Lancet 1998; 352: 719-25

Seminar

Primary pulmonary hypertension

Sean P Gaine, Lewis J Rubin

Primary pulmonary hypertension (PPH) is a progressive disease characterised by raised pulmonary vascular resistance, which results in diminished right-heart function due to increased right ventricular afterload. PPH occurs most commonly in young and middle-aged women; mean survival from onset of symptoms is 2-3 years. The aetiology of PPH is unknown, although familial disease accounts for roughly 10% of cases, which suggests a genetic predisposition. Current theories on pathogenesis focus on abnormalities in interaction between endothelial and smooth-muscle cells. Endothelial-cell injury may result in an imbalance in endothelium-derived mediators, favouring vasoconstriction. Defects in ion-channel activity in smooth-muscle cells in the pulmonary artery may contribute to vasoconstriction and vascular proliferation. Diagnostic testing primarily excludes secondary causes. Catheterisation is necessary to assess haemodynamics and to evaluate vasoreactivity during acute drug challenge. Decrease in pulmonary vascular resistance in response to acute vasodilator challenge occurs in about 30% of patients, and predicts a good response to chronic therapy with oral calcium-channel blockers. For patients unresponsive during acute testing, continuous intravenous epoprostenol (prostacyclin, PGI₂) improves haemodynamics and exercise tolerance, and prolongs survival in severe PPH (NYHA functional class lll-lV). Thoracic transplantation is reserved for patients who fail medical therapy. We review the progress made in diagnosis and treatment of PPH over the past 20 years.

Primary pulmonary hypertension (PPH) was first described over 100 years ago in a patient with right-heart failure whose necropsy showed no obvious reason for pulmonary arteriosclerosis.¹ The disorder was diagnosed as syphilitic pulmonary arteritis. In 1901, Ayerza noted the profound cyanosis associated with this disorder, and described the disorder as "cardiacos negros", but it was Dresdale and colleagues who first used the term primary pulmonary hypertension.²  In 1967, an epidemic of pulmonary hypertension in Europe was attributed to the widespread use of the appetite suppressant aminorex fumarate. Increased awareness of the disorder prompted a WHO symposium and monograph on diagnosis and treatment. In 1981, the US National Institutes of Health sponsored a PPH registry to outline the natural history of PPH, and in 1994 the International PPH Study Group clarified the role of appetite suppressants in the disorder. Study of the harmful effects of these drugs, including a link to cardiac-valve abnormalities, has led to their withdrawal from the North American and European markets.³

Definition and classification
Pulmonary hypertension is clinically defined as a mean pulmonary arterial pressure of more than 25 mm Hg at rest or 30 mm Hg during exercise.⁴ Although there are many causes and ways of classing the disorder,⁵ pulmonary hypertension is usually classed as either primary or secondary on clinical grounds. A diagnosis of primary pulmonary hypertension is made when all types of secondary pulmonary hypertension have been excluded on clinical grounds (figure 1).

Epidemiology
The estimated annual incidence of PPH in European and US studies is 1-2 cases per million people per year in the general population, and necropsy studies have shown a prevalence of 1300 per million.⁶ The incidence of PPH among users of appetite suppressants may be as high as 25-50 per million per year.⁷

The mean age at diagnosis of PPH is 36 years, although it can occur at any age,⁸ and the mean age at diagnosis is slightly higher in male than in female patients. There is a female excess of PPH in both adult disease (ratio women/men 1 · 7 - 3 · 5) and childhood familial PPH. The female excess may be explained by a low survival rate of male fetuses with PPH.⁹ Race has no bearing on the risk of PPH.⁸ Familial PPH acounts for roughly 10% of cases.¹⁰

Pathology
The normal pulmonary artery is a compliant structure with few muscle fibres, which allows the pulmonary vascular bed to function as a high-flow, low-pressure circuit. The vascular pathological features of PPH are not unique or diagnostic, and include smooth-muscle hypertrophy, intimal hyperplasia, and in-situ thrombosis (figure 2). More complex lesions can occur, including arteritis and the characteristic plexogenic lesion -- an aneurysmal dilatation of an arterial branch distal to an obstructed larger artery. The dilatation is filled with a mesh of endothelium-lined microchannels, which may originate from collateral channels off the bronchial circulation and may be the result of a form of angiogenesis (figure 2).

