Recently concluded multicenter studies have shown that none of an array of echocardiographic indicators of ventricular dyssynchrony have enough sensitivity and specificity for predicting response to cardiac resynchronization therapy (CRT). Inotropic contractile reserve (ICR) on dobutamine stress echocardiography can differentiate viable myocardium from scar and is a predictor of improvement in regional and global left ventricular function in patients with cardiomyopathy. Its role in patients undergoing CRT is unknown. The aim of this study was to evaluate the role of ICR in predicting response to CRT in patients with markedly remodeled left ventricles.
Fifty-four patients (mean age, 69 ± 11 years; 63% men) referred for clinically indicated CRT were evaluated. All patients underwent low-dose dobutamine stress echocardiography to assess for ICR, defined as an improvement in contractility in more than five of 16 left ventricular segments.
During a mean follow-up period of 206 ± 167 days, 31 patients (57%) were responders, as defined by a 5-point increase in ejection fraction after CRT. The presence of ICR was a stronger predictor of response to CRT (area under the curve, 0.94; χ 2 = 39.0; P < .0001) compared with dyssynchrony (area under the curve, 0.74; χ 2 = 10.07; P = .002). It was a significant predictor of response (odds ratio, 2.84; 95% confidence interval, 1.59 to 5.09; P < .0001), even after controlling for the other predictors, and provided incremental prognostic value beyond that provided by QRS duration and dyssynchrony (increase in area under the curve from 0.47 to 0.75 to 0.93; P = .030 and P = .008).
In patients referred for CRT, ICR was a stronger predictor of response and provided incremental value beyond that of current known predictors of response to CRT (dyssynchrony and QRS duration). Dobutamine stress echocardiography may have an important role in identifying CRT responders, and further multicenter studies are needed to confirm this.
Cardiac resynchronization therapy (CRT) improves survival and quality of life in patients with advanced heart failure on optimal medical management. The main approach to identifying patients who may benefit from CRT include a wide QRS complex on surface electrocardiography and, more recently, the presence of left ventricular (LV) mechanical dyssynchrony usually assessed by tissue Doppler and strain imaging. However, in the Predictors of Response to CRT (PROSPECT) study, none of an array of echocardiographic indicators of ventricular dyssynchrony on their own had enough sensitivity and specificity for predicting a significant CRT response.
The implantation of a biventricular pacing system for CRT is expensive and can be associated with some morbidity. Studies using magnetic resonance imaging have shown that the presence of transmural scar in the LV segments subjacent to the site of pacing results in nonresponse to CRT.
Inotropic contractile reserve (ICR) on dobutamine stress echocardiography has been shown to predict improvement in regional and global LV function in patients with ischemic and nonischemic cardiomyopathy. There are limited studies evaluating the role of ICR (viable myocardium) or its absence (scarred myocardium) in predicting response to CRT. Our objective was to evaluate the role of viable versus scarred myocardium as identified by ICR during dobutamine stress echocardiography in predicting response to CRT in patients with severely dilated left ventricles and very advanced and refractory heart failure on optimal medical management.
We prospectively enrolled 54 consecutive patients with severe LV dysfunction referred for CRT. The inclusion criteria were (1) New York Heart Association (NYHA) functional class III or IV, (2) QRS width ≥ 120 msec with a left bundle branch pattern or QRS ≥ 180 msec in patients with paced rhythm (measured in ≥3 leads on surface electrocardiography), (3) LV ejection fraction ≤ 35% for ≥9 months, and (4) optimal medical treatment (for ≥9 months).
The exclusion criteria were (1) hypertrophic or restrictive cardiomyopathy, (2) suspected acute myocarditis, (3) correctable valvulopathy, (4) acute coronary syndrome (within 3 months), (5) recent coronary revascularization (<3 months) or planned revascularization, (6) treatment-resistant hypertension, (7) severe obstructive lung disease, and (8) atrial fibrillation. The study was approved by the local institutional review board.
All images were acquired using a Vivid 7 ultrasound system (GE Vingmed Ultrasound AS, Horten, Norway) and a 3.5-MHz transducer. Standard echocardiographic views were used for conventional echocardiography with color flow, spectral Doppler, and Doppler tissue imaging. All patients also underwent low-dose dobutamine stress echocardiography for assessment of ICR before lead implantation. LV ejection fraction was calculated using a modified Simpson’s biplane method (GE EchoPAC BT05).
