title: Prolonged mechanical unloading reduces myofilament sensitivity to calcium and sarcoplasmic reticulum calcium uptake leading to contractile dysfunction.
abstract: BACKGROUND
  Prolonged unloading using left ventricular (LV) assist devices (LVADs) leads to unloading-induced atrophy with altered cardiomyocyte contractility. The causes for this time-dependent deterioration of myocardial function are unclear. Our aim was to determine the effects of prolonged mechanical unloading on cardiomyocyte function and, more specifically, on Ca(2+) cycling and myofilament sensitivity to Ca(2+).
  
  
  METHODS
  LV unloading was induced by heterotopic abdominal transplantation (UN) in rats for 5 weeks. Recipient hearts were used as controls (REC). LV myocytes were isolated and cardiomyocyte area measured by planimetry, sarcomere length measured by Fourier analysis of digitized cardiomyocyte images, and cytoplasmic [Ca(2+)] monitored using Indo-1. Myofilament sensitivity to Ca(2+) was assessed as the slope of the linear relationship between Indo-1 ratio and sarcomere shortening during relaxation.
  
  
  RESULTS
  UN cardiomyocyte area was smaller compared with REC (mean +/- SEM: UN 2,503 +/- 78 microm(2) [n = 132], REC 3,856 +/- 89 microm(2) [n = 116]; p < 0.001). UN cardiomyocytes had a smaller sarcomere shortening amplitude (UN 0.08 +/- 0.01 microm [n = 37], REC 0.11 +/- 0.01 microm [n = 38]; p < 0.01), despite normal Ca(2+) transient amplitude (UN 0.13 +/- 0.01 Indo-1 ratio units [n = 37], REC 0.11 +/- 0.01 Indo-1 ratio units [n = 38]; p = non-significant). Myofilament sensitivity to Ca(2+) was reduced in UN (UN 2.0 +/- 1.2 microm/ratio unit [n = 20], REC 3.7 +/- 0.4 microm/ratio unit [n = 22]; p < 0.01). Sarcoplasmic reticulum (SR) Ca(2+) uptake (assessed by 20 mmol/liter caffeine) was also reduced in UN (UN 84.3 +/- 0.79% relative contribution [n = 22], REC 89.8 +/- 0.67% relative contribution [n = 24]; p < 0.001).
  
  
  CONCLUSIONS
  Prolonged myocardial unloading causes depressed contractility due to reduced SR Ca(2+) uptake and myofilament sensitivity to Ca(2+). These effects may be relevant with regard to myocardial performance after prolonged LVAD support.
authors.affiliation: Imperial College London, National Heart and Lung Institute, Heart Science Centre, Harefield Hospital, Harefield, UK.
authors.forename: Gopal K R
authors.initials: GK
authors.lastname: Soppa
authors.forename: Joon
authors.initials: J
authors.lastname: Lee
authors.forename: Mark A
authors.initials: MA
authors.lastname: Stagg
authors.forename: Urszula
authors.initials: U
authors.lastname: Siedlecka
authors.forename: Samuel
authors.initials: S
authors.lastname: Youssef
authors.forename: Magdi H
authors.initials: MH
authors.lastname: Yacoub
authors.forename: Cesare M N
authors.initials: CM
authors.lastname: Terracciano
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D001284:Atrophy; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D004195:Disease Models, Animal; D016027:Heart Transplantation; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D006353:Heart-Assist Devices / Q000009:adverse effects*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D051381:Rats; D011917:Rats, Inbred Lew; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology*; D020257:Ventricular Remodeling
chemical_list: D002118:Calcium