Chapter 38 Complex Challenges of Pulmonary Hypertension

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1 Chapter 38 Complex Challenges of Pulmonary Hypertension John Gerard Coghlan Keywords Borderline pulmonary hypertension Chronic thromboembolic pulmonary hypertension (CTED) Complex challenges Diagnosis and classification Exercise-induced changes Left heart disease Pulmonary hypertension Pulmonary pressures Pulmonary veno-occlusive disease (PVOD) It is now well appreciated that pulmonary hypertension (PH) is a frequent complication of scleroderma and that it occurs in both of the major disease subsets. However, despite a much greater understanding of the different forms of pulmonary hypertension and the availability of effective treatments for different forms of this disease, it remains one of the most feared complications of scleroderma. Compared with other forms fo PAH, that which occurs in scleroderma has a significantly worse outcome, and this is especially in comparison with idiopathic PAH. Thus, the strategies that are used for PAH may need to be modified in the context of scleroderma, and this is discussed below. In addition, there are other common causes for pulmonary hypertension in scleroderma, and it is likely that more than one process leading to elevated pulmonary pressures may operate in individual cases. Thus, it is necessary to consider the contribution of pulmonary arterial hypertension as well as left heart disease, interstitial lung disease and other mechanisms such as pulmonary veno-occlusive disease and thromboembolic disease. This chapter reviews the complexity of managing pulmonary hypertension in scleroderma, gives particular focus to the application of licensed therapies for PAH and the extent to which an admixture of underlying mechanisms may operate that justify consideration in managing this complication. Guidelines for the Treatment of Pulmonary Arterial Hypertension (PAH): Evidence in Scleroderma International guidelines and consensus documents have done much to harmonize and standardize the management of medical conditions. In the field of pulmonary hypertension, they help spread good practice and significantly increase the probability of patients receiving evidence-based best practice care. When analysing the strength of the evidence base in one particular condition such as scleroderma, it is vital to remember that the benefits of standardization of care more than compensate for the consequent failure to act in accordance with limited, but apparently contradictory evidence base in most circumstances. A brief overview of the ESC/ERS guidelines consensus document is worthwhile, focusing on the robustness of the evidence base. Diagnosis and Classification The recent guidelines [ 1 ] have retained the clinical classification initially proposed at Evian and which has served the pulmonary hypertension community well. Slight modifications have been included that are not relevant to the scleroderma population. Thus, the three main groups of causes of pulmonary hypertension associated with scleroderma remain J.G. Coghlan, MD, FRCP ( ) Department of Cardiology, Royal Free Hospital, Hampstead, London, UK gerry.coghlan@nhs.net J. Varga et al. (eds.), Scleroderma: From Pathogenesis to Comprehensive Management, DOI / _38, Springer Science+Business Media, LLC

2 448 J.G. Coghlan distinct pulmonary arterial hypertension (group 1), left heart failure (group 2) and lung disease associated pulmonary hypertension (group 3). The treatment recommended for each of these groups remains mutually exclusive. Borderline Pulmonary Hypertension and Exercise-Induced Changes in Pulmonary Pressures The only critical changes to the definition, is the recognition of a new category of borderline pulmonary hypertension and the exclusion of exercise-induced pulmonary hypertension as a valid diagnostic category. This is due to work reviewing all the published literature on pulmonary pressures at rest, showing that the normal mean pulmonary artery pressure is mmhg thus, 20 mmhg represents two standard deviations above normal [ 2 ] and during exercise, showing that there is no clear upper limit of normal and no consistent evidence base, showing that findings are predictive of prognosis [ 3 ]. This will remain an area of controversy since an association with rapid escalation of pressures during gentle exercise and subsequent development of pulmonary arterial hypertension has been reported [ 4 ]. Further, a recent study from the Massachusetts General Hospital found that invasively documented exercise-induced pulmonary arterial hypertension (mpap > 30 mmhg, PCWP < 20 mmhg, PVR > 80 d.s/cm 5 ) identified a group of individuals with reduced maximum oxygen consumption on cardiopulmonary exercise testing [ 5 ]. Intriguingly, they noted that mildly elevated resting pulmonary pressures did not reliably identify this group. Pulmonary Hypertension Due to Left Heart Disease The definition of left heart disease associated pulmonary hypertension remains hemodynamically based (pulmonary capillary wedge pressure or left ventricular end-diastolic pressure of > 15 mmhg). It is of note that the analysis of normal catheter that has provided us with