Pulmonary hypertension is a dangerous disorder where the blood vessels that supply the lungs cannot carry sufficient blood, so pressure builds up in the pulmonary arteries. Thanks to new treatments, the chances of survival are better than they were even five years ago and research continues to improve our understanding of this illness.
The human body has two major areas of blood vessels that distribute from and return blood to the left and right sides of the heart. The left ventricle of the heart pumps oxygenated blood from the lungs into the arteries which supply blood to the body. The right ventricle pumps blood returning from the body’s veins into the arteries of the lungs to receive oxygen. The blood pressure in the lung or pulmonary arteries is normally signiﬁcantly lower than the pressure in the systemic circulation. As a whole, while the pressure in the general circulation is normally about 120/80 mmHg, in the pulmonary arteries it is only 25/15 mmHg. When pressure in the pulmonary circulation becomes abnormally elevated, it is referred to as pulmonary hypertension.
In pulmonary hypertension, the blood vessels that supply the lungs cannot carry sufﬁcient blood and so pressure builds up. Due to structural changes in the walls of the pulmonary arteries, the patient’s heart works harder, trying to force the blood through. If the high pressure has to be maintained over a longer period, eventually the heart may weaken, and less blood will circulate through the lungs to be loaded with oxygen. Patients then experience that even simple physical exercise will make them become tired and short of breath. The stress on the heart leads to enlargement of the ventricles and eventually fluid can build up in the liver and tissues, such as in the legs.
Pulmonary hypertension can be caused by diseases of the heart and the lungs, such as chronic obstructive pulmonary disease (COPD) or emphysema, failure of the left heart ventricle, or recurrent pulmonary blood clots travelling from the legs or pelvic veins, obstructing the pulmonary arteries. Pulmonary hypertension caused by other illnesses is called secondary pulmonary hypertension.
Pulmonary hypertension is deﬁned as a pulmonary artery systolic pressure higher than 30 mmHg or a pulmonary artery mean pressure higher than 20 mmHg secondary to either a pulmonary or a cardiac disorder. When the disease occurs without underlying heart and lung disorders or other illnesses, it is called primary pulmonary hypertension or idiopathic pulmonary hypertension. Whereas it is known that the arterial obstruction is caused by a building up of the smooth muscle cells that line the arteries, the underlying cause of the disease is poorly understood.
Pulmonary hypertension is estimated to affect approximately 100,000 people worldwide. There is no racial pattern. Most often affected are women of child-bearing age and children. The female-to-male ratio roughly is 6:1; however, the reasons for this female bias remain unknown. In Europe, primary pulmonary hypertension is responsible for approximately 200 deaths per year and has an incidence rate of approximately three cases per million per year.
The incidence and prevalence of secondary pulmonary hypertension are considerably higher. In general, the frequency of secondary pulmonary hypertension is increasing. In a recent surveillance report, the US Centres for Disease Control and Prevention (CDC) pointed to a fact that pulmonary hypertension should no longer be viewed as a rare illness but rather as an emerging chronic illness.
Treatment of pulmonary hypertension involves treating the underlying causes, using supplemental oxygen to increase blood oxygen levels, diuretics to remove fluid from the body, anticoagulants or blood-thinning medications to avoid embolism, and medicines that dilate blood vessels such as calcium channel blockers and angiotensin-converting-enzyme (ACE) inhibitors. These medicines produce a reduction in pulmonary vascular resistance by increasing the cardiac output and decreasing pulmonary artery pressure. They also improve the quality of life and survival rate. Cardiac glycosides are given for prevention and treatment of supraventricular arrhythmias and for patients who also have left heart failure.
Intravenous or subcutaneous prostacyclin, a prostaglandin derivative with systemic and pulmonary vasodilating and also blood-clotting inhibiting effects, is used in severe cases. An inhaled form of the prostacyclin analogue is also available.
Recently, medicines which mediate or block the effects of excess endothelin (ET) production have been introduced into therapy. ET is a potent mediator of blood vessel constriction and growth of smooth muscle in vascular walls. There are ET A and ET B receptors, which play signiﬁcantly different roles. The binding to ET A receptors located on smooth muscle cells causes vasoconstriction, whereas the binding to ET B receptors located on cells lining the inner surface of blood vessels causes vasodilatation through the production of nitric oxide (NO). This latter activity is thought to protect against excessive vasoconstriction.
Despite advances in various treatments, there still is no cure for pulmonary hypertension.
Low oxygen in the atmosphere aggravates pulmonary hypertension. Therefore, patients with the disease beneﬁt from breathing supplemental oxygen, even temporarily during air travel or travelling to high altitude destinations.
Finally, single or double lung transplantation is an established procedure for treating primary pulmonary hypertension. Without a transplant, most patients die two to ﬁve years after the disease is diagnosed. Transplantation may also be a possible treatment for severe secondary pulmonary hypertension if treatment of the underlying disorder fails.
Scientists are further investigating ET receptor antagonists. New molecules may prove to be effective not only in pulmonary hypertension but also in the treatment of a variety of diseases where the regulation of vascular constriction is important. One compound is in Phase 3 clinical trials and is considered to be 6,500 times more selective in the targeting of the ET A receptor versus the ET B receptor. Additional trials are being carried out to evaluate whether the combination of a prostacyclin analogue with an ET receptor antagonist will lead to better clinical results.
Research has also shown that a class of medicines known as phosphodiesterase 5 (PDE 5) inhibitors interact with receptors that affect blood flow in the lungs. One compound is under review by the US Food and Drug Administration (FDA) for the therapy of pulmonary hypertension. For the same molecule, the European Medicines Evaluation Agency (EMEA) has granted orphan drug designation for the treatment of pulmonary hypertension.
Another research compound which is based on vasoactive intestinal peptide has just entered into a Phase 2 clinical trial to treat patients with pulmonary arterial hypertension via inhalation. The molecule consists of 28 amino acids. It belongs to the glucagon-growth-hormone-releasing factor secretin super family and influences many aspects of pulmonary biology. The compound has received orphan drug designation for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension by the EMEA.
A genetic cause of the familial form of primary pulmonary hypertension has been established. It is caused by mutations in a gene called BMPR2, which encodes a transforming growth factor beta type II receptor that is located on the surface of smooth muscle cells and binds molecules of the tumour growth factor (TGF)-beta family. Binding triggers a series of biochemical reactions in the cell’s interior, ultimately affecting the smooth muscle cell’s behaviour. The mutations block this process. This discovery provides a means of genetic diagnosis and a potential target for the therapy of people with familial primary pulmonary hypertension.
Fifty per cent of patients with pulmonary hypertension survive ﬁve years from diagnosis. This is an improvement from only ﬁve years ago, when 50 per cent of patients survived only two to three years. As new treatments become available and research is providing greater understanding of the illness, prognosis continues to move in the right direction.