For Doppler tissue imaging, three apical views (for at least three consecutive beats) at high frame rates (140–200 frames/sec) using a narrow-sector image angle with the wall parallel to the ultrasound beam were acquired. Longitudinal tissue Doppler velocities were assessed from the basal and mid levels in the apical four-chamber, two-chamber, and long-axis views for a total of 12 sites. In each wall, two samples were placed at the basal and mid segments. Dyssynchrony was determined as the difference in time to peak velocity of opposing walls: inferoseptum to lateral wall (four-chamber view), anterior to inferior wall (two-chamber view), and anteroseptum to posterior wall (long-axis view). Opposing wall delay >65 msec was considered significant to define dyssynchrony. Interventricular dyssynchrony or delay was defined as the difference between left preejection intervals and right preejection intervals. Significant interventricular delay was defined as a delay ≥ 40 msec. The preejection intervals were quantified using pulsed Doppler imaging in the LV and right ventricular outflow tracts.
Low-Dose Dobutamine Echocardiographic Protocol
After acquisition of Doppler tissue images, low-dose dobutamine stress testing was performed. Beta-blockers were withheld the day before the test. Dobutamine was begun intravenously at a dose of 5 μg/kg/min and increased by 5 to 10 μg/kg/min every 3 min up to a maximum of 20 μg/kg/min or until a study end point was achieved. The end points for termination of dobutamine infusion included the development of new segmental wall motion abnormalities, attainment of 85% maximal predicted heart rate, presence of optimal ICR, or the development of significant adverse effects related to the dobutamine infusion.
Five standard echocardiographic views were obtained with each acquisition: parasternal long axis, parasternal short axis, apical four chamber, apical two chamber, and apical three chamber. The left ventricle was divided into 16 segments, as recommended by the American Society of Echocardiography, and a score was assigned to each segment at baseline, with each stage of stress, and during the recovery phase. Each segment was scored as follows: 1 = normal, 2 = mild to moderate hypokinesis (reduced wall thickening and excursion), 3 = severe hypokinesis (marked reduced wall thickening and excursion), 4 = akinesis (no wall thickening and excursion), and 5 = dyskinesis. Of note, none of the patients developed a biphasic response with the dose of dobutamine used.
ICR was defined as an improvement in contractility in more than five of the 16 LV segments. One experienced echocardiographer read the dobutamine stress echocardiograms, a separate blinded reader performed the Simpson’s calculations for ejection fraction, and a third blinded reader analyzed the Doppler tissue images. The readers were blinded to the patients’ demographics and other CRT and clinical data. The intraobserver and interobserver variability for ejection fraction and volumes is <5% in our laboratory, as published previously.
CRT Lead Placement and Programming
All CRT lead implantations were initially attempted percutaneously. Patients in whom percutaneous attempts failed were referred for robotic epicardial lead placement. The site of latest mechanical activation on echocardiography was identified, and the LV lead was placed as close to this as possible. Patients underwent complete transthoracic echocardiographic studies 1 day after CRT implantation to adjust the optimal atrioventricular delay and interventricular delay by maximizing LV inflow (mitral valve velocity-time integral) and outflow (aortic valve velocity-time integral) parameters. All devices were programmed to VDD or DDD mode at rates of 60 to 120 beats/min. Patients who were paced >90% of time were included in the study. No patients with lead malfunctions were included.
Functional evaluation was performed according to NYHA classification and the Minnesota Living With Heart Failure Questionnaire before implantation, 3 months after implantation, and at 1-year follow-up. Complete transthoracic echocardiography was repeated at 3 months and at the end of the follow-up period. Response to CRT was defined by an increase in ejection fraction of >5 points from baseline.
Percent changes in clinical NYHA class, quality-of-life score, ejection fraction, volumes, and tissue Doppler indices were calculated to evaluate post-CRT changes, using paired-samples t tests. All analysis was carried out using SPSS for Windows version 16.0 (SPSS, Inc., Chicago, IL). Continuous variables are reported as mean ± SD. Patient groups were compared using Student’s t tests (for normally distributed variables) or Wilcoxon’s rank-sum tests (for other variables) for continuous variables and χ 2 or Fisher’s exact tests for categorical variables.
