Chest ACCP Member Benefits
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Guest Access | Sign In via User Name/Password
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (25)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Voelkel, M. A.
Right arrow Articles by Voelkel, N. F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Voelkel, M. A.
Right arrow Articles by Voelkel, N. F.
(Chest. 2000;117:19-24.)
© 2000 American College of Chest Physicians

Hyperuricemia in Severe Pulmonary Hypertension*

Marc A. Voelkel, BSC; Kristine M. Wynne, RN; David B. Badesch, MD, FCCP; Bertron M. Groves, MD and Norbert F. Voelkel, MD

* From the Pulmonary Hypertension Center, University of Colorado Health Sciences Center, Denver, CO.

Correspondence to: Norbert F. Voelkel, MD, Division of Pulmonary Sciences and Critical Care Medicine, 4200 E. Ninth Ave, C272, Denver, CO 80262; e-mail: norbert.voelkel{at}uchsc.edu


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objective: Hyperuricemia occurs frequently in patients with myeloproliferative and lymphoproliferative disorders and in patients with congenital heart disease associated with polycythemia. Whether hyperuricemia is common in patients with severe pulmonary hypertension is not known.

Design, patients, measurements: In the Pulmonary Hypertension Center at the University of Colorado Health Sciences Center between September 1991 and August 1997, 442 consecutive patients were evaluated with right heart catheterization; 191 patients also had a measurement of the serum uric acid (UA) in close temporal proximity to the hemodynamic evaluation.

Results: Of the 191 patients with a complete data set, 99 patients had primary pulmonary hypertension (PPH) and 92 had secondary pulmonary hypertension. For the entire cohort with severe pulmonary hypertension (n = 191), there was a positive correlation between the natural logarithm of the serum UA (lnUA) and the mean right atrial pressure (RAP; r = 0.47; p < 0.001). When analyzed separately, the correlation between lnUA and RAP was stronger in the patients with PPH (r = 0.642; p < 0.001). This correlation cannot be explained by diuretic use or impaired hepatocellular function. Neither mean pulmonary artery pressure nor cardiac output was as well correlated with the RAP when compared with the lnUA. Some patients with PPH had serum UA measurements repeated during treatment with chronic IV prostacyclin infusion. Eleven of these 18 patients (61%) demonstrated a decrease in serum UA during prostacyclin treatment.

Conclusion: There is a positive correlation between the RAP elevation and the serum UA levels in patients with PPH. Serum UA levels drop in some, but not all PPH patients during chronic prostacyclin infusion therapy.

Key Words: ischemia • prostacyclin • pulmonary hypertension • right atrial pressure • uric acid


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Hyperuricemia is frequently associated with myeloproliferative or lymphoproliferative diseases such as leukemia or lymphoma1 2 3 or with cyanotic congenital heart disease.4 5 Increased nucleic acid metabolism is the mechanism for the hyperuricemia observed in the proliferative and myeloproliferative disorders, and polycythemia-related enhancement of purine metabolism is the mechanism in patients with congenital heart disease. Hyperuricemia has been recently reported in patients with ischemic heart disease.6 7 Uric acid (UA) can be released from ischemic tissues,8 9 including the heart, during angina,8 10 11 and hyperuricemia has been suggested as a risk factor for the development of atherothrombotic diseases.12 A possible explanation for this relates to the inhibition of adenosine diphosphate degradation by UA and the subsequent stabilization of platelet aggregates.12 In addition, hyperuricemia increases platelet adhesiveness,13 and patients with chronic, severe pulmonary hypertension (PH) are at a high risk to develop in situ pulmonary vascular thrombosis.14 In several of our patients with severe PH, we noted increased serum UA levels, and some of the patients referred to our center had been prescribed allopurinol by their primary care physician. Therefore, the purposes of the present study were to examine the prevalence of hyperuricemia in a large cohort of patients referred to a Pulmonary Hypertension Center; to assess whether hyperuricemia was related to hemodynamic variables and to other laboratory values; and to assess whether serum UA levels were influenced by the treatment of patients with primary pulmonary hypertension (PPH) with continuous IV prostacyclin infusion.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients
Four hundred forty-two patients referred for evaluation to the Pulmonary Hypertension Center at the University of Colorado Health Sciences Center and seen between January 1991 and August 1997 were included in this study. PH was present when the mean pulmonary artery pressure (PAP), assessed via right heart catheterization, was > 22 mm Hg. Once PH was established and patients with abnormal wedge pressures had been excluded, patients were classified as either having unexplained or secondary pulmonary hypertension (SPH). In the patients with unexplained PH, thromboembolic disease, obstructive pulmonary disease, interstitial lung diseases, and congenital cardiac abnormalities had been excluded. All 442 patients had a posteroanterior and lateral chest radiograph, pulmonary function testing, ventilation/perfusion scintigraphy, and ECG. Several received nocturnal polysomnographic studies to exclude sleep apnea. Other patients underwent high-resolution chest CT studies to exclude interstitial lung diseases. Following this evaluation, those who remained in the unexplained PH category were classified as having PPH.

