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Estimation of myocardial extracellular volume fraction with cardiac CT in subjects without clinical coronary artery disease: A feasibility study
Journal of Cardiovascular Computed Tomography xxx (2016) 1e5
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Journal of Cardiovascular Computed Tomography journal homepage: www.JournalofCardiovascularCT.com
Short communication
Estimation of myocardial extracellular volume fraction with cardiac CT in subjects without clinical coronary artery disease: A feasibility study Yoshie Kurita a, Kakuya Kitagawa a, *, Yusuke Kurobe a, Shiro Nakamori b, Hiroshi Nakajima b, Kaoru Dohi b, Masaaki Ito b, Hajime Sakuma a a b
Department of Radiology, Mie University Hospital, Tsu, Japan Department of Cardiology, Mie University Hospital, Tsu, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 1 September 2015 Received in revised form 2 February 2016 Accepted 21 February 2016 Available online xxx
Background: Use of CT for assessment of extracellular volume fraction (ECV) is a new approach toward the evaluation of diffuse and focal myocardial fibrosis. It has recently been demonstrated that a hybrid algorithm of half- and full-scan reconstruction can improve image quality of delayed-phase CT. Objective: The purpose of this study was to evaluate reproducibility of CT measurement of ECV of the myocardium using pre-contrast and delayed-phase CT, and to investigate the association between ECV and location, age and gender in subjects without clinical coronary artery disease. Methods: Thirty-eight subjects (ages 45e78, mean 65 years, 14 females) without coronary artery stenosis, stress perfusion deficits or myocardial delayed enhancement on comprehensive cardiac CT comprise the study population. Delayed-phase CT was reconstructed with the hybrid algorithm. ECV was calculated as a ratio of the change in Hounsfield unit of the myocardium and the left ventricular (LV) blood before and after contrast administration, multiplied by (1 hematocrit). Results: Good inter- and intra-observer agreement was observed in CT measurement of ECV (intraclass correlation coefficient: 0.968 and 0.971, respectively). Mean ECV was 26.1 ± 2.0% (range 22.6e30.0%), and was positively related to age (r ¼ 0.46, p ¼ 0.003). Mean ECV in males was lower compared with females (25.5 ± 2.0% vs. 27.1 ± 1.8%, p ¼ 0.02). There was no statistically significant difference in ECV between anterior, septal, inferior, and lateral segments. Conclusions: CT measurement of myocardial ECV showed high inter- and intra-observer reproducibility, and age-related increase and gender-related difference of ECV were demonstrated. This might enable additional CT evaluation of diffuse and focal myocardial fibrosis in various pathological conditions as part of a comprehensive cardiac CT examination. © 2016 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.
Keywords: Computed tomography CT delayed enhancement Extracellular matrix Myocardial fibrosis Myocardial extracellular volume fraction
1. Introduction Extracellular volume fraction (ECV) can be derived from precontrast CT and delayed-phase CT with iodinated contrast medium1e4. However, quantification of ECV has been limited to selected segments of the myocardium due to poor contrast-to-noise ratio and frequent artifacts of myocardial CT delayed enhancement. We
Abbreviations and acronyms: CAD, coronary artery disease; CI, confidence interval; CT, computed tomography; ECV, extracellular volume fraction; HU, hounsfield unit; ICC, intraclass correlation coefficient; LOA, limit of agreement; LV, left ventricle; MRI, magnetic resonance imaging. * Corresponding author. Department of Radiology, Mie University Hospital, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan. E-mail address: [email protected] (K. Kitagawa).
recently developed a method to reduce artifacts in myocardial CT delayed enhancement5. Improved image quality may allow reproducible ECV measurement in all myocardial segments. The purpose of this study was to evaluate reproducibility of CT measurement of myocardial ECV using pre-contrast and delayedphase CT, and to investigate the association between ECV, and to compare the association between ECV and location, age and gender in subjects without clinical coronary artery disease (CAD). 2. Methods 2.1. Study population This study was approved by the institutional review board. Written informed consent for the participation in the
http://dx.doi.org/10.1016/j.jcct.2016.02.001 1934-5925/© 2016 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.
Please cite this article in press as: Kurita Y, et al., Estimation of myocardial extracellular volume fraction with cardiac CT in subjects without clinical coronary artery disease: A feasibility study, Journal of Cardiovascular Computed Tomography (2016), http://dx.doi.org/10.1016/ j.jcct.2016.02.001
2
Y. Kurita et al. / Journal of Cardiovascular Computed Tomography xxx (2016) 1e5
Fig. 1. Image acquisition timeline of our comprehensive cardiac CT study. Pre-contrast CT, stress dynamic CT perfusion, rest coronary CT angiography and delayed-phase CT were performed in 40 minutes.
Fig. 2. Acquisition of delayed-phase CT. Delayed-phase CT were acquired using “shuttle-mode” with tube voltage of 80 kVp and tube current of 370 mAs, and reconstructed with B23f kernel. Four image stacks were acquired during a breath holding to be averaged into one final stack.
Fig. 3. Process of generating a subtraction image dataset from pre-contrast CT and delayed-phase CT. A subtraction image dataset was generated from pre-contrast CT and delayedphase CT by using an automatic image registration function of 3D workstation. In this example, attenuation on the delayed-phase CT was 93.8HU and 143.1HU in the myocardium and LV blood, respectively. Attenuation on the subtraction image (¼DHU) was 44.3HU in the myocardium and 92.8HU in the LV blood.
