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REVIEW CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION

Chronic thromboembolic pulmonary hypertension: a distinct disease entity Irene Lang Affiliation: Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria. Correspondence: Irene Lang, Medical University of Vienna, Internal Medicine II, Division of Cardiology, Waehringer, Geurtel, 18–20, 1090 Vienna, Austria. E-mail: [email protected]

ABSTRACT Chronic thromboembolic pulmonary hypertension (CTEPH) is a distinct subtype of pulmonary hypertension (PH). One disease hypothesis is that CTEPH results from the non-resolution of venous thromboembolism. CTEPH is characterised by the presence of obstructive fibrotic thromboembolic material in the major pulmonary vessels, with concomitant microvascular arteriopathy, resulting in progressive PH. The clinical presentation of CTEPH is similar to pulmonary arterial hypertension with nonspecific symptoms, but it is distinguished from pulmonary arterial hypertension by the presence of mismatched segmental defects on the ventilation/perfusion scan. The exact prevalence and incidence of CTEPH are unknown, but are thought to have been underestimated in the past. CTEPH is unique among the subgroups of PH in that it is potentially curable with pulmonary endarterectomy, a surgical intervention intended to remove the occlusive material from the pulmonary vasculature. However, in some patients the obstructions are technically inaccessible or the risk/benefit ratios are unfavourable, making the condition inoperable. It is thought that the involvement of the smaller, more distal vessels is a target for medical treatment. Untreated, CTEPH may result in right heart failure and death. The pathophysiological mechanisms which cause CTEPH are complex and have not yet been fully elucidated.

@ERSpublications CTEPH is distinct from other types of pulmonary hypertension, both in terms of its pathophysiology and treatment http://ow.ly/L54ag

Introduction Chronic thromboembolic pulmonary hypertension (CTEPH) is a distinct form of pulmonary hypertension (PH) characterised by mechanical obstruction of the pulmonary arteries, which is caused by the presence of organised fibrotic thrombi tightly attached to the medial layer of the elastic pulmonary arteries, replacing the normal intima [1]. This thromboembolic material may completely occlude the lumen of the affected artery, with associated pitting or roughening of the intimal surface, formation of bands and webs traversing the vascular lumen and partial recanalisation [2]. The consequences of this pulmonary artery occlusion are an increase in pulmonary vascular resistance with subsequent progressive PH and eventual right heart failure, which may be fatal [3, 4]. Although the pathogenesis of CTEPH is yet to be fully elucidated, it has long been understood that it arises as a complication of acute pulmonary embolism (PE) subsequent to venous thromboembolism (VTE) [2]. The pathophysiological mechanisms that prevent complete resolution of the embolic material in CTEPH are thought to be a misguided vascular remodelling process, which involves defective angiogenesis and delayed onset of fibrinolysis associated with endothelial dysfunction [5]. However, this historically accepted model for the pathogenesis of CTEPH has been subject to criticism, with those opposing it citing epidemiological data for PE and CTEPH, the demonstrable lack of some Received: Feb 06 2015 | Accepted after revision: March 14 2015 Conflict of interest: Disclosures can be found alongside the online version of this article at err.ersjournals.com Provenance: Publication of this peer-reviewed article was sponsored by Bayer Pharma AG, Berlin, Germany ( principal sponsor, European Respiratory Review issue 136). Copyright ©ERS 2015. ERR articles are open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.

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classic risk factors for VTE and the involvement of distal pulmonary artery disease in patients with CTEPH [6, 7]. Despite these past reservations, the thromboembolic basis of CTEPH is now well established [8].

Definition and diagnostic criteria PH is defined as a resting mean pulmonary arterial pressure (mPAP) of ⩾25 mmHg measured by invasive right heart catheterisation [1, 9]. There are a number of distinct types of PH, which have been classified in terms of their aetiological, clinical and diagnostic features [1, 10]. This system of classification has undergone numerous revisions and clarifications, the most recent of which took place at the Fifth World Symposium on PH held in Nice, France, in 2013 [11]. Within the classification system, groups 1, 3, 4 and 5 comprise pre-capillary PH, while post-capillary PH, which is pulmonary venous hypertension due to left heart failure, falls into group 2 [1]. CTEPH represents group 4 and has been classified independently of all other forms of PH, including group 1 pulmonary arterial hypertension (PAH), which can be difficult to distinguish from CTEPH clinically [11, 12]. A diagnosis of CTEPH can be made if, after 3 months of effective therapeutic anticoagulation, the patient’s mPAP is ⩾25 mmHg and their pulmonary capillary wedge pressure is ⩽15 mmHg, together with at least one mismatched segmental perfusion defect demonstrated by ventilation/perfusion (V′/Q′) scanning, multidetector computed tomography angiography or pulmonary angiography [5]. V′/Q′ scanning is the preferred and recommended screening test in patients suspected of having CTEPH, with the main distinction between CTEPH and PAH being the segmental distribution of major vessel defects [1, 13]. In contrast to patients with CTEPH, a V′/Q′ scan in a patient with PAH may appear normal, or show small peripheral unmatched and nonsegmental defects in perfusion [1]. A brief comparison of CTEPH and PAH is shown in table 1.

Clinical features and treatment Early identification and accurate diagnosis of CTEPH is challenging as the condition may be completely asymptomatic during its initial development and progression [2, 14]. This problem is further compounded by the clinical signs and symptoms of CTEPH being largely nonspecific [8]. As with other forms of PH, patients with CTEPH will typically present with progressive exertional dyspnoea and reduced exercise tolerance, in addition to which they may also have fatigue, syncope and/or haemoptysis [15]. As CTEPH

TABLE 1 Comparison of chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH) CTEPH Common pathophysiological link Common symptoms Aetiology

PAH

Microvascular arteriopathy resulting in endothelial dysfunction and vascular remodelling Dyspnoea, fatigue, weakness and syncope Unresolved emboli after PE Unknown aetiology in the absence of previous PE

Abnormal proliferation of endothelium and smooth muscle in vessel walls, small vessel thrombi are possible

Previous PE/VTE and recurrent VTE, infected pacemaker, ventriculoatrial shunt, splenectomy, antiphospholipid antibodies, and lupus anticoagulant Primarily affects the elderly of both sexes, episodic course with “honeymoon” periods

Genetic mutation, certain drugs/toxins, HIV, connective tissue disorders, congenital heart disease

Diagnosis

Segmental perfusion defects in V′/Q′ scan, pulmonary angiography, CT

No segmental perfusion defects in V′/Q′ scan, right heart catheterisation

Treatment

PEA surgery for suitable patients, balloon pulmonary angioplasty for segmental/ subsegmental disease, medical treatment targeting dysfunctional pathways in endothelial cells of inoperable patients

Medical treatment targeting dysfunctional pathways in endothelial cells

Risk factors

Disease phenotype

Typically affects young women, progressive course

PE: pulmonary embolism; VTE: venous thromboembolism; V′/Q′: ventilation/perfusion; CT: computed tomography; PEA: pulmonary endarterectomy. Information from [8].

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progresses into the more advanced stages of the disease and right ventricular dysfunction becomes more pronounced, the clinical manifestations of right heart failure may become more obvious [3, 8]. Underdiagnosis and delay in the diagnosis of CTEPH are concerning because, unlike other types of PH, CTEPH is potentially curable via surgical intervention in many patients [15]. Pulmonary endarterectomy (PEA) is a complex surgical procedure that involves the removal of the obstructive thromboembolic material from the patient’s pulmonary vasculature [16, 17]. This is possible in CTEPH, as opposed to other forms of PH, because initially the condition is the result of occlusion predominantly occurring in the central and proximal pulmonary arteries [2, 8]. However, a significant proportion of patients with CTEPH are unsuitable for PEA. This is most often due to involvement of the distal pulmonary vessels, the presence of significant comorbidities or the patient’s refusal to undergo an operation [18]. For patients with CTEPH who are inoperable, or who have persistent/recurrent PH after PEA, the only currently approved pharmacological treatment is the soluble guanylate cyclase stimulator riociguat [13]. Clinical data on the use of pharmacological treatment in CTEPH are reviewed in this issue of the European Respiratory Review [19]. Without treatment the prognosis for patients with CTEPH is poor, with higher mortality rates associated with higher mPAPs, highlighting the need for timely diagnosis and early surgical intervention where possible [13, 20–22].

Epidemiology CTEPH is understood to be a rare disease, with an epidemiology likely to be similar to that of PAH. There are significant obstacles to determining the overall incidence and prevalence of CTEPH accurately, and it is likely that they have been underestimated in the past [23]. Patients with CTEPH commonly lack an identifiable causative event due to the PE often being asymptomatic. In addition, initial symptoms may be nonspecific or absent. Other obstructing factors are referral bias and the possibility of CTEPH pre-existing in patients prior to PE [8, 23, 24]. Despite these inherent difficulties, the epidemiology of CTEPH has been an area of research interest, focused particularly on quantifying the rate of its occurrence following an acute PE. Early estimates suggested that CTEPH occurs in approximately 0.1–0.5% of patients who survive an episode of acute PE [2]. However, more recent prospective observational studies have reported the prevalence of CTEPH after acute PE as being between 0.4% and 9.1% [14, 25–32]. The wide range of estimates may have arisen due to differences in study design, patient populations or diagnostic methods and criteria, as well as a result of the obstacles mentioned above [32]. For example, some studies did not utilise right heart catheterisation to confirm the diagnosis of CTEPH [3, 14]. Previous arguments against the pathogenesis of CTEPH being thromboembolic in nature have cited the lack of a clearly documented history of either VTE or PE in approximately half of patients with CTEPH [6, 7]. These concerns have now largely been addressed, with findings from an international prospective registry of patients with CTEPH reporting a history of acute PE in 74.8% of all patients with CTEPH and a history of deep venous thrombosis in 56.1% [18]. These data, considered in the context of a proportion of patients in whom PE and VTE occurs without clinical symptoms, emphasise the natural history of CTEPH as a potential long-term consequence of PE [2].

Pathophysiology Understanding of the pathogenesis and subsequent progression of CTEPH has evolved within the conceptual framework of the condition as a dual pulmonary vascular disorder, with initial occlusion of proximal major vessels by nonresolution of a single or recurrent PE, which may trigger distal pulmonary arteriopathy and microvascular disease [5, 33, 34]. The aetiological factors that have been implicated are associated with aberrations in coagulation and thrombus resolution [5, 35, 36]. The most important risk factor for patients progressing from an acute PE to CTEPH is previous/recurrent PE or VTE. In a retrospective cohort study of cases from three European centres offering PEA, a comparison between patients with CTEPH and those with non-thromboembolic pre-capillary PAH found that a history of VTE and recurrent VTE were significantly more common in the CTEPH group than the PAH group (odds ratios of 4.5 and 14.5, respectively) [35]. A schematic overview of the pathophysiological concept of CTEPH is shown in figure 1. Coagulation and thrombus resolution Despite the link between CTEPH and VTE, some classic plasmatic thromboembolic risk factors including antithrombin, protein C and protein S deficiency, and factor V Leiden mutation have been found not to be associated with CTEPH [5, 37]. However, elevated plasma concentrations of factor VIII, lupus anticoagulant and antiphospholipid antibodies, all three of which are risk factors for VTE, have been found to be associated with CTEPH [35, 37, 38]. Fibrinolytic factors have also been investigated, but have not been found to be significantly abnormal in patients with CTEPH [39]. Further nonplasmatic specific

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VTE

Acute PE Infection and inflammation Immunity Genetics

Incomplete resolution and organisation of thrombus

Lack of thrombus angiogenesis

Development of fibrotic stenoses/occlusions Adaptive vascular remodelling of resistance vessels FIGURE 1 Schematic of the pathophysiological concept of chronic thromboembolic pulmonary hypertension following acute pulmonary embolism (PE). VTE: venous thromboembolism. Reproduced from [5] with permission from the publisher.

risk factors for VTE have also been identified as risk factors for CTEPH. Splenectomy, infected ventriculoatrial shunts, thyroid replacement therapy, malignancy and chronic inflammatory conditions, including osteomyelitis and inflammatory bowel disease, are all significantly associated with CTEPH and have a negative impact on prognosis [35, 40–42]. As with the other mechanisms involved in the pathogenesis of CTEPH, the causes of thrombus non-resolution have yet to be fully clarified. In otherwise healthy individuals, dissolution of large thrombi typically begins with initially rapid fibrinolysis followed by the formation of granulation tissue, similar to the process of wound healing, with a cellular response that leads to recruitment of leukocytes and endothelial progenitor cells with concomitant angiogenesis [43–46]. Initially, neutrophils are recruited into the resolving thrombus, where they promote ongoing fibrinolysis and collagenolysis. The neutrophils are followed by monocytes, which have a more expansive role involving the secretion or attraction of various chemokines, growth factors and proteases that promote thrombus reorganisation [8, 46]. These normal mechanisms of thrombus breakdown may be altered by the presence of inflammation and associated inflammatory markers, such as C-reactive protein, monocyte chemotactic protein-1, tumour necrosis factor-α and interferon-γ-induced protein-10, which have been found to be upregulated in patients with CTEPH [47–50]. There have also been abnormal fibrinogen variants reported in CTEPH, which may be more resistant to cleavage and resolution [36, 51, 52]. These include a significant association between CTEPH and the fibrinogen Aα polymorphism Thr312Ala, which has been shown to increase the resistance of fibrin to typical lytic processes [53, 54]. Taken together, these observations demonstrate a number of pathophysiological modalities that between them probably account for the non-resolution of thromboembolic material seen in CTEPH, although further investigation is required. Aberrations in angiogenesis during thrombus resolution have also been implicated in the pathogenesis of CTEPH. During normal angiogenesis, positive regulators of neovascularisation, such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF), are upregulated and cause endothelial activation [55]. VEGF and basic FGF are both found in organising thrombi, which suggests that they have a role in thrombus resolution and that augmenting the expression of these growth factors may enhance thrombus recanalisation [56]. Thromboembolic material removed from patients with CTEPH during PEA has been found to contain collagen-secreting cells. These cells may participate in the formation of a unique microenvironment within the organised thrombus that leads to dysfunctional endothelial cells, which do not support the process of angiogenesis [57, 58]. Downregulation of angiogenetic gene expression and a lack of functional endothelial cells in CTEPH thrombi may contribute to the failure of pulmonary vascular obstructions to resolve in these patients [5]. Major vessel and microvascular disease The characteristic transformation of thromboembolic material, in the elastic pulmonary arteries, into organised fibrotic scar tissue with tight attachments to the medial layer, replacing the normal intima, can result not only in complete occlusion of the vessel lumen but also in the formation of varying grades of stenosis, webs and bands [1]. As a result of the persistent obstruction of affected arteries in CTEPH, pulmonary blood flow is redistributed to non-occluded vessels [3]. Redirection of cardiac output subjects these pulmonary vessels to elevated blood pressures and increased shear stress, which, in conjunction with the potential presence of inflammation and vasculopathic mediators, results in progressive arteriopathy in

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the distal arteries and arterioles [3, 8]. This arteriopathic process in CTEPH results in endothelial dysfunction and vascular remodelling of the pulmonary microvasculature, which resembles the mechanisms underlying PAH and leads to the formation of plexiform lesions in both conditions [15, 34, 59]. The small vessel vascular remodelling in CTEPH is characterised by thickening of all three layers of the vascular wall, and hypertrophy or hyperplasia of the predominant cell type of each layer (fibroblasts, smooth muscle cells and endothelial cells, respectively); it may also involve abnormal proliferation of pulmonary arterial smooth muscle cells and the accumulation of putative endothelial progenitor cells [57, 60–62]. These microvascular changes cause further worsening of the patient’s PH, and therefore reciprocal deterioration of their clinical condition, explaining the progressive nature of CTEPH even in the absence of recurrent thromboembolic events [3]. Concomitant small vessel arteriopathy also accounts for the documented lack of a linear correlation between measurable haemodynamic variables and the degree of vascular obstruction in CTEPH, which distinguishes it from acute PE where this correlation does exist [60, 63].

