Pulmonary Hypertension

David B Badesch, University of Colorado Health Sciences Centre, Denver, Colorado, USA
Pulmonary hypertension is an abnormal increase in blood pressure within the lung circulation. This potentially fatal disorder was previously associated with a poor prognosis, but long-term survival is now possible with aggressive medical therapy and/or lung transplantation.

Secondary article
Article Contents
. Introduction . Primary Pulmonary Hypertension . Secondary Pulmonary Hypertension . Summary . Acknowledgements

Introduction
Pulmonary hypertension is an abnormal increase in the blood pressure within the lung circulation. It is typically dened as a mean pulmonary arterial pressure greater than 25 mmHg. Pulmonary hypertension has historically been classied by the underlying aetiology into primary and secondary categories. Although there is ongoing debate regarding changing this classication scheme, it continues to have clinical utility. Unexplained or primary pulmonary hypertension (PPH) is a potentially fatal disease of unknown cause. Although it has a predilection for young women, it can occur in both sexes and all ages. The diagnosis is one of exclusion, with all known secondary causes having been ruled out. Secondary pulmonary hypertension may occur as a result of a variety of underlying diseases, including congenital heart disease, collagen vascular disease, pulmonary thromboembolism, disease of the lung parenchyma such as interstitial lung disease or emphysema, obstructive sleep apnoea with nocturnal hypoxaemia, liver disease or previous intravenous drug use.

Autoimmunity may play a role in the pathogenesis of PPH. Low-titre positive antinuclear antibodies (ANAs) occur in patients with PPH (Rich et al., 1986). Autoantibodies to Ku, a deoxyribonucleic acid-binding protein, which are found in some patients with systemic lupus erythematosus, scleroderma, myositis and Sjo gren syndrome, have been reported in a subset of patients (23%) with PPH (Isern et al., 1992). We reported a small series of patients with coexistent PPH and hypothyroidism, again raising the possibility of an underlying autoimmune process (Badesch et al., 1993).

Epidemiology
PPH was previously rare, with an estimated incidence of 3001000 new cases per year in the United States, or approximately one to two new cases per million population annually. There appears to be a female:male predominance of approximately 1.7:1.0, the reason for which is unknown but hormonal inuences may play a role. Recently, considerable attention has been focused upon the potential role of appetite suppressant medications in triggering the development of PPH. Patients exposed to

Primary Pulmonary Hypertension

Aetiology and pathogenesis
The aetiology of PPH is, by denition, unknown, but it has been suggested that genetic predisposition, autoimmunity, viral infection, hormonal inuences, environmental and drug exposures, decient endogenous production of prostacyclin and/or nitric oxide (Christman et al., 1992; Giaid and Saleh, 1995) or excess production of endothelin (Giaid et al., 1993) may be involved. Pathologically, chronic pulmonary hypertension can be associated with plexiform lesions, concentric hypertrophy and/or in situ thrombosis. The plexiform lesion is characterized by focal medial disruption and aneurysmal dilatation of the vessel, with formation of a complex proliferative tuft of intimal cells and channels (Figure 1). While, historically, plexiform lesions have been associated with PPH, they can clearly be seen in long-standing secondary pulmonary hypertension as well.

Figure 1 Plexiform lesion associated with focal medial disruption (arrowhead) and aneurysmal dilatation of small pulmonary arteries, with formation of a complex proliferative tuft of intimal cells (large arrow) and channels (small arrows).

ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net

Pulmonary Hypertension

appetite suppressants for more than 3 months appear to have a relative odds ratio of approximately 23, or an annual incidence of 2346 new cases per million (Abenhaim et al., 1996; National Task Force, 1996). While this incidence is still relatively low, it represents a signicant increase over the background incidence of a potentially fatal disease. Interestingly, large numbers of patients exposed to appetite suppressant medications have not developed PPH, suggesting that a subgroup of individuals may be genetically predisposed and at risk for the development of PPH when exposed to a trigger factor. Such a hypothesis might be supported by the fact that 0.5% of patients infected with human immunodeciency virus (HIV) develop PPH, which is higher than the background incidence of PPH in the general population but clearly only a very small subpopulation of those with HIV (Speich et al., 1991). Also in support of the concept of genetic predisposition, approximately 6% of cases are recognized to have a familial component (Rich et al., 1987). In addition, it is possible that a number of patients with PPH not recognized as familial have an underlying genetic predisposition toward the development of pulmonary hypertension.

