AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Primary pulmonary hypertension (PPH) is a rare disease characterized by elevated pulmonary artery pressure with no apparent cause. PPH is also termed precapillary pulmonary hypertension or, more recently, idiopathic pulmonary arterial hypertension (IPAH). The diagnosis is usually made after excluding other known causes of pulmonary hypertension. Dresdale and colleagues first reported a hemodynamic account of IPAH in 1951. For additional resources, please visit Pulmonary Arterial Hypertension.

Pathophysiology

The pathophysiology of IPAH is poorly understood. An insult (eg, hormonal, mechanical, other) to the endothelium may occur, possibly in the setting of increased susceptibility to pulmonary vascular injury (ie, multiple hit theory), resulting in a cascade of events characterized by vascular scarring, endothelial dysfunction, and intimal and medial (smooth muscle) proliferation. At least 15-20% of patients with IPAH have a familial form, which has only recently been characterized. Some cases may be related to sporadic genetic defects. The most common genetic defect in these cases is related to the BMPR-II gene.

Early in the disease, as the pulmonary artery pressure increases because of increasing right ventricle work, thrombotic pulmonary arteriopathy occurs. Thrombotic pulmonary arteriopathy is characterized by in situ thrombosis of small muscular arteries of the pulmonary vasculature. In later stages, as the pulmonary pressure continues to rise, plexogenic pulmonary arteriopathy develops. This is characterized by a remodeling of the pulmonary vasculature with intimal fibrosis and replacement of normal endothelial structure.

Associated conditions

IPAH can be associated with portal hypertension (sometimes called portopulmonary hypertension), suggesting that patients with shunting of splanchnic blood, with or without liver disease, have a higher risk of developing PPH. Additionally, exposure of the pulmonary circulation to substances in the splanchnic circulation that normally are detoxified via the liver may contribute to the development of pulmonary hypertension. More research is necessary to better understand this relationship.

Patients with connective tissue diseases, namely the CREST (calcinosis cutis, Raynaud phenomenon, esophageal motility disorder, sclerodactyly, and telangiectasia) variant of scleroderma, systemic lupus erythematosus, and mixed connective tissue disease, are also predisposed to developing IPAH-like disease. This is now termed associated PAH, or APAH. However, the pathophysiologic nature of this predisposition is unclear. In the past, most experts used the term secondary pulmonary arterial hypertension for these diseases, indicating that, similar to IPAH, the process involves the precapillary circulation but is somehow caused by the underlying disease.

Other associations with IPAH include exposure to anorexigens and other alpha-adrenergic stimulants (eg, cocaine, amphetamines) and HIV seropositivity. How these associated conditions predispose to or cause PPH remains unknown.

In most cases of APAH, such as in connective tissue disease, the incidence of pulmonary hypertension is higher (>10% in some studies) than for IPAH, which has an incidence of 1-2 cases per million per year (see below).

Frequency

United States

IPAH is responsible for approximately 125-150 deaths per year and has an incidence rate of approximately 1-3 cases per million population per year. The incidence and prevalence of IPAH are considerably higher than those for pure IPAH.

International

The worldwide incidence of IPAH approximates that observed in the United States.

Mortality/Morbidity

IPAH has no cure. Untreated, IPAH leads to right-sided heart failure and death. The overall survival rate in one study was approximately 30% at 3 years. Prior to the 1990s, therapeutic options were limited. The recent emergence of prostacyclin analogues, endothelin receptor antagonists, and other novel drug therapies has greatly improved the outlook for patients with IPAH and IPAH-like diseases. In one study, the use of long-term prostacyclin agents resulted in a 5-year mortality rate greater than 65%. With newer therapies, perhaps in combination, these figures are expected to further improve.

Race

No racial predilection is recognized.

Sex

IPAH occurs at a female-to-male ratio ranging from 2-9:1, depending on the treatment center sampled; however, the reasons for this female predilection remain unknown.

Age

Typically, younger women of childbearing age develop IPAH. However, it can also affect women in their fifth and sixth decades of life or older.

CLINICAL

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History

The average time from symptom onset to diagnosis has been reported to be approximately 2 years. Despite recent attempts at increasing the awareness of PAH, especially APAH, this delay in diagnosis has not changed appreciably in recent years.

