Department of Cardiology, MOE Key Laboratory of Model Animal for Disease Study, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing University, Nanjing, China.
Division of Colorectal Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing University, Nanjing, China.
Cardiovasc Diabetol. 2024 Jul 5;23(1):236. doi: 10.1186/s12933-024-02342-8.
Owing to its unique location and multifaceted metabolic functions, epicardial adipose tissue (EAT) is gradually emerging as a new metabolic target for coronary artery disease risk stratification. Microvascular obstruction (MVO) has been recognized as an independent risk factor for unfavorable prognosis in acute myocardial infarction patients. However, the concrete role of EAT in the pathogenesis of MVO formation in individuals with ST-segment elevation myocardial infarction (STEMI) remains unclear. The objective of the study is to evaluate the correlation between EAT accumulation and MVO formation measured by cardiac magnetic resonance (CMR) in STEMI patients and clarify the underlying mechanisms involved in this relationship.
Firstly, we utilized CMR technique to explore the association of EAT distribution and quantity with MVO formation in patients with STEMI. Then we utilized a mouse model with EAT depletion to explore how EAT affected MVO formation under the circumstances of myocardial ischemia/reperfusion (I/R) injury. We further investigated the immunomodulatory effect of EAT on macrophages through co-culture experiments. Finally, we searched for new therapeutic strategies targeting EAT to prevent MVO formation.
The increase of left atrioventricular EAT mass index was independently associated with MVO formation. We also found that increased circulating levels of DPP4 and high DPP4 activity seemed to be associated with EAT increase. EAT accumulation acted as a pro-inflammatory mediator boosting the transition of macrophages towards inflammatory phenotype in myocardial I/R injury through secreting inflammatory EVs. Furthermore, our study declared the potential therapeutic effects of GLP-1 receptor agonist and GLP-1/GLP-2 receptor dual agonist for MVO prevention were at least partially ascribed to its impact on EAT modulation.
Our work for the first time demonstrated that excessive accumulation of EAT promoted MVO formation by promoting the polarization state of cardiac macrophages towards an inflammatory phenotype. Furthermore, this study identified a very promising therapeutic strategy, GLP-1/GLP-2 receptor dual agonist, targeting EAT for MVO prevention following myocardial I/R injury.
由于其独特的位置和多方面的代谢功能，心外膜脂肪组织（EAT）逐渐成为冠状动脉疾病风险分层的新代谢靶点。微血管阻塞（MVO）已被认为是急性心肌梗死患者预后不良的独立危险因素。然而，EAT 在 ST 段抬高型心肌梗死（STEMI）患者中 MVO 形成发病机制中的具体作用尚不清楚。本研究旨在评估 EAT 堆积与 STEMI 患者心脏磁共振（CMR）测量的 MVO 形成之间的相关性，并阐明其相关性的潜在机制。
首先，我们利用 CMR 技术探讨了 EAT 分布和数量与 STEMI 患者 MVO 形成之间的相关性。然后，我们利用 EAT 耗竭的小鼠模型探讨了在心肌缺血/再灌注（I/R）损伤的情况下，EAT 如何影响 MVO 的形成。我们还通过共培养实验进一步研究了 EAT 对巨噬细胞的免疫调节作用。最后，我们寻找了针对 EAT 的新治疗策略，以防止 MVO 的形成。
左房室 EAT 质量指数的增加与 MVO 的形成独立相关。我们还发现，DPP4 水平升高和 DPP4 活性升高似乎与 EAT 的增加有关。EAT 的堆积作为一种促炎介质，通过分泌炎症性 EVs，促进心肌 I/R 损伤中心肌巨噬细胞向炎症表型的转变。此外，我们的研究表明 GLP-1 受体激动剂和 GLP-1/GLP-2 受体双重激动剂的潜在治疗效果至少部分归因于其对 EAT 调节的影响。
我们的工作首次证明，EAT 的过度堆积通过促进心脏巨噬细胞向炎症表型极化，促进 MVO 的形成。此外，本研究确定了一种很有前途的治疗策略，即 GLP-1/GLP-2 受体双重激动剂，可靶向 EAT 预防心肌 I/R 损伤后的 MVO。
