Long-term prognostic impact of cystatin c on acute coronary syndrome octogenarians with diabetes mellitus
Long-term prognostic impact of cystatin c on acute coronary syndrome octogenarians with diabetes mellitus
Zhenhong Fu 0
Hao Xue 0
0 Equal contributors Department of Cardiology, Chinese People's Liberation Army General Hospital , 28 Fuxing Road, Beijing, Haidian District 100853 , People's Republic of China
Objective: Cystatin C (Cys C) is a marker of renal dysfunction. Prior studies have shown that blood Cys C is related to the prognosis of coronary heart disease. The aim of the present study was to evaluate the long-term prognostic impact of Cys C on acute coronary syndrome (ACS) octogenarians with diabetes mellitus (DM). Methods: We enrolled 660 consecutive ACS octogenarians who underwent coronary angiography and were classified into two groups based on diabetes. The baseline characters and Cys C level were measured on admission. Survival curve was calculated using the Kaplan-Meier method. Multivariate Cox regression was used to identify predictors of mortality and of major adverse cardiac events (MACE) rate. Results: There were 223 and 398 patients in groups DM and non-DM who fulfilled the follow-up. The average follow-up period was 28 (IQR 16-38) months. Diastolic blood pressure (DBP) was lower, ratios of hypertension and chronic renal failure (CRF), fasting blood glucose, HbA1c and Cys C levels were higher in DM group than those in non-DM group (P<0.01). The cumulative survival of DM group was significantly lower than that of non-DM group in the long term (P = 0.018). All cause mortality and MACE of DM group were higher than those of non-DM group (P<0.05). The plasma Cys C concentration (OR = 3.32, 95% CI = 1.18-10.92, P = 0.023) was the uniqueness independent predictor for long-term all cause mortality. The plasma Cys C concentration (OR = 2.47, 95% CI = 1.07-7.86, P = 0.029) and Genesis score (OR = 1.01, 95% CI = 1.00-1.03, P = 0.043) were independent predictors for MACE in DM group. ROC curve analysis showed that the predictive cut-off value of Cys C for mortality of DM group was 1.605 (0.718, 0.704). Conclusions: Cys C is an independent predictor for long-term mortality and MACE of ACS octogenarians with DM.
Acute coronary syndrome; Cystatin C; Octogenarian; Diabetes mellitus; Prognosis
The older population represents a growing proportion of
the general population. Octogenarian (age >80 years old)
will increase from the current ratio of 1 in 35 to more
than 1 in 12 by the year 2050 . The increasing
prevalence of coronary artery disease (CAD) is associated with
aging. Compared with younger patients, elderly patients
who undergo coronary angiography (CAG) present more
complex lesions, higher comorbidity, poorer clinical
outcomes and higher mortality [2,3].
Cystatin C (Cys C) is a cysteine protease inhibitor with
a low-molecular weight (13 kD) that is produced by all
nucleated cells at a constant rate. It is freely filtered
across the glomerular membrane and is not influenced
by age, sex, muscle mass, exercise or diet . Therefore,
the serum Cys C level is a superior marker for the
evaluation of renal function compared to other markers such
as serum creatinine or creatinine clearance . Over the
last few years it has been suggested that high Cys C
concentration is related directly to both inflammation and
atherosclerosis . Cys C level is also associated with
the prognosis of CAD in the general population [7-11].
Diabetes mellitus (DM) is an established risk factor and
equivalent of CAD. Patients with CAD and DM are at
very high risk, and the prognosis of these patients is
poor. Prior studies show a positive relationship of serum
Cys C level with the incidence of type 2 DM . The
findings strongly suggest Cys C is associated with not
only the development of cardiovascular disease (CVD)
but also the incidence of type 2 DM. Therefore, we
presume that Cys C plays an important role during
the short and long term prognosis of an ACS patient
To date, the prognostic value of Cys C in very old
(age >80) ACS patients, especially with DM, remains
unclear. The prior studies were simply focused on the
ACS patients at the age of about 60 years old.