Conclusions CTEPH is a distinct form of PH both in terms of its aetiology and the way in which it responds to treatment; it is the only subset of PH which is amenable to curative surgical intervention. The pathophysiological processes underpinning CTEPH are complex and have not yet been fully elucidated. In time, further research will continue to clarify these mechanisms and may provide greater insight into the potential overlap between the pathogenesis of microvascular arteriopathy in CTEPH and in PAH. While existing epidemiological data have firmly established the thromboembolic nature of this condition, there is still a large margin of error between different studies, the result of which is that the exact prevalence and incidence of CTEPH remain unknown. Advances in these fields may allow mutual clinical improvements in the diagnosis and management of patients with CTEPH.

Acknowledgements Editorial assistance was provided by Adelphi Communications Ltd (Bollington, UK), supported by Bayer Pharma AG.

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SEMINAR FOR CLINICIANS The Pathobiology of Chronic Thromboembolic Pulmonary Hypertension Irene M. Lang1, Peter Dorfmuller ¨ 2, and Anton Vonk Noordegraaf3 1

Division of Cardiology, Vienna General Hospital, Medical University of Vienna, Vienna, Austria; 2Department of Pathology and Institut National de la Sante´ et de la Recherche Medicale ´ UMR-S 999, Paris-South University, Marie Lannelongue Hospital, Le Plessis-Robinson, France; and 3Department of Pulmonology, Vrije Universiteit Medical Center, Amsterdam, the Netherlands

Abstract 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. Keywords: chronic thromboembolic pulmonary hypertension; coagulation; vascular biology; review

(Received in original form September 20, 2015; accepted in final form December 17, 2015 ) Correspondence and requests for reprints should be addressed to Irene Lang, M.D., Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Wahringer ¨ Gurtel ¨ 18-20, 1090 Vienna, Austria. E-mail: [email protected] Ann Am Thorac Soc Vol 13, Supplement 3, pp S215–S221, Jul 2016 Copyright © 2016 by the American Thoracic Society DOI: 10.1513/AnnalsATS.201509-620AS Internet address: www.atsjournals.org

Venous thromboembolism (VTE, i.e., deep-vein thrombosis or pulmonary embolism) is a common disorder with an annual incidence of approximately 1 or 2 cases per 1,000 in the general population (1). Long-term complications clinically manifest as chronic thromboembolic pulmonary hypertension (CTEPH) or venous postthrombotic syndrome. CTEPH is a rare and progressive pulmonary vascular disease with a poor outcome if left untreated. This article reviews current knowledge on the vascular pathobiology of CTEPH.

Pathology of CTEPH When dissecting lungs at autopsy of patients with CTEPH, residues of organized thromboembolic material can be found in large pulmonary arteries of the elastic type, corresponding to vessels greater than 500 mm in diameter. These lesions are frequently described as “bands and webs” adhering firmly and in irregular shape to the arterial wall. On histological examination, the bands and webs correspond to discrete areas of irregular intimal thickening composed of collagen, numerous fibroblasts, and sparse

Lang, Dorfmuller, ¨ and Noordegraaf: Pathobiology of CTEPH

inflammatory cells such as lymphocytes and hemosiderin-laden macrophages (2). In bulky thromboembolic lesions, small collections of capillary-like neovessels can be observed, presumably part of the clot organization. In lungs from autopsied or transplanted patients with CTEPH, these old lesions may be quasi-occlusive (Figure 1) and only partially recanalized by larger neovessels, which appear to connect to the systemic vasa vasorum (Figures 1A and 1B). The latter are hypertrophic and easily visible within the adventitia of large pulmonary arteries (Figure 1B).

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Figure 1. Lung histology (hematoxylin–eosin–saffron staining) from (A–H) transplanted patients with chronic thromboembolic pulmonary hypertension (CTEPH) and (I) an animal model. (A) Pulmonary artery (segmental level) with occluding, organized thromboembolus; note exuberant neoangiogenesis within the occlusion and a systemic vessel within the adventitia that appears connected to the neovessels (arrows). (B) Another example of an occluded elastic-type artery; this time the hilar bronchial arteries were injected with blue dye right after lung transplantation: the dye can be perceived within the vasa vasorum (arrow) and within multiple neovessels, suggesting a systemic origin of the latter. (C) Eccentric intimal fibrosis of a muscular-type pulmonary artery (top). (D) Microvascular disease with important remodeling of pulmonary vessels less than 100 mm, either arterioles or venules (arrows). (E) After injection of green dye into the hilar veins, not only septal veins (arrowhead, right), but also remodeled small venules (arrow, left) are highlighted, suggesting involvement of postcapillary vessels in microvascular disease. (F) Septal veins frequently present intimal, collagen-rich, near-occlusive fibrosis. (G) Areas with alveolar wall thickening are frequently present in occluded territories; alveolar walls comprise multiple layers of capillaries (circle) as seen in capillary hemangiomatosis or pulmonary veno-occlusive disease; note edema and numerous macrophages within the alveoli (arrows). (H) Central section with a bronchial division (asterisks); hypertrophic bronchial arteries (arrows) and hyperplasia of bronchial microvessels (arrowheads) can be observed, mostly in occluded territories. (I) Central section in a piglet model of CTEPH; blue dye has been injected into the bronchial circulation via the aortic ostia after sacrifice; note the injected hypertrophic bronchial arteries (left, arrowheads), which appear connected to the equally injected and strongly remodeled pulmonary veins running within the septa (right, arrows).

Smaller, muscular-type arteries less than 500 mm in diameter typically present with eccentric intimal thickening or colander-like remodeling (Figure 1A). Both lesion phenotypes are generally understood as arterial wall–adherent remainders of organized thrombotic material (3). Onionskin lesions and plexiform lesions, the typical histological hallmarks of idiopathic S216

pulmonary arterial hypertension, are usually not found. However, there is disagreement on whether plexiform lesions are sometimes encountered in CTEPH. Historically, Wagenvoort and Wagenvoort have distinguished colander lesions from proliferative plexiform lesions (4). On the other hand, Moser, Bloor, and others described plexiform lesions in their CTEPH

cohorts (5, 6). It can be challenging to discriminate cell-rich colander lesions from plexiform lesions. Because the origin of plexiform lesions is still not clear, a direct relation/connection with thrombotic events cannot be excluded. Alveolar walls may comprise multiple layers of capillaries as seen in capillary hemangiomatosis or pulmonary veno-occlusive disease (Figure 1G).

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SEMINAR FOR CLINICIANS To understand the pathogenesis of CTEPH the two following hypotheses can be considered: (1) CTEPH results from nonresolution of pulmonary thromboemboli; and (2) major vessel thrombi trigger progressive vascular disease affecting pulmonary resistance vessels.

Nonresolution of Thrombi in CTEPH Large pulmonary emboli, idiopathic presentation, and recurrent pulmonary embolisms appear to associate with poor resolution of thrombi and thus represent a risk for the development of CTEPH (7). In addition, inefficient anticoagulation may trigger thrombus growth. However, these factors do not serve to explain the development of CTEPH in most patients. Novel insights summarized below shed new light on mechanisms underlying nonresolution of thrombi. Nonclassical Thrombophilia

Although CTEPH is considered a venous thromboembolic disorder, classic thromboembolic risk factors are generally lacking. Lupus anticoagulant occurs in

about 10% of patients with CTEPH, and 20% of patients carry phospholipid antibodies, lupus anticoagulant, or both (8). The plasma level of factor VIII, a protein associated with both primary and recurrent VTE (9), was elevated in 39% of patients with CTEPH (8). No abnormalities of systemic fibrinolysis were identified (10), yet imbalances of cell-bound fibrinolysisassociated proteins have been reported (11, 12). In one series 15% of patients had an underlying autoimmune or hematologic disorder, for example, polycythemia vera (13). Blood group types A, B, and AB were significantly more common in patients with CTEPH compared with pulmonary arterial hypertension (PAH) (88 vs. 56%) (14), and compared with the general European population (15) (http://www.redcross.eu). Abnormal Fibrinogen

Abnormal variants of fibrinogen (16, 17) and abnormal fragmentation of fibrinogen by plasminogen activators (18) are alternative pathophysiological possibilities. In particular, the b15–42 fragment of the E-chain of fibrinogen may accumulate in CTEPH, and delays thrombus resolution in the vena cava mouse model (I.L., unpublished data) (Figure 2). In one study,

a significant difference was demonstrated in the fibrinogen A alpha-Thr312Ala genotype and allele frequencies between subjects with CTEPH and control subjects (19). In addition, the fibrinogen A alpha-Thr312Ala allele has been associated with an increased risk of VTE (20). All variations of fibrinogen found in patients with CTEPH including abnormalities of polymer structure (16, 21) are suspected to confer resistance to thrombolysis (18), the first step of venous thrombus resolution, and to modify subsequent resolution by exposing domains that are known to affect vascular remodeling, for example, the B-knob of the E-fragment of fibrin. Thrombus Infection with Staphylococcus aureus

Staphylococcal DNA, but not RNA, was detected in six of seven thrombi from human ventriculoatrial shunt carriers (22). The effects of staphylococcal infection on thrombus organization were examined in the stagnant-flow venous thrombosis model (Figure 2). Staphylococcal infection delayed thrombus resolution that was paralleled by up-regulation of transforming growth factor (TGF)-b and connective tissue growth factor.

Stagnant flow venous thrombosis

Day 1

Day 3

Day 7

Day 14

Day 28

Day 50

Figure 2. A mouse model of stagnant-flow venous thrombosis recapitulates the vascular remodeling of thrombosis. The most reproducible thrombus is created in adult female BALB/c mice (top left). In brief, stenosis is produced in the infrarenal inferior vena cava by placing a 5-0 Prolene thread alongside the vein, and tying a 4-0 silk suture around the vein (distant from nearby branches) (blue line, top right). The Prolene is then pulled to allow blood to continue to pass up the vein. Branches remain open. Within 8 hours stagnant flow venous thrombosis ensues. Thrombus cross-sectional areas on Days 1, 3, 7, 14, 28, and 50 after surgery are shown (bottom).

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Increased plasma levels of microparticles and anionic phospholipids as a consequence of splenectomy and presumably as a consequence of infection and cancer may explain abnormal thrombosis in CTEPH (3). In an analysis of surgically excised thrombi from rare cases of patients with CTEPH who had undergone previous splenectomy, we found enrichment of anionic phospholipids such as phosphatidylserine. Similar to human thrombi, phosphatidylserine accumulated in thrombi after splenectomy in a mouse model. A postsplenectomy state was associated with larger and more persistent thrombi. Higher counts of procoagulant platelet microparticles and increased leukocyte–platelet aggregates were observed in mice after splenectomy. Histological inspection revealed a decreased number of thrombus vessels. Phosphatidylserineenriched phospholipids specifically inhibited angiogenesis in a cell proliferation assay and in a sprouting assay (24). These data suggest that after splenectomy, an increase in circulating negatively charged phospholipids as a consequence of experimental thrombus induction is associated with an initial transient increase in thrombus volume by platelet activation, and, subsequently, with a delay of thrombus resolution by inhibition of thrombus angiogenesis. Deficient Angiogenesis

Mice with an endothelial cell–specific conditional deletion of vascular endothelial growth factor receptor 2/kinase insert domain protein receptor (VEGF-R2/Kdr) were used to clarify the role of angiogenesis in thrombus resolution. Endothelial cell– specific deletion of Kdr and subsequent ablation of thrombus vascularization delayed thrombus resolution. In accordance with these findings, vessel-specific mRNAs were low in organized human CTEPH thrombi, and vascular structures were focal and aberrant. CTEPH thrombi contained more vessel-specific gene expression than did acute femoral thrombi, coronary aspirates, and acute pulmonary emboli, but significantly less compared with organizing aortic thrombi, carotid thrombendarterectomy specimens, and subacute and organizing deep vein thrombi (23). Red CTEPH thrombi attenuated the angiogenic response induced by VEGF. S218

Medical conditions associated with the development of CTEPH, such as infection, impaired innate immunity, abnormal phospholipid species, and high levels of IFN-g–inducible protein 10 kD (IP-10) (25), may be compromising early thrombus angiogenesis, thus complicating thrombus resolution. Attenuated Leukocyte Migration

Platelet endothelial cell adhesion molecule 1 (PECAM-1) is involved in leukocyte migration and angiogenesis, which are key components of venous thrombus resolution. PECAM-1 is a single-chain glycopeptide receptor of 130 kD relative molecular weight and is expressed on platelets, endothelial cells, macrophages, neutrophils, lymphocytes, and bone marrow cells (26). The cytoplasmic domain of the molecule participates in intracellular signaling cascades via the immunoreceptor tyrosinebased inhibitory motif (27). PECAM-1 is involved in leukocyte transmigration and in regulation of leukocyte responses to inflammatory stimuli (28), which is a major determinant of venous thrombus resolution (29). A soluble form of PECAM-1 (sPECAM-1) is generated either by PECAM-1 proteolytic cleavage at the cell surface or by alternative splicing on cell activation (30). Therefore, sPECAM-1

OBSTRUCTED

exists at least in two isoforms: a truncated form that lacks the cytoplasmic tail and results from cell surface shedding, and a transmembrane-less form that comprises both the extracellular and cytoplasmic domains and originates from splicing out the transmembrane region. In the model, Pecam-12/2 thrombi were larger, persisted for longer periods of time, had fewer leukocytes and vessels, and more fibrosis. In humans, higher levels of truncated plasma sPECAM-1, possibly cleaved from cell surfaces, were found in patients with delayed thrombus resolution as assessed by duplex-based thrombus scoring relative to those whose thrombi resolved (median [25th/75th percentile], 92.5 [87.7/103.4] vs. 71.5 [51.1/81.0] ng/ml; P , 0.001). Furthermore, chronic venous thrombi in humans demonstrated an accumulation of cleaved PECAM-1, suggesting a regulatory role for PECAM-1 in venous thrombus resolution (31).

From Residual Thrombi to CTEPH The question then is why residual thrombi develop in a minority of patients to a progressive pulmonary vascular disease in

Low flow Low pressure

Thromboembolic obstructions

NON-OBSTRUCTED

High flow High pressure Smooth muscle cell proliferation and endothelial dysfunction + proliferation

Figure 3. Schematic presentation of a large pulmonary artery with (top) a residual clot and (bottom) a pulmonary artery without a clot. As a result of the increased resistance (top), the flow will be diverted to the nonobstructed artery (bottom), leading to high flow and pressure in this artery, inducing endothelial dysfunction and cell proliferation (vascular remodeling), resulting in a progressive narrowing of the nonobstructed artery (our hypothesis).

