© 2015, Wiley Periodicals, Inc. DOI: 10.1111/echo.12960
Echocardiography
ORIGINAL INVESTIGATIONS
The Relationship between Epicardial Fat Thickness and Endothelial Dysfunction in Type I Diabetes Mellitus € seyin Ayhan, M.D.,† Hacı Ahmet Kasapkara, M.D.,† Abdullah Nabi Aslan, M.D.,* Telat Kelesß, M.D.,† Hu , M.D.,* Bekir C Murat Akcßay, M.D.,† Tahir Durmaz, M.D.,† Cenk Sarı, M.D.,* Serdal Basßtug ß akır, M.D.,‡ and Engin Bozkurt, M.D.* *Department of Cardiology, Ankara Ataturk Education and Research Hospital, Ankara, Turkey; †Department of Cardiology, Faculty of Medicine, Yıldırım Beyazıt University, Ankara, Turkey; and ‡Department of Endocrinology, Faculty of Medicine, Yıldırım Beyazıt University, Ankara, Turkey
Background and Aim: Epicardial adipose tissue (EAT) is a new independent marker of coronary artery disease (CAD). The aim of this study was to investigate the relationship between epicardial fat thickness (EFT) and endothelial dysfunction (ED) in patients with type I diabetes mellitus (TIDM). Methods and Results: Seventy-six type I diabetic patients (diabetes duration 11.7 8,1 years, aged 30.6 10 years; female/male: 38/38) and 36 healthy controls were enrolled into the study. Fasting plasma glucose (FPG), lipid panel, glycosylated hemoglobin (HbA1C), high-sensitive C-reactive protein (hsCRP), and fibrinogen levels were determined. EFT was measured via two-dimensional (2D) M-mode echocardiography. Endothelial function was assessed as flow-mediated dilatation (FMD) at the brachial artery using high-resolution ultrasound. EFT was significantly higher in patients compared to controls (3.56 0.48 mm vs. 3.03 0.48 mm, P < 0.001). In addition, significant differences were observed between the patient and control groups in terms of FMD (6.70% 1.63 vs. 9.99% 1.84, respectively, P < 0.001). EFT was shown to be correlated negatively with FMD (r: 0.94, P < 0.001) and positively with hsCRP (r: 0.41, P < 0.001) and fibrinogen (r: 0. 31, P = 0.007). Multiple regression analysis showed EFT to be an independent factor influencing the endothelial function. Conclusion: There was inverse relationship between EFT and endothelial function in this study. EFT measured easily by transthoracic echocardiography may be a useful parameter in the assessment of patients with TIDM. (Echocardiography 2015;32:1745–1753) Key words: endothelial dysfunction, epicardial adipose tissue, type I diabetes mellitus
Micro- and macrovascular complications constitute the leading causes of morbidity and mortality in patients with diabetes mellitus.1–3 However, proven traditional risk factors for cardiovascular diseases could not explain this increased risk of cardiovascular mortality as a whole.4,5 Relation between cardiovascular diseases and type I diabetes mellitus (TIDM) is well known,6 and this is found to be related to chronic hyperglycemia, endothelial dysfunction, and chronic inflammation.7,8 Epicardial adipose tissue (EAT) that surrounds the coronary arteries is actually visceral fat tissue deposited around the heart between the myocardium and the pericardium. Several studies have demonstrated that EAT is not only an anatomic depot of fat but also may serve as a local Address for correspondence and reprint requests: Abdullah Nabi Aslan, M.D., Department of Cardiology, Ankara Ataturk Education and Research Hospital, Bilkent 06800, Ankara, Turkey. Fax: +90-3122912745; E-mail: [email protected]
source of proinflammatory cytokines related to coronary artery disease (CAD).9 Therefore, epicardial fat thickness (EFT) has been considered to be a possible cardiovascular risk indicator.10,11 Endothelial dysfunction is thought to be an early manifestation in the pathogenesis of the vascular complications in TIDM.12 It reflects the presence of phenotype prone to the atherosclerosis and accepted as a risk indicator for the atherosclerosis which is an independent risk factor for the development of cardiovascular events.13 Flow-mediated dilatation (FMD) measured from brachial artery is the most commonly used noninvasive method for the evaluation of endothelial function.14,15 It is usually measured from the brachial artery, and principle depends on the measurement of the arterial diameter response to the increased blood flow. In this study, we aimed to evaluate the relation between EFT and endothelial dysfunction in 1745
Aslan et al.
