Due to copyright issues, an electronic copy of the thesis must be ordered from the faculty. For the faculty to have time to process the order, the order must be received by the faculty at the latest 2 days before the public defence. Orders received later than 2 days before the defence will not be processed. After the public defence, please address any inquiries regarding the thesis to the candidate.
Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Professor Steven Niederer, King’s College London, UK
- Second opponent: Associate Professor Nils Kristian Skjærvold, Norwegian University of Science and Technology, Trondheim
- Third member and chair of the evaluation committee: Professor II Ida Gjervold Lunde, University of Oslo
Chair of the Defence
Professor William Edward Louch, University of Oslo
Principal Supervisor
Senior Researcher Espen W. Remme, Oslo University Hospital
Summary
The motion of the heart originates from the electrical activity in the sinoatrial node, which causes the atria to contract. The electrical pulse then propagates to the ventricles through the atrioventricular node and the right and left bundle branches causing the ventricles to rapidly depolarize and contract as the atria relaxes. Any disruption in this process will affect the heart’s efficiency and impair its function. In this thesis we have studied the conduction abnormality left bundle branch block (LBBB), which is a disturbance of the left main branch of the heart's specialized conduction system. This causes an activation delay of parts of the left ventricle (LV), which in turn leads to a reduction of systolic function, energetic inefficiency and also induces multiple changes at the organ, tissue, and protein levels that contribute to worsen contractile function, further challenging the heart. Cardiac resynchronization therapy (CRT) aims to solve this defect by attaching two pacing electrodes; on the right side of the septum and on the LV lateral wall, and sending electric impulses to these to resynchronize the left ventricle’s contraction. CRT is one of the most successful therapies for heart failure to have emerged in recent decades and has been shown to improve symptoms, reduce hospitalizations, promote reverse remodeling and decrease mortality. However, the response to this treatment varies strongly among patients and approximately thirty percent of them do not benefit significantly from it. A method to evaluate the acute effect of CRT during implantation may be used to improve the response rate, however, there is no consensus on which haemodynamic parameter should be used to identify response to CRT during implantation.
This thesis is based on three articles that aim to investigate the acute hemodynamic response to CRT and validate novel invasive and non-invasive methods for assessment of LV function in normal and dyssynchronous hearts.
In the first article, we focused on the abnormal systolic motion frequently observed in patients with LBBB, which has been proposed as a predictor of response to CRT. We hypothesized that this motion could be monitored with miniaturized motion sensors attached to the heart walls and thus give real time information of the impact of the pacemaker on the ventricle. For this purpose, an experimental study was carried out where sensors were attached to the septum and the lateral wall of the left ventricle measuring its diameter. We were then able to calculate a septal flash index based on the contraction pattern of the left ventricle during baseline, after induction of LBBB, and during CRT pacing. This enabled quantification of the early systolic motion of the LV and differentiation between normal or abnormal motion. After inducing LBBB the index significantly increased and was subsequently then reduced to approximately baseline values with adequate pacing. Thus, we were able to use this index to evaluate the acute improvements in LV function by CRT, and it could potentially be used to give real time feedback on the effect of CRT on the contraction pattern and thus help clinicians tailor treatments to each patient.
In the second article, we studied the use of the parameter time-to-peak LV pressure rise (Td) to reflect cardiac function in dyssynchronous heart failure. The hypothesis was that a reduction of Td would reflect resynchronization and that the measurement would be helpful to identify long-term volumetric responders to CRT. We tested this in an animal experimental study, and a clinical observational study with forty-five patients undergoing CRT implantation which were followed up for up to eighty-eight months. The main findings were that a prolongation of Td was associated with cardiac dyssynchrony and that a shortening of a prolonged Td with CRT accurately identified CRT responders, outperforming other hemodynamic parameters. Patients that responded to the treatment presented a higher Td at baseline than non-responders, and when paced, Td decreased while it increased in non- responders. Thus, Td showed potential of becoming a biomarker to predict long-term volumetric response in CRT candidates.
In the third and last article, we investigated if changes in the pulse arrival time (PAT) could be used to measure acute changes in the pre-ejection period during CRT implantation. The hypothesis was that this could then be used to evaluate acute CRT response non-invasively and in real time. The study showed that PAT was reduced with successful CRT both in animals and in LBBB patients with long-term response to CRT. A strong relationship was observed between changes in PAT and Td. This study indicates that PAT could be used as a simple, non-invasive method to assess the acute effects of CRT in real time. PAT did not shorten in patients who were classified as non-responders, which implies that it could also have the potential to identify long-term response in patients.
These were proof-of-concept studies with small sample sizes and thus, further studies are needed to clarify the validity of these parameters as biomarkers to predict long-term response in CRT patients. Overall, the findings in this thesis contribute to the understanding and assessment of the acute effect of CRT on cardiac function during dyssynchronous activation, and with different pacing configurations.
Additional information
Contact the research support staff.