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ObjectivesFor patients with a reduced left ventricular ejection fraction (LVEF) heart failure with reduced ejection fraction (HFrEF) and iron deficiency, administration of intravenous iron improves symptoms, exercise capacity and may in the following 12 months, reduce hospitalisations for heart failure. The Effectiveness ofIntravenous irontreatment versus standard care in patients with heart failure and iron deficiency (IRONMAN) trial evaluated whether the benefits of intravenous iron persist in the longer term and impact on morbidity and mortality.MethodsIRONMAN is a prospective, randomised, open-label, blinded endpoint (PROBE) event-driven trial. Patients aged ≥18 years with HFrEF (LVEF ≤45%) and evidence of iron deficiency (ferritin ResultsTrial recruitment was completed across 70 UK hospital sites in October 2021. Participants were followed until the end of March 2022. We plan to report the results by November 2022.ConclusionsIRONMAN will determine whether repeated doses of intravenous ferric derisomaltose are beneficial and safe for the long-term treatment of a broad range of patients with HFrEF and iron deficiency.Trial registration numberNCT02642562.

Exercise intolerance represents a typical feature of heart failure with preserved ejection fraction (HFpEF), and is associated with a poor quality of life, frequent hospitalizations, and increased all-cause mortality. The cardiopulmonary exercise test is the best method to quantify exercise intolerance, and allows detection of the main mechanism responsible for the exercise limitation, influencing treatment and prognosis. Exercise training programs improve exercise tolerance in HFpEF. However, studies are needed to identify appropriate type and duration. This article discusses the pathophysiology of exercise limitation in HFpEF, describes methods of determining exercise tolerance class, and evaluates prognostic implications and potential therapeutic strategies.

Hyperglycaemia at the time of myocardial infarction has an adverse effect on prognosis irrespective of a prior diagnosis of diabetes, suggesting glucose is the damaging factor. In ex vivo models of ischaemia, we demonstrated that deleterious effects of acutely elevated glucose are PKCα/β-dependent, and providing PKCα/β are inhibited, elevated glucose confers cardioprotection. Short pre-treatments with high glucose were used to investigate time-dependent glucose cardiotoxicity, with PKCα/β inhibition investigated as a potential mechanism to reverse the toxicity. Freshly isolated non-diabetic rat cardiomyocytes were exposed to elevated glucose to investigate the time-dependence toxic effects. High glucose challenge for >7.5 min was cardiotoxic, proarrhythmic and lead to contractile failure, whilst cardiomyocytes exposed to metabolic inhibition following 5-min high glucose, displayed a time-dependent protection lasting ∼15 min. This protection was further enhanced with PKCα/β inhibition. Cardioprotection was measured as a delay in contractile failure and KATP channel activation, improved contractile and Ca2+ transient recovery and increased cell survival. Finally, the effects of pre-ischaemic treatment with high glucose in a whole-heart coronary ligation protocol, where protection was evident with PKCα/β inhibition. Selective PKCα/β inhibition enhances protection suggesting glycaemic control with PKC inhibition as a potential cardioprotective therapeutics in myocardial infarction and elective cardiac surgery.

ObjectivesTo explore the ethnic differences in patients undergoing aortic valve (AV) intervention for severe aortic stenosis (AS) in Leicestershire, UK.MethodsRetrospective cohort study of all surgical aortic valve replacement (SAVR) and transcatheter aortic valve implantation (TAVI) at a single tertiary centre between April 2017 and March 2022, using local registry data.ResultsOf the 1231 SAVR and 815 TAVI performed, 6.5% and 3.7% were in ethnic minority patients, respectively. Based on the 2011 Census data for those with a Leicestershire postcode, crude cumulative rate of SAVR (n=489) was 0.64 per 1000 population overall and 0.69, 0.46 and 0.36 in White, Asian and Black populations, respectively; and 0.50 per 1000 population overall for TAVI (n=383), with 0.59, 0.16 and 0.06 for White, Asian and Black populations, respectively. Asians undergoing SAVR and TAVI were 5 and 3 years younger, respectively, than white patients with more comorbidities and a worse functional status.The age-adjusted cumulative rates for SAVR were 0.62 vs 0.72 per 1000 population for White and Asian patients and 0.51 vs 0.39 for TAVI. Asians were less likely to undergo SAVR and TAVI than White patients, with a risk ratio (RR) of 0.66 (0.50–0.87) and 0.27 (0.18–0.43), respectively, but the age-adjusted RR was not statistically significant.ConclusionThe crude rates of AV interventions are lower in Asian patients compared with the White population in Leicestershire, although age-adjusted rates were not statistically different. Further research to determine the sociodemographic differences in prevalence, incidence, mechanisms and treatment of AS across the UK is required.

Background Frailty is common in patients with chronic heart failure (CHF) and is associated with poor outcomes. The natural history of frail patients with CHF is unknown. Methods Frailty was assessed using the clinical frailty scale (CFS) in 467 consecutive patients with CHF (67% male, median age 76 years, median NT-proBNP 1156 ng/L) attending a routine follow-up visit. Those with CFS > 4 were classified as frail. We investigated the relation between frailty and treatments, hospitalisation and death in patients with CHF. Results 206 patients (44%) were frail. Of 291 patients with HF with reduced ejection fraction (HeFREF), those who were frail (N = 117; 40%) were less likely to receive optimal treatment, with many not receiving a renin–angiotensin–aldosterone system inhibitor (frail: 25% vs. non-frail: 4%), a beta-blocker (16% vs. 8%) or a mineralocorticoid receptor antagonist (50% vs 41%). By 1 year, there were 56 deaths and 322 hospitalisations, of which 25 (45%) and 198 (61%), respectively, were due to non-cardiovascular (non-CV) causes. Most deaths (N = 46, 82%) and hospitalisations (N = 215, 67%) occurred in frail patients. Amongst frail patients, 43% of deaths and 64% of hospitalisations were for non-CV causes; 58% of cardiovascular (CV) deaths were due to advancing HF. Among non-frail patients, 50% of deaths and 57% of hospitalisations were for non-CV causes; all CV deaths were due to advancing HF. Conclusion Frailty in patients with HeFREF is associated with sub-optimal medical treatment. Frail patients are more likely to die or be admitted to hospital, but whether frail or not, many events are non-CV. Graphical abstract

This phase Ib study compared the effects of AZD9977, a selective mineralocorticoid receptor modulator with predicted low hyperkalemia risk, with spironolactone on serum potassium (sK

