This study proved that cardiac- and neuro-inflammation can be assessed by TSPO targeted PET and gave insight into the heart-brain-network after MI. First, neuroinflammation post MI occurs independent from peripheral macrophages and derives from resident microglia. Second, peripheral macrophage depletion worsens early and late cardiac outcome and exaggerates acute neuroinflammation. This observation emphasizes the importance of balanced inflammation for adequate cardiac repair. Third, early treatment with enalapril to control inflammation lowers acute cardiac- and neuro-inflammation and improves cardiac function after MI. By contrast, delayed treatment with enalapril to attenuate remodeling lowers TSPO signal in remote myocardium in CHF, and improves contractile function. Fourth, TSPO may be a viable therapeutic target for chronic heart failure, acting independent of inflammation. Fifth, neuroinflammation in chronic heart failure is associated with declining cardiac function. Finally, whole body TSPO PET imaging provides quantitative non-invasive indication of peripheral macrophages and central microglial activation after acute MI, and may provide insight into altered mitochondrial biology in CHF. The systemic multi-organ-communication should be considered for application of heart failure therapy. TSPO PET provides a platform for image guided therapy after MI, in CHF, and neurodegenerative disease.
60 5.6.2 Future Direction
In this study, we did not measure cognitive response to MI, ACE inhibition, and TSPO inhibition. Earlier studies demonstrated impaired prefrontal memory in mice with CHF (130), which provides a framework for future experiments. The acute and chronic neuroinflammation observed here is consistent with mouse models of cognitive dysfunction (26,139). In addition, the cellular origin of the remote myocardial TSPO signal remains incompletely defined. However, immuno histology of heart failure remote myocardium also suggests localization to mitochondria in cardiomyocytes, which aligns with the upregulation of TSPO in CHF (90).
Because TSPO PET primarily reflects inflammation, we focused on these related mechanisms as influencing chronic cardiac function and recurrent neuroinflammation. Other factors, such as brain perfusion and sympathetic neuronal activation (97,105), may play a role in this observation, and should be investigated. Cardiac sympathetic activity could be assessed by performing PET scans using the tracer [18F]4F-MHPG (140). Whereas, brain sympathetic activity could be assessed e.g. by isolating hippocampal neurons from the animals post MI and performing patch-clamp studies (141,142).
In addition, one of the next steps could be to isolate and measure blood cytokines via liquid chromatography to identify upregulated cytokines post MI which may be responsible for the neuroinflammatory response. Finally, in the mouse model of myocardial infarction by ligation of the left coronary artery, the afferent and efferent nerve fibers are also ligated. This could affect the acute immune response in the infarct territory and influence the cardiac remodeling because of changes in the sympathetic innervation and changes in the neuropeptide signaling (101,117,143). TSPO PET scans could be done in a rat model of transthoracic, vascular-targeted, photo dynamically induced MI, which allows to occlude coronary arteries without injuring nerve fibers (144). Further investigations considering these points would give deeper insight into the connection of heart and brain after MI and improve therapeutic interventions.
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