NRSF-GNAO1 Pathway Contributes to the Regulation of Cardiac Ca2+ Homeostasis.

BACKGROUND: During the development of heart failure, a fetal cardiac gene program is reactivated and accelerates pathological cardiac remodeling. We previously reported that a transcriptional repressor, NRSF (neuron restrictive silencer factor), suppresses the fetal cardiac gene program, thereby maintaining cardiac integrity. The underlying molecular mechanisms remain to be determined, however. METHODS: We aim to elucidate molecular mechanisms by which NRSF maintains normal cardiac function. We generated cardiac-specific NRSF knockout mice and analyzed cardiac gene expression profiles in those mice and mice cardiac-specifically expressing a dominant-negative NRSF mutant. RESULTS: We found that cardiac expression of Gαo, an inhibitory G protein encoded in humans by GNAO1, is transcriptionally regulated by NRSF and is increased in the ventricles of several mouse models of heart failure. Genetic knockdown of Gnao1 ameliorated the cardiac dysfunction and prolonged survival rates in these mouse heart failure models. Conversely, cardiac-specific overexpression of GNAO1 in mice was sufficient to induce cardiac dysfunction. Mechanistically, we observed that increasing Gαo expression increased surface sarcolemmal L-type Ca2+ channel activity, activated CaMKII (calcium/calmodulin-dependent kinase-II) signaling, and impaired Ca2+ handling in ventricular myocytes, which led to cardiac dysfunction. CONCLUSIONS: These findings shed light on a novel function of Gαo in the regulation of cardiac Ca2+ homeostasis and systolic function and suggest Gαo may be an effective therapeutic target for the treatment of heart failure.

Effect of short-duration, limited rehabilitation on maintenance of the activities of daily living in patients with acute phase of COVID-19.

[Purpose] To determine whether short-duration, limited rehabilitation is effective in patients with COVID-19. [Participants and Methods] Single-center, retrospective, observational study. Thirty-six inpatients were classified into the three groups: a close contact (CC) group with a negative polymerase chain reaction (PCR) test (n=14); a PCR-positive (PP) group (n=15); and a PCR-positive and transfer (PT) group with severe COVID-19 patients who were transferred to an acute care hospital for treatment and then returned to our hospital (n=7). Short-duration, limited rehabilitation was provided to the CC and PP groups in isolated rooms by a therapist wearing full personal protective equipment, and we assessed the changes in their activities of daily living. [Results] The patients' clinical characteristics at baseline were similar among the three groups. Functional Independence Measure scores in the CC, PP, and PT groups were not different at baseline (69 ± 29, 53 ± 26, and 63 ± 32), but differed after control of COVID-19 (63 ± 25, 47 ± 24, and 32 ± 19). Multivariate regression analysis showed that the implementation of a customized self-exercise program and the Mini Nutritional Assessment Short-Form at baseline were independently associated with Functional Independence Measure score after control of COVID-19. [Conclusion] These results suggest that even short-duration, limited rehabilitation may be effective for preventing decreases in activities of daily living in patients with COVID-19.

Cutting Edge of Brain Natriuretic Peptide (BNP) Research　- The Diversity of BNP Immunoreactivity and Its Clinical Relevance.

