Atherosclerosis 237 (2014) 504e513
Contents lists available at ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
The CHADS2 and CHA2DS2-VASc scores predict adverse vascular function, ischemic stroke and cardiovascular death in high-risk patients without atrial fibrillation: Role of incorporating PR prolongation Yap-Hang Chan a, b, Kai-Hang Yiu a, Kui-Kai Lau c, Yuen-Fung Yiu a, Sheung-Wai Li d, Tai-Hing Lam b, Chu-Pak Lau a, Chung-Wah Siu a, e, 1, Hung-Fat Tse a, e, *, 1 a
Division of Cardiology, Queen Mary Hospital, The University of Hong Kong, China School of Public Health, The University of Hong Kong, China c Division of Neurology, Queen Mary Hospital, The University of Hong Kong, China d Department of Medicine, Tung Wah Hospital, China e Research Center of Heart, Brain, Hormone and Healthy Ageing, University of Hong Kong, China b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 15 October 2013 Received in revised form 9 August 2014 Accepted 11 August 2014 Available online 30 August 2014
Objectives: To investigate whether the CHADS2 and CHA2DS2-VASc scores have clinical utility for prediction of adverse vascular function and vascular dysfunction-mediated incident cardiovascular (CV) events among high-risk patients without atrial fibrillation (AF), and the additional value of incorporating PR prolongation to the scores. Methods: We analyzed 579 high-risk CV outpatients without clinical AF in a prospective cohort for newonset ischemic stroke, myocardial infarction (MI), congestive heart failure (CHF), and CV death. Brachial flow-mediated dilation (FMD) and nitroglycerin-mediated dilatation (NMD), carotid intima-media thickness (IMT) and pulse wave velocity (PWV) were determined. Results: Baseline CHADS2 score was associated with lower FMD (Pearson r ¼ 0.16, P < 0.001) and NMD (r ¼ 0.17, P < 0.001), higher carotid IMT (r ¼ 0.30, P < 0.001) and PWV (r ¼ 0.35, P < 0.001; similar for CHA2DS2-VASc score: All P < 0.05). After follow-up of 63 ± 11 months, 82 patients (14.2%) developed combined CV endpoint. ROC curve analysis showed that both CHADS2 and CHA2DS2-VASc scores were predictors for ischemic stroke (C-Statistic: CHADS2 0.70, P ¼ 0.004; CHA2DS2-VASc 0.68, P ¼ 0.010), MI (CHADS2 0.63, P ¼ 0.030; CHA2DS2-VASc 0.70, P ¼ 0.001), and CV death (CHADS2 0.63, P ¼ 0.022; CHA2DS2-VASc 0.65, P ¼ 0.011). Higher CHADS2 score was associated with reduced event-free survival from combined CV endpoints (log-rank ¼ 16.7, P < 0.001) with differences potentiated if stratified by CHA2DS2-VASc score (log-rank ¼ 29.2, P < 0.001). Incorporating PR prolongation, the CHA2DS2-VASc-PR score achieved the highest C-Statistic for CV death prediction (0.70, P < 0.001) superior to the CHADS2 score (chi-square: 12.1, P ¼ 0.0005). Conclusions: The CHADS2 and CHA2DS2-VASc predict vascular dysfunction and cardiovascular events in high-risk CV patients without clinical AF, with further improved performance incorporating PR prolongation. © 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: CHADS2 and CHA2DS2-VASc scores PR prolongation Vascular dysfunction Cardiovascular continuum Adverse cardiovascular events Risk prediction
1. Introduction
* Corresponding author. Cardiology Division, Department of Medicine, The University of Hong Kong, Rm 1928, Block K, Queen Mary Hospital, Hong Kong, China. Tel.: þ852 28553598; fax: þ852 28186304. E-mail address: [email protected] (H.-F. Tse). 1 Co-supervising authors contributed equally to this work. http://dx.doi.org/10.1016/j.atherosclerosis.2014.08.026 0021-9150/© 2014 Elsevier Ireland Ltd. All rights reserved.
