HIGH LEVELS OF RESISTIN IS A RISK FACTOR FOR CARDIOVASCULAR

EVENTS IN PATIENTS WITH ACUTE CORONARY SYNDROME

Bayu setia, Wayan Wita, AA Wiradewi Lestari,

Faculty of Medicine University Udayana / Sanglah Hospital Denpasar Indonesia

Abstract

Objective : To investigate the relationship between resistin plasma levels in patients with acute
coronary syndrome (ACS) as risk factor for cardiovascular event (CVE)
Methods :
This was a cohort prospective study of patients with ACS with 68 samples from February 2012
until January 2013. Relative risk was considered significantly minimal = 1,5. The cut off point
for low resistin was ≤ 2,33 ng/ml and the cut off point for high resistin was ≥ 2,33 ng/ml
Results :
The cardiovascular events were occured significantly with higher serum resistin levels in patient
with acute coronary syndrome with analysis cox proportional model HR 1,72 ,CI 95% ; 1,28 to
2,32, p = 0,01, and result of analysis cox proportional models of the effect resistin with
conventional risk (dyslipidemia, hypertension, diabetes mellitus, obesity, smoking and age on
inscidence of cardiovascular events HR 1,66, CI 95% ; 1,19 to 2,31, p = 0,01 Results showed
there was a significant relationship between high resistin and risk of cardiovascular event in
patient with acute coronary syndrome
Conclusions :
High resistin serum levels was independently associated with risk of cardiovascular event in
patients acute coronary syndrome

Keyword : Resistin, Cardiovascular Events, Acute Coronary Syndrom

BACKGROUND cysteine-rich proteins, collectively resistin-

Resistin recently is described as a
novel adipokine that suggested to play a role
in the development of insulin resistance and
obesity (1). It is known that inflammation
and endothelial dysfunction play a critical
role in plaque destabilization and
vulnerability. Inflammatory responses
stimulate resistin secretion and resistin can
also promotes production of
proinflammatory mediators such as
interleukin-6 (IL-6), tumour necrosis factor-
alpha (TNF-a), and IL-12, and hence
aggravates the proinflammatory response
(2).
Resistin is a 12.5 kDa sized C-
terminal cysteine-rich signaling peptide
(3,4). It is a member of a class of
like molecules, which have differential
tissue distribution (5). Resistin is secreted
predominantly by adipose tissue in human
and rodents. In particular, it is secreted
from adipocytes in both species and also
by macrophages within adipose tissue in
humans (3,4). It exists in three forms: a
trimer, a hexamer, and a monomer, with
the lower molecular weight form is the
most active form (6). Recently, functional
receptors for resistin were identified,
named decorin (7).
METHODS
Study population
We enrolled 68 consecutive patients
with diagnosis acute coronary syndrome
between February 2012 until January 2013.
Fourteen patients experienced group without those risk factors (Table 1).
cardiovascular events during follow-up. From clinical presentation, STEMI patients
Criterias for the diagnosis ACS were based had the most cardiovascular events (13
on the European Society of Cardiology patients, 19,1%) (Table 2). All data was
guidelines. We excluded patients who had distributed normally. The cut off point was
valvular heart disease, heart failure, hepatic determined using median value, low resistin
or renal dysfunction, evidence of active was < 2,33 ng/ml and high resistin was ≥
infective or neoplastic conditions, and 2,33 ng/ml.
chronic inflammatory diseases. The mean of cardiovascular events
Resistin assay, using ELISA, was onset in group with high resistin levels had
used for the quantitative determination of less survival cumulative than the group with
resistin hormone. The mean follow-up of the low resistin levels (Table 3 and Figure 1).
study population was 6 months. Analytic result of resistin levels
Cardiovascular events were defined effect on cardiovascular event incidence rate
as reinfarction, stroke, and cardiovascular showed that independent variable (resistin)
mortality. Cardiovascular events were influenced dependent variable
identified by exploring medical record and (cardiovascular events) with ratio 1,72 (CI
phone contacts. 95%;1,28 s.d 2,32) and p value = 0,01
Statistical analysis (Table 4). After controlled variables were
Statistical analysis was done by controlled, resistin still influenced
SPSS statistical software (SPSS for Window cardiovascular events with ratio 1,67 (CI
16,0). Kolmogorov-Sminornov test was used 95%;1,20-2,32) and p value = 0,01 (Table
to to determine normality data distribution. 5).
The Levene’s test analysis was used to
determine the homogenous of data. Non
parametric test was used to determine the
value of the median. Kapplan Meiyer and
Log Rank test were used to analyze the
relationship between independent variables
and cardiovascular events. Survival analysis
used test Cox proportional model. The risk
factors for cardiovascular mortality were
analysed with logistic regression. The
covariates were resistin, left ventricular
ejection fraction (LVEF), heart rate, urea,
and coronary artery bypass graft (CABG)
history. Data was expressed as mean ±
standard deviation. Statistical significance
was defined as p < 0.05.
RESULTS
The cardiovascular events were
higher in group with diabetes mellitus,
hypertension, and obesity than the group
without those risk factors. Conversely, the
cardiovascular events were less in group
with dyslipidemia and smoking than the
 Table 1
Data Characteristic

