Int J Clin Exp Med 2019;12(12):13627-13634 www.ijcem.com /ISSN:1940-5901/IJCEM0100556. Original Article E/Em ratio for assessment of major cardiovascular events in patients with post-infarction heart failure by cardiopulmonary exercise testing and ultrasonography. Ji Luo1, Yuke Zhang2, Lianjie Bai3, Yinghui Zhang3, Huilin Liu3. 1Department of Geriatrics Medicine, The Second Hospital of Shandong University, Jinan, Shandong Province, China; 2Department of Special Diagnosis and Treatment, 958 Hospital of Army PLA, Chongqing, China; 3Department of Ultrasonography, The Second Affiliated Hospital of Qiqihar Medical College, Qiqihar, Heilongjiang Province, China. Received August 5, 2019; Accepted October 8, 2019; Epub December 15, 2019; Published December 30, 2019. Abstract: Objective: To explore the value of the ratio of early diastolic transmittal velocity of mitral valve to early diastolic mitral annular velocity (E/Em) for major adverse cardiovascular events (MACE) in patients with post-in- farction heart failure by cardiopulmonary exercise testing (CPET) and ultrasonography. Methods: This study was a prospective study recruiting 90 patients with post-infarction heart failure (observation group) and 40 healthy subjects (control group). CPET combined with ultrasonography was used to detect the main cardiac indexes (E/Em ratio and Tei index) and the secondary indexes (left ventricular ejection fraction (LVEF), left ventricular end diastolic volume (LVEDV), and the serum brain natriuretic peptide (BNP) level). After 12 months of follow-up, the patients in the observation group was divided into MACE group (n = 20) and non-MACE group (n = 70), and the differences of the above indexes between the two groups were compared at 1, 6 and 12 months of follow-up. Results: The resting E/Em, Tei index and LVEDV in the observation group were higher than those in the control group. Compared with the control group, the proportion of E/Em > 15 and Tei index ≥ 0.47 increased, LVEF decreased and BNP increased in the observation group (all P < 0.05). After exercise, the resting E/Em, Tei index and LVEDV in the observation group were significantly increased, the proportion of E/Em > 15 and Tei index ≥ 0.47 increased, LVEF decreased and BNP increased (all P < 0.05). The E/Em, Tei index and LVEDV in the MACE group were higher than those in non- MACE group at 1, 6 and 12 months of follow-up, and the proportion of E/Em > 15 and Tei index ≥ 0.47 increased, LVEF decreased and BNP increased (all P < 0.05). ROC analysis showed that the accuracy of E/Em and Tei index in predicting MACE in the observation group was 0.875 and 0.834, respectively (P < 0.05). Conclusion: The E/Em ratio and Tei index measured by CPET and ultrasonography have good predictive value for MACE in patients with post-infarction heart failure.. Keywords: Cardiopulmonary exercise testing and ultrasonography, E/Em, post-infarction heart failure, major ad- verse cardiovascular events, Tei index. Introduction. Acute myocardial infarction (AMI) is a serious myocardial necrotic disease with myocardium unable to compensate and repair, which leads to decreased cardiac function and increased cardiac complications, such as acute and ch- ronic heart failure, and even sudden death. The extensive application of early revascularization has significantly increased the success rate of AMI treatment by saving dying myocardium, which also improves the survival of patients as well as prolongs the survival expectation .. However, the prevalence of post-infarction he- art failure was increased and turns out to be an important factor affecting the prognosis of pa- tients . Post-infarction heart failure is caused by early myocardial apoptosis or necrosis as well as gradual decline of cardiac systolic and diastolic functions, with clinical manifestations of exertional dyspnea and cardiogenic pulmo- nary edema. A study found that patients with post-infarction heart failure often experienced a first decline in diastolic function followed by an apparent decline in systolic function . The- refore, early assessment focusing on diastolic. http://www.ijcem.com. E/Em ratio for assessment of major cardiovascular events. 