Decoupling of the amygdala to other salience network regions in adolescent-onset recurrent major depressive disorder.

BACKGROUND: Recent meta-analyses of resting-state networks in major depressive disorder (MDD) implicate network disruptions underlying cognitive and affective features of illness. Heterogeneity of findings to date may stem from the relative lack of data parsing clinical features of MDD such as phase of illness and the burden of multiple episodes. METHOD: Resting-state functional magnetic resonance imaging data were collected from 17 active MDD and 34 remitted MDD patients, and 26 healthy controls (HCs) across two sites. Participants were medication-free and further subdivided into those with single v. multiple episodes to examine disease burden. Seed-based connectivity using the posterior cingulate cortex (PCC) seed to probe the default mode network as well as the amygdala and subgenual anterior cingulate cortex (sgACC) seeds to probe the salience network (SN) were conducted. RESULTS: Young adults with remitted MDD demonstrated hyperconnectivity of the left PCC to the left inferior frontal gyrus and of the left sgACC to the right ventromedial prefrontal cortex (PFC) and left hippocampus compared with HCs. Episode-independent effects were observed between the left PCC and the right dorsolateral PFC, as well as between the left amygdala and right insula and caudate, whereas the burden of multiple episodes was associated with hypoconnectivity of the left PCC to multiple cognitive control regions as well as hypoconnectivity of the amygdala to large portions of the SN. CONCLUSIONS: This is the first study of a homogeneous sample of unmedicated young adults with a history of adolescent-onset MDD illustrating brain-based episodic features of illness.

It still hurts: altered endogenous opioid activity in the brain during social rejection and acceptance in major depressive disorder.

The µ-opioid receptor (MOR) system, well known for dampening physical pain, is also hypothesized to dampen 'social pain.' We used positron emission tomography scanning with the selective MOR radioligand [(11)C]carfentanil to test the hypothesis that MOR system activation (reflecting endogenous opioid release) in response to social rejection and acceptance is altered in medication-free patients diagnosed with current major depressive disorder (MDD, n=17) compared with healthy controls (HCs, n=18). During rejection, MDD patients showed reduced endogenous opioid release in brain regions regulating stress, mood and motivation, and slower emotional recovery compared with HCs. During acceptance, only HCs showed increased social motivation, which was positively correlated with endogenous opioid release in the nucleus accumbens, a reward structure. Altered endogenous opioid activity in MDD may hinder emotional recovery from negative social interactions and decrease pleasure derived from positive interactions. Both effects may reinforce depression, trigger relapse and contribute to poor treatment outcomes.

Response of the µ-opioid system to social rejection and acceptance.

The endogenous opioid system, which alleviates physical pain, is also known to regulate social distress and reward in animal models. To test this hypothesis in humans (n=18), we used an µ-opioid receptor (MOR) radiotracer to measure changes in MOR availability in vivo with positron emission tomography during social rejection (not being liked by others) and acceptance (being liked by others). Social rejection significantly activated the MOR system (i.e., reduced receptor availability relative to baseline) in the ventral striatum, amygdala, midline thalamus and periaqueductal gray (PAG). This pattern of activation is consistent with the hypothesis that the endogenous opioids have a role in reducing the experience of social pain. Greater trait resiliency was positively correlated with MOR activation during rejection in the amygdala, PAG and subgenual anterior cingulate cortex (sgACC), suggesting that MOR activation in these areas is protective or adaptive. In addition, MOR activation in the pregenual ACC was correlated with reduced negative affect during rejection. In contrast, social acceptance resulted in MOR activation in the amygdala and anterior insula, and MOR deactivation in the midline thalamus and sgACC. In the left ventral striatum, MOR activation during acceptance predicted a greater desire for social interaction, suggesting a role for the MOR system in social reward. The ventral striatum, amygdala, midline thalamus, PAG, anterior insula and ACC are rich in MORs and comprise a pathway by which social cues may influence mood and motivation. MOR regulation of this pathway may preserve and promote emotional well being in the social environment.

Diagnosing HIV infection in patients presenting with glandular fever-like illness in primary care: are we missing primary HIV infection?

