title: Intracellular dyssynchrony of diastolic cytosolic [Ca²⁺] decay in ventricular cardiomyocytes in cardiac remodeling and human heart failure.
abstract: BACKGROUND
  Synchronized release of Ca²⁺ into the cytosol during each cardiac cycle determines cardiomyocyte contraction.
  
  
  OBJECTIVE
  We investigated synchrony of cytosolic [Ca²⁺] decay during diastole and the impact of cardiac remodeling.
  
  
  RESULTS
  Local cytosolic [Ca²⁺] transients (1-µm intervals) were recorded in murine, porcine, and human ventricular single cardiomyocytes. We identified intracellular regions of slow (slowCaR) and fast (fastCaR) [Ca²⁺] decay based on the local time constants of decay (TAUlocal). The SD of TAUlocal as a measure of dyssynchrony was not related to the amplitude or the timing of local Ca²⁺ release. Stimulation of sarcoplasmic reticulum Ca²⁺ ATPase with forskolin or istaroxime accelerated and its inhibition with cyclopiazonic acid slowed TAUlocal significantly more in slowCaR, thus altering the relationship between SD of TAUlocal and global [Ca²⁺] decay (TAUglobal). Na⁺/Ca²⁺ exchanger inhibitor SEA0400 prolonged TAUlocal similarly in slowCaR and fastCaR. FastCaR were associated with increased mitochondrial density and were more sensitive to the mitochondrial Ca²⁺ uniporter blocker Ru360. Variation in TAUlocal was higher in pig and human cardiomyocytes and higher with increased stimulation frequency (2 Hz). TAUlocal correlated with local sarcomere relengthening. In mice with myocardial hypertrophy after transverse aortic constriction, in pigs with chronic myocardial ischemia, and in end-stage human heart failure, variation in TAUlocal was increased and related to cardiomyocyte hypertrophy and increased mitochondrial density.
  
  
  CONCLUSIONS
  In cardiomyocytes, cytosolic [Ca²⁺] decay is regulated locally and related to local sarcomere relengthening. Dyssynchronous intracellular [Ca²⁺] decay in cardiac remodeling and end-stage heart failure suggests a novel mechanism of cellular contractile dysfunction.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
authors.forename: Felix
authors.initials: F
authors.lastname: Hohendanner
authors.forename: Senka
authors.initials: S
authors.lastname: Ljubojević
authors.forename: Niall
authors.initials: N
authors.lastname: MacQuaide
authors.forename: Michael
authors.initials: M
authors.lastname: Sacherer
authors.forename: Simon
authors.initials: S
authors.lastname: Sedej
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Biesmans
authors.forename: Paulina
authors.initials: P
authors.lastname: Wakula
authors.forename: Dieter
authors.initials: D
authors.lastname: Platzer
authors.forename: Sophie
authors.initials: S
authors.lastname: Sokolow
authors.forename: André
authors.initials: A
authors.lastname: Herchuelz
authors.forename: Gudrun
authors.initials: G
authors.lastname: Antoons
authors.forename: Karin
authors.initials: K
authors.lastname: Sipido
authors.forename: Burkert
authors.initials: B
authors.lastname: Pieske
authors.forename: Frank R
authors.initials: FR
authors.lastname: Heinzel
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D003971:Diastole; D004558:Electric Stimulation; D005043:Etiocholanolone / Q000031:analogs & derivatives / Q000494:pharmacology; D006333:Heart Failure / Q000503:physiopathology*; D006352:Heart Ventricles / Q000166:cytology*; D006801:Humans; D006984:Hypertrophy; D017379:Hypertrophy, Left Ventricular / Q000503:physiopathology; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D017202:Myocardial Ischemia / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D010647:Phenyl Ethers / Q000494:pharmacology; D017975:Ruthenium Compounds / Q000494:pharmacology; D012518:Sarcomeres / Q000648:ultrastructure; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors / Q000235:genetics; D034421:Sus scrofa; D013552:Swine; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D000814:Aniline Compounds; D007211:Indoles; C499849:NCX1 protein, mouse; D010647:Phenyl Ethers; C112020:Ru 360; D017975:Ruthenium Compounds; C430918:SEA 0400; D019831:Sodium-Calcium Exchanger; D005576:Colforsin; D005043:Etiocholanolone; D000252:Calcium-Transporting ATPases; C468128:Istaroxime; C000543:cyclopiazonic acid
keywords: calcium; diastole; heart failure; mitochondria; myocytes, cardiac; ventricular remodeling