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Pulmonary hypertension

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Pulmonary hypertension
Other namesPulmonary arterial hypertension, Ayerza syndrome
Micrograph showing arteries in pulmonary hypertensive with marked thickening of the walls.
SpecialtyPulmonology, cardiology
Usual onset20 to 60 years old
DurationLong term
CausesUnknown
Risk factorsFamily history, pulmonary embolism, HIV/AIDS, sickle cell disease, cocaine use, COPD, sleep apnea, living at high altitudes
Diagnostic methodFollowing ruling out other potential causes
TreatmentSupportive care, medications, lung transplant
MedicationEpoprostenol, treprostinil, iloprost, bosentan, ambrisentan, macitentan, sildenafil
Frequency1,000 new cases a year (US)

Pulmonary hypertension (PH or PHTN) is an increase of blood pressure in the arteries of the lungs. Symptoms include shortness of breath, syncope, tiredness, chest pain, swelling of the legs, and a fast heartbeat. The condition may make it difficult to exercise. Onset is typically gradual.

The cause is often unknown. Risk factors include a family history, prior blood clots in the lungs, HIV/AIDS, sickle cell disease, cocaine use, COPD, sleep apnea, living at high altitudes, and problems with the mitral valve. The underlying mechanism typically involves inflammation of the arteries in the lungs. Diagnosis involves first ruling out other potential causes.

There is no cure. Treatment depends on the type of disease. A number of supportive measures such as oxygen therapy, diuretics, and medications to inhibit clotting may be used. Medications specifically for the condition include epoprostenol, treprostinil, iloprost, bosentan, ambrisentan, macitentan, and sildenafil. A lung transplant may be an option in certain cases.

While the exact frequency of the condition is unknown, it is estimated that about 1,000 new cases occur a year in the United States. Females are more often affected than males. Onset is typically between 20 and 60 years of age. It was first identified by Ernst von Romberg in 1891.

Signs and symptoms

The symptoms of pulmonary hypertension include the following:

2

Less common signs/symptoms include non-productive cough and exercise-induced nausea and vomiting. 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. 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.

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. Evidence of tricuspid insufficiency and pulmonic regurgitation is also sought and, if present, is consistent with the presence of pulmonary hypertension.

Causes

In terms of 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 the classification was refined further at the third, fourth, and fifth World Symposia on PAH based on new understandings of disease mechanisms. The revised system developed at the fifth World Symposium on PAH in Nice was adapted further in subsequent European guidelines for the diagnosis and treatment of pulmonary hypertension, and provides the current framework for understanding pulmonary hypertension.

Classification

It can be one of seven different types. The Nice 2013 Updated Clinical Classification system (with adaptations from the more recent European guidelines shown in italics) can be summarized as follows:

Pathogenesis

Right ventricle (on left side)

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. The mechanisms involved in this narrowing process include vasoconstriction, thrombosis, and vascular remodeling (excessive cellular proliferation, fibrosis, and reduced apoptosis/programmed cell death in the vessel walls, caused by inflammation, disordered metabolism and dysregulation of certain growth factors). Over time, vascular remodeling causes the affected blood vessels to become progressively stiffer and thicker. This further increases the blood pressure within the lungs and impairs their blood flow. In common with other types of pulmonary hypertension, these changes result in an increased workload for the right side of the heart. The right ventricle is normally part of a low pressure system, with systolic ventricular 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 right ventricular adaptations (hypertrophy and increased contractility of the heart muscle) initially help to preserve stroke volume, ultimately these compensatory mechanisms are insufficient; 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.

In PVOD (WHO Group 1'), pulmonary blood vessel narrowing occurs preferentially (though not exclusively) in post-capillary venous blood vessels. PVOD shares several characteristics with PAH, but there are also some important differences, for example differences in prognosis and response to medical therapy.

Persistent pulmonary hypertension of the newborn occurs when the circulatory system of a newborn baby fails to adapt to life outside the womb; it is characterized by high resistance to blood flow through the lungs, right-to-left cardiac shunting and severe hypoxemia.

