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Prevention and management of cardiovascular disease is a key priority for the National Health Service (NHS); it is central to the NHS England Long Term Plan, and from April 2022 it also forms a large proportion of the Direct Enhanced Service Contract for all primary care networks. Diagnosis and management of hypertension, hypercholesterolaemia and atrial fibrillation are routine in primary care but, despite increasing prevalence, heart failure is arguably falling behind. Heart failure can be challenging to diagnose and there may be few initial symptoms when patients first present. However, patient quality of life and life expectancy dramatically improve with an early diagnosis and prompt initiation of treatment. This article provides a framework for initial diagnosis and management in primary care.

BACKGROUNDMineralocorticoid receptor (MR) activation induces fibrosis. Urinary proteomic profiling (UPP) detects thousands of sequenced peptides, mainly derived from collagen. No previous study applied UPP to generate insights in the antifibrotic actions of MR antagonism.METHODSBased on urine sample availability, subsets of the open HOMAGE trial (n=290; 23.8% women; median age: 73 years) and the double-blind PRIORITY trial (n=110; 21.8% women; 64 years) were analyzed as discovery and replication data sources. In the open HOMAGE trial, patients at risk of heart failure were randomized to usual therapy or usual therapy combined with spironolactone 25-50 mg/d. In the double-blind PRIORITY trial, type-2 diabetic patients with normal renal function were randomized to placebo or spironolactone 25 mg/d, both given on top of usual therapy. UPP relied on capillary electrophoresis coupled with mass spectrometry. In HOMAGE, the PICP/CITP ratio was calculated from serum PICP and serum CITP, which are markers of type-1 collagen synthesis and degradation, respectively. After rank-normalization of the biomarker distributions, between-group differences in the biomarker changes were analyzed by multivariable models. Correlations between the changes in urinary peptides and in serum CITP, derived from mature type-1 collagen, were compared between groups, using Fisher Z transform.RESULTSIn the HOMAGE and PRIORITY analytical subsets, patients had detectable signals of 1498 urinary peptides. Follow-up totaled 9 months in HOMAGE and was 30 months (median) in PRIORITY. All changes in urinary peptides that remained significantly different (PP≤0.0129). Correlations between changes from baseline to follow-up in urinary type-1 collagen fragments and CITP were positive often reaching significance if fragments increased during follow-up, but were nonsignificant if fragments decreased during follow-up. There were no between-group differences in these correlations.CONCLUSIONSMR antagonism predominantly reduces collagen-derived urinary peptides. Inhibition of collagen synthesis by lowering the amount available for breakdown may be a contributing mechanism.Clinical PerspectiveWhat Is New?Few studies addressed the association between urinary and serum markers of fibrosis and how MR antagonism influences urinary peptides derived from collagen.MR antagonism reduces collagen-derived urinary peptides. Inhibition of type-1 collagen synthesis by lowering the amount available for breakdown may be a contributing mechanism.Correlations between changes from baseline to follow-up in type-1 collagen and in CITP were positive if fragments increased during follow-up and nonsignificant if fragments decreased.What Are the Clinical Implications?Spironolactone inhibits fibrosis, supporting the use of MRAs in patients at risk of heart failure or chronic kidney disease.UPP profiling opens new research perspectives in documenting the antifibrotic properties of novel drug classes, such as nonsteroidal MR antagonists or sodium-glucose cotransporter-2 inhibitors.The development of novel medicines that would promote collagen degradation in addition to MRAs would strengthen the therapeutic armamentarium to modify fibrosis.GRAPHICAL ABSTRACT

