Choosing The Adaptive Cardiac Phase for Assessing Cardiac Dimensions Using Cardiac Computed Tomography for Heart Disease

Background: Choosing a suitable cardiac cycle to measure cardiac chamber dimensions and wall thickness can be a more accurate assessment of cardiovascular disease. Methods: Cardiac CT was performed on 137 patients for suspected coronary disease. The parameters of left atrium (LA), left ventricle (LV), right atrium (RA), and right ventricle (RV), as well as the wall thickness of LV were measured in different cardiac phases. The general linear mixed model was used to analyze differences in different phases and the correlation between these parameters and traditional risk factors. ROC analysis was performed to estimate LA enlargement. Results:The dimensions of LA, RA, and LV wall thickness achieved the maximum at the phase of 35%–45%, and the dimensions of LV and RV reached the maximum at 95%–5%. Whereas, the changes of LA-B (antero-posterior diameter), LV-D1 (basal dimension), RA-B (minor dimension) and RV-D2 (mid cavity dimension) were relatively more stable during the cardiac cycle. The maximum LA-B diameter(95%CI 36.92,38.48mm), LV-D1 diameter(95%CI 44.36,45.83mm), RA-B diameter(95%CI 48.75,50.61mm), and RV-D2 diameter(95%CI 30.83,32.84mm) and the maximum interventricular septum thickness( 95%CI 10.79,11.51mm) was acquired. Heart rate (HR) and smoking were potential indicators of LVD2 (mid cavity dimension), while HR and LV myocardial mass were potential indicators of LVD3 (apical-basal dimension). In phase 45%, the cut-off value of LA-A with 77.57mm has high specicity. Conclusion: Cardiac chamber dimensions and wall thickness vary with the cardiac phase. Choosing the adaptive cardiac phase for evaluating these parameters obtained by cardiac CT could provide a more accurate clinical measurement. end-diastole 9,10 . Moreover, different researchers have set different time points for systole and diastole in the cardiac cycle. This makes the assessment of the cardiac chamber dimensions inconsistent in the cardiac phase and results in different dimensions for the same structure. This would therefore lead to an inaccurate evaluation of the cardiac chamber dimensions and LV wall thickness. To date, there are no reports of measuring the cardiac chamber diameter and LV wall thickness of ten different cardiac cycles. Therefore, the rst aim of our study was to assess the dynamic changes of the cardiac chamber dimensions and wall thickness in ten cardiac phases. We used a more detailed division of cardiac cycles compared with other studies and information on accurate cardiac phases for the measurement of the maximum diameter, which is required to diagnose cardiac disease. The another purpose of our study was to explore which diameters of the four cardiac chambers were most stable with changes in cardiac cycle. view are the only recommended methods for assessing RA size 23 . RV function is an independent determinant of clinical status and prognosis in a number of pathologies, but its accurate quantication remains a challenge. As compared with LV, the unique features of the RV are its complex geometry, its wider range of loading conditions, and its greater heterogeneity of regional function. RV failure is usually caused by left heart dysfunction. Both conditions coexist 24 . Ventricular interdependence is not only manifested in function, but also in size, which is more obvious in diastole.


