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INTRODUCTION
Identification of patients with high risk for cardiovascular (CV) disease is important to justify more aggressive medical therapies for primary prevention.12 The coronary artery calcium score (CACS) has been used to non-invasively evaluate CV risk.3 CACS is correlated with coronary artery plaque burden, and previous studies have demonstrated a relationship between CACS and all-cause mortality independent of other established risk factors.45 However, CACS requires radiation exposure, equipment, training, and time, and is poorly reimbursed, thus limiting their routine use in daily practice.
Recently, there has been growing interest in the difference in inter-arm blood pressure (BP), especially because increased differences in systolic BP (SBP), and also weakly in diastolic BP (DBP), are associated with a greater risk of CV events, and also both all-cause and CV mortality.6789 Recent studies have also identified a correlation between the difference in inter-arm BP and target organ damage such as left ventricular mass index and carotid or brachial-femoral pulse wave velocities.1011 However, there are not much data on the relationship between the difference in inter-arm BP and coronary atherosclerotic disease, found by using CACS.
In the present study, therefore, we aimed to investigate whether the increased difference of inter-arm BP was independently associated with an abnormal CACS. Identification of an association between inter-arm BP difference and CACS may have significant implications for screening patients for atherosclerotic coronary artery disease (CAD).
MATERIALS AND METHODS
Study population
Included patients had at least 3 CV risk factors or an intermediate Framingham Risk Score (FRS; ≥10), were referred to the hospital with chest pain, and underwent evaluation of CAD between March 2012 and August 2014. A total of 261 patients who underwent coronary computed tomography angiography (CTA) at the discretion of their treating physician were included in the analysis. Patients with known CAD, a previous history of revascularization, peripheral artery disease, and those with significant valvular heart disease were excluded from the analysis. The study protocol was approved by the Institutional Review Board of Ulsan University Hospital, and is in accordance with the Declaration of Helsinki.
The presence of known CV risk factors, including smoking history, hypertension, diabetes mellitus, and dyslipidemia, were identified through history taking and using medical questionnaires. Smoking was classified as never, current, or ex-smoker, with smoking stopped less than 1 year before enrollment. Hypertension was diagnosed if patients had SBP ≥140 mm Hg or DBP ≥90 mm Hg, a history of hypertension or were using antihypertensive agents. Diabetes mellitus was diagnosed if patients had a fasting plasma glucose level ≥126 mg/dL on 2 separate days, a history of diabetes mellitus or were using antidiabetic agents. Dyslipidemia was diagnosed in patients with a history of using cholesterol-lowering medications or who had a fasting serum total cholesterol level ≥240 mg/dL or low-density lipoprotein cholesterol level ≥160 mg/dL. The FRS was used to estimate a 10-year risk of coronary heart disease, defined as angina pectoris, recognized or unrecognized myocardial infarction, coronary insufficiency, and cardiac death.12 The FRS score included age, gender, total cholesterol, high-density lipoprotein cholesterol, SBP, and use of anti-hypertensive agents as its individual components.
Measurement of blood pressure and inter-arm blood pressure difference
BP was synchronously measured in both arms by a trained nurse using separate cuff hoses in each electronic manometer (Omron HEM-7001-E; Omron Corp., Tokyo, Japan). The BP was measured 3 times at two-minute intervals in each patient on the day of the examination. Thus, the patients were instructed to sit for 5 minutes on a straight chair with BP cuffs wrapped around both arms before performing the BP measurements. Inter-arm BP difference was defined as right-arm BP minus left-arm BP. Then, the absolute value of the inter-arm BP difference was calculated.
Coronary artery calcium score using coronary computed tomography angiography
Coronary CTA was performed using a 0.8-mm thickness 256-slice multi-detector CT scanner (Brilliance iCT 256; Philips Medical Systems, Best, the Netherlands).13 Patients with a heart rate >65 bpm were given metoprolol 100 mg to reduce their heart rate down to ≤65 bpm. Scan parameters were as follows: tube voltage, 120 kVp; tube current, 100 mAs; 220 mm field of view; rotation time, 0.27 s/rotation; reconstructed slice thickness, 0.8-mm; signal acquisition at 80 % of the R-R interval. CACS was measured using the Extended Brilliance Workspace workstation (Philips Medical Systems) after reconstruction. CACS was automatically displayed in color by calcium scoring software. Quantitative CACS was measured with the scoring system described by Agatston.14 We excluded the patients with 0 of CACS.
Statistical analysis
Continuous variables are presented as mean±standard deviation, whereas categorical variables are expressed as absolute values and percentages. The Wilcoxon rank-sum test for independent samples was used to identify differences between continuous variables that were not normally distributed. Student's t-test was used to identify differences between normally distributed continuous variables. Differences between categorical variables were evaluated with the Fisher exact test. Bivariate correlation analysis with Spearman correlations was used to evaluate associations between variables. Multivariate logistic regression analysis was used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for the CACS and other variables. To evaluate whether inter-arm BP difference provides incremental value in predicting the CACS over traditional risk factors, we computed receiver operating characteristic (ROC) curves, and the DeLong method was then used to identify differences between ROC curves. All statistical analyses were done using SPSS version 18.0 (SPSS Inc., Chicago, IL, USA), and p<0.05 was considered significant.
RESULTS
The demographic and clinical characteristics of patients are presented in Table 1. Included patients had a mean age of 60.6±9.1 years, and 150 patients (57.0 %) were male. The mean value of inter-arm BP difference for SBP/DBP was 5.4/3.3 mm Hg, the mean value of FRS was 10.2±7.3, and CACS was 169.4±326.6. Table 2 shows the correlations of various parameters with the degree of CACS: Age (r=0.256, p<0.001), serum creatinine (r= 0.139, p=0.030), mean of right arm SBP (r=0.172, p=0.005), mean of left arm SBP (r=0.190, p=0.002), inter-arm SBP difference (r=0.152, p=0.014), and the FRS (r=0.278, p<0.001) showed a significant correlation with CACS.
As shown in Table 3, an inter-arm SBP difference ≥6 mm Hg was significantly associated with a CACS ≥300 (OR 2.17, 95% CI 1.12–4.22; p=0.022). This relationship was maintained even after adjustment for covariates including age ≥50 years, gender, hypertension, diabetes mellitus, dyslipidemia, body mass index, absolute inter-arm SBP difference, and FRS (OR 2.34, 95% CI 1.06–5.19; p=0.036). Additionally, the frequency of patients with increased inter-arm SBP difference was significantly different between patients stratified by CACS ≥300 (Table 4). Moreover, when the inter-arm SBP difference was added to a model that included the FRS, a significant improvement resulted in the ability to predict an abnormal CACS (≥300), shown in Fig. 1. Specifically, additional inclusion of inter-arm SBP difference to the FRS increased the area under the curve for predicting CACS ≥300, from 0.664 to 0.721 (p<0.0001).
DISCUSSION
The main findings in our study are; 1) increased inter-arm SBP difference (≥6 mm Hg) is an independent predictor for coronary atherosclerosis using CACS even after adjusting for known CV risk factors; 2) inter-arm SBP difference provides additional information for predicting severe coronary calcification compared to models based on known traditional risk factors.
Recently, a great deal of interest has been paid on the predictive value of inter-arm BP difference for clinical outcomes. Previous data have indicated that an increased difference in inter-arm SBP is associated with an increased risk of subclinical atherosclerosis, left ventricular hypertrophy, aortic aneurysms and aortic dissection, and CV disease.910151617 In addition, a recent meta-analysis, based on 9 studies including over 15617 patients,7 demonstrated that a greater difference in inter-arm SBP was a predictor of increased all-cause and CV mortality. However, there were some limitations to these previous studies. Most of the evidence on CV disease came from studies measuring BP sequentially in both arms, instead of synchronous measurements as in our study. Sequential BP measurements have been shown to overestimate the prevalence of an increased inter-arm BP difference.18 Also, there are a lack of studies assessing the correlation between inter-arm BP difference and coronary atherosclerosis using CACS as measured by coronary CTA. In this regard, our data give more meaningful information for significant association of synchronously measured inter-arm BP difference with CACS obtained from coronary CTA in outpatient daily practice.
CACS has been shown to provide an increased predictive value over traditional CV disease risk factors. Indeed, CACS is a robust predictor of CV events and all-cause mortality for individuals with an intermediate CV risk.4192021 Current guidelines give a Class IIa recommendation for the use of CACS in individuals at intermediate CV risk.2021 Moreover, a recent study suggested that an increasing CACS was significantly associated with a higher risk of all-cause mortality among patients with a very low CV risk factor profile.22 In the present study, our data showed that inter-arm SBP difference was significantly correlated with the degree of CACS. When we focused our analysis on CACS ≥300, as this is known to identify those at the highest risk of CV events,23 the cutoff value of inter-arm SBP difference ≥6 mm Hg was shown to be an independent predictor of CACS ≥300, especially in patients who had at least an intermediate risk of CV disease.
Although CACS is the most validated marker of coronary atherosclerosis among non-invasive imaging modalities, valid questions on radiation exposure and cost-effectiveness are major limitations to its repeated use in routine outpatient daily practice. In our study, additional inclusion of inter-arm SBP difference improved the ability of risk prediction models, which are based on traditional risk factors for coronary atherosclerosis such as FRS. In this regard, inter-arm SBP difference may be an alternative option for screening patients for coronary atherosclerosis.
The present study has several limitations. First, since our study had an observational study design, the identified associations do not necessarily confirm causation. Furthermore, due to the absence of randomization from the general population, generalization of our findings is restricted. However, because this study has important findings on the value of inter-arm SBP difference in patients who had at least an intermediate risk of CV disease, confirmation with larger randomized studies is needed. Second, we used multivariable analysis for FRS and incorporated known CAD risk factors such as age, hypertension, diabetes mellitus, and dyslipidemia that would be associated with inter-arm BP difference. However, we could not clearly adjust for other non-traditional risk factor for CAD. Finally, we enrolled those patients who had ≥3 CV risk factors or a predominantly intermediate FRS (FRS ≥10). Therefore, the application of our findings is limited to patients who had at least an intermediate risk of CV disease, and generalizability of our findings to patients with low risk of severe coronary calcification needs further confirmation.
In conclusion, an increased inter-arm SBP difference (≥6 mm Hg) is an independent predictor for coronary atherosclerosis using CACS and provides additional information for predicting severe coronary calcification, compared to models based on known traditional risk factors. Patients with evidence of increased inter-arm SBP difference may warrant a more thorough evaluation for coronary atherosclerotic disease with CACS.
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