AF as the commonest sustained cardiac arrhythmia, contributes to substantial morbidities and mortalities predominantly from thromboembolism and stroke which occur at an increased risk of five-fold, further escalating in the presence of risk factors [1]. The CHADS2 and CHA2DS2-VASc scores have shown promising values in early risk stratification of patients with non-valvular AF in terms of
Y.-H. Chan et al. / Atherosclerosis 237 (2014) 504e513
Glossary of abbreviations ACEI angiotensin-converting enzyme inhibitors AF atrial fibrillation ARB angiotensin receptor blockers BMI body-mass index CAD Coronary Artery Disease CCB calcium-channel blockers CHADS2 score see Appendix CHA2DS2-VASc score see Appendix CHF congestive heart failure CV cardiovascular ECG electrocardiogram FMD flow-mediated dilation HbA1c glycosylated hemoglobin A1c hs-CRP high-sensitivity C-reactive protein HDL high-density lipoprotein IMT carotid intima-media thickness LDL low-density lipoprotein MI myocardial infarction NMD nitroglycerin-mediated dilatation PWV Pulse Wave Velocity
intracardiac thrombogenesis and cardioembolism [2], thus allowing discriminatory and tailored initiation of antithrombotic treatments for effective risk reduction, balancing against the risks from treatment-related complications [1,3]. Interestingly, since the entry scoring criteria of the CHADS2 and CHA2DS2-VASc scores [4] are also important fundamental risk factors of atherosclerotic disease independent of the cardioembolic pathway, it is possible that such scores may have important applications for the prediction of a wider array of pathophysiologically-related vascular events beyond the conventional scope of AF. Indeed, a recent study showed that the CHADS2 score predicted subsequent stroke and death in patients with acute coronary syndrome who had no AF, at a performance level that was superior than when applied to patients with AF [5]. Furthermore, the CHADS2 score was found associated with intracerebral atherosclerosis in stroke patients with nonvalvular AF [6], suggesting that it may be a useful clinical composite marker to reflect the stage of vascular phenotype along the cardiovascular (CV) continuum progression [7]. Furthermore, adverse CV events as stroke [8], myocardial infarction (MI) [9] and congestive heart failure (CHF) [10] are pathophysiologically commonly characterized by abnormal vascular function. The potential role of the CHADS2 and CHA2DS2-VASc scores in predicting the level of vascular dysfunction and new-onset CV events in high-risk patients without AF may open up important opportunities in optimizing their individualized care for risk-reduction managements. Moreover, PR prolongation, or first-degree atrioventricular block on electrocardiogram (ECG), has recently been recognized a precursor to AF and is associated with adverse CV outcomes in the population [11,12] as well as in patients with established Coronary Artery Disease (CAD) [13]. It is thus of interest to know whether incorporating this novel marker into assessment in CV patients without AF may result in overall improved risk prediction. The purpose of this study is therefore three-fold: (1) to investigate the prediction utility of the CHADS2 and CHA2DS2-VASc scores among high-risk patients without clinical AF for new-onset vascular events; (2) to examine the relations between CHADS2 and CHA2DS2-VASc scores and surrogate indicators of vascular function to elucidate the pathophysiological basis; (3) to explore whether
505