From the entire cohort, medical records revealed that 191 patients had measurement of their serum UA in close temporal proximity to the right heart catheterization. Ninety-nine of these patients had PPH, and 92 had SPH.

Serum UA Measurement
Serum UA was measured using the Uric Acid Plus system (Boehringer; Mannheim, Germany) intended for the use by automated clinical chemistry analyzers. This test is a colorimetric assay based on the oxidation of UA by the specific enzyme uricase.

Statistical Analysis
Analysis of the data derived from the patient population was done using the Microsoft Excel Spreadsheet Program (Version 5; Microsoft; Redmond, CA). All variables were displayed graphically, and the statistical analysis was performed with the sample of the complete data set. Fisher’s covariant analysis, and multivariant regression analysis were performed using a StatView 4.1 program (SAS Institute; Cary, NC). The multivariant regression was tested using a standard operation of least squares regression. We checked for freedom from all assumptions in the model, in particular that the distribution was nonstochastic, that the error term was zero, that there was absence of heteroscedasticity, that there was absence of autocorrelation, and absence of exact collinearity of the variables. The hypothesis that the natural logarithm of serum UA (lnUA) levels fitted the data better than the nonlogarithmic data was tested using a F test of significance. Differences between data were accepted as statistically significant when p < 0.01 (Student’s two-tailed t test).


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The distribution of the patients among the diagnostic categories is shown in Figure 1 . Table 1 compares data from patients with PPH and those with SPH. Patients with PPH were on average slightly younger than the patients with SPH, and their PAP was higher: the mean ± SEM PAP in patients with PPH was 51.8 ± 1.6 mm Hg vs 42.9 ± 1.9 mm Hg in patients with SPH.



View larger version (15K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 1. Distribution of the patients with PH. Pts = patients; Htn = hypertension.

 

View this table:
[in this window]
[in a new window]

  		Table 1. PAP, Cardiac Output, RAP and Selected Laboratory Values in PPH and SPH Patients*

 
For the entire cohort of patients with PH (n = 191), there was a positive correlation between the lnUA and the mean PAP (r = 0.41; p < 0.0001) and the mean right atrial pressure (RAP), respectively (r = 0.486; p < 0.0001; Fig 2 )



View larger version (20K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 2. Correlation between lnUA and the mean RAP (n = 191; top), and the correlation between lnUA and the mean PAP (n = 191; bottom). ln(UA) = lnUA.

 
In contrast, the correlations between lnUA and mean PAP when analyzed separately for either PPH or SPH were less strong, and the correlation between lnUA and mean RAP in patients with SPH was considerably weaker (r = 0.194) when compared with the correlation between lnUA and mean RAP in patients with PPH (r = 0.642; p < 0.0001; Fig 3 ). When the correlation between lnUA and RAP was examined in the PPH patients who were—at the time of the right heart catheterization—not being treated with diuretics (n = 59), the correlation coefficient r was 0.684 (p < 0.0001).



View larger version (33K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 3. Top left: correlation between the lnUA and the mean RAP in patients with PPH (n = 99). Top right: correlation between lnUA and mean RAP in patients with SPH (n = 92). Bottom left: correlation between lnUA and mean PAP in patients with PPH (n = 99). Bottom right: correlation between lnUA and mean PAP in patients with SPH (n = 92).

