar" needs to be set higher, with more robust and clearer delineations aimed at parameters that correlate with long-term outcome; namely, exercise capacity and right heart function. Specifically, tests that accurately and noninvasively determine right ventricular function, such as cardiac magnetic resonance imaging and BNP/N-terminal pro-B-type natriuretic peptide, are emerging as promising indicators to serve as baseline predictors and treatment targets. Furthermore, studies focusing on outcomes have shown that no single test can reliably serve as a long-term prognostic marker and that composite treatment goals are more predictive of long-term outcome. It has been proposed that treatment goals be revised to include the following: modified New York Heart Association functional class I or II, 6-min walk distance 380 to 440 m, cardiopulmonary exercise test-measured peak oxygen consumption >15 ml/min/kg and ventilatory equivalent for carbon dioxide <45 l/min/l/min, BNP level toward "normal," echocardiograph and/or cardiac magnetic resonance imaging demonstrating normal/near-normal right ventricular size and function, and hemodynamics showing normalization of right ventricular function with right atrial pressure <8 mm Hg and cardiac index >2.5 to 3.0 l/min/m2. (J Am Coll Cardiol 2013;62:D73

  4. Endothelial HIF signaling regulates pulmonary fibrosis-associated pulmonary hypertension.

    PubMed

    Bryant, Andrew J; Carrick, Ryan P; McConaha, Melinda E; Jones, Brittany R; Shay, Sheila D; Moore, Christy S; Blackwell, Thomas R; Gladson, Santhi; Penner, Niki L; Burman, Ankita; Tanjore, Harikrishna; Hemnes, Anna R; Karwandyar, Ayub K; Polosukhin, Vasiliy V; Talati, Megha A; Dong, Hui-Jia; Gleaves, Linda A; Carrier, Erica J; Gaskill, Christa; Scott, Edward W; Majka, Susan M; Fessel, Joshua P; Haase, Volker H; West, James D; Blackwell, Timothy S; Lawson, William E

    2016-02-01

    Pulmonary hypertension (PH) complicating chronic parenchymal lung disease, such as idiopathic pulmonary fibrosis, results in significant morbidity and mortality. Since the hypoxia-inducible factor (HIF) signaling pathway is important for development of pulmonary hypertension in chronic hypoxia, we investigated whether HIF signaling in vascular endothelium regulates development of PH related to pulmonary fibrosis. We generated a transgenic model in which HIF is deleted within vascular endothelial cells and then exposed these mice to chronic intraperitoneal bleomycin to induce PH associated with lung fibrosis. Although no differences in the degree of fibrotic remodeling were observed, we found that endothelial HIF-deficient mice were protected against development of PH, including right ventricle and pulmonary vessel remodeling. Similarly, endothelial HIF-deficient mice were protected from PH after a 4-wk exposure to normobaric hypoxia. In vitro studies of pulmonary vascular endothelial cells isolated from the HIF-targeted mice and controls revealed that endothelial HIF signaling increases endothelial cell expression of connective tissue growth factor, enhances vascular permeability, and promotes pulmonary artery smooth muscle cell proliferation and wound healing ability, all of which have the potential to impact the development of PH in vivo. Taken together, these studies demonstrate that vascular endothelial cell HIF signaling is necessary for development of hypoxia and pulmonary fibrosis associated PH. As such, HIF and HIF-regulated targets represent a therapeutic target in these conditions.

  5. Understanding and treating pulmonary hypertension in congenital diaphragmatic hernia.

    PubMed

    Pierro, M; Thébaud, B

    2014-12-01

    Lung hypoplasia and pulmonary hypertension are classical features of congenital diaphragmatic hernia (CDH) and represent the main determinants of survival. The mechanisms leading to pulmonary hypertension in this malformation are still poorly understood, but may combine altered vasoreactivity, pulmonary artery remodeling, and a hypoplastic pulmonary vascular bed. Efforts have been directed at correcting the "reversible" component of pulmonary hypertension of CDH. However, pulmonary hypertension in CDH is often refractory to pulmonary vasodilators. A new emerging pattern of late (months after birth) and chronic (months to years after birth) pulmonary hypertension are described in CDH survivors. The true incidence and implications for outcome and management need to be confirmed by follow-up studies from referral centers with high patient output. In order to develop more efficient strategies to treat pulmonary hypertension and improve survival in most severe cases, the ultimate therapeutic goal would be to promote lung and vascular growth. PMID:25456753

  6. Potassium channels in pulmonary arterial hypertension.

    PubMed

    Boucherat, Olivier; Chabot, Sophie; Antigny, Fabrice; Perros, Frédéric; Provencher, Steeve; Bonnet, Sébastien

    2015-10-01

    Pulmonary arterial hypertension (PAH) is a devastating cardiopulmonary disorder with various origins. All forms of PAH share a common pulmonary arteriopathy characterised by vasoconstriction, remodelling of the pre-capillary pulmonary vessel wall, and in situ thrombosis. Although the pathogenesis of PAH is recognised as a complex and multifactorial process, there is growing evidence that potassium channels dysfunction in pulmonary artery smooth muscle cells is a hallmark of PAH. Besides regulating many physiological functions, reduced potassium channels expression and/or activity have significant effects on PAH establishment and progression. This review describes the molecular mechanisms and physiological consequences of potassium channel modulation. Special emphasis is placed on KCNA5 (Kv1.5) and KCNK3 (TASK1), which are considered to play a central role in determining pulmonary vascular tone and may represent attractive therapeutic targets in the treatment of PAH. PMID:26341985

  7. Trends in Pulmonary Hypertension Mortality and Morbidity

    PubMed Central

    Valle, Orlando; Gillum, Richard F.

    2014-01-01

    Context. Few reports have been published regarding surveillance data for pulmonary hypertension, a debilitating and often fatal condition. Aims. We report trends in pulmonary hypertension. Settings and Design. United States of America; vital statistics, hospital data. Methods and Material. We used mortality data from the National Vital Statistics System (NVSS) for 1999–2008 and hospital discharge data from the National Hospital Discharge Survey (NHDS) for 1999–2009. Statistical Analysis Used. We present age-standardized rates. Results. Since 1999, the numbers of deaths and hospitalizations as well as death rates and hospitalization rates for pulmonary hypertension have increased. In 1999 death rates were higher for men than for women; however, by 2002, no differences by gender remained because of the increasing death rates among women and the declining death rates among men; after 2003 death rates for women were higher than for men. Death rates throughout the reporting period 1999–2008 were higher for blacks than for whites. Hospitalization rates in women were 1.3–1.6 times higher than in men. Conclusions. Pulmonary hypertension mortality and hospitalization numbers and rates increased from 1999 to 2008. PMID:24991431

  8. [Diagnosis and treatment of pulmonary hypertension].

    PubMed

    Román, J Sánchez; Hernández, F J García; Palma, M J Castillo; Medina, C Ocaña

    2008-03-01

    Pulmonary arterial hypertension is an idiopathic process or can be associated with another circumstances (connective tissue diseases, congenital heart disease, portal hypertension, exposure to appetite suppressants or another drugs or infectious agents such as HIV). Most patients are diagnosed as the result of an evaluation of symptoms, whereas others are diagnosed incidentally or during screening of asymptomatic populations at risk. We reviews systematic screening for the approach to diagnosing pulmonary arterial hypertension. A diagnostic algorithm can guide the evaluation but it can be modified according to specific clinical circumstances. The number of therapeutic options has increased.in the last years. We reviews the use of calcium-channel blockers, prostacyclin (and analogues), endothelin-receptor antagonists, and phosphodiesterase-5 inhibitors, and the use of combination therapy, and provides specific recommendations about the actual treatment.

  9. [Novel immunopathological approaches to pulmonary arterial hypertension].

    PubMed

    Perros, Frédéric; Montani, David; Dorfmüller, Peter; Huertas, Alice; Chaumais, Marie-Camille; Cohen-Kaminsky, Sylvia; Humbert, Marc

    2011-04-01

    Inflammation is important for the initiation and the maintenance of vascular remodeling in the most commun animal models of pulmonary hypertension (PH), and its therapeutical targeting blocks PH development in these models. In human, pulmonary vascular lesions of PH are also the source of an intense chemokine production, linked to inflammatory cell recruitment. However, arteritis is uncommon in PH patients. Of note, current PH treatments have immunomodulatory properties. In addition, some studies have shown a correlation between levels of circulating inflammatory mediators and patients' survival. The study of autoimmunity in the pathophysiology of pulmonary arterial hypertension is becoming an area of intense investigation. New immunopathological approaches to PH should allow the development of innovative treatments for this very severe condition. PMID:21536178

  10. Challenges in pulmonary hypertension: managing the unexpected.

    PubMed

    Olsson, Karen M; Palazzini, Massimiliano

    2015-12-01

    The diverse challenges associated with diagnosis and management of patients with pulmonary hypertension are illustrated in this case-based review. Case 1 describes a patient diagnosed with pulmonary arterial hypertension (PAH) with right heart failure and active systemic lupus erythematosus who was effectively treated with an up-front triple combination of PAH therapies and immunosuppressive therapy. In case 2, a diagnosis of pulmonary veno-occlusive disease was reached after a combined approach of clinical suspicion, physical examination, and invasive and noninvasive tests. Cautious PAH therapy and high-dose diuretics provided clinical benefit in this patient and served as a bridge to lung transplantation. These cases highlight the need for ongoing follow-up of patients with PAH, comprising frequent assessment of treatment success and continued diagnostic evaluation.

  11. Molecular Mechanisms of Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension

    PubMed Central

    Leopold, Jane A.; Maron, Bradley A.

    2016-01-01

    Pulmonary arterial hypertension (PAH) is a devastating disease that is precipitated by hypertrophic pulmonary vascular remodeling of distal arterioles to increase pulmonary artery pressure and pulmonary vascular resistance in the absence of left heart, lung parenchymal, or thromboembolic disease. Despite available medical therapy, pulmonary artery remodeling and its attendant hemodynamic consequences result in right ventricular dysfunction, failure, and early death. To limit morbidity and mortality, attention has focused on identifying the cellular and molecular mechanisms underlying aberrant pulmonary artery remodeling to identify pathways for intervention. While there is a well-recognized heritable genetic component to PAH, there is also evidence of other genetic perturbations, including pulmonary vascular cell DNA damage, activation of the DNA damage response, and variations in microRNA expression. These findings likely contribute, in part, to dysregulation of proliferation and apoptosis signaling pathways akin to what is observed in cancer; changes in cellular metabolism, metabolic flux, and mitochondrial function; and endothelial-to-mesenchymal transition as key signaling pathways that promote pulmonary vascular remodeling. This review will highlight recent advances in the field with an emphasis on the aforementioned molecular mechanisms as contributors to the pulmonary vascular disease pathophenotype. PMID:27213345

  12. [Serotonin hypothesis and pulmonary artery hypertension].

    PubMed

    Kloza, Monika; Baranowska-Kuczko, Marta; Pędzińska-Betiuk, Anna; Jackowski, Konrad; Kozłowska, Hanna

    2014-06-06

    Pulmonary arterial hypertension (PAH) is a progressive, complex disease leading to the right ventricular failure and premature death. PAH is characterized by increased pulmonary arterial pressure, increased vascular resistance, pulmonary vascular remodeling and endothelial dysfunction. Pathomechanism of this disease is still unknown. It has been suggested, that endothelial dysfunction is caused by unbalance between vasodilators and vasoconstrictors e.g. serotonin (5-HT). Previously, serotonin hypothesis was linked to the anorexigens, derivatives of fenfluramine, which are serotonin transporter (SERT) substrates. Nowadays, it has been proved that all elements of serotonergic system within pulmonary circulation participate in the developement of PAH. The tryptophan hydroxylase 1 (Tph-1) catalyses synthesis of 5-HT from tryptophan in the pulmonary arterial endothelial cells. 5-HT mediates contraction of pulmonary vessels via 5-HT1B and 5-HT2A receptors. 5-HT is also transported into pulmonary arterial smooth muscle cells via SERT and through activation of reactive oxygen species and Rho-kinase may contribute to contraction or/and, via stimulation of transcription factors, lead to proliferation and remodelling. There is also increasing number of evidence about functional interaction between 5-HT1B receptor and SERT in modulation of vasoconstriction and proliferation in pulmonary arteries. This review discusses the role of 5-HT in the development of PAH and highlights possible therapeutic targets within serotonergic system.

  13. Definition, classification, and epidemiology of pulmonary arterial hypertension.

    PubMed

    Hoeper, Marius M

    2009-08-01

    Pulmonary arterial hypertension (PAH) is a distinct subgroup of pulmonary hypertension that comprises idiopathic PAH, familial/heritable forms, and PAH associated with connective tissue disease, congenital heart disease, portal hypertension, human immunodeficiency virus (HIV) infection, and some other conditions. The hemodynamic definition of PAH was recently revised: PAH is now defined by a mean pulmonary artery pressure at rest > or =25 mm Hg in the presence of a pulmonary capillary wedge pressure < or =15 mm Hg. The exercise criterion (mean pulmonary artery pressure > or =30 mm Hg during exercise) that was used in the old definition of PAH has been removed because there are no robust data that would allow defining an upper limit of normal for the pulmonary pressure during exercise. The revised classification of pulmonary hypertension still consists of five major groups: (1) PAH, (2) pulmonary hypertension due to left heart disease, (3) pulmonary hypertension due to chronic lung disease and/or hypoxia, (4) chronic thromboembolic pulmonary hypertension, and (5) miscellaneous forms. Modifications have been made in some of these groups, such as the addition of schistosomiasis-related pulmonary hypertension and pulmonary hypertension in patients with chronic hemolytic anemia to group 1.

  14. Gender, sex hormones and pulmonary hypertension.

    PubMed

    Austin, Eric D; Lahm, Tim; West, James; Tofovic, Stevan P; Johansen, Anne Katrine; Maclean, Margaret R; Alzoubi, Abdallah; Oka, Masahiko

    2013-04-01

    Most subtypes of pulmonary arterial hypertension (PAH) are characterized by a greater susceptibility to disease among females, although females with PAH appear to live longer after diagnosis. While this "estrogen paradoxȍ of enhanced female survival despite increased female susceptibility remains a mystery, recent progress has begun to shed light upon the interplay of sex hormones, the pathogenesis of pulmonary hypertension, and the right ventricular response to stress. For example, emerging data in humans and experimental models suggest that estrogens or differential sex hormone metabolism may modify disease risk among susceptible subjects, and that estrogens may interact with additional local factors such as serotonin to enhance the potentially damaging chronic effects of estrogens on the pulmonary vasculature. Regardless, it remains unclear why not all estrogenic compounds behave equally, nor why estrogens appear to be protective in certain settings but detrimental in others. The contribution of androgens and other compounds, such as dehydroepiandrosterone, to pathogenesis and possibly treatment must be considered as well. In this review, we will discuss the recent understandings on how estrogens, estrogen metabolism, dehydroepiandrosterone, and additional susceptibility factors may all contribute to the pathogenesis or potentially to the treatment of pulmonary hypertension, by evaluating current human, cell-based, and experimental model data.

  15. Riociguat: Something new in pulmonary hypertension therapeutics?

    PubMed

    Shanmugam, Elangovan; Jena, Amrita; George, Melvin

    2015-01-01

    Pulmonary hypertension (PH) continues to be a disease that is associated with woeful outcomes. The search for an ideal drug molecule for PH led to the discovery of riociguat, which is a first-in-class drug molecule that activates soluble guanylate cyclase. We conducted a systematic literature search using databases such as PubMed, Science Direct, Springer, Cochrane Reviews and Google Scholar to gather evidence generated from published clinical trials on the efficacy, safety, pharmacokinetics and regulatory status of riociguat. CHEST-1 and the PATENT-1 were phase-3 pivotal clinical trials that showed that riociguat was able to significantly improve the 6-min walk distance with 16 weeks of therapy as compared with the placebo arm. The drug also showed improvement in secondary outcome measures such as improvement in the pulmonary vascular resistance, N-terminal pro-brain natriuretic peptide levels, World Health Organization functional class, time to clinical worsening and Borg dyspnea score. The drug had a modest safety profile, with hypotension being the most bothersome adverse effect. These findings led to various regulatory agencies around the world granting approval for riociguat for the treatment of pulmonary arterial hypertension (PAH) and inoperable chronic thromboembolic pulmonary hypertension (CTEPH). The entry of a new class of drug for PAH and CTEPH therapy portends some hope for patients with a disease that is traditionally linked with a poor prognosis. PMID:25709345

  16. Gender, sex hormones and pulmonary hypertension

    PubMed Central

    Austin, Eric D.; Lahm, Tim; West, James; Tofovic, Stevan P.; Johansen, Anne Katrine; MacLean, Margaret R.; Alzoubi, Abdallah; Oka, Masahiko

    2013-01-01

    Most subtypes of pulmonary arterial hypertension (PAH) are characterized by a greater susceptibility to disease among females, although females with PAH appear to live longer after diagnosis. While this “estrogen paradoxȍ of enhanced female survival despite increased female susceptibility remains a mystery, recent progress has begun to shed light upon the interplay of sex hormones, the pathogenesis of pulmonary hypertension, and the right ventricular response to stress. For example, emerging data in humans and experimental models suggest that estrogens or differential sex hormone metabolism may modify disease risk among susceptible subjects, and that estrogens may interact with additional local factors such as serotonin to enhance the potentially damaging chronic effects of estrogens on the pulmonary vasculature. Regardless, it remains unclear why not all estrogenic compounds behave equally, nor why estrogens appear to be protective in certain settings but detrimental in others. The contribution of androgens and other compounds, such as dehydroepiandrosterone, to pathogenesis and possibly treatment must be considered as well. In this review, we will discuss the recent understandings on how estrogens, estrogen metabolism, dehydroepiandrosterone, and additional susceptibility factors may all contribute to the pathogenesis or potentially to the treatment of pulmonary hypertension, by evaluating current human, cell-based, and experimental model data. PMID:24015330

  17. Update on pulmonary arterial hypertension pharmacotherapy.

    PubMed

    Velayati, Arash; Valerio, Marcos G; Shen, Michael; Tariq, Sohaib; Lanier, Gregg M; Aronow, Wilbert S

    2016-06-01

    Pulmonary artery hypertension (PAH) refers to several subgroups of disease in which the mean pulmonary artery pressure (mPAP) is elevated to more than 25 mm Hg, pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg, and an elevated pulmonary vascular resistance (PVR) > 3 Wood units as confirmed by right heart catheterization. The prevalence and geographic distribution of PAH vary depending on the type and etiology of the disease. Despite enormous efforts in the research and development of therapeutic agents in the last twenty years, the disease remains relatively incurable and the overall prognosis remains guarded. Median survival for an untreated patient is 2.8 years. In the last three decades, there have been dramatic advances in understanding the molecular mechanisms and signaling pathways involved in the disease, resulting in emerging new treatment strategies. In the following pages, we will review currently approved treatments for PAH, as well as a new generation of investigational drugs. PMID:27232660

  18. [Pulmonary arterial hypertension: a flavor of autoimmunity].

    PubMed

    Perros, Frédéric; Humbert, Marc; Cohen-Kaminsky, Sylvia

    2013-01-01

    It is admitted that autoimmunity results from a combination of risks such as genetic background, environmental triggers, and stochastic events. Pulmonary arterial hypertension (PAH) shares with the so-called prototypic autoimmune diseases, genetic risk factors, female predominance and sex hormone influence, association with other chronic inflammatory and autoimmune diseases, defects in regulatory T cells function, and presence of autoantibodies. Case reports have been published indicating the beneficial effect of some immunosuppressive and anti-inflammatory therapies in PAH, supporting the potential role of immune mechanisms in the pathophysiology of the disease. In this review, we discuss the current knowledge on autoimmune mechanisms operating in PAH, especially mounting a local autoimmune response inside the pulmonary tissue, namely pulmonary lymphoid neogenesis. A better understanding of the role of autoimmunity in pulmonary vascular remodelling may help develop targeted immunomodulatory strategies in PAH. PMID:23859515

  19. Sex differences in the pulmonary circulation: implications for pulmonary hypertension

    PubMed Central

    Martin, Yvette N.

    2014-01-01

    Pulmonary arterial hypertension (PAH), a form of pulmonary hypertension, is a complex disease of multifactorial origin. While new developments regarding pathophysiological features and therapeutic options in PAH are being reported, one important fact has emerged over the years: there is a sex difference in the incidence of this disease such that while there is a higher incidence in females, disease outcomes are much worse in males. Accordingly, recent attention has been focused on understanding the features of sex differences in the pulmonary circulation and the contributory mechanisms, particularly sex hormones and their role in the pathological and pathophysiological features of PAH. However, to date, there is no clear consensus whether sex hormones (particularly female sex steroids) are beneficial or detrimental in PAH. In this review, we highlight some of the most recent evidence regarding the influence of sex hormones (estrogen, testosterone, progesterone, dehydroepiandrosterone) and estrogen metabolites on key pathophysiological features of PAH such as proliferation, vascular remodeling, vasodilation/constriction, and inflammation, thus setting the stage for research avenues to identify novel therapeutic target for PAH as well as potentially other forms of pulmonary hypertension. PMID:24610923

  20. [Pulmonary hypertension: definition, diagnostic and new classification].

    PubMed

    Seferian, Andrei; Simonneau, Gérald

    2014-09-01

    Pulmonary hypertension (PH): mean pulmonary arterial pressure (mPAP) ≥ 25 mm Hg on right heart catheterization at rest. Pulmonary arterial hypertension (PAH): mPAP ≥ 25 mm Hg, pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg and pulmonary vascular resistances (PVR) >3 Wood units. Patients with compatible symptoms (exertional dyspnea, syncopes, signes of right heart failure) can show signs of PH on cardiac echography and therefore need to be investigated in search of the cause of PH. After ruling out the frequent causes of PH (left heart and chronic respiratory diseases), the V/Q lung scan is used to screen for patients with post-embolic PH, that need to be further investigated hemodynamically and radiologically in order to decide operability. For the rest of the patients, only right heart catheterization can identify patients with precapillary PH and these patients must be further evaluated (clinically, by blood samples and by imaging techniques) in order to be classified in one the PH groups of the classification. For the future the discovery of novel risk factors and understanding the mechanism involved with the already known ones represent two major points of research.

  1. Pharmacologic treatments for pulmonary hypertension: exploring pharmacogenomics

    PubMed Central

    Duarte, Julio D; Hanson, Rebekah L; Machado, Roberto F

    2013-01-01

    Pulmonary hypertension (PH) is a disease with multiple etiologies and is categorized into five broad groups. Of these groups, pulmonary arterial hypertension (PAH) is the most studied and, therefore, all of the currently available drug classes (prostacyclin analogs, endothelin receptor antagonists and phosphodiesterase type 5 inhibitors) were developed to treat PAH. Thus, limited treatment data exist for the less-studied non-PAH forms of PH. Pharmacogenomics can be a tool to better understand the pathways involved in PH, as well as to improve personalization of therapy. However, little pharmacogenomic research has been carried out on this disease. New treatments for PH are on the horizon, deriving from both repurposed currently available drugs and novel therapeutics. PMID:23668740

  2. Standards of care in pulmonary hypertension.

    PubMed

    Barberà, Joan A; Escribano, Pilar; Morales, Pilar; Gómez, Miguel Á; Oribe, Mikel; Martínez, Angel; Román, Antonio; Segovia, Javier; Santos, Francisco; Subirana, María T

    2008-02-01

    Consensus Statement of the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR) and the Spanish Society of Cardiology (SEC). Substantial progress in the diagnosis and treatment of patients with pulmonary hypertension in recent years has led to significant improvement in survival. Evidence-based clinical practice guidelines issued by scientific societies reflect these new developments. However, certain clinically relevant issues have not been covered in consensus guidelines because of the lack of conclusive scientific evidence. Therefore, the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR) and the Spanish Society of Cardiology (SEC) have promoted the present consensus statement in order to define national standards of care in the evaluation and management of pulmonary hypertension in its various forms, as well as to outline a clinical pathway and the basic principles for organizing health care in this clinical setting, with special emphasis on the requirements for and functions of specialized referral units. To prepare the statement, SEPAR and SEC formed a task force composed of national experts in various aspects of pulmonary hypertension. The resulting consensus is based on international clinical guidelines, a review of available scientific evidence, and panel discussion among the task force members. The final statement, approved by all participants, underwent external review.

  3. Novel biomarkers for pulmonary arterial hypertension.

    PubMed

    Anwar, Anjum; Ruffenach, Gregoire; Mahajan, Aman; Eghbali, Mansoureh; Umar, Soban

    2016-01-01

    Pulmonary arterial hypertension is a deadly disease characterized by elevated pulmonary arterial pressures leading to right ventricular hypertrophy and failure. The confirmatory gold standard test is the invasive right heart catheterization. The disease course is monitored by pulmonary artery systolic pressure measurement via transthoracic echocardiography. A simple non-invasive test to frequently monitor the patients is much needed. Search for a novel biomarker that can be detected by a simple test is ongoing and many different options are being studied. Here we review some of the new and unique pre-clinical options for potential pulmonary hypertension biomarkers. These biomarkers can be broadly categorized based on their association with endothelial cell dysfunction, inflammation, epigenetics, cardiac function, oxidative stress, metabolism,extracellular matrix, and volatile compounds in exhaled breath condensate. A biomarker that can be detected in blood, urine or breath condensate and correlates with disease severity, progression and response to therapy may result in significant cost reduction and improved patient outcomes. PMID:27439993

  4. Targeted therapies in pulmonary arterial hypertension.

    PubMed

    Montani, David; Chaumais, Marie-Camille; Guignabert, Christophe; Günther, Sven; Girerd, Barbara; Jaïs, Xavier; Algalarrondo, Vincent; Price, Laura C; Savale, Laurent; Sitbon, Olivier; Simonneau, Gérald; Humbert, Marc

    2014-02-01

    Pulmonary arterial hypertension (PAH) is a rare disorder characterized by progressive obliteration of small pulmonary arteries that leads to elevated pulmonary arterial pressure and right heart failure. During the last decades, an improved understanding of the pathophysiology of the disease has resulted in the development of effective therapies targeting endothelial dysfunction (epoprostenol and derivatives, endothelin receptor antagonists and phosphodiesterase type 5 inhibitors). These drugs allow clinical, functional and hemodynamic improvement. Even though, no cure exists for PAH and prognosis remains poor. Recently, several additional pathways have been suggested to be involved in the pathogenesis of PAH, and may represent innovative therapies. In this summary, we review conventional therapy, pharmacological agents currently available for the treatment of PAH and the benefit/risk ratio of potential future therapies. PMID:24134901

  5. Definition, epidemiology and registries of pulmonary hypertension.

    PubMed

    Awdish, R; Cajigas, H

    2016-05-01

    Pulmonary arterial hypertension (PAH) is a subcategory of pulmonary hypertension (PH) that comprises a group of disorders with similar pulmonary vascular pathology. Though PH is common, the estimated incidence of IPAH is 1-3 cases per million, making it a rare disease. The hemodynamic definition of PAH is a mean pulmonary artery pressure at rest >OR = 25 mm Hg in the presence of a pulmonary capillary wedge pressure pulmonary vascular resistance (PVR) greater than 3 WU. Specific maneuvers during right heart catheterization can be utilized to disclose vasoreactivity and heart failure with preserved ejection fraction, which have implications for management. The inherent complexity in studying a rare disease that exhibits clinical overlap with a common syndrome necessitated the creation of registries. These registries have been indispensable in the characterization and mapping of the natural history of the disease. Equations and risk calculators derived from registries have given clinicians a basis for risk stratification and prognostication. The sequential accumulation of data since the registries began in the 1980s allows for comparisons to be made. Patients who are differentiated by treatment eras and environments can be contrasted. Variability among inclusion criteria similarly allows for comparisons of these subpopulations. This article provides an overview of available registries, highlights insights provided by each and discusses key issues around the interpretation and extrapolation of data from PAH registries. Registries have allowed us to appreciate the improvement in survival afforded by modern therapy and enhanced detection of this disease. Moving forward, a more global approach to registries is needed, as is enhanced collaboration and centralization.

  6. Oestrogen receptor alpha in pulmonary hypertension

    PubMed Central

    Wright, Audrey F.; Ewart, Marie-Ann; Mair, Kirsty; Nilsen, Margaret; Dempsie, Yvonne; Loughlin, Lynn; Maclean, Margaret R.

    2015-01-01

    Aims Pulmonary arterial hypertension (PAH) occurs more frequently in women with mutations in bone morphogenetic protein receptor type 2 (BMPR2) and dysfunctional BMPR2 signalling underpinning heritable PAH. We have previously shown that serotonin can uncover a pulmonary hypertensive phenotype in BMPR2+/− mice and that oestrogen can increase serotinergic signalling in human pulmonary arterial smooth muscle cells (hPASMCs). Hence, here we wished to characterize the expression of oestrogen receptors (ERs) in male and female human pulmonary arteries and have examined the influence of oestrogen and serotonin on BMPR2 and ERα expression. Methods and results By immunohistochemistry, we showed that ERα, ERβ, and G-protein-coupled receptors are expressed in human pulmonary arteries localizing mainly to the smooth muscle layer which also expresses the serotonin transporter (SERT). Protein expression of ERα protein was higher in female PAH patient hPASMCs compared with male and serotonin also increased the expression of ERα. 17β-estradiol induced proliferation of hPASMCs via ERα activation and this engaged mitogen-activated protein kinase and Akt signalling. Female mice over-expressing SERT (SERT+ mice) develop PH and the ERα antagonist MPP attenuated the development of PH in normoxic and hypoxic female SERT+ mice. The therapeutic effects of MPP were accompanied by increased expression of BMPR2 in mouse lung. Conclusion ERα is highly expressed in female hPASMCs from PAH patients and mediates oestrogen-induced proliferation of hPASMCs via mitogen-activated protein kinase and Akt signalling. Serotonin can increase ERα expression in hPASMCs and antagonism of ERα reverses serotonin-dependent PH in the mouse and increases BMPR2 expression. PMID:25765937

  7. Meandering right pulmonary vein associated with severe and progressive "idiopathic-like" pulmonary hypertensive vascular disease.

    PubMed

    Cuenca, Sofia; Bret, Montserrat; del Cerro, Maria Jesus

    2016-03-01

    Congenital anomalies of the pulmonary veins are rare. Meandering right pulmonary vein, considered a part of the Scimitar syndrome spectrum, is often an incidental finding during chest imaging. We present the case of a 4-year-old girl diagnosed with meandering pulmonary vein, who developed pulmonary hypertensive disease with an aggressive course, in spite of absence of hypoxia or elevated pulmonary wedge pressure.

  8. Pulmonary hypertension: diagnostic and therapeutic challenges

    PubMed Central

    Bazan, Isabel S; Fares, Wassim H

    2015-01-01

    Pulmonary hypertension (PH) is a hemodynamic and pathophysiologic state that can be found in multiple conditions with associated symptoms of dyspnea, decreased exercise tolerance, and progression to right heart failure. The World Health Organization has classified PH into five groups. The first group is pulmonary arterial hypertension (PAH), which can be idiopathic, heritable, due to drugs and toxins, or associated with conditions such as connective tissue diseases, congenital heart disease, portal hypertension, and others. The development of PAH is believed to result from smooth muscle cells and endothelial dysfunction that impairs production of vasodilators, including nitric oxide and prostacyclin. The importance of distinguishing this group from the other groups of PH is that there are PAH-specific drugs that target the molecular pathways that are pathogenic in the vascular derangements, leading to arterial hypertension, which should not be used in the other forms of PH. Other groups of PH include PH due to left heart disease, lung disease, chronic thromboembolic disease, as well as a miscellaneous category. Echocardiography is used to screen for PH and has varying sensitivity and specificity in detecting PH. Additionally, the right heart pressures estimated during echocardiogram often differ from those obtained during confirmatory testing with right heart catheterization. The most challenging PH diagnosis is in a case that does not fit one group of PH, but meets criteria that overlap between several groups. This also makes the treatment challenging because each group of PH is managed differently. This review provides an overview of the five groups of PH and discusses the diagnostic and therapeutic challenges of each. PMID:26316767

  9. Pulmonary hypertension: diagnostic and therapeutic challenges.

    PubMed

    Bazan, Isabel S; Fares, Wassim H

    2015-01-01

    Pulmonary hypertension (PH) is a hemodynamic and pathophysiologic state that can be found in multiple conditions with associated symptoms of dyspnea, decreased exercise tolerance, and progression to right heart failure. The World Health Organization has classified PH into five groups. The first group is pulmonary arterial hypertension (PAH), which can be idiopathic, heritable, due to drugs and toxins, or associated with conditions such as connective tissue diseases, congenital heart disease, portal hypertension, and others. The development of PAH is believed to result from smooth muscle cells and endothelial dysfunction that impairs production of vasodilators, including nitric oxide and prostacyclin. The importance of distinguishing this group from the other groups of PH is that there are PAH-specific drugs that target the molecular pathways that are pathogenic in the vascular derangements, leading to arterial hypertension, which should not be used in the other forms of PH. Other groups of PH include PH due to left heart disease, lung disease, chronic thromboembolic disease, as well as a miscellaneous category. Echocardiography is used to screen for PH and has varying sensitivity and specificity in detecting PH. Additionally, the right heart pressures estimated during echocardiogram often differ from those obtained during confirmatory testing with right heart catheterization. The most challenging PH diagnosis is in a case that does not fit one group of PH, but meets criteria that overlap between several groups. This also makes the treatment challenging because each group of PH is managed differently. This review provides an overview of the five groups of PH and discusses the diagnostic and therapeutic challenges of each. PMID:26316767

  10. Pulmonary hypertension in dogs: diagnosis and therapy.

    PubMed

    Kellihan, Heidi B; Stepien, Rebecca L

    2010-07-01

    Pulmonary hypertension (PH) has been recognized as a clinical syndrome for many years in veterinary medicine, but routine accurate clinical diagnosis in dogs was greatly enhanced by widespread use of echocardiography and Doppler echocardiography. Most cases of PH in veterinary medicine can be categorized as precapillary or postcapillary. These subsets of patients often differ with regard to clinical presentation, response to therapy, and prognosis. Effective medical therapy is now available to treat this often-devastating clinical complication of common chronic diseases, making accurate diagnosis even more important to patient longevity and quality of life.

  11. Clinical features of paediatric pulmonary hypertension: a registry study

    PubMed Central

    Berger, Rolf M F; Beghetti, Maurice; Humpl, Tilman; Raskob, Gary E; Ivy, D Dunbar; Jing, Zhi-Cheng; Bonnet, Damien; Schulze-Neick, Ingram; Barst, Robyn J

    2012-01-01

    Summary Background Paediatric pulmonary hypertension, is an important cause of morbidity and mortality, and is insufficiently characterised in children. The Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension (TOPP) registry is a global, prospective study designed to provide information about demographics, treatment, and outcomes in paediatric pulmonary hypertension. Methods Consecutive patients aged 18 years or younger at diagnosis with pulmonary hypertension and increased pulmonary vascular resistance were enrolled in TOPP at 31 centres in 19 countries from Jan 31, 2008, to Feb 15, 2010. Patient and disease characteristics, including age at diagnosis and at enrolment, sex, ethnicity, presenting symptoms, pulmonary hypertension classification, comorbid disorders, medical and family history, haemodynamic indices, and functional class were recorded. Follow-up was decided by the patients’ physicians according to the individual’s health-care needs. Findings 362 of 456 consecutive patients had confirmed pulmonary hypertension (defined as mean pulmonary artery pressure ≥25 mm Hg, pulmonary capillary wedge pressure ≤12 mm Hg, and pulmonary vascular resistance index ≥3 WU/m32). 317 (88%) patients had pulmonary arterial hypertension (PAH), which was idiopathic [IPAH] or familial [FPAH] in 182 (57%), and associated with other disorders in 135 (43%), of which 115 (85%) cases were associated with congenital heart disease. 42 patients (12%) had pulmonary hypertension associated with respiratory disease or hypoxaemia, with bronchopulmonary dysplasia most frequent. Finally, only three patients had either chronic thromboembolic pulmonary hypertension or miscellaneous causes of pulmonary hypertension. Chromosomal anomalies, mainly trisomy 21, were reported in 47 (13%) of patients with confirmed disease. Median age at diagnosis was 7 years (IQR 3–12); 59% (268 of 456) were female. Although dyspnoea and fatigue were the most frequent symptoms, syncope

  12. Multifactorial Etiology Pulmonary Hypertension in a Patient with Sarcoidosis

    PubMed Central

    Lucas Vinícius da Fonseca, Barreto; Felipe Naze Rodrigues, Cavalcante; Joselina Luzia Menezes, Oliveira; Marcos Antônio, Almeida-Santos; José Augusto Soares, Barreto-Filho; Antônio Carlos Sobral, Sousa

    2016-01-01

    Differential diagnosis between pre- and postcapillary pulmonary hypertension (PH) in patients with diastolic heart failure (DHF) is a challenge in clinical practice. The presence of PH is implicated in worse prognosis in patients with this disease. This case report approaches the process of investigation of pulmonary hypertension in adult patient with DHF, double mitral lesion, and sarcoidosis with poor clinical outcome. PMID:27800190

  13. [Patterns, predictors, and personalization in pulmonary arterial hypertension].

    PubMed

    Kawut, Steven M

    2014-06-01

    Epidemiologic patterns of pulmonary arterial hypertension differ by era and region and may shed light on the pathophysiology and treatment of the disease. New efforts to target one or more of the recently studied therapies could establish personalized medicine as standard care in pulmonary arterial hypertension. PMID:25164214

  14. Clinical characteristics of pulmonary hypertension in bronchiectasis.

    PubMed

    Wang, Lan; Jiang, Sen; Shi, Jingyun; Gong, Sugang; Zhao, Qinhua; Jiang, Rong; Yuan, Ping; Pudasaini, Bigyan; He, Jing; Jing, Zhicheng; Liu, Jinming

    2016-09-01

    Pulmonary hypertension (PH), as a complication of bronchiectasis, is associated with increased mortality. However, hemodynamic characteristics and the efficacy of pulmonary arterial hypertension (PAH) therapies in patients with bronchiectasis and PH remain unknown. Patients with bilateral bronchiectasis and concurrent PH were included in the study. Patient characteristics at baseline and during follow-up, as well as survival, were analyzed. This observational study was conducted in 36 patients with a mean age of 51.5 years (range, 17‒74 years). The 6 min walking distance was 300.8 ± 3.3 m. The mean pulmonary arterial pressure (PAP) was 41.5 ± 1.7 mmHg, cardiac output was 5.2 ± 1.4 L/min, and pulmonary vascular resistance was 561.5 ± 281.5 dyn∙s∙cm(-5). The mean PAP was > 35 mmHg in 75% of the cases. Mean PAP was inversely correlated with arterial oxygen saturation values (r =-0.45, P = 0.02). In 24 patients who received oral PAH therapy, systolic PAP was reduced from 82.4 ± 27.0 mmHg to 65.5 ± 20.9 mmHg (P = 0.025) on echocardiography after a median of 6 months of follow-up. The overall probability of survival was 97.1% at 1 year, 83.4% at 3 years, and 64.5% at 5 years. Given the results, we conclude that PH with severe hemodynamic impairment can occur in patients with bilateral bronchiectasis, and PAH therapy might improve hemodynamics in such patients. Prospective clinical trials focusing on this patient population are warranted. PMID:27527360

  15. Pulmonary hypertension in chronic interstitial lung diseases.

    PubMed

    Caminati, Antonella; Cassandro, Roberto; Harari, Sergio

    2013-09-01

    Pulmonary hypertension (PH) is a common complication of interstitial lung diseases (ILDs), particularly in idiopathic pulmonary fibrosis and ILD associated with connective tissue disease. However, other lung diseases, such as combined pulmonary fibrosis and emphysema syndrome, pulmonary Langerhans cell histiocytosis, and lymphangioleiomyomatosis, may also include PH in their clinical manifestations. In all of these diseases, PH is associated with reduced exercise capacity and poor prognosis. The degree of PH in ILDs is typically mild-to-moderate. However, some of these patients may develop a disproportionate increase in PH that cannot be justified solely by hypoxia and parenchymal injury: this condition has been termed "out-of-proportion" PH. The pathogenesis of PH in these diseases is various, incompletely understood and may be multifactorial. The clinical suspicion (i.e. increased dyspnoea, low diffusion capacity) and echocardiographic assessment are the first steps towards proper diagnosis of PH; however, right heart catheterisation remains the current gold standard for diagnosis of PH. At present, no specific therapies have been approved for the treatment of PH in patients with ILDs. PMID:23997057

  16. Overview of current therapeutic approaches for pulmonary hypertension

    PubMed Central

    Stamm, Jason A.; Risbano, Michael G.; Mathier, Michael A.

    2011-01-01

    There have been tremendous strides in the management of pulmonary hypertension over the past 20 years with the introduction of targeted medical therapies and overall improvements in surgical treatment options and general supportive care. Furthermore, recent data shows that the survival of those with pulmonary arterial hypertension is improving. While there has been tremendous progress, much work remains to be done in improving the care of those with secondary forms of pulmonary hypertension, who constitute the majority of patients with this disorder, and in the optimal treatment approach in those with pulmonary arterial hypertension. This article will review general and targeted medical treatment, along with surgical interventions, of those with pulmonary hypertension. PMID:22034603

  17. Pulmonary hypertension in chronic lung diseases.

    PubMed

    Seeger, Werner; Adir, Yochai; Barberà, Joan Albert; Champion, Hunter; Coghlan, John Gerard; Cottin, Vincent; De Marco, Teresa; Galiè, Nazzareno; Ghio, Stefano; Gibbs, Simon; Martinez, Fernando J; Semigran, Marc J; Simonneau, Gerald; Wells, Athol U; Vachiéry, Jean-Luc

    2013-12-24

    Chronic obstructive lung disease (COPD) and diffuse parenchymal lung diseases (DPLD), including idiopathic pulmonary fibrosis (IPF) and sarcoidosis, are associated with a high incidence of pulmonary hypertension (PH), which is linked with exercise limitation and a worse prognosis. Patients with combined pulmonary fibrosis and emphysema (CPFE) are particularly prone to the development of PH. Echocardiography and right heart catheterization are the principal modalities for the diagnosis of COPD and DPLD. For discrimination between group 1 PH patients with concomitant respiratory abnormalities and group 3 PH patients (PH caused by lung disease), patients should be transferred to a center with expertise in both PH and lung diseases for comprehensive evaluation. The task force encompassing the authors of this article provided criteria for this discrimination and suggested using the following definitions for group 3 patients, as exemplified for COPD, IPF, and CPFE: COPD/IPF/CPFE without PH (mean pulmonary artery pressure [mPAP] <25 mm Hg); COPD/IPF/CPFE with PH (mPAP ≥25 mm Hg); PH-COPD, PH-IPF, and PH-CPFE); COPD/IPF/CPFE with severe PH (mPAP ≥35 mm Hg or mPAP ≥25 mm Hg with low cardiac index [CI <2.0 l/min/m(2)]; severe PH-COPD, severe PH-IPF, and severe PH-CPFE). The "severe PH group" includes only a minority of chronic lung disease patients who are suspected of having strong general vascular abnormalities (remodeling) accompanying the parenchymal disease and with evidence of an exhausted circulatory reserve rather than an exhausted ventilatory reserve underlying the limitation of exercise capacity. Exertional dyspnea disproportionate to pulmonary function tests, low carbon monoxide diffusion capacity, and rapid decline of arterial oxygenation upon exercise are typical clinical features of this subgroup with poor prognosis. Studies evaluating the effect of pulmonary arterial hypertension drugs currently not approved for group 3 PH patients should focus on

  18. Pulmonary Artery Denervation Reduces Pulmonary Artery Pressure and Induces Histological Changes in an Acute Porcine Model of Pulmonary Hypertension

    PubMed Central

    Arnold, Nadine D.; Chang, William; Watson, Oliver; Swift, Andrew J.; Condliffe, Robin; Elliot, Charlie A.; Kiely, David G.; Suvarna, S. Kim; Gunn, Julian; Lawrie, Allan

    2015-01-01

    Background— Pulmonary arterial hypertension is a devastating disease with high morbidity and mortality and limited treatment options. Recent studies have shown that pulmonary artery denervation improves pulmonary hemodynamics in an experimental model and in an early clinical trial. We aimed to evaluate the nerve distribution around the pulmonary artery, to determine the effect of radiofrequency pulmonary artery denervation on acute pulmonary hypertension induced by vasoconstriction, and to demonstrate denervation of the pulmonary artery at a histological level. Methods and Results— Histological evaluation identified a circumferential distribution of nerves around the proximal pulmonary arteries. Nerves were smaller in diameter, greater in number, and located in closer proximity to the luminal aspect of the pulmonary arterial wall beyond the pulmonary artery bifurcation. To determine the effect of pulmonary arterial denervation acute pulmonary hypertension was induced in 8 pigs by intravenous infusion of thromboxane A2 analogue. Animals were assigned to either pulmonary artery denervation, using a prototype radiofrequency catheter and generator, or a sham procedure. Pulmonary artery denervation resulted in reduced mean pulmonary artery pressure and pulmonary vascular resistance and increased cardiac output. Ablation lesions on the luminal surface of the pulmonary artery were accompanied by histological and biochemical alteration in adventitial nerves and correlated with improved hemodynamic parameters. Conclusions— Pulmonary artery denervation offers the possibility of a new treatment option for patients with pulmonary arterial hypertension. Further work is required to determine the long-term efficacy and safety. PMID:26553697

  19. Treatment-Related Biomarkers in Pulmonary Hypertension

    PubMed Central

    Swaminathan, Aparna C.; Dusek, Alex C.

    2015-01-01

    Significant advances in the treatment of pulmonary arterial hypertension (PAH) over the last two decades have led to the introduction of multiple classes of oral therapy, but the disease remains devastating for many patients. Disease progression, in spite of oral monotherapy, is a major problem, and alternative therapy, such as infusion of prostacyclins, is cumbersome and carries considerable potential morbidity. Use of combination oral therapy, including drugs from both the endothelin receptor antagonist and phosphodiesterase-5 inhibitor classes, has increased, and there is some evidence to support this approach. Given the multiple options now available in pulmonary hypertension (PH) therapy, biomarkers to guide treatment decisions could be helpful. Here, we review the evidence for and against the clinical use of molecular biomarkers relevant to PH pathogenesis, emphasizing assayable markers that may also inform more rational selection of agents that influence pathways targeted by treatment. We emphasize the interactive nature of changes in mediators and messengers, such as endothelin-1, prostacyclin, brain natriuretic peptide (which has demonstrated biomarker utility), nitric oxide derivatives, and cyclic guanosine monophosphate, which play important roles in processes central to progression of PAH, such as vascular remodeling, vasoconstriction, and maladaptive right ventricular changes, and are relevant to its therapy. Accordingly, we propose that the identification and use of a molecular biomarker panel that assays these molecules in parallel and serially might, if validated, better inform unique patient phenotypes, prognosis, and the rational selection and titration of combination oral and other therapy in individual patients with PH/PAH. PMID:25611885

  20. A Contemporary Approach to Pulmonary Arterial Hypertension.

    PubMed

    Krishnan, Udhay; Horn, Evelyn M

    2016-09-01

    In recent years, there have been major changes in the landscape of pulmonary arterial hypertension therapy with the introduction of novel agents and innovative treatment strategies for this progressive disease. The aim of this review is to discuss the evolution in trial design in this field and highlight the salient features of recently published studies. We also summarize our approach to therapy selection in this chronic disease and identify areas for future exploration. The therapeutic armamentarium now includes 13 approved therapies. While most of these agents have been studied in small, short-term trials using the 6-min walk distance as a primary endpoint, there has been a shift in recent years toward larger, long-term, event-driven trials that utilize combined morbidity and mortality endpoints. The SERAPHIN and GRIPHON trials were two such studies, which led to the approval of the dual endothelin-receptor antagonist macitentan and the selective prostacyclin receptor antagonist selexipag, respectively. Other event-driven trials, like AMBITION and COMPASS-2, have provided valuable insight into the use of combined oral therapies in symptomatic patients. In conclusion, despite being a more manageable disease in the modern treatment era, pulmonary hypertension is still associated with considerable morbidity and much more work remains to be done in this field. Important questions remain about the most optimal way to manage patients and conduct trials going forward. PMID:27491673

  1. Changes in large pulmonary arterial viscoelasticity in chronic pulmonary hypertension.

    PubMed

    Wang, Zhijie; Lakes, Roderic S; Golob, Mark; Eickhoff, Jens C; Chesler, Naomi C

    2013-01-01

    Conduit pulmonary artery (PA) stiffening is characteristic of pulmonary arterial hypertension (PAH) and is an excellent predictor of mortality due to right ventricular (RV) overload. To better understand the impact of conduit PA stiffening on RV afterload, it is critical to examine the arterial viscoelastic properties, which require measurements of elasticity (energy storage behavior) and viscosity (energy dissipation behavior). Here we hypothesize that PAH leads to frequency-dependent changes in arterial stiffness (related to elasticity) and damping ratio (related to viscosity) in large PAs. To test our hypothesis, PAH was induced by the combination of chronic hypoxia and an antiangiogenic compound (SU5416) treatment in mice. Static and sinusoidal pressure-inflation tests were performed on isolated conduit PAs at various frequencies (0.01-20 Hz) to obtain the mechanical properties in the absence of smooth muscle contraction. Static mechanical tests showed significant stiffening of large PAs with PAH, as expected. In dynamic mechanical tests, structural stiffness (κ) increased and damping ratio (D) decreased at a physiologically relevant frequency (10 Hz) in hypertensive PAs. The dynamic elastic modulus (E), a material stiffness, did not increase significantly with PAH. All dynamic mechanical properties were strong functions of frequency. In particular, κ, E and D increased with increasing frequency in control PAs. While this behavior remained for D in hypertensive PAs, it reversed for κ and E. Since these novel dynamic mechanical property changes were found in the absence of changes in smooth muscle cell content or contraction, changes in collagen and proteoglycans and their interactions are likely critical to arterial viscoelasticity in a way that has not been previously described. The impact of these changes in PA viscoelasticity on RV afterload in PAH awaits further investigation. PMID:24223157

  2. Changes in Large Pulmonary Arterial Viscoelasticity in Chronic Pulmonary Hypertension

    PubMed Central

    Wang, Zhijie; Lakes, Roderic S.; Golob, Mark; Eickhoff, Jens C.; Chesler, Naomi C.

    2013-01-01

    Conduit pulmonary artery (PA) stiffening is characteristic of pulmonary arterial hypertension (PAH) and is an excellent predictor of mortality due to right ventricular (RV) overload. To better understand the impact of conduit PA stiffening on RV afterload, it is critical to examine the arterial viscoelastic properties, which require measurements of elasticity (energy storage behavior) and viscosity (energy dissipation behavior). Here we hypothesize that PAH leads to frequency-dependent changes in arterial stiffness (related to elasticity) and damping ratio (related to viscosity) in large PAs. To test our hypothesis, PAH was induced by the combination of chronic hypoxia and an antiangiogenic compound (SU5416) treatment in mice. Static and sinusoidal pressure-inflation tests were performed on isolated conduit PAs at various frequencies (0.01–20 Hz) to obtain the mechanical properties in the absence of smooth muscle contraction. Static mechanical tests showed significant stiffening of large PAs with PAH, as expected. In dynamic mechanical tests, structural stiffness (κ) increased and damping ratio (D) decreased at a physiologically relevant frequency (10 Hz) in hypertensive PAs. The dynamic elastic modulus (E), a material stiffness, did not increase significantly with PAH. All dynamic mechanical properties were strong functions of frequency. In particular, κ, E and D increased with increasing frequency in control PAs. While this behavior remained for D in hypertensive PAs, it reversed for κ and E. Since these novel dynamic mechanical property changes were found in the absence of changes in smooth muscle cell content or contraction, changes in collagen and proteoglycans and their interactions are likely critical to arterial viscoelasticity in a way that has not been previously described. The impact of these changes in PA viscoelasticity on RV afterload in PAH awaits further investigation. PMID:24223157

  3. Persistent pulmonary hypertension of the newborn.

    PubMed

    Sharma, Vinay; Berkelhamer, Sara; Lakshminrusimha, Satyan

    2015-01-01

    Persistent pulmonary hypertension of the newborn (PPHN) is characterized by elevated pulmonary vascular resistance resulting in right-to-left shunting of blood and hypoxemia. PPHN is often secondary to parenchymal lung disease (such as meconium aspiration syndrome, pneumonia or respiratory distress syndrome) or lung hypoplasia (with congenital diaphragmatic hernia or oligohydramnios) but can also be idiopathic. The diagnosis of PPHN is based on clinical evidence of labile hypoxemia often associated with differential cyanosis. The diagnosis is confirmed by the echocardiographic demonstration of - (a) right-to-left or bidirectional shunt at the ductus or foramen ovale and/or, (b) flattening or leftward deviation of the interventricular septum and/or, (c) tricuspid regurgitation, and finally (d) absence of structural heart disease. Management strategies include optimal oxygenation, avoiding respiratory and metabolic acidosis, blood pressure stabilization, sedation and pulmonary vasodilator therapy. Failure of these measures would lead to consideration of extracorporeal membrane oxygenation (ECMO); however decreased need for this rescue therapy has been documented with advances in medical management. While trends also note improved survival, long-term neurodevelopmental disabilities such as deafness and learning disabilities remain a concern in many infants with severe PPHN. Funded by: 1R01HD072929-0 (SL). PMID:27057331

  4. Pregnancy and pulmonary hypertension: a practical approach to management

    PubMed Central

    Condliffe, Robin; Wilson, Vicki J; Gandhi, Suarabh V; Elliot, Charlie A

    2013-01-01

    Pulmonary hypertension remains a major cause of cardiac maternal death in the developed world. Over the last two decades, effective therapies for pulmonary hypertension have been developed, improving symptoms and survival. Consequently, increasing numbers of women with pulmonary hypertension and childbearing potential exist, with a number considering pregnancy. Patients with pulmonary hypertension may also present for the first time during pregnancy or shortly following delivery. The last decade has seen increasing reports of women with pulmonary hypertension surviving pregnancy using a variety of approaches but there is still a significant maternal mortality at between 12% and 33%. Current recommendations counsel that patients with known pulmonary hypertension should be strongly advised to avoid pregnancy with the provision of clear contraceptive advice and termination of pregnancy should be considered in its eventuality. In patients who are fully informed and who have been counselled regarding the risks of continuing with pregnancy, there is growing evidence that a multi-professional approach with expert care in pulmonary hypertension centres may improve outlook, although the mortality remains high.

  5. Perioperative management of the patient with pulmonary hypertension.

    PubMed

    Fox, Daniel L; Stream, Amanda R; Bull, Todd

    2014-12-01

    Patients with pulmonary hypertension are at increased risk for perioperative morbidity and mortality. Elective surgery is generally discouraged in this patient population; however, there are times when surgery is deemed necessary. Currently, there are no guidelines for the preoperative risk assessment or perioperative management of subjects with pulmonary hypertension. The majority of the literature evaluating perioperative risk factors and mortality rates is observational and includes subjects with multiple etiologies of pulmonary hypertension. Subjects with pulmonary arterial hypertension, also referred to as World Health Organization group I pulmonary hypertension, and particularly those receiving pulmonary arterial hypertension-specific therapy may be at increased risk. Perioperative management of these patients requires a solid understanding and careful consideration of the hemodynamic effects of anesthetic agents, positive pressure ventilation and volume shifts associated with surgery in order to prevent acute right ventricular failure. We reviewed the most recent data regarding perioperative morbidity and mortality for subjects with pulmonary hypertension in an effort to better guide preoperative risk assessment and perioperative management by a multidisciplinary team. PMID:24828282

  6. Severe Pulmonary Arteriopathy Is Associated with Persistent Hypoxemia after Pulmonary Endarterectomy in Chronic Thromboembolic Pulmonary Hypertension

    PubMed Central

    Tanabe, Nobuhiro; Sakao, Seiichiro; Ishibashi-Ueda, Hatsue; Ishida, Keiichi; Naito, Akira; Kato, Fumiaki; Takeuchi, Takao; Sekine, Ayumi; Nishimura, Rintaro; Sugiura, Toshihiko; Shigeta, Ayako; Masuda, Masahisa; Tatsumi, Koichiro

    2016-01-01

    Background Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by occlusion of pulmonary arteries by organized chronic thrombi. Persistent hypoxemia and residual pulmonary hypertension (PH) following successful pulmonary endarterectomy (PEA) are clinically important problems; however, the underlying mechanisms remain unclear. We have previously reported that residual PH is closely related to severe pulmonary vascular remodeling and hypothesize that this arteriopathy might also be involved in impaired gas exchange. The purpose of this study was to evaluate the association between hypoxemia and pulmonary arteriopathy after PEA. Methods and Results Between December 2011 and November 2014, 23 CTEPH patients underwent PEA and lung biopsy. The extent of pulmonary arteriopathy was quantified pathologically in lung biopsy specimens. We then analyzed the relationship between the severity of pulmonary arteriopathy and gas exchange after PEA. We observed that the severity of pulmonary arteriopathy was negatively correlated with postoperative and follow-up PaO2 (postoperative PaO2: r = -0.73, p = 0.0004; follow-up PaO2: r = -0.66, p = 0.001), but not with preoperative PaO2 (r = -0.373, p = 0.08). Multivariate analysis revealed that the obstruction ratio and patient age were determinants of PaO2 one month after PEA (R2 = 0.651, p = 0.00009). Furthermore, the obstruction ratio and improvement of pulmonary vascular resistance were determinants of PaO2 at follow-up (R2 = 0.545, p = 0.0002). Severe pulmonary arteriopathy might increase the alveolar-arterial oxygen difference and impair diffusion capacity, resulting in hypoxemia following PEA. Conclusion The severity of pulmonary arteriopathy was closely associated with postoperative and follow-up hypoxemia. PMID:27571267

  7. Measurement of regional pulmonary blood volume in patients with increased pulmonary blood flow or pulmonary arterial hypertension

    SciTech Connect

    Wollmer, P.; Rozcovek, A.; Rhodes, C.G.; Allan, R.M.; Maseri, A.

    1984-01-01

    The effects of chronic increase in pulmonary blood flow and chronic pulmonary hypertension on regional pulmonary blood volume was measured in two groups of patients. One group of patients had intracardiac, left-to-right shunts without appreciable pulmonary hypertension, and the other consisted of patients with Eisenmenger's syndrome or primary pulmonary hypertension, i.e. patients with normal or reduced blood flow and severe pulmonary hypertension. A technique based on positron tomography was used to measure lung density (by transmission scanning) and regional pulmonary blood volume (after inhalation of /sup 11/CO). The distribution of pulmonary blood volume was more uniform in patients with chronic increase in pulmonary blood flow than in normal subjects. There were also indications of an absolute increase in intrapulmonary blood volume by about 15%. In patients with chronic pulmonary arterial hypertension, the distribution of pulmonary blood volume was also abnormally uniform. There was, however, no indication that overall intrapulmonary blood volume was substantially different from normal subjects. The abnormally uniform distribution of pulmonary blood volume can be explained by recruitment and/or dilatation of vascular beds. Intrapulmonary blood volume appears to be increased in patients with intracardiac, left-to-right shunts. With the development of pulmonary hypertension, intrapulmonary blood volume falls, which may be explained by reactive changes in the vasculature and/or obliteration of capillaries.

