Kidney outcomes with SGLT2 inhibitor vs. DPP4 inhibitor use in older adults with diabetes.

BACKGROUND AND HYPOTHESIS: While the kidney protective effects of sodium glucose co-transporter-2 (SGLT2) inhibitors have attracted much attention, there are limited real-world clinical data examining the effects of SGLT2 inhibitors on kidney function in older individuals. We aimed to compare the kidney outcomes between SGLT2 inhibitor and dipeptidyl peptidase 4 (DPP4) inhibitor use in older adults with diabetes. METHODS: Using a nationwide claims database, we studied 6 354 older adults (≥ 60 years of age) who had diabetes and newly initiated on SGLT2 inhibitors or DPP4 inhibitors. A 1:4 propensity score matching algorithm was used to compare changes in eGFR between SGLT2 inhibitor and DPP4 inhibitor users. The primary outcome was a decline in the rate of estimated glomerular filtration rate (eGFR), which was obtained using a linear mixed-effects model with an unstructured covariance. RESULTS: Following propensity score matching, 6 354 individuals including 1 271 SGLT2 inhibitor users and 5 083 DPP4 inhibitor users (median age: 68 [65-70] years); men, 60.4%; median eGFR:69.0 [59.1-79.0] ml/min/1.73 m2, median hemoglobin A1c [HbA1c]:6.9 [6.5-7.4]%) were analyzed. SGLT2 inhibitor users had a slower eGFR decline than did DPP4 inhibitor users (-0.97 [95% CI, -1.24 to -0.70] ml/min/1.73m2 vs. -1.83 [95% CI, -1.97 to -1.69] ml/min/1.73m2 per year; p for interaction < 0.001). This finding remained consistent across subgroups based on age, sex, body mass index, HbA1c level, renin-angiotensin system inhibitor use, and baseline eGFR. Additionally, the risk of a ≥ 20%, ≥ 30%, and ≥ 40% decrease in eGFR from baseline was significantly lower in SGLT2 inhibitor users than that in DPP4 inhibitor users. CONCLUSIONS: Our analysis, utilizing a nationwide epidemiological dataset, demonstrated that the decline in eGFR was slower in individuals aged ≥ 60 years with diabetes who were prescribed SGLT2 inhibitors compared to those prescribed DPP4 inhibitors, suggesting a potential advantage of SGLT2 inhibitors for kidney outcomes even in older individuals with diabetes.

Vaccine Therapy for Heart Failure Targeting the Inflammatory Cytokine Igfbp7.

BACKGROUND: The heart comprises many types of cells such as cardiomyocytes, endothelial cells (ECs), fibroblasts, smooth muscle cells, pericytes, and blood cells. Every cell type responds to various stressors (eg, hemodynamic overload and ischemia) and changes its properties and interrelationships among cells. To date, heart failure research has focused mainly on cardiomyocytes; however, other types of cells and their cell-to-cell interactions might also be important in the pathogenesis of heart failure. METHODS: Pressure overload was imposed on mice by transverse aortic constriction and the vascular structure of the heart was examined using a tissue transparency technique. Functional and molecular analyses including single-cell RNA sequencing were performed on the hearts of wild-type mice and EC-specific gene knockout mice. Metabolites in heart tissue were measured by capillary electrophoresis-time of flight-mass spectrometry system. The vaccine was prepared by conjugating the synthesized epitope peptides with keyhole limpet hemocyanin and administered to mice with aluminum hydroxide as an adjuvant. Tissue samples from heart failure patients were used for single-nucleus RNA sequencing to examine gene expression in ECs and perform pathway analysis in cardiomyocytes. RESULTS: Pressure overload induced the development of intricately entwined blood vessels in murine hearts, leading to the accumulation of replication stress and DNA damage in cardiac ECs. Inhibition of cell proliferation by a cyclin-dependent kinase inhibitor reduced DNA damage in ECs and ameliorated transverse aortic constriction-induced cardiac dysfunction. Single-cell RNA sequencing analysis revealed upregulation of Igfbp7 (insulin-like growth factor-binding protein 7) expression in the senescent ECs and downregulation of insulin signaling and oxidative phosphorylation in cardiomyocytes of murine and human failing hearts. Overexpression of Igfbp7 in the murine heart using AAV9 (adeno-associated virus serotype 9) exacerbated cardiac dysfunction, while EC-specific deletion of Igfbp7 and the vaccine targeting Igfbp7 ameliorated cardiac dysfunction with increased oxidative phosphorylation in cardiomyocytes under pressure overload. CONCLUSIONS: Igfbp7 produced by senescent ECs causes cardiac dysfunction and vaccine therapy targeting Igfbp7 may be useful to prevent the development of heart failure.

