Respiratory Medicine xxx (2015) 1e6

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Review article

Lung function in pulmonary hypertension A.T. Low a, *, A.R.L. Medford b, A.B. Millar c, R.M.R. Tulloh a a

University Hospitals Bristol NHS Foundation Trust, Upper Maudlin Street, Bristol, United Kingdom North Bristol Lung Centre, Southmead Hospital, Southmead Road, Bristol, United Kingdom c Academic Respiratory Unit, Southmead Hospital, Southmead Road, Bristol, United Kingdom b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 11 December 2014 Received in revised form 18 April 2015 Accepted 24 May 2015 Available online xxx

Breathlessness is a common symptom in pulmonary hypertension (PH) and an important cause of morbidity. Though this has been attributed to the well described pulmonary vascular abnormalities and subsequent cardiac remodelling, changes in the airways of these patients have also been reported and may contribute to symptoms. Our understanding of these airway abnormalities is poor with conflicting findings in many studies. The present review evaluates these studies for the major PH groups. In addition we describe the role of cardiopulmonary exercise testing in the assessment of pulmonary arterial hypertension (PAH) by evaluating cardiopulmonary interaction during exercise. As yet, the reasons for the abnormalities in lung function are unclear, but potential causes and the possible role of inflammation are discussed. Future research is required to provide a better understanding of this to help improve the management of these patients. © 2015 Elsevier Ltd. All rights reserved.

Keywords: Pulmonary hypertension Lung function tests Inflammation Idiopathic pulmonary arterial hypertension Congenital heart disease Pulmonary arterial hypertension

1. Introduction Pulmonary hypertension (PH) is associated with considerable morbidity and significant mortality [1e4]. This has been attributed to progressive right ventricular dysfunction due to chronic pressure overload causing myocardial hypertrophy and dilatation [5]. Symptoms are improved by medical therapies which reduce pulmonary vascular resistance and improve cardiac output for patients with pulmonary arterial hypertension (PAH) and some patients with chronic thromboembolic pulmonary hypertension (CTEPH)

Abbreviations: CHD-APAH, pulmonary arterial hypertension associated with congenital heart disease; COPD, chronic obstructive pulmonary disease; CPET, cardiopulmonary exercise testing; CTD-APAH, pulmonary arterial hypertension associated with connective tissue disease; CTEPH, chronic thromboembolic pulmonary hypertension; DLCO, carbon monoxide diffusing capacity; ELISA, enzymelinked immunosorbent assay; ET-1, Endothelin-1; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; IL, interleukin; ILD, interstitial lung disease; IPAH, idiopathic pulmonary arterial hypertension; PAH, pulmonary arterial hypertension; PETCO2, end tidal partial pressure of carbon dioxide; PH, Pulmonary hypertension; TLC, total lung capacity; TNFa, tumour necrosis factor alpha; VCO2, carbon dioxide production; VE, minute ventilation; VO2, oxygen consumption. * Corresponding author. Research Level 7, Queens Building, Bristol Royal Infirmary, Upper Maudlin Street, Bristol BS2 8HW, United Kingdom. E-mail addresses: [email protected] (A.T. Low), [email protected] (A.R.L. Medford), [email protected] (A.B. Millar), robert.tulloh@UHBristol. nhs.uk (R.M.R. Tulloh).

