Heart Failure Specialist Care and Long-Term Outcomes for Patients Admitted With Acute Heart Failure.

BACKGROUND: For patients with acute heart failure (HF), specialist HF care during admission improves diagnosis and treatments. OBJECTIVES: The authors aimed to investigate the association of HF specialist care with in-hospital and longer term prognosis. METHODS: The authors used data from the National Heart Failure Audit from January 1, 2018, to December 31, 2022, linked to electronic records for hospitalization and deaths. All-cause mortality was the primary outcome measure and in-hospital mortality the secondary outcome measure. RESULTS: Data for 227,170 patients admitted to hospital with HF (median age: 81 years; IQR: 72-88 years), were analyzed. Approximately 80% of acute HF admissions received support from HF specialists. Thirty-nine percent of patients (n = 70,720) were seen by a multidisciplinary team (HF physicians and HF specialist nurses [HFSNd]), 22% (n = 40,330) were seen by HFSNs alone, and the remaining 39% (n = 71,700) were seen exclusively by specialist HF physicians. At discharge, more patients who received HF specialist care were prescribed medical therapy for HF and had specialized follow-up. Conversely, diuretic agents were prescribed to fewer patients. HF specialist care was independently associated with a higher rate of prescribing HF therapies at discharge and a lower likelihood of receiving diuretic therapy (OR: 0.90 [95% CI: 0.86-0.95]; P < 0.001). HF specialist care was associated with better long-term survival (HR: 0.89 [95% CI: 0.87-0.90]; P < 0.001) and lower in-hospital mortality (OR: 0.92 [95% CI: 0.0.88-0.97]; P < 0.001). CONCLUSIONS: Receiving HF specialist care during admission for HF is associated with a higher rate of implementation of medical therapy, fewer discharges on diuretic therapy, and lower in-hospital and long-term mortality across the left ventricular ejection fraction spectrum, especially for patients with heart failure with reduced ejection fraction.

Disease progression in chronic heart failure is linear: Insights from multistate modelling.

AIMS: Understanding the pattern of disease progression in chronic heart failure (HF) may inform patient care and healthcare system design. We used a four-state Markov model to describe the disease trajectory of patients with HF. METHODS AND RESULTS: Consecutive patients (n = 4918) were enrolled (median age 75 [67-81] years, 61.3% men, 44% with HF and reduced ejection fraction). We generated a model by observing events during the first 2 years of follow-up. The model yielded surprisingly accurate predictions of how a population with HF will behave during subsequent years. As examples, the predicted transition probability from hospitalization to death was 0.11; the observed probabilities were 0.13, 0.14, and 0.16 at 3, 4, and 5 years, respectively. Similarly, the predicted transition intensity for rehospitalization was 0.35; the observed probabilities were 0.38, 0.34, and 0.35 at 3, 4, and 5 years, respectively. A multivariable model including covariates thought to influence outcome did not improve accuracy. Predicted average life expectancy was approximately 10 years for the unadjusted model and 13 years for the multivariable model, consistent with the observed mortality of 41% at 5 years. CONCLUSIONS: A multistate Markov chain model for patients with chronic HF suggests that the proportion of patients transitioning each year from a given state to another remains constant. This finding suggests that the course of HF at a population level is more linear than is commonly supposed and predictable based on current patient status.

Heart rate reactivity, recovery, and endurance of the incremental shuttle walk test in patients prone to heart failure.

