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European Journal of Heart Failure 2007 9(5):466-468; doi:10.1016/j.ejheart.2006.10.019
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© 2006 European Society of Cardiology

Elevated serum uric acid levels impair coronary microvascular function in patients with idiopathic dilated cardiomyopathy

Hakan Gullua,*, Dogan Erdogana, Mustafa Caliskana, Derya Toka, Sevsen Kulaksizoglub, Aylin Yildirira and Haldun Muderrisoglua

a Baskent University, Faculty of Medicine, Department of Cardiology Ankara, Turkey
b Baskent University, Faculty of Medicine, Department of Clinical Biochemistry Ankara, Turkey

* Corresponding author. Baskent University, Konya Teaching and Medical Research Center, Cardiology Department, Hoca Cihan Mah, Saray Cad, No 1, Selcuklu, Konya, Turkey. Tel.: +90 332 2570606x2111; fax: +90 332 2476886.E-mail address: gulluhakan{at}hotmail.com


   Abstract
Top
 Abstract
1. Background
 2. Aims
 3. Methods
 4. Results
 5. Conclusion
 References
 
In patients with idiopathic dilated cardiomyopathy (IDC), attenuated coronary flow reserve (CFR) and elevated serum uric acid levels have been reported. In this study, we investigated whether increased uric acid levels correlate with the degree of coronary microvascular dysfunction.

Serum uric acid levels were measured in 29 patients with IDC (mean age: 57.0±10.8 years, 10 female), and each patient also underwent transthoracic echocardiographic examination including CFR measurement. The study population was divided into two groups according to the median CFR value (lower CFR group and higher CFR group). Uric acid levels were significantly higher in the lower CFR group than in the higher CFR group (7.59±2.56 vs 4.80±0.80 mg/dL, P=0.000). CFR correlated significantly and inversely to serum uric acid (r=–0.570, P=0.001). Logistic regression analysis revealed that uric acid level was the only independent predictor of CFR (B=–1080, P=0.015).

We found a possibly clinically important negative association between serum uric acid levels and CFR in patients with IDC.

Key Words: Dilated cardiomyopathy • Coronary flow reserve • Uric acid

Received May 21, 2006; Revised September 19, 2006; Accepted October 31, 2006


   1. Background
Top
 Abstract
 1. Background
2. Aims
 3. Methods
 4. Results
 5. Conclusion
 References
 
A relationship between uric acid (UA) and impairment of peripheral vascular tone resulting in disrupted leg blood flow and the possible involvement of xanthine oxidase, in patients with HF has been reported [1]. Cicoira et al. [2] suggested an association between diastolic dysfunction, which is frequently encountered in patients with heart failure (HF) due to ischaemic dilated cardiomyopathy, and elevated serum UA levels. Previous studies have suggested an association between vascular endothelial function and serum UA levels [3,4]. In addition it has been suggested that in the absence of co-morbidities, hyperuricaemia attenuating nitric-oxide synthase activity impairs endothelial dependent vasodilation [3,5].


   2. Aims
Top
 Abstract
 1. Background
 2. Aims
3. Methods
 4. Results
 5. Conclusion
 References
 
The aim of this study was to assess whether increased UA levels in patients with IDC might correlate with the degree of coronary microvascular dysfunction represented by CFR.


