|Pulmonary arterial hypertension|
|Classification and external resources|
Micrograph showing a plexiform lesion of the lung, as seen in irreversible pulmonary hypertension. H&E stain.
In medicine, pulmonary hypertension (PH) is an increase of blood pressure in the pulmonary artery, pulmonary vein, or pulmonary capillaries, together known as the lung vasculature, leading to shortness of breath, dizziness, fainting, and other symptoms, all of which are exacerbated by exertion. Pulmonary hypertension can be a severe disease with a markedly decreased exercise tolerance and heart failure. It was first identified by Dr. Ernst von Romberg in 1891. According to the most recent classification, it can be one of five different types: arterial, venous, hypoxic, thromboembolic or miscellaneous.
Signs and symptoms 
Because symptoms may develop very gradually, patients may delay seeing a physician for years. Common symptoms are shortness of breath, fatigue, non-productive cough, angina pectoris, fainting or syncope, peripheral edema (swelling around the ankles and feet), and rarely hemoptysis (coughing up blood).
Pulmonary venous hypertension typically presents with shortness of breath while lying flat or sleeping (orthopnea or paroxysmal nocturnal dyspnea), while pulmonary arterial hypertension (PAH) typically does not.
A detailed family history is established to determine whether the disease might be familial. A history of exposure to drugs such as cocaine, methamphetamine, alcohol leading to cirrhosis, and tobacco leading to emphysema are considered significant. A physical examination is performed to look for typical signs of pulmonary hypertension, including a loud S2 (pulmonic valve closure sound), (para)sternal heave, jugular venous distension, pedal edema, ascites, hepatojugular reflux, clubbing etc. Evidence of tricuspid insufficiency is also sought and, if present, is consistent with the presence of pulmonary hypertension.
Causes and classification 
A 1973 meeting organized by the World Health Organization was the first to attempt classification of pulmonary hypertension. A distinction was made between primary and secondary PH, and primary PH was divided in the "arterial plexiform", "veno-occlusive" and "thromboembolic" forms. A second conference in 1998 at Évian-les-Bains also addressed the causes of secondary PH (i.e. those due to other medical conditions), and in 2003, the 3rd World Symposium on Pulmonary Arterial Hypertension was convened in Venice to modify the classification based on new understandings 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:
- WHO Group I - Pulmonary arterial hypertension (PAH)
- Idiopathic (IPAH)
- Familial (FPAH)
- Associated with other diseases (APAH): collagen vascular disease (e.g. scleroderma), congenital shunts between the systemic and pulmonary circulation, portal hypertension, HIV infection, drugs, toxins, or other diseases or disorders
- Associated with venous or capillary disease
- WHO Group II - Pulmonary hypertension associated with left heart disease
- Atrial or ventricular disease
- Valvular disease (e.g. mitral stenosis)
- 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
The classification does not include sickle cell disease, 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. Recent studies have been unable to find an association between human herpesvirus 8 and idiopathic pulmonary arterial hypertension.
Whatever the initial cause, pulmonary arterial hypertension (WHO Group I) involves the vasoconstriction or tightening of blood vessels connected to and within the lungs. This makes it harder for the heart to pump blood through the lungs, much as it is harder to make water flow through a narrow pipe as opposed to a wide one. Over time, the affected blood vessels become both stiffer and thicker, in a process known as fibrosis. This further increases the blood pressure within the lungs and impairs their blood flow. In addition, the increased workload of the heart causes hypertrophy of the right ventricle, making the heart less able to pump blood through the lungs, ultimately causing right heart failure (a condition known as cor pulmonale). As the blood flowing through the lungs decreases, the left side of the heart receives less blood. This blood may also carry less oxygen than normal. Therefore it becomes harder and harder for the left side of the heart to pump to supply sufficient oxygen to the rest of the body, especially during physical activity.
Pathogenesis in pulmonary venous hypertension (WHO Group II) is completely different. There is no obstruction to blood flow in the lungs. Instead, the left heart fails to pump blood efficiently, leading to pooling of blood in the lungs. This causes pulmonary edema and pleural effusions.
In hypoxic pulmonary hypertension (WHO Group III), the low levels of oxygen are thought to cause vasoconstriction or tightening of pulmonary arteries. This leads to a similar pathophysiology as pulmonary arterial hypertension.
In chronic thromboembolic pulmonary hypertension (WHO Group IV), the blood vessels are blocked or narrowed with blood clots. Again, this leads to a similar pathophysiology as pulmonary arterial hypertension.
Molecular pathology of PAH 
The molecular mechanism of pulmonary arterial hypertension (PAH) is not known yet, but it is believed that the endothelial dysfunction results in a decrease in the synthesis of endothelium-derived vasodilators such as nitric oxide and prostacyclin. Moreover, there’s a stimulation of the synthesis of vasoconstrictors such as thromboxane and vascular endothelial growth factor (VEGF). These results in a severe vasoconstriction and smooth muscle and adventitial hypertrophy characteristic of patients with PAH.
