Dietary vitamin C and vitamin E with the risk of aortic aneurysm and dissection: A prospective population-based cohort study.

BACKGROUND AND AIMS: The associations between dietary vitamin C (VC), vitamin E (VE) intake and aortic aneurysm and dissection (AAD) remain unclear. This study aimed to prospectively investigate the associations between dietary VC and VE with the incident risk of AAD. METHODS AND RESULTS: A total of 139 477 participants of UK Biobank cohort were included in the analysis. Dietary VC and VE consumptions were acquired through a 24-h recall questionnaire. Cox proportional regression models were used to examine the associations between VC, VE intake and the risk of AAD. Incident AAD was ascertained through hospital inpatient records and death registers. During a median follow-up of 12.5 years, 962 incident AAD events were documented. Both dietary VC [adjusted hazard ratio (HR), 0.77; 95 % confidence intervals (CI), 0.63-0.93; P-trend = 0.008] and VE (adjusted HR, 0.70; 95 % CI, 0.57-0.87; P-trend = 0.002) were inversely associated with incident AAD when comparing the participants in the highest quartile with those in the lowest. In subgroup analyses, the associations were more pronounced in participants who were over 60 years old, participants with smoking history, hypertension or hyperlipidemia, who were under the high risk of AAD. CONCLUSION: Higher dietary VC and VE intakes are associated with reduced risk of AAD. Our study emphasizes the importance of diet adjustment strategies targeted on VC and VE to lower the incidence rate of AAD especially in the high-risk population.

AHA Life's Essential 8 and new-onset CKD: a prospective cohort study from the UK Biobank.

BACKGROUND: The AHA has recently introduced a novel metric, Life's Essential 8, to assess cardiovascular health (CVH). Nevertheless, the association between varying levels of LE8 and the propensity for CKD is still unclear from a large prospective cohort. Our objective is to meticulously examine the relationship between LE8 and its associated susceptibilities to CKD. METHODS: A total of 251,825 participants free of CKD from the UK Biobank were included. Cardiovascular health was scored using LE8 and categorized as low, moderate, and high. Cox proportional hazard models were employed to evaluate the associations of LE8 scores with new-onset CKD. The genetic risk score for CKD was calculated by a weighted method. RESULTS: Over a median follow-up of 12.8 years, we meticulously documented 10,124 incident cases of CKD. Remarkably, an increased LE8 score correlated with a significant reduction of risk in new-onset CKD (high LE8 score vs. low LE8 score: HR = 0.300, 95% CI 0.270-0.330, p < 0.001; median LE8 score vs. low LE8 score: HR = 0.531, 95% CI 0.487-0.580, p < 0.001). This strong LE8-CKD association remained robust in extensive subgroup assessments and sensitivity analysis. Additionally, these noteworthy associations between LE8 scores and CKD remained unaffected by genetic predispositions to CKD. CONCLUSIONS: An elevated degree of CVH, as delineated by the discerning metric LE8, exhibited a pronounced and statistically significant correlation with a marked reduction in the likelihood of CKD occurrence.

U-shaped association between the triglyceride-glucose index and atrial fibrillation incidence in a general population without known cardiovascular disease.

OBJECTIVE: The triglyceride-glucose (TyG) index has been shown to be a new alternative measure for insulin resistance. However, no study has attempted to investigate the association of the TyG index with incident atrial fibrillation (AF) in the general population without known cardiovascular diseases. METHODS: Individuals without known cardiovascular diseases (heart failure, coronary heart disease, or stroke) from the Atherosclerosis Risk in Communities (ARIC) cohort were recruited. The baseline TyG index was calculated as the Ln [fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]. The association between the baseline TyG index and incident AF was examined using Cox regression. RESULTS: Of 11,851 participants, the mean age was 54.0 years; 6586 (55.6%) were female. During a median follow-up of 24.26 years, 1925 incidents of AF cases (0.78/per 100 person-years) occurred. An increased AF incidence with a graded TyG index was found by Kaplan‒Meier curves (P < 0.001). In multivariable-adjusted analysis, both < 8.80 (adjusted hazard ratio [aHR] = 1.15, 95% confidence interval [CI] 1.02, 1.29) and > 9.20 levels (aHR 1.18, 95% CI 1.03, 1.37) of the TyG index were associated with an increased risk of AF compared with the middle TyG index category (8.80-9.20). The exposure-effect analysis confirmed the U-shaped association between the TyG index and AF incidence (P = 0.041). Further sex-specific analysis showed that a U-shaped association between the TyG index and incident AF still existed in females but not in males. CONCLUSIONS: A U-shaped association between the TyG index and AF incidence is observed in Americans without known cardiovascular diseases. Female sex may be a modifier in the association between the TyG index and AF incidence.

