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Co-prevalence of Carotid Stenosis with Coronary Artery
Disease in Chinese Population With Paroxysmal Atrial
Fibrillation
Yuanyuan Gu,1 Laihui Feng, 1
1
and Yonghui Zhao2
Department of Neurology, Zhengzhou People’s Hospital, Zhengzhou,
Henan, China;
2
Department of Cardiology, Henan Provincial People’s Hospital,
Zhengzhou, Henan, China;
Correspondence: Yonghui Zhao
Address： Department of Cardiology, Henan Provincial People’s Hospital, 7
Wei-wu Avenue, Zhengzhou, 450003, PR China.
Tel：86-371-65580226
Email: [email protected]
Running title: Co-prevalence of Carotid Stenosis with Coronary Artery
Disease in AF population
Abstract:
Objectives: Co-prevalence of coronary artery disease (CAD) and carotid stenosis（CS） remains
unkown in AF population.
Methods: The study populations consisted of 192 consecutive Chinese patients with paroxysmal
AF (PAF) and without a history of previously diagnosed or previously excluded CAD. CAD was
evaluated using multislice computed tomography (MSCT). Before MSCT, all patients underwent
carotid ultrasonography to screen CS and intima-media thickness (IMT) and measurements of
other blood chemistries. On the basis of the results of MSCT, the patients were divided into the
CAD group and the non-CAD group.
Results: Based on MSCT, 32.3% patients were classified as having CAD. Echographic CS was
observed in 13.5% patients. Prevalence of echographic CS was 8.5%, 16.7%, 25.0%, and
41.7% in patients with 0-, 1-, 2-, and 3-vessel CAD, respectively (P<0.001). The co-prevalence
with CS and CAD was 7.8%. In CAD group, 24.2% patients had concomitant CS. Multivariate
stepwise logistic regression analysis showed that diabetes mellitus, max-IMT and
hyperhomocysteinemia (HHcY) were independently related to the presence of CAD (all P<0.001).
Conclusions: In Chinese patients with PAF, the prevalence of CAD was relatively high at 32.3%
as well as in Western countries. Coexistence of CS and CAD occurred in 7.8% of patients,
moreover, the prevalence of CS correlated with the severity of CAD. Diabetes mellitus, IMT and
HHcY were independently related to the presence of CAD. Screening of CS is recommended
especially in PAF patients with multi-vessel CAD.
Key words: Atrial fibrillation; Carotid stenosis; Coronary artery disease; Chinese
Introduction
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and accounts for a
quarter of ischemic strokes. 1 In addition, AF is associated with multiple symptoms, with
significant morbidity and mortality and with decreased quality of life. 2 The mortality rate of AF
patients is almost twice that of patients with normal sinus rhythm. Notably, this observation has
been attributed to an increased cardiac death due tounderlying heart disease3-4 rather than to
thromboembolism.5
Atherosclerosis is highly prevalent among patients with AF and may be one of its underlying
causes. A number of studies have reported an association of AF with coronary atherosclerosis6-8
and recent studies suggest an association with carotid atherosclerosis as well9-11. Moreover, in
patients with AF, presence of atherosclerotic vascular disease was proposed to amplify the risk for
thromboembolic stroke and vascular death.12-14 Coronary artery disease (CAD) is frequently
comorbid with carotid stenosis. An association between carotid atherosclerosis and CAD has
been well established. 15 However, no prior study had evaluated the co-prevalence of CAD with
carotid atherosclerosis simutaneously in patients with AF.
The present study aimed to investigate the co-prevalence of CAD with carotid atherosclerosis
and to determine predictors related to CAD in Chinese population with paroxysmal AF (PAF)
presenting without previously diagnosed or excluded CAD.
