Matthias Peltz

Perfusion Preservation versus Static Preservation for Cardiac Transplantation: Effects on Myocardial Function and Metabolism

INTRODUCTION Continuous perfusion of donor hearts for transplantation has received increasing interest, but the effects on cellular metabolism, myocyte necrosis, and myocardial edema are not well defined. METHODS Pig hearts were instrumented with sonomicrometry crystals and left ventricular catheters. Left ventricular function was quantified by the pre-load-recruitable stroke work (PRSW) relationship. Hearts were arrested with Celsior solution with 5.5 mM 13C-glucose added, and removed and stored in cold solution (n = 4) or placed in a device providing continuous perfusion of this solution at 10 ml/100 g/min (n = 4). After 4 hours of storage, left atrial samples were frozen, extracted, and analyzed by magnetic resonance spectroscopy. Hearts were then transplanted into recipient pigs and reperfused for 6 hours, with function measured hourly. At the end of the experiment, left ventricular water content and serum creatine kinase-MB isoenzyme levels were measured. RESULTS Baseline left ventricular function was similar in both groups. During reperfusion, the volume-axis intercept of the PRSW relationship was significantly lower in hearts stored with continuous perfusion (p < 0.05), suggesting reduced contractile impairment. Magnetic resonance spectroscopy revealed a decrease in tissue lactate in hearts that received continuous perfusion. Serum creatine kinase-MB isoenzyme levels were higher hearts that had static storage (30.8 +/- 9.0 vs 13.2 +/- 2.7 ng/ml; p < 0.05). Left ventricular water content was similar in both groups (0.797 +/- 0.012 vs 0.796 +/- 0.014; p = 0.45). CONCLUSIONS Donor hearts sustain less functional impairment after storage with continuous perfusion. This technique reduces tissue lactate accumulation and myocardial necrosis without increasing myocardial edema and appears promising as a method to improve results of cardiac transplantation.

HLA mismatches influence lung transplant recipient survival, bronchiolitis obliterans and rejection: Implications for donor lung allocation

BACKGROUND Human leukocyte antigen (HLA) histocompatibility is not considered when placing donor allografts for lung transplantation. We previously reported that fewer individual Class I (HLA-A and -B) and Class II (HLA-DR) antigen mismatches (MM) correlated with improved survival in lung transplant recipients. In this study we evaluated whether the effects of total HLA, Class I and Class II MM were more important determinants of: (1) recipient survival; (2) development of bronchiolitis obliterans (BO); and (3) freedom from acute rejection (AR). METHODS All adult primary cadaveric lung recipients transplanted between April 1, 1994, and June 30, 2004 entered in the OPTN database were included (n = 9,791). Groups were created based on the total number of HLA, Class I and Class II MM. Recipient survival, freedom from AR and freedom from BO were compared. Univariate data were computed using the Kaplan-Meier method and compared by log-rank test. Multivariate analysis was performed using the Cox proportional hazards method. RESULTS Univariate analysis identified significantly improved survival in recipients with fewer total HLA (p < 0.001) and Class I MM (p = 0.005). The incidence of BO was significantly lower in patients with fewer total Class I MM (p = 0.036). AR was influenced only by Class II MM (p = 0.005). By multivariate analysis, total HLA, Class I and Class II MM impacted recipient survival. Total HLA and Class I MM correlated with development of BO. Class II MM correlated with development of AR. CONCLUSION HLA MM are important determinants of lung transplant survival, BO and AR. These data suggest that donor-recipient HLA MM may warrant consideration when allocating organs for lung transplantation.

Influence of chronic total occlusions on coronary artery bypass graft surgical outcomes.

Abstract  Background: Presence of epicardial coronary artery chronic total occlusion (CTO) predicts higher referral rates for coronary bypass graft surgery (CABG). However, the impact of coronary artery CTO on CABG outcomes has never been systematically studied. Method: We examined one‐year outcomes in 605 consecutive Veterans, discharged post‐CABG between June 2005 and December 2008. Results: A coronary CTO was present in 256 patients (42%), predominantly (48.3%) in the right coronary artery distribution. Baseline clinical characteristics and medical therapy were similar in patients with and without a coronary CTO. A single CTO was present in 73.8%, and 26.2% patients had multiple CTO. All left anterior descending coronary artery CTO were successfully bypassed, as were >92% in left circumflex and right coronary arteries and 85% CTO in multiple coronary artery distributions. During the mean follow‐up of 348.9 ± 4.5 days, incidence of all‐cause death and myocardial infarction were similar in both groups (7.1% in CTO group and 7.4% in non‐CTO group; p = 0.97). CTO >20 mm in length constituted 74.9% and >40 mm 37.8%. One‐year survival post‐CABG was significantly lower in patients with CTO lengths >40 mm compared to ≤20 mm (p = 0.04). CTO >40 mm was an independent predictor of post‐CABG mortality controlling for age, number of CTO, comorbid diseases, clopidogrel use, severity of coronary artery disease, renal failure, and left ventricular ejection fraction. Conclusion: CABG achieves high success in grafting epicardial coronary vessels with CTO; however, presence of long coronary CTO (>40 mm) is an independent predictor of post‐CABG survival. (J Card Surg 2012;27:662‐667)

Myocardial perfusion characteristics during machine perfusion for heart transplantation.

