High Cardiometabolic Risk Research Articles

Early and accurate diagnosis of steatotic liver by artificial intelligence (AI)-supported ultrasonography

ObjectivesSteatotic liver disease is the most frequent chronic liver disease worldwide. Ultrasonography (US) is commonly employed for the assessment and diagnosis. Few information is available on the possible use of artificial intelligence (AI) to ameliorate the diagnostic accuracy of ultrasonography. Materials and methodsAn AI-based algorithm was developed using a dataset of US images. We prospectively enrolled 134 patients for algorithm validation. Patients underwent abdominal US and Proton Density Fat Fraction MRI scans (MRI-PDFF), assumed as reference technique. The hepatorenal index was manually calculated (HRIM) by 4 operators. An automatic hepatorenal index (HRIA) was obtained by the algorithm. The accuracy of HRIA to discriminate steatosis grades was evaluated by ROC analysis using MRI-PDFF cut-offs. ResultsOverweight was 40 % of subjects (BMI 26.4 kg/cm2). The median HRIA was 1.11 (IQR 0.32) and the average of 4 manually calculated HRIM was 1.08 (IQR 0.26), with a 15 % inter-operator variability. Both HRIA (R = 0.79, P < 0.0001) and HRIM (R = 0.69, P < 0.0001) significantly correlated with liver fat percentage (MRI-PDFF). According to MRI-PDFF, 32 % of enrolled subjects had steatosis. Discrimination capacity by AUC between patient with steatosis and patient without steatosis was better for HRIA than HRIM (AUC: 0.87 vs. 0.82, respectively). ROC analysis showed an AUC = 0.98 for HRIA with 1.64 cut-off in distinguishing between mild and moderate/severe groups. ConclusionsThe use of AI improves accuracy and speed of ultrasonography in the diagnosis of liver steatosis. Further studies should evaluate the routine use of this technique in the management of liver steatosis at high cardio-metabolic risk.

Screening and diagnosis of primary aldosteronism. Consensus document of all the Spanish Societies involved in the management of primary aldosteronism.

Primary aldosteronism (PA) is the most frequent cause of secondary hypertension (HT), and is associated with a higher cardiometabolic risk than essential HT. However, PA remains underdiagnosed, probably due to several difficulties clinicians usually find in performing its diagnosis and subtype classification. The aim of this consensus is to provide practical recommendations focused on the prevalence and the diagnosis of PA and the clinical implications of aldosterone excess, from a multidisciplinary perspective, in a nominal group consensus approach by experts from the Spanish Society of Endocrinology and Nutrition (SEEN), Spanish Society of Cardiology (SEC), Spanish Society of Nephrology (SEN), Spanish Society of Internal Medicine (SEMI), Spanish Radiology Society (SERAM), Spanish Society of Vascular and Interventional Radiology (SERVEI), Spanish Society of Laboratory Medicine (SEQC(ML)), Spanish Society of Anatomic-Pathology, Spanish Association of Surgeons (AEC).

Associations of overweight and obesity with cardiometabolic risk factor clusters among Korean adolescents

This study investigated the association between overweight, obesity, and cardiometabolic risk factor clusters in Korean adolescents. We included 2182 participants (1161 boys and 1021 girls) aged 12–18 years from the Korea National Health and Nutrition Examination Survey (2016–2021). Cardiometabolic risk factors include hypertension, high low-density lipoprotein cholesterol (LDL-C) level, low high-density lipoprotein cholesterol (HDL-C) level, hypertriglyceridemia, high fasting plasma glucose level, elevated alanine aminotransferase level, and hyperuricemia. The average age was 15.1 ± 0.1 years in both boys and girls. The proportion of subjects with ≥ 1, ≥ 2, and ≥ 3 cardiometabolic risk factors was 76.5%, 49.8%, and 22.7% in obese adolescents, and 60.5%, 24.0%, and 9.1%, in overweight adolescents, respectively. Compared to adolescents with underweight/normal weight, the odds ratios (ORs) and 95% confidence intervals for the clustering of cardiometabolic risk factors were at 2.76 (1.74–4.38) for ≥ 1; 3.75 (2.11–6.66) for ≥ 2; and 4.75 (1.70–13.25) for ≥ 3 factors in obese adolescents and 1.88 (1.26–2.81) for ≥ 1 factor in overweight adolescents. Overweight and obese adolescents exhibited high cardiometabolic risk clustering. Prevention and management of overweight/obesity in Korean adolescents are emerging to mitigate health risk associated with this condition.

Effects on cardiovascular risk factors of a low- vs high-glycemic index Mediterranean diet in high cardiometabolic risk individuals: the MEDGI-Carb study.

The role of dietary Glycemic Index (GI), independently of fiber intake, in modulating cardiovascular disease (CVD) risk among non-diabetic individuals has not been fully elucidated. To evaluate the effects of a low- versus a high-GI diet, based on a Mediterranean dietary pattern, on cardiometabolic risk factors in individuals at high CVD risk, participating in the MEDGI-Carb intervention study. 160 individuals, aged 30-69 years, BMI 25-37 kg/m2, with a waist circumference >102 cm (males) or >88 cm (females) and one feature of the metabolic syndrome, participated in a multi-national (Italy, Sweden, USA) randomized controlled parallel group trial. Participants were assigned to a low GI (< 55) or high-GI MedDiet ( > 70) for 12 weeks. The diets were isoenergetic and similar for available carbohydrate (270 g/d) and fiber (35 g/d) content. Fasting metabolic parameters were evaluated in the whole cohort, while an 8-h triglyceride profile (after standard breakfast and lunch) was evaluated only in the Italian cohort. Blood pressure and most fasting metabolic parameters improved at the end of the dietary intervention (time effect, p < 0.05 for all); however, no differences were observed between the low- and the high-GI MedDiet groups (time x group effect; p > 0.05 for all). Conversely, the low-GI diet, compared with high-GI diet, significantly reduced the 8-h triglyceride profile (p < 0.017, time*group effect) that was measured only in the Italian cohort. However, it induced a reduction of plasma triglycerides after lunch (tAUC) that was of only borderline statistically significance (p = 0.065). Consuming a low-GI in comparison with a high-GI MedDiet does not differentially affect the major cardiometabolic risk factors at fasting in individuals at increased cardiometabolic risk. Conversely, it could reduce postprandial plasma triglycerides. NCT03410719, ( https://clinicaltrials.gov ).

The potential of DNA methylation markers in the study of obesity

Obesity is a complex, heterogeneous, actively progressive disease manifested by excessive formation of adipose tissue in the body and usually has a high cardiometabolic risk and specific complications. Currently, new data are emerging that explain the pathogenesis of obesity not only by genetic variations and imbalance between energy intake and expenditure, but also by the influence of epigenetic mechanisms, such as DNA methylation. DNA methylation is the most studied epigenetic modification, whose status in the cell can be altered by various external and internal environmental factors, including diet, lifestyle, and hormones. These changes may lead to dysregulation of genes responsible for metabolic processes associated with the development of obesity. However, studies investigating epigenetic marks as potential mediators of obesity are heterogeneous in design, methodology, and results. This review discusses a conceptual framework analyzing the relationship between DNA methylation, obesity, inflammation, and response to weight loss, including after bariatric surgery, as well as material selection and methodology issues to consider when designing studies in this area.

Association of Fat Mass and Skeletal Muscle Mass with Cardiometabolic Risk Varied in Distinct PCOS Subtypes: A Propensity Score-Matched Case-Control Study.

(1) Background: polycystic ovarian syndrome (PCOS) is a heterogeneous syndrome with a constellation of cardiometabolic risk factors. We aimed to investigate if the association of body fat mass (BFM) and skeletal muscle mass (SMM) with cardiometabolic risk differed in PCOS subtypes. (2) Methods: 401 participants (245 PCOS and 156 controls) were assessed for anthropometric measurements, glucose-lipid profiles, reproductive hormones and body composition with propensity score-matched (PSM) analysis. The association of the cardiometabolic risk score (z score, calculated based on levels of obesity and gluco-lipid measurements) with BFM (estimated by trunk BFM/Height2) and SMM (estimated by SMM/Height2) was calculated. (3) Results: Trunk BFM/Height2 and SMM/Height2 were both positively associated with cardiometabolic risk in PCOS (trunk BFM/Height2, OR 2.33, 95% CI 1.49-3.65; SMM/Height2, OR 2.05, 95% CI 1.12-3.76). SMM/Height2 associated with increased cardiometabolic risk in obese PCOS (BMI ≥ 28 kg/m2, OR 2.27, 95% CI 1.15-4.47). For those with lower BMI (<28 kg/m2), trunk BFM/Height2 showed a higher OR in both groups (PCOS, OR 2.12, 95% CI 1.06-4.24; control 2.04, 95% CI 1.04-4.02). Moreover, distinct associations among BMI-stratified groups were validated in hierarchical clustering identifying metabolic and reproductive clusters. (4) Conclusions: BFM and SMM are synergistically associated with higher cardiometabolic risk in PCOS women. Although BFM contributes to increased cardiometabolic risk, SMM also plays a primary role in obese PCOS. Our results highlight the importance of body composition in the management of PCOS.

Lifestyle and mood correlates of cardiometabolic risk in people with serious mental illness on second-generation antipsychotic medications.

Cardiovascular morbidity and mortality are high in people with serious mental illness (SMI). This problem is mediated, at least in part, by metabolic side effects of second-generation antipsychotics (SGAs) and by unhealthy lifestyle behaviors. We asked whether oral glucose tolerance testing (oGTT) or hemoglobin A1c (HbA1c) is superior in identifying people with SMI at high cardiometabolic risk and whether this risk is shaped by mood, cognition, or lifestyle habits. We evaluated 40 patients with schizophrenia, schizoaffective, or bipolar disorder receiving SGAs by oGTT, HbA1c, comprehensive metabolic and lipid panels, and CRP. Mood was assessed using the Patient Health Questionnaire (PHQ-9), and cognition was assessed using the Saint Louis University Mental Status examination. Diet was assessed using the UK Diabetes and Diet Questionnaire (UKDDQ), and physical activity was assessed using daily step counts. Most patients had prediabetes (preDM) or diabetes mellitus (DM), 72.5% by oGTT, and 52.5% by HbA1c criteria. Pulse rates and insulin resistance indices (Homeostatic Model Assessment of Insulin Resistance, HOMA IR; Matsuda) were significantly different between patients classified as normal or with preDM/DM, using either oGTT or HbA1c criteria. Patients with preDM/DM by HbA1c but not oGTT criteria also had higher waist/hip ratios, triglyceride, and CRP levels (p<0.05). A strong negative correlation was found between average daily step counts and CRP levels (rho = -0.62, p<0.001). Higher UKDDQ scores, or unhealthier diet habits, were associated with higher fasting plasma glucose (rho = 0.28, p = 0.08), triglyceride levels (rho = 0.31, p = 0.05), and insulin resistance (HOMA IR: rho = 0.31, p = 0.06). Higher PHQ-9 scores correlated with lower 2h-oGTT glucose levels (rho = -0.37, p<0.05). OGTT screening is superior to HbA1c screening in detecting preDM and DM early. Patients identified with preDM/DM by oGTT or HbA1c screening are insulin-resistant and have higher pulse rates. Abdominal obesity, unfavorable lipid profiles, and higher CRP levels were noted in patients screened by HbA1c, but not by oGTT. Low physical activity, low depression scores, and unhealthy diet habits were associated with higher CRP and higher glucose and triglyceride levels, respectively. Future studies should assess the impact of specifically tailored individual lifestyle counseling and medical management interventions in this high-risk population.

Intrapancreatic fat deposition and nutritional treatment: the role of various dietary approaches.

Ectopic fat accumulation in various organs and tissues, such as the liver, muscle, kidney, heart, and pancreas, is related to impaired capacity of adipose tissue to accumulate triglycerides, as a consequence of overnutrition and an unhealthy lifestyle. Ectopic fat promotes organ dysfunction and is a key factor in the development and progression of cardiometabolic diseases. Interest in intrapancreatic fat deposition (IPFD) has developed in the last few years, particularly in relation to improvement in methodological techniques for detection of fat in the pancreas, and to growing evidence for the role that IPFD might have in glucose metabolism disorders and cardiometabolic disease. Body weight reduction represents the main option for reducing fat, and the evidence consistently shows that hypocaloric diets are effective in reducing IPFD. Changes in diet composition, independently of changes in energy intake, might offer a more feasible and safe alternative treatment to energy restriction. This current narrative review focused particularly on the possible beneficial role of the diet and its nutrient content, in hypocaloric and isocaloric conditions, in reducing IPFD in individuals with high cardiometabolic risk, highlighting the possible effects of differences in calorie quantity and calorie quality. This review also describes plausible mechanisms by which the various dietary approaches could modulate IPFD.

Treatment Options for High Cardiometabolic Risk Patients with Atherosclerosis

In 2020, coronary artery disease (CAD) affected over 20 million people and resulted in 382,820 deaths in the United States. Heart disease such as CAD and its precursor atherosclerosis have severe consequences such as limiting the amount of blood flow and reducing the flow of vital elements like oxygen to vital tissues and organs like the heart. Elderly adults, obese patients, patients with diabetes, and those with a genetic predisposition of increased Low-Density Lipids (LDLs), are at higher risk of developing atherosclerosis. This paper examines treatment options for atherosclerosis in people with high cardiometabolic risk and discusses their efficacy as well as their associated risks and benefits. First-line therapy includes medication such as statins, ACE Inhibitors, or diuretics along with appropriate lifestyle adjustments. If unsuccessful, second-line interventions offer increased risk reduction in patients with established coronary vascular disease and reduce the probability of recurrence of an acute cardiac event. This calls for the use of medication with higher risks such as beta blockers and anti-thrombotics and even surgical procedures such as bypass and angioplasties. Regardless of the patient’s condition, the first recommendation for preventing and managing atherosclerosis is lifestyle adjustment. Medications offer benefits but with varying levels of side effects. Thus, it is important to look at the specific conditions of each patient to find the most suitable medication. This paper looked at the existing magnitude of treatments for atherosclerosis and summarised which ones are best for patients with different conditions that put them at high risk for developing atherosclerosis.

Epidemiology and Management of Hypertension and Diabetes Mellitus in Patients with Mild Autonomous Cortisol Secretion: A Review.

Mild autonomous cortisol secretion (MACS) is associated with a higher cardiometabolic risk than that observed in patients with nonfunctioning adrenal adenomas and in the general population. In patients with MACS, the excess of glucocorticoids affects various metabolic pathways, leading to different manifestations of metabolic syndrome and other comorbidities. Hypertension and diabetes mellitus are two of the most common cardiometabolic comorbidities associated with MACS, reaching a prevalence of up to 80% and up to 40%, respectively. In addition, they are the comorbidities that experienced a greater improvement after adrenalectomy in patients with MACS. Hypertension pathogenesis is multifactorial, including the coexistence of comorbidities such as obesity or diabetes and the role of the different polymorphisms of the glucocorticoid receptor gene, among others. Glucocorticoid-induced diabetes mellitus is mainly related to the detrimental effects of glucocorticoids on insulin-dependent glucose uptake in peripheral tissues, gluconeogenesis and insulin secretion. There are no specific recommendations for hypertension and diabetes treatment in patients with MACS. Thus, considering the similar underlying pathogenesis of hypertension and diabetes mellitus in overt and mild hypercortisolism, our recommendation is to follow this general stepwise approach: surgically remove the adrenal culprit lesion to induce remission from hypercortisolism; control hypercortisolism with steroidogenesis inhibitors; and treat elevated blood pressure or high glucose levels using carefully selected anti-hypertensives and glucose-lowering medications if blood pressure and glucose levels remain uncontrolled, respectively. In this review, we summarize the epidemiology, physiopathology and management of diabetes mellitus and hypertension in patients with MACS.

Adherence to the Mediterranean diet and nuclear magnetic resonance spectroscopy biomarkers in older individuals at high cardiovascular disease risk: cross-sectional and longitudinal analyses

BackgroundThe Mediterranean diet (MedDiet) has been related to a decreased risk of cardiovascular disease (CVD) and diabetes. ObjectivesWe aimed to prospectively assess the relationship between adherence to the MedDiet and advanced lipoprotein subclass profiles and glucose metabolism and inflammation markers, as determined by nuclear magnetic resonance (NMR) spectroscopy. DesignWe conducted cross-sectional and longitudinal analyses within the framework of the PREvención con DIeta MEDiterránea study in 196 participants from the Reus-Tarragona center. Adherence to the MedDiet was assessed using a 14-item validated questionnaire [Mediterranean Diet Adherence Score (MEDAS)]. Plasma lipoprotein subclasses and molecular metabolite profiles were determined using NMR spectra collected on a Vantera Clinical Analyzer at baseline and after 1 y of follow-up. Baseline and 1-y categories of MEDAS were related to measures of lipoprotein atherogenicity and diabetes risk using multivariable-adjusted analysis of covariance models. ResultsCompared with participants in the lowest category of baseline MEDAS, those in the highest category showed higher concentrations of total high-density lipoprotein (HDL) particles and H1P HDL, lower concentrations of very low-density lipoprotein (VLDL)-triglyceride, smaller size of VLDL, and lower concentrations of very large VLDL, as well as lower concentrations of branched-chain amino acids, leucine, and GlycA and reduced Diabetes Risk Index (DRI) scores. In addition, participants who increased by 3 or more points in their 1-y MEDAS showed an increase in concentrations of H7P-HDL, H5P-HDL, and citrate, and reduced acetone and DRI scores compared with those with lesser adherence increases. ConclusionsIn older adults at high cardiometabolic risk, higher MEDAS was associated with modest beneficial changes in lipoprotein and glucose metabolism. The results suggest that lipoprotein subclass distribution and glycemic control are potential mechanisms behind the well-known salutary effects of MedDiet on CVD and diabetes risk. Future clinical trials exploring the effects of the MedDiet on advanced lipoprotein subclass profiles and glucose metabolism markers are needed to confirm the results of our study. Trial registration numberThis trial was registered at controlled-trials.com as ISRCTN35739639.

Epidemiology and diagnosis of primary aldosteronism. What have we learned from the SPAIN-ALDO registry?

To summarize the available data on the prevalence, clinical repercussion, and diagnosis of primary aldosteronism (PA) and to discuss the SPAIN-ALDO registry's findings, which is the largest PA patient registry in Spain. A comprehensive review of the literature focused on the prevalence, clinical presentation and diagnosis of PA was performed. PA is the most common cause of secondary arterial hypertension. In addition, PA patients have a higher cardio-metabolic risk than patients with essential arterial hypertension matched by age, sex, and blood pressure levels. However, despite its high prevalence and associated metabolic and cardiovascular complications, PA remains largely under-recognized, with less than 2% of people in at-risk populations ever tested. The diagnostic investigation is a multistep process, including screening, confirmatory testing, and subtype differentiation of unilateral from bilateral PA forms. Data from the SPAIN-ALDO registry have shed light on the cardiometabolic impact of PA and about the limitations in the PA diagnosis of these patients in Spain. The most common cause of secondary hypertension is PA. One of the most challenging aspects of the diagnosis is the differentiation between unilateral and bilateral PA because adrenal venous sampling is a difficult procedure that should be performed in experienced centers. Data from the SPAIN-ALDO registry have provided important information on the nationwide management of this pathology.

Promoting men's health through sports clubs: a rapid realist review

Abstract Background Traditional health promotion interventions have failed to engage men. Sports clubs offer male-friendly health promotion settings for men, but little is known about implementable intervention strategies and subsequent effects. This rapid realist review (RRR) aims to identify context, mechanisms and effects of health promotion interventions targeting men by or in collaboration with sports clubs. Methods The RRR methodology was developed in collaboration with a panel of Danish practice and policy representatives and international academics. A systematic literature search was conducted in February 2023 for studies published after 2013 in MEDLINE, Embase, and SportDiscus databases and through grey literature sources. Included studies: 1) targeted men aged 18+ years, 2) reported health promotion outcomes, and 3) were delivered primarily by or in collaboration with sports clubs. Results Fifty-two studies were included. Preliminary analyses indicate that interventions delivered through sports clubs show promise for engaging men with high cardiometabolic risk and producing favorable health outcomes. Preliminary findings from the realist synthesis show that if men felt a strong attachment to the sports club (context), it resonated with their feelings of social identity which outweighed a former reluctance to attend health programs (mechanism), and thus increased the men's likelihood for program engagement and health behavior change (outcome). Conclusions Our study indicates that men's health promotion through sports clubs is emergent. While great strides have been made to increase men's involvement in health promoting activities by delivering interventions through sports clubs, research has predominantly focused on select behaviours (e.g., physical activity), sub-groups (e.g., sports fans) and predominantly Caucasian, overweight, middle-aged men.

Independent and joint associations of cardiorespiratory fitness and lower-limb muscle strength with cardiometabolic risk in older adults.

The aim of this study was to investigate the independent and joint associations of low cardiorespiratory fitness and lower-limb muscle strength with cardiometabolic risk in older adults. A total of 360 community-dwelling older adults aged 60-80 years participated in this cross-sectional study. Cardiometabolic risk was based on the diagnosis of Metabolic Syndrome and poor Ideal Cardiovascular Health according to the American Heart Association guidelines. Cardiorespiratory fitness and lower-limb muscle strength were estimated using the six-minute walk and the 30-second chair stand tests, respectively. Participants in the 20th percentile were defined as having low cardiorespiratory fitness and lower-limb muscle strength. Poisson's regression was used to determine the prevalence ratio (PR) and 95% confidence intervals (CI) of Metabolic Syndrome and poor Ideal Cardiovascular Health. Participants with low cardiorespiratory fitness alone and combined with low lower-limb muscle strength were similarly associated with a higher risk for Metabolic Syndrome (PR 1.27, 95% CI 1.09-1.48, and PR 1.32, 95% CI 1.10-1.58, respectively), and poor Ideal Cardiovascular Health (PR 1.76, 95% CI 1.25-2.47, and PR 1.65, 95% CI 1.19-2.28, respectively). Low lower-limb muscle strength alone was not associated with a higher risk for either Metabolic Syndrome or poor Ideal Cardiovascular Health (PR 1.23, 95% CI 0.81-1.87, and PR 1.11, 95% CI 0.89-1.37, respectively). Low cardiorespiratory fitness alone or combined with low lower-limb muscle strength, but not low lower-limb muscle strength alone, was associated with a higher cardiometabolic risk in older adults. The assessment of physical fitness may be a "window of opportunity" to identify youngest-old adults with a high cardiovascular disease risk.

THU629 Cluster Analysis Identifies Distinct Subtypes Of PCOS

Abstract Disclosure: K. van der Ham: None. L.M. Moolhuijsen: None. K. Brewer: None. R. Sisk: None. Y.V. Louwers: None. J.A. Visser: None. A.E. Dunaif: None. J.S. Laven: None. Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive-age. The different criteria that are used to diagnose PCOS reflect the heterogeneity of the syndrome. However, PCOS diagnosed by NIH or Rotterdam criteria have a similar genetic architecture. Using Hierarchical Clustering (HC) in cohort of ∼900 NIH PCOS cases from European ancestry, we have previously identified discrete and stable PCOS clusters, which were designated “reproductive subtype” (high LH, FSH and SHBG) and “metabolic subtype” (high BMI, insulin and glucose); cases that did not belong to these clusters were designated “indeterminate subtype”. The subtypes appeared to capture biologically meaningful differences because assessment by a genome-wide association study indicated that they were characterized by distinct and novel genome-wide significant loci. In the current study, we tested the hypothesis that these subtypes would be present in an independent PCOS cohort diagnosed with Rotterdam criteria using the traits drivers (BMI, LH, FSH, DHEAS, SHBG, testosterone, fasting insulin and fasting glucose). We also compared two clustering methods, HC and K-means. We assessed whether the following additional traits not used for clustering differed between the subtypes thus identified: total follicle count (TFC), modified Ferriman-Gallwey score, and levels of anti-Müllerian hormone (AMH), estradiol, TSH, DHEA, cortisol, androstenedione, prolactin, LDL, HDL, triglyceride (TC) and cholesterol. European ancestry PCOS cases, n=2502, fulfilling Rotterdam criteria, aged 13-45 years, were included; n=1067 cases also fulfilled NIH criteria. In the Rotterdam cases, the reproductive subtype (n=450) had significantly (all P&amp;lt;0.001) higher TFC and levels of AMH and HDL compared to the metabolic (n=1067) and indeterminate (n=1026) subtypes. These findings suggest that clustering identifies a discrete reproductive subtype of cases with alterations in folliculogenesis, without using AMH and TFC to define the subtype. In contrast, the metabolic subtype had significantly (all P&amp;lt;0.001) higher TC and LDL levels compared to the other subtypes providing further evidence that this subtype identifies cases at higher cardiometabolic risk. The results were similar when the analysis was limited to NIH PCOS cases only. Comparing both clustering methods showed that there was consensus for 50% (metabolic) and 57% (reproductive) of PCOS cases. The cases in the non-consensus group showed a less pronounced metabolic and reproductive phenotype, both in the trait drivers and in the additional traits. Overall, our findings suggest that clustering algorithms capture etiologically distinct subtypes of PCOS diagnosed by both NIH and Rotterdam criteria. Further, our findings provide an example of the power of modern disease classification based on objective biologic differences rather than expert opinion. Presentation: Thursday, June 15, 2023

Fatty Liver Index (FLI) Identifies Not Only Individuals with Liver Steatosis but Also at High Cardiometabolic Risk.

A fatty liver index (FLI) greater than sixty (FLI ≥ 60) is an established score for metabolic dysfunction-associated steatotic liver disease (MASLD), which carries a high risk for diabetes and cardiovascular disease, while a FLI ≤ 20 rules out the presence of steatosis. Thus, we investigated whether FLI was associated with cardiometabolic risk factors, i.e., visceral (VAT), subcutaneous (SC), epicardial (EPI), extrapericardial (PERI), and total cardiac (CARD-AT) adipose tissue, hepatic fat ((by magnetic resonance imaging, MRI, and spectroscopy, MRS), and insulin resistance (IR, HOMA-IR and OGIS-index), and components of metabolic syndrome. All individuals with FLI ≥ 60 had MASLD, while none with FLI ≤ 20 had steatosis (by MRS). Subjects with FLI ≥ 60 had a higher BMI and visceral and cardiac fat (VAT > 1.7 kg, CARD-AT > 0.2 kg). FLI was positively associated with increased cardiac and visceral fat and components of metabolic syndrome. FLI, VAT, and CARD-AT were all associated with IR, increased blood pressure, cholesterol, and reduced HDL. For FLI ≥ 60, the cut-off values for fat depots and laboratory measures were estimated. In conclusion, FLI ≥ 60 identified not only subjects with steatosis but also those with IR, abdominal and cardiac fat accumulation, increased blood pressure, and hyperlipidemia, i.e., those at higher risk of cardiometabolic diseases. Targeted reduction of FLI components would help reduce cardiometabolic risk.

Recent Secular Trends of Body Mass Index in Individuals With Bipolar Disorders and in the General Population.

The aims of this study were to investigate secular trends and distribution of body mass index (BMI) among individuals with bipolar disorders and the general population between 2008 and 2019. Data were from the Swedish National Quality Register for Bipolar Disorder, where 24,423 adults with bipolar disorders were identified, and from the national Swedish Living Conditions Surveys, where 77,485 adults from the general population were identified. Quantile regression was used to compare the 15th, 50th, and 85th percentiles of BMI across age and study years. The study sample included 22,127 individuals with bipolar disorders (mean age, 48 years; 63% women) and 71,894 individuals from the general population (mean age, 52 years; 51% women). BMI percentiles were higher among individuals with bipolar disorders. At the 50th percentile, the BMI group differences were 1.1 (95% CI=0.8-1.14) for men and 1.8 (95% CI=1.5-2.1) for women. The gap was widest at the 85th BMI percentile: men, 2.3 (95% CI=1.8-2.8); women, 4.1 (95% CI=3.7-4.6). BMI increased over time in both study groups, but more in the group with bipolar disorders. The changes per decade in mean BMI were 0.4 (95% CI=0.3-0.5) among men in the general population, 1.1 (95% CI=0.7-1.4) among men with bipolar disorders, 0.6 (95% CI=0.5-0.7) among women in the general population, and 1.4 (95% CI=1.1-1.7) among women with bipolar disorders. Women with bipolar disorders had the highest prevalence and the greatest rate of increase of obesity. In 2019, the obesity prevalence was 33% among women and 29% among men with bipolar disorders, compared with 13% and 15%, respectively, among women and men in the general population. Adults with bipolar disorders had a higher BMI and a higher prevalence of obesity than the general population, indicating a higher cardiometabolic risk. Annually, BMI increased more in the group with bipolar disorders than in the general population, particularly among women and among those with high BMI.

Circulating miRNAs Detect High vs Low Visceral Adipose Tissue Inflammation in Patients Living With Obesity.

The severity of visceral adipose tissue (VAT) inflammation in individuals with obesity is thought to signify obesity subphenotype(s) associated with higher cardiometabolic risk. Yet, this tissue is not accessible for direct sampling in the nonsurgical patient. We hypothesized that circulating miRNAs (circ-miRs) could serve as biomarkers to distinguish human obesity subgroups with high or low extent of VAT inflammation. Discovery and validation cohorts of patients living with obesity undergoing bariatric surgery (n = 35 and 51, respectively) were included. VAT inflammation was classified into low/high based on an expression score derived from the messenger RNA levels of TNFA, IL6, and CCL2 (determined by reverse transcription polymerase chain reaction). Differentially expressed circ-miRs were identified, and their discriminative power to detect low/high VAT inflammation was assessed by receiver operating characteristic-area under the curve (ROC-AUC) analysis. Fifty three out of 263 circ-miRs (20%) were associated with high-VAT inflammation according to Mann-Whitney analysis in the discovery cohort. Of those, 12 (12/53 = 23%) were differentially expressed according to Deseq2, and 6 significantly discriminated between high- and low-VAT inflammation with ROC-AUC greater than 0.8. Of the resulting 5 circ-miRs that were differentially abundant in all 3 statistical approaches, 3 were unaffected by hemolysis and validated in an independent cohort. Circ-miRs 181b-5p, 1306-3p, and 3138 combined with homeostatic model assessment of insulin resistance (HOMA-IR) exhibited ROC-AUC of 0.951 (95% CI, 0.865-1) and 0.808 (95% CI, 0.654-0.963) in the discovery and validation cohorts, respectively, providing strong discriminative power between participants with low- vs high-VAT inflammation. Predicted target genes of these miRNAs are enriched in pathways of insulin and inflammatory signaling, circadian entrainment, and cellular senescence. Circ-miRs that identify patients with low- vs high-VAT inflammation constitute a putative tool to improve personalized care of patients with obesity.

Association of alpha-aminoadipic acid with cardiometabolic risk factors in healthy and high-risk individuals.

Plasma levels of the metabolite alpha-aminoadipic acid (2-AAA) have been associated with risk of type 2 diabetes (T2D) and atherosclerosis. However, little is known about the relationship of 2-AAA to other cardiometabolic risk markers in pre-disease states, or in the setting of comorbid disease. We measured circulating 2-AAA using two methods in 1) a sample of 261 healthy individuals (2-AAA Study), and 2) in a sample of 134 persons comprising 110 individuals with treated HIV, with or without T2D, a population at high risk of metabolic disease and cardiovascular events despite suppression of circulating virus, and 24 individuals with T2D without HIV (HATIM Study). We examined associations between plasma 2-AAA and markers of cardiometabolic health within each cohort. We observed differences in 2-AAA by sex and race in both cohorts, with higher levels observed in men compared with women, and in Asian compared with Black or white individuals (P<0.05). There was no significant difference in 2-AAA by HIV status within individuals with T2D in the HATIM Study. We confirmed associations between 2-AAA and dyslipidemia in both cohorts, where high 2-AAA associated with low HDL cholesterol (P<0.001) and high triglycerides (P<0.05). As expected, within the cohort of people with HIV, 2-AAA was higher in the setting of T2D compared to pre-diabetes or normoglycemia (P<0.001). 2-AAA was positively associated with body mass index (BMI) in the 2-AAA Study, and with waist circumference and measures of visceral fat volume in HATIM (all P<0.05). Further, 2-AAA associated with increased liver fat in persons with HIV (P<0.001). Our study confirms 2-AAA as a marker of cardiometabolic risk in both healthy individuals and those at high cardiometabolic risk, reveals relationships with adiposity and hepatic steatosis, and highlights important differences by sex and race. Further studies are warranted to establish molecular mechanisms linking 2-AAA to disease in other high-risk populations.

Circulating and Exosomal microRNA-33 in Childhood Obesity.

MicroRNA-33 may control a wide range of different metabolic functions. This study aims to assess the miR-33a circulating profile in normal-weight (N = 20) and obese (O = 30) adolescents and to correlate its expression levels to their metabolic parameters. In a subset of subjects, we compared circulating miR-33a with exosomal miR-33a. Metabolic parameters were altered in O, with initial hyperinsulinemia. Circulating miR-33a was significantly higher in O than in N (p = 0.0002). Significant correlations between miR-33a and auxological and metabolic indices (Insulin p = 0.01; Cholesterol p = 0.01; LDL p = 0.01; HbA1c p = 0.01) were found. Splitting our population (O + N) into two groups, according to the median value of mRNA expression miR-33a levels (0.701), irrespective of the presence or absence of obesity, we observed that those having a higher expression of miR-33a were more frequently obese (87.5% vs. 12.5%; p < 0.0001) and had significantly increased values of auxological and metabolic parameters. Exosomes extracted from plasma of N and O carried miR-33a, and its expression was lower in O (p = 0.026). No correlations with metabolic parameters were observed. While exosome miR-33a does not provide any advantage, circulating miR-33a can provide important indications in an initial phase of metabolic dysfunction, stratifying obese adolescents at higher cardiometabolic risk.