Studies on human tissue and animal models of heart failure have demonstrated changes in cellular Ca²⁺ handling and SR Ca²⁺ content (reviewed in Hassenfuss, 1998). We investigated regional cellular changes in a rabbit infarct model that exhibits left ventricular dysfunction (LVD), dilatation and propensity to arrhythmias.

Eight weeks after ligation of a large branch of the circumflex coronary artery under anaesthetic, hearts were removed after an overdose of Euthatal (100 mg kg^-1) and cells isolated from basal endocardial (ENDO) and epicardial (EPI) regions. Compared with sham-operated control animals, those with LVD had a significantly reduced ejection fraction, increased LV end-diastolic diameter and evidence of systemic congestion (data not shown). Voltage-clamp studies were performed on fura-2-loaded cells at 37 °C. Na⁺-Ca²⁺ exchanger (NCX) activity was estimated from the rate constant (RC) of Ca²⁺ decay after 10 mM caffeine application. SR Ca²⁺ pump (SERCA) function was estimated from the RC of Ca²⁺ decay after brief caffeine application in the presence of 10 mM Ni²⁺. SR Ca²⁺ content was determined from the integral of the NCX current induced by caffeine application. These measures were each performed after 30 s of 1 Hz stimulation and were corrected for non-NCX Ca²⁺ removal mechanisms. NCX current density was determined from the Ni²⁺-sensitive current in response to a ramp protocol, with major interfering currents blocked and pipette [Ca²⁺]_i buffered to 100 nM. Analysis was by Student’s t test, with significance at P ▓le│ 0.05.

In control EPI cells compared with control ENDO cells, NCX current density was significantly reduced (P = 0.002), SERCA activity was increased (P < 0.05) and there was increased SR Ca²⁺ load (P = 0.04, see Tables 1 and 2). NCX activity was not significantly different. Comparing LVD EPI cells with LVD ENDO cells, there was also reduced NCX current density (P = 0.02), but the differences in SERCA activity, SR load and NCX activity were not significant. In LVD compared with control, NCX current density was reduced by around a third in both ENDO and EPI cells (P < 0.001), and NCX activity was significantly reduced in EPI cells (P = 0.03) and there was a trend towards reduced activity in ENDO cells (P = 0.052). SERCA activity was reduced in LVD EPI cells compared with control (P = 0.03), but the difference between ENDO cells was not significant. SR Ca²⁺ content was significantly increased in LVD ENDO cells compared with control (P = 0.04), and there was a trend towards an increase in EPI cells (P = 0.25).

Overall, when ENDO and EPI results were pooled, there was a significant reduction in NCX current density and activity in LVD, with significantly increased SR Ca²⁺ load and a trend towards lower SERCA activity. The reduced NCX activity could impair diastolic relaxation, while enhancing SR Ca²⁺ load, thereby increasing the frequency of arrhythmogenic spontaneous Ca²⁺ release. It is also clear that regional differences exist in Ca²⁺ handling and SR Ca²⁺ content and this may assist in understanding the focal origin of certain arrhythmias.This work was supported by the British Heart Foundation.

Hassenfuss, G. (1998). Cardiovasc. Res. 37, 279-289.