Abstract
Background
Growing attempt to use left ventricular (LV) systolic (LVSIsys) and diastolic (LVSIdia) synchronicity indexes in the process of selecting potential responders to cardiac resynchronization therapy has created a need for normative reference values.
Hypothesis
This study sought: (1) to determine normal reference ranges for LVSIsys and LVSIdia, and (2) to assess their relationships to age and conventional parameters reflecting LV systolic and diastolic functions.
Methods
We recruited 160 healthy volunteers (104 men) free of any systemic or cardiovascular disease. Maximal difference and standard deviation of time to peak systolic and peak early diastolic myocardial velocities for LVSIsys and LVSIdia were measured using 6 and 12 segment models.
Results
Normal ranges for LVSIsys and LVSIdia obtained in this study were slightly higher than previously reported. The normal aging process did not significantly change LVSIsys, whereas LVSIdia progressively and consistently increased with age. Significant correlations were observed between LVSIdia and parameters representing LV diastolic function, that is, early mitral inflow velocity and its deceleration time, and early mitral annulus velocity. A physiologic increase in LV mass/Ht2.7 showed a weak, but significant correlation with LVSIdia (r = 0.15–0.22), but not with LVSIsys. On multivariate analysis, an age‐dependent increase in LVSIdia was confirmed.
Conclusions
In this study, we propose age‐specific reference ranges for LVSIsys and LVSIdia. LVSIsys remains stable throughout age groups, whereas LVSIdia progressively increases with age. We believe that the reference values provided here will be useful for defining abnormal LV synchronous contraction and relaxation. Copyright © 2010 Wiley Periodicals, Inc.
This work was presented in part at the Annual Scientific Session of the American Society of Echocardiography, Seattle, Washington, June 16–20, 2007.
Introduction
Cardiac resynchronization therapy (CRT) is currently regarded as an accepted therapeutic modality for patients with end‐stage, drug‐refractory heart failure.1 A wide QRS complex on electrocardiogram signifying electromechanical delay has been considered a prerequisite for selecting patients who are likely to benefit from this sophisticated treatment. However, a growing body of evidence suggests that electrocardiogram‐based QRS duration does not adequately reflect the presence of the left ventricular (LV) mechanical asynchrony, and that it is suboptimal for predicting a favorable response to CRT.2 Instead, the degree of LV systolic asynchrony assessed with tissue Doppler imaging (TDI) has emerged as a better predictor of CRT success.3, 4, 5 In addition, an increasing awareness of the high prevalence and clinical relevance of diastolic heart failure has stimulated interest in quantifying LV diastolic asynchrony.6, 7, 8 It is thus conceivable that any general use of LV systolic (LVSIsys) and diastolic synchronicity indexes (LVSIdia) should be preceded by establishment of their normal reference values. Although earlier studies have attempted to determine normal reference ranges for LVSIsys and LVSIdia, they seem to be limited due to the small number of subjects enrolled. Besides, “healthy, normal” subjects in previous studies were chosen solely based on clinical history, physical examination, electrocardiographic, and echocardiographic findings, thus subclinical coronary artery disease, which may be manifested as LV systolic or diastolic dyssynchrony in patients with preserved LV systolic function, might not have been completely excluded.9 In this context, the normal reference ranges for LVSIsys and LVSIdia remain to be directly addressed.
Recent technical developments have made noninvasive coronary computed tomographic angiography quite trustworthy in terms of eliminating any possibility of subclinical coronary artery disease.10 With the help of this state‐of‐the art technology, this study was undertaken with 160 “completely” healthy volunteers; (1) to set up normal reference ranges for TDI‐derived LVSIsys and LVSIdia stratified by age, and (2) to assess their relationships to age and conventional parameters reflective of LV systolic and diastolic functions.
