Forms Of Pulmonary Hypertension Research Articles

The causes, treatment, and outcome of pulmonary hypertension in Africa: Insights from the Pan African Pulmonary Hypertension Cohort (PAPUCO) Registry

BackgroundEpidemiology, aetiology, management and outcome data for various forms of pulmonary hypertension (PH) in Africa are scarce. MethodsA prospective, multinational cohort registry of 220 consecutive patients (97% of African descent) from 9 specialist centres in 4 African countries. The antecedents, characteristics and management of newly diagnosed PH plus 6-month survival were studied. ResultsThere were 209 adults (median age 48years [IQR 35, 64]) and 11 children (age range 1 to 17years). Most adults had advanced disease - 66% WHO Functional Class III-IV, median 6-minute walk test distance of 252m (IQR 120, 350) and median right ventricular systolic pressure 58mmHg (IQR 49, 74). Adults comprised 16% pulmonary arterial hypertension, 69% PH due to left heart disease, 11% PH due to lung disease and/or hypoxia, 2% chronic thromboembolic pulmonary hypertension, and 2% PH with unclear multifactorial mechanism. At 6-months, 21% of adults with follow-up data had died. On an adjusted basis (independent of sub-groups) mortality was associated with increasing functional impairment (p=0.021 overall - WHO Class IV versus I, OR 1.68 [95% CI 0.13, 4.36]) and presence of combined right atrial and ventricular hypertrophy (46% - OR 2.88, 95% CI 1.45, 5.72). Children commonly presented with dyspnoea, fatigue, cough, and palpitations with six and three children, respectively diagnosed with concurrent PH associated congenital heart disease and left heart disease. ConclusionsThese data provide new insights into PH from an African perspective, with clear opportunities to improve its prevention, treatment and outcomes. Trial RegistrationClinicalTrials.gov (NCT02265887).

Current concepts in the pathogenesis of chronic thromboembolic pulmonary hypertension.

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.

Antagonism of the thromboxane-prostanoid receptor is cardioprotective against right ventricular pressure overload.

Right ventricular (RV) failure is the primary cause of death in pulmonary arterial hypertension (PAH) and is a significant cause of morbidity and mortality in other forms of pulmonary hypertension. There are no approved therapies directed at preserving RV function. F-series and E-series isoprostanes are increased in heart failure and PAH, correlate to the severity of disease, and can signal through the thromboxane-prostanoid (TP) receptor, with effects from vasoconstriction to fibrosis. The goal of these studies was to determine whether blockade of the TP receptor with the antagonist CPI211 was beneficial therapeutically in PAH-induced RV dysfunction. Mice with RV dysfunction due to pressure overload by pulmonary artery banding (PAB) were given vehicle or CPI211. Two weeks after PAB, CPI211-treated mice were protected from fibrosis with pressure overload. Gene expression arrays and immunoblotting, quantitative histology and morphometry, and flow cytometric analysis were used to determine the mechanism of CPI211 protection. TP receptor inhibition caused a near normalization of fibrotic area, prevented cellular hypertrophy while allowing increased RV mass, increased expression of antifibrotic thrombospondin-4, and blocked induction of the profibrotic transforming growth factor β (TGF-β) pathway. A thromboxane synthase inhibitor or low-dose aspirin failed to replicate these results, which suggests that a ligand other than thromboxane mediates fibrosis through the TP receptor after pressure overload. This study suggests that TP receptor antagonism may improve RV adaptation in situations of pressure overload by decreasing fibrosis and TGF-β signaling.

Chronic thromboembolic pulmonary hypertension--a diagnostic and therapeutic update.