• Early symptoms are nonspecific. Often, neither the patient nor physician recognizes the presence of the disease, which leads to delays in diagnosis. Complicating matters, PPH requires an extensive workup in an attempt to elucidate an identifiable cause of the elevated pulmonary artery pressure.
• The most common symptoms reported in a national prospective study are as follows:
• • Dyspnea is present in 60%.
  • Weakness is present in 19%.
  • Recurrent syncope is present in 13%.
  • Women are more likely to be symptomatic than men.

Physical

Physical findings in persons with PAH can be quite variable.

• Physical examination of the cardiovascular system often reveals the following findings:
• • The pulmonic component of the second heart sound is usually increased, which may demonstrate fixed or paradoxic splitting in the presence of severe right ventricular dysfunction. Occasionally, the second heart sound may be palpable.
  • Pulmonic regurgitation (Graham Steell murmur) may also be apparent.
  • A murmur of tricuspid regurgitation can be present, and a right ventricular lift (heave) may be noted.
  • Jugular venous pulsations may be elevated in the presence of volume overload, right ventricular failure, or both. Large V waves are often present because of the commonly present severe tricuspid regurgitation.
• Other findings may include (1) hepatomegaly with palpable pulsations of the liver and (2) an abnormal abdominal-jugular reflex. Ascites is not uncommonly present in untreated patients or in patients with worsening decompensated right heart failure.
• Lung examination findings are usually normal.
• Extremity examination may reveal pitting edema of varying degrees. Patients who are bedridden may have presacral edema.

Causes

The strict definition of IPAH is pulmonary hypertension with no known cause. However, associations have been recognized (eg, liver cirrhosis, stimulant abuse, HIV infection; see Associated conditions in Pathophysiology).

DIFFERENTIALS

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Other Problems to be Considered

Anorexigen-associated pulmonary hypertension

WORKUP

Section 5 of 11  

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Lab Studies

• Antinuclear antibody (ANA): When performing a workup of a patient with possible PPH, excluding autoimmune disorders is important. However, up to 40% of patients with IPAH have been reported to have a positive ANA and have no other clinical manifestations of autoimmune disease. Most connective tissue diseases associated with pulmonary artery hypertension are diagnosed based on clinical results, with serology results used as adjunctive confirmation of the disease.
• Thyroid-stimulating hormone: Screen for thyroid abnormalities during the initial workup for IPAH because these abnormalities are common in patients with IPAH. Thyroid abnormalities may be the cause of or contribute to symptoms similar to IPAH. In addition, hyperthyroidism itself may lead to an elevation in pulmonary artery pressure.
• HIV testing: HIV-positive patients have a higher rate of IPAH compared with the general population; therefore, include an HIV test as part of the routine evaluation.
  

Imaging Studies

• Chest radiography: Chest radiography may be the first diagnostic step in the evaluation of a patient with dyspnea; however, for many patients with pulmonary artery hypertension, the findings do not help reveal the underlying etiology of the pulmonary hypertension. Chest radiography is useful for excluding interstitial and alveolar processes that may cause hypoxia-mediated pulmonary vasoconstriction.
• Echocardiography: This is extremely useful for assessing right and left ventricular function, estimating pulmonary systolic arterial pressure, and excluding congenital anomalies and valvular disease. Findings from echocardiography may demonstrate right-to-left shunting across a patent foramen ovale in approximately 33% of patients.
• High-resolution chest CT scanning and ventilation-perfusion lung scanning: These are frequently obtained to help exclude interstitial lung disease and thromboembolic disease.
• Pulmonary angiography: This test is occasionally required to help definitively exclude thromboembolic disease. While considered a high-risk procedure in patients with elevated pulmonary arterial pressures and/or right ventricular failure, a carefully performed study is generally safe.