AIMS: Few randomized trials assessed the changes over time in the chronotropic heart rate (HR) reactivity (CHR), HR recovery (HRR) and exercise endurance (EE) in response to the incremental shuttle walk test (ISWT). We addressed this issue by analysing the open HOMAGE (Heart OMics in Aging) trial. METHODS: In HOMAGE, 527 patients prone to heart failure were randomized to usual treatment with or without spironolactone (25-50 mg/day). The current sub-study included 113 controls and 114 patients assigned spironolactone (~70% on beta-blockers), who all completed the ISWT at baseline and at Months 1 and 9. Within-group changes over time (follow-up minus baseline) and between-group differences at each time point (spironolactone minus control) were analysed by repeated measures ANOVA, unadjusted or adjusted for sex, age and body mass index, and additionally for baseline for testing 1 and 9 month data. RESULTS: Irrespective of randomization, the resting HR and CHR did not change from baseline to follow-up, with the exception of a small decrease in the HR immediately post-exercise (-3.11 b.p.m.) in controls at Month 9. In within-group analyses, HR decline over the 5 min post-exercise followed a slightly lower course at the 1 month visit in controls and at the 9 month visits in both groups, but not at the 1 month visit in the spironolactone group. Compared with baseline, EE increased by two to three shuttles at Months 1 and 9 in the spironolactone group but remained unchanged in the control group. In the between-group analyses, irrespective of adjustment, there were no HR differences at any time point from rest up to 5 min post-exercise or in EE. Subgroup analyses by sex or categorized by the medians of age, left ventricular ejection fraction or glomerular filtration rate were confirmatory. Combining baseline and Months 1 and 9 data in both treatment groups, the resting HR, CHR and HRR at 1 and 5 min averaged 61.5, 20.0, 9.07 and 13.8 b.p.m. and EE 48.3 shuttles. CONCLUSIONS: Spironolactone on top of usual treatment compared with usual treatment alone did not change resting HR, CHR, HRR and EE in response to ISWT. Beta-blockade might have concealed the effects of spironolactone. The current findings demonstrate that the ISWT, already used in a wide variety of pathological conditions, is a practical instrument to measure symptom-limited exercise capacity in patients prone to developing heart failure because of coronary heart disease.

Treating iron deficiency in patients with heart failure: what, why, when, how, where and who.

For patients with heart failure and reduced or mildly reduced left ventricular ejection fraction, iron deficiency is common and associated with more severe symptoms, worse quality of life and an increased risk of hospitalisations and death. Iron deficiency can be swiftly, effectively and safely treated by administering intravenous iron, either as ferric carboxymaltose or ferric derisomaltose, which improves patient well-being and reduces the risk of hospitalisations including those for heart failure. However, the current definition of iron deficiency in heart failure has serious flaws. A serum ferritin <100 µg/L does not identify patients more likely to respond to intravenous iron. In contrast, patients with transferrin saturations <20%, most of whom are also anaemic, are more likely to have a beneficial response to intravenous iron. In this review, we summarise the available evidence for use of intravenous iron in heart failure and provide recommendations for targeted future research and practical considerations for the general cardiologist.

Heart failure with improved versus persistently reduced left ventricular ejection fraction: A comparison of the BIOSTAT-CHF (European) study with the ASIAN-HF registry.

AIMS: We investigated the prevalence, clinical characteristics, and prognosis of patients with heart failure (HF) with improved ejection fraction (HFimpEF). METHODS AND RESULTS: We used data from BIOSTAT-CHF including patients with a left ventricular ejection fraction (LVEF) ≤40% at baseline who had LVEF re-assessed at 9 months. HFimpEF was defined as a LVEF >40% and a LVEF ≥10% increase from baseline at 9 months. We validated findings in the ASIAN-HF registry. The primary outcome was a composite of time to HF rehospitalization or all-cause mortality. In BIOSTAT-CHF, about 20% of patients developed HFimpEF, that was associated with a lower primary event rate of all-cause mortality (hazard ratio [HR] 0.52, 95% confidence interval [CI] 0.28-0.97, p = 0.040) and the composite endpoint (HR 0.46, 95% CI 0.30-0.70, p < 0.001) compared with patients who remained in persistent HF with reduced ejection fraction (HFrEF). The findings were similar in the ASIAN-HF (HR 0.40, 95% CI 0.18-0.89, p = 0.024, and HR 0.29, 95% CI 0.17-0.48, p < 0.001). Five independently common predictors for HFimpEF in both BIOSTAT-CHF and ASIAN-HF were female sex, absence of ischaemic heart disease, higher LVEF, smaller left ventricular end-diastolic and end-systolic diameter at baseline. A predictive model combining only five predictors (absence of ischaemic heart disease and left bundle branch block, smaller left ventricular end-systolic and left atrial diameter, and higher platelet count) for HFimpEF in the BIOSTAT-CHF achieved an area under the curve of 0.772 and 0.688 in the ASIAN-HF (due to missing left atrial diameter and platelet count). CONCLUSIONS: Approximately 20-30% of patients with HFrEF improved to HFimpEF within 1 year with better clinical outcomes. In addition, the predictive model with clinical predictors could more accurately predict HFimpEF in patients with HFrEF.

