Author + information
- Received June 27, 2012
- Accepted July 17, 2012
- Published online November 13, 2012.
- Hirohiko Motoki, MD, PhD⁎,
- Allen G. Borowski, RDCS⁎,
- Kevin Shrestha, AB⁎,
- Richard W. Troughton, MB, ChB, PhD†,
- W.H. Wilson Tang, MD⁎,
- James D. Thomas, MD⁎ and
- Allan L. Klein, MD⁎,⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Allan L. Klein, Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, 9500 Euclid Avenue, Desk J1-5, Cleveland, Ohio 44195
Objectives This study sought to examine the ability of left ventricular (LV) global longitudinal strain (GLS) to assess disease severity in patients with chronic systolic heart failure (HF).
Background Left ventricular GLS is a sensitive measure of LV mechanics. Its relationship with standard clinical markers and long-term adverse events in chronic systolic HF is not well established.
Methods In 194 chronic systolic HF patients, we performed comprehensive echocardiography with assessment of GLS by velocity vector imaging averaged from apical 4-chamber and 2-chamber views. Death, cardiac transplantation, and HF hospitalization were tracked for 5 years.
Results In our study cohort (age 57 ± 14 years, left ventricular ejection fraction [LVEF] 26 ± 6%, median N-terminal pro-B-type natriuretic peptide [NT-proBNP] 1,158 pg/ml), the mean GLS was −7.1 ± 3.3%. The GLS worsened with increasing New York Heart Association functional class (rank-sum p < 0.0001) and higher NT-proBNP (r = 0.42, p < 0.0001). The GLS correlated with LV cardiac structure (LV mass index: r = 0.35, p < 0.0001; LV end-diastolic volume index: r = 0.43, p < 0.0001) and LVEF (r = −0.66, p < 0.0001). A lower magnitude of GLS was associated with worsening LV diastolic function (E/e' septal: r = 0.33, p < 0.0001), right ventricular (RV) systolic function (RV s': r = −0.30, p < 0.0001), and RV diastolic function (RV e'/a': r = 0.16, p = 0.033). GLS predicted long-term adverse events (hazard ratio: 1.55, 95% confidence interval: 1.21 to 2.00; p < 0.001). Worsening strain (GLS ≥−6.95%) predicted adverse events after adjustment for age, sex, ischemic etiology, E/e' septal, and NT-proBNP (hazard ratio: 2.04, 95% confidence interval: 1.09 to 3.94; p = 0.025) and age, sex, ischemic etiology, and LVEF (hazard ratio: 2.15, 95% confidence interval: 1.19 to 4.02; p = 0.011).
Conclusions In chronic systolic HF, worsening LV GLS is associated with more severe LV diastolic dysfunction and RV systolic and diastolic dysfunction, and provides incremental prognostic value to LVEF.
Left ventricular ejection fraction (LVEF) is a powerful predictor of death in patients with systolic heart failure (HF) (1,2). However, previous work demonstrated that the relationship between LVEF and mortality in patients with HF was inconsistent (3–5). In addition, LVEF quantification requires the manual endocardial tracking of end-diastolic and end-systolic frames from 2-dimensional imaging, which demands experience, is time consuming, and is restricted by a high level of measurement of operator and interobserver variability.
Left ventricular mechanics is a complex, coordinated action involving longitudinal contraction, circumferential shortening, and radial thickening. The need for formal quantitative assessment of myocardial systolic function remains a significant challenge. The recently developed speckle tracking imaging is an innovative method providing multidimensional myocardial deformation. A previous study reported that speckle tracking derived longitudinal and circumferential strain was as reliable as sonomicrometry and had real potential for quantification of LV deformation in an experimental model (6). Speckle-derived strain is more robust than tissue Doppler-derived strain, does not have angle dependency, and is easier to calculate. Although LV global longitudinal strain (GLS) is a sensitive measure of LV mechanics, its relationship with standard clinical markers and long-term adverse events in chronic systolic HF is not well established. We sought to examine the ability of LV GLS to assess disease severity in patients with chronic systolic HF.
