Prognostic Value of Uric Acid in Patients With Acute

Coronary Syndromes
Gjin Ndrepepa, MDa,*, Siegmund Braun, MDa, Hans-Ullrich Haase, MDb, Stefanie Schulz, MDa,
Sabine Ranftl, MDa, Martin Hadamitzky, MDa, Julinda Mehilli, MDa, Albert Schömig, MDa,b, and
Adnan Kastrati, MDa
The association between uric acid and cardiovascular disease is incompletely understood.
In particular, the prognostic value of uric acid in patients with acute coronary syndromes
who undergo percutaneous coronary intervention has not been studied. This study included
5,124 patients with acute coronary syndromes who underwent percutaneous coronary
intervention: 1,629 with acute ST-segment elevation myocardial infarction, 1,332 with
acute non–ST-segment elevation myocardial infarction, and 2,163 with unstable angina.
The primary end point was 1-year mortality. Patients were divided into quartiles according
to uric acid level as follows: quartile 1, 1.3 to <5.3 mg/dl; quartile 2, 5.3 to <6.3 mg/dl;
quartile 3, 6.3 to <7.5 mg/dl; and quartile 4, 7.5 to 18.4 mg/dl. There were 450 deaths during
follow-up: 80 deaths in quartile 1, 77deaths in quartile 2, 72 deaths in quartile 3, and 221
deaths in quartile 4 of uric acid (Kaplan-Meier estimates of 1-year mortality 6.4%, 6.2%,
5.6%, and 17.4%, respectively; unadjusted hazard ratio 3.05, 95% confidence interval 2.54
to 3.67, p <0.001 for fourth vs first quartile of uric acid). After adjustment for traditional
cardiovascular risk factors, renal function, and inflammatory status, the association be-
tween uric acid and mortality remained significant, with a 12% increase in the adjusted risk
for 1-year mortality for every 1 mg/dl increase in the uric acid level. Uric acid improved the
discriminatory power of the predictive model regarding 1-year mortality (absolute inte-
grated discrimination improvement 0.008, p ⴝ 0.005). In conclusion, elevated levels of uric
acid are an independent predictor of 1-year mortality across the whole spectrum of patients
with acute coronary syndromes treated with percutaneous coronary intervention. © 2012
Elsevier Inc. All rights reserved. (Am J Cardiol 2012;109:1260 –1265)

Acute coronary syndromes (ACS) remain a leading Methods

cause of morbidity and mortality worldwide.1–3 Despite the
application of various risk stratification schemes,4 ACS re- This study included 5,124 patients with ACS who un-
main poorly characterized in terms of risk prediction. Uric derwent PCI at the German Heart Center in Munich from
acid is the end product of purine catabolism in humans and March 2000 to December 2009. Of these, 1,629 patients
is readily tested in routine clinical practice. Although the had acute ST-segment elevation myocardial infarction
possibility of an association between elevated uric acid level (STEMI), 1,332 had acute non–ST-segment elevation acute
and cardiovascular disease has been recognized for ⬎130 myocardial infarction (NSTEMI), and 2,163 had unstable
years,5,6 the role of acid uric as a risk factor or a risk marker angina. The diagnosis of STEMI was based on the presence
for cardiovascular disease remains a debatable issue. The of chest pain lasting ⱖ20 minutes associated with typical
association between elevated uric acid and increased risk for changes on surface electrocardiography (ST-segment eleva-
mortality has been investigated in the general population,7,8 tion ⱖ0.1 mV in ⱖ2 limb leads or ⱖ0.2 mV in ⱖ2 contig-
and in patients with congestive heart failure,9 hyperten- uous precordial leads or complete left bundle branch block
sion,10 diabetes,11 angiographically confirmed coronary ar- of new onset). Unstable angina was diagnosed using Braun-
tery disease,12 and acute myocardial infarction.13–16 No wald’s criteria17 plus documentation of significant coronary
studies have addressed the prognostic value of this bio- artery disease on coronary angiography. Diagnosis of
marker across the whole spectrum of patients with ACS. NSTEMI required clinical and electrocardiographic criteria
Thus, the aim of this study was to investigate whether there similar to those of unstable angina plus elevated troponin T
is an association between acid uric level and mortality (⬎0.03 ␮g/L) or creatine kinase or creatine kinase-myocar-
across the whole spectrum of patients with ACS who un- dial band. In all included patients, the diagnosis of ACS was
dergo percutaneous coronary intervention (PCI). confirmed by coronary angiography. Weight and height
were measured with patients wearing light clothing without
shoes, and body mass index was calculated. The estimated
a
Deutsches Herzzentrum and b1. Medizinische Klinik Rechts der Isar,
glomerular filtration rate was calculated using the Cock-
Technische Universität, Munich, Germany. Manuscript received October croft-Gault formula.18 Detailed criteria of the diagnosis of
19, 2011; revised manuscript received and accepted December 11, 2011. cardiovascular risk factors are given in another publication
*Corresponding author: Tel: 49-89-12181535; fax: 49-89-12184053. from our group.19 Patients with acute inflammatory states,
E-mail address: [email protected] (G. Ndrepepa). known malignancies, or advanced kidney disease were not

