Prognostic ability of cystatin C and homocysteine plasma levels for long-term outcomes in very old acute myocardial infarction patients
Clinical Interventions in Aging
Prognostic ability of cystatin C and homocysteine plasma levels for long-term outcomes in very old acute myocardial infarction patients
Zhenhong Fu 1
Xia Yang 1
Mingzhi shen 0
hao Xue 1
geng Qian 1
Feng Cao 1
Jun guo 1
Wei Dong 1
Yundai Chen 1
0 Department of Cardiology, h ainan Branch of Chinese People's l iberation Army general hospital , sanya, hainan , China
1 Department of Cardiology , Chinese People's l iberation Army g eneral hospital, Beijing , China
PowerdbyTCPDF(ww.tcpdf.org) Background and aims: This study sought to evaluate the prognostic powers of combined use of cystatin C (Cys C) and homocysteine (Hcy) at predicting adverse events of patients .80 years old with acute myocardial infarction (AMI). Patients and methods: The analysis involved 753 patients .80 years old undergoing coronary angiography for chest pain in China from January 2006 to December 2012. Kaplan-Meier method was used for survival and major adverse cardiac events (MACE) rates. Multivariate Cox regression was performed to identify mortality predictors. Receiver operating characteristic curve analysis was performed to predict the cutoff values of Cys C and Hcy for all-cause mortality. Results: The duration of follow-up was 40-116 months (median, 63 months; interquartile range, 51-74 months). The long-term survival and event-free survival rates of AMI patients were significantly lower than those of unstable angina pectoris patients (P,0.05), and were significantly different according to the tertile concentration of Cys C of AMI patients (P,0.01). Cys C and Hcy were independent risk factors for long-term all-cause mortality (odds ratio [OR] =3.72 [2.27-6.09]; OR =1.59 [1.04-2.61]) and MACE (OR =2.83 [1.82-4.40]; OR =1.09 [1.04-1.21]) of AMI patients. The predictive cutoff value of Cys C was 1.815 mg/L (82.8%, 86.4%) and that of Hcy was 15.06 μmol/L (84.4%, 83.1%) in AMI patients. Combined use of both biomarker's cutoff values further increased the sensitivity and specificity of all-cause mortality. Conclusion: Cys C is a strong independent predictor of long-term all-cause death and MACE in very old AMI patients. The combined use of Cys C and Hcy further improves the predictive accuracy.
*These authors contributed equally
to this work
accepted that Cys C is a more sensitive marker of early renal
insufficiency.2–4 Cys C is a novel biomarker of cardiovascular
disease. Several studies have suggested that increased plasma
levels of Cys C are associated with the increased risk of
cardiovascular disease and mortality5,6 in the elderly7 and
in different patient populations.8,9 Serum Cys C may be a
predictor of disease severity in elderly hypertensive patients
18 with coronary heart disease.10 In addition, baseline Cys C
l-20u levels play a prognostic role in long-term adverse outcomes
-J2 of coronary artery disease (CAD) and heart failure.11 Serum
n1o Cys C has also been shown to correlate with angiographic
.172 coronary collateralization in patients with stable CAD12 and
613 associated with CAD and its severity.13 However, some other
..37 studies have confirmed that there is no causal relationship
y45 between plasma Cys C and CAD.14
/bm Homocysteine (Hcy) is a nonessential amino acid that is
.cso known as a marker of endothelial injury. Elevated total Hcy
se is known to be able to increase oxidative stress, diminish
.rvdoepww ll.syeuon vasodilation, stimulate the proliferation of vascular smooth
muscle cells, alter the elastic properties of the vascular wall,
/w an and thus increase the risk for atherosclerosis. There is a direct
tthp rspe association between total Hcy and coronary heart disease in
from roF the general population.15–17
ed Our earlier studies indicated that Cys C is an independent
lado risk factor for the prognosis of old acute coronary syndrome
onw (ACS) patients with diabetes,18 and Hcy is an independent
gnd risk factor for the outcome of old ACS patients too.19
igA However, prior studies were limited by sample size,
isn follow-up time, study population, and differences in the
itnno cutoff values. There were no novel markers associated
ltIrveen wWiethhyvpeorythleosnizge-dtetrhmat oCuytscoCmaensdoHfcvyewryeroeldindAeMpeIndpeantiternitssk.
stronger diagnostic power.