[6]. This, alongside improvements in general care, has coincided with a marked improvement in mortality with a 1 year survival for idiopathic PAH (IPAH) patients of 91e93% and a 5 year survival of 59e66% [7e9], compared to a median survival of 2.8 years and a 5 year survival of 24% prior to the advent of these therapies [10]. However, medical therapies are not curative. Many patients will remain symptomatic despite maximal treatment and can expect symptoms to increase as the disease progresses. In contrast, patients with PH due to other causes have no additional therapies to aid symptoms, with management directed at the underlying cause [6]. Breathlessness is the main symptom in PH, experienced almost universally in more advanced disease [11]. This is a complex symptom that can be caused by abnormalities of the cardiovascular, respiratory and neuromuscular systems in a variety of diseases [12,13]. Though the abnormalities of the cardiovascular system in PH are well described [5], it is unclear to what extent the respiratory system is affected. The abnormal pulmonary vessels could affect the function of their adjacent airways and contribute to symptoms. If the airways were affected in addition to the pulmonary vessels, this could represent another treatment target for a symptomatic group that remain difficult to treat despite the availability of newer drugs. Lung function assessment provides important information about the physiology of the lung and useful insight into a variety of

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disease processes [14]. This article aims to review the existing, often conflicting, literature in PH focusing on Group 1 e PAH, with coverage of the other major groups: Group 2 e PH due to left heart disease, Group 3 e PH due to chronic lung disease and Group 4 e CTEPH [15]. Group 5 e PH with unclear or multifactorial mechanisms has not been covered due to its heterogeneity and rarity of conditions. Cardiopulmonary exercise testing (CPET) has been covered in its own right as a more novel investigation, but as yet data is limited and so the review is restricted here to Group 1 e PAH. The potential role of inflammation and vasoactive mediators is discussed, and future direction for research suggested. 2. Group 1 e Pulmonary arterial hypertension 2.1. Idiopathic pulmonary arterial hypertension 2.1.1. Lung volumes 20-50% of patients with IPAH have lung restriction, defined as a total lung capacity (TLC) of less than 80% of predicted values [16,17]. The overall mean reduction in TLC is to 64e91% of predicted values in some studies [18e20], while others have reported that TLC is normal [21,22]. This variation may be in part due to the significant proportion of patients with unaffected lung volumes in IPAH. The most marked reductions in TLC have been reported in smaller case series which are more susceptible to the inclusion of more extreme cases [18,19]. The true overall abnormality is likely to be more modest as found in larger studies [20]. Studies that have reported a normal TLC also found a reduction in vital capacity that was offset by an increase in residual volume [21,22]. Thus while patients with IPAH may have lung restriction, TLC may normalise due to hyperinflation that can occur with airway obstruction in more severe disease [22]. The cause of lung restriction in patients with IPAH is unclear. While parenchymal changes in other lung conditions cause lung restriction, this does not occur in IPAH [23]. An explanation could be that the hypertrophied blood vessels may have a direct physical effect with encroachment resulting in a loss of distensibility through mechanical pressure on the airways. Some older, small studies have found reduced lung compliance in IPAH in keeping with this, but this was not associated with a reduction in lung volumes [24]. The hypertrophied pulmonary vessels, in addition to the ensuing cardiomegaly, could result in displacement of lung tissue within the thoracic space. While this is associated with lung restriction in PH due to left heart disease [25,26], this has not been evaluated in IPAH. The cause of these changes is thus currently unclear, while the impact on patients' symptoms has not been assessed. 2.1.2. Spirometry and expiratory flow 20-40% of patients with IPAH have airway obstruction based on a forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) ratio of less than 70% [19,27]. The overall mean FEV1/ FVC ratio is significantly reduced at 76% compared to 84% in controls (p < 0.001) [22]. The fact that many studies have reported an overall mean greater than 70% is therefore unsurprising as many patients will have a normal FEV1/FVC ratio [17,18,20,21,27]. However the conclusion that there is no evidence of airway obstruction in IPAH is an oversimplification [17,21]. Spirometry is a poor marker of peripheral airway obstruction as the peripheral airways contribute to less than 10% of total airway resistance [28]. Extensive small airway disease would therefore only lead to a small reduction in FEV1. Measures of mid-expiratory flow are more sensitive markers of peripheral airway obstruction and small airway disease [29] and are significantly reduced in IPAH. Flow-volume curves are curvilinear in appearance as a result [20,22]. Studies that have

