Pulmonary hypertension

Pulmonary hypertension
Micrograph showing pulmonary hypertensive arteriopathy with marked thickening of the tunica intima and tunica media.
Classification and external resources
Specialty Pulmonology, cardiology
ICD-10 I27.0, I27.2
ICD-9-CM 416.0, 416.8
DiseasesDB 10998
MedlinePlus 000112
eMedicine radio/583 med/1962 Secondary pulmonary hypertension Pediatric primary pulmonary hypertension Persistent newborn pulmonary hypertension
Patient UK Pulmonary hypertension
MeSH D006976

Pulmonary hypertension (PH or PHTN) 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, leg swelling and other symptoms.[1] Pulmonary hypertension can be a severe disease with a markedly decreased exercise tolerance. It was first identified by Ernst von Romberg in 1891.[2] According to the most recent classification, it can be one of six different types.[3]

Signs and symptoms

Tricuspid regurgitation

The signs/symptoms of pulmonary hypertension include the following:[4][5][6]

Less common signs/symptoms include non-productive cough and exercise-induced nausea and vomiting.[5] Coughing up of blood may occur in some patients, particularly those with specific subtypes of pulmonary hypertension such as heritable pulmonary arterial hypertension, Eisenmenger syndrome and chronic thromboembolic pulmonary hypertension.[7] 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.[8]

Other typical signs of pulmonary hypertension include an accentuated pulmonary component of the second heart sound, a right ventricular third heart sound, and parasternal heave indicating a hypertrophied right atrium. Signs of systemic congestion resulting from right-sided heart failure include jugular venous distension, ascites, and hepatojugular reflux.[5][6][9] Evidence of tricuspid insufficiency and pulmonic regurgitation is also sought and, if present, is consistent with the presence of pulmonary hypertension.[5][6][10]


In terms of causes and classification,[11] 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.[12] A second conference in 1998 at Évian-les-Bains also addressed the causes of secondary PH (i.e. those due to other medical conditions),[13] and in 2008, the 4th World Symposium on Pulmonary Arterial Hypertension was convened in Dana Point 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.[3] The system includes several improvements over the former 2004 Venice Classification system.

The Dana Point 2008 Updated Clinical Classification system can be summarized as follows:[3]


The pathogenesis of pulmonary arterial hypertension (WHO Group I) involves the narrowing 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 stiffer and thicker, in a process known as fibrosis. This further increases the blood pressure within the lungs and impairs their blood flow. In common with other types of pulmonary hypertension, 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. The right ventricle is normally part of a low pressure system, with pressures that are lower than those that the left ventricle normally encounters. As such, the right ventricle cannot cope as well with higher pressures, and although hypertrophy of the heart muscle helps initially, it ultimately leads to a situation where the right ventricular muscle cannot get enough oxygen to meet its needs and right heart failure follows. 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.[14][15]

Pathogenesis in pulmonary hypertension owing to left heart disease (WHO Group II) is completely different in that constriction or damage to the pulmonary blood vessels is not the issue. Instead, the left heart fails to pump blood efficiently, leading to pooling of blood in the lungs and back pressure within the pulmonary system. This causes pulmonary edema and pleural effusions.[16]

In hypoxic pulmonary hypertension (WHO Group III), the low levels of oxygen are thought to cause narrowing of the pulmonary arteries. This phenomenon is called hypoxic pulmonary vasoconstriction and it is initially a protective response designed to stop too much blood flowing to areas of the lung that are damaged and do not contain oxygen. When the damage is widespread and prolonged, this hypoxia-mediated vasoconstriction occurs across a large portion of the pulmonary vascular bed.[17][18]

In chronic thromboembolic pulmonary hypertension (WHO Group IV), the blood vessels are blocked or narrowed with recurrent blood clots, and these clots can lead to release of substances that cause the blood vessels to constrict. This combination of blocked or narrowed vessels and vasoconstriction once again increases the resistance to blood flow and so the pressure within the system rises.[19]

Molecular pathology

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.[20] Moreover, there is 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.[21]

Molecular pathway of vasodilation mediated by nitric oxide

In normal conditions, the nitric oxide synthase produces nitric oxide from L-arginine in presence of oxygen.[22] 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), 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.[23]

In the vascular endothelium, cGMP activates cGMP kinase or PKG (protein kinase G), which is an enzyme that belongs to a type of serine/threonine - specific protein kinase.[24] 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.[25] 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.[26]

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 (regulatory domain) 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.[23] 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.[26]


Phonocardiogram and jugular venous pulse tracing from a middle-aged man with pulmonary hypertension caused by cardiomyopathy. The jugular venous pulse tracing demonstrates a prominent a wave without a c or v wave being observed. The phonocardiograms (fourth left interspace and cardiac apex) show a murmur of tricuspid insufficiency and ventricular and atrial gallops.