PPH has three distinct pathological patterns:¹¹ plexogenic arteriopathy (30-60% of PPH patients); thrombotic arteriopathy (40-50% of PPH patients, and characterised by eccentric intimal fibrosis and evidence of recanalised in-situ thrombosis); and veno-occlusive disease. The pathological findings in PPH can be graded on a 6-point scale based on the severity of the disease: grade 1 refers to isolated medial hypertrophy and grade 6 necrotising arteritis.¹² Although there is no correlation between this scale and pulmonary-artery pressure, the ratio of the thickness of the medial and intimal areas to the total cross-sectional area is associated with response to vasodilators.¹³ Plexogenic arteriopathy is associated with a short survival time.¹⁴

Aetiology and pathogenesis
The aetiology of PPH is unknown. Current concepts of pathogenesis envisage individual susceptibility and a triggering stimulus as the initiating factors for pulmonary vascular injury and repair. Only small proportions of people in high-risk groups (users of appetite suppressants and HIV-1-infected people) develop pulmonary hypertension. The occurrence of PPH within families suggests genetic susceptibility. The inheritance pattern is autosomal dominant with a female-to-male ratio of two to one,¹⁰ and there is genetic anticipation (ie, the disorder occurs at younger ages and with increased severity in suceeding generations). Although the gene involved in familial PPH has not yet been identified, the likely region is on the long arm of chromosome 2 (q31).¹⁵ This region contains roughly 7 million bases and a directed approach has attempted to identify potential genes with vasoactive, proliferative, or thrombotic activities. However, no candidate gene has emerged to date.

The stimuli that may trigger PPH are diverse and include: ingested substances, such as appetite suppressants, monocrotaline extracts, inhaled solvents, methamphetamine, cocaine, contaminated rapeseed oil, and L-tryptophan; infections, particularly HIV-1; and inflammatory disorders -- PPH is associated with autoimmune thyroid disease and circulating antinuclear and anti-Ku antibodies. Different stimuli can produce identical patterns of vascular injury and repair. Vasoconstriction and medial hypertrophy occur early in the course of the disorder.¹⁶ These events may be secondary to endothelial-cell injury, which could lead either to a decrease in the production of endothelium-derived vasodilators or to an increase in vasoconstrictors (figure 3). Immunohistochemical studies ¹⁷ suggest that the expression of endothelial nitric oxide synthetase (eNOS; NOS III) is decreased in the pulmonary arteries of patients with PPH, and the urinary excretion of prostacyclin metabolites is also lowered. Blood concentrations of endothelin 1, a potent pulmonary vasoconstrictor, are raised in both primary and secondary pulmonary hypertension, and immunohistochemical staining has shown increased expression of endothelin in the pulmonary arteries of these patients.¹⁸

Other circulating vasoactive mediators may play a part in pulmonary hypertension. Plasma serotonin concentrations are raised in patients with PPH, and remain high after lung transplantation.¹⁹ The appetite suppressants fenfluramine and dexfenfluramine, which inhibit serotonin reuptake, may trigger PPH in susceptible people by increasing the local concentration of platelet-derived serotonin (a pulmonary vasoconstrictor, which promotes vascular growth). A defect in ion-channel activity in the smooth-muscle cells of the pulmonary artery may add to vasoconstriction. Intracellular calcium is an important regulator of smooth-muscle contraction and proliferation, and the voltage-gated K⁺ channels (K_v) that determine cytoplasmic concentrations of free Ca²⁺ may be defective in patients with PPH.²⁰

Vasoconstriction is followed by intimal proliferation and fibrosis, in-situ thrombosis, and plexogenic changes. Increased expression of vascular endothelial growth factor (VEGF), an endothelial-cell-specific mitogen produced by macrophages and vascular smooth muscle, may play a part in vascular remodelling.²¹

Symptoms and diagnostic tests
The earliest symptom in most cases of PPH is the gradual onset of shortness of breath after physical exertion. This shortness of breath is non-specific and is frequently ascribed to a lack of physical fitness. Thus, diagnosis of PPH is commonly delayed, sometimes for more than 2 years after the onset of symptoms.⁸ Other common signs and symptoms include chest pain from right-ventricular ischaemia, near syncope or syncope, tiredness, and peripheral oedema. Raynaud's phenomenon, which is associated with a worse prognosis, occurs in 10% of patients, almost all women.⁸ Hoarseness, from compression of the left recurrent laryngeal nerve by an enlarged pulmonary artery (Ortner's syndrome), can also occur. Haemoptysis is uncommon.

