Figure 4. Pathological contributions of I_NaL, CaMKII and ROS to maladaptive Ca²⁺ handling in cardiomyocytes isolated from mouse failing hearts.

A. i) Heart weight/body weight ratio and ii) fractional shortening (FS, %) of the left ventricular wall in male CD-1 mice subjected to transverse aortic constriction (TAC) for 4 weeks, compared to sham-operated, age- matched controls (sham). B. i) Western blots for oxidation of CaMKII at Met281/282 (ox-CaMKII) and Western Blot quantification, normalized to GAPDH (ii). Effects of ranolazine (10 μM), TTX (1 μM), CoQ10 (10 μM), KN-93 (3 μM), and KN-92 (3 μM) on levels of intracellular Na⁺ (C) and ROS (D) in myocytes isolated from TAC mice and paced at a rate of 1 Hz (N = 3-20, p<0.05), compared to baseline. E. Spontaneous Ca²⁺ release events following termination of 1 Hz stimulation of myocytes isolated from Sham-operated and TAC mice in the absence or presence of RAN (10μM), KN-93 (3 μM) or its inactive analog KN-92 (3 μM). *p<0.05 vs sham and †p<0.05 vs TAC without drugs.