Please cite this article in press as: Kurita Y, et al., Estimation of myocardial extracellular volume fraction with cardiac CT in subjects without clinical coronary artery disease: A feasibility study, Journal of Cardiovascular Computed Tomography (2016), http://dx.doi.org/10.1016/ j.jcct.2016.02.001
Y. Kurita et al. / Journal of Cardiovascular Computed Tomography xxx (2016) 1e5 Table 1 Baseline characteristics of the study population. Mean age, years Male sex, n (%) Body mass index, kg/m2 Normal, <25 kg/m2, n (%) Overweight, 25e30 kg/m2, n (%) Obese, 30e40 kg/m2, n (%) Risk factors Hypertension, n (%) Dyslipidemia, n (%) Diabetes, n (%) Smoking, n (%) History of coronary artery disease Prior known myocardial infarction, n (%) Prior PCI, n (%) Prior CABG, n (%) Estimated GFR (mL/min per 1.73 m2) Creatinine (mg/dL) Hematocrit (%)
65 ± 10 24 (63) 24.9 ± 4.4 21 (55) 11 (29) 6 (16) 25 18 15 18
(66) (47) (39) (47)
0 (0) 0 (0) 0 (0) 70 ± 12 0.81 ± 0.17 42 ± 5
Data are presented as mean ± standard deviation. CABG, coronary artery bypass grafting; PCI, percutaneous coronary intervention. GFR, glomerular filtration rate.
comprehensive cardiac CT study was obtained from each patient. Between March in 2012 and February in 2014, a total of 187 patients agreed to undergo comprehensive cardiac CT study as described in the method section. Inclusion criteria for the comprehensive cardiac protocol consisted of patients between 45 and 85 years old who were clinically referred for coronary CT angiography. Among them, we identified 48 subjects without high (100) calcium score, coronary artery stenosis, stress perfusion deficits or myocardial delayed enhancement. After exclusion of 9 subjects without hematocrit measurement within 2 months of CT study and 1 subject who was unable to hold the breath, 38 subjects comprise the study population. Median interval between hematocrit measurement and CT was 21.5 days (range 0 e 58 days). 2.2. CT Data acquisition and reconstruction All comprehensive cardiac CT examinations were performed using a second generation dual-source CT (Definition Flash, Siemens Healthcare, Forchheim, Germany). Pre-contrast and delayed-phase CT were performed as parts of comprehensive study including stress dynamic myocardial CT perfusion and resting coronary CTA (Fig.1). Pre-contrast CT images were acquired at end-systolic phase by using a method for acquiring delayed-phase CT as explained later. Contrast timing was determined by administering a test bolus of 10 mL of iopamidol (Iopamiron 370; Bayer-Schering Pharma, Berlin, Germany). Dynamic myocardial perfusion CT of 30 seconds at two alternate table positions6 was performed with adenosine administration and injection of 50 mL of iopamidol at a flow rate of 5 mL/ sec (a total of 120 ml of iopamidol), followed by 20 mL of saline. Prospectively electrocardiography-triggered coronary CT angiography was acquired 11 ± 2 minutes after the perfusion CT with Table 2 Radiation dose. Dose-length product Entire study protocol (mGy$cm) - Pre-contrast CT (mGy$cm) - Dynamic stress perfusion CT (mGy$cm) - Coronary CT angiography (mGy$cm) - Delayed-phase CT (mGy$cm) Estimated effective dose Entire study protocol (mSv)
3
60 mL of iopamidol. Seven minutes after the coronary CT angiography, end-systolic delayed-phase images were acquired without additional contrast medium administration, by using electrocardiography-triggered axial scan at two alternating table positions. Tube voltage and tube current setting was 80 kVp and 370 mAs. Four consecutive image stacks were acquired during one breath hold (Fig.2), and reconstructed with 1-mm slice thickness with a B23f kernel5. The four delayed-phase image stacks were, then, processed using a Volume Perfusion software (Syngo VPCT body, Siemens Healthcare, Forchheim, Germany) and averaged to one final image stack using non-rigid registration. The pre-contrast CT was performed with the same acquisition protocol used for delayed-phase CT. However, we acquired only one stack of pre-contrast CT to minimize radiation in the first 26 subjects (therefore, subsequent image averaging was not available), while in the other 12 subjects, acquisition and averaging of 4 stacks of pre-contrast CT were performed. 2.3. Image post-processing ECV was calculated with the following equation: ECV ¼ (DHUm/ DHUb)$(1Hct), where DHUm is the change in attenuation of the myocardium in Hounsfield unit (HU), DHUb is the change in attenuation of the blood, and Hct is the hematocrit level. The change in attenuation (DHU) was determined with the equation DHU ¼ HUdelayHUpre, where HUdelay and HUpre are attenuation at delayed-phase and pre-contrast CT, respectively1. In order to obtain DHU, pre-contrast images were subtracted from delayed-phase images on a workstation (Ziostation; Ziosoftware, Tokyo, Japan) using automatic image registration function employing rigid body alignment (Fig.3). The subtraction images were displayed in the cardiac short axis, and after manual determination of the subendocardial and subepicardial borders, the DHU in 16 American Heart Association myocardial segment were determined (Vitrea CT myocardial analysis, Vitral Images, Minnetonka, MN). DHUb was measured by placing a circular region of interest (200 mm2) in the LV cavity. The post-processing was performed by a radiologist. Intra- and inter-observer reproducibility were evaluated in randomly selected 20 subjects. 2.4. Estimation of radiation dose Effective radiation doses were estimated by multiplying the dose-length product reported by the scanner by a conversion factor of 0.014 mSv/mGy.cm7. 2.5. Statistical analysis Bland-Altman plot and intraclass correlation coefficients (ICC) were used to investigate intra- and interobserver variability. One way repeated measures analysis of variance was used to assess regional variation. We performed univariate analyses of the ECV versus age and gender. ICC were calculated with the IBM SPSS Statistics 21.0 (IBM Corporation, Armonk, NY). Other analyses were performed with the GraphPad PRISM 6 (GraphPad Software, Inc, La Jolla, CA).
