A Multisite Retrospective Review of Direct Oral Anticoagulants Compared to Warfarin in Adult Fontan Patients.

PURPOSE: Direct oral anticoagulants (DOACs) are not recommended in adult Fontan patients (Level of Evidence C). We hypothesized that DOACs are comparable to warfarin and do not increase thrombotic and embolic complications (TEs) or clinically significant bleeds. METHODS: We reviewed the medical records of adult Fontan patients on DOACs or warfarin at three major medical centers. We identified 130 patients: 48 on DOACs and 107 on warfarin. In total, they were treated for 810 months on DOACs and 5637 months on warfarin. RESULTS: The incidence of TEs in patients on DOACs compared to those on warfarin was not increased in a statistically significant way (hazard ratio [HR] 1.7 and p value 0.431). Similarly, the incidence of nonmajor and major bleeds in patients on DOACs compared to those on warfarin was also not increased in a statistically significant way (HR for nonmajor bleeds in DOAC patients was 2.8 with a p value of 0.167 and the HR for major bleeds was 2.0 with a p value 0.267). In multivariate analysis, congestive heart failure (CHF) was a risk factor for TEs across both groups (odds ratio [OR] = 4.8, 95% confidence interval [CI] = 1.3-17.6) and bleed history was a risk factor for clinically significant bleeds (OR = 6.8, 95% CI = 2.7-17.2). CONCLUSION: In this small, retrospective multicenter study, the use of DOACs did not increase the risk of TEs or clinically significant bleeds compared to warfarin in a statistically significant way.

Adolescents and adults with Fontan circulation: insights from the PREpArE-Fontan registry.

The Patient Registry for Adolescents and Adults with Stable Fontan Circulation aims to describe a contemporary cohort of Fontan patients who could be eligible for a clinical trial investigating macitentan, an endothelin receptor antagonist. This international, non-interventional, multicentre, cross-sectional, observational registry enrolled patients with "stable" Fontan circulation ≥10 years following extra-cardiac conduit or lateral tunnel procedure. Main exclusion criteria were NYHA functional class IV, reoperation of Fontan circulation, or signs of disease worsening. Patient characteristics at enrolment are described; available data were collected during a single registration visit. Of the 266 screened patients, 254 were included in this analysis. At enrolment, median (interquartile range) age was 24 (20;30) years, 37%/63% of patients were from the USA/Europe, 54% were male, 54%/47% had undergone extra-cardiac conduit/lateral tunnel procedures, and 95% were in NYHA functional class I or II. History of arrhythmia was more common in older patients and patients with lateral tunnel; overall prevalence was 19%. Most laboratory values were within the normal range but mean creatinine clearance was abnormally low (87.7 ml/min). Angiotensin-converting enzyme inhibitors were used by 48% of patients and their use was associated with creatinine clearance <90 ml/min (p = 0.007), as was Fontan completion at an older age (p = 0.007). 53.4% of patients had clinical characteristics that could potentially meet an endothelin receptor antagonist trial's eligibility criteria. The PREpArE-Fontan registry describes a cohort of patients who could potentially participate in an endothelin receptor antagonist trial and identified early subtle signs of Fontan failure, even in "stable" patients.

A genome-wide association study of congenital cardiovascular left-sided lesions shows association with a locus on chromosome 20.

Congenital heart defects involving left-sided lesions (LSLs) are relatively common birth defects with substantial morbidity and mortality. Previous studies have suggested a high heritability with a complex genetic architecture, such that only a few LSL loci have been identified. We performed a genome-wide case-control association study to address the role of common variants using a discovery cohort of 778 cases and 2756 controls. We identified a genome-wide significant association mapping to a 200 kb region on chromosome 20q11 [P= 1.72 × 10-8 for rs3746446; imputed Single Nucleotide Polymorphism (SNP) rs6088703 P= 3.01 × 10-9, odds ratio (OR)= 1.6 for both]. This result was supported by transmission disequilibrium analyses using a subset of 541 case families (lowest P in region= 4.51 × 10-5, OR= 1.5). Replication in a cohort of 367 LSL cases and 5159 controls showed nominal association (P= 0.03 for rs3746446) resulting in P= 9.49 × 10-9 for rs3746446 upon meta-analysis of the combined cohorts. In addition, a group of seven SNPs on chromosome 1q21.3 met threshold for suggestive association (lowest P= 9.35 × 10-7 for rs12045807). Both regions include genes involved in cardiac development-MYH7B/miR499A on chromosome 20 and CTSK, CTSS and ARNT on chromosome 1. Genome-wide heritability analysis using case-control genotyped SNPs suggested that the mean heritability of LSLs attributable to common variants is moderately high ([Formula: see text] range= 0.26-0.34) and consistent with previous assertions. These results provide evidence for the role of common variation in LSLs, proffer new genes as potential biological candidates, and give further insight to the complex genetic architecture of congenital heart disease.

