Abstract Background Acute heart failure (AHF) can cause myocardial injury and trigger an inflammatory response, contributing to poor clinical outcomes. Sacubitril/valsartan (Sac/Val) can attenuate myocardial injury and modulate immune response; however, its treatment effects on relevant cardio-inflammatory biomarkers in patients with AHF remain unclear. Purpose This study aimed to evaluate the effects of Sac/Val on cardio-inflammatory biomarkers in patients with AHF after haemodynamic stabilisation. Methods Program Angiotensin-Neprilysin Inhibition in Admitted Patients with Worsening Heart Failure (PREMIER) is an investigator-initiated, multicentre, prospective, randomised, open-label, blinded endpoint pragmatic trial for inpatients after an AHF event. After haemodynamic stabilisation within seven days of hospitalisation because of an AHF event, eligible patients were allocated either to switch to Sac/Val initiation from background angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (ACEI/ARB) therapy or to continue ACEI/ARB. Changes in cardiac troponin T (TnT), soluble ST2 (sST2), C-reactive protein (CRP), and growth differentiation factor-15 (GDF-15) levels from baseline to eight weeks were compared between participants treated with Sac/Val and ACEI/ARB. We compared the proportional changes in the geometric mean N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels by individual biomarker strata. Additionally, these analyses were conducted within subgroups defined by baseline left ventricular ejection fraction (LVEF <40% and ≥40%). Results This study included a total of 375 patients (median age; 75 years, 120 women) with complete biomarker data. The median NT-proBNP level was 1800 pg/mL, median LVEF was 37.0%, and 206 patients (54.9%) had an LVEF <40% at baseline. The baseline characteristics were similar between the arms. Compared to ACEI/ARB, Sac/Val showed modest reductions in the biomarkers, but these differences were not statistically significant (Figure 1). Although cardio-inflammatory biomarkers, excluding CRP, in patients with LVEF <40% were generally lower than those with LVEF ≥40%, Sac/Val did not cause greater reductions in those levels than ACEI/ARB irrespective of LVEF status. In biomarker-stratified analyses, Sac/Val led to greater reductions in NT-proBNP than ACEI/ARB among patients with higher TnT, sST2, and CRP levels and those with lower GDF-15 levels (Figure 2). The effect of the Sac/Val on NT-proBNP was significantly modified by the baseline CRP level (p = 0.020), and this effect was more pronounced in patients with LVEF <40%. Conclusions Sac/Val did not reduce the cardio-inflammatory biomarkers more than ACEI/ARB over eight weeks in patients with AHF after haemodynamic stabilisation within the PREMIER study. However, Sac/Val was associated with a greater NT-proBNP reduction in patients with a higher inflammatory status and an LVEF <40%, suggesting a potential benefit in this subpopulation.For image description, please refer to the figure legend and surrounding text.For image description, please refer to the figure legend and surrounding text.