  8. Pulmonary Hypertension in Hemodialysis Patients Following Repeated Endovascular Thrombectomy

    PubMed Central

    Hsieh, Mu-Yang; Lin, Lin; Chen, Tsung-Yan; Wang, Ren-Huei; Huang, Su-Chin; Liu, HsiuChiao; Lai, Chao-Lun; Pu, Shih-Yen; Tsai, Kuei-Chin; Wu, Chih-Cheng

    2016-01-01

    Background The prevalence of pulmonary hypertension is unusually high in Taiwanese patients with end-stage renal disease. Thrombosis of hemodialysis grafts is common and pulmonary embolism has been reported after endovascular thrombectomy. The aim of this study was to evaluate the relationship between pulmonary hypertension and endovascular thrombectomy of hemodialysis grafts. Methods One hundred and ten patients on hemodialysis via arteriovenous grafts were enrolled in our study. The mean pulmonary artery pressure (PAP) was measured by right heart catheterization. Clinical information was collected by review of medical records. Comorbid cardiopulmonary disease was evaluated by echocardiography and chest X-ray. The history of patient vascular access thrombosis was reviewed from database, hemodialysis records, and interviews with staff at hemodialysis centers. Results Fifty-two participants (47%) had pulmonary hypertension diagnosed by right heart catheterization. There was no difference in the number of thrombectomy procedures between patients with and without pulmonary hypertension. Based on multivariate analysis, the number of prior endovascular thrombectomy procedures did not correlate with mean PAP (F-value = 1.10, p = 0.30) nor was it associated with pulmonary hypertension (odds ratio = 0.92, p = 0.17). Conclusions Prior endovascular arteriovenous graft thrombectomies were not associated with pulmonary hypertension or increased mean PAP in end-stage renal disease patients on maintenance hemodialysis. PMID:27274170

  9. Noninvasive pulmonary artery wave intensity analysis in pulmonary hypertension.

    PubMed

    Quail, Michael A; Knight, Daniel S; Steeden, Jennifer A; Taelman, Liesbeth; Moledina, Shahin; Taylor, Andrew M; Segers, Patrick; Coghlan, Gerry J; Muthurangu, Vivek

    2015-06-15

    Pulmonary wave reflections are a potential hemodynamic biomarker for pulmonary hypertension (PH) and can be analyzed using wave intensity analysis (WIA). In this study we used pulmonary vessel area and flow obtained using cardiac magnetic resonance (CMR) to implement WIA noninvasively. We hypothesized that this method could detect differences in reflections in PH patients compared with healthy controls and could also differentiate certain PH subtypes. Twenty patients with PH (35% CTEPH and 75% female) and 10 healthy controls (60% female) were recruited. Right and left pulmonary artery (LPA and RPA) flow and area curves were acquired using self-gated golden-angle, spiral, phase-contrast CMR with a 10.5-ms temporal resolution. These data were used to perform WIA on patients and controls. The presence of a proximal clot in CTEPH patients was determined from contemporaneous computed tomography/angiographic data. A backwards-traveling compression wave (BCW) was present in both LPA and RPA of all PH patients but was absent in all controls (P = 6e(-8)). The area under the BCW was associated with a sensitivity of 100% [95% confidence interval (CI) 63-100%] and specificity of 91% (95% CI 75-98%) for the presence of a clot in the proximal PAs of patients with CTEPH. In conclusion, WIA metrics were significantly different between patients and controls; in particular, the presence of an early BCW was specifically associated with PH. The magnitude of the area under the BCW showed discriminatory capacity for the presence of proximal PA clot in patients with CTEPH. We believe that these results demonstrate that WIA could be used in the noninvasive assessment of PH. PMID:25659483

  10. Recapitulation of developing artery muscularization in pulmonary hypertension.

    PubMed

    Sheikh, Abdul Q; Lighthouse, Janet K; Greif, Daniel M

    2014-03-13

    Excess smooth muscle accumulation is a key component of many vascular disorders, including atherosclerosis, restenosis, and pulmonary artery hypertension, but the underlying cell biological processes are not well defined. In pulmonary artery hypertension, reduced pulmonary artery compliance is a strong independent predictor of mortality, and pathological distal arteriole muscularization contributes to this reduced compliance. We recently demonstrated that embryonic pulmonary artery wall morphogenesis consists of discrete developmentally regulated steps. In contrast, poor understanding of distal arteriole muscularization in pulmonary artery hypertension severely limits existing therapies that aim to dilate the pulmonary vasculature but have modest clinical benefit and do not prevent hypermuscularization. Here, we show that most pathological distal arteriole smooth muscle cells, but not alveolar myofibroblasts, derive from pre-existing smooth muscle. Furthermore, the program of distal arteriole muscularization encompasses smooth muscle cell dedifferentiation, distal migration, proliferation, and then redifferentiation, thereby recapitulating many facets of arterial wall development. PMID:24582963

  11. Reversible pre-capillary pulmonary hypertension due to dasatinib.

    PubMed

    Buchelli Ramirez, Herminia L; Álvarez Álvarez, Celso M; Rodríguez Reguero, José J; García Clemente, Marta M; Casan Clarà, Pere

    2014-05-01

    Pulmonary arterial hypertension and secondary pleural effusion have been reported in association with long-term therapy with the multi-tyrosine kinase inhibitor dasatinib, approved for the treatment of chronic myeloid leukemia. Here, we present the case of a 50-year-old man, diagnosed with chronic myeloid leukemia in August 2003, who developed pulmonary arterial hypertension after > 4 years of treatment with dasatinib. The complete remission of pulmonary arterial hypertension following dasatinib discontinuation suggests an etiological role of the drug in its development, although the administration of sildenafil may have played a therapeutic role. PMID:24149673

  12. Balloon Pulmonary Angioplasty: A Treatment Option for Inoperable Patients with Chronic Thromboembolic Pulmonary Hypertension

    PubMed Central

    Ogawa, Aiko; Matsubara, Hiromi

    2015-01-01

    In chronic thromboembolic pulmonary hypertension (CTEPH), stenoses or obstructions of the pulmonary arteries due to organized thrombi can cause an elevation in pulmonary artery resistance, which in turn can result in pulmonary hypertension. CTEPH can be cured surgically by pulmonary endarterectomy (PEA); however, patients deemed unsuitable for PEA due to lesion, advanced age, or comorbidities have a poor prognosis and limited treatment options. Recently, advances have been made in balloon pulmonary angioplasty for these patients, and this review highlights this recent progress. PMID:26664876

  13. Pulmonary arterial hypertension: a review in pharmacotherapy.

    PubMed

    Patel, Bhaumik B; Feng, Ying; Cheng-Lai, Angela

    2015-01-01

    Pulmonary arterial hypertension (PAH) is a progressive disease that remains incurable. The past 2 decades have witnessed many advances in PAH-directed therapies. More recently, 3 new oral agents have become available in the United States within the past 2 years. Treprostinil is now available in extended-release oral tablets. Macitentan is the third endothelin receptor antagonist approved for use, demonstrating benefits on morbidity and mortality among patients with PAH in an event-driven study. Riociguat is the first soluble guanylate cyclase stimulator that has been approved for use in the United States. This article reviews the clinical efficacy and safety of these 3 agents and the roles they play in the management of PAH. Additionally, we review the limitations of using surrogate markers such as change in 6-minute walk distance to assess disease progression.

  14. Advances in the management of chronic thromboembolic pulmonary hypertension.

    PubMed

    Papamatheakis, Demosthenes G; Kim, Nick H

    2015-09-01

    Chronic thromboembolic pulmonary hypertension (CTEPH), a potentially curable form of pulmonary hypertension with pulmonary thromboendarterectomy surgery, has been the focus of significant medical advances. In addition to new imaging modalities that are now used to help recognize and diagnose CTEPH, additional treatment options have emerged for inoperable cases. These include a newly approved medical therapy for inoperable disease or persistent/recurrent CTEPH as well as percutaneous balloon angioplasty of the pulmonary arteries. In this article, we summarize these recent advances in the field and review the related literature.

  15. Breath Analysis in Pulmonary Arterial Hypertension

    PubMed Central

    Cikach, Frank S.; Tonelli, Adriano R.; Barnes, Jarrod; Paschke, Kelly; Newman, Jennie; Grove, David; Dababneh, Luma; Wang, Sihe

    2014-01-01

    Background: Pulmonary arterial hypertension (PAH) is a progressive and devastating condition characterized by vascular cell proliferation and is associated with several metabolic derangements. We hypothesized that metabolic derangements in PAH can be detected by measuring metabolic by-products in exhaled breath. Methods: We collected breath and blood samples from patients with PAH at the time of right-sided heart catheterization (n = 31) and from healthy control subjects (n = 34). Breath was analyzed by selected ion flow tube-mass spectrometry in predetermined training and validation cohorts. Results: Patients with PAH were 51.5 ± 14 years old, and 27 were women (85%). Control subjects were 38 ± 13 years old, and 22 were women (65%). Discriminant analysis in the training set identified three ion peaks (H3O+29+, NO+56+, and O2+98+) and the variable age that correctly classified 88.9% of the individuals. In an independent validation cohort, 82.8% of the individuals were classified correctly. The concentrations of the volatile organic compounds 2-propanol, acetaldehyde, ammonia, ethanol, pentane, 1-decene, 1-octene, and 2-nonene were different in patients with PAH compared with control subjects. Exhaled ammonia was higher in patients with PAH (median [interquartile range]: 94.7 parts per billion (ppb) [70-129 ppb] vs 60.9 ppb [46-77 ppb], P < .001) and was associated with right atrial pressure (ρ = 0.57, P < .001), mean pulmonary artery pressure (ρ = 0.43, P = .015), cardiac index by thermodilution (ρ = −0.39, P = .03), pulmonary vascular resistance (ρ = 0.40, P = .04), mixed venous oxygen (ρ = −0.59, P < .001), and right ventricular dilation (ρ = 0.42, P = .03). Conclusions: Breathprint is different between patients with PAH and healthy control subjects. Several specific compounds, including ammonia, were elevated in the breath of patients with PAH. Exhaled ammonia levels correlated with severity of disease. PMID:24091389

  16. Notch3 signaling promotes the development of pulmonary arterial hypertension.

    PubMed

    Li, Xiaodong; Zhang, Xiaoxue; Leathers, Robin; Makino, Ayako; Huang, Chengqun; Parsa, Pouria; Macias, Jesus; Yuan, Jason X-J; Jamieson, Stuart W; Thistlethwaite, Patricia A

    2009-11-01

    Notch receptor signaling is implicated in controlling smooth muscle cell proliferation and in maintaining smooth muscle cells in an undifferentiated state. Pulmonary arterial hypertension is characterized by excessive vascular resistance, smooth muscle cell proliferation in small pulmonary arteries, leading to elevation of pulmonary vascular resistance, right ventricular failure and death. Here we show that human pulmonary hypertension is characterized by overexpression of NOTCH3 in small pulmonary artery smooth muscle cells and that the severity of disease in humans and rodents correlates with the amount of NOTCH3 protein in the lung. We further show that mice with homozygous deletion of Notch3 do not develop pulmonary hypertension in response to hypoxic stimulation and that pulmonary hypertension can be successfully treated in mice by administration of N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), a gamma-secretase inhibitor that blocks activation of Notch3 in smooth muscle cells. We show a mechanistic link from NOTCH3 receptor signaling through the Hairy and enhancer of Split-5 (HES-5) protein to smooth muscle cell proliferation and a shift to an undifferentiated smooth muscle cell phenotype. These results suggest that the NOTCH3-HES-5 signaling pathway is crucial for the development of pulmonary arterial hypertension and provide a target pathway for therapeutic intervention. PMID:19855400

  17. Pulmonary hypertension in COPD: old and new concepts.

    PubMed

    Barberà, J A; Peinado, V I; Santos, S

    2000-12-01

    Pulmonary hypertension is a common complication in chronic obstructive pulmonary disease (COPD). Its presence and severity is closely related to disease prognosis. Remodelling of pulmonary vessels is the principal causative factor of pulmonary hypertension in COPD. In advanced COPD, pulmonary vascular remodelling is related to the severity of arterial hypoxaemia. However, recent studies have shown that structural abnormalities and alterations of vascular function are also apparent in patients with mild COPD who do not have hypoxaemia and even in smokers with normal lung function. Pulmonary endothelium plays a crucial role in the regulation of vascular tone and cell growth of the vessel wall. Alterations of endothelial function in pulmonary arteries are apparent at the early stages of chronic obstructive pulmonary disease evolution. Potential mechanisms of endothelial damage at these initial stages include the effects of cigarette smoke components and inflammatory changes. The resultant alteration of pulmonary endothelium by these factors might predispose patients with mild chronic obstructive pulmonary disease to further vascular damage by additional factors, such as hypoxaemia, ultimately leading to pulmonary hypertension. PMID:11272628

  18. Primary pulmonary hypertension associated with human immunodeficiency virus infection.

    PubMed Central

    Golpe, R.; Fernandez-Infante, B.; Fernandez-Rozas, S.

    1998-01-01

    Several cardiorespiratory diseases can complicate human immunodeficiency virus infection. Primary pulmonary hypertension is a rare clinical disorder which carries a bad prognosis. More than 90 cases of HIV-associated primary pulmonary hypertension have been reported to date. Although its pathogenesis remains unknown, some evidence suggests a possible role for the virus itself in its development. Genetic susceptibility may also be implicated. The clinical and histopathologic features of this entity do not differ from those of classic primary pulmonary hypertension. The diagnosis requires a high degree of clinical suspicion and a careful evaluation to rule out causes of secondary pulmonary hypertension. In addition to supportive measures, anticoagulation and vasodilators have been used to treat this disorder, although sufficient data regarding long-term results with these therapies are lacking. PMID:9799910

  19. Contribution of live heartworms harboring in pulmonary arteries to pulmonary hypertension in dogs with dirofilariasis.

    PubMed

    Kitagawa, H; Sasaki, Y; Ishihara, K; Hirano, Y

    1990-12-01

    To investigate whether adult heartworms harboring in the pulmonary arteries contribute to pulmonary hypertension, we determined the cardio-pulmonary values immediately before and after removal of heartworms from the pulmonary arteries and before and after insertion of live worms in their place. In 10 heartworm-infected dogs, 8 to 46 worms were removed. The mean pulmonary arterial pressure fell significantly from 24.5 +/- 7.9 mmHg to 16.3 +/- 4.9 mmHg (p less than 0.01) immediately after removal. The right cardiac output decreased in 7 of the 10 cases. The total pulmonary resistance and right ventricular stroke work index also decreased. At 24 hours after removal, live heartworms were put back into the pulmonary arteries of their host dog. The mean pulmonary arterial pressure elevated significantly (p less than 0.01) immediately after insertion. The right cardiac output further decreased in 7 of the 10 dogs, and the total pulmonary resistance and right ventricular stroke work index increased. Separate from this, 12 to 42 heartworms were transplanted into the pulmonary arteries of 5 heartworm-free dogs. Immediately after transplantation, the pulmonary arterial pressure did not show any significant change. However, the stroke volume decreased, and the total pulmonary resistance increased. These facts suggest a contribution of live heartworms to the pulmonary hypertension, although there is a complicated interaction among the presence of heartworms, the pulmonary lesions and the pulmonary hypertension.

  20. Pulmonary arterial hypertension: a current review of pharmacological management.

    PubMed

    Sahni, Sonu; Ojrzanowski, Marcin; Majewski, Sebastian; Talwar, Arunabh

    2016-01-01

    Pulmonary hypertension (PHTN) is a rare and devastating disease characterized by progressive increases in pulmonary arterial pressure and pulmonary vascular resistance, which eventually leads to right ventricular failure and death. At present there is no cure for pulmonary arterial hypertension (PAH); however over the past decade targeted pharmaceutical options have become available for the treatment of PAH. Prior to evaluation for therapeutic options a definitive diagnosis of pulmonary arterial hypertension must be made via comprehensive physical exam and definitive diagnostic testing. Screening test of choice remains echocardiography and gold standard for definitive diagnosis is right heart catheterization. Once the establishment of a diagnosis of PAH is made therapeutic options may be a possibility based on a diagnostic algorithm and disease severity of the PAH patient. There are different classes of medications available with different mechanisms of actions which net a vasodilatory effect and improve exercise tolerance, quality of life as well and survival.

  1. Soluble Guanylate Cyclase: A new therapeutic target for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension

    PubMed Central

    Das Gupta, Asish; Bowman, Lindsay; D’Arsigny, Christine L.; Archer, Stephen L.

    2014-01-01

    Nitric oxide (NO) activates soluble guanylate cyclase (sGC) by binding its prosthetic heme group, thereby catalyzing cyclic guanosine monophosphate (cGMP) synthesis. cGMP causes vasodilation and may inhibit smooth muscle cell proliferation and platelet aggregation. The NO-sGC-cGMP pathway is disordered in pulmonary arterial hypertension (PAH), a syndrome in which pulmonary vascular obstruction, inflammation, thrombosis, and constriction ultimately lead to death from right heart failure. Expression of sGC is increased in PAH but its function is reduced by decreased NO bioavailability, sGC oxidation and the related loss of sGC’s heme group. Two classes of sGC modulators offer promise in PAH. sGC stimulators (e.g. riociguat) require heme-containing sGC to catalyze cGMP production, whereas sGC activators (e.g. cinaciguat) activate heme-free sGC. Riociguat is approved for PAH and yields functional and hemodynamic benefits similar to other therapies. Its main serious adverse effect is dose-dependent hypotension Riociguat is also approved for inoperable chronic thromboembolic pulmonary hypertension. PMID:25670386

  2. [Pulmonary hypertension associated with congenital heart disease and Eisenmenger syndrome].

    PubMed

    Calderón-Colmenero, Juan; Sandoval Zárate, Julio; Beltrán Gámez, Miguel

    2015-01-01

    Pulmonary arterial hypertension is a common complication of congenital heart disease (CHD). Congenital cardiopathies are the most frequent congenital malformations. The prevalence in our country remains unknown, based on birthrate, it is calculated that 12,000 to 16,000 infants in our country have some cardiac malformation. In patients with an uncorrected left-to-right shunt, increased pulmonary pressure leads to vascular remodeling and endothelial dysfunction secondary to an imbalance in vasoactive mediators which promotes vasoconstriction, inflammation, thrombosis, cell proliferation, impaired apotosis and fibrosis. The progressive rise in pulmonary vascular resistance and increased pressures in the right heart provocated reversal of the shunt may arise with the development of Eisenmenger' syndrome the most advanced form de Pulmonary arterial hypertension associated with congenital heart disease. The prevalence of Pulmonary arterial hypertension associated with CHD has fallen in developed countries in recent years that is not yet achieved in developing countries therefore diagnosed late as lack of hospital infrastructure and human resources for the care of patients with CHD. With the development of targeted medical treatments for pulmonary arterial hypertension, the concept of a combined medical and interventional/surgical approach for patients with Pulmonary arterial hypertension associated with CHD is a reality. We need to know the pathophysiological factors involved as well as a careful evaluation to determine the best therapeutic strategy.

  3. MicroRNAs and mesenchymal stem cells: hope for pulmonary hypertension

    PubMed Central

    Zhu, Zhaowei; Fang, Zhenfei; Hu, Xinqun; Zhou, Shenghua

    2015-01-01

    Pulmonary hypertension is a devastating and refractory disease and there is no cure for this disease. Recently, microRNAs and mesenchymal stem cells emerged as novel methods to treat pulmonary hypertension. More than 20 kinds of microRNAs may participate in the process of pulmonary hypertension. It seems microRNAs or mesenchymal stem cells can ameliorate some symptoms of pulmonary hypertension in animals and even improve heart and lung function during pulmonary hypertension. Nevertheless, the relationship between mesenchymal stem cells, microRNAs and pulmonary hypertension is not clear. And the mechanisms underlying their function still need to be investigated. In this study we review the recent findings in mesenchymal stem cells - and microRNAs-based pulmonary hypertension treatment, focusing on the potential role of microRNAs regulated mesenchymal stem cells in pulmonary hypertension and the role of exosomes between mesenchymal stem cells and pulmonary hypertension. PMID:26313730

  4. [Pulmonary hypertension: from molecular pathophysiology to haemodynamic abnormalities].

    PubMed

    Duong-Quy, S; Rivière, S; Bei, Y; Duong-Ngo, C; Le-Dong, N N; Hua-Huy, T; Dinh-Xuan, A T

    2012-10-01

    Pulmonary hypertension (PH) is a complex disorder resulting from many etiologies that cause disturbances of normal pulmonary haemodynamics. Recent breakthroughs have led to a better understanding of the pathophysiology of the disease. In PH, haemodynamic disturbances are closely linked to structural changes and excessive remodeling of pulmonary vessels, leading to progressive narrowing of the pulmonary vascular lumen. Imbalances between pulmonary vasoconstrictors and vasodilators on the one hand, and factors favoring cell proliferation and apoptosis on the other hand, probably account for most cases of PH. This review aims to update readers with the current knowledge on the molecular physiopathology of PH and how this can progress the therapeutic of this disorder.

  5. Sublingual Microcirculation in Pulmonary Arterial Hypertension

    PubMed Central

    Dababneh, Luma; Cikach, Frank; Alkukhun, Laith; Dweik, Raed A.

    2014-01-01

    Rationale: Pulmonary arterial hypertension (PAH) is a pulmonary vasculopathy that leads to failure of the right ventricle and premature death. Objectives: To determine whether the sublingual microcirculation is affected in patients with PAH compared with healthy age- and sex-matched control subjects. Methods: Using the CapiScope Handheld Video Capillaroscope we measured the sublingual microvasculature density, flow index, tortuosity, and curvature. Videos were acquired immediately after right heart catheterization, and determinations were made off-line by investigators blinded to the group assignment or hemodynamics. Measurements and Main Results: In this cross-sectional pilot study, we included 26 patients with PAH (age, mean ± SD, 56.7 ± 10 yr; 77% women) and 14 healthy control subjects (age, 53.1 ± 12 yr; 71% women). Sublingual microvasculature flow index was lower (2 ± 0.66 vs. 2.7 ± 0.37, P < 0.001) with higher heterogeneity index (0.63 ± 0.63 vs. 0.25 ± 0.25, P = 0.04) in patients with PAH than control subjects. Microvasculature density was similar between the groups, but tortuosity was more pronounced in patients than control subjects (tort 0: 45 ± 19 vs. 23.6 ± 12, P = 0.001 and tort 1: 0.2 ± 0.16 vs. 0.06 ± 0.04, P < 0.001). Conclusions: Patients with PAH showed lower sublingual microvasculature flow index and higher tortuosity compared with healthy age- and sex-matched control subjects. Further investigations are needed to assess whether this methodology can provide information on disease prognosis and/or response to therapy in this condition. PMID:24601682

  6. Epistatic interactions in idiopathic pulmonary arterial hypertension

    PubMed Central

    Vadapalli, Shivani; Satyanarayana, M. L.; Chaitra, K. L.; Rani, H. Surekh; Sastry, B.K.S.; Nallari, Pratibha

    2012-01-01

    BACKGROUND: Idiopathic pulmonary arterial hypertension (IPAH) is a poorly understood complex disorder, which results in progressive remodeling of the pulmonary artery that ultimately leads to right ventricular failure. A two-hit hypothesis has been implicated in pathogenesis of IPAH, according to which the vascular abnormalities characteristic of PAH are triggered by the accumulation of genetic and/or environmental insults in an already existing genetic background. The multifactor dimensionality reduction (MDR) analysis is a statistical method used to identify gene–gene interaction or epistasis and gene–environment interactions that are associated with a particular disease. The MDR method collapses high-dimensional genetic data into a single dimension, thus permitting interactions to be detected in relatively small sample sizes. AIM: To identify and characterize polymorphisms/genes that increases the susceptibility to IPAH using MDR analysis. MATERIALS AND METHODS: A total of 77 IPAH patients and 100 controls were genotyped for eight polymorphisms of five genes (5HTT, EDN1, NOS3, ALK-1, and PPAR-γ2). MDR method was adopted to determine gene–gene interactions that increase the risk of IPAH. RESULTS: With MDR method, the single-locus model of 5HTT (L/S) polymorphism and the combination of 5HTT(L/S), EDN1(K198N), and NOS3(G894T) polymorphisms in the three-locus model were attributed to be the best models for predicting susceptibility to IPAH, with a P value of 0.05. CONCLUSION: MDR method can be useful in understanding the role of epistatic and gene–environmental interactions in pathogenesis of IPAH. PMID:22754222

  7. [Inhaled iloprost, a selective pulmonary vasodilator. Clinical evidence from its use in perioperative pulmonary hypertension cardiovascular surgery].

    PubMed

    Santos-Martínez, Luis Efren; Baranda-Tovar, Francisco Martín; Telona-Fermán, Eslí; Barragán-García, Rodolfo; Calderón-Abbo, Moisés Cutiel

    2015-01-01

    Inhaled iloprost is one of the most recent drugs from prostanoids group's in the treatment of pulmonary arterial hypertension. His place in pulmonary hypertension seen in the perioperative cardiovascular surgery has not been defined. In this review we analyze pulmonary hypertension group's susceptibles of cardiac surgery and its importance, besides the current clinical evidence from drug use in this context. PMID:25450429

  8. [Inhaled iloprost, a selective pulmonary vasodilator. Clinical evidence from its use in perioperative pulmonary hypertension cardiovascular surgery].

    PubMed

    Santos-Martínez, Luis Efren; Baranda-Tovar, Francisco Martín; Telona-Fermán, Eslí; Barragán-García, Rodolfo; Calderón-Abbo, Moisés Cutiel

    2015-01-01

    Inhaled iloprost is one of the most recent drugs from prostanoids group's in the treatment of pulmonary arterial hypertension. His place in pulmonary hypertension seen in the perioperative cardiovascular surgery has not been defined. In this review we analyze pulmonary hypertension group's susceptibles of cardiac surgery and its importance, besides the current clinical evidence from drug use in this context.

  9. Saudi Guidelines on the Diagnosis and Treatment of Pulmonary Hypertension: Pregnancy in pulmonary hypertension

    PubMed Central

    Khan, Javed; Idrees, Majdy M.

    2014-01-01

    Pregnancy in pulmonary hypertension (PH) is known to be associated with high morbidity and mortality. The physiological changes occur during normal pregnancy, such as increase blood volume and cardiac output (CO) may be detrimental in PH patients. Several practice guidelines advise against pregnancy and even recommend termination of pregnancy. Occasionally PH may be diagnosed for the first time during pregnancy, as stress of pregnancy can unmask previously undiagnosed PH in an asymptomatic individual. This narrative review provides a detailed discussion about the physiologic parameters associated in pregnancy and their negative effect on the right ventricle. It also gives practical evidence-based recommendations about different management issues in PH pregnant patients. PMID:25076988

  10. Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension.

    PubMed

    Rabinovitch, Marlene; Guignabert, Christophe; Humbert, Marc; Nicolls, Mark R

    2014-06-20

    This review summarizes an expanding body of knowledge indicating that failure to resolve inflammation and altered immune processes underlie the development of pulmonary arterial hypertension. The chemokines and cytokines implicated in pulmonary arterial hypertension that could form a biomarker platform are discussed. Pre-clinical studies that provide the basis for dysregulated immunity in animal models of the disease are reviewed. In addition, we present therapies that target inflammatory/immune mechanisms that are currently enrolling patients, and discuss others in development. We show how genetic and metabolic abnormalities are inextricably linked to dysregulated immunity and adverse remodeling in the pulmonary arteries. PMID:24951765

  11. Diagnosis and Vasculopathy in Chronic Thromboembolic Pulmonary Hypertension

    PubMed Central

    2010-01-01

    Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by pulmonary hypertension caused by nonresolving thromboemboli of the pulmonary artery. However, up to 40% of CTEPH patients have had no clinically apparent acute pulmonary embolic episodes. In addition, both a female predominance and an association of HLA with CTEPH unrelated to deep vein thrombosis are observed in Japan, thus suggesting this condition to be a type of pulmonary vasculopathy. The key for making an accurate diagnosis is to consider CTEPH in any patients with dyspnea on exertion. Perfusion scans provide an excellent noninvasive tool for distinguishing between pulmonary arterial hypertension (PAH) and CTEPH, while CT angiography is useful for differentiating arteritis, tumor, and a congenital anomaly of the pulmonary artery from CTEPH. Pulmonary angiography (PAG) is still considered the gold standard for evaluating CTEPH. No subpleural perfusion in any segments by PAG with high pulmonary vascular resistance is might be related to small vessel disease, thus resulting in a poor outcome after surgery. Recent data suggest a potential therapeutic benefit of antiproliferative therapy for cells isolated from endarterectomized tissue. PMID:23555373

  12. CD133+ cells in pulmonary arterial hypertension.

    PubMed

    Foris, Vasile; Kovacs, Gabor; Marsh, Leigh M; Bálint, Zoltán; Tötsch, Martin; Avian, Alexander; Douschan, Philipp; Ghanim, Bahil; Klepetko, Walter; Olschewski, Andrea; Olschewski, Horst

    2016-08-01

    Circulating mononuclear cells may play an important role for the vascular remodelling in pulmonary arterial hypertension (PAH), but studies addressing multiple progenitor populations are rare and inconsistent.We used a comprehensive fluorescence-activated cell sorting analysis of circulating mononuclear cells in 20 PAH patients and 20 age- and sex-matched controls, and additionally analysed CD133(+) cells in the lung tissue of five PAH transplant recipients and five healthy controls (donor lungs).PAH patients were characterised by increased numbers of circulating CD133(+) cells and lymphopenia as compared with control. In PAH, CD133(+) subpopulations positive for CD117 or CD45 were significantly increased, whereas CD133(+)CD309(+), CD133(+)CXCR2(+) and CD133(+)CD31(+) cells were decreased. In CD133(+) cells, SOX2, Nanog, Ki67 and CXCR4 were not detected, but Oct3/4 mRNA was present in both PAH and controls. In the lung tissue, CD133(+) cells included three main populations: type 2 pneumocytes, monocytes and undifferentiated cells without significant differences between PAH and controls.In conclusion, circulating CD133(+) progenitor cells are elevated in PAH and consist of phenotypically different subpopulations that may be up- or downregulated. This may explain the inconsistent results in the literature. CD133(+) type 2 pneumocytes in the lung tissue are not associated with circulating CD133(+) mononuclear cells. PMID:27103380

  13. Updated treatment algorithm of pulmonary arterial hypertension.

    PubMed

    Galiè, Nazzareno; Corris, Paul A; Frost, Adaani; Girgis, Reda E; Granton, John; Jing, Zhi Cheng; Klepetko, Walter; McGoon, Michael D; McLaughlin, Vallerie V; Preston, Ioana R; Rubin, Lewis J; Sandoval, Julio; Seeger, Werner; Keogh, Anne

    2013-12-24

    The demands on a pulmonary arterial hypertension (PAH) treatment algorithm are multiple and in some ways conflicting. The treatment algorithm usually includes different types of recommendations with varying degrees of scientific evidence. In addition, the algorithm is required to be comprehensive but not too complex, informative yet simple and straightforward. The type of information in the treatment algorithm are heterogeneous including clinical, hemodynamic, medical, interventional, pharmacological and regulatory recommendations. Stakeholders (or users) including physicians from various specialties and with variable expertise in PAH, nurses, patients and patients' associations, healthcare providers, regulatory agencies and industry are often interested in the PAH treatment algorithm for different reasons. These are the considerable challenges faced when proposing appropriate updates to the current evidence-based treatment algorithm.The current treatment algorithm may be divided into 3 main areas: 1) general measures, supportive therapy, referral strategy, acute vasoreactivity testing and chronic treatment with calcium channel blockers; 2) initial therapy with approved PAH drugs; and 3) clinical response to the initial therapy, combination therapy, balloon atrial septostomy, and lung transplantation. All three sections will be revisited highlighting information newly available in the past 5 years and proposing updates where appropriate. The European Society of Cardiology grades of recommendation and levels of evidence will be adopted to rank the proposed treatments. PMID:24355643

  14. [Pulmonary arterial hypertension, bone marrow, endothelial cell precursors and serotonin].

    PubMed

    Ayme-Dietrich, Estelle; Banas, Sophie M; Monassier, Laurent; Maroteaux, Luc

    2016-01-01

    Serotonin and bone-marrow-derived stem cells participate together in triggering pulmonary hypertension. Our work has shown that the absence of 5-HT2B receptors generates permanent changes in the composition of the blood and bone-marrow in the myeloid lineages, particularly in endothelial cell progenitors. The initial functions of 5-HT2B receptors in pulmonary arterial hypertension (PAH) are restricted to bone-marrow cells. They contribute to the differentiation/proliferation/mobilization of endothelial progenitor cells from the bone-marrow. Those bone-marrow-derived cells have a critical role in the development of pulmonary hypertension and pulmonary vascular remodeling. These data indicate that bone-marrow derived endothelial progenitors play a key role in the pathogenesis of PAH and suggest that interactions involving serotonin and bone morphogenic protein type 2 receptor (BMPR2) could take place at the level of the bone-marrow. PMID:27687599

  15. The burden of pulmonary hypertension in resource-limited settings.

    PubMed

    Gidwani, Suman; Nair, Ajith

    2014-09-01

    Pulmonary vascular disease (PVD) is a significant global health problem and accounts for a substantial portion of cardiovascular disease in the developing world. Although there have been considerable advances in therapeutics for pulmonary arterial hypertension, over 97% of the disease burden lies within the developing world where there is limited access to health care and pharmaceuticals. The causes of pulmonary arterial hypertension differ between industrialized and developing nations. Infectious diseases-including schistosomiasis human immunodeficiency virus, and rheumatic fever-are common causes of PVD, as are hemoglobinopathies, and untreated congenital heart disease. High altitude and exposure to household air pollutants also contribute to a significant portion of PVD cases. Although diagnosis of pulmonary arterial hypertension requires the use of imaging and invasive hemodynamics, access to equipment may be limited. PVD therapies may be prohibitively expensive and limited to a select few. Prevention is therefore important in limiting the global PVD burden. PMID:25667181

  16. Pulmonary vascular reactivity in severe pulmonary hypertension associated with mixed connective tissue disease.

    PubMed Central

    Jolliet, P.; Thorens, J. B.; Chevrolet, J. C.

    1995-01-01

    Pulmonary vascular reactivity tests were performed in a young woman with mixed connective tissue disease and severe pulmonary hypertension. Vasoreactivity was documented in response to intravenous prostacyclin (PGI2), oral nifedipine, and inhaled nitric oxide, with quantitative differences. Nitric oxide produced a moderate lowering of pulmonary arterial pressure and resistance without any deleterious systemic effect. The use of nitric oxide in testing for pulmonary vasoreactivity merits further evaluation. Images PMID:7886662

  17. Regression of pulmonary artery hypertension due to development of a pulmonary arteriovenous malformation

    PubMed Central

    Hasan, Ashfaq; Sastry, B.K.S.; Aleem, M.A.; Reddy, Gokul; Mahmood, Syed

    2014-01-01

    Idiopathic Pulmonary Hypertension (IPAH) is characterized by elevated pulmonary arterial pressure in the absence of an identifiable underlying cause. The condition is usually relentlessly progressive with a short survival in the absence of treatment.1 We describe a patient of IPAH in whom the pulmonary artery pressures significantly abated with complete disappearance of symptoms, following spontaneous development of a pulmonary arterio-venous malformation (PAVM). PMID:25443608

  18. Why there is a need to discuss pulmonary hypertension other than pulmonary arterial hypertension?

    PubMed Central

    Papathanasiou, Athanasios; Nakos, George

    2015-01-01

    Pulmonary hypertension (PH) is a condition characterized by the elevation of the mean pulmonary artery pressure above 25 mmHg and the pulmonary vascular resistance above 3 wood units. Pulmonary arterial hypertension (PAH) is an uncommon condition with severe morbidity and mortality, needing early recognition and appropriate and specific treatment. PH is frequently associated with hypoxemia, mainly chronic obstructive pulmonary disease and DPLD and/or left heart diseases (LHD), mainly heart failure with reduced or preserved ejection fraction. Although in the majority of patients with PH the cause is not PAH, a significant number of published studies are still in regard to group I PH, leading to a logical assumption that PH due to other causes is not such an important issue. So, is there a reason to discuss PH other than PAH? Chronic lung diseases, mainly chronic obstructive lung disease and DPLD, are associated with a high incidence of PH which is linked to exercise limitations and a worse prognosis. Although pathophysiological studies suggest that specific PAH therapy may benefit such patients, the results presented from small studies in regard to the safety and effectiveness of the specific PAH therapy are discouraging. PH is a common complication of left heart disease and is related to disease severity, especially in patients with reduced ejection fraction. There are two types of PH related to LHD based on diastolic pressure difference (DPD, defined as diastolic pulmonary artery pressure - mean PAWP): Isolated post-capillary PH, defined as PAWP > 15 mmHg and DPD < 7 mmHg, and combined post-capillary PH and pre-capillary PH, defined as PAWP > 15 mmHg and DPD ≥ 7 mmHg. The potential use of PAH therapies in patients with PH related to left heart disease is based on a logical pathobiological rationale. In patients with heart failure, endothelial dysfunction has been proposed as a cause of PH and hence as a target for treatment, supported by the presence of

  19. Information experiences and needs in patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension.

    PubMed

    Ivarsson, Bodil; Ekmehag, Björn; Sjöberg, Trygve

    2014-01-01

    Background. Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are fatal, noncurable, but treatable diseases that strongly affect the patients. Objective. To describe patients' experience of information relating to PAH or CTEPH. Methods. A qualitative method using content analysis was applied. Seventeen patients (thirteen women and four men) aged 28-73 years from a regional PAH centre were individually interviewed. Results. Three categories that describe patients' experiences of information emerged: handling of information, struggling with feelings that also affect others, and vulnerability associated with uncertainty. The patients would have welcomed more information to relatives from the healthcare professionals. Shortcomings on communicating a prognosis were experienced. The mediated information and knowledge gave the patients insight into physical or psychosocial problems. Mutual exchange of information between patients and healthcare professionals were marred by different experiences of attitudes, behaviour, and ownership. Conclusions. In the future, healthcare organizations must struggle to achieve a holistic healthcare by making it more person-centred, and they must also promote cooperation between PAH centres and local healthcare providers. It is essential to determine the most appropriate and valuable path of information and communication and, thereby, the most cost-effective management of PAH or CTEPH. PMID:25197567

  20. Disrupted pulmonary vascular development and pulmonary hypertension in transgenic mice overexpressing transforming growth factor-alpha.

    PubMed

    Le Cras, Timothy D; Hardie, William D; Fagan, Karen; Whitsett, Jeffrey A; Korfhagen, Thomas R

    2003-11-01

    Pulmonary vascular disease plays a major role in morbidity and mortality in infant and adult lung diseases in which increased levels of transforming growth factor (TGF)-alpha and its receptor EGFR have been associated. The aim of this study was to determine whether overexpression of TGF-alpha disrupts pulmonary vascular development and causes pulmonary hypertension. Lung-specific expression of TGF-alpha in transgenic mice was driven with the human surfactant protein (SP)-C promoter. Pulmonary arteriograms and arterial counts show that pulmonary vascular development was severely disrupted in TGF-alpha mice. TGF-alpha mice developed severe pulmonary hypertension and vascular remodeling characterized by abnormally extensive muscularization of small pulmonary arteries. Pulmonary vascular development was significantly improved and pulmonary hypertension and vascular remodeling were prevented in bi-transgenic mice expressing both TGF-alpha and a dominant-negative mutant EGF receptor under the control of the SP-C promoter. Vascular endothelial growth factor (VEGF-A), an important angiogenic factor produced by the distal epithelium, was decreased in the lungs of TGF-alpha adults and in the lungs of infant TGF-alpha mice before detectable abnormalities in pulmonary vascular development. Hence, overexpression of TGF-alpha caused severe pulmonary vascular disease, which was mediated through EGFR signaling in distal epithelial cells. Reductions in VEGF may contribute to the pathogenesis of pulmonary vascular disease in TGF-alpha mice.

  1. [Role of gasotransmitters in the pathogenesis of pulmonary hypertension].

    PubMed

    Wang, Yan-fei; Jin, Hong-fang; Tang, Chao-shu; Du, Jun-bao

    2006-06-18

    Pulmonary hypertension is a complicated and important pathological process in the development of a variety of cardiovascular and pulmonary diseases, and directly affects the development of the diseases and their prognosis. but its mechanisms are still not fully understood. Therefore, to clarify the mechanisms is an important task in this field. Nitric oxide (NO) and carbon monoxide (CO) have special significance in pulmonary circulation as compared with other organs for their special biological properties including continuous production, fast transmission and extensive action, etc, which attracts great attention in the life science research and initiates the new research field of gasotransmitters. Hydrogen sulfide (H2S), which has been recognized as a toxic gas, can be endogenously produced in the body. We considered it to be a new cardiovascular regulatory gasotransmitter based on the studies of its synthesis and distribution in cardiovascular system and cardiovascular effects under physiologic and pathophysiologic conditions. We found it exerted a general regulatory significance in cardiovascular diseases. Based on the research of the three gasotransmitters in hypoxic and high pulmonary blood flow-induced pulmonary hypertension, it was found that the dysfunction of the gasotransmitter pathways was involved in the pathogenesis of pulmonary hypertension and the supplement of gasotransmitters could alleviate pulmonary hypertension and pulmonary vascular remodeling. The mechanisms included that they could regulate vessel dilation, correct the imbalance between smooth muscle cell proliferation and apoptosis, inhibit the excess synthesis and stimulate the degradation of collagen, therefore inhibiting abnormal accumulation of collagen, etc. All these results indicated the significant regulatory effects of gasotransmitters in the pathogenesis of pulmonary hypertension.

  2. Advances in the management of pediatric pulmonary hypertension.

    PubMed

    Oishi, Peter; Datar, Sanjeev A; Fineman, Jeffrey R

    2011-09-01

    Pulmonary hypertension is a rare disease in neonates, infants, and children, and is associated with substantial morbidity and mortality. An adequate understanding of the controlling pathophysiologic mechanisms is lacking. Moreover, a minority of research is focused specifically on neonatal and pediatric populations. Although therapeutic options have increased over the past several decades, they remain limited. In advanced pulmonary hypertension, progressive pulmonary vascular functional and structural changes ultimately cause increased pulmonary vascular impedance, right-ventricular failure, and death. Management includes the prevention and/or treatment of active pulmonary vasoconstriction, the support of right-ventricle function, treatment of the underlying disease (if possible), and the promotion of regressive remodeling of structural pulmonary vascular changes. Most currently available therapies augment or inhibit factors, or mediators of their downstream signaling cascades, that originate in the pulmonary vascular endothelium. These pathways include nitric-oxide/cyclic guanosine monophosphate (cGMP), prostacyclin, and endothelin-1. The ability to reverse advanced structural changes remains an as yet unattained goal. This paper reviews the epidemiology, pathophysiology, current treatments, and emerging therapies related to neonatal and pediatric pulmonary hypertension.

  3. [Heart pathology of extracardiac origin. IV. Pulmonary hypertension in chronic respiratory diseases].

    PubMed

    Barberà, J A

    1998-01-01

    Pulmonary hypertension is the major cardiovascular complication of chronic respiratory disorders and its development is a sign of poor prognosis. Pulmonary circulation is characterized by its low vascular tone and the response to hypoxia by vasoconstriction. Pulmonary endothelium plays an important role in modulating these characteristics. Structural abnormalities of pulmonary arteries in pulmonary hypertension affect preferentially the intimal layer and may damage the endothelial cells. Endothelial dysfunction of pulmonary arteries has been recognized in the different forms of pulmonary hypertension. Vasodilators are recommended for the treatment of primary pulmonary hypertension. However, in pulmonary hypertension associated with chronic respiratory disorders, both systemic and selective pulmonary vasodilators are not indicated since they may worsen gas exchange due to the inhibition of hypoxic vasoconstriction. The most effective treatment of pulmonary hypertension associated with chronic hypoxic lung diseases is long-term oxygen therapy. PMID:9522610

  4. Upregulated Copper Transporters in Hypoxia-Induced Pulmonary Hypertension

    PubMed Central

    Zimnicka, Adriana M.; Tang, Haiyang; Guo, Qiang; Kuhr, Frank K.; Oh, Myung-Jin; Wan, Jun; Chen, Jiwang; Smith, Kimberly A.; Fraidenburg, Dustin R.; Choudhury, Moumita S. R.; Levitan, Irena; Machado, Roberto F.; Kaplan, Jack H.; Yuan, Jason X.-J.

    2014-01-01

    Pulmonary vascular remodeling and increased arterial wall stiffness are two major causes for the elevated pulmonary vascular resistance and pulmonary arterial pressure in patients and animals with pulmonary hypertension. Cellular copper (Cu) plays an important role in angiogenesis and extracellular matrix remodeling; increased Cu in vascular smooth muscle cells has been demonstrated to be associated with atherosclerosis and hypertension in animal experiments. In this study, we show that the Cu-uptake transporter 1, CTR1, and the Cu-efflux pump, ATP7A, were both upregulated in the lung tissues and pulmonary arteries of mice with hypoxia-induced pulmonary hypertension. Hypoxia also significantly increased expression and activity of lysyl oxidase (LOX), a Cu-dependent enzyme that causes crosslinks of collagen and elastin in the extracellular matrix. In vitro experiments show that exposure to hypoxia or treatment with cobalt (CoCl2) also increased protein expression of CTR1, ATP7A, and LOX in pulmonary arterial smooth muscle cells (PASMC). In PASMC exposed to hypoxia or treated with CoCl2, we also confirmed that the Cu transport is increased using 64Cu uptake assays. Furthermore, hypoxia increased both cell migration and proliferation in a Cu-dependent manner. Downregulation of hypoxia-inducible factor 1α (HIF-1α) with siRNA significantly attenuated hypoxia-mediated upregulation of CTR1 mRNA. In summary, the data from this study indicate that increased Cu transportation due to upregulated CTR1 and ATP7A in pulmonary arteries and PASMC contributes to the development of hypoxia-induced pulmonary hypertension. The increased Cu uptake and elevated ATP7A also facilitate the increase in LOX activity and thus the increase in crosslink of extracellular matrix, and eventually leading to the increase in pulmonary arterial stiffness. PMID:24614111

  5. Extracellular matrix protein gene expression in atherosclerotic hypertensive pulmonary arteries.

    PubMed Central

    Botney, M. D.; Kaiser, L. R.; Cooper, J. D.; Mecham, R. P.; Parghi, D.; Roby, J.; Parks, W. C.

    1992-01-01

    Lobar pulmonary arteries from patients with unexplained pulmonary hypertension were obtained at the time of single-lung transplantation to determine the response of large elastic vessels to increased intraluminal pressure. Specifically, human pulmonary arteries were examined to determine if remodeling remained active at the time of surgery and whether remodeling was similar to previously reported remodeling observed in several animal models. Grossly, the hypertensive vessels appeared atherosclerotic. Histochemical stains revealed a thick, diffuse neointima in hypertensive vessels compared with normal vessels. Immunohistochemistry demonstrated elastin protein in the neointima and in situ hybridization studies demonstrated tropoelastin mRNA largely in the neointima. Similarly, immunohistochemistry and in situ hybridization detected cellular fibronectin, thrombospondin and type I collagen protein and mRNA within the thickened intima from hypertensive vessels. These studies provide evidence that hypertensive vessels in patients with severe chronic pulmonary hypertension are actively remodeling but that the pattern of remodeling is different from previously described animal models. Images Figure 1 Figure 2 Figure 3 PMID:1739129

  6. Pulmonary Hypertension and Vascular Abnormalities in Bronchopulmonary Dysplasia.

    PubMed

    Mourani, Peter M; Abman, Steven H

    2015-12-01

    Despite advances in the care of preterm infants, these infants remain at risk bronchopulmonary dysplasia (BPD), which results in prolonged need for supplemental oxygen, recurrent respiratory exacerbations, and exercise intolerance. Recent investigations have highlighted the important contribution of the developing pulmonary circulation to lung development, showing that these infants are also at risk for pulmonary vascular disease (PVD), including pulmonary hypertension (PH) and pulmonary vascular abnormalities. Several epidemiologic studies have delineated the incidence of PH in preterm infants and the impact on outcomes. These studies have also highlighted gaps in the understanding of PVD in BPD. PMID:26593082

  7. Chronic thromboembolic pulmonary hypertension, pregnancy, and a pulmonary endarterectomy: a rare challenge

    PubMed Central

    Biscotti, Mauer; Cleary, Kirsten; Smiley, Richard; Bacchetta, Matthew D.

    2016-01-01

    Abstract It is well described that patients with group 1 forms of pulmonary arterial hypertension have a high risk of mortality during pregnancy and in the early postpartum period. However, to the authors’ knowledge, the diagnosis and management of group 4 pulmonary hypertension due to chronic thromboembolic pulmonary hypertension (CTEPH) during pregnancy with early postpartum pulmonary endarterectomy (PEA) has not been previously reported. We report the case of a 28-year-old woman who received a diagnosis of CTEPH during her pregnancy, was managed as an inpatient by a multidisciplinary team throughout the pregnancy and early postpartum period, and underwent PEA 6 weeks after delivery. While the management of acute pulmonary embolus in pregnancy is well described, this unique case of CTEPH diagnosed during pregnancy illustrates several challenging management issues. PMID:27683616

  8. Chronic thromboembolic pulmonary hypertension, pregnancy, and a pulmonary endarterectomy: a rare challenge.

    PubMed

    Rosenzweig, Erika B; Biscotti, Mauer; Cleary, Kirsten; Smiley, Richard; Bacchetta, Matthew D

    2016-09-01

    It is well described that patients with group 1 forms of pulmonary arterial hypertension have a high risk of mortality during pregnancy and in the early postpartum period. However, to the authors' knowledge, the diagnosis and management of group 4 pulmonary hypertension due to chronic thromboembolic pulmonary hypertension (CTEPH) during pregnancy with early postpartum pulmonary endarterectomy (PEA) has not been previously reported. We report the case of a 28-year-old woman who received a diagnosis of CTEPH during her pregnancy, was managed as an inpatient by a multidisciplinary team throughout the pregnancy and early postpartum period, and underwent PEA 6 weeks after delivery. While the management of acute pulmonary embolus in pregnancy is well described, this unique case of CTEPH diagnosed during pregnancy illustrates several challenging management issues. PMID:27683616

  9. Chronic thromboembolic pulmonary hypertension, pregnancy, and a pulmonary endarterectomy: a rare challenge

    PubMed Central

    Biscotti, Mauer; Cleary, Kirsten; Smiley, Richard; Bacchetta, Matthew D.

    2016-01-01

    Abstract It is well described that patients with group 1 forms of pulmonary arterial hypertension have a high risk of mortality during pregnancy and in the early postpartum period. However, to the authors’ knowledge, the diagnosis and management of group 4 pulmonary hypertension due to chronic thromboembolic pulmonary hypertension (CTEPH) during pregnancy with early postpartum pulmonary endarterectomy (PEA) has not been previously reported. We report the case of a 28-year-old woman who received a diagnosis of CTEPH during her pregnancy, was managed as an inpatient by a multidisciplinary team throughout the pregnancy and early postpartum period, and underwent PEA 6 weeks after delivery. While the management of acute pulmonary embolus in pregnancy is well described, this unique case of CTEPH diagnosed during pregnancy illustrates several challenging management issues.

  10. Computer-assisted diagnostic tool to quantify the pulmonary veins in sickle cell associated pulmonary hypertension

    NASA Astrophysics Data System (ADS)

    Jajamovich, Guido H.; Pamulapati, Vivek; Alam, Shoaib; Mehari, Alem; Kato, Gregory J.; Wood, Bradford J.; Linguraru, Marius George

    2012-03-01

    Pulmonary hypertension is a common cause of death among patients with sickle cell disease. This study investigates the use of pulmonary vein analysis to assist the diagnosis of pulmonary hypertension non-invasively with CT-Angiography images. The characterization of the pulmonary veins from CT presents two main challenges. Firstly, the number of pulmonary veins is unknown a priori and secondly, the contrast material is degraded when reaching the pulmonary veins, making the edges of these vessels to appear faint. Each image is first denoised and a fast marching approach is used to segment the left atrium and pulmonary veins. Afterward, a geodesic active contour is employed to isolate the left atrium. A thinning technique is then used to extract the skeleton of the atrium and the veins. The locations of the pulmonary veins ostia are determined by the intersection of the skeleton and the contour of the atrium. The diameters of the pulmonary veins are measured in each vein at fixed distances from the corresponding ostium, and for each distance, the sum of the diameters of all the veins is computed. These indicators are shown to be significantly larger in sickle-cell patients with pulmonary hypertension as compared to controls (p-values < 0.01).

  11. The Warburg effect: A new story in pulmonary arterial hypertension.

    PubMed

    Peng, Hongyan; Xiao, Yunbin; Deng, Xicheng; Luo, Jingfei; Hong, Chenliang; Qin, Xuping

    2016-10-01

    Pulmonary arterial hypertension (PAH) is a rare yet fatal condition that is characterized by a continuous and notable elevation of pulmonary arterial pressure (PAP), resulting in right heart failure and death. Pulmonary arterial remodelling does not result from abnormal proliferation of pulmonary arterial vascular smooth muscle cells (PASMCs) but from pulmonary arterial endothelial cell (PAEC) dysfunction. However, the pathological mechanism of these two types of vascular cells in pulmonary artery remodelling is unclear. The Warburg effect describes aerobic glycolysis wherein cells commonly reprogram their energy metabolism to preferentially utilize glycolysis over oxidative phosphorylation for ATP production. Recent research has demonstrated that the Warburg effect plays a significant role in the development of PAH, which involves the abnormal proliferation of PASMCs and endothelial dysfunction. This review attempts to illustrate the functions of the Warburg effect in PAH, which may provide a new therapeutic target for PAH treatment.

  12. Recent Strategies in Treatment of Pulmonary Arterial Hypertension, A Review

    PubMed Central

    Fallah, Flora

    2015-01-01

    Pulmonary arterial hypertension (PAH) is a disease characterized by an elevation in pulmonary artery pressure that can lead to right ventricular failure and death. The pulmonary circulation has to accommodate the entire cardiac output in each cardiac cycle and evolution has adapted to this by making it a low-pressure high-flow system. However, pathology can affect both the arterial and venous components of this system. Pulmonary venous hypertension mainly refers to diseases that result in elevated venous pressure and occurs mainly from mitral valve and left-sided heart disease. Standard treatment options include oral anticoagulation, diuretics, oxygen supplementation, and for a small percentage of patients, calcium channel blockers. Newer treatments include prostacyclin analogues, endothelin receptor antago¬nists, and phosphodiesterase type 5 inhibitors. This article reviews the current treatments strategies for PAH and provides guidelines for its management. PMID:25946920

  13. Regulation of Ca2+ Signaling in Pulmonary Hypertension

    PubMed Central

    Won, Jun Yeon

    2013-01-01

    Understanding the cellular and molecular mechanisms involved in the development and progression of pulmonary hypertension (PH) remains imperative if we are to successfully improve the quality of life and life span of patients with the disease. A whole plethora of mechanisms are associated with the development and progression of PH. Such complexity makes it difficult to isolate one particular pathway to target clinically. Changes in intracellular free calcium concentration, the most common intracellular second messenger, can have significant impact in defining the pathogenic mechanisms leading to its development and persistence. Signaling pathways leading to the elevation of [Ca2+]cyt contribute to pulmonary vasoconstriction, excessive proliferation of smooth muscle cells and ultimately pulmonary vascular remodeling. This current review serves to summarize the some of the most recent advances in the regulation of calcium during pulmonary hypertension. PMID:23439762

  14. New-onset neonatal pulmonary hypertension associated with a rhinovirus infection.

    PubMed

    Patel, Nishit; The, Tiong G

    2012-01-01

    A 3.5-week-old male neonate who developed an upper and lower respiratory tract rhinovirus infection that was temporally associated with the development of severe pulmonary hypertension is described. Rhinovirus has not previously been associated with pulmonary hypertension. This child developed severe pulmonary hypertension with right ventricular failure, requiring mechanical ventilation, nitric oxide inhalation and, eventually, extracorporeal membrane oxygenation.

  15. Pulmonary rehabilitation and exercise in pulmonary arterial hypertension: An underutilized intervention

    PubMed Central

    Sahni, Sonu; Capozzi, Barbara; Iftikhar, Asma; Sgouras, Vasiliki; Ojrzanowski, Marcin; Talwar, Arunabh

    2015-01-01

    Pulmonary arterial hypertension (PAH) is a rare and devastating disease characterized by progressive increases in pulmonary arterial pressure and pulmonary vascular resistance which eventually leads to right ventricular failure and death. Early thought process was that exercise and increased physical activity may be detrimental to PAH patients however many small cohort trials have proven otherwise. In addition to the many pharmaceutical options, exercise and pulmonary rehabilitation have also been shown to increase exercise capacity as well as various aspects of psychosomatic health. As pulmonary and exercise rehabilitation become more widely used as an adjuvant therapy patient outcomes improve and physicians should consider this in the therapeutic algorithm along with pharmacotherapy. PMID:25960979

  16. [Transition from intravenous to subcutaneous prostacyclin in pulmonary hypertension].

    PubMed

    Escribano Subías, Pilar; Cea-Calvo, Luis; Tello de Menesses, Rocío; Gómez Sánchez, Miguel A; Delgado Jiménez, Juan F; Sáenz de la Calzada, Carlos

    2003-08-01

    Treatment of arterial pulmonary hypertension with epoprostenol (intravenous prostacyclin) improves survival and quality of life, but the need for an implanted central venous catheter is associated with frequent complications, that often (as in the case of infection or dislodgment) are serious and require catheter replacement. Treprostinil is a prostacyclin analogue suitable for continuous subcutaneous administration. We report the successful transition from intravenous epoprostenol to subcutaneuos treprostinil in four patients with severe pulmonary hypertension who suffered from serious complications associated with the epoprostenol infusion system.

  17. Macitentan in pulmonary arterial hypertension: The SERAPHIN trial.

    PubMed

    Said, Karim

    2014-01-01

    Major limitations of pulmonary arterial hypertension (PAH) drug trials include the small number of enrolled patients, short term follow up (12-16 weeks), and lack of morbidity and mortality primary endpoints. The recently published SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve cliNical outcome) trial represents an important landmark in the history of clinical trials in PAH being the largest and longest clinical study conducted thus far in PAH patients with morbidity and mortality events as primary endpoint. SERAPHIN trial investigated whether long-term treatment with the new endothelin receptor antagonist macitentan would reduce the risk of mortality and morbidity in PAH patients.

  18. Type 1 neurofibromatosis and pulmonary hypertension: a report of two cases and a review

    PubMed Central

    Malviya, Amit; Mishra, Sundeep; Kothari, Shyam S

    2012-01-01

    Pulmonary hypertension in type 1 neurofibromatosis is not well known and was previously attributed to diffuse fibrosing alveolitis and parenchymal tumours. More recently, cases of severe pulmonary hypertension due to pulmonary vasculopathy have been described. Involvement of vascular beds, both large and medium calibre vessels, but not pulmonary vasculature, in type 1 neurofibromatosis is well known. The authors describe two such cases and briefly review the literature. Pulmonary arterial hypertension in neurofibromatosis warrants further studies. PMID:27326022

  19. Severe Pulmonary Arterial Hypertension: Comprehensive Evaluation by Magnetic Resonance Imaging

    PubMed Central

    Ibrahim, El-Sayed H.; Bajwa, Abubakr A.

    2015-01-01

    Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary artery (PA) pressure, which negatively affects the right ventricular (RV) function. This report shows a patient with severe PAH, on whom a comprehensive MRI exam was performed to evaluate both PA and RV. New imaging sequences were implemented for obtaining additional parameters about the patient's condition. The results show the capabilities of the developed exam of providing complete picture of the cardiovascular system in PAH, which helps the physician optimize treatment. PMID:26435871

  20. Transcatheter Embolization of Pulmonary Artery False Aneurysm Associated with Primary Pulmonary Hypertension

    SciTech Connect

    Hiraki, T. Kanazawa, S.; Mimura, H.; Yasui, K.; Okumura, Y.; Dendo, S.; Yoshimura, K.; Takahara, M.; Hiraki, Y.

    2004-03-15

    A 29-year-old woman with primary pulmonary hypertension presented with recurrent hemoptysis. Contrast-enhanced CT of the chest demonstrated the enhanced mass surrounded by consolidation related to parenchymal hemorrhage. Pulmonary angiography suggested that the mass was a pulmonary artery false aneurysm. After a microcatheter was superselectively inserted into the parent artery of the falseaneurysm, the false aneurysm was successfully treated by transcatheterembolization with coils. Her hemoptysis has never recurred.

  1. Treatment and Prognosis of Pulmonary Hypertension in the Left Ventricular Assist Device Patient.

    PubMed

    Jensen, Christopher W; Goldstone, Andrew B; Woo, Y Joseph

    2016-06-01

    This review will discuss the medical management of pulmonary hypertension in patients with left ventricular assist devices. Although much has been written on the management of primary pulmonary hypertension, also called pulmonary arterial hypertension, this review will instead focus on the treatment of pulmonary hypertension secondary to left heart disease. The relevant pharmacotherapy can be divided into medications for treating heart failure, such as diuretics and β-blockers, and medications for treating pulmonary hypertension. We also discuss important preoperative considerations in patients with pulmonary hypertension; the relationships between left ventricular assist devices, pulmonary hemodynamics, and right heart failure; as well as optimal perioperative and long-term postoperative medical management of pulmonary hypertension. PMID:27241336

  2. Pulmonary Arterial Hypertension Associated with Congenital Portosystemic Shunts Treated with Transcatheter Embolization and Pulmonary Vasodilators.

    PubMed

    Sato, Haruka; Miura, Masanobu; Yaoita, Nobuhiro; Yamamoto, Saori; Tatebe, Shunsuke; Aoki, Tatsuo; Satoh, Kimio; Ota, Hideki; Takase, Kei; Sugimura, Koichiro; Shimokawa, Hiroaki

    2016-01-01

    Cardiopulmonary abnormalities are often present in patients with liver diseases. We herein report a case of congenital portosystemic shunts complicated by hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PoPH). A 57-year-old woman complained of dyspnea and was subsequently diagnosed with HPS and PoPH caused by congenital portosystemic shunts. Although shunt closure by transcatheter embolization was successfully performed, her dyspnea worsened and pulmonary artery pressure and pulmonary vascular resistance elevated. Conventional vasodilator therapy was started, resulting in an improvement of pulmonary hypertension (PH). In some patients with congenital portosystemic shunts, shunt closure could exacerbate PH, and vasodilator therapy may be effective. PMID:27580545

  3. Severe pulmonary hypertension in idiopathic nonspecific interstitial pneumonia

    PubMed Central

    Hallowell, Robert W.; Reed, Robert M.; Fraig, Mostafa; Horton, Maureen R.; Girgis, Reda E.

    2012-01-01

    Pulmonary hypertension (PH) is a common complication of interstitial lung disease (ILD), particularly in idiopathic pulmonary fibrosis (IPF) and ILD associated with connective tissue disease, where the underlying pathology is often a nonspecific interstitial pneumonia (NSIP) pattern. The degree of PH in ILD is typically mild to moderate and radiographic changes of ILD are usually prominent. We describe four patients with idiopathic NSIP and severe PH (mPAP > 40 mmHg). The average mean pulmonary artery pressure was 51±7 mmHg and pulmonary vascular resistance was 13±4 Wood's units. Pulmonary function was characterized by mild restriction (total lung capacity 63–94% predicted) and profound reductions in DLCO (19–53% predicted). Computed tomographic imaging revealed minimal to moderate interstitial thickening without honeycombing. In two of the cases, an initial clinical diagnosis of idiopathic pulmonary arterial hypertension was made. Both were treated with intravenous epoprostenol, which was associated with worsening of hypoxemia. All four patients died or underwent lung transplant within 4 years of PH diagnonsis. Lung pathology in all four demonstrated fibrotic NSIP with medial thickening of the small and medium pulmonary arteries, and proliferative intimal lesions that stained negative for endothelial markers (CD31 and CD34) and positive for smooth muscle actin. There were no plexiform lesions. Severe pulmonary hypertension can therefore occur in idiopathic NSIP, even in the absence of advanced radiographic changes. Clinicians should suspect underlying ILD as the basis for PH when DLCO is severely reduced or gas exchange deteriorates with pulmonary vasodilator therapy. PMID:22558525

  4. Statement on pregnancy in pulmonary hypertension from the Pulmonary Vascular Research Institute

    PubMed Central

    Kiely, David G.; Cockrill, Barbara A.; Safdar, Zeenat; Wilson, Victoria J.; Al Hazmi, Manal; Preston, Ioana R.; MacLean, Mandy R.; Lahm, Tim

    2015-01-01

    Abstract Pregnancy outcomes in patients with pulmonary hypertension remain poor despite advanced therapies. Although consensus guidelines recommend against pregnancy in pulmonary hypertension, it may nonetheless occasionally occur. This guideline document sought to discuss the state of knowledge of pregnancy effects on pulmonary vascular disease and to define usual practice in avoidance of pregnancy and pregnancy management. This guideline is based on systematic review of peer-reviewed, published literature identified with MEDLINE. The strength of the literature was graded, and when it was inadequate to support high-level recommendations, consensus-based recommendations were formed according to prespecified criteria. There was no literature that met standards for high-level recommendations for pregnancy management in pulmonary hypertension. We drafted 38 consensus-based recommendations on pregnancy avoidance and management. Further, we identified the current state of knowledge on the effects of sex hormones during pregnancy on the pulmonary vasculature and right heart and suggested areas for future study. There is currently limited evidence-based knowledge about both the basic molecular effects of sex hormones and pregnancy on the pulmonary vasculature and the best practices in contraception and pregnancy management in pulmonary hypertension. We have drafted 38 consensus-based recommendations to guide clinicians in these challenging topics, but further research is needed in this area to define best practices and improve patient outcomes. PMID:26401246

  5. Pulmonary artery segmentation and quantification in sickle cell associated pulmonary hypertension

    NASA Astrophysics Data System (ADS)

    Linguraru, Marius George; Mukherjee, Nisha; Van Uitert, Robert L.; Summers, Ronald M.; Gladwin, Mark T.; Machado, Roberto F.; Wood, Bradford J.

