Article: Pulmonary hypertension

In medicine, pulmonary hypertension (PH) is an increase in blood pressure in the pulmonary artery or lung vasculature. Depending on the cause, it can be a severe disease with a markedly decreased exercise tolerance and right-sided heart failure. It was first identified by Dr Ernst von Romberg in 1891^[1]. It can be one of five different types, arterial, venous, hypoxic, thromboembolic, or miscellaneous.

Signs and symptoms

A history usually reveals gradual onset of shortness of breath, fatigue, non-productive cough, angina pectoris, syncope (fainting), peripheral edema, and rarely hemoptysis. Pulmonary arterial hypertension (PAH) typically does not present with orthopnea or paroxysmal nocturnal dyspnea, while pulmonary venous hypertension typically does.

In order to establish the cause, the physician will generally conduct a thorough medical history. A detailed family history is taken to determine whether the disease might be familial. Physical examination is performed to look for typical signs of pulmonary hyertension including a loud P2 (pulmonic valve closure sound), (para)sternal heave, jugular venous distension, pedal edema, ascites, hepatojugular reflux, etc.

Causes

The most common cause of pulmonary hypertension is left heart failure leading to pulmonary venous hypertension. This may be due to systolic or diastolic malfunction of the left ventricle or due to valvular dysfunction such as mitral regurgitation or mitral stenosis. It usually manifests as pulmonary edema.

Common causes of pulmonary arterial hypertension (PAH) include HIV, scleroderma and other autoimmune disorders, cirrhosis and portal hypertension, sickle cell disease^[2], congenital heart disease, thyroid diseases^[3], and others. Use of weight loss pills such as Fen-Phen, Aminorex, fenfluramine (Pondimin), and phentermine led to the development of PAH in the past^[4]. Other causes include sarcoidosis, histiocytosis X, and fibrosing mediastinitis. Pulmonary embolism also leads to pulmonary hypertension, acutely as well as chronically. When none of these causes can be found, the disease is termed idiopathic pulmonary arterial hypertension (IPAH).

Lung diseases that lower oxygen in the blood (hypoxia) are well known causes of pulmonary hypertension, including COPD, interstitial lung disease, Pickwickian syndrome or obesity-hypoventilation syndrome, and possibly sleep apnea. Human herpesvirus 8, also associated with Kaposi's sarcoma, has been demonstrated in patients with PAH, suggesting that this virus may play a role in its development^[5].

When a family history exists, the disease is termed familial pulmonary arterial hypertension (FPAH). IPAH and FPAH are now considered to be genetic disorders linked to mutations in the BMPR2 gene, which encodes a receptor for bone morphogenic proteins^[6], as well as the 5-HT(2B) gene, which codes for a serotonin receptor^[7].

Diagnosis

Normal pulmonary arterial pressure in a person living at sea level has a mean value of 12–16 mm Hg (1600–2100 Pa). Definite pulmonary hypertension is present when mean pressures at rest exceed 25 mm Hg (3300 Pa). If mean pulmonary artery pressure rises above 30 mm Hg (4000 Pa) with exercise, that is also considered pulmonary hypertension.

Diagnosis of PAH requires the presence of pulmonary hypertension with two other conditions. Pulmonary artery occlusion pressure (PAOP or PCWP) must be less than 15 mm Hg (2000 Pa) and pulmonary vascular resistance (PVR) must be greater than 3 Wood units (240 dyn•s•cm^-5 or 2.4 mN•s•cm^-5).

Although pulmonary arterial pressure can be estimated on the basis of echocardiography, pressure sampling with a Swan-Ganz catheter provides the most definite measurement. PAOP and PVR can not be measured directly with echocardiography. Therefore diagnosis of PAH requires a cardiac catheterization. Swan-Ganz catheter can also measure the cardiac output, which is far more important in measuring disease severity than the pulmonary arterial pressure.

Other diagnostic tests generally include pulmonary function tests, blood tests, electrocardiography (ECG), arterial blood gas measurements, X-rays of the chest (followed by high-resolution CT scanning if interstitial lung disease is suspected), and ventilation-perfusion or V/Q scanning to exclude chronic thromboembolic pulmonary hypertension. Biopsy of the lung is usually not indicated unless the pulmonary hypertension is thought to be secondary to an underlying interstitial lung disease but is fraught with risks of bleeding because of high pressure. Clinical improvement is often measured by a "six-minute walk test", i.e. the distance a patient can walk in six minutes. Stability and improvement in this measurement correlate with reduced mortality.

Classification

Current classification

In 2003, the 3rd World Symposium on Pulmonary Arterial Hypertension was convened in Venice to modify the classification based on the new understanding of disease mechanisms. The revised system developed by this group provides the current framework for understanding pulmonary hypertension.

The system includes several improvements over the former 1998 Evian Classification system. Risk factor descriptions were updated, and the classification of congenital systemic-to pulmonary shunts was revised. A new classification of genetic factors in PH was recommended, but not implemented because available data were judged to be inadequate.

