bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association between prognosis and the use of angiotensin-converting enzyme inhibitors and/or angiotensin II receptor blocker in frail patients with heart failure with preserved ejection fraction
Authors: Sunaga A , Hikoso S , Tamaki S , Yano M , Hayashi T , Oeun B , Kida H , Sotomi Y , Dohi T , Okada K , Mizuno H , Nakatani D , Yamada T , Yasumura Y , Sakata Y 
Published: October 2022

Abstract

Background
The effectiveness of angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARB) has not been demonstrated in patients with heart failure with preserved ejection fraction (HFpEF). We recently reported significant interaction between the use of ACE-I and/or ARB (ACE-I/ARB) and frailty on prognosis in patients with HFpEF.

Purpose
In the present study, we examined the association between ACE-I/ARB and prognosis in patients with HFpEF stratified by the presence or absence of frailty.

Methods
We examined the association between the use of ACE-I/ARB and prognosis according to the presence (Clinical Frailty Scale (CFS) ≥5) or absence (CFS ≤4) of frailty in patients with HFpEF in a post-hoc analysis of registry data. Primary endpoint was the composite of all-cause mortality and heart failure admission. Secondary endpoints were all-cause mortality and heart failure admission.

Results
Of 1059 patients, median age was 83 years and 45% were male. Kaplan-Meier analysis showed that the risk of composite endpoint (log-rank P=0.001) and all-cause death (log-rank P=0.005) in patients with ACE-I/ARB was lower in those with CFS ≥5, but similar between patients with and without ACE-I/ARB in patients with CFS ≤4 (composite endpoint: log-rank P=0.830; all-cause death: log-rank P=0.192). In a multivariable Cox proportional hazards model, use of ACE-I/ARB was significantly associated with lower risk of the composite endpoint (hazard ratio = 0.52, 95% CI: 0.33–0.83, P=0.005) and heart failure admission (hazard ratio = 0.45, 95% CI: 0.25–0.83, P=0.010) in patients with CFS ≥5, but not in patients with CFS ≤4 (composite endpoint: hazard ratio = 1.41, 95% CI: 0.99–2.02, P=0.059; heart failure admission: hazard ratio = 1.43, 95% CI: 0.94–2.18, P=0.091). The association between ACE-I or ARB and prognosis did not significantly differ by CFS (CFS ≤4: log-rank P=0.562; CFS ≥5: log-rank P=0.100, for with ACE-I vs. ARB, respectively). Adjusted HRs for CFS 1–4 were higher than 1.0, but were less than 1.0 at CFS 5.

Conclusions
In patients with HFpEF, use of ACE-I/ARB was associated with better prognosis in patients with frailty as assessed with the CFS, but not in those without frailty.

Funding Acknowledgement
Type of funding sources: Private company. Main funding source(s): Roche
Sex-based differences in treatment outcomes in HFpEF: a systematic review
Authors: Moore C , Mordi I , Lang C C 
Published: October 2022

Abstract

Background
Heart failure with preserved ejection fraction (HFpEF) is the prevailing heart failure phenotype among women. Disease-modifying treatment in HFpEF has proved a challenge and little is known on sex-based differences in treatment outcomes in HFpEF.

Purpose
This systematic review aimed to identify drug and non-drug exercise randomized controlled trials that stratified treatment outcome by sex.

Methods
A systematic literature search of PubMed for randomised controlled trials that assessed treatment outcomes by sex (pre-specified, secondary, post-hoc analysis) for HFpEF was performed until January 2021.

Results
This systematic review included 36 drug and 2 exercise RCTs. There was an increased benefit in reducing the composite outcome of first and recurrent HF hospitalisation and cardiovascular death among women (HR 0.73, 95% CI 0.59–0.90) compared to men (HR 1.03, 95% CI, 0.84–1.25, p-interaction = 0.017) treated with sacubitril-valsartan. However, women (HR 1.41, 95% CI 1.02–1.97) had higher risk of new-onset AF compared to men (HR 0.79, 95% CI 0.55,1.14, p-interaction 0.019) taking sacubitril-valsartan, and men (Δ2.8, 95% CI 1.3–4.3) were more likely to show improvements in the KCCQ-CSS compared to women (Δ-0.6, 95% CI −2.1,0.8, p-interaction=0.003). There may be benefit among women treated with sacubitril-valsartan in lowering blood pressure and characteristic impedance. A superior risk reduction in all-cause mortality was reported in women treated with spironolactone (HR 0.66, 95% CI 0.48–0.90) when compared with men (HR 1.06, 95% CI 0.81–1.39, p-interaction=0.024). No differences in treatment outcomes by sex were reported with SGLT2 inhibitors or with exercise interventions in HFpEF.

Conclusions
Women may respond to HFpEF treatment differently than men. Identifying sex-based differences in treatment outcomes should be prioritised in future research and taken into consideration in the development of guidelines for the management of HFpEF.

Funding Acknowledgement
Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): British Heart Foundation
Trimetazidine in heart failure with preserved ejection fracton: a randomized, double-blind cross-over trial
Authors: Van De Bovenkamp A A , Bakermans A J , Geurkink K J T , Oosterveer F T P , De Man F S , De Kok W E M , Nederveen A J , Van Rossum A C , Handoko M L 
Published: October 2022

Abstract

Introduction
Impaired myocardial mitochondrial function plays an import role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). Left ventricular relaxation has a high energy demand, and there is evidence indicative of a causal relationship between observed impaired energy homeostasis and diastolic dysfunction. Improvement of mitochondrial function with metabolism-modulating drugs may be a promising novel therapeutic approach in HFpEF. Trimetazidine – a fatty acid oxidation inhibitor – shifts mitochondrial metabolism towards glucose oxidation, which results in higher mitochondrial oxygen efficiency. In this study we investigated whether trimetazidine improves diastolic function during exercise in HFpEF by improving the myocardial energy homeostasis.

Methods
The DoPING-HFpEF trial was a phase II single-center, double-blind, placebo-controlled, randomized cross-over trial. The study consisted of two treatment periods of three months separated by a 2-week wash-out period (Figure 1). Patients were treated with placebo or trimetazidine three times a day (or twice daily in case of an impaired kidney function). The primary endpoint was change in pulmonary capillary wedge pressure (PCWP) measured with right heart catheterization at multiple stages of exercise. Secondary endpoint was change in phosphocreatine (PCr)/adenosine triphosphate (ATP) ratio, an index of the myocardial energy status, measured with phosphorus-31 magnetic resonance (MR) spectroscopy. Additional exploratory endpoints were 6-minute-walking-distance, diastolic and systolic parameters measured with echocardiography or cardiac MR, NT-proBNP levels, and quality of life.

Results
Twenty-five HFpEF patients were included and completed the trial, 80% of which were included based on previously established elevated (exercise) PCWP, and 20% were included based on diastolic dysfunction grade ≥II on echocardiography and elevated NT-proBNP levels. There was no effect on the primary outcome PCWP at multiple levels of exercise, with an average change in PCWP of 0±4 (SD) mmHg (Figure 2A, P=0.97). Myocardial PCr/ATP in the trimetazidine arm was similar to placebo (Figure 2B, P=0.08). There was no change by trimetazidine in the exploratory parameters 6-minute walking distance, NT-proBNP, overall quality of life, or other parameters for diastolic function measured with echocardiography and cardiac MR. There was no indication of period or cross over effect.

Conclusion
Trimetazidine did not improve diastolic function or myocardial energy homeostasis in patients with HFpEF.

Funding Acknowledgement
Type of funding sources: Foundation. Main funding source(s): Dutch Heart Foundation (DHF) and “Out-of-the-Box” grant from the Amsterdam Cardiovascular Sciences (ACS) Institute, Amsterdam, The Netherlands.
Clinical trajectory and outcomes of patients with heart failure with preserved ejection fraction with normal or indeterminate diastolic function
Authors: Oeun B , Hikoso S , Nakatani D , Okada K , Dohi T , Sotomi Y , Kida H , Sunaga A , Sato T , Seo M , Yano M , Hayashi T , Yamada T , Yasumura Y , Sakata Y 
Published: October 2022

Abstract

Background
Heart failure (HF) with preserved ejection fraction (HFpEF) is a chronic and progressive disease, but limited therapeutic strategies are currently available. Although left ventricular diastolic dysfunction (DD) is a prominent mechanism of HFpEF, a certain number of patients with HFpEF have a normal diastolic function (ND) or indeterminate diastolic function (ID). With the progressive nature of HFpEF, diastolic function may change over time. However, the change of diastolic function, its predictor and prognosis in patients with clinically established HFpEF remains unknown.

