Pulmonary Hypertension a Rare but Important Cause of Dyspnoea

Respiratory Medicine PEER REVIEWED UPDATES FOR MEDICAL PRACTITIONERS Today Pulmonary hypertension A rare but important cause of dyspnoea

A REPRINT FROM APRIL 2019 THIS REPRINT IS SPONSORED AS AN EDUCATIONAL SERVICE BY ACTELION, A BUSINESS UNIT OF JANSSEN-CILAG PTY LTD ACN 000 129 975 1-5 KHARTOUM RD MACQUARIE PARK NSW 2113, AUSTRALIA TELEPHONE: 1800 226 334 www.janssen.com/australia DATE OF PREP: JULY 2019 CP-100012

© 2019 MEDICINE TODAY PTY LTD P 2 at Westmead Hospital, Sydney, NSW. Sydney, Hospital, Westmead at Medicine Sleep and Respiratory in Trainee Advanced an is Srinivasan Dr Australia. Foundation Lung Committee, Hypertension Arterial of Pulmonary the Chair and Sydney; Hospital, Westmead at Centre Expert Hypertension Pulmonary the of Director and Physician Sleep and aRespiratory is Michail Dr RESPIRATORY MEDICINE TODAY 2019 haemodynamic outcomes and survival. outcomeshaemodynamic and survival. and functional key to improving are treatment and diagnosis Early treatable. are hypertension of most forms pulmonary management, With advances in dyspnoea. increasing with gradually presentation nonspecific typically its of because stages early the in missed easily is that disease adevastating be can hypertension Pulmonary hypertension Pulmonary cath right-heart during measured at rest, or higher of mmHg 25 pressure artery nary pulmo by a mean It defined is pressure. DAVID MICHAIL dyspnoea of cause A rare but important FEATURE

RespiratoryMedicineToday eteri sation. A change to this threshold, threshold, tothis Achange sation. the mean pulmonary artery artery pulmonary mean the in increase by an characterised condition pathophysiological a (PH) is hypertension ulmonary PEER REVIEWED MB BS,FRACP;

; 4(1):6-12

MEERA SRINIVASANMEERA - early diagnosis and intervention, is the the is intervention, and diagnosis early allowing PH, with patients of recognition Increased malignancies. metastatic many for than poorer are that rates mortality morbidity, and high with condition tating posed. 20 more than of pressure artery pulmonary to a mean • are: groups diagnostic WHO The the guide which pathophy shared on groupsbased major five into WHO the by classified PH are cause that Conditions hypertension pulmonary of Classification disease. of this history natural the to alter campaigns management of current focus

where obstructive changes to the tothe changes obstructive where conditions comprises group this (PAH); hypertension arterial pulmonary as known Group 1–also 1 If untreated, PH can be adevas be PH can untreated, If MBBS(Hons)

mm sio th Hg, was recently pro recently was Hg, logical mechanisms, mechanisms, logical erapeutic approach. approach. erapeutic - - • • •

PH, typically a sequela of unresolved of unresolved asequela PH, typically thromboembolic Group 4– chronic or hypoxia disease lung tochronic Group 3– PH secondary disease heart toleft Group 2– PH secondary abnormality abnormality vascular pulmonary to increased small re sistance are the primary primary the are sistance pu lmonary arteries leading leading arteries lmonary

• Pulmonary hypertension (PH) is characterised by an elevation in pulmonary artery pressure at rest and presents with progressive breathlessness as the cardinal symptom. • PH can be associated with more than 50 different conditions, which are categorised into five groups based on pathophysiological mechanisms; accurate classification is crucial to management as treatment options and goals vary between groups. • As symptoms of PH can be vague or nonspecific, diagnosis is often delayed, with patients typically progressing to advanced disease before diagnosis. • Identifying patients early in the disease course can improve functional and haemodynamic outcomes. • Group 1 PH (pulmonary arterial hypertension [PAH]) is rare; if it is suspected then prompt referral of the patient to a specialist with an expert interest in PH is recommended. • Long-term management of patients with PAH, Group 4 (chronic thromboembolic) or Group 5 (unclear or multifactorial) PH should be delivered or co-ordinated through a designated PH clinic or service.

