Rick Schreurs

153 Summary SUMMARY Cardiac conductions disorders like left bundle branch block (LBBB) and first-degree atrioventricular (AV)-block may lead to diminished cardiac function and can ultimately lead to heart failure. Patients with LBBB with increased QRS duration (>130ms) and reduced left ventricular (LV) ejection fraction (<35%) are candidates for cardiac resynchronization therapy (CRT). The goal of CRT is to synchronize the electrical activation of both ventricles, ultimately leading to improved cardiac function. Patients benefit exists of decreased mortality and hospitalization rate and an increase in quality of life. However, at the individual level approximately a quarter of patients fulfilling the abovementioned criteria do not respond to this therapy. The response to CRT depends on several factors, one of them being the pacemaker setting for timing of atrial and ventricular activation. Optimization of these settings is often performed only once after the implantation of the pacemaker, but algorithms that enable ambulatory optimization have been introduced in recent years. Most of them are based on ECG or device-derived electrograms (like SyncAV, Adaptive CRT and QuickOpt), while there is one algorithm available that employs mechanical information derived from an accelerometer in a pacemaker lead (SonR). The application of CRT for patients with a wide QRS complex is well established, while considerably less is known about its use in patients with prolonged PR-interval (first-degree AV-block) and narrow QRS complex. The promising data here are until now only derived from subanalyses of randomized CRT-trials. The thesis as presented here has two main objectives. The first aim is to examine whether CRT also improves cardiac function in patients and animals with prolonged PR-interval and whether first-degree AV-block could be a new indication for this form of pacing therapy. The second objective is to explore new ways of optimizing pacemaker setting in CRT and relate them to acute hemodynamic outcome. In chapter 2 we start by reviewing the electrophysiological and hemodynamic changes that occur during CRT in both animals and patients. LBBB leads to interventricular dyssynchrony (IVD) with prolonged total activation time of the ventricles and causes wasted work. Next, we explain how CRT reduces this electrical dyssynchrony and results in an acute improvement of stroke volume and LV contractility (LV dP/dt max ). We continue by describing how pacing locations and alternative pacing modalities like multipoint and endocardial pacing influence the effect of CRT. Finally, the importance of optimizing pacemaker settings is explored by showing hemodynamic changes during a great variety of AV- and VV-delays. The goal of chapter 3 is to examine the effect of restoring AV-coupling in hearts with first- degree AV-block using animal experiments, computer modeling and patient studies. In the animal experiment we show that optimizing the AV-delay using biventricular (BiV) pacing, results in a significant increase in mean arterial pressure and cardiac output, compared to the reference setting with a prolonged AV-delay of 300ms. Similar results are found in heart S