the new definition of a normal mpap (<21 mmhg) [ 2 ] has not led to the adoption of a new definition of a normal wedge in the same study, the PCWP was mmhg, which would give an upper limit of normal of 14 mmhg. This group is treated as distinct because of the very different pathological findings (enlarged and thickened pulmonary veins, pulmonary capillary dilatation, interstitial oedema, alveolar haemorrhage and lymphatic vessel enlargement.) [6 ] and the failure of PAH-directed therapies to improve outcome (though one can argue that not all patients in heart failure trials have post-capillary pulmonary hypertension) [ 7 10 ]. This also remains an area of active research since post-capillary pulmonary hypertension remains an independent predictor of death [ 11 ], and trials of agents with different potential mechanisms of action are ongoing [ 12, 13 ]. Nevertheless, current data supports standard heart failure therapy for scleroderma patients with systolic heart failure and diuretic therapy for those with diastolic heart failure irrespective of the presence of pulmonary hypertension. The notion that solving the left heart problem rather than trying to directly treat the pulmonary pressures has been strongly supported by experience with left ventricular assist devices [ 14 ] and a recent trial of optimizing heart failure therapy to lower pulmonary pressures [15 ], demonstrating that the elevation of pulmonary pressures is dominantly passive even where disproportionate. Pulmonary Hypertension Due to Lung Disease and/or Hypoxia In the general population, lung disease associated pulmonary hypertension is usually fairly obvious; generally, it is mild in the setting of severe lung disease with effort limitation concordant with the reduction of lung performance rather than the modest elevation of pulmonary pressures [ 16, 17 ]. As with left heart disease out of proportion pulmonary hypertension occurs (mpap >40 mmhg has been proposed), and in such cases, medial hypertrophy has been found in at least some cases. In scleroderma, differentiating lung disease associated PH and PAH is rather more complex. Most scleroderma patients (>70%) have some parenchymal involvement and 15% with limited disease, and 35% of patients with diffuse disease have significant pulmonary fibrosis by 5 years of follow-up [ 18 ]. Further, pulmonary pressures are less elevated in scleroderma PAH [19 ], so the dividing lines between lung disease PH and PAH become blurred. For practical purposes, the entry criteria for the major clinical trials are used to differentiate those in whom advanced therapies have a supportive evidence base (FVC > 70% or 60% unless HRCT evidence of significant parenchymal lung disease and FEV1/FVC > 60%), although Well s criteria (HRCT > 20% lung involvement, or if doubt, on HRCT FVC < 70%) fits better with the clinical course of patients with scleroderma lung disease and will determine whether active treatment for lung disease is undertaken.

3 38 Complex Challenges of Pulmonary Hypertension 449 Chronic Thromboembolic Pulmonary Hypertension (CTED) CTED is remarkably rare in scleroderma (we have identified only two patients in over 500 patients); nevertheless, as a curable form of pulmonary hypertension, exclusion remains essential. A negative ventilation/perfusion scan is very reliable, but again in scleroderma, parenchymal abnormalities often mean that the scan is not entirely negative, and therefore not exclusive. In practice, therefore, CT pulmonary angiography at the same time as HRCT is the more usually way of excluding pulmonary thromboembolism. Resetting the CTPA to lung windows and confirming homogenous perfusion throughout the lung fields provide excellent reassurance that missing vessels have not been overlooked on the scans. Pulmonary Veno Occlusive Disease (PVOD) PVOD is a particularly refractory type of pulmonary hypertension, which, though sharing some pathological features with pulmonary arterial hypertension, has predominant involvement of the pulmonary venous vasculature, and like post-capillary pulmonary hypertension, patients can dramatically worsen if treated with pulmonary vasodilators. It is suggested that PVOD is much more common in patients with scleroderma and that this may explain the worse prognosis in patients with scleroderma. The evidence supporting this view comes from histopathological studies by Dorfmüller et al. [ 20 ] and clinical data from O Callaghan et al. [ 21 ]. However, it is difficult to be certain that this is really the problem; lymphadenopathy is common in scleroderma as is ground glass shadowing, leaving only interstitial oedema and septal hypertrophy to differentiate between scleroderma PAH with a degree of pulmonary interstitial disease from PVOD. Vasodilator Testing It is recognized that vasoreactivity is much less common in scleroderma-associated pulmonary arterial hypertension. However, because of the dramatic impact on survival in those few patients who exhibit vasoreactivity, vasodilator testing is still recommended in the guidelines for patients with scleroderma. Given the failure to identify any cases of chronic vasoreactivity in 139 patients with scleroderma-associated PAH at the