bluuebunny/crossref_metadata_2025_split huggingface dataset:
Maximum dose sacubitril/valsartan in heart failure with reduced ejection fraction: does atrial fibrillation compromise the benefits?
Authors: Monteiro E , Barbosa J , Guimaraes J , Fernandes D , Costa G , Gomes R , Rosa J , Campos G , Costa S , Baptista R , Franco F , Madeira M , Goncalves L 
Published: October 2022

Abstract

Background
In the PARADIGM-HF trial, sacubitril/valsartan (SV) was shown to be superior to enalapril in reducing hospitalizations for worsening heart failure (HF), cardiovascular mortality, and all-cause mortality in patients with heart failure with reduced ejection fraction (HFrEF). The 2021 ESC Guidelines recommends SV as a replacement for angiotensin-converting-enzyme inhibitors to reduce the risk of HF hospitalization and death. There is little information regarding the effects of SV according to atrial fibrillation (AF) status.

Purpose
The aim of this study was to compare the effects of maximum dose SV regarding symptomatic improvement, change in natriuretic peptides levels (NP) and left ventricular ejection fraction (LVEF) in patients with HFrEF with and without AF.

Methods
Retrospective analysis of 137 patients with HFrEF on maximum dose SV (97/103mg twice daily). Patients were divided into two groups according to AF status. Age, gender, relevant comorbidities, usual medication, baseline symptomatic status, NP levels and LVEF were assessed using the Mann-Whitney U or χ2 test (according to variable type) to ensure comparability between groups. Variation in NYHA class, NP levels and LVEF between baseline and 6-month follow-up was evaluated and compared between groups.

Results
Comparison between groups is presented in Table 1. In our studied population, ischemic aetiology was more common in the sinus rhythm group (49.5% vs 30.4%; p 0.034). There were no significant differences between groups regarding age, gender, hypertension, diabetes, and beta-blocker and mineralocorticoid receptor antagonist usage. At baseline, the AF group had higher NT-proBNP levels [median 1421 mg/dL (IQR 743–3087) vs 467 mg/dL (IQR 140–797); p&lt;0.001]. There were no significant differences regarding baseline NYHA class or LVEF. After 6 months of follow-up, reductions in NYHA class [−1 (IQR −2, −1) for AF; −1 (IQR −1, 0) for SR; p=0.437] and NT-proBNP levels [−358 mg/dL (IQR −2275, −47) for AF; −162 mg/dL (IQR −364, 27) for SR; p=0.156], as well as LVEF improvement [11% (IQR 3–15) for AF; 12% (IQR 7–21) for SR; p=0.201], displayed no statistically significant differences between the two groups.

Conclusions
Our study shows that the beneficial effects of SV on symptomatic status, NP levels and LVEF were not compromised by the presence of AF at baseline.

Funding Acknowledgement
Type of funding sources: None.
Relationship of tafamidis binding site occupancy, transthyretin stabilization, and disease modification in tafamidis treated transthyretin amyloid cardiomyopathy patients
Authors: Moody A T , Tess D A , Li Z , Bulawa C , Fleming J , Maurer T S 
Published: October 2022

Abstract

Introduction
Tafamidis inhibits progression of transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) by binding TTR tetramer and inhibiting its dissociation to monomers which can denature and result in amyloid fibril formation and deposition in cardiac tissue.

Purpose
While the phase 3 ATTR-ACT clinical data clearly demonstrated efficacy, quantification of TTR stabilization in patients and the degree to which the approved dose captures the full potential of the mechanism has yet to be assessed.

Methods
Isothermal titration calorimetry and subunit fraction exchange were used to determine affinities to the two binding sites on TTR. These values were used to develop a model of tafamidis binding to TTR in plasma that was applied to individual patient data to calculate TTR binding site occupancy and the change in total TTR levels induced by TTR stabilization. Population pharmacodynamic (PD) models were developed for three measures of disease progression, plasma NT-proBNP levels, Kansas City Cardiomyopathy Questionnaire – Overall Score (KCCQ-OS), and six-minute walk test (6MWT) distance, to evaluate patient response with the degree of TTR occupancy.

