Clinical Usefulness of the Serial Examination of Three-Dimensional Global Longitudinal Strain After the Onset of ST-Elevation Acute Myocardial Infarction

Abstract

Background: Two-dimensional (2D) and three-dimensional (3D) speckle tracking echocardiography (STE) after ST-elevation acute myocardial infarction (STEMI) can predict the prognosis. This study investigated the clinical significance of a serial 3D-STE can predict the prognosis after onset of STEMI.

Methods and Results: This study enrolled 272 patients (mean age, 65 years) with first-time STEMI treated with reperfusion therapy. At 24 h after admission, standard 2D echocardiography and 3D full-volume imaging were performed, and 2D-STE and 3D-STE were calculated. Within 1 year, 19 patients who experienced major adverse cardiac events (MACE; cardiac death, heart failure requiring hospitalization) were excluded. Among the 253 patients, 248 were examined with follow-up echocardiography. The patients were followed up for a median of 108 months (interquartile range: 96–129 months). The primary endpoint was the occurrence of a MACE; 45 patients experienced MACEs. Receiver operating characteristic curves and Cox hazard multivariate analysis showed that the 2D-global longitudinal strain (GLS) and 3D-GLS at 1-year indices were significant predictors of MACE. The Kaplan-Meier curve demonstrated that a 3D-GLS of >−13.1 was an independent predictor for MACE (log-rank χ²=165.5, P<0.0001). The deterioration of 3D-GLS at 1 year was a significant prognosticator (log-rank χ²=36.7, P<0.0001).

Conclusions: The deterioration of 3D-GLS measured by STE at 1 year after the onset of STEMI is the strongest predictor of long-term prognosis.

Post myocardial infarction (MI), left ventricular (LV) remodeling has been reported as a poor prognosticator that is highly associated with increased mortality.^1,2 Even after receiving the primary percutaneous coronary intervention (PCI), some patients experience LV remodeling. However, a recent study suggests that LV remodeling is not related to poor survival rate, but is rather associated with hospitalization due to heart failure (HF).³ Therefore, questions are raised about whether assessment using conventional dimensional analysis remains appropriate. Two-dimensional speckle tracking echocardiography (2D-STE) imaging enables us to assess the subtle LV dysfunctions in patients with various cardiac diseases including ST-elevation acute MI (STEMI).⁴ Moreover, the previous study has shown that three-dimensional (3D)-STE can estimate the changes in the LV region precisely, thereby identifying it as a promising tool for the accurate evaluation of regional wall motion.⁵ We have reported the superior utility of 3D-global longitudinal strain (GLS) in patients with STEMI compared to 2D-GLS in predicting LV remodeling and their 1-year prognosis.⁶ Moreover, we have demonstrated the clinical significance of 3D-STE in patients with STEMI for predicting long-term prognosis, which we have demonstrated as a more useful tool compared to 2D-STE.⁷ However, there are no data about the clinical implications of serial echocardiographic analysis after the onset of STEMI in the contemporary PCI era. Furthermore, the superiority of STE compared to the conventional assessment of LV structure and function remains unknown. Therefore, we conducted a pioneering study involving long-term follow-up examinations to investigate the clinical significance of follow-up 2D-STE and 3D-STE in terms of predicting the long-term prognosis of patients with STEMI.

Editorial p 620

Methods

Patients

We have previously reported the usefulness of the initial echocardiography early after onset of STEMI in this population.^6,7 This current paper discusses the role of follow-up echocardiography retrospectively. We screened 334 STEMI patients between April 2008 and June 2012 at the Yokohama City University Medical Center, Yokohama, Japan. All patients who had undergone reperfusion therapy using PCI within 12 h after symptom onset were enrolled. STEMI was defined as: (1) chest pain lasting >30 min; (2) ST-segment elevation of >0.1 mV within 2 contiguous leads on initial echocardiography; and (3) an elevation in creatinine phosphokinase (CPK) to twice the upper limit of the normal range. The protocol for patient selection is shown in Figure 1. The initial inclusion criteria were as follows: (1) age >20 years; and (2) patients who underwent successful revascularization of the infarct-related artery using primary PCI within 12 h after onset of symptoms. The exclusion criteria were as follows: (1) previous MI (n=15); (2) significant valvular heart disease (n=8); (3) chronic atrial fibrillation (n=19); and (4) inadequate myocardial tracking by 2D-STE or 3D-STE due to poor image quality (n=20). The final initial study population comprised 272 patients who underwent the first echocardiography approximately 24 h after admission (within 48 h). Reperfusion time was defined as the time from symptom onset to reperfusion (TIMI2). ^99mTc-sestamibi single-photon emission computed tomography (SPECT) was performed 7–14 days after PCI to estimate the final infarct size in 266 patients. Infarct size was defined as <50% of the uptake area, which was measured by an experienced radiological technologist (N.T.). During initial hospitalization, the highest levels of creatinine and plasma B-type natriuretic peptide (BNP) were also measured. Renal function was assessed based on the estimated glomerular filtration rate (eGFR). CPK level and myocardial band (MB) were first determined on admission, then at 3-h intervals during the first 24 h, at 6-h intervals for the next 2 days, and then daily until discharge. Within 1 year, 19 patients experienced adverse events, and they were excluded from the analysis.

