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.

Coronary artery disease and outcomes following transcatheter aortic valve implantation.

BACKGROUND: Aortic stenosis is a life-limiting condition for which transcatheter aortic valve implantation (TAVI) is an established therapy. Coronary artery disease (CAD) is frequently found in this patient group and optimal management in these patients remains uncertain. OBJECTIVES: We sought to examine the association of coexistent CAD on mortality and hospital readmission in patients undergoing TAVI. METHODS: In this observational cohort study, we examined patients who underwent TAVI and segregated them by the presence of obstructive epicardial CAD. The primary outcome was 3-year mortality with secondary outcomes being readmission for (1) all-causes, (2) a MACE (Major Adverse Cardiovascular Event) composite endpoint and (3) acute coronary syndrome. Subsidiary outcomes included patient angina and breathlessness scores. RESULTS: 898 patients underwent TAVI, of which 488 (54.3%) had unobstructed coronary arteries and 410 (45.7%) had obstructive CAD. Overall, n=298 (33.2%) patients experienced the primary mortality endpoint with no significant difference when stratified according to CAD (n=160 (32.9%) vs n=136 (33.2%), HR 0.98, CI 0.78 to 1.24). After multivariate analysis, the presence of CAD had no effect on the primary outcome (HR 0.98, CI 0.68 to 1.40). There was no significant difference in readmission for any cause (n=181, 37.1% (CAD) vs n=169, 41.2% (no CAD), p=0.23), including no significant difference on readmission for MACE (n=48, 9.8% (CAD) vs n=45, 11.0% (no CAD), p=0.11). CAD at the time of TAVI also did not alter breathlessness or angina scores before/after TAVI (p>0.05). CONCLUSION: Coexistent CAD had no significant association with mortality, any-cause readmission or symptoms for patients undergoing TAVI in our cohort.

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.

Symptoms and signs in patients with heart failure: association with 3-month hospitalisation and mortality.

OBJECTIVES: To determine the association between symptoms and signs reported in primary care consultations following a new diagnosis of heart failure (HF), and 3-month hospitalisation and mortality. DESIGN: Nested case-control study with density-based sampling. SETTING: Clinical Practice Research Datalink, linked to hospitalisation and mortality (1998-2020). PARTICIPANTS: Database cohort of 86 882 patients with a new HF diagnosis. In two separate analyses for (1) first hospitalisation and (2) death, we compared the 3-month history of symptoms and signs in cases (patients with HF with the event), with their respective controls (patients with HF without the respective event, matched on diagnosis date (±1 month) and follow-up time). Controls could be included more than once and later become a case. MAIN OUTCOME MEASURES: All-cause, HF and non-cardiovascular disease (non-CVD) hospitalisation and mortality. RESULTS: During a median follow-up of 3.22 years (IQR: 0.59-8.18), 56 677 (65%) experienced first hospitalisation and 48 146 (55%) died. These cases were matched to 356 714 and 316 810 HF controls, respectively. For HF hospitalisation, the strongest adjusted associations were for symptoms and signs of fluid overload: pulmonary oedema (adjusted OR 3.08; 95% CI 2.52, 3.64), shortness of breath (2.94; 2.77, 3.11) and peripheral oedema (2.16; 2.00, 2.32). Generic symptoms also showed significant associations: depression (1.50; 1.18, 1.82), anxiety (1.35; 1.06, 1.64) and pain (1.19; 1.10, 1.28). Non-CVD hospitalisation had the strongest associations with chest pain (2.93; 2.77, 3.09), fatigue (1.87; 1.73, 2.01), general pain (1.87; 1.81, 1.93) and depression (1.59; 1.44, 1.74). CONCLUSIONS: In the primary care HF population, routinely recorded cardiac and non-specific symptoms showed differential risk associations with hospitalisation and mortality.

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.

The Impact of Ferric Derisomaltose on Cardiovascular and Noncardiovascular Events in Patients With Anemia, Iron Deficiency, and Heart Failure With Reduced Ejection Fraction.

BACKGROUND: In some countries, intravenous ferric derisomaltose (FDI) is only licensed for treating iron deficiency with anemia. Accordingly, we investigated the effects of intravenous FDI in a subgroup of patients with anemia in the IRONMAN (Effectiveness of Intravenous (IV) Iron Treatment Versus Standard Care in Patients With Heart Failure and Iron Deficiency) trial. METHOD AND RESULTS: IRONMAN enrolled patients with heart failure, a left ventricular ejection fraction of ≤45%, and iron deficiency (ferritin <100 µg/L or transferrin saturation of <20%), 771 (68%) of whom had anemia (hemoglobin <12 g/dL for women and <13 g/dL for men). Patients were randomized, open label, to FDI (n = 397) or usual care (n = 374) and followed for a median of 2.6 years. The primary end point, recurrent hospitalization for heart failure and cardiovascular death, occurred less frequently for those assigned to FDI (rate ratio 0.78, 95% confidence interval 0.61-1.01; P = .063). First event analysis for cardiovascular death or hospitalization for heart failure, less affected by the coronavirus disease 2019 pandemic, gave similar results (hazard ratio 0.77, 95% confidence interval 0.62-0.96; P = .022). Patients randomized to FDI reported a better Minnesota Living with Heart Failure quality of life, for overall (P = .013) and physical domain (P = .00093) scores at 4 months. CONCLUSIONS: In patients with iron deficiency anemia and heart failure with reduced left ventricular ejection fraction, intravenous FDI improves quality of life and may decrease cardiovascular events.

Changing health related quality of life and outcomes in heart failure by age, sex and subtype.

Background: There are calls to integrate serial recordings of health related quality of life (HRQoL) into routine care, clinical trials and prognosis. Little is known about the relationship between change in HRQoL and outcomes in heart failure (HF) patients by age, sex and HF subtype. Method: From the Swedish Heart Failure Registry (SwedeHF; 2008-2019), patients were categorised by reduced (<40%, HFrEF), mildly-reduced (40-49%, HFmrEF) and preserved (≥50%, HFpEF) ejection fraction. HRQoL was measured using Euro-QoL-5D visual analogue scale (EQ5D-vas), collected at baseline and 1-year. Baseline EQ5D-vas scores were categorised by: "best" (76-100), "good" (51-75), "bad" (26-50), and "worst" (0-25). Change in EQ5D-vas was categorised as 'no significant change' (<5 points increase/decrease); some worsening (5-9 points decrease); considerable worsening (≥10 points decrease); some improvement (5-9 points increase); considerable improvement (≥10 points increase). Associations with admission and death were estimated and interactions with patient sub-groups tested. Findings: Among 23,553 patients (median age 74 [66-81] years, 8000 [34%] female), baseline EQ5D-vas was worse in older patients, women, and those with HFpEF compared to their respective counterparts. Compared to patients with the "best" EQ5D-vas, the adjusted associations for admission for those with "good", "bad" and "worst" EQ5D-vas were, respectively: HR 1.09 (1.04, 1.14), 1.27 (1.21, 1.33) and 1.39 (1.28, 1.51). Compared to no significant change in EQ5D-vas, the adjusted estimates for admission following some improvement, considerable improvement, some worsening and considerable worsening were, respectively: HR 0.91 (0.82, 1.01), 0.75 (0.70, 0.81), 1.04 (0.92, 1.16) and 1.25 (1.16, 1.35). Results were similar amongst groups and for HF admission and death. Interpretation: Change in HRQoL was an independent indicator of risk of admission and death in people with all HF subtypes, irrespective of age and sex. Funding: NIHR.

Biomarkers in heart failure: a focus on natriuretic peptides.

While progress has been made in the management of most aspects of cardiovascular disease, the incidence and prevalence of heart failure (HF) remains high. HF affects around a million people in the UK and has a worse prognosis than most cancers. Patients with HF are often elderly with complex comorbidities, making accurate assessment of HF challenging. A timely diagnosis and initiation of evidence-based treatments are key to prevent hospitalisation and improve outcomes in this population. Biomarkers have dramatically impacted the way patients with HF are evaluated and managed. The most studied biomarkers in HF are natriuretic peptides (NPs). Since their discovery in the 1980s, there has been an explosion of work in the field of NPs and they have become an important clinical tool used in everyday practice to guide diagnosis and prognostic assessment of patients with HF. In this article, we will review the physiology of NPs and study their biological effects. Then, we will discuss the role of NPs in the diagnosis, management and prognostication of patients with HF. We will also explore the role of NPs as a potential therapeutic agent.

Patient-Reported Status and Heart Failure Outcomes in Asia by Sex, Ethnicity, and Socioeconomic Status.

