DOI: 10.1148/radiol.2233010911
(Radiology 2002;223:820-827.)
© RSNA, 2002
Imaging Findings in Human Immunodeficiency Virus–related Pulmonary Hypertension: Report of Five Cases and Review of the Literature1
Alejandro N. Bugnone, MD,
Manuel Viamonte, Jr, MD and
Hernando Garcia, MD
1 From the Mount Sinai Medical Center of Miami, 4300 Alton Rd, Radiology Bldg, Office 218, Miami Beach, FL 33140. Received May 11, 2001; revision requested June 25; revision received August 17; accepted September 7. Address correspondence to A.N.B. (e-mail: bugnonea@hotmail.com).
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ABSTRACT
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Five cases of human immunodeficiency virus–related pulmonary hypertension and their imaging manifestations are reported. The radiologic findings vary from mild enlargement of the pulmonary trunk or the central pulmonary arteries at early stages to marked dilatation of the central pulmonary arteries and massive cardiomegaly due to right ventricular and right atrial enlargement at later stages of the disease.
© RSNA, 2002
Index terms: Acquired immunodeficiency syndrome (AIDS), 564.206 • Hypertension, pulmonary, 564.78 • Thorax, CT, 58.12116
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INTRODUCTION
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Radiologists have a central role in the diagnosis of the pulmonary complications of human immunodeficiency virus (HIV) infection. A relationship between HIV infection and pulmonary hypertension (PH) has been reported in 131 patients, in 111 of whom there was no other explainable cause for the development of PH (1). To our knowledge, there are no additional publications or case reports in the radiologic literature on HIV-related pulmonary hypertension (HIV-PH).
In this article, we describe the radiologic findings in five patients with HIV-PH as determined from our retrospective review. Our institutional review board does not require its approval or informed consent for such a review. We also present a brief overview of the reported cases in the medical literature, the imaging aspects of HIV-PH, and the current concepts regarding the pathophysiology of this disease.
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Case 1
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The patient was a 28-year-old woman who originally presented to another institution 5 years previously with shortness of breath and exertional dyspnea. A chest radiograph (Fig 1a) obtained at the time of the patient’s initial presentation demonstrated cardiomegaly and enlargement of the pulmonary trunk and central pulmonary vasculature with tapering of the peripheral pulmonary arterial branches. After secondary causes of PH were excluded, primary PH was diagnosed.
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Figure 1a. Case 1. A 28-year-old woman in whom PH was the first manifestation of HIV infection. (a) Posteroanterior chest radiograph reveals marked cardiomegaly and an enlarged pulmonary trunk (arrowhead). The right interlobar artery (arrow) measures 21 mm in transverse diameter. (b) Posteroanterior chest radiograph obtained 5 years later shows interval progression of the cardiomegaly. (c-e) Electron-beam CT pulmonary angiograms (130 keV, 633 mA, 3-mm collimation, 0.2-second exposure). (c) Transverse view at the level of the bifurcation of the pulmonary artery (window width, 500 HU; window level, 40 HU) shows enlargement of the main pulmonary artery (pa), which measures 43 mm in transverse diameter (dashed line). (d) Transverse image obtained at a lower level (window width, 500 HU; window level, 40 HU) shows dilatation of the right ventricle (rv) and right atrium (ra) and reversal of the interatrial (straight arrow) and interventricular (curved arrow) septa. Simultaneous opacification of the right and left cardiac chambers is noted. lv = left ventricle, la = left atrium. (e) Segmental artery-to-bronchus ratios greater than 1 (arrows) in the lower lobes can be observed on this transverse image obtained at a lower level (window width, 1,400 HU; window level, -300 HU). (f) A four-chamber view from an echocardiogram shows right ventricular (rv) and right atrial (ra) dilatation. Paradoxical movement of the interventricular septum (arrowhead) was observed at real-time imaging.