784 ± 178 32 (fixed, n ¼ 26) 128 (fixed, n ¼ 12) 354 (282e453) 139 (107e191) 128 (fixed) 11.0 ± 2.5
3. Results 3.1. Baseline demographics and radiation dose Table 1 shows the baseline characteristics of the study population. There were 24 men (63%) and 14 women. The mean age of study subjects was 65 years (range 45 to 78 years).
Please cite this article in press as: Kurita Y, et al., Estimation of myocardial extracellular volume fraction with cardiac CT in subjects without clinical coronary artery disease: A feasibility study, Journal of Cardiovascular Computed Tomography (2016), http://dx.doi.org/10.1016/ j.jcct.2016.02.001
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Y. Kurita et al. / Journal of Cardiovascular Computed Tomography xxx (2016) 1e5
Fig. 4. Patient- and segment-based reproducibility of ECV. Bland-Altman plots showing patient-based inter- (A) and intra- (B) observer reproducibility and segment-based inter- (C) and intra- (D) observer reproducibility.
The mean dose-length product for the whole comprehensive cardiac examination was 784 ± 178 Gy cm, corresponding to an estimated effective dose of 11.0 ± 2.5 mSv (Table 2). Radiation dose for the ECV measurement (a total of pre-contrast CT and delayedphase CT) was 2.2 mSv in 26 subjects with acquisition of only one stack for pre-contrast CT and 3.6 mSv in 12 subjects with acquisition of 4 stacks. 3.2. Myocardial ECV and its reproducibility Average attenuation on the subtraction image (¼DHU) was
43.1 ± 7.0 and 95.4 ± 15.8 for the myocardium and LV blood, respectively. The average ECV in each subject was 26.1 ± 2.0% (range 22.6 to 30.0%). On patient-based analysis, the mean interobserver difference was 0.07 ± 0.82% (95% limits of agreement [LOA]: 1.68 to 1.54%) (Fig. 4a), the mean intraobserver difference was 0.28 ± 0.72% (95% LOA: 1.13 to 1.68%) (Fig. 4b). The ICC for the interobserver and intraobserver measurements of the ECV were 0.968 (95% confidence interval [CI]: 0.922 to 0.987) and 0.971 (95% CI: 0.929 to 0.989), respectively. On segment-based analysis, the mean interobserver difference was 0.10 ± 1.55% (95% LOA: 3.14 to 2.94%) (Fig. 4c), the mean intraobserver difference was
Fig. 5. Regional variation of myocardial extracellular volume fraction. Values are presented as mean ± standard deviation together with number of subjects available for analysis.
Please cite this article in press as: Kurita Y, et al., Estimation of myocardial extracellular volume fraction with cardiac CT in subjects without clinical coronary artery disease: A feasibility study, Journal of Cardiovascular Computed Tomography (2016), http://dx.doi.org/10.1016/ j.jcct.2016.02.001
Y. Kurita et al. / Journal of Cardiovascular Computed Tomography xxx (2016) 1e5
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not completely normal subjects, but subjects with risk factors of CAD and clear indication for cardiac CT. Since our protocol included stress CT perfusion, minor ECV increase due to adenosine-induced vasodilatation might exist15. 5. Conclusions Reproducible evaluation of ECV in 16 segments of LV myocardium is possible with cardiac CT and agrees well with existing MRI results. This might enable additional CT evaluation of diffuse and focal myocardial fibrosis in various pathological conditions as part of a comprehensive cardiac CT examination. Funding sources Fig. 6. Scatter plot showing relationship between age and extracellular volume fraction. Extracellular volume fraction showed significant positive linear correlation with age (r ¼ 0.46, p ¼ 0.003). Blue and red circles represent men and women, respectively. Dotted lines indicate 95% prediction intervals. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
0.29 ± 1.36% (95% LOA: 2.37 to 2.94%) (Fig. 4d). The ICC for the interobserver and intraobserver measurements of the ECV were 0.921 (95% CI: 0.900 to 0.937) and 0.937 (95% CI: 0.921 to 0.950), respectively. 3.4. Association between ECV and location, age and gender Myocardial ECV decreased progressively toward the apical region (26.6 ± 2.1% vs. 26.0 ± 2.0% vs. 25.6 ± 2.8%, basal, mid, and apical slices, respectively; p ¼ 0.001 for trend). There was no differences between anterior (AHA segment #1,7,13), septal (#2,3,8,9,14), inferior (#4,10,15), lateral (#5,6,11,12,16) segments (25.6 ± 2.0% vs. 26.2 ± 1.7% vs. 26.4 ± 3.2% vs. 26.1 ± 2.8%, anterior, septal, inferior, lateral segments, respectively; p ¼ 0.16) (Fig. 5). On patient-based analysis, the myocardial ECV was positively correlated with age (r ¼ 0.46, p ¼ 0.003, Fig. 6). Mean ECV in males was lower compared with females (25.5 ± 2.0% vs. 27.1 ± 1.8%, males vs. females, p ¼ 0.02). 