a.zweerink

Selection criteria for Cardiac Resynchronization Therapy (CRT) are mainly based on the morphology and time duration of the QRS complex. Following guideline criteria, however, approximately one‐third of the patients implanted with CRT will not respond favorably. Over the last two decades, numerous studies have sought to determine variables associated with improved CRT response. It is now widely accepted that these factors include strict left bundle branch block (LBBB) morphology, longer QRS duration (QRSd), sinus rhythm, non‐ischemic etiology, younger age and female gender. On the other hand, consensus has still not been reached on the predictive value of cardiac imaging techniques in CRT candidates. On this matter, the role of myocardial strain parameters is especially debated. After the decision to implant CRT has been made, the question arises if device optimization strategies increases benefit from the therapy. This, again, is topic of significant debate and requires further research. The present thesis aims to investigate two strategies that can potentially increase effectiveness of CRT: (i) improved selection of potential responders prior to implantation using cardiac imaging techniques and (ii) optimized device settings afterwards in order to maximize hemodynamic benefits. Both strategies will be discussed below in part one (patient selection) and part two (device optimization), respectively.

Part IA Normalization of QRS duration to LV dimension
CRT provides electrical therapy for heart failure in the form of pacing pulses that resynchronize the ventricular contraction sequence affected by distorted electrical conduction. Being an electrical therapy for an electrical disease, it is not surprising that patient selection for CRT is guided by the electrical parameter QRSd. Increased QRSd, however, may arise from slow cell‐to‐cell conduction (i.e. true LBBB), or by increased conduction path length (dilation of the failing heart). Part IA of the thesis evaluates the theoretical concept that incorporation of left ventricular (LV) structural measurements in the assessment of electrical delay, by normalizing QRSd to LV size, improves prediction of CRT response. Chapter two provides a proof‐of‐principle study amongst thirty‐two patients who underwent CMR imaging before CRT implantation followed by invasive pressure‐volume loop measurements to obtain acute LV pump function changes during CRT. Normalization of QRSd to LV dimension (i.e. QRSd divided by LV dimension) improved correlation with acute LV pump function improvement by CRT. Different metrics of LV size (volumes; diameter; length; mass) all showed similar results in relation to QRSd and CRT response. In addition, women achieved more pump function improvement during CRT compared to men. This sex‐specific difference in CRT outcome may be partly ascribed to differences in LV size between both sexes. As the female heart is generally smaller, women have shorter QRSd compared to men. In order to reach the cut‐off QRSd value for CRT (guidelines are identical for men and women), female hearts will have more conduction delay compared to male hearts and might therefore be more amenable for successful treatment with CRT. These results were confirmed by Varma et al. who showed in a subsequent study that sex‐specific differences in the QRSd‐response relationship resolved after QRSd normalization to LV dimension.(1) Subsequently, chapter three extends the role of QRSd normalization to the prediction of clinical endpoints in a large population of two‐hundred‐fifty patients eligible for CRT. QRSd normalization improved prediction of survival after CRT implantation. Moreover, normalized QRSd yielded prognostic value in a prediction model together with age, atrial fibrillation, renal function and heart failure etiology. These findings indicate that a multi‐modality approach including electrical, structural and clinical parameters could potentially improve patient selection for CRT.