Long COVID refers to a multitude of symptoms that persist long after SARS-CoV-2 infection. Fatigue and breathlessness are the most common symptoms of long COVID across a range of studies. They are also cardinal symptoms of chronic heart failure (CHF). In this review, we propose that fatigue and breathlessness in patients with long COVID may be explained by skeletal muscle abnormalities, in a manner similar to patients with CHF. The ergoreflex is a cardiorespiratory reflex activated by exercise, which couples ventilation and cardiovascular function to exercise intensity. At least part of the symptomatology of CHF is related to abnormal skeletal muscle and an enhanced ergoreflex, resulting in heightened sympathetic, vasoconstrictor and ventilator drives. Similarly, SARS-CoV-2 infection results in a hyperinflammatory and hypercatabolic state. This leads to reduction in skeletal muscle mass and altered function. We postulate that the ergoreflex is chronically overstimulated, resulting in fatigue and breathlessness. Exercise training preserves muscle mass and function as well as reduces ergoreflex activation; therefore may have a role in improving symptoms associated with long COVID. Should the ergoreflex be proven to be an important pathophysiological mechanism of long COVID, tailored exercise interventions should be trialed with the aim of improving both symptoms and perhaps outcomes in patients with long COVID.

Tenascin-C is a marker of interstitial fibrosis. We assessed whether plasma Tenascin-C differed between heart failure with preserved ejection fraction (HFpEF) and asymptomatic controls and related to clinical outcomes. Prospective, observational study of 172 age- and sex-matched subjects (HFpEF n = 130; controls n = 42, age 73 ± 9, males 50%) who underwent phenotyping with 20 plasma biomarkers, echocardiography, cardiac MRI and 6-minute-walk-testing. The primary endpoint was the composite of all-cause death/HF hospitalisation. Tenascin-C was higher in HFpEF compared to controls (13.7 [10.8–17.3] vs (11.1 [8.9–12.9] ng/ml, p p During follow-up (median 1428 days), there were 61 composite events (21 deaths, 40 HF hospitalizations). In multivariable Cox regression analysis, Tenascin-C (adjusted hazard ratio [HR] 1.755, 95% confidence interval [CI] 1.305–2.360; p p = 0.039) were independently associated with adverse outcomes. In HFpEF, plasma Tenascin-C is higher compared to age- and sex-matched controls and a strong predictor of adverse outcomes. Trial registration: ClinicalTrials.gov: NCT03050593

A 46-year-old man presented following an episode of palpitations after a run. Symptoms were of sudden onset with palpitations, chest tightness and light-headedness, with a recorded heart rate of 240 beats/min. Three-lead ECG trace taken by the paramedics showed broad complex tachycardia with negative deflection in the inferior leads (see online supplementary files). ### Supplementary data [heartjnl-2020-316902supp001.pdf] ### Supplementary data [heartjnl-2020-316902supp002.pdf] ### Supplementary video [heartjnl-2020-316902supp003.avi] ### Supplementary video [heartjnl-2020-316902supp004.avi] Symptoms resolved spontaneously before arrival to the hospital. A strip from the 12-lead ECG on arrival is shown further. He reported a similar episode 2 weeks prior during a cycle ride. He had no significant medical history and was physically active, with a …

Background/aims Obstructive sleep apnoea is a public health problem that remains under recognised. Despite obstructive sleep apnoea being associated with the incidence and progression of heart failure, clinician awareness is lacking within and across clinical specialities. This study aimed to evaluate heart failure clinicians' knowledge, attitudes and clinical practice in the diagnosis and treatment of obstructive sleep apnoea. Methods This study used a web-based, cross-sectional survey, using the modified Obstructive Sleep Apnoea Knowledge and Attitudes questionnaire among heart failure clinicians in the UK. Results The survey was completed by 102 heart failure clinicians. Out of a possible score of 37, the median knowledge scores were 29 (78%; interquartile range 26–31), 26 (70%; interquartile range 22–28) and 18 (49%; interquartile range 16.5–23.5) for doctors, nurses and pharmacists, respectively. The majority of doctors and nurses felt that obstructive sleep apnoea was important; however, confidence in the identification and management of obstructive sleep apnoea was low across all three groups of clinicians. Conclusions There is a knowledge deficit regarding the diagnosis and treatment of obstructive sleep apnoea among heart failure clinicians.

Aims None of the existing studies on adherence have directly measured levels of all medications (or their metabolites) in patients with heart failure (HF). Methods and results We used liquid chromatography–tandem mass spectrometry to measure the presence of prescribed drugs (diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and mineralocorticoid receptor antagonists) in the urine of patients reviewed 4–6 weeks after hospitalization with HF. Patients were unaware that adherence was being assessed. Of the 341 patients studied, 281 (82.4%) were adherent, i.e. had all prescribed drugs of interest detectable in their urine. Conversely, 60 patients (17.6%) were partially or completely non-adherent. Notably, 24 of the 60 were non-adherent to only diuretic therapy and only seven out of all 341 patients studied (2.1%) were completely non-adherent to all prescribed HF drugs. There were no major differences in baseline characteristics between adherent and non-adherent patients. Conclusion Non-adherence, assessed using a single spot urine measurement of drug levels, was confirmed in one of five patients evaluated 4–6 weeks after hospitalization with HF.

Aims To report the extent and distribution of myocardial injury and its impact on left ventricular systolic function with cardiac magnetic resonance imaging (CMR) following spontaneous coronary artery dissection (SCAD) and to investigate predictors of myocardial injury. Methods and results One hundred and fifty-eight angiographically confirmed SCAD-survivors (98% female) were phenotyped by CMR and compared in a case–control study with 59 (97% female) healthy controls (44.5 ± 8.4 vs. 45.0 ± 9.1 years). Spontaneous coronary artery dissection presentation was with non-ST-elevation myocardial infarction in 95 (60.3%), ST-elevation myocardial infarction (STEMI) in 52 (32.7%), and cardiac arrest in 11 (6.9%). Left ventricular function in SCAD-survivors was generally well preserved with small reductions in ejection fraction (57 ± 7.2% vs. 60 ± 4.9%, P < 0.01) and increases in left ventricular dimensions (end-diastolic volume: 85 ± 14 mL/m2 vs. 80 ± 11 mL/m2, P < 0.05; end-systolic volume: 37 ± 11 mL/m2 vs. 32 ± 7 mL/m2, P 4 were associated with larger infarcts [>10% left ventricular (LV) mass]. Conclusion The majority of patients presenting with SCAD have no or small infarctions and preserved ejection fraction. Patients presenting with STEMI, TIMI 0/1 flow, multivessel SCAD and those with features of connective tissue disorders are more likely to have larger infarcts.