Univariate analysis was performed to determine the relationship between clinical and echocardiographic variables and responders to CRT. Multivariate logistic regression analysis was used to evaluate significant predictors of response to therapy. Two models were constructed. In the first model, the ICR and dyssynchrony variables were used as continuous variables (statistically more robust analysis), while in model 2, we used them as categorical variables. The criteria for entry was any baseline variables significant at P < .10. Variables that are known predictors of response on the basis of prior studies, QRS duration and dyssynchrony, were forced into the model. P values < .05 were considered significant.
From our study cohort of 54 patients referred for CRT, 23 patients (43%) were nonresponders and 31 patients (57%) were responders.
The demographics of the cohort are shown in Table 1 . The mean age was 69 years, with a mean baseline NYHA class of 3.2 ± 0.5 and a mean QRS duration of 147 ± 204 msec. Thirty-five percent of patients required epicardial lead placement. The patient population was optimally medically managed, with 85% on β-blockers and 93% on angiotensin-converting enzyme inhibitors or angiotensin receptor blockers.
|Parameter||Responders ( n = 31)||Nonresponders ( n = 23)||P|
|Age (y)||66 ± 11||72 ± 10||.06|
|Men||22 (71%)||12 (52%)||.157|
|Hypertension||22 (71%)||17 (74%)||.811|
|Diabetes||17 (55%)||9 (39%)||.253|
|CAD||14 (45%)||15 (65%)||.144|
|Nonischemic heart failure etiology||16 (52%)||6 (26%)||.06|
|QRS duration (msec)||147 ± 21||148 ± 20||.957|
|Follow-up (d)||233 ± 181||170 ± 142||.158|
|Endovascular||20 (64%)||15 (65%)||.957|
|Epicardial lead||11 (36%)||8 (35%)||.957|
|NYHA class (before CRT)||3.19 ± 0.48||3.26 ± 0.45||.598|
|NYHA class (after CRT)||2.32 ± 0.65||3.30 ± 0.47||<.0001|
|QOL score (before CRT)||65 ± 9||63 ± 7||.232|
|QOL score (after CRT)||51 ± 9||65 ± 7||<.0001|
|β-blockers||28 (90%)||18 (78%)||.217|
|ACE inhibitors/ARBs||29 (93%)||21 (91%)||.756|
|Diuretics||22 (71%)||17 (74%)||.811|
|Spironolactone||11 (35%)||6 (26%)||.462|
|Digoxin||7 (23%)||7 (30%)||.515|
Responders Versus Nonresponders
The baseline characteristics between the responder and nonresponder groups are summarized in Table 1 . The groups were well matched for the baseline characteristics, NYHA functional class, quality-of-life score, LV ejection fraction, and dyssynchrony measures at baseline ( Table 1 and 2 ).
|Parameter||Responders ( n = 31)||Nonresponders ( n = 23)||P|
|ICR||29 (93%)||13 (56%)||.001|
|Number of segments with ICR||9.1 ± 2.1||4.8 ± 1.9||<.0001|
|Dyssynchrony||22 (71%)||12 (52%)||.157|
|Before CRT||105 ± 19||111 ± 46||.560|
|After CRT||89 ± 19||105 ± 30||.029|
|Before CRT||85 ± 18||89 ± 28||.620|
|After CRT||62 ± 19||86 ± 27||.001|
|Ejection fraction (Simpson’s)|
|Before CRT||18 ± 6||18 ± 7||.933|
|After CRT||32 ± 12||16 ± 6||<.0001|
|Dyssynchrony (peak opposing wall delay)|
|Before CRT||84 ± 25||64 ± 20||.002|
|After CRT||29 ± 12||60 ± 30||.001|
|Before CRT||19 ± 6||19 ± 7||.881|
|After CRT||27 ± 9||17 ± 7||<.0001|
|Before CRT||597 ± 98||657 ± 146||.092|
|After CRT||788 ± 165||649 ± 85||<.0001|
After CRT, responders had a 27% improvement in NYHA functional class ( P < .0001), a 21% improvement in quality-of-life score ( P < .0001), a 78% improvement in LV ejection fraction ( P < .0001) ( Figure 1 A), a 16% decrease in LV end-diastolic volume index ( P < .0001), a 28% decrease in LV end-systolic volume index ( P < .0001), a 32% improvement in dP/dt ( P < .0001), a 37% increase in stroke index ( P < .0001), and a 47% decrease in dyssynchrony ( P < .0001) ( Tables 1 and 2 ).