patients with TIDM over at least 5 years of duration. To our knowledge, this is the first study in the literature that evaluates the EFT and FMD together in patients with TIDM. Methods: Study population was consisted of patients with TIDM for at least 5 years of duration admitted to the endocrinology polyclinic and consulted to the cardiology polyclinic due to cardiac complaints (chest pain, exertional dyspnea, palpitation, syncope) for further evaluation (ECG, echocardiography) between September 2012 and June 2013. Seventy-six patients between the ages of 18 and 63 years, who did not have any exclusion criteria, were included into the biochemical and echocardiographic study after detailed anamnesis was taken and physical examinations were performed. Control group was consisted of 36 healthy volunteers who were referred to cardiology clinic but without any cardiac disease. Patient and control groups were matched according to age, sex, body mass index (BMI), smoking status, and other coronary artery risk factors (family history, hyperlipidemia, and hypertension). Study protocol was approved by our hospital ethics committee, and study was performed according to Helsinki declaration. Patients under the age of 18 and over the age of 65, structural and functional heart disease, coronary artery disease, peripheral vascular disease, uncontrolled hypertension, cardiac arrhythmia, infection at the same time with the study, malignancy, pregnancy, other inflammatory diseases, smoking in the last 24 hours, patients who use vasoactive drugs, and patients who did not give informed consent form were excluded from the study. Patients: Participants were divided into two groups as the patient and the control groups. After informed consent was signed, age, sex, height, weight, comorbid diseases, and any drugs they are using were questioned and recorded. First of all, in order to exclude the structural heart disease, detailed echocardiographic examinations were performed, and in addition to routine echocardiographic parameters, EFT was measured and recorded. Measurement of Epicardial Fat Thickness: Epicardial fat thickness was measured in the echocardiography laboratory by the same operator performing the measurements blinded as to whether the subject was in the patient or in the control group. Echocardiographic examinations were performed while the patients were lying on 1746
the left lateral decubitus position with Vivid 7 Dimension echocardiography machine (Vingmed Ultrasound, GE, Horten, Norway). For the optimization of the measurements, patients were also monitorized with ECG. EFT was measured at the end of the diastole perpendicular to right ventricular free wall. A minimum of three measurements were taken from parasternal long, and the shortaxis views separated equally distant from each other for three consecutive cycles and averaged (Fig. 1). Biochemical Parameters: Biochemical and other parameters which have been shown to influence the FMD test or proven to be a cardiovascular risk were measured in the blood samples taken at the morning hours before echocardiographic examination, after 12 hours of fasting both in the patient and the control groups. Glucose, total cholesterol (TC), LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), and triglyceride (TG) levels were measured with enzymatic colorimetric analysis (Roche Diagnostics GmbH, Mannheim, Germany). HbA1C levels were measured with
A
B
Figure 1. Epicardial fat thickness measurement perpendicular to right ventricular free wall with the help of transthoracic echocardiography (arrows), A. Parasternal long-axis view and B. Parasternal short-axis view.
Epicardial Fat Thickness and Type I Diabetes Mellitus
thermo-system high-pressure liquid chromatography. HsCRP levels were measured with immunoturbidimetric method (Roche Diagnostics GmbH). Mean concentration range was accepted as 0–1.0 mg/L. Fibrinogen levels were measured with coagulation test in the plasma (STA, Diagnostica Stago, Asni eres sur Seine Cedex, France), and the mean concentration range was accepted as 185–450 mg/dL. Evaluation of the Endothelial Functions: Endothelial function was evaluated with high-resolution B-mode Doppler machine by analyzing brachial artery. Brachial artery B-mode examinations were performed with 13-mHz linear array transducer using Vivid 7 ultrasonography machine (Vingmed Ultrasound, GE, Horten, Norway). All of the ultrasonographic examinations were performed with the same operator who was blinded as to whether the subject was in the patient or control group. All of the images were stored in the digital media, and another researcher interpreted the stored images. FMD test was used to evaluate the endothelial function at the brachial artery. In this test, arterial diameter is measured in response to an increase in shear stress, which causes endothelium-dependent dilatation. The artery is scanned and the diameter measured during three conditions; at baseline, during reactive hyperemia, and finally after administration of sublingual nitroglycerin using a normal antianginal dose of 400 lg (Fig. 2). At baseline brachial artery, measurements were taken at first, second, and third minutes from an arterial segment before the induction of transient brachial ischemia and after at least 10 min supine rest.16 From these
