Impact of Longitudinal Myocardial Deformation on the Prognosis of Chronic Heart Failure PatientsCLINICAL PERSPECTIVE
Background— Longitudinal myocardial deformation indexes appear superior to left ventricular ejection fraction (LVEF) in assessing myocardial contractility. However, few studies have addressed the prognostic value of longitudinal motion markers (velocity, strain, and strain rate) in predicting outcome in heart failure patients.
Methods and Results— The study included 125 consecutive symptomatic heart failure patients (63±16 years, 77% male, LVEF=31±10%). All patients underwent a complete echocardiographic and clinical examination, and brain natriuretic peptide level was assessed in 93 patients. Longitudinal myocardial velocity by tissue Doppler imaging, global-ε, and strain rate by speckle tracking were computed from apical views (4-, 3-, and 2-chambers views) and compared with the occurrence of major adverse cardiac events. On the whole, peak longitudinal velocity, global-ε, and strain rate averaged 5±2 cm/s (range, 1 to 9), −8±3% (range, −3 to −18), and −0.33±0.16 s−1 (range, −0.83 to −0.05), respectively. During the follow-up period (266±177 days), major adverse cardiac events occurred in 47 (38%) patients (15 deaths, 29 recurrent heart failure, and 4 heart transplantations). By univariable analysis using Cox model global-ε, strain rate, and LVEF were associated with the occurrence of major adverse cardiac events, whereas only global-ε remained independently predictive of outcome by multivariate analysis.
Conclusions— In the heart failure population, longitudinal global strain by speckle tracking is superior to LVEF and other longitudinal markers in identifying patients with poor outcome.
Received September 21, 2009; accepted February 4, 2010.
Heart failure (HF) prevalence ranges between 2% and 3% in the general population,1 with increasing trend because of the population ageing and a survival improvement.2 Overall 4-year mortality rate averages 50%, with a large individual variability.3 Myocardial contractility is a strong outcome predictor, with a major impact on the medical decision.4,5 Consequently, myocardial contractility should be quantified by a sensitive and accurate method. In daily practice, systolic left ventricular (LV) contractility assessment is based on the LV ejection fraction (LVEF) measurement computed from apical views using echocardiographic imaging.6 However, several studies suggested that LVEF is poorly sensitive in detecting early myocardial dysfunction, whereas longitudinal myocardial velocity, strain, and strain rate (SR) appear to be more sensitive and specific.7–9 On the whole, SR values are less dependent of load conditions and may be superior to strain and velocity.10 Tissue Doppler imaging (TDI) is conventionally used to assess longitudinal myocardial velocity,11 whereas, for longitudinal strain and SR, speckle tracking appears to be less noised than TDI-derived data and provides accurate measurements correlated with sonomicrometry and cardiac MRI.12,13 TDI and, more recently, speckle tracking modality, are available on current echocardiography systems and can be used in daily practice to improve myocardial contractility assessment. However, assessment of all these contractile markers is time-consuming and cannot be routinely performed. The purpose of the present study is to define which longitudinal contractile marker is relevant for clinical decision by comparing their prognostic value in HF population.
Clinical Perspective on p 249
We prospectively enrolled 125 consecutive patients (age, 63±16 years; 77% men; Table 1) admitted for optimization of medical HF treatment. After discharge, 76%, 80%, and 60% of patients were receiving β-blocker, ACE inhibitor, and aldosterone antagonist therapy, respectively. Patients in atrial fibrillation were not excluded from the study. Clinical data and medical history were collected using a standard questionnaire. Before discharge, all patients underwent a complete echocardiographic examination.
A composite outcome that affects heart failure patient survival and quality of life was used to ensure a sufficient statistical power. The primary end point combined cardiovascular death (sudden death, death from HF, or unexplained death), recurrent hospitalization for HF, and cardiac transplantation or mechanical circulatory support. Follow-up information was obtained either from medical report or direct patient interview or from the referring physician. The time to follow-up was considered as the time to first defined cardiovascular events.
A standardized complete echocardiographic examination was performed before discharge using a commercially available Vivid 7 system (GE Vingmed, Horton, Norway). All data were stored digitally for off-line analysis on Echo-Pac PC software (V8.1 GE, Horton, Norway). LV volume and LVEF were computed from standard apical views according to the Simpson biplane method.6 Peak tricuspid annular systolic velocity (by TDI) and tricuspid annular plane systolic excursion (TAPSE) were used to assess right ventricular (RV) systolic function.14 The ratio of early transmitral velocity (E wave by conventional pulsed Doppler) to tissue Doppler mitral annular early diastolic velocity (e′ by TDI) was used to assess pulmonary capillary wedge pressure.
