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Original Article

An Imbalance between the Excretion of Thromboxane and Prostacyclin Metabolites in Pulmonary Hypertension

Brian W. Christman, M.D., Charles D. McPherson, M.D., John H. Newman, M.D., Gayle A. King, M.S., Gordon R. Bernard, M.D., Bertron M. Groves, M.D., and James E. Loyd, M.D.

N Engl J Med 1992; 327:70-75July 9, 1992

Abstract
Abstract

Background.

Constriction of small pulmonary arteries and arterioles and focal vascular injury are features of pulmonary hypertension. Because thromboxane A2 is both a vasoconstrictor and a potent stimulus for platelet aggregation, it may be an important mediator of pulmonary hypertension. Its effects are antagonized by prostacyclin, which is released by vascular endothelial cells. We tested the hypothesis that there may be an imbalance between the release of thromboxane A2 and prostacyclin in pulmonary hypertension, reflecting platelet activation and an abnormal response of the pulmonary vascular endothelium.

Full Text of Background....

Methods.

We used radioimmunoassays to measure the 24-hour urinary excretion of two stable metabolites of thromboxane A2 and a metabolite of prostacyclin in 20 patients with primary pulmonary hypertension, 14 with secondary pulmonary hypertension, 9 with severe chronic obstructive pulmonary disease (COPD) but no clinical evidence of pulmonary hypertension, and 23 normal controls.

Full Text of Methods....

Results.

The 24-hour excretion of 11-dehydro-thromboxane B2 (a stable metabolite of thromboxane A2) was increased in patients with primary pulmonary hypertension and patients with secondary pulmonary hypertension, as compared with normal controls (3224±482, 5392±1640, and 1145±221 pg per milligram of creatinine, respectively; P<0.05), whereas the 24-hour excretion of 2,3-dinor-6-keto-prostaglandin F1α (a stable metabolite of prostacyclin) was decreased (369± 106, 304±76, and 644± 124 pg per milligram of creatinine, respectively; P<0.05). The rate of excretion of all metabolites in the patients with COPD but no clinical evidence of pulmonary hypertension was similar to that in the normal controls.

Full Text of Results....

Conclusions.

An increase in the release of the vasoconstrictor thromboxane A2, suggesting the activation of platelets, occurs in both the primary and secondary forms of pulmonary hypertension. By contrast, the release of prostacyclin is depressed in these patients. Whether the imbalance in the release of these mediators is a cause or a result of pulmonary hypertension is unknown, but it may play a part in the development and maintenance of both forms of the disorder. (N Engl J Med 1992; 327:70–5.)

Full Text of Conclusions....

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Media in This Article

Figure 1Mean (±SE) Urinary Excretion of 11-Dehydro-thromboxane B2 in Normal Controls, Patients with Primary Pulmonary Hypertension, Patients with Miscellaneous Other Causes of Pulmonary Hypertension, and Patients with Pulmonary Hypertension Due to Collagen Vascular Disease (CVD).
Figure 2Mean (±SE) Urinary Excretion of 2,3-Dinor-6-keto-PGF1α in Normal Controls and in the Three Groups of Patients with Primary or Secondary Pulmonary Hypertension.

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Article

THE pathogenesis of pulmonary hypertension is incompletely understood. The histologic features of the small pulmonary arteries of patients with this disease suggest that the coagulation system on the endothelial surface may be activated as either a primary or a secondary process.1 2 3 4 5 6 Vasoconstriction is a variable feature of pulmonary hypertension; some patients, but not all, respond to vasodilator drugs with a substantial reduction in pulmonary vascular resistance and pressure.7 8 9 10 Thromboxane A2 is both a potent pulmonary vasoconstrictor and a procoagulant, whereas prostacyclin has opposing effects, and an imbalance between the release of these two mediators could be involved in the pathogenesis of the arteriopathy. To date, there is little direct evidence to support this hypothesis.11 , 12

