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Background: Diabetic heart dysfunction is a common complication of diabetes. Cell death is a core event that leads to diabetic heart dysfunction. However, the time sequence of cell death pathways and the precise time to intervene of particular cell death type remain largely unknown in the diabetic heart. This study aims to identify the particular cell death type that is responsible for diabetic heart dysfunction and to propose a promising therapeutic strategy by intervening in the cell death pathway. Methods: Type 2 diabetes models were established using db/db leptin receptor–deficient mice and high-fat diet/streptozotocin–induced mice. The type 1 diabetes model was established in streptozotocin-induced mice. Apoptosis and programmed cell necrosis (necroptosis) were detected in diabetic mouse hearts at different ages. G protein–coupled receptor–targeted drug library was searched to identify potential receptors regulating the key cell death pathway. Pharmacological and genetic approaches that modulate the expression of targets were used. Stable cell lines and a homemade phosphorylation antibody were prepared to conduct mechanistic studies. Results: Necroptosis was activated after apoptosis at later stages of diabetes and was functionally responsible for cardiac dysfunction. Cannabinoid receptor 2 (CB2R) was a key regulator of necroptosis. Mechanically, during normal glucose levels, CB2R inhibited S6 kinase–mediated phosphorylation of BACH2 at serine 520, thereby leading to BACH2 translocation to the nucleus, where BACH2 transcriptionally repressed the necroptosis genes Rip1 , Rip3 , and Mlkl . Under hyperglycemic conditions, high glucose induced CB2R internalization in a β-arrestin 2–dependent manner; thereafter, MLKL (mixed lineage kinase domain-like), but not receptor-interacting protein kinase 1 or 3, phosphorylated CB2R at serine 352 and promoted CB2R degradation by ubiquitin modification. Cardiac re-expression of CB2R rescued diabetes-induced cardiomyocyte necroptosis and heart dysfunction, whereas cardiac knockout of Bach2 diminished CB2R-mediated beneficial effects. In human diabetic hearts, both CB2R and BACH2 were negatively associated with diabetes-induced myocardial injuries. Conclusions: CB2R transcriptionally repressed necroptosis through interaction with BACH2; in turn, MLKL formed a negative feedback to phosphorylate CB2R. Our study provides the integrative view of a novel molecular mechanism loop for regulation of necroptosis centered by CB2R, which represents a promising alternative strategy for controlling diabetic heart dysfunction.

Background: Secreted frizzled-related protein 2 (sFRP2) plays an important role in metabolic syndrome and cardiovascular diseases (CVDs); However, its relevance with cardiometabolic diseases remains to be elucidated. We aimed to determine the serum levels of sFRP2 in patients at different stages of heart failure (HF) with or without type 2 diabetes mellitus (T2DM), and assess the correlation between circulating sFRP2 levels and cardiometabolic risk factors.Methods: In this study, serum samples from 277 patients visiting Zhongshan Hospital affiliated to Fudan University were collected. These patients were clinically diagnosed and categorized as five groups, including the control group, pre-clinical HF group, pre-clinical HF+T2DM group, HF group and HF+T2DM group. Serum sFRP2 levels were measured with enzyme-linked immunosorbent assay (ELISA) tests and the clinical characteristics of each patient were recorded. Spearman rank correlation analysis and multiple stepwise linear regression analysis were conducted. Univariate and multivariate logistic regression analysis were performed to screen risk factors for HF in patients with CVDs.Results: Serum sFRP2 levels were significantly lower in the HF+T2DM group compared with the other four groups. Spearman rank correlation analysis showed that sFRP2 was negatively correlated with parameters including patients' age, fasting plasma glucose (FPG), glycated hemoglobin A1c (HbA1c), cardiac troponin T (cTNT), N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (hs-CRP), left atrial dimension (LAD) and left ventricular posterior wall (LVPW), and positively correlated with hemoglobin, estimated glomerular filtration rate (eGFR), albumin, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and left ventricular ejection fraction (LVEF). However, in multiple regression analysis, significant associations with ln(sFRP2) were observed only in FPG, hs-CRP and LAD. Higher serum sFRP2 was significantly linked to lower odds of HF in patients with CVDs.Conclusion: sFRP2 progressively decreased when glucose homeostasis and cardiac function deteriorated. sFRP2 acted as a risk factor for HF in patients with CVDs, especially in those with concomitant T2DM.

This article compared the performance of 18 electrocardiographic (ECG) left ventricular hypertrophic (LVH) criteria and four P-wave indices for the diagnosis of echocardiographic (ECHO) LVH and left atrial enlargement (LAE), including the deepest S-wave amplitude added to the S-wave amplitude of lead V4 (SD +SV4 ) and P-wave terminal force in lead V1 (PTFV1 ). A total of 152 middle-aged hypertensive patients without evident cardiovascular diseases (CVDs) were enrolled. The gold standard for the diagnosis of LVH and LAE was ECHO left ventricular mass index (LVMI) and largest left atrial volume index (LAVI). For the detection of LVH, Sokolow-Lyon voltage, Cornell voltage, Cornell product, SD +SV4 , Manning, and R+S in any precordial lead had relatively higher sensitivity, especially SD +SV4 criteria. Their combination could further increase sensitivity (43% vs 29% [SD +SV4 ], P = 0.016). PTFV1 was the only criterion that had significant diagnostic value for ECHO LAE (AUC, 0.68; 95% CI: 0.54-0.73, P = 0.008). For middle-aged hypertensive patients without evident cardiovascular diseases, SD +SV4 had the highest sensitivity for the diagnosis of LVH and the combination of several ECG LVH criteria might further increase sensitivity. PTFV1 had significant diagnostic value for ECHO LAE.

OBJECTIVE To compare the risk of stroke and coronary heart disease (CHD) among various blood pressure (BP) levels in diabetic and people without diabetes Chinese patients. METHODS This cross-sectional study was part of Prospective Urban Rural Epidemiology China study. Patients aged 35 to70 years were recruited from 12 provinces of China between 2005 and 2009. The participants were classified into three groups: hypertension (HTN), high normal BP, and normal BP, and also into SBP and DBP quintiles. RESULTS A total of 42 959 patients were analyzed with 38 975 (90.7% of total population) people without diabetes and 3984 (9.3% of total population) diabetic patients. Among diabetic patients, the HTN group was associated with an increased risk of stroke (odds ratio, 3.03; 95% confidence interval, 1.47-6.25) and CHD (odds ratio, 2.21; 95% confidence interval, 1.45-3.38), when compared with normal BP group. Similar results were drawn in nondiabetic patients. However, no significant difference in risk of stroke or CHD was found between high normal BP and normal BP groups in either diabetic or nondiabetic patients. Risk of CHD and stroke increased significantly when SBP was above 125 mmHg or DBP above 72 mmHg in people without diabetes, whereas this trend was attenuated in diabetic patients. CONCLUSION HTN was associated with a two-fold increased risk of CHD and a three-fold increased risk of stroke compared with normotension irrespective of diabetes status. For diabetic patients with HTN, a more comprehensive method is essential for assessing cardiovascular risk.