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SEMINAR FOR CLINICIANS the form of CTEPH. Although initial inflammatory triggers might play an important role in the development of the disease, other factors such as redirection of flow to nonobstructed areas, vascular remodeling induced by abnormal shear stress (Figure 3), and opening of systemicto-pulmonary venous connections are factors presumably contributing to CTEPH vascular disease. Redirection of Flow to Nonobstructed Areas

A progressive course has been attributed to “secondary pulmonary arteriopathy” or “small-vessel disease.” This phenomenon was identified by Moser and Bloor in 1993 (5). Microvascular disease is thought to account for failure of pulmonary endarterectomy (PEA) and perioperative mortality (32, 33), as well as worsening of pulmonary pressures in patients with CTEPH over time (34). Research using an animal shunt model revealed that hyperdynamic flow leads to uncontrolled proliferation of endothelial cells in the pulmonary arterioles and pathologic vasoconstriction (35). Authors also reported that the pulmonary endothelium senses mechanical stretch and responds by enhancing vessel wall collagen synthesis, aggravating remodeling of small pulmonary arteries or arterioles (36). In an experimental CTEPH model, Boulate and coworkers demonstrated that CTEPH small-vessel disease is reversible and regresses after reperfusion of the pulmonary circulation (37). An analysis of lungs from 17 patients with CTEPH, including 9 patients with persistent pulmonary hypertension after PEA, showed that massive microvascular remodeling is present in such patients (38). The authors reported that microvascular disease affected both precapillary arterioles and postcapillary venules (Figures 1D and 1E). In a review (39), a histological example of a lung biopsy taken from lung supplied by a nonobstructed versus obstructed pulmonary artery of a single patient illustrates secondary pulmonary arteriopathy, predominantly in the territory distal to an open artery. We do have the clinical observation that hyperdynamic pulmonary artery flow in patients with an atrial septal defect can lead to endothelial dysfunction and arterial remodeling, causing PAH. TGF-b, one of the most important regulators of the effects

of biomechanical stimuli on endothelial cells, is up-regulated in CTEPH anastomoses between bronchial artery branches and precapillary pulmonary arterioles (40). The Role of the Bronchial Circulation

The bronchial circulation is not a mere bystander in the development of CTEPH. Systemic bronchial arteries and the vasa vasorum undergo hypertrophic remodeling in CTEPH (40, 41) (Figure 1H). It has been speculated that a decrease in postobstructive pulmonary artery pressure and an increase in the pressure gradient between bronchial arteries and pulmonary arteries might lead to an opening of preexisting bronchopulmonary arterial anastomoses (42, 43). Because anastomoses between bronchial artery branches and precapillary pulmonary arterioles, but also

between bronchial arteries and pulmonary veins, have been described in the past, a possible effect of systemic pressures on postcapillary pulmonary vessels and on the pulmonary capillary network appears possible (40, 44, 45). Until more recently, the postcapillary pulmonary vasculature has not been understood as a major component of CTEPH pathophysiology. Wagenvoort and Wagenvoort noted that pulmonary veins in CTEPH lungs showed arterialization and wall thickening as signs of increased pulmonary venous pressure (4). However, they attributed these observations to concomitant left heart failure and agerelated remodeling. By contrast, the aforementioned analysis of lungs from 17 patients with CTEPH and a piglet model suggest an increase in bronchopulmonary shunts bypassing pulmonary arterial

Symptomatic in ~50% of cases Venous thrombosis/Venous thromboembolism

Pulmonary embolism

Infection, inflammation Immunity (antiphospholipidantibodies, splenectomy) Genetic predisposition (blood groups non-0) Poor anticoagulation

Incomplete resolution and organization of thrombus Honeymoon period, CTEPVD Vascular webs, stenoses, occlusions

In situ thrombosis (high PAI-1, FVIII, APL) Uncleavable fibrinogen

High pressure/ shear stress in pulmonary arteries

Increased pulmonary vascular resistance/”secondary pulmonary arteriopathy”

CTEPH Figure 4. Current pathophysiological concept. Time course of chronic thromboembolic pulmonary hypertension (CTEPH) pathogenesis is illustrated by red arrows from top to bottom. The time interval between the venous thromboembolism event (top) and CTEPH (bottom) may be more than four decades (52). Several honeymoon periods may delay the diagnosis. Some patients may have a large clot, but still have normal resting hemodynamics, and qualify as having CTEPVD (chronic thromboembolic pulmonary vascular disease) (39). “Secondary pulmonary arteriopathy” labels the typical pulmonary vascular changes of small pulmonary arteries (,500 mm in diameter) that are the hallmark of pulmonary arterial hypertension. APL = anti-phospholipid antibodies; FVIII = factor VIII; PAI-1 = plasminogen activator inhibitor type 1.

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SEMINAR FOR CLINICIANS thromboembolic obstructions and the capillary bed, with a direct connection to the pulmonary veins (Figure 1I), which are commonly remodeled in CTEPH (Figure 1F). From this perspective, the transmission of systemic pressures to low pulmonary venous pressures would explain muscularization and fibrotic thickening of the veins, as well as a congestive repercussion on the capillary network leading to capillary proliferation. Dorfm¨uller and colleagues (38) described areas of hyperperfusion and/or congestion with hemangiomatosis-like multiplication of alveolar capillaries within septal boundaries (Figure 1G), possibly corresponding to the mosaic ground-glass pattern that can be observed in CT scans of patients with CTEPH.

afterload increase in CTEPH is different from that in acute pulmonary embolism, where only a complete occlusion of the artery causes an abrupt pressure rise that temporarily interrupts the circulation, and leads to systemic cardiovascular collapse, or even death. In CTEPH the process is much slower. Pulmonary vascular resistance depends mainly on the proximal vascular compartment (in the case of proximal CTEPH), which confers a better prognosis than if resistance were partitioned in the upstream (or capillary) compartment (in the case of distal CTEPH or PAH) (46). PEA provides acute reduction in RV afterload (47, 48), even at advanced stages of RV failure, with subsequent improvement in biventricular cardiac function and reduction in ventricular septal abnormalities and RV systolic wall stress (49, 50).

Right Ventricular Remodeling in CTEPH Summary The right ventricle is affected when at least one-half or more of the effective pulmonary vascular bed at rest is excluded from the circulation, which may be the case in the presence of only a few central obstructions. The physiology of residual volume (RV)

CTEPH is a dual vascular disorder, with stenoses, webs, and occlusions of the major pulmonary arteries and a “secondary arteriopathy” affecting small resistance vessels. Although the pathogenesis of

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CTEPH has not been reproduced in animal models, the association with venous thromboembolism leads to the speculation that CTEPH is a disorder of misguided vascular remodeling after pulmonary thromboembolism (Figure 4). Although in some instances genetic factors may play a role (non-O blood groups, rare thrombophilias, dysfibrinogenemias), leading to larger thrombus, together with elevated factor VIII and platelet activation (51), one current disease concept is that ancillary acquired factors are misguiding the vascular remodeling of thrombus resolution in various ways. What all of those have in common is that two key pathways are suppressed: thrombus angiogenesis and innate immune cell function. It is unclear whether similar mechanisms are contributing to “secondary pulmonary arteriopathy.” Understanding the mechanisms of regression of secondary pulmonary arteriopathy after alleviating major vessel obstruction in CTEPH may be a starting point for new treatment targets. n Author disclosures are available with the text of this article at www.atsjournals.org.

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SEMINAR FOR CLINICIANS 19 Suntharalingam J, Goldsmith K, van Marion V, Long L, Treacy CM, Dudbridge F, Toshner MR, Pepke-Zaba J, Eikenboom JC, Morrell NW. Fibrinogen Aa Thr312Ala polymorphism is associated with chronic thromboembolic pulmonary hypertension. Eur Respir J 2008; 31:736–741. 20 Le Gal G, Delahousse B, Lacut K, Malaviolle V, Regina S, Blouch MT, Couturaud F, Mottier D, Oger E, Gruel Y; Groupe d’Etudes sur la Thrombose des Hopitaux ˆ Universitaires du Grand Ouest. Fibrinogen Aa-Thr312Ala and factor XIII-A Val34Leu polymorphisms in idiopathic venous thromboembolism. Thromb Res 2007;121: 333–338. 21 Morris TA, Marsh JJ, Chiles PG, Kim NH, Noskovack KJ, Magana MM, Gruppo RA, Woods VL Jr. Abnormally sialylated fibrinogen g-chains in a patient with chronic thromboembolic pulmonary hypertension. Thromb Res 2007;119:257–259. 22 Bonderman D, Jakowitsch J, Redwan B, Bergmeister H, Renner MK, Panzenbock ¨ H, Adlbrecht C, Georgopoulos A, Klepetko W, Kneussl M, et al. Role for staphylococci in misguided thrombus resolution of chronic thromboembolic pulmonary hypertension. Arterioscler Thromb Vasc Biol 2008;28:678–684. 23 Alias S, Redwan B, Panzenbock ¨ A, Winter MP, Schubert U, Voswinckel R, Frey MK, Jakowitsch J, Alimohammadi A, Hobohm L, et al. Defective angiogenesis delays thrombus resolution: a potential pathogenetic mechanism underlying chronic thromboembolic pulmonary hypertension. Arterioscler Thromb Vasc Biol 2014;34: 810–819. 24 Frey MK, Alias S, Winter MP, Redwan B, Stubiger ¨ G, Panzenboeck A, Alimohammadi A, Bonderman D, Jakowitsch J, Bergmeister H, et al. Splenectomy is modifying the vascular remodeling of thrombosis. J Am Heart Assoc 2014;3:e000772. 25 Zabini D, Nagaraj C, Stacher E, Lang IM, Nierlich P, Klepetko W, Heinemann A, Olschewski H, Balint ´ Z, Olschewski A. Angiostatic factors in the pulmonary endarterectomy material from chronic thromboembolic pulmonary hypertension patients cause endothelial dysfunction. PLoS One 2012;7:e43793. 26 Xie Y, Muller WA. Molecular cloning and adhesive properties of murine platelet/endothelial cell adhesion molecule 1. Proc Natl Acad Sci USA 1993;90:5569–5573. 27 O’Brien CD, Cao G, Makrigiannakis A, DeLisser HM. Role of immunoreceptor tyrosine-based inhibitory motifs of PECAM-1 in PECAM-1–dependent cell migration. Am J Physiol Cell Physiol 2004; 287:C1103–C1113. 28 Privratsky JR, Tilkens SB, Newman DK, Newman PJ. PECAM-1 dampens cytokine levels during LPS-induced endotoxemia by regulating leukocyte trafficking. Life Sci 2012;90:177–184. 29 Saha P, Humphries J, Modarai B, Mattock K, Waltham M, Evans CE, Ahmad A, Patel AS, Premaratne S, Lyons OT, et al. Leukocytes and the natural history of deep vein thrombosis: current concepts and future directions. Arterioscler Thromb Vasc Biol 2011;31:506–512. 30 Goldberger A, Middleton KA, Oliver JA, Paddock C, Yan HC, DeLisser HM, Albelda SM, Newman PJ. Biosynthesis and processing of the cell adhesion molecule PECAM-1 includes production of a soluble form. J Biol Chem 1994;269:17183–17191. 31 Kellermair J, Redwan B, Alias S, Jabkowski J, Panzenboeck A, Kellermair L, Winter MP, Weltermann A, Lang IM. Platelet endothelial cell adhesion molecule 1 deficiency misguides venous thrombus resolution. Blood 2013;122:3376–3384. 32 Archibald CJ, Auger WR, Fedullo PF, Channick RN, Kerr KM, Jamieson SW, Kapelanski DP, Watt CN, Moser KM. Long-term outcome after pulmonary thromboendarterectomy. Am J Respir Crit Care Med 1999;160:523–528. 33 Jamieson SW, Kapelanski DP, Sakakibara N, Manecke GR, Thistlethwaite PA, Kerr KM, Channick RN, Fedullo PF, Auger WR. Pulmonary endarterectomy: experience and lessons learned in 1,500 cases. Ann Thorac Surg 2003;76:1457–1462, discussion 1462–1464. 34 Moser KM, Auger WR, Fedullo PF, Jamieson SW. Chronic thromboembolic pulmonary hypertension: clinical picture and surgical treatment. Eur Respir J 1992;5:334–342.

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35 Tworetzky W, Moore P, Bekker JM, Bristow J, Black SM, Fineman JR. Pulmonary blood flow alters nitric oxide production in patients undergoing device closure of atrial septal defects. J Am Coll Cardiol 2000;35:463–467. 36 Tozzi CA, Poiani GJ, Harangozo AM, Boyd CD, Riley DJ. Pressureinduced connective tissue synthesis in pulmonary artery segments is dependent on intact endothelium. J Clin Invest 1989;84:1005–1012. 37 Boulate D, Perros F, Dorfmuller P, Arthur-Ataam J, Guihaire J, Lamrani L, Decante B, Humbert M, Eddahibi S, Dartevelle P, et al. Pulmonary microvascular lesions regress in reperfused chronic thromboembolic pulmonary hypertension. J Heart Lung Transplant 2015;34:457–467. 38 Dorfmuller ¨ P, Gunther ¨ S, Ghigna MR, Thomas de Montpreville ´ V, Boulate D, Paul JF, Ja¨ıs X, Decante B, Simonneau G, Dartevelle P, et al. Microvascular disease in chronic thromboembolic pulmonary hypertension: a role for pulmonary veins and systemic vasculature. Eur Respir J 2014;44:1275–1288. 39 Lang IM, Madani M. Update on chronic thromboembolic pulmonary hypertension. Circulation 2014;130:508–518. 40 Mitzner W, Wagner EM. Vascular remodeling in the circulations of the lung. J Appl Physiol (1985) 2004;97:1999–2004. 41 Shimizu H, Tanabe N, Terada J, Masuda M, Sakao S, Kasahara Y, Takiguchi Y, Tatsumi K, Kuriyama T. Dilatation of bronchial arteries correlates with extent of central disease in patients with chronic thromboembolic pulmonary hypertension. Circ J 2008;72: 1136–1141. 42 Orell SR, Hultgren S. Anastomoses between bronchial and pulmonary arteries in pulmonary thromboembolic disease. Acta Pathol Microbiol Scand 1966;67:322–338. 43 Fadel E, Wijtenburg E, Michel R, Mazoit JX, Bernatchez R, Decante B, Sage E, Mazmanian M, Herve´ P. Regression of the systemic vasculature to the lung after removal of pulmonary artery obstruction. Am J Respir Crit Care Med 2006;173:345–349. 44 Charan NB, Turk GM, Czartolomny J, Andreazuk T. Systemic arterial blood supply to the trachea and lung in sheep. J Appl Physiol (1985) 1987;62:2283–2287. 45 Frazier AA, Galvin JR, Franks TJ, Rosado-De-Christenson ML. From the archives of the AFIP: pulmonary vasculature: hypertension and infarction. Radiographics 2000;20:491–524; quiz 530–531, 532. 46 Kim NH, Fesler P, Channick RN, Knowlton KU, Ben-Yehuda O, Lee SH, Naeije R, Rubin LJ. Preoperative partitioning of pulmonary vascular resistance correlates with early outcome after thromboendarterectomy for chronic thromboembolic pulmonary hypertension. Circulation 2004;109:18–22. 47 Reesink HJ, Marcus JT, Tulevski II, Jamieson S, Kloek JJ, Vonk Noordegraaf A, Bresser P. Reverse right ventricular remodeling after pulmonary endarterectomy in patients with chronic thromboembolic pulmonary hypertension: utility of magnetic resonance imaging to demonstrate restoration of the right ventricle. J Thorac Cardiovasc Surg 2007;133:58–64. 48 Surie S, Bouma BJ, Bruin-Bon RA, Hardziyenka M, Kloek JJ, Van der Plas MN, Reesink HJ, Bresser P. Time course of restoration of systolic and diastolic right ventricular function after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension. Am Heart J 2011;161:1046–1052. 49 Iino M, Dymarkowski S, Chaothawee L, Delcroix M, Bogaert J. Time course of reversed cardiac remodeling after pulmonary endarterectomy in patients with chronic pulmonary thromboembolism. Eur Radiol 2008;18:792–799. 50 Mauritz GJ, Vonk-Noordegraaf A, Kind T, Surie S, Kloek JJ, Bresser P, Saouti N, Bosboom J, Westerhof N, Marcus JT. Pulmonary endarterectomy normalizes interventricular dyssynchrony and right ventricular systolic wall stress. J Cardiovasc Magn Reson 2012;14:5. 51 Homoncik M, Gessl A, Ferlitsch A, Jilma B, Vierhapper H. Altered platelet plug formation in hyperthyroidism and hypothyroidism. J Clin Endocrinol Metab 2007;92:3006–3012. 52 Bonderman D, Jakowitsch J, Adlbrecht C, Schemper M, Kyrle PA, Schonauer ¨ V, Exner M, Klepetko W, Kneussl MP, Maurer G, et al. Medical conditions increasing the risk of chronic thromboembolic pulmonary hypertension. Thromb Haemost 2005;93:512–516.

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G ro u p 4 Pu l m o n a r y Hypertension Chronic Thromboembolic Pulmonary Hypertension: Epidemiology, Pathophysiology, and Treatment Nick H. Kim, MD KEYWORDS  Chronic thromboembolic pulmonary hypertension  Chronic thromboembolism  Pulmonary embolism  Pulmonary thromboendarterectomy  Pulmonary endarterectomy  Riociguat  Balloon pulmonary angioplasty

KEY POINTS

The first successful pulmonary thromboendarterectomy (PTE) for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH) was reported nearly 20 years before the introduction of both heart-lung transplantation and intravenous epoprostenol for the treatment of pulmonary arterial hypertension (PAH).1–3 Fast forward another 30 years, and much has evolved in our understanding and treatment of pulmonary hypertension (PH), and with that, so has our approach to the diagnosis and management of patients with CTEPH.