In terms of the diagnosis of pulmonary hypertension, dictates it 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. 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.[27][28] 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.[29]

Pulmonary artery catheter

Diagnosis of PAH requires the presence of pulmonary hypertension. Although pulmonary arterial pressure can be estimated on the basis of echocardiography,[30] pressure measurements with a Swan-Ganz catheter through the right side of the heart provide the most definite assessment.[31] 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.[31] Normal pulmonary arterial pressure in a person living at sea level has a mean value of 8–20 mm Hg (1066–2666 Pa) at rest. Pulmonary hypertension is present when mean pulmonary artery pressure exceeds 25 mm Hg (3300 Pa) at rest.[32]

Physical examination

Pulmonary artery hypertension and emphysema as seen on a CT scan with contrast

A physical examination is performed to look for typical signs of pulmonary hypertension (described above).,[28] and a detailed family history is established to determine whether the disease might be heritable.[33][34][35] A history of exposure to drugs such as benfluorex (a fenfluramine derivative), dasatinib, cocaine, methamphetamine, ethanol leading to cirrhosis, and tobacco leading to emphysema is considered significant.[6][36][37] Use of selective serotonin reuptake inhibitors during pregnancy (particularly late pregnancy) is associated with an increased risk of the baby developing persistent pulmonary hypertension of the newborn.[37]


A meta-analysis of doppler echocardiography for predicting right heart catheterization reported a sensitivity and specificity of 88% and 56%, respectively.[38]


Treatment of pulmonary hypertension is determined by whether the PH is arterial, venous, hypoxic, thromboembolic, or miscellaneous. The treatment is to optimize left ventricular function by the use of diuretics, digoxins, blood thinners, or to repair/replace the mitral valve or aortic valve.[39] Patients with left heart failure or hypoxemic lung diseases (groups II or III pulmonary hypertension) should not routinely be treated with vasoactive agents including prostanoids, phosphodiesterase inhibitors, or endothelin antagonists, as these are approved for the different condition called pulmonary arterial hypertension.[40] To make the distinction, doctors at a minimum will conduct cardiac catheterization of the right heart, echocardiography, chest CT, a six-minute walk test, and pulmonary function testing.[40] Using treatments for other kinds of pulmonary hypertension in patients with these conditions can harm the patient and wastes substantial medical resources.[40]

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.[10] 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.[41] Of these, only half of the patients are responsive to calcium channel blockers in the long term.[42]

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.[43]

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 (PDE-5) inhibitors, and prostacyclin derivatives.[44]


Prostacyclin (prostaglandin I2) is commonly considered the most effective treatment for PAH. Epoprostenol (synthetic prostacyclin) is given via continuous infusion that requires a semi-permanent central venous catheter. This delivery system can cause sepsis and thrombosis. Prostacyclin 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, and interruption can be fatal.[45] Other prostanoids have therefore been developed. Treprostinil 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 is also used in Europe intravenously and has a longer half life. Iloprost 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.

Endothelin receptor antagonists

The dual (ETA and ETB) endothelin receptor antagonist bosentan was approved in 2001. Sitaxentan (Thelin) was approved for use in Canada, Australia, and the European Union,[46] but not in the United States. In 2010, Pfizer withdrew Thelin worldwide because of fatal liver complications. A similar drug, ambrisentan is marketed as Letairis in the U.S. by Gilead Sciences.[47]

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.[48] PDE5 inhibitors are believed to increase pulmonary artery vasodilation, and inhibit vascular remodeling, thus lowering pulmonary arterial pressure and pulmonary vascular resistance.[49]

Tadalafil is taken orally, as well as sildenafil, and it is rapidly absorbed (serum levels are detectable at 20 minutes). The T1/2 (biological half-life) hovers around 17.5 hours in healthy subjects.[50] Moreover, if we consider pharmacoeconomic implications, patients that take tadalafil would pay two-thirds of the cost of sildenafil therapy.[51] However, there are some adverse effects of this drug such as headache, diarrhea, nausea, back pain, dyspepsia, flushing and myalgia.[52]

Activators of soluble guanylate cyclase

Soluble guanylate cyclase (sGC) is the intracellular receptor for NO. As of April 2009, the sGC activators cinaciguat and riociguat were undergoing clinical trials for the treatment of PAH.[53]


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). Lung transplantation cures pulmonary arterial hypertension, but leaves the patient with the complications of transplantation, and a post-surgical median survival of just over five years.[54]

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.[55]


Established clinical practice guidelines dictate the frequency of pulmonary nodule evaluation and surveillance,[40][56] patients are normally monitored through commonly available tests such as:


Cor pulmonale

The prognosis of pulmonary arterial hypertension (WHO Group I) has an untreated median survival of 2–3 years from time of diagnosis, with the cause of death usually being right ventricular failure (cor pulmonale).[57] A recent outcome study of those patients who had started treatment with bosentan (Tracleer) showed that 89% patients were alive at 2 years.[58] With new therapies, survival rates are increasing. For 2,635 patients enrolled in The Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL Registry) from March 2006 to December 2009, 1-, 3-, 5-, and 7-year survival rates were 85%, 68%, 57%, and 49%, respectively. For patients with idiopathic/familial PAH, survival rates were 91%, 74%, 65%, and 59%.[59] Levels of mortality are very high in pregnant women with severe pulmonary arterial hypertension (WHO Group I). Pregnancy is sometimes described as contraindicated in these women.[60][61][62]


The epidemiology of IPAH is about 125-150 deaths per year in the U.S., and worldwide the incidence is similar to the U.S. at 4 cases per million. However, in parts of Europe (France) indications are 6 cases per million of IPAH. Females have a higher incidence rate than males (2-9:1).[63]

Other forms of PH are far more common. In systemic scleroderma, the incidence has been estimated to be 8 to 12% of all patients;[64] in rheumatoid arthritis it is rare.[65] However, in systemic lupus erythematosus it is 4 to 14%,[66] and in sickle cell disease, it ranges from 20 to 40%.[67] Up to 4% of people who suffer a pulmonary embolism go on to develop chronic thromboembolic disease including pulmonary hypertension.[68] A small percentage of patients with COPD develop pulmonary hypertension with no other disease to explain the high pressure.[69] On the other hand, obesity-hypoventilation syndrome is very commonly associated with right heart failure due to pulmonary hypertension.[70]

Notable cases

See also


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