Pulmonary Vascular Disorders

Transcription

1 Progress in Respiratory Research 41 Pulmonary Vascular Disorders Bearbeitet von M. Humbert, R. Souza, G. Simonneau, F.J.F. Herth 1. Auflage Buch. X, 290 S. Hardcover ISBN Gewicht: 1090 g Weitere Fachgebiete > Medizin > Klinische und Innere Medizin > Pneumologie, Atmung, Asthma schnell und portofrei erhältlich bei Die Online-Fachbuchhandlung beck-shop.de ist spezialisiert auf Fachbücher, insbesondere Recht, Steuern und Wirtschaft. Im Sortiment finden Sie alle Medien (Bücher, Zeitschriften, CDs, ebooks, etc.) aller Verlage. Ergänzt wird das Programm durch Services wie Neuerscheinungsdienst oder Zusammenstellungen von Büchern zu Sonderpreisen. Der Shop führt mehr als 8 Millionen Produkte.

2 Chapter 1 Humbert M, Souza R, Simonneau G (eds): Pulmonary Vascular Disorders. Prog Respir Res. Basel, Karger, 2012, vol 41, pp 1 13 Updated Clinical Classification of Pulmonary Hypertension David Montani a c Gérald Simonneau a c a Université Paris-Sud, Faculté de Médecine, Kremlin- Bicêtre; b AP-HP, Centre National de Référence de l Hypertension Pulmonaire Sévère, Service de Pneumologie et Réanimation Respiratoire, Hôpital Antoine Béclère, Clamart; c INSERM U999, Hypertension Artérielle Pulmonaire: Physiopathologie et Innovation Thérapeutique, LabEx LERMIT, Centre Chirurgical, Marie-Lannelongue, Le Plessis-Robinson, France Abstract The fourth World Symposium on Pulmonary Hypertension and the conjoint ERS/ESC guidelines revise previous classifications of pulmonary hypertension (PH) in order to accurately reflect information published over the past 5 years. PH has been defined as an increase in mean pulmonary arterial pressure (mpap) 25 mm Hg at rest as assessed by right heart catheterization. No definition for PH on exercise was considered. PH was defined as precapillary when pulmonary capillary wedge pressure was 15 mm Hg associated with a normal or reduced cardiac output. In Group 1 (PAH), the term familial PAH has been replaced by heritable PAH, including sporadic idiopathic PAH with germline mutations and familial cases. Pulmonary veno- occlusive disease and pulmonary capillary hemangiomatosis have been individualized and designated as clinical Group 1. Group 2 pulmonary hypertension due to left heart diseases has been divided into three subgroups: systolic dysfunction, diastolic dysfunction, and valvular disease. Group 3 includes only chronic thromboembolic pulmonary hypertension without any distinction of proximal or distal forms. Copyright 2012 S. Karger AG, Basel The classification of pulmonary hypertension (PH) has gone through a series of changes since the first classification proposed in 1973 which designated only two categories, primary PH or secondary PH, depending on the presence or absence of identifiable causes or risk factors [1, 2]. During the second World Symposium on Pulmonary Arterial Hypertension held in France in 1998, a new classification was proposed which attempted to create categories of PH that shared similar pathogenesis, clinical features, and therapeutic options [3]. This classification defined homogenous groups of patients in order to conduct clinical trials and obtain approval for specific pulmonary arterial hypertension (PAH) therapies. In 2003, the 3rd World Symposium on Pulmonary Arterial Hypertension (Venice, Italy) proposed only minor changes, except for the introduction of the terms of idiopathic PAH, familial PAH, and/or associated PAH (table 1) defining three groups sharing broadly similar physiopathology and response to therapy. The other prominent change was to move pulmonary veno- occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH) from separate categories into a single subcategory of PAH. These two entities have many similarities with idiopathic PAH, including clinical presentation, hemodynamic characteristics, and risk factors, which justified placing them together in Group 1 (table 1). In 2008, the 4th World Symposium on Pulmonary Hypertension held in Dana Point (Calif., USA) and the consensus of an international group of experts revised previous classifications in order to accurately reflect information published over the previous 5 years, as well as to clarify some areas that were unclear. The current Dana Point classification is presented in table 2. Group 1: Pulmonary Arterial Hypertension The nomenclature of the subgroups and associated conditions has evolved since the first classification, and additional modifications were added in this revised classification. Group 1.1/1.2: Idiopathic and Heritable Pulmonary Arterial Hypertension Idiopathic PAH corresponds to sporadic disease in which there is neither a family history of PAH nor an identified risk factor. When PAH occurs in a familial context, germline mutations in the bone morphogenetic protein receptor 2 (BMPR2) gene, a member of the transforming growth

