Robert W. Elder

Features of portal hypertension are associated with major adverse events in Fontan patients: The VAST study

BACKGROUND Chronic congestive hepatopathy is known to cause hepatic fibrosis and portal hypertension in patients post-Fontan operation for single ventricle palliation. The clinical significance of these findings is not clear. We hypothesized that features of portal hypertension would be significantly related to major adverse events. METHODS A retrospective review of 73 adult and pediatric post-Fontan patients referred for a liver evaluation from 2001 to 2011 was performed. The relationship between features of portal hypertension (VAST score ≥2, 1 point each for Varices, Ascites, Splenomegaly or Thrombocytopenia) and a major adverse event (death, need for transplant, or hepatocellular carcinoma) was examined using logistic regression. RESULTS 73 post-Fontan patients (30% female, 73% Caucasian, 66% systemic left ventricle (SLV), mean age 24±11 years, mean interval from Fontan 17±6 years) were included in analysis. Features of portal hypertension (VAST score ≥2) were present in 26 (36%), and there were 19 major adverse events: death (n=12), transplant (n=6), and HCC (n=1). A significant relationship was found between VAST score ≥2 and major adverse events (OR=9.8, 95% CI [2.9-32.7]). After adjusting for time since Fontan, SLV, age, hemoglobin and type of failure, VAST score ≥2 remained significant (OR=9.1, 95% CI [1.4-57.6]). CONCLUSION Fontan patients with features of portal hypertension have a 9-fold increased risk for a major adverse event. Therapies targeted to manage clinical manifestations of portal hypertension, and early referral to heart transplant may help delay major adverse events. Future prospective studies are needed to confirm these findings.

Risk Factors for Major Adverse Events Late after Fontan Palliation

OBJECTIVE Risk factors for major adverse events late after Fontan palliation are unknown. Prior studies have suggested ventricular function and morphology as important risk factors. The aim of this study is to (1) characterize the late major adverse event profile in adult Fontan patients and (2) identify additional risk factors that may contribute to adverse outcomes. DESIGN AND SETTING A retrospective review of all adult patients >15 years post-Fontan seen at a tertiary academic center was conducted. Clinical, laboratory, cardiac data, and abdominal imaging were collected via chart review. Major adverse events (death, cardiac transplantation, or listing) were identified, and timing of events was plotted using Kaplan-Meier methods. Univariate and multivariate logistic regression was used to determine independent predictors of late-term events. RESULTS A total of 123 adult Fontan patients were identified (mean time post-Fontan 22.4 years [±4.4]). Major adverse events occurred in 19/123 patients (15%). In this 15-year survivor cohort, transplant-free survival rates were 94.6%, 82.9%, and 59.8% at 20, 25, and 30 years postoperation, respectively. Modes of death were Fontan failure with preserved function (4), congestive heart failure with decreased function (2), sudden death (2), thromboembolic event (1), post-Fontan conversion (2), and posttransplant (2). No differences in adverse outcomes were found based on morphology of the systemic ventricle, Fontan type, or systolic ventricular function. On the other hand, features of portal hypertension (OR 19.0, CI 4.7-77.3, P < .0001), presence of a pacemaker (OR 13.4, CI 2.6-69.8, P = .002), and systemic oxygen desaturation (OR 0.86, CI 0.75-0.98, P = .02) were risk factors for major adverse events in the multivariate analysis. CONCLUSIONS In adult Fontan patients surviving >15 years post-Fontan, portal hypertension, oxygen desaturation, and need for pacemaker were predictive of adverse events. Traditional measures may not predict late-term outcomes in adult survivors; further study of the livers role in late outcomes is warranted.

Beyond a Broken Heart: Circulatory Dysfunction in the Failing Fontan

Abstract The role of ventricular dysfunction in late morbidity and mortality of univentricular hearts has been described previously. However, a significant proportion of adult Fontan patients who die or require heart transplantation do so with preserved ventricular function. The clinical deterioration in patients who have undergone Fontan palliation requires a broader view of circulatory dysfunction, one that takes into account the complex interaction of regulatory systems affecting hepatic, renal, and pulmonary blood flow, in addition to cardiac function. This review focuses primarily on the pathophysiology of multiple organ involvement in this circulatory dysfunction, with particular focus on the consequences of hepatic dysfunction and portal hypertension. The authors discuss hepatic perfusion, both in health and disease, and review the current understanding of liver histopathology and liver disease in adult Fontan patients and similar clinicopathologic states. They compare and contrast features of postsinusoidal portal hypertension with more typical adult cirrhotic disease. Finally, they delineate the related effects of portal hypertensive physiology on the systemic and pulmonary vasculature, the kidney, and the heart itself and discuss how these changes affect the care of the adult Fontan patient.

Catheter-measured Hemodynamics of Adult Fontan Circulation: Associations with Adverse Event and End-organ Dysfunctions.

BACKGROUND In heart failure, a high systemic vascular resistance index (SVRI), high central venous pressure (CVP), and low cardiac index (CI) predict poor outcomes. Conversely, late hemodynamic manifestations of failing Fontan circulation and associations with end-organ dysfunction are not well understood. METHODS A retrospective review of right-heart catheterization data of adult Fontan patients between 2002 and 2014 was conducted. Relationships between hemodynamic variables and serious adverse events (death or heart transplant) were examined using the Cox proportional hazard analysis. Correlations between the hemodynamic measurements and signs of end-organ dysfunction (MELD-XI, Child-Pugh, VAST score, estimated glomerular filtration rate [eGFR]) were analyzed. RESULTS Sixty post-Fontan patients (85% systemic left ventricle, 40% atriopulmonary Fontan, mean age of 28 years, and mean time since Fontan operation of 21.9 years) were included. At baseline, those with an event were statistically younger, had lower transcutaneous oxygen saturations, were more likely to have an atriopulmonary Fontan, and were more likely to have a pacemaker. Eighteen experienced a cardiovascularly significant event. Using univariate analysis to compare the event and nonevent groups, mean CI was 2.8 ± 0.9 vs. 2.4 ± 0.5 L/min/m2 (P = .004), and CVP was 18.6 ± 6.5 vs. 16.1 ± 4.3 mmHg (P = .03). However, the statistical significances did not persist in the multivariate model. Higher CVP and pulmonary capillary wedge pressure (PCWP) were associated with higher MELD-XI and Child-Pugh scores, and the VAST score was only associated with PCWP. CONCLUSIONS Symptomatic adult Fontan patients who experienced an event manifested with a higher CI and CVP, although the multivariate Cox proportional hazard analysis did not yield any significant associations. The presences of hepatic dysfunction and portal venous outflow obstruction were associated with a higher CVP and PCWP. Renal dysfunction was prevalent but no statistically significant association between the hemodynamic measurements was identified, although trends toward a higher CVP and transpulmonary gradient were identified.

The Changing Epidemiology of Pediatric Endocarditis

The epidemiology of infective endocarditis (IE) appears to be related to changes in the management of children with congenital heart disease (CHD) and the virtual disappearance of rheumatic heart disease. To better understand these changes, we divide the history into: I. The pre-surgical era, II. The early years of CHD surgical intervention, correlated with introduction of antibiotics, III. The modern era of cardiac interventions. Microbiologic changes include an early predominance of viridans streptococci and an overtaking by staphylococci. Additionally, there have been advances in imaging that allow earlier detection of IE and a reduction in IE-related mortality.

Pediatric pulmonary arterial hypertension and hyperthyroidism: a potentially fatal combination.

