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Prediction of Cardiac Resynchronization Therapy Response

Value of Calibrated Integrated Backscatter Imaging
Originally publishedhttps://doi.org/10.1161/CIRCIMAGING.109.882324Circulation: Cardiovascular Imaging. 2010;3:86–93

Abstract

Background— Left ventricular (LV) fibrosis is important for the response to cardiac resynchronization therapy (CRT). Calibrated integrated backscatter derived by 2D echocardiography quantifies myocardial ultrasound reflectivity, which may provide a surrogate of LV fibrosis. The aim of the study was first, to investigate the relation of myocardial ultrasound reflectivity assessed with calibrated integrated backscatter on CRT response, and second, to explore the “myocardial ultrasound reflectivity–CRT response” relation in patients with ischemic and nonischemic heart failure (HF).

Methods and Results— One hundred fifty-nine patients with HF referred for CRT underwent an extensive echocardiographic evaluation at baseline and at 6-month follow-up. LV dyssynchrony was derived from speckle-tracking analysis. Calibrated integrated backscatter was obtained from the parasternal long-axis view. The mean value of calibrated integrated backscatter of the anteroseptal and posterior wall was used to estimate myocardial ultrasound reflectivity. CRT response was defined as reduction ≥15% of LV end-systolic volume. At baseline, LV dyssynchrony was significantly larger in responders as compared with nonresponders (188�96 ms versus 115�68 ms, P<0.001), and CRT responders showed less myocardial ultrasound reflectivity as compared with nonresponders (−20.8�3.0 dB versus −17.0�3.0 dB, P<0.001). In multivariable logistic regression analysis, independent predictors for CRT response were LV dyssynchrony, renal function, and myocardial ultrasound reflectivity. Importantly, myocardial ultrasound reflectivity provided an incremental value to CRT response (χ2 change=40, P<0.001). Considering patients with ischemic HF, the only independent predictor of CRT response was myocardial ultrasound reflectivity, whereas in patients with nonischemic HF, independent predictors of LV reverse remodeling were myocardial ultrasound reflectivity, LV dyssynchrony, and renal function.

Conclusions— Assessment of myocardial ultrasound reflectivity is important in the prediction of CRT response in ischemic and nonischemic patients.

Landmark randomized clinical trials have shown the benefits of cardiac resynchronization therapy (CRT) on heart failure (HF) symptoms, left ventricular (LV), function and survival.1,2 Thus far, despite current selection criteria,3 up to 30% of the patients do not show clinical response to CRT. Furthermore, considering LV reverse remodeling as end point of the treatment, nonresponse rate is even higher (40% to 45%).4

Clinical Perspective on p 86

Among different reasons proposed to explain the lack of response to CRT, the etiology of HF remains still controversial. In the CARE-HF trial, ischemic HF patients showed a reduction in LV volumes or improvement in LV function to a lesser degree than nonischemic HF patients.5,6 Previous data suggest that the extent and location of LV fibrosis strongly influence response to CRT in patients with ischemic etiology of HF.7–12 The presence of LV fibrosis also has been demonstrated in a mixed population of ischemic and nonischemic HF patients.13 However, particularly in nonischemic HF patients, little is known about the influence of the LV fibrosis on CRT response. At present, contrast-enhanced cardiac magnetic resonance (CMR) is considered the gold standard to detect LV fibrosis,14 but its use is limited by low availability.15 2D echocardiography imaging is more widely available than contrast-enhanced CMR, and ultrasonic integrated backscatter (IB) derived by 2D echocardiography provides information on myocardial ultrasound reflectivity, which may be a surrogate for fibrosis of the insonified tissue.16,17 Recent studies demonstrated the use of this technique in different groups of patients to characterize myocardial ultrasound reflectivity.18–20 The echocardiographic assessment of myocardial ultrasound reflectivity along with the evaluation of LV mechanical dyssynchrony may provide more comprehensive and valuable information to select candidates for CRT. In the current study, calibrated IB was used to quantify myocardial ultrasound reflectivity in HF candidates for CRT. The aim of the study was 2-fold: first, to investigate the influence of myocardial ultrasound reflectivity on CRT response in general, and second, to explore the “myocardial ultrasound reflectivity–CRT response” relation specifically in ischemic and nonischemic HF patients.

Methods

Patient Population and Protocol

A total of 184 consecutive HF patients scheduled for CRT were prospectively included. According to current guidelines, the inclusion criteria were: New York Heart Association (NYHA) functional class III-IV, sinus rhythm, LV ejection fraction (LVEF) ≤35%, and QRS duration ≥120 ms.3 Etiology of HF was considered ischemic in the presence of significant coronary artery disease (>50% stenosis in ≥1 major epicardial coronary artery) on coronary angiography and/or a history of myocardial infarction or revascularization.

All patients underwent a clinical and echocardiographic evaluation at baseline and 6 months after CRT assessing NYHA functional class, hemoglobin and renal function,21 LV volumes, and LVEF. Finally, the extent of myocardial ultrasound reflectivity was estimated as the mean of calibrated IB of the anteroseptal and posterior walls to (1) determine the role of myocardial ultrasound reflectivity on CRT response and (2) study the relation between myocardial ultrasound reflectivity and CRT response in ischemic and nonischemic HF patients.

Standard Echocardiography

All patients were imaged in the left lateral decubitus position using a commercially available system (Vingmed Vivid 7, General Electric-Vingmed, Milwaukee, Wis). Standard 2D images were obtained using a 3.5-MHz transducer and digitally stored in cine-loop format; the analysis was performed offline using EchoPAC version 7.0.0 (General Electric-Vingmed).

