Correlation Between Longitudinal Strain in the Apical Segments of the Left Ventricle at End-Systole Obtained by 2-Dimensional Speckle-Tracking Echocardiography and Left Ventricular Relaxation

Abstract

Background: It is well acknowledged that left ventricular (LV) contractile performance affects LV relaxation via LV elastic recoil. Accordingly, we aimed to investigate whether global longitudinal strain (GLS), particularly longitudinal strain at LV apical segments at end-systole (ALS), obtained by 2-dimensional speckle-tracking echocardiography could be used to assess LV relaxation.

Methods and Results: We enrolled 121 patients with suspected or definite coronary artery disease in whom echocardiography and diagnostic cardiac catheterization were performed on the same day. We obtained conventional echo-Doppler parameters and GLS, as well as ALS prior to catheterization. LV functional parameters were obtained from the LV pressure recorded using a catheter-tipped micromanometer. In all patients, GLS and ALS were significantly correlated with the time constant τ of LV pressure decay during isovolumetric relaxation (r=0.63 [P<0.001] and r=0.66 [P<0.001], respectively). Receiver operating characteristic curve analysis for identifying impaired LV relaxation (τ ≥48 ms) revealed that ALS greater than −22.3% was an optimal cut-off value, with 81.7% sensitivity and 82.4% specificity. Even in patients with preserved LV ejection fraction, the same ALS cut-off value enabled the identification of impaired LV relaxation with 70% sensitivity and 87.5% specificity.

Conclusions: The findings indicate that contractile dysfunction at LV apical segments slows LV relaxation via loss of LV elastic recoil, even in patients with preserved LVEF.

In patients with heart failure (HF), left ventricular (LV) diastolic dysfunction is a key cause of HF symptoms, regardless of LV ejection fraction (EF).^1–3 Several studies have focused on impaired LV relaxation as a major initial cause of HF symptoms, especially in patients with preserved LVEF.^4–6 LV relaxation mainly depends on the elastic recoil of LVs with good contractile performance, as well as on Ca²⁺ reuptake from the cytoplasm by the sarcoplasmic reticulum, driven by the sarcoplasmic reticulum Ca²⁺-ATPase.^6–11

In patients who underwent invasive LV pressure studies whose LVEF was ≥50% and whose transmitral flow velocity waveform showed an abnormal relaxation pattern, early diastolic mitral annular velocity was found to differ significantly between patients with LV relaxation time constants τ <48 and ≥48 ms, but there was considerable overlap in data points between the groups.¹² Accordingly, we tried to find a different parameter with which to define LV relaxation in patients with preserved LVEF. Two-dimensional speckle-tracking echocardiography (2D-STE) enables quantitative evaluation of myocardial deformation in the longitudinal direction. Using 2D-STE, one can evaluate LV contractile performance in the longitudinal direction in the whole LV wall as well as in local LV segments.

We have also reported previously that a normal LV apical wall contraction contributes substantially to maintaining LV elastic recoil, also called suction, from the perspective of blood flow dynamics during very early diastole, as well as to increasing the rate of LV relaxation in patients with coronary artery disease (CAD).¹⁰ Thus, the aim of the present study was to investigate whether global longitudinal strain (GLS) or longitudinal strain (LS) at the LV apical segments at end-systole (ALS) obtained by 2D-STE could be a surrogate for LV elastic recoil and useful in assessing LV relaxation in patients with suspected or definite CAD. Our hypothesis based on cardiac mechanics is shown in Supplementary Figure 1.

Methods

Study Population

This is a retrospective cross-sectional study based on our fixed database. 2D-STE images were newly reanalyzed using vendor-independent echo-image analysis software (TomTec-Arena; TomTec Imaging Systems, Munich, Germany). The study subjects were 155 consecutive patients enrolled from February 2006 to December 2009 who underwent both echocardiographic examination and cardiac catheterization for the purposes of diagnosing CAD, with a comprehensive LV pressure analysis on the same day. Patients with acute coronary syndrome, serum creatinine >1.5 mg/dL, frequent premature beats including atrial fibrillation/flutter, apparent hypertrophic cardiomyopathy, primary valvular heart disease, and inadequate echo image quality were excluded. In all, 121 patients were enrolled in the study (Table 1).

