Cardiometabolic Dysregulation Research Articles

The condition of myocardium reserves score from a cloud-based analytics platform of Holter ECG data indicates better cardiometabolic function in heart failure

Abstract Introduction Cardiometabolic dysregulation, particularly type 2 diabetes mellitus (T2DM), is associated with subtle myocardial pathologies, even in individuals without known cardiovascular disease. These subclinical changes, often undetectable by standard electrocardiogram (ECG) analytics, can offer valuable insights into the relationship between metabolic health and cardiac function. Novel ECG markers, developed through machine learning and artificial intelligence (AI), may provide the sensitivity needed to detect such changes. Aim This study aims to evaluate novel composite cardiac parameters from an analytics platform in the context of heart failure (HF), seeking to understand their relationship to cardiometabolic dysregulation. Methods Data from the MyoVasc study, a prospective cohort on HF, were analysed. Participants underwent extensive clinical phenotyping, including a Holter ECG assessment. Holter ECG data was processed based on machine learning and AI models on a cloud-based analytics platform (Cardiolyse, Helsinki, Finland), generating both traditional and proprietary ECG, and heart rate variability cardiac health markers. LASSO-penalized logistic regression adjusted for sex and age was performed to select the marker most strongly associated with T2DM. The identified marker was then evaluated in relation to cardiac function and structure as well as HF-related outcome. Results A total of 953 subjects (mean±SD age 64.6±10.5 years; 35.7% women) were included in the analyses. Symptomatic HF stage C/D was present in 54.8% (n=522) of subjects and diabetes mellitus in 22.4% (n=213). The Condition of Myocardium Reserves Score (CMRS) was the novel composite cardiac parameter selected based on its relationship with T2DM. In a Poisson regression model with robust variance adjusted for sex and age, a lower score was associated with T2DM (Prevalence ratio per SD 1.24, 95% confidence interval [1.14;1.36], P=0.0002). In multivariable linear regressions adjusted for traditional cardiovascular risk factors, comorbidities, and medication, a higher CMRS was associated with better global longitudinal strain (β per SD –0.82 [–1.11;–0.53], P<0.0001), diastolic function (left ventricular E/e’; β per SD –0.04 [–0.06;–0.01], P=0.0059) and systolic function (LV ejection fraction; β per SD 2.06 [1.46;2.67], P<0.0001). A lower CMRS independently predicted all-cause death (Hazard ratio per SD 1.25 [1.09;1.45], P=0.0020) and worsening of HF (HR per SD 1.44 [1.21;1.72], P<0.0001) in Cox regression analysis adjusted for the same confounders. Conclusion The Condition of Myocardium Reserves Score exhibited a strong association with cardiometabolic dysregulation. A higher CMRS indicated preserved cardiac function, while a lower score independently predicted increased risk of all-cause death and worsening HF. This novel score offers potential as a non-invasive tool for assessing cardiometabolic health and stratifying risk in patients with HF.

The Impact of Metabolic Syndrome on Postoperative Outcomes in Abdominal Body Contouring: A Propensity Score-Matched Nationwide Analysis.

Metabolic syndrome (MetS) represents cardiometabolic dysregulation, defined by hypertension, obesity, diabetes, and dyslipidemia. There remains a significant gap in our understanding of whether MetS impacts outcomes of abdominal body contouring procedures. We aimed to assess the influence of MetS on postoperative outcomes of abdominal body contouring by concurrent abdominoplasty and panniculectomy. The ACS-NSQIP database was utilized to identify patients who underwent concurrent abdominoplasty and panniculectomy procedures from 2012 to 2022. Through propensity score matching, distinct cohorts were established based on the presence of MetS, characterized by patients receiving medical interventions for diabetes mellitus and hypertension, with a body mass index exceeding 30kg/m2. Univariate and multivariate analyses were conducted to evaluate differences between groups. A total of 14,642 patients underwent abdominal body contouring from 2012 to 2022. Following propensity score matching, 730 patients were included in the analysis, with 365 in each group (MetS vs. non-MetS). Bivariate analysis revealed a longer hospital length of stay (2.3 vs. 1.6days; p = 0.007) in the MetS cohort compared to the non-MetS cohort. Patients diagnosed with MetS had an average length of stay of 0.6days longer than non-MetS patients (95% CI [0.17, 1.01]; p = 0.007). No noteworthy disparities were observed in the rates of 30-day wound complications, mild systemic, and severe systemic complications, and readmission rates between the groups. Our findings suggest that abdominal body contouring remains a secure option for patients with MetS. Nonetheless, the longer hospital length stays observed in patients with MetS may translate to increased overall costs to the healthcare system. Continued research is warranted to comprehensively assess the economic implications of MetS in the context of abdominal body contouring. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Association of adiposity, serum vitamin D, and dietary quality with cardiometabolic risk factors in children aged 6-12 years: findings from SEANUTS II Malaysia.