Chronic thromboembolic pulmonary hypertension (CTEPH), an important cause of severe pulmonary hypertension, is still underdiagnosed, mainly due to the insufficient use of V/Q scannning in patients with pulmonary hypertension. This article reviews the current diagnostic approach and discusses the therapeutic options in this particular form of pulmonary hypertension. Every patient with CTEPH should undergo an evaluation in a specialised centre with experience in pulmonary arterial endarteriectomy (PEA) as the potentially curative surgical technique. Partly unresolved questions regard the status of the recently described percutaneous transluminal pulmonary angioplasty and the best medical treatment in patients with inoperable or recurrent/persistent pulmonary hypertension after PEA.

Evolving Concepts of Pulmonary Hypertension Secondary to Left Heart Disease.

Pulmonary hypertension associated with left heart disease is the most common form of pulmonary hypertension. Although its pathophysiology remains incompletely understood, it is now well recognized that the presence of pulmonary hypertension is associated with a worse prognosis. Right ventricular failure has independent and additive prognostic value over pulmonary hypertension for adverse outcomes in left heart disease. Recently, several new terminologies have been introduced to better define and characterize the nature and severity of pulmonary hypertension. Several new treatment options including the use of pulmonary arterial hypertension specific therapies are being considered, but there is lack of evidence. Here, we review the recent advances in this field and summarize the diagnostic and therapeutic modalities of use in the management of pulmonary hypertension associated with left heart disease.

Chronic thromboembolic pulmonary hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) is a form of pulmonary hypertension (PH) characterized by the persistence of thromboembolic obstructing the pulmonary arteries as an organized tissue and the presence of a variable small vessel arteriopathy. The consequence is an increase in pulmonary vascular resistance resulting in progressive right heart failure. CTEPH is classified as group IV pulmonary hypertension according to the WHO classification of pulmonary hypertension. CTEPH is defined as precapillary pulmonary hypertension (mean pulmonary artery pressure ≥ 25 mmHg with a pulmonary capillary wedge pressure ≤ 15 mmHg) associated with mismatched perfusion defects on ventilation-perfusion lung scan and signs of chronic thromboembolic disease on computed tomography pulmonary angiogram and/or conventional pulmonary angiography, in a patient who received at least 3 months of therapeutic anticoagulation. CTEPH as a direct consequence of symptomatic pulmonary embolism (PE) is rare, and a significant number of CTEPH cases develop in the absence of history of PE. Thus, CTEPH should be considered in any patient with unexplained PH. Splenectomy, chronic inflammatory conditions such as inflammatory bowel disease, indwelling catheters and cardiac pacemakers have been identified as associated conditions increasing the risk of CTEPH. Ventilation-perfusion scan (V/Q) is the best test available for establishing the thromboembolic nature of PH. When CTEPH is suspected, patients should be referred to expert centres where pulmonary angiography, right heart catheterization and high-resolution CT scan will be performed to confirm the diagnosis and to assess the operability. Pulmonary endarterectomy (PEA) remains the gold standard treatment for CTEPH when organized thrombi involve the main, lobar or segmental arteries. This operation should only be performed by experienced surgeons in specialized centres. For inoperable patients, current ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension recommend the use of riociguat and say that off-label use of drugs approved for PAH and pulmonary angioplasty may be considered in expert centres.

The sGC stimulator riociguat inhibits platelet function in washed platelets but not in whole blood.

