Title: Defining the optimal heart rate range in patients with chronic heart failure - a new paradigm in personalisation of pacemaker programming.
Funder: Health Education England

Abstract: BACKGROUND: Patients with chronic heart failure (CHF) suffer exercise intolerance over the whole range of exercise, usually due to breathlessness and fatigue, probably the result of an interaction of limited cardiac output and peripheral factors. This limits their ability to perform even minor levels of exercise, impacting greatly on their daily activities of life such as going to local shops. Although a limitation in heart rate (HR) rise is a potential contributor to a lower cardiac output, HR-lowering medication is not associated with impaired submaximal or peak exercise capacity, and increasing HR during exercise in CHF patients does not increase exercise capacity. This paradox might be the result of a pathophysiological adaptation in CHF where the heightened contractile response to increased HR is blunted (abnormal force-frequency relationship (FFR)), and the HR at which there is peak contractility is lower with reduced contractility at rates above this. My proposal builds on the underpinning preliminary published work on pacemaker programming presented in section 4 and consists of two closely related sections; WORKPACKAGE 1 AIMS: 1) To document that I can identify an optimal HR-range for contractility in CHF patients with a cardiac CHAR(13) + CHAR(10)resynchronisation therapy (CRT) device (pacemaker or defibrillator). 2) To investigate whether the optimal HR-range (and time patients spend within this) is related to other markers CHAR(13) + CHAR(10)of CHF severity; symptoms, quality of life and submaximal and peak exercise capacity. WORKPACKAGE 2 AIM: 1) To investigate whether exercising above the optimal HR-range is associated with greater symptoms in patients with CHF and a CRT pacemaker. PLAN OF INVESTIGATION: I will invite 105 patients with stable CHF and a CRT device with a left ventricular ejection fraction 50% to attend the clinical research facility at Leeds General Infirmary. I will record demographic and clinical data, medical therapy, current symptomatic status, resting HR and blood pressure. The device will be programmed to 45 bts/min and, after four minutes, a further echocardiogram and blood pressure will be recorded. The base rate will be increased in 15 beat intervals, up to the age-expected maximum or the onset of patient symptoms (angina or breathlessness), with images and blood pressure recorded at each HR after four minutes of stabilisation. Images will be blinded and filed according to a unique study number with all clinical identifiers removed, including the HR data, and analysed offline for contractility at each HR. Contractility at each HR will be calculated using: [systolic blood pressure/end systolic pressure-volume index], and a smoothed graph plotted for each patient to define peak contractility, the slope of the FFR, and the optimal HR for contractility. At a second visit patients will perform a peak cardiopulmonary exercise test. From this cohort I will invite 28 consecutive unselected attendees to participate in a randomised, cross-over pilot study to establish the relevance to patients' symptoms of exercising at HR above the optimal range. These subjects will undergo two further exercise tests during which their device will randomly be programmed to increase HR to above that at which peak contractility occurs or to limit HR rise to below this. During the test, patients will score their symptoms, which will be related to contractility and cardiac output at each stage. SUMMARY OF PATIENT BENEFITS: 1) whether we can identify an optimal HR range in an unselected group of patients with CHF and CRT devices, and whether this is related to markers of severity 2) whether HR during exercise above the optimal range contributes disproportionately to symptoms during exercise. The long term aim is to provide evidence that individualised programming of their pacemaker in clinic can improve patients' symptoms during every day activities.

Lay abstract: The degree of heart rate lowering, an accepted endpoint in chronic heart failure (CHF) management, is related to improvements in longevity, hospitalisation rate and heart function but might contribute to fatigue. We have shown that increasing heart rates using pacemakers does not increase exercise capacity in CHF patients. This might be because the optimal heart rate range for contraction is narrower for patients with CHF. At higher heart rates, heart contraction might be less strong. We now want to examine the relationship between heart rate and heart contraction in patients with heart failure aiming to improve their quality of life.

Research activity codes: 5.3 MEDICAL DEVICES;7.1 INDIVIDUAL CARE NEEDS
Health categories: CARDIOVASCULAR