4. Discussion In this study, we demonstrated that ECV determination is technically feasible as part of a comprehensive cardiac CT examination in a standard clinical context without extra contrast medium at a moderate dose level. Reproducibility is excellent to enable further clinical studies on patients with pathologies, and the CTderived ECV in this study (26.1 ± 2.0%) is in good agreement with previous reports using magnetic resonance imaging (MRI) (24.8 e 26.7%)8e11. Linear relationship between myocardial ECV and age, higher ECV in women, and no difference between ventricular segments within a short-axis slice are all in line with previous MRI reports10,12,13. We could not find higher ECV in septal myocardium which was observed in one MRI study9. Since no difference has been reported in ECV in the long-axis direction of the LV myocardium in previous MR study10, lower ECV in apical region observed in our study might be explained by residual artifactual variations of CT number, and further investigation is required. 4.1. Study limitation The sample size was small, and no histological or MRI validation was available although preliminary results demonstrated a good agreement with MRI (see Figure 1 in Ref14). Our study cohort was
This work was supported by JSPS KAKENHI Grant Number 25461812. Disclosures None. Acknowledgements This work was supported by JSPS KAKENHI Grant Number 25461812. The authors have nothing to disclose. References 1. Nacif MS, Kawel N, Lee JJ, et al. Interstitial Myocardial Fibrosis Assessed as Extracellular Volume Fraction with Low-Radiation-Dose Cardiac CT. Radiology. 2012. 2. Nacif MS, Liu Y, Yao J, et al. 3D left ventricular extracellular volume fraction by low-radiation dose cardiac CT: Assessment of interstitial myocardial fibrosis. J Cardiovasc Comput Tomogr. 2012. 3. Bandula S, White SK, Flett AS, et al. Measurement of Myocardial Extracellular Volume Fraction by Using Equilibrium Contrast-enhanced CT: Validation against Histologic Findings. Radiology. 2013. 4. Treibel TA, Bandula S, Fontana M, et al. Extracellular volume quantification by dynamic equilibrium cardiac computed tomography in cardiac amyloidosis. J Cardiovasc Comput Tomogr. 2015. 5. Kurobe Y, Kitagawa K, Ito T, et al. Myocardial delayed enhancement with dualsource CT: Advantages of targeted spatial frequency filtration and image averaging over half scan reconstruction. J Cardiovasc Comput Tomogr. 2014. 6. Bamberg F, Becker A, Schwarz F, et al. Detection of Hemodynamically Significant Coronary Artery Stenosis: Incremental Diagnostic Value of Dynamic CTbased Myocardial Perfusion Imaging. Radiology. 2011;260:689e698. 7. Halliburton SS, Abbara S, Chen MY, et al. SCCT guidelines on radiation dose and dose-optimization strategies in cardiovascular CT. J Cardiovasc Comput Tomogr. 2011;5:198e224. 8. Lee JJ, Liu S, Nacif MS, et al. Myocardial T1 and extracellular volume fraction mapping at 3 tesla. J Cardiovasc Magn Reson. 2011;13:75. 9. Kawel N, Nacif M, Zavodni A, et al. T1 mapping of the myocardium: intraindividual assessment of post-contrast T1 time evolution and extracellular volume fraction at 3T for Gd-DTPA and Gd-BOPTA. J Cardiovasc Magn Reson. 2012;14:26. 10. Neilan TG, Coelho-Filho OR, Shah RV, et al. Myocardial Extracellular Volume Fraction From T1 Measurements in Healthy Volunteers and Mice: Relationship to Aging and Cardiac Dimensions. JACC Cardiovasc Imaging. 2013;6:672e683. 11. Ugander M, Oki AJ, Hsu LY, et al. Extracellular volume imaging by magnetic resonance imaging provides insights into overt and sub-clinical myocardial pathology. Eur Heart J. 2012;33:1268e1278. 12. Liu CY, Liu YC, Wu C, et al. Evaluation of age-related interstitial myocardial fibrosis with cardiac magnetic resonance contrast-enhanced T1 mapping: MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol. 2013;62: 1280e1287. 13. Sado DM, Flett AS, Banypersad SM, et al. Cardiovascular magnetic resonance measurement of myocardial extracellular volume in health and disease. Heart. 2012;98:1436e1441. 14. Kurita Y, Kitagawa K, Kurobe Y et al. Correlation of myocardial extracellular volume derived with CT and MRI. Data in Brief. submitted. 15. Mahmod M, Piechnik SK, Levelt E, et al. Adenosine stress native T1 mapping in severe aortic stenosis: evidence for a role of the intravascular compartment on myocardial T1 values. J Cardiovasc Magn Reson. 2014;16:92.