    2008-03-01

    Pulmonary arterial hypertension is a known complication associated with sickle-cell disease; roughly 75% of sickle cell disease-afflicted patients have pulmonary arterial hypertension at the time of death. This prospective study investigates the potential of image analysis to act as a surrogate for presence and extent of disease, and whether the size change of the pulmonary arteries of sickle cell patients could be linked to sickle-cell associated pulmonary hypertension. Pulmonary CT-Angiography scans from sickle-cell patients were obtained and retrospectively analyzed. Randomly selected pulmonary CT-Angiography studies from patients without sickle-cell anemia were used as negative controls. First, images were smoothed using anisotropic diffusion. Then, a combination of fast marching and geodesic active contours level sets were employed to segment the pulmonary artery. An algorithm based on fast marching methods was used to compute the centerline of the segmented arteries. From the centerline, the diameters at the pulmonary trunk and first branch of the pulmonary arteries were measured automatically. Arterial diameters were normalized to the width of the thoracic cavity, patient weight and body surface. Results show that the pulmonary trunk and first right and left pulmonary arterial branches at the pulmonary trunk junction are significantly larger in diameter with increased blood flow in sickle-cell anemia patients as compared to controls (p values of 0.0278 for trunk and 0.0007 for branches). CT with image processing shows great potential as a surrogate indicator of pulmonary hemodynamics or response to therapy, which could be an important tool for drug discovery and noninvasive clinical surveillance.

  6. Long-term treatment of pulmonary hypertension with aerosolized iloprost.

    PubMed

    Machherndl, S; Kneussl, M; Baumgartner, H; Schneider, B; Petkov, V; Schenk, P; Lang, I M

    2001-01-01

    Pulmonary arterial hypertension (PAH), defined as elevated pulmonary arterial pressure and pulmonary vascular resistance, is an end-point of a variety of conditions. The only therapy that has been shown to improve both quality of life and survival is intravenous prostacyclin (prostaglandin I2 (PGI2), epoprostenol). The effect of long-term aerosolized iloprost (Ilomedin, Schering, Berlin, Germany and Vienna, Austria), a stable prostacyclin analogue and potent vasodilator, on haemodynamics and functional status was investigated in 12 patients with severe pulmonary hypertension. Haemodynamic measurements and vasodilator testing by right heart catheterization were performed prior to and after long-term iloprost inhalation therapy. Haemodynamic improvement or increased exercise tolerance was not observed in any of the patients. After a mean+/-SD treatment period of 10+/-5 months, mean+/-SD pulmonary vascular resistance had increased from 11+/-3 Wood Units (mmHg.L(-1).min) to 13+/-4 Wood Units, with unchanged arterial oxygen saturation (92+/-4%, versus 91+/-4%). Within the study period, three patients went into right heart failure and had to be placed on intravenous epoprostenol. The authors conclude that inhaled iloprost in addition to conventional therapy in the presently recommended dose of 100 microg.day(-1) delivered in 8-10 2 h portions, is not an efficient vasodilator therapy in severe pulmonary hypertension. It remains to be shown whether dose increases and/or combination protocols will be effective, or whether inhalation of iloprost may be safe for selected cases of pulmonary hypertension.

  7. Managing the Patient with Pulmonary Hypertension: Specialty Care Centers, Coordinated Care, and Patient Support.

    PubMed

    Chakinala, Murali M; Duncan, Maribeth; Wirth, Joel

    2016-08-01

    Pulmonary hypertension remains a challenging condition to diagnose and manage. Decentralized care for pulmonary arterial hypertension (PAH) has led to shortcomings in the diagnosis and management of PAH. The Pulmonary Hypertension Association-sponsored Pulmonary Hypertension Care Center program is designed to recognize specialty centers capable of providing multidisciplinary and comprehensive care of PAH. Ideally, Pulmonary Hypertension Care Centers will comanage PAH patients with community-based practitioners and address the growing needs of this emerging population of long-term PAH patients. PMID:27443143

  8. Pulmonary hypertension in systemic lupus erythematosus: report of four cases and review of the literature

    SciTech Connect

    Perez, H.D.; Kramer, N.

    1981-08-01

    Pulmonary hypertension has been reported rarely in patients with systemic lupus erythematosus (SLE). During the past 31/2 yr we have observed pulmonary hypertension as a major clinical manifestation of their disease in four of 43 patients with well-documented SLE followed at out institution. Pulmonary hypertension could be attributed to underlying lung disease in three and was considered to be primary in the remaining patient. Neither hydralazine nor prednisone administration had any effect on the course of the pulmonary hypertension in these patients. The presence of pulmonary hypertension in the course of active SLE may be more common than previously recognized.

  9. Mycophenolate mofetil attenuates pulmonary arterial hypertension in rats

    SciTech Connect

    Suzuki, Chihiro; Takahashi, Masafumi . E-mail: masafumi@sch.md.shinshu-u.ac.jp; Morimoto, Hajime; Izawa, Atsushi; Ise, Hirohiko; Hongo, Minoru; Hoshikawa, Yasushi; Ito, Takayuki; Miyashita, Hiroshi; Kobayashi, Eiji; Shimada, Kazuyuki; Ikeda, Uichi

    2006-10-20

    Pulmonary arterial hypertension (PAH) is characterized by abnormal proliferation of smooth muscle cells (SMCs), leading to occlusion of pulmonary arterioles, right ventricular (RV) hypertrophy, and death. We investigated whether mycophenolate mofetil (MMF), a potent immunosuppresssant, prevents the development of monocrotaline (MCT)-induced PAH in rats. MMF effectively decreased RV systolic pressure and RV hypertrophy, and reduced the medial thickness of pulmonary arteries. MMF significantly inhibited the number of proliferating cell nuclear antigen (PCNA)-positive cells, infiltration of macrophages, and expression of P-selectin and interleukin-6 on the endothelium of pulmonary arteries. The infiltration of T cells and mast cells was not affected by MMF. In vitro experiments revealed that mycophenolic acid (MPA), an active metabolite of MMF, dose-dependently inhibited proliferation of human pulmonary arterial SMCs. MMF attenuated the development of PAH through its anti-inflammatory and anti-proliferative properties. These findings provide new insight into the potential role of immunosuppressants in the treatment of PAH.

  10. Novel Strategies in the Treatment of Pulmonary Arterial Hypertension.

    PubMed

    Madonna, Rosalinda; Cocco, Nino

    2016-01-01

    Pulmonary arterial hypertension (PAH) is a pathophysiological condition characterized by increased pulmonary vascular resistance (PVR), initially due to abnormal pulmonary vasoconstriction in response to endothelial injury. Recent studies confirmed the key role of endothelin (ET)-1 in the vasoconstriction and remodeling of pulmonary microcirculation during PAH. In responders patients, classical treatments for PAH are prostanoids, phosphodiesterase (PDE)-5 inhibitors and endothelin receptor antagonists (ERAs), which target prostaglandin I2, nitric oxide and endothelin pathways, respectively. Randomised, placebo-controlled trials have shown that ERAs improves haemodynamic parameters of the pulmonary circulation, functional capacity and clinical outcome in patients affected by PAH. Here, we will review the definition, classification and pathophysiology of PH. Furthermore, we will provide an up-to-date overview of currently recommended diagnostic and therapeutic work-up in PAH. PMID:26201488

  11. The emerging role of epigenetics in pulmonary hypertension.

    PubMed

    Gamen, Elisabetta; Seeger, Werner; Pullamsetti, Soni Savai

    2016-09-01

    Epigenetics is usually defined as the study of changes in phenotype and gene expression not related to sequence alterations, but rather the chemical modifications of DNA and of its associated chromatin proteins. These modifications can be acquired de novo, being inherited, and represent the way in which genome and environment interact. Recent evidence points to the involvement of epigenetic changes in the pathogenesis of pulmonary hypertension, as they can partly explain how environmental and lifestyle factors can impose susceptibility to pulmonary hypertension and can explain the phenotypic alteration and maintenance of the disease state.In this article, we review the epigenetic regulatory mechanisms that are mediated by DNA methylation, the post-translational modifications of histone tails and noncoding RNAs in the pathogenesis of pulmonary hypertension. Furthermore, pharmacological interventions aimed at epigenetic regulators/modifiers and their outcomes in different cellular and preclinical rodent models are discussed. Lastly, the remaining challenges and future directions in which to explore epigenetic-based therapies in pulmonary hypertension are discussed. PMID:27492834

  12. Electrophysiological studies in patients with pulmonary hypertension: a retrospective investigation.

    PubMed

    Bandorski, Dirk; Schmitt, Jörn; Kurzlechner, Claudia; Erkapic, Damir; Hamm, Christian W; Seeger, Werner; Ghofrani, Ardeschir; Höltgen, Reinhard; Gall, Henning

    2014-01-01

    Few studies have investigated patients with pulmonary hypertension and arrhythmias. Data on electrophysiological studies in these patients are rare. In a retrospective dual-centre design, we analysed data from patients with indications for electrophysiological study. Fifty-five patients with pulmonary hypertension were included (Dana Point Classification: group 1: 14, group 2: 23, group 3: 4, group 4: 8, group 5: 2, and 4 patients with exercised-induced pulmonary hypertension). Clinical data, 6-minute walk distance, laboratory values, and echocardiography were collected/performed. Nonsustained ventricular tachycardia was the most frequent indication (n = 15) for an electrophysiological study, followed by atrial flutter (n = 14). In summary 36 ablations were performed and 25 of them were successful (atrial flutter 12 of 14 and atrioventricular nodal reentrant tachycardia 4 of 4). Fluoroscopy time was 16 ± 14.4 minutes. Electrophysiological studies in patients with pulmonary hypertension are feasible and safe. Ablation procedures are as effective in these patients as in non-PAH patients with atrial flutter and atrioventricular nodal reentrant tachycardia and should be performed likewise. The prognostic relevance of ventricular stimulations and inducible ventricular tachycardias in these patients is still unclear and requires further investigation.

  13. Electrophysiological Studies in Patients with Pulmonary Hypertension: A Retrospective Investigation

    PubMed Central

    Bandorski, Dirk; Schmitt, Jörn; Kurzlechner, Claudia; Erkapic, Damir; Hamm, Christian W.; Seeger, Werner; Ghofrani, Ardeschir; Höltgen, Reinhard; Gall, Henning

    2014-01-01

    Few studies have investigated patients with pulmonary hypertension and arrhythmias. Data on electrophysiological studies in these patients are rare. In a retrospective dual-centre design, we analysed data from patients with indications for electrophysiological study. Fifty-five patients with pulmonary hypertension were included (Dana Point Classification: group 1: 14, group 2: 23, group 3: 4, group 4: 8, group 5: 2, and 4 patients with exercised-induced pulmonary hypertension). Clinical data, 6-minute walk distance, laboratory values, and echocardiography were collected/performed. Nonsustained ventricular tachycardia was the most frequent indication (n = 15) for an electrophysiological study, followed by atrial flutter (n = 14). In summary 36 ablations were performed and 25 of them were successful (atrial flutter 12 of 14 and atrioventricular nodal reentrant tachycardia 4 of 4). Fluoroscopy time was 16 ± 14.4 minutes. Electrophysiological studies in patients with pulmonary hypertension are feasible and safe. Ablation procedures are as effective in these patients as in non-PAH patients with atrial flutter and atrioventricular nodal reentrant tachycardia and should be performed likewise. The prognostic relevance of ventricular stimulations and inducible ventricular tachycardias in these patients is still unclear and requires further investigation. PMID:24977152

  14. [Pulmonary arterial hypertension associated to human immunodeficiency virus].

    PubMed

    Sandoval-Gutiérrez, José Luis; Santos-Martínez, Luis Efren; Rodríguez-Silverio, Juan; Baranda-Tovar, Francisco Martín; Rivera-Rosales, Rosa María; Flores-Murrieta, Francisco Javier

    2015-01-01

    From the advent of the highly effective antiretroviral treatment, the life expectancy of patients with human immunodeficiency virus has increased significantly. At present, the causes of death are non-infectious complications. Between them, the pulmonary arterial hypertension has a special importance. It is important early detection to establish the therapeutic, with the objective of preventing a fatal outcome to future. PMID:25577549

  15. [Clinical utility of inhaled iloprost in pulmonary arterial hypertension].

    PubMed

    Santos-Martínez, Luis Efren; Moreno-Ruiz, Luis Antonio; Jiménez-Santos, Moisés; Olmos-Temois, Sergio Gabriel; Bojorquez-Guerrero, Luis Armando; Baranda-Tovar, Francisco Martín

    2014-01-01

    Inhaled iloprost is a drug from the group of prostacyclins used in the treatment of pulmonary arterial hypertension. Its efficacy and safety have allowed its use as monotherapy and combination therapy. This review describes the product characteristics, amenable to treatment groups, and updated clinical evidence of drug use.

  16. [Pulmonary arterial hypertension associated to human immunodeficiency virus].

    PubMed

    Sandoval-Gutiérrez, José Luis; Santos-Martínez, Luis Efren; Rodríguez-Silverio, Juan; Baranda-Tovar, Francisco Martín; Rivera-Rosales, Rosa María; Flores-Murrieta, Francisco Javier

    2015-01-01

    From the advent of the highly effective antiretroviral treatment, the life expectancy of patients with human immunodeficiency virus has increased significantly. At present, the causes of death are non-infectious complications. Between them, the pulmonary arterial hypertension has a special importance. It is important early detection to establish the therapeutic, with the objective of preventing a fatal outcome to future.

  17. The pathophysiology of pulmonary hypertension in left heart disease.

    PubMed

    Breitling, Siegfried; Ravindran, Krishnan; Goldenberg, Neil M; Kuebler, Wolfgang M

    2015-11-01

    Pulmonary hypertension (PH) is characterized by elevated pulmonary arterial pressure leading to right-sided heart failure and can arise from a wide range of etiologies. The most common cause of PH, termed Group 2 PH, is left-sided heart failure and is commonly known as pulmonary hypertension with left heart disease (PH-LHD). Importantly, while sharing many clinical features with pulmonary arterial hypertension (PAH), PH-LHD differs significantly at the cellular and physiological levels. These fundamental pathophysiological differences largely account for the poor response to PAH therapies experienced by PH-LHD patients. The relatively high prevalence of this disease, coupled with its unique features compared with PAH, signal the importance of an in-depth understanding of the mechanistic details of PH-LHD. The present review will focus on the current state of knowledge regarding the pathomechanisms of PH-LHD, highlighting work carried out both in human trials and in preclinical animal models. Adaptive processes at the alveolocapillary barrier and in the pulmonary circulation, including alterations in alveolar fluid transport, endothelial junctional integrity, and vasoactive mediator secretion will be discussed in detail, highlighting the aspects that impact the response to, and development of, novel therapeutics.

  18. [Right heart adaptation to pulmonary arterial hypertension: physiology and pathobiology].

    PubMed

    Vonk-Noordegraaf, Anton; Haddad, François; Chin, Kelly M; Forfia, Paul R; Kawut, Steven M; Lumens, Joost; Naeije, Robert; Newman, John; Oudiz, Ronald J; Provencher, Steve; Torbicki, Adam; Voelkel, Norbert F; Hassoun, Paul M

    2014-10-01

    Survival in patients with pulmonary arterial hypertension (PAH) is closely related to right ventricular (RV) function. Although pulmonary load is an important determinant of RV systolic function in PAH, there remains a significant variability in RV adaptation to pulmonary hypertension. In this report, the authors discuss the emerging concepts of right heart pathobiology in PAH. More specifically, the discussion focuses on the following questions. 1) How is right heart failure syndrome best defined? 2) What are the uderlying molecular mechanisms of the failing right ventricle in PAH? 3) How are RV contractility and function and their prognostic implications best assessed? 4) What is the role of targeted RV therapy? Throughout the report, the authors highlight differences between right and left heart failure and outline key areas of future investigation. (J Am Coll Cardiol 2013;62:D22-33) a 2013 by the American College of Cardiology Foundation).

  19. Right heart adaptation to pulmonary arterial hypertension: physiology and pathobiology.

    PubMed

    Vonk-Noordegraaf, Anton; Haddad, François; Chin, Kelly M; Forfia, Paul R; Kawut, Steven M; Lumens, Joost; Naeije, Robert; Newman, John; Oudiz, Ronald J; Provencher, Steve; Torbicki, Adam; Voelkel, Norbert F; Hassoun, Paul M

    2013-12-24

    Survival in patients with pulmonary arterial hypertension (PAH) is closely related to right ventricular (RV) function. Although pulmonary load is an important determinant of RV systolic function in PAH, there remains a significant variability in RV adaptation to pulmonary hypertension. In this report, the authors discuss the emerging concepts of right heart pathobiology in PAH. More specifically, the discussion focuses on the following questions. 1) How is right heart failure syndrome best defined? 2) What are the underlying molecular mechanisms of the failing right ventricle in PAH? 3) How are RV contractility and function and their prognostic implications best assessed? 4) What is the role of targeted RV therapy? Throughout the report, the authors highlight differences between right and left heart failure and outline key areas of future investigation.

  20. Nitric oxide for the evaluation and treatment of pulmonary hypertension in congenital heart disease.

    PubMed Central

    Kovalchin, J P; Mott, A R; Rosen, K L; Feltes, T F

    1997-01-01

    The use of inhaled nitric oxide as a selective pulmonary vasodilator has expanded to include patients with congenital heart disease and pulmonary hypertension. The therapeutic and diagnostic roles of inhaled nitric oxide offer additional alternatives and benefits to these patients with pulmonary hypertension, particularly in the postoperative setting. This article reviews the background, mechanism of action, toxicities, and current clinical applications of inhaled nitric oxide in the child with congenital heart disease and pulmonary hypertension. PMID:9456484

  1. Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension.

    PubMed

    Guignabert, Christophe; Phan, Carole; Seferian, Andrei; Huertas, Alice; Tu, Ly; Thuillet, Raphaël; Sattler, Caroline; Le Hiress, Morane; Tamura, Yuichi; Jutant, Etienne-Marie; Chaumais, Marie-Camille; Bouchet, Stéphane; Manéglier, Benjamin; Molimard, Mathieu; Rousselot, Philippe; Sitbon, Olivier; Simonneau, Gérald; Montani, David; Humbert, Marc

    2016-09-01

    Pulmonary arterial hypertension (PAH) is a life-threatening disease that can be induced by dasatinib, a dual Src and BCR-ABL tyrosine kinase inhibitor that is used to treat chronic myelogenous leukemia (CML). Today, key questions remain regarding the mechanisms involved in the long-term development of dasatinib-induced PAH. Here, we demonstrated that chronic dasatinib therapy causes pulmonary endothelial damage in humans and rodents. We found that dasatinib treatment attenuated hypoxic pulmonary vasoconstriction responses and increased susceptibility to experimental pulmonary hypertension (PH) in rats, but these effects were absent in rats treated with imatinib, another BCR-ABL tyrosine kinase inhibitor. Furthermore, dasatinib treatment induced pulmonary endothelial cell apoptosis in a dose-dependent manner, while imatinib did not. Dasatinib treatment mediated endothelial cell dysfunction via increased production of ROS that was independent of Src family kinases. Consistent with these findings, we observed elevations in markers of endothelial dysfunction and vascular damage in the serum of CML patients who were treated with dasatinib, compared with CML patients treated with imatinib. Taken together, our findings indicate that dasatinib causes pulmonary vascular damage, induction of ER stress, and mitochondrial ROS production, which leads to increased susceptibility to PH development. PMID:27482885

  2. Clinical and haemodynamic evaluation of chronic thromboembolic pulmonary hypertension patients scheduled for pulmonary thromboendarterectomy. Is schistosomiasis hypertension an important confounding factor?

    PubMed Central

    Terra‐Filho, Mario; Mello, Marcos Figueiredo; Lapa, Mônica Silveira; Teixeira, Ricardo Henrique Oliveira Braga; Jatene, Fábio Biscegli

    2010-01-01

    INTRODUCTION: Chronic thromboembolic pulmonary hypertension is a disease affecting approximately 4,000 people per year in the United States. The incidence rate in Brazil, however, is unknown. The estimated survival for patients with chronic thromboembolic pulmonary hypertension without treatment is approximately three years. Pulmonary thromboendarterectomy for select patients is a potentially curative procedure when correctly applied. In Brazil, the clinical and hemodynamic profiles of chronic thromboembolic pulmonary hypertension patients have yet to be described. OBJECTIVES: To evaluate the clinical and hemodynamic characteristics of chronic thromboembolic pulmonary hypertension patients scheduled for pulmonary thromboendarterectomy in a referral center for chronic thromboembolic pulmonary hypertension treatment in Brazil. METHODS: From December 2006 to November 2009, patients were evaluated and scheduled for pulmonary thromboendarterectomy. The subjects were classified according to gender, age and functional class and were tested for thrombofilia and brain natriuretic peptide levels. RESULTS: Thirty‐five consecutive chronic thromboembolic pulmonary hypertension patients were evaluated. Two patients tested positive for schistosomiasis, and 31 were enrolled in the study (19 female, 12 male). The majority of patients were categorized in functional classes III and IV. Hemodynamic data showed a mean pulmonary vascular resistance (PVR) of 970.8 ± 494.36 dynas·s·cm‐5 and a low cardiac output of 3.378 ± 1.13 L/min. Linear regression revealed a direct relation between cardiac output and pulmonary vascular resistance. Paradoxical septal movement was strongly correlated with pulmonary vascular resistance and cardiac output (p = 0.001). Brain natriuretic peptide serum levels were elevated in 19 of 27 patients. CONCLUSIONS: In a referral center for pulmonary hypertension in Brazil, chronic thromboembolic pulmonary hypertension patients evaluated for pulmonary

  3. Diagnosis of pulmonary hypertension from radiographic estimates of pulmonary arterial size.

    PubMed Central

    Bush, A; Gray, H; Denison, D M

    1988-01-01

    The reported accuracy of radiographic measurements in predicting pulmonary hypertension is very variable. Measurements of right and left descending pulmonary artery diameter have been reported to provide a correct diagnosis in as many as 98% of patients. A study was carried out to determine the predictive value of measurements made from the chest radiographs of 50 normal subjects and of 27 patients undergoing right heart catheterisation for cardiac or pulmonary vascular disease, taking account of radiographic magnification. After such corrections a right descending pulmonary artery diameter over 16.7 mm or a left descending pulmonary artery diameter of over 16.9 mm distinguished 12 of 23 pulmonary hypertensive subjects, with no false positive results. The diameter was then arbitrarily squared (any differences between patients and control subjects being exaggerated) and the product was divided by either predicted or actual lung volume in an attempt to correct for body size. The new index distinguished 19 of 23 patients with pulmonary hypertension, with one false positive, when the divisor was actual lung volume; when predicted lung volume was used 18 of 23 patients were distinguished, again with one false positive result. PMID:3353884

  4. Estradiol improves pulmonary hemodynamics and vascular remodeling in perinatal pulmonary hypertension.

    PubMed

    Parker, T A; Ivy, D D; Galan, H L; Grover, T R; Kinsella, J P; Abman, S H

    2000-02-01

    Partial ligation of the ductus arteriosus (DA) in the fetal lamb causes sustained elevation of pulmonary vascular resistance (PVR) and hypertensive structural changes in small pulmonary arteries, providing an animal model for persistent pulmonary hypertension of the newborn. Based on its vasodilator and antimitogenic properties in other experimental studies, we hypothesized that estradiol (E(2)) would attenuate the pulmonary vascular structural and hemodynamic changes caused by pulmonary hypertension in utero. To test our hypothesis, we treated chronically instrumented fetal lambs (128 days, term = 147 days) with daily infusions of E(2) (10 microg; E(2) group, n = 6) or saline (control group, n = 5) after partial ligation of the DA. We measured intrauterine pulmonary and systemic artery pressures in both groups throughout the study period. After 8 days, we delivered the study animals by cesarean section to measure their hemodynamic responses to birth-related stimuli. Although pulmonary and systemic arterial pressures were not different in utero, fetal PVR immediately before ventilation was reduced in the E(2)-treated group (2.43 +/- 0.79 vs. 1.48 +/- 0.26 mmHg. ml(-1). min, control vs. E(2), P < 0.05). During the subsequent delivery study, PVR was lower in the E(2)-treated group in response to ventilation with hypoxic gas but was not different between groups with ventilation with 100% O(2). During mechanical ventilation after delivery, arterial partial O(2) pressure was higher in E(2) animals than controls (41 +/- 11 vs. 80 +/- 35 Torr, control vs. E(2), P < 0. 05). Morphometric studies of hypertensive vascular changes revealed that E(2) treatment decreased wall thickness of small pulmonary arteries (59 +/- 1 vs. 48 +/- 1%, control vs. E(2), P < 0.01). We conclude that chronic E(2) treatment in utero attenuates the pulmonary hemodynamic and histological changes caused by DA ligation in fetal lambs. PMID:10666122

  5. Prevalence of coronary artery-pulmonary artery collaterals in patients with chronic thromboembolic pulmonary hypertension.

    PubMed

    Lee, Noel S; Blanchard, Daniel G; Knowlton, Kirk U; McDivit, Anna M; Pretorius, Victor; Madani, Michael M; Fedullo, Peter F; Kerr, Kim M; Kim, Nick H; Poch, David S; Auger, William R; Daniels, Lori B

    2015-06-01

    This study sought to determine the prevalence of coronary artery-pulmonary artery collaterals in patients with chronic thromboembolic pulmonary hypertension (CTEPH) and to correlate their presence with the degree of clot burden. CTEPH is a treatable cause of severe pulmonary hypertension and right heart failure. Bronchopulmonary collateral vessels have been used as a supplementary diagnostic and prognostic tool for this disease. Coronary artery-pulmonary artery collaterals in this population have not been described. The coronary angiograms of 300 consecutive patients with CTEPH evaluated for pulmonary thromboendarterectomy (PTE) between January 1, 2007, and May 1, 2014, were examined. Of these patients, 259 (50% male; mean age, 58.3 ± 10.6 years) had cineangiographic images deemed adequate to definitively assess for the presence of coronary artery-pulmonary artery collaterals and were included in the final analyses. Pulmonary angiogram reports were reviewed for extent of pulmonary artery obstruction. The coronary angiograms of 259 age- and sex-matched control patients were also examined. Among 259 CTEPH patients with definitive imaging, 34 coronary artery-pulmonary artery collaterals were found in 28 patients (10.8%), versus 1 coronary artery-pulmonary artery collateral among control subjects (0.4%; P < 0.001). Compared with CTEPH patients without collaterals, patients with collaterals had a significantly higher prevalence of total occlusion of their right or left main pulmonary artery (P < 0.001) or lobar arteries (P < 0.001). In conclusion, the prevalence of coronary artery-pulmonary artery collaterals in CTEPH patients undergoing coronary angiography for possible PTE is approximately 11%. These vessels are associated with more severe pulmonary artery occlusion. PMID:26064456

  6. Saudi Guidelines on the Diagnosis and Treatment of Pulmonary Hypertension: Schistosomiasis and pulmonary arterial hypertension.

    PubMed

    Butrous, Ghazwan

    2014-07-01

    Schistosomiasis is caused by infection with the parasite Schistosoma, which is a flat-worm or fluke. The dominant species are Schistosoma mansoni, Schistosoma japonicum, and Schistosoma haematobium. Schistosomiasis is the third most common parasitic disease in the world after malaria and amoebiasis. It is endemic in more than 70 countries affecting about 200 million people worldwide, of whom 80% are in sub-Saharan Africa. There are pockets of infection in north-eastern Brazil, near the Yangtze River in China, and some pockets in south East Asia. In the East Mediterranean regions, the Schistosoma have been reported in Iraq and Egypt as well as in Sudan. The latter has the highest infection rate nowadays, particularly in the Al Jazeera area, due to the poor Schistosoma control program. In the Arabian peninsula, schistosomiasis has been reported in southwest part of Saudi Arabia, mainly in the Asir province and Jizan province, which lay in the southwest corner of Saudi Arabia and directly north of the border with Yemen. The efforts to control schistosomiasis have been very successful in Saudi Arabia due to the irrigation system control. However, the infection is prone in Yemen, where the schistosomiasis control is much less strict. Thus as a result, the problem still exists due to transmigration of the populations from both countries. As a cause of pulmonary arterial hypertension (PAH), schistosomiasis is still under diagnosed and undertreated. This article with give a highlight about the pathophysiology of the disease and both diagnostic and therapeutic strategies. PMID:25076995

  7. Chymase: a multifunctional player in pulmonary hypertension associated with lung fibrosis.

    PubMed

    Kosanovic, Djuro; Luitel, Himal; Dahal, Bhola Kumar; Cornitescu, Teodora; Janssen, Wiebke; Danser, A H Jan; Garrelds, Ingrid M; De Mey, Jo G R; Fazzi, Gregorio; Schiffers, Paul; Iglarz, Marc; Fischli, Walter; Ghofrani, Hossein Ardeschir; Weissmann, Norbert; Grimminger, Friedrich; Seeger, Werner; Reiss, Irwin; Schermuly, Ralph Theo

    2015-10-01

    Limited literature sources implicate mast-cell mediator chymase in the pathologies of pulmonary hypertension and pulmonary fibrosis. However, there is no evidence on the contribution of chymase to the development of pulmonary hypertension associated with lung fibrosis, which is an important medical condition linked with increased mortality of patients who already suffer from a life-threatening interstitial lung disease.The aim of this study was to investigate the role of chymase in this particular pulmonary hypertension form, by using a bleomycin-induced pulmonary hypertension model.Chymase inhibition resulted in attenuation of pulmonary hypertension and pulmonary fibrosis, as evident from improved haemodynamics, decreased right ventricular remodelling/hypertrophy, pulmonary vascular remodelling and lung fibrosis. These beneficial effects were associated with a strong tendency of reduction in mast cell number and activity, and significantly diminished chymase expression levels. Mechanistically, chymase inhibition led to attenuation of transforming growth factor β1 and matrix-metalloproteinase-2 contents in the lungs. Furthermore, chymase inhibition prevented big endothelin-1-induced vasoconstriction of the pulmonary arteries.Therefore, chymase plays a role in the pathogenesis of pulmonary hypertension associated with pulmonary fibrosis and may represent a promising therapeutic target. In addition, this study may provide valuable insights on the contribution of chymase in the pulmonary hypertension context, in general, regardless of the pulmonary hypertension form.

  8. Pulmonary arterial hypertension secondary to chronic left-sided cardiac dysfunction in dogs.

    PubMed

    Stepien, Rebecca L

    2009-09-01

    Pulmonary arterial hypertension is a description of a physiological finding rather than a diagnosis. Pulmonary arterial pressure is the result of interactions among pulmonary blood flow (right ventricular cardiac output), pulmonary vascular impedance and post-capillary pressure (typically reflecting left atrial pressure). When elevations in pulmonary arterial pressure (systolic/diastolic pulmonary arterial pressure > approximately 30/19 mmHg at rest) are accompanied by increased left atrial pressure, pulmonary arterial hypertension may be considered secondary to left-heart failure. Introduction of Doppler methods to diagnose pulmonary arterial hypertension has increased the awareness of the prevalence and importance of pulmonary arterial hypertension dogs with left-heart failure. Increasing understanding of the mechanism of development of pulmonary venous hypertension and reactive pulmonary arterial hypertension in dogs with left-heart disease has led to the development of successful additive therapies for progressive clinical signs in the setting of chronic therapy for congestive heart failure due to left-sided valvular and myocardial dysfunction. Because effective therapies for pulmonary arterial hypertension secondary to chronic left-sided cardiac dysfunction are now available, screening for pulmonary arterial hypertension should be a regular part of the Doppler echocardiographic examination in a clinical setting of chronic therapy for left-sided congestive heart failure due to valvular or myocardial disease.

  9. Right Ventricular Dysfunction in Systemic Sclerosis Associated Pulmonary Arterial Hypertension

    PubMed Central

    Tedford, Ryan J.; Mudd, James O.; Girgis, Reda E.; Mathai, Stephen C.; Zaiman, Ari L.; Housten-Harris, Traci; Boyce, Danielle; Kelemen, Benjamin W.; Bacher, Anita C.; Shah, Ami A.; Hummers, Laura K.; Wigley, Fredrick M.; Russell, Stuart D.; Saggar, Rajeev; Saggar, Rajan; Maughan, W. Lowell; Hassoun, Paul M.; Kass, David A.

    2013-01-01

    Background Systemic sclerosis associated pulmonary artery hypertension (SScPAH) has a worse prognosis compared to idiopathic pulmonary arterial hypertension (IPAH), with a median survival of 3 years after diagnosis often due to right ventricular (RV) failure. We tested if SScPAH or systemic sclerosis related pulmonary hypertension with interstitial lung disease (SSc-ILD-PH) imposes a greater pulmonary vascular load than IPAH and/or leads to worse RV contractile function. Methods and Results We analyzed pulmonary artery pressures and mean flow in 282 patients with pulmonary hypertension (166 SScPAH, 49 SSc-ILD-PH, 67 IPAH). An inverse relation between pulmonary resistance (RPA) and compliance (CPA) was similar for all three groups, with a near constant resistance × compliance product. RV pressure-volume loops were measured in a subset, IPAH (n=5) and SScPAH (n=7) as well as SSc without PH (SSc-no-PH, n=7) to derive contractile indexes (end-systolic elastance [Ees] and preload recruitable stroke work [Msw]), measures of right ventricular load (arterial elastance [Ea]), and RV-pulmonary artery coupling (Ees/Ea). RV afterload was similar in SScPAH and IPAH (RPA=7.0±4.5 vs. 7.9±4.3 Wood units; Ea=0.9±0.4 vs. 1.2±0.5 mmHg/mL; CPA=2.4±1.5 vs. 1.7±1.1 mL/mmHg; p>0.3 for each). Though SScPAH did not have greater vascular stiffening compared to IPAH, RV contractility was more depressed (Ees=0.8±0.3 vs. 2.3±1.1, p<0.01; Msw=21±11 vs. 45±16, p=0.01), with differential RV-PA uncoupling (Ees/Ea=1.0±0.5 vs. 2.1±1.0, p=.03). This ratio was higher in SSc-no-PH (Ees/Ea = 2.3±1.2, p=0.02 vs. SScPAH). Conclusions RV dysfunction is worse in SScPAH compared to IPAH at similar afterload, and may be due to intrinsic systolic function rather than enhanced pulmonary vascular resistive and/or pulsatile loading. PMID:23797369

  10. Diagnosis and management of persistent pulmonary hypertension of the newborn.

    PubMed

    Bendapudi, Perraju; Rao, Gopinath Gangadhara; Greenough, Anne

    2015-06-01

    Persistent pulmonary hypertension of new born (PPHN) is associated with mortality and morbidity; it may be idiopathic or secondary to a number of conditions. The mainstay of diagnosis and to exclude structural abnormalities is echocardiography. Brain type natriuretic peptide (BNP) levels are elevated in PPHN, but are insufficiently sensitive to contribute to routine diagnosis. Management includes improving oxygenation by optimising lung volume by ventilatory techniques and/or surfactant and administering pulmonary vasodilator agents. Inhaled nitric oxide (iNO), a selective pulmonary vasodilator, reduces the need for extracorporeal membrane oxygenation in term infants; it does not, however, improve mortality or have any long term positive effects in prematurely born infants or infants with congenital diaphragmatic hernia. Other pulmonary vasodilators have been reported in case series to be efficacious alone or in combination with iNO. Randomised trials with long term follow up are required to identify the optimum therapeutic strategies in PPHN. PMID:25765845

  11. Pulmonary vascular stiffness: measurement, modeling, and implications in normal and hypertensive pulmonary circulations.

    PubMed

    Hunter, Kendall S; Lammers, Steven R; Shandas, Robin

    2011-07-01

    This article introduces the concept of pulmonary vascular stiffness, discusses its increasingly recognized importance as a diagnostic marker in the evaluation of pulmonary vascular disease, and describes methods to measure and model it clinically, experimentally, and computationally. It begins with a description of systems-level methods to evaluate pulmonary vascular compliance and recent clinical efforts in applying such techniques to better predict patient outcomes in pulmonary arterial hypertension. It then progresses from the systems-level to the local level, discusses proposed methods by which upstream pulmonary vessels increase in stiffness, introduces concepts around vascular mechanics, and concludes by describing recent work incorporating advanced numerical methods to more thoroughly evaluate changes in local mechanical properties of pulmonary arteries. PMID:23733649

  12. Pulmonary Vascular Stiffness: Measurement, Modeling, and Implications in Normal and Hypertensive Pulmonary Circulations

    PubMed Central

    Hunter, Kendall S.; Lammers, Steven R.; Shandas, Robin

    2014-01-01

    This article introduces the concept of pulmonary vascular stiffness, discusses its increasingly recognized importance as a diagnostic marker in the evaluation of pulmonary vascular disease, and describes methods to measure and model it clinically, experimentally, and computationally. It begins with a description of systems-level methods to evaluate pulmonary vascular compliance and recent clinical efforts in applying such techniques to better predict patient outcomes in pulmonary arterial hypertension. It then progresses from the systems-level to the local level, discusses proposed methods by which upstream pulmonary vessels increase in stiffness, introduces concepts around vascular mechanics, and concludes by describing recent work incorporating advanced numerical methods to more thoroughly evaluate changes in local mechanical properties of pulmonary arteries. PMID:23733649

  13. Pulmonary arterial hypertension: an imaging review comparing MR pulmonary angiography and perfusion with multidetector CT angiography

    PubMed Central

    Junqueira, F P; Lima, C M A O; Coutinho, A C; Parente, D B; Bittencourt, L K; Bessa, L G P; Domingues, R C; Marchiori, E

    2012-01-01

    Pulmonary hypertension (PH) is a progressive disease that leads to substantial morbidity and eventual death. Pulmonary multidetector CT angiography (MDCTA), pulmonary MR angiography (MRA) and MR-derived pulmonary perfusion (MRPP) imaging are non-invasive imaging techniques for the differential diagnosis of PH. MDCTA is considered the gold standard for the diagnosis of pulmonary embolism, one of the most common causes of PH. MRA and MRPP are promising techniques that do not require the use of ionising radiation or iodinated contrast material, and can be useful for patients for whom such material cannot be used. This review compares the imaging aspects of pulmonary MRA and 64-row MDCTA in patients with chronic thromboembolic or idiopathic PH. PMID:22932061

  14. Quality of life among pulmonary hypertension patients in Finland

    PubMed Central

    Kukkonen, Merja; Puhakka, Airi; Halme, Maija

    2016-01-01

    Background The purpose of the study was to examine pulmonary hypertension (PH) patients’ quality of life (QOL) for the first time in Finland. Methods This was a non-interventional, cross-sectional study. The SF-36v2 questionnaire was sent to the PH patients who had been referred to or followed up on at the Helsinki University Central Hospital's pulmonary clinic for idiopathic pulmonary arterial hypertension, associated pulmonary arterial hypertension (APAH), or chronic thromboembolic PH (CTEPH). The patients were on pulmonary arterial hypertension (PAH) – specific drugs, were at least 18 years old, and had signed an informed consent. Results There were 62 patients who fulfilled the inclusion criteria, and 53% of respondents rated their health as moderate. Similarly, 55% of respondents rated their health status approximately the same compared to their situation 1 year ago. QOL was impaired in all other subscales, except for the mental health and mental component score. A majority of patients suffered from PH symptoms, which worsened their QOL. The greatest impact on their QOL was associated with a high World Health Organization (WHO) functional class (FC), poor performance in a 6-min walking test (6MWT), symptoms, oxygen therapy, elevated pro-brain natriuretic peptide, pericardial effusion, APAH etiology, and being retired from work. Conclusions The respondents had a reduced QOL, compared to the general population, in all other subscales, except for mental health. APAH patients had the worst QOL. Good results in functional capacity measures (WHO FC, 6MWT) were associated with a better QOL. Patients’ QOL can be improved by reducing the symptoms of PAH. PMID:26787306

  15. Decreased time constant of the pulmonary circulation in chronic thromboembolic pulmonary hypertension.

    PubMed

    MacKenzie Ross, Robert V; Toshner, Mark R; Soon, Elaine; Naeije, Robert; Pepke-Zaba, Joanna

    2013-07-15

    This study analyzed the relationship between pulmonary vascular resistance (PVR) and pulmonary arterial compliance (Ca) in patients with idiopathic pulmonary arterial hypertension (IPAH) and proximal chronic thromboembolic pulmonary hypertension (CTEPH). It has recently been shown that the time constant of the pulmonary circulation (RC time constant), or PVR × Ca, remains unaltered in various forms and severities of pulmonary hypertension, with the exception of left heart failure. We reasoned that increased wave reflection in proximal CTEPH would be another cause of the decreased RC time constant. We conducted a retrospective analysis of invasive pulmonary hemodynamic measurements in IPAH (n = 78), proximal CTEPH (n = 91) before (pre) and after (post) pulmonary endarterectomy (PEA), and distal CTEPH (n = 53). Proximal CTEPH was defined by a postoperative mean pulmonary artery pressure (PAP) of ≤25 mmHg. Outcome measures were the RC time constant, PVR, Ca, and relationship between systolic and mean PAPs. The RC time constant for pre-PEA CTEPH was 0.49 ± 0.11 s compared with post-PEA-CTEPH (0.37 ± 0.11 s, P < 0.0001), IPAH (0.63 ± 0.14 s, P < 0.001), and distal CTEPH (0.55 ± 0.12 s, P < 0.05). A shorter RC time constant was associated with a disproportionate decrease in systolic PAP with respect to mean PAP. We concluded that the pulmonary RC time constant is decreased in proximal CTEPH compared with IPAH, pre- and post-PEA, which may be explained by increased wave reflection but also, importantly, by persistent structural changes after the removal of proximal obstructions. A reduced RC time constant in CTEPH is in accord with a wider pulse pressure and hence greater right ventricular work for a given mean PAP.

  16. Pulmonary artery denervation for treatment of a patient with pulmonary hypertension secondary to left heart disease

    PubMed Central

    2016-01-01

    Abstract Pulmonary hypertension (PH) predicts poor outcome in patients with left heart disease. A 62-year-old man was referred for heart failure associated with ischemic cardiomyopathy. He received a diagnosis of combined postcapillary and precapillary PH secondary to left heart disease on the basis of hemodynamic parameters. After the pulmonary artery denervation procedure was performed, hemodynamic parameters were markedly improved, which resulted in a significant increase in functional capacity. PMID:27252851

  17. [Drug therapy of pulmonary arterial hypertension in 2014].

    PubMed

    Aschermann, Michael; Jansa, Pavel

    2014-04-01

    Pulmonary arterial hypertension (PAH) is a primary pulmonary arteriolar disease, characterized by a progressive increase in pulmonary vascular resistance and pressure in the pulmonary circulation. It progressively leads to hypertrophy of the right ventricle and with no treatment to its failure and patient´s death. Etiology of pulmonary hypertension (PH) has been reclassified repeatedly, most recently during the 4th World Symposium on Pulmonary Hypertension held in 2008 [1]. Currently, the first group contains PAH with either unknown or known cause (systemic connective tissue disease, liver disease, congenital heart disease, HIV infection, abuse of anorexic agents). Current drug therapy of PAH is divided into conventional (anticoagulant therapy, calcium channel blockers, therapy of chronic heart failure) and specific (prostanoids, endothelium receptor antagonists, phosphodiesterase 5 inhibitors). Patients with positive vasodilator test are indicated for the high doses treatment of calcium channel blockers. Patients with negative vasodilator test are indicated for chronic anticoagulant therapy and specific drug therapy either as mono-therapy, or as combined therapy. Recent years have brought a wide range of new treatments modalities, especially in the field of pharmacotherapy. In addition, other treatment modalities have been tested, for example application of stem cells. Drugs in research include several groups: 1. vasodilators: fasudil, adrenonedullin, activators and stimulators of guanylate cyclase, vasoactive intestinal peptide (VIP); 2. Anti-inflammatory agents: inhibitor of elastase, antagonist of B cells, immunosuppressive agents, inhibitor of HDAC1; 3. agents affecting metabolism: nitrites, PPAR antagonists, antioxidants, serotonin receptor antagonist and serotonin transporter blockers, statins, inhibitors of Rho-kinase; 4. apoptosis inductors of smooth muscle cells: tyrosine-kinase inhibitors, elastase inhibitors; 5. agents influencing vascular regeneration

  18. Controversies in pulmonary hypertension due to left heart disease

    PubMed Central

    Cheli, Martino

    2015-01-01

    Left heart failure is currently the most prevalent cause of pulmonary hypertension (PH) worldwide and this is due mainly to the increased left ventricular and pulmonary venous pressures seen in this condition. Still, a quota of patients with left heart failure will have a pulmonary arterial disease “disproportionate” to the initial increase of left-sided pressures. Whatever the mechanism involved, the appearance of PH is a powerful marker, as it determines decreased exercise tolerance and survival. To date, all trials using therapies approved for pulmonary arterial hypertension (PAH) failed to demonstrate a benefit in the context of heart failure (HF) without or with PH. In addition, the comparison among studies is limited by relevant differences in definitions, methodology, and timing of assessment. A novel rigorous hemodynamic classification based on the diastolic pulmonary gradient has been recently proposed to better characterize this form of PH. This will promote uniformity in patient populations and end-points for future clinical trials. PMID:25705390

  19. Role of oxidized lipids in pulmonary arterial hypertension.

    PubMed

    Sharma, Salil; Ruffenach, Grégoire; Umar, Soban; Motayagheni, Negar; Reddy, Srinivasa T; Eghbali, Mansoureh

    2016-09-01

    Pulmonary arterial hypertension (PAH) is a multifactorial disease characterized by interplay of many cellular, molecular, and genetic events that lead to excessive proliferation of pulmonary cells, including smooth muscle and endothelial cells; inflammation; and extracellular matrix remodeling. Abnormal vascular changes and structural remodeling associated with PAH culminate in vasoconstriction and obstruction of pulmonary arteries, contributing to increased pulmonary vascular resistance, pulmonary hypertension, and right ventricular failure. The complex molecular mechanisms involved in the pathobiology of PAH are the limiting factors in the development of potential therapeutic interventions for PAH. Over the years, our group and others have demonstrated the critical implication of lipids in the pathogenesis of PAH. This review specifically focuses on the current understanding of the role of oxidized lipids, lipid metabolism, peroxidation, and oxidative stress in the progression of PAH. This review also discusses the relevance of apolipoprotein A-I mimetic peptides and microRNA-193, which are known to regulate the levels of oxidized lipids, as potential therapeutics in PAH. PMID:27683603

  20. Role of oxidized lipids in pulmonary arterial hypertension.

    PubMed

    Sharma, Salil; Ruffenach, Grégoire; Umar, Soban; Motayagheni, Negar; Reddy, Srinivasa T; Eghbali, Mansoureh

    2016-09-01

    Pulmonary arterial hypertension (PAH) is a multifactorial disease characterized by interplay of many cellular, molecular, and genetic events that lead to excessive proliferation of pulmonary cells, including smooth muscle and endothelial cells; inflammation; and extracellular matrix remodeling. Abnormal vascular changes and structural remodeling associated with PAH culminate in vasoconstriction and obstruction of pulmonary arteries, contributing to increased pulmonary vascular resistance, pulmonary hypertension, and right ventricular failure. The complex molecular mechanisms involved in the pathobiology of PAH are the limiting factors in the development of potential therapeutic interventions for PAH. Over the years, our group and others have demonstrated the critical implication of lipids in the pathogenesis of PAH. This review specifically focuses on the current understanding of the role of oxidized lipids, lipid metabolism, peroxidation, and oxidative stress in the progression of PAH. This review also discusses the relevance of apolipoprotein A-I mimetic peptides and microRNA-193, which are known to regulate the levels of oxidized lipids, as potential therapeutics in PAH.

  1. Role of oxidized lipids in pulmonary arterial hypertension

    PubMed Central

    Ruffenach, Grégoire; Umar, Soban; Motayagheni, Negar; Reddy, Srinivasa T.; Eghbali, Mansoureh

    2016-01-01

    Abstract Pulmonary arterial hypertension (PAH) is a multifactorial disease characterized by interplay of many cellular, molecular, and genetic events that lead to excessive proliferation of pulmonary cells, including smooth muscle and endothelial cells; inflammation; and extracellular matrix remodeling. Abnormal vascular changes and structural remodeling associated with PAH culminate in vasoconstriction and obstruction of pulmonary arteries, contributing to increased pulmonary vascular resistance, pulmonary hypertension, and right ventricular failure. The complex molecular mechanisms involved in the pathobiology of PAH are the limiting factors in the development of potential therapeutic interventions for PAH. Over the years, our group and others have demonstrated the critical implication of lipids in the pathogenesis of PAH. This review specifically focuses on the current understanding of the role of oxidized lipids, lipid metabolism, peroxidation, and oxidative stress in the progression of PAH. This review also discusses the relevance of apolipoprotein A-I mimetic peptides and microRNA-193, which are known to regulate the levels of oxidized lipids, as potential therapeutics in PAH. PMID:27683603

  2. Role of oxidized lipids in pulmonary arterial hypertension

    PubMed Central

    Ruffenach, Grégoire; Umar, Soban; Motayagheni, Negar; Reddy, Srinivasa T.; Eghbali, Mansoureh

    2016-01-01

    Abstract Pulmonary arterial hypertension (PAH) is a multifactorial disease characterized by interplay of many cellular, molecular, and genetic events that lead to excessive proliferation of pulmonary cells, including smooth muscle and endothelial cells; inflammation; and extracellular matrix remodeling. Abnormal vascular changes and structural remodeling associated with PAH culminate in vasoconstriction and obstruction of pulmonary arteries, contributing to increased pulmonary vascular resistance, pulmonary hypertension, and right ventricular failure. The complex molecular mechanisms involved in the pathobiology of PAH are the limiting factors in the development of potential therapeutic interventions for PAH. Over the years, our group and others have demonstrated the critical implication of lipids in the pathogenesis of PAH. This review specifically focuses on the current understanding of the role of oxidized lipids, lipid metabolism, peroxidation, and oxidative stress in the progression of PAH. This review also discusses the relevance of apolipoprotein A-I mimetic peptides and microRNA-193, which are known to regulate the levels of oxidized lipids, as potential therapeutics in PAH.

  3. Pulmonary Arterial Hypertension: A Focus on Infused Prostacyclins.

    PubMed

    Stewart, Traci

    2016-01-01

    Pulmonary arterial hypertension (PAH) is characterized by vasoconstriction and cell proliferation in the pulmonary vasculature. Guideline-driven interventions with infused prostacyclin treatment are the mainstay for patients with advanced symptoms. Infused prostacyclin therapy is complex. It is critical to manage prostacyclin therapy with precision because boluses or interruptions can be fatal. Education of patients and inpatient staff nurses is necessary to prevent negative outcomes. Nurses are an essential part of the multidisciplinary team caring for patients with PAH. The diagnostic evaluation and treatment of PAH are reviewed here, and challenges associated with the care of patients on prostacyclin therapy are discussed. PMID:27598071

  4. Apoptosis-based therapy to treat pulmonary arterial hypertension

    PubMed Central

    Suzuki, Yuichiro J.; Ibrahim, Yasmine F.; Shults, Nataliia V.

    2016-01-01

    Pulmonary arterial hypertension (PAH) is rare, but patients who are diagnosed with this disease still suffer from a lack of satisfactory treatment strategies to prolong survival. While currently approved drugs for PAH have some benefits, these vasodilators only have limited efficacy for eliminating pulmonary vascular remodeling and reducing mortality. Thus, our laboratory has been exploring the use of aggressive drugs, which are capable of causing apoptotic cell death, to treat PAH. We have so far found that three classes of anti-tumor agents, including anthracyclines, taxanes, and proteasome inhibitors, are capable of reducing pulmonary vascular thickness in rats with PAH. These drugs kill cells in remodeled pulmonary vessels without affecting the normal, healthy pulmonary vasculature, revealing that proliferating vascular cells in PAH patients are more sensitive to drug-induced apoptosis compared to the differentiated phenotype that is physiologically important for smooth muscle contraction. Since many apoptosis-inducing drugs cause cardiotoxicity in cancer patients, and because PAH patients already have a weakened heart, we focus on finding biological mechanisms that may reverse pulmonary vascular remodeling without promoting cardiotoxicity. We found two agents, dexrazoxane and pifithrin-α, that selectively inhibit cardiac muscle apoptosis without affecting the drug-induced apoptosis of the proliferating pulmonary vascular cells. Thus, we propose that the addition of apoptosis-inducing drugs and cardioprotectants to PAH therapies may be effective in treating patients and preventing right heart failure.

  5. Macitentan for the treatment of pulmonary arterial hypertension.

    PubMed

    Kholdani, Cyrus A; Fares, Wassim H; Trow, Terence K

    2014-01-01

    Macitentan is the most recently approved dual endothelin-receptor antagonist (ERA) for the treatment of symptomatic pulmonary arterial hypertension. Compared to other available ERAs, it demonstrates superior receptor-binding properties, with consequently improved tissue penetration, and a longer duration of action allowing for once-daily dosing. It has a favorable adverse-effect profile, with notably no demonstrable increase in the risk of hepatotoxicity or peripheral edema, but like other ERAs, it is potentially limited by significant anemia. Phase I data have demonstrated a favorable drug-drug interaction profile and no need for dose adjustment with hepatic and renal impairment. In the pivotal SERAPHIN study, treatment of symptomatic pulmonary arterial hypertension patients with macitentan led to statistically significant improvements in functional class, exercise tolerance, and hemodynamic parameters, in addition to a reduction in morbidity in an event-driven long-term trial.

  6. Macitentan for the treatment of pulmonary arterial hypertension

    PubMed Central

    Kholdani, Cyrus A; Fares, Wassim H; Trow, Terence K

    2014-01-01

    Macitentan is the most recently approved dual endothelin-receptor antagonist (ERA) for the treatment of symptomatic pulmonary arterial hypertension. Compared to other available ERAs, it demonstrates superior receptor-binding properties, with consequently improved tissue penetration, and a longer duration of action allowing for once-daily dosing. It has a favorable adverse-effect profile, with notably no demonstrable increase in the risk of hepatotoxicity or peripheral edema, but like other ERAs, it is potentially limited by significant anemia. Phase I data have demonstrated a favorable drug–drug interaction profile and no need for dose adjustment with hepatic and renal impairment. In the pivotal SERAPHIN study, treatment of symptomatic pulmonary arterial hypertension patients with macitentan led to statistically significant improvements in functional class, exercise tolerance, and hemodynamic parameters, in addition to a reduction in morbidity in an event-driven long-term trial. PMID:25473292

  7. Biomarkers and prognostic indicators in pulmonary arterial hypertension.

    PubMed

    Jardim, Carlos; Souza, Rogerio

    2015-06-01

    Our understanding of the pathophysiology of pulmonary arterial hypertension (PAH) has increased substantially in the past decades. More accurate diagnosis and increased options for treatment have given researchers the opportunity to better explore the response to medical therapy and prognosis. As a result, the use of biomarkers and prognostic indicators for this devastating disease has been widely investigated. Biomarkers and prognostic indicators have also been more frequently incorporated into the design of new clinical trials. This approach has helped the pulmonary hypertension (PH) community step forward in the search for effective treatments for PAH. However, no single biomarker has shown significant superiority in predicting prognosis or patient response and an integrative approach is necessary to understand which combination of markers should be used in each of the clinical scenarios that characterize the management of PAH.

  8. Altered Immune Phenotype in Peripheral Blood Cells of Patients with Scleroderma-Associated Pulmonary Hypertension

    PubMed Central

    Risbano, Michael G; Meadows, Christina A; Coldren, Christopher D; Jenkins, Tiffany J.; Edwards, Michael G; Collier, David; Huber, Wendy; Mack, Douglas G; Fontenot, Andrew P; Geraci, Mark W; Bull, Todd M

    2010-01-01

    Pulmonary arterial hypertension is a common and fatal complication of scleroderma that may involve inflammatory and autoimmune mechanisms. Alterations in the gene expression of peripheral blood mononuclear cells have been previously described in patients with pulmonary arterial hypertension. Our goal is to identify differentially expressed genes in peripheral blood mononuclear cells in scleroderma patients with and without pulmonary hypertension as biomarkers of disease. Gene expression analysis was performed on a Microarray Cohort of scleroderma patients with (n=10) and without (n=10) pulmonary hypertension. Differentially expressed genes were confirmed in the Microarray Cohort and validated in a Validation Cohort of scleroderma patients with (n=15) and without (n=19) pulmonary hypertension by RT-qPCR. We identified inflammatory and immune-related genes including interleukin-7 receptor (IL-7R) and chemokine receptor 7 as differentially expressed in patients with scleroderma-associated pulmonary hypertension. Flow cytometry confirmed decreased expression of IL-7R on circulating CD4+ T-cells from scleroderma patients with pulmonary hypertension. Differences exist in the expression of inflammatory and immune-related genes in peripheral blood cells from patients with scleroderma-related pulmonary hypertension compared to those with normal pulmonary artery pressures. These findings may have implications as biomarkers to screen at-risk populations for early diagnosis and provide insight into mechanisms of scleroderma-related pulmonary hypertension. PMID:20973920

  9. Diffuse Pulmonary Arteriovenous Fistulas With Pulmonary Arterial Hypertension: Case Report and Review.

    PubMed

    Jiang, Rong; Gong, Su-Gang; Pudasaini, Bigyan; Zhao, Qin-Hua; Wang, Lan; He, Jing; Liu, Jin-Ming

    2016-04-01

    Pulmonary arteriovenous fistulas (PAVFs) are rare. Diffuse type PAVFs with pulmonary arterial hypertension (PAH) are even rarer and can elude anatomy imaging like a plain chest film or a computed tomography. The rapid blood flow that ensues due to lack of a capillary bed leads to various degrees of ischemia depending on the number and size of the PAVF. This is a case report of diffuse PAVF in a patient with PAH.This case report describes a patient with recurrent hemoptysis and chest pain. Systemic examination was unremarkable except for P2 attenuation on auscultation. Echocardiograghy showed confirmed pulmonary hypertension with mild dilation of right atrium and ventricle and a tricuspid regurgitation pressure gradient of 40 mm Hg and ruled out congenital heart diseases. Right heart catheterization revealed precapillary PAH with mean pulmonary arterial pressure of 88 mm Hg. Pulmonary angiography showed enlarged pulmonary arterial trunk and diffuse spiral tortuous pulmonary arterial branches indicting diffuse PAVFs. The patient was diagnosed as PAH and began treatment of 25 mg tid of sildenafil.The case highlights a rare and unique presentation of PAH.

  10. Diffuse Pulmonary Arteriovenous Fistulas With Pulmonary Arterial Hypertension: Case Report and Review.

    PubMed

    Jiang, Rong; Gong, Su-Gang; Pudasaini, Bigyan; Zhao, Qin-Hua; Wang, Lan; He, Jing; Liu, Jin-Ming

    2016-04-01

    Pulmonary arteriovenous fistulas (PAVFs) are rare. Diffuse type PAVFs with pulmonary arterial hypertension (PAH) are even rarer and can elude anatomy imaging like a plain chest film or a computed tomography. The rapid blood flow that ensues due to lack of a capillary bed leads to various degrees of ischemia depending on the number and size of the PAVF. This is a case report of diffuse PAVF in a patient with PAH.This case report describes a patient with recurrent hemoptysis and chest pain. Systemic examination was unremarkable except for P2 attenuation on auscultation. Echocardiograghy showed confirmed pulmonary hypertension with mild dilation of right atrium and ventricle and a tricuspid regurgitation pressure gradient of 40 mm Hg and ruled out congenital heart diseases. Right heart catheterization revealed precapillary PAH with mean pulmonary arterial pressure of 88 mm Hg. Pulmonary angiography showed enlarged pulmonary arterial trunk and diffuse spiral tortuous pulmonary arterial branches indicting diffuse PAVFs. The patient was diagnosed as PAH and began treatment of 25 mg tid of sildenafil.The case highlights a rare and unique presentation of PAH. PMID:27057843

  11. Pulmonary arterial hypertension due to pulmonary vascular amyloid deposition in a patient with multiple myeloma

    PubMed Central

    Hashimoto, Hirotsugu; Kurata, Atsushi; Mizuno, Hideaki; Nashiro, Tamaki; Hangaishi, Akira; Kuroda, Masahiko; Usuki, Kensuke; Horiuchi, Hajime

    2015-01-01

    Systemic amyloidosis is characterized by amyloid deposition throughout the body and subsequent dysfunction of various organs. Although pulmonary amyloidosis does occur, pulmonary hypertension (PH) caused by amyloidosis is extremely rare. In most of these cases, amyloid deposition occurred diffusely in alveolar septa, indicating that PH was due to lung disease and/or hypoxia. On the other hand, the mechanism of PH due to amyloid deposition in the pulmonary arteries has never been demonstrated. Here, we report the first case of PH due to amyloid deposition in pulmonary elastic arteries and muscular artery, which was complicated by multiple myeloma (MM). In the autopsy specimen of the patient, amyloid deposition was found mainly in the pulmonary arterial media, along with intimal thickening with luminal narrowing. PH thus appeared to be caused by marked decrease of pulmonary elasticity due to the amyloid deposition in the arterial media that resulted in stasis of the blood flow and subsequent luminal narrowing. Our present data demonstrates a new concept of PH caused by amyloidosis, namely, pulmonary arterial hypertension due to amyloidosis. PMID:26823900

  12. Quality of life in patients with chronic thromboembolic pulmonary hypertension.

    PubMed

    Mathai, Stephen C; Ghofrani, Hossein-Ardeschir; Mayer, Eckhard; Pepke-Zaba, Joanna; Nikkho, Sylvia; Simonneau, Gérald

    2016-08-01

    Patients with chronic thromboembolic pulmonary hypertension (CTEPH) experience debilitating symptoms that have a negative impact on their quality of life (QoL) in terms of physical capability, psychological wellbeing and social relationships. The use of QoL measurement tools is important in the assessment of treatment efficacy and in guiding treatment decisions. However, despite the importance of QoL, particularly to the patient, it remains under-reported in clinical studies of CTEPH therapy. CTEPH is unique in pulmonary hypertension in that it is potentially curable by surgery; however, a proportion of patients either have residual PH following surgery or are not operable. Although some patients with CTEPH have been treated off-label with pulmonary arterial hypertension-specific therapies, there have been few randomised controlled trials of these therapies in patients with CTEPH. Moreover, in these trials QoL outcomes are variably assessed, and there is little consistency in the tools used. Here we review the assessment of QoL in patients with CTEPH and the tools that have been used. We also discuss the effect of surgical intervention and medical therapies on QoL. We conclude that further studies of QoL in patients with CTEPH are needed to further validate the optimal QoL tools.