Patients and methods
We performed a prospective cohort study in Chinese People’s
Liberation Army (PLA) General Hospital cardiac center from
January 2006 to December 2012. A total of 720 patients
who were .80 years old, hospitalized for ACS, and
underwent coronary angiography examination were enrolled by
10 cardiologists. A total of 100 patients who were .80 years
old, hospitalized for chest tightness or chest pain, but whose
coronary angiography revealed nonobstructive stenosis were
enrolled in the control group. Exclusion criteria included
malignancy, severe valvular heart disease, primary pulmonary
hypertension, severe liver dysfunction, metabolic diseases,
and rheumatic immune diseases. The study was approved by
Chinese PLA General Hospital Ethics Service. All patients
provided written informed consent for this study including to
undergo coronary angiography examination and treatments
and to be followed up for outcomes in the longer term.
Demographic characteristics, cardiovascular risk factors
(primary hypertension, diabetes, hyperlipidemia, previous
myocardial infarction [MI], previous stroke, chronic renal
failure [CRF], and smoking), baseline blood features (total
cholesterol, low density lipoprotein-C, fasting blood glucose,
uric acid, Hcy, and Cys C), and clinical and treatment data
were collected by trained doctors after patient admission.
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 m2. Creatinine
was standardized using a calibration equation called Jaffe’s
Scr (mg/dL) = 0.795 × (enzymatic method
Scr [mg/dL]) + 0.29.
eGFR was calculated using the Chinese modified
Modification of Diet in Renal Disease equation:
eGFR (mL/min/1.73 m2) = 175 × standardized creatinine
(mg/dL)−1.234 × age (year)−0.179 ×
0.79 (if female).
Coronary angiogram acquisition and
analysis, and selection of treatment
Coronary angiograms were acquired during usual care with
cardiac catheter laboratory X-ray and information technology
equipment. All coronary angiograms were analyzed on a
single image analysis software platform. Quantitative
coronary analysis of the culprit vessel was performed by trained
observers using standard methods.
The severity of coronary stenosis was expressed by
Gensini score. The locations of coronary artery lesions and
proportion of those with multivessel disease were recorded.
According to the results of coronary angiography, intensive
drug therapy, percutaneous coronary intervention (PCI), or
coronary artery bypass grafting (CABG) were performed.
Patient grouping and study outcomes
Patients were divided into the unstable angina pectoris (UAP)
and the AMI groups according to the guidelines of American
College of Cardiology. Patients with chest pain and normal
angiography were enrolled as the control group. Patients were
followed up once every 12 months after discharge and major
adverse cardiac events (MACE) were recorded. The primary
outcomes of this study were all-cause death, MACE (including
recurrent MI, repeat revascularization [PCI or CABG]).
Allcause death was defined as death from any reason including
cardiovascular and non-cardiovascular causes. Recurrent
MI was defined as recurrent clinical features with new
electrocardiographic findings that were compatible with MI, or
increased levels of biochemical markers.
All statistical analyses were performed using SPSS software
version 19.0 (IBM Corporation, Armonk, NY, USA).
A P-value ,0.05 was considered to be statistically
significant. Categorical variables were expressed as number and
percentage. Most continuous variables followed a normal
distribution and were therefore presented as means together
with SDs. Those variables that did not follow a normal
distribution were presented as medians with interquartile range
(IQR). Differences in continuous variables between groups
were assessed by Student’s t-test or analysis of variance for
continuous data with normal distribution, or otherwise the
nonparametric Mann–Whitney test or Kruskal–Wallis H test.
