Study population

The study included 169 consecutive patients with HF who received CRT-D with a primary prevention indication for ICD. Informed consent was obtained from all patients, and the institutional review board approved the study.

All baseline clinical, electrocardiographic, and echocardiographic data were prospectively collected before CRT-D implantation. Patients were scheduled for regular CRT-D device follow-up to ensure that biventricular pacing was being maintained and arrhythmic events were not missed, at least every 3 months (and at the time of symptoms of arrhythmias). The primary study end point was first appropriate ICD therapy.

Device implantation

As previously described, device implantation was performed preferably with a single left pectoral incision, a left cephalic vein cut-down, and a left subclavian puncture. The defibrillation lead was positioned in the right ventricular apex. Transvenous implantation of the CRT device was successful in 159 patients (94%). The left ventricular pacing lead was placed in a tributary of the coronary sinus. A posterolateral branch was used in 72 patients (43%), a lateral branch in 27 patients (16%), posterior branch in 25 (15%), and an anterolateral branch in 35 patients (21%). In the remaining 10 patients, the left ventricular leads were surgically implanted. Adequate pacing and sensing properties of all leads and diaphragmatic stimulation with the left ventricular pacing lead were tested. The lowest effective defibrillation energy was assessed, and a safety margin of ≥10 J was used. Devices used were the InSync 7272, 7279, and 7298 (Medtronic, Inc., Minneapolis, Minnesota); the Renewal II (Guidant, Inc., St. Paul, Minnesota); and the Epic HF v-339 and Atlas HF v-341 (St. Jude Medical, Sylmar, California). For all patients, ICD programming was intended to avoid inappropriate therapy and tailored according to the clinical presentation. A 2-zone configuration was programmed in 138 patients (82%). The mean ventricular tachyarrhythmia detection rate was 349 ± 18 ms, and the mean fibrillation detection rate was 283 ± 15 ms. Atrioventricular delay was optimized by 2-dimensional echocardiography to provide the longest diastolic filling time and the highest left ventricular outflow tract velocity-time integral.

Interpretation of ICD events

Device interrogation was performed on a regular 3-month basis and otherwise incidentally according to patients’ symptoms. Stored intracardiac electrograms were analyzed to identify arrhythmic events and classify arrhythmias responsible for triggering overpacing or defibrillator therapy, according to accepted definitions as previously described by our group. Defibrillator therapy was considered appropriate when triggered by ventricular fibrillation or ventricular tachycardia.

Echocardiography

All patients were examined using a Sonos 7500 ultrasound system or an iE33 ultrasound system (Philips Medical Systems, Best, The Netherlands) with an S3 or S5-1 transducer according to the recommendations of the American Society of Echocardiography. left ventricular end-diastolic volume, left ventricular end-systolic volume, and the left ventricular ejection fraction (LVEF; by the modified biplane Simpson’s rule) were calculated from the apical 4-chamber and 2-chamber views. The degree of mitral regurgitation (graded I to IV) was assessed as the midsystolic jet area relative to left atrial area in the apical 4-chamber view. From the mitral inflow peak velocity of early (E) and late (A) diastolic filling, the E/A ratio and E-wave deceleration time were measured.

Tissue Doppler imaging

Tissue Doppler imaging was applied by placing the sample volume at the side of the medial and lateral mitral annulus in the apical 4-chamber view. Gain and filter settings were adjusted as needed to eliminate background noise and to allow a clear tissue signal. To acquire the highest tissue velocities, the angle between the Doppler beam and the longitudinal motion of the investigated structure was adjusted to a minimal level. The velocity and timing of the mitral annulus systolic wave (Sm) and early diastolic wave (E′) were recorded at end-expiration at a sweep speed of 75 or 100 mm/s and measured using electronic calipers with EnConcert software (Philips Medical Systems). Septal-to-lateral mechanical delay was measured from the onset of Sm. The Tei index, defined as isovolumic contraction time plus isovolumic relaxation time divided by left ventricular ejection time, and the dimensionless mitral E/E′ ratio (from the lateral mitral annulus) were calculated as previously described. For each patient, the average of 3 measurements was calculated.