  13. Quality of life in patients with chronic thromboembolic pulmonary hypertension

    PubMed Central

    Ghofrani, Hossein-Ardeschir; Mayer, Eckhard; Pepke-Zaba, Joanna; Nikkho, Sylvia; Simonneau, Gérald

    2016-01-01

    Patients with chronic thromboembolic pulmonary hypertension (CTEPH) experience debilitating symptoms that have a negative impact on their quality of life (QoL) in terms of physical capability, psychological wellbeing and social relationships. The use of QoL measurement tools is important in the assessment of treatment efficacy and in guiding treatment decisions. However, despite the importance of QoL, particularly to the patient, it remains under-reported in clinical studies of CTEPH therapy. CTEPH is unique in pulmonary hypertension in that it is potentially curable by surgery; however, a proportion of patients either have residual PH following surgery or are not operable. Although some patients with CTEPH have been treated off-label with pulmonary arterial hypertension-specific therapies, there have been few randomised controlled trials of these therapies in patients with CTEPH. Moreover, in these trials QoL outcomes are variably assessed, and there is little consistency in the tools used. Here we review the assessment of QoL in patients with CTEPH and the tools that have been used. We also discuss the effect of surgical intervention and medical therapies on QoL. We conclude that further studies of QoL in patients with CTEPH are needed to further validate the optimal QoL tools. PMID:27076580

  14. Leflunomide-induced pulmonary hypertension in a young woman with rheumatoid arthritis: a case report.

    PubMed

    Alvarez, Paulino A; Saad, Ariel K; Flagel, Santiago; Mazzocchi, Octavio; Blanco, Manuel Vazquez

    2012-06-01

    Leflunomide, a disease-modifying antirheumatic drug, has been shown to be effective in the management of rheumatoid arthritis (RA). Among other side effects, systemic hypertension has been described, and also a case of possible pulmonary hypertension (PH) has been reported. Symptomatic PH in RA is rare. We present a 28-year-old woman with a history of RA who consulted our hospital because of severe symptomatic pulmonary hypertension. Two years before admission, she was started on leflunomide. Due to previous evidence of the association of leflunomide with pulmonary hypertension, the drug was stopped. The patient became asymptomatic with normal pulmonary arterial pressure within a year. Given the poor prognosis of idiopathic pulmonary arterial hypertension, the recognition of potentially reversible causes is crucial. Until further evidence is available in a patient who develops pulmonary arterial hypertension, stopping leflunomide should be considered.

  15. Chronic Thromboembolic Pulmonary Hypertension. Epidemiology and Risk Factors.

    PubMed

    Delcroix, Marion; Kerr, Kim; Fedullo, Peter

    2016-07-01

    Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare complication of pulmonary embolism. As for most rare diseases, epidemiologic data are scarce, but recent registries suggest an incidence of at least 5 per million inhabitants per year. A history of massive or recurrent acute pulmonary embolism is observed in most patients with CTEPH, but the proportion of patients who develop CTEPH after acute pulmonary embolism is a matter of debate, further complicated by the possible misdiagnosis of CTEPH as acute pulmonary embolism. A complete resolution of thrombi is usually not achieved after acute pulmonary embolism, and the clinical relevance of a "postpulmonary embolism syndrome" with persistent perfusion defects and exercise intolerance is discussed. Risk factors most consistently associated with CTEPH are circulating anti-phospholipid antibodies or lupus anticoagulant, increased factor VIII, non-O blood groups, and chronic inflammatory diseases. There is no female predominance, and it is a disease of older age. Survival in the absence of specific surgical or medical treatment is poor and depends on the hemodynamic severity. PMID:27571001

  16. Chemotherapy-induced pulmonary hypertension: role of alkylating agents.

    PubMed

    Ranchoux, Benoît; Günther, Sven; Quarck, Rozenn; Chaumais, Marie-Camille; Dorfmüller, Peter; Antigny, Fabrice; Dumas, Sébastien J; Raymond, Nicolas; Lau, Edmund; Savale, Laurent; Jaïs, Xavier; Sitbon, Olivier; Simonneau, Gérald; Stenmark, Kurt; Cohen-Kaminsky, Sylvia; Humbert, Marc; Montani, David; Perros, Frédéric

    2015-02-01

    Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) characterized by progressive obstruction of small pulmonary veins and a dismal prognosis. Limited case series have reported a possible association between different chemotherapeutic agents and PVOD. We evaluated the relationship between chemotherapeutic agents and PVOD. Cases of chemotherapy-induced PVOD from the French PH network and literature were reviewed. Consequences of chemotherapy exposure on the pulmonary vasculature and hemodynamics were investigated in three different animal models (mouse, rat, and rabbit). Thirty-seven cases of chemotherapy-associated PVOD were identified in the French PH network and systematic literature analysis. Exposure to alkylating agents was observed in 83.8% of cases, mostly represented by cyclophosphamide (43.2%). In three different animal models, cyclophosphamide was able to induce PH on the basis of hemodynamic, morphological, and biological parameters. In these models, histopathological assessment confirmed significant pulmonary venous involvement highly suggestive of PVOD. Together, clinical data and animal models demonstrated a plausible cause-effect relationship between alkylating agents and PVOD. Clinicians should be aware of this uncommon, but severe, pulmonary vascular complication of alkylating agents. PMID:25497573

  17. Mitochondrial Haplogroups and Risk of Pulmonary Arterial Hypertension.

    PubMed

    Farha, Samar; Hu, Bo; Comhair, Suzy; Zein, Joe; Dweik, Raed; Erzurum, Serpil C; Aldred, Micheala A

    2016-01-01

    Pulmonary arterial hypertension (PAH) is a serious and often fatal disease. It is a panvasculopathy of the pulmonary microcirculation characterized by vasoconstriction and arterial obstruction due to vascular proliferation and remodeling and ultimately right ventricular failure. Mitochondrial dysfunction is a universal finding in pulmonary vascular cells of patients with PAH, and is mechanistically linked to disease origins in animal models of pulmonary hypertension. Mitochondria have their own circular DNA (mtDNA), which can be subgrouped into polymorphic haplogroup variants, some of which have been identified as at-risk or protective from cardiovascular and/or neurodegenerative diseases. Here, we hypothesized that mitochondrial haplogroups may be associated with PAH. To test this, mitochondrial haplogroups were determined in a cohort of PAH patients and controls [N = 204 Caucasians (125 PAH and 79 controls) and N = 46 African Americans (13 PAH and 33 controls)]. Haplogroup L was associated with a lower rate of PAH as compared to macrohaplogroups N and M. When haplogroups were nested based on ancestral inheritance and controlled for age, gender and race, haplogroups M and HV, JT and UK of the N macro-haplogroup had significantly higher rates of PAH compared to the ancestral L (L0/1/2 and L3) (all p ≤ 0.05). Overall, the findings suggest that mitochondrial haplogroups influence risk of PAH and that a vulnerability to PAH may have emerged under the selective enrichment of specific haplogroups that occurred with the migration of populations out of Africa. PMID:27224443

  18. Pulmonary arterial hypertension: a comparison between children and adults.

    PubMed

    Barst, R J; Ertel, S I; Beghetti, M; Ivy, D D

    2011-03-01

    The characteristics of pulmonary arterial hypertension (PAH), including pathology, symptoms, diagnosis and treatment are reviewed in children and adults. The histopathology seen in adults is also observed in children, although children have more medial hypertrophy at presentation. Both populations have vascular and endothelial dysfunction. Several unique disease states are present in children, as lung growth abnormalities contribute to pulmonary hypertension. Although both children and adults present at diagnosis with elevations in pulmonary vascular resistance and pulmonary artery pressure, children have less heart failure. Dyspnoea on exertion is the most frequent symptom in children and adults with PAH, but heart failure with oedema occurs more frequently in adults. However, in idiopathic PAH, syncope is more common in children. Haemodynamic assessment remains the gold standard for diagnosis, but the definition of vasoreactivity in adults may not apply to young children. Targeted PAH therapies approved for adults are associated with clinically meaningful effects in paediatric observational studies; children now survive as long as adults with current treatment guidelines. In conclusion, there are more similarities than differences in the characteristics of PAH in children and adults, resulting in guidelines recommending similar diagnostic and therapeutic algorithms in children (based on expert opinion) and adults (evidence-based).

  19. Current concepts in the pathogenesis of chronic thromboembolic pulmonary hypertension

    PubMed Central

    2016-01-01

    Abstract Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by fibrotic obstruction of the proximal pulmonary arteries, and it is believed to result from incomplete thrombus resolution after acute pulmonary embolism. While treatment for this condition with surgery and medical therapy has improved outcomes, our understanding of the molecular mechanisms underlying CTEPH is incomplete. Numerous risk factors have been associated with the development of CTEPH, including but not limited to acquired thrombophilias and chronic inflammatory states. A minority of patients with CTEPH have an abnormal fibrin structure that may delay thrombus resolution. Recently, examination of resected scar material in patients with CTEPH has suggested that deficient angiogenesis may play a role in thrombus nonresolution, and there is increasing interest in factors that drive intravascular scar formation. An additional challenge in CTEPH research is understanding the etiology and implications of the small-vessel disease present in many patients. Future work will likely be directed at understanding the pathways important to disease pathogenesis through further examinations of resected tissue material, continued work on animal models, and genomic approaches to identify alterations in gene expression or gene variants that may distinguish CTEPH from other forms of pulmonary hypertension. PMID:27252839

  20. Mitochondrial Haplogroups and Risk of Pulmonary Arterial Hypertension

    PubMed Central

    Farha, Samar; Hu, Bo; Comhair, Suzy; Zein, Joe; Dweik, Raed

    2016-01-01

    Pulmonary arterial hypertension (PAH) is a serious and often fatal disease. It is a panvasculopathy of the pulmonary microcirculation characterized by vasoconstriction and arterial obstruction due to vascular proliferation and remodeling and ultimately right ventricular failure. Mitochondrial dysfunction is a universal finding in pulmonary vascular cells of patients with PAH, and is mechanistically linked to disease origins in animal models of pulmonary hypertension. Mitochondria have their own circular DNA (mtDNA), which can be subgrouped into polymorphic haplogroup variants, some of which have been identified as at-risk or protective from cardiovascular and/or neurodegenerative diseases. Here, we hypothesized that mitochondrial haplogroups may be associated with PAH. To test this, mitochondrial haplogroups were determined in a cohort of PAH patients and controls [N = 204 Caucasians (125 PAH and 79 controls) and N = 46 African Americans (13 PAH and 33 controls)]. Haplogroup L was associated with a lower rate of PAH as compared to macrohaplogroups N and M. When haplogroups were nested based on ancestral inheritance and controlled for age, gender and race, haplogroups M and HV, JT and UK of the N macro-haplogroup had significantly higher rates of PAH compared to the ancestral L (L0/1/2 and L3) (all p ≤ 0.05). Overall, the findings suggest that mitochondrial haplogroups influence risk of PAH and that a vulnerability to PAH may have emerged under the selective enrichment of specific haplogroups that occurred with the migration of populations out of Africa. PMID:27224443

  1. Immune and Inflammatory Mechanisms in Pulmonary Arterial Hypertension

    PubMed Central

    El Chami, Hala; Hassoun, Paul M.

    2012-01-01

    Altered immunity and inflammation are increasingly recognized features of pulmonary arterial hypertension (PAH). This is suggested by infiltration of various inflammatory cells (e.g., macrophages, T and B lymphocytes), increased cytokine and growth factor (e.g., VEGF and PDGF) expression in remodeled pulmonary vessels, and the presence of circulating chemokines and cytokines. In certain diseases associated with PAH, increased expression of growth and transcriptional (e.g., Nuclear Factor of Activated T cells or NFAT) factors, and viral protein components (e.g., HIV-1 Nef), appear to contribute directly to recruitment of inflammatory cells in remodeled vessels, and may potentially serve as specific therapeutic targets. This section provides an overview of inflammatory pathways highlighting their potential role in pulmonary vascular remodeling in PAH and the possibility of future targeted therapy. PMID:23009917

  2. Pulmonary vascular wall stiffness: An important contributor to the increased right ventricular afterload with pulmonary hypertension

    PubMed Central

    Wang, Zhijie; Chesler, Naomi C.

    2011-01-01

    Pulmonary hypertension (PH) is associated with structural and mechanical changes in the pulmonary vascular bed that increase right ventricular (RV) afterload. These changes, characterized by narrowing and stiffening, occur in both proximal and distal pulmonary arteries (PAs). An important consequence of arterial narrowing is increased pulmonary vascular resistance (PVR). Arterial stiffening, which can occur in both the proximal and distal pulmonary arteries, is an important index of disease progression and is a significant contributor to increased RV afterload in PH. In particular, arterial narrowing and stiffening increase the RV afterload by increasing steady and oscillatory RV work, respectively. Here we review the current state of knowledge of the causes and consequences of pulmonary arterial stiffening in PH and its impact on RV function. We review direct and indirect techniques for measuring proximal and distal pulmonary arterial stiffness, measures of arterial stiffness including elastic modulus, incremental elastic modulus, stiffness coefficient β and others, the changes in cellular function and the extracellular matrix proteins that contribute to pulmonary arterial stiffening, the consequences of PA stiffening for RV function and the clinical implications of pulmonary vascular stiffening for PH progression. Future investigation of the relationship between PA stiffening and RV dysfunction may facilitate new therapies aimed at improving RV function and thus ultimately reducing mortality in PH. PMID:22034607

  3. Pulmonary Hypertension Among End-Stage Renal Failure Patients Following Hemodialysis Access Thrombectomy

    SciTech Connect

    Harp, Richard J.; Stavropoulos, S. William; Wasserstein, Alan G.; Clark, Timothy W.I.

    2005-01-15

    Purpose: Percutaneous hemodialysis thrombectomy causes subclinical pulmonary emboli without short-term clinical consequence; the long-term effects on the pulmonary arterial vasculature are unknown. We compared the prevalence of pulmonary hypertension between patients who underwent one or more hemodialysis access thrombectomy procedures with controls without prior thrombectomy.Methods: A retrospective case-control study was performed. Cases (n = 88) had undergone one or more hemodialysis graft thrombectomy procedures, with subsequent echocardiography during routine investigation of comorbid cardiovascular disease. Cases were compared with controls without end-stage renal disease (ESRD) (n = 100, group 1), and controls with ESRD but no prior thrombectomy procedures (n = 117, group 2). The presence and velocity of tricuspid regurgitation on echocardiography was used to determine the prevalence and grade of pulmonary hypertension; these were compared between cases and controls using the chi-square test and logistic regression.Results: The prevalence of pulmonary hypertension among cases was 52% (46/88), consisting of mild, moderate and severe in 26% (n = 23), 10% (n = 9) and 16% (n = 14), respectively. Prevalence of pulmonary hypertension among group 1 controls was 26% (26/100), consisting of mild, moderate and severe pulmonary hypertension in 14%, 5% and 7%, respectively. Cases had 2.7 times greater odds of having pulmonary hypertension than group 1 controls (p = 0.002). The prevalence of pulmonary hypertension among group 2 controls was 42% (49/117), consisting of mild, moderate and severe pulmonary arterial hypertension in 25% (n = 49), 10% (n = 12) and 4% (n = 5), respectively. Cases were slightly more likely to have pulmonary hypertension than group 2 controls (OR = 1.5), although this failed to reach statistical significance (p = 0.14).Conclusion: Prior hemodialysis access thrombectomy does not appear to be a risk factor for pulmonary arterial hypertension

  4. Saudi Guidelines on the Diagnosis and Treatment of Pulmonary Hypertension: Pulmonary arterial hypertension associated with connective tissue diseases

    PubMed Central

    Boueiz, Adel; Hassoun, Paul M.

    2014-01-01

    The explosive growth of medical literature on pulmonary hypertension (PH) has led to a steady increase in awareness of this disease within the medical community during the past decade. The recent revision of the classification of PH is presented in in the main guidelines. Group 1 PH or pulmonary arterial hypertension (PAH) is a heterogeneous group and includes PH due to inheritable, drug-induced, and toxin-induced causes and to such underlying systemic causes as connective tissue diseases, human immunodeficiency viral infection, portal hypertension, congenital heart disease, and schistosomiasis. Systemic sclerosis (SSc) is an autoimmune multisystem disorder, which affects over 240 persons per million in the United States.[1] Its manifestations are not confined to the skin but may also involve the lungs, kidneys, peripheral circulation, musculoskeletal system, gastrointestinal tract, and heart. The outcome of PAH associated with SSc is worse when compared to other subtypes of PAH. In this review, we summarize available information about the pulmonary vascular and cardiac manifestations of SSc with special emphasis on their prognostic implications as well as the peculiarity of their detection. PMID:25076994

  5. Anaesthetic Management of Caesarean Section in a Term Pregnancy with Ventricular Septal Defect and Pulmonary Hypertension with Severe Pulmonary Stenosis.

    PubMed

    Bhatia, Rohan; Kaeley, Nidhi; Bhatia, Ruby

    2016-06-01

    Pregnancy with pulmonary hypertension - WHO risk class IV cardiac disease is associated with significant haemodynamic burden due to cardiocirculatory changes which is a significant indirect cause of maternal mortality. We report a very rare case - primigravida term pregnancy with pulmonary hypertension, large ventricular septal defect (2.4 cm(2)), bidirectional shunt mainly left to right with severe pulmonary stenosis with peak gradient of 144mmHg. Caesarean section was done under general anaesthesia with successful maternal and neonatal outcome. PMID:27504386

  6. Irreversible pulmonary hypertension associated with Troglostrongylus brevior infection in a kitten.

    PubMed

    Crisi, Paolo E; Traversa, Donato; Di Cesare, Angela; Luciani, Alessia; Civitella, Carla; Santori, Domenico; Boari, Andrea

    2015-10-01

    A four month-old kitten was referred at the Veterinary Teaching Hospital of Teramo, Italy. Physical examination, echocardiography, thoracic radiography, copromicroscopy and biomolecular assays led to a diagnosis of severe parasitic bronchopneumonia by Troglostrongylus brevior complicated by pulmonary hypertension. A single administration of a spot on solution containing imidacloprid 10%/moxidectin 1% was effective in stopping larval shedding but clinical, radiographic and echocardiographic signs of bronchopneumonia and pulmonary hypertension still persisted after further follow-ups.While cases of pulmonary hypertension are known in infections by Aelurostrongylus abstrusus, this is the first report of irreversible pulmonary hypertension in a kitten with troglostrongylosis. PMID:26412548

  7. CT-Base Pulmonary Artery Measurementin the Detection of Pulmonary Hypertension

    PubMed Central

    Shen, Yongchun; Wan, Chun; Tian, Panwen; Wu, Yanqiu; Li, Xiaoou; Yang, Ting; An, Jing; Wang, Tao; Chen, Lei; Wen, Fuqiang

    2014-01-01

    Abstract To summarize the performance of CT-based main pulmonary artery diameter or pulmonary artery to aorta ratio (PA:A ratio) measurement in detection of pulmonary hypertension by a systematic review and meta-analysis. A comprehensive literature search was performed to identify studies determining diagnostic accuracy of main pulmonary artery diameter or PA:A ratio measurement for pulmonary hypertension. The Quality Assessment of Diagnostic Accuracy Studies tool was used to assess the quality of the included studies. A bivariate random-effects model was used to pool sensitivity, specificity, positive/negative likelihood ratio (PLR/NLR), and diagnostic odds ratio (DOR). Summary receiver operating characteristic (SROC) curves and area under the curve (AUC) were used to summarize overall diagnostic performance. This meta-analysis included 20 publications involving 2134 subjects. Summary estimates for main pulmonary artery diameter measurement in the diagnosis of pulmonary hypertension were as follows: sensitivity, 0.79 (95% CI 0.72–0.84); specificity, 0.83 (95% CI 0.75–0.89); PLR, 4.68 (95% CI 3.13–6.99); NLR, 0.26 (95% CI 0.20–0.33); DOR, 18.13 (95% CI 10.87–30.24); and AUC 0.87. The corresponding summary performance estimates for using the PA:A ratio were as follows: sensitivity, 0.74 (95% CI 0.66–0.80); specificity, 0.81 (95% CI 0.74–0.86); PLR, 3.83 (95% CI, 2.70–5.43); NLR, 0.33 (95% CI 0.24–0.44); DOR, 11.77 (95% CI 6.60–21.00); and AUC 0.84. Both main pulmonary artery diameter and PA:A ratio are helpful for diagnosing pulmonary hypertension. Nevertheless, the results of pulmonary artery measurement should be interpreted in parallel with the results of traditional tests such as echocardiography. PMID:25501096

  8. Pulmonary endarterectomy: the potentially curative treatment for patients with chronic thromboembolic pulmonary hypertension.

    PubMed

    Jenkins, David

    2015-06-01

    Pulmonary endarterectomy (PEA) is the treatment of choice to relieve pulmonary artery obstruction in patients with chronic thromboembolic pulmonary hypertension (CTEPH). It is a complex surgical procedure with a simple principle: removal of obstructive thromboembolic material from the pulmonary arteries in order to reduce pulmonary vascular resistance, relieve pulmonary hypertension (PH) and alleviate right ventricular dysfunction. In the majority of patients there is symptomatic and prognostic benefit. However, not all patients with CTEPH are suitable for treatment with PEA. Operability assessment is not always easy, being largely subjective and based on experience. It is therefore important that all patients are referred to an experienced CTEPH centre for careful evaluation of suitability for surgery. The most common reason for inoperability is distal vasculopathy accounting for a high proportion of the vascular resistance. Surgery requires cardiopulmonary bypass and periods of deep hypothermic circulatory arrest. Complications include reperfusion lung injury and persistent PH. However, with careful patient selection, surgical technique and post-operative management, PEA is a highly effective treatment with mortality rates <5% at experienced centres. Patients who are unsuitable for surgery may be candidates for medical therapy.

  9. Percutaneous transluminal pulmonary angioplasty for the treatment of chronic thromboembolic pulmonary hypertension: Challenges and future directions.

    PubMed

    Dimopoulos, Konstantinos; Kempny, Aleksander; Alonso-Gonzalez, Rafael; Wort, Stephen J

    2015-01-01

    Chronic thromboembolic pulmonary hypertension (CTEPH) is a common type of pulmonary hypertension, resulting from fibrotic transformation of pulmonary artery clots causing chronic obstruction of major pulmonary arteries and associated vascular remodeling in more distal vessels. The mainstay of CTEPH treatment is pulmonary endarterectomy (PEA), which has the potential to be curative but is possible in less than two thirds of cases. In inoperable patients and those with residual or recurrent CTEPH, medical therapy has been shown to be beneficial, albeit not curative. Balloon pulmonary angioplasty (BPA) is a percutaneous technique for the relief of chronic thromboembolic lesions, first reported over two decades ago. More recent case series have demonstrated that, as the technique is refined, results are improving. The potential indications for BPA are now expanding beyond inoperable CTEPH patients, with Shimura et al. demonstrating the aggressive nature of residual or recurrent CTEPH, treated successfully by BPA years after PEA. Major challenges lie ahead of BPA before it can take its place alongside PEA and medication in the treatment of CTEPH.

  10. Determinants of an elevated pulmonary arterial pressure in patients with pulmonary arterial hypertension.

    PubMed

    Sakao, Seiichiro; Voelkel, Norbert F; Tanabe, Nobuhiro; Tatsumi, Koichiro

    2015-01-01

    Given the difficulty of diagnosing early-stage pulmonary arterial hypertension (PAH) due to the lack of signs and symptoms, and the risk of an open lung biopsy, the precise pathological features of presymptomatic stage lung tissue remain unknown. It has been suggested that the maximum elevation of the mean pulmonary arterial pressure (P pa) is achieved during the early symptomatic stage, indicating that the elevation of the mean P pa is primarily driven by the pulmonary vascular tone and/or some degree of pulmonary vascular remodeling completed during this stage. Recently, the examination of a rat model of severe PAH suggested that the severe PAH may be primarily determined by the presence of intimal lesions and/or the vascular tone in the early stage. Human data seem to indicate that intimal lesions are essential for the severely increased pulmonary arterial blood pressure in the late stage of the disease.However, many questions remain. For instance, how does the pulmonary hemodynamics change during the course of the disease, and what drives the development of severe PAH? Although it is generally acknowledged that both pulmonary vascular remodeling and the vascular tone are important determinants of an elevated pulmonary arterial pressure, which is the root cause of the time-dependent progression of the disease? Here we review the recent histopathological concepts of PAH with respect to the progression of the lung vascular disease.

  11. Management of pulmonary hypertension in infants with congenital diaphragmatic hernia.

    PubMed

    Gien, J; Kinsella, J P

    2016-06-01

    In infants with congenital diaphragmatic hernia (CDH), a posterolateral diaphragmatic defect results in herniation of abdominal contents into the chest and compression of the intrathoracic structures. In the most severe cases, hypoplasia of the ipsilateral and contralateral lungs, severe pulmonary hypertension (PH) and left ventricular (LV) hypoplasia/dysfunction all contribute to increased mortality. The management of PH in CDH is complicated by structural and functional changes in the heart, pulmonary vasculature, airways and lung parenchyma; consequently, determining optimal management strategies is challenging. Treatment of PH in patients with CDH changes as the underlying pathophysiology evolves in the days and weeks after birth. During the early transition, the use of pulmonary vasodilators is limited by LV structural and functional abnormalities, and pulmonary vasodilators such as inhaled nitric oxide (iNO) may have a limited role (for example, stabilization for extracorporeal membrane oxygenation (ECMO), treatment of marked preductal desaturation and treatment of PH as LV performance improves). In contrast, subacute treatment of PH in CDH with iNO has an important role in recurrent or persistent PH and potentially improves survival. Chronic PH and vascular abnormalities may persist into childhood in patients with CDH, contributing to late mortality. It is unclear how pulmonary vasodilator therapies, such as iNO, sildenafil and bosentan, will modulate late outcomes in CDH with late/chronic PH. PMID:27225962

  12. Pulmonary Hypertension in Patients with Chronic Fibrosing Idiopathic Interstitial Pneumonias

    PubMed Central

    Hoeper, Marius M.; Behr, Juergen; Held, Matthias; Grunig, Ekkehard; Vizza, C. Dario; Vonk-Noordegraaf, Anton; Lange, Tobias J.; Claussen, Martin; Grohé, Christian; Klose, Hans; Olsson, Karen M.; Zelniker, Thomas; Neurohr, Claus; Distler, Oliver; Wirtz, Hubert; Opitz, Christian; Huscher, Doerte; Pittrow, David; Gibbs, J. Simon R.

    2015-01-01

    Background Pulmonary hypertension (PH) is a common finding in patients with chronic fibrosing idiopathic interstitial pneumonias (IIP). Little is known about the response to pulmonary vasodilator therapy in this patient population. COMPERA is an international registry that prospectively captures data from patients with various forms of PH receiving pulmonary vasodilator therapies. Methods We retrieved data from COMPERA to compare patient characteristics, treatment patterns, response to therapy and survival in newly diagnosed patients with idiopathic pulmonary arterial hypertension (IPAH) and PH associated with IIP (PH-IIP). Results Compared to patients with IPAH (n = 798), patients with PH-IIP (n = 151) were older and predominantly males. Patients with PH-IIP were treated predominantly with phosphodiesterase-5 inhibitors (88% at entry, 87% after 1 year). From baseline to the first follow-up visit, the median improvement in 6MWD was 30 m in patients with IPAH and 24.5 m in patients with PH-IIP (p = 0.457 for the difference between both groups). Improvements in NYHA functional class were observed in 22.4% and 29.5% of these patients, respectively (p = 0.179 for the difference between both groups). Survival rates were significantly worse in PH-IIP than in IPAH (3-year survival 34.0 versus 68.6%; p<0.001). Total lung capacity, NYHA class IV, and mixed-venous oxygen saturation were independent predictors of survival in patients with PH-IIP. Conclusions Patients with PH-IIP have a dismal prognosis. Our results suggest that pulmonary vasodilator therapy may be associated with short-term functional improvement in some of these patients but it is unclear whether this treatment affects survival. Trial Registration clinicaltrials.gov NCT01347216 PMID:26630396

  13. Use of inhaled iloprost in children with pulmonary hypertension.

    PubMed

    Moreno-Galdó, Antonio; Torrent-Vernetta, Alba; de Mir Messa, Inés; Rovira Amigo, Sandra; Gran Piña, Ferran; Gartner, Silvia; Albert Brotons, Dimpna

    2015-04-01

    Pulmonary hypertension (PH) in children is a serious disorder, for which the major goal of treatment is to prevent progressive vascular remodeling, and improve clinical status and survival. Iloprost is approved for the treatment of PH in adults; however, few studies have evaluated its effects in children. The objective of this study is to analyze the long-term effects of inhaled iloprost treatment in children with PH. A retrospective study was conducted in patients treated with iloprost between 2000 and 2012. Patients with left-right cardiac shunt and persistent PH of the newborn were excluded. The cohort comprised 22 patients (15 females) with a median age of 2.6 years. Twelve patients had pulmonary arterial hypertension including idiopathic (n = 6), hereditary (n = 2) and associated (congenital heart disease [n = 3], and schistosomiasis [n = 1]). One patient had pulmonary veno-occlusive disease, six patients had PH secondary to lung disease and three had multifactorial PH. Median mean pulmonary arterial pressure was 55 mmHg and median pulmonary vascular resistance was 15.5 Wood units. Good tolerability was observed, with the exception of one case of recurring abdominal pain. PH resolved in two patients, with functional capacity improvement in 10 patients and stabilization in three patients. The clinical condition of six patients deteriorated; two died, and two received lung transplants. In conclusion, the results of this uncontrolled study showed that iloprost was effective and well tolerated in children. However, further research is needed to support this study, as PH is a serious condition that can require organ transplantation or result in death. PMID:24729548

  14. Pulmonary hypertension in lymphangioleiomyomatosis: characteristics in 20 patients.

    PubMed

    Cottin, Vincent; Harari, Sergio; Humbert, Marc; Mal, Hervé; Dorfmüller, Peter; Jaïs, Xavier; Reynaud-Gaubert, Martine; Prevot, Grégoire; Lazor, Romain; Taillé, Camille; Lacronique, Jacques; Zeghmar, Sabrina; Simonneau, Gérald; Cordier, Jean-François

    2012-09-01

    This retrospective, multicentre study evaluated patients with lymphangioleiomyomatosis (LAM) and pre-capillary pulmonary hypertension (PH) by right heart catheterisation. It was conducted in 20 females with a mean ± SD age of 49 ± 12 yrs and a mean ± SD time interval between LAM and PH diagnoses of 9.2 ± 9.8 yrs. All, except for one patient, were receiving supplemental oxygen. 6-min walking distance was mean ± SD 340 ± 84 m. Haemodynamic characteristics were: mean pulmonary artery pressure (PAP) 32 ± 6 mmHg, cardiac index 3.5 ± 1.1 L · min(-1) · m(-2) and pulmonary vascular resistance (PVR) 376 ± 184 dyn · s · cm(-5). Mean PAP was >35 mmHg in only 20% of cases. The forced expiratory volume in 1 s was 42 ± 25%, carbon monoxide transfer factor was 29 ± 13%, and arterial oxygen tension (P(a,O(2))) was 7.4 ± 1.3 kPa in room air. Mean PAP and PVR did not correlate with P(a,O(2)). In six patients who received oral pulmonary arterial hypertension (PAH) therapy, the PAP decreased from 33 ± 9 mmHg to 24 ± 10 mmHg and the PVR decreased from 481 ± 188 dyn · s · cm(-5) to 280 ± 79 dyn · s · cm(-5). The overall probability of survival was 94% at 2 yrs. Pre-capillary PH of mild haemodynamic severity may occur in patients with LAM, even with mild pulmonary function impairment. PAH therapy might improve the haemodynamics in PH associated with LAM.

  15. Simultaneous pulmonary and systemic blood pressure and ECG Interval measurement in conscious, freely moving rats.

    PubMed

    Rey, Markus; Weber, Edgar W; Hess, Patrick D

    2012-03-01

    Here we evaluated the ability of a new, dual blood-pressure telemetry transmitter to simultaneously measure pulmonary and systemic blood pressure and the electrocardiogram in rats. The transmitter was implanted in normotensive and monocrotaline-induced pulmonary hypertensive Wistar rats, with sensing catheters placed in the pulmonary artery (channel 1) and descending aorta (channel 2). Biopotential electrodes were positioned to record an apex-based lead II electrocardiogram. Pulmonary and systemic arterial blood pressure and electrocardiographic waveforms were recorded between 2 and 12 wk after implantation of the transmitter. During this period, pulmonary arterial pressure progressively increased in monocrotaline-treated compared with saline-treated rats. The pharmacologic response of rats to reference compounds was measured by using the transmitter to validate the technique and to evaluate the ability of the device to transmit changes in blood pressure and the electrocardiogram. Validation against 2 Millar high-fidelity blood-pressure catheters confirmed the accuracy of the blood pressure data recorded with the transmitter. In addition, local tolerance of the associated catheters was confirmed by histologic examination. PMID:22776124

  16. Perioperative pharmacological management of pulmonary hypertensive crisis during congenital heart surgery.

    PubMed

    Brunner, Nathan; de Jesus Perez, Vinicio A; Richter, Alice; Haddad, François; Denault, André; Rojas, Vanessa; Yuan, Ke; Orcholski, Mark; Liao, Xiaobo

    2014-03-01

    Pulmonary hypertensive crisis is an important cause of morbidity and mortality in patients with pulmonary arterial hypertension secondary to congenital heart disease (PAH-CHD) who require cardiac surgery. At present, prevention and management of perioperative pulmonary hypertensive crisis is aimed at optimizing cardiopulmonary interactions by targeting prostacyclin, endothelin, and nitric oxide signaling pathways within the pulmonary circulation with various pharmacological agents. This review is aimed at familiarizing the practitioner with the current pharmacological treatment for dealing with perioperative pulmonary hypertensive crisis in PAH-CHD patients. Given the life-threatening complications associated with pulmonary hypertensive crisis, proper perioperative planning can help anticipate cardiopulmonary complications and optimize surgical outcomes in this patient population.

  17. Computational Simulation of the Pulmonary Arteries and its Role in the Study of Pediatric Pulmonary Hypertension

    PubMed Central

    Hunter, Kendall S.; Feinstein, Jeffrey A.; Ivy, D. Dunbar; Shandas, Robin

    2010-01-01

    The hemodynamic state of the pulmonary arteries is challenging to routinely measure in children due to the vascular circuit's position in the lungs. The resulting relative scarcity of quantitative clinical diagnostic and prognostic information impairs management of diseases such as pulmonary hypertension, or high blood pressure of the pulmonary circuit, and invites new techniques of measurement. Here we examine recent applications of macro-scale computational mechanics methods for fluids and solids – traditionally used by engineers in the design and virtual testing of complex metal and composite structures – applied to study the pulmonary vasculature, both in healthy and diseased states. In four subject areas, we briefly outline advances in computational methodology and provide examples of clinical relevance. PMID:21499523

  18. Possible role of anti-SSA/Ro antibodies in the pathogenesis of pulmonary hypertension

    PubMed Central

    Guerreso, Kelsey; Conner, Edward Alexander

    2016-01-01

    Introduction There are many different causes of pulmonary hypertension and the pathogenesis of the disease is still being elucidated. Although they are not the most common, autoimmunity and inflammation have been identified as possible causes. No one autoantibody has been identified as the definite cause of pulmonary hypertension. We present a rare association of anti-SSA/Ro antibodies and isolated pulmonary hypertension. Case presentation A 53 year old African American female presented with abdominal pain, nausea, weight loss, dyspnea and fatigue. Upon further exam she was found to have high titers of antinuclear antibodies and anti-SSA/Ro antibodies. This antibody profile would typically be suggestive of Sjögren's Syndrome, which is characterized by dry eyes and poor salivary gland function. However, since this patient did not have any symptoms consistent with the disease a diagnosis of Sjögren's Syndrome could not be made. A combination of laboratory, imaging and diagnostic studies were done that revealed a final diagnosis of pulmonary hypertension. Conclusion It is known that pulmonary hypertension has association with autoimmune diseases, however no clear markers yet exist. Anti-SSA/Ro antibodies have been rarely described in cases of pulmonary disease, and less so in pulmonary hypertension. This case describes a unique association between isolated pulmonary hypertension and anti-SSA/Ro antibody, thereby illustrating the need to investigate this autoantibody and others in the pathogenesis of autoimmune pulmonary hypertension. PMID:27222785

  19. Pathophysiological basis for anticoagulant and antithrombotic therapy in pulmonary hypertension.

    PubMed

    Lopes, Antonio Augusto

    2006-01-01

    In pulmonary hypertension (PH), thrombosis and thromboembolism may occur as primary events associated with inherited or acquired thrombophilia. Alternatively, in situ thrombosis may develop as a complication of pre-existing vasculopathy as in the case of idiopathic PH and related disorders (so called pulmonary arterial hypertension). In these disorders, a number of abnormalities has been described involving endothelial cells, platelets and other circulating cellular and soluble elements. These abnormalities are suggestive of a shift of pulmonary vascular microenvironment toward a procoagulant, prothrombotic and antifibrinolytic pattern. The abnormalities described so far include circulating antiphospholipid antibodies, increased plasma levels of platelet aggregating agents (serotonin, thromboxane), adhesion molecules (P-selectin, von Willebrand factor), antifibrinolytic enzymes (plasminogen activator inhibitor 1) and cytokines. Also, decreased endothelial production of natural anticoagulants (thrombomodulin) and platelet antiaggregating substances (nitric oxide, prostacyclin) have been demonstrated. The present review is focused on the procoagulant, prothrombotic and antifibrinolytic mechanisms so far identified in PH, in both clinical setting and animal models. Understanding of these mechanisms is crucial for a proper selection of anticoagulant and antithrombotic therapies and provides the rationale for development of novel therapeutic options.

  20. Right heart catheterisation: best practice and pitfalls in pulmonary hypertension.

    PubMed

    Rosenkranz, Stephan; Preston, Ioana R

    2015-12-01

    Right heart catheterisation (RHC) plays a central role in identifying pulmonary hypertension (PH) disorders, and is required to definitively diagnose pulmonary arterial hypertension (PAH). Despite widespread acceptance, there is a lack of guidance regarding the best practice for performing RHC in clinical practice. In order to ensure the correct evaluation of haemodynamic parameters directly measured or calculated from RHC, attention should be drawn to standardising procedures such as the position of the pressure transducer and catheter balloon inflation volume. Measurement of pulmonary arterial wedge pressure, in particular, is vulnerable to over- or under-wedging, which can give rise to false readings. In turn, errors in RHC measurement and data interpretation can complicate the differentiation of PAH from other PH disorders and lead to misdiagnosis. In addition to diagnosis, the role of RHC in conjunction with noninvasive tests is widening rapidly to encompass monitoring of treatment response and establishing prognosis of patients diagnosed with PAH. However, further standardisation of RHC is warranted to ensure optimal use in routine clinical practice. PMID:26621978

  1. MURC deficiency in smooth muscle attenuates pulmonary hypertension

    PubMed Central

    Nakanishi, Naohiko; Ogata, Takehiro; Naito, Daisuke; Miyagawa, Kotaro; Taniguchi, Takuya; Hamaoka, Tetsuro; Maruyama, Naoki; Kasahara, Takeru; Nishi, Masahiro; Matoba, Satoaki; Ueyama, Tomomi

    2016-01-01

    Emerging evidence suggests that caveolin-1 (Cav1) is associated with pulmonary arterial hypertension. MURC (also called Cavin-4) is a member of the cavin family, which regulates caveolar formation and functions together with caveolins. Here, we show that hypoxia increased Murc mRNA expression in the mouse lung, and that Murc-null mice exhibited attenuation of hypoxia-induced pulmonary hypertension (PH) accompanied by reduced ROCK activity in the lung. Conditional knockout mice lacking Murc in smooth muscle also resist hypoxia-induced PH. MURC regulates the proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) through Rho/ROCK signalling. Cav1 suppresses RhoA activity in PASMCs, which is reversed by MURC. MURC binds to Cav1 and inhibits the association of Cav1 with the active form of Gα13, resulting in the facilitated association of the active form of Gα13 with p115RhoGEF. These results reveal that MURC has a function in the development of PH through modulating Rho/ROCK signalling. PMID:27546070

  2. Pulmonary Veno-Occlusive Disease: A Newly Recognized Cause of Severe Pulmonary Hypertension in Dogs.

    PubMed

    Williams, K; Andrie, K; Cartoceti, A; French, S; Goldsmith, D; Jennings, S; Priestnall, S L; Wilson, D; Jutkowitz, A

    2016-07-01

    Pulmonary hypertension is a well-known though poorly characterized disease in veterinary medicine. In humans, pulmonary veno-occlusive disease (PVOD) is a rare cause of severe pulmonary hypertension with a mean survival time of 2 years without lung transplantation. Eleven adult dogs (5 males, 6 females; median age 10.5 years, representing various breeds) were examined following the development of severe respiratory signs. Lungs of affected animals were evaluated morphologically and with immunohistochemistry for alpha smooth muscle actin, desmin, CD31, CD3, CD20, and CD204. All dogs had pulmonary lesions consistent with PVOD, consisting of occlusive remodeling of small- to medium-sized pulmonary veins, foci of pulmonary capillary hemangiomatosis (PCH), and accumulation of hemosiderophages; 6 of 11 dogs had substantial pulmonary arterial medial and intimal thickening. Ultrastructural examination and immunohistochemistry showed that smooth muscle cells contributed to the venous occlusion. Increased expression of CD31 was evident in regions of PCH indicating increased numbers of endothelial cells in these foci. Spindle cells strongly expressing alpha smooth muscle actin and desmin co-localized with foci of PCH; similar cells were present but less intensely labeled elsewhere in non-PCH alveoli. B cells and macrophages, detected by immunohistochemistry, were not co-localized with the venous lesions of canine PVOD; small numbers of CD3-positive T cells were occasionally in and around the wall of remodeled veins. These findings indicate a condition in dogs with clinically severe respiratory disease and pathologic features resembling human PVOD, including foci of pulmonary venous remodeling and PCH.

  3. Platelets in Pulmonary Hypertension: a Causative Role or a Simple Association?

    PubMed Central

    Zanjani, Keyhan Sayadpour

    2012-01-01

    Pathophysiology of pulmonary arterial hypertension is based on three basic mechanisms: thrombotic pulmonary vascular lesions, vasoconstriction and vascular remodeling. Platelets are related to all of these mechanisms by their aggregation, production, storage and release of several mediators. The role of platelets is more prominent in some types of pulmonary arterial hypertension, including those which are secondary to inflammatory and infectious diseases, hemoglobinopathies, essential thrombocythemia, drugs, thromboembolism, and cardiac surgery. Most pulmonary antihypertensive drugs have a negative effect on platelets. In this review, the mechanisms of platelets association with pulmonary arterial hypertension, those types of pulmonary arterial hypertension with greatest platelet contribution to their pathophysiology, and the effects of pulmonary antihypertensive drugs on platelets are summarized. PMID:23056879

  4. Severe pulmonary arterial hypertension in an adult patient with total anomalous pulmonary venous connection operated in infancy.

    PubMed

    Martinez-Quintana, Efrén; Rodríguez-González, Fayna

    2016-01-01

    The goal of total anomalous pulmonary venous connection repair is to obtain an unobstructed communication between the pulmonary veins and the left atrium and removing intracardiac shunting. However, pulmonary venous obstruction orstenosis may be seen in 5-10% of patients, is usually evident in the first 6 months following surgery and may lead to pulmonary congestion, pulmonary arterial hypertension, and late mortality. In such cases, early intervention may be indicated before irreversible secondary changes occur. We present the case and the therapeutic approach of an adolescent patient with total anomalous pulmonary venous drainage to the superior vena cava operated in infancy who developed pulmonary venous obstruction and secondary severe pulmonary arterial hypertension. PMID:27209841

  5. The effect of sildenafil on right ventricular remodeling in a rat model of monocrotaline-induced right ventricular failure

    PubMed Central

    Bae, Hyun Kyung; Lee, Hyeryon; Kim, Kwan Chang

    2016-01-01

    Purpose Pulmonary arterial hypertension (PAH) leads to right ventricular failure (RVF) as well as an increase in pulmonary vascular resistance. Our purpose was to study the effect of sildenafil on right ventricular remodeling in a rat model of monocrotaline (MCT)-induced RVF. Methods The rats were distributed randomly into 3 groups. The control (C) group, the monocrotaline (M) group (MCT 60 mg/kg) and the sildenafil (S) group (MCT 60 mg/kg+ sildenafil 30 mg/kg/day for 28 days). Masson Trichrome staining was used for heart tissues. Western blot analysis and immunohistochemical staining were performed. Results The mean right ventricular pressure (RVP) was significantly lower in the S group at weeks 1, 2, and 4. The number of intra-acinar arteries and the medial wall thickness of the pulmonary arterioles significantly lessened in the S group at week 4. The collagen content also decreased in heart tissues in the S group at week 4. Protein expression levels of B-cell lymphoma-2 (Bcl-2)-associated X, caspase-3, Bcl-2, interleukin (IL)-6, matrix metalloproteinase (MMP)-2, endothelial nitric oxide synthase (eNOS), endothelin (ET)-1 and ET receptor A (ERA) in lung tissues greatly decreased in the S group at week 4 according to immunohistochemical staining. According to Western blotting, protein expression levels of troponin I, brain natriuretic peptide, caspase-3, Bcl-2, tumor necrosis factor-α, IL-6, MMP-2, eNOS, ET-1, and ERA in heart tissues greatly diminished in the S group at week 4. Conclusion Sildenafil alleviated right ventricular hypertrophy and mean RVP. These data suggest that sildenafil improves right ventricular function. PMID:27462355

  6. Pulmonary stenosis development and reduction of pulmonary arterial hypertension in atrioventricular septal defect: a case report

    PubMed Central

    Barth, Emeline; Bouvaist, Hélène; Marlière, Stéphanie; Ninet, Gérard; Vanzetto, Gérald

    2009-01-01

    A 24-year-old patient was admitted for dyspnoea and syncope. He had a previous history of complete atrio-ventricular septal defect and trisomy 21. At the age of 6 months, in 1984, cardiac catheterization revealed a quasi-systemic pulmonary arterial hypertension with a bidirectional shunt corresponding to an Eisenmenger syndrome. Corrective cardiac surgery was not performed at this time because surgical risk was considered too high. Until the age of 20 years old, he showed few symptoms while under medical treatment. But since 2006, his functional status became worse with an increased dyspnoea, syncopes, and severe cyanosis. In these conditions, haemodynamic parameters have been re-evaluated in 2006 and 2008. They highlighted a late and progressive development of a valvular and infundibular pulmonary stenosis leading to a normalisation of pulmonary arterial pressures. At the age of 24 , the patient underwent corrective cardiac surgery which was successful. Late development of both infundibular and valvular pulmonary stenosis have not been described before in non operated congenital ventricular septal defects, but development of one or the other abnormality would be found in 8% of patients. The physiopathological mechanism of this obstruction is unclear. Nevertheless, in unoperated congenital cardiac shunt lesions, reversibility of severe pulmonary arterial hypertension should be reconidered and re-assessed during follow up. PMID:19758423

  7. Changes in Right Ventricular Dysfunction After Balloon Pulmonary Angioplasty in Patients With Chronic Thromboembolic Pulmonary Hypertension.

    PubMed

    Tsugu, Toshimitsu; Murata, Mitsushige; Kawakami, Takashi; Minakata, Yugo; Kanazawa, Hideaki; Kataoka, Masaharu; Endoh, Jin; Tsuruta, Hikaru; Itabashi, Yuji; Maekawa, Yuichiro; Abe, Takayuki; Fukuda, Keiichi

    2016-10-01

    The aim was to investigate the effect of balloon pulmonary angioplasty (BPA) on right ventricular (RV) function in chronic thromboembolic pulmonary hypertension. Twenty-six patients with chronic thromboembolic pulmonary hypertension were enrolled and were divided into 2 groups, group H with high (>30 mm Hg) mean pulmonary arterial pressure and group L with low (25 to 30 mm Hg) mean pulmonary arterial pressure. RV function was assessed using 2-dimensional speckle-tracking echocardiography as well as 3-dimensional echocardiography, and RV dyssynchrony was assessed by the RV strain curves. Exercise capacity was evaluated by the 6-minute walk distance. RV dilatation was significantly reduced after BPA. In group H, RV ejection fraction, RV free wall longitudinal strain and RV dyssynchrony were all impaired before BPA and were ameliorated after BPA. In group L, RV ejection fraction as well as RV dyssynchrony were impaired without the reduction of RV free wall longitudinal strain and were improved after BPA, indicating that RV dysfunction may be attributable to the RV dyssynchrony in group L. Furthermore, RV dyssynchrony at baseline was the only parameter that was correlated with improvement in the 6-minute walk distance after BPA. RV dyssynchrony may affect RV function and could be the useful parameter for clinical outcome after BPA. PMID:27530827

  8. Chronic intrauterine pulmonary hypertension increases main pulmonary artery stiffness and adventitial remodeling in fetal sheep

    PubMed Central

    Morgan, Matthew R.; Galambos, Csaba; Hunter, Kendall S.; Abman, Steven H.

    2014-01-01

    Persistent pulmonary hypertension of the newborn (PPHN) is a clinical syndrome that is characterized by high pulmonary vascular resistance due to changes in lung vascular growth, structure, and tone. PPHN has been primarily considered as a disease of the small pulmonary arteries (PA), but proximal vascular stiffness has been shown to be an important predictor of morbidity and mortality in other diseases associated with pulmonary hypertension (PH). The objective of this study is to characterize main PA (MPA) stiffness in experimental PPHN and to determine the relationship of altered biomechanics of the MPA with changes in extracellular matrix (ECM) content and orientation of collagen and elastin fibers. MPAs were isolated from control and PPHN fetal sheep model and were tested by planar biaxial testing to measure stiffness in circumferential and axial vessel orientations. Test specimens were fixed for histological assessments of the vascular wall ECM constituents collagen and elastin. MPAs from PPHN sheep had increased mechanical stiffness (P < 0.05) and altered ECM remodeling compared with control MPA. A constitutive mathematical model and histology demonstrated that PPHN vessels have a smaller contribution of elastin and a greater role for collagen fiber engagement compared with the control arteries. We conclude that exposure to chronic hemodynamic stress in late-gestation fetal sheep increases proximal PA stiffness and alters ECM remodeling. We speculate that proximal PA stiffness further contributes to increased right ventricular impedance in experimental PPHN, which contributes to abnormal transition of the pulmonary circulation at birth. PMID:25326575

  9. Expression of mutant bone morphogenetic protein receptor II worsens pulmonary hypertension secondary to pulmonary fibrosis.

    PubMed

    Bryant, Andrew J; Robinson, Linda J; Moore, Christy S; Blackwell, Thomas R; Gladson, Santhi; Penner, Niki L; Burman, Ankita; McClellan, Lucas J; Polosukhin, Vasiliy V; Tanjore, Harikrishna; McConaha, Melinda E; Gleaves, Linda A; Talati, Megha A; Hemnes, Anna R; Fessel, Joshua P; Lawson, William E; Blackwell, Timothy S; West, James D

    2015-12-01

    Pulmonary fibrosis is often complicated by pulmonary hypertension (PH), and previous studies have shown a potential link between bone morphogenetic protein receptor II (BMPR2) and PH secondary to pulmonary fibrosis. We exposed transgenic mice expressing mutant BMPR2 and control mice to repetitive intraperitoneal injections of bleomycin for 4 weeks. The duration of transgene activation was too short for mutant BMPR2 mice to develop spontaneous PH. Mutant BMPR2 mice had increased right ventricular systolic pressure compared to control mice, without differences in pulmonary fibrosis. We found increased hypoxia-inducible factor (HIF)1-α stabilization in lungs of mutant-BMPR2-expressing mice compared to controls following bleomycin treatment. In addition, expression of the hypoxia response element protein connective tissue growth factor was increased in transgenic mice as well as in a human pulmonary microvascular endothelial cell line expressing mutant BMPR2. In mouse pulmonary vascular endothelial cells, mutant BMPR2 expression resulted in increased HIF1-α and reactive oxygen species production following exposure to hypoxia, both of which were attenuated with the antioxidant TEMPOL. These data suggest that expression of mutant BMPR2 worsens secondary PH through increased HIF activity in vascular endothelium. This pathway could be therapeutically targeted in patients with PH secondary to pulmonary fibrosis.

  10. Expression of mutant bone morphogenetic protein receptor II worsens pulmonary hypertension secondary to pulmonary fibrosis

    PubMed Central

    Robinson, Linda J.; Moore, Christy S.; Blackwell, Thomas R.; Gladson, Santhi; Penner, Niki L.; Burman, Ankita; McClellan, Lucas J.; Polosukhin, Vasiliy V.; Tanjore, Harikrishna; McConaha, Melinda E.; Gleaves, Linda A.; Talati, Megha A.; Hemnes, Anna R.; Fessel, Joshua P.; Lawson, William E.; Blackwell, Timothy S.; West, James D.

    2015-01-01

    Abstract Pulmonary fibrosis is often complicated by pulmonary hypertension (PH), and previous studies have shown a potential link between bone morphogenetic protein receptor II (BMPR2) and PH secondary to pulmonary fibrosis. We exposed transgenic mice expressing mutant BMPR2 and control mice to repetitive intraperitoneal injections of bleomycin for 4 weeks. The duration of transgene activation was too short for mutant BMPR2 mice to develop spontaneous PH. Mutant BMPR2 mice had increased right ventricular systolic pressure compared to control mice, without differences in pulmonary fibrosis. We found increased hypoxia-inducible factor (HIF)1-α stabilization in lungs of mutant-BMPR2-expressing mice compared to controls following bleomycin treatment. In addition, expression of the hypoxia response element protein connective tissue growth factor was increased in transgenic mice as well as in a human pulmonary microvascular endothelial cell line expressing mutant BMPR2. In mouse pulmonary vascular endothelial cells, mutant BMPR2 expression resulted in increased HIF1-α and reactive oxygen species production following exposure to hypoxia, both of which were attenuated with the antioxidant TEMPOL. These data suggest that expression of mutant BMPR2 worsens secondary PH through increased HIF activity in vascular endothelium. This pathway could be therapeutically targeted in patients with PH secondary to pulmonary fibrosis. PMID:26697175

  11. A virtual community: concerns of patients with pulmonary hypertension.

    PubMed

    Matura, Lea Ann; McDonough, Annette; Aglietti, Lianne M; Herzog, Jessica L; Gallant, Kelly A

    2013-05-01

    Pulmonary Hypertension (PH) is a complex disorder characterized by elevated pressures in the pulmonary artery that cause right heart failure and eventually leads to death. Treatment regimens can be complex and mortality is high. The purpose of this study was to determine how people with PH are using an online Discussion Board. Qualitative descriptive methodology was used to analyze a convenience sample of self-identified patients with PH. Internet posts to an online Discussion Board from January 1, 2010 to December 31, 2010 were analyzed for common themes. Five hundred forty-nine individuals with PH posted to the Discussion Board. Four themes emerged: Uncertainty and Concern, Guidance and Validation, Support, and Refocusing Life. People with PH are using the Internet to answer questions about PH and seeking support. Future research needs to be conducted to further explore the needs and concerns of people with PH to provide tailored interventions.

  12. Pregnancy as a possible trigger for heritable pulmonary arterial hypertension.

    PubMed

    Limoges, Maude; Langleben, David; Fox, Benjamin D; Shear, Roberta; Wieczorek, Paul; Rudski, Lawrence G; Hirsch, Andrew M; Schlesinger, Robert D; Lesenko, Lyda

    2016-09-01

    It is unclear whether pregnancy is a trigger or accelerant for idiopathic pulmonary arterial hypertension (PAH). Alternatively, its frequency close to the onset of symptoms and diagnosis in the idiopathic PAH population may represent a coincidence in a disease that predominates in young women. We describe a carrier of a BMPR2 gene mutation who had an uneventful first pregnancy but had aggressive PAH during her second pregnancy and now has ongoing heritable PAH. The possible role of pregnancy as a trigger in this vulnerable patient is discussed. Databases of patients with heritable PAH should be explored to see whether pregnancy is related to overt manifestation of the disease. PMID:27683615

  13. Macitentan for the treatment of pulmonary arterial hypertension.

    PubMed

    Spikes, L; Williamson, T; Satterwhite, L

    2014-06-01

    Macitentan is a novel, dual endothelin receptor antagonist recently approved for the treatment of WHO Group I pulmonary arterial hypertension. Its pharmacologic mechanism of action as well as the pharmacokinetics, pharmacodynamics and potential drug-drug interactions have been demonstrated in multiple phase I and II trials. The pivotal randomized, placebo-controlled, event-driven clinical trial revealed a significant reduction in morbidity. The most common adverse events were rarely clinically significant, nor did they result in a high rate of discontinuation. Of note, macitentan is contraindicated in pregnant women due to embryo-fetal toxicity.

  14. Pregnancy as a possible trigger for heritable pulmonary arterial hypertension

    PubMed Central

    Langleben, David; Fox, Benjamin D.; Shear, Roberta; Wieczorek, Paul; Rudski, Lawrence G.; Hirsch, Andrew M.; Schlesinger, Robert D.; Lesenko, Lyda

    2016-01-01

    Abstract It is unclear whether pregnancy is a trigger or accelerant for idiopathic pulmonary arterial hypertension (PAH). Alternatively, its frequency close to the onset of symptoms and diagnosis in the idiopathic PAH population may represent a coincidence in a disease that predominates in young women. We describe a carrier of a BMPR2 gene mutation who had an uneventful first pregnancy but had aggressive PAH during her second pregnancy and now has ongoing heritable PAH. The possible role of pregnancy as a trigger in this vulnerable patient is discussed. Databases of patients with heritable PAH should be explored to see whether pregnancy is related to overt manifestation of the disease. PMID:27683615

  15. Pulmonary arterial hypertension associated with neurofibromatosis type 1.

    PubMed

    Carrascosa, Miguel F; Larroque, Isabel Celemín; Rivero, Juan-Luis García; García, José-Antonio Saiz-Quevedo; Hoz, Marta Cano; Ares, Miguel Ares; López, Xabier Arrastio; Caviedes, José-Ramón Salcines

    2010-01-01

    The authors report a case of severe pulmonary arterial hypertension (PAH) in a 75-year-old woman who had received a diagnosis of neurofibromatosis type 1 (NF1) 23 years before. She presented with progressive dyspnoea and recurrent syncope. Even though the patient initially improved after starting supportive and specific treatment for PAH, she then deteriorated and died from respiratory failure 11 months after the diagnosis of PAH. Prompt recognition of such an unusual association between PAH and NF1 and appropriate therapeutic intervention could ameliorate quality of life and prolong survival in this patient population. PMID:22798089

  16. Pregnancy as a possible trigger for heritable pulmonary arterial hypertension

    PubMed Central

    Langleben, David; Fox, Benjamin D.; Shear, Roberta; Wieczorek, Paul; Rudski, Lawrence G.; Hirsch, Andrew M.; Schlesinger, Robert D.; Lesenko, Lyda

    2016-01-01

    Abstract It is unclear whether pregnancy is a trigger or accelerant for idiopathic pulmonary arterial hypertension (PAH). Alternatively, its frequency close to the onset of symptoms and diagnosis in the idiopathic PAH population may represent a coincidence in a disease that predominates in young women. We describe a carrier of a BMPR2 gene mutation who had an uneventful first pregnancy but had aggressive PAH during her second pregnancy and now has ongoing heritable PAH. The possible role of pregnancy as a trigger in this vulnerable patient is discussed. Databases of patients with heritable PAH should be explored to see whether pregnancy is related to overt manifestation of the disease.

  17. KCNK3: new gene target for pulmonary hypertension?

    PubMed

    Girerd, Barbara; Perros, Frédéric; Antigny, Fabrice; Humbert, Marc; Montani, David

    2014-08-01

    Recently, KCNK3 has been identified as a new predisposing gene for pulmonary arterial hypertension (PAH) by whole-exome sequencing. Mutation in KCNK3 gene is responsible for the first channelopathy identified in PAH. PAH due to KCNK3 mutations is an autosomal dominant disease with an incomplete penetrance as previously described in PAH due to BMPR2 mutations. This discovery represents an important advance for genetic counselling, allowing identification of high risk relatives for PAH and possible screening for PAH in KCNK3 mutation carriers. PMID:24742047

  18. Depression in pulmonary arterial hypertension: An undertreated comorbidity

    PubMed Central

    Verma, Sameer; Sahni, Sonu; Vijayan, Vannan K; Talwar, Arunabh

    2016-01-01

    Pulmonary arterial hypertension (PAH) is a debilitating condition leading to progressive decline in functional capacity. As a result, PAH can lead to psychological impairment that can impact the overall disease status. The medical community has developed several screening questionnaires in order to assess depression in their patients allowing physicians to be at the forefront of recognizing clinical depression. There is a suggestion that depression symptomatology is more prevalent in the PAH population. The aim of this article is to review the current thought process about diagnosis and management of depression in PAH patients. PMID:26933309

  19. Pulmonary hypertension associated with sarcoidosis: mechanisms, haemodynamics and prognosis

    PubMed Central

    Nunes, H; Humbert, M; Capron, F; Brauner, M; Sitbon, O; Battesti, J‐P; Simonneau, G; Valeyre, D

    2006-01-01

    Background Pulmonary hypertension (PH) is a rare complication of sarcoidosis, although it is not uncommon in advanced disease. Methods A retrospective series of 22 sarcoidosis patients (16 men) of mean (SD) age 46 (13) years with PH was divided into two groups depending on the absence (stage 0: n = 2, stage II: n = 4, stage III: n = 1) or presence (n = 15) of radiographic pulmonary fibrosis at the time of PH diagnosis. Results In both groups PH was moderate to severe and there was no response to acute vasodilator challenge. In non‐fibrotic cases no other cause of PH was found, suggesting a specific sarcoidosis vasculopathy, although no histological specimens were available. In cases with fibrosis there was no correlation between haemodynamics and lung volumes or arterial oxygen tensions, suggesting other mechanisms for PH in addition to pulmonary destruction and hypoxaemia. These included extrinsic arterial compression by lymphadenopathies in three cases and histologically proven pulmonary veno‐occlusive disease in the five patients who underwent lung transplantation. Ten patients received high doses of oral prednisone for PH (stage 0: n  =  1, stage II: n  =  4 and stage IV: n  =  5); three patients without pulmonary fibrosis experienced a sustained haemodynamic response. Survival of the overall population was poor (59% at 5 years). Mortality was associated with NYHA functional class IV but not with haemodynamic parameters or with lung function. Conclusion Two very different phenotypes of sarcoidosis combined with PH are observed depending on the presence or absence of pulmonary fibrosis. PH is a severe complication of sarcoidosis. PMID:16227329

  20. [Relevant issues in the pathology and pathobiology of pulmonary hypertension].