Table 1. Comparisons of Clinical Characteristics, Cardiac Catheterization Data, and Medications Among All Patients and Those With Preserved and Reduced LVEF Separately

	All patients (n=121)	Preserved LVEF (n=87)	Reduced LVEF (n=34)	P value
Age (years)	68±9	69±8	65±12	0.07
Male sex (%)	82.0	78.2	91.2	0.10
Height (cm)	160.7±7.3	160.1±7.3	162.4±7.1	0.14
Weight (kg)	60.8±9.9	61.1±10.1	59.8±9.3	0.53
Body mass index (kg/m2)	23.4±2.8	23.7±2.9	22.6±2.5	0.050
HR (beats/min)	63.5±12.6	62.7±12.7	65.6±12.2	0.25
Mean BP (mmHg)	89.1±11.5	89.6±11.4	88.0±11.8	0.52
τ (ms)	49.9±9.8	46.6±8.0	58.4±9.1	<0.001
Peak positive dP/dt (mmHg/s)	1,450±350	1,560±320	1,180±290	<0.001
Peak negative dP/dt (mmHg/s)	−1,650±440	−1,810±390	−1,220±250	<0.001
LVEDP (mmHg)	15.6±5.9	14.9±5.3	17.4±6.9	0.07
Comorbidities and medications (%)
Hypertension	60.7	63.6	52.9	0.36
Hyperlipidemia	81.1	75.0	64.7	0.32
Diabetes	32.8	30.7	38.2	0.43
History of admission due to HF	17.2	9.1	38.2	<0.001
CAD	82.6	86.2	73.5	0.16
Angina pectoris	33.1	43.7	5.9	<0.001
Prior MI	42.1	33.3	64.7	0.002
Anterior wall	20.7	16.1	32.4	0.047
Inferior wall	9.9	11.5	5.9	0.35
Lateral wall	4.1	3.3	2.9	0.68
Posterior wall	3.3	2.3	5.9	0.32
Combined	4.9	0	17.6	<0.001
Prior PCI	8.3	9.2	2.9	0.24
Atypical chest pain without CAD	6.6	9.2	0	0.067
DCM	8.3	1.1	26.5	<0.001
Exercise stress test positive	2.5	3.4	0	0.27
Diuretics	25.6	14.9	79.4	<0.001
ACEIs or ARBs	50.4	43.7	67.6	0.02
β-blockers	43.8	37.9	58.8	0.04
Calcium channel blockers	32.2	39.1	14.7	0.01
Statins	60.3	60.9	58.8	0.83
Oral hypoglycemic drugs	27.2	27.5	26.5	0.90

Data are presented as the mean±SD or frequency (%). ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BP, blood pressure; CAD, coronary artery disease; DCM, dilated cardiomyopathy; EDVI, end-diastolic volume index; ESVI, end-systolic volume index; HR, heart rate; LVEDP, left ventricular end-diastolic pressure; LVEF, left ventricular ejection fraction; MI, myocardial infarction; PCI, percutaneous coronary intervention; τ, time constant of left ventricular pressure decay during isovolumic relaxation.

All patients had chest symptoms and/or a clinical course needing diagnostic cardiac catheterization, including positive exercise stress tests, abnormal myocardial perfusion scintigram findings, and a previous history of myocardial infarction (MI) or coronary revascularization. According to the findings of coronary angiography and left ventriculography, 100 patients were diagnosed as having CAD, 51 of whom had prior MI. The remaining 21 patients were diagnosed as having dilated cardiomyopathy, had a positive stress test without CAD, and atypical chest pain with a non-specifically abnormal electrocardiogram. The frequency of each disease is given in Table 1. In this study, the cut-off value for preserved LVEF was set at ≥50%.

This study was performed in accordance with the Declaration of Helsinki and the study protocol was approved by the Ethical Guidelines Committee of Nagoya City University Graduate School of Medical Sciences. Written informed consent regarding the participation in cardiac catheterization, including a comprehensive pressure analysis, was obtained from all patients on admission. Informed consent was again obtained for the present study using an opt-out system.

Acquisition of Echocardiographic Data

Before cardiac catheterization, echocardiographic examinations were performed (Sequoia 512C; Siemens, Mountain View, CA, USA). According to the guidelines proposed by American Society of Echocardiography,⁵ peak blood inflow velocities from the left atrium to the LV during both early (E) and late (A) diastole were acquired in the apical 4-chamber view using the pulsed Doppler method. In the same plane, the velocity profiles of mitral annular movement were acquired using the same method at both the medial and lateral side corners. The peak velocities during systole (s′) and early diastole (e′) were obtained as the averaged values of both sides. Two-dimensional digital cine-loop images were acquired in the apical 2-, 3-, and 4-chamber views. The averaged frame rate of 2D imaging was 60 frames/s.

