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The long-term prognostic value of E/e’ in patients with ST segment elevation myocardial infarction

Objectives This study aimed to evaluate the long-term prognostic value of E/e’ ratio in patients with ST-segment elevation myocardial infarction (STEMI). Methods We retrospectively assessed 314 patients who underwent primary coronary interventions between January 2010 and December 2015. The included patients were classified into two groups according to the E/e’ ratios: E/e’<15 (n = 245) and E/e’≥15 (n = 69). We investigated the incidence of major adverse cardiac events (MACEs) from the event to the final follow-up period of at least three years. Results A total of 55 cases of MACEs occurred during the follow-up. The E/e’≥15 group showed a significantly higher rate of MACEs than the E/e’<15 group (34.8% vs. 12.7%, p < 0.001). Among the MACE, the percentage of cardiac deaths (17.4% vs. 0.4%, p < 0.001) was higher in the E/e’≥15 group than in the E/e’<15 group. In the multivariable model, E/e’≥15 was demonstrated as the strongest prognostic factor for MACEs (hazard ratio [HR], 2.597; 95% confidence interval [CI], 1.294–5.211; p = 0.007) and cardiac death (HR, 27.537; 95% CI, 3.287–230.689; p = 0.002), while left ventricular ejection fraction (LVEF) was not. Neither the discrepancy of systolic nor diastolic function between initial and follow-up echocardiography affected the overall prevalence of MACEs. A disparity was observed between the two groups, with a significant increase in the rate of MACEs in the E/e’≥15 group (log-rank test, p < 0.001). Conclusion The baseline E/e’≥15 in patients with STEMI after successful reperfusion is the strongest predictor of poor long-term clinical outcomes among those analyzed.


Introduction
Despite technical advances in the field of coronary intervention, the development of major adverse cardiac events (MACEs) after acute myocardial infarction (MI) remains a major cause of mortality and morbidity worldwide. 1,2 Effective risk stratification is crucial for high-risk patients to decide on early aggressive management, which may improve the overall clinical outcomes. 3 Prior studies have suggested various predictors of MACEs in patients with MI, including high-scoring systems (SYNTAX, TIMI, and GRACE), infarct size, and certain echocardiographic parameters. 1,4 MI induces direct damage and necrosis of the myocytes, leading to the impairment of cardiac function. 5 However, several data on patients with ST segment elevation MI (STEMI) alone exist, resulting from a high percentage of critical initial conditions. 2,6,7 Because of its heterogeneous pathophysiology, STEMI is considered as a differentiated disease entity compared with non-ST segment elevation MI (NSTEMI). 8,9 Furthermore, predicting clinical outcomes in STEMI applying left ventricular ejection fraction (LVEF) and left ventricular (LV) diastolic function still remains controversial. 1 The role of LV diastolic function, evaluated by the E/e' ratio, has emerged as an important predictor of outcome in patients with STEMI since LV diastolic dysfunction precedesLV systolic dysfunction after myocardial ischemia occurs. 10,11 Nevertheless, some problems with the E/e' ratio in the STEMI field remain. For example, there remains a need for data with a longer follow-up period regarding the association with cardiac deaths and the clinical implications of follow-up echocardiographic parameters. 1,6,12 Hence, we aimed to investigate the clinical implications of the E/e' ratio with long-term MACEs in patients with ST-elevation myocardial infarction (STEMI).

Study population
A total of 314 consecutive patients presenting with STEMI who visited the emergent department at Haeundae Paik Hospital between January 2010 and December 2015 were analyzed in the study. The inclusion criteria were STEMI episode in which emergent percutaneous coronary intervention (PCI) was performed within 12 h from the symptom onset, and age 18 years. A total of 334 patients with STEMI were initially included in the study; however, twenty patients were excluded due to omission of initial echocardiographic data, intervention after 12 h of symptom onset, or uncertain diagnosis. STEMI was defined according to the guidelines of the American College of Cardiology and European Society of Cardiology guidelines. 13,14 The ethical review board of our institution approved this retrospective study and waived the requirement for informed consent requirement (IRB no. HPIRB 2020-07-014). This study was conducted in accordance with the principles of the Declaration of Helsinki.