Anomalous Left Coronary Artery From the Right Sinus of Valsalva in a Patient Presenting with ST-Segment Elevation in Lead aVR: A Case Report.

BACKGROUND: Anomalous coronary artery origins appear in roughly 1% of coronary angiograms, and up to 15% of syncope and sudden cardiac death events can be attributed to anomalous coronaries. Patients with an anomalous coronary artery arising from the opposite sinus may initially present with syncope and electrocardiographic findings of ischemia. CASE REPORT: We describe a case in which an adolescent male presented with exercise-induced angina and syncope, and his initial electrocardiogram (ECG) showed diffuse ST-segment depression with ST-segment elevation in lead aVR. Cardiac catheterization revealed there was no coronary ostium in the left coronary cusp, and the left coronary artery had an anomalous origin from the right cusp. The patient received urgent left internal mammary artery-to-left anterior descending artery coronary bypass and a saphenous vein graft to the ramus intermedius. After he underwent 6 months of medical therapy with ß-blockade and angiotensin-receptor blockade, his left ventricular systolic function improved to low-normal level (left ventricular ejection fraction, approximately 50%). WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: ST-segment elevation in lead aVR is strongly prognostic for left main or triple-vessel coronary artery disease. However, in patients who present with syncope and few other coronary artery disease risk factors, this ECG finding should be suggestive of an ischemic event caused by an anomalous left coronary artery. Early recognition of this pattern of clinical signs and ECG findings by an emergency physician could be critical for making the correct diagnosis and risk stratifying the patient for early coronary angiography and urgent surgical revascularization.

Thrombolytics for late superior caval vein thrombus in a patient with tricuspid atresia and single-lung Glenn anastomosis.

BACKGROUND: Those with cyanotic heart disease have an elevated bleeding risk but also are hypercoaguable. Treating haemodynamically significant thrombi in this unique cohort poses a monumental challenge. Case A 29-year-old women with tricuspid atresia and left pulmonary artery atresia presented with superior caval vein syndrome. She had a right modified Blalock-Taussig shunt as a neonate. A left modified Blalock-Taussig shunt performed later failed to establish flow to her left lung. At age 5, she had a Fontan procedure to the right lung but could not tolerate the physiology and had a low cardiac output syndrome. The Fontan was taken down and she was left with a Glenn anastamosis to the right pulmonary artery. She did well for years until she had dyspnea, upper extremity oedema and "facial fullness". On examination she was tachycardic, hypotensive, and more desaturated than baseline. She also had facial plethora. Decision-making Echocardiogram showed a large 9 × 3 mm nearly occlusive thrombus in the superior caval vein at the bifurcation of the left and right innominate veins. An emergent venogram confirmed the location and size of the thrombus. Given the thrombus burden and potential for distal embolisation through the Glenn to the single functional lung, we chose to treat the patient with thrombolytics. She had uncomplicated ICU course and was sent home on warfarin. Follow-up echocardiogram showed complete resolution of clot. CONCLUSION: This case shows the importance of history and physical exam in caring for this complex cohort of adult patients with CHD.

Surgical device therapy for heart failure in the adult with congenital heart disease.

Individuals with adult congenital heart disease (ACHD) are at a great risk for heart failure, and the underlying anatomic features are important predictors of heart failure. As the ACHD population grows older, multiple events, including years of an altered physiology, the neurohormonal cascade, and many still unknown, culminate in ventricular failure. Surgical device therapy is an effective method in supporting patients with heart failure. Ventricular assist devices have been used with success in bridging ACHD patients to heart transplantation or destination therapy.

Dronedarone for the Treatment of Atrial Arrhythmias in Adults With Congenital Heart Disease.

