==== Front Chin Med J (Engl)Chin. Med. JCMJChinese Medical Journal0366-6999Medknow Publications & Media Pvt Ltd India 30058581CMJ-131-183410.4103/0366-6999.237395Original ArticleExcitation-Contraction Coupling Time is More Sensitive in Evaluating Cardiac Systolic Function 心肌电-机械耦联参数评价心脏收缩功能的优越性 Gao Juan 1Zhu Min 1Yu Hai-Yi 1Wang Shi-Qiang 2Feng Xin-Heng 1Xu Ming 11 Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing 100191, China2 State Key Laboratory of Membrane Biology, College of Life Sciences, Peking University, Beijing 100871, ChinaAddress for correspondence: Dr. Ming Xu, Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Key Laboratory of Molecular Cardiovascular Sciences of Ministry of Education, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Beijing 100191, China E-Mail: xuminghi@bjmu.edu.cn05 8 2018 131 15 1834 1839 12 3 2018 Copyright: © 2018 Chinese Medical Journal2018This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Background: Pressure overload-induced myocardial hypertrophy is a key step leading to heart failure. Previous cellular and animal studies demonstrated that deteriorated excitation–contraction coupling occurs as early as the compensated stage of hypertrophy before the global decrease in left ventricular ejection fraction (LVEF). This study was to evaluate the cardiac electromechanical coupling time in evaluating cardiac systolic function in the early stage of heart failure. Methods: Twenty-six patients with Stage B heart failure (SBHF) and 31 healthy controls (CONs) were enrolled in this study. M-mode echocardiography was performed to measure LVEF. Tissue Doppler imaging (TDI) combined with electrocardiography (ECG) was used to measure cardiac electromechanical coupling time. Results: There was no significant difference in LVEF between SBHF patients and CONs (64.23 ± 8.91% vs. 64.52 ± 5.90%; P = 0.886). However, all four electromechanical coupling time courses (Qsb: onset of Q wave on ECG to beginning of S wave on TDI, Qst: onset of Q wave on ECG to top of S wave on TDI, Rsb: top of R wave on ECG to beginning of S wave on TDI, and Rst: top of R wave on ECG to top of S wave on TDI) of SBHF patients were significantly longer than those of CONs (Qsb: 119.19 ± 35.68 ms vs. 80.30 ± 14.81 ms, P < 0.001; Qst: 165.42 ± 60.93 ms vs. 129.04 ± 16.97 ms, P = 0.006; Rsb: 82.43 ± 33.66 ms vs. 48.30 ± 15.18 ms, P < 0.001; and Rst: 122.37 ± 36.66 ms vs. 93.25 ± 16.72 ms, P = 0.001), and the Qsb, Rsb, and Rst time showed a significantly higher sensitivity than LVEF (Rst: P =0.032; Rsb: P = 0.003; and Qsb: P = 0.004). Conclusions: The cardiac electromechanical coupling time is more sensitive than LVEF in evaluating cardiac systolic function. 摘要 背景： 压力负荷引起的心肌肥厚是引起心力衰竭的重要因素之一，前期的细胞实验和动物实验表明在心脏收缩功能（左心室射血分数）下降之前，心肌细胞兴奋-收缩耦联效率已经发生下降。本研究的目的是为检测心肌电-机械耦联参数在心力衰竭早期对心脏收缩功能的评价作用。 方法： 26名心力衰竭B期患者和31名健康志愿者纳入此研究中，使用M型超声心动图测量左心室射血分数（LVEF），超声心动图组织多普勒联合心电图用于测量心肌的电-机械耦联参数。 结果： 与健康志愿者相比，心力衰竭B期患者的LVEF值未显著降低（64.23±8.91 vs. 64.52±5.90 %; P=0.886）。然而，心力衰竭B期患者心肌电-机械耦联参数均明显延长（Qsb：心电图Q波的波谷至组织多普勒S波起点的时间；Qst：心电图Q波的波谷至组织多普勒S波波峰的时间；Rsb：心电图R波的波峰至组织多普勒S波起点的时间；Rst：心电图上R波的波峰至组织多普勒上S波波峰的时间）（Qsb: 119.19 ± 35.68 vs. 80.30 ±14.81 ms, P<0.001; Qst: 165.42 ± 60.93 vs. 129.04 ± 16.97 ms, P=0.006; Rsb: 82.43 ± 33.66 vs. 48.30 ±15.18 ms, P<0.001; Rst: 122.37 ±36.66 vs. 93.25 ± 16.72 ms, P=0.001）。此外，Qsb，Rsb与Rst 的敏感性明显高于LVEF（Rst: P=0.032; Rsb: P=0.003; Qsb: P=0.004）。 结论： 研究结果显示心肌电-机械耦联参数在评价心脏收缩功能方面比LVEF更加敏感。 Excitation–Contraction CouplingsHeart FailureLeft Ventricular Dysfunction ==== Body INTRODUCTION Heart failure is a major public health concern and the most common cause for hospitalization.[1] The standard treatment of heart failure fails to improve cardiac systolic function in more than a third of patients with Stage C or D heart failure.[2] Increasing evidence suggests that heart failure is preventable and treatable in the early stage.