pulmonary embolism is crucial to ensuring management is tar- Group 1. Pulmonary arterial • Group 5 – PH with unclear or geted to the underlying pathophysiology. hypertension multifactorial mechanisms.2 For example, selective pulmonary vaso PAH (Group 1 PH) is a progressive and Conditions included in the five WHO dilators are the only proven drug therapies often devastating condition. Proliferative diagnostic groups are listed in Box 1.2 for patients with PAH and Group 4 PH. changes in the lung microcirculation lead These WHO diagnostic groups aredi stinct However, their use to treat patients with PH to increased pulmonary vascular resistance. from the WHO functional class system in other groups may precipitate pulmonary If untreated, this results in right heart (Classes I to IV), which was adapted from oedema or other adverse cardiac events remodelling and ultimately right heart the NYHA functional class system. (Group 2 PH) or exacerbate hypoxia and failure and death. Historically, patients with Accurate diagnosis of the PH group breathlessness (Group 3 PH). PAH had a grim prognosis, but in the past

RespiratoryMedicineToday 3 FEATURE PULMONARY HYPERTENSION CONTINUED

1. WHO classification of pulmonary hypertension2

1. Pulmonary arterial hypertension 2. Pulmonary hypertension due to 4. Chronic thromboembolic pulmonary 1.1 Idiopathic left heart disease hypertension and other pulmonary artery 1.2 Heritable 2.1 Left ventricular systolic dysfunction obstructions 1.3 Drug and toxin induced 2.2 Left ventricular diastolic dysfunction 5. Pulmonary hypertension with unclear 1.4 Associated with: 2.3 Valvular disease and/or multifactorial mechanisms 1.4.1 connective tissue disease 2.4 Congenital/acquired left heart 5.1 Haematological disorders: 1.4.2 HIV infection inflow/outflow tract obstruction and myeloproliferative disorders, 1.4.3 portal hypertension congenital cardiomyopathies splenectomy 1.4.4 congenital heart diseases 2.5 Other 5.2 Systemic disorders: sarcoidosis, 1.4.5 schistosomiasis 3. Pulmonary hypertension due to lung pulmonary Langerhans cell 1’. Pulmonary veno-occlusive disease disease and/or hypoxia histiocytosis, lymphangioleiomyomatosis, and/or pulmonary capillary 3.1 Chronic obstructive pulmonary disease neurofibromatosis, vasculitis haemangiomatosis 3.2 Interstitial lung disease 5.3 Metabolic disorders: glycogen 1’’. Persistent pulmonary hypertension 3.3 Other pulmonary diseases with mixed storage and Gaucher disease, of the newborn obstructive and restrictive patterns thyroid disorders 3.4 Sleep-disordered breathing 5.4 Others: tumoural obstruction, fibrosing 3.5 Alveolar hypoventilation disorders mediastinitis, chronic renal failure on 3.6 Chronic exposure to high altitude dialysis 3.7 Developmental lung diseases

