We previously established an interpretable combinatorial data-mining framework to identify combinations of clinical factors predictive of heart failure. Because hypertension (HT) is a major contributor to heart failure, accurate prediction of new-onset HT is critically important for prevention. To identify combinations of clinical factors predictive of HT onset using a novel limitless-arity multiple-testing procedure (LAMP) and to estimate the probability of developing HT. We analyzed 2,610,286 individuals without HT who underwent annual health check-ups starting in 2005-2015 and were followed for 5 consecutive years without missing data. Using the LAMP method, we systematically identified statistically significant combinations of fewer than four clinical factors associated with HT onset. Among 28,618 subjects used for rule discovery, 4802 combinations predictive of HT onset were identified. The remaining 2,581,668 individuals were classified into one group with no predictive combinations (G0) and 20 groups (G1-G20) according to increasing numbers of predictive combinations. The incidence of HT increased stepwise with the number of predictive combinations, as confirmed by Kaplan-Meier analyses (p < 0.001). Receiver-operating characteristic analysis demonstrated a moderate discriminative performance (area under the curve = 0.69). We identified combinations of routine clinical parameters that predict new-onset HT in the general population. A greater number of matching predictive combinations was associated with a proportionally higher probability of developing HT. This interpretable combinatorial data-mining framework may enable risk stratification for HT and support early preventive strategies.

Mineralocorticoid receptor antagonists (MRAs) are often underutilized in patients with heart failure (HF), particularly those with diabetes and/or chronic kidney disease (CKD). However, the impact of concurrent diabetes and CKD on the efficacy and safety of eplerenone in acute HF remains uncertain. The EARLIER trial enrolled patients with acute HF, who were randomized to receive eplerenone or placebo for 6 months. Patients were categorized based on the presence of diabetes and/or CKD (defined by eGFR < 45 ml/min/1.73 m2 or UACR ≥ 30 mg/g), and the associations between diabetes/CKD categories and cardiovascular outcomes were assessed. The effects of eplerenone on HF-related outcomes (i.e., cardiovascular death, HF hospitalization, worsening HF, or out-of-hospital diuretic intensification) and adverse events were also assessed across diabetes/CKD status. Among 300 patients (mean age 67 ± 13 years; 73

Background The collection of race and ethnicity data in clinical trials using standardized categories is recommended by the US Food and Drug Administration, although this is primarily for domestic reasons. The applicability and understanding of the categories in multinational trials are uncertain. Methods We analyzed patient‐level data from 13 major heart failure trials, examining race and ethnicity data recorded by country, as recommended by the Food and Drug Administration: “American Indian or Alaska Native,” “Asian,” “Black or African American,” “Native Hawaiian or Other Pacific Islander,” and “White” for race and “Hispanic or Latino” as a minimum for ethnicity (with an expanded list of ethnicities available). Results Of the 54 087 patients studied, approximately 32.3% were women. In the United States, 77% of patients were reported to be of White race and 19% of Black race with very few assigned to another race category (1% Asian, 0.7% Native American, 0.2% Native Hawaiian or other Pacific islander, and 1.4% “other”). In Europe, race was almost uniformly reported as White, and a similar racial homogeneity was reported in Asia (Asian race). Conversely, in Latin America, 8.9% of patients were described as “American Indian or Alaska Native,” with a very high proportion in specific countries (eg, 36% in Guatemala and 21% in Mexico). In the United States, 6.2% of participants were reported to have Hispanic/Latino ethnicity but most patients in Latin America were reported to have this ethnicity; conversely, few patients had this ethnicity reported outside the Americas, including in Spain and Portugal. Among patients designated as Asian race, specific ethnicities (eg, Indian, Japanese etc) almost completely overlapped with the country of origin. Conclusions This study highlights the challenges of applying standardized race and, particularly, ethnicity categories in global clinical trials. A multistakeholder approach is needed to improve the collection of race and ethnicity data in clinical trials.