13628 Int J Clin Exp Med 2019;12(12):13627-13634. function is of great significance to identify high- risk patients, provide positive clinical interven- tion and improve survival outcomes.. Echocardiography is widely used in assessing the overall cardiac function, the phases of myo- cardial motion, and the intra- and extra-cardiac anatomical variations, such as myocardial isch- emia, cardiomyopathy, valvular disease, and congenital heart disease. It has the advantages of low cost, repeatable detection, image pres- ervation, and better detection accuracy. In ad- dition, the ultrasonic testing technologies, such as three-dimensional ultrasound, tissue Dopp- ler imaging and speckle tracking imaging have been developing continuously. Quantitative de- tection of the ratio of early diastolic transmittal velocity (E) to late diastolic transmittal velocity (A) of mitral valves, that is, E/A ratio, can reflect left ventricular filling pressure (LVFP) . LVFP is mainly affected by diastolic mitral opening and closing degree and flow velocity. Myocardial ischemia often leads to mitral dysfunction and LVFP elevation at first, and then causes left atrial pressure elevation, pulmonary circulation pressure elevation, and pulmonary vascular tis- sue remodeling, finally resulting in pulmonary congestion, pulmonary edema, increased ven- tricular systolic load, and left ventricular systol- ic dysfunction . However, E/A has some false negatives. The ratio of E to early diastolic mitral annular velocity (Em) (E/Em) can more accura- tely reflect left ventricular relaxation . Be- sides, the ratio of E/Em has good consistency with direct detection of left ventricular end dia- stolic pressure by invasive left cardiac catheter- ization or detection of pulmonary capillary wed- ge pressure by Swan-Ganz catheter, with fewer influencing factors and better stability . In addition, Tei index detected by ultrasonography is used to evaluate the overall work capacity of the heart, independent of ventricular geometry, two-dimensional image quality, blood pressure and heart rate, but only related to changes in cardiac preload . Although there was previ- ous studies on application of E/Em ratio or Tei index in evaluating cardiac function, whether there is any connection between the two re- mains unclear, let alone the accuracy in evalu- ating cardiac function under exercise load. Therefore, this study explored the value of E/ Em ratio and Tei index for major adverse cardio- vascular events (MACE) in patients with post- infarction heart failure by cardiopulmonary ex-. ercise testing (CPET) and ultrasonography, in order to provide a reference for the application of ultrasound in heart diseases.. Materials and methods. Patients. This study was a prospective study recruiting 90 patients with post-infarction heart failure admitted to The Second Affiliated Hospital of Qiqihar Medical College from April 2017 to April 2018 (observation group) and 40 healthy subjects (control group). Inclusion criteria: (1) Patients meeting the diagnostic criteria for post-infarction heart failure and with cardiac function grade I-II ; (2) Patients going through the CPET without serious adverse reactions; (3) Patients with reliable and unbiased ultrasonic examination data; (4) Patients with complete clinical data. The study obtained the informed consent of patients and the approval of the Ethics Committee of The Second Affiliated Hos- pital of Qiqihar Medical University. Exclusion cri- teria: (1) Patients with significant heart failure manifestations in the past month, and those taking cardiotonic and diuretic drugs; (2) Pa- tients with obesity, arrhythmia, and cerebral apoplexy; (3) Patients with liver and kidney dys- function and MACE; (4) Patients with malignant tumors.. Research methods. CPET combined with ultrasonography was used to detect the main cardiac function indexes (E/ Em ratio and Tei index) and the secondary indexes (left ventricular ejection fraction (LVEF), left ventricular end diastolic volume (LVEDV) and serum brain natriuretic peptide (BNP) le- vel). The differences of the above indexes be- tween the observation group and the control group, and before and after exercise in the observation group were compared. After 12 months of follow-up by regular telephone and outpatient visits, the patients in the observa- tion group were divided into MACE group (n = 20) and non-MACE group (n = 70), and the dif- ferences of the above indexes between the two groups were compared at 1, 6 and 12 months of follow-up. MACE included aggravated or new heart failure, readmission, target vessel recon- struction and sudden cardiac death.. E/Em ratio for assessment of major cardiovascular events. 