15 to 20 years their functional status and life the pulmonary arteries in the setting of the diagnosis of PH is often overlooked, expectancy have improved significantly with mechanical obstruction by unresolved contributing to delayed management. major developments in targeted drug thrombus. The underlying pathophysiology Particularly in patients with PAH or Group treatments. is similar to that of PAH. Where possible, 4 PH, opportunities are often missed to surgical intervention with pulmonary diagnose and treat disease at an early, poten- Group 2. PH secondary to left endarterectomy is the preferred treatment, tially reversible stage before significant heart disease as it has the potential to ‘cure’ PH. However, pulmonary vascular remodelling. A high PH secondary to left heart disease (e.g. interventional radiological approaches or index of suspicion is required as id entifying ventricular or valvular disease) is the most targeted drug therapy can be used in patients patients early in the disease course and common type of PH. Treatment of the under- deemed unsuitable for surgery because of referring them to specialists with specific lying disease and risk factor modification their pulmonary vasculature status, comor- expertise in PH can improve functional and are key to management. Stiffness of the left bidities or functional state. haemodynamic outcomes (see the case ventricle (heart failure with preserved history in Box 2).3,4 ejection fraction) is increasingly identified Group 5. PH with unclear or as a cause of PH. multifactorial mechanisms Diagnosis Group 5 PH includes conditions whose Diagnosis of PH requires a comprehensive Group 3. PH secondary to lung pathophysiology does not fit within set of investigations to confirm that haemo disease or hypoxia Groups 1 to 4 PH. The mechanism driving dynamic criteria are met and to identify PH secondary to lung disease, sleep- abnormal pulmonary artery pressures in the aetiology and severity of the condition. disordered breathing or hypoxia is rela- patients with Group 5 PH is often unclear. Involvement of a multidisciplinary team tively common. Optimising the underlying The most common cause of PH in this group with expertise in cardiology, respiratory condition with appropriate therapy, sup- is sarcoidosis. medicine, imaging and connective tissue plemental oxygen and respiratory support diseases is recommended. Given the com- is the key to management. Typically, Presentation plexity of managing patients with PH, patients do not benefit from targeted drug Clinical features of PH are nonspecific and referral to a clinic with expert medical, treatment. include dyspnoea, fatigue, generalised nursing, pharmacological and psycholog- weakness and, in later stages, chest pain, ical support is also recommended. Group 4. Chronic thromboembolic PH syncope and evidence of right heart failure. A diagnostic algorithm that highlights Chronic thromboembolic PH is thought to Given the nonspecific nature of these symp- the complexities involved in accurate diag- occur secondary to vascular remodelling of toms and the broad differential diagnosis, nosis of PH and the need for early referral

4 RespiratoryMedicineToday UNEXPLAINED BREATHLESSNESS? Is it Pulmonary Arterial Hypertension?1

ACT EARLY before more damage is done2

References: 1. Galie N, et al. European Heart Journal. 2016; 37: (4): 67-119. 2. Lau EMT, et al. Eur Heart J. 2011; 32: 2489-2498. Actelion, a business unit of Janssen-Cilag Pty Ltd. ACN 000 129 975. 1-5 Khartoum Rd Macquarie Park NSW 2113, Australia. Telephone: 1800 226 334 www.janssen.com/australia Date of Prep: June 2019 CP-99204. ACTE 6977MTR BBK06/19

ACTE 6977 Respiratory Feature Medicine Today Journal Ad.indd 1 27/6/19 11:31 am FEATURE PULMONARY HYPERTENSION CONTINUED

