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Status of hypertension and coronary stenosis in asymptomatic type 2 diabetic patients: Analysis from Coronary Computed Tomographic Angiography Registry
International Journal of Cardiology 174 (2014) 282–287
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Status of hypertension and coronary stenosis in asymptomatic type 2 diabetic patients: Analysis from Coronary Computed Tomographic Angiography Registry Eun-Ho Choo a,1, Jin-Jin Kim a,1, Byung-Hee Hwang b,1, Ik Jun Choi a,1, Mineok Chang a,1, Sungmin Lim a,1, Yoon-Seok Koh c,1, Hun Jun Park a,1, Pum-Joon Kim a,1, Seung-Hwan Lee d,1, Keon-Ho Yoon d,1, Jung-Im Jung e,1, Wook Sung Chung a,1, Ki-Bae Seung a,1, Jae-Hyung Cho d,⁎,1,2, Kiyuk Chang a,⁎⁎,1,2 a
Cardiovascular Center and Cardiology Division, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea Cardiovascular Center and Cardiology Division, St. Paul's Hospital, The Catholic University of Korea, Seoul, Republic of Korea c Cardiovascular Center and Cardiology Division, Uijeongbu St Mary's Hospital, The Catholic University of Korea, Uijeongbu, Republic of Korea d Division of Endocrinology, Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea e Department of Radiology, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea b
a r t i c l e
i n f o
Article history: Received 5 January 2014 Received in revised form 28 March 2014 Accepted 1 April 2014 Available online 12 April 2014 Keywords: Hypertension Diabetes Asymptomatic ischemia Coronary artery disease Blood pressure control Computed tomography
a b s t r a c t Background: Limited data exist regarding the prevalence of coronary artery disease (CAD) as well as clinical outcomes in asymptomatic diabetic patients with normotension, controlled hypertension, and uncontrolled hypertension. Methods: We enrolled 935 consecutive asymptomatic type 2 diabetic patients without known CAD. Coronary computed tomography angiography was used to evaluate the prevalence and severity of CAD. Blood pressure was measured at baseline. Patients were assigned to one of the three groups: normotension (n = 314), controlled hypertension (systolic blood pressure (SBP) b 140 mmHg with treatment, n = 458), or uncontrolled hypertension (SBP ≥ 140 mmHg with or without treatment, n = 163). Results: Obstructive CAD (≥50% stenosis) increased from the prevalence in normotensive patients (33%) to that in patients with controlled (40%) or uncontrolled hypertension (52%) (p = 0.003). The incidence of obstructive CAD in multivessel or left main CAD also increased across the three groups (13%, 21%, 32%, respectively, p b 0.001). A multivariate logistic regression analysis showed that uncontrolled hypertension was an independent predictor of obstructive CAD (adjusted odds ratio, 2.13; 95% confidence interval (CI), 1.42 to 3.21, p b 0.001). During a median follow-up of 3.1 years, uncontrolled hypertension was associated with increased risk of cardiac death or myocardial infarction compared to the risk in normotensive patients (hazard ratio, 6.11; 95% CI, 1.65 to 22.6, p = 0.007). Conclusion: In asymptomatic type 2 diabetic patients, uncontrolled hypertension was associated with increased risk of CAD and poor clinical outcomes. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Type 2 diabetes is associated with an increased risk of coronary artery disease (CAD). Population-based studies have demonstrated ⁎ Correspondence to: J.-H. Cho, Division of Endocrinology, Department of Internal Medicine, Seoul St. Mary's Hospital, Seochogu, Banpodong 505, Seoul 137-701, Republic of Korea. ⁎⁎ Correspondence to: K. Chang, Cardiovascular Center and Cardiology Division, Seoul St. Mary's Hospital, Seochogu, Banpodong 505, Seoul 137-701, Republic of Korea. Tel.: +82 2 2258 6032; fax: +82 2 2258 1138. E-mail addresses: [email protected] (J.-H. Cho), [email protected] (K. Chang). 1 This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. 2 Dr. Chang and Dr. Cho equally contributed to this article.
http://dx.doi.org/10.1016/j.ijcard.2014.04.001 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
that patients with type 2 diabetes show a 2- to 4-fold increased in the number of cardiovascular events [1,2]. Moreover, diabetic individuals with hypertension have a considerably increased risk of developing cardiovascular diseases [3]. Randomized trials have demonstrated that lowering of systolic blood pressure (SBP) under 140 mmHg reduces the occurrence of cardiovascular disease in diabetic patients [4,5]. Therefore, current guidelines recommend the routine measurement of BP and maintenance of SBP ≤ 140 mmHg [6,7]. However, previous outcomes-based analyses generally have lacked information about the prevalence, extent, and severity of coronary artery disease (CAD) in diabetic individuals according to BP. Coronary computed tomography angiography (CCTA) is a novel noninvasive CAD screening method that infers the presence of coronary atherosclerosis by direct visualization of luminal stenoses. Because
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myocardial ischemia is often silent in diabetic patients [8–10], CCTA can be used to reduce cardiovascular morbidity and mortality by detecting CAD early in asymptomatic diabetic patients. Previous studies have shown that diabetic patients have a higher burden of coronary disease than non-diabetic patients by CCTA [11]. CCTA findings of CAD in asymptomatic diabetic patients were associated with future cardiac events [12–14]. However, there is limited data on coronary atherosclerosis in diabetes patients with hypertension, especially with regard to the presence of hypertension or hypertension control in this patient population. Thus, the objective of this study was to evaluate the prevalence of CAD by CCTA and examine its association with outcomes in asymptomatic diabetic patients with normotension, controlled hypertension, and uncontrolled hypertension. 2. Methods 2.1. Study design We enrolled consecutive asymptomatic patients with type 2 diabetes who underwent 64-slice, dual-source CCTA at two hospitals affiliated with The Catholic University of Korea between January 2006 and December 2010. Patients were eligible for this study if they were N30 years of age and had no angina or angina-equivalent symptoms. Asymptomatic status was confirmed using the Rose questionnaire for angina [15]. We excluded patients with type 1 diabetes, with known or suspected CAD, with a history of prior myocardial infarction (MI), coronary revascularization, or cardiac transplantation, those on treatment with anti-anginal medication, with ventricular and supraventricular arrhythmias, or those with contraindications for the use of iodinated contrast. A structured interview was performed by a physician or allied health professional before the CCTA examination to document demographic and clinical data, as well as each patient's height, weight, and baseline BP. BP was measured in a seated position, after a minimum rest period of 5 min. Three separate measurements were taken and the lower of the last two measurements was recorded as the blood pressure prior to CCTA. Patients were diagnosed as hypertensive if they had hypertension diagnosed by a physician, BP ≥ 140/85 mmHg, or if they were taking antihypertensive medication. Information on medical history at baseline, including a history of treatment with antihypertensive agents, antiplatelet agents, lipid-lowering agents, or anti-diabetic medications, was abstracted from clinicians' medical records. All medications were maintained for at least one month before BP measurement. The diagnosis of type 2 diabetes mellitus was made using the criteria of the American Diabetes Association. Subjects with a fasting blood glucose ≥ 126 mg/dL, glycated hemoglobin ≥ 6.5%, and/or a post-challenge blood glucose (2 h after a 75 g oral glucose load) ≥ 200 mg/dL were diagnosed with diabetes. Onset of diabetes was defined as the time point when diabetes was diagnosed by an attending physician. Information on diabetes onset in patients with known diabetes was obtained through self report or, when indeterminate by patient report, from examination of the medical record. Duration of diabetes was calculated as the difference between the patient's current age and age at onset of diabetes. 