Although body mass index (BMI) is widely used as a simple tool to assess obesity, it has certain limitations and inaccuracies. It is known that visceral adipose tissue is closely related to cardiometabolic risks and all-cause mortality; however, precise measurement methods for visceral fat (magnetic resonance imaging and computed tomography) cannot be widely used. Thus, simple but accurate alternatives are valuable. Studies have shown that waist circumference-to-height ratio (WHtR) might be a superior and more accurate variable in assessing central or visceral adiposity as well as predicting risks of diabetes and other cardiometabolic diseases. Furthermore, WHtR cutoff values can be consistent across different races, age, and genders, making it a universal metric worth promoting and applying.

Background: Obesity is commonly linked with heart failure (HF) with preserved ejection fraction, with diastolic dysfunction playing an important role in this type of HF. However, diastolic function has not been well clarified in obese patients free of overt comorbidities. We aimed to comprehensively assess diastolic function in adults with uncomplicated obesity by combining left atrial (LA) and left ventricular (LV) strain and ventricular volume-time curve based on cardiac magnetic resonance (CMR), and to evaluate its association with body fat distribution. Methods: A cross-sectional study was conducted with 49 uncomplicated obese participants and 43 healthy controls who were continuously recruited in West China Hospital, Sichuan University from September 2019 to June 2022. LA strain indices [total, passive, and active strains (epsilon(s), epsilon(e), and epsilon(a)) and peak positive, early negative, and late negative strain rates (SRs, SRe, and SRa)], LV strain rates [peak diastolic strain rate (PDSR) and peak systolic strain rate (PSSR)], and LV volume-time curve parameters [peak filling rate index (PFRI) and peak ejection rate index (PERI)] were measured. Body fat distribution was assessed by dual-energy X-ray absorptiometry. Correlation between body fat distribution and LA and LV function was evaluated by multiple linear regression. Results: The obese participants had impaired diastolic function, manifested as lower LV circumferential and longitudinal PDSR (1.3 +/- 0.2 vs. 1.5 +/- 0.3 s(-1), P=0.014; 0.8 +/- 0.2 vs. 1.1 +/- 0.2 s(-1), P<0.001), LV PFRI (3.5 +/- 0.6 vs. 3.9 +/- 0.7 s(-1), P=0.012), and declined LA reservoir function [epsilon(s) and SRs (46.4%+/- 8.4% vs. 51%+/- 12%, P=0.045; 1.9 +/- 0.5 vs. 2.3 +/- 0.5 s(-1), P<0.001)] and conduit function [epsilon(e) and SRe (30.8%+/- 8.0% vs. 35.5%+/- 9.8%, P=0.019; -3.1 +/- 0.8 vs. -3.5 +/- 1.0 s(-1), P=0.030)] compared with controls. The LA pumping function (epsilon(a) and SRa) and LV systolic function [LV ejection fraction (LVEF), PSSR and PERI] were not different between obese and control participants. Multivariable analysis indicated that trunk fat had independent relationships with LA epsilon(e) (beta=-0.520, P<0.001) and LV circumferential PDSR (beta=-0.418, P=0.003); visceral fat and peripheral fat were associated with LV longitudinal PDSR (beta=-0.342, P=0.038; beta=0.376, P=0.024); gynoid fat was associated with LA epsilon(s) (beta=0.384, P=0.014) and PFRI (beta=0.286, P=0.047) in obesity. Conclusions: The obese participants (uncomplicated obese adults with preserved LVEF) had impaired subclinical diastolic function. Central adipose tissue deposits (trunk fat and visceral fat) may exhibit inverse relationships with LV and LA function in obesity. However, peripheral adipose tissue deposits (peripheral fat and gynoid fat) may show positive relationships with LV and LA function.

