Abstract

Aims

Strain rate imaging provides direct information on intrinsic myocardial function and may improve the diagnostic of diastolic dysfunction in heart failure with normal ejection fraction (HFNEF). We therefore correlated global strain with pressure–volume (PV) loop analysis and compared it with flow and tissue Doppler measurements.

Methods and results

Longitudinal two-dimensional strain rate and flow and tissue Doppler (TDI) indices were measured simultaneously and correlated with diastolic indices of PV relationship obtained by a conductance catheter in 21 patients with HFNEF and 12 controls. HFNEF patients showed a reduced global strain rate during isovolumetric relaxation (SRIVR) [0.27 (0.12–0.39) vs. 0.44 (0.29–0.56) s−1, P = 0.028]. Global strain rate during early (SRE) and late (SRL) diastole did not defer from controls. Their ratios with early transmitral flow, E/SRIVR and E/SRE, were both elevated in HFNEF [3.68 (2.57–7.52) vs. 1.73 (1.47–2.37) m, P = 0.007 and 1.13 (0.76–1.36) vs. 0.83 (0.57–1.04) m, P = 0.030]. SRE and SRIVR correlated with left ventricular (LV) relaxation τ (r = 0.40 and 0.47, P < 0.05); E/SRIVR and E/SRE with LV end-diastolic pressure (r = 0.49 and 0.57, P < 0.01) and LV stiffness constant β (r = 0.42 and 0.43, P < 0.01). Neither of the strain rate indices were significantly more accurate than TDI (area under the curve: SRE 0.55, SRIVR 0.70, E′/A′ 0.72, E/SRE 0.75, E/SRIVR 0.80, and E/E′ 0.83).

Conclusion

Strain rate imaging is accurate in detecting increased LV stiffness in HFNEF, but it is not superior to already established TDI analysis including E/E′ in patients with only mild degree of disease.

Introduction

More than 50% of patients with heart failure have been presented with normal ejection fraction (HFNEF) and diastolic dysfunction.1,2 Thus, the need of an objective and accurate diagnostic approach that is also applicable for everyday clinic practice has been emphasized.1,3–6 However, it has already been established that mitral flow Doppler alone with its 40–70% specificity has severe limitations in reliable detection of the diastolic dysfunction in HFNEF.7–10 Tissue Doppler imaging (TDI) parameters including the left ventricular (LV) filling index and transmitral flow velocity to annular velocity ratio (E/E′) were found to be useful for the determination of filling pressures and LV stiffness.7,8,11,12 Nonetheless, these are still only indirect measures of ventricular filling which do not provide specific information on intrinsic passive diastolic properties of the LV.13 LV filling index E/E′ with its wide borderline values has also some limitations in characterization of diastolic function,1,8,14 particularly when left atrial pressure is low.15 This involves especially its role in young patients with borderline symptoms. Strain and strain rate measurements are new quantitative indices of intrinsic cardiac deformation in real time16 and are presumed to be independent of translational motion and other through-plane motion effects in contrast to myocardial velocities.12,14,17 Accordingly, the ratios of early mitral flow and strain rate during early diastole and during isovolumetric relaxation period have recently been shown to predict the LV filling pressure.18 These findings raise the question whether or not strain rate imaging provides more accurate information for analysing diastolic function in HFNEF than does tissue Doppler and LV filling index E/E′. Therefore, we performed a clinical study in order to directly compare the strain rate parameters in HFNEF with PV loop analysis obtained by invasive conductance catheter measurements.19

Methods

Patient population

Twenty-one patients with stable heart failure symptoms despite normal EF admitted to department of cardiology who underwent a conductance catheterization procedure and showed impaired relaxation and/or increased LV stiffness were included in the study. All patients had exercise dyspnoea and/or exercise intolerance, quantified by 6 min walk test and by elevated N-terminal-pro-brain natriuretic peptide (NT-proBNP) plasma levels (Elecsys 2010, Roche Diagnostics, Germany). Patients with acute or decompensated heart failure were not included. These patients were compared with 12 control patients who had been admitted for evaluation of chest discomfort, with no symptoms of heart failure, and with normal EF. Atrial fibrillation, valvular disease, significant coronary artery disease as obtained by angiography, and lung diseases as obtained by X-ray and functional test had been excluded in both groups. Six controls and three HFNEF patients have been already included in our previous study.8 All patients gave written informed consent for invasive diagnostic procedures. The research protocol was approved by the local institutional Ethics Committee.

