bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cerebral saturation is associated with physical activity and post-discharge mortality in heart failure patients
Authors: Zaghi A , Holm H , Korduner J , Bachus E , Molvin J , Jujic A , Nezami Z , Dieden A , Magnusson M 
Published: October 2022

Abstract

Background
The cross-sectional relationship between heart failure (HF) and cerebral oxygenation has been studied in the past but the prognostic significance of this relationship has been limited. Here, we aimed to assess the role of cerebral tissue oxygen saturation (SctO2) as a risk factor for HF mortality and rehospitalization as well as evaluate the association between SctO2 with physical activity in a Swedish prospective HF cohort.

Methods
Ninety-five patients hospitalized for HF (mean age 70 years; 21% women) were examined with near-infrared spectroscopy (NIRS) and screened for physical activity derived from questionnaires in the Swedish national public health survey. The median follow-up time to death and re-hospitalization was 1377 (interquartile range, 245–2392) and 293 (14–2363) days, respectively. Associations between SctO2 at rest, post-discharge mortality and re-hospitalization were analyzed using multivariable Cox regression analysis adjusted for age, sex, body-mass index, smoking, prevalence of atrial fibrillation, prevalence of diabetes and systolic blood pressure. The associations between SctO2 and self-reported physical activity were explored by using logistic regression analysis adjusted for the aforementioned risk factors.

Results
A total of 25 patients (26%) reported to be engaged in physical activity less than one hour throughout the week. In the fully adjusted Cox regression model, low SctO2 at rest was associated with post-discharge mortality (HR, 0.77; CI, 0.66–0.91; p=0.002). However, low SctO2 was not associated with post-discharge rehospitalization risk (HR, 0.94; CI, 0.88–1.01; p=0.092). In the fully adjusted logistic regression models, low SctO2 at rest was associated with decreased physical activity (&lt;1h per week), (OR 1.22; CI, 1.05–1.42; p=0.01).

Conclusion
We have demonstrated that low cerebral tissue oxygen saturation at rest is associated with post-discharge mortality in patients hospitalized for HF, independently of traditional risk factors. In addition, low cerebral tissue oxygen saturation at rest is associated with low physical activity. These findings highlight the role of cerebral saturation as a risk factor for cardiovascular prognosis, as well as underline the potential importance of taking cerebral perfusion into account when treating for heart failure.

Funding Acknowledgement
Type of funding sources: None.
Treatment with activin type ii receptor antibody improves cardiac function in mice after myocardial infarction
Authors: Bao W B , Haskins N H , Gonzalez C G , Ryden-Markinhutha K R , Gill B G , Guo L G , Jennbacken K J , Wang Q W , Hagvall S H 
Published: October 2022

Abstract

Background
Activin type ii receptor (ActRII) binding to its natural ligands including myostatin, activin, and growth development factor 11 negatively regulates muscle growth. Blockade of the ligands/ActRII signaling with human ActRII monoclonal antibody has been shown to increase body lean mass and reduce fat mass in patients with type 2 diabetes. However, the blockade effect on the ligands/ActRII signaling in heart failure with or without cardiac cachexia remains controversial. We hypothesized that the blockade effect on the ligands/ActRII signaling with a murine ActRII monoclonal antibody would improve cardiac function in a mouse model of heart failure.

Methods
Under anesthesia with isoflurane in oxygen, C57BL/6 mice were subjected to sham surgery or myocardial infarction (MI) by ligation of left anterior descending coronary artery to induce heart failure. Mice were randomized into treatment groups based on ejection fraction measured by Vevo 3100 Imaging System two weeks after MI. MI mice were treated weekly with vehicle (n=11), 10 mg/kg (n=12), or 20 mg/kg (n=12) ActRII antibody by subcutaneous injection for 8 weeks. Cardiac function was determined by Vevo 3100 Imaging system at 4, 8 weeks post-treatment, respectively. Body lean and fat mass were determined by Bruker's Whole Body Composition Analyzer. Myocardial infarct size was determined by Masson's trichrome staining on heart sections.

Results
Myocardial infarction markedly impaired cardiac function in mice. Ejection fraction reduced to 21.3±1.9% in MI mice compared to 56.3±1.2% in sham-operated mice (p&lt;0.0001). Weekly treatment with 10 mg/kg or 20 mg/kg antibody significantly improved ejection fraction to 32.1±2.8%, and 35.9±2.9%, respectively (p&lt;0.01 and p&lt;0.001). Antibody treatment in MI mice also reduced MI-induced lung congestion by 5% and 8% (p&lt;0.01), respectively. However, heart weight and myocardial infarct size in antibody treated mice were comparable to those in vehicle-treated mice. Moreover, antibody treatment dose-dependently increased body weight, which is further confirmed by increases in muscle mass and body lean mass measured by gravimetric analysis and body composition analyzer.

