Fig. 2

Regulation of cardiac conduction and arrhythmias by CCRR in HF mice. a Slowing of conduction velocity (CV) in HF and restoration by CCRR overexpression. CV was determined by optical mapping techniques with a voltage-sensitive dye to define the cardiac activation. CV values were calculated from the gradient of the scalar field of 12-ms isochronal activation maps along the septal apex–base axis: CV = distance/12 ms. Note that CV was substantially decreased in HF and this conduction slowing was restored in the hearts pretreated with the lentivirus carrying the CCRR gene for overexpression (Lv-CCRR), but not with the negative control construct (Lv-NC). Viral vectors were administered by intracavity injection (directly injected into the left ventricular chamber). The Sham group underwent the same surgical procedures without TAC. ^*P < 0.05 HF or Lv-NC vs. Sham-control; ^#P  < 0.05 Lv-CCRR vs. HF; n = 4 mice for each group. b Antiarrhythmic effects of CCRR overexpression in a mouse model of HF. The incidence and duration of ventricular tachycardia (VT) induced by programmed stimuli were determined from ECG recordings. Note that the arrhythmogenicity was significantly enhanced in HF hearts, which was considerably suppressed by Lv-CCRR, but not by Lv-NC. The red lines in the ECG traces indicate VT duration, and the values within the parentheses in the bar charts indicate VT incidence. ^*P < 0.05 HF or Lv-NC vs. Sham-control; ^#P < 0.05 Lv-CCRR vs. HF. c Slowing of cardiac conduction induced by CCRR knockdown in healthy mice. The lentivirus vector engineered to contain a CCRR siRNA (Lv-siCCRR) was injected into the left ventricular chamber to silence myocardial CCRR. Lv-siCCRR caused a remarkable decrease in cardiac CV, whereas the negative control (Lv-siNC) failed to elicit any significant changes. The Sham group received the same surgical procedures without injecting vectors. ^*P < 0.05 Lv-siCCRR vs. Sham-Control; n = 4 mice for each group. d Pro-arrhythmic effects of CCRR knockdown in healthy mice. A prominent finding here is that knockdown of endogenous CCRR by Lv-siCCRR was sufficient to induce VT in otherwise healthy hearts. ^*P < 0.05 Lv-siCCRR vs. Sham-Control. (Mean ± SEM; ANOVA followed by Dunnett’s test for multiple group comparisons, Student t test for two group comparisons, and χ²-test for nonparametric data set comparisons)