Title: Distal ventricular pacing and intraventricular gradient reduction for symptomatic relief in drug refractory hypertrophic cardiomyopathy patients with mid-cavity obstruction
Funder: Health Education England

Abstract: Background Hypertrophic cardiomyopathy (HCM), the most common familial heart disease, is characterised by left ventricular (LV) hypertrophy (LVH). Obstruction to LV emptying may also be present and in symptomatic patients, reduction of LV outflow obstruction is a frequent therapeutic target of surgical or percutaneous ablation. Such invasive options are not available for the more anatomically complex LV mid-cavity obstruction (LVMCO), and patients often experience severe drug-refractory exertional symptoms. In a small group of such individuals, we have pioneered the use of distal LV pacing to reduce the magnitude of LVMCO and to improve symptoms. AimsOur primary aim is to demonstrate that LV pacing can substantially reduce the magnitude of obstruction in LVMCO. The study's power calculations are based on pilot data for acute gradient changes. The overarching secondary aim is to assess the need for, and feasibility of, a multi centre study of pacing in symptomatic LVMCO. A small blinded cross-over study under dichotomous pacemaker settings will provide the statistical and methodological justification for a multi-site randomised control trial powered by conventional and/or novel measures of patient benefit. Plan of investigation A single centre, prospective, randomised controlled blind crossover trial of 25 HCM patients. Baseline assessment will be completed prior to a haemodynamic study at the time of pacemaker implantation. We will make invasive measurements of acute gradient changes during multi-site LV (and right ventricular) pacing. Randomisation into back-up or active pacing will occur after device implantation and cross-over will take place at 6 months. Assessments at baseline, 6 months and study end (1 year) will include imaging and pacemaker data as well as assessments of symptoms and exercise performance. Summary of potential benefits to patients and the NHS The research proposal may lead to novel treatments for a group of patients with severely limiting and currently untreatable symptoms. If positive, the study would change international guidelines on the management of these patients. Potential long-term benefits to society include a reduction in emergency admissions, improvement in the burdens of severe chronic disability and lowered risks of HCM-related mortality.

Lay abstract: Aim(s) of the research The main aim of this study is to assess the immediate effects of a pacemaker on reducing abnormally high pressures in the hearts of patients with obstructive hypertrophic cardiomyopathy (HCM). We wish to assess whether patients get symptomatic and physical benefits from the pacemaker. The information we collect will be used to design a much larger research trial of patient benefit. Background to the research HCM is the most common inherited heart disease, affecting 1 in 500 of the general population. It is characterised by abnormal thickening of the heart muscle. The various patterns of thickening of the muscle in the main pumping chamber, or left ventricle (LV), can result in obstruction to blood flow within the heart, raising the pressures in the heart and placing extra strain on the heart muscle. The obstruction can cause patients to suffer from symptoms such as shortness of breath and chest pain, along with poor exercise tolerance, and dizzy spells. In very symptomatic patients with the commonest type of obstruction, we can perform either an open heart or keyhole operation to reduce the muscle where it is causing obstruction. However, in 1 of every 10 HCM patients, the obstruction is deep within the LV where a ring of thick muscle blocks blood flow when it contracts. These patients provide a challenge for doctors, as this type of obstruction is much less suitable for open heart or keyhole operation. An alternative is to use a cardiac pacemaker to alter the timing of the contraction in the ring of thick muscle such that different parts of the ring contract at different times and thereby reduce obstruction to blood flow. Our early experience with this new treatment shows that carefully placing the pacemaker wires can reduce the obstruction and improve patient symptoms. We wish to improve our knowledge of this treatment for patients with severe symptoms for whom there are no other treatment options. Our key questions include: How much can we reduce the obstruction by? How important is choosing which part of the heart the pacemaker activates first? Does reducing obstruction in this way make patients better in the short and long term? Design and methods We will investigate this type of pacing in 25 HCM patients, many of whom are having the pacemaker for other reasons. While the pacemaker is being fitted, we will temporarily place the pacemaker wires in different parts of the heart and directly measure the effect pacing there has on the obstruction. After the pacemaker has been fitted, we will divide the patients into two groups. One group will have the pacemaker turned on' for 6 months and then off' for 6 months. The second group will have this the other way around. In order to assess if patients truly feel better because of the pacing rather than from the placebo effect, patients will not be told if their pacemaker is off or on. During this time, patients' symptoms will be assessed by questionnaire, and physical performance measures will be evaluated by exercise testing. At the end of the study, after all tests have been completed, the patients' treatment will be unmasked to them. We will discuss their symptoms, and their pacemaker will be left with the programming set-up (pacing or not pacing) that they felt better in. Patient and public involvement A range of research bodies and patient groups have been involved with this project. These groups have helped with study design and documents, and will continue to support the delivery of this research for its duration. A research steering group that includes patient representatives will help oversee the study. Dissemination Results will be distributed at a local level via our Let's talk hearts' seminar series in the community, and to the medical community through conferences and journal publications. Results will be shared directly with patients via the charity Cardiomyopathy UK through its website and annual conferences. The main focus of distribution will be how our findings can improve treatment options for HCM patients. In turn, we hope this will lead to long-term benefits for individual patients and the NHS as a whole.

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