Background Recently, the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) proposed a four-domain approach to assess frailty in patients with heart failure (HF), to tailor treatment and potentially improve outcomes. The efficacy of such approach in detecting frailty and predicting outcome in patients with HF is unknown. Aim To study the prevalence and prognostic value of four different types of frailty deficits: clinical, physical, cognitive and social frailty in ambulatory patients with HF. Methods We assessed prospectively consecutive patients attending a routine follow-up visit. Patients with ≥5 non-HF comorbidities were classified as having a clinical deficit. Those who scored ≥3 using the Fried criteria were classified as having a physical deficit. Those who failed to complete a clock test accurately were classified as having a cognitive deficit. Those who lived alone or in a residential home were classified as having a social deficit. All patients were followed for a minimum of 1 year. The primary end point is all-cause mortality. Results We enrolled 467 patients (67% male, median (25th–75th centile) age 76 (69–82) years, median (25th–75th centile) NT-proBNP 1156 (469–2463) ng/L). 65% of patients had clinical deficits, 52% had a physical deficit, 39% had a social deficit and 18% had a cognitive deficit. 28% had 2, 19% had 3, 8% of patients had all 4 deficits; 16% had none. An increasing number of frailty deficits was associated with worse symptoms, higher NT-proBNP and less likelihood of being prescribed guideline-indicated HF treatment. During a median follow-up of 554 days, 82 patients died. The presence of any frailty deficit was associated with increased risk of mortality. (Figure 1) The more frailty deficit a patient had, the higher the risk of mortality (Figure 2). A base model (including age, body mass index, NYHA class and log [NT-proBNP]) for predicting mortality at 1 year achieved a C-statistic of 0.78. Addition of all four deficits improved the performance of the base model (C-statistic = 0.82). Conclusion Clinical, physical, cognitive and social deficits are common in patients with HF and are associated with a poor outcome. Future studies should evaluate how a domain-based approach can be used to optimise care for frail patients with HF. Funding Acknowledgement Type of funding sources: None. Figure 1Figure 2

Peritoneal ultrafiltration (PuF) has been employed for severe heart failure (HF), but evidence for its benefit is lacking. The Peritoneal Dialysis for Heart Failure (PDHF) study was a multicenter prospective randomized controlled trial which aimed to investigate this issue. The trial stopped early due to inadequate recruitment. We describe methods, trial activity, and lessons learned. The trial aimed to recruit 130 participants with severe diuretic-resistant HF (New York Heart Association [NYHA] 3/4) and chronic kidney disease (CKD) stage 3/4 on optimal medical treatment for ≥ 4 weeks from 6 UK centers. Participants were randomized to either continuation of conventional HF treatment or to additionally receiving PuF (1 overnight exchange using Icodextrin dialysate). Primary outcome was change in 6-minute walk test (6MWT) between baseline and 28 weeks (end of trial). Secondary outcomes were changes in patient reported quality of life as assessed by the Kansas City Cardiomyopathy Questionnaire, short form 36 (SF 36) health survey results, hospitalization, and mortality. Over a 2-year period, 290 patients were screened from which only 20 met inclusion criteria and 10 were recruited. Reasons for ineligibility were fluctuating estimated glomerular filtration rate (eGFR), suboptimal HF treatment, frailty, and patients being too unwell for randomization. Barriers to recruitment included patient frailty, with some participants considered only when they were at end of life, unwillingness to engage in an invasive therapy, and suboptimal coordination between cardiology and renal services. This is a challenging patient group in which to perform research, and lessons learned from the peritoneal dialysis (PD)-HF trial will be helpful in the planning of future studies in this area.

Key points Acute hyperglycaemia at the time of a heart attack worsens the outcome for the patient. Acute hyperglycaemia is not limited to diabetic patients and can be due to a stress response in non-diabetics. This study suggests that the damaging cardiac effects of hyperglycaemia can be reversed by selective PKC inhibition. If PKCα/β isoforms are inhibited, then high glucose itself becomes protective against ischaemic damage. Selective PKC inhibition may therefore be a useful therapeutic tool to limit the damage that can occur during a heart attack by stress-induced hyperglycaemia. Abstract Hyperglycaemia has a powerful association with adverse prognosis for patients with acute coronary syndromes (ACS). Previous work shows that high glucose prevents ischaemic preconditioning and causes electrical and mechanical disruption via protein kinase C α/β (PKCα/β) activation. The present study aimed to: (i) determine whether the adverse clinical association of hyperglycaemia in ACS can be replicated in preclinical cellular models of ACS and (ii) determine the importance of PKCα/β activation to the deleterious effect of glucose. Freshly isolated rat, guinea pig or rabbit cardiomyocytes were exposed to simulated ischaemia after incubation in the presence of normal (5 mm) or high (20 mm) glucose in the absence or presence of small molecule or tat-peptide-linked PKCαβ inhibitors. In each of the four conditions, the following hallmarks of cardioprotection were recorded using electrophysiology or fluorescence imaging: cardiomyocyte contraction and survival, action potential stability and time to failure, intracellular calcium and ATP, mitochondrial depolarization, ischaemia-sensitive leak current, and time to Kir 6.2 opening. High glucose alone resulted in decreased cardiomyocyte contraction and survival; however, it also imparted cardioprotection in the presence of PKCα/β inhibitors. This cardioprotective phenotype displayed improvements in all of the measured parameters and decreased myocardium damage during whole heart coronary ligation experiments. High glucose is deleterious to cellular and whole-heart models of simulated ischaemia, in keeping with the clinical association of hyperglycaemia with an adverse outcome in ACS. PKCαβ inhibition revealed high glucose to show a cardioprotective phenotype in this setting. The results of the present study suggest the potential for the therapeutic application of PKCαβ inhibition in ACS associated with hyperglycaemia.

