Introduction

Pulmonary arterial hypertension (PAH) is a collective term for a group of conditions characterized by progressive elevation of the mean pulmonary arterial pressure (mPAP) to more than 25mmHg at rest or more than 30mmHg on exercise. PAH represents one subgroup of a larger group of conditions known as pulmonary hypertension. The different types of pulmonary arterial hypertension are united by histological similarities and a raised pulmonary vascular resistance (PVR). PAH is a rare disease, with an incidence of 2.5-7.1 cases/million. However, patients who have PAH have a poor life expectancy with a five-year survival rate of around 77%. PAH can cause complications including cor pulmonale and arrhythmias. It is typically managed by supportive therapies for symptom control and medical therapies such as calcium channel blockers, endothelin receptor antagonists, phosphodiesterase type 5 inhibitors and prostaglandin analogues.

Classification

As stated above, PAH is a subgroup of PH, specifically PH Class I as defined by the WHO. The classes of PH are:
  • Class I: Pulmonary arterial hypertension
  • Class II: Pulmonary hypertension owing to left heart disease
  • Class III: Pulmonary hypertension secondary to Chronic Obstructive Pulmonary Disease (COPD)
  • Class IV: Pulmonary hypertension owing to chronic thromboemboli
  • Class V: Pulmonary hypertension owing to multiple miscellaneous causes

Following a symposium in 2008, PAH is subdivided into its own five categories:
  • 1.1 - Idiopathic PAH
  • 1.2 - Hereditary PAH
  • 1.3 - PAH associated with other conditions (including connective tissue disorders, associated HIV infection, cirrhosis with portal hypertension congenital heart disease, schistosomiasis and chronic haemolytic anaemia)
  • 1.4 - PAH associated with venous or capillary conditions (including pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis)
  • 1.5 PAH of the newborn

Alongside this aetiological classification, PAH can be classified according to the patient's functional capacity (New York Heart Association/WHO classification)
  • I - No limitations during day-to-day physical activity
  • II - Mild limitations during day-to-day physical activity
  • III - Marked limitation during day-to-day physical activity
  • IV - Unable to perform day-to-day physical activity and also may have symptoms at rest.

Epidemiology

  • Incidence: 0.40 cases per 100,000 person-years
  • Peak incidence: 40-50 years
  • Sex ratio: 1:1
Condition Relative
incidence
Chronic heart failure500.00
Angina pectoris375.00
Pulmonary embolism175.00
Pulmonary arterial hypertension1
<1 1-5 6+ 16+ 30+ 40+ 50+ 60+ 70+ 80+

Aetiology

The most common mutation in patients with hereditary PAH is thought to be in the BMPR2 gene. BMPR2 is an important protein that prevents the proliferation of endothelial cells of the pulmonary arteries. When this is inactivated, it can result in over-proliferation of the endothelial cells, resulting in pulmonary arterial hypertension. However, only around 20% of those with a mutated BMPR2 gene develop PAH, leading researchers to believe there are other environmental and genetic factors implicated in the development of PAH.

Multiple other conditions can result in PAH, including:
  • Scleroderma, an autoimmune condition that results in increased collagen deposition within the skin and blood vessels. In the lungs, this leads to fibrosis of the pulmonary arteries, causing PAH.
  • HIV infection promotes chronic activation of the immune system and release of proinflammatory cytokines and growth factors. This triggers proliferation of the endothelium of the pulmonary arteries, resulting in PAH.
  • Persistent pulmonary hypertension of the newborn is a rare condition occurring in around 2/1000 live births, particularly affecting difficult births. The foetal circulation is characterised by a high pulmonary vascular resistance and a low systemic vascular resistance. Failure to switch from foetal to adult circulation following birth can result in sustained increased pulmonary vascular resistance, ultimately resulting in PAH.

Pathophysiology

In PAH, there is disruption in three major signalling pathways:
  • Nitric oxide pathway
  • Prostacyclin pathway
  • Endothelin pathway

The nitric oxide and prostacyclin pathways are disrupted reducing in impaired pulmonary arterial vasodilations. There is concurrent increase in the endothelin pathway which results in increased vasoconstriction.

