Pulmonary Hypertension

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64 Pulmonary Hypertension

Lewis J. Rubin

Pulmonary hypertension (PH) is defined as a pulmonary artery mean pressure (PAPm) of 25 mm Hg or greater and may be precapillary or postcapillary in etiology. Postcapillary causes include processes affecting the left side of the heart (e.g., left ventricular systolic or diastolic dysfunction, mitral stenosis or regurgitation, aortic valvular disease) or, more rarely, the pulmonary veins (pulmonary veno-occlusive disease). Management of postcapillary PH typically involves treating the underlying left-sided cardiac process. Medications used to treat precapillary PH are often not only ineffective for postcapillary PH but may in fact be harmful, potentially leading to the development of pulmonary edema.

Precapillary PH, or pulmonary arterial hypertension (PAH), can be idiopathic (IPAH—previously known as primary pulmonary hypertension [PPH]) or may occur in association with a variety of underlying disease processes such as collagen vascular disease, portal hypertension, congenital systemic-to-pulmonary shunts, drug or toxin exposure, or HIV infection.1 IPAH is principally a disease of young women, but it can affect all age groups and both sexes. A genetic predisposition may underlie a substantial proportion of these cases.2–8

Initial therapy may be directed at an underlying cause or contributing factor, such as using continuous positive airway pressure (CPAP) and supplemental oxygen for PH associated with obstructive sleep apnea. Following identification and treatment of underlying associated disorders and contributing factors, specific therapy for PAH should be considered. IPAH carried a very poor prognosis (median survival approximately 2.8 years from the date of diagnosis) through the mid-1980s. Subsequently, a number of therapeutic options have been developed, and seven have been approved by the U.S. Food and Drug Administration (FDA), falling into three classes of drugs: (1) prostacyclins, including intravenous epoprostenol, treprostinil (subcutaneously, intravenously, and by inhalation), and inhaled iloprost; (2) endothelin receptor antagonists (bosentan, ambrisentan); and (3) phosphodiesterase type-5 inhibitors, including sildenafil and tadalafil. Other agents being studied for PAH include guanylate cyclase activators, tyrosine kinase inhibitors, and vasoactive intestinal peptide (VIP).

image Diagnosis

Symptoms, Signs, and Clinical History

Because of the insidious onset of symptoms, PAH is often advanced at the time of diagnosis. Dyspnea on exertion is a common presenting symptom, but it is sometimes attributed to deconditioning or other cardiorespiratory ailment. Chest pain, mimicking angina pectoris, may occur. Patients with advanced disease may present with syncope or signs and symptoms of right-sided heart failure, including lower extremity edema, jugular venous distention, and ascites.

The clinical history should focus initially on exclusion of underlying causes of PH. Important clues to an underlying condition might include previous history of a heart murmur, deep venous thrombosis or pulmonary embolism, Raynaud’s phenomenon, arthritis, arthralgias, rash, heavy alcohol consumption, hepatitis, heavy snoring, daytime hypersomnolence, morning headache, and morbid obesity. A careful family history should be obtained. Medication exposures, particularly to appetite suppressants and amphetamines, should be noted. Cocaine is a powerful vasoconstrictor and may contribute to the development of PH. Intravenous drug abuse has been associated with the development of PAH.

Physical Examination

Signs of PAH may not become apparent until late in the disease. Findings such as an accentuated second heart sound, a systolic murmur over the left sternal border, jugular venous distention, peripheral edema, and/or ascites might suggest the presence of PH and right ventricular dysfunction. Associated systemic diseases such as collagen vascular disease or liver disease may also become apparent during routine examination.

Laboratory Evaluation

Laboratory evaluation can provide important information in detecting associated disorders and contributing factors. A collagen vascular screen including antinuclear antibodies, rheumatoid factor, and erythrocyte sedimentation rate is often helpful in detecting autoimmune disease, although some patients with IPAH will have a low-titer positive antinuclear antibody test.9 The scleroderma spectrum of disease, particularly limited scleroderma, or the CREST syndrome (calcinosis, Raynaud’s phenomenon, esophageal dysfunction, sclerodactyly, telangiectasias), has been associated with an increased risk for the development of PAH.10,11 Liver function tests (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase) may be elevated in patients with right ventricular failure and passive hepatic congestion but may also be associated with underlying liver disease. Liver disease with portal hypertension has been associated with the development of PH. Thyroid disease may occur with increased frequency in patients with IPAH and should be excluded with thyroid function testing.12 Human immunodeficiency virus (HIV) testing and hepatitis serologic studies should be considered in patients at risk. Routine laboratory studies such as complete blood cell count, complete metabolic panel, prothrombin time, and partial thromboplastin time are recommended during the initial evaluation and as indicated to monitor the patient’s long-term clinical status.

Echocardiography

Doppler echocardiography is useful in estimating the severity of PH and detecting left-sided heart disease. Findings may include enlargement of the right ventricle, flattening of the interventricular septum, and compression of the left ventricle. Bubble contrast echocardiography may detect a right-to-left shunt, but exclusion of a left-to-right intracardiac shunt may require cardiac catheterization with an oximetry series. Echocardiography may be a useful noninvasive means of long-term follow-up,13,14 although not all patients have suitable echocardiographic windows.

Radiographic Evaluation and Exclusion of Thromboembolic Disease

Chest radiography may reveal enlargement of the central pulmonary vessels and evidence of right ventricular enlargement. Evidence of parenchymal lung disease may be apparent. When parenchymal lung disease is suspected, pulmonary function testing and high-resolution computed tomography (CT) of the chest may be indicated. Ventilation/perfusion (V/Q) lung scanning should be performed in an attempt to exclude chronic recurrent pulmonary thromboembolic disease, which is among the most preventable and treatable causes of PH. Diffuse mottled perfusion can be seen in IPAH, whereas larger segmental and subsegmental mismatched defects are suggestive of chronic recurrent pulmonary thromboembolic disease. Intermediate results on V/Q lung scanning may require pulmonary arteriography to obtain a definitive diagnosis. Although contrast medium–enhanced CT has been popularized recently for the diagnosis of acute pulmonary thromboembolic disease, there is limited experience with this technique in chronic thromboembolic disease. Accordingly, we recommend caution at present in using contrast-enhanced CT to exclude chronic recurrent thromboembolic disease.

Pulmonary Function Testing

Pulmonary function testing is indicated to detect underlying parenchymal lung disease. The diffusing capacity is often reduced in pulmonary vascular disease, consistent with impaired gas exchange.

Right-Sided Heart Catheterization and Vasoreactivity Testing

Right-sided heart catheterization remains an important part of the evaluation. Left-sided heart dysfunction and intracardiac shunts can be excluded, the degree of PH can be accurately quantified, and cardiac output can be measured. Pulmonary vascular resistance can then be calculated. Acute pulmonary vasoreactivity can be assessed using a short-acting agent such as prostacyclin (epoprostenol), inhaled nitric oxide, or intravenous adenosine.1 The consensus definition of a positive acute vasodilator response in a PAH patient is a fall of PAPm of at least 10 mm Hg to ≤40 mm Hg, with an increased or unchanged cardiac output. The primary objective of acute vasodilator testing in patients with PAH is to identify patients who might be effectively treated with oral calcium channel blockers. The acute response to a short-acting agent such as prostacyclin has been shown to be predictive of the response to a calcium channel blocker.14 Unstable patients or those in severe right-sided heart failure who would not be candidates for treatment with calcium channel blockers need not undergo vasodilator testing.

image Treatment

General Care

Warfarin, Oxygen, Diuretics, Digoxin, and Vaccination

Improved survival has been reported with oral anticoagulation in IPAH.15,16 The target International Normalized Ratio (INR) in these patients is 1.5 to 2.5. Anticoagulation of patients with PAH due to other underlying processes such as scleroderma or congenital heart disease is controversial. Generally, patients with PAH treated with chronic intravenous epoprostenol are anticoagulated in the absence of contraindications, owing in part to the additional risk of catheter-associated thrombosis.

Hypoxemia is a pulmonary vasoconstrictor and can contribute to the development or progression of PAH. It is generally considered important to maintain oxygen saturations at greater than 90% at all times. Supplemental oxygen use is more controversial in patients with Eisenmenger physiology but may decrease the need for phlebotomy and potentially reduce the occurrence of neurologic dysfunction and complications.

Diuretics are indicated in patients with evidence of right ventricular failure and volume overload (i.e., peripheral edema and/or ascites). Careful dietary restriction of sodium and fluid intake is important in the management of patients with PAH with right-sided heart failure. Rapid and excessive diuresis may produce systemic hypotension, renal insufficiency, and syncope. Serum electrolytes and measures of renal function should be followed closely in patients receiving diuretic therapy.

Although not extensively studied in PAH, digitalis is sometimes utilized in refractory right ventricular failure or atrial dysrhythmias. Drug levels should be followed closely, particularly in patients with impaired renal function.

Because of the potentially devastating effects of respiratory infections in PAH, immunization against influenza and pneumococcal pneumonia is recommended.

Calcium Channel Blockers

Patients with IPAH who respond to vasodilators and calcium channel blockers15 generally have improved survival. Unfortunately, this tends to represent a relatively small proportion of patients, comprising fewer than 20% of IPAH patients and even fewer patients with other causes of PAH.

Prostanoids

Prostacyclin, a metabolite of arachidonic acid produced primarily in vascular endothelium, is a potent systemic and pulmonary vasodilator that also has antiplatelet aggregatory effects. A relative deficiency of endogenous prostacyclin may contribute to the pathogenesis of PAH.17

Epoprostenol

Epoprostenol therapy is complicated by the need for continuous intravenous infusion. The drug is unstable at room temperature and is generally best kept cold before and during infusion. It has a very short half-life in the bloodstream (<6 minutes), is unstable at acidic pH, and cannot be taken orally. Because of the short half-life, the risk of rebound worsening with abrupt/inadvertent interruption of the infusion, and its effects on peripheral veins, it should be administered through an indwelling central venous catheter. Common side effects of epoprostenol therapy include headache, flushing, jaw pain with initial mastication, diarrhea, nausea, a blotchy erythematous rash, and musculoskeletal aches and pain (predominantly involving the legs and feet). These tend to be dose dependent and often respond to a cautious reduction in dose. Severe side effects can occur with overdosage of the drug. Acutely, overdosage can lead to systemic hypotension. Chronic overdosage can lead to the development of a hyperdynamic state and high-output cardiac failure.18 Abrupt or inadvertent interruption of the epoprostenol infusion should be avoided because this may lead to a rebound worsening of PH, with symptomatic deterioration and even death. Other complications of chronic intravenous therapy with epoprostenol include line-related infections (which can range from small exit-site reactions to tunnel infections and cellulitis to bacteremic infections with sepsis), catheter-associated venous thrombosis, systemic hypotension, thrombocytopenia, and ascites.

Treprostinil

Treprostinil, a prostacyclin analog with a half-life of 3 hours, is stable at room temperature. An international placebo-controlled, randomized trial demonstrated that treprostinil improved exercise tolerance, although the 16-meter median difference between treatment groups in 6-minute walk distance was relatively modest.19 Treprostinil also improved hemodynamic parameters. Common side effects included headache, diarrhea, nausea, rash, and jaw pain. Side effects related to the infusion site were common (85% of patients complained of infusion-site pain, and 83% had erythema or induration at the infusion site). Treprostinil is also approved for intravenous delivery based on bioequivalence with the subcutaneous route and is also approved as an inhaled preparation administered in doses of 6 to 54 µg, 4 times daily.20

Inhaled Iloprost

Iloprost is a chemically stable prostacyclin analog with a serum half-life of 20 to 25 minutes.21 In IPAH, acute inhalation of iloprost resulted in a more potent pulmonary vasodilator effect than acute nitric oxide inhalation.21,22 In uncontrolled and controlled studies of iloprost for various forms of PAH,23,24 inhaled iloprost at a total daily dose of 30 to 200 µg divided in 6 to 12 inhalations improved functional class, exercise capacity, and pulmonary hemodynamics for periods up to 1 year of follow-up. The treatment was generally well tolerated except for mild coughing, minor headache, and jaw pain in some patients. The most important drawback of inhaled iloprost is the relatively short duration of action, requiring the use of 6 to 9 inhalations a day.

Beraprost

Beraprost sodium is an orally active prostacyclin analog25 that is absorbed rapidly in fasting conditions. It has been evaluated in peripheral vascular disorders such as intermittent claudication,26 Raynaud’s phenomenon, and digital necrosis in systemic sclerosis,27 with variable results. Although several small, open, uncontrolled studies reported beneficial hemodynamic effects with beraprost in patients with IPAH, two randomized double-blind, placebo-controlled trials have shown only modest improvement and suggest that beneficial effects of beraprost may diminish with time.28,29

Endothelin Receptor Antagonists

Endothelin-1 is a vasoconstrictor and a smooth muscle mitogen that may contribute to the pathogenesis of PAH. Endothelin-1 expression, production, and concentration in plasma30,31 and lung tissue32 are elevated in patients with PAH, and these levels are correlated with disease severity.

Bosentan

Bosentan is a dual endothelin receptor blocker that has been shown to improve pulmonary hemodynamics and exercise tolerance and delay the time to clinical worsening in PAH patients falling into NYHA Classes III and IV.33,34 The most frequent and potentially serious side effect with bosentan is dose-dependent abnormal hepatic function (as indicated by elevated levels of alanine aminotransferase and/or aspartate aminotransferase). Because of the risk of potential hepatoxicity, the FDA requires that liver function tests be performed at least monthly in patients receiving this drug. Bosentan may also be associated with the development of anemia, which is typically mild; hemoglobin/hematocrit should be checked regularly.

Ambrisentan

Ambrisentan is a selective endothelin-A receptor antagonist that has been shown to be effective in PAH.35 The usual doses are 5 to 10 mg daily.

Phosphodiesterase Inhibitors

Phosphodiesterases (PDEs) are enzymes that hydrolyze the cyclic nucleotides, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), and limit their intracellular signaling. Drugs that selectively inhibit cGMP-specific PDEs (or type 5 PDE5 inhibitors) augment the pulmonary vascular response to endogenous or inhaled nitric oxide in models of PH.36–37 PDE5 is strongly expressed in the lung, and PDE5 gene expression and activity are increased in chronic PH.38

Sildenafil

Sildenafil is a potent specific PDE5 inhibitor that is approved for erectile dysfunction. Recent reports have shown that sildenafil blocks acute hypoxic pulmonary vasoconstriction in healthy adult volunteers and acutely reduces PAPm in patients with PAH.39 In comparison with inhaled nitric oxide, sildenafil produced similar reductions in PAPm; but unlike nitric oxide, sildenafil also had apparent systemic hemodynamic effects. When combined with inhaled nitric oxide, sildenafil appears to augment and prolong the effects of inhaled nitric oxide,40 and it appears to prevent rebound pulmonary vasoconstriction after acute withdrawal of inhaled nitric oxide.41 Several randomized studies have demonstrated sildenafil’s efficacy in PAH, both as monotherapy and in combination with epoprostenol.42,43 Sildenafil treatment in animal models with experimental lung injury reduced PAP, but gas exchange worsened owing to impaired V/Q mismatch.44,45 Accordingly, caution is advised when using sildenafil to treat PH in patients with severe lung disease.