[3] Thus, it is important to develop an earlier and more sensitive evaluation index of cardiac systolic function during the early stage of heart failure. Excitation–contraction (E-C) coupling is an important indicator of cardiomyocyte contractile function.[4] Our previous study suggests that the efficiency between a single L-type channel and its controlled-Ca2+-release channels decrease before the appearance of cardiac systolic and cardiomyocyte contractile dysfunction at the early stage of heart failure in animal models.[5] The basic characteristics of E-C coupling are a series of stereotyped events that are responsible for the rapid mechanical contraction response of muscle fibers to an initial electrical event at the surface.[678] Thus, we speculated whether the electromechanical coupling of the cardiac muscle is a more sensitive indicator in the evaluation of cardiac systolic function compared with left ventricular ejection fraction (LVEF) in the early stage of heart failure patients. Echocardiogram (echo) and electrocardiogram (ECG) are widely used to evaluate the structural changes and mechanical activity[9] and the electrical activity of the heart,[10] respectively. However, no specific medical test can detect the cardiac electromechanical coupling efficiency. The Q wave on ECG represents the beginning of ventricular electrical activity and the S wave on tissue Doppler imaging (TDI) represents the beginning of ventricular systolic activity. The time course from Q wave to S wave reflects the electromechanical coupling efficiency of left ventricular. Thus, we aimed to measure ventricular electromechanical coupling time course by combining TDI measurement of echo and ECG measurement and study its role in the evaluation of cardiac systolic function. METHODS Ethical approval The procedure was approved by the Ethics Committee of Peking University Third Hospital (Approval No. IRB00006761-2016125) and in accordance with the Declaration of Helsinki 1975, as revised in 2000. All individuals provided written informed consent before taking part in this study. Study population We consecutively evaluated 26 patients with Stage B heart failure (SBHF) and 31 age- and sex-matched healthy controls (CONs). All CONs were recruited before the initiation of the study. CONs did not have a history of hypertension, diabetes, cardiovascular disease, or cerebrovascular disease. SBHF patients were diagnosed with hypertensive myocardial hypertrophy by echo (interventricular septum [IVS] thickness ≥11 mm or left ventricular posterior wall [LVPW;d] ≥11 mm or left ventricular mass index [LVMI] ≥115 g/cm2). Volunteers with inflammatory disease, with allergy, who are taking drugs that affect the immune or endocrine system, and/or with alcoholism were excluded from the study. Echocardiographic measurement Echo was performed as described previously.[11] A Vivid GE 7 color ultrasonic diagnostic instrument (GE, Fairfield, CT, USA) with a probe of 1.7–3.4 MHz frequency was used to measure the IVS, LVPW;d, Left ventricular end-diastolic dimension (LVEDD), and Left ventricular end-systolic dimension (LVESD) in M-mode echo. Relative wall thickness (RWT) was calculated using the following formula: RWT = (2 × LVPW;d)/LVEDD. The left ventricular mass (LVM) and LVMI were calculated according to the Devereux formula: LVM (g) = 0.8 × 1.04 × ([IVS + LVPW;d + LVEDD]3 − LVEDD3) + 0.6, LVMI (g/m2) = LVM/BSA, respectively, the body surface area (BSA) was calculated as follows: BSA = 0.0061 × height (cm) + 0.0128 × weight (kg) − 0.1529. LVEF was calculated by the Teicholz method. The values of three consecutive cardiac cycles were measured. Electromechanical coupling time measurement ECG was performed as described previously.