High variability in assays of blood markers of collagen turnover in cardiovascular disease: Implications for research and clinical practice.

AIMS: Fibrosis is a common feature of many chronic diseases, including heart failure, which can have deleterious effects on cardiac structure and function that are associated with adverse outcomes. By-products of collagen synthesis and degradation, such as carboxy- and amino-terminal pro- or telo-peptides of collagen type I and III (PICP, PINP, PIIINP, and CITP) have been extensively investigated as markers of fibrosis. Although the majority of studies report on the reproducibility of their assay results, there is no a comparison of biomarker assays across studies. Therefore, we conducted a systematic review adhering to PRISMA guidelines. METHODS AND RESULTS: The search terms employed in Medline were: 'collagen AND cardiac' or 'collagen AND heart'. This query yielded a total of 1049 articles. Thereafter, specific search criteria were applied: (i) original English-language papers; (ii) human studies; (iii) in-vivo investigations; and (iv) blood/serum/plasma samples. Overall, 89 studies were identified (42 on PIIINP, 32 on PICP, 29 on CITP, and 17 on PINP). The range of reported values for PIIINP was between 0.06 to 11 800 µg/l; for PICP 0.006 to 1265 µg/l; for CITP 0.3 to 5450 µg/l; for PINP 0.15 to 80 µg/l. Extreme variations in values for fibrosis biomarkers were observed across studies, especially when different assays were used, but also with the same assays. CONCLUSIONS: Our findings show that it is challenging to ascertain normal ranges or compare studies for the measurement of fibrosis biomarkers. Given the potential implications for clinical practice and current lack of awareness of these issues, this subject warrants comprehensive acknowledgement and understanding.

Outpatient treatment of decompensated heart failure: A systematic review and study level meta-analysis.

Patients with acutely decompensated heart failure (ADHF) are usually admitted to hospital for management. There is growing interest in delivering intravenous (IV) diuretic therapy at home, in the community or at hospital day-care units; the safety and effectiveness of outpatient-based management (OPM) for ADHF has not been established. We conducted a systematic literature review and meta-analysis to investigate the short-term safety and effectiveness of OPM compared with inpatient management (IPM) of ADHF. Pre-specified endpoints were 30 day mortality and 30 day hospitalization. The meta-analysis was conducted using RevMan 5.4 software. Twenty-nine studies of OPM were identified, including 7683 patients. Only five studies directly compared OPM (n = 1303) with IPM (n = 2047), including three observational studies, and two randomized controlled trials (RCTs). The other 24 studies only stated OPM outcomes. For the five studies comparing IPM versus OPM, patients were generally aged >75 years and of similar age for each strategy, with a similar proportion of men (56%). In a study-level, aggregate analysis, 30 day all-cause mortality was 9.3% (121/1303) for OPM, compared with 15.6% (320/2047) for IPM [OR 0.29 (95% CI 0.09, 0.93) P = 0.04]. Four studies reported 30 day all-cause hospitalization; 22.0% for IPM versus 16.8% for OPM [OR 0.73 (95% CI 0.61, 0.89), P = 0.001]. In the two RCTs, we found no difference in 30 day mortality or hospitalization. In observational studies, OPM of ADHF is associated with lower 30 day hospitalization and lower 30 day mortality; such differences were not observed in two small, single-centre RCTs. A substantial, multicentre RCT is required to confirm the safety and effectiveness of OPM for ADHF.

Outcomes of Cardiac Resynchronization Therapy by New York Heart Association Class: A Patient-Level Meta-Analysis.

