Int J Cardiovasc Imaging (2015) 31:193–203
DOI 10.1007/s10554-014-0541-6
ORIGINAL PAPER
A prospective two-center study on the associations
between microalbuminuria, coronary atherosclerosis and long-
term clinical outcome in asymptomatic patients with type 2
diabetes mellitus: evaluation by coronary CT angiography
Jin-Jin Kim • Byung-Hee Hwang • Ik Jun Choi • Eun-Ho Choo • Sungmin Lim
Yoon-Seok Koh • Jong Min Lee • Pum-Joon Kim • Ki-Bae Seung •
Seung-Hwan Lee • Jae-Hyung Cho • Jung Im Jung • Kiyuk Chang
Received: 8 June 2014 / Accepted: 23 September 2014 / Published online: 4 October 2014
Ó Springer Science+Business Media Dordrecht 2014
Abstract This study assessed the associations between
microalbuminuria in asymptomatic patients with type 2
diabetes and the presence, extent, and severity of coronary
atherosclerosis, as measured by coronary computed
tomography angiography (CCTA), and the long-term
clinical outcomes. In total, the study enrolled 284 consec-
utive eligible asymptomatic patients with type 2 diabetes
and without known coronary artery disease (CAD), who
then underwent CCTA and 24 h urine albumin measure-
ments. Microalbuminuria was defined as 30–300 mg/day
urinary albumin excretion. Obstructive CAD, as measured
J.-J. Kim
I. J. Choi
E.-H. Choo
S. Lim
P.-J. Kim