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Figure 1b. Case 1. A 28-year-old woman in whom PH was the first manifestation of HIV infection. (a) Posteroanterior chest radiograph reveals marked cardiomegaly and an enlarged pulmonary trunk (arrowhead). The right interlobar artery (arrow) measures 21 mm in transverse diameter. (b) Posteroanterior chest radiograph obtained 5 years later shows interval progression of the cardiomegaly. (c-e) Electron-beam CT pulmonary angiograms (130 keV, 633 mA, 3-mm collimation, 0.2-second exposure). (c) Transverse view at the level of the bifurcation of the pulmonary artery (window width, 500 HU; window level, 40 HU) shows enlargement of the main pulmonary artery (pa), which measures 43 mm in transverse diameter (dashed line). (d) Transverse image obtained at a lower level (window width, 500 HU; window level, 40 HU) shows dilatation of the right ventricle (rv) and right atrium (ra) and reversal of the interatrial (straight arrow) and interventricular (curved arrow) septa. Simultaneous opacification of the right and left cardiac chambers is noted. lv = left ventricle, la = left atrium. (e) Segmental artery-to-bronchus ratios greater than 1 (arrows) in the lower lobes can be observed on this transverse image obtained at a lower level (window width, 1,400 HU; window level, -300 HU). (f) A four-chamber view from an echocardiogram shows right ventricular (rv) and right atrial (ra) dilatation. Paradoxical movement of the interventricular septum (arrowhead) was observed at real-time imaging.
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Figure 1c. Case 1. A 28-year-old woman in whom PH was the first manifestation of HIV infection. (a) Posteroanterior chest radiograph reveals marked cardiomegaly and an enlarged pulmonary trunk (arrowhead). The right interlobar artery (arrow) measures 21 mm in transverse diameter. (b) Posteroanterior chest radiograph obtained 5 years later shows interval progression of the cardiomegaly. (c-e) Electron-beam CT pulmonary angiograms (130 keV, 633 mA, 3-mm collimation, 0.2-second exposure). (c) Transverse view at the level of the bifurcation of the pulmonary artery (window width, 500 HU; window level, 40 HU) shows enlargement of the main pulmonary artery (pa), which measures 43 mm in transverse diameter (dashed line). (d) Transverse image obtained at a lower level (window width, 500 HU; window level, 40 HU) shows dilatation of the right ventricle (rv) and right atrium (ra) and reversal of the interatrial (straight arrow) and interventricular (curved arrow) septa. Simultaneous opacification of the right and left cardiac chambers is noted. lv = left ventricle, la = left atrium. (e) Segmental artery-to-bronchus ratios greater than 1 (arrows) in the lower lobes can be observed on this transverse image obtained at a lower level (window width, 1,400 HU; window level, -300 HU). (f) A four-chamber view from an echocardiogram shows right ventricular (rv) and right atrial (ra) dilatation. Paradoxical movement of the interventricular septum (arrowhead) was observed at real-time imaging.
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Figure 1d. Case 1. A 28-year-old woman in whom PH was the first manifestation of HIV infection. (a) Posteroanterior chest radiograph reveals marked cardiomegaly and an enlarged pulmonary trunk (arrowhead). The right interlobar artery (arrow) measures 21 mm in transverse diameter. (b) Posteroanterior chest radiograph obtained 5 years later shows interval progression of the cardiomegaly. (c-e) Electron-beam CT pulmonary angiograms (130 keV, 633 mA, 3-mm collimation, 0.2-second exposure). (c) Transverse view at the level of the bifurcation of the pulmonary artery (window width, 500 HU; window level, 40 HU) shows enlargement of the main pulmonary artery (pa), which measures 43 mm in transverse diameter (dashed line). (d) Transverse image obtained at a lower level (window width, 500 HU; window level, 40 HU) shows dilatation of the right ventricle (rv) and right atrium (ra) and reversal of the interatrial (straight arrow) and interventricular (curved arrow) septa. Simultaneous opacification of the right and left cardiac chambers is noted. lv = left ventricle, la = left atrium. (e) Segmental artery-to-bronchus ratios greater than 1 (arrows) in the lower lobes can be observed on this transverse image obtained at a lower level (window width, 1,400 HU; window level, -300 HU). (f) A four-chamber view from an echocardiogram shows right ventricular (rv) and right atrial (ra) dilatation. Paradoxical movement of the interventricular septum (arrowhead) was observed at real-time imaging.