Royal Free [ 22 ] and identical experience in Beclere (Sitbon) [ 23 ], despite a significant incidence of acute vasoreactivity, it is reasonable to postulate that the loss of 2 3 months of potentially effective therapy while demonstrating that there is no chronic response is futile. The validity of this view is acknowledged in the guidelines. Treatment In the guidelines, it is recognized that scleroderma-associated PAH has been included in all pivotal trials and that while efficacy cannot, in most instances, be independently demonstrated for this subgroup, the magnitude and direction of response is indistinguishable from the response seen in those with idiopathic PAH. On this basis, it is recommended that the same treatment algorithm should apply to scleroderma PAH as in IPAH. It follows that as no blinded head to head trials have been performed, there is no evidence base suggesting that any of the available drugs should be recommended as first-line therapy. Summary of Specific Evidence in Scleroderma Patients Standard therapies for right heart failure, such as diuretics and digoxin, are used in scleroderma patients; though no specific evidence exists, there is little reason to doubt their efficacy. Oxygen therapy is symptomatically beneficial, particularly in patients with significant interstitial lung disease associated with scleroderma. As in IPAH, the evidence base is non-existent in scleroderma-associated PAH, but expert recommendation is that oxygen is used where symptomatically beneficial or to

4 450 J.G. Coghlan maintain saturations above 90%. Anticoagulation with coumarin agents has been shown to be beneficial in idiopathic, heritable and anorexigen-induced PAH, and the rationale for therapy is the same in scleroderma PAH (reducing pulmonary intravascular thrombosis) [24 ]. However, the presence of anaemia or a bleeding diathesis, such as the GAVE syndrome, may preclude such treatment. Limited evidence exists for immunosuppressive agents; a subgroup of MCTD and SLE patients may exhibit good treatment response, but not for scleroderma PAH [ 25 ]. Calcium channel blockers are useful for Raynaud s rather than PAH in CTD patients. Randomized clinical trials have shown that three groups of agents are beneficial. These include (1) the endothelin receptor antagonists (ETRA): bosentan and ambrisentan, (2) the phosphodiesterase type-5 inhibitors (PDE-5I): sildenafil and tadalafil, and (3) the prostanoids: epoprostenol, treprostinil and iloprost [ 26 ]. The only therapy that has been specifically evaluated in a multicentre randomized controlled trial in CTD-PAH is intravenous epoprostenol. In a population with SScPAH, the primary endpoint 6MWD, was significantly improved at 12 weeks in the 56 patients treated with epoprostenol compared with 55 patients that received conventional therapy alone (median treatment effect +108 m), and significant improvements were observed in a number of haemodynamic endpoints [ 27 ]. Despite this success, follow-up registries failed to show a clear improvement in survival [ 28, 29 ]. Determining the efficacy of other prostanoids in the scleroderma population is difficult, varying from no apparent benefit is seen with oral beraprost [ 30 ], to probable benefit in the subpopulation of 90 patients with CTD-PAH in the subcutaneous treprostinil trial [ 31 ]. However, the mixed population in the treprostinil trial (45 SSc patients, 25 cases of SLE and 20 patients diagnosed with MCTD/overlap syndromes) renders it unclear if the SSc population benefited. The most extensive data on the treatment of scleroderma is found in trials and registries with endothelin receptor antagonists; however, even here, the situation remains far from clear. Sixty-six patients who had SScPAH were included in three pivotal trials with Bosentan, but these have not been analysed separately from the other 33 patients with CTD-PAH [ ]. The response to therapy of this subgroup was consistent with the overall study population (similar in magnitude and direction), but no significant changes were observed. A prospective open-label study (TRUST) of bosentan in CTD-PAH reported improvement in functional class and 92% survival at 48 weeks [ 35 ] and a 70% 3-year survival [ 36 ] ; 42 of the 53 patients enrolled had scleroderma. Follow-up registry data in SScPAH [ 28 ] show that survival is significantly improved when compared to historical data. Sitaxsentan, a highly selective endothelin A antagonist, has the strongest evidence base in CTD-PAH; it has, however, been voluntarily withdrawn from the market by Pfizer because of several instances of hypersensitivity hepatic injury leading to death in a number of cases. It is not possible to extract the effect on the scleroderma population, although scleroderma patients form the largest cohort in all analyses. In the three double-blind trials [ ], there was no statistically significant difference on 6-min walking distance in the subpopulation with CTD in any individual trial. Post hoc analysis of the 119 patients with CTD-PAH allocated to the effective dose (100 mg), 58 of whom received placebo and 61 treated [ 40 ] the 6-min walk distance increased by 25 m on treatment; the placebo corrected benefit was 38 m ( p = 0.007). Post hoc analysis of the open-label follow-up of the STRIDE 2X trial, suggested a significant prognostic benefit for sitaxentan over bosentan [ 41 ]. Baseline differences in the numbers with scleroderma in the STRIDE-2X and differences in the management of sitaxsentan and bosentan patients exhibiting drug intolerance or clinical deterioration meant that it was difficult to assert that the observed effect on even this hard end point was real rather than due to study design. An attempt to replicate these findings in a further open-label registry failed to reproduce the findings; however, the 1-year mortality was very low (4%), and a trend (non-significant) for increased time to clinical worsening relative to bosentan was still evident, in a population with a balanced prevalence of scleroderma in each group. [ 42 ]. Ambrisentan has been evaluated in two pivotal trials (designed to allow amalgamation of the results) which included 124 patients with CTD-PAH (80% scleroderma or mixed connective tissue disease (MCTD)); the 6MWD improved by nearly 20 m in the 5- and 10-mg groups (net benefit over placebo 26 m ( p = ns)) [43 ]. Data on file from the 2-year extension study indicates that the rate of clinical worsening for the CTD population was almost identical to that of the total population [ 44 ]. Two phosphodiesterase-5 inhibitors have completed pivotal trials in PAH. In the Super trial, 62 patients with CTD-PAH were randomized to one of the three treatment arms. The direction and magnitude of benefit was similar to the overall trial effect, but not significant because of population size [ 45 ]. In the Phirst trial, 95 CTD-PAH patients were randomized to each of the three tadalafil treatment arms or placebo; similar improvements in 6-min walk distance and time to clinical worsening were observed, again not reaching significance in the subgroup [ 46 ]. As the largest subgroup, the bulk of published data deals with SScPAH. PAH-specific therapy during the era of monotherapy ( ) improved the prognosis for patients with PAH associated with SSc; the 3-year survival is 67% for patients in World Health Organization functional classes (WHO FC) I/II, decreasing to 48% for WHO FC III and 21% for WHO FC IV patients with SSc [ 8 ].

5 38 Complex Challenges of Pulmonary Hypertension 451 Combination Therapy While the evidence base for monotherapy is far from satisfactory, it is evident that the magnitude and direction of efficacy is similar in the CTD-PAH subgroups and it is clear that the most recalcitrant group (SSc-associated PAH) has benefited through improved survival in all registries of oral therapies. The focus of clinical investigation has now moved to combination therapy and is gradually shifting toward time to clinical worsening as the more important endpoint. Unfortunately, to date, the trend for including relatively small numbers of CTD-PAH patients and not performing prespecified analysis of this subgroup continues. In the PACES-1 trial of sildenafil added to epoprostenol, 45 patients had CTD-PAH (31 with SSc) the dominant benefit in terms of reducing mortality was seen in those with a 6-min walk distance of less than 325 m [ 47 ]. This is where one finds the bulk of the CTD-PAH population, and this has tended to be the population with the greatest contribution to clinical events; it is conceivable that this subpopulation will become a significant contributor to improved outcome as the primary endpoint shifts to time to clinical worsening. Monitoring Response to Treatment The availability of multiple treatments in a progressive condition mandates close follow-up and modification of treatment where either deterioration has occurred or the response is inadequate. The ESC guidelines recommend a series of clinical and biometric assessments to be assessed regularly in patients with PAH and give recommendations in respect of treatment decisions based on the overall findings. Intriguingly, of the assessments recommended only change in functional class, persistence of clinical evidence of right heart failure, failure to reduce pulmonary vascular resistance (PVR) in response to therapy [48 ] and change in NTproBNP [ 49 ] have been shown to be associated with improved survival. Change in 6MWD in response to therapy has not been found to correlate with outcome [ 48 ], and the other parameters while prognostically relevant at baseline and exhibiting threshold effects during follow-up in some registries are not backed by a consistent evidence base even in IPAH. Although TAPSE (tricuspid annular plane velocity) and pericardial effusion have been selected as the echocardiographic parameters of choice, these have been found predictive only as baseline variables [ 50 ], and the findings in this regard are not consistent. Nevertheless, on the basis of the limited evidence available and backed by expert consensus, the proposed variables discriminate clearly between those who have an excellent response to treatment (better prognosis) and those who are failing to respond (worse prognosis). Further, by identifying these as the chosen characteristics, studies assessing their reliability and relative merit are now being performed [ 51 ]. We now need to consider how applicable such measures are in the scleroderma population. Assessing the prognosis and response to therapy in scleroderma is complicated by the multisystem nature of the disease (variable degrees of cardiac, pulmonary, gastrointestinal and musculoskeletal pathology) and the older age of the patients [ 52 ]. The most obvious difference between scleroderma patients and IPAH patients from the pivotal trials has been the less impressive response in terms of change in 6MWD. Analysis of the National UK registry population showed that the median baseline walking distance was only 332 m and that while those who walked further had a better prognosis; change in 6MWD at 3 months did not predict outcome [ 53 ]. Thus, as in IPAH baseline but not change in 6MWD predicts outcome, but the distance covered is less, making 500 m an unrealistic target for most scleroderma patients. Neither echocardiographic nor cardiopulmonary exercise test parameters associated with survival have been determined in patients with scleroderma, and in one small study ( N = 49) baseline, haemodynamics were not predictive of outcome [ 49 ] ; however, Launay et al. in a cohort of 40 CTD patients with baseline and follow-up catheters identified functional class and cardiac index greater or less than 2.7 l/min/m 2 as predictive on multivariable analysis [ 54 ]. The evidence base in scleroderma in respect of predictors of outcome and the relevance of change in these parameters in response to therapy is therefore too incomplete to propose an alternative to the ESC guidelines. There is a clear need for further studies of this important aspect of patient management. Is Scleroderma PAH Different? Although cardiac involvement in systemic sclerosis is well recognized, its role in pulmonary hypertension is poorly understood. In pulmonary arterial hypertension, scleroderma heart disease potentially underlies the lower workload tolerance of the right ventricle, while 10 15% of pulmonary hypertension in patients with systemic sclerosis is post-capillary [ 22, 55 ].

6 452 J.G. Coghlan The lower pulmonary pressures and lower PVR at presentation in systemic sclerosis [ 19, 52 ] have a number of potential explanations: the multisystem nature of the disease resulting earlier presentation and a preponderance of non-cardiac/pah deaths, PVOD may be more common and associated with, less tolerance of high pressures, the more progressive nature of SScPAH may leave insufficient time for right ventricular adaptation, the older age of the population may underpin the lesser ability of the heart to respond, or finally cardiac involvement may blunt cardiac tolerance of higher pressures. Plexiform lesions stained for endothelin 1. Such lesions are common in IPAH but found less frequently in SScPAH potentially reflecting the shorter duration of disease in SScPAH as the number of plexiform lesions appears to increase with duration of disease. Slide courtest of Giaid A et al In SSc PAH, by contrast, concentric hypertrophy of the small pulmonary arteries dominates. As a multisystem disease, it is no surprise that a number of patients with mild to moderate PH in association with scleroderma have a high mortality not explained by their PH. In a review of Royal Free scleroderma-associated PH , 17 of 172 patients had significant co-morbidity (six associated cardiac disease, mainly coronary artery disease, eight lung fibrosis, and one each severe musculoskeletal involvement, gastrointestinal disease and renal failure); this group, despite mild haemodynamic impairment, had the worst outcome (25% in year survival) ( RFH unpublished data). It is reasonable to consider that even where PAH is advanced, the ability to survive pulmonary hypertensive crises and general medical emergencies

7 38 Complex Challenges of Pulmonary Hypertension 453 Fig Typical NSIP Fig Typical PVOD is compromised. So the poor prognosis may reflect general medical issues. Another possibility that has not yet been formally excluded is that patients with SSc labelled as having IPAH may, in fact, have left heart or lung disease-associated mild PH and respond poorly because we are treating the wrong condition. In theory, left heart disease should be easily identified; however, the wedge pressure is by no means always accurately measured and can underestimate left atrial pressure in diuretictreated patients. Second, there is no formal definition of how much lung disease is required to cause pulmonary hypertension. In IPAH, the very high pressures seen help to prevent confusion with the relatively few patients with disproportionate PH in the setting of lung disease. In SSc, where 80% of patients have some lung involvement and pulmonary pressures are often in the mmhg range, it is much more difficult to be certain that an accurate diagnosis has been made. Overlap between CT findings of PVIOD and SSc-associated NSIP ground glass shadowing, and lymphadenopathy shared by both conditions. Septal lines are characteristically very prominent in PVOD, but are also modestly increased in SScNSIP. Figs 38.1 and Pulmonary veno-occlusive disease is reported to occur more frequently in systemic sclerosis patients; further, the clinical presentation and poor response to therapy share many characteristics [ 56 ]. PVOD is associated with a lower gas transfer than is usual in IPAH; the 6MWD is lower in most, though not all, series; baseline and post exercise oxygen saturations are lower; and response to therapy is poor. The characteristic HRCT features of PVOD are centrilobular ground-glass opacities and septal lines thus, confusion with pulmonary fibrosis and alveolitis in systemic sclerosis is certainly possible [ 57 ]. To date, there have been no large series of patients with PVOD published; thus, while the condition is stated to be haemodynamically indistinguishable from IPAH, a modestly less advanced haemodynamic profile cannot be excluded.