Study design and patient population
The ADEPT (Assessment of Doppler Echocardiography Prognosis and Therapy) study was a prospective, single-center, cohort study of ambulatory patients with chronic systolic HF (New York Heart Association [NYHA] functional classes II to IV) seen at the outpatient cardiology clinics at the Cleveland Clinic between May 1, 2001, and June 30, 2003. Eligible patients were 18 to 75 years of age, with LVEF ≤35%. Patients were excluded by mitral stenosis or mitral valve surgery; severe mitral regurgitation (>3+); severe aortic stenosis (peak velocity >4 m/s) or regurgitation; significant hepatic or renal dysfunction; or atrial fibrillation during echocardiography examination. This study was approved by the Cleveland Clinic institutional review board. Informed consent was obtained from all subjects. Patients underwent echocardiographic evaluation of systolic and diastolic performance as well as plasma sample collection. Adverse events (all-cause mortality, cardiac transplantation, or HF hospitalization) were prospectively tracked for 5 years by scheduled telephone follow-up and validated by chart review, as previously described (7).
Comprehensive transthoracic echocardiography was performed by highly experienced research sonographers using commercially available HDI 5000 (Phillips Medical Systems, Bothell, Washington), and Acuson Sequoia (Siemens Medical Solutions USA Inc., Malvern, Pennsylvania) machines. Two-dimensional and color Doppler imaging were performed in standard parasternal and apical views. The LV systolic and diastolic indexes were acquired as previously outlined in the ADEPT trial (7). All images were stored online digitally and were measured with offline software (Syngo Dynamics 9.0 software, Siemens Medical Solutions) later by an independent investigator who was blinded to the clinical data (7). The LVEF and cardiac volumes were measured using the Simpson biplane method, as previously described (8). Measurements were averaged over 3 cycles, and 2 experienced individuals who were blinded from the clinical data made all measurements.
LV GLS/circumferential strain measurements
The LV GLS/global circumferential strain (GCS) measurements were performed offline using dedicated software (Velocity Vector Imaging, Siemens Medical Solutions). One cardiac cycle was acquired from a parasternal short-axis view at the midpapillary level for GCS, and from apical 4-chamber and 2-chamber views for GLS; the endocardial border was traced manually in the end-diastolic frame. The software subsequently and automatically traced the borders in the other frames. The vectors of the velocities of the endocardial points were then displayed and overlaid onto the B-mode images. In segments with poor tracking (assessed subjectively), endocardial borders were readjusted until better tracking was achieved. If this was unattainable, that segment was excluded. Graphical displays of deformation parameters for each segment were then generated automatically and were used for measurement of LV longitudinal strain values (Fig. 1). The software calculated average strain values for 6 LV segments for apical 4- and 2-chamber views. Peak global strain was defined as the peak negative value on the strain curve during the entire cardiac cycle, as previously described (9). We obtained GLS and GCS only in the case of adequate tracking quality ≥5 of the 6 segments per view. Any view in which 2 or more segments could not be tracked was not included in the analysis, and the remaining apical views were averaged to calculate GLS and GCS. All measurements were made by individual research personnel blinded from data analyses.
Interobserver and intraobserver variabilities
The interobserver and intraobserver variabilities for LV GLS were studied in a group of 30 randomly selected subjects by 1 observer repeated twice and by 2 investigators who were unaware of the other's measurements and of the study time point. The bias (mean difference) and limits of agreement (1.96 SD of difference) between the first and second measurements were determined.
Continuous variables are summarized as mean ± SD if normally distributed, and as median and interquartile range if nonnormally distributed. Normality was assessed by the Shapiro-Wilk W test. Spearman's rank correlation method was used as a nonparametric measure of association between GLS and clinical and echocardiographic indices. The Wilcoxon or Kruskal-Wallis rank-sums tests were used to compare differences in GLS across clinical categories, and proportions were compared using contingency table analysis. The Cox proportional hazards regression model was used to assess the clinical risk associated with increasing continuous standardized increments of GLS. The optimal receiver-operating characteristic (ROC) curve cutoff value for prediction of adverse clinical events was chosen as the value maximizing sensitivity plus specificity. The proportional hazards assumption was verified with log (time) versus log (−log [survival]) plots. Kaplan-Meier survival plots were calculated from baseline to time of adverse event and compared using the log-rank test. The incremental value of LV GLS over baseline clinical and echocardiographic characteristics to assess the risk for cardiovascular events was studied by calculating the improvement in global chi-square. Statistical analyses were performed with using JMP 9.0.0 (SAS Institute, Cary, North Carolina). All p values reported are from 2-sided tests, and a p value < 0.05 was considered statistically significant.