Pathogenesis in pulmonary hypertension due 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. In the absence of pulmonary blood vessel narrowing, the increased back pressure is described as ‘isolated post-capillary pulmonary hypertension’ (older terms include ‘passive’ or ‘proportionate’ pulmonary hypertension or ‘pulmonary venous hypertension’). However, in some patients, the raised pressure in the pulmonary vessels triggers a superimposed component of vessel narrowing, which further increases the workload of the right side of the heart. This is referred to as ‘post-capillary pulmonary hypertension with a pre-capillary component’ or ‘combined post-capillary and pre-capillary pulmonary hypertension’ (older terms include ‘reactive’ or ‘out-of-proportion’ pulmonary hypertension).

In pulmonary hypertension due to lung diseases and/or hypoxia (WHO Group 3), low levels of oxygen in the alveoli (due to respiratory disease or living at high altitude) cause constriction 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 alveolar hypoxia is widespread and prolonged, this hypoxia-mediated vasoconstriction occurs across a large portion of the pulmonary vascular bed and leads to an increase in pulmonary arterial pressure, with thickening of the pulmonary vessel walls contributing to the development of sustained pulmonary hypertension.

In CTEPH (WHO Group 4), the initiating event is thought to be blockage or narrowing of the pulmonary blood vessels with unresolved blood clots; these clots can lead to increased pressure and shear stress in the rest of the pulmonary circulation, precipitating structural changes in the vessel walls (remodeling) similar to those observed in other types of severe pulmonary hypertension. This combination of vessel occlusion and vascular remodeling once again increases the resistance to blood flow and so the pressure within the system rises.

Molecular pathology

Three major signaling pathways involved in the pathogenesis of pulmonary arterial hypertension

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 is a stimulation of the synthesis of vasoconstrictors such as thromboxane and vascular endothelial growth factor (VEGF). These results in a severe vasoconstriction and vascular smooth muscle and adventitial hypertrophy characteristic of patients with PAH.

Nitric oxide-soluble guanylate cyclase pathway

In normal conditions, the vascular endothelial nitric oxide synthase produces nitric oxide from L-arginine in presence of oxygen.

This nitric oxide diffuses into neighboring cells (including vascular smooth muscle cells and platelets), where it increases the activity of the enzyme soluble guanylate cyclase, leading to increased formation of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP). The cGMP then activates cGMP-dependent kinase or PKG (protein kinase G). Activated PKG promotes vasorelaxation (via a reduction of intracellular calcium levels), alters the expression of genes involved in smooth muscle cell contraction, migration and differentiation, and inhibits platelet activation. Nitric oxide–soluble guanylate cyclase signaling also leads to anti-inflammatory effects.

Phosphodiesterase type 5 (PDE5), which is abundant in the pulmonary tissue, hydrolyzes the cyclic bond of cGMP. Consequently, the concentration of cGMP (and thus PKG activity) decreases.

Endothelin

Endothelin-1 is a peptide (comprising 21 amino acids) that is produced in endothelial cells. It acts on the endothelin receptors ETA and ETB in various cell types including vascular smooth muscle cells and fibroblasts, leading to vasoconstriction, hypertrophy, proliferation, inflammation, and fibrosis. It also acts on ETB receptors in endothelial cells; this leads to the release of both vasoconstrictors and vasodilators from those cells, and clears endothelin-1 from the system.

Prostacyclin (and thromboxane)

Prostacyclin is synthesized from arachidonic acid in endothelial cells. In vascular smooth muscle cells, prostacyclin binds mainly to the prostaglandin I receptor. This sends a signal to increase adenylate cyclase activity, which leads to increased synthesis of cyclic adenosine monophosphate (cAMP). This in turn leads to increased cAMP-dependent protein kinase or PKA (protein kinase A) activity, ultimately promoting vasodilation and inhibiting cell proliferation. Prostacyclin signaling also leads to anti-thrombotic, anti-fibrotic, and anti-inflammatory effects. Levels of cAMP (which mediates most of the biological effects of prostacyclin) are reduced by phosphodiesterases 3 and 4. The vasoconstrictor thromboxane is also synthesized from arachidonic acid. In PAH, the balance is shifted away from synthesis of prostacyclin towards synthesis of thromboxane. fac

