Gregory Perens

Diverse morphologic manifestations of cardiac allograft vasculopathy: A pathologic study of 64 allograft hearts

BACKGROUND Cardiac allograft vasculopathy (CAV) is a major limitation to the long-term success of cardiac transplantation. Although there are published descriptions of the lesions, there have been no studies delineating the pathology of CAV in a large series of patients who underwent retransplantation for CAV. METHODS We reviewed archival records and microscopic sections of surgically explanted hearts from 64 patients who underwent cardiac retransplantation: 54 adults (18 to 70 years old) and 10 children (3 to 15 years old). Vascular lesions were categorized as showing intimal fibromuscular hyperplasia, atherosclerosis and/or inflammation. The degree of luminal narrowing was estimated from gross descriptions and microscopic sections. RESULTS In total, 75% of hearts had evidence of acute cellular rejection, mostly mild. Intramyocardial arteries showed primarily intimal fibromuscular hyperplasia and inflammation with no atheromas present. Large and branch epicardial coronary arteries were narrowed in at least one artery of all hearts. Lesions in the epicardial coronary arteries were composed of intimal fibromuscular hyperplasia, atherosclerosis and/or inflammation affecting one or more vascular layers (intima, media and adventitia). Severe CAV with >75% luminal narrowing was seen in the LAD in 17% of hearts, the LCx in 17% and the RCA in 22% of hearts. Two hearts had severe narrowing of the left main coronary artery. Nineteen arteries had luminal thrombi. All hearts had narrowing of smaller epicardial branch coronary arteries that was often severe. Atheromas were present in arteries of adults and children; thus, not all atheromas could be considered pre-existing prior to transplantation. Both arteries and veins showed intimal hyperplasia and inflammation. CONCLUSIONS CAV is a pathologically multifaceted disorder that affects large and small epicardial coronary arteries of adults and children, with different types of lesions: intimal fibromuscular hyperplasia; atherosclerosis; and/or inflammation (vasculitis). Therapies to address this disease must take into account the protean nature of the vascular lesions.

Initial Experience with Sildenafil, Bosentan, and Nitric Oxide for Pediatric Cardiomyopathy Patients with Elevated Pulmonary Vascular Resistance before and after Orthotopic Heart Transplantation.

Background. Although pulmonary hypertension complicating dilated cardiomyopathy has been shown to be a significant risk factor for graft failure after heart transplantation, the upper limits of pulmonary vascular resistance (PVR) that would contraindicate pediatric heart transplantation are not known. Methods. A retrospective review of all pediatric orthotopic heart transplant (OHT) performed at our institution from 2002 to 2007 was performed. Seven patients with PVR > 6 Woods units (WU) prior to transplant were compared pre- and postoperatively with 20 matched controls with PVR < 6 WU. All pulmonary vasodilator therapies used are described as well as outcomes during the first year posttransplant. Results. The mean PVR prior to transplantation in the 7 study cases was 11.0 ± 4.6 (range 6–22) WU, compared to mean PVR of 3.07 ± 0.9 WU (0.56–4.5) in the controls (P = .27 × 10−6). All patients with elevated PVR were treated pre-OHT with either Sildenafil or Bosentan. Post-OHT, case patients received a combination of sildenafil, iloprost, and inhaled nitric oxide. All 7 case patients survived one year post-OHT, and there was no statistical difference between cases and controls for hospital stay, rejection/readmissions, or graft right ventricular failure. Mean PVR in the cases at one and three months post-OHT was not significantly different between the two groups. Only one of the cases required prolonged treatment with iloprost after OHT. Conclusions. A PVR above 6 WU should not be an absolute contraindication to heart transplantation in children.

Growth and weight gain of prepubertal children after cardiac transplantation.

Abstract:  This study evaluated changes in growth parameters after pediatric heart transplantation and identified factors associated with the changes after pediatric heart transplantation (OHT). We retrospectively evaluated the somatic growth of 46 children <11 yr of age who underwent OHT for changes in weight, height, and BMI. The patient age range was 3.5 months to 10.7 yr. Gain in Z score for weight and BMI was significant at six months post‐OHT (mean weight Z score changed from −1.1 to −0.1 and mean BMI Z score changed from −0.1 to 1.3; p < 0.001). After six months post‐OHT, there was no further significant change in weight or BMI Z score. Height Z score did not show significant change from pre‐OHT at six months, one yr, or two yr post‐OHT. Eight patients (17%) became overweight during the two‐yr follow‐up period as evidenced by a BMI Z score > 2. Multivariate analysis showed length of steroid treatment as a predictor for negative height Z score change, and age at transplant as a predictor for positive height Z score change. Post‐OHT, weight significantly increases without proportional increases in height, resulting in a significant proportion of these children becoming obese. Length of steroid therapy is negatively related to the “catch‐up” linear growth following OHT.

