Suppression of electrical alternans may be antiarrhythmic. Our previous computer simulations have suggested that increasing the rapid component of the delayed rectifier K+ current ( IKr) suppresses alternans. To test this hypothesis, IKr in isolated canine ventricular myocytes was increased by infection with an adenovirus containing the gene for the pore-forming domain of IKr [human ether-a-go-go gene (HERG)]. With the use of the perforated or whole cell patch-clamp technique, action potentials recorded at different pacing cycle lengths (CLs) were applied to the myocytes as the command waveforms. HERG infection markedly increased peak IKr during the action potential (from 0.54 ± 0.03 pA/pF in control to 3.60 ± 0.81 pA/pF). Rate-dependent alterations of peak IKr were similar for freshly isolated myocytes and HERG-infected myocytes. In both cell types, IKr increased when CL decreased from 1,000 to 500 ms and then decreased progressively as CL decreased further. During alternans at CL = 170 ms, peak IKr was larger for the short than for the long action potential for both groups, but the difference in peak IKr was larger for HERG-infected myocytes. The voltage at which peak IKr occurred was significantly less negative in HERG-infected myocytes, in association with shifts of the steady-state voltage-dependent activation and inactivation curves to less negative potentials. Pacing at short CL induced stable alternans in freshly isolated myocytes and in cultured myocytes without HERG infection, but not in HERG-infected myocytes. These data support the idea that increasing IKr may be a viable approach to suppressing electrical alternans.
Large Amplitude Rate-Dependent Mechanical Alternans may Precede Arrhythmogenesis in Human Heart Failure and are Linked to Electrical Alternans via Abnormal Calcium Handling