Journal
EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY
Volume 49, Issue 2, Pages e54-e62Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/ejcts/ezv397
Keywords
Myocardium; Mitochondria; Ischaemia; reperfusion injury; Levosimendan; Delta Psi m; Ca2+
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Levosimendan (LS) is increasingly used in case of myocardial failure after cardiac surgery. The impact of LS on myocardial mitochondrial functions, such as respiratory chain function (RCF), mitochondrial membrane potential (Delta Im), Ca2+ handling, mitochondrial permeability transition pore (mPTP) opening and ATP during ongoing ischaemia/reperfusion (IR) injury, is not well understood. Depending on LS, I/R injury or the combination of both, we analysed myocardial functions in a retrograde Langendorff-model followed by the analysis of subsarcolemmal mitochondrial (SSM) functions. Rat hearts were divided into four study groups; two were subjected to 30 min of perfusion without (control) or with the application of 1.4 A mu mol/20 min LS (Levo). Experiments were repeated with hearts being subjected to 40 min of normothermic stop-flow ischaemia and 30 min of reperfusion without (IR) or with LS application (Levo-IR). Systolic left ventricular pressure (LVPsys), left ventricular contractility (LVdp/dt(max)) and coronary flow were determined. SSM were analysed regarding RCF, Delta Im, ATP, and Ca2+ retention capacity (CRC), Ca2+-induced swelling and Ca2+ fluxes after (re)perfusion. I/R injury suppressed LVdp/dt(max) (1381 +/- 927 vs 2464 +/- 913 mmHg/s; P = 0.01 at 30 min (re-)perfusion time). IR revealed complex I-V state3 (19.1 +/- 7.4 vs 27.6 +/- 11.0 nmolO(2)/min; P < 0.044) and II-V state3 (20.6 +/- 6.8 vs 37.3 +/- 9.10 molO(2)/min; P < 0.0001) suppression and Levo limited I-V (14.8 +/- 11.1 vs 27.6 +/- 11.0 nmolO(2)/min; P < 0.001) and II-V (24.1 +/- 6.4 vs 37.3 +/- 9.10 molO(2)/min; P < 0.0001) function. After energizing, Delta Im hypopolarization was observed in Levo (0.76 +/- 0.04 vs 0.84 +/- 0.04; P = 0.02), IR (0.75 +/- 0.06 vs 0.84 +/- 0.04; P = 0.007) and Levo-IR (0.75 +/- 0.06 vs 0.06 +/- 0.04; P = 0.01). IR (AUC: 626 vs 292; P = 0.023) and Levo-IR (AUC: 683 vs 292, P = 0.003) increased Ca2+-induced mPTP-opening susceptibility. CRC declined in IR (6.4 +/- 2.1 vs 10.5 +/- 2.6; P = 0.04) or Levo (6.5 +/- 2.0 vs 10.5 +/- 2.6; P = 0.023). Ca2+ uptake was delayed in IR and Levo-IR without LS impact (P < 0.0001). Ca2+ liberation was increased in Levo-IR. ATP synthesis was reduced in Levo (0.49 +/- 0.14 vs 0.74 +/- 0.14; P = 0.002) and Levo-I/R (0.34 +/- 0.18 vs 0.74 +/- 0.14; P < 0.002). LS limited RCF at complex IV and V with Delta Im hypopolarization suggesting a specific-dependent pathway. Ca2+ redistribution from SSM by LS during I/R injury possibly prevents from Ca2+ overload due to mPTP flickering. LS-induced mPTP flickering did not promote permanent Ca2+-induced mPTP opening. LS-dependent inhibition of ATP generation presumably resulted from complex IV and V limitations and lowered Delta Im. However, a resulting impact of limited ATP synthesis on myocardial recovery remains arguable.
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