Intravenous iron for heart failure, iron deficiency definitions, and clinical response: the IRONMAN trial.

BACKGROUND AND AIMS: What is the relationship between blood tests for iron deficiency, including anaemia, and the response to intravenous iron in patients with heart failure? METHODS: In the IRONMAN trial, 1137 patients with heart failure, ejection fraction ≤ 45%, and either serum ferritin < 100 µg/L or transferrin saturation (TSAT) < 20% were randomized to intravenous ferric derisomaltose (FDI) or usual care. Relationships were investigated between baseline anaemia severity, ferritin and TSAT, to changes in haemoglobin from baseline to 4 months, Minnesota Living with Heart Failure (MLwHF) score and 6-minute walk distance achieved at 4 months, and clinical events, including heart failure hospitalization (recurrent) or cardiovascular death. RESULTS: The rise in haemoglobin after administering FDI, adjusted for usual care, was greater for lower baseline TSAT (Pinteraction < .0001) and ferritin (Pinteraction = .028) and more severe anaemia (Pinteraction = .014). MLwHF scores at 4 months were somewhat lower (better) with FDI for more anaemic patients (overall Pinteraction = .14; physical Pinteraction = .085; emotional Pinteraction = .043) but were not related to baseline TSAT or ferritin. Blood tests did not predict difference in achieved walking distance for those randomized to FDI compared to control. The absence of anaemia or a TSAT ≥ 20% was associated with lower event rates and little evidence of benefit from FDI. More severe anaemia or TSAT < 20%, especially when ferritin was ≥100 µg/L, was associated with higher event rates and greater absolute reductions in events with FDI, albeit not statistically significant. CONCLUSIONS: This hypothesis-generating analysis suggests that anaemia or TSAT < 20% with ferritin > 100 µg/L might identify patients with heart failure who obtain greater benefit from intravenous iron. This interpretation requires confirmation.

Is atrial fibrillation in HFpEF a distinct phenotype? Insights from multiparametric MRI and circulating biomarkers.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF) frequently co-exist. There is a limited understanding on whether this coexistence is associated with distinct alterations in myocardial remodelling and mechanics. We aimed to determine if patients with atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) represent a distinct phenotype. METHODS: In this secondary analysis of adults with HFpEF (NCT03050593), participants were comprehensively phenotyped with stress cardiac MRI, echocardiography and plasma fibroinflammatory biomarkers, and were followed for the composite endpoint (HF hospitalisation or death) at a median of 8.5 years. Those with AF were compared to sinus rhythm (SR) and unsupervised cluster analysis was performed to explore possible phenotypes. RESULTS: 136 subjects were included (SR = 75, AF = 61). The AF group was older (76 ± 8 vs. 70 ± 10 years) with less diabetes (36% vs. 61%) compared to the SR group and had higher left atrial (LA) volumes (61 ± 30 vs. 39 ± 15 mL/m2, p < 0.001), lower LA ejection fraction (EF) (31 ± 15 vs. 51 ± 12%, p < 0.001), worse left ventricular (LV) systolic function (LVEF 63 ± 8 vs. 68 ± 8%, p = 0.002; global longitudinal strain 13.6 ± 2.9 vs. 14.7 ± 2.4%, p = 0.003) but higher LV peak early diastolic strain rates (0.73 ± 0.28 vs. 0.53 ± 0.17 1/s, p < 0.001). The AF group had higher levels of syndecan-1, matrix metalloproteinase-2, proBNP, angiopoietin-2 and pentraxin-3, but lower level of interleukin-8. No difference in clinical outcomes was observed between the groups. Three distinct clusters were identified with the poorest outcomes (Log-rank p = 0.029) in cluster 2 (hypertensive and fibroinflammatory) which had equal representation of SR and AF. CONCLUSIONS: Presence of AF in HFpEF is associated with cardiac structural and functional changes together with altered expression of several fibro-inflammatory biomarkers. Distinct phenotypes exist in HFpEF which may have differing clinical outcomes.

A novel, small-volume subcutaneous furosemide formulation delivered by an abdominal patch infusor device in patients with heart failure: results of two phase I studies.