3 Table 1. Venice clinical classification of PH (2003) 1. PAH 1.1. Idiopathic PAH 1.2. Familial PAH 1.3. Associated with PAH: Collagen vascular disease Congenital systemic-to-pulmonary shunts Portal hypertension HIV infection Drugs and toxins Other (thyroid disorders, glycogen storage disease, Gaucher s disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy) 1.4. Associated with significant venous or capillary involvement PVOD PCH 1.5. Persistent PH of the newborn 2. PH with left heart disease 2.1. Left- sided atrial or ventricular heart disease 2.2. Left- sided valvular heart disease 3. PH associated with lung diseases and/or hypoxemia 3.1. Chronic obstructive pulmonary disease 3.2. Interstitial lung disease 3.3. Sleep-disordered breathing 3.4. Alveolar hypoventilation disorders 3.5. Chronic exposure to high altitude 3.6. Developmental abnormalities 4. PH due to chronic thrombotic and/or embolic disease 4.1. Thromboembolic obstruction of proximal pulmonary arteries 4.2. Thromboembolic obstruction of distal pulmonary arteries 4.3. Nonthrombotic pulmonary embolism (tumor, parasites, foreign material) 5. Miscellaneous Sarcoidosis, histiocytosis X, lymphangiomatosis, compression of pulmonary vessels (adenopathy, tumor, fibrosing mediastinitis) factor- β (TGF- β) signaling family, can be detected in about 70% of cases [4, 5]. Recently, it has been suggested that PAH patients carrying a BMPR2 mutation had more severe disease and were less likely to demonstrate vasoreactivity than idiopathic PAH patients without a BMPR2 mutation [6 8]. More rarely, mutations in activin receptor- like kinase type 1 (ACVRL1 or ALK1) or endoglin genes, also coding for members of the TGF- β signaling family, have been identified in patients with PAH, predominantly with coexistent hereditary hemorrhagic telangiectasia. Table 2. Updated clinical classification of PH (Dana Point, 2008) 1. PAH 1.1 Idiopathic 1.2 Heritable BMPR ALK1, endoglin (with or without hereditary hemorrhagic telangiectasia ) Unknown 1.3 Drug- and toxin- induced 1.4 Associated with Connective tissue diseases HIV infection Portal hypertension Congenital heart diseases Schistosomiasis Chronic hemolytic anemia 1.5 Persistent PH of the newborn 1 PVOD and/or PCH 2. PH due to left heart disease 2.1 Systolic dysfunction 2.2 Diastolic dysfunction 2.3 Valvular disease 3. PH due to lung diseases and/or hypoxia 3.1 Chronic obstructive pulmonary disease 3.2 Interstitial lung disease 3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern 3.4 Sleep- disordered breathing 3.5 Alveolar hypoventilation disorders 3.6 Chronic exposure to high altitude 3.7 Developmental abnormalities 4. CTEPH 5. PH with unclear multifactorial mechanisms 5.1 Hematologic disorders: myeloproliferative disorders splenectomy 5.2 Systemic disorders, sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis 5.3 Metabolic disorders: glycogen storage disease, Gaucher s disease, thyroid disorders 5.4 Other: tumoral obstruction, fibrosing mediastinitis, chronic renal failure on dialysis. Main modifications to the previous Venice classification are set in bold. 2 Montani Simonneau

4 Table 3. Updated risk factors and associated conditions for PAH Definite Aminorex Fenfluramine Dexfenfluramine Toxic rapeseed oil Benfluorex Possible Cocaine Phenylpropanolamine St. John s wort Chemotherapeutic agents SSRI Likely Unlikely Amphetamines Oral contraceptives L-tryptophan Estrogen Methamphetamines Cigarette smoking BMPR2 mutations have also been detected in 11 40% of apparently idiopathic cases with no family history [9, 10]. Indeed, the distinction between idiopathic and familial PAH with BMPR2 mutations is artificial, as all patients with a BMPR2 mutation have heritable disease. In addition, BMPR2 mutations were identified in only 70% families with PAH. Thus, it was decided to abandon the term familial PAH in favor of the term heritable PAH. Heritable forms of PAH include idiopathic PAH with germline mutations (mainly BMPR2, but also ACVRL1 or endoglin) and familial cases with or without identified mutations [11, 12]. Genetic testing should be performed as a part of a comprehensive