Objective:Glucocorticoid-induced leucine zipper (GILZ) deficiency has been shown to exacerbate angiotensin-induced cardiomyocyte hypertrophy and diastolic dysfunction. However, the specific role of the long isoform of GILZ (L-GILZ) in cardiac function remains unclear. This study aimed to investigate the role of L-GILZ in maintaining cardiac function and its protective effects against pressure overload-induced hypertrophy and dysfunction. Methods:Institute of Cancer Research mice were used in this study. The human L-GILZ gene or short hairpin RNA targeting mouse L-GILZ was introduced via adeno-associated virus 9 under the control of the cardiac troponin-T promoter, ensuring cardiac-specific overexpression or knockdown. Luciferase and short hairpin RNA targeting LacZ served as respective controls. L-GILZ expression was analyzed by western blot analysis and real-time polymerase chain reaction, while extracellular signal-regulated kinase (ERK) phosphorylation was assessed via western blot analysis. RNA sequencing was performed to evaluate gene expression changes following L-GILZ knockdown. Pressure overload was induced by transverse aortic constriction (TAC), and echocardiography was used to assess cardiac function. Results:TAC-induced pressure overload reduced L-GILZ expression but not GILZ expression. Cardiac-specific overexpression of human L-GILZ was successfully achieved in mouse hearts, with no detectable expression in other organs. L-GILZ overexpression significantly attenuated TAC-induced cardiac hypertrophy, dysfunction, and ERK phosphorylation. Conversely, L-GILZ knockdown led to hypertrophy, cardiac dysfunction, and enhanced ERK phosphorylation. RNA sequencing revealed that L-GILZ knockdown reduced the expression of mitochondria-associated genes, including cytochrome c oxidase, adenosine triphosphate synthase, and mitochondrial nicotinamide adenine dinucleotide (reduced form) dehydrogenase. Conclusion:L-GILZ plays a critical role in maintaining cardiac function and homeostasis. Cardiac-specific overexpression of L-GILZ may serve as a potential therapeutic strategy for preventing and treating cardiac hypertrophy and heart failure.

Background:Chronic obstructive pulmonary disease (COPD) is one of the most common comorbidities in patients with chronic heart failure (CHF). A growing number of patients are suffering from both COPD and CHF, and these conditions worsen each other. Inhaled bronchodilator therapy with long-acting muscarinic antagonist (LAMA) and long-acting β2-agonist (LABA) in combination is currently the mainstay of treatment for COPD. However, the effect of LAMA/LABA on HF with COPD remains unknown. Methods and Results:The COPD-HF trial is a multicenter, double-arm, open-label, exploratory, investigator-initiated clinical study to investigate the effect of LAMA/LABA on HF in patients suffering from both COPD and CHF. The participants are randomly assigned (1 : 1) to the LAMA/LABA (tiotropium+olodaterol FDC (fixed-dose combination) 5/5 ug) group (once a day, 2 inhalations) or non-pharmacological treatments for COPD as a control group. The planned number of patients to be enrolled in this trial is 54 in total (27 in each group). The participants are followed up for 12 weeks with and without LAMA/LABA. The primary endpoint is the change in plasma B-type natriuretic peptide levels from the baseline to the end of this study (12 weeks). Conclusions:The COPD-HF trial will investigate the efficacy of LAMA/LABA on HF in patients with COPD and CHF.

Breast cancer affects females from puberty onward, with incidence rates increasing with age. Although metabolic syndrome (MetS) has reportedly increased the incidence of almost all cancers, no clear consensus on the role of MetS in breast cancer development exists. We aimed to clarify the effects of MetS on breast cancer incidence. To investigate this relationship, we analyzed Japanese healthcare data of females from 2005 to 2020 and examined the incidence of breast cancer. MetS was evaluated based on the Japanese criteria or the NCEP ATP III guidelines at enrollment. Of 1,144,791 participants without missing data in our general public cohort, 32,775 with breast cancer at the beginning of the observation period were excluded; 54,330 participants with breast cancer were identified during the observation period. Both pre-stage MetS and MetS, defined using the Japanese criteria, were associated with the less frequent incidence of breast cancer (hazard ratios [HRs], 0.90; 95

Background: Heart failure patients are deficient in B-type natriuretic peptide (BNP) but the significance of subclinical BNP deficiency is unclear. Methods and Results: A total of 1,398 subjects without cardiovascular disease, with left ventricular ejection fraction (LVEF) >= 50% and BNP level <100 pg/mL, were selected from a 2005-2008 health checkup in Arita-cho, Japan, and divided into 2 groups: with and without LV diastolic dysfunction (DD+ or DD-). We performed propensity score matching on non-cardiac factors affecting BNP levels and analyzed 470 subjects in each group (372/940 men; median age, 66 years). The DD(+) group showed higher lateral E/e', an index of estimated left ventricular filling pressure, and greater prevalence of concentric hypertrophy (CH) despite similar BNP levels, suggesting a relative deficiency of BNP in DD(+) compared with DD(-). Multivariable logistic regression analysis revealed an increase in BNP correlated with decreased odds of CH (adjusted odds ratio [aOR] 0.663, 95% confidence interval (CI) 0.484-0.909, P=0.011), whereas an increase in lateral E/e' was associated with increased odds of CH (aOR, 2.881; 95% CI, 1.390-5.973; P=0.004). Furthermore, CH in combination with diastolic dysfunction independently predicted major adverse cardiovascular events (hazard ratio 3.272, 95% CI 1.215-8.809; P=0.019). Conclusions: Relative BNP deficiency was associated with CH, which had a poor prognosis in patients with diastolic dysfunction.