Background Proenkephalin (PENK), a stable endogenous opioid biomarker related to renal function, has prognostic utility in acute and chronic heart failure. We investigated the prognostic utility of PENK in heart failure with preserved ejection fraction (HFpEF), and its relationship to renal function, Body Mass Index (BMI), and imaging measures of diastolic dysfunction. Methods In this multicentre study, PENK was measured in 522 HFpEF patients (ejection fraction > 50%, 253 male, mean age 76.13 ± 10.73 years) and compared to 47 age and sex-matched controls. The primary endpoint was 2-years composite of all-cause mortality and/or heart failure rehospitalisation (HF). A subset (n = 163) received detailed imaging studies. Results PENK levels were raised in HFpEF (median [interquartile range] 88.9 [62.1–132.0]) compared to normal controls (56.3 [47.9–70.5]). PENK was correlated to urea, eGFR, Body Mass Index and E/e′ (rs 0.635, − 0.741, − 0.275, 0.476, respectively, p

Funding Acknowledgements Type of funding sources: Other. Main funding source(s): National Institute for Health Research Leicester Cardiovascular Biomedical Research Centre Background Quantifying pulmonary transit time (PTT) from cardiac magnetic resonance (CMR) first pass perfusion imaging is a novel technique for the evaluation of haemodynamic congestion in heart failure. Previous studies have demonstrated that PTT is prolonged in patients with heart failure with reduced ejection fraction (HFrEF) and that it provides independent prognostic information in this patient group. However, the potential diagnostic and prognostic roles of PTT assessment in patients with heart failure with preserved ejection fraction (HFpEF) remain to be established. Aim To compare PTT in healthy controls and in patients with HFpEF, and to determine the prognostic value of PTT in HFpEF. Methods In a prospective, observational study, HFpEF and age-matched control subjects underwent multi-parametric CMR at 3-Tesla, comprising quantitative left ventricular volumetric assessment using a standard steady-state free precession (SSFP) pulse sequence, and first-pass perfusion imaging at rest using a T1-weighted segmented inversion recovery gradient echo sequence (following injection of 0.04mmol/kg of contrast). PTT was calculated as the time interval between the peaks of signal intensity curves in the right and left ventricular blood pools (defined on the basal slice of the rest perfusion images). The primary endpoint was the composite of death or hospitalisation with heart failure. Results 88 HFpEF patients (age 73 ± 9 years, 51% male, EF 56.4 ± 5.6%) and 40 controls (age 73 ± 5 years, 43% male, EF 58.5 ± 4.7%) were studied. PTT was comparable in HFpEF patients (7.7 ± 3.8s) and in healthy controls (7.5 ± 1.8, p = 0.69). Normalised to cardiac cycle lengths, PTT remained comparable in HFpEF patients and healthy controls (8.5 ± 4.0 cardiac cycles versus 7.8 ± 1.6 cardiac cycles, respectively, p = 0.19). In the HFpEF group, during median follow-up of 3.4 years, there were 38 events (25 hospitalisations with heart failure, 13 deaths); a significant relationship between survival and PTT was not demonstrated (HR 1.06 [0.99,1.14] for a one-unit increase, p = 0.098). Conclusion In HFpEF, PTT is not prolonged compared with PTT in healthy subjects. Unlike in HFrEF, PTT does not appear to be diagnostically or prognostically significant in HFpEF. Figure 1: Graph showing signal intensity curves in the right (red) and left (green) ventricular blood pools Figure 2: Kaplan-Meier plot showing comparable rates of the composite endpoint in patients with PTT greater/less than median PTT (8 cardiac cycles)

The pathophysiological and clinical significance of microvascular dysfunction (MVD) in patients with heart failure with preserved ejection fraction (HFpEF) remains uncertain.The aim of this study was to use cardiovascular magnetic resonance to: 1) quantify coronary microvascular function; 2) examine the relationship between perfusion and fibrosis; and 3) evaluate the impact of MVD and fibrosis on long-term clinical outcomes.In a prospective, observational study, patients with HFpEF and control subjects underwent multiparametric cardiovascular magnetic resonance (comprising assessment of left ventricular volumetry, perfusion, and fibrosis [focal by late gadolinium enhancement and diffuse by extracellular volume]). The primary endpoint was the composite of death or hospitalization with heart failure.One hundred and one patients with HFpEF (mean age 73 ± 9 years, mean ejection fraction 56% ± 5%) and 43 control subjects (mean age 73 ± 5 years, mean ejection fraction 58% ± 5%) were studied. Myocardial perfusion reserve (MPR) was lower in patients with HFpEF versus control subjects (1.74 ± 0.76 vs 2.22 ± 0.76; P = 0.001). MVD (defined as MPR 2.0) was present in 70% of patients with HFpEF (vs 48% of control subjects; P = 0.014). There was no significant linear correlation between MPR and diffuse fibrosis (r = -0.10; P = 0.473) and no difference in MPR between those with and without focal fibrosis (mean difference -0.03; 95% CI: -0.37 to 0.30). In the HFpEF group, during median follow-up of 3.1 years, there were 45 composite events. MPR was independently predictive of clinical outcome following adjustment for clinical, blood, and imaging parameters (1 SD increase: HR: 0.673 [95% CI: 0.463 to 0.978; P = 0.038]; HR: 0.694 [95% CI: 0.491 to 0.982; P = 0.039]; and HR: 0.690 [95% CI: 0.489 to 0.973; P = 0.034], respectively).MVD is highly prevalent among patients with HFpEF and is an independent predictor of prognosis. The lack of correlation between MVD and fibrosis may challenge the assertion of a direct causal link between these entities. (Developing Imaging and Plasma Biomarkers in Describing Heart Failure With Preserved Ejection Fraction [DIAMONDHFpEF]; NCT03050593).