AIMS: Subcutaneous (SC) furosemide has potential advantages over intravenous (IV) furosemide by enabling self-administration or administration by a lay caregiver, such as facilitating early discharge, preventing hospitalizations, and in palliative care. A high-concentration, pH-neutral furosemide formulation has been developed for SC administration via a small patch infusor pump. We aimed to compare the bioavailability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of a new SC furosemide formulation with conventional IV furosemide and describe the first use of a bespoke mini-pump to administer this formulation. METHODS AND RESULTS: A novel pH-neutral formulation of SC furosemide containing 80 mg furosemide in ∼2.7 mL (infused over 5 h) was investigated. The first study was a PK/PD study of SC furosemide compared with 80 mg IV furosemide administered as a bolus in ambulatory patients with heart failure (HF). The primary outcome was absolute bioavailability of SC compared with IV furosemide. The second study investigated the same SC furosemide preparation delivered by a patch infusor in patients hospitalized with HF. Primary outcome measures were treatment-emergent adverse events, infusion site pain, device performance, and PK measurements.The absolute bioavailability of SC furosemide in comparison to IV furosemide was 112%, resulting in equivalent diuresis and natriuresis. When SC furosemide was administered via the patch pump, there were no treatment-emergent adverse events and 95% of participants reported no/minor discomfort at the infusion site. CONCLUSION: The novel preparation of SC furosemide had similar bioavailability to IV furosemide. Administration via a patch pump was feasible and well tolerated.

The Relationship Between Cardiac Troponin in People Hospitalised for Exacerbation of COPD and Major Adverse Cardiac Events (MACE) and COPD Readmissions.

Background: No single biomarker currently risk stratifies chronic obstructive pulmonary disease (COPD) patients at the time of an exacerbation, though previous studies have suggested that patients with elevated troponin at exacerbation have worse outcomes. This study evaluated the relationship between peak cardiac troponin and subsequent major adverse cardiac events (MACE) including all-cause mortality and COPD hospital readmission, among patients admitted with COPD exacerbation. Methods: Data from five cross-regional hospitals in England were analysed using the National Institute of Health Research Health Informatics Collaborative (NIHR-HIC) acute coronary syndrome database (2008-2017). People hospitalised with a COPD exacerbation were included, and peak troponin levels were standardised relative to the 99th percentile (upper limit of normal). We used Cox Proportional Hazard models adjusting for age, sex, laboratory results and clinical risk factors, and implemented logarithmic transformation (base-10 logarithm). The primary outcome was risk of MACE within 90 days from peak troponin measurement. Secondary outcome was risk of COPD readmission within 90 days from peak troponin measurement. Results: There were 2487 patients included. Of these, 377 (15.2%) patients had a MACE event and 203 (8.2%) were readmitted within 90 days from peak troponin measurement. A total of 1107 (44.5%) patients had an elevated troponin level. Of 1107 patients with elevated troponin at exacerbation, 256 (22.8%) had a MACE event and 101 (9.0%) a COPD readmission within 90 days from peak troponin measurement. Patients with troponin above the upper limit of normal had a higher risk of MACE (adjusted HR 2.20, 95% CI 1.75-2.77) and COPD hospital readmission (adjusted HR 1.37, 95% CI 1.02-1.83) when compared with patients without elevated troponin. Conclusion: An elevated troponin level at the time of COPD exacerbation may be a useful tool for predicting MACE in COPD patients. The relationship between degree of troponin elevation and risk of future events is complex and requires further investigation.

Aortic valve intervention rates in patients of different ethnicity with severe aortic stenosis in Leicestershire, UK.

OBJECTIVES: To explore the ethnic differences in patients undergoing aortic valve (AV) intervention for severe aortic stenosis (AS) in Leicestershire, UK. METHODS: Retrospective 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. RESULTS: Of 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. CONCLUSION: The 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.

Intravenous ferric derisomaltose in patients with heart failure and iron deficiency in the UK (IRONMAN): an investigator-initiated, prospective, randomised, open-label, blinded-endpoint trial.

