Methods

Patients were selected for CRT device implantations according to current guidelines and criteria: (1) severe heart failure (New York Heart Association functional class III or IV) despite optimal medical treatment, (2) an LVEF <35%, and (3) prolonged QRS duration (>120 ms). Of 80 consecutive patients who underwent de novo dual-chamber CRT device implantations at 2 institutions from June 2007 to June 2012, patients with external LV assist devices (n = 4), acquired second- or third-degree AV block (n = 7), persistent atrial tachycardia and/or atrial fibrillation (n = 12), and upgraded pacemakers from right ventricular apical pacing (n = 5) and those without follow-up data (n = 4) were excluded from this study. Ultimately, 48 patients maintained in sinus rhythm and with intrinsic AV conduction were retrospectively analyzed. The study protocol conformed to the Declaration of Helsinki and was accepted by each hospital’s ethics committee. Written informed consent was obtained from all patients. All patients underwent baseline evaluations and echocardiographic examinations, including evaluations of dyssynchrony before and 6 months after CRT.

Before hospital discharge, optimization of the AV and ventricular-ventricular intervals was performed by echocardiography or an intracardiac electrocardiographically guided timing cycle optimization algorithm. Echocardiographic images were all obtained before CRT device implantation and 6 months after implantation. LV volumes were determined using the method previously reported. The grade of mitral regurgitation was assessed according to the guidelines of the American Society of Echocardiography. We calculated the overlap ratio of the E and A waves. This overlap ratio was defined as in Figure 1 . In Figure 1 , ‘a’ is the interval between a point of intersection of the E and A waves and the termination of the E wave, while ‘b’ is the interval between the peak of the E wave and the termination of the E wave. The overlap ratio of the E and A waves was calculated as (a/b) × 100%. When the E and A waves were completely separated, the overlap ratio of the E and A waves was 0%. When the E and A waves were totally fused, the overlap ratio was 100%. We determined the level of intraventricular and interventricular mechanical dyssynchrony with using M-mode echocardiography and tissue Doppler imaging. A septal-posterior wall motion delay obtained on M-mode imaging in the parasternal long-axis view of ≥130 ms or the opposing wall delay between the anteroseptal-to-posterior wall or the septal-to-lateral wall of ≥65 ms was defined as intraventricular mechanical dyssynchrony. Interventricular electromechanical delay was the difference between the LV pre-ejection period and the right ventricular pre-ejection period. An interventricular electromechanical delay of ≥40 ms was defined as interventricular dyssynchrony. A reduction in the LV end-systolic volume of >15% at 6 months after CRT was used as an objective measure of response to CRT in this study.

Overlap ratio of the E and A waves. The overlap ratio of the E and A waves is measured as follows: ‘a’ is the interval between the point of the intersection of the E and A waves and the termination of the E wave, while ‘b’ is the interval between the peak of the E wave and the termination of the E waves. The overlap ratio of the E and A waves is calculated as (a/b) × 100%. When the E and A waves are completely separated, the overlap ratio of the E and A waves is 0%. When the E and A waves are totally fused, the overlap ratio of the E and A waves is 100%.

Continuous variables are expressed as mean ± SD. Factors were determined using chi-square tests, and between-group comparisons were made using Mann-Whitney U tests for continuous variables and Fisher’s exact tests for dichotomous variables. Only variables with p values <0.05 on univariate analysis were entered into a multivariate logistic regression analysis to identify independent factors of CRT response. A p value <0.05 was considered statistically significant. Receiver-operating characteristic curves were generated, and the area under the curve was determined as a measure of the ability to predict a positive response at any cut-off value. JMP version 9.0 (SAS Institute Inc., Cary, North Carolina) was used for all statistical tests.

Results

Patient characteristics are listed in Table 1 . β blockers were administered in 47 patients: carvedilol (average dose 8.5 ± 6 mg) in 42 patients, bisoprolol (2.8 ± 0.3 mg) in 2 patients, metoprolol (40 ± 20 mg) in 2 patients, and atenolol (12.5 mg) in 1 patient. The various analyses of the echocardiographic measurements are listed in Table 2 . At 6-month follow-up, 23 patients (48%) were CRT responders. Three patients in the nonresponder group experienced progression to persistent atrial fibrillation, whereas all patients in the responder group maintained sinus rhythm. The 2 groups were generally comparable in terms of baseline demographic, clinical, and echocardiographic characteristics ( Tables 1 and 2 ). The overlap ratio of the E and A waves was higher in the responder group than in the nonresponder group (44 ± 34% vs 19 ± 23%, p = 0.006). New York Heart Association functional class and electrocardiographic and echocardiographic parameters 6 months after CRT device implantation are listed in Table 3 . Significant reductions in heart rate were more frequently observed in the responder group than in the nonresponder group (67 ± 10 vs 76 ± 10 beats/min, p = 0.004), although the incidence of patients increasing the doses of β blockers was similar between the responder group and the nonresponder group (39% vs 36%, p = NS). New York Heart Association functional class improved in 91% of the responders and only 40% of the nonresponders (p = 0.0002). Representative cases in the 2 groups are shown in Figure 2 .

Table 3

Exercise tolerance and electrocardiographic and echocardiographic parameters at 6 months after cardiac resynchronization therapy device implantation

Variable	Overall (n = 48)	Responders (n = 23)	Nonresponders (n = 25)	p Value
New York Heart Association class I/II/III/IV	6/21/14/7	6/14/3/0	0/7/11/7	0.002
Heart rate (beats/min)	72 ± 11	67 ± 10	76 ± 10	0.004
PQ interval (ms)	158 ± 47	139 ± 30	173 ± 53	0.01
QRS duration (ms)	141 ± 22	141 ± 23	142 ± 22	0.95
B-type natriuretic peptide (pg/ml)	324 ± 361	135 ± 129	505 ± 418	0.0003
Echocardiographic parameters
LVEF (%)	31 ± 12	40 ± 9	22 ± 6	0.0001
Deceleration time of the E wave (ms)	185 ± 66	202 ± 52	170 ± 75	0.11
DFT/RR	0.48 ± 0.08	0.50 ± 0.07	0.46 ± 0.08	0.08
Overlap ratio of the E and A waves (%)	13 ± 23	10 ± 16	16 ± 28	0.36

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