Targeting the extracellular matrix to improve the outcome of patients with heart failure

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 A-D 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.