Latest ventricular INCB18424 activation was found epicardially in the LV lateral wall with individual differences in the orientation of the area of latest activation. This inhomogeneity may reflect the individual differences in the underlying substrate of heart failure. This typical ventricular activation pattern in LBBB patients may be due to a slowing of conduction within the intrinsic conduction system, a prolongation of intramural activation times because of areas of slow conduction tissue or altered cell-to-cell coupling, which therefore results in a kind of functional block. Interestingly, this activation pattern was also visible in control patients during RV pacing. This indicates that also RV pacing in patients without structural heart disease results in similar activation patterns comparable to CHF patients with LBBB. This kind of functional block in the LV is dependent on pacing site and can be reversed by biventricular stimulation. Due to impaired conduction abilities and cell-to-cell coupling properties unphysiologic RV pacing show more detrimental effects in CHF patients as compared to RV pacing in patients without structural heart disease. Patients without structural heart disease may be able to temporarily compensate the negative effects of RV pacing on septal and left ventricular depolarization whereas in CHF patients the functional reserve is limited and the negative effects on hemodynamic behavior are immediately obvious. However, in CHF patients deterioration of ventricular activation due to complete LBBB can be reversed by stimulation close to the site of latest left ventricular activation. Most of the time this can be achieved using an epicardial lead which is positioned in a posterolateral branch of the coronary veins. NICE facilitates the identification of target sites for optimal lead placement and may also be helpful in determining responders to CRT. Current guidelines for selection of patients for CRT are based on QRS duration and NICE may have the potential to help to refine this process as it enables visualization of ventricular electroanatomic activation noninvasively. Nevertheless, simultaneous endocardial RV and epicardial LV pacing during CRT results in a different activation pattern as compared to native activation via the intrinsic conduction system. There are some controversial data about potential proarhythmogenic effects of CRT due to the reversal of epicardial and endocardial activation. However, prospective randomized studies did not find any excess mortality due to sudden death during biventricular pacing. Nevertheless, patients with reduced ventricular function have an increased risk of malignant ventricular tachyarrhythmias. Catheter ablation of the substrate of such a tachycardia is feasible but the procedure can be complicated if the focus of the arrhythmia is located within the epicardium. NICE has the potential to discriminate whether it is of epicardial or endocardial origin and it may therefore be useful for planning such procedures.