Patients and Protocols

The study group comprised 301 consecutive patients selected among 399 patients with STEMIs at Yokohama City University Medical Center (Yokohama, Japan). Patients with prior myocardial infarctions, chronic atrial fibrillation, unacceptable image quality, or chronic renal failure treated with dialysis were excluded. All subjects successfully underwent reperfusion therapy by percutaneous coronary intervention (PCI) <12 hours after symptom onset and were discharged from the hospital. Myocardial infarction was defined according to the European Society of Cardiology and American College of Cardiology guidelines. Lesions with clinically significant residual stenosis underwent PCI during initial hospitalization. The presence of hypertension was defined as blood pressure >140/90 mm Hg. Dyslipidemia was defined as plasma levels of fasting triglycerides ≥ 150 mg/dL and/or fasting total cholesterol ≥ 200 mg/dL and/or low-density lipoprotein cholesterol ≥ 130 mg/dL. Patients without prior diagnoses of diabetes mellitus underwent a 75-g oral glucose tolerance test while they were in stable condition, ≥4 days after admission. After an overnight fast, venous blood samples were taken for the measurement of plasma glucose levels at baseline, 60 min, and 120 min after the glucose load. Diabetes mellitus was defined as a fasting blood glucose level ≥ 126 mg/dL or blood glucose ≥ 200 mg/dL 120 min after glucose load. Hemodynamic status was defined using the Killip classification, and we defined patients with Killip class ≥ 2 as being in critical status. A large infarction was defined as a peak creatine phosphokinase level ≥ 3,000 IU/L. All patients were followed for 4 years (mean, 51.7 ± 19.0 months; follow-up rate, 98%) at regular visits to their attending physicians or by telephone interviews. The primary end point was the incidence of cardiac death or heart failure (HF) requiring readmission. HF was defined according to the Framingham criteria for congestive HF. All patients provided written informed consent. The study protocol was approved by our institution’s ethics committee.

Echocardiography

Echocardiography was performed about 2 weeks (mean, 13.6 ± 8.1 days; during convalescence) after symptom onset by an experienced observer blinded to all angiographic and clinical data in the convalescent stage. All patients were examined in the left lateral position using precordial two-dimensional and Doppler echocardiography. An Aplio ultrasound system (SSA-770A; Toshiba Corporation, Tokyo, Japan) with a 2.5-MHz phased-array transducer was used. The LV ejection fraction (EF) was calculated using the biplane modified Simpson’s method. LV mass was calculated using Devereux’s equation. According to the recommendations of the American Society of Echocardiography, LV hypertrophy was defined as an increase in LV mass index to higher than the cutoff value of 131 g/m ² for men and 113 g/m ² for women. Left atrial (LA) volume was calculated using the area-length method from apical four-chamber and two-chamber views and was indexed to body surface area. Severe LA enlargement was defined as LA volume index > 40 mL/m ² . Mitral inflow was assessed in the apical four-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-wave and A-wave peak velocities, TM-DT, and A-wave duration were measured from the mitral inflow profile. Patients were categorized according to TM-DT. In these analyses, TM-DT < 140 msec was considered abnormally abbreviated. DTI of the mitral annulus was performed from the apical four-chamber view, using a 1-mm to 2-mm sample volume placed at the septal side in 301 patients by careful use of the spectral pulse Doppler method averaged from three cardiac cycles. We rejected the e′ value when we were not able to measure three stable cycles. Therefore, we ultimately checked e′ in 301 patients. Septal e′ has excellent reproducibility, as previously reported by Hillis et al. Lateral e′ values were obtained in 237 of 301 patients; therefore, the mean E/e′ values were also calculated in these 237 patients. Previous studies have confirmed the excellent reproducibility of this measurement and demonstrated that an E/e′ ratio > 15 is the best Doppler predictor of elevated mean LV diastolic pressure. An elevated E/e′ ratio was therefore prospectively defined as E/e′ >15. The guidelines of the American Society of Echocardiography and the European Association of Echocardiography recommend that mitral inflow pattern by itself can be used to estimate LV filling pressures with reasonable accuracy in patients with reduced EFs and that E/e′ should be calculated in patients with preserved EFs. Peak velocities of systolic, early diastolic, and atrial contraction waves were obtained from pulmonary venous flow. To obtain the deceleration time of pulmonary venous flow (PV-DT), a line was drawn from the peak early diastolic velocity along the fall in initial velocity and extrapolated to the baseline. In this study, PV-DT < 150 msec was considered abnormally abbreviated. By visually comparing the mitral regurgitation (MR) color flow jet area with the atrial area in multiple views, MR was graded as absent, slight, moderate, or severe. Color gain was adjusted just below the level of noise.

Biochemical Markers

Blood samples were obtained about 2 weeks after onset. Hemoglobin, creatinine, and plasma brain natriuretic peptide (BNP) were measured. Renal function was assessed on the basis of the estimated glomerular filtration rate, calculated using the abbreviated four-variable Modification of Diet in Renal Disease equation. BNP levels were measured directly using a specific fluoroenzyme-immunometric assay kit (TOSOH AIA-PACK BNP; TOSOH Corporation, Tokyo, Japan). Cutoff values for each marker were defined according to previous reports.

