Prognostic Significance of a Combination of QRS Score and E/e′ Obtained 2 Weeks After the Onset of ST-Elevation Myocardial Infarction

Noriaki Iwahashi; Masaomi Gohbara; Jin Kirigaya; Takeru Abe; Mutsuo Horii; Hironori Takahashi; Masami Kosuge; Yohei Hanajima; Eiichi Akiyama; Kozo Okada; Yasushi Matsuzawa; Nobuhiko Maejima; Kiyoshi Hibi; Toshiaki Ebina; Kouichi Tamura; Kazuo Kimura

doi:10.1253/circj.CJ-20-0486

Abstract

Background: The early mitral inflow velocity to mitral early diastolic velocity ratio (E/e′) and electrocardiogram (ECG) determination of QRS score are useful for risk stratification in patients with ST-elevation myocardial infarction (STEMI).

Methods and Results: In this study, 420 consecutive patients (357 male; mean [±SD] age 63.6±12.2 years) with first-time STEMI who successfully underwent primary percutaneous coronary intervention within 12 h of symptom onset were followed-up for 5 years (median follow-up 67 months). Echocardiography, ECG, and blood samples were obtained 2 weeks after onset. Infarct size was estimated by the QRS score after 2 weeks (QRS-2wks) and creatine phosphokinase-MB concentrations (peak and area under the curve). The primary endpoint was death from cardiac causes or rehospitalization for heart failure (HF). During follow-up, 21 patients died of cardiac causes and 62 had HF. Multivariate Cox proportional hazard analysis showed that mean E/e′ (hazard ratio [HR] 1.152; 95% confidence interval [CI] 1.088–1.215; P<0.0001), QRS-2wks (HR 1.153; 95% CI 1.057–1.254; P<0.0001), and hypertension (HR 1.702; 95% CI 1.040–2.888; P=0.03) were independent predictors of the primary endpoint. Kaplan-Meier curve analysis showed that patients with QRS-2wks >4 and mean E/e′ >14 were at an extremely high risk of cardiac death or HF (log rank, χ²=116.3, P<0.0001).

Conclusions: In patients with STEMI, a combination of QRS-2wks and mean E/e′ was a simple but useful predictor of cardiac death and HF.

The outcomes of patients following acute myocardial infarction (AMI) are usually predicted on the basis of infarct size, as assessed by QRS scores determined using electrocardiography (ECG),¹ cardiac enzyme levels, and scintigraphy or delayed contrast-enhanced magnetic resonance imaging (DE-MRI). The gold standard in vivo techniques for quantification of infarct size are DE-MRI and scintigraphy; however, these methods are not universally available.² Conversely, an ECG does not require any special equipment to estimate infarct size,³^,⁴ and we previously reported on the usefulness of a QRS score to predict poor myocardial perfusion in patients with anterior AMI.⁵

Elevated left ventricular (LV) filling pressures are clearly associated with poor functional and clinical outcomes following the onset of AMI. The ratio of early transmitral flow velocity (E) to early diastolic mitral annual velocity (e′) has been shown to be an accurate non-invasive predictor of elevated mean LV diastolic pressure in patients with preserved systolic function.⁶ Previously, we reported the usefulness of E/e′ 2 weeks after the onset of STEMI in predicting long-term prognosis.⁷

We think that STEMI evaluations should be performed during the stable phase.⁷ Thus, the present study was designed to determine the best variable that would serve as an accurate predictor of outcomes 2 weeks after the onset of first-time STEMI in conjunction with the QRS score, as estimated by ECG. Furthermore, we assessed the ability of the combination of E/e′ and QRS score to predict prognosis following first-time STEMI.

Methods

The study protocol is illustrated in the Supplementary Figure. In all, 520 consecutive patients with STEMI at Yokohama City University Medical Center, Yokohama, Japan, between May 2005 and December 2012 were reviewed for this study. Patients with a prior myocardial infarction, chronic atrial fibrillation, chronic renal failure treated by dialysis, insufficient or unacceptable echocardiographic images, and those who had undergone emergency coronary artery bypass surgery were excluded. Of the remaining 461 patients, 41 met the criteria for an abnormal ECG (left or right bundle branch block, LV hypertrophy or ventricular pacing) and were also excluded, leaving 420 patients for analysis.

