Diagnosis: Secundum atrial septal defect and secondary pulmonary hypertension with plexogenic arteriopathy (Eisenmenger syndrome)

Comment: Isolated atrial septal defect (ASD) of the secundum type may be associated with pulmonary hypertension (Eisenmenger syndrome). In one series of 702 adults with ASD, 40 (6%), ages 19-75, had vascular obstruction with a pulmonary vascular resistance (PVR) over 7 U/m2. Of the 40, 34 (85%) were women. Those who underwent surgical correction did well: 85% survived at 5 y and 80% at 10 y. Hypertension progressed in those who had medical management, and 70% were alive after 5 y and 41% at 10 y. There was no predictable relationship between a person's age and PVR. The authors advocated surgical correction for those with PVR < 10 U/m2, medical management for those with PVR >15 U/m2, and operation for those with PVR between 10 and 15 depending on other clinical factors [1].

Obstetric outcome in patients with pulmonary hypertension depends on the function of the heart: antepartum elevation of the right atrial pressure and low cardiac output are poor prognostic signs [2].

Discussion: Primary Pulmonary Hypertension

Introduction: Pulmonary hypertension accompanies many diseases of the heart and lungs. When it occurs without known underlying disease, it is called primary. The primary forms of pulmonary hypertension may affect mainly the arteries, the veins, or the capillary bed. In the last case, a capillary proliferation invasively obstructs both veins and arteries.

Classification of Primary Pulmonary Hypertension

Plexogenic pulmonary arteriopathy (PPA) also occurs in a variety of conditions that are classified as secondary PPA (Table 1).

Table 1. Entities associated with PPA (Secondary PPA) [3]

Congenital heart disease

Aminorex ingestion

Familial [4]

Cirrhosis of liver

Toxic oil ingestion [5]

Oral contraceptive therapy [6]


Intravenous drug use (talc)

Thromboembolism (rare) [7]

Collagen-vascular disease

HIV infection [8]

Clinical features of PPA: Dyspnea on exertion progressing gradually to dyspnea at rest is the hallmark of pulmonary hypertension. Fatigue, weakness, substernal chest pain, syncope, hemoptysis (from dilation lesions), hoarseness (from compression of the recurrent laryngeal nerve between the dilated left pulmonary artery and the bronchus), and peripheral edema from heart failure may also occur. On physical examination, a loud second pulmonic sound, a left parasternal heave, distended neck veins, and hepatic enlargement may be present. Up to 30% of those with primary disease have Raynaud phenomenon or anti-nuclear antibodies. Erythrocytosis, microangiopathic hemolytic anemia, and thrombocytopenia may be present [9].

Lung volumes and mechanics are usually normal. Nevertheless, pulmonary function tests showing a restrictive ventilatory pattern have been reported. In a small group of selected patients with primary pulmonary hypertension, 5 of 8 had mean vital capacity and total lung capacity of 50% and 64%, respectively [10]. Even data from the Primary Pulmonary Hypertension Registry show small lung volumes in some patients [11]. PaO2 is normal or decreased with an increased alveolar-arterial oxygen difference. The PaCO2 and DLCO are decreased. Wasted ventilation is increased during exercise [9].

Radiographic changes: The heart shows RVH, and there is an increase in the cardiothoracic ratio. Dilation of the right and left pulmonary arteries with comparative reduction in the vascular markings in the peripheral lung fields is characteristic [9].

Usefulness of lung biopsy: It has been argued that a lung biopsy does not guide therapy or establish prognosis and that clinical tests alone will establish a diagnosis of primary pulmonary hypertension [12]. Biopsy is useful in making the diagnosis when an underlying disease cannot be excluded.

Differential diagnosis: Congenital heart disease is the major correctable cause of PPA. Pulmonary hypertension associated with cirrhosis of the liver can remit following liver transplantation [13]. Treatment of HIV-associated pulmonary hypertension with anti-retroviral agents ameliorates it [14]. Other causes of PPA listed in Table 1, extensive thromboemboli, interstitial lung disease, chronic airflow obstruction, and embolic cancer may also be associated with pulmonary hypertension. Diagnosis of veno-occlusive disease is not always possible without a biopsy, but the presence of an increased capillary wedge pressure and Kerley B lines on the chest radiograph suggest that diagnosis.

