The landscape of pulmonary hypertension medicine has changed greatly over the past quarter of a century and our understanding of this disease has increased greatly. In the 1980s the National Institute of Health (NIH) in the US developed a registry to capture epidemiological data in order to enhance the understanding of this rare disease.¹ Patients with pulmonary hypertension (PH) of unknown cause were classified as ‘primary’ PH with all other forms considered ‘secondary’. This registry identified the typical primary PH patient as a young female with a median survival of less than three years from the time of diagnosis.^1,2 There were no treatments available apart from a very small group of calcium channel blocker responders;³ aside from these, lung transplantation was the only option.  

Progress in the field

During the 1990s a major advance was made with the approval of prostacyclin therapy.⁴ Epoprostanol, a synthetic form of prostacyclin, is a potent pulmonary artery vasodilator with anti-proliferative and anti-platelet properties. The half-life of epoprostanol is a matter of seconds thereby requiring continuous infusion. Administration is therefore cumbersome, with many side-effects and potential complications from indwelling catheters. Nevertheless, it was the first truly effective drug and resulted in improved survival and thus opened the door to what has been a very productive period of research and drug development in the interim.⁴ Since the approval of epoprostanol in the mid 1990s we have enhanced our understanding of the pathophysiology of this disease, discovered the genetic pathways responsible for a considerable subset of patients, BMPR2 mutations,^5,6 altered the classification system to a more clinically useful one⁷ and developed a number of oral drugs, which have improved quality and duration of life. Nevertheless, despite this progress, it remains a lethal disease with many challenges at both a diagnostic and therapeutic level. 

Definition and classification

Pulmonary hypertension in its broadest definition refers to elevated mean pulmonary artery pressures of ≥ 25mmHg at rest, performed on right heart catheterisation.⁷ The terms primary and secondary PH are no longer used and in their place a more thorough and clinically applicable classification has evolved, comprising five distinct groupings with shared characteristics (see Table 1). What was once primary PH is now idiopathic pulmonary arterial hypertension (IPAH) and is grouped together with conditions that display similar features clinically and pathologically, such as connective tissue disease, congenital heart disease, HIV and liver disease associated PH (see Table 1). These conditions are classed as Group I pulmonary arterial hypertension (PAH) and all demonstrate similar features of arteriolar remodelling, with vessel wall hypertrophy and luminal compromise. This results in increasing strain on the right heart, ultimately leading to right heart failure. The therapies we now have at our disposal target these damaged pulmonary arteries with a view to reversing the remodelling effects and promoting vasodilation, thereby reducing the load on the right heart. 

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In Ireland we now have 10 approved therapies for PAH (Group I), which target three distinct molecular pathways:  

Prostacyclin therapies such as epoprostanol, treprostinil and iloprost, administered intravenously, subcutaneously and inhaled respectively. These all require a significant amount of education and training and have a predictable side-effect profile including headache, light-headedness, flushing and jaw pain

Very recently a new oral prostacyclin receptor agonist, selexipag, has been approved which will be easier to administer but perhaps less potent than parenteral prostanoid therapy⁸

There are three oral therapies, sildenafil, tadalafil and riociguat, which act on the nitric oxide pathway, either indirectly by inhibiting phosphodiesterase type 5 (PDE5i) or directly by stimulating soluble guanylate cyclase (sGC) a naturally occurring vasodilator. 

Finally we have a further three oral therapies, bosentan, ambrisentan and macitentan, which block endothelin receptors thereby antagonising the vasoconstrictive properties of naturally occurring endothelin. 

Utilising upfront combinations of oral therapies targeting different pathways is proving to be an effective strategy for the treatment of PAH⁹ with the addition of parenteral prostanoid therapy in more advanced disease. 

Pulmonary hypertension Groups II – V

Group II PH is caused by left heart disease, also termed pulmonary venous hypertension (PVH). This is the commonest form of pulmonary hypertension. The elevated pressures in the left heart transmit through the pulmonary circulation across to the right side. Systolic and diastolic heart failure and valvular heart disease are among the most frequent causes of pulmonary venous hypertension (see Table 1).