From the standard apical views (4- and 2-chamber) LV volumes and LVEF were calculated according to the American Society of Echocardiography guidelines.22 At 6-month follow-up, patients were classified as echocardiographic responders based on a reduction ≥15% of LV end-systolic volume (LVESV).4

Mechanical Dyssynchrony

In the current study 2 types of mechanical dyssynchrony were assessed: the interventricular mechanical dyssynchrony and the intra-LV mechanical dyssynchrony (LV dyssynchrony). Interventricular mechanical dyssynchrony was quantified using the interventricular mechanical dyssynchrony index.2 LV dyssynchrony was assessed using speckle-tracking echocardiography.23 LV dyssynchrony was derived from the radial strain curves obtained at the 2D gray-scale images of the midventricular short-axis (frame rate ranged from 45 to 100 frames/s). As previously described, LV dyssynchrony was defined as the time to peak radial strain difference between the anteroseptal and posterior segments.24

Calibrated IB

Calibrated IB is a parameter based on gray-scale 2D images that evaluates myocardial ultrasound reflectivity. In the heart, the pericardium is the anatomic structure with the highest content of fibrosis and with the highest ultrasound reflectivity, whereas blood pool has the lowest ultrasound reflectivity because no fibrous tissue exists. The myocardium shows an intermediate ultrasound reflectivity and this reflectivity may increase together with the amount of fibrosis.16,18–20 Gray-scale 2D images were obtained at parasternal long-axis view, with frame rates between 80 and 120 frames/s, depending on the sector width, and 3 cardiac cycles were stored in cine-loop format for the offline analysis (EchoPAC version 7.0.0, General Electric-Vingmed). A fixed 9�9-mm region of interest was positioned in the midmyocardium of the anteroseptal and posterior walls of the LV, and a fixed 2�3-mm region of interest was positioned in the pericardium. A measure of myocardial ultrasound reflectivity or tissue density was obtained with calibrated IB by subtracting pericardial IB intensity from myocardial IB intensity of the LV anteroseptal and LV posterior walls. The measurements of calibrated IB were performed at a fixed point in the cardiac cycle (peak of the QRS complex) and expressed in decibels.16,18–20 The mean value of calibrated IB of the LV anteroseptal and posterior walls was calculated to indicate the myocardial ultrasound reflectivity (Figure 1).16

Figure 1. Example of assessment of LV fibrosis in the anteroseptal and posterior walls with calibrated IB. A fixed 9�9-pixel region of interest was positioned in the midmyocardium of the anteroseptal wall (ASW) and posterior wall (PW), and a fixed 2�3-pixel region of interest was positioned in the pericardium. In this patient example, calibrated IB for the ASW is calculated by subtracting the pericardial IB intensity (−1.1 dB) from the ASW IB intensity (−17.6 dB), and the calibrated IB for the PW is calculated by subtracting the pericardial IB intensity (−1.1 dB) from the PW IB intensity (−21.4 dB). This results in calibrated IB of the ASW and PW of −16.5 dB and −20.3 dB, respectively. Accordingly, the mean calibrated IB was −18.4 dB.

CRT Implantation

All patients received a biventricular pacemaker with cardioverter-defibrillator function (Contak Renewal, Cognis, Boston Scientific St Paul, Minn; or InSync Sentry, Consulta, Medtronic Inc, Minneapolis, Minn; Lumax 340 HF-T, Biotronik, Berlin, Germany). The right atrial and ventricular leads were positioned conventionally. All LV leads were implanted transvenously and placed preferably in a (postero)lateral vein. A coronary sinus venogram was obtained using a balloon catheter, followed by the insertion of the LV pacing lead. An 8F guiding catheter was used to place the LV lead (Easytrak, Boston Scientific, or Attain-SD, Medtronic, or Corox OTW Biotronik) in the coronary sinus.

Statistical Analysis

Continuous variables are presented as mean�standard deviation. Categorical data are presented as numbers and percentages. The unpaired t test was used to compare continuous variables between HF patients with versus without 6-month follow-up, responders versus nonresponders, and ischemic versus nonischemic HF patients. Paired t test was used to compare baseline and 6-month follow-up data either in responders and nonresponders. The χ2 test was used to compare categorical variables. To determine the reproducibility of calibrated IB, 20 HF patients were randomly selected. For each of the selected patients, the measurements of calibrated IB were repeated by the same observer in a blinded fashion and at a separate time (1 week later). To evaluate interobserver variability, a second independent observer reanalyzed the same data set.

Intraobserver and interobserver variabilities were assessed using intraclass correlation coefficients.

Linear regression analysis was performed to assess the correlation between the relative change of LVESV and calibrated IB in the overall population, in ischemic and nonischemic HF patients.

To identify variables related to a positive response to CRT, univariable and multivariable logistic regression analyses were performed including baseline clinical (age, sex, etiology, NYHA functional class, QRS duration, renal function, and hemoglobin) and baseline echocardiographic (LVESV, LVEF, LV dyssynchrony, calibrated IB) characteristics of the patients. Only variables with P<0.10 in univariable analysis were entered as covariates in the multivariable model. The multivariable logistic regression analysis was performed using a forward selection method with entry probability value <0.05. Model discrimination was assessed using c-statistic and model calibration using Hosmer-Lemeshow statistic. Odds ratios (ORs) and 95% CIs were calculated. To increase clinical utility, OR and 95% CI of continuous variables were reported as per 1 year increase in age, per 10 ms increase in QRS width at baseline, per 30 mL/min increase in estimated glomerular filtration rate, per 1 mmol/L increase in hemoglobin, per 50 mL increase in LVESV, per 5% increase in LVEF, per 50 ms increase in LV dyssynchrony, and per 5 dB increase in calibrated IB. The incremental value of myocardial ultrasound reflectivity over other variables was assessed by calculating the global χ2 test for each model. To identify variables related to a positive response to CRT in the subgroups of patients with ischemic and nonischemic etiology of heart failure, univariable and multivariable logistic regression analyses were performed, including the same baseline variables as indicated above, using the same inclusion criteria for the multivariable logistic regression analysis.