8 454 J.G. Coghlan Table 38.1 Response to RV pressure overload according to age group Parameter Age <50 years Age years Age ³70 years Number FC 1 or 2, 3, 4 (%) 20%, 56%, 24% 13%, 61%, 26% 19%, 57%, 24% Heart rate (bpm) 86 ± ± ± 14 PCW (mmhg) 9 ± 3 10 ± 3 10 ± 3 mpap (mmhg) 39 ± ± ± 12 PVR (d.s/cm 5 ) 593 ± ± ± 316 Since radiology (at baseline) is no longer regarded as sufficient to exclude PVOD, it is conceivable that the worse prognosis in systemic sclerosis PAH is due to pulmonary venous involvement. Unlike IPAH, reduced gas transfer and modest reduction in arterial oxygenation are the norms in scleroderma, so histology may be the only reliable way of proving that PVOD is not very common in this population. Nevertheless, the relative rarity of pulmonary oedema on prostanoids therapy seen in the pivotal study [ 58 ] and in registries is markedly different from reported experience in PVOD. Further, the systemic sclerosis population does not behave in a dichotomous fashion, with a majority exhibiting an excellent response to therapy but a substantial minority (those with PVOD) exhibiting a very poor response. If pulmonary venous vasculopathy underlies the worse prognosis associated with scleroderma, then there must be a gradation of venous involvement from subclinical through to florid rather than a distinct entity of PVOD within this population. In patients with IPAH presenting in functional class 2, mean pulmonary pressures have already reached 50 mmhg, and progression to functional class 3 and 4 is evidenced by reducing cardiac index and increasing pulmonary vascular resistance. By contrast, patients presenting in functional class 2 with systemic sclerosis-associated PAH have a mean PAP of only 34 mmhg, with a PVR of less than 400 d.s/cm 5 [ 59 ], while functional class 3 patients have a mean PAP of more than 40 mmhg and a PVR averaging over 650 d.s/cm 5 [ 4 ]. From this, we can deduce that patients with IPAH have a substantial asymptomatic period before presentation, but being unable to screen for IPAH, we have no understanding of the time course associated with asymptomatic disease progression. By contrast, we have some insight into the onset and progression of chronic thromboembolic pulmonary hypertension (CTEPH). Around 4% of patients with acute pulmonary embolic disease progress to CTEPH without resolution of the initial insult; thus, in these individuals, at least the rate of onset of increase RV workload can be said to be very rapid. Yet, the mean PAP at presentation in CTEPH patients is identical to severe IPAH [ 60 ], suggesting that right ventricular adaptation is fairly rapid. While suggestive, this is not proof, since CTEPH is a heterogeneous population, some of whom have had failure to resolve after an acute episode, while others may have had an insidious onset of disease, and to date, no subgroup analysis has been performed to see if differences exist between these populations. From our population of SScPAH patients, we can chart the progression from mild to severe PAH in over 100 individuals, while this is almost always associated with an increase in mean PAP, there is no association with rate of progression and maximum mean PAP reached, again suggesting that rate of progression is not the primary determinant of mean PAP. Older hearts may be less able to adapt to increased workload, and the scleroderma population is clearly older than the IPAH population. One way of addressing this question is to analyse the haemodynamics in PAH patients according to age. In Table 38.1 a of the presenting haemodynamics and functional class by age group in SScPAH patients from the Royal Free Hospital, we see no evidence that age impacts the ability of the right ventricle to mount an adequate haemodynamic response. Supportive evidence comes from the CTEPH population, which, though older than the IPAH patients at presentation, have almost identical haemodynamics [ 60 ]. A much better understanding of the onset and nature of PAH in SSc is required, and the DETECT study which is now nearing completion of the cross-sectional stage will provide better insight into this process over the next few years. This study will also provide evidence-based methods for screening for early scleroderma-associated PH and allow us to focus on the relative contributors to symptomatic progression and prognosis, in a way that presently we cannot. Group 2 PH Left heart disease associated pulmonary hypertension diagnosis and management.