OBJECTIVES: The aim of the study was to examine the prevalence of HIV infection in patients presenting in primary care with glandular fever (GF)-like illness. METHODS: Samples from primary care submitted for a GF screen between April 2009 and June 2010 were identified. Samples without an HIV request were anonymized and retrospectively tested using a 4th-generation HIV antigen/antibody screening test. Reactive samples were further confirmed by an HIV antibody only test, with or without a p24 antigen assay. Antibody avidity testing based on the Recent HIV Infection Testing Algorithm (RITA) was used to identify individuals with evidence of recent acquisition (within 4-5 months). RESULTS: Of 1046 GF screening requests, concomitant HIV requests were made in 119 patients. Excluding one known positive patient, 2.5% (three of 118) tested HIV positive. Forty-five (4.3%) had a subsequent HIV test through another consultation within 1 year; of these, 4.4% (two of 45) tested positive. Of the remaining 882 patients, 694 (78.7%) had samples available for unlinked anonymous HIV testing, of which six (0.9%) tested positive. The overall HIV prevalence was 1.3% (11 of 857), with 72.7% (eight of 11) of cases missed at initial primary care presentation. Four of the nine (44.4%) available positive samples had evidence of recent acquisition, with three (75.0%) missed at initial primary care presentation. CONCLUSION: Low levels of HIV testing in patients presenting in primary care with GF-like illness are resulting in a significant number of missed HIV and seroconversion diagnoses. Local policy should consider adopting an opt-out strategy to include HIV testing routinely within the GF-screening investigation panel.

Immunologic risk stratification of pediatric heart transplant patients by combining HLA-EMMA and PIRCHE-II.

Human leukocyte antigen (HLA) molecular mismatch is a powerful biomarker of rejection. Few studies have explored its use in assessing rejection risk in heart transplant recipients. We tested the hypothesis that a combination of HLA Epitope Mismatch Algorithm (HLA-EMMA) and Predicted Indirectly Recognizable HLA Epitopes (PIRCHE-II) algorithms can improve risk stratification of pediatric heart transplant recipients. Class I and II HLA genotyping were performed by next-generation sequencing on 274 recipient/donor pairs enrolled in the Clinical Trials in Organ Transplantation in Children (CTOTC). Using high-resolution genotypes, we performed HLA molecular mismatch analysis with HLA-EMMA and PIRCHE-II, and correlated these findings with clinical outcomes. Patients without pre-formed donor specific antibody (DSA) (n=100) were used for correlations with post-transplant DSA and antibody mediated rejection (ABMR). Risk cut-offs were determined for DSA and ABMR using both algorithms. HLA-EMMA cut-offs alone predict the risk of DSA and ABMR; however, if used in combination with PIRCHE-II, the population could be further stratified into low-, intermediate-, and high-risk groups. The combination of HLA-EMMA and PIRCHE-II enables more granular immunological risk stratification. Intermediate-risk cases, like low-risk cases, are at a lower risk of DSA and ABMR. This new way of risk evaluation may facilitate individualized immunosuppression and surveillance.

Ex vivo cryoablation of Wolff-Parkinson-white in a donor heart prior to pediatric heart transplantation.

This report describes the use of a donor heart with ventricular pre-excitation for pediatric orthotopic heart transplantation and the successful surgical cryoablation of the donor heart prior to transplantation. The issues related to the preoperative evaluation and surgical management of the donor heart with Wolff-Parkinson White syndrome are discussed.

Practice variation in the diagnosis of acute rejection among pediatric heart transplant centers: An analysis of the pediatric heart transplant society (PHTS) registry.

BACKGROUND: Freedom from rejection in pediatric heart transplant recipients is highly variable across centers. This study aimed to assess the center variation in methods used to diagnose rejection in the first-year post-transplant and determine the impact of this variation on patient outcomes. METHODS: The PHTS registry was queried for all rejection episodes in the first-year post-transplant (2010-2019). The primary method for rejection diagnosis was determined for each event as surveillance biopsy, echo diagnosis, or clinical. The percentage of first-year rejection events diagnosed by surveillance biopsy was used to approximate the surveillance strategy across centers. Methods of rejection diagnosis were described and patient outcomes were assessed based on surveillance biopsy utilization among centers. RESULTS: A total of 3985 patients from 56 centers were included. Of this group, 873 (22%) developed rejection within the first-year post-transplant. Surveillance biopsy was the most common method of rejection diagnosis (71.7%), but practices were highly variable across centers. The majority (73.6%) of first rejection events occurred within 3-months of transplantation. Diagnosis modality in the first-year was not independently associated with freedom from rejection, freedom from rejection with hemodynamic compromise, or overall graft survival. CONCLUSIONS: Rejection in the first-year after pediatric heart transplant occurs in 22% of patients and most commonly in the first 3 months post-transplant. Significant variation exists across centers in the methods used to diagnose rejection in pediatric heart transplant recipients, however, these variable strategies are not independently associated with freedom from rejection, rejection with hemodynamic compromise, or overall graft survival.

Pediatric transplantation in the United States, 1997-2006.

This article represents the sixth annual review of the current state of pediatric transplantation in the United States from the Scientific Registry of Transplant Recipients (SRTR). It presents updated trends, discussion of analyses presented during the year by the SRTR to the committees of the Organ Procurement and Transplantation Network (OPTN) and discussion of important issues currently facing pediatric organ transplantation. Unless otherwise stated, the statistics in this article are drawn from the reference tables of the 2007 OPTN/SRTR Annual Report. In this article, pediatric patients are defined as candidates, recipients or donors aged 17 years or less. Data for both graft and patient survival are reported as unadjusted survival, unless otherwise stated (adjusted patient and graft survival are available in the reference tables). Short-term survival (3 month and 1 year) reflects outcomes for transplants performed in 2004 and 2005; 3-year survival reflects transplants from 2002 to 2005; and 5-year survival reports on transplants performed from 2000 to 2005. Details on the methods of analysis employed may be found in the reference tables themselves or in the technical notes of the 2007 OTPN/SRTR Annual Report, both available online at http://www.ustransplant.org.

Twenty-year experience with heart transplantation for infants and children with restrictive cardiomyopathy: 1986-2006.

Idiopathic restrictive cardiomyopathy (RCM) is a rare cardiomyopathy in children notable for severe diastolic dysfunction and progressive elevation of pulmonary vascular resistance (PVR). Traditionally, those with pulmonary vascular resistance indices (PVRI) >6 W.U. x m(2) have been precluded from heart transplantation (HTX). The clinical course of all patients transplanted for RCM between 1986 and 2006 were reviewed. Preoperative, intraoperative and postoperative variables were evaluated. A total of 23 patients underwent HTX for RCM, with a mean age of 8.8 +/- 5.6 years and a mean time from listing to HTX of 43 +/- 60 days. Preoperative and postoperative (114 +/- 40 days) PVRI were 5.9 +/- 4.4 and 2.9 +/- 1.5 W.U. x m(2), respectively. At time of most recent follow-up (mean = 5.7 +/- 4.6 years), the mean PVRI was 2.0 +/- 1.0 W.U. x m(2). Increasing preoperative mean pulmonary artery pressure (PA) pressure (p = 0.04) and PVRI > 6 W.U. x m(2) (chi(2)= 7.4, p < 0.01) were associated with the requirement of ECMO postoperatively. Neither PVRI nor mean PA pressure was associated with posttransplant mortality; 30-day and 1-year actuarial survivals were 96% and 86%, respectively. Five of the seven patients with preoperative PVRI > 6 W.U. x m(2) survived the first postoperative year. We report excellent survival for patients undergoing HTX for RCM despite the high proportion of high-risk patients.

Acute pulmonary embolism in pediatric patients awaiting heart transplantation.

Acute pulmonary embolism with infarction can delay urgently needed heart transplantation and increase the postoperative pulmonary complications. Few data are available concerning pulmonary embolization in the pediatric patient with end-stage congestive heart failure. Sixty-two consecutive pediatric patients awaiting heart transplantation were monitored for evidence of acute pulmonary embolism. Acute pulmonary infarction was documented by ventilation-perfusion scan, pulmonary angiography or pathologic examination in six patients. The prevalence differed by diagnosis; 5 of 36 patients with dilated cardiomyopathy and 1 of 20 patients with congenital heart disease developed acute pulmonary embolism with infarction. No significant difference in age at the time of transplantation evaluation, duration of congestive heart failure, presence of cardiac arrhythmias or degree of cardiac dysfunction was seen between patients with and without pulmonary embolism. Two-dimensional echocardiography failed to detect the presence of an intracardiac thrombus in four of the six patients. Two patients who developed acute pulmonary infarction are alive after successful heart transplantation. The remaining four patients died within 6 weeks of initiation of anticoagulant therapy before transplantation could safely be performed. In summary, pediatric patients with end-stage congestive heart failure are at risk for acute pulmonary embolism. No specific clinical factor identified those patients who developed acute pulmonary infarction. Anticoagulant therapy is strongly recommended in the pediatric patient with poor ventricular function awaiting heart transplantation.

Heart transplantation in children with congenital heart disease.

OBJECTIVES: The aim of this study was to describe heart transplantation in children with congenital heart disease and to compare the results with those in children undergoing transplantation for other cardiac diseases. BACKGROUND: Reports describe decreased survival after heart transplantation in children with congenital heart disease compared with those with cardiomyopathy. However, transplantation is increasingly being considered in the surgical management of children with complex congenital heart disease. Present-day results from this group require reassessment. METHODS: The diagnoses, previous operations and indications for transplantation were characterized in children with congenital heart disease. Pretransplant course, graft ischemia time, post-transplant survival and outcome (rejection frequency, infection rate, length of hospital stay) were compared with those in children undergoing transplantation for other reasons (n = 47). RESULTS: Thirty-seven children (mean [+/- SD] age 9 +/- 6 years) with congenital heart disease underwent transplantation; 86% had undergone one or more previous operations. Repair of extracardiac defects at transplantation was necessary in 23 patients. Causes of death after transplantation were donor failure in two patients, surgical bleeding in two, pulmonary hemorrhage in one, infection in four, rejection in three and graft atherosclerosis in one. No difference in 1- and 5-year survival rates (70% vs. 77% and 64% vs. 65%, respectively), rejection frequency or length of hospital stay was seen between children with and without congenital heart disease. Cardiopulmonary bypass and donor ischemia time were significantly longer in patients with congenital heart disease. Serious infections were more common in children with than without congenital heart disease (13 of 37 vs. 6 of 47, respectively, p = 0.01). CONCLUSIONS: Despite the more complex cardiac surgery required at implantation and longer donor ischemic time, heart transplantation can be performed in children with complex congenital heart disease with success similar to that in patients with other cardiac diseases.

Corticotropin-releasing hormone messenger RNA distribution and stress-induced activation in the thalamus.

Corticotropin-releasing hormone plays a critical role in mediating the stress response. Brain circuits hypothesized to mediate stress include the thalamus, which plays a pivotal role in distributing sensory information to cortical and subcortical structures. In situ hybridization revealed neurons containing corticotropin-releasing hormone messenger RNA in the posterior thalamic nuclear group and the central medial nucleus of the thalamus, which interfaces with the ventral posteromedial nucleus (parvicellular part). These regions are of interest because they process somatosensory and visceral information. In the first experiment, the effect of acute stress on thalamic corticotropin-releasing hormone messenger RNA levels was assessed. Rats restrained for 1 h and killed 1 h later were found to have increased corticotropin-releasing hormone messenger RNA in the posterior thalamic nuclear group. The time course of these changes was examined in a second experiment in which rats were killed immediately or 3 h after restraint. While no changes occurred in the thalamus immediately after restraint, 3 h after restraint, increases in corticotropin-releasing hormone messenger RNA occurred in both the posterior thalamic nuclear group and the central medial-ventral posteromedial nucleus (parvicellular part) of the thalamus. A different pattern of activation was observed in the paraventricular nucleus of the hypothalamus with increased corticotropin-releasing hormone messenger RNA immediately after restraint, but not 1 or 3 h later. In addition to the stress-induced changes, a prominent decrease in baseline thalamic corticotropin-releasing hormone messenger RNA was observed from 1000 to 1300 h. These results show that the thalamus contains corticotropin-releasing hormone messenger RNA that increases after restraint stress, indicating a role for thalamic corticotropin-releasing hormone systems in the stress response. Stress-induced changes in thalamic corticotropin-releasing hormone messenger RNA expression appears to be regulated differently than that in the paraventricular nucleus of the hypothalamus, and may be influenced by diurnal mechanisms.

Serial echocardiographic measurements of the pulmonary autograft in the aortic valve position after the Ross operation in a pediatric population using normal pulmonary artery dimensions as the reference standard.

Serial echocardiographic measurements of the annulus and sinus were obtained in children before the Ross operation, and early and late postoperatively. Values were compared with normal standards for the aorta and pulmonary artery (PA). There was no significant difference between PA annulus measurements before surgery and the corresponding autograft immediately afterward (1.73 +/- 0.60 cm preoperatively; 1. 63 +/- 0.58 cm postoperatively, p = NS). Late after surgery the mean annulus diameter was enlarged compared with the normal aorta (DeltaZ 1.9 +/- 2.4), but remained relatively unchanged compared with the normal PA (DeltaZ 0.7 +/- 1.1, p <0.01). In contrast, the autograft sinus was dilated early after surgery (1.83 +/- 0.58 cm preoperatively; 2.18 +/- 0.73 cm postoperatively, p <0.01). Mean sinus Z score further increased compared with both the aorta (DeltaZ 1.3 +/- 1.7) and PA (DeltaZ 1.3 +/- 1.6). Use of standard PA measurements may be important in the assessment of autograft enlargement. Minimal change in autograft Z scores over time suggests that annulus enlargement is mainly due to somatic growth. In contrast, the autograft sinus showed an immediate and continued disproportionate increase in size over time, suggesting that sinus enlargement is largely due to passive dilation.

Quantitative effects of myocardial edema on the left ventricular pressure-volume relation. Influence of cardioplegia osmolarity over two hours of ischemic arrest.

We previously studied edema and left ventricular pressure-volume relations in a porcine heart model in which edema occurred even with hyperosmolar crystalloid cardioplegia. This susceptibility to edema was attributed to venous occlusion and an initial 20-minute period of ischemia. Results did not demonstrate reversal of edema by hyperosmolar perfusates. Accordingly, in the present study, heart weight, myocardial water content, and left ventricular pressure-volume curves were measured before and after perfusion-induced edema in eight isolated, arrested, hypothermic porcine hearts. Cardioplegic solution was infused 2.1 +/- 0.8 minutes after the onset of ischemia, and the atrioventricular ring was not clamped during the administration of cardioplegic solution. Cardioplegic solution (1 L) was infused at intervals of 33 +/- 6 minutes at 4 degrees C. Solution osmolarity was 380 (Stanford solution) or 294 mOsm/L (Plegisol solution). The perfusion sequence was 380-1, 380-2, 294-1, 380-3. Pressure-volume relations were assessed with the use of left ventricular volume at a pressure of 10 mm Hg and the ventricular chamber stiffness constant, beta, derived from P = alpha e beta V. Perfusions 380-1 and 380-2 did not affect the pressure-volume curve. Perfusion 294-1 increased heart weight and water content (p < 0.05) and decreased left ventricular volume at 10 mm Hg compared with perfusions 380-1, 380-2, and 380-3. In addition, beta increased (0.023 +/- 0.005 versus 0.029 +/- 0.006, p < 0.05) after perfusion 294-1, compared with 380-1. Correlation coefficients for linear regressions between left ventricular volume at 10 mm Hg and heart weight and water content were r = 0.84 and r = 0.70, respectively. We conclude that under conditions similar to those used clinically, the left ventricle of the pig does not develop edema with Stanford solution (380 mOsm/L). Edema does follow Plegisol solution (294 mOsm/L) cardioplegia. Edema and reduced compliance are incompletely reversed by hypertonic cardioplegia. The porcine left ventricle can usefully replicate the clinical model.

Pediatric heart transplantation after operations involving the pulmonary arteries.

A prohibitive perioperative mortality has been previously ascribed to pediatric heart transplantation after palliative operations for congenital heart disease involving the pulmonary arteries. Of 46 children who have undergone heart transplantation at our institution between June 1984 and February 1990, 7 (15%; mean age 8 +/- 3 years; range 1 to 18 years) have previously undergone such operations: right ventricle to pulmonary artery conduit/homograft for levo-transposition of the great arteries (2), Waterston shunt for tricuspid and pulmonary atresia (1), pulmonary artery banding for single ventricle (1), Fontan procedure for single ventricle (1), first-stage Norwood procedure for hypoplastic left heart syndrome (1), and classic right Blalock-Taussig shunt for atrioventricular canal with pulmonic stenosis (1). Three categories of pulmonary artery anatomy that require different approaches to reconstruction at the time of transplantation are recognized: abnormalities of position, pulmonary outflow obstruction, and previous systemic- or atrial-pulmonary connections. At operation, individualized pulmonary arterial reconstruction was employed, including use of previously created right ventricular-pulmonary artery conduits/homografts and angioplasty (with and without pericardial patches). Transplantation was successful in all patients. Posttransplant right ventricular-pulmonary artery pressure gradients and pulmonary vascular resistance indices were acceptable, with a tendency to decrease with time. Two patients had critical right ventricular failure postoperatively; one of them required support with extracorporeal membrane oxygenation. There was no perioperative mortality, with three deaths occurring from 5 to 39 months after transplantation. All surviving patients are in New York Heart Association functional class I. Techniques borrowed from the repair of congenital cardiac lesions can be applied to subgroups of children undergoing heart transplantation. Additional length of donor aorta and pulmonary artery should be harvested for possible use in designing pulmonary artery connections. Previous palliative operations involving the pulmonary arteries with associated complex pulmonary artery anatomy are not of themselves an insurmountable obstacle to successful heart transplantation.

Diastolic function in the heterotopic rat heart transplant model. Effects of edema, ischemia, and rejection.

Decreased systolic ventricular function and compliance and increased left ventricular edema and mass have been demonstrated in cardiac allograft rejection. Whether decreased left ventricular compliance in rejection is caused by myocardial edema has not been examined, and compliance in the Ono-Lindsey model has not been reported. Heterotopic rat abdominal cardiac transplantation was performed in ACI isografts (n = 24) and in ACI to Lewis allografts (n = 24). Subgroups were studied on posttransplantation days 0, 1, 3, and 5 (each n = 6). Both transplanted hearts and native hearts were arrested with potassium for the assessment of myocardial water content, heart weight, and the left ventricular pressure-volume relation. In transplanted hearts, myocardial water content did not change in isografts but increased on posttransplantation day 5 in allografts (81.1% on posttransplantation day 5 versus 76.1% on day 0, 77.2% on day 1, and 77.5% on day 3, p < 0.05). Wet and dry heart weight also increased on posttransplantation day 5 in allografts (p < 0.05). The left ventricular pressure-volume relation in transplanted hearts shifted to the left when compared with that in native hearts in all subgroups; these volume differences were statistically significant (p < 0.01) for all pressures above 7.5 mm Hg. This pattern was similar in isografts and allografts on posttransplantation days 0, 1, and 3, and no significant differences between isografts and allografts were demonstrated. On posttransplantation day 5, however, the pressure after a 0.05 ml injection in allografts was greater in transplanted hearts than in native hearts (24 +/- 3 versus 3 +/- 1 mm Hg, p < 0.01). The pressure difference between transplanted and native hearts was also significantly greater in allografts than in isografts (22 +/- 2 versus 6 +/- 1 mm Hg, p < 0.01), indicating an increase in stiffness of allografts. Thus edema and impaired diastolic properties occur concurrently with allograft rejection. Left ventricular volume is abnormal from posttransplantation days 0 to 5 in transplanted hearts but not native hearts in the Ono-Lindsey model with current methods, apparently because of ischemic injury during transplantation.

Effects of crystalloid, blood, and University of Wisconsin perfusates on weight, water content, and left ventricular compliance in an edema-prone, isolated porcine heart model.

Coronary perfusion with blood and cardioplegic solutions was examined in isolated, arrested, hypothermic porcine hearts. Myocardial water content, heart weight, and left ventricular diastolic pressure-volume curves were measured before and after coronary perfusion. Statistics were based on exponential curve fitting to pressure-volume data and analysis of variance. Thirty-two pig hearts were divided into five experimental groups and a control group; after control measurements, each experimental group underwent three successive coronary perfusions with 1 L of unmodified blood or a solution of controlled osmolarity, 150 mOsm/L (diluted Plegisol solution), 280 mOsm/L (Plegisol solution and albumin), 334 mOsm/L (University of Wisconsin solution), or 380 mOsm/L (Stanford solution). After each perfusion, measurements were repeated. All experiments were completed within 90 minutes. The first perfusion was delayed 20 minutes after excision of the heart to allow for instrumentation. Each experimental group demonstrated a statistically significant increase in heart weight and myocardial water content and a significant decrease in left ventricular compliance after perfusion. Changes were less pronounced with blood than crystalloids. Edema effects were minimized but not prevented by hyperosmolarity. University of Wisconsin solution appeared unique in minimizing progressive edema after the first perfusion. Over the 81 perfusions studied, changes in left ventricular compliance were linearly related to heart weight and water content. We conclude that in this model, in which edema sensitivity is increased by delayed perfusion and venous occlusion, edema is minimized but not eliminated by whole blood and University of Wisconsin solution. The model appears useful in assessing properties of cardioplegia vehicles intended for use in the injured myocardium.