Echocardiographic analysis
Initial echocardiography was performed within one week of the event using a Siemens ACUSON SC 2000 machine (Siemens Healthineers, Germany). We assessed the necessary echocardiographic parameters in accordance with the American Society of Echocardiography. 15,16 LV systolic dysfunction was defined as LVEF <40%. Mitral inflow velocity and deceleration time were acquired using a spectrum pulsed-wave Doppler with an apical 4-chamber view. Additionally, tissue Doppler was performed in an apical 4chamber view to assess the mitral annulus motion by placing the sample volume on the anterior, posterior, septal, and lateral mitral annulus. E/e' was automatically calculated from the computer by dividing the early trans-mitral inflow velocity (E) by the septal mitral annular early diastolic velocity (e'). Color Doppler was obtained from the apical four, three, and two chambers for grading mitral valve regurgitation. We determined an E/e' 15 as abnormal according to the current guidelines. 15

Clinical outcome and definitions
The primary endpoint was long-term MACE with a minimum follow-up of 3 years (mean, 64 months; median, 58 months). MACE was defined as a composite of cardiac death, non-fatal myocardial infarction (MI), repeat revascularization, and/or cerebrovascular accident (CVA). The secondary endpoint was incidence of cardiac death. Cardiac death was defined as death of cardiac origin unless apparent non-cardiac death was established.

Statistical analysis
Continuous variables are reported as mean ± standard deviation, and categorical variables are expressed as numbers and percentages. Differences between the two groups were analyzed using the c 2 test or Student's t-test, as appropriate. A paired t-test was performed to compare the initial to the follow-up echocardiographic data. We used the Cox proportional hazards model with multivariate analysis to assess the clinical association between E/e' and MACE. A receiver operating characteristic (ROC) curve and the area under the curve were analyzed to verify the predictive ability of the variables for poor prognosis. The cumulative event-free survival curves were described using the KaplaneMeier method, and the discrepancy between the curves was analyzed using the log-rank test. p-value was set at p < 0.05. The overall analysis was performed using Predictive Analytics Software (PASW) Statistics 22.0 for Windows (Statistical Package for the Social Sciences, SPSS Inc., Chicago, IL, USA).

Baseline and procedural characteristics
A total of 314 STEMI patients who underwent primary PCI were included in the current study. The baseline characteristics and laboratory findings of the patients are summarized in Table 1. The overall mean age of the total population was 64.8 ± 11.9 years and majority of the patients were men (77.7%). Significant differences in age, sex, hypertension, and diabetes were observed, whereas no differences were found in the percentages of previous vascular events, smoking status, initial blood pressure, and use of antiplatelet agents. Interestingly, the E/e'15 group showed a significantly higher initial heart rate, higher percentages of Killip class 2, and LVEF <40%. Laboratory variables revealed significantly higher initial troponin I, serum creatinine levels, pro brain natriuretic peptide (BNP), and highly sensitive C-reactive protein levels, while hemoglobin, triglycerides, and low-density lipoprotein (LDL) levels were significantly lower. This cholesterol paradox might have resulted from the higher percentage of hypertensive patients who received serial medical examinations and monitoring.
The percentage of drug-eluting stent (DES) implantation in the culprit lesion was approximately 93.9%. The radial approach was significantly more common in the E/e'<15 group (93.5%) than in the E/e'15 group (82.6%). The left anterior descending artery was the most common culprit vessel in the abnormal E/e' group (59.4% vs. 39.5%), while the right coronary artery was the most common in the normal E/e' group. Among the total population, 63.4% had multivessel coronary diseases. The percentage of 3-vessel coronary disease, chronic total occlusion, thrombus aspiration, and the use of an intra-aortic balloon pump were significantly higher in the abnormal E/e' group than in the normal group.