Type 2 diabetes (T2D) is a disease characterized by heterogeneously progressive loss of islet β cell insulin secretion usually occurring after the presence of insulin resistance (IR) and it is one component of metabolic syndrome (MS), and we named it metabolic dysfunction syndrome (MDS). The pathogenesis of T2D is not fully understood, with IR and β cell dysfunction playing central roles in its pathophysiology. Dyslipidemia, hyperglycemia, along with other metabolic disorders, results in IR and/or islet β cell dysfunction via some shared pathways, such as inflammation, endoplasmic reticulum stress (ERS), oxidative stress, and ectopic lipid deposition. There is currently no cure for T2D, but it can be prevented or in remission by lifestyle intervention and/or some medication. If prevention fails, holistic and personalized management should be taken as soon as possible through timely detection and diagnosis, considering target organ protection, comorbidities, treatment goals, and other factors in reality. T2D is often accompanied by other components of MDS, such as preobesity/obesity, metabolic dysfunction associated steatotic liver disease, dyslipidemia, which usually occurs before it, and they are considered as the upstream diseases of T2D. It is more appropriate to call "diabetic complications" as "MDS-related target organ damage (TOD)", since their development involves not only hyperglycemia but also other metabolic disorders of MDS, promoting an up-to-date management philosophy. In this review, we aim to summarize the underlying mechanism, screening, diagnosis, prevention, and treatment of T2D, especially regarding the personalized selection of hypoglycemic agents and holistic management based on the concept of "MDS-related TOD".

Abstract Background Obesity is often associated with multiple comorbidities. However, whether obese subjects with hyperlipidemia in the absence of other complications have worse cardiac indices than metabolically healthy obese subjects is unclear. Therefore, we aimed to determine the effect of hyperlipidemia on subclinical left ventricular (LV) function in obesity and to evaluate the association of cardiac parameters with body fat distribution. Materials and methods Ninety-two adults were recruited and divided into 3 groups: obesity with hyperlipidemia (n = 24, 14 males), obesity without hyperlipidemia (n = 25, 13 males), and c ntrols (n = 43, 25 males). LV strain parameters (peak strain (PS), peak diastolic strain rate (PDSR), peak systolic strain rate) derived from cardiovascular magnetic resonance tissue tracking were measured and compared. Dual-energy X-ray absorptiometer was used to measure body fat distribution. Correlations of hyperlipidemia and body fat distribution with LV strain were assessed by multivariable linear regression. Results Obese individuals with preserved LV ejection fraction showed lower global LV longitudinal, circumferential, and radial PS and longitudinal and circumferential PDSR than controls (all P < 0.05). Among obese patients, those with hyperlipidemia had lower longitudinal PS and PDSR and circumferential PDSR than those without hyperlipidemia (− 12.8 ± 2.9% vs. − 14.2 ± 2.7%, 0.8 ± 0.1 s−1 vs. 0.9 ± 0.3 s−1, 1.2 ± 0.2 s−1 vs. 1.4 ± 0.2 s−1; all P < 0.05). Multivariable linear regression demonstrated that hyperlipidemia was independently associated with circumferential PDSR (β = − 0.477, P < 0.05) in obesity after controlling for growth differences, other cardiovascular risk factors, and central fat distribution. In addition, android fat had an independently negative relationship with longitudinal and radial PS (β = − 0.486 and β = − 0.408, respectively; all P < 0.05); and visceral fat was negatively associated with longitudinal PDSR (β = − 0.563, P < 0.05). Differently, gynoid fat was positively correlated with circumferential PS and PDSR and radial PDSR (β = 0.490, β = 0.481, and β = 0.413, respectively; all P < 0.05). Conclusion Hyperlipidemia is independently associated with subclinical LV diastolic dysfunction in obesity. Central fat distribution (android and visceral fat) has a negative association, while peripheral fat distribution (gynoid fat) has a positive association on subclinical LV function. These results suggest that appropriate management of hyperlipidemia may be beneficial for obese patients, and that the differentiation of fat distribution in different regions may facilitate the precise management of obese patients. Clinical trials registration Effect of lifestyle intervention on metabolism of obese patients based on smart phone software (ChiCTR1900026476).

Diabetic alveolar bone defect (DABD) causes persistent bacterial infection, prolonged inflammation, and delayed bone healing, making it a considerable clinical challenge. In this study, by integrating silver nanoclusters (AgNCs) and M2 macrophage-derived extracellular vesicles (M2EVs), a multifunctional DNA-based hydrogel, called Agevgel, is developed with antibacterial, anti-inflammatory, immunomodulatory, and osteogenic properties to promote DABD rebuilding. AgNCs are tightly embedded into the DNA scaffolds and exhibit effective anti-bacterial activity, while immunomodulatory M2EVs are encapsulated within the shape-variable DNA scaffolds and exhibit potent anti-inflammatory and osteogenic properties. The results reveal that Agevgel effectively prolongs the local retention time and bioactivity of M2EVs in vivo. In particular, the sustained release of M2EVs can last for at least 7 days when applying Agevgel to DABD. Compared to free M2EVs or Aggel (AgNCs encapsulated within the DNA hydrogel) treatments, the Agevgel treatment accelerates the defect healing rate of alveolar bone and dramatically improves the trabecular architecture. Mechanistically, Agevgel plays a key role in regulating macrophage polarization and promoting the expression of proliferative and osteogenic factors. In summary, Agevgel provides a comprehensive treatment strategy for DABD with a great clinical translational value, highlighting the application of DNA hydrogels as an ideal bioscaffolds for periodontal diseases.

Background Abdominal ectopic fat deposition and excess visceral fat depots in obesity may be related to cardiovascular disease (CVD) as both are involved in the metabolic syndrome (MetS). The awareness of the link between abdominal adiposity and subclinical cardiac remodeling would help improve treatment and outcome. Besides, liver fibrosis has also shown a potential relationship with cardiac dysfunction. Thus, we aimed to investigate the associations of magnetic resonance (MR)-based abdominal adiposity and hepatic shear stiffness with subclinical left ventricular (LV) remodeling while taking account of MetS-related confounders in adults free of overt CVD. Methods This was an exploratory, prospective study of 88 adults (46 subjects with obesity, 42 healthy controls) who underwent 3 T cardiac and body MR exams. Measures of abdominal MR included hepatic and pancreatic proton density fat fraction (H-PDFF and P-PDFF), hepatic shear stiffness by MR elastography, and subcutaneous and visceral adipose tissue (SAT and VAT). Cardiac measures included epicardial adipose tissue (EAT) and parameters of LV geometry and function. Associations were assessed using Pearson correlation and multivariable linear regression analyses, in which age, sex, and MetS-related confounders were adjusted for. Results The LV ejection fractions of all participants were within the normal range. Higher H-PDFF, P-PDFF, SAT and VAT were independently associated with lower LV global myocardial strain parameters (radial, circumferential and longitudinal peak strain [PS], longitudinal peak systolic strain rate and diastolic strain rate) (β = − 0.001 to − 0.41, p < 0.05), and P-PDFF, SAT and VAT were independently and positively associated with LV end-diastolic volume and stroke volume (β = 0.09 to 3.08, p ≤ 0.02) in the over-all cohort. In the obesity subgroup, higher P-PDFF and VAT were independently associated with lower circumferential and longitudinal PS, respectively (β = − 0.29 to − 0.05, p ≤ 0.01). No independent correlation between hepatic shear stiffness and EAT or LV remodeling was found (all p ≥ 0.05). Conclusions Ectopic fat depositions in the liver and pancreas, and excess abdominal adipose tissue pose a risk of subclinical LV remodeling beyond MetS-related CVD risk factors in adults without overt CVD. VAT may play a more considerable role as a risk factor for subclinical LV dysfunction than does SAT in individuals with obesity. The underlying mechanisms of these associations and their longitudinal clinical implications need further investigation.