Figure 1.

The protocol used in this study. Patients with first ST-elevation myocardial infarction (STEMI) who have undergone the reperfusion therapy within 12 h after onset were enrolled. The initial study population comprised 272 patients who underwent echocardiography approximately 24 h after admission (within 48 h). Within 1 year, 19 patients experienced adverse events. The second echocardiography was performed repeatedly at 1 year for 248 patients. Left ventricular (LV) structure and function, including speckle tracking echocardiography (STE), were repeatedly assessed. Serial echocardiography was likewise assessed. The patients were followed up for a median of 108 months from the second echocardiography (IQR 96–129 months; follow-up rate=100%) at regular visits to their attending physicians or by telephone interviews. The primary endpoint was occurrence of late major adverse cardiac events (MACE; incidence of cardiac death and heart failure [HF] hospitalization) during the second follow-up period. The secondary endpoint was all-cause mortality during the second follow-up period.

The second echocardiography was performed repeatedly within 1 year in 248 patients. Then, we checked LV structure and function, including STE, repeatedly. The serial echocardiography was assessed by using conventional 2D echocardiography and STE including 3D-STE. The patients were followed up for a median of 108 months from the second echocardiography (interquartile range [IQR], 96–129 months; follow-up rate=100%) on regular visits to their attending physicians or by telephone interviews. All events were followed up by a hospital visit or telephonic interview with an experienced cardiovascular physician blinded to the clinical details and outcomes. Telephone calls were conducted with patients, physicians, and the next of kin if the patients had been treated at another hospital. The primary endpoint was the occurrence of late major adverse cardiac events (MACE; incidence of cardiac death and HF hospitalization) during the second follow-up period. The secondary endpoint was all-cause mortality during the second follow-up period. HF was defined according to the Framingham criteria.

The Institutional Review Board (Yokohama City University Medical Center) waived the requirement for individual informed consent according to the “opt-out” principle in a retrospective study. Patients could opt out of the database if they wished. Patients/the public were not involved in conducting this research. The study protocol was approved by our institute’s ethics committee (Yokohama City University, Center for Novel and Exploratory Clinical Trials. Reference number: B200900018) and the provisions of the Declaration of Helsinki (UMIN000041995).

Echocardiography

Both 2D and 3D echocardiography were examined using iE33 (Philips Medical System; Andover, MA, USA) by an experienced cardiologist (N.I.). The patients were examined in the left lateral or supine position based on the results of the precordial 2D and 3D echocardiography. LV volumes (end-diastolic volume [EDV], end-systolic volume [ESV]), and ejection fraction [EF]) were calculated using 3D echocardiography. Left atrial (LA) volume was calculated using the area length method. The mitral inflow peak early velocity (E)/mitral annular peak early velocity (e’) or the E/e’ ratio was calculated. The severity of mitral regurgitation (MR) was visually assessed. Based on previous guidelines, 3D full-volume data were acquired from the apical views while the patients held their breath, using a matrix array transducer (X3-1; Philips Medical Systems).⁸ To ensure the inclusion of the entire LV region within the pyramidal scan volume with a relatively high volume rate, data sets from 4 cardiac cycles were acquired using the wide-angle mode, wherein multiple wedge-shaped sub-volumes were acquired with electrocardiographic gating for at least 5- to 7-s single breath holds (stitched data).