Conversely, in nonresponders, there were no improvements in the above parameters, with a 4% decline in quality-of-life score ( P = .016) and a 13% decline in LV ejection fraction ( P = .026) ( Figure 1 B).
From the cohort of 54 patients referred for CRT, 42 patients (78%) had ICR, of whom 29 (69%) were responders and 13 (31%) were nonresponders. Among the 12 patients with no or minimal ICR, only two patients (17%) were responders. ICR was thus able to identify responders to CRT with a positive predictive value of 69% and a negative predictive value of 83%. The positive and negative predictive value for patients with ischemic and nonischemic cardiomyopathy are summarized in Table 3 .
|Parameter||Positive predictive value (%)||Negative predictive value (%)|
There was a strong positive correlation ( r = 0.77, P < .0001) between the number of segments showing ICR and the percentage improvement in ejection fraction after CRT ( Figure 2 ). Using a receiver-operating characteristic curve (area under the curve [AUC], 0.94; Figure 3 ), a cutoff of more than segments with ICR predicted response to CRT with sensitivity of 97% and specificity of 83%.
From the cohort of 54 patients referred for CRT, 34 patients (63%) had intraventricular dyssynchrony, of whom 22 (65%) were responders and 12 (35%) were nonresponders. Among the 20 patients without intraventricular dyssynchrony, nine patients (45%) were responders, and the other 11 (55%) were nonresponders. Intraventricular dyssynchrony was thus able to identify responders to CRT with a positive predictive value of 65% and a negative predictive value of 55%. The positive and negative predictive values for patients with ischemic and nonischemic cardiomyopathy are summarized in Table 3 .
Using a receiver-operating characteristic curve (AUC, 0.74; Figure 3 ), a cutoff of >65 msec maximal opposing wall delay (dyssynchrony) predicted response to CRT with sensitivity of 71% and specificity of 56%.
From the cohort of 54 patients referred for CRT, 23 patients (43%) had interventricular dyssynchrony, of whom 21 (91%) were responders and two (9%) were nonresponders. Among the 31 patients without interventricular dyssynchrony, 10 (32%) were responders and the other 21 (68%) were nonresponders. Interventricular dyssynchrony was thus able to identify responders to CRT with a positive predictive value of 91% and a negative predictive value of 68%. The positive and negative predictive values for patients with ischemic and nonischemic cardiomyopathy are summarized in Table 3 .
Using a receiver-operating characteristic curve (AUC, 0.83), a cutoff of >40 msec interventricular mechanical delay (dyssynchrony) predicted response to CRT with sensitivity of 68% and specificity of 91%.
ICR Versus Dyssynchrony
ICR (continuous variable) was a stronger predictor of response to CRT (χ 2 = 39.0, P < .0001) compared with either intraventricular (continuous variable) (χ 2 = 10.1, P = .002) or interventricular (continuous variable) (χ 2 = 19.2, P < .0001) dyssynchrony. ICR was a stronger predictor of response to CRT compared with QRS duration (AUC, 0.94, 95% confidence interval [CI], 0.83–0.98 vs AUC, 0.47, 95% CI, 0.31–0.63; P < .0001), dyssynchrony (opposing wall delay) (AUC, 0.94, 95% CI, 0.83–0.98 vs AUC, 0.74, 95% CI, 0.59–0.84; P = .002), or dyssynchrony (interventricular mechanical delay) (AUC, 0.94, 95% CI, 0.83–0.98 vs AUC, 0.83, 95% CI, 0.70–0.92; P = .07) ( Figure 3 ).
The univariate and multivariate predictors of response to CRT are listed in Table 4 . The presence of ICR (continuous or categorical) was a significant predictor of response to CRT even after controlling for the current known predictors of response ( Table 3 ). For each additional segment showing ICR, the likelihood of response to CRT increased by 2.6-fold. The response rates for various combinations of dyssynchrony and ICR (categorical) are shown in Figure 4 .