Brain (or B-type) natriuretic peptide (BNP) is a cardiac hormone produced in the heart and an established biochemical marker for heart failure (HF) because the level in plasma increases in proportion to disease severity. Recently, the diversity of BNP molecular forms in the peripheral circulation, which includes mature BNP (BNP1-32) and its metabolites (BNP3-32, BNP4-32, and BNP5-32), was demonstrated. Moreover, studies showed that unprocessed BNP prohormone (proBNP) is also secreted from the heart, and its secretion is increased in patients with HF. Interestingly, BNP1-32, its metabolites, and proBNP are all detected as immunoreactive BNP by the currently available BNP assay system. Current N-terminal proBNP (NT-proBNP) assay systems also can react to both NT-proBNP and proBNP. In addition, the N-terminal region of proBNP and NT-proBNP are often O-glycosylated, which may result in underestimation of total NT-proBNP level, which includes both glycosylated and non-glycosylated NT-proBNP, by the NT-proBNP assay system. More recently, we have shown that miR30-GALNT-dependent O-glycosylation in the N-terminal region of proBNP affects the processing of proBNP and contributes to its secretion from the heart. The level of proBNP relative to BNP (proBNP/BNP ratio) in the coronary sinus is higher in patients with more severe HF. The proBNP/BNP ratio and the deglycosylated NT-proBNP level may be new and clinically useful biomarkers of HF.

Adrenomedullin as a Biomarker of Heart Failure.

Adrenomedullin (AM) is a vasodilatory peptide originally discovered in human pheochromocytoma tissue. Although AM is highly expressed in the adrenal glands, heart, lungs, and kidneys, vascular endothelium and smooth muscle are thought to be the main source of plasma AM. The AM precursor is processed to AM-glycine, which is then converted to AM-mature through C-terminal amidation. In this process, mid-regional pro-adrenomedullin (MR-proAM) is also produced. Plasma AM, AM-mature, AM-glycine, and MR-proAM levels are all higher in patients with heart failure than healthy subjects in proportional to the disease severity. All molecular forms of AM are prognostic markers for heart failure.

Reciprocal expression of MRTF-A and myocardin is crucial for pathological vascular remodelling in mice.

Myocardin-related transcription factor (MRTF)-A is a Rho signalling-responsive co-activator of serum response factor (SRF). Here, we show that induction of MRTF-A expression is key to pathological vascular remodelling. MRTF-A expression was significantly higher in the wire-injured femoral arteries of wild-type mice and in the atherosclerotic aortic tissues of ApoE(-/-) mice than in healthy control tissues, whereas myocardin expression was significantly lower. Both neointima formation in wire-injured femoral arteries in MRTF-A knockout (Mkl1(-/-)) mice and atherosclerotic lesions in Mkl1(-/-); ApoE(-/-) mice were significantly attenuated. Expression of vinculin, matrix metallopeptidase 9 (MMP-9) and integrin ß1, three SRF targets and key regulators of cell migration, in injured arteries was significantly weaker in Mkl1(-/-) mice than in wild-type mice. In cultured vascular smooth muscle cells (VSMCs), knocking down MRTF-A reduced expression of these genes and significantly impaired cell migration. Underlying the increased MRTF-A expression in dedifferentiated VSMCs was the downregulation of microRNA-1. Moreover, the MRTF-A inhibitor CCG1423 significantly reduced neointima formation following wire injury in mice. MRTF-A could thus be a novel therapeutic target for the treatment of vascular diseases.

Pro-B-type natriuretic peptide is cleaved intracellularly: impact of distance between O-glycosylation and cleavage sites.

We investigated the molecular mechanism underlying the processing of pro-B-type natriuretic peptide (proBNP). Rat neonatal atrial and ventricular myocytes were cultured separately. We examined the molecular forms of secreted and intracellular BNP in atrial and ventricular myocytes; levels of corin and furin mRNA in atrial and ventricular myocytes; the effect their knockdown on proBNP processing; plasma molecular forms of BNP from rats and humans with and without heart failure; and the impact of the distance between the glycosylation and cleavage sites in wild-type and mutant human proBNP, expressed in rat myocytes transfected with lentiviral vectors. BNP was the major molecular form secreted by atrial and ventricular myocytes. Transfection of furin siRNA reduced proBNP processing in both atrial and ventricular myocytes; however, transfection of corin siRNA did not reduce it. BNP was the major molecular form in rat plasma, whereas proBNP was the major form in human plasma. The relative fraction of human BNP in rat myocytes expressing human proBNP was about 60%, but increasing the distance between the glycosylation and cleavage sites through mutation, increased the processed fraction correspondingly. These results suggest that proBNP is processed into BNP intracellularly by furin. The level of proBNP processing is lower in humans than rats, most likely due to the smaller distance between the O-glycosylation and cleavage sites in humans.