Longitudinal Myocardial Function
Peak systolic mitral annular velocity (S) using pulsed TDI was determined from the lateral wall. Global systolic longitudinal strain (global-ε) and SR were computed using speckle tracking analysis. For strain processing, the peak of the R wave on the ECG was used as the reference time point for end-diastole. Global-ε was obtained by averaging the 16 regional longitudinal strain curves computed from high-frame-rate (>50; mean, 74±17) apical views (4-chamber, 2-chamber, 3-chamber). On the whole, 132 of 2000 (6.5%) segments were excluded from global strain calculation because of inadequate tracking. Peak global SR was computed from the first derivative global strain curve during isovolumic contraction period (Figure 1).
B-Type Natriuretic Peptide Measurements
Venous blood samples for B-type natriuretic peptide (BNP) assessment were drawn the day of echocardiography in 93 patients (76%). Chilled EDTA tubes were centrifuged immediately at 4000g (4°C) for 15 minutes. Separated plasma samples were processed by immunofluorescence assay (Beckman-Coulter, Biosite, Paris, France). The assay detection limit was 1 pg/mL. The interassay and intra-assay variations were 5% and 4%, respectively.
To assess the predictive value of global longitudinal myocardial indexes (peak S by TDI, global-ε, and SR) in identifying primary outcome in HF patients, we used a Cox model analysis adjusted to other covariables. Continuous variables with normal distribution were expressed as mean±SD and skewed variables as median and quartiles. Dichotomous data were expressed as percentages. To compare numeric data between 2 groups, an unpaired Student t test was used with skewed variables (as BNP level) log-transformed for all statistical comparison. Nominal variables were compared using χ2 test or Fisher test. Pearson correlation was used to compare longitudinal myocardial shortening indexes to LVEF and BNP levels. Univariate analysis of primary outcome was performed using a Cox model analysis. Proportional hazards assumption was checked graphically by plotting scaled Schoenfeld residuals against time with LOWESS smoothing function15 used to test for nonproportionality. Variables from univariate analysis with P<0.2 were included in multivariate Cox analysis to identify independent predictor of outcome. For multivariate analysis, 2 models were used, the first (n=93) including and the second (n=123) without including BNP level. To determine the optimal global-ε cutoff value, the Youden test16 was performed from data computed from receiver-operating characteristic curves. Survival curves were established by the Kaplan-Meier estimation method, and the event rates were compared using the log-rank test. Two-tailed probability values <0.05 were considered statistically significant.
Of the 125 patients enrolled (age, 63±16 years; 77% men; Table 1), LVEF averaged 31±10% (range, 10 to 49) and HF etiology was ischemic in 52% (n=65), with 61% (n=74) of patients severely symptomatic (New York Heart Association functional class ≥III) at inclusion. Blood pressure and heart rate averaged 126±23 mm Hg and 76±15 bpm, respectively. Mean BNP level at discharge was 1031±1182 pg/mL (median, 697; range, 10 to 6554).
End-diastolic and systolic volumes averaged 191±71 mL (range, 62 to 415) and 134±62 mL (range, 39 to 349), respectively. E/e′ ratio and systolic pulmonary blood pressure averaged 16±9 (range, 4 to 39) and 45±11 mm Hg (range, 30 to 72), respectively. RV dysfunction was observed in 33% (n=41) when defined by TAPSE <15 mm (17±4 mm, range, 7 to 28) and 53% (n=65) using tricuspid annular systolic velocity <10 cm/s (mean, 9±3 cm/s; range, 3 to 16).
Longitudinal Shortening Indexes
Peak systolic mitral velocity by TDI (Smitral), global-ε, and peak SR by speckle tracking averaged 5±2 cm/s (range, 1 to 9), −8±3% (range, −18 to −2), and −0.42±0.15 s−1 (range, −0.83 to −0.17), respectively. Correlation between LVEF and longitudinal myocardial contractile markers was good with global-ε (r=−0.72 P<0.0001, Figure 2), moderate with SR (r=−0.58, P>0.0001), and poor with Smitral by TDI (r=0.26, P=0.01). Similarly, correlation with BNP level was better for global-ε (r=−0.45 P<0.0001, Figure 1) and peak SR (r=−0.46 P<0.0001) than for Smitral (r=−0.16, P=0.16). Importantly, pulmonary capillary wedge pressure (by E/e′ ratio) correlated with global strain (r=0.46, P<0.0001), Smitral (r=−0.39, P<0.0001), and global SR (r=0.38, P<0.001) as well.