Conclusion
ActRII antibody dose-dependently improved cardiac function independent of myocardial infarct size post-MI. Although antibody significantly increased body weight and lean mass, it did not significantly increase heart weight, indicating that antibody treatment did not cause adverse remodeling post-MI while it remarkably improved cardiac function. Our data suggest that ActRII antibody could be a novel treatment for heart failure with reduced ejection fraction and may be particularly beneficial in patients with cachexia.

Funding Acknowledgement
Type of funding sources: None.
Efficacy and safety of sacubitril valsartan in heart failure compared to renin angiotensin aldosterone system inhibitors: a systematic review and meta analysis of randomised controlled trials
Authors: Hernandez A V , Pasupuleti V , Scarpelli N , Malespini J , Banach M , Bielecka-Dabrowa A M 
Published: October 2022

Abstract

Background
Benefits and harms of the use of LCZ696 (sacubitril/valsartan, S/V), a combination of a neprilysin inhibitor and an angiotensin receptor blocker (ARB), in heart failure (HF) are unknown.

Purpose
To systematically assess benefits and harms of S/V as compared to angiotensin converting enzyme inhibitors (ACEI) or ARB in patients with HF.

Methods
We searched for randomised controlled trials (RCTs) evaluating S/V vs. ACEI or ARB in acute or chronic HF adult patients. Primary outcomes were HF hospitalisation and cardiovascular [CV] mortality; secondary outcomes were all-cause mortality, decline in renal function, myocardial dysfunction, quality of life (QoL), systolic blood pressure (SBP), diastolic blood [DBP], and adverse events (AEs) including worsening renal function (SCr≥2 mg/dL), hyperkalaemia (K+≥5.5 mmol/L), symptomatic hypotension (SBP&lt;100 mmHg), and angio-oedema. Inverse variance random-effects meta-analyses were conducted and effects expressed as hazard ratios (HR), relative risks (RR) or mean difference (MD) and their 95% confidence intervals (CI). GRADE methodology was used to assess the certainty of evidence (CoE).

Results
We selected 11 RCTs (n=18766). Follow-up times ranged between 2 and 48 months; the average age of participants was 61 to 73 years-old. Five RCTs had ACEIs as control, five RCTs had ARBs as control, and one RCT had both ACEI and ARB as control. Six RCTs had low risk of bias; five RCTs had unclear risk of bias. S/V reduced the hazard of HF hospitalisations by 20% (HR 0.80, 95% CI 0.68–0.94; 3 RCTs; I2=65%; high CoE), CV mortality by 14% (HR 0.86, 95% CI 0.73 to 1.01; 2 RCTs; I2=57%; high CoE) and all-cause mortality by 11% (HR 0.89, 95% CI 0.78–1.00; 3 RCTs; I2=36%; high CoE) compared to ACEI or ARB control (Figure 1). S/V slightly improved KCCQ-QoL scores (MD 1.36 points, 95% CI 0.49 to 2.24; 6 RCTs; I2=54%). S/V did not affect LVEF and E/E' but reduced NTproBNP (SMD −0.34, 95% CI −0.52 to −0.16; 3 RCTs; I2=62%), and hs-TNT (Ratio of differences 0.84, 95% CI 0.79–0.88; 2 RCTs; I2=0%). SBP and DBP were reduced by 4 mmHg and 3 mmHg, respectively, and hypotension was increased (RR 1.69, 95% CI 1.33–2.15; 9 RCTs; I2=65%; high CoE) with S/V. Also, S/V reduced the hazard of decline in renal function by 33% (HR 0.67, 95% CI 0.39–1.14; 2RCTs; I2=78%; high CoE); hyperkalaemia and angioedema events were similar between S/V and controls.

Conclusions
Sacubitril/valsartan had better clinical and intermediate outcomes in HF in comparison to ACEI or ARB. Decline of renal function was less frequent with S/V in comparison to controls, and there was no difference in decline of renal function or angioedema and hyperkalaemia events. However, sacubitril/valsartan was associated with more symptomatic hypotension events vs. controls.

