Atherosclerosis 297 (2020) 40–46

Contents lists available at ScienceDirect

Atherosclerosis
journal homepage: www.elsevier.com/locate/atherosclerosis

Association of variability in uric acid and future clinical outcomes of patient T

with coronary artery disease undergoing percutaneous coronary
intervention
Su Shen Lima,e, Ya-Ling Yanga,d,e, Su-Chan Chena,d,e, Cheng-Hsueh Wua,b,e,
Shao-Sung Huanga,b,d,e, Wan Leong Chana,c,d, Shing-Jong Lina,b,d,e, Jaw-Wen Chena,b,c,d,e,
Chia-Yu Choua, Ju-Pin Pana,d,e, Min-Ji Charnga,d,e, Ying-Hwa Chena,d,e, Tao-Cheng Wua,d,e,
Tse-Min Lua,d,e, Pai-Feng Hsua,d,e, Po-Hsun Huanga,d,e, Hao-Min Chenga,c,d,e,
Chin-Chou Huanga,c,d,e, Shih-Hsien Sunga,d,e, Yenn-Jiang Lina,d,e, Hsin-Bang Leua,b,d,e,∗
a
Division of Cardiology, Department of Medicine, Taiwan
b
Healthcare and Management Center, Taiwan
c
Department of Medical Education, Taipei Veterans General Hospital, Taipei, Taiwan
d
Faculty of Medicine, Taiwan
e
Institute of Clinical Medicine and Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan

HIGHLIGHTS

• High uric acid (UA) variability is associated with increased risk of developing future adverse outcome in coronary artery disease (CAD) patients after percu-
taneous coronary intervention (PCI).
• Both higher UA variability and average UA value were significantly associated with a higher CV event occurrence.
• High UA variability had greater impact than high average UA value in patients with CAD.

ARTICLE INFO ABSTRACT

Keywords: Background and aims: Hyperuricemia is independently associated with cardiovascular disease (CVD) and is
Inter-visit uric acid variability considered to be one of the major risk factors for CVD. However, the impact of inter-visit uric acid (UA)
Coronary artery disease variability on cardiovascular risk remains undetermined.
Major adverse cardiovascular events Methods: We enrolled 3202 patients with coronary artery disease (CAD), who received successful coronary in-
Hyperuricemia
tervention, in a cohort from Taipei Veterans General Hospital from 2006 to 2015. All post-baseline visits UA
Mortality
measurements using standard deviation (SD) were analyzed to correlate with long-term outcome. The primary
outcome was the composite of cardiac death, nonfatal MI, nonfatal stroke (MACE). The secondary event was
MACE and hospitalization for heart failure.
Results: During an average 65.06 ± 32.1-month follow-up, there were 66 cardiovascular deaths, 175 nonfatal
myocardial infarctions, 64 nonfatal strokes, 287 hospitalizations for heart failure, and 683 revascularization
procedures. There was a linear association between high UA SD and future adverse events. Compared to the
lowest quartile SD, subjects in the highest quartile SD had a higher risk of MACE (HR: 2.53, 95% CI: 1.78–3.59),
myocardial infarction (HR: 2.43, 95% CI: 1.53–3.86), cardiovascular death (HR: 6.45, 95% CI: 2.52–16.55),
heart failure-related hospitalization (HR: 3.43, 95% CI: 2.32–5.05), and total major CV events (HR: 2.72, 95% CI:
2.09–3.56). Furthermore, compared to the average achieved on-treatment UA value, increasing UA SD had a
stronger association of higher risk of developing MACE (HR: 1.51, 95% CI: 1.36–1.68), myocardial infarction
(HR: 1.37, 95% CI: 1.38–1.68), ischemic stroke (HR: 1.43, 95% CI: 1.13–1.82), CV death (HR: 1.77, 95% CI:
1.50–2.11), HF (HR: 1.43, 95% CI: 1.29–1.58), and total major CV events (HR: 1.46, 95% CI: 1.34–1.58).
Conclusions: High UA variability is associated with a higher risk of developing future cardiovascular events,

∗
Corresponding author. Healthcare and Management Center, Division of Cardiology, Taipei Veterans General Hospital, No. 201, Section 2, Shih-Pai Road, Taipei,
Taiwan.
E-mail address: hsinbangleu@gmail.com (H.-B. Leu).