EPIDEMIOLOGY CTEPH is a complication of pulmonary embolism.4,5 Although the true incidence of CTEPH following acute pulmonary embolism remains unknown, reports have ranged widely from 0.4% to 9.1%.4,6–10 The variability of the incidence reports

may reflect differences in patient selection and methodology across these reports. Whether these rates represent true incidence of CTEPH after acute pulmonary embolism, or combination of incident and prevalent cases remains speculative. For example, in the series of Pengo and colleagues,4 no additional CTEPH was detected beyond 2 years from the initial acute pulmonary embolism, and one of the cases reportedly developed near-systemic PH within just 5 months from the acute event. The characteristics of these cases arguably raise concerns that the series of Pengo and colleagues4 may not be solely an incident series of CTEPH occurring after acute pulmonary embolism, but rather one that unintentionally included both incident and previously unrecognized CTEPH cases. Additional efforts are currently under way to prospectively capture incident cases of CTEPH by screening after acute, first-time pulmonary

Disclosures: Consultancy/Speakers Bureau: Actelion, Bayer; Board Member: CTEPH.com. Division of Pulmonary and Critical Care Medicine, University of California, San Diego, 9300 Campus Point Drive, MC 7381, La Jolla, CA 92037, USA E-mail address: [email protected] Cardiol Clin 34 (2016) 435–441 http://dx.doi.org/10.1016/j.ccl.2016.04.011 0733-8651/16/$ – see front matter Ó 2016 Elsevier Inc. All rights reserved.

cardiology.theclinics.com

 Pulmonary embolism history can be absent in chronic thromboembolic pulmonary hypertension (CTEPH).  Negative computed tomography pulmonary angiogram does not rule out CTEPH.  Pulmonary thromboendarterectomy remains the treatment of choice for CTEPH.  Operability assessment should be performed by an experienced CTEPH team.

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Kim embolism cases to better assess the true incidence of CTEPH. Nevertheless, any measurement or estimate of CTEPH incidence after acute pulmonary embolism may underestimate the overall burden of CTEPH because as many as 25% to 30% of patients with CTEPH are diagnosed without a prior clinical history of pulmonary embolism, and nearly half of these patients may not have a history of deep venous thrombosis.11,12 Therefore, a key take-home point when evaluating patients presenting with PH is that the lack of a venous thromboembolism history should not exclude CTEPH as a possibility. Table 1 shows epidemiologic data used to estimate the incidence of CTEPH to better appreciate the scope of CTEPH in the United States.13 The calculations shown are based on the CTEPH incidence rate reported from Klok and colleagues.7 This study included the largest pulmonary embolism series (866 consecutive cases) screened for CTEPH following standard diagnostic guidelines including right heart catheterization. Even using this lower range of the reported incidence rates after pulmonary embolism, approximately 3400 cases of CTEPH in the United States might be expected each year. Combined with the approximately 30% of CTEPH cases operated without a history of prior pulmonary embolism, the overall estimate of new CTEPH cases diagnosed in the United States each year jumps to nearly 5000 new CTEPH cases per year. An important question today then is: Where are these patients with CTEPH and how are they being treated? Although precise data on the number of PTE surgeries performed in the United States is not known, estimated 300 to 400 PTEs are being performed in the United States per year today. However, based on estimates from Table 1, this represents fewer than 8% of incident CTEPH

Table 1 Estimated annual incidence of CTEPH in the United States Estimates PE cases per year13 Incidence of CTEPH after PE7 CTEPH cases after PE per year Additional 30% of CTEPH cases per year without prior pulmonary embolism Total overall CTEPH cases estimated per year

600,000 0.57% 3420 1466

4886

Abbreviations: CTEPH, chronic thromboembolic pulmonary hypertension; PE, pulmonary embolism.

cases being operated annually. Even when accounting for the limitations of such extrapolated estimates, there appears to be a large discrepancy between number of potentially surgically treatable cases and surgically treated volume. Table 2 lists the plausible reasons behind this large gap. In addition to possibly inaccurate incidence rates, cases of CTEPH may not be properly diagnosed, and if diagnosed, may not be referred for surgical treatment as recommended consistently by best practice guidelines.14,15 One particular diagnostic pitfall in CTEPH is the failure to obtain a lung ventilation perfusion (VQ) scan to screen for CTEPH during the workup of PH.16 Computed tomography (CT) pulmonary angiography is often (erroneously) used in place of the VQ scan. Unfortunately, CT pulmonary angiography lacks adequate sensitivity to detect

Table 2 Potential explanations for the gap between estimated CTEPH incidence from Table 1, and the relatively small number of PTE cases performed in the United States Explanation

Result

Assumptions are incorrect Examples: Error in true  PE estimate may not incidence be accurate of CTEPH  Some PE cases may have had CTEPH already (ie, not incident PE)  CTEPH true incidence may be lower CTEPH is not being diagnosed Examples: CTEPH is  Failure to recognize/ underestimated diagnose CTEPH  CTEPH Incorrectly diagnosed as PAH  CTEPH Incorrectly diagnosed as recurrent pulmonary embolism Under referral for CTEPH evaluation/treatment Examples: CTEPH is  Providers not aware underestimated of PTE surgery or have limited access  Operability is being decided locally  Medical treatment is elected instead of PTE Abbreviations: CTEPH, chronic thromboembolic pulmonary hypertension; PAH, pulmonary arterial hypertension; PE, pulmonary embolism; PTE, pulmonary thromboendarterectomy.

Group 4 PH CTEPH detection, and therefore cannot reliably rule out CTEPH, whereas the VQ scan is more sensitive.14,17 Fig. 1 show an example of an abnormal VQ scan and the corresponding CT angiogram done in the same patient, which was read as “negative for pulmonary embolism.” The CT reading is correct; there is no pulmonary embolism. However, there is evidence of CTEPH with eccentric lining material in the left descending pulmonary artery, segmental webs, bronchial collaterals, and right ventricular hypertrophy (not shown on this image). These sometimes-subtle defects suggestive of CTEPH on CT can be overlooked leading to a false negative study. So with a negative pulmonary embolism report, this CT pulmonary angiogram may contribute to eventual misdiagnosis of PAH when the patient in actuality has CTEPH. On a VQ scan, pulmonary embolism and CTEPH appear identical in revealing perfusion defects – and hence bypassing the need for additional training for the radiologist or reviewer. But for CT pulmonary angiograms, acute pulmonary embolism and chronic thromboembolic disease of CTEPH appear quite differently despite sharing similar perfusion defects on VQ scan.

PATHOPHYSIOLOGY OF CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION Although linked with pulmonary embolism, the pathophysiologic development of CTEPH extends beyond thrombosis. In one large registry, more than two-thirds of patients with CTEPH had no identifiable coagulopathy contributing to susceptibility.11 Of the numerous types of thrombophilia, lupus anticoagulant and antiphospholipid syndrome have been associated with CTEPH in only 10% to 20% of reported cases. Therefore, the

efforts to understand the pathogenesis of CTEPH have focused beyond thrombosis. Multiple medical comorbidities are more commonly present in patients with CTEPH than those with PAH.18 These conditions may offer clues to potential pathogenic mechanisms contributing to the development of CTEPH. In a large series comparing CTEPH and PAH populations, the presence of ventriculoatrial (VA) shunt, infected pacemaker, or history of splenectomy had the highest odds ratios for the development of CTEPH, higher even than a history of recurrent venous thromboembolism. Although the precise link between these associated comorbidities and CTEPH is not known, inflammation and infection have been hypothesized as contributors for the development of CTEPH in these at-risk populations.5,19 In a report from Bonderman and colleagues,19 of 7 consecutively operated VA shunt associated CTEPH cases, 6 had staphylococcal DNA isolated from the endarterectomized tissue. They also found that in a murine model of inferior vena cava thrombosis that staphylococcal infection delayed resolution of thrombi and decreased expression of macrophages, cells that are vital to thrombus resolution. More recently, a group from Belgium studied 52 operated CTEPH cases and reported associated abnormalities in neovascularization.20 The endarterectomized specimens were also noted to have abundance of macrophages, lymphocytes, and neutrophils within the chronic thromboembolic material. With elevations in numerous proinflammatory markers and cytokines in CTEPH compared with controls, a compelling case can be made for active inflammatory process contributing to the development of CTEPH. Furthermore, Zabini and colleagues21 reported that both interferon gamma-induced protein 10 (IP-10) and interleukin-6 levels were positively and negatively correlated with hemodynamics and exercise capacity, respectively, in

Fig. 1. (A) VQ scan showing multiple segmental and subsegmental perfusion defects. (B) CT pulmonary angiogram revealed no pulmonary embolism, but on closer review demonstrates signs of chronic disease.

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Kim CTEPH. IP-10 is associated with fibroblast migration and activation, which may be important in the development of chronic intimal fibrosis of the pulmonary arteries in CTEPH. Together with prior reports of abnormal fibrinolysis in some cases of CTEPH, the research focus has once again been shifted away from simply a problem of thrombosis, to a failure to adequately clear the thrombotic insult, influenced potentially by multiple factors including an inflammatory response, infection, and fibrin resistance.5,22 The role of small vessel abnormalities in the lungs of patients with CTEPH has received a recent major update from the work of Dorfmuller and colleagues.23 In their histopathologic report of 17 CTEPH cases with either distal, inoperable CTEPH, or residual PH after pulmonary endarterectomy, the scope of small vessel involvement of CTEPH was found to extend beyond the precapillary small arteries. They found significant disease in the pulmonary venous and capillary systems, similar to that seen in pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis, respectively, as well as impressive systemicpulmonary anastomoses and hypertrophied bronchial collaterals. These observations are important reminders that CTEPH is not just chronic thrombus with varying degrees of precapillary changes similar to idiopathic PAH, but rather, a more complex disease with heterogeneous and less predictable involvement of the entire pulmonary circulation and associated collateral vasculature. As the microvasculature in CTEPH appears to be different from PAH, it is not a stretch to surmise that the RV in CTEPH may also be different compared with that of other forms of PH. The primary location of vascular resistance in the pulmonary circulation appears to affect the RV afterload

differently. In a canine model of PH, Pagnamenta and colleagues24 reported differences in RV afterload between proximal versus distal obstruction of the pulmonary arterial bed. Using models of proximal pulmonary artery ensnarement and distal micro-embolization to differentiate proximal versus distal pulmonary vascular obstruction, the investigators noted that for similar degrees of PH, the RV time constant was lower and the RV afterload higher for the proximal obstruction model. MacKenzie and colleagues25 also observed differences between CTEPH and PAH. For a given mean pulmonary arterial pressure, the RV time constant was significantly shorter in CTEPH compared with PAH. For similar degree of PH, the investigators concluded that the RV in CTEPH has greater burden of work than in PAH. This may explain the observations reported by Giusca and colleagues26 when comparing echocardiograms from varying causes of PH. In this report, patients with CTEPH exhibited the lowest tricuspid annular plane systolic excursion (indicating lower RV contractility) and the smallest RV fractional area change compared with both patients with PAH and patients with Eisenmenger syndrome. Taken together, these findings suggest that the RV in CTEPH may not adapt as well to the type of afterload posed by CTEPH (proximal disease component) as other forms of PH. This may have implications on RV recovery and targeting of therapies for CTEPH. For example, the RV in CTEPH may have differential recovery or response depending on whether we relieve the proximal mechanical disease versus the microvascular component. The pathophysiology of CTEPH therefore is multifaceted and goes beyond thrombosis (Fig. 2). In reviewing the treatment of CTEPH, it is helpful to consider these various components Fig. 2. Pathophysiology of CTEPH goes beyond thrombosis.

Group 4 PH

Box 1 Steps to take after chronic thromboembolic pulmonary hypertension (CTEPH) diagnosis 1. Chronic anticoagulation therapy 2. Refer for pulmonary thromboendarterectomy (PTE) considerationa 3. If deemed not to be a surgical candidate, consider the following options 4a. Medical therapy for inoperable disease 4b. Consider referral for balloon pulmonary angioplasty option 4c. Consider second opinion for possible PTE 5. If not responding/candidate for any above treatments, refer for lung transplantation a Can be initially a remote review by a CTEPH team of pertinent records and images.

to better understand treatment priorities as well as some limitations, and potentially future opportunities, of our current approach.

TREATMENT The first steps after CTEPH diagnosis should always include chronic anticoagulation and consideration of PTE surgery.14 Box 1 outlines a simplified stepwise approach to every case of newly diagnosed CTEPH. The optimal method of chronic anticoagulation has not been studied. Despite the availability of newer oral anticoagulant therapies, it is unknown if these agents are safe and effective in the treatment or maintenance

phase of CTEPH.27 In addition to chronic anticoagulation, all patients should be referred to a CTEPH team for operability assessment.14 The determination of operability combines objective data, such as patient factors, hemodynamics, and imaging, but critically also hinges on surgical or center experience (Fig. 3). Such subjectivity needs to be considered when interpreting treatment decisions. For example, an inexperienced reviewer turning a case down for surgery is possibly depriving that patient of a potentially curative surgical intervention. PTE remains the principal treatment of choice for CTEPH. The surgery is not an embolectomy or thrombectomy, but a true endarterectomy, involving stripping of the inner layer of both pulmonary arteries to restore distal blood flow and relieve the PH. Following successful PTE, compliance to chronic anticoagulation therapy should obviate the need for second surgery. For patients with CTEPH deemed inoperable due to technically distal (unreachable) disease, or for patients with residual PH following PTE, riociguat is the only approved medical therapy.28 It should be noted that riociguat (or any other off-label PAH-targeted medical therapy) should not be prescribed for patients with operable CTEPH. The risks and benefits of these treatments in CTEPH have not been adequately tested and such patients should undergo PTE surgery without delay.29 In addition to riociguat, select patients with inoperable CTEPH may be candidates for percutaneous transluminal pulmonary angioplasty, also referred to as balloon pulmonary angioplasty (BPA).14,30,31 Although recent refinements have made this procedure a safer and viable alternative Fig. 3. CTEPH operability assessment requires consideration of multiple and both objective and subjective factors.

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Kim when conventional therapy is not available, patient selection and treatment need to be performed by experienced specialists, much like the case with PTE surgery. Significant complications, including procedure-related deaths, have been reported with an overall complication rates as high as 60%.30,32 Finally, the precise role of BPA in the treatment algorithm of CTEPH and its relation to PTE and medical therapy remain unclear and in need of clarification.

SUMMARY CTEPH is a unique and important type of PH, one that may dramatically respond to timely and appropriate intervention. There is a growing awareness worldwide of CTEPH and its pathogenesis is being better defined, but more work is needed in both awareness and pathogenesis. Treatment options have expanded to include targeted, effective medical therapy for eligible patients, as well as an emerging catheter-based interventions. Due to the many nuances of CTEPH, all such treatment decisions should be coordinated with an experienced CTEPH team to provide the best and most appropriate treatment for the individual patient.

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ESC/ERS GUIDELINES

2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS)

Authors/Task Force Members: Nazzareno Galie`* (ESC Chairperson) (Italy), Marc Humbert* a (ERS Chairperson) (France), Jean-Luc Vachiery c (Belgium), Simon Gibbs (UK), Irene Lang (Austria), Adam Torbicki (Poland), Ge´rald Simonneaua (France), Andrew Peacocka (UK), Anton Vonk Noordegraafa (The Netherlands), Maurice Beghettib (Switzerland), Ardeschir Ghofrania (Germany), Miguel Angel Gomez Sanchez (Spain), Georg Hansmannb (Germany), Walter Klepetkoc (Austria), Patrizio Lancellotti (Belgium), Marco Matuccid (Italy), Theresa McDonagh (UK), Luc A. Pierard (Belgium), Pedro T. Trindade (Switzerland), Maurizio Zompatorie (Italy) and Marius Hoepera (Germany) * Corresponding authors: Nazzareno Galie`, Department of Experimental, Diagnostic and Specialty Medicine –DIMES, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy, Tel: +39 051 349 858, Fax: +39 051 344 859, Email: [email protected] Marc Humbert, Service de Pneumologie, Hoˆpital Biceˆtre, Universite´ Paris-Sud, Assistance Publique Hoˆpitaux de Paris, 78 rue du Ge´ne´ral Leclerc, 94270 Le Kremlin-Bicetre, France, Tel: +33 145217972, Fax: +33 145217971, Email: [email protected] ESC Committee for Practice Guidelines (CPG) and National Cardiac Societies document reviewers: listed in Appendix a Representing the European Respiratory Society; bRepresenting the Association for European Paediatric and Congenital Cardiology; cRepresenting the International Society for Heart and Lung Transplantation; dRepresenting the European League Against Rheumatism; and eRepresenting the European Society of Radiology.

