Department of Advanced Medical and Surgical Sciences, Università degli Studi della Campania "Luigi Vanvitelli", Piazza Miraglia, 2, 80138, Naples, Italy.
Mediterranea Cardiocentro, Naples, Italy.
Cardiovasc Diabetol. 2022 Aug 5;21(1):146. doi: 10.1186/s12933-022-01573-x.
High glycated-hemoglobin (HbA1c) levels correlated with an elevated risk of adverse cardiovascular outcomes despite renin-angiotensin system (RAS) inhibition in type-2 diabetic (T2DM) patients with reduced ejection fraction. Using the routine biopsies of non-T2DM heart transplanted (HTX) in T2DM recipients, we evaluated whether the diabetic milieu modulates glycosylated ACE2 (GlycACE2) levels in cardiomyocytes, known to be affected by non-enzymatic glycosylation, and the relationship with glycemic control.
We investigated the possible effects of GlycACE2 on the anti-remodeling pathways of the RAS inhibitors by evaluating the levels of Angiotensin (Ang) 1-9, Ang 1-7, and Mas receptor (MasR), Nuclear-factor of activated T-cells (NFAT), and fibrosis in human hearts.
We evaluated 197 first HTX recipients (107 non-T2DM, 90 T2DM). All patients were treated with angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) at hospital discharge. Patients underwent clinical evaluation (metabolic status, echocardiography, coronary CT-angiography, and endomyocardial biopsies). Biopsies were used to evaluate ACE2, GlycACE2, Ang 1-9, Ang 1-7, MasR, NAFT, and fibrosis.
GlycACE2 was higher in T2DM compared tonon-T2DM cardiomyocytes. Moreover, reduced expressions of Ang 1-9, Ang 1-7, and MasR were observed, suggesting impaired effects of RAS-inhibition in diabetic hearts. Accordingly, biopsies from T2DM recipients showed higher fibrosis than those from non-T2DM recipients. Notably, the expression of GlycACE2 in heart biopsies was strongly dependent on glycemic control, as reflected by the correlation between mean plasma HbA1c, evaluated quarterly during the 12-month follow-up, and GlycACE2 expression.
Poor glycemic control, favoring GlycACE2, may attenuate the cardioprotective effects of RAS-inhibition. However, the achievement of tight glycemic control normalizes the anti-remodeling effects of RAS-inhibition.
https://clinicaltrials.gov/ NCT03546062.
尽管在射血分数降低的 2 型糖尿病（T2DM）患者中使用了肾素-血管紧张素系统（RAS）抑制剂，但高糖化血红蛋白（HbA1c）水平与不良心血管结局风险升高相关。利用 T2DM 受者非 T2DM 心脏移植（HTX）的常规活检，我们评估了糖尿病环境是否会调节已知受非酶糖基化影响的糖基化 ACE2（GlycACE2）在心肌细胞中的水平，以及与血糖控制的关系。
我们通过评估血管紧张素（Ang）1-9、Ang 1-7 和 Mas 受体（MasR）、核因子活化 T 细胞（NFAT）和纤维化的水平，研究 GlycACE2 对 RAS 抑制剂抗重塑途径的可能影响。
我们评估了 197 例首次 HTX 受者（107 例非 T2DM，90 例 T2DM）。所有患者在出院时均接受血管紧张素转换酶抑制剂（ACE-I）或血管紧张素受体阻滞剂（ARB）治疗。患者接受临床评估（代谢状态、超声心动图、冠状动脉 CT 血管造影和心内膜心肌活检）。活检用于评估 ACE2、GlycACE2、Ang 1-9、Ang 1-7、MasR、NAFT 和纤维化。
与非 T2DM 心肌细胞相比，T2DM 中的 GlycACE2 更高。此外，观察到 Ang 1-9、Ang 1-7 和 MasR 的表达减少，表明糖尿病心脏中 RAS 抑制作用受损。相应地，T2DM 受者的活检显示比非 T2DM 受者的活检具有更高的纤维化。值得注意的是，GlycACE2 在心脏活检中的表达强烈依赖于血糖控制，这反映在 12 个月随访期间每季度评估的平均血浆 HbA1c 与 GlycACE2 表达之间的相关性。
较差的血糖控制有利于 GlycACE2，可能会减弱 RAS 抑制的心脏保护作用。然而，实现严格的血糖控制可使 RAS 抑制的抗重塑作用正常化。