Stimulation of soluble guanylyl cyclase (sGC) is a valuable therapeutic strategy for the treatment of several cardiovascular diseases. The sGC stimulator riociguat has been approved for the treatment of two forms of pulmonary hypertension. Platelets contain large amounts of sGC and play a key role in the regulation of haemostasis. Therefore, we investigated the effects of riociguat on platelet function. The effect of riociguat treatment on human platelet activation and aggregation was investigated. The sGC-specific effects of riociguat were determined by comparing wild-type and platelet-specific sGC-knockout mice. Riociguat induced cGMP synthesis and subsequent PKG activation in human platelets, suggesting that the inhibitory effects are mediated by cGMP signalling. This finding was confirmed when sGC-knockout platelets were not inhibited by riociguat. In washed human platelets, 100 nM riociguat reduced ADP-induced GPIIb/IIIa activation, while a 10-fold higher concentration was required to reduce convulxin-stimulated GPIIb/IIIa activation. Riociguat inhibited ADP-induced platelet shape change and aggregation, while ATP-induced shape change remained unaffected. However, in PRP and whole blood, 50-100 μM riociguat was required to inhibit platelet activation and aggregation. Riociguat in combination with iloprost significantly inhibited platelet aggregation, even in whole blood. Riociguat inhibits platelet activation in whole blood only at concentrations above 50 μM, while the plasma concentrations in riociguat-treated patients are 150 to 500 nM. This finding indicates that riociguat treatment does not affect platelet function in patients. Nevertheless, the possibility that riociguat acts synergistically with iloprost to inhibit platelet activation should be considered.

Calcium channel blockers for pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is one of several forms of pulmonary hypertension: a chronic disease of the pulmonary vasculature. The mean age at diagnosis is around 50 years old, with increasing prevalence in people over 70 years old (10% to 17%). The median survival to be approximately seven years with one-, three-, five-, and seven-year survival rates from time of diagnostic right-sided heart catheterization were 85%, 68%, 57%, and 49%, respectively. Several studies showed that calcium channel blockers (CCBs) reduce right ventricular hypertrophy and improve long-term haemodynamics in PAH. To evaluate the clinical efficacy and harms of CCBs for people with PAH. The search strategy was provided by the Cochrane Airways Group Trials Search Co-ordinator. The following databases were searched from their inception until September 2014: the Cochrane Airways Group Register of Trials (CAGR); the Cochrane Central Register of Controlled Clinical Trials (CENTRAL) (The Cochrane Library,Issue 8 2014); MEDLINE (1948 to September 2014); EMBASE (1974 to September 2014); ClinicalTrials.gov; WHO trial portal; the Chinese Biomedical Databases (1979 to September 2014); CNKI: the Chinese Journals Full Text Database (1979 to September 2014), the Chinese Journals Full Text Database Century Journals (1979 to September 2014), the Chinese Doctoral Degree Thesis Full Text Database (1979 to September 2014), the Chinese Outstanding Master Degree Thesis Full Text Database (1979 to September 2014); VIP Database (1989 to September 2014) and WANFANG Database (1993 to September 2014). No language restriction was applied. Fully published randomized controlled trials (RCTs) comparing CCBs with placebo or other treatment, or comparing CCBs as an adjunct to other treatments with other treatments alone, in patients with PAH. We used standard methods expected by Cochrane. We found one RCT to include in this review but it was published only in abstract form with no data for evaluation. Currently, as there is lack of valid evidence, the efficacy and safety of CCBs is unproven in the treatment of PAH. However, the search strategy used for this review did identify four controlled clinical trials without randomization, three of which suggested treatment with CCBs may be beneficial in PAH. No adverse side effects of CCBs were reported. Confirmation of these findings by RCTs is recommended.

