Ca2+ sensitizer superior to catecholamine during myocardial stunning?
BACKGROUND
After open-chest cardiac surgery, ventricular function remains depressed (myocardial stunning). Catecholamines (epinephrine) improve ventricular function by increasing the intracellular Ca(2+) concentration. In parallel, the oxygen consumption is increased, so that the hitherto intact myocardium can be jeopardized. In the very insufficient ventricle, epinephrine can even become ineffective. Since Ca(2+) sensitizers provide another therapeutic avenue, the effects of epinephrine and levosimendan on postischemic hemodynamics were investigated.


METHODS
After hemodynamic steady state, isolated, blood (erythrocyte-enriched Krebs-Henseleit solution)-perfused rabbit hearts were subjected to 25 min normothermic, no-flow ischemia and 20 min reperfusion. Heart rate (HR), cardiac output (CO), left ventricular pressure (LVP), coronary blood flow (CBF), and arterio-venous oxygen difference (AVDO(2)) were recorded during reperfusion and after administration of either epinephrine (n=16; 0.03 micromol), or levosimendan (n=11; 0.75 micromol) or epinephrine plus levosimendan (n=5).


RESULTS
Epinephrine increased HR (19%, p=0.01) and improved hemodynamics in terms of CO (62%, p=0.0006), stroke volume SV (46%, p=0.02), stroke work W (158%, p=0.01), LVP(max) (58%, p=0.0001), maximal pressure increase dP/dt(max)(140%, p=0.0004), minimal pressure increase dP/dt(min) (104%, p=0.0002), LVP(ed) (-26%, p=0.02), and increased coronary resistance CR (31%, p=0.05). Epinephrine impaired hemodynamics in terms of AVDO(2) (+63%, p=0.003), myocardial oxygen consumption MVO(2) (+67%, p=0.0003) and MVO(2)/beat (+36%, p=0.01). External efficiency eta was increased by 92% (p=0.02). Levosimendan in postischemic hearts increased HR (32%, p=0.009) and improved hemodynamics in terms of CO (85%, p=0.01), SV (44%, p=0.03), W (115%, p=0.04), LVP(max) (95%, p=0.04), dP/dt(max) (133%, p=0.009), dP/dt(min) (121%, p=0.007), LVP(ed) (-63%, p=0.0006), and CR (-17%; n.s., p=0.1). It altered hemodynamics in terms of AVDO(2) (+7.0%; n.s., p=0.3) and MVO(2) (+32%, p=0.007) and MVO(2)/beat (+2.3%; n.s., p=0.4). External efficiency was increased by 307% (p=0.04). In five additional extremely dysfunctional rabbit hearts, epinephrine was ineffective. Additional levosimendan increased hemodynamics in terms of HR (56%; n.s., p=0.1), CO (159%, p=0.04), SV (89%, p=0.03), W (588%, p=0.02), LVP(max) (168%, p=0.03), dP/dt(max) (102%, p=0.005), dP/dt(min) (78%, p=0.006), LVP(ed) (-98%, p=0.0006), and CR (-50%, p=0.02). It altered hemodynamics in terms of AVDO(2) (-11%; n.s., p=0.05), MVO(2) (+131%, p=0.04) and MVO(2)/beat (+171%, p=0.03). External efficiency was increased by 212% (p=0.04).


CONCLUSIONS
In contrast to epinephrine, levosimendan improves ventricular function without increasing oxygen demand, thereby considerably improving external efficiency. Even during epinephrine resistance in extremely dysfunctional hearts, levosimendan successfully improves ventricular function.
Meyer
Katrin
K
Research Group Experimental Surgery, Department of Thoracic and Cardiovascular Surgery, University Hospital Düsseldorf, Moorenstrasse 5, Düsseldorf, Germany. katrin.meyer@med.uni-duesseldorf.de
Klocke
Reinhard C
RC
Schipke
Jochen D
JD
Gams
Emmeran
E
Korbmacher
Bernhard
B
D000818:Animals; D002118:Calcium / Q000502:physiology*; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D003326:Coronary Circulation / Q000187:drug effects; D003971:Diastole / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004837:Epinephrine / Q000494:pharmacology / Q000627:therapeutic use*; D006439:Hemodynamics / Q000187:drug effects; D006835:Hydrazones / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000150:complications; D017682:Myocardial Stunning / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D010101:Oxygen Consumption / Q000187:drug effects; D011724:Pyridazines / Q000494:pharmacology / Q000627:therapeutic use*; D011817:Rabbits; D000077464:Simendan; D013599:Systole / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology / Q000627:therapeutic use; D014665:Vasodilator Agents / Q000494:pharmacology / Q000627:therapeutic use
D002316:Cardiotonic Agents; D006835:Hydrazones; D011724:Pyridazines; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D000077464:Simendan; D002118:Calcium; D004837:Epinephrine