2D-Speckle Tracking Echocardiography

The 2D-STE was measured using vendor-independent 2D speckle-tracking software (2D Cardiac Performance Analysis Ver 1.3; TomTec Imaging Systems, Germany). The longitudinal strain was measured by manually tracing the endocardial border in 3 apical views (4-chamber, 2-chamber, and 3-chamber views). After a frame-by-frame speckle-tracking analysis of the LV endocardium that averaged over 2 cardiac cycles, the software provided regional strain curves of 6 segments (4 segments in the apical view) from which the peak regional strain value was calculated. The global strain was calculated as the peak strain value from the average of 16 segmental strain curves (2D-GLS).

3D-Speckle Tracking Echocardiography

The 3D-STE was measured using vendor-independent 3D speckle-tracking software (4D LV Analysis, version 3.1; TomTec Imaging Systems, Germany) by 2 investigators (N.I. and M.H.). After importing 3D full-volume data sets, the apical 4-chamber, 2-chamber, and 3-chamber views, and 3 short-axis views at the end-diastolic phase were automatically extracted. Non-foreshortened apical views were identified to select the point of the apex and the center of the mitral annular line connecting both sides of the mitral annulus with the largest LV long-axis dimensions, after which the 3D endocardial surface was automatically reconstructed. The manual adjustments of the endocardial surface were performed when necessary. The same procedure was performed at the end-systolic phase. The software performed 3D speckle-tracking analysis throughout the cardiac cycle. For 3D strain analysis, LV was automatically divided into 16 segments using standard segmentation schemes. The software provided segmental longitudinal strain time curves, from which peak global strain and average peak strain at 3 LV levels (basal, midventricular, and apical) were determined (3D-GLS). When tracking appeared inappropriate, the endocardial surface was manually re-traced. If tracking was still inaccurate, participants were excluded from the analysis. The Supplementary Figure shows a representative case of the 3D-STE analysis. The left panels show the endocardial tracking, whereas the right panels show the longitudinal strain curves. We defined the strain values at the infarction segment and non-infarction segment separately.

Reproducibility

Reproducibility [N.I. and J.K. examined the inter observer reproducibility] in 2D-STE and 3D-STE was assessed in 20 randomly selected participants in this study, and the agreement between 3D-GLS and 2D-GLS was assessed using the Bland-Altman analysis, with predefined accuracy set as 95% limits of agreement ±2 SD. We previously reported the reproducibility of the initial echocardiography. Therefore, we analyzed the second echocardiography in this study.^6,7

Statistical Analysis

Most continuous variables were not normally distributed (as evaluated by Kolmogorov-Smirnov tests). For uniformity, summary statistics for all continuous variables are presented as medians with the 25th and 75th percentiles (IQR). Categorical data are summarized as frequencies and percentages. We used the t-test for continuous variables and the Chi-squared test for categorical variables to compare positive and negative variables for MACE. To determine the optimal threshold of 2D- and 3D-STE for the prediction of endpoints, receiver operating characteristic (ROC) curve analysis was applied. We compared the area under curves (AUCs) of 2D-GLS, 3D-GLS, LVEF and LA volume index at 1 year using the DeLong method.⁹ In addition, we obtained cut-off values for the LV strain with 2D-GLS and 3D-GLS. We drew the Kaplan-Meier curves for MACE experienced by the 4 groups categorized based on the cut-off values of 2D-GLS and 3D-GLS, as determined by ROC curves. The log-rank test was used to evaluate differences among the groups. Next, pairwise models were examined. We adopted the Cox proportional hazard models for the prediction of MACE with all independent variables. Because there are some collinearities among parameters, we analyzed variance inflation factors (VIF) to check the presence of multicollinearity as VIF<4.0. Then, we analyzed the multiple Cox proportional hazard analysis using either 2D-GLS or 3D-GLS. Because LVEF is calculated by LVEDVI and LVESVI, we selected LVEF as the parameter of systolic function. All statistical tests were 2-sided. For all tests, a P value of <0.05 was considered statistically significant. Statistical analyses were performed using JMP Pro 15 (SAS Institute, Inc., Cary, NC, USA).

Results

Baseline Data of the Study Population

Table 1 shows the baseline characteristics of the patients who underwent the initial (n=272) and the second (n=248) echocardiography tests. Table 2 shows the parameters of the initial and the second echocardiography tests. Twelve months after discharge, 19 patients experienced MACE. There were no patients with atrial fibrillation who underwent a 2nd echocardiography at 1 year in this study.

