© 2014, Wiley Periodicals, Inc. DOI: 10.1111/echo.12782
Echocardiography
Coronary Flow Velocity Reserve in Patients with Ascending Aorta Aneurysm € lhan Yu € ksel Kalkan, M.D.,* Mustafa Gu € r, M.D.,† Hakan Ucßar, M.D.,* Ahmet Oytun Baykan, M.D.,* Gu € an Acele, M.D.,* Taner Sßeker, M.D.,* Omer lu, M.D.,* Armag Sßen, M.D.,* Onur Kaypakli, M.D.,* Hazar Harbaliog and Murat C ß ayli, M.D.‡ *Department of Cardiology, Adana Numune Training and Research Hospital, Adana, Turkey; †Department of Cardiology, Kafkas University School of Medicine, Kars, Turkey; and ‡Department of Cardiology, Dicle University School of Medicine, Diyarbakir, Turkey
Background: Ascending aorta aneurysms (AAA) are one of the leading causes of morbidity and mortality. Impairment in coronary flow may contribute to cardiovascular consequences in AAA patients. Coronary flow velocity reserve (CFVR) has been considered an important diagnostic index of the functional capacity of coronary arteries noninvasively. The aim of this study was to evaluate, by noninvasive CVFR, whether patients with AAA demonstrate significant coronary microvascular dysfunction in the absence of coronary artery disease (CAD). Methods: We prospectively included 44 patients with thoracic AAA in the absence of concomitant CAD (30 men, 14 women; mean age 57.5 8.4 years). A total of 36 patients without aortic dilatation (mean age 55.2 9.9 years) were selected as the control group. Coronary flow velocities in the distal left anterior descending (LAD) artery were measured using transthoracic echocardiography. CFVR was calculated as the hyperemic to resting coronary diastolic peak velocities ratio. Results: Compared with controls, patients with AAA had higher baseline LAD peak diastolic coronary flow velocities (28.3 5.8 vs. 25.2 4.5 cm/sec, P = 0.01), lower hyperemic LAD flow velocities (54.0 10.3 vs. 57.2 12.7 cm/sec, P = 0.220), and consequently lower CFVR (1.9 0.3 vs. 2.3 0.5, P < 0.001). Multivariate linear regression analysis showed that CFVR was independently associated only with aortic systolic diameter (AoSD) (b = 0.679, P = 55 years of age.1 Most of them are diagnosed commonly on an imaging study performed for an unrelated indication. Thoracic AA occur with an estimated incidence of 5.6–10.4 cases per 100,000 patient-years and an estimated prevalence of up to 4.2% of the general population without hypertension.2 Although it is a relatively rare pathology when compared to other cardiovascular disorders, the extensive complications of untreated or undiagnosed aneurysms elevate its clinical importance. In previous studies, it has been shown that patients with AA, particularly ascending aorta aneurysms (AAA), had high prevalence of coexistent coronary artery disease (CAD) and these patients were at high risk of carAddress for correspondence and reprint requests: Ahmet Oytun Baykan, Department of Cardiology, Adana Numune Training and Research Hospital, Adana 01120, Turkey. Fax: (+ 90) 322 338 33 69; E-mail: [email protected]
diac morbidity.3,4 Aortic aneurysms are associated with vascular remodeling, reduced capillary density, and elevated left ventricular (LV) end-diastolic pressure, which causes perfusion abnormalities and may result in impairment in coronary flow hemodynamics.5 Deterioration in coronary functional capacity, as well as microvascular dysfunction is considered to represent an early stage of coronary atherosclerosis and may contribute to these cardiovascular consequences in AA patients.6 Transthoracic Doppler echocardiography– derived coronary flow velocity reserve (CFVR), defined as the ratio of hyperemic to baseline coronary blood flow, has been considered an important diagnostic index of the functional capacity of coronary arteries noninvasively.7 The diagnostic accuracy of CFVR has been shown to be high (sensitivity of 86% and specificity of 70%) in predicting significant dysfunction of the left anterior descending (LAD) artery with a cutoff value of 40 mm) in the absence of concomitant CAD in this single center study (30 men, 14 women; mean age 57.5 8.4 years). A total of 36 patients without aortic dilatation (mean age 55.2 9.9 years) and normal coronary angiography were