Development of a human heart‐sized perfusion system for metabolic imaging studies using hyperpolarized [1‐¹³C]pyruvate MRI

Abstract

Purpose Increasing worldwide demand for cardiac transplantation has spurred new developments to increase the donor pool. Normothermic preservation of heart grafts for transplantation is an emerging strategy to improve the utilization of marginal grafts. Hyperpolarized MR using metabolic tracers such as [1‐13C]pyruvate, provide a novel means of investigating metabolic status without the use of ionizing radiation. We demonstrate the use of this methodology to examine ex vivo perfused porcine heart grafts. Methods Hearts from three 40‐kg Danish domestic pigs were harvested and subsequently perfused in Langendorff mode under normothermic conditions, using an MR‐compatible perfusion system adapted to the heart. Proton MRI and hyperpolarized [1‐13C]pyruvate were used to investigate and quantify the functional and metabolic status of the grafts. Results Hearts were perfused with whole blood for 120 min, using a dynamic contrast‐enhanced perfusion experiment to verify successful myocardial perfusion. Hyperpolarized [1‐13C]pyruvate MRI was used to assess the metabolic state of the myocardium. Functional assessment was performed using CINE imaging and ventricular pressure data. High lactate and modest alanine levels were observed in the hyperpolarized experiment. The functional assessment produced reduced functional parameters. This suggests an altered functional and metabolic profile compared with corresponding in vivo values. Conclusion We investigated the metabolic and functional status of machine‐perfused porcine hearts. Utilizing hyperpolarized methodology to acquire detailed myocardial metabolic information—in combination with already established MR methods for cardiac investigation—provides a powerful tool to aid the progress of donor heart preservation.

Normothermic Machine Perfusion Systems: Where Do We Go From Here?

“…62,63 Future perspectives in organ monitoring for NMP systems include the application of noninvasive imaging technologies. In particular, magnetic resonance approaches under development can assess metabolic state, 64 microcirculation, 65 and organ function. 66,67 Hyperspectral imaging represents a novel technology of increasing interest for monitoring organ microcirculation, functional biomarkers, water, hemoglobin, or tissue oxygenation.…”

“…The administration of therapies through the perfusate has several benefits that make NMP an attractive therapeutic option, including more efficient delivery, lower doses, and reduced unwanted side effects in nontarget organs. 174 The immunomodulatory properties of mesenchymal stem cells 57–159 and multipotent adult progenitor cells 160–162 have shown beneficial effects during liver, lung, and kidney NMP, presumably due to their immunomodulatory properties, which prompt both anti-inflammatory and regenerative responses. 157,160–162 In human models, initially discarded kidneys 160 and livers 161 treated with multipotent adult progenitor cells or preterm-neonate progenitor cells 162 exhibited improved viability, even meeting established criteria.…”

Novel Imaging Technologies for Accurate Assessment of Cardiac Allograft Performance

“…Magnetic resonance imaging (MRI) utilizes strong magnetic fields to polarize hydrogen atoms within the tissue to generate a radio frequency signal used to create images of organs within the body [ 31 ]. Since hydrogen atoms are naturally abundant in water and fat, MRI produces superior soft tissue contrast capable of functional, anatomical, and metabolic imaging [ 32 ]. Conventional MRI has been utilized experimentally to measure wall motion and intramyocardial strain in human hearts revived using a four-chamber working perfusion system adapted to be MRI compatible [ 33 ].…”

“…This hyperpolarized substrate is added to the perfusate, metabolized by the organ over time, and traced chemically and spatially via MR imaging. For cardiac graft assessment [1- 13 C] pyruvate has recently been tested as tracer due to its central role in cellular metabolism as it leads to energy production and the formation of lactate, alanine, and carbon dioxide [ 32 , 42 ]. The resulting metabolic profile correlated with aspects of Langendorff machine perfused porcine hearts were the pyruvate signal was only localized in the myocardium and not in the chambers of the heart [ 32 ].…”

“…For cardiac graft assessment [1- 13 C] pyruvate has recently been tested as tracer due to its central role in cellular metabolism as it leads to energy production and the formation of lactate, alanine, and carbon dioxide [ 32 , 42 ]. The resulting metabolic profile correlated with aspects of Langendorff machine perfused porcine hearts were the pyruvate signal was only localized in the myocardium and not in the chambers of the heart [ 32 ]. Furthermore, differences in the metabolic profile of machine perfused heart and in vivo measurement were significant and correlated with differences in functional measurements, which indicates good sensitivity of this MRI method [ 32 ].…”