https://doi.org/10.1016/j.atherosclerosis.2020.01.025
Received 23 August 2019; Received in revised form 9 January 2020; Accepted 29 January 2020
Available online 30 January 2020
0021-9150/ © 2020 Elsevier B.V. All rights reserved.
S.S. Lim, et al.
suggesting the importance of maintaining stable serum UA levels and avoiding large fluctuations in CAD patients
after percutaneous coronary intervention (PCI).
1. Introduction
Cardiovascular disease (CVD) is one of the leading causes of mor-
tality worldwide, accounting for approximately 31% of all deaths [1].
Atherosclerosis is no longer seen as cholesterol simply accumulating
within blood vessels but as a sustained, dynamic, and inflammatory
process affecting the vasculature [2,3]. Therefore, the identification of
patients at high risk for developing future complications is important
toward ensuring optimal patient outcome, especially after coronary
intervention.
Uric acid (UA) is the final breakdown product of purine metabolism.
The degradation of purine nucleotides is regulated by the xanthine-
oxidoreductase enzyme, which converts hypoxanthine to xanthine and
xanthine to UA [4]. Accumulation of UA is well known to cause
monosodium urate (MSU) crystal deposition in the joints and kidneys,
leading to the development of gout and kidney stones [5]. Moreover,
experimental and epidemiological studies suggest that elevated levels of
UA are associated with developing hypertension, obesity, insulin re-
sistance, dyslipidemia, diabetes mellitus, kidney disease, cardiovascular
and cerebrovascular events [6]. These findings are indicative of a po-
tentially critical connection between UA and CVD.
Recently, clinical observations have demonstrated that increased
variability in cardiovascular parameters including blood pressure, body
mass index (BMI), glucose and cholesterol levels, are associated with an
increased risk of future cardiovascular events [7–9]. While fluctuations
in serum UA (SUA) are known to prolong the inflammatory process of a
gout attack [10], the impact of UA variability on cardiovascular risk
remains undermined. Furthermore, whether SUA variability or overall
level has more prognostic relevance in terms of CVD remains unclear.
Therefore, the present study aimed to explore the association between
SUA variability and nonfatal myocardial infarction, ischemic stroke,
cardiovascular death, and hospitalization due to congestive heart
failure in patients with CAD after PCI.
2. Materials and methods
2.1. Study population
This retrospective, single-center observation study included parti-
cipants with symptomatic CAD who received coronary intervention
between July 2006 and December 2015 at the Taipei Veteran General
Hospital, Taiwan. Diagnosis for CAD included positive results to stress
test, history of angina with ischemic change on ECG recording, myo-
cardial infarction attack, or angina symptom with significant stenosis
lesion in coronary computed tomography angiography (CCTA).
Symptomatic patients who received percutaneous coronary interven-
tion (PCI) either with coronary stenting or balloon angioplasty were
eligible for enrollment.
All procedures were conducted in accordance with the Declaration
of Helsinki and were approved by the Ethics Committee and
Independent Review Board of the Taipei Veterans General Hospital.
2.2. Baseline characteristics and biochemical data
After enrollment, coronary intervention procedures and treatment
strategies were recorded. Baseline characteristics were collected from
every patient including sex, age, history of hypertension, diabetes,
hyperlipidemia, smoking, family history of premature CAD, and cere-
bral vascular disease. Furthermore, biochemical data describing renal