The purpose of this study was to determine whether pulmonary hypertension leads to alterations in the formation of thromboxane and prostacyclin. Thromboxane A2 is extremely labile in the circulation, undergoing rapid (half-life, ≤30 seconds) hydration of the oxane ring to yield thromboxane B2. Unfortunately, because of ex vivo platelet activation, measurements of plasma thromboxane B2 concentrations are unlikely to provide valid evidence of global in vivo platelet activation.13 Therefore, we elected to measure two stable urinary indexes of thromboxane generation in vivo representing both major pathways (β-oxidation and 11-dehydrogenation) of thromboxane B2 metabolism.14 Since it would be unlikely for both enzyme systems to be affected in parallel, this approach adds specificity to the test of the hypothesis that there has been an increase in the production of thromboxane B2 in the circulation. We measured 24-hour urinary excretion of two metabolites of thromboxane (2,3-dinor-thromboxane B2 and 11-dehydro-thromboxane B2) and a stable metabolite of prostacyclin (2,3-dinor-6-keto-prostaglandin F1α [PGF1α]) in patients with primary pulmonary hypertension, patients with known collagen vascular disease and secondary pulmonary hypertension, patients with miscellaneous other causes of secondary pulmonary hypertension, patients with chronic obstructive pulmonary disease (COPD) but no evidence of pulmonary hypertension, and normal controls.

Methods

Patients and Subjects

All patients with pulmonary hypertension had right-sided cardiac catheterization. Primary pulmonary hypertension was defined as pulmonary hypertension (mean pulmonary-artery pressure, >30 mm Hg) with a normal pulmonary-artery wedge pressure and no evidence on catheterization of the presence of a left-to-right intra-cardiac shunt. All patients had cardiac output measured by thermodilution or by the Fick principle. The following equation was used to calculate pulmonary vascular resistance: (mean pulmonary-artery pressure — pulmonary-artery wedge pressure)/cardiac output. Patients with primary pulmonary hypertension had no evidence of primary liver disease, no clinical or serologic evidence of collagen vascular disease, a normal lung perfusion scan, and no apparent airway or interstitial pulmonary disease on the basis of a chest radiography or spirometry.

Collagen vascular disease was diagnosed on the basis of clinical features and a positive serum antinuclear-antibody test. All patients with collagen vascular disease complicated by pulmonary hypertension were referred after the diagnosis had been made and were evaluated by cardiac catheterization to determine whether therapy with vasodilators was appropriate. No patients had catheterization solely for the purpose of this study. In patients with miscellaneous causes of pulmonary hypertension, the diagnosis was established by documenting pulmonary hypertension with cardiac catheterization and by the associated clinical features of each disease. No patient was receiving nonsteroidal antiinflammatory drugs (including aspirin) at the time of the study. In all patients with pulmonary hypertension, a 24-hour urine specimen was collected and refrigerated on the day before cardiac catheterization. The volume of urine was recorded, and a 50-ml aliquot was frozen at -40°C for later analysis.

Patients with COPD were recruited from the outpatient population at Vanderbilt University Medical Center. Pulmonary function was assessed with a Gould 2100 pulmonary-function device (SensorMedics, Yorba Linda, Calif.). The entrance criteria included a ratio of forced expiratory volume in one second to forced vital capacity that was less than 60 percent of the predicted value and the absence of acute medical problems. None of these patients had clinical evidence of cor pulmonale, and none had an increased pulmonic component of the second heart sound or persistent edema of the ankles, supporting the absence of pulmonary hypertension in these patients. Normal subjects were recruited from the Center for Lung Research laboratories. No subject was taking nonsteroidal antiinflammatory drugs (including aspirin), and no subject was known to have an acute or chronic illness. Because the urine samples from patients with COPD were collected at a different date from those from patients with pulmonary hypertension, a second group of normal subjects was enrolled and their urine specimens were assayed concurrently with those of the patients with COPD.

Approval for this study was obtained from the institutional review boards of Vanderbilt University and the University of Colorado. Informed consent was obtained from all patients enrolled in the study.

