Increased Hs-CRP/adiponectin ratio is associated with increase carotid intima-media thickness
Lipids in Health and Disease
Increased Hs-CRP/adiponectin ratio is associated with increase carotid intima-media thickness
Huocheng Liao 3
Zhiming Li 2
Dongdan Zheng 1
Jianping Liu 3
Yan Liu 3
Chun Xiao 3
Hongguang Wang 0 4
0 Internal Medicine-Cardiovascular Department, Dongying People's Hospital of Shandong Province , NO.137, Nanyi Road, Dongying, Shangdong Province , China
1 Department of Cardiology, The First Affiliated Hospital of Sun Yat-sen University , Guangzhou , China
2 Department of Cardiology, Huizhou Municipal Central Hospital , 41st Eling North RD, Huicheng District, Huizhou , China
3 Department of Cardiology, the 3rd People's Hospital , Huizhou , China
4 Internal Medicine-Cardiovascular Department, Dongying People's Hospital of Shandong Province , NO.137, Nanyi Road, Dongying, Shangdong Province , China
Background: High sensitivity C-reactive protein (Hs-CRP) and adiponectin (APN) are two critical cytokines and exert inverse effects on atherosclerosis initiation and progression. The purpose of our study was to investigate the value of Hs-CRP and ANP ratio (Hs-CRP/APN ratio) on evaluating atherosclerosis progression. Method: One hundred sixty consecutive participants underwent carotid intima-media thickness (CIMT) measured by ultrasound were enrolled and drawn fasting blood samples for plasma levels Hs-CRP and APN, serum levels of lipid profiles and fasting blood glucose evaluation. Other anthropometrics and clinical status were collected by questionnaire. All participants were divided into 4 groups according to the baseline Hs-CRP/APN ratio and underwent CIMT measurement every 6 months. CIMT increment and composite cardiovascular endpoints were compared after 24 months' follow-up. Results: At baseline, body mass index (BMI), smoking, diabetic mellitus, usage of statins, Hs-CRP and APN independently correlated with Hs-CRP/APN ratio as analyzed by spearman rank correlation. Smoking, serum level of LDL-C, plasma level of Hs-CRP and Hs-CRP/APN ratio were positively correlated with CIMT while usage of statins and plasma level of APN were negatively correlated with CIMT as analyzed by multiple linear regression analysis. After 24 months' follow-up, the progression of CIMT was the most prominent in the fourth quartile of baseline Hs-CRP/APN ratio. In addition, the incidence of composite cardiovascular endpoint was also higher in the fourth quartile as compared to the other 3 lower quartiles. Conclusion: Hs-CRP/APN ratio was a useful predictor to discriminate subjects who were at increased risk of atherosclerosis progression.
High sensitivity C-reactive protein; Adiponectin; Atherosclerosis
In the past decades, accumulating evidence from basic
and clinical studies consistently demonstrate that
inflammation plays pivotal and complicated roles in the initiation
and progression of atherosclerosis and atherosclerotic
cardiovascular diseases [1-3]. Notably, increased serum
level of inflammatory cytokines portends a higher
incidence of cardiovascular events such as myocardial
infarction and ischemic stroke [4,5]. Therefore, guidelines have
recommended that inflammatory cytokines such as high
sensitivity C-reactive protein (Hs-CRP) should be
integrated into the algorithm of cardiovascular risk evaluation
[1,6]. Knowingly, Hs-CRP is a non-specific inflammatory
cytokine, and by means of increasing inflammatory cells
infiltration, augmenting oxidative stress, impairing
endothelial function as well as decreasing nitric oxide (NO)
production, Hs-CRP accelerates the formation and
disruption of atherosclerotic plaque [7-9]. On the contrary,
adiponectin (APN) is a cardio-protective cytokine due to
its capability to inhibiting inflammatory cytokines such as
interleukin-6, TNF- and Hs-CRP expressions,
downregulating monocytes chemoattractant proein-1 (MCP-1)
expression, increasing NO generation as well as enhancing
myocardial blood perfusion [10-13].