selected as the control group. Patients with severe valvular heart disease, history of myocardial infarction, wall-motion abnormalities, heart failure, severe pulmonary disease, and contraindications to adenosine were excluded. Moreover, we excluded patients with secondary etiologic disorders, such as genetically triggered aneurysms, inflammatory diseases, or trauma-associated aneurysms, as well as patients with bicuspid aortic valves and coarctation of aorta. We only included patients with isolated idiopathic or degenerative ascending AA in the present study. After taking detailed medical history and complete physical examination, each participant was questioned for major cardiovascular risk factors such as age, sex, diabetes mellitus (DM), smoking status, and hypertension (HT). In addition, systolic blood pressure (SBP), diastolic blood pressure (DBP), and initial heart rate were recorded. All patients underwent electrocardiography (ECG), comprehensive transthoracic Doppler echocardiography, and noninvasive assessment of CFVR in the distal part of the LAD during the same examination. The study was conducted according to the recommendations set forth by
976
the Declaration of Helsinki on Biomedical Research Involving Human Subjects. The Institutional Ethics Committee approved the study protocol and each participant provided written informed consent. Echocardiography: Standard two-dimensional (2D), pulsed-wave Doppler, and tissue Doppler echocardiographic examinations were performed using commercially available equipment (Vivid-7; GE Vingmed Sound, Horten, Norway) with a 2.5–3.5 MHz transducer. Simultaneous ECG recordings were also obtained. One echocardiographer who was blinded to the patients’ clinical and laboratory data interpreted each echocardiographic examination independently. All patients were examined at rest in the left lateral decubitus position. M-mode echocardiograms were recorded from the parasternal window at rest to determine left ventricle dimensions. LV ejection fraction (LVEF) was determined using the Simpson’s method and LV mass was calculated according to the suggestions of the American Society of Echocardiography.11 After data were collected in M-mode in the parasternal long-axis view, LV end-diastolic diameter (LVEDD), LV end-systolic diameter, end-diastolic left atrial diameter (LAD), end-diastolic LV interventricular septum (IVS), and left posterior wall (PW) thickness were measured. Inferior wall and PW thickness were also measured by 2D echocardiography from the short-axis parasternal view at the mitral valve level. Aortic systolic diameter (AoSD) and aortic diastolic diameter (AoDD) were measured by M-mode at a level of 3–4 cm above the aortic valve from a transthoracic parasternal long-axis view, at the time of maximum aortic anterior motion, and at the peak of the QRS complex, respectively. Also, 2D measurements of the aortic root end-diastolic dimensions were made in the parasternal long-axis views at 4 levels: (1) the annulus (defined echocardiographically as the hinge points of the aortic cusps); (2) the sinuses of Valsalva; (3) the supra-aortic ridge; and (4) the proximal ascending aorta. The measurements were made perpendicular to the long axis of the aorta using the leading edge technique in the views showing the largest aortic diameters.12 The diagnosis of AAA was determined solely from the morphologic analysis of the aorta, and dilation was suspected in the case of an aortic root dimension at the sinus of Valsalva greater than the upper limit of the 95% confidence interval of the overall distribution. CFVR Measurements: Visualization of the distal LAD coronary artery was performed with a modified, foreshortened,
Coronary Flow Reserve and Ascending Aorta Aneurysm
