Figure 1.
In vivo data from 1 month (1 Mo), 4 month (4 Mo), and 4 month HF with sustained AF (4 Mo HF+AF) canine groups.
A. Representative ECG recording from a 4 month HF+AF dog showing the absence of P waves and irregularly irregular QRS complexes characteristic of AF. B. LVFS was similarly decreased in the 1 month HF, 4 month HF and the 4 month HF+AF groups compared to baseline. (p<0.05 vs baseline). C. Atrial contractility was decreased in 4 month HF and 4 month HF+AF groups compared to baseline. (p<0.05, N = 5–7 per group).
Figure 2.
IKCa inhibition does not alter repolarization in control ventricular cells.
A. Representative action potential tracing before and after 100 nM apamin recorded at 1 Hz. B. APD50 and C. APD90 dose response data (0–100 nM apamin) recorded at stimulation rates of 0.5, 1 and 2 Hz. (p = NS, n = 5–11 cells per group; 8 animals). The Grubb’s test for outlier data was applied and one cell was rejected and is not included in the summary data.
Figure 3.
Apamin modulates ventricular repolarization during HF.
Representative action potential of a 1 month (A) HF and 4 month HF(B) ventricular cell before and after apamin superfusion. C. Summary data of APD50 in control,1 month and 4 month HF before and after apamin treatment. No difference between 1 month HF, 4 month HF and control is observed (2–8 animals per group). Apamin treatment of 1 month HF cells causes a prolongation only at 2 Hz(p<0.05), likewise apamin treatment of 4 month HF cells causes a prolongation at 0.5 Hz (p<0.05) and 1 Hz (p<0.05). D. Apamin prolongs APD90 in both 1 and 4 month HF (p<0.05).
Figure 4.
IKca contributes to ventricular repolarization stability in canine HF, and HF increases SK3 expression.
A. Beat to beat variability of APD90 (BTBV, ms) is unchanged in both 1 month or 4 month HF vs. controls. IKCa block increases the BTBV in the 4 month, but not the 1 month HF group (p<0.05 vs control, 1 month HF and 4 month HF; 2–8 animals per group). B. Representative AP tracings of control, 1 month HF and 4 month HF during superfusion with 100 nm apamin. C. Representative blots of SK2 and SK3. D. SK3 in the 1 and 4 month HF groups is increased (p<0.05 vs control) while SK2 is unchanged (N = 4–5).
Figure 5.
Apamin modulates ventricular repolarization in end-stage human HF.
A. Representative action potential recorded at 1 Hz from an end-stage human HF ventricular myocyte before and after apamin. B. Apamin superfusion prolongs APD50 and APD90 in end-stage human HF ventricular myocytes at all rates (p<0.05 vs baseline, n = 7). C. Apamin superfusion increases (p<0.05 vs baseline) BTBV (ms) at 2 Hz. D. Representative action potential showing late phase 3 EADs after apamin superfusion. E. Apamin treatment increases EAD incidence in failing human ventricular myocytes. (p<0.05 vs baseline) F. Representative blots of control and end-stage human HF SK2 and SK3 proteins (SK2 p = 0.556 and SK3 p = 0.141 vs. control). HF: N = 7 (4 male/3 female); age = 52±13 years and LV ejection fraction of 14.5±5.2%; non-failing controls: n = 5 (2 male/3 female); age = 47±12 years.
Figure 6.
IKCa block does not affect repolarization in normal or diseased atrial myocytes.
A.100 nM apamin does not affect atrial APD50 in any of the studied groups (i.e. control, 4 month HF and 4 month HF+AF, n = 7–9 cells per group) B. 100 nM apamin shortened the APD90 in controls at 0.5 and 1 Hz. (p<0.05). HF+AF had a shorter baseline APD90 compared to control and HF (p<0.05), however no change in APD90 was observed after apamin treatment in either 4 month HF or 4 month HF+AF groups. (n = 7–9 cells per groups) C and D. Atrial action potential tracings before and after apamin treatment from the 4 month HF group and the 4 month HF+ AF group (2–6 animals per group).
Figure 7.
Atrial SK expression and calcium transients in chronic HF with and without AF.
A. Representative Western blots of SK2 and SK3. B. SK2 and SK3 are increased 3- and 2-fold, respectively in the 4 month HF atria. (p<0.05 vs control and 4 month HF+AF) No differences between control and 4 month HF+AF were found in any of the subunits. (N = 3) C. Representative calcium transient line scans. D. Calcium transient amplitude was decreased in the 4 month HF and 4 month HF+AF groups compared to control (p<0.05 vs control; 3–8 animals per group).
Figure 8.
Apamin does not modulate repolarization in end-stage human HF atrial myocytes.
A. Representative atrial action potential tracing recorded at 1 Hz. B and C. Apamin did not change APD50 or APD90 in human atrial myocytes. (n = 3) D. Apamin superfusion did not increase BTBV (ms). E. Representative SK2 and SK3 Western blots. F. HF increased SK2 and SK3 expression in left atrial tissue (p<0.05 vs non-failing). HF: N = 4 (2 male/2 female); age = 56±4 years and LV ejection fraction of 14.5±1.1%; non-failing controls: n = 4 (2 male/2 female); age = 46±14 years.