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Figure 1e. Case 1. A 28-year-old woman in whom PH was the first manifestation of HIV infection. (a) Posteroanterior chest radiograph reveals marked cardiomegaly and an enlarged pulmonary trunk (arrowhead). The right interlobar artery (arrow) measures 21 mm in transverse diameter. (b) Posteroanterior chest radiograph obtained 5 years later shows interval progression of the cardiomegaly. (c-e) Electron-beam CT pulmonary angiograms (130 keV, 633 mA, 3-mm collimation, 0.2-second exposure). (c) Transverse view at the level of the bifurcation of the pulmonary artery (window width, 500 HU; window level, 40 HU) shows enlargement of the main pulmonary artery (pa), which measures 43 mm in transverse diameter (dashed line). (d) Transverse image obtained at a lower level (window width, 500 HU; window level, 40 HU) shows dilatation of the right ventricle (rv) and right atrium (ra) and reversal of the interatrial (straight arrow) and interventricular (curved arrow) septa. Simultaneous opacification of the right and left cardiac chambers is noted. lv = left ventricle, la = left atrium. (e) Segmental artery-to-bronchus ratios greater than 1 (arrows) in the lower lobes can be observed on this transverse image obtained at a lower level (window width, 1,400 HU; window level, -300 HU). (f) A four-chamber view from an echocardiogram shows right ventricular (rv) and right atrial (ra) dilatation. Paradoxical movement of the interventricular septum (arrowhead) was observed at real-time imaging.
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Figure 1f. Case 1. A 28-year-old woman in whom PH was the first manifestation of HIV infection. (a) Posteroanterior chest radiograph reveals marked cardiomegaly and an enlarged pulmonary trunk (arrowhead). The right interlobar artery (arrow) measures 21 mm in transverse diameter. (b) Posteroanterior chest radiograph obtained 5 years later shows interval progression of the cardiomegaly. (c-e) Electron-beam CT pulmonary angiograms (130 keV, 633 mA, 3-mm collimation, 0.2-second exposure). (c) Transverse view at the level of the bifurcation of the pulmonary artery (window width, 500 HU; window level, 40 HU) shows enlargement of the main pulmonary artery (pa), which measures 43 mm in transverse diameter (dashed line). (d) Transverse image obtained at a lower level (window width, 500 HU; window level, 40 HU) shows dilatation of the right ventricle (rv) and right atrium (ra) and reversal of the interatrial (straight arrow) and interventricular (curved arrow) septa. Simultaneous opacification of the right and left cardiac chambers is noted. lv = left ventricle, la = left atrium. (e) Segmental artery-to-bronchus ratios greater than 1 (arrows) in the lower lobes can be observed on this transverse image obtained at a lower level (window width, 1,400 HU; window level, -300 HU). (f) A four-chamber view from an echocardiogram shows right ventricular (rv) and right atrial (ra) dilatation. Paradoxical movement of the interventricular septum (arrowhead) was observed at real-time imaging.
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The patient was referred for lung transplantation; she was then found to be seropositive for HIV. The patient received antiretroviral drug therapy for 5 years without developing any other obvious HIV-related disease. She was referred to our medical center because of a worsening of exercise intolerance and for evaluation and treatment of the PH.
A chest radiograph (Fig 1b) obtained at that time revealed enlargement of the heart, right ventricle, and pulmonary trunk. To exclude chronic pulmonary embolism, a ventilation-perfusion lung scan was obtained, but it revealed no evidence of segmental perfusion abnormalities. On the perfusion scan, radiotracer activity was identified in the kidneys and brain, a finding indicative of a right-to-left shunt.
An electron-beam computed tomographic (CT) pulmonary angiogram demonstrated no evidence of filling defects and revealed an enlarged main pulmonary artery that measured 43 mm in transverse diameter (Fig 1c) and marked dilatation of the right ventricle and right atrium with protrusion of the interventricular and interatrial septa into the left ventricle and left atrium, respectively (Fig 1d). Simultaneous opacification of the right and left cardiac chambers was noted. The segmental artery-to-bronchus ratio was greater than 1 in more than four bronchopulmonary segments (Fig 1e). No parenchymal abnormalities or areas of abnormal calcification in the pulmonary arteries were observed on the CT scan obtained before administration of contrast material.
An echocardiogram with a "bubble study" showed dilatation of the right cardiac chambers (Fig 1f), regurgitation at the tricuspid and pulmonic valves, and a right-to-left shunt at the level of the interatrial septum. A transesophageal echocardiogram revealed the presence of a 5-mm patent foramen ovale. Cardiac catheterization revealed a pulmonary artery pressure of 67/38 mm Hg, a right ventricular pressure of 67/18 mm Hg, a right atrial pressure of 19/17 mm Hg, and a pulmonary capillary wedge pressure of 18 mm Hg.