Please cite this article in press as: Kurita Y, et al., Estimation of myocardial extracellular volume fraction with cardiac CT in subjects without clinical coronary artery disease: A feasibility study, Journal of Cardiovascular Computed Tomography (2016), http://dx.doi.org/10.1016/ j.jcct.2016.02.001
Contents lists available at ScienceDirect
Journal of Cardiovascular Computed Tomography journal homepage: www.JournalofCardiovascularCT.com
Short communication
Estimation of myocardial extracellular volume fraction with cardiac CT in subjects without clinical coronary artery disease: A feasibility study Yoshie Kurita a, Kakuya Kitagawa a, *, Yusuke Kurobe a, Shiro Nakamori b, Hiroshi Nakajima b, Kaoru Dohi b, Masaaki Ito b, Hajime Sakuma a a b
Department of Radiology, Mie University Hospital, Tsu, Japan Department of Cardiology, Mie University Hospital, Tsu, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 1 September 2015 Received in revised form 2 February 2016 Accepted 21 February 2016 Available online xxx
Background: Use of CT for assessment of extracellular volume fraction (ECV) is a new approach toward the evaluation of diffuse and focal myocardial fibrosis. It has recently been demonstrated that a hybrid algorithm of half- and full-scan reconstruction can improve image quality of delayed-phase CT. Objective: The purpose of this study was to evaluate reproducibility of CT measurement of ECV of the myocardium using pre-contrast and delayed-phase CT, and to investigate the association between ECV and location, age and gender in subjects without clinical coronary artery disease. Methods: Thirty-eight subjects (ages 45e78, mean 65 years, 14 females) without coronary artery stenosis, stress perfusion deficits or myocardial delayed enhancement on comprehensive cardiac CT comprise the study population. Delayed-phase CT was reconstructed with the hybrid algorithm. ECV was calculated as a ratio of the change in Hounsfield unit of the myocardium and the left ventricular (LV) blood before and after contrast administration, multiplied by (1 hematocrit). Results: Good inter- and intra-observer agreement was observed in CT measurement of ECV (intraclass correlation coefficient: 0.968 and 0.971, respectively). Mean ECV was 26.1 ± 2.0% (range 22.6e30.0%), and was positively related to age (r ¼ 0.46, p ¼ 0.003). Mean ECV in males was lower compared with females (25.5 ± 2.0% vs. 27.1 ± 1.8%, p ¼ 0.02). There was no statistically significant difference in ECV between anterior, septal, inferior, and lateral segments. Conclusions: CT measurement of myocardial ECV showed high inter- and intra-observer reproducibility, and age-related increase and gender-related difference of ECV were demonstrated. This might enable additional CT evaluation of diffuse and focal myocardial fibrosis in various pathological conditions as part of a comprehensive cardiac CT examination. © 2016 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.
Keywords: Computed tomography CT delayed enhancement Extracellular matrix Myocardial fibrosis Myocardial extracellular volume fraction
1. Introduction Extracellular volume fraction (ECV) can be derived from precontrast CT and delayed-phase CT with iodinated contrast medium1e4. However, quantification of ECV has been limited to selected segments of the myocardium due to poor contrast-to-noise ratio and frequent artifacts of myocardial CT delayed enhancement. We
Abbreviations and acronyms: CAD, coronary artery disease; CI, confidence interval; CT, computed tomography; ECV, extracellular volume fraction; HU, hounsfield unit; ICC, intraclass correlation coefficient; LOA, limit of agreement; LV, left ventricle; MRI, magnetic resonance imaging. * Corresponding author. Department of Radiology, Mie University Hospital, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan. E-mail address: [email protected] (K. Kitagawa).
recently developed a method to reduce artifacts in myocardial CT delayed enhancement5. Improved image quality may allow reproducible ECV measurement in all myocardial segments. The purpose of this study was to evaluate reproducibility of CT measurement of myocardial ECV using pre-contrast and delayedphase CT, and to investigate the association between ECV, and to compare the association between ECV and location, age and gender in subjects without clinical coronary artery disease (CAD). 2. Methods 2.1. Study population This study was approved by the institutional review board. Written informed consent for the participation in the
http://dx.doi.org/10.1016/j.jcct.2016.02.001 1934-5925/© 2016 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.
Please cite this article in press as: Kurita Y, et al., Estimation of myocardial extracellular volume fraction with cardiac CT in subjects without clinical coronary artery disease: A feasibility study, Journal of Cardiovascular Computed Tomography (2016), http://dx.doi.org/10.1016/ j.jcct.2016.02.001
2
Y. Kurita et al. / Journal of Cardiovascular Computed Tomography xxx (2016) 1e5
Fig. 1. Image acquisition timeline of our comprehensive cardiac CT study. Pre-contrast CT, stress dynamic CT perfusion, rest coronary CT angiography and delayed-phase CT were performed in 40 minutes.
Fig. 2. Acquisition of delayed-phase CT. Delayed-phase CT were acquired using “shuttle-mode” with tube voltage of 80 kVp and tube current of 370 mAs, and reconstructed with B23f kernel. Four image stacks were acquired during a breath holding to be averaged into one final stack.
Fig. 3. Process of generating a subtraction image dataset from pre-contrast CT and delayed-phase CT. A subtraction image dataset was generated from pre-contrast CT and delayedphase CT by using an automatic image registration function of 3D workstation. In this example, attenuation on the delayed-phase CT was 93.8HU and 143.1HU in the myocardium and LV blood, respectively. Attenuation on the subtraction image (¼DHU) was 44.3HU in the myocardium and 92.8HU in the LV blood.