ESC entities having participated in the development of this document: ESC Associations: Acute Cardiovascular Care Association (ACCA), European Association for Cardiovascular Prevention & Rehabilitation (EACPR), European Association of Cardiovascular Imaging (EACVI), European Association of Percutaneous Cardiovascular Interventions (EAPCI), European Heart Rhythm Association (EHRA), Heart Failure Association (HFA). ESC Councils: Council for Cardiology Practice (CCP), Council on Cardiovascular Nursing and Allied Professions (CCNAP), Council on Cardiovascular Primary Care (CCPC). ESC Working Groups: Cardiovascular Pharmacotherapy, Cardiovascular Surgery, Grown-up Congenital Heart Disease, Pulmonary Circulation and Right Ventricular Function, Valvular Heart Disease. The content of these European Society of Cardiology (ESC) and European Respiratory Society (ERS) Guidelines has been published for personal and educational use only. No commercial use is authorized. No part of the ESC/ERS Guidelines may be translated or reproduced in any form without written permission from the ESC and/or ERS. Permission can be obtained upon submission of a written request to Oxford University Press, the publisher of the European Heart Journal or from the European Respiratory Journal and the party authorized to handle such permissions on behalf of the ESC and ERS. Disclaimer: The ESC/ERS Guidelines represent the views of the ESC and ERS and were produced after careful consideration of the scientific and medical knowledge and the evidence available at the time of their publication. The ESC and ERS are not responsible in the event of any contradiction, discrepancy and/or ambiguity between the ESC/ERS Guidelines and any other official recommendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encouraged to take the ESC/ERS Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic or therapeutic medical strategies; however, the ESC/ERS Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate and accurate decisions in consideration of each patient’s health condition and in consultation with that patient and, where appropriate and/or necessary, the patient’s caregiver. Nor do the ESC/ERS Guidelines exempt health professionals from taking into full and careful consideration the relevant official updated recommendations or guidelines issued by the competent public health authorities, in order to manage each patient’s case in light of the scientifically accepted data pursuant to their respective ethical and professional obligations. It is also the health professional’s responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription. Published on behalf of the European Society of Cardiology. All rights reserved. & 2015 European Society of Cardiology & European Respiratory Society. This article is being published concurrently in the European Heart Journal (10.1093/eurheartj/ehv317) and the European Respiratory Journal (10.1183/13993003.01032-2015). The articles are identical except for minor stylistic and spelling differences in keeping with each journal’s style. Either citation can be used when citing this article.

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Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT)

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ESC/ERS Guidelines

Document Reviewers: Victor Aboyans (CPG Review Coordinator) (France), Antonio Vaz Carneiro (CPG Review Coordinator) (Portugal), Stephan Achenbach (Germany), Stefan Agewall (Norway), Yannick Allanored (France), Riccardo Asteggiano (Italy), Luigi Paolo Badano (Italy), Joan Albert Barbera`a (Spain), He´le`ne Bouvaist (France), He´ctor Bueno (Spain), Robert A. Byrne (Germany), Scipione Carerj (Italy), Grac¸a Castro (Portugal), Çetin Erol (Turkey), Volkmar Falk (Germany), Christian Funck-Brentano (France), Matthias Gorenflob (Germany), John Grantonc (Canada), Bernard Iung (France), David G. Kiely (UK), Paulus Kirchhof (Germany/UK), Barbro Kjellstrom (Sweden), Ulf Landmesser (Switzerland), John Lekakis (Greece), Christos Lionis (Greece), Gregory Y. H. Lip (UK), Stylianos E. Orfanos a (Greece), Myung H. Parkc (USA), Massimo F. Piepoli (Italy), Piotr Ponikowski (Poland), Marie-Pierre Revel e (France), David Rigau a (ERS methodologist) (Switzerland), Stephan Rosenkranz (Germany), Heinz Vo¨ller (Germany), and Jose Luis Zamorano (Spain) The disclosure forms of all experts involved in the development of these guidelines are available on the ESC website http://www.escardio.org/guidelines

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Table of Contents Abbreviations and acronyms . . . . . . . . . . . . . . . . . . . . . 1. Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Definitions and classifications . . . . . . . . . . . . . . . . . . . . 3.1 Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Classifications . . . . . . . . . . . . . . . . . . . . . . . . . 4. Epidemiology and genetics of pulmonary hypertension . . . 4.1 Epidemiology and risk factors . . . . . . . . . . . . . . . . 4.2 Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Pulmonary hypertension diagnosis . . . . . . . . . . . . . . . . 5.1 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.1 Clinical presentation . . . . . . . . . . . . . . . . . . . 5.1.2 Electrocardiogram . . . . . . . . . . . . . . . . . . . . 5.1.3 Chest radiograph . . . . . . . . . . . . . . . . . . . . . 5.1.4 Pulmonary function tests and arterial blood gases 5.1.5 Echocardiography . . . . . . . . . . . . . . . . . . . . . 5.1.6 Ventilation/perfusion lung scan . . . . . . . . . . . . 5.1.7 High-resolution computed tomography, contrast enhanced computed tomography, and pulmonary angiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.8 Cardiac magnetic resonance imaging . . . . . . . . . 5.1.9 Blood tests and immunology . . . . . . . . . . . . . . 5.1.10 Abdominal ultrasound scan . . . . . . . . . . . . . . 5.1.11 Right heart catheterization and vasoreactivity . . 5.1.12 Genetic testing . . . . . . . . . . . . . . . . . . . . . . 5.2 Diagnostic algorithm . . . . . . . . . . . . . . . . . . . . . . 6. Pulmonary arterial hypertension (group 1) . . . . . . . . . . . 6.1 Clinical characteristics . . . . . . . . . . . . . . . . . . . . . 6.2 Evaluation of severity . . . . . . . . . . . . . . . . . . . . . 6.2.1 Clinical parameters, imaging and haemodynamics 6.2.2 Exercise capacity . . . . . . . . . . . . . . . . . . . . . 6.2.3 Biochemical markers . . . . . . . . . . . . . . . . . . .

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6.2.4 Comprehensive prognostic evaluation and risk assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.5 Definition of patient status . . . . . . . . . . . . . . . . . 6.2.6 Treatment goals and follow-up strategy . . . . . . . . . 6.3 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.1 General measures . . . . . . . . . . . . . . . . . . . . . . . 6.3.1.1 Physical activity and supervised rehabilitation . . . 6.3.1.2 Pregnancy, birth control, and post-menopausal hormonal therapy . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.1.3 Elective surgery . . . . . . . . . . . . . . . . . . . . . . 6.3.1.4 Infection prevention . . . . . . . . . . . . . . . . . . . 6.3.1.5 Psychosocial support . . . . . . . . . . . . . . . . . . 6.3.1.6 Adherence to treatments . . . . . . . . . . . . . . . . 6.3.1.7 Travel . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.1.8 Genetic counselling . . . . . . . . . . . . . . . . . . . 6.3.2 Supportive therapy . . . . . . . . . . . . . . . . . . . . . . 6.3.2.1 Oral anticoagulants . . . . . . . . . . . . . . . . . . . . 6.3.2.2 Diuretics . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.2.3 Oxygen . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.2.4 Digoxin and other cardiovascular drugs . . . . . . 6.3.2.5 Anaemia and iron status . . . . . . . . . . . . . . . . 6.3.3 Specific drug therapy . . . . . . . . . . . . . . . . . . . . . 6.3.3.1 Calcium channel blockers . . . . . . . . . . . . . . . 6.3.3.2 Endothelin receptor antagonists . . . . . . . . . . . 6.3.3.3 Phosphodiesterase type 5 inhibitors and guanylate cyclase stimulators . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.3.4 Prostacyclin analogues and prostacyclin receptor agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3.3.5 Experimental compounds and strategies . . . . . . 6.3.4 Combination therapy . . . . . . . . . . . . . . . . . . . . . 6.3.5 Drug interactions . . . . . . . . . . . . . . . . . . . . . . . 6.3.6 Balloon atrial septostomy . . . . . . . . . . . . . . . . . .

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Guidelines † Pulmonary hypertension † Pulmonary arterial hypertension † Chronic thromboembolic pulmonary hypertension † Congenital heart disease † Connective tissue disease † Heart failure † Respiratory failure † Endothelin receptor antagonists † Phosphodiesterase type 5 inhibitors † Prostacyclin analogues † Lung disease † Left heart disease

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ESC/ERS Guidelines

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Abbreviations and acronyms ALAT ASAT APAH BAS BMPR2 BNP BPA BREATHE CAV1 CCB cGMP CHD CI CMR CO COPD Cpc-PH CPET CPFE CT CTD CTPA CTEPH DLCO DPAH DPG EACVI ECG ECMO EIF2AK4 EMA ERA FC FDA HAART HIV HF-pEF HPAH HRCT ICU INR IPAH Ipc-PH IPF i.v. IVC LA

alanine aminotransferase aspartate aminotransferase associated pulmonary arterial hypertension balloon atrial septostomy bone morphogenetic protein receptor 2 brain natriuretic peptide balloon pulmonary angioplasty Bosentan Randomised trial of Endothelin Antagonist THErapy caveolin-1 calcium channel blocker cyclic guanosine monophosphate congenital heart disease cardiac index cardiac magnetic resonance cardiac output chronic obstructive pulmonary disease combined post-capillary and pre-capillary pulmonary hypertension cardiopulmonary exercise testing combined pulmonary fibrosis and emphysema computed tomography connective tissue disease computed tomography pulmonary angiogram chronic thromboembolic pulmonary hypertension diffusing capacity of the lung for carbon monoxide drug-induced pulmonary arterial hypertension diastolic pressure gradient (diastolic PAP 2 mean PAWP) European association of cardiovascular imaging electrocardiogram extracorporeal membrane oxygenation eukaryotic translation initiation factor 2 alpha kinase 4 European Medicines Agency endothelin receptor antagonist functional class US Food and Drug Administration highly active antiretroviral therapy human immunodeficiency virus heart failure with preserved left ventricular ejection fraction heritable pulmonary arterial hypertension high resolution computed tomography intensive care unit international normalized ratio idiopathic pulmonary arterial hypertension isolated post-capillary pulmonary hypertension idiopathic pulmonary fibrosis intravenous inferior vena cava left atrium/atrial

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6.3.7 Advanced right ventricular failure . . . . . . . . . . . . . 6.3.7.1 Intensive care unit management . . . . . . . . . . . 6.3.7.2 Right ventricle assistance . . . . . . . . . . . . . . . . 6.3.8 Transplantation . . . . . . . . . . . . . . . . . . . . . . . . 6.3.9 Treatment algorithm . . . . . . . . . . . . . . . . . . . . . 6.3.10 Diagnosis and treatment of pulmonary arterial hypertension complications . . . . . . . . . . . . . . . . . . . . 6.3.10.1 Arrhythmias . . . . . . . . . . . . . . . . . . . . . . . 6.3.10.2 Haemoptysis . . . . . . . . . . . . . . . . . . . . . . . 6.3.10.3 Mechanical complications . . . . . . . . . . . . . . . 6.3.11 End of life care and ethical issues . . . . . . . . . . . . 7. Specific pulmonary (arterial) hypertension subsets . . . . . . . . 7.1 Paediatric pulmonary arterial hypertension . . . . . . . . . 7.1.1 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1.2 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2 Pulmonary arterial hypertension associated with adult congenital heart disease . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.1 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.2 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3 Pulmonary arterial hypertension associated with connective tissue disease . . . . . . . . . . . . . . . . . . . . . . . . 7.3.1 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3.2 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4 Pulmonary arterial hypertension associated with portal hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4.1 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4.2 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.5 Pulmonary arterial hypertension associated with human immunodeficiency virus infection . . . . . . . . . . . . . . . . . . . 7.5.1 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.5.2 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.6 Pulmonary veno-occlusive disease and pulmonary capillary haemangiomatosis . . . . . . . . . . . . . . . . . . . . . . 7.6.1 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.6.2 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8. Pulmonary hypertension due to left heart disease (group 2) . . 8.1 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9. Pulmonary hypertension due to lung diseases and/or hypoxia (group 3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.1 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.2 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10. Chronic thromboembolic pulmonary hypertension (group 4) 10.1 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.2 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.2.1 Surgical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.2.2 Medical . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.2.3 Interventional . . . . . . . . . . . . . . . . . . . . . . . . . 11. Pulmonary hypertension with unclear and/or multifactorial mechanisms (group 5) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12. Definition of a pulmonary hypertension referral centre . . . . 12.1 Facilities and skills required for a referral centre . . . . . 13. To do and not to do messages from the guidelines . . . . . . . 14. Web addenda . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15. Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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left heart disease left ventricle/ventricular magnetic resonance New York Heart Association nitric oxide N-terminal pro-brain natriuretic peptide pulmonary artery arterial carbon dioxide pressure arterial oxygen pressure pulmonary arterial hypertension pulmonary arterial pressure mean pulmonary arterial pressure systolic pulmonary arterial pressure pulmonary artery wedge pressure pulmonary artery systolic pressure pulmonary capillary haemangiomatosis phosphodiesterase type 5 inhibitor pulmonary embolism pulmonary endarterectomy pulmonary function tests pulmonary hypertension porto-pulmonary hypertension persistent pulmonary hypertension of the newborn PVOD pulmonary veno-occlusive disease PVR pulmonary vascular resistance RA right atrium RAP right atrial pressure RCT randomized controlled trial RHC right heart catheterization RV right ventricle/ventricular 6MWD/6MWT 6-minute walking distance/6-minute walking test SCD sickle cell disease sGC soluble guanylate cyclase SSc systemic sclerosis SvO2 mixed venous oxygen saturation SVR systemic vascular resistance TAPSE tricuspid annular plane systolic excursion t.i.d. three times a day TGF-b transforming growth factor b TPG transpulmonary pressure gradient (mean PAP 2 mean PAWP) TRV tricuspid regurgitant velocity VE/VCO2 minute ventilation – carbon dioxide production relationship V/Q ventilation/perfusion WHO-FC World Health Organization functional class WU Wood units

1. Preamble Guidelines summarize and evaluate all available evidence on a particular issue at the time of the writing process, with the aim of assisting health professionals in selecting the best management strategies for an individual patient with a given condition, taking into account the impact on outcome, as well as the risk – benefit

ratio of particular diagnostic or therapeutic means. Guidelines and recommendations should help health professionals to make decisions in their daily practice. However, the final decisions concerning an individual patient must be made by the responsible health professional(s) in consultation with the patient and caregiver as appropriate. A great number of Guidelines have been issued in recent years by the European Society of Cardiology (ESC) and by the European Respiratory Society (ERS), as well as by other societies and organisations. Because of the impact on clinical practice, quality criteria for the development of guidelines have been established in order to make all decisions transparent to the user. The recommendations for formulating and issuing ESC Guidelines can be found on the ESC website (http://www.escardio.org/Guidelines-&-Education/ Clinical-Practice-Guidelines/Guidelines-development/WritingESC-Guidelines). ESC Guidelines represent the official position of the ESC on a given topic and are regularly updated. Members of this Task Force were selected by the ESC and ERS to represent professionals involved with the medical care of patients with this pathology. Selected experts in the field undertook a comprehensive review of the published evidence for management (including diagnosis, treatment, prevention and rehabilitation) of a given condition according to ESC Committee for Practice Guidelines (CPG) policy and approved by the ERS. A critical evaluation of diagnostic and therapeutic procedures was performed, including assessment of the risk – benefit ratio. Estimates of expected health outcomes for larger populations were included, where data exist. The level of evidence and the strength of the recommendation of particular management options were weighed and graded according to predefined scales, as outlined in Tables 1 and 2. The experts of the writing and reviewing panels provided declaration of interest forms for all relationships that might be perceived as real or potential sources of conflicts of interest. These forms were compiled into one file and can be found on the ESC website (http:// www.escardio.org/guidelines). Any changes in declarations of interest that arise during the writing period must be notified to the ESC and ERS and updated. The Task Force received its entire financial support from the ESC and ERS without any involvement from the healthcare industry. The ESC CPG supervises and coordinates the preparation of new Guidelines produced by task forces, expert groups or consensus panels. The Committee is also responsible for the endorsement process of these Guidelines. The ESC Guidelines undergo extensive review by the CPG and external experts, and in this case by ERS-appointed experts. After appropriate revisions the Guidelines are approved by all the experts involved in the Task Force. The finalized document is approved by the CPG and by ERS for publication in the European Heart Journal and in the European Respiratory Journal. The Guidelines were developed after careful consideration of the scientific and medical knowledge and the evidence available at the time of their dating. The task of developing ESC/ERS Guidelines covers not only integration of the most recent research, but also the creation of educational tools and implementation programmes for the recommendations. To implement the guidelines, condensed pocket guideline versions, summary slides, booklets with essential messages,

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LHD LV MR NYHA NO NT-proBNP PA PaCO2 PaO2 PAH PAP PAPm PAPs PAWP PASP PCH PDE-5i PE PEA PFTs PH PoPH PPHN

ESC/ERS Guidelines

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ESC/ERS Guidelines

Table 1

Classes of recommendations Classes of recommendations Class I

Evidence and/or general agreement that a given treatment or procedure is beneficial, useful, effective.