Epicardial-derived adrenomedullin drives cardiac hyperplasia during embryogenesis.

BACKGROUND: Growth promoting signals from the epicardium are essential for driving myocardial proliferation during embryogenesis. In adults, these signals become reactivated following injury and promote angiogenesis and myocardial repair. Therefore, identification of such paracrine factors could lead to novel therapeutic strategies. The multi-functional peptide adrenomedullin (Adm 5 gene, AM 5 protein) is required for normal heart development. Moreover, elevated plasma AM following myocardial infarction offers beneficial cardioprotection and serves as a powerful diagnostic and prognostic indication of disease severity. RESULTS: Here, we developed a new model of Adm overexpression by stabilizing the Adm mRNA through gene-targeted replacement of the endogenous 30 untranslated region. As expected, Admhi/hi mice express three-times more AM than controls in multiple tissues, including the heart. Despite normal blood pressures, Admhi/hi mice unexpectedly showed significantly enlarged hearts due to increased cardiac hyperplasia during development. The targeting vector was designed to allow for reversion to wild-type levels by means of Cre-mediated modification. Using this approach, we demonstrate that AM derived from the epicardium, but not the myocardium or cardiac fibroblast, is responsible for driving cardiomyocyte hyperplasia. CONCLUSIONS: AM is produced by the epicardium and drives myocyte proliferation during development, thus representing a novel and clinically relevant factor potentially related to mechanisms of cardiac repair after injury.

Effect of comorbid heart failure assessed by plasma B-type natriuretic peptide level on the activities of daily living in patients with hospitalization-associated disability after aspiration pneumonia.

PURPOSE: We investigated the effects of comorbid heart failure on rehabilitation outcomes in patients with hospitalization-associated disability after aspiration pneumonia (AP). METHODS: This study included 134 patients with hospitalization-associated disability after AP. Patients were classified into heart failure (B-type natriuretic peptide (BNP) ≧100 pg/ml, n = 39) and non-heart failure (BNP < 100 pg/ml, n = 95) groups, and the rehabilitation outcomes of both groups were compared. RESULTS: Rehabilitation effectiveness was lower in heart failure group than in non-heart failure group (21.1 ± 22.6% vs 36.2 ± 30.8, p < 0.01). The rate of independent walking at discharge in heart failure group (28.2%) was significantly lower than in non-heart failure group (53.7%). Multiple linear regression analysis revealed that age, male, handgrip strength, quadriceps strength, functional oral intake scale, Mini Nutritional Assessment Short Form, and BNP were significantly associated with rehabilitation effectiveness. DISCUSSION: Results suggest that comorbid heart failure has a negative impact on rehabilitation outcomes in patients with hospital-associated disability after AP.

Relationship between Improvement in Physical Activity and Three Nutritional Assessment Indicators in Patients Admitted to a Convalescent Rehabilitation Ward.