    PubMed

    Tuder, Rubin M; Archer, Stephen L; Dorfmüller, Peter; Erzurum, Serpil C; Guignabert, Christophe; Michelakis, Evangelos; Rabinovitch, Marlene; Schermuly, Ralph; Stenmark, Kurt R; Morrell, Nicholas W

    2014-10-01

    Knowledge of the pathobiology of pulmonary hypertension (PH) continues to accelerate. However, fundamental gaps remain in our understanding of the underlying pathological changes in pulmonary arteries and veins in the different forms of this syndrome. Although PH primarily affects the arteries, venous disease is increasingly recognized as an important entity. Moreover, prognosis in PH is determined largely by the status of the right ventricle, rather than the levels of pulmonary artery pressures. It is increasingly clear that although vasospasm plays a role, PH is an obstructive lung panvasculopathy. Disordered metabolism and mitochondrial structure, inflammation, and dysregulation of growth factors lead to a proliferative, apoptosis-resistant state. These abnormalities may be acquired, genetically mediated as a result of mutations in bone morphogenetic protein receptor-2 or activin-like kinase-1, or epigenetically inherited (as a result of epigenetic silencing of genes such as superoxide dismutase-2). There is a pressing need to better understand how the pathobiology leads to severe disease in some patients versus mild PH in others. Recent recognition of a potential role of acquired abnormalities of mitochondrial metabolism in the right ventricular myocytes and pulmonary vascular cells suggests new therapeutic approaches, diagnostic modalities, and biomarkers. Finally, dissection of the role of pulmonary inflammation in the initiation and promotion of PH has revealed a complex yet fascinating interplay with pulmonary vascular remodeling, promising to lead to novel therapeutics and diagnostics. Emerging concepts are also relevant to the pathobiology of PH, including a role for bone marrow and circulating progenitor cells and microribonucleic acids. Continued interest in the interface of the genetic basis of PH and cellular and molecular pathogenetic links should further expand our understanding of the disease. (J Am Coll Cardiol 2013;62:D4-12) a 2013 by the

  1. Severe pulmonary arterial hypertension due to Angiostrongylosus vasorum in a dog.

    PubMed

    Nicolle, Audrey P; Chetboul, Valérie; Tessier-Vetzel, Dominique; Carlos Sampedrano, Carolina; Aletti, Edouard; Pouchelon, Jean-Louis

    2006-08-01

    A dog was presented with a history of dyspnea, coughing, and ascites. Angiostrongylosis and severe pulmonary arterial hypertension (PAH) were found, as well as a marked discordance between the electrical and mechanical events of the heart. Pulmonary arterial hypertension related to Angiostrongylus vasorum has rarely been reported.

  2. Caffeine causes pulmonary hypertension syndrome (ascites) in broilers.

    PubMed

    Kamely, M; Torshizi, M A Karimi; Rahimi, S; Wideman, R F

    2016-04-01

    Pulmonary hypertension syndrome (PHS), or ascites, is characterized by elevated pulmonary arterial pressure and pulmonary vascular resistance accompanied by right ventricular hypertrophy (RVH) and fluid accumulation in the abdominal cavity. Experimental models are required for triggering PHS to study the pathogenesis of this syndrome and to select resistant genetic lines. Caffeine increases vascular resistance and promotes systemic hypertension in mammals, but a similar effect of caffeine on the pulmonary circulation had not previously been demonstrated. Two experiments were conducted to evaluate the impact of caffeine alone (Exp. 1) or in combination with cold temperature (Exp. 2) on parameters associated with PHS in young broiler chicks. In Exp. 1, 288 chicks were distributed among 24 pens and brooded at standard environmental temperatures, and on d 3 through 42 caffeine was added to the water at doses of 0 (control), 6.25, 12.5, 25, 50, and 100 mg/(kg BW·d). In Exp. 2, 192 chicks were distributed among 16 pens and brooded at cool environmental temperatures, and on d 3 through 42 caffeine was added to the water at doses of 0 (control), 15, 30, and 45 mg/(kg BW·d). In Exp. 1 caffeine administered at or above 12.5 mg/(kg BW·d) induced severe PHS and resulted in acute mortality and RVH ( < 0.05). Hematocrit also slightly increased by caffeine supplementation ( = 0.07). In Exp. 2 caffeine-treated broilers exposed to cold temperatures remarkably exhibited PHS incidences and developed RVH with right ventricular to total ventricular weight ratios of 30% or greater. Moreover, hematocrit significantly increased because of caffeine supplementation in cool ambient temperature ( = 0.002). Our data demonstrate that caffeine induces high incidences of PHS in broilers, which is exacerbated by exposure to low temperatures. PMID:27136008

  3. Epidemiology of Pulmonary Hypertension in Left Heart Disease.

    PubMed

    Guha, Ashrith; Amione-Guerra, Javier; Park, Myung H

    2016-01-01

    Pulmonary hypertension (PH) in the setting of left side heart disease is associated with adverse outcomes. The exact prevalence of PH in the different pathologies that affect the left ventricle, however, is difficult to access with the current literature. The lack of a standard definition of PH in older studies, the different modalities to assess pulmonary artery pressures and the varying disease severity, all account for the great variability in the reported prevalence of PH. PH can accompany heart failure (HF) with reduced (HFrEF) or preserved ejection fraction (HFpEF) as well as mitral and aortic valve disease; in any of these instances it is important to recognize whether the elevation of pulmonary pressures is driven by elevated left ventricular pressures only (isolated post-capillary PH) or if there is an accompanying remodeling component in the pulmonary arterioles (combined post-capillary and pre-capillary PH). The objective of this review is to describe the definitions, prevalence and the risk factors associated with the development of PH in the setting of HFrEF, HFpEF and valvular heart disease. PMID:27402130

  4. Drug-induced pulmonary arterial hypertension: a recent outbreak.

    PubMed

    Montani, David; Seferian, Andrei; Savale, Laurent; Simonneau, Gérald; Humbert, Marc

    2013-09-01

    Pulmonary arterial hypertension (PAH) is a rare disorder characterised by progressive obliteration of the pulmonary microvasculature resulting in elevated pulmonary vascular resistance and premature death. According to the current classification PAH can be associated with exposure to certain drugs or toxins, particularly to appetite suppressant intake drugs, such as aminorex, fenfluramine derivatives and benfluorex. These drugs have been confirmed to be risk factors for PAH and were withdrawn from the market. The supposed mechanism is an increase in serotonin levels, which was demonstrated to act as a growth factor for the pulmonary artery smooth muscle cells. Amphetamines, phentermine and mazindol were less frequently used, but are considered possible risk factors, for PAH. Dasatinib, dual Src/Abl kinase inhibitor, used in the treatment of chronic myelogenous leukaemia was associated with cases of severe PAH, potentially in part reversible after dasatinib withdrawal. Recently, several studies have raised the issue of potential endothelial dysfunction that could be induced by interferon, and a few cases of PAH have been reported with interferon therapy. PAH remains a rare complication of these drugs, suggesting possible individual susceptibility, and further studies are needed to identify patients at risk of drug-induced PAH. PMID:23997051

  5. Pulmonary Hypertension Due to Common Respiratory Conditions: Classification, Evaluation and Management Strategies

    PubMed Central

    Fein, Daniel G.; Zaidi, Ali N.; Sulica, Roxana

    2016-01-01

    Pulmonary hypertension (PH) due to chronic respiratory disease and/or hypoxia is classified as World Health Organization (WHO) Group III pulmonary hypertension. The patients most commonly encountered in clinical practice with group III PH include those with chronic obstructive lung disease (COPD), diffuse parenchymal lung disease, and sleep-disordered breathing. The purpose of this review is to outline the variable clinical significance of pulmonary hypertension in the most common pulmonary disease states and how a clinician may approach the management of these patients. PMID:27571110

  6. Pulmonary Hypertension Due to Common Respiratory Conditions: Classification, Evaluation and Management Strategies.

    PubMed

    Fein, Daniel G; Zaidi, Ali N; Sulica, Roxana

    2016-01-01

    Pulmonary hypertension (PH) due to chronic respiratory disease and/or hypoxia is classified as World Health Organization (WHO) Group III pulmonary hypertension. The patients most commonly encountered in clinical practice with group III PH include those with chronic obstructive lung disease (COPD), diffuse parenchymal lung disease, and sleep-disordered breathing. The purpose of this review is to outline the variable clinical significance of pulmonary hypertension in the most common pulmonary disease states and how a clinician may approach the management of these patients. PMID:27571110

  7. [Successful pregnancy in a patient with idiopathic pulmonary arterial hypertension. Case report].

    PubMed

    Szenczi, Orsolya; Karlócai, Kristóf; Bucsek, László; Rigó, János

    2016-04-10

    Idiopathic pulmonary arterial hypertension is characterized by progressive increase in pulmonary arterial pressure and pulmonary vascular resistance which lead to right ventricular failure and death. Pregnancy in patients with idiopathic pulmonary arterial hypertension is contraindicated because of the high maternal and fetal mortality. The authors present a case of successful pregnancy and delivery of a patient with idiopathic pulmonary arterial hypertension in Hungary for the first time. The aim of the report was to demonstrate that management and treatment of idiopathic pulmonary arterial hypertension in a pregnant woman is a complex and multidisciplinary task that should involve obstetrician, cardiologist and anesthesiologist. Those patients who become pregnant and do not wish to terminate the pregnancy must be referred to obstetric centers where a multidiciplinary approach is taken.

  8. Pulmonary Hypertension Secondary to Partial Anomalous Pulmonary Venous Return in an Elderly.

    PubMed

    Koester, Stefan; Lee, Justin Z; Lee, Kwan S

    2016-01-01

    Background. Partial anomalous pulmonary venous return (PAPVR) is an uncommon congenital abnormality, which may present in the adult population. It is often associated with sinus venosus defect (SVD). The diagnosis and therapy for this condition may be challenging. Case Presentation. We describe a case of an elderly woman who presented with NYHA Class IV dyspnea and was suspected to have symptomatic pulmonary hypertension. She was later found to have anomalous right upper pulmonary vein return to the superior vena cava and associated SVD with bidirectional shunting. Therapeutic options were discussed and medical management alone with aggressive diuresis and sildenafil was adopted. Follow-up visits revealed success in the planned medical therapy. Conclusions. PAPVR is a rare congenital condition that may present during late adulthood. The initial predominant left-to-right shunting associated with this anomaly may go undetected for years with the gradual development of pulmonary hypertension and right heart failure due to right heart volume overload. Awareness of the condition is important, as therapy is time-sensitive with early detection potentially leading to surgical therapy as a viable option. PMID:27006835

  9. An international physician survey of pulmonary arterial hypertension management

    PubMed Central

    Hinzmann, Barbara; Heinz, Sabina; Gall, Henning; Jenkins, David; Kim, Nick H.; Lang, Irene

    2016-01-01

    Abstract We conducted an international study to evaluate practices in the diagnosis and management of pulmonary arterial hypertension (PAH) globally across different geographic regions. Between July and October 2012, PAH-treating physicians completed a 15-minute online questionnaire and provided patient record data for their 3 or 5 most recent patients with PAH. Overall, 560 physicians (Europe: 278; United States: 160; Argentina: 53; Japan: 69) completed the questionnaire and provided data for 2,618 patients. The proportion of physicians who described themselves as working in or affiliated with a specialized pulmonary hypertension center ranged from 13% in Argentina to 74% in the United States. At the time of diagnosis, patients’ New York Heart Association functional class differed significantly between regions. At the time of last assessment, functional class had improved overall, and differences between regions had largely disappeared. A large proportion of patients did not undergo right heart catheterization for the diagnosis of PAH (Europe: 7%–21%; United States: 21%; Japan: 19%; Argentina: 51%). Variations in management included greater use of phosphodiesterase 5 inhibitors in the United States than in Europe and Japan and greater use of triple or greater combination therapy in Japan than in other regions. Results from this study, which includes a global aspect of PAH care, demonstrate that there are significant differences in PAH management between regions and low adherence to guidelines recommending right heart catheterization for the diagnosis of PAH. PMID:27683611

  10. An international physician survey of pulmonary arterial hypertension management.

    PubMed

    Preston, Ioana R; Hinzmann, Barbara; Heinz, Sabina; Gall, Henning; Jenkins, David; Kim, Nick H; Lang, Irene

    2016-09-01

    We conducted an international study to evaluate practices in the diagnosis and management of pulmonary arterial hypertension (PAH) globally across different geographic regions. Between July and October 2012, PAH-treating physicians completed a 15-minute online questionnaire and provided patient record data for their 3 or 5 most recent patients with PAH. Overall, 560 physicians (Europe: 278; United States: 160; Argentina: 53; Japan: 69) completed the questionnaire and provided data for 2,618 patients. The proportion of physicians who described themselves as working in or affiliated with a specialized pulmonary hypertension center ranged from 13% in Argentina to 74% in the United States. At the time of diagnosis, patients' New York Heart Association functional class differed significantly between regions. At the time of last assessment, functional class had improved overall, and differences between regions had largely disappeared. A large proportion of patients did not undergo right heart catheterization for the diagnosis of PAH (Europe: 7%-21%; United States: 21%; Japan: 19%; Argentina: 51%). Variations in management included greater use of phosphodiesterase 5 inhibitors in the United States than in Europe and Japan and greater use of triple or greater combination therapy in Japan than in other regions. Results from this study, which includes a global aspect of PAH care, demonstrate that there are significant differences in PAH management between regions and low adherence to guidelines recommending right heart catheterization for the diagnosis of PAH.

  11. An international physician survey of pulmonary arterial hypertension management

    PubMed Central

    Hinzmann, Barbara; Heinz, Sabina; Gall, Henning; Jenkins, David; Kim, Nick H.; Lang, Irene

    2016-01-01

    Abstract We conducted an international study to evaluate practices in the diagnosis and management of pulmonary arterial hypertension (PAH) globally across different geographic regions. Between July and October 2012, PAH-treating physicians completed a 15-minute online questionnaire and provided patient record data for their 3 or 5 most recent patients with PAH. Overall, 560 physicians (Europe: 278; United States: 160; Argentina: 53; Japan: 69) completed the questionnaire and provided data for 2,618 patients. The proportion of physicians who described themselves as working in or affiliated with a specialized pulmonary hypertension center ranged from 13% in Argentina to 74% in the United States. At the time of diagnosis, patients’ New York Heart Association functional class differed significantly between regions. At the time of last assessment, functional class had improved overall, and differences between regions had largely disappeared. A large proportion of patients did not undergo right heart catheterization for the diagnosis of PAH (Europe: 7%–21%; United States: 21%; Japan: 19%; Argentina: 51%). Variations in management included greater use of phosphodiesterase 5 inhibitors in the United States than in Europe and Japan and greater use of triple or greater combination therapy in Japan than in other regions. Results from this study, which includes a global aspect of PAH care, demonstrate that there are significant differences in PAH management between regions and low adherence to guidelines recommending right heart catheterization for the diagnosis of PAH.

  12. An international physician survey of pulmonary arterial hypertension management.

    PubMed

    Preston, Ioana R; Hinzmann, Barbara; Heinz, Sabina; Gall, Henning; Jenkins, David; Kim, Nick H; Lang, Irene

    2016-09-01

    We conducted an international study to evaluate practices in the diagnosis and management of pulmonary arterial hypertension (PAH) globally across different geographic regions. Between July and October 2012, PAH-treating physicians completed a 15-minute online questionnaire and provided patient record data for their 3 or 5 most recent patients with PAH. Overall, 560 physicians (Europe: 278; United States: 160; Argentina: 53; Japan: 69) completed the questionnaire and provided data for 2,618 patients. The proportion of physicians who described themselves as working in or affiliated with a specialized pulmonary hypertension center ranged from 13% in Argentina to 74% in the United States. At the time of diagnosis, patients' New York Heart Association functional class differed significantly between regions. At the time of last assessment, functional class had improved overall, and differences between regions had largely disappeared. A large proportion of patients did not undergo right heart catheterization for the diagnosis of PAH (Europe: 7%-21%; United States: 21%; Japan: 19%; Argentina: 51%). Variations in management included greater use of phosphodiesterase 5 inhibitors in the United States than in Europe and Japan and greater use of triple or greater combination therapy in Japan than in other regions. Results from this study, which includes a global aspect of PAH care, demonstrate that there are significant differences in PAH management between regions and low adherence to guidelines recommending right heart catheterization for the diagnosis of PAH. PMID:27683611

  13. Infantile Hepatic Hemangioendothelioma: An Uncommon Cause of Persistent Pulmonary Hypertension in a Newborn Infant.

    PubMed

    Chatmethakul, Trassanee; Bhat, Ramachandra; Alkaabi, Maryam; Siddiqui, Abdul; Peevy, Keith; Zayek, Michael

    2016-07-01

    Multifocal and diffuse infantile hepatic hemangioendotheliomas commonly present with signs of high-output congestive heart failure. In addition, prolonged persistent pulmonary overcirculation eventually leads to the development of pulmonary hypertension at a later age. We report a 2-day old, full-term infant with multifocal, large infantile hepatic hemangioendothelioma, who presented with an early onset of pulmonary hypertension, managed successfully with supportive care and systemic therapy directed toward the involution of infantile hepatic hemangioendothelioma.

  14. Infantile Hepatic Hemangioendothelioma: An Uncommon Cause of Persistent Pulmonary Hypertension in a Newborn Infant

    PubMed Central

    Chatmethakul, Trassanee; Bhat, Ramachandra; Alkaabi, Maryam; Siddiqui, Abdul; Peevy, Keith; Zayek, Michael

    2016-01-01

    Multifocal and diffuse infantile hepatic hemangioendotheliomas commonly present with signs of high-output congestive heart failure. In addition, prolonged persistent pulmonary overcirculation eventually leads to the development of pulmonary hypertension at a later age. We report a 2-day old, full-term infant with multifocal, large infantile hepatic hemangioendothelioma, who presented with an early onset of pulmonary hypertension, managed successfully with supportive care and systemic therapy directed toward the involution of infantile hepatic hemangioendothelioma. PMID:27468364

  15. Bosentan in Pulmonary Hypertension Associated with Fibrotic Idiopathic Interstitial Pneumonia

    PubMed Central

    Corte, Tamera J.; Keir, Gregory J.; Dimopoulos, Konstantinos; Howard, Luke; Corris, Paul A.; Parfitt, Lisa; Foley, Claire; Yanez-Lopez, Monica; Babalis, Daphne; Marino, Philip; Maher, Toby M.; Renzoni, Elizabeth A.; Spencer, Lisa; Elliot, Charlie A.; Birring, Surinder S.; O’Reilly, Katherine; Gatzoulis, Michael A.; Wells, Athol U.

    2014-01-01

    Rationale: Pulmonary hypertension (PH) associated with fibrotic idiopathic interstitial pneumonia (IIP; idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia) confers important additional morbidity and mortality. Objectives: To evaluate the safety and clinical efficacy of the dual endothelin-1 receptor antagonist bosentan in this patient group. Methods: In a randomized, double-blind, placebo-controlled study, 60 patients with fibrotic IIP and right heart catheter confirmed PH were randomized 2:1 to bosentan (n = 40) or placebo (n = 20). The primary study endpoint was a fall from baseline pulmonary vascular resistance index (PVRi) of 20% or more over 16 weeks. Measurements and Main Results: Sixty patients (42 men; mean age, 66.6 ± 9.2 yr), with a mean pulmonary artery pressure of 36.0 (± 8.9) mm Hg, PVRi 13.0 (± 6.7) Wood Units/m2 and reduced cardiac index of 2.21 (± 0.5) L/min/m2 were recruited to the study. Accounting for deaths and withdrawals, paired right heart catheter data were available for analysis in 39 patients (bosentan = 25, placebo = 14). No difference in the primary outcome was detected, with seven (28.0%) patients receiving bosentan, and four (28.6%) receiving placebo achieving a reduction in PVRi of greater than or equal to 20% (P = 0.97) at 16 weeks. There was no change in functional capacity or symptoms between the two groups at 16 weeks, nor any difference in rates of serious adverse events or deaths (three deaths in each group). Conclusions: This study shows no difference in invasive pulmonary hemodynamics, functional capacity, or symptoms between the bosentan and placebo groups over 16 weeks. Our data do not support the use of the dual endothelin-1 receptor antagonist, bosentan, in patients with PH and fibrotic IIP. Clinical trial registered with www.clinicaltrials.gov (NCT 00637065). PMID:24937643

  16. Notch Activation of Ca2+ Signaling in the Development of Hypoxic Pulmonary Vasoconstriction and Pulmonary Hypertension

    PubMed Central

    Smith, Kimberly A.; Voiriot, Guillaume; Tang, Haiyang; Fraidenburg, Dustin R.; Song, Shanshan; Yamamura, Hisao; Yamamura, Aya; Guo, Qiang; Wan, Jun; Pohl, Nicole M.; Tauseef, Mohammad; Bodmer, Rolf; Ocorr, Karen; Thistlethwaite, Patricia A.; Haddad, Gabriel G.; Powell, Frank L.; Makino, Ayako; Mehta, Dolly

    2015-01-01

    Hypoxic pulmonary vasoconstriction (HPV) is an important physiological response that optimizes the ventilation/perfusion ratio. Chronic hypoxia causes vascular remodeling, which is central to the pathogenesis of hypoxia-induced pulmonary hypertension (HPH). We have previously shown that Notch3 is up-regulated in HPH and that activation of Notch signaling enhances store-operated Ca2+ entry (SOCE), an important mechanism that contributes to pulmonary arterial smooth muscle cell (PASMC) proliferation and contraction. Here, we investigate the role of Notch signaling in HPV and hypoxia-induced enhancement of SOCE. We examined SOCE in human PASMCs exposed to hypoxia and pulmonary arterial pressure in mice using the isolated perfused/ventilated lung method. Wild-type and canonical transient receptor potential (TRPC) 6−/− mice were exposed to chronic hypoxia to induce HPH. Inhibition of Notch signaling with a γ-secretase inhibitor attenuates hypoxia-enhanced SOCE in PASMCs and hypoxia-induced increase in pulmonary arterial pressure. Our results demonstrate that hypoxia activates Notch signaling and up-regulates TRPC6 channels. Additionally, treatment with a Notch ligand can mimic hypoxic responses. Finally, inhibition of TRPC6, either pharmacologically or genetically, attenuates HPV, hypoxia-enhanced SOCE, and the development of HPH. These results demonstrate that hypoxia-induced activation of Notch signaling mediates HPV and the development of HPH via functional activation and up-regulation of TRPC6 channels. Understanding the molecular mechanisms that regulate cytosolic free Ca2+ concentration and PASMC proliferation is critical to elucidation of the pathogenesis of HPH. Targeting Notch regulation of TRPC6 will be beneficial in the development of novel therapies for pulmonary hypertension associated with hypoxia. PMID:25569851

  17. Copper Dependence of Angioproliferation in Pulmonary Arterial Hypertension in Rats and Humans

    PubMed Central

    Mizuno, Shiro; Guignabert, Christophe; Al Hussaini, Aysar A.; Farkas, Daniela; Ruiter, Gerrina; Kraskauskas, Donatas; Fadel, Elie; Allegood, Jeremy C.; Humbert, Marc; Noordegraaf, Anton Vonk; Spiegel, Sarah; Farkas, Laszlo; Voelkel, Norbert F.

    2012-01-01

    Obliteration of the vascular lumen by endothelial cell growth is a hallmark of many forms of severe pulmonary arterial hypertension. Copper plays a significant role in the control of endothelial cell proliferation in cancer and wound-healing. We sought to determine whether angioproliferation in rats with experimental pulmonary arterial hypertension and pulmonary microvascular endothelial cell proliferation in humans depend on the proangiogenic action of copper. A copper-depleted diet prevented, and copper chelation with tetrathiomolybdate reversed, the development of severe experimental pulmonary arterial hypertension. The copper chelation–induced reopening of obliterated vessels was caused by caspase-independent apoptosis, reduced vessel wall cell proliferation, and a normalization of vessel wall structure. No evidence was found for a role of super oxide–1 inhibition or lysyl–oxidase–1 inhibition in the reversal of angioproliferation. Tetrathiomolybdate inhibited the proliferation of human pulmonary microvascular endothelial cells, isolated from explanted lungs from control subjects and patients with pulmonary arterial hypertension. These data suggest that the inhibition of endothelial cell proliferation by a copper-restricting strategy could be explored as a new therapeutic approach in pulmonary arterial hypertension. It remains to be determined, however, whether potential toxicity to the right ventricle is offset by the beneficial pulmonary vascular effects of antiangiogenic treatment in patients with pulmonary arterial hypertension. PMID:22162909

  18. Liposomal Fasudil, a Rho-Kinase Inhibitor, for Prolonged Pulmonary Preferential Vasodilation in Pulmonary Arterial Hypertension

    PubMed Central

    Gupta, Vivek; Gupta, Nilesh; Shaik, Imam H.; Mehvar, Reza; McMurtry, Ivan F.; Oka, Masahiko; Nozik-Grayck, Eva; Komatsu, Masanobu; Ahsan, Fakhrul

    2013-01-01

    Current pharmacological interventions for pulmonary arterial hypertension (PAH) require continuous infusions, multiple inhalations, or oral administration of drugs that act on various pathways involved in the pathogenesis of PAH. However, invasive methods of administration, short duration of action, and lack of pulmonary selectivity result in noncompliance and poor patient outcomes. In this study, we tested the hypothesis that encapsulation of an investigational anti-PAH molecule fasudil (HA-1077), a Rho-kinase inhibitor, into liposomal vesicles results in prolonged vasodilation in distal pulmonary arterioles. Liposomes were prepared by hydration and extrusion method and fasudil was loaded by ammonium sulfate-induced transmembrane electrochemical gradient. Liposomes were then characterized for various physicochemical properties. Optimized formulations were tested for pulmonary absorption and their pharmacological efficacy in a monocrotaline (MCT) induced rat model of PAH. The entrapment efficiency of optimized liposomal fasudil formulations was between 68.1±0.8% and 73.6±2.3%, and the cumulative release at 37°C was 98–99% over a period of 5 days. Compared to intravenous (IV) fasudil, a ~10 fold increase in the terminal plasma half-life was observed when liposomal fasudil was administered as aerosols. The t1/2 of IV fasudil was 0.39±0.12 h. and when given as liposomes via pulmonary route, the t1/2 extended to 4.71±0.72 h. One h after intratracheal instillation of liposomal fasudil, mean pulmonary arterial pressure (MPAP) was reduced by 37.6±5.7% and continued to decrease for about 3 h, suggesting that liposomal formulations produced pulmonary preferential vasodilation in MCT induced PAH rats. Overall, this study established the proof-of-principle that aerosolized liposomal fasudil is a feasible option for a non-invasive, controlled release and pulmonary preferential treatment of PAH. PMID:23353807

  19. Altered artery mechanics and structure in monocrotaline pulmonary hypertension.

    PubMed

    Langleben, D; Szarek, J L; Coflesky, J T; Jones, R C; Reid, L M; Evans, J N

    1988-11-01

    Pulmonary hypertension in rats, induced by an injection of monocrotaline, is associated with changes in the wall structure of the pulmonary arterial bed. We have studied the effects of this remodeling on mechanical properties of cylindrical pulmonary artery segments from rats 21 days after monocrotaline (MCT) injection. Resting and active (KCl induced) circumference-tension relationships were established for segments of extrapulmonary and intrapulmonary arteries isolated from the hilum and the fifth lateral branch from the axial pathway (all preacinar). The thicknesses of the vessel wall, the media, and adventitia were measured at several positions around the circumference of the artery by computerized analysis of histological cross sections of the segments fixed at a standard circumference. Resting and active stress were also calculated. The study shows that active circumferential tension and active stress are reduced in vessels from MCT-treated rats. Based on our findings, it is unlikely that altered contractile function of preacinar arteries contributes significantly to the increased vascular resistance seen in this model. PMID:3145283

  20. Peripheral airways obstruction in idiopathic pulmonary artery hypertension (primary).

    PubMed

    Fernandez-Bonetti, P; Lupi-Herrera, E; Martinez-Guerra, M L; Barrios, R; Seoane, M; Sandoval, J

    1983-05-01

    The mechanical properties of the lung were studied in ten nonsmokers with idiopathic pulmonary artery hypertension (IPAH) (mean pulmonary artery pressure 65.7 +/- 30 mm Hg). In the routine lung test, residual volume was found to be abnormal (greater than 120 percent of the predicted) in seven patients, and measured airway resistance was normal in eight out of the ten patients. A decreased FEF 75-85 percent, abnormal values for the helium-air flow ratios and increased closing capacities were documented in eight of ten patients in whom lung elastic recoil was normal (six of ten) or increased (four of ten). These features suggest peripheral airways obstruction (PAO) which was also supported by histopathologic findings in three cases (one biopsy and two necropsies). The observed changes in lung compliance could be related to the behavior of the coupling of the air-space and vascular compartments. The etiology of PAO in IPAH patients is not known, but our results indicate that both the peripheral airways and the pulmonary circulation are affected. The knowledge of PAO in IPAH patients could help to better understand the observed V/Q inequality in this entity. PMID:6839814

  1. The limits of oral therapy in pulmonary arterial hypertension management

    PubMed Central

    Liu, Qian-Qian; Jing, Zhi-Cheng

    2015-01-01

    Pulmonary arterial hypertension (PAH) is a devastating disease in which remodeling of the small pulmonary arteries leads to a progressive increase in pulmonary vascular resistance and right-sided heart failure. Over the past decade, new treatments for PAH, such as the use of ERAs, PDE-5 inhibitors and prostacyclin analogs, have brought about dramatic improvements in clinical outcomes. Epoprostenol infusion therapy has been shown to improve hemodynamics, functional status, and survival, and it remains the gold standard for treatment of patients with severe PAH. Many agents, approved for PAH are always delivered in pill form. Although oral therapy occupies an important position, it has some drawbacks and limitations in PAH management. For patients in World Health Organization functional class IV and with severe right heart failure, there are few data on the long-term survival of patients treated with oral medications. Further research, exploration, and clinical experience with oral therapy in severe PAH and combination therapy will redefine its position in PAH management. PMID:26648729

  2. Prostanoid therapies in the management of pulmonary arterial hypertension

    PubMed Central

    LeVarge, Barbara L

    2015-01-01

    Prostacyclin is an endogenous eicosanoid produced by endothelial cells; through actions on vascular smooth-muscle cells, it promotes vasodilation. Pulmonary arterial hypertension (PAH) is characterized by elevated mean pulmonary artery pressure due to a high pulmonary vascular resistance state. A relative decrease in prostacyclin presence has been associated with PAH; this pathway has thus become a therapeutic target. Epoprostenol, the synthetic equivalent of prostacyclin, was first utilized as short-term or bridging therapy in the 1980s. Further refinement of its long-term use via continuous intravenous infusion followed. A randomized controlled trial by Barst et al in 1996 demonstrated functional, hemodynamic, and mortality benefits of epoprostenol use. This work was a groundbreaking achievement in the management of PAH and initiated a wave of research that markedly altered the dismal prognosis previously associated with PAH. Analogs of prostacyclin, including iloprost and treprostinil, exhibit increased stability and allow for an extended array of parenteral and non-parenteral (inhaled and oral) therapeutic options. This review further examines the pharmacology and clinical use of epoprostenol and its analogs in PAH. PMID:25848300

  3. Connective tissue disease-associated pulmonary arterial hypertension

    PubMed Central

    Howard, Luke S.

    2015-01-01

    Although rare in its idiopathic form, pulmonary arterial hypertension (PAH) is not uncommon in association with various associated medical conditions, most notably connective tissue disease (CTD). In particular, it develops in approximately 10% of patients with systemic sclerosis and so these patients are increasingly screened to enable early detection. The response of patients with systemic sclerosis to PAH-specific therapy appears to be worse than in other forms of PAH. Survival in systemic sclerosis-associated PAH is inferior to that observed in idiopathic PAH. Potential reasons for this include differences in age, the nature of the underlying pulmonary vasculopathy and the ability of the right ventricle to cope with increased afterload between patients with systemic sclerosis-associated PAH and idiopathic PAH, while coexisting cardiac and pulmonary disease is common in systemic sclerosis-associated PAH. Other forms of connective tissue-associated PAH have been less well studied, however PAH associated with systemic lupus erythematosus (SLE) has a better prognosis than systemic sclerosis-associated PAH and likely responds to immunosuppression. PMID:25705389

  4. Perioperative risk and management in patients with pulmonary hypertension.

    PubMed

    Minai, Omar A; Yared, Jean-Pierre; Kaw, Roop; Subramaniam, Kathirvel; Hill, Nicholas S

    2013-07-01

    Pulmonary hypertension (PH) is a known risk factor for perioperative complications. Unlike in the case of cardiac surgery, PH is currently not listed as an independent risk factor for postoperative complications in guidelines for the management of noncardiac surgery. Despite the paucity of data, though, patients with PH are often counseled against having elective procedures because early and sudden postoperative deaths have been reported. Patients with PH are unable to accommodate alterations in right ventricular (RV) preload or afterload induced by fluid shifts, medications, or changes in the autonomic nervous system precipitated by hypoxia or hypercapnia. These factors become magnified in situations of added stress such as surgical intervention. Systemic hypotension and arrhythmias may precipitate RV ischemia, further worsening RV function. Patient and surgical characteristics and choice of anesthetic technique are crucial factors in perioperative management. The two main principles of perioperative management are the prevention of systemic hypotension (risk of RV ischemia) and the prevention of acute elevations in pulmonary arterial pressure (risk of RV failure). Close monitoring, optimization of systemic BP, pain control, oxygenation and ventilation, avoidance of exacerbating factors, and use of vasopressors and pulmonary vasodilators as necessary are essential elements of management. Understanding the pathophysiology, cause, and severity of PH in the individual perioperative patient allows accurate risk assessment, optimization of PH and RV function prior to surgery, and appropriate intraoperative and postoperative management.

  5. Pulmonary Hypertension and Indicators of Right Ventricular Function

    PubMed Central

    von Siebenthal, Célia; Aubert, John-David; Mitsakis, Periklis; Yerly, Patrick; Prior, John O.; Nicod, Laurent Pierre

    2016-01-01

    Pulmonary hypertension (PH) is a rare disease, whose underlying mechanisms are not fully understood. It is characterized by pulmonary arterial vasoconstriction and vessels wall thickening, mainly intimal and medial layers. Several molecular pathways have been studied, but their respective roles remain unknown. Cardiac repercussions of PH are hypertrophy, dilation, and progressive right ventricular dysfunction. Multiple echocardiographic parameters are being used, in order to assess anatomy and cardiac function, but there are no guidelines edited about their usefulness. Thus, it is now recommended to associate the best-known parameters, such as atrial and ventricular diameters or tricuspid annular plane systolic excursion. Cardiac catheterization remains necessary to establish the diagnosis of PH and to assess pulmonary hemodynamic state. Concerning energetic metabolism, free fatty acids, normally used to provide energy for myocardial contraction, are replaced by glucose uptake. These abnormalities are illustrated by increased 18F-fluorodeoxyglucose (18F-FDG) uptake on positron emission tomography/computed tomography, which seems to be correlated with echocardiographic and hemodynamic parameters. PMID:27376066

  6. Complex inheritance in Pulmonary Arterial Hypertension patients with several mutations.

    PubMed

    Pousada, Guillermo; Baloira, Adolfo; Valverde, Diana

    2016-01-01

    Pulmonary Arterial Hypertension (PAH) is a rare and progressive disease with low incidence and prevalence, and elevated mortality. PAH is characterized by increased mean pulmonary artery pressure. The aim of this study was to analyse patients with combined mutations in BMPR2, ACVRL1, ENG and KCNA5 genes and to establish a genotype-phenotype correlation. Major genes were analysed by polymerase chain reaction (PCR) and direct sequencing. Genotype-phenotype correlation was performed. Fifty-seven (28 idiopathic PAH, 29 associated PAH group I) were included. Several mutations in different genes, classified as pathogenic by in silico analysis, were present in 26% of PAH patients. The most commonly involved gene was BMPR2 (12 patients) followed by ENG gene (9 patients). ACVRL1 and KCNA5 genes showed very low incidence of mutations (5 and 1 patients, respectively). Genotype-phenotype correlation showed statistically significant differences for gender (p = 0.045), age at diagnosis (p = 0.035), pulmonary vascular resistance (p = 0.030), cardiac index (p = 0.035) and absence of response to treatment (p = 0.011). PAH is consequence of a heterogeneous constellation of genetic arrangements. Patients with several pathogenic mutations seem to display a more severe phenotype. PMID:27630060

  7. Complex inheritance in Pulmonary Arterial Hypertension patients with several mutations

    PubMed Central

    Pousada, Guillermo; Baloira, Adolfo; Valverde, Diana

    2016-01-01

    Pulmonary Arterial Hypertension (PAH) is a rare and progressive disease with low incidence and prevalence, and elevated mortality. PAH is characterized by increased mean pulmonary artery pressure. The aim of this study was to analyse patients with combined mutations in BMPR2, ACVRL1, ENG and KCNA5 genes and to establish a genotype-phenotype correlation. Major genes were analysed by polymerase chain reaction (PCR) and direct sequencing. Genotype-phenotype correlation was performed. Fifty-seven (28 idiopathic PAH, 29 associated PAH group I) were included. Several mutations in different genes, classified as pathogenic by in silico analysis, were present in 26% of PAH patients. The most commonly involved gene was BMPR2 (12 patients) followed by ENG gene (9 patients). ACVRL1 and KCNA5 genes showed very low incidence of mutations (5 and 1 patients, respectively). Genotype-phenotype correlation showed statistically significant differences for gender (p = 0.045), age at diagnosis (p = 0.035), pulmonary vascular resistance (p = 0.030), cardiac index (p = 0.035) and absence of response to treatment (p = 0.011). PAH is consequence of a heterogeneous constellation of genetic arrangements. Patients with several pathogenic mutations seem to display a more severe phenotype. PMID:27630060

  8. The limits of oral therapy in pulmonary arterial hypertension management.

    PubMed

    Liu, Qian-Qian; Jing, Zhi-Cheng

    2015-01-01

    Pulmonary arterial hypertension (PAH) is a devastating disease in which remodeling of the small pulmonary arteries leads to a progressive increase in pulmonary vascular resistance and right-sided heart failure. Over the past decade, new treatments for PAH, such as the use of ERAs, PDE-5 inhibitors and prostacyclin analogs, have brought about dramatic improvements in clinical outcomes. Epoprostenol infusion therapy has been shown to improve hemodynamics, functional status, and survival, and it remains the gold standard for treatment of patients with severe PAH. Many agents, approved for PAH are always delivered in pill form. Although oral therapy occupies an important position, it has some drawbacks and limitations in PAH management. For patients in World Health Organization functional class IV and with severe right heart failure, there are few data on the long-term survival of patients treated with oral medications. Further research, exploration, and clinical experience with oral therapy in severe PAH and combination therapy will redefine its position in PAH management. PMID:26648729

  9. Right Ventricular Hemodynamics in Patients with Pulmonary Hypertension

    NASA Astrophysics Data System (ADS)

    Browning, James; Fenster, Brett; Hertzberg, Jean; Schroeder, Joyce

    2012-11-01

    Recent advances in cardiac magnetic resonance imaging (CMR) have allowed for characterization of blood flow in the right ventricle (RV), including calculation of vorticity and circulation, and qualitative visual assessment of coherent flow patterns. In this study, we investigate qualitative and quantitative differences in right ventricular hemodynamics between subjects with pulmonary hypertension (PH) and normal controls. Fifteen (15) PH subjects and 10 age-matched controls underwent same day 3D time resolved CMR and echocardiography. Echocardiography was used to determine right ventricular diastolic function as well as pulmonary artery systolic pressure (PASP). Velocity vectors, vorticity vectors, and streamlines in the RV were visualized in Paraview and total RV Early (E) and Atrial (A) wave diastolic vorticity was quantified. Visualizations of blood flow in the RV are presented for PH and normal subjects. The hypothesis that PH subjects exhibit different RV vorticity levels than normals during diastole is tested and the relationship between RV vorticity and PASP is explored. The mechanics of RV vortex formation are discussed within the context of pulmonary arterial pressure and right ventricular diastolic function coincident with PH.

  10. Taurine, cardiopulmonary hemodynamics, and pulmonary hypertension syndrome in broilers.

    PubMed

    Ruiz-Feria, C A; Wideman, R F

    2001-11-01

    Previous studies have suggested cardiac taurine is released into the plasma in response to hypoxemia (low blood oxygen levels) during the pathogenesis of pulmonary hypertension syndrome (PHS, ascites). In the present study, broilers reared under cool temperature conditions (16 C) were provided tap water (control group), tap water supplemented with taurine, or tap water supplemented with the taurine transport antagonist beta-alanine. When compared with control values, taurine supplementation consistently elevated free taurine concentrations in the plasma but not in cardiac tissues, whereas beta-alanine supplementation consistently reduced free taurine concentrations in cardiac tissues but not in the plasma. Neither the incidence of PHS nor specific predictors of PHS susceptibility (electrocardiogram Lead II S-wave amplitude, % saturation of hemoglobin with oxygen, heart rate, right to total ventricular weight ratio) were affected by taurine or beta-alanine supplementation. Cardiopulmonary hemodynamic evaluations were conducted to compare control and beta-alanine supplemented broilers breathing room air or air containing 12% oxygen (low oxygen challenge). While breathing room air, the betaalanine-supplemented broilers had higher baseline values for cardiac output (186.2 vs. 146.9 mL/min/kg BW) and pulmonary arterial pressure (27.4 vs. 22.4 mm Hg), similar values for mean systemic arterial pressure (100 vs. 104 mm Hg) and pulmonary vascular resistance (0.062 vs. 0.064 resistance units), and lower values for total peripheral resistance (0.228 vs. 0.296 resistance units) when compared with control broilers breathing room air. During low oxygen challenges, the beta-alanine-supplemented broilers exhibited larger reductions in cardiac output, mean systemic arterial pressure, and pulmonary arterial pressure and greater increases in pulmonary vascular resistance than control broilers. These observations indicate that beta-alanine-supplemented broilers breathing room air had

  11. Angiostatic Factors in the Pulmonary Endarterectomy Material from Chronic Thromboembolic Pulmonary Hypertension Patients Cause Endothelial Dysfunction

    PubMed Central

    Zabini, Diana; Nagaraj, Chandran; Stacher, Elvira; Lang, Irene M.; Nierlich, Patrick; Klepetko, Walter; Heinemann, Akos; Olschewski, Horst; Bálint, Zoltán; Olschewski, Andrea

    2012-01-01

    Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare disease with persistent thrombotic occlusion or stenosis of the large pulmonary arteries resulting in pulmonary hypertension. Surgical removal of the neointimal layer of these vessels together with the non-resolved thrombus consisting of organized collagen-rich fibrotic areas with partly recanalized regions is the treatment of choice (pulmonary endarterectomy, PEA). The present study investigates endothelial cells isolated from such material as well as factors present in the surgical PEA material, which may contribute to impairment of recanalization and thrombus non-resolution. We observed muscularized vessels and non-muscularized vessels in the PEA material. The isolated endothelial cells from the PEA material showed significantly different calcium homeostasis as compared to pulmonary artery endothelial cells (hPAECs) from normal controls. In the supernatant (ELISA) as well as on the tissue level (histochemical staining) of the PEA material, platelet factor 4 (PF4), collagen type I and interferon-gamma-inducible 10 kD protein (IP-10) were detected. CXCR3, the receptor for PF4 and IP-10, was particularly elevated in the distal parts of the PEA material as compared to human control lung (RT-PCR). PF4, collagen type I and IP-10 caused significant changes in calcium homeostasis and affected the cell proliferation, migration and vessel formation in hPAECs. The presence of angiostatic factors like PF4, collagen type I and IP-10, as recovered from the surgical PEA material from CTEPH patients, may lead to changes in calcium homeostasis and endothelial dysfunction. PMID:22916307

  12. The A2B adenosine receptor modulates pulmonary hypertension associated with interstitial lung disease

    PubMed Central

    Karmouty-Quintana, Harry; Zhong, Hongyan; Acero, Luis; Weng, Tingting; Melicoff, Ernestina; West, James D.; Hemnes, Anna; Grenz, Almut; Eltzschig, Holger K.; Blackwell, Timothy S.; Xia, Yang; Johnston, Richard A.; Zeng, Dewan; Belardinelli, Luiz; Blackburn, Michael R.

    2012-01-01

    Development of pulmonary hypertension is a common and deadly complication of interstitial lung disease. Little is known regarding the cellular and molecular mechanisms that lead to pulmonary hypertension in patients with interstitial lung disease, and effective treatment options are lacking. The purpose of this study was to examine the adenosine 2B receptor (A2BR) as a regulator of vascular remodeling and pulmonary hypertension secondary to pulmonary fibrosis. To accomplish this, cellular and molecular changes in vascular remodeling were monitored in mice exposed to bleomycin in conjunction with genetic removal of the A2BR or treatment with the A2BR antagonist GS-6201. Results demonstrated that GS-6201 treatment or genetic removal of the A2BR attenuated vascular remodeling and hypertension in our model. Furthermore, direct A2BR activation on vascular cells promoted interleukin-6 and endothelin-1 release. These studies identify a novel mechanism of disease progression to pulmonary hypertension and support the development of A2BR antagonists for the treatment of pulmonary hypertension secondary to interstitial lung disease.—Karmouty-Quintana, H., Zhong, H., Acero, L., Weng, T., Melicoff, E., West, J. D., Hemnes, A., Grenz, A., Eltzschig, H. K., Blackwell, T. S., Xia, Y., Johnston, R. A., Zeng, D., Belardinelli, L., Blackburn, M. R. The A2B adenosine receptor modulates pulmonary hypertension associated with interstitial lung disease. PMID:22415303

  13. Perioperative management of pulmonary hypertension during lung transplantation (a lesson for other anaesthesia settings).

    PubMed

    Rabanal, J M; Real, M I; Williams, M

    2014-10-01

    Patients with pulmonary hypertension are some of the most challenging for an anaesthesiologist to manage. Pulmonary hypertension in patients undergoing surgical procedures is associated with high morbidity and mortality due to right ventricular failure, arrhythmias and ischaemia leading to haemodynamic instability. Lung transplantation is the only therapeutic option for end-stage lung disease. Patients undergoing lung transplantation present a variety of challenges for anaesthesia team, but pulmonary hypertension remains the most important. The purpose of this article is to review the anaesthetic management of pulmonary hypertension during lung transplantation, with particular emphasis on the choice of anaesthesia, pulmonary vasodilator therapy, inotropic and vasopressor therapy, and the most recent intraoperative monitoring recommendations to optimize patient care.

  14. Perioperative management of pulmonary hypertension during lung transplantation (a lesson for other anaesthesia settings).

    PubMed

    Rabanal, J M; Real, M I; Williams, M

    2014-10-01

    Patients with pulmonary hypertension are some of the most challenging for an anaesthesiologist to manage. Pulmonary hypertension in patients undergoing surgical procedures is associated with high morbidity and mortality due to right ventricular failure, arrhythmias and ischaemia leading to haemodynamic instability. Lung transplantation is the only therapeutic option for end-stage lung disease. Patients undergoing lung transplantation present a variety of challenges for anaesthesia team, but pulmonary hypertension remains the most important. The purpose of this article is to review the anaesthetic management of pulmonary hypertension during lung transplantation, with particular emphasis on the choice of anaesthesia, pulmonary vasodilator therapy, inotropic and vasopressor therapy, and the most recent intraoperative monitoring recommendations to optimize patient care. PMID:25156939

  15. Versican accumulates in vascular lesions in pulmonary arterial hypertension.

    PubMed

    Chang, Ya-Ting; Chan, Christina K; Eriksson, Inger; Johnson, Pamela Y; Cao, Xiaofang; Westöö, Christian; Norvik, Christian; Andersson-Sjöland, Annika; Westergren-Thorsson, Gunilla; Johansson, Staffan; Hedin, Ulf; Kjellén, Lena; Wight, Thomas N; Tran-Lundmark, Karin

    2016-09-01

    Pulmonary arterial hypertension (PAH) is a lethal condition for which there is no effective curative pharmacotherapy. PAH is characterized by vasoconstriction, wall thickening of pulmonary arteries, and increased vascular resistance. Versican is a chondroitin sulfate proteoglycan in the vascular extracellular matrix that accumulates following vascular injury and promotes smooth-muscle cell proliferation in systemic arteries. Here, we investigated whether versican may play a similar role in PAH. Paraffin-embedded lung sections from patients who underwent lung transplantation to treat PAH were used for immunohistochemistry. The etiologies of PAH in the subjects involved in this study were idiopathic PAH, scleroderma, and congenital heart disease (atrial septal defect) with left-to-right shunt. Independent of the underlying etiology, increased versican immunostaining was observed in areas of medial thickening, in neointima, and in plexiform lesions. Western blot of lung tissue lysates confirmed accumulation of versican in patients with PAH. Double staining for versican and CD45 showed only occasional colocalization in neointima of high-grade lesions and plexiform lesions. In vitro, metabolic labeling with [(35)S]sulfate showed that human pulmonary artery smooth-muscle cells (hPASMCs) produce mainly chondroitin sulfate glycosaminoglycans. In addition, hypoxia, but not cyclic stretch, was demonstrated to increase both versican messenger RNA expression and protein synthesis by hPASMCs. Versican accumulates in vascular lesions of PAH, and the amount of versican correlates more with lesion severity than with underlying etiology or inflammation. Hypoxia is a possible regulator of versican accumulation, which may promote proliferation of pulmonary smooth-muscle cells and vascular remodeling in PAH. PMID:27683612

  16. Versican accumulates in vascular lesions in pulmonary arterial hypertension

    PubMed Central

    Chan, Christina K.; Eriksson, Inger; Johnson, Pamela Y.; Cao, Xiaofang; Westöö, Christian; Norvik, Christian; Andersson-Sjöland, Annika; Westergren-Thorsson, Gunilla; Johansson, Staffan; Hedin, Ulf; Kjellén, Lena; Wight, Thomas N.; Tran-Lundmark, Karin

    2016-01-01

    Abstract Pulmonary arterial hypertension (PAH) is a lethal condition for which there is no effective curative pharmacotherapy. PAH is characterized by vasoconstriction, wall thickening of pulmonary arteries, and increased vascular resistance. Versican is a chondroitin sulfate proteoglycan in the vascular extracellular matrix that accumulates following vascular injury and promotes smooth-muscle cell proliferation in systemic arteries. Here, we investigated whether versican may play a similar role in PAH. Paraffin-embedded lung sections from patients who underwent lung transplantation to treat PAH were used for immunohistochemistry. The etiologies of PAH in the subjects involved in this study were idiopathic PAH, scleroderma, and congenital heart disease (atrial septal defect) with left-to-right shunt. Independent of the underlying etiology, increased versican immunostaining was observed in areas of medial thickening, in neointima, and in plexiform lesions. Western blot of lung tissue lysates confirmed accumulation of versican in patients with PAH. Double staining for versican and CD45 showed only occasional colocalization in neointima of high-grade lesions and plexiform lesions. In vitro, metabolic labeling with [35S]sulfate showed that human pulmonary artery smooth-muscle cells (hPASMCs) produce mainly chondroitin sulfate glycosaminoglycans. In addition, hypoxia, but not cyclic stretch, was demonstrated to increase both versican messenger RNA expression and protein synthesis by hPASMCs. Versican accumulates in vascular lesions of PAH, and the amount of versican correlates more with lesion severity than with underlying etiology or inflammation. Hypoxia is a possible regulator of versican accumulation, which may promote proliferation of pulmonary smooth-muscle cells and vascular remodeling in PAH.

  17. Versican accumulates in vascular lesions in pulmonary arterial hypertension

    PubMed Central

    Chan, Christina K.; Eriksson, Inger; Johnson, Pamela Y.; Cao, Xiaofang; Westöö, Christian; Norvik, Christian; Andersson-Sjöland, Annika; Westergren-Thorsson, Gunilla; Johansson, Staffan; Hedin, Ulf; Kjellén, Lena; Wight, Thomas N.; Tran-Lundmark, Karin

    2016-01-01

    Abstract Pulmonary arterial hypertension (PAH) is a lethal condition for which there is no effective curative pharmacotherapy. PAH is characterized by vasoconstriction, wall thickening of pulmonary arteries, and increased vascular resistance. Versican is a chondroitin sulfate proteoglycan in the vascular extracellular matrix that accumulates following vascular injury and promotes smooth-muscle cell proliferation in systemic arteries. Here, we investigated whether versican may play a similar role in PAH. Paraffin-embedded lung sections from patients who underwent lung transplantation to treat PAH were used for immunohistochemistry. The etiologies of PAH in the subjects involved in this study were idiopathic PAH, scleroderma, and congenital heart disease (atrial septal defect) with left-to-right shunt. Independent of the underlying etiology, increased versican immunostaining was observed in areas of medial thickening, in neointima, and in plexiform lesions. Western blot of lung tissue lysates confirmed accumulation of versican in patients with PAH. Double staining for versican and CD45 showed only occasional colocalization in neointima of high-grade lesions and plexiform lesions. In vitro, metabolic labeling with [35S]sulfate showed that human pulmonary artery smooth-muscle cells (hPASMCs) produce mainly chondroitin sulfate glycosaminoglycans. In addition, hypoxia, but not cyclic stretch, was demonstrated to increase both versican messenger RNA expression and protein synthesis by hPASMCs. Versican accumulates in vascular lesions of PAH, and the amount of versican correlates more with lesion severity than with underlying etiology or inflammation. Hypoxia is a possible regulator of versican accumulation, which may promote proliferation of pulmonary smooth-muscle cells and vascular remodeling in PAH. PMID:27683612

  18. Imatinib in pulmonary arterial hypertension: c-Kit inhibition.

    PubMed

    Farha, Samar; Dweik, Raed; Rahaghi, Franck; Benza, Raymond; Hassoun, Paul; Frantz, Robert; Torres, Fernando; Quinn, Deborah A; Comhair, Suzy; Erzurum, Serpil; Asosingh, Kewal

    2014-09-01

    Pulmonary arterial hypertension (PAH) is a progressive disease characterized by severe remodeling of the pulmonary artery resulting in increased pulmonary artery pressure and right ventricular hypertrophy and, ultimately, failure. Bone marrow-derived progenitor cells play a critical role in vascular homeostasis and have been shown to be involved in the pathogenesis of PAH. A proliferation of c-Kit(+) hematopoietic progenitors and mast cells has been noted in the remodeled vessels in PAH. Imatinib, a tyrosine kinase inhibitor that targets c-Kit, has been shown to be beneficial for patients with PAH. Here we hypothesize that the clinical benefit of imatinib in PAH could be related to c-Kit inhibition of progenitor cell mobilization and maturation into mast cells. As a corollary to the phase 3 study using imatinib in PAH, blood samples were collected from 12 patients prior to starting study drug (baseline) and while on treatment at weeks 4 and 24. Eight were randomized to imatinib and 4 to placebo. Circulating c-Kit(+) and CD34(+)CD133(+) hematopoietic progenitors as well as biomarkers of mast cell numbers and activation were measured. Circulating CD34(+)CD133(+) and c-Kit(+) progenitor cells as well as c-Kit(+)/CD34(+)CD133(+) decreased with imatinib therapy (all P < 0.05). In addition, total tryptase, a marker of mast cell load, dropped with imatinib therapy (P = 0.02) and was related to pulmonary vascular resistance (R = 0.7, P = 0.02). The findings support c-Kit inhibition as a potential mechanism of action of imatinib in PAH and suggest that tryptase is a potential biomarker of response to therapy. PMID:25621158

  19. Pulmonary vascular effects of pulsed inhaled nitric oxide in COPD patients with pulmonary hypertension

    PubMed Central

    Hajian, Bita; De Backer, Jan; Vos, Wim; Van Holsbeke, Cedric; Ferreira, Francisca; Quinn, Deborah A; Hufkens, Annemie; Claes, Rita; De Backer, Wilfried

    2016-01-01

    Introduction Severe chronic obstructive pulmonary disease (COPD) is often associated with secondary pulmonary hypertension (PH), which worsens prognosis. PH can be lowered by oxygen, but also by inhaled nitric oxide (NO), which has the potential to improve the health status of these patients. NO is an important mediator in vascular reactions in the pulmonary circulation. Oral compounds can act through NO-mediated pathways, but delivering pulsed inhaled NO (iNO) directly to the airways and pulmonary vasculature could equally benefit patients. Therefore, a proof-of-concept study was performed to quantify pulmonary blood vessel caliber changes after iNO administration using computed tomography (CT)-based functional respiratory imaging (FRI). Methods Six patients with secondary PH due to COPD received “pulsed” iNO in combination with oxygen for 20 minutes via a nasal cannula. Patients underwent a high-resolution CT scan with contrast before and after iNO. Using FRI, changes in volumes of blood vessels and associated lobes were quantified. Oxygen saturation and blood pressure were monitored and patients were asked about their subjective feelings. Results Pulmonary blood vessel volume increased by 7.06%±5.37% after iNO. A strong correlation (Ω20=0.32, P=0.002) was obtained between ventilation and observed vasodilation, suggesting that using the pulsed system, iNO is directed toward the ventilated zones, which consequently experience more vasodilation. Patients did not develop oxygen desaturation, remained normotensive, and perceived an improvement in their dyspnea sensation. Conclusion Inhalation of pulsed NO with oxygen causes vasodilation in the pulmonary circulation of COPD patients, mainly in the well-ventilated areas. A high degree of heterogeneity was found in the level of vasodilation. Patients tend to feel better after the treatment. Chronic use trials are warranted. PMID:27462149

  20. Main pulmonary arterial wall shear stress correlates with invasive hemodynamics and stiffness in pulmonary hypertension

    PubMed Central

    Kheyfets, Vitaly O.; Schroeder, Joyce D.; Dunning, Jamie; Shandas, Robin; Buckner, J. Kern; Browning, James; Hertzberg, Jean; Hunter, Kendall S.; Fenster, Brett E.

    2016-01-01

    Abstract Pulmonary hypertension (PH) is associated with proximal pulmonary arterial remodeling characterized by increased vessel diameter, wall thickening, and stiffness. In vivo assessment of wall shear stress (WSS) may provide insights into the relationships between pulmonary hemodynamics and vascular remodeling. We investigated the relationship between main pulmonary artery (MPA) WSS and pulmonary hemodynamics as well as markers of stiffness. As part of a prospective study, 17 PH patients and 5 controls underwent same-day four-dimensional flow cardiac magnetic resonance imaging (4-D CMR) and right heart catheterization. Streamwise velocity profiles were generated in the cross-sectional MPA in 45° increments from velocity vector fields determined by 4-D CMR. WSS was calculated as the product of hematocrit-dependent viscosity and shear rate generated from the spatial gradient of the velocity profiles. In-plane average MPA WSS was significantly decreased in the PH cohort compared with that in controls (0.18 ± 0.07 vs. 0.32 ± 0.08 N/m2; P = 0.01). In-plane MPA WSS showed strong inverse correlations with multiple hemodynamic indices, including pulmonary resistance (ρ = −0.74, P < 0.001), mean pulmonary pressure (ρ = −0.64, P = 0.006), and elastance (ρ = −0.70, P < 0.001). In addition, MPA WSS had significant associations with markers of stiffness, including capacitance (ρ = 0.67, P < 0.001), distensibility (ρ = 0.52, P = 0.013), and elastic modulus (ρ = −0.54, P = 0.01). In conclusion, MPA WSS is decreased in PH and is significantly associated with invasive hemodynamic indices and markers of stiffness. 4-D CMR–based assessment of WSS may represent a novel methodology to study blood-vessel wall interactions in PH. PMID:27076906

  1. A translational preclinical model of interstitial pulmonary fibrosis and pulmonary hypertension: mechanistic pathways driving disease pathophysiology

    PubMed Central

    Jarman, Elizabeth R.; Khambata, Valerie S.; Yun Ye, Li; Cheung, Kenneth; Thomas, Matthew; Duggan, Nicholas; Jarai, Gabor

    2014-01-01

    Abstract Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease, in which a decline in patient prognosis is frequently associated with the onset of pulmonary hypertension (PH). Animal models exhibiting principle pathophysiological features of IPF and PH could provide greater insight into mechanistic pathways underlying disease progression and a means for evaluating novel therapeutic approaches for intervention. Here, we describe an in vivo disease model, in which animals develop progressive interstitial pulmonary fibrosis and associated PH, as defined by the presence of fibrotic foci adjacent to areas of alveolar injury and remodeling of the pulmonary vasculature. Associated changes in physiological parameters included a decline in lung function and increase in mean pulmonary arterial pressure (mPAP) >25 mmHg. The early fibrotic pathology is associated with a profibrogenic microenvironment, elevated levels of the matrix metalloproteases, MMP‐2, MMP‐7, and MMP‐12, TIMP‐1, the chemoattractant and mitogen, PDGF‐β, and the chemokines CCL2 and CXCL12, that are associated with the recruitment of macrophages, mast cells, and fibrocytes. Principle mechanistic pathways associated with disease pathogenesis are upregulated in the lungs and pulmonary arteries, with sustained increases in gene transcripts for the profibrotic mediator TGF‐β1 and components of the TGF‐β signaling pathway; PAI‐1, Nox‐4, and HIF‐1α. Therapeutic treatment with the ALK‐5/TGF‐β RI inhibitor SB‐525334 reversed established pulmonary fibrosis and associated vascular remodeling, leading to normalization in clinically translatable physiological parameters including lung function and hemodynamic measurements of mPAP. These studies highlight the application of this model in validating potential approaches for targeting common mechanistic pathways driving disease pathogenesis. PMID:25214520

  2. Resolution of pulmonary hypertension complication during venovenous perfusion-induced systemic hyperthermia application.

