Pulmonary hypertension and right ventricular failure. Part X. Prostanoids in the treatment of primary pulmonary arterial hypertension

In a series of articles the authors discuss literature data concerning epidemiology of pulmonary arterial hypertension (PAH), its modern classification; peculiarities of its pathogenesis and treatment in various diseases and conditions. The tenth communication contains consideration of results of controlled trials of prostacyclin and its synthetic analogues in patients with primary (idiopathic) PAH, and PAH associated with diffuse diseases of connective tissue, congenital heart disease, HIV-infection. Continuous intravenous infusion of prostacyclin (epoprostenol) has made a revolution in the treatment of patient with severe PAH because its long-term use is associated with improvement of survival of patients refractory to high doses of calcium antagonists. Subcutaneous administration of treprostinil and especially inhaled iloprost substantially widen possibilities of prolonged use of prostanoids in patients with various forms of PAH. Literature data on application of different prostanoids for long term treatment of patients with PAH, their side effects, indications and counterindications for their administration are analyzed in this communication.     

Pulmonary hypertension and right ventricular failure. Part XII. Nitrous oxide and phosphodiesterase inhibitors in the treatment of primary pulmonary arterial hypertension

In a series of articles the authors discuss literature data concerning epidemiology of pulmonary arterial hypertension (PAH), its modern classification; peculiarities of its pathogenesis and treatment in various diseases and conditions. The twelfth communication contains consideration of inhaled nitrous oxide and three available inhibitors of phosphodiesterase type 5 (sildenafil, tadalafil, and vardenafil). The place of nitrous oxide in diagnostics and short term treatment of PAH is discussed. Analysis of results of randomized controlled studies assessing efficacy and safety of sildenafil in patients with primary (idiopathic) PAH and PAH associated with connective tissue diseases and congenital heart diseases with systemic-to-pulmonary shunts is presented.     

Pulmonary hypertension and right ventricular failure. Part VI. Classification and pathomorphology of primary pulmonary arterial hypertension

In a series of articles the authors discuss literature data concerning epidemiology of pulmonary hypertension (PH), its modern classification; peculiarities of its pathogenesis and treatment in various diseases and conditions. In the sixth communication they present classification of PH accepted at the Third World PH Symposium (venice, Italy, 2003). This classification abandons terms "primary" and "secondary" PH. Primary PH which is now recommended to be called "idiopathic pulmonary arterial hypertension" is grouped in one category with familial cases of PH, PH associated with administration of anorexigens, collagen vascular disease, congenital systemic to pulmonary shunts, portal hypertension and hyperthyroidism, as well as with pulmonary veno-occlusive disease and and pulmonary capillary hemangiomatosis, taking into consideration similarity of histopathological changes of vascular tree, pathophysiology and therapeutic approaches in these forms of PH.     

Pulmonary hypertension and right ventricular failure. Part VII. Epidemiology, risk factors, and pathogenesis of primary (idiopathic) pulmonary arterial hypertension

In a series of articles the authors discuss literature data concerning epidemiology of pulmonary arterial hypertension (PAH), its modern classification; peculiarities of its pathogenesis and analysis of results of epidemiological and cohort studies. Rate of new cases of PAH is 1-2, prevalence - approximately 15 cases per million of adult population. This part contains detailed discussion of definite, probable and possible risk factors of PAH which comprise some drugs (anorexigens, amphetamines, meta- amphetamines), HIV infection, collagen vascular diseases, congenital systemic-to-pulmonary shunts, portal hypertension, and some hematological diseases. Analysis of literature data concerning interaction of genetic predisposition and factors of internal and external environment in pathogenesis of PAH as well as presentation of direct and indirect proofs of key role of serotonin in pathogenesis of PAH of various genesis are also included.     

Pulmonary hypertension and right ventricular failure. Part XIV. Differentiated therapy of primary (idiopathic) and associated forms of pulmonary arterial hypertension

In a series of articles the authors discuss literature data concerning epidemiology of pulmonary arterial hypertension (PAH), its modern classification, peculiarities of its pathogenesis and treatment in various diseases and conditions. The last 14-th communication contains consideration of issues of differentiated administration of modern pulmonary vasodilators to patients with PAH taking into account etiology and severity of the disease, availability of evidence based efficacy and safety data, method of application, and contraindications. In patients with PAH of II and III functional class (FC) endothelin receptor blocker bosentan is believed to be the drug of first choice. Bosentan can be administered orally. In patients with significant liver involvement phosphodiesterase inhibitor type 5 sildenafil should be used instead of bosentan for long term treatment of PAH. Sildenafil also can be taken orally. If bosentan is not sufficiently effective it can be combined with sildenafil; inhalations of prostanoid iloprost can be added to this combination when necessary. Is this tiple combination is not effective iloprost inhalations can be replaced by subcutaneous treprostinil or continuous intravenous infusion of epoprostenol. In patients with IV FC PAH therapy is started with subcutaneous administration of treprostinil or infusion of epoprostenol, while bosentan or/and sildenafil is added when necessary.     

