Pulmonary hypertension is a relatively rare disease with sub-classifications according to aetiology and effect on patient activity. In pulmonary arterial hypertension (PAH) vasoconstriction and the obliteration of small arteries increases resistance within the pulmonary vasculature forcing the right side of the heart to work harder, leading to right ventricular failure. Traditionally, treatments were limited and included non-selective vasoconstrictors and diuretics. However in recent years several pharmacological developments have resulted in therapies which can slow disease progression, alleviate symptoms and increase life expectancy of some types of pulmonary hypertension.
Prevalence
Recent studies have produced higher prevalence estimations of pulmonary hypertension than previously anticipated. In 1997, Rubin estimated PPH incidence rates of 1 to 2 per 1 million people in the general population, with highest incidence in the age range of 20 to 40, in the New England Journal of Medicine. The study also describes how the condition is more common in women than in men, with a ratio of 1.7:1. The following year, Gaine and Rubin went on to estimate a low total prevalence of around 2 to 3 million sufferers, in The Lancet.
However, in 2011, Kirson et al. calculated far higher prevalence rates than these previous estimates and an increasing risk with age, as published in the Bayer periodical Current Medical Research and Opinion. By analysing medical insurance claims in the US it was found that 109 individuals per million under the age of 65, and 451 individuals per million over the age of 65 are afflicted with PAH. It has also been estimated that 15 to 52 individuals per million in Europe are afflicted by PAH.
Definition and Symptoms
PAH is defined as a blood pressure within the pulmonary arteries of more than 25 mmHg at rest or 30 mmHg upon exertion.
People with pulmonary hypertension may have a significantly decreased tolerance of exercise. Symptoms include shortness of breath, fatigue, angina, palpitations, oedema (particularly swelling of the ankles or feet), dizziness, and fainting, and are exacerbated by physical exertion. There is no shortness of breath while sleeping or lying down amongst sufferers of PAH, however sufferers of pulmonary venous hypertension may experience these symptoms.
Aetiology
Pulmonary hypertension can be idiopathic (of no known cause), known as primary pulmonary hypertension (PPH), or a result of underlying conditions, known as secondary pulmonary hypertension.
Classification
Clinical classification is according to cause or mechanism of the disease. There has been much debate over the classification and sub-classification of PH. According to the 4th and most recent World Symposium on Primary Pulmonary Hypertension, in 2008, there are five major classes of pulmonary hypertension:
Group 1. Pulmonary Arterial Hypertension (PAH)
- Idiopathic
- Familial, resulting in increased prevalence rates within families.
- Associated with diseases such as congenital systemic pulmonary shunts, HIV infection, drugs, toxins, or other diseases or disorders.
Characteristically, in Group 1, PAH, blood pressure is elevated due to increased resistance within the pulmonary vasculature. This is typically due to cellular changes in the walls of small pulmonary arteries. Arterial walls demonstrate increased thickness and smooth muscle cells produce neointima and plexiform lesions, which obstruct blood flow and increase resistance in the arteries. Obliteration of small pulmonary arteries, results in greater difficulty meeting the bodies oxygenation requirements. The right hand side of the heart must pump harder and faster, increasing pressure within the vessels. This results in weakening of the heart, leading to right ventricular failure (heart failure), as described by Shanthi et al. in a review published in The Cochrane Library subsidiary Cochrane Airways Group, in 2009. According to the 4th World Symposium on Primary Pulmonary Hypertension, in 2008, right ventricular heart failure is the most common cause of death in pulmonary hypertension.
Pulmonary hypertension has a genetic link in more than 6% of cases. Mutations of genes encoding the type II bone morphogenic protein receptor, activin receptor-like kinase type 1, and endoglin have all been linked to PAH. The BMPII gene, which codes for the type II bone morphogenic protein receptor, have been found in approximately 80% of families with familial PAH, according to the 4th World Symposium on Primary Pulmonary Hypertension, in 2008. This figure is reported as 60% according by Delcroix et al. in a European study published in 2003 in the European Respiratory Monograph. Both reports agree that mutations of the gene were found in 25% of idiopathic, or sporadic PAH.
Pulmonary hypertension may be associated with various conditions such as connective tissue disease, congenital systemic pulmonary shunts (defects from birth meaning that ventilation within the alveoli of the lungs is compromised), portal hypertension, HIV infection and certain drugs or toxins, as listed in an appraisal of drugs for the treatment of hypertension in 2007 by the National Institute for Clinical Excellence in Britain, an organisation which aims to improve health outcomes by appraising treatment efficacy and providing guidelines to physicians. Drugs that are known or suspected as risk factors include Aminorex, Fenfluramine, cocaine, and amphetamines. Recent changes to this subgroup of Group 1 are that schistosomiasis and chronic hemolytic anemia now appear as separate entities since the 4th World Symposium on Primary Pulmonary Hypertension, in 2008.
Group 1ii) PH Associated with venous or capillary disease
- Pulmonary veno-occlusive disease
- Pulmonary capillary hemangiomatosis
It was decided at the 4th World Symposium on Primary Pulmonary Hypertension, that pulmonary hypertension associated with venous or capillary disease should form a separate group, close to group 1, but not within it, in order to make Group 1 more homogenous.
Group 2. Pulmonary Hypertension due to left heart disease;
- Atrial or ventricular disease
- Valvular disease such as mitral stenosis
Raised venous pressure is commonly caused by congestive heart failure. The left side of the heart pumps blood inefficiently, resulting in a backwards pressure through the pulmonary veins and accumulation of blood in the lungs.
Group 3. Pulmonary Hypertension due to lung diseases and/or hypoxia.
- Chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD)
- Alveolar hyperventilation and sleep-disordered breathing
- Long-term exposure to extreme altitudes
- Developmental lung defects
Group 4. Chronic Thromboembolic Hypertension;
- Pulmonary embolism in which an intravascular mass or masses have lodged within the proximal or distal pulmonary vasculature.
- Embolism due to cancer, parasites or other type.
Group 5. Miscellaneous.
Classification of pulmonary hypertension can also be performed in terms of how severely physical activity is impaired. The World Health Organisation (WHO) lists four groups into which patients can be divided according to physical impairment:
- Patients are not limited in thei
- ual activities. Symptoms such as fatigue and angina are not exacerbated by normal exercise.
- Patients are mildly limited in t
- physical activities, as normal exercise causes increase in smptoms. No discomfort at rest.
- Patients are considerably restri
- in their physical activities, but still no discomfort at rest.
- Patients are not able to undergo
- physical activity and may show symptoms of right ventricular failure at rest.
Treatment
Before the development of disease-specific therapy, pulmonary hypertension carried a median survival length of 2.8 years following diagnosis. Treatment of PAH, for example, was limited to non-selective vasodilators, such as calcium channel blockers, that decrease the resistance of the pulmonary vascular system, according to an article published in the British Medical Journal subsidiary Thorax, in 2001.
Several therapeutic advances in the past 10 years, however, have resulted in a broader range of treatments for the various modalities of pulmonary hypertension. Treatment of the underlying cause can in some cases lead to resolution of the problem. However, idiopathic PAH is progressive and ultimately fatal.
Treatments for PAH aim to prevent and slow disease progression, prevent thrombosis in the pulmonary arteries, alleviate symptoms, increase exercise tolerance and increase life expectancy. Pharmacological treatments vary according to aetiology, and severity of the condition. Supplemental oxygen may be used in patients with low oxygen saturation levels or breathing difficulties. Some individuals with unresponsive conditions are also referred for lung or heart-lung transplants.
Current standard pharmacological treatments for PAH include anticoagulants, digoxin, and diuretics in order to reduce blood volume. Some idiopathic cases of PAH respond to calcium channel blockers which cause vascular smooth muscle relaxation, and therefore vasodilation.
Development of synthetic prostacyclin in recent years has led to several new therapies with various modes of delivery. Prostacyclin results in vasodilation, prevents platelet aggregation and inhibits vascular proliferation, slowing the progression of changes to the pulmonary arterial walls. Epoprostenol from GlaxoSmithKline is suitable for PAH patients who are in WHO functional class III and IV of functional impairment, that is considerably or totally restricted from physical activities. It is administered via continuous intravenous infusion as it has a short half life. Iloprost from Schering, which is inhaled six to nine times daily, is a more stable analogue of epoprostenol and increases exercise tolerance and reduces symptoms in WHO class III patients. In 2006 nine randomized controlled trials (RCTs) of prostacyclin or one of its analogues were systematically reviewed by Shanthi et al. in the Cochrane Airways Group. The study concluded that intravenous prostacyclin, in addition to standard treatment, can result in up to 12 weeks improvement in exercise capacity, and improvement in WHO functional class. There was also evidence to suggest that orally administered or inhaled prostacyclin may be safer, and may also be effective.
Other pharmacological developments include endothelin receptor antagonists such as orally administered bosentan and sitaxentan, which aim to improve exercise capacity in WHO functional class III patients. A 2008 Cochrane review of endothelin receptor antagonists by Liu et al. from the Cochrane Colaboration looked at 11 RCTs involving these drugs. It was found that endothelin receptor antagonists increase exercise capacity, improve the WHO functional class and alleviate dyspnoea in PAH patients in WHO functional class II and III. A trend of lower mortality amongst PAH patients, particularly idiopathic PAH was discovered.
Further studies are needed in order to compare the effectiveness of newer pharmacological treatments with the standard treatments of diuretics, anticoagulants and digoxin in the treatment of various classifications of pulmonary hypertension. As data is collected, evidence may indicate the most effective treatments or combination of treatments for each underlying cause and functional class.
References
British Medical Journal; Thorax (2001) "New insights into the pathogenesis and treatment of primary pulmonary hypertension" (accessed July 06, 2011)
New England Journal of Medicine (1997) "Primary pulmonary hypertension" (accessed September 10, 2011)
The Lancet (1998) "Primary pulmonary hypertension" (accessed September 10, 2011
Current Medical Research Opinion (2011) "Prevalence of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension in the United States" (accessed September 10, 2011)
The National Institute for Clinical Excellence (2007) "Health Technology Appraisal, Drugs for the Treatment of Pulmonary Hypertension, Final Scope" (access July 07, 2011)
Journal of American College of Cardiology (2009)"The 4th World Symposium on Pulmonary Hypertension" (accessed September 10, 2011)
The American Family Physician (2001) "Diagnosis and treatment of pulmonary hypertension" (accessed July 06, 2011)
The Cochrane Library, Cochrane Airways Groups (2009) "Prostacyclin for pulmonary hypertension in adults" (accessed July 06, 2011)
The Cochrane Library, Cochrane Airways Groups (2009) " Endothelin receptor antagonists for pulmonary arterial hypertension" (accessed 13 September, 2011)
European Respiratory Society Monograph; (2003) " Pulmonary vascular pathology; a clinical update " (accessed September 11, 2011)
Heart (2004) "Long term survival in primary pulmonary hypertension" (accessed July 06, 2011)
Disclaimer: The information contained in this article is for educational purposes only and should not be used for diagnosis or to guide treatment without the opinion of a health professional. Any reader who is concerned about his or her health should contact a doctor for advice.
Clare Jackson - Clare enjoys research and has a range of interests. With a background in scientific writing she likes to include lots of information in ...