Introduction
The heart is a hollow organ at the center of the circulatory system. Rhythmic contractions and dilations by the contraction of myocardial cells pump the blood. Assessing the dimensions of the cardiac chambers is useful for diagnosis of cardiac disease, risk strati cation, and therapeutic decision making. For example, left atrial (LA) enlargement is associated with an increased risk of adverse cardiovascular events, such as atrial brillation, myocardial infarction, congestive heart failure, and stroke 1,2 . Left ventricular (LV) enlargement is associated with an array of cardiac pathologies, including cardiomyopathy, ischemia, and valvular heart disease. These conditions can remain clinically silent until late in their progression. It is therefore important to recognize changes in cardiac chamber dimensions early in the course of these diseases. Additionally, LV wall thickness is a predictor of mortality and morbidity in heart disease and can aid decision making in some clinical guidelines 3 . Right heart function is an independent determinant of clinical status and prognosis in many congenital and acquired disease states. Therefore, obtaining accurate diameters of the cardiac chambers is crucial to clinical decision-making, intervention, and operation decisions for cardiac diseases. Since the enlargement of the LA was more signi cant, we also measured this group of patients.
Considering these factors, there are many imaging approaches for evaluating the size of the cardiac chambers. Echocardiography is the most commonly used noninvasive modality, but it is heavily dependent on the sonographer's skills and has poor repeatability. Cardiac MRI is considered the reference standard for evaluating cardiac size and function, but it is costly and time-consuming 4 . Therefore, cardiac MRI is rarely performed as an initial investigation for evaluating cardiac size. Cardiac computed tomography (CT) is performed with retrospective electrocardiography (ECG) gating could provide heart images with high time resolution, and reconstruct multi-phase images of the cardiac cycle 5,6 . It can comprehensively evaluate lesions that cause the heart to enlarge for many reasons, and is emerging as a promising tool with respect to quantifying chamber volumes and cardiac structure 7,8 .
It is well-known that cardiac chamber dimensions and LV wall thickness change with the cardiac cycle, but the law is unknown. When the cardiac diameter is largest or smallest, and which is the best cardiac phase to evaluate the chamber size and wall thickness are also ambiguous. In recent years, many scholars have studied how cardiac chamber dimensions change with the cardiac cycle on CT, but most studies of cardiac chamber size have focused on end-systole and end-diastole 9,10 . Moreover, different researchers have set different time points for systole and diastole in the cardiac cycle. This makes the assessment of the cardiac chamber dimensions inconsistent in the cardiac phase and results in different dimensions for the same structure. This would therefore lead to an inaccurate evaluation of the cardiac chamber dimensions and LV wall thickness. To date, there are no reports of measuring the cardiac chamber diameter and LV wall thickness of ten different cardiac cycles. Therefore, the rst aim of our study was to assess the dynamic changes of the cardiac chamber dimensions and wall thickness in ten cardiac phases. We used a more detailed division of cardiac cycles compared with other studies and information on accurate cardiac phases for the measurement of the maximum diameter, which is required to diagnose cardiac disease. The another purpose of our study was to explore which diameters of the four cardiac chambers were most stable with changes in cardiac cycle.

Methods
This study was conducted in accordance with the the Declaration of Helsinki (2000 EDITION), and an application for the exemption of patients' informed consent was approved by the Institutional Review Board of our hospital, due to the retrospective nature of the study. So all written informed consent forms are waived.

Patient selection
Two hundred consecutive patients underwent cardiac CT scans for suspected coronary disease between August and December 2019. Patients with normal cardiac chamber dimensions or LA enlargement on echocardiography (within three months of the CT study) and who were at least 18 years of age were enrolled. Exclusion criteria included patients with severe arrhythmia, pacemakers, cardiovascular surgical procedures, known heart disease and motion artifact. Patients with structural or functional abnormalities of the heart detected by echocardiography were also excluded.

CT scanning protocol
All CT angiography (CTA) scans were acquired using a 256-slice scanner (Philips Brilliance iCT; Philips Medical Systems, Cleveland, OH, USA) with retrospective ECG-gating. The scanning range is from the bifurcation of the pulmonary artery to the level of the diaphragm with a thickness of 0.5 cm.
The scan is automatically triggered by setting the region of interest in the descending aorta (the threshold value was set as 250 Houns eld units [Hu]). A high-pressure syringe was used to inject 75-85 mL of contrast agent (Iopamidol 370 mg/mL) through the elbow vein. Subsequently, 40 mL of physiological saline was injected at the same rate with a ow rate of 5.0-5.5 mL/s. We used 120 kv for patients with body weight ≥ 75 kg, 100 kV for patients with body weight < 75 kg, 1200 mAs/slice for patients with body mass index (BMI) ≥ 24, and 900 mAs/slice for patients with BMI < 24.