Differences in categorical variables between groups were
assessed using the chi-square test. Multiple Cox proportional
regression analysis (odds ratio [OR], 95% CI) was used to
identify potential clinical predictors of all-cause death and
MACE. Survival analysis was performed using Kaplan–
Meier method. Survival curves were used to investigate the
effect of different diagnoses and Cys C on long-term all-cause
death and MACE. Receiver operating characteristic (ROC)
curves were constructed for discrimination between surviving
and dead patients. The areas under the curve (AUC) were
compared by using Hanley and McNeil method.
Baseline characteristics for the overall
Of the 720 patients in this cohort, 580 patients had UAP,
140 patients had AMI, and 699 patients (699/720, 97.08%)
provided informed consent and agreed to participate in the
study. A total of 100 patients were enrolled in the control
group, 93 of whom provided informed consent and agreed
to participate in the study (93/100, 93%).
Compared with the UAP and control groups, the AMI
group had lower systolic blood pressure (SBP), diastolic
blood pressure (DBP), and eGFR (P,0.01) but higher heart
rate, plasma fasting blood glucose, uric acid, Hcy, and Cys C
levels (P,0.01). The proportion of previous MI in the UAP
group was significantly higher than that in the AMI group
(P,0.01). There were no significant differences in the above
indicators between the UAP group and the control group
In the AMI group, the Cys C level and Hcy level were
decreased with eGFR level (P,0.01). Further analysis
indicated that the Hcy level was positively correlated with
Cys C level (r=0.720, P=0.001) and negatively correlated
with eGFR (r=−0.531, P=0.001), and the Cys C level was
negatively correlated with eGFR (r=−0.743, P=0.001).
The left ventricular ejection fraction (LVEF) in the AMI
group was significantly lower than that in the UAP group
(P,0.01) and the LVEF of the UAP group was significantly
lower than that of the control group (P,0.01). No
significant differences were found in other general conditions and
clinical data (Table 1).
severity of CAD and choice of treatment
We compared the severity of CAD and the choice of clinical
treatment strategy between the UAP and AMI groups. The
proportion of lesions in the left anterior descending (LAD)
artery, left circumflex (LCX) artery, and right coronary artery
(RCA) in the AMI group was significantly higher than those
in the UAP group (P,0.01). The proportion of patients
with multivessel disease and the severity of coronary artery
stenosis (Gensini score) were also significantly higher in the
AMI group than those in the UAP group (P,0.01). There
was no significant difference in the proportion of left main
(LM) lesion between the two groups (P.0.05).
All patients accepted to undertake intensive medication.
The proportion of PCI in the AMI group was higher than
that in the UAP group (P,0.01), and the proportion of only
intensive drug therapy in the AMI group was lower than that
in the UAP group (P,0.01). The proportion of CABG in the
two groups was similar (P.0.05).
For the selection of the PCI target vessel, the proportion
of LAD interventions in the AMI group was higher than that
in the UAP group (P,0.01). There were no significant
differences between the two groups in the proportions of LM,
LCX, and RCA interventions (P.0.05). The ratio of stent
implantation in the AMI group was higher than that in the
UAP group (P,0.05). There was no significant difference
in the number of stents implanted between the two groups
(P.0.05) (Table 2).
Baseline blood feature
egFr (ml/min/1.73 m 2)
Cys C (mg/l)
Notes: Data are shown as mean ± sD or n (%). Con versus UAP group ∆∆P,0.01; Con versus AMI group #P,0.05, ##P,0.01; UAP versus AMI group **P,0.01. Bold figures
indicate significant difference (P,0.05).
Abbreviations: ACeI, angiotensin converting enzyme inhibitor; ArB, angiotensin receptor blocker; AMI, acute myocardial infarction; BMI, body mass index; Con, control;
CRF, chronic renal failure; Cys C, cystatin C; DBP, diastolic blood pressure; DM, diabetes mellitus; EF, ejection fraction; eGFR, estimated glomerular filtration rate;
FBg, fasting blood glucose; hcy, homocysteine; hDl-C, high density lipoprotein-C; hr, heart rate; lDl-C, low density lipoprotein-C; MI, myocardial infarction; sBP, systolic
blood pressure; TC, total cholesterol; Tg, triglyceride; UA, uric acid; UAP, unstable angina pectoris; Con, control.
long-term prognosis of patients
One hundred and thirty patients with AMI, 534 patients
with UAP, and 89 cases in the control group had long-term
follow-up data completed.
