Rick Schreurs

129 General discussion GENERAL DISCUSSION The review of the literature on cardiac resynchronization therapy (CRT) in chapter 2 describes what is known about the electrophysiological and hemodynamic changes that occur during CRT in both animals and patients. It starts by explaining how left bundle branch block (LBBB) induced dyssynchronous contraction of the heart results in impaired cardiac function because of an increase in wasted work. This also explains how CRT is able to electromechanically resynchronize the contraction of the ventricles and improve pump function. At least two factors are important for achieving the best possible benefit of CRT: the presence of clear dyssynchrony (like LBBB) and the use of optimal timing between atrial and ventricular stimulation. This thesis investigated 1) whether CRT may be able to improve ventricular filling and cardiac function in hearts with prolonged atrioventricular delay (first degree AV-block) in the absence of ventricular dyssynchrony ( chapters 3 and chapter 4 ) and 2) novel ways to optimize pacemaker settings in order to create the best possible ventricular filling as well as ventricular resynchronization ( chapters 5 and chapter 6 ). Where CRT is currently only indicated for heart failure patients with ventricular dyssynchrony (preferably LBBB), the results presented in chapter 3 provide strong evidence that restoring proper AV-coupling in first degree AV-block can improve hemodynamic function. In heart failure patients and animals optimizing the AV-delay using biventricular (BiV) pacing resulted in an increase in mean arterial pressure and stroke volume. This was achieved by an improvement in ventricular filling. Optimization of timing of passive (E) and active (A) ventricular filling resulted in an increase of forward flow over the mitral valve and a decrease in diastolic mitral regurgitation (MR). Computer simulations using the CircAdapt model were used to further unravel the influence of ventricular filling on the hemodynamic outcome. Furthermore, we showed that right ventricular (RV) pacing-induced dyssynchrony abrogates the hemodynamic benefits of better AV-coupling and should therefore be avoided. In conclusion, BiV pacing might be therapeutic option in patients with heart failure and prolonged PR-interval that is currently not part of the guidelines. Chapter 4 uses the porcine model of total AV-block to investigate the interplay between interatrial delay (IAD, dependent on among other atrial sensing or atrial pacing) and interventricular dyssynchrony (IVD, influenced by ventricular pacing site) on filling of both ventricles. While commonly AV-delay is only considered for the LV, the serial coupling between the pulmonary and systemic circulation makes it likely that proper filling of both ventricles is important. The results in this study clearly show that the optimal AV-delay, quantified as the AV-delay with the highest relative increase in cardiac output, differs between the left side and right side of the heart. We propose the mean effective AV-delay as an alternative parameter, that is based on timings of mechanical activation of all four heart chambers, to predict optimal BiV function. We showed that this parameter can estimate 7