More complex than expected?

We read with interest the excellent article by Aass et al. [1], in which they demonstrate the beneficial effect of polarizing (or rather non-depolarizing) St. Thomas-based cardioplegia when compared with conventional depolarizing cardioplegic arrest in a large animal model. The positive impact on systolic left ventricular function during reperfusion is evident in this clinically relevant situation, while there was little difference in G-protein-coupled receptor kinase 2 phosphorylation or other cellular outcome parameters. The authors discuss the potential role of ß-adrenergic desensitization and plasma membrane ion fluxes, but we believe that another phenomenon may also play a role: contractile protein Ca²⁺sensitivity. Indeed, prolonged depolarization ultimately not only leads to cytosolic Ca²⁺accumulation, which is usually considered detrimental but also induces adaptive responses, such as protein kinase C (PKC)ε-mediated phosphorylation of troponin I and/or T. This can impair post-ischaemic systolic function but protects the contractile apparatus from relaxation deficit and contracture [2]. Non-depolarizing arrest may prevent Ca²⁺overload for some time, preserving contractile protein Ca²⁺sensitivity and hence post-ischaemic systolic function. However, problems arise when ischaemia is prolonged and the net Ca²⁺influx during reperfusion cannot rapidly be counteracted. Then, preserved—or ‘unprotected’—Ca²⁺sensitivity impairs relaxation, resulting in a stiff and failing heart [3]. The ischaemia-reperfusion protocol used by the authors reflects the typical clinical scenario in that is subcritical with 60 min cold cardioplegic arrest, where preserved or increased Ca²⁺sensitivity translates in better systolic function. Non-depolarizing cardioplegia has also been tested in other experimental models with promising results, as elegantly summarized in the review article by Dobson et al. [4], but few, if any, of those used critical ischaemia-reperfusion protocols. Of course, direct measurement of Ca²⁺sensitivity requires simultaneous recordings of contractile force and cytosolic Ca²⁺, which is very difficult in large animals, but it would be interesting to see whether a more critical ischaemic injury would unmask the deleterious effects of preserved Ca²⁺sensitization. After all, traditional K⁺-induced cardioplegic arrest works very well for our daily routine cases, but it is the more extreme situations that continue to give us trouble. If our hypothesis is true, we feel that a temporarily lower systolic function, easily treated by adrenergic stimulation, is less problematic than a stiff heart with poorly reversible contracture. Clearly, more experimentation is warranted, which is a very good thing for such an experienced group of surgical researchers and a lately somewhat neglected field.

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