Characteristics Events Without events

% %
Male 21,8% 78,2%
Female 15,4% 84,6%
Dyslipidemia 16,7% 83,3%
Without 50% 50%
dyslipidemia
Obesity 24,3% 75,7%
Without obesity 16,1% 83,9%
Smoking 17,6% 82,4%
Without smoking 23,6% 76,4%
Hypertension 28,9% 71,1%
Without 10% 90%
hypertension
DM 36,4% 63,6%
Without DM 17,5% 82,5%

Table 2
Clinical Presentation of ACS with Cardiovascular Events

ACS Events (%) Without Events (%)

UAP 1 (1,5 %) 11 (16,2)
NSTEMI 0 (0%) 11 (16,2%)
STEMI 13 (19,1%) 32 (47,0%)
TOTAL 14 (20,6%) 54 (79,4%)

Table 3

Kaplan-Meier Analytical Result of The Mean Difference of Onset Cardiovascular Events

Between Subjects Group with High and Low Resistin Levels

Resistin Mean Events SE Events Log Rank P value

Levels Onset Onset Chi-square
High 130,412 12,98 5,982 0,01
Low 168,853 6,68
Total 149,632 7,66
 Figure 1

Table 4

Cox Proportional Model Analytical Result Resistin Effect to Cardiovascular Events

P CI 95% HR
Variables value Hazard Ratio Lower Limit Upper Limit
Resistin 0,01 1,718 1,275 2,315

Table 5
Cox Proportional Model Analytical Result Resistin Effect, Dyslipidemia, DM,
Hypertension, Obesity, Smoking, and Age to Cardiovascular Events Incidence