0002-9149/12/$ – see front matter © 2012 Elsevier Inc. All rights reserved. www.ajconline.org
doi:10.1016/j.amjcard.2011.12.018
 Coronary Artery Disease/Uric Acid in Acute Coronary Syndromes 1261

Table 1
Baseline demographic and angiographic characteristics
Variable Quartile 1 Quartile 2 Quartile 3 Quartile 4 p Value
(n ⫽ 1,271) (n ⫽ 1,261) (n ⫽ 1,300) (n ⫽ 1,292)

Age (years) 67.7 (59.2, 76.4) 67.0 (58.8, 74.5) 68.1 (59.1, 75.2) 69.7 (61.2, 77.5) ⬍0.001
Women 546 (43.0%) 293 (23.2%) 250 (19.2%) 273 (21.1%) ⬍0.001
Body mass index (kg/m2) 25.7 (23.4, 28.1) 26.3 (24.5, 29.0) 27.4 (25.0, 29.8) 27.7 (25.0, 30.5) ⬍0.001
Diabetes mellitus 352 (27.7%) 303 (24.0%) 346 (26.6%) 430 (33.3%) ⬍0.001
Arterial hypertension 785 (61.8%) 802 (63.6%) 826 (63.5%) 742 (57.4%) 0.003
Current smoker 295 (23.2%) 281 (22.3%) 272 (20.9%) 235 (18.2%) 0.011
Hypercholesterolemia (ⱖ240 mg/dl) 758 (59.6%) 817 (64.8%) 816 (62.8%) 810 (62.7%) 0.062
Previous myocardial infarction 268 (21.1%) 284 (22.5%) 344 (26.5%) 394 (30.5%) ⬍0.001
Previous coronary artery bypass surgery 156 (12.3%) 156 (12.4%) 171 (13.2%) 189 (14.6%) 0.261
Clinical presentation ⬍0.001
Unstable angina 525 (41.3%) 550 (43.6%) 604 (56.5%) 484 (37.5%)
NSTEMI 281 (22.1%) 323 (25.6%) 299 (23.0%) 429 (33.2%)
STEMI 465 (36.6%) 388 (30.8%) 397 (30.5%) 379 (29.3%)
Cardiogenic shock 38 (3.0%) 42 (3.3%) 51 (3.9%) 146 (11.3%) ⬍0.001
Number of coronary artery narrowed ⬍0.001
1 310 (24.4%) 272 (21.5%) 258 (19.8%) 197 (15.2%)
2 342 (26.9%) 340 (27.0%) 360 (27.7%) 314 (24.3%)
3 619 (48.7%) 649 (51.5%) 682 (52.5%) 781 (60.4%)
Multivessel disease 961 (75.6%) 989 (78.5%) 1,042 (80.2%) 1,095 (84.8%) ⬍0.001
Left ventricular ejection fraction (%) 54.0 (45.0, 61.0) 55.0 (45.0, 61.0) 54.0 (44.0, 61.0) 49.0 (37.0, 58.0) ⬍0.001
Uric acid (mg/dl) 4.6 (4.0, 5.0) 5.8 (5.5, 6.0) 6.8 (6.5, 7.1) 8.5 (7.9, 9.5) ⬍0.001
Serum creatinine (mg/dl) 0.9 (0.7, 1.0) 0.9 (0.8, 1.1) 1.0 (0.9, 1.3) 1.2 (1.0, 1.5) ⬍0.001
Glomerular filtration rate (ml/min) 79.2 (61.1, 100.4) 82.6 (63.4, 105.1) 79.8 (59.3, 102.0) 63.2 (44.4, 88.1) ⬍0.001
C-reactive protein (mg/L) 3.4 (1.2, 11.7) 3.2 (1.2, 9.6) 3.6 (1.4, 11.2) 5.8 (1.9, 17.7) ⬍0.001

Data are expressed as median (25th percentile, 75th percentile) or number of patients (percentage).

included in the present study. Written informed consent was 3.4 to 7.0 mg/dl (202.3 to 416.5 ␮mol/L) and for women is
obtained from all patients. The study was carried out in 2.4 to 5.7 mg/dl (142.8 to 339.2 ␮mol/L).
accordance with the Declaration of Helsinki and was ap- The primary end point of the study was all-cause mor-
proved by the institutional ethics committee. tality. Nonfatal myocardial infarction, stroke, and target
Angiographic data were analyzed in the quantitative an- lesion revascularization were also evaluated. The follow-up
giographic core laboratory. Coronary artery disease was protocol after discharge consisted of a phone interview at
confirmed by the presence of coronary stenoses ⱖ50% 1 month after the procedure, a visit at 6 months, and a
luminal obstruction in ⱖ1 of the 3 main coronary arteries. phone interview at 12 months. Information about death
Offline analysis of digital angiograms was performed in the was obtained from hospital records, death certificates, or
core laboratory using an automated edge detection system phone contact with relatives of the patient or the referring
(CMS; Medis Medical Imaging Systems, Leiden, The Neth- physician. Patients who had cardiac symptoms underwent
erlands). The global left ventricular ejection fraction was complete clinical, electrocardiographic, and laboratory
determined by left ventricular angiography using the area- evaluations. Follow-up information was obtained and ad-
length method. The diagnosis of stroke required confirma- judication of adverse events was performed by medical
tion by computed tomography or magnetic resonance im- staff members unaware of clinical diagnosis, therapy
aging of the head. Stent implantation and periprocedural received, or uric acid levels.
care were performed according to standard criteria. Postin- The normality of data distribution was assessed using a
terventional antiplatelet therapy consisted of clopidogrel 1-sample Kolmogorov-Smirnov test. Data are presented as
(300 or 600 mg as a loading dose followed by 75 mg/day for medians with 25th and 75th percentiles or as counts and
ⱖ4 weeks to 6 months) and aspirin (200 mg/day adminis- proportions (percentages). Categorical data were compared
tered orally and continued indefinitely). Drug-eluting stents using chi-square test. Continuous data were compared using
were implanted in 3,366 patients (66%). Kruskal-Wallis rank-sum tests. A multiple linear regression
Blood samples were obtained before angiography in all model was used to identify the independent correlates of
patients. The uric acid concentration in plasma was deter- uric acid level. All variables listed in Table 1 were entered
mined with an enzymatic colorimetric test on a Cobas In- into the model. Survival analysis was performed by apply-
tegra 800 analyzer (Roche Diagnostics GmbH, Mannheim, ing the Kaplan-Meier method. Univariate and multivariate
Germany). Uricase cleaves uric acid to form allantoin and Cox proportional-hazards models were used to assess the
hydrogen peroxide, which reacts to form a quinoneimine association between uric acid (entered into the model as
dye. The measuring range in plasma is 0.20 to 25 mg/dl a continuous variable) and 1-year mortality. All variables
(11.9 to 1,500 ␮mol/L). The lower detection limit of the test listed in Table 1 and the interaction between gender and
is 0.20 mg/dl (11.9 ␮mol/l). The reference range for men is uric acid level were entered into the model. The discrim-
1262 The American Journal of Cardiology (www.ajconline.org)

Table 2
Correlates of uric acid concentration obtained by multiple linear
regression model
Variable ␤ p Value

Age 0.025 ⬍0.001

Female gender ⫺0.974 0.001
Body mass index 0.138 ⬍0.001
Diabetes mellitus ⫺0.115 0.035
Clinical presentation (STEMI vs angina) ⫺0.200 ⬍0.001
Cardiogenic shock 0.655 ⬍0.001
Previous coronary artery bypass surgery ⫺0.178 0.020
Left ventricular ejection fraction ⫺0.016 ⬍0.001
Glomerular filtration rate ⫺0.025 ⬍0.001

inatory power of the model regarding mortality with and

without the inclusion of uric acid was assessed by cal-
culating the C statistic in the Cox proportional-hazards Figure 1. Kaplan-Meier curves of 1-year mortality in various quartiles of
uric acid level.
model and the integrated discrimination improvement
according to Pencina et al.20 All analyses were performed
using S-plus (Insightful Corporation, Seattle, Washing- Table 3
ton). Two-tailed p values ⬍0.05 were considered to in- Correlates of 1-year mortality and hazard ratios calculated by univariate
Cox proportional-hazards model
dicate statistical significance.
Variable Unadjusted HR p Value
(95% CI)
Results
Uric acid (1 mg/dl increase) 1.31 (1.26–1.36) ⬍0.001
A total of 5,124 patients with ACS were included in Age (10-year increase) 1.89 (1.72–2.07) ⬍0.001
the study. Quartiles of uric acid concentrations were as Male gender 1.45 (1.20–1.77) ⬍0.001
follows: quartile 1, 1.3 to ⬍5.3 mg/dl; quartile 2, 5.3 to Diabetes mellitus 1.83 (1.52–2.21) ⬍0.001
⬍6.3 mg/dl; quartile 3, 6.3 to ⬍7.5 mg/dl; and quartile 4, Body mass index (5 kg/m2 increase) 0.69 (0.60–0.78) ⬍0.001
7.5 to 18.4 mg/dl. Smoking 0.68 (0.52–0.87) 0.002
Table 1 lists baseline characteristics according to quar- Hypercholesterolemia 0.56 (0.46–0.67) ⬍0.001
tiles of uric acid. Patients with uric acid levels in the upper Arterial hypertension 0.43 (0.36–0.52) ⬍0.001
quartile were older, were less often women, and had higher Previous myocardial infarction 1.30 (1.06–1.59) 0.010
Clinical presentation (STEMI, 2.08 (1.85–2.34) ⬍0.001
body mass indexes. The upper quartile included higher
NSTEMI, unstable angina)
proportions of those with previous myocardial infarction, Cardiogenic shock 12.49 (10.21–15.29) ⬍0.001
diabetes, and multivessel disease and lower proportions of Glomerular filtration rate (30 ml/min 3.33 (2.94–3.85) ⬍0.001
those with arterial hypertension and current smoking. These decrease)
patients presented more often with cardiogenic shock, had Baseline C-reactive protein (1 mg/L 1.02 (1.01–1.03) ⬍0.001
lower left ventricular ejection fractions, had lower glomer- increase)
ular filtration rates, and had higher creatinine and C-reactive Left ventricular ejection fraction (10% 1.87 (1.73–2.01) ⬍0.001
protein levels. There were also differences among patients decrease)
of various uric acid quartiles with regard to clinical presen- Multivessel disease (vs single-vessel 2.93 (2.10–4.11) ⬍0.001
tation (Table 1). Only 137 patients (2.7%) were receiving disease)
allopurinol on admission, with no difference among the
groups (p ⫽ 0.11).
Independent determinants of uric acid level were identi- 3.67, p ⬍0.001 for fourth quartile vs first quartile; Figure 1).
fied using multivariate linear regression (see “Methods” for The other univariate associates of 1-year mortality are listed
the variables entered into the model). The following vari- in Table 3.
ables were identified by the model as independently asso- The association between uric acid and 1-year mortality
ciated with elevated levels of uric acid: elderly age, male was assessed also according to clinical presentation of the
gender, higher body mass index, absence of diabetes, clin- patients. There were 234 deaths among patients with
ical presentation, cardiogenic shock, lack of previous coro- STEMI (n ⫽ 1,629) within the first year after PCI: 113
nary artery bypass surgery, left ventricular ejection fraction, among those in quartile 4 (n ⫽ 379) and 121 among those
and glomerular filtration rate (Table 2). in quartiles 1 to 3 (Kaplan-Meier estimates of 1-year mor-
There were 450 deaths within the first year of follow-up. tality 30.7% and 9.8%, respectively; HR 3.56, 95% CI 2.80
Deaths according to quartile of uric acid were as follows: 80 to 4.52, p ⬍0.001). There were 153 deaths among patients
deaths in quartile 1, 77 in quartile 2, 72 in quartile 3, and with NSTEMI (n ⫽ 1,332) within the first year after PCI: 85
221 in quartile 4 (Kaplan-Meier estimates of 1-year mortal- in quartile 4 (n ⫽ 429) and 68 in quartiles 1 to 3 (Kaplan-
ity 6.4%, 6.2%, 5.6%, and 17.4%, respectively; unadjusted Meier estimates of 1-year mortality 21.1% and 7.0%, re-
hazard ratio [HR] 3.05, 95% confidence interval [CI] 2.54 to spectively; HR 2.80, 95% CI 2.06 to 3.80, p ⬍0.001). There
 Coronary Artery Disease/Uric Acid in Acute Coronary Syndromes 1263