Hypokalemia is a common disorder in clinical settings; however, nonmolecular diagnostic testing cannot explain some causes of hypokalemia. To determine the etiology of clinically unexplained hypokalemia without hypertension (CUHypoNH) and to obtain a diagnostic yield of monogenic hypokalemia without hypertension in adults (MHNHA), we enrolled 82 patients with CUHypoNH for whole-exome sequencing or targeted gene sequencing of genes associated with 4000 monogenic disorders. Through molecular diagnosis, 25 patients were diagnosed with monogenic hypokalemia, and a diagnostic yield of 30.5% was obtained. Among patients with MHNHA, 18 patients (18/82, 22.0% and 72% of MHNHA) with Gitelman syndrome accounted for the largest proportion. Among the 29 diagnostic variants found, eight mutations have not been reported previously; these include three point mutations, one frameshift mutation, and four exon deletions. Based on the clinical presentation of patients with CUHypoNH, the diagnostic yield of monogenic hypokalemia was the highest for chronic asymptomatic hypokalemia (8/11, 72.7%). Twenty-one patients had concomitant hypomagnesemia, when accompanied with hypocalciuria, the molecular diagnostic yield of Gitelman syndrome increased to 88.2%. Overall, this study on hospitalized adult patients explored the etiology of CUHypoNH using high-throughput sequencing. Molecular diagnosis of CUHypoNH is clinically significant in guiding precision treatment and improving disease prognosis.

To the Editor: Primary aldosteronism, characterized by hypertension, with or without hypokalemia, is the most frequent form of endocrine hypertension, which is mostly caused by bilateral adrenal hyperplasia or aldosterone-producing adrenocortical adenomas (APAA). However, it can also be induced by aldosterone-producing adrenocortical carcinoma (APAC), which is rare. Because of the rarity and malignancy, the clinical characteristics of APAC and the differences between APAC and APAA remain unclear, and the pre-surgical diagnosis of APAC is valuable. Therefore, we aimed to compare the clinical features of APAA and APAC by extracting data from APAC patient case reports and APAA clinical literature and developing pre-surgery diagnostic criteria for APAC. To identify all APAC cases, we searched articles published from inception to June 2021 in PubMed, Embase, the Cochrane library, and three Chinese databases (China National Knowledge Infrastructure, Wanfang Database, and VIP Database) by using the terms "adrenocortical carcinoma", "primary aldosteronism", and "hyperaldosteronism". The inclusion criterion was an unequivocal APAC diagnosis. Available information was extracted, and the clinical features of APAC were analyzed. Additionally, literature that described APAA clinical characteristics (sample size of ≥100 participants) was systematically reviewed by searching the PubMed database. Clinical data from these publications were summarized using a one-arm meta-analysis. The results are expressed as mean ± standard deviation (SD) for normally distributed data and as median and range for non-normally distributed data, unless otherwise stated. Categorical variables were described as numbers and percentages. Methods for statistical analysis are shown in [Supplementary Methods, https://links.lww.com/CM9/B221]. This study was approved by the Ethics Committee of Sichuan University West China Hospital (No. 2021-169). A total of 107 APAC cases [Supplementary Table 1, https://links.lww.com/CM9/B221] were identified, and we also included four APAC cases from our hospital [Supplementary Table 2, https://links.lww.com/CM9/B221] to establish the APAC database. For the APAA group, ten clinical studies were included [Supplementary Table 3, https://links.lww.com/CM9/B221]. The characteristics of APAC and APAA are summarized in [Table 1]. Table 1 - Demographic and clinical features of PA induced by APAC and APAA. APAC (N = 111) APAA (N = 2609) Variable Results n Results n P value Age (years) 46.1 ± 15.5 111 49.2 ± 2.5 1559 0.30 Gender (M/F) 51/59 110 684/748 1432 0.84 Duration of disease (months) 18.0 (0.3–300.0) 53 127.0 ± 38.9 1325 <0.01 Hypertension (present/absent) 103/6 109 – – – Systolic blood pressure (mmHg) 185.1 ± 3.5 86 161.5 ± 6.0 2435 <0.01 Diastolic blood pressure (mmHg) 110.0 (60.0–190.0) 84 99.1 ± 3.3 2435 <0.01 Hypokalemia (present/absent) 99/7 106 509/57 566 0.20 Plasma potassium level (mmol/L) 2.4 (1.4–5.5) 99 3.2 ± 0.2 1432 <0.01 Hypernatremia (present/absent) 13/34 47 – – – Plasma sodium level (mmol/L) 142.4 ± 7.1 46 141.7 ± 2.2 147 0.30 Side of tumor (L/R) 43/53 96 72/80 152 0.75 Maximum tumor diameter (cm) 8.0 (2.0–35.0) 95 1.7 ± 0.7 884 <0.01 Tumor mass weight (g) 150.0 (18.5–2750.0) 43 – – – Metastasis (present/absent) 15/40 55 – – – Relative value of PAC∗ 2.9 (0.9–532.2) 59 – – – PAC (ng/dL) 58.3 (7.2–4790.0) 62 24.2 ± 5.5 1432 <0.01 Low renin (present/absent) 43/14 57 – – – Relative value of PRA∗ 0.2 (0–0.8) 33 – – – PRA (ng · mL−1 · h−1) 0.2 (0–3.0) 40 0.4 ± 0.2 1018 <0.01 ARR (ng/dL per ng · mL−1 · h−1)† 13.0 (0.9–798.3) 54 2.5 ± 0.8 1024 <0.01 Cortisol excess (present/absent) 20/50 70 – – – Androgen excess (present/absent) 3/38 41 – – – Results were expressed as n, mean ± SD in normally distributed data, and median plus range in the case of non-normally distributed data. Because the original data of APAA group is unavailable, the results were analyzed by using one-arm meta-analysis.∗Because the serum aldosterone and renin test methods and the range of normal values varied remarkably, relative value of PAC was calculated as the multiple of the normal upper limit, relative value of plasma renin activity was calculated as the multiple of the normal lower limit.†ARR was calculated as the multiple of the cut-off point (30 ng/dL per ng · mL−1 · h−1). APAA: Aldosterone-producing adrenocortical adenoma; APAC: Aldosterone-producing adrenocortical carcinoma; ARR: Aldosterone to renin ratio; F: Female; L: Left; M: Male; N: Number; PA: Primary aldosteronism; PAC: Plasma aldosterone concentration; PRA: Plasma renin activity; R: Right; SD: Standard deviation. –: Not applicable. According to the available information, hypertension and hypokalemia were present in 94.5% (103/109) and 93.4% (99/106) of APAC cases, respectively. The mean systolic blood pressure in APAC patients was 185.1 mmHg (standard deviation [SD]: 3.5 mmHg), and the median diastolic blood pressure was 110.0 mmHg (range: 60.0–190.0 mmHg), and the median plasma potassium level was 2.4 mmol/L (IQR: 1.4–5.5 mmol/L), both of which reached statistical significance compared with APAA (P < 0.01). Additionally, compared with APAA, plasma aldosterone concentration (PAC) was higher in APAC (58.3 ng/dL [IQR: 7.2–4790.0 ng/dL] vs. 24.2 ng/dL [SD: 5.5 ng/dL], P < 0.01), plasma renin activity (PRA) was lower in APAC (0.2 [IQR: 0.1–0.5] vs. 0.4 [SD: 0.2] ng·mL−1·h−1, P < 0.01), and the elevated fold change of aldosterone to renin ratio (ARR) value was higher in APAC (13.0 [IQR: 0.9–798.3] vs. 2.5 [SD: 0.8]· ng/dL·per ng·mL−1·h−1, P < 0.01). APAC tumor diameter and weight varied widely, from 2.0 cm to 35.0 cm (median value: 8.0 cm) and from 18.5 g to 2750.0 g (median value: 150.0 g), respectively. A significant difference in tumor size was noted between APAC and APAA because the mean APAA tumor diameter was only 1.7 cm (SD: 0.7 cm) (P < 0.01). Metastases were found in 15 patients at the initial diagnosis [Supplementary Table 4, https://links.lww.com/CM9/B221]. Detailed imaging and pathological information were lacking in most articles, and the available data are summarized in [Supplementary Tables 5 and 6, https://links.lww.com/CM9/B221]. In terms of treatments, anti-hypertensive medications, including spironolactone and adrenalectomy, were administered to 87 patients, while chemotherapy, radiotherapy, and mitotane were administered to 22, 3, and 26 patients, respectively. The available follow-up information indicated tumor recurrence in 42/82 (51.2%) patients, and 29/82 (35.4%) patients died during the follow-up period. The leading cause of death was tumor relapse or metastases, accounting for 69.0% (20/29) of all