Other Tests

• ECG: Results are often abnormal in patients with PPH, revealing right atrial enlargement, right axis deviation, right ventricular hypertrophy, and characteristic ST depression and T-wave inversions in the anterior leads. Some patients have few or no abnormal ECG findings; thus, normal ECG results do not exclude a diagnosis of PPH.
• Pulmonary function and cardiopulmonary exercise testing: Assessment of ventilatory efficiency and mechanical lung function can help differentiate intrinsic pulmonary vascular disease from cardiac deconditioning and restrictive or obstructive lung disease. In patients with PPH, values for peak exercise oxygen consumption, oxygen pulse, and ventilator equivalents (ratio of expired volume to carbon dioxide output at the anaerobic threshold) during exercise are abnormal to varying degrees.
• Diagnostic algorithms: Several diagnostic algorithms have been proposed in the literature that are useful for helping complete a thorough workup, which may be necessary to exclude all reasonable causes of secondary pulmonary hypertension. In 2004, an American College of Chest Physicians (ACCP) consensus statement was published, with diagnostic and treatment recommendations.
• Sleep study: Sleep apnea must be excluded as a contributor or cause of pulmonary hypertension if the patient's history suggests this diagnosis.

Procedures

• Cardiac catheterization: This is the criterion standard test to definitively confirm a PPH diagnosis. Excluding left-sided heart disease, including diastolic dysfunction, is especially important in these patients because of major treatment implications. Catheterization is also performed to determine vasoreactive status, which may have implications in the initiation and titration of high-dose calcium channel blocker (CCB) therapy.
• Catheter placement for long-term therapy: The initiation of intravenous therapy with epoprostenol (EPO) requires placement of a central venous catheter and detailed instruction on the long-term use of vasodilator therapy.
• Lung biopsy: When the etiology of pulmonary hypertension is still in doubt, a lung biopsy may be necessary.

Histologic Findings

Several histologic subtypes are associated with pulmonary arteriopathy in PPH, one of which involves in situ thrombosis. Thrombotic pulmonary arteriopathy may be observed, with or without plexiform lesions. It is characterized by in situ thrombosis of small muscular arteries of the pulmonary vasculature. Thrombotic pulmonary arteriopathy is often present at earlier stages of PPH (ie, before the development of plexogenic pulmonary arteriopathy) or as an irreversible lesion in later stages. Platelet activation and increased circulating procoagulant factors are observed.

Staging

Traditionally, New York Heart Association/World Health Organization functional classification is used to grade PPH disease severity. This grading system has obvious limitations because it is subjective.

Other means to characterize disease severity include hemodynamic findings after right-sided heart catheterization, exercise capacity (eg, peak exercise oxygen consumption, 6-min walk distance), and clinical severity of heart failure signs found during the physical examination. More recent studies show that the echocardiographically determined eccentricity index, a marker of interventricular septum flattening, is a prognostic indicator. Positive findings for serum troponin and the presence of a pericardial effusion are also of prognostic utility, indicating a worse prognosis.

