Anitha S. John

Clinical Outcomes and Improved Survival in Patients With Protein-Losing Enteropathy After the Fontan Operation

BACKGROUND Patients with protein-losing enteropathy (PLE) following the Fontan operation have a reported 50% mortality at 5 years after diagnosis. OBJECTIVES The aim of this study was to review outcomes in patients with PLE following the Fontan operation. METHODS From 1992 to 2010, 42 patients (55% male) with PLE following the Fontan operation were identified from clinical databases at the Mayo Clinic. Data were collected retrospectively. RESULTS Mean age at PLE diagnosis was 18.9 ± 11.0 years. Initial Fontan operation was performed at 10.1 ± 10.8 years of age. Mean time from Fontan operation to PLE diagnosis was 8.4 ± 14.2 years. Survival was 88% at 5 years. Decreased survival was seen in patients with high Fontan pressure (mean >15 mm Hg; p = 0.04), decreased ventricular function (ejection fraction <55%; p = 0.03), and New York Heart Association functional class >2 at diagnosis (p = 0.04). Patients who died had higher pulmonary vascular resistance (3.8 ± 1.6 Wood units [WU] vs. 2.1 ± 1.1 WU; p = 0.017), lower cardiac index (1.6 ± 0.4 l/min/m(2) vs. 2.7 ± 0.7 l/min/m(2); p < 0.0001), and lower mixed venous saturation (53% vs. 66%; p = 0.01), compared with survivors. Factors were assessed at the time of PLE diagnosis. Treatments used more frequently in survivors with PLE included spironolactone (21 [68%]), octreotide (7 [21%]), sildenafil (6 [19%]), fenestration creation (15 [48%]), and relief of Fontan obstruction (7 [23%]). CONCLUSIONS PLE remains difficult to treat; however, in the current era, survival has improved with advances in treatment. Further study is needed to better understand the mechanism of disease and ideal treatment strategy.

Hepatic pathology may develop before the Fontan operation in children with functional single ventricle: An autopsy study

OBJECTIVE Liver fibrosis has emerged as an important long-term complication of the Fontan operation. We aimed to describe liver histology at autopsy in patients who had undergone the Fontan operation and to determine whether patient variables are associated with the degree of fibrosis. METHODS A review was performed of all patients with a history of the Fontan operation who died and underwent autopsy at our institution from 1980 to 2009. Autopsy liver slides were evaluated independently by 2 pathologists. RESULTS Twenty-two patients were studied. The median interval between Fontan and death was 20 days (range, 1 day-17.5 years). Portal fibrosis was observed in 20 (91%) patients and sinusoidal fibrosis was observed in 17 (77%) patients. Using simple linear regression, time from the Fontan operation was significantly associated with the degree of portal fibrosis on Ishak (P = .03) and modified Scheuer fibrosis (P = .02) scales. Significant portal fibrosis was observed in 8 (57%) of the 14 patients who died 30 days or less after the Fontan operation. In these 14 patients, severity of portal fibrosis was associated with length of hospitalization after pre-Fontan cardiac operations (P = .03) and pre-Fontan mean right atrial pressure (P = .04). CONCLUSIONS At autopsy, hepatic fibrosis was commonly observed in patients who had undergone the Fontan operation. Portal fibrosis has been previously unrecognized in this population. Significant portal fibrosis occurred in most who died soon after the Fontan procedure and was associated with pre-Fontan morbidity. Hepatic disease in the single-ventricle population is multifactorial and may begin before the Fontan operation.

Cardiopulmonary Bypass During Pregnancy

BACKGROUND Cardiac surgery during pregnancy carries significant maternal and fetal risk and is typically considered after failure of medical therapy. We sought to determine the maternal and neonatal outcomes of cardiopulmonary bypass during pregnancy. METHODS Twenty-one pregnant patients undergoing cardiothoracic surgery were identified from the Mayo Clinic surgical database (1976 to 2009). Maternal and neonatal outcomes were reviewed. RESULTS Operations included 8 aortic valve replacements, 6 mitral valve repair-replacements, 2 myxoma excisions, 1 patent foramen ovale closure, 1 myectomy, 2 aortic aneurysm repairs, and 1 prosthetic aortic valve thrombectomy. Median cardiopulmonary bypass time was 53 minutes (range 16 to 185). Twelve patients (57%) required emergent surgery with a median gestational age (GA) of 25 weeks (range 7 to 35.5). Seven patients underwent cesarean section immediately prior to sternotomy delivering viable infants (median GA 31 weeks). In the remaining patients, three additional preterm births occurred, all in operations performed at an early GA (13 to 15 weeks). Median follow-up was 16 months (range 3 to 305). All patients improved to New York Heart Association functional class I or II. One early maternal death occurred 2 days after emergent mechanical aortic valve thrombectomy and 3 late maternal deaths occurred 2, 10, and 19 years postoperatively. Three fetal deaths occurred in mothers with additional medical comorbidities. CONCLUSIONS In the current era, cardiothoracic surgery can be performed with relative safety during pregnancy. Fetal complications (prematurity and death) are associated with urgent, high-risk surgery, maternal comorbidity, and early GA. Emergent surgery appears to confer a higher risk of maternal death.