2.2. Endpoints and follow-up The primary outcome of this analysis was a composite of cardiac death and MI. The secondary outcome was a composite of all-cause death, MI, and stroke. All-cause deaths were attributed to cardiac events unless a non-cardiac cause of death could be clearly identified. MI was defined as the presence of symptoms and new electrocardiographic changes that were compatible with MI, or cardiac markers that were expressed at least two-fold above the normal limit. Stroke was defined as the presence of a new focal neurologic deficit, with signs or symptoms lasting more than 24 h, thought to be vascular in origin. Follow-up was performed by each local institution by a dedicated physician and/ or research nurse blinded to the CCTA results. Any clinical events were determined by direct interview and/or telephone contact, and/or review of medical records. Mortality data was validated using unique personal identification numbers from the National Population Registry of the Korea National Statistical Office. Our study protocol was approved by the ethics committee at each participating center and conducted according to the principles of the Declaration of Helsinki. All patients provided written informed consent. 2.3. Imaging protocol and image reconstruction All patients were in normal sinus rhythm and were able to hold their breath as required for CCTA. Patients with a heart rate N 70 beats per minute (bpm) were administered intravenous esmolol at a dose of 3 mg at 5 minute intervals, up to a total dose of 15 mg. If the patient's heart rate did not drop to b70 bpm, CCTA was performed at the lowest heart rate. Imaging was performed using a 64-slice, dual-source CT scanner (SOMATOM Definition, Siemens, Forchheim, Germany). Each patient underwent an unenhanced, prospectively-triggered coronary calcium scan prior to CCTA. Approximately 80–110 mL of iodinated contrast (Iomeron 350, iomeprol, Bracco, Milano, Italy) was
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injected during CCTA. Timing of contrast administration was optimized for uniform enhancement of the coronary arteries. We used a standard retrospective ECG-gated scanning protocol with 0.6 mm slice collimation, 330 ms gantry rotation time, 120 kVp tube voltage, and a maximum tube current of 400 mAs. All scans were performed using ECG-controlled tube current modulation. Estimated radiation doses ranged from 5 to 14 mSv. Images were reconstructed immediately after scan completion to identify coronary artery images that were free of motion artifact. Reconstructed CT image data was transferred to a computer workstation for post-processing, including axial, multiplanar reformatting, maximum intensity projection, and shsort-axis cross-sectional views. Irrespective of the image quality, every arterial segment in every patient was scored in an intent-to-diagnose fashion.
2.4. Image analysis Scans were analyzed by two radiologists with experience interpreting several thousand CCTAs. Coronary segments were visually scored for the presence of coronary plaque using a 16-segment coronary artery model in an intent-to-diagnose fashion, according to the guidelines of the Society of Cardiovascular Computed Tomography [16]. Only segments with a diameter N1.5 mm were included in our analysis. Coronary plaques were identified as structures N1 mm2 within or adjacent to the coronary artery lumen, and which could be clearly distinguished from the vessel lumen and the surrounding pericardial tissue. The severity of stenosis of a coronary artery lumen was scored as none (0% luminal stenosis), nonobstructive (plaques with narrowing of the coronary artery lumen b 50%), or obstructive (plaques with a maximum stenosis ≥ 50%). CAD was diagnosed based on the maximum intra-luminal stenosis in any of the segments of the major epicardial coronary arteries, with a threshold of ≥50% stenosis. For each patient, we calculated the number of diseased vessels as zero, one, two, three, or left main (LM) coronary artery disease. The severity and extent of CAD was measured by several coronary CT angiography scores [13,17], including the coronary artery calcium score (CACS), segment involvement score (SIS), and segment stenosis score (SSS). The CACS was assessed with dedicated software (Siemens CalciumScore; Siemens, Forchheim, Germany). Coronary artery calcium was identified as a dense area in the coronary artery that exceeded the threshold of 130 HU. An overall Agaston score was recorded for each patient. The SIS was calculated as the total number of coronary artery segments exhibiting plaque, irrespective of the degree of luminal stenosis within each segment (minimum = 0; maximum = 16). The SSS was used as a measure of overall coronary artery plaque extent. Each coronary segment was graded as having absent to severe plaque (i.e., scores from 0 to 3), based on the extent of obstruction of the coronary luminal diameter. The extent scores of each of the 16 segments were summed to yield a total score that ranged from 0 to 48. Plaque characteristics were described as calcified plaque (N130 HU), non-calcified plaque (b130 HU) and mixed plaque for each segment.
2.5. Statistical analysis Patients were assigned to one of the three groups: normotension, controlled hypertension (SBP b 140 mmHg with antihypertensive medication), or uncontrolled hypertension (SBP ≥ 140 mmHg with or without antihypertensive medication). Continuous variables are presented as means ± standard deviation (SD), or medians (interquartile ranges) for skewed variables. Categorical variables are shown in absolute numbers and percentages. Baseline characteristics of the three BP groups were compared using analysis of variance for continuous variables and chi-square testing for categorical variables. The study population was also classified into groups of increasing coronary stenosis (participants without coronary stenosis, with b50% coronary stenosis, and with significant coronary stenosis). The prevalence of hypertension was then compared among these three groups. All variables in Table 1 were entered into a univariate logistic regression model. A multivariate logistic regression model was constructed using the backward variable selection method and variables that were significant (p b 0.05) by univariate logistic regression. Multivariate logistic regression analysis was performed to identify independent predictors of significant coronary stenosis, as detected by CCTA. The effects of BP on outcomes were assessed by Kaplan–Meier analysis and Cox proportional hazard regression, using the normotensive group as a reference for analyses. All analyses were two-tailed. Clinical significance was defined as p b 0.05. Statistical analyses were performed with the statistical package SPSS version 20.0 (SPSS Inc., Chicago, IL, USA) and MedCalc version 12.7 (MedCalc Software, Mariakerke, Belgium).
3. Results 3.1. Baseline characteristics and status of hypertension We enrolled 935 asymptomatic diabetic patients who underwent CCTA. Mean age was 63 years old, and 60% were male. Patients had a mean body mass index (BMI) of 24. They had carried a diagnosis of diabetes for a median of 10 years, and 23% were using insulin. Within this population, 33.6% of patients were normotensive, 49% had controlled hypertension, and 17.4% had uncontrolled hypertension (Table 1).
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Table 1 Baseline characteristics of the study patients.
Demographic and clinical data Age, year Male (%) Current smoker (%) Prior stroke (%) Body mass index, kg/m2 Blood pressure, mmHg Systolic Diastolic Duration of diabetes, year HbA1C, % Total cholesterol, mL/dL Triglyceride, mL/dL HDL cholesterol, mL/dL LDL cholesterol, mL/dL Creatinine, mg/dL Oral hypoglycemic agents (%) Insulin (%) Aspirin (%) Statin (%)
Normotension (N = 314)
Controlled hypertension (N = 458)
Uncontrolled hypertension (N = 163)
p for trend
61.2 ± 9.5 203(64.6) 42(13.4) 7(2.2) 23.4 ± 3.0
64.4 ± 9.3 266(58.1) 62(13.5) 48(10.5) 24.7 ± 3.3
65.0 ± 10.4 88(54.0) 32(19.6) 20(12.3) 25.1 ± 3.2
b0.001 0.017 0.111 b0.001 b0.001
118.9 ± 9.7 73.1 ± 7.8 10(3–15) 7.3(6.6–9.2) 169.2 ± 37.2 98(68–148.5) 48.9 ± 13.3 95.5 ± 30.9 0.89 ± 0.18 248(79.0) 61(19.4) 105(33.4) 139(44.3)
121.9 ± 10.0 74.3 ± 9.0 10(5–18) 7.2(6.5–8.9) 166.5 ± 34.8 116(85–169) 46.4 ± 10.7 92.5 ± 29.4 0.93 ± 0.24 385(84.1) 111(24.2) 252(55.0) 274(59.8)
147.7 ± 10.3 82.3 ± 11.2 10(5–20) 7.9(6.7–9.3) 175.6 ± 46.5 124.5(86.8–186.8) 47.8 ± 12.2 96.6 ± 41.0 0.94 ± 0.22 135(82.8) 40(24.5) 78(47.8) 91(55.8)
b0.001 b0.001 0.090 0.039 0.033 b0.001 0.015 0.255 0.040 0.176 0.137 b0.001 0.002
363(79.3) 75(16.4) 75(16.4) 75(16.4) 20(4.4)
96(58.9) 28(17.2) 28(17.2) 28(17.2) 12(7.4)
b0.001 0.807 0.573 0.210 0.150 b0.001
0(0) 216(47.2) 134(29.3) 108(23.6)
46(28.2) 42(25.8) 35(21.5) 40(24.5)
Anti-hypertensive medication (%) ACE inhibitor or ARB Beta blocker Calcium channel blocker Diuretics Alpha blocker Number of antihypertensive medication 0 1 2 ≥3
Data are presented as mean ± SD, median (interquartile range) and number (percentage) where appropriate. HDL = high density lipoprotein, LDL = low density lipoprotein, ACE = angiotensin converting enzyme, and ARB = angiotensin receptor blocker.
Patients with hypertension were more likely to be older, have a history of a cerebrovascular accident, have a high BMI, high triglycerides, low high-density lipoprotein (HDL), and be on treatment with aspirin and statin drugs, compared to normotensive patients. Patients with uncontrolled hypertension had inferior glycemic control, higher total
cholesterol, and higher triglycerides than those with controlled hypertension. The frequency of use of renin–angiotensin system blocking agents and the number of antihypertensive medications were lower in patients with uncontrolled hypertension compared to patients with controlled hypertension.
Table 2 Coronary computed tomographic angiography data of the study patients.
Coronary artery calcium score 0 1–99 100–399 ≥400 Presence of CAD (%) None Nonobstructive CAD (stenosis: 1–49%) Obstructive CAD (stenosis ≥ 50%) Prevalence of plaque characteristics (%) Calcified Non-calcified Mixed Number of involved vessels; obstructive CAD (%) None 1 vessel disease 2 vessel disease 3 vessel disease or left main CAD Segment involve score Segment involve score ≥ 5 Segment stenosis score Segment stenosis score ≥ 5
Normotension (N = 314)
Controlled hypertension (N = 458)
Uncontrolled hypertension (N = 163)
p for trend
99(31.5) 107(34.1) 69(22.0) 39(12.4)
99(21.6) 156(34.1) 111(24.2) 92(20.1)
35(21.5) 43(26.4) 39(23.9) 46(28.2)
79(25.2) 131(41.7) 104(33.1)
89(19.4) 183(40.0) 186(40.6)
27(16.6) 51(31.3) 85(52.1)
0.018 0.043 b0.001
132(42.0) 127(40.4) 91(29.0)
217(47.4) 191(41.7) 207(45.2)
78(47.9) 72(44.2) 82(50.3)
0.158 0.447 b0.001
210(66.8) 63(20.1) 25(8.0) 16(5.1) 1.75 ± 2.28 39(12.4) 2.71 ± 3.83 71(22.6)
272(59.4) 88(19.2) 47(10.3) 51(11.1) 2.32 ± 2.61 89(19.4) 3.81 ± 5.01 138(30.1)
78(47.9) 33(20.2) 29(17.8) 23(14.1) 2.88 ± 2.92 42(25.8) 4.91 ± 5.53 67(41.1)
b0.001 0.973 0.002 0.001 b0.001 b0.001 b0.001 b0.001
b0.001
Data are presented as mean ± SD and number (percentage) where appropriate. CAD = coronary artery disease.
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Table 3 Independent predictors of significant coronary stenosis.
Age (increase by 1 year) Male Duration of diabetes (Increase by 1 year) Insulin use Normotension Controlled hypertension Uncontrolled Hypertension
Adjusted odds ratio
95% CI
p value
1.02 1.85 1.04 1.46 Reference 1.30 2.13
1.01–1.04 1.38–2.49 1.02–1.06 1.04–2.06
0.011 b0.001 b0.001 0.03
0.95–1.78 1.42–3.21
0.104 b0.001
CI = confidence interval.
3.4. Clinical outcomes and status of hypertension Fig. 1. Segment involvement score according to the status of hypertension.
3.2. CCTA findings and status of hypertension As shown in Table 2, there was an increasing prevalence of obstructive CAD, from 33% among normotensive patients, to 41% among those with controlled hypertension, and 52% among those with uncontrolled hypertension (p b 0.001). We observed a stepwise increase in the prevalence of obstructive CAD, in multiple vessels or in the left main coronary artery, from normotensive to patients with uncontrolled hypertension (13%, 21%, and 32%, respectively; p b 0.001). CACS, SIS, and SSS increased significantly with decreasing control of hypertension (Fig. 1). When patients were categorized according to the severity of luminal stenosis, patients with obstructive CAD had higher systolic blood pressures and a higher prevalence of hypertension compared to those with non-obstructive CAD and those without obstruction (Fig. 2).
During a median follow-up of 3.1 years, 44 deaths (4.7%), 19 cardiac deaths (2.0%), 5 MIs (0.5%), and 21 strokes (2.2%) were recorded in our study population. For the primary endpoint of our study, uncontrolled hypertension was associated with an increased incidence of the composite of cardiac death and MI (Hazard ratio[HR], 6.11; 95% confidence interval[CI], 1.65 to 22.6, p = 0.007). Whereas, the incidence of the composite of cardiac death and MI did not differ between patients with controlled hypertension and normotension (HR, 2.45; 95% CI, 0.68 to 8.79, p = 0.168) (Fig. 3). The presence of obstructive CAD and obstructive CAD in multiple vessels or in the left main coronary artery by CCTA also correlated with an increased risk of cardiac death or MI (Supplemental Fig. S1). The secondary outcome, the composite of all-cause death, MI, and stroke, was significantly increased in patients with uncontrolled hypertension (HR, 2.88; 95% CI, 1.45 to 5.70, p = 0.002), but not in patients with controlled hypertension (HR, 1.45; 95% CI, 0.77 to 2.74, p = 0.25) (Supplemental Fig. S2).