Funding Acknowledgement
Type of funding sources: None.
First-in-man trial of b3-adrenoreceptor agonist treatment in chronic heart failure – impact on diastolic function
Authors: Bahrami H , Hasselbalch R , Soeholm H , Thomsen J , Soegaard M , Kofoed K , Valeur N , Boesgaard S , Fry N , Moeller J , Raja A , Koeber L , Iversen K , Rasmussen H , Bundgaard H 
Published: October 2022

Abstract

Background
Diastolic dysfunction (DD) in heart failure (HF) is associated with increased myocardial cytosolic calcium, and calcium-efflux via the sodium-calcium-exchanger depends on the sodium gradient. Beta-3-adrenoceptor (β3-AR)-agonist lowers cytosolic sodium and has been shown to reverse organ congestion.

Purpose
To assess whether β3-AR-agonist treatment improves DD.

Methods
In a first-in-man randomized controlled, double-blind trial, we assigned 70 patients with HF with reduced ejection fraction (HFrEF) (NYHA II–III) and LVEF &lt;40% to receive mirabegron (300 mg/day) or placebo for 6 months, in addition to recommended HF-therapy. Patients were assessed with echocardiography and cardiac computed tomography (CCT) at baseline and follow-up. DD was graded according to the current American/European guidelines.

Results
Baseline and follow-up echocardiographic data were available in 57 patients (59±11 years, 88% male, 49% ischemic heart disease). Baseline LVEF was 34%±8%. No significant change in DD grade was found between the groups at follow-up, p=0.72. Neither was there any clinical differences in any singular diastolic parameters within or between groups by echocardiography (E/e' placebo: 13.3±6.9 to 12.6±5.1, p=0.19 vs. mirabegron: 12.0±5.7 to 12.8±7.9, p=0.67, mean difference 1.12 [95% CI −1.68 to 4.3], p=0.37), or CCT (left atrial max volume index: between group mean difference 0.2 [95% CI −6.2 to 5.6] ml/m2, p=0.91).

Conclusions
In patients with HFrEF, no improvement nor worsening in DD gradings or singular diastolic parameters after β3-AR stimulation compared to placebo were identified. The findings add to previous literature questioning the role of impaired Na+-Ca2+ mediated Ca2+ export as a major culprit in DD.

Funding Acknowledgement
Type of funding sources: Foundation. Main funding source(s): The Heart Centre Research Foundation, RigshospitaletThe Novo Nordic Foundation
Adherence and discontinuation of optimal heart failure therapies according to age
Authors: Garred C H , Zahir D , Butt J H , Ravn P B , Bruhn J , Gislason G , Fosboel E L , Torp-Pedersen C , Petrie M C , McMurray J J V , Koeber L , Schou M 
Published: October 2022

Abstract

Background
Guideline-recommended disease-modifying pharmacological therapies for heart failure (HF) with reduced ejection fraction are underutilized, particularly among elderly patients.

Purpose
We examined adherence with and discontinuation of evidence-based HF pharmacotherapy, comprising of angiotensin-converting enzyme inhibitors (ACEi)/angiotensin-II receptor blockers (ARB), beta-blockers (BB) and mineralocorticoid receptor antagonists (MRA), according to age.

Methods
Using Danish nationwide registries, we included patients with a first HF diagnosis between 2011 and 2018. Patients were stratified into three age groups, &lt;65 years (reference group), 65–79 years, and ≥80 years. The average daily drug dose was calculated as median proportions of target doses one year after inclusion. Adherence was estimated by the proportion of days covered (PDC), i.e., the total number of days with the drug available for a patient alive for the whole first year of the follow-up period. Discontinuation was defined as a break of &gt;90 days, and the 5-year risk of discontinuation according to age groups was estimated with the Aalen-Johansen estimator. Multivariable Cox regression models were used to evaluate the treatment discontinuation rate according to age groups.

Results
We included a total of 29,482 patients (&lt;65 9,449 (25.4% female), 65–79 13,746 (33.1%), ≥80 6,287 (46.3%)). Advancing age was associated with lower median proportions of daily target doses (ACEi 100%, 88%, 63%; ARB 75%, 67%, 50%; BB 75%, 56%, 44%), and lower adherence (ACEi/ARB 79.1%, 77.5%, 69.4%; BB 79.1%, 78.6%, 73.8%), in the &lt;65, 65–79 and ≥80 age groups respectively, one year after inclusion. Age ≥80 was associated with a higher 5-year risk of discontinuation; cumulative incidence, ACEi/ARB 41%, 44%, 51%; BB 38%, 35%, 39%, in the same age group order as above (adjusted hazard ratio: ACEi/ARB 1.60 [95% CI, 1.51–1.69]; BB 1.33 [95% CI, 1.25–1.41]). Conversely, the risk of discontinuation of MRAs differed little with age (&lt;65 50%, 65–79 54%, ≥80 56%), although MRA initiation in the most elderly was less frequent (&lt;65 33%, 65–79 33%, ≥80 22%).