2. Case history: a middle-aged woman with progressive dyspnoea

Case history Case history continued Amy is a 46-year-old executive assistant with progressively worsening During winter, Amy develops a flu-like illness and has a presyncopal dyspnoea on exertion. She used to enjoy sport and was always active. episode. Her GP records an ECG, which is abnormal, and refers her However, in the past few years, her breathlessness has worsened, to a cardiologist for further investigation. An echocardiogram shows and she has stopped playing sport and gained 10 kg in weight elevated pulmonary artery pressures. Amy is referred to a tertiary (body mass index, 32 kg/m2). She was diagnosed with asthma in her hospital PH clinic where she undergoes right-heart catheterisation early 20s and takes regular budesonide-formoterol and as-required and is diagnosed with PAH (Group 1 PH). salbutamol. Initially she found the inhalers of benefit but now she She begins targeted therapy with a phosphodiesterase type 5 struggles to walk up the stairs at work. Her symptoms are attributed inhibitor and an endothelin receptor antagonist. Her symptoms to lack of fitness, obesity and asthma. and pulmonary artery pressures improve dramatically. She is followed up every six months, and her condition remains stable for Learning points several years. • Pulmonary arterial hypertension (PAH) is rare, with an estimated prevalence of 15 cases per million. Historically, it was reported Learning points to affect women aged in their mid-30s. Current registries show a • An intercurrent illness such as a respiratory infection, pulmonary female predominance but a mean age at diagnosis of 50 to embolism, ischaemic heart disease or comorbid heart failure can 65 years.3 exacerbate underlying PH and trigger acute decompensation. • Despite improvements in disease awareness, a long delay • Presyncope and syncope represent impaired cardiac reserve and between onset of symptoms and diagnosis remains a barrier to indicate severe disease. initiating treatment. Registry data show delays in diagnosis of over • Simple investigations may show abnormalities that alert the 2 years, with 75% of patients presenting with severe symptoms.4 clinician to the possibility of PH. For example, chest radiography • A high index of suspicion for pulmonary hypertension (PH) is may show enlargement of the central pulmonary arteries, and an required as the typical presenting symptoms of dyspnoea, fatigue ECG may show right axis deviation, right ventricular hypertrophy and exercise intolerance are nonspecific. PH should be suspected or right ventricular strain. However, many patients do not have especially if the patient fails to respond to therapy for more clearcut signs on examination or screening investigations. common causes of breathlessness. • Targeted therapy to reduce pulmonary vascular resistance can • Symptoms, exercise endurance and haemodynamics are result in significant clinical and physiological improvement in important prognostic indicators in patients with PAH. Hence, many patients with PAH. identification of the condition at an early stage is crucial to improving patient outcomes. and multidisciplinary team involvement detected by echocardiography. capillary wedge pressure are essential in is shown in the Flowchart.5 In most cases, transthoracic echocardi evaluation of left heart causes of elevated ography is performed on the basis of clinical pulmonary artery pressure. In addition, Transthoracic echocardiography suspicion of PH. However, transthoracic vasoreactivity challenge testing with a Patients with suspected PH are recom- echocardiography screening for PH is short-acting pulmonary vasodilator (e.g. mended to undergo transthoracic echo recommended for asymptomatic patients inhaled nitric oxide) can identify a small cardiography. If tricuspid regurgitation is in the following risk groups: subset of patients with PAH who have present then the systolic pulmonary artery • patients with systemic sclerosis significant vasoreactivity and are best pressure can be estimated. Isolated or • first-degree relatives of patients managed with high-dose calcium channel severe dilation of the right ventricle or diagnosed with hereditary PAH blockers. atrium may be a clue to PH if systolic • patients with portal hypertension pulmonary artery pressure cannot be who are candidates for liver Management estimated. GPs can help the supervising transplantation. Targeted drug treatments are available for cardiologist by stating in the referral that patients with PAH and some cases of PH is suspected. If possible, patients Right-heart catheterisation chronic thromboembolic PH. The man- should be referred to an echocardiography Right-heart catheterisation is needed for a agement of patients with other types of service with experience investigating definitive diagnosis of PAH and clarification PH is discussed above (see specific PH suspected PH. Stress echocardiography of the prognosis, as well as to quantify pul- groups). may provide additional information. How- monary artery pressure. Accurate measure- The targeted treatments comprise ever, occasionally PH is present and not ment of cardiac output and pulmonary pulmonary vasodilators that target the

