The study included 82 consecutive HF patients, who underwent CRT implantation at Cardiology Department at Hospital of Lithuanian University of Health Sciences Kaunas Clinics, between January 2009 and December 2011. All patients met the following inclusion criteria: NYHA class III or IV despite optimal medical therapy, LBBB, QRS width ≥ 120 ms and LVEF ≤ 35%. Patients with previously implanted pacemaker or defibrillator, recent myocardial infarction or coronary artery bypass graft surgery (≤6 months), or decompensated HF were excluded.

Ischemic cardiomyopathy (ICMP) was diagnosed in patients with previous myocardial infarction, or coronary artery bypass graft surgery, or percutaneous coronary intervention (balloon and/or stent angioplasty), or angiografically documented significant coronary artery disease and history of angina pectoris.

All patients were in sinus rhythm, electrocardiogram at rest was recorded (measured on surface electrocardiogram leads, at a paper speed of 25 mm/s) and QRS duration was measured at baseline and after 12 months post CRT implantation.

Clinical evaluation and two-dimensional echocardiography were performed before CRT device implantation and repeated at 12 months of follow-up. Clinical evaluation included assessment of NYHA class and performance of 6 minute walk test (6-MWT). At 12 months of follow-up, patients, who achieved improvement in NYHA of at least 1 class and a ≥ 15% increase in 6-MWT, were classified as clinical responders.

Before the study all patients signed informed consent approved by Local Ethics Committee (Kaunas Regional Biomedical Research Ethics Committee, ref. n. BE-2-54).

Blood samples for uric acid concentration were taken one to two days before CRT implantation and were analysed in the laboratory of Lithuanian University of Health Sciences Hospital Kaunas Clinics.

Echocardiography was performed in all patients at rest in the lateral decubitus position, at baseline before device implantation and was repeated at 12-months follow-up. Transthoracic Doppler echocardiography was performed using a GE Vivid 7 system (GE Vingmed Ultrasound AS N-3190, Horten, Norway) with an M4S transducer. Standard transthoracic echocardiographic measurements were performed according to the Guidelines of the American Society of Echocardiography [6]. A standard evaluation of LV volumes was performed, and LVEF was calculated according to the Simpson’s equation. To minimize variability of measurements, all echo/Doppler evaluations were performed and analysed by the same physician, also the same transducer position and sample volume location were maintained throughout the recordings. All images were digitally stored for off-line analysis (EchoPac V.6.0.0; GE Vingmed).

Echocardiographic response was defined as an increase in LVEF of ≥ 5% and decrease of left ventricular end-systolic volume (LVESV) and left ventricular end-diastolic volume (LVEDV) by ≥ 15%.

CRT implantation was performed through the subclavian or axillary vein access. Coronary sinus venogram was obtained using balloon catheter. LV lead was inserted into the posterolateral vein, which was selected according to anatomical characteristics of the vessels enter the appropriate electrode. The optimal position of the LV lead was defined according to LV lead impedance, threshold and no nervus phrenicus stimulation. The right atrial lead was conventionally positioned in the right atrium appendage and right ventricular lead in to the ventricular septum or right ventricular apex. Finally, all leads were connected to a dual chamber biventricular CRT device. The optimal atrioventricular (AV) delay was determined during simultaneous biventricular pacing by the simplified mitral inflow method: a long AV interval (200 ms) was programmed and gradually reduced by 20 ms, until A-wave truncation was observed.

Statistical analysis was performed using IBM SPSS statistical software (SPSS v.21.0 for Mac OS X). Normally distributed continuous variables were presented as mean ± SD and were compared using Student t-test for paired and unpaired data. Statistical significance of differences between groups was analysed by Mann–Whitney U test for non-parametric continuous variables and categorical variables were compared using the maximum likelihood (ML) Chi-square test. Correlation between continuous variables was analysed by Spearman rank correlation test. Receiver operating characteristic (ROC) curve was used to determine a cut-off point of categorical predictors. Variables significant in univariate analysis were added to logistic regression to determine independent predictors of response to CRT. Stepwise variable selection with forward selection and backward elimination demonstrated identical results. Precision of the model was verified with the Hosmer-Lemeshow test of goodness of fit test. A p value < 0.05 was considered statistically significant.

At 12 months follow-up 54 (71.1%) of patients had a significant improvement in NYHA class (p < 0.001). Distribution of NYHA class at baseline and after 12 months post CRT implantation is provided in Figure 2. An increase in 6-MWT by ≥ 15% was observed in 57 (75%) patients (p = 0.001). Mean increase in 6-MWT post CRT was 121.2 ± 66.1 m in clinical responders and 11.3 ± 27 m in non-responders (p = 0.001). Combined clinical response (improvement in NYHA class ≥ 1 class and/or ≥ 15% increase in the 6-MWT) was achieved in 63 (82.9%) patients (Table 2).

Compared to responders, non-responders were more likely to have ischemic cardiomyopathy (63.5% vs 36.5%, p = 0.01). Echocardiographic response was observed in 87.3% combined clinical responders (p = 0.03).

At 12 months of follow-up, LVEF increase of ≥ 5% was observed in 81.6% patients. Increase in LVEF was higher in patients with non-ICMP (11.2 ± 8.0 vs 7.7 ± 7.1; p = 0.04). Combined echocardiographic response (LVEF increase ≥ 5%, and/or LVESV decrease ≥ 15% and/or LVEDV decrease ≥15%) was established in 81.6% of the overall study population (Table 2). Compared to responders, non-responders were more likely to have lower LVEF, larger LVEDD, LVESD diameters and LV and LA volumes, AF and VT episodes at baseline, although only LV diameters, LAV, AF, VT achieved statistical significance (Table 3). Also, a negative association of warfarin use and echocardiographic response was found (p = 0.01). No significant differences in QRS duration, gender, age and CRT type between echocardiographic responders and non-responders were found.

Significant univariate predictors of favourable echocardiographic response after 12 months included smaller LVEDD (OR 0.89, 95% CI 0.82 - 0.97; p = 0.01) and LVESD (OR 0.91, 95% CI 0.85 - 0.98; p = 0.01). Lower uric acid concentration was associated with better echocardiographic response (OR 0.99, 95% CI 0.99 - 1.0; p = 0.01). The precision of the model was verified with the Hosmer-Lemeshow test of goodness of fit test (p = 0.1).

Non-ischemic HF etiology was an independent predictor of a positive clinical response (OR 4.89, 95% CI 1.39 - 17.15; p = 0.01). The precision of the model was verified with the Hosmer-Lemeshow test of goodness of fit test (p = 0.49).

Only four parameters (Table 4) selected by regression analysis reached statistically significant cut-off values in ROC analyses, with sensitivity ranging from 59% to 81% and specificity from 61% to 77% (Figure 3).

Multiple stepwise regression analysis identified LVEDD of less than 75 mm (OR 5.60, 95% CI 1.36 - 18.61; p = 0.01) as the strongest independent predictor of favourable echocardiographic response, and non-ischemic HF etiology as the independent predictor of positive clinical response (OR 4.88, 95% CI 1.39 - 17.15; p = 0.01).