K.-B. Seung
K. Chang (&)
Cardiovascular Center and Cardiology Division, Seoul St.
Mary’s Hospital, The Catholic University of Korea, Banpodong
505, Seochogu, Seoul 137-701, Republic of Korea
e-mail: kiyuk@catholic.ac.kr
B.-H. Hwang
Cardiovascular Center and Cardiology Division, St. Paul’s
Hospital, The Catholic University of Korea, Seoul, Republic of
Korea
Y.-S. Koh
J. M. Lee
Cardiovascular Center and Cardiology Division, Uijeongbu St
Mary’s Hospital, The Catholic University of Korea,
Uijeongbu, Republic of Korea
S.-H. Lee
J.-H. Cho
Division of Endocrinology, Department of Internal Medicine,
Seoul St. Mary’s Hospital, The Catholic University of Korea,
Seoul, Republic of Korea
J. I. Jung (&)
Department of Radiology, Seoul St. Mary’s Hospital, The
Catholic University of Korea, Banpodong 505, Seochogu,
Seoul 137-701, Republic of Korea
e-mail: jijung@catholic.ac.kr
•
by CCTA, was defined as maximum intra-luminal stenosis
C50 %. Patients with and without microalbuminuria were
compared in terms of obstructive CAD prevalence, and the
extent and severity of coronary atherosclerosis. They were
evaluated using the following data: coronary artery calcium
score (CACS), atheroma burden obstructive score (ABOS),
segment involvement score (SIS) and segment stenosis
score (SSS). All-cause mortality within a follow-up period
of 5 years was also compared. Compared to patients
without microalbuminuria, patients with microalbuminuria
were more likely to have obstructive CAD (p = 0.004).
Microalbuminuria was associated with higher ABOS
(p = 0.010), SIS (p = 0.029), and SSS (p = 0.011),
except for CACS (p = 0.058). Multivariable analyses
adjusted for conventional cardiovascular risk factors
revealed that microalbuminuria was an independent pre-
dictor of obstructive CAD [odds ratio 2.255, confidence
intervals (CI) 1.121–4.538, p = 0.023] and all-cause
mortality (hazard ratio 3.469, CI 1.319–9.121, p = 0.012).
In asymptomatic patients with type 2 diabetes, microal-
buminuria was associated with increased risk of CAD and
poorer clinical outcomes.
Keywords Microalbuminuria
Diabetes
Coronary CT
angiography
Introduction
Type 2 diabetes is associates with an increased risk of
coronary artery disease (CAD). Population-based studies
have shown that patients with type 2 diabetes have a 2- to
fourfold increase in the number of cardiovascular events
compared to subjects without type 2 diabetes [1, 2]. Vari-
ous risk factors of CAD have been identified. Of these,
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microalbuminuria is considered an independent predictor
of CAD and cardiovascular death not only in patients with
diabetes and/or hypertension, but also in healthy individ-
uals [3, 4].
Coronary computed tomography angiography (CCTA)
has emerged recently as a noninvasive imaging modality
for the detection or exclusion of CAD since it allows the
extent and severity of coronary atherosclerosis to be mea-
sured [5]. Two studies using CCTA found that asymp-
tomatic patients with type 2 diabetes had a higher
prevalence of coronary atherosclerosis than subjects with-
out diabetes [6, 7]. Moreover, recent multicenter studies
have shown that CCTA-detected coronary atherosclerosis
is highly useful for predicting mortality and other major
adverse cardiac events [8, 9].
In the pre-CCTA era, several studies investigated the
association between microalbuminuria and CAD prognosis
in patients with diabetes [10–12], but these outcome-based
analyses did not assess the prevalence, extent, and severity
of coronary atherosclerosis. The aim of the present study
was to evaluate the association between microalbuminuria
in asymptomatic patients with type 2 diabetes, as well as
the presence, extent, and severity of coronary atheroscle-
rosis, through CCTA measurement, and to assess the
associated long-term clinical outcome.
Methods
Study population
The CRONOS-ADM (CoROnary CT aNgiography evalu-
ation for clinical OutcomeS in Asymptomatic patients with
type 2 Diabetes Mellitus) registry is a large, prospective
observational registry of demographic, clinical, laboratory
and coronary CT angiographic data, with long-term clinical
outcome of asymptomatic patients with type 2 diabetes
without a history of CAD. Since the primary objective of
the CRONOS-ADM registry was to assess whether
screening for coronary atherosclerosis with the use of
CCTA would beneficially affect clinical outcome in
asymptomatic patients with type 2 diabetes, the registry
was composed of two separate populations: a CCTA group
versus a non-CCTA group.
Consecutive asymptomatic patients of more than
30 years of age with type 2 diabetes undergoing CCTA
were prospectively enrolled into a CCTA group from the
division of endocrinology and cardiology at two affiliated
hospitals of The Catholic University of Korea between
January 2006 and December 2010: Seoul St. Mary’s Hos-
pital, Seoul, Korea and St. Vincent’s Hospital, Suwon,
Korea. Within 3 months of enrollment, two age- and sex-
matched asymptomatic patients with type 2 diabetes were
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Int J Cardiovasc Imaging (2015) 31:193–203
simultaneously enrolled into a non-CCTA group. The
present study only analyzed the CCTA group to evaluate
the presence, extent, and severity of coronary atheroscle-
rosis according to the presence of microalbuminuria.
Patients were excluded if they had type 1 diabetes,
angina or angina-equivalent symptoms by the Rose ques-
tionnaire [13], or if already taking anti-angina medication,
history of myocardial infarction (MI), coronary revascu-
larization (either by percutaneous coronary intervention or
bypass), cardiac transplantation, absence of stable sinus
rhythm during investigation, life-threatening conditions, or
contraindications for the use of iodinated contrast media.
Patients with estimated glomerular filtration rate (eGFR)
\30 mL/min/1.73 m2 were also excluded.
There was no industry involvement in the design, con-
duct or analysis of the study. This prospective observa-
tional study was approved by the institutional review board
of our institution and performed in accordance with
strengthening the reporting of observational studies in
epidemiology guidelines [14]. All patients provided written
informed consent.
Before the CCTA examination, the patients underwent a