All patients underwent reperfusion therapy by primary percutaneous coronary intervention (pPCI) within 12 h after the onset of symptoms. The diagnosis of STEMI was based on chest pain lasting for >30 min but <12 h, in association with ECG changes (new-onset ST-segment elevation ≥1 mm in at least 2 extremity leads or ≥2 mm in at least 2 contiguous precordial leads). The diagnosis was confirmed by coronary angiography. The medication at discharge for all patients in this study is given in Table 1. Patients were followed-up for a median of 67 months (interquartile range [IQR] 56–74 months) after their first hospitalization through regular visits to their physicians or through telephone interviews, who were not treating the attending patients (M.H.), he belongs to the division of cardiology at the same time labolatory division, thereby he doesn’t treat the patients principally. The primary endpoint was cardiac death or rehospitalization for heart failure (HF).

Table 1. Baseline Characteristics in All Patients and in Patients Stratified According to the Primary Endpoint and E/e′

	All patients (n=420)	Primary endpoint			Averaged-E/e′ >14.0
	All patients (n=420)	No (n=337)	Yes (n=83)	P value	No (n=303)	Yes (n=117)	P value
Age (years)	63.0±12.0	62.3±12.1	68.8±11.6	<0.0001	61.4±11.9	68.5±11.7	<0.0001
Female sex	63 (15)	50 (15)	13 (16)	0.85	37 (12)	26 (22)	0.01
BSA (m²)	1.71±0.19	1.72±0.18	1.66±0.19	0.01	1.72±0.18	1.66±0.18	0.006
Medical history
Smoking history	324 (77)	255 (76)	69 (83)	0.14	239 (79)	85 (73)	0.17
Hypertension	229 (55)	168 (50)	61 (73)	0.0001	150 (50)	79 (68)	0.0007
Glycemic disorder				0.29			0.006
NGT	102 (24)	85 (25)	17 (21)		73 (24)	29 (25)
IGT	147 (35)	121 (36)	26 (31)		119 (39)	28 (24)
Diabetes	171 (41)	131 (39)	40 (48)		111 (37)	60 (51)
Culprit lesions
LMT	7 (2)	4 (1)	3 (4)	0.15	3 (1)	4 (3)	0.25
LAD	196 (47)	153 (45)	43 (51)		142 (48)	54 (47)
LCx	59 (14)	46 (14)	13 (16)		40 (13)	19 (16)
RCA	158 (37)	134 (40)	24 (29)		118 (38)	40 (34)
Reperfusion time (min)	192±155	190±159	199±137	0.07	179±142	223±180	0.001
No-reflow/slow flow	70 (16)	50 (15)	20 (24)	0.03	41 (13)	29 (16)	0.005
Peak CPK (IU/L)	1,941 [929–3,764]	1,921 [913–3,511]	1,958 [1,040–5,470]	0.12	1,893 [928–3,385]	2,350 [951–5,371]	0.09
Peak CPK-MB (IU/L)	185 [90–339]	179 [88–319]	259 [100–473]	0.01	168 [94–308]	226 [89–462]	0.04
AUC_CPK (IU/L)	55,762 [29,478–106,715]	52,806 [29,376–100,262]	73,728 [31,587–144,121]	0.03	51,527 [29,483–97,721]	74,525 [30,824–131,165]	0.02
AUC_CPK-MB(IU/L)	4,860 [2,573–8,400]	4,630 [2,526–8,083]	6,166 [2,963–11,168]	0.01	4,512 [2,559–7,868]	6,163 [2,680–10,503]	0.01
Electrocardiography
QRS-adm	2.63±2.53	2.35±2.27	3.78±3.28	<0.0001	2.38±21.8	3.27±3.18	0.02
QRS-PCI	3.93±2.96	3.58±2.71	5.37±3.51	<0.0001	3.74±2.68	4.44±3.54	0.001
QRS-2wks	2.69±2.63	2.33±2.35	4.28±3.14	<0.0001	2.33±2.30	3.67±3.17	<0.0001
ST resolution				0.12			0.3
Good or fair	292 (70)	245 (73)	47 (57)		215 (71)	77 (66)
Absent, <30%	128 (30)	92 (27)	36 (43)		88 (29)	40 (34)
Multivessel coronary disease	139 (33)	104 (31)	35 (43)	0.11	97 (32)	42 (36)	0.22
Killip classification			<0.0001				0.001
I	346 (82)	291 (86)	55 (66)		263 (87)	83 (71)
II	34 (8)	27 (8)	7 (9)		19 (6)	15 (13)
III	20 (5)	8 (3)	12 (14)		9 (3)	11 (9)
IV	20 (5)	11 (3)	9 (11)		12 (4)	8 (7)
Biochemical markers at 2 weeks
BNP (pg/mL)	159±201	122±129	302±331	<0.0001	121±147	254±276	<0.0001
eGFR (mL/min/1.73 m²)	63.0±18.0	64.6±17.1	56.6±2.4	<0.0001	65.6±17.7	56.2±18.1	<0.0001
Hemoglobin (g/dL)	13.0±1.8	13.3±1.8	11.7±1.4	<0.0001	13.3±1.7	12.2±1.7	<0.0001
HbA1c (%)	6.2±1.4	6.2±1.5	6.3±1.3	0.24	6.2±1.5	6.3±1.4	0.42
Medications at discharge
Aspirin	419 (99)	337 (100)	82 (99)	0.92	303 (100)	116 (99)	0.91
ACE inhibitor/ARB	382 (91)	308 (92)	74 (91)	0.64	280 (92)	102 (87)	0.17
β-blocker	312 (75)	252 (75)	60 (72)	0.64	223 (74)	89 (76)	0.6
Statins	400 (95)	322 (96)	78 (94)	0.55	290 (96)	110 (94)	0.46
Diuretics	33 (8)	14 (4)	19 (25)	<0.0001	12 (4)	21 (19)	<0.0001