After she showed a good response to a trial of epoprostenol (endogenous form, prostacyclin), the patient was started on chronic continuous intravenous epoprostenol infusion therapy, to which she had an adequate response.
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Case 2
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The patient was a 48-year-old man who initially presented to another institution with a 1-year history of slowly progressive exertional dyspnea. After an adequate clinical work-up, primary PH was diagnosed, and the patient was referred for lung transplantation; he was then found to have HIV infection. The patient later developed right-sided cardiac failure, at which time he was referred to our institution for reevaluation and treatment. A chest radiograph revealed cardiomegaly and enlarged pulmonary arteries (Fig 2). Echocardiograms showed mild right chamber dilatation, tricuspid regurgitation, and paradoxical septal movement. Cardiac catheterization revealed a pulmonary artery pressure of 71/46 mm Hg (mean, 58 mm Hg) and a pulmonary capillary wedge pressure of 8 mm Hg. The vascular resistance was 1,200 dynes·sec·cm-5. The patient was treated with phenoxybenzamine and later with continuous intravenous infusion of epoprostenol; he showed improvement in symptoms.
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Figure 2. Case 2. A 48-year-old man in whom PH was the first manifestation of HIV infection. Posteroanterior chest radiograph shows slight prominence of central pulmonary arteries; the right interlobar artery (arrow) measures 19 mm in transverse diameter.
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Case 3
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The patient was a 30-year-old man with a 5-year history of HIV infection who initially presented to another institution with shortness of breath on exertion. Chest radiographs demonstrated enlargement of the central pulmonary vasculature. The results of pulmonary function tests were normal, and no further work-up was conducted at that time. Six months later, a chest radiograph revealed cardiomegaly. Echocardiograms demonstrated pericardial effusion, right atrial and ventricular dilatation, and signs of PH (calculated mean pulmonary arterial pressure: 48 mm Hg). CT pulmonary angiograms showed enlargement of the pulmonary trunk, mild dilatation of the right ventricle, and a pericardial effusion (Fig 3a). There was no evidence of pulmonary emboli. The pericardial fluid was analyzed and found to be a transudate. No etiologic factor could be found for the pericardial effusion, which was considered to be idiopathic. Several collagen-vascular diagnostic panels were negative.
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Figure 3a. Case 3. A 30-year-old man with HIV and PH. (a) Transverse CT pulmonary angiogram (120 keV; 240 mA; 3-mm collimation; window width, 400 HU; window level, 40 HU) demonstrates pericardial effusion (arrow) and right ventricular (rv) dilatation. (b) Selective left pulmonary angiogram obtained in an anteroposterior orientation demonstrates an enlarged left pulmonary artery (lpa) and pruning of the vascular tree in the peripheral vessels, predominantly in the lower lobe branches (arrowheads). Similar findings were observed on the right-side angiogram.
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Figure 3b. Case 3. A 30-year-old man with HIV and PH. (a) Transverse CT pulmonary angiogram (120 keV; 240 mA; 3-mm collimation; window width, 400 HU; window level, 40 HU) demonstrates pericardial effusion (arrow) and right ventricular (rv) dilatation. (b) Selective left pulmonary angiogram obtained in an anteroposterior orientation demonstrates an enlarged left pulmonary artery (lpa) and pruning of the vascular tree in the peripheral vessels, predominantly in the lower lobe branches (arrowheads). Similar findings were observed on the right-side angiogram.
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Three months later, a follow-up echocardiogram revealed worsening of the PH (calculated mean pulmonary arterial pressure: 70 mm Hg). A ventilation-perfusion scan was negative for pulmonary embolism. Cardiac catheterization and a pulmonary angiogram revealed a main pulmonary artery pressure of 97/17 mm Hg (mean, 50 mm Hg) and enlarged central pulmonary arteries with pruning of the peripheral pulmonary vascularity (Fig 3b) but revealed no evidence of filling defects. Other causes of secondary PH were excluded, and HIV-PH was diagnosed. After 2 years of therapy with intravenous epoprostenol infusion, the patient experienced improvement in symptoms, and his pulmonary artery pressure returned to almost normal levels.