The clinical development of sGC modulators, riociguat and vericiguat

Clinical background The NO – sGC – cyclic GMP pathway is a key pathway to regulate vascular tone. Its stimulation leads to vasodilatation; NO deficiency leads to vasoconstriction, inflammation and fibrotic remodelling. Riociguat and vericiguat are two representatives of modulators of the soluble guanylate cyclase and are able to increase cyclic GMP even in conditions of NO deficiency. Riociguat, a first lead sGC stimulator, was developed in two different forms of pulmonary hypertension (PH). PH is a rare, severe disease which untreated has a high morbidity and mortality. It is characterized by endothelial dysfunction, NO deficiency, vascular remodelling and results and devastating increases of the mean pulmonary artery pressure above 25 mm Hg. This condition leads to right heart failure, is associated with impaired exercise capacity and death. Riociguat has been successfully developed in two different forms of PH, pulmonary arterial hypertension (PAH, WHO group 1), and chronic thromboembolic pulmonary hypertension (CTEPH, WHO group 4). It was shown to significantly improve exercise capacity, time to clinical worsening, and also led to meaningful hemodynamic improvements. Riociguat (Trade name: Adempas) is now the first approved medical treatment for patients with CTEPH who are not eligible to undergo surgery, or who have residual disease after pulmonary endarterectomy. Riociguat's ongoing clinical development program includes PH-IIP and diffuse cutaneous sclerodermia, as well as an exploratory study in cystic fibrosis. Vericiguat is currently in late stage clinical development for the treatment of heart failure with reduced and also with preserved ejection fraction (HFrEF and HFpEF). Data from the LEPHT trial with riociguat in patients with PH due to left heart disease hint to the usefulness of sGC modulation in patients with heart failure. The SOCRATRES program studies the efficacy and safety of vericiguat in patients with HFrEF and HFpEF and assesses its effect on ventricular decongestion, as measured by the biomarker NT-pro BNP, and left atrial size. Results of that program will be reported later this year.

Current Concepts in Management of Pulmonary Hypertension: Fighting the Old Demon with Modern Weapons.

Pulmonary hypertension in children is a rare disease associated with high morbidity and mortality. The pathogenesis is not fully understood. Diagnostic evaluation focuses on ruling out other etiologies of pulmonary hypertension and prognosticating the disease. Congenital heart disease and left sided heart disease associated pulmonary hypertension are more common in children. Therapies for idiopathic pulmonary hypertension have evolved over the past decade. Phosphodiesterase 5 inhibitors (sildenafil, tadalafil), endothelin antagonists (Bosentan and ambrisentan) and prostanoids are the classes of drugs shown to be useful in pulmonary hypertension. However, use of these drugs in children is based on extrapolation of adult usage and on expert consensus rather than based on randomized controlled trial evidence. Despite these advances, the outcomes of various forms of pulmonary hypertension remain poor, especially in India, where some forms of therapy are not available and children often are diagnosed at an advanced stage of disease.

Pulmonary hypertension in obstructive sleep apnea: is it clinically significant? A critical analysis of the association and pathophysiology.

The development of pulmonary hypertension is a poor prognostic sign in patients with obstructive sleep apnea (OSA) and affects both mortality and quality of life. Although pulmonary hypertension in OSA is traditionally viewed as a result of apneas and intermittent hypoxia during sleep, recent studies indicate that neither of these factors correlates very well with pulmonary artery pressure. Human data show that pulmonary hypertension in the setting of OSA is, in large part, due to left heart dysfunction with either preserved or diminished ejection fraction. Longstanding increased left heart filling pressures eventually lead to pulmonary venous hypertension. The combination of hypoxic pulmonary vasoconstriction and pulmonary venous hypertension with abnormal production of mediators will result in vascular cell proliferation and aberrant vascular remodeling leading to pulmonary hypertension. These changes are in many ways similar to those seen in other forms of pulmonary hypertension and suggest shared mechanisms. The majority of patients with OSA do not receive a diagnosis and are undertreated. Appreciating the high prevalence and understanding the mechanisms of pulmonary hypertension in OSA would lead to better recognition and management of the condition.

Pulmonary hypertension: Possible genetic causes and therapeutic options

Pulmonary hypertension (PH) is a severe disease, which is usually only recognized at a late stage. It is characterized by dyspnea and right heart insufficiency. In some forms of pulmonary hypertension, such as the rare pulmonary arterial hypertension (PAH) and PAH associated with congenital heart defects, genetic factors have been identified. This article summarizes the general and supportive therapies for PH, targeted pharmaceutical treatment for PAH and non-operable chronic thromboembolic pulmonary hypertension. To achieve acceptable survival rates, it is essential to transfer patients to an expert center at an early stage for further differential diagnostics and therapy.