Abstract Background/Introduction N-terminal pro-B-type natriuretic peptide (NT-proBNP) reduction is a key surrogate for heart failure (HF) outcomes. The PREMIER trial showed that in-hospital sacubitril/valsartan (Sac/Val) initiation yielded a greater 8-week NT-proBNP reduction than angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker (ACEi/ARB) in Japanese patients with acute heart failure (AHF). However, clinical characteristics associated a clinically meaningful NT-proBNP reduction remain undefined. Notably, atrial fibrillation (AF) can elevate the natriuretic peptide levels via atrial structural remodelling, complicating the interpretation of NT-proBNP changes. Purpose To identify independent predictors of ≥ 50% NT-proBNP reduction by Week 8 in patients with AHFand to further explore if they differed by baseline AF status (non-AF vs AF). Methods This post-hoc analysis of the multicentre, randomised PREMIER trial included 376 (Sac/Val n=183, ACEi/ARB n=193) patients haemodynamically stabilised after an AHF event. Independent predictors of achieving the reduction in NT-proBNP were identified using multivariable logistic regression in the AF-stratified cohorts. Interaction tests within the AF cohort tested treatment effect modification by baseline characteristics. Results Overall, 39.7% of patients achieved a ≥ 50% NT-proBNP reduction by Week 8. Its independent predictors included Sac/Val use (adjusted odds ratio [aOR] 2.21, 95% confidence interval [CI] 1.32 to 3.67), younger age (aOR 1.98 per 10-year decrease, 95% CI 1.29 to 3.04), de novo HF (aOR 2.40, 95% CI 1.41 to 4.10), higher baseline NT-proBNP (aOR 3.06 per 2-fold increase), and higher systolic blood pressure (aOR 1.44 per 10 mm Hg increase, 95% CI 1.03 to 2.02) (Figure 1). Stratified by AF status (non-AF n=214, AF n=162), 43.4% of non-AF and 34.6 % of AF cohorts achieved the reduction in NT-proBNP. In the non-AF cohort, Sac/Val use remained an independent predictor of response (aOR 3.12, 95% CI 1.57 to 6.21). Conversely, in the AF cohort, Sac/Val use was not a significant predictor (aOR 1.33, 95% CI 0.53 to 3.33). Instead, higher baseline NT-proBNP (aOR 4.07, 95% CI 2.09 to 7.93) and lower left ventricular ejection fraction (LVEF) (aOR 3.38 per 10% decrease, 95% CI 1.23 to 9.29) were significant predictors (Figures 1 and 2). Interaction analysis in the AF cohort showed that HF chronicity modified treatment effect (P=0.026): Sac/Val tended to favour NT-proBNP change (−25% [95% CI −43 to 10%]) in patients with de novo HF, but not in those with a history of HF (+36% [95% CI −3 to 91%]). Conclusions Predictors of NT-proBNP response in stabilised patients after an AHF event differed by AF status. In non-AF, Sac/Val was the primary driver of NT-proBNP reduction, whereas in AF, NT-proBNP response depended on some background HF status. Our findings highlight a need for a patient-centric therapeutic approach for this population.For image description, please refer to the figure legend and surrounding text.For image description, please refer to the figure legend and surrounding text.

In the PREMIER study, early initiation of sacubitril/valsartan (Sac/Val) led to a greater reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels over 8 weeks compared to renin-angiotensin system (RAS) inhibitors in stabilized patients after acute heart failure (AHF) hospitalization. However, the effect of this treatment on echocardiographic parameters remains unknown. In this post-hoc sub-study of the PREMIER trial, we sought to evaluate the treatment effects of Sac/Val on left ventricular (LV) reverse remodeling in stabilized patients after AHF. The PREMIER study was a physician-initiated, multicenter, prospective, randomized, open-label trial enrolling stabilized Japanese inpatients after AHF. This sub-study compared the changes from baseline echocardiographic parameters at 8 weeks between patients treated with Sac/Val and RAS inhibitors. Among the full analysis set of the PREMIER study, this analysis included 206 patients (mean age 73 years; 64 females [31.1%]), who had echocardiographic data (Figure 1). The Sac/Val group (n=94) significantly improved LV functional and morphological parameters at 8 weeks (Figure 2). Compared with the control group (n=112), preload-dependent parameters improved significantly, including LV end-diastolic volume index (mean: −5.1 mL/m²; 95% CI: −10.2 to −0.04; p = 0.047) and tricuspid regurgitation peak velocity (mean: −0.17 m/s; 95% CI: −0.31 to −0.03; p = 0.016). In a subgroup analysis stratified by left ventricular ejection fraction (LVEF), the reverse remodeling effect was primarily observed in patients with LVEF < 40%. Early Sac/Val initiation after AHF hospitalization significantly improved LV function and morphology, particularly in patients with LVEF < 40%, supporting its role in LV reverse remodeling.

