Definition and Causes

Pulmonary hypertension is a hemodynamic state defined by a resting mean pulmonary artery pressure at or above 25 mm Hg.¹ Because this definition is based on hemodynamic criteria, pulmonary hypertension can be the result of a variety of diseases of different causes. Pulmonary arterial hypertension (PAH), however, should be distinctly differentiated from pulmonary venous hypertension resulting from left heart disease. PAH is characterized by elevations in the pulmonary arterial pressure and pulmonary vascular resistance (PVR) leading to right ventricular failure and premature death. Thus, the definition of PAH also requires normal pulmonary artery occlusion (or wedge) pressure to exclude elevations of pulmonary artery pressure simply as a compensation for elevated pressures in the left heart. PAH is commonly caused by or associated with an underlying pulmonary, cardiac, or systemic disease (associated PAH [APAH], previously known as secondary pulmonary hypertension). Rarely, PAH is present in the absence of an identifiable cause or associated underlying disease and is referred to as idiopathic PAH (IPAH) or primary PAH (PPH). A familial form of IPAH (FPAH) accounts for about 6% of cases.²

The small case series on elevated pulmonary artery pressures in otherwise healthy young individuals in the 1950s and 1960s and the epidemic of anorexigenic-associated PAH in Europe led to the first World Health Organization (WHO) conference on PPH in 1973.³ The 1973 conference provided a pathology-based classification of the disease. Pulmonary hypertension was previously classified into two categories: primary or secondary, depending on the absence or presence of identifiable causes or risk factors. The diagnosis of PPH was one of exclusion after ruling out all causes of pulmonary hypertension. The second WHO conference on pulmonary hypertension, held in Evian, France, in 1998,⁴ classified pulmonary hypertension based on similarities in the clinical features⁴ and was revised in Venice, Italy, in 2003 to reflect a treatment-based approach to pulmonary hypertension classification.⁵ The 4th world symposium on pulmonary hypertension took place in Dana Point, California in 2008, and provided slight modifications to the classification scheme⁶ (Box 1). Most notably, familial PAH is now referred to as heritable, with further breakdown into the genetic abnormality identified, if any. Schistosomiasis and chronic hemolytic anemia are now part of category 1 disease as associated conditions to reflect their unique importance as causative factors of PAH. Chronic thromboembolic pulmonary hypertension is no longer divided into proximal and distal, as improvements in surgical technique make this partitioning obsolete. Finally, the miscellaneous category is expanded, and now includes many conditions previously included in the “other” category of associated PAH. The latter change recognizes the complexity and our poor understanding of the link between these conditions and pulmonary hypertension. PAH can be associated with a variety of known diseases, such as connective tissue diseases, portal hypertension, and human immunodeficiency virus (HIV) infection, in addition to the classic idiopathic form (see Box 1). All these conditions are believed to share equivalent obstructive pathologic changes of the pulmonary microcirculation, suggesting shared pathobiologic processes among the different processes leading to PAH.⁶

Parts of this review pertain to some but not all forms of pulmonary hypertension. The terms pulmonary hypertension, PAH, APAH, FPAH, and IPAH are used carefully as they are defined here, and they should not be viewed as interchangeable. Although the old term primary pulmonary hypertension is currently not in common use, it will still be used here when historically appropriate and for practical purposes can be considered interchangeable with the more current term IPAH. Much of the discussion of pathophysiology focuses on IPAH because it is the most carefully defined and studied form. The etiology, classification, and therapy sections pertain to PAH in general, reflecting the direction in the field. Pulmonary venous hypertension is a separate entity and is not discussed further.

Back to Top

Prevalence and Risk Factors

While PAH remains a rare disease, it is being increasingly recognized. Recent large multicenter registries have provided low estimates of category 1 PAH prevalence of 15.0 cases/million of adult inhabitants and incidence of 2.4 cases/million of adult inhabitants/yr in France⁷, and 10.6 and 2.0, respectively in the United States.⁸ The age and gender distribution of the disease appears to have evolved over time. The mean age was 36 years in patients entered into the 1980’s National Institutes of Health registry, with a female to male ratio of 1.7.⁹ Contemporary registries from France and the United States described a mean age at diagnosis of 50 years¹⁰ While the French registry confirmed the female-to-male ratio of 1.6,⁷ the US registry depicts a much higher female preponderance, with a female to male ratio of 3.9.¹⁰. The reasons behind this shifting epidemiology are not known.