Other pathways

The three pathways described above are all targeted by currently available medical therapies for PAH. However, several other pathways have been identified that are also altered in PAH and are being investigated as potential targets for future therapies. For example, the mitochondrial enzyme pyruvate dehydrogenase kinase (PDK) is pathologically activated in PAH, causing a metabolic shift from oxidative phosphorylation to glycolysis and leading to increased cell proliferation and impaired apoptosis. Expression of vasoactive intestinal peptide, a potent vasodilator with anti-inflammatory and immune-modulatory roles, is reduced in PAH, while expression of its receptor is increased. Plasma levels of serotonin, which promotes vasoconstriction, hypertrophy and proliferation, are increased in patients with PAH, although the role played by serotonin in the pathogenesis of PAH remains uncertain. The expression or activity of several growth factors (including platelet-derived growth factor, basic fibroblast growth factor, epidermal growth factor, and vascular endothelial growth factor) is increased and contributes to vascular remodeling in PAH. Focusing only on the pulmonary vasculature provides an incomplete picture of PAH; the ability of the right ventricle to adapt to the increased workload varies between patients and is an important determinant of survival. The molecular pathology of PAH in the right ventricle is therefore also being investigated, and recent research has shifted to consider the cardiopulmonary unit as a single system rather than two separate systems. Importantly, right ventricular remodeling is associated with increased apoptosis; this is in contrast to pulmonary vascular remodeling which involves inhibition of apoptosis.

Diagnosis

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.
Pulmonary artery catheter
Severe tricuspid regurgitation

In terms of the diagnosis of pulmonary hypertension, it has five major types, and a series of tests must be performed to distinguish pulmonary arterial hypertension from venous, hypoxic, thromboembolic, or unclear multifactorial varieties. PAH is diagnosed after exclusion of other possible causes of pulmonary hypertension.

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), and a detailed family history is established to determine whether the disease might be heritable. 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. 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.

Echocardiography

If pulmonary hypertension is suspected based on the above assessments, echocardiography is performed as the next step. A meta-analysis of Doppler echocardiography for predicting the results of right heart catheterization reported a sensitivity and specificity of 88% and 56%, respectively. Thus, Doppler echocardiography can suggest the presence of pulmonary hypertension, but right heart catherization (described below) remains the gold standard for diagnosis of PAH. Echocardiography can also help to detect congenital heart disease as a cause of pulmonary hypertension.

Exclude other diseases

If the echocardiogram is compatible with a diagnosis of pulmonary hypertension, common causes of pulmonary hypertension (left heart disease and lung disease) are considered and further tests are performed accordingly. These tests generally include electrocardiography (ECG), pulmonary function tests including lung diffusion capacity for carbon monoxide and arterial blood gas measurements, X-rays of the chest and high-resolution computed tomography (CT) scanning.

Ventilation/perfusion scintigraphy

If heart disease and lung disease have been excluded, a ventilation/perfusion scan is performed to rule out CTEPH. If unmatched perfusion defects are found, further evaluation by CT pulmonary angiography, right heart catheterization, and selective pulmonary angiography is performed.

Right heart catheterization

Although pulmonary arterial pressure (PAP) can be estimated on the basis of echocardiography, pressure measurements with a Swan-Ganz catheter inserted through the right side of the heart provide the most definite assessment. Pulmonary hypertension is defined as a mean PAP of at least 25 mm Hg (3300 Pa) at rest, and PAH is defined as precapillary pulmonary hypertension (i.e. mean PAP ≥ 25 mm Hg with pulmonary arterial occlusion pressure ≤ 15 mm Hg and pulmonary vascular resistance > 3 Wood Units). PAOP and PVR 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; this can be used to calculate the cardiac index, which is far more important in measuring disease severity than the pulmonary arterial pressure. Mean PAP (mPAP) should not be confused with systolic PAP (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.