Therefore, the aim of the present study is to evaluate
longterm prognostic impact of plasma Cys C on Chinese
ACS octogenarians with DM.
From January 2006 to December 2011, a total of 660
consecutive patients with ACS (age > 80 years old), who
were referred to our hospital for percutaneous coronary
intervention (PCI), were enrolled in this study. The
inclusion criteria were: (1) patients with a complete
clinical history; (2) a diagnosis of ACS that was classified
as unstable angina pectoris (UAP), non-ST-segment
elevated myocardial infarction (NSTEMI) or ST-segment
elevated myocardial infarction (STEMI)  and (3)
recent coronary angiography (CAG). Those with acute
infection, chronic hepatic dysfunction, nutritional
derangements, malignancy, severe valvular heart disease,
severe heart failure, dysthyroidism or other severe
medical illnesses were excluded.
All patients consented in written to their participation
in the study, and the study agreement was approved by
the Chinese Peoples Liberation Army General Hospital
research ethics committee and complied with the
Declaration of Helsinki.
The clinical characteristics of all patients were recorded
on admission. These included age, gender, heart rate
(HR), body mass index (BMI), systolic and diastolic
blood pressure (SBP, DBP), eject fraction (EF), diabetes,
primary hypertension, hyperlipidemia, previous
myocardial infarction (MI), previous stroke, chronic renal failure
(CRF), smoking history, and cardiovascular medication.
Fasting blood samples were drawn prior to angiography to
evaluate blood biochemistry. The fasting blood glucose
(FBG), HbA1c, triglyceride (TG), total cholesterol (TC),
low density lipoprotein-C (LDL-C), serum creatinine
(CRE), urea nitrogen (BUN), and Cys C were analyzed. For
all patients, renal function was assessed using the baseline
estimated glomerular filtration rate (eGFR). Impaired renal
function was defined as an eGFR <60 mL/min/1.73 m .
The creatinine was standardized using a calibration
equation called Jaffes kinetic method :
Scr mg=dl 0:795 enzymatic method Scrmg=dL 0:29
The estimated glomerular filtration rate (eGFR) was
calculated using the Chinese modified Modification of
Diet in Renal Disease (C-MDRD) equation :
eGFR ml=min=1:73 m2 175
standardized creatine mg=dl
age year 0:179
CAG was performed on all patients after admission.
CAD was defined as an obstructive lesion causing 50%
reduction of lumen diameter in at least one of the
coronary arteries. The severity of CAD was evaluated using
the Gensini score .
The 8 variables used in the GRACE risk model
included older age, Killip class, systolic blood pressure,
ST-segment deviation, cardiac arrest during
presentation, serum creatinine level, positive initial cardiac
biomarkers, and heart rate. The sum of scores was applied
to determine the corresponding all cause mortality
inhospital and from hospital discharge to 6 months .
Gensini and GRACE scores for each enrolled patient
were recorded by observers who were blinded to the
results of laboratory tests and grouping.
Population grouping and follow-up
Our patients were divided into DM group and non-DM
group. The definition of DM was such that a person had
an FBG higher than 7 mmol/L, or a 2 hour PBG or
random glucose higher than 11.1 mmol/L. All patients were
regularly followed at 6-month intervals for the first 12
months, and thereafter every 12 months. All patients
were advised to contact the outpatient clinic as soon as
possible after a symptomatic event. Long-term outcomes
during the follow-up were compared between the two
A major adverse cardiac event (MACE) included any
of the following: death for any cause, MI, and need for
repeat revascularization (repeat PCI or coronary artery
bypass grafting (CABG)).
Continuous variables were expressed as the mean
standard deviation (SD) or median (with inter quartile
range (IQR)). The t test was used if continuous variables
were normally distributed, while the Wilcoxon
twosample test was used if continuous variables were not
normally distributed. Categorical data were summarized
as frequency. The chi-square test was used to compare
categorical variables. Survival rates were calculated
according to the Kaplan-Meier method. Survival time was
defined as from the date of coronary angiography to the
date of death as verified during the follow-up.