Methods
Study Population
The study populations consisted of 192 consecutive patients with drug-refractory PAF referred
to multislice computed tomography (MSCT) for coronary evaluation, due to an elevated risk
profile and/or chest pain during the period June 2010 to October 2012. PAF was defined as
self-terminating episodes of AF lasting≤7 days. Patients with previously diagnosed or previously
excluded CAD, dilated or hypertrophic cardiomyopathy and contraindications to MSCT were
excluded, as well as patients who were not in sinus rhythm during MSCT examination. All
patients gave written informed consent to participate in this study. The study was approved by the
local ethical committee.
Evaluation of Risk Factor Variables
Before MSCT, we evaluated the risk factor variables including sex, age, body mass index,
hypertension, diabetes mellitus, hyperlipidemia, smoking, familial history of CAD, estimated
glomerular filtration rate (eGFR), hyperhomocysteinemia (HHcY) and previous transient ischemic
attack (TIA) or stroke. HHcY was defined as a tHcy level of ≥12.0μmol/L. eGFR was calculated
using the modification of diet in renal disease formula.
MSCT Coronary Angiography
MSCT coronary angiograms obtained with 64-slice scanners (LightSpeed VCT, GE Medical
Systems) were was performed to investigate the presence of CAD. Both the original axial dataset
and curved multiplanar reconstructions were used. Medical Imaging Systems). CAD was defined
as a lumen diameter stenosis of >50% in≥1 major coronary artery. Each patient was classified as
follows according to the number of diseased vessels: 0-vessel disease (ie, patients without
diseased vessels ), 1-vessel disease (ie, patients with disease in 1 vessel ), 2-vessel disease (ie,
patients with disease in 2 vessels or left main trunk disease without right coronary artery stenosis ),
3-vessel disease (ie, patients with disease in 3 vessels or left main trunk disease with right
coronary artery stenosis ).
Assessment of Carotid Atherosclerosis
Atherosclerosis of carotid artery was analyzed by duplex ultrasound scanning within a month
before coronary angiography in the all enrolled patients. A commercially available machine
(Vingmed; General Electric) with a 10-MHz linear array transducer was used. Scanning of the
extracranial common carotid artery(CCA), the carotid bulb(Bul), and the internal carotid
artery(ICA) in the neck was performed bilaterally in three different longitudinal projections as
well as transverse projections, and the site of greatest thickness, including plaque lesions, was
sought along the arterial walls by B-mode and color Doppler ultrasound. The max-IMT is the
greatest carotid IMT in the observation-possible areas of the CCA, Bul and ICA.16 We defined
echographic carotid stenosis as the carotid atherosclerosis with area stenosis of >50% or peak
systolic velocity of >200 cm/s on CCA, the carotid bifurcation, and ICA. All scans were
conducted by experienced laboratory technicians and physicians, who had no prior knowledge of
the patient’s clinical characteristics.
Statistical Analysis
Data analysis was performed using the SPSS software (version 11.0, SPSS Inc). Continuous
variables were expressed as mean±SD. Two-sided unpaired t test was performed for continuous
variables andχ2 test (or Fisher’s exact test when appropriate) for discrete variables. Multivariate
stepwise logistic regression analysis was performed to detect independent predictors of CAD
using factors that had significant relation in univariate analysis. A value of P<0.05 was considered
statistically significant.
Results
Patient Characteristics
Overall, 192 patients with PAF presenting without previously diagnosed or excluded CAD.
were included and analysed. Noninvasive coronary angiography was successfully performed in all
the patients of the study population in sinus rhythm. Mean heart rate during the MSCT scan was
68±6 bpm among the entire patient population. Based on MSCT, 74patients (38.5%) were
demonstrated as having no coronary artery stenosis, whereas 56（29.2%）showed nonobstructive
coronary artery stenosis and the remaining 62 (32.3%) patients were classified as having CAD
with at least 1 significant (≥50%) coronary luminal narrowing.