During a median follow-up period of 283 days (25% to 75% IQ; 90 to 429 days; range, 2 to 550 days), 47 (37.6%) patients reached the primary outcome end point: 29 (23.2%) hospitalized for recurrent HF, 4 (3.2%) referred for cardiac assistance (n=3) or heart transplant (n=1), and 15 (11.2%) deaths including 14 from cardiovascular reasons and 1 patient from pancreatic cancer. After the first episode of recurrent HF (160±87 days), 3 of the 29 patients died of cardiovascular reasons and 1 was referred to heart assistance. Only 2 (1.6%) patients were lost to follow-up, excluded from prognosis analysis.
Univariable analysis using the Cox model (Figure 3 and Table 2) showed that LV contractile markers associated with adverse cardiac events included LVEF (odds ratio [OR]=0.50, P<0.0001), global-ε, (OR=1.2, P<0.0001), and SR by speckle tracking (OR=1.41, P=0.002), whereas no significant correlation was found with Smitral by TDI. The other significant variables were NYHA functional class (OR=1.73, P=0.001), systolic blood pressure (OR=0.86, P=0.003), heart rate (OR=1.23, P=0.03), BNP level (OR=1.62, P<0.0001), TAPSE (0.92, P=0.03), and LV end-diastolic volume (OR=1.05, P=0.03).
By multivariate analysis model including (n=93) and not including (n=123) BNP level, only NYHA functional class and global-ε remained predictive of cardiovascular events (Figure 4). A global-ε cutoff >−9% identified patients with poor outcome with a sensitivity and specificity of 83% and 54%, respectively (Figure 5). Negative and positive predictive values associated were 84% and 53%, respectively. Kaplan-Meier analysis showed that the risk of major cardiac events was 5.1-fold greater (2.6 to 10.2, P<0.0001, Figure 5) in patients with than without global-ε <−9%.
Intraobserver reproducibility was 7% for longitudinal global strain, 9% for SR, 14% for systolic peak mitral annular velocity by TDI, and 8% for LVEF. The interobserver reproducibility was 8% for longitudinal strain, 12% for SR, 20% for systolic peak mitral annular velocity, and 10% for LVEF by Simpson biplane.
Myocardial function assessment plays an important role in the prognosis and affects the medical decision in HF and valvular diseases.4,5,17 In daily practice, myocardial contractility is based on LVEF by echocardiography using the Simpson biplane model. However, LVEF lacks sensitivity to accurately identify myocardial contractility impairment, which first affects endocardial layers and longitudinal component. In addition, LVEF depends on load conditions and relies on the experience of the operator.18 In the present study, we demonstrated that longitudinal global strain (by speckle tracking) is superior to LVEF, SR, and tissue Doppler imaging in predicting outcome in HF patients. This information highlights the importance to evaluate the impact of medical decision (device implantation and valvular replacement) based on longitudinal global strain value rather than LVEF measurement.