Background The guidelines recommend the initiation or up-titration of heart failure (HF) treatments following an HF hospitalization; however, concerns about adverse events may limit the use of mineralocorticoid receptor antagonists (MRAs). Patient profiles or disease severity might impact adverse events associated with MRA therapy in acute HF. Methods The EARLIER trial included patients with acute HF who were randomized to eplerenone or placebo over 6 months. Adverse events (i.e., worsening renal function [WRF], hyperkalemia, hypotension, and volume depletion/dehydration) were assessed. HF-related outcome included a composite of all-cause mortality, HF re-hospitalization, investigator-reported worsening HF and out-of-hospital diuretic intensification. Results In 297 patients (mean age: 67 ± 13 years; 73% males), adverse events were observed: 44.4% experienced WRF (>20% drop in estimated glomerular filtration rate[eGFR] and/or investigator-reported WRF), 8.4% had hyperkalemia (potassium >5.5 mmol/L and/or investigator-reported hyperkalemia), 27.9% experienced hypotension (systolic blood pressure[SBP] <90 mmHg and/or investigator-reported hypotension), and 16.8% had investigator-reported volume depletion/dehydration. Eplerenone vs. placebo did not elevate the incidence of these events (all-p-values>0.0 5). Multivariable analyses revealed that, irrespective of treatment allocation, older age (>7 5 years), prevalent diabetes, symptomatic congestion, and microalbuminuria were associated with increased risk of WRF. Baseline eGFR<60 ml/min/1.73m2 and SBP < 90 mmHg predicted hyperkalemia and hypotension, respectively, while older patients were more likely to experience volume depletion/dehydration. However, these patient profiles did not alter the benefit of eplerenone on outcomes (HR [9 5%CI] = 0.53 [0.29 to 0.97], P = 0.04; all-p-for-interaction>0.10). Conclusion Eplerenone did not increase adverse events compared with placebo in acute HF. Importantly, disease severity and comorbidity burden greatly influence adverse events, but not benefit from eplerenone.

Background: Patients hospitalized for acute heart failure (AHF) have high degrees of congestion, which may be associated with albuminuria. Mineralocorticoid receptor antagonists (MRAs) have natriuretic effects, possibly diminishing the degree of albuminuria. However, early changes in albuminuria, their prognostic value and interaction with MRA therapy remain unclear in AHF. Methods: The EARLIER trial included patients with AHF who were randomized to receive eplerenone or placebo over 6 months. Urine albumin-to-creatinine ratio (UACR) at admission and week 1 were measured, and Cox proportional hazards models were used for analyses. Results: Among 296 patients (mean age, 67±13years; 72% male), median B-type natriuretic peptide was 386 (190-660) pg/ml, and mean left ventricular ejection fraction was 30±8%. Patients with an UACR of ≥30 mg/g at admission had more severe congestion and poorer exercise capacity compared to those without (all-P<0.01). From admission to week 1, UACR levels significantly decreased (P<0.01), without significant differences between treatment groups (P>0.10). UACR levels at both admission (adjusted-HR [95% CI]=1.23 [1.03-1.47]) and week 1 (adjusted-HR [95% CI]=1.23 [1.01-1.50]) were associated with the risk of cardiovascular death and hospitalization. Additionally, eplerenone vs. placebo reduced the risk of a composite of all-cause mortality, HF re-hospitalization, investigator-reported worsening HF, and/or out-of-hospital diuretic intensification (HR [95% CI]= 0.53 [0.29-0.97]), irrespective of the severity of albuminuria (P-for-interaction>0.10). Conclusion: In patients with AHF, the degree of albuminuria at both admission and week 1 was associated with post-discharge prognosis. Although eplerenone did not reduce albuminuria levels, the benefit from eplerenone was consistent regardless of the albuminuria severity.

Although angiotensin II receptor blockers (ARBs) are more effective in women for either reduction of blood pressure or heart failure (HF), the gender disparities and the impact of class/drug effects on ARBs in relation to cardiac hypertrophy and HF remain unclear. We aimed to investigate the sex-based and drug-specific differences in left ventricular (LV) mass reduction with ARBs. We employed the cohort of 193 hypertensive patients with HF and an LV ejection fraction of ≥ 45

This study aims to investigate the role of claudin-5 (Cldn5) in cardiac structural integrity. Proteomic analysis was performed to screen the protein profiles in enlarged left atrium from atrial fibrillation (AF) patients. Cldn5 shRNA adeno-associated virus (AAV) or siRNA was injected into the mouse left ventricle or added into HL1 cells respectively to knockdown Cldn5 in cardiomyocytes to observe whether the change of Cldn5 influences cardiac morphology and function, and affects those protein expressions stem from the proteomic analysis. Mitochondrial density and membrane potential were also measured by Mitotracker staining and JC-1 staining under the confocal microscope in HL1 cells. Cldn5 was reduced in cardiomyocytes from the left atrial appendage of AF patients compared to non-AF donors. Proteomic analysis showed 83 proteins were less abundant and 102 proteins were more abundant in AF patients. KEGG pathway analysis showed less abundant CACNA2D2, CACNB2, MYL2 and MAP6 were highly associated with dilated cardiomyopathy. Cldn5 shRNA AAV injection caused severe cardiac atrophy, dilation and myocardial dysfunction in mice. The decreases in mitochondrial numbers and mitochondrial membrane potentials in HL1 cells were observed after Cldn5 knockdown. We demonstrated for the first time the mechanism of Cldn5 downregulation-induced myocyte atrophy and myocardial dysfunction might be associated with the downregulation of CACNA2D2, CACNB2, MYL2 and MAP6, and mitochondrial dysfunction in cardiomyocytes.

Since many people die of either cancers or cardiovascular diseases worldwide, it is important to find the clinical pitfall that provokes cardiovascular diseases and cancer overall. Since metabolic syndrome (MetS) is largely linked to cardiovascular diseases, we have come to consider that MetS, even in its early state, may prime the occurrence of cancers overall. Indeed, the importance of MetS in causing pancreatic cancer has been proved using our large medical database. We analyzed Japanese healthcare and clinical data in 2005, who were followed up until 2020 and we examined the incidence of major cancers. At the enrollment, we examined the presence or absence of MetS judged by either Japanese criteria or NCEP/ATPIII. Of 2.7 million subjects without missing data, 102,930; 200,231; 237,420; 63,435; 76,172; and 2,422 subjects suffered lung, stomach, colon, liver and prostate cancer, respectively, and myelogenous leukemia during follow-up. MetS, defined by Japanese criteria, increased (p < 0.005 each) the incidence of cancer with a hazard ratio (HR) of 1.03–1.47 for lung, stomach, colon, liver, prostate cancers, and myelogenous leukemia. According to Japanese criteria, cancer incidence in the pre-stage MetS group was comparable to the MetS group. The results were almost identical when we defined MetS using NCEP ATP III. Taken together, we conclude that MetS is linked to majority of cancers.

Background Although previous studies have showed that metabolic syndrome is one of the contributors of pancreatic cancer, there is no clear consensus that early stages of metabolic syndrome are linked to increased incidence of pancreatic cancer. Therefore, we confirmed the linkage between metabolic syndrome and pancreatic cancer, and shown that even early stage of metabolic syndrome is linked to pancreatic cancer in the retrospective observational study. Methods We recruited approximately 4.6 million Japanese in 2005 and followed up these subjects for more than 10 years. At the time of the enrollment, after obtaining clinical data with prescribed drugs and examining the presence or absence of metabolic syndrome (MetS), we followed up on these subjects with and without MetS to examine the incidence of pancreatic cancer. The modified criteria of the National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATPIII) were used to define MetS. Findings During the 40.7-month average follow-up period for 2,707,296 subjects with complete data for identifying MetS and important risk factors without pancreatic cancer before the enrollment, 87,857 suffered from pancreatic cancer. Pancreatic cancers occurred in 16,154 of 331,229 subjects (4.9%) in the MetS group and 71,703 of 2,376,067 patients (3.0%) in the non-MetS group (hazard ratio (HR), 1.37; 95% confidence interval [CI], 1.34-1.39; p < 0.0001 after the adjustment with age, smoking and sex). As the number of the constituent factors of MetS increased from one to five, the incidence of pancreatic cancer correspondingly increased (HR: 1.11, 1.23, 1.42, 1.66 and 2.03 using Cox proportional hazard models, p < 0.0001 each). When we defined MetS using the Japanese criteria, the results are in accord with the results using NCEP/ATPIII. Especially pre-metabolic syndrome (pre-MetS) in the Japanese criteria was tightly linked to the incidence of pancreatic cancers. Interpretation MetS is confirmed to be linked to pancreatic cancer. Although we cannot conclude causality. We also demonstrated the link between pre-MetS and pancreatic cancer. Copyright (c) 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Strain TC023T, a Gram-positive, long, rod-shaped, spore-forming anaerobe, was isolated from the faeces of a heart failure mouse model. The strain formed greyish-white coloured colonies with a convex elevation on brain–heart infusion medium supplemented with 0.1 % sodium taurocholate, incubated at 37 °C for 2 days. Taxonomic analysis based on the 16S rRNA gene sequence showed that TC023T belonged to the genus Turicibacter, and was closely related to Turicibacter bilis MMM721T (97.6 %) and Turicibacter sanguinis MOL361T (97.4 %). The whole genome of the strain has a G+C content of 37.3 mol%. The average nucleotide identity and genome-to-genome distance between TC023T and Turicibacter bilis MMM721T were 77.6 % and 24.3 %, respectively, and those with Turicibacter sanguinis MOL361T were 75.4 % and 24.3 %, respectively. These genotypic, phenotypic, and biochemical analyses indicated that the isolate represents a novel species in the genus Turicibacter, and the name Turicibacter faecis sp. nov. is proposed. The type strain is TC023T (RIMD 2002001T=TSD 372T).