program that includes genetic counseling and discussion of the risks, benefits, and limitations of such testing [13]. Group 1.3: Drug- and Toxin- Induced PAH A number of risk factors for the development of PAH have been included in the previous classifications [3, 14]. In the current classification, the categorization of risk factors and the likelihood of developing PAH have been modified (table 3). Aminorex, fenfluramine derivatives, and toxic rapeseed oil represent the only identified definite risk factors for PAH [3, 14]. Souza et al. [15] recently demonstrated that this subgroup of PAH shares clinical, functional, hemodynamic, and genetic features with idiopathic PAH, suggesting that fenfluramine exposure represents a potential trigger for PAH without influencing its clinical course. The association of fenfluramine and dexfenfluramine intake with the development of PAH was confirmed by the Surveillance Of Pulmonary Hypertension In America (SOPHIA), which enrolled 1,335 subjects at tertiary PH centers in the United States between 1998 and 2001 [16]. Benfluorex is a benzoate ester that shares similar structural and pharmacologic characteristics with dexfenfluramine and fenfluramine. The active and common metabolite of each of these molecules is norfenfluramine, which itself has a chemical structure similar to that of the amphetamines. Given its pharmacological properties, benfluorex would be expected to have similar toxic effects to the fenfluramine derivatives. We recently reported an outbreak of valvular diseases and PAH associated with benfluorex use in France and the drug has now been completely withdrawn from the market. A novel finding was that St. John s wort (OR: 3.6 vs. thromboembolic PH) and over- the- counter antiobesity agents containing phenylpropanolamine (OR: 5.2 vs. thromboembolic PH) also increased the risk of developing idiopathic PAH. The SOPHIA study examined intake of a variety of nonselective monoamine reuptake inhibitors, selective serotonin reuptake inhibitors, antidepressants, and anxiolytics, and found no increased risk for developing PAH [16]. However, a case- control study of selective serotonin reuptake inhibitor use during pregnancy showed an increased risk (OR: 6.1) in the offspring of developing persistent PH of the newborn [17]. Based on this study, selective serotonin reuptake inhibitors were reclassified in the possible category. Amphetamine use represents a likely risk factor, although they are frequently used in combination with fenfluramine. A recent comprehensive retrospective study suggested a strong relationship with the use of methamphetamines (inhaled, smoked, oral, or intravenous) and the occurrence of idiopathic PAH [18]. Based primarily on the results of this study, methamphetamine use is now considered a very likely risk factor for the development of PAH. Group 1.4.1: Pulmonary Arterial Hypertension Associated with Connective Tissue Diseases PAH associated with connective tissue diseases represents an important clinical subgroup. The prevalence of PAH has been well established only for systemic sclerosis. Two recent prospective studies using echocardiography as a screening method and right heart catheterization for confirmation found a prevalence of PAH of between 7 and 12% [19, 20]. Several long- term studies suggest the outcome of patients with PAH associated with systemic sclerosis is markedly worse than that of patients with idiopathic PAH. However, PAH does not represent the only cause of PH in systemic sclerosis. Pulmonary hypertension due to lung fibrosis [21], diastolic left heart dysfunction [22], and primary cardiac involvement [23] are also frequent, emphasizing the importance of a complete evaluation with right heart catheterization to accurately classify its etiology so as to determine appropriate treatment. Updated Clinical Classification of PH 3