two-chamber view obtained by sliding the transducer on the upper part and medially from an apical two-chamber view. Coronary flow in the distal LAD was examined by color Doppler flow mapping over the epicardial part of the anterior wall, with the color Doppler velocity range set in the range of 10–20 cm/sec. The left ventricle was imaged on the long-axis cross section, and the ultrasound beam was then inclined laterally. The spectral Doppler signals of the distal LAD displayed the characteristic biphasic flow pattern, with a diastolic dominant flow and a smaller systolic component (Fig. 1). Peak systolic flow velocity and peak diastolic flow velocity (PDFV) were measured at baseline and under hyperemic conditions that were obtained with i.v. infusion of adenosine (140 lg/kg per min) over 3–6 minutes. An average PDFV was calculated from more than 3 cardiac cycles, and blood pressure and heart rate were also measured for the same cycles. CFVR was calculated as the ratio of hyperemic to baseline peak diastolic flow velocities.13 All echocardiograms, as well as CFVR measurements, were recorded and interpreted online on hard disks for offline analysis by another observer blinded to patient data. Intra-observer and inter-observer variability in CFVR and other echocardiographic data were evaluated from 12 randomly selected patients with AAA and calculated as the absolute difference divided by the average of the 2 observations. Mean intra-observer and inter-observer variability were 3.9 2.4% and 4.1 3.2%, respectively. Statistical Analysis: The analyses were performed using the SPSS software (Statistical Package for the Social Sciences,
A
Version 20.0; SSPS Inc., Chicago, IL, USA). Continuous variables were expressed as mean SD, and categorical variables as percentages. Comparisons of categorical and continuous variables between the 2 groups were performed using the chi-square test and independent samples t-test, respectively. Analysis of normality was performed with the Kolmogorov–Smirnov test. Power calculation of multiple regression test in patients with AAA was performed with F-test using statistical data analysis and graphics software (NCSS) power analysis and sample size (PASS). Power of multiple regression test was 100% when alpha was considered as 0.05 in 44 patients with AAA regarding the CFVR and aortic diameter. The correlations between CFVR with echocardiographic, clinical, and laboratory parameters were assessed by the Pearson correlation test. Multiple linear regression analysis was performed to identify the independent associations of CFVR. All significant parameters in the Pearson correlation analysis were selected in the multivariate model. A 2tailed P < 0.05 was considered statistically significant. Results: Clinical, laboratory, and echocardiographic characteristics of the whole cohort, including patients with AAA and controls are presented in Table I. There were no statistical significant differences in age, sex, body mass index, smoking status, medications used, and presence of hypertension, diabetes, and hyperlipidemia between patients with AAA and controls. The laboratory findings of the 2 groups were similar (P > 0.05 for all) except for high-density lipoprotein, triglyceride, and creatinine levels.
B
Figure 1. Assessment of coronary flow velocity reserve (CFVR). A. Mid-to-distal segment of the left anterior descending (LAD) coronary artery in color-coded transthoracic Doppler echocardiography. B. Spectral Doppler coronary blood flow in mid-to-distal segment of the LAD. S = systole; D = diastole.
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Baykan, et al.
TABLE I Comparison of Clinical, Laboratory, and Echocardiographic Characteristics between the Groups Variables Baseline characteristics Age (years) Gender (male) BMI (kg/m2) Hypertension, n (%) Diabetes, n (%) Smoking, n (%) Hyperlipidemia, n (%) Family history, n (%) Laboratory findings Glucose (mg/dL) Total cholesterol (mg/dL) Triglyceride (mg/dL) LDL-C (mg/dL) HDL-C (mg/dL) Creatinine (mg/dL) Hemoglobin (mg/dL) Echocardiography LVEDD (mm) LAD (mm) IVS (mm) PW (mm) LVEF (%) AoSD (mm) AoDD (mm) LV mass (g/m2) Use of cardiovascular medications, n (%) Statins OADs ACEI or ARBs b-blockers ASA
Patients with AAA (n = 44)
Control Group (n = 36)
P-Value
57.5 8.4 30 (68.2%) 26.4 5.2 25 (56.8%) 6 (13.6%) 21 (47.7%) 12 (29.5%) 11 (27.3%)
55.2 9.9 19 (52.8%) 24.9 5.1 17 (47.2%) 7 (19.4%) 16 (44.4%) 11 (30.6%) 6 (16.7%)
0.262 0.120 0.401 0.264 0.344 0.473 0.469 0.265
102.7 206.3 186.1 136.2 39.2 0.89 14.6
10.1 34.9 96.0 32.1 9.6 0.19 5.0
100.6 212.2 136.9 148.5 46.4 0.74 14.3