All statistical tests were 2-sided, and a probability value <0.05 was considered significant. The statistical software program SPSS 16.0 (SPSS Inc, Chicago, Ill, was used for statistical analysis.

The authors had full access to the data and take responsibility for its integrity. All authors have read and agree to the manuscript as written.

Results

In 13 (7%) of 184 patients, calibrated IB analysis was not feasible due to suboptimal gray-scale 2D images with poor differentiation between myocardium and pericardium, and these patients were excluded from the analysis. Furthermore, of the 171 patients included, 12 (7%) did not complete the 6-month follow-up; 4 patients died, 2 patients had LV pacing switched off due to intolerable phrenic stimulation, and 6 patients were lost to follow-up. Therefore, baseline and 6-month follow-up data were available for 159 patients.

Patient Population

The general characteristics of the overall patient population are summarized in Table 1.

Table 1. Baseline Characteristics of Patients With Heart Failure

Overall HF Patients (n=171)HF Patients With 6-Month Follow-Up (n=159)HF Patients Without 6-Month Follow-Up (n=12)HF Patients With vs Without 6-Month Follow-Up, P Value
Age, y66�1066�1066�100.99
Sex, male/female132/39123/369/30.85 (df=1)
NYHA class, III/IV157/14147/1210/20.27 (df=1)
QRS duration, ms154�32154�32150�200.63
Estimated glomerular filtration rate, mL/min70.9�33.270.9�33.270.8�33.00.99
Hemoglobin, mmol/L8.2�0.98.2�0.98.3�0.80.64
Etiology, n (%)
    Ischemic99 (58)93 (58)6 (50)0.57 (df=1)
    Nonischemic72 (42)66 (42)6 (50)
Medication, n (%)
    ACE inhibitors154 (90)144 (91)10 (83)0.69 (df=1)
    �-blockers149 (87)137 (86)12 (100)0.35 (df=1)
    Diuretics and/or
    Spironolactone145 (85)134 (84)11 (92)0.74 (df=1)
(Postero)lateral LV lead, n (%)161 (94)151 (95)10 (83)0.28
LVEDV, mL218�81218�81240�860.35
LVESV, mL167�71167�71190�700.28
LVEF, %25�725�722�60.12
Interventricular dyssynchrony, ms39�2833�2933�170.96
LV dyssynchrony, ms157�92157�92155�810.96
Calibrated IB, dB−19.2�3.7−19.2�3.7−18.8�3.00.70

The mean age was 66�10 years, and 132 patients were male. Importantly, 58% of the patients had ischemic etiology of HF; the mean LV end-diastolic volume (LVEDV) was 218�81 mL, and the mean LVEF was 25�7%. No significant differences were observed between HF patients with and without 6-month follow-up data.

Calibrated IB

The mean myocardial ultrasound reflectivity of the LV at baseline quantified with calibrated IB was −19.2�3.7 dB. The intraobserver and interobserver agreements for calibrated IB were 0.91 and 0.92, respectively.

In addition, myocardial ultrasound reflectivity was not related to QRS duration (r=0.09, P=0.24), whereas a weak but significant inverse relation between myocardial ultrasound reflectivity and renal function (r=−0.17, P=0.039) was observed.

Responders Versus Nonresponders

Table 2 shows the baseline clinical characteristics of CRT responders and nonresponders. There were no differences in clinical characteristics, although nonresponders showed a trend to higher prevalence of ischemic etiology (P=0.10). Conversely, QRS duration, estimated glomerular filtration rate, and hemoglobin were higher in responders as compared with nonresponders. There were no differences in baseline LV volumes and LVEF for responders and nonresponders (Table 3). LV dyssynchrony was significantly larger in responders as compared with nonresponders (188�96 ms versus 115�68 ms, P<0.001), whereas only a trend toward a larger interventricular dyssynchrony in responders as compared with nonresponders was observed (41�23 ms versus 35�33 ms, P=0.17). Finally, CRT responders showed lower myocardial ultrasound reflectivity as compared with nonresponders (−20.8�3.0 dB in responders versus −17.0�3.0 dB in nonresponders, P<0.001; Table 3).

