Pulmonary Hypertension in Adults with Congenital Heart Disease: Real-World Data from the International COMPERA-CHD Registry

Introduction: Pulmonary hypertension (PH) is a common complication in patients with congenital heart disease (CHD), aggravating the natural, post-operative, or post-interventional course of the underlying anomaly. The various CHDs differ substantially in characteristics, functionality, and clinical outcomes among each other and compared with other diseases with pulmonary hypertension. Objective: To describe current management strategies and outcomes for adults with PH in relation to different types of CHD based on real-world data. Methods and results: COMPERA (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension) is a prospective, international PH registry comprising, at the time of data analysis, >8200 patients with various forms of PH. Here, we analyzed a subgroup of 680 patients with PH due to CHD, who were included between 2007 and 2018 in 49 specialized centers for PH and/or CHD located in 11 European countries. At enrollment, the patients’ median age was 44 years (67% female), and patients had either pre-tricuspid shunts, post-tricuspid shunts, complex CHD, congenital left heart or aortic disease, or miscellaneous other types of CHD. Upon inclusion, targeted therapies for pulmonary arterial hypertension (PAH) included endothelin receptor antagonists, PDE-5 inhibitors, prostacyclin analogues, and soluble guanylate cyclase stimulators. Eighty patients with Eisenmenger syndrome were treatment-naïve. While at inclusion the primary PAH treatment for the cohort was monotherapy (70% of patients), with 30% of the patients on combination therapy, after a median observation time of 45.3 months, the number of patients on combination therapy had increased significantly, to 50%. The use of oral anticoagulants or antiplatelets was dependent on the underlying diagnosis or comorbidities. In the entire COMPERA-CHD cohort, after follow-up and receiving targeted PAH therapy (n = 511), 91 patients died over the course of a 5-year follow up. The 5-year Kaplan–Meier survival estimate for CHD associated PH was significantly better than that for idiopathic PAH (76% vs. 54%; p < 0.001). Within the CHD associated PH group, survival estimates differed particularly depending on the underlying diagnosis and treatment status. Conclusions: In COMPERA-CHD, the overall survival of patients with CHD associated PH was dependent on the underlying diagnosis and treatment status, but was significantly better as than that for idiopathic PAH. Nevertheless, overall survival of patients with PAH due to CHD was still markedly reduced compared with survival of patients with other types of CHD, despite an increasing number of patients on PAH-targeted combination therapy

RACHS-1 score as predictive factor for postoperative ventilation time in children with congenital heart disease

Background: Congenital heart disease is the most frequent malformation in newborns. The postoperative mortality of these patients can be assessed with the Risk Adjustment in Congenital Heart Surgery-1 (RACHS-1) score. This study evaluates whether the RACHS-1 score can also be used as a predictor for the length of postoperative ventilation and what is the influence of age. Material and Methods: In a retrospective study over the period from 2007 to 2013, all patient records were evaluated: 598 children with congenital heart disease and cardiac surgery were identified and 39 patients have been excluded because of additional comorbidities. For evaluation of mortality, 559 patients could be analysed, after exclusion of 39 deceased patients, 520 cases remained for analysis of postoperative ventilation. Results: Overall mortality was 7% with a dependency on RACHS-1 categories. The median length of postoperative ventilation rose according to the RACHS-1 categories: RACHS-1 category 1: 9 hours (interquartile range (IQR) 7-13 hours), category 2: 30 hours (IQR 12-85 hours), category 4: 58 hours (IQR 13-135 hours), category 4: 71 hours (IQR 29-165 hours), and category 6: 189 hours (IQR 127-277 hours). Some of the RACHS-1 subgroups differed significantly from the categories, especially the repair of tetralogy of Fallot with a longer ventilation time and strong variability. Younger age was an independent factor for longer postoperative ventilation. Conclusion: RACHS-1 is a good predictor for the length of postoperative ventilation after cardiac surgery with the exception of some subgroups. Younger age is another independent factor for longer postoperative ventilation. These data provide better insight into ventilation times and allow better planning of operations in terms of available intensive care beds

Emerging clinical applications of strain imaging and three-dimensional echocardiography for the assessment of ventricular function in adult congenital heart disease

Management of congenital heart disease (CHD) in adults (ACHD) remains an ongoing challenge due to the presence of residual hemodynamic lesions and development of ventricular dysfunction in a large number of patients. Echocardiographic imaging plays a central role in clinical decision-making and selection of patients who will benefit most from catheter interventions or cardiac surgery.. Recent advances in both strain imaging and three-dimensional (3D)-echocardiography have significantly contributed to a greater understanding of the complex pathophysiological mechanisms involved in CHD. The aim of this paper is to provide an overview of emerging clinical applications of speckle-trading imaging and 3D-echocardiography in ACHD with focus on functional assessment, ventriculo-ventricular interdependency, mechanisms of electromechanical delay, and twist abnormalities in adults with tetralogy of Fallot (TOF), a systemic RV after atrial switch repair or in double discordance ventricles, and in those with a Fontan circulation

Stenting the Fontan pathway in paediatric patients with obstructed extracardiac conduits