Class II

Conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of the given treatment or procedure.

Class IIa

Weight of evidence/opinion is in favour of usefulness/efficacy.

Should be considered

Class IIb

Usefulness/efficacy is less well established by evidence/opinion.

May be considered

Class III

Evidence or general agreement that the given treatment or procedure is not useful/effective, and in some cases may be harmful.

Is not recommended

Level of evidence

Level of evidence A

Data derived from multiple randomized clinical trials or meta-analyses.

Level of evidence B

Data derived from a single randomized clinical trial or large non-randomized studies.

Level of evidence C

Consensus of opinion of the experts and/ or small studies, retrospective studies, registries.

summary cards for non-specialists and an electronic version for digital applications (smartphones, etc.) are produced. These versions are abridged and thus, if needed, one should always refer to the full text version, which is freely available on the ESC website. The National Societies of the ESC are encouraged to endorse, translate and implement all ESC Guidelines. Implementation programmes are needed because it has been shown that the outcome of disease may be favourably influenced by the thorough application of clinical recommendations. Surveys and registries are needed to verify that real-life daily practice is in keeping with what is recommended in the guidelines, thus completing the loop between clinical research, writing of guidelines, disseminating them and implementing them into clinical practice. Health professionals are encouraged to take the ESC/ERS Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic or therapeutic medical strategies. However, the ESC/ERS Guidelines do not override in any way whatsoever the individual responsibility of health professionals to make appropriate and accurate decisions in consideration of each patient’s health condition and in consultation with that patient and the patient’s caregiver where

Is recommended/is indicated

appropriate and/or necessary. It is also the health professional’s responsibility to verify the rules and regulations applicable to drugs and devices at the time of prescription.

2. Introduction Pulmonary hypertension (PH) is a pathophysiological disorder that may involve multiple clinical conditions and can complicate the majority of cardiovascular and respiratory diseases. The composition of the guidelines task force reflects the multidisciplinary nature of PH, including members of different medical societies, associations and working groups. The current document follows the two previous ESC and ERS Guidelines, published in 2004 and 2009, focusing on clinical management of PH. A systematic literature review was performed from MEDLINEw to identify new studies published since 2009 concerning the topic of PH. Task force members selected studies based on relevance and appropriateness. The main changes and adaptations as compared with the 2009 ESC and ERS PH guidelines are as follows: † The table of contents structure has been simplified, with three initial general chapters including classifications, basic aspects and differential diagnosis, two chapters for pulmonary arterial hypertension (PAH) and one chapter each for PH due to left heart disease (LHD), lung disease and/or hypoxia, chronic thromboembolic pulmonary hypertension (CTEPH) and unclear and/or multifactorial mechanisms. † New wordings and parameters for the haemodynamic definition of post-capillary PH subgroups have been adopted. Pulmonary vascular resistance (PVR) has been included in the haemodynamic definition of PAH. † An updated common clinical classification for adult and paediatric patients is reported. † New advances in pathology, pathobiology, genetics, epidemiology and risk factors are reported.

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Table 2

Suggested wording to use

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ESC/ERS Guidelines

3. Definitions and classifications 3.1 Definitions PH is defined as an increase in mean pulmonary arterial pressure (PAPm) ≥25 mmHg at rest as assessed by right heart catheterization (RHC).1 Available data have shown that the normal PAPm at rest is 14 + 3 mmHg with an upper limit of normal of approximately 20 mmHg.1,2 The clinical significance of a PAPm between 21 and 24 mmHg is unclear. Patients presenting with a pulmonary artery pressure (PAP) in this range should be carefully followed when they are at risk for developing PAH [e.g. patients with connective tissue disease (CTD) or family members of patients with heritable PAH (HPAH)].1 Due to the lack of reliable data that define which levels of exercise-induced changes in PAPm or PVR have prognostic implications, a disease entity ‘PH on exercise’ cannot be defined and should Table 3

not be used.1 A recent retrospective study has proposed a definition of PH on exercise with the combination of PAPm and total PVR data, but no outcome prospective validation has been provided.3 The term PAH describes a group of PH patients characterized haemodynamically by the presence of pre-capillary PH, defined by a pulmonary artery wedge pressure (PAWP) ≤15 mmHg and a PVR .3 Wood units (WU) in the absence of other causes of precapillary PH such as PH due to lung diseases, CTEPH or other rare diseases.1 According to various combinations of PAP, PAWP, cardiac output (CO), diastolic pressure gradient (DPG) and PVR, assessed in stable clinical conditions, different haemodynamic definitions of PH are shown in Table 3 together with their corresponding clinical classification (Table 4).1,4 The reasons for the updated definitions of post-capillary PH are reported in the specific section (8.0).

3.2 Classifications The clinical classification of PH is intended to categorize multiple clinical conditions into five groups according to their similar clinical presentation, pathological findings, haemodynamic characteristics and treatment strategy.5 The clinical classification may be updated when new data are available on the above features or when additional clinical entities are considered. A comprehensive version of the clinical classification is presented in Table 4.6 A condensed version is provided in a web addenda (Web Table I). The new findings are as follows: † New conditions that are frequently found in children have been included in different clinical groups in order to provide a comprehensive classification appropriate to both adult and paediatric patients. † Recently identified gene mutations have been included in the HPAH subgroup of clinical group 1 (PAH). The new mutations are more rare as compared with the traditional bone morphogenetic protein receptor 2 (BMPR2) mutations (Table 4). † Pre-capillary PH associated with chronic haemolytic anaemia appears to be significantly different from other forms of PAH in

Haemodynamic definitions of pulmonary hypertensiona Characteristicsa

Clinical group(s)b

PH

PAPm ≥25 mmHg

All

Pre-capillary PH

PAPm ≥25 mmHg PAWP ≤15 mmHg

1. Pulmonary arterial hypertension 3. PH due to lung diseases 4. Chronic thromboembolic PH 5. PH with unclear and/or multifactorial mechanisms

Post-capillary PH

PAPm ≥25 mmHg PAWP >15 mmHg

2. PH due to left heart disease 5. PH with unclear and/or multifactorial mechanisms

Isolated post-capillary PH (Ipc-PH)

DPG 3 WUc

CO ¼ cardiac output; DPG ¼ diastolic pressure gradient (diastolic PAP – mean PAWP); mPAP ¼ mean pulmonary arterial pressure; PAWP ¼ pulmonary arterial wedge pressure; PH ¼ pulmonary hypertension; PVR ¼ pulmonary vascular resistance; WU ¼ Wood units. a All values measured at rest; see also section 8.0. b According to Table 4. c Wood Units are preferred to dynes.s.cm25.

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† An updated diagnostic algorithm has been provided in an independent chapter and novel screening strategies are proposed in the web addenda. † The importance of expert referral centres in the management of PH patients has been highlighted in both the diagnostic and treatment algorithms. † New developments on PAH severity evaluation and on treatments and treatment goals are reported, including combination therapy and two new recently approved drugs. The treatment algorithm has been updated accordingly. † The chapters on PH due to LHD and lung diseases have been updated. The term ‘out of proportion PH’ has been abandoned in both conditions. † New diagnostic and treatment algorithms are reported in the CTEPH chapter, including general criteria for operability and balloon pulmonary angioplasty (BPA) and a newly approved drug. † A short chapter on PH due to unclear and/or multifactorial mechanisms has been added.

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Table 4 Comprehensive clinical classification of pulmonary hypertension (updated from Simonneau et al.5) 1. Pulmonary arterial hypertension 1.1 Idiopathic 1.2 Heritable 1.2.1 BMPR2 mutation 1.2.2 Other mutations 1.3 Drugs and toxins induced 1.4 Associated with: 1.4.1 Connective tissue disease 1.4.3 Portal hypertension 1.4.4 Congenital heart disease (Table 6) 1.4.5 Schistosomiasis 1’. Pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis

1”. Persistent pulmonary hypertension of the newborn 2. Pulmonary hypertension due to left heart disease 2.1 Left ventricular systolic dysfunction 2.2 Left ventricular diastolic dysfunction 2.3 Valvular disease obstruction and congenital cardiomyopathies 2.5 Congenital /acquired pulmonary veins stenosis 3. Pulmonary hypertension 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 lung diseases (Web Table III) 4. Chronic thromboembolic pulmonary hypertension and other pulmonary artery obstructions 4.1 Chronic thromboembolic pulmonary hypertension 4.2 Other pulmonary artery obstructions 4.2.1 Angiosarcoma 4.2.2 Other intravascular tumors 4.2.3 Arteritis 4.2.4 Congenital pulmonary arteries stenoses 4.2.5 Parasites (hydatidosis) 5. Pulmonary hypertension with unclear and/or multifactorial mechanisms 5.1 Haematological disorders: chronic haemolytic anaemia, myeloproliferative disorders, splenectomy 5.2 Systemic disorders, sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis 5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4 Others: pulmonary tumoral thrombothic microangiopathy, osing mediastinitis, chronic renal failure (with/without dialysis), segmental pulmonary hypertension BMPR2 ¼ bone morphogenetic protein receptor, type 2; EIF2AK4 ¼ eukaryotic. translation initiation factor 2 alpha kinase 4; HIV ¼ human immunodeficiency virus.

Table 5 Important pathophysiological and clinical definitions 1. Pulmonary hypertension (PH) is a haemodynamic and pulmonary arterial pressure ≥25 mmHg at rest as assessed by right heart catheterization (Table 3). PH can be found in multiple clinical conditions (Table 4). 2. Pulmonary arterial hypertension (PAH, group 1) is a clinical condition characterized by the presence of pre-capillary PH (Table 3) and pulmonary vascular resistance >3 Wood units, in the absence of other causes of pre-capillary PH such as PH due to lung diseases, chronic thromboembolic PH, or other rare diseases (Table 4). PAH includes different forms that share a similar clinical picture and virtually identical pathological changes of the lung microcirculation (Table 4). 3. exercise’.

Table 6 Clinical classification of pulmonary arterial hypertension associated with congenital heart disease (updated from Simonneau et al. 5) 1. Eisenmenger’s syndrome Includes all large intra- and extra-cardiac defects which begin as systemic-to-pulmonary shunts and progress with time to severe elevation of PVR and to reversal (pulmonary-to-systemic) or bidirectional shunting; cyanosis, secondary erythrocytosis, and multiple organ involvement are usually present. 2. PAH associated with prevalent systemic-to-pulmonary shunts • Correctablea • Non-correctable Includes moderate to large defects; PVR is mildly to moderately increased, systemic-to-pulmonary shunting is still prevalent, whereas cyanosis at rest is not a feature.

3. PAH with small/coincidental defects b Marked elevation in PVR in the presence of small cardiac defects (usually ventricular septal defects 1.0

Right ventricular

Flattening of the interventricular septum (left ventricular eccentricity index >1.1 in systole and/or diastole)

Early diastolic pulmonary regurgitation velocity >2.2 m/sec

acceleration time 21 mm with decreased inspiratory collapse (25 mm.

PA ¼ pulmonary artery. a Echocardiographic signs from at least two different categories (A/B/C) from the list should be present to alter the level of echocardiographic probability of pulmonary hypertension.

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5.1.3 Chest radiograph In 90% of patients with IPAH the chest radiograph is abnormal at the time of diagnosis.34 Findings in patients with PAH include central pulmonary arterial dilatation, which contrasts with ‘pruning’ (loss) of the peripheral blood vessels. Right atrium (RA) and RV enlargement may be seen in more advanced cases. A chest radiograph may assist in differential diagnosis of PH by showing signs suggesting lung disease (group 3, Table 4) or pulmonary venous congestion due to LHD (group 2, Table 4). Chest radiography may help in distinguishing between arterial and venous PH by respectively demonstrating increased and decreased artery:vein ratios.35 Overall, the degree of PH in any given patient does not correlate with the extent of radiographic abnormalities. As for ECG, a normal chest radiograph does not exclude PH.

ESC/ERS Guidelines

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solely on Doppler transthoracic echocardiography measurements is not suitable for screening for mild, asymptomatic PH. Other echocardiographic variables that might raise or reinforce suspicion of PH independent of TRV should always be sought. Conclusions derived from an echocardiographic examination should aim to assign a level of probability of PH. This ESC Guideline suggests grading the probability of PH based on TRV at rest and on the presence of additional pre-specified echocardiographic variables suggestive of PH (Table 8A). The probability of PH may then be judged as high, intermediate or low. When interpreted in a clinical context, the echocardiographic result is required to decide the need for cardiac catheterization in individual patients. In order to facilitate and standardize assignment to the level of probability of PH, several additional echocardiographic signs are proposed in addition to criteria based on TRV (Table 8B). These signs provide assessment of the RV size and pressure overload, the pattern of blood flow velocity out of the RV, the diameter of the PA and an estimate of RAP.43 – 45 Their measurement has been defined in recommendations endorsed by the EACVI.43,44 The recommended plan for further patient investigation based on echocardiographic probability of PH is shown in Table 9 for symptomatic patients. In the Web addendum, a similar table (Web Table IX) for screening for asymptomatic patients with risk factors for PAH or with incidental findings suggesting the possibility of PH on ECG or lung imaging is provided. Echocardiography can be helpful in detecting the cause of suspected or confirmed PH. Two-dimensional, Doppler and contrast examinations can be used to identify CHD. High pulmonary blood flow found on pulsed wave Doppler in the absence of a detectable shunt or significant dilatation of proximal PA despite only moderate PH may warrant transoesophageal examination with contrast or cardiac magnetic resonance (CMR) imaging to exclude sinus

Table 9 Diagnostic management suggested according to echocardiographic probability of pulmonary hypertension in patients with symptoms compatible with pulmonary hypertension, with or without risk factors for pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension Echocardiographic probability of PH Low

Intermediate

High

Without risk factors or associated condition for PAH or CTEPH d

Classa

Level b

Alternative diagnosis should be considered

IIa

C

Alternative diagnosis, echo follow-up, should be considered

IIa

Further investigation of PH may be considerede

IIb

Further investigation of PH (including RHCe) is recommended

I

With risk factors or associated conditions for PAH or CTEPHc

Classa

Level b

Echo follow-up should be considered

IIa

C

C

Further assessment of PH including RHC should be considerede

IIa

B

C

Further investigation of PHe including RHC is recommended

I

C

Ref c

45, 46

CTEPH ¼ chronic thromboembolic pulmonary hypertension; Echo ¼ echocardiographic; PAH ¼ pulmonary arterial hypertension; PH ¼ pulmonary hypertension; RHC ¼ right heart catheterization. a Class of recommendation. b Level of evidence. c Reference(s) supporting recommendations. d These recommendations do not apply to patients with diffuse parenchymal lung disease or left heart disease. e Depending on the presence of risk factors for PH group 2, 3 or 5. Further investigation strategy may differ depending on whether risk factors/associated conditions suggest higher probability of PAH or CTEPH – see diagnostic algorithm.