Increased cardiometabolic risk among children is increasingly becoming a concern, with evidence indicating that obesity, diet, and serum 25-hydroxyvitamin D (25(OH)D) are associated with cardiometabolic risk. However, such studies among Malaysian children are scarce. Thus, this study explores the associations between adiposity, dietary quality, and 25(OH)D, with cardiometabolic risk factors among Malaysian children aged 4-12 years. Data of 479 children (mean age: 8.2±2.3 years old, 52% females) from the South East Asian Nutrition Surveys (SEANUTS II) Malaysia, were included in this analysis. Adiposity (percentage of body fat) was assessed with bioelectrical impedance technique. Dietary quality was assessed using 24 h dietary recall and calculated as mean adequacy ratio. Vitamin D was assessed based on serum 25-hydroxyvitamin D (25(OH)D). Measurements of cardiometabolic risk factors included waist circumference (WC), mean arterial pressure (MAP), fasting blood glucose (FBG), high-density lipoprotein (HDL), triglyceride, and high-sensitivity C-reactive protein, and cardiometabolic risk cluster score (siMS) was calculated. Overall, higher adiposity was positively associated with all cardiometabolic risk factors (WC, ß = 0.907; 95% CI=0.865, 0.948; MAP, ß = 0.225; 95% CI=0.158, 0.292; HDL, ß = -0.011; 95% CI = -0.014, -0.009; Triglyceride, ß = 0.012; 95% CI=0.009, 0.016; FBG, ß = 0.006; 95% CI=0.002, 0.011) and siMS score (ß = 0.033; 95% CI=0.029, 0.037). Serum 25(OH)D was inversely associated with siMS score (ß = -0.002; 95% CI = -0.004, -0.000008) and positively associated with HDL (ß = 0.002; 95% CI=0.0001, 0.003). Our findings suggest that adiposity is a key determinant of adverse cardiometabolic risk factors in children, while serum 25(OH)D may be associated with overall cardiometabolic health. Interventions to reduce obesity are needed to mitigate the deleterious consequences of cardiometabolic dysregulation in children.

The Impact of Metabolic Syndrome on Post-Operative Outcomes in Abdominal Body Contouring: A Propensity Score-Matched Nationwide Analysis

Abstract Goals/Purpose Metabolic syndrome (MetS) represents cardiometabolic dysregulation, defined by hypertension, obesity, diabetes, and dyslipidemia. Its prevalence is on the rise, affecting approximately 47.3% of U.S. adults. In recent years, MetS has been associated with an elevated risk of postoperative complications. However, there remains a significant gap in our understanding of how patients with MetS fare after abdominal body contouring procedures. The objective of this study is to assess the influence of MetS on postoperative outcomes of abdominal body contouring by concurrent abdominoplasty and panniculectomy. Methods/Technique The ACS-NSQIP database was utilized to identify patients who underwent concurrent abdominoplasty and panniculectomy procedures from 2015 to 2021. Through propensity score matching, distinct cohorts were established based on the presence of MetS, characterized by patients receiving medical interventions for diabetes mellitus and hypertension, with a body mass index exceeding 30kg/m2. Disparities among groups were assessed via unpaired T-tests and Fisher's Exact tests. Logistic regression models were constructed to evaluate the occurrence of mild and severe systemic complications, reoperation rates, and wound complications between these groups. Results/Complications A total of 13,346 patients underwent abdominal body contouring. Following propensity score matching, 586 patients were included in the analysis, with 293 in each group (MetS vs. non-MetS). Bivariate analysis revealed a longer hospital length of stay (2.4 vs. 1.7 days; p=0.002) and higher readmission rates (11.9 vs. 6.5; p=0.031) in the MetS group in comparison to the non-MetS cohort. While surgical-related reasons for readmission were predominant across both groups, statistically significant differences were observed only for medical-related reasons (p=0.028). Logistic regression models demonstrated a statistically significant elevated likelihood of 30-day readmission in the MetS group (OR 1.96; 95% CI 1.091-3.507; p=0.024). No noteworthy disparities were observed in the rates of 30-day wound complications, mild systemic, and severe systemic complications between the groups. Conclusion Our findings revealed no increase in postoperative wound and systemic complications among patients with MetS who underwent concurrent abdominoplasty and panniculectomy. This suggests that abdominal body contouring remains a secure option for patients with MetS. Nonetheless, the higher readmission rates and longer hospital length stays observed in patients with MetS may potentially translate to increased overall costs. Continued research is warranted to comprehensively assess the economic implications of MetS in the context of abdominal body contouring.

Association of clinical symptoms and cardiometabolic dysregulations in patients with schizophrenia spectrum disorders.

