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ABSTRACT |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Serum uric acid (UA), the final product of purine degradation, has been proposed to be a marker for
impaired oxidative metabolism and a possible predictor of mortality in patients with chronic heart
failure. To elucidate whether serum UA correlates with the severity and the mortality of primary pulmonary hypertension (PPH), serum UA was assessed in 90 patients with PPH together with other clinical variables. Right heart catheterization was performed in all patients. Serum UA was significantly
elevated in patients with PPH compared with age-matched control subjects (7.5 ± 2.5 versus 4.9 ± 1.2 mg/ml, p < 0.001). Serum UA negatively correlated with cardiac output (r = 
0.52, p < 0.001)
and positively correlated with total pulmonary resistance (r = 0.57, p < 0.001). Serum UA significantly decreased from 7.1 ± 1.9 to 5.9 ± 1.6 mg/dl with vasodilator therapy, associated with a reduction in total pulmonary resistance from 22 ± 6 to 17 ± 7 Wood units. During a mean follow-up period
of 31 mo, 53 patients died of cardiopulmonary causes. Among noninvasive variables, serum UA was
independently related to mortality by a multivariate Cox proportional-hazards analysis. The Kaplan-Meier survival curves according to the median value of serum UA demonstrated that patients with
high serum UA had a significantly higher mortality rate than did those with low serum UA (log-rank
test, p < 0.01). These results suggest that serum UA increases in proportion to the clinical severity of
PPH and has independent association with long-term mortality of patients with PPH.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Serum uric acid (UA), the final product of purine degradation, has been shown to be increased in hypoxic states such as chronic heart failure (1, 2), cyanotic congenital heart disease (3), and obstructive pulmonary disease (4). Because tissue ischemia and hypoxia deplete adenosine triphosphate (ATP) and promote degradation of adenine nucleotides to inosine, hypoxanthine, xanthine, and UA (7, 8), increased serum UA levels may reflect impaired oxidative metabolism in such diseases (1, 2, 9). Interestingly, serum UA levels have recently been shown to have strong, independent association with long-term mortality of patients with chronic heart failure (10, 11).
Primary pulmonary hypertension (PPH) is an uncommon, but life-threatening, disease characterized by the progressive pulmonary hypertension, ultimately producing severe right ventricular (RV) failure associated with markedly reduced cardiac output and mild hypoxia (12). These findings raise the possibility that serum UA levels may also increase in patients with severe PPH. However, few data exist regarding the pathophysiologic and clinical significance of serum UA in patients with PPH. Thus, the purposes of this study were (1) to assess the association between serum UA levels and the severity of PPH; (2) to investigate whether serum UA levels are related to the mortality of patients with PPH.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Study Subjects
Of the 102 consecutive patients in whom PPH was diagnosed in our
institute between September 1, 1980 and April 30, 1998, nine patients
were excluded because of the absence of serum UA data and three
patients were excluded because of the presence of renal failure (serum creatinine 
1.5 mg/dl). The remaining 90 patients (35 men and
55 women, mean age: 31 ± 16 yr) were enrolled in this study. PPH was
defined as pulmonary hypertension unexplained by any secondary
cause, based on the criteria of the National Institutes of Health registry on PPH (13). Five patients (6%) were classified as New York
Heart Association (NYHA) functional Class II, 72 (80%) as Class III,
and 13 (14%) as Class IV. Coronary risk factors, which might influence serum UA levels (15), were rare in the study population: hypertension in two patients, hyperlipidemia in three, and diabetes mellitus in one. Diuretics were required in 46 patients: loop diuretic
(furosemide) in 44 and thiazide in two. Thirty age-matched healthy
volunteers (14 men and 16 women, mean age: 34 ± 12 yr) served as
control subjects. None of them had any history of cardiovascular, renal, respiratory, hepatic, or metabolic disease, and none were taking
any drugs. All subjects provided informed consent.
