Intracellular Dyssynchrony of Diastolic Cytosolic [Ca2+] Decay in Ventricular Cardiomyocytes in Cardiac Remodeling and Human Heart Failure
Rationale: 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.
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 standard deviation of TAUlocal (SDTAU) as a measure of dyssynchrony was not related to the amplitude or the timing of local Ca2+ release. Stimulation of SERCA with forskolin or istaroxime accelerated, its inhibition with cyclopiazonic acid slowed TAUlocal significantly more in slowCaR, thus altering the relationship between SDTAU and global [Ca2+] decay (TAUglobal). NCX-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 following trans-aortic constriction (TAC), 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.
- Received January 14, 2013.
- Revision received June 29, 2013.
- Accepted July 3, 2013.