Initial and follow-up echocardiographic parameters
Echocardiographic parameters of the study cohort are presented in Table 2(mean: 3 days; median: 3.56 days). The overall average E/ e' ratio was 12.7 ± 7.0. Approximately 22% of the total population showed abnormal E/e' values. These patients had a significantly lower LVEF, more dilated left ventricular end dimensions, more elevated left ventricular mass, higher maximal tricuspid regurgitation velocity (TR Vmax), and shorter deceleration time. Furthermore, they were more likely to have mitral regurgitation that was over grade II. Among the total population, 34 patients (10.8%) had diastolic dysfunction higher than grade II.
We also collected follow-up echocardiographic data, which were recorded in approximately 75.5% of the included study cohort (mean: 24.85 months; median: 15.63 months). Among these patients, 32 (13.8%) showed deterioration of diastolic dysfunction grade, while 34 patients (14.7%) showed recovery. The overall LVEF deteriorations was observed in 28 patients (11.8%), and recovery was documented in 68 patients (28.7%). The average follow-up LVEF was 51.7 ± 9.8%, which showed a significant increase (p < 0.001) between the initial LVEF, whereas the E/e' ratio was 11.8 ± 5.4 without a significant decrease (p ¼ 0.134).

Clinical outcomes according to E/e' (Table 3)
During the follow-up period, 55 MACEs (17.5%) occurred. The overall percentage of MACE was significantly higher in those with an abnormal E/e' ratio than in those with a normal E/e' ratio (34.8% vs. 12.7%, p < 0.001). Cardiac death was the only component of MACEs and was significantly higher in those with abnormal E/e' ratios than in those with normal E/e' ratios (17.4% vs. 0.4%, P < 0.001). Meanwhile, the other components of MACE (non-fatal MI, repeat revascularization, and CVA) were not significantly  different between the two groups. Among the 13 events of cardiac death, eight cases occurred during the index hospitalization, of which seven cases involved patients with abnormal E/e' ratios.

Predictors of MACEs and cardiac death
On univariate analysis, age, diabetes, initial heart rate, Killip class II, trans-mitral E velocity, septal e' velocity, serum creatinine, pro BNP, initial diastolic grade II, TR Vmax, intervention approach site, E/e'15, and LVEF <40% were identified as independent risk factors for MACE. On multivariate Cox analysis, wherein the wellknown risk factors and all the independent factors of the univariate model were adjusted, an E/e' ratio 15 was shown as a powerful predictive factor (hazard ratio [HR], 2.597; 95% confidence interval [CI], 1.297e5.211; p ¼ 0.007). The other relevant prognostic factors were diabetes (HR, 2.271; 95% CI, 1.153e4.471; p ¼ 0.018) and initial heart rate (HR, 1.018; 95% CI, 1.002e1.033; p ¼ 0.028). Fig. 1 shows the survival curve for MACE constructed according to E/e' ratio and LVEF. Although LVEF and E/e' provide a distinct separation of the curve (log-rank chi-square ¼ 9.283; p ¼ 0.002), stratification by E/e' ratio revealed a more distinct separation (log-rank chisquare ¼ 22.575, p < 0.001), suggesting a higher capability to predict MACE.
In addition, we evaluated individual predictors of cardiac death (Table 4). For cardiac death, an E/e' ratio15 (HR: 27.537; 95% CI: 3.287e230.689; p ¼ 0.002) and initial heart rate (HR: 1.037; 95% CI: 1.009e1.066; p ¼ 0.010) were the only significant predictors after adjusting for univariate predictors of outcome. An E/e' ratio 15 was identified as the strongest predictor of cardiac death, which was more predominant in cardiac death than in MACE.

