Enhancing Metabolism of Donor Hearts for Cardiac Transplantation
Cobert, Michael Louis
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Congestive heart failure is a major health problem that affects millions of patients and represents a major cost to the health care system. Heart transplantation remains the most effective treatment for end-stage heart failure. However, transplantation can only be offered to a small fraction of patients with this disease due to the inadequate supply of available organs. A major factor limiting the donor pool relates to the poor ischemic tolerance of hearts removed and stored prior to implantation. Currently used heart preservation techniques involve storage of the organ near 0ºC to minimize donor organ metabolism and limit ongoing deterioration of the organ during storage prior to implantation (static storage). A new technique (machine perfusion preservation) is under development and works by perfusing the organ with oxygenated preservation solution. This method may extend the donor ischemic interval and may permit utilization of less-than-optimal donor hearts - thus expanding the donor pool for cardiac transplantation. This strategy has been used successfully for kidney transplantation in the clinical arena and initial experimental evidence suggests that it appears promising for preserving hearts as well. However, optimal myocardial perfusion conditions and techniques have not yet been defined. In fact, available preservation solutions do not contain substrates that are metabolized by the heart and available perfusion devices do not reliably deliver oxygen and substrates to the capillary bed. We believe that optimizing machine perfusion conditions in a manner designed to increase cardiac metabolism will improve the support of cellular processes, improve donor heart preservation, and potentially reverse myocardial injury sustained during the events leading to brain death. We have examined methods to optimize metabolism in two ways. First, we identified substrates which, when added to the circulating preservation solution, maximize myocardial metabolism. Our initial experiments were conducted in a rat model of ex vivo perfusion preservation. Hearts were perfused with cold, oxygenated organ preservation solution (University of Wisconsin Machine Perfusion Solution) supplemented with carefully-selected candidate carbon-13 (13C) labeled myocardial substrates. Magnetic resonance spectroscopy (MRS) was used to define the substrate or substrate combination that maximized oxidative metabolism during the storage interval. Second, conventional strategies of heart machine perfusion preservation have to date utilized antegrade coronary perfusion whereby the preservation solution is delivered into the ascending aorta. Prior studies have demonstrated that certain perfusion conditions allow the aortic valve to become incompetent, leading to reduced perfusate delivery and poor myocardial preservation. We proposed an alternate strategy that exploits perfusion through the coronary sinus (as is currently utilized for cardioplegia delivery during cardiac surgery) to overcome this limitation of antegrade delivery. We defined optimal retrograde coronary perfusion parameters in a well established canine model of heart transplantation. Regional perfusate flow delivery and high energy phosphate levels were determined over a range of coronary sinus flow rates. We subsequently compared antegrade and retrograde machine perfusion preservation techniques (and to conventional static storage) in the canine transplantation model to define the optimal preservation strategy. In these experiments myocardial function was quantified using load-independent technique, and metabolic state was measured using magnetic resonance spectroscopy to define substrate utilization parameters. An inherent limitation to transplanting hearts, especially those stored for long intervals, is predicting the suitability of the organ prior to implantation. In our human heart experiments, we applied a magic angle spinning (MAS) magnetic resonance spectroscopy technique to quantify the metabolic state of the heart prior to implantation. In these studies, after completion of the storage interval, MAS was performed on micro-biopsies of left ventricular tissue. Data from these experiments have allowed us to define optimal machine perfusion techniques to allow safe application of this technique into the clinical arena. This offers the potential to significantly expand the pool of useable donor hearts for transplantation. Findings in the proposed experiments may have wider applications in preserving myocardium during other (non-transplant) forms of cardiac surgery and in improving machine perfusion preservation of other organs.