Chronic kidney disease has been reported to be associated with an increased incidence of stent thrombosis (ST) in patients undergoing percutaneous coronary intervention (PCI) with drug-eluting stent (DES). Renal impairment is also linked to a gradual elevation in residual platelet reactivity, enhancing risks for cardiovascular events, especially in patients with hemodialysis (HD). However, the clinical outcomes after DES thrombosis in patients with HD compared with non-HD have not been fully elucidated. The purpose of the current analysis was to assess the clinical outcomes in patients with HD after treatment for ST following DES implantation. From the REAL-ST (Retrospective Multicenter Registry of ST After First- and Second-Generation Drug-Eluting Stent Implantation) registry, this study evaluated 655 patients with DES thrombosis. Patients were divided into two groups: the HD group (n=59) and the non-HD groups (n=596). The primary endpoint was the cumulative 3-year incidence of all-cause death after the index ST events. Target lesion revascularization (TLR) and recurrent stent thrombosis (RST) were also assessed. With regard to the timing of ST, late ST was more frequently observed in the HD group (55.9％ vs. 9.7％, P=0.001), while early ST and very late ST were less likely to occur in the HD group than in the non-HD group (20.3% vs. 41.8%, P<0.0001; 23.7% vs. 48.5%, P=0.0003, respectively). Regarding clinical presentation at the time of ST, non-ST-segment elevation myocardial infarction, unstable angina and cardiac arrest were more frequently observed in the HD group than in the non-HD group. The median follow-up duration from the index procedure was 3.2 years (interquartile range: 2.0-5.2 years). The HD group showed significantly higher 3-year incidences of all-cause death (48.2% vs. 22.9%, P=0.007) and TLR (36.2% vs. 17.5%, P=0.0003) compared with the non-HD group after the index ST event. Cumulative 3-year incidence of RST was not significantly different between the HD and the non-HD groups (7.3％ vs. 5.9％, P=0.88). After adjustment for baseline differences, the increased risks in the HD group relative to the non-HD group remained significant for all-cause death (adjusted hazard ratio, 1.85 [95%CI 1.19-2.88]; P=0.007) and TLR (adjusted hazard ratio, 2.62 [95%CI 1.62-4.55]; P=0.0006). Patients with HD were associated with significantly higher risks of all-cause death and TLR after the index DES thrombosis event.

BACKGROUND Elevated levels of triglyceride (TG) and non-high-density lipoprotein cholesterol (non-HDL-C) are regarded as a residual lipid risk in low-density lipoprotein cholesterol (LDL-C)-lowering therapy. This study investigated the association between lipid risk stratified by TG and non-HDL-C and the prognosis of patients with coronary artery disease (CAD), and the association between stratified lipid risk and flow-mediated dilatation (FMD) index.Methods and Results: The 624 CAD patients enrolled in flow-mediated dilation (FMD)-J study A were divided into 4 groups: low-risk group (n=413) with TG <150 mg/dL and non-HDL-C <170 mg/dL; hyper-TG group (n=180) with TG ≥150 mg/dL and non-HDL-C <170 mg/dL; hyper-non-HDL group (n=12) with TG <150 mg/dL and non-HDL-C ≥170 mg/dL; and high-risk group (n=19) with TG ≥150 mg/dL and non-HDL-C ≥170 mg/dL. Comparison of the groups showed the cumulative incidence of a 3-point major adverse cardiovascular event (MACE) was different and highest in the high-risk group in all the patients (P=0.009), and in patients with a FMD index ≥7.0% (P=0.021), but not in those with a FMD index <7.0%. Multivariable regression analysis showed that high lipid risk (P=0.019) and FMD <7.0% (P=0.040) were independently correlated with the incidence of a 3-point MACE. CONCLUSIONS Novel stratification of lipid risk, simply using TG and non-HDL-C levels, combined with FMD measurement, is useful for predicting cardiovascular outcomes in patients with CAD.