measurements, the widest diameter was accepted as reference value for the maximum dilatation capacity and used for FMD calculations. Then, brachial artery measurements were repeated following a period of transient ischemia which is induced by inflation of a sphygmomanometer cuff to 250 mmHg and then deflation of it around the forearm for five minutes. Flow-mediated dilatation was accepted as percent change of the vessel diameter compared to baseline value and calculated with the FMD = [(MaxD-BD/BD] 9 100 formula. Maximum time velocity integral was measured at baseline and 15th second of hyperemia in which the hyperemic flow was maximal to evaluate the hyperemic stimulus. Hyperemic flow ratio was defined as ratio (%) of the flow at 15th second to baseline flow. Finally, after 10 minutes of rest, 0.4 mg nitroglycerine was given sublingually, and after 3 minutes, brachial artery diameter and flow were recorded to evaluate the nitroglycerine-mediated dilatation (NMD). With this measurement, nitroglycerine-dependent but endothelium independent dilatation was evaluated. Similar to FMD, NMD is accepted as percent change in the diameter after sublingual nitroglycerine compared to baseline diameter. More than 10% dilatation was accepted as normal, and less than 10% dilatation was accepted as abnormal.17 Statistical Analysis: Analysis of the data was performed with SPSS for Windows 17.0 program (Statistical Package for Social Sciences Inc., Chicago, IL, USA). Significance of the mean differences between groups was calculated with Student’s t-test, and
Figure 2. Brachial artery diameter was measured at baseline (after at least 10 min supine rest), after reactive hyperemia (induced by inflation of a sphygmomanometer cuff to 250 mmHg and then deflation of it) and finally after the nitroglycerine administration. A 13-mHz linear array, high-resolution ultrasound transducer was used to provide B-mode images of the brachial artery, proximal to the forearm cuff.
1747
Aslan et al.
differences in the median values of the groups were evaluated with Mann–Whitney U-test. Nominal variables were evaluated with chi-square test. Correlation analysis was performed with Pearson test. Independent relation between the EFT and FMD was evaluated with multiple linear regression analysis. P-values
Echocardiography
ORIGINAL INVESTIGATIONS
The Relationship between Epicardial Fat Thickness and Endothelial Dysfunction in Type I Diabetes Mellitus € seyin Ayhan, M.D.,† Hacı Ahmet Kasapkara, M.D.,† Abdullah Nabi Aslan, M.D.,* Telat Kelesß, M.D.,† Hu , M.D.,* Bekir C Murat Akcßay, M.D.,† Tahir Durmaz, M.D.,† Cenk Sarı, M.D.,* Serdal Basßtug ß akır, M.D.,‡ and Engin Bozkurt, M.D.* *Department of Cardiology, Ankara Ataturk Education and Research Hospital, Ankara, Turkey; †Department of Cardiology, Faculty of Medicine, Yıldırım Beyazıt University, Ankara, Turkey; and ‡Department of Endocrinology, Faculty of Medicine, Yıldırım Beyazıt University, Ankara, Turkey
Background and Aim: Epicardial adipose tissue (EAT) is a new independent marker of coronary artery disease (CAD). The aim of this study was to investigate the relationship between epicardial fat thickness (EFT) and endothelial dysfunction (ED) in patients with type I diabetes mellitus (TIDM). Methods and Results: Seventy-six type I diabetic patients (diabetes duration 11.7 8,1 years, aged 30.6 10 years; female/male: 38/38) and 36 healthy controls were enrolled into the study. Fasting plasma glucose (FPG), lipid panel, glycosylated hemoglobin (HbA1C), high-sensitive C-reactive protein (hsCRP), and fibrinogen levels were determined. EFT was measured via two-dimensional (2D) M-mode echocardiography. Endothelial function was assessed as flow-mediated dilatation (FMD) at the brachial artery using high-resolution ultrasound. EFT was significantly higher in patients compared to controls (3.56 0.48 mm vs. 3.03 0.48 mm, P < 0.001). In addition, significant differences were observed between the patient and control groups in terms of FMD (6.70% 1.63 vs. 9.99% 1.84, respectively, P < 0.001). EFT was shown to be correlated negatively with FMD (r: 0.94, P < 0.001) and positively with hsCRP (r: 0.41, P < 0.001) and fibrinogen (r: 0. 31, P = 0.007). Multiple regression analysis showed EFT to be an independent factor influencing the endothelial function. Conclusion: There was inverse relationship between EFT and endothelial function in this study. EFT measured easily by transthoracic echocardiography may be a useful parameter in the assessment of patients with TIDM. (Echocardiography 2015;32:1745–1753) Key words: endothelial dysfunction, epicardial adipose tissue, type I diabetes mellitus