level as independent correlates of 1-year mortality (Table

4). Of note, for every 1 mg/dl increase in the uric acid
concentration, the adjusted risk for 1-year mortality in-
creased by 12%. There was no interaction between gender
and uric acid regarding 1-year mortality (p for interaction ⫽
0.792). This demonstrates no difference according to gender
in the association between uric acid and 1-year mortality.
For the end point of all-cause mortality, the C statistic of
the model without the inclusion of uric acid was 0.860.
After adding uric acid to the model, the C statistic was
0.863. The inclusion of uric acid in the multivariate model
was associated with a significant improvement of the dis-
criminatory power of the model regarding the prediction of
1-year mortality (absolute integrated discrimination im-
provement 0.008, relative integrated discrimination im-
Figure 2. Estimates of 1-year mortality in patients in the lower 3 quartiles
versus quartile 4.
provement 4.0%, p ⫽ 0.005).

Table 4 Discussion
Correlates of 1-year mortality and hazard ratios calculated by
multivariate Cox proportional-hazards model
The main findings of the present study can be summa-
rized as follows. First, elevated levels of uric acid in patients
Variable Adjusted HR p Value with ACS treated with PCI are an independent correlate of
(95% CI) 1-year mortality. For every 1 mg/dl increase in uric acid
Uric acid (1 mg/dl increase) 1.12 (1.06–1.18) ⬍0.001 level, the adjusted risk for 1-year mortality was increased by
Age (10-year increase) 1.30 (1.12–1.51) ⬍0.001 12%. Second, subgroup analyses in patients with STEMI,
Diabetes mellitus 1.42 (1.12–1.80) 0.003 NSTEMI, and unstable angina showed that elevated levels
Clinical presentation (STEMI vs 1.41 (1.19–1.67) ⬍0.001 of uric acid predict an increased risk for 1-year mortality
unstable angina) across the whole spectrum of patients with ACS. Last,
Cardiogenic shock 4.66 (3.44–6.31) ⬍0.001 elevated levels of uric acid did not predict the occurrence of
Multivessel disease (vs single-vessel 2.06 (1.35–3.14) ⬍0.001
nonfatal myocardial infarction or stroke or the need for
disease)
Glomerular filtration rate (30 ml/min 1.68 (1.34–2.09) ⬍0.001
target lesion revascularization over the first year after PCI.
decrease) In a series of 1,124 patients with acute myocardial in-
Left ventricular ejection fraction 1.37 (1.25–1.51) ⬍0.001 farction, Kojima et al13 showed that serum level of uric acid
(10% decrease) correlated closely with Killip class and predicted the devel-
Baseline C-reactive protein (1 mg/L 1.01 (1.00–1.02) 0.009 opment of congestive heart failure and short- and long-term
increase) mortality. In a recent study, Lazzeri et al14 demonstrated in
466 patients with STEMI who underwent primary PCI ⬍12
hours after the onset of symptoms that uric acid level was an
were 63 deaths in patients with unstable angina (n ⫽ 2,163) independent predictor of in-hospital mortality. More re-
within the first year after PCI: 23 in quartile 4 (n ⫽ 484) and cently, the same group showed in a larger series of patients
40 in quartiles 1 to 3 (Kaplan-Meier estimates of 1-year with STEMI (856 patients) that uric acid predicted the
mortality 4.8% and 2.4%, respectively; HR 1.99, 95% CI occurrence of complications in the intensive cardiac care
1.20 to 3.30, p ⫽ 0.007). Mortality estimates according to unit but not early mortality after adjustment for renal func-
clinical presentation are listed in Figure 2. tion and degree of myocardial necrosis.15 In another recent
Nonfatal myocardial infarction occurred in 205 patients: study of patients with acute myocardial infarction and im-
60 in quartile 1, 42 in quartile 2, 49 in quartile 3, and 54 in paired renal function treated with PCI, elevated levels of
quartile 4 (Kaplan-Meier estimates of nonfatal myocardial uric acid predicted short-term and long-term mortality in all
infarction 4.8%, 3.4%, 3.8%, and 4.5%, respectively; p ⫽ degrees of renal dysfunction.16 Of note, elevated uric acid
0.306). Stroke occurred in 58 patients: 12 in quartile 1, 18 levels predicted death in patients who developed contrast-
in quartile 2, 16 in quartile 3, and 12 in quartile 4 (Kaplan- induced nephropathy.16 The subgroup analysis from our
Meier estimates of stroke 1.0%, 1.5%, 1.2%, and 1.0%, study that included 1,629 patients with STEMI demon-
respectively; p ⫽ 0.635). Target lesion revascularization strated that patients in quartile 4 of uric acid (7.5 to 18.4
was required in 982 patients: 243 in quartile 1, 238 in mg/dl) had a 3.5-fold increase in the risk for 1-year mor-
quartile 2, 280 in quartile 3, and 221 in quartile 4 (Kaplan- tality compared to patients in the lower 3 quartiles (uric acid
Meier estimates of target lesion revascularization 20.5%, concentration 1.3 to ⬍7.5 mg/dl).
20.1%, 23.0%, and 20.1%, respectively; p ⫽ 0.261). In the present study, we found that elevated levels of uric
The multivariate Cox proportional-hazards model (see acid were associated with increased risk for 1-year mortality
“Methods” for the variables entered into the model) identi- across the whole spectrum of patients with ACS. Mecha-
fied uric acid, age, diabetes, presentation pattern, cardio- nisms responsible for the increase in the risk for mortality
genic shock, multivessel disease, glomerular filtration rate, with the increase in the uric acid level are not entirely clear.
the left ventricular ejection fraction, and C-reactive protein Analysis of the predictors of elevated uric acid level dem-
1264 The American Journal of Cardiology (www.ajconline.org)

