Max B. Mitchell

Preconditioning of Isolated Rat Heart Is Mediated by Protein Kinase C

Catecholamines have been implicated in the phenomenon of ischemic preconditioning. We have previously demonstrated that ischemic preconditioning against postischemic mechanical dysfunction in the isolated rat heart is mediated by the alpha 1-adrenergic receptor. The purpose of this study was to delineate the signal transduction of preconditioning distal to the alpha 1-adrenergic receptor. Our results suggest that (1) transient ischemia and alpha 1-adrenergic receptor-induced preconditioning is inhibited by protein kinase C (PKC) antagonists, (2) functional protection against global ischemia/reperfusion injury can be induced by infusion of diacylglycerol, the second messenger of the alpha 1-adrenergic pathway, and (3) transient ischemia and alpha 1-adrenergic preconditioning are both characterized by similar translocation of PKC-delta to the sarcolemma of myocardium. These findings suggest that PKC is an effector of preconditioning in the isolated rat heart.

Preconditioning against myocardial dysfunction after ischemia and reperfusion by an alpha 1-adrenergic mechanism.

Preconditioning may find ready applicability in humans facing scheduled global cardiac ischemia-reperfusion (IR) during bypass or transplantation, where such a maneuver is feasible before arrest. Our objective was to delineate and exploit the endogenous preconditioning mechanism triggered by transient ischemia (TI) and thereby attenuate myocardial postischemic mechanical dysfunction by clinically acceptable means. Preconditioning by 2 minutes of TI followed by 10 minutes of normal perfusion protected isolated rat left ventricle function assessed after 20 minutes of global, 37 degrees C ischemia and 40 minutes of reperfusion. Final recovery of developed pressure (DP) was improved (91.5 +/- 1.9% of equilibration DP versus unconditioned IR control, 57.4 +/- 2.4%, P < .01) and was accompanied by increased contractility (+/- dP/dt). Norepinephrine release increased after TI, and reserpine pretreatment abolished TI preconditioning. This suggests that endogenous norepinephrine mediates functional preconditioning in rat. Brief pretreatment (2 minutes) with exogenous norepinephrine reproduced the protection (89.1 +/- 1.4%) of postischemic function. Functional protection persisted after the hemodynamic effects had resolved. Norepinephrine-induced preconditioning was simulated by phenylephrine and blocked by alpha 1-adrenergic receptor antagonist. TI preconditioning was similarly lost after selective alpha 1-adrenergic receptor blockade. We conclude that transient ischemic preconditioning is mediated by the sympathetic neurotransmitter release and alpha 1-adrenergic receptor stimulation. Although the postreceptor mechanism remains unclear, functional protection after IR does not seem related to the magnitude of ATP depletion and elevation of resting pressure during ischemia. Rather, the endogenous mechanisms facilitate both recovery of mechanical function and ATP repletion during reperfusion.

Berlin Heart EXCOR Pediatric Ventricular Assist Device for Bridge to Heart Transplantation in US Children

Background— Recent data suggest that the Berlin Heart EXCOR Pediatric ventricular assist device is superior to extracorporeal membrane oxygenation for bridge to heart transplantation. Published data are limited to 1 in 4 children who received the device as part of the US clinical trial. We analyzed outcomes for all US children who received the EXCOR to characterize device outcomes in an unselected cohort and to identify risk factors for mortality to facilitate patient selection. Methods and Results— This multicenter, prospective cohort study involved all children implanted with the Berlin Heart EXCOR Pediatric ventricular assist device at 47 centers from May 2007 through December 2010. Multiphase nonproportional hazards modeling was used to identify risk factors for early (<2 months) and late mortality. Of 204 children supported with the EXCOR, the median duration of support was 40 days (range, 1–435 days). Survival at 12 months was 75%, including 64% who reached transplantation, 6% who recovered, and 5% who were alive on the device. Multivariable analysis identified lower weight, biventricular assist device support, and elevated bilirubin as risk factors for early mortality and bilirubin extremes and renal dysfunction as risk factors for late mortality. Neurological dysfunction occurred in 29% and was the leading cause of death. Conclusions— Use of the Berlin Heart EXCOR has risen dramatically over the past decade. The EXCOR has emerged as a new treatment standard in the United States for pediatric bridge to transplantation. Three-quarters of children survived to transplantation or recovery; an important fraction experienced neurological dysfunction. Smaller patient size, renal dysfunction, hepatic dysfunction, and biventricular assist device use were associated with mortality, whereas extracorporeal membrane oxygenation before implantation and congenital heart disease were not.

