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Abstract
Cancer is often associated with cachexia, cardiovascular symptoms and autonomic dysregulation. We tested whether extracardiac cancer directly affects the innervation of left ventricular myocardium. Mice injected with Lewis lung carcinoma cells (tumor group, TG) or PBS (control group, CG) were analyzed after 21 days. Cardiac function (echocardiography), serum levels of TNF-α and Il-6 (ELISA), structural alterations of cardiomyocytes and their innervation (design-based stereology) and levels of innervation-related mRNA (quantitative RT-PCR) were analysed. The groups did not differ in various functional parameters. Serum levels of TNF-α and Il-6 were elevated in TG. The total length of axons in the left ventricle was reduced. The number of dense core vesicles per axon profile was reduced. Decreased myofibrillar volume, increased sarcoplasmic volume and increased volume of lipid droplets were indicative of metabolic alterations of TG cardiomyocytes. In the heart, the mRNA level of nerve growth factor was reduced whereas that of β1-adrenergic receptor was unchanged in TG. In the stellate ganglion of TG, mRNA levels of nerve growth factor and neuropeptide Y were decreased and that of tyrosine hydroxylase was increased. In summary, cancer induces a systemic pro-inflammatory state, a significant reduction in myocardial innervation and a catabolic phenotype of cardiomyocytes in the mouse. Reduced expression of nerve growth factor may account for the reduced myocardial innervation.
Highlights
Cancer cachexia is a complex syndrome clinically manifesting as progressive loss of body weight with or without decreased food intake, and it is correlated with a poor prognosis [1]
The hypothesis was based on several reports on functional changes of the heart in patients suffering from a variety of forms of cancer [6,7,8,9] and the observation of degenerative structural lesions of cardiomyocytes in cancer cachexia [2]
In agreement with our hypothesis, we observed a pronounced reduction of the total length of axons innervating left ventricular cardiomyocytes and the number of neuropeptide storing organelles, large dense core vesicles (LDCV), in these axons
Summary
Cancer cachexia is a complex syndrome clinically manifesting as progressive loss of body weight with or without decreased food intake, and it is correlated with a poor prognosis [1]. A link has been hypothesized between cancer fatigue syndrome (a combination of dyspnea, exercise limitation and muscle weakness) and clinically non-overt heart failure, suggesting the fatigue symptoms to arise from autonomic dysfunction [10]. These studies clearly point to an involvement of the cardiac innervation in cancer cachexia, systematic studies on this topic are lacking so far
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