Hemodynamic Studies
Diagnostic right heart catheterization was performed while the subjects were in a stable condition during hospitalization. Baseline hemodynamic variables, including mean pulmonary arterial pressure, mean right atrial pressure, pulmonary capillary wedge pressure, and mean systemic arterial pressure were measured at end-expiration in all patients. Cardiac output was measured by Fick's method (20). Total pulmonary resistance was calculated by dividing mean pulmonary arterial pressure by cardiac output.
Blood Sampling for UA Measurement
For measurement of serum UA, creatinine, triglyceride, total-cholesterol, fasting glucose, and total-bilirubin, venous blood was drawn after an overnight fast within a week of the first diagnostic catheterization. No changes in the clinical status or medication regimens occurred between blood sampling and cardiac catheterization studies. Serum UA levels were determined by the uricase-peroxidase method (21). Because of the sex difference in serum UA levels (22, 23), different median values for men and women were used to separate the high UA group from the low UA group.
Echocardiographic Assessment
Two-dimensional echocardiography was performed in 87 patients with PPH using Toshiba SSH-120A (Toshiba, Tokyo, Japan). Parasternal short-axis views were obtained at the papillary muscle level of the left ventricle (LV) using a 3.5-MHz sector transducer. The longest (L) and the shortest (S) diameters of the LV cavity were measured at the point of maximal deformity in early diastole. The LV deformity index was calculated as L/S (24).
Vasodilator Therapy
We particularly examined 19 patients with PPH who underwent vasodilator therapy: 8 to 30 ng/kg per min of intravenous prostacyclin in four patients, 5 to 12 ng/kg per min of intravenous prostaglandin E1 in six patients, and 60 to 180 µg/d of beraprost sodium, an orally active prostacyclin analogue, in nine patients. The mean follow-up period was 44 d (range, 29 to 70 d). Medications other than vasodilators were unchanged during the period. Right heart catheterization was performed prior to and during vasodilator therapy. Blood sampling for UA measurement was performed within a week prior to cardiac catheterization. No changes in the clinical status or medication regimens occurred between blood sampling and cardiac catheterization studies.
Survival Analysis
Survival was estimated from the date of the first sampling of UA to June 30, 1998, or the cardiopulmonary death of the patient. Patients who died of noncardiopulmonary causes or those who underwent transplantation were removed from the analysis at the time point.
Statistical Analysis
Numerical values were expressed as mean ± SD. Comparisons of variables between two groups were made by Fisher's exact test or Student's unpaired t test. Comparisons of serum UA levels among four groups were made using one-way analysis of variance, followed by Scheffe's multiple comparison test. Correlation coefficients between serum UA levels and hemodynamic variables were calculated by linear regression analysis. Multiple regression analysis was applied to determine independent relations of clinical parameters with serum UA levels. The effects of long-term therapy on serum UA were analyzed by the Student's paired t test. The independent association of serum UA with survival was tested by multivariate Cox proportional hazards regression analysis. Survival curves were derived using the Kaplan-Meier method and were compared using log-rank test. A p value < 0.05 was considered statistically significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Serum UA Levels
Serum UA levels were significantly elevated in patients with PPH compared with 30 control subjects (7.5 ± 2.5 versus 4.9 ± 1.2 mg/dl, p < 0.001). Serum UA levels increased in proportion to the severity of NYHA functional class (Figure 1). When the sex difference in serum UA levels was considered, serum UA levels were significantly elevated in patients with PPH compared with that in control subjects in each sex (Figure 2). Demographic, hemodynamic, and blood gas data of the patients grouped according to the median value of serum UA in each sex (men, 8.9 mg/dl; women, 6.4 mg/dl) are summarized in Table 1. There were no significant differences between the high UA group and the low UA group in age, sex, body surface area, serum total-cholesterol, triglyceride, or fasting glucose. Serum creatinine levels were higher in the high UA group than in the low UA group. Heart rate, total pulmonary resistance, and mean right atrial pressure were significantly higher in the high UA group than in the low UA group. Cardiac output and mixed venous oxygen saturation were significantly lower in the high UA group than in the low UA group. Furosemide was more frequently used in the high UA group than in the low UA group. In the high UA group, however, there was no significant difference in serum UA levels between those patients who received furosemide and those who did not (9.2 ± 1.9, n = 30 versus 9.9 ± 1.2 mg/dl, n = 14).
