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Intracellular dyssynchrony of diastolic cytosolic [Ca²⁺] decay in ventricular cardiomyocytes in cardiac remodeling and human heart failure.
- Source :
-
Circulation research [Circ Res] 2013 Aug 16; Vol. 113 (5), pp. 527-38. Date of Electronic Publication: 2013 Jul 03. - Publication Year :
- 2013
-
Abstract
- Rationale: Synchronized release of Ca²⁺ into the cytosol during each cardiac cycle determines cardiomyocyte contraction.<br />Objective: We investigated synchrony of cytosolic [Ca²⁺] decay during diastole and the impact of cardiac remodeling.<br />Methods and 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.<br />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.
- Subjects :
- Aniline Compounds pharmacology
Animals
Calcium Signaling drug effects
Calcium-Transporting ATPases antagonists & inhibitors
Calcium-Transporting ATPases metabolism
Colforsin pharmacology
Cytosol metabolism
Diastole
Electric Stimulation
Etiocholanolone analogs & derivatives
Etiocholanolone pharmacology
Humans
Hypertrophy
Hypertrophy, Left Ventricular physiopathology
Indoles pharmacology
Mice
Mitochondria, Heart drug effects
Mitochondria, Heart metabolism
Myocardial Ischemia physiopathology
Myocytes, Cardiac drug effects
Myocytes, Cardiac pathology
Phenyl Ethers pharmacology
Ruthenium Compounds pharmacology
Sarcomeres ultrastructure
Sarcoplasmic Reticulum drug effects
Sarcoplasmic Reticulum enzymology
Sodium-Calcium Exchanger antagonists & inhibitors
Sodium-Calcium Exchanger genetics
Sus scrofa
Swine
Calcium Signaling physiology
Heart Failure physiopathology
Heart Ventricles cytology
Myocytes, Cardiac physiology
Ventricular Remodeling physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4571
- Volume :
- 113
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Circulation research
- Publication Type :
- Academic Journal
- Accession number :
- 23825358
- Full Text :
- https://doi.org/10.1161/CIRCRESAHA.113.300895