Simultaneous performance of echocardiography and pressure–volume loop measurements

All patients interrupted their medication 24 h before the tests were done. Transthoracic echocardiography was performed by VIVID System Seven (2.5 MHz probe, GE Ultrasound) simultaneously with the conductance catheterization in the supine position. Three standard apical views (grey scale and tissue colour Doppler), mitral flow and tissue PW-Doppler, were obtained at the same time during PV loop registration in end-expiration. Echocardiographic loops were marked for the corresponding PV loop sequence. Cardiac cycles were recorded in a cineloop format and stored digitally for subsequent off-line analysis at ECHOPAC PC Workstation. The off-line analysis was performed by an independent investigator who was blinded for all information obtained from the invasive analysis.

Echocardiographic analysis

Mitral flow and tissue PW-Doppler velocities were recorded in the apical four-chamber view according to the standard procedure.20 Mitral inflow measurements included peak early (E) and peak late (A) flow velocities, the E/A ratio, the deceleration time of early mitral flow velocity (DT), and the isovolumetric relaxation time (IVRT) at rest and during Valsalva manoeuvre. During TDI, a 1.5 mm sample volume was placed at the leaflet origin of the mitral annulus.21 Background noise is eliminated by adequate gains and filters adjustment. In order to avoid the error of tissue Doppler measurements due to angle dependence, we kept the angle between the PW-Doppler beam and the movement direction of the wall to <15°. The systolic (S′), the early (E′), and the late (A′) diastolic peak velocities were measured at the lateral and septal sites. Accordingly, the ratio of early to late annular velocity (E′/A′) and LV filling index as the transmitral flow velocity to annular velocity ratio (E/E′) were determined for each patient. Chamber dimensions were evaluated using standard procedures, including LV mass index (LVMI)22 and left atrial volume index (LAVI).23

Global strain and strain rate

Myocardial deformation measurements were performed using tissue speckle tracking. Three cardiac cycles were recorded in apical four-, two-chamber, and long-axis views using grey-scale acquisition at a frame rate over 80 s−1. In each view, a global longitudinal strain and strain rate curve were obtained, including all LV myocardial segments (six segments per view),24 using standard ECHOPAC application for two-dimensional (2D) strain analysis. Figure 1 illustrates the strain and strain rate curves and undertaken measurements representatively. The average value of peak systolic longitudinal strain and peak systolic strain rate from all three views was then calculated as global strain (SISYS) and global strain rate (SRSYS), respectively.12,20,25 Similarly, peak global strain rate during early (SRE) and late (SRL) diastole and during isovolumetric relaxation (SRIVR) was determined. Diastolic indices E/SRE and E/SRIVR were calculated as proposed previously.18 LV filling index obtained from the lateral mitral annulus (E/Elat) was used for comparison, since our previous study8 demonstrated that E/Elat was the most accurate for detection of diastolic dysfunction in patients with mild HFNEF.

Figure 1

Representative curves of longitudinal two-dimensional strain (A) and strain rate (B). Segmental strain/rate curves are presented by continuous lines and the global strain/rate curve by interrupted line. SISYS, indicates systolic strain; SIMAX, maximal strain; SRIVR, strain rate during isovolumetric relaxation; SRE, strain rate during early and SRL, during late diastole; SRSYS, systolic strain rate.

Figure 1

Representative curves of longitudinal two-dimensional strain (A) and strain rate (B). Segmental strain/rate curves are presented by continuous lines and the global strain/rate curve by interrupted line. SISYS, indicates systolic strain; SIMAX, maximal strain; SRIVR, strain rate during isovolumetric relaxation; SRE, strain rate during early and SRL, during late diastole; SRSYS, systolic strain rate.

Pressure–volume measurements by conductance catheter method

The conductance catheter was used to assess PV measurements in all patients as described recently.8 Briefly, systolic and diastolic LV function was obtained by LV end-diastolic pressure (LVEDP), isovolumetric relaxation (τ), minimal and maximal rate of LV pressure change (dP/dtmin and dP/dtmax), LV maximal pressure (LVP), stroke volume (SV), and EF. We calculated the average slope of the end-diastolic PV relationship to determine functional LV chamber stiffness (LV stiffness b) and the exponential curve fit to the diastolic LV PV points to determine how rapidly stiffness increases with increasing pressure (LV stiffness β). Thus, the end-diastolic PV relationship was fitted with an exponential relation to obtain the chamber stiffness constant. Although not absolutely load-insensitive,26 this technique defines more precisely the natural curvilinear relation of PV and still represents an established method for comparing LV stiffness among different subgroups. Diastolic dysfunction was considered to be present if an IVRT constant was prolonged (τ ≥ 48 ms), and an LVEDP was elevated (≥16 mmHg) and/or an LV stiffness constant β (≥0.015 mL−1) and/or LV stiffness b (≥0.19 mmHg/mL) was increased in clinically symptomatic patients despite normal EF. These cut-off values were defined as values corresponding to the 90th percentiles of our control patients.8