structured interview with a physician or allied health pro-
fessional to ascertain the demographic and clinical data,
and to obtain additional anthropometric data, including the
height, weight, and waist-to-hip ratio. Patients underwent
blood and urine laboratory testing. The blood samples were
collected in the morning after an overnight fast to measure
the serum hemoglobin A1C, fasting plasma glucose, and
lipid profiles. All laboratory tests were performed using
standard methods.
Type 2 diabetes mellitus was diagnosed by using the
2010 criteria of the American Diabetes Association,
namely, fasting glucose C126 mg/dl, glycated hemoglobin
(HbA1C) C6.5 % or C48 mmol/mol, and/or post-chal-
lenge glucose (glucose at 2 h after a 75 g oral glucose load)
C200 mg/dl [15]. Patients with a self-reported or docu-
mented history of type 2 diabetes, or treatment with oral
antidiabetics or insulin were also considered to be diabetic.
Diabetes onset was defined as the point in time when the
attending physicians made the diagnosis. The information
on diabetes onset in patients with known type 2 diabetes
was obtained through self-report. If it was not possible to
determine when a patient was diagnosed by interviewing
the patient, their medical records were examined. The
duration of diabetes was calculated as the difference
between the current age of the patient and the age at dia-
betes onset.
Systemic arterial hypertension was diagnosed if the
systolic and/or diastolic blood pressure exceeded 140 and/
or 90 mmHg, or if there was a history of hypertension,
which was evident through the use of antihypertensive
medications. A current smoker was defined as current
Int J Cardiovasc Imaging (2015) 31:193–203
smoking or cessation of smoking within 6 months before
the study enrollment. An ex-smoker was defined as a per-
son who was formerly a daily smoker but currently did not
smoke at all for more than 6 months. Patients were con-
sidered to have a positive smoking history when they were
defined as either current smokers or ex-smokers. Whether
or not there was a family history of premature coronary
heart disease was determined by asking the patients.
Scan protocol and image reconstruction
CCTA were performed with a 64-slice MDCT (LightSpeed
VCT 64; GE Healthcare, Milwaukee, WI, USA) or a dual
source CT (DSCT) (Somatom definition, Siemens Health-
care, Forchheim, Germany). Scan protocols for each CT
scanner were as follows: for the 64-slice MDCT san pro-
tocol, slice collimation of 64 9 0.625 mm; gantry rotation
time of 350 ms; pitch of 0.2; tube voltage of 100–120 kV
(depending on BMI); tube current of 600 mAs. The ECG-
triggered tube current modulation was switched on to
reduce the radiation dose. Heart rates of all patients were
determined 1 h before examinations. If heart rate was [65
beats per minute (bpm), the patient was orally administered
40–80 mg of oral beta-blocker propranolol hydrochloride
(indenol at 40 mg/tablet) was given to patients except those
with contraindications to beta-blockers. A 0.3 mg sublin-
gual dose of nitroglycerin was administered just before the
scan. A two-phase contrast medium protocol was used for
adjusting the scan duration. The first phase consisted of
administration of 80 mL of iodinated contrast agent
(iopromide, Ultravist 370; Schering AG, Berlin, Germany)
at a rate of 5.0 mL/s for 16 s, while the s phase included
50 mL of 15 % contrast medium and 85 % saline solution
at a rate of 5.0 mL/s for 10 s. A test bolus of 15–20 mL at a
rate of 4–5 mL/s was administered with sequential scan-
ning every 2 s at the level of the left main (LM) coronary
artery, with the region of interest set as the aortic root in
order to determine the optimum scan delay for each patient.
Next, for the DSCT scan protocol, slice collimation
2 9 32 9 0.6 mm by means of a z-flying focal spot, gantry
rotation time 330 ms, pitch 0.2–0.5, tube voltage 100–120
kVp (depending on BMI), and reference tube current 320
mAs. Scans were performed with ECG-controlled tube
current modulation. In each patient, 80 mL of iodinated
contrast (Iomeron 350, Iomeprol, Bracco, Milano, Italy)
were injected at a flow rate of 5 mL/s followed by 50 mL
of contrast mixture (15 % contrast medium and 85 % sal-
ine solution) at the same rate. Contrast material adminis-
tration was controlled by bolus tracking in the ascending
aorta (signal attenuation threshold 120 HU). The scan delay
was 7 s. In the absence of contraindications, patents with a
heart rate [80 bpm received an intravenous selective
beta1-blocker, esmolol (Jeil Brevibloc, Jeil Phama Co.,
195
Ltd., Seoul, Korea) 1 h before the scan and a 0.3 mg
sublingual dose of nitroglycerin was administered just
before the scan. Estimated radiation doses ranged from 5 to
14 mSv.
Images were reconstructed immediately after complet-
ing the scan to identify motion-free coronary artery images.
The reconstructed CT image data were transferred to a
computer workstation (MDCT: Advantage Windows 4.3,
GE Healthcare, Milwaukee, WI, USA; DSCT: Syngo
Multimodality Workplace, version 2008, Siemens Health-
care, Forchheim, Germany) for post-processing, including
axial, multiplanar reformat, maximum intensity projection,
and short-axis cross-sectional views. In all individuals,
irrespective of the image quality, every arterial segment
was scored in an intent-to-diagnose fashion.
CCTA analysis
All scans were analyzed by two radiologists with experi-
ence in interpreting over several thousand CCTA scans. In
direct accordance with the Society of Cardiovascular
Computed Tomography guidelines, coronary segments
were visually scored for the presence of coronary plaque by
using a 16-segment coronary artery model in an intent-to-
diagnose fashion [16]. Only segments with a diameter
[1.5 mm were included for analysis. Coronary plaques
came into consideration when structures [1 mm2 were
detected within or adjacent to the coronary artery lumen
and could be clearly distinguished from the vessel lumen
and the surrounding pericardial tissue.
The severity of luminal diameter stenosis was scored as
none (0 % luminal stenosis), nonobstructive (plaques with
maximum stenosis \50 %), obstructive (plaques with
maximum stenosis C50 %) or severe obstructive (plaques
with maximum stenosis C70 %). A diagnosis of CAD was