Purpose
To investigate the clinical trajectory and outcomes of patients with HFpEF with ND or ID and to identify factors associated with progression from ND or ID at discharge to DD at 1-year follow-up.

Methods
Using data from a prospective multicenter observational study of patients with HFpEF, we extracted 289 patients with HFpEF with ND or ID at discharge who had echocardiographic data at 1-year follow-up for the re-evaluation of diastolic function. Diastolic function was assessed according to the 2016 American Society of Echocardiography recommendations. Patients were classified according to the absence or presence of progression from ND or ID to DD at 1 year. The primary endpoint was a composite of all-cause death and HF rehospitalization.

Results
Median age was 81 years, and 138 (47.8%) patients were female. At 1 year, 107 (37%) patients progressed to DD. During a median follow-up of 709 days, the composite endpoint occurred in 90 (31.1%) patients. Compared to patients without progression to DD, those with progression to DD had a significantly higher cumulative incidence rate of the composite endpoint (incidence rate: 11.7/100 person-year versus 23.3/100 person-year, P&lt;0.001). Progression to DD (adjusted HR: 2.014, 95% CI: 1.239–3.273, P=0.005) was independently associated with the composite endpoint. Age (adjusted OR: 1.046, 95% CI: 1.008–1.087, P=0.018), body mass index (BMI) (adjusted OR: 1.107, 95% CI: 1.029–1.192, P=0.006), and serum albumin (adjusted OR: 0.459, 95% CI: 0.216–0.974, P=0.042) were independently associated with progression from ND or ID to DD at 1 year.

Conclusion
More than one-third of patients with HFpEF with ND or ID progressed to DD at 1 year and had poor clinical outcomes. Age, BMI, and serum albumin were independently associated with this progression.

Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This work was supported by grants from Japan Society for the Promotion of Science KAKENHI (No. JP 17K09496) and Japan Agency for Medical Research and Development (No. JP16lk1010013).
Reduction in heart failure hospitalizations by sacubitril/valsartan; a post-hoc analysis of the PARALLAX trial
Authors: Wachter R , Pieske B , Baldridge A , Ibram G , Zhao Z , Shah S J 
Published: October 2022

Abstract

Background
The PARALLAX trial recently showed a significant reduction in plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations by angiotensin receptor neprilysin inhibition with sacubitril/valsartan (S/V) compared to standard medical therapy (SMT) in patients with heart failure and ejection fraction ≥40%. As NT-proBNP reductions have been associated with a reduction in future heart failure hospitalizations (HHF), we aimed to investigate the impact of S/V on this endpoint in comparison to standard medical therapy.

Methods
The PARALLAX study was a 24-week, randomized, active-controlled, parallel group study to evaluate S/V compared to SMT for comorbidities. Eligible patients were stratified into three strata according to their individual RASi treatment (ACEi, ARB, ACEi/ARB-naïve) and randomized within each stratum 1:1 to S/V (N=1281; target dose (td), 97/103 mg b.i.d.) or individual comparator (N=1285; enalapril (td 10 mg b.i.d), valsartan (160 mg b.i.d.), or placebo). Hospitalizations for cardiac failure reported as serious adverse events by investigators were analysed in this post-oc secondary analysis.

Results
2566 patients with heart failure and LVEF ≥40%, were randomized to receive either S/V or SMT according to RASi stratum (n=1,016 ACE inhibitor stratum, n=1,174 ARB stratum, n=326 no RAS stratum). After 12 weeks, adjusted geometric mean ratio of NT-proBNP showed a 16.4% greater reduction sith S/V vs. SMT (p&lt;0.0001). S/V reduced the risk for cardiac failure events leading to hospitalization by 51% (hazard ratio (HR) 0.49; 95% CI 0.30, 0.81; p=0.005). Similar results were obtained in all three strata: HR 0.55 (0.25–1.19) in ACE inhibitor stratum, HR 0.50 (024–1.02) in ARB stratum and HR 0.37 (0.10–1.38) in no RAS stratum.

Conclusion
The significant reduction of NT-proBNP plasma levels by S/V in comparison to SMT in PARALLAX was associated with a significant reduction in heart failure hospitalisations. These results, together with evidence from the PARAGON trial, support the use of S/V in HFpEF for avoiding heart failure hospitalizations.

Funding Acknowledgement
Type of funding sources: Private company. Main funding source(s): Novartis
Digoxin improves systolic cardiac function in patients with AF and HFpEF: the RATE-AF randomised trial
Authors: Bunting K V , Mehta S , Gill S K , Steeds R P , Kotecha D 
Published: October 2022

Abstract

Background
The RAte control Therapy Evaluation in permanent AF trial (RATE-AF; NCT02391337) was the first head-to-head controlled trial of beta-blockers versus digoxin in patients with permanent atrial fibrillation (AF) and symptoms of heart failure. Patients randomised to digoxin had similar physical-related quality of life and heart rate, with significantly improved functional class, reduced N-terminal pro-brain natriuretic peptide (NT-proBNP) and substantially less adverse events. The impact of rate control therapy on measures of cardiac function is not currently understood.

Purpose
To compare the effect of digoxin versus beta-blockers on systolic and diastolic cardiac function according to heart failure sub-type.

Methods
Blinded echocardiograms assessing systolic and diastolic function were performed at baseline and 12 month follow-up, using a robust method to account for rhythm irregularity (average of three index-beats acquired in appropriate cardiac cycles). Outcomes were the change in left-ventricular ejection fraction (LVEF), systolic tissue Doppler velocity (s'), stroke volume, global longitudinal strain (GLS), diastolic tissue Doppler (e'), mitral E wave deceleration time, E/e', pulmonary vein diastolic deceleration time, isovolumic relaxation time and left atrial ejection fraction. Analyses were stratified by baseline LVEF (≥50%, 40–50% and &lt;40%).

Results
160 patients were randomised, of which 145 patients survived to 12-month follow-up with median age 75 years (IQR 69–82) and 44% women. Median baseline heart rate was 96 beats/min (IQR 86–112), blood pressure 135/85 mmHg (IQR 124/77–146/91), NTproBNP 1049 pg/mL (744–1463) and mean NYHA class 2.4 (SD 0.6). In 119 patients with LVEF ≥50% at baseline, diastolic and systolic parameters improved over time with digoxin therapy. There was a significantly greater improvement in systolic function in 63 patients on digoxin compared to 67 with beta-blockers; Figure 1. Patients randomised to digoxin had a higher LVEF at follow-up (adjusted mean difference [AMD] 2.3%, 95% CI 0.3–4.2; p=0.021), higher s' (1.1cm/s, 1.0–1.2; p=0.003) and higher stroke volume (6.5mL, 0.4–12.6; p=0.037) compared to beta-blockers, without any difference in diastolic parameters (Figure 2). In 16 patients with LVEF 40–50% at baseline, s' significantly increased with digoxin compared to beta-blockers (AMD 1.5 cm/s, 1.2–1.7; p=0.001), with no difference for other systolic or diastolic parameters. 10 patients with LVEF &lt;40% at baseline showed no difference between digoxin and beta-blockers for any echocardiographic measures.

Conclusion
Patients randomised to digoxin with permanent AF, heart failure symptoms and preserved LVEF have significantly greater improvement in multiple parameters of systolic function compared to conventional treatment with beta-blockers.

Funding Acknowledgement
Type of funding sources: Public Institution(s). Main funding source(s): National Institute of Health Research
Role of left atrial strain response to exercise in the transition from the preclinical to overt heart failure
Authors: Jasic-Szpak E , Woznicka A K , Serafin A , Kotwica T , Ponikowski P , Przewlocka-Kosmala M , Kosmala W 
Published: October 2022

Abstract

Impaired left ventricular (LV) functional reserve has been shown to contribute to exercise intolerance in heart failure. Little is known about the role of left atrial (LA) functional response to exertion in this context. LA strain has recently emerged as a valuable diagnostic marker reflecting both LA and LV performance.