Results
In vitro binding data of wild-type TTR confirmed tafamidis binds two sites of TTR with negative cooperativity and provided precise estimates of the binding affinity to TTR and albumin. Modeling individual patient data of tafamidis exposure and increased TTR plasma levels using the in vitro derived binding affinity values confirms single site binding is consistent with complete tetramer stabilization. Patients given 80 mg tafamidis meglumine, the clinically approved dose for ATTR-CM, had a 92% reduction in unbound, unstabilized TTR, which correlated with a 53% decrease in NT-proBNP elevation, a 56% decrease in KCCQ-OS worsening and a 49% reduced decline in the 6MWT. For 100% receptor occupancy and stabilization, the expected effects on these measures are 58%, 61%, and 54% for NT-proBNP, KCCQ-OS, and 6MWT, respectively.

Conclusions
These results demonstrate a quantitative relationship between TTR stabilization, the mechanism of action of tafamidis, and accepted laboratory and patient-based outcomes in ATTR-CM. These results also support the value of TTR stabilization as a clinically beneficial treatment option which maintains the protein in its physiologically active form within the body.

Funding Acknowledgement
Type of funding sources: Private company. Main funding source(s): This study was sponsored by Pfizer.
Aggressive combined pharmacotherapy for heart failure reduces new onset atrial fibrillation
Authors: Tokutome M , Matsukawa R , Noma A , Kisanuki H , Nakashima H , Watanabe T , Sakemi T , Okabe K , Okahara A , Kawai S , Matsuura H , Masuda S , Mukai S 
Published: October 2022

Abstract

Backgrounds
Heart failure (HF) is a risk factor for new onset atrial fibrillation (AF), and the new onset AF is associated with a worse prognosis in HF patients. It has been reported that renin-angiotensin system inhibitor (RASi), β-blocker and mineral-corticoid receptor antagonist (MRA) prevent the new onset AF in HF patients. However, the effect of combined pharmacotherapy including angiotensin receptor neprilysin inhibitor (ARNI) and sodium glucose co-transporter 2 inhibitor (SGLT2i) on AF is unknown. We investigated the impact of contemporary regimen of combined pharmacotherapy for HF (RASi/ARNI+β-blocker+MRA+SGLT2i) on new onset AF.

Methods and results
We retrospectively studied rEF and mrEF patients without AF admitted to our hospital due to decompensated HF between 2015 and 2021 (n=366). Long-term (The mean follow-up was 635±421 days) incidence of new onset AF was investigated with regard to medical therapies. Patients were divided into 2 groups; patients with ≤2 HF drugs (n=181) and patients with ≥3 HF drugs (n=185). Patients with ≤2 HF drugs group were older (77.3 vs 67.0 years old, P&lt;0.001), had a poorer renal function (Cre: 1.66 vs 1.09 mg/dl, P&lt;0.001), and had a higher rate of ischemic heart disease (52 vs 38%, P=0.009), whereas left ventricular systolic function was better (EF: 31.9 vs 27.3%, P&lt;0.001). There were 19 (10.5%) new onsets AF in the ≤2 HF drugs group, whereas only 7 (3.8%) had new onsets AF in the ≥3 HF drugs group (HR 0.36, 95% CI 0.15–0.85, P=0.01). All-cause death and hospitalization for HF were fewer in the ≥3 HF drugs group. A multivariate analysis revealed that ≥3 HF drugs use was an independent negative predictor of new onset AF (HR 0.37, 95% CI 0.15–0.93, P=0.03). Even after a propensity score matching of the clinical variables, the incidence of new onset AF was consistently fewer in the ≥3 HF drugs group (HR 0.36, 95% CI 0.13–0.99, P=0.04). Finally, patients with new onset AF had a higher rate of hospitalization for HF in the studied population (HR 9.68, 95% CI 5.67–16.5, P&lt;0.01).

Conclusion
Aggressive combined pharmacotherapy for HF may be associated with fewer new onset AF in patients with HF.