TREATMENT

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Medical Care

• Anticoagulation
• • Several studies, using both univariate and multivariate analyses, show that survival is increased when the patient is treated with anticoagulant therapy, regardless of histopathologic subtype. However, these studies were retrospectively performed. No randomized, controlled clinical trials of anticoagulation in PPH exist; thus, the data are mostly consensus-driven rather than based on prospective evidence-based medicine.
  • Use warfarin to maintain an international normalized ratio of 1.5- to 2-times the control value, provided the patient has no contraindications to anticoagulation.
• Other oral agents
• • Use digoxin therapy to improve right ventricular function in patients with right ventricular failure. However, no randomized controlled clinical study has been performed to validate this strategy for patients with PPH.
  • Use diuretics to manage peripheral edema. The use of loop diuretics (eg, furosemide, bumetanide) requires potassium supplementation and close monitoring of serum potassium. Potassium-sparing diuretics may have a role in ameliorating the sometimes-intractable hypokalemia observed with daily diuretic use.
  • Use oxygen supplementation in those patients with resting or exercise-induced hypoxemia. Use caution if patients have a left-to-right shunt via a patent foramen ovale (see Imaging Studies) because supplemental oxygen in these instances may provide little or no benefit.
• Conventional oral vasodilator therapy
• • Until recently, CCBs had been the most widely used class of drugs for IPAH. These drugs are thought to act on the vascular smooth muscle to dilate the pulmonary resistance vessels and lower the pulmonary artery pressure. Several studies report clinical and hemodynamic benefits from the use of long-term calcium channel blockade. The use of these drugs produces a reduction in pulmonary vascular resistance by increasing the cardiac output and decreasing pulmonary artery pressure. It also improves the quality of life and survival rate, in patients who are proven "responders" to such therapy.
  • Only use CCBs on patients without overt evidence of right-sided heart failure. A cardiac index of less than 2 L/min/m² or elevated right atrial pressure above 15 mm Hg is evidence that CCBs may worsen right ventricular failure and, thus, are of no benefit. This is potentially harmful to patients with PPH.
  • In general, high doses of CCBs are used in patients with PPH; however, only patients with an acute vasodilator response to an intravenous or inhaled pulmonary vasodilator challenge (eg, with adenosine, EPO, nitric oxide) derive any long-term benefit from CCBs (this corresponds to <20% of patients with PPH and probably <10% of patients with secondary, PPH-like pulmonary artery hypertension).
  • Similarly, patients without an acute vasodilator response to a vasodilator challenge have a worse prognosis on long-term oral vasodilator therapy compared with those who have an initial response.
  • Importantly, realize that the absence of an acute response to intravenous or inhaled vasodilators does not preclude the use of intravenous vasodilator therapy. In fact, continuous intravenous vasodilator therapy is strongly suggested for these patients because CCBs are contraindicated.
  • This illustrates the importance of performing vasoreactivity testing in patients with PPH. Intravenous EPO or adenosine or inhaled nitric oxide are used most commonly for acute vasodilator testing. Oxygen, nitroprusside, and hydralazine should not be used as pulmonary vasodilator testing agents.
  • Only up to 25% of patients with PPH demonstrate significant pulmonary vasoreactivity. If patients demonstrate vasoreactivity and are candidates for high-dose CCB therapy, administer a CCB challenge to stable patients to determine the vasodilator response. Perform this in the critical care unit with a balloon flotation catheter in the pulmonary artery. Administer oral nifedipine every hour (diltiazem can be used if resting tachycardia is present) until a 20% decrease in pulmonary artery pressure and pulmonary vascular resistance is observed or systemic hypotension or other adverse effects preclude further drug administration.
  • Calculate the daily dosage requirement at half the total initial effective dose, and administer this every 6-8 hours. Typical doses of nifedipine and diltiazem can reach 240 mg/d and 900 mg/d, respectively. Use caution when withdrawing CCBs because rebound pulmonary hypertension has been reported with the cessation of vasodilator therapy.
• Approved pulmonary vasodilator medications currently available in the United States for PPH are as follows:
• • Epoprostenol (Flolan) - Intravenous, parenteral (see Medication); prostacyclin analogue, sometimes referred to as a "prostanoid"
  • Treprostinil (Remodulin) - Intravenous or subcutaneous, parenteral (see Medication); prostacyclin analogue, sometimes referred to as a "prostanoid"
  • Iloprost (Ventavis) - Nebulized inhalation; prostacyclin analogue, sometimes referred to as a "prostanoid"
• • Bosentan (Tracleer) - Oral; endothelin antagonist, or ERA
  • Ambrisentan (Letairis) - Oral; endothelin antagonist, or ERA
  • Sildenafil (Revatio) - Oral
  • Note: While the above agents are often referred to as pulmonary vasodilator medications, their actions are likely pleiotropic, affecting endothelial function and intimal and smooth muscle proliferation. Their ability to dilate pulmonary arteries and thereby lower pulmonary arterial pressure is modest in most cases.
• Future therapies
• • Clinical trials are under way to determine the safety and efficacy of several new therapies that include oral and inhaled prostanoids, phosphodiesterase inhibitors, and other novel agents.
  • Efforts are currently focused on prostacyclin analogues, newer endothelin antagonists, and phosphodiesterase-5 inhibitors (see below).

Surgical Care

• A single- or double-lung transplant is indicated for patients who do not respond to medical therapy. Simultaneous cardiac transplantation may not be necessary even with severe right ventricular dysfunction; however, this is dependent on the transplant institution.
• Atrial septostomy is a palliative procedure that may afford some benefit to patients with deteriorating conditions. This procedure works by allowing interatrial right-to-left shunting to occur, thus delivering more overall oxygen content to the respiring tissues, albeit with a lower overall saturation.

Diet

• No specific diet is recommended; however, a low-sodium and low-fluid diet is recommended for those with significant volume overload due to right ventricular failure.
• Patients taking warfarin must limit their intake of vitamin K–containing foods, such as green leafy and coliform vegetables.
• L-arginine supplementation (a precursor to nitric oxide) may be helpful; however, more studies are needed to confirm its role in the management of IPAH.

Activity

• Few data are available on cardiopulmonary rehabilitation. The generally accepted recommendation is that patients with pulmonary hypertension and heart failure perform mild symptom-limited aerobic activity and avoid complete bed rest. Isometric exercises (weight lifting) are contraindicated.
  

MEDICATION

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Current pulmonary vascular therapies appear to exert their actions on the pulmonary circulation by mechanisms that remain poorly defined. Clearly, the magnitude of the pulmonary vasodilator actions of prostanoids and endothelin antagonists do not account for the degree of clinical benefit observed with these drugs. Rather, additional effects on the endothelial health of the pulmonary circulation and on the inhibition of pathologic intimal fibrosis and smooth muscle proliferation are likely to be the predominant mechanisms involved in the treatment responses.

Drug Category: Parenteral vasodilators

For patients in whom CCBs fail to respond or with an inability to tolerate CCBs with NYHA types III and IV right-sided heart failure.

Drug Name	Treprostinil (Remodulin)
Description	Used to treat PAH. Structurally very similar to EPO but stable at room temperature and has much longer half-life; therefore, can be given as an SC continuous infusion via a much smaller pump. Elicits direct vasodilation of pulmonary and systemic arterial vessels and inhibits platelet aggregation. Vasodilation reduces right and left ventricular afterload and increases cardiac output and stroke volume. Recently FDA approved for IV use as a bioequivalent of subcutaneous treprostinil, using same delivery pump used for epoprostenol. Dosing is similar to SC delivery.
Adult Dose	1.25 ng/kg/min SC via continuous infusion initially; may increase by 1.25 ng/kg/min qwk for 4 wk, then may increase by 2.5 ng/kg/min qwk; if initial dose not tolerated, decrease to 0.625 ng/kg/min, then slowly titrate upward; must slowly taper if discontinued (potential for severe rebound pulmonary hypertension and death) Subsequent dose: Titrate based on follow-up outpatient evaluation; currently, no upper limit defined; most patients derive optimal benefit with 25-40 ng/kg/min; doses exceeding 40 ng/kg/min after 1 y of therapy are not uncommon; IV dosing is similar to that used in SC delivery
Pediatric Dose	Not established; dosing is based on body weight
Contraindications	Documented hypersensitivity
Interactions	Additive hypotensive effect with antihypertensive agents or diuretics; may increase risk of bleeding with other antiplatelet drugs (eg, aspirin) or anticoagulants (eg, warfarin, heparin)
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	May cause infusion site pain and irritation; common adverse effects include diarrhea, jaw pain, edema, vasodilatation, and nausea (typical effects of prostanoids); do not discontinue abruptly

Drug Category: Phosphodiesterase (type 5) Enzyme Inhibitor

The antiproliferative effects of the phosphodiesterase type 5 pathway, which regulates cyclic guanosine monophosphate hydrolysis, may be significant in the long-term treatment of pulmonary hypertension with PDE5 inhibitors such as sildenafil.

Drug Category: Inhaled vasodilators

Inhaled PGI₂ synthetic analogues are an alternative to parenteral administration and an attempt to limit systemic adverse effects.

Drug Category: Oral pulmonary hypertension agents

ERAs are alternative therapy to parenteral prostacyclin agents. Given PO. Competitively bind to ET-1 receptors endothelin-A and endothelin-B, causing reduction in PAP, PVR, and mean RAP. Indicated for treatment of PAH in patients with WHO class III or IV symptoms to improve exercise ability and decrease rate of clinical deterioration.