Consecutive images were analyzed offline, and the LV volumes at both end-systole and end-diastole were computed using the modified Simpson’s method. LVEF was then calculated. Both end-systolic volume (ESV) and end-diastolic volume (EDV) were indexed to the body surface area of each patient (ESVI and EDVI, respectively). Cuff-measured blood pressure of the brachial artery and heart rate were obtained in patients in the supine position just after echocardiographic examination.

LS Obtained by 2D-STE

LV myocardial LS was analyzed offline in apical 2-, 3-, 4-chamber views using TomTec-Arena software. A sampling line was set semiautomatically along the LV endocardium just after manual setting of 3 reference points on both corners of the mitral annulus and LV apex (Figure 1A). The initial frame, which corresponds to zero strain, was set at LV end-diastole. In each plane, the LV wall was automatically divided into 6 segments according to the guidelines of the American Society of Echocardiography.¹³ The strain profiles were obtained as the averaged temporal change in LS values during 2 consecutive cardiac cycles in all 6 segments and in 2 apical segments separately in each plane. A representative profile is shown in Figure 1B; peak strain values at end-systole (Points A and A′) and LS values at the flexion points just before atrial contraction (Points B and B′) were obtained in each plane. GLS was obtained as the averaged LS value at the points A and A′ in 3 planes. Maximal apical segment LS values at end-systole (ALS) were also obtained from the strain profiles at the apical segments in 3 planes in the same manner as the GLS measurement. ALS and GLS were automatically computed. The changes in LS values during early diastole were calculated as the numerical differences between B and A (B′ and A′) both in the whole LV and in the apical segments (early diastolic global LS change and early diastolic apical LS change, respectively).

Figure 1.

(A) Schematic representation of segmentation in the left ventricular (LV) wall in apical 4-chamber view obtained by 2-dimensional speckle-tracking echocardiographic imaging. A sampling line was set semiautomatically. Three reference points (red circles) needed to be set on both corners of the mitral annulus and LV apex. Global longitudinal strain (GLS) was computed from the whole sampling line set on the endocardium of the LV wall. Longitudinal strain (LS) at the apical segments (ALS) was obtained at the 2 apical segments (blue area). (B) Schematic representation of an LS profile. The profile was obtained during 2 consecutive cardiac cycles in the apical 4- and 2-chamber views. GLS and ALS were computed automatically (points A and A′). The flexion points (B and B′) were determined manually, focusing on the change in strain value with respect to frame. The changes in early diastolic LS (EDLSC) in the whole LV wall and in the apical segments were obtained by numerically subtracting A (A′) from B (B′).

Cardiac Catheterization

Diagnostic cardiac catheterization was performed after echocardiography. Before contrast medium was injected into the LV or coronary artery, LV pressure was measured using a catheter-tipped micromanometer (SPC-454D; Millar Instruments, Houston, TX, USA). LV pressure waveforms were recorded on a polygraph system (RMC-3000; Nihon Kohden, Tokyo, Japan). Based on the waveform of recorded pressure, the peak values of the first derivatives of LV pressure increase and decrease (maximum and minimum dP/dt, respectively) and the pressure at end-diastole (EDP) were computed. A time constant τ of LV pressure decay during isovolumetric relaxation was also computed using the method of Weiss et al.¹⁴ In addition, the inertia force of late systolic aortic flow was obtained from the LV pressure (p)−dP/dt relationship in a cardiac cycle (phase loop), as reported previously.^10,11,15,16

Statistical Analysis

Data were analyzed using SPSS version 17.0 (SPSS Inc., Chicago, IL, USA). Normally distributed data are presented as the mean±SD, whereas data with a skewed distribution are presented as the median with interquartile range (IQR). Frequency data are presented as percentages (%). Indexed LV volume data were transformed logarithmically for use in linear regression analyses (log-LVESVI).

The significance of differences in parameters between 2 groups was determined using Student’s unpaired t-test. The significance of differences in prevalence between 2 groups was determined using the Chi-squared test. Relationships between 2 parameters were evaluated using Pearson’s or Spearman’s method as appropriate.

In addition, univariable and multivariable linear regression analyses were performed to determine which independent variables would significantly affect the value of τ. In univariable regression analyses, we used mean blood pressure, heart rate, LVEF, log-LVESVI, averaged s′, and ALS as the parameters possibly defining τ. We also used conventional Doppler LV diastolic function parameters, such as E-wave velocity, A-wave velocity, E/A ratio, averaged e′, and the E/averaged e′ ratio as the parameters possibly defining τ. Variables with P<0.1 in the univariable regression analysis were included in the multivariable stepwise regression analysis as possible independent parameters. Two-sided P<0.05 was considered statistically significant.