BACKGROUND: For patients with heart failure, reduced left ventricular ejection fraction and iron deficiency, intravenous ferric carboxymaltose administration improves quality of life and exercise capacity in the short-term and reduces hospital admissions for heart failure up to 1 year. We aimed to evaluate the longer-term effects of intravenous ferric derisomaltose on cardiovascular events in patients with heart failure. METHODS: IRONMAN was a prospective, randomised, open-label, blinded-endpoint trial done at 70 hospitals in the UK. Patients aged 18 years or older with heart failure (left ventricular ejection fraction ≤45%) and transferrin saturation less than 20% or serum ferritin less than 100 µg/L were eligible. Participants were randomly assigned (1:1) using a web-based system to intravenous ferric derisomaltose or usual care, stratified by recruitment context and trial site. The trial was open label, with masked adjudication of the outcomes. Intravenous ferric derisomaltose dose was determined by patient bodyweight and haemoglobin concentration. The primary outcome was recurrent hospital admissions for heart failure and cardiovascular death, assessed in all validly randomly assigned patients. Safety was assessed in all patients assigned to ferric derisomaltose who received at least one infusion and all patients assigned to usual care. A COVID-19 sensitivity analysis censoring follow-up on Sept 30, 2020, was prespecified. IRONMAN is registered with ClinicalTrials.gov, NCT02642562. FINDINGS: Between Aug 25, 2016, and Oct 15, 2021, 1869 patients were screened for eligibility, of whom 1137 were randomly assigned to receive intravenous ferric derisomaltose (n=569) or usual care (n=568). Median follow-up was 2·7 years (IQR 1·8-3·6). 336 primary endpoints (22·4 per 100 patient-years) occurred in the ferric derisomaltose group and 411 (27·5 per 100 patient-years) occurred in the usual care group (rate ratio [RR] 0·82 [95% CI 0·66 to 1·02]; p=0·070). In the COVID-19 analysis, 210 primary endpoints (22·3 per 100 patient-years) occurred in the ferric derisomaltose group compared with 280 (29·3 per 100 patient-years) in the usual care group (RR 0·76 [95% CI 0·58 to 1·00]; p=0·047). No between-group differences in deaths or hospitalisations due to infections were observed. Fewer patients in the ferric derisomaltose group had cardiac serious adverse events (200 [36%]) than in the usual care group (243 [43%]; difference -7·00% [95% CI -12·69 to -1·32]; p=0·016). INTERPRETATION: For a broad range of patients with heart failure, reduced left ventricular ejection fraction and iron deficiency, intravenous ferric derisomaltose administration was associated with a lower risk of hospital admissions for heart failure and cardiovascular death, further supporting the benefit of iron repletion in this population. FUNDING: British Heart Foundation and Pharmacosmos.

Selective protein kinase C inhibition switches time-dependent glucose cardiotoxicity to cardioprotection.

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/ß-dependent, and providing PKCα/ß are inhibited, elevated glucose confers cardioprotection. Short pre-treatments with high glucose were used to investigate time-dependent glucose cardiotoxicity, with PKCα/ß 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/ß 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/ß inhibition. Selective PKCα/ß inhibition enhances protection suggesting glycaemic control with PKC inhibition as a potential cardioprotective therapeutics in myocardial infarction and elective cardiac surgery.

Rationale and design of a randomised trial of intravenous iron in patients with heart failure.

OBJECTIVES: For 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 of Intravenous iron treatment 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. METHODS: IRONMAN 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 <100 µg/L and/or TSAT <20%) were enrolled if they had either a current or recent hospitalisation for heart failure or elevated plasma concentrations of a natriuretic peptide. Participants were randomised to receive, or not to receive, intravenous ferric derisomaltose in addition to guideline-recommended therapy for HFrEF. Every 4 months, intravenous iron was administered if either ferritin was <100 µg/L or, provided ferritin was ≤400 µg/L, TSAT was <25%. The primary endpoint is a composite of total hospitalisations for heart failure and cardiovascular death. Hospitalisation and deaths due to infection are safety endpoints. RESULTS: Trial 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. CONCLUSIONS: IRONMAN 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 NUMBER: NCT02642562.

Effect of AZD9977 and spironolactone on serum potassium in heart failure with preserved or mildly reduced ejection fraction, and renal impairment: A randomized trial.

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+ ) in patients with heart failure (HF) with preserved or mildly reduced ejection fraction (EF; ≥40%), and renal impairment. Patients with HF with EF greater than or equal to 40% and estimated glomerular filtration rate of 40-70 ml/min/1.73 m2 were randomized to once-daily AZD9977 100 mg or spironolactone 25 mg for 14 days, up-titrated to AZD9977 200 mg or spironolactone 50 mg for another 14 days. The primary end point was relative change (%) in sK+ for AZD9977 versus spironolactone (baseline to day 28). Serum/urinary electrolytes, fractional excretion (FE) of Na+ /K+ , plasma aldosterone, cortisol, and renin, and safety were also assessed. Sixty-eight patients were randomized (AZD9977, n = 33; spironolactone, n = 35). Mean (SD) age was 73.0 (8.5) years, 51.5% men. Mean sK+ change from baseline to day 28 was 5.7% (AZD9977) and 4.2% (spironolactone), and 1.5% and 4.2% at day 14. Relative change (95% confidence interval) in sK+ with AZD9977 versus spironolactone was -0.3% (-5.3% to 4.4%; day 28), and 3.4% (-0.8% to 7.5%; day 14). Median increase from baseline in plasma aldosterone at day 28 was 89.8 pmol/L for AZD9977 and 67.4 pmol/L for spironolactone. Median FE of K+ was 12.9% (AZD9977) and 10.1% (spironolactone). AZD9977 was well-tolerated. No discontinuations due to hyperkalemia occurred with either treatment. Evidence of target engagement for AZD9977 with a favorable safety profile, supports further evaluation of AZD9977 in patients with HF and renal impairment.

