Angiotensin-converting enzyme inhibitor treatment early after myocardial infarction attenuates acute cardiac and neuroinflammation without effect on chronic neuroinflammation

Abstract

Purpose 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. Methods 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. Results 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. Conclusions 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.

Quantification of Macrophage-Driven Inflammation During Myocardial Infarction with 18F-LW223, a Novel TSPO Radiotracer with Binding Independent of the rs6971 Human Polymorphism

“…In the rat MI model used in this study, we demonstrated that the majority of TSPO expression (BP TC ) was within the infarct region of the MI cohort, which was in agreement with ex-vivo analysis. However, it should be noted that in non-infarcted myocardium in other MI/cardiomyopathy models of heart failure, there is significant TSPO expression, indicating that TSPO may have a wider role in the failing heart (53,54).…”

Cognitive impairment in myocardial infarction and heart failure

“…51,52 Iba1 + cells and CD11b + cells increased after MI in whole brain area. 14,53 Microglia displayed a significant loss of complexity as indicated by a significantly reduced average number of total sholl's intersections that occurred in a time-dependent manner of MI condition. Changes in microglial morphology were already detectable at 8-week post-MI and became progressively to be more deramified at 14-and 16-week post-MI.…”

“…Fluorescence immunostaining demonstrated a colocalization of Iba1 and TSPO in cerebral cortex and that signal was higher in the MI group than controls. 53 Therefore, the authors suggest that the brain TSPO signals can be used to identify microglial activity. 53 The activated microglia also induced a neurotoxic A1 subtype of astrocytes, and the morphology changes of astrocyte were found at week 14 following MI.…”

“…53 Therefore, the authors suggest that the brain TSPO signals can be used to identify microglial activity. 53 The activated microglia also induced a neurotoxic A1 subtype of astrocytes, and the morphology changes of astrocyte were found at week 14 following MI. 19 Astrocytes are divided into two subtypes; A1 astrocyte is an activated subtype, which secretes a neurotoxin that results in neuronal cell death, 57 and the markers of A1 are Serping 1 and C3, which were increased following MI.…”

“…The evidence supports this idea that whole-body TSPO PET identifies myocardial macrophage infiltration and neuroinflammation after MI. 53 It has been shown that moderate doses of angiotensin converting enzyme inhibitors (ACEIs) exhibited anti-inflammatory action, 53 with their effects on neurohumoral activation. 65 Enalapril is an ACEI that primarily used in patients with hypertension and HF, which is the one of risk factors for dementia.…”