13629 Int J Clin Exp Med 2019;12(12):13627-13634. Detection methods. The E/Em ratio and Tei index at resting state and peak motion were detected by transtho- racic echocardiography, and LVEF and LVEDV were measured 10 min after exercise. The Vivid E9 color Doppler echocardiography (GE Com- pany, USA) was employed in this study with the probe frequency of 2.5-4.5 MHz. The main ex- amination processes were as follows: the pa- tients took the lateral position. With limb leads connected, the electrocardiogram (ECG) was synchronized. The ultrasonic probe was placed at the apex, and dynamic two-dimensional im- ages of apical long axis, four-chamber and two- chamber were sequentially acquired during sinus rhythm. The overall motion amplitude of the heart, obvious segmented contradictory motion, and abnormality in the anatomical structure inside and outside the cardiac cavity were assessed. Then, the apical four-chamber viewer was locked. Under the guidance of color flow imaging, pulse Doppler recorded the mitral valve flow spectrum (E), and tissue Doppler imaging recorded the longitudinal velocity spectrum in the side of left ventricle of mitral annulus (Em) . Each data contained at least 3 cardiac cycles and were averaged to save images for analysis. Simplified biplane Simpson method was used to calculate LVEF and LVEDV.. CPET adopted symptom-limited exercise toler- ance test in the modified Bruce protocol . The specific method was as follows: Max-II car- diopulmonary exercise tester (PHYSIO DYNE, USA) was used in this study. β-blockers were discontinued on the day of examination, and the blood pressure at the last 1 min of each load level and ratings of perceived exertion were recorded. Oxygen uptake was calculated every 30 seconds with system-owned software, and the synchronous 12-lead ECG was con- nected to record the ECG and heart rate chang- es. Patients with intolerable breathing difficul- ties and other discomforts should stop exercise in time. Quantitative determination of termina- tion exercise included: systolic pressure obvi- ously increased (more than 230 mmHg) before reaching the target heart rate; blood pressure decreased by at least 10 mmHg compared with that in resting state; grade 2 or above angina pectoris appeared during exercise accompa- nied by severe arrhythmia, such as atrial or ven- tricular tachycardia and frequent premature. beats, which can be relieved only by stopping exercise; acute myocardial ischemia-induced ECG changes occurred, i.e. transient ST seg- ment depression ≥ 0.5 mm or elevation ≥ 1 mm for 2 consecutive limb leads or chest leads; diz- ziness, paleness, shortness of breath and other discomforts occurred; patients reached the target heart rate, that is, the percentage of maximum heart rate was 70%-80%, and the respiratory exchange ratio was ≥ 1.1.. Radioimmunoassay (Sigma Company, USA) was used to detect BNP level, and the opera- tion was carried out according to the instruc- tions. The normal reference value was less than 150 pg/mL.. Statistical methods. Statistical software SPSS20.0 was used to an- alyze the collected data. The measurement da- ta were analyzed by t-test. The comparison of E/Em ratio, Tei index, LVEDV, LVEF and BNP at 1, 6 and 12 months of follow-up was performed by repeated measurement analysis of variance. And the count data were analyzed by χ2 test. A value of P < 0.05 was considered statistically significant.. Results. Comparison of general data. There was no significant difference in general data between the two groups (P > 0.05). See Table 1.. Comparison of observation indexes. The resting E/Em, Tei index and LVEDV in the observation group were higher than those in the control group. And the proportion of E/Em > 15 and Tei index ≥ 0.47 increased, LVEF de- creased and BNP increased (all P < 0.05). See Table 2.. Comparison of indexes before and after exer- cise in the observation group. The resting E/Em, Tei index and LVEDV in the observation group were significantly increased after exercise. And the proportion of E/Em > 15 and Tei index ≥ 0.47 increased, LVEF decreased and BNP increased (all P < 0.05). See Table 3 and Figure 1.. E/Em ratio for assessment of major cardiovascular events. 13630 Int J Clin Exp Med 2019;12(12):13627-13634. Comparison of follow-up indexes between MACE group and non-MACE group. The E/Em, Tei index and LVEDV in the MACE group were higher than those in the non-MACE group at 1, 6 and 12 months of follow-up. And the proportion of E/Em > 15 and Tei index ≥. rately screen high-risk patients is of great sig- nificance for early prevention and improvement of survival and prognosis.. Most patients with post-infarction heart failure have no obvious clinical symptoms at rest or during slight exercise, with normal systolic func-. Table 1. Comparison of general data ( _ x ± sd, n (%)). Group Control group (n = 40) Observation group (n = 90) t/χ2 P Male/female 20/20 50/40 0.344 0.558 Age (year) 62.8±7.9 63.5±8.6 0.326 0.649 