Through the biofabrication technology using cellular aggregates (spheroids), an artificial blood vessel derived from autologous cells of human dermal fibroblast was successfully produced and is expected to be applied clinically. However, the production period remains a major problem, and the organizational construction must be optimized. It is necessary to focus on the formation and fusion of multicellular spheroids (MCS) derived from human dermal fibroblast (HDFB) and consider what affects MCS formation and fusion because these are the basis of tissue construction. In this study, we evaluated HDFB-derived MCS formation and fusion as the basis of the manufacturing process, focusing on the PI3K/AKT cascade in biofabrication technology using MCS. HDFB were used to assess the degree of MCS formation and fusion. TGF-β1 was used as an activator of the PI3K/AKT pathway, whereas LY294002 and COA-Cl were used as its inhibitors. Compared with the control group, the suppression of the PI3K/AKT pathway significantly inhibited MCS formation and fusion, whereas the activation of the PI3K/AKT pathway significantly promoted MCS formation and fusion. We identified six genes (ITGB1, PTK2, MAP2K1, PDK1, GJA1, and PI3KR1) related to cell adhesion in the PI3K/AKT pathways and confirmed a significant difference in gene expression. This study showed that the formation and fusion of HDFB-derived MCS were inhibited by suppressing the PI3K/AKT cascade, whereas it was promoted by activating the cascade with TGF-β1. This research may help elucidate the mechanism of MCS formation and fusion and optimize MCS and tissue construction, which are the basis for tissue engineering technology, and contribute to the development of regenerative medicine.

AIMS Cancer survivors have a greater risk of cardiovascular disease (CVD). Although Life's Simple 7 is used for CVD risk stratification in a general population, its utility in cancer survivors remains unknown. We aimed to clarify the association of Life's Simple 7 with incident CVD among cancer survivors. Furthermore, we analyzed the relationship between the change in Life's Simple 7 and the subsequent CVD risk. METHODS This retrospective observational study was conducted using the JMDC Claims Database, and we analyzed 53,974 patients with a prior history of breast, colorectal, or stomach cancer, which is a common cancer site in the Japanese population. The median age was 54 years, and 37.8% were men. We modified the original definition of Life's Simple 7 and identified the following (modified) ideal Life's Simple 7 cardiovascular health metrics: nonsmoking, body mass index < 25 kg/m2, physical activity at goal, optimal dietary habits, untreated fasting plasma glucose < 100 mg/dL, untreated blood pressure < 120/80 mmHg, and untreated total cholesterol < 200 mg/dL. The primary endpoint was composite CVD outcome, including myocardial infarction, angina pectoris, stroke, and heart failure. RESULTS Over a mean follow-up period of 975 ± 794 days, 3,150 composite CVD outcomes were recorded. The risk of CVD events increased with a greater number of non-ideal Life's Simple 7. The hazard ratio per 1-point increase in non-ideal Life's Simple 7 was 1.15 (95% CI:1.12-1.18). Furthermore, a 1-point increase in non-ideal Life's Simple 7 over one year was associated with subsequent CVD risk (Hazard ratio 1.12, 95% CI:1.06-1.19). CONCLUSIONS Life's Simple 7 could be applicable for CVD risk stratification even among cancer survivors. Optimizing Life's Simple 7 may prevent the development of CVD in cancer survivors.

Abstract Background/Introduction Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been reported to have beneficial effects on heart failure in large clinical trials; however, the underlying mechanism is still unclear. Purpose The purpose of this study is to elucidate the mechanism of cardioprotective effect of empagliflozin in heart failure. Methods Eight-week-old mice deficient in cardiac and skeletal muscle-specific manganese superoxide dismutase, a mouse model of dilated cardiomyopathy (MnSOD-cKO mice), were given food mixed with or without 10 mg/kg empagliflozin for seven weeks and evaluated. Mitochondrial function in the cardiac muscle were measured by a high-resolution respirometer, Oxygraph-2K. Respiratory gas analysis were performed by indirect calorimetry (ARCO 2000) to estimate the energy consumption and energetic substrates. Results The survival rate (P=0.015) and cardiac fibrosis (P=0.036) were significantly improved in the empagliflozin group. The capacity of oxidative phosphorylation in cardiac mitochondria was significantly improved by empagliflozin. Blood lactate levels were decreased in the empagliflozin group, indicating that energy such as ATP could be produced without resorting to anaerobic metabolism. Respiratory gas analysis revealed significant improvement in energy expenditure along with increase in food intake. Respiratory quotient was not different between the two groups, showing the consumption of the carbohydrate to fat rate was not changed by empagliflozin in this study. Ketone levels in blood and HbA1c were neither significantly different between the two groups. Although a moderate amount glucose was excreted in urine in the empagliflozin group (128.3±20.4 mg/day, 0.51±0.08 kcal/day), the available energy substrates in the whole body nonetheless expanded because of the increased caloric intake (10.58±0.72 in control group vs. 13.55±0.08 kcal/day in empagliflozin group, P=0.018). Conclusion(s) We have shown that empagliflozin improved myocardial mitochondrial function and increased energy metabolism, which was accompanied by adequate energy intake and uptake, even in heart failure. Empagliflozin decreased myocardial fibrosis and improved prognosis in failing murine hearts through positive energetical properties including mitochondrial function. The finding that empagliflozin modulates cardiac metabolism in a positive way provides a novel mechanism for the cardioprotective effect of SGLT2 inhibitors in heart failure. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Boehringer Ingelheim Empa improved prognosis in HFEmpa improved mitochondrial function