Measurement of Urinary Metabolites of Thromboxane A2 and Prostacyclin

The methods used were a modification of those previously described by Ciabattoni et al.15 and Fitzgerald et al.16 Immunoreactive 2,3-dinor-thromboxane B2, 11-dehydro-thromboxane B2, and 2,3,-dinor-6-keto-PGF1α were extracted with ethyl acetate from 3 ml of urine that had been acidified to pH 3.5 with formic acid. The samples were then applied to preconditioned octadecylsilyl cartridges (C18 PrepSeps, Waters, Milford, Mass.), rinsed with water and hexane, and eluted with ethyl acetate. The analytes were subsequently separated by thin-layer chromatography with use of the ascending technique, with mobile phases of ethyl acetate:acetone: acetic acid (48:2:1, vol/vol/vol) and chloroform:methanol:acetic acid:water (45:5:0.25:0.2, vol/vol/vol/vol) for the separation of thromboxane and prostacyclin metabolites, respectively. Compounds were localized by concurrent chromatography of authentic standards subsequently visualized with 10 percent phosphomolybdic acid in ethanol.17 After the appropriate silica segments had been eluted, the metabolites were quantified by competitive radioimmunoassay (2,3-dinor-thromboxane B2 and 11-dehydro-thromboxane B2) or enzyme-linked immunosorbent assay (2,3-dinor-6-keto-PGF1α), as previously described.15 , 16 Antibodies for the radioimmunoassay were obtained from Advanced Magnetics (Cambridge, Mass.) (2,3-dinor-thromboxane B2 and 2,3-dinor-6-keto-PGF1α) and Dupont—New England Nuclear (Boston) (11-dehydro-thromboxane B2). The 2,3-dinor-thromboxane antibody cross-reacted with thromboxane B2 (100 percent), 6-keto-PGF1α (0.09 percent), and 2,3-dinor-6-keto-PGF1α (0.02 percent). The 2,3-dinor-6-keto-PGF1α antibody cross-reacted with 6-keto-PGF1α 100 percent), thromboxane B2 (0.05 percent), and 2,3-dinor-thromboxane B2 (0.015 percent). The antibody directed against 11-dehydro-thromboxane B2 cross-reacted with thromboxane B2 (0.32 percent) and 6-keto-PGF1α (<0.0005 percent). All samples were run in duplicate, and the values were averaged. The yield was corrected by analysis of separate samples enriched with 100,000 disintegrations per minute of Radio-labeled thromboxane B2 or 6-keto-PGF1α (New England Nuclear). The urinary creatinine concentration was measured in each patient to allow for the normalization of the excretion of urinary metabolites.

Statistical Analysis

Data are presented as means ±SE. To determine whether comparisons among groups were valid, we first performed a nonparametric analysis of variance (Kruskal—Wallis test)18 using Minitab statistical software (State College, Pa.). Where permitted, differences between groups were tested for by the two-tailed Mann—Whitney test.18 All P values of less than 0.05 were considered to indicate statistical significance.

Results

Thirty-four patients with pulmonary hypertension, 9 patients with severe COPD without evidence of pulmonary hypertension, and two groups of normal subjects (n = 14 and n = 9) constituted the study group. Twenty of the patients (14 women and 6 men) had primary pulmonary hypertension, 5 of whom were receiving vasodilator therapy with a calcium-channel blocker (diltiazem) at the time of the study. Six patients (all women) with secondary pulmonary hypertension had collagen vascular disease — three with scleroderma, two with systemic lupus erythematosus, and one with mixed connective-tissue disease. Two of the six were receiving prednisone, one diltiazem, and one hydroxychloroquine. Eight patients (five women and three men) had other causes of pulmonary hypertension — two with Eisenmenger's syndrome due to an atrial septal defect, two with cirrhosis of the liver, and one each with COPD, idiopathic hypoventilation, idiopathic pulmonary fibrosis, and mitral stenosis. Of these eight patients, two were receiving diltiazem and two were receiving angiotensin-converting—enzyme inhibitors.