Physical examination may suggest that a patient has a systemic disease associated with secondary pulmonary hypertension, and therefore PPH can be ruled out. Cutaneous telangiectasia and scierodactyly are signs of scleroderma. Systemic hypertension may suggest obstructive sleep apnoea or left-ventricular diastolic dysfunction. Clubbing is not a feature of PPH, and may instead be caused by congenital heart disease, lung disease, or liver disease.

The signs of PPH will depend on the severity of the disorder.⁸ The most common signs are an accentuated second heart sound in the pulmonary region, and a right-ventricular S4 gallop. Patients with severe right-ventricular hypertrophy may have a heave that is palpable along the left sternal border, and a palpable bulge in the second left intercostal space over the pulmonary-outflow tract. The neck veins may have a prominent "a" wave, caused by a non-compliant right ventricle. As the right ventricle expands, "v" waves indicative of tricuspid regurgitation may be seen. When right ventricular decompensation and right-heart failure develop, pressure in the jugular vein rises. Dilatation of the pulmonary-valve annulus or the right-ventricular outflow tract produces a soft-blowing diastolic murmur along the upper left sternal border-the Graham-Steell murmur of pulmonary regurgitation. A right-ventricular S3 gallop signifies advanced right-heart failure.

The aim of diagnostic testing in patients with suspected PPH is to exclude secondary causes of pulmonary hypertension and to assess severity. At initial screening, blood tests should include liver-function tests and assays for antibodies to HIV-1, and serological studies should aim to exclude occult collagen vascular disease (figure 1). PPH patients may test positive for antinuclear antibodies in low titre and without other evidence of rheumatological disease. Chest radiography shows that the central pulmonary arteries are prominent and lung fields are clear.⁸ Chest radiography is also useful to exclude secondary causes of pulmonary hypertension such as parenchymal lung disease. Electrocardiography commonly shows right-axis deviation, right-ventricular hypertrophy and T-wave changes that suggest strain.⁸ Echocardiography is in many cases the first test to raise the possibility of pulmonary hypertension, and it can also help to exclude congenital heart disease or postcapillary causes of pulmonary hypertension, such as mitral-valve disease or left-ventricular dysfunction. Echocardiography can show dilatation of the right heart chambers, right-ventricular hypertrophy, and paradoxical movement of the septum.⁸ Impaired left-ventricular filling may also be seen, with severe dilatation of the right heart chambers. Echocardiography also allows the response to therapy to be monitored.²² Doppler studies may be used to estimate pulmonary-artery systolic pressure, by measuring either systolic flow velocity across the pulmonary valve or regurgitant flow across the tricuspid valve. Transoesophageal echocardiography is more sensitive than transthoracic techniques to assess intracardiac defects such as a patent foramen ovale.

Pulmonary-function tests should be done to exclude significant parenchymal or airway disorders. Patients with severe PPH may have a mild restrictive pattern or a low diffusion capacity, which does not correlate with the severity of pulmonary hypertension.⁸ Arterial blood gases can show a chronic respiratory alkalosis, and hypoxaemia caused by ventilation-perfusion mismatching. Severe hypoxaemia is caused by decreased cardiac output with ventilation-perfusion mismatching, or with intracardiac shunting through a patent foramen ovale. Cardiopulmonary stress testing can be used to monitor the response to therapy and reveals a characteristic pattern of exercise limitation, with reduced maximum oxygen consumption and an exaggerated ventilatory response.²³ The 6 min walk test gives useful information on resting haemodynamics and long-term survival.²⁴ The ventilation-perfusion lung scan is required to exclude chronic thromboembolic disease. Pulmonary angiography should be done when segmental or subsegmental perfusion defects suggest unresolved large-vessel chronic thromboembolic disease. Pulmonary angiography will show characteristic pruning of distal vessels in patients with PPH, rather than the webs, bands, and cutoffs of patients with chronic thromboembolic disease. Polysomnography is recommended in patients with daytime sleepiness, since 10-20% of patients with sleep apnoea have pulmonary hypertension.²⁵

Cardiac catheterisation is the most important test in the assessment of pulmonary hypertension. Catheterisation is necessary to fully assess right and left heart haemodynamics, the presence of shunts, and vasoreactivity during acute drug trials. Pulmonary haemodynamics should be assessed comprehensively, since these parameters correlate with survival.²⁶ Acute vasodilator testing is an important component of the haemodynamic assessment, since the responses to acute challenge with vasodilators is predictive of the long-term response to oral vasodilator therapy. To minimise risk, short-acting titratable agents such as inhaled nitric oxide,²⁷ intravenous prostacyclin,²⁸ or adenosine are used for acute vasoreactivity testing.