The median interval from symptom onset to diagnosis remains unacceptably high at 1.1 years in current registry data,¹⁰ unchanged from the experience from the 1980’s.⁹ Survival has improved somewhat, with 3-year survival of 48% in the NIH registry¹¹, compared to 67% in both US¹² and French¹³ contemporary registries.

Familial Pulmonary Hypertension

In the national registry for PPH, 12 (6%) of the 187 enrolled patients had a first-degree relative affected by the same disease process. Familial PPH appears to be inherited as an autosomal dominant trait with a variable but low genetic penetrance, and some persons inherit the trait without exhibiting the phenotype. Furthermore, genetic anticipation affects the gene penetrance, with subsequent generations developing PPH at an earlier age. In 1997, the gene for familial IPAH was mapped to chromosome 2q31-32. In 2000, the bone morphogenetic protein receptor 2 (BMPR2) gene was identified as the actual gene for familial IPAH and its product was recognized as being a transforming growth factor β (TGF-β) receptor. Mutations in BMPR2 were also found in 13 (26%) of 50 patients with sporadic or nonfamilial IPAH in one series, suggesting a role of this receptor in the disease. Those discoveries in the genetics of familial IPAH have opened the way to a better understanding of the pathogenesis of IPAH.^14-16

Hospitalization and Death

Although the idiopathic form (IPAH/PPH) is rare, other forms of pulmonary hypertension are fairly common. Death rates for primary pulmonary hypertension as the underlying cause of death have increased since 1979, and the number of all cases is likely higher than that reported because of difficulties in detecting the disease. A report by the Centers for Disease Control and Prevention (CDC) published in November 2005 described trends between 1980 and 2002 in diagnosed pulmonary hypertension–related deaths and hospitalizations. These are the only national surveillance data available for pulmonary hypertension. Because pulmonary hypertension might be more likely to be reported secondary to other diseases, the report presented data for pulmonary hypertension as any contributing cause of death or as anylisted hospital diagnosis. The report compiled mortality data from the National Vital Statistics System (NVSS) and hospital discharge data from the National Hospital Discharge Survey (NHDS) for 1980 to 2002 and Medicare hospital claims data for 1990 to 2002.

Since 1980, the numbers of deaths and hospitalizations and the rates of death and hospitalization have increased for pulmonary hypertension, particularly among women and older adults. Between 1980 and 2000, death rates were higher for men than women; however, by 2002, no difference in rate was observed because of increasing death rates among women and declining death rates among men. Hospitalization rates were higher for men than for women until 1995; after 1995, higher rates were observed among women. Death rates since 1985 and Medicare hospitalization rates throughout the reporting period between 1990 and 2002 have been higher for blacks than for whites. In addition, two distinct geographic clusters were observed for the highest hospitalization rates in the Medicare population, and the highest death rates for pulmonary hypertension were in the western United States and in the Appalachian region.

The report concluded that although pulmonary hypertension historically has been considered a disease of women of childbearing age, it affects all ages and racial populations. Older women represent the majority of patients and decedents with this condition.¹⁷

Back to Top

Pathophysiology and Natural History

Pulmonary arterial hypertension affects the small muscular arteries and arterioles and is histologically characterized by endothelial and smooth muscle cell proliferation, medial hypertrophy, and thrombosis in situ. The hypertensive pulmonary arteriopathy seen in patients with IPAH affects the muscular arteries and arterioles and probably represents a combination of injury and repair. Several different histopathologic patterns can be seen, none of which is pathognomonic, however, because the diagnosis of IPAH still relies on excluding secondary causes.

Plexigenic pulmonary arteriopathy is the most common lesion seen in IPAH. It is characterized by medial hypertrophy, fibrotic intimal lesions that can compose organized thrombi, and destructive lesions involving the entire arterial wall. Another lesion is thrombotic pulmonary arteriopathy defined by the presence of organized mural thrombi resulting from thrombosis in situ in the setting of an intact arterial wall and a nondilated vessel. The pattern of an increased thickness of the medial smooth muscle wall, the duplication of the elastic laminae in muscular arteries, and the muscularization of the arterioles form the third type of histopathologic lesion in IPAH, referred to as isolated medial hypertrophy. This rare pattern can actually precede the formation of the plexigenic lesions and is believed to be reversible with treatment.