BACKGROUND: Data on the benefits of cardiac resynchronization therapy (CRT) in patients with severe heart failure symptoms are limited. We investigated the relative effects of CRT in patients with ambulatory New York Heart Association (NYHA) IV versus III functional class at the time of device implantation. METHODS AND RESULTS: In this meta-analysis, we pooled patient-level data from the MIRACLE (Multicenter InSync Randomized Clinical Evaluation), MIRACLE-ICD (Multicenter InSync Implantable Cardioversion Defibrillation Randomized Clinical Evaluation), and COMPANION (Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure) trials. Outcomes evaluated were time to the composite end point of the first heart failure hospitalization or all-cause mortality, and time to all-cause mortality alone. The association between CRT and outcomes was evaluated using a Bayesian hierarchical Weibull survival regression model. We assessed if this association differed between NYHA III and IV groups by adding an interaction term between CRT and NYHA class as a random effect. A sensitivity analysis was performed by including data from RAFT (Resynchronization-Defibrillation for Ambulatory Heart Failure). Our pooled analysis included 2309 patients. Overall, CRT was associated with a longer time to heart failure hospitalization or all-cause mortality (adjusted hazard ratio [aHR], 0.79 [95% credible interval [CI], 0.64-0.99]; posterior probability or P=0.044), with a similar association with time to all-cause mortality (aHR, 0.78 [95% CI, 0.59-1.03]; P=0.083). Associations of CRT with outcomes were not significantly different for those in NYHA III and IV classes (ratio of aHR, 0.72 [95% CI, 0.30-1.27]; P=0.23 for heart failure hospitalization/mortality; ratio of aHR, 0.70 [95% CI, 0.35-1.34]; P=0.27 for all-cause mortality alone). The sensitivity analysis, including RAFT data, did not show a significant relative CRT benefit between NYHA III and IV classes. CONCLUSIONS: Overall, there was no significant difference in the association of CRT with either outcome for patients in NYHA functional class III compared with functional class IV.

Predictors of the efficacy of His bundle pacing in patients with a prolonged PR interval: A stratified analysis of the HOPE-HF randomized controlled trial.

AIMS: The randomized, double-blind, placebo-controlled HOPE-HF trial assessed the benefit of atrio-ventricular (AV) delay optimization delivered using His bundle pacing. It recruited patients with left ventricular ejection fraction ≤40%, PR interval ≥200 ms, and baseline QRS ≤140 ms or right bundle branch block. Overall, there was no significant increase in peak oxygen uptake (VO2max) but there was significant improvement in heart failure specific quality of life. In this pre-specified secondary analysis, we evaluated the impact of baseline PR interval, echocardiographic E-A fusion, and the magnitude of acute high-precision haemodynamic response to pacing, on outcomes. METHODS AND RESULTS: All 167 randomized participants underwent measurement of PR interval, acute haemodynamic response at optimized AV delay, and assessment of presence of E-A fusion. We tested the impact of these baseline parameters using a Bayesian ordinal model on VO2max, quality of life and activity measures. There was strong evidence of a beneficial interaction between the baseline acute haemodynamic response and the blinded benefit of pacing for VO2 (Pr 99.9%), Minnesota Living With Heart Failure (MLWHF) (Pr 99.8%), MLWHF physical limitation score (Pr 98.9%), EQ-5D visual analogue scale (Pr 99.6%), and exercise time (Pr 99.4%). The baseline PR interval and the presence of baseline E-A fusion did not have this reliable ability to predict the clinical benefit of pacing over placebo across multiple endpoints. CONCLUSIONS: In the HOPE-HF trial, the acute haemodynamic response to pacing reliably identified patients who obtained clinical benefit. Patients with a long PR interval (≥200 ms) and left ventricular impairment who obtained acute haemodynamic improvement with AV-optimized His bundle pacing were likely to obtain clinical benefit, consistent across multiple endpoints. Importantly, this gradation can be reliably tested for before randomization, but does require high-precision AV-optimized haemodynamic assessment to be performed.

Loop diuretic utilisation with or without heart failure: impact on prognosis.

BACKGROUND & AIMS: Many patients are prescribed loop diuretics without a diagnostic record of heart failure. Little is known about their characteristics and prognosis. METHODS: Glasgow regional health records (2009-2016) were obtained for adults with cardiovascular disease or taking loop diuretics. Outcomes were investigated using Cox models with hazard ratios adjusted for age, sex, socioeconomic deprivation, and co-morbid disease (adjHR). RESULTS: Of 198,898 patients (median age 65 years; 55% women), 161,935 (81%) neither took loop diuretics nor had a diagnostic record of heart failure (reference group), 23,963 (12%) were taking loop diuretics but had no heart failure recorded, 7,844 (4%) had heart failure recorded and took loop diuretics and 5,156 (3%) had heart failure recorded but were not receiving loop diuretics.Five-year mortality was only slightly higher for heart failure in absence of loop diuretics (22%; adjHR: 1.2 [95% CI 1.1-1.3]), substantially higher for those taking loop diuretics with no heart failure recorded (40%; adjHR: 1.8 [95% CI 1.7-1.8]) and highest for heart failure treated with loop diuretics (52%; adjHR: 2.2 [95% CI 2.0-2.2]). CONCLUSIONS: For patients with cardiovascular disease, many are prescribed loop diuretics without a diagnosis of heart failure being recorded. Mortality is more strongly associated with loop diuretic use than with a heart failure record. The diagnosis of heart failure may be often missed, or loop diuretic use is associated with other conditions with a prognosis similar to heart failure, or inappropriate loop diuretic use increases mortality; all might be true.