Pathophysiologic Principles in the Management of Severe PAH

In the face of tremendous advances in our understanding of the pathophysiology and new treatment options, for many patients, pulmonary arterial hypertension (PAH) remains a progressive condition. The often-relentless reduction in the cross-sectional area of the pulmonary vasculature leads to progressive increase in right ventricular (RV) afterload. Although the right ventricle can adapt to an increase in afterload, progression of the pulmonary vasculopathy in PAH causes many patients to develop progressive RV failure.1 Alternately, for those with other forms of pulmonary hypertension, worsening lung disease or cardiac disease may destabilize the RV function. Acute RV decompensation may be triggered by disorders that lead to either an acute increase in cardiac demand (such as sepsis, surgery, or pregnancy), or an increase in ventricular afterload (such as an interruption in medical therapy or pulmonary embolism), or destabilization of a compensated RV (such as arrhythmia or volume overload). The poor reserve of the RV, RV ischemia, and adverse RV influence on left ventricular filling may lead to a global reduction in oxygen delivery and multi-organ failure.2 The goals of this article are to provide an approach to right heart failure in the context of an increase in its afterload. This article will focus on pathophysiologic principles on which to build an approach to medical therapies. Mechanical and surgical strategies will be the focus in the accompanying article by Dr de Perrot.

Distinct Forms of Pulmonary Hypertension Complicate Hereditary Hemorrhagic Telangiectasia

Pulmonary hypertension (PH) associated with hereditary hemorrhagic telangiectasia (HHT) occurs most commonly as a consequence of high-output heart failure related to excessive shunting through visceral vascular malformations. A smaller number of HHT patients develop a form of heritable pulmonary arterial hypertension, characterized by an elevated pulmonary vascular resistance with normal left heart filling pressures. In this review, we will discuss the clinical manifestations of HHT in general, the pathophysiology behind the different forms of PH associated with HHT, and the clinical care of the HHT patient with PH.

New Thematic Series

HomeCirculationVol. 130, No. 20New Thematic Series Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBNew Thematic SeriesRecent Advances in Pulmonary Hypertension Jane A. Leopold, MD and Bradley A. Maron, MD Jane A. LeopoldJane A. Leopold Co-Series Editors Search for more papers by this author and Bradley A. MaronBradley A. Maron Co-Series Editors Search for more papers by this author Originally published11 Nov 2014https://doi.org/10.1161/CIRCULATIONAHA.114.013548Circulation. 2014;130:1771Pulmonary hypertension is associated with a high degree of morbidity and mortality in patients with World Health Organization Group 1 pulmonary hypertension (pulmonary artery hypertension) as well as Groups 2 to 5 pulmonary hypertension (pulmonary hypertension attributable to left heart disease, lung disease, thromboembolic disease, and miscellaneous causes, respectively). Historically, the underlying cause of pulmonary hypertension coupled with a defining hemodynamic profile has been used for the clinical classification of patients into different groups, in part, to facilitate management. Over the past several years, advances in the field have increased our understanding of the pathobiology, clinical course, and treatment outcomes for patients with pulmonary hypertension. Along these lines, recent findings from randomized, clinical trials have demonstrated efficacy of novel therapeutics and expanded treatment options for this important cardiopulmonary disease.In this thematic series in Circulation on Recent Advances in Pulmonary Hypertension, a group of experts will discuss progress in the field and remaining controversies that are likely to have broad applicability to patients with different forms of pulmonary hypertension. The topics reviewed will cover practical considerations in the care of patients with pulmonary hypertension, such as clinical diagnosis, therapeutic interventions, use of noninvasive imaging to evaluate pulmonary vascular-right ventricular function, and the role of mechanical support for the failing right ventricle. Next, select populations of patients with pulmonary hypertension who clinicians may encounter in practice will be discussed, including patients with congenital heart disease, human immunodeficiency virus, or those who develop pulmonary hypertension as a consequence of exposure to high altitude. The series will also provide a focused review of current end points used in clinical trials and their attendant limitations as a consideration for how to interpret findings from previous studies as well as design future trials in this field. Finally, recent translational advances with clinical implications for patients with pulmonary hypertension in the areas of cellular metabolism, neurohumoral signaling, and sex hormones will be reviewed. Together, the reviews in this series aim to provide the reader with a state-of-the art view of diagnostic modalities and therapeutic interventions as well as an introduction to new frontiers in the care of patients afflicted with this heterogeneous and complex disease. Previous Back to top Next FiguresReferencesRelatedDetails November 11, 2014Vol 130, Issue 20 Advertisement Article InformationMetrics © 2014 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.114.013548 Originally publishedNovember 11, 2014 PDF download Advertisement SubjectsHeart Failure

