Title: The long-term safety and efficacy of optimising pacemaker heart rate rise in chronic heart failure: effects on quality of life, exercise capacity and cardiac function (The OPT-Contractility study).
Funder: Department of Health and Social Care

Abstract: Research Questions: Is there a link between CHF status and the proportion of time spent above and below the critical HR? Does 6mths of personalised HR programming improve exercise capacity and QoL in people with CHF and a pacemaker? Background: Patients with chronic heart failure (CHF) suffer breathlessness and fatigue limiting their exercise capacity, therefore reducing quality of life (QoL). I have shown that a limited heart rate (HR) rise is not a contributor to this (JACC 2016) and that a mechanism for this is the impaired relationship between HR rise and cardiac contraction (force-frequency relationship (FFR)) in CHF (JACC-HF 2017). I have also shown in a single centre randomised, double-blind cross-over study that controlling HR to within the optimal range for contractility acutely improves exercise time in CHF patients (JACC-HF 2017). The present application builds upon these data. Aims and objectives: To examine the relationship between CHF status and the proportion of time spent above and below the critical HR? Examine whether 6mths of personalised HR programming, based upon the FFR, improves exercise capacity and QoL in people with CHF and a pacemaker. Methods: Study 1: All surviving participants of my previous study (n=90) will be invited to attend the Leeds NIHR cardiovascular clinical research facility when I will repeat the cardiac ultrasound. I will collect information on HR trends from their pacemaker and record the percentage of time spent above and below the critical HR. I will explore the relationship between these data and changes in CHF status. Study 2: 80 patients with stable symptomatic CHF and a pacemaker will be randomised between personalised and standard pacemaker heart rate rise settings in a single centre, double blind randomised controlled pilot trial. All participants will undergo an assessment of the FFR, using their pacemaker to increase HR in stages, whilst I measure contractility at each stage in order to calculate the optimal HR range. Participants will perform a treadmill-based cardiopulmonary exercise test and will then be randomised (1:1) to either personalised rate-response programming based upon the FFR assessment or standard settings, (based on the Astrand formula of 220-age). Participants will return for repeat of the baseline assessments at 6m. The primary outcome measure is change in exercise capacity, measured by treadmill walk distance, secondary endpoints will include QoL and changes in cardiac function. Timelines for delivery: I aim to have the first study completed and published 2 years into the fellowship and the second published towards the end of year 5. Anticipated impact and dissemination: Of the 500,000 people with CHF in the UK, 1 in 3 will have a pacemaker. And, despite optimal therapy including pacemakers, people with CHF commonly remain symptomatic. This study will demonstrate whether I can improve their QoL by optimising their pacemaker, taking into account their own physiology. My dissemination plan includes publishing my work in high-end peer reviewed journals and presenting at international conferences, meaning my work has the potential to influence pacemaker therapy at an international level.

Lay abstract: Aims: To explore the longer-term relationship between heart rate (HR) rise, exercise capacity and quality-of-life (QoL) in patients with chronic heart failure (CHF). Background: Over 500,000 people in the UK suffer from CHF, the defining symptom of which is reduced exercise capacity which leads to reduced QoL. 1 in 3 patients with CHF have a pacemaker device which can increase their HR during exercise. Many patients with CHF have a reduced HR increase during exercise, commonly thought to contribute to reduced exercise capacity. I have shown that increasing HR during exercise (using the accepted one-size-fits-all method) does not improve exercise capacity in patients with CHF and pacemakers (JACC, 2016). Following this I found that personalising HR increases during exercise, based on the pumping power of the patient's own heart, led to better exercise capacity than using this one-size-fits-all method (JACC-HF, in press). I propose that applying my technique to identify the optimal HR range for each participant and personalising the programming of their pacemaker could improve QoL by improving exercise capacity in people with CHF. Design: The proposed fellowship has two parts: Study 1 - All 90 participants from my previous fellowship will be recalled. I will collect symptoms, medication, hospitalisation information and repeat the heart ultrasound scan. These data will be compared with those from their first visit to identify changes in their condition. Using data from their pacemaker I will relate the amount of time their HR is above their optimal level to whether their condition has deteriorated or remained stable; Study 2 I will examine whether personalised HR programming has longer-term effects on exercise capacity, QoL and heart function. 80 participants will be invited for a baseline visit during which I will assess QoL, heart function, optimal HR range and exercise capacity by a treadmill walk test. Participants will then be randomly allocated to one of two groups: personalised or standard pacemaker settings. In the personalised group, the pacemaker will be programmed to maintain the HR within the patient's individual optimal range. In the standard care group patients will have standard HR rise settings based on their age. Programming will be carried out by a colleague to achieve double-blinding. Follow-up assessments of symptoms, QoL, cardiac function and exercise capacity will be assessed after 6months. Patient and public involvement and engagement: PPIE involvement for this proposal is built on our ongoing relationship with the Leeds Cardiovascular PPI group, who were instrumental in guiding my previous fellowship. Our PPI group were informed of the progress and results of my current fellowship at our quarterly meetings, this naturally led to their involvement in developing the idea and design of the current application as they were keen to see if the acute improvements in exercise capacity would translate into improved QoL, and were particularly interested in the idea of personalisation of settings rather than a one-size-fits-all model. The study design was refined in partnership with two patients with CHF and pacemakers. We agreed that exercise time on a treadmill was a relevant and reproducible measure of exercise capacity and that an improvement of almost one minute, shown in my previous work, would have a beneficial effect on daily life. We also agreed that a recognised scoring system combining symptoms, hospitalisation, and mortality to allocate patients into stable', improved' or worse' was an appropriate and patient-orientated secondary outcome. Dissemination: Via scientific journals, abstracts at national and international conferences, patient groups such as Arrhythmia Alliance, Pumping Marvellous and the lay press. My PPIE advisers have offered to help me disseminate results to participants and help develop a strategy for wider public dissemination.

Research activity codes: 6.3 MEDICAL DEVICES
Health categories: CARDIOVASCULAR