Reoperative homograft right ventricular outflow tract reconstruction

BACKGROUND Homografts are implanted in the right ventricular outflow tract (RVOT) of children, with the knowledge that reoperation might be required. We reviewed 14 years of homograft RVOT reconstruction to assess the feasibility of homograft replacement and to determine risk factors for homograft survival. METHODS From February 1985 through March 1999, 223 children (age 5 days to 16.9 years) underwent primary RVOT reconstruction with an aortic or pulmonary homograft. Of these, 35 patients underwent homograft explant at the implanting hospital with insertion of a second homograft from 2 months to 13.3 years after the first implantation. The primary operation and reoperation patient groups were compared with regard to incidence of early death, late death, homograft-related intervention without explant, and homograft explant. RESULTS Actuarial survival and event-free curves for initial and replacement homografts were not significantly different. Univariable analysis was performed for the following risk factors: weight (p < 0.0001), age (p < 0.003), homograft diameter (p < 0.0001), homograft type (p < 0.01), surgery date (not significant [NS]), gender (NS), Blood Group match (NS), and type of distal anastomosis (NS). Multivariable analysis of significant univariable risks revealed small homograft diameter to be a significant risk factor (p < 0.001) for replacement. CONCLUSIONS The RVOT homografts eventually require replacement. Patient and homograft survival for replacement homografts is similar to primary homografts. Reoperative homograft RVOT reconstruction is possible, with reasonably low morbidity and mortality.

Ruptured mesenteric artery aneurysm in a patient with alpha1-antitrypsin deficiency: Etiologic implications

Clinical observations suggest that some aneurysms may be manifestations of intrinsic tissue abnormalities or systemic disease. Several investigators have reported reduced elastin content and increased elastase activity in infrarenal aortic aneurysms. Alpha 1-antitrypsin is the primary serum protease inhibitor modulating elastase activity. Elevated elastase activity caused by reduced alpha 1-antitrypsin inhibition, theoretically, could contribute to aneurysm formation. We report a case of ruptured middle colic artery aneurysm in a patient with multiple visceral artery aneurysms and profound alpha 1-antitrypsin deficiency. Reported middle colic artery aneurysms are reviewed, and etiologic implications are discussed.

Outcome of Extracorporeal Membrane Oxygenation for Early Primary Graft Failure After Pediatric Heart Transplantation

OBJECTIVES We sought to analyze the indications and outcome of extracorporeal membrane oxygenation (ECMO) for early primary graft failure and determine its impact on long-term graft function and rejection risk. BACKGROUND Early post-operative graft failure requiring ECMO can complicate heart transplantation. METHODS A retrospective review of all children requiring ECMO in the early period after transplantation from 1990 to 2007 was undertaken. RESULTS Twenty-eight (9%) of 310 children who underwent transplantation for cardiomyopathy (n = 5) or congenital heart disease (n = 23) required ECMO support. The total ischemic time was significantly longer for ECMO-rescued recipients compared with our overall transplantation population (276 +/- 86 min vs. 242 +/- 70 min, p < 0.01). The indication for transplantation, for ECMO support, and the timing of cannulation had no impact on survival. Hyperacute rejection was uncommon. Fifteen children were successfully weaned off ECMO and discharged alive (54%). Mean duration of ECMO was 2.8 days for survivors (median 3 days) compared with 4.8 days for nonsurvivors (median 5 days). There was 100% 3-year survival in the ECMO survivor group, with 13 patients (46%) currently alive at a mean follow-up of 8.1 +/- 3.8 years. The graft function was preserved (shortening fraction 36 +/- 7%), despite an increased number of early rejection episodes (1.7 +/- 1.6 vs. 0.7 +/- 1.3, overall transplant population, p < 0.05) and hemodynamically comprising rejection episodes (1.3 +/- 1.9 vs. 0.7 +/- 1.3, overall transplant population, p < 0.05). CONCLUSIONS Overall survival was 54%, with all patients surviving to at least 3 years after undergoing transplantation. None of the children requiring >4 days of ECMO support survived. Despite an increased number of early and hemodynamically compromising rejections, the long-term graft function is similar to our overall transplantation population.