Age at job initiation and risk of coronary heart disease: findings from the UK biobank cohort study.

BACKGROUND: Commencing work at an early age has been linked to various risk factors for coronary heart disease (CHD), such as shift work and intensive job strain. However, the relationship between starting work too early and CHD risk remains largely unclear. We examined the association between age at job initiation and the risk of CHD. METHODS: UK Biobank participants aged 38 to 70 years without cardiovascular disease who provided data on their age at job initiation were included. The primary outcome was CHD, which was ascertained using hospital and death records. The hazard ratios (HRs) and 95% confidence interval (CIs) for the association between age at job initiation and CHD were calculated using multivariable Cox regression. RESULTS: Of the 501,971 participants, 114,418 eligible participants were included in the final analysis. The median age at job initiation was 19.0 years. During the mean follow-up of 12.6 years, 6,130 (5.4%) first CHD events occurred. We observed that age at job initiation was inversely associated with CHD (HR 0.98, 95% CI 0.97-0.99), and the association was potentially J-shaped. The HRs for the < 17-year, 17-18-year, and 19-21-year age groups were 1.29 (95%CI 1.18-1.41), 1.12 (95% CI 1.03-1.22) and 1.05 (95% CI 0.97-1.14), respectively, compared with those of the ≥ 22-year group. CONCLUSIONS: Age at job initiation was associated with incident CHD, which was independent of socioeconomic status. Participants who commenced employment before the age of 19 years exhibited a higher risk of developing CHD later in adulthood.

Association of motor index scores with fall incidence among community-dwelling older people.

BACKGROUND: Several kinds of motor dysfunction have been studied for predicting future fall risk in community-dwelling older individuals. However, no study has tested the ability of the fine motor index (FINEA) and gross motor index (GROSSA) to predict the risk of falling, as well as the specific fall type. OBJECTIVE: We investigated the associations of FINEA/GROSSA scores with fall risk, explained falls, and unexplained falls. METHODS: A total of 6267 community-dwelling adults aged ≥ 50 years from the Irish Longitudinal Study on Aging (TILDA) cohort were included. First, the associations of FINEA and GROSSA scores with the history of total falls, explained falls and unexplained falls were assessed in a cross-sectional study and further verified in a prospective cohort after 2 years of follow-up by Poisson regression analysis. RESULTS: We found that high FINEA and GROSSA scores were positively associated with almost all fall histories (FINEA scores: total falls: adjusted prevalence ratio [aPR] = 1.28, P = 0.009; explained falls: aPR = 1.15, P = 0.231; unexplained falls: aPR = 1.88, P < 0.001; GROSSA scores: total falls: aPR = 1.39, P < 0.001; explained falls: aPR = 1.28, P = 0.012; unexplained falls: aPR = 2.18, P < 0.001) in a cross-sectional study. After 2 years of follow-up, high FINEA scores were associated with an increased incidence of total falls (adjusted rate ratio [aRR] = 1.42, P = 0.016) and explained falls (aRR = 1.51, P = 0.020) but not with unexplained falls (aRR = 1.41, P = 0.209). High GROSSA scores were associated with an increased incidence of unexplained falls (aRR = 1.57, P = 0.041) and were not associated with either total falls (aRR = 1.21, P = 0.129) or explained falls (aRR = 1.07, P = 0.656). Compared with individuals without limitations in either the FINEA or GROSSA, individuals with limitations in both indices had a higher risk of falls, including total falls (aRR = 1.35, P = 0.002), explained falls (aRR = 1.31, P = 0.033) and unexplained falls (aRR = 1.62, P = 0.004). CONCLUSION: FINEA scores were positively associated with accidental falls, while GROSSA scores were positively associated with unexplained falls. The group for whom both measures were impaired showed a significantly higher risk of both explained and unexplained falls. FINEA or GROSSA scores should be investigated further as possible tools to screen for and identify community-dwelling adults at high risk of falling.

Interleukin-33 alleviates diabetic cardiomyopathy through regulation of endoplasmic reticulum stress and autophagy via insulin-like growth factor-binding protein 3.

Prolonged endoplasmic reticulum (ER) stress is the key driving force behind diabetic cardiomyopathy (DCM). Autophagy is extensively implicated in adaptive mechanisms for cell survival. Interleukin-33 (IL-33) is known to be a potent cardiac protector, but its roles in DCM, ER stress, and autophagy are currently unknown. We aimed to explore the effects of IL-33 on DCM and characterize the roles that ER stress and autophagy play in DCM. The effects of IL-33 on DCM, ER stress, and autophagy were characterized both in db/db mice and in palmitic acid (PA)-treated cardiomyocytes. The manipulators of ER stress and autophagy were used to clarify their roles in DCM remittance conferred by IL-33. Gene expression analysis was used to identify IL-33-dependent regulators of ER stress and autophagy. Both db/db mice and PA-treated cells presented with enhanced levels of ER stress, apoptosis, and lipid deposition, as well as impaired autophagy, all of which could be reversed by IL-33. Treatment with IL-33 improved the cardiac diastolic function of diabetic mice. Nonselective autophagy inhibitors, such as 3-methyladenine (3-MA) or wortmannin, abolished the protective effects of IL-33, resulting in an increase in both ER stress and apoptosis. Strikingly, insulin-like growth factor-binding protein 3 (IGFBP3) was identified as the gene most significantly differentially expressed between IL-33 and control groups. Knockdown of IGFBP3 expression, similar to the effect of nonselective autophagy inhibitors, resulted in high levels of ER stress, impaired autophagy, and apoptosis that were not rescued upon treatment with IL-33. IL-33 abates DCM by alleviating ER stress and promoting autophagy. IGFBP3 is essential for IL-33-induced ER stress resolution and autophagic enhancement during DCM.

C-reactive protein derived from perivascular adipose tissue accelerates injury-induced neointimal hyperplasia.

AIM: Inflammation within the perivascular adipose tissue (PVAT) in obesity plays an important role in cardiovascular disorders. C-reactive protein (CRP) level in obesity patients is significantly increased and associated with the occurrence and progression of cardiovascular disease. We tested the hypothesis CRP derived from PVAT in obesity contributes to vascular remodeling after injury. METHODS: A high-fat diet (HFD) significantly increased CRP expression in PVAT. We transplanted thoracic aortic PVAT from wild-type (WT) or transgenic CRP-expressing (CRPTG) mice to the injured femoral artery in WT mice. RESULTS: At 4 weeks after femoral artery injury, the neointimal/media ratio was increased significantly in WT mice that received PVAT from CRPTG mice compared with that in WT mice that received WT PVAT. Transplanted CRPTG PVAT also significantly accelerated adventitial macrophage infiltration and vasa vasorum proliferation. It was revealed greater macrophage infiltration in CRPTG adipose tissue than in WT adipose tissue and CRP significantly increased the adhesion rate of monocytes through receptor Fcγ RI. Proteome profiling showed CRP over-expression promoted the expression of chemokine (C-X-C motif) ligand 7 (CXCL7) in adipose tissue, transwell assay showed CRP increased monocyte migration indirectly via the induction of CXCL7 expression in adipocytes. CONCLUSION: CRP derived from PVAT was significantly increased in HFD mice and promoted neointimal hyperplasia after vascular injury.

Pericardial application as a new route for implanting stem-cell cardiospheres to treat myocardial infarction.