BACKGROUND Optimal parameters for machine perfusion preservation of hearts prior to transplantation have not been determined. We sought to define regional myocardial perfusion characteristics of a machine perfusion device over a range of conditions in a large animal model. METHODS Dog hearts were connected to a perfusion device (LifeCradle, Organ Transport Systems, Inc, Frisco, TX) and cold perfused at differing flow rates (1) at initial device startup and (2) over the storage interval. Myocardial perfusion was determined by entrapment of colored microspheres. Myocardial oxygen consumption (MVO(2)) was estimated from inflow and outflow oxygen differences. Intra-myocardial lactate was determined by (1)H magnetic resonance spectroscopy. RESULTS MVO(2) and tissue perfusion increased up to flows of 15 mL/100 g/min, and the ratio of epicardial:endocardial perfusion remained near 1:1. Perfusion at lower flow rates and when low rates were applied during startup resulted in decreased capillary flow and greater non-nutrient flow. Increased tissue perfusion correlated with lower myocardial lactate accumulation but greater edema. CONCLUSIONS Myocardial perfusion is influenced by flow rates during device startup and during the preservation interval. Relative declines in nutrient flow at low flow rates may reflect greater aortic insufficiency. These factors may need to be considered in clinical transplant protocols using machine perfusion.

Sirolimus use and incidence of venous thromboembolism in cardiac transplant recipients

Sirolimus is an immunosuppressive agent increasingly used in cardiac transplant recipients in the setting of allograft vasculopathy or worsening renal function. Recently, sirolimus has been associated with increased risk of venous thromboembolism (VTE) in lung transplant recipients. To investigate whether this association is also present in cardiac transplant recipients, we retrospectively reviewed the charts of 67 cardiac transplant recipients whose immunosuppressive regimen included sirolimus and 134 matched cardiac transplant recipients whose regimen did not include sirolimus. Rates of VTE were compared. Multivariable Cox proportional hazards models tested the association of sirolimus use with VTE. A higher incidence of VTE was seen in patients treated with vs. without sirolimus (8/67 [12%] vs. 9/134 [7%], log‐rank statistic: 4.66, p = 0.03). Lower body mass index (BMI) and total cholesterol levels were also associated with VTE (p < 0.05). The association of sirolimus with VTE persisted when adjusting for BMI (hazard ratio [95% confidence interval]: 2.96 [1.13, 7.75], p = 0.03) but not when adjusting for total cholesterol (p = 0.08). These data suggest that sirolimus is associated with an increased risk of VTE in cardiac transplant recipients, a risk possibly mediated through comorbid conditions. Larger, more conclusive studies are needed. Until such studies are completed, a heightened level of awareness for VTE in cardiac transplant recipients treated with sirolimus appears warranted.

Importance of Organ Preservation Solution Composition in Reducing Myocardial Edema during Machine Perfusion for Heart Transplantation

OBJECTIVE Machine perfusion preservation has been used experimentally to extend the storage interval of donor hearts. We previously demonstrated that machine perfusion with glucose-supplemented Celsior preservation solution led to superior reperfusion function but resulted in increased myocardial edema compared with conventional static preservation. We hypothesized that other solutions that contain an oncotic agent, such as University of Wisconsin Machine Perfusion Solution (UWMPS), might reduce graft edema development while maintaining myocardial oxidative metabolism during long-term storage. METHODS Canine hearts were stored and perfused in a perfusion preservation device (LifeCradle; Organ Transport Systems) after cardioplegic arrest and donor cardiectomy. Hearts were perfused either with glucose-supplemented Celsior (which lacks an oncotic agent) or UWMPS (which contains hydroxyethyl starch) at 5 degrees C in the perfusion device over 10 hours. Oxygen consumption (MVO(2)), lactate accumulation, regional flow distribution, and myocardial water content were measured. RESULTS Hearts in both groups continued to extract oxygen over the entire perfusion interval. Lactate accumulation was minimal in both groups. Both solutions delivered perfusate evenly to all regions of myocardium. Heart weight increase (Celsior 31.3 +/- 4.3%, UWMPS -3.3 +/- 1.9%) and final myocardial water content (Celsior 80.2 +/- 1.3%, UWMPS 75.9 +/- 0.3%) were higher in the Celsior group (P < .005). CONCLUSIONS Donor hearts can be supported by a perfusion device over relatively extended storage intervals. These organs continue to undergo oxidative metabolism with little lactate accumulation. An oncotic agent appears to be important in limiting increases in myocardial water content. UWMPS appears to be superior for perfusion preservation of myocardium by reducing edema development during storage.