Lung biopsy is rarely necessary in the diagnosis of PPH, and should be used only when the clinical diagnosis is unclear.

Management
Although there is no cure for PPH, there have been advances in both medical and surgical treatment. Physical activity should be limited, and medications that can aggravate pulmonary hypertension should be avoided -- vasoactive decongestants, cardiodepressant antihypertensive drugs such as ß-adrenergic blockers, and agents that interfere with warfarin or potentiate the degree of anticoagulation, such as non-steroidal anti-inflammatory drugs. Places with low concentrations of ambient oxygen, such as high altitudes or unpressurised aircraft, may exacerbate PPH, and some patients may need supplementary oxygen. The haemodynamic stresses of pregnancy, particularly immediately post-partum, are poorly tolerated. The importance of effective contraception should be emphasised, but oral contraceptives should not be taken by patients with PPH since they may increase the risk of thrombosis and may exacerbate PPH.²⁹ Hormone-replacement therapy appears to have no adverse effects on PPH in postmenopausal women.

Medical therapy
The rationale for vasodilator therapy is based on the premise that vasoconstriction to varying degrees is a feature of PPH. Almost every type of vasodilator has been tried in the past, but there have been no prospective randomised trials of oral vasodilator therapy for PPH. Non-controlled studies have shown improved haemodynamics, exercise tolerance, and survival in some patients treated with oral vasodilators. However, the cardiopulmonary haemodynamic changes that will occur with vasodilator use in an individual patient are unpredictable, and thus an initial trial with short-acting agents should be undertaken during right-heart catheterisation before chronic oral therapy is started (figure 4).³⁰ Characteristics that predict a long-term response to calcium-channel blockers are a substantial reduction in pulmonary-artery pressure with an unchanged or improved cardiac output and an unchanged systemic blood pressure in response to nitric oxide or epoprostenol. Unfortunately, less than 30% of patients fall into this "responder" category. The doses of calcium-channel blockers given for PPH are larger than those used to treat systemic hypertension, although dose and tolerance varies between patients. The most commonly used vasodilators are nifedipine and diltiazem, but newer antihypertensive drugs such as nicardipine and amlodipine are also used to treat PPH. Abrupt discontinuation of treatment with calcium-channel blockers can lead to rebound pulmonary hypertension, which may be fatal. There are no baseline demographic or haemodynamic predictors of responsiveness to treatment with vasodilators, and thus it is not known whether responsiveness to treatment is a sign of early PPH, or a sign of a subset of PPH.

It is unclear whether an increase in cardiac output without any change in the pulmonary-artery pressure is a positive response to treatment. Although increased cardiac output may lead to improved exertional symptoms, right-ventricular work may be increased, which can lead to right-heart failure. Patients with systemic hypotension, oxygen desaturation, or a decline in cardiac output are not likely to benefit from oral vasodilator therapy, and this therapy may actually produce further clinical deterioration.

Continuous intravenous epoprostenol (prostacyclin, PGI₂) has been shown to improve haemodynamics, to improve tolerance of exercise, and to prolong survival in severe PPH (New York Heart Association functional class III-IV) that has not responded to conventional medical therapy.^{24, 31, 32} Epoprostenol therapy was initially used as a bridge to lung transplantation, although it has also emerged as an alternative to transplantation in some patients. The half-life of epoprostenol in the blood is short (3-5 min), and thus it has to be given by continuous intravenous infusion. Epoprostenol has vascular effects other than vasodilatation when given chronically, possibly due to antiplatelet or antiproliferative properties (figure 5):²⁴ a lack of response to acute vasodilator treatment does not preclude a positive response to chronic vasodilator treatment. Minor side-effects include jaw pain, headache, rash, diarrhoea, and joint pain, particularly in the ankle and foot. More serious side-effects are caused by the drug-delivery system, and include catheter-related infections and pump malfunction which causes abrupt, potentially life-threatening discontinuation of drug delivery. Epoprostenol therapy is contraindicated for use in patients with pulmonary veno-occlusive disease since it may induce acute pulmonary oedema by increasing bloodflow towards a downstream obstruction. Epoprostenol dose must be gradually increased during the first year of therapy to prevent symptom recurrence. The mechanism behind this increasing need over time is unknown, but it may be due to increasing drug degradation or to increased production of endogenous countermediators such as thromboxane.