Of the 207 patients in the ADEPT study, 194 (93.7%) patients had GLS that could be measured in both 4- and 2-chamber views. The average frame rate of the clips for GLS analysis was 30.0 ± 1.2 frames/s. The coefficient of variation of intraobserver variability for GLS was 7.5 ± 6.1%. The coefficient of variation of interobserver variability was 8.0 ± 7.9%. The bias and limits of agreement of intraobserver and interobserver variabilities were 0.3 ± 2.3% and 0.4 ± 2.2%, respectively. The baseline clinical and echocardiographic parameters are summarized in Table 1. For the study population as a whole, the average GLS was −7.1 ± 3.3%. The GLS worsened with increasing NYHA class (p < 0.0001) and higher N-terminal pro-B-type natriuretic peptide (NT-proBNP [r = 0.42, p < 0.0001]).
Relationship between GLS and cardiac structure/function
As expected, lower magnitude (i.e., more impaired) GLS correlated with LV structure (LV end-diastolic volume index: r = 0.43, p < 0.0001) and LVEF (r = −0.66, p < 0.0001) (Fig. 2). More impaired GLS was associated with worsening LV diastolic function (transmitral flow peak early diastolic filling velocity to peak early diastolic velocity of the mitral annulus ratio [E/e' septal]: r = 0.33, p < 0.0001), worsening right ventricular (RV) systolic and diastolic function (peak systolic velocity of the tricuspid annulus [RV s']: r = −0.30, p < 0.0001, peak early diastolic velocity of the tricuspid annulus to peak late diastolic velocity of the tricuspid annulus ratio [RV e'/a']: r = 0.16, p = 0.033) (Table 2).
Predictors of cardiac events
The composite endpoint of death, cardiac transplantation, or heart failure hospitalization occurred in 40% of patients (i.e., 78 of 194 patients), and death or cardiac transplantation occurred in 34% of patients (66 of 194 patients). More impaired LV GLS predicted long-term adverse events and was a stronger predictor than LV GCS (Table 3). In multivariate Cox proportional hazards analysis, more impaired LV GLS (≥−6.95%) predicted adverse events after adjustment for age, sex, ischemic etiology, and measures of LV and RV systolic and diastolic function including LVEF, RV s', E/e' septal, E/e' lateral, E/e' average, and RV e'/a' in addition to NT-proBNP (Table 3). Worsening LV GLS (≥−6.95%) was related to an increased risk of adverse events in patients with HF of both an ischemic and nonischemic etiology, while worsening LV GCS (≥−7.15%) predicted adverse events only in patients with nonischemic etiology (Figs. 3A and 3B). By analysis, the area under the ROC curve of GLS was the greatest with an optimal ROC cutoff point of −6.95% (Fig. 4). In Kaplan-Meier analysis, worsening LV GLS (≥−6.95%) predicted long-term adverse events (Fig. 5A). Worse LV GLS (≥−6.95%) remained a predictor of adverse events in patients with LVEF ≥25% or <25% (p < 0.05 for both) (Fig. 5B). Patients with LVEF <25% did slightly worse than patients with LVEF ≥25%, as expected in both subgroups with LV GLS <−6.95% or ≥−6.95%. However, the difference between LVEF <25% or ≥25% was still not significant within these subgroups (LV GLS <−6.95% group: LVEF ≥25% vs. <25%, p = 0.591; LV GLS >−6.95% group: LVEF ≥25% vs. <25%, p = 0.526). The incremental value of LV GLS to predict cardiac events is shown in Figure 6. The LV GLS provides an additional benefit over conventional parameters (clinical features, LVEF, and s' septal).