Methods
Study Population
Volunteers who visited the Health Care Center at our hospital for a general routine check‐up and did not show any laboratory abnormality including electrocardiographic and echocardiographic findings were initial candidates for the current study. History of cardiovascular or systemic diseases was also considered as another exclusion criterion. Among them, subjects < 40 years old had to undergo a modified Bruce protocol‐based treadmill test and those ≥ 40 years old had to undergo both a treadmill test and a computed tomographic coronary angiography in order to rule out the presence of subclinical coronary artery disease. Volunteers who had a stenosis of > 25% in any coronary artery on a computed tomographic coronary angiography or who did not reach at least 85% of age‐predicted maximal heart rate during the treadmill test were excluded. Subjects aged ≥ 50 years were screened with carotid Doppler examination and those who had a stenosis of ≥ 50% of lumen diameter in any carotid artery were excluded as well. QRS duration was measured from the surface electrocardiogram using the widest QRS complex from lead II. The study protocol was approved by the institutional review board of our hospital and written informed consent was obtained from all participants before study enrollment.
Echocardiographic Analysis
Transthoracic echocardiograms were obtained using commercially available equipment (Vivid 7, GE Medical System, Horten, Norway) with volunteers in a left lateral decubitus position. Routine standard echocardiographic examination included measurements of LV systolic and diastolic dimensions, wall thicknesses, LV ejection fraction (LVEF), and a pulsed‐wave Doppler examination of mitral inflow. The modified biplane Simpson's method was used to calculate LVEF. Peak early (E) and late (A) diastolic velocities of mitral inflow were measured using pulsed‐wave Doppler with the sample volume at the tip of the mitral valve. Systolic (S′), and early (E′) and late (A′) diastolic mitral annular velocities were measured in the apical 4‐chamber view at the septal side of the mitral annulus using pulsed‐wave TDI. LV mass was calculated with the Devereux formula.11 To make the relation between the LV mass and height (Ht) linear, LV mass was adjusted for height by dividing it with Ht2.7.12
After standard echocardiographic examination, TDI mode was again activated in the apical 4‐chamber, 2‐chamber, and long‐axis views for off‐line LV synchrony measurements. Great care was taken to get the highest frame rate (at least 100 frames/sec) with pulse repetition frequency, color saturation, sector width, and depth optimized. Three consecutive heart beats were digitally stored in cineloop format by an independent echocardiographer for later off‐line analysis with the aid of a dedicated software package (EchoPac 5.0.1, GE Medical System, Chalfont St. Giles, UK). Myocardial velocity curves were reconstructed with a sample volume of 5 × 5 mm placed at the center of the basal and mid myocardial segments as parallel as possible to the motional vector of the myocardial segments analyzed. Semiautomatic tracking of the region of interest was performed to maintain the sample volume in the region of interest throughout the cardiac cycle if the velocity signal is not obvious. The time to peak myocardial systolic velocity during ejection phase (Ts) and the time to peak myocardial early diastolic velocity (Te) were measured with reference to QRS complex3, 6, 7, 8 (Figure). Motion of the anterior mitral leaflet was tracked using the color M‐mode TDI technique to determine cardiac time intervals.13 After Ts and Te values of 12 LV myocardial segments (6 basal and 6 mid) had been procured, the following LV synchrony indexes were calculated:
Standard deviations of Ts (Ts‐SD‐12) and Te (Te‐SD‐12) for 12 segments.
Maximal difference of Ts (Ts‐max‐12) and Te (Te‐max‐12) for 12 segments.
Standard deviations of Ts (Ts‐SD‐6) and Te (Te‐SD‐6) for 6 basal segments.
Maximal difference of Ts (Ts‐max‐6) and Te (Te‐max‐6) for 6 basal segments.
Figure 1.
A representative example of measuring the time to peak systolic and peak early diastolic velocities in a 47‐year‐old female. White line: the onset of QRS complex. (Refer to the online version for color illustration). Abbreviations: AVC, aortic valve closure; AVO, aortic valve opening; MVC, mitral valve closure; MVO, mitral valve opening
Statistical Analysis
All values are expressed as mean ± SD or as number (percentages). For comparison of parametric variables between age groups, analysis of variance with Sheffe correction was employed. Fisher's exact test was used for categorical variables. Linear regression analysis was performed to investigate the correlation between parametric variables. Multivariate linear regression analysis using the enter algorithm was performed to ensure whether age‐dependent changes in LVSIdia occurred independently of QRS duration and the alteration of LV mass/Ht2.7 occurring with age. All statistical analyses were performed using SPSS 13.0 (SPSS Inc., Chicago, IL), and a P value of <.05 was considered statistically significant.