We investigated the relationship between three nutritional indicators, the Mini Nutritional Assessment-Short Form (MNA-SF), Geriatric Nutritional Risk Index (GNRI), and Controlling Nutrition Status (CONUT), and physical activity at discharge in patients admitted to convalescent rehabilitation wards. The study included 1601 patients (77 ± 12 years, male 46.2%) discharged from convalescent rehabilitation wards between April 2018 and September 2023. MNA-SF, GNRI, and CONUT scores were obtained on admission. Patients were divided into two groups according to their level of Functional Independence Measure (FIM) walk score at discharge. The walking group (n = 1181, FIM walk score ≥ 5, 76 ± 13 years, male 47.2%) was significantly younger than the wheelchair group (n = 420, 79 ± 12 years, FIM walk score < 5, male 43.8%) and had significantly higher MNA-SF (6.5 ± 2.5 vs. 4.7 ± 2.4) and GNRI (93.1 ± 12.4 vs. 86.7 ± 10.9) scores and significantly lower CONUT (3.1 ± 2.3 vs. 3.9 ± 2.3) scores than the wheelchair group (all p < 0.01). Multivariate logistic regression analysis showed that age, handgrip strength, Functional Oral Intake Scale, and MNA-SF score were independently associated with walking ability at discharge (all p < 0.01). In addition, MNA-SF scores were independently associated with Rehabilitation Effectiveness. These results suggest that nutritional status, particularly MNA-SF scores on admission, is associated with improvement of physical activity at discharge.

Transcriptional regulation of the fetal cardiac gene program.

Reactivation of the fetal cardiac gene program in adults is a reliable marker of cardiac hypertrophy and heart failure. Normally, genes within this group are expressed in the fetal ventricles during development, but are silent after birth. However, their expression is re-induced in the ventricular myocardium in response to various cardiovascular diseases, and potentially plays an important role in the pathological process of cardiac remodeling. Thus, analysis of the molecular mechanisms that govern the expression of fetal cardiac genes could lead to the discovery of transcriptional regulators and signaling pathways involved in both cardiac differentiation and cardiac disease. In this review we will summarize what is currently known about the transcriptional regulation of the fetal cardiac gene program.

[Clinical significance of BNP as a biomarker for cardiac disease--from a viewpoint of basic science and clinical aspect].

BNP was discovered in the porcine brain extract in 1988. Subsequent studies have demonstrated that BNP is a cardiac hormone in humans. Plasma level of BNP is increased in patients with heart failure more than ANP. Therefore, BNP measurements as a biomarker for heart failure spread all over our country and all over the world. Now the guideline in the world recognizes that BNP is a useful biomarker for diagnosis for acute and chronic heart failure. However, the usefulness of "BNP-guided therapy for heart failure" is still controversial at present, because randomized-controlled studies have shown the neutral results. Although more than twenty years have passed since its discovery, recent studies have shown the new findings in BNP research. I describe here the recent advance of BNP research.

CNP, the Third Natriuretic Peptide: Its Biology and Significance to the Cardiovascular System.

The natriuretic peptide family consists of three biologically active peptides: ANP, BNP, and CNP. CNP is more widely expressed than the other two peptides, with significant levels in the central nervous system, osteochondral system, and vascular system. The receptor that is mainly targeted by CNP is GC-B, which differs from GC-A, the receptor targeted by ANP and BNP. Consequently, the actions of CNP differ somewhat from those of ANP and BNP. CNP knockout leads to severe dwarfism, and there has been important research into the role of CNP in the osteochondral system. As a result, a CNP analog is now available for clinical use in patients with achondroplasia. In the cardiovascular system, CNP and its downstream signaling are involved in the regulatory mechanisms underlying myocardial remodeling, cardiac function, vascular tone, angiogenesis, and fibrosis, among others. This review focuses on the roles of CNP in the cardiovascular system and considers its potential for clinical application in the treatment of cardiovascular diseases.

B-Type Natriuretic Peptide (BNP) Revisited-Is BNP Still a Biomarker for Heart Failure in the Angiotensin Receptor/Neprilysin Inhibitor Era?