6 RespiratoryMedicineToday endothelin, nitric oxide or prostacyclin pathways, which are involved in pulmonary A suggested algorithm for the diagnostic work-up of patients 5 vasoconstriction and dilation (Figure).5 with pulmonary hypertension * These treatments fall into four major Patient presents with symptoms, signs or history suggesting PH classes: • phosphodiesterase type 5 inhibitors (e.g. sildenafil and tadalafil) – PAH Transthoracic echocardiography to assess the probability of PH • soluble guanylate cyclase stimulators (e.g. riociguat) – PAH and Group 4 PH • endothelin receptor antagonists High probability of PH Low probability of PH (e.g. bosentan, macitentan and ambrisentan) – PAH • prostacyclins and prostacyclin Assess for left heart disease and lung disease: Consider other causes analogues (e.g. epoprostenol, iloprost • clinical features of symptoms • ECG and selexipag [the last is not PBS listed]) • lung function testing – PAH. • chest x-ray In addition, calcium channel blockers • CT of chest may be useful in the small proportion of • arterial blood gas test patients with PAH who show an acute vasodilator response on vasoreactivity challenge testing. Is a diagnosis of left heart disease or lung disease confirmed? Most patients with PAH are managed with combination therapy, particularly if they have moderate or severe disease. Combination therapy is ideally instituted Yes No upfront or in a rapid stepwise fashion. The complexities of these medications and Are there signs of severe PH or Refer to PH specialist centre their interactions and side effects mean right ventricular dysfunction? that patients are best managed through designated PH prescribing centres. Is pulmonary embolism confirmed on VQ scan or CT pulmonary angiogram? When and where to refer patients Yes No with PH PH is rare and may coexist with more com- Refer to PH Treat underlying Yes No mon causes of breathlessness (see the case specialist centre disease history in Box 3). If there is evidence sup- porting the presence of a common cause Assess for possible CTEPH with: Perform right-heart of breathlessness then it is reasonable to • right-heart catheterisation +/- catheterisation treat this. A patient’s failure to respond • pulmonary angiography rapidly as expected to treatment should raise a red flag for the clinician, indicating Is mPAP >25 mmHg + PAWP <15 mmHg a need for referral. If PH is suspected then + PVR >3 Wood units? prompt referral to a specialist with an inter- Abbreviations: est in PH is crucial (see the case history in CTEPH = chronic thromboembolic Box 4). pulmonary hypertension; Yes No Local expertise often determines the mPAP = mean pulmonary artery pressure; PAH = pulmonary arterial hypertension; referral pathway. Both cardiologists and PAWP = pulmonary artery wedge pressure; PAH is likely: Consider other PH = pulmonary hypertension; respiratory physicians, along with some • specific diagnostic tests causes of rheumatologists, have expertise in the PVR = pulmonary vascular resistance; VQ = ventilation-perfusion. to determine cause symptoms assessment and management of patients * Reproduced from Moonen A, et al. (e.g. autoimmune and with PH. A small number of designated Cardiology Today 2018; 8(2): 64-73.5 HIV serology) centres are approved to prescribe PH

RespiratoryMedicineToday 7 FEATURE PULMONARY HYPERTENSION CONTINUED

Figure. Molecular mechanisms of action of drugs used to treat pulmonary arterial hypertension (PAH). The key targets of PAH therapy are the Endothelin pathway Nitric oxide pathway Prostacyclin pathway endothelin, nitric oxide and prostacyclin pathways. In PAH, there is upregulation of vasoconstricting endothelin-1 and L-arginine Pro-endothelin-1 Arachidonic acid decreased production of vasodilatory nitric oxide and prostacyclin. The Endothelin-1 Nitric oxide Prostacyclin endothelin pathway can be blocked by Vasoconstriction & proliferation (Vasodilation & anti-proliferation) (Vasodilation & anti-proliferation) selective or nonselective endothelin-1 receptor antagonists (ERA). The nitric ET IP receptor ET B oxide pathway can be enhanced by A sGC PDE-5 Sildenafil stimulator inhibitors Tadalafil stimulation of soluble guanylate cyclase (sGC) or inhibition of phosphodiesterase Riociguat cAMP + - type-5 (PDE-5). The prostacyclin pathway - - sGC PDE5 - + + can be enhanced by prostanoid Selective GTP cGMP GMP Prostanoid Non-prostanoid Dual ERA analogues or non -prostanoid IP receptor ERA analogues IP receptor Epoprostenol agonist agonists.* Ambrisentan Bosentan Macitentan Treprostinol Selexipag Abbreviations: cAMP = cyclic adenosine Iloprost monophosphate; cGMP = cyclic guanosine monophosphate; GTP = guanosine triphosphate. * Reproduced from Moonen A, et al. Cardiology Today 2018; 8(2): 64-73.5