Vascular changes of PPA: Arteries are divided into 3 types: elastic, muscular, and precapillary arterioles. Both axial and supernumerary vessels have been described [15]. Study of the spectrum of changes in PPA indicates that the first changes are medial thickening of the arteries and extension of muscle into the arterioles. This thickening may be followed by patchy, cellular, intimal proliferation and fibrosis, plexiform lesions, thrombosis, dilation lesions, or necrotizing arteritis [16]. Thickening of the arterial adventitia and thickening of the intima and adventitia of small veins has also been described [17]. The Heath-Edwards numerical grading system [18], which was proposed for describing pulmonary vascular changes associated with congenital heart disease (implying a stepwise progression from Grades I to VI [medial hypertrophy, cellular and then fibrous intimal thickening, plexiform lesions, dilation lesions, and necrotizing arteritis]) should probably be replaced by the descriptive terms given below [19].

Types of Lesions in Plexogenic Arteriopathy

Development of plexiform lesions: These lesions are found in most cases of PPA, and, although infrequent, usually signify irreversible pulmonary hypertension. The earliest change is a proliferation of granulation tissue at branch points, either axial or supernumerary. This tissue destroys the media (and elastic layers) and involves intima and adventitia. The granulation tissue is composed of stroma, myofibroblasts, capillaries, and inflammatory cells comprising eosinophils, mast cells, lymphocytes, and macrophages [20]. The new capillaries anastomose with bronchial arteries and possibly with proximal and distal supernumeraries. Two outcomes have been observed: enlargement and muscularization of one or more channels, or development of a discrete plexiform lesion with multiple lumens, no media, and 1 or no elastic layer. The distal, thin-walled channels may dilate via collateral flow to become so-called dilation lesions. Although plexiform lesions are characteristic, they occurred in only 4 to 7% of vessels examined in 2 series and are not seen in all cases of PPA [17,19].

Thrombosis of muscular arteries, a lesion recently added to plexogenic arteriopathy, may occur from damage to the anticoagulant activity of the endothelium. When it occurs in the setting of generalized medial thickening and patchy intimal proliferation, it also signifies PPA. The thrombi may be fresh, organized, or recanalized and occur in the same sized, small muscular arteries that show plexiforms. It is impossible to distinguish them from thromboemboli, histologically. Plexiform lesions can be mistaken for recanalized thrombi, and the elastic van Gieson stain helps to distinguish the two: elastic layers are intact around thrombi but destroyed around plexiform lesions. Thrombi are also common in the late stage of pulmonary hypertension as a result of low blood flow. They may occur in the main pulmonary arteries, as well as in smaller branches [21]. Combinations of plexiform and thrombotic lesions occur in the hypertension associated with aminorex, portal hypertension [22], the toxic oil syndrome [5], and HIV-related pulmonary hypertension [23]. These findings in hypertension of multiple causes suggest that plexiform and thrombotic lesions are both manifestations of the same process and do not represent separate entities.

Rarely, medial thickening with or without intimal proliferation is the only lesion in primary pulmonary hypertension [24]. Also, a necrotizing arteritis, either segmental or circumferential, sometimes occurs as the sole finding in addition to medial thickening.

Summary--Morphogenesis of Plexiform and Dilation Lesions

Note: The pathogenesis of the necrotizing arteritis is not known.

Changes in large pulmonary arteries: The large elastic arteries develop secondary atherosclerosis with subsequent dilation. This development in young persons with little atherosclerosis in the systemic circuit emphasizes the role of hypertension as a cause.

Associated findings: In most cases, end-stage plexiform and dilation lesions are present and the evolving proliferative lesions are not seen. Nevertheless, remaining clues to the inflammatory stage are collections of lymphoid cells around damaged vessels and in their walls. Morphologic evidence from scanning electron microscopy shows distortion of the normal endothelial surface pattern, and transmission electron microscopy shows an increase in protein-synthesizing organelles in endothelial cells [25]. A possible role for mast cells in plexogenic arteriopathy is suggested by their increased numbers in the lung (>50/mm2) and their location throughout the parenchyma, compared to normal lungs that have fewer numbers (<5/mm2) usually confined to perivascular and subpleural connective tissue [26]. Finally, a relation of neuroendocrine cell hyperplasia to plexogenic arteriopathy of primary pulmonary hypertension has been noted. In a patient who underwent lung biopsy that showed changes of pulmonary hypertension 5 years before lung transplant, the excised lung showed a marked hyperplasia of neuroendocrine cells with immunoreactivity to bombesin and calcitonin compared to the biopsy [27].

