Novel heat shock protein 90 inhibitor improves cardiac recovery in a rodent model of donation after circulatory death

Objective: Organ donation after circulatory death (DCD) is a potential solution for the shortage of suitable organs for transplant. Heart transplantation using DCD donors is not frequently performed due to the potential myocardial damage following warm ischemia. Heat shock protein (HSP) 90 has recently been investigated as a novel target to reduce ischemia/reperfusion injury. The objective of this study is to evaluate an innovative HSP90 inhibitor (HSP90i) as a cardioprotective agent in a model of DCD heart. Methods: A DCD protocol was initiated in anesthetized Lewis rats by discontinuation of ventilation and confirmation of circulatory death by invasive monitoring. Following 15 minutes of warm ischemia, cardioplegia was perfused for 5 minutes at physiological pressure. DCD hearts were mounted on a Langendorff ex vivo heart perfusion system for reconditioning and functional assessment (60 minutes). HSP90i (0.01 mu mol/L) or vehicle was perfused in the cardioplegia and during the first 10 minutes of ex vivo heart perfusion reperfusion. Following assessment, pro-survival pathway signaling was evaluated by western blot or polymerase chain reaction. Results: Treatment with HSP90i preserved left ventricular contractility (maximum + dP/dt, 2385 +/- 249 vs 1745 +/- 150 mm Hg/s), relaxation (minimum -dP/dt, -1437 +/- 97 vs 1125 +/- 85 mm Hg/s), and developed pressure (60.7 +/- 5.6 vs 43.9 +/- 4.0 mm Hg), when compared with control DCD hearts (All P = .001). Treatment abrogates ischemic injury as demonstrated by a significant reduction of infarct size (2,3,5-triphenyl-tetrazolium chloride staining) of 7 +/- 3% versus 19 +/- 4% (P = .03), troponin T release, and mRNA expression of Bax/Bcl-2 (P < .05). Conclusions: The cardioprotective effects of HSP90i when used following circulatory death might improve transplant organ availability by expanding the use of DCD hearts.

Automated summary

This study investigates the use of a HSP90 inhibitor as a cardioprotective agent in DCD hearts, showing promising results in preserving ventricular function and reducing ischemic injury. These findings suggest that HSP90i could potentially expand the use of DCD hearts and improve organ availability for transplantation.