Recurrent Protein‐losing Enteropathy and Tricuspid Valve Insufficiency in a Transplanted Heart: A Causal Relationship?

This case report describes a toddler who developed a protein‐losing enteropathy (PLE) 4 years after orthotopic heart transplantation (OHT). He was born with a hypoplastic left heart syndrome for which he underwent a successful Norwood procedure, a Hemi–Fontan palliation, and a Fontan palliation at 18 months of age. Fifteen months following the Fontan operation, he developed a PLE and Fontan failure requiring OHT. Four years after OHT, he developed a severe tricuspid regurgitation and a PLE. His PLE improved after tricuspid valve replacement. It is now 2 years since his tricuspid valve replacement and he remains clinically free of ascites and peripheral edema with a normal serum albumin level. His prosthetic tricuspid valve is functioning normally.     

Usefulness of heparin therapy in protein-losing enteropathy associated with single ventricle palliation

This retrospective study was designed to evaluate the effectiveness of subcutaneous heparin therapy for the treatment of protein-losing enteropathy (PLE) associated with single-ventricle palliation and to evaluate the side effects of long-term heparin use. PLE affects 4% to 13% of Fontan operative survivors. Five-year survival after onset of PLE is only 46% to 59%. We studied a cohort of patients with single-ventricle palliation who developed PLE and were treated with subcutaneous heparin. Seventeen patients were included in the study. Symptoms of PLE appeared on average 43 months after surgical palliation. At diagnosis of PLE, mean albumin level was 2.0 +/- 0.4 g/dl. At cardiac catheterization, mean systemic venous pressure was 11.6 mm Hg. Subjective symptomatic improvement on heparin therapy occurred in 13 patients (76%). Three patients (18%) went into clinical remission. Compared with the period before initiation of heparin, there was no significant difference in the number of hospital admissions (p = 0.99) or albumin infusions (p = 0.88) during the first year of heparin therapy. Five patients had x-rays of their thoracolumbar spine, and 9 patients had bone mineral analyses; all scans were grossly abnormal. In conclusion, subcutaneous heparin therapy leads to subjective improvement of PLE symptoms in most patients; however, it does not change the need for frequent albumin infusions and does not increase the rate of remission above that for standard medical therapy.     

Results of transcatheter Fontan fenestration to treat protein losing enteropathy.

Transcatheter fenestration to create an interatrial communication has been used to treat patients with protein losing enteropathy (PLE) after Fontan operation. No systematic data have been reported assessing the results of this procedure. Our institutional database was queried to identify patients after Fontan operation who had transcatheter fenestration to treat PLE. Clinical notes, laboratory data, echocardiograms, and cardiac catheterization data were reviewed. From 1995 to 2005, 16 transcatheter fenestration procedures were performed in seven patients. Median age at fenestration was 18 years (range 13-41 years). Median duration of follow-up was 3.6 years (range 0.2-10.4 years). Techniques for fenestration included blade/balloon septostomy, stent placement, Amplatzer-fenestrated ASD device, and balloon dilation of previous stent. Size of the fenestration created was 5.2 +/- 1.1 mm. Systemic venous pressure remained unchanged after fenestration. Cardiac index increased significantly. Reduction of ascites and edema was noted after 9 of the 16 procedures. Ten of 16 (63%) of fenestrations spontaneously occluded. Three patients are free of ascites although recurrence of PLE occurred in all. One patient with a patent fenestration continues to have ascites. Two patients had Fontan takedown. One patient had conversion to a fenestrated extracardiac conduit Fontan and died postoperatively. The results of transcatheter Fontan fenestration are often disappointing. Maintaining fenestration patency is difficult. Even after "successful" fenestration, resolution of PLE may be incomplete and recurrences have occurred in all. Early consideration should be given to Fontan takedown or cardiac transplant in severely symptomatic patients with PLE who do not respond to fenestration. Transcatheter fenestration may be a bridge to a definitive procedure.     

Growth of children with a functionally single ventricle following palliation at moderately increased altitude

