Early reperfusion hemodynamics predict recovery in rat hearts: a potential approach towards evaluating cardiac grafts from non-heart-beating donors

Abstract

Aims: Cardiac grafts from non-heartbeating donors (NHBDs) could significantly increase organ availability and reduce waiting-list mortality. Reluctance to exploit hearts from NHBDs arises from obligatory delays in procurement leading to periods of warm ischemia and possible subsequent contractile dysfunction. Means for early prediction of graft suitability prior to transplantation are thus required for development of heart transplantation programs with NHBDs.

Methods and results: Hearts (n = 31) isolated from male Wistar rats were perfused with modified Krebs-Henseleit buffer aerobically for 20 min, followed by global, no-flow ischemia (32°C) for 30, 50, 55 or 60 min. Reperfusion was unloaded for 20 min, and then loaded, in working-mode, for 40 min. Left ventricular (LV) pressure was monitored using a micro-tip pressure catheter introduced via the mitral valve. Several hemodynamic parameters measured during early, unloaded reperfusion correlated significantly with LV work after 60 min reperfusion (p<0.001). Coronary flow and the production of lactate and lactate dehydrogenase (LDH) also correlated significantly with outcomes after 60 min reperfusion (p<0.05). Based on early reperfusion hemodynamic measures, a composite, weighted predictive parameter, incorporating heart rate (HR), developed pressure (DP) and end-diastolic pressure, was generated and evaluated against the HR-DP product after 60 min of reperfusion. Effective discriminating ability for this novel parameter was observed for four HR*DP cut-off values, particularly for ≥20 *10(3) mmHg*beats*min(-1) (p<0.01).

Conclusion: Upon reperfusion of a NHBD heart, early evaluation, at the time of organ procurement, of cardiac hemodynamic parameters, as well as easily accessible markers of metabolism and necrosis seem to accurately predict subsequent contractile recovery and could thus potentially be of use in guiding the decision of accepting the ischemic heart for transplantation.

Figure 1. Perfusion protocol.

Hearts (n = 31) were perfused for 20 min in aerobic working-mode, followed by global, no-flow ischemia. Four different ischemic periods at 32°C were investigated: 30 min (n = 6), 50 min (n = 5), 55 min (n = 15) and 60 min (n = 5). Hearts were then reperfused for 60 min, with the first 20 min in an unloaded-mode.

Figure 2. Post-ischemic contractile recovery.

Functional recovery at 60 min reperfusion in hearts subjected to various periods of ischemia at 32°C. A) Heart rate (HR) - developed pressure (DP) product B) HR - DP - dP/dt_max product C) HR - peak systolic pressure product.

Figure 3. Spearman correlations between predictive and outcome parameters.

All predictive parameters were measured at 10-min reperfusion except for LDH, which was calculated as percent change between 5- and 10-min reperfusion. Outcome parameters were measured at 60-min reperfusion and either taken as absolute value (60’) or percentage of mean pre-ischemic value (%).

Figure 4. ROC analysis for composite predictive parameter.

ROC analysis for a novel, composite hemodynamic-based predictive parameter of functional recovery after ischemia based on early reperfusion measures of HR-DP product and EDP. Discriminating ability of this composite predictive parameter was evaluated using absolute values of HR*DP (mmHg*beats*min⁻¹) with the following event threshold cut-off values: ≥8*10³, ≥10*10³, ≥15*10³, and ≥20 *10³.

Figure 5. Schematic representation of NHBD-heart procurement/evaluation/transplantation process in a potential clinical scenario.

Following a precipitating event (e.g. trauma accident, removal of life-support) leading to cardio-circulatory arrest, the heart is subjected to a variable period of warm ischemia and an obligatory hands-off period. Once invasive interventions are permitted, we propose that the heart could first be reperfused in situ or ex vivo in an unloaded manner for 10 minutes, during which time predictive parameters could be measured for graft evaluation. Immediately following this 10-minute period, and in the event that evaluation predicts a positive outcome, cardioplegia could be commenced and the heart prepared for transport.