11.3 44.7 81.5 49.4 10.3 0.16 1.4
0.742 0.508 0.017 0.183 0.002
Echocardiography
Coronary Flow Velocity Reserve in Patients with Ascending Aorta Aneurysm € lhan Yu € ksel Kalkan, M.D.,* Mustafa Gu € r, M.D.,† Hakan Ucßar, M.D.,* Ahmet Oytun Baykan, M.D.,* Gu € an Acele, M.D.,* Taner Sßeker, M.D.,* Omer lu, M.D.,* Armag Sßen, M.D.,* Onur Kaypakli, M.D.,* Hazar Harbaliog and Murat C ß ayli, M.D.‡ *Department of Cardiology, Adana Numune Training and Research Hospital, Adana, Turkey; †Department of Cardiology, Kafkas University School of Medicine, Kars, Turkey; and ‡Department of Cardiology, Dicle University School of Medicine, Diyarbakir, Turkey
Background: Ascending aorta aneurysms (AAA) are one of the leading causes of morbidity and mortality. Impairment in coronary flow may contribute to cardiovascular consequences in AAA patients. Coronary flow velocity reserve (CFVR) has been considered an important diagnostic index of the functional capacity of coronary arteries noninvasively. The aim of this study was to evaluate, by noninvasive CVFR, whether patients with AAA demonstrate significant coronary microvascular dysfunction in the absence of coronary artery disease (CAD). Methods: We prospectively included 44 patients with thoracic AAA in the absence of concomitant CAD (30 men, 14 women; mean age 57.5 8.4 years). A total of 36 patients without aortic dilatation (mean age 55.2 9.9 years) were selected as the control group. Coronary flow velocities in the distal left anterior descending (LAD) artery were measured using transthoracic echocardiography. CFVR was calculated as the hyperemic to resting coronary diastolic peak velocities ratio. Results: Compared with controls, patients with AAA had higher baseline LAD peak diastolic coronary flow velocities (28.3 5.8 vs. 25.2 4.5 cm/sec, P = 0.01), lower hyperemic LAD flow velocities (54.0 10.3 vs. 57.2 12.7 cm/sec, P = 0.220), and consequently lower CFVR (1.9 0.3 vs. 2.3 0.5, P < 0.001). Multivariate linear regression analysis showed that CFVR was independently associated only with aortic systolic diameter (AoSD) (b = 0.679, P = 55 years of age.1 Most of them are diagnosed commonly on an imaging study performed for an unrelated indication. Thoracic AA occur with an estimated incidence of 5.6–10.4 cases per 100,000 patient-years and an estimated prevalence of up to 4.2% of the general population without hypertension.2 Although it is a relatively rare pathology when compared to other cardiovascular disorders, the extensive complications of untreated or undiagnosed aneurysms elevate its clinical importance. In previous studies, it has been shown that patients with AA, particularly ascending aorta aneurysms (AAA), had high prevalence of coexistent coronary artery disease (CAD) and these patients were at high risk of carAddress for correspondence and reprint requests: Ahmet Oytun Baykan, Department of Cardiology, Adana Numune Training and Research Hospital, Adana 01120, Turkey. Fax: (+ 90) 322 338 33 69; E-mail: [email protected]
diac morbidity.3,4 Aortic aneurysms are associated with vascular remodeling, reduced capillary density, and elevated left ventricular (LV) end-diastolic pressure, which causes perfusion abnormalities and may result in impairment in coronary flow hemodynamics.5 Deterioration in coronary functional capacity, as well as microvascular dysfunction is considered to represent an early stage of coronary atherosclerosis and may contribute to these cardiovascular consequences in AA patients.6 Transthoracic Doppler echocardiography– derived coronary flow velocity reserve (CFVR), defined as the ratio of hyperemic to baseline coronary blood flow, has been considered an important diagnostic index of the functional capacity of coronary arteries noninvasively.7 The diagnostic accuracy of CFVR has been shown to be high (sensitivity of 86% and specificity of 70%) in predicting significant dysfunction of the left anterior descending (LAD) artery with a cutoff value of 40 mm) in the absence of concomitant CAD in this single center study (30 men, 14 women; mean age 57.5 8.4 years). A total of 36 patients without aortic dilatation (mean age 55.2 9.9 years) and normal coronary angiography were