Please cite this article in press as: Kurita Y, et al., Estimation of myocardial extracellular volume fraction with cardiac CT in subjects without clinical coronary artery disease: A feasibility study, Journal of Cardiovascular Computed Tomography (2016), http://dx.doi.org/10.1016/ j.jcct.2016.02.001
Y. Kurita et al. / Journal of Cardiovascular Computed Tomography xxx (2016) 1e5 Table 1 Baseline characteristics of the study population. Mean age, years Male sex, n (%) Body mass index, kg/m2 Normal, <25 kg/m2, n (%) Overweight, 25e30 kg/m2, n (%) Obese, 30e40 kg/m2, n (%) Risk factors Hypertension, n (%) Dyslipidemia, n (%) Diabetes, n (%) Smoking, n (%) History of coronary artery disease Prior known myocardial infarction, n (%) Prior PCI, n (%) Prior CABG, n (%) Estimated GFR (mL/min per 1.73 m2) Creatinine (mg/dL) Hematocrit (%)
65 ± 10 24 (63) 24.9 ± 4.4 21 (55) 11 (29) 6 (16) 25 18 15 18
(66) (47) (39) (47)
0 (0) 0 (0) 0 (0) 70 ± 12 0.81 ± 0.17 42 ± 5
Data are presented as mean ± standard deviation. CABG, coronary artery bypass grafting; PCI, percutaneous coronary intervention. GFR, glomerular filtration rate.
comprehensive cardiac CT study was obtained from each patient. Between March in 2012 and February in 2014, a total of 187 patients agreed to undergo comprehensive cardiac CT study as described in the method section. Inclusion criteria for the comprehensive cardiac protocol consisted of patients between 45 and 85 years old who were clinically referred for coronary CT angiography. Among them, we identified 48 subjects without high (100) calcium score, coronary artery stenosis, stress perfusion deficits or myocardial delayed enhancement. After exclusion of 9 subjects without hematocrit measurement within 2 months of CT study and 1 subject who was unable to hold the breath, 38 subjects comprise the study population. Median interval between hematocrit measurement and CT was 21.5 days (range 0 e 58 days). 2.2. CT Data acquisition and reconstruction All comprehensive cardiac CT examinations were performed using a second generation dual-source CT (Definition Flash, Siemens Healthcare, Forchheim, Germany). Pre-contrast and delayed-phase CT were performed as parts of comprehensive study including stress dynamic myocardial CT perfusion and resting coronary CTA (Fig.1). Pre-contrast CT images were acquired at end-systolic phase by using a method for acquiring delayed-phase CT as explained later. Contrast timing was determined by administering a test bolus of 10 mL of iopamidol (Iopamiron 370; Bayer-Schering Pharma, Berlin, Germany). Dynamic myocardial perfusion CT of 30 seconds at two alternate table positions6 was performed with adenosine administration and injection of 50 mL of iopamidol at a flow rate of 5 mL/ sec (a total of 120 ml of iopamidol), followed by 20 mL of saline. Prospectively electrocardiography-triggered coronary CT angiography was acquired 11 ± 2 minutes after the perfusion CT with Table 2 Radiation dose. Dose-length product Entire study protocol (mGy$cm) - Pre-contrast CT (mGy$cm) - Dynamic stress perfusion CT (mGy$cm) - Coronary CT angiography (mGy$cm) - Delayed-phase CT (mGy$cm) Estimated effective dose Entire study protocol (mSv)
3
60 mL of iopamidol. Seven minutes after the coronary CT angiography, end-systolic delayed-phase images were acquired without additional contrast medium administration, by using electrocardiography-triggered axial scan at two alternating table positions. Tube voltage and tube current setting was 80 kVp and 370 mAs. Four consecutive image stacks were acquired during one breath hold (Fig.2), and reconstructed with 1-mm slice thickness with a B23f kernel5. The four delayed-phase image stacks were, then, processed using a Volume Perfusion software (Syngo VPCT body, Siemens Healthcare, Forchheim, Germany) and averaged to one final image stack using non-rigid registration. The pre-contrast CT was performed with the same acquisition protocol used for delayed-phase CT. However, we acquired only one stack of pre-contrast CT to minimize radiation in the first 26 subjects (therefore, subsequent image averaging was not available), while in the other 12 subjects, acquisition and averaging of 4 stacks of pre-contrast CT were performed. 2.3. Image post-processing ECV was calculated with the following equation: ECV ¼ (DHUm/ DHUb)$(1Hct), where DHUm is the change in attenuation of the myocardium in Hounsfield unit (HU), DHUb is the change in attenuation of the blood, and Hct is the hematocrit level. The change in attenuation (DHU) was determined with the equation DHU ¼ HUdelayHUpre, where HUdelay and HUpre are attenuation at delayed-phase and pre-contrast CT, respectively1. In order to obtain DHU, pre-contrast images were subtracted from delayed-phase images on a workstation (Ziostation; Ziosoftware, Tokyo, Japan) using automatic image registration function employing rigid body alignment (Fig.3). The subtraction images were displayed in the cardiac short axis, and after manual determination of the subendocardial and subepicardial borders, the DHU in 16 American Heart Association myocardial segment were determined (Vitrea CT myocardial analysis, Vitral Images, Minnetonka, MN). DHUb was measured by placing a circular region of interest (200 mm2) in the LV cavity. The post-processing was performed by a radiologist. Intra- and inter-observer reproducibility were evaluated in randomly selected 20 subjects. 2.4. Estimation of radiation dose Effective radiation doses were estimated by multiplying the dose-length product reported by the scanner by a conversion factor of 0.014 mSv/mGy.cm7. 2.5. Statistical analysis Bland-Altman plot and intraclass correlation coefficients (ICC) were used to investigate intra- and interobserver variability. One way repeated measures analysis of variance was used to assess regional variation. We performed univariate analyses of the ECV versus age and gender. ICC were calculated with the IBM SPSS Statistics 21.0 (IBM Corporation, Armonk, NY). Other analyses were performed with the GraphPad PRISM 6 (GraphPad Software, Inc, La Jolla, CA).