incorporating PR prolongation to the CHADS2 and CHA2DS2-VASc scores will improve the overall risk prediction for vascular events among high-risk patients without AF. 2. Subjects and methods 2.1. Study population and design In this prospective cohort study, we included 597 consecutive high-risk patients with CAD or risk equivalent (prior CAD: 328 [55%]; ischemic stroke: 131 [22%]; diabetes mellitus: 310 [52%]) from internal medicine outpatient clinics during the period from Sep 2005 to Apr 2008. Patients with the following conditions were excluded: recent MI, unstable angina, coronary revascularization, stroke or acute heart failure within the past 6 months; dilated cardiomyopathy, significant valvular heart disease, chronic AF, cardioembolic stroke, New York Heart Association class III or IV heart failure, significant renal impairment with creatinine >220 mmol/L, liver failure and clinical/biochemical evidence for concomitant inflammatory disease. All participants had stable diet pattern and CV medications for at least 3 months prior to recruitment. As the objective of the study is to investigate the role of the CHADS2 and CHA2DS2-VASc scores in atherosclerotic vascular events commonly characterized by adverse vascular function, as opposed to the conventional use of the scores in stroke prediction in AF presumably secondary to cardioembolism, we preemptively included patients with established atherosclerotic diseases; and diabetes which is a well established cause of atherosclerosis and a recognized coronary disease risk equivalent, as part of the advanced cardiovascular continuum [7]. Conditions which may impact on cardiovascular risks through predominantly nonatherosclerotic mechanistic pathways were not included to enhance the homogeneity of the study sample. Recent cardiovascular events in the past 6 months were excluded to avoid transient fluctuations in vascular function parameters. Written informed consent was obtained for all patients. The study was approved by Ethics Committee of University of Hong Kong. During the prospective follow-up (Dec 2007 to May 2012), occurrence of new-onset ischemic stroke, MI, CHF and CV death were retrieved and ascertained from the medical records and discharge summaries of the Clinical Management System (CMS), the territory-wide computerized clinical data network of all public hospitals in Hong Kong. Primary endpoints of the study were ischemic stroke, CV death and new-onset MI. Secondary endpoints were vascular function parameters and combined CV endpoints which included occurrences of any primary endpoints or CHF. We defined CV death as death directly resulting from circulatory disturbances as acute MI, acute/acute-on-chronic heart failure, cardiac arrhythmias, or ischemic/ haemorrhagic stroke. CAD was diagnosed in the presence of any of the following: history of MI [14]; history suggestive of angina pectoris objectively evidenced by inducible ischemia on exercise treadmill or single photon emission computed tomography (SPECT); and the presence of coronary atherosclerosis was defined by coronary angiography, computed tomography or magnetic resonance imaging. Diagnosis of ischemic stroke was made on the basis of clinical examinations and computed tomography or magnetic resonance brain imaging [15]. As a result, at the end of study 579 patients with complete data on CHADS2 and CHA2DS2-VASc scores and CV outcomes were available for analysis. 2.2. Baseline demographic, clinical and laboratory assessments Baseline demographic data, CV risk factors and medications were documented. Hypertension was defined as either resting systolic/diastolic blood pressure 140/90 mmHg at two different
506
Y.-H. Chan et al. / Atherosclerosis 237 (2014) 504e513
clinic visits or on medications. Diabetes mellitus was defined as serum fasting glucose 7.0 mmol/L or on medications. Hypercholesterolemia was defined as a fasting total plasma cholesterol level of >200 mg/dL or on cholesterol-lowering medications. Smoking status was recorded as past smoker, current smoker or non-smoker. Family history of CAD was considered positive in first-degree relatives with diseases diagnosed at an age younger than 55 years. Long-term physical activity level was defined as nil, regular, or irregular exercise. Body-mass index (BMI) was calculated as weight in kilograms divided by square of height in meters. The CHADS2 and CHA2DS2-VASc scores were calculated [4] according to each constituent criteria including prior CHF, hypertension, age 65e74/75 years, diabetes mellitus, prior stroke/transient ischemic attack, presence of vascular disease, and female sex category. Fasting blood was collected for biochemical analysis of serum low-density/highdensity lipoprotein (LDL/HDL)-cholesterol, triglycerides, glucose, HbA1c, creatinine, and high-sensitivity C-reactive protein (hs-CRP). 2.3. Flow-mediated dilatation (FMD) Vascular ultrasound was performed with a high-resolution ultrasound system (Agilent Sonos 5500, Philips, USA) using a 7.5 MHz linear array transducer by an experienced operator. Patients were studied in the fasting state. To avoid systematic differences in diurnal variation of vascular reactivity, all studies were performed in the morning (time range: 0900e1200). All vasoactive medications, cigarette smoking, caffeine drink and alcohol consumption were withheld for at least 12 h before the assessment. As previously described [16e18] longitudinal scans of the brachial artery were obtained at rest, and then FMD was induced by inflation of a pneumatic tourniquet placed on the forearm to a pressure of 250 mm Hg for 5 min. The cuff was then released, and serial imaging of the brachial artery was recorded for 5 min. The brachial artery was allowed to return to baseline. Finally, the brachial artery was then measured again at 5 min after the administration of 400 mg sublingual nitroglycerin spray. FMD was defined as the percentage change in the brachial artery diameter by 1 min after cuff deflation from that of the baseline scan. Nitroglycerinmediated dilatation (NMD) was defined as the percentage change in the brachial artery diameter by 5 min after nitrate administration. Interobserver variability testing for FMD measurement revealed an interclass correlation coefficient (ICC) (2-way mixed, random-effect model, absolute agreement) of 0.83 (95% CI [0.22e0.97], P ¼ 0.012), with a mean absolute difference of 0.6 ± 0.8%. 2.4. Carotid intimaemedia thickness (IMT) All subjects were examined in a supine position. Briefly [17], carotid IMT was determined by measuring the distance between the lumen-intima and media-adventitia border of the vascular wall with the use of electronic calipers. Each ultrasonic scan was performed in the anterior, lateral, and posterior projections of the right and left carotid arteries. Three IMT measurements were made on the near and far walls of the left and right common carotid arteries, carotid bifurcation, and internal carotid arteries. The mean IMT was calculated by averaging the estimates from 12 previously selected segments in the carotid arteries. Plaque thickness was incorporated in IMT measurement. Intraobserver variability study showed ICC ¼ 0.97 (P < 0.001). 2.5. Arterial stiffness As previously described [18,19], arterial stiffness was measured non-invasively using VP-2000 System (Colin Corp., USA) by an
Table 1 Baseline clinical characteristics, CHADS2 and CHA2DS2-VASc scores of study participants stratified by combined cardiovascular (CV) endpoints of new-onset ischemic stroke, MI, CHF and CV death (n ¼ 579).a No such events Combined CV P-value (n ¼ 497) endpoints (n ¼ 82) Male [n (%)] Age (years) Body mass index (kgm2) Coronary artery disease [n (%)] Prior stroke [n (%)] Diabetes mellitus [n (%)] Hypertension [n (%)] Hyperlipidemia [n (%)] Current/past smoker [n (%)] Regular physical activity [n (%)] Resting pulse rate (min1) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) LDL-cholesterol (mg/dL) HDL-cholesterol (mg/dL) Triglycerides (mg/dL) Fasting glucose (%) HbA1c (%) hs-CRP (mg/L) Creatinine (mmol/L) Medications ACEI/ARB [n (%)] Beta-blockers [n (%)] Calcium channel blockers [n (%)] Aspirin [n (%)] Statin [n (%)] FMD (%) NMD (%) Carotid IMT (mm) PWV (cm/s) PR interval (ms) QRS duration (ms) CHADS2 Score Mean 0e1, n (%) 2, n (%) 3, n (%) CHA2DS2-VASc Score Mean 0e2, n (%) 3, n (%) 4e5, n (%) 6, n (%)
333 (67%) 64.3 ± 11.1 25.4 ± 3.5 269 (54%) 107 (22%) 255 (51%) 319 (64%) 307 (63%) 204 (42%) 176 (36%) 59.5 ± 20.4 139.0 ± 19.4
59 (72%) 74.6 ± 7.3 24.8 ± 3.2 54 (66%) 24 (29%) 45 (55%) 61 (74%) 56 (73%) 46 (56%) 27 (33%) 67.4 ± 20.0 151.4 ± 22.1
0.38
Contents lists available at ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
The CHADS2 and CHA2DS2-VASc scores predict adverse vascular function, ischemic stroke and cardiovascular death in high-risk patients without atrial fibrillation: Role of incorporating PR prolongation Yap-Hang Chan a, b, Kai-Hang Yiu a, Kui-Kai Lau c, Yuen-Fung Yiu a, Sheung-Wai Li d, Tai-Hing Lam b, Chu-Pak Lau a, Chung-Wah Siu a, e, 1, Hung-Fat Tse a, e, *, 1 a
Division of Cardiology, Queen Mary Hospital, The University of Hong Kong, China School of Public Health, The University of Hong Kong, China c Division of Neurology, Queen Mary Hospital, The University of Hong Kong, China d Department of Medicine, Tung Wah Hospital, China e Research Center of Heart, Brain, Hormone and Healthy Ageing, University of Hong Kong, China b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 15 October 2013 Received in revised form 9 August 2014 Accepted 11 August 2014 Available online 30 August 2014
Objectives: To investigate whether the CHADS2 and CHA2DS2-VASc scores have clinical utility for prediction of adverse vascular function and vascular dysfunction-mediated incident cardiovascular (CV) events among high-risk patients without atrial fibrillation (AF), and the additional value of incorporating PR prolongation to the scores. Methods: We analyzed 579 high-risk CV outpatients without clinical AF in a prospective cohort for newonset ischemic stroke, myocardial infarction (MI), congestive heart failure (CHF), and CV death. Brachial flow-mediated dilation (FMD) and nitroglycerin-mediated dilatation (NMD), carotid intima-media thickness (IMT) and pulse wave velocity (PWV) were determined. Results: Baseline CHADS2 score was associated with lower FMD (Pearson r ¼ 0.16, P < 0.001) and NMD (r ¼ 0.17, P < 0.001), higher carotid IMT (r ¼ 0.30, P < 0.001) and PWV (r ¼ 0.35, P < 0.001; similar for CHA2DS2-VASc score: All P < 0.05). After follow-up of 63 ± 11 months, 82 patients (14.2%) developed combined CV endpoint. ROC curve analysis showed that both CHADS2 and CHA2DS2-VASc scores were predictors for ischemic stroke (C-Statistic: CHADS2 0.70, P ¼ 0.004; CHA2DS2-VASc 0.68, P ¼ 0.010), MI (CHADS2 0.63, P ¼ 0.030; CHA2DS2-VASc 0.70, P ¼ 0.001), and CV death (CHADS2 0.63, P ¼ 0.022; CHA2DS2-VASc 0.65, P ¼ 0.011). Higher CHADS2 score was associated with reduced event-free survival from combined CV endpoints (log-rank ¼ 16.7, P < 0.001) with differences potentiated if stratified by CHA2DS2-VASc score (log-rank ¼ 29.2, P < 0.001). Incorporating PR prolongation, the CHA2DS2-VASc-PR score achieved the highest C-Statistic for CV death prediction (0.70, P < 0.001) superior to the CHADS2 score (chi-square: 12.1, P ¼ 0.0005). Conclusions: The CHADS2 and CHA2DS2-VASc predict vascular dysfunction and cardiovascular events in high-risk CV patients without clinical AF, with further improved performance incorporating PR prolongation. © 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: CHADS2 and CHA2DS2-VASc scores PR prolongation Vascular dysfunction Cardiovascular continuum Adverse cardiovascular events Risk prediction
1. Introduction
* Corresponding author. Cardiology Division, Department of Medicine, The University of Hong Kong, Rm 1928, Block K, Queen Mary Hospital, Hong Kong, China. Tel.: þ852 28553598; fax: þ852 28186304. E-mail address: [email protected] (H.-F. Tse). 1 Co-supervising authors contributed equally to this work. http://dx.doi.org/10.1016/j.atherosclerosis.2014.08.026 0021-9150/© 2014 Elsevier Ireland Ltd. All rights reserved.
AF as the commonest sustained cardiac arrhythmia, contributes to substantial morbidities and mortalities predominantly from thromboembolism and stroke which occur at an increased risk of five-fold, further escalating in the presence of risk factors [1]. The CHADS2 and CHA2DS2-VASc scores have shown promising values in early risk stratification of patients with non-valvular AF in terms of
Y.-H. Chan et al. / Atherosclerosis 237 (2014) 504e513
Glossary of abbreviations ACEI angiotensin-converting enzyme inhibitors AF atrial fibrillation ARB angiotensin receptor blockers BMI body-mass index CAD Coronary Artery Disease CCB calcium-channel blockers CHADS2 score see Appendix CHA2DS2-VASc score see Appendix CHF congestive heart failure CV cardiovascular ECG electrocardiogram FMD flow-mediated dilation HbA1c glycosylated hemoglobin A1c hs-CRP high-sensitivity C-reactive protein HDL high-density lipoprotein IMT carotid intima-media thickness LDL low-density lipoprotein MI myocardial infarction NMD nitroglycerin-mediated dilatation PWV Pulse Wave Velocity
intracardiac thrombogenesis and cardioembolism [2], thus allowing discriminatory and tailored initiation of antithrombotic treatments for effective risk reduction, balancing against the risks from treatment-related complications [1,3]. Interestingly, since the entry scoring criteria of the CHADS2 and CHA2DS2-VASc scores [4] are also important fundamental risk factors of atherosclerotic disease independent of the cardioembolic pathway, it is possible that such scores may have important applications for the prediction of a wider array of pathophysiologically-related vascular events beyond the conventional scope of AF. Indeed, a recent study showed that the CHADS2 score predicted subsequent stroke and death in patients with acute coronary syndrome who had no AF, at a performance level that was superior than when applied to patients with AF [5]. Furthermore, the CHADS2 score was found associated with intracerebral atherosclerosis in stroke patients with nonvalvular AF [6], suggesting that it may be a useful clinical composite marker to reflect the stage of vascular phenotype along the cardiovascular (CV) continuum progression [7]. Furthermore, adverse CV events as stroke [8], myocardial infarction (MI) [9] and congestive heart failure (CHF) [10] are pathophysiologically commonly characterized by abnormal vascular function. The potential role of the CHADS2 and CHA2DS2-VASc scores in predicting the level of vascular dysfunction and new-onset CV events in high-risk patients without AF may open up important opportunities in optimizing their individualized care for risk-reduction managements. Moreover, PR prolongation, or first-degree atrioventricular block on electrocardiogram (ECG), has recently been recognized a precursor to AF and is associated with adverse CV outcomes in the population [11,12] as well as in patients with established Coronary Artery Disease (CAD) [13]. It is thus of interest to know whether incorporating this novel marker into assessment in CV patients without AF may result in overall improved risk prediction. The purpose of this study is therefore three-fold: (1) to investigate the prediction utility of the CHADS2 and CHA2DS2-VASc scores among high-risk patients without clinical AF for new-onset vascular events; (2) to examine the relations between CHADS2 and CHA2DS2-VASc scores and surrogate indicators of vascular function to elucidate the pathophysiological basis; (3) to explore whether
505