Background:\ud A small minority of people with coronavirus disease 2019 (COVID‐19) develop a severe illness, characterised by inflammation, microvascular damage and coagulopathy, potentially leading to myocardial injury, venous thromboembolism (VTE) and arterial occlusive events. People with risk factors for or pre‐existing cardiovascular disease may be at greater risk.\ud \ud Objectives:\ud To assess the prevalence of pre‐existing cardiovascular comorbidities associated with suspected or confirmed cases of COVID‐19 in a variety of settings, including the community, care homes and hospitals. We also assessed the nature and rate of subsequent cardiovascular complications and clinical events in people with suspected or confirmed COVID‐19.\ud \ud Search methods:\ud We conducted an electronic search from December 2019 to 24 July 2020 in the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, covid‐19.cochrane.org, ClinicalTrials.gov and EU Clinical Trial Register.\ud \ud Selection criteria:\ud We included prospective and retrospective cohort studies, controlled before‐and‐after, case‐control and cross‐sectional studies, and randomised controlled trials (RCTs). We analysed controlled trials as cohorts, disregarding treatment allocation. We only included peer‐reviewed studies with 100 or more participants, and excluded articles not written in English or only published in pre‐print servers.\ud \ud Data collection and analysis:\ud Two review authors independently screened the search results and extracted data. Given substantial variation in study designs, reported outcomes and outcome metrics, we undertook a narrative synthesis of data, without conducting a meta‐analysis. We critically appraised all included studies using the Joanna Briggs Institute (JBI) checklist for prevalence studies and the JBI checklist for case series.\ud \ud Main results:\ud We included 220 studies. Most of the studies originated from China (47.7%) or the USA (20.9%); 9.5% were from Italy. A large proportion of the studies were retrospective (89.5%), but three (1.4%) were RCTs and 20 (9.1%) were prospective.\ud \ud Using JBI’s critical appraisal checklist tool for prevalence studies, 75 studies attained a full score of 9, 57 studies a score of 8, 31 studies a score of 7, 5 studies a score of 6, three studies a score of 5 and one a score of 3; using JBI’s checklist tool for case series, 30 studies received a full score of 10, six studies a score of 9, 11 studies a score of 8, and one study a score of 5\ud \ud We found that hypertension (189 studies, n = 174,414, weighted mean prevalence (WMP): 36.1%), diabetes (197 studies, n = 569,188, WMP: 22.1%) and ischaemic heart disease (94 studies, n = 100,765, WMP: 10.5%) are highly prevalent in people hospitalised with COVID‐19, and are associated with an increased risk of death. In those admitted to hospital, biomarkers of cardiac stress or injury are often abnormal, and the incidence of a wide range of cardiovascular complications is substantial, particularly arrhythmias (22 studies, n = 13,115, weighted mean incidence (WMI) 9.3%), heart failure (20 studies, n = 29,317, WMI: 6.8%) and thrombotic complications (VTE: 16 studies, n = 7700, WMI: 7.4%).\ud \ud Authors' conclusions:\ud This systematic literature review indicates that cardiometabolic comorbidities are common in people who are hospitalised with a COVID‐19 infection, and cardiovascular complications are frequent. We plan to update this review and to conduct a formal meta‐analysis of outcomes based on a more homogeneous selected subsample of high‐certainty studies.

Aims: \ud Liquid chromatography-mass spectrometry (LC-MS/MS) is an objective new technique to assess non-adherence to medications. We used this method to study the prevalence, predictors and outcomes of non-adherence in patients with heart failure with reduced left ventricular ejection fraction (HFrEF).\ud \ud Methods and results: \ud This study included 1296 patients with HFrEF from BIOSTAT-CHF, a study that aimed to optimise guideline-recommended therapies. Angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists, β-blockers and loop diuretics were measured in a single spot urine sample at 9 months using LC-MS/MS. The relationship between medication non-adherence and the composite endpoint of all-cause death or heart failure hospitalisation, over a median follow-up of 21 months, was evaluated. Non-adherence to at least one prescribed medication was observed in 45.9% of patients. The strongest predictor of non-adherence was non-adherence to any of the other medication classes (P

Sodium glucose cotransporter 2 inhibitors (SGLT2i) have emerged as a class of medications with positive cardiovascular (CV) effects across a spectrum of patients with and without type 2 diabetes (T2D). In heart failure with reduced ejection fraction, there is clear evidence that SGLT2i reduce hospitalisations and mortality regardless of the presence of diabetes, and they are now recognised as the fourth pillar of pharmacological management. Recent trial data also indicate promising effects in heart failure with preserved ejection fraction. In patients with T2D and atherosclerotic CV diseases, multiple CV outcomes trials have shown reductions in major adverse CV events. Meta-analysis of these trials also shows lower rates of incident and recurrent atrial fibrillation with SGLT2i. Concerns regarding utilisation in patients with chronic kidney disease have been allayed in trials showing SGLT2i in fact have renoprotective effects. Questions still remain regarding the safety of SGLT2i in the acute heart failure setting and immediately post myocardial infarction, as well as in patients with more advanced stages of chronic kidney disease. Furthermore, studies are underway evaluating SGLT2i in patients with heart valve disease, where positive effects on left ventricular remodelling may, for example, improve functional mitral regurgitation. In this review, we summarise the available evidence of recent CV outcomes trials of SGLT2i, focusing particularly on the application of these agents across various CV diseases. We detail evidence to support increased utilisation of these drugs, which in many cases will reduce mortality and improve quality of life in patients routinely encountered by the CV specialist physician.

Aims The aim of the study was to assess the association of P‐selectin with outcomes in heart failure with preserved ejection fraction (HFpEF). Methods and results This is a prospective, observational study of 130 HFpEF patients who underwent clinical profiling, blood sampling, 6 min walk testing, Minnesota Living with Heart Failure Questionnaire evaluation, echocardiography, cardiovascular magnetic resonance imaging, calculation of the Meta‐Analysis Global Group in Chronic Heart Failure (MAGGIC) risk scores, and blinded plasma P‐selectin measurement. Patients were followed up for the endpoint of all‐cause mortality. The HFpEF subgroup with higher P‐selectin levels [overall median 26 372, inter‐quartile range (19 360–34 889) pg/mL] was associated with lower age, higher heart rate, less prevalent atrial fibrillation, more frequent current smoking status, and lower right ventricular end‐diastolic volumes. During follow‐up (median 1428 days), there were 38 deaths. Following maximal sensitivity and specificity receiver operating characteristic curve analysis, P‐selectin levels above 35 506 pg/mL were associated with greater risk of all‐cause mortality [hazard ratio (HR) 2.700; 95% confidence interval (CI) 1.416–5.146; log‐rank P = 0.002]. Following multivariable Cox proportional hazards regression analysis and when added to MAGGIC scores, only P‐selectin (adjusted HR 1.707; 95% CI 1.099–2.650; P

There is a paucity of data characterizing right ventricular performance in heart failure with preserved ejection fraction (HFpEF) using the gold standard of cardiovascular magnetic resonance imaging (CMR). We aimed to assess the proportion of right ventricular systolic dysfunction (RVD) in HFpEF and the relation to clinical outcomes. As part of a single-centre, prospective, observational study, 183 subjects (135 HFpEF, and 48 age- and sex-matched controls) underwent extensive characterization with CMR. transthoracic echocardiography, blood sampling and six-minute walk testing. Patients were followed for the composite endpoint of death or HF hospitalization. RVD (defined as right ventricular ejection fraction