Reproducibility of strain rate indices

Repeat analysis of 10 randomly selected studies was performed by a second observer. Mean interobserver difference for SRIVR was 0.019 ± 0.05 s−1, and for SRE, it was 0.03 ± 0.06 s−1.

Statistical analysis

SPSS software (version 16.0, SPSS Inc., Chicago, IL, USA) was used for statistical analysis. Descriptive characteristics of continuous variables were expressed as median values with the first and third quartiles. Two-sample comparisons between HFNEF patients and controls were performed using t-test if variables were normally distributed: the Mann–Whitney U-test for not normally distributed data and the χ2 test for categorical data. Correlation analyses between echocardiographic and PV loop diastolic indices were provided using Pearson's correlation coefficients. Linear regression analyses were performed to determine the exact relations between strain rate indices and LV stiffness. Receiver operating characteristic (ROC) curve analysis was used to compare the diagnostic accuracy of different parameters. Significant differences between areas under the curve were tested by the method of Hanley and McNeil.27 A P-value <0.05 was considered statistically significant in all analyses. The authors had full access to the data and take over the responsibility for its integrity. All authors have read and approved the manuscript as written.

Results

Patient characteristics

The study included 17 women and 16 men with a median age of 50 (39–60) years. HFNEF patients had arterial hypertension (n = 19), diabetes mellitus (n = 3), and/or obesity (n = 7). HFNEF patients were characterized with increased NYHA classifications, increased serum NT-proBNP levels, and tended to be overweight (Table 1). There was no difference between groups with respect to age or sex. In HFNEF patients, LV was not dilated (LV end-diastolic volume index <97 mL/m2), but LAVI and LVMI were increased. All LA and LV dimensions are listed in Table 1.

Table 1

Patient characteristics [variable expressed as median (25–75% quartile)]

 Controls (n = 12) HFNEF (n = 21) P-value 
Demographics 
 Men, n (%) 6 (50) 10 (48) 0.590 
 Age (years) 47 (35–59) 51 (43–60) 0.155 
 NYHA II–III, n (%) 0 (0) 19 (90) — 
 NT-proBNP (pg/mL) 46 (18–96) 161 (87–232) 0.011 
 6 min walk test (m) 504 (402–546) 339 (298–410) 0.001 
 BMI (kg/m223.1 (21.4–27.5) 27.2 (21.9–31.7) 0.116 
Heart dimensions 
 LA parasternal (mm) 34 (31–35) 39 (34–42) 0.089 
 LAVI (mL/m216 (12–22) 27 (19–31) 0.004 
 Septum (mm) 9 (8–10) 12 (10–13) 0.001 
 Posterior wall (mm) 9 (8–11) 11 (10–12) 0.001 
 LVEDD (mm) 47 (45–51) 48 (45–52) 0.674 
 LVMI (g/m286 (74–95) 114 (101–133) 0.002 
 EDWS (kdynes/cm213 (10–21) 27 (18–33) 0.003 
 LVEDVI (mL/m288 (63–97) 79 (66–96) 0.854 
Concomitant disease, n (%) 
 Arterial hypertension 1 (8) 19 (86) <0.001 
 Diabetes mellitus 0 (0) 3 (10) — 
 Obesity (BMI > 30 kg/m21 (8) 7 (33) 0.115 
 Hyperlipoproteinaemia 5 (42) 11 (52) 0.488 
 Smoking 1 (8) 7 (33) 0.115 
 Controls (n = 12) HFNEF (n = 21) P-value 
Demographics 
 Men, n (%) 6 (50) 10 (48) 0.590 
 Age (years) 47 (35–59) 51 (43–60) 0.155 
 NYHA II–III, n (%) 0 (0) 19 (90) — 
 NT-proBNP (pg/mL) 46 (18–96) 161 (87–232) 0.011 
 6 min walk test (m) 504 (402–546) 339 (298–410) 0.001 
 BMI (kg/m223.1 (21.4–27.5) 27.2 (21.9–31.7) 0.116 
Heart dimensions 
 LA parasternal (mm) 34 (31–35) 39 (34–42) 0.089 
 LAVI (mL/m216 (12–22) 27 (19–31) 0.004 
 Septum (mm) 9 (8–10) 12 (10–13) 0.001 
 Posterior wall (mm) 9 (8–11) 11 (10–12) 0.001 
 LVEDD (mm) 47 (45–51) 48 (45–52) 0.674 
 LVMI (g/m286 (74–95) 114 (101–133) 0.002 
 EDWS (kdynes/cm213 (10–21) 27 (18–33) 0.003 
 LVEDVI (mL/m288 (63–97) 79 (66–96) 0.854 
Concomitant disease, n (%) 
 Arterial hypertension 1 (8) 19 (86) <0.001 
 Diabetes mellitus 0 (0) 3 (10) — 
 Obesity (BMI > 30 kg/m21 (8) 7 (33) 0.115 
 Hyperlipoproteinaemia 5 (42) 11 (52) 0.488 
 Smoking 1 (8) 7 (33) 0.115 

BMI, body mass index; NYHA, New York Heart Association class; LA, left atrial diameter; LAVI, left atrial volume index; LVEDD, LV end-diastolic diameter; LVMI, LV mass index; LVEDVI, LV end-diastolic volume index; EDWS, end-diastolic wall stress.

Cardiac performance, systolic, and diastolic function of the left ventricle

According to the PV loop analysis, there was no significant difference between HFNEF patients and controls regarding indices of cardiac performance and LV systolic function (Table 2). HFNEF patients showed an impaired relaxation with prolonged τ (+19%, P = 0.006) compared with control patients, whereas dP/dtmin did not differ significantly (+8%, P = 0.116). Their LVEDP, LV stiffness b, and stiffness constant β were all significantly increased by 67, 53, and 145%, respectively (Table 2). The peak systolic annular velocity S′ and global systolic myocardial strain and strain rate indices did not differ among the two groups (Table 3).

Table 2

Left ventricular systolic and diastolic parameters in patients with HFNEF compared with controls [variable expressed as median (25–75% quartile)]

 Controls (n = 12) HFNEF (n = 21) P-value 
Cardiac performance 
 HR (min−178 (69–89) 75 (69–85) 0.304 
 EF (%) 65 (60–75) 64 (60–70) 0.359 
 SV (mL) 109 (94–120) 103 (86–126) 0.793 
 ESV (mL) 60 (42–88) 59 (46–75) 0.822 
 EDV (mL) 165 (122–181) 162 (136–195) 0.600 
 CO (L/min) 7.8 (7.0–10.4) 7.5 (6.8–9.4) 0.549 
Systolic indices 
 ESP (mmHg) 117 (112–127) 136 (116–151) 0.053 
 dP/dtmax (mmHg/s) 1555 (1425–1800) 1446 (1310–1648) 0.098 
EES (mmHg/mL) 0.8 (0.6–1.2) 1.0 (0.7–1.7) 0.391 
Diastolic indices 
 LVEDPa (mmHg) 6.5 (5.6–9.2) 14.1 (10.2–18.0) <0.001 
 LVPmin (mmHg) 1 (0–3) 5 (3–9) <0.001 
 dP/dtmin (mmHg/s) −1948 (−1863 to −2162) −1805 (−1613 to −2039) 0.116 
 τa (ms) 43 (41–47) 51 (45–60) 0.006 
 Stiffness constant βa (mL−10.011 (0.009–0.014) 0.027 (0.015–0.035) <0.001 
 LV stiffness ba (mmHg/mL) 0.15 (0.10–0.17) 0.23 (0.18–0.30) <0.001 
 Controls (n = 12) HFNEF (n = 21) P-value 
Cardiac performance 
 HR (min−178 (69–89) 75 (69–85) 0.304 
 EF (%) 65 (60–75) 64 (60–70) 0.359 
 SV (mL) 109 (94–120) 103 (86–126) 0.793 
 ESV (mL) 60 (42–88) 59 (46–75) 0.822 
 EDV (mL) 165 (122–181) 162 (136–195) 0.600 
 CO (L/min) 7.8 (7.0–10.4) 7.5 (6.8–9.4) 0.549 
Systolic indices 
 ESP (mmHg) 117 (112–127) 136 (116–151) 0.053 
 dP/dtmax (mmHg/s) 1555 (1425–1800) 1446 (1310–1648) 0.098 
EES (mmHg/mL) 0.8 (0.6–1.2) 1.0 (0.7–1.7) 0.391 
Diastolic indices 
 LVEDPa (mmHg) 6.5 (5.6–9.2) 14.1 (10.2–18.0) <0.001 
 LVPmin (mmHg) 1 (0–3) 5 (3–9) <0.001 
 dP/dtmin (mmHg/s) −1948 (−1863 to −2162) −1805 (−1613 to −2039) 0.116 
 τa (ms) 43 (41–47) 51 (45–60) 0.006 
 Stiffness constant βa (mL−10.011 (0.009–0.014) 0.027 (0.015–0.035) <0.001 
 LV stiffness ba (mmHg/mL) 0.15 (0.10–0.17) 0.23 (0.18–0.30) <0.001 

HR, heart rate; EF, ejection fraction; SV, stoke volume; ESV, end-systolic volume; EDV, end-diastolic volume; CO, cardiac output; ESP, end-systolic pressure; dP/dtmax, maximum rate of pressure change; EES, end-systolic elastance; LVEDP, LV end-diastolic pressure; dP/dtmin, minimal rate of LV pressure change; τ, isovolumetric relaxation time; LV stiffness b, slope of end-diastolic PV relationship (dP/dV); stiffness constant β, exponential curve fit to end-diastolic PV relationship.

aDiagnostic criteria.

Table 3

Diastolic indices of conventional, tissue Doppler imaging, and strain rate echocardiography [variable expressed as median (25–75% quartile)]

 Controls (n = 12) HFNEF (n = 21) P-value 
Mitral flowa 
E (m/s) 0.70 (0.61–0.80) 0.83 (0.71–0.95) 0.028 
A (m/s) 0.58 (0.45–0.65) 0.72 (0.58–0.88) 0.020 
E/A 1.31 (1.13–1.48) 1.12 (0.89–1.33) 0.098 
 DT (m/s) 184 (170–208) 217 (185–248) 0.108 
 IVRT (m/s) 87 (85–92) 97 (85–103) 0.303 
Tissue Doppler 
Slateral (m/s) 0.09 (0.06–0.11) 0.08 (0.05–0.10) 0.647 
Elateral (m/s) 0.12 (0.09–0.15) 0.08 (0.06–0.12) 0.047 
Alateral (m/s) 0.06 (0.05–0.09) 0.07 (0.05–0.09) 0.523 
E′/Alateral 1.58 (1.29–2.12) 1.20 (0.83–1.59) 0.039 
E/Elateral 6.8 (5.04–7.01) 13.0 (8.5–15.6) 0.002 
Strain/rate 
 SRSYS (s−1−0.77 (−0.73–0.93) −0.79 (−0.68– −1.05) 0.694 
 SISYS, (%) −15.1 (−13.6 to −17.2) −16.2 (−11.7 to −19.6) 0.533 
 SRIVR (s−10.44 (0.29–0.56) 0.27 (0.12–0.39) 0.028 
 SRE (s−10.99 (0.79–1.18) 0.82 (0.61–0.97) 0.058 
 SRL (s−10.66 (0.56–0.91) 0.57 (0.44–0.87) 0.431 
 SRE/L (s−11.38 (1.09–1.60) 1.35 (1.07–1.72) 0.970 
E/SRE (m) 0.83 (0.57–1.04) 1.13 (0.76–1.36) 0.030 
E/SRIVR (m) 1.73 (1.47–2.37) 3.68 (2.57–7.52) 0.007 
 Controls (n = 12) HFNEF (n = 21) P-value 
Mitral flowa 
E (m/s) 0.70 (0.61–0.80) 0.83 (0.71–0.95) 0.028 
A (m/s) 0.58 (0.45–0.65) 0.72 (0.58–0.88) 0.020 
E/A 1.31 (1.13–1.48) 1.12 (0.89–1.33) 0.098 
 DT (m/s) 184 (170–208) 217 (185–248) 0.108 
 IVRT (m/s) 87 (85–92) 97 (85–103) 0.303 
Tissue Doppler 
Slateral (m/s) 0.09 (0.06–0.11) 0.08 (0.05–0.10) 0.647 
Elateral (m/s) 0.12 (0.09–0.15) 0.08 (0.06–0.12) 0.047 
Alateral (m/s) 0.06 (0.05–0.09) 0.07 (0.05–0.09) 0.523 
E′/Alateral 1.58 (1.29–2.12) 1.20 (0.83–1.59) 0.039 
E/Elateral 6.8 (5.04–7.01) 13.0 (8.5–15.6) 0.002 
Strain/rate 
 SRSYS (s−1−0.77 (−0.73–0.93) −0.79 (−0.68– −1.05) 0.694 
 SISYS, (%) −15.1 (−13.6 to −17.2) −16.2 (−11.7 to −19.6) 0.533 
 SRIVR (s−10.44 (0.29–0.56) 0.27 (0.12–0.39) 0.028 
 SRE (s−10.99 (0.79–1.18) 0.82 (0.61–0.97) 0.058 
 SRL (s−10.66 (0.56–0.91) 0.57 (0.44–0.87) 0.431 
 SRE/L (s−11.38 (1.09–1.60) 1.35 (1.07–1.72) 0.970 
E/SRE (m) 0.83 (0.57–1.04) 1.13 (0.76–1.36) 0.030 
E/SRIVR (m) 1.73 (1.47–2.37) 3.68 (2.57–7.52) 0.007 