Results
Clinical and Conventional Echocardiographic Data
The study population was composed of 160 subjects (104 males, age 44.9 ± 2.7 years [range, 11–72 years]). Clinical and conventional echocardiographic results across age deciles are summarized in Table 1.
Table 1.
Clinical and Conventional Echocardiographic Data
| All Volunteers (n = 160) | (≤30 yrs) (n = 29) | (31–40 yrs) (n = 26) | (41–50 yrs) (n = 50) | (51–60 yrs) (n = 35) | (≥61 yrs) (n = 20) | P Value | |
|---|---|---|---|---|---|---|---|
| Clinical profiles | |||||||
| Male (%) | 104 (65.0%) | 22 (75.9%) | 20 (76.9%) | 31 (62.0%) | 18 (51.4%) | 13 (65.0%) | 0.20 |
| Weight (Kg) | 64.1±10.3 | 65.1±11.7 | 66.9±10.2 | 65.3±10.2 | 61.9±8.6 | 60.1±10.6 | 0.11 |
| Height (cm) | 166.5±8.1 | 170.4±8.3 | 169.1±5.5 | 166.2±7.9 | 163.1±7.0a | 164.4±9.7 | 0.001 |
| Heart rate (/min) | 66±11 | 68±11 | 68±11 | 65±10 | 64±9 | 69±13 | 0.17 |
| QRS duration on ECG | 93.6±12.1 | 85.7±17.6 | 94.8±9.9 | 95.6±9.3b | 97.0±10.5a | 92.6±9.2 | 0.001 |
| Echocardiographic data | |||||||
| M‐mode parameters | |||||||
| LVIDs (mm) | 29.5±4.1 | 31.5±4.2 | 30.3±3.8 | 30.0±3.7 | 27.3±4.1a | 28.4±3.6 | <0.001 |
| LVIDd (mm) | 47.8±4.4 | 49.0±4.9 | 47.8±4.0 | 48.4±4.3 | 46.5±4.0 | 46.4±4.6 | 0.10 |
| IVSd (mm) | 8.9±1.2 | 8.4±1.2 | 8.8±1.3 | 9.1±1.2 | 9.2±1.2 | 8.9±1.0 | 0.10 |
| LVPWd (mm) | 8.6±1.3 | 8.0±1.3 | 8.0±1.3 | 8.7±1.4 | 9.1±1.3b | 8.8±0.9 | 0.003 |
| LV mass/Ht2.7 (g/m2.7) | 35.9±7.7 | 32.1±5.5 | 33.2±8.0 | 37.5±7.1 | 38.7±8.0b | 36.4±8.6 | 0.002 |
| 2‐D parameters | |||||||
| LVESV (ml) | 35.9±10.3 | 42.6±11.2 | 38.8±8.6 | 36.2±9.9 | 30.5±6.9a,c | 30.5±9.9a | <0.001 |
| LVEDV (ml) | 98.8±21.3 | 111.8±23.7 | 102.8±20.0 | 99.3±19.2 | 89.9±15.9a | 87.5±21.7a | <0.001 |
| LVEF (%) | 64.0±4.8 | 62.3±4.0 | 62.2±4.0 | 63.8±5.4 | 66.2±4.2b,c | 65.5±4.7 | 0.002 |
| Doppler parameters | |||||||
| E (m/sec) | 0.65±0.15 | 0.77±0.15 | 0.70±0.17 | 0.63±0.14a | 0.61±0.12a | 0.57±0.12a | <0.001 |
| A (m/sec) | 0.52±0.14 | 0.40±0.10 | 0.48±0.12 | 0.50±0.10a | 0.59±0.11a,d,g | 0.71±0.14a,d,e | <0.001 |
| DT (msec) | 195±39 | 173±28 | 167±32 | 198±34d | 211±39a,d | 228±30a,d,g | <0.001 |
| E/A ratio | 1.34±0.50 | 2.00±0.49 | 1.51±0.39 | 1.30±0.36a | 1.06±0.22a,d | 0.84±0.24a,d,e | <0.001 |
| S′ (m/sec) | 0.08±0.01 | 0.08±0.01 | 0.08±0.01 | 0.07±0.01 | 0.07±0.01 | 0.07±0.01 | 0.10 |
| E′ (m/sec) | 0.08±0.02 | 0.11±0.01 | 0.09±0.02 | 0.08±0.02a | 0.06±0.02a,d,h | 0.05±0.01a,d,e | <0.001 |
| A′ (m/sec) | 0.07±0.02 | 0.06±0.01 | 0.07±0.02 | 0.08±0.01a | 0.08±0.01b | 0.09±0.02a,d | <0.001 |
| E′/A′ ratio | 1.11±0.45 | 1.71±0.38 | 1.27±0.39a | 1.02±0.31a,c | 0.85±0.22a,d | 0.67±0.22a,d,e | <0.001 |