ache and morbid obesity. A careful family history should be taken to recognize familial cases. Medication exposures, particularly to appetite suppressants and amphetamines, should be reviewed. Cocaine is a powerful vasoconstrictor and may contribute to the development of pulmonary hypertension. Intravenous drug abuse has been associated with the development of pulmonary hypertension, and underlying mechanisms may include the direct eects of amphetamines or talc embolization with obliteration of small pulmonary arterioles. Physical examination Signs of pulmonary hypertension may not become apparent on physical examination until late in the disease. Findings such as an accentuated second heart sound, a systolic murmur over the left sternal border, jugular venous distension, peripheral oedema and/or ascites may suggest the presence of pulmonary hypertension and right ventricular dysfunction. While these ndings are not always specic, they are useful in both diagnosis and follow-up of patients with pulmonary hypertension. Other 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 secondary causes of pulmonary hypertension. A collagen vascular screen which includes ANAs, rheumatoid factor and erythrocyte sedimentation rate is often helpful in detecting autoimmune disease, although some patients with PPH have a low-titre positive ANA (Rich et al., 1986). The scleroderma spectrum of disease, particularly limited scleroderma or the CREST (Calcinosis, Raynauds phenomenon, Esophageal dysfunction, Sclerodactyly, Telangiectasia) syndrome, has been associated with an increased risk for the development of pulmonary hypertension (Salerni et al., 1977; Ungerer et al., 1983). Liver function test results may be altered (increased levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase) in patients with right ventricular failure due to passive hepatic congestion, but may also be associated with underlying liver disease. Liver disease with portal hypertension has been associated with the development of pulmonary hypertension (Groves et al., 1990). Thyroid disease may occur with increased frequency in patients with PPH, and should be excluded with thyroid function testing (Badesch et al., 1993). HIV testing and hepatitis serologies should be considered in patients at increased risk. Routine laboratory studies such as complete blood count, complete metabolic panel, prothrombin time and partial thromboplastin time are recommended during the initial evaluation, and as indicated to monitor the patients long-term clinical status.

Diagnosis
A general algorithm for the diagnosis and treatment of pulmonary hypertension is shown in Figure 2. Presenting symptoms and signs Owing to the insidious onset of symptoms in PPH, the disease is often advanced at the time of diagnosis. Dyspnoea on exertion is a common presenting symptom, but is often attributed to deconditioning or some other respiratory or cardiac ailment. Chest pain occurs relatively commonly, and may mimic angina pectoris. The cause of chest pain is unknown, but may reect right ventricular ischaemia. Patients with advanced disease may present with syncope or signs and symptoms of right heart failure, including lower extremity oedema, jugular venous distension and ascites. Syncope tends to occur when the cardiac output is low and unable to accommodate physical activity or change in position. Clinical history The clinical history should focus initially on the exclusion of underlying secondary causes of pulmonary hypertension (see Table 1), which may require additional consideration with respect to therapy. Important clues to an underlying secondary condition might include a previous history of a heart murmur, deep venous thrombosis or pulmonary embolism, Raynaud phenomenon, arthritis, arthralgia, rash, heavy alcohol consumption, hepatitis, heavy snoring, daytime hypersomnolence, morning head2

ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net

Pulmonary Hypertension

Patient with suspected pulmonary hypertension History or examination suggestive of a secondary cause thromboembolic disease collagen vascular disease left heart disease congestive heart disease liver disease sleep apnoea underlying lung disease left heart disease No history or physical examination suggesting a secondary cause Initial screening evaluation for pulmonary hypertension chest radiography ECG ECHO with bubble contrast Detailed evaluation for underlying secondary hypertension routine labs: SMA-19, CBC, urinalysis collagen vascular screen: ANA profile, RF, ESR, anti-SCL 70, anti-Ku hypercoagulable screen: PT/PTT, anticardiolipin, lupus anticoagulant, etc. V/Q lung scan full PFTs with lung volumes and chest CT with thin sections if indicated by sleep study if indicated by oximetry at rest and with exertion

Evaluation directed by above and focused

Secondary cause determined Specific treatment of underlying disease No secondary cause apparent unexplained or primary pulmonary hypertension

Right heart catheterization possibly with acute vasodilator Unfavourable response to vasodilator Consider treatment with oxygen, diuretic and anticoagulation if indicated Favourable response to acute vasodilator testing Trial of chronic oral vasodilator and possibly evaluate for lung transplantation usually a calcium channel blocker occasionally an ACE inhibitor in patients with collagen vascular disease

No response to chronic oral vasodilator

Consider treatment with oxygen, diuretic and anticoagulation if indicated Frequent regular follow-up with ECHO and/or right heart catheterization

Progression of pulmonary hypertension

Favourable response to oral vasodilator

Consider continuous infusion and evaluate for possible lung transplantation

Continue to follow closely with periodic ECHO and/or right heart catheterization

Figure 2 General diagnostic and treatment algorithm. This overview of the authors general approach to the patient with suspected pulmonary hypertension requires significant individualization. In addition, it should be noted that diagnostic and therapeutic techniques are changing rapidly. ACE, angiotensin-converting enzyme; ANA, antinuclear antibodies; CBC, complete blood count; CT, computed tomography; ECG, electrocardiogram; ECHO, echocardiography; ESR, erythrocyte sedimentation rate; PFT, pulmonary function test; PT, prothrombin time; PTT, partial thromboplastin time; RF, rheumatoid factor; SMA-19, sequential multiple analyser-19, complete chemistry panel.

Radiographic evaluation Chest radiography may reveal enlargement of the central pulmonary vessels and evidence of right ventricular

enlargement (Figure 3). Additionally, parenchymal lung disease may be apparent. When parenchymal lung disease is suspected, pulmonary function testing and high-resolution computed tomography of the chest may be indicated.
3

ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net

Pulmonary Hypertension

Table 1 Causes of secondary pulmonary hypertension Collagen vascular disease (scleroderma, MCTD, SLE) Congenital heart disease (ASD, VSD, PDA) Left ventricular dysfunction Parenchymal lung disease (COPD, IPF) Portopulmonary hypertension Pulmonary venoocclusive disease Schistosomiasis Sleep apnoea Thromboembolic disease Valvular heart disease
ASD, atrial septal defect; COPD, chronic obstructive pulmonary disease; IPF, idiopathic pulmonary brosis; MCTD, mixed connective tissue disease; PDA, patent ductus arteriosus; SLE, systemic lupus erythematosus; VSD, ventricular septal defect.

may detect a right to left shunt, but exclusion of a left to right intracardiac shunt may require cardiac catheterization. Echocardiography may also be a useful noninvasive means of long-term follow-up (Hinderliter et al., 1997), although not all patients have suitable echocardiographic windows. Ventilation perfusion lung scan and pulmonary angiography Ventilationperfusion lung scanning should be performed in an attempt to exclude chronic recurrent pulmonary thromboembolic disease, which is among the most treatable and preventable causes of pulmonary hypertension. The ventilation perfusion lung scan is most useful when results are at either extreme (i.e. if there is clearly a high probability, or a normal to low probability, for pulmonary embolism). Intermediate results on ventilationperfusion lung scanning may require pulmonary arteriography to obtain a denitive diagnosis. Diuse mottled perfusion can be seen in PPH, whereas segmental and subsegmental mismatched defects are common in chronic pulmonary thromboembolic disease. Pulmonary arteriography should be performed with caution in patients with suspected thromboembolic disease and

Echocardiography Doppler echocardiograpy is useful in estimating the severity of pulmonary hypertension and detecting left ventricular dysfunction and valvular heart disease. Findings in PPH may include enlargement of the right ventricle, attening of the interventricular septum, and compression of the left ventricle. Bubble contrast echocardiography

Figure 3 Chest radiograph of patient with severe primary pulmonary hypertension. The posterior anterior and lateral chest radiographs of this patient demonstrate marked enlargement of the cardiac silhouette, prominence of the main pulmonary artery outflow tract, filling in of the retrosternal air space, and a paucity of peripheral pulmonary vascular markings.

ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net

Pulmonary Hypertension

pulmonary hypertension, preferably utilizing nonionic contrast material and beginning with small selective injections, in an attempt to avoid acute right ventricular decompensation. Pulmonary function testing Pulmonary function testing, including spirometry, lung volumes and diusing capacity, is indicated to detect underlying parenchymal lung disease. In PPH, as with other pulmonary vascular diseases, the diusing capacity is often reduced, consistent with impaired gas exchange. Oximetry testing of patients at rest, with exertion, and nocturnally is useful in detecting hypoxaemia and the need for supplemental oxygen. This can be very important, as hypoxaemia is a potent pulmonary vasoconstrictor and may contribute to the progression to pulmonary hypertension. Polysomnography Polysomnography should be considered in patients at risk for sleep-disordered breathing and those demonstrating signicant nocturnal desaturation. Such patients may have symptoms consistent with sleep-disordered breathing such as snoring, witnessed apnoeic periods, daytime hypersomnolence or morning headaches. Treatment with nasal continuous positive airway pressure or bilevel positive airway pressure should be instituted as indicated. Right heart catheterization Right heart catheterization remains an important part of the evaluation. Left heart dysfunction and intracardiac shunts can be excluded, the degree of pulmonary hypertension can be accurately quantied, and the cardiac output measured. From these data, the pulmonary vascular resistance can be calculated. Acute pulmonary vasoreactivity can be assessed using a short-acting agent such as prostacyclin (epoprostenol), inhaled nitric oxide or adenosine (Groves et al., 1993). The acute response to a shortacting agent, such as prostacyclin, has been shown to be predictive of the response to agents such as calcium blockers. If the patient with PPH is refractory to acutely administered vasodilators in the presence of severe symptomatic pulmonary hypertension, consideration should be given to continuous intravenous prostacyclin.

Treatment
Historically, treatment of PPH has been dicult, although therapeutic options have recently improved. Current treatment of PPH includes oxygen, diuretics, oral vasodilators (calcium channel antagonists), anticoagulation with coumadin, prostacyclin and, occasionally, digitalis. Prostacyclin has been shown to improve survival, haemodynamics and quality of life in patients with PPH previously refractory to conventional therapy (Barst et al., 1996).

Lung transplantation remains an option for those refractory to medical therapy. A general algorithm for the evaluation and treatment of patients with pulmonary hypertension is shown in Figure 2, which can be adapted to the individual patients situation. Oxygen therapy is utilized to treat and/or prevent hypoxaemia, which can cause vasoconstriction and worsening of pulmonary hypertension. Diuretics are indicated in patients with evidence of right ventricular failure (i.e. peripheral oedema and/or ascites). Maintaining a reasonable intravascular volume with diuretics, and careful dietary restriction of sodium and uid intake, is important in the long-term management of patients with PPH. However, rapid and excessive diuresis may lead to hypotension, renal insuciency and syncope. Serum electrolytes and indices of renal function should be followed closely. Treatment with oral vasodilators benets approximately 2530% of patients with PPH. Agents that have been utilized include calcium channel blockers, hydralazine and angiotensin-converting inhibitors (e.g. captopril). Of the vasodilators, the calcium channel blockers, particularly nifedipine and diltiazem, have been shown to improve pulmonary haemodynamics and survival in a select group of patients (Rich et al., 1992). As noted previously, acute vasoreactivity should be formally assessed with haemodynamic monitoring before the initiation of chronic vasodilator therapy. Digitalis is occasionally indicated for patients with right ventricular failure and atrial dysrhythmias. Levels must be followed closely, especially in patients with impaired renal function. Anticoagulation is recommended in patients with PPH in the absence of contraindications. In situ microscopic thrombosis has been documented in some patients with PPH. In addition, patients with right ventricular failure and resultant venous stasis are probably at increased risk for thromboembolism. Improved survival has been reported with oral anticoagulation in patients with PPH (Fuster et al., 1984; Rich et al., 1992). The target international normalized ratio (INR) in patients with PPH treated with coumadin is approximately 1.52.0, but this varies somewhat from centre to centre. Prostacyclin is a metabolite of arachidonic acid produced primarily in vascular endothelium; it is a potent vasodilator, aecting both the pulmonary and systemic circulations. It also has antiplatelet aggregatory eects. In a multicentre, randomized controlled trial, continuously infused prostacyclin plus conventional therapy (oral vasodilators, anticoagulation, etc.) was compared to conventional therapy alone. The prostacyclin-treated group demonstrated improved survival and exercise tolerance, increased cardiac output, and decreased pulmonary vascular resistance (Barst et al., 1996). The use of prostacyclin has been approved by the US Food and Drug Administration (FDA) for the treatment of severe PPH.
5

ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net

Pulmonary Hypertension

Because of the complexity of administration of prostacyclin (chronic indwelling catheters, reconstitution of the drug, operation of the infusion pump, etc.) and the relative rarity of PPH, strong consideration should be given to referring patients to centres of excellence in pulmonary hypertension. Long-term administration of continuously infused prostacyclin has been reported to be of benet in patients with severe PPH. Barst et al. (1994) reported long-term benet in a small group of patients from several centres involved in the earliest clinical usage of prostacyclin. More recently, Shapiro et al. (1997) and McLaughlin et al. (1998) have described sustained benet in larger numbers of patients with continuously infused prostacyclin. It appears that decreases in mean pulmonary artery pressure and pulmonary vascular resistance, and improvement in cardiac output, can be sustained over a period of years in many patients. The present authors experience would support improved functional capacity and survival over the long term with continuously infused prostacyclin. Aggressive medical therapy, including continuously infused prostacyclin, may now be more than a bridge to lung transplantation for those demonstrating sustained benet. Lung transplantation is reserved for patients with severe PPH who do not respond to aggressive medical therapy. Owing to the relatively high initial operative and perioperative risks associated with lung transplantation for PPH, as well as the signicant long-term risks of infection and rejection, lung transplantation should not be considered a cure for pulmonary hypertension. Whether single lung, bilateral lung or heartlung transplantation is the procedure of choice is still the subject of controversy. The authors centre tends to prefer bilateral lung transplantation for patients with PPH, and reserves heartlung transplantation for those with pulmonary hypertension occurring in association with uncorrectable congenital heart disease, or patients having signicant left ventricular dysfunction or valvular disease. While the prognosis in PPH was previously thought to be very poor, this appears to be changing. The National Institutes of Health Registry on Primary Pulmonary Hypertension, conducted in the 1980s, suggested a median survival of approximately 2.8 years from the date of diagnosis (DAlonzo et al., 1991). The Registry was conducted before the development of recent treatment strategies, including calcium channel antagonists, anticoagulation with warfarin, continuously infused prostacyclin (epoprestenol) and lung transplantation. We are now optimistic regarding the long-term eectiveness of aggressive medical therapy, used in combination with lung transplantation if necessary.

Secondary Pulmonary Hypertension

Aetiology and Pathogenesis
Secondary pulmonary hypertension occurs as a result of a variety of underlying diseases (Table 1) aecting the pulmonary vasculature directly or indirectly. Some underlying disease processes appear directly to aect the structure and function of the lung circulation (e.g. limited scleroderma or the CREST syndrome). Others may lead to the development of pulmonary hypertension through the development of chronic hypoxaemia. Examples include interstitial lung disease, emphysema and obstructive sleep apnoea. Congenital heart disease is thought to lead to the development of pulmonary hypertension by causing chronically increased blood ow through the lung circulation, which ultimately leads to remodelling of the pulmonary arteries and arterioles, with a subsequent rise in pulmonary vascular resistance.

Epidemiology
Secondary pulmonary hypertension is signicantly more common than PPH. In the authors referral centre, the ratio of patients with secondary versus primary disease is approximately 10:1. Patients are seen from a broad age range and both sexes.

Diagnosis
In general, the diagnostic evaluation of patients with suspected secondary pulmonary hypertension is very similar to that described above for PPH. A careful history and physical examination are often followed by chest radiography, ventilationperfusion lung scanning, echocardiography, selected laboratory studies, pulmonary function testing and right heart catheterization if indicated. However, if a secondary cause becomes apparent, the diagnostic approach is often focused on the underlying process.

Treatment
Treatment of secondary pulmonary hypertension can be thought of as having two components: (1) treatment of the underlying disease process, and (2) treatment directed at the pulmonary hypertension itself. Treatment targeted at the pulmonary hypertension is evolving to resemble more closely the therapeutic approach to PPH. Recognition that some forms of secondary pulmonary hypertension respond to therapeutic interventions in a manner similar to PPH has led to discussion of reclassifying the disease, to blur the distinction between primary and secondary disease.

ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net

Pulmonary Hypertension

Underlying lung disease Some forms of secondary pulmonary hypertension may respond to treatment of the underlying disease alone. Examples include pulmonary hypertension occurring secondary to underlying lung disease, such as chronic obstructive pulmonary disease (COPD) or interstitial lung disease. The attempted use of vasodilating medications in these situations has the potential to worsen ventilation perfusion matching and hypoxaemia. Treatment of COPD with bronchodilators and supplemental oxygen can often result in improvement or slowing of the progression of pulmonary hypertension. Chronic recurrent thromboembolic disease Pulmonary hypertension occurring secondary to chronic recurrent thromboembolic disease also requires specic therapy directed at the underlying process. Anticoagulation is used in the absence of contraindications to prevent extension of thrombus and recurrent embolization. Placement of an inferior vena caval lter may be indicated to provide a protective barrier against pulmonary embolization in patients with a contraindication to anticoagulation, or in those with severe pulmonary hypertension receiving anticoagulation but requiring an additional method of protection. The majority of pulmonary emboli emanate from deep venous thrombosis in the lower extremities. Patients with severe pulmonary hypertension and evidence of extensive chronic changes in the proximal pulmonary arteries due to thromboembolic disease may be candidates for pulmonary thromboendarterectomy in highly specialized centres (Jamieson et al., 1993). Collagen vascular disease Pulmonary hypertension occurs with increased frequency in the scleroderma spectrum of disease, including diuse scleroderma, limited scleroderma (the CREST syndrome) and overlap syndrome. These multisystem diseases are characterized by connective tissue and vascular abnormalities, with vascular lesions being prominent in aected tissues (Al-Sabbagh et al., 1989). Pulmonary hypertension occurs in up to 33% of patients with diuse scleroderma and in 1050% of those with the CREST syndrome (Ungerer et al., 1983; Stupi et al., 1986), where it is a leading cause of death (Salerni et al., 1977; Thurm et al., 1991). Pulmonary hypertension occurring in the scleroderma spectrum of disease may be associated with interstitial pulmonary brosis, or consist of a direct proliferative vascular involvement of small and medium-sized pulmonary arteries and arterioles with smooth muscle hyperplasia, medial hypertrophy and intimal proliferation (Salerni et al., 1977; Young and Mark, 1978; Stupi et al., 1986). Principal involvement of the pulmonary vasculature is more common in the CREST syndrome, while patients with pulmonary hypertension and diuse scleroderma

more frequently have interstitial lung disease (Salerni et al., 1977). There are no proven eective therapies for patients with pulmonary hypertension secondary to the scleroderma spectrum of disease. Small numbers of patients have responded to captopril (Alpert et al., 1992), nifedipine (Ocken et al., 1983; Fudman and Kelling, 1985; Glikson et al., 1990; Alpert et al., 1991; Skakis et al., 1991) and prazosin. In an acute study of intravenous epoprostenol involving seven patients with scleroderma (two diuse, ve limited disease), six demonstrated a fall in mean pulmonary artery pressure and pulmonary vascular resistance (Menon et al., 1998). In a small study of pulmonary hypertension secondary to connective tissue disease, longterm infusion therapy with a prostacyclin analogue, iloprost, resulted in improvement in New York Heart Association (NYHA) functional class and quality of life, but a variable haemodynamic response (Mata et al., 1994). Results from a single-centre, uncontrolled study suggest that chronic, continuously infused, epoprostenol can produce haemodynamic and symptomatic responses in severe pulmonary hypertension refractory to conventional medical therapy occurring in patients with connective tissue disease (Humbert et al., 1998). A recently completed multicentre randomized controlled trial demonstrated that continuous intravenous infusion of epoprostenol plus conventional therapy in patients with pulmonary hypertension secondary to the scleroderma spectrum of disease resulted in improvement in exercise capacity, cardiopulmonary haemodynamics, NYHA functional class, and indices of dyspnoea, compared with conventional therapy alone (Badesch et al., 1998). This was the rst prospective randomized trial of therapy for secondary pulmonary hypertension. While important pathogenic dierences exist, various intrinsic pulmonary vascular diseases may share similar therapeutic responses. Although the results of this study apply specically to pulmonary hypertension occurring in the scleroderma spectrum of disease, the therapeutic implications for a broader group of patients are intriguing.

Summary
Pulmonary hypertension is an abnormal increase in blood pressure within the lung circulation. It may be idiopathic (primary) or occur in association with some underlying disease process (secondary). This potentially fatal disorder was previously associated with a poor prognosis, but longterm survival is now possible with aggressive medical therapy and/or lung transplantation. Therapies developed for use in the treatment of PPH may also have utility in the treatment of some forms of secondary pulmonary hypertension. Although the shared response to some forms of therapy is leading to eorts to reclassify pulmonary
7

ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net

Pulmonary Hypertension

hypertension, eective treatment of secondary pulmonary hypertension may also require that the associated or underlying disease process be specically addressed.

Acknowledgements
Portions of this chapter have been previously published in a review in Womens Health in Primary Care (1999) 6: 489 503, including Figure 2; they are reproduced here with permission.

References
Abenhaim L, Moridea Y, Brenot F et al. for the International Primary Pulmonary Hypertension Study Group (1996) Appetite-suppressant drugs and the risk of primary pulmonary hypertension. New England Journal of Medicine 335: 609616. Alpert MA, Pressly TA, Mukerji V et al. (1991) Acute and long-term eects of nifedipine on pulmonary and systemic hemodynamics in patients with pulmonary hypertension associated with diuse systemic sclerosis, the CREST syndrome and mixed connective tissue disease. American Journal of Cardiology 68: 16871691. Alpert MA, Pressly TA, Mukerji V, Lambert CR and Mukerji B (1992) Short- and long-term hemodynamic eects of captopril in patients with pulmonary hypertension and selected connective tissue disease. Chest 102: 14071412. Al-Sabbagh MR, Steen VD, Zee BC et al. (1989) Pulmonary arterial histology and morphometry in systemic sclerosis: A casecontrol autopsy study. Journal of Rheumatology 16: 10381042. Badesch DB, Wynne KM, Bonvallet S et al. (1993) Hypothyroidism and primary pulmonary hypertension: an autoimmune pathogenetic link? Annals of Internal Medicine 119: 4446. Badesch DB, Brundage BH, McGoon MD et al. (1998) Continuous intravenous epoprostenol versus standard therapy in pulmonary hypertension due to scleroderma: a twelve-week randomized trial. Presented to the American Heart Association, 71st Scientic Sessions, 11 November, 1998, and published in Circulation no. 3226 (supplement I): I614. Barst RJ, Rubin LJ, McGoon MD et al. (1994) Survival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin. Annals of Internal Medicine 121: 409415. Barst RJ, Rubin LJ, Long WA et al. for the Primary Pulmonary Hypertension Study Group (1996) A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. New England Journal of Medicine 334: 296301. Christman BW, McPherson CD, Newman JH et al. (1992) An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. New England Journal of Medicine 327: 70 75. DAlonzo GE, Barst RJ, Ayres SM et al. (1991) Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Annals of Internal Medicine 115: 343349. Fudman EJ and Kelling DG Jr (1985) Transient eect of nifedipine on pulmonary hypertension of systemic sclerosis. Journal of Rheumatology 12: 11911192. Fuster V, Steele PM, Edwards WD et al. (1984) Primary pulmonary hypertension: natural history and importance of thrombosis. Circulation 70: 580587.