Differences between pairs of survival curves were tested by
the log-rank test. A Cox proportional hazards model
was used to identify predictors of mortality. Odds ratios
(ORs) were reported with corresponding 95% confidence
intervals (CIs). Receiver operating characteristic (ROC)
curves were constructed for discrimination between
survived and dead patients. The areas under the curve
(AUC) were compared by using Hanley and McNeil
method. All P values were two-sided, and a P value < 0.05
was considered statistically significant. Statistical analysis
was performed using the Statistical Package for Social
Sciences, version 17.0 (SPSS, Chicago, Illinois).
Baseline characteristics of patients
Baseline clinical characteristics and clinical event data
were fully documented for 621 (621/660, 94.09%)
enrolled patients during the follow-up period. 14 patients
in DM group and 25 patients in non-DM group were
lost during the follow-up because of the wrong
telephone number. Of the 621 patients, 223 (35.91%)
patients had diabetes and 398 (64.09%) patients did not
have diabetes (1: 1.78). The ratio of ACS octogenarians
with DM was over one third.
The baseline clinical characteristics of the two groups
were shown in Table 1. As compared with those in the
non-DM group, patients in DM group had lower DBP
(P<0.01) and higher level of FBG (P<0.01) and HbA1c
(P<0.01), while other characteristics including age,
gender, HR, BMI, TG, TC, LDL-C, SBP, EF, Genesis score
and GRACE risk score were not different (P>0.05). The
morbidities of hypertension and CRF were higher in DM
group than in non-DM group (P<0.01). Among renal
function indicators, only plasma Cys C concentration in
DM group was higher than that in non-DM group (1.55
(IQR 1.24-1.90) vs. 1.38 (IQR 1.23-1.78) mg/L, P = 0.009).
In addition, no differences were found in medication use
and treatment strategies between the two groups. No
differences were found in ACS type (P>0.05).
Long- term clinical outcomes
The duration of the follow-up was between 13 and 79
months (median 28 months, IQR 1638 months).
During the follow-up period, 40 patients (17.94%) died and
15 patients (6.73%) experienced reinfarction or
revascularization, and the rate of MACE was 24.67% in DM
group. 44 patients (11.06%) died and 25 patients (6.28%)
experienced reinfarction or revascularization, and the
rate of MACE was 17.34% in non-DM group. The all
cause mortality and MACE rate in DM group were higher
than those in non-DM group (P = 0.011, P = 0.037). The
rates of reinfarction and revascularization were not
significantly different between the two groups (P>0.05). Figure 1
shows the Kaplan-Meier survival curve for all-cause death
according to diabetes. There was a significant difference
between the two groups (P = 0.018). DM group had a high
risk of all-cause death.
Concentration of Cys C relative to all-cause death
according to quartile analysis was compared between
DM group and non-DM group. Quartiles (Q) ranges of
Cys C were: Q1: 1.11(0.52-1.22), Q2: 1.31(1.23-1.43), Q3:
1.59(1.44-1.82), and Q4: 2.23(1.83-5.12) mg/L. As
detailed in Figure 2, the mortality of each quarter in DM
group was higher than that in non-DM group. The
differences increased along with concentration of Cys C,
and in ranges Q3 (P = 0.016) and Q4 (P = 0.036) the
differences were significant. The mortality increased with
the concentration of Cys C and the tendency was
Figure 2 Quartile analysis comparing the concentration of
Cys C to the mortality of DM and non-DM group.
Figure 3 ROC curves for Cys C and other renal function
indicators for discrimination between survived and dead
patients in DM group.
significant in DM group (P = 0.0001). While in non-DM
group, the mortality was higher than others only in
range Q4 (P = 0.01), and the differences in ranges Q1 to
Q3 were not significant.
Risk factors associated with mortality during follow-up
We performed a Cox regression analysis to determine the
factors that were associated with all cause death in DM
group and non-DM group at the end of the follow-up.
After being adjusted for age, gender, heart rate, BMI, TG,
TC, LDL-C, FBG, HBA1c, SBP, DBP and EF, the plasma
Cys C concentration (OR = 3.32, 95% CI = 1.18-10.92,
P = 0.023) was the unique independent predictor for
longterm mortality, and the plasma Cys C concentration
(OR = 2.47, 95% CI = 1.07-7.86, P = 0.029) and Genesis
score (OR = 1.01, 95% CI = 1.00-1.03, P = 0.043) were
independent predictors for MACE in DM group.
Diagnostic power of Cys C and other renal function
indicators for mortality during follow-up
The respective predictive cut-off values were constructed
according to the ROC curves for Cys C and other renal
function indicators for discrimination between survived
and dead patients in DM group (Figure 3). Using these
cut-off points, Cys C showed higher sensitivity and
specificity with a greater area under the ROC curve than
other biomarkers (Table 2). The predictive cut-off value
of Cys C for mortality of DM group was 1.605 mg/L.
In the present study, we have found that plasma Cys C
concentration was an independent predictor for
longterm mortality and MACE in ACS octogenarians with
DM after controlling for conventional cardiovascular
risk factors, but not for those without DM. To the best
of our knowledge, our study is the first prospective
cohort study to enroll a large number of Chinese ACS
octogenarians with DM, the duration of the follow-up is
the longest (from 13 month to 79 month) and the
follow-up rate is the highest.
Previous studies show that mild renal insufficiency is
a major risk factor for CVD and predicts the worst
outcomes . In recent years, general studies have
indicated that Cys C was proposed as a more reliable marker
of renal function than serum creatinine , particularly
in the detection of small reductions in GFR . Factors
that influence serum creatinine levels do not affect Cys
C levels. In the present study, we found that among the
respective predictive cut-off values, Cys C showed higher
sensitivity and specificity with a greater area under the
ROC curve than other renal function biomarkers.
However, some other studies reported that serum Cys C had
limited predictive capacity for the early detection of
acute kidney injury after cardiopulmonary bypass
surgery in infants and young children. The main reasons
lied in the difference in enrolled population. The age in
those other studies was younger than 3 year old .
Study has demonstrated that high Cys C concentration
is related directly to both inflammation and
atherosclerosis . Cys C has also been shown to be independent
prognostic information in cardiovascular disease in the
general population [23-27]. In addition, study has also
suggested that patients with higher Cys C concentration
appear to have high risk of CAD, and the level of Cys C
was also related to long term all cause and cardiovascular
mortality in patients referred to coronary angiography
Table 2 Performances of measures of renal function for prediction of mortality
CI= confidence interval, AUC= areas under the curve. Cys C= Cystatin C, CRE= serum creatinine, BUN= blood urea nitrogen, e-GFR= estimated glomerular
[24,28,29]. Consistent studies have reported Cys C
concentration was associated with all cause death risk for
non-STEMI ACS , and prognostic value for patients
with STEMI undergoing primary PCI . On the
contrary, a study has shown Cys C concentration was not
related to the new onset DM . The main reasons lied in
the difference in enrolled population and the combined
disease. The main diseases in the study were hypertension
with pre-diabetes, and the average years were 69.4 year
old. In the present study, we found that the prognosis
value of Cys C in ACS octogenarians with DM was
independent of renal function impaired, and plasma Cys C
concentration played the most obvious role and was an
effective indicator for all cause mortality. Cys C as a cysteine
proteinase inhibitor may play an important role in the
pathogenesis of atherosclerosis. Cys C is associated with
cardiovascular risk factors as well as inflammation, which
may promote atherosclerosis. Some studies have suggested
that inflammatory cytokines related to atherosclerosis
stimulate lysosomal cathepsins, which may be associated
with increased Cys C levels to counterbalance the
elastolytic activity of cathepsins . All these effects may cause
the worse vascular endothelial damage, inflammation and
atherosclerosis in DM patients.