Canonical Wnt/β-catenin signaling in epicardial fibrosis of failed pediatric heart allografts with diastolic dysfunction.

BACKGROUND Failed pediatric heart allografts with diastolic dysfunction exhibit severe epicardial fibrosis. The molecular mechanism underlying this process is poorly understood. Canonical Wnt/β-catenin signaling plays an important role in epithelial-mesenchymal transition and is implicated in fibrosing diseases. In this study, we tested the hypothesis that canonical Wnt/β-catenin signaling is activated in epicardial fibrosis of end-stage dysfunctional pediatric allografts. METHODS Fourteen explanted heart grafts of 12 patients who had undergone 14 heart transplantations were used for immunohistochemical staining of β-catenin and its nuclear binding partners, T-cell factor/lymphoid enhancer factor family transcriptional factors. Fourteen age-matched native hearts from patients who had undergone first heart transplantation without evidence of epicardial fibrosis were used as controls. RESULTS AND CONCLUSIONS Epicardial fibroblasts from explanted allografts demonstrated nuclear accumulation of β-catenin. These cells also showed nuclear positivity for T-cell factor 4. No T-cell factor 3 expression was present in the epicardium. T-cell factor 1 and lymphoid enhancer factor 1 were observed in lymphocytes, but not in other cell types of the epicardium. These findings suggest an association between canonical Wnt/beta-catenin signaling and epicardial fibrosis of failed pediatric heart allografts. Should activation of this pathway be shown to be causal to epicardial fibrosis in this setting, then inhibition of this pathway may help to prevent this devastating process.

Clinico‐pathologic findings in end‐stage pediatric heart transplant grafts

Abstract:  The pathologic patterns existing in end‐stage pediatric heart transplant grafts may help explain the symptoms and changes seen by echocardiography and angiography in these children. Retrospective chart review and pathologic study of explanted heart grafts was performed on 12 patients that had undergone 14 heart re‐transplantations. Clinical status, echocardiographic and catheterization data at the time of transplantation were correlated to the pathologic findings. At re‐OHT, eight were inpatients with heart failure symptoms and/or inotropic support requirements. Echocardiograms were abnormal in all prior to re‐OHT with significant diastolic dysfunction, but LVEF >40% in all but one. There was significant epicardial fibrosis in all grafts, and all had severe CAV of epicardial arteries. However, intramyocardial coronary disease was mild in nine (64%) grafts. Moderate or severe interstitial fibrosis occurred in only three grafts, and in a perivascular distribution in eight. End‐stage pediatric heart allografts have severe epicardial CAV and epicardial fibrosis, with relative sparing of the myocardium. Epicardial disease with sparing of the myocardium may explain the restrictive hemodynamics and relatively preserved systolic function present in these grafts at the time of re‐OHT.

Bosentan for Increased Pulmonary Vascular Resistance in a Patient with Single Ventricle Physiology and a Bidirectional Glenn Shunt

We present a case of the successful use of bosentan for increased pulmonary vascular resistance (PVR) in a 10-year-old male who underwent late single ventricle surgical palliation for double-inlet left ventricle with pulmonary artery banding and a bidirectional Glenn shunt. The patient was treated with bosentan for 16 weeks, with decreases in mean pulmonary artery pressure from 23 to 16 mmHg on the right and from 31 to 21 mmHg on the left, and a decrease of the transpulmonary gradient by 7–8 mmHg. Cardiopulmonary exercise testing demonstrated an increase in peak oxygen consumption (VO2) by 8% and peak work rate by 10%. Bosentan is a relatively new oral therapy option for increased PVR in patients with single ventricle physiology and bidirectional Glenn shunts.

The corrected QT interval before and after heart transplantation.

Heart donor candidates have severe neurologic injuries that have been associated with significant prolongation of the corrected QT (QTc) interval. Screening for an underlying abnormality of cardiac repolarization such as the long-QT syndrome thus becomes difficult. The aims of this study were to establish normal values and determine factors associated with prolongation of pre- and post-transplantation QTc intervals in a large cohort of heart transplantation donors and recipients. The medical records of 179 donors and 112 recipients were reviewed for historical, electrocardiographic, and neuroimaging data. After linear regression analysis, gunshot wounds were associated with the shortest mean pre-transplantation QTc interval of 447 +/- 51 ms (p = 0.016), whereas all other mechanisms of brain injury were associated with markedly prolonged QTc intervals. Overall, the mean QTc interval decreased from 467 +/- 58 to 446 +/- 47 ms (p <0.001), the mean QRS duration increased from 87 +/- 16 to 98 +/- 21 ms (p <0.001), and the mean QT dispersion did not change significantly after transplantation. The only factor associated with a prolonged QTc interval in the post-transplantation period was hypokalemia, with a mean QTc of 468 +/- 37 ms (p = 0.047). In conclusion, the mechanism of donor brain injury is associated with alterations in the pre-transplantation QTc interval, with the shortest intervals related to gunshot wounds. Fewer than 5% of the donor population was found to have QTc interval > or =580 ms. For those afflicted by gunshot wounds, <5% had QTc intervals > or =550 ms. This information can be used in pre-transplantation donor assessment, and post-transplantation management can be tailored to avoid the occurrence of ventricular arrhythmia.

First report of a de novo 18q11.2 microdeletion including GATA6 associated with complex congenital heart disease and renal abnormalities

Deletions of the long arm of chromosome 18 have been previously reported in many patients. Most cases involve the more distal regions of the long arm (18q21.1‐>qter). However, proximal interstitial deletions involving 18q11.2 are extremely rare. Here we report on a 14‐month‐old female with a 4.7 Mb (19,667,062–24,401,876 hg19) de novo interstitial deletion within chromosomal band 18q11.2, which includes GATA6 and 24 other RefSeq genes. The clinical features of our patient include complex congenital heart defects, a double outlet right ventricle, a subaortic ventricular septal defect, D‐malposed great arteries, an atrial septal defect, a dysplastic aortic valve and patent ductus arteriosus. In addition, she had renal anomalies—a duplicated collecting system on the left and mild right hydronephrosis. These heart and renal defects are not reported in other patients with 18q proximal interstitial deletions. Heterozygous point mutations in GATA6, encoding for a zinc finger transcription factor, have been shown to cause congenital heart defects. Given the well‐established biological role of GATA6 in cardiac development, a deletion of GATA6 is very likely responsible for our patients complex congenital heart defects. This is the smallest and most proximal 18q11.2 deletion involving GATA6 that is associated with complex congenital heart disease and renal anomalies.

Successful Treatment of Eosinophilic Pleural Effusions Following Congenital Heart Surgery

We report two children, age 7 months and 5 years, who underwent surgery for congenital heart disease and developed persistent pleural effusions with elevated eosinophil counts. Given the elevation of eosinophil counts in both blood and pleural fluid of these patients, it was considered that an allergic response might have caused the persistent effusion. In both cases, the effusion resolved within 48 hours after treatment with corticosteroids was begun. It is possible that postoperative eosinophilic pleural effusion may represent a subgroup of effusions that are more likely to respond to treatment with corticosteroids.

A Novel Association of Biventricular Cardiac Noncompaction and Diabetic Embryopathy: Case Report and Review of the Literature

Diabetic embryopathy refers to a constellation of congenital malformations arising in the setting of poorly controlled maternal diabetes mellitus. Cardiac abnormalities are the most frequently observed findings, with a 5-fold risk over normal pregnancies. Although a diverse spectrum of cardiac defects has been documented, cardiac noncompaction morphology has not been associated with this syndrome. In this report, we describe a novel case of biventricular cardiac noncompaction in a neonate of a diabetic mother. The patient was a late preterm female with right anotia, caudal dysgenesis, multiple cardiac septal and aortic arch defects, and biventricular cardiac noncompaction. Examination of both ventricles demonstrated spongy myocardium with increased myocardial trabeculation greater than 50% left ventricular thickness and greater than 75% right ventricular thickness, with hypoplasia of the bilateral papillary muscles, consistent with noncompaction morphology. Review of the literature highlights the importance of gene expression and epigenomic regulation in cardiac embryogenesis.