These changes result in increased contractility of the arteries, dysfunction of the endothelium, over-proliferation of the endothelial cells and the vascular smooth muscle cells, and an increased thrombotic risk.

The increased contractility and dysfunction of the endothelium particularly affect the small arteries, which results in increased pulmonary vascular resistance and pulmonary arterial pressure.

Clinical features

Initially, patients with PAH present with problems related to right ventricular dysfunction leading to reduced organ perfusion. These symptoms particularly present on exertion when there is higher demand placed on the heart. Symptoms include:
  • Dyspnoea (presenting complaint in 60% of cases)
  • Fatigue
  • Weakness
  • Angina
  • Syncope
  • Cough, sometimes with haemoptysis
  • Hypotension
  • Hoarseness
    • Related to compression of the left recurrent laryngeal nerve.

As the disease progresses, patients may have symptoms during periods of rest. In advanced cases, patients may get abdominal distention and peripheral oedema. The symptoms closely resemble those of heart failure and it can be difficult to differentiate between the two.

Physical signs of PAH include:
  • Cyanosis
  • Left parasternal heave
  • Signs on auscultation of the heart including
    • Tricuspid regurgitation murmur (pansystolic)
    • Pulmonary regurgitation murmur (diastolic)
    • Accentuation of the pulmonary component of the second heart sound

When examining a patient with possible PAH, it is important to also look for any underlying signs of an aetiological cause, e.g. signs of scleroderma, interstitial lung disease or cirrhosis.

Investigations

Investigations that should be performed include:
  • Chest X-ray. May show central pulmonary arterial dilatation and in more severe cases enlargement of the right side of the heart. It may also help to differentiate between PAH and other causes of pulmonary hypertension such as due to left heart disease or lung disease.
  • ECG. In mild and moderate cases ECG is likely to be normal in PAH. In more severe cases, ECG may show abnormalities related to damage to the right side of the heart including:
    • Right axis deviation
    • Right bundle branch block
    • Right ventricular hypertrophy
    • QTc prolongation
  • Pulmonary function tests to look for causes of PH related to lung disease e.g. COPD.
  • Echocardiogram. Transthoracic echocardiogram (TTE) can be used to estimate the mPAP, based on analysis of the peak tricuspid regurgitation velocity (TRV), and look at the effects of PAH on the heart.
  • High-resolution CT scan or cardiac MRI can be used to assess the size, morphology, and function of the right ventricle and to look for clues as to the underlying cause.
  • 6-minute walking distance (6MWD) is used to assess the patient's symptoms and the severity of their disease.
  • B-type natriuretic peptide (BNP, also known as brain natriuretic peptide) if elevated can suggest a raised mPAP and pulmonary vascular resistance, which can signify PAH.
  • If after these investigations a diagnosis of PAH is suspected, right heart catheterization (RHC) is required to diagnose it. These should only be performed by experienced clinicians in expert centres. In RHC, pressure measurements are made in multiple locations including the pulmonary artery, right ventricle, and right atrium to determine the blood pressure within these structures.

Differential diagnosis

The differential diagnosis for PAH includes other causes of pulmonary hypertension, heart failure and lung diseases such as COPD.
  • Congestive heart failure presents with many similar symptoms to PAH, including dyspnoea, cough and peripheral oedema. It is difficult to analyze diastolic function on echocardiogram and so often patients with diastolic heart failure will be diagnosed with PAH. However, signs on echo such as left ventricular hypertrophy, delayed diastole and PAP <30 can help to differentiate heart failure from PH.
  • Other causes of pulmonary hypertension, for example, left heart failure, COPD and interstitial lung disease. RCH, evidence of the aetiological cause of disease on imaging, and pulmonary function testing can be used to help diagnose the cause of PH.
  • Cardiac conditions such as coronary artery disease and valvular disease can lead to poor functioning of the heart. These cardiac conditions can cause fluid to back up into the pulmonary venous system and can cause pulmonary venous hypertension. Investigations such as ECG and echo can be used to look for evidence of these cardiac diseases.
  • Pulmonary embolism can result in blockage of the pulmonary arteries and hence result in pulmonary hypertension. This can be investigated by performing a good history and examination and imaging including CT pulmonary angiograms or ventilation-perfusion scanning

Management

PAH is a complicated, rare syndrome and will typically be managed by a specialist. The main aims of treatment for PAH are to improve the patient's quality of life and prolong their survival.