Funding Acknowledgement
Type of funding sources: None.
Effects of sacubitril valsartan on renal function in adults with heart failure: a systematic review and meta analysis of randomised controlled trials
Authors: Hernandez A V , Barboza J J , Pasupuleti V , Piscoya A , Roman Y M 
Published: October 2022

Abstract

Background
Sacubitril/valsartan (S/V) may have beneficial effects on renal outcomes in patients with heart failure (HF) receiving angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB).

Purpose
To systematically evaluate the effects of sacubitril/valsartan on renal function in adults with HF.

Methods
Five databases were searched for randomised controlled trials (RCTs) comparing S/V (LCZ696) vs. ACEI or ARB in adult HF patients until January 2022. Doubling serum creatinine levels was the primary outcome. Acute kidney injury (AKI)&gt;50% decline of estimated glomerular filtration rate (eGFR), and hyperkalaemia (serum K+ &gt;5.5 mmol/L) were secondary outcomes. Inverse variance random-effects meta-analyses were used, and effects of S/V on outcomes were described with relative risks (RR) and their 95% confidence intervals (CI). Subgroup analyses by type of HF (chronic vs. acute), and LVEF (&lt;40% vs &gt;40%) were performed. We used the RoB 2.0 tool for risk of bias assessments of RCTs. GRADE methods were used to rate the certainty of evidence (CoE).

Results
Eight RCTs (n=15859) were included; four in chronic HF and four in acute HF. Mean age was 66.2 (SD 5.5) years-old, and 34.1% were female. The median follow-up across RCTs was 36 weeks. In comparison to ACEI/ARB, S/V was associated with lower risk of doubling serum creatinine (RR 0.77; 95% CI 0.72–0.83; I2=0%; moderate CoE). S/V did not reduce the risk of AKI (RR 0.88; 95% CI 0.72–1.08; I2=0%; low CoE), &gt;50% decline of eGFR (RR 0.65; 95% CI 0.37–1.17; I2=45%; very low CoE), and hyperkalaemia (RR 1.01; 95% CI 0.81–1.25; I2=44%; very low CoE). Two RCTs had high risk of bias and two had some concerns of bias. Subgroup analyses were consistent with main analyses for the primary outcome.

Conclusions
In adults with heart failure, S/V reduced doubling creatinine compared to ACEI/ARB, but did not reduce risks of AKI, &gt;50% decline in eGFR or hyperkalaemia. Subgroup analyses by type of HF and LVEF were consistent with main analyses.

Funding Acknowledgement
Type of funding sources: None.
Is it possible to start quadruple therapy in patients with a new diagnosis of HF and reduced ejection fraction? Real-life data from the TIDY-HF registry
Authors: Esteban Fernandez A , Gomez Otero I , Rodriguez Santamarta M , Fluvia Brugues P , Pastor F , Perez Rivera J A , Bonilla J L , Lopez Fernandez S , Lopez A , Segura Aumente J M , Martinez V , Garcia Pinilla J M , Vazquez Lopez-Ibor J , Sanchez Munoz E , Sole E 
Published: October 2022

Abstract

Background
The 2021 European heart failure (HF) guidelines recommended treatment with an inhibitor of the renin-angiotensin-aldosterone axis (RAAS), a beta-blocker (BB), a mineralocorticoid receptor antagonist (MRA), and a cotransporter sodium-glucose type 2 inhibitor (SGLT2) in patients with HF and left ventricular ejection fraction (LVEF) ≤40%. However, there is little evidence on implementing quadruple therapy in clinical practice.

Purpose
Study the implementation of quadruple therapy in patients with a new diagnosis of HF and reduced ejection fraction in clinical practice.

Methods
A prospective multicenter registry (38 centers in Spain) was carried out, including all patients newly diagnosed with HF with LVEF ≤40% in clinical practice. Their baseline and laboratory characteristics were recorded and their pharmacological treatment: at baseline (discharged from hospitalization or first outpatient visit within a maximum period of 1 month after the echocardiographic diagnosis), one month, and 3 months later.