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Case 4
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The patient was a 40-year-old man with a 10-year history of HIV infection and multiple psychiatric and medical problems, including cirrhosis of the liver. At the time of the patient’s admission because of a cerebellar stroke, a chest radiograph revealed slight enlargement of the pulmonary arteries and decreased peripheral vascularity (Fig 4b). When this radiograph was compared with a radiograph obtained 3 years earlier (Fig 4a), slight enlargement of the pulmonary trunk, probably due to PH, was revealed. CT pulmonary angiograms demonstrated a pulmonary trunk that measured 35 mm (Fig 4c), a segmental artery-to-bronchus ratio greater than 1 in more than three bronchopulmonary segments, and no evidence of filling defects in the pulmonary arteries. An echocardiogram showed pulmonic insufficiency, slight right ventricular and atrial enlargement, and signs of PH. Cardiac catheterization revealed a pulmonary artery pressure of 72/25 mm Hg (mean, 46 mm Hg), a right ventricular pressure of 72/9 mm Hg, and pulmonary vascular resistance of 500 dynes · sec · cm-5. The cause of the PH in this case could have been the HIV or the concomitant liver disease (portopulmonary hypertension). The patient began receiving phenoxybenzamine, which adequately controlled the PH.
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Figure 4a. Case 4. A 40-year-old HIV-positive man with no pulmonary symptoms. (a) Posteroanterior chest radiograph shows an enlarged pulmonary trunk (straight arrow) without evidence of central pulmonary artery enlargement; the right interlobar artery (curved arrow) measures 16 mm. (b) A posteroanterior chest radiograph obtained 3 years later shows slight dilatation of the central pulmonary arteries. The right interlobar artery (arrow) measures 20 mm. (c) Transverse CT pulmonary angiogram (120 keV; 240 mA; 3-mm collimation; window width, 400 HU; window level, 40 HU) demonstrates an enlarged main pulmonary artery (pa), which measures 35 mm at the level of the bifurcation.
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Figure 4b. Case 4. A 40-year-old HIV-positive man with no pulmonary symptoms. (a) Posteroanterior chest radiograph shows an enlarged pulmonary trunk (straight arrow) without evidence of central pulmonary artery enlargement; the right interlobar artery (curved arrow) measures 16 mm. (b) A posteroanterior chest radiograph obtained 3 years later shows slight dilatation of the central pulmonary arteries. The right interlobar artery (arrow) measures 20 mm. (c) Transverse CT pulmonary angiogram (120 keV; 240 mA; 3-mm collimation; window width, 400 HU; window level, 40 HU) demonstrates an enlarged main pulmonary artery (pa), which measures 35 mm at the level of the bifurcation.
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Figure 4c. Case 4. A 40-year-old HIV-positive man with no pulmonary symptoms. (a) Posteroanterior chest radiograph shows an enlarged pulmonary trunk (straight arrow) without evidence of central pulmonary artery enlargement; the right interlobar artery (curved arrow) measures 16 mm. (b) A posteroanterior chest radiograph obtained 3 years later shows slight dilatation of the central pulmonary arteries. The right interlobar artery (arrow) measures 20 mm. (c) Transverse CT pulmonary angiogram (120 keV; 240 mA; 3-mm collimation; window width, 400 HU; window level, 40 HU) demonstrates an enlarged main pulmonary artery (pa), which measures 35 mm at the level of the bifurcation.
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Case 5
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The patient was a 40-year-old man with a 14-year history of HIV infection who was undergoing therapy with multiple antiretroviral drugs. The patient had complications from HIV, including cytomegalovirus retinitis and gastritis and Kaposi sarcoma of the skin. He presented to our institution with a 10-month history of progressive exertional dyspnea. A chest radiograph (Fig 5) showed moderate cardiomegaly and prominence of the right ventricle and central pulmonary arteries. A ventilation-perfusion scan was negative for pulmonary emboli. Echocardiograms revealed severe right atrial and ventricular enlargement with tricuspid regurgitation. The estimated pulmonary artery pressure was 90 mm Hg. Cardiac catheterization revealed a pulmonary pressure of 68/32 mm Hg (mean, 46 mm Hg) and a pulmonary vascular resistance of 746 dynes·sec·cm-5.
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Figure 5. Case 5. A 40-year-old man with a 14-year history of HIV and a 10-month history of exertional dyspnea. Posteroanterior chest radiograph demonstrates moderate cardiomegaly and enlargement of the pulmonary trunk (straight arrow) and hilar pulmonary arteries. The curved arrow indicates the right pulmonary artery.