The duration of follow-up was 40–116 months (median,
63 months; IQR, 51–74 months). The all-cause mortality rates
were 50.0% (65/130), 25.47% (136/534), and 12.36% (11/89)
for the AMI, UAP, and control groups (P,0.0001),
respectively. For cardiovascular mortality, the long-term rates were
34.62% (45/130) for AMI patients, 12.92% (69/534) for
UAP patients, and 5.62% (5/89) for control group patients
(P,0.0001). For non-cardiovascular mortality, the
longterm rates were 15.38% (20/130) for AMI patients, 12.55%
(67/534) for UAP patients, and 6.74% (6/89) for control
group patients. The ratios of cardiovascular mortality to
non-cardiovascular mortality were 2.25, 1.03, and 0.83 for
AMI, UAP, and control group patients (P,0.0001),
respectively. The recurrence of MI and repeat PCI was 4.62%
(6/130) and 3.85% (5/130) for AMI patients, 3.56% (19/534)
and 9.36% (50/534) for UAP patients, 1.12% (1/89) and 0%
(0/89) for control group patients. The MACE rates were
58.46% (76/130), 38.39% (205/534), and 13.48% (12/89) for
AMI, UAP, and control group patients (P,0.0001),
respectively. There was a significant difference in the incidence
of MACE, all-cause mortality, cardiovascular mortality,
non-cardiovascular mortality, and repeat PCI between the
Kaplan–Meier survival curves analysis showed that
long-term survival (P,0.0001) and event-free survival
(P,0.0001) rates were significantly different between the
three groups. The long-term survival and event-free survival
rates of AMI patients were significantly lower than those of
UAP patients (P,0.05) (Figure 1A and B).
long-term prognostic independent risk
Cox regression analysis was performed to determine the
factors that were associated with all-cause death and MACE at the
end of follow-up. After being adjusted for general conditions
(sex, body mass index, SBP, DBP, and LVEF), risk factors
(diabetes mellitus [DM], hypertension, hyperlipidemia,
previous MI, stroke, and CRF), and blood biochemistry indicators
(triglyceride, total cholesterol, high density lipoprotein-C,
low density lipoprotein-C, fasting blood glucose, and uric
acid), age, heart rate, eGFR, Hcy, and Cys C were found to
be independent risk factors for all-cause mortality in AMI
patients. Age, heart rate, DBP, eGFR, Hcy, and Cys C were
independent risk factors for MACE in AMI patients. Heart
rate, eGFR, Hcy, and Cys C were independent risk factors for
all-cause mortality in UAP patients. Cys C was an
independent risk factor for MACE in UAP patients (Table 3).
The concentration of Cys C related to all-cause death
according to tertile was compared between the AMI and the
UAP groups. According to the triplicate of plasma Cys C,
patients were divided into three groups. Tertiles (T) ranges of
Cys C were group T1: 0.99 (0.46–1.22) mg/L, group T2: 1.37
(1.23–1.63) mg/L, and group T3: 2.10 (1.64–7.69) mg/L. There
were 34 AMI patients and 184 UAP patients in group T1, 26
AMI patients and 196 UAP patients in group T2, 70 AMI
patients and 154 UAP patients in group T3. All-cause
mortalities in the T3 group were significantly higher than those in T1
and T2 groups for both AMI and UAP patients (Figure 2).
Cox regression analysis showed that Cys C was an
independent risk factor for all-cause mortality in the T2 group
(OR =2.28, 95% CI =1.89–2.62, P=0.003) and the T3 group
(OR =5.23, 95% CI =2.52–10.87, P=0.000) of AMI patients
and in the T3 group (OR =2.59, 95% CI =2.12–3.16,
P=0.001) of UAP patients.
