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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). References 1. Wolf PA, D’Agostino RB, Belanger AJ, Kannel WB. Probability of stroke: a risk profile from the Framingham Study. Stroke. 1991;22: 312–318. 2. Paquette M, Roy D, Talajic M, Newman D, Couturier A, et al. Role of gender and personality on quality-of-life impairment in intermittent atrial fibrillation. Am J Cardiol. 2000; 86(7): 764–768. 3. Krahn AD, Manfreda J, Tate RB, Mathewson FA, et al. The natural history of atrial fibrillation: incidence, risk factors, and prognosis in the Manitoba Follow-Up Study. Am J Med. 1995;98:476–484. 4. Psaty BM, Manolio TA, Kuller LH, Kronmal RA, et al. Incidence of and risk factors for atrial fibrillation in older adults. Circulation. 1997;96:2455–2461. 5. Dries DL, Exner DV, Gersh BJ, Domanski MJ, et al. 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