Receiver operating characteristic (ROC) curve analysis for each echocardiographic parameter was used to determine the optimal cut-off value for detecting impaired LV relaxation. Prolonged τ ≥48 ms was considered the gold standard of impaired LV relaxation.¹⁷ Using this cut-off value for abnormal LV relaxation, we calculated the sensitivity, specificity, and positive predictive value (PPV) for identifying impaired LV relaxation. Finally, intra and inter-variability of the LS measurements were assessed in GLS, ALS, and changes in early diastolic GLS and in early diastolic ALS using intraclass correlation coefficients (ICCs) in 20 patients randomly selected from all patients.

Results

Patient Characteristics

The demographic and cardiac catheterization data of all patients, and of patients with preserved and reduced LVEF, are summarized in Table 1. No significant differences were found in age, sex, height, weight, constitutions, mean blood pressure, heart rate, or comorbidities between patients with preserved and reduced LVEF. Diuretics, β-blockers, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers were administered more frequently in patients with reduced than preserved LVEF.

The data obtained during cardiac catheterization are also presented in Table 1. In patients with reduced LVEF, the time constant τ was significantly longer and the peak maximum and minimum dP/dt were significantly lower than in patients with preserved LVEF. However, LVEDP did not differ significantly between patients with preserved and reduced LVEF.

LV LS and Other Echocardiographic Parameters

The value of each LS parameter is presented in Table 2. Both GLS and ALS were significantly greater in patients with preserved than reduced LVEF; similar findings was observed for both early diastolic global LS and early diastolic apical LS changes. In patients with preserved LVEF, changes in both ALS and early diastolic apical LS were significantly greater than changes in GLS and early diastolic global LS (−23.7±6.6% vs. −17.9±3.5% [P<0.001] and −14.7±5.6% vs. −10.2±2.9% [P<0.001], respectively). In contrast, in patients with reduced LVEF, changes in both ALS and early diastolic apical LS did not differ significantly from changes in GLS and early diastolic global LS (−10.7±6.0% vs. −10.0±3.5% [P=0.55] and −5.8±4.3% vs. −5.1±2.6% [P=0.45], respectively). In all patients and in those with preserved LVEF, the GLS and the change in early diastolic global LS were significantly correlated with both τ and peak negative dP/dt (Table 3). Furthermore, the changes in ALS and early diastolic global LS were significantly correlated with both τ and peak negative dP/dt in the same categories of patients (Table 3). The LS in other-than-apical segments (basal and mid segments) was significantly but apparently weakly correlated with the time constant τ. GLS and ALS were significantly correlated in all patients (r=0.90, P<0.001) and in patients with preserved LVEF (r=0.80, P<0.001).

Table 2. Comparisons of Echocardiographic Examination Parameters Among All Patients and Those With Preserved and Reduced LVEF Separately

	All patients (n=121)	Preserved LVEF (n=87)	Reduced LVEF (n=34)	P value
LVEF (%)	57.9±14.8	65.86± 7.8	38.2±9.2	<0.001
LVEDVI (mL/m2)	46 [38–60]	42 [36–51]	75 [62–91]	<0.001
LVESVI (mL/m2)	16 [12–31]	14 [11–18]	44 [35–63]	<0.001
E-wave velocity (cm/s)	66.0±18.1	67.0±15.3	63.5±23.8	0.45
A-wave velocity (cm/s)	77.5±20.7	82.1±19.4	65.8±19.6	<0.001
E/A ratio	0.9±0.5	0.9±0.3	1.1±0.8	0.06
Averaged s′ (cm/s)	7.3±1.8	7.9±1.7	5.7±1.1	<0.001
Averaged e′ (cm/s)	6.6±1.8	7.0±1.7	5.4±1.6	<0.001
E/averaged e′ ratio	10.8±4.3	10.0±3.0	12.7±6.0	0.02
GLS (%)	−15.7±5.0	−17.9±3.5	−10.0±3.5	<0.001
ALS (%)	−20.0±8.7	−23.7±6.6	−10.7±6.0	<0.001
EDLSC (%)
Whole	−8.7±3.6	−10.2±2.9	−5.1±2.6	<0.001
Apex	−12.2±6.6	−14.7±5.6	−5.8±4.3	<0.001
BMLS (%)	−13.8±3.9	−15.4±3.0	−9.7±3.0	<0.001

Unless indicated otherwise, data are given as the mean±SD or median [interquartile range]. ALS longitudinal strain in the apical segments at end-systole; A-wave velocity, peak inflow velocity during late diastole; BMLS, basal and mid longitudinal strain at end-systole; EDLSC, early diastolic longitudinal strain change; E-wave velocity, peak inflow velocity during early diastole; e′, mitral annular velocity during early diastole in septal or lateral side; GLS, global longitudinal strain; LVEF, left ventricular ejection fraction; LVESVI, left ventricular end-systolic volume index; s′, mitral annular velocity during systole in septal or lateral side.

