Methods

A total of 32 consecutive patients with heart failure and nonischemic dilated cardiomyopathy, who had been implanted with a CRT device according to current guidelines at the Institute of Cardiology, University of Bologna, were included in the present prospective study. For each patient, significant coronary artery disease had been ruled out by angiography. All patients were in sinus rhythm. The pharmacologic treatment regimen was the optimal one tolerated at implantation and was kept constant throughout the study period. An echocardiographic-guided optimization of CRT programming was performed immediately after implantation according to conventional clinical practice.

All patients were assessed using equilibrium technetium-99m radionuclide angiography with bicycle exercise both at baseline (within 4 days of CRT implantation) and after 3 months of continuous biventricular pacing. CRT was switched off between implantation and baseline radionuclide angiography to avoid pacing-induced variations in LV function. At baseline, radionuclide images at rest and during exercise were acquired during spontaneous rhythm and 10 minutes after activation of biventricular pacing. At 3 months, the images were acquired during biventricular pacing only. Bicycle exercise was performed with a fixed workload of 25 W, and exercise image acquisition started when at least a 10-beat increase in heart rate had been achieved. The investigation conformed to the principles outlined in the Declaration of Helsinki. The local ethics committee approved the study protocol, and all patients provided written informed consent for participation.

Radionuclide angiography was performed as previously described. In particular, modified in vivo/in vitro red blood cell labeling using 2 to 3 mg stannous pyrophosphate was performed 15 minutes before injection of about 925 MBq technetium-99m. Planar imaging was obtained in the “best septal separation” left anterior oblique view, with patients in the semisupine position, using a dual-headed gamma camera (Prism 2000 XP, Philips Medical Systems, Best, The Netherlands) equipped with a parallel-hole, high-resolution collimator. Data were collected in frame mode, excluding extrasystolic and postextrasystolic beats (beat length window <10%), with 32 frames acquired at rest and 24 during exercise (128 × 128 matrix). Imaging acquisition ended when a total count of ≥6 million were recorded at rest and ≥4 million during exercise. A background-corrected, time-activity curve was obtained by a semiautomated edge-detection method with a variable region of interest and verified visually and modified manually, if necessary.

The global LV systolic function was assessed by measuring the LV ejection fraction (LVEF) and peak ejection rate. The LVEF was computed on the basis of the relative end-diastolic and end-systolic counts, as previously described. The peak ejection rate was calculated from the time-activity curve as the maximum ejection rate during systole. Regional LV function was assessed by measuring the regional LVEF according to a standard 5-segment LV model. In detail, the ventricle was intersected orthogonally into 5 divisions, corresponding to the upper (basal) and lower (mid-apical) septum, apex, and inferolateral and posterolateral wall. For each segment, EF was quantified from the relative end-diastolic and end-systolic counts. The regional EF of the dyskinetic segments is expressed as a negative value. The response to CRT was defined by an absolute increase in global LVEF of ≥5% at mid-term follow-up.

Phase images were generated from the scintigraphic data using a commercially available computer program. As previously described, the phase program assigns a phase angle to each pixel of the phase image, derived from the first Fourier harmonic of time. The phase angle corresponds to the relative sequence and pattern of ventricular contraction during the cardiac cycle. Phase images were generated using a continuous color scale, corresponding to phase angles from 0° to 360°. The mean phase angles were computed for the LV and right ventricular blood pools as the arithmetic mean phase angle for all pixels in the ventricular region of interest. Interventricular dyssynchrony was expressed as the absolute value of the difference between the LV and right ventricular mean phase angles. Intraventricular dyssynchrony was expressed as the standard deviation of the mean phase angle for the LV blood pool. Both inter- and intraventricular dyssynchrony are expressed in angles (°). The intraobserver and interobserver variability, expressed by the coefficient of variation (%) between 2 assessments, was 5.0% and 7.4% for LVEF and 4.4% and 4.3% for the LV mean phase angle, respectively.

All data were analyzed using a commercially available statistical package (Statistica, StatSoft, Tulsa, Oklahoma). All continuous variables were tested for normal distribution using the Kolmogorov-Smirnov test and are presented as the mean ± SD if a normal distribution was confirmed. Analysis of variance for repeated measures and a 2-sided paired t test were performed for comparisons between data obtained at baseline and during follow-up, at rest and during exercise. p Values <0.0 were considered statistically significant.

Results

The patient characteristics at baseline are listed in Table 1 . All patients had LBBB on surface electrocardiogram and received a CRT device with defibrillation capabilities. The LV lead position was anterior/anterolateral in 2 patients (6%) and lateral/posterolateral in 30 (94%). Bicycle exercise was well tolerated, and all patients completed the study protocol without any complications. A similar rest-to-exercise increase in heart rate was reached during each bicycle test (19 ± 5 beats/min during spontaneous rhythm; 17 ± 7 beats/min during CRT at baseline; 20 ± 5 beats/min at 3 months; p = NS between the time points).

The time- and exercise-related changes in global LV function and dyssynchrony in the entire study population are listed in Table 2 . The LVEF and peak ejection rate, reflecting LV systolic function, were significantly improved by CRT at the 3-month follow-up point (p <0.001 and p <0.05 vs spontaneous rhythm, respectively). A trend toward an increase in the peak ejection rate was also observed at baseline (p = 0.07 vs spontaneous rhythm at rest). Intraventricular dyssynchrony decreased at rest both at baseline (p = 0.03 vs spontaneous rhythm) and after 3 months (p <0.001 and p = 0.03 vs spontaneous rhythm and CRT at baseline, respectively). However, a decrease in intraventricular dyssynchrony during exercise occurred only at the 3-month follow-up. Interventricular dyssynchrony decreased over time only during exercise (p <0.001 vs spontaneous rhythm both at baseline and after 3 months).