Data are given as the mean±SD, n (%), or median [interquartile range]. ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; BNP, B-type natriuretic peptide; BSA, body surface area; CPK, creatine phosphokinase; E/e′, early mitral inflow velocity to mitral early diastolic velocity ratio; eGFR, estimated glomerular filtration rate; IGT, impaired glucose tolerance; LAD, left anterior descending coronary artery; LCx, left circumflex coronary artery; LMT, left main trunk; NGT, normal glucose tolerance; QRS-2wks, QRS score 2 weeks after the onset of symptoms; QRS-adm, QRS score on admission; QRS-PCI, QRS score after percutaneous coronary intervention; RCA, right coronary artery.

All patients provided informed consent, and the study protocol was approved by the Yokohama City University, Center for Novel and Exploratory Clinical Trials Ethics Committee (Reference no. D1308002). In addition, the study was registered with the UMIN Clinical Trials Registry (UMIN000020083).

Echocardiography was performed approximately 2 weeks (mean [±SD] 13.4±5.9 days, during convalescence) after STEMI onset by experienced observers (N.I., M.G.) who were blinded to all angiographic and clinical data. Patients were examined in the left lateral position using precordial 2-dimensional and Doppler echocardiography. Aplio (SSA-770A; Toshiba), iE33 (Philips Medical System) and Vivid q and VividE9 (GE Vingmed, Horten, Norway) ultrasound systems were used in this study. LV ejection fraction (LVEF) and left atrial (LA) volume were calculated using the biplane modified Simpson’s method from apical 4- and 2-chamber views. LA volume was divided by body surface area to yield the LA volume index (LAVI). Transmitral flow (TM) was assessed in the apical 4-chamber view using pulsed-wave Doppler echocardiography with the Doppler beam aligned parallel to the direction of flow and the sample volume at the leaflet tips. E- and A-wave peak velocities and deceleration times (TM-Dct) were measured from the mitral inflow profile. Tissue Doppler imaging of the mitral annulus was performed in the apical 4-chamber view using a 1- to 2-mm sample volume placed at both the septal and lateral sides; the mean of the values was used. Mean values for the primary measurements were obtained from 3 cardiac cycles, including systolic (s′), early diastolic (e′), and late diastolic (a′) velocities. E/e′ was obtained at the septal (septal E/e′) and lateral (lateral E/e′) sides of the mitral annulus and then averaged (mean E/e′). Peak velocities of systolic, diastolic, and atrial contraction waves were derived from pulmonary venous flow (PV). To calculate the deceleration time of diastolic waves (PV-Dct), a line was drawn from the peak early diastolic velocity along the fall in initial velocity and extrapolated to baseline. By visually comparing the mitral regurgitation (MR) color flow jet area with the atrial area in multiple views, MR was graded as absent, mild, moderate or severe, with moderate and severe MR defined as significant MR.⁸ Color gain was adjusted just below the level of noise.

A 12-lead ECG was recorded on admission (QRS-adm), after the PCI (QRS-PCI), and 2 weeks after onset (QRS-2wks) at a paper speed of 25 mm/s and an amplification of 10 mm/mV. ST-segment elevation was measured 0.08 s after the J point by 2 cardiologists who were blinded to all other clinical data. ST-segment elevation was calculated as the sum of ST-segment elevations in Leads I, aV_L, and V_1–6 for anterior AMI and Leads II, III, aV_F, and V_5–6 for non-anterior AMI.

In addition to ST-segment measurements, we calculated a 32-point QRS score,⁴^,⁹ which has been validated in patients with AMI and is strongly correlated with both infarct size¹⁰ and prognosis.¹¹ ST-segment resolution was categorized as complete (>70%), partial (30–70%), or absent (<30%) to assess myocardial reperfusion.¹²^,¹³ Figure 1 shows representative traces of QRS-2wks and averaged E/e′.