Discussion
The principal point of the current study was that an E/e' ratio 15 was the strongest variable predicting the long-term adverse cardiac outcomes in patients with STEMI after successful coronary intervention and showed superiority over LVEF and other confounding factors. Furthermore, the study revealed that the initial E/ e' ratio was the only echocardiographic parameter that predicted poor prognosis after adjustment, whereas the disparities of the E/e' ratio or LVEF between the initial and follow-up echocardiography were not associated with long-term MACEs.
Previous studies have emphasized the importance of diastolic function and compared it to the systolic function in acute MI patients, since diastolic parameters reflect multifactorial mechanisms that include both intrinsic and extrinsic factors which influence the overall heart function. 17,18 Diastolic dysfunction mainly occurs due to the impairment of myocardial relaxation and increased LV stiffness. 7 Several diastolic function parameters that were introduced and used for predicting the clinical outcome in acute MI include the LV filling pattern, deceleration time, LA volume index, Tei index, and E/e' ratio. 12,19,20 According to the latest recommendations, the E/e' ratio and mitral annular early diastolic velocity (e') using pulsewave Doppler are strongly recommended for the assessment of LV diastolic dysfunction. 21 The early mitral inflow velocity increases while e' decreases under elevated LV filling pressure. 22 Therefore, the E/e' ratio is useful for diagnosing heart failure with preserved LVEF and objectively reflects pulmonary capillary wedge pressure. 23,24 Among the established prognostic factors, several studies have demonstrated the ascendancy of the E/e' ratio over other variables. 6,20,25 However, these studies were conducted in patients with acute MI, in which reperfusion therapy timing was different. To reduce such bias, we only included patients with STEMI who   26 The present study followed the criteria described in previous literature and derived the results. Our study demonstrated significantly lower MACE-free survival rates in both E/e' ratio 15 and LVEF <40% during the follow-up period, whereas an E/e' ratio 15 was the only significant predictive factor for MACE on multivariate analysis. Moreover, we independently assessed the risk factors for cardiac death as one of the components of MACEs, while several studies have focused on all-cause mortality. 1,6,27 An abnormal E/e' ratio has been shown to be a powerful risk factor for all-cause death across studies. According to Iwahashi et al, an E/e' ratio 15 observed two weeks after a STEMI event was shown as the strongest predictive factor of cardiac death and a strong prognostic implication of an abnormal E/e' ratio compared to the LVEF, which is consistent with our study, emphasizing the role of E/e' ratio as a powerful prognostic factor for adverse outcomes. 19 Moreover, Moller et al reported that abnormal LV filling patterns are associated with LV dilatation and may predict the risk of cardiac death after the first episode of MI. 3 The difference between prior studies and the current study is that we identified that an E/e'ratio 15 was the more powerful factor in predicting cardiac death than total MACE. Certain factors have previously been reported as predictors of adverse clinical outcomes after STEMI, which have been related to decreased LVEF, deterioration of LVEF, and left anterior descending artery (LAD) as the culprit vessel. 28,29 Hospitalization due to adverse cardiac events may be associated with such issues. However, although higher percentages of decreased LVEF and LAD involvement were observed in the abnormal E/e' ratio group, this result did not influence the overall MACEs. Furthermore, hospitalization due to cardiac problems was not included in the present study after adjusting for the previously mentioned variables. In the present study, the E/e' ratio did not significantly decrease on the follow-up echocardiography. In addition, Subramaniyan et al. showed no significant improvement in the E/e' ratio after PCI in patients with STEMI, which supported that PCI is not the only factor affecting the E/e' ratio. 28 The current study has the strength of long follow-up. Compared to prior studies in which the follow-up period ranged from six months to two years, we only included patients with at least a three-year follow-up, which was the longest duration among previous studies. 1,6,25,28 Therefore, the results of our study may provide a powerful consensus that the role of the initial E/e' ratio as a predictor for MACE or cardiac death does not end in the short term but is maintained for a long time.
Our study had several limitations. First, because this was a single-center study, with a small number of participants. However, we included patients with a relatively strict criteria and an extended follow-up duration, which may have strengthened the reliability of the results. Second, this is a retrospective study. Third, the patients who were unable to undergo echocardiography due to extremely unstable conditions or sudden cardiac death were excluded and a quarter of total study patients lack the follow-up echocardiographic data. Since the study focused on echocardiographic parameters, initial echocardiographic data were mandatory for all included patients to avoid study bias. Finally, the LA volume index was not measured and was not included as an obligatory parameter at our center. To overcome this shortcoming, we supplemented the variables including TR Vmax, diastolic grade, and other factors. Further larger studies are necessary to support the long-term prognostic implications of the E/e'ratio for predicting adverse clinical outcomes, including cardiac death, in patients with STEMI.

Conclusion
An initial E/e' ratio 15 in patients with STEMI after successful reperfusion was the strongest predictor of adverse clinical outcomes, including cardiac death among the analyzed variables. The current data suggest that the diastolic dysfunction may play a crucial role in the risk stratification of patients with STEMI.

Declaration of competing interest
The author(s) declared no potential conflicts of interest.