Other

For people considered likely to have PAH based on the above tests, the specific associated condition is then determined based on the physical examination, medical/family history and further specific diagnostic tests (for example, serological tests to detect underlying connective tissue disease, HIV infection or hepatitis, ultrasonography to confirm the presence of portal hypertension, echocardiography/cardiac magnetic resonance imaging for congenital heart disease, laboratory tests for schistosomiasis, and high resolution CT for PVOD and pulmonary capillary hemangiomatosis). Routine lung biopsy is discouraged in patients with PAH, because of the risk to the patient and because the findings are unlikely to alter the diagnosis and treatment.

  • 4 month old with pulmonary hypertension as seen on ultrasound
  • 4 month old with pulmonary hypertension as seen on ultrasound
  • 4 month old with pulmonary hypertension as seen on ultrasound
  • 4 month old with pulmonary hypertension as seen on ultrasound 4 month old with pulmonary hypertension as seen on ultrasound
  • Long standing pulmonary hypertension

Treatment

Treatment of pulmonary hypertension is determined by whether it is arterial (PAH), venous, hypoxic, thromboembolic, or has an unclear/multifactorial mechanism. Since the 1990s, a number of agents have been introduced for the treatment of pulmonary hypertension; these are mostly specific for PAH. The trials supporting the use of these agents have been relatively small, and the only measure consistently used as a primary endpoint to assess their efficacy has been the "6 minute walk test", although more recent trials are moving towards more patient-centered endpoints such as “time to clinical worsening”. Patients are normally monitored through commonly available tests such as: • pulse oximetry • arterial blood gas tests • serial ECG tests • serial echocardiography/cardiac magnetic resonance imaging • functional class • 6-minute walk test or cardiopulmonary exercise test • blood tests for B-type natriuretic peptide/N-terminal prohormone of B-type natriuretic peptide Right heart catheterization is also suggested for follow-up of patients with PAH.

Pulmonary arterial hypertension

Many pathways are involved in the abnormal proliferation and contraction of the smooth muscle cells of the pulmonary arteries in patients with PAH. Three of these pathways are important since they have been targeted with drugs — the endothelin pathway (targeted with endothelin receptor antagonists), the nitric oxide–soluble guanylate cyclase pathway (targeted with PDE5 inhibitors and a soluble guanylate cyclase stimulator), and the prostacyclin pathway (targeted with prostacyclin derivatives). For patients with PAH, the choice of treatment is guided by the severity of their symptoms and the degree of limitation in their ability to perform physical activities, which can be assessed using the World Health Organization (WHO) functional classification. Briefly, the classification (which is a modified version of the New York Heart Association functional classification) is graded from functional class I (no limitation or symptoms) to functional class IV (unable to carry out any physical activity without symptoms; breathlessness and/or fatigue may even be present while at rest). Recommended individual treatments according to WHO functional class may be summarized as follows: oral therapies targeting the endothelin or nitric oxide–soluble guanylate cyclase pathways for patients in WHO functional class II; oral, inhaled, or parenteral therapies targeting any of the three key pathways for patients in WHO functional class III; and intravenous prostacyclin derivative for patients in WHO functional class IV. Combinations of more than one agent may also be used – these are described in a separate section below.

General measures and supportive therapy General measures include avoidance of pregnancy, immunization against influenza and pneumococcal pneumonia, psychosocial support (patient support groups may play an important role in this regard and patients should be advised to join such groups), supervised exercise training (while avoiding strenuous physical activity), avoidance of exposure to high altitude without supplemental oxygen, and avoidance of non-essential surgery. Supportive medical therapies include oxygen, diuretics, and oral anticoagulants; correction of anemia and/or iron status may also be considered.

Calcium channel blockers High dose calcium channel blockers are useful in only 5% of patients with idiopathic PAH 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 intravenous adenosine, epoprostenol, acetylcholine, or tolazoline or inhaled nitric oxide are considered vasoreactive. Of these, only half of the patients are responsive to calcium channel blockers in the long term.