Figure 1.

Representative electrocardiograms and echocardiography in patients with (Case 1) and without (Case 2) the primary endpoint. Case 1: this patient experienced the primary endpoint (heart failure rehospitalization) during follow-up. In this patient, the QRS score determined 2 weeks after the onset of symptoms (QRS-2wks) was 9 (Left) and the mean early mitral inflow velocity to mitral early diastolic velocity ratio (E/e′) was 23.0 (Right). The culprit lesion in this patient was in Segment 6, the peak creatine phospho kinase (CPK) concentration was 6,055 IU/L, and final TIMI grade was 2. Case 2: in this patient, in whom the primary endpoint was not seen had a QRS-2wks of 0 (Left) and a mean E/e′ of 8.0 (Right). The culprit lesion in this patient was at Segment 7, the peak CPK concentration was 680 IU/L, and the final TIMI grade was 33.

Coronary angiography was performed according to standard criteria. All patients received an intravenous bolus injection of 5,000 IU heparin and intracoronary isosorbide dinitrate (2–2.5 mg). Epicardial blood flow in the infarct-related artery and the myocardial perfusion grade were graded according to the definitions set by the Thrombolysis in Myocardial Infarction (TIMI) group.¹⁴ We determined the no-reflow phenomenon because it has been reported as a prognosticator.¹⁵ The diagnosis of no-reflow required that the following criteria be met: (1) angiographic evidence of reopening of an occluded coronary artery with no evidence of flow-limiting residual stenosis (>50%), dissection, spasm, or apparent thrombus; and (2) angiographic documentation of a TIMI flow grade ≤2.

Cardiac enzyme concentrations were determined on admission, at 3-h intervals during the first 24 h, at 6-h intervals for the next 2 days, and then daily until discharge. Peak concentrations of creatine phosphokinase (CPK)-MB and the area under the curve (AUC) for CPK-MB were calculated by the linear-trapezoidal method to identify the extent of myocardial injury.¹⁶

Blood samples were obtained 2 weeks after onset, based on a previous study.¹⁷ Hemoglobin, creatinine, and plasma B-type natriuretic peptide (BNP) were measured. Renal function was assessed on the basis of the estimated glomerular filtration rate (eGFR), which was calculated using the abbreviated 4-variable Modification of Diet in Renal Disease equation.

All examinations (echocardiography, ECG, and biochemical markers) were performed during the initial hospitalization.

Statistical Analysis

Statistical analyses were performed using JMP Pro 12.0 (SAS Institute, Cary, NC, USA). Results are expressed as the mean±SD for continuous variables and as frequency counts with percentages for categorical variables. Continuous variables were compared using Student’s t-test and the Mann-Whitney U-test, as appropriate, whereas categorical variables were compared using the χ² test.

Survival was plotted according to the Kaplan-Meier method, and event-free survival rates were compared using the log-rank test. We entered mean E/e′ into univariate and multivariate analysis according to the guidelines of the American Society of Echocardiography (ASE) and the European Association of Cardiovascular Imaging (EACVI).⁶ Cox proportional hazard models with forward selection of independent variables from 4 categories (patient, echocardiography, CPK, and ECG) were used to assess the usefulness of the indices as predictors of the primary endpoint. The most significant from each category were included in the model. Kaplan-Meier curves were examined according to cut-off values of E/e′ >14 (ASE/EACVI guideline⁶) and QRS-2wks >4 (receiver operating characteristic [ROC] analysis). In the Cox hazard analyses, AUC_CPK and AUC_CPK-MB values were divided by 1,000 because they were so high. Three types of QRS scores were measured, but QRS-2wks was selected and used in the multivariate analysis because it was the strongest of the 3 QRS scores.

For all analyses, 2-tailed P<0.05 was considered significant.

Results

Baseline characteristics according to the presence of the primary endpoint and using a cut-off for mean E/e′ of 14.0 are given in Table 1. Over a median follow-up period of 67 months, 21 patients died of cardiac causes (14 HF, 7 arrhythmia) and 62 had HF.

Table 2 summarizes echocardiographic characteristics. Patients who developed the primary endpoint had a significantly higher rate of the presence of significant MR, tissue Doppler imaging velocities were lower, and E/e′ was higher. Patients with a mean E/e′ >14.0 had worse systolic function (as determined by LVEF and wall motion score), a larger LA, lower tissue Doppler imaging velocities, and higher E/e′.