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(EACVI), a registered branch of the ESC, and the reader is referred to these for further instruction.43,44 The estimation of systolic PAP is based on the peak tricuspid regurgitation velocity (TRV) taking into account right atrial pressure (RAP) as described by the simplified Bernoulli equation. RAP can be estimated by echocardiography based on the diameter and respiratory variation in diameter of the inferior vena cava (IVC): an IVC diameter ,2.1 cm that collapses .50% with a sniff suggests a normal RA pressure of 3 mmHg (range 0 – 5 mmHg), whereas an IVC diameter .2.1 cm that collapses ,50% with a sniff or ,20% on quiet inspiration suggests a high RA pressure of 15 mmHg (range 10 – 20 mmHg). In scenarios in which the IVC diameter and collapse do not fit this paradigm, an intermediate value of 8 mmHg (range 5 –10 mmHg) may be used. The EACVI recommends such an approach rather than using a fixed value of 5 or 10 mmHg for PA systolic pressure (PASP) estimations. However, given the inaccuracies of RAP estimation and the amplification of measurement errors by using derived variables, we recommend using the continuous wave Doppler measurement of peak TRV (and not the estimated PASP) as the main variable for assigning the echocardiographic probability of PH. When peak TRV is technically difficult to measure (trivial or mild tricuspid regurgitation) some laboratories use contrast echocardiography [e.g. agitated saline administered by intravenous (i.v.) injection], which may improve the Doppler signal, allowing measurement of peak TRV velocity. Unfortunately, despite the strong correlation of TRV with a tricuspid regurgitation pressure gradient, Dopplerderived pressure estimation may be inaccurate in the individual patient. In patients with severe tricuspid regurgitation, TRV may be significantly underestimated and cannot be used to exclude PH. Overestimation may also occur.44 PH cannot be reliably defined by a cut-off value of TRV. Consequently, estimation of PAP based

Page 12 of 58 venosus atrial septal defect and/or anomalous pulmonary venous return. In cases of suspicion of LV diastolic dysfunction, Doppler echocardiographic signs should be assessed even if their reliability is considered low. RHC should be considered when the diagnosis remains uncertain after non-invasive investigations (see section 8.1). The practical clinical value of exercise Doppler echocardiography in the identification of cases with PH limited to exercise is uncertain because of the lack of validated criteria and prospective confirmatory data.

5.1.7 High-resolution computed tomography, contrast-enhanced computed tomography, and pulmonary angiography CT imaging is a widely available tool that can provide important information on vascular, cardiac, parenchymal and mediastinal abnormalities. It may suggest the diagnosis of PH (PA or RV enlargement), identify a cause of PH such as CTEPH or lung disease, provide clues as to the form of PAH (e.g. oesophageal dilation in SSc or congenital cardiac defects such as anomalous pulmonary venous drainage) and also provide prognostic information.50 CT may raise a suspicion of PH in symptomatic patients or those examined for unrelated indications by showing an increased PA diameter (≥29 mm) and pulmonary:ascending aorta diameter ratio (≥1.0). A segmental artery:bronchus ratio .1 : 1 in three or four lobes has been reported to have high specificity for PH.51,52 High-resolution CT provides detailed views of the lung parenchyma and facilitates the diagnosis of interstitial lung disease and emphysema. High-resolution CT may also be very helpful where there is a clinical suspicion of PVOD. Characteristic changes of interstitial oedema with diffuse central ground-glass opacification and thickening of interlobular septa support the diagnosis of PVOD; additional findings may include lymphadenopathy, pleural shadows and

effusions.53 Pulmonary capillary haemangiomatosis is suggested by diffuse bilateral thickening of the interlobular septa and the presence of small, centrilobular, poorly circumscribed nodular opacities. However, ground-glass abnormalities are also present in PAH, occurring in more than one-third of patients.50 Contrast CT angiography of the PA is helpful in determining whether there is evidence of surgically accessible CTEPH. It can delineate the typical angiographic findings in CTEPH, such as complete obstruction, bands and webs and intimal irregularities, as accurately and reliably as digital subtraction angiography.54,55 With this technique, collaterals from bronchial arteries can be identified. Traditional pulmonary angiography is required in most patients for the workup of CTEPH to identify those who may benefit from pulmonary endarterectomy (PEA) or BPA.56,57 Angiography can be performed safely by experienced staff in patients with severe PH using modern contrast media and selective injections. Angiography may also be useful in the evaluation of possible vasculitis or pulmonary arteriovenous malformations, but CT angiography has similar or even higher accuracy for both diagnoses, and is less invasive.58,59 5.1.8 Cardiac magnetic resonance imaging CMR imaging is accurate and reproducible in the assessment of RV size, morphology and function and allows non-invasive assessment of blood flow, including stroke volume, CO, pulmonary arterial distensibility and RV mass. In patients with suspected PH, the presence of late gadolinium enhancement, reduced pulmonary arterial distensibility and retrograde flow have high predictive value for the identification of PH; however, no single CMR measurement can exclude PH.60 – 62 In patients with PH, CMR may also be useful in cases of suspected CHD if echocardiography is not conclusive. Contrast-enhanced and unenhanced MR angiography have a potential in the study of the pulmonary vasculature in patients with suspected CTEPH, particularly in clinical scenarios such as suspected chronic embolism in pregnant women, young patients or when iodine-based contrast media injection is contraindicated.63 CMR provides useful prognostic information in patients with PAH both at baseline and at follow-up.64 – 66 5.1.9 Blood tests and immunology Blood tests are not useful in diagnosing PH, but are required to identify the aetiology of some forms of PH as well as end organ damage. Routine biochemistry, haematology and thyroid function tests are required in all patients, as well as a number of other specific blood tests. Liver function tests may be abnormal because of high hepatic venous pressure, liver disease and/or endothelin receptor antagonist (ERA) therapy. Hepatitis serology should be performed if clinical abnormalities are noted. Thyroid disease is common in PAH and may develop during the course of the disease. This should always be considered in cases of abrupt deterioration. Serological testing is required to detect underlying CTD, hepatitis and human immunodeficiency virus (HIV). Up to 40% of patients with IPAH have elevated antinuclear antibodies usually in a low titre (1:80). It is important to look for evidence of SSc since this disease has a relatively high prevalence of PAH. Limited scleroderma typically has antinuclear antibodies, including anti-centromere, dsDNA, anti-Ro, U3-RNP, B23, Th/To and U1-RNP. Diffuse scleroderma is

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5.1.6 Ventilation/perfusion lung scan A ventilation/perfusion (V/Q) lung scan should be performed in patients with PH to look for CTEPH. The V/Q scan has been the screening method of choice for CTEPH because of its higher sensitivity compared with CT pulmonary angiogram (CTPA), especially in inexperienced centres.47 A normal- or low-probability V/Q scan effectively excludes CTEPH with a sensitivity of 90 –100% and a specificity of 94 – 100%; however, many V/Q scans are not diagnostic. While in PAH the V/Q lung scan may be normal, it may also show small peripheral unmatched and non-segmental defects in perfusion. A caveat is that unmatched perfusion defects may also be seen in other pulmonary vascular disease such as PVOD. While a V/Q scan is still recommended as the screening test of choice, ventilation scans are often replaced with either a recent chest radiograph or a recent high-resolution CT of the lungs, but such practices are not really evidence-based. Also, CT is preferred in many centres since it is more readily available. A few studies suggest that single photon emission CT, also a nuclear medicine technique, could be superior to V/Q planar scan and CTPA, but these results need more extensive evaluation.48 More recently, newer techniques such as threedimensional magnetic resonance (MR) perfusion mapping, have been demonstrated to be as sensitive as traditional perfusion scintigraphy in screening for CTEPH; MR can also be used as a radiationfree modality to assess both ventilation and perfusion in CTEPH.49

ESC/ERS Guidelines

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typically associated with a positive U3-RNP. Patients with systemic lupus erythematosus may have anticardiolipin antibodies. Patients with CTEPH should undergo thrombophilia screening, including antiphospholipid antibodies, anticardiolipin antibodies and lupus anticoagulant. HIV testing is required in PAH. N-terminal pro-brain natriuretic peptide (NT-proBNP) may be elevated in patients with PH and is an independent risk predictor in these patients. 5.1.10 Abdominal ultrasound scan Similar to blood tests, abdominal ultrasound may be useful for identification of some of the clinical entities associated with PAH. Abdominal ultrasound may confirm but not formally exclude portal hypertension. The use of contrast agents and the addition of a colour Doppler examination may improve the accuracy of the diagnosis.67 Portal hypertension can be reliably confirmed or excluded by measurement of the gradient between free and occluded (wedge) hepatic vein pressure at the time of RHC.68

† The external pressure transducer should be zeroed at the midthoracic line in a supine patient, halfway between the anterior sternum and the bed surface.70 This represents the level of the LA. † Pressure measurements should be made in the PA, PA wedge position, RV and RA. Where a balloon catheter is used, it should be inflated in the RA, from where the catheter should be advanced until it reaches the PAWP position. Repeated deflations and inflations of the balloon in the end pulmonary arteries should be avoided because this has been associated with rupture of the

†

†

†

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5.1.11 Right heart catheterization and vasoreactivity RHC is required to confirm the diagnosis of PAH and CTEPH, to assess the severity of haemodynamic impairment and to undertake vasoreactivity testing of the pulmonary circulation in selected patients (Table 10). When performed at expert centres, these procedures have low morbidity (1.1%) and mortality (0.055%) rates.69 The threshold to perform left heart catheterization in addition to RHC should be low in patients with clinical risk factors for coronary artery disease or heart failure with preserved ejection fraction, as well as in patients with echocardiographic signs of systolic and/or diastolic LV dysfunction. Specific recommendations for catheterization of patients with LHD or lung disease in addition to Table 10 are described in Tables 31 and 33, respectively. Measurement of LV enddiastolic pressure is also important to avoid misclassification of patients with an elevated PAWP when this is unexpected and may be inaccurate [absence of risk factors for heart failure with preserved ejection fraction, normal left atrial (LA) size and absence of echocardiographic markers of elevated LV filling pressures]. The interpretation of invasive haemodynamics should be made in the context of the clinical picture and imaging, in particular echocardiography. Cardiac catheterization should be performed after the completion of other investigations so that it can answer specific questions that may arise from these investigations and avoid an unnecessary procedure where an alternative diagnosis is revealed. RHC is a technically demanding procedure that requires meticulous attention to detail to obtain clinically useful information. To obtain high-quality results and to be of low risk to patients, the procedure should be limited to expert centres. Particular attention should be paid to the following issues:

†

pulmonary arteries. The PAWP is a surrogate of LA pressure and should be recorded as the mean of three measurements. Blood sampling should also be considered with the balloon inflated in the wedge position to confirm that a true PAWP measurement has been taken, as this should have the same saturation as systemic blood. All pressure measurements should be determined at the end of normal expiration (breath holding is not required). Alternatively, assuming that negative inspiratory and positive expiratory intrathoracic pressures cancel each other out, averaging pulmonary vascular pressures over several respiratory cycles is also acceptable, except in dynamic hyperinflation states.70 Ideally, high-fidelity tracings that can be printed on paper should be used rather than small moving traces on a cardiac monitor. Noninvasive blood pressure should be recorded at the time of the procedure if left heart catheterization is not undertaken. Blood samples for oximetry should be taken from the high superior vena cava, IVC and PA at a minimum. Systemic arterial blood oxygen (O2) saturation should also be determined. A stepwise assessment of O2 saturation should be performed in every patient with a pulmonary arterial O2 saturation .75% and whenever a left-to-right shunt is suspected. CO should be measured using thermodilution or the direct Fick method. Thermodilution measured in triplicate is the preferred method because it can provide reliable measurements even in patients with low CO and/or severe tricuspid regurgitation.71 In patients with intracardiac shunts, thermodilution may be inaccurate because of early recirculation of the injectate. The direct Fick method requires direct measurement of O2 uptake, a technique that is not widely available. The indirect Fick method, which uses estimated values of O2 uptake, is acceptable but lacks reliability. Pulmonary vasoreactivity testing for identification of patients suitable for high-dose calcium channel blocker (CCB) treatment is recommended only for patients with IPAH, HPAH or drug-induced PAH. It should be performed at the time of RHC. In all other forms of PAH and PH the results can be misleading and responders are rare. Inhaled nitric oxide (NO) at 10–20 parts per million (ppm) is the standard of care for vasoreactivity testing, but i.v. epoprostenol, i.v. adenosine or inhaled iloprost can be used as alternatives (Web Table IV). A positive acute response is defined as a reduction of the mean PAP ≥10 mmHg to reach an absolute value of mean PAP ≤40 mmHg with an increased or unchanged CO. Only about 10% of patients with IPAH will meet these criteria. The use of CCBs, O2, phosphodiesterase type 5 inhibitors or other vasodilators for acute vasoreactivity testing is discouraged. Interpretation of the PAWP at a single point in time needs to be performed in a clinical context. In many patients with LHD, PAWP may be reduced to ,15 mmHg with diuretics.72 – 74 For this reason, the effect of an acute volume challenge on left heart filling pressures has been considered.75 Limited data suggest that a fluid bolus of 500 ml appears to be safe and may discriminate patients with PAH from those with LV diastolic dysfunction.76,77 Further evaluation of administering a fluid challenge is required before this can be considered for routine clinical practice. Similarly, exercise haemodynamics to identify patients with LV diastolic dysfunction is likely to be useful,2,78,79 but lacks standardisation and requires further evaluation.17 Furthermore, PAWP may underestimate LV end-diastolic pressure.80

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† Derived variables calculated from the RHC measurements should include transpulmonary pressure gradient (TPG) and PVR. A PVR .3 WU is required for the diagnosis of PAH.1 PVR is commonly used but has the disadvantage of being a composite variable that is highly sensitive to changes in both flow and filling pressure and may not reflect changes in the pulmonary circulation at rest.81,82 The DPG between the mean PAWP and diastolic PAP is less affected by flow and filling pressures81 but may not be of prognostic value.83 DPG may have a role in patients suspected of having PH related to LHD, as discussed in section 8.4 † Coronary angiography may be required in the presence of angina, risk factors for coronary artery disease and listing for PEA or lung transplantation. It may identify left main stem coronary artery compression by an enlarged PA as well as coronary artery disease. Recommendations for right and left heart catheterization and vasoreactivity testing are summarised in the Tables 10 and 11.

Recommendations RHC is recommended to confirm the diagnosis of pulmonary arterial hypertension (group 1) and to support treatment decisions

Classa Levelb Ref.c

I

C

In patients with PH, it is recommended to perform RHC in expert centres (see section 12) as it is technically demanding and may be associated with serious complications

I

RHC should be considered in pulmonary arterial hypertension (group 1) to assess the treatment effect of drugs (Table 16)

IIa

C

RHC is recommended in patients with congenital cardiac shunts to support decisions on correction (Table 24)

I

C

RHC is recommended in patients with PH due to left heart disease (group 2) or lung disease (group 3) if organ transplantation is considered

I

C

When measurement of PAWP is unreliable, left heart catheterization should be considered to measure LVEDP

IIa

C

B

RHC may be considered in patients with suspected PH and left heart disease or lung disease to assist in the differential diagnosis and support treatment decisions

IIb

C

RHC is indicated in patients with CTEPH (group 4) to confirm the diagnosis and support treatment decisions

I

C

69

CTEPH ¼ chronic thromboembolic pulmonary hypertension; LVEDP ¼ left ventricular end-diastolic pressure; PAWP ¼ pulmonary artery wedge pressure; PH ¼ pulmonary hypertension; RHC ¼ right heart catheterization. a Class of recommendation. b Level of evidence. c Reference(s) supporting recommendations.