Body mass index (kg/m2) 23.5±2.7 23.3±2.5 0.158 0.865 STEMI/NSTEMI 55/35 Course of disease after infarction (month) 20.5±7.6 New York heart function I/II 45/45 Smoking 14 (35.0) 29 (32.2) 0.097 0.756 Hypertension 11 (27.5) 20 (22.2) 0.425 0.515 Diabetes 6 (15.0) 10 (11.1) 0.388 0.533 Note: STEMI, ST elevation myocardial infarction; NSTEMI, non-ST elevation myocardial infarction.. Table 2. Comparison of observation indexes ( _ x ± sd, n (%)). Group Control group. (n = 40) Observation. group (n = 90) t/χ2 P. E/Em 8.64±2.36 16.28±4.52 20.326 0.000 E/Em > 15 2 (5.0) 20 (22.22) 5.842 0.016 Tei index 0.33±0.16 0.68±0.25 18.625 0.000 Tei index ≥ 0.47 3 (7.5) 26 (28.89) 7.310 0.007 LVEDV (mL) 135.86±32.54 186.79±45.26 22.236 0.000 LVEF (%) 56.23±6.54 50.24±7.53 5.326 0.009 BNP (pg/mL) 132.65±32.58 452.36±56.32 45.236 0.000 Note: E, early diastolic transmittal velocity; Em, early diastolic mitral annular velocity; LVEDV, left ventricular end diastolic volume; LVEF, left ventricular ejection fraction; BNP, brain natriuretic peptide.. Table 3. Comparison of indexes before and after exercise in the observation group (. _ x ± sd, n (%)). Group Rest state (n = 90). After motion (n = 90). t/χ2 P. E/Em 16.28±4.52 19.63±5.27 13.524 0.000 E/Em > 15 20 (22.22%) 48 (53.33%) 18.529 0.016 Tei index 0.68±0.25 0.86±0.33 14.528 0.000 Tei index ≥ 0.47 26 (28.89%) 50 (55.56%) 13.117 0.000 LVEDV (mL) 186.79±45.26 232.65±64.52 28.625 0.000 LVEF (%) 50.24±7.53 48.52±9.63 4.528 0.012 BNP (pg/mL) 452.36±56.32 659.53±85.54 35.264 0.000 Note: E, early diastolic transmittal velocity; Em, early diastolic mitral annular velocity; LVEDV, left ventricular end diastolic volume; LVEF, left ventricular ejection fraction; BNP, brain natriuretic peptide.. 0.47 increased, LVEF decreased and BNP increased (all P < 0.05). See Figure 2 and Table 4.. Receiver operating characteristic curve (ROC) analysis. Taking E/Em ratio and Tei index as diagnostic indexes, MACE as diag- nostic results, ROC analysis found that, in the observation group, the area under the curve, 95% confi- dence interval, P value, sensitivi- ty, and specificity of E/Em ratio for predicting MACE were 0.875, 0.823-0.902, 0.005, 86.5%, and 75.9% respectively, while those of Tei index were 0.834, 0.811-0.923, 0.011, 85.5%, and 76.8%, respec- tively. See Figure 3.. Discussion. Clinical studies have found that diastolic function declines in early post-infarction heart failure, while indexes of systolic function decline such as LVEF, BNP and LVEDV are in the normal range . The de- tection rate of diastolic function decline is 50-80% and diastolic dysfunction largely contributes to MACE at early stage. How to accu-. E/Em ratio for assessment of major cardiovascular events. 13631 Int J Clin Exp Med 2019;12(12):13627-13634. Figure 1. The ratio of E/Em at rest state and peak of motion by transthoracic echocardiography. A. E peak before motion. B. Em before motion; C. E peak after motion; D. Em after motion. E, early diastolic transmittal velocity; Em, early diastolic mitral annular velocity.. Figure 2. Comparison of follow-up indexes between MACE group and non-MACE group. A. E/Em ratio; B. Tei index; C. LVEDV; D. LVEF; E. BNP. #P < 0.05, compared with non-MACE group at the same time of follow-up. E, early diastolic transmittal velocity; Em, early diastolic mitral annular velocity; LVEDV, left ventricular end diastolic volume; LVEF, left ventricular ejection fraction; BNP, brain natriuretic peptide; MACE, major adverse cardiovascular events.. E/Em ratio for assessment of major cardiovascular events. 13632 Int J Clin Exp Med 2019;12(12):13627-13634. tion and the cardiac pumping work meeting the basic dynamic needs. Even if the LVFP increas- es, the cardiac preload can be reduced by increasing cardiac ejection volume. However, once the activity levels increased, there will be prolonged diastolic filling duration, increased mitral regurgitation, and lifted LVFP. But at this point, failing to increase Em accordingly, the E/ Em is definitely increased [12, 13]. In the obser- vation group, there were certain proportions of E/Em > 15 and Tei index ≥ 0.47 in both resting and exercise states, suggesting that objective and accurate reference intervals of E/Em and Tei index need to be established to improve the diagnostic value. Both the E/Em and Tei index are accurate indexes for ultrasonography to reflect the cardiac systolic and diastolic func- tions, especially E/Em primarily indicates the early cardiac diastolic function. Attention should be paid to eliminate the interference of valvular diseases, and ventricular hypertrophy. the cardiac diastolic function was too worn down to satisfy the increase of cardiac work, resulting in the obvious decrease of cardiac function.. Researches showed that, E/Em and Tei index had good correlation with LVEF and BNP. LVEF is the main index to measure the work of left ventricular ejection and BNP is the sensitive index to evaluate the degree of heart failure [18, 19]. By analyzing the correlation of E/Em and Tei index with LVEF and BNP, it was found that cardiac ultrasound detection of E/Em and Tei index had good accuracy for evaluating car- diac function. As a screening and early diagno- sis method for heart diseases, ultrasonography is simple and convenient to operate, low in cost, widely used, and has better sensitivity and accuracy for evaluating heart function. Therefore, E/Em and Tei index for early assess- ment of post-infarction heart failure by echo-. Table 4. Comparison of the proportion of E/Em > 15 and Tei index ≥ 0.47 between MACE group and non-MACE group (n (%)). Group MACE group . (n = 20) non-MACE. group (n = 70) χ2 P. E/Em > 15 in follow-up For 1 month 5 (25.0%) 5 (7.14%) 5.022 0.025 For 6 month 7 (35.0%) 8 (11.43%) 4.641 0.031 For 12 month 10 (50.0%) 13 (18.57%) 8.076 0.004 Tei index ≥ 0.47 For 1 month 4 (20.0%) 4 (5.71%) 3.920 0.048 For 6 month 6 (30.0%) 6 (8.57%) 4.466 0.035 For 12 month 8 (40.0%) 10 (14.29%) 4.922 0.027 Note: E, early diastolic transmittal velocity; Em, early diastolic mitral annular veloc- ity; MACE, major adverse cardiovascular events.. Figure 3. ROC analysis of the value of E/Em and Tei index in predicting the MACE. A. E/Em ratio; B. Tei index. E, early diastolic transmittal velocity; Em, early diastolic mitral annular velocity; MACE, major adverse cardiovascular events; ROC, receiver operating characteristic curve.. and mitral insufficiency caused by severe hypertension [14, 15].. CPET increases the need for cardiac work. The systolic func- tion of patients with early heart failure basically meets the exercise load, but the diastolic function cannot increase in re- sponse. Therefore, during the CPET, the heart rate of the pa- tient was accelerated, and the diastolic duration was short- ened more obviously than the systolic duration. At this time, the peak flow velocity of mitral annulus decreased, resulting in a significant increase in E/ Em [16, 17]. E/Em with no obvious difference in resting state showed obvious differ- ences after exercise load. The results of this study also con- firmed that the E/Em, Tei index and LVEDV of the patients after CPET were significantly higher than those in the resting state. The proportion of E/EM > 15 and Tei index ≥ 0.47 increased, LVEF value decreased and se- rum BNP level increased. The above results suggested that. E/Em ratio for assessment of major cardiovascular events. 13633 Int J Clin Exp Med 2019;12(12):13627-13634. cardiography undoubtedly provides great con- venience for clinical application [20, 21].. Patients with post-infarction heart failure have a high incidence of MACE, which is also an im- portant reason affecting the survival and prog- nosis of patients. Studies have confirmed th- at, early diastolic function decline, myocardial energy metabolism disorder, myocardial apop- tosis and continuous necrosis are important mechanisms of MACE [22, 23]. Therefore, early and accurate measurement of diastolic func- tion is of great significance to objectively evalu- ate MACE. Through follow-up, it was found that the E/Em and Tei index in the two groups of patients was gradually increased, but the in- crease was more significant in the MACE group, which reconfirmed the application values of E/ Em and Tei index in patients with post-infarc- tion heart failure .. To point out the innovation, by using CPET and ultrasonography, this study improved the diag- nosis value of E/Em ratio and Tei index to patients with post-infarction heart failure, whi- ch well reflects the change of LVEDV, LVEF and BNP and predicts the occurrence of MACEs. But the study fell short in further analyzing the diagnostic value of E/Em and Tei Index in evalu- ating the occurrence of MACEs. What’s more, whether E/Em ratio and Tei index are correlat- ed with LVEDV, LVEF and BNP still has an influ- ence on the results. Besides, only after a larger sample is analyzed can E/Em > 15 and Tei index ≥ 0.47 be applied as critical values for routine evaluation.. In conclusion, the E/Em ratio and Tei index measured by CPET and ultrasonography has good predictive value for MACE in patients with post-infarction heart failure.. Disclosure of conflict of interest. None.. 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