The regional EF during spontaneous rhythm and CRT-induced changes over time at rest and during exercise are shown in Figure 1 . During spontaneous rhythm, an inhomogeneous contraction pattern was seen, with the regional EF severely depressed in the septum compared to the lateral wall (LW). CRT induced significant variations in the regional contraction pattern. Upper septum EF was markedly improved at baseline (p <0.001 vs spontaneous rhythm, both at rest and during exercise) and increased further after 3 months (p = 0.018 and p = 0.001 vs CRT baseline at rest and during exercise, respectively). Similar changes were observed for lower septum EF. In contrast, posterolateral wall EF decreased during CRT both at baseline and after 3 months (p <0.05 vs spontaneous rhythm, both at rest and during exercise). The inferolateral wall EF significantly decreased at rest at baseline (p <0.001 vs spontaneous rhythm) but not at the 3-month follow-up point. During exercise, a decrease in the inferolateral wall EF was observed both at baseline and after 3 months (p <0.05). The apex EF improved at the 3-month follow-up at rest (p = 0.03 vs spontaneous rhythm) and during exercise (p = 0.003 vs baseline).

Variations in global and regional EF at rest and during exercise at different points: during spontaneous rhythm, immediately after CRT activation (CRT baseline), and after 3 months of follow-up (CRT 3 months). Black columns refer to rest, and striped to exercise. CRT = cardiac resynchronization therapy. ^* p <0.05 versus spontaneous rhythm at rest; ^§ p <0.05 versus spontaneous rhythm during exercise; °p <0.05 versus CRT baseline at rest; ^p <0.05 versus CRT baseline during exercise; ^# p <0.05 versus CRT at 3 months at rest.

At the mid-term follow-up point, 17 patients (53%) had responded to CRT. No significant differences in the baseline patient characteristics were observed between those with and without a response. The global and regional LV function variables in the 2 groups are reported in Table 3 . By definition, in those with a response, the global LVEF increased at 3 months at rest and during exercise (p <0.001 vs spontaneous rhythm). Intraventricular dyssynchrony decreased during CRT both at baseline (p = 0.04 at rest and p = 0.06 during exercise) and after 3 months (p = 0.002 vs spontaneous rhythm at rest and p ≤0.001 vs spontaneous rhythm and baseline during exercise). In those without a response, no significant change in the global LVEF was observed. At 3 months, a trend was seen toward a decrease in intraventricular dyssynchrony at rest (p = 0.07 vs spontaneous rhythm).

Table 3

Radionuclide angiography variables of global left ventricular (LV) function, intraventricular dyssynchrony, and regional ejection fraction (EF), at baseline and 3 months of follow-up stratified by response

Variable	Responders (n = 17)			Nonresponders (n = 15)
	Spontaneous	Baseline CRT	3-mo CRT	Spontaneous	Baseline CRT	3-mo CRT
Global left ventricular ejection fraction (%)
At rest	28 ± 7	28 ± 8	40 ± 11 ⁎ †	23 ± 10	23 ± 10	24 ± 9
During exercise	27 ± 7	29 ± 8	38 ± 12 ⁎ †	23 ± 10	23 ± 11	23 ± 10
Intraventricular dyssynchrony (°)
At rest	49 ± 26	39 ± 20 ⁎ ‡	28 ± 20 ⁎	51 ± 25	49 ± 24	43 ± 20 ‡
During exercise	52 ± 20	47 ± 20	34 ± 19 ⁎ †	54 ± 25	56 ± 25	54 ± 24
Upper septum ejection fraction (%)
At rest	−1 ± 12	14 ± 8 ⁎	22 ± 19 ⁎	6 ± 6	17 ± 9 ⁎	22 ± 13 ⁎ †
During exercise	2 ± 15	17 ± 10 ⁎	27 ± 13 ⁎ †	10 ± 10	19 ± 10 ⁎	23 ± 12 ⁎
Lower septum ejection fraction (%)
At rest	18 ± 14	24 ± 12	32 ± 19 ⁎	14 ± 11	17 ± 11	21 ± 11 ⁎
During exercise	19 ± 10	22 ± 7	31 ± 16 ⁎ †	15 ± 11	20 ± 11 ⁎	23 ± 11 ⁎
Posterolateral wall ejection fraction (%)
At rest	54 ± 13 ‡	37 ± 17 ⁎	50 ± 18 † ‡	36 ± 11	33 ± 13	26 ± 13 ⁎ † ‡
During exercise	48 ± 15	38 ± 17 ⁎	43 ± 19	36 ± 11	27 ± 15	20 ± 12 ⁎ †
Inferolateral wall ejection fraction (%)
At rest	48 ± 14 ‡	31 ± 16 ⁎	48 ± 17 † ‡	31 ± 12	25 ± 13	21 ± 12 ⁎ ‡
During exercise	40 ± 14	32 ± 14 ⁎	40 ± 19 †	31 ± 15	23 ± 12	16 ± 9 ⁎ †
Apex ejection fraction (%)
At rest	32 ± 13	28 ± 9	41 ± 14 ⁎ † ‡	19 ± 13	18 ± 13	18 ± 12
During exercise	30 ± 10	28 ± 10	36 ± 13 ⁎ †	20 ± 15	20 ± 14	18 ± 10

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