   3. Methods
Top
 Abstract
 1. Background
 2. Aims
 3. Methods
4. Results
 5. Conclusion
 References
 
The study population was composed of 29 patients with IDC, left ventricular ejection fraction less than 45% and angiographically normal coronary arteries (mean age: 57.0±10.8, 10 female). Exclusion criteria were: any identifiable cause of dilated cardiomyopathy, smoking, cardiac rhythm other than sinus, or serum creatinine >1.8 mg/dL. All subjects were on standard therapy for heart failure with carvedilol, digoxin, lisinopril, spironolactone, furosemide, and aspirin, optimized according to each patient's clinical status. Fasting blood glucose, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglyceride and high-sensitivity C-reactive protein (hsCRP) were measured. Serum UA levels were determined using the validated enzymatic colourimetric method (Aeroset Clinical Chemistry Analyzer, Abbott Lab., Abbott Park, IL, USA). Each subject was examined using an Acuson Sequoia C256® Echocardiography System equipped with 3V2c broadband and 5V2c high-resolution transducers with second harmonic capability (Acuson Corp, Mountain View, CA, USA). All subjects had Doppler recordings of the LAD with a dipyridamole infusion. Coronary diastolic peak velocities were measured at baseline and after dipyridamole infusion (0.84 mg/kg over 6 min) by averaging the highest 3 Doppler signals for each measurement. CFR was defined as the ratio of hyperaemic to baseline diastolic peak velocities [6,7]. One investigator who was blinded to the subjects' data performed all of the echocardiographic examinations. Two echocardiographers separately performed off-line measurements from videotape records. Absolute difference between the two measurements was 0.075±0.070, and relative difference was 0.038±0.037. Our institutional ethics committee approved the study protocol and each subject provided written informed consent.

For comparison analysis, Mann-Whitney U test, and for correlation analysis Spearman's correlation test was used. For multivariate analysis, logistic regression analysis was performed.


   4. Results
Top
 Abstract
 1. Background
 2. Aims
 3. Methods
 4. Results
5. Conclusion
 References
 
The overall study population was divided into two groups according to the median CFR value. The lower CFR group (14 patients, 4 female, mean CFR: 1.72±0.16) and the higher CFR group (14 patients, 6 female, mean CFR: 2.38±0.30). The demographic, biochemical, and echocardiographic characteristics of the two groups are summarized in Table 1. Serum UA levels were significantly higher in the lower CFR group than in the higher CFR group (7.59±2.56 vs 4.80±0.80 mg/dL, P=0.001, respectively). Blood urea nitrogen (20.2±8.9 vs 15.0±4.2 mg/dL, P=0.056) and creatinine (1.15±0.33 vs 0.89±0.20 mg/dL, P=0.015) values were higher in the lower CFR group than in the higher CFR group respectively (Table 1). Total cholesterol values (4.06±0.80 vs 4.98±0.83 mmol/L, P=0.006) and LDL cholesterol (2.41±0.63 vs 3.06±0.55 mmol/L, P=0.007) were significantly lower in the lower CFR group than in the higher CFR group (Table 1). hsCRP values were higher in the lower CFR group (5.73±3.64 vs 3.24±3.07 mg/L, P=0.056) (Table 1). Table 2 shows the significant correlations between CFR and the other study variables. CFR correlated significantly and inversely to serum UA (r=–0.570, P=0.001), blood urea nitrogen, creatinine and hsCRP, and positively to total cholesterol, triglyceride and LDL cholesterol (Table 2). Fig. 1 shows the nonlinear association between UA and CFR values, and the best model is the S model as for estimating coronary flow reserve by uric acid. In a logistic regression model when CFR entered as dependent, and serum UA, blood urea nitrogen, creatinine, total cholesterol, LDL-cholesterol, and hsCRP as independents, only serum UA level was the independent predictor of CFR (P=0.015).


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  		Table 1 Demographic, biochemical, and coronary flow measurements for the lower CFR and the higher CFR groups

 


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  		Table 2 Spearman's correlation matrix (showing significant correlations between CFR and other variables)

 


Figure 01
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  		Fig. 1 Graph showing the nonlinear association between uric acid values and coronary flow reserve (r=–0.570). The best model is the S model as CFR=e3.509/UA for estimating coronary flow reserve by uric acid.