Results
On 1th of March 2022, 349 patients were included, with baseline treatment data in 289. The mean age was 65.0±14.2 years, and 72.1% were men. The mean LVEF was 28.5±7.3%, with 57.6% in NYHA II and 29.1% in NYHA III–IV. The most frequent causes of cardiomyopathy were: ischemic (25.1%), tachycardiomyopathy (16.6%), and idiopathic (15.7%). 46.4% were dyslipidemic, 57.5% hypertensive and 33.3% diabetic. 65.1% of the patients were in sinus rhythm. Before HF diagnosis, 44.6% had been treated with RAASi, 22.8% with BB, 7.8% with MRA, 8.1% with iSGLT2, and 24.5% with diuretics. The drugs used at baseline and the changes during follow-up are shown in Table 1.

Conclusions
According to our cohort, almost 60% of newly diagnosed patients with HF and reduced LVEF start quadruple therapy during the first month after diagnosis, with sacubitril/valsartan being the preferred RAASi in most cases. The implementation of drugs with prognostic benefit is above 70% at baseline and exceeds 80% at one month of follow-up, with a progressive reduction in loop diuretics during follow-up.

Funding Acknowledgement
Type of funding sources: Foundation. Main funding source(s): Spanish Society of Cardiology
Chronic mitochondrial fusion promotor as a novel pharmacological intervention to alleviate left ventricular dysfunction in rats with chronic myocardial infarction
Authors: Piamsiri C , Jinawong K , Maneechote C , Arunsak B , Chattipakorn S C , Chattipakorn N 
Published: October 2022

Abstract

Background
Decreased cardiac mitochondrial fusion associated with increased mitochondrial dysfunction has been demonstrated in acute myocardial infarction pathology. However, whether this pathophysiologic process is associated with myocardial injury in chronic myocardial infarction (CMI) is still unclear. Recently, a novel pharmacological intervention to promote mitochondrial fusion using mitochondrial fusion promotor-M1 (M1) has been shown to exert cardioprotection against myocardial ischemia and reperfusion injury. However, the roles of M1 in CMI has never been investigated.

Purpose
We investigated the potential cardioprotective benefits of chronic treatment with mitochondrial fusion promotor-M1 in rats with chronic MI model.

Methods
Adult male Wistar rats were assigned to the sham group (n=5) and the CMI group (n=15), which was induced by a permanent left anterior descending coronary occlusion. After 1 week of operation, rats in the CMI group were randomly divided into 3 subgroups which was treated with one of the followings: 1) vehicle (3% DMSO/day, ip, CON, n=5), 2) enalapril (10 mg/kg/day, po, ENA, n=5), or 3) mitochondrial fusion promotor-M1 (2 mg/kg/day, ip, M1, n=5) once daily for 4 weeks. In the end, echocardiography for the left ventricular (LV) function was performed, and the heart was removed to determine the mitochondrial function and malondialdehyde (MDA) level for oxidative stress.

Results
CMI rats that received vehicle showed significantly impaired LV function and cardiac mitochondrial function as evidenced by a 60% reduction in LV ejection fraction (LVEF) along with increased mitochondrial reactive oxygen species (ROS) production, mitochondrial depolarization and mitochondrial swelling, respectively, when compared with the sham rats (Fig. 1A–D). The CMI rats also exhibited a higher cardiac tissue MDA level than those of sham rats, further indicating cardiac oxidative stress (Fig. 1E). Interestingly, chronic treatment with either enalapril or M1 effectively attenuated CMI-induced mitochondrial dysfunction and oxidative stress upregulation, thus increasing LVEF (27% improvement for both ENA and M1), when compared with the vehicle group (Fig. 1A).

Conclusion
Long-term promotion of mitochondrial fusion mitigated cardiac mitochondrial dysfunction and oxidative stress, eventually culminating in improved LV function in rats with CMI. These findings suggest that chronic modulation of mitochondrial fusion could be a promising pharmacological intervention to improve LV function in CMI.

Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): 1. The National Science and Technology Development Agency Thailand2. The Thailand Research Fund (RGJ)
Timing of initiation of sodium-glucose co-transporter 2 inhibitor in patients with diabetes and chronic cardiac failure
Authors: Sun W , Yan B 
Published: October 2022

Abstract

Purpose
Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of first hospitalization for heart failure (HHF) in patients with type 2 diabetes. We aimed to evaluate the impact of early initiation of SGLT2 inhibitors on recurrent HHF in diabetic patients with chronic cardiac failure.

Methods
We retrospectively analyzed 1,363 consecutive diabetic patients with chronic cardiac failure with index HHF between August 2015 and August 2020 in 16 public hospitals in Hong Kong who were prescribed SGLT2i (empagliflozin=1,009, 74% and dapagliflozin =354, 26%).Patients who initiated SGLT2i at discharge of index HHF were compared to those who were not. Risk of recurrent HHF was compared, using adjusted sub-distribution hazard ratios (aSHR) derived from Fine and Gray regression models, accounting for death as competing risk, adjusting for age, gender, concurrent medications. Comparisons were also conducted between initiation of SGLT2i ≤30 vs &gt;30 days; and ≤90 vs. &gt;90 days after discharge.

Results
Of 1,363 patients (mean age 63.9±11.6, female 34.6%), 85% had no history of previous HHF at enrollment, 11.9% had up to 2 and 3.1% and 3.1% ≥3 HHF in the past 5 years. SGLT2i was initiated in 37.4% of patients at discharge of index HHF and the median time from index HHF to SGLT2i initiation for the other patients was 4.2 (IQR: 0–20.4) months. During a median follow-up of 1.3 (IQR: 0.2–2.7) years, initiation of SGLT2i at discharge was associated with lower risk of recurrent HHF (aSHR = 0.79, 95% CI: 0.68–0.92). Similar effect was observed between SGLT2i initiation ≤30 vs. &gt;30 days (aSHR = 0.82, 95% CI: 0.70–0.95) but not between ≤90 vs. &gt;90 days (P=0.19).

Conclusion
Among patients with diabetes and chronic cardiac failure, the risk of recurrent HHF was reduced when SGLT2 was initiated early after index HHF.

Funding Acknowledgement
Type of funding sources: None.
Heart failure with improved ejection fraction (HFimpEF) in patients treated with sacubitril/valsartan (SV)
Authors: Kong M G , Suh J , Moon I K , Lee K Y , Jang H J , Kim J S , Choi I J 
Published: October 2022

Abstract

Introduction
Several studies demonstrated that patients with improvement of left ventricular ejection fraction (LVEF) and symptoms had good prognosis in heart failure with reduced ejection fraction (HFrEF). Based on these results, new classification of HF according to LVEF was currently proposed. Sacubitril/valsartan (SV) is recommended as one of the first-line therapy of HFrEF patients. SV reduced hospitalization for HF and cardiovascular mortality compared to enalapril in PARADIGM-HF trial. However, it is unclear that patients with improvement of LVEF also have better prognosis compared to patients without LVEF improvement among patients treated with SV.

Purpose
We aimed to evaluate the clinical characteristics and outcomes of heart failure with improved ejection fraction (HFimpEF) in heart failure with reduced ejection fraction (HFrEF) patients treated with SV.

Methods
We analyzed 230 patients with HFrEF taking SV in a multicenter retrospective cohort (RECORD-SV registry) from 2017 to 2019. Enrolled 230 patients were performed baseline and 1-year follow-up echocardiography. Based on 2 echocardiographic results, we defined “HFimpEF” as HF with a baseline LVEF ≤40%, ≥10% increase from baseline LVEF and a follow-up measurement of LVEF &gt;40%. Others were defined as “Persistent HFrEF”. We analyzed and compared clinical characteristics and outcomes between two groups. Primary endpoint was a composite outcome of all-cause death and hospitalization for HF (HHF).