The Venice 2003 Revised Classification system can be summarized as follows^[8]:

• WHO Group I - Pulmonary arterial hypertension (PAH)
• WHO Group II - Pulmonary hypertension associated with left heart disease
• WHO Group III - Pulmonary hypertension associated with lung diseases and/or hypoxemia
• WHO Group IV - Pulmonary hypertension due to chronic thrombotic and/or embolic disease
• WHO Group V - Miscellaneous

Previous terminology

The terms primary and secondary pulmonary hypertension (PPH and SPH) were formerly used to classify the disease. This led to the assumption that only the primary disease should be treated, and the secondary variety should be ignored. In fact all forms of pulmonary arterial hypertension are treatable. Unfortunately, this classification system still persists in the minds of many physicians, and probably leads to many patients with being denied treatment. This nihilistic approach to pulmonary arterial hypertension may also contribute to underdiagnosis. It is estimated that there are about 100,000 patients with PAH in the US, but only 15-20,000 have been diagnosed. Many others have been misdiagnosed as COPD, asthma, or congestive heart failure.

The term primary pulmonary hypertension (PPH) has now been replaced with idiopathic pulmonary arterial hypertension (IPAH).

Epidemiology

IPAH is a rare disease with an annual incidence is about 1-10 in 1,000,000. Women are almost three times as likely to present with IPAH than men.

Other forms of PAH are far more common. In scleroderma the incidence has been estimated to be 6 to 60% of all patients, in rheumatoid arthritis up to 21%, in systemic lupus erythematosus 4 to 14%, in portal hypertension between 2 to 5%, in HIV about 0.5%, and in sickle cell disease ranging from 20 to 40%.

Diet pills such as Fen-Phen produced an annual incidence of 25-50 per million.

Treatment

Treatment is determined by whether the PH is arterial, venous, hypoxic, thromboembolic, or miscellaneous. Since pulmonary venous hypertension is synonymous with congestive heart failure, the treatment is to optimize left ventricular function by the use of diuretics, beta blockers, ACE inhibitors, etc., or to repair/replace the mitral valve.

In PAH, lifestyle changes, digoxin, diuretics, oral anticoagulants, and oxygen therapy are considered conventional therapy, but have never been proven to be beneficial in a randomized, prospective manner.

High dose calcium channel blockers are useful in only 5% of IPAH patients who are vasoreactive by Swan-Ganz catheter. Unfortunately, calcium channel blockers have been largely misused, being prescribed to many patients with non-vasoreactive PAH, leading to excess morbidity and mortality.

Vasoactive substances

Prostacyclin (prostaglandin I₂) is commonly considered the most effective treatment for PAH. Epoprostenol (synthetic prostacyclin, marketed as Flolan®) is given via continuous infusion that requires a semi-permanent central venous catheter. This delivery system can cause sepsis and thrombosis. Flolan® is unstable, and therefore has to be kept on ice during administration. Since it has a half-life of 3 to 5 minutes, the infusion has to be continuous (24/7), and interruption can be fatal. Other prostanoids have therefore been developed. Treprostinil (Remodulin®) can be given intravenously or subcutaneously, but the subcutaneous form can be very painful. Iloprost (Ventavis®) is the only inhaled form of this class of drug approved for use in the US and Europe. Iloprost (Ilomedin®) is also used in Europe intravenously.

Endothelin receptor antagonists were the first oral medication developed for PAH. Bosentan (marketed as Tracleer®) was approved in 2001 and is a dual (ET_A and ET_B) receptor antagonist. Two selective endothelin receptor antagonists (ET_A only) are in the final stages of approval: sitaxsentan and ambrisentan.

Sildenafil, a selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5), was approved for the treatment of PAH in 2005. It is marketed for PAH as Revatio®.

Surgical

Atrial septostomy is a surgical procedure that creates a communication between the right and left atria. It relieves pressure on the right side of the heart, but at the cost of lower oxygen levels in blood (hypoxia). It is best performed in experienced centers. Lung transplantation cures pulmonary arterial hypertension, but leaves the patient with the complications of transplantation, and a survival of about 5 years.

Pulmonary thromboendarterectomy (PTE) is a surgical procedure that is used for chronic thromboembolic pulmonary hypertension. It is the surgical removal of an organized thrombus (clot) along with the lining of the pulmonary artery; it is a large and very difficult procedure that is currently performed in San Diego, California and a few other centers. Case series show remarkable success in most patients.

Treatment for hypoxic and miscellaneous varieties of pulmonary hypertension have not been established. However, studies of several agents are currently enrolling patients. Many physicians will treat these diseases with the same medications as for PAH, until better options become available.

Prognosis

The NIH IPAH registry from the 1980's showed an untreated median survival of 2-3 years from time of diagnosis, with the cause of death usually being right ventricular failure (cor pulmonale). Although this figure is widely quoted, it is probably irrelevant today. Outcomes have changed dramatically over the last two decades. This maybe because of newer drug therapy, better overall care, and earlier diagnosis (lead time bias). A recent outcome study of those patients who had started treatment with bosentan (Tracleer®) showed that 86% patients were alive at 3 years. With multiple agents now available, combination therapy is increasingly used. Impact of these agents on survival is not known, since many of them have been developed only recently. It would not be unreasonable to expect median survival to extend past 10 years in the near future.