A prospective, single centre, observational cohort study at University Hospital Southampton NHS Foundation Trust of 50 consecutive patients with Heart Failure with reduced Ejection Fraction and Ejection Fraction ≤35% who are eligible for sacubitril/valsartan (Entresto) initiation as per European Society of Cardiology guidelines.

Participants will have baseline and repeat cardiac magnetic resonance imaging (CMR) scans after 4-6 months of Entresto therapy. The CMR scans will be compared.

Clinical outcomes at 6 months including combined outcome of death and/or heart failure hospitalisation, KCCQ-12 questionnaire, 6-minute walk test, routine blood tests and NTproBNP will also be described.

This study will be the first to examine the effects of sacubitril/valsartan (Entresto) therapy on left ventricular reverse remodelling in patients with symptomatic HFrEF as demonstrated by Cardiac Magnetic Resonance Imaging.

The landmark trial PARADIGM-HF (2014) showed that a new drug sacubitril/valsartan (Entresto) was superior to a well-established drug (ACE-Inhibitors) for patients with severe heart failure. Entresto resulted in a 20% reduction in risk of death and hospitalisations, as well as improving quality of life and symptoms. This represented a major breakthrough in heart failure treatment and guidelines changed to recommend Entresto for patients in whom heart function had not improved on conventional heart failure drug treatments.

At the same point as recommending Entresto, international heart failure guidelines also recommend an Implantable Cardioverter-Defibrillator (ICD). An ICD is a device which can detect and treat potentially life-threatening heart rhythm abnormalities, which may occur in patients with persistently severe heart failure. The risk of complications associated with ICD implantation is not insignificant, up to 15%. Currently, there is a lack of consensus between clinicians regarding when best to offer ICD implantation in relation to Entresto treatment.

The exact mechanism of how Entresto achieves its beneficial effect is not fully understood. There are studies describing an improvement in heart function on Echocardiography (ultrasound). Some studies suggest a reduction in abnormal heart rhythms. There are however, no studies describing the effects of Entresto on heart tissue or function described on Cardiac Magnetic Resonance (CMR) Imaging. CMR is a specialised non-invasive scan which is excellent at looking at characteristics of heart tissue and is the gold standard for calculating heart function.

The study will enrol 50 patients who have been referred for Entresto treatment. Participants will undergo a baseline CMR to evaluate heart characteristics and function before being started on Entresto. After 6 months, participants will receive another CMR and the two scans will be compared for differences in heart size, function and tissue characteristics.

The Investigators hypothesize that there will be an improvement in a variety of CMR parameters and the findings will help better understand the mechanisms by which this is achieved e.g. reduction in fibrosis (subtle scarring) of heart tissue. The Investigators also believe a proportion of patients will avoid the need for an ICD, due to improvement in heart function.

Inclusion Criteria:

• ≥18 years
• HFrEF EF ≤35% despite optimisation of ACE-Inhibitor, Beta Blocker & Mineralocorticoid Receptor Antagonist and referred for Entresto initiation
• Symptomatic NYHA II-III
• Able and willing to provide informed consent
• Able to undergo Cardiac Magnetic Resonance Imaging (CMR) scan

Exclusion Criteria:

• Pre-existing cardiac device (i.e. pacemaker/defibrillator)
• Symptomatic hypotension (BP <95mmHg) - [PARADIGM exclusion]
• Severe renal failure (GFR <30)
• Hyperkalaemia (K >5.4mmol/L)
• History of angioedema
• Diagnosis of amyloidosis, sarcoidosis or HCM
• Myocardial infarction or revascularisation within the last 40 days
• Valve disease expected to require surgery
• Life expectancy <2 years secondary to any other cause (i.e. malignancy)
• Pregnancy

Patients with symptomatic severe Heart Failure with reduced Ejection Fraction.

TBC