Table 1. Patient Characteristics According to the Presence of MACE Within 12 Months

Category	1st echocardiography (n=272)	2nd echocardiography (n=248)
Patients background
Age (years)	65 (57–73)	64 (56–73)
Sex male, n (%)	222 (82)	206 (83)
BSA (m2)	1.71 (1.58–1.83)	1.71 (1.58–1.83)
sBP (mmHg)	110 (100–120)	110 (100–120)
dBP (mmHg)	60 (56–68)	64 (56–68)
HR (beats/min)	72 (66–80)	64 (60–70)
Risk factors
Hypertension (yes)	168 (62)	149 (61)
Diabetes mellitus (yes)	75 (28)	67 (27)
Anterior MI (yes)	144 (53)	127 (51)
MVD, n (%)	87 (34)	76 (32)
Killip >1	71 (26)	58 (23)
Reperfusion time (min)	135 (99–220)	130 (99–212)
Peak CPK (IU/L)	3,019±3,280	2,761±2,867
Peak CPK-MB (IU/L)	273±274	247±229
Biochemical markers
HbA1c (%)	5.7 (5.3–6.2)	5.7 (5.3–6.2)
Admission BNP (pg/mL)	26.8 (11.8–78.2)	26.5 (26.7–72.7)
Maximum BNP (pg/mL)	91.7 (42.5–204.3)	86.2 (39.7–176.3)
eGFR (mL/min/1.73 m2)	63.1 (52.1–77.7)	63.5 (52.4–77.8)
MIBI SPECT
Infarct size (IS)	6.3 (0–32)	5.5 (0–28)
Mediation at discharge
β-blocker, n (%)	228 (84)	210 (85)
ACE inhibitor/ARB, n (%)	259 (96)	237 (96)
Statins, n (%)	267 (99)	248 (99)

Data are given as the mean±SD, n (%), or median [interquartile range]. ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BNP, B-type natriuretic peptide; BSA, body surface area; CPK, creatine phosphokinase; dBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HbA1c, glycohemoglobin A1c; HR, heart rate; MACE, major adverse cardiac event; MB, myocardial band; MI, myocardial infarction; MIBI, ^99mTc Methoxy-isobutyl-isonitrile; MVD, multi vessel disease; sBP, systolic blood pressure; SPECT, single photon emission computed tomography.

Table 2. Cardiac Parameters of the 1st and 2nd Echocardiography

	1st echocardiography (n=272)	2nd echocardiography (n=248)	P value*
Echocardiography
LVEDVI (mL/m2)	63.1±20.3	66.2±21.6	<0.0001
LVESVI (mL/m2)	31.3±16.2	30.3±17.1	0.29
LVEF (%)	52±12.5	56±12.1	0.03
LAVI (mL/m2)	35.1±12.2	40.2±13.4	0.02
TMF
E wave (cm/s)	74±21	73±25	0.75
A wave (cm/s)	82±23	76±21	0.002
Dct (ms)	213±67	211±66	0.84
E/e’	13.4±5.7	12.6±7.1	<0.0001
MR moderate~ (yes)	21 (8)	10 (3)	0.001
Speckle tracking
2D-GLS (%)	−12.4±3.4	−14.9±3.6	<0.0001
Infarct zone	−8.4±3.5	−14.0±4.8	<0.0001
Non-infarct zone	−12.5±4.0	−15.8±34.2	<0.0001
3D-GLS (%)	−12.5±3.0	−14.6±3.6	<0.0001
Infarct zone	−8.7±2.9	−14.1±4.1	<0.0001
Non-infarct zone	−12.7±3.8	−15.6±3.9	<0.0001

Data are given as the mean±SD, n (%), or median [interquartile range]. *P values are for 1st echocardiography vs. 2nd echocardiography. A, late diastolic; Dct, deceleration time; E, early diastolic wave velocity; e’, early diastolic velocity of mitral annulus; EDVI, end-diastolic volume index; EF, ejection fraction; ESVI, end-systolic volume index; GLS, global longitudinal strain; LAVI, left atrial volume index; LV, left ventricular; MR, mitral regurgitation; TMF, trans mitral flow; 2D, 2-dimensional; 3D, 3-dimensional.