Baseline characteristics of each group and their medication are shown in Table 1. CAD and
non-CAD groups did not differ as to mean age (68.9±8.0 vs. 69.4±9.0 years), male gender
(72.3% vs. 70.8%) and duration of AF (2.0±0.8 vs. 1.9±1.0). There was no significant difference
between the 2 groups with regard to the incidence of body mass index (24.5±3.3 vs. 25.5±3.8
kg/m2), history of TIA/stroke (6.5% vs. 5.4% ), hypertension (61.3% vs. 58.5%) and dyslipidemia
(61.3% vs. 59.2%). Furthermore, there was no significant difference between the 2 groups in terms
of familial history of CAD(21.0% vs. 22.3%), smoking history (61.3% vs. 62.3%), eGFR(73±17
vs. 77±18) and concomitant medications. Nevertheless, compared with non-CAD patients, CAD
patients more often had diabetes mellitus(38.7% vs. 26.2%, P=0.018) and had significantly higher
tHcy(22.2±3.4 vs. 10.8±2.8μmol/L, P<0.001) underlying more subjects with HHcY (59.7% vs.
21.5%, P<0.001)) in CAD group. On ultrasonography, CAD patients presented with more higher
max-IMT versus non-CAD patients(2.55±0.90 vs.1.63±0.85 mm, P<0.001).
Association between Carotid Stenosis and Severity of CAD
In CAD group, a total of 30 patients (48.4%) had 1-vessel disease, 20 patients (32.2%) had
2-vessel disease, and 12 patients (19.4%) had 3-vessel disease. We performed further analysis on
the distribution of carotid stenoses according to the extent of CAD (Figure 1). The distribution of
echographic carotid stenosis in the groups with different degrees of CAD was 8.5%, 16.7%,
25.0%, and 41.7% of patients with 0-, 1-, 2-, and 3-vessel disease, respectively (P<0.001), which
suggests the extent of CAD has a strong association with echographic carotid stenosis . Of the
entire study population, 26(13.5%) patients had carotid stenosis and 15(7.8%) patients had
concomitant carotid stenosis in addition to CAD. In CAD group, 15(24.2%) patients had carotid
stenosis.
Independent Predictors of CAD
For the multiple logistic regression analysis, several risk factors, namely, age, male gender,
smoking, diabetes mellitus, hypertension, high body mass index, high LDL-C levels, high TG
levels, low HDL levels, low eGFR, HHCY and max-IMT were adjusted. The results showed that
the presence of CAD is independently associated with HHcY (odds ratio[OR], 2.12; 95%
confidence interval[CI], 2.12-5.24; P<0.001), diabetes mellitus (OR, 2.08; 95%CI, 1.36-3.06;
P<0.001) and Max-IMT(OR, 3.08; 95%CI, 2.34-5.14; P<0.001).
Discussion
This is the first study using anatomic assessment to examine the prevalence of coexisting CAD
and carotid atherosclerosis among patients with PAF and without previously diagnosed or
excluded CAD. Our main findings were: (1) the prevalence of CAD was unexpectedly high in
the sample Chinese population, (2) 7.8% patients had coexisting carotid stenosis and CAD and
prevalence of carotid stenosis correlated with the severity of CAD, and (3) diabetes mellitus,
Table 1. Characteristics of 192 PAF patients with and without coronary artery disease
Variables
Male gender
Age(years)
Duration of AF(years)
Risk factors
Diabetes mellitus
Body mass index (kg/m2)
Past or current smoking
Familial history of CAD
History of TIA/stroke
Hypertension
SBP (mmHg)
DBP (mmHg)
Dyslipidemia
LDL-C (mg/DL)
HDL-C (mg/DL)
TG (mg/DL)
HHcY
tHcy (μmol/L)
eGFR(mL/min./1.73m2)
max-IMT(mm)
Medications
Aspirin
Beta-blockers
Calcium channel blockers
ACEI/ARB
Statin
CAD
(＋) n=62
(－) n=130
P value
45(72.3)
68.9±8.0
2.0±0.8
92(70.8)
69.4±9.0
1.9±1.0
0.545
0.254
0.190
24(38.7)
24.5±3.3
38(61.3)
13(21.0)
4(6.5)
38(61.3)
140±8
73±6
38(61.3)
120±32
48±11
140±33
37(59.7)
22.2±3.4
73±17
2.55±0.90
34(26.2)
25.5±3.8
81(62.3)
29(22.3)
7(5.4)
75(58.5)
138±10
70±8
77(59.2)
118±29
50±10
138±40
28(21.5)
10.8±2.8
77±18
1.63±0.85
0.018
0.324
0.274
0.732
0.108
0.112
0.106
0.209