In normal conditions, the nitric oxide synthase produces nitric oxide from L-arginine in presence of oxygen. Adenylate-cyclase and gualynate-cyclase are activated in presence of nitric oxide and these enzymes produce cAMP and cGMP respectively. The cGMP is produced by a type of guanylate cyclase (which is a kind of pyrophosphate-liase cyclase): the soluble guanylate cyclase (or sGC), that catalyzes the formation of cGMP from GTP. sGC is a heterodimer made up of one α subunit and one β sub-unit in each chain. It also contains a prosthetic heme group, required for NO binding. The union of NO and sGC produces a conformational enzyme change that stimulates cGMP production.
In the vascular endothelium, cGMP activates cGMP kinase or PKG (protein kinase G), which is a enzyme that belongs to a type of serine/threonine - specific protein kinase. PKG is a dimer composed of two similar polypeptides chains that share a common molecular structure. Each subunit contains a catalytic domain and regulatory domain. GMP-kinase activates potassium channels and subsequently the inhibition of calcium channels. Thus, this process leads to a reduction of intracellular calcium and finally a vasodilation.
Phosphodiesterase type V (PDE5), which is abundant in the pulmonary tissue, is a metalohydrolase that hydrolyzes the cyclic bond of cGMP in the presence of divalent cations (Zn2+). Actually, Zn2+ union is necessary for PDE5 activity. In the N-terminal region (catalytic center) of PDE5 there is an aminoacid sequence (residues 142-526) that joins cGMP. This sequence of PDE5 is divided in two domains; GAF-A and GAF-B; but only GAF-A has the necessary affinity to bind cGMP. This union increases the catalytic activity and it is stabilized by a close serine phosphorylation (performed by a kinase). Consequently, the concentration of cGMP decreases and the vasodilation is stopped.
Patients with PAH produce less NO and others vasodilators and produce more vasoconstrictors. Consequently, this molecular pathway doesn’t work properly and it results in a constant vasoconstriction. For this reason, NO and PDE5 inhibitors such as tadalafil or sildenafil are possible therapies. Tadalafil, for example, causes a vasodilation mediated by nitric oxide in the pulmonary endothelium.
Because pulmonary hypertension can be of five major types, a series of tests must be performed to distinguish pulmonary arterial hypertension from venous, hypoxic, thromboembolic, or miscellaneous varieties..
A physical examination is performed to look for typical signs of pulmonary hypertension. These include altered heart sounds, such as a widely split S2 or second heart sound, a loud P2 or pulmonic valve closure sound (part of the second heart sound), (para)sternal heave, possible S3 or third heart sound, and pulmonary regurgitation. Other signs include an elevated jugular venous pressure, peripheral edema (swelling of the ankles and feet), ascites (abdominal swelling due to the accumulation of fluid), hepatojugular reflux, and clubbing.
Further procedures are required to confirm the presence of pulmonary hypertension and exclude other possible diagnoses. These generally include pulmonary function tests; blood tests to exclude HIV, autoimmune diseases, and liver disease; 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 due to an underlying interstitial lung disease; further, lung biopsies are fraught with risks of bleeding due to the high intrapulmonary blood 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 better survival. Blood BNP level is also being used now to follow progress of patients with pulmonary hypertension.
Diagnosis of PAH requires the presence of pulmonary hypertension. Although pulmonary arterial pressure can be estimated on the basis of echocardiography, pressure measurements with a Swan-Ganz catheter through the right side of the heart provides the most definite assessment. PAOP (pulmonary artery occlusion pressure) and PVR (pulmonary vascular resistance) cannot be measured directly with echocardiography. Therefore diagnosis of PAH requires right-sided cardiac catheterization. A Swan-Ganz catheter can also measure the cardiac output, which is far more important in measuring disease severity than the pulmonary arterial pressure.
Normal pulmonary arterial pressure in a person living at sea level has a mean value of 12–16 mm Hg (1600–2100 Pa). Pulmonary hypertension is present when mean pulmonary artery pressure exceeds 25 mm Hg (3300 Pa) at rest or 30 mm Hg (4000 Pa) with exercise.
Mean pulmonary artery pressure (mPAP) should not be confused with systolic pulmonary artery pressure (sPAP), which is often reported on echocardiogram reports. A systolic pressure of 40 mm Hg typically implies a mean pressure of more than 25 mm Hg. Roughly, mPAP = 0.61•sPAP + 2.
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 or aortic 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. The criteria for vasoreactivity have changed. Only those patients whose mean pulmonary artery pressure falls by more than 10 mm Hg to less than 40 mm Hg with an unchanged or increased cardiac output when challenged with adenosine, epoprostenol, or nitric oxide are considered vasoreactive. Of these, only half of the patients are responsive to calcium channel blockers in the long term.
