The Effect of Udenafil on Heart Rate and Blood Pressure in Adolescents With the Fontan Circulation.

The Fontan Udenafil Exercise Longitudinal (FUEL) trial showed that treatment with udenafil was associated with improved exercise performance at the ventilatory anaerobic threshold in children with Fontan physiology. However, it is not known how the initiation of phosphodiesterase 5 inhibitor therapy affects heart rate and blood pressure in this population. These data may help inform patient selection and monitoring after the initiation of udenafil therapy. The purpose of this study is to evaluate the effects of udenafil on vital signs in the cohort of patients enrolled in the FUEL trial. This international, multicenter, randomized, double-blind, placebo-controlled trial of udenafil included adolescents with single ventricle congenital heart disease who had undergone Fontan palliation. Changes in vital signs (heart rate [HR], systolic [SBP] and diastolic blood pressure [DBP]) were compared both to subject baseline and between the treatment and the placebo groups. Additional exploratory analyses were performed to evaluate changes in vital signs for prespecified subpopulations believed to be most sensitive to udenafil initiation. Baseline characteristics were similar between the treatment and placebo cohorts (n = 200 for each). The groups demonstrated a decrease in HR, SBP, and DBP 2 hours after drug/placebo administration, except SBP in the placebo group. There was an increase in SBP from baseline to after 6-min walk test in the treatment and placebo groups, and the treatment group showed an increase in HR (87.4 ± 15.0 to 93.1 ± 19.4 beats/min, p <0.01) after exercise. When comparing changes from baseline to the 26-week study visit, small decreases in both SBP (-1.9 ± 12.3 mm Hg, p = 0.03) and DBP (-3.0 ± 9.6 mm Hg, p <0.01) were seen in the treatment group. There were no clinically significant differences between treatment and placebo group in change in HR or blood pressure in the youngest age quartile, lightest weight quartile, or those on afterload-reducing agents. In conclusion, initiation of treatment with udenafil in patients with Fontan circulation was not associated with clinically significant changes in vital signs, implying that for patients similar to those enrolled in the FUEL trial, udenafil can be started without the requirement for additional monitoring after initial administration.

Sudden Cardiac Arrest During a Sedated Cardiac Magnetic Resonance Study in a Nonsyndromic Child with Evolving Supravalvar Aortic Stenosis Due to Familial ELN Mutation.

Supravalvar aortic stenosis (SVAS) is a less common but clinically important form of left ventricular outflow tract obstruction, and commonly associated with Williams syndrome (WS). SVAS outside of WS may also occur sporadically or in a familial form, often with identifiable mutations in the elastin (ELN) gene. While risk of sudden cardiac death in patients with SVAS has been extensively described in the context of WS, less is known about risk in patients with isolated SVAS. We report a case of a nonsyndromic two-year-old boy with evolving manifestations of SVAS who developed sudden cardiac arrest and death during a sedated cardiac magnetic resonance imaging study. A strong family history of SVAS was present and targeted genetic testing identified an ELN gene mutation in the boy's affected father and other paternal relatives. We review risk factors found in the literature for SCA in SVAS patients and utilize this case to raise awareness of the risk of cardiac events in these individuals even in the absence of WS or severe disease. This case also underscores the importance of genetic testing, including targeted panels specifically looking for ELN gene mutations, in all patients with SVAS even in the absence of phenotypic concerns for WS or other genetic syndromes.

Impact of Udenafil on Echocardiographic Indices of Single Ventricle Size and Function in FUEL Study Participants.

BACKGROUND: The FUEL trial (Fontan Udenafil Exercise Longitudinal) demonstrated statistical improvements in exercise capacity following 6 months of treatment with udenafil (87.5 mg po BID). The effect of udenafil on echocardiographic measures of single ventricle function in this cohort has not been studied. METHODS: The 400 enrolled participants were randomized 1:1 to udenafil or placebo. Protocol echocardiograms were obtained at baseline and 26 weeks after initiation of udenafil/placebo. Linear regression compared change from baseline indices of single ventricle systolic, diastolic and global function, atrioventricular valve regurgitation, and mean Fontan fenestration gradient in the udenafil cohort versus placebo, controlling for ventricular morphology (left ventricle versus right ventricle/other) and baseline value. RESULTS: The udenafil participants (n=191) had significantly improved between baseline and 26 weeks visits compared to placebo participants (n=195) in myocardial performance index (P=0.03, adjusted mean difference [SE] of changes between groups -0.03[0.01]), atrioventricular valve inflow peak E (P=0.009, 3.95 [1.50]), and A velocities (P=0.034, 3.46 [1.62]), and annular Doppler tissue imaging-derived peak e' velocity (P=0.008, 0.60[0.23]). There were no significant differences in change in single ventricle size, systolic function, atrioventricular valve regurgitation severity, or mean fenestration gradient. Participants with a dominant left ventricle had significantly more favorable baseline values of indices of single ventricle size and function (lower volumes and areas, E/e' ratio, systolic:diastolic time and atrioventricular valve regurgitation, and higher annular s' and e' velocity). CONCLUSIONS: FUEL participants who received udenafil demonstrated a statistically significant improvement in some global and diastolic echo indices. Although small, the changes in diastolic function suggest improvement in pulmonary venous return and/or augmented ventricular compliance, which may help explain improved exercise performance in that cohort. REGISTRATION: URL: https://clinicaltrials.gov; Unique Identifier: NCT02741115.

Mitral Annular Disjunction Associated With Fatal Ventricular Arrhythmia in an Adolescent With Marfan Syndrome.

We discuss an adolescent with Marfan syndrome and a previous aortic valve-sparing root replacement who was found to have mitral annular disjunction on surveillance cardiac imaging in the setting of recurrent palpitations. Ambulatory heart rate monitoring incidentally captured a fatal ventricular arrhythmia, a well-recognized but underappreciated cause of sudden cardiac death in patients with Marfan syndrome. (Level of Difficulty: Advanced.).

Consensus Guidelines for the Prevention and Management of Periprocedural Complications of Transcatheter Patent Ductus Arteriosus Closure with the Amplatzer Piccolo Occluder in Extremely Low Birth Weight Infants.

Transcatheter closure of patent ductus arteriosus (PDA) in premature infants is a feasible, safe, and an effective alternative to surgical ligation and may be performed with an implant success rate of 97%. Major procedural complications related to transcatheter PDA closure in extremely low birth weight (ELBW) infants are relatively infrequent (< 3%) ,but may be associated with a fatality if not optimally managed. Operators performing transcatheter PDA closures should be knowledgeable about these potential complications and management options. Prompt recognition and treatment are often necessary to avoid serious consequences. With strict guidelines on operator training, proctoring requirements, and technical refinements, transcatheter PDA closure in ELBW infants can be performed safely with low complication rates. This article summarizes the consensus guidelines put forward by a panel of physicians for the prevention and management of periprocedural complications of transcatheter PDA closure with the Amplatzer Piccolo Occluder in ELBW infants.

Aspirin Use and Transcatheter Pulmonary Valve Replacement, the Need for Consistency.

Transcatheter pulmonary valve replacement (TPVR) is a staple in the pediatric cardiac catheterization lab. Despite the ubiquitous use of this procedure, guidelines for antithrombosis post pulmonary valve replacement are non-existent. A survey was sent out via email to the members of the Congenital Cardiovascular Interventional Study Consortium (CCISC) and the Pediatric and Adult Interventional Cardiac Symposium (PICS-AICS). Responses were received from 109 cardiologists who perform this procedure. Following TPVR 76.5% of respondents use only Aspirin, while the remainder prescribe a second antithrombotic agent at discharge. The majority (78%) of respondents do not educate patients about avoiding enteric formulations of aspirin, and another 86% do not educate patients about the need to avoid proton pump inhibitors (PPI). In addition, 67% do not advise against concomitant use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). Lastly, the survey showed a wide discrepancy in prescribed dose with 56% choosing to always prescribe 70-100 mg regardless of weight, 28% choosing to do weight-based dosing, and 7.5% choosing 325 mg regardless of weight. In a survey sent out to pediatric cardiac interventionalists worldwide, a significant discrepancy was noted in antithrombotic regimens used following TPVR. We hypothesize that these discrepancies may contribute to early valve failure and suggest the need for further study and the development of unified antithrombosis guidelines following TPVR.

Pediatric Cushing syndrome: An early sign of an underling cancer predisposition syndrome.

Beckwith-Wiedemann syndrome (BWS) is a genetic overgrowth and cancer predisposition syndrome that can be associated with a spectrum of clinical features including isolated lateralized overgrowth, macrosomia, macroglossia, organomegaly, omphalocele/umbilical hernia, and distinct facial features. Because of a range of clinical presentations and molecular defects involving Chromosome 11p15, many cases will fall within what is now being defined as the Beckwith-Wiedemann spectrum (BWSp). Cushing syndrome (CS) in infants is a rare neuroendocrinological disease associated with hypercortisolism that has rarely been reported in patients with BWS. Here, we describe the first case of a 5-month-old male with CS secondary to paternal uniparental disomy of Chromosome 11p without additional clinical signs or symptoms of BWS. This case continues to expand the phenotypic spectrum of BWSp.

Fate of the Left Pulmonary Artery and Thoracic Aorta After Transcatheter Patent Ductus Arteriosus Closure in Low Birth Weight Premature Infants.

