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Electrical remodeling in hearts from a calcium-dependent mouse model of hypertrophy and failure

Complex nature of k⁺ current changes and action potential duration

Ilona Bodi, PhD, James N. Muth, PhD, Harvey S. Hahn, MD^*, Natasha N. Petrashevskaya, PhD, Marta Rubio, MPharm, Sheryl E. Koch, PhD, Gyula Varadi, PhD and Arnold Schwartz, PhD, FACC, FAHA^,*

^* Division of Cardiology, Department of Internal Medicine, Cincinnati, Ohio, USA
Institute of Molecular Pharmacology and Biophysics, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

View larger version (19K): [in a new window]   Figure 1 Differences in the action potential (AP) shape and duration in nontransgenic (Ntg) and transgenic (Tg) myocytes. Representative APs were recorded in single ventricular myocytes isolated from Ntg (2- and 8-month-old) and Tg mice (2-, 4-, 8-, and 9- to 12-month-old) (A). Effect of 4-aminopyridine (4-AP) on AP duration (B and C). Examples of AP recordings from mouse cardiomyocytes derived from eight-month-old Ntg (B) and Tg (C) mice before and after application of 250 µM 4-AP and washout.

View larger version (30K): [in a new window]   Figure 2 Comparison of IK1 in nontransgenic (Ntg) and trangenic (Tg) animals. Averaged peak current density-voltage relation plotted for cells from 2-, 4-, 8-, and 9- to 12-month-old Ntg and Tg mice, respectively (A). Families of representative current traces elicited from a holding potential of –40 mV using voltage steps of 500 ms from –140 mV to +100 mV in 20 mV increments (B) from Ntg (C) as compared with Tg (D) myocyte.

View larger version (37K): [in a new window]   Figure 3 Voltage-dependent activation of Ito in mouse ventricular myocytes. Plots showing the voltage-dependence of the current density of Ito,peak at 2-, 4-, 8-, and 9- to 12-month-old cardiomyocytes (A) and Ito,peak-Isus (B). Families of Ito from 4-month-old Ntg (D) and Tg (E, F) myocytes were recorded during a series of voltage clamps from a holding potential of –40 mV to selected test potentials ranging from –40 mV to +80 mV (C).

View larger version (58K): [in a new window]   Figure 4 Steady-state inactivation of Ito and ICa and inactivation properties of Ito in myocytes from 9- to 12-month-old nontransgenic (Ntg) and transgenic (Tg) mice. Representative current tracings for voltage-dependence of steady-state inactivation of Ito are displayed from Ntg and Tg cardiac myocytes (A, right panel). Voltage dependence of Ito inactivation was assessed using a double-pulse-protocol (A, left panel). The data are normalized to the largest peak Ito and ICa currents measured using a prepulse of –100 mV versus –80 mV (Ito/Imax or ICa/Imax). The total peak outward current includes a steady-state component that may not represent Ito. Data were fit to Boltzmann equation as follows: I = Imax/1+exp (Vm-V0.5)/k, where I is recorded current, Imax is maximum current, Vm is membrane potential, V0.5 is potential where inactivation is 50%, and k is the slope factor. Mean voltage-dependent inactivation curve of ICa for Ntg and Tg myocytes, respectively (B). Inactivation decay courses of Ito recorded during 680 ms depolarizing voltage steps to test potential +40 mV. The time courses were determined in individual Ntg and Tg cells (9- to 12-month-old) using the double exponential fits (using the Chebyshev algorithm of CLAMPFIT) to the decay phases of the currents (C and D) by the equation I(t) = Afast[exp(–t/fast] + Aslow[exp(–t/slow)] + A: Afast and Aslow being the maximal amplitude; fast and slow being the time constants of the fast and slow components of inactivation, respectively. Time zero was set next to the peak of the outward current. C and D show the fast and slow components of Ito inactivation at different depolarization potentials in Ntg and Tg cardiac myocytes. Continued on next page. (E and F) Superimposed original current recordings showing time-course of recovery from inactivation of Ito in Ntg and Tg cells. Capacitive transients were partially removed for clarity. (G) Plots showing reactivation of Ito in Ntg and Tg myocytes. Both curves were well-fitted by double exponential function.

View larger version (44K): [in a new window]   Figure 5 Representative Western blots showing densities of Kv1.4, Kv4.2, and Kv4.3 proteins (A). GAPDH was used as internal control to normalize for differences in loading. Samples were done in duplicates. Histogram depicting levels of Kv1.4 protein levels normalized to GAPDH in 2-, 4-, and 8-month-old transgenic (Tg) and nontransgenic (Ntg) ventricular membrane fractions (B). – = Ntg; + = Tg.

View larger version (74K): [in a new window]   Figure 6 Representative M-mode echocardiographic tracings are shown from 8-month-old nontransgenic (Ntg) (A) and transgenic (Tg) (B) mice. IVS = intraventricular septum; LV = left ventricle; PW = posterior wall.