made on the basis of the maximum intra-luminal stenosis in
any of the segments of the major epicardial coronary
arteries at the C50 % stenosis threshold. Obstructive CAD
in the diagonal branches, obtuse marginal branches, and
posterolateral branches was considered to be part of the left
anterior descending (LAD) artery, left circumflex (LCX)
artery, and right coronary artery (RCA) system, respec-
tively. Depending on the coronary artery dominance, the
posterior descending artery was considered to be part of the
RCA or LCX system. For each patient, the number of
diseased vessels was calculated through the assignation of
one, two, three, or LM coronary artery vessels.
The extent and severity of the coronary atherosclerosis
was measured by several coronary CT angiographic scores
[17, 18], including the coronary artery calcium score
(CACS), the atheroma burden obstructive score (ABOS),
the segment involvement score (SIS), and the segment
stenosis score (SSS). The CACS was assessed by applying
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dedicated software (Smartscore version 3.5, GE Health-
care, Milwaukee, WI, USA; Aquarius 3D Workstation,
TeraRecon, San Mateo, CA, USA). Coronary artery cal-
cium was identified as a dense area in the coronary artery
that exceeded the threshold of 130 Hounsfield units [19].
An overall Agaston score was recorded for each patient.
The ABOS was defined as the number of plaques with
[50 % stenosis in the entire coronary artery tree. The SIS
was calculated as the total number of coronary artery
segments that exhibited plaque, irrespective of the degree
of luminal stenosis within each segment (minimum = 0;
maximum = 16). The SSS was used as a measure of the
overall extent of the coronary atherosclerosis. In order to
determine the SSS, each individual coronary segment was
graded as having no to severe plaque (i.e., scores from 0 to
3) based on the extent of the obstruction of the coronary
luminal diameter. The extent scores of all 16 individual
segments were then summed to yield a total score ranging
from 0 to 48.
Statistical analysis
The baseline and biochemical characteristics were sum-
marized as mean ± standard deviation (SD) for continuous
variables, and as absolute numbers and percentages for
discrete variables. The presence of microalbuminuria in
each patient was evaluated by measuring the albumin in
their urine over a 24-h collection period. Urine albumin
concentration was measured by a commercially available
radioimmunoassay kit (Immunotech, Prague, Czech
Republic). Microalbuminuria was defined as levels of uri-
nary albumin excretion between 30 and 300 mg/day [20].
Patients with and without microalbuminuria were com-
pared in terms of these variables as well as the CCTA
results by using either an independent sample t test or
Mann–Whitney U test for continuous variables, and either
a Chi square or Fisher’s exact test for categorical variables,
as appropriate.
The eGFR was calculated using the 4-variable Modifi-
cation of Diet in Renal Disease (MDRD) Study equation
[21]. In this study, only the patients with eGFR C60 mL/
min/1.73 m2 were included for analysis because patients
with eGFR \60 mL/min/1.73 m2 were defined as those
with stages 3–5 CKD, irrespective of albuminuria [20].
Patients were then divided into two groups (an eGFR of
60–89 mL/min/1.73 m2 or an eGFR of C90 mL/min/
1.73 m2) to define the impact of microalbuminuria on
coronary atherosclerosis separately by the existence of
CKD.
To identify independent predictors of obstructive CAD,
as detected by CCTA, multivariable, stepwise logistic
regression analyses were performed and odds ratios (OR)
with 95 % confidence intervals (CI) were generated.
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Different models were constructed by adjusting for con-
founding risk variables such as age, sex, hypertension,
body mass index, diabetes duration, smoking history,
HbA1C levels, low-density lipoprotein (LDL) cholesterol
levels, and administration of statin.
Patients’ follow-up was performed by each institution
by a dedicated physician. The primary endpoint of this
registry was all-cause mortality. The data for cardiac death
were also collected. All clinical outcomes of interest were
confirmed by source document and were centrally adjudi-
cated by a local events committee at the Cardiovascular
Center of Seoul St. Mary’s Hospital consisting of an
independent group of clinicians whose members were
unaware of patient status. For validation of complete fol-
low-up data, information on censored survival data and
cause of death was obtained from the Korean Office of
Statistics.
Cumulative event rates were calculated with the Kap-
lan–Meier method and compared by using log-rank statis-
tics. To assess the relationship between the presence of
microalbuminuria and all-cause mortality, Cox propor-
tional hazards analysis was performed, first unadjusted and
then adjusted for age, sex, and hypertension. This analysis
generated hazard ratios (HR) with 95 % CIs. Bilateral
p \ 0.05 was considered to indicate statistical significance.
All data were analyzed by using SAS 9.2 (SAS Institute,
Cary, NC, USA).
Results
Characteristics of the overall study population
and the groups with and without microalbuminuria
The baseline characteristics of the study cohort are shown
in Table 1. Between January 2006 and December 2010,
955 asymptomatic patients with type 2 diabetes under-
went CCTA. Of these, 671 were excluded: 16 (1.7 %)
because they had CAD, 78 (8.2 %) because eGFR is
\60 mL/min/1.73 m2, 550 (57.6 %) because the albumin
in their 24 h urine had not been measured, and 27 (2.8 %)
because their urinary albumin excretion exceeded
300 mg/day. Thus, 284 patients (166 males/118 females)
were eligible for the study analyses. These patients were
divided into two groups according to the presence of
microalbuminuria.
The mean age of the overall patient cohort was
64.9 ± 9.5 years, the mean body mass index was
24.3 ± 3.2 kg/m2, and the mean duration of diabetes was
13.1 ± 9.8 years. When the patients with and without
microalbuminuria were compared in terms of baseline
characteristics, those with microalbuminuria had signifi-
cantly longer duration of diabetes.
Int J Cardiovasc Imaging (2015) 31:193–203 197

