Intracellular Dyssynchrony of Diastolic Cytosolic [Ca 2+ ] Decay in Ventricular Cardiomyocytes in Cardiac Remodeling and Human Heart Failure

• DOI: 10.1161/circresaha.113.300895
• Publication Date: 2013-07-04T08:38:16Z
• Authors: Felix Hohendanner; Senka Ljubojević; Niall MacQuaide; Michael Sacherer; Simon Sedej; Liesbeth Biesmans; Paulina Wakula; Dieter Platzer; Sophie Sokolow; André Herchuelz; Gudrun Antoons; Karin Sipido; Burkert Pieske; Frank R. Heinzel
• Keywords: mitochondria; Pathologie générale; calcium; diastole; Physiologie générale; cardiac; heart failure; myocytes; ventricular remodeling; 3. Good health

Rationale :

Synchronized release of Ca 2+ into the cytosol during each cardiac cycle determines cardiomyocyte contraction.

Objective:

We investigated synchrony of cytosolic [Ca 2+ ] decay during diastole and the impact of cardiac remodeling.

Methods and Results:

Local cytosolic [Ca 2+ ] transients (1-µm intervals) were recorded in murine, porcine, and human ventricular single cardiomyocytes. We identified intracellular regions of slow (slowCaR) and fast (fastCaR) [Ca 2+ ] decay based on the local time constants of decay (TAU local ). The SD of TAU local as a measure of dyssynchrony was not related to the amplitude or the timing of local Ca 2+ release. Stimulation of sarcoplasmic reticulum Ca 2+ ATPase with forskolin or istaroxime accelerated and its inhibition with cyclopiazonic acid slowed TAU local significantly more in slowCaR, thus altering the relationship between SD of TAU local and global [Ca 2+ ] decay (TAU global ). Na + /Ca 2+ exchanger inhibitor SEA0400 prolonged TAU local similarly in slowCaR and fastCaR. FastCaR were associated with increased mitochondrial density and were more sensitive to the mitochondrial Ca 2+ uniporter blocker Ru360. Variation in TAU local was higher in pig and human cardiomyocytes and higher with increased stimulation frequency (2 Hz). TAU local 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 TAU local was increased and related to cardiomyocyte hypertrophy and increased mitochondrial density.

Conclusions:

In cardiomyocytes, cytosolic [Ca 2+ ] decay is regulated locally and related to local sarcomere relengthening. Dyssynchronous intracellular [Ca 2+ ] decay in cardiac remodeling and end-stage heart failure suggests a novel mechanism of cellular contractile dysfunction.