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Introduction: The incidence of arrhythmia in heart failure with non-reduced ejection fraction (HFnon-rEF) in patients who have a history of hospitalisation is unclear. The aim of this study is to investigate the usefulness of an implantable loop recorder (ILR) for arrhythmia detection including atrial fibrillation (AF) in HFnon-rEF patients after discharge., Methods and Analysis: This is a multicentre single arm study to evaluate the usefulness of ILR for detecting arrhythmia. The eligible patients are HFnon-rEF patients (left ventricular ejection fraction ≥40%) aged ≥20 years with a history of hospitalisation. The ILR will be implanted for qualified patients, and ECGs will be monitored and recorded for 1 year to check for arrhythmias. The primary endpoint is new-onset 6 min or more persistent AF detected by ILR. Secondary endpoints are 30 s or more persistent supraventricular tachycardia and ventricular tachycardia, 3 s or more persistent pause, bradycardia with 40 beats per minutes or lower heart rate, AF burden, all-cause death, cardiovascular death, hospital readmission due to exacerbation of HF, acute coronary syndrome, ischaemic or haemorrhagic stroke, non-pharmacological therapy such as pacemaker implantation and ablation., Conclusions: This study is expected to provide valuable findings regarding arrhythmia in HFnon-rEF patients, and elucidate a potential new therapeutic approach for HFnon-rEF., Trial Registration Number: This trial has been registered in the Japan Registry of Clinical Trials (jRCT) (Trial Registration: jRCTs052210060)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: A mineralocorticoid receptor antagonist (MRA) is effective in patients with chronic heart failure; however, the effects of the early initiation of an MRA in patients with acute heart failure (AHF) have not been elucidated., Methods and Results: In this multicentre, randomized, double-blind, placebo-controlled, parallel-group study, we focused on the safety and effectiveness of the treatment with eplerenone, a selective MRA in 300 patients with AHF, that is, 149 in the eplerenone group and 151 in the placebo group in 27 Japanese institutions. The key inclusion criteria were (i) patients aged 20 years or older and (ii) those with left ventricular ejection fraction of ≤40%. The primary outcome was a composite of cardiac death or first re-hospitalization due to cardiovascular disease within 6 months. The mean age of the participants was 66.8 years, 27.3% were women, and the median levels of brain natriuretic peptide were 376.0 pg/mL. The incidences of the primary outcome were 19.5% in the eplerenone group and 17.2% in the placebo group [hazard ratio (HR): 1.09, 95% confidence interval (CI): 0.642-1.855]. In prespecified secondary outcomes, HR for the composite endpoint, cardiovascular death, or first re-hospitalization due to heart failure within 6 months was 0.55 (95% CI: 0.213-1.434). The safety profile for eplerenone was as expected., Conclusion: The early initiation of eplerenone in patients with AHF could safely be utilized. The reduction of the incidence of a composite of cardiovascular death or first re-hospitalization for cardiovascular diseases by eplerenone is inconclusive because of inadequate power., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Background: Urinary neutrophil gelatinase-associated lipocalin (U-NGAL) is an early predictor of acute kidney injury and adverse events in various diseases; however, in acute decompensated heart failure patients, its significance remains poorly understood. This study aimed to investigate the prognostic value of U-NGAL on the first day of admission for the occurrence of acute kidney injury and long-term outcomes in acute decompensated heart failure patients., Methods and Results: We studied 260 acute decompensated heart failure patients admitted to our department between 2011 and 2014 by measuring U-NGAL in 24-hour urine samples collected on the first day of admission. Primary end points were all-cause death, cardiovascular death, and heart failure admission. Patients were divided into 2 groups according to their median U-NGAL levels (32.5 μg/gCr). The high-U-NGAL group had a significantly higher occurrence of acute kidney injury during hospitalization than the low-U-NGAL group ( P =0.0012). Kaplan-Meier analysis revealed that the high-U-NGAL