5 In systemic lupus erythematosis [24, 25] and mixed connective tissue diseases [26, 27], the prevalence of PAH remains unknown, but likely occurs less frequently than in systemic sclerosis. In the absence of chronic lung disease, PAH has been reported infrequently in other connective tissue diseases such as Sjögren s syndrome [28], polymyositis [29], or rheumatoid arthritis [30]. Group 1.4.2: HIV Infection PAH is a rare but well- established complication of HIV infection [31, 32]. HIV- associated PAH has clinical, hemodynamic, and histologic characteristics similar to those seen in idiopathic PAH. Epidemiologic data in the early 1990s, a time when therapy with highly active antiretroviral therapy was not yet available, indicated a prevalence of 0.5% [33]. The prevalence of HIV- associated PAH was evaluated more recently and showed a stable prevalence of 0.46% [34]. Uncontrolled studies suggest that patients with severe HIVassociated PAH could benefit from specific PAH therapies, such as bosentan or continuous intravenous epoprostenol [35, 36]. Interestingly, normalization of hemodynamics has been reported with specific PAH therapies in a substantial number of cases [37]. Group 1.4.3: Portopulmonary Hypertension Portopulmonary hypertension (PoPH) is defined by the development of PAH associated with increased pressure in the portal circulation [38, 39]. Prospective hemodynamic studies have shown that 2 6% of patients with portal hypertension had PH [40, 41]. However, right heart catheterization is mandatory for the diagnosis of PoPH, as several mechanisms may increase pulmonary artery pressure in the setting of advanced liver disease: hyperdynamic circulatory state with high cardiac output, fluid overload, and diastolic dysfunction. Pulmonary vascular resistance (PVR) is usually normal in these cases. Pathologic changes in the small arteries appear identical to those seen in idiopathic PAH. A recent multicenter case- control study identified that female gender and autoimmune hepatitis were independent risk factors for the development of PoPH and that hepatitis C infection was associated with a decreased risk [42]. A recent, large cohort study of PoPH showed that long- term prognosis was related to the presence and severity of cirrhosis as well to cardiac function [43]. Group 1.4.4: Congenital Heart Diseases A significant proportion of patients with congenital heart disease, in particular those with systemic- to- pulmonary shunts, will develop PAH if left untreated. Eisenmenger s syndrome is defined as congenital heart disease with an initial large systemic- to- pulmonary shunt that induces progressive pulmonary vascular disease and PAH, with resultant reversal of the shunt and central cyanosis [44, 45]. It represents the most advanced form of PAH associated with congenital heart disease. It has been reported that a large proportion of patients with congenital heart disease develop some degree of PAH [46 48]. The prevalence of PAH associated with congenital systemic- topulmonary shunts in Europe and North America has been estimated between 1.6 and 12.5 cases per million adults, with 25 50% of this population affected by Eisenmenger s syndrome. The histopathologic and pathobiologic changes seen in patients with PAH associated with congenital systemic- to- pulmonary shunts, in particular endothelial dysfunction, are similar to those observed in idiopathic or other associated forms of PAH. Following the Dana Point meeting, it was decided to update the pathologic and pathophysiologic classification of congenital heart disease with systemic- to- pulmonary shunts (table 4) in order to provide a more detailed description of each condition, with the result that four quite distinct phenotypes were individualized (table 5). Group 1.4.5: Schistosomiasis In the new classification, PH associated with schistosomiasis was included in Group 1 even though it was subcategorized in Group 4 as PH due to chronic embolic disease in the previous classification. Embolic obstruction of pulmonary arteries by schistosoma eggs was thought to be the primary mechanism responsible for the development of PH [49]. However, it has recently been demonstrated that PH associated with schistosomiasis may have similar clinical presentation and histologic findings as idiopathic PAH [50, 51]. The mechanism of PAH in patients with schistosomiasis is probably multifactorial including PoPH, a frequent complication of this disease [52], and local vascular inflammation, whereas mechanical obstruction by schistosoma eggs seems to play a minor role. More than 200 million people are infected and 4 8% will develop hepatosplenic disease. PAH associated with schistosomiasis represents a frequent form of PAH, especially in countries where the infection is endemic. Data from a recent study based on invasive hemodynamics provided evidence showing the prevalence of PAH in patients with hepatosplenic disease to be 4.6%. The prevalence of postcapillary hypertension (3.0%) was also important, reinforcing the need for invasive hemodynamics for the specific diagnosis of PAH in schistosomiasis [53]. 4 Montani Simonneau