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p < 0.05 versus NYHA functional Class II; 
p < 0.05 versus NYHA functional Class III.
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Serum UA Levels and Hemodynamic Variables
Serum UA levels negatively correlated with cardiac output (r = 0.52, p < 0.001) and positively correlated with total pulmonary resistance (r = 0.57, p < 0.001). These correlations in
each sex are shown in Figure 3. Serum UA levels did not significantly correlate with heart rate, mean systemic arterial pressure, or pulmonary capillary wedge pressure. Serum UA levels significantly correlated with mixed venous saturation (r = 0.48, p < 0.001), but not with arterial oxygen saturation (r = 0.13). Serum UA levels showed a significant negative correlation with the degree of systemic oxygen delivery (arterial oxygen saturation × cardiac output) (r = 0.54, p < 0.001).
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In multivariate analysis, serum UA levels were related to cardiac output, serum creatinine levels, and sex, but were independent of age, body surface area, mean systemic arterial pressure, serum total-cholesterol, triglyceride, fasting glucose, furosemide dose, and alcohol intake (Table 2).
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Effects of Vasodilator Treatment on Serum UA Levels
After vasodilator therapy, total pulmonary resistance was significantly decreased from 22 ± 6 to 17 ± 7 Wood units (p < 0.05). Under these conditions, serum UA levels were also reduced from 7.1 ± 1.9 to 5.9 ± 1.6 mg/dl (p < 0.05). The decrease in serum UA showed a significant correlation with the decrease in total pulmonary resistance (Figure 4).
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Serum UA Levels and Mortality
During a mean follow-up period of 31 ± 37 mo, 53 patients died of cardiopulmonary causes: 38 patients died of progressive RV failure and 15 patients died suddenly, indicative of cardiopulmonary death. One patient died as a result of a traffic accident, and one underwent transplantation during the follow-up period.
Among noninvasive variables, i.e., age, sex, NYHA functional class, heart rate, serum UA, arterial oxygen saturation, LV deformity index, serum total-bilirubin, and the absence of vasodilator therapy, serum UA levels, LV deformity index, and the absence of vasodilator therapy were independently related to mortality in PPH by multivariate Cox proportional-hazards analysis (Table 3). The Kaplan-Meier survival curves grouped according to the median value of serum UA for each sex demonstrated that patients with high serum UA had a significantly lower survival rate than did those with low serum UA (log-rank test, p < 0.01, respectively) (Figure 5).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In the present study, we demonstrated for the first time that (1) serum UA levels were elevated in patients with PPH, and that (2) serum UA levels negatively correlated with cardiac output and positively correlated with total pulmonary resistance. We also demonstrated that (3) serum UA levels decreased in association with a reduction of total pulmonary resistance during vasodilator therapy. Finally, we demonstrated that (4) among noninvasive variables, serum UA was independently related to the mortality by a multivariate analysis, and that (5) patients with high serum UA levels had a significantly lower survival rate than did those with low serum UA levels, from the Kaplan-Meier survival curves according to the median value of UA for each sex. These results suggest that serum UA levels increase in proportion to the clinical severity of PPH and have strong, independent association with long-term mortality of patients with PPH.
Increased Serum UA Levels in PPH
In the present study, serum UA levels independently correlated with cardiac output, serum creatinine levels, and sex in multivariate analysis. Earlier studies have shown that tissue ischemia deplete ATP and activate the purine nucleotide degradation pathway to UA, resulting in urate overproduction in the heart, lungs, liver, and skeletal muscle (2, 6, 25, 26). In fact, production of UA has been shown to increase in proportion to the severity of hypoxia in patients with chronic obstructive pulmonary disease and obstructive sleep apnea (4, 5). Alternatively, hyperuricemia in cyanotic congenital heart disease has been shown to be attributable partly to enhanced urate reabsorption secondary to renal hypoperfusion (27). Considering the close relation between serum UA and cardiac output, it is interesting to speculate that tissue hypoperfusion and hypoxia resulting from reduced cardiac output in severe PPH induce both overproduction of UA and impaired UA excretion, leading to increased serum levels in patients with PPH. In addition, the significant relations between serum UA and serum creatinine imply that impaired renal excretion of UA may be one of contributors to hyperuricemia. Further studies are necessary to determine the mechanisms responsible for hyperuricemia in patients with PPH.