group exhibited a worse prognosis than the low-U-NGAL group in all-cause death (hazard ratio 2.07; 95%CI 1.38-3.12, P =0.0004), cardiovascular death (hazard ratio 2.29; 95%CI 1.28-4.24, P =0.0052), and heart failure admission (hazard ratio 1.77; 95%CI 1.13-2.77, P =0.0119). The addition of U-NGAL to the estimated glomerular filtration rate significantly improved the predictive accuracy of all-cause mortality ( P =0.0083)., Conclusions: In acute decompensated heart failure patients, an elevated U-NGAL level on the first day of admission was related to the development of clinical acute kidney injury and independently associated with poor prognosis., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Soluble fms-like tyrosine kinase-1 (sFlt-1), an endogenous inhibitor of vascular endothelial growth factor and placental growth factor, is involved in the pathogenesis of cardiovascular disease. However, the significance of sFlt-1 in heart failure has not been fully elucidated. We found that sFlt-1 is decreased in renal failure and serves as a key molecule in atherosclerosis. In this study, we aimed to investigate the role of the decreased sFlt-1 production in heart failure, using sFlt-1 knockout mice. sFlt-1 knockout mice and wild-type mice were subjected to transverse aortic constriction and evaluated after 7 days. The sFlt-1 knockout mice had significantly higher mortality (52% versus 15%; P=0.0002) attributable to heart failure and showed greater cardiac hypertrophy (heart weight to body weight ratio, 8.95±0.45 mg/g in sFlt-1 knockout mice versus 6.60±0.32 mg/g in wild-type mice; P<0.0001) and cardiac dysfunction, which was accompanied by a significant increase in macrophage infiltration and cardiac fibrosis, than wild-type mice after transverse aortic constriction. An anti-placental growth factor-neutralizing antibody prevented pressure overload-induced cardiac hypertrophy, fibrosis, and cardiac dysfunction. Moreover, monocyte chemoattractant protein-1 expression was significantly increased in the hypertrophied hearts of sFlt-1 knockout mice compared with wild-type mice. Monocyte chemoattractant protein-1 inhibition with neutralizing antibody ameliorated maladaptive cardiac remodeling in sFlt-1 knockout mice after transverse aortic constriction. In conclusion, decreased sFlt-1 production plays a key role in the aggravation of cardiac hypertrophy and heart failure through upregulation of monocyte chemoattractant protein-1 expression in pressure-overloaded heart., (© 2016 American Heart Association, Inc.)

In patients with acute decompensated heart failure (ADHF), sex differences considering clinical and pathophysiologic features are not fully understood. We investigated sex differences in left ventricular (LV) ejection fraction (LVEF), plasma B-type natriuretic peptide (BNP) levels, and prognostic factors in patients with ADHF in Japan. We studied 748 consecutive ADHF patients of 821 patients registered in the ADHF registry between January 2007 and December 2014. Patients were divided into four groups based on sex and LVEF [reduced (ejection fraction, or EF, <50%, heart failure with reduced EF, or HFrEF) or preserved (EF ≥50%, heart failure with preserved LVEF, or HFpEF)]. The primary endpoint was the combination of cardiovascular death and heart failure (HF) admission. The present study consisted of 311 female patients (50% HFrEF, 50% HFpEF) and 437 male patients (63% HFrEF, 37% HFpEF). There was significant difference between sexes in the LVEF distribution profile. The ratio of HFpEF patients was significantly higher in female patients than in male patients (P= 0.0004). Although there were no significant sex differences in median plasma BNP levels, the prognostic value of BNP levels was different between sexes. Kaplan-Meier analysis revealed that the high BNP group had worse prognosis than the low BNP group in male but not in female patients. In multivariate analysis, log transformed BNP at discharge predicted cardiovascular events in male but not in female HF patients (female, hazard ratio: 1.169; 95% confidence interval: 0.981-1.399;P= 0.0806; male, hazard ratio: 1.289; 95% confidence interval: 1.120-1.481;P= 0.0004). In patients with ADHF, the distribution of LV function and the prognostic significance of plasma BNP levels for long-term outcome were different between the sexes., (Copyright © 2016 the American Physiological Society.)

Background: Heart failure (HF) with preserved (HFpEF) left ventricular ejection fraction (LVEF) is a syndrome with complex pathophysiology. Little is known about changes in LVEF that occur over time in HFpEF patients. A fundamental clinical question about HFpEF is whether HFpEF is an early manifestation of HF with reduced LVEF (HFrEF). If so, which patients with HFpEF are likely to show a decline in LVEF to less than 50%? The aim of the present study was to examine longitudinal changes in LVEF in patients with HFpEF., Methods and results: Among 279 consecutive HFpEF patients admitted as emergencies, we examined 100 who underwent echocardiography at least 1 year after discharge. EF >50% was used as the definition of HFpEF. During a mean duration from hospitalization to follow-up echocardiography of 31.5 months, 11% of patients had LVEF ≤50% (mildly reduced LVEF), known as mildly reduced (HFmrEF). The utility of LVEF during hospitalization to predict HFmrEF was assessed with receiver-operating characteristic curve analysis. A cutoff value of 55% had sensitivity of 90.9% and specificity of 97.7%. Logistic regression analysis indicated that LVEF ≤55% and ischemic etiology were strong predictors of progression from HFpEF to HFmrEF (odds ratio [OR] 435, 95% confidence interval [CI] 52.65-10,614, P<0.0001 and OR 10.9, 95% CI 2.60-74.80, P=0.0007, respectively)., Conclusions: The present study suggests that HFpEF patients with LVEF ≤55% may progress to HFmrEF in the future.

Background: The renin-angiotensin system (RAS) is activated in heart failure (HF) as a compensatory mechanism, being related to cardiac remodeling and poor prognosis. Although RAS inhibitors are used as first-line drugs for HF, plasma renin activity (PRA) is upregulated by RAS inhibitors via a negative feedback mechanism. The clinical significance of PRA during RAS inhibitor therapy is poorly understood in acute decompensated HF (ADHF). Therefore we examined the impact of PRA in HF patients already receiving RAS inhibitors., Methods and Results: Of 611 consecutive patients with ADHF and emergency admission to hospital, we studied the impact of PRA on the prognosis of ADHF in 293 patients already receiving RAS inhibitors before admission. The patients were divided into 2 groups according to median PRA (≥ vs. <3.4 ng·ml(-1)·h(-1)). During a mean follow-up of 29.0 months, there were 124 deaths from all causes. Kaplan-Meier analysis showed that all-cause and cardiovascular mortality were significantly higher in patients with high PRA than low PRA (log-rank P=0.0002 and P<0.0001, respectively). Log PRA was an independent predictor of all-cause and cardiovascular death (HR, 1.194; 95% CI: 1.378-2.678, P<0.0001; and HR, 2.559; 95% CI: 1.610-4.144, P<0.0001, respectively)., Conclusions: PRA was associated with an increased risk of all-cause and cardiovascular mortality in ADHF patients already receiving RAS inhibitors, suggesting that PRA would be a useful biomarker during ADHF treatment.

Background: Renal impairment is a common comorbidity and the strongest risk factor for poor prognosis in acute decompensated heart failure (ADHF). In clinical practice, renal function is labile during episodes of ADHF, and often worsens after discharge. The significance of worsening of renal function (WRF) after discharge has not been investigated as extensively as baseline renal function at admission or WRF during hospitalization., Methods and Results: Among 611 consecutive patients with ADHF emergently admitted to our hospital, 233 patients with 3 measurements of serum creatinine (SCr) level measurements (on admission, at discharge, and 1 year after discharge) were included in the present study. Patients were divided into 2 groups according to the presence or absence of WRF at 1 year after discharge (1y-WRF), defined as an absolute increase in SCr >0.3 mg/dL (>26.5 μmol/L) plus a ≥25% increase in SCr at 1 year after discharge compared to the SCr value at discharge. All-cause and cardiovascular mortality were assessed as adverse outcomes. During a mean follow-up of 35.4 months, 1y-WRF occurred in 48 of 233 patients. There were 66 deaths from all causes. All-cause and cardiovascular mortality were significantly higher in patients with 1y-WRF (log-rank P<0.0001 and P<0.0001, respectively) according to Kaplan-Meier analysis. In a multivariate Cox proportional hazards model, 1y-WRF was a strong and independent predictor of all-cause and cardiovascular mortality. Hemoglobin and B-type natriuretic peptide at discharge, as well as left ventricular ejection fraction <50%, were independent predictors of 1y-WRF., Conclusions: In patients with ADHF, 1y-WRF is a strong predictor of all-cause and cardiovascular mortality., (© 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: Despite marked improvements in treatment strategies for heart failure (HF), the mortality rate of elderly patients with HF is still high. Detailed causes of death have not been fully understood., Methods and Results: We studied 459 consecutive patients with acute decompensated HF (ADHF) emergently admitted to our hospital from 2007 to 2011. Patients were divided into 2 groups: <75 years old (younger group; n = 225) and ≥75 years old (elderly group; n = 234). All-cause death, cardiovascular death, and noncardiovascular death were assessed as adverse outcomes. Compared with the younger group, the elderly group was characterized by a higher proportion of women and hypertensive patients and higher left ventricular ejection fraction. During a mean follow-up of 20.7 months, a total of 174 patients (37.9%) died. All-cause death was significantly higher in the elderly group than in the younger group (46.6% vs 28.9%; P < .0001), and this difference was caused by an increase in noncardiovascular deaths (20.9% vs 9.3%; P < .001), especially deaths due to infection (10.7% vs 4.0%; P < .01). Cardiovascular deaths did not differ between the 2 groups., Conclusions: Noncardiovascular deaths, most of which were caused by infection, were frequent among elderly patients with ADHF., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Aims: After extraction of an infected cardiac implantable electronic device (CIED) in a pacemaker-dependent patient, a temporary pacemaker wire may be required for long periods during antibiotic treatment. Loss of capture and under sensing are commonly observed over time with temporary pacemaker wires, and patient mobility is restricted. The use of an externalized permanent active-fixation pacemaker lead connected to a permanent pacemaker generator for temporary pacing may be beneficial because of improved lead stability, and greater patient mobility and comfort. The aim of this study was to investigate the efficacy and safety of a temporary permanent pacemaker (TPPM) system in patients undergoing transvenous lead extraction due to CIED infection., Methods and Results: Of 47 patients who underwent lead extraction due to CIED infection over a 2-year period at our centre, 23 were pacemaker dependent and underwent TPPM implantation. A permanent pacemaker lead was implanted in the right ventricle via the internal jugular vein and connected to a TPPM generator, which was secured externally at the base of the neck. The TPPM was used for a mean of 19.4 ± 11.9 days (median 18 days, range 3-45 days), without loss of capture or sensing failure in any patient. Twelve of 23 patients were discharged home or to a nursing facility with the TPPM until completion of antibiotic treatment and re-implantation of a new permanent pacemaker., Conclusion: External TPPMs are safe and effective in patients requiring long-term pacing after infected CIED removal.

Background: Accumulating evidence suggests that hematopoiesis, especially erythropoiesis, is disturbed in heart failure (HF) for many reasons. Low hemoglobin and red blood cell distribution width have emerged as prognostic indicators of HF independent of classic predictors. The prognostic implication of mean corpuscular volume (MCV) in HF, however, is unknown. In this context, we investigated the relationship between MCV and prognosis of acute decompensated HF (ADHF)., Methods and Results: This retrospective cohort study consisted of 458 consecutive patients with ADHF who had emergency admission to hospital. Patients were divided into 2 groups: MCV ≤100fl (non-macrocytic group, n=400); and MCV >100fl (macrocytic group, n=58). The relationship between MCV and all-cause death was tested using Cox proportional hazard models, adjusting for other predictors. Mean patient age was 72.4 years and mean MCV was 93.0±7.1fl. Hemoglobin was significantly lower in the macrocytic group than the non-macrocytic group. During the mean follow-up of 20.8 months, a total of 173 deaths (37.9%) occurred. Kaplan-Meier analysis showed that all-cause death was significantly higher in the macrocytic group (log-rank P<0.0001). Cox proportional hazards analysis indicated that macrocytosis was an independent predictor of all-cause death (hazard ratio, 2.288; 95% confidence interval: 1.390-3.643; P=0.0015) after adjustment in the multivariate model., Conclusions: It is proposed for the first time that MCV is an independent predictor of all-cause death in patients with ADHF.