Frequency of lesions in patients with primary pulmonary hypertension: A study of the histopathology of lung lesions was performed on a sample of patients in the Primary Pulmonary Hypertension Registry [19]. Of the 49 with plexogenic arteriopathy, 25 (51%) had plexiform lesions ± recanalized thrombi, 19 (39%) had thrombotic lesions alone, 4 (8%) had medial thickening and intimal fibrosis alone, and one had only medial thickening. Classification was done on 5 slides/case, and EVG stains were reviewed in a subset of patients. In another study of 76 patients with pulmonary arterial hypertension, 74% had plexiform lesions, 17% had thrombotic lesions alone, and 9% had medial and intimal thickening alone [16].

Clinico-pathologic correlations: After histologic classification, clinical differences between patients with plexiform and thrombotic lesions were identified. Patients with plexiform lesions were found to have higher pulmonary artery pressure, higher pulmonary vascular resistance, and lower cardiac indexes than patients with thrombotic lesions alone. Perfusion lung scans (low probability for thromboemboli in all cases) showed patchy, non-segmental defects in 7 of 8 patients with thrombotic, but in none of 9 patients with plexiform lesions. Patients with plexiform lesions had a mean age of 29 and a female to male ratio of 3:1, whereas patients with thrombotic lesions had a mean age of 37 and a female to male ratio of 1:1. The median survival was 102 days for patients with plexiform lesions and 858 days for patients with thrombotic lesions [28] .

Pathogenetic mechanisms: Although we do not know the pathogenetic mechanisms involved, there is increasing evidence that endothelial cell injury is a common pathway [29, 30]. Much is now known about endothelium-derived, vasoactive substances and endothelium-platelet interactions. Their regulation by shear stress or the immune system has been proposed. More specifically, there are reports of thrombocytopenia in plexogenic arteriopathy [31, 32]. Other reports cite an imbalance favoring thromboxane (a vasoconstrictor and procoagulant) over prostacyclin (a vasodilator) [33], or an increase in endothelin-1 (a vasoconstrictor) [34,35] in the urine or blood of these patients. The link between endothelial damage and vascular remodeling is less clear although endothelin-1 is a mitogen for smooth muscle cells and fibroblasts; and platelets are rich in growth factors.

Therapy: Patients are often managed with anticoagulation and vasodilators. Bilateral lung transplantation is now an option [9].


1. Steele P, Fuster V, Cohen M, Ritter D, McGoon D. Isolated atrial septal defect with pulmonary vascular obstructive disease--long-term follow-up and prediction of outcome after surgical correction. Circulation 1987; 76:1037-1042.

2. Weeks S, Smith J. Obstetric anaesthesia in patients with primary pulmonary hypertension. Can J Anaesth 1991; 38:814-816.

3. Wagenvoort C, Wagenvoort N. Pathology of Pulmonary Hypertension. New York, John Wiley & Sons, 1977.

4. Loyd J, Atkinson J, Pietra G, Virmani R, Newman J. Heterogeneity of pathologic lesions in familial primary pulmonary hypertension. Am Rev Respir Dis 1988; 138:952-957.

5. Gómez-Sánchez M, Saenz de la Calzada C, Gomez-Pajuelo C, Martinez-Tello F, Mestre de Juan M, James T. Clinical and pathologic manifestations of pulmonary vascular disease in the toxic oil syndrome. J Am Coll Cardiol 1991; 18:1539-1545.

6. Kleiger R, Boxer M, Ingham R, Harrison D. Pulmonary hypertension in patients using oral contraceptives: a report of six cases. Chest 1976; 69:143-147.

7. Moser K, Bloor C. Pulmonary vascular lesions occurring in patients with chronic major vessel thromboembolic pulmonary hypertension. Chest 1993; 103:685-692.

8. de Chadarévian J-P, Lischner H, Karmazin N, Pawel B, Schultz T. Pulmonary hypertension and HIV infection: new observations and review of the syndrome. Mod Pathol 1994; 7:685-689.

9. Rubin L. Pulmonary vasculitis and primary pulmonary hypertension. In: J Murray, J Nadel (eds): Textbook of Respiratory Medicine, 2nd ed. Philadelphia, WB Saunders, 1994, pp 1693-1704.

10. Horn M, Ries A, Neveu C, Moser K. Restrictive ventilatory pattern in precapillary pulmonary hypertension. Am Rev Respir Dis 1983; 128:163-165.

11. Rich S, Dantzker D, Ayres S, Bergofsky E, Brundage B. Detre K, Fishman A, et al. Primary pulmonary hypertension. A national prospective study. Ann Intern Med 1987; 107:216-223.