Abbreviations: A, late mitral inflow velocity; A′, late diastolic mitral annular velocity; DT, deceleration time of E velocity; E, early mitral inflow velocity; E′, early diastolic mitral annular velocity; ECG, electrocardiogram; IVSd, diastolic interventricular septal thickness; LVEF, left ventricular ejection fraction; LVES(D)V, left ventricular end‐systolic (diastolic) volume; LVIDs(d), left ventricular systolic (diastolic) dimension; LVPWd, diastolic left ventricular posterior wall thickness; S′, systolic mitral annular velocity.
a P<0.01 versus Group 1; b P<0.05 versus Group 1; c P<0.05 versus Group 2; d P<0.01 versus Group 2; e P<0.01 versus Group 3; f P<0.01 versus Group 4; g P<0.05 versus Group 3; h P<0.05 versus Group 3
Systolic LV Synchronicity Indexes
LVSIsys with differentiation into age deciles are described in Table 2, in conjunction with the data for the entire population without age breakdown. Mean values of LVSIsys were slightly higher than previously reported (Table 2).6, 7 There was no significant change in LVSIsys as age advanced. QRS duration (range, 50–118 msec) did not show any significant correlation with LVSIsys. Likewise, we failed to demonstrate a significant association between the LVSIsys and LV mass/Ht2.7 despite a wide range of LV mass in our population (range, 14.7–61.2 g/m2.7). In association with conventional parameters representing LV systolic function, S′ displayed weak negative correlations with LVSIsys (r = − 0.26 − 0.30); however LVEF did not (Table 3).
Table 2.
LV Systolic and Diastolic Synchronicity Indexes by Age Deciles
| All Volunteers (n = 160) | (≤30 yrs) (n = 29) | (31–40 yrs) (n = 26) | (41–50 yrs) (n = 50) | (51–60 yrs) (n = 35) | (≥61 yrs) (n = 20) | P Value | Previous Reportsd | |
|---|---|---|---|---|---|---|---|---|
| Systolic indexes | ||||||||
| Ts‐max‐6 | 51.5±37.1 | 50.1±36.5 | 54.6±37.8 | 54.7±41.4 | 47.5±32.5 | 48.9±35.8 | 0.85 | |
| Ts‐max‐12 | 77.1±41.6 | 70.6±32.0 | 76.7±42.4 | 83.8±43.1 | 77.6±38.6 | 69.5±53.3 | 0.32 | 54±23 |
| Ts‐SD‐6 | 20.6±15.4 | 20.2±15.4 | 22.2±16.2 | 22.0±16.9 | 18.6±13.1 | 19.5±15.5 | 0.78 | |
| Ts‐SD‐12 | 25.1±14.4 | 23.9±12.6 | 26.1±16.1 | 26.9±14.7 | 24.0±12.6 | 22.7±16.9 | 0.81 | 17.6±7.9 |
| Diastolic indexes | ||||||||
| Te‐max‐6 | 35.8±15.0 | 29.2±12.8 | 32.8±16.8 | 35.7±14.6 | 40.3±11.8 | 41.6±17.9 | 0.01 | |
| Te‐max‐12 | 68.8±29.0 | 46.5±14.7 | 59.5±27.2 | 72.5±22.6a | 79.1±32.8b | 85.4±33.0b,c | <0.001 | 63±25 |
| Te‐SD‐6 | 13.6±5.6 | 11.0±4.6 | 12.4±6.6 | 13.8±5.5 | 15.1±4.6 | 15.3±6.4 | 0.02 | |
| Te‐SD‐12 | 21.2±8.3 | 15.2±4.2 | 18.2±7.9 | 21.6±6.2a | 24.8±9.4b,c | 26.0±9.5b,c | <0.001 | 19.5±7.1 |
Abbreviations: Te, time to peak myocardial early diastolic velocity; Ts, time to peak myocardial systolic velocity during ejection phase. Standard deviations of Ts (Ts‐SD‐12) and Te (Te‐SD‐12) for 12 segments. Maximal difference of Ts (Ts‐max‐12) and Te (Te‐max‐12) for 12 segments. Standard deviations of Ts (Ts‐SD‐6) and Te (Te‐SD‐6) for 6 basal segments. Maximal difference of Ts (Ts‐max‐6) and Te (Te‐max‐6) for 6 basal segments.
