Family history of coronary heart disease is more strongly associated with coronary than with carotid atherosclerosis in healthy asymptomatic adults

Atherosclerosis 233 (2014) 584e589

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Family history of coronary heart disease is more strongly associated with coronary than with carotid atherosclerosis in healthy asymptomatic adults Beomseok Suh a, Dong Wook Shin a, b, *, Seung-Pyo Lee c, Haewon Lee a, Hyejin Lee a, Eun-Ah Park d, BeLong Cho a, b a

Department of Family Medicine, Seoul National University Hospital, Seoul, Republic of Korea Health Promotion Center, Seoul National University Hospital, Seoul, Republic of Korea Cardiovascular Center and Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea d Department of Radiology and Institute of Radiation Medicine, Seoul National University Hospital, Seoul, Republic of Korea b c

a r t i c l e i n f o

a b s t r a c t

Article history: Received 28 June 2013 Received in revised form 31 December 2013 Accepted 21 January 2014 Available online 29 January 2014

Objective: To investigate the potentially different relationship between family history (FH) of coronary heart disease (CHD) and carotid or coronary atherosclerosis. Methods: Asymptomatic healthy Korean adults older than 30 years who received both coronary CTA and carotid USG as part of a self-referred health check-up were retrospectively investigated (N ¼ 662). Multivariable logistic regression analysis was employed to investigate the relationship between FH of CHD and either coronary CTA or carotid USG results. Results: Adjusted for major CVD risk factors, FH of CHD was significantly associated with presence of any plaque in coronary arteries (aOR 2.10, 95% CI 1.07e4.16) and significant coronary stenosis (aOR 4.92, 95% CI 1.58e15.4), but was not associated with presence of any plaque in carotid arteries (aOR 1.27, 95% CI 0.61e2.63) and increased carotid IMT (aOR 1.44, 95% CI 0.40e5.22). Addition of FH of CHD had significant incremental predictive value to models for any coronary plaque (AUC 0.781 vs. 0.786, p ¼ 0.0351), and significant coronary stenosis (AUC 0.772 vs. 0.808, p ¼ 0.0129), but not for any carotid plaque (AUC 0.748 vs. 0.748, p ¼ 0.528), and increased carotid IMT (AUC 0.778 vs. 0.783, p ¼ 0.591). Conclusion: To our knowledge, our study is the first to show specific comparative evidence that FH of CHD is more strongly associated with coronary than with carotid atherosclerosis. Our results suggest FH of CHD adds predictive value specifically to coronary atherosclerosis, but not carotid atherosclerosis, and suggest the possibility that screening for coronary atherosclerosis (via CAC) among low to intermediate risk asymptomatic adults with FH of CHD may be beneficial, who otherwise would not be screened according to traditional risk algorithms. Ó 2014 Elsevier Ireland Ltd. All rights reserved.

Keywords: Subclinical atherosclerosis Coronary computed tomography angiography Coronary artery stenosis Carotid ultrasonography Carotid intima media thickness Family history of coronary heart disease

1. Background Early detection for cardiovascular disease (CVD) may be beneficial because the majority of patients with sudden cardiac death or nonfatal myocardial infarction are silent prior to the attacks [1]. Traditional CVD risk assessment algorithms are clinically applied to estimate the future event risk [2,3], but often have limited predictive power.

* Corresponding author. Department of Family Medicine & Health Promotion Center, Seoul National University Hospital, 101 Daehakro, Jongnogu, Seoul 110-744, Republic of Korea. Tel.: þ82 2 2072 0847; fax: þ82 2 766 3276. E-mail address: [email protected] (D.W. Shin). 0021-9150/$ e see front matter Ó 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.atherosclerosis.2014.01.046

Noninvasive measures of subclinical atherosclerosis, such as coronary artery calcium (CAC), coronary computed tomography angiography (CTA) and carotid ultrasonography (USG), are associated positively and strongly with future incidence of cardiovascular disease (CVD), and improve predictive power [4e6]. With the recent addition of evidence, these noninvasive tests have been considered to be implemented into traditional risk algorithms; in particular, CAC has been suggested for use in risk stratification of intermediate risk, low to intermediate risk, and diabetic individuals in recent guidelines [7,8]. However, an interesting observation is that these tests often do not concur and do not necessarily have overlapping outcomes and clinical implications. The results of CAC and carotid intima media thickness (CIMT) have only moderate degree of agreement within