 

   5. Conclusion
Top
 Abstract
 1. Background
 2. Aims
 3. Methods
 4. Results
 5. Conclusion
References
 
This study suggests that UA levels are significantly higher in subjects with impaired CFR. At the same time, both blood urea nitrogen and creatinine levels were elevated in the group with impaired CFR. However, serum UA level is the only independent predictor of impaired coronary flow reserve. The clinical and prognostic importance of serum UA values has been suggested in patients with heart failure [2,8,9]. The impaired CFR in hyperuricaemic patients with IDC suggested by our study, may be explained by oxygen free radical-mediated endothelial damage resulting from increased xanthine oxidase activity [10,11]. Both myocardial and/or peripheral tissue hypoperfusion, resulting from decreased cardiac output and arterial hypoxaemia caused by pulmonary alveolar hypoperfusion due to increased pulmonary capillary wedge pressure, may cause decreased O2 pressures in capillary endothelial cells. The vicious circle of endothelial damage, microvascular dysfunction, capillary endothelial hypoxemia, and free radical production may contribute to poorer prognosis in patients with IDC.

We have found that patients with impaired CFR have lower total cholesterol, LDL cholesterol, and triglyceride values in accordance with a study by Sezgin et al. [12], which reported that decreased lipoprotein concentrations in patients with IDC indicate poorer prognosis.

The association between serum UA levels and CFR in patients with IDC suggests that inhibition of xanthine oxidase with allopurinol may theoretically result in an improvement in coronary microvascular function in patients with IDC.


   References
Top
 Abstract
 1. Background
 2. Aims
 3. Methods
 4. Results
 5. Conclusion
 References
 

  1. Anker S.D., Leyva F., Poole-Wilson P.A., Kox W.J., Stevenson J.C., Coats A.J. Relation between serum uric acid and lower limb blood flow in patients with chronic heart failure. Heart (Jul 1997) 78(1):39–43.[Abstract/Free Full Text]
  2. Cicoira M., Zanolla L., Rossi A., et al. Elevated serum uric acid levels are associated with diastolic dysfunction in patients with dilated cardiomyopathy. Am Heart J (2002) 143:1107–1111.[CrossRef][Web of Science][Medline]
  3. Kato M., Hisatome I., Tomikura Y., et al. Status of endothelial dependent vasodilation in patients with hyperuricemia. Am J Cardiol (2005) 96:1576–1578.[CrossRef][Web of Science][Medline]
  4. Erdogan D., Gulu H., Caliskan M., et al. Coronary flow reserve and coronary microvascular functions are strongly related to serum uric acid concentrations in healthy adults. Coron. Artery Dis. (2006) 17(1):7–14.[CrossRef][Web of Science][Medline]
  5. Erdogan D., Gullu H., Caliskan M., et al. Relationship of serum uric acid to measures of endothelial function and atherosclerosis in healthy adults. Int J Clin Pract (2005) 59:1276–1282.[CrossRef][Web of Science][Medline]
  6. Korcarz C.E., Stein J.H. Noninvasive assessment of coronary flow reserve by echocardiography: technical considerations. J Am Soc Echocardiogr (2004) 17(6):704–707.[CrossRef][Web of Science][Medline]
  7. Youn H.J., Foster E. Demonstration of coronary artery flow using transthoracic Doppler echocardiography. J Am Soc Echocardiogr (2004) 17(2):178–185.[CrossRef][Web of Science][Medline]
  8. Leyva F., Anker S., Swan J.W., et al. Serum uric acid as an index of impaired oxidative metabolism in chronic heart failure. Eur Heart J (1997) 8:858–865.
  9. Leyva F., Anker S.D., Godsland I.F., et al. Uric acid in chronic heart failure: a marker of chronic inflammation. Eur Heart J (1998) 19:1814–1822.[Abstract/Free Full Text]
  10. Johnson R.J., Kang D.H., Feig D., et al. Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease? Hypertension (2003) 41:1183–1190.[Abstract/Free Full Text]
  11. Many A., Hubel C.Q.A., Roberts J.M. Hyperuricemia and xanthine oxidase in preeclampsia, revisited. Am J Obstet Gynecol (1996) 174:288–291.[CrossRef][Web of Science][Medline]
  12. Sezgin N., Sezgin A.T., Gullu H., et al. Decreased serum lipoprotein levels as a guide for clinical severity in patients with idiopathic dilated cardiomyopathy. Tohoku J Exp Med (2005) 206:219–224.[CrossRef][Web of Science][Medline]

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This Article
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