The pathogenesis of IPAH remains speculative and involves a combination of noxious stimuli affecting a predisposed vasculature. Until recently, the prevailing understanding about the pathogenesis of pulmonary hypertension was that the elevated pulmonary vascular resistance seems to result from an imbalance between locally produced vasodilators such as nitric oxide and prostacyclin and vasoconstrictors such as endothelin and thromboxane (vasoconstriction theory). Based on more recent evidence, however, our current understanding of the disease is changing to reflect the role of vascular wall remodeling in the form of proliferating endothelial and smooth muscle cells and abnormalities in the extracellular matrix that contribute to the increased pulmonary vascular resistance. The most obvious predisposing factors are the mutations in the BMPR2 gene that result in FPAH and some cases of sporadic IPAH. The epidemic of PAH that developed in users of appetite-suppressant drugs, probably through the drug’s serotoninergic effect, is an example of a noxious stimulus causing PAH. However, because only 0.1% of aminorex users were actually affected, other predisposing factors must exist for IPAH in exposed persons.

PAH is also associated with connective tissue diseases without any obvious pathophysiologic link. The possibility of an autoimmune injury leading to the vasculopathy has been proposed. Deficiency of thyroid hormone, either through a shared autoimmune insult to both the thyroid gland and the pulmonary vasculature, or the loss of a vasomotor role of the thyroid hormone has also been found to be associated with IPAH. Furthermore, the paracrine actions of the vascular endothelium appear dysfunctional in PAH, resulting in abnormal proliferation of vascular smooth muscle and endothelial cells, which might contribute to the observed increased pulmonary vascular resistance in this disease.²

Many advances have been made in revealing the pathogenesis of PAH. In many instances, however, the cause or effect explanation for the observed abnormalities remains blurred, because initial diagnosis in most patients is at advanced stages of pulmonary hypertension.

Back to Top

Pathobiologic Basis of Therapy

The median life expectancy from the time of diagnosis in patients with IPAH before the availability of disease-specific therapy was 2.8 years. Discoveries in three main pathobiologic pathways (nitric oxide, endothelin, and prostacyclin) have revolutionized our approach to the treatment of PAH and allowed the development of effective therapies that have changed the course of this previously uniformly fatal disease. Newer and probably more effective therapies are likely to develop as our understanding of remodeling and thrombosis improves.²

Nitric Oxide

The endothelium-derived relaxing factor nitric oxide (NO) has been shown to play a pivotal role in the pathobiology of IPAH. As a potent pulmonary vasodilator, NO that is produced locally in the lungs has profound effects on smooth muscle relaxation and proliferation, maintaining the normal pulmonary vascular tone. The unique lung anatomy with the close proximity of the airways to the blood vessels allows NO that is produced in high levels in the upper and lower airways by nitric oxide synthase II (NOSII) to affect the pulmonary vascular tone in concert with the low NO levels that are produced by nitric oxide synthase III (NOSIII) in the vascular endothelium. Patients with IPAH have low levels of NO in their exhaled breath, and the severity of the disease inversely correlates with NO reaction products in bronchoalveolar lavage fluid.^18-20 Exogenous administration of NO gas by inhalation is probably the most effective and specific therapy for IPAH, but cost and unresolved technical difficulties in the delivery system of inhaled NO have limited the use of NO gas to testing for vasoreactivity during pulmonary artery catheterization.

Endothelin-1

Endothelin-1 is a peptide produced by the vascular endothelium that has potent vasoconstrictive and proliferative paracrine actions on the vascular smooth muscle cells. The pulmonary circulation plays an important role in the production and clearance of endothelin-1, and this physiologic balance is reflected in the circulating levels of endothelin-1. Patients with pulmonary hypertension, IPAH in particular, have an increased expression of endothelin-1 in pulmonary vascular endothelial cells, and serum endothelin-1 levels are increased in patients with pulmonary hypertension.^21,22

Prostacyclin

The endothelium also produces prostacyclin (PGI2) by cyclooxygenase metabolism of arachidonic acid. Prostacyclin causes vasodilation throughout the human circulation and is an inhibitor of platelet aggregation by its action on platelet adenylate cyclase. The final enzyme in the production of PGI2 is prostacyclin synthase. The remodeled pulmonary vasculature in lung tissue obtained from patients with severe IPAH expresses low levels of prostacyclin synthase when compared with normal lung tissue. In addition, PGI2 metabolites are diminished in the urine of patients with pulmonary hypertension, further emphasizing the role of prostacyclin in this disease.^23,24

Remodeling

In addition to the pulmonary vasoconstriction that results from the dysregulation of the local endothelial mediators as discussed above, pulmonary vascular remodeling seems to play a major role in the increased vascular resistance seen in IPAH. An abnormal proliferation of endothelial cells occurs in the irreversible plexogenic lesion. Those proliferating endothelial cells are monoclonal in origin, raising the possibility that a random somatic mutation may be one of the initial steps leading to sporadic IPAH. In addition, pulmonary vascular smooth muscle cells that normally have a low rate of multiplication undergo proliferation and hypertrophy. Those smooth cell changes arise from the loss of the antimitogenic endothelial substances (e.g., PGI2 and NO) and an increase in mitogenic substances (e.g., endothelin-1). Other stimuli arise from locally activated platelets, which release thromboxane A2 and serotonin; thromboxane A2 and serotonin act as growth-promoting substances on the vascular smooth muscle cells. In fact, elevated blood levels of serotonin are found in patients with IPAH; the source of serotonin may be an abnormality in the platelets, which is the main source of this substance in the human circulation. Pulmonary vascular smooth cell hyperplasia also correlates with polymorphism and overexpression of a serotonin transporter, which might constitute an additional factor in a person’s genetic susceptibility to developing IPAH. On the other hand, the pulmonary artery smooth muscle cells in IPAH appear to be in an abnormally depolarized state. This abnormal resting potential results in a heightened state of vasoconstriction secondary to increased levels of cytosolic Ca2⁺ and seems to relate to a primary dysfunction or downregulation of the voltage-gated K⁺ channels.

In addition to the smooth muscle cell proliferation, abnormalities in extracellular matrix contribute to the medial hypertrophy in PAH. Through a dynamic process of matrix protein degradation and synthesis triggered by the high flow and pressure in the pulmonary vasculature, the extracellular matrix is remodeled, contributing to the obliterative changes seen in the pulmonary arteries.^2,25

Thrombosis

In a large retrospective series that looked at lung tissue obtained from autopsy material from patients with IPAH, 22 out of 56 pathologic specimens had evidence of thrombi confined to the small muscular arteries. This was atypical for the classic appearance of venous thromboembolism, and the concept of thrombosis in situ in IPAH emerged. Whether the prothrombotic milieu is a consequence or a cause of the vasculopathy, pulmonary arterial hypertension remains debatable. The determinants of this increased propensity for thrombosis arise at the microvasculature level, where the dysfunctional endothelium loses the anticoagulant properties that usually prevent intravascular clotting of blood material. Instead, the procoagulation mediators that are usually inhibited under physiologic conditions seem to be activated. In fact, blood thrombin activity is increased in patients with pulmonary hypertension, indicating activation of intravascular coagulation, whereas soluble thrombomodulin, a cell membrane protein that acts as an important site of thrombin binding and coagulation inactivation, is decreased. In addition, PGI2 and NO, both inhibitors of platelet aggregation, are decreased at the level of the injured endothelial cell, as discussed earlier. Circulating platelets in patients with PAH seem to be in a continuous state of activation and contribute to the prothrombotic milieu by aggregating at the level of the injured endothelial cells.^2,25

Back to Top

Signs and Symptoms

The manifestation of pulmonary hypertension is nonspecific, leading to delays in evaluation and diagnosis. The clinical suspicion of pulmonary hypertension should arise in any case of dyspnea without overt signs of specific heart or lung disease or in patients with underlying lung or heart disease whenever there is increasing dyspnea unexplained by the underlying disease itself. The symptoms of pulmonary hypertension can also include fatigue, weakness, angina, syncope, and abdominal distention. Symptoms at rest are reported only in very advanced cases.^1,26

The physical signs of pulmonary hypertension include left parasternal lift, loud pulmonary component of the second heart sound (P₂ ), pansystolic murmur of tricuspid regurgitation, diastolic murmur of pulmonary insufficiency, and right ventricular S₃. Jugular vein distention, hepatomegaly, peripheral edema, ascites, and cool extremities may be seen in patients with advanced disease. Central cyanosis might also be present. The lung examination is usually normal.

The clinical suspicion is also raised when symptoms and signs are present in subjects with conditions that can be associated with PAH, such as connective tissue diseases, cirrhosis of the liver, HIV infection, and congenital heart diseases. Pulmonary hypertension can sometimes be suspected when abnormal electrocardiographic, chest radiograph, or echocardiographic findings are detected in the course of procedures performed for other clinical reasons. ^1,26

Back to Top

Diagnosis

The diagnosis is now more clearly defined and follows the currently accepted clinical classification.⁶ Algorithms are available for various investigative tests and procedures that exclude other causes and ensure an accurate diagnosis of PAH.²⁶ The diagnostic process of pulmonary hypertension requires a series of investigations that are intended to make the diagnosis, to clarify the clinical class of pulmonary hypertension and the type of PAH, and to evaluate the functional and hemodynamic impairments. For practical purposes a sequential approach is recommended that starts with clinical suspicion of pulmonary hypertension leading to detection of the disease followed by confirmation and determination of severity. Due to the nonspecific manifestation of pulmonary hypertension, awareness by health care professionals in primary care settings is crucial for early detection and appropriate referral. Once pulmonary hypertension is detected, further evaluation should be performed at a specialized center. This typically includes testing to identify the clinical class and the functional capacity, which are essential to planning appropriate therapy. Figure 1 outlines the recommend approach.

The electrocardiogram might show right ventricular hypertrophy, right-axis deviation, or right atrial enlargement. Radiographic signs of pulmonary hypertension include enlarged main and hilar pulmonary arterial shadows (>17 mm) with attenuation of peripheral pulmonary vascular markings (pruning) and right ventricular enlargement. Although these findings may be helpful in advanced cases, they are neither specific nor sensitive enough by themselves. Echocardiography is usually the first test to suggest pulmonary hypertension. Pulmonary artery catheterization is usually required to confirm the presence and severity of pulmonary hypertension. It may also be useful in establishing the cause and determining the severity.

a) Echocardiography:

This diagnostic modality is very helpful in detecting or excluding significant pulmonary hypertension (Figure 2-3), but it has limitations mainly due to the technique itself and experience of the operator. Systolic pulmonary artery pressure is estimated using tricuspid insufficiency jet velocity based on the simplified Bernoulli’s equation: (Figure 4)

[4 x (TRV)² + RA pressure]

When this velocity is >2.8 m/s pulmonary hypertension may be present, especially if there is associated dilation or dysfunction of the right ventricle.^1,27,28 Not uncommonly echocardiography over or underestimates the systolic pulmonary pressure measured by right heart catheterization.^29,30

Echocardiography measures several variables that provide prognostic information in patients with pulmonary hypertension. Some of these variables are: RV function, the presence of pericardial effusion, right atrial area, Tricuspid Annular Plane Systolic Excursion (TAPSE), left ventricular eccentricity index, etc.³¹

b) Right Heart Catheterization:

This procedure is currently required for the diagnosis of pulmonary hypertension and it also used for management and prognostication. Right heart catheterization measures right atrial pressure, mean pulmonary artery pressure (mean PAP), pulmonary artery occlusion pressure (PAOP) (Figures 5-10), cardiac output (CO) by thermodilution / indirect Fick and mixed venous oxygen saturation. Right heart catheterization provides data to calculate the pulmonary vascular resistance (mPAP-PAOP)/CO and transpulmonary gradient (mPAP-PAOP). In addition right heart catheterization evaluates pulmonary vasoreactivity and helps in the diagnosis of left-to-right intracardiac shunts (e.g. ASD, VSD and PDA).

The Normal resting mean PAP is 14 ± 3 mm Hg. Pulmonary hypertension is present when the mean PAP is ≥25 mmHg. The normal PAOP is from 6-12 mmHg. Of note is that pressure measurements are performed at the end of expiration, ideally on paper tracings. The normal pulmonary vascular resistance is 0.3-1.6 Wood Units. Transpulmonary gradient is normally ≤12 mmHg.

Pre-capillary PH is defined as mean PAP ≥25 mm Hg in association with PAOP ≤15 mm Hg and a pulmonary vascular resistance (PVR) >3 Wood units. Post-capillary PH is characterized by a mean PAP ≥25 mm Hg in association with PAOP >15 mm Hg and PVR ≤3 Wood units.^26,27 This differentiation in pre- and post-capillary PH is important as it narrows the differential diagnosis and also has treatment implications.

Pulmonary artery occlusion pressure is the RHC determination that is subject to the greatest error in measurement and interpretation. For this reason careful attention should be exercised when obtaining this measurement or reviewing a right heart catheterization report. Five criteria are used to evaluate whether a PAOP measurement is valid: a) PAOP is less than the diastolic PAP, b) the tracing is compatible with the atrial pressure waveform, c) the fluoroscopic image demonstrates a stationary catheter after inflation, d) free flow is present within the catheter (flush test), e) highly oxygenated blood (capillary) is obtained from the distal port in occlusion position.³² If PAOP is not reliable then left ventricular end-diastolic pressure is measured and used instead of the former.

