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Results of On-Pump Versus Off-Pump Coronary Artery Bypass Grafting

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Commentary: Does a “less is more” approach reduce delirium in patients undergoing coronary artery bypass grafting?

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Background: A recent meta-analysis incorporating 59 randomized controlled trials (RCTs) of off-pump versus on-pump (conventional) coronary artery bypass grafting (CABG) suggests that there appears to be a beneficial effect of off-pump CABG on post-operative (30-day or in-hospital) stroke but neither all-cause mortality nor myocardial infarction. To determine whether off-pump CABG reduces late all-cause mortality, we performed a meta-analysis of RCTs of off-pump versus on-pump CABG. Methods: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched through January 2012. Eligible studies were RCTs of off-pump versus on-pump CABG and reporting late (≥1-year) all-cause mortality as an outcome. For each RCT, data regarding mortality in both the off-pump and on-pump CABG groups were used to generate odds ratios (ORs) and 95% confidence intervals (CIs). Results: Eighteen RCTs enrolling 5358 patients were identified. Pooled analysis suggested a significant increase in late total mortality among patients randomized to off-pump versus on-pump CABG in the fixed-effects model (OR, 1.35; 95% CI, 1.07-1.70; P =0.01; Figure). There was minimal trial heterogeneity ( P =0.87) and accordingly little difference in the pooled result from the random-effects modeling. Mortality increase remained significant even after elimination of the largest and highest-weight RCT (Randomized On/Off Bypass [ROOBY] study) (OR, 1.32; 95% CI, 1.01-1.72; P =0.04). In general, exclusion of any single RCT from the analysis did not substantively alter the overall result of our analysis. There was no evidence of significant publication bias. Conclusions: Off-pump rather than on-pump CABG appears to significantly increase late (≥1-year) mortality

Cumulative Sum Curves and Their Prediction Limits

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Long-Term Survival After On-Pump and Off-Pump Coronary Artery Bypass Grafting

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Interactions between the transmembrane domains of phospholamban (PLB) and the cardiac Ca2+ pump (SERCA2a) have been investigated by chemical cross-linking. Specifically, C-terminal, transmembrane residues 45-52 of PLB were individually mutated to Cys, then cross-linked to V89C in the M2 helix of SERCA2a with the thiol-specific cross-linking reagents Cu2+-phenanthroline, dibromobimane, and bismaleimidohexane. V49C-, M50C-, and L52C-PLB all cross-linked strongly to V89C-SERCA2a, coupling to 70-100% of SERCA2a molecules. Residues 45-48 and 51 of PLB also cross-linked to V89C of SERCA2a, but more weakly. Evidence for the mechanism of PLB regulation of SERCA2a was provided by the conformational dependence of cross-linking. In particular, the required absence of Ca2+ for cross-linking implicated the E2 conformation of SERCA2a, and its enhancement by ATP confirmed E2 x ATP as the conformation with the highest affinity for PLB. In contrast, E2 phosphorylated with inorganic phosphate (E2P) and E2 inhibited by thapsigargin (E2 x TG) both failed to cross-link to PLB. These results with transmembrane PLB residues are completely consistent with cytoplasmic PLB residues studied previously, suggesting that the dissociation of PLB from the Ca2+ pump is complete, not partial, when the pump binds Ca2+ (E1 x Ca2) or adopts the E2P or E2 x TG conformations. V49C of PLB cross-linked to 100% of SERCA2a molecules, suggesting that this residue might have functional importance for regulation. Indeed, we found that mutation of Val49 to smaller side-chained residues V49A or V49G augmented PLB inhibition, whereas mutation to the larger hydrophobic residue, V49L, prevented PLB inhibition. A model for the interaction of PLB with SERCA2a is presented, showing that Val49 fits into a constriction at the lumenal end of the M2 helix of SERCA, possibly controlling access of PLB to its binding site on SERCA.

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