Carotid intima-media thickness (CIMT), an early and
sensitive indicator for subclinical atherosclerosis, is
significantly associated with plasma levels of Hs-CRP and APN
as reported by previous studies [14,15]. With respect to
the aforementioned mechanisms by which Hs-CRP and
APN exert on cardiovascular system, we hypothesized that
Hs-CRP and APN ratio (Hs-CRP/APN ratio) might be
useful as an indicator to help us discriminate the status of
atherosclerosis. Thus that, we conducted a pilot study to
investigate the relationship between Hs-CRP/APN ratio
and CIMT in population without overt cardiovascular
diseases, and then we consecutively measured CIMT in
the follow-up 24 months so as to determine the value of
Hs-CRP/APN ratio in predicting CIMT progression and
future cardiovascular events.
Study population enrollment
One hundred and sixty consecutive subjects were
randomly enrolled from January 2011 to January 2012, and
all subjects were underwent CIMT measurement by
duplex ultrasound. Written informed consent was obtained
and the ethics committee of the 3rd Peoples Hospital of
Huizhou approved present study. Subjects who initially
without overt cardiovascular diseases, which defined as
angina pectoris, previous myocardial infarction, transient
ischemia attack or ischemic stroke and peripheral artery
diseases, were ruled in, and those with a previous history
of atherosclerotic cardiovascular diseases or baseline
level of Hs-CRP >10 mg/L, which indicated intensively
infectious diseases or collagen diseases or potential
tumors, were ruled out.
Demographic and clinical characteristics collection
Demographic and clinical characteristics such as age,
gender, body mass index (BMI), smoking status,
hypertension or current anti-hypertension therapy,
dyslipidemia or use of lipid-lowering medications and diabetic
mellitus were obtained by the means of computerized
Fasting blood samples were drawn from each participant
and transferred on ice to center laboratory for analysis.
An IMMAGE automatic immunoassay system
(BeckmannCoulter) was used to examine plasma level of Hs-CRP.
Intra-assay variability coefficient lied between 3.5-5.0%, and
inter-assay variability coefficient between 4.0-7.5%, and
limited detection level was 0.2 mg/L. APN was measured
by a high sensitivity Human adiponectin ELISA kit (BioCat
GmbH) with intra-assay variability coefficient lied
between 4.0-5.5% and inter-assay variability coefficient
between 5.0-7.5%. Triglyceride (TG), total cholesterol
(TC), low density lipoprotein-cholesterol (LDL-C), high
density lipoprotein-cholesterol (HDL-C) and fasting
blood glucose were also measured by Automatic
Biochemistry Analyzer (Beckman coulter UniCel DxC 800
Carotid intima-media thickness measurement
Ultrasonic examination was performed with an 8.5 MHz
linear array transducer. The initial and follow-up
measurements were performed by two investigators who
were blinded to the characteristics of all participants.
Common carotid artery (one milimeter below the
carotid artery bifurcation) was chosen to evaluate CIMT
on both sides. The average inter-observers reliability
coefficient was 0.95 (95% confidence interval (CI) 0.93
to 0.96, p < 0.05) and the intra-observer reliability
coefficient 0.93 (95% CI 0.91 to 0.94, p < 0.05). The values
of CIMT were averaged by the left and right CIMT
values. The absolute annual change of CIMT was
determined by the following formula: (final value minus
baseline value) divided by the total follow up years.
All subjects were followed up for the occurrence of first
cardiovascular events, including myocardial infarction,
ischemic stroke, and cardiovascular diseases related
death. Total follow-up lasted for 24 months.
All analyses were performed by SPSS16.0 package. All
values were expressed as mean SD or percentage.
Correlation between Hs-CRP/APN ratio with demographic
and clinical characteristics were evaluated by Pearson
correlation or Spearman rank correlation as appropriate.