0.122
0.482
0.324
0.422
<0.001
<0.001
0.246
<0.001
50(80.6)
30(48.3)
18(29.0)
32(51.6)
44(71.0)
106(81.5)
65(50.0)
45(34.6)
63(48.5)
89(68.5)
0.344
0.242
0.128
0.105
0.112
Abbreviation: CAD, coronary artery disease; TIA, transient ischemic attack; SBP, systolic blood
pressure; DBP, diastolic blood pressure; LDL-C, low density lipoprotein cholesterol; HDL-C, high
density lipoprotein cholesterol; TG, triglyceride;
HHcY, hyperhomocysteinemia; ACEI,
angiotensin-converting enzyme inhibitor; tHcy, total plasma homocysteine; eGFR, estimated
glomerular filter rate; IMT, intima-media thickness; ARB, angiotensin receptor blocker.
All values are expressed as the mean±SD or a number with the percentage of subjects in
parentheses. P-values represent the comparison of PAF patients with and without CAD by
unpaired-t, Mann-Whitney U, or Chi-square test.
Table 2. Multivariate logistic regression analysis for coronary artery disease.
CAD
Variables
Odds Ratio
Max-IMT(mm)
Diabetes mellitus
HHcY
3.08
2.08
2.12
95% CI
2.34-5.14
1.36-3.06
212-5.24
P value
<0.001
<0.001
<0.001
Abbreviation: Multivariate logistic regression analysis was performed with the
presence of CAD as a dependent variable, and age, gender (male), hypertension,
dyslipidemia, smoking history, eGFR, diabetes mellitus, HHcY and max-IMT and as
independent variables. Values are odds ratios with 95% confidence intervals.
Figure 1. Bar graph showing distribution of carotid stenosis among PAF patients according to the
extent of CAD. VD indicates vessels disease; All VD denotes CAD in 1≥vessel；Multi-VD
denotes CAD in 2≥vessel.
IMT and HHcY were independently related to the presence of CAD.
The prevalence of AF in the US population is expected to increase from 2.3 million in 2001 to
5.6 million in 2050.17 In several reports from Western countries, CAD is reported to be highly
common among patients with AF with the prevalence of 18–41%.7,8,18 In contrast, in Japanese
patients with nonvalvular AF, the prevalence of CAD was relatively low (6.4%)19; these
investigators thought that the disparities in the prevalence of CAD between Japan and Western
countries might be linked to differences in patients’ backgrounds. In the present study, the
prevalence of CAD was 32.3%, which was consistent with that of Western countries, and was
related to the inclusion of patients with suspicion of CAD and the change in lifestyle toward
Western habit in Chinese population. In 261 consecutive patients with AF, Kralev et al.8 repoeted
that the prevalence of CAD was 34% in the overall patients and 41% in patients >70 years;
notably, 21% of patients underwent a percutaneous coronary intervention (PCI) or coronary artery
bypass graft (CABG). In CAD group from the present study, 51.6% of patients had multi-vessel
diseases which could need PCI or CABG. Once diagnosed with AF, the presence of CAD has been
shown to be related with recurrent AF episodes20, presence of symptoms (including arrhythmic,
heart failure, and angina symptoms)21 and increased risk of death22,23. Moreover, epidemiological
data disclosed that ischemic heart disease is one of the most common underlying cause of death
among patients with AF.24
Only small number of studies have investigated the potential relationship between AF and
carotid atherosclerosis11,25,26. In a population-based survey by Willeit et al.11subjects with carotid
atherosclerosis were more likely to develop AF than subjects without (OR, 1.8; 95%CI, 1.1–3.1;
P=0.021).Chen et al. reported increased IMT and arterial stiffness were associated with lone AF. In
a retrospective cohort study, Harthun et al25 found patients with AF have a substantially higher risk
of stroke and death after carotid endarterectomy(OR, 2.45; P < 0001). A prospective study
reported that carotid stenosis (40% to 100%) and AF were significant independent risk factors for