function, lipid profiles, UA levels, and medications were also collected.
41
Atherosclerosis 297 (2020) 40–46
To evaluate the inter-visit variability of these markers, they were de-
termined at baseline and upon every outpatient visit during the follow-
up period.
2.3. UA variability measurement
Every post-baseline visit SUA measurement was included for ana-
lysis. Variability was assessed every three months at the outpatient
clinic. Inter-visit variability was defined as the standard deviation (SD)
of the UA values between visits. For the primary analysis, we used the
intra-individual SD of uric acid across visits as our variability of uric
acid. For patients with missing UA values, the available values from
other time points were used to calculate variability. The number of
measurements per participant ranged as follows: 3 measurements
(n = 1378 or 43%), 4 measurement (n = 346 or 11%) and more than 5
measurements (n = 1478 or 46%). Similar variability measurements
for other biochemical markers using SD as the primary means of re-
presenting variability (e.g., lipoprotein variability and blood pressure
variability measurements) have also been used in other studies [11].
2.4. Clinical follow-up and endpoints
All participants were followed-up every three months after enroll-
ment. The primary outcome was MACE, a composite of cardiovascular
death, nonfatal myocardial infarction, or nonfatal stroke. The key sec-
ondary outcome was a composite of the primary outcome plus hospi-
talization for congestive heart failure (total major CV events).
Myocardial infarction was confirmed in patients presenting with is-
chemic symptoms with elevated serum cardiac enzyme levels and/or
characteristic ECG changes. Ischemic stroke was confirmed as an ob-
struction within a blood vessel supplying blood to the brain with ima-
ging evidence by either MRI or CT scan and new neurological deficit
lasting for at least 24 h. The protocol for CV event follow-up was per-
formed as previously described [12,13].
2.5. Statistical analyses
The baseline characteristics of patients were compared according to
quartiles of baseline UA variability (SD). Quantitative variables were
expressed as a mean and standard deviation in the presence of normal
or median distribution and interquartile range in the presence of
asymmetric distribution. Qualitative variables were presented in both
absolute frequencies (number of patients) and relative frequencies
(percentage). Comparisons of continuous variables between groups
were achieved using an ANOVA test, while subgroup comparisons of
categorical variables were assessed by χ2 or Fisher's exact test. The
primary and secondary outcomes were described by an overall per-
centage and expressed by means of proportions with a 95% confidence
interval (CI). The event-free survival rate was calculated using the
Kaplan–Meier (KM) method, with significance evaluation using log-
rank tests. For the primary analysis, an unstratified log-rank test was
used to compare overall survival between the quartiles of UA varia-
bility. Multiple regression analysis was carried out using a Cox pro-
portional hazard regression analysis adjusted for age, sex, BMI, history
of hypertension, diabetes, medications including statins, and serum
levels of LDL and HDL to evaluate whether UA variability was an in-
dependent factor in determining the occurrence of primary and sec-
ondary endpoints including cardiac death, nonfatal MI, nonfatal stroke,
hospitalization for heart failure and revascularization procedures.
Subsequent subgroup analysis was performed to investigate the effects
S.S. Lim, et al. Atherosclerosis 297 (2020) 40–46