E/A, the ratio of early (E) to late (A) mitral flow peak velocities; DT, deceleration time of early mitral flow; IVRT, isovolumetric relaxation time; S′, systolic; E′, early; and A′, late diastolic peak velocities of mitral annulus at lateral site; E′/A′ ratio; E/E′, LV filling index; SISYS, systolic strain; SRIVR, strain rate during isovolumetric relaxation; SRE, strain rate during early; SRL, during late diastole; SRE/L, strain rate early-to-late ratio; SRSYS, systolic strain rate.

aPseudo-normal filling pattern excluded.

Conventional and tissue Doppler echocardiography vs. pressure–volume loop analysis

Flow Doppler indices are summarized in Table 3 showing increased E-wave and A-wave in patients with HFNEF compared with controls. IVRT correlated with relaxation index dP/dtmin (r = 0.34, P = 0.049), whereas A was related to LV stiffness b (r = −0.38, P = 0.028). E and E/A tended to correlate with LVEDP but did not reach a statistical significance. Neither of conventional indices were related to the stiffness constant β. TDI indices E′ and E′/A′ ratio were significantly decreased and the LV filling index E/E′ was found to be two-fold increased in HFNEF (Table 3). TDI indices correlated with LVEDP (E′: r = −0.39, P = 0.034; E′/A′: r = −0.41, P = 0.018) and with LV stiffness b (E′: r = −0.42, P = 0.023; E′/A′: r = −0.32, P = 0.051). The filling index E/E′ showed the strongest correlations with LVEDP, LV stiffness b, and constant β (r = 0.57, 0.61, and 0.64 respectively; P < 0.001).

Global strain and strain rate vs. pressure–volume loop analysis

No differences in global strain measurements were seen between HFNEF and controls (Table 3). No relation was observed between strain indices and invasive diastolic parameters.

Patients with HFNEF showed a significantly decreased global strain rate during isovolumetric relaxation (SRIVR) (−38%, P = 0.035) when compared with controls (Table 3). The global strain rate during early (SRE) and late (SRL) diastole in HFNEF patients did not differ significantly from controls. As expected, SRIVR and SRE correlated moderately with τ (r = 0.47, P = 0.006 and r = 0.40, P = 0.022, respectively) (Figure 2) and SRL did not. Neither SRE nor SRL solely was related to the LVEDP or LV stiffness indices. E/SRIVR correlated moderately with LVEDP (r = 0.54, P = 0.004), LV stiffness b (r = 0.50, P = 0.003), and LV stiffness constant β (r = 0.42, P = 0.016) and E/SRE was related more strongly to the LVEDP (r = 0.57, P < 0.001) but only moderately to LV stiffness constant β (r = 0.43, P = 0.014) (Figure 2).

Figure 2

Linear regression between pressure–volume loop and strain rate indices. SRE and SRIVR correlate with relaxation index τ (A); E/SRE and E/SRIVR with end-diastolic pressure, LVEDP(B), and LV stiffness constant β (C) (r, correlation coefficient; P, significance level).