a P<0.05 versus Group 1; b P<0.005 versus Group 1; c P<0.05 versus Group 2; d Refer to the references 15 and 16
Table 3.
Correlations of LV Systolic Synchronicity Indexes with QRS Duration, LV mass/Ht2.7, LVEF, and S′
| Ts‐max‐6 | Ts‐max‐12 | Ts‐SD‐6 | Ts‐SD‐12 | |||||
|---|---|---|---|---|---|---|---|---|
| r | P value | r | P value | r | P value | r | P value | |
| QRS duration | 0.01 | 0.86 | 0.04 | 0.63 | 0.001 | 0.99 | 0.01 | 0.89 |
| LV mass/Ht2.7 | 0.08 | 0.32 | 0.16 | 0.07 | 0.08 | 0.33 | 0.12 | 0.12 |
| LVEF | −0.06 | 0.49 | 0.01 | 0.87 | −0.04 | 0.58 | 0.001 | 0.99 |
| S′ | −0.30 | <0.001 | −0.27 | <0.001 | −0.27 | 0.001 | −0.26 | 0.001 |
Abbreviations: Ht, height; LV, left ventricular; LVEF, left ventricular ejection fraction; Te, time to peak myocardial early diastolic velocity; Ts, time to peak myocardial systolic velocity during ejection phase; S′, systolic mitral annular velocity. Standard deviations of Ts (Ts‐SD‐12) and Te (Te‐SD‐12) for 12 segments. Maximal difference of Ts (Ts‐max‐12) and Te (Te‐max‐12) for 12 segments. Standard deviations of Ts (Ts‐SD‐6) and Te (Te‐SD‐6) for 6 basal segments. Maximal difference of Ts (Ts‐max‐6) and Te (Te‐max‐6) for 6 basal segments
Diastolic LV Synchronicity Indexes
QRS duration on electrocardiogram exhibited a weak, but statistically significant correlation with LVSIdia, which was not the case between LVSIsys and QRS duration. A weak correlation was also evident between LV mass/Ht2.7 and LVSIdia (Table 4). Of note, unlike LVSIsys, LVSIdia progressively increased in parallel with age increment, with the greatest value observed in the most advanced age group (Table 2). To elucidate whether age‐associated changes in LVSIdia were independent of other variables, multivariate analysis was performed with age, LV mass/Ht2.7, QRS duration, and LV ejection fraction as independent variables. As a result, progressive increments of age‐related LVSIdia took place independently of LV mass/Ht2.7, QRS duration, and LV ejection fraction (Table 4). It is also noteworthy that significant correlations were observed between parameters representing LV diastolic function and LVSIdia (Table 5). When mitral inflow and mitral annulus velocity were applied to differentiate categories of LV diastolic function (normal vs impaired relaxation) in a manner described previously,14 differences between LVSIdia for these 2 groups could be clearly demonstrated (Table 6).
Table 4.