Hospital length of stay after lung transplantation: Independent predictors and association with early and late survival

BACKGROUND Duration of index hospitalization after lung transplantation (LTx) is an important variable that has not received much attention. We sought to determine independent predictors of prolonged hospital length of stay (LOS) and its association with early and late outcomes. METHODS The United Network of Organ Sharing database was queried for adult patients undergoing LTx between 2006 and 2014 (N = 14,320). Patients with dual organ or previous transplantation and patients who died during the first 25 days after LTx were excluded (n = 12,647, mean age 55.2 years ± 13.1). Primary outcome was prolonged LOS (>25 days) (3,251/12,647; 25.7%). Donor, recipient, and procedure-related variables were analyzed as potential predictors of prolonged LOS. Association of prolonged LOS with 1-year and 5-year survival was evaluated using Cox proportional hazards analysis. RESULTS Independent predictors of prolonged LOS included serum albumin, lung allocation score, functional status, and need of extracorporeal membrane oxygenation or ventilator support at the time of transplant; donor age >40 years; gender mismatch (female donor to male recipient); donor body mass index; African American ethnicity; ischemic time >6 hours; and double LTx. Prolonged LOS was independently associated with increased mortality at 1 year (hazard ratio, 3.96; 95% confidence interval, 3.48-4.50; p < 0.001) and 5 years (hazard ratio, 2.00; 95% confidence interval, 1.79-2.25; p < 0.001). CONCLUSIONS A significant proportion of patients have a prolonged LOS after LTx, and several recipient, donor, and procedure-related variables are independent predictors of this outcome. Patients with prolonged LOS after LTx have significantly increased risk of death at 1 year and 5 years.

Contemporary analysis of incidence of post-operative atrial fibrillation, its predictors, and association with clinical outcomes in lung transplantation

BACKGROUND Atrial fibrillation (AF) is a common complication after lung transplantation (LT). Since the lung allocation score (LAS) was implemented in 2005, there has been significant evolution in the practice of LT, necessitating re-evaluation of this arrhythmia. METHODS One hundred thirty-one patients undergoing LT between January 2011 and April 2013 were reviewed retrospectively to assess the occurrence of AF and its outcomes (mortality, morbidity measures, treatment strategies). Uni- and multivariate logistic regression models were constructed to ascertain predictors of AF. RESULTS Forty-six patients (35.1%) developed post-operative AF at 4.65 ± 3.68 days post-LT. The AF group was older (60.07 vs 54.48 years, p = 0.01), and had higher rates of cardiopulmonary bypass (CPB) (73.33% vs 43.53%, p = 0.001). There was no difference in mortality, ICU length of stay (LOS) and ventilator days; however, the AF group had a significantly higher mean hospital LOS by 8.43 days (17.09 vs 25.52, p = 0.04). Age (OR = 1.04, p = 0.03) and CPB (OR = 3.68, p = 0.002) were identified as predictors of AF by stepwise logistic regression after adjusting for gender, history of AF, type of LT, pulmonary hypertension and LT indication. In the AF group, 78.26% of patients required combination therapy. Anti-arrhythmics were used in 52.17% of patients. Dofetilide/ibutilide use was not associated with increased mortality. A total of 97.82% were in sinus rhythm at discharge. CONCLUSIONS To our knowledge, this is the first study to examine post-operative AF exclusively in the post-LAS era. Incidence of AF after LT is 35%. It increases hospital LOS, but not mortality. Management of AF is challenging and dofetilide/ibutilide serve as effective adjuncts to current therapy.

Differences in regional myocardial perfusion, metabolism, MVO2, and edema after coronary sinus machine perfusion preservation of canine hearts.

Machine perfusion improves solid organ preservation for transplantation. We have demonstrated that antegrade perfusion preservation of hearts is superior to cold storage but may be limited by aortic valve incompetence. We hypothesized that retrograde perfusion (RP) through the coronary sinus may provide more reliable perfusate delivery to the heart. This study was designed to determine the optimal perfusion parameters and evaluate regional flow after RP of canine hearts. After donor cardiectomy, canine hearts (n = 6) were established in a perfusion device (LifeCradle, Organ Transport Systems, Inc., Frisco, TX) through a coronary sinus catheter. Hearts were perfused at 5°C over flow rates from 10 to 35 ml/100 g myocardium/min for 20 minutes at each flow rate. Colored microspheres were used to quantify tissue perfusion. Oxygen consumption (MVO2) and perfusion parameters were measured. At end-perfusion, tissue was collected for proton magnetic resonance spectroscopy (1H MRS), microsphere analysis, and determination of myocardial edema. MVO2 increased up to flow rates of 20 ml/100 g/min. Right ventricular (RV) perfusion was reduced at all flow rates. Increased lactate/alanine ratios by 1H MRS and reduced myocardial water content were noted in RV samples. RP results in excellent left ventricular (LV) perfusion. RV perfusion is reduced and oxidative metabolism in the right ventricle may not be maintained by RP. Further studies to evaluate effects of reduced RV perfusion by RP on functional recovery after transplantation are warranted.

Predictors of outcome among patients on extracorporeal membrane oxygenation as a bridge to lung transplantation

There is a lack of data regarding clinical variables associated with successful bridge to lung transplantation (LT) using extracorporeal membrane oxygenation (ECMO) support.