Follow up

During the second follow-up period (Figure 1) after the second echocardiography, 48 patients experienced MACE (late MACE: 22 patients experienced cardiac death, 26 patients experienced HF), and 44 patients died from all causes (22 cardiovascular deaths, 22 non-cardiovascular deaths). We then determined the predictors for late MACE.

Table 3 shows Cox proportional hazard models to predict late prognosis according to the indices at 1 year. Univariate analysis shows age, LVEDVI, LVESVI, LVEF, LAVI, E/e’, MR grade, 2D-GLS, and 3D-GLS as the significant predictors. Multivariate model 1 using 2D-GLS showed that age, E/e’ and 2D-GLS were significant predictors. Multivariate model 2 analysis using 3D-GLS showed that age, LAVI and 3D-GLS were significant predictors.

Table 3. Cox Proportional Hazard Analysis to Predict Late MACE by Using the 2nd Echocardiography

	Univariate			Multivariate 1			Multivariate 2
	HR	95% CI	P value	HR	95% CI	P value	HR	95% CI	P value
Clinical indices
Age (years)	1.08	1.05–1.11	<0.0001	1.05	1.01–1.09	0.01	1.04	1.01–1.09	0.0001
Gender, female (yes)	0.75	0.37–1.52	0.45	1.06	0.32–3.49	0.92	1.04	0.30–3.58	0.94
Infarct size (%)	1.02	0.99–1.03	0.1	0.98	0.96–1.01	0.12	0.98	0.96–1.00	0.11
Conventional echocardiography
Systolic function
LVEDVI (mL/m2)	1.02	1.00–1.03	0.005	–	–	–	–	–	–
LVESVI (mL/m2)	1.02	1.01–1.03	0.004	–	–	–	–	–	–
LVEF (%)	0.96	0.93–0.98	0.0004	0.96	0.92–1.01	0.15	0.99	0.94–1.04	0.77
Diastolic function
LAVI (mL/m2)	1.03	1.01–1.05	<0.0001	1.01	0.98–1.03	0.63	1.02	1.00–1.03	0.03
E/e’	1.06	1.03–1.10	<0.0001	1.06	1.02–1.11	0.001	1.04	0.99–1.03	0.06
MR moderate~ (yes)	2.71	1.07–6.83	0.03	1.03	0.31–3.34	0.96	1.25	0.37–4.23	0.72
Speckle tracking
2D-GLS (%)	1.49	1.36–1.62	<0.0001	1.61	1.38–1.88	<0.0001	–	–	–
3D-GLS (%)	1.38	1.28–1.48	<0.0001	–	–	–	1.53	1.35–1.74	<0.0001

CI, confidence interval; HR, hazard ratio; – not selected. Other abbreviations are defined in Table 1 and Table 2.

We also analyzed the clinical role of serial change in echocardiography. Table 4 shows the Cox proportional hazard analysis according to the value of the change of the echocardiography after 1 year. Univariate analysis shows LAVI, E/e’, 2D-GLS, and 3D-GLS as the significant predictors. Multivariate model 1 using 2D-GLS showed that both ∆LAVI and ∆2D-GLS were significant predictors. Multivariate model 2 using 3D-GLS showed that both ∆E/e’ and ∆3D-GLS were significant predictors.

Table 4. Cox Proportional Hazard Analysis to Predict Late MACE by Change in Echocardiography

	Univariate			Multivariate 1			Multivariate 2
	HR	95% CI	P value	HR	95% CI	P value	HR	95% CI	P value
Conventional echocardiography
Systolic function
ΔLVEDVI (mL/m2)	1.01	0.99–1.03	0.11	–	–	–	–	–	–
ΔLVESVI (mL/m2)	1.01	0.99–1.02	0.14	–	–	–	–	–	–
ΔLVEF (%)	1.001	0.99–1.02	0.71	0.99	0.84	0.79	0.98	0.95–1.02	0.36
Diastolic function
ΔLAVI (mL/m2)	1.04	1.01–1.06	0.001	1.04	1.01–1.06	0.004	1.02	0.99–1.04	0.11
ΔE/e’	1.04	1.01–1.07	0.04	1.04	0.99–1.08	0.05	1.06	1.01–1.11	0.02
ΔMR grade	1.11	0.79–1.54	0.55	1.04	0.75–1.44	0.88	1.15	0.81–1.82	0.42
Speckle tracking
Δ2D-GLS (%)	1.26	1.09–1.44	0.001	1.42	1.19–1.69	<0.0001	–	–	–
Δ3D-GLS (%)	1.47	1.26–1.73	<0.0001	–	–	–	1.49	1.25–1.77	<0.0001

Δ, the change of. Other abbreviations are defined in Tables 1–3.