Figure 2

Linear regression between pressure–volume loop and strain rate indices. SRE and SRIVR correlate with relaxation index τ (A); E/SRE and E/SRIVR with end-diastolic pressure, LVEDP(B), and LV stiffness constant β (C) (r, correlation coefficient; P, significance level).

Receiver operating characteristic curve analysis

According to the ROC curve analysis, the strain rate indices were not more accurate in detecting diastolic dysfunction in HFNEF patients than were the tissue Doppler and LV filling index. Neither of the strain rate indices reached the area under the ROC curve (AUC) of the LV filling index (SRE 0.55, SRL 0.47, SRE/L 0.59, SRIVR 0.70, E/SRE 0.75, E/SRIVR 0.80 vs. E/E′ 0.83) (Figure 3). In a formal comparison according to the described method,27 the AUC for E/E′ was not significantly larger when compared with E/SRIVR or E/SRE. SRIVR and E/SRIVR are shown to be the most accurate to diagnose diastolic dysfunction according to the ROC analysis, in particular compared with the SRE. E/SRIVR was able to recognize 17 of 21 patients with diastolic dysfunction in HFNEF which is more than E/A (13 of 21) and similar to E/E′ (18 of 21).

Figure 3

Receiver operating characteristic analysis. The ability of strain rate indices to detect an abnormal diastolic function in HFNEF. Area under the curve of SRE is 0.55, SRIVR 0.70, E′/A′ 0.72, E/SRE 0.75, E/SRIVR 0.80, and E/E′ 0.83.

Figure 3

Receiver operating characteristic analysis. The ability of strain rate indices to detect an abnormal diastolic function in HFNEF. Area under the curve of SRE is 0.55, SRIVR 0.70, E′/A′ 0.72, E/SRE 0.75, E/SRIVR 0.80, and E/E′ 0.83.

Discussion

With this study, we showed that strain rate imaging and its global longitudinal diastolic indices were closely related in patients with HFNEF. Compared with TDI and LV filling index E/E′, strain rate echocardiography revealed similar accuracy in diagnosing diastolic dysfunction in patients with only mild HFNEF. The distinctive value of this study lies in simultaneously performed strain measurements during invasive pressure–volume relationship analysis of LV obtained by the conductance catheter.

In the clinical routine, several echocardiographic approaches are used in order to investigate diastolic function in HFNEF, including comprehensive echocardiography and TDI.14 A superior role of TDI and E/E′ has been recently proved in detecting advanced7,11,21,28 but also mild8,29 diastolic dysfunction in HFNEF, confirmed also by the present study. However, the role of strain and strain rate imaging in diagnosing diastolic dysfunction is still under investigation.14,30,31 Significant changes of strain rate measurement have been described in patients with coronary heart disease,32–35 arterial hypertension,36 and hypertrophic cardiomyopathy (HCM).3,37,38 In ischaemic myocardium, strain rate imaging distinguished post-systolic shortening of overloaded and viable myocardium from passive recoil of non-contracting and necrotic myocardium.12,32,33 Since also global changes of LV function could be analysed using a 2D strain method,24 the question is raised whether strain rate imaging can be also helpful in diagnosing diastolic dysfunction HFNEF.18,39 The analysis of tissue deformation can yield additional information to recognize already mild HFNEF, particularly when TDI measurements reveal borderline or normal results.40,41 This is of interest in younger patients without any extensive LV hypertrophy (LVH) as in HCM or markedly increased filling pressures or distinct regional motion changes as seen in post-myocardial infarction patients.

Strain rate during early diastole (SRE) and isovolumetric relaxation (SRIVR)

As the myocardial lengthening is associated with the onset of mitral inflow into the LV, the changes in global strain rate may be early markers for disturbances of global diastolic function.41 Since Garcia-Fernandez et al.42 proved that up to 40% of the segments may have measurable regional diastolic motion abnormalities, although mitral flow Doppler remains normal, measuring of global 2D strain appears to be even more important. In agreement with Wang et al.,18 SRE and SRIVR are shown to be useful for detecting abnormalities in early diastolic phase43 while correlating with the time constant of LV relaxation (τ). In patients with HCM3 and advanced diastolic heart failure,18 a reduction of SRE and SRIVR was associated with global diastolic dysfunction. We found similar results in HFNEF patients with only mild diastolic dysfunction. Beside by LV relaxation, SRE is shown to be influenced by preload conditions and LV stiffness.44,45 However, we could not confirm those findings, most likely because of only mild changes in our population compared with others.

