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Molecular Imaging of Myocardial Inflammation and the Progression of Heart Failure

Subject Area Nuclear Medicine, Radiotherapy, Radiobiology
Term from 2016 to 2022
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 319331954
 
Final Report Year 2020

Final Report Abstract

A heart attack (myocardial infarction, MI) cuts off blood flow and oxygen delivery to the heart muscle. This results in abnormal function, changes to heart geometry, and heart failure. Heart failure is the inability to maintain pump function to provide oxygen and nutrients to the body. Early after the injury, white blood cells invade the damaged heart to initiate healing and repair in an organized inflammatory response. Too much or too little inflammation can lead to worse outcome. But it is difficult to determine which patients will develop heart failure. The severity of inflammation is thought to relate to disease progression, and is a promising drug target. We aimed to develop an imaging assay to visualize inflammation after acute MI. Two imaging probes identify separate parts of the inflammatory response to tissue injury. One probe targets a protein called TSPO on pro-inflammatory macrophages, which remove damaged cells and promote further inflammation. Another probe targets a chemokine receptor, CXCR4, which is a signal to recruit reparative cells to the site of injury. This probe identified a wider range of white blood cells. We tested these probes in a mouse model that mimics human MI, by surgically blocking an artery supplying the heart muscle. Early inflammation was imaged using either method. Late heart function was measured by magnetic resonance imaging. Images showed high TSPO signal in the injury site from 3-7d after MI. Microscopy displayed high content of macrophages in the damaged region, corresponding to the image intensity. Animals with a higher signal went on to worse heart function 8 weeks later. Similarly, a high CXCR4 signal was seen at the injury site from 1-3d after MI. Cell counting showed that the signal corresponded to high levels of pro-inflammatory white blood cells including neutrophils and macrophages. Again, animals with a higher CXCR4 signal at 1d or 3d had worse outcome, including ventricle rupture, when the edge of the scar tissue breaks due to weakening of the tissue. Late function was also lower in animals with higher CXCR4 signal. The imaging assays could predict which mice would develop more severe heart failure. We then tested whether the images could identify the ideal timing of treatment to control the inflammation. At 3d after MI, when the image signal indicated risk for rupture or heart failure, we gave a drug to block CXCR4 and arrest recruitment of white blood cells. For comparison, we also treated mice at a time when the image signal was not elevated at 7d after MI. We found that timed blockade of CXCR4 at 3d reduced the incidence of ventricle rupture and improved the late cardiac function compared to untreated MI mice. Blocking CXCR4 at 7d after MI did not improve the late function. Cell counting confirmed that the white blood cells present in the heart after treatment were shifted to more reparative types. This suggests that the imaging assays could guide therapy in a clinical setting. Taken together, molecular imaging of inflammation early after MI provides added value predict late outcome in mice. Since patients show wider variability in early inflammatory response to injury, imaging could identify those at higher risk to develop heart failure. These assays could also direct the best timing for molecular therapy to improve outcome. This imaging work builds the foundation for a personalized medicine approach, giving the right treatment, to the right patient, at the right time.

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