Table 2. Clinical Characteristics of Responders Versus Nonresponders at Baseline

Responders (n=91)Nonresponders (n=68)P Value
Age, y65�967�110.43
Sex, male/female71/2052/160.85 (df=1)
Medication, n (%)
    ACE inhibitors83 (91)61 (90)0.95 (df=1)
    �-blockers78 (86)59 (87)0.96 (df=1)
    Diuretics and/or
Spironolactone77 (85)57 (84)0.96 (df=1)
Etiology, n (%)
    Ischemic48 (53)45 (66)
    Nonischemic43 (47)23 (44)0.10 (df=1)
QRS duration, ms159�32148�320.028
Estimated glomerular filtration rate, mL/min76�3164�350.023
Hemoglobin, mmol/L8.4�0.98.0�0.90.040
NYHA class, III/IV85/662/60.60 (df=1)

Table 3. Standard Echocardiographic Variables and Calibrated IB in Responders vs Nonresponders at Baseline and 6-Month Follow-Up

Responders (n=91)Nonresponders (n=68)P Value (Responders vs Nonresponders)
*P<0.001, baseline versus 6-month follow-up.
P<0.05, baseline versus 6-month follow-up.
LVEDV, mL
    Baseline223�81211�800.34
    6-mo follow-up186�71*212�840.045
LVESV, mL
    Baseline173�72159�690.22
    6-mo follow-up123�57*161�730.001
LVEF, %
    Baseline24�726�70.058
    6-mo follow-up36�8*26�7<0.001
LV dyssynchrony, ms
    Baseline188�96115�68<0.001
    6-mo follow-up80�132*125�1210.032
Calibrated IB, dB
    Baseline−20.8�3.0−17.0�3.0<0.001
    6-mo follow-up−21.9�3.2−15.6�3.5<0.001

At 6-month follow-up, only responders showed a significant decrease in LVEDV and LVESV (by definition), with a significant increase in LVEF (Table 3). In addition, responders revealed a more synchronous LV contraction after 6 months of CRT, whereas in nonresponders the LV dyssynchrony remained unchanged (Table 3).

Of note, the relative change in LVESV (ΔLVESV%) at 6-month follow-up was significantly related to calibrated IB (r=0.50, P<0.001; Figure 2A).

Figure 2. A, Relation between the relative change of LVESV at 6-month follow-up (ΔLVESV) and calibrated IB in the overall population. B, Relation between the δ LVESV in ischemic HF patients and calibrated IB. C, Relation between the ΔLVESV in nonischemic HF patients and calibrated IB.

Prediction of LV Reverse Remodeling

At univariable logistic regression, ischemic etiology, QRS duration, estimated glomerular filtration rate, hemoglobin, LV dyssynchrony, and calibrated IB were significantly related to LV reverse remodeling at 6-month follow-up (Table 4). At multivariable logistic regression analysis, the independent predictors of response to CRT were estimated glomerular filtration rate, LV dyssynchrony, and calibrated IB (Table 4). Furthermore, calibrated IB had incremental value over LV dyssynchrony and estimated glomerular filtration rate for prediction of response to CRT (χ2 change=40, P<0.001, degree of freedom=1).

Table 4. Multivariable Logistic Regression Analysis for Prediction of Response to CRT (Defined as Reduction in LVESV ≥15%)

Dependent Variable: Response to CRT at 6-Month Follow-UpUnivariable AnalysisMultivariable Analysis
OR (95% CI)P ValueOR (95% CI)P Value
c-Statistic: 0.89. Hosmer-Lemeshow test: χ2=9.5, P=0.30 (df=8).
Independent variables
    Age, per 1 y0.98 (0.96–1.02)0.42
    Female sex1.09 (0.52–2.31)0.82
    Ischemic etiology0.58 (0.30–1.09)0.09
    NYHA class IV0.73 (0.22–2.37)0.60
    QRS width at baseline, per 10 ms1.12 (1.01–1.24)0.029
    Estimated glomerular filtration rate, per 30 mL/min1.43 (1.04–1.96)0.0261.93 (1.26–2.95)0.003
    Hemoglobin, per 1 mmol/L1.46 (1.01–2.12)0.043
    LVESV at baseline, per 50 mL1.15 (0.92–1.45)0.22
    LVEF at baseline, per 5%0.80 (0.63–1.01)0.060
    LV dyssynchrony at baseline, per 50 ms1.77 (1.38–2.28)<0.0011.90 (1.39–2.59)<0.001
    Calibrated IB, per 5 dB0.11 (0.05–0.24)<0.0010.10 (0.04–0.25)<0.001

Ischemic Versus Nonischemic Etiology of HF

Of the 159 patients with 6-month follow-up data, 93 patients had ischemic etiology of HF, whereas 66 had a nonischemic HF. The baseline clinical characteristics were not different between patients with ischemic and nonischemic cardiomyopathy. Conversely, patients with ischemic cardiomyopathy had significantly higher LVEF (26�7% versus 23�7%, P<0.001) and less LV dyssynchrony (144�92 ms versus 175�90 ms, P=0.036) as compared with patients with nonischemic cardiomyopathy. In addition, myocardial ultrasound reflectivity estimated with calibrated IB was higher in patients with ischemic as compared with nonischemic cardiomyopathy (−18.5�3.8 dB versus −20.2�3.0 dB, P=0.002). Finally, the relationship between the relative change of LVESV at 6-month follow-up and calibrated IB was stronger in patients with ischemic cardiomyopathy (r=0.56, P<0.001; Figure 2B) as compared with patients with nonischemic HF (r=0.35, P=0.005; Figure 2C).

Prediction of LV Reverse Remodeling in Ischemic Etiology

In the subgroup of patients with ischemic HF, in univariable logistic regression, LVEF, LV dyssynchrony, and calibrated IB were significantly related to LV reverse remodeling at 6-month follow-up (Table 5). In multivariable logistic regression analysis, the only independent predictor of response to CRT was calibrated IB (Table 5).