Overstimulation of the ergoreflex-A possible mechanism to explain symptoms in long COVID.

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.

Prevalence and Prognostic Significance of Microvascular Dysfunction in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: The pathophysiological and clinical significance of microvascular dysfunction (MVD) in patients with heart failure with preserved ejection fraction (HFpEF) remains uncertain. OBJECTIVES: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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).

Benefits of sodium glucose cotransporter 2 inhibitors across the spectrum of cardiovascular diseases.

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.

Diagnostic accuracy of screening questionnaires for obstructive sleep apnoea in adults in different clinical cohorts: a systematic review and meta-analysis.

PURPOSE: The majority of individuals with clinically significant obstructive sleep apnoea (OSA) are undiagnosed and untreated. A simple screening tool may support risk stratification, identification, and appropriate management of at-risk patients. Therefore, this systematic review and meta-analysis evaluated and compared the accuracy and clinical utility of existing screening questionnaires for identifying OSA in different clinical cohorts. METHODS: We conducted a systematic review and meta-analysis of observational studies assessing the diagnostic value of OSA screening questionnaires. We identified prospective studies, validated against polysomnography, and published to December 2020 from online databases. To pool the results, we used random effects bivariate binomial meta-analysis. RESULTS: We included 38 studies across three clinical cohorts in the meta-analysis. In the sleep clinic cohort, the Berlin questionnaire's pooled sensitivity for apnoea-hypopnoea index (AHI) ≥ 5, ≥ 15, and ≥ 30 was 85%, 84%, and 89%, and pooled specificity was 43%, 30%, and 33%, respectively. The STOP questionnaire's pooled sensitivity for AHI ≥ 5, ≥ 15, and ≥ 30 was 90%, 90%, and 95%, and pooled specificity was 31%, 29%, and 21%. The pooled sensitivity of the STOP-Bang questionnaire for AHI ≥ 5, ≥ 15, and ≥ 30 was 92%, 95%, and 96%, and pooled specificity was 35%, 27%, and 28%. In the surgical cohort (AHI ≥ 15), the Berlin and STOP-Bang questionnaires' pooled sensitivity were 76% and 90% and pooled specificity 47% and 27%. CONCLUSION: Among the identified questionnaires, the STOP-Bang questionnaire had the highest sensitivity to detect OSA but lacked specificity. Subgroup analysis considering other at-risk populations was not possible. Our observations are limited by the low certainty level in available data.

Right Side of the Heart Pulmonary Circulation Unit Involvement in Left-Sided Heart Failure: Diagnostic, Prognostic, and Therapeutic Implications.

Although long neglected, the right side of the heart (RH) is now widely accepted as a pivotal player in heart failure (HF) either with reduced or preserved ejection fraction. The chronic overload of the pulmonary microcirculation results in an initial phase characterized by right ventricular (RV) hypertrophy, right atrial dilation, and diastolic dysfunction. This progresses to overt RH failure when RV dilation and systolic dysfunction lead to RV-pulmonary arterial (RV-PA) uncoupling with low RV output. In the context of its established relevance to progression of HF, clinicians should consider assessment of the RH with information from clinical assessment, biomarkers, and imaging. Notably, no single parameter can predict prognosis alone in HF. Assessments simultaneously should encompass RV systolic function, pulmonary pressures, an estimation of RV-PA coupling, and RH morphologic features. Despite a large volume of evidence indicating the relevance of RH function to the clinical syndrome of HF, evidence-based management strategies are lacking. Targeting RH dysfunction in HF should be an objective of future investigations, being an unmet need in the current management of HF.