Giaid A, Yanagisawa M, Langleben D et al. (1993) Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. New England Journal of Medicine 328: 17321739. Giaid A and Saleh D (1995) Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. New England Journal of Medicine 333: 214221. Glikson M, Pollack A, Dresner-Feigin R, Galun E and Rubinow A (1990) Nifedipine and prazocin in the management of pulmonary hypertension in CREST syndrome. Chest 98: 750761. Groves BM, Brundage BH, Elliot CG et al. (1990) Pulmonary hypertension associated with hepatic cirrhosis. In: Fishman AP (ed.) The Pulmonary Circulation; Normal and Abnormal, pp. 359369. Philadelphia: University of Pennsylvania Press. Groves BM, Badesch DB, Turkevich D et al. (1993) Correlation of acute prostacyclin response in primary (unexplained) pulmonary hypertension with ecacy of treatment with calcium channel blockers and survival. In: Weir EK, Hume JR and Reeves JT (eds). Ion Flux in Pulmonary Vascular Control, pp. 317330. New York: Plenum. Hinderliter AL, Park WW, Barst RJ et al for the Primary Pulmonary Hypertension Study Group (1997) Eects of chronic infusion of epoprostenol (prostacyclin) on echocardiographic measures of right heart structure and function in primary pulmonary hypertension. Circulation 95: 14791486. Humbert M, Sanchez O, Fartoukh M et al.(1998) Treatment of severe pulmonary hypertension secondary to connective tissue diseases with continuous IV epoprostenol (prostacyclin). Chest 114: 80S82S. Isern RA, Yaneva M, Weiner E et al. (1992) Autoantibodies in patients with primary pulmonary hypertension: association with anti-Ku. American Journal of Medicine 93: 307312. Jamieson SW, Auger WR, Fidulo PF et al. (1993) Experience and results with 150 pulmonary thromboendarterectomy operations over a 29 month period. Journal of Thoracic and Cardiovascular Surgery 106: 116127. McLaughlin VV, Genthner DE, Panella MM and Rich S (1998) Reduction in pulmonary vascular resistance with long-term epoprostenol (prostacyclin) therapy in primary pulmonary hypertension. New England Journal of Medicine 338: 273277. Mata JDL, Gomez-Sanchez MA, Aranzana M and Gomez-Reino JJ (1994) Long-term iloprost infusion therapy for severe pulmonary hypertension in patients with connective tissue diseases. Arthritis and Rheumatism 37: 15281533. Menon N, McAlpine L, Peacock AJ and Madhok R (1998) The acute eects of prostacyclin on pulmonary hemodynamics in patients with pulmonary hypertension secondary to systemic sclerosis. Arthritis and Rheumatism 41: 466469. National Task Force on the Prevention and Treatment of Obesity (1996) Long-term pharmacotherapy in the management of obesity. Journal of the American Medical Association 276: 19071915. Ocken S, Reinitz E and Strom J (1983) Nifedipine treatment for pulmonary hypertension in a patient with systemic sclerosis. Arthritis and Rheumatism 26: 794796. Rich S, Kieras K, Hart K et al. (1986) Antinuclear antibodies in primary pulmonary hypertension. Journal of the American College of Cardiology 8: 13071311. Rich S, Dantzker DR, Ayres SM et al. (1987) Primary pulmonary hypertension: a national prospective study. Annals of Internal Medicine 107: 216223. Rich S, Kaufman E and Levy PS (1992) The eect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. New England Journal of Medicine 327: 7681. Salerni R, Rodnan GP, Leon DF and Shaver JA (1977) Pulmonary hypertension in the CREST syndrome variant of progressive systemic sclerosis (scleroderma). Annals of Internal Medicine 86: 394399.

ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net

Pulmonary Hypertension

Skakis P, Kyriakidis M, Vergos C et al. (1991) Cardiopulmonary hemodynamics in systemic sclerosis and response to nifedipine and captopril. American Journal of Medicine 90: 541546. Shapiro SM, Oudiz RJ, Cao T et al. (1997) Primary pulmonary hypertension: improved long-term eects and survival with continuous intravenous epoprostenol infusion. Journal of the American College of Cardiology 30: 343349. Speich R, Jenni R, Opravil M, Pfab M and Russi EW (1991) PPH in HIV infection. Chest 100: 1268.

Stupi AM, Steen VD, Owens GR et al.(1986) Pulmonary hypertension in the CREST syndrome variant of systemic sclerosis. Arthritis and Rheumatism 29: 515524. Thurm CA, Wigley FM, Dole WP and Wise RA (1991) Failure of vasodilator infusion to alter pulmonary diusing capacity in systemic sclerosis. American Journal of Medicine 90: 547552. Ungerer R, Tashkin D, Furst D et al. (1983) Prevalence and clinical correlates of pulmonary arterial hypertension in progressive systemic sclerosis. American Journal of Medicine 75: 6574. Young RH and Mark GJ (1978) Pulmonary vascular changes in scleroderma. American Journal of Medicine 64: 9981004.

ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net