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All other causes of secondary PH were excluded, and HIV-PH was diagnosed. The patient was treated with phenoxibenzamine and responded well to treatment for 2 years. The patient was admitted to our institution with a respiratory infection in May 2001; he died of multisystem organ failure 12 days after admission. Examination of specimens obtained at autopsy revealed plexogenic arteriopathy affecting the lungs and signs of cor pulmonale, cardiomegaly, right ventricular dilatation, and hypertrophy.
The Table provides a summary of data in the five patients.
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Discussion
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PH is defined as a situation in which there is a mean pulmonary arterial pressure of 30 mm Hg or greater. PH can be classified as precapillary or postcapillary. Precapillary PH may be the result of diseases that decrease the cross-sectional area of the pulmonary vascular bed, either by affecting the lung parenchyma (eg, pulmonary fibrosis) or by affecting the pulmonary vessels (eg, pulmonary thromboembolism, vasculitis, and primary PH). Precapillary PH may also be the result of processes that cause pulmonary arterial vasoconstriction (eg, hypoxia, anorexigenic drugs). Causes of postcapillary PH include diseases that increase pulmonary venous pressure (eg, left heart failure, mitral valve disease, left atrial tumors, pulmonary veno-occlusive disease, and mediastinal fibrosis).
Initial cases of HIV-PH in patients with hemophilia and HIV infection were described in 1987 by Kim and Factor (1) and in 1988 by Goldsmith and associates (2). It was initially thought that lyophilized factor VIII or the hemophilia itself was the cause of the PH seen in these patients, until new cases in which the patients had HIV infection but not hemophilia were reported in 1989 (4,5).
Patient Demographics
At the time this article was completed, to our knowledge, 131 cases of HIV-PH have been reported (1,6); our five cases bring the total to 136. Among the reported patients, 55% are men, the mean age at presentation is 33 years (range, 2–56 years), and the mean time of diagnosis of PH after the diagnosis of HIV infection is 33 months. Of the 136 patients, 111 (82%) had no other conditions that could explain the development of PH. There is no correlation between the CD4 cell count or past pulmonary infections and the presence of PH. Other conditions that can cause PH in patients with HIV infection are pulmonary thromboembolism, pulmonary veno-occlusive disease, portopulmonary hypertension, and talc granulomas (7,8). The latter are often seen in intravenous drug abusers.
Clinical Findings
The main symptom of patients with HIV-PH is dyspnea (1,6,9,10). Other symptoms include pedal edema, nonproductive cough, fatigue, and syncope (1,4,6,10,11). Laboratory studies usually reveal hypoxemia (5). The mean pulmonary arterial systolic and diastolic pressures are 67 mm Hg ± 18 (SD) and 40 mm Hg ± 11, respectively (1). Results of pulmonary function tests usually demonstrate a mild restrictive pattern. Results of pulmonary stress tests demonstrate mild to moderate desaturation with exercise. Morbidity and mortality in patients with HIV-PH are higher than in patients with primary PH. The 8-month survival rate is 51% for untreated patients, compared with a 68% 1-year survival rate for patients with primary PH (6). The prognosis is unrelated to the duration of HIV infection or to the viral load (6). However, a recent report described a statistically significant difference in the degree of PH between HIV-positive patients with and without acquired immunodeficiency syndrome (AIDS): the former group had higher pulmonary pressures (12). Treatment methods include the use of calcium channel blockers, epoprostenol (administered either as a continuous intravenous infusion or in an inhaled or oral form), and the experimental use of nitrous oxide or endothelin-receptor blockers.
Imaging Findings
The most common findings on chest radiographs are similar to those observed in primary PH. The early radiographic findings are often subtle and include slight enlargement of the pulmonary trunk. Later in the disease, enlarged central pulmonary arteries with tapering of the vessels at the periphery of the lungs are observed, and the heart will appear enlarged as a result of right ventricular and right atrial dilatation. The finding of a right interlobar artery that measures more than 16 mm on a frontal erect chest radiograph can be used as an objective assessment of pulmonary artery dilatation (13).
In contrast to patients with primary PH, in whom enlargement of the pulmonary arteries is the main radiographic finding, in patients with HIV-PH, cardiomegaly and enlarged pulmonary arteries are observed in similar proportions (72% and 71%, respectively) (1). Cardiomegaly is caused by dilatation of the right ventricle. Myogenic factors could predispose the right ventricular myocardium to early dilatation; future studies should investigate this. Pericardial effusion for which no etiologic factor could be found occurred in the patient in case 3 of our series.