Micro- and macrovascular complications constitute the leading causes of morbidity and mortality in patients with diabetes mellitus.1–3 However, proven traditional risk factors for cardiovascular diseases could not explain this increased risk of cardiovascular mortality as a whole.4,5 Relation between cardiovascular diseases and type I diabetes mellitus (TIDM) is well known,6 and this is found to be related to chronic hyperglycemia, endothelial dysfunction, and chronic inflammation.7,8 Epicardial adipose tissue (EAT) that surrounds the coronary arteries is actually visceral fat tissue deposited around the heart between the myocardium and the pericardium. Several studies have demonstrated that EAT is not only an anatomic depot of fat but also may serve as a local Address for correspondence and reprint requests: Abdullah Nabi Aslan, M.D., Department of Cardiology, Ankara Ataturk Education and Research Hospital, Bilkent 06800, Ankara, Turkey. Fax: +90-3122912745; E-mail: [email protected]
source of proinflammatory cytokines related to coronary artery disease (CAD).9 Therefore, epicardial fat thickness (EFT) has been considered to be a possible cardiovascular risk indicator.10,11 Endothelial dysfunction is thought to be an early manifestation in the pathogenesis of the vascular complications in TIDM.12 It reflects the presence of phenotype prone to the atherosclerosis and accepted as a risk indicator for the atherosclerosis which is an independent risk factor for the development of cardiovascular events.13 Flow-mediated dilatation (FMD) measured from brachial artery is the most commonly used noninvasive method for the evaluation of endothelial function.14,15 It is usually measured from the brachial artery, and principle depends on the measurement of the arterial diameter response to the increased blood flow. In this study, we aimed to evaluate the relation between EFT and endothelial dysfunction in 1745
Aslan et al.
patients with TIDM over at least 5 years of duration. To our knowledge, this is the first study in the literature that evaluates the EFT and FMD together in patients with TIDM. Methods: Study population was consisted of patients with TIDM for at least 5 years of duration admitted to the endocrinology polyclinic and consulted to the cardiology polyclinic due to cardiac complaints (chest pain, exertional dyspnea, palpitation, syncope) for further evaluation (ECG, echocardiography) between September 2012 and June 2013. Seventy-six patients between the ages of 18 and 63 years, who did not have any exclusion criteria, were included into the biochemical and echocardiographic study after detailed anamnesis was taken and physical examinations were performed. Control group was consisted of 36 healthy volunteers who were referred to cardiology clinic but without any cardiac disease. Patient and control groups were matched according to age, sex, body mass index (BMI), smoking status, and other coronary artery risk factors (family history, hyperlipidemia, and hypertension). Study protocol was approved by our hospital ethics committee, and study was performed according to Helsinki declaration. Patients under the age of 18 and over the age of 65, structural and functional heart disease, coronary artery disease, peripheral vascular disease, uncontrolled hypertension, cardiac arrhythmia, infection at the same time with the study, malignancy, pregnancy, other inflammatory diseases, smoking in the last 24 hours, patients who use vasoactive drugs, and patients who did not give informed consent form were excluded from the study. Patients: Participants were divided into two groups as the patient and the control groups. After informed consent was signed, age, sex, height, weight, comorbid diseases, and any drugs they are using were questioned and recorded. First of all, in order to exclude the structural heart disease, detailed echocardiographic examinations were performed, and in addition to routine echocardiographic parameters, EFT was measured and recorded. Measurement of Epicardial Fat Thickness: Epicardial fat thickness was measured in the echocardiography laboratory by the same operator performing the measurements blinded as to whether the subject was in the patient or in the control group. Echocardiographic examinations were performed while the patients were lying on 1746
the left lateral decubitus position with Vivid 7 Dimension echocardiography machine (Vingmed Ultrasound, GE, Horten, Norway). For the optimization of the measurements, patients were also monitorized with ECG. EFT was measured at the end of the diastole perpendicular to right ventricular free wall. A minimum of three measurements were taken from parasternal long, and the shortaxis views separated equally distant from each other for three consecutive cycles and averaged (Fig. 1). Biochemical Parameters: Biochemical and other parameters which have been shown to influence the FMD test or proven to be a cardiovascular risk were measured in the blood samples taken at the morning hours before echocardiographic examination, after 12 hours of fasting both in the patient and the control groups. Glucose, total cholesterol (TC), LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), and triglyceride (TG) levels were measured with enzymatic colorimetric analysis (Roche Diagnostics GmbH, Mannheim, Germany). HbA1C levels were measured with
A
B
Figure 1. Epicardial fat thickness measurement perpendicular to right ventricular free wall with the help of transthoracic echocardiography (arrows), A. Parasternal long-axis view and B. Parasternal short-axis view.