Differences in the Association of Lifestyle-Related Modifiable Risk Factors with Incident Cardiovascular Disease Between Individuals with and without Diabetes.

AIMS: Individuals with diabetes have a high risk of developing cardiovascular disease (CVD). Little was known whether the association between modifiable risk factors and incident CVD would change according to the presence of diabetes. METHODS: In this study, we analyzed 4,132,006 individuals including 173,262 individuals (4.2%) with diabetes registered in the JMDC Claims Database, and compared the association between modifiable risk factors and risk of CVD between individuals with and without diabetes. RESULTS: The median age was 44 years, and 57.5% were men. Multivariable Cox regression analyses showed that the relationship of obesity, hypertension, and dyslipidemia with incident CVD was attenuated in individuals with diabetes, whereas that of non-ideal eating habits, smoking, and physical inactivity with incident CVD was pronounced in those with diabetes. The hazard ratio per 1-point increase in non-ideal lifestyle-related factors was 1.03 [95% confidence interval (CI) 1.03-1.04] in individuals with non-diabetes, whereas 1.09 [95% CI 1.07-1.11] in individuals with diabetes (p-value for interaction < 0.001). Further, hazard ratios for developing CVD were 1.02 [95% 1.01-1.04] in individuals not having diabetes, whereas 1.09 [95% CI 1.04-1.13] in individuals having diabetes for the increase of lifestyle-related factor after 1-year follow-up (p-value for interaction 0.007). CONCLUSION: Our analysis utilizing a nationwide epidemiological dataset presented that the relationship of lifestyle-related factors with incident CVD would be pronounced in people having diabetes, suggesting that the maintenance of a healthy lifestyle would play a more important role in the development of CVD in individuals having diabetes. (244 words).

Our investigation utilizing a nationwide epidemiological cohort showed a pronounced relationship of lifestyle-related factors with incident CVD in individuals with diabetes. The HRs (95% CI) for the occurrence of CVD events showed a progressive increase with each additional lifestyle-related factor. This trend was more prominent among individuals with diabetes than those without diabetes. The association between changes in the number of lifestyle-related factors over a year and the risk of developing CVD was also more pronounced in individuals with diabetes. These results suggest that maintaining healthy lifestyle habits would be more important for the CVD prevention in individuals having diabetes.

Five pimarane diterpenoids from Kaempferia champasakensis and their cytotoxic activities.

A phytochemical investigation of Kaempferia champasakensis rhizomes led to the isolation of five new pimarane diterpenes, kaempferiols E-I (1-5). The structures of 1-5 were elucidated by extensive spectroscopic techniques, including HR-ESI-MS, UV, IR, and 1D and 2D NMR. The absolute configurations of 1-3 were determined by the modified Mosher method, and those of 4 and 5 were established by ECD calculations. Further cytotoxic assay for all isolated compounds against three human cancer cell lines, lung cancer (A549), cervical cancer (HeLa), and breast cancer (MCF-7) indicated that 5 showed moderate cytotoxic activities against the three tested cell lines, with IC50 values of 44.78, 25.97, and 41.39 Mµ for A549, HeLa, and MCF-7 cell lines, respectively.

Significance of eGFR and proteinuria for cardiovascular disease in individuals beyond 85 years.

BACKGROUND: There are limited data on how advancing age influences prediction of CVD risk based on the estimated glomerular filtration rate (eGFR) and proteinuria, especially in older adults, including those aged ≥ 85 years. This study aimed to clarify the association of eGFR and proteinuria with CVD outcomes and the impact of age on this association. METHODS: The distribution of eGFR and urine protein in Japan was assessed retrospectively using real-world administrative claims and health checkup data collected between April 2014 and November 2022. We investigated the associations of these two parameters with the incidence of CVD, with an emphasis on the impact of aging. RESULTS: We assessed 1 829 020 individuals for distribution of eGFR and proteinuria; after excluding those with known CVD, their association with CVD risk was examined in 1 040 101 individuals aged ≥ 40 years. The prevalence of impaired kidney function (eGFR <60 mL/min/1.73 m2) increased with age, being 0.7%, 9.2%, 21.9%, 40.2%, and 60.2% at the ages of 18-39, 40-64, 65-74, 75-84, and ≥ 85 years (P for trend < 0.001); similarly, the proportion with positive proteinuria increased with age, being 2.7%, 4.3%, 5.6%, 9.2%, and 15.8%, respectively (P for trend < 0.001). Both eGFR and urine protein were identified to be independent risk factors for CVD. Hazard ratios for CVD increased significantly when eGFR was <45 mL/min/1.73 m2 at the ages of 40-64, 65-74, and 75-84 and <30 mL/min/1.73 m2 at ≥ 85 years, while proteinuria remained significantly associated with a high CVD risk regardless of age. These findings were consistent even when analyzed separately by sex. CONCLUSIONS: This study identified eGFR and urine dipstick proteinuria to be independent risk factors for CVD, even among individuals aged ≥ 85 years. However, the contribution of eGFR to the CVD risk was attenuated by aging, whereas proteinuria remained less affected by advancing age.

Serum Soluble IL-2 Receptors Are Elevated in Febrile Illnesses and Useful for Differentiating Clinically Similar Malignant Lymphomas from Kikuchi Disease: A Cross-Sectional Study.

Background: The use of serum soluble interleukin 2 receptor (sIL-2R) for the diagnosis of febrile illnesses has not been examined. In this study, febrile patients were classified according to etiology and disease, and serum sIL-2R levels were evaluated. We determined whether serum sIL-2R is a useful marker for differentiating between malignant lymphoma (ML) and non-ML patients and between patients with ML and Kikuchi disease, which present similar clinical manifestations. Methods: This study was a cross-sectional study and included 344 patients with uncomplicated hemophagocytic syndrome, who had a fever of 38 °C or higher within 1 week of admission to our institution. Patient serum sIL-2R was measured, and the serum sIL-2R values are shown as median and IQR. Results: Serum sIL-2R increased above the upper reference limit in all disease groups with fever. The serum sIL-2R level in ML patients (n = 13) was 4760 (2120-6730) U/mL and significantly higher (p < 0.001) than the level of 998 (640-1625) U/mL in non-ML patients (n = 331). The serum sIL-2R level in ML patients (n = 13) was also significantly higher (p < 0.001) compared with that in patients with Kikuchi disease (n = 20; 705 (538-1091) U/mL). Conclusions: Serum sIL-2R tends to exceed the upper reference limit in patients with febrile illnesses. We conclude that the measurement of serum sIL-2R is useful for differentiating ML from non-ML and ML from Kikuchi disease.

Body Fat Distribution and Left Atrial Reverse Remodeling After Catheter Ablation for Atrial Fibrillation.

Background: Emerging evidence suggests a pathophysiological link between obesity and atrial fibrillation (AF). However, the contribution of body fat distribution to left atrial (LA) remodeling and its reversibility remain unclear in nonobese AF patients. Objectives: The purpose of this study was to investigate the association of body fat distribution with LA size and reverse remodeling (LARR). Methods: In total, 116 nonobese patients with AF (88 men, age 63 ± 11 years) who underwent first catheter ablation (CA) were included. Body fat distribution was assessed with bioelectrical impedance, and body fat percentage (BF%) and central fat percentage (CF%) were calculated. Patients were categorized by body size metrics (body mass index [BMI] and waist-to-hip [W/H] ratio) and fat parameters (BF% and CF%). Echocardiography was performed before and 6 months after CA. Multivariable logistic regression was used to examine the association between the 4 metrics (ie, BMI, W/H ratio, BF%, and CF%) and a lack of LARR (<15% reduction or increase in the LA volume index). Results: Body size metrics and adiposity measures were not independently associated with baseline LA size. Six months after CA, the higher W/H ratio and CF% groups exhibited persistent LA enlargement compared to their counterparts (both P < 0.01). In the multivariable analysis, W/H ratio and CF% were associated with a lack of LARR (adjusted ORs of 3.86 and 2.81 per 0.10 and 10% increase, respectively, both P < 0.01). The combined assessment of CF% with W/H ratio provided complementary risk stratification for persistent LA enlargement. Conclusions: Central adiposity was associated with a lack of LARR after CA, highlighting the importance of assessing body fat distribution even in nonobese patients.

Three neo-Clerodane Diterpenoids from Tinospora cordifolia Stems and Their Arginase Inhibitory Activities.

Three neo-clerodane diterpenoids, including two new tinocordifoliols A (1) and B (2) and one known tinopanoid R (3), were isolated from the ethyl acetate-soluble fraction of the 70% ethanol extract of Tinospora cordifolia stems. The structures were elucidated by various spectroscopic methods, including one dimensional (1D) and 2D-NMR, high resolution-electrospray ionization (HR-ESI)-MS, and electronic circular dichroism (ECD) data. The T. cordifolia extract and all isolated compounds 1-3 possessed arginase I inhibitory activities. Among them, 3 exhibited moderate competitive inhibition of human arginase I (IC50 = 61.9 µM). Furthermore, docking studies revealed that the presence of a ß-substituted furan in 3 may play a key role in the arginase I inhibitory activities.

Age-Dependent Relationship of Physical Inactivity with Incident Cardiovascular Disease: Analysis of a Large Japanese Cohort.

BACKGROUND: There have been limited studies examining age-dependent associations between physical inactivity and cardiovascular disease (CVD). We aimed to clarify the age-dependent relationship of physical inactivity with incident CVD. METHODS: We analyzed 1,097,424 participants aged 18-105 years without a history of CVD enrolled in the DeSC database (median age, 63 years; 46.4% men). We categorized participants into the following 4 groups based on age: ≤44 years (n=203,835), 45-64 years (n=403,619), 65-79 years (n=437,236), ≥80 years (n=52,734). We used three physical inactivity components gained from the self-reported questionnaire during a health checkup. The outcomes were composite CVD events including myocardial infarction, stroke, and heart failure, and each CVD event. RESULTS: During a mean follow-up of 3.2±1.9 years, 81,649 CVD events were observed. The hazard ratios of three physical inactivity components for CVD events increased with age category (P for interaction <0.001). For example, the hazard ratio (95% confidence interval) of physical inactivity defined as not doing light, sweaty exercise for 30 minutes at least twice a week for incident CVD in the groups aged ≤44 years, 45-64 years, 65-79 years, and ≥80 years were 0.97 (0.88-1.05), 1.08 (1.05-1.12), 1.12 (1.10-1.15), and 1.17 (1.12-1.21), respectively (P for interaction <0.001). This association was consistent across subtypes of CVD, including heart failure, myocardial infarction, and stroke. CONCLUSIONS: The association of physical inactivity with a higher risk of developing CVD increased with age. Preventive efforts for physical activity optimization may be more valuable in older people.

Chronic Tonsillitis and IgA Nephropathy: Findings From a Nationwide Japanese Cohort Study.

RATIONALE & OBJECTIVE: Little is known regarding the association between chronic tonsillitis and the onset of IgA nephropathy (IgAN). In the present study, we examined the potential relationship between chronic tonsillitis and a subsequent risk of developing IgAN. STUDY DESIGN: Observational cohort study. SETTING: & Participants: 4,311,393 individuals without a history of IgAN identified between January 2005 to May 2022 within a Japanese nationwide epidemiological database, the JMDC Claims Database, representing health claims to over 60 insurers. EXPOSURE: Comorbid chronic tonsillitis based on diagnosis codes. OUTCOME: IgAN occurrence. ANALYTICAL APPROACH: Cause-specific Cox proportional hazards analysis adjusting for potential confounding factors were employed to estimate hazard ratios (HRs). RESULTS: Comorbid chronic tonsillitis was identified in 12,842 individuals, constituting 0.3% of the cohort. The cohort had a median age of 44 years (interquartile range: 36-53), and males accounted for 57.9%, with a follow-up of 1,089 days (interquartile range: 532-1,797), during which 2,653 cases of IgAN developed. Cumulative incidence curve showed a higher cumulative incidence of IgAN in individuals with chronic tonsillitis compared to their counterparts without this condition. Multivariable cause-specific analysis further demonstrated that individuals with chronic tonsillitis had an elevated risk of developing IgAN, with a HR of 2.72 (95% confidence interval: 1.79-4.14). LIMITATIONS: Potential residual confounders, and lack of consideration for ethnic distinctions. CONCLUSIONS: Using a largescale epidemiological dataset, these findings suggest a relationship between chronic tonsillitis and an elevated risk of IgAN development in the general Japanese population.

The potential of the transformer-based survival analysis model, SurvTrace, for predicting recurrent cardiovascular events and stratifying high-risk patients with ischemic heart disease.

