Association Between Hypertension and Coronary Artery Disease as Assessed by Coronary Computed Tomography

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1 Original Paper Association Between Hypertension and Coronary Artery Disease as Assessed by Coronary Computed Tomography Ryoko Mitsutake, MD, PhD; Shin-ichiro Miura, MD, PhD; Yuhei Shiga, MD; Yoshinari Uehara, MD, PhD; Keijiro Saku, MD, PhD Multidetector row computed tomography (MDCT) enables the accurate noninvasive assessment of coronary artery stenosis and plaque imaging. The characteristics of patients who have coronary artery disease (CAD) as assessed by MDCT coronary computed tomography (CT) are not well known. Participants consisted of 13 consecutive patients with suspected CAD who underwent coronary CT. The authors quantified patient characteristics, including the prevalence of hypertension (HTN), hyperlipidemia and diabetes mellitus (DM), visceral fat area (VFA) and subcutaneous fat area using CT, and plasma levels of metabolic factors, including adiponectin and leptin. Although plasma levels of adiponectin in men and leptin in women were significantly associated with chronic kidney disease, there were no differences in these levels between patients with and without CAD. HTN was most significantly associated with the presence of CAD by multivariate logistic regression analysis (men, P=.2; women, P=.48). Finally, the percentage From the Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan Address for correspondence: Shin-ichiro Miura, MD, PhD, Associate Professor of Medicine, Department of Cardiology, Fukuoka University School of Medicine 7-4-1, Nanakuma, Jonan-ku, Fukuoka , Japan Manuscript received July 13, 1; revised October 24, 1; accepted October 28, 1 doi: /j x of CAD significantly increased as systolic blood pressure increased (trend, P=.2) in men but not women. In conclusion, hypertension was significantly associated with CAD as assessed by coronary CT. J Clin Hypertens (Greenwich). 11;13: ª 1 Wiley Periodicals, Inc. Multidetector row computed tomography (MDCT) has become more widely available in many general hospitals and enables the accurate noninvasive assessment of coronary artery stenosis 1 and calcification 2,3 and plaque imaging. 4 Invasive coronary angiography (CAG) is performed for patients who are strongly suspected to have coronary artery disease (CAD) based on the judgment of a specialized cardiologist. On the other hand, since noncardiologists care for patients with the metabolic syndrome (MetS), which is the cluster of abdominal obesity, hyperlipidemia (HL), hypertension (HTN), and glucose intolerance, and since MetS is induced by the dysregulation of adipocytokines, such as adiponectin and is associated with increased CAD, 6 8 they often have to judge whether patients should undergo MDCT coronary angiography (coronary CT). The characteristics of patients who should receive coronary CT as screening for CAD are unknown, and there are no criteria for patient selection. Therefore, we analyzed the backgrounds of patients who underwent coronary CT at Fukuoka University Hospital and identified the characteristics, including cardiac risk factors, of those with CAD. 198 THE JOURNAL OF CLINICAL HYPERTENSION VOL. 13 NO. 3 MARCH 11

2 METHODS A total of 13 consecutive patients who were clinically suspected of having CAD according to abnormal electrocardiography and or chest symptoms (such as chest pain or chest discomfort) or who had at least one cardiac risk factor (smoking, abdominal obesity, HL, HTN, and or diabetes mellitus [DM]) were enrolled in this study. All patients underwent coronary CT between July 6 and August 8. The protocol in this study was approved by the ethics committee of Fukuoka University Hospital, and all participants gave their informed consent to participate. We evaluated coronary stenosis using MDCT as previously described. 