Conclusion
Among a nationwide cohort of HF patients, advanced age was associated with lower proportions of daily target doses, lower adherence, and a higher rate of discontinuation of ACEi/ARB and BBs. Focus on treatment adherence and optimal dosages among elderly HF patients could improve outcomes.

Funding Acknowledgement
Type of funding sources: None.
Real-world eligibility and cost-effectiveness analysis for empagliflozin in patients with heart failure
Authors: Kim E S , Park S K , Youn J C 
Published: October 2022

Abstract

Background/Introduction
Empagliflozin was approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for reducing cardiovascular mortality and heart failure (HF) hospitalization in both patients with HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF).

Purpose
Limited data are available on the generalizability of empagliflozin to clinical practice. Therefore, we evaluated real-world eligibility and cost-effectiveness based on a nationwide prospective HF registry.

Methods
For the study, 3108 HFrEF and 2070 HFpEF patients from the Korean Acute Heart Failure (KorAHF) registry were analysed. Eligibility was estimated by FDA and EMA label criteria and by inclusion and exclusion criteria of EMPEROR-Reduced and EMPEROR-Preserved trials. The cost-effectiveness analysis was performed using the decision tree model, where effectiveness was the avoidance of the first hospitalization.

Results
Among the KorAHF patients, 91.4% met FDA & EMA label criteria, while 44.7% met the clinical trial criteria. The main factor for exclusion in the clinical trial-based empagliflozin eligibility was low systolic blood pressure, including 18.7% of HFrEF and 11.0% of HFpEF patients. Other factors were acute (&lt;4 weeks) myocardial infarction and impaired renal function (eGFR &lt;20 mL/min/1.73 m2 or requiring dialysis). The overall expected hospitalization rate and cost reduction were 3.6 and US$ 14,885 per 100 eligible HF patients per year. In HFrEF patients, hospitalization rate and cost reduction were 4.8 and US$ 28,442. However, in HFpEF, the cost was increased by US$ 7,576, while hospitalization reduction was 1.7.

Conclusion(s)
There is a large discrepancy of real-world eligibility for empagliflozin between FDA & EMA labels and clinical trial criteria. The cost-effectiveness benefit was more evident in patients with HFrEF than HFpEF. The efficacy and safety of empagliflozin in real-world patients should be further investigated for a broader range of clinical applications.

Funding Acknowledgement
Type of funding sources: Other. Main funding source(s): This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Minister of Science and Information and Communication Technologies (NRF-2021R1F1A1063430), by the Catholic Medical Center Research Foundation (2022), and by the Research of Korea Centers for Disease Control and Prevention (2010-E63003-00, 2011-E63002-00, 2012-E63005-00, 2013-E6300300, 2014-E63003-01, 2015-E63003-02, 2016-ER6303-00, and 2017-ER6303-01).
Prevalent and incident anaemia in PARADIGM-HF and effect of sacubitril/valsartan
Authors: Curtain J , Adamson C , Jhund P S , Desai A S , Lefkowitz M P , Rizkala A R , Rouleau J L , Swedberg K , Zile M R , Solomon S D , Packer M , McMurray J J V 
Published: October 2022

Abstract

Background
Anaemia is common in patients with HFrEF and is associated with poor clinical outcomes. Although they reduce rates of mortality and heart failure hospitalization, renin-angiotensin (RAS) blockers lower haemoglobin and may induce anaemia. Concomitant neprilysin inhibition might ameliorate this effect of RAS blockers.

Purpose
We investigated the effect of sacubitril/valsartan compared with enalapril on clinical outcomes, according to anaemia status, and on haemoglobin levels in PARADIGM-HF.

Methods
Patient characteristics and clinical outcomes were compared between patients with and without anaemia (defined as haemoglobin &lt;120 g/L in women and &lt;130 g/L in men) at baseline. We investigated the effect of randomized treatment (sacubitril/valsartan or enalapril) on clinical outcomes according to anaemia status at screening. We also examined the effect of treatment on change in haemoglobin from baseline and on the incidence of anaemia. The primary endpoint in PARADIGM-HF was the composite of heart failure hospitalization or cardiovascular death.

