Calcium sensitisation impairs diastolic relaxation in post-ischaemic myocardium: implications for the use of Ca(2+) 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.
Choi
Yeong-Hoon
YH
Heart Center of the University of Cologne, Department of Cardiothoracic Surgery, Cologne, Germany. yh.choi@uk-koeln.de
Cowan
Douglas B
DB
Wahlers
Thorsten C W
TC
Hetzer
Roland
R
Del Nido
Pedro J
PJ
Stamm
Christof
C
D000818:Animals; D017301:Ca(2+) Mg(2+)-ATPase / Q000037:antagonists & inhibitors; D002118:Calcium / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000502:physiology; D003600:Cytosol / Q000378:metabolism; D003931:Diacetyl / Q000031:analogs & derivatives / Q000494:pharmacology; D003971:Diastole / Q000187:drug effects / Q000502:physiology; D004298:Dopamine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006835:Hydrazones / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000503:physiopathology; D017682:Myocardial Stunning / Q000378:metabolism / Q000503:physiopathology; D009924:Organ Culture Techniques; D009930:Organic Chemicals / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology; D011817:Rabbits; D000077464:Simendan; D016277:Ventricular Function, Left / Q000187:drug effects
D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D006835:Hydrazones; D009930:Organic Chemicals; D011724:Pyridazines; C062763:ORG 30029; C004717:diacetylmonoxime; D000077464:Simendan; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D017301:Ca(2+) Mg(2+)-ATPase; D003931:Diacetyl; D002118:Calcium; D004298:Dopamine