Purpose: 

We previously showed that intermittent dyssynchrony, induced by ventricular pacing immediately upon reperfusion, induces cardioprotection (pacing-postconditioning, (PPC). We hypothesized that stretch, rather than ischemic stimuli, triggers cellular pathways involved in PPC in male and female hearts.

Methods: 

Isolated ejecting male and female rabbit hearts were subjected to 30 minutes coronary occlusion and 2 hours reperfusion. PPC consisted of 10 cycles of 30-sec intervals of ventricular pacing alternated with atrial pacing during early reperfusion. For gender differences the following groups were studied: (n=5-7/group): control (males and females), PPC (males and females). For pathways study only female rabbits were used in the following groups, control, PPC in combination with selective inhibitors of the adenosine receptor (8-SPT), AT1 receptor (Candesartan), mitochondrial K⁺_ATP channel (5HD), PKC (Chelerythrine), and PI3K (Wortmannin) and the microtubule depolymerizer (Colchicine). In addition we increased preload by raising the level of the atrial reservoir (stretch, no pacing). Infarct size and area at risk were determined using TTC and blue dye. Lactate release was determined in the coronary effluent. In 5 control and 5 PPC hearts fluorescent microspheres were injected during early reperfusion to measure myocardial blood flow (MBF) in the reperfused region during both ventricular and atrial pacing.

Results: 

Infarct size (IS) following PPC, normalized to area at risk, was significantly smaller in male and female hearts (23.5±4% and 26.0±5%, respectively) compared to controls (47.3±3% and 48.7±2% p<0.0001). In female hearts following PPC or stretch, IS is significantly smaller (26.0±5% and 22.6±2%, respectively) than in control hearts (47.3±3% p<0.0001). In the early reperfusion phase, ventricular pacing did not change lactate release or MBF, indicating that PPC does not cause graded reperfusion. 8-SPT and Candesartan did not affect the protection gained from pacing (24.6±7% and 20±2% respectively p<0.001). Colchicine abrogated the protection by PPC, indicating a role for microtubule in PPC. Furthermore, 5HD, Chelerythrine and Wortmannin abrogated the protection provided by PPC (infarct sizes: 49.0±5%, 45.0±4%, 49.6±4%, and 52.5±2% respectively).

Conclusions: 

These results support the idea that PPC protects male and female hearts through a stretch mediated trigger, not involving graded reperfusion or adenosine and angiotensin receptors. Although upstream signaling differs PPC shares downstream signaling pathways with ischemic postconditioning.