Pulmonary vascular reactivity could help identify pulmonary hypertension patients that would benefit from calcium channel blockers. It is defined as a drop in mPAP of ≥10 mmHg to an absolute level <40 mmHg. A positive test is observed in 10-15% of patients with IPAH. However a half of these patients will have long-term CCB response. A positive test is rarely observed in PH other than idiopathic PAH or anorexigen associated PAH.³³

To screen for left-to-right shunt, blood samples are obtained at the SVC and pulmonary artery. If the difference is more than 7%, then further sampling is indicated to identify the location of the shunt.

c) Additional Workup:

The rest of the workup is directed at excluding or confirming the presence of underlying diseases and assessing the degree of functional impairment. Pulmonary function testing is needed to exclude underlying lung disease. Ventilation-perfusion lung scanning or spiral computed tomography (CT) scans of the chest are obtained to rule out chronic thromboembolic pulmonary hypertension (CTEPH), a potentially curable cause of pulmonary hypertension. Normal scans essentially exclude surgically accessible chronic thromboembolic disease, but abnormal or indeterminate scans need to be followed by pulmonary angiography, which is the definitive test for diagnosing CTEPH. High-resolution CT scans of the chest are useful in looking for parenchymal lung diseases. Serologic testing is useful in looking for an underlying associated connective tissue disease. Overnight oximetry or polysomnography is useful in detecting obstructive sleep apnea contributing to pulmonary hypertension. A cardiopulmonary exercise test or the simpler and more widely available 6-minute walk test is used to assess functional capacity.^1,26,34-36

Back to Top

Treatment

Medical Treatment

General Measures

Studies suggest that oral anticoagulation improves survival in IPAH and is recommended in all these patients unless there is a contraindication. The recommended target international normalized ratio (INR) is approximately 1.5 to 2.5. The role of anticoagulation in other forms of PAH is less clear. Supplemental oxygen should be used to maintain oxygen saturation greater than 90%, especially because hypoxemia is a major cause of pulmonary vasoconstriction. Diuretics are indicated for right ventricular volume overload, and digoxin is reserved for patients with refractory right ventricular failure and for rate control in atrial flutter or fibrillation.^26,36,37 Specific vasodilator therapy is discussed later. Recent treatment guidelines^36,37 suggest that the choice of a specific agent should be guided by the severity of the disease based on patient symptoms, baseline hemodynamics, and disease progression (Table 1 and Figure 11).

Calcium Channel Blockers

Patients with IPAH who exhibit acute vasoreactivity during right heart catheterization have improved survival with long-term use of calcium channel blockers. Thus, these agents should be considered in all patients who have significant and definite responses to a short-acting vasodilator. Unfortunately, a very small proportion (approximately 5%) of IPAH patients qualify for and benefit from long-term therapy with oral calcium channel blockers.^26,33,36

Prostanoids

Epoprostenol delivered by continuous intravenous infusion improves exercise capacity, hemodynamic variables, and survival in IPAH patients and is the treatment of choice for severely ill patients. Epoprostenol therapy, however, is complicated by the instability of the drug at room temperature and the need for continuous intravenous infusion because of the drug’s short half-life. Common side effects include headache, flushing, jaw pain, diarrhea, nausea, skin rash, and musculoskeletal pain. Catheter-related complications include infection and thrombosis.

Treprostinil is a stable prostacyclin analogue with a longer half-life, which allows subcutaneous or intravenous administration. In addition to side effects seen with epoprostenol, patients receiving treprostinil subcutaneously might also experience pain at the infusion site.

The main impediment to the use of prostanoids has been the parenteral route of delivery.^36,37 Two inhaled prostanoid analogues are currently approved by the FDA for treatment of patients with IPAH. These include iloprost and treprostinil. Due to the relatively short duration of action, these have to be used several times daily [treprostinil four times/day and iloprost six to nine times/day]. Common side effects include cough, flushing, and headache. Inhaled therapies may be useful as an adjunct to oral therapy. Orally administered prostanoids are under development.