In-situ thrombosis, which is caused by dysfunctional pulmonary vascular endothelium, and deep-venous thrombosis, which is secondary to right-heart failure and impaired mobility, are potential complications of PPH. Two uncontrolled trials have suggested improved survival for PPH patients treated with anticoagulants.^{33, 34} We recommend that the international normalised ratio (INR) be maintained between 1:5 and 2:5 with warfarin. Heparin given subcutaneously may be used for patients for whom warfarin is contraindicated, although osteoporosis is an undesirable side-effect of long-term heparin use.

Supplementary oxygen is rarely of benefit unless a patient has hypoxaemia at rest or with physical activity. The criteria for prescribing oxygen in PPH are similar to those used for patients with chronic obstructive lung disease. Diuretics are used to control oedema, because of the increased intravascular volume of advanced right-heart failure or drug-induced oedema in patients receiving high-dose calcium-channel blockers. Spironolactone, an aldosterone antagonist, is helpful as an adjunct to loop diuretics if a patient has ascites. Treatment with digoxin is controversial but it may counteract the negative inotropic effect of calcium-channel blockers and reverse the neurohumoural activation which occurs with right-heart failure.

Surgical therapy
The poor prognosis of PPH has encouraged the development of transplantation techniques: the first successful heart-lung transplantation was done on a patient with PPH. However, experience with pulmonary thromboendarterectomy for chronic thromboembolic disease has shown that right-ventricular dysfunction was reversible when normal pulmonary-artery pressures were restored. Single or bilateral lung transplantation is now done for patients with severe PPH, and heart-lung transplantation is reserved for patients with left-heart disease or congenital structural abnormalities.^{35, 36} Life expectancy after lung transplantation is shorter than for heart, liver, or kidney transplantation, particularly for PPH patients.

Blade-balloon atrial septostomy decreases right-heart filling pressures in patients with severe right-sided heart failure that does not respond to diuretics. The technique is also used in patients with recurrent syncope due to underfilling of the left heart. A right-to-left shunt in the atria allows decompression of the right heart and improved filling of the left-sided chambers. The oxygen desaturation which results should be offset by the overall improvement in cardiac output and systemic oxygen delivery.

Prognosis
The prognosis for untreated PPH is poor. In a series of 137 cases from the UK, the median survival time was 3 · 4 years.³⁷ Among 200 patients enrolled on the US National Institutes of Health Registry, the mean life expectancy was 2 · 5 years from diagnosis of PPH. Research in France gave similar results.³⁸ The National Institutes of Health study showed 64% survival at 1 year and 48% survival at 3 years. The results were not affected by age, age at onset, sex, symptom duration, a positive test for antinuclear antibodies, family history, use of oral contraceptives, pregnancy, or smoking status.

In patients with PPH, stroke volume index, cardiac index, right-atrial pressure, and mean pulmonary-artery pressure at catheterisation are linked to survival.²⁶ Patients who respond to chronic therapy with calcium-channel blockers have a 95% chance of a 5-year life-expectancy when anticoagulant therapy is used at the same time.³⁴ Epoprostenol has increased survival in patients who are unresponsive to oral vasodilators, and is associated with a 5-year survival comparable with or better than survival after lung transplantation.³⁹

Future directions
New therapeutic approaches in PPH are directed at targeting pathogenetic mechanisms and improving drug delivery. The encouraging results with epoprostenol in patients with advanced non-vasoconstrictive PPH suggest that the idea that PPH is irreversible should be re-examined. Treatments now being developed include thromboxane-synthesis inhibitors and receptor antagonists, specific phosphodiesterase inhibitors, endothelin-receptor antagonists, and prostacyclin analogues. Cicaprost, an oral prostacyclin analogue, is available in Japan, although its long-term efficacy remains to be shown. Inhalation therapy with iloprost, a stable analogue of prostacyclin, is being tested in a large-scale prospective study in Europe. A new long-acting stable analogue of prostacyclin, 15AU81 (UT-15), which is biologically active when delivered transdermally, is also under development. Treatment with inhaled nitric oxide or oral nitric oxide donors has not yet been discounted as a possible approach in some patients. The pulmonary vascular bed is also suited to gene therapy, with gene transfer of prostacyclin synthetase or nitric oxide synthetase as future possibilities.