We compared the echocardiographic indices at 1 year using ROC curves with the DeLong method (Figure 2), 3D-GLS (red line), 2D-GLS (green line), LAVI (brown line) and LVEF (blue line). There was significant differences among the 4 parameters (P<0.0001), and there were significant differences between each parameter, except between LAVI and LVEF (3D-GLS vs. 2D-GLS, P=0.03; 2D-GLS vs. LAVI, P<0.0001; LAVI vs. LVEF, P=0.09). As determined by ROC curves, the cut-off value of 2D-GLS at 1 year was −14.1, sensitivity was 0.74, 1-specificity was 0.60, and AUC=0.836, P<0.0001. The cut-off value of 3D-GLS at 1 year was −13.1, sensitivity was 0.867, 1-specificity was 0.662, and AUC=0.901, P<0.0001. The patients’ characteristics according to the 3D-GLS value at 1 year are shown in the Supplementary Table.

Figure 2.

Receiver operating characteristic (ROC) analyses of global longitudinal strain at 1 year for the prediction of late major adverse cardiac events (MACE) using 3-dimensional global longitudinal strain (3D-GLS; red line), 2-dimentional (2D)-GLS (green line), left atrial volume index (LAVI; brown line) and left ventricular ejection fraction (LVEF; blue line). There were significant differences among the 4 parameters to predict late MACE (P<0.0001), and there were significant differences between each parameter, except between LAVI and LVEF (3D-GLS vs. 2D-GLS, P=0.03; 2D-GLS vs. LAVI, P<0.0001; LAVI vs. LVEF, P=0.09). As determined by ROC curves, the cut-off value of 2D-GLS at 1 year was −14.1, sensitivity was 0.74, 1-specificity was 0.60, and AUC=0.836, P<0.0001. The cut-off value of 3D-GLS at 1 year was −13.1, sensitivity was 0.867, 1-specificity was 0.662, and AUC=0.901, P<0.0001.

We analyzed a Kaplan-Meier curve to predict late MACE (after 1 year). Figure 3A shows the Kaplan-Meier curves for the prediction of MACE according to 2D-GLS=−14.1. There was a significant difference between the 2 curves (Log-rank χ²=78.7, P<0.0001). Figure 3B shows the Kaplan-Meier curves for the prediction of MACE according to 3D-GLS=−13.1. There was a significant difference between the 2 curves (Log-rank χ²=165.5, P<0.0001). Figure 3C shows the Kaplan-Meier curves for the prediction of MACE according to the deterioration of 2D-GLS. There was a significant difference between the 2 curves (Log-rank χ²=4.95, P=0.02). Figure 3D shows the Kaplan-Meier curves for the prediction of MACE according to the deterioration of 3D-GLS. There was a significant difference between the 2 curves (Log-rank χ²=36.7, P<0.0001). These 4 figures demonstrate the clinical usefulness of serial GLS measurements to predict late MACE. Table 5 shows the univariate and multivariate Cox proportional hazard analysis for all-cause death. Model 1 showed age and 2D-GLS, and model 2 showed age and 3D-GLS were the independent predictors.

Figure 3.

Kaplan-Meier curves for the prediction of late major adverse cardiac events (MACE). (A) Prediction of MACE according to the 2D-GLS=−14.1. There was a significant difference between the 2 curves (Log-rank χ²=78.7, P<0.0001). (B) Prediction of MACE according to the 3D-GLS=−13.1. There was a significant difference between the 2 curves (Log-rank χ²=165.5, P<0.0001). (C) Prediction of MACE according to the deterioration of 2D-GLS. There was a significant difference between the 2 curves (Log-rank χ²=4.95, P=0.02). (D) Prediction of MACE according to the deterioration of 3D-GLS. There was a significant difference between the 2 curves (Log-rank χ²=36.7, P<0.0001).