of UA variability on other risk factors for cardiovascular events, such as
age, sex, history of diabetes mellitus, hypertension, and baseline levels
of LDL and HDL. Statistical significance was inferred at a two-sided p-
value < 0.05. To assess the predictive accuracy of the UA SD for car-
diovascular outcome, we used a receiver operating characteristic (ROC)
curve for censored data and the area under the ROC curve (AUC) as the
criterion. An AUC of 0.5 indicates no predictive ability, whereas a value
of 1 represents perfect predictive ability. The statistical significance of
the difference between 2 ROC curves was evaluated with the method of
DeLong et al. [14] Data were analyzed using SPSS software (version 20,
SPSS, Chicago, IL). A p value of < 0.05 was considered to indicate
statistical significance.
3. Results
3.1. Baseline characteristics
A total of 3202 patients with CAD who underwent successful cor-
onary intervention were enrolled in this study. The baseline char-
acteristics of the participants according to quartiles of UA variability
are presented in Table 1. Mean patients’ age was 68.8 ± 12.5 years, of
which 83.1% were male, 39.2% had diabetes mellitus, mean BMI was
25.39 kg/m2, and mean UA value was 6.52 ± 1.89 mg/dl. The SD of
quartiles of UA were 0.31 ± 0.14 (Q1), 0.67 ± 0.10 (Q2),
1.12 ± 0.18 (Q3), and 2.35 ± 0.83 (Q4). Subjects in the higher
quartiles of UA variability tended to be older, have higher systolic blood
pressure (SBP), higher baseline UA, worse renal function, unfavorable
lipid profiles, higher smoking rates, more underlying comorbidities
including diabetes mellitus, chronic kidney disease, and peripheral ar-
terial occlusion disease (p for trend < 0.05).
3.2. Major cardiovascular events during follow-up
Clinical follow-up was carried out with all patients for a mean
period of 65.6 ± 32.1 months. During this time, there was 66 cardi-
ovascular deaths, 175 cardiac nonfatal myocardial infarctions, 64
nonfatal strokes, 287 hospitalizations for heart failure, and 683 re-
vascularization procedures. Supplementary Table 1 shows the baseline
and follow-up values for UA and lipid profiles. There were significant
improvements in the lipid profiles (p < 0.001) in the study population
but the UA values remained the same during the follow-up period.
Supplementary Fig. 1 shows the incidence of an observed event ac-
cording to UA variability and illustrates the increased incidence of
adverse events with high variability in UA level (p for trend < 0.05).

