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 Ca(2+) prevents the Ca(2+) elevation associated arrhythmogenicity and potentiates the inotropic effect of catecholamines. On the other hand, we hypothesised that Ca(2+) 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 (MvO(2)) were measured, and cytosolic Ca(2+) was monitored by rhod-2 surface spectrofluorometry. During reperfusion, ORG 30029 (250 microM) and levosimendan (0.5 microM) were used as Ca(2+) sensitisers (ORG, n=6, Levo, n=6), Ca(2+) de-sensitisation was induced with butanedione-monoxime (5mM, 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 microM) and parathyroid hormone (0.05 microM) were used. RESULTS: As expected, ischaemia/reperfusion induced moderate cytosolic calcium overload. Dopamine increased LV contractility and MvO(2) by augmenting the amplitude of the Ca(2+) transient, but relaxation was unchanged due to faster diastolic Ca(2+) removal. Dopamine-induced Ca(2+) 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 Ca(2+) handling, and MvO(2) 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 Ca(2+) 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 Ca(2+) sensitisation were unmasked. CONCLUSIONS: Calcium sensitisation improves systolic function and energetic efficiency. However, Ca(2+) sensitisers should be used with caution during post-ischaemic reperfusion, as they may exacerbate myocardial stunning and thus impair cardiac output.