Long-term outcomes in children with pulmonary arterial hypertension treated with bosentan in real-world clinical settings

Treatment algorithms in pediatric pulmonary arterial hypertension (PAH) are derived from clinical trials in adult populations and from clinical practice, but experience in children is limited. In this retrospective cohort study, we analyzed outcomes in a previously identified cohort of 86 consecutive children with PAH treated with bosentan as part of their treatment regimen. All children with idiopathic PAH or heritable PAH and PAH associated with congenital heart disease or connective tissue disease who started bosentan treatment from May 2001 to April 2003 in 2 tertiary pediatric referral centers were followed, with data collection ending August 2006. Eighty-six children (37 male, 49 female) 11 ± 5 years of age with idiopathic/heritable PAH (n = 36), PAH associated with congenital heart disease (n = 48), or PAH associated with connective tissue disease (n = 2) received bosentan as monotherapy (n = 42) or as an add-on to pre-existing continuous intravenous epoprostenol or subcutaneous treprostinil (n = 44). Median observation period was 39 months (range 2 to 60). Thirty-four patients (40%) received ≥1 additional PAH-specific therapy during follow-up. At end of data collection, 25 patients (29%) remained on bosentan, 43 (50%) had stopped bosentan, 11 (13%) had died while on bosentan, and 7 were lost to follow-up. At 4 years, the Kaplan-Meier estimate of disease progression in patients while on bosentan was 54% (7 patients at risk) with a survival estimate of 82% (16 patients at risk). Risk factors significantly associated with survival were World Health Organization functional class and indexed pulmonary vascular resistance. In conclusion, outcome in children with PAH managed with current treatment regimens appears favorable. However, despite current therapy options, disease progression remains a concern.     

Pulmonary arterial hypertension (PAH) in connective tissue diseases

Pulmonary arterial hypertension (PAH) is characterized by progressive obliteration of the small pulmonary vascular bed as a result of vascular proliferation and remodelling of the vessel wall leading to permanently increased pulmonary vascular resistance and elevated pulmonary artery pressures, which result in right heart failure and premature death. Pathologic processes behind the complex vascular changes associated with PAH include vasoconstrictor/vasodilator imbalance, thrombosis, misguided angiogenesis and inflammation. Besides idiopathic PAH, it can also occur in association with portal hypertension, HIV infection, congenital cardiac left-to-right shunts and connective tissue diseases (CTD). Unfortunately, despite recent major improvements in PAH treatment, no current therapy can yet cure this devastating condition. This review will briefly highlight epidemiology, pathogenesis, and diagnostic and treatment options known so far for PAH occurring in connection with CTD.     

Pulmonary hypertension and right ventricular failure. Part III. Patients with congenital heart disease

In a series of articles the authors discuss literature data concerning epidemiology of pulmonary hypertension, its modern classification, peculiarities of its pathogenesis and treatment in various diseases and conditions. In the third lecture they consider peculiarities of pathogenesis of pulmonary hypertension and right ventricular failure in patients with congenital heart defects, and present literature data on drug treatment and other curative interventions in pulmonary hypertension in patients with Eisenmenger syndrome.     

Prevalence of pulmonary arterial hypertension in patients with connective tissue diseases: a systematic review of the literature