Table 2. Echocardiographic Parameters in All Patients and in Patients Stratified According to the Primary Endpoint and E/e′

	All patients (n=420)	Primary endpoint			Averaged-E/e′ >14.0
	All patients (n=420)	No (n=337)	Yes (n=83)	P value	No (n=303)	Yes (n=117)	P value
Vital signs
SBP (mmHg)	123±20	123±21	123±19	0.938	123±21	123±19	0.938
DBP (mmHg)	69±12	70±13	67±10	0.167	69±14	69±10	0.978
Heart rate (beats/min)	69±12	68±11	76±13	<0.0001	65±10	69±12	0.01
2D and color Doppler echocardiography
LVEDVI (mL/m²)	60.8±17.7	59.1±16.7	65.4±20.4	0.01	58.7±17.7	64.1±18.1	0.005
LVESVI (mL/m²)	28.3±12.6	27.5±11.5	34.1±15.5	0.001	27.8±11.8	31.0±17.3	0.026
LVEF (%)	55.4±12.6	56.6±28.2	50.8±11.7	0.002	54.6±9.1	53.1±11.4	0.2
Wall motion score	21.0±4.3	20.7±3.7	22.6±5.7	0.164	20.3±3.6	22.8±5.1	0.003
LAVI (mL/m²)	30.2±10.8	29.6±10.1	32.5±13.2	0.03	29.2±10.1	32.8±12.3	0.003
MR ≥ moderate	34 (9)	18 (5)	16 (19)	0.038	11 (3)	23 (19)	0.0008
Transmitral flow
Peak E wave (cm/s)	81.0±23.2	78.9±17.5	91.6±23.1	<0.0001	74.6±19.9	97.8±23.4	<0.0001
Peak A wave (cm/s)	83.2±23.3	84.4±19.5	79.3±26.8	0.13	81.0±20.4	86.8±30.3	0.01
E/A	0.97±0.43	0.93±0.37	1.15±0.38	0.0004	0.92±0.33	1.12±0.75	<0.0001
TM-Dct (ms)	216.0±52.6	221.0±57.6	196.1±63.3	0.001	220.3±51.0	204.6±57.3	0.008
A-duration (ms)	137.4±25.0	139.4±28.4	127.0±32.4	0.46	139.2±25.6	131.0±22.5	0.05
Pulmonary venous flow
Peak S wave (cm/s)	52.3±14.4	51.9±13.7	55.3±17.9	0.25	51.0±14.1	53.8±15.4	0.775
Peak D wave (cm/s)	39.1±13.2	37.2±12.1	42.1±19.6	0.16	37.1±9.3	41.7±15.1	0.09
Peak A wave (cm/s)	33.6±18.3	33.0±19.2	34.7±11.8	0.07	33.0±20.5	34.0±10.3	0.18
PV-Dct (ms)	208.4±71.4	217.9±71.6	177.1±58.1	0.01	220.0±71.5	197.1±69.9	0.02
A-duration (ms)	130.3±23.1	130.4±24.1	130.2±22.3	0.78	129.4±26.4	132.4±35.0	0.43
Tissue Doppler
Septal s′ (cm/s)	7.0±1.8	7.1±1.8	6.4±1.4	0.002	7.1±1.7	6.5±1.5	0.02
Septal e′ (cm/s)	7.0±1.7	7.2±1.8	6.2±1.5	<0.0001	7.3±1.7	6.2±1.5	<0.0001
Septal a′ (cm/s)	9.3±2.5	9.7±2.6	8.2±4.6	<0.0001	9.6±2.6	8.8±2.4	0.0008
Septal E/e′	12.2±4.3	11.3±3.4	15.5±4.8	<0.0001	10.4±2.7	16.8±4.1	<0.0001
Lateral s′ (cm/s)	7.8±2.5	8.0±2.6	7.2±2.2	0.003	8.0±2.5	7.5±2.0	0.07
Lateral e′ (cm/s)	8.7±2.4	9.0±2.2	7.7±1.8	<0.0001	9.2±2.2	7.5±2.0	<0.0001
Lateral a′ (cm/s)	11.0±2.7	11.4±2.2	9.7±2.6	<0.0001	11.3±2.5	10.4±3.5	0.001
Lateral E/e′	9.9±4.5	9.4±3.7	12.9±5.2	<0.0001	8.7±2.2	13.9±5.4	<0.0001
Mean s′ (cm/s)	7.5±2.0	7.6±3.2	6.7±1.9	0.541	7.6±1.9	7.0±2.3	0.04
Mean e′ (cm/s)	7.4±1.8	7.6±1.7	6.5±1.4	<0.0001	7.8±1.7	6.2±1.5	<0.0001
Mean a′ (cm/s)	10.0±2.7	10.3±2.7	8.7±5.6	<0.0001	10.3±2.6	9.3±2.8	0.0001
Mean E/e′	12.3±3.9	11.5±3.4	15.3±4.7	<0.0001	10.5±2.0	17.1±4.1	<0.0001