4. Discussion 3.3. Predictors of obstructive CAD Of all enrolled patients, 375 (40.1%) had obstructive CAD. Patient with obstructive CAD were more likely to be older, male, have a history of cerebrovascular accident, uncontrolled hypertension, longer history of diabetes, and diabetes that required treatment with insulin (Supplemental Table S1). Older age, male sex, longer history of diabetes and insulin use, and uncontrolled hypertension were independent predictors of obstructive CAD in a multivariate logistic regression model (Table 3).
We evaluated the prevalence, severity, extent, and predictors of CAD, as well as clinical outcomes, in asymptomatic patients with type 2 diabetes, according to their level of hypertension. We found that obstructive CAD was more prevalent and more extensive in asymptomatic type 2 diabetic patients with uncontrolled hypertension than those with controlled hypertension or normal BPs. Additionally, SBP and the prevalence of hypertension increased significantly in patients with obstructive CAD. Uncontrolled hypertension was independently associated with obstructive CAD in asymptomatic patients with type 2 diabetes. Finally, the uncontrolled hypertension in asymptomatic patients with
Fig. 2. Systolic blood pressure level and percentage of hypertension in asymptomatic type 2 diabetic patients with normal coronary arteries, with nonobstructive coronary stenosis, and with obstructive coronary stenosis.
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Fig. 3. Kaplan–Meier curves for cardiac death and myocardial infarction in patients with normotension, controlled hypertension, and uncontrolled hypertension.
type 2 diabetes was associated with an increased risk of poor cardiovascular outcomes. Based on the findings of the 10-year Framingham heart study which showed that increased blood pressure, despite antihypertensive treatment at baseline, was associated with poor cardiovascular outcomes, SBP and treatment for hypertension at baseline are currently recognized as cardiovascular risk factors [18,19]. The Framingham risk score is also used to predict future cardiovascular risk in diabetic patients [20,21]. In our study, the prevalence and complexity of CAD, as defined by CCTA, increased gradually with the degree of hypertension. Similar to previous studies, patients in our study with diffuse coronary atherosclerosis and accelerated disease progression by CCTA had poor clinical outcomes [14,17]. The CAD findings in patients with uncontrolled hypertension might have led to the increased rate of cardiovascular events. To the best of our knowledge, our study is the first to demonstrate the impact of hypertension on the prevalence and severity of CAD, and its clinical relevance in asymptomatic diabetic patients. Strict control of hypertension has been associated with reduced complications and mortality from diabetes. Therefore, the American Diabetes Association recommends that diabetic patients maintain SBP ≤ 140 mmHg. However, previous studies consistently demonstrate that most diabetic patients do not achieve the recommended level of BP control [22–24]. Seventeen percent of patients in our study needed intensive BP control due to underuse of antihypertensive agents, including renin–angiotensin system blockers. We reemphasize the crucial importance of tight BP control to prevent cardiovascular mortality and morbidity in hypertensive diabetic patients. Patients with uncontrolled hypertension in this study also showed poor glycemic control and poor lipid profiles. More than one-fourth of cases of uncontrolled hypertension did not achieve the target BP despite receiving ≥ 3 antihypertensive drugs. Previous studies suggest that metabolic risk factors, such as insulin resistance and dyslipidemia, might interfere with BP control despite intensive treatment [25,26]. Low compliance or inadequate treatment might play a role in the link between uncontrolled hypertension and poor metabolic profile. In addition to uncontrolled hypertension, several risk factors were independent predictors of obstructive CAD. Older age, male sex, and a longer duration of diabetes were also cardiovascular risk factors in the United Kingdom Prospective Diabetes Study [27]. Glycated hemoglobin, smoking, and serum cholesterol levels were not independent correlates with the prevalence of CAD in our study. Interestingly, insulin use was an independent predictor of obstructive CAD. The requirement for insulin treatment in patients with type 2 diabetes may reflect higher underlying insulin resistance that leads to more prevalent cardiovascular disease compared to those who do not use insulin [28]. In addition, insulin treatment for type 2 diabetes may directly promote endothelial
dysfunction and progression of vascular disease [29]. Further studies are needed to determine the effect of insulin treatment on atherosclerosis in patients with type 2 diabetes. The overall prevalence of obstructive CAD in this study was about 40%, which is within the expected range based on previous CCTA studies in diabetic patients [11,12,14]. In comparison to exercise electrocardiography or myocardial perfusion scintigraphy [30,31], obstructive CAD in CCTA might lead to an over-diagnosis of significant coronary stenosis in asymptomatic diabetic patients. However, CCTA has a high accuracy for detecting CAD at an early stage [32,33] and is less expensive and equally effective compared to stress echocardiograpy [34]. In addition, percutaneous coronary interventions and intensive medical therapy with worse CCTA findings can reduce event rates among patients with abnormal CCTA studies [35]. Thus, selective CCTA imaging of patients with high-risk profiles, such as uncontrolled hypertension, microalbuminuria, multiple cardio-metabolic risks, thick carotid intimal media thickness, and family history of premature coronary artery disease [30,36–38], might enhance the benefit of CCTA in asymptomatic diabetic patients. There were several limitations in our study. First, the number of enrolled patients was relatively small, and all patients were Asian. Thus, additional studies in other ethnic groups should be performed. Second, given the observation nature of the present study, detection of events and patient followup were less rigorous than those of randomized, controlled trials. Despite data collection by dedicated study nurses, review of insurance records, and thorough investigation of survival status, nonfatal events (e.g., MI, stroke) may have been underreported. Third, we assessed hypertension status with two BP readings at one visit instead of two or more properly measured readings at each of two or more visits. Fourth, we did not collect data about changes in BP, antihypertensive agents, antiplatelet agents, statins, or diabetes medications during the followup. However, this study demonstrates the impact of BP control until CCTA measurement on the development of CAD and future cardiovascular events. 5. Conclusions In conclusion, patients with asymptomatic type 2 diabetes and uncontrolled hypertension had greater burdens of CAD and worse clinical outcomes than those with normotension and controlled hypertension. Tight BP control could alleviate the progression of vascular atherosclerosis to reduce future cardiovascular complications in asymptomatic patients with type 2 diabetes. Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ijcard.2014.04.001. References [1] Becker A, Bos G, de Vegt F, et al. Cardiovascular events in type 2 diabetes: comparison with nondiabetic individuals without and with prior cardiovascular disease. 10-year follow-up of the Hoorn Study. Eur Heart J 2003;24:1406–13. [2] Schramm TK, Gislason GH, Kober L, et al. Diabetes patients requiring glucoselowering therapy and nondiabetics with a prior myocardial infarction carry the same cardiovascular risk: a population study of 3.3 million people. Circulation 2008;117:1945–54. [3] Adler AI, Stratton IM, Neil HA, et al. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ 2000;321:412–9. [4] Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ 1998;317:703–13. [5] Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010;362:1575–85. [6] Standards of medical care in diabetes—2013. Diabetes Care 2013;36(Suppl. 1): S11–66. [7] Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial
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Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Status of hypertension and coronary stenosis in asymptomatic type 2 diabetic patients: Analysis from Coronary Computed Tomographic Angiography Registry Eun-Ho Choo a,1, Jin-Jin Kim a,1, Byung-Hee Hwang b,1, Ik Jun Choi a,1, Mineok Chang a,1, Sungmin Lim a,1, Yoon-Seok Koh c,1, Hun Jun Park a,1, Pum-Joon Kim a,1, Seung-Hwan Lee d,1, Keon-Ho Yoon d,1, Jung-Im Jung e,1, Wook Sung Chung a,1, Ki-Bae Seung a,1, Jae-Hyung Cho d,⁎,1,2, Kiyuk Chang a,⁎⁎,1,2 a
Cardiovascular Center and Cardiology Division, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea Cardiovascular Center and Cardiology Division, St. Paul's Hospital, The Catholic University of Korea, Seoul, Republic of Korea c Cardiovascular Center and Cardiology Division, Uijeongbu St Mary's Hospital, The Catholic University of Korea, Uijeongbu, Republic of Korea d Division of Endocrinology, Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea e Department of Radiology, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea b
a r t i c l e
i n f o
Article history: Received 5 January 2014 Received in revised form 28 March 2014 Accepted 1 April 2014 Available online 12 April 2014 Keywords: Hypertension Diabetes Asymptomatic ischemia Coronary artery disease Blood pressure control Computed tomography
a b s t r a c t Background: Limited data exist regarding the prevalence of coronary artery disease (CAD) as well as clinical outcomes in asymptomatic diabetic patients with normotension, controlled hypertension, and uncontrolled hypertension. Methods: We enrolled 935 consecutive asymptomatic type 2 diabetic patients without known CAD. Coronary computed tomography angiography was used to evaluate the prevalence and severity of CAD. Blood pressure was measured at baseline. Patients were assigned to one of the three groups: normotension (n = 314), controlled hypertension (systolic blood pressure (SBP) b 140 mmHg with treatment, n = 458), or uncontrolled hypertension (SBP ≥ 140 mmHg with or without treatment, n = 163). Results: Obstructive CAD (≥50% stenosis) increased from the prevalence in normotensive patients (33%) to that in patients with controlled (40%) or uncontrolled hypertension (52%) (p = 0.003). The incidence of obstructive CAD in multivessel or left main CAD also increased across the three groups (13%, 21%, 32%, respectively, p b 0.001). A multivariate logistic regression analysis showed that uncontrolled hypertension was an independent predictor of obstructive CAD (adjusted odds ratio, 2.13; 95% confidence interval (CI), 1.42 to 3.21, p b 0.001). During a median follow-up of 3.1 years, uncontrolled hypertension was associated with increased risk of cardiac death or myocardial infarction compared to the risk in normotensive patients (hazard ratio, 6.11; 95% CI, 1.65 to 22.6, p = 0.007). Conclusion: In asymptomatic type 2 diabetic patients, uncontrolled hypertension was associated with increased risk of CAD and poor clinical outcomes. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Type 2 diabetes is associated with an increased risk of coronary artery disease (CAD). Population-based studies have demonstrated ⁎ Correspondence to: J.-H. Cho, Division of Endocrinology, Department of Internal Medicine, Seoul St. Mary's Hospital, Seochogu, Banpodong 505, Seoul 137-701, Republic of Korea. ⁎⁎ Correspondence to: K. Chang, Cardiovascular Center and Cardiology Division, Seoul St. Mary's Hospital, Seochogu, Banpodong 505, Seoul 137-701, Republic of Korea. Tel.: +82 2 2258 6032; fax: +82 2 2258 1138. E-mail addresses: [email protected] (J.-H. Cho), [email protected] (K. Chang). 1 This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. 2 Dr. Chang and Dr. Cho equally contributed to this article.
http://dx.doi.org/10.1016/j.ijcard.2014.04.001 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
that patients with type 2 diabetes show a 2- to 4-fold increased in the number of cardiovascular events [1,2]. Moreover, diabetic individuals with hypertension have a considerably increased risk of developing cardiovascular diseases [3]. Randomized trials have demonstrated that lowering of systolic blood pressure (SBP) under 140 mmHg reduces the occurrence of cardiovascular disease in diabetic patients [4,5]. Therefore, current guidelines recommend the routine measurement of BP and maintenance of SBP ≤ 140 mmHg [6,7]. However, previous outcomes-based analyses generally have lacked information about the prevalence, extent, and severity of coronary artery disease (CAD) in diabetic individuals according to BP. Coronary computed tomography angiography (CCTA) is a novel noninvasive CAD screening method that infers the presence of coronary atherosclerosis by direct visualization of luminal stenoses. Because
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myocardial ischemia is often silent in diabetic patients [8–10], CCTA can be used to reduce cardiovascular morbidity and mortality by detecting CAD early in asymptomatic diabetic patients. Previous studies have shown that diabetic patients have a higher burden of coronary disease than non-diabetic patients by CCTA [11]. CCTA findings of CAD in asymptomatic diabetic patients were associated with future cardiac events [12–14]. However, there is limited data on coronary atherosclerosis in diabetes patients with hypertension, especially with regard to the presence of hypertension or hypertension control in this patient population. Thus, the objective of this study was to evaluate the prevalence of CAD by CCTA and examine its association with outcomes in asymptomatic diabetic patients with normotension, controlled hypertension, and uncontrolled hypertension. 2. Methods 2.1. Study design We enrolled consecutive asymptomatic patients with type 2 diabetes who underwent 64-slice, dual-source CCTA at two hospitals affiliated with The Catholic University of Korea between January 2006 and December 2010. Patients were eligible for this study if they were N30 years of age and had no angina or angina-equivalent symptoms. Asymptomatic status was confirmed using the Rose questionnaire for angina [15]. We excluded patients with type 1 diabetes, with known or suspected CAD, with a history of prior myocardial infarction (MI), coronary revascularization, or cardiac transplantation, those on treatment with anti-anginal medication, with ventricular and supraventricular arrhythmias, or those with contraindications for the use of iodinated contrast. A structured interview was performed by a physician or allied health professional before the CCTA examination to document demographic and clinical data, as well as each patient's height, weight, and baseline BP. BP was measured in a seated position, after a minimum rest period of 5 min. Three separate measurements were taken and the lower of the last two measurements was recorded as the blood pressure prior to CCTA. Patients were diagnosed as hypertensive if they had hypertension diagnosed by a physician, BP ≥ 140/85 mmHg, or if they were taking antihypertensive medication. Information on medical history at baseline, including a history of treatment with antihypertensive agents, antiplatelet agents, lipid-lowering agents, or anti-diabetic medications, was abstracted from clinicians' medical records. All medications were maintained for at least one month before BP measurement. The diagnosis of type 2 diabetes mellitus was made using the criteria of the American Diabetes Association. Subjects with a fasting blood glucose ≥ 126 mg/dL, glycated hemoglobin ≥ 6.5%, and/or a post-challenge blood glucose (2 h after a 75 g oral glucose load) ≥ 200 mg/dL were diagnosed with diabetes. Onset of diabetes was defined as the time point when diabetes was diagnosed by an attending physician. Information on diabetes onset in patients with known diabetes was obtained through self report or, when indeterminate by patient report, from examination of the medical record. Duration of diabetes was calculated as the difference between the patient's current age and age at onset of diabetes. 