onstrated that elevated uric acid level is associated with 2. Fox KA, Goodman SG, Anderson FA Jr, Granger CB, Moscucci M,
factors that connote a more adverse cardiovascular risk Flather MD, Spencer F, Budaj A, Dabbous OH, Gore JM; GRACE
Investigators. From guidelines to clinical practice: the impact of hos-
profile. Expectedly, impaired renal function was an inde- pital and geographical characteristics on temporal trends in the man-
pendent correlate of elevated uric acid level. Of note, agement of acute coronary syndromes. The Global Registry of Acute
impaired renal function is known to be a powerful indepen- Coronary Events (GRACE). Eur Heart J 2003;24:1414 –1424.
dent predictor of short- and long-term mortality in patients 3. Kolansky DM. Acute coronary syndromes: morbidity, mortality, and
pharmacoeconomic burden. Am J Manag Care 2009;15(suppl):S36 –S41.
with ACS treated with PCI.21 Thus, the prognostic power of 4. de Araújo Gonçalves P, Ferreira J, Aguiar C, Seabra-Gomes R. TIMI,
uric acid may be conveyed by cardiovascular risk accumu- PURSUIT, and GRACE risk scores: sustained prognostic value and
lated in patients with increased levels of this biomarker. interaction with revascularization in NSTE-ACS. Eur Heart J 2005;
However, the preservation of an independent association 26:865– 872.
between uric acid and mortality after adjustment for cardio- 5. Mohamed FA. On Bright’s disease, and its essential symptoms. Lancet
1879;1:399 – 401.
vascular risk and other relevant clinical variables shows that 6. Haig A. On uric acid and arterial tension. BMJ 1889;1:288 –291.
uric acid offers prognostic information beyond that medi- 7. Culleton BF, Larson MG, Kannel WB, Levy D. Serum uric acid and
ated by risk factors that are clustered in patients with ele- risk for cardiovascular disease and death: the Framingham Heart
vated uric acid levels. Moreover, the inclusion of uric acid Study. Ann Intern Med 1999;131:7–13.
8. Fang J, Alderman MH. Serum uric acid and cardiovascular mortality
in the multivariate model alongside the other variables sig- the NHANES I epidemiologic follow-up study 1971-1992. JAMA
nificantly improved the predictive power of the model re- 2000;283:2404 –2410.
garding mortality, suggesting that uric acid per se may 9. Anker SD, Doehner W, Rauchhaus M, Sharma R, Francis D, Knosalla
contribute to increased cardiovascular risk. A large body of C, Davos CH, Cicoira M, Shamim W, Kemp M, Segal R, Osterziel KJ,
evidence links uric acid with the promotion of atheroscle- Leyva F, Hetzer R, Ponikowski P, Coats AJ. Uric acid and survival in
chronic heart failure: validation and application in metabolic, func-
rosis and vascular adverse events. It has been shown that tional, and hemodynamic staging. Circulation 2003;107:1991–1997.
increased levels of uric acid may be a marker of increased 10. Franse LV, Pahor M, Di Bari M, Shorr RI, Wan JY, Somes GW,
xanthine oxidase activity, which is a major source of oxygen Applegate WB. Serumuric acid, diuretic treatment and risk of cardio-
free radicals.22,23 Thus, elevated uric acid level may be a vascular events in the Systolic Hypertension in the Elderly Program
(SHEP). J Hypertens 2000;18:1149 –1154.
marker of increased oxidative stress. Furthermore, it has 11. Lehto S, Niskanen L, Rönnemaa T, Laakso M. Serum uric acid is a
been reported that uric acid is linked with insulin resis- strong predictor of stroke in patients with non-insulin-dependent dia-
tance,24 increased lipid peroxidation,25 and increased plate- betes mellitus. Stroke 1998;29:635– 639.
let adhesiveness and activation.26 The association of uric 12. Bickel C, Rupprecht HJ, Blankenberg S, Rippin G, Hafner G, Daun-
acid with proinflammatory states27 or even a direct inflam- hauer A, Hofmann KP, Meyer J. Serum uric acid as an independent
predictor of mortality in patients with angiographically proven coro-
matory role through the induction of cytokine secretion28 nary artery disease. Am J Cardiol 2002;89:12–17.