Background Quantifying the activity of the adrenomedullin system might help to monitor and guide treatment in acute heart failure (AHF) patients. The aims were to (1) identify AHF patients with marked benefit or harm from specific treatments at hospital discharge and (2) predict mortality by quantifying the adrenomedullin system activity. Methods This was a prospective multicentre study. AHF diagnosis and phenotype were centrally adjudicated by two independent cardiologists among patients presenting to the emergency department with acute dyspnoea. Adrenomedullin system activity was quantified using the biologically active component, bioactive adrenomedullin (bio-ADM), and a prohormone fragment, midregional proadrenomedullin (MR-proADM). Bio-ADM and MR-proADM concentrations were measured in a blinded fashion at presentation and at discharge. Interaction with specific treatments at discharge and the utility of these biomarkers on predicting outcomes during 365-day follow-up were assessed. Results Among 1886 patients with adjudicated AHF, 514 patients (27.3%) died during 365-day follow-up. After adjusting for age, creatinine, and treatment at discharge, patients with bio-ADM plasma concentrations above the median (> 44.6 pg/mL) derived disproportional benefit if treated with diuretics (interaction p values n = 764) (interaction p values p p Conclusions Quantifying the adrenomedullin’s system activity may help to personalise post-discharge diuretic treatment and enable accurate risk-prediction in AHF.

Aims The effects of serelaxin, a recombinant form of human relaxin-2 peptide, on vascular function in the coronary microvascular and systemic macrovascular circulation remain largely unknown. This mechanistic, clinical study assessed the effects of serelaxin on myocardial perfusion, aortic stiffness, and safety in patients with stable coronary artery disease (CAD). Methods and results In this multicentre, double-blind, parallel-group, placebo-controlled study, 58 patients were randomized 1:1 to 48 h intravenous infusion of serelaxin (30 µg/kg/day) or matching placebo. The primary endpoints were change from baseline to 47 h post-initiation of the infusion in global myocardial perfusion reserve (MPR) assessed using adenosine stress perfusion cardiac magnetic resonance imaging, and applanation tonometry-derived augmentation index (AIx). Secondary endpoints were: change from baseline in AIx and pulse wave velocity, assessed at 47 h, Day 30, and Day 180; aortic distensibility at 47 h; pharmacokinetics and safety. Exploratory endpoints were the effect on cardiorenal biomarkers [N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hsTnT), endothelin-1, and cystatin C]. Of 58 patients, 51 were included in the primary analysis (serelaxin, n = 25; placebo, n = 26). After 2 and 6 h of serelaxin infusion, mean placebo-corrected blood pressure reductions of −9.6 mmHg (P = 0.01) and −13.5 mmHg (P = 0.0003) for systolic blood pressure and −5.2 mmHg (P = 0.02) and −8.4 mmHg (P = 0.001) for diastolic blood pressure occurred. There were no between-group differences from baseline to 47 h in global MPR (−0.24 vs. −0.13, P = 0.44) or AIx (3.49% vs. 0.04%, P = 0.21) with serelaxin compared with placebo. Endothelin-1 and cystatin C levels decreased from baseline in the serelaxin group, and there were no clinically relevant changes observed with serelaxin for NT-proBNP or hsTnT. Similar numbers of serious adverse events were observed in both groups (serelaxin, n = 5; placebo, n = 7) to 180-day follow-up. Conclusion In patients with stable CAD, 48 h intravenous serelaxin reduced blood pressure but did not alter myocardial perfusion.

Introduction Heart failure with preserved ejection fraction (HFpEF) accounts for approximately 50% of symptomatic heart failure. A recently proposed paradigm for the pathophysiology of HFpEF postulates a central inflammatory aetiology with coronary microvascular function at its core. However, the pathophysiological and clinical significance of microvascular dysfunction in HFpEF remains uncertain. Purpose Utilising cardiovascular magnetic resonance (CMR), we sought to (1) quantify coronary microvascular function, (2) evaluate the impact of microvascular dysfunction and fibrosis on long-term clinical outcomes and (3) examine the relationship between myocardial perfusion and fibrosis. Methods In a prospective, observational study, 147 subjects (104 HFpEF without a prior history or CMR evidence of coronary artery disease, and 43 asymptomatic controls) underwent multiparametric CMR, comprising left ventricular volumetric assessment, absolute quantitation of myocardial blood flow [MBF] during adenosine stress (140mcg/kg/min) and at rest, and evaluation of diffuse myocardial fibrosis (extracellular volume [ECV]). The primary endpoint was the composite of death or hospitalisation with heart failure. Results 104 HFpEF patients (mean age 73±9 years, mean ejection fraction 56%) and 43 controls (mean age 73±5 years, mean ejection fraction 58%) were studied. There was no significant difference in resting MBF (1.10±0.42ml/min/g in HFpEF subjects vs 1.00±0.38 ml/min/g in controls, p=0.23), though hyperaemic MBF was lower in HFpEF subjects (1.66±0.68 ml/min/g vs 1.97±0.59 ml/min/g, p=0.01). Myocardial perfusion reserve [MPR] was also lower in HFpEF subjects (1.73±0.75 vs 2.22±0.76; p Conclusion Microvascular dysfunction is highly prevalent in HFpEF and is associated with adverse clinical outcomes. The lack of correlation between abnormal myocardial perfusion and fibrosis challenges the assertion of a direct causal link between these entities. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): NIHR, BHF

In the COVID-19 pandemic, patients who are older and residents of long-term care facilities (LTCF) are at greatest risk of worse clinical outcomes. We reviewed discharge criteria for hospitalised COVID-19 patients from 10 countries with the highest incidence of COVID-19 cases as of 26 July 2020. Five countries (Brazil, Mexico, Peru, Chile and Iran) had no discharge criteria; the remaining five (USA, India, Russia, South Africa and the UK) had discharge guidelines with large inter-country variability. India and Russia recommend discharge for a clinically recovered patient with two negative reverse transcription polymerase chain reaction (RT-PCR) tests 24 h apart; the USA offers either a symptom based strategy—clinical recovery and 10 days after symptom onset, or the same test-based strategy. The UK suggests that patients can be discharged when patients have clinically recovered; South Africa recommends discharge 14 days after symptom onset if clinically stable. We recommend a unified, simpler discharge criteria, based on current studies which suggest that most SARS-CoV-2 loses its infectivity by 10 days post-symptom onset. In asymptomatic cases, this can be taken as 10 days after the first positive PCR result. Additional days of isolation beyond this should be left to the discretion of individual clinician. This represents a practical compromise between unnecessarily prolonged admissions and returning highly infectious patients back to their care facilities, and is of particular importance in older patients discharged to LTCFs, residents of which may be at greatest risk of transmission and worse clinical outcomes.