The Use of Oral Budesonide in Adolescents and Adults With Protein-Losing Enteropathy After the Fontan Operation

BACKGROUND Approximately 5% to 15% of patients develop protein-losing enteropathy (PLE) after the Fontan operation. Oral controlled release (CR) budesonide has been used as a treatment strategy, but its use in the older Fontan population has not been described. METHODS Seven patients with refractory PLE after the Fontan operation were started on oral CR-budesonide at 9 mg. After 3 to 9 months, the dose was weaned to 3 mg. Response to treatment was assessed by clinical evaluation, serum albumin levels, and fecal α-1 antitrypsin clearance when available. RESULTS Median age at last evaluation was 20 years (range, 16 to 32 years). Six patients had increases in serum albumin levels but only 4 patients had symptomatic improvement. Systemic side effects included: cushingoid features (5), adrenal insufficiency (4), and new-onset type 2 diabetes mellitus (2). One patient had improvement in cushingoid features after weaning CR-budesonide to 3 mg. Older patients (ages 27 to 32 years) had the worst side effect profiles and were the most refractory to treatment. These patients had sonographic evidence of hepatic cirrhosis but normal serum liver function tests. Two deaths occurred: 1 from sepsis 1 month after CR-budesonide initiation and 1 from respiratory arrest 5 months after CR-budesonide discontinuation. CONCLUSIONS CR-budesonide can be used to treat PLE in certain patients, but careful assessment of hepatic function should be performed before initiation of therapy as systemic side effects can limit treatment. Normal serum liver function tests do not preclude hepatic dysfunction in the Fontan patient, and it is important to perform radiographic assessments as well.

Clinical research priorities in adult congenital heart disease

BACKGROUND Adult congenital heart disease (ACHD) clinicians are hampered by the paucity of data to inform clinical decision-making. The objective of this study was to identify priorities for clinical research in ACHD. METHODS A list of 45 research questions was developed by the Alliance for Adult Research in Congenital Cardiology (AARCC), compiled into a survey, and administered to ACHD providers. Patient input was sought via the Adult Congenital Heart Association at community meetings and online forums. The 25 top questions were sent to ACHD providers worldwide via an online survey. Each question was ranked based on perceived priority and weighted based on time spent in ACHD care. The top 10 topics identified are presented and discussed. RESULTS The final online survey yielded 139 responses. Top priority questions related to tetralogy of Fallot (timing of pulmonary valve replacement and criteria for primary prevention ICDs), patients with systemic right ventricles (determining the optimal echocardiographic techniques for measuring right ventricular function, and indications for tricuspid valve replacement and primary prevention ICDs), and single ventricle/Fontan patients (role of pulmonary vasodilators, optimal anticoagulation, medical therapy for preservation of ventricular function, treatment for protein losing enteropathy). In addition, establishing criteria to refer ACHD patients for cardiac transplantation was deemed a priority. CONCLUSIONS The ACHD field is in need of prospective research to address fundamental clinical questions. It is hoped that this methodical consultation process will inform researchers and funding organizations about clinical research topics deemed to be of high priority.

Liver health in adults with Fontan circulation: A multicenter cross-sectional study

Objectives: Liver disease is an important contributor to morbidity and mortality in patients after Fontan surgery. There has been no large‐scale survey of liver health in this population. We sought to explore the prevalence and predictors of liver disease in a multicenter cohort of adults with Fontan physiology. Methods: Subjects were recruited from 6 adult congenital heart centers. Demographics; clinical history; and laboratory, imaging, and histopathology data were obtained. Results: Of 241 subjects (median age 25.8 years [11.8‐59.4], median time since Fontan 20.3 years [5.4‐34.5]), more than 94% of those who underwent testing (208 of 221) had at least 1 abnormal liver‐related finding. All hepatic imaging (n = 54) and liver histology (n = 68) was abnormal. Subjects with abnormal laboratory values had higher sinusoidal fibrosis stage (2 vs 1, P = .007) and higher portal fibrosis stage (3 vs 1, P = .003) compared with those with all normal values. Low albumin correlated with lower sinusoidal fibrosis stage (1 vs 2; P = .02) and portal fibrosis stage (0 vs 3, P = .002); no other liver studies correlated with fibrosis. Regenerative nodules were seen on 33% of histology specimens. Conclusions: Regardless of modality, findings of liver disease are common among adults with Fontan circulation, even those appearing clinically well. Cirrhosis is present in up to one‐third of subjects. Correlations between hepatic fibrosis stage and clinical history or findings on noninvasive testing are few. Further research is needed to identify patients at risk for more severe liver disease and to determine the best methods for assessing liver health in this population.

Thrombospondin-1 (TSP-1) up-regulates tissue inhibitor of metalloproteinase-1 (TIMP-1) production in human tumor cells: Exploring the functional significance in tumor cell invasion

Thrombospondin-1 (TSP-1), a matrix-bound adhesive glycoprotein, has been shown to modulate tumor progression. We previously demonstrated that TSP-1 up-regulates matrix metalloproteinases MMP-2 and MMP-9. Our studies suggested that the balance between MMPs and tissue inhibitors of metalloproteinases (TIMPs) is a key determinant in tumor cell invasion. We now report that TSP-1 up-regulates TIMP-1 expression in both human breast and prostate cancer cell lines. The effect of TSP-1 on TIMP-1 expression was examined in human breast adenocarcinoma cell lines (MDA-MB-231) and human prostate cancer cell lines (PC3-NI and PC3-ML) treated with exogenous TSP-1. TIMP-1 expression was also examined in TSP-1 stably transfected breast cancer cell line (MDA-MB-435). Northern and western blot analysis revealed TIMP-1 mRNA and TIMP-1 protein expression increased with increasing concentrations of TSP-1. This effect was inhibited by antibodies against the type I repeat domain of TSP-1 further suggesting that TSP-1 mediates TIMP-1 secretion. Inhibition of TSP-1 induced TIMP-1 levels increased tumor cell invasion. We conclude that TSP-1 is involved in influencing the critical balance between MMPs and their inhibitors, maintaining the controlled degradation of the extracellular matrix needed to support metastasis and our results may provide an explanation for the divergent activities reported for TSP-1 in tumor progression.

Clinical Experience With the Subcutaneous Implantable Cardioverter–Defibrillator in Adults With Congenital Heart Disease

Background—Sudden cardiac death is a major contributor to mortality for adults with congenital heart disease. The subcutaneous implantable cardioverter–defibrillator (ICD) has emerged as a novel tool for prevention of sudden cardiac death, but clinical performance data for adults with congenital heart disease are limited. Methods and Results—A retrospective study involving 7 centers over a 5-year period beginning in 2011 was performed. Twenty-one patients (median 33.9 years) were identified. The most common diagnosis was single ventricle physiology (52%), 9 palliated by Fontan operation and 2 by aortopulmonary shunts: d-transposition of the great arteries after Mustard/Senning (n=2), tetralogy of Fallot (n=2), aortic valve disease (n=2), and other biventricular surgery (n=4). A prior cardiac device had been implanted in 7 (33%). The ICD indication was primary prevention in 67% and secondary in 33% patients. The most common reason for subcutaneous ICD placement was limited transvenous access for ventricular lead placement (n=10) followed by intracardiac right-to-left shunt (n=5). Ventricular arrhythmia was induced in 17 (81%) and was converted with ⩽80 Joules in all. There was one implant complication related to infection, not requiring device removal. Over a median follow-up of 14 months, 4 patients (21%) received inappropriate and 1 (5%) patient received appropriate shocks. There was one arrhythmic death related to asystole in a single ventricle patient. Conclusions—Subcutaneous ICD implantation is feasible for adults with congenital heart disease patients. Most candidates have single ventricle heart disease and limited transvenous options for ICD placement. Despite variable anatomy, this study demonstrates successful conversion of induced ventricular arrhythmia and reasonable rhythm discrimination during follow-up.

Management of cardiac myxoma during pregnancy: A case series and review of the literature

Cardiac myxomas are the most common primary benign tumors of the heart. The reported incidence during pregnancy is extremely low with only 17 reported cases in the medical literature. Standard therapy involves surgical resection given the potential for embolization. In the pregnant patient, however, the risks of embolization must be balanced against the risk of cardiopulmonary bypass to the mother and the fetus. We present two cases of cardiac myxoma diagnosed during pregnancy and review the presentation and management strategies of previously reported cases. In conclusion, successful surgical resection of the myxomas during pregnancy was performed in both of our cases. Given the rarity of cases, individual multidisciplinary assessment and management strategies are essential.

Clinical outcomes of adult survivors of pulmonary atresia with intact ventricular septum.

BACKGROUND There are no studies on the long term clinical outcomes and complications in the adult patient with pulmonary atresia with intact ventricular septum (PA/IVS). This study reviews our experience with a limited group of adult survivors of PA/IVS seen in our adult congenital clinics. METHODS Twenty adult patients with PA/IVS (1998 to 2009) were identified from Mayo Clinic adult congenital heart disease databases. Surgical history and clinical outcomes were reviewed. RESULTS Mean age at last evaluation was 29 years (19-39 years). There were five deaths within the study period (1998-2009). Median age at death was 32 years (30-37 years). Seven patients underwent the Fontan operation, eight patients had a biventricular repair, and five patients remained with palliative shunts. All patients required re-interventions in adulthood. Tricuspid valve (TV) (n=5), pulmonary valve (PV)/conduit (n=6), and mitral valve (n=2) replacements were the most frequent re-intervention in the biventricular repair subset. Atrial arrhythmias were present in 80% of the total cohort, the highest rate among Fontan repairs (n=7) and biventricular repairs (n=7). Ventricular arrhythmias occurred in 15% of the cohort. CONCLUSIONS Although limited in number, the adult PA/IVS patients in this series continue to have high rates of morbidity and mortality, with arrhythmias and need for re-operations as the major causes. Patients with biventricular repairs had the highest re-intervention rate in adulthood. While this subset of patients might not be representative of all adult PA/IVS survivors, continued follow-up at centers with expertise in adult congenital cardiology is recommended for all patients.