Treatment focuses on the left heart with management of systemic hypertension and pre-load reduction with diuretics.¹⁰ Group III PH comprises diseases of the lung such as chronic obstructive pulmonary disease (COPD) and pulmonary fibrosis, often in advanced stages with associated hypoxaemia. Lung damage and hypoxaemia can lead to pulmonary vasoconstriction and remodelling. The focus of treatment within this group is oxygen therapy and management of the underlying lung problem.¹⁰ The targeted therapies used for PAH have no role in Group II and III disease. Group IV comprises chronic thromboembolic pulmonary hypertension (CTEPH).¹¹ Whether a clot travels from the peripheral circulation or develops de novo in the lungs is not known, but it is perhaps a mix of both. Approximately 4% of large acute pulmonary emboli will go on to develop CTEPH. The clot burden leads to an elevation in pulmonary vascular resistance, right heart pressures and eventually right heart failure. A subset of these patients has the potential to be cured with a surgical procedure called pulmonary endarterectomy. Riociguat is the only oral therapy approved for the treatment of CTEPH and is typically reserved for those who are inoperable candidates.¹² Finally Group V comprises unclear multifactorial causes of PH which have no approved therapies.

Epidemiology

Updated registry data from France and the US describe the incidence of IPAH at around two to six per million.^13,14 However, up to 15% of systemic sclerosis patients and 5% of congenital heart disease patients will develop pulmonary hypertension.^15,16 The incidence of PAH is about 15 per million and, taking all causes together, the incidence is 97 per million. Mean age at diagnosis for IPAH is 55,¹⁷ much older than the 30 year old mean of ‘primary’ PH described in the NIH registry in the 1980s.¹⁸ This perhaps reflects an increasing awareness and diagnosis. 

Signs and symptoms

The principal symptom of PH is dyspnoea. Other symptoms include fatigue, weakness and angina. As the disease progresses patients may develop dizziness and syncope.  Given the rather non-specific nature of the symptoms the diagnosis is often delayed. The signs of pulmonary hypertension are those of right heart failure with jugular venous distension and pitting oedema of the lower limbs and sacrum. Palpation of the precordium may reveal a palpable P2 and right ventricular heave. Auscultation demonstrates a loud pulmonary component to the second heart sound and tricuspid regurgitation murmur. The lungs of patients with PH are typically clear unless they have Group II or III disease. 

Diagnosis

In order to diagnose PH one must first have a clinical suspicion coupled with the typical signs and symptoms outlined above. Some tests which aid diagnosis include an ECG demonstrating RV strain and P pulmonale and a chest x-ray demonstrating cardiomegaly with fullness at the level of the aortopulmonary window. There is no diagnostic blood test. The best serological marker is an elevated brain natriuretic peptide (BNP) in response to right ventricular strain; however this is neither sensitive nor specific for the diagnosis of PH and is better used as an aid to treatment and as a prognostic indicator.^19,20

The best screening tool is an echo which may demonstrate findings of right heart failure such as a dilated right ventricle and/or right atrium, flattening or paradoxical movement of the interventricular septum and elevated estimations of right heart pressures using Doppler techniques.²¹ However, the gold standard diagnostic test remains right heart catheterisation (RHC). Diagnosis is confirmed on RHC with an elevated mean pulmonary artery pressure of ≥ 25mmHg at rest combined with an elevation in pulmonary vascular resistance (> 3 wood units) and a normal wedge pressure (≤ 15mmhg), a surrogate for normal left atrial pressure.⁷ Patients with Group II pulmonary venous hypertension will typically have an elevated wedge pressure indicating the presence of left heart disease. 

The future

Despite the advances in our understanding of the pathophysiology and the development of a number of new medications in recent years, there remain many challenges in the management of pulmonary hypertension. The diagnosis is often delayed; however increasing awareness among the medical community will help with this. We know also that with earlier diagnosis and earlier introduction of targeted therapies patients have improved outcomes.^22,23 Patients are now living longer and this brings challenges in terms of resources, however, prognosis remains poor and medications are not curative, merely palliative, so a lot more needs to be done. 

Finally, there is a need to maintain the progress that has been made over the past two decades with continued research and development. A recent focus on developing genetic modifying therapies, which have proved so successful in cystic fibrosis, may bring exciting advances to the field of pulmonary hypertension in the not too distant future.²⁴

References

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