[12] The TDI echo combined with ECG was used to evaluate the four time courses (Qsb, Qst, Rsb, and Rst) in all six walls of the left ventricle, namely the lateral wall (Lat), anterior wall (Ant), inferior wall (Inf), posterior wall (PW), posterior ventricular septum (Pivs), and anterior ventricular septum (Aivs). The time measurement module of Vivid GE 7 color ultrasonic diagnostic instrument was used to detect the time course of Qsb, Qst, Rsb, and Rst. Qsb time course is from the onset of Q wave on ECG to beginning of S wave on TDI. Qst time course is from the onset of Q wave on ECG to top of S wave on TDI. Rsb time course is from the top of R wave on ECG to beginning of S wave on TDI. Rst time course is from the top of R wave on ECG to top of S wave on TDI. Statistical analysis All statistical analyses were conducted using SPSS software version 19.0 (SPSS Inc., Chicago, IL, USA). The data are expressed as mean ± standard deviation (SD). The results were compared using Student's t-test. A value of P < 0.05 was considered statistically significant. Sensitivity and specificity analyses were conducted using MedCalc version 14 software (MedCalc Inc., Ostend, Belgium), and a P < 0.05 was considered statistically significant. RESULTS Clinical characteristics of Stage B heart failure patients and healthy controls The clinical characteristics of SBHF patients and CONs are given in Table 1. There were no significant differences in age, body mass index (BMI), and heart rate (HR) between SBHF and CON groups (age: 46.00 ± 11.56 vs. 42.65 ± 13.61, t = −1.006, P = 0.319; BMI: 25.00 ± 3.12 vs. 23.75 ± 3.01, t = −1.541, P = 0.129, HR: 74.73 ± 13.75 vs. 72.35 ± 9.58 t = −0.766, P < 0.001). The systolic blood pressure (SBP) and diastolic blood pressure (DBP) in SBHF patients were significantly higher than those of CONs (SBP: 156.23 ± 25.14 vs. 118.77 ± 8.88, t = −7.299, P < 0.001;DBP: 93.04 ± 15.76 vs. 71.58 ± 9.07, t = −6.426, P < 0.001) [Table 1]. Table 1 Comparison of the general characteristics of study population Items CONs (n = 31) SBHF patients (n = 26) t P Age (year) 42.65 ± 13.61 46.00 ± 11.56 −1.006 0.319 BMI (kg/m2) 23.75 ± 3.01 25.00 ± 3.12 −1.541 0.129 HR (beats/min) 72.35 ± 9.58 74.73 ± 13.75 −0.766 0.447 SBP (mmHg) 118.77 ± 8.88 156.23 ± 25.14 −7.229 <0.001 DBP (mmHg) 71.58 ± 9.07 93.04 ± 15.76 −6.426 <0.001 Data are expressed as mean ± SD. BMI: Body mass index; HR: Heart rate; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; SD: Standard deviation; CONs: Healthy controls; SBHF: Stage B heart failure. Standard echocardiographic parameters of Stage B heart failure patients and healthy controls Echocardiographic data showed that the indexes reflecting myocardial hypertrophy in SBHF patients were much higher than those in CONs. As shown in Table 2, the thickness of IVS and LVPW;d significantly increased in SBHF patients compared with those of CONS (IVS: 12.14 ± 1.17 vs. 8.09 ± 1.06, t = −13.702, P < 0.001; LVPW;d: 11.78 ± 0.94 vs. 8.13 ± 0.89, t = −15.017, P < 0.001). RWT and LVMI were significantly higher in SBHF patients than in CONs (RWT: 0.45 ± 0.04 vs. 0.34 ± 0.04, t = −9.974, P < 0.001; LVMI: 134.07 ± 30.37 vs. 75.96 ± 14.24, t = −8.964, P < 0.001). The average LVEDD and LVESD in SBHF patients were larger than those in CONs (LVEDD: 52.54 ± 4.71 vs. 48.1 ± 3.38, t = −4.136, P < 0.001, LVESD: 33.52 ± 5.28 vs. 29.84 ± 2.71, t = −3.222, P = 0.003). SBHF patients had significantly lower than those in CONs for the E/A and E/Em ratios (E/A: 0.98 ± 0.49 vs. 1.34 ± 0.40, t = 3.053, P = 0.003, E/Em: 10.28 ± 3.80 vs. 5.72 ± 0.65, t = −5.687, P < 0.001). However, there was no significant difference in LVEF between SBHF patients and CONs (64.23 ± 8.91 vs. 64.52 ± 5.90, t = 0.145, P = 0.886). Table 2 Comparison of M-mode echocardiographic measurement parameters Items CONs (n = 31) SBHF patients (n = 26) t P IVS (mm) 8.09 ± 1.06 12.14 ± 1.17 −13.702 <0.001 LVPW;d (mm) 8.13 ± 0.89 11.78 ± 0.94 −15.017 <0.001 LVEDD (ml) 48.10 ± 3.38 52.54 ± 4.71 −4.136 <0.001 LVESD (ml) 29.84 ± 2.71 33.52 ± 5.28 −3.222 0.003 RWT 0.34 ± 0.04 0.45 ± 0.04 −9.974 <0.001 LVMI (g/m2) 75.96 ± 14.24 134.07 ± 30.37 −8.964 <0.001 LVEF (%) 64.52 ± 5.90 64.23 ± 8.91 0.145 0.886 E/A 1.34 ± 0.40 0.98 ± 0.49 3.053 0.003 E/Em 5.72 ± 1.65 10.28 ± 3.80 −5.687 <0.001 Data are expressed as mean ± SD. IVS: Inter-ventricular septum; LVPW;d: Left ventricular posterior wall; LVEDD: Left ventricular end-diastolic dimension; LVESD: Left ventricular end-systolic dimension; RWT: Relative wall thickness; LVMI: Left ventricular mass index; LVEF: Left ventricular ejection fraction; SD: Standard deviation; CONs: Healthy controls; SBHF: Stage B heart failure; ECG: Electrocardiography; TDI: Tissue Doppler imaging. Electromechanical coupling time parameters of Stage B heart failure patients and healthy controls Four cardiac electromechanical coupling time courses in Lat of the left ventricle (Lat-Rst, Lat-Rsb, Lat-Qst, and Lat-Qsb) of CONs [Figure 1a] and SBHF patients [Figure 1b] were evaluated by TDI echo combined with ECG. The measurement showed that the four electromechanical coupling parameters in SBHF patients were all longer than those in CONs [Lat-Rst: 122.37 ± 36.66 vs. 93.25 ± 16.72, t = −3.696, P = 0.001, Figure 1c; Lat-Rsb: 82.43 ± 33.66 vs. 48.30 ± 15.18, t = −4.779, P < 0.001, Figure 1d; Lat-Qst: 165.42 ± 60.93 vs. 129.04 ± 16.97, t = −2.951, P = 0.006, Figure 1e; Lat-Qsb: 119.19 ± 35.68 ms vs. 80.30 ± 14.81 ms, t = −5.196, P < 0.001, Figure 1f, respectively] [Table 3]. In addition, the sensitivity and specificity analyses showed that the Lat-Rst, Lat-Rsb, and Lat-Qsb were significantly better than LVEF [Rst: P = 0.032, Figure 2a; Rsb: P = 0.003, Figure 2b; and Qsb: P = 0.004, Figure 2d]. While, the sensitivity and specificity of Lat-Qst was not significantly different from the LVEF [P = 0.126, Figure 2c] similar trends were also observed in the Pivs, Ant, Inf, PW, and Aivs [Table 3]. Figure 1 Cardiac electromechanical coupling time in SBHF patients and CONs. Representative images of TDI combined with ECG to measure the electromechanical coupling time in the lateral wall of the left ventricle (Lat) of CON subjects (a) and SBHF patients (b). Statistical data of Lat-Rst (c), Lat-Rsb (d), Lat-Qst (e), and Lat-Qsb (f) in SBHF patients group and CON group. Data are mean ± SD. *P < 0.05 versus CON. CONs: Healthy controls; TDI: Tissue Doppler imaging; ECG: Electrocardiography; SBHF: Stage B heart failure; Rst: From the top of R wave on ECG to the top of S wave on TDI; Rsb: From the top of R wave on ECG to the beginning of S wave on TDI; Qst: From the onset of Q wave on ECG to the top of S wave on TDI; Qsb: From the onset of Q wave on ECG to the beginning of S wave on TDI; SD: Standard deviation. Table 3 Comparison of cardiac E-C coupling measurement parameters of study population Items CONs (n = 31) SBHF patients (n = 26) t P Lat-Qsb (ms) 80.30 ± 14.81 119.19 ± 35.68 −5.196 <0.001 Lat-Qst (ms) 129.04 ± 16.97 165.42 ± 60.93 −2.951 0.006 Lat-Rsb (ms) 48.30 ± 15.18 82.43 ± 33.66 −4.779 <0.001 Lat-Rst (ms) 93.25 ± 16.72 122.37 ± 36.66 −3.696 0.001 Pivs-Qsb (ms) 80.32 ± 17.35 109.11 ± 28.35 −4.516 <0.001 Pivs-Qst (ms) 127.80 ± 20.45 154.07 ± 38.45 −3.131 0.003 Pivs-Rsb (ms) 48.87 ± 13.70 73.88 ± 22.45 −4.960 <0.001 Pivs-Rst (ms) 74.20 ± 11.57 92.96 ± 34.32 −2.663 0.012 Ant-Qsb (ms) 79.37 ± 12.47 114.89 ± 37.51 −4.619 <0.001 Ant-Qst (ms) 127.00 ± 16.13 162.46 ± 57.69 −3.037 0.005 Ant-Rsb (ms) 47.84 ± 12.94 79.86 ± 31.27 −4.882 <0.001 Ant-Rst (ms) 92.19 ± 16.13 125.29 ± 51.84 −3.132 0.004 Inf-Qsb (ms) 82.47 ± 17.81 106.22 ± 23.63 −4.323 <0.001 Inf-Qst (ms) 127.42 ± 22.58 153.41 ± 40.29 −2.926 0.006 Inf-Rsb (ms) 50.13 ± 16.60 74.23 ± 19.23 −5.078 <0.001 Inf-Rst (ms) 97.85 ± 22.51 119.5 ± 33.3 −2.914 0.005 PW-Qsb (ms) 81.89 ± 17.35 112.1 ± 30.53 −4.476 <0.001 PW-Qst (ms) 130.30 ± 17.76 160.96 ± 54.28 −2.759 0.010 PW-Rsb (ms) 49.28 ± 14.77 78.47 ± 27.37 −4.873 <0.001 PW-Rst (ms) 95.14 ± 17.73 128.76 ± 44.65 −3.608 0.001 Aivs-Qsb (ms) 83.33 ± 17.45 103.6 ± 25.1 −3.476 0.001 Aivs-Qst (ms) 125.10 ± 20.17 153.35 ± 36.64 −3.677 0.001 Aivs-Rsb (ms) 51.13 ± 13.84 70.78 ± 21.2 −4.056 <0.001 Aivs-Rst (ms) 93.34 ± 17.84 117.03 ± 32.22 −3.486 0.001 Data are expressed as mean ± SD. Lat: Lateral wall of left ventricle; Pivs: Posterior ventricular septum of left ventricle; Ant: Anterior wall of left ventricle; Inf: Inferior wall of left ventricle; PW: Posterior wall of left ventricle; Aivs: Anterior ventricular septum of left ventricle; Qsb: From the onset of Q wave on ECG to the beginning of S wave on TDI; Qst: From the onset of Q wave on ECG to the top of S wave on TDI; Rsb: From the top of R wave on ECG to the beginning of S wave on TDI; Rst: From the top of R wave on ECG to the top of S wave on TDI; SD: Standard deviation; CONs: Healthy controls; SBHF: Stage B heart failure; ECG: Electrocardiography; TDI: Tissue Doppler imaging; E-C: Excitation-contraction. Figure 2 Comparison of sensitivity and specificity between Lat-Rst and LVEF, P = 0.032 (a), between Lat-Rsb and LVEF, P = 0.003 (b), between Lat-Qst and LVEF, P = 0.126 (c), and between Lat-Qsb and LVEF, P = 0.004 (d). LVEF: Left ventricular ejection fraction; Rst: From the top of R wave on ECG to the top of S wave on TDI; Rsb: From the top of R wave on ECG to the beginning of S wave on TDI; Qst: From the onset of Q wave on ECG to the top of S wave on TDI; Qsb: From the onset of Q wave on ECG to the beginning of S wave on TDI. DISCUSSION The results of our research suggested that the electromechanical coupling time is more sensitive and specific than LVEF in evaluating cardiac systolic function [Figure 2a, 2b, and 2d]. These results suggested that electromechanical coupling time is a potential index in evaluating cardiac systolic function in SBHF patients. The Qsb time course was used to detect systolic asynchrony in patients with regional myocardial dysfunction.[13] In our study, the Qsb, Qst, Rsb, and Rst time course were chosen to evaluate the cardiac systolic function. S wave of TDI represents the beginning of systolic activity of left ventricular, and Q wave on ECG represents the beginning of mechanical activity of left ventricular. Hence, we detected the time course from the Q wave to the beginning of S wave to represent the efficiency that the electrical activity transferred into mechanical activity. As the beginning of S wave was sometimes unclear in TDI, therefore, we supplement the time course of Qst, which is from the Q wave on ECG to the top of S wave on TDI representing the efficiency of electromechanical coupling efficiency. In additional, Rsb and Rst time course were measured to avoid the uncertainty of the Q wave. Regarding the effects of electromechanical coupling time, the following factors need to be discussed. First, HR is related with the electrical and mechanical activities of the heart.[1415] To determine the effects of HR in electromechanical coupling time, the electromechanical coupling time with or without HR correction in SBHF patients and CONs was analyzed in our study. The results showed that the electromechanical coupling durations were all significant longer in SBHF patients than those in CONs with or without HR correction [Supplementary Table 1], which indicates that HR has no significant influence in the prolongation of electromechanical coupling in the SBHF group. Supplementary Table 1 Comparison of electromechanical coupling time measurement parameters without HR corrected Items CONs (n = 31) SBHF patients (n = 26) t P Lat-Qsb 67.68 ± 14.55 97.31 ± 29.62† 4.652 <0.001 Lat-Qst 108.2 ± 13.85 134 ± 41.85* 3.008 0.005 Lat-Rsb 40.92 ± 14.01 68.38 ± 29.06† 4.401 <0.001 