Patients with schizophrenia spectrum disorders (SSD) have a shortened life expectancy related to cardiovascular diseases. We investigated the association of cognitive, positive, and negative symptoms with cardiometabolic dysregulations in SSD patients. Overall, 1,119 patients from the Genetic Risk and Outcome in Psychosis (GROUP) study were included. Cognitive function, positive and negative symptoms were assessed at baseline, 3-year, and 6-year. Cardiometabolic biomarkers were measured at 3-year follow-up. We used linear and multinomial logistic regression models to test the association between cardiometabolic biomarkers and clinical trajectories and performed mediation analyzes, while adjusting for clinical and demographic confounders. Cognitive performance was inversely associated with increased body mass index (mean difference [β], βhigh=-1.24, 95% CI=-2.28 to 0.20, P=0.02) and systolic blood pressure (βmild=2.74, 95% CI=0.11 to 5.37, P=0.04). The severity of positive symptoms was associated with increased glycated hemoglobin (HbA1c) levels (βlow=-2.01, 95% CI=-3.21 to -0.82, P=0.001). Increased diastolic blood pressure (ORhigh-decreased=1.04, 95% CI=1.01 to 1.08, P=0.02; ORhigh-increased=1.04, 95% CI=1.00 to 1.08, P=0.048) and decreased high-density lipoprotein (OR high-increased=6.25, 95% CI=1.81 to 21.59, P=0.004) were associated with more severe negative symptoms. Increased HbA1c (ORmoderate=1.05, 95% CI=1.01 to 1.10, P=0.024; ORhigh=1.08, 95% CI=1.02 to 1.14, P=0.006) was associated with more severe positive symptoms. These associations were not mediated by antipsychotics. We showed an association between cardiometabolic dysregulations and clinical and cognitive symptoms in SSD patients. The observed associations underscore the need for early identification of patients at risk of cardiometabolic outcomes.

Unveiling the Therapeutic Potential of SGLT2 inhibitors and Oral Ketone Ester in Heart Failure with Preserved Ejection Fraction: A Comprehensive Exploration of Cardiac Function, Structure, and Metabolism in a Rat Model

BackgroundThis study investigated the potential efficacy of SGLT2 inhibitors empagliflozin and oral ketone supplementation as treatments for heart failure with preserved ejection fraction (HFpEF), which is often associated with obesity and type 2 diabetes mellitus. Methods20-week-old obese ZSF-1 rats were given different treatments for 12 weeks, including vehicle, empagliflozin, ketone ester (KE), or a combination of empagliflozin and KE. Cardiac magnetic resonance imaging (CMR) and hyperpolarized carbon-13 (13C) labeled pyruvate magnetic resonance spectroscopy imaging were used to evaluate cardiac function and metabolism, while histological and molecular markers of cardiac remodeling were assessed in the left ventricle. ResultsThe untreated HFpEF rats exhibited obesity, diabetes, cardiac hypertrophy, atrial enlargement, lung congestion, and increased cardiomyocyte size and cardiac expression of atrial natriuretic peptide (ANP) and fibrosis marker col1a1 and TIMP1. The treatment groups exhibited decreased body weight, increased circulating ketone levels, and reduced blood glucose levels. All treatment regimens significantly attenuated ventricular hypertrophy, atrial enlargement, and lung congestion. Furthermore, all treatments significantly reduced cardiomyocyte size and the expression of ANP and fibrosis marker. The combination of empagliflozin and KE showed the greatest improvement in diastolic function and cardiac ATP levels. Interestingly, hyperpolarized [1-13C] pyruvate detected a decrease in lactate/pyruvate ratio in the hearts treated with empagliflozin. ConclusionObese ZSF1 rats exhibit features of clinical HFpEF with predominant background of obesity and diabetes. A combination of empagliflozin and KE has greater benefits in treating HFpEF. Targeting cardiometabolic dysregulation may be a promising approach for HFpEF treatment.

Metabolic syndrome after childhood trauma: a 9-year longitudinal analysis.

Childhood trauma (CT) has been cross-sectionally associated with metabolic syndrome (MetS), a group of biological risk factors for cardiometabolic disease. Longitudinal studies, while rare, would clarify the development of cardiometabolic dysregulations over time. Therefore, we longitudinally investigated the association of CT with the 9-year course of MetS components. Participants (N = 2958) from the Netherlands Study of Depression and Anxiety were assessed four times across 9 years. The CT interview retrospectively assessed childhood emotional neglect and physical, emotional, and sexual abuse. Metabolic outcomes encompassed continuous MetS components (waist circumference, triglycerides, high-density lipoprotein [HDL] cholesterol, blood pressure [BP], and glucose) and count of clinically elevated MetS components. Mixed-effects models estimated sociodemographic- and lifestyle-adjusted longitudinal associations of CT with metabolic outcomes over time. Time interactions evaluated change in these associations. CT was reported by 49% of participants. CT was consistently associated with increased waist (b = 0.32, s.e. = 0.10, p = 0.001), glucose (b = 0.02, s.e. = 0.01, p < 0.001), and count of MetS components (b = 0.04, s.e. = 0.01, p < 0.001); and decreased HDL cholesterol (b = -0.01, s.e.<0.01, p = .020) and systolic BP (b = -0.33, s.e. = 0.13, p = 0.010). These associations were mainly driven by severe CT and unaffected by lifestyle. Only systolic BP showed a CT-by-time interaction, where CT was associated with lower systolic BP initially and with higher systolic BP at the last follow-up. Over time, adults with CT have overall persistent poorer metabolic outcomes than their non-maltreated peers. Individuals with CT have an increased risk for cardiometabolic disease and may benefit from monitoring and early interventions targeting metabolism.

Abstract 13962: Exploring the Therapeutic Potential of SGLT2 Inhibitors and Oral Ketone Ester in HFpEF: A Comprehensive Exploration of Cardiac Function, Structure, and Metabolism in a Rat Model

Introduction: This study aimed to assess the potential efficacy of the SGLT2 inhibitor empagliflozin and oral ketone ester supplementation as treatments for heart failure with preserved ejection fraction (HFpEF), which is commonly associated with obesity and type 2 diabetes mellitus. Methods: Twenty-week-old obese ZSF-1 rats were initially fed a high-fat diet (HFD) to establish and maintain the phenotype. Subsequently, the rats were randomly assigned to different treatment groups. These groups consisted of a control group receiving only the high-fat diet (HFD), as well as groups receiving empagliflozin, ketone ester (DeltaG®, KE), or a combination of both in addition to the HFD. Cardiac magnetic resonance imaging (CMR) and hyperpolarized carbon-13 (13C) labeled pyruvate magnetic resonance spectroscopy imaging were used to evaluate cardiac function and metabolism. Histological and molecular markers of cardiac remodeling were assessed in the left ventricle. Results: Untreated HFpEF rats exhibited obesity, diabetes, cardiac hypertrophy, atrial enlargement, lung congestion, increased cardiomyocyte size and fibrosis, as well as elevated expression of atrial natriuretic peptide (ANP), col1a1 (fibrosis marker), and TIMP1. The treatment groups displayed decreased body weight, increased circulating ketone levels, and reduced blood glucose levels. All treatment regimens significantly mitigated ventricular hypertrophy, atrial enlargement, and lung congestion. Furthermore, they reduced cardiomyocyte size, ANP expression, fibrosis marker expression, and increased cardiac ATP levels. CMR revealed that the combination of empagliflozin and KE resulted in improvement in diastolic function. Hyperpolarized [1-13C] pyruvate imaging revealed a decrease in lactate/pyruvate ratio in empagliflozin-treated hearts, indicating improved oxidative metabolism. Conclusions: The findings of this study suggest that targeting cardiometabolic dysregulation holds promise as an effective approach for the treatment of HFpEF. While both empagliflozin or KE alone demonstrated improvements in cardiac energetics and remodeling, the combination of empagliflozin and KE yielded the most notable benefits in enhancing cardiac diastolic function.

Abstract 15000: Renal Denervation Improves Cardiac Function and Mitigates Pathophysiological Changes in a Novel Murine Model of Heart Failure With Preserved Ejection Fraction

Introduction: Heart Failure with Preserved Ejection Fraction (HFpEF) is a multifaceted disease, intricately linked with sympathetic nervous system activation. Despite advancements, therapeutic options for HFpEF remain constrained, largely due to a dearth of fitting preclinical models. Renal denervation (RDN), an emerging intervention, holds potential in attenuating sympathetic activity and ameliorating HFpEF high-risk factors such as hypertension and insulin resistance. Aims: our study is designed to establish a multifactorial HFpEF mouse model and assess the therapeutic implications of RDN. Methods: Aged 12-month-old male C57BL/6N mice were exposed to a high-fat diet (60% calories from lard) and L-NAME (0.5 g/L in drinking water) over a 5-week period to generate a multi-hit HFpEF model. The efficacy of the model was assessed through a range of methods, encompassing echocardiography, histology, exercise exhaustion tests, serum NT-proBNP measurements, and intraperitoneal glucose tolerance tests. Upon successful model establishment, mice were randomized to receive either bilateral renal denervation or a sham operation. The subsequent impact of RDN on the aforementioned parameters was then evaluated. Results: In C57BL/6N mice, a cardiometabolic HFpEF phenotype was effectively induced through a multi-hit approach encompassing a high-fat diet, L-NAME administration, and aging. This potent combination triggered obesity and glucose intolerance, culminating in the emergence of characteristic HFpEF features such as cardiac hypertrophy, fibrosis, preserved fractional shortening with impaired deformation, atrial enlargement, lung congestion, hypertension and decreased exercise endurance. Intervention with RDN mitigated this cardiometabolic dysregulation and enhanced cardiac function, as demonstrated by reductions in cardiac hypertrophy, myocardial fibrosis, atrial weight, NT-proBNP levels, lung congestion, and improved exercise endurance. Conclusions: Our study suggests that RDN effectively mitigates cardiac function and structure in a multi-hit HFpEF mouse model, indicating its potential as a promising therapeutic strategy for HFpEF.

Guideline adherence for cardiometabolic monitoring of patients prescribed antipsychotic medications in primary care: a retrospective observational study

BackgroundDespite their known effectiveness, antipsychotics possess significant cardiometabolic adverse event profiles. Guidelines emphasise routine monitoring, however, practices are known to be suboptimal.AimTo investigate the level of cardiometabolic monitoring among people prescribed antipsychotic therapy in primary care, and patient-related factors that may influence monitoring patterns.MethodData were collected for patients with mental disorders and prescribed antipsychotics at two general practices in England (February 2016–February 2021). The main outcome measures were the proportion of patients with evidence of monitoring for cardiometabolic parameters (body composition, anthropometrics, lipids, glucose outcomes). Regression analysis was used to explore factors predicting monitoring practices.ResultsData from 497 patients were included. The proportion of patients receiving cardiometabolic monitoring at least once yearly varied across different parameters. Patients were mostly monitored for BP (92.0%), body weight (BMI > 85.0%) and HDL (72.0%), but to a lesser extent for other lipid parameters (non-HDL < 2.0%) and blood glucose (< 2.0%). Ageing (OR:2.0–7.0, p < 0.001) and chronic conditions (e.g., CVD and Type 2 DM, p < 0.05) were associated with frequent cardiometabolic monitoring. Conversely, antipsychotics with high metabolic risks (olanzapine), patients prescribed antipsychotic polypharmacy (≥ 2 antipsychotics) and cardiometabolic dysregulations (e.g., dyslipidaemias) did not improve monitoring frequencies.ConclusionCardiometabolic health monitoring was generally infrequent, irregular, and did not change in response to abnormal test results or antipsychotic treatment with high cardiometabolic risks, suggesting more efforts need to be made to ensure the guidelines for cardiometabolic monitoring are followed. Future studies should investigate practices by using a large UK primary care database.

Dapagliflozin Attenuates Heart Failure With Preserved Ejection Fraction Remodeling and Dysfunction by Elevating β-Hydroxybutyrate-activated Citrate Synthase.

Heart failure with preserved ejection fraction (HFpEF) is highly prevalent, accounting for 50% of all heart failure patients, and is associated with significant mortality. Sodium-glucose cotransporter subtype inhibitor (SGLT2i) is recommended in the AHA and ESC guidelines for the treatment of HFpEF, but the mechanism of SGLT2i to prevent and treat cardiac remodeling and dysfunction is currently unknown, hindering the understanding of the pathophysiology of HFpEF and the development of novel therapeutics. HFpEF model was induced by a high-fat diet (60% calories from lard) + N [w] -nitro- l -arginine methyl ester ( l -NAME-0.5 g/L) (2 Hit) in male Sprague Dawley rats to effectively recapture the myriad phenotype of HFpEF. This study's results showed that administration of dapagliflozin (DAPA, SGLT2 inhibitor) significantly limited the 2-Hit-induced cardiomyocyte hypertrophy, apoptosis, inflammation, oxidative stress, and fibrosis. It also improved cardiac diastolic and systolic dysfunction in a late-stage progression of HFpEF. Mechanistically, DAPA influences energy metabolism associated with fatty acid intake and mitochondrial dysfunction in HFpEF by increasing β-hydroxybutyric acid (β-OHB) levels, directing the activation of citrate synthase, reducing acetyl coenzyme A (acetyl-CoA) pools, modulating adenosine 5'-triphosphate production, and increasing the expression of mitochondrial oxidative phosphorylation system complexes I-V. In addition, following clinical DAPA therapy, the blood levels of β-OHB and citrate synthase increased and the levels of acetyl-CoA in the blood of HFpEF patients decreased. SGLT2i plays a beneficial role in the prevention and treatment of cardiac remodeling and dysfunction in HFpEF model by attenuating cardiometabolic dysregulation.

Shorter telomere length predicts poor antidepressant response and poorer cardiometabolic indices in major depression

Telomere length (TL) is a marker of biological aging, and shorter telomeres have been associated with several medical and psychiatric disorders, including cardiometabolic dysregulation and Major Depressive Disorder (MDD). In addition, studies have shown shorter TL to be associated with poorer response to certain psychotropic medications, and our previous work suggested shorter TL and higher telomerase activity (TA) predicts poorer response to Selective Serotonin Reuptake Inhibitor (SSRI) treatment. Using a new group of unmedicated medically healthy individuals with MDD (n = 48), we sought to replicate our prior findings demonstrating that peripheral blood mononuclear cell (PBMC) TL and TA predict response to SSRI treatment and to identify associations between TL and TA with biological stress mediators and cardiometabolic risk indices. Our results demonstrate that longer pre-treatment TL was associated with better response to SSRI treatment (β = .407 p = .007). Additionally, we observed that TL had a negative relationship with allostatic load (β = − .320 p = .017) and a cardiometabolic risk score (β = − .300 p = .025). Our results suggest that PBMC TL reflects, in part, the cumulative effects of physiological stress and cardiovascular risk in MDD and may be a biomarker for predicting SSRI response.

Weight Gain and Metabolic Changes in Patients With First-Episode Psychosis or Early-Phase Schizophrenia Treated With Olanzapine: A Meta-Analysis.

Patients with first-episode psychosis or early-phase schizophrenia are susceptible to olanzapine-associated weight gain and cardiometabolic dysregulation. This meta-analysis characterized weight and metabolic effects observed during olanzapine treatment in randomized clinical trials in this vulnerable patient population. PubMed, EMBASE, and Dialog were searched for randomized controlled trials (RCTs) reporting weight or cardiometabolic outcomes associated with olanzapine treatment in first-episode psychosis or early-phase schizophrenia. Random-effects meta-analysis and meta-regression were conducted using R v4.0.5. Of 1203 records identified, 26 RCTs informed the analyses. The meta-analytic mean (95% CI) weight gain was 7.53 (6.42-8.63) kg in studies (n = 19) that reported weight gain with olanzapine treatment. Stratified by duration, the mean (95% CI) weight gain was significantly higher in studies >13 weeks in duration than in those lasting ≤13 weeks: 11.35 (10.05-12.65) vs 5.51 (4.73-6.28) kg, respectively. Despite between-study variability, increases from baseline in most glycemic and lipid parameters were generally small in studies of both ≤13 and >13 weeks. There were no correlations, however, between weight gain and metabolic parameter changes when stratified by study duration. In RCTs enrolling patients with first-episode psychosis or early-phase schizophrenia, olanzapine was consistently associated with weight gain that was greater in studies lasting >13 weeks compared with those of ≤13 weeks. Metabolic changes observed across studies suggest that RCTs may underestimate metabolic sequelae vs real-world treatment observations. Patients with first-episode psychosis or early-phase schizophrenia are vulnerable to olanzapine-associated weight gain; strategies minimizing olanzapine-associated weight gain should be carefully considered.

Central androgen action reverses hypothalamic astrogliosis and atherogenic risk factors induced by orchiectomy and high-fat diet feeding in male mice.

Hypogonadism in males confers elevated cardiovascular disease (CVD) risk by unknown mechanisms. Recent radiological evidence suggests that low testosterone (T) is associated with mediobasal hypothalamic (MBH) gliosis, a central nervous system (CNS) cellular response linked to metabolic dysfunction. To address mechanisms linking CNS androgen action to CVD risk, we generated a hypogonadal, hyperlipidemic mouse model with orchiectomy (ORX) combined with hepatic PCSK9 overexpression. After 4 wk of high-fat, high-sucrose diet (HFHS) consumption, despite equal body weights and glucose tolerance, androgen-deficient ORX mice had a more atherogenic lipid profile and increased liver and leukocyte inflammatory signaling compared with sham-operated control mice. Along with these early CVD risk indicators, ORX markedly amplified HFHS-induced astrogliosis in the MBH. Transcriptomic analysis further revealed that ORX and high-fat diet feeding induced upregulation of inflammatory pathways and downregulation of metabolic pathways in hypothalamic astrocytes. To interrogate the role of sex steroid signaling in the CNS in cardiometabolic risk and MBH inflammation, central infusion of T and dihydrotestosterone (DHT) was performed on ORX mice. Central DHT prevented MBH astrogliosis and reduced the liver inflammatory signaling and monocytosis induced by HFHS and ORX; T had a partial protective effect. Finally, a cross-sectional study in 41 adult men demonstrated a positive correlation between radiological evidence of MBH gliosis and plasma lipids. These findings demonstrate that T deficiency in combination with a Western-style diet promotes hypothalamic gliosis concomitant with increased atherogenic risk factors and provide supportive evidence for regulation of lipid metabolism and cardiometabolic risk determinants by the CNS action of sex steroids.NEW & NOTEWORTHY This study provides evidence that hypothalamic gliosis is a key early event through which androgen deficiency in combination with a Western-style diet might lead to cardiometabolic dysregulation in males. Furthermore, this work provides the first evidence in humans of a positive association between hypothalamic gliosis and LDL-cholesterol, advancing our knowledge of CNS influences on CVD risk progression.

Design of the Think PHRESH longitudinal cohort study: Neighborhood disadvantage, cognitive aging, and Alzheimer’s disease risk in disinvested, Black neighborhoods

BackgroundBlack Americans have disproportionately higher rates and earlier onset of Alzheimer’s disease and related dementias (ADRD) relative to White Americans. We currently lack a comprehensive understanding of how the lived experience and broader societal factors, including cumulative exposure to structural racism and the mechanisms underlying the risks, may contribute to elevated ADRD risk in Black Americans.MethodsThe Think PHRESH study builds on existing, community-based research infrastructure, from the ongoing Pittsburgh Hill/Homewood Research on Neighborhood Change and Health (PHRESH) studies, to examine the contributions of dynamic neighborhood socioeconomic conditions across the lifecourse to cognitive outcomes in mid- and late-life adults living in two historically disinvested, predominantly Black communities (anticipated n = 1133). This longitudinal, mixed-methods study rests on the premise that neighborhood racial segregation and subsequent disinvestment contributes to poor cognitive outcomes via factors including (a) low access to educational opportunities and (b) high exposure to race- and socioeconomically-relevant stressors, such as discrimination, trauma, and adverse childhood events. In turn, these cumulative exposures foster psychological vigilance in residents, leading to cardiometabolic dysregulation and sleep disruption, which may mediate associations between neighborhood disadvantage and ADRD risk. This premise recognizes the importance of potential protective factors that may promote cognitive health, including neighborhood social cohesion, safety, and satisfaction. The proposed study will leverage our existing longitudinal data on risk/protective factors and biobehavioral mediators and will include: (1) up to three waves of cognitive assessments in participants ages 50 years + and one assessment in participants ages 35–49 years; clinical adjudication of ADRD will be completed in participants who are 50+, (2) extensive surveys of risk and protective factors, (3) two assessments of blood pressure and objectively measured sleep, (4) a comprehensive assessment of life and residential history; and (5) two rounds of in-depth qualitative interviews to reveal lifecourse opportunities and barriers experienced by Black Americans in achieving optimal cognitive health in late life.DiscussionUnderstanding how structural racism has influenced the lived experience of Black Americans, including dynamic changes in neighborhood conditions over time, is critical to inform multi-level intervention and policy efforts to reduce pervasive racial and socioeconomic disparities in ADRD.

Hypertensive disorders of pregnancy share common cfDNA methylation profiles

Hypertensive disorders of pregnancy (HDP) contribute substantially to perinatal morbidity and mortality. Epigenetic changes point towards cardio-metabolic dysregulation for these vascular disorders. In early pregnancy, epigenetic changes using cell free DNA (cfDNA) are largely unexplored. We aimed to investigate these in HDP between 11 and 14 weeks of gestation by analysis of cfDNA methylation profiles in patients with hypertensive disorders. We identified patients without chronic hypertension but with subsequent development of preeclampsia (PE) (n = 11), with chronic hypertension (HT) but without PE development (n = 14), and lacking both PE and HT (n = 422). We matched patients according to PE risk factors into three groups (n = 5 each group): (1) PE: no HT but PE development, (2) HT: chronic hypertension but no PE and (3) Control: no PE or HT. We successfully optimized our cfDNA isolation process prior to whole genome bisulfite sequencing. Analysis of cfDNA methylation changes indicate a common predisposition in PE and HT groups, chiefly of maternal origin. Assessment of significant differentially methylated regions and annotated genes point towards a common cardiovascular predisposition in preeclampsia and hypertension groups in the first trimester. We postulate the pivotal role of the maternal cardiovascular system in HDP, which is already evident in the first trimester.

Cardiometabolic dysregulation and cognitive decline: potential role of depressive symptoms

Abstract Background Previous studies have examined associations of cardiometabolic factors with depression and cognition separately. Aims To determine if depressive symptoms mediate the association between cardiometabolic factors and cognitive decline in two community studies. Methods Data for the analyses were drawn from the Rotterdam Study, the Netherlands (n = 2940), the Whitehall II study, UK (n = 4469) and the Canadian Longitudinal Study on Aging, Canada (n = 13,720). Results Mediation analyses suggested a direct association between cardiometabolic factors and cognitive decline and an indirect association through depression: poorer cardiometabolic status at time 1 was associated with a higher level of depressive symptoms at time 2 (standardised regression coefficient 0.07 and 0.06, respectively), which, in turn, was associated with greater cognitive decline between time 2 and time 3 (standardised regression coefficient of -0.15 and -0.41, respectively). Conclusions Evidence from three independent cohort studies suggest an association between cardiometabolic dysregulation and cognitive decline and that depressive symptoms tend to precede this decline. Key messages • Cardiometabolic dysregulation and depression might increase cognitive decline. • The association between cardiometabolic dysregulation and cognitive decline might be mediated by depression.

Association of BMI trajectories with cardiometabolic risk among low-income Mexican American children.