The clinical characteristics of the three groups of patients with pulmonary hypertension are shown in Table 1Table 1Clinical Characteristics of Patients with Primary Pulmonary Hypertension or Pulmonary Hypertension Due to Collagen Vascular Disease or Other Causes.*. There was a trend for patients with collagen vascular disease to have had symptoms for a shorter period, but the only significant difference among the groups was a lower pulmonary vascular resistance in the patients with other causes of pulmonary hypertension than in the patients in the other two groups.

The nine patients with COPD but no evidence of pulmonary hypertension, all men, were older (61±2 years) than the patients with pulmonary hypertension, and all had a long history of smoking (93±12 pack-years). Seven of the patients with COPD were smoking at the time of enrollment in the study. All nine patients with COPD had severe airway obstruction, with a marked reduction in the forced expiratory volume in one second (1.39±0.15 liters), the ratio of forced expiratory volume in one second to forced vital capacity (42±3 percent of the predicted value), and single-breath diffusing capacity (64±8 percent of the predicted value), with normal total lung capacity (6.86±0.35 liters). One patient with severe airway obstruction had a normal single-breath diffusing capacity. The mean value in the other eight patients was 56±5 percent of the predicted value. The majority of the nine patients with COPD were being treated with sustained-release theophylline and inhaled β-agonists. One patient was receiving long-term therapy with prednisone (10 mg per day).

The excretion of metabolites of thromboxane and prostacyclin in patients with pulmonary hypertension is shown in Figures 1Figure 1Mean (±SE) Urinary Excretion of 11-Dehydro-thromboxane B2 in Normal Controls, Patients with Primary Pulmonary Hypertension, Patients with Miscellaneous Other Causes of Pulmonary Hypertension, and Patients with Pulmonary Hypertension Due to Collagen Vascular Disease (CVD). and 2Figure 2Mean (±SE) Urinary Excretion of 2,3-Dinor-6-keto-PGF1α in Normal Controls and in the Three Groups of Patients with Primary or Secondary Pulmonary Hypertension., respectively. Because some of the urinary samples were used up during the development of the assay for 2,3-dinor-6-keto-PGF1α, we had fewer measurements of this metabolite than of 11-dehydro-thromboxane B2 in each group. The 24-hour excretion of 11-dehydro-thromboxane B2 was increased in patients with primary pulmonary hypertension and patients with secondary pulmonary hypertension, as compared with normal controls (3224±482, 5392±1640, and 1145±221 pg per milligram of creatinine, respectively; P<0.05). The 24-hour excretion of 2,3-dinor-6-keto-PGF1α was decreased in both groups of patients with pulmonary hypertension, as compared with the normal controls: 369±106 pg per milligram of creatinine in those with primary pulmonary hypertension, 304±76 in those with secondary pulmonary hypertension, and 644± 124 in normal controls (P<0.05). Patients with all forms of pulmonary hypertension excreted larger amounts of 11-dehydro-thromboxane B2 than did normal controls or patients with COPD but no evidence of pulmonary hypertension (Fig. 1 and 2, Table 2Table 2Excretion of Metabolites of Thromboxane and Prostacyclin in Nine Patients with COPD but No Evidence of Pulmonary Hypertension and Nine Normal Controls.*). Patients with primary pulmonary hypertension, as well as the group of patients with secondary causes of pulmonary hypertension, excreted less of the prostacyclin metabolite than did normal controls (Fig. 2). There was, however, overlap among the groups for both of these measurements. Urinary excretion of the dinor metabolite of thromboxane was elevated in the patients with pulmonary hypertension (P<0.05), but the increase was not statistically significant in the subgroup of patients with primary pulmonary hypertension, as compared with normal controls (P = 0.077) (data not shown). There were no significant differences between the nine patients with COPD and the normal controls in the excretion of any metabolite (Table 2).