Aims A high, Doppler-derived, tricuspid regurgitation velocity (TRV) indicates pulmonary hypertension, which may contribute to right ventricular dysfunction and worsening tricuspid regurgitation leading to systemic venous congestion, reflected by an increase in inferior vena cava (IVC) diameter. We hypothesized that venous congestion rather than pulmonary hypertension would be more strongly associated with prognosis. Methods and results 895 patients with chronic heart failure (CHF) (median (25th and 75th centile) age 75 (67–81) years, 69% men, LVEF 44 (34–55)% and NT-proBNP 1133 (423–2465) pg/ml) were enrolled. Compared to patients with normal IVC (n = 504, 56%), those with high TRV but normal IVC (n = 85, 9%) were older, more likely to be women and to have LVEF ≥ 50%, whilst those with dilated IVC but normal TRV (n = 142, 16%) had more signs of congestion and higher NT-proBNP. Patients (n = 164, 19%) with both dilated IVC and high TRV had the most signs of congestion and the highest NT-proBNP. During follow-up of 860 (435–1121) days, 239 patients died. Compared to those with both normal IVC and TRV (reference), patients with high TRV but normal IVC did not have a significantly increased mortality (HR: 1.41; CI: 0.87–2.29; P = 0.16). Risk was higher for patients with a dilated IVC but normal TRV (HR: 2.51; CI: 1.80–3.51; P P Conclusion Amongst ambulatory patients with CHF, a dilated IVC is more closely associated with an adverse prognosis than an elevated TRV. Graphical Abstract

OBJECTIVES This study sought to further understand the mechanisms underlying effect of spironolactone and assessed its impact on multiple plasma protein biomarkers and their respective underlying biologic pathways.BACKGROUND In addition to their beneficial effects in established heart failure (HF), mineralocorticoid receptor antagonists may act upstream on mechanisms, preventing incident HF. In people at risk for developing HF, the HOMAGE (Heart OMics in AGEing) trial showed that spironolactone treatment could provide antifibrotic and antiremodeling effects, potentially slowing the progression to HF.METHODS Baseline, 1-month, and 9-month (or last visit) plasma samples of HOMAGE participants were measured for protein biomarkers (n = 276) by using Olink Proseek-Multiplex cardiovascular and inflammation panels (Olink, Uppsala, Sweden). The effect of spironolactone on biomarkers was assessed by analysis of covariance and explored by knowledgebased network analysis. RESULTS A total of 527 participants were enrolled; 265 were randomized to spironolactone (25 to 50 mg/day) and 262 to standard care ("control"). The median (interquartile range) age was 73 years (69 to 79 years), and 26% were female. Spironolactone reduced biomarkers of collagen metabolism (e.g., COL1A1, MMP-2); brain natriuretic peptide; and biomarkers related to metabolic processes (e.g., PAPPA), inflammation, and thrombosis (e.g., IL17A, VEGF, and urokinase). Spironolactone increased biomarkers that reflect the blockade of the mineralocorticoid receptor (e.g., renin) and increased the levels of adipokines involved in the anti-inflammatory response (e.g., RARRES2) and biomarkers of hemostasis maintenance (e.g., tPA, UPAR), myelosuppressive activity (e.g., CCL16), insulin suppression (e.g., RETN), and inflammatory regulation (e.g., IL-12B).CONCLUSIONS Proteomic analyses suggest that spironolactone exerts pleiotropic effects including reduction in fibrosis, inflammation, thrombosis, congestion, and vascular function improvement, all of which may mediate cardiovascular protective effects, potentially slowing progression toward heart failure. (HOMAGE [Bioprofiling Response to Mineralocorticoid Receptor Antagonists for the Prevention of Heart Failure]; NCT02556450) (C) 2021 by the American College of Cardiology Foundation.