 
Table 2 compares the values for linear and logarithmic, lnUA, correlations. As can be seen, in all instances, the logarithmic correlations are somewhat stronger than the linear correlations, and the level of significance of these correlations is also greater for the logarithmic correlations.


View this table:
[in this window]
[in a new window]

  		Table 2. Comparison of Linear and Logarithmic Correlations*

 
The remainder of the correlation analysis is summarized in Table 3 . Whereas we found modest correlations between serum creatinine levels and the lnUA values and serum bilirubin levels and the lnUA, neither elevated serum creatinine nor elevated bilirubin apparently explains the correlation between RAP and lnUA.


View this table:
[in this window]
[in a new window]

  		Table 3. PPH Correlation Analysis (n = 99)*

 
It is of further interest that neither mean PAP nor the cardiac output were reliable predictors of an elevated mean RAP. For the entire cohort of PH patients (n = 191), the coefficient of correlation r between mean PAP and mean RAP was 0.396 (p < 0.001) and between cardiac output and mean RAP was 0.351 (p < 0.001).

Eighteen patients had measurements of UA before and during treatment with continuous IV prostacyclin infusion, which has been shown to improve survival of patients with PPH.15 Eleven of the 18 patients demonstrated a decrease in the serum UA levels while being treated with prostacyclin (Fig 4 ).



View larger version (25K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 4. Change in the serum UA levels in the patients chronically treated with continuous IV prostacyclin infusion.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We found elevated serum UA levels in a large number of patients with PPH and most frequently in those with elevated mean RAP. Since an elevated RAP is a reflection of right heart failure, it is possible that the elevation of serum UA is related to right heart failure. We believe that this is supported by our data. First, the correlation between RAP and lnUA is stronger for the PPH group than for the SPH group. A possible explanation for the weaker RAP/lnUA correlation in SPH is that in these patients, generally, the disease is more slowly progressive, and right heart failure is not as frequently observed as in the PPH group. In our retrospective analysis, we found that 24 of 92 patients with SPH had a RAP > 10 mm Hg, whereas 42 of 99 patients with PPH had a RAP > 10 mm Hg. Furthermore, the correlation between RAP/lnUA was stronger than the correlation between PAP/lnUA, suggesting that the serum UA elevation is not merely a function of the elevated right ventricular afterload.

When we compared the linear correlations between serum UA levels and the hemodynamic variables with the correlations where the lnUA was used (Table 2) , we found that the correlations were slightly stronger for lnUA. As far as the relationship between serum UA and RAP is concerned (the relationship that was characterized by the lower "r value"), analysis of the data using either UA or lnUA resulted in comparable r values.

If the serum UA elevation in PPH is a consequence of right heart failure, then this raises the question of whether a low cardiac output, hypoperfusion, and liver congestion account for the serum UA elevation. A recent study7 found elevated serum UA levels in patients with chronic heart failure due to coronary artery disease or idiopathic dilated cardiomyopathy. In this latter study, a significant correlation (r = - 0.50) between serum UA levels and maximal oxygen uptake, and between serum UA and serum creatinine (r = 0.58) was found. Interestingly, the authors looked for but did not find a correlation between serum UA levels and the left ventricular ejection fraction. Likewise, our data in PPH patients show a modest relationship between serum creatinine and serum UA levels (r = 0.393, p < 0.002) and no relationship between serum UA levels and the cardiac output. However, elevated creatinine levels were not found in all PPH subjects with elevated UA serum levels. Sixteen of 99 PPH patients with an elevated RAP (> 10 mm Hg) had normal serum creatinine levels (<= 1.0 mg/dL). This implies that a reduced glomerular filtration by itself could not account for the high UA serum levels in some or all of the PPH patients. However, we cannot rule out impairment of UA clearance in these patients.

Liver congestion is common in patients with severe PH. Echocardiography in severe PH indicated increased inferior vena cava diameters in association with an elevated RAP.16 Serum studies indicated elevations in serum bilirubin and transaminases. However, as was the case with the elevation of serum creatinine levels, there were a number of PPH patients in this study who had elevated RAP values without abnormal liver function tests. It therefore is unlikely that a low cardiac output per se or venous congestion secondary to right heart failure are responsible for the elevation of UA in PPH patients with increased RAP.

