The synthesis and secretion of melatonin by the pineal gland regulates the normal diurnal rhythm in humans and is controlled by sympathetic neurons from the superior cervical ganglion (SCG). The SCG also provides innervation to the heart, and individuals with heart disease experience a disrupted diurnal rhythm and reduced levels of melatonin. However, the mechanisms responsible for this disruption and the contribution of pineal gland innervation are unknown.
In a recent study, Ziegler et al. investigated whether the neurons that control the pineal gland are impaired in heart disease. The authors stained post-mortem pineal gland tissue for the sympathetic marker tyrosine hydroxylase, which revealed gland denervation in individuals with heart disease compared with healthy controls. Transverse aortic constriction (TAC) in mice to induce left ventricular pressure overload and cardiac hypertrophy resulted in a reduced melatonin plasma concentration after four weeks, disruption of the diurnal rhythm, and denervation of the pineal gland. The latter pathology was also seen in a mouse model of heart failure with preserved ejection fraction. Morphometric and histopathological analyses of SCG in mice with cardiac pressure overload revealed significant hypertrophy and fibrotic scarring. This finding was confirmed in post-mortem samples from individuals with heart disease and shown to correlate with levels of myocardial fibrosis, which prompted a prospective clinical study investigating SCG size (measured by quantitative ultrasonography) as a potential imaging biomarker for heart failure. SCG was significantly enlarged in individuals with heart failure, and SCG size inversely correlated with ejection fraction. Furthermore, the authors found high numbers of macrophages in the SCG of TAC-mice. Analysing mRNA expression of cells within the SCG revealed a marked increase in macrophages (identified using the macrophage marker CD68) and a substantial reduction in pineal gland-innervating neurons expressing melatonin receptor 1A (Mtnr1a) in the SCG of TAC-mice versus controls. These effects were prevented by injections of the macrophage inhibitor clodronate into the SCG. Co-culture of sympathetic neurons and proinflammatory macrophages, with subsequent inhibition of macrophage activation, suggested that activated macrophages mediate the loss of sympathetic neurons in the pineal gland.
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