Table 5. Univariable and Multivariable Logistic Regression Analysis for Prediction of Response to CRT (Defined as Reduction in LVESV ≥15%) in Ischemic Heart Failure

Dependent Variable: Response to CRT at 6-Month Follow-UpUnivariable AnalysisMultivariable Analysis
OR (95% CI)P ValueOR (95% CI)P Value
c-Statistic: 0.87. Hosmer-Lemeshow test: χ2=12.6, P=0.13 (df=8).
Independent variables
    Age, per 1 y0.98 (0.94–1.03)0.45
    Female sex0.68 (0.23–2.02)0.49
    QRS width at baseline, per 10 ms1.13 (1.00–1.27)0.053
    Estimated glomerular filtration rate, per 30 mL/min1.30 (0.90–1.89)0.16
    Hemoglobin, per 1 mmol/L1.51 (0.91–2.48)0.11
    LVESV at baseline, per 50 mL1.21 (0.89–1.66)0.23
    LVEF at baseline, per 5%0.71 (0.51–0.99)0.041
    LV dyssynchrony at baseline, per 50 ms1.37 (1.06–1.78)0.017
    Calibrated IB, per 5 dB0.07 (0.02–0.23)<0.0010.07 (0.02–0.23)<0.001

Prediction of LV Reverse Remodeling in Nonischemic Etiology

In the subgroup of patients with nonischemic etiology of HF, in univariable logistic regression, estimated glomerular filtration rate, LV dyssynchrony, and calibrated IB were significantly related to LV reverse remodeling at 6-month follow-up (Table 6). In multivariable logistic regression analysis, these variables were all independent predictors of response to CRT (Table 6).

Table 6. Univariable and Multivariable Logistic Regression Analysis for Prediction of Response to CRT (Defined as Reduction in LVESV ≥15%) in Nonischemic Heart Failure

Dependent Variable: Response to CRT at 6-Month Follow-UpUnivariable AnalysisMultivariable Analysis
OR (95% CI)P ValueOR (95% CI)P Value
c-Statistic: 0.94. Hosmer-Lemeshow test: χ2=2.5, P=0.96 (df=8).
Independent variables
    Age, per 1 y0.99 (0.94–1.05)0.86
    Female sex0.99 (0.33–2.95)0.99
    QRS width at baseline, per 10 ms1.04 (0.85–1.28)0.67
    Estimated glomerular filtration rate, per 30 mL/min1.93 (1.04–3.56)0.0365.76 (1.55–21.4)0.009
    Hemoglobin, per 1 mmol/L1.29 (0.72–2.29)0.39
    LVESV at baseline, per 50 mL1.03 (0.73–1.45)0.86
    LVEF at baseline, per 5%1.02 (0.70–1.49)0.87
    LV dyssynchrony at baseline, per 50 ms4.03 (1.90–8.58)<0.0016.94 (2.14–22.48)0.001
    Calibrated IB, per 5 dB0.20 (0.06–0.60)0.0040.06 (0.01–0.60)0.017

Discussion

The current study investigated the role of LV fibrosis in the prediction of CRT response and demonstrated that (1) myocardial ultrasound reflectivity assessed with calibrated IB together with LV mechanical dyssynchrony and renal function were the major determinants of LV reverse remodeling after CRT; (2) myocardial ultrasound reflectivity assessed with calibrated IB provided incremental value over LV mechanical dyssynchrony and renal function for prediction of CRT response; (3) myocardial ultrasound reflectivity was the only independent predictor of CRT response in patients with ischemic HF; (4) myocardial ultrasound reflectivity was also an independent determinant of CRT response in nonischemic HF.

Myocardial Ultrasound Reflectivity With Calibrated IB

Currently, contrast-enhanced CMR provides accurate assessment of the extent of LV fibrosis with high spatial resolution, but CMR remains limited for daily practice.14 2D echocardiography permits assessment of myocardial ultrasound reflectivity or tissue density using calibrated IB analysis. The analysis of myocardial reflectivity with IB relies on the quantification of ultrasonic energy returned to the transducer after interactions with individual scattering elements within the myocardium.16–20,25 Picano et al16 showed a modest but significant relation (r=0.55, P<0.05) between the percent connective tissue area determined in histological sections of myocardial biopsies obtained from the LV septum and the ultrasonic reflectivity of the same region of myocardium assessed with 2D echocardiography. Moreover, experimental and clinical studies demonstrated the usefulness of this technique for the detection of subtle alterations of myocardial function and structure.17–20,25 In an animal model, Perez et al17 found that myocardial areas with increased IB corresponded histologically to discrete fibrocalcific lesions, whereas areas with normal IB corresponded to normal myocardium.

The present study explored the value of calibrated IB to estimate myocardial ultrasound reflectivity as a surrogate of LV fibrosis in HF patients who are candidates for CRT. No significant relation was found between myocardial ultrasound reflectivity and QRS duration. Furthermore, although QRS duration was larger in nonischemic as compared with ischemic HF patients (162�25 ms versus 149�35 ms, P=0.006), myocardial ultrasound reflectivity was higher in ischemic as compared with nonischemic HF patients (−18.5�3.8dB versus −20.2�3.0 dB, P=0.002). These results extend the findings of previous studies indicating the lack of relation between the QRS duration and fibrosis in dilated cardiomyopathy.26 Therefore, the extent of fibrosis or a surrogate such as myocardial ultrasound reflectivity cannot be estimated by the QRS duration on the surface ECG. In addition, renal function was weakly but significantly related to myocardial ultrasound reflectivity, underscoring that worse renal function was associated with higher IB reflectivity (possibly indicating more extensive LV fibrosis).27