Part IB Myocardial strain imaging
In CRT, electrical resynchronization leads to LV pump function improvement by mechanical re‐coordination of contraction between different regions of the LV walls, especially between the septum and lateral wall. A more homogenous work distribution increases LV pump function efficiency and results in larger external work to eject blood.(2) Therefore, the purpose of CRT may be referred to as mechanical re‐coordination rather than electrical resynchronization therapy. This concept is supported by results from the PROSPECT trial where numerous dyssynchrony parameters were unable to predict CRT outcome.(3) Whether detection of mechanical discoordination (systolic stretching of segments) rather than dyssynchrony (regional timing differences between segments) yields additional value in the prediction of LV pump function improvement after CRT remains to be proven. Part 1B of this thesis evaluates the role of myocardial strain imaging to improve patient selection for CRT. In chapter four regional strain measurements are combined with LV pressure curves to calculate myocardial work distribution.(4) Contribution of the septum to total LV work varies widely in CRT candidates with LBBB, and the lower the septal contribution to total myocardial work (or the higher the septal waste) at baseline the higher the acute improvement in pump function that can be achieved during CRT. These results are confirmed in a subsequent study by Vecera et al. who showed that wasted septal work strongly predicted CRT response after one year.(5) Myocardial strain imaging therefore provides an insight in the negative effect of LBBB on myocardial work and energy utilization, and reflects the potential benefit that can be achieved by CRT. In our small‐scale study, all patients underwent CMR tagging (CMR‐TAG) to obtain high‐quality regional strain curves. Availability of CMR‐TAG, however, is very limited in clinical practice. Therefore, the role of other non‐invasive imaging techniques such as CMR feature tracking (CMR‐FT) and speckle tracking echocardiography (STE) is of interest. Chapter five provides a comparison of strain values obtained with CMR‐FT and STE versus ‘gold standard’ CMR‐TAG. Twenty‐seven CRT‐candidates, prospectively included in the Markers And Response to CRT (MARC) study, underwent CMR imaging and echocardiographic examination. Both CMR‐FT and STE techniques showed to be potentially valuable alternatives for CMR‐TAG, especially in the evaluation of mechanical discoordination. Subsequently, chapter six provides echocardiographic follow‐up data in these patients allowing to compare predictive value for CRT response of different strain parameters using multiple imaging techniques. Of all strain parameters, measuring end‐systolic septal strain (ESSsep) showed strongest relation with CRT response after one year, irrespective of imaging technique. ESSsep reflects fiber length change of the septum throughout systole. Detection of septal discoordination with higher ESSsep values (i.e. septal stretching instead of contraction) at baseline was associated with more extensive reverse remodeling after CRT. Moreover, measuring ESSsep by any available imaging technique showed to be additive to present guideline criteria (QRS morphology; QRSd). The application of strain imaging has yet not been included in daily practice, but it is likely to become a useful application when evaluating heart failure patients for CRT implantation. This may be of particular interest in CRT candidates with unfavorable patient characteristics (non‐strict LBBB morphology, shorter QRSd), in whom benefit from CRT is doubted. Subsequently, the novel segment length in cine (SLICE) strain technique is introduced. The purpose of SLICE is to provide the clinician a simplified strain analysis technique to estimate benefit from CRT by analyzing standard CMR cine images, based on previous findings. More specifically, SLICE consists of a series of manual frame‐to‐frame segment length measurements between anatomic landmarks on standard short‐axis CMR cines. In a first step, SLICE was validated to ‘gold standard’ CMR tagging in twenty‐seven patients of the MARC population (chapter seven). SLICE‐derived strain values showed good agreement with CMR‐TAG and good‐to‐excellent reproducibility. An advantage of the SLICE technique is that it obviates the need for additional CMR scanning sequences (i.e. CMR‐TAG) or commercial post‐processing software tools (i.e. CMR‐FT). However, strain parameters that require SLICE analysis of the entire strain curve may take a long processing time (up to 60 minutes). Subsequently, SLICE analysis was performed in fifty‐seven MARC patients who underwent standard CMR examination in chapter eight. Predictive value of different SLICE‐derived strain parameters were compared with ESSsep showing the strongest relation to reverse remodeling after CRT. These results are in line with earlier CMR‐TAG, CMR‐FT and STE findings, indicating that ESSsep is a robust predictor of CRT response. In a multivariable analysis, ESSsep showed to be an independent predictor of CRT response together with age at implant and QRSAREA derived by vector‐loop ECG analysis. A great advantage of the ESSsep parameter is that it requires only two (end‐systolic and end‐diastolic) segment length measurements and can be performed in under ten minutes, making this a fast and straightforward technique. Lastly, the role of the SLICE‐ESSsep measurement was extended to the prediction of clinical outcome after CRT in a large population of CRT candidates. Chapter nine presents a two‐center study including two‐hundred‐eighteen patients who underwent CMR imaging including late gadolinium enhancement (LGE) prior to CRT implantation. The main findings of this study were that a positive ESSsep at baseline was associated with two‐ to three‐fold lower rate of all‐cause mortality and HF events after CRT implantation. However, predictive value ESSsep was confounded by regional scarring of the septum, indicating that SLICE should be combined with LGE to exclude septal scarring as the cause of septal stretching. In clinical practice, CMR imaging is increasingly used to screen candidates by measuring LVEF combined with LGE imaging to guide LV lead placement.(6) Additional SLICE analysis of the septum could potentially improve diagnostic yield of CMR and guide future patient selection for CRT.

Part II Device optimization
In part two of this thesis several CRT optimization strategies are evaluated. The first two chapters are part of the OPTICARE‐QLV (Optimization of Cardiac Resynchronization Therapy with a Quadripolar Left Ventricular Lead) study. The main aim of the OPTICARE‐QLV study was to relate electrical parameters (Q on surface ECG to LV sensing interval, QLV) to acute hemodynamic response in CRT using quadripolar LV leads as described in chapter ten. Forty‐eight heart failure patients with LBBB were prospectively enrolled and underwent both electrical and invasive pressure‐volume loop measurements directly after CRT implantation. Although there was a large variation in acute hemodynamic CRT response between different electrodes of the quadripolar lead, electrical parameters (QLV; QLV/QRSd) were unable to identify the most beneficial pacing electrode of a quadripolar lead. Therefore, optimization of the pacing configuration of CRT with a quadripolar LV lead should rely on functional assessment of cardiac function, instead of local electrical delay. Acute CRT response can be assessed by invasive hemodynamic testing in order to optimize device settings. Typically, the maximum rate of LV pressure rise (dP/dtmax) is used as an index of ventricular performance. Alternatively, stroke work (SW) can be measured from pressure‐volume loops. Chapter eleven evaluates the acute effect of dP/dtmax versus SW guided CRT optimization, and relates acute hemodynamic changes to long‐term CRT response. It was demonstrated that hemodynamic optimization of the LV pacing electrode and AV delay in CRT with quadripolar leads result in approximately one‐third additional improvement in the parameter used for optimization (either dP/dtmax or SW). Improvement in one parameter, however, did not coincide with the other indicating two different mechanisms. Whereas dP/dtmax optimization favored LV contractility, SW optimization improved ventricular‐arterial coupling leading to higher stroke volume and ejection. Acute changes in SW showed high predictive value for prediction of long‐term CRT response, whereas predictive value of dP/dtmax change was non‐significant. Pressure‐volume guided hemodynamic optimization may therefore be considered a potential strategy to use the full potential of CRT with quadripolar leads. Lastly, chapter twelve summarizes recent literature on the role of cardiac implantable electronic devices (ICD; CRT) for treatment of chronotropic incompetence (CI) in HF patients. A substantial part of the HF population is presently equipped with an implanted device offering the unique opportunity to study HR dynamics and deliver pacemaker therapy. Rate‐adaptive pacing has shown favorable effects on both exercise capacity and survival in a well selected subset of HF patients with manifest CI. Advances in device technology by incorporating additional physiological activity sensors and the detection of CI using a device histogram‐based heart rate score might improve future treatment of CI in the HF population.

Clinical implications
Patients with HF, reduced ejection fraction and wide QRS on the electrocardiogram are recommended for CRT by the present guidelines. Electrical resynchronization typically results in narrowing of the QRS complex and leads to LV pump function improvement by mechanical re‐coordination of LV contraction. Previous studies showed that CRT candidates with narrow QRS complexes yield no benefit (or derived harm) from CRT.(7) On the other hand, not every patient with wide QRS complex benefits from the therapy. Therefore additional selection criterion are needed to reduce the rate of non‐response. Current guidelines on CRT justify the use of cardiac imaging only to estimate LV ejection fraction. However, information on cardiac dimensions could potentially add to the predictive value of QRS duration as demonstrated in the first part of the thesis (QRSd normalization). In addition, assessment of cardiac mechanics may also be used to further improve patient selection for CRT. Although parameters of mechanical dyssynchrony (regional timing differences) showed inconsistent results, mechanical discoordination (systolic stretching) of the septum provides added value to guideline parameters in the prediction of LV pump function improvement after CRT, irrespective of imaging technique. When comparing different imaging techniques, CMR has unique advantages over echocardiography in accurately and reproducibly quantifying LV size and function and by enabling the detection of myocardial scar tissue. Additional SLICE analysis of the septum further increases diagnostic yield of CMR and may therefore be considered the first‐choice imaging modality in the work‐up of CRT candidates. Performing CMR imaging is in particular of interest in patients in whom benefit from CRT is doubted (old age, ischemic cardiomyopathy, non‐strict LBBB morphology). In case CMR imaging shows severe LV dilatation (low QRSd/LVEDV ratio), lack of septal discoordination (negative SLICE‐ESSsep), and extensive myocardial scarring (especially of the septum), CRT may be withheld in these patients. Because different types of parameters yielded predictive value in multivariable analysis, a multimodality work‐up including clinical parameters, electrical (ECG) assessment and mechanical (CMR) analysis seems legitimate before undergoing invasive CRT implantation. After the decision has been made for CRT implantation, device optimization strategies may be considered to use the full potential of CRT with quadripolar leads. Electrical (i.e. QRS duration; QLV) and echocardiographic (i.e. stroke volume; mitral flow) parameters are most widely used in clinical practice although convincing scientific evidence for these methods is lacking. Pressure‐volume guided hemodynamic optimization in CRT using a conductance catheter results in approximately one‐third additional LV pump function improvement on top of conventional CRT. Although invasive hemodynamic optimization is unfeasible in clinical practice, the concept of volume (instead of pressure) ‐based optimization may guide future implementation of non‐invasive surrogates such as intra‐cardiac impedance measured between leads, or CRT stimulation in the CMR environment (see future perspectives). Lastly, reversal of CI by rate‐adaptive pacing algorithms may increase clinical benefit from device implantation. Strategies to improve CRT as investigated in the thesis are summarized in figure 1.