found no evidence of airway obstruction have not utilised these measures [17,21]. Therefore whilst the majority of patients with IPAH may have normal FEV1/FVC ratios, clinicians should assess flowevolume curves as well to ensure adequate assessment for small airway disease has been conducted. As with lung volumes the cause for these changes is unknown. While intimal and medial thickening of the pulmonary arteries is seen histologically, whether these encroach on the adjacent airways to affect airflow and cause airway obstruction is unknown [23]. Inflammation and mucus plugging can cause airway obstruction in other lung diseases, though histological evidence of this occurring in IPAH is limited [30]. However, systemic inflammation is a feature of IPAH with increasing evidence that this may play an important role in its pathogenesis [31]. Lung tissue analysis in IPAH has demonstrated the presence of perivascular inflammatory cell infiltrates consisting of T cells, B cells and macrophages [32], while recent pathology specimens of explanted lungs in PAH due to a range of causes demonstrated perivascular and interstitial inflammation in addition to the known vascular changes [23]. In IPAH patients, the use of enzyme-linked immunosorbent assays (ELISA) on venous samples show that serum levels of inflammatory cytokines including interleukin (IL)-1b, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, and tumour necrosis factor alpha (TNFa) are significantly elevated when compared to controls [33,34]. These may play an important role in arterial remodelling [35]. Protein movement from the systemic circulation into the airways has been shown to occur, and this can increase in the presence of inflammation due to effects on epithelial permeability [36,37]. If an overspill of these inflammatory mediators and cells into the airways occurs, the resulting airway inflammation could account for the airway obstruction seen. Similarly an overspill of vasoactive mediators into the airways could cause bronchoconstriction. Endothelin-1 (ET-1) is thought to play a key role in the vascular changes seen in PAH as it is a potent vasoconstrictor with the ability to stimulate the proliferation of pulmonary arterial smooth muscle cells [38]. Specific radioimmunoassay has demonstrated raised venous plasma levels of ET-1 in IPAH, associated causes and secondary causes when compared to healthy volunteers [39]. ET-1 can also cause bronchoconstriction both in vitro [40], and in vivo when inhaled by asthmatics [41]. ET-1 has also been found in bronchoalveolar lavage samples of COPD patients [42], and in greater concentration in patients with cystic fibrosis in induced sputum samples [43]. Likewise, the production of nitric oxide by endothelial cells is decreased in PAH [44]. Nitric oxide induces vasodilatation and can also cause airway dilatation [45]. Whether levels of inflammatory mediators and vasoactive mediators are increased in the airways is however unknown. Though the airway abnormalities described may be viewed as mild, this leads to exercise related dynamic hyperinflation which may contribute to symptoms and reduced exercise capacity [46,47]. Studies regarding treatment of airway obstruction are limited, and it is unknown if bronchodilators can improve symptoms [48]. 2.1.3. Gas transfer Three quarters of IPAH patients will have abnormal gas transfer (carbon monoxide diffusing capacity (DLCO) of less than 80% predicted) with a mean across studies of 59e71% of predicted values [17,19,20,22,49]. When adjustments have been made to account for smoking, DLCO has remained abnormal suggesting a true abnormality in IPAH [17]. It is unlikely that this reduction in DLCO can be explained purely by ventilation-perfusion mismatch, as the alveolar volume and TLC at rest are very closely matched [17]. Further analysis of gas transfer in patients with IPAH demonstrates that both pulmonary membrane diffusion capacity and the pulmonary

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capillary blood volume participating in alveolar gas exchange are reduced [50,51]. Reductions in pulmonary membrane diffusion capacity may be due to thickening of the alveolar capillary membrane due to endothelial cell proliferation. While reductions in pulmonary capillary blood volume may be the result of increased pulmonary vascular resistance, reduced cardiac output and local thrombosis [51].