Table 1
Baseline characteristics of subjects at baseline and according to the uric acid variability.
All subjects (n = 3202) Q1 (n = 800) Q2 (n = 796) Q3 (n = 803) Q4 (n = 803) p-value

Uric acid variability, mg/dL 1.12 ± 0.89 0.31 ± 0.14 0.67 ± 0.10 1.12 ± 0.18 2.35 ± 0.83 < 0.001
Age, years 68.76 ± 12.49 66.95 ± 12.41 67.03 ± 12.89 69.54 ± 12.48 71.48 ± 11.61 < 0.001
Gender, male, n (%) 2660 (83.1) 663 (82.9) 687 (86.3) 648 (80.7) 662 (82.4) 0.025
Body mass index, kg/m2 25.39 ± 3.66 25.28 ± 3.42 25.33 ± 3.51 25.41 ± 3.84 25.53 ± 3.89 0.731
Systolic blood pressure, mmHg 128.03 ± 18.17 127.04 ± 17.47 125.84 ± 16.45 129.13 ± 19.41 130.15 ± 18.94 < 0.001
Diastolic blood pressure, mmHg 71.75 ± 11.00 72.47 ± 10.18 71.68 ± 10.59 71.81 ± 11.50 71.04 ± 11.65 0.090
Uric acid, mg/dL 6.52 ± 1.89 6.09 ± 1.50 6.30 ± 1.53 6.49 ± 1.81 7.20 ± 2.39 < 0.001
Total cholesterol, mg/dL 172.76 ± 40.67 175.49 ± 38.25 174.37 ± 42.47 170.40 ± 39.35 170.80 ± 42.29 0.026
Triglyceride, mg/dL 139.34 ± 87.87 131.39 ± 79.17 134.86 ± 82.42 144.93 ± 92.60 146.16 ± 95.45 0.001
HDL-C, mg/dL 42.90 ± 11.89 43.69 ± 11.54 43.16 ± 11.15 43.24 ± 12.72 41.54 ± 11.98 0.002
LDL-C, mg/dL 106.42 ± 34.41 108.66 ± 33.19 109.09 ± 36.17 103.63 ± 33.19 104.35 ± 34.71 0.001
Glucose, mg/dL 121.60 ± 41.54 119.16 ± 38.40 120.87 ± 42.42 122.78 ± 41.52 123.42 ± 43.49 0.265
eGFR, mL/min/1.73m2 63.36 ± 26.03 70.96 ± 23.33 70.32 ± 25.66 59.80 ± 25.56 52.45 ± 24.85 < 0.001
Chronic disease
Stroke, n (%) 182 (5.7) 42 (5.3) 39 (4.9) 53 (6.6) 48 (6) 0.461
Hypertension, n (%) 2849 (89) 710 (88.8) 701 (88.1) 729 (90.8) 709 (88.3) 0.287
Diabetes mellitus, n (%) 1254 (39.2) 268 (33.5) 269 (33.8) 346 (43.1) 371 (46.2) < .001
PAOD, n (%) 147 (4.6) 26 (3.3) 25 (3.1) 36 (4.5) 60 (7.5) < 0.001
Hyperlipidemia, n (%) 1498 (46.8) 386 (48.3) 404 (50.8) 372 (46.3) 336 (41.8) 0.003
ACS, n (%) 1111 (34.7) 228 (28.5) 270 (33.9) 270 (33.6) 343 (42.7) < 0.001
Medications
ACEI, n (%) 665 (20.8) 179 (22.4) 173 (21.7) 158 (19.7) 155 (19.3) 0.343
ARB, n (%) 1257 (39.3) 291 (36.4) 307 (38.6) 329 (41) 330 (41.1) 0.166
Beta blocker, n (%) 1528 (47.7) 388 (48.5) 397 (49.9) 380 (47.3) 363 (45.2) 0.288
CCB, n (%) 1178 (36.8) 275 (34.4) 268 (33.7) 330 (41.1) 305 (38) 0.007
Statins, n (%) 1890 (59) 508 (63.5) 514 (64.6) 454 (56.5) 414 (51.6) < 0.001
Diuretics, n (%) 363 (11.3) 73 (9.1) 66 (8.3) 102 (12.7) 122 (15.2) < 0.001
Urate lowering agent, n (%) 300 (9.4) 36 (4.5) 56 (7) 73 (9.1) 135 (16.8) < 0.001
CAD
SVD, n (%) 934 (29.2) 256 (32) 266 (33.4) 229 (28.5) 183 (22.8) < 0.001
DVD, n (%) 1035 (32.3) 260 (32.5) 246 (30.9) 270 (33.6) 259 (32.3)
TVD, n (%) 1232 (38.5) 283 (35.4) 284 (35.7) 304 (37.9) 361 (45)
Stents
DES stents, n 1.88 ± 1.10 1.85 ± 1.07 1.88 ± 1.14 1.83 ± 1.01 1.94 ± 1.19 0.559
DES stents size, mm 3.01 ± 0.36 3.04 ± 0.37 3.00 ± 0.34 3.01 ± 0.35 3.00 ± 0.36 0.323
DES stents length, mm 24.15 ± 5.89 23.91 ± 5.78 24.16 ± 6.17 24.36 ± 5.79 24.23 ± 5.83 0.697
BMS stents, n 1.48 ± 0.74 1.42 ± 0.71 1.50 ± 0.71 1.52 ± 0.80 1.49 ± 0.72 0.447
BMS stents size, mm 3.17 ± 0.54 3.14 ± 0.53 3.20 ± 0.55 3.20 ± 0.56 3.16 ± 0.51 0.461
BMS stents length, mm 21.64 ± 6.60 20.96 ± 6.35 21.58 ± 6.96 21.87 ± 6.28 22.03 ± 6.77 0.283

