[Na+]i and the driving force of the Na+/Ca2+-exchanger in heart failure

Objective: Diastolic calcium is increased in myocytes from failing hearts despite up-regulation of the principal calcium extruding mechanism the Na+/Ca2+-exchanger (NCX). We hypothesize that increased diastolic calcium ([Ca2+](i)) is secondary to increased cytosolic sodium ([Na+](i)) and decreased driving force of NCX (DeltaG(exch)). Methods: The stimulation rate dependence of simultaneously measured cytosolic sodium ([Na+](i)), calcium transients ([Ca2+](i)) and action potentials were determined with SBFI, indo-1 and the perforated patch technique in midmural left ventricular myocytes isolated from rabbits with pressure and volume overload induced heart failure (HF) and in age matched controls. Dynamic changes of DeltaG(exch) were calculated. Results: With increasing stimulation frequency, 0.2-3 Hz (all data HF versus control): [Na+](i) increased (6.4 to 10.8 versus 3.8 to 6.4 mmol/l), diastolic [Ca2+](i) increased (142 to 219 versus 47 to 98 nmol/l), calcium transient amplitude decreased in HF (300 to 250 nmol/l) but increased in control (201 to 479 nmol/l), action potential duration (APD(90).) decreased (380 to 260 versus 325 to 205 ms) and time averaged DeltaG(exch) decreased (6.8 to 2.8 versus 8.7 to 6.4 kJ/mol). With increasing stimulation rate the forward mode time integral of DeltaG(exch) decreased in HF by about 30%, the reversed mode time integral increased about ninefold and the duration of reversed mode operation more than sixfold relative to control. Conclusions: [Na+](i) is increased in HF and the driving force of NCX is decreased. NCX exerts thermodynamic control over diastolic calcium. Disturbed diastolic calcium handling in HF is due to decreased forward mode DeltaG(exch) secondary to increased [Na+](i) and prolongation of the action potential. Enhanced reversed mode DeltaG(exch) may account for increased contribution of NCX to e-c coupling in HF. (C) 2003 European Society of Cardiology. Published by Elsevier Science B.V. All rights reserved.