Myocardial Ultrasound Reflectivity and CRT Response

Previous studies showed that beyond mechanical dyssynchrony, the quantification of myocardial fibrosis is an important pathophysiological determinant of CRT response. In particular, studies performed with nuclear imaging and contrast-enhanced CMR underscored the importance of the assessment of LV fibrosis for clinical and echocardiographic response to CRT.7,10–12,28,29 For example, White et al29 studied 23 HF patients with previous myocardial infarction and demonstrated that the extent of scar tissue in the LV, assessed with contrast-enhanced CMR, was significantly less in CRT responders as compared with nonresponders (1.0% versus 24.7%, P=0.002). Furthermore, a recent study from Bilchick et al13 used CMR to assess both mechanical dyssynchrony and LV fibrosis in a small group of 20 HF patients with ischemic and nonischemic etiology referred for CRT. The authors showed that the combined approach (assessment of mechanical dyssynchrony and quantification of LV fibrosis) significantly improved predictive accuracy for clinical CRT response.

In the current study, mechanical dyssynchrony and myocardial ultrasound reflectivity (a potential surrogate of LV fibrosis) were comprehensively evaluated with 2D echocardiography techniques (speckle-tracking imaging and calibrated IB). Myocardial ultrasound reflectivity was larger in nonresponders as compared with responders (−17.0�3.0 dB versus −20.8�3.0 dB, respectively, P<0.001). Moreover, myocardial ultrasound reflectivity was directly related to the extent of reverse remodeling after CRT and provided incremental value over LV dyssynchrony and renal function for prediction of CRT response, in line with previous studies.24,30,31

Myocardial Ultrasound Reflectivity in Patients With Ischemic and Nonischemic HF

Various studies have focused on the relation between LV fibrosis and CRT response in ischemic HF patients.7,10–12,28,29 In particular, Ypenburg et al11 demonstrated in 34 ischemic HF patients the close relation between the total scar burden assessed with contrast-enhanced CMR and LV reverse remodeling after CRT (r=0.91, P<0.05). In the present study, in ischemic HF patients, the amount of myocardial ultrasound reflectivity was not only significantly related to LV reverse remodeling but also was the strongest independent predictor of LV reverse remodeling. These findings underscore the relevance of this indirect parameter of LV fibrosis for CRT response in the setting of ischemic HF.

Few studies have reported on the presence of LV fibrosis in patients with nonischemic dilated cardiomyopathy,14,32 but none have explored the relation between LV fibrosis and CRT response in patients with nonischemic HF. The current results demonstrated a significant direct relation between the extent of myocardial ultrasound reflectivity, as a potential surrogate of LV fibrosis, and LV reverse remodeling after CRT. Moreover, in nonischemic HF patients, myocardial ultrasound reflectivity was an important and independent predictor of CRT response. Accordingly, the current findings underscore the role of the assessment of myocardial ultrasound reflectivity to improve CRT response rate in nonischemic HF patients.

Study Limitations

As previously described,16,18–20 calibrated IB assessed in the anteroseptal and posterior wall was used to detect myocardial ultrasound reflectivity. The measurement of calibrated IB in the anteroseptal and posterior wall is dependent on ultrasound machine settings (focus, depth, gain, and insonation angle). These settings were adjusted in all patients to optimize the image quality for offline analysis. In addition, by correcting calibrated IB of the anteroseptal and posterior walls for the calibrated IB of the pericardium, the effect of these technical issues on the accuracy of this analysis may be minimized. In addition, no independent technique as CMR was used to prove the association between myocardial ultrasound reflectivity and fibrosis. However, previous studies showed a potential relation between myocardial ultrasound reflectivity and fibrosis.16,17

Conclusion

In the current study, myocardial ultrasound reflectivity assessed with calibrated IB was related to CRT response. In particular, myocardial ultrasound reflectivity provided incremental value to CRT response over mechanical LV dyssynchrony and renal function. Furthermore, myocardial ultrasound reflectivity was a strong determinant of LV reverse remodeling after CRT, both in ischemic and nonischemic HF patients.

Sources of Funding

Dr Bax received grants from Medtronic, Boston Scientific, Biotronik, St Jude Medical, BMS Medical Imaging, Edwards Lifesciences, and GE Healthcare. Dr Schalij received grants from Biotronik, Medtronic, and Boston Scientific. Dr Nucifora was financially supported by the Research Fellowship of the European Association of Percutaneous Cardiovascular Interventions.

Disclosures

None.

Footnotes

Correspondence to Jeroen J. Bax, MD, PhD, Department of Cardiology, Leiden University Medical Center, Albinusdreef 2, 2333ZA Leiden, The Netherlands. E-mail