Tadalafil

The FDA recently approved tadalafil, another PDE5 inhibitor previously approved for erectile dysfunction, for the treatment of PAH based on a randomized clinical trial.46 Side effects appear similar to sildenafil. The recommended dosage is 40 mg daily.

Nitric Oxide

Nitric oxide contributes to maintenance of normal vascular function and structure. It is particularly important in normal adaptation of the lung circulation at birth, and impaired nitric oxide production may contribute to the development of neonatal PH. L-Arginine is the sole substrate for nitric oxide synthase and thus is essential for nitric oxide production.

Inhaled Nitric Oxide

Inhaled nitric oxide has been shown to have potent and selective pulmonary vasodilator effects during brief treatment of adults with IPAH.47 It is a potent pulmonary vasodilator in newborns with PH (persistent pulmonary hypertension of the newborn [PPHN]), children with congenital heart disease, and patients with postoperative PH, acute respiratory distress syndrome, or undergoing lung transplantation.48 It is of substantial benefit in PPHN, decreasing the need for support with extracorporeal membrane oxygenation (ECMO).49 Although inhaled nitric oxide has been used in diverse clinical settings, especially in intensive care medicine, FDA approval for this therapy is limited to newborns with hypoxemic respiratory failure at this time.

In chronic PAH, the use of inhaled nitric oxide has been primarily for acute testing of pulmonary vasoreactivity during cardiac catheterization1 (see earlier) or for acute stabilization of patients during deterioration.

Lung Transplantation

Lung transplantation for PAH is generally reserved for patients whose condition is failing despite the best available medical therapy. Whereas lung transplantation is challenging in general, it is even more so in the group of patients with PAH.50 Worldwide, overall survival is approximately 77% at 1 year and 44% at 5 years.51 Survival in PAH patients undergoing lung transplantation is 66% to 75% at 1 year (one center has reported 1- and 5-year actuarial survival of 75% and 57%, respectively).52 The higher early mortality in PAH patients may be related to higher anesthetic and operative risks, the need for cardiopulmonary bypass,53 and the increased occurrence of postoperative reperfusion pulmonary edema in patients with PAH undergoing single lung transplantation. In this situation, reperfusion pulmonary edema may be aggravated by the increased blood flow to the newly engrafted lung. In addition, V/Q mismatching can be particularly severe.54 Most centers therefore seem to prefer bilateral lung transplantation for patients with PAH.55 The timing of transplantation in PAH is challenging. It is probably most useful in patients showing clear evidence of deterioration such as decline in functional capacity and the development of right-sided heart failure despite maximal medical therapy.

image Special Situations in the Intensive Care Unit

Deep Venous Thrombosis Prophylaxis

Patients with PAH are likely at increased risk for the occurrence of deep venous thrombosis (DVT) and are certainly at increased risk for poor outcomes as a consequence of the development of DVT. Patients with PAH are prone to a more sedentary lifestyle and to chronic venous congestion of the lower extremities owing to increased right-sided cardiac filing pressures. Hospitalization in the ICU, often with discontinuation of anticoagulation in anticipation of invasive procedures, likely places these patients at even higher risk for DVT. For these reasons, meticulous attention must be paid to DVT prophylaxis.

Procedures and Surgery

Procedures and surgery in patients with PAH can be associated with substantially increased operative and perioperative risks, and appropriate precautions should be undertaken to optimize outcomes. As always, careful consideration should be given to whether an invasive procedure is absolutely necessary.

Vasovagal Events

Patients with severe PAH are particularly prone to vasovagal events, which can lead to severe consequences including syncope, cardiopulmonary arrest, and death. Pain, nausea, vomiting, or even a bowel movement can lead to a vasovagal event in patients with severe PAH. Cardiac output may be particularly dependent on heart rate in this situation, and the bradycardia and systemic vasodilatation that accompany a vasovagal event can therefore result in an abrupt decrease in systemic arterial pressure. Patients should therefore have close monitoring of their heart rate during invasive procedures, with ready availability of atropine or a similar agent.