CONTEXT Patients with pulmonary arterial hypertension (PAH) who develop hyperthyroidism are at risk for acute cardiopulmonary decompensation and death. CASES AND SETTING We present a series of eight idiopathic PAH/heritable PAH pediatric patients who developed hyperthyroidism between 1999 and 2011. Institutional Review Board approval was obtained; informed consent was waived due to the retrospective nature of the series. All eight patients were receiving iv epoprostenol; five of the eight patients presented with acute cardiopulmonary decompensation in the setting of hyperthyroidism. In the remaining three patients, hyperthyroidism was detected during routine screening of thyroid function tests. The one patient who underwent emergency thyroidectomy was the only survivor of those who presented in cardiopulmonary decline. EVIDENCE SYNTHESIS Aggressive treatment of the hyperthyroid state, including emergency total thyroidectomy and escalation of targeted PAH therapy and β-blockade when warranted, may prove lifesaving in these patients. Prompt thyroidectomy or radioactive iodine ablation should be considered for clinically stable PAH patients with early and/or mild hyperthyroidism to avoid potentially life-threatening cardiopulmonary decompensation. CONCLUSIONS Although the association between hyperthyroidism and PAH remains poorly understood, the potential impact of hyperthyroidism on the cardiopulmonary status of PAH patients must not be ignored. Hyperthyroidism must be identified early in this patient population to optimize intervention before acute decompensation. Thyroid function tests should be checked routinely in patients with PAH, particularly those on iv epoprostenol, and urgently in patients with acute decompensation or symptoms of hyperthyroidism.

Hypercalcemia in Patients with Williams-Beuren Syndrome

OBJECTIVE To evaluate the timing, trajectory, and implications of hypercalcemia in Williams-Beuren syndrome (WBS) through a multicenter retrospective study. STUDY DESIGN Data on plasma calcium levels from 232 subjects with WBS aged 0-67.1 years were compared with that in controls and also with available normative data. Association testing was used to identify relevant comorbidities. RESULTS On average, individuals with WBS had higher plasma calcium levels than controls, but 86.7% of values were normal. Nonpediatric laboratories overreport hypercalcemia in small children. When pediatric reference intervals were applied, the occurrence of hypercalcemia dropped by 51% in infants and by 38% in toddlers. Across all ages, 6.1% of the subjects had actionable hypercalcemia. In children, actionable hypercalcemia was seen in those aged 5-25 months. In older individuals, actionable hypercalcemia was often secondary to another disease process. Evidence of dehydration, hypercalciuria, and nephrocalcinosis were common in both groups. Future hypercalcemia could not be reliably predicted by screening calcium levels. A subgroup analysis of 91 subjects found no associations between hypercalcemia and cardiovascular disease, gastrointestinal complaints, or renal anomalies. Analyses of electrogradiography data showed an inverse correlation of calcium concentration with corrected QT interval, but no acute life-threatening events were reported. CONCLUSIONS Actionable hypercalcemia in patients with WBS occurs infrequently. Although irritability and lethargy were commonly reported, no mortality or acute life-threatening events were associated with hypercalcemia and the only statistically associated morbidities were dehydration, hypercalciuria, and nephrocalcinosis.

Half a Century’s Experience With the Superior Cavopulmonary (Classic Glenn) Shunt

BACKGROUND Five decades after its introduction, the Glenn shunt remains an integral step for patients undergoing single-ventricle palliation. We performed a longitudinal follow-up of the original cohort of patients who underwent Glenn shunt. METHODS We performed a retrospective study of the original cohort of patients who underwent Glenn shunt at Yale between 1958 and 1988. Electronic medical records and chart review up to current era were used to collect data. RESULTS Ninety-one patients underwent a Glenn shunt at an average age of 6.6 ± 2.5 years, of which 89 were classic Glenn shunts. Median overall survival was 43 years (range, 2 to 56; 95% confidence interval [CI], 39.5 to 46.5) while median survival from the Glenn shunt was 31.4 years (range, 0 to 45; 95% CI, 23.9 to 38.9). Forty-six patients died, 7 in the early postoperative period and 39 late deaths. Twenty-six patients were lost to follow-up. Nineteen patients remain alive with active clinical follow-up, 6 of whom still live with their classic Glenn shunt without conversion to bidirectional Glenn. Twenty-six patients (31%) developed pulmonary arteriovenous fistula with 11 patients (42%) requiring coil embolization. No patient developed thrombosis of the Glenn shunt. There were a total of 28 patients who developed arrhythmias, mostly in the tricuspid atresia group (n = 16), with the majority being atrial tachyarrhythmias (48%). Sixteen patients required permanent pacemaker placement for sinus node dysfunction. CONCLUSIONS The Glenn shunt continues to provide excellent staged palliation in single-ventricle patients and a bridge to two-ventricle repair. Arrhythmias and pulmonary arteriovenous fistulas were common among single-ventricle cohort. Quality-of-life evaluation of the surviving patients would be an important outcome measure for future investigation.