In addition, previous studies show age was a very
important risk factor for predicting prognosis of ACS
patients in general population. In GRACE study, age was
the most important factor affecting in-hospital and
sixmonth discharge mortality, However, for very old
patients (age >80 years old), the ratio of age score was too
high in the GRACE risk score, and all patients enrolled
in our study were at very high risk according to GRACE
risk score. The need of searching for new biomarkers
with better and more accurate profiles to evaluate
prognosis of these very high risk ACS patients at the age
of > 80 years old has been very intense. Our results
indicated, Cys C concentration was an intense
biomarker for evaluation of prognosis of Chinese ACS
octogenarians with DM and was not influenced by
age. This is the first time to define the cutoff value of
Cys C concentration for predicting all cause mortality
in ACS octogenarians with DM.
As we know, the proportion of ACS with DM in
elderly patients is significantly higher than that in the
general population, the patients are usually very high-risk
groups and have many complications, and the prognosis
of them is poor. Therefore the risk stratification in these
patients is particularly important. Finding accurate
indicators which can be used to determine the prognosis of
these patients emerges as a target of interest. In our
study, we analyzed the general conditions and
comorbidities in DM and non-DM patients, and the ratio of DM
in the observed Chinese ACS octogenarians was over
one third, which was higher than the prior reports by
about 20-30% [33,34]. The Cys C level was significantly
different, while severity of coronary artery (Genesis
score), GRACE risk score as well as general renal
function indicators were not significantly different between
DM and non-DM patients. All the enrolled patients had
complex, multi-vessel and diffuse coronary artery
lesions, and were at very high risk. The results of our
study were not completely consistent with the usual
concepts that the renal function was obviously poor and
coronary artery lesions were complicated in DM patients
than those in non-DM patients. It was thus clear that
the impact of DM on the renal function and coronary
artery lesions severity was small in very old age patients.
Some limitations must be considered. Our study was
similar to other single center registries in that it offered
observational data on nonrandomized patients. In
addition, plasma Cys C levels was measured at a single
point in the present study.
All cause mortality and MACE of ACS octogenarians
with DM were higher than those of ACS octogenarians
without DM. Plasma Cys C level was an independent
predictor for long-term mortality and MACE of ACS
octogenarians with DM, while not for non-DM patients.
Plasma Cys C level was an accurate biomarker for
predicting the long term prognosis for ACS octogenarians
ACEI: Angiotensin converting enzyme inhibitor; ACS: Acute coronary
syndrome; ARB: Angiotensin receptor blocker; AUC: Areas under the curve;
BMI: Body mass index; BUN: Urea nitrogen; CAD: Coronary artery disease;
CAG: Coronary angiography; CABG: Coronary artery bypass grafting;
CI: Confidence interval; CRE: Serum creatinine; CRF: Chronic renal failure;
CVD: Cardiovascular disease; Cys C: Cystatin C; DBP: Diastolic blood pressure;
DM: Diabetes mellitus; EF: Eject fraction; e-GFR: Estimated glomerular
filtration rate; FBG: Fasting blood glucose; HR: Heart rate; IQR: Inter quartile
range; LDL-C: Low density lipoprotein-C; MACE: Major adverse cardiac events;
MI: Myocardial infarction; NSTEMI: Non-ST-segment elevated myocardial
infarction; OR: Odds ratio; PCI: Percutaneous coronary angiography;
ROC: Receiver operating characteristic curves; SBP: Systolic blood pressure;
SD: Standard deviation; STEMI: ST-segment elevated myocardial infarction;
TG: Triglyceride; TC: Total cholesterol; UAP: Unstable angina pectoris.
ZF, HX, YC designed the research and drafted the manuscript. JG, LC, LG, HL,
ZS performed the PCI. WD followed up patients and recorded the results.
All authors read and approved the final manuscript.
This study was supported by the National Science and Technology Pillar
Program of China (fund number 2009BAI86B04) and Chinese PLA General
Hospital scientific and technical innovation Project (fund number 12ZMP02).
The authors thank all the numerous physicians and study nurses who
participated in data collection.
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