Pulmonary arterial hypertension (PAH) is a progressive and life-threatening disease. Understanding of PAH prevalence remains limited, but PAH has been reported as a frequent complication in connective tissue diseases. This study estimated prevalence of PAH in patients with connective tissue diseases and prevalence of idiopathic PAH using a systematic review of the literature. We searched PubMed through May 19, 2012 for all studies on prevalence of PAH in patients with connective tissue diseases or prevalence of idiopathic PAH. To be included, studies had to be in English, have humans as subjects, and determine prevalence within a time interval of up to 2 years. Studies only investigating pediatric patients were excluded. Pooled prevalence estimates were calculated. Twenty studies were identified in the review. Seventeen of the 20 studies reported prevalence of PAH in connective tissue diseases and three reported prevalence of idiopathic PAH. The pooled prevalence estimate of idiopathic PAH was 12 cases per million population (95 % CI 5 cases per million to 22 cases per million) with estimates ranging from 5.9 cases per million population to 25 cases per million population. The pooled prevalence estimate of PAH in patients with connective tissue diseases was 13 % (95 % CI, 9.18 % to 18.16 %) with reported estimates ranging from 2.8 % to 32 %. Prevalence of PAH in patients with connective tissue diseases was substantially higher than that of idiopathic PAH based on pooled prevalence estimates. Comparisons of PAH prevalence in persons with connective tissue disease and idiopathic PAH using a large observational study would be helpful in better assessing relative prevalence.     

Pulmonary hypertension and right ventricular failure. Part IX. Traditional therapy of primary pulmonary arterial hypertension

In a series of articles the authors discuss literature data concerning epidemiology of pulmonary hypertension (PH), its modern classification; peculiarities of its pathogenesis and treatment in various diseases and conditions. In the nine communication they describe presentations of PH and methods of its instrumental diagnostics. This part also contains discussion of problems of differential diagnosis of diseases which can be complicated by PH, contemplation of natural course of primary (idiopathic) PH and factors determining its prognosis.     

Investigation of pulmonary hypertension

Pulmonary hypertension (PH) is defined by a mean pulmonary artery pressure (PAPm) superior than 25mmHg at rest or superior than 30mmHg with exercise. The classification of PH differentiates between "secondary" PH which results from a well-known disease, such as PH due to thromboembolic disease (obstructive PH), left cardiac failure (passive PH), or chronic respiratory diseases (hypoxic PH), and pulmonary arterial hypertension (PAH). PAH is a rare disease characterized by a progressive increase of pulmonary vascular resistance leading to right ventricular failure. PAH is classified as idiopathic, familial, or associated with various conditions (connective tissue diseases, congenital heart diseases with systemic-to-pulmonary shunts, portal hypertension, infection with the human immunodeficiency virus, or appetite-suppressant drugs). Transthoracic Doppler echocardiography is the investigation of choice for non invasive detection of PAH but right-heart catheterization is necessary to confirm the diagnosis of PAH and determine its mechanism. Pulmonary function tests and chest CT scan may detect an underlying chronic pulmonary disease (hypoxic PH). Lung perfusion scan and contrast-enhanced chest spiral CT scan can lead to the diagnosis of thromboembolic PH, which is to be confirmed by pulmonary angiography. Assessment of the severity of PH is based on clinical parameters (NYHA, right heart failure), functional tests (six-minute walk test), echocardiography and hemodynamics. Characterization of PH is essential in the management of PH because it determines the appropriate treatment: an etiological treatment in passive, obstructive or hypoxemic PH, or vasodilatator and antiproliferative therapies in PAH.     

Pulmonary hypertension and right ventricular failure. Part VIII. Diagnosis, course, and prognosis of primary (idiopathic) pulmonary arterial hypertension

In a series of articles the authors discuss literature data concerning epidemiology of pulmonary hypertension (PH), its modern classification; peculiarities of its pathogenesis and treatment in various diseases and conditions. In the eight communication they describe presentations of PH and methods of its instrumental diagnostics. This part also contains discussion of problems of differential diagnosis of diseases which can be complicated by PH, contemplation of natural course of primary (idiopathic) PH and factors determining its prognosis.     

Pulmonary arterial hypertension in systemic lupus erythematosus

Pulmonary hypertension (PH) is a serious complication of connective tissue diseases. The prevalence of PH in systemic lupus erythematosus (SLE) ranges from 0.5 to 17.5%, depending on whether echocardiography or right heart catheterization is used as the gold standard for diagnosis. The recent guidelines for the diagnosis and treatment of pulmonary hypertension include several potential causes of PH in SLE, including: a primary vasculopathy similar to idiopathic pulmonary arterial hypertension (PAH); left heart diseases; post-thromboembolic disease; hypoxia and fibrosis resulting from interstitial lung disease; and the infrequent SLE-associated pulmonary veno-occlusive disease. The pathogenesis of PAH associated with lupus is yet unclear, but likely includes a role for the genetic background, the presence of antiphospholipid antibodies, and some level of endothelial dysfunction. The evolution of SLE-associated PH is highly variable and difficult to elicit because the published series have used heterogeneous inclusion criteria. Optimal therapeutic management of PAH associated with lupus is unclear because no dedicated randomized controlled trial is yet available. Treatment usually includes arterial pulmonary vasodilators and immunosuppressive agents when the patients have NYHA functional class II, III or IV dyspnea.     