Results
From 230 patients, 65 patients with HFimpEF and 165 patients with Persistent HFrEF were analyzed. The median follow-up duration was 557 days (interquartile range 364 to 727 days). Patients with HFimpEF had a higher prevalence of female gender (50.8% vs. 30.3%) and de novo HF (44.6% vs. 21.2%). There were no significant differences for age, etiology (ischemic vs. non-ischemic), diabetes, atrial fibrillation, hypertension, and HF medications including SV dose between two groups. Patients with HFimpEF showed lower rate of all-cause death or HHF as a primary endpoint compared to patients with persistent HFrEF (6.2% vs. 22.4%; IPTW adjusted HR 0.24; 95% CI 0.13–0.46; p&lt;0.001) (Table 1). It was also shown that HFimpEF patients had a reduced risk of primary endpoint in the Kaplan-Meier curves compared with persistent HFrEF (Log-rank p=0.045) (Figure 1). We demonstrated that Non-prior MI (adjusted OR 7.29; 95% CI 1.50–35.36; p=0.014) and de novo HF (adjusted OR 4.33; 95% CI 1.70–11.04; p=0.002) were independent prognostic factors of HFimpEF in HFrEF patients treated with SV.

Conclusions
HFimpEF patients had better clinical outcomes compared to those with persistent HFrEF in HFrEF patients treated with SV. Non-prior MI and de novo HF were independent predictors of HFimpEF in patients treated with SV.

Funding Acknowledgement
Type of funding sources: None.
Effects of angiotensin receptor-neprilysin inhibitors (ARNIs) on the glucose and fat metabolism biomarkers leptin and fructosamin
Authors: Ohnewein B , Shomanova Z , Jirak P , Topf A , Froeb E J , Pogoda C , Granitz C , Lichtenauer M , Hoppe U , Reinecke H , Pistulli R , Motloch L J 
Published: October 2022

Abstract

Background
Heart Failure with reduced ejection fraction (HFrEF) has a life time risk about 20% among adults aged 40 years or older and a 5-year mortality rate about 60% [1,2]. However novel therapies have shown to improve this outcome. One novel agent are angiotensin receptor-neprilysin inhibitors (ARNIs) that increase the BNP levels via inhibiting neprilsyin [3]. This has beneficial effects on heart failure by reducing preload, inflammation and fibrosis. Neprilysin also interacts with leptin and is known to correlate with the incidence and progression of heart failure if chronically elevated [4]. Furthermore beneficial affects of ARNI therapy on glucose metabolism were reported in a post-hoc analysis of the PARADIGM-HF trial [5]. In this study we aim to investigate the effect of ARNI therapy on the fat metabolism markers leptin and on the glucose metabolism marker fructosamin.

Methods
In total, we included 74 patients with HFrEF with ischemic (N=37) and non-ischemic (n=37) origin in the present study. The mean NYHA class was II–III, the mean BMI 28 (SD 6.3). Patients had well established heart failure therapy before starting ARNI therapy with sacubitril/valsartan. 88% of patients were on ACE-inhibitors, 86% on beta blockers and 68% on mineralocorticoid receptor antagonists. Serum samples were obtained and analyzed for leptin, fructosamin and pBNP before and 3–6 month after ARNI therapy. The clinical parameters LVEF and NYHA class were assessed before and 3–6 month after ARNI therapy.

Results
Baseline leptin level was 15.0 (SD 17.2), baseline fructosamin level was 370.1 (SD 167.7) and baseline pBNP level was 1494.9 (SD 1281.4). Under therapy a significant improvement of ejection fraction from 29,8% to 37,5% (7,7 SD 8,5 P≤0.001), an improvement of NYHA stadium from 2.46 (SD 0.62) to 1.96 (SD 0.63, p=0.005) and a significant decrease of pBNP (562.1 SD 1256.4, p=0.018) was found. Along with that, a significant increase in leptin levels (3.6 SD 8.85, p=0.012) and a significant increase in fructosamine levels (93.5 SD 160.6, p=0.013) was shown.

Conclusion
Under therapy with ARNI we showed a sufficient therapy response with improvement of ejection fraction and decrease of pBNP in line with literature. Surprisingly metabolism biomarkers did significantly worsen under the first three to six month after new ARNI therapy. To distinguish between a side effect of ARNI therapy or consequence of heart failure itself further investigations are needed.

Funding Acknowledgement
Type of funding sources: None.