Shiro Ishihara

Post-translational modifications enhance NT-proBNP and BNP production in acute decompensated heart failure

BACKGROUND Increases in plasma B-type natriuretic peptide (BNP) concentrations in those with acutely decompensated heart failure (ADHF) has been mainly attributed to an increase in NPPB gene transcription. Recently, proBNP glycosylation has emerged as a potential regulatory mechanism in the production of amino-terminal (NT)-proBNP and BNP. The aim of the present study was to investigate proBNP glycosylation, and corin and furin activities in ADHF patients. METHODS AND RESULTS Plasma levels of proBNP, NT-proBNP, BNP, as well as corin and furin concentration and activity were measured in a large cohort of 683 patients presenting with ADHF (n = 468), non-cardiac dyspnoea (non-ADHF: n = 169) and 46 patients with stable chronic heart failure (CHF); the degree of plasma proBNP glycosylation was assessed in a subset of these patients (ADHF: n = 49, non-ADHF: n = 50, CHF: n = 46). Our results showed a decrease in proBNP glycosylation in ADHF patients that paralleled NT-proBNP overproduction (ρ = -0.62, P < 0.001) but less so to BNP. In addition, we observed an increase in furin activity that is positively related to the plasma levels of proBNP, NT-proBNP and BNP overproduction (all P < 0.001, all ρ > 0.88), and negatively related to the degree of proBNP glycosylation (ρ = -0.62, P < 0.001). CONCLUSION These comprehensive results provide a paradigm for the post-translational modification of natriuretic peptides in ADHF: as proBNP glycosylation decreases, furin activity increases. This synergistically amplifies the processing of proBNP into BNP and NT-proBNP. CLINICAL TRIAL REGISTRATION http://clinicaltrials.gov/. Identifier: NCT01374880.

Precipitating factors and 90‐day outcome of acute heart failure: a report from the intercontinental GREAT registry

Several clinical conditions may precipitate acute heart failure (AHF) and influence clinical outcome. In this study we hypothesized that precipitating factors are independently associated with 90‐day risk of death in AHF.

Heart failure oral therapies at discharge are associated with better outcome in acute heart failure: a propensity-score matched study

Heart failure oral therapies (HFOTs), including beta‐blockers (BB), renin–angiotensin system inhibitors (RASi) and mineralocorticoid receptor antagonists, administered before hospital discharge after acute heart failure (AHF) might improve outcome. However, concerns have been raised because early administration of HFOTs may worsen patients condition. We hypothesized that HFOTs at hospital discharge might be associated with better post‐discharge survival.

East Asia may have a better 1-year survival following an acute heart failure episode compared with Europe: results from an international observational cohort: East Asia may have a better 1-year survival following an acute heart failure episode compared with Europe: results from an international observational

Acute heart failure (AHF) is a major health problem worldwide and trials to assess novel therapies are increasingly global, as a means to reduce costs, expedite timelines, provide broad applicability, and satisfy regulatory authorities.The significant geographic differences in patient characteristics, outcomes, and treatment effect may affect trial results and raise important questions about generalizability of the results to a broader population.

Reassessing Phase II Heart Failure Clinical Trials: Consensus Recommendations

The increasing burden and the continued suboptimal outcomes for patients with heart failure underlines the importance of continued research to develop novel therapeutics for this disorder. This can only be accomplished with successful translation of basic science discoveries into direct human application through effective clinical trial design and execution that results in a substantially improved clinical course and outcomes. In this respect, phase II clinical trials play a pivotal role in determining which of the multitude of potential basic science discoveries should move to the large and expansive registration trials in humans. A critical examination of the phase II trials in heart failure reveals multiple shortcomings in their concept, design, execution, and interpretation. To further a dialogue on the challenges and potential for improvement and the role of phase II trials in patients with heart failure, the Food and Drug Administration facilitated a meeting on October 17, 2016, represented by clinicians, researchers, industry members, and regulators. This document summarizes the discussion from this meeting and provides key recommendations for future directions.

New-onset atrial fibrillation in critically ill patients and its association with mortality: A report from the FROG-ICU study

BACKGROUND Atrial fibrillation (AFib) is associated with adverse outcome in critical illness, but whether this effect is independent from other risk factors remains uncertain. New-onset AFib during critical illness may be independently associated with increased in-hospital and long-term risk of death. METHODS FROG-ICU was a prospective, observational, multi-centre cohort study designed to investigate the outcome of critically ill patients. Inclusion criteria were invasive mechanical ventilation and/or treatment with a positive inotropic agent for >24 h. Heart rhythm was assessed at inclusion and during ICU stay with digital ECG recordings. Among patients who had AFib during ICU stay, new-onset and recurrent AFib were diagnosed in patients without and with previous history of AFib, respectively. Primary endpoint was in-hospital mortality; secondary endpoint was 1-year mortality among ICU survivors. RESULTS The study included 1841 critically ill patients. During ICU stay, AFib occurred in 343 patients (19%). New-onset AFib (n = 212) had higher in-hospital mortality compared to no AFib (47 vs. 23%, P < 0.001) or recurrent AFib (34%, P = 0.032). New-onset AFib showed increased risk of in-hospital death after multivariable adjustment compared to no AFib (OR 1.6, P = 0.003) or recurrent AFib (OR 1.8, P = 0.02). Among the 1464 ICU-survivors, new-onset AFib during ICU stay showed higher post-ICU risk of death compared to no AFib (HR 2.2, P < 0.001). After multivariable adjustment, new-onset AFib showed higher post-ICU risk of death compared to no AFib (HR 1.6, P = 0.03). CONCLUSION New-onset AFib is independently associated with in-hospital and post-ICU risk of death in critically ill patients.

Long-term Hemodialysis Corrects Left Ventricular Dyssynchrony in End-stage Renal Disease: A Study with Gated Technetium-99m Sestamibi Myocardial Perfusion Single-photon Emission Computed Tomography

INTRODUCTION Left ventricular (LV) dyssynchrony is common in patients with end-stage renal disease (ESRD), and echocardiographic assessment has shown that it can be improved by a single session of hemodialysis (HD). The aim of this study was to assess the effects of chronic HD on LV dyssynchrony in patients ESRD by means of gated technetium-99m sestamibi myocardial perfusion single-photon emission computed tomography (GSPECT) with phase analysis. MATERIALS AND METHODS Twelve patients with ESRD underwent GSPECT and echocardiography before the start of long-term HD (baseline) and 3 months later. In addition, 7 control subjects matched for age and sex underwent GSPECT and echocardiography within a 2-month period. To evaluate LV dyssynchrony, both histogram bandwidth (HBW) and phase standard deviation (PSD) were determined with phase analysis of GSPECT images. The end-diastolic volume (EDV), end-systolic volume (ESV), and ejection fraction were also measured with GSPECT, and the LV mass index (LVMI) was measured with echocardiography. The LV dyssynchrony, volume, function, and mass were compared among control subjects, patients with ESRD at baseline, and patients with ESRD after 3 months of chronic HD. RESULTS The LV dyssynchrony, volume, and mass at baseline were significantly greater in patients with ESRD than in control subjects (HBW, 65.5°±54.4° vs. 22.3°±7.5°, P<0.05; PSD, 21.0°±15.5° vs. 7.6°±5.5°, P<0.05; EDV, 105.7±29.2 vs. 72.3±13.9 mL, P<0.05; ESV, 44.3±22.1 vs. 20.9±10.3 mL, P<0.05; LVMI, 136.5±48.3 vs. 65.4±5.6 g/m(2), P<0.01). From baseline to the third month of chronic HD, there were significant increases in EDV (78.6±25.4 vs. 105.7±29.2 mL, P<0.01) and ESV (27.6±16.2 vs. 44.3±22.1 mL, P<0.01) and significant decreases in HBW (65.5°±54.4° vs. 31.0°±15.7°, P<0.01) and PSD (21.0°±15.5° vs. 10.0°±8.2°, P<0.01). CONCLUSION Chronic HD decreased LV dyssynchrony and volume in patients with ESRD. Serial phase analysis of GSPECT images is a useful method of assessing the effects of long-term HD on LV dyssynchrony and volume in patients with ESRD.