Independent correlation between Hs-CRP/APN ratio
and other variables with CIMT were determined by
multiple linear regressions. Subjects were divided into four
groups according to the baseline quartiles of Hs-CRP/
APN ratio. Comparison of CIMT value of each quartile
at the same time point, and comparison of CIMT
increment of each quartile during follow-up were operated by
one-way ANOVA. A p value < 0.05 was considered to be
Baseline characteristics and relationship between Hs-CRP/
APN ratio and other variables
As shown in Table 1, the age of participants was 55.3
4.8 years and 45.0% of participants were female.
Approximately 58.1% were cigarette smoker, BMI was 26.5 4.1
Kg/m2, 45.0% with diabetic mellitus, 53.1% with
hypertension and nearly 51.9% with anti-hypertension therapy,
current statins usage were 49.3%. Plasma levels of Hs-CRP
and APN were 6.9 1.8 mg/L and 10.8 2.2 g/L,
respectively, and the Hs-CRP/APN ratio was 0.6 0.2.
Correlation between Hs-CRP/APN ratio and other variables
was shown in Table 1. For all the variables, BMI, smoking,
diabetic mellitus, usage of statins, and plasma levels of
Hs-CRP and APN significantly correlated with Hs-CRP/
APN ratio (all p values < 0.05).
Table 1 Baseline characteristics and relationship between
Hs-CRP/APN ratio and other variables (n = 160)
Diabetic mellitus (%)
Usage of statins (%)
correlated with CIMT (p < 0.05), and other variables
including smoking, serum level of LDL-C, plasma level
of Hs-CRP and Hs-CRP/APN ratio were positively
correlated with CIMT (p < 0.05).
Comparison of CIMT within quartiles of Hs-CRP/APN ratio
According to baseline Hs-CRP/APN ratio, participants
were divided into four quartiles. Hs-CRP/APN ratio from
the first to the fourth quartile was 0.10 0.03, 0.34 0.06,
0.50 0.10 and 0.68 0.13, respectively. As presented in
Table 3, CIMT was significantly different between each
quartile at the same time point and the increment of
CIMT in the fourth quartile was the greatest when
compared to the other 3 groups.
Comparison of clinical events
During the 24 months follow-up, there were totally 4
cases of myocardial infarction and 6 cases of ischemic
stroke occurred. Notably, the incidence of composite
endpoint was higher in the fourth quartile (6 cases) than
the other 3 groups as shown in Table 4. In the fourth
quartile, the first episode of clinical event happened in
the first ten month, while it was in the eighteenth
month when the first clinical event occurred in the first
Our present study shows that in participants without
overt atherosclerotic cardiovascular diseases, increased
baseline Hs-CRP/APN ratio portends a higher risk of
CIMT progression and a higher incidence of
cardiovascular events during 24 months follow-up. Future study
is imperative in investigating whether decreasing
HsCRP/APN ratio could result in better cardiovascular
Previously, a substantial number of studies have reported
the association between cardiovascular risk factors and
plasma levels of Hs-CRP and APN. For example, BMI was
reported positively correlated with Hs-CRP level while
negatively with APN level [15,16], which therefore might
partially explain the positive relationship between BMI
and Hs-CRP/APN ratio in our current study. Smoking
is a crucial risk factor contributing to continuous
systemic inflammation due to its effects on impairing
endothelial function and promoting vascular
inflammation . Commonly, in population with long-term
cigarette smoking, the plasma level of Hs-CRP was
increased therefore resulting in the increased Hs-CRP/
APN ratio. Accordingly, most of the complications of
diabetes mellitus resulted from endothelial dysfunction
and activation [18,19], which characterized by reduced
NO production and inflammatory cytokines
upregulation and subsequently leaded to plasma levels of
Hs-CRP increase and APN decrease. Previously, many
Spearmans rank correlation coefficient (r) is shown.