2.2. Endpoints and follow-up The primary outcome of this analysis was a composite of cardiac death and MI. The secondary outcome was a composite of all-cause death, MI, and stroke. All-cause deaths were attributed to cardiac events unless a non-cardiac cause of death could be clearly identified. MI was defined as the presence of symptoms and new electrocardiographic changes that were compatible with MI, or cardiac markers that were expressed at least two-fold above the normal limit. Stroke was defined as the presence of a new focal neurologic deficit, with signs or symptoms lasting more than 24 h, thought to be vascular in origin. Follow-up was performed by each local institution by a dedicated physician and/ or research nurse blinded to the CCTA results. Any clinical events were determined by direct interview and/or telephone contact, and/or review of medical records. Mortality data was validated using unique personal identification numbers from the National Population Registry of the Korea National Statistical Office. Our study protocol was approved by the ethics committee at each participating center and conducted according to the principles of the Declaration of Helsinki. All patients provided written informed consent. 2.3. Imaging protocol and image reconstruction All patients were in normal sinus rhythm and were able to hold their breath as required for CCTA. Patients with a heart rate N 70 beats per minute (bpm) were administered intravenous esmolol at a dose of 3 mg at 5 minute intervals, up to a total dose of 15 mg. If the patient's heart rate did not drop to b70 bpm, CCTA was performed at the lowest heart rate. Imaging was performed using a 64-slice, dual-source CT scanner (SOMATOM Definition, Siemens, Forchheim, Germany). Each patient underwent an unenhanced, prospectively-triggered coronary calcium scan prior to CCTA. Approximately 80–110 mL of iodinated contrast (Iomeron 350, iomeprol, Bracco, Milano, Italy) was
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injected during CCTA. Timing of contrast administration was optimized for uniform enhancement of the coronary arteries. We used a standard retrospective ECG-gated scanning protocol with 0.6 mm slice collimation, 330 ms gantry rotation time, 120 kVp tube voltage, and a maximum tube current of 400 mAs. All scans were performed using ECG-controlled tube current modulation. Estimated radiation doses ranged from 5 to 14 mSv. Images were reconstructed immediately after scan completion to identify coronary artery images that were free of motion artifact. Reconstructed CT image data was transferred to a computer workstation for post-processing, including axial, multiplanar reformatting, maximum intensity projection, and shsort-axis cross-sectional views. Irrespective of the image quality, every arterial segment in every patient was scored in an intent-to-diagnose fashion.
2.4. Image analysis Scans were analyzed by two radiologists with experience interpreting several thousand CCTAs. Coronary segments were visually scored for the presence of coronary plaque using a 16-segment coronary artery model in an intent-to-diagnose fashion, according to the guidelines of the Society of Cardiovascular Computed Tomography [16]. Only segments with a diameter N1.5 mm were included in our analysis. Coronary plaques were identified as structures N1 mm2 within or adjacent to the coronary artery lumen, and which could be clearly distinguished from the vessel lumen and the surrounding pericardial tissue. The severity of stenosis of a coronary artery lumen was scored as none (0% luminal stenosis), nonobstructive (plaques with narrowing of the coronary artery lumen b 50%), or obstructive (plaques with a maximum stenosis ≥ 50%). CAD was diagnosed based on the maximum intra-luminal stenosis in any of the segments of the major epicardial coronary arteries, with a threshold of ≥50% stenosis. For each patient, we calculated the number of diseased vessels as zero, one, two, three, or left main (LM) coronary artery disease. The severity and extent of CAD was measured by several coronary CT angiography scores [13,17], including the coronary artery calcium score (CACS), segment involvement score (SIS), and segment stenosis score (SSS). The CACS was assessed with dedicated software (Siemens CalciumScore; Siemens, Forchheim, Germany). Coronary artery calcium was identified as a dense area in the coronary artery that exceeded the threshold of 130 HU. An overall Agaston score was recorded for each patient. The SIS was calculated as the total number of coronary artery segments exhibiting plaque, irrespective of the degree of luminal stenosis within each segment (minimum = 0; maximum = 16). The SSS was used as a measure of overall coronary artery plaque extent. Each coronary segment was graded as having absent to severe plaque (i.e., scores from 0 to 3), based on the extent of obstruction of the coronary luminal diameter. The extent scores of each of the 16 segments were summed to yield a total score that ranged from 0 to 48. Plaque characteristics were described as calcified plaque (N130 HU), non-calcified plaque (b130 HU) and mixed plaque for each segment.
2.5. Statistical analysis Patients were assigned to one of the three groups: normotension, controlled hypertension (SBP b 140 mmHg with antihypertensive medication), or uncontrolled hypertension (SBP ≥ 140 mmHg with or without antihypertensive medication). Continuous variables are presented as means ± standard deviation (SD), or medians (interquartile ranges) for skewed variables. Categorical variables are shown in absolute numbers and percentages. Baseline characteristics of the three BP groups were compared using analysis of variance for continuous variables and chi-square testing for categorical variables. The study population was also classified into groups of increasing coronary stenosis (participants without coronary stenosis, with b50% coronary stenosis, and with significant coronary stenosis). The prevalence of hypertension was then compared among these three groups. All variables in Table 1 were entered into a univariate logistic regression model. A multivariate logistic regression model was constructed using the backward variable selection method and variables that were significant (p b 0.05) by univariate logistic regression. Multivariate logistic regression analysis was performed to identify independent predictors of significant coronary stenosis, as detected by CCTA. The effects of BP on outcomes were assessed by Kaplan–Meier analysis and Cox proportional hazard regression, using the normotensive group as a reference for analyses. All analyses were two-tailed. Clinical significance was defined as p b 0.05. Statistical analyses were performed with the statistical package SPSS version 20.0 (SPSS Inc., Chicago, IL, USA) and MedCalc version 12.7 (MedCalc Software, Mariakerke, Belgium).
3. Results 3.1. Baseline characteristics and status of hypertension We enrolled 935 asymptomatic diabetic patients who underwent CCTA. Mean age was 63 years old, and 60% were male. Patients had a mean body mass index (BMI) of 24. They had carried a diagnosis of diabetes for a median of 10 years, and 23% were using insulin. Within this population, 33.6% of patients were normotensive, 49% had controlled hypertension, and 17.4% had uncontrolled hypertension (Table 1).
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Table 1 Baseline characteristics of the study patients.
