Donor heart preservation with a novel hyperpolarizing solution: Superior protection compared with University of Wisconsin solution

Abstract

Extending donor heart preservation time would offer several advantages. Surgical results would likely improve because it has been demonstrated with present solutions that cold ischemic times inversely correlate with postoperative survival. 1 It also would allow for O ne of the most significant limitations in heart transplantation is the relatively short preservation time that current preservation solutions offer. Safe organ preservation can be maintained for only 4 hours.Objectives: A donor heart preservation solution was designed to use hyperpolarized arrest with the adenosine triphosphate-sensitive potassium-channel opener pinacidil. This solution contained concentrations of potassium, sodium, calcium, magnesium, lactobionate, and the buffer histidine specifically chosen to minimize intracellular calcium accumulation associated with prolonged ischemia.Methods: Twenty-four rabbit hearts were randomly assigned to receive 1 of 3 preservation solutions in a crystalloid-perfused Langendorff model: (1) prototype solution containing a 0.5 mmol/L concentration of pinacidil, (2) prototype solution without pinacidil as control, and (3) University of Wisconsin solution. Thirty minutes of initial perfusion preceded baseline data acquisition. Data comprised left ventricle pressure-volume curves generated by inflating an intraventricular latex balloon. After cardioplegic administration, hearts underwent 4 hours of hypothermic storage, followed by 60 minutes of reperfusion and postischemic data acquisition.Results: Postischemic developed pressure was better preserved by pinacidil solution (92.4% ± 4.5%) than by the control (74.9% ± 3.4%, P = .01) and University of Wisconsin solutions (66.7% ± 5.1%, P = .001). Diastolic negative dP/dT was better preserved by pinacidil solution (104.4% ± 10.2%) than by the control (80.2% ± 4.2%, P = .034) and University of Wisconsin solutions (71.7% ± 7.0%, P = .015). Diastolic compliance, expressed as baseline/postischemic diastolic slope ratios, was more poorly preserved by University of Wisconsin solution (0.67 ± 0.07) than by the pinacidil (0.88 ± 0.05, P = .041) and control solutions (0.87 ± 0.05, P = .021). Postischemic coronary flow was higher in hearts exposed to pinacidil solution (77.8% ± 3.0%) than in those exposed to the control (66.8% ± 2.4%) and University of Wisconsin solutions (70.9% ± 4.0%, P = .07). Conclusions:The superiority of the pinacidil solution in this experiment demonstrated that hyperpolarized arrest with potassium-channel openers improves donor heart preservation when administered in a novel histidinebuffered lactobionate-enriched vehicle.

K channel therapeutics at the bedside

“…3 upper panel) [27][28][29][30][31]. Additional, subcellular sites of potassium channel opener action have been identified, including the inner membrane of the mitochondria where a protective outcome has been linked to prevention of mitochondrial Ca 2+ overload [27,[35][36][37][38], modulation of reactive oxygen species generation [35,39], and preservation of energetics and nucleotide pools [35][36][37][38][39][40][41][42][43][44][45].…”

Effects of Donor Pre-Treatment With Dopamine on Survival After Heart Transplantation

“…Abundant intracellular calcium aggravates mitochondrial damage, with the consequence that the mitochondrial membrane potential ultimately breaks down (29). Strategies that reduce intracellular calcium with novel hyperpolarizing preservation solutions have been shown to ameliorate ischemic damage during cold preservation in experimental heart transplantation (27). We were able to demonstrate that dopamine decelerates the deleterious amplification loop of intracellular calcium accumulation, and subsequent ATP consumption by scavenging of reactive oxygen species (9,30).…”

“…There is evidence that ischemic time negatively affects allograft survival in adult heart transplantation (25). Cellular cardiac damage after prolonged cold ischemia is in part ascribed to oxidative stress (26,27). Under cold storage conditions, the accumulation of reactive oxygen species leads to an increased release of calcium ions from intracellular stores, and from the extracellular environment through store-operated channels (28).…”

Progress Towards a More Physiologic Approach to Donor Heart Preservation: The Advantages of Hyperpolarized Arrest

“…6,8,13 Depolarizing hyperkalemic cardioplegia has been increasingly linked to left ventricular dysfunction, arrhythmia, microvascular damage, apoptosis, and drastic ionic fluxes. 14 -18 In previous studies, we have used pinacidil, a non-selective K ATP channel opener, and seen advantages over the depolarizing UW solution.…”

“…We have previously shown the benefits of using pinacidil, a non-specific potassium adenosine triphosphate (K ATP ) channel agonist, in the preservation of cardiac function and physiology [5][6][7][8] after global ischemia. Hyperpolarized cardiac arrest using a K ATP channel opener has been shown to be beneficial in the maintenance of cardiac energy stores after prolonged ischemia and cold storage.…”