Cardiomyocyte Ca2+ handling and structure is regulated by degree and duration of mechanical load variation |
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Authors: | Michael Ibrahim Punam Kukadia Urszula Siedlecka James E. Cartledge Manoraj Navaratnarajah Sergiy Tokar Carin Van Doorn Victor T. Tsang Julia Gorelik Magdi H. Yacoub Cesare M. Terracciano |
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Affiliation: | Heart Science Centre, National Heart and Lung Institute, Imperial College London, , London, UK |
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Abstract: | Cardiac transverse (t)‐tubules are altered during disease and may be regulated by stretch‐sensitive molecules. The relationship between variations in the degree and duration of load and t‐tubule structure remains unknown, as well as its implications for local Ca2+‐induced Ca2+ release (CICR). Rat hearts were studied after 4 or 8 weeks of moderate mechanical unloading [using heterotopic abdominal heart–lung transplantation (HAHLT)] and 6 or 10 weeks of pressure overloading using thoracic aortic constriction. CICR, cell and t‐tubule structure were assessed using confocal‐microscopy, patch‐clamping and scanning ion conductance microscopy. Moderate unloading was compared with severe unloading [using heart‐only transplantation (HAHT)]. Mechanical unloading reduced cardiomyocyte volume in a time‐dependent manner. Ca2+ release synchronicity was reduced at 8 weeks moderate unloading only. Ca2+ sparks increased in frequency and duration at 8 weeks of moderate unloading, which also induced t‐tubule disorganization. Overloading increased cardiomyocyte volume and disrupted t‐tubule morphology at 10 weeks but not 6 weeks. Moderate mechanical unloading for 4 weeks had milder effects compared with severe mechanical unloading (37% reduction in cell volume at 4 weeks compared to 56% reduction after severe mechanical unloading) and did not cause depression and delay of the Ca2+ transient, increased Ca2+ spark frequency or impaired t‐tubule and cell surface structure. These data suggest that variations in chronic mechanical load influence local CICR and t‐tubule structure in a time‐ and degree‐dependent manner, and that physiological states of increased and reduced cell size, without pathological changes are possible. |
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Keywords: | assist device Ca2+ handling excitation– contraction coupling |
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