Background In the UK, approximately half of patients with heart failure and a reduced ejection fraction (HeFREF) are discharged from hospital on triple therapy (angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB), beta-blockers (BB), and mineralocorticoid receptor antagonists (MRA). It is unknown what proportion of patients would be eligible for uptitration of medicines prior to discharge, nor how many might be eligible for initiation of sacubitril-valsartan or sodium-glucose co-transporter-2 inhibitors (SGLT2I).Methods Between 2012 and 2017, 1,277 patients admitted with suspected heart failure were enrolled at a single hospital serving a local community around Kingston-Upon-Hull, UK. Eligibility for sacubitril-valsartan or SGLT2I was based on entry criteria for the PIONEER-HF, DAPA-HF and EMPEROR-Reduced trials.Results 455 patients had HeFREF with complete data on renal function, heart rate and systolic blood pressure (SBP) on discharge. 83% were taking an ACEI/ARB, 85% a BB and 63% MRA on discharge (figure 1). More than 60% were eligible for sacubitril-valsartan and more than 70% for SGLT2i (figure 2). Among those not already receiving a each drug, 37%, 28%, and 49% were eligible to start ACEI/ARB, BB, or MRA respectively (tables 1 and 2). Low SBP (Conclusion Most patients admitted for heart failure are eligible for initiation of life prolonging medications prior to discharge. A hospital admission may be a common missed opportunity to improve treatment for HeFREF

BACKGROUND: Adipose tissue influences the expression and degradation of circulating biomarkers. We aimed to identify the biomarker profile and biological meaning of biomarkers associated with obesity to assess the effect of spironolactone on the circulating biomarkers and to explore whether obesity might modify the effect of spironolactone. METHODS AND RESULTS: Protein biomarkers (n = 276) from the Olink Proseek-Multiplex cardiovascular and inflammation panels were measured in plasma collected at baseline, 1 month and 9 months from the HOMAGE randomized controlled trial participants. Of the 510 participants, 299 had obesity defined as an increased waist circumference (≥102 cm in men and ≥88 cm in women). Biomarkers at baseline reflected adipogenesis, increased vascularization, decreased fibrinolysis, and glucose intolerance in patients with obesity at baseline. Treatment with spironolactone had only minor effects on this proteomic profile. Obesity modified the effect of spironolactone on systolic blood pressure (Pinteraction = 0.001), showing a stronger decrease of blood pressure in obese patients (-14.8 mm Hg 95% confidence interval -18.45 to -11.12) compared with nonobese patients (-3.6 mm Hg 95% confidence interval -7.82 to 0.66). CONCLUSIONS: Among patients at risk for heart failure, those with obesity have a characteristic proteomic profile reflecting adipogenesis and glucose intolerance. Spironolactone had only minor effects on this obesity-related proteomic profile, but obesity significantly modified the effect of spironolactone on systolic blood pressure. ispartof: JOURNAL OF CARDIAC FAILURE vol:28 issue:5 pages:778-786 ispartof: location:United States status: published

Aims: \ud Left ventricular ejection fraction (LVEF) can provide haemodynamic information and may influence the response to spironolactone and other heart failure (HF) therapies. We aimed to study patient characteristics and circulating protein associations with LVEF, and whether LVEF influenced the response to spironolactone.\ud \ud Methods and results: \ud HOMAGE enrolled patients aged >60 years at high risk of developing HF with a LVEF ≥45%. Overall, 527 patients were randomized to either spironolactone or standard of care for ≈9 months, and 276 circulating proteins were measured using Olink® technology. A total of 364 patients had available LVEF determined by the Simpson's biplane method. The respective LVEF tertiles were: tertile 1: 65% (n = 121). Patients with a LVEF >65% had smaller left ventricular chamber size and volumes, and lower natriuretic peptide levels. Compared to patients with a LVEF 65% had higher levels of circulating c-c motif chemokine ligand-23 and interleukin-8, and lower levels of tissue plasminogen activator, brain natriuretic peptide (BNP), S100 calcium binding protein A12, and collagen type I alpha 1 chain (COL1A1). Spironolactone significantly reduced the circulating levels of BNP and COL1A1 without significant treatment-by-LVEF heterogeneity: BNP change β = −0.36 log2 and COL1A1 change β = −0.16 log2 (p 0.1 for both). Spironolactone increased LVEF from baseline to month 9 by 1.1% (p = 0.007).\ud \ud Conclusion: \ud Patients with higher LVEF had higher circulating levels of chemokines and inflammatory markers and lower levels of stretch, injury, and fibrosis markers. Spironolactone reduced the circulating levels of natriuretic peptides and type 1 collagen, and increased LVEF.