Table 3. Results of Univariate Linear Regression Analyses of Invasive Parameters in All Patients and Patients With Preserved LVEF

	Peak positive dP/dt (mmHg/s)				Peak negative dP/dt (mmHg/s)				τ (ms)
	All patients		Patients with preserved LVEF		All patients		Patients with preserved LVEF		All patients		Patients with preserved LVEF
	r	P value	r	P value	r	P value	r	P value	r	P value	r	P value
Mean BP (mmHg)	0.17	0.08	0.18	0.11	−0.24	0.01	−0.26	0.02	−0.01	0.92	−0.08	0.50
HR (beats/min)	0.14	0.14	0.31	0.004	−0.09	0.32	−0.23	0.03	−0.12	0.21	−0.24	0.03
LVEF (%)	0.58	<0.001	0.27	0.01	−0.66	<0.001	−0.29	0.006	−0.53	<0.001	−0.16	0.13
Log-LVESVI (mL/m2)	−0.52	<0.001	−0.26	0.01	0.68	<0.001	0.34	<0.001	0.60	<0.001	0.31	0.003
E-wave velocity (cm/s)	0.17	0.06	0.24	0.03	−0.13	0.17	−0.15	0.17	0.01	0.88	0.02	0.83
A-wave velocity (cm/s)	0.39	<0.001	0.34	0.002	−0.37	<0.001	−0.22	0.04	−0.35	<0.001	−0.17	0.11
E/A ratio	−0.20	0.04	−0.08	0.44	0.21	0.02	0.09	0.43	0.35	<0.001	0.21	0.052
Averaged s′ (cm/s)	0.50	<0.001	0.37	0.001	−0.49	<0.001	−0.24	0.02	−0.45	<0.001	−0.25	0.02
Averaged e′ (cm/s)	0.30	0.001	0.20	0.07	−0.42	<0.001	−0.22	0.04	−0.42	<0.001	−0.28	0.01
E/averaged e′ ratio	−0.15	0.11	−0.01	0.90	0.01	0.01	0.09	0.42	0.35	<0.001	0.25	0.02
GLS (%)	−0.59	<0.001	−0.37	<0.001	0.72	<0.001	0.49	<0.001	0.63	<0.001	0.41	<0.001
ALS (%)	−0.60	<0.001	−0.42	<0.001	0.77	<0.001	0.63	<0.001	0.66	<0.001	0.50	<0.001
EDLSC (%)
Whole	−0.44	<0.001	−0.18	0.11	0.59	<0.001	0.43	<0.001	0.56	<0.001	0.33	<0.001
Apex	−0.49	<0.001	−0.27	0.01	0.66	<0.001	0.47	<0.001	0.59	<0.001	0.39	<0.001
BMLS (%)	−0.51	<0.001	−0.27	0.01	−0.58	<0.001	−0.27	0.01	−0.52	<0.001	−0.25	0.02

Abbreviations as in Tables 1,2.

ROC curve analysis to determine the most beneficial LS parameters for identifying a prolonged τ demonstrated that ALS was superior to other LS parameters in all patients. The area under the curve (AUC) for ALS was 0.85 (95% confidence interval [CI] 0.78–0.92; Figure 2). In patients with preserved LVEF, the ALS was also more useful than the other parameters in detecting a prolonged τ (Figure 3). In all patients, the optimal cut-off value of ALS for detecting τ ≥48 ms was −22.3% (Figure 2), with a sensitivity, specificity, and PPV of 81.7%, 82.4%, and 86.6%, respectively. Even in patients with preserved LVEF, ALS was the most effective parameter to identify prolonged τ (Figure 3). The optimal cut-off value of ALS in patients with preserved LVEF was also −22.3%, with a sensitivity, specificity, and PPV of 70.0%, 87.5%, and 82.4%, respectively.

Figure 2.

Receiver operating characteristic curve analysis to detect impaired left ventricular (LV) relaxation in all patients. The area under the curve (AUC) of longitudinal strain at the apical segments (ALS) was larger than that of the other parameters. The optimal cut-off value for ALS for detecting prolonged time constant τ was −22.3% at Point A. CI, confidence interval; EDLSC, changes in early diastolic longitudinal strain; GLS, global longitudinal strain.

Figure 3.