Recommendations

Classa Levelb Ref.c

Vasoreactivity testing is indicated only in expert centres

I

C

69

Vasoreactivity testing is recommended in patients with IPAH, HPAH and PAH associated with drugs use to detect patients who can be treated with high doses of a CCB

I

C

84,85

A positive response to vasoreactivity testing is defined as a reduction of mean PAP ≥10 mmHg to reach an absolute value of mean PAP ≤40 mmHg with an increased or unchanged cardiac output

I

C

85,86

Nitric oxide is recommended for performing vasoreactivity testing

I

C

85,86

Intravenous epoprostenol is recommended for performing vasoreactivity testing as an alternative

I

C

85,86

Adenosine should be considered for performing vasoreactivity testing as an alternative

IIa

C

87,88

Inhaled iloprost may be considered for performing vasoreactivity testing as an alternative

IIb

C

89,90

The use of oral or intravenous CCBs in acute vasoreactivity testing is not recommended

III

C

Vasoreactivity testing to detect patients who can be safely treated with high doses of a CCB is not recommended in patients with PAH other than IPAH, HPAH and PAH associated with drugs use and is not recommended in PH groups 2, 3, 4 and 5

III

C

CCB ¼ calcium channel blocker; HPAH ¼ heritable pulmonary arterial hypertension; IPAH ¼ idiopathic pulmonary arterial hypertension; PAP ¼ pulmonary arterial pressure; PAH ¼ pulmonary arterial hypertension. a Class of recommendation. b Level of evidence. c Reference(s) supporting recommendations.

5.1.12 Genetic testing The availability of molecular genetic diagnosis has opened up a new field for patient care, including genetic counselling for PAH (developed in section 6.3.1.8).26 Genetic testing and counselling follows strict local regulations that set the conditions for prescribing and conducting reviews of the genetic characteristics of a patient. The ethical principles are to inform patients properly to avoid harm, to allow patients to preserve their autonomy (disclosure about the process, risks and benefits of the genetic test without external pressures) and to allow equal access to genetic counselling and testing. Patients with sporadic or familial PAH or PVOD/PCH should be advised about the availability of genetic testing and counselling because of the strong possibility that they carry a disease-causing mutation. Trained professionals should offer counselling

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Table 10 Recommendations for right heart catheterization in pulmonary hypertension

Table 11 Recommendations for vasoreactivity testing

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and testing to the patient. Genetic counselling and BMPR2 mutation screening (point mutations and large rearrangements) should be offered by referral centres to patients with IPAH considered to be sporadic or induced by anorexigens and to patients with a family history of PAH. When no BMPR2 mutations are identified in familial PAH patients or in IPAH patients ,40 years old, or when PAH occurs in patients with a personal or familial history of hereditary haemorrhagic telangiectasia, screening of the ACVRL1 and ENG genes may be performed. If no mutations in the BMPR2, ACVRL1 and ENG genes are identified, screening of rare mutations may be considered (KCNK3, CAV1, etc.).

Patients with sporadic or familial PVOD/PCH should be tested for EIF2AK4 mutations.28 The presence of a bi-allelic EIF2AK4 mutation is sufficient to confirm a diagnosis of PVOD/PCH without performing a hazardous lung biopsy for histological confirmation.

5.2 Diagnostic algorithm The diagnostic algorithm is shown in Figure 1: the diagnostic process starts after the suspicion of PH and echocardiography compatible with PH (according to the different levels of PH probability reported in Tables 8 and 9) and continues with the identification of the more

Symptoms, signs, history suggestive of PH

Echocardiographic probability of PH (Table 8)

Consider other causes and/or follow-up (Table 9)

Consider left heart disease and lung diseases by symptoms, signs, risk factors, ECG, PFT+DLCO, chest radiograph and HRCT, arterial blood gases (Table 9)

Yes

Yes

Diagnosis of left heart diseases or lung diseases confirmed?

No signs of severe PH/RV dysfunction

Signs of severe PH/RV dysfunction

No V/Q scana Mismatched perfusion defects?

Treat underlying disease

Yes

No

Refer to PH expert centre

CTEPH possible: CT pulmonary angiography, RHC +/- Pulmonary Angiography

Refer to PH expert centre

Yes

RHC (Table 10) mPAP 25 mmHg, PAWP 15 mmHg, PVR >3 Wood units

PAH likely Specific diagnostic tests

No

Consider other causes

CTD

CHD

Drugs - Toxin

Portoppulmonaryy

HIV

Schistosomiasis

Group 5

Heritable PVOD/PCH

Idiopathic PVOD/PCH

Idiopathic PAH

Heritable PAH

CHD = congenital heart diseases; CT = computed tomography; CTD = connective tissue disease; CTEPH = chronic thromboembolic pulmonary hypertension; pressure; PA = pulmonary angiography; PAH = pulmonary arterial hypertension; PAWP = pulmonary artery wedge pressure; PFT = pulmonary function tests; PH = pulmonary hypertension; PVOD/PCH = pulmonary veno-occlusive disease or pulmonary capillary hemangiomathosis; PVR = pulmonary vascular resistance; RHC = right heart catheterisation; RV = right ventricular; V/Q = ventilation/perfusion. a CT pulmonary angiography alone may miss diagnosis of chronic thromboembolic pulmonary hypertension.

Figure 1 Diagnostic algorithm.

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Low

High or intermediate

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Table 12 Recommendations for diagnostic strategy

Recommendations

Classa Levelb Ref.c

Echocardiography is recommended as a first-line non-invasive diagnostic investigation in case of suspicion of PH

I

C

Ventilation/perfusion or perfusion lung scan is recommended in patients with unexplained PH to exclude CTEPH

I

C

47

Contrast CT angiography of the PA is recommended in the workup of patients with CTEPH

I

C

93

Routine biochemistry, haematology, immunology, HIV testing and thyroid function tests are recommended in all patients with PAH to identify the specific associated condition

I

C

Abdominal ultrasound is recommended for the screening of portal hypertension

I

C

67

Lung function test with DLCO is recommended in the initial evaluation of patients with PH

I

C

36

High-resolution CT should be considered in all patients with PH

IIa

C

94

Pulmonary angiography should be considered in the workup of patients with CTEPH

IIa

C

Open or thoracoscopic lung biopsy is not recommended in patients with PAH

III

C

CT ¼ computed tomography; CTEPH ¼ chronic thromboembolic pulmonary hypertension; DLCO ¼ diffusing capacity of the lung for carbon monoxide; PAH ¼ pulmonary arterial hypertension; PH ¼ pulmonary hypertension. a Class of recommendation. b Level of evidence. c Reference(s) supporting recommendations.

6. Pulmonary arterial hypertension (group 1) 6.1 Clinical characteristics The clinical characteristics of PAH are not specific and can be derived from the general description reported in section 5.1.1. More detailed descriptions of the individual PAH subsets are reported in the section 7.

6.2 Evaluation of severity 6.2.1 Clinical parameters, imaging and haemodynamics Clinical assessment remains a key part of the evaluation of patients with PH, as it provides valuable information for determining disease severity, improvement, deterioration or stability. Elementary parts of history taking between follow-up visits include changes in exercise capacity, episodes of chest pain, arrhythmia, haemoptysis or

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common clinical groups of PH [group 2 (LHD) and group 3 (lung diseases)], then distinguishes group 4 (CTEPH) and finally makes the diagnosis and recognizes the different types in group 1 (PAH) and the rarer conditions in group 5. PAH should be considered in the differential diagnosis of exertional dyspnoea, syncope, angina and/or progressive limitation of exercise capacity, particularly in patients without apparent risk factors, symptoms or signs of common cardiovascular and respiratory disorders. Special awareness should be directed towards patients with associated conditions and/or risk factors for the development of PAH, such as family history, CTD, CHD, HIV infection, portal hypertension or a history of drug or toxin intake known to induce PAH (Table 7). In everyday clinical practice such awareness may be low. More often PH is found unexpectedly on transthoracic echocardiography requested for another indication. If transthoracic echocardiography is compatible with a high or intermediate probability of PH (Table 9), a clinical history, symptoms, signs, ECG, chest radiograph, pulmonary function tests (PFTs, including DLCO, arterial blood gases analysis and nocturnal oximetry, if required) and high-resolution CT of the chest are requested to identify the presence of group 2 (LHD) or group 3 (lung diseases) PH. In case of an echocardiographic low probability of PH (Table 9), no additional investigations are required and other causes for the symptoms should be considered together with follow-up. If the diagnosis of left heart or lung diseases is confirmed, the appropriate treatment for these conditions should be considered. In the presence of severe PH and/or RV dysfunction, the patient should be referred to a PH expert centre where additional causes of PH can be explored. If the diagnosis of left heart or lung diseases is not confirmed, a V/Q lung scan should be performed for the differential diagnosis between CTEPH and PAH. Concurrently the patient should be referred to a PH expert centre. If the V/Q scan shows multiple segmental perfusion defects, a diagnosis of group 4 (CTEPH) PH should be suspected.91 The final diagnosis of CTEPH (and the assessment of suitability for PEA) will require CT pulmonary angiography, RHC and selective pulmonary angiography. The CT scan may also show signs suggestive of group 1′ (PVOD). If a V/Q scan is normal or shows only subsegmental ‘patchy’ perfusion defects, a diagnosis of group 1 (PAH) or the rarer conditions of group 5 should be considered. In Table 9, further management according to the probability of PH is given, including indications for RHC. Additional specific diagnostic tests, including haematology, biochemistry, immunology, serology, ultrasonography and genetics, will allow the final diagnosis to be refined. Open or thoracoscopic lung biopsy entails a substantial risk of morbidity and mortality.92 Because of the low likelihood of altering the diagnosis and treatment, biopsy is not recommended in PAH patients. The recommendations for a diagnostic strategy are reported in the Table 12. The pulmonary arterial hypertension screening programme is reported in the Web Addenda.

ESC/ERS Guidelines

ESC/ERS Guidelines

follow-up strategy. There is no evidence that an approach involving regular RHC is associated with better outcomes than a predominantly non-invasive follow-up strategy. However, there is consensus among experts that RHC should be performed whenever therapeutic decisions can be expected from the results, which may include changes in medications and/or decisions regarding listing for transplantation. 6.2.2 Exercise capacity The 6-minute walking test (6MWT), a submaximal exercise test, remains the most widely used exercise test in PH centres. The test is easy to perform, inexpensive and familiar to patients and centres. As with all PH assessments, 6MWT results must always be interpreted in the clinical context. The 6-minute walking distance (6MWD) is influenced by several factors, including sex, age, height, weight, comorbidities, need for O2, learning curve and motivation. Nevertheless, test results are usually given in absolute numbers rather than percent predicted. Absolute values, but not changes in 6MWD, provide prognostic information, but there is no single threshold that is applicable for all patients (see below).96,99,116 – 118 It is recommended to use the Borg score at the end of the 6MWT to determine the level of effort. In addition, some studies suggest that adding peripheral O2 measurements and heart rate response may improve the prognostic relevance, but these findings await independent confirmation.119,120 Cardiopulmonary exercise testing (CPET) is usually performed as a maximal exercise test and provides important information on exercise capacity as well as on gas exchange, ventilator efficacy and cardiac function during exercise. Most PH centres use an incremental ramp protocol, although the test has not yet been standardized for this patient population. Patients with PAH show a typical pattern with a low end-tidal partial pressure of carbon dioxide (pCO2), high ventilator equivalents for carbon dioxide (VE/VCO2), low oxygen pulse (VO2/HR) and low peak oxygen uptake (peak VO2).121 Several variables determined by CPET provide prognostic information, although peak VO2 is most widely used for therapeutic decision making.106,122 – 125 The diagnostic and prognostic information provided by CPET add to that provided by the 6MWT.122 6.2.3 Biochemical markers There is still no specific marker for PAH or pulmonary vascular remodelling, although a wide variety of biomarkers have been explored in the field. These can be grouped into markers of vascular dysfunction [asymmetric dimethylarginine (ADMA), endothelin-1, angiopoeitins, von Willebrand factor],126 – 131 markers of inflammation (C-reactive protein, interleukin 6, chemokines),132 – 135 markers of myocardial stress (atrial natriuretic peptide, brain natriuretic peptide (BNP)/ NT-proBNP, troponins),97,118,136 – 139 markers of low CO and/or tissue hypoxia [pCO2, uric acid, growth differentiation factor 15 (GDF15), osteopontin]38,140 – 142 and markers of secondary organ damage (creatinine, bilirubin).97,137 This list is constantly growing, but so far BNP and NT-proBNP remain the only biomarkers that are widely used in the routine practice of PH centres as well as in clinical trials. BNP/ NT-proBNP levels correlate with myocardial dysfunction and provide prognostic information at the time of diagnosis and during follow-up assessments.143 They are not specific for PH, but can be elevated in almost any heart disease. BNP/NT-proBNP levels tend to have a high

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syncope and changes in medications, as well as adherence to the prescribed drugs. Physical examination provides information on the presence or absence of peripheral or central cyanosis, enlarged jugular veins, oedema, ascites and pleural effusions and on heart rate, rhythm and blood pressure. The World Health Organization functional class (WHO-FC) (Web Table V), despite its interobserver variability,95 remains one of the most powerful predictors of survival, not only at diagnosis, but also during follow-up.96 – 98 A worsening FC is one of the most alarming indicators of disease progression, which should trigger further diagnostic studies to identify the causes of clinical deterioration.97,99 As RV function is a key determinant of exercise capacity and outcome in patients with PH, echocardiography remains an important follow-up tool. In contrast to common belief, the estimated systolic PAP (PAPs) at rest is usually not prognostic and not relevant for therapeutic decision making.96,97,100 An increase in PAPs does not necessarily reflect disease progression and a decrease in PAPs does not necessarily signal improvement. A comprehensive echocardiographic assessment includes a description of chamber sizes, particularly of the RA and RV area, the magnitude of tricuspid regurgitation, the LV eccentricity index and RV contractility, which can be determined by several variables, including RV longitudinal systolic strain/strain rate and RV fractional area change, Tei index and tricuspid annular plane systolic excursion (TAPSE).101 – 108 Three-dimensional echocardiography may achieve a better estimation than standard two-dimensional assessment, but underestimations of volumes and ejection fractions have been reported.109 Speckle tracking improves the quantification of RV function.110 Given the complex geometry of the RV, none of these variables alone is sufficient to describe RV function, and the overall impression of an experienced physician is often more important than single variables. Echocardiography during exercise provides additional information on RV function. Of note, a marked increase (.30 mmHg) of PAPs during exercise reflects better RV function and is associated with a better long-term outcome than a modest or no increase.111 This so-called contractile reserve has recently been shown to be an independent prognostic marker in patients with severe PH.111 CMR imaging is more accurate for the assessment of RV morphology and function than echocardiography and also allows measurement of stroke volume and CO. A number of CMR prognostic markers have been identified, including increased RV volume, reduced LV volume, reduced RV ejection fraction and reduced stroke volume. There is some evidence that follow-up CMR studies may have utility in the long-term management of PAH by identifying RV failure prior to the development of clinical features.64,66,112,113 Haemodynamics assessed by RHC provide important prognostic information, both at the time of diagnosis and during follow-up. RA pressure, cardiac index (CI) and mixed venous oxygen saturation (SvO2) are the most robust indicators of RV function and prognosis, whereas PAPm provides little prognostic information (except for CCB responders).96,97,99,100,114 Non-invasive assessment of CO by rebreathing techniques71 or bioreactance115 has not yet been sufficiently validated to allow routine clinical use and therapeutic decision making. There are still uncertainties around the optimal timing of followup RHC. Strategies vary between centres, from regular invasive haemodynamic assessments to a predominantly non-invasive

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ESC/ERS Guidelines

variability and should be interpreted in the clinical context. There are no clear advantages of using BNP versus NT-proBNP. BNP appears to have a slightly tighter correlation with pulmonary haemodynamics and is less affected by kidney function, whereas NT-proBNP seems to be a stronger predictor of prognosis.137

Table 13 Risk assessment in pulmonary arterial hypertension Determinants of prognosis a (estimated 1-year mortality)

Low risk 10%

Clinical signs of right heart failure

Present

Absent

Absent

Progression of symptoms

No

Slow

Rapid

Syncope

No

Occasional syncopeb

Repeated syncopec

WHO functional class

I, II

III

IV

>440 m

165–440 m

15 ml/min/kg (>65% pred.) VE/VCO2 slope