Cardiac resynchronization is a recommended therapy for patients with advanced heart failure, under optimized medical treatment with reduced left ventricular ejection fraction and prolonged QRS, nevertheless, still 30% of the population do not respond to standard biventricular implantation.

Non-response can be explained by a combination of factors including sub-optimal patient selection, placement of the pacing lead over a zone of slow conduction, insufficient correction of mechanical dyssynchrony including sub-optimal lead implantation. Few data distinguish true non-responders from patients in which effective resynchronization was not delivered through standard biventricular implantation.

Triple-site cardiac resynchronization pacing (stimulation at three ventricular sites) has been proposed to improve synchrony and thus the response rate in (Cardiac Resynchronisation Therapy) CRT recipients.

The frequent failure of CRT in non-Left Bundle Branch Block (non-LBBB) patients is suspected to be due to more complex and heterogeneous forms of electrical/mechanical dyssynchronies needing more complex and individualized pacing configurations to be corrected.

Acute studies during implant show that standard biventricular pacing provides optimal mechanical improvement only in a minority of patients. In a peri-operative echo-guided leads placement procedure most of non-improved patients could be successfully mechanically resynchronized. A significant number of patients required optimized placement of right ventricular (RV) lead and/or triple-site configurations.

These studies led to the hypothesis that more complex and individualized pacing configurations (Triple-site biventricular) might increase the number of responders to CRT.

To assess this hypothesis, this study will be conducted in Class II-ambulatory IV patients indicated for CRT with wide QRS (≥ 140 ms) and non-LBBB. Patients will be randomized in a 1:1 configuration:

• Standard biventricular pacing (1 right ventricular/1 left ventricular (1RV/1LV)) through classical implantation procedure without peri-operative optimization
• Triple-site biventricular pacing with individual optimization of the placement of the third lead by peri-operative echo guidance.

The objective of the optimization process is to improve LV efficiency and to decrease the left pre-ejection interval (LPEI, defined as the time interval between the onset of QRS and the onset of LV ejection) as much as possible compared with a standard biventricular configuration by moving a second right ventricular lead at different locations.

LPEI is simple to measure, with good inter- and intra-observer reproducibility and its utility has previously been strongly suggested.

Reduction in LPEI results in decreased duration of ventricular systole and is associated with improved LV filling and reduced interventricular delay.

The primary objective of this study is to demonstrate that individually optimized, triple-site biventricular pacing is superior to standard biventricular pacing in reverse ventricular modeling as demonstrated by Echo Left Ventricle End-Systolic Volume (LVESV) at 1 year in patients with non-LBBB morphology without increasing the risk of serious procedure and/or device related adverse events at 30 days.

Inclusion Criteria:

• Age > 18 years
• Stable heart failure with New York Heart Association (NYHA) functional class II, III or ambulatory IV
• Stable optimized medical regimen according to medical guidelines (No change in heart failure medication for at least 1 month prior to enrollment)
• Left ventricular ejection fraction (LVEF) ≤ 35%
• Intrinsic QRS duration ≥ 140 msec
• Non-typical left bundle branch block (LBBB) morphology on 12-lead surface ECG
• Signed and dated informed consent

Exclusion Criteria:

• Typical LBBB according to Strauss criteria
• Unstable heart failure
• Permanent or long-lasting persistent Atrial Fibrillation
• Unstable angina, acute Myocardial Infarction (MI), Coronary Artery Bypass-Grafting (CABG), or Percutaneous Transluminal Coronary Angioplasty (PTCA) within 90 days prior to enrollment (intervention)
• Conventional pacemaker indication
• Previous implant with a pacemaker or an Implantable Cardioverter-Defibrillator (ICD)
• Renal Failure (Glomerular filtration rate (GFR) < 30 ml/min/1.73m2)
• Pregnant women
• Already included in another clinical study that could confound the results of this study
• Life expectancy < 12 months
• Mechanical heart valve or indication for valve repair or replacement
• Recent Cerebro-Vascular Accident (CVA) or Transient Ischemic Attack (TIA) (within the previous 3 months)
• Heart transplant