A number of agents have recently been introduced for primary and secondary PAH. The trials supporting the use of these agents have been relatively small, and the only measure consistently used to compare their effectivity is the "6 minute walk test". Many have no data on mortality benefit or time to progression.
Vasoactive substances 
Many pathways are involved in the abnormal proliferation and contraction of the smooth muscle cells of the pulmonary arteries in patients with pulmonary arterial hypertension. Three of these pathways are important since they have been targeted with drugs — endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and prostacyclin derivatives.
Because inexpensive generic drugs for this disease are not widely available, the World Health Organization does not include them in its model list of essential medicines.
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. An increased risk of sepsis with intravenous Remodulin has been reported by the CDC. Iloprost (Ilomedin) is also used in Europe intravenously and has a longer half life. Iloprost (marketed as Ventavis) was the only inhaled form of prostacyclin approved for use in the US and Europe, until the inhaled form of treprostinil was approved by the FDA in July 2009 and is marketed under the trade name Tyvaso. The inhaled form of administration has the advantage of selective deposition in the lungs with less systemic side effects, however coughing and throat irritation commonly occur. Oral and inhaled forms of Remodulin are under development. Beraprost is an oral prostanoid available in South Korea and Japan.
Endothelin receptor antagonists 
The dual (ETA and ETB) endothelin receptor antagonist bosentan (marketed as Tracleer) was approved in 2001. Sitaxentan, a selective endothelin receptor antagonist that blocks only the action of ETA, has been approved for use in Canada, Australia, and the European Union, to be marketed under the name Thelin. Sitaxentan has not been approved for marketing by the U.S. Food and Drug Administration (FDA). In 2010, Thelin was withdrawn by Pfizer due to severe side effects. A new trial to address the FDA's concerns will begin in 2008. A similar drug, ambrisentan is marketed as Letairis in U.S. by Gilead Sciences. In addition, another dual/nonselective endothelin antagonist, Actelion-1, from the makers of Tracleer, will enter clinical trials in 2008.
Phosphodiesterase type 5 inhibitors 
The U.S. FDA approved Sildenafil, a selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5), for the treatment of PAH in 2005. It is marketed for PAH as Revatio. In 2009, they also approved Tadalafil, another PDE5 inhibitor, marketed under the name Adcirca. PDE5 inhibitors are believed to increase pulmonary artery vasodilation, and inhibit vascular remodeling, thus lowering pulmonary arterial pressure and pulmonary vascular resistance.
Tadalafil is taken orally, as well as sildenafil, and it is rapidly absorbed (serum levels are detectable at 20 minutes). The recommended dose is 40mg in one single dose per day and the T1/2 (biological half-life) hovers around 17.5 hours in healthy subjects. Moreover, if we consider pharmacoeconomic implications, patients that take tadalafil would pay ⅔ of the cost of sildenafil therapy. However, there are some adverse effects of this drug such as headache, diarrhea, nausea, back pain, dyspepsia, flushing and myalgia.
Activators of soluble guanylate cyclase 
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).
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 very difficult, major procedure that is currently performed in a few select centers. Case series show remarkable success in most patients.
Treatment regimens 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. Such treatment is called off-label use.
Patients are normally monitored through commonly available tests such as:
- pulse oximetry
- arterial blood gas tests
- chest X-rays
- serial ECG tests
- serial echocardiography
- spirometry or more advanced lung function studies
The NIH IPAH registry from the 1980s 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 may be 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 89% patients were alive at 2 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.
Idiopathic pulmonary arterial hypertension is a rare disease with an incidence of about 2-3 per million per year and a prevalence of about 15 per million. Adult females are almost three times as likely to present with IPAH than adult males. The presentation of IPAH within children is more evenly split along gender lines.
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 per year.
Pulmonary venous hypertension is exceedingly common, since it occurs in most patients symptomatic with congestive heart failure.
Up to 4% of people who suffer a pulmonary embolism go on to develop chronic thromboembolic disease including pulmonary hypertension.
Only about 1.1% of patients with COPD develop pulmonary hypertension with no other disease to explain the high pressure. Sleep apnea is usually associated with only very mild pulmonary hypertension, typically below the level of detection. On the other hand Pickwickian syndrome (obesity-hypoventilation syndrome) is very commonly associated with right heart failure due to pulmonary hypertension.
See also 
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|Wikimedia Commons has media related to: Pulmonary hypertension|
- The Merck Manual Home Edition: Pulmonary Hypertension
- Pulmonary Hypertension Association
- PH Central - the internet resource for Pulmonary Arterial Hypertension
- Facts About Primary Pulmonary Hypertension from the National Heart, Lung, and Blood Institute (NHLBI)
- Webcast: The Changing World of Pulmonary Arterial Hypertension Therapies - American College of CHEST Physicians
- GeneReviews/NCBI/NIH/UW entry on Heritable Pulmonary Arterial Hypertension
- OMIM entries on Heritable Pulmonary Arterial Hypertension