Receiver operating characteristic curve analysis to identify impaired left ventricular (LV) relaxation in patients with preserved LV ejection fraction (EF). The optimal cut-off value for longitudinal strain at the apical segments (ALS) in patients with preserved LVEF was −22.3% at Point B. CI, confidence interval; EDLSC, changes in early diastolic longitudinal strain; GLS, global longitudinal strain.

Effect of Diabetes on ALS

Among patients with preserved LVEF, 30.7% had diabetes (Table 1). There was no significant difference in ALS in patients with preserved LVEF with and without DM (−23.9±5.7% vs. −23.5±6.9%, respectively; P>0.05).

Estimation of τ Using Echocardiographic Parameters

The relationships between τ and echocardiographic parameters in univariable regression analyses in all patients are presented in Table 3. Multivariable analyses were used to determine which echocardiographic parameters could estimate τ (Table 4). According to the results of the ROC analyses of all 4 LS parameters, ALS was chosen as a representative independent LS variable for determining the value of τ in all regression models (Figure 4). In Model I, multivariable stepwise linear regression analysis for estimating τ revealed that ALS, E/A ratio, and averaged e′ were the parameters significantly related to τ (R²=0.48, P<0.001). In Model II, which used log-LVESVI instead of the LVEF used in Model I, log-LVESVI and ALS were identified as variables significantly related to τ (R²=0.45, P<0.001). Additional statistical analyses were performed for patients with preserved LVEF. Multivariable stepwise linear regression analyses for estimating τ in patients with preserved LVEF revealed that ALS was the only significant determinant in Models III and IV (R²=0.23 and P<0.001 in each model) (Table 4).

Table 4. Results of Multivariate Stepwise Linear Regression Analyses for τ in All Patients and Patients With Preserved LVEF

Variables	All patients				Patients with preserved LVEF
	Model I (R2=0.48)		Model II (R2=0.45)		Model III (R2=0.23)		Model IV (R2=0.23)
	β	P value	β	P value	β	P value	β	P value
ALS (%)	0.50	<0.001	0.46	<0.001	0.49	<0.001	0.49	<0.001
LVEF (%)	−0.04	0.69			0.17	0.14
Log-LVESVI (mL/m2)			0.27	0.01			0.08	0.50
Averaged s′ (cm/s)	0.082	0.43	−0.01	0.88	−0.04	0.71	−0.04	0.71
Averaged e′ (cm/s)	−0.18	0.03	−0.10	0.20	−0.12	0.23	−0.12	0.23
A-wave velocity (cm/s)	−0.03	0.76	−0.07	0.34	−0.07	0.46	−0.07	0.46
E/A ratio	0.20	<0.01	0.14	0.06	0.15	0.13	0.15	0.13
E/averaged e′ ratio	−0.07	0.54	0.11	0.16	0.13	0.19	0.13	0.19

Abbreviations as in Tables 1,2.

Figure 4.

(A) Receiver operator characteristic (ROC) curve analyses for detecting impaired left ventricular (LV) relaxation using longitudinal strain at the apical segments (ALS) and conventional LV early diastolic functional parameters in all patients. The AUC for ALS was larger than those of the other parameters. (B) ROC curve analyses for detecting impaired LV relaxation in patients with preserved LV ejection fraction (EF). The AUC for ALS was also larger than that for other parameters in this group of patients. e′, mitral annular velocity during early diastole in septal or lateral side; LVESVI, left ventricular end-systolic volume index; s′, mitral annular velocity during systole in septal or lateral side.

Correlations Between ALS and Inertia Force of Late Systolic Aortic Flow and the Time Constant τ

The relationship between ALS and inertia force of late systolic aortic flow was significant in all patients (r=−0.72, P<0.001) and in patients with preserved LVEF (r=−0.61, P<0.001). The relationship between ALS and log-LVESVI, a surrogate for LV elastic recoil, was significant in all patients (r=0.75, P<0.001) and in patients with preserved LVEF (r=0.51, P<0.001). The relationship between ALS and the time constant τ was also significant in all patients (r=0.66, P<0.001) and in patients with preserved LVEF (r=0.50, P<0.001; Supplementary Figure 2).

Reproducibility of LS Measurements

In 20 patients randomly selected from all patients, ICCs for measurements obtained by a single observer on 2 separate occasions were r=0.909 (95% CI 0.779–0.964; P<0.001) for GLS, r=0.927 (95% CI 0.822–0.971; P<0.001) for ALS, r=0.738 (95% CI 0.437–0.890; P<0.001) for early diastolic GLS change, and r=0.822 (95% CI 0.595–0.927; P<0.001) for early diastolic ALS change. The ICCs for measurements performed by 2 separate observers were r=0.887 (95% CI 0.731–0.955; P<0.001) for GLS, r=0.935 (95% CI 0.839–0.974; P<0.001) for ALS, r=0.768 (95% CI 0.492–0.904; P<0.001) for early diastolic GLS change, and r=0.821(95% CI 0.593–0.927; P<0.001) for early diastolic ALS change.