BACKGROUND: Atrial tachyarrhythmias are common and difficult to treat in adults with congenital heart disease. Dronedarone has proven effective in patients without congenital heart disease, but data are limited about its use in adults with congenital heart disease of moderate to great complexity. METHODS: A single-center, retrospective chart review of 21 adults with congenital heart disease of moderate to great complexity who were treated with dronedarone for atrial tachyarrhythmias was performed. RESULTS: The median (IQR) age at dronedarone initiation was 35 (27.5-39) years. Eleven patients (52%) were male. Ten patients (48%) had New York Heart Association class I disease, 10 (48%) had class II disease, and 1 (5%) had class III disease. Ejection fraction at initiation was greater than 55% in 11 patients (52%), 35% to 55% in 9 patients (43%), and less than 35% in 1 patient (5%). Prior treatments included ß-blockers (71%), sotalol (38%), amiodarone (24%), digoxin (24%), and catheter ablation (38%). Rhythm control was complete in 5 patients (24%), partial in 6 (29%), and inadequate in 10 (48%). Two patients (10%) experienced adverse events, including nausea in 1 (5%) and cardiac arrest in 1 (5%), which occurred 48 months after initiation of treatment. There were no deaths during the follow-up period. The median (IQR) follow-up time for patients with complete or partial rhythm control was 20 (1-54) months. CONCLUSION: Dronedarone can be effective for adult patients with congenital heart disease and atrial arrhythmias for whom more established therapies have failed, and with close monitoring it can be safely tolerated.

De novo thrombus on an atrial septal defect device 3 years after its implantation.

The secundum atrial septal defect (ASD) is noted to occur in 1 per 1,500 live births and is the fourth most common congenital heart defect (CHD) [Anzai et al. in Am J Cardiol 93:426-431, 2004]. Early complications with percutaneous closure of secundum ASDs include device malposition and embolization, arrhythmias (primarily atrial fibrillation), pericardial effusion, residual shunt, and thrombus development on the left atrial disk [Chessa et al. in J Am Coll Cardiol 39:1061-1065, 2002, Co-Burn and William in Moss and Adams' Heart disease in infants, children and adolescents including fetus and young adults. Williams and Wilkins, Baltimore, 1995]. We present a patient with a very late complication of device thrombus after percutaneous secundum ASD device closure.

Transcatheter thrombectomy of acute pulmonary embolism in an adult Fontan patient: a case report.

Background: The Fontan operation is a well-described palliative procedure for functional single-ventricle patients. This population has an increased risk of thrombo-embolic events. Adequate imaging, and therefore diagnosis, requires an understanding of the unique anatomy and physiology of a Fontan. Optimal strategies for the prevention and treatment of thrombo-embolic complications in the Fontan population are poorly defined. Case summary: A 28-year-old female with a history of Ebstein anomaly of the tricuspid valve status post-Fontan presented with chest pain and acute hypoxia. Computed tomographic angiography (CTA) reported a submassive pulmonary embolism (PE). She was initiated on a heparin drip. Catheterization demonstrated elevated Fontan pressures and a large thrombus in the right lower pulmonary artery that was removed with an aspiration device. The patient was transitioned to a direct oral anticoagulant (DOAC) following the procedure. Discussion: Thrombotic complications are common in the adult Fontan population. Given the morbidity and mortality associated with this complication, the use of proper imaging techniques is imperative. Traditional CTA imaging for PE in Fontan patients often has contrast filling defects related to their anatomy and physiology. Utilization of adequate imaging techniques helps decrease cost and additional radiation exposure. In addition, it avoids inappropriate hospitalization, need for anticoagulation, and potential need for catheterization toconfirm or exclude the presence of PE. For Fontan patients with a thrombus, prior event, and no contraindications, current guidelines recommend oral anticoagulation with a vitamin K antagonist; however, there are increasing data on the use of DOACs in this population.

Safety and utility of CardioMEMS device for remote pulmonary artery monitoring in paediatric Fontan patients: a case series.

Background: Patients with single ventricle congenital heart disease who undergo total cavo-pulmonary anastomosis (Fontan surgery) suffer from elevated pulmonary artery pressure (PAP), which leads to multiple adverse sequelae. Traditionally, the Fontan pressures are assessed via invasive haemodynamic catheterization that exposes these medically fragile patients to the risks of vascular injury and anaesthesia. While the CardioMEM remote PAP monitor has been extensively used in adults with heart failure, the safety of this device has not been established in children. Case summary: We report safety and utility of this device in eight paediatric Fontan patients. Our patients ranged from 9 to 18 years of age. There were no reported complications related to the implantation of the CardioMEMS device in our population. Discussion: This is the first case series of safety of CardioMEMS device in paediatric Fontan Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation patients. Our experience indicates that the device may be safely utilized for the management of Fontan-related complications in this vulnerable population.