Effect of Neprilysin Inhibition on Left Ventricular Remodeling in Patients With Asymptomatic Left Ventricular Systolic Dysfunction Late After Myocardial Infarction.

BACKGROUND: Patients with left ventricular (LV) systolic dysfunction after myocardial infarction are at a high risk of developing heart failure. The addition of neprilysin inhibition to renin angiotensin system inhibition may result in greater attenuation of adverse LV remodeling as a result of increased levels of substrates for neprilysin with vasodilatory, antihypertrophic, antifibrotic, and sympatholytic effects. METHODS: We performed a prospective, multicenter, randomized, double-blind, active-comparator trial comparing sacubitril/valsartan 97/103 mg twice daily with valsartan 160 mg twice daily in patients ≥3 months after myocardial infarction with a LV ejection fraction ≤40% who were taking a renin angiotensin system inhibitor (equivalent dose of ramipril ≥2.5 mg twice daily) and a ß-blocker unless contraindicated or intolerant. Patients in New York Heart Association class ≥II or with signs and symptoms of heart failure were excluded. The primary outcome was change from baseline to 52 weeks in LV end-systolic volume index measured using cardiac magnetic resonance imaging. Secondary outcomes included other magnetic resonance imaging measurements of LV remodeling, change in NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity cardiac troponin I, and a patient global assessment of change questionnaire. RESULTS: From July 2018 to June 2019, we randomized 93 patients with the following characteristics: mean age, 60.7±10.4 years; median time from myocardial infarction, 3.6 years (interquartile range, 1.2-7.2); mean LV ejection fraction, 36.8%±7.1%; and median NT-proBNP, 230 pg/mL (interquartile range, 124-404). Sacubitril/valsartan, compared with valsartan, did not significantly reduce LV end-systolic volume index; adjusted between-group difference, -1.9 mL/m2 (95% CI, -4.9 to 1.0); P=0.19. There were no significant between-group differences in NT-proBNP, high-sensitivity cardiac troponin I, LV end-diastolic volume index, left atrial volume index, LV ejection fraction, LV mass index, or patient global assessment of change. CONCLUSIONS: In patients with asymptomatic LV systolic dysfunction late after myocardial infarction, treatment with sacubitril/valsartan did not have a significant reverse remodeling effect compared with valsartan. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03552575.

Exercise Intolerance in Heart Failure with Preserved Ejection Fraction.

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.

Plasma P-selectin is a predictor of mortality in heart failure with preserved ejection fraction.

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 < 0.017) and myocardial infarction detected by cardiovascular magnetic resonance imaging (HR 2.377; 95% CI 1.114-5.075; P < 0.025) remained significant predictors. In a final model comprising all three parameters, only P-selectin (HR 1.447; 95% CI 1.130-1.853; P < 0.003) and MAGGIC scores (HR 1.555; 95% CI 1.136-2.129; P < 0.006) remained independent predictors of death. Adding P-selectin (0.618, P = 0.035) improved the area under the receiver operating characteristic curve for mortality prediction for MAGGIC scores (0.647, P = 0.009) to 0.710, P < 0.0001. CONCLUSIONS: Plasma P-selectin is an independent predictor of mortality and provides incremental prognostic information beyond MAGGIC scores in HFpEF.

Non-adherence to heart failure medications predicts clinical outcomes: assessment in a single spot urine sample by liquid chromatography-tandem mass spectrometry (results of a prospective multicentre study).

AIMS: 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). METHODS AND RESULTS: 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, ß-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 < 0.0005). Regional differences within Europe were observed. On multivariable analyses, non-adherence to ACEi/ARBs and ß-blockers was associated with an increased risk of the composite endpoint [hazard ratio (HR) 1.38, 95% confidence interval (CI) 1.09-1.95, P = 0.008 and HR 1.48, 95% CI 1.12-1.96, P = 0.006, respectively). Non-adherence to ß-blockers was also associated with an increased risk of death (HR 2.48, 95% CI 1.67-3.68, P < 0.0005). Patients who were non-adherent to loop diuretics were healthier and had a decreased risk of the composite endpoint (HR 0.69, 95% CI 0.51-0.93, P = 0.014). Non-adherence to mineralocorticoid receptor antagonists was not related to any clinical outcome. CONCLUSION: Non-adherence to medications, assessed by a single urine test, is common and predicts clinical outcomes in patients with HFrEF.

The need for improved discharge criteria for hospitalised patients with COVID-19-implications for patients in long-term care facilities.

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.