Aims: 

Heart failure (HF) is associated with decreased contraction and propensity for arrhythmias, both of which are related to altered Ca²⁺ handling. The purpose of our study was to test the hypothesis of a link between the cardiac ryanodine receptor (RyR2) and Ca²⁺ -dependent ionic currents, such as I_CaL and I_K1, potentially involved in arrhythmias.

Methods: 

Effects of HF (vs. Sham) were assessed 8 weeks after left coronary artery ligation (PMI) in 250-280 g Wistar rats. Echocardiography confirmed that PMI rats had impaired systolic function. Whole-cell patch-clamp experiments were performed (22-24°C). Abrupt changes in pacing rate (from 0.1 Hz to 2 Hz) were used to assess propensity of single ventricular myocytes to trigger arrhythmias. [Ca²⁺]_i transients and Ca²⁺ sparks were recorded using fluorescent Ca²⁺ dye Fluo-4 AM. Ca²⁺ load in the sarcoplasmic reticulum (SR) was estimated using caffeine.

Results: 

In all HF cells, Ito was decreased, and the AP was prolonged. However, we identified two subsets of cells with distinct Ca²⁺ handling features. One set of cells exhibited increased Ca²⁺ sparks occurrence, decreased [Ca²⁺]_i transients and decreased SR Ca²⁺ load. We determined that leaky RyR2 were associated with inhibition of I_K1, slow inactivation of I_CaL, longer APs, loss of adaptation of AP duration to high pacing rate and triggering of delayed afterdepolarizations (DADs). The other type of cells had normal (vs. Sham) RyR2 activity, Ca²⁺ handling, I_CaL and I_K1, but high pacing rate promoted dramatic prolongation of APs (due to enhanced facilitation of I_CaL) with occurrence of EADs.

Conclusion: 

The physiological status of RyR2 determines occurrence of either EADs or DADs with key roles of, respectively, I_CaL and I_K1.