Trends in cardiovascular disease incidence among 22 million people in the UK over 20 years: population based study.

OBJECTIVE: To investigate the incidence of cardiovascular disease (CVD) overall and by age, sex, and socioeconomic status, and its variation over time, in the UK during 2000-19. DESIGN: Population based study. SETTING: UK. PARTICIPANTS: 1 650 052 individuals registered with a general practice contributing to Clinical Practice Research Datalink and newly diagnosed with at least one CVD from 1 January 2000 to 30 June 2019. MAIN OUTCOME MEASURES: The primary outcome was incident diagnosis of CVD, comprising acute coronary syndrome, aortic aneurysm, aortic stenosis, atrial fibrillation or flutter, chronic ischaemic heart disease, heart failure, peripheral artery disease, second or third degree heart block, stroke (ischaemic, haemorrhagic, and unspecified), and venous thromboembolism (deep vein thrombosis or pulmonary embolism). Disease incidence rates were calculated individually and as a composite outcome of all 10 CVDs combined and were standardised for age and sex using the 2013 European standard population. Negative binomial regression models investigated temporal trends and variation by age, sex, and socioeconomic status. RESULTS: The mean age of the population was 70.5 years and 47.6% (n=784 904) were women. The age and sex standardised incidence of all 10 prespecified CVDs declined by 19% during 2000-19 (incidence rate ratio 2017-19 v 2000-02: 0.80, 95% confidence interval 0.73 to 0.88). The incidence of coronary heart disease and stroke decreased by about 30% (incidence rate ratios for acute coronary syndrome, chronic ischaemic heart disease, and stroke were 0.70 (0.69 to 0.70), 0.67 (0.66 to 0.67), and 0.75 (0.67 to 0.83), respectively). In parallel, an increasing number of diagnoses of cardiac arrhythmias, valve disease, and thromboembolic diseases were observed. As a result, the overall incidence of CVDs across the 10 conditions remained relatively stable from the mid-2000s. Age stratified analyses further showed that the observed decline in coronary heart disease incidence was largely restricted to age groups older than 60 years, with little or no improvement in younger age groups. Trends were generally similar between men and women. A socioeconomic gradient was observed for almost every CVD investigated. The gradient did not decrease over time and was most noticeable for peripheral artery disease (incidence rate ratio most deprived v least deprived: 1.98 (1.87 to 2.09)), acute coronary syndrome (1.55 (1.54 to 1.57)), and heart failure (1.50 (1.41 to 1.59)). CONCLUSIONS: Despite substantial improvements in the prevention of atherosclerotic diseases in the UK, the overall burden of CVDs remained high during 2000-19. For CVDs to decrease further, future prevention strategies might need to consider a broader spectrum of conditions, including arrhythmias, valve diseases, and thromboembolism, and examine the specific needs of younger age groups and socioeconomically deprived populations.

2-Year Outcomes of an Atrial Shunt Device in HFpEF/HFmrEF: Results From REDUCE LAP-HF II.