LJR is supported by an academic award in vascular disease from the National Heart, Lung, and Blood Institute, Bethesda, MD, USA.

References

1. Romberg E. Ueber skierose der Lungen arterie. Dtsch Archiv Kli Med 1891; 48: 197-206.8
   
2. Dresdale DT, Schultz M, Michtom RJ. Primary pulmonary hypertension: clinical and haemodynamic study. Am J Med 195 1; 11: 686-705.
   
3. Connolly H, Crary J, McGoon M, et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med 1997; 337: 581-88.
   
4. Rubin L. ACCP consensus statement: primary pulmonary hypertension. Chest 1987; 104: 236-50.
   
5. Wood P. Pulmonary hypertension with special reference to the vasoconstrictive factor. Br Heart J 1958; 2: 557-70.
   
6. McDonnell P, Toye P, Hutchins G. Primary pulmonary hypertension and cirrhosis: are they related? Am Rev Respir Dis 1983; 127: 437-41.
   
7. Abenhaim L, Moride Y, Brenot F, et al. Appetite-suppressant drugs and the risk of primary pulmonary hypertension: International Primary Pulmonary Hypertension study group. N Engl J Med 1996; 335: 609-16.
   
8. Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension: a national prospective study. Ann Intern Med 1987; 107: 216-23.
   
9. Loyd JE, Butler MG, Foround TM, et al. Genetic anticipation and abnormal gender ratio at birth in familial primary pulmonary hypertension. Am J Respir Crit Care Med 1995; 152: 93-97.
   
10. Loyd J, RK, Newman J. Familial primary pulmonary hypertension: clinical patterns. Am Rev Respir Dis 1984; 129: 194-97.
    
11. Hatano S, Strasser T. Primary pulmonary hypertension. Geneva: WHO, 1975: 1-46.
    
12. Heath D, Edwards JE. The pathology of hypertensive pulmonary vascular disease: a description of six grades of structural changes in the pulmonary arteries with special reference to congenital cardiac septal defects. Circulation 1958; 18: 533-47.
    
13. Palevsky HI, Schloo BL, Pietra GG. Primary pulmonary hypertension: vascular structure, morphometry and responsiveness to vasodilator agents. Circulation 1989; 80: 1207-21.
    
14. Pietra GG, Edwards WD, Kay JM, et al. Histopathology of pulmonary hypertension: a qualitative and quantitative study of pulmonary blood vessels from 58 patients in National Heart, Lung, and Blood Institute Primary Pulmonary Hypertension Registry. Circulation 1989; 80: 1198-206.
    
15. Nichols W, Koller D, Slovis B, et al. Localization of the gene for familial primary pulmonary hypertension to chromosome 2q31-32. Nat Genet 1997; 15: 277-80.
    
16. Wagenvoort C, Wagenvoort N. Primary pulmonary hypertension: a pathological study of the lung vessels in 156 clinically diagnosed cases. Circulation 1970; 42: 1163-84.
    
17. Giaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med 1995; 333: 214-21.
    
18. Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 1993; 328: 1732-39.
    
19. Herve P, Launay JM, Scrobohaci ML, et al. Increased plasma serotonin in primary pulmonary hypertension. Am J Med 1995; 99: 249-54.
    
20. Yuan X-J, Wang J, Juhaszova M, Game S, Rubm L. Attenuated K+ channel gene transcription in primary pulmonary hypertension. Lancet 1998; 352: 726-27.
    
21. Voelkel N, Tuder R, Weir E. Pathophysiology of primary pulmonary hypertension: from physiology to molecular mechanisms. In: Rubin L, Rich S, eds. Primary pulmonary hypertension. New York: Marcel Dekker, 1997: 83-130.
    
22. Hinderliter AL, Willis PW, Barst RJ, et al. Effects of long-term infusion of prostacyclin (epoprostenol) on echocardiographic measures of right ventricular structure and function in primary pulmonary hypertension: Primary Pulmonary Hypertension study group. Circulation 1997; 95: 1479-86.
    
23. D'Alonzo G, Gianotti LA, Pohil RL, et al. Comparison of progressive exercise performance of normal subjects and patients with primary pulmonary hypertension. Chest 1987; 92: 57-62.
    
24. Barst RJ, Rubin U, Long WA, et al. A comparison of continous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension: the Primary Pulmonary Hypertension study group. N Engl J Med 1996; 334: 296-302.
    