Data are given as the mean±SD or n (%). A, late diastolic; DBP, diastolic blood pressure; E, early diastolic; E/e′, early mitral inflow velocity to mitral early diastolic velocity ratio; LAVI, left atrial volume index; LVEDVI, left ventricular end-diastolic volume index; LVESVI, left ventricular end-systolic volume index; LVEF, left ventricular ejection fraction; MR, mitral regurgitation; s′, e′, a′, peak velocities of systolic, diastolic, and atrial contraction waves, respectively; PV-Dct, pulmonary venous flow deceleration time; SBP, systolic blood pressure; TM-Dct, transmitral flow deceleration time.

Univariate and multivariate associations with the primary endpoint by QRS scores are summarized in Table 3. On multivariate analysis, QRS-2wks was the strongest predictor among the 3 QRS scores. Table 4 shows results of univariate and multivariate analyses for the primary endpoint for all indices. On univariate analysis, age, mean E/e′, AUC_CPK, and QRS-2wks were the strongest indices in each group. On the multivariate analysis, hypertension, QRS-2wks and mean E/e′ were independent indices predicting the primary endpoint.

Table 3. Results of Univariate and Multivariate Analyses for the Primary Endpoint by QRS Score

	Univariate analysis		Multivariate analysis
	HR (95% CI)	P value	HR (95% CI)	P value
QRS-adm	1.217 (1.113–1.335)	<0.0001	0.983 (0.831–1.158)	0.841
QRS-PCI	1.208 (1.117–1.312)	0.0002	0.980 (0.810–1.184)	0.842
QRS-2wks	1.267 (1.163–1.383)	<0.0001	1.312 (1.074–1.612)	0.007

CI, confidence interval; QRS-2wks, QRS score 2 weeks after the onset of symptoms; QRS-adm, QRS score on admission; QRS-PCI, QRS score after percutaneous coronary intervention; HR, hazard ratio.

Table 4. Results of Univariate and Multivariate Analyses for the Primary Endpoint by All Indices

	Univariate analysis		Multivariate analysis
	HR (95% CI)	P value	HR (95% CI)	P value
Age	1.052 (1.032–1.084)	<0.0001	1.018 (0.996–1.041)	0.105
Female sex	1.292 (0.776–2.149)	0.323
Anterior MI	1.442 (0.891–2.348)	0.137
Hypertension	2.772 (1.651–4.807)	<0.0001	1.702 (1.040–2.888)	0.03
Diabetes	1.463 (0.901–2.373)	0.12
LVEF	0.961 (0.938–0.984)	0.0006
LAVI	1.024 (1.003–1.045)	0.03
TM-Dct	0.991 (0.987–0.996)	0.0004
Mean E/e′	1.212 (1.138–1.300)	<0.0001	1.152 (1.088–1.215)	<0.0001
AUC_CPK (/1,000)	1.0005 (1.02–1.008)	0.0004
AUC_CPK-MB (/1,000)	1.06 (1.02–1.104)	0.001	1.001 (0.999–1.002)	0.938
ST-resolution, absent	0.490 (0.299–0.807)	0.005
No-reflow	2.179 (1.072–4.152)	0.032
BNP	1.002 (1.002–1.003)	<0.0001	1.001 (0.999–1.001)	0.107
QRS-2wks	1.209 (1.112–1.307)	<0.0001	1.153 (1.057–1.254)	0.001

OR, odds ratio. Other abbreviations as in Tables 1–3.

Next, Kaplan-Meier curves were analyzed using these 2 variables. Figure 2 shows that QRS-2wks >4 was also associated with a poor prognosis (log rank statistics, χ²=40.0, P<0.0001), which was defined according to ROC curves (AUC=0.685, sensitivity=0.848, 1–specificity=0.287, P<0.0001). Figure 3 shows HF-free survival in patients dichotomized according to mean E/e′ >14.0 based on current guidelines.⁶ Kaplan-Meier curve analysis confirmed that higher morbidity was associated with an elevated E/e′ (log rank statistics, χ²=69.3, P<0.0001).

Figure 2.

Kaplan-Meier survival curves in patients classified according to a QRS score determined 2 weeks after the onset of symptoms (QRS-2wks) of >4 or ≤4. The outcomes differed significantly between these 2 groups (log-rank statistic, χ²=40.0, P<0.0001).