B. Suh et al. / Atherosclerosis 233 (2014) 584e589

individuals [9e11], and each test has some variability in the potential for predicting future CVD [12]: for example, CAC has higher predictive value of incident CHD than CIMT [6,13]. Therefore, whether and how to use these tests for early detection in clinical practice remains a matter of debate [14,15]. Family history (FH) of coronary heart disease (CHD) is a major risk factor for CVD [16,17], with a conservative estimate of 2-fold increase in risk [18,19]. However, studies suggest stronger association between FH of CHD with CHD compared to ischemic stroke [20], suggesting different genetic effects on CHD versus ischemic stroke. FH of CHD has also been positively associated with presence of coronary plaques and significant stenosis [21], and increased CIMT [22]. If the association between FH of CHD and subclinical atherosclerosis is different between sites, it may provide useful information in the selection of appropriate methods for a given individual. However, to our knowledge there has been no previous study on the direct comparison of the association of FH of CHD with coronary and carotid atherosclerosis. In this study, we investigated the comparative association of FH of CHD to different aspects of subclinical atherosclerosis by simultaneously measuring coronary CTA and carotid USG. 2. Methods 2.1. Study population We retrospectively enrolled 732 consecutive Korean individuals older than 30 years who simultaneously received both CTA with 64slice multidetector row computed tomography (MDCT) and Carotid Ultrasonography (Carotid USG) for general routine self-referred health evaluation in Seoul National University Hospital (SNUH) from January 2010 to December 2011. Subjects with atypical chest pain (n ¼ 12) and cardiac type chest pain (n ¼ 7), those with previous history of myocardial infarction/angina, coronary revascularization, or coronary bypass surgery history (n ¼ 43), and those with insufficient medical records (n ¼ 7) were excluded. As a result, a total of 662 asymptomatic Korean adults older than 30 years were enrolled. This retrospective study was approved by the SNUH institutional review board and the requirement for informed consent was waived. 2.2. Major CVD risk factor assessment All subjects were asked whether they had chest pain and was categorized as non-cardiac, atypical, and typical, according to the Rose angina questionnaire [23]. Medical history of myocardial infarction, angina, stroke, hypertension, diabetes mellitus, hyperlipidemia, FH of CHD, current medication profile, and smoking status were inquired by self-reported questionnaire and medical interview prior to health screening (which was reviewed by retrospective chart review). FH of CHD was defined as history of CHD among first degree relatives (including both parents and siblings) at any age. Total cholesterol (TC), triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDLC), fasting plasma glucose, hemoglobin A1c level were measured after at least 12-h fasting period on the same day of the study. Hypertension was defined as history of hypertension and/or use of antihypertensive medication or a blood pressure 140/90 mmHg. Diabetes was defined as history of diabetes and/or use of oral hypoglycemic medication or subcutaneous insulin or a fasting plasma glucose 126 mg/dL or hemoglobin A1c 6.5%. Hyperlipidemia was defined as history of hyperlipidemia and/or use of lipid lowering agents or LDL-C 160 mg/dL or TC  240 mg/dL. Framingham risk score of subjects was calculated, and risk groups were categorized

585

into low (<10%), intermediate (10e20%), and high (>20%), as described previously [24]. 2.3. Coronary CTA data acquisition & analysis Methods used for coronary CTA data acquisition and analysis in this study have been described elsewhere [25]. In brief, all CT examinations were performed using a dual source scanner (Somatom Definition; Siemens Medical Solutions, Germany), scans performed using the retrospective ECG-gated mode with ECG pulsing. Data were processed using three-dimensional software (Rapidia; INFINITT, Korea) and the images were in consensus assessed by 2 experienced radiologists. The presence of coronary stenosis and/or plaques was anatomically assessed based on a modified model of the coronary tree with 15 segments [26]. The stenoses were evaluated semi-quantitatively and described as the percentage of lumen diameter reduction (estimated as multiples of 5%). Each segment was categorized as significant (50% lumen diameter reduction) or non-significant (<50% lumen diameter reduction), as previously implemented [27,28]. Plaques were defined as structures >1 mm2 within and/or adjacent to the vessel lumen, clearly distinguished from the lumen and surrounding pericardial tissue, and were visually classified for character of the atherosclerotic plaque in each arterial segment, in which the most stenotic portion was characterized if there were multiple plaque lesions per segment, into one of following: non-calcified, calcified, or mixed plaque. 2.4. Carotid USG data acquisition & analysis Carotid USG was performed using the LOGIQ 7.0 system (GE Medical Systems, USA) to measure IMT and carotid plaques. Both common carotid arteries were thoroughly scanned from proximal to distal to the bifurcation. IMT was measured at the far wall of each common carotid artery about 1 cm proximal to the carotid bulb. If IMT was increased at both sides, the thicker measurement was selected. Increased IMT was defined when the average IMT was 1.0 mm, as a criterion previously reported [29], and also confirmed to be more than 2 standard deviations higher than agespecific average IMT among healthy Korean subjects [30]. Carotid plaques were defined according to the Mannheim Consensus, as focal structures encroaching into the arterial lumen of at least 0.5 mm or 50% of the surrounding IMT value, or demonstrates a thickness >1.5 mm as measured from the media-adventitia interface to the intimaelumen interface [29]. When a plaque was present, IMT was measured at the nearest plaque-free point. All measurements were taken by specialized radiologists. 2.5. Statistical analysis Multivariable logistic regression models consisting of FH of CHD as the main independent variable, adjusted for age, sex, BMI, smoking status, hypertension, diabetes, and hyperlipidemia as independent covariates were constructed to predict the following 4 separate dependent variables (as measures of coronary or carotid atherosclerosis): (1) presence of any plaque type at any coronary artery segment on coronary CTA, (2) significant coronary stenosis (defined as stenosis 50%) on coronary CTA, (3) presence of any plaque in either common carotid artery on carotid USG, and (4) significantly increased IMT (defined as IMT 1.0 mm) on carotid USG. Kappa (k) coefficients were determined to evaluate the magnitude of agreement between the four different aspects of coronary and carotid atherosclerosis investigated in this study. Incremental predictive values of adding FH of CHD into the multivariable logistic regression models for presence of coronary plaque,

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significant coronary stenosis, presence of carotid plaque, and significantly increased carotid IMT were compared by determining areas under the receiver operating characteristics curve (ROC AUC). Likelihood ratio test (LRT) based on standard errors of each ROC was carried out to test the statistical significance of the difference in ROC AUC values [31]. Fischer’s exact test for association was used when parametric methods were judged to be inappropriate. All statistical analysis was performed under STATA version 12.1 (StataCorp, College Station, Texas, USA). All results were considered significant for p-values less than 0.05. 3. Results 3.1. Characteristics of study population As shown in Table 1, the mean age was 55.8  9.4 years (range 30e82), 58.5% were male, 14.6% were classified as having diabetes, 39.3% as hypertension, and 42.4% as hyperlipidemia. The prevalence of FH of CHD was 7.7%. Upon coronary CTA, 32.0% of subjects were observed to have any plaque, whereas upon carotid USG, 25.2% of subjects were observed to have any plaque. Significant coronary stenosis was found in 4.1% of subjects, whereas significantly increased carotid IMT was observed in 5.6% of subjects. Among those with significant coronary stenosis, 25.9% was observed to have extensive disease, having significant stenosis in more than one vessel, as shown in Table 1. Mean maximum coronary stenosis was 22.6  24.1 in those with presence of any coronary plaque, 25.4  8.7 in those with stenosis <50%, and 73.9  15.5 in those with stenosis 50%. 3.2. Correlation between different aspects of coronary and carotid atherosclerosis All four aspects of coronary and carotid atherosclerosis investigated in this study, presence of any coronary plaque, significant coronary stenosis, presence of any carotid plaque, and significantly increased carotid IMT were all significantly correlated to each other except between significant coronary stenosis and significantly increased carotid IMT (k ¼ 0.016, p ¼ 0.337). A higher correlation was observed between the presence of any coronary plaque and the presence of any carotid plaque (k ¼ 0.371, p < 0.0001) (Table 2). 3.3. Comparative relationship between family history of coronary heart disease with coronary and carotid atherosclerosis FH of CHD was shown to be significantly associated with the presence of coronary plaque (aOR 2.10, 95% CI 1.07e4.16) and significant coronary stenosis (aOR 4.92, 95% CI 1.58e15.4) after adjusting for all other major CVD risk factors (i.e. age, sex, BMI, smoking, diabetes, hypertension, hyperlipidemia). In contrast, no significant associations between FH of CHD with carotid plaque (aOR 1.27, 95% CI 0.61e2.63) and significantly increased carotid IMT (aOR 1.44, 95% CI 0.40e5.22) were observed (Table 3). 3.4. Additive predictive value of FH of CHD to coronary and carotid atherosclerosis The predictive model for any coronary plaque had a significantly higher predictive value when FH of CHD was included (AUC 0.786) compared to when it was not (AUC 0.781; LRT p ¼ 0.0351) (despite the difference in AUC being marginal). In contrast, the predictive model for any carotid plaque did not have a significantly higher predictive value when FH of CHD was included (AUC 0.748) compared to when it was not (AUC 0.748; LRT p ¼ 0.528) (Table 3).

Table 1 Characteristics of study population (N ¼ 662). 55.8  9.4

Age, years Sex Female Male BMI Normal (<23 kg/m2) Overweight (23e24.9 kg/m2) Obese (25 kg/m2) Smoking Never Former Current Diabetes No Yes Hypertension No Yes Hyperlipidemia No Yes FH of CHD No Yes FBS, mg/dl Hb A1c, % SBP, mm Hg DBP, mm Hg TC, mg/dl LDL-C, mg/dl HDL-C, mg/dl Low Framingham risk Intermediate Framingham risk High Framingham risk Coronary atherosclerosis e coronary CTA Absence of any plaque Presence of any plaque Maximum coronary stenosis 0% 0%  Stenosis <50% 50% 1 Vessel disease 2 Vessel disease 3 Vessel disease Carotid atherosclerosis e carotid USG Absence of any plaque Presence of any plaque Carotid IMT <1.0 mm Carotid IMT 1.0 mm

275 (41.5%) 387 (58.5%) 255 (38.5%) 202 (30.5%) 205 (31.0%) 360 (54.4%) 190 (28.7% 112 (16.9%) 565 (85.4%) 97 (14.6%) 402 (60.7%) 260 (39.3%) 381 (57.6%) 281 (42.4%) 611 (92.3%) 51 (7.7%) 93.6  18.9 5.9  0.6 126.6  15.2 76.6  10.6 195.5  33.6 125.9  32.4 53.7  13.5 447 (67.5%) 176 (26.6%) 39 (5.9%) 450 (68.0%) 212 (32.0%) 520 (78.5%) 115 (17.4%) 27 (4.1%) 20 (3.0%) 7 (1.1%) 0 (0%) 495 (74.8%) 167 (25.2%) 625 (94.4%) 37 (5.6%)

*Continuous variables are described as mean  standard deviation; Categorical variables are described as number (proportion in percentage). *Abbreviations: N, number; BMI, body mass index; FH, family history; CHD, coronary heart disease; FBS, fasting blood sugar; Hb A1c, hemoglobin A1c; SBP, systolic blood pressure; DBP, diastolic blood pressure; TC, total cholesterol; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; CTA, computed tomography angiography; USG, ultrasonography; IMT, intima media thickness. Table 2 Agreement between different aspects of coronary and carotid atherosclerosis determined by kappa coefficients. Presence of plaque (coronary CTA) Presence of plaque (Coronary CTA) Coronary stenosis 50% Presence of plaque (Carotid USG) Carotid IMT 1.0 mm

Coronary stenosis 50%

Presence of plaque (carotid USG)

1 0.157 p < 0.0001 0.371 p < 0.0001 0.126 p < 0.0001

1 0.113 p < 0.0001 0.016 p ¼ 0.337

1 0.180 p < 0.0001

*Abbreviations: CTA, computed tomography angiography; USG, ultrasonography; IMT, intima media thickness.

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Table 3 Comparison in association between family history of coronary heart disease and subclinical atherosclerosis and additive predictive value (N ¼ 662). Coronary atherosclerosis

FH of CHD No Yes ROC AUC without FH of CHD added ROC AUC with FH of CHD added LRT

Carotid atherosclerosis

Coronary plaque aOR (95% CI)

Coronary stenosis 50% aOR (95% CI)

Carotid plaque aOR (95% CI)

Carotid IMT 1.0 mm aOR (95% CI)

1 2.10 (1.07e4.16) p ¼ 0.032 0.781 0.786 p ¼ 0.0351

1 4.92 (1.58e15.4) p ¼ 0.006 0.772 0.808 p ¼ 0.0129

1 1.27 (0.61e2.63) p ¼ 0.523 0.748 0.748 p ¼ 0.528

1 1.44 (0.40e5.22) p ¼ 0.577 0.778 0.783 p ¼ 0.591

Multivariate logistic regression analysis adjusted for age, sex, BMI, smoking, diabetes, hypertension, and hyperlipidemia. Predictive value for each assessment of subclinical atherosclerosis when FH of CHD is added or not to the regression models are compared by ROC AUC and LRT. *Abbreviations: N, number; aOR, adjusted odds ratio; CI, confidence interval; p, p-value; IMT, intima media thickness; FH, family history; CHD, coronary heart disease; ROC AUC, receiver operator curve area under curve; LRT, likelihood-ratio test.

The predictive model for significant coronary stenosis had a significantly higher predictive value when FH of CHD was included (AUC 0.808) compared to when it was not (AUC 0.772; LRT p ¼ 0.0129). In contrast, the predictive model for significantly increased carotid IMT did not have a significantly higher predictive value when FH of CHD was included (AUC 0.783) compared to when it was not (AUC 0.778, LRT p ¼ 0.591) (Table 3). 3.5. Association of FH of CHD with significant coronary stenosis in different Framingham risk groups FH of CHD was significantly associated with significant coronary stenosis only in those with low Framingham risk (Fischer’s exact test p ¼ 0.001), and 10.5% of those with FH of CHD among low risk subjects were shown to have significant coronary stenosis (Table 4). 3.6. Association of FH of CHD with number of coronary artery segments with plaques by subtype FH of CHD was significantly associated with the number of coronary artery segments with non-calcified plaque (b 0.238, 95% CI 0.092e0.383), determined by multivariable linear regression analysis for number of coronary segments, and adjusted to major CVD risk factors. However, adjusted for major CVD risk factors, FH of CHD was not associated with the number of coronary artery segments with calcified/mixed plaque (b 0.177, 95% CI 0.188e 0.542) (Table 5). 4. Discussion Our study investigated a relatively large number of asymptomatic generally healthy adults who simultaneously received coronary CTA and carotid USG. To our knowledge, our study is the first to directly compare the relationship between FH of CHD with coronary CTA and carotid IMT. Our results suggest that the association between FH of CHD and coronary CTA findings (both presence of plaque and significant coronary stenosis) is markedly stronger than that between FH of CHD and increased carotid IMT or presence of carotid plaque. FH of CHD is associated with increased carotid IMT [22,32], CAC [33,34], and coronary stenosis and plaque [21]. Notably, genetic backgrounds are associated with increased CAC and carotid IMT, with 40% of the inter-individual variability attributable to the effects of individual genes even after adjusting for other shared established risk factors [35,36]. Premature FH of CHD was associated with carotid IMT in a large, community-based study [22], even after adjusting for other cardiovascular risk factors, which suggests the influence of genetic effects. Genetic testing is not clinically

applicable (yet), nonetheless, we have clinical information in FH that may reflect on such genetic effects. For this reason, our study focused particularly on FH of CHD and its comparative association with subclinical atherosclerosis. We evaluated the relationship between different measures of atherosclerosis, namely, coronary and carotid (Table 2). The magnitude of agreement between coronary and carotid plaque was 0.371, indicating only weak-to-moderate association, and no significant agreement between increased carotid IMT and significant coronary stenosis was observed (k ¼ 0.016, p ¼ 0.337). This result is consistent with previous reports [37] and deserves attention because it implies that the indications for carotid and coronary screening may need to be individualized. It also suggests that coronary atherosclerosis and carotid atherosclerosis, although looking very similar and sharing common risk factors, may be distinct disease with different genetic effects. This reinforces the importance of our study’s main implication that FH of CHD is more

Table 4 Association of FH of CHD with significant coronary stenosis in different Framingham risk groups (N ¼ 662).