Prostaglandins 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. Prostacyclin is unstable, and Flolan has to be kept on ice during administration, but a thermostable formulation has been developed more recently (marketed as Veletri and Caripul) that does not usually require ice packs. Once infused, prostacyclin has a half-life of 3 to 5 minutes, so the infusion has to be continuous, and interruption can be fatal. Other prostanoids have therefore been developed. Treprostinil (marketed as Remodulin) is sufficiently stable to be administered at room temperature and can be given intravenously or subcutaneously; in the US, additional formulations are available that can be given via inhalation (under the brand name Tyvaso) or orally (under the brand name Orenitram). The subcutaneous form can be very painful. An increased risk of sepsis with intravenous Remodulin has been reported by the CDC. Iloprost is a stable prostacyclin analog that can be administered via inhalation (under the brand name Ventavis); in some countries outside the US it is also available for intravenous administration (under the brand name Ilomedin). The inhaled form of administration has the advantage of selective deposition in the lungs with reduced systemic side effects; however, coughing and throat irritation commonly occur. Beraprost is an oral prostanoid available in South Korea and Japan. An oral prostacyclin receptor agonist, selexipag (marketed as Uptravi) was approved by the US Food and Drug Administration (FDA) in December 2015 and became available to patients in the US in January 2016.

Endothelin receptor antagonists Endothelin receptor antagonists are taken orally. The dual (ETA and ETB) endothelin receptor antagonist bosentan (marketed as Tracleer) was approved in the US in 2001 and in Europe in 2002. Sitaxentan (Thelin), a selective endothelin receptor antagonist that blocks only the action of ETA, was approved for use in Canada, Australia, and the European Union, 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 US and as Volibris in Europe. In addition, macitentan (Opsumit), another dual/nonselective endothelin receptor antagonist from the makers of Tracleer, was approved for use in Europe and the US in 2013.

Phosphodiesterase type 5 (PDE5) inhibitors The US FDA and the European Medicines Agency (EMA) approved sildenafil, a selective inhibitor of cGMP specific PDE5, for the treatment of PAH in 2005. It is marketed for PAH as Revatio. In 2008 and 2009, the EMA and the US FDA 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 and sildenafil are taken orally. Tadalafil is rapidly absorbed (serum levels are detectable at 20 minutes). The T1/2 (biological half-life) hovers around 17.5 hours in healthy subjects. Moreover, if we consider pharmacoeconomic implications, patients who take tadalafil would pay ⅔ of the cost of sildenafil therapy. However, the relative costs will be affected by the emerging availability of generic versions of sildenafil as patents on the original branded versions expire. The side effect profile of tadalafil is similar to that of sildenafil; the most common adverse effects of tadalafil (based on clinical trial data) are headache, nausea, back pain, dyspepsia, flushing, myalgia, pain in extremity (including limb discomfort) and nasopharyngitis.

Soluble guanylate cyclase stimulation Soluble guanylate cyclase stimulators increase cGMP production via a dual mode of action: they increase the sensitivity of soluble guanylate cyclase to low levels of endogenous nitric oxide and they also directly stimulate soluble guanylate cyclase independently of nitric oxide (by contrast, PDE5 inhibitors reduce degradation of cGMP and thus depend on sufficient upstream nitric oxide–cGMP signaling). The resulting increase in cGMP levels promotes vasodilation and inhibits vascular remodeling, fibrosis, and inflammation. The soluble guanylate cyclase stimulator riociguat (marketed as Adempas) was approved for the treatment of PAH (as well as inoperable CTEPH and persistent/recurrent CTEPH after surgical treatment) by the US FDA in 2013 and by the EMA in 2014. It is the first approved drug of its class. Riociguat is taken orally three times daily; the doctor titrates the dose up or down from the starting dose in a stepwise manner depending on tolerability and blood pressure. The most common adverse effects (based on clinical trial data) are headache, dizziness, dyspepsia, peripheral edema, nausea, diarrhea, and vomiting. Because riociguat and PDE5 inhibitors act on the same signaling pathway (with the former increasing cGMP production and the latter decreasing cGMP removal), taking them together may lead to augmented blood-pressure-lowering effects and thus increase the risk of developing hypotension; use of riociguat in combination with a PDE5 inhibitor is therefore contraindicated.

