Calcium sensitisation impairs diastolic relaxation in post-ischaemic myocardium: implications for the use of Ca2+ sensitising inotropes after cardiac surgery

Background: Calcium sensitising inotropes are increasingly being used in cardiac surgical patients. Theoretically, increasing contractile protein sensitivity to Ca2+ prevents the Ca2+ elevation associated arrhythmogenicity and potentiates the inotropic effect of catecholamines. On the other hand, we hypothesised that Ca2+ sensitisation exacerbates post-ischaemic myocardial stunning by impairing diastolic relaxation, which might have deleterious effects in postoperative cardiac surgical patients. Methods: In an isolated rabbit heart model, 45 min normothermic ischaemia with potassium-induced cardioplegic arrest was followed by 120 min reperfusion. Isovolumetric left ventricular (LV) function and myocardial oxygen consumption (MvO2) were measured, and cytosolic Ca2+ was monitored by rhod-2 surface spectrofluorometry. During reperfusion, ORG 30029 (250 μM) and levosimendan (0.5 μM) were used as Ca2+ sensitisers (ORG, n = 6, Levo, n = 6), Ca2+ de-sensitisation was induced with butanedione-monoxime (5 mM, BDM, n = 6), and dopamine (20 nM) served as a representative catecholamine (n = 6). To counteract the PDE III inhibiting properties of ORG and Levo, IGF-1 (0.1 μM) and parathyroid hormone (0.05 μM) were used. Results: As expected, ischaemia/reperfusion induced moderate cytosolic calcium overload. Dopamine increased LV contractility and MvO2 by augmenting the amplitude of the Ca2+ transient, but relaxation was unchanged due to faster diastolic Ca2+ removal. Dopamine-induced Ca2+ handling was unchanged after uncoupling the Mg-ATPase with BDM, and MvO2 decreased in proportion with the reduced LV mechanical work load. ORG improved contractility without apparent effects on Ca2+ handling, and MvO2 remained constant despite increased contractile work. Conversely, ORG induced a rightward shift of the diastolic pressure-volume relationship in post-ischaemic hearts (diastolic pressure at 0.8 ml balloon volume 14.3 ± 5 mmHg, p = 0.01 vs control), but not in non-ischaemic control hearts. With levosimendan, the Ca2+ sensitising effects were less pronounced (7.6 ± 3 mmHg, p = 0.4 vs control). By counteracting the PDE inhibiting effects of ORG and Levo using parathyroid hormone and IGF-1, the negative lusotropic effects of Ca2+ sensitisation were unmasked. Conclusions: Calcium sensitisation improves systolic function and energetic efficiency. However, Ca2+ sensitisers should be used with caution during post-ischaemic reperfusion, as they may exacerbate myocardial stunning an