Department of Nuclear Medicine, Hannover Medical School, Carl Neuberg-Str. 1, D-30625, Hannover, Germany.
Eur J Nucl Med Mol Imaging. 2020 Jul;47(7):1757-1768. doi: 10.1007/s00259-020-04736-8. Epub 2020 Mar 3.
Myocardial infarction (MI) triggers a local inflammatory response which orchestrates cardiac repair and contributes to concurrent neuroinflammation. Angiotensin-converting enzyme (ACE) inhibitor therapy not only attenuates cardiac remodeling by interfering with the neurohumoral system, but also influences acute leukocyte mobilization from hematopoietic reservoirs. Here, we seek to dissect the anti-inflammatory and anti-remodeling contributions of ACE inhibitors to the benefit of heart and brain outcomes after MI.
C57BL/6 mice underwent permanent coronary artery ligation (n = 41) or sham surgery (n = 9). Subgroups received ACE inhibitor enalapril (20 mg/kg, oral) either early (anti-inflammatory strategy; 10 days treatment beginning 3 days prior to surgery; n = 9) or delayed (anti-remodeling; continuous from 7 days post-MI; n = 16), or no therapy (n = 16). Cardiac and neuroinflammation were serially investigated using whole-body macrophage- and microglia-targeted translocator protein (TSPO) PET at 3 days, 7 days, and 8 weeks. In vivo PET signal was validated by autoradiography and histopathology.
Myocardial infarction evoked higher TSPO signal in the infarct region at 3 days and 7 days compared with sham (p < 0.001), with concurrent elevation in brain TSPO signal (+ 18%, p = 0.005). At 8 weeks after MI, remote myocardium TSPO signal was increased, consistent with mitochondrial stress, and corresponding to recurrent neuroinflammation. Early enalapril treatment lowered the acute TSPO signal in the heart and brain by 55% (p < 0.001) and 14% (p = 0.045), respectively. The acute infarct signal predicted late functional outcome (r = 0.418, p = 0.038). Delayed enalapril treatment reduced chronic myocardial TSPO signal, consistent with alleviated mitochondrial stress. Early enalapril therapy tended to lower TSPO signal in the failing myocardium at 8 weeks after MI (p = 0.090) without an effect on chronic neuroinflammation.
Whole-body TSPO PET identifies myocardial macrophage infiltration and neuroinflammation after MI, and altered cardiomyocyte mitochondrial density in chronic heart failure. Improved chronic cardiac outcome by enalapril treatment derives partially from acute anti-inflammatory activity with complementary benefits in later stages. Whereas early ACE inhibitor therapy lowers acute neuroinflammation, chronic alleviation is not achieved by early or delayed ACE inhibitor therapy, suggesting a more complex mechanism underlying recurrent neuroinflammation in ischemic heart failure.
心肌梗死（MI）引发局部炎症反应，协调心脏修复，并导致并发神经炎症。血管紧张素转换酶（ACE）抑制剂治疗不仅通过干扰神经体液系统来减轻心脏重构，还影响急性白细胞从造血库中的动员。在这里，我们试图剖析 ACE 抑制剂对心脏和大脑的抗炎和抗重塑作用，以改善 MI 后的结局。
C57BL/6 小鼠接受永久性冠状动脉结扎（n=41）或假手术（n=9）。亚组接受 ACE 抑制剂依那普利（20mg/kg，口服）治疗，早期（抗炎策略；在手术前 3 天开始治疗 10 天；n=9）或延迟（抗重塑；从 MI 后 7 天开始连续治疗；n=16），或不治疗（n=16）。使用全身巨噬细胞和小胶质细胞靶向转移蛋白（TSPO）PET 在 3 天、7 天和 8 周时连续研究心脏和神经炎症。体内 PET 信号通过放射性自显影和组织病理学进行验证。
与假手术相比，心肌梗死在 3 天和 7 天引起梗死区域的 TSPO 信号升高（p<0.001），同时大脑 TSPO 信号升高（+18%，p=0.005）。在 MI 后 8 周时，远程心肌 TSPO 信号增加，与线粒体应激一致，与复发性神经炎症相对应。早期依那普利治疗使心脏和大脑的急性 TSPO 信号降低 55%（p<0.001）和 14%（p=0.045）。急性梗死信号预测晚期功能结局（r=0.418，p=0.038）。延迟依那普利治疗减轻慢性心肌 TSPO 信号，与减轻线粒体应激一致。早期依那普利治疗倾向于降低 MI 后 8 周时衰竭心肌的 TSPO 信号（p=0.090），但对慢性神经炎症无影响。
全身 TSPO PET 可识别 MI 后的心肌巨噬细胞浸润和神经炎症，以及慢性心力衰竭时的心肌细胞线粒体密度变化。依那普利治疗改善慢性心脏结局部分来自于急性抗炎活性，在后期有互补的益处。尽管早期 ACE 抑制剂治疗可降低急性神经炎症，但早期或延迟 ACE 抑制剂治疗并不能实现慢性缓解，这表明缺血性心力衰竭中复发性神经炎症存在更复杂的机制。