Combination therapy The treatment algorithm that emerged from the fifth World Symposium on PAH advised that initial combination therapy with more than one agent may be considered for patients in WHO functional class III or IV. This algorithm was adapted further in subsequent European guidelines. In Europe, the decision to start treatment with monotherapy or combination therapy is based on the patient’s risk level (low, intermediate, or high risk of clinical worsening or death), which is determined by a comprehensive assessment of the patient including at least one measurement of exercise capacity and evaluation of right ventricular function as well as WHO functional class. Patients at low or intermediate risk can be treated with initial monotherapy or initial oral combination therapy, whereas initial combination therapy including an intravenous prostacyclin derivative should be considered for patients at high risk. For patients already receiving medical treatment for PAH, treatment guidelines recommend sequential combination therapy (stepwise addition of further PAH therapies) for those who do not show an adequate clinical response. The clinical response can be assessed against defined treatment goals such as reaching functional class I–II or achieving a 6-minute walk test distance of > 440 m (an approach known as “goal-oriented therapy”).

Surgical treatment Surgical treatments are important options for patients who do not show an adequate clinical response to maximal medical therapy. Balloon 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 and improves cardiac output, at the cost of lower oxygen levels in blood (hypoxia). The improvement in cardiac output is thought to lead to an overall improvement in oxygen transport despite the hypoxia. Lung transplantation can cure PAH; though it leaves the patient with the complications of transplantation, it can improve the patient’s quality of life as well as prolonging survival. Up to three-quarters of patients with pulmonary hypertension who receive a lung transplant survive to 5 years post-transplant and up to two-thirds survive to 10 years. Eligibility for lung transplantation should be considered after an inadequate clinical response to initial therapy, and the patient should be referred for lung transplantation soon after the inadequate clinical response is confirmed on maximal medical therapy.

Pulmonary hypertension due to left heart disease

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. Patients with left heart failure should not routinely be treated with vasoactive agents including prostanoids, phosphodiesterase inhibitors, or endothelin receptor antagonists, as these are approved specifically for PAH. Using PAH treatments for pulmonary hypertension due to left heart disease can harm the patient in certain situations (for example, selective pulmonary vasodilation in the context of elevated left-sided cardiac filling pressures may increase the risk of pulmonary edema) and wastes substantial medical resources.

Pulmonary hypertension due to lung diseases and/or hypoxia

Similar to patients with left heart failure, patients with pulmonary hypertension due to lung diseases and/or hypoxia should not routinely be treated with PAH-specific therapies; this could harm the patient in certain situations (for example, non-selective vasodilation could worsen hypoxemia by worsening ventilation/perfusion mismatch) and wastes substantial medical resources.

Chronic thromboembolic pulmonary hypertension

Pulmonary endarterectomy Pulmonary endarterectomy (PEA) is a surgical procedure that is used for CTEPH. 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, but it can be curative, with most patients experiencing substantial relief from their symptoms and near normalization of their hemodynamics.Post-operative outcomes are also improving as experience of the technique grows, and it is currently the treatment of choice for operable CTEPH. Operability should be assessed by an expert team comprising an experienced PEA surgeon and CTEPH physicians.

Soluble guanylate cyclase stimulation The soluble guanylate cyclase stimulator riociguat (marketed as Adempas) is the first PAH medical therapy to receive approval from the US FDA and the EMA as a treatment for inoperable CTEPH and for persistent/recurrent CTEPH after PEA. As noted above, assessment of operability is very important and should only be carried out by an expert CTEPH team.

Balloon pulmonary angioplasty Balloon pulmonary dilation (angioplasty) has shown beneficial effects in patients with CTEPH in several small studies. However, multiple procedures are required in each patient, the risk of restenosis is uncertain, and the criteria for selecting angioplasty versus PEA are unclear. Nevertheless, this procedure is rapidly gaining attention worldwide, and recent European guidelines advise that it may be considered for patients who have inoperable CTEPH or an unfavorable ratio of risk to benefit for PEA.

Pulmonary hypertension with unclear multifactorial mechanisms

Treatment regimens for unclear multifactorial 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.

Prognosis

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). A recent outcome study of those patients who had started treatment with bosentan (Tracleer) showed that 89% patients were alive at 2 years. 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%. 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.

Epidemiology

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).

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

Notable cases

See also

References

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