In the present study, we demonstrated the prognostic significance of LV GLS in ambulatory patients with chronic systolic HF. The GLS is an independent prognosticator to predict cardiac events in HF regardless of age, LVEF, and E/e', and has greater prognostic power than LVEF. We also showed that: 1) GLS decreased with increasing NYHA class and higher NT-proBNP; 2) GLS correlated with LV cardiac structure and LVEF; 3) lower GLS was associated with worse LV diastolic function, RV systolic function, and RV diastolic function; 4) GLS >−6.95% predicted adverse events after adjustment for age, E/septal e', and NT-proBNP and LVEF; and 5) the measurement of GLS is simple, highly feasible, and shows excellent reproducibility.
Global 2-dimensional strain as a new prognosticator
Recently, Cho et al. (9) demonstrated that GCS of the left ventricle was an independent predictor of cardiac events and appeared to be a better parameter than LVEF for prognostic stratification in patients with acute HF using speckle tracking imaging. We showed that LV GLS played an important role in predicting the 5-year outcome in patients with chronic systolic HF. Although the study by Cho et al. (9) incorporated only patients with acute HF with better LVEF (34 ± 13%) and shorter follow up (39 ± 17 months) than our study, global 2-dimensional speckle tracking strain parameters may provide more useful information than LVEF regarding patient outcome. However, little is known about which parameters are more robust in predicting patient outcomes between longitudinal and circumferential strain.
Previous studies based on tissue Doppler and speckle tracking echocardiography revealed that the initial deformation of ventricular contraction affects the longitudinal axis, whereas radial function is preserved in the early phase regardless of the physiopathological model (10–13). In a prospective epidemiologic study, LV long-axis function rather than short-axis function independently predicted survival in chronic HF (14). Our results showing better sensitivity of GLS for predicting patient outcomes than GCS and LVEF might be supported by these previous reports. In the second phase of ventricular dysfunction progression, the initially compensating midwall fibers alter their contraction, leading first to the deterioration of circumferential and then radial deformations (15). Thus, the longitudinal deformation component could be a strong and sensitive prognostic factor that is a less severe but earlier visible marker of myocardial contraction alteration.
LV longitudinal function
Many studies have shown that measurement of LV longitudinal motion by the mitral annular excursion or velocities has been a good index of LV function and also a predictor of prognosis in heart failure (14,16–19). In this study, we showed that decreased longitudinal “mechanics” was associated with increased cardiac events of both ischemic and nonischemic cardiomyopathy. Moreover, LV GLS has significant incremental value over conventional clinical and echocardiographic parameters, including longitudinal velocity. Thus, LV GLS could be a robust prognosticator in both ischemic and nonischemic cardiomyopathy. Because subendocardial fibers, which are mainly longitudinally oriented, are more susceptible to ischemia, it might be expected that the longitudinal function is altered earlier than the midwall function (6). Hence, in early ischemic conditions, subendocardial dysfunction is likely to selectively affect the longitudinally directed fibers and manifest itself as decreased LVEF and longitudinal strain. Transmural infarct is also associated with a reduction of long-axis function (20). Furthermore, previous studies reported that the fiber shortening is markedly reduced in idiopathic dilated cardiomyopathy (21). All deformational parameters, including longitudinal, circumferential, radial strain, and torsion, were decreased in idiopathic dilated cardiomyopathy (22). Thus, the myocardial fibers that contribute to deformation (not only to the circumferential but also the longitudinal direction) might be affected by the disease process in patients with nonischemic cardiomyopathy and might alter the magnitude of longitudinal strain as well as circumferential strain.
RV function on the prognosis of HF
There is a strong clinical impact of RV function parameters on the prognosis of HF patients (23). It is conceivable that the statistical weight of GLS would have been diminished when we took it into account. Although the difficulty in obtaining RVEF limits the use of this echocardiographic parameter, we could evaluate RV function by using the tissue Doppler imaging of the tricuspid annulus (24). As a result, more impaired LV GLS still predicted adverse events after adjustment RV systolic and diastolic function in multivariate Cox proportional hazards analysis. Nevertheless, RV dysfunction tends to strongly be related to the severity of the disease process, and GLS could be a robust parameter to predict adverse cardiac events in chronic systolic HF.