2.2. Congenital heart disease associated pulmonary arterial hypertension Early studies of lung function in CHD-APAH have perpetuated the inaccurate view that PAH has little effect on lung function in CHD [24,52,53]. The findings of these studies are however limited by the inclusion of PH due to left heart disease and chronic lung disease [24], a focus on lung compliance with incomplete reporting of measured lung function values [52] and the omission of many parameters now routinely measured including peak expiratory flow rate, FEV1, TLC, and mid-expiratory flows [24,52,53]. In other studies, normal lung function was reported in case series of less than 5 patients with no controls for comparison [54,55]. The early notion of normal lung function in CHD-APAH is therefore questionable. In addition the management of CHD has changed markedly over recent decades resulting in demographic changes for both CHD and CHD-APAH [56]. These early studies are thus not applicable to current patients with CHD-APAH. More recent studies have shown changes in lung function that are similar to those seen in IPAH, though available data is largely derived from smaller case series often with no CHD controls for comparison. In addition some differences exist. As with IPAH, TLC has variously been reported as between 81 and 99% predicted in CHD-APAH. This suggests that lung volumes could be modestly reduced, consistent with lung restriction, or indeed normal [16,20,27,57,58]. The reported differences could be due to the effects of cardiothoracic surgery and associated scoliosis which is common in this patient group. In a group of 32 Eisenmenger's patients where only a small number had scoliosis or previous surgery the overall TLC was normal, which supports this hypothesis [58]. However, no comparison of lung function between those with and without surgery and scoliosis was made. The focus on Eisenmenger's patients in this study also limits its relevance to other CHD-APAH groups, such that while other studies have demonstrated lung restriction, the cause, as well as the effect on patient symptoms remains unclear. In keeping with IPAH, more than 40% of patients with CHDAPAH have an FEV1/FVC ratio of less than 70% [58]. The overall mean FEV1/FVC ratio has been reported as normal [16], or only modestly reduced [20,27,57], however where flowevolume curves have been assessed, these are curvilinear in appearance [20] and mid-expiratory flow values are reduced to half of predicted values [16,20,27,57]. This supports the presence of mild-moderate airway obstruction affecting the peripheral airways. As with IPAH, the cause of airway obstruction is unknown, though the conditions share histological [23] and pathophysiological characteristics [59], with aberrations of vasoactive [60] and inflammatory mediators [61] playing a similar role. The possibility of overspill of these mediators may thus be a potential mechanism as might direct encroachment of hypertrophied vessels. DLCO is reduced to 62e77% of predicted values [16,20,57,58]. As the histological findings are similar to those in IPAH, this may also be due to a reduction in pulmonary capillary blood volume and pulmonary membrane diffusion capacity as a consequence of increased pulmonary vascular resistance, reduced cardiac output and endothelial cell proliferation [51].