Aims The HOMAGE randomized trial found that spironolactone reduced left atrial volume index (LAVI), E:A ratio, and a marker of collagen type I synthesis (procollagen type I C-terminal propeptide) in patients at risk of heart failure (HF). Previous trials showed that patients with HF, preserved ejection fraction and low serum collagen type I C-terminal telopeptide to matrix metalloproteinase-1 ratio (CITP:MMP-1), associated with high collagen cross-linking, had less improvement in diastolic function with spironolactone. We evaluated the interaction between serum CITP:MMP-1 and spironolactone on cardiac function in the HOMAGE trial.Methods and results Patients at risk of HF were randomized to spironolactone (n = 260) or not (n = 255). Blood sampling and echocardiography were done at baseline, one and nine months. CITP:MMP-1 was used as an indirect measure of collagen cross-linking. Higher baseline CITP:MMP-1 (i.e. lower collagen cross-linking) was associated with greater reductions in LAVI with spironolactone at both one (p = 0.003) and nine (p = 0.01) months, but no interaction was observed for E:A ratio. Spironolactone reduced LAVI after one and nine months only for those patients in the third tertile of CITP:MMP-1 (estimated lowest collagen cross-linking) [mean difference(sspiro/control): -1.77 (95% confidence interval, CI -2.94 to -0.59) and -2.52 (95% CI -4.46 to -0.58) mL/m(2); interaction p(across-tertiles) = 0.005; interaction p(third tertile) = 0.008] with a similar trend for N-terminal pro-B-type natriuretic peptide which was consistently reduced by spironolactone only in the lowest collagen cross-linking tertile [mean differences(spiro/control): -0.47 (95% CI -0.66 to -0.28) and -0.31 (95% CI -0.59 to -0.04) ng/L; interaction p(across-tertiles) = 0.09; interaction p(third tertile) < 0.001].Conclusions These findings suggest that, for patients at risk of HF, the effects of spironolactone on left atrial remodelling may be more prominent in patients with less collagen cross-linking (indirectly assessed by serum CITP:MMP-1).[GRAPHICS]Patients at risk of heart failure from the HOMAGE clinical trial were classified according to the baseline degree of myocardial collagen cross-linking, non-invasively assessed by the serum collagen type I C-terminal telopeptide (CITP) to matrix metalloproteinase-1 (MMP-1) ratio (CITP:MMP-1). As highly cross-linked collagen fibres are more resistant to degradation and CITP is a cross-linked peptide, for a given MMP-1 quantity less CITP will be released and, subsequently, serum CITP:MMP-1 will be lower. Whereas patients with low collagen cross-linking (high CITP:MMP-1) benefit from the cardioprotective effects of treatment with spironolactone on left atrial remodelling [i.e. a decrease in left atrial volume index (LAVI)] and on N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, these beneficial effects are not found in patients with higher collagen cross-linking (low CITP:MMP-1).

Introduction In the last year of life, patients with heart failure (HF) may experience increasing symptoms and hospitalisation, but there are few data from UK populations. Whether there are differences between HF phenotypes in the pattern of admissions is not known. We explored the frequency, causes, and pattern of hospitalisation for patients with HF in the 12 months preceding death. Methods This is a retrospective analysis of patients recruited prospectively over two decades at a community HF clinic in Kingston upon Hull, UK. Patients with HF who died before August 2020 were included. We divided the cohort into three phenotypes: i) heart failure with reduced ejection fraction (HeFREF), ii) heart failure with normal ejection fraction (HeFNEF) with N-terminal pro B-type natriuretic peptide (NTproBNP) 125-399 ng/L, and iii) HeFNEF with NTproBNP ≥400 ng/L. The primary outcome was hospital admissions in the last year of life, classified as: HF, other cardiovascular (CV), or non-cardiovascular (non-CV). The primary cause of hospital admission using ICD-10 criteria was used. Results Among 4925 patients, the median (Q1-Q3) age at death was 81 (75-87). 38% of patients were female. There were 9127 hospital admissions. The median (Q1-Q3) number of hospitalisations per patient was 2 (1-3) and days spent in hospital in the last year of life was 12 (2-25). 83% of patients had at least one hospitalisation; 20% had at least one HF hospitalisation; 24% had at least one CV hospitalisation; 70% had at least one non-CV hospitalisation. 54% of deaths were as an in-patient. HF admissions were a minority in all phenotypes, but most common in HeFREF. In each group, at least two thirds of admissions were non-CV. 6% of the admissions in 2020 (prior to August) were for COVID-19. Hospitalisations increased in the three months prior to death (figure 1). Conclusion In the last year of life in patients with HF, most hospitalisations are for non-CV causes regardless of HF phenotype. Conflict of Interest None