Kaplan–Meier survival curves analysis showed that
long-term survival (P,0.0001) and event-free survival
(P,0.0001) rates were significantly different according to
the tertile concentration of Cys C in AMI patients. Group T3
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showed the lowest long-term survival and event-free survival
rates (Figure 3A and B).
Diagnostic powers of Cys C and hcy for
long-term all-cause death
The respective predictive cutoff values were constructed
according to the ROC curves of Cys C and Hcy for
discrimination between surviving and dead patients in
the AMI group (Figure 4). The AUC of Cys C was 0.892
(95% CI =0.836–0.948, P=0.0001) and the predictive cutoff
value for all-cause mortality was 1.815 mg/L (sensitivity
82.8%, specificity 86.4%). The AUC of Hcy was 0.904
(95% CI =0.849–0.958, P=0.0001) and predictive cutoff
value for all-cause mortality was 15.06 μmol/L (sensitivity
84.4%, specificity 83.1%).
According to the cutoff values of Cys C and Hcy, AMI
patients were divided into three groups: group 1 (Cys
C #1.815 mg/L and Hcy #15.06 μmol/L), group 2 (Cys
C .1.815 mg/L and Hcy #15.06 μmol/L or Cys C #1.815 mg/L
and Hcy .15.06 μmol/L), and group3 (Cys C .1.815 mg/L
and Hcy .15.06 μmol/L). The mortality rates were 10.7%
(6/56), 56.3% (9/16), and 86.2% (50/58), respectively, in
groups 1, 2, and 3 (P,0.0001). A further rise in mortality
was noted if the patients presented with two biomarkers
higher than the cutoff values derived from the ROC analysis
(group 3). This result implied that elevation of the
biomarkers was helpful for discriminating the development of
The key findings of this study are as follows: 1) baseline
Cys C is a strong predictor of all-cause death and MACE in
elderly patients admitted with both AMI and UAP; 2) the
predictive ability of Cys C in elderly AMI patients is far higher
than that in elderly UAP patients; 3) the predictive ability
of Cys C in elderly AMI patients increases with increasing
concentrations of Cys C; 4) the predictive ability of the
combined use of Cys C and Hcy in elderly AMI patients is
stronger than Cys C or Hcy alone; and 5) with the extension
of follow-up time, the effect of Cys C on prognosis is more
obvious in elderly AMI patients.
Accurate screening and assessment of the risk factors for
the long-term outcomes play a major role in AMI patients,
especially for very old patients. In recent years, a number
of large, randomized, controlled clinical trials have been
conducted. The GRACE20 study showed that eight factors
were predictors of death for ACS, wherein age was the most
powerful one. Some of our results were consistent with results
of the GRACE study; for example, the heart rate was higher,
and the SBP and the ejection fraction were lower in the AMI
group than those in the UAP group, so that the number of
all-cause deaths in the AMI group was higher than that in
the UAP group. However, since age was the most important
factor and all of the patients in our study were older than 80,
the GRACE scores were all higher than 140, and thus were
in the very high-risk group. Therefore, there is a need for
some new variables to further help the risk stratification for
death and MACE.
Some new biomarkers have showed improved GRACE
risk score prediction of clinical outcomes21–26 and some new
risk assessment tools incorporating new biomarkers for
cardiovascular events in ACSs have been created too.27–31
All of the improvements of these risk prediction tools were
mainly to improve the accuracy of the prognosis of ACS.
However, until now, there is no assessment tool for the
long-term prognosis of AMI patients over 80 years old.
Our study suggests that, in addition to the traditional
factors in the GRACE score, plasma Cys C and Hcy are
independent risk factors for extremely long-term all-cause
mortality and MACE in elderly AMI patients, and their
combined use resulted in better evaluation. There was a strong
positive relation between Cys C and Hcy.
DM is a traditional risk factor for poor prognosis of ACS.