Relationship between CIMT and Hs-CRP/APN ratio and
Relationship between CIMT and Hs-CRP/APN ratio and
other variables was shown in Table 2. Notably, CIMT
significantly correlated with smoking, serum level of
LDL-C, usage of statins, plasma levels of Hs-CRP and
APN, and Hs-CRP/APN ratio. Specifically, usage of
statins and plasma level of APN were negatively
Table 2 Relationship between CIMT and Hs-CRP/APN ratio
and other variables
Table 3 Comparison of CIMT within quartiles of Hs-CRP/APN ratio
1st (n = 40)
2nd (n = 40)
3rd (n = 40)
4th (n = 40)
Denote: 1st = the first quartile, 2nd = the second quartile, 3rd = the third quartile, and 4th = the fourth quartile; *P < 0.05, versus baseline level of CIMT at the same
quartile, #P < 0.05, versus the first quartile of CIMT at the same time point.
primary and secondary studies have revealed the
pleiotropic effects of statins, which was largely ascribed to
the reduction of Hs-CRP level and increase NO
production [20,21]. Therefore, it was no wonder that statins
was negatively correlated with Hs-CRP/APN ratio.
However, In the future, to assess whether modifying
above factors could result in a favorable Hs-CRP/APN
ratio is imperative.
Carotid intima-media thickness (CIMT) has been
broadly considered an important parameter to identify
an early status of atherosclerosis, and measure of CIMT
could facilitate physicians to discriminate those who are
at increased risk of cardiovascular events [22,23]. In
current study, smoking, serum level of LDL-C, usage of
statins, plasma levels of Hs-CRP and APN, and Hs-CRP/
APN ratio were found significantly correlated with
CIMT as evaluated by multiple linear regression analysis.
Based on previous studies [17-21], it was reasonable to
explain the relationship between CIMT and
cardiovascular risk factors such as smoking and LDL-C.
Nevertheless, this was the first time we reported that Hs-CRP/
APN ratio was also significantly associated with CIMT.
Since plasma level of Hs-CRP and APN were affected
by many conditions as reported above, it was not
possible for us to conclude that Hs-CRP/APN ratio was an
independent risk factor for CIMT progression. However,
because Hs-CRP/APN ratio could reflect a broader
spectrum of pathophysiological situation in terms of
both pro-inflammation and anti-inflammation, we
believed that incorporating Hs-CRP/APN ratio into
cardiovascular risk assessment was useful and helpful for
improving the capacity of risk discrimination. Outcome
Table 4 Comparison of clinical events
Cardiovascular events 1st 2nd 3rd 4th
(n = 40) (n = 40) (n = 40) (n = 40)
from our follow-up study was also supported for our
reasoning. All participants were follow-up for 24 months and
underwent serials CIMT measurement every 6 months.
Results showed that the progression of CIMT was more
significant in the fourth quartile of Hs-CRP/APN ratio.
Additionally, the incidence of composite outcomes was
also higher in the fourth quartile than that of the other 3
lower quartiles, indicating that baseline Hs-CRP/APN
ratio was a useful parameter for helping us to identify
those who were at increased risk of cardiovascular events.
Finally, there were some limitations of current study.
First of all, the sample size was not large enough.
Secondly, because current study was an observational study,
one could not make definite causal relationship between
Hs-CRP/APN ratio and CIMT progression and
cardiovascular events. Additionally, there were some inhere
biases of observational studies which physicians should
bear in mind when interpreted current study.
In conclusion, according to our current study, Hs-CRP/
APN ratio was a useful predictor for atherosclerosis
progression and clinical events. Because Hs-CRP/APN
ratio highly correlated with BMI, smoking, diabetic
mellitus, usage of statins, and meanwhile baseline Hs-CRP/
APN ratio significantly correlated with CIMT
progression and the incidence of clinical events, we considered
that further study should be focused on lifestyle
modification, glucose control and usage of statins so as to
find out whether tough control of these risks factors
and more intensive therapy with statins could improve
the Hs-CRP/APN ratio which finally results in better
The authors declare that they have no competing interests.