    PubMed

    Ballard-Croft, Cherry; Wang, Dongfang; Jones, Cameron; Wang, Jingkun; Pollock, Robert; Jubak, Bob; Topaz, Stephen; Zwischenberger, Joseph B

    2013-01-01

    We are developing a venovenous perfusion-induced systemic hyperthermia (vv-PISH) system for advanced cancer treatment. The vv-PISH system consistently delivered hyperthermia to adult healthy swine, but significant pulmonary hypertension developed during the heating phase. The goal of this study was to develop a method to prevent pulmonary hypertension. We hypothesized that pulmonary hypertension results from decreased priming solution air solubility, which causes pulmonary gas embolism. Healthy adult sheep (n = 3) were used to establish a standard vv-PISH sheep model without priming solution preheating. In subsequent sheep (n = 7), the priming solution was preheated (42-46°C) and the hyperthermia circuit flushed with CO2. All sheep survived the experiment and achieved 2 hours of 42°C hyperthermia. In the group lacking priming solution preheating, significant pulmonary hypertension (35-44 mm Hg) developed. In the sheep with priming solution preheating, pulmonary artery pressure was very stable without pulmonary hypertension. Blood electrolytes were in physiologic range, and complete blood counts were unaffected by hyperthermia. Blood chemistries revealed no significant liver or kidney damage. Our simple strategy of priming solution preheating completely resolved the problem of pulmonary hypertension as a milestone toward developing a safe and easy-to-use vv-PISH system for cancer treatment.

  3. Resolution of pulmonary hypertension complication during venovenous perfusion-induced systemic hyperthermia application.

    PubMed

    Ballard-Croft, Cherry; Wang, Dongfang; Jones, Cameron; Wang, Jingkun; Pollock, Robert; Jubak, Bob; Topaz, Stephen; Zwischenberger, Joseph B

    2013-01-01

    We are developing a venovenous perfusion-induced systemic hyperthermia (vv-PISH) system for advanced cancer treatment. The vv-PISH system consistently delivered hyperthermia to adult healthy swine, but significant pulmonary hypertension developed during the heating phase. The goal of this study was to develop a method to prevent pulmonary hypertension. We hypothesized that pulmonary hypertension results from decreased priming solution air solubility, which causes pulmonary gas embolism. Healthy adult sheep (n = 3) were used to establish a standard vv-PISH sheep model without priming solution preheating. In subsequent sheep (n = 7), the priming solution was preheated (42-46°C) and the hyperthermia circuit flushed with CO2. All sheep survived the experiment and achieved 2 hours of 42°C hyperthermia. In the group lacking priming solution preheating, significant pulmonary hypertension (35-44 mm Hg) developed. In the sheep with priming solution preheating, pulmonary artery pressure was very stable without pulmonary hypertension. Blood electrolytes were in physiologic range, and complete blood counts were unaffected by hyperthermia. Blood chemistries revealed no significant liver or kidney damage. Our simple strategy of priming solution preheating completely resolved the problem of pulmonary hypertension as a milestone toward developing a safe and easy-to-use vv-PISH system for cancer treatment. PMID:23820278

  4. Pulmonary Hypertension and Computed Tomography Measurement of Small Pulmonary Vessels in Severe Emphysema

    PubMed Central

    Matsuoka, Shin; Washko, George R.; Yamashiro, Tsuneo; Estepar, Raul San Jose; Diaz, Alejandro; Silverman, Edwin K.; Hoffman, Eric; Fessler, Henry E.; Criner, Gerard J.; Marchetti, Nathaniel; Scharf, Steven M.; Martinez, Fernando J.; Reilly, John J.; Hatabu, Hiroto

    2010-01-01

    Rationale: Vascular alteration of small pulmonary vessels is one of the characteristic features of pulmonary hypertension in chronic obstructive pulmonary disease. The in vivo relationship between pulmonary hypertension and morphological alteration of the small pulmonary vessels has not been assessed in patients with severe emphysema. Objectives: We evaluated the correlation of total cross-sectional area of small pulmonary vessels (CSA) assessed on computed tomography (CT) scans with the degree of pulmonary hypertension estimated by right heart catheterization. Methods: In 79 patients with severe emphysema enrolled in the National Emphysema Treatment Trial (NETT), we measured CSA less than 5 mm2 (CSA<5) and 5 to 10 mm2 (CSA5−10), and calculated the percentage of total CSA for the lung area (%CSA<5 and %CSA5–10, respectively). The correlations of %CSA<5 and %CSA5–10 with pulmonary arterial mean pressure (\\documentclass[10pt]{article} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{pmc} \\usepackage[Euler]{upgreek} \\pagestyle{empty} \\oddsidemargin -1.0in \\begin{document} \\begin{equation*}\\overline{Ppa}\\end{equation*}\\end{document}) obtained by right heart catheterization were evaluated. Multiple linear regression analysis using \\documentclass[10pt]{article} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{pmc} \\usepackage[Euler]{upgreek} \\pagestyle{empty} \\oddsidemargin -1.0in \\begin{document} \\begin{equation*}\\overline{Ppa}\\end{equation*}\\end{document} as the dependent outcome was also performed. Measurements and Main Results: The %CSA<5 had a significant negative correlation with \\documentclass[10pt]{article} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage

  5. The role of endothelin-1 in pulmonary arterial hypertension

    PubMed Central

    Chester, Adrian H.; Yacoub, Magdi H.

    2014-01-01

    Pulmonary arterial hypertension (PAH) is a rare but debilitating disease, which if left untreated rapidly progresses to right ventricular failure and eventually death. In the quest to understand the pathogenesis of this disease differences in the profile, expression and action of vasoactive substances released by the endothelium have been identified in patients with PAH. Of these, endothelin-1 (ET-1) is of particular interest since it is known to be an extremely powerful vasoconstrictor and also involved in vascular remodelling. Identification of ET-1 as a target for pharmacological intervention has lead to the discovery of a number of compounds that can block the receptors via which ET-1 mediates its effects. This review sets out the evidence in support of a role for ET-1 in the onset and progression of the disease and reviews the data from the various clinical trials of ET-1 receptor antagonists for the treatment of PAH. PMID:25405182

  6. Psychosocial Burdens of Pulmonary Arterial Hypertension: A Discussion Paper.

    PubMed

    Doyle-Cox, Carolyn; Brousseau, Carolynne; Tulloch, Heather; Mielniczuk, Lisa M; Davies, Ross A; Sherrard, Heather; Clark, Lorraine

    2016-01-01

    Pulmonary arterial hypertension is an uncommon and devastating chronic illness with no known cure. Little is known about the disease, and even less about the psychosocial burdens. While it is important to create awareness about the physical aspects of the disease, it is equally important to create awareness about the psychosocial burdens patients and their families face. We reviewed the literature to better understand these psychosocial burdens, which include impact from physical limitations, emotional strains, financial burdens, social isolation, lack of intimacy in relationships, and an overall lack of information. The findings can be used to assist health care providers to understand the psychosocial challenges that are being experienced by patients and families in order to better provide supportive care. The creation of a standardized tool to assess the psychosocial burdens at each clinic visit can benefit health care providers by addressing challenges faced and facilitate subsequent referral to appropriate specialists.

  7. Macitentan for the treatment of pulmonary arterial hypertension.

    PubMed

    DuBrock, Hilary M; Channick, Richard N

    2014-08-01

    Macitentan is a novel dual endothelin receptor antagonist recently approved for the treatment of symptomatic pulmonary arterial hypertension (PAH). Compared to other endothelin receptor antagonists, in vitro and in vivo studies have demonstrated that macitentan has improved tissue targeting, a longer duration of action and an improved safety profile. Macitentan is available as a once daily oral medication and has been well tolerated in clinical trials. The recently published Study with an Endothelin Receptor Antagonist in PAH to Improve cliNical Outcomes (SERAPHIN), which was the first event-driven trial ever done in PAH, also demonstrated the benefit of macitentan on reducing the likelihood of a composite endpoint of morbidity and mortality events without a significant difference in mortality.

  8. Macitentan (Opsumit) for the treatment of pulmonary arterial hypertension.

    PubMed

    Clarke, Megan; Walter, Claire; Agarwal, Richa; Kanwar, Manreet; Benza, Raymond L

    2014-07-01

    The endothelin pathway is a key pathway for the pathogenesis of pulmonary arterial hypertension (PAH). Antagonism of this pathway is recommended as initial therapy in low-risk patient with PAH to inhibit fibrosis, cell proliferation, and inflammation caused by endothelin. Prior to October 2013, ambrisentan, a selective ETA receptor antagonist and bosentan, a dual ETA/ETB antagonist, were the only currently available agents for PAH targeting the endothelin pathway. Based on the results of the SERAPHIN trial, macitentan (brand name Opsumit®), a new ETA/ETB antagonist, has been US FDA approved to delay disease progression and reduce hospitalizations for PAH. SERAPHIN is the first ERA trial to use an event-driven strategy with a composite primary end point of morbidity or mortality. Previous trials have focused on short-term outcomes, such as improved 6-min walk distance and WHO functional class.

  9. Connective tissue disease-related pulmonary arterial hypertension.

    PubMed

    Thakkar, Vivek; Lau, Edmund M T

    2016-02-01

    Over the past two decades, there have been several advances in the assessment and management of connective tissue disease-related pulmonary arterial hypertension (CTD-PAH) that improved outcomes of the treatment of this lethal disease, and this will be the focus of this study. Systemic sclerosis is the leading cause of CTD-PAH, followed by systemic lupus erythematosus, mixed connective tissue disease, idiopathic inflammatory myositis, rheumatoid arthritis, and Sjogren's syndrome. Clinical registries have been invaluable in informing about the burden of disease, risk and prognostic factors, and temporal trends with respect to treatment and outcome in CTD-PAH. The major advances have centered on improved disease classification and diagnostic criteria, screening and early diagnosis, the emergence of evidence-based therapies including combination goal-orientated treatment strategies, and the establishment of centers with expertise in PAH.

  10. Connective tissue disease-related pulmonary arterial hypertension.

    PubMed

    Thakkar, Vivek; Lau, Edmund M T

    2016-02-01

    Over the past two decades, there have been several advances in the assessment and management of connective tissue disease-related pulmonary arterial hypertension (CTD-PAH) that improved outcomes of the treatment of this lethal disease, and this will be the focus of this study. Systemic sclerosis is the leading cause of CTD-PAH, followed by systemic lupus erythematosus, mixed connective tissue disease, idiopathic inflammatory myositis, rheumatoid arthritis, and Sjogren's syndrome. Clinical registries have been invaluable in informing about the burden of disease, risk and prognostic factors, and temporal trends with respect to treatment and outcome in CTD-PAH. The major advances have centered on improved disease classification and diagnostic criteria, screening and early diagnosis, the emergence of evidence-based therapies including combination goal-orientated treatment strategies, and the establishment of centers with expertise in PAH. PMID:27421214

  11. Pulmonary Hypertension in the Era of Mechanical Circulatory Support.

    PubMed

    Krishnamurthy, Yamini; Cooper, Lauren B; Parikh, Kishan S; Felker, G Michael; Milano, Carmelo A; Rogers, Joseph G; Hernandez, Adrian F; Patel, Chetan B

    2016-01-01

    Left heart disease (LHD) represents the most common cause of pulmonary hypertension (PH), and is associated with worse prognosis compared with LHD without PH. In addition, PH due to LHD may prevent patients from receiving heart transplantation, because of risk of perioperative right ventricular failure. Current literature lacks comprehensive descriptions and management strategies of PH due to LHD. In this review, we summarize the literature that is available to highlight the definition, pathogenesis, and prognosis of PH due to LHD. Furthermore, we discuss the use of mechanical circulatory support (MCS) in this population. Finally, we provide recommendations regarding the management and reassessment of PH due to LHD in the specific context of MCS. PMID:27442856

  12. New trial designs and potential therapies for pulmonary artery hypertension.

    PubMed

    Gomberg-Maitland, Mardi; Bull, Todd M; Saggar, Rajeev; Barst, Robyn J; Elgazayerly, Amany; Fleming, Thomas R; Grimminger, Friedrich; Rainisio, Maurizio; Stewart, Duncan J; Stockbridge, Norman; Ventura, Carlo; Ghofrani, Ardeschir H; Rubin, Lewis J

    2013-12-24

    A greater understanding of the epidemiology, pathogenesis, and pathophysiology of pulmonary artery hypertension (PAH) has led to significant advances, but the disease remains fatal. Treatment options are neither universally available nor always effective, underscoring the need for development of novel therapies and therapeutic strategies. Clinical trials to date have provided evidence of efficacy, but were limited in evaluating the scope and duration of treatment effects. Numerous potential targets in varied stages of drug development exist, in addition to novel uses of familiar therapies. The pursuit of gene and cell-based therapy continues, and device use to help acute deterioration and chronic management is emerging. This rapid surge of drug development has led to multicenter pivotal clinical trials and has resulted in novel ethical and global clinical trial concerns. This paper will provide an overview of the opportunities and challenges that await the development of novel treatments for PAH.

  13. Psychosocial Burdens of Pulmonary Arterial Hypertension: A Discussion Paper.

    PubMed

    Doyle-Cox, Carolyn; Brousseau, Carolynne; Tulloch, Heather; Mielniczuk, Lisa M; Davies, Ross A; Sherrard, Heather; Clark, Lorraine

    2016-01-01

    Pulmonary arterial hypertension is an uncommon and devastating chronic illness with no known cure. Little is known about the disease, and even less about the psychosocial burdens. While it is important to create awareness about the physical aspects of the disease, it is equally important to create awareness about the psychosocial burdens patients and their families face. We reviewed the literature to better understand these psychosocial burdens, which include impact from physical limitations, emotional strains, financial burdens, social isolation, lack of intimacy in relationships, and an overall lack of information. The findings can be used to assist health care providers to understand the psychosocial challenges that are being experienced by patients and families in order to better provide supportive care. The creation of a standardized tool to assess the psychosocial burdens at each clinic visit can benefit health care providers by addressing challenges faced and facilitate subsequent referral to appropriate specialists. PMID:27159936

  14. Histoenzymological and ultrastructural investigations regarding the role of the endogenous peroxidase at the pulmonary level in cardiogenic pulmonary hypertension.

    PubMed

    Nicolau, N; Butur, G; Dezideriu, L

    1993-01-01

    We found optically and ultrastructurally endogenous peroxidase in 90 intraoperatory pulmonary biopsies taken from patients with valvular cardiopathies and different degrees of pulmonary hypertension. The enzymatic activity increases proportionally to the pulmonary hypertension and it reaches its maximum in severe cases of hemosiderosis. Ultrastructurally we found two reaction types namely: 1) in peroxisomes of circulating monocytes turning into tissue ones, in medium or slight pulmonary hypertension (PHT) and 2) (as granular reactions on the nuclear membrane and endoplasmic reticle in alveolar macrophages, granular pneumocytes in aggravating and severe medium PHT. The presence of both these two types of reaction in the same cell demonstrates the passing stages from circulating macrophages to tissue ones attesting a transitional process of the phagocytic cells. PMID:7849279

  15. Heart Rate Variability and Arrhythmic Burden in Pulmonary Hypertension.

    PubMed

    Witte, C; Meyer Zur Heide Genannt Meyer-Arend, J U; Andrié, R; Schrickel, J W; Hammerstingl, C; Schwab, J O; Nickenig, G; Skowasch, D; Pizarro, C

    2016-01-01

    A growing body of evidence indicates that sudden cardiac death constitutes a major cause of mortality in pulmonary hypertension (PH). As validated method to evaluate cardiac autonomic system dysfunction, alterations in heart rate variability (HRV) are predictive of arrhythmic events, particularly in left ventricular disease. Here, we sought to determine the clinical value of HRV assessment in PH. Sixty-four patients were allocated to different PH-subgroups in this prospectively conducted trial: 25 patients with pulmonary arterial hypertension (PAH), 11 patients with chronic thromboembolic PH (CTEPH), and 28 patients with COPD-induced PH. All patients underwent 24-h Holter electrocardiogram for HRV assessment by time- and frequency-domain analysis. Arrhythmic burden was evaluated by manual analysis and complementary automatic measurement of premature atrial and ventricular contractions. The results were compared to 31 healthy controls. The PAH patients offered a significantly higher mean heart rate (78.6 ± 10.4 bpm vs. 70.1 ± 10.3 bpm, p = 0.04), a higher burden of premature ventricular contractions (p < 0.01), and decreases in HRV (SDNN: p < 0.01; SDANN: p < 0.01; very low frequency: p < 0.01; low frequency/high frequency ratio: p < 0.01; total power: p = 0.02). In CTEPH patients, only the amount of premature ventricular contractions differed from controls (p < 0.01), whereas in COPD both premature atrial contraction count and frequency-domain-based HRV manifested significant differences. In conclusion, PAH appears to be primarily affected by HRV alterations and ventricular arrhythmic burden, indicating a high risk for malignant arrhythmic events. PMID:27241509

  16. Baseline Characteristics of the Korean Registry of Pulmonary Arterial Hypertension.

    PubMed

    Chung, Wook-Jin; Park, Yong Bum; Jeon, Chan Hong; Jung, Jo Won; Ko, Kwang-Phil; Choi, Sung Jae; Seo, Hye Sun; Lee, Jae Seung; Jung, Hae Ok

    2015-10-01

    Despite recent advances in understanding of the pathobiology and targeted treatments of pulmonary arterial hypertension (PAH), epidemiologic data from large populations have been limited to western countries. The aim of the Korean Registry of Pulmonary Arterial Hypertension (KORPAH) was to examine the epidemiology and prognosis of Korean patients with PAH. KORPAH was designed as a nationwide, multicenter, prospective data collection using an internet webserver from September 2008 to December 2011. A total of 625 patients were enrolled. The patients' mean age was 47.6 ± 15.7 yr, and 503 (80.5%) were women. The diagnostic methods included right heart catheterization (n = 249, 39.8%) and Doppler echocardiography (n = 376, 60.2%). The etiologies, in order of frequency, were connective tissue disease (CTD), congenital heart disease, and idiopathic PAH (IPAH) (49.8%, 25.4%, and 23.2%, respectively). Patients with WHO functional class III or IV at diagnosis were 43.4%. In total, 380 (60.8%) patients received a single PAH-specific treatment at the time of enrollment, but only 72 (18.9%) patients received combination therapy. Incident cases during the registry represented 297 patients; therefore, the incidence rate of PAH was 1.9 patients/yr/million people. The 1st-, 2nd-, and 3rd-yr estimated survival rates were 90.8%, 87.8%, and 84.4%, respectively. Although Korean PAH patients exhibited similar age, gender, and survival rate compared with western registries, they showed relatively more CTD-PAH in the etiology and also systemic lupus erythematosus among CTD-PAH. The data suggest that earlier diagnosis and more specialized therapies should be needed to improve the survival of PAH patients.

  17. Pulmonary vascular disease in mice xenografted with human BM progenitors from patients with pulmonary arterial hypertension

    PubMed Central

    Farha, Samar; Lichtin, Alan; Graham, Brian; George, Deepa; Aldred, Micheala; Hazen, Stanley L.; Loyd, James; Tuder, Rubin

    2012-01-01

    Hematopoietic myeloid progenitors released into the circulation are able to promote vascular remodeling through endothelium activation and injury. Endothelial injury is central to the development of pulmonary arterial hypertension (PAH), a proliferative vasculopathy of the pulmonary circulation, but the origin of vascular injury is unknown. In the present study, mice transplanted with BM-derived CD133+ progenitor cells from patients with PAH, but not from healthy controls, exhibited morbidity and/or death due to features of PAH: in situ thrombi and endothelial injury, angioproliferative remodeling, and right ventricular hypertrophy and failure. Myeloid progenitors from patients with heritable and/or idiopathic PAH all produced disease in xenografted mice. Analyses of hematopoietic transcription factors and colony formation revealed underlying abnormalities of progenitors that skewed differentiation toward the myeloid-erythroid lineage. The results of the present study suggest a causal role for hematopoietic stem cell abnormalities in vascular injury, right ventricular hypertrophy, and morbidity associated with PAH. PMID:22745307

  18. Dramatic and sustained responsiveness of pulmonary Langerhans cell histiocytosis-associated pulmonary hypertension to vasodilator therapy

    PubMed Central

    May, Adam; Kane, Garvan; Yi, Eunhee; Frantz, Robert; Vassallo, Robert

    2014-01-01

    Pulmonary Langerhans cell histiocytosis (PLCH) is an uncommon diffuse lung disease characterized by the abnormal accumulation of Langerhans' cells around small airways and other distal lung compartments. Although pulmonary hypertension (PH) is a frequent complication of PLCH, the role of advanced PH therapies for PLCH-related PH is not well-established. We describe a PLCH patient with severe, disease-related PH that responded unexpectedly well to advanced PH therapy with sustained improvement over a 10 year follow-up period. This case indicates that PLCH-associated PH may, in certain instances, be highly responsive to advanced PH therapies and emphasizes the importance of trialing these therapies among patients with PLCH-related PH. PMID:26029568

  19. Epigenetic modulation as a therapeutic approach for pulmonary arterial hypertension

    PubMed Central

    Kim, Jun-Dae; Lee, Aram; Choi, Jihea; Park, Youngsook; Kang, Hyesoo; Chang, Woochul; Lee, Myeong-Sok; Kim, Jongmin

    2015-01-01

    Pulmonary arterial hypertension (PAH) is a rare but progressive and currently incurable disease, which is characterized by vascular remodeling in association with muscularization of the arterioles, medial thickening and plexiform lesion formation. Despite our advanced understanding of the pathogenesis of PAH and the recent therapeutic advances, PAH still remains a fatal disease. In addition, the susceptibility to PAH has not yet been adequately explained. Much evidence points to the involvement of epigenetic changes in the pathogenesis of a number of human diseases including cancer, peripheral hypertension and asthma. The knowledge gained from the epigenetic study of various human diseases can also be applied to PAH. Thus, the pursuit of novel therapeutic targets via understanding the epigenetic alterations involved in the pathogenesis of PAH, such as DNA methylation, histone modification and microRNA, might be an attractive therapeutic avenue for the development of a novel and more effective treatment. This review provides a general overview of the current advances in epigenetics associated with PAH, and discusses the potential for improved treatment through understanding the role of epigenetics in the development of PAH. PMID:26228095

  20. Neuroinflammation in pulmonary hypertension: concept, facts, and relevance.

    PubMed

    Hilzendeger, Aline M; Shenoy, Vinayak; Raizada, Mohan K; Katovich, Michael J

    2014-09-01

    Pulmonary hypertension (PH) is a progressive lung disease characterized by elevated pressure in the lung vasculature, resulting in right-sided heart failure and premature death. The pathogenesis of PH is complex and multifactorial, involving a dysregulated autonomic nervous system and immune response. Inflammatory mechanisms have been linked to the development and progression of PH; however, these are usually restricted to systemic and/or local lung tissue. Inflammation within the CNS, often referred to as neuroinflammation involves activation of the microglia, the innate immune cells that are found specifically in the brain and spinal cord. Microglial activation results in the release of several cytokines and chemokines that trigger neuroinflammation, and has been implicated in the pathogenesis of several disease conditions such as Alzheimer's, Parkinson's, hypertension, atherosclerosis, and metabolic disorders. In this review, we introduce the concept of neuroinflammation in the context of PH, and discuss possible strategies that could be developed for PH therapy based on this concept. PMID:25090964

  1. Epigenetic modulation as a therapeutic approach for pulmonary arterial hypertension.

    PubMed

    Kim, Jun-Dae; Lee, Aram; Choi, Jihea; Park, Youngsook; Kang, Hyesoo; Chang, Woochul; Lee, Myeong-Sok; Kim, Jongmin

    2015-01-01

    Pulmonary arterial hypertension (PAH) is a rare but progressive and currently incurable disease, which is characterized by vascular remodeling in association with muscularization of the arterioles, medial thickening and plexiform lesion formation. Despite our advanced understanding of the pathogenesis of PAH and the recent therapeutic advances, PAH still remains a fatal disease. In addition, the susceptibility to PAH has not yet been adequately explained. Much evidence points to the involvement of epigenetic changes in the pathogenesis of a number of human diseases including cancer, peripheral hypertension and asthma. The knowledge gained from the epigenetic study of various human diseases can also be applied to PAH. Thus, the pursuit of novel therapeutic targets via understanding the epigenetic alterations involved in the pathogenesis of PAH, such as DNA methylation, histone modification and microRNA, might be an attractive therapeutic avenue for the development of a novel and more effective treatment. This review provides a general overview of the current advances in epigenetics associated with PAH, and discusses the potential for improved treatment through understanding the role of epigenetics in the development of PAH. PMID:26228095

  2. Pulmonary vascular morphology as an imaging biomarker in chronic thromboembolic pulmonary hypertension

    PubMed Central

    Ross, J. C.; Agarwal, M.; González, G.; Come, C. E.; Diaz, A. A.; Vegas-Sánchez-Ferrero, G.; Hunsaker, A.; San José Estépar, R.; Waxman, A. B.; Washko, G. R.

    2016-01-01

    Abstract Patients with chronic thromboembolic pulmonary hypertension (CTEPH) have morphologic changes to the pulmonary vasculature. These include pruning of the distal vessels, dilation of the proximal vessels, and increased vascular tortuosity. Advances in image processing and computer vision enable objective detection and quantification of these processes in clinically acquired computed tomographic (CT) scans. Three-dimensional reconstructions of the pulmonary vasculature were created from the CT angiograms of 18 patients with CTEPH diagnosed using imaging and hemodynamics as well as 15 control patients referred to our Dyspnea Clinic and found to have no evidence of pulmonary vascular disease. Compared to controls, CTEPH patients exhibited greater pruning of the distal vasculature (median density of small-vessel volume: 2.7 [interquartile range (IQR): 2.5–3.0] vs. 3.2 [3.0–3.8]; P = 0.008), greater dilation of proximal arteries (median fraction of blood in large arteries: 0.35 [IQR: 0.30–0.41] vs. 0.23 [0.21–0.31]; P = 0.0005), and increased tortuosity in the pulmonary arterial tree (median: 4.92% [IQR: 4.85%–5.21%] vs. 4.63% [4.39%–4.92%]; P = 0.004). CTEPH was not associated with dilation of proximal veins or increased tortuosity in the venous system. Distal pruning of the vasculature was correlated with the cardiac index (R = 0.51, P = 0.04). Quantitative models derived from CT scans can be used to measure changes in vascular morphology previously described subjectively in CTEPH. These measurements are also correlated with invasive metrics of pulmonary hemodynamics, suggesting that they may be used to assess disease severity. Further work in a larger cohort may enable the use of such measures as a biomarker for diagnostic, phenotyping, and prognostic purposes. PMID:27162616

  3. Pulmonary artery endothelium resident endothelial colony-forming cells in pulmonary arterial hypertension

    PubMed Central

    Duong, Heng T.; Comhair, Suzy A.; Aldred, Micheala A.; Mavrakis, Lori; Savasky, Benjamin M.; Erzurum, Serpil C.; Asosingh, Kewal

    2011-01-01

    Proliferative pulmonary vascular remodeling is the pathologic hallmark of pulmonary arterial hypertension (PAH) that ultimately leads to right heart failure and death. Highly proliferative endothelial cells known as endothelial colony-forming cells (ECFC) participate in vascular homeostasis in health as well as in pathological angiogenic remodeling in disease. ECFC are distinguished by the capacity to clonally proliferate from a single cell. The presence of ECFC in the human pulmonary arteries and their role in PAH pathogenesis is largely unknown. In this study, we established a simple technique for isolating and growing ECFC from cultured pulmonary artery endothelial cells (PAEC) to test the hypothesis that ECFC reside in human pulmonary arteries and that the proliferative vasculopathy of PAH is related to greater numbers and/or more proliferative ECFC in the pulmonary vascular wall. Flow cytometric forward and side scatter properties and aggregate correction were utilized to sort unmanipulated, single PAEC to enumerate ECFC in primary PAEC cultures derived from PAH and healthy lungs. After 2 weeks, wells were assessed for ECFC formation. ECFC derived from PAH PAEC were more proliferative than control. A greater proportion of PAH ECFC formed colonies following subculturing, demonstrating the presence of more ECFC with high proliferative potential among PAH PAEC. Human androgen receptor assay showed clonality of progeny, confirming that proliferative colonies were single cell-derived. ECFC expressed CD31, von Willebrand factor, endothelial nitric oxide synthase, caveolin-1 and CD34, consistent with an endothelial cell phenotype. We established a simple flow cytometry method that allows ECFC quantification using unmanipulated cells. We conclude that ECFC reside among PAEC and that PAH PAEC contain ECFC that are more proliferative than ECFC in control cultures, which likely contributes to the proliferative angiopathic process in PAH. PMID:22530103

  4. Speckle Tracking Echocardiography to Evaluate for Pulmonary Hypertension in Chronic Obstructive Pulmonary Disease.

    PubMed

    Rice, Jessica L; Stream, Amanda R; Fox, Daniel L; Geraci, Mark W; Vandivier, R William; Dorosz, Jennifer L; Bull, Todd M

    2016-10-01

    Pulmonary hypertension (PH) is a common complication of chronic obstructive pulmonary disease (COPD), increasing morbidity and mortality. Current echocardiographic measures have poor predictive value for the diagnosis of PH in COPD. Right ventricular (RV) strain obtained by speckle tracking echocardiography (STE) is a measure of myocardial deformation which correlates with RV function and survival in subjects with pulmonary arterial hypertension. We hypothesized that RV strain measurements would be feasible and correlate with invasive hemodynamic measurements in patients with COPD. Retrospective analysis of RV strain values from subjects with severe COPD with echocardiogram within 48 hours of right heart catheterization was performed. First, 54 subjects were included in the analysis. Right ventricular systolic pressure (RVSP) and RV strain could be estimated in 31% and 57%, respectively. Then, 61% had RV-focused apical views, and of those, RV strain could be obtained for 94%. RV free wall strain correlated with PVR (r = 0.41, p = 0.02). Subjects with pulmonary vascular resistance (PVR) > 3 Wood units (WU) had less negative (worse) RV free wall strain values than those with PVR ≤ 3 WU, with a median strain of -20 (-23, -12) versus -23 (-29, -15), p < 0.05. A receiver operating characteristic curve demonstrated an RV free wall strain of > -23 to be 92% sensitive and 44% specific for identifying PVR > 3 WU (AUC 0.71). RV strain estimates are feasible in the majority of subjects with severe COPD. RV strain correlates with PVR and may improve screening for PH in subjects with COPD.

  5. Bone morphogenetic protein signalling in heritable versus idiopathic pulmonary hypertension

    PubMed Central

    Dewachter, Laurence; Adnot, Serge; Guignabert, Christophe; Tu, Ly; Marcos, Elisabeth; Fadel, Elie; Humbert, Marc; Dartevelle, Philippe; Simonneau, Gérald; Naeije, Robert; Eddahibi, Saadia

    2009-01-01

    Mutations in gene encoding for bone morphogenetic protein type 2 receptor (BMPR-2) have been reported in pulmonary arterial hypertension (PAH), but their functional relevance remains incompletely understood. BMP receptors expression was evaluated in human lungs and in cultured pulmonary artery smooth muscle cells (PASMCs) isolated from 19 idiopathic PAH patients and 9 heritable PAH patients with demonstrated BMPR-2 mutations. BMP4-treated PASMCs were assessed for Smad and p38MAPK signaling associated to mitosis and apoptosis. Lung tissue and PASMCs from heritable PAH patients presented with decreased BMPR-2 expression and variable increases in BMPR-1A and BMPR-1B expressions, while a less important decreased BMPR-2 expression was observed in PASMCs from idiopathic PAH patients. Heritable PAH PASMCs showed no increased phosphorylation of Smad1/5/8 in the presence of BMP4, which actually activated the p38MAPK pathway. Individual responses varied from one mutation to another. PASMCs from PAH patients presented with an in vitro proliferative pattern, which could be inhibited by BMP4 in idiopathic PAH, not in heritable PAH. PASMCs from idiopathic PAH and more so from heritable presented an inhibition of BMP4-induced apoptosis. Most heterogenous BMPR-2 mutations are associated with defective Smad signaling compensed for by an activation of p38MAPK signaling, accounting for PASMC proliferation and deficient apoptosis. PMID:19324947

  6. Comparative Effectiveness of Oral Medications for Pulmonary Arterial Hypertension.

    PubMed

    Igarashi, Ataru; Inoue, Sachie; Ishii, Tomonori; Tsutani, Kiichiro; Watanabe, Hiroshi

    2016-07-27

    Pulmonary arterial hypertension (PAH) is a disease that imposes a significant burden on patients. Although multiple treatment options for PAH are available, head-to-head comparisons are difficult to conduct. Network meta-analysis (NMA) can be a useful alternative for direct comparison to estimate the relative effectiveness of multiple treatments. The objective of the present study was to conduct a systematic review and NMA to evaluate the relative effectiveness among oral PAH medications.Data collection was performed by searching the Cochrane Central Register of Controlled Trials (CENTRAL) and Ichushi-Web. Randomized controlled trials (RCTs) assessing at least 1 of the following 3 outcome measurements; 6-minute walk distance test (6MWD), WHO functional class (WHOFC), and mean pulmonary artery pressure (mPAP) were included (PROSPERO registration number: CRD42015016557). Outcomes were evaluated by estimating the differences in the mean change from baseline or by estimating the odds ratios. Analyses were performed using WinBUGS 1.4.3.Seven double-blind RCTs were eligible. NMA results showed similar improvements in 6MWD for all medications assessed. Bosentan and sildenafil caused a statistically significant improvement in WHOFC compared to other medications.The relative effectiveness of oral PAH medications could be compared using NMA, which suggested the superiority of bosentan and sildenafil in the improvement of WHOFC. PMID:27385603

  7. Impact of pulmonary hypertension on tricuspid valve function.

    PubMed

    Casa, Lauren D C; Dolensky, Joseph R; Spinner, Erin M; Veledar, Emir; Lerakis, Stamatios; Yoganathan, Ajit P

    2013-04-01

    Pulmonary arterial hypertension (PAH) results in increased right ventricle (RV) afterload leading to RV remodeling, tricuspid regurgitation (TR), and RV failure. Though characterizing the mechanisms of TR in PAH may suggest new treatment strategies, the mechanisms leading to TR in PAH have not been characterized. In the present study, eleven porcine tricuspid valves were studied in an in vitro right heart simulator. Annular dilatations of 1.2 and 1.4 times normal area, papillary muscle (PM) displacement simulating concentric RV dilatation and eccentric RV dilatation due to concomitant left ventricle dysfunction, and two levels of PAH hemodynamics were simulated independently and in combination. Relative TR, tenting area (TA) along each coaptation line, and coaptation area (CA) of each leaflet were quantified. Results showed a significant increase (p ≤ 0.05) in TR with both increased mean pulmonary artery pressure (mPAP) and annular dilatation of 1.4 times normal. Increased mPAP significantly decreased TA but tended to increase CA, while PM displacement significantly increased TA but did not affect CA, suggesting competing effects of transvalvular pressure and leaflet tethering. Annular dilatation significantly decreased anterior and posterior CA but did not affect TA. These results may inform future TV repairs in PAH to reduce TR and improve RV hemodynamics.

  8. [Phosphodiesterase-5 inhibitors for the treatment of pulmonary arterial hypertension].

    PubMed

    Beltrán-Gámez, Miguel E; Sandoval-Zárate, Julio; Pulido, Tomás

    2015-01-01

    In experimental and clinical cardiology, phosphodiesterase type 5 (PDE-5) inhibitors have brought scientific interest as a therapeutic tool in pulmonary arterial hypertension (PAH) management in recent years. Phosphodiesterases are a superfamily of enzymes that inactivate cyclic adenosine monophosphate and cyclic guanosine monophosphate, the second messengers of prostacyclin and nitric oxide. The rationale for the use of PDE-5 inhibitors in PAH is based on their capacity to overexpresss the nitric oxide pathway pursued inhibition of cyclic guanosine monophosphate hydrolysis. By increasing cyclic guanosine monophosphate levels it promotes vasodilation, antiproliferative and pro-apoptotic effects that may reverse pulmonary vascular remodeling. There is also evidence that these drugs may directly enhance right ventricular contractility through an increase in cyclic adenosine monophosphate mediated by the inhibition of the cyclic guanosine monophosphate -sensitive PDE-3. Sildenafil, tadalafil and vardenafil are 3 specific PDE-5 inhibitors in current clinical use, which share similar mechanisms of action but present some significant differences regarding potency, selectivity for PDE-5 and pharmacokinetic properties. Sildenafil received approval in 2005 by the Food and Drug Administration and the European Medicines Agency and tadalafil in 2009 by the Food and Drug Administration and the European Medicines Agency for the treatment of PAH in patients classified as NYHA/WHO functional class II and III. In Mexico, sildenafil and tadalafil were approved by Comisión Federal de Protección contra Riesgos Sanitarios for this indication in 2010 and 2011, respectively. PMID:26047999

  9. Pulmonary Hypertension – New Trends of Diagnostic and Therapy

    PubMed Central

    Pesto, Senad; Begic, Zijo; Prevljak, Sabina; Pecar, Ehlimana; Kukavica, Nihad; Begic, Edin

    2016-01-01

    Pulmonary hypertension is a pathophysiological state hemodynamically defined as the increase of the mean pulmonary arterial pressure above 25, or 30 mmHg at rest, measured by catheterization of the right heart. Laboratory findings usually reveals polycythemia, the ECG right ventricle hypertrophy, and x-ray characteristic of diseased branches (echocardiography and biomarkers such as B-type natriuretic peptide (BNP) and N-terminal pro-BNP hormones are potentially helpful tools in identifying PH). Echocardiography can be found the increase of the right atrium and ventricle, right ventricular hypertrophy, abnormal contraction of the interventricular septum, left ventricular diastolic dysfunction and decreased left ventricular size, with reduced volumes of systole and end diastole. Doppler confirming tricuspid regurgitation. Pharmacological therapy would represent a use: Calcium Channel Blockers, Prostacyclin Analogues, Endothelin Receptor Antagonists and Phosphodiesterase-5 Inhibitors. Alpha adrenergic antagonists, endothelial receptor subtype A (Bosentan, Tracller) with treatment of the underlying disease or anticongestive therapy, are recommended. In case of inadequate response to treatment with a specific drug, guidelines recommend the combined use of drugs from the basic three groups, using their synergism. PMID:27703295

  10. [Phosphodiesterase-5 inhibitors for the treatment of pulmonary arterial hypertension].

    PubMed

    Beltrán-Gámez, Miguel E; Sandoval-Zárate, Julio; Pulido, Tomás

    2015-01-01

    In experimental and clinical cardiology, phosphodiesterase type 5 (PDE-5) inhibitors have brought scientific interest as a therapeutic tool in pulmonary arterial hypertension (PAH) management in recent years. Phosphodiesterases are a superfamily of enzymes that inactivate cyclic adenosine monophosphate and cyclic guanosine monophosphate, the second messengers of prostacyclin and nitric oxide. The rationale for the use of PDE-5 inhibitors in PAH is based on their capacity to overexpresss the nitric oxide pathway pursued inhibition of cyclic guanosine monophosphate hydrolysis. By increasing cyclic guanosine monophosphate levels it promotes vasodilation, antiproliferative and pro-apoptotic effects that may reverse pulmonary vascular remodeling. There is also evidence that these drugs may directly enhance right ventricular contractility through an increase in cyclic adenosine monophosphate mediated by the inhibition of the cyclic guanosine monophosphate -sensitive PDE-3. Sildenafil, tadalafil and vardenafil are 3 specific PDE-5 inhibitors in current clinical use, which share similar mechanisms of action but present some significant differences regarding potency, selectivity for PDE-5 and pharmacokinetic properties. Sildenafil received approval in 2005 by the Food and Drug Administration and the European Medicines Agency and tadalafil in 2009 by the Food and Drug Administration and the European Medicines Agency for the treatment of PAH in patients classified as NYHA/WHO functional class II and III. In Mexico, sildenafil and tadalafil were approved by Comisión Federal de Protección contra Riesgos Sanitarios for this indication in 2010 and 2011, respectively.

  11. Imaging the heart in pulmonary hypertension: an update.

    PubMed

    Grünig, Ekkehard; Peacock, Andrew J

    2015-12-01

    Noninvasive imaging of the heart plays an important role in the diagnosis and management of pulmonary hypertension (PH), and several well-established techniques are available for assessing performance of the right ventricle, the key determinant of patient survival. While right heart catheterisation is mandatory for establishing a diagnosis of PH, echocardiography is the most important screening tool for early detection of PH. Cardiac magnetic resonance imaging (CMRI) is also a reliable and practical tool that can be used as part of the diagnostic work-up. Echocardiography can measure a range of haemodynamic and anatomical variables (e.g. pericardial effusion and pulmonary artery pressure), whereas CMRI provides complementary information to echocardiography via high-resolution, three-dimensional imaging. Together with echocardiography and CMRI, techniques such as high-resolution computed tomography and positron emission tomography may also be valuable for screening, monitoring and follow-up assessments of patients with PH, but their clinical relevance has yet to be established. Technological advances have produced new variants of echocardiography, CMRI and positron emission tomography, and these permit closer examination of myocardial architecture, motion and deformation. Integrating these new tools into clinical practice in the future may lead to more precise noninvasive determination of diagnosis, risk and prognosis for PH.

  12. Increased Mutagen Sensitivity and DNA Damage in Pulmonary Arterial Hypertension

    PubMed Central

    Federici, Chiara; Drake, Kylie M.; Rigelsky, Christina M.; McNelly, Lauren N.; Meade, Sirena L.; Comhair, Suzy A. A.; Erzurum, Serpil C.

    2015-01-01

    Rationale: Pulmonary arterial hypertension (PAH) is a serious lung condition characterized by vascular remodeling in the precapillary pulmonary arterioles. We and others have demonstrated chromosomal abnormalities and increased DNA damage in PAH lung vascular cells, but their timing and role in disease pathogenesis is unknown. Objectives: We hypothesized that if DNA damage predates PAH, it might be an intrinsic cell property that is present outside the diseased lung. Methods: We measured DNA damage, mutagen sensitivity, and reactive oxygen species (ROS) in lung and blood cells from patients with Group 1 PAH, their relatives, and unrelated control subjects. Measurements and Main Results: Baseline DNA damage was significantly elevated in PAH, both in pulmonary artery endothelial cells (P < 0.05) and peripheral blood mononuclear cells (PBMC) (P < 0.001). Remarkably, PBMC from unaffected relatives showed similar increases, indicating this is not related to PAH treatments. ROS levels were also higher (P < 0.01). DNA damage correlated with ROS production and was suppressed by antioxidants (P < 0.001). PBMC from patients and relatives also showed markedly increased sensitivity to two chemotherapeutic drugs, bleomycin and etoposide (P < 0.001). Results were consistent across idiopathic, heritable, and associated PAH groups. Conclusions: Levels of baseline and mutagen-induced DNA damage are intrinsically higher in PAH cells. Similar results in PBMC from unaffected relatives suggest this may be a genetically determined trait that predates disease onset and may act as a risk factor contributing to lung vascular remodeling following endothelial cell injury. Further studies are required to fully characterize mutagen sensitivity, which could have important implications for clinical management. PMID:25918951

  13. Pulmonary hypertension in rheumatoid arthritis--relation with the duration of the disease.

    PubMed

    Udayakumar, N; Venkatesan, S; Rajendiran, C

    2008-07-21

    Isolated pulmonary hypertension with clinical implication is rare in rheumatoid arthritis. We sought to study the prevalence of pulmonary arterial hypertension in an unselected population of 45 patients with rheumatoid arthritis (classified according to the ARA criteria) without cardiac disease and corresponding age and sex matched controls by Doppler echocardiography. The pulmonary artery systolic pressure was higher in patients with Rheumatoid Arthritis (27.49+/-12.66 mm Hg) than in controls (20.40+/-8.88) (p=0.003). Incidence of pulmonary artery systolic pressure>30 mm Hg suggesting pulmonary hypertension was significantly higher in patients with RA (26.7% versus 4.5% in controls; p=0.03) and 20% of patients had pulmonary hypertension without lung disease or cardiac disease evident on pulmonary function testing, and echocardiogram respectively. There was also a strong correlation between the pulmonary artery pressure and the disease duration (r=0.68, p<0.0001) suggesting a subclinical involvement of the pulmonary vasculature with disease progression and may be relevant to the high incidence of cardiovascular deaths observed in patients with Rheumatoid Arthritis.

  14. 5-Hydroxytryptamine receptors mediating vasoconstriction in pulmonary arteries from control and pulmonary hypertensive rats.

    PubMed Central

    MacLean, M. R.; Sweeney, G.; Baird, M.; McCulloch, K. M.; Houslay, M.; Morecroft, I.

    1996-01-01

    1. We investigated 5-hydroxytryptamine (5-HT)-receptor mediated vasoconstriction in the main, first branch and resistance pulmonary arteries removed from control and pulmonary hypertensive rats. Contractile responses to 5-HT, 5-carboxamidotryptamine (5-CT, non-selective 5-HT1 agonist), and sumatriptan (5-HT1D-like receptor agonist) were studied. The effects of methiothepin (non-selective 5-HT1 + 2-receptor antagonist) and ketanserin (5-HT2A receptor antagonist) and GR55562 (a novel selective 5-HT1D receptor antagonist) on 5-HT-mediated responses were also studied. Basal levels of adenosine 3':5'-cyclic monophosphate ([cyclic AMP]i) and guanosine 3':5'-cyclic monophosphate ([cyclic GMP]i) were determined and we assessed the degree of inherent tone in the vessels under study. 2. 5-HT was most potent in the resistance arteries. pEC50 values were 5.6 +/- 0.1, 5.3 +/- 0.1, 5.0 +/- 0.2 in the resistance arteries, pulmonary branch and main pulmonary artery, respectively (n = at least 5 from 5 animals). The sensitivity to, and maximum response of, 5-HT was increased in all the arteries removed from the chronic hypoxic (CH) rats. In CH rats the pEC50 values were 5.9 +/- 0.2, 6.3 +/- 0.2, 6.4 +/- 0.2 and the increase in the maximum response was 35%, 51% and 41% in the resistance arteries, pulmonary branch and main pulmonary artery, respectively. Sumatriptan did not contract any vessel from the control rats whilst 5-CT did contract the resistance arteries. In the CH rats, however, they both contracted the resistance arteries (responses to sumatriptan were small) (pEC50: 5-CT; 5.4 +/- 0.2) and the pulmonary artery branches (pEC50: sumatriptan, 5.4 +/- 0.2; 5-CT, 5.4 +/- 0.2). 5-CT also caused a contraction in the main pulmonary artery (pEC50: 6.0 +/- 0.3). 3. Ketanserin (1 nM-1 microM) caused a competitive antagonism of the 5-HT response in all vessels tested. In control rats, the estimated pKb values for ketanserin in resistance arteries, pulmonary branches and main pulmonary

  15. HIF2α–arginase axis is essential for the development of pulmonary hypertension

    PubMed Central

    Cowburn, Andrew S.; Crosby, Alexi; Macias, David; Branco, Cristina; Colaço, Renato D. D. R.; Southwood, Mark; Toshner, Mark; Crotty Alexander, Laura E.; Morrell, Nicholas W.; Chilvers, Edwin R.; Johnson, Randall S.

    2016-01-01

    Hypoxic pulmonary vasoconstriction is correlated with pulmonary vascular remodeling. The hypoxia-inducible transcription factors (HIFs) HIF-1α and HIF-2α are known to contribute to the process of hypoxic pulmonary vascular remodeling; however, the specific role of pulmonary endothelial HIF expression in this process, and in the physiological process of vasoconstriction in response to hypoxia, remains unclear. Here we show that pulmonary endothelial HIF-2α is a critical regulator of hypoxia-induced pulmonary arterial hypertension. The rise in right ventricular systolic pressure (RVSP) normally observed following chronic hypoxic exposure was absent in mice with pulmonary endothelial HIF-2α deletion. The RVSP of mice lacking HIF-2α in pulmonary endothelium after exposure to hypoxia was not significantly different from normoxic WT mice and much lower than the RVSP values seen in WT littermate controls and mice with pulmonary endothelial deletion of HIF-1α exposed to hypoxia. Endothelial HIF-2α deletion also protected mice from hypoxia remodeling. Pulmonary endothelial deletion of arginase-1, a downstream target of HIF-2α, likewise attenuated many of the pathophysiological symptoms associated with hypoxic pulmonary hypertension. We propose a mechanism whereby chronic hypoxia enhances HIF-2α stability, which causes increased arginase expression and dysregulates normal vascular NO homeostasis. These data offer new insight into the role of pulmonary endothelial HIF-2α in regulating the pulmonary vascular response to hypoxia. PMID:27432976

  16. Pulmonary Hypertension in Elderly Patients with Diastolic Dysfunction and Preserved Ejection Fraction

    PubMed Central

    Afshar, Majid; Collado, Fareed; Doukky, Rami

    2012-01-01

    Purpose: Patients with diastolic dysfunction may have a disproportionate degree of elevation in pulmonary pressure, particularly in the elderly. Higher pulmonary vascular resistance in the elderly patients with heart failure but preserved ejection fraction suggests that beyond the post-capillary contribution of pulmonary venous congestion, a pre-capillary component of pulmonary arterial hypertension occurs. We aim to identify if pulmonary vascular resistance in elderly patients with diastolic dysfunction is disproportionately higher than patients with systolic dysfunction independent of filling pressures. Methods: 389 patients identified retrospectively between 2003- 2010; elderly with preserved ejection fraction, elderly with depressed ejection fraction, and primary arterial hypertension who underwent right-heart catheterization at Rush University. Results: No significant difference in pulmonary vascular resistance between systolic and diastolic dysfunction. The mean difference in pulmonary vascular resistance was not statistically significant at 0.40 mmHg·min/l (95% CI -3.03 to 3.83) with similar left ventricular filling pressures with mean difference of 3.38 mmHg (95% CI, -1.27 to 8.02). When adjusted for filling pressures, there remained no difference in pulmonary vascular resistance for systolic and diastolic dysfunction. The mean pulmonary vascular resistance is more elevated in systolic heart failure compared to diastolic heart failure with means 3.13 mmHg·min/l and 3.52 mmHg·min/l, respectively. Conclusion: There was no other association identified for secondary pulmonary hypertension other than diastolic dysfunction and chronic venous pulmonary hypertension. Our results argue against any significant arterial remodeling that would lead to disproportionate pre-capillary hypertension, and implies that treatment should focus on lowering filling pressure rather than treating the pulmonary vascular tree. PMID:22282715

  17. [Transition from prostacyclin to bosentan in five patients with severe pulmonary hypertension: the switch is possible].

    PubMed

    Flox Camacho, Angela; Escribano Subías, Pilar; Tello de Meneses, Rocío; Delgado Jiménez, Juan; Gómez Sánchez, Miguel A; Sáenz de la Calzada, Carlos

    2006-07-01

    Prostacyclin improves symptoms, exercise tolerance, and survival in patients with pulmonary arterial hypertension. However, the difficulty of administration (whether intravenous, subcutaneous, or by inhalation) often causes side effects that can reduce the patient's quality of life and which may sometimes be serious. Bosentan, an orally active endothelin receptor antagonist, improves functional class and exercise tolerance in these patients. We describe the successful transition from prostacyclin to bosentan in five patients with severe pulmonary arterial hypertension who suffered serious side effects with prostacyclin treatment.

  18. Pulmonary hypertensive crisis following ethanol sclerotherapy for a complex vascular malformation.

    PubMed

    Cordero-Schmidt, G; Wallenstein, M B; Ozen, M; Shah, N A; Jackson, E; Hovsepian, D M; Palma, J P

    2014-09-01

    Anhydrous ethanol is a commonly used sclerotic agent for treating vascular malformations. We describe the case of a full-term 15-day-old female with a complex venolymphatic malformation involving the face and orbit. During treatment of the lesion with ethanol sclerotherapy, she suffered acute pulmonary hypertensive crisis. We discuss the pathophysiology of pulmonary hypertension related to ethanol sclerotherapy, and propose that hemolysis plays a significant role. Recommendations for evaluation, monitoring and management of this complication are also discussed.

  19. A study of magnesium deficiency in human and experimental pulmonary hypertension.

    PubMed

    Chaumais, Marie-Camille; Lecerf, Florence; Fattal, Soly; Savale, Laurent; Günther, Sven; Huertas, Alice; Montani, David; Perros, Frederic; Humbert, Marc; German-Fattal, Michèle

    2012-03-01

    Pulmonary hypertension (PH) is defined as an increase in mean pulmonary arterial pressure above 25 mmHg. Pulmonary vasoconstriction, cellular proliferation, inflammation, and oxidative stress are involved in the pathophysiology of PH. Since hypomagnesemia was reported to promote endothelial cell dysfunction leading to inflammation and oxidative stress, we investigated the potential involvement of magnesium (Mg) deficiency in experimental and human PH. Our results indicate that Mg deficiency has no impact on hypoxia-induced PH development or severity, and that no reduction in Mg plasma concentration was observed in patients with severe pulmonary arterial hypertension. Thus, hypomagnesemia does not appear to play a role in the pathophysiology of experimental and human pulmonary hypertension. PMID:22433438

  20. Prevalence of Pulmonary Hypertension in the General Population: The Rotterdam Study

    PubMed Central

    Moreira, Eduardo M.; Gall, Henning; Leening, Maarten J. G.; Lahousse, Lies; Loth, Daan W.; Krijthe, Bouwe P.; Kiefte-de Jong, Jessica C.; Brusselle, Guy G.; Hofman, Albert; Stricker, Bruno H.; Ghofrani, Hossein A.; Franco, Oscar H.; Felix, Janine F.

    2015-01-01

    Background Pulmonary hypertension is characterized by increased pulmonary artery pressure and carries an increased mortality. Population-based studies into pulmonary hypertension are scarce and little is known about its prevalence in the general population. We aimed to describe the distribution of echocardiographically-assessed pulmonary artery systolic pressure (ePASP) in the general population, to estimate the prevalence of pulmonary hypertension, and to identify associated factors. Methods Participants (n = 3381, mean age 76.4 years, 59% women) from the Rotterdam Study, a population-based cohort, underwent echocardiography. Echocardiographic pulmonary hypertension was defined as ePASP>40 mmHg. Results Mean ePASP was 26.3 mmHg (SD 7.0). Prevalence of echocardiographic pulmonary hypertension was 2.6% (95%CI: 2.0; 3.2). Prevalence was higher in older participants compared to younger ones (8.3% in those over 85 years versus 0.8% in those between 65 and 70), and in those with underlying disorders versus those without (5.9% in subjects with COPD versus 2.3%; 9.2% in those with left ventricular systolic dysfunction versus 2.3%; 23.1% in stages 3 or 4 left ventricular diastolic dysfunction versus 1.9% in normal or stage 1). Factors independently associated with higher ePASP were older age, higher BMI, left ventricular diastolic dysfunction, COPD and systemic hypertension. Conclusion In this large population-based study, we show that pulmonary hypertension as measured by echocardiography has a low prevalence in the overall general population in the Netherlands, but estimates may be higher in specific subgroups, especially in those with underlying diseases. Increased pulmonary arterial pressure is likely to gain importance in the near future due to population aging and the accompanying prevalences of underlying disorders. PMID:26102085

  1. Automated 3D Volumetry of the Pulmonary Arteries based on Magnetic Resonance Angiography Has Potential for Predicting Pulmonary Hypertension

    PubMed Central

    Rengier, Fabian; Wörz, Stefan; Melzig, Claudius; Ley, Sebastian; Fink, Christian; Benjamin, Nicola; Partovi, Sasan; von Tengg-Kobligk, Hendrik; Rohr, Karl; Kauczor, Hans-Ulrich; Grünig, Ekkehard

    2016-01-01

    Purpose To demonstrate feasibility of automated 3D volumetry of central pulmonary arteries based on magnetic resonance angiography (MRA), to assess pulmonary artery volumes in patients with pulmonary hypertension compared to healthy controls, and to investigate the potential of the technique for predicting pulmonary hypertension. Methods MRA of pulmonary arteries was acquired at 1.5T in 20 patients with pulmonary arterial hypertension and 21 healthy normotensive controls. 3D model-based image analysis software was used for automated segmentation of main, right and left pulmonary arteries (MPA, RPA and LPA). Volumes indexed to vessel length and mean, minimum and maximum diameters along the entire vessel course were assessed and corrected for body surface area (BSA). For comparison, diameters were also manually measured on axial reconstructions and double oblique multiplanar reformations. Analyses were performed by two cardiovascular radiologists, and by one radiologist again after 6 months. Results Mean volumes of MPA, RPA and LPA for patients/controls were 5508 ± 1236/3438 ± 749, 3522 ± 934/1664 ± 468 and 3093 ± 692/1812 ± 474 μl/(cm length x m2 BSA) (all p<0.001). Mean, minimum and maximum diameters along the entire vessel course were also significantly increased in patients compared to controls (all p<0.001). Intra- and interobserver agreement were excellent for both volume and diameter measurements using 3D segmentation (intraclass correlation coefficients 0.971–0.999, p<0.001). Area under the curve for predicting pulmonary hypertension using volume was 0.998 (95% confidence interval 0.990–1.0, p<0.001), compared to 0.967 using manually measured MPA diameter (95% confidence interval 0.910–1.0, p<0.001). Conclusions Automated MRA-based 3D volumetry of central pulmonary arteries is feasible and demonstrated significantly increased volumes and diameters in patients with pulmonary arterial hypertension compared to healthy controls. Pulmonary artery

  2. Pulmonary Hypertension and Other Potentially Fatal Pulmonary Complications in Systemic Juvenile Idiopathic Arthritis

    PubMed Central

    Kimura, Yukiko; Weiss, Jennifer E.; Haroldson, Kathryn L.; Lee, Tzielan; Punaro, Marilynn; Oliveira, Sheila; Rabinovich, Egla; Riebschleger, Meredith; Antón, Jordi; Blier, Peter R.; Gerloni, Valeria; Hazen, Melissa M; Kessler, Elizabeth; Onel, Karen; Passo, Murray H; Rennebohm, Robert M; Wallace, Carol A; Woo, Patricia; Wulffraat, Nico

    2015-01-01

    Objectives Systemic Juvenile Idiopathic Arthritis (sJIA) is characterized by fevers, rash and arthritis, for which IL1 and IL6 inhibitors appear effective. Pulmonary artery hypertension (PAH), interstitial lung disease (ILD) and alveolar proteinosis (AP) have been recently reported in sJIA patients with increased frequency. Our aim was to characterize and compare these cases to a larger cohort of sJIA patients. Methods sJIA patients who developed PAH, ILD and/or AP were identified through an electronic listserv, and their demographic, sJIA and pulmonary disease characteristics, and medication exposure information were collected. These features were compared to a cohort of sJIA patients enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry. Results Patients (N=25) were significantly (p<0.05) more likely than the CARRA registry cohort (N=389) to be female, have more systemic features, and to have been exposed to an IL-1 inhibitor, tocilizumab, infliximab, corticosteroids, intravenous immunoglobulin, cyclosporine and cyclophosphamide. Eighty% were diagnosed after 2004. Twenty (80%) patients had MAS during their disease course and 15 (60%) had MAS at pulmonary diagnosis. Sixteen patients had PAH, 5 AP and 7 ILD. Seventeen (68%) patients were taking or recently (≤1 month) discontinued a biologic agent at pulmonary symptom onset; 12 (48%) were taking anti-IL1 therapy (primarily anakinra). Seventeen (68%) patients died at a mean of 8.8 months from pulmonary diagnosis. Conclusions PAH, AP and ILD are under-recognized complications of sJIA which are frequently fatal. These may be the result of severe uncontrolled systemic disease activity, and may be influenced by medication exposure. PMID:23139240

  3. A Simple Echocardiographic Prediction Rule for Hemodynamics in Pulmonary Hypertension

    PubMed Central

    Opotowsky, Alexander R.; Ojeda, Jason; Rogers, Frances; Prasanna, Vikram; Clair, Mathieu; Moko, Lilamarie; Vaidya, Anjali; Afilalo, Jonathan; Forfia, Paul R.