Table 1 Baseline No microalbuminuria Microalbuminuria p value

characteristics (mg/24 h) (mg/24 h)

Number (n = 284) 218 66

Age (years) 64.6 ± 9.2 65.9 ± 10.3 0.339
Age C65 years (%) 113 (51.8) 37 (56.1) 0.547
Male (%) 125 (57.3) 41 (62.1) 0.490
Body mass index (kg/m2) 24.2 ± 3.1 24.6 ± 3.6 0.389
Body mass index (kg/m2 \25) 91 (55.2) 29 (50.0) 0.498
Waist–Hip ratio 0.95 ± 0.07 0.98 ± 0.07 0.072
Duration of diabetes (year) 12.1 ± 9.3 16.6 ± 10.7 0.001
Hypertension (%) 123 (56.4) 40 (60.6) 0.732
Duration of hypertension (years) 9.6 ± 8.8 7.6 ± 7.2 0.243
Smoking history (%) 52 (29.4) 25 (41.0) 0.095
Previous CVA (%) 26 (12.9) 11 (17.5) 0.359
Laboratory findings
Hemoglobin (mg/dL) 13.6 ± 1.5 13.3 ± 1.6 0.303
Glucose (mL/dL) 151.6 ± 59.7 172.8 ± 74.1 0.036
Postprandial plasma glucose (mL/dL) 207.6 ± 70.3 234.8 ± 95.1 0.056
HbA1C (%) 8.5 ± 2.2 9.2 ± 2.1 0.029
Cr (mg/dL) 0.87 ± 0.14 0.89 ± 0.18 0.384
2
GFR (mL/min/1.73 m ) 86.2 ± 18.1 85.6 ± 18.2 0.838
Total cholesterol (mL/dL) 166.0 ± 36.7 173.8 ± 40.7 0.149
Triglyceride (mL/dL) 133.9 ± 91.0 149.1 ± 96.5 0.245
HDL cholesterol (mL/dL) 49.2 ± 13.5 45.4 ± 13.1 0.045
LDL cholesterol (mL/dL) 96.4 ± 36.4 103.1 ± 37.7 0.301
Calcium (mg/dL) 9.06 ± 0.48 9.08 ± 0.45 0.818
Phosphorus (mg/dL) 3.60 ± 0.57 3.67 ± 0.75 0.599
Data are given as mean ± SD hs-CRP (mg/L) 1.06 ± 3.01 1.11 ± 2.78 0.932
or n (%) Medication use
CVA cerebrovascular accident, Oral hypoglecemic agents 146 (67.6) 30 (45.5) 0.001
GFR glomerular filtration rate,
HbA1C glycosylated Insulin 18 (8.3) 7 (10.6) 0.570
hemoglobin, HDL high-density Both OHA and insulin 31 (14.4) 25 (37.9) \0.001
lipoprotein, LDL low-density Aspirin 105 (51.5) 30 (50.8) 0.933
lipoprotein, hs-CRP high-
Statin 113 (51.8) 36 (54.5) 0.699
sensitivity C-reactive protein,
OHA oral hypoglycemic agent, Beta-blocker 22 (10.1) 12 (18.2) 0.076
ACE angiotensin converting ACE inhibitor or ARB 99 (45.4) 40 (60.6) 0.031
enzyme, ARB angiotensin Diuretics 49 (22.5) 12 (18.2) 0.457
receptor blocker

The patients with microalbuminuria also had significantly
higher fasting glucose and HbA1C levels than the patients
without microalbuminuria, but the two groups did not differ
in creatinine and eGFR levels. The patients with microal-
buminuria were more likely to be treated with both oral
hypoglycemic agents and insulin, and angiotensin-convert-
ing enzyme inhibitors or an angiotensin receptor blocker.
CCTA CAD findings
The CCTA results are summarized in Table 2. In total, 57
patients (20.1 %) had normal coronary arteries, as
determined by CCTA. Nonobstructive CAD was detected
in 103 patients (36.3 %), while obstructive CAD was
detected in 124 patients (43.7 %). Severe obstructive CAD
was observed in 34 patients (12.0 %).
Patients with microalbuminuria were significantly more
likely to have obstructive and severe obstructive CAD than
those without microalbuminuria (obstructive, p = 0.004;
severe obstructive, p \ 0.001). They were also more likely
to have obstructive two-vessel disease (2VD) and three-
vessel disease (3VD) or LM disease (2VD, p = 0.021;
3VD or LM disease, p = 0.017). Severe obstructive CAD
showed similar results (2VD, p = 0.036, 3VD or LM

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Table 2 CCTA findings No microalbuminuria Microalbuminuria p value

(mg/24 h) (mg/24 h)