Improvement of rejection-induced diastolic abnormalities in rat cardiac allografts with inducible nitric oxide synthase inhibition.

OBJECTIVE: Inhibition of inducible nitric oxide synthase (nitric oxide II) activity has been proposed as a method to attenuate capillary leak and edema during rejection of heterotopically transplanted rat hearts. Myocardial edema has previously been implicated in diastolic dysfunction during allograft rejection. Accordingly, we tested the hypothesis that inducible nitric oxide synthase inhibition with aminoguanidine would alleviate left ventricular stiffening and myocardial edema formation in 4-day heterotopic rat heart allografts. METHODS: Passive left ventricular filling was studied in American Cancer Institute Lewis rats receiving heterotopic heart transplants receiving either aminoguanidine, a selective nitric oxide synthase inhibitor (n = 6); dexamethasone (1 mg. kg(-1). d(-1) administered subcutaneously) for 4 days after transplantation (n = 6); or intravenous saline solution (n = 6). American Cancer Institute-to-American Cancer Institute isografts (n = 6) were used as controls. RESULTS: Serum nitrite/nitrate levels in the aminoguanidine group (18 +/- 3 mmol/L) and dexamethasone group (22 +/- 4 mmol/L) were reduced versus the intravenous saline group (144 +/- 36 mmol/L [SEM]) to levels seen in controls (25 +/- 9 mmol/L). Left ventricular volume at 15 mm Hg for the aminoguanidine group was increased versus that for the intravenous saline solution group, similar to that for controls, and reduced versus dexamethasone-treated animals. Myocardial water content for the aminoguanidine-treated animals (78.3% +/- 0.4%) was similar to those of intravenous saline-treated animals (78.0% +/- 0. 3%) but greater than those of controls (77.1% +/- 0.2%) and dexamethasone-treated animals (76.7% +/- 0.3%). CONCLUSIONS: Nitric oxide II inhibition with aminoguanidine minimizes the reduction in left ventricular filling that is seen with allograft rejection through a mechanism that is not associated with attenuation of myocardial edema.

Arrhythmias in pediatric heart transplant recipients: prevalence and association with death, coronary artery disease, and rejection.

To ascertain the prevalence and types of arrhythmias occurring after heart transplantation in children, all available 24-hour ambulatory ECGs (mean, 1.5/patient), and 12-lead surface ECGs (mean, 27/patient) obtained from 59 orthotopic pediatric heart transplant recipients (mean age, 9.7 +/- 5.9 years) were examined. Correlation of the appearance of arrhythmias with the occurrence of rejection, coronary artery disease, or death was investigated. Of the 59 patients, 24 (41%) were found to have arrhythmias including chronic sinus tachycardia (eight patients), sinus bradycardia (four patients), supraventricular tachyarrhythmias (nine patients), significant ventricular premature depolarization (seven patients), and nonsustained ventricular tachyarrhythmias (seven patients). The occurrence of arrhythmias was not significantly associated with the number of rejections per patient month of survival. However, a significant proportion of patients with supraventricular (seven of nine patients; p = 0.006) and ventricular (six of seven patients; p = 0.02) tachyarrhythmias experienced a rejection episode in association with the onset of the rhythm abnormality. The presence of coronary artery disease was significantly associated with the presence of ventricular tachyarrhythmias (p = 0.03). Graft survival was significantly lower in those patients with arrhythmias as compared with the arrhythmia-free group (58% versus 86%, p = 0.02). The results suggest that the appearance of arrhythmias in a pediatric heart transplant recipient should prompt a search for the presence of rejection and/or coronary artery disease.