Telehealth multidisciplinary prenatal consultation during the COVID-19 pandemic: enhancing patient care coordination while maintaining high provider satisfaction.

OBJECTIVE: Comprehensive fetal care centers address congenital anomalies by developing pre- and post-natal care plans in a multidisciplinary format. To reduce exposure during the Coronavirus Infectious Disease-2019 (COVID-19) pandemic, the Centers for Medicare & Medicaid Services (CMS) broadened access to telehealth services. We assessed provider satisfaction with the rapid transition from in-person prenatal visits to multidisciplinary consultations via telehealth as an adaptive response to the pandemic. METHODS: Patients referred to an urban academic fetal care center during the first 6 weeks of the COVID-19 pandemic underwent advanced imaging including fetal MRI, focused ultrasound, and fetal echocardiography. Subsequently, multidisciplinary telehealth consultations occurred with all providers attending virtually. Patients were given the option of attending the multidisciplinary telehealth consultation in a conference room in the hospital or from home. During these meetings, relevant images were reviewed with all participants via screen sharing through a secure video platform. Provider satisfaction with the telehealth paradigm was assessed using an electronic survey. RESULTS: Twenty-two surveys were administered with a response rate of 82%. 89% of providers were highly satisfied with the telehealth format. 72% of providers would prefer the multidisciplinary telehealth format to an in-person visit for future visits after COVID-19 restrictions are lifted. 22% of providers would leave the choice to the patient's family. One provider preferred in-person visits. Some providers noted that virtual conferences limited the ability to draw pictures, show educational materials, and provide emotional support. CONCLUSION: Providers were overwhelmingly supportive of continuing multidisciplinary telehealth conferences for complex prenatal consultations, even after restrictions are lifted, which has led to the continuation of this model for the duration of the pandemic. Providers highlighted the convenience and improved care coordination across specialties. Further studies to examine the patient experience with virtual consultations are warranted.

Pulmonary Embolism After Vaginal Delivery in a Fontan Patient.

The Fontan procedure was created to address the mixing of pulmonary and systemic venous return in patients with a single functional ventricle. The patient in this case with a Fontan repair experienced multiple pulmonary emboli 10 days post-partum. We outline management and recommendations when treating these patients. (Level of Difficulty: Beginner.).

Management of Heart Failure in Adult Congenital Heart Disease.

Heart failure (HF) in the adult with congenital heart disease (ACHD) is associated with high morbidity and mortality and has been implicated as the leading cause of death in this patient population. The diagnosis of HF in ACHD involves a combination of clinical suspicion from subjective patient history, anatomic imaging, functional diagnostic studies, and rhythm evaluation. Once diagnosed, the approach to management of HF in this population varies widely and by lesion. Unfortunately, there is a paucity of literature available delineating the optimal management of these patients, making clinical decision-making extremely challenging. In this review, we aim to summarize available evidence to help guide the diagnosis and management of HF in ACHD.

Novel oral anticoagulant use in adult Fontan patients: A single center experience.

OBJECTIVE: Adult Fontan patients are at increased risk for thrombosis and thromboembolic complications leading to increased morbidity and mortality. Most are prescribed antiplatelet or anticoagulant therapy for thromboprophylaxis; novel oral anticoagulants (NOACs) are uncommonly used given lack of data on their use in this population and generalized concerns regarding Fontan patients' abnormal coagulation. We report the largest single-center experience with the use of NOACs for treatment and prophylaxis of thrombosis and thromboembolism in adult Fontan patients. RESULTS: A retrospective chart review identified 21 patients (11 female, 10 male), median age 33 years (18-50) at first initiation, who were prescribed a NOAC on 27 different occasions. The main indications for anticoagulation were arrhythmia (N = 12), thrombosis (N = 8), and persistent right to left shunts (N = 2); one patient was initially on anticoagulation for arrhythmia but restarted for thrombosis. The most common indications for initiation of a NOAC over warfarin were patient/provider preference (N = 11), labile international normalized ratio (INR) (N = 5), initiation of therapy elsewhere (N = 3), and history of poor clinical follow-up (N = 2). Over a cumulative 316 months of patient therapy, one new thrombotic event was noted. No major or nonmajor bleeding events occurred, and 10 patients experienced minor bleeding that did not require the cessation of therapy. One patient died from multiorgan system failure following an unwitnessed, out of hospital arrest. At present, 10 patients remain on NOAC therapy in the setting of ongoing arrhythmia (N = 4), history of stroke (N = 2), history of pulmonary embolism (N = 2), history of deep vein thrombosis (N = 1), and history of right ventricle thrombus (N = 1). CONCLUSIONS: While our study is limited by size, our results suggest that NOACs may be a non-inferior alternative to traditional anticoagulation and that further study is warranted.

Neurocognitive and executive functioning in adult survivors of congenital heart disease.

OBJECTIVE: Congenital heart disease (CHD) can affect the developing central nervous system, resulting in neurocognitive and behavioral deficits. Preoperative neurological abnormalities as well as sequelae of the open heart operations required to correct structural abnormalities of the heart contribute to these deficits. There are few studies examining the neurocognitive functioning of adults with CHD. This study sought to investigate multiple domains of neurocognitive functioning in adult survivors of CHD who had childhood cardiac surgery with either moderate or severe disease complexity. DESIGN: A total of 48 adults (18-49 years of age) who had undergone cardiac surgery for CHD prior to five years of age participated in the study. CHD severity was classified as moderate or severe according to the 32nd Bethesda Guidelines. A computerized battery of standardized neurocognitive tests (CNS-Vital Signs), a validated rating scale of executive functioning, and demographic questionnaires were administered. RESULTS: There were no significant differences between the moderate CHD group and normative data on any cognitive measure. In contrast, the severe CHD group differed from norms in multiple domains: psychomotor speed, processing speed, complex attention, reaction time, and on the overall neurocognitive index. Number of surgeries was strongly related to worse executive functioning. There was no association between age at first surgery or time since last surgery and neuropsychological functioning. Number of surgeries was also unrelated to neurocognitive test performance. CONCLUSIONS: Patients with severe CHD performed significantly worse on measures of processing speed, attention, and executive functioning. These findings may be useful in the long-term care of adults with congenital heart disease.

Whole exome sequencing in 342 congenital cardiac left sided lesion cases reveals extensive genetic heterogeneity and complex inheritance patterns.

BACKGROUND: Left-sided lesions (LSLs) account for an important fraction of severe congenital cardiovascular malformations (CVMs). The genetic contributions to LSLs are complex, and the mutations that cause these malformations span several diverse biological signaling pathways: TGFB, NOTCH, SHH, and more. Here, we use whole exome sequence data generated in 342 LSL cases to identify likely damaging variants in putative candidate CVM genes. METHODS: Using a series of bioinformatics filters, we focused on genes harboring population-rare, putative loss-of-function (LOF), and predicted damaging variants in 1760 CVM candidate genes constructed a priori from the literature and model organism databases. Gene variants that were not observed in a comparably sequenced control dataset of 5492 samples without severe CVM were then subjected to targeted validation in cases and parents. Whole exome sequencing data from 4593 individuals referred for clinical sequencing were used to bolster evidence for the role of candidate genes in CVMs and LSLs. RESULTS: Our analyses revealed 28 candidate variants in 27 genes, including 17 genes not previously associated with a human CVM disorder, and revealed diverse patterns of inheritance among LOF carriers, including 9 confirmed de novo variants in both novel and newly described human CVM candidate genes (ACVR1, JARID2, NR2F2, PLRG1, SMURF1) as well as established syndromic CVM genes (KMT2D, NF1, TBX20, ZEB2). We also identified two genes (DNAH5, OFD1) with evidence of recessive and hemizygous inheritance patterns, respectively. Within our clinical cohort, we also observed heterozygous LOF variants in JARID2 and SMAD1 in individuals with cardiac phenotypes, and collectively, carriers of LOF variants in our candidate genes had a four times higher odds of having CVM (odds ratio = 4.0, 95% confidence interval 2.5-6.5). CONCLUSIONS: Our analytical strategy highlights the utility of bioinformatic resources, including human disease records and model organism phenotyping, in novel gene discovery for rare human disease. The results underscore the extensive genetic heterogeneity underlying non-syndromic LSLs, and posit potential novel candidate genes and complex modes of inheritance in this important group of birth defects.