References

  • 1 Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, Kocovic DZ, Packer M, Clavell AL, Hayes DL, Ellestad M, Trupp RJ, Underwood J, Pickering F, Truex C, McAtee P, Messenger J. Cardiac resynchronization in chronic heart failure. N Engl J Med. 2002; 346: 1845–1853.CrossrefMedlineGoogle Scholar
  • 2 Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, Tavazzi L. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005; 352: 1539–1549.CrossrefMedlineGoogle Scholar
  • 3 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–e235.LinkGoogle Scholar
  • 4 Chung ES, Leon AR, Tavazzi L, Sun JP, Nihoyannopoulos P, Merlino J, Abraham WT, Ghio S, Leclercq C, Bax JJ, Yu CM, Gorcsan J III, St John SM, De SJ, Murillo J. Results of the Predictors of Response to CRT (PROSPECT) trial. Circulation. 2008; 117: 2608–2616.LinkGoogle Scholar
  • 5 Cleland J, Freemantle N, Ghio S, Fruhwald F, Shankar A, Marijanowski M, Verboven Y, Tavazzi L. Predicting the long-term effects of cardiac resynchronization therapy on mortality from baseline variables and the early response a report from the CARE-HF (Cardiac Resynchronization in Heart Failure) Trial. J Am Coll Cardiol. 2008; 52: 438–445.CrossrefMedlineGoogle Scholar
  • 6 Wikstrom G, Blomstrom-Lundqvist C, Andren B, Lonnerholm S, Blomstrom P, Freemantle N, Remp T, Cleland JG. The effects of aetiology on outcome in patients treated with cardiac resynchronization therapy in the CARE-HF trial. Eur Heart J. 2009; 30: 782–788.CrossrefMedlineGoogle Scholar
  • 7 Bleeker GB, Kaandorp TA, Lamb HJ, Boersma E, Steendijk P, de RA, van der Wall EE, Schalij MJ, Bax JJ. Effect of posterolateral scar tissue on clinical and echocardiographic improvement after cardiac resynchronization therapy. Circulation. 2006; 113: 969–976.LinkGoogle Scholar
  • 8 Hummel JP, Lindner JR, Belcik JT, Ferguson JD, Mangrum JM, Bergin JD, Haines DE, Lake DE, DiMarco JP, Mounsey JP. Extent of myocardial viability predicts response to biventricular pacing in ischemic cardiomyopathy. Heart Rhythm. 2005; 2: 1211–1217.CrossrefMedlineGoogle Scholar
  • 9 Rocchi G, Bertini M, Biffi M, Ziacchi M, Biagini E, Gallelli I, Martignani C, Cervi E, Ferlito M, Rapezzi C, Branzi A, Boriani G. Exercise stress echocardiography is superior to rest echocardiography in predicting left ventricular reverse remodelling and functional improvement after cardiac resynchronization therapy. Eur Heart J. 2009; 30: 89–97.MedlineGoogle Scholar
  • 10 Ypenburg C, Schalij MJ, Bleeker GB, Steendijk P, Boersma E, Dibbets-Schneider P, Stokkel MP, van der Wall EE, Bax JJ. Impact of viability and scar tissue on response to cardiac resynchronization therapy in ischaemic heart failure patients. Eur Heart J. 2007; 28: 33–41.CrossrefMedlineGoogle Scholar
  • 11 Ypenburg C, Roes SD, Bleeker GB, Kaandorp TA, de RA, Schalij MJ, van der Wall EE, Bax JJ. Effect of total scar burden on contrast-enhanced magnetic resonance imaging on response to cardiac resynchronization therapy. Am J Cardiol. 2007; 99: 657–660.CrossrefMedlineGoogle Scholar
  • 12 Chalil S, Foley PW, Muyhaldeen SA, Patel KC, Yousef ZR, Smith RE, Frenneaux MP, Leyva F. Late gadolinium enhancement-cardiovascular magnetic resonance as a predictor of response to cardiac resynchronization therapy in patients with ischaemic cardiomyopathy. Europace. 2007; 9: 1031–1037.CrossrefMedlineGoogle Scholar
  • 13 Bilchick KC, Dimaano V, Wu KC, Helm RH, Weiss RG, Lima JA, Berger RD, Tomaselli GF, Bluemke DA, Halperin HR, Abraham T, Kass DA, Lardo AC. Cardiac magnetic resonance assessment of dyssynchrony and myocardial scar predicts function class improvement following cardiac resynchronization therapy. J Am Coll Cardiol Cardiovasc Imaging. 2008; 1: 561–568.CrossrefMedlineGoogle Scholar
  • 14 Iles L, Pfluger H, Phrommintikul A, Cherayath J, Aksit P, Gupta SN, Kaye DM, Taylor AJ. Evaluation of diffuse myocardial fibrosis in heart failure with cardiac magnetic resonance contrast-enhanced T1 mapping. J Am Coll Cardiol. 2008; 52: 1574–1580.CrossrefMedlineGoogle Scholar
  • 15 Abraham TP, Kass D, Tonti G, Tomassoni GF, Abraham WT, Bax JJ, Marwick TH. Imaging cardiac resynchronization therapy. J Am Coll Cardiol Img. 2009; 2: 486–497.CrossrefGoogle Scholar
  • 16 Picano E, Pelosi G, Marzilli M, Lattanzi F, Benassi A, Landini L, L'Abbate A. In vivo quantitative ultrasonic evaluation of myocardial fibrosis in humans. Circulation. 1990; 81: 58–64.CrossrefMedlineGoogle Scholar
  • 17 Perez JE, Barzilai B, Madaras EI, Glueck RM, Saffitz JE, Johnston P, Miller JG, Sobel BE. Applicability of ultrasonic tissue characterization for longitudinal assessment and differentiation of calcification and fibrosis in cardiomyopathy. J Am Coll Cardiol. 1984; 4: 88–95.CrossrefMedlineGoogle Scholar
  • 18 Mottram PM, Haluska B, Yuda S, Leano R, Marwick TH. Patients with a hypertensive response to exercise have impaired systolic function without diastolic dysfunction or left ventricular hypertrophy. J Am Coll Cardiol. 2004; 43: 848–853.CrossrefMedlineGoogle Scholar
  • 19 Wong CY, O'Moore-Sullivan T, Leano R, Byrne N, Beller E, Marwick TH. Alterations of left ventricular myocardial characteristics associated with obesity. Circulation. 2004; 110: 3081–3087.LinkGoogle Scholar