In the present study, there was no significant correlation between serum UA levels and arterial oxygen saturation. In contrast, serum UA levels showed a significant negative correlation with the degree of systemic oxygen delivery (arterial oxygen saturation × cardiac output). It is possible that arterial oxygen decreased sufficiently to enhance tissue hypoxia resulting from the reduced cardiac output but insufficiently to have an independent association with serum UA levels.
Earlier studies have shown that an increase in serum UA levels is related to hypertension, hyperlipidemia, and diabetes mellitus (15). However, multivariate analysis demonstrated that serum UA levels did not independently correlate with blood pressure, serum total-cholesterol, serum triglyceride, or serum fasting glucose in patients with PPH. This discrepancy may be explained by the low prevalence of these risk factors in patients with PPH. Diuretic therapy is known to affect serum UA metabolism (28). However, despite the constant diuretic doses, serum UA levels decreased in association with a reduction of total pulmonary resistance during vasodilator therapy. In addition, serum UA levels did not independently correlate with diuretic doses in multivariate analysis. In the high UA group, there was no significant difference in serum UA levels between those patients who received furosemide and those who did not. These results suggest that diuretic use may not be a major contributor to hyperuricemia in PPH and are consistent with the previous reports to investigate serum UA levels in patients with chronic heart failure (1, 2).
Serum UA Levels and Mortality
Previous studies have shown that the mortality in PPH correlates with RV hemodynamic variables obtained invasively such as mean pulmonary arterial pressure, cardiac output, and mean right atrial pressure (29, 30). However, a simple, noninvasive, and repeatedly available assessment of the mortality would be more desirable. Interestingly, serum UA levels have recently been shown to have a strong, independent association with long-term mortality of patients with left-sided heart failure (10, 11). However, whether serum UA can predict the mortality in PPH had remained unknown. In the present study, among nine noninvasive variables, serum UA, LV deformity index, and the absence of vasodilator therapy were independently related to mortality in PPH by multivariate analysis. These results suggest that serum UA levels may provide additional prognostic information to that obtained by conventional noninvasive assessment. It is interesting to speculate that impaired oxidative metabolism indicated by high UA levels (1, 9) may be associated with poor outcome in patients with PPH. Furthermore, the Kaplan-Meier survival curves according to the median value of UA demonstrated that patients with high serum UA levels had a significantly lower survival rate than did those with low serum UA levels. Thus, serum UA levels may serve as a prognostic indicator of PPH, which may complement invasive standard prognostic markers such as RV hemodynamic variables.
Clinical Implication
Measurement of serum UA is simple, noninvasive, relatively inexpensive, and routinely available. Although several noninvasive markers for the severity of PPH such as neurohormones (31), echocardiographic parameters (32), and radionuclide imaging findings (33) have been proposed, UA measurement may also serve as a noninvasive indicator for the severity of PPH. Indeed, as indicated in the follow-up by vasodilator therapy, serum UA levels decreased in association with a reduction in total pulmonary resistance. Under these conditions, determination of serum UA levels can be repeatedly performed for the evaluation of the the effect of vasodilator treatment in outpatients with PPH as well as patients in the hospital.
Study Limitations
First, because of the sex difference in serum UA levels (22, 23), different values should be used for each sex to evaluate the clinical severity and mortality of patients with PPH.
Second, three patients with renal failure were excluded from this study because they may have a marked elevation in serum UA levels caused by the disorder (34). Serum UA measurement may not be useful in such patients for the evaluation of the severity of PPH.
Finally, diuretic use may have augmented the difference in serum UA levels between patients with PPH and control subjects who did not receive any diuretics. Nevertheless, multivariate analysis demonstrated that serum UA levels in patients with PPH were significantly correlated with cardiac output, serum creatinine levels, and sex, independent of furosemide dose.
Conclusions
Serum UA levels increase in proportion to the clinical severity of PPH and have strong, independent association with long-term mortality of patients with PPH.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Noritoshi Nagaya, M.D., Division of Cardiology, Department of Medicine, National Cardiovascular Center, 5-7-1 Fujishirodai, Suita, Osaka 565, Japan.
(Received in original form December 9, 1998 and in revised form March 5, 1999).
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INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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 R. J. Barst, M. McGoon, A. Torbicki, O. Sitbon, M. J. Krowka, H. Olschewski, and S. Gaine Diagnosis and differential assessment of pulmonary arterial hypertension J. Am. Coll. Cardiol., June 16, 2004; 43(12_Suppl_S): 40S - 47S. [Abstract] [Full Text] [PDF]
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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]
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A. Peacock, R. Naeije, N. Galie, and J.T. Reeves End points in pulmonary arterial hypertension: the way forward Eur. Respir. J., June 1, 2004; 23(6): 947 - 953. [Abstract] [Full Text] [PDF]
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 M. R. Wilkins Selective or Nonselective Endothelin Receptor Blockade in Pulmonary Arterial Hypertension Am. J. Respir. Crit. Care Med., February 15, 2004; 169(4): 433 - 434. [Full Text] [PDF]
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R. Budhiraja, R. M. Tuder, and P. M. Hassoun Endothelial Dysfunction in Pulmonary Hypertension Circulation, January 20, 2004; 109(2): 159 - 165. [Full Text] [PDF]
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D. Chemla, V. Castelain, P. Herve, Y. Lecarpentier, and S. Brimioulle Haemodynamic evaluation of pulmonary hypertension Eur. Respir. J., November 1, 2002; 20(5): 1314 - 1331. [Abstract] [Full Text] [PDF]
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D. Shitrit, D. Bendayan, A. Bar-Gil-Shitrit, M. Huerta, B. Rudensky, G. Fink, and M. R. Kramer Significance of a Plasma D-dimer Test in Patients With Primary Pulmonary Hypertension Chest, November 1, 2002; 122(5): 1674 - 1678. [Abstract] [Full Text] [PDF]
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H. Saito, M. Nishimura, E. Shibuya, H. Makita, I. Tsujino, K. Miyamoto, and Y. Kawakami Tissue Hypoxia in Sleep Apnea Syndrome Assessed by Uric Acid and Adenosine Chest, November 1, 2002; 122(5): 1686 - 1694. [Abstract] [Full Text] [PDF]
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R. Wensel, C. F. Opitz, S. D. Anker, J. Winkler, G. Hoffken, F. X. Kleber, R. Sharma, M. Hummel, R. Hetzer, and R. Ewert Assessment of Survival in Patients With Primary Pulmonary Hypertension: Importance of Cardiopulmonary Exercise Testing Circulation, July 16, 2002; 106(3): 319 - 324. [Abstract] [Full Text] [PDF]
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 K. Fukuchi, K. Hayashida, N. Nakanishi, M. Inubushi, S. Kyotani, N. Nagaya, and Y. Ishida Quantitative Analysis of Lung Perfusion in Patients with Primary Pulmonary Hypertension J. Nucl. Med., June 1, 2002; 43(6): 757 - 761. [Abstract] [Full Text] [PDF]
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 H Oya, N Nagaya, T Satoh, F Sakamaki, S Kyotani, M Fujita, N Nakanishi, and K Miyatake Haemodynamic correlates and prognostic significance of serum uric acid in adult patients with Eisenmenger syndrome Heart, July 1, 2000; 84(1): 53 - 58. [Abstract] [Full Text] [PDF]
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