Pulmonary hypertension: A different kind of pressure

More than 25 million people who suffer from a disease that is not easy to diagnose and can be fatal - pulmonary hypertension - commemorated World Pulmonary Hypertension Day last Sunday.

Many are familiar with the disease called hypertension (high blood pressure), which is an elevated blood pressure measured by a cuff around the arm. This reflects the systemic pressure throughout the body that is generated when the left ventricle of the heart contracts.

A less commonly known condition is called pulmonary hypertension (PH), which is high blood pressure that occurs in the arteries of the lungs.

In PH, the blood vessels in the lungs constrict and become narrowed due to cellular proliferation, remodeling and obstruction of smaller pulmonary blood vessels. They become structurally and functionally abnormal. This makes it harder for the right ventricle of the heart to pump blood through the lungs to reach the left side of the heart and to the rest of the body.

This increases stress to the right ventricle, resulting in its enlargement and subsequent weakening, eventually leading to right heart failure.

When this happens, not enough oxygen gets delivered to the rest of the body, resulting in symptoms and eventually premature death from progressive right heart failure or an abnormal heart rhythm.

For diagnosis to be proven, people need to undergo an invasive procedure called right heart catheterisation (RHC).

By definition, PH exists when the mean pulmonary artery pressure (PAP) is more than 25 mmHg in the presence of a normal pulmonary capillary wedge pressure (PCWP) of less than 15 mmHg.

The RHC is usually performed in specialised cardiac catheterisation laboratories by cardiologists in Malaysia.

How common is PH and who gets it?

Although PH is an uncommon condition, it is widely accepted that it's under-diagnosed. The occurrence of the disease in the general community has been estimated to be anywhere between 30 and 50 cases per million population.

There is no data for Malaysia at the moment.

In childhood, the condition affects both genders, but after puberty, it is more common in females (approximately two to one ratio).

There is a heritable form of PH and 70 per cent of these individuals have a mutation in the gene for Bone Morphogenetic Protein Receptor II (BMPR II). This condition is inherited and people with this mutation have a 10-20 per cent chance of developing PH.

PH is also common amongst people with connective tissue diseases such as scleroderma spectrum of disease (up to 27 per cent), systemic lupus erythematosus (up to 14 per cent) and rheumatoid arthritis (up to 20 per cent).

Uncorrected congenital "hole in the heart" diseases with large shunts such as atrial septal defects, ventricular septal defects and patent ductus arteriosus can also act as trigger factors.

Users of appetite suppressants such as aminorex, fenfluramine phentermine (Fen-Phen) and dexfenfluramine phentermine (Dex-Phen) for longer than three months have a 23-fold higher risk of developing PH, hence the reason why these drugs are now banned.

Other causes include blood disorders such as sickle cell disease, obstructive sleep apnoea, survivors of deep vein thrombosis and pulmonary embolism, advanced chronic obstructive airways disease and even HIV infection.

It is very important to screen patients with these conditions for PH as early detection and treatment may provide significant benefits.

Classification of PH

PH was first described by Dr Ernst Von Romberg in 1891. It is a broad name for a group which currently consists of five distinct types of chronic disease that affects the heart and lungs:

Group 1: Pulmonary Arterial Hypertension (including idiopathic, heritable, drugs/toxin induced, congenital heart disease, HIV, connective tissue disease)

Group 2 : PH associated with left heart disease

Group 3 : PH associated with respiratory disease

Group 4 : PH due to chronic thromboembolic disease

Group 5 : PH due to miscellaneous cause

Individuals with PH can experience a range of symptoms depending on the severity and underlying cause of their disease. In general, the most common symptoms are:



·Dizziness and sometimes syncope on activity and when standing up

·Sensation of racing heart beat (palpitations )

·Chest pain, particularly on activity


·Swollen legs and ankle

Early symptoms of PH are often subtle and common to other conditions such as asthma, chronic pulmonary disease and even systemic hypertension and are frequently overlooked. Diagnosis is made when other causes have been excluded first.

Often, this results in delayed diagnosis and treatment. The right heart continues to fail and this leads to worsening symptoms such as increasing fatigue, abdominal distension due to ascites, enlarged and tender liver, ankle swelling, coughing up blood stained sputum, having to sleep in a propped up position with several pillows (orthopnoea) and bluish lips and nails (cyanosis).

How is PH diagnosed?

A high index of suspicion is important as the symptoms are common to many other diseases affecting the heart and lungs. It begins with a thorough medical and family history evaluation with physical examination.

Blood tests, ECG, chest x ray, lung function test, lung ventilation/perfusion scanning and 2D echocardiogram are also useful.

The "gold standard" in confirming the diagnosis is RHC, where a small plastic tube is advanced into the right side of the heart and pulmonary vessels to measure pressures and oxygen saturations. This small tube or catheter is introduced from a vein in the neck or groin under local anaesthetic. This procedure is carried out in the cardiac catheterisation laboratory.

Treatment of pulmonary arterial hypertension

A sub group of PH is called pulmonary arterial hypertension (PAH). Though there are a number of causes of PAH, a significant number of patients suffer from PAH without any known cause. This was previously called primary pulmonary hypertension but is now referred to as idiopathic pulmonary arterial hypertension.

In the 1980s, there was no specific medical treatment for PAH. The average survival after diagnosis was two years and 10 months, and the only therapy that could be resorted to when patients deteriorated was a heart and lung transplant.

Since 1996, a number of drugs have been studied that improve blood flow to the lungs in patients with pulmonary hypertension, and appear to relieve their symptoms and improve their survival. These drugs are referred to as pulmonary vasodilators.

Before the advent of these drugs, the physician was limited to general measures and conventional medications, which are still applicable in the treatment of patients.

Physicians need to strike a balance between encouraging low levels of exercise and prohibiting excessive physical exertion, which may exceed the capacity of the limited function of the heart and lungs.

Oxygen can be administered to those who develop low oxygen levels in their blood as a result of their disease. Respiratory infections can be prevented to some extent by the use of flu and pneumococcal vaccines. However, if patients develop infections, these should be promptly treated.

Female patients with child bearing potential should avoid pregnancy. The increase demand on the heart and lungs in pregnancy is often not tolerated and can result in death in up to 50 per cent of PAH patients. Hence safe and effective contraception in women who can become pregnant is mandatory.

Medications that may be helpful include:

1. Warfarin - for prevention of blood clots from developing in the lungs. This can be prescribed in patients if their risk of bleeding (a side effect of the medication) is low.

2. Diuretics (frusemide, spironolactone) - this is useful to remove fluid accumulation in patients who have developed heart failure.

3. Digoxin - this medication is useful for heart failure, or to control fast and irregular heart rate.

Calcium antagonists are a group of drugs used to treat systemic hypertension, and has been used to treat patients with PAH. A small proportion of patients with PAH do respond to calcium antagonist. These drugs can dilate the pulmonary vessels in susceptible patients.

However, the identification of such responsive patients is from the cardiac catheterisation and the performance of a vasodilator challenge test. If the test is negative, then the use of this group of drugs is generally ineffective and disappointing.

In 1996, a study was published reporting on the use of a continuous intravenous infusion of a drug called epoprostenolol (currently not registered in Malaysia). It showed that patients who received it had a longer life span than those who were on conventional medications.

Many studies followed, and currently there are five drugs which are available to treat PAH in Malaysia. These are bosentan and ambrisentan (belonging to a group called endothelin antagonist), iloprost (a prostaglandin type of drug, similar to epoprostenol), and sildenafil and tadalafil (drugs approved for treating erectile dysfunction, but found to be useful for PAH as well).

These drugs are expensive (monthly cost of between RM3,000 (S$1,240) to RM10,000) and it is almost impossible for patients with PAH to be able to afford them, especially on a long term basis.

Most patients will require government assistance or subsidy to be treated with these medications. Some patients have good response to one of these pulmonary vasodilators, but often after several years, the patients become unwell again as the disease progresses, and a second pulmonary vasodilator drug may need to be added.

A registry of patients with PAH from the US revealed that the average survival has improved to more than seven years with modern therapies, including pulmonary vasodilators.

Ultimately, if the patient has poor response, then a lung or heart-lung transplant may need to be considered provided that the patients are suitable for this procedure, and there is a suitable donor.