12. Nicod P, Moser K. Primary pulmonary hypertension. The risk and benefit of lung biopsy. Circulation 1989; 80:1486-1488.

13. Koneru B, Ahmed S, Weisse A, Grant G, McKim K. Resolution of pulmonary hypertension of cirrhosis after liver transplantation. Transplantation 1994; 58:1133-1135.

14. Opravil M, Pechère M, Speich R, Joller-Jemelka H, Jenni R, Russi E, Hirschel B, et al. HIV-associated primary pulmonary hypertension. A case control study. Am J Respir Crit Care Med 1997; 155:990-995.

15. Elliott F, Reid L. Some new facts about the pulmonary artery and its branching pattern. Clin Radiol 1965; 16:193-198.

16. Burke A, Farb A, Virmani R. The pathology of primary pulmonary hypertension. Mod Pathol 1991; 4:269-282.

17. Chazova I, Loyd J, Zhdanov V, Newman J, Belenkov Y, Meyrick B. Pulmonary artery adventitial changes and venous involvement in primary pulmonary hypertension. Am J Pathol 1995; 146:389-397.

18. Heath D, Edwards J. 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; 18:533-547.

19. Pietra G, Edwards W, Kay J, Rich S, Kernis J, Schloo B, Ayres S, et al. Histopathology of primary pulmonary hypertension. A qualitative and quantitative study of pulmonary blood vessels from 58 patients in the National Heart, Lung, and Blood Institute, Primary Pulmonary Hypertension Registry. Circulation 1989; 80:1198-1206.

20. Tuder R, Groves B, Badesch D, Voelkel N. Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. Am J Pathol 1994; 144:275-285.

21. Moser K, Fedullo P, Finkbeiner W, Golden J. Do patients with primary pulmonary hypertension develop extensive central thrombi? Circulation 1995; 91:741-745.

22. Weir E, Archer S, Edwards J. Chronic primary and secondary thromboembolic pulmonary hypertension. Chest 1988; 93:149s-153s.

23. Mette S, Palevsky H, Pietra G, Williams T, Bruder E, Prestipino A, Patrick A, et al. Primary pulmonary hypertension in association with human immunodeficiency virus infection. A possible viral etiology for some forms of hypertensive pulmonary arteriopathy. Am Rev Respir Dis 1992; 145:1196-1200.

24. Anderson T, Larsen E, Wyse G, Lester W. Primary pulmonary hypertension for 30 years. Am J Cardiol 1991; 68:284-285.

25. Rabinovitch M. Structure and function of the pulmonary vascular bed: an update. Cardiol Clinics 1989; 7:895-914.

26. Heath D, Yacoub M. Lung mast cells in plexogenic pulmonary arteriopathy. J Clin Pathol 1991; 44:1003-1006.

27. Heath D, Smith P, Gosney J, Mulcahy D, Fox K, Yacoub M, Harris P. The pathology of the early and late stages of primary pulmonary hypertension. Br Heart J 1987; 58:204-213.

28. Rich S, Pietra G, Kieras K, Hart K, Brundage B. Primary pulmonary hypertension: radiographic and scintigraphic patterns of histologic subtypes. Ann Intern Med 1986; 105:499-502.

29. Vane J, Anggard E, Botting R. Regulatory functions of the vascular endothelium. N Engl J Med 1990; 323:27-36.

30. Ware J, Heistad D. Platelet-endothelium interactions. N Engl J Med 1993; 328:628-635.

31. Edwards B, Weir E, Edwards W, Ludwig J, Dykoski R, Edwards J. Coexistent pulmonary and portal hypertension: morphologic and clinical features. J Am Coll Cardiol 1987; 10:1233-1238.

32. Jubelirer S. Primary pulmonary hypertension. Its association with microangiopathic hemolytic anemia and thrombocytopenia. Arch Intern Med 1991; 151:1221-1223.

33. Christman B, McPherson C, Newman J, King G, Bernard G, Groves B, Loyd J. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med 1992; 327:70-75.

34. Cacoub P, Dorent R, Nataf P, Carayon A, Riquet M, Noe E, Piette J, et al. Endothelin-1 in the lungs of patients with pulmonary hypertension. Cardiovasc Res 1997; 33:196-200.

35. Stewart D, Levy R, Cernacek P, Langleben D. Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease? Ann Intern Med 1991; 114:464-469.

Clinical summary

Table of Contents

Last revised 5/11/97

Copyright 1997 Martha L. Warnock. All rights reserved.