Myocardial wall stress, cytokines, hormones, and ischemia all stimulate B-type (or brain) natriuretic peptide (BNP) gene expression. Within the myocardium, ProBNP-108, a BNP precursor, undergoes glycosylation, after which a portion is cleaved by furin into mature BNP-32 and N-terminal proBNP-76, depending on the glycosylation status. As a result, active BNP, less active proBNP, and inactive N-terminal proBNP all circulate in the blood. There are three major pathways for BNP clearance: (1) cellular internalization via natriuretic peptide receptor (NPR)-A and NPR-C; (2) degradation by proteases in the blood, including neprilysin, dipeptidyl-peptidase-IV, insulin degrading enzyme, etc.; and (3) excretion in the urine. Because neprilysin has lower substrate specificity for BNP than atrial natriuretic peptide (ANP), the increase in plasma BNP after angiotensin receptor neprilysin inhibitor (ARNI) administration is much smaller than the increase in plasma ANP. Currently available BNP immunoassays react with both mature BNP and proBNP. Therefore, BNP measured with an immunoassay is mature BNP + proBNP. ARNI administration increases mature BNP but not proBNP, as the latter is not degraded by neprilysin. Consequently, measured plasma BNP initially increases with ARNI administration by the amount of the increase in mature BNP. Later, ARNI reduces myocardial wall stress, and the resultant reduction in BNP production more than offsets the increase in mature BNP mediated by inhibiting degradation by neprilysin, which lowers plasma BNP levels. These results suggest that even in the ARNI era, BNP can be used for diagnosis and assessment of the pathophysiology and prognosis of heart failure, though the mild increases early during ARNI administration should be taken into consideration.

Cardiac Peptides-Current Physiology, Pathophysiology, Biochemistry, Molecular Biology, and Clinical Application.

The heart has long been considered a pumping organ, consisting of muscles [...].

Zinc-finger protein 90 negatively regulates neuron-restrictive silencer factor-mediated transcriptional repression of fetal cardiac genes.

Neuron-restrictive silencer factor (NRSF) is a zinc-finger transcription factor that binds to specific DNA sequences (NRSE) to repress transcription. By down-regulating the transcription of its target genes, NRSF contributes to the regulation of various biological processes, including neuronal differentiation, carcinogenesis and cardiovascular homeostasis. We previously reported that NRSF regulates expression of the cardiac fetal gene program, and that attenuation of NRSF-mediated repression contributes to genetic remodeling in hearts under pathological conditions. The precise molecular mechanisms and signaling pathways via which NRSF activity is regulated in pathological conditions of the heart remain unclear, however. In this study, to search for regulators of NRSF, we carried out yeast two-hybrid screening using NRSF as bait and identified zinc-finger protein (Zfp) 90 as a novel NRSF-binding protein. NRSF and Zfp90 colocalized in the nucleus, with the zinc-finger DNA-binding domain of the former specifically interacting with the latter. Zfp90 inhibited the repressor activity of NRSF by inhibiting its binding to DNA, thereby derepressing transcription of NRSF-target genes. Knockdown of Zfp90 by siRNA led to reduced expression of NRSF-target fetal cardiac genes, atrial and brain natriuretic peptide genes, and conversely, overexpression of Zfp90 in ventricular myocardium resulted in significant increases in the expression of these genes. Notably, expression of Zfp90 mRNA was significantly upregulated in mouse and human hearts with chronic heart failure. Collectively, these results suggest that Zfp90 functions as a negative regulator of NRSF and contributes to genetic remodeling during the development of cardiac dysfunction.

Diverse molecular forms of plasma B-type natriuretic peptide in heart failure.

Recent studies have shown that not only plasma B-type natriuretic peptide (BNP)-32, but also plasma proBNP-108 is increased in heart failure (HF), and that the current BNP-32 assay kit crossreacts with proBNP-108. It also was shown that both BNP-32 and proBNP-108 were higher in HF than in normal. The proBNP-108/total BNP (BNP-32 + proBNP-108) ratio was widely distributed and patients with HF with ventricular overload had higher proBNP-108/total BNP ratio than HF patients with atrial overload. Consistent with this finding, proBNP-108 was the major molecular form in ventricular tissue, and BNP-32 was the major molecular form in atrial tissue. In addition, proBNP-108 was the major molecular form of BNP in pericardial fluid. The proBNP-108/total BNP ratio increased with deterioration of HF and decreased with improvement of HF. Thus, not only BNP-32, but also proBNP-108 is increased in HF and the proBNP-108/total BNP ratio also rises in association with pathophysiological conditions such as ventricular overload. A new hypothesis that O-glycosylation at Thr71 in a region close to the cleavage site impairs proBNP-108 processing was proposed. In the future, the precise mechanism of increased proBNP-108 in HF should be elucidated.