Lat-Rst 78.19 ± 13.98 104.6 ± 36.10* 3.517 0.001 Pivs-Qsb 66.38 ± 12.68 95.88 ± 25.44† 5.38 <0.001 Pivs-Qst 106.3 ± 13.25 134.3 ± 32.89† 4.337 <0.001 Pivs-Rsb 41.83 ± 15.08 65.31 ± 21.40† 4.843 <0.001 Pivs-Rst 77.23 ± 14.04 99.58 ± 30.54† 3.646 <0.001 Ant-Qsb 67.6 ± 13.09 93.96 ± 30.09† 4.411 <0.001 Ant-Qst 106.7 ± 14.19 134.7 ± 46.99* 3.151 0.003 Ant-Rsb 41.46 ± 11.95 66.81 ± 27.73† 4.337 <0.001 Ant-Rst 77.63 ± 14.78 107.4 ± 43.25† 3.352 0.002 Inf-Qsb 69.17 ± 15.78 94.73 ± 24.40† 4.596 <0.001 Inf-Qst 107.6 ± 20.52 136.7 ± 35.00† 3.742 <0.001 Inf-Rsb 42.11 ± 15.42 66.08 ± 20.78† 4.992 <0.001 Inf-Rst 82.38 ± 19.56 106.8 ± 29.61† 3.604 <0.001 PW-Qsb 67.56 ± 15.56 92.73 ± 24.19† 4.572 <0.001 PW-Qst 108 ± 19.56 132.6 ± 40.56* 2.786 0.009 PW-Rsb 41.59 ± 13.09 64.27 ± 21.13† 4.759 <0.001 PW-Rst 79.71 ± 14.41 103.7 ± 33.49* 3.403 0.002 Aivs-Qsb 69.91 ± 15.42 94.62 ± 25.28† 4.351 <0.001 Aivs-Qst 104.8 ± 15.73 138 ± 36.46* 4.323 <0.001 Aivs-Rsb 43.07 ± 12.61 64.58 ± 21.1† 4.558 <0.001 Aivs-Rst 78.19 ± 13.98 104.6 ± 36.10* 4.155 <0.001 Data are expressed as mean ± SD. Lat: Lateral wall of left ventricle; Pivs: Posterior ventricular septum of left ventricle; Ant: Anterior wall of left ventricle; Inf: Inferior wall of left ventricle; PW: Posterior wall of left ventricle; Aivs: Anterior ventricular septum of left ventricle; Qsb: from the onset of Q wave on ECG to the beginning of S wave on TDI; Qst: From the onset of Q wave on ECG to the top of S wave on TDI; Rsb: From the top of R wave on ECG to the beginning of S wave on TDI; Rst: From the top of R wave on ECG to the top of S wave on TDI; SD: Standard deviation; CONs: Healthy controls; SBHF: Stage B heart failure; ECG: Electrocardiography; TDI: Tissue Doppler imaging; *P<0.05; †: P<0.01. Second, the homogeneity of the heart might influence the electromechanical coupling time. In our study, we selected participants with pressure overload-induced heart failure, which is known to lead to homogenous cardiac remodeling.[1617] We detected electromechanical coupling time course in six walls of the left ventricle (including Lat, Ant, Inf, PW, Aivs, and Pivs) in SBHF patients and CONs, and the results showed that the indexes of electromechanical coupling time were all significantly longer than those of CONs in six walls of left ventricle [Table 3]. This suggested that, in pressure overload-induced SBHF, the electromechanical time would not be significantly influenced by the scanning position of TDI. Third, age affects cardiac function and structure, especially cardiac diastolic function.[1819] To determine the influence of age, we compared the electromechanical coupling time in two control groups with significant different ages. The results show that there is no significant difference in electromechanical coupling durations between these two groups [Supplementary Table 2]. Thus, it suggests that the electromechanical coupling duration is not influenced by age. Supplementary Table 2 Comparison of electromechanical coupling time measurement in CONs of SBHF patients and CONs of athletes Items CONs of SBHF patients (n = 31) CONs of athletes (n = 15) t P Age (year) 42.7 ± 13.6 28.87 ± 4.26 4.855 <0.001 Lat-Qsb (ms) 80.3 ± 14.81 79.14 ± 16.02 −0.044 0.965 Lat-Qst (ms) 129 ± 16.97 128.8 ± 20.2 −1.014 0.316 Lat-Rsb (ms) 48.3 ± 15.18 52.2 ± 12.73 0.308 0.759 Lat-Rst (ms) 93.25 ± 16.72 98.35 ± 15.09 −0.873 0.387 Pivs-Qsb (ms) 80.32 ± 17.35 82.19 ± 21.78 −0.303 0.764 Pivs-Qst (ms) 127.8 ± 20.45 137 ± 29.67 −1.21 0.233 Pivs-Rsb (ms) 48.87 ± 13.7 49.48 ± 16.31 −0.132 0.896 Pivs-Rst (ms) 74.2 ± 11.57 74.86 ± 10.33 −0.189 0.851 Ant-Qsb (ms) 79.37 ± 12.47 79.64 ± 14.27 −0.063 0.95 Ant-Qst (ms) 127 ± 16.13 132.4 ± 22.39 −0.911 0.367 Ant-Rsb (ms) 47.84 ± 12.94 47.87 ± 12.93 −0.006 0.995 Ant-Rst (ms) 92.19 ± 16.13 95.3 ± 18.2 −0.575 0.569 Inf-Qsb (ms) 82.47 ± 17.81 83.91 ± 26.23 −0.212 