Data are expressed as mean ± SD, or n (%).

HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; eGFR, estimated glomerular filtration rate; PAOD, peripheral artery oc-
clusive disease; ACS, acute coronary syndrome; ACEI, angiotensin-converting-enzyme inhibitor; ARB, angiotensin II receptor blocker; CCB, calcium channel blocker;
SD, standard deviation, SVD, single vessel disease; DVD, double vessel disease; TVD, triple vessel disease; DES, drug-eluting stent; BMS, bare metal stent.

42
S.S. Lim, et al.
Fig. 1. Kaplan–Meier estimates of cumulative survival by quartiles of UASD in future risk of (A) AMI, (B) MACE, (C) CV death, (D) CHF, (E) ischemic stroke and (F)
total CV event.
Adjusted for age, gender, hypertension, diabetes mellitus and HMG-CoA reductase inhibitors.
The incidence of future events including cardiovascular death, nonfatal
MI, nonfatal stroke, major adverse cardiovascular event (MACE, com-
bined of CV death, MI and ischemic stroke), CHF and total events in-
creased in subjects with increasing UA variability. Fig. 1 shows the
Kaplan–Meier curves assessing the occurrence of future adverse events
according to quartiles of UA SD. There were significant stepwise re-
lationships between increasing quartiles of UA SD and cumulative
events including myocardial infarctions, cardiovascular deaths, heart
failure hospitalizations, MACEs, ischemic stroke and total major CV
events (log-rank p < 0.01).
3.3. Risk of major cardiovascular events according to quartile of UA
variability
Table 2 shows the risk of future events including nonfatal MI,
nonfatal stroke, cardiovascular death, heart failure, and total major CV
event according to the quartiles of UA variability after adjustment for
age, sex, hypertension, diabetes, BMI, renal function, statin and diure-
tics use. Compared to the lower variability (reference group), patients
with high variability (Q4) had a significantly higher risk of MACE (HR:
2.53, 95% CI: 1.78–3.59), myocardial infarction (HR: 2.43, 95% CI:
1.53–3.86), cardiovascular death (HR: 6.45, 95% CI: 2.52–16.55), heart
failure-related hospitalization (HR: 3.43, 95% CI: 2.32–5.05), and total
major CV events (HR: 2.72, 95% CI: 2.09–3.56) (Table 2 and
Supplementary Fig. 2). Supplementary Fig. 3 shows the subgroup
analysis of the association of future risk of increasing UA SD quartile
among the different sexes, ages, BMIs, histories of DM, HTNs, lipid
profile, renal function, ejection function (EF) and whether enrollment
from ACS. Higher UA variability (SD) was independently associated
with higher risk of developing adverse event, especially among these
with lower EF and ACS.
43
Atherosclerosis 297 (2020) 40–46
3.4. Comparing the strength of association of inter-visit UA variability to
overall average UA value
The results of this study indicate that higher UA SD is associated
with an increased risk of adverse future events. Next, we wanted to
know whether UA SD or UA average on treatment contributes more to
future CV risk. Fig. 2 depicts the relationship between CV risk and UA
SD or UA average. UA SD significantly associated with an increased risk
of experiencing MACE (HR: 1.51, 95% CI: 1.36–1.68), myocardial in-
farction (HR: 1.37, 95% CI: 1.38–1.59), ischemic stroke (HR: 1.43, 95%
CI: 1.13–1.82), CV death (HR: 1.77, 95% CI: 1.50–2.11), HF (HR: 1.43,
95% CI: 1.29–1.58) and total major CV events (HR: 1.46, 95% CI:
1.34–1.58). However, average UA value was not associated with is-
chemic stroke and CV death.
3.5. Improvement in predictive performance
To evaluate improvement in predictive performance of considering
UA average and UA SD, the AUCs of UA and UA SD were assessed by
ROC curve over the follow-up duration. Fig. 3 showed the ROC curves
of UA SD and UA average related to CV outcomes. The AUC by adding
UA SD to UA average was significantly increased for predicting MACE
(0.616 vs. 0.535, p = 0.001), AMI (0.579 vs. 0.550, p = 0.049), is-
chemic stroke (0.594 vs. 0.502, p = 0.037), CV death (0.707 vs. 0.539,
p = 0.003) CHF (0.666 vs. 0.635, p < 0.001), and total CV events
(0.636 vs. 0.583, p < 0.001).
4. Discussion
The present study is the first to demonstrate the association of inter-
visit UA variability and future cardiovascular outcome in patients with
S.S. Lim, et al. Atherosclerosis 297 (2020) 40–46

Table 2 baseline comorbidities and medication use. Furthermore, this study

Hazard ratios and 95% confidence intervals of MACE, myocardial infarction, showed that both higher UA SD and achieved average on-treatment UA
cardiovascular death, congestive heart failure, total cardiovascular events. value were significantly associated with a higher CV event occurrence.
Events (n) Follow-up Incidence rate (per Adjust HR UA SD had greater impact and improved predictive performance, sug-
duration (person- 1000 person years) (95% CI) gesting that maintaining low and consistent UA values in patients with
years) CAD associates with better clinical outcome.
High serum UA (SUA) levels are reported to strongly associate with
MACE
Q1 45 51,648 0.87 1 (ref) prevalent disorders including hypertension, diabetes, obesity, and renal
Q2 54 51,390 1.05 1.09 (0.73–1.62) disease [6,15–17]. Although the causal relationship between SUA va-
Q3 73 51,841 1.41 1.53 (1.05–2.22) lues and CV events has been long debated, population-based studies
Q4 114 51,841 2.20 2.53 (1.78–3.59)
have shown that hyperuricemia is an independent risk factor for CVD
p for trend < 0.001
Myocardial infarction
[18], a prospective cohort study of 90,393 subjects conducted in
Q1 26 52,048 0.50 1 (ref) Taiwan concluded high serum uric acid level is associated with all
Q2 41 51,788 0.79 1.45 (0.89–2.37) causes, total CVD, and ischemic stroke in the Taiwanese general po-
Q3 46 52,243 0.88 1.68 (1.04–2.73) pulation [19]. Recently, a Mendelian randomization (MR) study con-
Q4 62 52,243 1.19 2.43 (1.53–3.86)
ducted by Pan et al. suggested a possible causal relationship between
p for trend 0.001
Ischemic stroke UA and CVD in the Chinese population [20], emphasizing the im-
Q1 15 52,872 0.28 1 (ref) portance of avoiding high UA levels for risk reduction in patients with
Q2 8 52,608 0.15 0.45 (0.19–1.07) CAD. Although the biological mechanism is still not clear, investigation
Q3 17 53,070 0.32 1.06 (0.53–2.14)
studies have leaded to more understanding of UA metabolism and helps
Q4 24 53,070 0.45 1.61 (0.84–3.09)
p for trend 0.022
to elucidate the role of UA in the pathogenesis of CVD. UA can induce
Cardiovascular death oxidative stress by activating nicotinamide adenine dinucleotide
Q1 5 53,288 0.09 1 (ref) phosphate-oxidase (NADPH). Rats with hyperuricemia induced with an
Q2 9 53,022 0.17 1.71 (0.57–5.11) uricase inhibitor showed increased oxidative stress and developed hy-
Q3 16 53,488 0.30 2.90 (1.06–7.94)
pertension that could be blocked by antioxidant treatment [21,22]. In
Q4 36 53,488 0.67 6.45 (2.51–16.55)
p for trend < 0.001 addition, UA crystals can induce an inflammatory response by stimu-
Congestive heart failure lating the release of chemokines (e.g., monocyte chemoattractant pro-
Q1 33 51,056 0.65 1 (ref) tein-1, MCP-1), inflammatory markers (e.g., high-sensitivity C-reactive
Q2 44 50,801 0.87 1.23 (0.78–1.93) protein), and the activation of vasoconstrictive mediators (e.g.,
Q3 87 51,247 1.70 2.36 (1.58–3.53)
Q4 123 51,247 2.4 3.43 (2.32–5.05)
thromboxane, endothelin-1 and angiotensin II) [22,23]. Furthermore,
p for trend < 0.001 hyperuricemia is proven to cause endothelial dysfunction in humans by
Total cardiovascular event reducing NO bioavailability [24–26] and the use of UA-lowering agents
Q1 75 49,624 1.51 1 (ref) improves endothelial function [27,28]. Moreover, UA may also stimu-
Q2 92 49,376 1.86 1.13 (0.83–1.53)
late the renin-angiotensin system (RAS), thus further contributing to
Q3 141 49,810 2.83 1.76 (1.33–2.34)
Q4 205 49,810 4.11 2.72 (2.09–3.56) vascular smooth cell growth, arterial functional impairment, and stif-
p for trend < 0.001 fening [29,30].
Patients with higher UA variability had higher percentage users of
Adjusted for age, gender, hypertension, diabetes mellitus, renal function, diuretics, urate lowering agents, worse eGFR and more comorbidities,
diuretics and HMG-CoA reductase inhibitors. MACE, major adverse cardiovas- suggesting a group at risk. After considering comorbidities and medi-
cular events.
cation including chronic kidney disease, urate lowering agents and
diuretics use, higher UA variability was still independently associated
CAD after coronary intervention. High inter-visit UA variability, mea-
with future risk of developing myocardial infarction, ischemic stroke,
sured via higher SD of intra-individual SUA, was associated with a
cardiovascular mortality, HF hospitalization, and MACE. Furthermore,
graded increase in the risk of myocardial infarction, ischemic stroke,
this correlation is more prominent in patients with ACS and lower
cardiovascular mortality, HF hospitalization, and MACE independent of

Fig. 2. Hazard ratios and 95% confidence intervals of increasing UA SD and UA average on treatment to future risk of developing MACE, AMI, ischemic stroke, CV
death, CHF, and total CV event in CAD patients after PCI.