Aim
To investigate the association between LA strain response to exercise and exercise capacity across different stages of heart failure with preserved ejection fraction (HFpEF).

Methods
Transthoracic echocardiography (including peak atrial longitudinal strain (PALS) and LV global longitudinal strain (GLS) assessment) was performed at rest and immediately post exercise test in 55 patients with stage A, 62 patients with stage B and 54 patients with stage C HFpEF.

Results
There was a progressive worsening of peak oxygen uptake from stage A through stage B to stage C, which was accompanied by a gradual impairment of changes from rest to exercise in PALS, GLS, tissue early diastolic velocity e', LA ejection fraction and E/e' ratio (Table 1). In multivariable analysis including LV and LA components of cardiac functional reserve, changes from rest to exercise in PALS (beta 0.34, SE 0.07, p&lt;0.001), e' (beta 0.29, SE 0.07, p&lt;0.001) and GLS (beta 0.17, SE 0.07, p=0.014) were among the independent correlates of exercise capacity. However, after adjustment for age, sex and beta-blocker treatment, only the former two remained statistically significant.

Conclusions
LA strain response to exercise progressively deteriorates from stage A through stage B to stage C HFpEF, and is independently associated with exercise capacity. Accordingly, it might be considered in the risk stratification of the transition from the asymptomatic phase to overt HFpEF.

Funding Acknowledgement
Type of funding sources: None.
Response to heart failure treatment in patients with anthracyclines and trastuzumab induced left ventricular dysfunction
Authors: Del Castillo S , Fileni L , Llamedo C , Capdeville S , Scarponi C , Belziti C , Falconi M , Perez De Arenaza D , Rossi E , Pizarro R 
Published: October 2022

Abstract

Background
Chemotherapy treatments with anthracyclines and Trastuzumab are widely used in different hematologic or solid malignancies but myocardial injury and left ventricular dysfunction, usually called cardiotoxicity (CTX), is a frequent adverse effect. Some studies have demonstrated that early detection and treatment of CTX is essential for the recovery of left ventricular ejection fraction (LVEF), however its behavior after starting treatment is not well established.

Purpose
Evaluate the behavior of LVEF after starting treatment for heart failure in patients with diagnosis of CTX.

Methods
Patients with diagnosis of solid or hematologic malignancies scheduled to receive therapy including anthracyclines and/or trastuzumab were prospectively included. Echocardiogram was performed before starting treatment, and then 3 and 6 months after. CTX was defined, according to guidelines, as a drop of LVEF ≥10% to a value &lt;53% and in these patients treatment of left ventricular dysfunction with B blockers and Enalapril/Losartan was promptly initiated and up-titrated to the maximal tolerated dose. Myocardial injury was defined as a drop of LVEF ≥10% and a value ≥53%, with a watchful waiting strategie, considering these patients as a control group. LVEF was re-evaluated 6 months after starting treatment or after diagnosis of myocardial injury. Primary endpoint was defined as a recovery of LVEF ≥10%.

Results
Of a total of 141 patients of the entire cohort (mean age 56±15 years, 85,8% women and 61,7% with diagnosis of breast cancer),17 patients (12%) met criteria of CTX and 21 (14,9%) of myocardial injury. There were no differences in relation to clinical characteristics or chemotherapy schemes between groups. In patients with CTX (intervention group), 88,2% reached the primary endpoint of recovery of LVEF ≥10% while only 23,8% did it in the control group (p&lt;0,001). Patients with CTX had lowest LVEF at baseline, however no significant differences were observed at 12 months of follow up. Figure 1 represents the behavior of LVEF at baseline, 3, 6 and 12 months. A paired before-after analysis was performed between LVEF at baseline and at 12 months. Patients who received treatment showed no differences in LVEF (63,3±7,2% vs 61,5±9,6%, p=0,5). In contrast, patients who did not receive treatment showed a significant drop in LVEF (72,7±4,4% vs 66,2±5,4%; p&lt;0,001) (figure 2).

Conclusion
Treatment of left ventricular dysfunction in patients with CTX is associated with a greater recovery of LVEF.

Funding Acknowledgement
Type of funding sources: None.