Demographic and clinical data Age, year Male (%) Current smoker (%) Prior stroke (%) Body mass index, kg/m2 Blood pressure, mmHg Systolic Diastolic Duration of diabetes, year HbA1C, % Total cholesterol, mL/dL Triglyceride, mL/dL HDL cholesterol, mL/dL LDL cholesterol, mL/dL Creatinine, mg/dL Oral hypoglycemic agents (%) Insulin (%) Aspirin (%) Statin (%)
Normotension (N = 314)
Controlled hypertension (N = 458)
Uncontrolled hypertension (N = 163)
p for trend
61.2 ± 9.5 203(64.6) 42(13.4) 7(2.2) 23.4 ± 3.0
64.4 ± 9.3 266(58.1) 62(13.5) 48(10.5) 24.7 ± 3.3
65.0 ± 10.4 88(54.0) 32(19.6) 20(12.3) 25.1 ± 3.2
b0.001 0.017 0.111 b0.001 b0.001
118.9 ± 9.7 73.1 ± 7.8 10(3–15) 7.3(6.6–9.2) 169.2 ± 37.2 98(68–148.5) 48.9 ± 13.3 95.5 ± 30.9 0.89 ± 0.18 248(79.0) 61(19.4) 105(33.4) 139(44.3)
121.9 ± 10.0 74.3 ± 9.0 10(5–18) 7.2(6.5–8.9) 166.5 ± 34.8 116(85–169) 46.4 ± 10.7 92.5 ± 29.4 0.93 ± 0.24 385(84.1) 111(24.2) 252(55.0) 274(59.8)
147.7 ± 10.3 82.3 ± 11.2 10(5–20) 7.9(6.7–9.3) 175.6 ± 46.5 124.5(86.8–186.8) 47.8 ± 12.2 96.6 ± 41.0 0.94 ± 0.22 135(82.8) 40(24.5) 78(47.8) 91(55.8)
b0.001 b0.001 0.090 0.039 0.033 b0.001 0.015 0.255 0.040 0.176 0.137 b0.001 0.002
363(79.3) 75(16.4) 75(16.4) 75(16.4) 20(4.4)
96(58.9) 28(17.2) 28(17.2) 28(17.2) 12(7.4)
b0.001 0.807 0.573 0.210 0.150 b0.001
0(0) 216(47.2) 134(29.3) 108(23.6)
46(28.2) 42(25.8) 35(21.5) 40(24.5)
Anti-hypertensive medication (%) ACE inhibitor or ARB Beta blocker Calcium channel blocker Diuretics Alpha blocker Number of antihypertensive medication 0 1 2 ≥3
Data are presented as mean ± SD, median (interquartile range) and number (percentage) where appropriate. HDL = high density lipoprotein, LDL = low density lipoprotein, ACE = angiotensin converting enzyme, and ARB = angiotensin receptor blocker.
Patients with hypertension were more likely to be older, have a history of a cerebrovascular accident, have a high BMI, high triglycerides, low high-density lipoprotein (HDL), and be on treatment with aspirin and statin drugs, compared to normotensive patients. Patients with uncontrolled hypertension had inferior glycemic control, higher total
cholesterol, and higher triglycerides than those with controlled hypertension. The frequency of use of renin–angiotensin system blocking agents and the number of antihypertensive medications were lower in patients with uncontrolled hypertension compared to patients with controlled hypertension.
Table 2 Coronary computed tomographic angiography data of the study patients.
Coronary artery calcium score 0 1–99 100–399 ≥400 Presence of CAD (%) None Nonobstructive CAD (stenosis: 1–49%) Obstructive CAD (stenosis ≥ 50%) Prevalence of plaque characteristics (%) Calcified Non-calcified Mixed Number of involved vessels; obstructive CAD (%) None 1 vessel disease 2 vessel disease 3 vessel disease or left main CAD Segment involve score Segment involve score ≥ 5 Segment stenosis score Segment stenosis score ≥ 5
Normotension (N = 314)
Controlled hypertension (N = 458)
Uncontrolled hypertension (N = 163)
p for trend
99(31.5) 107(34.1) 69(22.0) 39(12.4)
99(21.6) 156(34.1) 111(24.2) 92(20.1)
35(21.5) 43(26.4) 39(23.9) 46(28.2)
79(25.2) 131(41.7) 104(33.1)
89(19.4) 183(40.0) 186(40.6)
27(16.6) 51(31.3) 85(52.1)
0.018 0.043 b0.001
132(42.0) 127(40.4) 91(29.0)
217(47.4) 191(41.7) 207(45.2)
78(47.9) 72(44.2) 82(50.3)
0.158 0.447 b0.001
210(66.8) 63(20.1) 25(8.0) 16(5.1) 1.75 ± 2.28 39(12.4) 2.71 ± 3.83 71(22.6)
272(59.4) 88(19.2) 47(10.3) 51(11.1) 2.32 ± 2.61 89(19.4) 3.81 ± 5.01 138(30.1)
78(47.9) 33(20.2) 29(17.8) 23(14.1) 2.88 ± 2.92 42(25.8) 4.91 ± 5.53 67(41.1)
b0.001 0.973 0.002 0.001 b0.001 b0.001 b0.001 b0.001
b0.001
Data are presented as mean ± SD and number (percentage) where appropriate. CAD = coronary artery disease.
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Table 3 Independent predictors of significant coronary stenosis.
Age (increase by 1 year) Male Duration of diabetes (Increase by 1 year) Insulin use Normotension Controlled hypertension Uncontrolled Hypertension
Adjusted odds ratio
95% CI
p value
1.02 1.85 1.04 1.46 Reference 1.30 2.13
1.01–1.04 1.38–2.49 1.02–1.06 1.04–2.06
0.011 b0.001 b0.001 0.03
0.95–1.78 1.42–3.21
0.104 b0.001
CI = confidence interval.
3.4. Clinical outcomes and status of hypertension Fig. 1. Segment involvement score according to the status of hypertension.
3.2. CCTA findings and status of hypertension As shown in Table 2, there was an increasing prevalence of obstructive CAD, from 33% among normotensive patients, to 41% among those with controlled hypertension, and 52% among those with uncontrolled hypertension (p b 0.001). We observed a stepwise increase in the prevalence of obstructive CAD, in multiple vessels or in the left main coronary artery, from normotensive to patients with uncontrolled hypertension (13%, 21%, and 32%, respectively; p b 0.001). CACS, SIS, and SSS increased significantly with decreasing control of hypertension (Fig. 1). When patients were categorized according to the severity of luminal stenosis, patients with obstructive CAD had higher systolic blood pressures and a higher prevalence of hypertension compared to those with non-obstructive CAD and those without obstruction (Fig. 2).
During a median follow-up of 3.1 years, 44 deaths (4.7%), 19 cardiac deaths (2.0%), 5 MIs (0.5%), and 21 strokes (2.2%) were recorded in our study population. For the primary endpoint of our study, uncontrolled hypertension was associated with an increased incidence of the composite of cardiac death and MI (Hazard ratio[HR], 6.11; 95% confidence interval[CI], 1.65 to 22.6, p = 0.007). Whereas, the incidence of the composite of cardiac death and MI did not differ between patients with controlled hypertension and normotension (HR, 2.45; 95% CI, 0.68 to 8.79, p = 0.168) (Fig. 3). The presence of obstructive CAD and obstructive CAD in multiple vessels or in the left main coronary artery by CCTA also correlated with an increased risk of cardiac death or MI (Supplemental Fig. S1). The secondary outcome, the composite of all-cause death, MI, and stroke, was significantly increased in patients with uncontrolled hypertension (HR, 2.88; 95% CI, 1.45 to 5.70, p = 0.002), but not in patients with controlled hypertension (HR, 1.45; 95% CI, 0.77 to 2.74, p = 0.25) (Supplemental Fig. S2).