44
S.S. Lim, et al.
Fig. 3. ROC curves of UA SD and UA average to CV outcomes. (A) UA SD and UA average to MACE. (B) UA SD and UA average to total AMI. (C) UA SD and UA
average to ischemic stroke. (D) UA SD and UA average to CV death. (E) UA SD and UA average to CHF. (F) UA SD and UA average to total CV event.
LVEF. In the current study, ROC curve analysis demonstrated sub-
stantial increase in the prognostic prediction value when adding UA
variability to serum UA values, indicates that UA variability seems to
confer greater impact than overall average SUA value. Actually, the
reason why greater UA variability results in higher risk remains un-
determined, but clinical observation showed the fluctuations in UA
level may exacerbate the inflammatory process underlying gout [31],
suggesting that fluctuations in UA level may prolong inflammation.
Because SUA level has been related to oxidative stress, inflammation,
endothelial dysfunction, and the magnitude of activation of the RAS
system, UA fluctuation may antagonize these important issues and thus
contribute to disease progression. A surge of UA in the blood is known
to increase the crystallization rate of urate, which stimulates an im-
mune reaction and inflammatory response. This may indicate that a
large fluctuation in SUA level can be deleterious [32–34]. Additional
large-scale studies focusing on SUA level fluctuation are needed to
further elucidate these issues. A previous observational study focusing
on SUA and mortality in subjects without gout arthritis found a U-
shaped relationship between SUA and both all-cause and CV mortality,
indicating that individuals with SUA levels at either extreme are at
higher risk for deleterious events [35]. Recently, the Febuxostat for
Cerebral and CaRdiorenovascular Events PrEvEntion StuDy (FREED)
compared febuxostat and conventional therapy with lifestyle mod-
ification in subjects with hyperuricemia, showed febuxostat had lower
serum level of uric acid (4.50 ± 1.52 vs. 6.76 ± 1.45 mg/dL, p <
0.001) and lower risk of composite of cardiovascular events than
45
Atherosclerosis 297 (2020) 40–46
lifestyle medication [36]. In that study, lower and stable serum level of
uric acid was associated with lower risk of primary endpoints and it was
in accordance with our study finding of maintaining lower and con-
sistent serum level of uric acid is associated with lower future risk of
cardiovascular events. However, a controversial study was reported
recently. The Cardiovascular Safety of Febuxostat and Allopurinol in
Patients with Gout and Cardiovascular Morbidities (CARES) trial, which
included 6190 patients with gout and CVD, showed that patients who
received febuxostat had lower SUA levels but higher all-cause mortality
and cardiovascular mortality than those who received allopurinol [32].
The exact mechanism remains unknown and study with placebo group
is needed to elucidate whether the results of CARES study are due to
harmful effect of febuxostat or beneficial effects of allopurinol. Our
study demonstrated higher UA variability was associated with in-
creased higher future risk even considering medication and underlying
comorbidities. However, our study is an observation study, not clinical
trial designed for investigating the causality. Further research is re-
quired to uncover the causal mechanism underlying the association
between UA variability and CVD.
In conclusion, in patients with CAD receiving PCI, greater inter-visit
variability in SUA level is significantly associated with future adverse
cardiovascular outcomes, including cardiovascular mortality, MACE,
myocardial infarction, ischemic stroke, congestive heart failure, and
total cardiovascular events. This observation suggests the UA variability
is associated with increased risk and highlights the importance of
achieving stable SUA levels and avoiding large fluctuations.
S.S. Lim, et al.
Funding Information
Taiwan Association for integration of cardiology and surgery,
Grant/Award Number: TAICS-107-2-Y2.
CRediT authorship contribution statement
Su Shen Lim: Writing - original draft, Data curation, Formal ana-
lysis. Ya-Ling Yang: Data curation, Formal analysis. Su-Chan Chen:
Data curation, Formal analysis. Cheng-Hsueh Wu: Data curation,
Formal analysis. Shao-Sung Huang: Data curation, Formal analysis.
Wan Leong Chan: Data curation, Formal analysis. Shing-Jong Lin:
Data curation, Formal analysis. Jaw-Wen Chen: Data curation, Formal
analysis. Chia-Yu Chou: Funding acquisition. Ju-Pin Pan: Funding
acquisition. Min-Ji Charng: Data curation, Formal analysis. Ying-Hwa
Chen: Data curation, Formal analysis. Tao-Cheng Wu: Data curation,
Formal analysis. Tse-Min Lu: Data curation, Formal analysis. Pai-Feng
Hsu: Data curation, Formal analysis. Po-Hsun Huang: Data curation,
Formal analysis. Hao-Min Cheng: Data curation, Formal analysis.
Chin-Chou Huang: Methodology, Resources, Software. Shih-Hsien
Sung: Data curation, Formal analysis. Yenn-Jiang Lin: Supervision.
Hsin-Bang Leu: Conceptualization, Supervision, Writing - review &
editing, Data curation, Formal analysis.
Declaration of competing interest
The authors declared they do not have anything to disclose re-
garding conflict of interest with respect to this manuscript.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.atherosclerosis.2020.01.025.
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