selected as the control group. Patients with severe valvular heart disease, history of myocardial infarction, wall-motion abnormalities, heart failure, severe pulmonary disease, and contraindications to adenosine were excluded. Moreover, we excluded patients with secondary etiologic disorders, such as genetically triggered aneurysms, inflammatory diseases, or trauma-associated aneurysms, as well as patients with bicuspid aortic valves and coarctation of aorta. We only included patients with isolated idiopathic or degenerative ascending AA in the present study. After taking detailed medical history and complete physical examination, each participant was questioned for major cardiovascular risk factors such as age, sex, diabetes mellitus (DM), smoking status, and hypertension (HT). In addition, systolic blood pressure (SBP), diastolic blood pressure (DBP), and initial heart rate were recorded. All patients underwent electrocardiography (ECG), comprehensive transthoracic Doppler echocardiography, and noninvasive assessment of CFVR in the distal part of the LAD during the same examination. The study was conducted according to the recommendations set forth by
976
the Declaration of Helsinki on Biomedical Research Involving Human Subjects. The Institutional Ethics Committee approved the study protocol and each participant provided written informed consent. Echocardiography: Standard two-dimensional (2D), pulsed-wave Doppler, and tissue Doppler echocardiographic examinations were performed using commercially available equipment (Vivid-7; GE Vingmed Sound, Horten, Norway) with a 2.5–3.5 MHz transducer. Simultaneous ECG recordings were also obtained. One echocardiographer who was blinded to the patients’ clinical and laboratory data interpreted each echocardiographic examination independently. All patients were examined at rest in the left lateral decubitus position. M-mode echocardiograms were recorded from the parasternal window at rest to determine left ventricle dimensions. LV ejection fraction (LVEF) was determined using the Simpson’s method and LV mass was calculated according to the suggestions of the American Society of Echocardiography.11 After data were collected in M-mode in the parasternal long-axis view, LV end-diastolic diameter (LVEDD), LV end-systolic diameter, end-diastolic left atrial diameter (LAD), end-diastolic LV interventricular septum (IVS), and left posterior wall (PW) thickness were measured. Inferior wall and PW thickness were also measured by 2D echocardiography from the short-axis parasternal view at the mitral valve level. Aortic systolic diameter (AoSD) and aortic diastolic diameter (AoDD) were measured by M-mode at a level of 3–4 cm above the aortic valve from a transthoracic parasternal long-axis view, at the time of maximum aortic anterior motion, and at the peak of the QRS complex, respectively. Also, 2D measurements of the aortic root end-diastolic dimensions were made in the parasternal long-axis views at 4 levels: (1) the annulus (defined echocardiographically as the hinge points of the aortic cusps); (2) the sinuses of Valsalva; (3) the supra-aortic ridge; and (4) the proximal ascending aorta. The measurements were made perpendicular to the long axis of the aorta using the leading edge technique in the views showing the largest aortic diameters.12 The diagnosis of AAA was determined solely from the morphologic analysis of the aorta, and dilation was suspected in the case of an aortic root dimension at the sinus of Valsalva greater than the upper limit of the 95% confidence interval of the overall distribution. CFVR Measurements: Visualization of the distal LAD coronary artery was performed with a modified, foreshortened,
Coronary Flow Reserve and Ascending Aorta Aneurysm