Introduction Neurohormonal activation in patients with chronic heart failure (CHF) causes plasma volume expansion which, if untreated, leads to overt venous congestion. Plasma volume status (PVS) can be estimated using formulae based on a patient's sex, weight, haemoglobin and haematocrit. Such non-invasive methods to assess congestion may be useful, particularly in the wake of the COVID-19 pandemic. We compared the clinical value of two measures of PVS in a cohort of unselected outpatients with CHF (The Hull LifeLab). Methods Patients with an echocardiogram, N-terminal pro Btype natriuretic peptide (NTproBNP) and complete data on signs and symptoms were evaluated (n=3505). CHF was defined as signs and symptoms of the disease and either left ventricular systolic dysfunction (LVSD) worse than mild, or LVSD mild or better and raised N-terminal pro-B-type natriuretic peptide (NTproBNP) levels (>125 ng/L). Two formulae to estimate PVS were used: (a) Hakim formula (based on estimations of actual and ideal plasma volume calculated from weight and haemoglobin - H-PVS);and (b) Duarte formula (calculated from haematocrit and haemoglobin - D-PVS) (figure 1). Patients were split into quartiles of H-PVS and D-PVS. Variance inflation factor (VIF) was used to assess co-linearity between both measures and other variables. Outcome measures were all cause mortality, and mortality or heart failure hospitalisation. Multivariable Cox regression, Harrel's C-statistic and Akaike's Information Criterion (AIC) were used to assess the prognostic utility of each measure of PVS. Results Patients in the highest quartile (most congested) of DPVS or H-PVS had higher NTproBNP levels, were more likely to have severe symptoms and signs, and be prescribed a loop diuretic than those in lower quartiles (table 1 and 2). Patients in the highest quartile paradoxically weighed much less than those in those lowest quartiles. H-PVS and D-PVS were strongly correlated with one another (r=0.79;P

Aims Uncontrolled blood pressure (BP) increases the risk of developing heart failure (HF). The effect of spironolactone on BP of patients at risk of developing HF is yet to be determined. To evaluate the effect of spironolactone on the BP of patients at risk for HF and whether renin can predict spironolactone’s effect. Methods and results HOMAGE (Heart OMics in Aging) was a prospective multicentre randomized open-label blinded endpoint (PROBE) trial including 527 patients at risk for developing HF randomly assigned to either spironolactone (25–50 mg/day) or usual care alone for a maximum of 9 months. Sitting BP was assessed at baseline, Months 1 and 9 (or last visit). Analysis of covariance (ANCOVA), mixed effects models, and structural modelling equations was used. The median (percentile25–75) age was 73 (69–79) years, 26% were female, and >75% had history of hypertension. Overall, the baseline BP was 142/78 mmHg. Patients with higher BP were older, more likely to have diabetes and less likely to have coronary artery disease, had greater left ventricular mass (LVM), and left atrial volume (LAV). Compared with usual care, by last visit, spironolactone changed SBP by −10.3 (−13.0 to −7.5) mmHg and DBP by −3.2 (−4.8 to −1.7) mmHg (P Conclusion Spironolactone had a clinically important BP-lowering effect. Spironolactone should be considered for lowering blood pressure in patients who are at risk of developing HF.