0.833 Inf-Qst (ms) 127.4 ± 22.58 136.7 ± 32.31 −1.068 0.292 Inf-Rsb (ms) 50.13 ± 16.6 50.33 ± 16.45 −0.035 0.972 Inf-Rst (ms) 97.85 ± 22.51 108.1 ± 27.27 −1.262 0.214 PW-Qsb (ms) 81.89 ± 17.35 83.01 ± 24.57 −0.159 0.874 PW-Qst (ms) 130.3 ± 17.76 138.3 ± 28.92 −1.057 0.297 PW-Rsb (ms) 49.28 ± 14.77 50.19 ± 12.69 −0.166 0.869 PW-Rst (ms) 95.14 ± 17.73 102.2 ± 23.91 −1.003 0.322 Aivs-Qsb (ms) 83.33 ± 17.45 85.18 ± 24.94 −0.269 0.79 Aivs-Qst (ms) 125.1 ± 20.17 132.3 ± 28.81 −0.899 0.374 Aivs-Rsb (ms) 51.13 ± 13.84 51.51 ± 10.19 −0.07 0.945 Aivs-Rst (ms) 93.34 ± 17.84 96.39 ± 24.43 −0.587 0.56 Data are expressed as mean ± SD. Lat: Lateral wall of left ventricle; Pivs: Posterior ventricular septum of left ventricle; Ant: Anterior wall of left ventricle; Inf: Inferior wall of left ventricle; PW: Posterior wall of left ventricle; Aivs: Anterior ventricular septum of left ventricle; Qsb: From the onset of Q wave on ECG to the beginning of S wave on TDI; Qst: From the onset of Q wave on ECG to the top of S wave on TDI; Rsb: From the top of R wave on ECG to the beginning of S wave on TDI; Rst: From the top of R wave on ECG to the top of S wave on TDI; SD: Standard deviation; CONs: Healthy controls; SBHF: Stage B heart failure; ECG: Electrocardiography; TDI: Tissue Doppler imaging. Finally, cardiac hypertrophy can be divided into pathological cardiac hypertrophy and physiological cardiac hypertrophy. To determine whether the electromechanical coupling time is associated with physiological cardiac hypertrophy, we detected the electromechanical coupling time in athletes with exercise-induced hypertrophy,[2021] [Supplementary Tables 3 and 4]. The measurement results showed that the athletes' myocardium was characterized by hypertrophy, but their electromechanical coupling time was not significantly longer than that of CONs [Supplementary Table 5]. These results showed that the electromechanical coupling time course can be a potential index to distinguish between pathological cardiac hypertrophy and physiological cardiac hypertrophy. Supplementary Table 3 Comparison of the general characteristics Items CONs (n = 15) Athletes (n = 23) t P Age (year) 28.87 ± 4.26 21.09 ± 3.31 −6.318 <0.001 BMI (kg/m2) 22.07 ± 1.59 21.86 ± 2.37 −0.288 0.775 HR (bpm) 76.13 ± 10.51 59.09 ± 7.92 −5.698 <0.001 SBP (mmHg) 117.14 ± 8.33 111.95 ± 8.89 −1.762 0.087 DBP (mmHg) 66.29 ± 8.64 69.35 ± 8.02 1.094 0.281 Data are expressed as mean ± SD. BMI: Body mass index; HR: Heart rate; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; SD: Standard deviation; CONs: Healthy controls. Supplementary Table 4 Comparison of M-mode echocardiographic measurement parameters Items CONs (n = 15) Athletes (n = 23) t P IVS (mm) 8.17 ± 0.94 9.41 ± 1.23 3.323 0.002 LVPW;d (mm) 8.10 ± 0.76 9.44 ± 1.27 4.076 <0.001 LVEDD (ml) 49.56 ± 3.44 54.54 ± 3.51 4.314 <0.001 LVESD (ml) 31.09 ± 0.15 34.46 ± 3.11 3.199 0.003 RWT 0.33 ± 0.33 0.35 ± 0.49 1.360 0.182 LVMI 83.51 ± 14.88 109.06 ± 20.48 4.161 <0.001 LVEF (%) 60.33 ± 5.21 65.39 ± 4.21 3.298 0.002 E/A 1.60 ± 0.34 2.11 ± 0.13 2.912 0.006 E/Em 0.05 ± 0.01 0.05 ± 0.01 0.451 0.655 Data are expressed as mean ± SD. IVS: Inter-ventricular septum; LVPW;d: Left ventricular posterior wall; LVEDD: Left ventricular end-diastolic dimension; LVESD: Left ventricular end-systolic dimension; RWT: Relative wall thickness; LVMI: Left ventricular mass index; LVEF: Left ventricular ejection fraction; SD: Standard deviation; CONs: Healthy controls. Supplementary Table 5 Comparison of electromechanical coupling time measurement parameters Items CONs (n = 15) Athletes (n = 23) t P Lat-Qsb 80.52 ± 18.65 79.41 ± 16.02 −0.197 0.845 Lat-Qst 135.62 ± 26.91 128.80 ± 20.20 −0.893 0.378 Lat-Rsb 46.83 ± 16.44 52.2 ± 12.73 1.136 0.264 Lat-Rst 98.58 ± 23.56 98.35 ± 15.09 −0.012 0.991 Pivs-Qsb 82.02 ± 22.67 82.46 ± 14.93 0.047 0.962 Pivs-Qst 137.76 ± 30.70 130.98 ± 20.3 −0.685 0.498 Pivs-Rsb 49.48 ± 16.31 56.29 ± 9.48 1.390 0.180 Pivs-Rst 75.43 ± 10.47 58.1 ± 7.78 −5.698 <0.001 Ant-Qsb 80.27 ± 14.65 81.96 ± 16.81 0.420 0.677 Ant-Qst 133.81 ± 22.60 130.19 ± 21.63 −0.283 0.779 Ant-Rsb 47.71 ± 13.45 55.35 ± 12.74 1.674 0.104 Ant-Rst 96.52 ± 18.33 99.15 ± 16.25 0.647 0.522 Inf-Qsb 83.91 ± 27.39 84.82 ± 16.37 0.123 0.903 Inf-Qst 136.55 ± 33.88 123.36 ± 35.11 −1.082 0.290 Inf-Rsb 50.37 ± 17.25 54.37 ± 11.37 0.810 0.424 Inf-Rst 107.62 ± 28.55 97.05 ± 16.27 −1.418 0.167 PW-Qsb 82.91 ± 26.05 83.42 ± 15.9 0.055 0.956 PW-Qst 140.21 ± 30.01 128.74 ± 28.48 −0.864 0.395 PW-Rsb 46.51 ± 16.88 57.08 ± 10.57 1.529 0.138 PW-Rst 104.22 ± 24.42 99.35 ± 16.12 −0.387 0.701 Aivs-Qsb 84.86 ± 26.27 83.68 ± 19.79 −0.184 0.855 Aivs-Qst 133.38 ± 30.12 134.94 ± 22.92 0.283 0.779 Aivs-Rsb 51.19 ± 19.26 56.06 ± 14.62 0.742 0.464 Aivs-Rst 97.19 ± 25.60 104.32 ± 19.74 1.618 0.116 Data are expressed as mean ± SD. Lat: Lateral wall of left ventricle; Pivs: Posterior ventricular septum of left ventricle; Ant: Anterior wall of left ventricle; Inf: Inferior wall of left ventricle; PW: Posterior wall of left ventricle; Aivs: Anterior ventricular septum of left ventricle; Qsb: From the onset of Q wave on ECG to the beginning of S wave on TDI; Qst: From the onset of Q wave on ECG to the top of S wave on TDI; Rsb: From the top of R wave on ECG to the beginning of S wave on TDI; Rst: From the top of R wave on ECG to the top of S wave on TDI; SD: Standard deviation; CONs: Healthy controls; ECG: Electrocardiography; TDI: Tissue Doppler imaging. E/A and E/Em were most used index in evaluating cardiac diastolic function. Aging and hypertension are remarkably related cardiac diastolic function, and cardiac diastolic dysfunction often occurs first in hypertension-induced cardiac hypertrophy.[22] In our study, cardiac diastolic function was significantly decreased in SBHF patients compared with CONs. This is reasonable, for the SBHF patients with remarkable cardiac hypertrophy. For the LVEF in SBHF patients was not significantly decreased, a more sensitive index for evaluating cardiac systolic function is urgently needed. The electromechanical coupling time course in our study related with the systolic mechanical activity of the heart, and our results showed that electromechanical coupling time course was significantly longer than CONs. In addition, the sensitivity and specificity of electromechanical coupling time are better than LVEF. These results showed that the electromechanical coupling time in our study was a potential index to evaluate cardiac systolic function but not the diastolic function. However, there are still some limitations in our study. One limitation is the lack of follow-up study in humans. Moreover, the sample size is not big enough, and different types of heart failure need to be studied in the future. In conclusion, SBHF patients have already prolonged electromechanical coupling time but with normal LVEF compared with CONs. Our study provides a potential index for evaluating cardiac systolic function in heart failure at a much earlier stage of heart failure. Supplementary information is linked to the online version of the paper on the Chinese Medical Journal website. Supplementary Materials Click here for additional data file. Financial support and sponsorship This study was supported by grants from the National Natural Science Foundation of China (no. 91339105 and no. 81625001) and the Beijing Municipal Science and Technology Commission (no. Z141100000214006). Conflicts of interest There are no conflicts of interest. Acknowledgments We thank athletes from General Administration of Sport of China and healthy volunteers for assistance with evaluating the changes of left ventricular structure and systolic function. 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