Aims This study aimed to assess plasma fibroblast growth factor 23 (FGF23) in patients with heart failure with preserved ejection fraction (HFpEF) and its relation to inflammation, renal function, clinical and imaging characteristics, exercise capacity, and prognosis. Methods and results We performed a prospective, observational study of 172 age‐matched and sex‐matched subjects (HFpEF n = 130; controls n = 42, age 73 ± 9, female 50%) who underwent plasma biomarker sampling, echocardiography, cardiac magnetic resonance imaging, and 6 min walk testing (6MWT). The primary endpoint was the composite of all‐cause death or HF hospitalization. FGF23 was higher in HFpEF compared with controls (62 [42–105] vs. 34 [22–41] pg/mL, P

Background Frailty is common in patients with chronic heart failure (CHF) and is associated with poor outcomes. We investigated the relation between frailty and treatments, hospitalisation and death in patients with CHF. Methods Frailty was assessed using the clinical frailty scale (CFS) in 467 consecutive patients with CHF (67% male, median (IQR) age 76 (69-82) years, median (IQR) NT-proBNP 1156 (469-2463) ng/L) attending a routine follow-up visit. Those with CFS>4 were classified as frail. We studied the primary cause of death and hospitalisations, ascertained from electronic records, autopsy reports and death certificates, within 1 year of enrolment. Results 206 patients (44%) were frail. Frail patients with heart failure with reduced ejection fraction (HFrEF) were less likely to receive optimal treatment, with many not receiving an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (frail: 25% vs non-frail: 4%), a beta-blocker (16% vs 8%) or a mineralocorticoid receptor antagonist (50% vs 41%). After 1 year, there were 56 deaths and 322 hospitalisations, 46 (82%) and 215 (67%) of which, respectively, occurred in frail patients. 43% of deaths in frail patients were due to non-cardiovascular causes (non-frail: 50%), commonly infections (60%). 58% of cardiovascular deaths in frail patients were due to HF progression (non-frail:100%). (Figure 1) 64% of hospitalisations in frail patients were due to non-cardiovascular causes (non-frail: 57%), commonly infections (34%) and falls (30%). 59% of cardiovascular hospitalisations in frail patients were due to decompensated HF (non-frail: 63%). (Figure 2) Conclusion Frailty in patients with CHF is associated with sub-optimal medical treatment for HFrEF and a high rate of non-cardiovascular events, suggesting that interventions not directed to treating CHF might be appropriate. Conflict of Interest None

Background: There are multiple risk factors for heart failure, but contemporary temporal trends according to sex, socioeconomic status, and ethnicity are unknown. Methods: Using a national UK general practice database linked to hospitalizations (1998–2017), 108 638 incident heart failure patients were identified. Differences in risk factors among patient groups adjusted for sociodemographic factors and age-adjusted temporal trends were investigated using logistic and linear regression. Results: Over time, a 5.3 year (95% CI, 5.2–5.5) age difference between men and women remained. Women had higher blood pressure, body mass index, and cholesterol than men ( P P =0.002). Diabetes mellitus prevalence increased more in men than in women (interaction P P 2 ), and lower smoking reductions (−1.2% versus −1.7%) than the most affluent. Ethnicity trend differences were insignificant, but South Asians were overall 6 years and the black group 9 years younger than whites. South Asians had more ischemic heart disease (+16.5% [95% CI, 14.3–18.6]), hypertension (+12.5% [95% CI, 10.5–14.3]), and diabetes mellitus (+24.3% [95% CI, 22.0–26.6]), and the black group had more hypertension (+12.3% [95% CI, 9.7–14.8]) and diabetes mellitus (+13.1% [95% CI, 10.1–16.0]) but lower ischemic heart disease (−10.6% [95% CI, −13.6 to −7.6]) than the white group. Conclusions: Population groups show distinct risk factor trend differences, indicating the need for contemporary tailored prevention programs.

Cardiovascular disease is an enormous socioeconomic burden worldwide and remains a leading cause of mortality and disability despite significant efforts to improve treatments and personalize healthcare. Heart failure is the main manifestation of cardiovascular disease and has reached epidemic proportions. Heart failure follows a loss of cardiac homeostasis, which relies on a tight regulation of gene expression. This regulation is under the control of multiple types of RNA molecules, some encoding proteins (the so-called messenger RNAs) and others lacking protein-coding potential, named noncoding RNAs. In this review article, we aim to revisit the notion of regulatory RNA, which has been thus far mainly confined to noncoding RNA. Regulatory RNA, which we propose to abbreviate as regRNA, can include both protein-coding RNAs and noncoding RNAs, as long as they contribute, directly or indirectly, to the regulation of gene expression. We will address the regulation and functional role of messenger RNAs, microRNAs, long noncoding RNAs, and circular RNAs (ie, regRNAs) in heart failure. We will debate the utility of regRNAs to diagnose, prognosticate, and treat heart failure, and we will provide directions for future work. ispartof: CIRCULATION vol:141 issue:4 pages:313-328 ispartof: location:United States status: published

AIMS: EMPEROR-Preserved is an ongoing trial evaluating the effect of empagliflozin in patients with heart failure with preserved ejection fraction (HFpEF). This report describes the baseline characteristics of the EMPEROR-Preserved cohort and compares them with patients enrolled in prior HFpEF trials. METHODS AND RESULTS: EMPEROR-Preserved is a phase III randomized, international, double-blind, parallel-group, placebo-controlled trial in which 5988 symptomatic HFpEF patients [left ventricular ejection fraction (LVEF) >40%] with and without type 2 diabetes mellitus (T2DM) have been enrolled. Patients were required to have elevated N-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations (i.e. >300 pg/mL in patients without and >900 pg/mL in patients with atrial fibrillation) along with evidence of structural changes in the heart or documented history of heart failure hospitalization. Among patients enrolled from various regions (45% Europe, 11% Asia, 25% Latin America, 12% North America), the mean age was 72 ± 9 years, 45% were women. Almost all patients had New York Heart Association class II or III symptoms (99.6%), and 23% had prior heart failure hospitalization within 12 months. Thirty-three percent of the patients had baseline LVEF of 41-50%. The mean LVEF (54 ± 9%) was slightly lower while the median NT-proBNP [974 (499-1731) pg/mL] was higher compared with previous HFpEF trials. Presence of comorbidities such as diabetes (49%) and chronic kidney disease (50%) were common. The majority of the patients were on angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitors (80%) and beta-blockers (86%), and 37% of patients were on mineralocorticoid receptor antagonists. CONCLUSION: When compared with prior trials in HFpEF, the EMPEROR-Preserved cohort has a somewhat higher burden of comorbidities, lower LVEF, higher median NT-proBNP and greater use of mineralocorticoid receptor antagonists at baseline. Results of the EMPEROR-Preserved trial will be available in 2021. ispartof: EUROPEAN JOURNAL OF HEART FAILURE vol:22 issue:12 pages:2383-2392 ispartof: location:England status: published