Recent large clinical trials have revealed that sodium–glucose cotransporter 2 (SGLT2) inhibitors improve cardiovascular outcomes not only in patients with heart failure with reduced ejection fraction, but also in patients with heart failure with mildly reduced or preserved ejection fraction (HFpEF). However, the effect of SGLT2 inhibitors on left ventricular (LV) diastolic function is still controversial. The TOP-HFPEF trial (Efficacy of Tofogliflozin on Left Ventricular Diastolic Dysfunction in Patients with Heart Failure with Preserved Ejection Fraction and Type 2 Diabetes Mellitus) is a multicenter, double-arm, open-label, confirmatory, investigator-initiated clinical study to investigate the effect of SGLT2 inhibitor on LV diastolic function in patients with HFpEF and type 2 diabetes mellitus. The participants are randomly assigned (1:1) to the tofogliflozin group (20 mg once daily) or the control group (administration or continuation of antidiabetic drugs other than SGLT2 inhibitors). The estimated number of patients to be enrolled in this trial is 90 in total (45 in each group). The participants are followed up for 52 weeks with tofogliflozin or control drugs. The primary endpoint is the change in E/e′ assessed by echocardiography from the baseline to the end of this study (52 weeks). This trial will also evaluate the effects of tofogliflozin on cardiovascular events, biomarkers, other echocardiographic parameters, the occurrence of atrial fibrillation, and renal function. The TOP-HFPEF trial will clarify the efficacy of an SGLT2 inhibitor, tofogliflozin, on LV diastolic function in patients with HFpEF and type 2 diabetes mellitus.

BACKGROUND & AIMS:Enteral nutrition in older adults is often associated with intolerance, a phenomenon not well-understood in the context of gastroesophageal reflux disease (GERD). This observational study aimed to evaluate serum potassium levels as an independent prognostic factor for unplanned enteral nutrition discontinuation in older adults with GERD. METHODS:We conducted a retrospective analysis of 213 consecutive patients with GERD who received enteral nutrition at our institution from April 2018 to March 2023. The dietary assessment involved extracting relevant nutritional information from the patients' medical records. The incidence of enteral nutrition discontinuation due to complications was monitored over a 30-day period after initiation. RESULTS:Patients were categorized into three groups based on initial serum potassium levels: low (<4.0 mmol/L), intermediate (4.0-4.5 mmol/L), and high (≥4.5 mmol/L). During the follow-up, 35 % of patients experienced events leading to the discontinuation of enteral nutrition. Higher potassium levels correlated with an increased risk of unplanned discontinuation of enteral nutrition (log-rank P = 0.002). Multivariate Cox proportional hazards analysis identified serum potassium level as an independent predictor of unplanned discontinuation (hazard ratio: 1.700 [95 % confidence interval: 1.100-2.627] per 1 mmol/L, P = 0.017). CONCLUSIONS:Serum potassium level is a robust independent predictor of unplanned enteral nutrition discontinuation in older adults with GERD. Our findings suggest that monitoring and adjusting potassium levels may be essential for improving outcomes in this vulnerable population.