INTRODUCTION: Ischemic heart disease is a leading cause of death worldwide, and its importance is increasing with the aging population. The aim of this study was to evaluate the accuracy of SurvTrace, a survival analysis model using the Transformer-a state-of-the-art deep learning method-for predicting recurrent cardiovascular events and stratifying high-risk patients. The model's performance was compared to that of a conventional scoring system utilizing real-world data from cardiovascular patients. METHODS: This study consecutively enrolled patients who underwent percutaneous coronary intervention (PCI) at the Department of Cardiovascular Medicine, University of Tokyo Hospital, between 2005 and 2019. Each patient's initial PCI at our hospital was designated as the index procedure, and a composite of major adverse cardiovascular events (MACE) was monitored for up to two years post-index event. Data regarding patient background, clinical presentation, medical history, medications, and perioperative complications were collected to predict MACE. The performance of two models-a conventional scoring system proposed by Wilson et al. and the Transformer-based model SurvTrace-was evaluated using Harrell's c-index, Kaplan-Meier curves, and log-rank tests. RESULTS: A total of 3938 cases were included in the study, with 394 used as the test dataset and the remaining 3544 used for model training. SurvTrace exhibited a mean c-index of 0.72 (95% confidence intervals (CI): 0.69-0.76), which indicated higher prognostic accuracy compared with the conventional scoring system's 0.64 (95% CI: 0.64-0.64). Moreover, SurvTrace demonstrated superior risk stratification ability, effectively distinguishing between the high-risk group and other risk categories in terms of event occurrence. In contrast, the conventional system only showed a significant difference between the low-risk and high-risk groups. CONCLUSION: This study based on real-world cardiovascular patient data underscores the potential of the Transformer-based survival analysis model, SurvTrace, for predicting recurrent cardiovascular events and stratifying high-risk patients.

Substrate Flexibilities of Norbelladine Synthase and Noroxomaritidine/Norcraugsodine Reductase for Hydroxylated and/or Methoxylated Aldehydes.

Amaryllidaceae alkaloids are structurally diverse natural products with a wide range biological properties, and based on the partial identification of the biosynthetic enzymes, norbelladine would be a common intermediate in the biosynthetic pathways. Previous studies suggested that norbelladine synthase (NBS) catalyzed the condensation reaction of 3,4-dihydroxybenzaldehyde and tyramine to form norcraugsodine, and subsequently, noroxomaritidine/norcraugsodine reductase (NR) catalyzed the nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reduction of norcraugsodine to generate norbelladine. However, recent studies have highlighted possible alternative Amaryllidaceae alkaloid biosynthetic pathways via the formation of isovanillin and vanillin from the 4-O- and 3-O-methylation reactions of 3,4-dihydroxybenzaldehyde, respectively. Herein, we focused on NpsNBS and NpsNR, which were initially identified from Narcissus pseudonarcissus, and explored their substrate recognition tolerance by performing condensation reactions of tyramine with various benzaldehyde derivatives, to shed light on the Amaryllidaceae alkaloid biosynthetic pathway from the viewpoint of the enzymatic properties. The assays revealed that both NpsNBS and NpsNR lacked the abilities to produce 4'-O- and 3'-O-methylnorbelladine from isovanillin and vanillin with tyramine, respectively. These observations thus suggested that Amaryllidaceae alkaloids are biosynthesized from norbelladine, formed through the condensation/reduction reaction of 3,4-dihydroxybenzaldehyde with tyramine.

Heart failure promotes multimorbidity through innate immune memory.

Patients with heart failure (HF) often experience repeated acute decompensation and develop comorbidities such as chronic kidney disease and frailty syndrome. Although this suggests pathological interaction among comorbidities, the mechanisms linking them are poorly understood. Here, we identified alterations in hematopoietic stem cells (HSCs) as a critical driver of recurrent HF and associated comorbidities. Bone marrow transplantation from HF-experienced mice resulted in spontaneous cardiac dysfunction and fibrosis in recipient mice, as well as increased vulnerability to kidney and skeletal muscle insults. HF enhanced the capacity of HSCs to generate proinflammatory macrophages. In HF mice, global chromatin accessibility analysis and single-cell RNA-seq showed that transforming growth factor-ß (TGF-ß) signaling was suppressed in HSCs, which corresponded with repressed sympathetic nervous activity in bone marrow. Transplantation of bone marrow from mice in which TGF-ß signaling was inhibited similarly exacerbated cardiac dysfunction. Collectively, these results suggest that cardiac stress modulates the epigenome of HSCs, which in turn alters their capacity to generate cardiac macrophage subpopulations. This change in HSCs may be a common driver of repeated HF events and comorbidity by serving as a key carrier of "stress memory."

New 19(10 → 9)abeo-euphane-type triterpenoids from Trichilia dregeana leaves and NO production inhibitory activities.

Phytochemical investigation of the EtOAc soluble fraction from leaves of Trichilia dregeana Sond. (Meliaceae) afforded naturally rare four new pentacyclic triterpenoids (1-4), together with five known pentacyclic analogs (5-8, and 11) and two steroids (9 and 10). Their structures were elucidated by extensive spectroscopic techniques such as 1D and 2D NMR and HRESIMS data analyses. The absolute configuration of 1 was determined by using the single-crystal X-ray diffraction analysis. The nitric oxide (NO) production inhibitory assay indicated that the EtOAc fraction as well as 4 and 7 inhibited the NO production in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells with the IC50 values of 83.53 µg/mL and 81.31 and 85.71 µM, respectively. Compounds 1-4 are rare 19(10 â†’ 9)abeo-euphane-type triterpenoids bearing a 3,10-ether bridge. To the best of our knowledge, this study is the first isolation of triterpenoids with the 3,10-ether bridge in their skeleton from the genus Trichilia, providing new insights into the chemodiversity of the terpenoids in T. dregeana.

Change in Body Mass Index and Cardiovascular Outcomes in Patients With Cancer.

OBJECTIVE: To investigate the association between body mass index (BMI) changes and the risk of cardiovascular disease (CVD) in patients with cancer. PATIENTS AND METHODS: This retrospective observational study used data from the JMDC Claims Database obtained between January 2005, and April 2021. We included 52,344 individuals (median [IQR] age, 53 years [46 to 60 years]; 23,584 [45.1%] men) with cancer and no prior CVD. Patients were classified into 3 groups based on the percentage change in BMI from the initial health checkup to the checkup 1 year later: -5.0% or less (BMI loss), -5.0% to 5.0% (stable BMI), and 5.0% or more (BMI gain). The primary end point was composite CVD events including heart failure, atrial fibrillation, ischemic heart disease, and stroke. RESULTS: During a median follow-up period of 763 days (IQR, 369 to 1274 days), 3124 composite CVD events were observed. Compared with stable BMI, the hazard ratios (HRs) of BMI loss and gain for CVD events were 1.16 (95% CI, 1.00 to 1.34) and 1.10 (95% CI, 0.96 to 1.25), respectively. A U-shaped association was observed between the BMI changes and CVD events, particularly for nonatherosclerotic CVD outcomes including heart failure and atrial fibrillation. Compared with stable BMI, both BMI loss and gain increased the risk of heart failure (HR, 1.30; 95% CI, 1.08 to 1.57 and HR, 1.22; 95% CI, 1.02 to 1.47, respectively) and atrial fibrillation (HR, 1.70; 95% CI, 1.18 to 2.45 and HR, 1.55; 95% CI, 1.07 to 2.24, respectively). CONCLUSION: Cancer survivors with BMI loss and gain were at greater risk of CVD. Body mass index loss is associated with a higher risk of CVD.

Awareness of Being Prescribed Antihypertensive Medications and Cardiovascular Outcomes.

BACKGROUND: Hypertension is a major cause of cardiovascular disease (CVD). In patients with hypertension, unawareness of the disease often results in poor blood pressure control and increases the risk of CVD. However, data in nationwide surveys regarding the proportion of unaware individuals and the implications of such on their clinical outcomes are lacking. We aimed to clarify the association between unawareness of being prescribed antihypertensive medications among individuals taking antihypertensive medications and the subsequent risk of developing CVD.Methods and Results: This retrospective cohort study analyzed data from the JMDC Claims Database, including 313,715 individuals with hypertension treated with antihypertensive medications (median age 56 years). The primary endpoint was a composite of myocardial infarction, angina pectoris, stroke, heart failure, and atrial fibrillation. Overall, 19,607 (6.2%) individuals were unaware of being prescribed antihypertensive medications. During the follow-up period, 33,976 composite CVD endpoints were documented. Despite their youth, minimal comorbidities, and the achievement of better BP control with a reduced number of antihypertensive prescriptions, unawareness of being prescribed antihypertensive medications was associated with a greater risk of developing composite CVD. Hazard ratios of unawareness of being prescribed antihypertensive medications were 1.16 for myocardial infarction, 1.25 for angina pectoris, 1.15 for stroke, 1.36 for heart failure, and 1.28 for atrial fibrillation. The results were similar in several sensitivity analyses, including the analysis after excluding individuals with dementia. CONCLUSIONS: Among individuals taking antihypertensive medications, assessing the awareness of being prescribed antihypertensive medications may help identify those at high risk for CVD-related events.

Mitochondrial fractions located in the cytoplasmic and peridroplet areas of white adipocytes have distinct roles.

The role of mitochondria in white adipocytes (WAs) has not been fully explored. A recent study revealed that brown adipocytes contain functionally distinct mitochondrial fractions, cytoplasmic mitochondria, and peridroplet mitochondria. However, it is not known whether such a functional division of mitochondria exists in WA. Herein, we observed that mitochondria could be imaged and mitochondrial DNA and protein detected in pellets obtained from the cytoplasmic layer and oil layer of WAs after centrifugation. The mitochondria in each fraction were designated as cytoplasmic mitochondria (CMw) and peridroplet mitochondria (PDMw) in WAs, respectively. CMw had higher ß-oxidation activity than PDMw, and PDMw was associated with diacylglycerol acyltransferase 2. Therefore, CMw may be involved in ß-oxidation and PDMw in droplet expansion in WAs.

Sex Differences in the Association Between Depression and Incident Cardiovascular Disease.

Background: Depression is a known risk factor for cardiovascular disease (CVD), but the potential sex differences in this association remain unclear. Objectives: The aim of this study was to investigate the association between depression and subsequent CVD events, and to explore potential sex differences. Methods: The authors conducted a retrospective analysis using the JMDC Claims Database between 2005 and 2022. The study population included 4,125,720 individuals aged 18 to 75 years without a history of cardiovascular disease or renal failure and missing data at baseline. Participants were followed up for a mean of 1,288 days to assess the association between depression and subsequent CVD events, such as myocardial infarction, angina pectoris, stroke, heart failure, and atrial fibrillation. Results: Our analysis revealed a significant association between depression and subsequent composite CVD events in both men and women, with a stronger association observed in women. The HR for the composite endpoint was 1.64 (95% CI: 1.59-1.70) in women and 1.39 (95% CI: 1.35-1.42) in men after multivariable adjustment (P for interaction <0.001). Furthermore, the individual components of the composite endpoint were also associated with depression in both men and women, each of which was also observed to be more strongly associated in women. Conclusions: Our study provides evidence of a significant association between depression and subsequent CVD events in both men and women, with a more pronounced association observed in women. These findings highlight the importance of addressing depression and tailoring prevention and management strategies according to sex-specific factors.

Unawareness of being prescribed medications for diabetes and incident cardiovascular disease.

BACKGROUND: Some patients with diabetes are unaware that they are prescribed medications for diabetes. The purpose of this study is to determine, using a Japanese nationwide epidemiologic database, the association between unawareness of being prescribed medication for diabetes and the risk of developing cardiovascular disease (CVD) in patients with diabetes. METHODS: This observational cohort study analyzed data from the JMDC Claims Database between 2005 and 2022, including 94,048 patients with diabetes treated with medications. The primary endpoint was a composite endpoint including myocardial infarction (MI), stroke, heart failure (HF), and atrial fibrillation (AF). RESULTS: We identified 7561 composite CVD endpoints during a mean follow-up of 1199 ±â€¯902 days. Overall, 7779 (8.3 %) patients were unaware of being prescribed medications for diabetes. Those who did not know they were prescribed drugs were younger and had better glycemic control, but these individuals were at higher risk of developing combined CVD [hazard ratio (HR) 1.13, 95 % confidence interval (95 % CI) 1.04-1.22]. HRs of unawareness of being prescribed medications for diabetes were 1.33 (95 % CI 1.06-1.68) for MI, 1.13 (95 % CI 0.97-1.31) for stroke, 1.10 (95 % CI 1.00-1.21) for HF, and 1.19 (95 % CI 0.97-1.47) for AF, respectively. CONCLUSIONS: In patients with diabetes taking medications for diabetes, even if they are young and have good glycemic control, unawareness of being prescribed medications for diabetes was associated with a greater risk of developing CVD. It is important that they receive adequate education from their healthcare providers to accurately identify their treatment status.