9 Briefly, all patients were scanned by 64-MDCT on an Aquilion 64 (Toshiba, Tokyo, Japan). The use of b-blockers and nitroglycerin before scanning was left to the physician s discretion. A 7-mL bolus of contrast media (Omnipaque, 3 mg iodine ml; Daiichi Sankyo Co, Ltd., Tokyo, Japan) was injected at a flow rate of 3.6 ml s and was followed by 3 ml of contrast agent and 3 ml of saline solution, each at a flow rate of 1.8 ml s, with a dual injector. The region of interest was placed within the ascending aorta, and the scan was started when the CT density reached 1 HU higher than the baseline CT density. The scan was performed between the tracheal bifurcation and diaphragm with the following parameters: collimation width,. mm; rotation speed.4 s rotation; tube voltage, 13 kv; and effective tube current, 36 ma. Any narrowing of the normal contrast-enhanced lumen to <% that could be identified in multiplanar reconstructions or cross-sectional images was defined as significant coronary stenosis in CAD. Body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), serum levels of triglycerides (TGs), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), uric acid (UA), fasting plasma glucose, hemoglobin A 1c (HbA 1c ), smoking status (current vs nonsmokers), family history (myocardial infarction [MI], angina pectoris, or sudden death), and medication use were collected as cardiovascular risk factors in all patients. BP was determined as the mean of two measurements obtained in an office setting by the conventional cuff method using a mercury sphygmomanometer after at least minutes of rest. All blood samples were drawn in the morning after the patients had fasted overnight. Concentrations of TGs, HDL-C, LDL-C, and UA were measured by enzymatic methods, as described previously. 1 Plasma levels of adiponectin and leptin were determined with adiponectin 11 and leptin 12 enzyme-linked immunosorbent assay kits, respectively. The characteristics of patients, including the history of HTN, HL, DM, and history of smoking, were obtained from medical records. Patients who had a current SBP DBP 14 9 mm Hg or were receiving antihypertensive therapy were considered to have HTN. Patients with LDL-C 14 mg dl and or TGs 1 mg dl or who were receiving lipid-lowering therapy were defined as having hyperlipidemia. DM was defined using the American Diabetes Association criteria. BMI was calculated as weight (kg) height (m) 2. Hyperuricemia was defined as a serum UA level of 7. mg dl or the administration of UA-lowering drugs. MetS was diagnosed by the criteria published by the Examination Committee of Criteria for Diagnosis of Metabolic Syndrome in Japan in : visceral fat area (VFA) 1 cm 2 and the presence of >2 of the following: high BP (SBP 13 mm Hg or DBP 8 mm Hg or taking an antihypertensive drug) or dyslipidemia (TGs 1 mg dl or 4 mg dl HDL-C or taking a lipid-lowering drug) or high fasting glucose (fasting glucose 11 mg dl or taking a glucose-lowering drug). Patients were classified according to the number of components of the MetS. For the measurement of VFA, subcutaneous fat area (SFA) and waist circumference was performed. These values were measured from CT cross-sectional scans at the level of the umbilicus using software (Fat Scan; N2 System, Hyogo, Japan). The National Kidney Foundation 13 has defined CKD as a glomerular filtration rate (GFR) of <6 ml min 1.73 m 2. Estimated GFR (egfr) was determined using the abbreviated equation as modified for Japanese by the Japanese Society of Nephrology based on the Modification of Diet in Renal Disease study 14 ; (age [years]) ).3 (serum Cr [mg dl]) )1.14 [.742 if female]. 14 Statistical analysis was performed using the Stat View statistical software package (Stat View ; SAS Institute Inc, Cary, NC) at Fukuoka University (Fukuoka, Japan). Data are shown as the mean standard deviation (SD). Categoric and continuous variables were compared between the groups by a chi-square analysis and analysis of variance followed by Fisher PLSD, respectively. A value of P<. was considered significant. Multivariate analysis was performed by a logistic regression analysis for independent variables that were related to the presence or absence of CAD. VOL. 13 NO. 3 MARCH 11 THE JOURNAL OF CLINICAL HYPERTENSION 199

3 Table I. Patients Clinical Characteristics All HTN()) HTN(+) Age, y a Men, % Family history, % Smoking, % BMI, kg m a Hypertension, % 69 1 SBP DBP, mm Hg a 8112 a Hyperlipidemia, % TG, mg dl HDL-C, mg dl LDL-C, mg dl DM, % HbA1c, % Fasting glucose, mg dl HU, % a Uric acid, mg dl a Medication use, % ARB or ACEI 39 2 a CCB a Statin a Leptin, ng ml a Adiponectin, mg ml SFA VFA, cm a a WC, cm a CKD, % a egfr, ml min 1.73 m a MetS, % a CKD, % a Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; BMI, body mass index; CAD, coronary artery disease; CCB, calcium channel blocker; CKD, chronic kidney disease; DBP, diastolic blood pressure; DM, diabetes mellitus; egfr; estimated glomerular filtration rate; HDL-C, high-density lipoprotein