incorporating PR prolongation to the CHADS2 and CHA2DS2-VASc scores will improve the overall risk prediction for vascular events among high-risk patients without AF. 2. Subjects and methods 2.1. Study population and design In this prospective cohort study, we included 597 consecutive high-risk patients with CAD or risk equivalent (prior CAD: 328 [55%]; ischemic stroke: 131 [22%]; diabetes mellitus: 310 [52%]) from internal medicine outpatient clinics during the period from Sep 2005 to Apr 2008. Patients with the following conditions were excluded: recent MI, unstable angina, coronary revascularization, stroke or acute heart failure within the past 6 months; dilated cardiomyopathy, significant valvular heart disease, chronic AF, cardioembolic stroke, New York Heart Association class III or IV heart failure, significant renal impairment with creatinine >220 mmol/L, liver failure and clinical/biochemical evidence for concomitant inflammatory disease. All participants had stable diet pattern and CV medications for at least 3 months prior to recruitment. As the objective of the study is to investigate the role of the CHADS2 and CHA2DS2-VASc scores in atherosclerotic vascular events commonly characterized by adverse vascular function, as opposed to the conventional use of the scores in stroke prediction in AF presumably secondary to cardioembolism, we preemptively included patients with established atherosclerotic diseases; and diabetes which is a well established cause of atherosclerosis and a recognized coronary disease risk equivalent, as part of the advanced cardiovascular continuum [7]. Conditions which may impact on cardiovascular risks through predominantly nonatherosclerotic mechanistic pathways were not included to enhance the homogeneity of the study sample. Recent cardiovascular events in the past 6 months were excluded to avoid transient fluctuations in vascular function parameters. Written informed consent was obtained for all patients. The study was approved by Ethics Committee of University of Hong Kong. During the prospective follow-up (Dec 2007 to May 2012), occurrence of new-onset ischemic stroke, MI, CHF and CV death were retrieved and ascertained from the medical records and discharge summaries of the Clinical Management System (CMS), the territory-wide computerized clinical data network of all public hospitals in Hong Kong. Primary endpoints of the study were ischemic stroke, CV death and new-onset MI. Secondary endpoints were vascular function parameters and combined CV endpoints which included occurrences of any primary endpoints or CHF. We defined CV death as death directly resulting from circulatory disturbances as acute MI, acute/acute-on-chronic heart failure, cardiac arrhythmias, or ischemic/ haemorrhagic stroke. CAD was diagnosed in the presence of any of the following: history of MI [14]; history suggestive of angina pectoris objectively evidenced by inducible ischemia on exercise treadmill or single photon emission computed tomography (SPECT); and the presence of coronary atherosclerosis was defined by coronary angiography, computed tomography or magnetic resonance imaging. Diagnosis of ischemic stroke was made on the basis of clinical examinations and computed tomography or magnetic resonance brain imaging [15]. As a result, at the end of study 579 patients with complete data on CHADS2 and CHA2DS2-VASc scores and CV outcomes were available for analysis. 2.2. Baseline demographic, clinical and laboratory assessments Baseline demographic data, CV risk factors and medications were documented. Hypertension was defined as either resting systolic/diastolic blood pressure 140/90 mmHg at two different
506
Y.-H. Chan et al. / Atherosclerosis 237 (2014) 504e513
clinic visits or on medications. Diabetes mellitus was defined as serum fasting glucose 7.0 mmol/L or on medications. Hypercholesterolemia was defined as a fasting total plasma cholesterol level of >200 mg/dL or on cholesterol-lowering medications. Smoking status was recorded as past smoker, current smoker or non-smoker. Family history of CAD was considered positive in first-degree relatives with diseases diagnosed at an age younger than 55 years. Long-term physical activity level was defined as nil, regular, or irregular exercise. Body-mass index (BMI) was calculated as weight in kilograms divided by square of height in meters. The CHADS2 and CHA2DS2-VASc scores were calculated [4] according to each constituent criteria including prior CHF, hypertension, age 65e74/75 years, diabetes mellitus, prior stroke/transient ischemic attack, presence of vascular disease, and female sex category. Fasting blood was collected for biochemical analysis of serum low-density/highdensity lipoprotein (LDL/HDL)-cholesterol, triglycerides, glucose, HbA1c, creatinine, and high-sensitivity C-reactive protein (hs-CRP). 