Background: In heart failure (HF), symptoms and health-related quality of life (HRQoL) are known to vary among different HF subgroups, but evidence on the association between changing HRQoL and outcomes has not been evaluated. Objectives: The authors sought to investigate the relationship between changing symptoms, signs, and HRQoL and outcomes by sex, ethnicity, and socioeconomic status (SES). Methods: Using the ASIAN-HF (Asian Sudden Cardiac Death in Heart Failure) Registry, we investigated associations between the 6-month change in a "global" symptoms and signs score (GSSS), Kansas City Cardiomyopathy Questionnaire overall score (KCCQ-OS), and visual analogue scale (VAS) and 1-year mortality or HF hospitalization. Results: In 6,549 patients (mean age: 62 ± 13 years], 29% female, 27% HF with preserved ejection fraction), women and those in low SES groups had higher symptom burden but lower signs and similar KCCQ-OS to their respective counterparts. Malay patients had the highest GSSS (3.9) and lowest KCCQ-OS (58.5), and Thai/Filipino/others (2.6) and Chinese patients (2.7) had the lowest GSSS scores and the highest KCCQ-OS (73.1 and 74.6, respectively). Compared to no change, worsening of GSSS (>1-point increase), KCCQ-OS (≥10-point decrease) and VAS (>1-point decrease) were associated with higher risk of HF admission/death (adjusted HR: 2.95 [95% CI: 2.14-4.06], 1.93 [95% CI: 1.26-2.94], and 2.30 [95% CI: 1.51-3.52], respectively). Conversely, the same degrees of improvement in GSSS, KCCQ-OS, and VAS were associated with reduced rates (HR: 0.35 [95% CI: 0.25-0.49], 0.25 [95% CI: 0.16-0.40], and 0.64 [95% CI: 0.40-1.00], respectively). Results were consistent across all sex, ethnicity, and SES groups (interaction P > 0.05). Conclusions: Serial measures of patient-reported symptoms and HRQoL are significant and consistent predictors of outcomes among different groups with HF and provide the potential for a patient-centered and pragmatic approach to risk stratification.

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.

Efficacy of empagliflozin in heart failure with preserved versus mid-range ejection fraction: a pre-specified analysis of EMPEROR-Preserved.

The EMPEROR-Preserved trial showed that the sodium-glucose co-transporter 2 inhibitor empagliflozin significantly reduces the risk of cardiovascular death or hospitalization for heart failure (HHF) in heart failure patients with left ventricular ejection fraction (LVEF) > 40%. Here, we report the results of a pre-specified analysis that separately evaluates these patients stratified by LVEF: preserved (≥ 50%) (n = 4,005; 66.9%) or mid-range (41-49%). In patients with LVEF ≥ 50%, empagliflozin reduced the risk of cardiovascular death or HHF (the primary endpoint) by 17% versus placebo (hazard ratio (HR) 0.83; 95% confidence interval (CI): 0.71-0.98, P = 0.024). For the key secondary endpoint, the HR for total HHF was 0.83 (95%CI: 0.66-1.04, P = 0.11). For patients with an LVEF of 41-49%, the HR for empagliflozin versus placebo was 0.71 (95%CI: 0.57-0.88, P = 0.002) for the primary outcome (Pinteraction = 0.27), and 0.57 (95%CI: 0.42-0.79, P < 0.001) for total HHF (Pinteraction = 0.06). These results, together with those from the EMPEROR-Reduced trial in patients with LVEF < 40%, support the use of empagliflozin across the full spectrum of LVEF in heart failure.

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.

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.

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.

Developing a core outcome set for patient-reported symptom monitoring to reduce hospital admissions for patients with heart failure.

AIMS: In patients with heart failure (HF), hospitalization rates are increasing, particularly for non-HF causes and over half may be avoidable. Self-monitoring of symptoms plays a key part in the early identification of deterioration. Our objective was to develop expert consensus for a core outcome set (COS) of symptoms to be monitored by patients, using validated single-item patient-reported outcome measures (PROMs), focused on the key priority of reducing admissions in HF. METHODS AND RESULTS: A rigorous COS development process incorporating systematic review, modified e-Delphi and nominal group technique (NGT) methods. Participants included 24 HF patients, 4 carers, 29 HF nurses, and 9 doctors. In three Delphi and NGT rounds, participants rated potential outcomes on their importance before a HF or a non-HF admission using a 5-point Likert scale. Opinion change between rounds was assessed and a two-thirds threshold was used for outcome selection.Item generation using systematic review identified 100 validated single-item PROMs covering 34 symptoms or signs, relevant to admission for people with HF. De-duplication and formal consensus processes, resulted in a COS comprising eight symptoms and signs; shortness of breath, arm or leg swelling, abdomen bloating, palpitations, weight gain, chest pain, anxiety, and overall health. In the NGT, a numerical rating scale was selected as the optimal approach to symptom monitoring. CONCLUSION: Recognition of a range of HF-specific and general symptoms, alongside comorbidities, is an important consideration for admission prevention. Further work is needed to validate and integrate the COS in routine care with the aim of facilitating faster identification of clinical deterioration.

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.