Chest CT, CT pulmonary angiography, and electron-beam CT are useful for the evaluation of the cardiac and vascular changes seen in HIV-PH, as well as for excluding the presence of other diseases that could explain the PH. The most common findings are enlarged central pulmonary arteries with peripheral vessels that abruptly decrease in caliber and associated cardiomegaly. Evaluation of the main pulmonary artery on transverse images is performed at the level of its bifurcation at a right angle to its long axis, lateral to the ascending aorta (13). A diameter of 29 mm or greater has a sensitivity of 87% and specificity of 89% for the diagnosis of PH (13). If this finding is associated with a segmental artery-to-bronchus ratio greater than 1 in three or more pulmonary lobes, the specificity is 100% (13,14). A pulmonary artery-to-aortic ratio greater than 1 also has a strong correlation with PH, especially in patients younger than 50 years of age (15).
Abnormalities in cardiac anatomy may be visualized at contrast-enhanced CT, electron-beam CT, or during CT pulmonary angiography. At our institution, electron-beam CT pulmonary angiography with fast acquisition has been particularly useful in enabling the evaluation of the pulmonary vascularity and the size of the right chambers with the same study. Right ventricular and right atrial dilatation, with reversal of the curvature of the interatrial and interventricular septa, can be seen at electron-beam CT or multi-section CT. Dynamic flow studies can be performed to help assess whether intracardiac shunts are present.
Ventilation-perfusion scans are usually interpreted as indicating a normal or low probability of pulmonary embolism. This finding is nonspecific but useful for excluding pulmonary embolism as a cause of PH.
Magnetic resonance (MR) imaging can also be performed to help evaluate PH. In addition to the anatomic changes in the pulmonary artery and the heart, decreased arterial blood flow on gated spin-echo MR images is seen in 92% of patients with pulmonary arterial hypertension (16).
Echocardiograms in 98% of patients with HIV-PH typically show right ventricular dilatation of various degrees, depending on the stage of the disease (1).
Pathophysiologic Findings
Plexogenic pulmonary arteriopathy has been revealed in 95% of patients with HIV-PH and no other explainable causes of PH in whom lung tissue was examined microscopically. Intimal fibrosis was revealed in the remaining 5% of patients. Cool and associates (17) performed three-dimensional computer reconstruction analysis with cell-specific markers and demonstrated the structure of the plexiform lesions and the severity of occlusion along the entire length of the affected vessels. The plexiform lesion is a complex multichannel lesion of proliferative vascular endothelium with proximal luminal narrowing that is produced by a dysregulation of endothelial cell growth. It has been proposed that the plexiform lesion seen in primary PH represents a form of neoplastic process occurring in the endothelial cells because monoclonal proliferation of these cells was observed in patients with primary but not secondary PH (18,19).
The presence of HIV or viral DNA has not been demonstrated in pulmonary endothelial cells (20), but it is believed that HIV itself causes the PH by several indirect mechanisms that produce vasoconstriction and plexiform arteriopathy. It is thought that the existence of different triggering mechanisms acting on genetically predisposed patients explains why PH is not seen in all patients with HIV infection.
Genetic predisposition.—It is now well known that there is a familial form of primary PH (21,22). Its gene has been located in the long arm of chromosome 2 (23,24). Morse and associates (25) compared the frequency of HLA antigen types in 10 patients with HIV-PH with their frequency in matched control subjects. They found an increased incidence of HLA-DR6 and HLA-DR52. This or another yet unknown genetic predisposition may alter the response of the endothelium to increased circulating growth factors (like endothelin-1) that are seen in HIV-infected patients and/or may produce increased secretion of local growth or other factors within the pulmonary capillary bed. The combination of these two phenomena may predispose the pulmonary endothelium to develop the plexiform lesion. This may be the reason why PH is not seen in all patients with HIV and may account for its low incidence in the HIV-infected population—it may be seen only in those patients with a genetic predisposition.