Myocardial function assessment remains a challenging part of the echocardiographic examination. Accuracy and reproducibility of the results still depend on operator experience.18,19 Moreover, LVEF is poorly sensitive in identifying early changes in myocardial function that may be detected using longitudinal motion quantification.7,20 Several automatic methods for longitudinal motion assessment have been proposed and so far, only TDI has reached a clinical application.4,5 However, mitral annular velocity by TDI conventionally used to quantify global LV function11,21 was found poorly correlated with LVEF, BNP level, and the outcome of HF patients in the present study. These negative results may be explained by the limitations of tissue Doppler signal-to-noise ratio, which is particularly reduced by the misalignment issue of the Doppler sample volume,22, especially in HF patients with severe LV enlargement and myocardial dysfunction.23 As an alternative to TDI, a new non–angle-dependent image processing algorithm based on speckle tracking analysis has recently been developed. Several studies reported that regional strain amplitude derived from speckle tracking correlates with sonomicrometry and MRI strain measurements.12,13 In the present study, strain curves from the 16 segments were averaged to compute a global-ε and SR to assess global myocardial function. The correlation observed between LVEF and longitudinal global-ε and SR is consistent with previous findings.24,25 The use of speckle tracking to assess LV systolic function offers the main advantage to provide a fast and simultaneous quantification of both regional and global myocardial function. In addition, global-ε and SR from apical views consider all segments of the myocardium compared with the Simpson biplane model (16-segment versus 12-segment model) and mitral annular velocity by TDI and thus may be more accurate in assessing myocardial contractility. Moreover, the quantification of myocardial contractility by speckle tracking is not based on LV volume changes measurement and consequently does not rely on a geometric model unsuitable for patients with complex LV deformation. Indeed, this advantage of speckle tracking over the Simpson method has been demonstrated by Brown et al,25 who reported that in patients with >5 abnormal contractile segments, global-ε by speckle tracking correlated better with LVEF by MRI than LVEF derived from 2D echocardiography using the Simpson biplane model. Furthermore, global-ε and SR by speckle tracking is easy and fast to compute and especially does not require a specific training to ensure a good reproducibility.24
However, an exact linear correlation of longitudinal global strain and SR with LVEF should not be expected because longitudinal motion partly contributes to LVEF value. Indeed, impaired myocardial contractility appears to first affect the endocardial layers, explaining that longitudinal motion markers may be more sensitive than LVEF in identifying early changes of myocardial contractility.9,26 Longitudinal motion may be quantified either by strain or SR, which is supposed to be load independent10 and superior to strain in assessing myocardial contractility and prognosis. However, our data demonstrate that both strain and SR values correlate with pulmonary wedge pressure estimated using E/e′ ratio. In addition, SR does not appear to be superior to strain in predicting outcome in HF patients. Superiority of strain over SR may also be related to less noised data, allowing an easier assessment of peak value. The use of longitudinal global strain by speckle tracking in assessing LV contractility should be encouraged in clinical practice for its good reproducibility and ability to stratify the outcome of HF patients. The negative predictive value (84%) of global strain (<−9%) is particularly interesting in identifying patients at low risk of cardiac events. Despite its limited specificity (54%) and positive predictive value (53%), a severe reduced global strain >−9% indicates an increase of the risk of cardiac events by 5.1. This suggests that these patients may require a more aggressive medical treatments and monitoring.
Myocardial contractility was assessed by 2D imaging, although 3D echocardiography or cardiac cine-MRI may provide better LVEF25 and volume measurements. However, comparison with 2D LVEF, largely available, better reflects current clinically practices. In addition, the study was focused on longitudinal strain data, which are known to be a sensitive marker of early LV dysfunction. Available short-axis data have not been included in the analysis because the strain data from the whole myocardium (16-segment model) cannot be obtained in all patients. The primary end point of the study was a composite outcome that included recurrent HF, cardiac assistance, and death. However, most of events (n=47) reported were recurrent HF (29/47, 62%). Future study including a larger number of patients should address the individual impact of longitudinal global on HF mortality and also on the occurrence of ventricular arrhythmia and recurrent myocardial ischemia.
Impaired longitudinal global strain >−9% is associated with an increase of cardiovascular events in HF patients. Importantly, longitudinal global strain by speckle tracking appears to be superior to SR and LVEF in predicting outcome in chronic HF. This highlights the need of future studies assessing the impact of medical decision based on strain measurement rather than LVEF.
Rosamond W, Flegal K, Furie K, Go A, Greenlund K, Haase N, Hailpern SM, Ho M, Howard V, Kissela B, Kittner S, Lloyd-Jones D, McDermott M, Meigs J, Moy C, Nichol G, O'Donnell C, Roger V, Sorlie P, Steinberger J, Thom T, Wilson M, Hong Y. Heart disease and stroke statistics: 2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2008; 117: e25–e146.
Schaufelberger M, Swedberg K, Koster M, Rosen M, Rosengren A. Decreasing one-year mortality and hospitalization rates for heart failure in Sweden: data from the Swedish Hospital Discharge Registry 1988 to 2000. Eur Heart J. 2004; 25: 300–307.
Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJ, Ponikowski P, Poole-Wilson PA, Stromberg A, van Veldhuisen DJ, Atar D, Hoes AW, Keren A, Mebazaa A, Nieminen M, Priori SG, Swedberg K, Vahanian A, Camm J, De Caterina R, Dean V, Funck-Brentano C, Hellemans I, Kristensen SD, McGregor K, Sechtem U, Silber S, Tendera M, Widimsky P, Zamorano JL. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur Heart J. 2008; 29: 2388–2442.
Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW, Antman EM, Smith SC Jr, Adams CD, Anderson JL, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation. 2005; 112: e154–235.
Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise J, Solomon S, Spencer KT, St John Sutton M, Stewart W. Recommendations for chamber quantification. Eur J Echocardiogr. 2006; 7: 79–108.
Lafitte S, Perlant M, Reant P, Serri K, Douard H, DeMaria A, Roudaut R. Impact of impaired myocardial deformations on exercise tolerance and prognosis in patients with asymptomatic aortic stenosis. Eur J Echocardiogr. 2009; 10: 414–419.
Richand V, Lafitte S, Reant P, Serri K, Lafitte M, Brette S, Kerouani A, Chalabi H, Dos Santos P, Douard H, Roudaut R. An ultrasound speckle tracking (two-dimensional strain) analysis of myocardial deformation in professional soccer players compared with healthy subjects and hypertrophic cardiomyopathy. Am J Cardiol. 2007; 100: 128–132.
Koyama J, Ray-Sequin PA, Falk RH. Longitudinal myocardial function assessed by tissue velocity, strain, and strain rate tissue Doppler echocardiography in patients with AL (primary) cardiac amyloidosis. Circulation. 2003; 107: 2446–2452.
Greenberg NL, Firstenberg MS, Castro PL, Main M, Travaglini A, Odabashian JA, Drinko JK, Rodriguez LL, Thomas JD, Garcia MJ. Doppler-derived myocardial systolic strain rate is a strong index of left ventricular contractility. Circulation. 2002; 105: 99–105.
Ghio S, Recusani F, Klersy C, Sebastiani R, Laudisa ML, Campana C, Gavazzi A, Tavazzi L. Prognostic usefulness of the tricuspid annular plane systolic excursion in patients with congestive heart failure secondary to idiopathic or ischemic dilated cardiomyopathy. Am J Cardiol. 2000; 85: 837–842.
Vahanian A, Baumgartner H, Bax J, Butchart E, Dion R, Filippatos G, Flachskampf F, Hall R, Iung B, Kasprzak J, Nataf P, Tornos P, Torracca L, Wenink A. Guidelines on the management of valvular heart disease: the Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology. Eur Heart J. 2007; 28: 230–268.
Troughton RW, Prior DL, Frampton CM, Nash PJ, Pereira JJ, Martin M, Fogarty A, Morehead AJ, Starling RC, Young JB, Thomas JD, Lauer MS, Klein AL. Usefulness of tissue Doppler and color M-mode indexes of left ventricular diastolic function in predicting outcomes in systolic left ventricular heart failure (from the ADEPT study). Am J Cardiol. 2005; 96: 257–262.
Lim P, Mitchell-Heggs L, Buakhamsri A, Thomas JD, Grimm RA. Impact of left ventricular size on tissue Doppler and longitudinal strain by speckle tracking for assessing wall motion and mechanical dyssynchrony in candidates for cardiac resynchronization therapy. J Am Soc Echocardiogr. 2009; 22: 695–701.
Belghitia H, Brette S, Lafitte S, Reant P, Picard F, Serri K, Lafitte M, Courregelongue M, Dos Santos P, Douard H, Roudaut R, DeMaria A. Automated function imaging: a new operator-independent strain method for assessing left ventricular function. Arch Cardiovasc Dis. 2008; 101: 163–169.
Brown J, Jenkins C, Marwick TH Use of myocardial strain to assess global left ventricular function: a comparison with cardiac magnetic resonance and 3-dimensional echocardiography. Am Heart J. 2009; 157: 102 e101–105.
Several studies have suggested that longitudinal myocardial deformation indices (velocity, strain, and strain rate) are superior to left ventricular ejection fraction in identifying early changes in myocardial contractility. To clarify the clinical utility of these different markers, we compared the accuracy of peak systolic longitudinal velocity by tissue Doppler imaging as well as by strain and strain rate by speckle tracking to the left ventricular ejection fraction in predicting outcome in a heart failure population. We demonstrated that in this population, impaired longitudinal global strain by speckle tracking >−9% was the best predictor of outcome, with an increase of the risk of cardiac events by 5.1. These results suggest that the use of longitudinal global strain by speckle tracking in assessing left ventricular contractility should be encouraged in clinical practice because of its good reproducibility and ability to better stratify the outcome of heart failure. Future studies should be performed to validate the potential impact of global longitudinal strain on medical decision-making.
Drs Nahum and Bensaid contributed equally to this work.