2.3. Flow-mediated dilatation (FMD) Vascular ultrasound was performed with a high-resolution ultrasound system (Agilent Sonos 5500, Philips, USA) using a 7.5 MHz linear array transducer by an experienced operator. Patients were studied in the fasting state. To avoid systematic differences in diurnal variation of vascular reactivity, all studies were performed in the morning (time range: 0900e1200). All vasoactive medications, cigarette smoking, caffeine drink and alcohol consumption were withheld for at least 12 h before the assessment. As previously described [16e18] longitudinal scans of the brachial artery were obtained at rest, and then FMD was induced by inflation of a pneumatic tourniquet placed on the forearm to a pressure of 250 mm Hg for 5 min. The cuff was then released, and serial imaging of the brachial artery was recorded for 5 min. The brachial artery was allowed to return to baseline. Finally, the brachial artery was then measured again at 5 min after the administration of 400 mg sublingual nitroglycerin spray. FMD was defined as the percentage change in the brachial artery diameter by 1 min after cuff deflation from that of the baseline scan. Nitroglycerinmediated dilatation (NMD) was defined as the percentage change in the brachial artery diameter by 5 min after nitrate administration. Interobserver variability testing for FMD measurement revealed an interclass correlation coefficient (ICC) (2-way mixed, random-effect model, absolute agreement) of 0.83 (95% CI [0.22e0.97], P ¼ 0.012), with a mean absolute difference of 0.6 ± 0.8%. 2.4. Carotid intimaemedia thickness (IMT) All subjects were examined in a supine position. Briefly [17], carotid IMT was determined by measuring the distance between the lumen-intima and media-adventitia border of the vascular wall with the use of electronic calipers. Each ultrasonic scan was performed in the anterior, lateral, and posterior projections of the right and left carotid arteries. Three IMT measurements were made on the near and far walls of the left and right common carotid arteries, carotid bifurcation, and internal carotid arteries. The mean IMT was calculated by averaging the estimates from 12 previously selected segments in the carotid arteries. Plaque thickness was incorporated in IMT measurement. Intraobserver variability study showed ICC ¼ 0.97 (P < 0.001). 2.5. Arterial stiffness As previously described [18,19], arterial stiffness was measured non-invasively using VP-2000 System (Colin Corp., USA) by an
Table 1 Baseline clinical characteristics, CHADS2 and CHA2DS2-VASc scores of study participants stratified by combined cardiovascular (CV) endpoints of new-onset ischemic stroke, MI, CHF and CV death (n ¼ 579).a No such events Combined CV P-value (n ¼ 497) endpoints (n ¼ 82) Male [n (%)] Age (years) Body mass index (kgm2) Coronary artery disease [n (%)] Prior stroke [n (%)] Diabetes mellitus [n (%)] Hypertension [n (%)] Hyperlipidemia [n (%)] Current/past smoker [n (%)] Regular physical activity [n (%)] Resting pulse rate (min1) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) LDL-cholesterol (mg/dL) HDL-cholesterol (mg/dL) Triglycerides (mg/dL) Fasting glucose (%) HbA1c (%) hs-CRP (mg/L) Creatinine (mmol/L) Medications ACEI/ARB [n (%)] Beta-blockers [n (%)] Calcium channel blockers [n (%)] Aspirin [n (%)] Statin [n (%)] FMD (%) NMD (%) Carotid IMT (mm) PWV (cm/s) PR interval (ms) QRS duration (ms) CHADS2 Score Mean 0e1, n (%) 2, n (%) 3, n (%) CHA2DS2-VASc Score Mean 0e2, n (%) 3, n (%) 4e5, n (%) 6, n (%)
333 (67%) 64.3 ± 11.1 25.4 ± 3.5 269 (54%) 107 (22%) 255 (51%) 319 (64%) 307 (63%) 204 (42%) 176 (36%) 59.5 ± 20.4 139.0 ± 19.4
59 (72%) 74.6 ± 7.3 24.8 ± 3.2 54 (66%) 24 (29%) 45 (55%) 61 (74%) 56 (73%) 46 (56%) 27 (33%) 67.4 ± 20.0 151.4 ± 22.1
0.38