3. Case history: a man with dyspnoea and underlying cardiopulmonary disease

Case history Case history continued Richard, aged 68 years, has been attending a cardiology clinic Richard’s breathlessness progresses and he presents to the annually since a myocardial infarction treated with a coronary stent emergency department with clinical signs of right heart failure. six years earlier. He reports gradually worsening dyspnoea on He is admitted and an echocardiogram reveals severe pulmonary exertion over several months to years and now struggles to walk hypertension with right ventricular dilatation. Right-heart around the block. He denies anginal symptoms or other chest pain, catheterisation confirms the diagnosis of elevated pulmonary cough, sputum production, paroxysmal nocturnal dyspnoea, artery pressure and elevated pulmonary vascular resistance, with orthopnoea or wheeze. a normal pulmonary capillary wedge pressure. These features Richard is an ex-smoker with a 30 pack-year history. He has a confirm a diagnosis of predominantly Group 1 PH – pulmonary past diagnosis of mild-to-moderate chronic obstructive pulmonary arterial hypertension (PAH) – with a potential past contribution disease (COPD), which has been stable for many years on from Group 2 and Group 3 PH. tiotropium treatment. He has never seen a respiratory physician. Richard is commenced on a phosphodiesterase type 5 inhibitor He takes aspirin, rosuvastatin and telmisartan. His most recent and an endothelin receptor antagonist. His symptoms decrease echocardiogram was several years ago and showed a mildly and a repeat echocardiogram shows improvement in right reduced left ventricular ejection fraction of 50%. There was no ventricular size and function. His results on the 6-minute walk test comment on right heart function or pulmonary pressure. His also improve. symptoms are attributed to deconditioning and underlying Learning points COPD. • Patients with risk factors for Group 2 and Group 3 PH can still Learning points have PAH if their pulmonary artery pressures are out of proportion • Although Richard has underlying cardiopulmonary disease, his to the severity of their cardiorespiratory disease and where new symptoms are out of proportion to the extent of disease and significant left heart disease is excluded during right-heart do not appear to be related either to an exacerbation of COPD or catheterisation. to worsening ischaemic heart disease. Decline in patients with • Even patients with severe COPD typically develop only mild-to- otherwise stable cardiopulmonary conditions should alert the moderate PH. clinician to an alternative aetiology. • Some patients with underlying cardiopulmonary disease • Cardiologists and respiratory physicians not regularly treating and PAH may benefit from treatment with pulmonary vasodilator patients with pulmonary hypertension (PH) may not specifically therapy in combination with optimisation of their underlying look for this condition if there is no pre-existing clinical history. diseases. They should be managed in centres with experience Absence of PH reported in an echocardiogram does not exclude in PH, preferably in the context of a well-conducted clinical the condition. trial.

8 RespiratoryMedicineToday 4. Case history: a woman with hypertension and previous pulmonary embolism

Case history Case history continued Margaret, aged 64 years, presents to her GP with dyspnoea and Margaret’s GP refers her for a CT pulmonary angiogram, which shows lower limb swelling. She has a past history of hypertension and chronic thrombus in the left main pulmonary artery and radiological had a large, unprovoked pulmonary embolism five years ago. evidence of pulmonary hypertension (PH). The GP refers her to a She was treated with warfarin for 18 months but then moved respiratory physician, who refers her on to a tertiary hospital PH interstate and was lost to follow up. She is no longer taking clinic. Right-heart catheterisation and selective digital subtraction anticoagulation treatment. The dyspnoea has worsened gradually pulmonary angiography confirm severe PH secondary to CTEPH. over several months, and she reports atypical chest pain when Margaret undergoes surgical pulmonary endarterectomy. Her climbing stairs. symptoms and pulmonary artery pressures improve dramatically.

Learning points Learning points • Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare • Some patients with CTEPH may obtain complete cure with complication of pulmonary embolism with an incidence of 0.5 to surgical management by pulmonary endarterectomy. Increasingly, 4% after acute symptomatic pulmonary embolism. balloon pulmonary angioplasty is being used in cases where • CTEPH should be considered in patients who present with surgery is not feasible. persistent dyspnoea after a pulmonary embolism, even those who • Early diagnosis is again important in identifying patients who may appear to have had adequate treatment for the embolism. benefit from surgery and in instituting treatment at an early, • Currently, there is no recommendation to screen all patients after potentially curable stage. a pulmonary embolism with CT pulmonary angiography or • Although CT pulmonary angiography often show features of ventilation-perfusion scanning because of the low incidence of CTEPH, ventilation-perfusion nuclear lung scanning is regarded as CTEPH. However, the failure to make a full functional recovery the best diagnostic test. Any persistent mismatched perfusion should prompt further evaluation. defect warrants further evaluation. Some patients can have • CTEPH affects the sexes equally, with a median age at diagnosis persistent ventilation-perfusion inequality but have normal of 63 years. pulmonary pressures at rest when tested. This is referred to as • As with pulmonary arterial hypertension, there is typically a long chronic thromboembolic disease and can contribute to dyspnoea delay between onset of symptoms and diagnosis, with high rates with activity. These patients should be monitored for the of misdiagnosis. development of PH. • Patients not suitable for pulmonary endarterectomy can be managed with targeted medical therapies. They require lifelong anticoagulation. • Patients with CTEPH should be assessed and managed at dedicated CTEPH centres.

