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Background/Introduction Early detection of worsening congestion in heart failure (HF) patients can prompt timely interventions and potentially decrease hospital admissions. Accordingly, standard care recommendations include the monitoring of symptoms and daily weighing at home. However, most patients with worsening HF do not appear to weigh themselves during the weeks prior to the hospital admission. Up to half of hospital admissions were associated with moderate to severe peripheral oedema and that oedema was strongly associated with subsequent prognosis. This suggests a missed opportunity for clinicians to respond rapidly to early changes in congestion. Purpose A camera-based technology linked to artificial intelligence software for remote home-monitoring of lower-leg volume was developed, that, unlike daily weights, does not require patient adherence. The main aims of our pilot randomised cross-over trial were to determine the feasibility of data-collection and blinding of randomisation and to estimate event rates to inform the design of future trials of the AI device. Methods Single-centre, pilot, double-blind, randomised cross-over trial in patients with HF at increased risk of decompensated HF requiring hospital admission. The main outcome measure was the proportion of participants that provided information on each available study day (ie: on the days they were alive and out of hospital over 30 days) of leg volume data, weight. Patients received guideline-recommended care and were asked to report worsening symptoms or weight gain. Patients were randomly assigned to having device monitoring data concealed or disclosed to a physician (as alerts) for two periods of 30 days. Results Between March and June 2021, we enrolled 27 patients (median [IQR] age 75 years [63–78], 41% women, 48% with a left ventricular ejection fraction >50%). For each monitoring period, participants accrued 29 days alive and out of hospital. Only 37% of patients weighed themselves on at lea

Introduction In England and Wales, heart failure (HF) was the primary diagnosis for >81,000 hospital admissions in 2016-17, with a 30-day readmission rate of nearly 20%. The National HF Audit reports that half of these admissions were associated with moderate or severe peripheral oedema. Conventionally, leg oedema is assessed and graded by a healthcare professional (HCP). A serial measurement of weight is an alternative method of assessing water retention at home but this relies on patient compliance.The Heartfelt device uses high-resolution cameras to generate 3D images of the lower legs and calculates volumes with a precision of about 20mLs without the need for active patient input. Linking Artificial Intelligence algorithms may then be applied to inform either the patient or a healthcare professional of appropriate actions. Methods The Lancashire Objective Volume Evaluation of leg oedema in Heart Failure (LOVE-HF) artificial intelligence research programme consists of two pilot randomised controlled, cross-over trials (each with 30 patients and 30 day assessment periods), a registry and screening log (the latter to permit comparison of baseline characteristics to ensure generalisability). Patients with HF who received IV diuretics (within <6 months) or with peripheral oedema despite receiving at least 80 mg/day of oral furosemide (or equivalent), will be enrolled in LOVE-HF (comparing the Heartfelt device on top of standard care to standard care: figure 1) and LOVE-HF-2 (comparing the Heartfelt device to weight monitoring: figure 2). The efficacy outcome of interest is ‘number of days alive out of hospital’. Secondary outcomes include serious adverse events, quality of life, mental wellbeing, hopelessness scores and HF-symptoms.

Introduction The work described in this thesis looks particularly but not exclusively at two recently developed molecules which have dual enzyme inhibitor activity. Omapatrilat, a molecule which inhibits both angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP), and SLV 306 (active metabolite KC12615) a compound with both NEP and endothelin converting enzyme (ECE) inhibiting properties. Neurohumoral activation characterises the complex chronic heart failure syndrome. Clearly there is value in antagonizing neurohumoral systems likely to have detrimental effects in patients with heart failure, while simultaneously augmenting potentially desirable neurohumoral mediators. However enzyme inhibitors which act on multiple vasoactive mediators with complex interactions have unpredictable effects. Omapatrilat has received much attention following demonstration of a powerful hypotensive effect but a higher than expected incidence of angioedema in patients with hypertension or heart failure. GW660511X is another dual ACE/NEP inhibitor at an earlier stage in development. The pharmacodynamic profile of neither the ACE inhibitor activity nor the NEP inhibitor activity of GW 660511X has been fully described in humans. SLV 306 is the first orally available molecule of its kind and its NEP and ECE inhibitory properties have not previously been demonstrated in humans either in vitro or in vivo. The intention of this thesis is further characterisation of these molecules and their therapeutic potential while utilising their inhibitory properties in further investigation of the human neurohumoral system. I specifically consider the possible mediators of the impressive hypotensive effects of these molecules and of the unexpected and potentially life threatening side effects associated with them. Having demonstrated the complex neurohumoral substrate of these molecules I go on to report, for the first time in heart failure patients, the benefits of a more specific approach

