Title: Predicting pacemaker-related left ventricular systolic dysfunction
Funder: Health Education England

Abstract: This research aims to address the clinical question:Can we identify people at risk of developing pacemaker-associated left ventricular (LV) remodelling before pacemaker implantation?Background:Right ventricular (RV) pacing causes LV dyssynchrony, which in susceptible patients, triggers LV remodelling thereby contributing to a 40-60% prevalence of reduced LV systolic function in people with pacemakers. I have proven that adverse remodelling in the presence of a pacemaker is progressive, and that in patients who are not pacemaker dependant, reprogramming to reduce RV pacing improves cardiac function. In those who develop LV dysfunction, but in whom reprogramming is not possible (pacing dependent) a second procedure to upgrade to a cardiac resynchronisation therapy (CRT) device can be undertaken. There is currently, no sufficient way prior to the first implant, to predict whether the patient is susceptible to RV pacing and at risk of LV dysfunction. Such information would allow personalisation of the prescription of the first device. Remodelling in response to RV pacing could be partly due to a maladaptive response to heterogenous myocardial loading conditions secondary to dyssynchrony. I hypothesise that regions of myocardium that will adapt poorly to dyssynchrony and the consequent abnormal mechanical load, can be identified before implantation using regional patterns of 'Myocardial Work' obtained by cardiac ultrasound.My pilot work has shown that LV Myocardial Work patterns are heterogenous in patients who develop LV dysfunction after pacemaker implantation. Moreover, CRT has been shown to correct heterogenous Myocardial Work in patients with Heart Failure. Aims and objectives1. To assess the relationship between Myocardial Work patterns and pacemaker-associated LV remodelling.2. To develop and validate a model that predicts pacemaker-associated LV remodelling before pacemaker implantation. MethodsWorkstream oneUtilising stored images from the NIHR 'Optimising Pacemaker Therapy' prospective cohort study, associations will be explored between non-invasive regional Myocardial Work measures and LV remodelling from baseline (6 weeks post) to 12 months after pacemaker implantation (n=100). This will enable me focus the key measurements to be collected prospectively in workstream two. Workstream two A prospective observational cohort study to assess the value of non-invasive Myocardial Work measures prior to, and immediately post-implant, in predicting 6 week and 6 month LV remodelling (2a). Multivariable regression analysis will identify a combination of regional Myocardial Work measurements and clinical variables to stratify individual risk of pacemaker-associated LV remodelling. The constructed model will be validated in a retrospective dataset of pacemaker patients in Leuven (Belgium)(2b).Timelines for DeliveryWorkstream 1 will be complete by month 8. Workstream 2a recruitment will take place over 18 months with 6 months to complete follow-up and 6 months for analysis and dissemination.Anticipated Impact and DisseminationThe findings will be presented at national and international conferences to drive discussions and published in peer-reviewed journals. Industry partners will disseminate via training sessions (worldwide audience). My data will drive the development of new protocols by which patients can receive a tailored pacemaker prescription which will be tested through a large multi-centre clinical trial beyond this fellowship that I will lead.

Lay abstract: Implantable pacemakers consist of a battery and one or two leads to the heart and prevent slow heart beats by delivering an electrical pulse 'on demand' to the heart when necessary. I have shown that since a pacemaker-beat is not normal, people with pacemakers, and especially those who need pacemaker-beats most of the time, and those with a previous heart attack, have a higher risk of developing progressive heart muscle weakness or heart failure which causes breathlessness and fatigue, hospitalisations and shortens life expectancy. I also proved that this can be avoided in some by programming the pacemaker to reduce the amount of pacemaker-beats. This is impossible in people who have persistently slow heart beats who rely on their pacemaker to stimulate nearly all of their heart beats, meaning they are more at risk of heart failure. A more complex pacemaker system could help these people but there are no easy options. We could: Implant a standard pacemaker, monitor people for heart failure and 'upgrade' the pacemaker to a more complex system in a second operation. Implant a more complex system at the first operation.Neither option is ideal. Although the first targets only those who develop heart failure, symptoms often develop late after heart function deteriorates, the deterioration is often irreversible, and requires a second procedure. The second option may prevent heart failure altogether, but is not available in all hospitals, is a more difficult procedure, is more expensive, devices have shorter battery lives, and is not necessary in those patients who will not develop heart failure. This problem would not exist if, before the first implantation, we had a simple test, available in all hospitals, that could tell us which patients are likely to develop heart failure.During my NIHR-PhD fellowship I worked with the team in Belgium on a new way to assess heart contraction using cardiac ultrasound which may be able to do this. My fellowship will investigate whether these ultrasound measurements, recorded before pacemaker implantation, identify people more likely to develop heart failure and could therefore guide better device selection from the outset. To achieve this I will: Use existing ultrasound images from 100 people recorded shortly after ( Assess how the heart's contraction changes over time and whether deteriorating function can be predicted at the pre-implant scan by inviting 248 people to have an ultrasound scan before pacemaker implantation, immediately afterwards, 6 weeks and 6 months later to coincide with pacemaker appointments. This research has been developed with the Patient and Public Involvement and Engagement group of the Leeds NIHR Cardiovascular Clinical Research Facility. People with pacemakers emphasised how important it was to be able to 'identify people at risk' using a simple test to provide the right pacemaker for each person upfront. They felt a cardiac ultrasound scan was acceptable as a potential way to predict risk, and most had undergone one before their pacemaker implantation. They suggested performing assessments at usual follow-up intervals. The results will be presented to local patient collaborators first to allow them to comment on the presentation and interpretation and then to national charities and patient groups including Pumping Marvellous, and health professionals at conferences.My long-term aim is to carry out a randomised controlled trial testing whether using the scanning technique to guide which type of pacemaker is implanted, leads to lower rates of heart failure and preserved heart function.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR