The Na⁺/Ca²⁺ exchange inhibitor SEA0400 limits intracellular Ca²⁺ accumulation and improves recovery of ventricular function when added to cardioplegia

The Na⁺/Ca²⁺ exchange inhibitor SEA0400 prevents myocardial injury in models of global ischemia and reperfusion. We therefore evaluated its potential as a cardioplegia additive.

Isolated rat cardiomyocytes were exposed to hypoxia (45 min) followed by reperfusion. During hypoxia, cells were protected using cardioplegia with (n = 25) or without (n = 24) SEA0400 (1 μM), or were not protected with cardioplegia (hypoxic control, n = 8). Intracellular Ca²⁺ levels were measured using Ca²⁺ sensitive dye (fura-2 AM). Isolated rat hearts were arrested using cardioplegia with (n = 7) or without (n = 6) SEA0400 (1 μM) then reperfused after 45 min of ischemia. Left ventricular (LV) function, troponin release, and mitochondrial morphology were evaluated.

Cardiomyocytes exposed to hypoxia without cardioplegia had poor survival (13%). Survival was significantly improved when cells were protected with cardioplegia containing SEA0400 (68%, p = 0.009); cardioplegia without SEA0400 was associated with intermediate survival (42%). Cardiomyocytes exposed to hypoxia alone had a rapid increase in intracellular Ca²⁺ (305 ± 123 nM after 20 minutes of ischemia). Increases in intracellular Ca²⁺ were reduced in cells arrested with cardioplegia without SEA0400; however cardioplegia containing SEA0400 was associated with the lowest intracellular Ca²⁺ levels (110 ± 17 vs. 156 ± 42 nM after 45 minutes of ischemia, p = 0.004). Hearts arrested with cardioplegia containing SEA0400 had better recovery of LV work compared to cardioplegia without SEA0400 (23140 ± 2264 vs. 7750 ± 929 mmHg.μl, p = 0.0001). Troponin release during reperfusion was lower (0.6 ± 0.2 vs. 2.4 ± 0.5 ng/mL, p = 0.0026), and there were more intact (41 ± 3 vs. 22 ± 5%, p < 0.005), and fewer disrupted mitochondria (24 ± 2 vs. 33 ± 3%, p < 0.05) in the SEA0400 group.

SEA0400 added to cardioplegia limits accumulation of intracellular Ca²⁺ during ischemic arrest in isolated cardiomyocytes and prevents myocardial injury and improves recovery of LV function in isolated hearts.