Introduction The work described in this thesis looks particularly but not exclusively at two recently developed molecules which have dual enzyme inhibitor activity. Omapatrilat, a molecule which inhibits both angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP), and SLV 306 (active metabolite KC12615) a compound with both NEP and endothelin converting enzyme (ECE) inhibiting properties. Neurohumoral activation characterises the complex chronic heart failure syndrome. Clearly there is value in antagonizing neurohumoral systems likely to have detrimental effects in patients with heart failure, while simultaneously augmenting potentially desirable neurohumoral mediators. However enzyme inhibitors which act on multiple vasoactive mediators with complex interactions have unpredictable effects. Omapatrilat has received much attention following demonstration of a powerful hypotensive effect but a higher than expected incidence of angioedema in patients with hypertension or heart failure. GW660511X is another dual ACE/NEP inhibitor at an earlier stage in development. The pharmacodynamic profile of neither the ACE inhibitor activity nor the NEP inhibitor activity of GW 660511X has been fully described in humans. SLV 306 is the first orally available molecule of its kind and its NEP and ECE inhibitory properties have not previously been demonstrated in humans either in vitro or in vivo. The intention of this thesis is further characterisation of these molecules and their therapeutic potential while utilising their inhibitory properties in further investigation of the human neurohumoral system. I specifically consider the possible mediators of the impressive hypotensive effects of these molecules and of the unexpected and potentially life threatening side effects associated with them. Having demonstrated the complex neurohumoral substrate of these molecules I go on to report, for the first time in heart failure patients, the benefits of a more specific approach

Introduction The work described in this thesis looks particularly but not exclusively at two recently developed molecules which have dual enzyme inhibitor activity. Omapatrilat, a molecule which inhibits both angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP), and SLV 306 (active metabolite KC12615) a compound with both NEP and endothelin converting enzyme (ECE) inhibiting properties. Neurohumoral activation characterises the complex chronic heart failure syndrome. Clearly there is value in antagonizing neurohumoral systems likely to have detrimental effects in patients with heart failure, while simultaneously augmenting potentially desirable neurohumoral mediators. However enzyme inhibitors which act on multiple vasoactive mediators with complex interactions have unpredictable effects. Omapatrilat has received much attention following demonstration of a powerful hypotensive effect but a higher than expected incidence of angioedema in patients with hypertension or heart failure. GW660511X is another dual ACE/NEP inhibitor at an earlier stage in development. The pharmacodynamic profile of neither the ACE inhibitor activity nor the NEP inhibitor activity of GW 660511X has been fully described in humans. SLV 306 is the first orally available molecule of its kind and its NEP and ECE inhibitory properties have not previously been demonstrated in humans either in vitro or in vivo. The intention of this thesis is further characterisation of these molecules and their therapeutic potential while utilising their inhibitory properties in further investigation of the human neurohumoral system. I specifically consider the possible mediators of the impressive hypotensive effects of these molecules and of the unexpected and potentially life threatening side effects associated with them. Having demonstrated the complex neurohumoral substrate of these molecules I go on to report, for the first time in heart failure patients, the benefits of a more specific approach

Introduction The work described in this thesis looks particularly but not exclusively at two recently developed molecules which have dual enzyme inhibitor activity. Omapatrilat, a molecule which inhibits both angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP), and SLV 306 (active metabolite KC12615) a compound with both NEP and endothelin converting enzyme (ECE) inhibiting properties. Neurohumoral activation characterises the complex chronic heart failure syndrome. Clearly there is value in antagonizing neurohumoral systems likely to have detrimental effects in patients with heart failure, while simultaneously augmenting potentially desirable neurohumoral mediators. However enzyme inhibitors which act on multiple vasoactive mediators with complex interactions have unpredictable effects. Omapatrilat has received much attention following demonstration of a powerful hypotensive effect but a higher than expected incidence of angioedema in patients with hypertension or heart failure. GW660511X is another dual ACE/NEP inhibitor at an earlier stage in development. The pharmacodynamic profile of neither the ACE inhibitor activity nor the NEP inhibitor activity of GW 660511X has been fully described in humans. SLV 306 is the first orally available molecule of its kind and its NEP and ECE inhibitory properties have not previously been demonstrated in humans either in vitro or in vivo. The intention of this thesis is further characterisation of these molecules and their therapeutic potential while utilising their inhibitory properties in further investigation of the human neurohumoral system. I specifically consider the possible mediators of the impressive hypotensive effects of these molecules and of the unexpected and potentially life threatening side effects associated with them. Having demonstrated the complex neurohumoral substrate of these molecules I go on to report, for the first time in heart failure patients, the benefits of a more specific approach