cholesterol; HTN, hypertension; HU, hyperuricemia; LDL-C, low-density lipoprotein cholesterol; MetS, metabolic syndrome; SBP, systolic blood pressure; SFA, subcutaneous fat area; TG, triglycerides; VFA, visceral fat area; WC, waist circumference. Continuous variables are expressed as mean standard deviation. a P <. vs HT ()). RESULTS Table I shows the clinical characteristics of the 13 patients, who consisted of 277 (4%) men and 236 (46%) women. The percentages of HTN, HL, DM, and MetS were 68%, 8%, 4%, and 41%, respectively. The mean age was 6411 years, BMI was 244 kg m 2,andVFAwas12263 cm 2.In addition, the percentages of the use of angiotensin II receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEIs), calcium channel blockers (CCBs), and statins were 39%, 4%, and 3%, respectively. Patients in the HTN (+) group were older; had higher BMI, BP, HU, and uric acid levels; more ARB or ACEI, CCB, and statin use; and increased liptin, SFA, VFA, WC, CKD, egfr, MetS, and CAD presence compared with the HTN ()) group. On the other hand, percentage of sex, family history, smoking hyperlipidemia, and DM were similar between HTN ()) and HTN (+) groups. As shown in Figure 1, percentage of CAD in men significantly increased as the number of metabolic factors increased (trend, P<.), while there was no similar relation in women (P=.12). In addition, although plasma levels of adiponectin in men andleptininwomenweresignificantlyassociated with CKD, there were no differences in these levels between patients with and without CAD (Figure 2). Next, we examined the associations between the presence of CAD as assessed by coronary CT and (model 1) or 8 (model 2) possible factors by logistic regression analysis (Table II). Since MetS is associated with DM, HTN, hyperlipidemia, and VFA, and since leptin and adiponectin are also associated THE JOURNAL OF CLINICAL HYPERTENSION VOL. 13 NO. 3 MARCH 11

4 Patients With CAD, % Men (Trend, P<.) Women (Trend, P=.12) Metabolic Factors, No. the presence of CAD in model 2, we analyzed percentage of CAD according to SBP levels (<1 mm Hg, mm Hg, mm Hg, and 16 mm Hg) (Figure 3) and DBP levels (<8 mm Hg, 8 84 mm Hg, 8 89 mm Hg, and 9 mm Hg). Percentage of CAD significantly increased as SBP increased (trend, P=.2) in men, while there was no similar association in women (trend, P=.21). Percentage of CAD according to DBP did not show significant changes in men (trend, P=.133) or women (trend, P=.38). Figure 1. The prevalence of coronary artery disease (CAD) according to the number of metabolic factors ( 4) in men and women. with MetS, we excluded these factors from the analysis. In model 1, CAD was significantly associated with MetS (P=.13) and age (P=.14) in men and age in women (P=.6). In addition, CAD was significantly associated with HTN in men (P=.2) and in women (P=.48) in model 2. Since HTN was most significantly associated with DISCUSSION In the present study, we demonstrated a significant association between HTN and CAD as assessed by coronary CT. The 8 factors in Table II are independent risk factors for CAD. 1 Although plasma leptin might also be a risk factor for CAD, there is no consensus regarding this point. 16,17 In this study, HTN was the most important factor associated with the presence or absence of CAD among the 8 factors considered, although it is well known that the A. Plasma Adiponectin, μg/ml 1 1 * (-) ( + ) (-) ( + ) Plasma Leptin, ng/ml * (-) ( + ) (-) (+) B. Male Female Male Female CKD CKD Plasma Adiponectin, μg/ml 1 1 (-) (+) (-) (+) Plasma Leptin, ng/ml NS (-) (+) (-) (+) Male Female Male Female CAD CAD Figure 2. Plasma levels of adiponectin and leptin in the presence (+) or absence ()) of chronic kidney disease (CKD) (A) and coronary artery disease (CAD) (B) in men and women. *P<. vs CKD ()) group. NS indicates not significant. VOL. 13 NO. 3 MARCH 11 THE JOURNAL OF CLINICAL HYPERTENSION 1