Pulmonary hypertension in connective tissue diseases: an update

Pulmonary hypertension (PH) is a relatively commoner complication of systemic sclerosis (SSc) with estimated prevalence ranging between 8% and 12% as compared to much lower figures in other connective tissue diseases (CTD). It is a major cause of morbidity and mortality in CTDs. PH is classified into five major groups. CTD‐associated PH belongs to group 1 PH, also known as pulmonary arterial hypertension (PAH). Around 30% of scleroderma‐related deaths are due to PAH. Underlying pathogenesis is related to pulmonary vasculopathy involving small vessels. The Evidence‐based Detection of Pulmonary Arterial Hypertension in Systemic sclerosis (DETECT) algorithm outperforms the current European Society of Cardiology/European Respiratory Society guidelines as a screening tool in SSc‐PAH; it can, therefore, suggest when to refer a patient for right heart catheterization. CTD‐PAH patients constitute at least 20% of patients included in all major trials of PH‐specific therapy and the results are comparable to those of idiopathic PAH. The role of anticoagulation in CTD‐PAH is associated with a high risk‐benefit ratio with the caveat of its potential role in those with severe disease. There appears to be no role of immunosuppression in scleroderma‐PAH; however, immunosuppressive agents, namely the combination of glucocorticoids and pulse cyclophosphamide / possibly mycophenolate, may result in clinical improvement in a subset of patients with systemic lupus erythematosus and mixed connective tissue disease‐related PAH.     

Pulmonary hypertension and right ventricular failure. Part XIII. Surgical methods of treatment of various forms of pulmonary arterial hypertension

In a series of articles the authors discuss literature data concerning epidemiology of pulmonary arterial hypertension (PAH), its modern classification; peculiarities of its pathogenesis and treatment in various diseases and conditions. The 13-th communication contains consideration of surgical and interventional procedures used in treatment of patients with severe PAH when drug therapy is not feasible or ineffective. Discussion of criteria of selection of patients for lung transplantation, balloon atrial septostomy, and pulmonary thromboendarterectomy, as well as immediate and long term results of these surgical interventions is also presented. Balloon atrial septostomy is usually performed as a " bridge " to lung transplantation. Pulmonary thromboendarterectomy is used in patients with severe PAH caused by chronic pulmonary artery thromboembolism when 3 month intravenous therapy with epoprostenol turns out to be ineffective.     

Effects of long-term bosentan in children with pulmonary arterial hypertension

OBJECTIVES: This study investigated the long-term outcome of children with pulmonary arterial hypertension (PAH) treated with bosentan therapy, with or without concomitant prostanoid therapy. BACKGROUND: Bosentan, an oral endothelin ET(A)/ET(B) receptor antagonist, improves hemodynamics and exercise capacity in adults with PAH; however, limited data are available on its long-term effects in children. METHODS: In this retrospective study, 86 children with PAH (idiopathic, associated with congenital heart or connective tissue disease) started bosentan with or without concomitant intravenous epoprostenol or subcutaneous treprostinil therapy. Hemodynamics, World Health Organization (WHO) functional class, and safety data were collected. RESULTS: At the cutoff date, 68 patients (79%) were still treated with bosentan, 13 (15%) were discontinued, and 5 (6%) had died. Median exposure to bosentan was 14 months. In 90% of the patients (n = 78), WHO functional class improved (46%) or was unchanged (44%) with bosentan treatment. Mean pulmonary artery pressure and pulmonary vascular resistance decreased (64 +/- 3 mm Hg to 57 +/- 3 mm Hg, p = 0.005 and 20 +/- 2 U x m2 to 15 +/- 2 U x m2, p = 0.01, respectively; n = 49). Kaplan-Meier survival estimates at one and two years were 98% and 91%, respectively. The risk for worsening PAH was lower in patients in WHO functional class I/II at bosentan initiation than in patients in WHO class III/IV at bosentan initiation. CONCLUSIONS: These data suggest that bosentan, an oral endothelin ET(A)/ET(B) receptor antagonist, with or without concomitant prostanoid therapy, is safe and efficacious for the treatment of PAH in children.     