Table 5. Cox Proportional Hazard Analysis to Predict Death by Using the 2nd Echocardiography

	Univariate			Multivariate 1			Multivariate 2
	HR	95% CI	P value	HR	95% CI	P value	HR	95% CI	P value
Clinical indices
Age (years)	1.11	1.08–1.15	<0.0001	1.09	1.05–1.13	<0.0001	1.09	1.05–1.13	<0.0001
Gender, female (yes)	0.54	0.28–1.06	0.06	0.69	0.27–1.75	0.44	0.65	0.26–1.64	0.37
Infarct size	1.01	0.98–1.02	0.66	0.97	0.97–1.01	0.1	0.97	0.96–1.01	0.11
Conventional echocardiography
Systolic function
LVEDVI (mL/m2)	1.01	0.99–1.02	0.28	–	–	–	–	–	–
LVESVI (mL/m2)	1	0.99–1.02	0.18	–	–	–	–	–	–
LVEF (%)	0.97	0.94–0.99	0.01	0.96	0.93–1.01	0.06	0.97	0.93–1.01	0.09
Diastolic function
LAVI (mL/m2)	1.03	1.02–1.05	<0.0001	1.01	0.90–1.02	0.43	1.01	0.99–1.03	0.25
E/e’	1.07	1.05–1.10	<0.0001	1.02	0.98–1.04	0.45	1.02	0.97–1.05	0.16
MR moderate~ (yes)	2.06	0.63–6.63	0.27	1.37	0.39–4.78	0.82	1.52	0.44–5.23	0.51
Speckle tracking
2D-GLS (%)	1.35	1.23–1.49	<0.0001	1.77	1.43–2.25	<0.0001	–	–	–
3D-GLS (%)	1.3	1.20–1.40	<0.0001	–	–	–	1.44	1.22–1.68	<0.0001

Abbreviations are defined in Table 1–3.

Reproducibility

Bland-Altman plot analysis revealed a bias of 0.165 for 2D-GLS calculated by 2 observers, with 95% limits of agreement ranging from −0.765 to −0.077. This was also observed in the 3D-GLS analysis, which revealed a bias of 0.110, as calculated by 2 observers, with 95% limits of agreement ranging from −0.588 to −0.128.

Discussion

In this pioneering study, we investigated the clinical significance of follow-up 2D-STE and 3D-STE in terms of predicting the long-term prognosis of patients with STEMI. This study demonstrated that 3D-GLS at 1 year after reperfusion therapy can be the strongest predictors of patients’ 10-year prognosis after STEMI; second was 2D-GLS. These are stronger than the conventional LV remodeling parameters (LVEDVI, LVESVI, and LVEF). Furthermore, serial changes of GLS were stronger predictors than the changes demonstrated for conventional echocardiographic parameters. GLS was an independent predictor for all-cause death, but EF was not. Therefore, we suggest the evaluation of cardiac function using serial strain imaging after the onset of STEMI; 3D-STE was especially useful.

Some exceptional findings distinguish our study from existing literature. First, we performed 2D and 3D echocardiography at 24 h after the onset of STEMI. Moreover, we examined echocardiography 1 year after symptom onset repeatedly. Second, we studied only those patients who had their first STEMI with reperfusion within 12 h of symptom onset whose CPK was greater than twice the upper limit of normal range. Third, we analyzed infarct size using SPECT. Fourth, we analyzed not only 3D-STE, but also 2D-STE findings using vendor-independent software. There are significant differences among strain values calculated by different vendor software.¹⁰ Finally, the patients were followed up for a long period of time.^11,12 Thus, we were able to adequately exhibit serial echocardiographic analysis including 2D and 3D strain analysis after the onset of STEMI.