Potential pitfalls when interpreting plasma BNP levels in heart failure practice.

B-type (or brain) natriuretic peptide (BNP) is synthesized in cardiac myocytes and released constitutively into the circulation. Pressure/volume overload, neurohumoral factors, cytokines, and ischemia enhance BNP gene expression, and then precursor proBNP is produced. It has been thought that proBNP is cleaved into active BNP molecule and inactive marker molecule NT-proBNP intracellularly by processing enzyme furin, and they are released into the circulation. However, recent studies have shown that considerable amount of uncleaved proBNP circulates in the blood. The commercially available BNP assay kits consist of two antibodies that sandwich the BNP molecule. Therefore, if proBNP is present, BNP assay kit cross-reacts to proBNP and measures it as BNP. Therefore, it should be noted that the current BNP value is proBNP plus BNP. BNP and NT-proBNP have been established as a biomarker for heart failure patients presenting dyspnea. But many pitfalls are present for interpreting the BNP value. For example, the presence of renal dysfunction, age, female sex, atrial fibrillation, inflammation, hyperthyroidism, use of sacubitril/valsartan, and macro-proBNPemia overestimate BNP value, whereas the presence of obesity, immediately after acute coronary syndrome onset, and pericardial effusion underestimate BNP value. In the management for heart failure patients, BNP plays an important role. Therefore, clinicians should note the pitfall of interpretation of BNP and we describe the mechanism involved.

Effect of heart failure and malnutrition, alone and in combination, on rehabilitation effectiveness in patients with hip fracture.

BACKGROUND & AIMS: Heart failure and malnutrition are known to each negatively affect a patient's ability to improve their activities of daily living (ADL) through rehabilitation. Here, we investigated whether the negative effects of malnutrition and heart failure on ADL are additive in patients after hip fracture. METHODS: This retrospective observational cohort study included 155 patients with hip fracture admitted to convalescent rehabilitation wards. Nutritional status was measured with the Geriatric Nutritional Risk Index (GNRI). Heart failure was assessed using plasma B-type natriuretic peptide (BNP) levels. Based on their GNRIs and BNP levels, patients were classified into four groups: a high GNRI (≥92)-low BNP (<100 pg/ml) group (n = 54); high GNRI-high BNP (≥100 pg/ml) group (n = 7); low GNRI (<92)-low BNP group (n = 67); and low GNRI-high BNP group (n = 27). The main outcome was rehabilitation effectiveness (REs). To confirm above hypothesis, heart failure was also assessed by American College of Cardiology/American Heart Association (ACC/AHA) stage classification, whereas nutrition was assessed by Mini Nutritional Assessment Short Form (MNA-SF), either. RESULTS: REs in the high GNRI-low BNP group, high GNRI-high BNP group, low GNRI-low BNP group, and low GNRI-high BNP group were 64.8 ± 22.6%, 36.0 ± 22.0%, 40.6 ± 23.6% and 28.5 ± 25.9%, respectively. REs was higher in the high GNRI-low BNP group than in other three groups, and REs in the low GNRI-low BNP group was higher than in the low GNRI-high BNP group. When we evaluated heart failure by ACC/AHA stage classification instead of BNP, or evaluated nutrition by MNA-SF instead of GNRI, the similar results were demonstrated. Multiple linear regression analyses revealed that age (p < 0.01), handgrip strength (p < 0.01), GNRI (p < 0.05), and BNP (p < 0.01) were significantly associated with REs. CONCLUSIONS: These results suggest that malnutrition and heart failure are independently associated with REs and that they have an additive negative effect on improvement of ADL in elderly patients with hip fractures.

Effects of Banafine® , a fermented green banana-derived acidic glycoconjugate, on influenza vaccine antibody titer in elderly patients receiving gastrostomy tube feeding.

Immunosenescence can negatively affect cytokine production in elderly and may impair poor antibody responses to influenza vaccination and infection. Herein, the effects of Banafine® administration on influenza vaccine antibody titer in elderly patients (average age ∼80 years) receiving gastrostomy tube feeding were examined. In the double-blind, single-center, randomized clinical studies, 30 elderly bedridden patients were administered Banafine® or placebo for 8 weeks. At week 4, all patients received influenza vaccination against H1N1, H3N2, B/Yamagata, or B/Victoria. Blood biochemical indices and serum antibody titers were assessed. Banafine® administration significantly increased hemagglutination inhibition titers in response to vaccination against H1N1, H3N2, and B/Yamagata in the elderly patients (P < 0.05). Moreover, the seroconversion rate against H1N1 (47.1%) and H3N2 (29.4%) and seroprotection rate against H1N1 (71.4%) and both B strains (31.3% and 12.5%, respectively) were increased for the Banafine® group. These results suggest that Banafine® administration can increase antibody responses to influenza vaccination in bedridden hospitalized patients, and potentially modulate immune function in the elderly. PRACTICAL APPLICATION: Literature review suggested that most of the synbiotics are based on innate immunity, strain specific (probiotics), and are not consistently observed. Herein, in clinical studies we demonstrate that administration of Banafine® , a plant-based glycoconjugate, can increase antibody levels in bedridden hospitalized elderly patients following influenza vaccination.

Molecular ratio of mature B-type natriuretic peptide in acute heart failure: an indicator for ventricular contractile recovery.

AIMS: The methodology to distinguish between the heart failure (HF) with recovered ejection fraction (HFrecEF) and those with continuously reduced ejection fraction (EF) (HFcrEF) on admission has not been established. We recently demonstrated that the ratio of plasma levels of pro-B-type natriuretic peptide (proBNP) to total BNP (proBNP plus mature BNP) is decreased on admission in patients with mild acute HF, but not in severe acute HF as a compensatory mechanism for activating cyclic GMP via increases of bioactive mature BNP. We aimed to test the hypothesis that the ratio of bioactive mature BNP to total BNP is associated with reverse remodelling capacity in patients with HF with reduced EF. METHODS AND RESULTS: Plasma proBNP and total BNP were measured in patients with acute decompensated HF by using specific and sensitive enzyme immunochemiluminescent assay. Estimated percent mature BNP (%emBNP) was calculated as ([total BNP - proBNP]/total BNP) × 100. We retrospectively identified the patients with reduced EF (≤40%, on admission) who had echocardiographic data after discharge (n = 93). We defined patients with increased EF by >10% during the follow-up term (median, 545 days) after the admission as HFrecEF group. We compared patient characteristics, %emBNP, and other biomarkers between HFrecEF and HFcrEF. Of the enrolled patients with HFrecEF (n = 32) and HFcrEF (n = 61), on admission, %emBNP was significantly higher in HFrecEF than in HFcrEF (44.1% vs. 36.9%; P < 0.05). There were no significant differences in left ventricular EF on admission between the two groups. The univariate analysis revealed that %emBNP on admission was associated with HFrecEF occurrence rate (P < 0.05), in contrast both total BNP and high-sensitive cardiac troponin-T levels were not associated with HFrecEF occurrence rate. CONCLUSIONS: The ratio of mature BNP to total BNP in plasma at the time of hospital admission may be predictive of left ventricular contractile recovery. Preservation of the capacity to convert proBNP to mature BNP, but not myocardial injury itself, is associated with future ventricular contractile recovery.