This case report describes abrupt heart rate fallings below the lower pacing rate limit in a patient with cardiac resynchronization therapy (CRT). Interrogated information including stored episodes or data regarding the lead did not show any device problems and only simultaneous intracardiac electrogram revealed the cause, T-wave oversensing during biventricular pacing. At this moment, CRT has become an established modality for patients with severe heart failure. However, bradycardia below the lower rate limit during biventricular pacing due to T-wave oversensing would exacerbate heart failure in patients with CRT. We should notice this latent risk and correct the malfunction immediately., (©2010, The Authors. Journal compilation ©2010 Wiley Periodicals, Inc.)

Placental growth factor and vascular endothelial growth factor increase angiogenesis and promote healing after acute myocardial infarction (MI), but the significance of soluble Fms-like tyrosine kinase-1 (sFlt-1), an antagonist of placental growth factor and vascular endothelial growth factor, in the setting of acute MI has not been elucidated. The development of acute heart failure in the immediate period after MI is a dreaded complication, but there are no useful biomarkers that identify patients at risk of acute heart failure. We wished to investigate the clinical significance of circulating sFlt-1 during acute MI. We enrolled 174 patients with acute MI, and arterial blood sampling was performed. Plasma levels of sFlt-1 were measured by enzyme-linked immunosorbent assay and their relation to clinical parameters was analyzed. Circulating levels of sFlt-1 on admission were significantly increased in patients with acute MI compared to controls (528.1 +/- 290.9 vs 355.7 +/- 205.0 pg/ml, p <0.001). Circulating levels of sFlt-1 on admission were significantly higher in patients who developed severe acute heart failure requiring mechanical circulatory support devices compared to those with stable hemodynamics (611.4 +/- 373.6 vs 494.6 +/- 243.9 pg/ml, p = 0.016). Moreover, circulating levels of sFlt-1 on admission were directly related to duration of hospitalization. Multivariate logistic analysis showed that hemodynamic instability was predicted by sFlt-1 on admission and left ventricular systolic pressure. In conclusion, the circulating level of sFlt-1 is increased in patients with acute MI, and the sFlt-1 level on admission is a promising biomarker for the development of severe acute heart failure after MI.

Objective: To obtain a better understanding of the pharmacokinetics of atrial and brain natriuretic peptides (ANP and BNP, respectively), two peptide mediators used in the treatment of congestive heart failure (CHF). Although both peptides exert their effects by binding to a common receptor (natriuretic peptide receptor A) with about the same affinity, their respective loading and maintenance doses differ., Methods: Sixteen CHF patients were randomized to be infused for 2 h with alpha-human ANP (0.05 microg/kg per minute) or BNP (0.01 microg/kg per minute). Plasma concentrations of both peptides were measured 0, 2, 5, 15, 30, 60 and 120 min post-infusion. The pharmacokinetic parameters were then calculated using a 1-compartment model., Results: The plasma BNP concentrations in the ANP and BNP groups before infusion were 464.7 +/- 339.8 and 506.8 +/- 332.5 pg/ml, respectively. Following infusion, ANP disappeared from the circulation more rapidly than BNP: their plasma half-lives were 2.4 +/- 0.7 and 12.1 +/- 3.0 min, and their total body clearance volumes were 48.2 +/- 24.1 and 10.1 +/- 2.7 ml/min per kilogram, respectively., Conclusion: ANP has a shorter half-life in the plasma of CHF patients than BNP, which suggests that it controls hemodynamics more readily than BNP.