Editors' ChoiceHeart Transplantation

Working on inflammatory injury in heart transplant

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Science Translational Medicine  24 Jun 2020:
Vol. 12, Issue 549, eabc8950
DOI: 10.1126/scitranslmed.abc8950

Abstract

Ex vivo perfusion for preservation of donor hearts may be improved by preventing inflammatory tissue injury, including through mechanical work.

Heart failure remains a leading cause of morbidity and mortality worldwide, and it is projected to afflict over 8 million Americans by 2030. A heart transplant is the only curative option for these patients, and preservation of precious donor organs for transplant is of critical importance. Donated hearts are most commonly subjected to static cold storage, which deprives the tissues of necessary oxygen, nutrients, and electromechanical stimulation, thus providing a limited time window before heart function wanes and the organs become unusable. Ex situ heart perfusion (ESHP) is an emergent technique that allows for continued perfusion of the beating heart, supplying required oxygen and nutrients, which may better preserve the tissue. Yet, organ function continues to decline throughout ESHP, possibly due to inflammatory tissue injury.

Here, Hatami et al. explore the relationship between inflammation and tissue response over the course of extended ESHP. Explanted pig hearts were tested either without circulatory load (non-working mode, NWM) or with simulated physiological load (working mode, WM), achieved by increasing pressure into the left atrium during ESHP. Loss of the heart’s contractile function occurred over time in both cases but was better preserved in WM. Interestingly, the hearts operating in WM expressed reduced biomarkers of inflammation when compared to the NWM group, and expression was comparable with that observed in freshly harvested tissue, which had not experienced ESHP. To probe the effect of inflammation on the myocardium, the authors looked toward metrics of oxidative and endoplasmic reticular stress that can be activated by inflammation and negatively affect tissue viability. Both oxidative and endoplasmic reticular stress markers were typically elevated in NWM, as was troponin-1 (an indicator of cardiomyocyte cell death). The exact mechanisms underlying preservation of heart function in WM have yet to be fully elucidated, but the results indicate that inflammation is a critical driver of acute tissue damage attenuated under these conditions. It also remains to be seen whether acute tissue stress is reversible, such as following successful transplantation.

This work breaks ground in two important ways. First, it indicates that perfusion in the working state may provide longer-lasting donor heart preservation, thus improving the technology’s ability to expand the donor organ pool. Moreover, it highlights the involvement of inflammatory tissue injury in functional decline of perfused hearts. This opens the door to the use of concurrent anti-inflammatory measures, including further exploration of antifouling pump components and drug interventions, which may limit innate immune activation.

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