Statistical analysis

All statistics were analyzed using SPSS version 16 for Windows (SPSS, Inc., Chicago, Illinois). Descriptive statistics for nominal data were compared using the chi-square test or Fisher’s exact test and are expressed as frequencies and percentages. After checking for normality, mean values and SDs were calculated for normally distributed continuous variables. Baseline values were compared using an unpaired Student’s t test or a Mann-Whitney U test, if appropriate. Each variable was evaluated by univariate analysis for the study end point of appropriate ICD therapy. Univariate Cox regression analysis identified baseline variables that were significantly associated with appropriate ICD therapy. Significantly associated variables (p <0.10) were then integrated into multivariate analysis using Cox proportional-hazards modeling with stepwise selection for time to appropriate ICD therapy. All hazard ratios are adjusted for age, gender, hypertension, diabetes, QRS duration, history of atrial arrhythmias, ischemic cause of HF, history of coronary artery bypass grafting, and the use of amiodarone, digoxin, diuretics, and angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. The proportional-hazards assumptions were then validated in the final model for each categorical variable through the visual inspection of log-log plots. For continuous variables, the linearity assumption was checked graphically using the residuals plots. There were no signs of violation of the assumptions. Patients not reaching the study end point were censored at the date of most recent follow-up. Receiver-operating characteristic curves were used to define the best cut-off value of the LVEF that was associated with appropriate ICD therapy. All tests were conducted on a 2-tailed basis with the intention to accept a chance probability of 5% (p <0.05).

Patient characteristics

The study included 169 patients (mean age 60 ± 12 years, 125 men). Eighty-four patients (50%) had ischemic HF, and 85 patients (50%) had nonischemic HF. Baseline clinical characteristics of the study population are listed in Table 1 .

CRT-D outcomes

During a mean follow-up period of 654 ± 394 days (range 250 to 1,637), 24 patients (14%) died, 19 from cardiovascular causes (sudden cardiac death in 3, exacerbation of HF in 14, and cerebrovascular accidents in 2), and 2 patients underwent heart transplantation. Thirty-five patients (21%) sustained ventricular tachyarrhythmias requiring appropriate ICD therapy (successful antitachycardia pacing therapy in 17, unsuccessful antitachycardia pacing followed by shock therapy in 9, and direct shock therapy in 9). Of the 3 patients who experienced sudden cardiac death, 2 had been treated with appropriate ICD therapy before sudden cardiac death. The mean cycle length was 289 ± 45 ms. Fifteen patients had ICD therapy for fast ventricular tachycardia (>240 beats/minute) or ventricular fibrillation. The mean duration from CRT-D implantation until the first appropriate ICD intervention was 252 ± 286 days. The mean annual rate of ICD therapy was approximately 8.5% during 4 years of follow-up ( Figure 1 ). Baseline characteristics of patients with and without appropriate ICD therapy are listed in Table 1 . Patients with appropriate ICD therapy had decreased LVEFs (p = 0.001) and peak systolic mitral annular velocities (p = 0.001), increased left ventricular end-systolic volumes (p = 0.03) and E/E′ ratios (p = 0.001), and shorter distances walked in 6 minutes (p = 0.02) and more often were receiving digitalis therapy (p = 0.02).

Cumulative annual risk for appropriate defibrillator therapy in HF recipients of CRT-D. VF = ventricular fibrillation; VT = ventricular tachycardia.

As listed in Table 2 , univariate analysis using Cox proportional-hazards ratios showed that nonsustained ventricular tachycardia (p = 0.001), digitalis therapy (p = 0.01), a severely (<20%) decreased LVEF (p < 0.001), and an increased E/E′ ratio (p = 0.006) were significantly associated with appropriate ICD therapy. In a multivariate model using a forward selection algorithm, only a history of nonsustained ventricular tachycardia detected on 24-hour Holter monitoring (p = 0.001), a decreased LVEF (p = 0.001), and digitalis therapy (p = 0.08) remained independent predictors of ventricular tachyarrhythmia requiring appropriate ICD therapy. Patients with 0 (n = 46), 1 (n = 36), 2 (n = 73), and 3 (n = 14) risk factors for appropriate ICD therapy had a 7%, 14%, 27%, and 64% incidence of appropriate ICD therapy ( Figure 2 ). The incidence of appropriate ICD therapy for fast ventricular tachycardia or ventricular fibrillation was 0%, 6%, 10%, and 43% for patients with 0 (n = 46), 1 (n = 36), 2 (n = 73), and 3 (n = 14) risk factors for appropriate ICD therapy, respectively ( Figure 2 ).

Table 2

Cox regression analyses of clinical and echocardiographic variables: predictors of ventricular tachyarrhythmia (appropriate implantable cardioverter-defibrillator therapy)

Variable	Univariables in the Equation		Multivariables in the Equation
	HR (95% CI)	p Value	HR (95% CI)	p Value
History of nonsustained ventricular tachycardia	3.060 (1.555–6.020)	0.001	3.681 (1.647–8.230)	0.001
Use of digitalis	2.399 (1.233–4.668)	0.010	1.952 (0.920–4.142)	0.082
Left ventricular ejection fraction (%)	0.742 (0.645–0.853)	0.000	0.750 (0.648–0.869)	0.000
E/E′ ratio	1.081 (1.022–1.143)	0.006	1.031 (0.958–10.110)	0.415

CI = confidence interval; HR = hazard ratio.

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