Epicardial Fat Thickness and Type I Diabetes Mellitus
thermo-system high-pressure liquid chromatography. HsCRP levels were measured with immunoturbidimetric method (Roche Diagnostics GmbH). Mean concentration range was accepted as 0–1.0 mg/L. Fibrinogen levels were measured with coagulation test in the plasma (STA, Diagnostica Stago, Asni eres sur Seine Cedex, France), and the mean concentration range was accepted as 185–450 mg/dL. Evaluation of the Endothelial Functions: Endothelial function was evaluated with high-resolution B-mode Doppler machine by analyzing brachial artery. Brachial artery B-mode examinations were performed with 13-mHz linear array transducer using Vivid 7 ultrasonography machine (Vingmed Ultrasound, GE, Horten, Norway). All of the ultrasonographic examinations were performed with the same operator who was blinded as to whether the subject was in the patient or control group. All of the images were stored in the digital media, and another researcher interpreted the stored images. FMD test was used to evaluate the endothelial function at the brachial artery. In this test, arterial diameter is measured in response to an increase in shear stress, which causes endothelium-dependent dilatation. The artery is scanned and the diameter measured during three conditions; at baseline, during reactive hyperemia, and finally after administration of sublingual nitroglycerin using a normal antianginal dose of 400 lg (Fig. 2). At baseline brachial artery, measurements were taken at first, second, and third minutes from an arterial segment before the induction of transient brachial ischemia and after at least 10 min supine rest.16 From these
measurements, the widest diameter was accepted as reference value for the maximum dilatation capacity and used for FMD calculations. Then, brachial artery measurements were repeated following a period of transient ischemia which is induced by inflation of a sphygmomanometer cuff to 250 mmHg and then deflation of it around the forearm for five minutes. Flow-mediated dilatation was accepted as percent change of the vessel diameter compared to baseline value and calculated with the FMD = [(MaxD-BD/BD] 9 100 formula. Maximum time velocity integral was measured at baseline and 15th second of hyperemia in which the hyperemic flow was maximal to evaluate the hyperemic stimulus. Hyperemic flow ratio was defined as ratio (%) of the flow at 15th second to baseline flow. Finally, after 10 minutes of rest, 0.4 mg nitroglycerine was given sublingually, and after 3 minutes, brachial artery diameter and flow were recorded to evaluate the nitroglycerine-mediated dilatation (NMD). With this measurement, nitroglycerine-dependent but endothelium independent dilatation was evaluated. Similar to FMD, NMD is accepted as percent change in the diameter after sublingual nitroglycerine compared to baseline diameter. More than 10% dilatation was accepted as normal, and less than 10% dilatation was accepted as abnormal.17 Statistical Analysis: Analysis of the data was performed with SPSS for Windows 17.0 program (Statistical Package for Social Sciences Inc., Chicago, IL, USA). Significance of the mean differences between groups was calculated with Student’s t-test, and
Figure 2. Brachial artery diameter was measured at baseline (after at least 10 min supine rest), after reactive hyperemia (induced by inflation of a sphygmomanometer cuff to 250 mmHg and then deflation of it) and finally after the nitroglycerine administration. A 13-mHz linear array, high-resolution ultrasound transducer was used to provide B-mode images of the brachial artery, proximal to the forearm cuff.
1747
Aslan et al.
differences in the median values of the groups were evaluated with Mann–Whitney U-test. Nominal variables were evaluated with chi-square test. Correlation analysis was performed with Pearson test. Independent relation between the EFT and FMD was evaluated with multiple linear regression analysis. P-values
