This research focuses on the role of abnormal electrical conduction and contraction (“dyssynchrony”) on cardiac pump function and on the interaction between the different cell types in the heart in the development of heart failure.Abnormal electrical conduction imposes major disturbances in the coordination of contraction (“dyssynchrony”) and causes considerable redistribution of mechanical load within the ventricles. As a consequence, a series of myocardial adaptation processes occur, which eventually only worsen overall ventricular pump function. 

Since a decade, heart failure patients with dyssynchrony are treated with Cardiac Resynchronization Therapy (CRT): pacing of the right and left ventricle simultaneously. Although the outcome in large randomized clinical trials is very positive, there is still a large variability in the outcome between patients and between centers. Therefore, a major focus of the research group, headed by Prof. Frits Prinzen, is to better understand the mechanisms of CRT and how it can be improved. Points of attention are better diagnosis of the patient and better application of the therapy. Possible improvements of the diagnosis are more detailed analysis of ECG and echocardiographic measurements and the use of various biomarkers in the blood. Application of CRT may be improved by using better positioning of the pacemaker electrodes, using more pacemaker electrodes and better timing of stimulation of both ventricles. These issues are studied in experimental animals as well as patients and, in collaboration with the department of Biomedical Engineering, computer models.

Our group:

Main research questions:

• Finding better site(s) for pacing in CRT, such as the endocardium of the left ventricle.
• Optimize the time interval between stimulation of the atrium, right and left ventricle using novel, smart tools.
• Investigate the interaction between LBBB and other abnormalities, like myocardial infarction and mitral valve insufficiency.
• Investigate cellular and molecular adaptations in dyssynchronous hearts, a study that is performed in close collaboration with Dr. Frans van Nieuwenhoven.
• Search biomarkers that better predict the success of CRT. Biomarkers include electrical, mechanical and molecular markers.

These questions are investigated using measurements in animals as well as patients and using mathematical models of the heart. 

Animal models

In the late 1990s the group has, as first in the world, developed a model for inducing left bundle branch block, the major source of dyssynchrony, in dogs. Several publications have proven that this large animal model replicates the clinical situation quite well. Consequently, findings in the animal studies proved to be applicable in patients.

Highly advanced measurements in this large animal model can be performed in our fully equipped operating rooms, run by expert technicians. The facilities allow performing a wide range of sterile surgeries and innovative measurements on cardiac electrophysiology, mechanics, perfusion and hemodynamics.
 

Electrical mapping

Using a combination of multi-electrode bands around the ventricles, multipolar catheters and plunge electrodes, detailed three dimensional electrical maps of activation and repolarization are determined.

In the figure above, data from the electrical maps is converted into color-coded 3D-maps of electrical activation in a normal dog heart and in one with LBBB.

Hemodynamics

Pressure-Volume loops for ultimate hemodynamic analysis, for example about the effect of CRT.

Echocardiography

All clinically used echocardiographic measurements are also performed in the dogs, ranging from M-mode to B-mode, Doppler and speckle tracking. The figure shows measurements in a dog with LBBB.

MRI

Highly detailed anatomy and geometry of the heart as well as infarct size (late-enhancement gadolinium) are derived from MRI scans, using a clinical 1.5T scanner. Also, MRI tagging is performed for highly detailed measurement of myocardial deformation (“strains”).  

Clinical studies

These studies are performed in collaboration with Dr. Kevin Vernooy and Yuri Blaauw (cardiologists).
Important studies are the role of the vectorcardiogram in optimization of CRT response. The figure below shows that during CRT the size of the vector loop depends on the atrioventricular delay. The delay yielding smallest vector loops also provides the best hemodynamic performance. The approach to use vectorcardiography for CRT optimization is novel and promising, due to its ease. 

For finding the best site of pacing on the left ventricle the electrical activation of the coronary sinus (CS) and its tributaries is assessed intra-operatively using 3D electro-anatomic mapping (Ensite Navx, with a small guidewire to sense activation and to test pacing performance (thresholds, phrenic nerve stimulation). In the figure the red region indicates scar, the coronary veins are color-coded based on measurement of activation time (blue=late) and dots indicate pacing, blue dots indicate sites where pacing results in phrenic nerve stimulation.

Computer simulations

These studies are performed in collaboration with the Department of Biomedical Engineering (Prof. Delhaas, Dr. Lumens).

Two approaches are used:

• A geometrically simple model (“CircAdapt”), that enables realistic and almost real-time beat-to-beat simulation of cardiovascular system mechanics and hemodynamics under a wide variety of (patho-) physiological conditions such as left bundle branch block and ventricular pacing. Using this model contribution of left and right ventricular walls to total pump function can be estimated as well as the contribution of each wall segment to the total output of the heart. Muscle fiber shortening patterns of individual segments proved to closely mimick those in patients receiving CRT (see figure). Currently the CircAdapt model is being made patient-specific, which implies that data from the patient are entered in the model. This version of the model can then be used to “test” pacing strategies in silico.

• A finite element model of the heart. This model can approach the real anatomy closely. It is composed of thousands of elements, each of which can be given specific properties, like orientation, stiffness, and contractility of the muscle fibers as well as the sequence of electrical activation. This model is capable to explore the influence of many factors on the benefit of CRT.
  
  

Collaboration with Lugano (CH)

The group has a strong collaboration with the Cardiocentro Ticino (CCT, cardiovascular clinic; Prof. Auricchio) and with the Università della Svizzera Italiana

(USI, Prof. Krause). While highly advanced measurements in patients are performed at CCT, advanced computer modeling studies are performed at USI. The latter is possible because of the presence of a Monte Rosa supercomputer that is capable to solve very complicated problems.

Examples of studies are the simulation of the complete cardiac electrophysiology (from ion channel to surface ECG) in a model with up to 2 million elements and the analysis of electrophysiological and mechanical parameters of electro-anatomical measuring systems (e.g. NOGA).

The figure shows the close relationship between the computer simulations and clinical and laboratory measurements, the latter performed primarily in Maastricht.