Avoidance of Hypoxemia and Hypercarbia

Hypoxemia and hypercarbia are both pulmonary vasoconstrictors and can contribute to the worsening of PH. Oversedation can lead to ventilatory insufficiency and precipitate clinical deterioration. Caution should be utilized in laparoscopic procedures in which carbon dioxide is used for abdominal insufflation, because absorption can lead to hypercarbia. The induction of anesthesia and intubation for surgical procedures can be a particularly high-risk time for patients with PAH, because they are at risk for vagal events, hypoxemia, hypercarbia, and shifts in intrathoracic pressure with associated changes in cardiac filling pressures.

Pregnancy

The hemodynamic changes in pregnancy are substantial, and volume shifts occur immediately postpartum, with cardiac filling pressures increasing as a result of decompression of the vena cava and the return of uterine blood into the systemic circulation. The changes induced by pregnancy impose a significant hemodynamic stress in women with IPAH, leading to an estimated 30% to 50% mortality rate.56,57 A meta-analysis of the outcome of pulmonary vascular disease and pregnancy reported a maternal mortality rate of 36% in Eisenmenger’s syndrome, 30% in IPAH, and 56% in secondary PH.58 Because of high maternal and fetal morbidity and mortality rates, most experts recommend effective contraception and early fetal termination in the event of pregnancy.59 There have been case reports of successful treatment of pregnant IPAH patients with chronic intravenous epoprostenol,60–62 inhaled nitric oxide,63–65 and oral calcium channel blockers.66 Endothelin receptor antagonists are classified as teratogenic and should be avoided in this setting. In general, management includes early hospitalization for monitoring, supportive therapy with cautious fluid management, supplemental oxygen, diuretics, and dobutamine, as needed. The use of a pulmonary artery catheter for close hemodynamic monitoring and titration of vasodilator and cardiotonic therapy has been recommended. Recommendations regarding mode of delivery remain controversial.

Portopulmonary Hypertension

Patients with chronic liver disease have an increased prevalence of pulmonary vascular disease.67,68 Two forms of pulmonary vascular disease can complicate chronic liver disease: the hepatopulmonary syndrome and portopulmonary hypertension. Both tend to occur in patients with chronic, late-stage liver disease, and each may increase the risk associated with liver transplantation.

Hypoxemia and intrapulmonary shunting characterize the hepatopulmonary syndrome. Shunting may be manifest echocardiographically by the late appearance (after three to five cardiac cycles) of bubble contrast in the left side of the heart. Treatment is generally supportive, with supplemental oxygen. The syndrome may improve in some patients after liver transplantation. Severe hepatopulmonary syndrome may increase the risk associated with undergoing liver transplantation.

Portopulmonary hypertension occurs in patients with chronic, late-stage liver disease and/or portal hypertension.69 Portopulmonary hypertension often differs hemodynamically from IPAH, and these differences may affect the approach to therapy. Patients with portopulmonary hypertension have lower pulmonary arterial diastolic and mean pressures, higher cardiac outputs, and lower pulmonary and systemic resistances.70 Later-stage patients may develop hemodynamic findings more similar to those of patients with IPAH, and this group may have a poorer prognosis and be at higher risk with attempted liver transplantation. It is occasionally possible to make a borderline candidate for liver transplantation an acceptable one through aggressive treatment of the PAH. Supplemental oxygen should be used as needed to maintain saturations ≥ 91% at times. Diuretic therapy should be utilized to control volume overload, edema, and ascites. Anticoagulant therapy has not been carefully studied in this population and should probably be avoided in patients with significant coagulopathy due to impaired hepatic synthetic capability and in patients at increased risk of bleeding due to gastroesophageal varices. There have been a number of case reports and small case series describing the use of intravenous epoprostenol for treatment of portopulmonary hypertension.71–75 Interestingly, some patients may demonstrate improvement in their PH after liver transplantation.76 Other patients may develop worsening of their PH well after transplantation. It may be possible to wean an occasional patient off epoprostenol after liver transplantation. This should probably be done very gradually under close observation. The development of increasing dyspnea, fluid retention, or fatigue should prompt reevaluation and reinstitution of epoprostenol if necessary. Because of its potential for hepatoxicity, caution is advised in using the oral endothelin antagonists in this population.

Key Points

1 The evaluation of patients with pulmonary hypertension (PH) is directed at the detection of underlying contributing factors and associated conditions such as left-sided cardiac dysfunction, underlying congenital heart disease, pulmonary thromboembolic disease, collagen vascular disease, parenchymal lung disease, obstructive sleep apnea, liver disease, amphetamine or appetite suppressant use, intravenous drug abuse, or human immunodeficiency virus (HIV) infection.
2 Patients with severe PH are particularly prone to vasovagal events, and when these occur they can lead to severe consequences, including syncope, cardiopulmonary arrest, and death.
3 Hypoxemia and hypercarbia are both pulmonary vasoconstrictors and can contribute to the worsening of pulmonary hypertension.
4 The induction of anesthesia and intubation for surgical procedures can be a particularly high-risk time for patients with PAH, as they are at risk for vagal events, hypoxemia, hypercarbia, and shifts in intrathoracic pressure with associated changes in cardiac filling pressures.

Annotated References

Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N Engl J Med. 1996;334(5):296-302.

This prospective, multicenter, randomized, and controlled trial showed that chronic therapy with intravenous epoprostenol improved exercise capacity, cardiopulmonary hemodynamics, and survival in patients with IPAH.

Fuster V, Steele PM, Edwards WD, Gersh BJ, McGoon MD, Frye RL. Primary pulmonary hypertension: natural history and the importance of thrombosis. Circulation. 1984;70(4):580-587.

This early study suggested that anticoagulation with warfarin improved survival in patients with IPAH.

International PPH ConsortiumLane KB, Machado RD, Pauciulo MW, et al. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. Nat Genet. 2000;26(1):81-84.

Deng Z, Morse JH, Slager SL, et al. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet. 2000;67(3):737-744.

These seminal papers report that mutations in the BMPR2 gene, encoding a TGF-beta receptor, cause familial PAH. This important discovery may provide critical insight into the mechanisms underlying the development of IPAH and ultimately lead to better-targeted and more effective therapy.

Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med. 1992;327(2):76-81.

This study showed that a subset of patients with IPAH demonstrate vasoreactivity and will respond to chronic therapy with oral calcium channel blockers. It also supported the concept that anticoagulation with warfarin may improve survival in IPAH.

Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346(12):896-903.

This international, prospective, multicenter, randomized, placebo-controlled, double-blind trial showed that endothelin receptor blockade with bosentan improved exercise capacity in patients with IPAH and PAH occurring in association with collagen vascular disease.

References

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2 Lane KB, et al. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. The International PPH Consortium. Nat Genet. 2000;26:81-84.

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15 Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med. 1992;327:76-81.

16 Fuster V, et al. Primary pulmonary hypertension: Natural history and the importance of thrombosis. Circulation. 1984;70:580-587.

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27 Vayssairat M. Preventive effect of an oral prostacyclin analog, beraprost sodium, on digital necrosis in systemic sclerosis. French Microcirculation Society Multicenter Group for the Study of Vascular Acrosyndromes. J Rheumatol. 1999;26:2173-2178.

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31 Yamane K. Endothelin and collagen vascular disease: A review with special reference to Raynaud’s phenomenon and systemic sclerosis. Intern Med. 1994;33:579-582.

32 Giaid A, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med. 1993;328:1732-1739.

33 Channick RN, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: A randomised placebo-controlled study. Lancet. 2001;358:1119-1123.

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