25. Kessler R, Chaouat A, Weitzenblum E, et al. Pulmonary hypertension in the obstructive sleep apnea syndrome: prevalence, causes and therapeutic consequences. Eur Respir J 1 996; 9: 787-94.
    
26. D'Alonzo G, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension: results from a national prospective registry. Ann Intern Med 1991; 115: 343-49.
    
27. Pepke-Zaba J, Higenbottam TW, Dinh-Xuan AT, Stone D, Wallwork J. Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension. Lancet 1991; 338: 1 173-74.
    
28. Rubin L, Groves B, Reeves J, et al. Prostacyclin-induced acute pulmonary vasodilation in primary pulmonary hypertension. Circulation 1982; 66: 334-38.
    
29. Oakley C, Sommerville J. Oral contraceptives and progressive pulmonary vascular disease. Lancet 1968; i: 890-91.
    
30. Weir E, Rubin L, Ayres S, et al. The acute administration of vasodilators in primary pulmonary hypertension: experience from the National Institutes of Health Registry on primary pulmonary hypertension. Am Rev Respir Dis 1989; 140: 1 623-30.
    
31. Higenbonam T, Wells F, Wheeldon D, Wallwork J. Long-term treatment of primary pulmonary hypertension with continuous intravenous epoprostenol (prostacyclin). Lancet 1984; i: 1046-47.
    
32. Rubin LJ, Mendoza J, Hood M, et al. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol): results of a randomized trial. Ann Intern Med 1990; 112: 485-91.
    
33. 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: 580-87.
    
34. 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.
    
35. Higenbottam TW, Spiegelhalter D, Scott JP, et al. Prostacyclin (epoprostenol) and heart-lung transplantation as treatments for severe pulmonary hypertension. Br Heart J 1993; 70: 366-70.
    
36. Pasque MK, Kaiser LR, Dresler CM, Trulock E, Triantafillou AN, Cooper JD. Single lung transplantation for pulmonary hypertension: technical aspects and immediate hemodynamic results. J Thorac Cardiovasc Surg 1992; 103: 475-81.
    
37. Oakley C. Primary pulmonary hypertension: case series from the United Kingdom. Chest 1994; 105 (suppl): 29S-32S.
    
38. Brenot F. Primary pulmonary hypertension: case series from France. Chest 1994; 105 (suppl): 33S-36S.
    
39. Gaine S, Rubin L. Medical and surgical treatment options for pulmonary hypertension. Am J Med Sci 1998; 315: 179-84.

Further Reading

Pathology

Bjornsson J, Edwards WD. Primary pulmonary hypertension: a histopathological study of 80 cases. Mayo Clin Proc 1985; 60: 16-25.

Wagenvoort C, Mulder P. Thrombotic lesions in primary plexiogenic arteriopathy. Chest 1993; 103: 844-49.

Aetiology

The International Primary Pulmonary Hypertension Study (IPPHS). Chest 1994; 105 (suppl): 37S-41S.

Fishman AP. Dietary pulmonary hypertension. Circ Res 1974; 35: 657-60.

Gurtner H. Aminorex and pulmonary hypertension. Coron Vasa 1985; 27: 160-71.

Langleben D. Familial primary pulmonary hypertension. Chest 1994; 105 (suppl): 13S-16S.

Loyd JE, Slovis B, Philips JA III, et al. The presence of genetic anticipation suggests that the molecular basis of familial primary pulmonary hypertension may be trinucleotide repeat expansion. Chest 1997; 111 (suppl): 82S-83S.

Mette S, Palevsky H, Pietra G, et al. Primary pulmonary hypertension in association with human immunodeficiency virus infection. Am Rev Respir Dis 1992; 145: 1196-200.

Schaiberger P, Kennedy T, Miller F, Gal J, Petty T. Pulmonary hypertension associated with long-term inhalation of "crank" methamphetamine. Chest 1993; 104: 614-16.

Pathogenesis

Christman B, McPherson C, Newman J, et al. An Imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med 1992; 327: 70-75.

Isern R, Yaneva W, Weiner E, et al. Autoantibodies in patients with pulmonary hypertension: association with anti-Ku. Am J Med 1992; 93: 307-12.

Rich S, Kieras K, Hart K, Groves B, Stobo J, Brundage BH. Antinuclear antibodies in primary pulmonary hypertension. J Am Col Cardiol 1986; 8: 1307-11.