Abstract Aims Little is known about the impact of sodium glucose co‐transporter 2 (SGLT2) inhibitors on cardiac biomarkers, such as natriuretic peptides, in type 2 diabetes (T2D) patients with concomitant chronic heart failure (CHF). We compared the effect of canagliflozin with glimepiride, based on changes in N‐terminal pro‐brain natriuretic peptide (NT‐proBNP), in that patient population. Methods and results Patients with T2D and stable CHF, randomized to receive canagliflozin 100 mg or glimepiride (starting‐dose: 0.5 mg), were examined using the primary endpoint of non‐inferiority of canagliflozin vs. glimepiride, defined as a margin of 1.1 in the upper limit of the two‐sided 95% confidence interval (CI) for the group ratio of percentage change in NT‐proBNP at 24 weeks. Data analysis of 233 patients showed mean left ventricular ejection fraction (LVEF) at randomization was 57.6 ± 14.6%, with 71% of patients having a preserved LVEF (≥50%). Ratio of NT‐proBNP percentage change was 0.48 (95% CI, −0.13 to 1.59, P = 0.226) and therefore did not meet the prespecified non‐inferiority margin. However, NT‐proBNP levels did show a non‐significant trend lower in the canagliflozin group [adjusted group difference; −74.7 pg/mL (95% CI, −159.3 to 10.9), P = 0.087] and also in the subgroup with preserved LVEF [−58.3 (95% CI, −127.6 to 11.0, P = 0.098]). Conclusions This study did not meet the predefined primary endpoint of changes in NT‐proBNP levels, with 24 weeks of treatment with canagliflozin vs. glimepiride. Further research is warranted to determine whether patients with heart failure with preserved ejection fraction, regardless of diabetes status, could potentially benefit from treatment with SGLT2 inhibitors.

N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a screening marker for heart failure. A previous study demonstrated the positive association between NT-proBNP level and chronic kidney disease (CKD) incidence in individuals aged ≥65 years in the United States. As no report has described the relationship between NT-proBNP level and CKD incidence in Asian populations, we investigated this in the Japanese population.

Results D uring the follow-up period (median 55 months), coronary events were observed in 55 patients. Receiver-operating characteristic curve analysis identified a PMR of 1.4 as the optimal cutoff for predicting prognosis. Multivariate Cox regression analysis identified the presence of plaques with PMRs 1.4 as the significant independent predictor of coronary events (hazard ratio: 3.96; 95% confidence interval: 1.92 to 8.17; p < 0.001) compared with the presence of CAD (hazard ratio: 3.56; 95% confidence interval: 1.76 to 7.20; p < 0.001) and other traditional risk factors. Among the 4 groups based on PMR cutoff and the presence of CAD, coronary event–free survival was lowest in the group with PMRs 1.4 and CAD and highest in the group with PMRs <1.4 but no CAD. Importantly, the group with PMRs 1.4 and no CAD had an intermediate rate of coronary events, similar to the group with PMRs <1.4 and CAD.