Image analysis
Multi-phase reconstructions were done from 5-95% in increments of 10% on a 256-slice spiral CT scanning workstation. The reconstruction vision of 10 cardiac cycles was extended to the entire thorax. All images were transferred to a post-processing workstation (Philips Intelli Space Portal system) and loaded into the cardiac viewer application. Two experienced observers (both with three years of experience in the interpretation of cardiac CT images) who were blinded to the echocardiographic data independently reviewed the reconstructed CT images on a dedicated post-processing workstation.
The left atrial maximum transverse diameter (LA-A) and antero-posterior diameter (LA-B) were to be traced manually on an image showing the right inferior pulmonary vein insertion 11 . The thoracic vertebral diameter was measured at the same level 12 . The left atrial-vertebral ratio (LAssVR) was then obtained by dividing the LA diameter by the vertebral diameter (Fig. 1A). The left ventricular basal dimension (LVD1), mid cavity dimension (LVD2) and apical-basal dimension (LVD3) in different cardiac phases were measured in the long-axis view of LV 13 (Fig. 1D). LV wall thickness(including 16 segmentations) at the basal, mid, and apical segments in different cardiac phases were measured in the short-axis view of the LV (Fig. 1C). The right atrial major dimension (RA-A), minor dimension (RA-B), right ventricular basal dimension (RVD1), mid cavity dimension (RVD2), and apical-basal dimension (RVD3) in different cardiac phases were measured in the apical four-chamber multiplanar reconstruction view 14,15 (Fig. 1B).

Statistical analysis
The statistical software package R (Version 3.6.1; R Core Team, 2019) was used to perform analyses. Qualitative data were expressed by frequency and percentage, while quantitative data were expressed by mean ± standard deviation. Differences in wall thickness and cardiac chamber dimensions between cardiac cycles were detected using linear mixed model. The relationship between LV-D2/LV-D3 and clinical characteristics were also estimated by linear mixed model. ROC analyze together with area under curve, sensitivity and speci city were used to estimate the diagnosis value of single and combined parameters for left atrial enlargement. Intra-and inter-observer variability for reproducibility were assessed using intraclass correlation coe cient (ICCs). The signi cance level was set at p < 0.05.

Baseline characteristics
We enrolled a total of 126 subjects (65 males and 61 females, mean age 55 years, range 47-77 years) with normal chamber dimensions and 118 subjects (61 men and 57 women, mean age 54 years, range 30-77 years) with normal wall thickness, 11 patients( 6 men and 5 women, mean age 58 years, range 55-74 years) with LA enlargement. Table 1 shows the clinical characteristics of the study population.       Table 2 list the mean ± sd of LV chamber dimensions (LVD1, LVD2, LVD3) in different cardiac phases, Fig. 2A shows Results from univariate analysis revealed that body surface area (BSA), heart rate (HR), LV-myocardial mass (LVMM), smoking, and diabetes were signi cantly related to LV-D2 and LV-D3 (Table 3). Multivariate analysis demonstrated that HR and smoking were potential indicators of LV-D2, and that HR and LVMM were potential indicators of LV-D3. One unit change in HR was associated with 0.187 unit decrease in the LV-D2. The average LV-D2 of smokers is 2.830 mm higher than that of non-smokers. The other variables were not signi cantly related to LV-D2. One unit change in HR was associated with 0.164 unit decease in the LV-D3, while one unit change in LVMM was associated with 0.124 unit increase in the LV-D3. Abbreviations as in Table 1   Table 4 lists the mean ± sd of LV wall thickness at the basal, mid, and apical segments in different cardiac phases. Figure 10.60 ± 2.14 mm, and 9.15 ± 2.03 mm, respectively. The variation of Septum, Ant, Ant-Lat, and Inf in the cardiac cycles were of statistical signi cance. In the three segments, the wall changes of the basal segment were the more stable than middle and apical segments.    In addition, the comparison of clinical characteristics and cardiac parameters between male and female subjects revealed signi cant discrepancy in individual characteristics, including age, BSA, HR, LVMM, smoking, drinking, and diabetes. These differences were also signi cantly related to gender.