Drug Name	Ambrisentan (Letairis)
Description	Endothelin receptor antagonist indicated for pulmonary arterial hypertension in patients with WHO class II or III symptoms. Improves exercise ability and decreases progression of clinical symptoms. Inhibits vessel constriction and elevation of blood pressure by competitively binding to endothelin-1 receptors ETA and ETB in endothelium and vascular smooth muscle. This leads to significant increase in cardiac index associated with significant reduction in pulmonary artery pressure, pulmonary vascular resistance, and mean right atrial pressure. Because of the risks of hepatic injury and teratogenic potential, only available through the Letairis Education and Access Program (LEAP). Prescribers and pharmacies must register with LEAP in order to prescribe and dispense. For more information, see http://www.letairis.com or call (866) 664-LEAP (5327).
Adult Dose	5 mg PO qd initially; may increase to 10 mg PO qd if 5 mg/d tolerated; do not chew, crush, or split tab
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Glycoprotein-P, OATP, UGTs (ie, 1A9S, 2B7S, 1A3S), CYP2C19, and CYP3A substrate; coadministration with CYP3A (eg, cyclosporine, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin) or 2C19 inhibitors (eg, omeprazole) may decrease elimination and therefore increase serum levels; CYP3A and 2C19 inducers (eg, rifampin) may increase metabolism and therefore decrease serum levels
Pregnancy	X - Contraindicated; benefit does not outweigh risk
Precautions	Common adverse effects include peripheral edema, nasal congestion, sinusitis, and facial flushing; caution with mild hepatic impairment or history of moderate-to-severe hepatic impairment; hepatic injury may occur (monitor bilirubin, ALT, and AST values at baseline and then monthly); may use in women of childbearing potential only after negative pregnancy test result and must use 2 reliable methods of contraception (unless tubal sterilization or Copper T 380A or LNg 20 IUD inserted); may decrease hemoglobin and hematocrit values (monitor at baseline, 1 mo, and then periodically)

FOLLOW-UP

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Further Inpatient Care

• Patients on EPO or IV treprostinil therapy must have a central venous catheter placed surgically and receive their initial dose in an inpatient setting. This allows for monitoring of acute adverse effects and provides the opportunity for the patient and support personnel to master the drug preparation and administration technique before discharge.

Further Outpatient Care

• Currently, no precise dosage adjustment algorithm is available for patients with IPAH who are on vasodilator therapy.
• Monitor the patient with frequent physical examinations, and focus the history on heart failure symptoms and adverse effects of medications.
• Echocardiography has been used in several studies to serially monitor changes in the right ventricular–right atrial pressure gradient and the right and left ventricular chamber sizes.
• Findings from other noninvasive modalities (eg, electron-beam CT measurements of cardiac chamber sizes) correlate with hemodynamic improvements in pulmonary physiology.
• More recently, cardiopulmonary exercise testing, serial invasive hemodynamic testing, and 6-minute walk testing have been used to monitor the disease status of patients with IPAH.

Complications

• Advanced right-sided heart failure with hepatic congestion
• Pedal edema
• Pleural effusions
• Ascites
• Worsening dyspnea on exertion

Prognosis

• The mortality rate for untreated IPAH is approximately 50% at 3 years (varies with severity at presentation). With EPO therapy, this has increased to higher than 65% at 5 years. Data on long-term survival in patients treated with other pulmonary vascular therapies are emerging. Patients whose disease progresses and is unresponsive to medical treatments either undergo transplantation or die of progressive right-sided heart failure.

Patient Education

• Patient and physician education about this rare fatal disease is paramount.
• If applicable, instruct patients on how to administer their daily parenteral medication.
• For excellent patient education materials, see eMedicine's Lung and Airway Center and Heart and Blood Vessels Center.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Treating PAH requires significant education regarding and exposure to the available therapies for IPAH and the potential complications. Because IPAH is relatively rare, management is best left to expert personnel at centers with regular exposure to these patients. Failure to heed this advice can result in medicolegal pitfalls should patient outcome be less than optimal.

MULTIMEDIA

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Media file 1:  CADD Legacy ambulatory infusion pump. Courtesy SIMS Deltec, St. Paul, Minn.
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Media file 2:  Two-dimensional short-axis echocardiogram image. Note the flattened interventricular septum due to right ventricular overload.
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Media type:  Image

REFERENCES

Section 11 of 11

• Authors and Editors
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• References

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Article Last Updated: Aug 29, 2007