4. Discussion 3.3. Predictors of obstructive CAD Of all enrolled patients, 375 (40.1%) had obstructive CAD. Patient with obstructive CAD were more likely to be older, male, have a history of cerebrovascular accident, uncontrolled hypertension, longer history of diabetes, and diabetes that required treatment with insulin (Supplemental Table S1). Older age, male sex, longer history of diabetes and insulin use, and uncontrolled hypertension were independent predictors of obstructive CAD in a multivariate logistic regression model (Table 3).
We evaluated the prevalence, severity, extent, and predictors of CAD, as well as clinical outcomes, in asymptomatic patients with type 2 diabetes, according to their level of hypertension. We found that obstructive CAD was more prevalent and more extensive in asymptomatic type 2 diabetic patients with uncontrolled hypertension than those with controlled hypertension or normal BPs. Additionally, SBP and the prevalence of hypertension increased significantly in patients with obstructive CAD. Uncontrolled hypertension was independently associated with obstructive CAD in asymptomatic patients with type 2 diabetes. Finally, the uncontrolled hypertension in asymptomatic patients with
Fig. 2. Systolic blood pressure level and percentage of hypertension in asymptomatic type 2 diabetic patients with normal coronary arteries, with nonobstructive coronary stenosis, and with obstructive coronary stenosis.
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Fig. 3. Kaplan–Meier curves for cardiac death and myocardial infarction in patients with normotension, controlled hypertension, and uncontrolled hypertension.
type 2 diabetes was associated with an increased risk of poor cardiovascular outcomes. Based on the findings of the 10-year Framingham heart study which showed that increased blood pressure, despite antihypertensive treatment at baseline, was associated with poor cardiovascular outcomes, SBP and treatment for hypertension at baseline are currently recognized as cardiovascular risk factors [18,19]. The Framingham risk score is also used to predict future cardiovascular risk in diabetic patients [20,21]. In our study, the prevalence and complexity of CAD, as defined by CCTA, increased gradually with the degree of hypertension. Similar to previous studies, patients in our study with diffuse coronary atherosclerosis and accelerated disease progression by CCTA had poor clinical outcomes [14,17]. The CAD findings in patients with uncontrolled hypertension might have led to the increased rate of cardiovascular events. To the best of our knowledge, our study is the first to demonstrate the impact of hypertension on the prevalence and severity of CAD, and its clinical relevance in asymptomatic diabetic patients. Strict control of hypertension has been associated with reduced complications and mortality from diabetes. Therefore, the American Diabetes Association recommends that diabetic patients maintain SBP ≤ 140 mmHg. However, previous studies consistently demonstrate that most diabetic patients do not achieve the recommended level of BP control [22–24]. Seventeen percent of patients in our study needed intensive BP control due to underuse of antihypertensive agents, including renin–angiotensin system blockers. We reemphasize the crucial importance of tight BP control to prevent cardiovascular mortality and morbidity in hypertensive diabetic patients. Patients with uncontrolled hypertension in this study also showed poor glycemic control and poor lipid profiles. More than one-fourth of cases of uncontrolled hypertension did not achieve the target BP despite receiving ≥ 3 antihypertensive drugs. Previous studies suggest that metabolic risk factors, such as insulin resistance and dyslipidemia, might interfere with BP control despite intensive treatment [25,26]. Low compliance or inadequate treatment might play a role in the link between uncontrolled hypertension and poor metabolic profile. In addition to uncontrolled hypertension, several risk factors were independent predictors of obstructive CAD. Older age, male sex, and a longer duration of diabetes were also cardiovascular risk factors in the United Kingdom Prospective Diabetes Study [27]. Glycated hemoglobin, smoking, and serum cholesterol levels were not independent correlates with the prevalence of CAD in our study. Interestingly, insulin use was an independent predictor of obstructive CAD. The requirement for insulin treatment in patients with type 2 diabetes may reflect higher underlying insulin resistance that leads to more prevalent cardiovascular disease compared to those who do not use insulin [28]. In addition, insulin treatment for type 2 diabetes may directly promote endothelial
dysfunction and progression of vascular disease [29]. Further studies are needed to determine the effect of insulin treatment on atherosclerosis in patients with type 2 diabetes. The overall prevalence of obstructive CAD in this study was about 40%, which is within the expected range based on previous CCTA studies in diabetic patients [11,12,14]. In comparison to exercise electrocardiography or myocardial perfusion scintigraphy [30,31], obstructive CAD in CCTA might lead to an over-diagnosis of significant coronary stenosis in asymptomatic diabetic patients. However, CCTA has a high accuracy for detecting CAD at an early stage [32,33] and is less expensive and equally effective compared to stress echocardiograpy [34]. In addition, percutaneous coronary interventions and intensive medical therapy with worse CCTA findings can reduce event rates among patients with abnormal CCTA studies [35]. Thus, selective CCTA imaging of patients with high-risk profiles, such as uncontrolled hypertension, microalbuminuria, multiple cardio-metabolic risks, thick carotid intimal media thickness, and family history of premature coronary artery disease [30,36–38], might enhance the benefit of CCTA in asymptomatic diabetic patients. There were several limitations in our study. First, the number of enrolled patients was relatively small, and all patients were Asian. Thus, additional studies in other ethnic groups should be performed. Second, given the observation nature of the present study, detection of events and patient followup were less rigorous than those of randomized, controlled trials. Despite data collection by dedicated study nurses, review of insurance records, and thorough investigation of survival status, nonfatal events (e.g., MI, stroke) may have been underreported. Third, we assessed hypertension status with two BP readings at one visit instead of two or more properly measured readings at each of two or more visits. Fourth, we did not collect data about changes in BP, antihypertensive agents, antiplatelet agents, statins, or diabetes medications during the followup. However, this study demonstrates the impact of BP control until CCTA measurement on the development of CAD and future cardiovascular events. 5. Conclusions In conclusion, patients with asymptomatic type 2 diabetes and uncontrolled hypertension had greater burdens of CAD and worse clinical outcomes than those with normotension and controlled hypertension. Tight BP control could alleviate the progression of vascular atherosclerosis to reduce future cardiovascular complications in asymptomatic patients with type 2 diabetes. Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ijcard.2014.04.001. References [1] Becker A, Bos G, de Vegt F, et al. Cardiovascular events in type 2 diabetes: comparison with nondiabetic individuals without and with prior cardiovascular disease. 10-year follow-up of the Hoorn Study. Eur Heart J 2003;24:1406–13. [2] Schramm TK, Gislason GH, Kober L, et al. Diabetes patients requiring glucoselowering therapy and nondiabetics with a prior myocardial infarction carry the same cardiovascular risk: a population study of 3.3 million people. Circulation 2008;117:1945–54. [3] Adler AI, Stratton IM, Neil HA, et al. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ 2000;321:412–9. [4] Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ 1998;317:703–13. [5] Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010;362:1575–85. [6] Standards of medical care in diabetes—2013. Diabetes Care 2013;36(Suppl. 1): S11–66. [7] Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial
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