In 15 patients randomly selected from patients with preserved LVEF, ICCs for measurements obtained by a single observer on 2 separate occasions were r=0.944 (95% CI 0.836–0.982; P<0.001) for GLS, r=0.960 (95% CI 0.880–0.987; P<0.001) for ALS, r=0.867 (95% CI 0.637–0.955 P<0.001) for early diastolic GLS change, and r=0.855 (95% CI 0.607–0.951; P<0.001) for early diastolic ALS change. The ICCs for measurements performed by 2 separate observers were r=0.805 (95% CI 0.496–0.933; P<0.001) for GLS, r=0.798 (95% CI 0.481–0.930; P<0.001) for ALS, r=0.610 (95% CI 0.139–0.856; P=0.008) for early diastolic GLS change, and r=0.720 (95% CI 0.327–0.901; P=0.001) for early diastolic ALS change.

In 15 patients randomly selected from patients with reduced LVEF, ICCs for measurements obtained by a single observer on 2 separate occasions were r=0.962 (95% CI 0.891–0.987; P<0.001) for GLS, r=0.962 (95% CI 0.892–0.987; P<0.001) for ALS, r=0.566 (95% CI 0.096–0.830; P=0.011) for early diastolic GLS change, and r=0.851 (95% CI 0.613–0.947; P<0.001) for early diastolic ALS change. The ICCs for measurements performed by 2 separate observers were r=0.920 (95% CI 0.780–0.973; P<0.001) for GLS, r=0.966 (95% CI 0.902–0.988; P<0.001) for ALS, r=0.504 (95% CI 0.009–0.801; P=0.023) for early diastolic GLS change, and r=0.429 (95% CI −0.086 to 0.764; P=0.048) for early diastolic ALS change.

Discussion

This study demonstrates that the ALS obtained by 2D-STE is applicable for the non-invasive assessment of LV relaxation in patients with suspected and definite CAD including prior MI. An ALS of high magnitude may produce an inertia force of late systolic aortic flow as well as remarkable LV elastic recoil, speeding up LV relaxation and causing suction of blood from the left atrium into the LV during early diastole.

Relationship Between Myocardial Contractility and Relaxation

It is well acknowledged that myocardial fibers store potential energy during systole and that the release of this energy during very early diastole speeds up LV relaxation. This phenomenon, called LV elastic recoil, speeds up LV relaxation independently of Ca²⁺ reuptake from the cytoplasm by the sarcoplasmic reticulum.^6–11 The time constant τ proposed by Weiss et al,¹⁴ which was computed by the mono-exponential fitting of LV pressure decay with zero asymptote, and minimal dP/dt are known to reflect both Ca²⁺ reuptake by the sarcoplasmic reticulum and LV elastic recoil.^6–11 We and Sugawara et al have also reported that LVs with relatively good contractile performance can give inertia to the blood ejected from the LV into the ascending aorta during early systole.^10,11 In late systole, the LV contraction maintains wall tension against wall stress but stops accelerating the flow of ejected blood. Thus, LV pressure starts to fall during late systole. However, in late systole, blood is still being ejected from the LV into the ascending aorta with the inertia force of late systolic aortic flow until the aortic valve closes. The late systolic aortic flow with the inertia force causes LV end-systolic unloading and makes the LVESV much smaller compared with LVs without the inertia force of late systolic aortic flow.^10,11,18,19 In the present study, stronger LV contraction produced fast LV relaxation via LV elastic recoil as an effect of the inertia force. Thus, if LV contractile performance was not enough to generate the inertia force, it could not augment LV relaxation via LV elastic recoil, even in patients with preserved LVEF, as we reported previously.^10,18,19 In the range of LVEF ≥50%, LV LS can sensitively uncover mildly reduced LV contractile performance.^20,21

In the present study, we assessed the relationships between the LV relaxation time constant τ and GLS and ALS, which are surrogates of LV contractile performance or elastic recoil. Ito et al reported a similar result, namely that GLS obtained by magnetic resonance imaging was significantly correlated with the invasively obtained LV relaxation time constant τ in patients with HF with preserved LVEF, but Ito et al did not assess the relationship between LV local wall motion and τ.²²