Framingham risk Low Framingham risk Intermediate Framingham risk High

FH FH FH FH FH FH

of of of of of of

CHD CHD CHD CHD CHD CHD

() (þ) () (þ) () (þ)

Coronary stenosis <50%

Coronary stenosis 50%

N (%)

N (%)

p

406 34 152 11 31 1

3 4 12 1 7 0

0.001

(99.3) (89.5) (92.7) (91.7) (81.6) (100.0)

(0.7) (10.5) (7.3) (8.3) (18.4) (0.0)

0.614 0.821

p-values upon analysis by Fisher’s exact test. *Abbreviations: N, number; p, p-value; FH, family history; CHD, coronary heart disease.

Table 5 Association of FH of CHD with number of coronary artery segments with plaques by subtype (N ¼ 662). Number of coronary segments with calcified/mixed plaque b (95% CI) FH of CHD No 1 Yes 0.177 (0.188e0.542) p ¼ 0.342

Number of coronary segments with non-calcified plaque b (95% CI) 1 0.238 (0.092e0.383) p ¼ 0.001

Multivariate linear regression analysis adjusted for age, sex, BMI, smoking, diabetes, hypertension, and hyperlipidemia. *Abbreviations: N, number; b, beta coefficient; aOR, adjusted odds ratio; CI, confidence interval; p, p-value; FH, family history; CHD, coronary heart disease.

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strongly associated with significant coronary stenosis compared with increased carotid IMT. In our study, a discrepancy was clearly shown to exist between the association of FH of CHD with coronary atherosclerosis and the association of FH of CHD with carotid atherosclerosis. This implies there may be a difference in the relationship between FH of CHD and CHD and the relationship between FH of CHD and stroke. In other words, FH of CHD may be more likely to induce coronary atherosclerosis and clinical CHD, rather than carotid atherosclerosis and ischemic stroke (although this difference may be partially explained by stroke being also caused by non-atherosclerosis pathophysiology, such as atrial fibrillation). This hypothesis is consistent with and supported by previous studies that investigated the association of FH of CHD with CHD and the association of FH of CHD and ischemic stroke together [20,38]. For example, FH of CHD was more strongly associated with CHD (adjusted HR 1.98, 95% CI 1.48e2.78 in male; 2.49, 95% CI 1.46e4.24 in female) than with stroke (adjusted HR ¼ 1.03, 95% CI 0.67e1.60 in male; 1.45, 95% CI, 0.80e2.62 in female) [20]. Other studies also suggested that FH of CHD is significantly associated with CHD [38e40], but not with ischemic stroke [41]. With the development of various noninvasive tests for subclinical atherosclerosis, such as coronary CTA, CAC, and carotid USG, specific indications for each screening tool are needed for unequivocal use in the clinical setting. Many studies have evaluated comparative predictive values. One study [42] found that CAC is associated more strongly than IMT with coronary stenosis by conventional coronary angiography, while another [6] suggested that CAC has higher predictive value of incident CHD than carotid IMT. In addition to stronger association of FH of CHD with coronary atherosclerosis, our results show that FH of CHD significantly adds predictive value to significant coronary stenosis, but not to carotid USG. Collectively, our results suggest higher pretest probability of subclinical atherosclerosis in coronary CTA than in carotid USG among subjects with first degree FH of CHD. This may be biologically attributed to differences in the anatomical involvement, as initiation, speed of development, and phenotypic expression of atherosclerotic lesions have been shown to be artery-related [43], most likely subject to varying genetic influence and susceptibility to risk factors, however, this is a topic beyond the scope of this study. Our results are consistent with current guidelines that recommend screening for CHD in asymptomatic subjects with FH of premature CHD only among low risk subjects [44], as FH of CHD was associated with significant coronary stenosis specifically among low risk subjects according to our data (Table 4), although the low number of high FRS risk subjects should be taken into consideration as a possible source of error. It is important to note that current guidelines recommend screening for CHD in asymptomatic subjects with FH of premature CHD via CAC [7], but no such guidelines are available in terms of coronary CTA. Although CAC data was not available, we used number of coronary segments with calcified/mixed plaque as a tentative surrogate variable to CAC, as the higher the number of segments with calcified/mixed plaque the higher the chances to be detected via CAC. According to our analysis, FH of CHD was not significantly associated with the number of segments with calcified/mixed plaque, although the magnitude of association tended toward significant association if the statistical power were greater (b 0.177, 95% CI 0.188e0.542) (Table 5). In contrast, FH of CHD was clearly shown to be significantly associated with the number of coronary segments with non-calcified plaque (b 0.238, 95% CI 0.092e0.383). This result has important clinical implications, as it suggests that coronary CTA may successfully screen those at risk among subjects with positive FH of CHD by detecting non-calcified plaque that would otherwise go undetected via CAC. Although

screening via coronary CTA showed no significant benefit compared to that of CAC in a previous study [45], future large-scale prospective studies are warranted to properly evaluate whether screening for CHD via coronary CTA instead of CAC may be beneficial in the case of asymptomatic subjects with a positive FH of CHD in particular. There are several limitations to our study. First, our assessment of FH of CHD includes all age for first degree relatives’ CHD incidents. Although many studies show premature FH of CHD as the major CVD risk factor, there are previous studies that show FH of CHD at any age is still a major risk factor, albeit at a modestly lower risk [40,46]. Second, although past medical history and FH of CHD was inquired by both self-reported questionnaire and medical interview, data was acquired via retrospective chart review, prone to inter-observer variation. However, we checked the reliability of our data via random resampling of 50 subjects and found the agreement to be high (agreement rate 98.0%, k ¼ 0.89). Third, it was a retrospective study; however, data was procured from consecutive patients. Fourth, because the prevalence of subjects with FH of CHD was low (unfortunately lack of previous data on the prevalence of FH of CHD among Koreans made assessment of our data difficult), as well as the prevalence of significant coronary stenosis, some of our analysis failed to reach sufficient statistical power. Fifth, a quantitative comparison between the association of FH of CHD with coronary and carotid atherosclerosis could not be made as our assessment of coronary and carotid atherosclerosis was not completely synonymous (i.e. USG vs. CTA). However, our results were consistent in many aspects to justify qualitative assertions. In conclusion, our study is the first to show specific comparative evidence that FH of CHD is more strongly associated with coronary atherosclerosis than with carotid atherosclerosis. Furthermore, our analysis additionally shows evidence that FH of CHD has additive predictive value to coronary atherosclerosis than just major cardiovascular risk factors. Collectively, our results suggest the possibility that screening for coronary atherosclerosis (via CAC) among low to intermediate risk asymptomatic adults with FH of CHD may be beneficial, who otherwise would not be screened according to traditional risk algorithms. Funding None received. Conflict of interest None disclaimed. References [1] Myerburg M, Robert J, Interian A, et al. Frequency of sudden cardiac death and profiles of risk. Am J Cardiol 1997;80:10e9. [2] Nasir K, Michos ED, Blumenthal RS, et al. Detection of high-risk young adults and women by coronary calcium and National Cholesterol Education Program Panel III guidelines. J Am Coll Cardiol 2005;46:1931e6. [3] Akosah KO, Schaper A, Cogbill C, et al. Preventing myocardial infarction in the young adult in the first place: how do the National Cholesterol Education Panel III guidelines perform? J Am Coll Cardiol 2003;41:1475e9. [4] Greenland P, Bonow RO, Brundage BH, et al. ACCF/AHA 2007 clinical expert consensus document on coronary artery calcium scoring by computed tomography in global cardiovascular risk assessment and in evaluation of patients with chest pain: a report of the American College of Cardiology Foundation Clinical Expert Consensus Task Force (ACCF/AHA Writing Committee to Update the 2000 Expert Consensus Document on Electron Beam Computed Tomography) developed in collaboration with the Society of Atherosclerosis Imaging and Prevention and the Society of Cardiovascular Computed Tomography. J Am Coll Cardiol 2007;49:378. [5] Lorenz MW, Markus HS, Bots ML, et al. Prediction of clinical cardiovascular events with carotid intima-media thickness. Circulation 2007;115:459e67. [6] Folsom AR, Kronmal RA, Detrano RC, et al. Coronary artery calcification compared with carotid intima-media thickness in the prediction of

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