The bidirectional Glenn and Fontan procedures are empirically performed as interim and definitive procedures in children with a functionally single ventricle. The optimal stage of palliation, nonetheless, remains unknown. During childhood, growth is a fundamental measure of response to therapy. Growth may be influenced by the degree of cyanosis, the volume load on the ventricle, and cardiac performance. Thus, the weight and stature of children with a functionally single ventricle who underwent a bidirectional Glenn procedure or a Fontan procedure were studied to determine the effect of each intervention on growth. Z scores for weight and stature were retrospectively determined prior to palliation, at yearly intervals for 4 years, and from long-term measurements until 18 years of age in all patients with at least 2 years of observation following palliation. Growth was evaluated in 54 patients with a bidirectional Glenn procedure, and 65 patients with a Fontan procedure. The Z scores for weight were improved after each method of surgical palliation. Stature, however, was improved only following the bidirectional Glenn procedure. Growth was impaired in patients who developed protein losing enteropathy. Weight improved only during the initial 2 years after the Fontan procedure in patients who had a surgical fenestration. Over the long-term, patients who underwent a Fontan procedure were more likely to have a Z score less than -2.0 for weight and stature than patients who underwent only a bidirectional Glenn procedure. Late mortality and the incidence of heart transplantation were increased in patients who experienced a decrease in their rate of growth, defined as a negative change of more than one Z score in weight or stature, following the Fontan procedure. In conclusion, at moderately increased altitude, children with a functionally single ventricle grow more appropriately following the bidirectional Glenn procedure than following the Fontan procedure. A decrease in the rate of growth is associated with a poor prognosis following the Fontan procedure.     

Decompression of the thoracic duct: A novel transcatheter approach

In patients with total cavopulmonary connections, elevated central venous pressures (CVP) have detrimental effects on the lymphatic system causing an imbalance in fluid production and drainage of the interstitium. This combination may result in life‐threatening lymphatic complications including plastic bronchitis (PB), protein losing enteropathy (PLE), chylothorax, and ascites. While embolization of the abnormal lymphatics has greatly improved outcomes from these complications, alternative treatment strategies have been proposed that would result in improved lymphatic drainage while leaving the lymphatic system intact. We report two novel transcatheter approaches for thoracic duct (TD) decompression in two patients who developed PLE after completion of the Fontan procedure as part of staged palliation for congenital heart disease. In addition, one patient had severe concurrent PB. In both patients, a connection was created between a left superior vena cava (LSVC) to the left atrium allowing for a nonsurgical method to decompress the TD. This procedure resulted in significant clinical and laboratory improvement of both patients' PLE and other symptoms of lymphatic dysfunction.     

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/m² vs. 2.7 ± 0.7 l/min/m²; 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.     

Reversal of protein losing enteropathy with prednisone in adults with modified Fontan operations: long term palliation or bridge to cardiac transplantation?

Protein losing enteropathy (PLE), defined as severe loss of serum protein into the intestine, occurs in 4-13% of patients after the Fontan procedure and carries a dismal prognosis with a five year survival between 46% and 59%. Chronically raised systemic venous pressure is thought to be responsible for the development of PLE in these patients, with perhaps superimposed immunological or inflammatory factors. The success rate of contemporary medical, transcatheter, and surgical treatments attempting to reduce systemic venous pressure ranges from 19% to 40%. Prednisone treatment for PLE has been tried, with variable success rates reported in children. The effect of prednisone in adult patients with PLE after the Fontan procedure is largely unknown. Two cases of PLE in adults (a 39 year old woman and a 25 year old man) after modified Fontan procedure who responded dramatically to oral prednisone treatment are reported, suggesting that a trial of this "non-invasive" treatment should be considered as long term palliation or bridge to cardiac transplantation.     

Somatic Growth after Fontan and Mustard Palliation

Objective. Patients with complex congenital heart disease frequently develop early growth failure; however, the long‐term outcome for growth after surgery for single ventricle or anatomic right ventricle as systemic ventricle is not clear. This study was designed to determine long‐term growth in patients following the Fontan and Mustard operations. Method. We retrospectively reviewed the growth parameters of children who had previously undergone the Fontan (n = 80) or Mustard (n = 66) palliation at the Riley Hospital for Children, Indiana. Results. Both the Fontan and Mustard groups had normal height and weight at birth. At the time of their Fontan or Mustard palliation, there was a significant retardation in weight (Z‐score: ?0.98 and ?1.79, respectively) and height (Z‐score: ?0.96 and ?1.03, respectively). Both cohorts postoperatively demonstrated significant catch‐up in their weights. Although the Mustard group normalized their heights, the Fontan patients continued to demonstrate short statures in long‐term follow‐up. Conclusion. Children with single ventricles and those with palliated d‐loop transposition of the great arteries suffer somatic growth delay prior to definitive surgery, despite being of normal size at birth. Catch‐up growth in weight occurs after the Fontan and Mustard operations. In the Mustard population, height also normalizes, whereas in patients with univentricular circulation, height remains abnormally low.     

Protein‐Losing Enteropathy after Fontan Operation

Protein‐losing enteropathy (PLE) is a poorly understood and enigmatic disease process affecting patients with single ventricle after Fontan operation. In those afflicted, PLE after Fontan operation results in significant morbidity and mortality. The pathophysiology of the disease is unknown; however, a proposed mechanism incorporates a combination of phenomena including: (1) altered hemodynamics, specifically low cardiac output; (2) increased mesenteric vascular resistance; (3) systemic inflammation; and (4) altered enterocyte basal membrane glycosaminoglycan make‐up. A paradigm for the clinical management of PLE after Fontan operation is proposed.     

Single ventricle palliation: greater risk of complications with the Fontan procedure than with the bidirectional Glenn procedure alone

BACKGROUND: This study was performed to evaluate and compare the early, intermediate, and long-term outcomes of the bidirectional Glenn procedure and Fontan procedure in patients who live at moderately high altitude. METHODS: The outcome of each method of palliation for patients with a functionally single ventricle was retrospectively evaluated from a review of medical records. RESULTS: The bidirectional Glenn procedure was performed in 177 patients from October 1984 to June 2004. The Fontan procedure was performed in 149 patients from June 1978 to June 2004. Cardiovascular death or heart transplantation occurred in 8% of patients after the bidirectional Glenn procedure and 17% of patients after the Fontan procedure. Complications of systemic thromboembolic events, bleeding associated with anticoagulation therapy, protein losing enteropathy, and arrhythmias requiring implantation of a pacemaker, cardioversion, or radiofrequency ablation occurred in 7% of patients after the bidirectional Glenn procedure and 47% of patients after the Fontan procedure. Cardiovascular deaths and heart transplantation occurred less frequently when the Fontan procedure was performed in patients with a previous bidirectional Glenn procedure. However, the actuarial transplant-free survival and freedom from complications was not superior for a subgroup of patients who had a Fontan procedure after a bidirectional Glenn procedure in comparison to a subgroup of patients who had a bidirectional Glenn procedure alone. CONCLUSIONS: The bidirectional Glenn procedure can be used for long-term palliation of patients with a functionally single ventricle. Additional palliation with a Fontan procedure may increase the risk of stroke, protein losing enteropathy and arrhythmias without improving survival.     

Outcome of single ventricle and total anomalous pulmonary venous connection

Management of patients with single-ventricle physiology is significantly affected by anomalies of pulmonary venous return at all stages, whether primary palliation, bidirectional Glenn shunt, or completion of Fontan circulation. We treated 25 patients with pulmonary venous anomalies and single ventricle by staged palliation, from June 1996 to May 2005. Visceral heterotaxy with atrial isomerism was present in 19 of them. Primary palliation with a systemic-to-pulmonary artery shunt was undertaken in 15 patients. There were 5 early deaths, of which 4 were due to obstruction of pulmonary venous return. A bidirectional Glenn shunt was constructed in 17 patients including 10 who had it as a primary palliative procedure. There were 7 early deaths after the bidirectional Glenn procedure; only one was due to pulmonary venous obstruction. Five patients attained completion of the Fontan procedure. There was one early death after the Fontan operation. Anomalous pulmonary venous return can significantly complicate the management of patients with single ventricle, with an impact on survival in early infancy. Palliation with the aim of instituting extracardiac conduit Fontan circulation allows greater latitude and more streamlined management.     

Liver Nodules after the Fontan Operation: Role of Magnetic Resonance Elastography

Hepatic dysfunction after the Fontan surgical palliation runs an indolent course. Moreover, there is no standard method of evaluating hepatic dysfunction. Magnetic resonance elastography has emerged as an advanced screening tool for preclinical detection of hepatic fibrosis and cirrhosis. We describe the case of a patient who had undergone Fontan palliation, and then developed liver nodules and elevated tumor markers 18 years later. Her case illustrates the challenges in diagnostic management of hepatic dysfunction and the potential role of magnetic resonance elastography in monitoring these patients.     

Percutaneous catheter aspiration thrombectomy for the occluded stents of pulmonary artery in children with single ventricle physiology after fontan surgery

Successful surgical palliation with the Fontan procedure allows survival into adulthood for many patients born with single ventricle (SV) physiology, but the limited studies reported incidence of perioperative and long‐term complications including thromboembolic events. Chronic pulmonary embolism is a common complication in patients with Fontan circulation, and may have serious consequences. Percutaneous intervention may be less invasive option for such a high‐risk population than surgery is. We described two patients who developed complete thrombosis of the left pulmonary artery following catheter placement of a stent in this vessel shortly after Fontan surgery. Percutaneous catheter aspiration thrombectomy was successfully performed. Percutaneous catheter aspiration thrombectomy may be considered as a viable option in acute thrombus in children with SV physiology after Fontan surgery. © 2014 Wiley Periodicals, Inc.     

Protein‐losing Enteropathy after the Fontan Operation: Associations and Predictors of Clinical Outcome

Objective. We sought to define what clinical parameters were related to the ultimate outcome in Fontan patients who had developed protein‐losing enteropathy (PLE). Background. PLE is a serious complication of the Fontan operation. Several preoperative and perioperative findings are associated with later PLE. However, there is limited information regarding postoperative abnormalities contributing to or influencing outcome in PLE. Methods. We evaluated 44 consecutive Fontan patients with PLE. A matched control group of Fontan patients without PLE was used for comparison (matched‐pair analyses). Kaplan–Meier and Cox proportional hazard methods were used for survival analyses. Results. Median age was 18 years (range 4–48 years). Short‐axis and apical fractional area change (ΔFA) were less in PLE patients than in controls (50 vs. 57% [P < .0001] and 49 vs. 54% [P = .01]). Five and 10‐year actuarial survival rates for the PLE group were 49 ± 9% and 30 ± 11%. Deceleration time <120 milliseconds (hazard ratio [HR] = 9.2, P = .04), New York Heart Association classification III or IV (HR = 4.0, P = .01), and lower serum albumin (HR = 0.30, P = .04) were independent predictors of mortality in those with PLE. Conclusion. Mild reduction in ΔFA was the only late echocardiographic finding associated with development of PLE. However, short deceleration time, poor New York Heart Association (NYHA) class, and low serum albumin identify a group of patients at the greatest risk for death. Presence of these findings in a PLE patient should lead to aggressive management strategies and may warrant early consideration of transplantation.     

Somatic growth in children with single ventricle physiology impact of physiologic state.

OBJECTIVES: We sought to define somatic growth patterns for patients with single ventricle (SV) physiology and associated factors. BACKGROUND: Infants with SV physiology might have somatic growth retardation associated with volume overload and hypoxemia, which might improve after surgical palliation. METHODS: We reviewed 126 patients (35% male) who underwent the Fontan procedure from 1994 to 2004. Demographic data, hemodynamic variables, and surgical procedures were recorded. Serial weights and heights were converted to z-scores. Linear regression analysis adjusted for repeated measures was used to model growth trends. RESULTS: Median z-score for weight was -0.7 at birth, -1.6 before bidirectional cavopulmonary shunt (BCPS), -0.7 before Fontan procedure, and -0.7 after Fontan procedure. A significant decline in z-scores for weight was seen before BCPS, which was reversed after the hemi-Fontan and stabilized after Fontan procedure. The z-scores for weight before the BCPS were lower in patients with lower birth weight (p < 0.01), nutritional difficulties (p = 0.01), and higher right atrial pressures (p = 0.02). After the BCPS, impaired growth was seen in patients who had systemic venous collaterals (p < 0.01). Patients who had collaterals embolized had the same growth trends as patients with no collaterals (p = 0.29). CONCLUSIONS: Infants with SV physiology show impaired somatic growth before BCPS. Although catch-up growth occurs after BCPS, effective interventions such as more intensive nutritional strategies before BCPS might be targeted at this high-risk population. The presence of systemic venous collaterals might impede growth secondary to hemodynamic impairment. Embolization of collaterals might allow for maximum growth potential.     

Efficacy of add-on aldosterone receptor blocker in uncontrolled hypertension

BACKGROUND: Uncontrolled hypertension (UH) may be caused by hyperaldosteronism, and some experts recommend the routine use of aldosterone antagonists in this condition. The purpose of this study was to evaluate the efficacy of this approach and to characterize those who respond effectively to an add-on aldosterone antagonist. METHODS: We retrospectively analyzed the effectiveness of spironolactone, an aldosterone antagonist, used as add-on therapy, compared with a standard add-on treatment, in patients referred to a hypertension clinic with UH despite the use of two or more antihypertensive drugs. RESULTS: A total of 340 patients (186 male) with an average age of 63 +/- 14 years were followed for at least 3 months. Of the patients, 42 received add-on spironolactone and 298 received an additional antihypertensive drug other than spironolactone. Baseline characteristics were similar in both groups. Blood pressure (BP) decreased significantly in both groups. In patients who received spironolactone, BP decreased by 23.2/12.5 mm Hg from 165 +/- 27/94 +/- 15 to 142 +/- 25/81 +/- 9 mm Hg, whereas in patients who received other add-on therapy BP decreased by 7.6/5.8 mm Hg from 160 +/- 24/91 +/- 12 to 152 +/- 20/85 +/- 11 mm Hg (P < .05). Patients who received spironolactone had lower serum potassium levels than those who did not receive spironolactone 3.8 +/- 0.4 v 4.5 +/- 0.5 mmol/L respectively (P < .001). Potassium levels <4 mmol/L were associated with a greater reduction in BP. CONCLUSIONS: Add-on spironolactone is a highly effective add-on treatment in UH, mainly in patients with low serum potassium levels. Further studies assessing serum potassium as a marker for treatment approach are needed to establish the role of aldosterone antagonists in the management of UH.     

Fontan术后蛋白丢失性肠病的机制和治疗研究综述

蛋白丢失性肠病（PLE）是Fontan术后的并发症之一,Fontan术后出现PLE提示预后不良。目前无特异有效的治疗方法。本综述通过分析PLE的病理生理、肠系膜病理解剖、治疗有效病例的特征,探讨PLE发生的机制,分析Fontan术后出现PLE的危险因素并提出治疗建议。     

Course of tricuspid atresia in the Fontan era

Tricuspid atresia is an uncommon form of congenital heart disease and long-term survival was rare before the Fontan era. It was thought that the long-term survival of patients with tricuspid atresia would be improved by the introduction of the Fontan procedure and its subsequent modifications. This study reviews the clinical course of 84 patients with tricuspid atresia identified in the first year of life in the Fontan era. Prior palliative operations, their results and their ultimate application for the Fontan procedure were considered. Eleven patients died before surgical intervention and 5 did not undergo catheterization or echocardiographic confirmation before death. Five children underwent the Fontan procedure without prior palliation and 1 child does not require palliation at the present time. Sixty-seven patients (80%) had surgical procedures before evaluation for the suitability of a Fontan operation. Thirty-four patients had a second surgical palliation and 9 patients had a third palliation. The surgical mortalities for the first, second and third palliative surgery were 17.9, 17.6 and 0%, respectively. Thirty-two patients (38%) underwent the Fontan procedure and 2 deaths occurred (6%). An estimate of the probability of surviving for 1 year was 64% (95% confidence limits 54 to 74%) and that of 8 years was 55% (95% confidence limits 44 to 66%).     

Modulation of aldosterone levels by −344 C/T CYP11B2 polymorphism and spironolactone use in resistant hypertension

Interindividual variability in plasma aldosterone levels comprises environmental and genetic sources. Increased aldosterone levels have been associated with higher risk of hypertension and target-organ damage related to hypertension. Aldosterone excess and intravascular volume expansion are implicated in pathophysiology of resistant hypertension (RH). We sought to investigate whether −344 C/T polymorphism (rs1799998) in aldosterone synthase gene (CYP11B2) is associated with plasma aldosterone levels in patients with resistant hypertension. Sixty-two patients with resistant hypertension were enrolled in this cross-sectional study. Genotypes were obtained by allelic discrimination assay using real time polymerase chain reaction. Multivariable linear regression was used to identify whether TT genotype was a predictor of aldosterone levels. No differences in clinical and laboratorial parameters were found among genotype groups. We found an additive effect of the T allele on plasma aldosterone concentration in RH. Also, there was higher aldosterone levels in TT homozygous under use of spironolactone compared with C carriers and compared with TT subjects who was not under use of spironolactone. TT genotype and the use of spironolactone were significant predictors of aldosterone levels in RH subjects. Plasma aldosterone concentration is significantly associated with −344 C/T CYP11B2 polymorphism and with the treatment with spironolactone in resistant hypertensive subjects.     

LONG TERM SPIRONOLACTONE AND THE ADRENAL CORTEX IN ESSENTIAL HYPERTENSION

In view of recent evidence that spironolactone may inhibit synthesis of corticosteroids by a direct effect on the adrenal cortex, adrenocortical function was studied in eight patients with essential hypertension who had been treated with spironolactone from 3 months to 14 years. Their 24 h renal excretion of adrenocorticoid metabolites and the responses of cortisol, aldosterone and 18-hydroxy-1 l-deoxycorticosterone (18-OH-DOC) to an incremental infusion of tetracosactrin (1–24 ACTH) were compared with those in eight patients with recently diagnosed essential hypertension who had received no spironolactone. The spironolactone-treated group had a significantly higher excretion of aldosterone, whilst the excretion of other adrenocorticoid metabolites did not differ. The same group also required less tetracosactrin to stimulate a detectable rise of plasma cortisol and 18-OH-DOC, they had greater plasma 18-OH-DOC responses at all infusion rates and, at the lowest infusion rates, had greater aldosterone responses. These results indicate that long-term spironolactone therapy does not inhibit adrenocortical function and may have some stimulatory effects.