    2012-01-01

    Background Pulmonary hypertension (PH) has diverse causes with heterogeneous physiology compelling distinct management. Differentiating patients with primarily elevated pulmonary vascular resistance (PVR) from those with PH predominantly due to elevated left sided filling pressure is critical. Methods and Results We reviewed hemodynamics, echocardiography, and clinical data for 108 patients seen at a referral PH clinic with transthoracic echocardiogram and right heart catheterization within 1 year. We derived a simple echocardiographic prediction rule to allow hemodynamic differentiation of PH due to pulmonary vascular disease (PHPVD, defined as pulmonary artery wedge pressure (PAWP) ≤ 15mmHg and PVR >3WU). Age averaged 61.3±14.8 years, μPAWP and PVR were 16.4±7.1mmHg and 6.3±4.0WU respectively, and 52 (48.1%) patients fulfilled PHPVD hemodynamic criteria. The derived prediction rule ranged from −2 to +2 with higher scores suggesting higher probability of PHPVD: +1 point for left atrial AP dimension<3.2cm; +1 for presence of a mid-systolic notch or acceleration time<80msec; −1 for lateral mitral E:e′>10; −1 for left atrial AP dimension>4.2cm. PVR increased stepwise with score (for −2, 0 and +2, μPVR were 2.5, 4.5, and 8.1WU) while the inverse was true for PAWP (corresponding μPAWP were 21.5, 16.5 and 10.4mmHg). Among subjects with complete data, the score had an AUC of 0.921 for PHPVD. A score ≥ 0 had 100% sensitivity and 69.3% positive predictive value for PHPVD, with 62.3% specificity. No patients with a negative score had PHPVD. Patients with a negative score and acceleration time >100msec had normal PVR (μPVR=1.8WU, range=0.7–3.2WU). Conclusions We present a simple echocardiographic prediction rule that accurately defines PH hemodynamics facilitates improved screening and focused clinical investigation for PH diagnosis and management. PMID:22914595

  4. Isorhynchophylline protects against pulmonary arterial hypertension and suppresses PASMCs proliferation

    SciTech Connect

    Guo, Haipeng; Zhang, Xin; Cui, Yuqian; Deng, Wei; Xu, Dachun; Han, Hui; Wang, Hao; Chen, Yuguo; Li, Yu; Wu, Dawei

    2014-07-18

    Highlights: • We focus on PASMCs proliferation in the pathogenesis of PAH. • Isorhynchophylline inhibited PASMCs proliferation and alleviated PAH. • IRN blocked PDGF-Rβ phosphorylation and its downstream signal transduction. • IRN regulated cyclins and CDKs to arrest cell cycle in the G0/G1 phase. • We reported IRN has the potential to be a candidate for PAH treatment. - Abstract: Increased pulmonary arterial smooth muscle cells (PASMCs) proliferation is a key pathophysiological component of pulmonary vascular remodeling in pulmonary arterial hypertension (PAH). Isorhynchophylline (IRN) is a tetracyclic oxindole alkaloid isolated from the Chinese herbal medicine Uncaria rhynchophylla. It has long been used clinically for treatment of cardiovascular and cerebrovascular diseases. However, very little is known about whether IRN can influence the development of PAH. Here we examined the effect of IRN on monocrotaline (MCT) induced PAH in rats. Our data demonstrated that IRN prevented MCT induced PAH in rats, as assessed by right ventricular (RV) pressure, the weight ratio of RV to (left ventricular + septum) and RV hypertrophy. IRN significantly attenuated the percentage of fully muscularized small arterioles, the medial wall thickness, and the expression of smooth muscle α-actin (α-SMA) and proliferating cell nuclear antigen (PCNA). In vitro studies, IRN concentration-dependently inhibited the platelet-derived growth factor (PDGF)-BB-induced proliferation of PASMCs. Fluorescence-activated cell-sorting analysis showed that IRN caused G0/G1 phase cell cycle arrest. IRN-induced growth inhibition was associated with downregulation of Cyclin D1 and CDK6 as well as an increase in p27Kip1 levels in PDGF-BB-stimulated PASMCs. Moreover, IRN negatively modulated PDGF-BB-induced phosphorylation of PDGF-Rβ, ERK1/2, Akt/GSK3β, and signal transducers and activators of transcription 3 (STAT3). These results demonstrate that IRN could inhibit PASMCs proliferation and

  5. Transforming growth factor-beta 1 is decreased in remodeling hypertensive bovine pulmonary arteries.

    PubMed Central

    Botney, M D; Parks, W C; Crouch, E C; Stenmark, K; Mecham, R P

    1992-01-01

    The development of pulmonary hypertension in hypoxic newborn calves is associated with a complex pattern of increased tropoelastin and type I procollagen synthesis and deposition by smooth muscle cells in large elastic pulmonary arteries compared to normoxic controls. We examined the possibility that transforming growth factor-beta 1 (TGF-beta 1) may be associated with the production of extracellular matrix protein in this model of pulmonary hypertension. Medial smooth muscle cells in both normotensive and hypertensive vessels, as assessed by immunohistochemistry, were the major source of TGF-beta 1. Staining was confined to foci of smooth muscle cells in the outer media and appeared greater in normotensive than hypertensive vessels. Consistent with the immunohistochemistry, a progressive, age-dependent increase in normotensive pulmonary artery TGF-beta 1 mRNA was observed after birth, whereas TGF-beta 1 mRNA remained at low, basal levels in hypertensive, remodeling pulmonary arteries. These observations suggest that local expression of TGF-beta 1 is not associated with increased extracellular matrix protein synthesis in this model of hypoxic pulmonary hypertension. Images PMID:1569202

  6. The A2B adenosine receptor modulates pulmonary hypertension associated with interstitial lung disease.

    PubMed

    Karmouty-Quintana, Harry; Zhong, Hongyan; Acero, Luis; Weng, Tingting; Melicoff, Ernestina; West, James D; Hemnes, Anna; Grenz, Almut; Eltzschig, Holger K; Blackwell, Timothy S; Xia, Yang; Johnston, Richard A; Zeng, Dewan; Belardinelli, Luiz; Blackburn, Michael R

    2012-06-01

    Development of pulmonary hypertension is a common and deadly complication of interstitial lung disease. Little is known regarding the cellular and molecular mechanisms that lead to pulmonary hypertension in patients with interstitial lung disease, and effective treatment options are lacking. The purpose of this study was to examine the adenosine 2B receptor (A(2B)R) as a regulator of vascular remodeling and pulmonary hypertension secondary to pulmonary fibrosis. To accomplish this, cellular and molecular changes in vascular remodeling were monitored in mice exposed to bleomycin in conjunction with genetic removal of the A(2B)R or treatment with the A(2B)R antagonist GS-6201. Results demonstrated that GS-6201 treatment or genetic removal of the A(2B)R attenuated vascular remodeling and hypertension in our model. Furthermore, direct A(2B)R activation on vascular cells promoted interleukin-6 and endothelin-1 release. These studies identify a novel mechanism of disease progression to pulmonary hypertension and support the development of A(2B)R antagonists for the treatment of pulmonary hypertension secondary to interstitial lung disease.

  7. World Health Organization Pulmonary Hypertension group 2: pulmonary hypertension due to left heart disease in the adult--a summary statement from the Pulmonary Hypertension Council of the International Society for Heart and Lung Transplantation.

    PubMed

    Fang, James C; DeMarco, Teresa; Givertz, Michael M; Borlaug, Barry A; Lewis, Gregory D; Rame, J Eduardo; Gomberg-Maitland, Mardi; Murali, Srinivas; Frantz, Robert P; McGlothlin, Dana; Horn, Evelyn M; Benza, Raymond L

    2012-09-01

    Pulmonary hypertension associated with left heart disease is the most common form of pulmonary hypertension encountered in clinical practice today. Although frequently a target of therapy, its pathophysiology remains poorly understood and its treatment remains undefined. Pulmonary hypertension in the context of left heart disease is a marker of worse prognosis and disease severity, but whether its primary treatment is beneficial or harmful is unknown. An important step to the future study of this important clinical problem will be to standardize definitions across disciplines to facilitate an evidence base that is interpretable and applicable to clinical practice. In this current statement, we provide an extensive review and interpretation of the current available literature to guide current practice and future investigation. At the request of the Pulmonary Hypertension (PH) Council of the International Society for Heart and Lung Transplantation (ISHLT), a writing group was assembled and tasked to put forth this document as described above. The review process was facilitated through the peer review process of the Journal of Heart and Lung Transplantation and ultimately endorsed by the leadership of the ISHLT PH Council. PMID:22884380

  8. Sodium hydrosulfide prevents hypoxia-induced pulmonary arterial hypertension in broilers.

    PubMed

    Yang, Y; Zhang, B K; Liu, D; Nie, W; Yuan, J M; Wang, Z; Guo, Y M

    2012-01-01

    1. The aim of the study was to determine if H(2)S is involved in the development of hypoxia-induced pulmonary hypertension in broilers, a condition frequently observed in a variety of cardiac and pulmonary diseases. 2. Two-week-old broilers were reared under normoxic conditions or exposed to normobaric hypoxia (6 h/day) with tissue levels of H(2)S adjusted by administering sodium hydrosulfide (NaHS, 10 µmol/kg body weight/day). Mean pulmonary arterial pressure, right ventricular mass, plasma and tissue H(2)S levels, the expression of cystathionine-β-synthase (CSE) and vascular remodeling were determined at 35 d of age. 3. Exposure to hypoxia-induced pulmonary arterial hypertension was characterized by elevated pulmonary pressure, right ventricular hypertrophy and vascular remodeling. This was accompanied by decreased expression of CSE and decreased concentrations of plasma and tissue H(2)S. 4. Hypoxia-induced pulmonary hypertension was significantly reduced by administration of NaHS but this protective effect was largely abolished by D, L-propargylglycerine, an inhibitor of CSE. 5. The results indicate that H(2)S is involved in the development of hypoxia-induced pulmonary hypertension. Supplementing NaHS or H(2)S could be a strategy for reducing hypoxia-induced hypertension in broilers.

  9. Estrogens and development of pulmonary hypertension - Interaction of estradiol metabolism and pulmonary vascular disease

    PubMed Central

    Tofovic, Stevan P.

    2010-01-01

    Severe pulmonary arterial hypertension (PAH) is characterized by clustered proliferation of endothelial cells in the lumina of small size pulmonary arteries resulting in concentric obliteration of the lumina and formation of complex vascular structures known as plexiform lesions. This debilitating disease occurs more frequently in women, yet both animal studies in classical models of PAH and limited clinical data suggest protective effects of estrogens: the estrogen paradox in pulmonary hypertension. Little is known about the role of estrogens in PAH, but one line of evidence strongly suggests that the vascular protective effects of 17β-estradiol (estradiol; E2) are mediated largely by its downstream metabolites. Estradiol is metabolized to 2-hydroxyestradiol (2HE) by CYP1A1/CYP1B1, and 2HE is converted to 2-methoxyestradiol (2ME) by catechol-O-methyl transferase. 2ME is extensively metabolized to 2-methoxyestrone, a metabolite that lacks biologic activity but which may be converted back to 2ME. 2ME has no estrogenic activity and its effects are mediated by estrogen receptors-independent mechanism(s). Notably, in systemic and pulmonary vascular endothelial cells, smooth muscle cells, and fibroblasts 2ME exerts stronger anti-mitotic effects than E2 itself. E2 and 2ME, despite having similar effects on other cardiovascular cells, have opposing effects on endothelial cells; that is, in endothelial cells, E2 is pro-mitogenic, pro-angiogenic and anti- apoptotic, whereas 2ME is antimitogenic, anti-angiogenic and pro-apoptotic. This may have significant ramifications in severe PAH that involves uncontrolled proliferation of monoclonal, apoptosis resistant endothelial cells. Based on its cellular effects, 2ME should be expected to attenuate the progression of disease and provide protection in severe PAH. In contrast, E2, due to its mitogenic, angiogenic, and anti-apoptotic effects (otherwise desirable in normal, quiescent endothelial cells), may even adversely affect

  10. Chronic thromboembolic pulmonary arterial hypertension: a review of the literature and novel therapeutic approaches.

    PubMed

    Androulakis, Emmanuel; Lioudaki, Eirini; Christophides, Theodoros; Ahmad, Mahmood; Fayed, Hossam; Laskar, Nabila; Schreiber, Benjamin

    2015-06-01

    Chronic thromboembolic pulmonary hypertension is defined as pulmonary hypertension (PH) caused by single or recurrent pulmonary emboli and is characterized by chronic obstruction of the pulmonary arteries leading to increased vascular resistance and PH. Also, progressive remodeling may occur in occluded and nonoccluded territories. Better understanding of the underlying mechanisms and risk factors could improve diagnosis and allow appropriate interventions. Pulmonary endarterectomy is an established approach and is considered the definitive treatment for chronic PH, resulting from thromboembolic disease. Furthermore, percutaneous transluminal pulmonary angioplasty is technically feasible, especially for those with peripheral-type of the disease. In addition, several agents, including prostanoids, endothelin receptor antagonists and phosphodiesterase type-5 inhibitors, have been tested in selected patients yielding promising results. Several novel agents are under investigation, and extensive research is currently in progress aiming to resolve uncertainties in the understanding and treatment of the disease.

  11. Rescue Treatment with L-Citrulline Inhibits Hypoxia-Induced Pulmonary Hypertension in Newborn Pigs

    PubMed Central

    Dikalova, Anna; Kaplowitz, Mark R.; Cunningham, Gary; Summar, Marshall; Aschner, Judy L.

    2015-01-01

    Infants with cardiopulmonary disorders associated with hypoxia develop pulmonary hypertension. We previously showed that initiation of oral L-citrulline before and continued throughout hypoxic exposure improves nitric oxide (NO) production and ameliorates pulmonary hypertension in newborn piglets. Rescue treatments, initiated after the onset of pulmonary hypertension, better approximate clinical strategies. Mechanisms by which L-citrulline improves NO production merit elucidation. The objective of this study was to determine whether starting L-citrulline after the onset of pulmonary hypertension inhibits disease progression and improves NO production by recoupling endothelial NO synthase (eNOS). Hypoxic and normoxic (control) piglets were studied. Some hypoxic piglets received oral L-citrulline starting on Day 3 of hypoxia and continuing throughout the remaining 7 days of hypoxic exposure. Catheters were placed for hemodynamic measurements, and pulmonary arteries were dissected to assess NO production and eNOS dimer-to-monomer ratios (a measure of eNOS coupling). Pulmonary vascular resistance was lower in L-citrulline–treated hypoxic piglets than in untreated hypoxic piglets but was higher than in normoxic controls. NO production and eNOS dimer-to-monomer ratios were greater in pulmonary arteries from L-citrulline–treated than from untreated hypoxic animals but were lower than in normoxic controls. When started after disease onset, oral L-citrulline treatment improves NO production by recoupling eNOS and inhibits the further development of chronic hypoxia–induced pulmonary hypertension in newborn piglets. Oral L-citrulline may be a novel strategy to halt or reverse pulmonary hypertension in infants suffering from cardiopulmonary conditions associated with hypoxia. PMID:25536367

  12. Updated Evidence-Based Treatment Algorithm in Pulmonary Arterial Hypertension

    PubMed Central

    Barst, Robyn J.; Gibbs, J. Simon; Ghofrani, Hossein A.; Hoeper, Marius M.; McLaughlin, Vallerie V.; Rubin, Lewis J.; Sitbon, Olivier; Tapson, Victor; Galiè, Nazzareno

    2009-01-01

    Uncontrolled and controlled clinical trials with different compounds and procedures are reviewed to define the risk-benefit profiles for therapeutic options in pulmonary arterial hypertension (PAH). A grading system for the level of evidence of treatments based on the controlled clinical trials performed with each compound is used to propose an evidence-based treatment algorithm. The algorithm includes drugs approved by regulatory agencies for the treatment of PAH and/or drugs available for other indications. The different treatments have been evaluated mainly in idiopathic PAH, heritable PAH, and in PAH associated with the scleroderma spectrum of diseases or with anorexigen use. Extrapolation of these recommendations to other PAH subgroups should be done with caution. Oral anticoagulation is proposed for most patients; diuretic treatment and supplemental oxygen are indicated in cases of fluid retention and hypoxemia, respectively. High doses of calcium channel blockers are indicated only in the minority of patients who respond to acute vasoreactivity testing. Nonresponders to acute vasoreactivity testing, or responders who remain in World Health Organization (WHO) functional class III, should be considered candidates for treatment with either an oral phosphodiesterase-5 inhibitor or an oral endothelin-receptor antagonist. Continuous intravenous administration of epoprostenol remains the treatment of choice in WHO functional class IV patients. Combination therapy is recommended for patients treated with PAH monotherapy who remain in New York Heart Association functional class III. Atrial septostomy and lung transplantation are indicated for refractory patients or where medical treatment is unavailable. PMID:19555861

  13. Development of macitentan for the treatment of pulmonary arterial hypertension.

    PubMed

    Selej, Mona; Romero, Alain J; Channick, Richard N; Clozel, Martine

    2015-11-01

    Pulmonary arterial hypertension (PAH) is a serious, chronic condition that, without early recognition and treatment, leads to progressive right heart failure and death. The dual endothelin receptor antagonist macitentan was designed through a deliberate discovery process to maximize endothelin-axis blockade while improving adverse-effect profiles compared with previous compounds. Macitentan's efficacy was demonstrated in an event-driven morbidity and mortality study of treatment-naive and background PAH therapy-treated symptomatic patients. Compared to placebo, 10 mg of macitentan significantly reduced the relative risk of morbidity and mortality by 45%, primarily by delaying PAH worsening, most prominently in World Health Organization (WHO) functional class II and III PAH patients. Macitentan reduced the incidence of the composite end point of PAH-related hospitalizations and mortality and improved WHO FC and exercise capacity (6-min walk distance). Furthermore, it significantly improved cardiopulmonary hemodynamics and quality of life, and had a favorable safety and tolerability profile. To date, this was the largest and longest prospective trial for PAH. Macitentan, currently the only approved oral PAH treatment shown to be safe and effective in delaying long-term progression and reducing PAH-related hospitalizations, has changed treatment paradigms from goal-directed to long-term outcome-oriented therapy.

  14. Epoprostenol sodium for treatment of pulmonary arterial hypertension

    PubMed Central

    Saito, Yukihiro; Nakamura, Kazufumi; Akagi, Satoshi; Sarashina, Toshihiro; Ejiri, Kentaro; Miura, Aya; Ogawa, Aiko; Matsubara, Hiromi; Ito, Hiroshi

    2015-01-01

    The release of endogenous prostacyclin (PGI2) is depressed in patients with pulmonary arterial hypertension (PAH). PGI2 replacement therapy by epoprostenol infusion is one of the best treatments available for PAH. Here, we provide an overview of the current clinical data for epoprostenol. Epoprostenol treatment improves symptoms, exercise capacity, and hemodynamics, and is the only treatment that has been shown to reduce mortality in patients with idiopathic PAH (IPAH) in randomized clinical trials. We have reported that high-dose epoprostenol therapy (>40 ng/kg/min) also results in marked hemodynamic improvement in some patients with IPAH. High-dose epoprostenol has a pro-apoptotic effect on PAH-PASMCs via the IP receptor and upregulation of Fas ligand (FasL) in vitro. However, long-term intravenous administration of epoprostenol is sometimes associated with catheter-related infections and leads to considerable inconvenience for the patient. In the future, the development of new routes of administration or the development of powerful PGI2 analogs, IP-receptor agonists, and gene and cell-based therapy enhancing PGI2 production with new routes of administration is required. PMID:25999730

  15. The molecular targets of approved treatments for pulmonary arterial hypertension

    PubMed Central

    Humbert, Marc; Ghofrani, Hossein-Ardeschir

    2016-01-01

    Until recently, three classes of medical therapy were available for the treatment of pulmonary arterial hypertension (PAH)—prostanoids, endothelin receptor antagonists and phosphodiesterase type 5 (PDE5) inhibitors. With the approval of the soluble guanylate cyclase stimulator riociguat, an additional drug class has become available targeting a distinct molecular target in the same pathway as PDE5 inhibitors. Treatment recommendations currently include the use of all four drug classes to treat PAH, but there is a lack of comparative data for these therapies. Therefore, an understanding of the mechanistic differences between these agents is critical when making treatment decisions. Combination therapy is often used to treat PAH and it is therefore important that physicians understand how the modes of action of these drugs may interact to work as complementary partners, or potentially with unwanted consequences. Furthermore, different patient phenotypes mean that patients respond differently to treatment; while a certain monotherapy may be adequate for some patients, for others it will be important to consider alternating or combining compounds with different molecular targets. This review describes how the four currently approved drug classes target the complex pathobiology of PAH and will consider the distinct target molecules of each drug class, their modes of action, and review the pivotal clinical trial data supporting their use. It will also discuss the rationale for combining drugs (or not) from the different classes, and review the clinical data from studies on combination therapy. PMID:26219978

  16. The Characteristics of Treated Pulmonary Arterial Hypertension Patients in Ontario

    PubMed Central

    Vaid, Haris M.; Camacho, Ximena; Granton, John T.; Mamdani, Muhammad M.; Yao, Zhan; Singh, Samantha; Juurlink, David N.; Gomes, Tara

    2016-01-01

    Background. There are no Canadian prevalence studies on pulmonary arterial hypertension (PAH) to date. We described the characteristics of treated PAH patients and the healthcare utilization and costs associated with PAH in a population of public drug plan beneficiaries in Ontario, Canada. Methods. A retrospective cross-sectional analysis was conducted between April 2010 and March 2011 to identify treated PAH patients using population-based health administrative databases. We investigated demographic and clinical characteristics of treated PAH patients and conducted a cohort study to determine treatment patterns, healthcare utilization, and associated costs, over a one-year follow-up period (March 2012). Results. We identified 326 treated PAH cases in Ontario's publicly funded drug plan. Overall mean age was 59.4 years (±20.3 years) and over 77% of cases were women (n = 251). Combination therapy was used to treat 22.9% (n = 69) of cases, costing an average of $4,569 (SD $1,544) per month. Median monthly healthcare costs were $264 (IQR $96–$747) for those who survived and $2,021 (IQR $993–$6,399) for those who died over a one-year period, respectively (p < 0.01). Conclusions. PAH care in Ontario is complex and has high healthcare costs. This data may help guide towards improved patient management. PMID:27445555

  17. Redox biology in pulmonary arterial hypertension (2013 Grover Conference Series)

    PubMed Central

    2015-01-01

    Abstract Through detailed interrogation of the molecular pathways that contribute to the development of pulmonary arterial hypertension (PAH), the separate but related processes of oxidative stress and cellular metabolic dysfunction have emerged as being critical pathogenic mechanisms that are as yet relatively untargeted therapeutically. In this review, we have attempted to summarize some of the important existing studies, to point out areas of overlap between oxidative stress and metabolic dysfunction, and to do so under the unifying heading of redox biology. We discuss the importance of precision in assessing oxidant signaling versus oxidant injury and why this distinction matters. We endeavor to advance the discussion of carbon-substrate metabolism beyond a focus on glucose and its fate in the cell to encompass other carbon substrates and some of the murkiness surrounding our understanding of how they are handled in different cell types. Finally, we try to bring these ideas together at the level of the mitochondrion and to point out some additional points of possible cognitive dissonance that warrant further experimental probing. The body of beautiful science regarding the molecular and cellular details of redox biology in PAH points to a future that includes clinically useful therapies that target these pathways. To fully realize the potential of these future interventions, we hope that some of the issues raised in this review can be addressed proactively. PMID:26697167

  18. Redox biology in pulmonary arterial hypertension (2013 Grover Conference Series).

    PubMed

    Fessel, Joshua P; West, James D

    2015-12-01

    Through detailed interrogation of the molecular pathways that contribute to the development of pulmonary arterial hypertension (PAH), the separate but related processes of oxidative stress and cellular metabolic dysfunction have emerged as being critical pathogenic mechanisms that are as yet relatively untargeted therapeutically. In this review, we have attempted to summarize some of the important existing studies, to point out areas of overlap between oxidative stress and metabolic dysfunction, and to do so under the unifying heading of redox biology. We discuss the importance of precision in assessing oxidant signaling versus oxidant injury and why this distinction matters. We endeavor to advance the discussion of carbon-substrate metabolism beyond a focus on glucose and its fate in the cell to encompass other carbon substrates and some of the murkiness surrounding our understanding of how they are handled in different cell types. Finally, we try to bring these ideas together at the level of the mitochondrion and to point out some additional points of possible cognitive dissonance that warrant further experimental probing. The body of beautiful science regarding the molecular and cellular details of redox biology in PAH points to a future that includes clinically useful therapies that target these pathways. To fully realize the potential of these future interventions, we hope that some of the issues raised in this review can be addressed proactively.

  19. Pulmonary Hypertension Can Be a Sequela of Prior Pneumocystis Pneumonia

    PubMed Central

    Swain, Steve D.; Han, Soo; Harmsen, Ann; Shampeny, Katie; Harmsen, Allen G.

    2007-01-01

    Improved treatment regimens have reduced fatalities from opportunistic diseases, such as Pneumocystis pneumonia, in AIDS patients. However, serious chronic conditions, including pulmonary hypertension (PH), are increasing in this group. We report here that when CD4 T cells in Pneumocystis-infected mice are temporally depleted and then allowed to return, the extended inflammation results in PH that persists after Pneumocystis is eliminated. Using this model of PH, we have found that i) the onset of PH is correlated with the return of CD4 T cells, but PH persists after CD4 levels diminish; ii) vascular remodeling accompanies PH, but whereas temporary medial hypertrophy is evident with transient PH in immunocompetent mice, persistent PH is associated with perivascular fibrosis; iii) elevated levels of the fibrotic mediator FIZZ1 are found in bronchoalveolar lavage fluid of mice with persistent PH; and iv) although Th2-related mechanisms may be involved in PH etiology, PH still occurs in interleukin-4 receptor-deficient mice under these conditions. Overall, the data presented here demonstrate that the immune response to an infectious disease pathogen, such as Pneumocystis, can, when perturbed and prolonged, lead to later development of a serious chronic condition such as PH. PMID:17640969

  20. Pharmacologic Therapy for Pulmonary Arterial Hypertension in Adults

    PubMed Central

    Taichman, Darren B.; Chung, Lorinda; Klinger, James R.; Lewis, Sandra; Mandel, Jess; Palevsky, Harold I.; Rich, Stuart; Sood, Namita; Rosenzweig, Erika B.; Trow, Terence K.; Yung, Rex; Elliott, C. Gregory; Badesch, David B.

    2014-01-01

    OBJECTIVE: Choices of pharmacologic therapies for pulmonary arterial hypertension (PAH) are ideally guided by high-level evidence. The objective of this guideline is to provide clinicians advice regarding pharmacologic therapy for adult patients with PAH as informed by available evidence. METHODS: This guideline was based on systematic reviews of English language evidence published between 1990 and November 2013, identified using the MEDLINE and Cochrane Library databases. The strength of available evidence was graded using the Grades of Recommendations, Assessment, Development, and Evaluation methodology. Guideline recommendations, or consensus statements when available evidence was insufficient to support recommendations, were developed using a modified Delphi technique to achieve consensus. RESULTS: Available evidence is limited in its ability to support high-level recommendations. Therefore, we drafted consensus statements to address many clinical questions regarding pharmacotherapy for patients with PAH. A total of 79 recommendations or consensus statements were adopted and graded. CONCLUSIONS: Clinical decisions regarding pharmacotherapy for PAH should be guided by high-level recommendations when sufficient evidence is available. Absent higher level evidence, consensus statements based upon available information must be used. Further studies are needed to address the gaps in available knowledge regarding optimal pharmacotherapy for PAH. PMID:24937180

  1. The Characteristics of Treated Pulmonary Arterial Hypertension Patients in Ontario.

    PubMed

    Vaid, Haris M; Camacho, Ximena; Granton, John T; Mamdani, Muhammad M; Yao, Zhan; Singh, Samantha; Juurlink, David N; Gomes, Tara

    2016-01-01

    Background. There are no Canadian prevalence studies on pulmonary arterial hypertension (PAH) to date. We described the characteristics of treated PAH patients and the healthcare utilization and costs associated with PAH in a population of public drug plan beneficiaries in Ontario, Canada. Methods. A retrospective cross-sectional analysis was conducted between April 2010 and March 2011 to identify treated PAH patients using population-based health administrative databases. We investigated demographic and clinical characteristics of treated PAH patients and conducted a cohort study to determine treatment patterns, healthcare utilization, and associated costs, over a one-year follow-up period (March 2012). Results. We identified 326 treated PAH cases in Ontario's publicly funded drug plan. Overall mean age was 59.4 years (±20.3 years) and over 77% of cases were women (n = 251). Combination therapy was used to treat 22.9% (n = 69) of cases, costing an average of $4,569 (SD $1,544) per month. Median monthly healthcare costs were $264 (IQR $96-$747) for those who survived and $2,021 (IQR $993-$6,399) for those who died over a one-year period, respectively (p < 0.01). Conclusions. PAH care in Ontario is complex and has high healthcare costs. This data may help guide towards improved patient management. PMID:27445555

  2. Initial dual oral combination therapy in pulmonary arterial hypertension.

    PubMed

    Sitbon, Olivier; Sattler, Caroline; Bertoletti, Laurent; Savale, Laurent; Cottin, Vincent; Jaïs, Xavier; De Groote, Pascal; Chaouat, Ari; Chabannes, Céline; Bergot, Emmanuel; Bouvaist, Hélène; Dauphin, Claire; Bourdin, Arnaud; Bauer, Fabrice; Montani, David; Humbert, Marc; Simonneau, Gérald

    2016-06-01

    Treatment for pulmonary arterial hypertension (PAH) has been underpinned by single-agent therapy to which concomitant drugs are added sequentially when pre-defined treatment goals are not met.This retrospective analysis of real-world clinical data in 97 patients with newly diagnosed PAH (86% in New York Heart Association functional class III-IV) explored initial dual oral combination treatment with bosentan plus sildenafil (n=61), bosentan plus tadalafil (n=17), ambrisentan plus tadalafil (n=11) or ambrisentan plus sildenafil (n=8).All regimens were associated with significant improvements in functional class, exercise capacity, dyspnoea and haemodynamic indices after 4 months of therapy. Over a median follow-up period of 30 months, 75 (82%) patients were still alive, 53 (71%) of whom received only dual oral combination therapy. Overall survival rates were 97%, 94% and 83% at 1, 2 and 3 years, respectively, and 96%, 94% and 84%, respectively, for the patients with idiopathic PAH, heritable PAH and anorexigen-induced PAH. Expected survival rates calculated from the French equation for the latter were 86%, 75% and 66% at 1, 2 and 3 years, respectively.Initial combination of oral PAH-targeted medications may offer clinical benefits, especially in PAH patients with severe haemodynamic impairment. PMID:26989105

  3. Clinical and molecular genetic features of hereditary pulmonary arterial hypertension.

    PubMed

    Brenner, Laura; Chung, Wendy K

    2011-10-01

    Pulmonary arterial hypertension (PAH) is a rare disorder that may be hereditary (HPAH), idiopathic (IPAH), or associated with either drug-toxin exposures or other medical conditions. Familial cases have long been recognised and are usually due to mutations in the bone morphogenetic protein receptor type 2 gene (BMPR2), or, much less commonly, two other members of the transforming growth factor-β superfamily, activin-like kinase-type 1 (ALK1), and endoglin (ENG), which are associated with hereditary hemorrhagic telangiectasia. In addition, approximately 20% of patients with IPAH carry mutations in BMPR2. Clinical testing for BMPR2 mutations is available and may be offered to HPAH and IPAH patients but should be preceded by genetic counselling, since lifetime penetrance is only 10% to 20%, and there are currently no known effective preventative measures. Identification of a familial mutation can be valuable in reproductive planning and identifying family members who are not mutation carriers and thus will not require lifelong surveillance. With advances in genomic technology and with international collaborative efforts, genome-wide association studies will be conducted to identify additional genes for HPAH, genetic modifiers for BMPR2 penetrance, and genetic susceptibility to IPAH. In addition, collaborative studies of BMPR2 mutation carriers should enable identification of environmental modifiers, biomarkers for disease development and progression, and surrogate markers for efficacy end points in clinical drug development, thereby providing an invaluable resource for trials of PAH prevention.

  4. Pulmonary arterial hypertension in idiopathic inflammatory myopathies: Data from the French pulmonary hypertension registry and review of the literature.

    PubMed

    Sanges, Sébastien; Yelnik, Cécile M; Sitbon, Olivier; Benveniste, Olivier; Mariampillai, Kuberaka; Phillips-Houlbracq, Mathilde; Pison, Christophe; Deligny, Christophe; Inamo, Jocelyn; Cottin, Vincent; Mouthon, Luc; Launay, David; Lambert, Marc; Hatron, Pierre-Yves; Rottat, Laurence; Humbert, Marc; Hachulla, Eric

    2016-09-01

    Occurrence of pulmonary arterial hypertension (PAH) in idiopathic inflammatory myopathies (IIMs) without extensive interstitial lung disease (ILD) has rarely been described in the medical literature. This study aimed to report all cases with association of PAH and IIM in the French Pulmonary Hypertension (PH) Registry, to identify IIM features associated with the presence of PAH, and to describe treatment modalities of these patients.All cases of IIM-PAH were retrieved from the French PH Registry, which gathers PH patients prospectively enrolled by 27 referral hospital centers across France. Patients were excluded if they had an extensive ILD or overlap syndrome. Characteristics of IIM-PAH patients were compared with a control group of IIM patients without PH.Among the 5223 PH patients in the Registry, 34 had a diagnosis of IIM. Among them, 3 IIM-PAH patients (2 females and 1 male) had no evidence of extensive ILD or overlap syndrome, and were included in this study. In these 3 patients, dermatomyositis (DM) was the only identified IIM. One patient had autoantibodies classically associated with IIM (anti-Ku). PAH had always developed after IIM onset, was severe in all cases, and led to a marked functional impairment.By pooling our cases with 6 patients previously reported in the literature, and comparing them with a control cohort of 35 IIM patients without PH, we identify several IIM characteristics possibly associated with PAH occurrence, including DM subtype (78% vs 46%; P = 0.02), skin involvement (P = 0.04), anti-SSA antibodies (P = 0.05), and peripheral microangiopathy (P = 0.06).Overall, IIM-PAH patients were managed by corticosteroids and/or immunosuppressants, either alone or combined with PAH therapy. Patients did not seem to respond to IIM treatment alone.Our study reports for the first time the rare but possible association of PAH and IIM in a large prospective PH Registry. In that setting, PAH seems associated with DM, skin involvement, peripheral

  5. Pulmonary arterial hypertension in idiopathic inflammatory myopathies: Data from the French pulmonary hypertension registry and review of the literature.

    PubMed

    Sanges, Sébastien; Yelnik, Cécile M; Sitbon, Olivier; Benveniste, Olivier; Mariampillai, Kuberaka; Phillips-Houlbracq, Mathilde; Pison, Christophe; Deligny, Christophe; Inamo, Jocelyn; Cottin, Vincent; Mouthon, Luc; Launay, David; Lambert, Marc; Hatron, Pierre-Yves; Rottat, Laurence; Humbert, Marc; Hachulla, Eric

    2016-09-01

    Occurrence of pulmonary arterial hypertension (PAH) in idiopathic inflammatory myopathies (IIMs) without extensive interstitial lung disease (ILD) has rarely been described in the medical literature. This study aimed to report all cases with association of PAH and IIM in the French Pulmonary Hypertension (PH) Registry, to identify IIM features associated with the presence of PAH, and to describe treatment modalities of these patients.All cases of IIM-PAH were retrieved from the French PH Registry, which gathers PH patients prospectively enrolled by 27 referral hospital centers across France. Patients were excluded if they had an extensive ILD or overlap syndrome. Characteristics of IIM-PAH patients were compared with a control group of IIM patients without PH.Among the 5223 PH patients in the Registry, 34 had a diagnosis of IIM. Among them, 3 IIM-PAH patients (2 females and 1 male) had no evidence of extensive ILD or overlap syndrome, and were included in this study. In these 3 patients, dermatomyositis (DM) was the only identified IIM. One patient had autoantibodies classically associated with IIM (anti-Ku). PAH had always developed after IIM onset, was severe in all cases, and led to a marked functional impairment.By pooling our cases with 6 patients previously reported in the literature, and comparing them with a control cohort of 35 IIM patients without PH, we identify several IIM characteristics possibly associated with PAH occurrence, including DM subtype (78% vs 46%; P = 0.02), skin involvement (P = 0.04), anti-SSA antibodies (P = 0.05), and peripheral microangiopathy (P = 0.06).Overall, IIM-PAH patients were managed by corticosteroids and/or immunosuppressants, either alone or combined with PAH therapy. Patients did not seem to respond to IIM treatment alone.Our study reports for the first time the rare but possible association of PAH and IIM in a large prospective PH Registry. In that setting, PAH seems associated with DM, skin involvement, peripheral

  6. Dynamic blood flow and wall shear stress in pulmonary hypertensive disease.

    PubMed

    Postles, Arthur; Clark, Alys R; Tawhai, Merryn H

    2014-01-01

    This study provides new model of pulsatile flow in the pulmonary circulation in health and pulmonary hypertensive disease. Structural vascular remodeling typical of pulmonary hypertensive disease was implemented in the model by progressively altering the mechanical properties of the arterial geometry and progressively increasing the inlet pulse pressure (PP). The transmission of PP throughout the tree was shown to increase in advanced stages of disease, creating the potential for a `vicious-cycle' of damage to vasculature. Wall shear stress (WSS) was shown to be highest in the terminal arteries of the model and increased significantly with disease. A further trend observed in WSS results was that high WSS values began to `climb' the arterial tree towards the proximal vessels as disease progressed. This suggests a link between WSS and distal remodeling in pulmonary hypertensive disease, which initiates in the small muscular arteries and arterioles and spreads into larger arteries as the disease progresses. PMID:25571282

  7. [The role of cardiopulmonary exercise testing in the assessment of pulmonary hypertension].

    PubMed

    Dumitrescu, D; Rosenkranz, S

    2008-10-01

    Cardiopulmonary exercise testing (CPET) is an important diagnostic instrument for early detection, differential diagnosis and follow-up evaluation in pulmonary hypertension (PH). A pulmonary vasculopathy as the underlying cause for pulmonary arterial hypertension (PAH) can be detected in early stages by measuring gas exchange during exercise. There are characteristic patterns which are typically seen in patients with PAH. Regarding follow-up assessments, CPET can quantify cardiopulmonary exercise capacity in a more differentiated way than global exercise tests like the 6-minute walking distance. Different pathophysiological mechanisms accounting for pulmonary hypertension can be separately evaluated by CPET. Although tremendous progress has been made regarding sensor technology and data processing, CPET is still a method that is technically challenging. In order to obtain reliable results, strict quality control is of crucial importance. Additionally, standardization of result display, independent of equipment manufacturers or institutions, is desirable, in order to ensure a uniform interpretation of results. PMID:18814090

  8. [Anesthetic Management for Non-cardiac Surgery in a Patient with Severe Pulmonary Arterial Hypertension].

    PubMed

    Ohno, Sho; Niiyama, Yukitoshi; Murouchi, Takeshi; Yamakage, Michiaki

    2016-05-01

    Severe pulmonary arterial hypertension is a significant risk factor for anesthetic management in patients undergoing even non-cardiac surgery. A 64-year-old female patient with severe pulmonary arterial hypertension was scheduled to undergo inguinal hernioplasty. Preoperative systolic pulmonary arterial pressure was 115 mmHg. We selected monitored anesthesia care with 0.2-0.5 μg x kg(-1) x hr(-1) dexmedetomidine and ultrasound-guided iliohypogastric block. Thereafter, LiDCOrapid was used to acquire the hemodynamic responses during surgery. Continuous iliohypogastric block produced postoperative pain relief and the supplemental analgesic was not needed. The monitored anesthesia care by dexmedetomidine and ultrasound guided continuous iliohypogastric block would be a safe procedure for patients with severe pulmonary arterial hypertension undergoing non-cardiac surgery. LiDCO rapid could be low invasive and useful as a hemodaynamic monitor in such a case. PMID:27319099

  9. Chlorogenic acid inhibits hypoxia-induced pulmonary artery smooth muscle cells proliferation via c-Src and Shc/Grb2/ERK2 signaling pathway.

    PubMed

    Li, Qun-Yi; Zhu, Ying-Feng; Zhang, Meng; Chen, Li; Zhang, Zhen; Du, Yong-Li; Ren, Guo-Qiang; Tang, Jian-Min; Zhong, Ming-Kang; Shi, Xiao-Jin

    2015-03-15

    Chlorogenic acid (CGA), abundant in coffee and particular fruits, can modulate hypertension and vascular dysfunction. Hypoxia-induced pulmonary artery smooth muscle cells (PASMCs) proliferation has been tightly linked to vascular remodeling in pulmonary arterial hypertension (PAH). Thus, the present study was designed to investigate the effect of CGA on hypoxia-induced proliferation in cultured rat PASMCs. The data showed that CGA potently inhibited PASMCs proliferation and DNA synthesis induced by hypoxia. These inhibitory effects were associated with G1 cell cycle arrest and down-regulation of cell cycle proteins. Treatment with CGA reduced hypoxia-induced hypoxia inducible factor 1α (HIF-1α) expression and trans-activation. Furthermore, hypoxia-evoked c-Src phosphorylation was inhibited by CGA. In vitro ELISA-based tyrosine kinase assay indicated that CGA was a direct inhibitor of c-Src. Moreover, CGA attenuated physical co-association of c-Src/Shc/Grb2 and ERK2 phosphorylation in PASMCs. These results suggest that CGA inhibits hypoxia-induced proliferation in PASMCs via regulating c-Src-mediated signaling pathway. In vivo investigation showed that chronic CGA treatment inhibits monocrotaline-induced PAH in rats. These findings presented here highlight the possible therapeutic use of CGA in hypoxia-related PAH. PMID:25666384

  10. A case of sinus venosus atrial septal defect misdiagnosed as primary pulmonary hypertension.

    PubMed

    Sharma, Awadhesh Kr; Nath, Ranjit Kumar; Pandit, Neeraj

    2016-01-01

    We present a case of sinus venosus atrial septal defect in a patient who was previously diagnosed as having primary pulmonary hypertension in a tertiary care center. Our findings are based on 2-dimensional trans-thoracic echocardiography, chest X-ray and surface electrocardiogram. A 26-year-old man, previously diagnosed as a case of primary pulmonary hypertension, presented to the emergency department (ED) with chest pain and breathlessness on exertion. Cardiac biomarkers were within their normal ranges. Surface electrocardiogram showed right atrial and ventricular overload with right axis deviation. Chest imaging noted enlarged central pulmonary vascularity with bilateral plethoric lung fields. Trans-thoracic echocardiography showed a dilated right atria and ventricle with severe tricuspid regurgitation and severe pulmonary artery hypertension with an intact atrial septum. Surprisingly, the transoesophageal echocardiogram revealed the presence of a sinus venous superior vena cava-type atrial septal defect with the right pulmonary vein draining into the right atria. In this full-text version, we present a more detailed discussion of sinus-venous atrial septal defect associated with partial anomalous pulmonary venous return that was wrongly diagnosed as a case of primary pulmonary hypertension in a tertiary care center. PMID:27445029

  11. The effect of exercise training on the pulmonary arterial system in patients with pulmonary hypertension.

    PubMed

    Arena, Ross; Cahalin, Lawrence P; Borghi-Silva, Audrey; Myers, Jonathan

    2015-01-01

    Given the unique and clinically ominous pathology associated with pulmonary arterial (PA) hypertension (PH) and its implications for the eventual deterioration of right ventricular function, exercise training (ET) was historically not recommended. More recently, a body of literature demonstrating the safety and efficacy of ET in PH has emerged. The primary focus of this review is to provide a synopsis of current evidence assessing the effects of ET on the PA system in patients with PH. The current body of evidence is relatively small and it is not clear if ET improves PA function or vessel characteristics. Nevertheless, studies have consistently found ET leads to numerous clinically relevant benefits including increased: 1) aerobic capacity, 2) muscle strength, 3) exercise tolerance, and 4) quality of life. Thus, ET, given its clinical benefits, is likely to enjoy increased utilization in patients with PH.

  12. Oestradiol ameliorates monocrotaline pulmonary hypertension via NO, prostacyclin and endothelin-1 pathways.

    PubMed

    Yuan, Ping; Wu, Wen-Hui; Gao, Lan; Zheng, Ze-Qi; Liu, Dong; Mei, Han-Ying; Zhang, Zhuo-Li; Jing, Zhi-Cheng

    2013-05-01

    Pulmonary hypertension continues to be a serious clinical problem with high mortality. As oestrogen is a potential vasodilator of the pulmonary circulation, this study examined the mechanisms by which 17β-oestradiol improves monocrotaline (MCT)-induced pulmonary hypertension. Female Sprague-Dawley rats underwent bilateral ovariectomy or sham operations. The rats received MCT (50 mg·kg(-1)) and were treated with 17β-oestradiol (1 mg·kg(-1) per day) for either 5 weeks or only from week 4 to week 5. Plasma 17β-oestradiol concentrations were decreased in sham-operated, MCT-treated rats when compared with sham-operated rats (17.7 ± 4.7 versus 50.3 ± 15.4 pg·mL(-1); p=0.029). The 17β-oestradiol anabolic enzyme cytochrome P450 (CYP)-19 was decreased by MCT treatment, while the catabolic enzymes CYP-1A1 and -1B1 were increased. Ovariectomised and MCT-treated rats had more severe pulmonary hypertension. 17β-oestradiol suppressed pulmonary arterial smooth muscle cell proliferation and macrophage infiltration, and enhanced apoptosis by increasing nitric oxide (NO) and prostacyclin (prostaglandin (PG)I2) levels and reducing endothelin (ET)-1 levels. Phosphoinositide-3-kinase (PI3K) and Akt phosphorylations were markedly increased, but were inhibited by 17β-oestradiol treatment in rats with pulmonary hypertension. Oestrogen deficiency may aggravate development of pulmonary hypertension. 17β-oestradiol improved pulmonary hypertension via activation of the PI3K/Akt pathway to regulate NO, PGI2 and ET-1 expression.

  13. [Vasodilation effects of prostaglandin E1 in patients with precapillary pulmonary hypertension].

    PubMed

    Munclinger, M; Kautzner, J; Serf, B

    1990-04-01

    Prostaglandin E1. (Prostavasin, Schwarz, FRG) was administered in a short-term infusion, 5-30 ng/kg/min., to five patients with precapillary pulmonary hypertension associated with lung disease. Significant pulmonary vasodilatation characterized by a drop of the median pressure in the pulmonary artery by 15% and of the pulmonary vascular resistance by 31% was achieved only in two patients. The authors observed a minimal incidence of side-effects; systemic hypotension observed in three patients was an undesirable manifestaútion. Prostaglandin E1 extends possibilities of a vasodilatating influence on precapillary pulmonary hypertension in lung disease. With regard to the different individual reactivity of patients it should be administered in this indication only under conditions of haemodynamic monitoring.

  14. Chronic Thromboembolic Pulmonary Hypertension and Assessment of Right Ventricular Function in the Piglet.

    PubMed

    Noly, Pierre-Emmanuel; Guihaire, Julien; Coblence, Matthieu; Dorfmüller, Peter; Fadel, Elie; Mercier, Olaf

    2015-11-04

    An original piglet model of Chronic Thromboembolic Pulmonary Hypertension (CTEPH) associated with chronic Right Ventricular (RV) dysfunction is described. Pulmonary Hypertension (PH) was induced in 3-week-old piglets by a progressive obstruction of the pulmonary vascular bed. A ligation of the left Pulmonary Artery (PA) was performed first through a mini-thoracotomy. Second, weekly embolizations of the right lower pulmonary lobe were done under fluoroscopic guidance with n-butyl-2-cyanoacrylate during 5 weeks. Mean Pulmonary Arterial Pressure (mPAP) measured by ritght heart catheterism, increased progressively, as well as Right Atrial pressure and Pulmonary Vascular Resistances (PVR) after 5 weeks compared to sham animals. Right Ventricular (RV) structural and functional remodeling were assessed by transthoracic echocardiography (RV diameters, RV wall thickness, RV systolic function). RV elastance and RV-pulmonary coupling were assessed by Pressure-Volume Loops (PVL) analysis with conductance method. Histologic study of the lung and the right ventricle were also performed. Molecular analyses on RV fresh tissues could be performed through repeated transcutaneous endomyocardial biopsies. Pulmonary microvascular disease in obstructed and unobstructed territories was studied from lung biopsies using molecular analyses and pathology. Furthermore, the reliability and the reproducibility was associated with a range of PH severity in animals. Most aspects of the human CTEPH disease were reproduced in this model, which allows new perspectives for the understanding of the underlying mechanisms (mitochondria, inflammation) and new therapeutic approaches (targeted, cellular or gene therapies) of the overloaded right ventricle but also pulmonary microvascular disease.

  15. Selective endothelin-A receptor blockade attenuates endotoxin-induced pulmonary hypertension and pulmonary vascular dysfunction

    PubMed Central

    2014-01-01

    Abstract Endothelin-1 is a potent mediator of sepsis-induced pulmonary hypertension (PH). The pulmonary vascular effects of selective blockade of endothelin receptor subtype A (ETAR) during endotoxemia remain unknown. We hypothesized that selective ETAR antagonism attenuates endotoxin-induced PH and improves pulmonary artery (PA) vasoreactivity. Adult male Sprague-Dawley rats (250–450 g) received lipopolysaccharide (LPS; Salmonella typhimurium; 20 mg/kg intraperitoneally) or vehicle 6 hours before hemodynamic assessment and tissue harvest. The selective ETAR antagonist sitaxsentan (10 or 20 mg/kg) or vehicle was injected intravenously 3 hours after receipt of LPS. Right ventricular systolic pressure, mean arterial pressure (MAP), cardiac output (CO), oxygenation (P/F ratio), and serum bicarbonate were measured. Bronchoalveolar lavage (BAL) cell differential and lung wet-to-dry ratios were obtained. Endothelium-dependent and endothelium-independent vasorelaxations were determined in isolated PA rings. PA interleukin (IL)-1β, IL-6, tumor necrosis factor α (TNF-α), and inducible nitric oxide synthase (iNOS) messenger RNA (mRNA) were measured. LPS caused PH, decreased MAP, CO, and serum bicarbonate, and increased PA IL-1β, IL-6, TNF-α, and iNOS mRNA. Sitaxsentan attenuated sepsis-induced PH and increased MAP. The P/F ratio, CO, serum bicarbonate, and BAL neutrophilia were not affected by sitaxsentan. In isolated PA rings, while not affecting phenylephrine-induced vasocontraction or endothelium-dependent relaxation, sitaxsentan dose-dependently attenuated LPS-induced alterations in endothelium-independent relaxation. PA cytokine mRNA levels were not significantly attenuated by ETAR blockade. We conclude that ETAR blockade attenuates endotoxin-induced alterations in systemic and PA pressures without negatively affecting oxygenation. This protective effect appears to be mediated not by attenuation of sepsis-induced cardiac dysfunction, acidosis, or alveolar

  16. Efficacy of cardiac rehabilitation after balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension

    PubMed Central

    Fukui, Shigefumi; Ogo, Takeshi; Takaki, Hiroshi; Ueda, Jin; Tsuji, Akihiro; Morita, Yoshiaki; Kumasaka, Reon; Arakawa, Tetsuo; Nakanishi, Michio; Fukuda, Tetsuya; Yasuda, Satoshi; Ogawa, Hisao; Nakanishi, Norifumi; Goto, Yoichi

    2016-01-01

    Objective To determine safety and efficacy of cardiac rehabilitation (CR) initiated immediately following balloon pulmonary angioplasty (BPA) in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) who presented with continuing exercise intolerance and symptoms on effort even after a course of BPA; 2–8 sessions/patient. Methods Forty-one consecutive patients with inoperable CTEPH who underwent their final BPA with improved resting mean pulmonary arterial pressure of 24.7±5.5 mm Hg and who suffered remaining exercise intolerance were prospectively studied. Participants were divided into two groups just after the final BPA (6.8±2.3 days): patients with (CR group, n=17) or without (non-CR group, n=24) participation in a 12-week CR of 1-week inhospital training followed by an 11-week outpatient programme. Cardiopulmonary exercise testing, haemodynamics, and quality of life (QOL) were assessed before and after CR. Results No significant between-group differences were found for any baseline characteristics. At week 12, peak oxygen uptake (VO2), per cent predicted peak VO2 (70.7±9.4% to 78.2±12.8%, p<0.01), peak workload, and oxygen pulse significantly improved in the CR group compared with the non-CR group, with a tendency towards improvement in mental health-related QOL. Quadriceps strength and heart failure (HF) symptoms (WHO functional class, 2.2–1.8, p=0.01) significantly improved within the CR group. During the CR, no patient experienced adverse events or deterioration of right-sided HF or haemodynamics as confirmed via catheterisation. Conclusions The combination of BPA and subsequent CR is a new treatment strategy for inoperable CTEPH to improve exercise capacity to near-normal levels and HF symptoms, with a good safety profile. PMID:27220694

  17. IGF-1 signaling in neonatal hypoxia-induced pulmonary hypertension: Role of epigenetic regulation.

    PubMed

    Yang, Qiwei; Sun, Miranda; Ramchandran, Ramaswamy; Raj, J Usha

    2015-10-01

    Pulmonary hypertension is a fatal disease characterized by a progressive increase in pulmonary artery pressure accompanied by pulmonary vascular remodeling and increased vasomotor tone. Although some biological pathways have been identified in neonatal hypoxia-induced pulmonary hypertension (PH), little is known regarding the role of growth factors in the pathogenesis of PH in neonates. In this study, using a model of hypoxia-induced PH in neonatal mice, we demonstrate that the growth factor insulin-like growth factor-1 (IGF-1), a potent activator of the AKT signaling pathway, is involved in neonatal PH. After exposure to hypoxia, IGF-1 signaling is activated in pulmonary endothelial and smooth muscle cells in vitro, and the IGF-1 downstream signal pAKT(S473) is upregulated in lungs of neonatal mice. We found that IGF-1 regulates ET-1 expression in pulmonary endothelial cells and that IGF-1 expression is regulated by histone deacetylases (HDACs). In addition, there is a differential cytosine methylation site in the IGF-1 promoter region in response to neonatal hypoxia. Moreover, inhibition of HDACs with apicidin decreases neonatal hypoxia-induced global DNA methylation levels in lungs and specific cytosine methylation levels around the pulmonary IGF-1 promoter region. Finally, HDAC inhibition with apicidin reduces chronic hypoxia-induced activation of IGF-1/pAKT signaling in lungs and attenuates right ventricular hypertrophy and pulmonary vascular remodeling. Taken together, we conclude that IGF-1, which is epigenetically regulated, is involved in the pathogenesis of pulmonary hypertension in neonatal mice. This study implicates a novel HDAC/IGF-1 epigenetic pathway in the regulation of hypoxia-induced PH and warrants further study of the role of IGF-1 in neonatal pulmonary hypertensive disease. PMID:25921925

  18. Equivalent Dipole Vector Analysis for Detecting Pulmonary Hypertension

    NASA Technical Reports Server (NTRS)

    Harlander, Matevz; Salobir, Barbara; Toplisek, Janez; Schlegel, Todd T.; Starc, Vito

    2010-01-01

    Various 12-lead ECG criteria have been established to detect right ventricular hypertrophy as a marker of pulmonary hypertension (PH). While some criteria offer good specificity they lack sensitivity because of a low prevalence of positive findings in the PH population. We hypothesized that three-dimensional equivalent dipole (ED) model could serve as a better detection tool of PH. We enrolled: 1) 17 patients (12 female, 5 male, mean age 57 years, range 19-79 years) with echocardiographically detected PH (systolic pulmonary arterial pressure greater than 35 mmHg) and no significant left ventricular disease; and 2) 19 healthy controls (7 female, 12 male, mean age 44, range 31-53 years) with no known heart disease. In each subject we recorded a 5-minute high-resolution 12-lead conventional ECG and constructed principal signals using singular value decomposition. Assuming a standard thorax dimension of an adult person with homogenous and isotropic distribution of thorax conductance, we determined moving equivalent dipoles (ED), characterized by the 3D location in the thorax, dipolar strength and the spatial orientation, in time intervals of 5 ms. We used the sum of all ED vectors in the second half of the QRS complex to derive the amplitude of the right-sided ED vector (RV), if the orientation of ED was to the right side of the thorax, and in the first half the QRS to derive the amplitude of the left-sided vector (LV), if the orientation was leftward. Finally, the parameter RV/LV ratio was determined over an average of 256 complexes. The groups differed in age and gender to some extent. There was a non-significant trend toward higher RV in patients with PH (438 units 284) than in controls (280 plus or minus 140) (p = 0.066) but the overlap was such that RV alone was not a good predictor of PH. On the other hand, the RV/LV ratio was a better predictor of PH, with 11/17 (64.7%) of PH patients but only in 1/19 (5.3%) control subjects having RV/LV ratio greater than or

  19. Mechanisms of hypoxic pulmonary vasoconstriction and their roles in pulmonary hypertension: new findings for an old problem

    PubMed Central

    Ward, Jeremy P.T.; McMurtry, Ivan F.

    2009-01-01

    Hypoxic pulmonary vasoconstriction (HPV) normally optimises ventilation-perfusion matching in the lung, but leads to pulmonary hypertension under conditions of global hypoxia. The past few years have provided some major advances in our understanding of this complex phenomenon, but significant controversy remains concerning many of the key underlying mechanisms. On balance, recent evidence is most consistent with an elevation in mitochondria-derived reactive oxygen species as a key event for initiation of HPV, with consequent Ca2+ release from intracellular ryanodine-sensitive stores, although the activation pathways and molecular identity of the associated Ca2+ entry pathways remain unclear. Recent studies have also raised our perception of the critical role played by Rho kinase in both sustained HPV and the development of pulmonary hypertension, further promoting Rho kinase and the pathways regulating its activity and expression as important therapeutic targets. PMID:19297247

  20. Novel biomarkers for risk stratification in pulmonary arterial hypertension

    PubMed Central

    Zelniker, Thomas; Uhlmann, Lorenz; Spaich, Sebastian; Friedrich, Jörg; Preusch, Michael R.; Meyer, Franz J.; Katus, Hugo A.

    2015-01-01

    Risk stratification in pulmonary arterial hypertension (PAH) is paramount to identifying individuals at highest risk of death. So far, there are only limited parameters for prognostication in patients with PAH. 95 patients with confirmed PAH were included in the present analysis and followed for a total of 4 years. Blood samples were analysed for serum levels of N-terminal pro-brain natriuretic peptide, high-sensitivity troponin T (hsTnT), pro-atrial natriuretic peptide (proANP), growth differentiation factor 15, soluble fms-like tyrosine kinase 1 and placental growth factor. 27 (28.4%) patients died during a follow-up of 4 years. Levels of all tested biomarkers, except for placental growth factor, were significantly elevated in nonsurvivors compared with survivors. Receiver operating characteristic analyses demonstrated that cardiac biomarkers had the highest power in predicting mortality. In particular, proANP exhibited the highest area under the curve, followed by N-terminal pro-brain natriuretic peptide and hsTnT. Furthermore, proANP and hsTnT added significant additive prognostic value to the established markers in categorical and continuous net reclassification index. Moreover, after Cox regression, proANP (hazard ratio (HR) 1.91), hsTnT (HR 1.41), echocardiographic right ventricular impairment (HR 1.30) and 6-min walk test (HR 0.97 per 10 m) remained the only significant parameters in prognostication of mortality. Our data suggest benefits of the implementation of proANP and hsTnT as additive biomarkers for risk stratification in patients with PAH.

  1. The heart and pulmonary arterial hypertension in systemic sclerosis.

    PubMed

    Vandecasteele, Els H; De Pauw, Michel; Brusselle, Guy; Decuman, Saskia; Piette, Yves; De Keyser, Filip; Smith, V

    2016-02-01

    Systemic sclerosis (SSc) is an autoimmune connective tissue disease characterized by vasculopathy and progressive fibrosis of the skin and visceral organs (gastrointestinal tract, heart, kidneys and lungs). Although the prevalence is low, SSc is a disease with high morbidity and mortality. Since pulmonary arterial hypertension (PAH) associated with SSc (SSc-PAH) and clinically evident cardiac involvement is associated with increased mortality, the cardiac complications and PAH in SSc are reviewed. Both diffuse cutaneous (DcSSc) and limited cutaneous (LcSSc) subgroups are at risk for cardiac involvement and SSc-PAH. Cardiac involvement can be divided in pericardial involvement, myocardial involvement and rhythm disturbances and mostly occurs asymptomatically. However, when symptomatic, it is associated with a poor prognosis. Screening for asymptomatic cardiac involvement should be considered in SSc in order to initiate treatment in an early stage. However, there are no randomized controlled trials on treatment options for cardiac involvement in SSc. SSc-PAH is a devastating complication of SSc, which can develop early in DcSSc and LcSSc. Screening for PAH should be performed since screening leads to earlier diagnosis and earlier treatment is associated with a better prognosis. Today, screening is performed by clinical judgement and echocardiography. Recently the DETECT algorithm, a 2-step screening algorithm is proposed in a SSc-subgroup at increased risk for PAH, but further validation is needed. Despite current treatment options with prostacyclins, endothelin-1 receptor antagonists and phosphodiesterase type-5 inhibitors, mortality remains high. Several promising new treatment options for PAH are evaluated in phase II and III clinical trials. PMID:27075793

  2. Phase I safety study of ranolazine in pulmonary arterial hypertension

    PubMed Central

    Schilz, Robert; Mediratta, Anuj; Addetia, Karima; Coslet, Sandra; Thomeas, Vasiliki; Gillies, Hunter; Oudiz, Ronald J.