KEY POINTS: Cardiospheres (CSps) are a promising new form of cardiac stem cells with advantage over other stem cells for myocardial regeneration, but direct implantation of CSps by conventional routes has been limited due to potential embolism. We have implanted CSps into the pericardial cavity and systematically demonstrated its efficacy regarding myocardial infarction. Stem cell potency and cell viability can be optimized in vitro prior to implantation by pre-conditioning CSps with pericardial fluid and hydrogel packing. Transplantation of optimized CSps into the pericardial cavity improved cardiac function and alleviated myocardial fibrosis, increased myocardial cell survival and promoted angiogenesis. Mechanistically, CSps are able to directly differentiate into cardiomyocytes in vivo and promote regeneration of myocardial cells and blood vessels through a paracrine effect with released growth factors as potential paracrine mediators. These findings establish a new strategy for therapeutic myocardial regeneration to treat myocardial infarction. ABSTRACT: Cardiospheres (CSps) are a new form of cardiac stem cells with an advantage over other stem cells for myocardial regeneration. However, direct implantation of CSps by conventional routes to treat myocardial infarction has been limited due to potential embolism. We have implanted CSps into the pericardial cavity and systematically assessed its efficacy on myocardial infarction. Preconditioning with pericardial fluid enhanced the activity of CSps and matrix hydrogel prolonged their viability. This shows that pretransplant optimization of stem cell potency and maintenance of cell viability can be achieved with CSps. Transplantation of optimized CSps into the pericardial cavity improved cardiac function and alleviated myocardial fibrosis in the non-infarcted area, and increased myocardial cell survival and promoted angiogenesis in the infarcted area. Mechanistically, CSps were able to directly differentiate into cardiomyocytes in vivo and promoted regeneration of myocardial cells and blood vessels in the infarcted area through a paracrine effect with released growth factors in pericardial cavity serving as possible paracrine mediators. This is the first demonstration of direct pericardial administration of pre-optimized CSps, and its effectiveness on myocardial infarction by functional and morphological outcomes with distinct mechanisms. These findings establish a new strategy for therapeutic myocardial regeneration to treat myocardial infarction.

Sirt5 improves cardiomyocytes fatty acid metabolism and ameliorates cardiac lipotoxicity in diabetic cardiomyopathy via CPT2 de-succinylation.

RATIONALE: The disruption of the balance between fatty acid (FA) uptake and oxidation (FAO) leads to cardiac lipotoxicity, serving as the driving force behind diabetic cardiomyopathy (DbCM). Sirtuin 5 (Sirt5), a lysine de-succinylase, could impact diverse metabolic pathways, including FA metabolism. Nevertheless, the precise roles of Sirt5 in cardiac lipotoxicity and DbCM remain unknown. OBJECTIVE: This study aims to elucidate the role and underlying mechanism of Sirt5 in the context of cardiac lipotoxicity and DbCM. METHODS AND RESULTS: The expression of myocardial Sirt5 was found to be modestly elevated in diabetic heart failure patients and mice. Cardiac dysfunction, hypertrophy and lipotoxicity were exacerbated by ablation of Sirt5 but improved by forced expression of Sirt5 in diabetic mice. Notably, Sirt5 deficiency impaired FAO without affecting the capacity of FA uptake in the diabetic heart, leading to accumulation of FA intermediate metabolites, which mainly included medium- and long-chain fatty acyl-carnitines. Mechanistically, succinylomics analyses identified carnitine palmitoyltransferase 2 (CPT2), a crucial enzyme involved in the reconversion of fatty acyl-carnitines to fatty acyl-CoA and facilitating FAO, as the functional succinylated substrate mediator of Sirt5. Succinylation of Lys424 in CPT2 was significantly increased by Sirt5 deficiency, leading to the inactivation of its enzymatic activity and the subsequent accumulation of fatty acyl-carnitines. CPT2 K424R mutation, which mitigated succinylation modification, counteracted the reduction of enzymatic activity in CPT2 mediated by Sirt5 deficiency, thereby attenuating Sirt5 knockout-induced FAO impairment and lipid deposition. CONCLUSIONS: Sirt5 deficiency impairs FAO, leading to cardiac lipotoxicity in the diabetic heart through the succinylation of Lys424 in CPT2. This underscores the potential roles of Sirt5 and CPT2 as therapeutic targets for addressing DbCM.

Low remnant cholesterol and the subsequent risk of new-onset atrial fibrillation: A prospective cohort study.

BACKGROUND: Atrial fibrillation (AF) is a common arrhythmia with high morbidity and mortality implications. Several studies have described a paradoxical inverse relationship between serum cholesterol and the risk of AF, but it remains unknown whether remnant cholesterol (RC) is associated with AF incidence. OBJECTIVE: This study aims to prospectively investigate the association between RC and AF. METHODS: A total of 392,783 participants free of AF at baseline from the UK Biobank were included for the analysis. Cox proportional hazards model, subgroup analysis, and sensitivity analyses were used to evaluate the independent association between RC levels and the risk of new-onset AF. Furthermore, we performed a discordance analysis by using the median cutoff points of low-density lipoprotein cholesterol (LDL-C) and RC. RESULTS: After a median follow-up of 12.8 years (interquartile range 12.0-13.6 years), a total of 23,558 participants experienced incident AF. Compared with the highest RC level, the lower RC level was associated with an increased risk of AF incidence (quartile 1 vs quartile 4: hazard ratio 1.396; 95% confidence interval [CI] 1.343-1.452). The results remained robust across a series of sensitivity analyses. In the discordance analyses, a significantly higher risk of AF was observed in participants with discordant low RC/high LDL-C levels than in those with concordant high RC/LDL-C levels. In the low LDL-C group, RC reduction even contributed to an additional 15.8% increased rate of incident AF (low RC/low LDL-C: hazard ratio 1.303; 95% CI 1.260-1.348 vs high RC/low LDL-C: hazard ratio 1.125; 95% CI 1.079-1.172). CONCLUSION: Low RC levels were associated with an increased risk of incident AF independent of traditional cardiovascular risk factors.

Performance of ChatGPT on the Chinese Postgraduate Examination for Clinical Medicine: Survey Study.

BACKGROUND: ChatGPT, an artificial intelligence (AI) based on large-scale language models, has sparked interest in the field of health care. Nonetheless, the capabilities of AI in text comprehension and generation are constrained by the quality and volume of available training data for a specific language, and the performance of AI across different languages requires further investigation. While AI harbors substantial potential in medicine, it is imperative to tackle challenges such as the formulation of clinical care standards; facilitating cultural transitions in medical education and practice; and managing ethical issues including data privacy, consent, and bias. OBJECTIVE: The study aimed to evaluate ChatGPT's performance in processing Chinese Postgraduate Examination for Clinical Medicine questions, assess its clinical reasoning ability, investigate potential limitations with the Chinese language, and explore its potential as a valuable tool for medical professionals in the Chinese context. METHODS: A data set of Chinese Postgraduate Examination for Clinical Medicine questions was used to assess the effectiveness of ChatGPT's (version 3.5) medical knowledge in the Chinese language, which has a data set of 165 medical questions that were divided into three categories: (1) common questions (n=90) assessing basic medical knowledge, (2) case analysis questions (n=45) focusing on clinical decision-making through patient case evaluations, and (3) multichoice questions (n=30) requiring the selection of multiple correct answers. First of all, we assessed whether ChatGPT could meet the stringent cutoff score defined by the government agency, which requires a performance within the top 20% of candidates. Additionally, in our evaluation of ChatGPT's performance on both original and encoded medical questions, 3 primary indicators were used: accuracy, concordance (which validates the answer), and the frequency of insights. RESULTS: Our evaluation revealed that ChatGPT scored 153.5 out of 300 for original questions in Chinese, which signifies the minimum score set to ensure that at least 20% more candidates pass than the enrollment quota. However, ChatGPT had low accuracy in answering open-ended medical questions, with only 31.5% total accuracy. The accuracy for common questions, multichoice questions, and case analysis questions was 42%, 37%, and 17%, respectively. ChatGPT achieved a 90% concordance across all questions. Among correct responses, the concordance was 100%, significantly exceeding that of incorrect responses (n=57, 50%; P<.001). ChatGPT provided innovative insights for 80% (n=132) of all questions, with an average of 2.95 insights per accurate response. CONCLUSIONS: Although ChatGPT surpassed the passing threshold for the Chinese Postgraduate Examination for Clinical Medicine, its performance in answering open-ended medical questions was suboptimal. Nonetheless, ChatGPT exhibited high internal concordance and the ability to generate multiple insights in the Chinese language. Future research should investigate the language-based discrepancies in ChatGPT's performance within the health care context.

Alterations of NMR-Based Lipoprotein Profile Distinguish Unstable Angina Patients with Different Severity of Coronary Lesions.

Non-invasive detection of unstable angina (UA) patients with different severity of coronary lesions remains challenging. This study aimed to identify plasma lipoproteins (LPs) that can be used as potential biomarkers for assessing the severity of coronary lesions, determined by the Gensini score (GS), in UA patients. We collected blood plasma from 67 inpatients with angiographically normal coronary arteries (NCA) and 230 UA patients, 155 of them with lowGS (GS ≤ 25.4) and 75 with highGS (GS > 25.4), and analyzed it using proton nuclear magnetic resonance spectroscopy to quantify 112 lipoprotein variables. In a logistic regression model adjusted for four well-known risk factors (age, sex, body mass index and use of lipid-lowering drugs), we tested the association between each lipoprotein and the risk of UA. Combined with the result of LASSO and PLS-DA models, ten of them were identified as important LPs. The discrimination with the addition of selected LPs was evaluated. Compared with the basic logistic model that includes four risk factors, the addition of these ten LPs concentrations did not significantly improve UA versus NCA discrimination. However, thirty-two selected LPs showed notable discrimination power in logistic regression modeling distinguishing highGS UA patients from NCA with a 14.9% increase of the area under the receiver operating characteristics curve. Among these LPs, plasma from highGS patients was enriched with LDL and VLDL subfractions, but lacked HDL subfractions. In summary, we conclude that blood plasma lipoproteins can be used as biomarkers to distinguish UA patients with severe coronary lesions from NCA patients.

Depressive symptoms, anxiety and social stress are associated with diminished cardiovascular reactivity in a psychological treatment-naive population.

BACKGROUND: There is now an increasing appreciation of how psychological health can contribute to cardiovascular disease, called the mind-heart connection. A blunted cardiovascular reactivity to depression and anxiety may be responsible for the potential mechanism, however, with inconsistent results. Anti-psychological drugs have an effect on the cardiovascular system and, thus, may disturb their relationship. However, in treatment-naive individuals with psychological symptoms, no research has specifically evaluated the relationship between psychological state and cardiovascular reactivity. METHODS: We included 883 treatment-naive individuals who came from a longitudinal cohort study of Midlife in the United States. Symptoms of depression, anxiety, and stress were assessed by the Center for Epidemiologic Studies Depression Scale (CES-D), Spielberger Trait Anxiety Inventory (STAI), the Liebowitz Social Anxiety scale (LSAS) and the Perceived Stress Scale (PSS), respectively. Cardiovascular reactivity was measured using standardized, laboratory-based stressful tasks. RESULTS: Treatment-naive individuals with depressive symptoms (CES-D ≥ 16), anxiety symptoms (STAI ≥ 54), and higher stress levels (PSS ≥ 27) had lower cardiovascular reactivity as assessed by systolic blood pressure (SBP) reactivity, diastolic blood pressure (DBP) reactivity and heart rate (HR) reactivity (P < 0.05). Pearson analyses showed that psychological symptoms were correlated with lower SBP reactivity, DBP reactivity, and heart rate reactivity (P < 0.05). Multivariate linear regression showed that depression and anxiety were negatively related to lower cardiovascular reactivity (SBP, DBP and HR reactivity) after full adjustments (P < 0.05). Stress was associated with reduced SBP and DBP reactivity but with a nonsignificant association with HR reactivity (P = 0.056). CONCLUSION: Depression, anxiety, and stress symptoms are associated with blunted cardiovascular reactivity in treatment-naive adult Americans. These findings suggest that blunted cardiovascular reactivity is an underlying mechanism linking psychological health and cardiovascular diseases.

Association of Body Mass Index and Abdominal Obesity with Incidence of Atrial Fibrillation in Heart Failure with Preserved Ejection Fraction.

INTRODUCTION: The association between obesity and atrial fibrillation (AF) incidence in heart failure with preserved ejection fraction (HFpEF) patients is currently unclear. Our analyses and results are based on the whole Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial (placebo and spironolactone). METHOD: A total of 2138 subjects without baseline AF were included in the trial. Kaplan-Meier (K-M) curves and Cox regression with hazard ratios (HRs) and confidence intervals (CIs) were used to assess the incidence of AF with obesity. Of 2138 HFpEF patients without baseline AF, 1165 were obese (body mass index [BMI]≥30 kg/m2). RESULT: The K-M curve showed obese patients developed AF more than overweight (25≤ BMI ≤29.9 kg/m2) patients (p=0.013), confirmed by multivariable analysis, while there's no statistical difference between overweight and normal weight (18.5≤ BMI ≤24.9 kg/m2) patients. The occurrence of AF increased by 3% for every kg/m2 increase in BMI (adjusted HR, aHR: 1.03; 95% CI: 1.00-1.06), with a positive linear association (p for nonlinear: 0.145). Obesity was associated with AF incidence (aHR: 1.62; 95% CI: 1.05-2.50) compared with non-obesity (including overweight and normal-weight patients). CONCLUSION: Abdominal obesity was associated with increased AF incidence (aHR: 1.70; 95% CI: 1.04-2.77), and AF incidence rose by 18% per centimeter in circumference (aHR: 1.18; 95% CI: 1.04-1.34). Obesity and abdominal obesity increase the incidence of AF in HFpEF patients. Further studies need to determine whether there is a difference in AF in response to spironolactone across obese HFpEF pheno groups.

Moderate heart rate reduction promotes cardiac regeneration through stimulation of the metabolic pattern switch.

As a biological pump, the heart needs to consume a substantial amount of energy to maintain sustained beating. Myocardial energy metabolism was recently reported to be related to the loss of proliferative capacity in cardiomyocytes (CMs). However, the intrinsic relationship between beating rate and proliferation in CMs and whether energy metabolism can regulate this relationship remains unclear. In this study, we find that moderate heart rate reduction (HRR) induces CM proliferation under physiological conditions and promotes cardiac regenerative repair after myocardial injury. Mechanistically, moderate HRR induces G1/S transition and increases the expression of glycolytic enzymes in CMs. Furthermore, moderate HRR induces a metabolic pattern switch, activating glucose metabolism and increasing the relative proportion of ATP production by the glycolytic pathway for biosynthesis of substrates needed for proliferative CMs. These results highlight the potential therapeutic role of HRR in not only acute myocardial protection but also long-term CM restoration.

Macrophage-Targeted Sonodynamic/Photothermal Synergistic Therapy for Preventing Atherosclerotic Plaque Progression Using CuS/TiO2 Heterostructured Nanosheets.

Sonodynamic therapy (SDT) and photothermal therapy (PTT) are two effective strategies for the treatment of atherosclerotic plaques. However, the low yield of reactive oxygen species (ROS) of conventional organic sonosensitizers and the low biosafety of hyperthermia limit the therapeutic efficacy of SDT and PTT. Herein, we report copper sulfide/titanium oxide heterostructure nanosheets modified with hyaluronic acid (HA) and PEG (HA-HNSs) for low-intensity sonodynamic and mild-photothermal synergistic therapy for early atherosclerotic plaques. CuS/TiO2 heterostructure nanosheets (HNSs) show high electron-hole separation efficiency and superior sonodynamic performance, because it has high surface energy crystal facets as well as a narrow band. Moreover, HNSs exhibit intense absorbance in the NIR-II region, which endows the nanosheets with excellent photothermal performance. With a further modification of HA, HA-HNSs can selectively target intraplaque proinflammatory macrophages through CD44-HA interaction. Because SDT reduces the expression of heat shock protein 90 and PTT facilitates the sonocatalytic process, the combination of SDT and PTT based on HA-HNSs could synergistically induce proinflammatory macrophage apoptosis. More importantly, the synergistic therapy prevents the progression of early atherosclerotic plaque by removing lesional macrophages and mitigating inflammation. Taken together, this work provides a macrophage-targeting sonodynamic/photothermal synergistic therapy, which is an effective translational clinical intervention for early atherosclerotic plaques.

IL-6 and IL-8 are likely associated with psychological status in treatment naïve general population.

BACKGROUND: Levels of inflammatory markers are elevated in patients with psychological disorders. However, anti-psychological drugs have an effect on proinflammatory cytokine production and disturb their relationship. Limited evidence focuses on the inflammatory marker profile of psychological status before treatment. This study aimed to investigate the inflammatory biomarker profiles of psychological treatment-naive individuals. METHODS: We included 790 psychological treatment-naive individuals from a longitudinal cohort study of Midlife in the United States (MIDUS). Symptoms of depression, anxiety, and stress were assessed by the Center for Epidemiologic Studies Depression Scale (CES-D) subscales, the Social Anxiety Scale (STAI), and Liebowitz Social Anxiety Scale (LSAS), the Perceived Stress Scale (PSS), respectively. RESULTS: Spearman correlation analysis showed that a higher CESD total score was correlated with higher CRP (p=0.009), IL-6 (p=0.007), fibrinogen (p=0.036), E-selectin (p=0.018), ICAM-1 (p=0.013), and IL-8 (p=0.05) levels. Multivariate linear regression analysis showed that the CESD total score was positively associated with the levels of IL-6 (p=0.024) after adjustments. Moreover, the perceived stress score (PSS) was negatively associated with the levels of IL-8 (p=0.025). However, these associations were not significant after multiple testing (p=0.088, 0.091, respectively). LIMITATIONS: The casual relationship cannot be drawn due to the cross-sectional design CONCLUSION: Overall, our results suggested IL-6 and IL-8 might play a important role in the pathogenesis of psychological disorder. Larger and longitude studies are needed to confirm our results.

Usefulness of B-Type Natriuretic Peptide for Predicting the Risk of Stroke in Patients With Heart Failure With Preserved Ejection Fraction.

Background B-type natriuretic peptide (BNP) is a well-known biomarker for prognosis in heart failure with patients with preserved ejection fraction. However, the clinical predictive ability of BNP for the risk of stroke in HFpEF is not clear. Methods and Results A total of 799 patients with HFpEF from the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial were included. Association of baseline BNP with risk of stroke was assessed using the Cox proportional hazard model. The discriminatory ability of BNP was expressed using the C index. The improvement in 5-year stroke prediction was assessed by C statistic, categorical net reclassification improvement index, and relative integrated discrimination improvement. A total of 34 (4.3%) patients among the 799 patients with HFpEF experienced stroke events over a median of 2.85 years of follow-up. The stroke group showed a higher BNP level than the nonstroke group (375 pg/mL versus 241 pg/mL, respectively; P=0.006). Higher BNP levels were associated with increased risk of stroke after multivariable adjustment (hazard ratio, 3.29 [95% CI, 1.51-7.16]) and had a moderate performance for stroke prediction (C index, 0.67). Adding BNP to CHADS2/CHA2DS2-VASc/R2CHADS2 scores improved their predictive value for stroke (CHADS2: C index, 0.67; BNP+CHADS2: C index, 0.77; net reclassification improvement, 40.9%; integrated discrimination improvement, 3.0%; CHA2DS2-VASc: C index, 0.64; BNP+CHA2DS2-VASc: C index, 0.74; net reclassification improvement, 41.4%; integrated discrimination improvement, 2.2%; R2CHADS2: C index, 0.70; BNP+R2CHADS2: C index, 0.78; net reclassification improvement, 40.9%; integrated discrimination improvement, 3.2%). Conclusions BNP is associated with an increased risk of stroke in patients with HFpEF and may be a valuable biomarker for stroke prediction in HFpEF.

Liver fibrosis scores and atrial fibrillation incidence in heart failure with preserved ejection fraction.

AIM: Non-alcoholic fatty liver disease (NAFLD)-related advanced liver fibrosis (Stage 3 or 4) was reported to be linked to worse prognosis in patients with heart failure with preserved ejection fraction (HFpEF). This study aims to assess the relationship between liver fibrosis scores and new-onset atrial fibrillation (AF) incidence in patients with HFpEF in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial. METHODS AND RESULTS: Baseline liver fibrosis levels, assessed by NAFLD fibrosis score (NFS) or Fibrosis-4 index (FIB-4), with AF incidence were expressed as hazard ratios (HRs) using the Cox proportional hazard model. The risk for advanced fibrosis was estimated to be 21.5% (447/2072) as assessed by FIB-4 (>3.25) and 4.2% (88/2072) as assessed by NFS (>0.676) in HFpEF patients without baseline AF. After a median follow-up of 3.11 years, 106 new-onset AF cases occurred. In multivariate analysis, elevated NFS [NFS = -1.455-0.676: HR 2.44, 95% confidence interval (CI) 1.27-4.68; NFS > 0.676: HR 3.36, 95% CI 1.27-6.80; per 1 unit increase: HR 1.15, 95% CI 1.01-1.32], not FIB-4 (FIB-4 = 1.45-3.25: HR 1.02, 95% CI 0.67-1.55; FIB-4 > 3.25: HR 1.69, 95% CI 0.76-3.79; per 1 unit increase: HR 1.13, 95% CI 0.93-1.37), was associated with increased AF incidence. The NFS (C-index 0.662), not FIB-4 (C-index 0.531), had a moderate predictive ability in predicting incident AF. CONCLUSIONS: Among patients with HFpEF, the risk of advanced liver fibrosis is associated with an increased incidence of new-onset AF and may be a novel predictor for new-onset AF. Additional studies are needed to confirm our results.