BACKGROUND: The REDUCE LAP-HF II (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure II) trial found that, compared with a sham procedure, the Corvia Atrial Shunt did not improve outcomes in heart failure with preserved or mildly reduced ejection fraction. However, after 12-month follow-up, "responders" (peak-exercise pulmonary vascular resistance <1.74 WU and absence of a cardiac rhythm management device) were identified. OBJECTIVES: This study sought to determine: 1) the overall efficacy and safety of the atrial shunt vs sham control after 2 years of follow-up; and 2) whether the benefits of atrial shunting are sustained in responders during longer-term follow-up or are offset by adverse effects of the shunt. METHODS: The study analyzed 2-year outcomes in the overall REDUCE LAP-HF II trial, as well as in responder and nonresponder subgroups. The primary endpoint was a hierarchical composite of cardiovascular death or nonfatal ischemic/embolic stroke, total heart failure events, and change in health status. RESULTS: In 621 randomized patients, there was no difference between the shunt (n = 309) and sham (n = 312) groups in the primary endpoint (win ratio: 1.01 [95% CI: 0.82-1.24]) or its individual components at 2 years. Shunt patency at 24 months was 98% in shunt-treated patients. Cardiovascular mortality and nonfatal ischemic stroke were not different between the groups; however, major adverse cardiac events were more common in those patients assigned to the shunt compared with sham (6.9% vs 2.7%; P = 0.018). More patients randomized to the shunt had an increase in right ventricular volume of ≥30% compared with the sham control (39% vs 28%, respectively; P < 0.001), but right ventricular dysfunction was uncommon and not different between the treatment groups. In responders (n = 313), the shunt was superior to sham (win ratio: 1.36 [95% CI: 1.02-1.83]; P = 0.037, with 51% fewer HF events [incidence rate ratio: 0.49 [95% CI: 0.25-0.95]; P = 0.034]). In nonresponders (n = 265), atrial shunting was inferior to sham (win ratio: 0.73 [95% CI: 0.54-0.98]). CONCLUSIONS: At 2 years of follow-up in REDUCE LAP-HF II, there was no difference in efficacy between the atrial shunt and sham groups in the overall trial group. The potential clinical benefit identified in the responder group after 1 and 2 years of follow-up is currently being evaluated in the RESPONDER-HF (Re-Evaluation of the Corvia Atrial Shunt Device in a Precision Medicine Trial to Determine Efficacy in Mildly Reduced or Preserved Ejection Fraction Heart Failure) trial. (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure II [REDUCE LAP-HF II]; NCT03088033).

A nationwide, population-based study on specialized care for acute heart failure throughout the COVID-19 pandemic.

AIMS: The COVID-19 pandemic disrupted the delivery of care for patients with heart failure (HF), leading to fewer HF hospitalizations and increased mortality. However, nationwide data on quality of care and long-term outcomes across the pandemic are scarce. METHODS AND RESULTS: We used data from the National Heart Failure Audit (NHFA) linked to national records for hospitalization and deaths. We compared pre-COVID (2018-2019), COVID (2020), and late/post-COVID (2021-2022) periods. Data for 227 250 patients admitted to hospital with HF were analysed and grouped according to the admission year and the presence of HF with (HFrEF) or without reduced ejection fraction (non-HFrEF). The median age at admission was 81 years (interquartile range 72-88), 55% were men (n = 125 975), 87% were of white ethnicity (n = 102 805), and 51% had HFrEF (n = 116 990). In-hospital management and specialized cardiology care were maintained throughout the pandemic with an increasing percentage of patients discharged on disease-modifying medications over time (p < 0.001). Long-term outcomes improved over time (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.90-0.95, p < 0.001), mainly driven by a reduction in cardiovascular death. Receiving specialized cardiology care was associated with better long-term outcomes both for those who had HFrEF (HR 0.79, 95% CI 0.77-0.82, p < 0.001) and for those who had non-HFrEF (HR 0.87, 95% CI 0.85-0.90, p < 0.001). CONCLUSIONS: Despite the disruption of healthcare systems, the clinical characteristics of patients admitted with HF were similar and the overall standard of care was maintained throughout the pandemic. Long-term survival of patients hospitalized with HF continued to improve after COVID-19, especially for HFrEF.

Percutaneous repair of moderate-to-severe or severe functional mitral regurgitation in patients with symptomatic heart failure: Baseline characteristics of patients in the RESHAPE-HF2 trial and comparison to COAPT and MITRA-FR trials.