Number (n = 284) 218 66

Normal (%) 49 (22.5) 8 (12.1) 0.066
Nonobstructive (1–49 %) 84 (38.5) 19 (28.8) 0.149
CAD by stenosis C50 % (%) 85 (39.0) 39 (59.1) 0.004
CAD by stenosis C70 % (%) 17 (7.8) 17 (25.8) \0.001
Vessels affected; stenosis C50 % (%)
1VD (%) 47 (21.6) 14 (21.2) 0.952
2VD (%) 25 (11.5) 15 (22.7) 0.021
3VD or LM disease (%) 13 (6.0) 10 (15.2) 0.017
Data are given as mean ± SD
or n (%) Vessels affected; stenosis C70 % (%)
CCTA coronary computed 1VD (%) 10 (4.6) 7 (10.6) 0.081
tomography angiography, CAD 2VD (%) 6 (2.8) 6 (9.1) 0.036
coronary artery disease, VD 3VD or LM disease (%) 1 (0.5) 4 (6.1) 0.011
vessel disease, LM left main

Logistic regression analysis

The presence of microalbuminuria associated indepen-

dently with obstructive CAD after adjusting for age, sex,
and the presence of hypertension (Fig. 2, model 1: OR
2.182, CI 1.225–3.884, p = 0.008). These associations
remained significant even after controlling for body mass
index, diabetes duration, and smoking status (model 2: OR
2.278, CI 1.160–4.473, p = 0.017). Additional adjustment
for HbA1C levels, LDL cholesterol levels, and the use of
statins did not significantly affect the results (model 3: OR
2.255, CI 1.121–4.538, p = 0.023). Therefore, the pre-
sence of microalbuminuria associated with an increased
risk of obstructive CAD, independent of conventional
cardiovascular risk factors.

Fig. 1 Coronary computed tomography angiographic scores. The

differences between the groups with and without microalbuminuria in
terms of coronary artery calcium score, atheroma burden obstructive
score, segment involvement score, and segment stenosis score are
shown. Most scores were significantly higher in the patients with
microalbuminuria than in the patients without microalbuminuria
except coronary artery calcium score
disease, p = 0.011). Compared to the patients without
microalbuminuria, the patients with microalbuminuria had
significantly higher ABOS (p = 0.010), SIS (p = 0.029),
and SSS (p = 0.011), except CACS (p = 0.058 by Mann–
Whitney U test), as indicated by their CCTA scans (Fig. 1).
Patients were subdivided into two groups according to
the eGFR 60–89 mL/min/1.73 m2 or C90 mL/min/
1.73 m2. In patients with eGFR 60–89 mL/min/1.73 m2,
the CCTA CAD findings were similar with those of overall
participants. However, in patients with eGFR C90 mL/
min/1.73 m2, there were no significant differences between
the patients with and without microalbuminuria. The
results of subgroup analysis are summarized in Table 3.
Presence of microalbuminuria and risk of all-cause
mortality
During the median follow-up period of 3.5 years (inter-
quartile range 2.3–4.8), there were 9 deaths (4.1 %) in the
patients without microalbuminuria, and 9 deaths (13.6 %)
in those with microalbuminuria. Patients with microalbu-
minuria had a significantly higher all-cause death rate than
the patients without microalbuminuria (p = 0.017). In
addition, the presence of microalbuminuria associated with
an increased risk of all-cause mortality (Fig. 3). Even after
adjusting for conventional risk factors (age, sex, and
hypertension), the presence of microalbuminuria was an
independent predictor of all-cause mortality (HR 3.469, CI
1.3196–9.121, p = 0.012).
In addition, the presence of microalbuminuria associated
with an increased all-cause of mortality in patients with
eGFR 60–89 mL/min/1.73 m2 (Fig. 4a). However, there
was no significant group difference in all-cause of

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Table 3 Subgroup analysis

60 B eGFR \ 90 mL/min/1.73 m2 eGFR C 90 mL/min/1.73 m2
No microalbuminuria Microalbuminuria p value No microalbuminuria Microalbuminuria p value
(mg/24 h) (mg/24 h) (mg/24 h) (mg/24 h)

Number (n = 284) 143 42 75 24

Baseline characteristics
Age (years) 65.8 ± 8.8 68.8 ± 9.2 0.059 62.4 ± 9.7 60.9 ± 10.4 0.527
Male (%) 74 (51.7) 26 (61.9) 0.246 51 (68.0) 15 (62.5) 0.619
Body mass index (kg/m2) 24.3 ± 2.9 24.9 ± 3.7 0.288 24.1 ± 3.3 24.2 ± 3.5 0.934
Waist–Hip ratio 0.95 ± 0.08 0.98 ± 0.07 0.156 0.95 ± 0.06 0.97 ± 0.05 0.312
Duration of diabetes (year) 12.9 ± 9.3 18.6 ± 10.8 0.001 10.6 ± 9.0 12.9 ± 9.6 0.271
Hypertension (%) 86 (60.1) 25 (59.5) 0.943 37 (49.3) 15 (62.5) 0.261
Duration of hypertension 9.2 ± 8.3 8.0 ± 8.0 0.556 10.4 ± 9.9 7.1 ± 6.3 0.270
(years)
Smoking history (%) 29 (26.4) 13 (34.2) 0.355 23 (34.3) 12 (52.2) 0.130
Previous CVA (%) 16 (12.2) 7 (17.5) 0.391 10 (14.1) 4 (17.4) 0.740
CCTA Findings
Normal (%) 33 (23.1) 3 (7.1) 0.022 16 (21.3) 5 (20.8) 0.958
Nonobstructive (1–49 %) 60 (42.0) 13 (31.0) 0.199 24 (32.0) 6 (25.0) 0.516
CAD by stenosis C50 % (%) 50 (35.0) 26 (61.9) 0.002 35 (46.7) 13 (54.2) 0.522
CAD by stenosis C70 % (%) 11 (7.7) 12 (28.6) \0.001 6 (8.0) 5 (20.8) 0.129
Vessels affected; stenosis C50 % (%)
1VD (%) 28 (19.6) 9 (21.4) 0.792 19 (25.3) 5 (20.8) 0.654
2VD (%) 14 (9.8) 10 (23.8) 0.017 11 (14.7) 5 (20.8) 0.528
3VD or LM disease (%) 8 (5.6) 7 (16.7) 0.047 5 (6.7) 3 (12.5) 0.397
Calcium score (Agaston) 241.3 ± 489.5 429.1 ± 636.9 0.030* 287.6 ± 619.0 232.9 ± 382.7 0.729*
Atheroma burden obstructive 0.81 ± 1.49 1.81 ± 2.06 0.005 1.20 ± 1.88 1.63 ± 2.65 0.388
score
Segment involve score 1.97 ± 2.41 3.14 ± 2.96 0.022 2.29 ± 2.99 2.50 ± 2.87 0.765
Segment stenosis score 3.00 ± 4.05 5.71 ± 5.74 0.006 3.87 ± 5.47 4.67 ± 6.16 0.547
Data are given as mean ± SD or n (%)
CCTA coronary computed tomography angiography, CAD coronary artery disease, VD vessel disease, LM left main
* Statistical significance test was done by Mann–Whitney U test

mortality between patients with and without microalbu-
minuria whose had normal renal function (Fig. 4b).
Discussion
This prospective two-center study revealed that, compared
to patients without microalbuminuria, asymptomatic
patients with type 2 diabetes without a history of CAD with
microalbuminuria had a higher prevalence, extent, and
severity of coronary atherosclerosis, as well as all-cause
mortality. Furthermore, after adjusting for coexisting risk
factors, microalbuminuria was an independent predictor of
both obstructive CAD (as measured by CCTA) and all-
cause mortality. To our knowledge, this study is the first to
examine the effect of microalbuminuria on not only the
prevalence, extent, and severity of CCTA-measured coro-
nary atherosclerosis in asymptomatic patients with type 2
diabetes, but also the long-term clinical outcome of such
patients. There findings suggest that microalbuminuria may
be a risk marker for more advanced coronary atheroscle-
rosis, in which case, the subgroup of asymptomatic type 2
diabetic patients with microalbuminuria would benefit in
particular from closer follow-up and more aggressive pre-
ventive strategies.
There is considerable evidence showing that diabetes is
a major risk factor for CAD, which is the most common
cause of mortality in diabetic patients [22–24]. However,
previous studies have also shown that diabetic patients vary
widely in terms of their development of CAD and that this
risk depends on the presence of concomitant cardiovascular
risk factors [25, 26]. Thus, it remains unclear whether