Endothelial factors.—Vascular tone and vascular cell replication are regulated by the balance between vasodilators, such as epoprostenol, and vasoconstrictors, such as thromboxane-A2 and endothelin-1. It has been found that glycoprotein gp-120 (an envelope protein of HIV) stimulates the production of endothelin-1 in a concentration-dependent manner (26). Chronically increased expression of endothelin-1 has been found in patients with HIV infection (6). Endothelin-1 acts as a vasoconstrictor and mitogen and thus may contribute to the proliferation of endothelial and smooth muscle cells in the pulmonary vascular bed that is seen in patients with HIV-PH. A decrease in the expression of prostacyclin synthase (the enzyme that produces prostacyclin) has also been demonstrated in patients with HIV-PH, as well as in patients with primary PH and portopulmonary hypertension (23). These elevated levels of endothelin-1 and decreased levels of prostacyclin, combined with abnormal regulation (possibly due to genetic predisposition) of the vasodilation/vasoconstriction balance and the endothelial cell replication process, lead to elevated pulmonary arterial pressure.
Potassium channels.—The potassium channels control the transmembrane potential of smooth muscle cells and platelets. The inhibition of these channels produces depolarization and increased intracellular calcium (25), which leads to vasoconstriction and cellular replication in the vascular bed (21) and release of serotonin in the platelets, which produces further vasoconstriction. Alteration in the potassium channels is now recognized as the process by which hypoxia causes PH (27,28). In patients with primary PH, there is reduced expression of these channels, probably due to a genetic cause (21). In patients with HIV-PH, there is inhibition in the expression of a subtype of potassium channels (Kv1.3) by the glycoprotein gp-160 (29). The Kv1.3 potassium channels are also found in T-lymphocytes (30), the target of the HIV virus, suggesting that an immunologic mechanism, which has not yet been clearly determined, is involved in HIV-PH.
Other Causes of PH in Patients with HIV
Portopulmonary hypertension.—The prevalence of PH in patients with portal hypertension is approximately 2% (31). Portal hypertension is thought to damage the pulmonary endothelium by causing elevated levels of endothelin-1 or other toxic substances because these substances are not cleared by the liver (32). Almost all patients have the plexogenic variant of PH. It is impossible to distinguish the cause of PH in patients who have HIV infection or AIDS and cirrhosis or hepatitis. Only 13% of the reported patients with HIV infection or AIDS and PH had coexistent liver disease (6). It is known that patients with portopulmonary hypertension will have an outcome that is determined by the status of their underlying liver function (21). In contrast, patients with untreated HIV-PH have a rapid progression and a poor prognosis, which are independent of the status of any underlying diseases (6).
Talc granulomas.—Talc granulomas that obstruct the small pulmonary arteries are another cause of PH that is sometimes seen in intravenous drug abusers who are infected with HIV (7,8).
Pulmonary thromboembolic disease.—Pulmonary thromboembolic disease represents another cause of PH in chronic HIV patients, but it is uncommon, being found only in 3% of patients with PH and HIV or AIDS (6).
Conclusion
Enlargement of the pulmonary trunk or the central pulmonary arteries with or without dilatation of the right cardiac chambers in an HIV-positive patient should raise the suspicion of HIV-PH; recognizing this disease at an early stage is important so that early treatment, which helps prevent progression and the associated hemodynamic complications that result in a poor prognosis for untreated patients, can be implemented. The development of PH is not related to the length of the disease, the viral load, the CD4 cell count, or the presence of other complications of HIV infection. There is evidence that HIV-PH, even if it is similar to primary PH, is a distinct pathophysiologic entity in which a genetic predisposition, combined with endocrine and/or bioelectric factors indirectly produced by HIV, results in vasoconstriction and triggering of the development of a plexogenic lesion, which in turn produces increased precapillary pulmonary arterial pressure.
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FOOTNOTES
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Abbreviations: AIDS = acquired immunodeficiency syndrome,
HIV = human immunodeficiency virus,
HIV-PH = HIV–related PH,
PH = pulmonary hypertension
Author contributions: Guarantor of integrity of entire study, A.N.B.; study concepts, A.N.B., M.V., H.G.; study design, A.N.B., M.V.; literature research, A.N.B.; clinical studies, H.G.; data acquisition, A.N.B.; data analysis/interpretation, A.N.B., M.V., H.G.; manuscript preparation, A.N.B.; manuscript definition of intellectual content, A.N.B., M.V., H.G.; manuscript editing, A.N.B.; manuscript revision/review and final version approval, A.N.B., M.V., H.G.
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ABSTRACT
INTRODUCTION