The patients should also be offered supportive therapy for symptom management. Supportive therapies include:
  • Diuretic treatment. Used in patients with fluid retention and oedema (choice of diuretic should be left to the physician and patient).
  • Oral anticoagulants. There is a higher risk of thrombotic events taking place in patients with PAH, due to both pathophysiological mechanisms of coagulation linked to PAH and increased likelihood of immobility compared to the general population. Anticoagulant therapy is recommended for all patients with idiopathic PAH and for patients with advanced PAH due to other conditions.
  • Long term oxygen therapy. This is recommended in patients who have an arterial blood oxygen pressure that is consistently less than 8kPa. There is no clear evidence for the use of long term oxygen therapy in patients with PAH with a higher arterial blood oxygen pressure.
  • Treatment of other conditions that arise secondary to PAH including anaemia and atrial tachyarrhythmias.

There are some measures that can be used prognostically to lower pulmonary blood pressure and help to slow the disease course. Initially, patients should be treated with calcium channel blockers (such as nifedipine, diltiazem, and amlodipine) if they have a positive response to acute vasoreactivity testing (where patients are administered a small dose of a short-acting vasodilator and have a decrease in mPAP of at least 10mmHg). Only a small minority of patients have a response to vasoreactivity testing and can be administered calcium channel blockers. If after 3-4 months of therapy, then additional therapy should be initiated. Calcium-channel blockers prevent the opening of calcium channels in the cells, reducing the influx of calcium and thereby reducing vasoconstriction and causing vasodilation.

Alternative options for therapy include:
  • Endothelin receptor antagonists such as ambrisentan, bosentan or macitentan. These drugs work by blocking the action of endothelin on endothelin receptors, preventing vasoconstriction
  • Phosphodiesterase type 5 (PDE5) inhibitors such as sildenafil, tadalafil or vardenafil. These drugs work by blocking the action of PDE5 on cyclic GMP in the smooth muscle cells of the arterioles in the lungs, reducing pulmonary blood pressure.
  • Prostacyclin analogues such as epoprostenol, iloprost or treprostinil. They elicit the same effect as prostacyclin, which is a potent vasodilator and is also involved in platelet plug formation.

Other therapies, such as balloon atrial septostomy (creation of an inter-atrial right-to-left shunt) and lung transplantation should be considered in the most severe cases, particularly patients who fail on medical therapies and remain in NYHC Class III-IV.

Complications

Cor pulmonale is a notable complication that can arise from PAH. Pulmonary hypertension can lead to overflow of the pulmonary arteries back into the right ventricle, ultimately leaving to right ventricular hypertrophy and right heart failure. This is called cor pulmonale. Patients with cor pulmonale may present with :
  • Peripheral oedema
  • Raised jugular venous pressure (JVP)
  • Hepatomegaly
  • Parasternal heave.

Arrhythmias are a common complication of PAH, particularly atrial flutter and atrial fibrillation. They can both result in worsening of symptoms, deterioration of right ventricular function, and a high mortality rate.

Haemoptysis is also a common complication of PAH, particularly in hereditary PAH and in PAH associated with congenital heart disease. It is associated with a high mortality rate and may need emergency treatment.

Dilatation of the pulmonary arteries may also result in complications including
  • Aneurysms
  • Dissection
  • Compression of other structures within the mediastinum for example:
    • Bronchi
    • Recurrent laryngeal nerves.

Prognosis

PAH is a serious condition that significantly impacts life expectancy. An article published by the Taiwan Society of Cardiology in 2017 suggested that the 5-year survival rate was around 77%. Factors that suggest a poor prognosis include:
  • Deterioration in WHO/NYHC functional class
  • Increased serum uric acid level
  • Low 6 minute walking distance at initial assessment