Effects of Apical Wall Motion Abnormalities on the Generation of Inertia Force

We previously reported that LVs with abnormal apical wall motion due to CAD failed to produce the inertia force and could not speed up LV relaxation.^10,18 We thought that normal LV apical wall motion is essential to provide the inertia force for the late systolic aortic flow. Accordingly, in this study we focused on LV contractile performance at the apical segments in addition to the contractile performance of the whole LV. Our study demonstrated that, in patients with preserved LVEF, ALS was greater than GLS. In contrast, in patients with reduced LVEF, ALS was not significantly different from GLS. In patients with preserved LVEF, as shown in this study, LV apical wall motion is generally maintained and the ALS should have an effect on LV relaxation because the inertia force of late systolic aortic flow will enhance elastic recoil.

Parameters Related to the LV Relaxation Time Constant τ

As shown Figures 2 and 3, of GLS, ALS, changes in early diastolic global LS, and changes in early diastolic apical LS, ALS had the largest AUC and highest utility in identifying an LV relaxation time constant τ ≥48 ms in all patients and in those with preserved LVEF. Changes in early diastolic global LS and early diastolic apical LS are the parameters determined by both LV filling pressure and LV relaxation, such as the transmitral E-wave is determined by both effects.⁵ Thus, it should be possible to use changes in early diastolic global LS and early diastolic apical LS to detect an LV relaxation time constant τ ≥48 ms; however, both parameters were inferior to ALS.

In the multivariable stepwise regression Model II, in which log-LVESVI, a classical index of LV elastic recoil,^6,7 was used as an independent parameter instead of LVEF, only ALS and log-LVESVI were selected as parameters defining τ. In patients with preserved LVEF, the ALS was the only parameter defining τ (Models III and IV). The longitudinal myocardial contractile performance at LV apical segments plays a key role in producing LV elastic recoil and speeding up LV relaxation. This finding is consistent with our previous finding that normal LV apical wall motion is crucial for generating the inertia force of late systolic aortic flow.¹⁰

Heterogeneity of Segmental LS in the LV Wall

Hurlburt et al,²³ using 2D-STE, found no heterogeneity in LS in the LV wall in normal subjects. In contrast, Levy et al,²⁴ in a systematic review and meta-analysis, reported that heterogeneity in LS in local LV wall segments was detected using 2D-STE in children. The meta-analysis demonstrated a significant (P<0.001) apex-to-base (highest-to-lowest) gradient of the mean values of LS in the LV free wall in normal children throughout maturation. The present study demonstrated apex-to-base heterogeneity in LS at end-systole in adult patients with preserved LVEF, even though the patients had suspected or definite CAD. A compensatory increase in local contractile performance in the LV apical segments against its decrease outside the apical segments may have contributed to this phenomenon in this group of patients.

Effect of Diabetes on ALS

Diabetes is a well acknowledged comorbidity of HF with preserved LVEF.²⁵ However, in the present study, diabetes had no effect on ALS in patients with preserved LVEF.

Reproducibility of LS Measurements

ICCs for LS measurements were acceptable for 4 LS parameters in 2 different settings (intra- and interobserver variability), with r >0.70 except for the intra-observer variability in measurements of changes in early diastolic GLS in patients with reduced LVEF and the interobserver variability in measurements of changes in early diastolic GLS and ALS in patients with reduced LVEF. The GLS and ALS values were computed automatically; however, in measurements of the changes in early diastolic GLS and ALS, the timing of the end of early diastole (B and B′ in Figure 1) was visually determined on the time-strain curves. This procedure and the fact that patients had reduced LVEF would have contributed to ICCs <0.7. However, all ICCs were statistically significant.

Study Limitations

The present study is a small retrospective study designed to investigate the coupling between LV contractile performance and LV relaxation in patients with suspected or definite CAD. We used a relatively old database; however, strain analysis was performed using TomTec-Arena software, which enables strain data to be obtained -independent of vendor-specific algorithms for computing myocardial strains.

Conclusions

ALS analysis provides a noninvasive assessment of LV elastic recoil and LV relaxation not only over a wide range of LVEF, but also in patients with preserved LVEF. The findings of this study may contribute to the diagnosis of early stage LV diastolic dysfunction that may later lead to HF with preserved LVEF.

Sources of Funding

This study did not receive any specific funding.

Disclosures

N.O. is an Associate Editor of Circulation Journal. None of the remaining authors has a conflict of interest to declare.

IRB Information

The Internal Review Board of Nagoya City University Graduate School of Medical Sciences approved this clinical investigation (Reference no. 60-17-0081).

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-20-1162

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