Genetics of pulmonary hypertension.

The identification of the genetic basis for heritable predisposition to pulmonary arterial hypertension (PAH) has altered the clinical and research landscape for PAH patients and their care providers. This review aims to describe the genetic discoveries and their impact on clinical medicine. Since the landmark discovery that bone morphogenetic protein receptor type II (BMPR2) mutations cause the majority of cases of familial PAH, investigators have discovered mutations in genes that cause PAH in families without BMPR2 mutations, including the type I receptor ACVRL1 and the type III receptor ENG (both associated with hereditary hemorrhagic telangiectasia), caveolin-1 (CAV1), and a gene (KCNK3) encoding a two-pore potassium channel. Mutations in these genes cause an autosomal-dominant predisposition to PAH in which a fraction of mutation carriers develop PAH (incomplete penetrance). In 2014, scientists discovered mutations in eukaryotic initiation factor 2 alpha kinase 4 (EIF2AK4) that cause pulmonary capillary hemangiomatosis and pulmonary veno-occlusive disease, an autosomal recessively inherited disorder. The discovery that some forms of pulmonary hypertension are heritable and can be genetically defined adds important opportunities for physicians to educate their patients and their families to understand the potential risks and benefits of genetic testing.

Vascular receptor autoantibodies in pulmonary arterial hypertension associated with systemic sclerosis.

Systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH) portends worse outcome than other forms of PAH. Vasoconstrictive and vascular remodeling actions of endothelin (ET) 1 and angiotensin (Ang) II via endothelin receptor type A (ETAR) and Ang receptor type-1 (AT1R) activation are implicated in PAH pathogenesis. We hypothesized that stimulating autoantibodies (Abs) targeting and activating AT1R and ETAR may contribute to SSc-PAH pathogenesis, and tested their functional and biomarker relevance. Anti-AT1R and -ETAR Abs were detected by ELISA in different cohorts of patients and tested in vitro and in an animal model for their pathophysiological effects. The Abs were significantly higher and more prevalent in patients with SSc-PAH (n = 81) and connective tissue disease-associated PAH (n = 110) compared with other forms of PAH/pulmonary hypertension (n = 106). High anti-AT1R and anti-ETAR Abs predicted development of SSc-PAH and SSc-PAH-related mortality in a prospective analysis. Both Abs increased endothelial cytosolic Ca(2+) concentrations in isolated perfused rat lungs, which could be blocked by respective specific receptor antagonists. Ab-mediated stimulation of intralobar pulmonary rat artery ring segments increased vasoconstrictive responses to Ang II and ET-1, and implicated cross-talk between both pathways demonstrated by reciprocal blockade with respective antagonists. Transfer of SSc-IgG containing both autoantibodies into healthy C57BL/6J mice led to more abundant vascular and airway α-smooth muscle actin expression and inflammatory pulmonary vasculopathy. Anti-AT1R and -ETAR Abs are more frequent in SSc-PAH/connective tissue disease-PAH compared with other forms of pulmonary hypertension, and serve as predictive and prognostic biomarkers in SSc-PAH. Both antibodies may contribute to SSc-PAH via increased vascular endothelial reactivity and induction of pulmonary vasculopathy.

