Regional neuroinflammation-mediated cardiac sympathetic activity contributes to impaired cardiac function after cerebral stroke

Background Ischemic stroke has been shown to be associated with an elevated risk of heart failure development. Activation of the immune system and sympathetic nervous system may be potential mediators for this brain-heart crosstalk. Molecular imaging may provide mechanistic insights. We hypothesized that neuroinflammation-driven sympathetic activation contributes to cardiac dysfunction after stroke such that selective beta-1 adrenoreceptor inhibition could spare cardiac function. Methods C57BL/6N mice underwent surgical cerebral stroke by transient 30min middle artery occlusion (MCAo, n=14) or sham surgery (n=8). MCAo mice were randomized to receive beta-1-adrenoceptor blocker metoprolol (10 mg/kg/d, p.o.) starting from the day of MCAo (n=7) or vehicle (n=7). Positron emission tomography (PET) using translocator protein (TSPO) ligand 18F-GE-180 measured brain inflammation at 1d, 7d and 21d after stroke. Stroke size and cardiac function were assessed by magnetic resonance imaging at 1 and 3 weeks after injury. Results TSPO PET imaging revealed an increased neuroinflammation in the injured brain hemisphere at 7d after MCAo compared to sham (4.6±1.0 vs 2.6±0.7% injected dose (ID)/g, p<0.001) and contralateral hemisphere (4.6±1.0 vs 3.6±0.4%ID/g, p=0.05). This elevation was preserved and comparable between metoprolol- and vehicle-treated mice (3.9±0.4 vs 4.6±1.0%ID/g, p=0.16). TSPO signal remained comparable between metoprolol-treated and untreated mice (p=0.91) 3 weeks after MCAo but there was no difference in TSPO signal between injured and contralateral hemisphere (Untreated: 2.7±0.4 vs 2.9±1.0%ID/g, p>0.99; Metoprolol: 2.5±0.6 vs 2.5±0.6%ID/g, p=0.89). Likewise cardiac TSPO signal, reflecting an amalgam of cardiomyocyte mitochondria and inflammatory cells, was similar between metoprolol and vehicle treated MCAo mice (5.0±1 vs 4.2± 0.6%ID/g, p=0.23). MCAo evoked a moderate decline in left ventricular ejection fraction (LVEF) compared to sham mice (49.9±2.5 vs 66.1±3.5%, p<0.001). Treatment with metoprolol tended to spare cardiac function 3 weeks after MCAo compared to vehicle (54.0±3.3 vs 49.9±2.5%, p=0.058). Conclusion MCAo induced neuroinflammation in the injured cerebral region, declining over 3 weeks. Concurrently, we observed a decline in cardiac function. Blockade of beta-1-adrenoceptors partially spared cardiac function, supporting the contribution of sympathetic neuronal activity to cardiac dysfunction after stroke. Imaging of regional neuroinflammation after stroke may identify susceptibility to sympathetic overactivity in the heart and guide intervention to mediate this brain-heart crosstalk.PET imaging and MRI of MCAo Comparison of cardiac function