Instead, we hypothesize that the site of UA production in severe PPH may be either the ischemic lung tissue or the ischemic right ventricle, or both. It is well known that congenital, cyanotic heart disease is associated with hyperuricemia.4 5 In this setting, polycythemia is apparently the important contributing factor.4 In our group of PPH patients, we did not encounter polycythemia and most of our patients were not hypoxemic. Nevertheless, in PPH patients, pulmonary vascular remodeling and obstructive arteriopathy17 may cause regional inhomogeneity of lung parenchyma perfusion. Underperfused, ischemic areas of the PPH lung may be characterized by cells with a hypoxia/anoxia-activated xanthine oxidase, yet the relationship between elevated RAP and lung tissue oxygenation is unclear. On the other hand, right ventricular ischemia may be determined by right ventricular wall stress and RAP.18 Although the normal human heart contains only small amounts of xanthine oxidase,8 19 20 21 a significant amount of hypoxanthine can be released into the coronary sinus during atrial pacing-induced angina in patients with ischemic heart disease.10 In PPH, approximately 50% of the patients describe anginal chest pain and their ECG demonstrates signs of right ventricular ischemia.22 Our retrospective analysis of the data does not allow us to grade the degree of chest pain in patients with and without elevated serum UA levels, nor is it our practice to follow the PPH patients with repeated hemodynamic studies. Thus we cannot determine whether the RAP decreased in those patients who showed a gradual decrease in serum UA levels during chronic prostacyclin infusion therapy or whether the RAP remained elevated in those patients where the UA values remained unchanged. Whether prostacyclin can affect UA clearance is likewise unknown.

In conclusion, the results of this study establish that hyperuricemia is common in patients with severe PH. In addition, there is a strong positive correlation between the degree of RAP elevation and serum UA levels in patients with PPH who are not treated with diuretics. Further, UA levels decrease in some but not all of the patients treated with continuous prostacyclin infusion. We hypothesize that the serum UA levels are higher in those patients with angina and right-sided cardiac ischemia, and speculate that continuous prostacyclin treatment may improve right ventricular myocardial blood flow. This, in turn, may reduce the ischemia-related cardiac UA production and release. A prospective study measuring serum UA levels, ECG ischemia, and right ventricular wall strain criteria in PPH patients before and after the onset of continuous prostacyclin treatment would begin to address such a hypothesis.


   Acknowledgements
 
The authors wish to thank Marvin I. Schwarz, MD, for his critical reading of this manuscript and Ms. Bridget Coleman for preparing the manuscript.


   Footnotes
 
Abbreviations: lnUA = natural logarithm of the serum uric acid; PAP = pulmonary artery pressure; PH = pulmonary hypertension; PPH = primary pulmonary hypertension; RAP = right atrial pressure; SPH = secondary pulmonary hypertension; UA = uric acid

Supported in part by a grant from the PPH Cure Foundation.