Lung transplantation with cardiopulmonary bypass exaggerates pulmonary vasomotor dysfunction in the transplanted lung

Pulmonary vascular resistance is significantly increased in the transplanted lung. If cardiopulmonary bypass is required, the transplanted lung is reperfused with activated blood elements, which might exacerbate the reperfusion injury. The purpose of this study was to examine the influence of cardiopulmonary bypass on the following mechanisms of pulmonary vasomotor control in a dog model of autologous lung transplantation: (1) endothelium-dependent cyclic guanosine monophosphate-mediated relaxation (response to acetylcholine), (2) endothelium-independent cyclic guanosine monophosphate-mediated relaxation (response to nitroprusside), and (3) beta-adrenergic cyclic adenosine monophosphate-mediated relaxation (response to isoproterenol). Autologous right lung transplants were performed with (n = 4 dogs) and without (n = 5 dogs) bypass. Lungs were stored in cold saline solution (4 degrees C, 3 hours) before reimplantation. Pulmonary vasomotor control mechanisms were studied in isolated pulmonary arterial rings immediately after harvest and 1 hour after reimplantation. Ten rings were studied in each group at each time. Statistical analysis was by analysis of variance. Without bypass, endothelium-dependent cyclic guanosine monophosphate-mediated relaxation and beta-adrenergic cyclic adenosine monophosphate-mediated relaxation were significantly impaired, although endothelium-independent cyclic guanosine monophosphate-mediated relaxation was not. Use of bypass produced significantly greater impairment of both endothelium-dependent cyclic guanosine monophosphate-mediated relaxation and beta-adrenergic cyclic adenosine monophosphate-mediated relaxation. In addition, use of bypass produced significant dysfunction of endothelium-independent cyclic guanosine monophosphate-mediated relaxation as well. We conclude that using cardiopulmonary bypass to perform lung transplantation greatly exaggerates pulmonary vasomotor dysfunction in the transplanted lung. This dysfunction may contribute to significantly higher pulmonary vascular resistance in the transplanted lung if cardiopulmonary bypass is used.

Reoperation for Left Atrioventricular Valve Regurgitation After Atrioventricular Septal Defect Repair

BACKGROUND Left atrioventricular valve regurgitation (LAVVR) is a major cause of morbidity after atrioventricular septal defect (AVSD) repair. This study evaluates the outcomes of repair and replacement of the left atrioventricular valve after AVSD correction, as well as factors predictive of durability of valve repair. METHODS Between January 1983 and March 2007, 31 patients underwent reoperation for LAVVR after AVSD repair (23 valve repairs and 8 valve replacements). Median age at primary repair was 5.0 months and time to reoperation was 5.0 months. The distribution of AVSD morphology was 9 primum, 5 transitional, and 17 complete. RESULTS Early postoperative mortality was 6.4% (2 of 31). Survival at 10 years was 88.1%. At a mean follow-up of 8.2 years, 86% of hospital survivors were in New York Heart Association class I. Overall freedom from reintervention at 10 years was 67.2%. Among patients undergoing primary repair, 6 of 23 underwent subsequent replacement. Follow-up LAVVR in those who did not require subsequent valve replacement was mild or less in 92.8%. Factors that demonstrated a trend toward durable repair included the use of patch augmentation rather than primary cleft closure (p = 0.02) and earlier timing to repair (less than 2 months; p = 0.03). Significant cardiomyopathy developed in 21.4% of patients after prosthetic valve replacement (3 of 14). CONCLUSIONS Surgical management of LAVVR after AVSD repair can be performed with excellent midterm outcomes. However, both repair and replacement are associated with a high incidence of reoperation. Nonetheless, an aggressive reparative approach should be pursued to avoid the morbidity of pediatric left atrioventricular valve replacement that includes anticoagulation, inevitable reoperation, and cardiomyopathy.

Secondary pulmonary hypertension does not adversely affect outcome after single lung transplantation.

OBJECTIVE Primary and secondary pulmonary hypertension have been associated with poor outcomes after single lung transplantation. Some groups advocate double lung transplantation and the routine use of cardiopulmonary bypass during transplantation in this population. However, the optimal procedure for these patients remains controversial. The goal of our study was to determine the safety of single lung transplantation without cardiopulmonary bypass in patients with secondary pulmonary hypertension. METHODS We retrospectively reviewed 76 consecutive patients with pulmonary parenchymal disease who underwent single lung transplantation from 1992 to 1998. Recipients were stratified according to preoperative mean pulmonary artery pressure. Secondary pulmonary hypertension was defined as parenchymal lung disease with a preoperative mean pulmonary artery pressure of 30 mm Hg or more. Patients with primary pulmonary hypertension or Eisenmengers syndrome were excluded from analysis. RESULTS Eighteen of 76 patients had secondary pulmonary hypertension. No patient with secondary pulmonary hypertension required cardiopulmonary bypass, whereas 1 patient without pulmonary hypertension required bypass. After the operation, no significant differences were seen in lung injury as measured by chest radiograph score and PaO(2)/FIO(2) ratio, the requirement for inhaled nitric oxide, the length of mechanical ventilation, the intensive care unit or hospital length of stay, and 30-day survival. There were no differences in the forced expiratory volume in 1 second or 6-minute walk at 1 year, or the incidence of rejection, infection, or bronchiolitis obliterans syndrome greater than grade 2. Survival at 1, 2, and 4 years after transplantation was 86%, 79%, and 65%, respectively, in the low pulmonary artery pressure group and 81%, 81%, and 61%, respectively, in the group with secondary pulmonary hypertension (P >.2). CONCLUSION We found that patients with pulmonary parenchymal disease and concomitant secondary pulmonary hypertension had successful outcomes as measured by early and late allograft function and appear to have acceptable long-term survival after single lung transplantation. Our results do not support the routine use of cardiopulmonary bypass or double lung transplantation for patients with this disorder.

Constructive Priming Of Myocardium Against Ischemia-reperfusion Injury

ABSTRACT Ischemia and ischemic stress hormones induce endogenous cardiac protection against ischemia-reperfusion (I/R) injury. Although ischemia and ischemic stress hormones are accompanied by increased [Ca2+], it is unknown whether either opening of the sarcoplasmic reticular ryanodine Ca2+ channel (SR RyR) or inhibition of Ca2+ uptake by the sarcoendoplasmic reticular Ca2+-ATPase (SERCA) prior to I/R can similarly induce post-l/R functional protection. To study this, isolated, crystalloid perfused Sprague-Dawley rat hearts were used to assess the effects of inducing a pre-ischemic [Ca2+], load by either priming the SR RyR with ryanodine (Ry, 5 nM/2 min) or by transient blockade of the SERCA 10 min prior to global I/R (20 min). A pre-ischemic Ca2+ load by either SR RyR activation or SERCA blockade improved post-ischemic myocardial functional recovery (developed pressure, end diastolic pressure, coronary flow, heart rate, and left ventricular creatine kinase activity). We conclude that 1) Ca2+-induced myocardial functional protection involves the SR Ca2+ source, 2) a pre-ischemic Ca2+ load induced with either Ry or thapsigargin constructively primes against myocardial I/R injury, and 3) Ca2+-induced cardioadaptation to I/R injury may have important therapeutic implications prior to planned ischemic events such as cardiac allograft preservation and cardiac bypass surgery.