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Abstract Objective To delineate the metabolomic differences in plasma samples between patients with coronary artery disease (CAD) and those with concomitant CAD and type 2 diabetes mellitus (T2DM), and to pinpoint distinctive metabolites indicative of T2DM risk. Method Plasma samples from CAD and CAD-T2DM patients across three centers underwent comprehensive metabolomic and lipidomic analyses. Multivariate logistic regression was employed to discern the relationship between the identified metabolites and T2DM risk. Characteristic metabolites' metabolic impacts were further probed through hepatocyte cellular experiments. Subsequent transcriptomic analyses elucidated the potential target sites explaining the metabolic actions of these metabolites. Results Metabolomic analysis revealed 192 and 95 significantly altered profiles in the discovery (FDR

Abstract Background The relationship between the combined hematological parameters and echocardiography and long‐term prognosis in patients with coronary artery disease (CAD) remains unclear. Methods We examined the ability of hematological parameters to predict all‐cause death and major adverse cardiovascular events (MACE) based on Lasso Cox regression analysis. The significant predictors of hematological parameters from the Lasso Cox model were analyzed via multivariate Cox regression analysis and by adjusting for echocardiographic data. We calculated the continuous net reclassification improvement (cNRI) and integrated discrimination improvement (IDI) of the hematological parameters to assess the improvement in prediction. Results A low hemoglobin and lymphocyte ratio and high hematocrit, red blood cell distribution width‐coefficient of variation, and monocyte ratio significantly increased the risk of MACE and death in CAD patients. Neutrophil‐to‐lymphocyte ratio was associated with MACE but not death in CAD patients. After adjustment for echocardiographic parameters, hemoglobin, hematocrit, and lymphocyte ratio remained independently related to death and MACE. The addition of hematological and echocardiographic parameters to the Framingham risk score model significantly improved the area under the curve of mortality (0.794 vs. 0.713, p = 0.0007) and reclassification with cNRI of 30.6% (p = 0.002) and IDI of 0.055 (p

Transforming growth factor β (TGF-β)/Smad3 signaling plays a central role in chronic heart disease. Here, we report that targeting Smad3 with a Smad3 inhibitor SIS3 in an established mouse model of hypertension significantly improved cardiac dysfunctions by preserving the left ventricle (LV) ejection fraction (LVEF) and LV fractional shortening (LVFS), while reducing the LV mass. In addition, SIS3 treatment also halted the progression of myocardial fibrosis by blocking α-smooth muscle actin-positive (α-SMA+) myofibroblasts and collagen matrix accumulation, and inhibited cardiac inflammation by suppressing interleukin (IL)-1β, tumor necrosis factor alpha (TNF-α), monocyte chemotactic protein 1 (MCP1), intercellular cell adhesion molecule-1 (ICAM1) expression, and infiltration of CD3+ T cells and F4/80+ macrophages. Interestingly, treatment with SIS3 did not alter levels of high blood pressure, revealing a blood pressure-independent cardioprotective effect of SIS3. Mechanistically, treatment with SIS3 not only directly inactivated TGF-β/Smad3 signaling but also protected cardiac Smad7 from Smurf2-mediated proteasomal ubiquitin degradation. Because Smad7 functions as an inhibitor for both TGF-β/Smad and nuclear factor κB (NF-κB) signaling, increased cardiac Smad7 could be another mechanism through which SIS3 treatment blocked Smad3-mediated myocardial fibrosis and NF-κB-driven cardiac inflammation. In conclusion, SIS3 is a therapeutic agent for hypertensive heart disease. Results from this study demonstrate that targeting Smad3 signaling with SIS3 may be a novel and effective therapy for chronic heart disease.

BackgroundSystemic immune inflammation is a key mediator in the progression of coronary artery disease (CAD), concerning various metabolic and lipid changes. In this study, the relationship between the inflammatory index and metabolic profile in patients with CAD was investigated to provide deep insights into metabolic disturbances related to inflammation.MethodsWidely targeted plasma metabolomic and lipidomic profiling was performed in 1,234 patients with CAD. Laboratory circulating inflammatory markers were mainly used to define general systemic immune and low-grade inflammatory states. Multivariable-adjusted linear regression was adopted to assess the associations between 860 metabolites and 7 inflammatory markers. Least absolute shrinkage and selection operator (LASSO) logistic-based classifiers and multivariable logistic regression were applied to identify biomarkers of inflammatory states and develop models for discriminating an advanced inflammatory state.ResultsMultiple metabolites and lipid species were linearly associated with the seven inflammatory markers [false discovery rate (FDR)

Lipoprotein (a) [Lp(a)] is a genetically determined risk factor of coronary artery disease (CAD). Previous genome-wide association studies (GWASs), which were mostly carried out in Caucasians, have identified many Lp(a)-associated SNPs. Here, we performed a GWAS on Lp(a) levels and further explored the relationships between Lp(a)-associated SNPs and CAD severity in 1,403 Han Chinese subjects. We observed that elevated Lp(a) levels were significantly associated with the increased synergy between percutaneous coronary intervention with TAXUS and cardiac surgery (SYNTAX) score and the counts of heavily calcified lesions and long-range lesions (LRLs; P < 0.05), which are defined as lesions spanning >20 mm. Moreover, we identified four independent SNPs, namely, rs7770628, rs73596816, and rs6926458 in LPA, and rs144217738 in SLC22A2, that were significantly associated with Lp(a) levels. We also found that rs7770628 was associated with high SYNTAX scores [odds ratio (OR) (95% CI): 1.37 (1.05–1.80), P = 0.0213, false discovery rate (FDR) = 0.0852], and that rs7770628 and rs73596816 were associated with high risk of harboring LRLs [OR (95% CI): 1.53 (1.17–2.01), P = 0.0018, FDR = 0.0072 and 1.72 (1.19–2.49), P = 0.0040, FDR = 0.0080, respectively]. Our study was a large-scale GWAS to identify Lp(a)-associated variants in the Han Chinese population. Our findings highlight the importance and potential of Lp(a) intervention and expand our understanding of CAD prevention and treatment.

BACKGROUND: Previous studies have reported inconsistent results with positive, negative, and J-shaped associations between alcohol consumption and the hazard of aortic aneurysm and dissection (AAD). This study aimed to examine the connections between weekly alcohol consumption and the subsequent risk of AAD. METHODS: The UK Biobank study is a population-based cohort study. Weekly alcohol consumption was assessed using self-reported questionnaires and the congenital risk of alcohol consumption was also evaluated using genetic risk score (GRS). Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for the associations between alcohol consumption and AAD. Several sensitivity analyses were performed to assess the robustness of the results. RESULTS: Among the 388,955 participants (mean age: 57.1 years, 47.4% male), 2,895 incident AAD cases were documented during a median follow-up of 12.5 years. Compared with neverdrinkers, moderate drinkers (adjusted HR: 0.797, 95%CI: 0.646-0.984, P<0.05) and moderateheavy drinkers (adjusted HR: 0.794, 95%CI: 0.635-0.992, P<0.05) were significantly associated with a decreased risk of incident AAD. Interaction-based subgroup analysis revealed that the protective effect of moderate drinking was reflected mainly in participants younger than 65 years and women. CONCLUSION: Our findings support a protective effect of moderate alcohol consumption on AAD, but are limited to participants younger than 65 years and women. [ABSTRACT FROM AUTHOR]