has also been reported. Studies have also shown that ele- 13. Kojima S, Sakamoto T, Ishihara M, Kimura K, Miyazaki S, Yamagishi
vated uric acid levels cause endothelial dysfunction, leading M, Tei C, Hiraoka H, Sonoda M, Tsuchihashi K, Shimoyama N,
to reduced nitric oxide levels,29,30 known to have a pivotal Honda T, Ogata Y, Matsui K, Ogawa H; Japanese Acute Coronary
Syndrome Study (JACSS) Investigators. Prognostic usefulness of se-
role in the promotion of atherosclerosis and the genesis of rum uric acid after acute myocardial infarction (the Japanese Acute
acute vascular events. Nevertheless, in the present study, we Coronary Syndrome Study). Am J Cardiol 2005;96:489 – 495.
did not find any significant association between the occur- 14. Lazzeri C, Valente S, Chiostri M, Sori A, Bernardo P, Gensini GF.
rence of nonfatal myocardial infarction, stroke, or the need Uric acid in the acute phase of ST elevation myocardial infarction
for repeat revascularization after PCI and uric acid level. It submitted to primary PCI: its prognostic role and relation with inflam-
matory markers: a single center experience. Int J Cardiol 2010;138:
may be hypothesized that myocardial infarctions occurring 206 –209.
in the setting of hyperuricemia may be more often fatal, and 15. Lazzeri C, Valente S, Chiostri M, Picariello C, Gensini GF. Uric acid
thus they are accounted as deaths. in the early risk stratification of ST-elevation myocardial infarction.
An interesting finding of the present study was the un- Intern Emerg Med. In press.
16. Kowalczyk J, Francuz P, Swoboda R, Lenarczyk R, Sredniawa B,
equal distribution of mortality in different uric acid quar- Golda A, Kurek T, Mazurek M, Podolecki T, Polonski L, Kalarus Z.
tiles, with a significant steep increase in mortality in patients Prognostic significance of hyperuricemia in patients with different
in quartile 4 (⬎7.5 mg/dl) compared to the lower 3 quar- types of renal dysfunction and acute myocardial infarction treated with
tiles, suggesting a threshold effect. Kojima et al13 also percutaneous coronary intervention. Nephron Clin Pract 2010;116:
reported that the best cut-off of uric acid level regarding c114 – c122.
17. Hamm CW, Braunwald E. A classification of unstable angina revis-
mortality prediction in patients with acute myocardial in- ited. Circulation 2000;102:118 –122.
farction was 447 ␮mol/L, which closely coincides with the 18. Cockcroft DW, Gault MH. Prediction of creatinine clearance from
fourth quartile cutoff (7.5 mg/dl) in the present study. serum creatinine. Nephron 1976;16:31– 41.
The present study had some limitations. Although the 19. Ndrepepa G, Braun S, Iijima R, Keta D, Byrne RA, Schulz S, Mehilli
J, Schömig A, Kastrati A. Total leucocyte count, but not C-reactive
patients were prospectively collected, the analysis in es- protein, predicts 1-year mortality in patients with acute coronary syn-
sence is retrospective. Because of the very limited number dromes treated with percutaneous coronary intervention. Clin Sci
of patients receiving allopurinol therapy, the impact of this (Lond) 2009;116:651– 658.
drug on prognosis could not be assessed. Although 1-year 20. Pencina MJ, D’Agostino RB Sr, D’Agostino RB Jr, Vasan RS. Evaluating
follow-up is typical for interventional studies, a longer fol- the added predictive ability of a new marker: from area under the ROC
curve to reclassification and beyond. Stat Med 2008;27:157–172.
low-up period would have been desirable. 21. Seyfarth M, Kastrati A, Mann JF, Ndrepepa G, Byrne RA, Schulz S,
Mehilli J, Schömig A. Prognostic value of kidney function in patients
1. Fox KA, Cokkinos DV, Deckers J, Keil U, Maggioni A, Steg G. The with ST-elevation and non-ST-elevation acute myocardial infarction
ENACT study: a pan-European survey of acute coronary syndromes. treated with percutaneous coronary intervention. Am J Kidney Dis
Eur Heart J 2000;21:1440 –1449. 2009;54:830 – 839.
 Coronary Artery Disease/Uric Acid in Acute Coronary Syndromes 1265

