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Eur J Cardiothorac Surg 2005;27:501-507
© 2005 Elsevier Science NL

Pharmacological preconditioning with monophosphoryl lipid A improves post ischemic diastolic function and modifies TNF-alpha synthesis

^a Department of Cardiothoracic Surgery, Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, 6 Witzman St., Tel Aviv, 64239, Israel
^b Department of Cardiac Surgery, Ludwig-Maximilians University, Munich, Germany

Received 9 August 2004; received in revised form 25 November 2004; accepted 26 November 2004.

^* Corresponding author. Tel.: +972 3 6973322; fax: +972 3 6974439. (E-mail: sharonyn{at}netvision.net.il).

Objective: Pharmacologic preconditioning represents an attractive myocardial protection strategy. Tumor necrosis factor-alpha plays an important role in myocardial ischemia-reperfusion injury. We aimed to determine the effect of Monophosphoryl lipid A-induced delayed preconditioning on diastolic and systolic left ventricular function and tumor necrosis factor-alpha synthesis during ischemia and reperfusion. Methods: Rats (n=10) were pretreated with Monophosphoryl lipid A (350µg/kg) or vehicle (n=9). Twenty-four hours later, the hearts were isolated and perfused on a Langendorff apparatus. Hemodynamic measurements, tumor necrosis factor-alpha mRNA expression and protein content were studied after stabilization (baseline), after 35min of global ischemia and at 40min of reperfusion. Results: Left ventricular developed pressure and peak rate of left ventricular developed pressure (dP/dt) rise were comparable between the animals in the control and Monophosphoryl lipid A treated groups during baseline but were higher in Monophosphoryl lipid A group at reperfusion (74±4 vs 51±5mmHg, 3340±172 vs 2240±156mmHg/s, respectively, P<0.01). dP/dt fall was significantly lower in the MLA group (2630±225v 1580±210mmHg/s, P<0.01) at 40min of reperfusion as well as end diastolic pressure. Baseline tumor necrosis factor-alpha mRNA (expressed as arbitrary densitometry units) were higher in the Monophosphoryl lipid A group (1.3±0.1 vs 0.5±0.03, P<0.05) but remained constant after ischemia and reperfusion (1.3±0.1 and 1.4±0.03, P=0.2), while further increase was observed in the control group (from 1.0±0.1 to 1.4±0.1, P<0.05). Tumor necrosis factor-alpha protein content from heart effluent in the control group was increased during reperfusion (79±30 and 200±22pg/ml, P<0.05) but was undetectable in the Monophosphoryl lipid A group. Marked TNF-alpha immunostaining of left ventricular tissue was observed only in the control group but no TNF-alpha staining was evident in the Monophosphoryl lipid A treated group at 40min of reperfusion. Conclusion: Monophosphoryl lipid A-induced preconditioning renders the heart more tolerant to ischemia-reperfusion in terms of left ventricular diastolic and systolic function, and prevents tumor necrosis factor-alpha production during ischemia, through aborting the translation phase of tumor necrosis factor-alpha synthesis.

Key Words: Preconditioning • TNF-alpha • Ischemia-reperfusion

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