First, we used 2 kinds of echocardiographic vendors (HDI 5000 and Acuson Sequoia). However, there was no significant difference in distribution of LV strain between these 2 vendors (HDI vs. Sequoia: −7.2 ± 3.2% vs. −6.9 ± 3.1%). Thus, vendor difference did not play an important role in the relationship between depressed GLS and adverse cardiac events. Second, frame rates of analyzed images were relatively low. However, Shin et al. (25) performed a validation study to compare the global peak systolic strain rate at low (30 frames/s) and high frame rates (mean 72 frames/s) (25). They found no significant difference, and good correlation was observed between 2 different frame rates in LV peak strain measures. Furthermore, prior studies have shown that this frame rate was feasible for acquiring strain curve, and velocity vector imaging showed predictive value at these frame rates (26,27). Third, we analyzed LV GLS data from the apical 4- and 2-chamber views. Additional analysis of the apical long-axis view provided optimal information for longitudinal strain. Despite these limitations, LV GLS using velocity vector imaging was a straightforward approach with promise for clinical utility for predicting adverse cardiovascular events in patients with HF.
In chronic systolic HF, LV GLS is associated with more severe LV diastolic dysfunction and RV systolic and diastolic dysfunction, and provides incremental prognostic value to LVEF.
The authors acknowledge the secretarial assistance of Marie Campbell.
The ADEPT study was supported by the American Society of Echocardiography Outcomes Research Award and GlaxoSmithKline Pharmaceuticals. Dr. Tang is a consultant to and has received grant support from Medtronic, Inc., St. Jude Medical, and Abbott Laboratories. All other authors have reported they have no relationships relevant to the contents of this paper to disclose. John Gorcsan, MD, served as Guest Editor for this paper.
- Abbreviations and Acronyms
- peak late diastolic velocity of the mitral annulus
- peak early diastolic velocity of the mitral annulus
- ejection fraction
- global circumferential strain
- global longitudinal strain
- heart failure
- left ventricle/left ventricular
- N-terminal pro-B-type natriuretic peptide
- New York Heart Association
- receiver-operating characteristic
- right ventricle/right ventricular
- peak systolic velocity of the mitral annulus
- Received June 27, 2012.
- Accepted July 17, 2012.
- American College of Cardiology Foundation
- St. John Sutton M.,
- Pfeffer M.A.,
- Moye L.,
- et al.
- Curtis J.P.,
- Sokol S.I.,
- Wang Y.,
- et al.
- Reant P.,
- Labrousse L.,
- Lafitte S.,
- et al.
- Cho G.Y.,
- Marwick T.H.,
- Kim H.S.,
- Kim M.K.,
- Hong K.S.,
- Oh D.J.
- Serri K.,
- Reant P.,
- Lafitte M.,
- et al.
- Wang J.,
- Khoury D.S.,
- Yue Y.,
- Torre-Amione G.,
- Nagueh S.F.
- Yu C.M.,
- Chau E.,
- Sanderson J.E.,
- et al.
- Sveälv B.G.,
- Olofsson E.L.,
- Andersson B.
- Willenheimer R.,
- Cline C.,
- Erhardt L.,
- Israelsson B.
- Nikitin N.P.,
- Loh P.H.,
- Silva R.,
- et al.
- (2005) Independent and incremental prognostic value of early mitral annulus velocity in patients with impaired left ventricular systolic function. J Am Coll Cardiol 45:272–277.
- Chan J.,
- Hanekom L.,
- Wong C.,
- Leano R.,
- Cho G.Y.,
- Marwick T.H.
- MacGowan G.A.,
- Shapiro E.P.,
- Azhari H.,
- et al.
- Shin S.H.,
- Hung C.L.,
- Uno H.,
- et al.
- Suffoletto M.S.,
- Dohi K.,
- Cannesson M.,
- Saba S.,
- Gorcsan J. III.