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2.3. Connective tissue disease associated pulmonary arterial hypertension The study of lung function in patients with CTD-APAH is problematic due to the potential for coexisting ILD. In a Chinese cohort of 37 patients with CTD-APAH, a similar pattern of abnormal lung function to both IPAH and CHD-APAH was described with reductions in TLC, mid-expiratory flows and DLCO [20]. However, it is unclear what proportion of these patients may have had coexisting lung disease, as measures to exclude affected individuals were not described. Abnormalities of dynamic and static lung volumes in CTD-PAH thus remain undetermined. DLCO is reduced in systemic sclerosis in conjunction with PAH in the absence of ILD [62,63]. Both isolated and disproportionate reductions in DLCO in relation to other lung function parameters can thus indicate the presence of associated PAH [64]. The detection of PAH in systemic sclerosis can be further improved by pairing DLCO abnormalities with echocardiographic findings [65]. This has been suggested as a screening method to identify those in need of further assessment by right heart catheterisation [66]. 3. Group 2 e Pulmonary hypertension due to left heart disease Lung restriction is found in PH due to left heart disease with reductions in both TLC and FVC, while airway obstruction is uncommon [67,68]. Heart size measured by echocardiography correlates with lung volume reductions as determined by spirometry and radiological evidence [26]. Reductions in cardiac volume following heart transplantation also correlate with improvements in lung volumes [25]. This suggests that lung restriction is at least in part due to cardiomegaly causing displacement of lung tissue within the thoracic space. Pulmonary venous congestion may also contribute to lung restriction as rapid saline solution infusions lead to reductions in TLC and FVC [69], while diuresis leads to improvements in these parameters [70]. DLCO is reduced in PH due to left heart disease [71]. Pulmonary oedema may account for this through thickening of the alveolarcapillary membrane, as improvements in DLCO have been reported following the use of diuretics [72]. However impairments in DLCO persist despite ultrafiltration [73] and despite reduced pulmonary congestion following heart transplantation [74] suggesting that the reduction in DLCO may be independent of lung fluid content. Persistent pulmonary venous hypertension may cause remodelling of the alveolar-capillary membrane that would account for the persistent effects on gas transfer [75]. 4. Group 3 e Pulmonary hypertension due to chronic lung disease The development of PH in chronic lung disease is complex but is in part related to hypoxic vasoconstriction and parenchymal damage [76,77]. However PH has a variable association with the degree of lung damage as assessed radiologically and by lung function [78]. The prevalence of PH is increased in more severe COPD and ILD [79]. However the severity of PH does not correlate with the severity of the lung condition as assessed by flows and volumes [80,81] and many patients will have severe PH which may be disproportionate to relatively preserved lung function [82,83]. This is also a frequent finding in patients with combined pulmonary fibrosis and emphysema [84]. The development of PH in patients with chronic lung disease thus does not appear to worsen these aspects of airway physiology. Reduced DLCO is a more consistent finding in PH due to chronic lung disease. While lung disease alone can result in a reduction in

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DLCO, the presence of PH is associated with a further worsening of DLCO. This correlates with severity and may be out of keeping with abnormalities of other parameters [82,84,85]. DLCO may thus help to identify patients with PH who deteriorate despite stable lung volumes, and PH should be suspected in chronic lung disease where the DLCO is disproportionately low in relation to other lung function values. 5. Group 4 e Chronic thromboembolic pulmonary hypertension A restrictive lung pattern has been reported in patients with CTEPH with a modest overall reduction in TLC to 91.1% predicted [16]. As with the other conditions discussed, not all patients with CTEPH are affected. Several case series, and a report from a large US based centre on their experience of over 250 patients with CTEPH, report that 20e29% of patients have lung restriction, with no evidence of airway obstruction [16,18,86]. Pulmonary emboli can result in persistent parenchymal scarring in some patients which may account for this lung restriction as the extent of this scarring on high resolution computed tomography correlates with lung function [87]. Lung function does not correlate with the size of the proximal pulmonary arteries, suggesting that reduction in lung volume is not due to displacement by proximal vessel hypertrophy and dilatation [87]. DLCO is reported as reduced to 40e60% in patients with CTEPH, though this is limited to case series with small numbers of patients [19], or have included IPAH patients in their analysis [55]. This reduction in gas transfer is due to proportional reductions in both pulmonary capillary blood flow and pulmonary membrane diffusion capacity [50]. 6. Cardiopulmonary exercise testing in Group 1 e PAH End tidal partial pressure of CO2 (PETCO2) at rest is reduced on CPET reflecting abnormal gas exchange in PAH in keeping with reductions in DLCO [88]. CPET testing provides further information regarding gas exchange during exercise. In health, exercise would result in increased recruitment of the pulmonary vascular bed resulting in a rise in PETCO2 [89]. In PAH, PETCO2 decreases further, and the ventilatory equivalent for carbon dioxide (VE/VCO2) percentage and slope increases due to a worsening of gas exchange during exercise [88]. This is due to a ventilation-perfusion mismatch caused by reduced recruitment of the pulmonary vascular bed [90]. Though other abnormalities of lung function at rest have been described, ventilatory reserve at peak exercise is maintained and it has thus been suggested that respiratory function abnormalities have little impact on exercise capacity [17]. However, exercise limitation is related to dynamic hyperinflation, as inspiratory capacity progressively reduces during CPET testing, with an increase in inspiratory capacity-TLC percentage in PAH and CTEPH patients [46]. This occurs in patients with reduced midexpiratory flows at rest despite a preserved FEV1/FVC ratio suggesting that exertional dyspnoea may in part be due to airway obstruction not detected by standard spirometry [47]. CPET changes provide useful prognostic information. The VE/ VCO2 slope is typically 43e47 compared to 25 in controls [49,91,92], while a study of 84 patients with IPAH identified a VE/ VCO2 slope of greater than 54 as being associated with increased mortality [93]. Peak oxygen consumption (VO2) also correlates with mortality in PAH and is typically reduced to 10e15 ml/kg/min [49,91,92,94,95]. Patients with a peak VO2  10.4 ml/kg with a peak systolic BP of 120 have a worse 12 month survival rate (23%) compared to patients with only 1 or neither of these risk factors (79% and 97% respectively) based on the survival data of 86 patients