Figure 3.

Kaplan-Meier survival curves in patients classified according to a mean early mitral inflow velocity to mitral early diastolic velocity ratio (E/e′) of >14.0 or ≤14.0. The outcomes differed significantly between these 2 groups (log-rank statistic, χ²=69.3, P<0.0001).

Patients were divided into 4 groups using cut-off values of 4 for QRS-2wks and 14.0 for mean E/e′: Group A, QRS-2wks ≤4 and mean E/e′ ≤14.0 (n=224); Group B, QRS-2wks >4 and mean E/e′ ≤14.0 (n=79); Group C, QRS-2wks ≤4 and mean E/e′ >14.0 (n=71); and Group D, QRS-2wks >4 and mean E/e′ >14.0 (n=46). Figure 4 shows the Kaplan-Meier curves for these 4 groups. There were significant differences among the 4 groups in the primary endpoint (log rank statistics, χ²=116.3, P<0.0001). We show pairwise comparisons and revealed the higher risk associated with Group D. The hazard ratio (HR) for Group D vs. Group A was 12.13 (P<0.0001). The characteristics of the patients divided by 4 groups are displayed in Supplementary Table 1. Patients in Groups C and D were older and were more likely to have hypertension and diabetes than patients in Groups A and B.

Figure 4.

(Left) Kaplan-Meier curve for 4 groups according to mean early mitral inflow velocity to mitral early diastolic velocity ratio (E/e′) and QRS scores determined 2 weeks after the onset of symptoms (QRS-2wks): Group A, QRS-2wks ≤4 and mean E/e′ ≤14.0 (n=224); Group B, QRS-2wks >4 and mean E/e′ ≤14.0 (n=79); Group C, QRS-2wks ≤4 and mean E/e′ >14.0 (n=71); and Group D, QRS-2wks >4 and mean E/e′ >14.0 (n=46). The 4 groups differed significantly with regard to the primary endpoint (log-rank statistic, χ²=116.3, P<0.0001). (Right) Pairwise comparisons.

Further, multivariate analysis was conducted according to the ultrasound system used (Aplio, n=234; iE33, n=91; Vivid q, n=95). In these analyses, mean-E/e′ was found to be an independent predictor of the primary endpoint, regardless of the machine, with HRs of 1.27, (95% CI 1.19–1.35, P<0.0001), 1.28 (95% CI 1.16–1.41, P<0.0001), 1.36 (95% CI 1.20–1.54, P<0.0001) for the Aplio, iE33, and Vivid q, respectively. Finally, subgroup analysis was performed on groups according to EF of 50% (Supplementary Table 1; EF >50%, n=285; EF ≤50%, n=135). Multivariate analysis revealed that among patients with EF >50%, both QRS-2wks and mean E/e′ were significant predictors of the primary endpoint. Among patients with EF ≤50%, mean E/e′ was an independent predictor of the primary endpoint and QRS-2wks had a tendency to predict the primary endpoint.

Discussion

The main findings of this study were as follows: (1) QRS scores were significant prognosticators regardless of the timing after the onset of STEMI, with infarct size as estimated by QRS-2wks being strongest predictor; and (2) the predictive value of the combination of QRS-2wks and mean E/e′ was excellent based on the results of Kaplan-Meier curve analysis.

In the present study, the QRS score may provide additional information to E/e′. E/e′ itself enables hemodynamic and functional condition to be assessed, and we have previously reported the usefulness of E/e′ in patients with STEMI at 2 weeks.⁷ Therefore, we believe that the combination of infarct size as estimated by the QRS score and the mean E/e′ at 2 weeks can be a simple and convenient predictor of outcome in patients with first-time STEMI. Moreover we emphasize that both ECG and echocardiography should be performed, even at a patient’s bedside. Previous studies have reported that ECG markers and the QRS score are not able to accurately predict infarct size when the ECG is acquired in the acute setting after a reperfused myocardial infarction.¹⁸ The ECG results in the present study were analyzed not only in the acute phase, but also 2 weeks after the myocardial infarction, and the QRS score determined at 2 weeks was the best among the 3 QRS scores evaluated.