Endothelin-Receptor Antagonists

Two endothelin receptor antagonists are currently approved by the FDA. Bosentan, an orally administered endothelin receptor antagonist, is approved to improve walking distance, functional class, and time to clinical worsening in patients with PAH. The main side effect is the asymptomatic increase in liver enzyme levels, which necessitates monitoring liver function at least monthly in all patients receiving the medication. Another endothelin receptor antagonist, ambrisentan, is also approved to improve functional class, walking distance, and reduce time to clinical worsening in patients with PAH.³⁹ Ambrisentan does not require monthly monitoring of liver function tests. Potential side effects of endothelin receptor antagonists include anemia, edema, teratogenicity, testicular atrophy, and male infertility.

Phosphodiesterase-5 Inhibitors

Two phosphodiesterase type 5 inhibitors (PDE5i), sildenafil and tadalafil⁴⁰ are currently approved by the FDA for use in patients with PAH. By inhibiting PDE5, these medications stabilize cyclic guanosine monophosphate (cGMP, the second messenger of nitric oxide), allowing a more sustained effect of endogenous nitric oxide, an indirect but effective and practical way of using the NO-cGMP pathway.

Combination therapy

Patients with PAH may experience clinical and hemodynamic deterioration despite treatment with a single agent. This circumstance requires the addition on a second agent to slow disease progression and aid in clinical improvement.^36,37 Different combinations have been tried, however current guidelines do not favor a particular combination over others. Several studies are on-going to compare the efficacy of single agent versus combination therapy. Failure of combination therapy requires consideration for parenteral therapy and surgical intervention such as lung transplantation.

Surgery

Atrial Septostomy

The role of balloon atrial septostomy in the treatment of PAH patients is uncertain but might be beneficial in the setting of severe disease with recurrent syncope or right heart failure (or both) despite maximal medical therapy. The procedure can also be used as a bridge to lung transplantation. The rationale for its use is that the controlled creation of an atrial septal defect would allow right-to-left shunting, leading to increased systemic output and systemic oxygen transport despite the accompanying fall in systemic arterial oxygen saturation. The shunt at the atrial level would also allow decompression of the right atrium and right ventricle, alleviating signs and symptoms of right heart failure. Balloon atrial septostomy is a high-risk procedure and should be performed only in experienced centers to reduce the procedural risks.^36,37

Lung Transplantation

Lung transplantation has been used in treatment for pulmonary hypertension since the 1980s, even before current medical therapies were available. It is indicated in PAH patients with advanced disease that is refractory to available medical therapy. Single and bilateral lung transplantations have been performed for IPAH, but most transplant centers currently perform bilateral lung transplantation to minimize postoperative complications. The 3- and 5- year survival rates after lung and heart-lung transplantation are approximately 55% and 45%, respectively.^36,37

Pulmonary Thromboendarterectomy

Pulmonary thromboendarterectomy provides a potential surgical cure and should be considered in all patients with chronic thromboembolic PAH (CTEPH) affecting central pulmonary arteries. Pulmonary angiography is required to confirm surgical accessibility of chronic thromboemboli. The procedure requires cardiopulmonary bypass and involves dissecting well-organized thromboembolic material as well as part of the intimal layer of the pulmonary arterial bed. Patients with suspected CTEPH should be referred to centers experienced in the procedure for consideration of this procedure. In patients with operable CTEPH, pulmonary thromboendarterectomy is the treatment of choice because it improves hemodynamics, functional status, and survival.^36,37

Back to Top

Considerations for Special Populations

Portopulmonary Hypertension

PAH is a well-recognized complication of chronic liver diseases. Portal hypertension rather than the liver disease itself seems to be the main determining risk factor for developing pulmonary hypertension. The mechanism remains unknown but the presence of portosystemic shunt might allow vasoconstrictive and vasoproliferative substances, normally cleared by the liver, to reach the pulmonary circulation. The fraction of patients with portopulmonary hypertension in the National Institutes of Health (NIH) registry was 8%, and it can be seen in up to 10% of patients evaluated for liver transplantation. Thus, echocardiographic screening for detecting pulmonary hypertension in patients with liver disease is appropriate in symptomatic patients and is recommended in candidates for liver transplantation.

Pulmonary artery catheterization should be performed in all patients with increased right ventricular pressure on echocardiography. Hemodynamically, patients with portopulmonary hypertension might have a significantly higher cardiac output and significantly lower systemic vascular resistance and pulmonary vascular resistance than patients with other forms of PAH.

