(A) Heart rate (bpm) of the family members without the mutation (–/–) or heterozygous for the RyR₂^R420Q mutation (+/–), male (M) and females (F). n = 4 M–/–, 4 M+/–, 7 F–/–, and 5 F+/–. Two-way ANOVA revealed a genotype statistical difference at P = 0.006. (B) Recovery of an exercise testing in a 57-year-old female carrier of the RyR₂^R420Q mutation depicting a junctional escape beat (JE) overcoming a pause caused by a ventricular ectopy and then followed by a burst of bidirectional ventricular tachycardia (BDVT), with a period of sinus rhythm (SR) in between. (C) Representative examples of ECG recordings obtained before (top panels) and following (bottom panels) epinephrine (2 mg/Kg) + caffeine (120 mg/Kg) injection (i.p.) in a WT mouse (left) and a KI mouse (right). The KI mouse shows BDVT after epinephrine/caffeine administration, characteristic of CPVT mice. (D) After injection, all of the KI mice (n = 7) show BDVT, but none of the WT show BDVT (n = 5). (E) Sinus heart rhythm (SHR), calculated from PP intervals recorded during daytime. KI female mice (n = 9) beat slower than WT (n = 10). No difference was found for the males (WT n = 10 vs. KI n = 11). (F) Isoproterenol (ISO, 1 mg/kg, i.p.) decreased the RR interval in both WT (male n = 6 and female n = 7) and KI (male n = 6 and female n = 6) mice. The KI females decreased proportionally more than WT. Ratio represents the RR interval after ISO injection normalized by the RR interval in the same animal before ISO injection. (G) Carbachol (CCH, 0.25 mg/kg, i.p.) increased the RR intervals in all mice. WT male n = 7, WT female n = 7, KI male n = 7, KI female n = 6. (H) ECG example of a KI mouse after ISO injection showing JE overcoming a transient severe decrease in sinus rate. Scale bar: 10 s. Below, a portion of the same ECG is shown. Scale bar: 200 ms. (I) Proportion of animals presenting JEs after ISO injection. (J) Two JEs during a self-terminating SAN dysfunction period induced by ventricular ectopies during the exercise testing in a 35-year-old female carrier of the RyR₂^R420Q mutation. For the box and whisker plots, the horizontal line in each box is the median and the square represents the mean, while the box displays the ± SEM and the whiskers extends from minimum to maximum values, with the individual data shown on the left. The bar graph represents the mean ± SEM, with individual data on the bar graph. White bar represents WT and gray bar represents KI, while the diagonal stripes stand for females, and vertical stripes indicate ISO stimulation. *P < 0.05; **P < 0.01 by Student’s t test.