784 ± 178 32 (fixed, n ¼ 26) 128 (fixed, n ¼ 12) 354 (282e453) 139 (107e191) 128 (fixed) 11.0 ± 2.5
3. Results 3.1. Baseline demographics and radiation dose Table 1 shows the baseline characteristics of the study population. There were 24 men (63%) and 14 women. The mean age of study subjects was 65 years (range 45 to 78 years).
Please cite this article in press as: Kurita Y, et al., Estimation of myocardial extracellular volume fraction with cardiac CT in subjects without clinical coronary artery disease: A feasibility study, Journal of Cardiovascular Computed Tomography (2016), http://dx.doi.org/10.1016/ j.jcct.2016.02.001
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Y. Kurita et al. / Journal of Cardiovascular Computed Tomography xxx (2016) 1e5
Fig. 4. Patient- and segment-based reproducibility of ECV. Bland-Altman plots showing patient-based inter- (A) and intra- (B) observer reproducibility and segment-based inter- (C) and intra- (D) observer reproducibility.
The mean dose-length product for the whole comprehensive cardiac examination was 784 ± 178 Gy cm, corresponding to an estimated effective dose of 11.0 ± 2.5 mSv (Table 2). Radiation dose for the ECV measurement (a total of pre-contrast CT and delayedphase CT) was 2.2 mSv in 26 subjects with acquisition of only one stack for pre-contrast CT and 3.6 mSv in 12 subjects with acquisition of 4 stacks. 3.2. Myocardial ECV and its reproducibility Average attenuation on the subtraction image (¼DHU) was
43.1 ± 7.0 and 95.4 ± 15.8 for the myocardium and LV blood, respectively. The average ECV in each subject was 26.1 ± 2.0% (range 22.6 to 30.0%). On patient-based analysis, the mean interobserver difference was 0.07 ± 0.82% (95% limits of agreement [LOA]: 1.68 to 1.54%) (Fig. 4a), the mean intraobserver difference was 0.28 ± 0.72% (95% LOA: 1.13 to 1.68%) (Fig. 4b). The ICC for the interobserver and intraobserver measurements of the ECV were 0.968 (95% confidence interval [CI]: 0.922 to 0.987) and 0.971 (95% CI: 0.929 to 0.989), respectively. On segment-based analysis, the mean interobserver difference was 0.10 ± 1.55% (95% LOA: 3.14 to 2.94%) (Fig. 4c), the mean intraobserver difference was
Fig. 5. Regional variation of myocardial extracellular volume fraction. Values are presented as mean ± standard deviation together with number of subjects available for analysis.
Please cite this article in press as: Kurita Y, et al., Estimation of myocardial extracellular volume fraction with cardiac CT in subjects without clinical coronary artery disease: A feasibility study, Journal of Cardiovascular Computed Tomography (2016), http://dx.doi.org/10.1016/ j.jcct.2016.02.001
Y. Kurita et al. / Journal of Cardiovascular Computed Tomography xxx (2016) 1e5
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not completely normal subjects, but subjects with risk factors of CAD and clear indication for cardiac CT. Since our protocol included stress CT perfusion, minor ECV increase due to adenosine-induced vasodilatation might exist15. 5. Conclusions Reproducible evaluation of ECV in 16 segments of LV myocardium is possible with cardiac CT and agrees well with existing MRI results. This might enable additional CT evaluation of diffuse and focal myocardial fibrosis in various pathological conditions as part of a comprehensive cardiac CT examination. Funding sources Fig. 6. Scatter plot showing relationship between age and extracellular volume fraction. Extracellular volume fraction showed significant positive linear correlation with age (r ¼ 0.46, p ¼ 0.003). Blue and red circles represent men and women, respectively. Dotted lines indicate 95% prediction intervals. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
0.29 ± 1.36% (95% LOA: 2.37 to 2.94%) (Fig. 4d). The ICC for the interobserver and intraobserver measurements of the ECV were 0.921 (95% CI: 0.900 to 0.937) and 0.937 (95% CI: 0.921 to 0.950), respectively. 3.4. Association between ECV and location, age and gender Myocardial ECV decreased progressively toward the apical region (26.6 ± 2.1% vs. 26.0 ± 2.0% vs. 25.6 ± 2.8%, basal, mid, and apical slices, respectively; p ¼ 0.001 for trend). There was no differences between anterior (AHA segment #1,7,13), septal (#2,3,8,9,14), inferior (#4,10,15), lateral (#5,6,11,12,16) segments (25.6 ± 2.0% vs. 26.2 ± 1.7% vs. 26.4 ± 3.2% vs. 26.1 ± 2.8%, anterior, septal, inferior, lateral segments, respectively; p ¼ 0.16) (Fig. 5). On patient-based analysis, the myocardial ECV was positively correlated with age (r ¼ 0.46, p ¼ 0.003, Fig. 6). Mean ECV in males was lower compared with females (25.5 ± 2.0% vs. 27.1 ± 1.8%, males vs. females, p ¼ 0.02). 