HL, ZL, JL and YL performed this study, DZ performed statistic analyses, and
CX and HW designed this study, and HL and ZL wrote this article. All authors
read and approved the final manuscript.
Huocheng Liao and Zhiming Li co-first authors.
We appreciate very much for the kindly help from Dr. Junzhong Su.
1. Libby P , Ridker PM , Maseri A : Inflammation and atherosclerosis. Circulation 2002 , 105 : 1135 - 1143 .
2. Kuller LH , Tracy RP : The role of inflammation in cardiovascular disease . Arterioscler Thromb Vasc Biol 2000 , 20 : 901 .
3. Ridker PM , Danielson E , Fonseca FA , Genest J , Gotto AM Jr, Kastelein JJ , Koenig W , Libby P , Lorenzatti AJ , MacFadyen JG , Nordestgaard BG , Shepherd J , Willerson JT , Glynn RJ : Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein . N Engl J Med 2008 , 359 : 2195 - 2207 .
4. Blake GJ , Rifai N , Buring JE , Ridker PM : Blood pressure, C-reactive protein, and risk of future cardiovascular events . Circulation 2003 , 108 : 2993 - 2999 .
5. Tanne D , Benderly M , Goldbourt U , Haim M , Tenenbaum A , Fisman EZ , Matas Z , Adler Y , Zimmlichman R , Behar S : C-reactive protein as a predictor of incident ischemic stroke among patients with preexisting cardiovascular disease . Stroke 2006 , 37 : 1720 - 1724 .
6. Stone NJ , Robinson JG , Lichtenstein AH , Bairey Merz CN , Blum CB , Eckel RH , Goldberg AC , Gordon D , Levy D , Lloyd-Jones DM , McBride P , Schwartz JS , Shero ST , Smith SC Jr, Watson K , Wilson PW : 2013 ACC/ AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines . Circulation 2014 , 129 : S1 - 1S45 .
7. Pasceri V , Willerson JT , Yeh ET : Direct proinflammatory effect of C-reactive protein on human endothelial cells . Circulation 2000 , 102 : 2165 - 2168 .
8. Devaraj S , Xu DY , Jialal I: C-reactive protein increases plasminogen activator inhibitor-1 expression and activity in human aortic endothelial cells: implications for the metabolic syndrome and atherothrombosis . Circulation 2003 , 107 : 398 - 404 .
9. Verma S , Li SH , Badiwala MV , Weisel RD , Fedak PW , Li RK , Dhillon B , Mickle DA : Endothelin antagonism and interleukin-6 inhibition attenuate the proatherogenic effects of C-reactive protein . Circulation 2002 , 105 : 1890 - 1896 .
10. Ouchi N , Kihara S , Arita Y , Maeda K , Kuriyama H , Okamoto Y , Hotta K , Nishida M , Takahashi M , Nakamura T : Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin . Circulation 1999 , 100 : 2473 - 2476 .
11. Ouchi N , Kihara S , Arita Y , Nishida M , Matsuyama A , Okamoto Y , Ishigami M , Kuriyama H , Kishida K , Nishizawa H , Hotta K , Muraguchi M , Ohmoto Y , Yamashita S , Funahashi T , Matsuzawa Y : Adipocyte-derived plasma protein, adiponectin, suppresses lipid accumulation and class A scavenger receptor expression in human monocyte-derived macrophages . Circulation 2001 , 103 : 1057 - 1063 .
12. Okamoto Y , Arita Y , Nishida M , Muraguchi M , Ouchi N , Takahashi M , Igura T , Inui Y , Kihara S , Nakamura T , Yamashita S , Miyagawa J , Funahashi T , Matsuzawa Y : An adipocyte-derived plasma protein, adiponectin, adheres to injured vascular walls . Horm Metab Res 2000 , 32 : 47 - 50 .