    2015-01-01

    Abstract Pulmonary arterial hypertension (PAH) causes right ventricular ischemia, dysfunction, and failure. PAH patients may benefit from antianginal agents based on a shared pathophysiology with left ventricular ischemia. A single-center, randomized, placebo-controlled trial (1∶1) to assess the acute vasoreactivity and safety of ranolazine in PAH was conducted. Plasma samples for pharmacokinetic (PK) studies were drawn during hemodynamic measurements at 0, 60, 90, 120, 240, and 360 minutes from a Swan-Ganz catheter. All patients received 500-mg doses, uptitrated to 1,000 mg at week 4, monthly evaluations, and a complete objective assessment after 12 weeks, followed by an open-label extension. Thirteen patients were randomized and 12 enrolled (6 ranolazine, 6 placebo). All patients completed the acute phase; 10 completed the 12-week study. There were no acute changes in invasive hemodynamics. At 12 weeks ranolazine was well tolerated. Only 1 of the 5 patients on ranolazine had a serum concentration considered to be in the therapeutic range. Two serious adverse events required early withdrawal (both in the ranolazine group); gastrointestinal complaints were the most common adverse event. Efficacy measures did not demonstrate any differences between treatment groups. During the open-label trial, 2 additional patients reached a therapeutic concentration. Ranolazine in PAH appears safe, without acute hemodynamic effects after a 500-mg dose. Ranolazine administrated to PAH patients receiving background PAH therapies did not consistently reach therapeutic levels. Future studies should first perform PK analysis in PAH patients receiving PAH therapies and explore the safety and tolerability of the higher doses perhaps necessary to achieve therapeutic levels in PAH patients. (Trial registration: Clinicaltrials.gov identifier NCT01757808.) PMID:26697176

  3. Bisoprolol in idiopathic pulmonary arterial hypertension: an explorative study.

    PubMed

    van Campen, Jasmijn S J A; de Boer, Karin; van de Veerdonk, Mariëlle C; van der Bruggen, Cathelijne E E; Allaart, Cor P; Raijmakers, Pieter G; Heymans, Martijn W; Marcus, J Tim; Harms, Hendrik J; Handoko, M Louis; de Man, Frances S; Vonk Noordegraaf, Anton; Bogaard, Harm-Jan

    2016-09-01

    While beta-blockers are considered contraindicated in pulmonary arterial hypertension (PAH), the prognostic significance of sympathetic nervous system over-activity suggests a potential benefit of beta-blocker therapy. The aim of this randomised, placebo-controlled, crossover, single centre study was to determine the effects of bisoprolol on right ventricular ejection fraction (RVEF) in idiopathic PAH (iPAH) patients. Additional efficacy and safety parameters were explored.Patients with optimally treated, stable iPAH (New York Heart Association functional class II/III) were randomised to placebo or bisoprolol. Imaging and functional measurements were performed at baseline, crossover and end of study.18 iPAH patients were included, because inclusion faltered before enrolment of the targeted 25 patients. 17 patients completed 6 months of bisoprolol, 15 tolerated bisoprolol, one patient required intravenous diuretics. Bisoprolol was associated with a lower heart rate (17 beats per minute, p=0.0001) but RVEF remained unchanged. A drop in cardiac index (0.5 L·min(-1)·m(-2), p=0.015) was observed, along with a trend towards a decreased 6-min walking distance (6MWD).Although careful up-titration of bisoprolol was tolerated by most patients and resulted in a decreased heart rate, no benefit of bisoprolol in iPAH was demonstrated. Decreases in cardiac index and 6MWD suggest a deteriorated cardiac function. The results do not favour the use of bisoprolol in iPAH patients. PMID:27390285

  4. Pulmonary arterial hypertension among Filipino patients with connective tissue diseases.

    PubMed

    Santos Estrella, Paul V; Lin, Yih Chang; Navarra, Sandra V

    2007-01-01

    We describe the clinical features, therapies, and clinical course of pulmonary arterial hypertension (PAH) in a group of Filipinos with connective tissue diseases (CTDs). We retrospectively reviewed the records of patients diagnosed with PAH by a two-dimensional echocardiogram as a tricuspid regurgitant jet of more than 25 mmHg. All patients had underlying CTDs, defined by the American College of Rheumatology criteria, and were seen at the rheumatology clinics of the University of Santo Tomas Hospital and the St. Luke's Medical Center, Philippines. Of the 33 patients (32 women) included in the analysis, there were 14 patients with systemic lupus erythematosus (SLE), 12 with scleroderma, 5 with mixed connective tissue disease (MCTD), 1 with primary antiphospholipid syndrome (APS), and 1 with dermatomyositis. The average age at PAH diagnosis was 38 +/- 14 years (mean +/- SD), and the mean duration of illness from CTD to PAH diagnosis was 53 +/- 52 months. Twelve patients had died at the time of this report, with a median duration of 15 months (range 1-57 months) from PAH diagnosis to mortality: six of these had scleroderma, five with SLE, and one with APS. The following therapies were used in this group of patients: low molecular weight heparin, warfarin, calcium-channel blockers, aspirin, cyclophosphamide, bosentan, iloprost, and sildenafil. We have described the clinical profile of PAH in a group of Filipino patients with CTDs, most commonly SLE. Various forms of pharmacologic therapies were used among these patients. Mortality remains high, particularly among those with underlying scleroderma. Early recognition and treatment are crucial in order to provide a better outcome for these patients.

  5. Mesenchymal Stromal Cells Expressing Heme Oxygenase-1 Reverse Pulmonary Hypertension

    PubMed Central

    Liang, Olin D.; Mitsialis, S. Alex; Chang, Mun Seog; Vergadi, Eleni; Lee, Changjin; Aslam, Muhammad; Fernandez-Gonzalez, Angeles; Liu, Xianlan; Baveja, Rajiv; Kourembanas, Stella

    2012-01-01

    Pulmonary arterial hypertension (PAH) remains a serious disease, and, while current treatments may prolong and improve quality of life, search for novel and effective therapies is warranted. Using genetically-modified mouse lines, we tested the ability of bone marrow-derived stromal cells (MSCs), to treat chronic hypoxia-induced PAH. Recipient mice were exposed for five weeks to normobaric hypoxia (8%–10% O2), MSC preparations were delivered through jugular vein injection and their effect on PAH was assessed after two additional weeks in hypoxia. Donor MSCs derived from wild-type (WT) mice or Heme Oxygenase-1 (HO-1) null mice (Hmox1KO) conferred partial protection from PAH when transplanted into WT or Hmox1KO recipients, whereas treatment with MSCs isolated from transgenic mice harboring a human HO-1 transgene under the control of surfactant protein C promoter (SHO1 line) reversed established disease in WT recipients. SH01-MSC treatment of Hmox1KO animals, which develop right ventricular (RV) infarction under prolonged hypoxia, resulted in normal RV systolic pressure, significant reduction of RV hypertrophy and prevention of RV infarction. Donor MSCs isolated from a bitransgenic mouse line with doxycycline-inducible, lung-specific expression of HO-1 exhibited similar therapeutic efficacy only upon doxycycline treatment of the recipients. In vitro experiments indicate that potential mechanisms of MSC action include modulation of hypoxia-induced lung inflammation and inhibition of smooth muscle cell proliferation. Cumulative, our results demonstrate that MSCs ameliorate chronic hypoxia – induced PAH and their efficacy is highly augmented by lung-specific HO-1 expression in the transplanted cells, suggesting an interplay between HO-1 dependent and HO-1 independent protective pathways. PMID:20957739

  6. Serotonin 2B Receptor Antagonism Prevents Heritable Pulmonary Arterial Hypertension

    PubMed Central

    Schroer, Alison K.; Chen, Peter; Ryzhova, Larisa M.; Gladson, Santhi; Shay, Sheila; Hutcheson, Joshua D.; Merryman, W. David

    2016-01-01

    Serotonergic anorexigens are the primary pharmacologic risk factor associated with pulmonary arterial hypertension (PAH), and the resulting PAH is clinically indistinguishable from the heritable form of disease, associated with BMPR2 mutations. Both BMPR2 mutation and agonists to the serotonin receptor HTR2B have been shown to cause activation of SRC tyrosine kinase; conversely, antagonists to HTR2B inhibit SRC trafficking and downstream function. To test the hypothesis that a HTR2B antagonist can prevent BMRP2 mutation induced PAH by restricting aberrant SRC trafficking and downstream activity, we exposed BMPR2 mutant mice, which spontaneously develop PAH, to a HTR2B antagonist, SB204741, to block the SRC activation caused by BMPR2 mutation. SB204741 prevented the development of PAH in BMPR2 mutant mice, reduced recruitment of inflammatory cells to their lungs, and reduced muscularization of their blood vessels. By atomic force microscopy, we determined that BMPR2 mutant mice normally had a doubling of vessel stiffness, which was substantially normalized by HTR2B inhibition. SB204741 reduced SRC phosphorylation and downstream activity in BMPR2 mutant mice. Gene expression arrays indicate that the primary changes were in cytoskeletal and muscle contractility genes. These results were confirmed by gel contraction assays showing that HTR2B inhibition nearly normalizes the 400% increase in gel contraction normally seen in BMPR2 mutant smooth muscle cells. Heritable PAH results from increased SRC activation, cellular contraction, and vascular resistance, but antagonism of HTR2B prevents SRC phosphorylation, downstream activity, and PAH in BMPR2 mutant mice. PMID:26863209

  7. Effect of aerosolized milrinone during drug-induced pulmonary hypertension in lambs.

    PubMed

    Gelvez, Javier; Fakioglu, Harun; Olarte, Jose L; Soliz, Amed; Totapally, Balagangadhar R; Torbati, Dan

    2004-07-01

    We tested whether aerosolized milrinone in lambs selectively reduces drug-induced acute pulmonary hypertension without reducing the mean systemic blood pressure (MSBP). Seven, 2-3-week-old lambs were anesthetized (50 mg/kg ketamine), paralyzed (0.1 mg/kg vecuronium bromide) and mechanically ventilated. A femoral artery, pulmonary artery, and jugular vein were catheterized for continuous monitoring of MSBP, mean pulmonary artery pressure, periodic gas-exchange analyses, and determination of cardiac output by thermodilution technique. An Airlife Misty nebulizer was used in a dry state to establish a stable baseline of an inspired fraction of oxygen (FiO(2)) at 0.21. Acute pulmonary hypertension with hypoxemia was then induced by increasing the mean pulmonary artery pressure up to 30-35% of the MSBP using 2-6 microg/kg/min of Thromboxane A(2) mimetic (U-46619), intravenously. The lambs were then subjected to 15 min of saline nebulization without milrinone followed by 30 min saline nebulization with a relatively high concentration of milrinone (10 mg/ml, total dose of 40 mg). Aerosolized milrinone had no effect on systemic or pulmonary artery pressure during combined acute pulmonary hypertension and hypoxemia. We speculate that our nebulization procedures failed to deliver sufficient amount of milrinone for producing a detectable hemodynamic effect. PMID:15082033

  8. High-altitude pulmonary hypertension: a pathophysiological entity to different diseases.

    PubMed

    Maggiorini, M; Léon-Velarde, F

    2003-12-01

    Pulmonary hypertension is a hallmark of high-altitude pulmonary oedema (HAPE) and of congestive right heart failure in subacute mountain sickness (SMS) and chronic mountain sickness (CMS) in the Himalayas and in the end-stage of CMS (Monge's disease) in the Andes. There are studies to suggest that transmission of excessively elevated pulmonary artery pressure and/or flow to the pulmonary capillaries leading to alveolar haemorrhage is the pathophysiological mechanism of HAPE. In the Himalayas, HAPE was successfully prevented by extending the acclimatisation period from a few days to 5 weeks, however, this did not prevent the occurrence of congestive right heart failure after several weeks of stay at 6,000 m. This leads to the concept that rapid remodelling of the small precapillary arteries prevents HAPE but not the development of right heart failure in SMS and CMS. Unresponsiveness of pulmonary hypertension to oxygen at high altitude and its complete resolution only after weeks of stay at low altitude suggest that structural rather than functional changes are its pathophysiological mechanism. Since pulmonary hypertension at high altitude is the driving force leading to high-altitude pulmonary oedema and "high-altitude right heart failure" in newcomers and residents of high altitude, the authors propose to adjust current terminology accordingly.

  9. Impairment of pulmonary vascular reserve and right ventricular systolic reserve in pulmonary arterial hypertension

    PubMed Central

    2014-01-01

    Background Exercise capacity is impaired in pulmonary arterial hypertension (PAH). We hypothesized that cardiovascular reserve abnormalities would be associated with impaired hemodynamic response to pharmacological stress and worse outcome in PAH. Methods Eighteen PAH patients (p) group 1 NYHA class II/III and ten controls underwent simultaneous right cardiac catheterization and intravascular ultrasound at rest and during low dose-dobutamine (10 mcg/kg/min) with trendelenburg (DST). We estimated cardiac output (CO), pulmonary vascular resistance (PVR) and capacitance (PC), and PA elastic modulus (EM). We concomitantly measured tricuspid annular plane systolic excursion (TAPSE), RV myocardial peak systolic velocity (Sm) and isovolumic myocardial acceleration (IVA) in PAH patients. Based on the rounded mean + 2 SD of the increase in mPAP in our healthy control group during DST (2.8 + 1.8 mm Hg), PAH p were divided into two groups according to mean PA pressure (mPAP) response during DST, 1: ΔmPAP > 5 mm Hg and 2: ΔmPAP ≤ 5 mm Hg. Cardiovascular reserve was estimated as the change (delta, Δ) during DST compared with rest, including ΔmPAP with respect to ΔCO (ΔmPAP/ΔCO). All patients were prospectively followed up for 2 years. Results PAH p showed significant lower heart rate and CO increase than controls during DST, with a significant mPAP and pulse PAP increase and higher ΔmPAP/ΔCO (p < 0.05). Neither hemodynamic, IVUS and echocardiographic data were different between both PAH groups at rest. In group 1, DST caused a higher ΔEM, ΔmPAP/ΔCO, ΔPVR, and ΔTAPSE than group 2, with a lower IVA increase and a negative ΔSV (p < 0.05). TAPSE correlated with mPAP and RVP (p < 0.05) and, IVA and Sm correlated with CO (p < 0.05). ΔEM correlated with ΔmPAP and ΔIVA with ΔCO (p < 0.05). There were two deaths/pulmonary transplantations in group 1 and one death in group 2 during the follow-up (p > 0.05). Conclusions

  10. AMBITION: An important piece in the therapeutic puzzle of pulmonary arterial hypertension

    PubMed Central

    Said, Karim

    2015-01-01

    It is believed that simultaneous targeting of two or more of the three pathogenic pathways of pulmonary arterial hypertension (the endothelin, nitric oxide, and prostacyclin pathways) is associated with additive or synergistic effects with subsequent increasing efficacy and improving outcomes. However, there is lack of evidence to guide the use of combination strategy among pulmonary arterial hypertension patients and many questions remain to be answered. One of these vital questions is whether the strategy of upfront initiation of combination therapy could improve patients outcomes compared to the strategy of initial monotherapy. The recently published AMBITION trial represents an important forward step towards answering this question by comparing a strategy of first-line combination therapy (ambrisentan and tadalafil) versus first-line monotherapy (ambrisentan or tadalafil) in patients with pulmonary arterial hypertension. PMID:26779523

  11. Considerations for numerical modeling of the pulmonary circulation--a review with a focus on pulmonary hypertension.

    PubMed

    Kheyfets, V O; O'Dell, W; Smith, T; Reilly, J J; Finol, E A

    2013-06-01

    Both in academic research and in clinical settings, virtual simulation of the cardiovascular system can be used to rapidly assess complex multivariable interactions between blood vessels, blood flow, and the heart. Moreover, metrics that can only be predicted with computational simulations (e.g., mechanical wall stress, oscillatory shear index, etc.) can be used to assess disease progression, for presurgical planning, and for interventional outcomes. Because the pulmonary vasculature is susceptible to a wide range of pathologies that directly impact and are affected by the hemodynamics (e.g., pulmonary hypertension), the ability to develop numerical models of pulmonary blood flow can be invaluable to the clinical scientist. Pulmonary hypertension is a devastating disease that can directly benefit from computational hemodynamics when used for diagnosis and basic research. In the present work, we provide a clinical overview of pulmonary hypertension with a focus on the hemodynamics, current treatments, and their limitations. Even with a rich history in computational modeling of the human circulation, hemodynamics in the pulmonary vasculature remains largely unexplored. Thus, we review the tasks involved in developing a computational model of pulmonary blood flow, namely vasculature reconstruction, meshing, and boundary conditions. We also address how inconsistencies between models can result in drastically different flow solutions and suggest avenues for future research opportunities. In its current state, the interpretation of this modeling technology can be subjective in a research environment and impractical for clinical practice. Therefore, considerations must be taken into account to make modeling reliable and reproducible in a laboratory setting and amenable to the vascular clinic. Finally, we discuss relevant existing models and how they have been used to gain insight into cardiopulmonary physiology and pathology.

  12. “A small leak will sink a great ship”: hypoxia-inducible factor and group III pulmonary hypertension

    PubMed Central

    Bryant, Andrew J.; Scott, Edward W.

    2016-01-01

    Pulmonary hypertension complicating idiopathic pulmonary fibrosis, also known as secondary pulmonary hypertension, represents a major source of morbidity and mortality in affected patients. While the study of primary pulmonary arterial hypertension has yielded several therapies, the same is not true for the treatment of pulmonary hypertension secondary to pulmonary fibrosis. Recent studies have indicated an important role of hypoxia-inducible factor (HIF) – a regulatory protein that is vital in adaptation to hypoxic conditions – in the development of secondary pulmonary hypertension. HIF influences development of hypoxia-induced pulmonary hypertension through alteration in voltage-gated potassium channels and homeostatic calcium regulation, resulting in disruption of endothelial cell-cell communication, and eventual vascular remodeling. This article summarizes salient literature related to HIF and secondary pulmonary hypertension, in addition to proposing a final common pathway in known mechanistic pathways that result in endothelial barrier integrity loss – vascular “leak” – primarily through a shared endothelial-epithelial signaling protein family, CCN. PMID:27446973

  13. Vascular effects of sildenafil in patients with pulmonary fibrosis and pulmonary hypertension: an ex vivo/in vitro study.

    PubMed

    Milara, Javier; Escrivá, Juan; Ortiz, José Luis; Juan, Gustavo; Artigues, Enrique; Morcillo, Esteban; Cortijo, Julio

    2016-06-01

    Sildenafil improves the 6-min walking distance in patients with idiopathic pulmonary fibrosis (IPF) and right-sided ventricular systolic dysfunction.We analysed the previously unexplored role of sildenafil on vasoconstriction and remodelling of pulmonary arteries from patients with IPF and pulmonary hypertension (PH) ex vivo Pulmonary arteries from 18 donors without lung disease, nine IPF, eight PH+IPF and four PH patients were isolated to measure vasodilator and anti-contractile effects of sildenafil in isometric organ bath. Ventilation/perfusion was explored in an animal model of bleomycin lung fibrosis.Sildenafil relaxed serotonin (5-HT) pre-contracted pulmonary arteries in healthy donors and IPF patients and, to a lesser extent, in PH+IPF and PH. Sildenafil inhibited 5-HT dose-response contraction curve mainly in PH+IPF and PH, but not in healthy donors. Sildenafil did not impair the ventilation/perfusion mismatching induced by bleomycin. Pulmonary arteries from PH+IPF patients showed a marked expression of phosphodiesterse-5 and extracellular matrix components. Sildenafil inhibited pulmonary artery endothelial and smooth muscle cell to mesenchymal transition by inhibition of extracellular regulated kinases 1 and 2 (ERK1/2) and SMAD3 phosphorylation.These results suggest an absence of direct relaxant effect and a prominent anti-contractile and anti-remodelling role of sildenafil in PH+IPF pulmonary arteries that could explain the beneficial effects of sildenafil in IPF with PH phenotype. PMID:27009174

  14. A brief overview of mouse models of pulmonary arterial hypertension: problems and prospects

    PubMed Central

    Gomez-Arroyo, Jose; Saleem, Sheinei J.; Mizuno, Shiro; Syed, Aamer A.; Bogaard, Harm J.; Abbate, Antonio; Taraseviciene-Stewart, Laimute; Sung, Yon; Kraskauskas, Donatas; Farkas, Daniela; Conrad, Daniel H.; Nicolls, Mark R.

    2012-01-01

    Many chronic pulmonary diseases are associated with pulmonary hypertension (PH) and pulmonary vascular remodeling, which is a term that continues to be used to describe a wide spectrum of vascular abnormalities. Pulmonary vascular structural changes frequently increase pulmonary vascular resistance, causing PH and right heart failure. Although rat models had been standard models of PH research, in more recent years the availability of genetically engineered mice has made this species attractive for many investigators. Here we review a large amount of data derived from experimental PH reports published since 1996. These studies using wild-type and genetically designed mice illustrate the challenges and opportunities provided by these models. Hemodynamic measurements are difficult to obtain in mice, and right heart failure has not been investigated in mice. Anatomical, cellular, and genetic differences distinguish mice and rats, and pharmacogenomics may explain the degree of PH and the particular mode of pulmonary vascular adaptation and also the response of the right ventricle. PMID:22307907

  15. RNA Sequencing Analysis Detection of a Novel Pathway of Endothelial Dysfunction in Pulmonary Arterial Hypertension

    PubMed Central

    Rhodes, Christopher J.; Im, Hogune; Cao, Aiqin; Hennigs, Jan K.; Wang, Lingli; Sa, Silin; Chen, Pin-I; Nickel, Nils P.; Miyagawa, Kazuya; Hopper, Rachel K.; Tojais, Nancy F.; Li, Caiyun G.; Gu, Mingxia; Spiekerkoetter, Edda; Xian, Zhaoying; Chen, Rui; Zhao, Mingming; Kaschwich, Mark; del Rosario, Patricia A.; Bernstein, Daniel; Zamanian, Roham T.; Wu, Joseph C.; Snyder, Michael P.

    2015-01-01

    Rationale: Pulmonary arterial hypertension is characterized by endothelial dysregulation, but global changes in gene expression have not been related to perturbations in function. Objectives: RNA sequencing was used to discriminate changes in transcriptomes of endothelial cells cultured from lungs of patients with idiopathic pulmonary arterial hypertension versus control subjects and to assess the functional significance of major differentially expressed transcripts. Methods: The endothelial transcriptomes from the lungs of seven control subjects and six patients with idiopathic pulmonary arterial hypertension were analyzed. Differentially expressed genes were related to bone morphogenetic protein type 2 receptor (BMPR2) signaling. Those down-regulated were assessed for function in cultured cells and in a transgenic mouse. Measurements and Main Results: Fold differences in 10 genes were significant (P < 0.05), four increased and six decreased in patients versus control subjects. No patient was mutant for BMPR2. However, knockdown of BMPR2 by siRNA in control pulmonary arterial endothelial cells recapitulated 6 of 10 patient-related gene changes, including decreased collagen IV (COL4A1, COL4A2) and ephrinA1 (EFNA1). Reduction of BMPR2-regulated transcripts was related to decreased β-catenin. Reducing COL4A1, COL4A2, and EFNA1 by siRNA inhibited pulmonary endothelial adhesion, migration, and tube formation. In mice null for the EFNA1 receptor, EphA2, versus control animals, vascular endothelial growth factor receptor blockade and hypoxia caused more severe pulmonary hypertension, judged by elevated right ventricular systolic pressure, right ventricular hypertrophy, and loss of small arteries. Conclusions: The novel relationship between BMPR2 dysfunction and reduced expression of endothelial COL4 and EFNA1 may underlie vulnerability to injury in pulmonary arterial hypertension. PMID:26030479

  16. Pulmonary hypertension in patient with elevated homocystein level and blast injuries.

    PubMed

    Zuljević, Ervin; Redzepi, Gzim; Plestina, Sanja; Vidjak, Vinko; Loncarić, Vlasta; Jakopović, Marko; Samarzija, Miroslav

    2009-03-01

    38-year-old man had chronic deep venous thrombosis (DVT) as a result of multiple injuries caused by an explosion of grenade 12 years ago, with recurrent pulmonary thromboembolisms and pulmonary hypertension which was unrecognized for a decade. Patient was admitted with a progressive dyspnea and exercise intolerance (NYHA II). The diagnosis was established according to clinical symptoms, transthoracic echocardiography, phlebography, lung scintigraphy and pulmonary angiography. Oral anticoagulant therapy was introduced and cava filter indicated to implant. During phlebography a floating thrombus was found in the inferior cava vein underneath renal vein. Implantation was delayed and patient received systemic fibrinolytic therapy with streptokinase (7500 000 UI within 4 days), followed by heparin infusion and warfarin. Post-fibrinolytic phlebography showed clear lumen of inferior vena cava. Fibrinolysis had also affected pulmonary hypertension-systolic pressure in the right ventricle measured by Doppler echocardiography decreased from 90 to 65 mmHg. Permanent intravenous cava filter was implanted. PMID:19408648

  17. Sildenafil in heart failure with reactive pulmonary hypertension (Sildenafil HF) clinical trial (rationale and design).

    PubMed

    Guglin, Maya; Rajagopalan, Navin; Anaya, Paul; Charnigo, Richard

    2016-06-01

    In this article, we present the rationale and design of the Sildenafil HF trial (ClinicalTrials.gov identifier: NCT02304705). We will randomize patients with heart failure and reactive pulmonary hypertension (pulmonary capillary wedge pressure > 15 mmHg, pulmonary vascular resistance > 3 Wood units) into two groups: the treatment group receiving sildenafil 20 mg 3 times a day and a matching placebo group. The duration of intervention will be 3 months. The primary outcome is 6-minute walk distance. Key features of this trial include (1) that reactive pulmonary hypertension is an inclusion criterion, (2) that patients will be enrolled regardless of left ventricular ejection fraction, and (3) that clinical stability in the 3 months preceding enrollment is not required. PMID:27252841

  18. Sildenafil in heart failure with reactive pulmonary hypertension (Sildenafil HF) clinical trial (rationale and design)

    PubMed Central

    2016-01-01

    Abstract In this article, we present the rationale and design of the Sildenafil HF trial (ClinicalTrials.gov identifier: NCT02304705). We will randomize patients with heart failure and reactive pulmonary hypertension (pulmonary capillary wedge pressure > 15 mmHg, pulmonary vascular resistance > 3 Wood units) into two groups: the treatment group receiving sildenafil 20 mg 3 times a day and a matching placebo group. The duration of intervention will be 3 months. The primary outcome is 6-minute walk distance. Key features of this trial include (1) that reactive pulmonary hypertension is an inclusion criterion, (2) that patients will be enrolled regardless of left ventricular ejection fraction, and (3) that clinical stability in the 3 months preceding enrollment is not required. PMID:27252841

  19. Vasovagal response secondary to permanent contraception device in pulmonary arterial hypertension

    PubMed Central

    Cope, Jessica; Alnuaimat, Hassan

    2015-01-01

    Abstract Adequate contraception is an essential component of managing pulmonary hypertension in women of childbearing age. Intrauterine devices are a popular contraceptive choice for many women but are associated with a risk of vagal response upon placement in certain patients with pulmonary hypertension, which may not be well tolerated. More recently, newer permanent contraception devices have emerged in the market, such as the Essure. We describe the first case, to our knowledge, of vagal-associated response due to an Essure device placement. PMID:26697184

  20. Diagnosis and Treatment of Pulmonary Arterial Hypertension and Atrial Fibrillation in an Adult Chimpanzee (Pan troglodytes)

    PubMed Central

    Lammey, Michael L; Doane, Cynthia J; Gigliotti, Andrew; Lee, D Rick; Sleeper, Meg M

    2008-01-01

    This report describes the diagnosis and treatment of pulmonary arterial hypertension (PAH) in an adult male captive chimpanzee. Although cardiovascular disease in general is common in human and great apes, diagnosis and treatment of PAH in nonhuman primates are uncommon. In the case we present, the adult chimpanzee was diagnosed with an arrhythmia during an annual physical examination and later with PAH during a scheduled cardiovascular evaluation. PAH can either be primary or secondary and can lead to right ventricular overload and heart failure. This description is the first case study of pulmonary arterial hypertension in a great ape species. PMID:18947173

  1. Pulmonary arterial hypertension combined with a high cardiac output state: Three remarkable cases

    PubMed Central

    Spruijt, Onno A.; Bogaard, Harm-Jan; Vonk-Noordegraaf, Anton

    2013-01-01

    A congenital extrahepatic portosystemic venous shunt (CEPVS), also known as an Abernethy malformation, is a rare cause of pulmonary arterial hypertension (PAH). In this case series, we describe three male patients of 30, 23, and 27 years of age with PAH due to a CEPVS. In all three patients, a right heart catheterization revealed a high cardiac output. The aim of this case series is to make pulmonary hypertension physicians aware of the possibility of a CEPVS when PAH is accompanied with a high cardiac output state. PMID:24015348

  2. Interdisciplinary networks for the treatment of childhood pulmonary vascular disease: what pulmonary hypertension doctors can learn from pediatric oncologists.

    PubMed

    Hansmann, Georg

    2013-12-01

    The pathobiology of pulmonary arterial hypertension (PAH) is complex and multifactorial. None of the current therapies has been shown to be universally effective or able to reverse advanced pulmonary vascular disease, characterized by plexiform vascular lesions, or to prevent right ventricular failure in advanced PAH. It is thus unlikely that only one factor, pathway, or gene mutation will explain all forms and cases. Pediatric oncologists recognized a need for intensified, collaborative research within their field more than 40 years ago and implemented major clinical and translational networks worldwide to achieve evidence-based "tailored therapies." The similarities in the pathobiology (e.g., increased proliferation and resistance to apoptosis in vascular cells and perivascular inflammation) and the uncertainties in the proper treatment of both cancer and pulmonary hypertension (PH) have led to the idea of building interdisciplinary networks among PH centers to achieve rapid translation of basic research findings, optimal diagnostic algorithms, and significant, sustained treatment results. Such networks leading to patient registries, clinical trials, drug development, and innovative, effective therapies are urgently needed for the care of children with PH. This article reviews the current status, limitations, and recent developments in the field of pediatric PH. It is suggested that the oncologists' exemplary networks, concepts, and results in the treatment of acute lymphoblastic leukemia are applicable to future networks and innovative therapies for pediatric pulmonary hypertensive vascular disease and right ventricular dysfunction.

  3. Pulmonary arterial responses to reactive oxygen species are altered in newborn piglets with chronic hypoxia-induced pulmonary hypertension

    PubMed Central

    Fike, Candice D.; Aschner, Judy L.; Slaughter, James C.; Kaplowitz, Mark R.; Zhang, Yongmei; Pfister, Sandra L.

    2011-01-01

    Reactive oxygen species (ROS) have been implicated in the pathogenesis of pulmonary hypertension. ROS might mediate vascular responses, at least in part, by stimulating prostanoid production. Our goals were to determine if the effect of ROS on vascular tone is altered in resistance pulmonary arteries (PRA) of newborn piglets with chronic hypoxia-induced pulmonary hypertension and the role, if any, of prostanoids in ROS-mediated responses. In cannulated, pressurized PRA, ROS generated by xanthine (X) plus xanthine oxidase (XO) had minimal effect on vascular tone in control piglets but caused significant vasoconstriction in hypoxic piglets. Both cyclooxygenase inhibition with indomethacin and thromboxane synthase inhibition with dazoxiben significantly blunted constriction to X+XO in hypoxic PRA. X+XO increased prostacyclin production (70±8%) by a greater degree than thromboxane production (50±6%) in control PRA; this was not the case in hypoxic PRA where the increases in prostacyclin and thromboxane production were not statistically different (78±13% versus 216±93%, respectively). Thromboxane synthase expression was increased in PRA from hypoxic piglets while prostacyclin synthase expression was similar in PRA from hypoxic and control piglets. Under conditions of chronic hypoxia, altered vascular responses to ROS may contribute to pulmonary hypertension by a mechanism that involves the prostanoid vasoconstrictor, thromboxane. PMID:21516056

  4. Stiffening of the Extrapulmonary Arteries From Rats in Chronic Hypoxic Pulmonary Hypertension.

    PubMed

    Drexler, E S; Bischoff, J E; Slifka, A J; McCowan, C N; Quinn, T P; Shandas, R; Ivy, D D; Stenmark, K R

    2008-01-01

    Changes in the compliance properties of large blood vessels are critical determinants of ventricular afterload and ultimately dysfunction. Little is known of the mechanical properties of large vessels exhibiting pulmonary hypertension, particularly the trunk and right main artery. We initiated a study to investigate the influence of chronic hypoxic pulmonary hypertension on the mechanical properties of the extrapulmonary arteries of rats. One group of animals was housed at the equivalent of 5000 m elevation for three weeks and the other held at ambient conditions of ~1600 m. The two groups were matched in age and gender. The animals exposed to hypobaric hypoxia exhibited signs of pulmonary hypertension, as evidenced by an increase in the RV/(LV+S) heart weight ratio. The extrapulmonary arteries of the hypoxic animals were also thicker than those of the control population. Histological examination revealed increased thickness of the media and additional deposits of collagen in the adventitia. The mechanical properties of the trunk, and the right and left main pulmonary arteries were assessed; at a representative pressure (7 kPa), the two populations exhibited different quantities of stretch for each section. At higher pressures we noted less deformation among the arteries from hypoxic animals as compared with controls. A four-parameter constitutive model was employed to fit and analyze the data. We conclude that chronic hypoxic pulmonary hypertension is associated with a stiffening of all the extrapulmonary arteries. PMID:27096124

  5. Perioperative management of patients with severe pulmonary hypertension in major orthopedic surgery: experience-based recommendations

    PubMed Central

    Seyfarth, Hans-Jürgen; Gille, Jochen; Sablotzki, Armin; Gerlach, Stefan; Malcharek, Michael; Gosse, Andreas; Gahr, Ralf H.; Czeslick, Elke

    2015-01-01

    Introduction: It is known that pulmonary hypertension is associated with worse outcome in both cardiac and non-cardiac surgery. The aims of our retrospective analysis were to evaluate the outcomes of our patients with pulmonary hypertension undergoing major orthopedic surgery and to give experience-based recommendations for the perioperative management. Material and methods: From 92 patients with pulmonary hypertension undergoing different kinds of surgical procedures from 2011–2014 in a tertiary academic hospital we evaluated 16 patients with major orthopedic surgery for perioperative morbidity and mortality. Results: Regarding the in-hospital morbidity and mortality, one patient died postoperatively due to pulmonary infection and right heart failure (6.25%) and 6 patients suffered significant postoperative complications (37.5%; bleeding = 1, infection = 1, wound healing deficits = 3; dysrhythmia = 1). Conclusion: Our data show that major orthopedic surgery is feasible with satisfactory outcome even in cases of severe pulmonary hypertension by an individualized, disease-adapted interdisciplinary treatment concept. PMID:26504732

  6. Comparison of nifedipine and captopril in children with pulmonary hypertension due to bronchopneumonia.

    PubMed

    Uner, A; Dogan, M; Demirtas, M; Açikgöz, M; Temel, H; Kaya, A; Caksen, H

    2008-10-01

    This study included 40 children, who were diagnosed with pneumonia and pulmonary hypertension (from the radiographic and clinical features), was performed at Yuzuncu Yil University Faculty of Medicine, Department of Pediatrics, from September 2003 to July 2005. Patients who had pneumonia and congenital heart disease or systemic hypertension or renal and liver disease together were excluded from the study. Blood gas analysis and oxygen concentration, measured with pulse oximetry, were performed in all patients. Besides chest X-ray, electrocardiography and echocardiographic search was also carried out. Echocardiographic examination was performed by using M mode, two-dimensional echocardiography and colored Doppler sonotron Vingmed CFM 725. At echocardiographic examination, pulmonary hypertension is defined as above 35 mmHg of pulmonary artery pressure. For echocardiographic examination, patients with pulmonary hypertension were divided into two groups. Captopril (2 mg/kg/day, three doses a day) and nifedipine (0.5 mg/kg/day, three doses a day) were given to the first and the second group, respectively. Echocardiography was performed daily until normal pulmonary artery pressure was achieved. At the beginning of the treatment, the patients were treated with double antibiotics and antibiotic change was carried out in needed cases at the follow up. Digoxin was administered to the cases of respiratory infection with heart failure. PMID:18304952

  7. Sphingosine kinase 1/sphingosine 1-phosphate signalling pathway as a potential therapeutic target of pulmonary hypertension

    PubMed Central

    Xing, Xi-Qian; Li, Yan-Li; Zhang, Yu-Xuan; Xiao, Yi; Li, Zhi-Dong; Liu, Li-Qiong; Zhou, Yu-Shan; Zhang, Hong-Yan; Liu, Yan-Hong; Zhang, Li-Hui; Zhuang, Min; Chen, Yan-Ping; Ouyang, Sheng-Rong; Wu, Xu-Wei; Yang, Jiao

    2015-01-01

    Pulmonary hypertension is characterized by extensive vascular remodelling, leading to increased pulmonary vascular resistance and eventual death due to right heart failure. The pathogenesis of pulmonary hypertension involves vascular endothelial dysfunction and disordered vascular smooth muscle cell (VSMC) proliferation and migration, but the exact processes remain unknown. Sphingosine 1-phosphate (S1P) is a bioactive lysophospholipid involved in a wide spectrum of biological processes. S1P has been shown to regulate VSMC proliferation and migration and vascular tension via a family of five S1P G-protein-coupled receptors (S1P1-SIP5). S1P has been shown to have both a vasoconstrictive and vasodilating effect. The S1P receptors S1P1 and S1P3 promote, while S1P2 inhibits VSMC proliferation and migration in vitro in response to S1P. Moreover, it has been reported recently that sphingosine kinase 1 and S1P2 inhibitors might be useful therapeutic agents in the treatment of empirical pulmonary hypertension. The sphingosine kinase 1/S1P signalling pathways may play a role in the pathogenesis of pulmonary hypertension. Modulation of this pathway may offer novel therapeutic strategies. PMID:26550106

  8. Sphingosine kinase 1/sphingosine 1-phosphate signalling pathway as a potential therapeutic target of pulmonary hypertension.

    PubMed

    Xing, Xi-Qian; Li, Yan-Li; Zhang, Yu-Xuan; Xiao, Yi; Li, Zhi-Dong; Liu, Li-Qiong; Zhou, Yu-Shan; Zhang, Hong-Yan; Liu, Yan-Hong; Zhang, Li-Hui; Zhuang, Min; Chen, Yan-Ping; Ouyang, Sheng-Rong; Wu, Xu-Wei; Yang, Jiao

    2015-01-01

    Pulmonary hypertension is characterized by extensive vascular remodelling, leading to increased pulmonary vascular resistance and eventual death due to right heart failure. The pathogenesis of pulmonary hypertension involves vascular endothelial dysfunction and disordered vascular smooth muscle cell (VSMC) proliferation and migration, but the exact processes remain unknown. Sphingosine 1-phosphate (S1P) is a bioactive lysophospholipid involved in a wide spectrum of biological processes. S1P has been shown to regulate VSMC proliferation and migration and vascular tension via a family of five S1P G-protein-coupled receptors (S1P1-SIP5). S1P has been shown to have both a vasoconstrictive and vasodilating effect. The S1P receptors S1P1 and S1P3 promote, while S1P2 inhibits VSMC proliferation and migration in vitro in response to S1P. Moreover, it has been reported recently that sphingosine kinase 1 and S1P2 inhibitors might be useful therapeutic agents in the treatment of empirical pulmonary hypertension. The sphingosine kinase 1/S1P signalling pathways may play a role in the pathogenesis of pulmonary hypertension. Modulation of this pathway may offer novel therapeutic strategies. PMID:26550106

  9. 17β-Estradiol Attenuates Conduit Pulmonary Artery Mechanical Property Changes With Pulmonary Arterial Hypertension.

    PubMed

    Liu, Aiping; Tian, Lian; Golob, Mark; Eickhoff, Jens C; Boston, Madison; Chesler, Naomi C

    2015-11-01

    Pulmonary arterial hypertension (PAH), a rapidly fatal vascular disease, strikes women more often than men. Paradoxically, female PAH patients have better prognosis and survival rates than males. The female sex hormone 17β-estradiol has been linked to the better outcome of PAH in females; however, the mechanisms by which 17β-estradiol alters PAH progression and outcomes remain unclear. Because proximal pulmonary arterial (PA) stiffness, one hallmark of PAH, is a powerful predictor of mortality and morbidity, we hypothesized that 17β-estradiol attenuates PAH-induced changes in mechanical properties in conduit proximal PAs, which imparts hemodynamic and energetic benefits to right ventricular function. To test this hypothesis, female mice were ovariectomized and treated with 17β-estradiol or placebo. PAH was induced in mice using SU5416 and chronic hypoxia. Extra-lobar left PAs were isolated and mechanically tested ex vivo to study both static and frequency-dependent mechanical behaviors in the presence or absence of smooth muscle cell activation. Our static mechanical test showed significant stiffening of large PAs with PAH (P<0.05). 17β-Estradiol restored PA compliance to control levels. The dynamic mechanical test demonstrated that 17β-estradiol protected the arterial wall from the PAH-induced frequency-dependent decline in dynamic stiffness and loss of viscosity with PAH (P<0.05). As demonstrated by the in vivo measurement of PA hemodynamics via right ventricular catheterization, modulation by 17β-estradiol of mechanical proximal PAs reduced pulsatile loading, which contributed to improved ventricular-vascular coupling. This study provides a mechanical mechanism for delayed disease progression and better outcome in female PAH patients and underscores the therapeutic potential of 17β-estradiol in PAH. PMID:26418020

  10. Loss of alveolar membrane diffusing capacity and pulmonary capillary blood volume in pulmonary arterial hypertension

    PubMed Central

    2013-01-01

    Background Reduced gas transfer in patients with pulmonary arterial hypertension (PAH) is traditionally attributed to remodeling and progressive loss of pulmonary arterial vasculature that results in decreased capillary blood volume available for gas exchange. Methods We tested this hypothesis by determination of lung diffusing capacity (DL) and its components, the alveolar capillary membrane diffusing capacity (Dm) and lung capillary blood volume (Vc) in 28 individuals with PAH in comparison to 41 healthy individuals, and in 19 PAH patients over time. Using single breath simultaneous measure of diffusion of carbon monoxide (DLCO) and nitric oxide (DLNO), DL and Dm were respectively determined, and Vc calculated. Dm and Vc were evaluated over time in relation to standard clinical indicators of disease severity, including brain natriuretic peptide (BNP), 6-minute walk distance (6MWD) and right ventricular systolic pressure (RVSP) by echocardiography. Results Both DLCO and DLNO were reduced in PAH as compared to controls and the lower DL in PAH was due to loss of both Dm and Vc (all p < 0.01). While DLCO of PAH patients did not change over time, DLNO decreased by 24 ml/min/mmHg/year (p = 0.01). Consequently, Dm decreased and Vc tended to increase over time, which led to deterioration of the Dm/Vc ratio, a measure of alveolar-capillary membrane functional efficiency without changes in clinical markers. Conclusions The findings indicate that lower than normal gas transfer in PAH is due to loss of both Dm and Vc, but that deterioration of Dm/Vc over time is related to worsening membrane diffusion. PMID:23339456

  11. Macrophage bone morphogenic protein receptor 2 depletion in idiopathic pulmonary fibrosis and Group III pulmonary hypertension.

    PubMed

    Chen, Ning-Yuan; D Collum, Scott; Luo, Fayong; Weng, Tingting; Le, Thuy-Trahn; M Hernandez, Adriana; Philip, Kemly; Molina, Jose G; Garcia-Morales, Luis J; Cao, Yanna; Ko, Tien C; Amione-Guerra, Javier; Al-Jabbari, Odeaa; Bunge, Raquel R; Youker, Keith; Bruckner, Brian A; Hamid, Rizwan; Davies, Jonathan; Sinha, Neeraj; Karmouty-Quintana, Harry

    2016-08-01

    Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease of unknown etiology. The development of pulmonary hypertension (PH) is considered the single most significant predictor of mortality in patients with chronic lung diseases. The processes that govern the progression and development of fibroproliferative and vascular lesions in IPF are not fully understood. Using human lung explant samples from patients with IPF with or without a diagnosis of PH as well as normal control tissue, we report reduced BMPR2 expression in patients with IPF or IPF+PH. These changes were consistent with dampened P-SMAD 1/5/8 and elevated P-SMAD 2/3, demonstrating reduced BMPR2 signaling and elevated TGF-β activity in IPF. In the bleomycin (BLM) model of lung fibrosis and PH, we also report decreased BMPR2 expression compared with control animals that correlated with vascular remodeling and PH. We show that genetic abrogation or pharmacological inhibition of interleukin-6 leads to diminished markers of fibrosis and PH consistent with elevated levels of BMPR2 and reduced levels of a collection of microRNAs (miRs) that are able to degrade BMPR2. We also demonstrate that isolated bone marrow-derived macrophages from BLM-exposed mice show reduced BMPR2 levels upon exposure with IL6 or the IL6+IL6R complex that are consistent with immunohistochemistry showing reduced BMPR2 in CD206 expressing macrophages from lung sections from IPF and IPF+PH patients. In conclusion, our data suggest that depletion of BMPR2 mediated by a collection of miRs induced by IL6 and subsequent STAT3 phosphorylation as a novel mechanism participating to fibroproliferative and vascular injuries in IPF. PMID:27317687

  12. A consensus approach to the classification of pediatric pulmonary hypertensive vascular disease: Report from the PVRI Pediatric Taskforce, Panama 2011

    PubMed Central

    del Cerro, Maria Jesus; Abman, Steven; Diaz, Gabriel; Freudenthal, Alexandra Heath; Freudenthal, Franz; Harikrishnan, S.; Haworth, Sheila G.; Ivy, Dunbar; Lopes, Antonio A.; Raj, J. Usha; Sandoval, Julio; Stenmark, Kurt; Adatia, Ian

    2011-01-01

    Current classifications of pulmonary hypertension have contributed a great deal to our understanding of pulmonary vascular disease, facilitated drug trials, and improved our understanding of congenital heart disease in adult survivors. However, these classifications are not applicable readily to pediatric disease. The classification system that we propose is based firmly in clinical practice. The specific aims of this new system are to improve diagnostic strategies, to promote appropriate clinical investigation, to improve our understanding of disease pathogenesis, physiology and epidemiology, and to guide the development of human disease models in laboratory and animal studies. It should be also an educational resource. We emphasize the concepts of perinatal maladaptation, maldevelopment and pulmonary hypoplasia as causative factors in pediatric pulmonary hypertension. We highlight the importance of genetic, chromosomal and multiple congenital malformation syndromes in the presentation of pediatric pulmonary hypertension. We divide pediatric pulmonary hypertensive vascular disease into 10 broad categories. PMID:21874158

  13. Heme biosynthesis modulation via δ-aminolevulinic acid administration attenuates chronic hypoxia-induced pulmonary hypertension

    PubMed Central

    Alhawaj, Raed; Patel, Dhara; Kelly, Melissa R.; Sun, Dong

    2015-01-01

    This study examines how heme biosynthesis modulation with δ-aminolevulinic acid (ALA) potentially functions to prevent 21-day hypoxia (10% oxygen)-induced pulmonary hypertension in mice and the effects of 24-h organoid culture with bovine pulmonary arteries (BPA) with the hypoxia and pulmonary hypertension mediator endothelin-1 (ET-1), with a focus on changes in superoxide and regulation of micro-RNA 204 (miR204) expression by src kinase phosphorylation of signal transducer and activator of transcription-3 (STAT3). The treatment of mice with ALA attenuated pulmonary hypertension (assessed through echo Doppler flow of the pulmonary valve, and direct measurements of right ventricular systolic pressure and right ventricular hypertrophy), increases in pulmonary arterial superoxide (detected by lucigenin), and decreases in lung miR204 and mitochondrial superoxide dismutase (SOD2) expression. ALA treatment of BPA attenuated ET-1-induced increases in mitochondrial superoxide (detected by MitoSox), STAT3 phosphorylation, and decreases in miR204 and SOD2 expression. Because ALA increases BPA protoporphyrin IX (a stimulator of guanylate cyclase) and cGMP-mediated protein kinase G (PKG) activity, the effects of the PKG activator 8-bromo-cGMP were examined and found to also attenuate the ET-1-induced increase in superoxide. ET-1 increased superoxide production and the detection of protoporphyrin IX fluorescence, suggesting oxidant conditions might impair heme biosynthesis by ferrochelatase. However, chronic hypoxia actually increased ferrochelatase activity in mouse pulmonary arteries. Thus, a reversal of factors increasing mitochondrial superoxide and oxidant effects that potentially influence remodeling signaling related to miR204 expression and perhaps iron availability needed for the biosynthesis of heme by the ferrochelatase reaction could be factors in the beneficial actions of ALA in pulmonary hypertension. PMID:25659899

  14. Veno-venous extracorporeal membrane oxygenation bridging to pharmacotherapy in pulmonary arterial hypertensive crisis.

    PubMed

    Srivastava, Mukta C; Ramani, Gautam V; Garcia, Jose P; Griffith, Bartley P; Uber, Patricia A; Park, Myung H

    2010-07-01

    We report the case of a treatment-naive patient with pulmonary arterial hypertension who presented with decompensated right ventricular failure and cardiogenic shock. Unstable hemodynamics, hypoxia and end-organ hypoperfusion limited up-titration of pharmacotherapy. Mechanical circulatory support with veno-venous extracorporeal membrane oxygenation (VV-ECMO) was initiated to permit dose titration of pulmonary vasodilator therapy. VV-ECMO was weaned after 10 days of support, with successful transition to intravenous epoprostenol and oral sildenafil.

  15. Veno-venous extracorporeal membrane oxygenation bridging to pharmacotherapy in pulmonary arterial hypertensive crisis.

    PubMed

    Srivastava, Mukta C; Ramani, Gautam V; Garcia, Jose P; Griffith, Bartley P; Uber, Patricia A; Park, Myung H

    2010-07-01

    We report the case of a treatment-naive patient with pulmonary arterial hypertension who presented with decompensated right ventricular failure and cardiogenic shock. Unstable hemodynamics, hypoxia and end-organ hypoperfusion limited up-titration of pharmacotherapy. Mechanical circulatory support with veno-venous extracorporeal membrane oxygenation (VV-ECMO) was initiated to permit dose titration of pulmonary vasodilator therapy. VV-ECMO was weaned after 10 days of support, with successful transition to intravenous epoprostenol and oral sildenafil. PMID:20417127

  16. High incidence of pulmonary arterial hypertension in systemic sclerosis patients with anti-centriole autoantibodies.

    PubMed

    Hamaguchi, Yasuhito; Matsushita, Takashi; Hasegawa, Minoru; Ueda-Hayakawa, Ikuko; Sato, Sinichi; Takehara, Kazuhiko; Fujimoto, Manabu

    2015-09-01

    Systemic sclerosis (SSc)-related autoantibodies are useful tools in identifying clinically homogenous subsets of patients and predicting their prognosis. In this report, we described five SSc patients with anti-centriole antibodies. All five patients were females and had digital ulcers/gangrene. Four of five (80%) patients had pulmonary arterial hypertension (PAH). None of the five patients had active pulmonary fibrosis or developed renal crisis. Anti-centriole antibodies may be a marker for PAH and digital ulcers/gangrene.

  17. Treatment of patients with chronic thrombo embolic pulmonary hypertension: focus on riociguat

    PubMed Central

    Smith, Zachary R; Makowski, Charles T; Awdish, Rana L

    2016-01-01

    Chronic thromboembolic pulmonary hypertension (CTEPH) is a disease of the pulmonary vascular bed that is characterized by elevations in the mean pulmonary artery pressure in the setting of perfusion defects on ventilation–perfusion scan, and subsequently confirmed by pulmonary angiography. CTEPH, or World Health Organization (WHO) group 4 pulmonary hypertension, is a result of unresolved thromboembolic obstruction in the pulmonary arteries. Pulmonary endarterectomy (PEA) is the treatment of choice for CTEPH as it is a potentially curative therapy. However, up to one-third of patients are not candidates for the surgery, either due to distal and inaccessible nature of the lesions or comorbid conditions. Due to remodeling that occurs in nonobstructed pulmonary vessels, a portion of patients who have undergone PEA have residual CTEPH after the procedure, attributable to high shear stress prior to PEA. This phenomenon has led to the understanding of a so-called “two-compartment model” of CTEPH, opening the door to pharmacologic treatment strategies. In 2013, riociguat, a soluble guanylate cyclase stimulator, was approved in the US and Europe for the treatment of inoperable or persistent/recurrent CTEPH. This article reviews the current management of CTEPH with a focus on riociguat. PMID:27354811

  18. Supraventricular Arrhythmias in Patients With Pulmonary Arterial Hypertension.

    PubMed

    Cannillo, Margherita; Grosso Marra, Walter; Gili, Sebastiano; D'Ascenzo, Fabrizio; Morello, Mara; Mercante, Lorena; Mistretta, Elisa; Salera, Davide; Zema, Domenica; Bissolino, Arianna; Fusaro, Enrico; Marra, Sebastiano; Libertucci, Daniela; Gaita, Fiorenzo

    2015-12-15

    The onset of supraventricular arrhythmias (SVA) may be associated with clinical worsening in patients with pulmonary arterial hypertension (PAH). However, limited data have been reported, especially at long-term follow-up. Aim of this study was to investigate the incidence of SVA in our patients with PAH, the risk factors correlated to their onset and the prognostic impact. All consecutive patients with PAH without history of SVA were enrolled. Incidence of new SVA was investigated and also the risk factors for SVA. Primary end point of the study was the impact of SVA on a composite of all-cause mortality and re-hospitalization, whereas mortality was the secondary end point. Seventy-seven patients were enrolled. No significant differences in the clinical or instrumental baseline characteristics between the 2 study groups were reported. During a median follow-up of 35 months (interquartile range 21.5 to 53.5), 17 (22%) patients experienced SVA. Development of SVA was associated with worsening of prognostic parameters at the follow-up: increasing of World Health Organization (WHO) functional class (p = 0.005) and N-terminal-pro-brain natriuretic peptide (NT-proBNP) (p = 0.018) and reduction of 6-minute walking distance (p = 0.048), tricuspid annular plane systolic excursion (TAPSE) (p = 0.041), and diffusing capacity of the lung for carbon monoxide (p = 0.025). The primary end point occurred in 13 patients (76%) in the SVA group and in 22 patients (37%) in the group without SVA (p = 0.004), whereas 9 patients (53%) among those with SVA died during the follow-up compared with 8 (13%) among those without (p = 0.001). At multivariate analysis, development of SVA was independently associated with an increased risk to meet the both primary (hazard ratio 2.13; 95% confidence interval 1.07 to 4.34; p = 0.031) and secondary (hazard ratio 4.1; 95% confidence interval 1.6 to 10.6; p = 0.004) end points. In conclusion, during the 3-year follow-up period, 1/3 of patients with

  19. Clinical Implications of Hemoptysis in Patients with Pulmonary Arterial Hypertension

    PubMed Central

    Cantu, Jose; Wang, Degang; Safdar, Zeenat

    2013-01-01

    Introduction Pulmonary arterial hypertension (PAH) is a disabling disease that may result in haemoptysis. Patients with congenital heart disease associated PAH (CHD-APAH) may have a survival advantage when compared with patients with other types of PAH presenting with haemoptysis. The effects of aetiology and sub-sequent management choice of haemoptysis in PAH patients is not well-defined. Methods We conducted outcome analysis in CHD-APAH vs. all other subtypes of PAH patients presenting with haemoptysis to The Methodist Hospital. Twenty-one patients were identified, thirteen patients in the CHD-APAH group and eight patients in the non-CHD group. We evaluated outcomes related to treatment (bronchial artery embolization vs. conservative management), hospital length of stay, mortality rates and survival in this cohort. Results The CHD-APAH and non-CHD groups had similar baseline demographic, haemodynamic and laboratory values except BMI was higher in the non-CHD group and haematocrit was higher in the CHD-APAH group. Twenty-eight-day mortality (0% vs. 31%) and 1-year mortality (0% vs. 54%) was lower in the CHD-APAH patients as compared with non-CHD group. A statistically significant difference was found in the survival rate in favour of CHD-APAH group for the total follow-up period (p = 0.02). Although not statistically significant, patients treated with BAE had shorter length of stay (4.0 days ± 4.0 vs. 13.7 days ± 22.5; p = 0.26). There was recurrent haemoptysis in 43% of patients treated with BAE. Conclusion Haemoptysis in PAH patients is a serious event with a high mortality rate. CHD-APAH seems to confer a survival advantage, independent of therapy utilised. Termination of haemoptysis with BAE is rapid with relatively few complications except for frequent re-bleeding episodes. Further studies are needed to determine the risk factors that may predispose PAH patients to excessive mortality from haemoptysis and to identify an optimal therapeutic modality. PMID

  20. Angiotensin II prevents hypoxic pulmonary hypertension and vascular changes in rat

    SciTech Connect

    Rabinovitch, M.; Mullen, M.; Rosenberg, H.C.; Maruyama, K.; O'Brodovich, H.; Olley, P.M. )

    1988-03-01

    Angiotensin II, a vasoconstrictor, has been previously demonstrated to produce a secondary vasodilatation due to release of prostaglandins. Because of this effect, the authors investigated whether infusion of exogenous angiotensin II via miniosmopumps in rats during a 1-wk exposure to chronic hypobaric hypoxia might prevent pulmonary hypertension, right ventricular hypertrophy, and vascular changes. They instrumented the rats with indwelling cardiovascular catheters and compared the hemodynamic and structural response in animals given angiotensin II, indomethacin in addition to angiotensin II (to block prostaglandin production), or saline with or without indomethacin. They then determine whether angiotensin II infusion also prevents acute hypoxic pulmonary vasoconstriction. They observed that exogenous angiotensin II infusion abolished the rise in pulmonary artery pressure, the right ventricular hypertrophy, and the vascular changes induced during chronic hypoxia in control saline-infused rats with or without indomethacin. The protective effects of angiotensin II was lost when indomethacin was given to block prostaglandin synthesis. During acute hypoxia, both antiotensin II and prostacyclin infusion similarly prevented the rise in pulmonary artery pressure observed in saline-infused rats and in rats given indomethacin or saralasin in addition to angiotensin II. Thus exogenous angiotensin II infusion prevents chronic hypoxic pulmonary hypertension, associated right ventricular hypertrophy, and vascular changes and blocks acute hypoxic pulmonary hypertension, and this is likely related to its ability to release vasodilator prostaglandins.

  1. Punicalagin Prevents Hypoxic Pulmonary Hypertension via Anti-Oxidant Effects in Rats.

    PubMed

    Shao, Jingyun; Wang, Peng; Liu, An; Du, Xusheng; Bai, Jie; Chen, Mingwei

    2016-01-01

    Punicalagin (PG), a major bioactive ingredient in pomegranate juice, has been proven to have anti-oxidative stress properties and to exert protective effects on acute lung injuries induced by lipopolysaccharides. This study aimed to investigate the effects of PG treatment on hypoxic pulmonary hypertension (HPH) and the underlying mechanisms responsible for the effects. Rats were exposed to 10% oxygen for 2 wk (8 h/day) to induce the HPH model. PG (5, 15, 45[Formula: see text]mg/kg) was orally administered 10[Formula: see text]min before hypoxia each day. PG treatments at the doses of 15 and 45[Formula: see text]mg/kg/d decreased the mean pulmonary arterial pressure (mPAP) and alleviated right ventricular hypertrophy and vascular remodeling in HPH rats. Meanwhile, PG treatment attenuated the hypoxia-induced endothelial dysfunction of pulmonary artery rings. The beneficial effects of PG treatment were associated with improved nitric oxide (NO)-cGMP signaling and reduced oxidative stress, as evidenced by decreased superoxide generation, gp91[Formula: see text] expression and nitrotyrosine content in the pulmonary arteries. Furthermore, tempol's scavenging of oxidative stress also increased NO production and attenuated endothelial dysfunction and pulmonary hypertension in HPH rats. Combining tempol and PG did not exert additional beneficial effects compared to tempol alone. Our study indicated for the first time that PG treatment can protect against hypoxia-induced endothelial dysfunction and pulmonary hypertension in rats, which may be induced via its anti-oxidant actions. PMID:27222062

  2. Impact of residual stretch and remodeling on collagen engagement in healthy and pulmonary hypertensive calf pulmonary arteries at physiological pressures.

    PubMed

    Tian, Lian; Lammers, Steven R; Kao, Philip H; Albietz, Joseph A; Stenmark, Kurt R; Qi, H Jerry; Shandas, Robin; Hunter, Kendall S

    2012-07-01

    Understanding the mechanical behavior of proximal pulmonary arteries (PAs) is crucial to evaluating pulmonary vascular function and right ventricular afterload. Early and current efforts focus on these arteries' histological changes, in vivo pressure-diameter behavior and mechanical properties under in vitro mechanical testing. However, the in vivo stretch and stress states remain poorly characterized. To further understand the mechanical behavior of the proximal PAs under physiological conditions, this study computed the residual stretch and the in vivo circumferential stretch state in the main pulmonary arteries in both control and hypertensive calves by using in vitro and in vivo artery geometry data, and modeled the impact of residual stretch and arterial remodeling on the in vivo circumferential stretch distribution and collagen engagement in the main pulmonary artery. We found that the in vivo circumferential stretch distribution in both groups was nonuniform across the vessel wall with the largest stretch at the outer wall, suggesting that collagen at the outer wall would engage first. It was also found that the circumferential stretch was more uniform in the hypertensive group, partially due to arterial remodeling that occurred during their hypoxic treatment, and that their onset of collagen engagement occurred at a higher pressure. It is concluded that the residual stretch and arterial remodeling have strong impact on the in vivo stretch state and the collagen engagement and thus the mechanical behavior of the main pulmonary artery in calves. PMID:22237861

  3. Electrocardiogram-based scoring system for predicting secondary pulmonary hypertension: A cross-sectional study

    PubMed Central

    Palamaner Subash Shantha, Ghanshyam; Patel, Nimesh Kirit; Boruah, Pranjal; Nanavaty, Sukrut; Chandran, Sindu; Sethi, Arjinder; Sheth, Jignesh

    2014-01-01

    Objectives In this study, we have developed an electrocardiogram-based scoring system to predict secondary pulmonary hypertension. Design A cross-sectional study. Setting Single tertiary-care hospital in Scranton, Pennsylvania, USA. Participants Five hundred and fifty-two consecutive patients undergoing right heart catheterization between 2006 and 2009. Main outcome measures Surface electrocardiogram was assessed for R-wave in lead V1 ≥ 6mm, R-wave in V6 ≤ 3mm, S-wave in V6 ≥ 3mm, right atrial enlargement, right axis deviation and left atrial enlargement. Pulmonary hypertension was defined as mean pulmonary artery pressure ≥25 mmHg, determined by right heart catheterization. Results A total of 297 (54%) patients in the study cohort had pulmonary hypertension. In total, 332 patients from the study cohort formed the development cohort and the remaining 220 patients formed the validation cohort. In the development cohort, based on log odds ratios of association, RAE, LAE, RAD, R-wave in V1 ≥ 6 mm were assigned scores of 5, 2, 2 and 1, respectively, to form a 10-point scoring system “Scranton PHT (SP) score”. SP scores of 5 points and 7 points in DC showed C-statistic of 0.83 and 0.89, respectively, for discriminating pulmonary hypertension. C-statistic for RAE alone was significantly lower compared to an SP score of 7 (0.83 vs. 0.89, P = 0.021). The reliability of SP score in the validation cohort was acceptable. Conclusion SP score provides a good point-of-care tool to predict pulmonary hypertension in patients with clinical suspicion of it. PMID:25396053

  4. Contribution of calcium-activated chloride channel to elevated pulmonary artery pressure in pulmonary arterial hypertension induced by high pulmonary blood flow

    PubMed Central

    Wang, Kai; Chen, Chuansi; Ma, Jianfa; Lao, Jinquan; Pang, Yusheng

    2015-01-01

    The correlation between calcium-activated chloride channel (CaCC) and pulmonary arterial hypertension (PAH) induced by high pulmonary blood flow remains uncertain. In this study, we investigated the possible role and effects of CaCC in this disease. Sixty rats were randomly assigned to normal, sham, and shunt groups. Rats in the shunt group underwent abdominal aorta and inferior vena cava shunt surgery. The pulmonary artery pressure was measured by catheterization. Pathological changes, right ventricle hypertrophy index (RVHI), arterial wall area/vessel area (W/V), and arterial wall thickness/vessel external diameter (T/D) were analyzed by optical microscopy. Electrophysiological characteristics of pulmonary arterial smooth muscle cells (PASMCs) were investigated using patch clamp technology. After 11 weeks of shunting, PAH and pulmonary vascular structural remodeling (PVSR) developed, accompanied by increased pulmonary pressure and pathological interstitial pulmonary<