Title: Targeting the extracellular matrix to improve the outcome of patients with heart failure
Funder: Department of Health and Social Care

Abstract: Background Heart failure (HF) is one of the most important problems facing the health and wealth of the nation. Almost a million people in the UK have HF and, importantly, many more are at risk of developing it. HF is the most common reason for hospitalisation in older people and 50% of patients die within 5 years of diagnosis. Urgent action is needed. Extracellular matrix (ECM) expansion, primarily due to excess collagen, is central to HF pathophysiology (interstitial heart disease). Cardiac magnetic resonance (CMR) imaging accurately and reproducibly quantifies the space the ECM occupies. The aim of this work is to improve the outcome and quality of life of patients with HF and people at risk of HF. The work represents a new approach to HF, centred around the ECM. Plan of investigation Work package 1 Aim: To improve the identification of patients with HF, and people at risk of developing HF, who are at risk of an adverse outcome. One reason why HF prognosis remains poor is that identification of patients at risk of an adverse outcome continues to be inadequate. ECM volume measured using CMR shows considerable promise as a prognostic factor, however it is not known if it provides incremental value to current HF prognostic models. The incremental prognostic utility of CMR ECM quantification in people at risk of HF and patients with HF will be evaluated in a prospective cohort study of 3,800 patients with stage AD HF undergoing clinical CMR (NCT02326324; recruitment started 01/15, 530 recruited). Known prognostic factors will be collected at baseline alongside CMR ECM volume. Outcome data will be collected via the Health and Social Care Information Centre. 3.5 year follow-up. Multivariable prognostic models will be developed using survival analysis methodology, compared to existing models and validated using independent datasets. Work package 2 Aim: To determine the clinical efficacy of an antifibrotic agent in patients with HF. Approximately half of patients with HF have a preserved left ventricular ejection fraction (HFpEF). Crucially, there is currently NO therapy that improves prognosis or quality of life in these patients. Pirfenidone is a novel antifibrotic agent. In patients with interstitial lung disease it leads to ECM regression, which has translated into proven clinical effectiveness. The clinical efficacy of pirfenidone in HFpEF will be evaluated in a phase II RCT. Patients with HFpEF and ECM expansion will be randomised to pirfenidone or placebo in order to determine if pirfenidone leads to ECM regression in HFpEF. Work package 3 Aim: To significantly add to our understanding of the biological mechanisms of HF and the action of the antifibrotic agent ECM expansion is widely hypothesised to exert its deleterious effect by impairing myocyte capillary blood supply leading to myocyte energy starvation. In this hypothesis-driven mechanistic work embedded in the clinical trial in Work Package 2, 31Phosphorus magnetic resonance spectroscopy will be used to determine if ECM expansion is associated with impaired myocardial energetics and if pirfenidone-related ECM regression leads to an improvement. Benefits to patients and the NHS More effective identification of patients with an increased risk of adverse outcome will better guide intervention (personalised medicine), in a more timely (preventative) manner, and thus Work Package 1 could lead to significant and immediate benefits for patients and the NHS. If the efficacy of pirfenidone in HFpEF is demonstrated, and supported by the mechanistic evaluation, it will rapidly lead to a clinical effectiveness study. If this in turn was successful, it would have an enormous impact on patients with HFpEF and would lead to very significant improvements for the NHS.

Lay abstract: Background Heart failure is a condition where the heart does not pump blood around the body as well as it should. Nearly a million people in the UK have heart failure, and many more are at risk of developing it. It is the most common reason why older people are admitted to hospital. Around half of people die within 5 years of being diagnosed. As such, heart failure is one of the most important health problems facing the UK. Urgent action is needed now. Scarring of the heart muscle is key to the development of heart failure. Magnetic resonance imaging (MRI scanning) of the heart provides an accurate measurement of the amount of scarring in the heart. The proposed research aims to improve the outcome and quality of life of patients with heart failure and those at risk of developing it. It represents a new approach to heart failure, centred around heart scarring. It comprises three parts: Design and methods Part 1 One reason why the prognosis of heart failure patients is poor is that we are not very good at identifying which patients are at risk of dying from it. This is true for patients who have heart failure, and, importantly, also true for people who have not yet developed heart failure but have conditions that predispose to it. Heart scarring, measured by MRI scanning, is a promising indicator of prognosis. However, it is not known if it provides more information than existing indicators. This study will assess whether heart muscle scarring, measured by MRI scanning, improves the identification of people who are at risk of poor prognosis. The amount of heart scarring and known indicators of prognosis will be recorded for people with heart failure, and people at risk of developing it, who are undergoing clinical heart MRI scanning. They will then be followed up in order to find out if heart muscle scarring provides additional information with regards to prognosis and is therefore helpful for guiding patient management. Part 2 It is known that in about half of patients with heart failure, the pumping function of the heart is normal. Crucially, there are NO treatments for this kind of heart failure. Scarring of the heart appears to be particularly important in these patients. Pirfenidone is a relatively new treatment that reduces scar tissue. In patients with lung scarring it reduces the amount of scar tissue. This leads to an improvement in quality of life and prognosis in these patients. This study will assess if pirfenidone reduces the amount of heart scarring in patients with heart failure with normal pumping function. Patients with heart scarring will be given pirfenidone or a dummy drug (placebo) for 1 year. The change in the amount of heart scarring will be compared between those receiving pirfenidone and those receiving placebo. Part 3 It is not known why heart scarring is bad. One possibility is that when heart cells are surrounded by scar tissue they do not get a good enough blood supply, and therefore do not have the energy they need to work properly. This study will use MRI scanning to assess heart muscle energy in the patients included in the study in Part 2. The relationship between heart scarring and energy will be measured, and the effect of pirfenidone on heart energy will be assessed. Patient and public involvement This research has been identified as a priority by patients and members of the public. The projects have been designed, and will be carried out, through an active and on going collaborative partnership with patients with heart failure and their carers. Impact and dissemination If we are able to identify patients at an increased risk of poor prognosis it will allow treatments to be given to patients who will get the most benefit. It will also potentially mean treatments can be given to prevent the development of heart failure. If pirfenidone is shown to work in heart failure, it will lead on to a larger trial assessing whether it improves prognosis of patients with heart failure. Therefore, the proposed research could lead to enormous improvements in the care of patients with heart failure. Video and written summaries of the results, made in conjunction with patients involved with the research, will be put onto a widely-accessed patient-led heart failure charity website (http://pumpingmarvellous.org). Results will also be published in scientific journals, presented at scientific meetings, and patients involved with the research will take part in presentations to patient groups.

Research activity codes: 6.1 PHARMACEUTICALS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR