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Abstract Aims Chronic kidney disease (CKD) increases the risk of morbidity and mortality in patients with heart failure (HF). Guidelines recommend assessing CKD using the urinary albumin-to-creatinine ratio (UACR), as albuminuria is strongly associated with the risk of incident HF and outcomes in chronic HF; however, its prognostic role in acute HF (AHF) remains unclear. We evaluated if albuminuria was associated with adverse outcomes in individuals hospitalized with AHF in Renal Optimization Strategies Evaluation-Acute Heart Failure (ROSE-AHF). Methods There were 339 participants with baseline UACR, 248 with UACR at Day 7 and 237 with both measurements for assessing change in UACR. Associations of baseline, Day 7 and change in UACR with all-cause mortality at 6 months and the composite of first HF hospitalization or cardiovascular mortality at 2 months were assessed with Cox proportional hazards models. We assessed for effect modification by treatment arm and diabetes status. Results The mean age was 70 years, 73.2% were male, 55.8% had diabetes mellitus, the mean estimated glomerular filtration rate was 45 mL/min/1.73 m2 and mean UACR was 208 mg/g. There were 65 deaths and 82 HF hospitalizations or cardiovascular deaths. Baseline UACR was not associated with either outcome; however, there was a significant interaction by diabetes status for all-cause mortality (P = 0.022) such that baseline UACR was associated with the risk of death in non-diabetics [hazard ratio (HR) 2.58, 95% CI 1.00, 6.66, P = 0.050 third tertile versus first tertile], but not diabetics. Neither Day 7 UACR nor the change in UACR were associated with outcomes. Conclusions Albuminuria is largely not associated with the risk of death, cardiovascular death, or HF hospitalization in AHF, except admission UACR is associated with the risk of death in non-diabetics.

Pierisin-1 was serendipitously discovered as a strong cytotoxic and apoptosis-inducing protein from pupae of the cabbage butterfly Pieris rapae against cancer cell lines. This 98-kDa protein consists of the N-terminal region (27 kDa) and C-terminal region (71 kDa), and analysis of their biological function revealed that pierisin-1 binds to cell surface glycosphingolipids on the C-terminal side, is taken up into the cell, and is cleaved to N- and C-terminal portions, where the N-terminal portion mono-ADP-ribosylates the guanine base of DNA in the presence of NAD to induce cellular genetic mutation and apoptosis. Unlike other ADP-ribosyltransferases, pieisin-1 was first found to exhibit DNA mono-ADP-ribosylating activity and show anti-cancer activity in vitro and in vivo against various cancer cell lines. Pierisin-1 was most abundantly produced during the transition from the final larval stage to the pupal stage of the cabbage butterfly, and this production was regulated by ecdysteroid hormones. This suggests that pierisn-1 might play a pivotal role in the process of metamorphosis. Moreover, pierisin-1 could contribute as a defense factor against parasitization and microbial infections in the cabbage butterfly. Pierisin-like proteins in butterflies were shown to be present not only among the subtribe Pierina but also among the subtribes Aporiina and Appiadina, and pierisin-2, -3, and -4 were identified in these butterflies. Furthermore, DNA ADP-ribosylating activities were found in six different edible clams. Understanding of the biological nature of pierisin-1 with DNA mono-ADP-ribosylating activity could open up exciting avenues for research and potential therapeutic applications, making it a subject of great interest in the field of molecular biology and biotechnology.

Whether sodium–glucose cotransporter-2 inhibitors (SGLT2is) reduce ventricular arrhythmias and sudden cardiac death is controversial. Ventricular repolarization heterogeneity is associated with ventricular arrhythmias; however, the effect of SGLT2is on ventricular repolarization in patients with heart failure with reduced ejection fraction (HFrEF) has not been fully investigated. We prospectively evaluated 31 HFrEF patients in sinus rhythm who were newly started on dapagliflozin 10 mg/day. Changes in QT interval, corrected QT interval (QTc), QT dispersion (QTD), corrected QTD (QTcD), T peak to T end (TpTe), TpTe/QT ratio, and TpTe/QTc ratio were evaluated at 1-year follow-up. QT interval, QTc interval, QTD, QTcD, TpTe, and TpTe/QTc ratio decreased significantly at 1-year follow-up (427.6 ± 52.6 ms vs. 415.4 ± 35.1 ms; p  = 0.047, 437.1 ± 37.3 ms vs. 425.6 ± 22.7 ms; p  = 0.019, 54.1 ± 11.8 ms vs. 47.6 ± 14.7 ms; p  = 0.003, 56.0 ± 11.2 ms vs. 49.4 ± 12.3 ms; p  = 0.004, 98.0 ± 15.6 ms vs. 85.5 ± 20.9 ms; p  = 0.018, and 0.225 ± 0.035 vs. 0.202 ± 0.051; p  = 0.044, respectively). TpTe/QT ratio did not change significantly (0.231 ± 0.040 vs. 0.208 ± 0.054; p  = 0.052). QT interval, QTD, and TpTe were significantly reduced 1 year after dapagliflozin treatment in patients with HFrEF. The beneficial effect of dapagliflozin on the heterogeneity of ventricular repolarization may contribute to the suppression of ventricular arrhythmias. Registry information https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000049428 . Registry number: UMIN000044902.

In patients hospitalized for acute decompensation of heart failure (HF), the impact of angiotensin receptor-neprilysin inhibitor (ARNI) on diuresis and renal function has not been fully investigated. Patients with HF and reduced ejection fraction who were hospitalized for acute decompensation and newly initiated ARNI after hemodynamic stabilization were enrolled. Changes in urine volume (UV), body weight, estimated glomerular filtration rate (eGFR), and urine N-acetyl-beta-d-glucosaminidase (uNAG) levels before and after ARNI initiation were investigated. Changes in the diuretic response [DR, calculated as urine volume/(intravenous furosemide volume/40 mg)], N-terminal pro-brain natriuretic peptide (NT-proBNP), hematocrit, and plasma volume (PV) were also evaluated. A total of 60 patients were enrolled. ARNI was initiated at a median of 6 [5, 7] days after hospitalization. After initiation of ARNI, body weight, NT-proBNP, and PV decreased. UV and DR increased only on the day of ARNI initiation (delta UV 400 ± 957 ml and delta DR 1100 ± 3107 ml/40 mg furosemide) and then decreased to baseline levels. In the multivariable linear regression analysis, younger age, higher BMI, and higher NT-proBNP levels were significantly associated with greater UV after ARNI initiation. eGFR and uNAG did not significantly change after the initiation of ARNI [delta eGFR -1.7 ± 12.0 mL/min/1.73 m 2 and delta uNAG 2.0 (−5.6, 6.9) IU/L]. In patients hospitalized for HF, the initiation of ARNI was associated with a small and transient increase in UV and DR, and was not associated with worsening of renal function or tubular injury.

Background The global use of angiotensin receptor neprilysin inhibitor (ARNI) in clinical practice, especially in patients with heart failure and below-normal ejection fraction (HFbnEF), has not been thoroughly evaluated. We aimed to investigate the characteristics, outcomes, and adverse events in patients treated with ARNI for HF with reduced (HFrEF), below-normal (HFbnEF), and supranormal left ventricular EF (HFsnEF). Methods This observational study analyzed data from the electronic healthcare records (EHR) of patients with HF treated with ARNI between 2015 and 2022 in North and South America, Europe, the Middle East, Africa, and Asia–Pacific. Based on the left ventricular EF, patients were categorized as HFrEF (< 40%), HFbnEF (40–60%), and HFsnEF (> 60%). Mortality and the incidence of adverse events were investigated. Results Of the 11,141 patients analyzed, HFrEF, HFbnEF and HFsnEF accounted for 74%, 22%, and 4%, respectively. Patients with a higher EF were more likely to be older, female, and obese. Hypertension and atrial fibrillation were the most common in HFsnEF. Systolic blood pressure was lower and natriuretic peptide levels were higher in the lower EF groups. Mortality was lowest in HFbnEF (7.7 per 100 patient-years follow-up in HFrEF, 5.8 in HFmrEF, and 6.0 in HFsnEF). Similarly, hypotension and acute kidney injury were the least frequent in HFbnEF. Incidence of elevated serum potassium levels was similar between the groups. Conclusions In this analysis of large-scale EHR, ARNI was mainly used in HFrEF and HFbnEF, consistent with previous randomized trials and pooled analyses. Adverse events were less common in HFbnEF.

Background The mechanisms underlying cardiorenal benefits of finerenone remain unclear. This mechanistic trial aimed to evaluate the effects of finerenone on vascular stiffness, as assessed using the cardio-ankle vascular index (CAVI), and cardiorenal biomarkers in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). Methods Eligible patients with T2D and CKD (estimated glomerular filtration rate [eGFR], 25 to < 90 mL/min/1.73 m 2 ; urinary albumin-to-creatinine ratio [UACR], 30 to < 3500 mg/g Cr) were randomly allocated to receive either dose-adjusted finerenone or matching placebo. The primary endpoint was the change in CAVI at week 24. The key secondary endpoint was the proportional change in UACR from baseline over 24 weeks. As an exploratory analysis, changes in circulating proteins were measured by using the Olink® Target 96 Cardiovascular III and Inflammation panels. Results This investigator-initiated, multicentre, prospective, two-arm parallel, placebo-controlled, double-blind, randomised clinical trial was conducted at 13 sites in Japan. Among 102 patients randomised, 101 (66.3% men; median age, 73 years; eGFR, 56.2 mL/min/1.73 m 2 ; and UACR, 193.8 mg/g Cr) were analysed. Changes in CAVI at week 24 were − 0.023 (95% confidence interval [CI], − 0.299 to 0.254) for finerenone and 0.011 (95% CI, − 0.245 to 0.267) for placebo. The group difference was − 0.057 (95% CI, − 0.428 to 0.314; P  = 0.760). Compared with placebo, finerenone led to a 29% reduction in UACR levels at weeks 12 (group ratio 0.706 [95% CI, 0.504 to 0.989; P  = 0.043]) and 24 (0.709 [95% CI, 0.506 to 0.994; P  = 0.046]). Finerenone also resulted in an early and sustained eGFR decline over 24 weeks, without increasing levels of urinary biomarkers of acute tubular injury. Finerenone, compared with placebo, was associated with nominal changes in the expression of 11 proteins among the 181 circulating proteins tested. Conclusions Finerenone did not affect changes in vascular stiffness but led to a significant and sustained reduction in albuminuria in patients with T2D and CKD. The clinical benefits of finerenone may result from lowering intraglomerular pressure rather than from its effect on vascular stiffness. Registration ClinicalTrial.gov (NCT05887817) and Japan Registry of Clinical Trials (jRCTs021230011). Graphical abstract This mechanistic clinical trial involving patients with T2D and CKD found that 24-week finerenone therapy did not significantly reduce CAVI from baseline compared with placebo (−0.057; 95% CI, −0.428 to 0.314), led to a 29% reduction (group ratio [finerenone vs. placebo] of 0.71) in UACR levels, and was associated with nominal changes in 11 circulating proteins (six upregulated and five downregulated) over 24 weeks. CAVI, cardio-ankle vascular index; CI, confidence interval; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; T2D, type 2 diabetes; UACR, urinary albumin-to-creatinine ratio.

•Prompt initiation of diuretic therapy was not correlated with faster decongestion in acute heart failure.•The timing of decongestion but not diuretics was associated with better biomarker trajectories.•Residual congestion rather than the timing of decongestion or diuretics predicted prognosis. Prompt treatment may mitigate the adverse effects of congestion in the early phase of heart failure (HF) hospitalization, which may lead to improved outcomes. We analyzed 814 acute HF patients for the relationships between time to first intravenous loop diuretics, changes in biomarkers of congestion and multiorgan dysfunction, and 1-year composite end point of death or HF hospitalization. B-type natriuretic peptide (BNP), high sensitivity cardiac troponin I (hscTnI), urine and serum neutrophil gelatinase–associated lipocalin, and galectin 3 were measured at hospital admission, hospital day 1, 2, 3 and discharge. Time to diuretics was not correlated with the timing of decongestion defined as BNP decrease ≥ 30% compared with admission. Earlier BNP decreases but not time to diuretics were associated with earlier and greater decreases in hscTnI and urine neutrophil gelatinase–associated lipocalin, and lower incidence of the composite end point. After adjustment for confounders, only no BNP decrease at discharge was significantly associated with mortality but not the composite end point (p = 0.006 and p = 0.062, respectively). In conclusion, earlier time to decongestion but not the time to diuretics was associated with better biomarker trajectories. Residual congestion at discharge rather than the timing of decongestion predicted a worse prognosis.

In patients with heart failure (HF) with reduced ejection fraction (HFrEF), malnutrition can be associated with intestinal congestion and systemic inflammation. These relationships have not been fully investigated in HF with mildly reduced EF (HFmrEF) and with preserved EF (HFpEF). We analyzed 420 patients with HF who underwent right heart catheterization. The relationships between hemodynamic parameters, C-reactive protein, and the controlling nutritional (CONUT) score were investigated in HFrEF, HFmrEF and HFpEF. The CONUT score of all patients was 2 [1, 4] (median [interquartile range]), and was not significantly different between the left ventricular EF (LVEF) categories (2 [1, 3] for HFrEF, 2 [1, 3] for HFmrEF, and 3 [1, 4] for HFpEF, p  = 0.279). In multivariate linear regression analyses, there was a significant association between CRP and the CONUT score in HFmrEF and HFpEF, while brain natriuretic peptide and right atrial pressure were significantly associated with the CONUT score in HFrEF. Higher CONUT scores predicted a higher incidence of the composite endpoint of death or HF hospitalization within 12 months without an interaction with LVEF ( p  = 0.980). The CONUT score was an independent predictor of the composite endpoint, death, and HF hospitalization after adjustment for confounders in the multivariate analysis. In conclusion, inflammation was associated with malnutrition in HFmrEF and HFpEF, while congestion was an independent predictor of malnutrition in HFrEF. Malnutrition predicted worse outcomes regardless of LVEF.

Volcanic gases erupt from the seafloor in several regions around Japan. Volcanological and geochemical gas seep studies have mainly focused on coastal shallow-water areas that are relatively accessible and important to human society. Shallow-water CO 2 seeps are thought to foreshadow future marine environments that may develop if CO 2 emissions are not drastically reduced. Thus, CO 2 seeps provide important insights for assessing and projecting the impacts of ocean acidification on marine ecosystems. This study is the first to investigate two shallow-water CO 2 seeps near Japan from the perspective of ocean acidification. We observed biotic transitions and reduced biodiversity around these CO 2 seeps, as well as high CO 2 concentrations, low pH, and low calcium carbonate saturation—conditions expected to occur by the end of this century unless anthropogenic CO 2 emissions are significantly reduced. These results suggest that, from a marine life conservation perspective, it is essential to mitigate ocean acidification through substantial reductions in anthropogenic CO 2 . Shallow-water CO 2 seeps serve as natural experimental sites that illustrate ocean acidification and its effects on marine ecosystems. Given that the shallow-water CO 2 seeps examined in this study are both located in geoparks, study tours and ecotourism field trips should utilize these sites to enhance awareness of the consequences of ocean acidification and climate change.