4. Discussion In this study, we demonstrated that ECV determination is technically feasible as part of a comprehensive cardiac CT examination in a standard clinical context without extra contrast medium at a moderate dose level. Reproducibility is excellent to enable further clinical studies on patients with pathologies, and the CTderived ECV in this study (26.1 ± 2.0%) is in good agreement with previous reports using magnetic resonance imaging (MRI) (24.8 e 26.7%)8e11. Linear relationship between myocardial ECV and age, higher ECV in women, and no difference between ventricular segments within a short-axis slice are all in line with previous MRI reports10,12,13. We could not find higher ECV in septal myocardium which was observed in one MRI study9. Since no difference has been reported in ECV in the long-axis direction of the LV myocardium in previous MR study10, lower ECV in apical region observed in our study might be explained by residual artifactual variations of CT number, and further investigation is required. 4.1. Study limitation The sample size was small, and no histological or MRI validation was available although preliminary results demonstrated a good agreement with MRI (see Figure 1 in Ref14). Our study cohort was
This work was supported by JSPS KAKENHI Grant Number 25461812. Disclosures None. Acknowledgements This work was supported by JSPS KAKENHI Grant Number 25461812. The authors have nothing to disclose. References 1. Nacif MS, Kawel N, Lee JJ, et al. Interstitial Myocardial Fibrosis Assessed as Extracellular Volume Fraction with Low-Radiation-Dose Cardiac CT. Radiology. 2012. 2. Nacif MS, Liu Y, Yao J, et al. 3D left ventricular extracellular volume fraction by low-radiation dose cardiac CT: Assessment of interstitial myocardial fibrosis. J Cardiovasc Comput Tomogr. 2012. 3. Bandula S, White SK, Flett AS, et al. Measurement of Myocardial Extracellular Volume Fraction by Using Equilibrium Contrast-enhanced CT: Validation against Histologic Findings. Radiology. 2013. 4. Treibel TA, Bandula S, Fontana M, et al. Extracellular volume quantification by dynamic equilibrium cardiac computed tomography in cardiac amyloidosis. J Cardiovasc Comput Tomogr. 2015. 5. Kurobe Y, Kitagawa K, Ito T, et al. Myocardial delayed enhancement with dualsource CT: Advantages of targeted spatial frequency filtration and image averaging over half scan reconstruction. J Cardiovasc Comput Tomogr. 2014. 6. Bamberg F, Becker A, Schwarz F, et al. Detection of Hemodynamically Significant Coronary Artery Stenosis: Incremental Diagnostic Value of Dynamic CTbased Myocardial Perfusion Imaging. Radiology. 2011;260:689e698. 7. Halliburton SS, Abbara S, Chen MY, et al. SCCT guidelines on radiation dose and dose-optimization strategies in cardiovascular CT. J Cardiovasc Comput Tomogr. 2011;5:198e224. 8. Lee JJ, Liu S, Nacif MS, et al. Myocardial T1 and extracellular volume fraction mapping at 3 tesla. J Cardiovasc Magn Reson. 2011;13:75. 9. Kawel N, Nacif M, Zavodni A, et al. T1 mapping of the myocardium: intraindividual assessment of post-contrast T1 time evolution and extracellular volume fraction at 3T for Gd-DTPA and Gd-BOPTA. J Cardiovasc Magn Reson. 2012;14:26. 10. Neilan TG, Coelho-Filho OR, Shah RV, et al. Myocardial Extracellular Volume Fraction From T1 Measurements in Healthy Volunteers and Mice: Relationship to Aging and Cardiac Dimensions. JACC Cardiovasc Imaging. 2013;6:672e683. 11. Ugander M, Oki AJ, Hsu LY, et al. Extracellular volume imaging by magnetic resonance imaging provides insights into overt and sub-clinical myocardial pathology. Eur Heart J. 2012;33:1268e1278. 12. Liu CY, Liu YC, Wu C, et al. Evaluation of age-related interstitial myocardial fibrosis with cardiac magnetic resonance contrast-enhanced T1 mapping: MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol. 2013;62: 1280e1287. 13. Sado DM, Flett AS, Banypersad SM, et al. Cardiovascular magnetic resonance measurement of myocardial extracellular volume in health and disease. Heart. 2012;98:1436e1441. 14. Kurita Y, Kitagawa K, Kurobe Y et al. Correlation of myocardial extracellular volume derived with CT and MRI. Data in Brief. submitted. 15. Mahmod M, Piechnik SK, Levelt E, et al. Adenosine stress native T1 mapping in severe aortic stenosis: evidence for a role of the intravascular compartment on myocardial T1 values. J Cardiovasc Magn Reson. 2014;16:92.
Please cite this article in press as: Kurita Y, et al., Estimation of myocardial extracellular volume fraction with cardiac CT in subjects without clinical coronary artery disease: A feasibility study, Journal of Cardiovascular Computed Tomography (2016), http://dx.doi.org/10.1016/ j.jcct.2016.02.001