Stewart D, Levy R, Cernacek P, et al. Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease? Ann Intern Med 1991; 114: 464-69.

Tuder R. Plexiform lesions in primary pulmonary hypertension may represent an abnormal form of angiogenesis. Crit Care Med 1994; 15: 207-14.

Diagnosis

Anderson G, Reid L, Simon G. The radiographic appearances in primary and thromboembolic pulmonary hypertension. Clin Radiol 1973; 24: 113-20.

D'Alonzo G, Bower J, Dantzker DR. Differentiation of patients with primary and thromboembolic pulmonary hypertension. Chest 1984; 85: 457-61.

Louie EK. Rich S, Brundage BH. Doppler echocardiographic assessment of impaired left ventricular filling in patients with right ventricular pressure overload due to primary pulmonary hypertension. J Am Coll Cardiol 1986; 8: 1298-306.

Moser KM, Page G, Ashburn W, et al. Perfusion scans provide a guide to which patients with apparent primary pulmonary hypertension merit plexiogenic angiography. West J Med 1988; 148: 167-70.

Rubin L, Rich S. Medical management. In: Rubin L, Rich S, eds. Primary pulmonary hypertension. New York: Marcel Dekker, 1997; 271-86.

Weitzenblum E, Krieger J, Apprill M, et al. Daytime pulmonary hypertension in patients with obstructive sleep apnea syndrome. Am Rev Respir Dis 1988; 138: 345-49.

Treatment

Bando K, Armitage JM, Paradis IL, et al. Indications for and results of single, bilateral, and heart-lung transplantation for pulmonary hypertension. J Thorac Cardiovasc Surg 1994; 108: 1056-65.

Griffith BP, Hardesty RL, Armitage JM, et al. A decade of lung transplantation. Ann Surg 1993; 218: 310-20.

Hausknecht M, Sims R, Nihill M, Cashion W. Successful palliation of primary pulmonary hypertension by atrial septostomy. Am J Cardiol 1990; 65: 1045-46.

Kerstein D, Levy PS, Hsu DT, Hordof AJ, Gersony WM, Barst RJ. Blade balloon atrial septostomy improves survival in patients with severe primary pulmonary hypertension. Circulation 1995; 91: 2028-35.

Kuo PC, Johnson LB, Plotkin JS, Howell CD, Bartlett ST, Rubin LJ. Continuous intravenous infusion of epoproàtenol for the treatment of portopulmonary hypertension. Transplantation 1997; 63: 604-06.

Olschewski H, Walmrath D, Schermuly R, Ghofrani A, Grimminger F, Seeger W. Aerosolized prostacyclin and iloprost in severe pulmonary hypertension. Ann Intern Med 1996; 124: 820-24.

Reitz BA, Wallwork JL, Hunt SA, et al. Heart-lung transplantation: successful therapy for patients with pulmonary vascular disease. N Engl J Med 1982; 306: 557-64.

Snell GI, Salamonsen RE, Bergin P, Esmore DS, Khan S, Williams TJ. Inhaled nitric oxide used as a bridge to heart-lung transplantation in a patient with end-stage pulmonary hypertension. Am J Respir Crit Care Med 1995; 151: 1263-66.

Prognosis

Barst RJ, Rubin U, McGoon MD, CaIdwell EJ, Long WA, Levy PS. Survival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin. Ann Intern Med 1994; 121: 409-15.

Glanville AR, Burke CM, Theodore J, Robin ED. Primary pulmonary hypertension: length of survival in patients referred for heart-lung transplantation. Chest 1987; 91: 675-81.

Shapiro SM, Oudiz RJ, Cao T, et al. Primary pulmonary hypertension: improved long-term effects and survival with continuous intravenous epoprostenol infusion. J Am Coil Cardiol 1997; 30: 343-49.

Division of Pulmonary and Critical Care Medicine, University of Maryland School of Medicine, 10 S Pine Street Room 800,Baltimore, MD 21201, USA (S P Gaine MD, Prof L J Rubin MD)

Correspondence to: Dr Sean P Gaine

This article is presented with the permission of Dr. Sean Gaine and Lancet.

Advanced Search

Home

About PHC

Contact Us

Site Map

Disclaimer

Volunteer

Donate to PHCentral

Register for WebBoard - Online Support for Patients and Caregivers

Already registered? Log in here

Need Webboard help? Frequently asked Questions

Contact the Webboard Moderators