The vascular bed in COPD: pulmonary hypertension and pulmonary vascular alterations.

The loss of pulmonary vessels has been shown to be related to the severity of pulmonary hypertension in patients with chronic obstructive pulmonary disease (COPD). The severity of hypoxaemia is also related to pulmonary hypertension and pulmonary vascular resistance in these patients, suggesting that the hypoxic condition probably plays an important role in this form of pulmonary hypertension. However, pulmonary hypertension also develops in patients with mild COPD without hypoxaemia. Oxygen supplementation therapy often fails to reverse the pulmonary hypertension in these COPD patients, thus suggesting that the pulmonary vascular alterations in those patients may involve different sites of the pulmonary vasculature or a different form of vascular remodelling. It has recently been demonstrated that pulmonary vascular remodelling, resulting in pulmonary hypertension in COPD patients, can develop independently from parenchymal destruction and loss of lung vessels. We wonder whether the changes in the lung microenvironment due to hypoxia and vessel loss have a causative role in the development of pulmonary hypertension in patients with COPD. Herein we review the pathobiological features of the pulmonary vasculature in COPD patients and suggest that pulmonary hypertension can occur with and without emphysematous lung tissue destruction and with and without loss of lung vessels.

L-citrulline provides a novel strategy for treating chronic pulmonary hypertension in newborn infants.

Effective therapies are urgently needed for infants with forms of pulmonary hypertension that develop or persist beyond the first week of life. The L-arginine nitric oxide (NO) precursor, L-citrulline, improves NO signalling and ameliorates pulmonary hypertension in newborn animals. In vitro studies demonstrate that manipulating L-citrulline transport alters NO production. Strategies that increase the supply and transport of L-citrulline merit pursuit as novel approaches to managing infants with chronic, progressive pulmonary hypertension.

Chronic Thromboembolic Pulmonary Hypertension (CTEPH) – Potential Role of Multidetector-Row CT (MD-CT) and MR Imaging in the Diagnosis and Differential Diagnosis of the Disease

Chronic thromboembolic pulmonary hypertension (CTEPH) can be defined as pulmonary hypertension (resting mean pulmonary arterial pressure of 25 mm Hg or more determined at right heart catheterization) with persistent pulmonary perfusion defects. It is a rare, but underdiagnosed disease with estimated incidences ranging from 0.5% to 3.8% of patients after an acute pulmonary embolism (PE), and in up to 10% of those with a history of recurrent PE. CTEPH is the only form of pulmonary hypertension that can be surgically treated leading to normalization of pulmonary hemodynamics and exercise capacity in the vast majority of patients. The challenges for imaging in patients with suspected CTEPH are fourfold: the imaging modality should have a high diagnostic accuracy with regard to the presence of CTEPH and allow for differential diagnosis. It should enable detection of patients suitable for PEA with great certainty, and allow for quantification of PH by measuring pulmonary hemodynamics (mPAP and PVR), and finally, it can be used for therapy monitoring. This overview tries to elucidate the potential role of ECG-gated multidetector CT pulmonary angiography (MD-CTPA) and MR imaging, and summarizes the most important results that have been achieved so far. Generally speaking, ECG-gated MD-CTPA is superior to MR in the assessment of parenchymal and vascular pathologies of the lung, and allows for the assessment of cardiac structures. The implementation of iodine maps as a surrogate for lung perfusion enables functional assessment of lung perfusion by CT. MR imaging is the reference standard for the assessment of right heart function and lung perfusion, the latter delineating typical wedge-shaped perfusion defects in patients with CTEPH. New developments show that with MR techniques, an estimation of hemodynamic parameters like mean pulmonary arterial pressure and pulmonary vascular resistance will be possible. CT and MR imaging should be considered as complementary investigations providing comprehensive information in patients with CTEPH.