Received for publication November 6, 1998. Accepted for publication August 10, 1999.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Krakoff, IH (1965) Studies of uric acid biosynthesis in the chronic leukemias. Arthritis Rheum 8,722-779
  2. Hershfield, MS, Seegmiller, JE (1977) Regulation of de novo synthesis purine synthesis in human lymphoblasts: similar rates of de novo synthesis during growth by normal cells and mutants deficient in hypoxanthine-guanine phosphoribosyltransferase activity. J Biol Chem 252,6002-6010[Free Full Text]
  3. De Conti, RC, Balabresi, P (1966) Use of allopurinol for prevention and control of hyperuricemia in patients with neoplastic disease. N Engl J Med 274,481-486
  4. Somerville, J (1961) Gout in cyanotic congenital heart disease. Br Heart J 23,31-34
  5. Dearth, JC, Tompkins, RB, Giuliani, ER, et al (1978) Hyperuricemia in congenital heart disease. Am J Dis Child 132,900-902[Abstract]
  6. Mace, SE, Newman, AJ, Leibman, J (1984) Impairment of urate excretion in patients with cardiac disease. Am J Dis Child 138,1067-1070[Abstract]
  7. Leyva, F, Anker, S, Swan, JW, et al (1997) Serum uric acid as an index of impaired oxidative metabolism in chronic heart failure. Eur Heart J 18,858-865[Abstract/Free Full Text]
  8. Chambers, DE, Parks, DA, Patterson, G, et al (1985) Xanthine oxidase as a source of free radical damage in myocardial ischemia. J Mol Cell Cardiol 17,145-152[ISI][Medline]
  9. Elsayed, NM, Nakashima, JM, Pothlethwait, EM (1993) Measurement of uric acid as a marker of oxygen tension in the lung. Arch Biochem Biophys 302,228-232[CrossRef][ISI][Medline]
  10. Edlund, A, Berglund, B, Van Dorne, D, et al (1985) Coronary flow regulation in patients with ischemic heart disease: release of purines and prostacyclin and the effect of inhibitors of prostaglandin formation. Circulation 71,1113-1120[Abstract/Free Full Text]
  11. Downey, JM, Hearse, DJ, Yellon, DM (1988) The role of xanthine oxidase during myocardial ischemia in several species including man. Mol Cell Cardiol 20,55-63
  12. Newland, H (1975) Hyperuricemia in coronary, cerebral and peripheral arterial disease: an explanation. Med Hypotheses 1,152-155[CrossRef][Medline]
  13. Smythe, HA, Ogryzlo, MA, Murphy, EA, et al (1965) The effect of sulfinpyrazone (Anturan) on platelet economy and blood coagulation in man. Can Med Assoc J 92,818
  14. Wagenvoort, CA, Mulder, PH (1993) Thrombotic lesions in primary plexogenic arteriopathy. Chest 103,844-849[Abstract/Free Full Text]
  15. Barst, RJ, Rubin, LJ, McGoon, MD, et al (1994) Survival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin. Ann Intern Med 121,409-415[Abstract/Free Full Text]
  16. Iskandrian, AS, Kane, SA (1981) Real-time vena cava ultrasonography: normal and abnormal findings and its use in assessing right-heart function. Circulation 64,1018-1025[Abstract/Free Full Text]
  17. Voelkel NF, Tuder RM, Weir EK. Pathophysiology of primary pulmonary hypertension: from physiology to molecular mechanisms. In: LJ Rubin, Rich S, eds. Primary pulmonary hypertension: lung biology in health and disease (vol 99). New York, NY: Marcel Dekker, 1997; 83–129
  18. Quaife, RA, Lynch, D, Groves, B, et al (1996) Elevated right ventricular circumferential wall stress inversely correlates with right ventricular systolic function in primary pulmonary hypertension [abstract]. Circulation (Suppl A),3780
  19. Huizer, T, de Jong, JW, Nelson, JA, et al (1989) Urate production by human heart. J Mol Cell Cardiol 21,691-695[CrossRef][ISI][Medline]
  20. Elsayed, NM, Tierney, DF (1989) Hyperoxia and xanthine dehycrogenase/oxidase activities in rat lung and heart. Arch Biochem Biophys 273,281-286[CrossRef][ISI][Medline]
  21. Muxfeldt, M, Schaper, W (1987) The activity of xanthine oxidase in heart of pigs, guinea pigs, rabbits, rats and humans. Basic Res Cardiol 82,486-492[CrossRef][ISI][Medline]
  22. Voelkel, NF, Reeves, JT (1979) Primary pulmonary hypertension. Moser, KM eds. Pulmonary vascular diseases: lung biology in health and disease (vol 14) ,573-628 Marcel Dekker New York, NY.



This article has been cited by other articles:


Home page
 J Am Coll CardiolHome page
M. M. Hoeper, R. J. Oudiz, A. Peacock, V. F. Tapson, S. G. Haworth, A. E. Frost, and A. Torbicki
End points and clinical trial designs in pulmonary arterial hypertension: Clinical and regulatory perspectives
J. Am. Coll. Cardiol., June 16, 2004; 43(12_Suppl_S): 48S - 55S.
[Abstract] [Full Text] [PDF]

Home page
 NEJMHome page
P. F. Fedullo, W. R. Auger, K. M. Kerr, and L. J. Rubin
Chronic Thromboembolic Pulmonary Hypertension
N. Engl. J. Med., November 15, 2001; 345(20): 1465 - 1472.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (25)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Voelkel, M. A.
Right arrow Articles by Voelkel, N. F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Voelkel, M. A.
Right arrow Articles by Voelkel, N. F.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS