Exploring the Mechanistic Link Between Obesity and Heart Failure.

PURPOSE OF REVIEW: Among subtypes of cardiovascular disease, obesity has a potent and unique association with heart failure (HF) that is unexplained by traditional cardiovascular risk mediators. The concomitant rise in the prevalence of obesity and HF necessitates better understanding of their relationship to develop effective prevention and treatment strategies. The purpose of this review is to provide mechanistic insight regarding the link between obesity and HF by elucidating the direct and indirect pathways linking the two conditions. RECENT FINDINGS: Several direct pathophysiologic mechanisms contribute to HF risk in individuals with excess weight, including hemodynamic alterations, neurohormonal activation, hormonal effects of dysfunctional adipose tissue, ectopic fat deposition with resulting lipotoxicity and microvascular dysfunction. Obesity further predisposes to HF indirectly through causal associations with hypertension, dyslipidemia, and most importantly, diabetes via insulin resistance. Low levels of physical activity and fitness further influence HF risk in the context of obesity. These various processes lead to myocardial injury and cardiac remodeling that are reflected by abnormalities in cardiac biomarkers and cardiac function on myocardial imaging. Understanding and addressing obesity-associated HF is a pressing clinical and public health challenge which can be informed by a deeper understanding of the complex pathways linking these two conditions together.

A Synopsis of the Evidence for the Science and Clinical Management of Cardiovascular-Kidney-Metabolic (CKM) Syndrome: A Scientific Statement From the American Heart Association.

A growing appreciation of the pathophysiological interrelatedness of metabolic risk factors such as obesity and diabetes, chronic kidney disease, and cardiovascular disease has led to the conceptualization of cardiovascular-kidney-metabolic syndrome. The confluence of metabolic risk factors and chronic kidney disease within cardiovascular-kidney-metabolic syndrome is strongly linked to risk for adverse cardiovascular and kidney outcomes. In addition, there are unique management considerations for individuals with established cardiovascular disease and coexisting metabolic risk factors, chronic kidney disease, or both. An extensive body of literature supports our scientific understanding of, and approach to, prevention and management for individuals with cardiovascular-kidney-metabolic syndrome. However, there are critical gaps in knowledge related to cardiovascular-kidney-metabolic syndrome in terms of mechanisms of disease development, heterogeneity within clinical phenotypes, interplay between social determinants of health and biological risk factors, and accurate assessments of disease incidence in the context of competing risks. There are also key limitations in the data supporting the clinical care for cardiovascular-kidney-metabolic syndrome, particularly in terms of early-life prevention, screening for risk factors, interdisciplinary care models, optimal strategies for supporting lifestyle modification and weight loss, targeting of emerging cardioprotective and kidney-protective therapies, management of patients with both cardiovascular disease and chronic kidney disease, and the impact of systematically assessing and addressing social determinants of health. This scientific statement uses a crosswalk of major guidelines, in addition to a review of the scientific literature, to summarize the evidence and fundamental gaps related to the science, screening, prevention, and management of cardiovascular-kidney-metabolic syndrome.

Cardiovascular-Kidney-Metabolic Health: A Presidential Advisory From the American Heart Association.

Cardiovascular-kidney-metabolic health reflects the interplay among metabolic risk factors, chronic kidney disease, and the cardiovascular system and has profound impacts on morbidity and mortality. There are multisystem consequences of poor cardiovascular-kidney-metabolic health, with the most significant clinical impact being the high associated incidence of cardiovascular disease events and cardiovascular mortality. There is a high prevalence of poor cardiovascular-kidney-metabolic health in the population, with a disproportionate burden seen among those with adverse social determinants of health. However, there is also a growing number of therapeutic options that favorably affect metabolic risk factors, kidney function, or both that also have cardioprotective effects. To improve cardiovascular-kidney-metabolic health and related outcomes in the population, there is a critical need for (1) more clarity on the definition of cardiovascular-kidney-metabolic syndrome; (2) an approach to cardiovascular-kidney-metabolic staging that promotes prevention across the life course; (3) prediction algorithms that include the exposures and outcomes most relevant to cardiovascular-kidney-metabolic health; and (4) strategies for the prevention and management of cardiovascular disease in relation to cardiovascular-kidney-metabolic health that reflect harmonization across major subspecialty guidelines and emerging scientific evidence. It is also critical to incorporate considerations of social determinants of health into care models for cardiovascular-kidney-metabolic syndrome and to reduce care fragmentation by facilitating approaches for patient-centered interdisciplinary care. This presidential advisory provides guidance on the definition, staging, prediction paradigms, and holistic approaches to care for patients with cardiovascular-kidney-metabolic syndrome and details a multicomponent vision for effectively and equitably enhancing cardiovascular-kidney-metabolic health in the population.

Precision subclassification of type 2 diabetes: a systematic review.

BACKGROUND: Heterogeneity in type 2 diabetes presentation and progression suggests that precision medicine interventions could improve clinical outcomes. We undertook a systematic review to determine whether strategies to subclassify type 2 diabetes were associated with high quality evidence, reproducible results and improved outcomes for patients. METHODS: We searched PubMed and Embase for publications that used 'simple subclassification' approaches using simple categorisation of clinical characteristics, or 'complex subclassification' approaches which used machine learning or 'omics approaches in people with established type 2 diabetes. We excluded other diabetes subtypes and those predicting incident type 2 diabetes. We assessed quality, reproducibility and clinical relevance of extracted full-text articles and qualitatively synthesised a summary of subclassification approaches. RESULTS: Here we show data from 51 studies that demonstrate many simple stratification approaches, but none have been replicated and many are not associated with meaningful clinical outcomes. Complex stratification was reviewed in 62 studies and produced reproducible subtypes of type 2 diabetes that are associated with outcomes. Both approaches require a higher grade of evidence but support the premise that type 2 diabetes can be subclassified into clinically meaningful subtypes. CONCLUSION: Critical next steps toward clinical implementation are to test whether subtypes exist in more diverse ancestries and whether tailoring interventions to subtypes will improve outcomes.

In people with type 2 diabetes there may be differences in the way people present, including for example, their symptoms, body weight or how much insulin they make. We looked at recent publications describing research in this area to see whether it is possible to separate people with type 2 diabetes into different subgroups and, if so, whether these groupings were useful for patients. We found that it is possible to group people with type 2 diabetes into different subgroups and being in one subgroup can be more strongly linked to the likelihood of developing complications over others. This might mean that in the future we can treat people in different subgroups differently in ways that improves their treatment and their health but it requires further study.

Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine.

Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.

NT-proBNP Reference Intervals in Healthy U.S. Children, Adolescents, and Adults.

BACKGROUND: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a cardiac biomarker used in the clinical management of heart failure. We sought to create updated reference intervals for NT-proBNP for healthy US children, adolescents, and adults. METHODS: We identified a population of healthy individuals using the 1999 to 2004 cycles of the National Health and Nutrition Examination Survey (NHANES). We measured serum NT-proBNP in 12 346 adults and 15 752 children and adolescents with the Elecsys NT-proBNP assay on the Roche e601 autoanalyzer. We compared 4 methods for reference interval calculation, and presented the final reference intervals using the robust method partitioned by age and sex categories. RESULTS: NT-proBNP values were available for 1949 healthy adults and 5250 healthy children and adolescents. NT-proBNP concentrations in males and females varied according to age, being higher in early childhood, relatively lower in late adolescence, and highest through middle age and older age. Females tended to have higher NT-proBNP concentrations compared to men from late adolescence until middle age. The upper reference limit, or 97.5th percentile, for 50 to 59 year-old men was 225 ng/L (90% CI: 158 to 236), and for 50 to 59 year-old women, 292 ng/L (90% CI: 242 to 348). CONCLUSIONS: Among healthy individuals, NT-proBNP concentrations varied greatly according age and sex. The reference intervals presented here should inform future clinical decision limits and suggest that age- and sex-specific intervals may be necessary to more precisely characterize risk.

Associations of N-terminal pro-B-type natriuretic peptide, estimated glomerular filtration rate, and mortality in US adults.

BACKGROUND: NT-proBNP is an important predictor of mortality but is inversely related to estimated glomerular filtration rate (eGFR). Whether the prognostic value of NT-proBNP is similar at different levels of kidney function is unknown. AIMS: We evaluated the association of NT-proBNP with eGFR and its implications for all-cause and cardiovascular mortality risk in the general population. METHODS: We included adults without prior cardiovascular disease from the National Health and Nutrition Examination Survey (NHANES) 1999 to 2004. We used linear regression to characterize the cross-sectional associations of NT-proBNP with eGFR. We used Cox regression to assess the prospective associations of NT-proBNP with mortality across categories of eGFR. RESULTS: Among 11,456 participants (mean age 43 years, 48% female, 71% White, 11% Black), there was an inverse association between NT-proBNP and eGFR, which was stronger in those with more impaired kidney function. Per 15-unit decrease in eGFR, NT-proBNP was 4.3-fold higher for eGFR<30; 1.7-fold higher for eGFR 30 to 60, 1.4-fold higher for eGFR 61 to 90, 1.1-fold higher for eGFR 91 to 120 mL/min/1.73 m2. Over a median 17.6 years of follow-up, 2,275 deaths (622 cardiovascular) occurred. Higher NT-proBNP was associated with higher all-cause (HR per doubling of NT-proBNP: 1.20, 95% CI: 1.16-1.25) and cardiovascular mortality (HR: 1.34, 95% CI 1.25-1.44). Associations were similar across eGFR categories (P-interaction >.10). Adults with NT-proBNP≥450 pg/mL and eGFR<60 mL/min/1.73m2 had 3.4-fold higher all-cause mortality and 5.5-fold higher cardiovascular mortality risk, compared to those with NT-proBNP<125 pg/mL and eGFR>90 mL/min/1.73m2. CONCLUSION: Despite its strong inverse association with eGFR, NT-proBNP has robust associations with mortality across the full range of kidney function in the general US adult population.

Systematic review of precision subclassification of type 2 diabetes.

Heterogeneity in type 2 diabetes presentation, progression and treatment has the potential for precision medicine interventions that can enhance care and outcomes for affected individuals. We undertook a systematic review to ascertain whether strategies to subclassify type 2 diabetes are associated with improved clinical outcomes, show reproducibility and have high quality evidence. We reviewed publications that deployed 'simple subclassification' using clinical features, biomarkers, imaging or other routinely available parameters or 'complex subclassification' approaches that used machine learning and/or genomic data. We found that simple stratification approaches, for example, stratification based on age, body mass index or lipid profiles, had been widely used, but no strategy had been replicated and many lacked association with meaningful outcomes. Complex stratification using clustering of simple clinical data with and without genetic data did show reproducible subtypes of diabetes that had been associated with outcomes such as cardiovascular disease and/or mortality. Both approaches require a higher grade of evidence but support the premise that type 2 diabetes can be subclassified into meaningful groups. More studies are needed to test these subclassifications in more diverse ancestries and prove that they are amenable to interventions.

Global Prevalence of Prediabetes.

OBJECTIVE: To estimate the global, regional, and national prevalence of prediabetes, defined by impaired glucose tolerance (IGT) or impaired fasting glucose (IFG). RESEARCH DESIGN AND METHODS: We reviewed 7,014 publications for high-quality estimates of IGT (2-h glucose, 7.8-11.0 mmol/L [140-199 mg/dL]) and IFG (fasting glucose, 6.1-6.9 mmol/L [110-125 mg/dL]) prevalence for each country. We used logistic regression to generate prevalence estimates for IGT and IFG among adults aged 20-79 years in 2021 and projections for 2045. For countries without in-country data, we extrapolated estimates from countries with available data with similar geography, income, ethnicity, and language. Estimates were standardized to the age distribution for each country from the United Nations. RESULTS: Approximately two-thirds of countries did not have high-quality IGT or IFG data. There were 50 high-quality studies for IGT from 43 countries and 43 high-quality studies for IFG from 40 countries. Eleven countries had data for both IGT and IFG. The global prevalence of IGT in 2021 was 9.1% (464 million) and is projected to increase to 10.0% (638 million) in 2045. The global prevalence of IFG in 2021 was 5.8% (298 million) and is projected to increase to 6.5% (414 million) in 2045. The 2021 prevalence of IGT and IFG was highest in high-income countries. In 2045, the largest relative growth in cases of IGT and IFG would be in low-income countries. CONCLUSIONS: The global burden of prediabetes is substantial and growing. Enhancing prediabetes surveillance is necessary to effectively implement diabetes prevention policies and interventions.

Heart Failure and Obesity: The Latest Pandemic.

The marked rise in rates of obesity, which is most prominent among individuals from socio-economically disadvantaged circumstances, has been a powerful contributor to the rising prevalence of heart failure (HF). Obesity has indirect effects on HF through the development of several metabolic risk factors, but also direct adverse effects on the myocardium. Obesity contributes to myocardial dysfunction and HF risk through multiple mechanisms, including hemodynamic changes, neurohormonal activation, endocrine and paracrine effects of adipose tissue, ectopic fat deposition and lipotoxicity. These processes principally result in concentric left ventricular (LV) remodeling and predominant increase in the risk for HF with preserved LV ejection fraction (HFpEF). Despite the excess risk for HF associated with obesity, there is a well described obesity paradox in which individuals with overweight and grade I obesity have better survival than those with normal weight and underweight. Despite the obesity paradox among individuals with prevalent HF, intentional weight loss is associated with improvements in metabolic risk factors, myocardial dysfunction and quality of life, in a dose-response fashion. In matched observational studies of bariatric surgery patients, marked weight loss is associated with decreased risk for developing HF, as well as improved cardiovascular disease (CVD) outcomes in those with existing HF. Ongoing clinical trials using powerful new obesity pharmacotherapies in individuals with obesity and CVD may provide definitive information regarding the cardiovascular impact of weight loss. Given the powerful contribution of rising obesity prevalence to rates of HF, addressing these intertwined epidemics is a clinical and public health priority.

The Assessment of the Quality of Life in Children with Chronic Liver Disease.

BACKGROUND: Improvement in the quality of life (QoL) of patients with chronic diseases is as important as medical care. This study aimed to evaluate the QoL of children with chronic liver diseases and to determine related factors. METHODS: For this study, 101 children with chronic liver disease, 100 healthy controls, and their parents were included. The Pediatric Quality of Life Scale (PedsQL) was used to evaluate health-related QoL; higher scores indicate better QoL. Patients were evaluated before and after initiation of treatment and being educated about their illness. RESULTS: The mean patient age was 12.9 ± 3.9 years. Total PedsQL scores of the patients and the healthy control group were 38.6 ± 18.9 and 55.4 ± 14.3, respectively (P = .01). The scores of the parents of the patient and control groups were 35.4 ± 14.2 and 54.0 ± 16.9, respectively (P = .02). Patient and parent scores were positively correlated. Significantly higher scores were found in the 5-10 age group compared to the 10-15 and 15-18 age groups in the psychosocial score category. An increase in the QoL scores of patients who were started on medication other than steroid treatment was observed in the sixth month of treatment (35.8 ± 13.4 vs. 33.6 ± 8.9, P = .01, respectively). CONCLUSION: Both children with chronic liver diseases and their parents have a perceived lower QoL than healthy peers. The effect of chronic liver disease on psychosocial health is more pronounced in children older than 10 years. The quality of life is inversely proportional to the severity of the disease. It was observed that primary or symptomatic treatments have a positive impact on the perception of QoL, with the exception of steroid treatment.

Low bone density, vertebral fracture and FRAX score in kidney transplant recipients: A cross-sectional cohort study.

BACKGROUND: Kidney transplantation (KT) recipients are at increased risk of low bone density (LBD) and fractures. In this retrospective study, we investigated bone mineral density (BMD), vertebral fractures, calculated risk for major osteoporotic fractures (MOF), and hip fractures in the KT recipients. PATIENTS-METHOD: Patients who completed at least one year after KT were included in the analysis. Demographic, clinical, and laboratory data were recorded. Measurements of BMD were performed by dual-energy X-ray absorptiometry. Vertebral fractures were assessed using semi-quantitative criteria with conventional radiography. The ten-year risk for MOF and hip fracture were calculated using the FRAX@ tool with BMD. RESULTS: One hundred fifty-three KT recipients were included in the study. The population included 77 women. The mean age at evaluation was 46,5±11,9 years. Seventy-eight (50.9%) patients had normal femoral neck BMD while osteoporosis and osteopenia at the femoral neck were present in 12 (7.8%) and 63 (41.1%) of the patients, respectively. Age at evaluation was the risk factor for LBD (OR 1.057; 95% CI 1.024-1.091; p = 0.001). In female KT recipients, LBD was principally affected by menopausal status whereas in males, mammalian target of rapamycin (mTOR) inhibitor use and lower BMI levels were the risk factors. The prevalent vertebral fracture was found in 43.4% of patients. In multivariate analysis, only steroid use (OR 0.121; 95% CI 0.015-0.988; p = 0.049) was found to be associated with prevalent fracture. Among all KT recipients, 1.9% had a high MOF probability (≥20% risk of fracture), and 23.5% had high hip fracture probability (≥3% risk of hip fracture) according to FRAX. CONCLUSION: Exploring the prevalence of LBD and vertebral fracture and the risk factors would help clinicians to modify long-term follow-up strategies. Furthermore, the high hip fracture risk probability in our cohort suggested that there is a need for longitudinal studies to confirm the validity of the FRAX tool in the transplant population.

External validation of the Toronto hepatocellular carcinoma risk index in Turkish cirrhotic patients.

OBJECTIVES: Toronto hepatocellular carcinoma risk index is developed to stratify cirrhotic patients according to 10-year hepatocellular carcinoma risk. We aimed to validate the performance of Toronto hepatocellular carcinoma risk index in a large Turkish cohort. MATERIALS AND METHODS: We retrospectively reviewed the database of 1287 cirrhotic patients followed-up in a 10-year period (February 2008 to January 2018). All patients were stratified into three groups based on the Toronto hepatocellular carcinoma risk index score as follows: low-risk, < 120; intermediate risk, 120 to 240; and high risk, > 240. Area under the curve and optimal cutoff value of Toronto hepatocellular carcinoma risk index were obtained from receiver operator curve. To reveal the parameters related with hepatocellular carcinoma development, logistic regression analysis was conducted. The cumulative incidences of hepatocellular carcinoma were calculated using the Kaplan-Meier method, and the curves were compared using the log-rank test. RESULTS: Out of 403 enrolled patients, 57 developed hepatocellular carcinoma. The median Toronto hepatocellular carcinoma risk index value was higher in hepatocellular carcinoma (+) group comparing to hepatocellular carcinoma (-) group [267 (70-366) vs. 224 (36-366), P < 0.001]. Out of 57 detected hepatocellular carcinomas, 45 (78.9%) were high risk, 11 (19.3%) were intermediate risk, and only one (1.8%) was low risk at the entry. The area under the curve of the Toronto hepatocellular carcinoma risk index to predict hepatocellular carcinoma was 0.750 (95% confidence interval, 0.683-0.817, P < 0.001). The optimal cutoff value of Toronto hepatocellular carcinoma risk index was 239.5, giving a sensitivity of 78.9% and specificity of 62.7%. As a result, Toronto hepatocellular carcinoma risk index remained to be the only significant parameter that has an affect on hepatocellular carcinoma development [adjusted-odds ratio: 1.016 (95% confidence interval, 1.007-1.024), P<0.001]. CONCLUSION: The present study validated the performance of Toronto hepatocellular carcinoma risk index in Turkish cirrhotic patients to predict hepatocellular carcinoma risk, which can be considered as a tool for personalized surveillance.