Our study found that, although the proportion of DM in the
AMI group was similar to that in the UAP group, the fasting
blood glucose level in the AMI group was significantly higher
than that in the UAP group. These results indicated that firstly
AMI was a stressful condition, which may cause acute
hyperglycemia; secondly, poor control of the blood glucose level
may aggravate poor prognosis in old AMI patients. Our results
were in agreement with another recent study that indicated
that blood glucose level on admission $160 mg/dL was an
independent predictor of mortality in ACS patients.32
The ratios of multivessel disease and coronary artery
severe stenosis in the AMI group were higher than those in
UAP patients. In the real world, for elderly AMI patients, the
ratio of partial revascularization is higher than total
revascularization, and the number of implanted stents was relatively
less. During the procedure of PCI, as the critical artery, LAD
was more often chosen as the target vessel and implanted
stents. Similarly, the proportion of CABG remained low in
the selection of revascularization strategy in elderly AMI
patients, which may be related to the prevalence of more
cardiovascular risk factors in very old patients.
Plasma Cys C concentrations in the AMI group were
significantly higher than that of the UAP or the control group,
and no significant difference was found between the latter two
groups, although coronary artery stenosis was severe in the
UAP group. In this study, the level of Cys C in the control
group was significantly higher than that in 60-year-old AMI
Baseline Cys C is a strong independent predictor of long-term
and stable coronary heart disease patients.33–35
all-cause death and MACE in very old patients admitted with
These results suggest that in the elderly population, the
both AMI and UAP; the predictive ability of Cys C in very
plasma Cys C level generally increased, but there was no
obviold AMI patients increases with increasing concentrations
ous correlation between the severity of coronary artery stenosis
of Cys C; the combined use of Cys C and Hcy improves the
and the Cys C level. Cys C was associated with coronary plaque
predictive accuracy in very old AMI patients. Cys C and Hcy
instability. When AMI occurred, due to coronary plaque
rupmay thus represent novel biomarkers for long-term outcomes
ture, local inflammatory factors and platelets were activated,
in very old AMI patients.
and the Cys C level increased quickly. This may explain why
Cys C was closely related with AMI, and more obvious in the
elderly population. However, the causal relationship between
This study was supported by the Chinese PLA Medical
the two aspects needs to be confirmed by further study.
Science and Technology Youth Cultivate Project (fund
Previous studies of our group found that Cys C was an
number 2014QNP104) and National Natural Science
independent risk factor for prognosis in old ACS patients with
Foundation of China (fund numbers 81500269, 81500202,
DM18 and Hcy was an independent risk factor for prognosis
in old ACS patients. In this study, the study population was
further refined and the follow-up time was extended. The
.rvdoepww ll.syeuon results showed that the predictive ability for all-cause death
and MACE of Cys C in old AMI patients was far higher
/w an than that in old UAP patients and the predictive ability of
ttp rs Cys C increased with increasing concentration of Cys C in
old AMI patients. Hcy was also an independent risk factor
for all-cause death and MACE in old AMI patients. The
combined use of Cys C and Hcy improved the accuracy for
long-term outcomes evaluation.
This study analyzed the incidences of all-cause death,
cardiovascular death, and non-cardiovascular death among
the three groups. The results showed that not only all-cause
death but also death from cardiovascular versus
non-cardiovascular causes of the AMI group was twice as high as those
of the UAP and control groups. More patients in the AMI
group died of cardiovascular disease with direct risk factors.
Our results were also significantly higher than a recent large
scale study (wherein the 10-year all-cause mortality rate in
Chinese AMI patients was 44.7%).36
This study had several limitations that should be discussed.
The first is sample size. Although our study enrolled over
800 very old patients, the AMI groups contained only
135 patients; additional validation in the AMI group with
larger samples might be needed. The second limitation is that
our study was based on a single center registry that offered
observational data on nonrandomized patients. The third
limitation is that this study analyzed systolic function only;
we did not collect diastolic function data.
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The authors report no conflicts of interest in this work.
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