Multivariate Linear Regression Analyses of Factors That Correlate with a Variety of LV Diastolic Synchronicity Indexes
| For Te‐max‐6 | ||||
|---|---|---|---|---|
| Standardized Coefficients (β) | 95% P Value | Confidence Interval | Multiple R Value for Model | |
| Age | 0.22 | 0.01 | 0.06–0.46 | 0.36 |
| QRS duration | 0.14 | 0.08 | −0.02–0.36 | |
| LV mass/Ht2.7 | 0.09 | 0.29 | −0.14–0.48 | |
| LVEF | 0.10 | 0.20 | −0.7–0.81 | |
| For Te‐max‐12 | ||||
| Standardized Coefficients (β) | 95% P Value | Confidence Interval | Multiple R Value for Model | |
| Age | 0.45 | <0.001 | 0.68–1.41 | 0.45 |
| QRS duration | 0.04 | 0.56 | −0.25–0.46 | |
| LV mass/Ht2.7 | 0.01 | 0.89 | −0.54–0.62 | |
| For Te‐SD‐6 | ||||
| Standardized Coefficients (β) | 95% P Value | Confidence Interval | Multiple R Value for Model | |
| LVEF | −0.06 | 0.42 | −1.29–0.54 | |
| Age | 0.20 | 0.02 | 0.01–0.16 | 0.36 |
| QRS duration | 0.13 | 0.10 | −0.01–0.13 | |
| LV mass/Ht2.7 | 0.14 | 0.09 | −0.16–0.22 | |
| LVEF | 0.10 | 0.21 | −0.67–0.30 | |
| For Te‐SD‐12 | ||||
| Standardized Coefficients (β) | 95% P Value | Confidence Interval | Multiple R Value for Model | |
| Age | 0.44 | <0.001 | 0.19–0.40 | 0.47 |
| QRS duration | 0.06 | 0.44 | −0.06–0.14 | |
| LV mass/Ht2.7 | 0.04 | 0.59 | −0.12–0.21 | |
| LVEF | −0.03 | 0.67 | −0.32–0.20 | |
Abbreviations: Ht, height; LV, left ventricular; LVEF, left ventricular ejection fraction; Te, time to peak myocardial early diastolic velocity; Ts, time to peak myocardial systolic velocity during ejection phase;. Standard deviations of Ts (Ts‐SD‐12) and Te (Te‐SD‐12) for 12 segments. Maximal difference of Ts (Ts‐max‐12) and Te (Te‐max‐12) for 12 segments. Standard deviations of Ts (Ts‐SD‐6) and Te (Te‐SD‐6) for 6 basal segments. Maximal difference of Ts (Ts‐max‐6) and Te (Te‐max‐6) for 6 basal segments
Table 5.
Relation Between LV Diastolic Synchronicity Indexes and QRS duration, LV mass/Ht2.7, and Parameters for LV Diastolic Function
| Te‐max‐6 | Te‐max‐12 | Te‐SD‐6 | Te‐SD‐12 | |||||
|---|---|---|---|---|---|---|---|---|
| r | P Value | r | P Value | r | P Value | r | P Value | |
| QRS duration | 0.19 | 0.02 | 0.14 | 0.08 | 0.18 | 0.02 | 0.15 | 0.05 |
| LV mass/Ht2.7 | 0.17 | 0.03 | 0.15 | 0.06 | 0.22 | 0.007 | 0.18 | 0.02 |
| E velocity | −0.23 | 0.004 | −0.50 | <0.001 | −0.23 | 0.003 | −0.51 | <0.001 |
| A velocity | 0.20 | 0.01 | 0.18 | 0.03 | 0.19 | 0.02 | 0.21 | 0.008 |
| DT | 0.21 | 0.007 | 0.38 | <0.001 | 0.21 | 0.007 | 0.39 | <0.001 |
| E/A ratio | −0.30 | <0.001 | −0.46 | <0.001 | −0.30 | <0.001 | −0.49 | <0.001 |
| E′ | −0.35 | <0.001 | −0.49 | <0.001 | −0.35 | <0.001 | −0.51 | <0.001 |
| A′ | 0.11 | 0.10 | 0.08 | 0.34 | 0.10 | 0.22 | 0.10 | 0.22 |
| E′/A′ ratio | −0.28 | 0.001 | −0.37 | <0.001 | −0.27 | 0.001 | −0.39 | <0.001 |
Abbreviations: A, late mitral inflow velocity; A′, late diastolic mitral annular velocity; DT, deceleration time of E velocity; E, early mitral inflow velocity; E′, early diastolic mitral annular velocity; Ht, height; LV, left ventricular; Te, time to peak myocardial early diastolic velocity; Ts, time to peak myocardial systolic velocity during ejection phase;. Standard deviations of Ts (Ts‐SD‐12) and Te (Te‐SD‐12) for 12 segments. Maximal difference of Ts (Ts‐max‐12) and Te (Te‐max‐12) for 12 segments. Standard deviations of Ts (Ts‐SD‐6) and Te (Te‐SD‐6) for 6 basal segments. Maximal difference of Ts (Ts‐max‐6) and Te (Te‐max‐6) for 6 basal segments
Table 6.