The ratio of 11-dehydro-thromboxane B2 to 2,3-dinor-6-keto-PGF1α is a rough index of the relative activity of the opposing stimuli that modulate local vascular tone and platelet activation. This ratio was 9.8±1.4 in patients with primary pulmonary hypertension, as compared with 2.6±0.6 in normal controls (P<0.004). The ratio was 2.5±0.7 in the nine patients with COPD and 2.1±0.4 in the second group of normal controls (Fig. 3Figure 3Ratio of Urinary 11-Dehydro-thromboxane B2 to 2,3-Dinor-6-keto-PGF1α in Patients with Primary Pulmonary Hypertension, Normal Controls, Patients with Severe COPD, and a Second Group of Normal Controls Analyzed Concurrently with the Patients with COPD.). None of these patients with COPD or the normal controls had ratios above 5.7; by contrast, 8 of 10 patients with primary pulmonary hypertension had ratios above 8.

No correlation was found between hemodynamic variables (mean pulmonary-artery pressure and pulmonary vascular resistance) and the excretion of 11-dehydro-thromboxane B2 or 2,3-dinor-6-keto-PGF1α or in the ratio of 11-dehydro-thromboxane B2 to 2,3-dinor-6-keto-PGF1α. Age, sex, the duration of symptoms, and smoking habits did not influence the excretion of thromboxane metabolites. Furthermore, there was no correlation between the single-breath diffusing capacity and the excretion of 2,3-dinor-6-keto-PGF1α (r = -0.083) in the patients with COPD.

Patients with pulmonary hypertension who were receiving diltiazem (n = 8) had a lower mean pulmonary-artery pressure (39±5 vs. 56±3 mm Hg) and level of pulmonary vascular resistance (8.5±2.2 vs. 15.3±1.5 mm Hg per liter per minute) than did untreated patients (n = 26). However, there were no significant differences in the urinary excretion of the metabolites between treated and untreated patients (11-dehydro-thromboxane B2, 5346±1220 vs. 3743±892 pg per milligram of creatinine; 2,3-dinor-6-keto-PGF1α, 445±143 vs. 191 ±63 pg per milligram of creatinine).

Discussion

We found that the urinary excretion of a stable metabolite of thromboxane, 11-dehydro-thromboxane B2, was elevated in the groups of patients with primary or secondary pulmonary hypertension, as compared with normal controls, but not in a group of patients with COPD who had no evidence of pulmonary hypertension. These findings imply that a sustained elevation of pulmonary-artery pressure, regardless of the cause, is associated with persistent activation of platelets, which are the primary source of urinary thromboxane metabolites. The decreased excretion of the metabolite of prostacyclin in patients with primary or secondary pulmonary hypertension suggests that endothelial-cell function is impaired in pulmonary hypertension. The finding of a normal rate of excretion of 2,3-dinor-6-keto-PGF1α in patients with COPD but no evidence of pulmonary hypertension and the lack of correlation between the excretion of this metabolite and single-breath diffusing capacity in these patients imply that the decrease seen in patients with pulmonary hypertension is not due to a reduction in the pulmonary-capillary surface area. The imbalance between the release of thromboxane, a vasoconstrictor, and prostacyclin, a vasodilator, may contribute to the development or maintenance of pulmonary hypertension.

What possible mechanisms among these diverse causes of pulmonary hypertension might explain the increase in the generation of thromboxane? The pathogenesis of vascular injury in the lungs has perhaps best been studied in scleroderma. The pathologic lesions in the lungs are similar to those of primary pulmonary hypertension and include medial hypertrophy, intimal hyperplasia, and plexiform lesions.19 , 20 In scleroderma, the findings of increased numbers of circulating-platelet aggregates and elevated levels of beta-thromboglobulin and platelet factor 4 point to platelet activation as a component of the vasculopathy.21 Pulmonary hypertension in systemic lupus erythematosus is well described, although uncommon, and histopathological studies usually reveal medial hypertrophy without plexiform lesions.22 , 23 Because a number of other organs, especially the kidneys, can be involved in collagen vascular diseases, it is possible that thromboxane may be generated at sites other than (or in addition to) the lungs. It is noteworthy that low titers of antinuclear antibodies are present in about 20 percent of patients with primary pulmonary hypertension.24 Patients with Eisenmenger's syndrome and patients with pulmonary hypertension due to cirrhosis of the liver have pulmonary vascular lesions that are indistinguishable from those of primary pulmonary hypertension.25 , 26 Mitral stenosis causes reactive pulmonary hypertension with microvascular injury and leakage of blood into the interstitium.3 Thus, it is not surprising that the rates of formation and excretion of thromboxane are increased in patients with these diverse diseases associated with pulmonary hypertension.