two-chamber view obtained by sliding the transducer on the upper part and medially from an apical two-chamber view. Coronary flow in the distal LAD was examined by color Doppler flow mapping over the epicardial part of the anterior wall, with the color Doppler velocity range set in the range of 10–20 cm/sec. The left ventricle was imaged on the long-axis cross section, and the ultrasound beam was then inclined laterally. The spectral Doppler signals of the distal LAD displayed the characteristic biphasic flow pattern, with a diastolic dominant flow and a smaller systolic component (Fig. 1). Peak systolic flow velocity and peak diastolic flow velocity (PDFV) were measured at baseline and under hyperemic conditions that were obtained with i.v. infusion of adenosine (140 lg/kg per min) over 3–6 minutes. An average PDFV was calculated from more than 3 cardiac cycles, and blood pressure and heart rate were also measured for the same cycles. CFVR was calculated as the ratio of hyperemic to baseline peak diastolic flow velocities.13 All echocardiograms, as well as CFVR measurements, were recorded and interpreted online on hard disks for offline analysis by another observer blinded to patient data. Intra-observer and inter-observer variability in CFVR and other echocardiographic data were evaluated from 12 randomly selected patients with AAA and calculated as the absolute difference divided by the average of the 2 observations. Mean intra-observer and inter-observer variability were 3.9 2.4% and 4.1 3.2%, respectively. Statistical Analysis: The analyses were performed using the SPSS software (Statistical Package for the Social Sciences,
A
Version 20.0; SSPS Inc., Chicago, IL, USA). Continuous variables were expressed as mean SD, and categorical variables as percentages. Comparisons of categorical and continuous variables between the 2 groups were performed using the chi-square test and independent samples t-test, respectively. Analysis of normality was performed with the Kolmogorov–Smirnov test. Power calculation of multiple regression test in patients with AAA was performed with F-test using statistical data analysis and graphics software (NCSS) power analysis and sample size (PASS). Power of multiple regression test was 100% when alpha was considered as 0.05 in 44 patients with AAA regarding the CFVR and aortic diameter. The correlations between CFVR with echocardiographic, clinical, and laboratory parameters were assessed by the Pearson correlation test. Multiple linear regression analysis was performed to identify the independent associations of CFVR. All significant parameters in the Pearson correlation analysis were selected in the multivariate model. A 2tailed P < 0.05 was considered statistically significant. Results: Clinical, laboratory, and echocardiographic characteristics of the whole cohort, including patients with AAA and controls are presented in Table I. There were no statistical significant differences in age, sex, body mass index, smoking status, medications used, and presence of hypertension, diabetes, and hyperlipidemia between patients with AAA and controls. The laboratory findings of the 2 groups were similar (P > 0.05 for all) except for high-density lipoprotein, triglyceride, and creatinine levels.
B
Figure 1. Assessment of coronary flow velocity reserve (CFVR). A. Mid-to-distal segment of the left anterior descending (LAD) coronary artery in color-coded transthoracic Doppler echocardiography. B. Spectral Doppler coronary blood flow in mid-to-distal segment of the LAD. S = systole; D = diastole.
977
Baykan, et al.
TABLE I Comparison of Clinical, Laboratory, and Echocardiographic Characteristics between the Groups Variables Baseline characteristics Age (years) Gender (male) BMI (kg/m2) Hypertension, n (%) Diabetes, n (%) Smoking, n (%) Hyperlipidemia, n (%) Family history, n (%) Laboratory findings Glucose (mg/dL) Total cholesterol (mg/dL) Triglyceride (mg/dL) LDL-C (mg/dL) HDL-C (mg/dL) Creatinine (mg/dL) Hemoglobin (mg/dL) Echocardiography LVEDD (mm) LAD (mm) IVS (mm) PW (mm) LVEF (%) AoSD (mm) AoDD (mm) LV mass (g/m2) Use of cardiovascular medications, n (%) Statins OADs ACEI or ARBs b-blockers ASA
Patients with AAA (n = 44)
Control Group (n = 36)
P-Value
57.5 8.4 30 (68.2%) 26.4 5.2 25 (56.8%) 6 (13.6%) 21 (47.7%) 12 (29.5%) 11 (27.3%)
55.2 9.9 19 (52.8%) 24.9 5.1 17 (47.2%) 7 (19.4%) 16 (44.4%) 11 (30.6%) 6 (16.7%)
0.262 0.120 0.401 0.264 0.344 0.473 0.469 0.265
102.7 206.3 186.1 136.2 39.2 0.89 14.6
10.1 34.9 96.0 32.1 9.6 0.19 5.0
100.6 212.2 136.9 148.5 46.4 0.74 14.3
11.3 44.7 81.5 49.4 10.3 0.16 1.4
0.742 0.508 0.017 0.183 0.002