with IPAH [94]. When assessed in CTEPH and associated causes, peak VO2 levels below 13.4 ml/kg were associated with worse survival rates [95]. Reductions in peak VO2 have also been shown to correlate with severity of IPAH [92] and can predict clinical stability [93]. CPET abnormalities in PAH improve with treatment [96e99] and it has been suggested that a peak VO2 of >15 ml/kg/min should be used as a treatment goal as it is associated with a better prognosis [100]. It is a reproducible test that is increasingly being used in the assessment of PAH [101]. However, CPET testing and interpretation is highly technical, and it is thus essential that centres have the necessary expertise and experience to ensure results are sufficiently reliable if it is to be used to guide management decisions [102]. The use of CPET in other PH groups is currently limited due to a paucity of studies in this area and is in need of further investigation. 7. Conclusions Breathlessness is a common symptom in PH and many patients remain breathless despite optimal treatment. Vascular abnormalities and their impact on symptoms are well described [6], but differences in lung function are less well recognised. The abnormalities seen can be modest and it has been suggested that they are unlikely to contribute significantly to patients' symptoms [17]. However, by promoting dynamic hyperinflation during exertion there may be an impact on symptoms and exercise capacity [46,47]. Ignoring these aspects may be to the detriment of patients with PH. A full understanding of the lung function abnormalities in PH patients may provide unique treatment targets and should be the aim of future studies. The use of CPET has provided an additional understanding of airway physiology during exercise as well as proving a useful adjunct in the assessment of Group 1 e PAH, though further study for other groups is needed. The use of other lung function techniques such as multiple-breath washout which is advocated as a more sensitive measure of peripheral airway obstruction may also improve our understanding of the respiratory component of breathlessness in these patients [103]. The cause of these changes in PAH is unknown, though the causes in other groups of PH may provide some insight into the potential pathology. In addition, inflammatory and vasoactive mediators that are known to be present in the pulmonary vessels could have an effect on airway function if present in the adjacent airways [31,38]. Sampling the airways either through the use of bronchoscopy or non-invasively by sputum induction would enable the use of ELISAs or multiple analyte assays to determine this. Research into this area could provide valuable insight into the underlying processes for these abnormalities. A better understanding of this may provide novel targets for potential therapies to help improve the management of these symptomatic patients in the future. Conflicts of interest AT Low, ARL Medford and AB Millar have no conflicts of interest to declare. RMR Tulloh has received educational grants and speaker fees from Pfizer, Actelion, Encysive and GSK. References [1] M. Oswaldmammosser, E. Weitzenblum, E. Quoix, G. Moser, A. Chaouat, C. Charpentier, R. Kessler, Prognostic factors in copd patients receiving long-

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