Difference in LV Diastolic Synchronicity Indexes According to the Category of LV Diastolic Function
| Normal Diastolic Function (n = 82) | Impaired Relaxation (n = 78) | P Value | |
|---|---|---|---|
| Te‐max‐6 | 31.9±12.4 | 40.0±16.4 | <0.001 |
| Te‐max‐12 | 58.8±23.6 | 79.3±30.5 | <0.001 |
| Te‐SD‐6 | 12.2±4.7 | 15.0±6.1 | 0.001 |
| Te‐SD‐12 | 18.1±6.3 | 24.3±8.9 | <0.001 |
Abbreviations: Te, time to peak myocardial early diastolic velocity; Ts, time to peak myocardial systolic velocity during ejection phase. Standard deviations of Ts (Ts‐SD‐12) and Te (Te‐SD‐12) for 12 segments. Maximal difference of Ts (Ts‐max‐12) and Te (Te‐max‐12) for 12 segments. Standard deviations of Ts (Ts‐SD‐6) and Te (Te‐SD‐6) for 6 basal segments. Maximal difference of Ts (Ts‐max‐6) and Te (Te‐max‐6) for 6 basal segments
Interobserver and Intraobserver Variabilities
Interobserver and intraobserver variabilities of Ts and Te measured at 360 segments of 30 subjects showed good agreements (interobserver correlations: r = 0.89, standard error of the estimate [SEE] = 18.1 for Ts and r = 0.90, SEE = 13.9 for Te, both P < 0.001; intraobserver correlations: r = 0.91, SEE = 16.7 for Ts and r = 0.92, SEE = 18.4 for Te, both P < 0.001).
Discussion
The present study illustrates normal reference values for TDI‐derived LVSIsys and LVSIdia in a community‐based cohort of “completely” healthy volunteers. As a whole, the mean LVSIsys and LVSIdia found in this study are slightly higher compared with the previously reported results.6, 7 The reasons for this discrepancy are unclear, but it may be partially explained by the larger number of subjects enrolled in the present study. With regard to LVSIdia, the fraction of subjects who had impaired relaxation pattern of LV diastolic function is likely to have contributed to the discrepancy between our findings and the earlier published values. This explanation is supported by LVSIdia subgroup analysis as shown in Table 5; that is, recruitment of a larger proportion of subjects with impaired relaxation leads to a rise in normal values for LVSIdia if it is represented altogether without classification of subgroups based on the LV diastolic function.
Systolic LV Synchronicity Indexes
Although TDI has become the most widely used echocardiographic technique for assessing LV synchrony, normal reference ranges for TDI‐derived LVSIsys and LVSIdia are not clearly defined.