9 38 Complex Challenges of Pulmonary Hypertension 455 Extensive myocardial fibrosis from a patient with SSc cardiac fibrosis.

10 456 J.G. Coghlan Extensive scleroderma-associated myocardial fibrosis as shown by late gadolinium enhancement using CMR scanning. Note near circumferential enclosure of left ventricle by a white band of fibrotic tissue. Extensive vasculopathy involving veins (a and b), capillary bed (c) and small pulmonary arteries (d) noted by Rich and Rabinovitch in occasional patients with post-capillary PH and a presumed permissive genotype. Slide courtesy of Rich S. et al Cardiac involvement in SSc is common; on MRI scanning, abnormalities are evident in over 50%, and these include mid-wall fibrosis in around 15% [ 61 ]. Coronary disease does not, however, appear to be increased in prevalence [ 62 ]. The multi-hit hypothesis of PAH raises the possibility that secondary reactive pulmonary hypertension might be more common in SSc patients with left heart disease. The concept that elevated left ventricular end-diastolic pressure leads to a reactive pulmonary vasculopathy that may independently contribute to mortality and morbidity has gained increased traction recently. Lam et al. have suggested that disproportionate PH occurs in up to 70% of patients with diastolic dysfunction [ 63 ] based, however, on echocardiographic estimation of systolic and capillary pulmonary pressures. Initially following the work of Doyle et al. in mitral stenosis, it was felt that any reactive vasculopathy identified in post-capillary pulmonary hypertension was likely to represent a protective response [ 6 ]. This was based on their finding of modest muscularisation without significant intimal proliferation confined to the lower zone pulmonary vessels. Upper zone vessels that did not show these adaptive changes were prone to pulmonary oedema, but lower zone vessels exhibited resistance to alveolar transudation. The possibility of a subpopulation with a permissive genotype was postulated by Rich and Rabinovitch to explain the occasional finding of extensive pulmonary vasculopathy with arterialisation of the pulmonary veins and muscularisation of the arteries [ 64 ]. Animal work supported this concept with evidence of interstitial remodeling of the alveolar capillary complex in heart failure models [ 65 ]. Clinical studies have shown that heart failure is associated with gas transfer abnormalities that correlate with prognosis and are improved by prognostically beneficial treatments such as ACE inhibitors. Additional supportive data comes from Giaid et al. showing that endothelin-1 expression in the pulmonary vessels is proportionate to the severity of pressure elevation even in secondary pulmonary hypertension (though of note only 5 of the 17 patients reported had left heart disease) [ 66 ]. Finally, abnormal endothelial function in patients with disproportionate PH is

11 38 Complex Challenges of Pulmonary Hypertension 457 suggested by the finding of reduced vasoconstrictive response to the nitric oxide antagonist L-NMMA in eight patients with post-capillary pulmonary hypertension and elevated pulmonary vascular resistance, but not seen in nine heart failure patients with normal PVR [ 67 ]. All these findings suggest that pulmonary vascular remodeling in response to venous hypertension is an active process that may, thus, be amenable to intervention. The problem arises when one considers effective therapies used in post-capillary pulmonary hypertension. The prevalence of disproportionate PH in mitral stenosis is around 15% [ 68 ]. In this work, disproportionate elevation was considered to be present when the pulmonary systolic pressure exceeded 60 mmhg. Post-valvuloplasty pressures fall modestly (PVR to ) however over the next year pressures essentially normalize (PASP to mmhg), and patients are equally asymptomatic and have equivalent event free survival when compared to those without disproportionate pulmonary hypertension. Such data are backed up by experience with left ventricular assist devices used as a bridge to transplantation in patients with disproportionate PH and left heart failure where reversal of PH is the norm in patients and persists while offloading continues [ 69 ]. Finally Drazner et al. found in 1,000 patients undergoing catheterization for transplant assessment that pulmonary artery systolic pressure was strongly correlate with pulmonary capillary wedge pressure across the entire spectrum of pressures [ 70 ], suggesting that passive elevation of pulmonary pressures is very much the dominant contributor to post capillary pulmonary hypertension. All efforts to treat heart failure with pulmonary vasodilators in phase III clinical trials to date have failed. Epoprostenol, bosentan and darusentan, despite excellent short-term haemodynamic effects, have failed to improve or worsened the clinical outcome in patients, while nitric oxide led to acute elevations of wedge pressure. Sildenafil has been used in chronic open-label studies of heart failure and reduced pulmonary pressures [ 71 ] and has also been shown to improve alveolar gas conductance [72 ]. Large-scale studies are required to fully evaluate sildenafil and other agents such as riociguat. Whether disproportionate elevation of pulmonary pressures is more common in scleroderma has yet to be established. To date, there is no adequate definition of disproportionate elevation, and no histological basis for any clinical suppositions of disproportionality. From this, it follows that the primary focus of treatment in SSc PH group 2 must be lowering left-sided filling pressures. This cannot, however, always be achieved, and clarity that independent PAH has not also developed is much more difficult. Group 3 PH As with heart disease, lung disease is common in scleroderma. It follows that individuals will occasionally have both PAH and lung disease. Unlike heart disease, there is very little clarity about how to define whether there is sufficient lung disease to explain any observed PH. Consensus opinion and trial design have set some boundaries; thus, an FVC or TLC of less than 70% of predicted or an FEV1/FVC of less than 50% is generally accepted as evidence of sufficient lung disease to cause elevations of pulmonary pressures [ 1 4, ]. In addition, it is accepted that substantial fibrosis on CT scanning (>20% of volume) or extensive emphysema can cause PH even if the volumes and airway function do not meet these criteria [ 73 ]. Pragmatically therefore, more moderate lung disease than above on CT and lung function testing are regarded as inadequate to cause PH, and by exclusion, a diagnosis of PAH is reached. This leaves a significant number of cases where we still have a very poor evidence base. Where severe lung disease remains static by all measures, but the patient is deteriorating in association with evidence of elevated pulmonary pressures is this PAH? Does the severity of pressure elevation provide insights is, for example, a transpulmonary gradient in excess of 30 mmhg or a pulmonary vascular resistance of more than 500 dynes.ses/cm 5 [ 74 ] so abnormal as to mandate consideration of an independent vascular component? While we can speculate on such matters, obtaining hard data is difficult; there is no randomized controlled data from such populations that suggests benefit. The histology of scleroderma-associated PAH is associated with relatively few plexiform lesions and thus difficult to differentiate from the muscularisation that can occur in hypoxic lung disease-associated PH. the mechanism of death is often right ventricular failure in both conditions. All we really know for sure is that treatment with pulmonary vasodilators rarely leads to worsening of saturations; thus, this potential adverse consequence of treatment is not seen in real life. But treatment may raise false hopes and expose the patient to unproven toxins; treatment with pulmonary vasodilators owes more to alternative medicine practice than science; nevertheless, some suggest that inaction is unethical [75 ]. Pending further data, we should aim to optimize management of the lung condition, maintain oxygenation, symptomatically treat resultant heart failure and where possible, obtain lung tissue to further understand the mechanism contributing to PH.

12 458 J.G. Coghlan Conclusion The treatment of scleroderma-associated PAH has transformed to outlook in this condition, and while results may not be as good as is seen in IPAH, in scleroderma, there is the opportunity for early diagnosis and treatment denied to others. While more effective treatments are urgently required, there is much we can achieve already. Looking to the future, we also need to understand the role of the heart and the overlap with lung disease much more thoroughly than is presently possible. References 1. Galiè N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: the task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J. 2009;30(20): Badesch BD, Champion HC, Gomez-Sanchez MA, et al. 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