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Fig. 2 Association between the presence of microalbuminuria and
obstructive coronary artery disease, as detected by coronary computed
tomography angiography. Microalbuminuria associated indepen-
dently with obstructive coronary artery disease, as indicated by the
odds ratios (OR) and 95 % confidence intervals (CI) obtained from
multivariate logistic regression analyses with adjustments for several
Fig. 3 Cumulative survival of patients with and without microalbu-
minuria. The patients with microalbuminuria had a higher rate of all-
cause mortality than the patients without microalbuminuria
diabetes alone can be considered equivalent to CAD when
assessing the risk of future cardiovascular events [27–30].
In this regard, microalbuminuria has been found to be an
important risk factor that can be used to estimate the
prevalence of CAD or CAD-associated mortality in
patients with diabetes [31–33]. The mechanisms behind the
adverse effect of microalbuminuria on cardiovascular risk
are poorly understood. However, microalbuminuria may be
an index of generalized vascular damage because it
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Int J Cardiovasc Imaging (2015) 31:193–203
variables, as follows. Model 1 adjusted for age, sex, and hypertension;
Model 2 adjustment of model 1 plus for body mass index, diabetes
duration, and smoking history; Model 3 adjustment of model 2 plus
for glycosylated hemoglobin levels, low-density lipoprotein choles-
terol levels, and administration of statin
correlates with markers of endothelial dysfunction and
inflammation, both of which are directly involved in ath-
erosclerosis [34].
The present study showed that asymptomatic type 2
diabetic patients with microalbuminuria indeed had higher
rates of obstructive CAD and all-cause mortality than those
without microalbuminuria. This study also found that even
after adjustment for coexisting risk factors, microalbu-
minuria remained an independent predictor of not only
CCTA-measured obstructive CAD, but also all-cause
mortality. By using CCTA to directly measure the extent
and severity of coronary atherosclerosis in asymptomatic
patients with type 2 diabetes, this study provided non-
invasive coronary anatomy data to support prior pivotal
studies suggesting that microalbuminuria may have prog-
nostic importance in identifying asymptomatic patients
with type 2 diabetes who have a high cardiovascular risk
[31, 32].
Previous studies demonstrated an elevated risk of all-
cause mortality associated with decreased eGFR [35, 36].
To minimize this confounding factor, we subdivided
patients in the CRONOS-ADM registry according to eGFR
in the following ranges: 60–89 mL/min/1.73 m2 and
C90 mL/min/1.73 m2. Presence of microalbuminuria is an
important factor in determining the incidence, extent, and
severity of coronary atherosclerosis in patients with eGFR
60–89 mL/min/1.73 m2. Also, they have higher all-cause
mortality compared to patients without microalbuminuria.
However, in patients with normal renal function, there is no
Int J Cardiovasc Imaging (2015) 31:193–203
Fig. 4 Cumulative survival according to presence of microalbumin-
uria in patients with or without reduced estimated glomerular
filtration rate. a Survival analysis of patients with mildly reduced
significant difference according to the presence of micro-
albuminuria. Therefore, microalbuminuria is significantly
associated with an increased risk of prevalence, severity,
and extent of coronary atherosclerosis as well as all-cause
mortality, regardless of eGFR in patients with mildly
decreased eGFR.
The current American Diabetes Association consensus
guidelines recommend that patients with type 2 diabetes be
screened for CAD if they present with cardiovascular
symptoms [37]. However, there is no detailed consensus
regarding the evaluation of CAD in asymptomatic patients
with type 2 diabetes. Similarly, professional societal
appropriate-use criteria generally endorse the use of CCTA
to assess CAD in symptomatic low-to-intermediate risk
patients [38]. However, coronary atherosclerosis involves a
prolonged asymptomatic developmental phase, and its first
manifestations often result in sudden cardiac death or
nonfatal MI [39]. Regardless of the cause of ischemia, it is
clear that reduced appreciation of ischemic pain can impair
the timely recognition of myocardial ischemia or infarction
and thereby delay appropriate therapy [40]. The present
study has demonstrated that microalbuminuria may be a
marker for high cardiovascular risk and that CAD screen-
ing by noninvasive CCTA in the subgroup of asymptomatic
patients who have type 2 diabetes with microalbuminuria
may be warranted. However, large-scale controlled clinical
trials that determine whether routine CAD screening of this
subgroup improves clinical outcome are further required.
Despite the important findings of this study and its
clinical implications regarding CAD management in
asymptomatic patients with type 2 diabetes, the present
study had some limitations. First, the sample size was
201
eGFR (eGFR 60–89 mL/min/1.74 m2). b Survival analysis of patients
with normal renal function (eGFR C90 mL/min/1.74 m2)
relatively small and thus did not allow for separate analyses
between genders or stratification according to cardiovas-
cular risks. Second, this study had an observational design,
which means that it cannot yet be said with certainty that
there is a causal association between microalbuminuria and
long-term clinical outcome in asymptomatic patients with
type 2 diabetes. Moreover, as with any observational study,
despite including many variables in our analyses, it remains
possible that other hidden factors affected the relationship
observed between microalbuminuria, CAD, and mortality
in asymptomatic patients with type 2 diabetes. In addition,
this study was only conducted at two centers. This means
that the ability to generalize these results in other patient
population under different settings remains unclear. Third,
information about the patients’ medications and glucose
control (as reflected by HbA1C levels) during the 5 year
follow-up period after CCTA was not available. Thus,
although patients with microalbuminuria had worse
HbA1C levels when they underwent CCTA than patients
without microalbuminuria, the effect of longitudinal dia-
betic control or medication changes on all-cause mortality
after the CCTA investigation could not be ascertained.
Conclusions
This prospective two-center study of asymptomatic
patients with type 2 diabetes showed that microalbuminuria
is significantly associated with a greater prevalence, extent,
and severity of coronary atherosclerosis. Furthermore,
microalbuminuria was proven to be an independent pre-
dictor of all-cause mortality.
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Conflict of interest None.
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