AIM: The RESHAPE-HF2 trial is designed to assess the efficacy and safety of the MitraClip device system for the treatment of clinically important functional mitral regurgitation (FMR) in patients with heart failure (HF). This report describes the baseline characteristics of patients enrolled in the RESHAPE-HF2 trial compared to those enrolled in the COAPT and MITRA-FR trials. METHODS AND RESULTS: The RESHAPE-HF2 study is an investigator-initiated, prospective, randomized, multicentre trial including patients with symptomatic HF, a left ventricular ejection fraction (LVEF) between 20% and 50% with moderate-to-severe or severe FMR, for whom isolated mitral valve surgery was not recommended. Patients were randomized 1:1 to a strategy of delivering or withholding MitraClip. Of 506 patients randomized, the mean age of the patients was 70 ± 10 years, and 99 of them (20%) were women. The median EuroSCORE II was 5.3 (2.8-9.0) and median plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) was 2745 (1407-5385) pg/ml. Most patients were prescribed beta-blockers (96%), diuretics (96%), angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitors (82%) and mineralocorticoid receptor antagonists (82%). The use of sodium-glucose cotransporter 2 inhibitors was rare (7%). Cardiac resynchronization therapy (CRT) devices had been previously implanted in 29% of patients. Mean LVEF, left ventricular end-diastolic volume and effective regurgitant orifice area (EROA) were 31 ± 8%, 211 ± 76 ml and 0.25 ± 0.08 cm2, respectively, whereas 44% of patients had mitral regurgitation severity of grade 4+. Compared to patients enrolled in COAPT and MITRA-FR, those enrolled in RESHAPE-HF2 were less likely to have mitral regurgitation grade 4+ and, on average, HAD lower EROA, and plasma NT-proBNP and higher estimated glomerular filtration rate, but otherwise had similar age, comorbidities, CRT therapy and LVEF. CONCLUSION: Patients enrolled in RESHAPE-HF2 represent a third distinct population where MitraClip was tested in, that is one mainly comprising of patients with moderate-to-severe FMR instead of only severe FMR, as enrolled in the COAPT and MITRA-FR trials. The results of RESHAPE-HF2 will provide crucial insights regarding broader application of the transcatheter edge-to-edge repair procedure in clinical practice.

Urinary proteomic signature of mineralocorticoid receptor antagonism by spironolactone: evidence from the HOMAGE trial.

OBJECTIVE: Heart failure (HF) is characterised by collagen deposition. Urinary proteomic profiling (UPP) followed by peptide sequencing identifies parental proteins, for over 70% derived from collagens. This study aimed to refine understanding of the antifibrotic action of spironolactone. METHODS: In this substudy (n=290) to the Heart 'Omics' in Ageing Study trial, patients were randomised to usual therapy combined or not with spironolactone 25-50 mg/day and followed for 9 months. The analysis included 1498 sequenced urinary peptides detectable in ≥30% of patients and carboxyterminal propeptide of procollagen I (PICP) and PICP/carboxyterminal telopeptide of collagen I (CITP) as serum biomarkers of COL1A1 synthesis. After rank normalisation of biomarker distributions, between-group differences in their changes were assessed by multivariable-adjusted mixed model analysis of variance. Correlations between the changes in urinary peptides and in serum PICP and PICP/CITP were compared between groups using Fisher's Z transform. RESULTS: Multivariable-adjusted between-group differences in the urinary peptides with error 1 rate correction were limited to 27 collagen fragments, of which 16 were upregulated (7 COL1A1 fragments) on spironolactone and 11 downregulated (4 COL1A1 fragments). Over 9 months of follow-up, spironolactone decreased serum PICP from 81 (IQR 66-95) to 75 (61-90) µg/L and PICP/CITP from 22 (17-28) to 18 (13-26), whereas no changes occurred in the control group, resulting in a difference (spironolactone minus control) expressed in standardised units of -0.321 (95% CI 0.0007). Spironolactone did not affect the correlations between changes in urinary COL1A1 fragments and in PICP or the PICP/CITP ratio. CONCLUSIONS: Spironolactone decreased serum markers of collagen synthesis and predominantly downregulated urinary collagen-derived peptides, but upregulated others. The interpretation of these opposite UPP trends might be due to shrinking the body-wide pool of collagens, explaining downregulation, while some degree of collagen synthesis must be maintained to sustain vital organ functions, explaining upregulation. Combining urinary and serum fibrosis markers opens new avenues for the understanding of the action of antifibrotic drugs. TRIAL REGISTRATION NUMBER: NCT02556450.