E/e′ has been shown to be a strong non-invasive predictor of prognosis even in patients with STEMI,⁷^,¹⁹ and we have reconfirmed its usefulness in the present study. It is preferable to use the mean E/e′ obtained from the septal and lateral sides of the mitral annulus in order to predict LV filling pressures. Therefore, we measured e′ at both sides and obtained a mean of these values, as recommended by the ASE/EACVI.⁶ The ASE recommendations for the evaluation of LV diastolic function by echocardiography suggest that the mean of the septal and lateral e′ should be used to assess LV filling pressure in patients with regional dysfunction.²⁰ However, current ASE/EACVI guidelines recommend that a cut-off value of 14.0 for mean E/e′ be used.⁶ Thus, we used a mean E/e′ of 14.0 as the cut-off value in the present study. Furthermore, to reduce the effects of confounding factors, we only studied patients who had experienced a first STEMI with successful reperfusion within 12 h after symptom onset, thereby making our study design more robust.

Multivariate analysis in the present study showed that the presence of hypertension was a significant predictor for the primary endpoint. We think this is due to the deterioration of LV function after STEMI induced by hypertension.²¹ Previous studies have emphasized the importance and prognostic implications of diastolic function after AMI, and patients with hypertension seem predisposed to develop diastolic dysfunction as a result of LV hypertrophy and fibrosis of the myocardial wall.²¹ This may explain why hypertension was a significant predictor for the primary endpoint in the present study.

The combination of QRS score and mean E/e′ >14.0 at 2 weeks had significant potential to estimate prognosis based on infarct size. To the best of our knowledge, the present study is the first to explore the combination of QRS score and E/e′. This study demonstrated that, based on the results of univariate analysis, infarct size as estimated by QRS-2wks had a higher prognostic value than LVEF (Table 4). This is due to LVEF being poorly correlated with infarct size when measured by MRI²² because LVEF reflects global LV contraction, whereas the infarct area and reduced function reflect regional factors. Moreover, the QRS score has been shown to be significantly related to both infarct size and transmurality on a DE-MRI.³ Another study reported that the QRS scores may take into account elements of intraventricular conduction,²³ and so are useful indicators even for non-STEMI²⁴ and non-ischemic heart disease.²⁵ Recent studies have reported that a higher QRS score can predict microvascular obstruction²⁶ and prognosis after an AMI.¹^,⁵ We think this is why QRS scores were stronger prognosticators compared with infarct size estimated by AUC_CPK-MB.

Recently, strain analysis has been accepted even for patients with STEMI.²⁷ However, tissue Doppler echocardiography does not require special equipment and provides reliable assessment of hemodynamics even in patients with decompensated HF.²⁸^,²⁹ Conversely, in the case of patients with a preserved EF, an elevated E/e′ may be the best method to detect increased LV filling pressure.⁶ The present study explored hemodynamic condition (E/e′) and functional condition (QRS score) simultaneously, thereby making evaluation easy and convenient for patients with a first STEMI. Mean E/e′ and QRS-2wks were useful, especially in patients with a preserved EF (>50%; Supplementary Table 2). However, we think that it is important for us to train echocardiography and ECG analysis in our daily practice.

The mortality due to STEMI has improved significantly as the use of pPCI has increased worldwide. However, there is still a margin for improvement. ECG and echocardiography do not require any special equipment to estimate infarct size.³^,⁴^,²⁷ The prognosis of a STEMI after early reperfusion therapy can be easily predicted by comprehensive echocardiography used in conjunction with ECG, which has the potential to balance the efficiency of care and possible cost reductions corresponding to a decrease in rehospitalization. We think that improving the mortality of patients in Group D (Figure 3) may be the next focus for further improving the outcomes of STEMI.

Study Limitations

This was a small study conducted in a single center. In addition, 41 patients were excluded because of confounding ECG factors. As such, we needed to exclude patients with atrial fibrillation, bundle branch block, and severe LV hypertrophy (Cornell or Sokolow-Lyon voltage criteria). However, the strict entry criteria enabled us to demonstrate that the QRS score is a clinically useful predictor of adverse events. We defined infarct size using CPK-MB, not troponin. However, we calculated infarct size by AUC_CPK and AUC_CPK-MB to determine appropriate values. Further prospective studies in a larger number of patients are needed to confirm our results.

Conclusions

We conclude that the QRS score is a significant prognosticator regardless of the timing after the onset of STEMI. In particular, infarct size estimated by QRS obtained 2 weeks after the onset of STEMI was the strongest predictor among the QRS scores. The predictive value of the combination of QRS-2wks and mean E/e′ was excellent. Combining these variables resulted in high predictive accuracy in patients with first-time reperfused STEMI. Of not, both these evaluations can be performed at the bedside.

Sources of Funding

This study did not receive any specific fundings.

Disclosures

K.K., M.K. are members of Circulation Journal ’ Editorial Team. The remaining authors have no conflicts of interest to declare.

IRB Information

This study was approved by Yokohama City University, Center for Novel and Exploratory Clinical Trials (Reference no. D1308002).

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-20-0486

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