The treatment of portopulmonary hypertension can be challenging and is not well standardized. The general approach is similar to that in IPAH, except that anticoagulation is not recommended because of the risk of bleeding, and bosentan is avoided because of the potential for hepatoxicity.^41,42

Pulmonary Arterial Hypertension in Hypoxic Lung Disease

Pulmonary hypertension in the setting of chronic hypoxia due to underlying lung disease represents a challenging area for evaluation and management. Although chronic hypoxia is a recognized cause of pulmonary hypertension, it would rarely lead to severe pulmonary hypertension. Nonetheless, patients with advanced chronic obstructive pulmonary disease (COPD)⁴³ and interstitial lung disease who develop pulmonary hypertension tend to have a worse outcome. Thus, patients with chronic hypoxia who have a marked elevation in pulmonary pressure should be evaluated for other causes of the pulmonary hypertension.

The questions of when the pulmonary hypertension is disproportionate to the underlying lung disease and whether vasodilator therapy would be of any benefit remain unanswered. The current opinion suggests that, in general, mean pulmonary artery pressures greater than 50 mm Hg are out of proportion to underlying lung disease. The first-line and most important therapy in these cases is supplemental oxygen. Unfortunately, none of the medical treatments developed for pulmonary arterial hypertension has been shown to be effective in these patients.

This situation may be different for sleep apnea because effective therapy is available for the underlying disease. When mild pulmonary hypertension is associated with the sleep apnea, the first line of therapy should be directed at treating the sleep apnea followed by re-evaluation for pulmonary hypertension. If pulmonary hypertension persists despite adequate therapy for sleep apnea, consideration should be given to treating the pulmonary hypertension as a separate disease.⁴³

Surgery

Elective surgery involves an increased risk in patients with PAH. The increased risk is proportionate to the severity of the disease. It is not clear which type of anesthesia is advisable, but probably local and regional anesthesia are better tolerated than general anesthesia. Surgery preferably is performed at referral centers with experienced anesthesia and pulmonary hypertension teams that can deal with potential complications.⁴⁴ Anticoagulant treatment should be interrupted for as short a period as possible. In patients with CTEPH, bridging with heparin is recommended to minimize the time off anticoagulation.

Pregnancy

Although successful pregnancies have been reported in IPAH patients, pregnancy and delivery in PAH patients are associated with an increased mortality rate of 30% to 50%, and pregnancy should be avoided or terminated. An appropriate method of birth control is highly recommended in all women with pulmonary hypertension who have childbearing potential. Unfortunately, there is no current consensus on the most appropriate birth control method in PAH patients. Because of the increased risk of thrombosis with estrogen-based contraception, some experts suggest the use of estrogen-free products, surgical sterilization, or barrier methods.^26,36

Air Travel

Because hypoxia can worsen vasoconstriction in PAH patients, it is best to avoid or prepare for hypoxic situations such as going to high altitude or flying. Supplemental oxygen should be considered in all PAH patients planning to travel by air. A flight simulation test before the flight can help determine oxygen needs at altitude.^26,36

Back to Top

Summary

• Pulmonary arterial hypertension (PAH) refers to a group of diseases characterized by high pulmonary artery pressure that can be the end results of a variety of disease states and underlying conditions. Idiopathic PAH (IPAH) affects a predominantly young and productive population and is more common in female patients than male patients.
• The workup of a patient with suspected pulmonary hypertension is designed to confirm the diagnosis, exclude or confirm the presence of an underlying cause, and assess the severity of the disease.
• IPAH is histologically characterized by endothelial and smooth muscle cell proliferation, medial hypertrophy, and thrombosis in situ.
• The pathogenesis of PAH remains speculative. An elevated pulmonary vascular resistance seems to result from an imbalance between locally produced vasodilators and vasoconstrictors, in addition to vascular wall remodeling. Several mediators, including nitric oxide, prostacyclin, and endothelin, appear to play a central role in the pathobiology of PAH.
• Currently available specific therapies for pulmonary hypertension are based on our understanding of the metabolic pathways of these mediators. Future therapies will likely reflect our improved understanding of the proliferative and vascular remodeling pathways.

Back to Top

Suggested Readings

• Humbert, M., O. Sitbon, and G. Simonneau. 2004. Treatment of pulmonary arterial hypertension. N Engl J Med 351(14):1425-36.
• Dweik, R. 2002. Pulmonary hypertension and the search for the selective pulmonary vasodilator. Lancet 360(9337):886.
• Heresi, G. A., and R. A. Dweik. 2007. Pulmonary hypertension: evaluation and management. Compr Ther 33(3):150-61.
• Heresi, G. A., and R. A. Dweik. 2009. Sarcoidosis-associated pulmonary hypertension. One size does not fit all. Chest 135(6):1410-2.

Back to Top