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How cells outside the heart can affect the heart beat: The role of pulmonary vein sleeve cells for the development of atrial fibrillation

Rietdorf, Katja; Masoud, Said; McDonald, Fraser and Bootman, Martin (2015). How cells outside the heart can affect the heart beat: The role of pulmonary vein sleeve cells for the development of atrial fibrillation. In: Gordon Conference on Calcium Signalling, 7-12 June 2015, Newry, Maine, USA.

URL: https://www.grc.org/programs.aspx?id=12388
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Abstract

We are interested in the role of pulmonary vein sleeve cells (PVCs) in ageing-related heart defects such as atrial fibrillation. During atrial fibrillation the atrial chambers do not follow action potentials propagating from the sino-atrial node, but rather display rapid (~300 Hz) electrical signals that prevent coordinated atrial contraction. Although atrial fibrillation is not immediately fatal, it is debilitating because the atrial component of blood pumping is absent. Moreover, the pooling of blood within the atrial chambers can lead thrombus formation. Blood clots can travel from the heart to the brain and cause strokes.

PVCs are present outside the heart, and form a sheath around the pulmonary veins. It is well established that PVCs are a source of ectopic action potentials that can propagate into the heart via the left atrial chamber. Ablation procedures that electrically isolate the PVCs at their junctions with the left atrial chamber are commonly used to treat atrial fibrillation. Ageing is established as the biggest risk factor for the development of atrial fibrillation, and this is most probably due to altered ion homeostasis and the generation of ectopic electrical activity in PVCs. We have used electron microscopy, fluorescence imaging and immunostaining to explore the ageing-related changes in PVC structure and function that may underlie the generation of ectopic action potentials.

We compared the responses to electrical field stimulation and the level of spontaneous calcium activity in PVCs from young and aged mice (24 vs. 3 month-old C57BL/J6 mice), and found that PVCs from 24 month-old mice are less likely to respond to electrical field stimulation than those from 3 month-old mice (9.4 ± 9.4% vs. 43.4 ± 10.1% for 1 Hz stimulation). They also have a tendency to show higher levels of spontaneous calcium transients (0.6 ± 0.1 vs. 1.0 ± 0.2 Hz). These results are indicating an altered calcium homeostasis in aged mice.
We also compared the ultrastructure of PVCs in aged versus young mice. In particular, we observed that PVCs from 24 month-old mice contained more mitochondria (14.2 ± 1.1 vs. 18.4 ± 1.4 / 25 µm2) that were also enlarged (0.7 ± 0.02 vs. 1.0 ± 0.1 µm2) and heterogeneous in shape. Since mitochondria are important calcium buffers in cardiomyocytes, these changes in mitochondria are likely to impact on cardiac calcium homeostasis. Moreover, we found that PVCs from aged mice contained lipofuscin; lipid-containing granules arising from fatty acid oxidation and lysosomal/mitochondrial damage, which were absent in PVCs from young mice. Myofibres in PVCs from 3 month-old mice were less organised than those in age-matched ventricular cardiomyocytes. The organisation of PVC myofibres did not appreciably alter with ageing, whereas myofibres in ventricular cardiomyocytes became less organised in 24 month-old mice.

Overall, our results indicate that there are significant changes in the ultrastructure and function of contractile cells within the heart, and that PVCs are less organised that other cardiomyocytes and become increasingly prone to spontaneous calcium signalling during ageing.

Item Type: Conference or Workshop Item
Academic Unit/School: Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
Faculty of Science, Technology, Engineering and Mathematics (STEM)
Interdisciplinary Research Centre: Biomedical Research Network (BRN)
Health and Wellbeing PRA (Priority Research Area)
Item ID: 44177
Depositing User: Katja Rietdorf
Date Deposited: 06 Oct 2015 09:55
Last Modified: 11 Sep 2017 15:32
URI: http://oro.open.ac.uk/id/eprint/44177
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