IntroductionThe pathophysiology of heart failure with preserved ejection fraction (HFpEF) remains incompletely defined. We aimed to characterize HFpEF compared to heart failure with reduced ejection fraction (HFrEF) and asymptomatic hypertensive or non-hypertensive controls.Materials and methodsProspective, observational study of 234 subjects (HFpEF n = 140; HFrEF n = 46, controls n = 48, age 73±8, males 49%) who underwent echocardiography, cardiovascular magnetic resonance imaging (CMR), plasma biomarker analysis (panel of 22) and 6-minute walk testing (6MWT). The primary end-point was the composite of all-cause mortality and/or HF hospitalization.ResultsCompared to controls both HF groups had lower exercise capacity, lower left ventricular (LV) EF, higher LV filling pressures (E/E', B-type natriuretic peptide [BNP], left atrial [LA] volumes), more right ventricular (RV) systolic dysfunction, more focal and diffuse fibrosis and higher levels of all plasma markers. LV remodeling (mass/volume) was different between HFpEF (concentric, 0.68±0.16) and HFrEF (eccentric, 0.47±0.15); pConclusionsHFpEF is a distinct pathophysiological entity compared to age- and sex-matched HFrEF and controls. HFpEF and HFrEF are associated with similar adverse outcomes. Inflammation is common in both HF phenotypes but cardiomyocyte stretch/stress is greater in HFrEF.

ObjectivesTo investigate ethnic differences in susceptibility to bradycardias in South Asian and white European patients in the UK by determining rates of permanent pacemaker (PPM) implantation for sinus node dysfunction (SND) and atrioventricular block (AVB) in each ethnic group.MethodsWe carried out a retrospective cohort study into new PPM implantation during the period from 1 May 2006 to 31 March 2014, in patients of South Asian and Caucasian ethnicity resident in Leicestershire, UK. Numbers of individuals at risk in each ethnic group were derived from UK National Census data of 2011. Crude, and age-standardised incidence rates and risk ratios per 1000 population of PPM implantation were calculated for Caucasians and South Asians.ResultsDuring the study period, 4883 individuals from the Leicestershire population of 980 328 underwent PPM implantation, a cumulative implantation rate of 4.98/1000 population. The population cumulative PPM implantation rate for SND was 1.74/1000, AVB 2.83/1000 and other indications 0.38/1000 population. The crude incidence in Caucasians (6.15/1000 population) was higher than in South Asians (1.07/1000 population) and remained higher after age standardisation (5.60/1000 vs 2.03/1000, PConclusionsRates of PPM implantation are lower in South Asians residing in the UK, compared with Caucasians. This observation raises the possibility of lower inherent susceptibility to bradycardias in South Asians compared with Caucasians. Studies aimed at identifying underlying mechanisms, including possible genetic differences, are warranted.

Purpose of Review The purpose of this review is to describe the extent and scope of acute heart failure (AHF), place it within its clinical context and highlight some of the difficulties in defining it as a pathophysiological entity. Recent Findings A diagnosis of AHF is made when patients present acutely with signs and symptoms of heart failure, often with decompensation of pre-existing cardiomyopathy. The most current guidelines classify based on clinical features at initial presentation and are used to both risk stratify and guide the management of haemodynamic compromise. Despite this, AHF remains a diagnosis with a poor prognosis and there is no therapy proven to have long-term mortality benefits. Summary We provide an introduction to AHF and discuss its definition, causes and precipitants. We also present epidemiological and demographic data to suggest that there is significant patient heterogeneity and that AHF is not a single pathology, but rather a range of pathophysiological entities. This poses a challenge when designing clinical trials and may, at least in part, explain why the results in this area have been largely disappointing.

Outcome measures used for the clinical evaluation of patients with acute heart failure differ between studies and may neither adequately address the characteristic presenting symptoms and signs nor reflect the pathophysiological processes involved. In-hospital worsening of heart failure (WHF) is associated with poor outcomes and thus a potential endpoint conveying clinically meaningful prognostic information. Current definitions of WHF are based on the combination of worsening symptoms and signs and the intensification of treatment during admission. Definitions vary across studies and do not fully account for baseline therapy or circumstances in which there is failure to respond to treatment. Further, there are limited data to inform healthcare professionals as to which patients are most at risk of developing in-hospital WHF. In this opinion piece, we review the definitions for WHF used in recent and ongoing clinical trials and propose a novel definition, which captures failure to respond to treatment as well as clinical worsening (deterioration of symptoms and signs) of the patient's condition. Such a definition, applied consistently across studies, would help clarify the characteristics of patients likely to develop in-hospital WHF, allow comparative assessments of the effectiveness of interventions, and help guide appropriate patient management in order to improve outcomes.

Cardiovascular disease, and particularly heart failure, is still a serious health care issue for which novel treatments and biomarkers are needed. The RNA family comprises different subgroups, among which the small-sized microRNAs and the larger long non-coding RNAs have shown some potential to aid in moving personalized health care of heart failure patients a step forward. Here, members of the Cardiolinc network review the recent findings suggesting that the less well-known circular RNAs may constitute a novel reservoir of therapeutic targets and biomarkers of heart failure. The knowledge of the mode of biogenesis of circular RNAs will first be reported, followed by a description of different features that make these RNA molecules of interest for the heart failure community. The functions of circular RNAs in the heart will be described, with some emphasis given to their regulation in the failing heart. Circulating in the bloodstream, circular RNAs have appeared as potential biomarkers and recent findings associated with the use of circular RNAs as heart failure biomarkers will be discussed. Finally, some directions for future research will be provided.