Inflammation in pulmonary arterial hypertension. P. Dorfmüller, F. Perros, K. Balabanian, M. Humbert. #ERS Journals Ltd 2003. ABSTRACT: Inflammatory mechanisms appear to play a significant role in some types of pulmonary hypertension (PH), including monocrotaline-induced PH in rats and pulmonary arterial hypertension of various origins in humans, such as connective tissue diseases (scleroderma, systemic lupus erythematosus, mixed connective disease), human immunodeficiency virus infection, or plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal (M) protein and skin changes (POEMS) syndrome.Interestingly, some patients with severe pulmonary arterial hypertension associated with systemic lupus erythematosus have experienced significant improvements with immunosuppressive therapy, emphasising the relevance of inflammation in a subset of patients presenting with PH. Patients with primary PH (PPH) also have some immunological disturbances, suggesting a possible role for inflammation in the pathophysiology of this disease. A subset of PPH patients have been shown to have circulating autoantibodies, including antinuclear antibodies, as well as elevated circulating levels of the pro-infammatory cytokines, interleukins -1 and -6. Lung histology has also revealed inflammatory infiltrates in the range of plexiform lesions in patients displaying severe PPH, as well as an increased expression of the chemokines regulated upon activation, normal T-cell expressed and secreted (RANTES) and fractalkine.Further analysis of the role of inflammatory mechanisms is necessary to understand whether this component of the disease is relevant to its pathophysiology. Pulmonary arterial hypertension (PAH) is characterised by an elevated mean pulmonary artery pressure o25 mmHg at rest, with a normal pulmonary artery wedge pressure. This severe condition leads to progressive right heart failure and ultimately death [1]. The Evian Classification reflects recent advances in the understanding of pulmonary hypertensive diseases, and recognises the similarity between "unexplained" pulmonary hypertension (PH) (primary PH (PPH)) and PAH of certain known aetiologies, such as collagen vascular diseases, human immunodeficiency virus (HIV) infection, portal hypertension, congenital systemic-to-pulmonary shunts and anorexigen exposure [2].PAH results from chronic obstruction of small pulmonary arteries, which is due, at least in part, to endothelial and vascular smooth muscle cell dysfunction and proliferation [3]. The recent discovery that a significant proportion of patients with familial, as well as sporadic, PPH have germline mutations of genes encoding receptor members of the transforming growth factor (TGF)-b family (bone morphogenetic protein receptor-II and activin receptor-like kinase-1), suggests that dysfunctional TGF-b signalling could lead to an abnormal proliferation of pulmonary vascular cells [4,5]. Although these major advances have improved the understanding of PAH, more information is needed to evaluate th...

Pulmonary veno-occlusive disease (PVOD) is currently classified as a subgroup of pulmonary arterial hypertension (PAH) and accounts for 5-10% of cases initially considered to be idiopathic PAH. PVOD has been described as idiopathic or complicating other conditions, including connective tissue diseases, HIV infection, bone marrow transplantation, sarcoidosis and pulmonary Langerhans cell granulomatosis. PVOD shares broadly similar clinical presentation, genetic background and haemodynamic characteristics with PAH. Compared to PAH, PVOD is characterised by a higher male/female ratio, higher tobacco exposure, lower arterial oxygen tension at rest, lower diffusing capacity of the lung for carbon monoxide, and lower oxygen saturation nadir during the 6-min walk test. High-resolution computed tomography (HRCT) of the chest can be suggestive of PVOD in the presence of centrilobular ground-glass opacities, septal lines and lymph node enlargement. Similarly, occult alveolar haemorrhage is associated with PVOD. A noninvasive diagnostic approach using HRCT of the chest, arterial blood gases, pulmonary function tests and bronchoalveolar lavage could be helpful for the detection of PVOD patients and in avoiding high-risk surgical lung biopsy for histological confirmation. PVOD is characterised by a poor prognosis and the possibility of developing severe pulmonary oedema with specific PAH therapy. Lung transplantation is the treatment of choice. Cautious use of specific PAH therapy can, however, be helpful in some patients.KEYWORDS: Alveolar haemorrhage, BMPR2, computed tomography, diffusing capacity of the lung for carbon monoxide, pulmonary arterial hypertension, pulmonary veno-occlusive disease P ulmonary arterial hypertension (PAH) is a severe condition characterised by elevated pulmonary artery pressure leading to right heart failure and death [1,2]. Pulmonary veno-occlusive disease (PVOD) is classified as a subgroup of PAH and accounts for 5-10% of histological forms of cases initially considered to be idiopathic PAH. Even though the first welldocumented case of PVOD was described .70 yrs ago, the characteristics and pathophysiology of this disease remain poorly understood [3,4]. While pulmonary vascular pathology of idiopathic or familial PAH is characterised by a major remodelling of small pre-capillary pulmonary arteries with typical plexiform and/or thrombotic lesions, PVOD preferentially affects the post-capillary venous pulmonary vessels [5,6]. Despite this anatomical histological difference, PVOD has a very similar clinical presentation to PAH but is characterised by a worse prognosis and the possibility that severe pulmonary oedema can develop with specific PAH therapy, justifying the importance of diagnosing this disease. A definitive diagnosis of PVOD requires histological analysis of a lung sample [7,8]; however, surgical lung biopsy is a high-risk procedure in these patients and the development of a less invasive diagnostic approach would be preferable [9][10][11]. The present manuscript will summa...

IntroductionPulmonary vascular dysfunction, pulmonary hypertension (PH), and resulting right ventricular (RV) failure occur in many critical illnesses and may be associated with a worse prognosis. PH and RV failure may be difficult to manage: principles include maintenance of appropriate RV preload, augmentation of RV function, and reduction of RV afterload by lowering pulmonary vascular resistance (PVR). We therefore provide a detailed update on the management of PH and RV failure in adult critical care.MethodsA systematic review was performed, based on a search of the literature from 1980 to 2010, by using prespecified search terms. Relevant studies were subjected to analysis based on the GRADE method.ResultsClinical studies of intensive care management of pulmonary vascular dysfunction were identified, describing volume therapy, vasopressors, sympathetic inotropes, inodilators, levosimendan, pulmonary vasodilators, and mechanical devices. The following GRADE recommendations (evidence level) are made in patients with pulmonary vascular dysfunction: 1) A weak recommendation (very-low-quality evidence) is made that close monitoring of the RV is advised as volume loading may worsen RV performance; 2) A weak recommendation (low-quality evidence) is made that low-dose norepinephrine is an effective pressor in these patients; and that 3) low-dose vasopressin may be useful to manage patients with resistant vasodilatory shock. 4) A weak recommendation (low-moderate quality evidence) is made that low-dose dobutamine improves RV function in pulmonary vascular dysfunction. 5) A strong recommendation (moderate-quality evidence) is made that phosphodiesterase type III inhibitors reduce PVR and improve RV function, although hypotension is frequent. 6) A weak recommendation (low-quality evidence) is made that levosimendan may be useful for short-term improvements in RV performance. 7) A strong recommendation (moderate-quality evidence) is made that pulmonary vasodilators reduce PVR and improve RV function, notably in pulmonary vascular dysfunction after cardiac surgery, and that the side-effect profile is reduced by using inhaled rather than systemic agents. 8) A weak recommendation (very-low-quality evidence) is made that mechanical therapies may be useful rescue therapies in some settings of pulmonary vascular dysfunction awaiting definitive therapy.ConclusionsThis systematic review highlights that although some recommendations can be made to guide the critical care management of pulmonary vascular and right ventricular dysfunction, within the limitations of this review and the GRADE methodology, the quality of the evidence base is generally low, and further high-quality research is needed.

Acute right ventricular failure in the setting of pulmonary arterial hypertension (PAH) often requires hospitalisation in intensive care units (ICU) to manage the subsequent low cardiac output and its consequences. There are very few data on these acute events.We recorded demographic, clinical and biological data and therapy in consecutive patients suffering from acute right heart failure requiring catecholamine treatment in the ICU of the French referral centre for pulmonary hypertension. These variables were analysed according to the survival status in ICU.46 patients were included, the mean age was 50.3 yrs. ICU mortality was 41%. We found no difference in terms of demographics, clinical data, last haemodynamic measurements at admission. Systemic arterial pressure was significantly lower in the subgroup of patients whose clinical course was fatal. Plasma brain natriuretic peptide (BNP), C-reactive protein (CRP), serum sodium and creatinine at admission correlated with survival. Demonstration of an infection during the ICU stay was associated with a worse prognosis.These preliminary results underline the importance of some simple clinical and biological parameters in the prognostic evaluation of acute heart failure in the setting of PAH. Whether these parameters can guide therapy needs to be further investigated.

Abbreviations: COPD, chronic obstructive pulmonary disease; FEV 1 , forced expiratory volume in 1 second; LOS, length of stay 837 www.thoraxjnl.com

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, essentially in the screening proposing criteria for estimating the presence of PH mainly based on tricuspid regurgitation peak velocity and systolic artery pressure (sPAP). The therapy of PAH consists of non-specific drugs including oral anticoagulation and diuretics as well as PAH specific therapy. Diuretics are one of the most important treatment in the setting of PH because right heart failure leads to fluid retention, hepatic congestion, ascites and peripheral edema. Current recommendations propose oral anticoagulation aiming for targeting an International Normalized Ratio (INR) between 1.5-2.5. Target INR for patients displaying chronic thromboembolic PH is between 2–3. Better understanding in pathophysiological mechanisms of PH over the past quarter of a century has led to the development of medical therapeutics, even though no cure for PAH exists. Several specific therapeutic agents were developed for the medical management of PAH including prostanoids (epoprostenol, trepoprostenil, iloprost), endothelin receptor antagonists (bosentan, ambrisentan) and phosph...

In IPAH, c-kit(+) cells infiltrate pulmonary arterial lesions and may participate to vascular remodeling. Therefore, c-kit may represent a potential target for innovative PAH therapy.

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