deaths. The Kaplan–Meier survival analysis suggested a median survival time of 1460 days for APAC (standard error [SE], 425 days; 95% confidence interval [CI], 607–2293 days) [Supplementary Figure 1A, https://links.lww.com/CM9/B221] and a median time for both tumor recurrence and death of 365 days (SE, 97 days; 95% CI, 219–511 days) [Supplementary Figure 1B, https://links.lww.com/CM9/B221]. When APAC patients were divided into non-metastatic and metastatic groups at initial diagnosis, a significantly longer survival time (median value: 1550 days, 95% CI, 0–3687 days) was found in non-metastatic patients than in metastatic patients (median value, 146 days; 95% CI, 0–436 days) (P ≤ 0.01) [Supplementary Figure 1C, https://links.lww.com/CM9/B221]. For time to either death or recurrence, age (≥45.4 years) and metastasis at diagnosis attained statistical significance in the Kaplan–Meier analysis. However, Cox regression did not find any significant prognostic predictive factors. Although the diagnosis of APAC is mostly based on Weiss criteria,[1] our analysis showed that APAC had several unique clinical features compared with APAA, including larger tumor size, higher PAC, lower PRA, higher ARR, higher prevalence of cortisol cosecretion and possible androgen cosecretion, higher blood pressure, and lower potassium level. We found that tumor size was the most specific and sensitive marker for differentiating APAC and APAA. Therefore, we developed pre-surgery diagnostic criteria for APAC [Supplementary Tables 7 and 8, https://links.lww.com/CM9/B221]. If PA patients with adrenal glands are established, the following items might be useful in differentiating APAC and APAA: (1) tumor size: if the tumor size is >2.8 cm, there is a very high risk of APAC (sensitivity, 96.8%; specificity, 95.0%); if the tumor size is >3.5 cm, APAC is almost clinically definite (sensitivity, 88.4%; specificity, 99.5%); (2) metastasis: if the patient has metastasis, APAC is almost clinically definite (specificity, 100.0%; sensitivity, 37.5%). (3) ARR: if the elevated fold change of ARR is >4.6 ng/dL per ng · mL−1 · h−1, there is a very high risk of APAC (sensitivity, 70.4%; specificity, 99.5%). (4) PAC: if the PAC is >38.4 ng/dL, there is a very high risk of APAC (sensitivity, 62.5%; specificity, 99.5%). (5) Elevated androgen levels: if the patient has elevated androgen levels simultaneously, APAC is almost clinically definite (specificity, approximately 100.0%; sensitivity, 7.3%). APAC is a rare disease with a poor prognosis that was first reported by Foye and Feichtmeir[2] in 1955. In 2005, Seccia et al[3] created a database of 58 published APAC cases. We updated this database by including APAC cases reported after 2005 and adding Chinese cases to obtain more accurate results for APAC clinical characteristics. Kaplan–Meier analysis in Seccia et al's[3] study revealed that the median APAC patient survival was 546 days, and the time-lapse between surgery and either tumor recurrence or death was 212 days. However, the results from our updated APAC database suggested a median survival time of 1460 days, while the median time for either tumor recurrence or death was 365 days, which are both longer than Seccia's results. This increase in survival probably resulted from an earlier diagnosis and more advanced treatment of this disease. In addition, a higher 2-year survival rate was found in APAC patients diagnosed after 2005 (12/29, 41.4%) than in those diagnosed before 2005 (16/54, 30.2%). Current guidelines[4,5] suggest that surgical resection with the goal of a microscopically free margin (R0 resection) is the critical treatment in localized ACC patients. For metastatic or recurrent ACC, chemotherapy and mitotane are the most frequent treatments. However, a better prognosis and longer survival of APAC are still needed, and more tools are needed to achieve these improvements. Funding This research was supported by a grant from the 1·3·5 project for disciplines of excellence, West China Hospital, Sichuan University (No. ZYGD18017). Conflicts of interest None.