RV parameters in different cardiac cycles
Upper and lower reference limits were higher in men than in women. Therefore, we generated cardiac parameters reference ranges on cardiac CT in different cardiac phases for both genders for our population in supplemental material.

Reproducibility
Inter-and intraobserver ICCs were determined randomly among 126 patients.

Discussion
This is the rst study to conduct a detailed dynamic evaluation of the cardiac chamber dimensions and wall thickness with the reconstruction of ten cardiac phases in whole cardiac cycle. This allows us to choose the correct cardiac phase for measuring the maximum diameter required to predict cardiac disease. The dimensions of the cardiac chamber and wall thickness changes dynamically in different cardiac phases and match the physiological phase of that cycle 16 . We also found that LA-B, LV-D1, RA-B and RV-D2 were more stable than other diameters in the cardiac cycle. Therefore, we believe that the four diameters are most suitable for evaluating the condition of the heart on noncardiac CT images.
LA size is a marker of the severity and chronicity of diastolic dysfunction 17 . These LA diameters measured on a conventional axial cross-section can be used for detecting of patients with possible LA enlargement on routine chest CTA, prompting con rmatory evaluation with echocardiography. LV is an integral part of the heart's pumping function. Historically, linear dimension of LV was measured at the base of the LV in the long-axis view.
However, the base of the LV does not re ect the true (maximal) diameter of the ellipsoid mode, leading to underestimation of chamber size 19 .
Measurement of linear dimensions at the midventricular level (LV-D2) better re ects the ellipsoid geometry of the LV cavity and provides a more accurate estimate of LV mass and size as compared with the traditionally recommended basal level 13 . In addition, the LV contains obliquely-oriented myo bers super cially, longitudinally-oriented myo bers in the subendocardium, and predominantly circular bers in between. This contributes to the more complex movement of the LV, including torsion, translation, rotation, and thickening 20 . It is di cult to comprehensively evaluate the size of the chamber using a single diameter measurement method. Therefore, in this study, we measured three dimensions of LV in different cardiac phases. Multivariate analysis demonstrated that HR and smoking are potential indicators of LV-D2. HR and LVMM are potential indicators of LV-D3.
The ventricular septum is the central structure of both ventricles.The helical ventricular band model explains the close relationship between biventricular function and ventricular septum 21 . Perhaps this is one of the reasons why myocardial wall hypertrophy rst appears as ventricular septal hypertrophy. In this study, the ventricular septum thickness was signi cantly related to age and hypertension.
There is increasing evidence that RA enlargement is an outcome predictor in various cardiac conditions 22 . To date, diameters and areas measured in the apical four-chamber view are the only recommended methods for assessing RA size 23 .
RV function is an independent determinant of clinical status and prognosis in a number of pathologies, but its accurate quanti cation remains a challenge. As compared with LV, the unique features of the RV are its complex geometry, its wider range of loading conditions, and its greater heterogeneity of regional function. RV failure is usually caused by left heart dysfunction. Both conditions coexist 24 . Ventricular interdependence is not only manifested in function, but also in size, which is more obvious in diastole.

Limitations
The most obvious limitation of this study was the radiation dose generated by using CT. However, the radiation dose was at a safe level and CT was necessary for evaluating coronary artery disease. Moreover, it was a cross-sectional study, and only patients with clear image qualities were evaluated.
Our research requires further follow-up.

Conclusion
This study provides applicable quanti cation cardiac CT cardiac chamber dimensions and LV wall thickness reference ranges in different cardiac phases. Reconstruction and measurement performed in the maximum phase using cardiac CT could result in a more accurate diameter in cardiac disease assessment during the varied cardiac cycle. Declarations