Objectives An unobstructed extracardiac conduit (ECC) is essential for optimal Fontan haemodynamics. We aimed to evaluate the feasibility and results of percutaneous transcatheter stenting of the ECC in paediatric patients with a significant Fontan pathway obstruction. Methods Our institutional database was searched to identify all Fontan patients who had a stent placed in their ECC. Medical records, cardiac catheterisation data and echocardiographic investigations were reviewed. Vessel diameters were normalised to account for differences in body surface area. Results Nineteen Fontan patients (age 6.5+/-3.2 years; male 78.9%) with a significant stenosis of their Dacron ECC graft were identified. Seven patients presented with protein-losing enteropathy (36.8%). An ECC obstruction was suspected on echocardiography in only 6/19 patients (31.6%). The mean minimum diameter of the ECC was 8.3+/-2.4 mm. A stenosis of >45% was seen in the majority of patients (n=12, 63.1%). Significant correlations between the severity of the ECC obstruction and Fontan pathway vessel diameters were found (all p<0.05). Stenting was successful in all children. The ECC diameter increased significantly after stenting (p<0.0001). An acute clinical benefit of ECC stenting was observed in 18/19 (94.7%) patients. ECC patency was good during a mean follow-up of 1.8+/-0.9 years. Conclusions The feasibility and acute results of percutaneous transcatheter ECC stenting are promising and may provide a good alternative to postpone surgery to a later age. The mechanisms contributing to the development of ECC stenoses are likely multifactorial

Towards a proposal for a universal diagnostic definition of protein-losing enteropathy in Fontan patients: a systematic review

Objective A standardised diagnostic definition of protein-losing enteropathy (PLE) in Fontan patients serves both patient care and research. The present study determined whether a diagnostic definition of PLE was routinely used in published clinical Fontan studies, and to identify potentially relevant diagnostic criteria for composing a uniform PLE definition. Methods A systematic review was conducted in adherence to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) recommendations. Published clinical Fontan studies that were written in English and included at least four patients with PLE were selected. PLE definitions were quantitatively analysed using a lateral thinking tool in which definitions were fractionated into constituent pieces of information (building blocks or diagnostic criteria). Results We identified 364 papers. In the final analysis, data from 62 published articles were extracted. A diagnostic definition of PLE was used in only 27/62 (43.5%) of selected studies, and definitions were very heterogeneous. We identified eight major diagnostic criteria. Hypoalbuminaemia (n=23 studies, 85.2%), clinical presentation (n=18, 66.7%), documentation of enteric protein loss (n=16, 59.3%) and exclusion of other causes of hypoproteinaemia (n=17, 63.0%), were the most frequently used diagnostic criteria. Most studies used three diagnostic variables (n=13/27, 48.1%). Cutoff values for laboratory parameters (serum albumin, protein or faecal alpha-1-antitrypsin) were frequently incorporated in the PLE definition (n=16, 59.3%). Conclusions Establishment of a universally accepted PLE definition for routine use in clinical research and daily practice is required. The diagnostic criteria may help constitute a diagnostic PLE definition

Thyroid dysfunction in pediatric Fontan patients is associated with unfavorable hemodynamic status and severity of protein-losing enteropathy: A report from the Fontan care network

Background: Thyroid dysfunction may have adverse effects on Fontan hemodynamics. Data on thyroid function in pediatric Fontan patients with or without protein-losing enteropathy (PLE) are limited. Methods: This retrospective multicenter study included 67 Fontan patients (median age 10.9 years; 35.8% female; 28.4% PLE) in whom thyroid function testing was performed. Results: Subclinical hypothyroidism (SHT) was present in 16 (23.9%) patients. Subjects with SHT had significantly lower systolic blood pressure (p = 0.014) and body weight z-score (p = 0.006), were in a worse New York Heart Association (NYHA) functional class (p = 0.004), were more often pacing dependent (p = 0.007), and were more likely to have PLE (p = 0.033, 8/19 (42.1%) patients). Serum thyroid stimulating hormone (TSH) levels were significantly higher in patients with NYHA class ≥ II (p = 0.005), significant atrioventricular valve regurgitation (p = 0.023), elevated serum natriuretic peptides (p = 0.031), and in those with PLE (p = 0.002). Patients with active PLE had significantly higher TSH levels than those in remission (p = 0.003). A strong inverse relationship was found between lower free triiodothyronine (fT3) levels and natriuretic peptides (r: −0.599, p = 0.040). Using binary logistic regression analysis we found that worse NYHA class was an independent predictor of SHT (OR 4.2; 95% CI 1.1–16.1, p = 0.036). Conclusions: Subclinical thyroid dysfunction is common in Fontan, particularly in patients with hemodynamic derangements and PLE. Future studies are needed to address the prognostic implications of thyroid dysfunction in the Fontan population

Low serum 25-hydroxyvitamin D levels and secondary hyperparathyroidism in Fontan patients

Background Limited data exist on the vitamin D status in Fontan patients. We determined the prevalence and potential risk factors of vitamin D deficiency in this patient subset. Methods and results Data were collected from 27 Fontan patients (55.6% male, mean age 8.15.3 years). Protein-losing enteropathy was diagnosed in six patients (22.2%). Vitamin D deficiency was defined as a serum 25-hydroxyvitamin D level of <20 ng/ml. The neutrophil-to-lymphocyte ratio, a marker of systemic inflammation, was calculated. Associations between laboratory measurements and patient characteristics were explored. Mean serum 25-hydroxyvitamin D level was 14.1 +/- 10.4 ng/ml. Vitamin D deficiency was found in 19/27 patients (70.3%). Only skin type was associated with vitamin D deficiency (p=0.04). Hyperparathyroidism was present in 5/21 (23.8%) patients, and was more prevalent in patients with protein-losing enteropathy (p<0.001). Parathyroid hormone levels correlated with parameters of systemic inflammation (neutrophil-to-lymphocyte ratio: r=0.484, p=0.026; relative lymphocyte count: r=-0.635, p=0.002). Vitamin D supplementation significantly increased serum 25-hydroxyvitamin D levels (p<0.0001), and was accompanied by a reduction in parathyroid hormone concentrations (p=0.032). Conclusions A high prevalence of vitamin D deficiency was found among Fontan patients, independent of age, time after Fontan procedure, ventricular morphology, and presence of protein-losing enteropathy. A potentially important link between parathyroid hormone levels and systemic inflammation is suggested