BackgroundThe aim of this study was to identify distinct trajectories of BMI growth from 2 to 7.5 years and examine their associations with markers of cardiometabolic risk at age 7.5 years among a sample of low-income Mexican American children.MethodsThis longitudinal cohort study recruited 322 mother–child dyads to participate prenatally and at child age 2, 3, 4.5, 6, and 7.5 years. Child height/weight, waist circumference, and blood pressure were assessed at each time point. Blood was collected from child at 7.5 years.ResultsCovarying for birthweight, three BMI trajectories were identified: Low-Stable BMI (73% of the sample), High-Stable BMI (5.6% of the sample), and Increasing BMI over time (21.4% of the sample). The High-Stable and Increasing BMI classes had higher waist circumference and systolic blood pressure and lower HDL-c than the Low-Stable BMI class (ps < 0.05). Among children with BMIs below the 85th percentile, 16% had three or more cardiometabolic risk indicators.ConclusionsBMI classes were consistent with existing literature. For youth, standard medical practice is to examine cardiometabolic risk indicators when BMI is high; however, this practice would miss 16% of youth in our sample who exhibit cardiometabolic risk but do not screen in based on BMI.Impact Research indicates Mexican American youth are at risk for cardiometabolic dysregulation relative to other ethnic groups, yet there is a paucity of longitudinal research.An Increasing BMI and a High-Stable BMI class were associated with larger waist circumference, higher systolic blood pressure, and lower HDL cholesterol than the Low-Stable BMI class.BMI trajectories in childhood predict cardiometabolic risk indicators. As the sole screener for deciding when to test cardiometabolic indicators, BMI alone will miss some children exhibiting cardiometabolic dysregulation.

Status and transition of normal-weight central obesity and the risk of cardiovascular diseases: A population-based cohort study in China

Background and aimsCardiovascular disease (CVD) has become a growing public health concern. Normal weight central obesity (NWCO) has emerged as a potential risk factor for cardiometabolic dysregulation. To date, the association between NWCO and new-onset CVDs remains unclear. We aimed to evaluate the associations of NWCO and its longitudinal transitions with cardiovascular risks in middle-aged and older Chinese. Methods and resultsData were from the China Health and Retirement Longitudinal Study 2011–2018. NWCO was defined as the combination of a body mass index (BMI) of <24.0 kg/m2 and a waist circumference (WC) of >85 cm in males or >80 cm in females. CVDs included heart diseases and stroke. Cause-specific hazard models and subdistribution hazard models with all-cause death as the competing event were applied. In 2011, 9856 participants without prior CVDs were included, of whom 1814 developed CVDs during a 7-year follow-up. Compared to normal weight and non-central obesity (NWNCO), NWCO was significantly associated with new-onset CVDs, with cause-specific hazard ratios (cHRs) and 95% confidence intervals (CIs) of 1.21 (1.04–1.41) for heart diseases and 1.40 (1.11–1.76) for stroke. From 2011 to 2013, 571 NWNCO participants developed NWCO who subsequently demonstrated a 45% higher risk of CVDs than those with maintained NWNCO. ConclusionNWCO and transition from NWNCO to NWCO are associated with higher risks of CVDs. Identification and prevention of NWCO may be useful in the management of CVDs.

Cardiometabolic risk, biomarkers of low-grade subclinical inflammation and flavonoid intake: A cross-sectional study in Argentina

BackgroundFlavonoids, the most abundant polyphenols present in the diet, may help to reduce the risk of cardiometabolic disease. Hence, the aim of this study was to know the potential associations between flavonoid source food intake, markers of low-grade inflammation and cardiometabolic risk status. Methods194 adult subjects attending at the Cardiology Division, Hospital Nacional de Clínicas, Córdoba, Argentina participated in the study. A validated food-frequency questionnaire was applied to establish the flavonoid source food intake. Clinical-pathological and anthropometric variables [height, weight, and waist circumference, and serum concentrations of high-sensitive C-reactive protein (hs-CRP) and cytokines (INF-γ, TNFα, IL-6, IL-8, IL-10, IL-18, IL-23) were measured. A cardiometabolic risk clustering score was constructed and correlation’s coefficients and multiple linear regression models were used to assess the relation between flavonoid source foods consumption of and markers of low-grade inflammation. Results40.4% of the subjects were obese and 60.3% showed a very high risk of developing cardiovascular diseases according to the WC classification. 43.3% had a high risk of cardiometabolic dysregulation and the hs-CRP levels indicated a high risk of developing cardiovascular disease in the future both in men and women. The predominant intake of flavonoids was from source food of flavanones, flavones and flavonols. Negative associations between isoflavone source food intake and TNFα, IL-6 and IL-8 concentrations (P ≤ 0.05) were observed. ConclusionsThe results of the present study provide evidence of the inverse association between isoflavone source foods intake and inflammation. Further studies are needed to confirm retrieved association.