The decrease in the excretion of 2,3-dinor-6-keto-PGF1α in patients with pulmonary hypertension contrasts with findings in patients with acute myocardial infarction or deep venous thrombosis, in whom the excretion of metabolites of both thromboxane and prostacyclin is increased.27 , 28 Evidence suggestive of decreased prostacyclin synthesis in patients with pulmonary hypertension as compared with normal controls has also been reported by Rich et al., who measured serum levels of 6-keto-PGF1α.12 In addition, cultured pulmonary-artery endothelial cells isolated from calves with pulmonary hypertension induced by living at high altitudes have a diminished capacity to synthesize prostacyclin.29 Decreased prostacyclin synthesis could both permit coagulation to occur at the endothelial surface and impair local vasodilation, contributing to the pulmonary hypertension.

Intravenous prostacyclin has been used to treat patients with primary pulmonary hypertension. Rubin and coworkers9 noted an improvement in cardiac output, pulmonary vascular resistance, and exercise tolerance in patients treated for eight weeks with a continuous infusion of a preparation of prostacyclin (epoprostenol sodium). Although the predominant action of prostacyclin may have been as a pulmonary vasodilator, the continued fall in pulmonary-artery pressure and vascular resistance during the study suggests that the drug may have had other beneficial effects on the pulmonary vascular bed. Pulmonary vasoconstriction is known to occur in primary pulmonary hypertension,8 , 10 and a considerable number of patients with primary pulmonary hypertension respond to vasodilator drugs with a reduction in pulmonary vascular resistance.10 In one study, a thromboxane synthetase inhibitor rapidly reduced pulmonary vascular resistance in 60 percent of patients with primary pulmonary hypertension.12 However, it is possible that, late in the course of pulmonary hypertension, inhibition of thromboxane synthesis may have little therapeutic efficacy because the vascular lesions are fixed and widespread.

Other mediators may participate in the development and maintenance of pulmonary hypertension, including endothelin-130 and serotonin.31 , 32 In addition, the recently described deficiency of endothelium-derived relaxing factor in pulmonary arterial tissue obtained from patients with cystic fibrosis and α1-antitrypsin deficiency might contribute to the development of pulmonary hypertension.33

A characteristic feature of many forms of pulmonary hypertension is arteriopathy of small pulmonary vessels, leading to an increase in pulmonary vascular resistance and pressure. Although it is clear that our finding of increased urinary excretion of a thromboxane metabolite does not allow the identification of specific causes of pulmonary hypertension, the data support a role for platelet activation in many diseases resulting in pulmonary hypertension. The reduced excretion of 2,3-dinor-6-keto-PGF1α in patients with pulmonary hypertension suggests that they have an altered endothelial capacity for prostacyclin synthesis. A local discrepancy between platelet activation and prostacyclin synthesis would tend to amplify vascular injury, perhaps facilitating vasoconstriction and the vascular remodeling that is characteristic of these disorders. This study provides support for approaches to the treatment of pulmonary hypertension that are designed to reduce the formation of platelet thromboxane without decreasing the synthesis of prostacyclin by endothelial cells.

Supported by grants from the National Institutes of Health (HL 39952, 41952, 43167, and 19153), the Elliot Newman Clinical Research Center (5 MOIRR0095), the St. Thomas Foundation, and the Francis Families Foundation and by an American Lung Association Research Award.

Source Information

From the Center for Lung Research, Vanderbilt University School of Medicine, Nashville (B.W.C., C.D.M., J.H.M., G.A.K., G.R.B., J.E.L.), and the Division of Cardiology, University of Colorado Health Sciences Center, Denver (B.M.G.). Address reprint requests to Dr. Christman at the Division of Pulmonary and Critical Care Medicine, B-1308 Vanderbilt Medical Center North, Nashville, TN 37232.

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