medications. Expedited referral to one of delayed diagnosis of PH remains common. of Cardiology (ESC) and the European Respiratory these centres should facilitate final inves- Diagnosis and management of patients Society (ERS). Eur Respir J 2015; 46: 903-975. tigation, diagnosis and treatment with with PH is complex and best undertaken 3. Hoeper MM, Simon R, Gibbs J. The changing landscape of pulmonary arterial hypertension and appropriate medications. This maximises in de signated PH clinics. RMT implications for patient care. Eur Respir Rev 2014; the therapeutic benefits and can provide 23: 450-457. informed supportive care to patients and References 1. Galiè N, McLaughlin VV, Rubin LJ, Simonneau G. 4. Farber HW, Miller DP, Poms AD, et al. Five-year their carers. An overview of the 6th World Symposium on outcomes of patients enrolled in the REVEAL Pulmonary Hypertension. Eur Respir J 2019; 53: Registry. Chest 2015; 148: 1043-1054. Conclusion 1802148. 5. Moonen A, Thakkar V, Cordina R, Lau E. With advances in management, PH has 2. Galiè N, Humbert M, Vachiery JL, et al. 2015 Pulmonary hypertension. What you need to know. evolved into a treatable disease with ESC/ERS Guidelines for the diagnosis and Cardiology Today 2018; 8(2): 64-73. improved survival. Early diagnosis and treatment of pulmonary hypertension: The Joint treatment are key to improving functional Task Force for the Diagnosis and Treatment of COMPETING INTERESTS: Dr Michail has received and haemodynamic outcomes. However, Pulmonary Hypertension of the European Society honoraria from Actelion. Dr Srinivasan: None.

RespiratoryMedicineToday 9 UNEXPLAINED BREATHLESSNESS? Is it Pulmonary Arterial Hypertension?1

ACT EARLY before more damage is done2

This reprint is provided as an educational service by Actelion, a Business Unit of Janssen-Cilag Pty Ltd. The opinions expressed in this reprint are those of the authors and not necessarily those of Actelion, a Business Unit of Janssen-Cilag Pty Ltd or the publisher. Some products and/or indications mentioned may not be approved for use in Australia. Please review Product Information, available from the manufacturer, before prescribing any agent mentioned in this reprint.

The sponsorship of this reprint does not imply approval or otherwise of any of the sponsor’s products by the authors or publisher. References: 1. Galie N, et al. European Heart Journal. 2016; 37: (4): 67-119. 2. Lau EMT, et al. Eur Heart J. 2011; 32: 2489-2498. Actelion, a business unit of Janssen-Cilag Pty Ltd. ACN 000 129 975. 1-5 Khartoum Rd Macquarie Park NSW 2113, Australia. Telephone: 1800 226 334 www.janssen.com/australia Date of Prep: June 2019 CP-99204. ACTE 6977MTR BBK06/19

ACTE 6977 Respiratory Feature Medicine Today Journal Ad.indd 1 27/6/19 11:31 am UNEXPLAINED BREATHLESSNESS? Is it Pulmonary Arterial Hypertension?1

ACT EARLY before more damage is done2

ACTE 6977 Respiratory Feature Medicine Today Journal Ad.indd 1 27/6/19 11:31 am Respiratory Medicine PEER REVIEWED UPDATES FOR MEDICAL PRACTITIONERS Today