13. Arita Y , Kihara S , Ouchi N , Maeda K , Kuriyama H , Okamoto Y , Kumada M , Hotta K , Nishida M , Takahashi M , Nakamura T , Shimomura I , Muraguchi M , Ohmoto Y , Funahashi T , Matsuzawa Y : Adipocyte-derived plasma protein adiponectin acts as a platelet-derived growth factor-BB-binding protein and regulates growth factor-induced common postreceptor signal in vascular smooth muscle cell . Circulation 2002 , 105 : 2893 - 2898 .
14. Wang TJ , Nam BH , Wilson PW , Wolf PA , Levy D , Polak JF , D'Agostino RB , O'Donnell CJ : Association of C-reactive protein with carotid atherosclerosis in men and women: the Framingham Heart Study . Arterioscler Thromb Vasc Biol 2002 , 22 : 1662 - 1667 .
15. Yang WS , Lee WJ , Funahashi T , Tanaka S , Matsuzawa Y , Chao CL , Chen CL , Tai TY , Chuang LM : Weight reduction increases plasma levels of an adipose-derived anti-inflammatory protein, adiponectin . J Clin Endocrinol Metab 2001 , 86 : 3815 - 3819 .
16. Greenfield JR , Samaras K , Jenkins AB , Kelly PJ , Spector TD , Gallimore JR , Pepys MB , Campbell LV : Obesity is an important determinant of baseline serum C-reactive protein concentration in monozygotic twins, independent of genetic influences . Circulation 2004 , 109 : 3022 - 3028 .
17. Hasday JD , Bascom R , Costa JJ , Fitzgerald T , Dubin W : Bacterial endotoxin is an active component of cigarette smoke . Chest 1999 , 115 : 829 - 835 .
18. Tabit CE , Shenouda SM , Holbrook M , Fetterman JL , Kiani S , Frame AA , Kluge MA , Held A , Dohadwala MM , Gokce N , Farb MG , Rosenzweig J , Ruderman N , Vita JA , Hamburg NM : Protein kinase C-beta contributes to impaired endothelial insulin signaling in humans with diabetes mellitus . Circulation 2013 , 127 : 86 - 95 .
19. Rahimi Z , Rahimi Z , Shahvaisi-Zadeh F , Sadeghei S , Vessal M , Yavari N : eNOS 4a/b polymorphism and its interaction with eNOS G894T variants in type 2 diabetes mellitus: modifying the risk of diabetic nephropathy . Dis Markers 2013 , 34 : 437 - 443 .
20. Yamazaki D , Ishida M , Watanabe H , Nobori K , Oguma Y , Terata Y , Koyama T , Iino K , Kosaka T , Ito H : Comparison of anti-inflammatory effects and high-density lipoprotein cholesterol levels between therapy with quadruple-dose rosuvastatin and rosuvastatin combined with ezetimibe . Lipids Health Dis 2013 , 12 : 9 .
21. Qu HY , Xiao YW , Jiang GH , Wang ZY , Zhang Y , Zhang M : Effect of atorvastatin versus rosuvastatin on levels of serum lipids, inflammatory markers and adiponectin in patients with hypercholesterolemia . Pharm Res 2009 , 26 : 958 - 964 .
22. Balla J , Magyar MT , Bereczki D , Valikovics A , Nagy E , Barna E , Pl A , Balla G , Csiba L , Blask G : Serum levels of platelet released CD40 ligand are increased in early onset occlusive carotid artery disease . Dis Markers 2006 , 22 : 133 - 140 .
23. Davidson MH , Rosenson RS , Maki KC , Nicholls SJ , Ballantyne CM , Mazzone T , Carlson DM , Williams LA , Kelly MT , Camp HS , Lele A , Stolzenbach JC : Effects of fenofibric acid on carotid intima-media thickness in patients with mixed dyslipidemia on atorvastatin therapy: randomized, placebo-controlled study (FIRST) . Arterioscler Thromb Vasc Biol 2014 , 34 : 1298 - 1306 .