5 Table II. Factors that Contribute to Coronary Artery Disease Men Women OR (9% CI) P Value OR (9% CI) P Value Model 1 Age 1.3 ( ) ( ).6 Smoking.87 (. 1.) (.92.63).77 Family history 1.37 ( ).41.9 (.4 2.6).89 CKD 1. ( ) ( ).268 MetS 1.97 ( ) (.4 1.6).61 Model 2 Age 1.3 (1. 1.6) ( ).234 Smoking.82 ( ) (.81.38).128 Family history 1.36 ( ) ( ).86 HTN 2.94 (1.4.89) (1.1.3).48 HL 1.16 ( ) ( ).261 DM.77 ( ) ( ).619 CKD 1.4 ( ).99.8 ( ).69 VFA 1. (.99 1.) ( ).6 Abbreviations: CI, confidence interval; CKD, chronic kidney disease; DM, diabetes mellitus; HL, hyperlipidemia; HTN, hypertension; MetS, metabolic syndrome; OR, odds ratio; VFA, visceral fat area. Patients with CAD (%) Mal e (Tren d, P<. 2) Female (Trend, P=.21) < SBP, mmhg 16 Figure 3. The prevalence of coronary artery disease (CAD) according to the systolic blood pressure level in men and women. clustering of metabolic disorders induces CAD. In a meta-analysis of individual data for 1 million adults in 61 prospective studies, 18 cardiovascular morbidity and mortality risk were shown to increase with an increase in BP. In Japan, NIPPON DATA8 reported that elevated SBP is an independent risk factor for CAD mortality for men of all ages. 19 Although HTN is an independent risk factor for CAD, there are several possible reasons why HTN was the most important independent risk factor for the presence of CAD in this study. First, the percentages of medication use (ARB ACEI, 39%; CCB, 4%) were relatively low, although 68% of all patients had HTN, and the levels were relatively high (SBP, 136 mm Hg; DBP, 7912 mm Hg). In fact, percentage of CAD in men significantly increased as SBP increased: 48% of men with SBP 14 mm Hg showed CAD (Figure 3). Thus, there is a problem associated with the control of BP in patients with HTN among our study patients. Second, although CKD is an independent risk factor for all-cause death or CAD in the general population and CKD may contribute to the severity of CAD associated with the progression of coronary artery calcification, 21 CKD did not show a stronger association than HTN in this study. Cardiac and renal dysfunction frequently coexist. Although the cardio-renal syndrome represents the sum total of an adversarial relation and clinically manifests as worsening renal function, the average egfr was 6818 ml min 1.73 m 2 and there were no patients with severe renal dysfunction because patients with 1. mg dl Cr underwent coronary CT in this study. Third, we do not know why HTN is a more important risk factor than DM and HL. Since the blood levels of LDL-C and HbA 1c are mg dl and 6.7%2.%, respectively, there is not so good control for preventing CAD. Nonetheless, HL and DM are less important factors for the presence of CAD than HTN. It takes a long time for coronary atherosclerosis to progress. Although we analyzed the prevalence of and attempts to control HTN, DM, and HL, we do not have data about the duration of these diseases. Adiponectin and leptin are produced by adipose tissue and are known to play an important role in 2 THE JOURNAL OF CLINICAL HYPERTENSION VOL. 13 NO. 3 MARCH 11

6 the development of MetS. 22 There have been several reports about the relationship between adiponectin or leptin and BP. For example, there is a strong correlation between leptin plasma concentrations and renal sympathetic activation, as shown in men with widely differing degrees of adiposity. 23 Patients with hypertension appear to have significantly lower plasma adiponectin levels than normotensive patients. 24 Since plasma levels of leptin may be associated with HTN in this study, dysfunction of this adipocytokine-induced visceral fat accumulation may also interact with HTN. LIMITATIONS There are several limitations in this study. First, although the patients in this study were clinically suspected of having CAD or had at least one cardiac risk factor, more than half of the patients were considered to not have CAD by coronary CT. The possibility of a patient selection bias would change the results. Second, although this is the cross-sectional nature of the study design, we can observe an association between clinical parameters. Third, the evaluation of coronary stenosis with severe coronary calcification was not performed using coronary CT. In this study, all segments were assessed according to the 1-segment American Heart Association coronary artery model. 2 Since 88 (17.2%) patients had at least one unevaluable segment on MDCT because of severe calcification and motion artifacts, they could not be evaluated by MDCT. Overall, 1 coronary artery segments of 13 patients (total 769) were assessed. Of the total 769 segments, 118 (1.%) and 243 (3.2%) segments could not be evaluated by MDCT because of severe calcification and motion artifacts, respectively. Thus, we used 7334 segments (9.3%) for further analysis. Fourth, although we understand that the newer 12-slice CT should give superior results, 64-slice MDCT is still more widely available in many general hospitals. 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