Since SRIVR occurs before the mitral valve opens and therefore is less dependent from valvular and annular pathology, it is expected that SRIVR better reflects the intrinsic myocardial characteristics of the LV during early LV expansion. But, direct simultaneous comparison during conductance catheterization revealed only a weak correlation of SRIVR with LV stiffness coefficient. Moreover, this correlation was dependent on arterial systolic pressure and stroke volume. According to this, SRIVR as a parameter of early diastolic relaxation seams to be influenced by late systolic recoil and arterial load, similar to E′ and SRE.18,46–48 Therefore, SRE and SRIVR reflect rather the LV relaxation and preload changes which have a limited role in the detection of diastolic dysfunction due to disturbed LV compliance.

Analogous to the LV filling index E/E′, Wang et al.18 introduced recently the ratio of E and SRE (E/SRE) and the ratio of E and SRIVR (E/SRIVR) for the assessment of LV filling pressure. Similar findings have been recently reported;3,49 however, they investigated patients with coronary artery disease, regional abnormalities, dilated cardiomyopathy, valvular disease, and HCM which were characterized by more severe diastolic dysfunction compared with our study population. Even in patients with mild degree of disease diagnosed by PV loop analysis, E/SRE was significantly related to the LV filling pressure, independent from arterial load. Nevertheless, according to the ROC analysis, E/SRE was not able to recognize more HFNEF patients with diastolic dysfunction than E/E′. We could confirm the clinical utility of E/SRE and E/SRIVR to predict LV filling pressures. However, there was a wide variation in this correlation and therefore these results should be discussed with caution. Moreover, the E/SRIVR ratio was also positively associated with increasing LV stiffness constant which supports the hypothesis that strain rate could depict intrinsic information of myocardial structure and function. However, when compared with E/E′, E/SRIVR ratio was not significantly more accurate in diagnosing diastolic dysfunction in our HFNEF patients with mild degree of disease as Wang et al.18,46 suggested. The crucial differences lay in the study cohort characteristics. More than 70% of the patients in the study of Wang et al. had coronary artery disease and/or significant valvular disease, which can significantly influence both relaxation and compliance properties of the LV and contribute to the different results regarding strain rate imaging. Nevertheless, despite those discrepancies, it is indisputable that strain rate imaging has its advantages in diagnosing diastolic dysfunction12,14 and its further role in everyday clinical practice has to be defined yet in larger trials.

Strain rate during late diastolic lengthening (SRL)

In contrast to the SRE, strain rate during the late diastolic filling was related neither with LV relaxation nor compliance indices obtained by PV loop analysis. This was surprising since it was discussed that the strain rate pattern after the early lengthening wave depends mainly on LV passive recoil processes in late diastole. Impairment of early diastolic filling is usually compensated by the augmentation of LV filling during atrial systole incrementing the late ventricular lengthening. The changes of left atrial function seemed not to be affected significantly in our HFNEF population with mild abnormalities and thus no abnormalities are found in the late diastolic lengthening.

Accuracy of global longitudinal strain rate in detecting diastolic dysfunction in HFNEF

Since analysing deformation and providing direct information on intrinsic myocardial function, it might be expected that strain rate allows a more accurate assessment of cardiac dysfunction in HFNEF. However, in our study, strain rate measurements alone did not reveal significant advantages over TDI measurements in our HFNEF population. On the based of ROC curve analyses, none of strain rate indices were significantly superior to the established TDI analysis including LV filling index E/E′ (Figure 3). Therefore, due to distinctive off-line analysis, the clinical application of global strain rate is rational in clinical cases when TDI and E/E′ reveal unequivocal results and patients might have regional disturbances.

Conclusion

Strain rate imaging is helpful to recognize diastolic dysfunction and to better understand myocardial pathomechanisms in HFNEF, particularly in patients with borderline results in TDI analysis. Prospective clinical studies with larger population size have to show the significance of both TDI and strain rate imaging in providing prognosis relevant results in HFNEF. But at least in patients without severe co-morbidity or severe regional dysfunction because of LVH or scar formation, this technique does not promise advantages in diagnosing diastolic dysfunction in HFNEF compared with E/E′ in the clinical routine.

Conflict of interest: none declared.

Funding

This study was supported by the Deutsche Forschungsgesellschaft (DFG, SFB-TR-19, B5, Z2).

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