In medicine, pulmonary hypertension (PH) or pulmonary artery hypertension (PAH) 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.
Signs and symptoms
A history usually reveals gradual onset of shortness of breath, fatigue, angina pectoris, syncope (fainting) and peripheral edema.
In order to establish the cause, the physician will generally conduct a thorough medical history and physical examination. A detailed family history is taken to determine whether the disease might be familial.
Normal pulmonary arterial pressure in a person living at sea level has a mean value of 12-16mmHg. Definite pulmonary hypertension is present when mean pressures at rest exceed 25 mmHg. Although pulmonary arterial pressure can be estimated on the basis of echocardiography, pressure sampling with a Swan-Ganz catheter provides the most definite measurement.
Diagnostic tests generally involve blood tests, electrocardiography, arterial blood gas measurements, X-rays of the chest (generally followed by high-resolution CT scanning). A biopsy of lung tissue, angiography with endoluminal biopsy of the pulmonary artery, or biopsy of any associated skin lesions, is often attempted to obtain tissue for histopathological investigation.
Clinical improvement is often measured in a "six-minute walking test", i.e. the distance a patient can walk in six minutes.
Causes and mechanisms
Pulmonary hypertension can be primary (occurring without an obvious cause) or secondary (a result of other disease processes.)
Primary pulmonary hypertension (PPH) is considered a genetic disorder. It has been linked to mutations in the BMPR2 gene, which encodes a receptor for bone morphogenic proteins (Deng et al, 2000), as well as the 5-HT(2B) gene, which codes for a serotonin receptor (Blanpain et al, 2003). Recently, characteristic proteins of human herpesvirus 8 (also known for causing Kaposi sarcoma) were identified in vascular lesions of PPH patients (Cool et al, 2003). However, it is not understood what roles these genes and viral particles play in PPH. PPH has also been associated to the use of appetite suppressants (e.g. Fen-phen, see Abenhaim et al, 1996). While genetic susceptibility to adverse drug reactions is suspected, the cause of the disease is still largely unknown.
PPH is very rare but often fatal. Patients usually have no symptoms until they reach their late twenties or early thirties. It is characterized by elevated pulmonary vascular resistance attributable to the abnormal thickening of the vessel wall and narrowing of the lumen of arterioles in the lungs.
Secondary pulmonary hypertension (SPH) is often due to chronic obstructive pulmonary disease (COPD). Other factors that have been linked to secondary pulmonary hypertension are:
A common consequence of chronic pulmonary hypertension is cor pulmonale (right sided heart failure) believed to be caused by the increased load on the right ventricle and atrium of the heart. A chest radiograph (X-ray) will often reveal an enlarged right atrium and ventricle, and prominent pulmonary arteries. An ECG will often demonstrate right ventricular hypertrophy or strain. Oedema and fluid retention follow.
Classification of Pulmonary Hypertension
Venice 2003 Revised Classification of Pulmonary Hypertension
In 2003, the 3rd World Symposium on Pulmonary Hypertension was convened to modify classification based on the new understanding of disease mechanisms. The revised system developed by this group provides the current frame work for understanding pulmonary hypertension.
The system includes several improvements over the former 1998 Evian Classification system. The terms "primary" and "secondary" were discontinued because they had limited diagnostic value. In addition, new classifications were added, including primary veno-occclusive disease(PVOD). 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:
- WHO Group I Pulmonary arterial hypertension(PAH)
- WHO Group II Pulmonary hypertension with left heart disease
- WHO Group III Pulmonary hypertension associated with lung diseases and/or hypoxemia
- WHO Group IV Pulmonary hpertension due to chronic throbotic and/or embolic disease
- WHO Group V Miscellaneous
These terms are currently in use, but they are not yet as commonly used as the old terms of PPH and SPH.
Women are almost twice as likely to present with PPH than men.
Treatment is determined by the condition underlying the cause of the hypertension. For instance, long term oxygen therapy has been proven to be useful in patients with chronic obstructive pulmonary disease, and when the pulmonary hypertension is due to chronic thromboembolism, inferior vena caval filter insertion or pulmonary endarterectomy can be performed.
In PPH, lifestyle changes, digoxin, diuretics, oral anticoagulants, oxygen therapy and vasodilators are the mainstays of treatment. Synthetic prostacyclin (an eicosanoid) per continuous infusion is tried occasionally in some types of pulmonary hypertension. Prostacyclin is available in three forms: by catheter (Flolan), subcutaneously (Remodulin), and recently approved is an inhaled version called Ventavis®.
A recent addition is bosentan (marketed as Tracleer®), an endothelin receptor antagonist. Two new oral medications are in the final stages of approval: Thelin and Ambriesatan.
Pulmonary thromboendarterectomy (PTE) is a surgical procedure that is used when pharmaceutical management fails. It is the surgical removal of thrombus (clot) and the lining of the pulmonary artery; it is a large and difficult procedure which is currently performed in San Diego, California. Case series show remarkable success in selected patients.
Several studies have reported a mean survival of 2-3 years from time of diagnosis with the cause of death usually being right ventricular failure (cor pulmonale).
- Abenhaim L, Moride Y, Brenot F et al. Appetite-Suppressant Drugs and the Risk of Primary Pulmonary Hypertension. N Engl J Med 1996;335:609-16. Abstract.
- Blanpain C, Le Poul E, Parma J, Knoop C, Detheux M, Parmentier M, Vassart G, Abramowicz MJ. Serotonin 5-HT(2B) receptor loss of function mutation in a patient with fenfluramine-associated primary pulmonary hypertension. Cardiovasc Res., 2003;60(3):518-28. Abstract
- Cool CD, Rai PR, Yeager ME, Hernandez-Saavedra D, Serls AE, Bull TM, Geraci MW, Brown KK, Routes JM, Tuder RM, Voelkel NF. Expression of Human Herpesvirus 8 in Primary Pulmonary Hypertension. N Engl J Med 2003;349:1113-22.
- Curnock AL, Dweik RA, Higgins BH, Saadi HF, Arroliga AC. High prevalence of hypothyroidism in patients with primary pulmonary hypertension. Am J Med Sci. 1999;318:289-292.
- Deng Z, Morse JH, Slager SL, et al. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet 2000;67:737-44.
- Gladwin MT, Sachdev V, Jison ML, Shizukuda Y, Plehn JF, Minter K, Brown B, Coles WA, Nichols JS, Ernst I, Hunter LA, Blackwelder WC, Schechter AN, Rodgers GP, Castro O, Ognibene FP. Pulmonary Hypertension as a Risk Factor for Death in Patients with Sickle Cell Disease. N Engl J Med 2004;350:886-95.