new thromboembolic stroke26. In the present study, 13.5% PAF patients with had carotid stenosis;
importantly, 24.2% PAF patients with CAD had concomitant carotid stenosis. Many studies have
demonstrated that patients with significant carotid stenosis have an increased risk of stroke after
CABG; moreover, CAD is the most common cause of morbidity and mortality with carotid artery
endovascular intervention. 27,28
In the present study, diabetes mellitus, IMT and HHcY predicted independently the presence of
CAD. It has been reported that diabetes mellitus was an independent predictor of CAD and was
also associated with more advanced CAD. 29 Though CAD is a major cause of death and
impairment of quality of life in patients with type 2 diabetes mellitus, however, CAD generally
is detected at an advanced stage and an asymptomatic stage is often missed; 16 therefore, its early
detection and intervention is critical in the management of these patients. Carotid IMT, a marker
of early atherosclerosis and vascular remodeling that can be assessed quickly, non-invasively,
and cheaply with high-resolution ultrasound, is correlated with conventional coronary risk factors.
Previous studies have shown that carotid IMT is associated with cardiovascular events and
extent of CAD among patients with known or suspected CAD or type 2 diabetes. 10,11,16 Moreover,
by receiver operator characteristic curve analyses, the area under the curve for max-IMT was
higher than that for mean-IMT(0.73 vs. 0.64). 30 In type 2 diabetic patients without apparent
cardiovascular disease, the addition of max-IMT to conventional risk factors substantially
improves the risk stratification for CAD.16 Homocysteine is a metabolic product of methionine.
The proposed mechanisms responsible for these effects include endothelial dysfunction,
accelerated oxidation of LDL-C, impairment of flow-mediated endothelium-derived relaxing
factor with subsequent reduction in arterial vasodilation, platelet activation, and oxidative stress.
Prior studies found that tHcy levels are correlated with coronary atherosclerosis and stroke and
can be used to predict mortality in patients with CAD.31,32 Hsieh et al. 32 reported HHcY can
predict the presence of CAD and tHcy levels are significantly associated with the extent of
coronary atherosclerosis in patients with carotid stenosis.
Limitations
There may be limitations in this study. First, we only studied a group of consecutive patients
with only PAF and without . The findings may not be applicable to the patients with
non-paroxysmal AF. Second, the non-randomized design of this single centre investigation
might have potentially influenced the comparative analysis. Third, no prognostic data were
available. A larger study, with follow-up data, may provide more conclusive information. While
caution is therefore needed in the interpretation of our data, we consider it improbable that
these limitations have influenced our main findings.
Conclusions
In Chinese patients with PAF presenting without previously diagnosed or excluded CAD, the
prevalence of CAD was unexpectedly high at 32.3% as in Western countries. Coexistence of
carotid stenosis and CAD occurred at 7.8% patients, moreover, the prevalence of carotid stenosis
correlated with the severity of CAD. Diabetes mellitus, IMT and HHcY were independently
related to the presence of CAD. Screening of carotid stenosis is recommended especially in PAF
patients with multi-vessel CAD.
Conflicts of interest:
The authors had
this article.
no
conflicts of
interest
to declare in relation to
acknowledgement:
The present study was supported by the Cutting-edge and Basic Research
Project of Henan Province (122300410136).
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