It has been reported that there is no difference in long-term survival between LV remodelers and non-LV remodelers. LV remodelers also experience a higher rate of hospitalization due to HF, even during the contemporary PCI era.³ We think these results are due to the prevalence of early reperfusion therapy and medical treatment. Primary PCI has revolutionized the management of STEMI and dramatically improved outcomes. The conventional strategy for the examination of LV remodeling is by quantitative measurement. In contrast, STE measurements are qualitative assessments of LV anatomy and function. Therefore, in the contemporary era, we believe that serial LV function should be measured using STE analysis in patients with STEMI. Although LVEDVI increased in many cases, the strain parameters in most of the analyzed patients improved. We think this is mainly because strain can evaluate stunned myocardium.¹³ We emphasize that the absolute change of strain parameters should be checked; consequently, strain parameters were increased in many cases. Accordingly, we can recommend using STE, especially 3D-STE, as a new strategy in the evaluation of cardiac remodeling after the onset of STEMI. We think this evaluation could be the new assessment of LV remodeling for STEMI in the contemporary PCI era and we can manage cardiac function appropriately using 3D-GLS. Accordingly, we should emphasize the lifestyle modification more aggressively based on the serial 3D-GLS examinations. During the study period, we could not prescribe the new cardioprotective drugs such as inhibitors of the sodium-glucose cotransporter or sacubitril valsartan;^14,15 however, the results presented here suggest that we may be able to determine the patients who are eligible for these cardioprotective drugs, thereby potentially improving patient prognosis.¹⁶ Further investigation and clinical evidence are needed to confirm these issues.

Previous guidelines recommend the assessment of conventional LV function as a reproducible index that can be used to identify improvement or worsening of patients’ conditions.^17,18 As demonstrated previously, GLS indicates infarct size after MI, which partially contributes to its prognostic value.¹⁹ Furthermore, strain analysis can reveal transmurality.²⁰ As longitudinally arranged sub-endocardial fibers are at the maximum risk of injury during MI, there is a risk of adverse LV remodeling. It has been reported that longitudinal strain itself predicts LV remodeling.²¹ Strain analysis can evaluate accurate LV function without a tethering effect.²² We found that 3D-STE was more advantageous than 2D-STE, likely due to the ability of 3D-STE to examine the whole heart as compared to 2D-STE.²³ We have already reported the clinical usefulness of bedside echocardiography including tissue Doppler and STE.^6,24,25 Notably, we have found that even 2D-STE is better than the conventional assessment at 1 year in the current study. We believe that this is due to the situation of the examination. Specifically, since the second echocardiography was performed during a less urgent situation, hence allowing us to examine the patient more easily, the position was not as limited when compared to the first echocardiography, which was conducted during an emergency.

Clinical Implications

Our study has confirmed that strain imaging at 1 year, especially using 3D-GLS, can predict long-term prognosis after STEMI. The prognosis after STEMI can be precisely predicted in the acute phase by using STE. Moreover, serial changes of STE enabled us to predict the prognosis more precisely compared with using other conventional echocardiographic parameters. Thus, we strongly believe that STE is a better tool for evaluating the deterioration and improvement of LV function than conventional methods; 3D-STE, in particular, would be the best to use. We believe that the strategy of the evaluation of STEMI should shift to the evaluation by 3D-STE.

Study Limitations

This study has several limitations. First, this was a retrospective, single-center study, thus limiting the generalizability of it. Second, the analyses by 2D- and 3D-STE were performed using offline software. Third, because the initial echocardiographic examinations were performed at the bedside, scanning the patients was technically challenging. However, we observed a learning curve in obtaining appropriate data from full-volume 3D images, as demonstrated by differences in the first and second echocardiography results wherein the investigators underwent thorough training and undertook careful examination on a daily basis.²⁶ Fourth, infarct size estimation in all patients was performed by scintigraphy and CPK/MB. We did not perform cardiac MRI or measured troponin levels. Although these are some minor limitations, we recommend this newly developed method as it offers improved treatment options for cardiac patients.

Conclusions

Our study shows that 3D-GLS after 1 year is a useful tool for the prediction of long-term prognosis in patients with STEMI who have undergone reperfusion therapy. We recommend the serial assessment of cardiac function by using 3D-STE in patients with STEMI. At 1 year, both 2D- and 3D-GLS were useful, but 3D-GLS was the best predictor for MACE. Further studies are needed to confirm the usefulness of STE in determining STEMI prognosis.

Author Contributions

All authors read and approved the final manuscript.

Disclosures

K.K. and M.K. are Editorial Members for Circulation Journal.

IRB Information

Yokohama City University, Center for Novel and Exploratory Clinical Trials, approved this study (Reference number: B200900018).

Data Availability

1. The individual deidentified participant data will be shared.

2. All analyzable data sets related to the study will be shared.

3. The study protocol and statistical analysis plan will be available.

4. The data will be available immediately following publication, and ending 10 years after publication.

5. Anyone who wishes to access the data should contact the corresponding author.

6. The data will be shared in Microsoft Excel files via email, upon request.

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-21-0815

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