In this study, we found that the aging process exerts no significant effect on LVSIsys, which may be useful because age per se does not need to be taken into account in assessments of the extent of LV systolic asynchrony. Among the various LVSIsys, Ts‐SD‐6 and Ts‐SD‐12 appear to be superior to the maximal differences in Ts obtained at different myocardial segments for the following reasons; first, when either tachycardia (>100 bpm) or bradycardia (<60 bpm) is present, a greater degree of change in Ts‐max‐6 or Ts‐max‐12 may be more pronounced due to the alteration in 1 cardiac cycle length, compared to Ts‐SD‐6 or Ts‐SD‐12.6 Second, the standard deviation of Ts‐SD‐6 or Ts‐SD‐12 is relatively lower than those of other indexes, which gives these 2 indexes a substantial advantage over others from the perspective of clinical application.
According to earlier reports, a low S′ was shown to be linked to systolic asynchrony and S′ was suggested to be a more sensitive index of changes in LV systolic function in comparison with LVEF.15, 16 In our study, LVSIsys, although weak, displayed a significant correlation with S′, but not with LVEF, suggesting that a subtle alteration in LV systolic function, as reflected by S′, in healthy normal subjects can contribute to LV systolic dyssynchrony. To date, CRT response has been usually judged on the basis of LV volume or LVEF response. Yet, based on our finding, beneficial effect of CRT on LV systolic function might be better estimated using S′, warranting the investigations regarding this issue in the foreseeable future.
Diastolic LV Synchrony Indexes
LVSIdia have attracted less attention and have not been extensively scrutinized, though its presence has been described in patients with coronary artery disease with normal LV systolic function,9 in those with LV hypertrophy,17 and more recently in those with systolic and diastolic heart failure.6, 7, 8 Given the increasing recognition of the vital role of LV diastolic function in producing congestive heart failure symptoms, the recent focus placed on LVSIdia is probably a logical step in view of broadening the pathophysiologic understanding of heart failure.
In this study, unlike LVSIsys, LVSIdia showed a weak, but significant correlation with LVmass/Ht2.7, offering the impression that a “physiologic” increase in LV mass occurring during the course of the aging process (even within normal range) may be a causative factor for LV diastolic asynchrony. The effect of LV mass increment on LV diastolic asynchrony is easily expected to be enhanced in the setting of hypertension, aortic stenosis, or heart failure, as demonstrated by Wang et alwhere correlation coefficient between LV mass index and diastolic time delay was 0.79 as contrasted with that in our normal population (r = 0.15–0.22).8 They also suggested the possible reduction in LVSIdia with optimal medical therapy in patients with heart failure. Since the “pathologic” myocardial hypertrophy induced by hypertension or aortic stenosis can be revered with antihypertensive medication or aortic valve replacement, respectively, the reversibility of LV diastolic asynchrony by medical or surgical treatment is of clinical relevance. This issue is worthy of interrogation in view of the current endeavor made to reveal the precise mechanisms of the LV diastolic asynchrony development.8
LVSIdia was shown to vary by age; the more advanced age, the more increase in LVSIdia. This was further confirmed by multivariate analysis adjusting for LVEF, LV mass/Ht2.7, and QRS duration. In addition, our current observation concerning the close relation between LVSIdia and conventional diastolic parameters indicates that coordinated myocardial relaxation is progressively distorted just by the natural aging process, which is again verified by the clear difference in LVSIdia between subjects with normal relaxation and those with impaired relaxation in terms of LV diastolic function (Table 5). Taken together, interpretation of LVSIdia should be referred to age in order to determine normality or severity of abnormality.
Study Limitations
The purported angle‐dependency of the TDI technique is an inherent limitation. In addition, given the vulnerability of TDI to tethering and translational myocardial motion, strain rate imaging may be a more appropriate tool for LV systolic or diastolic synchronicity assessments. However, those effects may not be germane to this study, because they primarily affect peak velocity measurements and not the time to peak systolic velocity. Furthermore, although strain rate imaging technique is theoretically a promising and interesting tool, it is highly susceptible to signal noise, and as such, interobserver correlation is unsatisfactory,3, 18 which is an important pragmatic limitation that compromises the clinical acceptability of strain rate imaging.
Conclusions
Age‐specific normal reference ranges for TDI‐derived LVSIsys and LVSIdia are presented here. LVSIsys remain stable throughout the age group, whereas LVSIdia increase in a stepwise manner with age, requiring that interpretation of LVSIdia should be referred to age in order to determine normality or severity of abnormality.
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