Evaluation of a Screening Program to Detect Critical Congenital Heart Defects in Newborns

OBJECTIVES To report the results of and to identify problems with implementing a screening program to detect critical congenital heart defects (CCHDs) in newborns by using differential pulse oximetry (POx). METHODS Charts of all live-born infants from 4 Yale-New Haven health system hospitals in Connecticut between January 1 and December 31, 2014, were reviewed. RESULTS Of 10 589 newborns, 171 (1.6%) underwent an echocardiogram before screening, 10 320 (97.5%) were screened by POx, and 98 (0.9%) were not screened. Thirteen newborns (0.1%) were diagnosed with a CCHD. No infants with CCHDs were identified through POx screening (POxS) alone. Eleven (85%) were already suspected of having a CCHD lesion on the basis of prenatal ultrasound, 1 (8%) was diagnosed because of clinical concern before undergoing screening, and 1 (8%) had a false-negative screening result, but a CCHD was identified after an echocardiogram was performed because a murmur was heard. Four infants with a positive POx screen showed noncritical cardiac lesions by echocardiogram. The majority of infants were screened within the recommended 24 to 72 hours of age interval and had POx screens that were interpreted and documented correctly. Of 10 316 infants with negative POx screens, 52.1% were still in the Yale-New Haven Hospital health system at 1 year of age and no CCHD lesions were listed in their charts. CONCLUSIONS Although a CCHD screening program was effectively implemented, perhaps because most children with a CCHD (85%) were detected antenatally by ultrasound, in our hospital system POxS did not lead to a substantial increase in the early identification of CCHDs.

Modern Incidence of Complete Heart Block in Patients with L‐looped Ventricles: Does Univentricular Status Matter?

OBJECTIVE Individuals with L-transposition of the great arteries and two normally sized ventricles are at risk for complete heart block. Little is known about the incidence of complete heart block in those with a single ventricle L-transposition of the great arteries. In this study, we compare the incidence of complete heart block in a modern cohort of patients with L-looped single ventricle anatomy to patients with L-transposition of the great arteries and two ventricles. METHODS We conducted a retrospective cohort study of patients with L-transposition of the great arteries who were seen at Yale-New Haven Hospital between 2001 and 2013. Patients were classified as having isolated L-transposition of the great arteries (group I), L-transposition of the great arteries and major cardiac defects with two-ventricle anatomy (group II), or L-transposition of the great arteries and single ventricle anatomy (group III). We recorded the age of onset and the circumstances of CHB in each group. We calculated the incidence rate of complete heart block and compared this between the groups. RESULTS We identified 64 patients with L-transposition of the great arteries, median age of 21 years (range 6 months-52 years): 21 in group I, 15 in group II, and 28 in group III. In total, 15 subjects developed complete heart block, incidence of 21.9% and rate of 1.3% per person years. Although group III patients were significantly less likely to develop complete heart block than dual ventricle patients (7.1% vs. 33% and 40%, P = .01), this difference is not significant when only spontaneous complete heart block was analyzed (P = .16). CONCLUSION All patients with L-transposition of the great arteries have similar risk of spontaneous complete heart block and should be routinely screened for this complication.