Repolarization abnormalities in cardiomyocytes of dogs with chronic heart failure: role of sustained inward current

We previously showed that a canine model of chronic heart failure (HF) prod uced by multiple coronary microembolizations manifests ventricular arrhythm ias similar to those observed in patients with chronic HF. In the present s tudy, we used single canine cardiomyocytes isolated from the left ventricle (LV) of normal dogs (n = 13) and dogs with HF (n = 15) to examine the cell ular substrate of these arrhythmias. Action potentials (APs) and ion curren ts were measured by perforated and whole cell patch clamp. respectively. We found prolonged APs and alterations of AP duration resulting in early afte rdepolarizations (EADs) at the low pacing rates of 0.5 Hz and 0.2 Hz. Na+ c hannel blockers saxitoxin (STX, 100 nM) and lidocaine (90 mu M) reduced AP duration dispersion and abolished EADs in HF cardiomyocytes. The steady-sta te current (I-ss)-voltage relation, in the voltage range from - 25 mV to 25 mV analogous to the AP plateau level, was significantly shifted inward in HF cardiomyocytes, STX and lidocaine shifted the I-ss-voltage relationship in an outward direction. The shifts produced by both drugs was significantl y greater in cardiomyocytes of dogs with HF. indicating an increase in inwa rd current. In the experimental configuration in which K+ currents were blo cked, the density of the steady-state Ca2+ current (I-Ca) was found to decr ease in HF cardiomyocytes by approximately 33%. In contrast, the density of the steady-state Na+ current (I-Na) significantly (P < 0.01) increased in HF cardiomyocytes (0.17 +/- 0.06 pA/pF compared with normal cells (0.08 +/- 0.02 pA/pF). The relative contribution of I-Na to the net inward current w as greater in HF cardiomyocytes, as evident from the increased ratio of I-N a, I-Ca (from 0.22 to 0.68). These observations support a hypothesis that a nomalous repolarization of HF cardiomyocytes is due, at least in part, to a n increased steady-state inward Na+ current.