Statistical Analyses

Statistical analyses were performed using JMP version 9.0 (SAS Institute Inc., Cary, NC). Results are expressed as mean ± SD for continuous variables. Qualitative data are presented as number (percentage). Continuous variables were compared using Student’s t test and the Mann-Whitney U test as appropriate. Categorical variables are presented as frequency counts, and intergroup comparisons were analyzed using χ ² tests. Survival was plotted according to the Kaplan-Meier method, and mortality rates were compared using the log-rank test. Potential independent predictors were identified by Cox proportional-hazards analysis. All univariate predictors were then entered into a multiple regression analysis, with entry and retention set at a significance level of P < .05. To determine the most appropriate combination of variables, factors represented by a nominal scale were converted to dummy variables. The incremental value of E/e′ ratio was assessed in four modeling steps. The first step consisted of fitting a multivariate model of clinical parameters. Second, BNP data were added. Third, LV EF and LA volume index were added sequentially. Next, early diastolic/late diastolic wave velocity of mitral inflow (TM-E/A) was included. Finally, E/e′ was added to these analyses. The change in overall log likelihood ratio χ ² was used to assess the increment of predictive power at each step. SPSS version 19 (SPSS, Inc., Chicago, IL) was used for calculations. For all analyses, P values < .05 were considered to indicate statistical significance.

Characteristics of Patients

Table 1 shows the characteristics of the patients. Patients were divided into two groups on the basis of E/e′ ratio (E/e′ > 15, n = 80; E/e′ ≤ 15, n = 231), as described previously. The clinical characteristics of the groups differ, with higher proportions of older age, presence of hypertension, diuretic therapy, Killip class ≥ 2, higher creatine phosphokinase–MB, BNP > 180 pg/mL, and hemoglobin < 11 g/dL in the group with E/e′ ratios > 15. The proportions of patients taking aspirin, β-blockers, angiotensin-converting-enzyme inhibitors or angiotensin receptor blockers, or statins at discharge were similar in the two groups.

Echocardiographic characteristics are shown in Table 2 . Because the subjects had not had prior myocardial infarctions and underwent successful reperfusion therapy, LV systolic function was generally preserved, with a mean EF of 55.3 ± 10.1% among all subjects 2 weeks after onset. Patients with E/e′ ratios > 15 had poorer systolic function, as indicated by the EF and higher filling pressure, as suggested by higher E-wave velocity and shorter TM-DT or PV-DT. This group of patients was also more likely to have moderate MR. No patient had severe MR.

Predictors of Outcomes

During follow-up, cardiac death and HF occurred in 45 patients (cardiac death in 10 and readmission for HF in 35). While 28 of 70 patients with E/e′ ratios > 15 had primary end points, 17 of 231 patients with E/e′ ratios > 15 had primary end points ( Table 1 ). Seven patients died of malignancies (gastric cancer in four, colon cancer in two, and lung cancer in one), and three died of pneumonia during follow-up. Univariate and multivariate associations with primary end points are shown in Table 3 . On univariate analysis, age > 75 years, plasma BNP > 180 pg/mL, EF < 40%, early TM-E/A > 1.0, TM-DT < 140 msec, and E/e′ > 15 were associated with the primary end points. Because both TM-E/A and TM-DT are closely related, stepwise regression models were used to ascertain the useful independent predictors. Multivariate analysis showed that E/e′ > 15 was the strongest predictor (hazard ratio, 3.702; 95% confidence interval, 1.895–7.391; P = .0001), followed by TM-E/A > 1.0. When we combined E/e′ > 15 and TM-E/A > 1.0, accuracy for predicting outcomes was further enhanced on multivariate analysis using dummy variables (hazard ratio, 7.373; 95% confidence interval, 3.529–16.528; P < .0001). Figure 1 shows representative echocardiographic findings and x-rays of patients with the primary end point. Figure 2 shows plots of E/e′ and E/A and the distribution of patients with the primary end point. Twenty-one of 45 patients (47%) with the primary end point belonged to the group with E/e′ > 15 and E/A > 1.0; in contrast, only seven patients (5%) with E/e′ ≤ 15 and E/A ≤ 1.0 ( n = 148) had the primary end point. Figures 3 to 5 show Kaplan-Meier curves in patients dichotomized according to E/e′ > 15 ( n = 70) or E/e′ ≤ 15 ( n = 231) (χ ² = 51.856, P < .0001; Figure 3 ), E/A > 1.0 ( n = 118) or E/A ≤ 1.0 ( n = 183) (χ ² = 9.832, P = .017; Figure 4 ), and E/e′ > 15 with E/A > 1.0 ( n = 35) or others ( n = 266) (χ ² = 91.007, P < .0001; Figure 5 ). Figure 6 shows the incremental value of assessment of E/e′ in predicting the primary end points. Significant improvements were achieved using E/A in combination with E/e′.

Table 3

Univariate and multivariate Cox proportional-hazards analysis

Variables	Univariate			Multivariate
	HR	95% CI	P	HR	95% CI	P
Age > 75 y	1.809	1.362–2.444	<.0001	1.494	0.742–3.001	.2590.333
Female gender	1.613	0.224–1.112	.174
eGFR < 60 mL/min/1.73 m 2	1.84	0.708–4.786	.21
Hb < 11 g/dL	2.459	0.794–7.616	.118
BNP > 180 pg/mL	1.026	1.019–1.032	<.0001	2.449	1.173–5.144	.017
MVD	1.203	0.396–3.660	.745
Reperfusion time > 360 min	3.429	0.996–10.675	.051
Anterior myocardial infarction	2.38	0.787–7.193	.124
LVH	1.775	0.928–3.675	.084
Peak CPK > 3,000 IU/L	1.779	0.732–3.653	.087
LV EF < 40%	2.212	0.489–0.914	.014	1.905	0.855–3.972	.11
LAVI ≥ 40 mL/m 2	1.401	0.628–2.811	.387
TM-E/A > 1.0	4.936	2.035–11.971	.0004	3.053	1.584–6.125	.0008
TM-DT < 140 msec	3.625	0.915–14.356	.067
PV-DT < 150 msec	3.759	1.019–13.869	.056
Moderate MR	3.233	0.809–12.903	.097
E/e′ > 15	14.029	5.802–38.408	<.0001	3.702	1.895–7.391	.0001

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