Results
Of 8239 participants with a baseline haemoglobin measurement, 1677 (20.4%) were anaemic. Compared to those without anaemia, patients with anaemia had a more severe heart failure profile, worse kidney function, greater neurohormonal derangement and worse clinical outcomes. Sacubitril/valsartan, compared to enalapril, reduced the risk of the primary endpoint similarly in patients with anaemia (HR 0.84, 95% CI 0.71–1.00) and without anaemia (HR 0.78, 95% CI 0.71–0.87), p-value for interaction=0.478. Between baseline and 12 months, haemoglobin decreased by 1.5 (95% CI 1.7 to 1.2) g/L with sacubitril/valsartan compared with 2.3 (2.6 to 2.0) g/L with enalapril group: mean difference 0.8 (95% CI 0.5 to 1.2) g/L, p&lt;0.001. The between-treatment difference apparent by 12 months, persisted up to 36 months. Patients assigned to sacubitril/valsartan were less likely to develop new anaemia at 12 months [321 of 2806 (11.4%)] compared to patients randomized to enalapril [440 of 2384 (15.6%)], odds ratio 0.70 (95% CI 0.60–0.81), p&lt;0.001.

Conclusions
Compared to enalapril, sacubitril/valsartan reduced mortality and hospitalization in HFrEF patients with and without anaemia. Haemoglobin decreased less with sacubitril/valsartan and the incidence of new anaemia was lower in the sacubitril/valsartan group compared with the enalapril group.

Funding Acknowledgement
Type of funding sources: Private company. Main funding source(s): PARADIGM-HF was funded by Novartis.
Effects of sodium glucose cotransporter 2 inhibitors on the risk of hyperkalemia in patients on mineralocorticoid receptor antagonist: a systematic review and meta-analysis
Authors: Cordovez R A B , Denila R A , Rivera K , Patricio M 
Published: October 2022

Abstract

Background
Occurrence of hyperkalemia has been a great limitation in the full implementation of a guideline-directed medical therapy especially in patients with heart failure. Recent developments have exhibited the positive role of SGLT2 inhibitors, not only on the cardiovascular outcomes but also conferred renal protection.

Purpose
We explored the effects of SGLT2i and MRA combination on the risk of developing hyperkalemia.

Methods
Randomized controlled trials on SGLT2i versus placebo in patients already on MRA regardless of heart failure status reporting outcomes of potassium homeostasis were searched using Pubmed, CENTRAL, and ScienceDirect. Outcome of interest was the effects on the risk of hyperkalemia. Pooled hazard ratios with 95% confidence intervals were used as effect estimates using fixed-effects model.

Results
Four studies were included with a total of 8,996 patients. There was a significant reduction on the risk of hyperkalemia in the MRA with SGLT2i group (HR 0.53, 95% CI 0.39–0.73, p&lt;0.0001) compared to MRA without SGLT2i group.

Conclusion
SGLT2i provides significant risk reduction on the development of hyperkalemia in patients already on a mineralocorticoid receptor antagonist.

Funding Acknowledgement
Type of funding sources: None.
Omecamtiv mecarbil for the management of heart failure: a meta-analysis of randomized controlled trials
Authors: Silva M M C A , Fernandes A , Hurtado V , Fernandes G , Cardoso R , Andersson C 
Published: October 2022

Abstract

Background
Omecamtiv mecarbil (OM) is a selective cardiac myosin activator that promotes contractility in patients with Heart Failure with Reduced Ejection Fraction (HFrEF). We aimed to study the clinical outcomes of OM in this population.

Methods
PubMed, Cochrane CENTRAL Registry of Controlled Trials, and ClinicalTrials.gov were searched for randomized controlled trials (RCTs) that compared OM with placebo for the management of HFrEF. Efficacy and safety data were summarized with odds ratios (OR) and a 95% confidence interval (CI) using a fixed-effect model predicting low heterogeneity between studies.

Results
Four RCTs were included, totalizing 9,364 patients, 4,779 treated with OM and 4,585 with placebo. Mean age ranged from 63–66 years, 15–22% female, ejection fraction 26–29%, ischemic etiology 53–66%. Length of follow up ranged from 1 to 21 months. There was no difference in the outcomes all cause death (OR 0.99, 95% CI 0.9–1.1, p=0.91), cardiovascular death (OR 1.01, 95% CI 0.91–1.12, p=0.87) and heart failure events or hospitalizations (OR 0.96, 95% CI 0.87–1.05, p=0.35), Figure.

Conclusion
In a meta-analysis of 4 RCTs, OM showed no difference compared with placebo in the risk of all-cause death, cardiovascular death, or heart failure events among patients with HFrEF.

Funding Acknowledgement
Type of funding sources: None.