22. Landmesser U, Spiekermann S, Dikalov S, Tatge H, Wilke R, Kohler potential mechanisms for free radical generation. Am J Cardiol
C, Harrison DG, Hornig B, Drexler H. Vascular oxidative stress and 1991;68:392–395.
endothelial dysfunction in patients with chronic heart failure: role of 26. Alderman M, Aiyer KJ. Uric acid: role in cardiovascular disease and
xanthine-oxidase and extracellular superoxide dismutase. Circulation effects of losartan. Curr Med Res Opin 2004;20:369 –379.
2002;106:3073–3078. 27. Ruggiero C, Cherubini A, Ble A, Bos AJ, Maggio M, Dixit VD,
23. Ogino K, Kato M, Furuse Y, Kinugasa Y, Ishida K, Osaki S, Kinu- Lauretani F, Bandinelli S, Senin U, Ferrucci L. Uric acid and inflam-
gawa T, Igawa O, Hisatome I, Shigemasa C, Anker SD, Doehner W. matory markers. Eur Heart J 2006;27:1174 –1181.
Uric acid-lowering treatment with benzbromarone in patients with 28. Sánchez-Lozada LG, Nakagawa T, Kang DH, Feig DI, Franco M,
heart failure: a double-blind placebo-controlled crossover preliminary Johnson RJ, Herrera-Acosta J. Hormonal and cytokine effects of uric
study. Circ Heart Fail 2010;3:73– 81. acid. Curr Opin Nephrol Hypertens 2006;15:30 –33.
24. Baldwin W, McRae S, Marek G, Wymer D, Pannu V, Baylis C, 29. Khosla UM, Zharikov S, Finch JL, Nakagawa T, Roncal C, Mu W,
Johnson RJ, Sautin YY. Hyperuricemia as a mediator of the pro- Krotova K, Block ER, Prabhakar S, Johnson RJ. Hyperuricemia
inflammatory endocrine imbalance in the adipose tissue in a murine induces endothelial dysfunction. Kidney Int 2005;67:1739 –1742.
model of the metabolic syndrome. Diabetes 2011;60:1258 –1269. 30. Sánchez-Lozada LG, Tapia E, López-Molina R, Nepomuceno T, Soto V,
25. De Scheerder IK, van de Kraay AM, Lamers JM, Koster JF, de Jong Avila-Casado C, Nakagawa T, Johnson RJ, Herrera-Acosta J, Franco M.
JW, Serruys PW. Myocardial malondialdehyde and uric acid release Effects of acute and chronic L-arginine treatment in experimental hyperuri-
after short-lasting coronary occlusions during coronary angioplasty: cemia. Am J Physiol Renal Physiol 2007;292:F1238–F1244.