Pulmonary arterial hypertension and rheumatic diseases--from diagnosis to treatment

Survival rates in pulmonary arterial hypertension (PAH) associated with rheumatic diseases, in particular connective tissue diseases such as systemic sclerosis, are even lower than in idiopathic PAH. These low survival rates highlight the need for early diagnosis and treatment in these patients. Transthoracic Doppler-echocardiography is most often used for diagnostic screening of patients at risk. Other screening tests are serum pro-brain-natriuretic peptide (pro-BNP) and diffusion capacity for carbon monoxide (DLCO), which appear to be changed early in the course of the PAH associated with connective tissue diseases. The diagnosis needs to be confirmed by right heart catheterization, which is recommended in all patients with suspected PAH. Besides the conventional background therapy, a number of specific therapies have been evaluated in randomized controlled trials in the recent years. These therapies include prostacyclins and prostacyclin analogues, endothelin-receptor antagonists and phosphodiesterase-5 inhibitors. Response to treatment can be measured by exercise capacity (e.g. 6 min walk distance) and pro-BNP, although certain aspects of validation for these outcome measures are lacking in PAH associated with connective tissue diseases.     

An epidemiological study of pulmonary arterial hypertension.

All hospitalisations for pulmonary arterial hypertension (PAH) in the Scottish population were examined to determine the epidemiological features of PAH. These data were compared with expert data from the Scottish Pulmonary Vascular Unit (SPVU). Using the linked Scottish Morbidity Record scheme, data from all adults aged 16-65 yrs admitted with PAH (idiopathic PAH, pulmonary hypertension associated with congenital heart abnormalities and pulmonary hypertension associated with connective tissue disorders) during the period 1986-2001 were identified. These data were compared with the most recent data in the SPVU database (2005). Overall, 374 Scottish males and females aged 16-65 yrs were hospitalised with incident PAH during 1986-2001. The annual incidence of PAH was 7.1 cases per million population. On December 31, 2002, there were 165 surviving cases, giving a prevalence of PAH of 52 cases per million population. Data from the SPVU were available for 1997-2006. In 2005, the last year with a complete data set, the incidence of PAH was 7.6 cases per million population and the corresponding prevalence was 26 cases per million population. Hospitalisation data from the Scottish Morbidity Record scheme gave higher prevalences of pulmonary arterial hypertension than data from the expert centres (Scotland and France). The hospitalisation data may overestimate the true frequency of pulmonary arterial hypertension in the population, but it is also possible that the expert centres underestimate the true frequency.     

Pulmonary arterial hypertension in connective tissue diseases

Pulmonary arterial hypertension (PAH) may complicate diverse connective tissue diseases (CTDs). Approximately 10% of patients with systemic sclerosis develop PAH, the prevalence being much lower in other CTDs. However, PAH is an important contributor to morbidity and mortality in all forms of CTD. Despite similarities in presentation, hemodynamic perturbations, and pathogenesis, patients with CTD-associated PAH (CTD-PAH) usually have a poorer response to PAH-specific medications and poorer prognosis than patients with idiopathic PAH (IPAH). Select patients with CTD-PAH may be candidates for lung transplantation, but results are less favorable than for IPAH because of comorbidities and complications specifically associated with CTD.     

Narrative review: the enigma of pulmonary arterial hypertension: new insights from genetic studies

Pulmonary arterial hypertension (PAH) occurs as an idiopathic disease (formerly called primary pulmonary hypertension) and as a consequence of other illnesses. These illnesses include connective tissue diseases, portal hypertension, diet and stimulant drug use, HIV infection, and congenital heart disease. Inherited susceptibility to PAH occurs in families and is almost always due to mutations in genes of the TGF-beta family of receptors. The most common mutation leading to PAH is in bone morphogenetic protein receptor type 2 (BMPR2), originally discovered to be involved in bone healing. Mutations in BMPR2 have also been found in patients with idiopathic PAH, although the true prevalence of this susceptibility has not been determined. About 20% of individuals with a BMPR2 mutation develop symptomatic pulmonary hypertension. Evidence is growing that imbalanced activation of other TGF-beta receptors coupled with reduced activity of mutated BMPR2 increases the likelihood of development of PAH. Many signaling systems have been found to participate in PAH, including K channels, serotonin, angiopoietin, and cyclooxygenases. An interaction of these signaling systems with BMPR2 is a focus of research in PAH. Approaches to altering the imbalance of activation of BMPR2 and other TGF-beta receptors may yield future therapies for PAH.