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Ca²⁺ sensitizer superior to catecholamine during myocardial stunning?

^a Research Group Experimental Surgery, Duesseldorf, Germany
^b Department of Thoracic and Cardiovascular Surgery, University Hospital Duesseldorf, Germany
^c Department of Internal Medicine, Marienhospital Vechta, University Hospital Duesseldorf, Germany

Received 14 January 2008; received in revised form 21 April 2008; accepted 22 April 2008.

^_* Corresponding author. Address: Research Group Experimental Surgery, Department of Thoracic and Cardiovascular Surgery, University Hospital Düsseldorf, Moorenstrasse 5, D-40225 Duesseldorf, Germany. Tel.: +49 211 8119955; fax: +49 211 8116996. (Email: katrin.meyer{at}med.uni-duesseldorf.de).

Background: After open-chest cardiac surgery, ventricular function remains depressed (myocardial stunning). Catecholamines (epinephrine) improve ventricular function by increasing the intracellular Ca²⁺ 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 Ca²⁺ 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 (AVDO₂) were recorded during reperfusion and after administration of either epinephrine (n = 16; 0.03 µmol), or levosimendan (n = 11; 0.75 µmol) 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 AVDO₂ (+63%, p = 0.003), myocardial oxygen consumption MVO₂ (+67%, p = 0.0003) and MVO₂/beat (+36%, p = 0.01). External efficiency 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 AVDO₂ (+7.0%; n.s., p = 0.3) and MVO₂ (+32%, p = 0.007) and MVO₂/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 AVDO₂ (–11%; n.s., p = 0.05), MVO₂ (+131%, p = 0.04) and MVO₂/beat (+171%, p = 0.03). External efficiency was increased by 212% (p = 0.04). Conclusion: 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.

Key Words: Myocardial stunning • Ca²⁺ sensitizing • Oxygen consumption • Ischemia/reperfusion • External efficiency • Catecholamine resistance