CI 95% HR
Variables P Value Hazard Lower Upper
Ratio Limit Limit
Resistin 0,01 1,665 1,195 2,319
Obesity 0,63 1,347 0,318 4,590
Dyslipidemia 0,33 0,334 0,087 1,287
Smoking 0,93 0,954 0,318 2,865
Hypertension 0,35 1,926 0,494 7,506
DM 0,52 1,535 0,395 4,590
Age 0,60 1,016 0,959 1,076
Discussions
CAD severely threats human health
by increasing morbidity. Among its multiple
risk factors, insulin resistance is considered
as one of the new independent
cardiovascular risk factors. Resistin was first
reported by Steppan et al (7). Extensively
acts on the insulin targeted organs and
influences the metabolism of glucose and
lipids via affecting signal transduction
pathways and the transcription of the
enzymes related to metabolism, resulting in
insulin resistance (8,9). Insulin resistance
may directly promotes the development of
CAD. Several studies proposed that resistin
is the effector molecule that links the
metabolic syndrome and insulin resistance
to atherosclerotic burden, possibly through
triggering inflammatory processes (10,11).
Resistin may contributes to the
atherosclerotic process by activation of
endothelial cells leading to endothelial
dysfunction and thereby stimulating mul-
tiple pro-atherosclerotic pathways (9,10,12).
The endothelium represents an important
point of convergence of cardiovascular and
metabolic pathways, since insulin resistance
di-rectly promotes endothelial dysfunction
(13), which is considered as an early and
integral step of atherosclerotic vascular
disease (15,16). Resistin promotes smooth
muscle cell proliferation through activation
of extra-cellular signal-regulated kinase 1/2
and phosphatidylinositol 3-kinase pathways
(16). Resistin induces endothelin-1 promoter
activity via the AP-1 site, up-regulates
adhesion molecules and chemoki-nes, and
down-regulates tumor necrosis factor re-
ceptor-associated factor-3 (17,18).
In this study, resistin influence was
proved as one of inflammation factors to
atherosclerosis progressivity in patients with
acute coronary syndrome then cardiovacular
events occured. After we got median levels
2,33 ng/ml and divided into < 2,33 ng/ml for
low resistin levels group and ≥ 2,33 ng/ml
for high resistin levels, we got survival rate
between the groups was significant, 130
days vs 169 days. It showed that the survival
of patients with high resistin levels (130
days) was less than the patients with low
resistin levels (160 days). This low survival
was caused by progressive inflammation in
patient with cardiovascular events. This
progressive inflammation process could be
predicted with high resistin levels (≥ 2,33
ng/ml) (Table 3 and Figure 1).
After 6 months follow up, from 34
ACS patients with high resistin levels, 11
patients had cardiovascular events. The
result was analyzed using bivariate and
multivariate anaysis to control confounding
factors (hypertension, DM, obesity,
smoking, age, dyslipidemia). Cardiovascular
events risk was two times signihigher in
group with high resistin levels than low
resistin levels group. and the result was
statistically significant.
Conclusion
High resistin serum levels was
independently associated with risk of
cardiovascular events in patients acute
coronary syndrome.
References
1. Jung HS, Park KH, Cho YM, Chung SS,
Cho HJ, Cho SY, et al. Resistin is
secreted from macrophages in atheromas
and promotes atherosclerosis.
Cardiovasc Res 2006; 69: 76-85.
2. Patel L, Buckels AC, Kinghorn IJ,
Murdock PR, Holbrook JD, Plumpton C,
et al. Resistin is expressed in human
macrophages and directly regulated by
PPAR gamma activators. Biochem
 Biophys Res Commun 2003; 300:472-
476.
3. Momiyama Y, Ohmori R, Uto-Kondo H,
Tanaka N, Kato R,Taniguchi H, et al.
Serum resistin levels and
cardiovascularevents in patients
undergoing percutaneous coronary
intervention. J Atheroscler Thromb
2011; 18: 108-114.
4. Chu S, Ding W, Li K, Pang Y, Tang C.
Plasma resistin associated with
myocardium injury in patients with acute
coronary syndrome. Circ J 2008; 72:
1249-1253.
5. Al-Daghri N, Chetty R, McTernan PG,
Al-Rubean K, Al-Attas O, Jones AF, et
al. Serum resistin is associated with C-
reactive protein and LDL cholesterol in
type 2 diabetes and coronary artery
disease in a Saudi population.
Cardiovasc Diabetol 2005; 4: 10.
6. Verma S, Li SH, Wang CH, Fedak PW,
Li RK, Weisel RD, et al. Resistin
promotes endothelial cell activation:
further evidence of adipokine-
endothelial interaction. Circulation 2003;
108: 736-740.
7. Rajala, M.W., Obici, S., Scherer, P.E.,
Rossetti, L., 2003. Adipose-derived
resistin and gut-derived resistin-like
molecule-beta selectively impair insulin
action on glu-cose production. J. Clin.
Invest., 111(2):225-230.
8. Reilly, M.P., Lehrke, M., Wolfe, M.L.,
Rohatgi, A., Lazar, M.A., Rader, D.J.,
2005. Resistin is an inflammatory
marker of atherosclerosis in humans.
Circulation,111(7):932-939.
9. Steppan, C.M., Bailey, S.T., Bhat, S.,
Brown, E.J., Banerjee, R.R., Wright,
C.M., Patel, H.R., Ahima, R.S., Lazar,
M.A., 2001a. The hormone resistin links
obesity to dia-betes. Nature,
409(6818):307-312.
10. Kawanami, D., Maemura, K., Takeda,
N., Harada, T., Nojiri, T., Imai, Y.,
Manabe, I., Utsunomiya, K., Nagai, R.,
2004.Direct reciprocal effects of resistin
and adiponectin on vascular endothelial
cells: a new insight into adipocyto-kine-
endothelial cell interactions. Biochem.
Biophys. Res.Commun., 314(2):415-
419.
11. Chen C, Jiang J, Lü JM, Chai H, Wang
X, et al. (2010) Resistin decreases
expression of endothelial nitric oxide
synthase through oxidative stress in
human coronary artery endothelial cells.
Am J Physiol Heart Circ Physiol 299:
H193-201.
12. Jung HS, Park KH, Cho YM, Chung SS,
Cho HJ, et al. (2006) Resistin is secreted
from macrophages in atheromas and
promotes atherosclerosis .Cardiovasc
Res 69: 76-85.
13. Weikert C, Westphal S, Berger K,
Dierkes J, Möhlig M, et al. (2008)
Plasma resistin levels and risk of
myocardial infarction and ischemic
stroke. J Clin Endocrinol Metab 93:
2647-2653.
14. Efstathiou SP, Tsiakou AG, Tsioulos DI,
Panagiotou TN, Pefanis AV, et al.
(2007) Prognostic significance of
plasma resistin levels in patients with
atherothrombotic ischemic stroke. Clin
Chim Acta 378: 78-85.
15. Jamaluddin MS, Weakley SM, Yao Q,
Chen C (2012) Resistin: functional roles
and therapeutic considerations for
 cardiovascular disease. Br J Pharmacol
165: 622-632.
16. Qatanani M, Szwergold NR, Greaves
DR, Ahima RS, Lazar MA (2009)
Macrophage-derived human resistin
exacerbates adipose tissue inflammation
and insulin resistance in mice. J Clin
Invest 119: 531-539.
17. Degawa-Yamauchi M, Bovenkerk JE,
Juliar BE, Watson W, Kerr K, et al.
(2003) Serum resistin (FIZZ3) protein is
increased in obese humans. J Clin
Endocrinol Metab 88: 5452-5455.
18. Vendrell J, Broch M, Vilarrasa N,
Molina A, Gómez JM, et al. (2004)
Resistin, adiponectin, ghrelin, leptin, and
proinflammatory cytokines: relationships
in obesity. Obes Res 12: 962-971.