  • 20 Yuda S, Fang ZY, Marwick TH. Association of severe coronary stenosis with subclinical left ventricular dysfunction in the absence of infarction. J Am Soc Echocardiogr. 2003; 16: 1163–1170.CrossrefMedlineGoogle Scholar
  • 21 Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976; 16: 31–41.CrossrefMedlineGoogle Scholar
  • 22 Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS, Solomon SD, Spencer KT, Sutton MS, Stewart WJ. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr. 2005; 18: 1440–1463.CrossrefMedlineGoogle Scholar
  • 23 Leitman M, Lysyansky P, Sidenko S, Shir V, Peleg E, Binenbaum M, Kaluski E, Krakover R, Vered Z. Two-dimensional strain-a novel software for real-time quantitative echocardiographic assessment of myocardial function. J Am Soc Echocardiogr. 2004; 17: 1021–1029.CrossrefMedlineGoogle Scholar
  • 24 Suffoletto MS, Dohi K, Cannesson M, Saba S, Gorcsan J III. Novel speckle-tracking radial strain from routine black-and-white echocardiographic images to quantify dyssynchrony and predict response to cardiac resynchronization therapy. Circulation. 2006; 113: 960–968.LinkGoogle Scholar
  • 25 Logan-Sinclair R, Wong CM, Gibson DG. Clinical application of amplitude processing of echocardiographic images. Br Heart J. 1981; 45: 621–627.CrossrefMedlineGoogle Scholar
  • 26 Yamada T, Fukunami M, Ohmori M, Iwakura K, Kumagai K, Kondoh N, Tsujimura E, Abe Y, Nagareda T, Kotoh K. New approach to the estimation of the extent of myocardial fibrosis in patients with dilated cardiomyopathy: use of signal-averaged electrocardiography. Am Heart J. 1993; 126: 626–631.CrossrefMedlineGoogle Scholar
  • 27 Salvetti M, Muiesan ML, Paini A, Monteduro C, Bonzi B, Galbassini G, Belotti E, Movilli E, Cancarini G, Gabiti-Rosei E. Myocardial ultrasound tissue characterization in patients with chronic renal failure. J Am Soc Nephrol. 2007; 18: 1953–1958.CrossrefMedlineGoogle Scholar
  • 28 Sciagra R, Giaccardi M, Porciani MC, Colella A, Michelucci A, Pieragnoli P, Gensini G, Pupi A, Padeletti L. Myocardial perfusion imaging using gated SPECT in heart failure patients undergoing cardiac resynchronization therapy. J Nucl Med. 2004; 45: 164–168.MedlineGoogle Scholar
  • 29 White JA, Yee R, Yuan X, Krahn A, Skanes A, Parker M, Klein G, Drangova M. Delayed enhancement magnetic resonance imaging predicts response to cardiac resynchronization therapy in patients with intraventricular dyssynchrony. J Am Coll Cardiol. 2006; 48: 1953–1960.CrossrefMedlineGoogle Scholar
  • 30 Delgado V, Ypenburg C, van Bommel RJ, Tops LF, Mollema SA, Marsan NA, Bleeker GB, Schalij MJ, Bax JJ. Assessment of left ventricular dyssynchrony by speckle tracking strain imaging comparison between longitudinal, circumferential, and radial strain in cardiac resynchronization therapy. J Am Coll Cardiol. 2008; 51: 1944–1952.CrossrefMedlineGoogle Scholar
  • 31 Fung JW, Szeto CC, Chan JY, Zhang Q, Chan HC, Yip GW, Yu CM. Prognostic value of renal function in patients with cardiac resynchronization therapy. Int J Cardiol. 2007; 122: 10–16.CrossrefMedlineGoogle Scholar
  • 32 Bogun FM, Desjardins B, Good E, Gupta S, Crawford T, Oral H, Ebinger M, Pelosi F, Chugh A, Jongnarangsin K, Morady F. Delayed-enhanced magnetic resonance imaging in nonischemic cardiomyopathy: utility for identifying the ventricular arrhythmia substrate. J Am Coll Cardiol. 2009; 53: 1138–1145.CrossrefMedlineGoogle Scholar
circcvimCirc Cardiovasc ImagingCirculation: Cardiovascular ImagingCirc Cardiovasc Imaging1941-96511942-0080Lippincott Williams & WilkinsCLINICAL PERSPECTIVE012010

According to current guidelines, candidates for cardiac resynchronization therapy (CRT) are patients in New York Heart Association functional class III-IV heart failure with left ventricular (LV) ejection fraction ≤35% and QRS duration ≥120 ms. However, by applying these selection criteria, more than one third of the patients do not show clinical response nor LV reverse remodeling. Among several factors that determine a favorable response to CRT, the amount of LV fibrosis as assessed, for example, with cardiac magnetic resonance has been shown to be an important issue. The current study demonstrates that myocardial ultrasound reflectivity is an important determinant of CRT response in the overall heart failure population, together with the presence of LV mechanical dyssynchrony and renal function. Moreover, in the ischemic subgroup of heart failure patients, myocardial ultrasound reflectivity was found to be the only independent determinant of LV reverse remodeling after CRT. In the nonischemic subgroup of heart failure patients, myocardial ultrasound reflectivity was still an independent predictor of CRT response. Several pathophysiological issues must be addressed to optimize selection of CRT patients. Different imaging modalities provide information about dyssynchrony, and echocardiography has provided useful albeit controversial data in these patients. Myocardial ultrasound reflectivity with calibrated integrated backscatter imaging may provide additional data to aid in the selection of candidates for CRT.