Transcatheter patent ductus arteriosus closure (TCPC) is an emerging treatment for low birth weight extremely premature neonates (EPNs). Left pulmonary artery (LPA) and descending aorta (DAO) obstruction are described device-related complications, however, data on mid- and long-term vascular outcomes are lacking. A retrospective analysis of EPNs who underwent successful TCPC at our institution from 03/2013 to 12/2018 was performed. Two-dimensional echocardiography and spectral Doppler velocities from various time points before and after TCPC were used to identify LPA and DAO flow disturbances. A total of 44 EPNs underwent successful TCPC at a median (range) procedural weight of 1150 g (755-2500 g). Thirty-two (73%) patients were closed with the AVP II and 12 (27%) with the Amplatzer Piccolo device. LPA and DAO velocities on average remained within normal limits and improved spontaneously in long-term follow up (26.1 months, range 1-75 months). One patient, who had concerning LPA flow characteristics immediately after device implant (peak velocity 2.6 m/s) developed progressive LPA stenosis requiring stent placement 3 months post-procedure. In the remaining infants, including 7 (16%) who developed LPA and 3 (7%) who developed DAO flow disturbances (range 2-2.4 m/s), all had progressive normalization of flow velocities over time. TCPC can be performed safely in EPNs with a low incidence of LPA and DAO obstruction. In the absence of significant progressive vascular obstruction in the early post-procedure period, mild increases in LPA and DAO flow velocities tend to improve spontaneously and normalize in long-term follow-up.

Utility of Three-Dimensional (3D) Modeling for Planning Structural Heart Interventions (with an Emphasis on Valvular Heart Disease).

PURPOSE OF REVIEW: Advanced imaging has played a vital role in the contemporary, rapid rise of structural heart interventions. 3D modeling and printing has emerged as one of the most recent imaging tools and the implementation of 3D modeling is expected to increase with further advances in imaging, print hardware, and materials. RECENT FINDINGS: 3D modeling can be used to educate patients and clinical teams, provide ex vivo procedural simulation, and improve outcomes. Intra-procedural success rates may be improved, and post-procedural complications can be predicted more robustly with appropriate application of 3D modeling. Recent advances in technology have increased the availability of this tool, such that there can be more ready adoption into a routine clinical workflow. Familiarity with 3D modeling and its current utilization and role in structural interventions will help inform how to approach and adapt this exciting new technology.

Vogt-Koyanagi-Harada (VKH) syndrome: A new perspective for healthcare professionals.

Vogt-Koyanagi-Harada syndrome (VKH syndrome) is a rare granulomatous inflammatory disease that affects the melanin pigment producing melanocytes and mainly affects the pigmented structures such as eyes, ear, skin, meninges, and hair. VKT is an autoimmune disorder, which is mainly a T CD4+ Th1 lymphocyte-mediated aggression to melanocytes, in individuals with a genetic predisposition, in particular, the presence of HLA-DRB1 * 0405 allele. Melanin usually gives color to skin, hair, and eyes. Melanin is also found in the retina, where it plays a role in normal vision. This disease mainly leads to vision and hearing disturbances, followed by dermal problems. The most common symptoms include vitiligo, headaches, hair loss (alopecia), and hearing loss. This article describes the various signs and symptoms of VKH disease and its pathogenesis.

Results of the FUEL Trial.

BACKGROUND: The Fontan operation creates a total cavopulmonary connection, a circulation in which the importance of pulmonary vascular resistance is magnified. Over time, this circulation leads to deterioration of cardiovascular efficiency associated with a decline in exercise performance. Rigorous clinical trials aimed at improving physiology and guiding pharmacotherapy are lacking. METHODS: The FUEL trial (Fontan Udenafil Exercise Longitudinal) was a phase III clinical trial conducted at 30 centers. Participants were randomly assigned udenafil, 87.5 mg twice daily, or placebo in a 1:1 ratio. The primary outcome was the between-group difference in change in oxygen consumption at peak exercise. Secondary outcomes included between-group differences in changes in submaximal exercise at the ventilatory anaerobic threshold, the myocardial performance index, the natural log of the reactive hyperemia index, and serum brain-type natriuretic peptide. RESULTS: Between 2017 and 2019, 30 clinical sites in North America and the Republic of Korea randomly assigned 400 participants with Fontan physiology. The mean age at randomization was 15.5±2 years; 60% of participants were male, and 81% were white. All 400 participants were included in the primary analysis with imputation of the 26-week end point for 21 participants with missing data (11 randomly assigned to udenafil and 10 to placebo). Among randomly assigned participants, peak oxygen consumption increased by 44±245 mL/min (2.8%) in the udenafil group and declined by 3.7±228 mL/min (-0.2%) in the placebo group (P=0.071). Analysis at ventilatory anaerobic threshold demonstrated improvements in the udenafil group versus the placebo group in oxygen consumption (+33±185 [3.2%] versus -9±193 [-0.9%] mL/min, P=0.012), ventilatory equivalents of carbon dioxide (-0.8 versus -0.06, P=0.014), and work rate (+3.8 versus +0.34 W, P=0.021). There was no difference in change of myocardial performance index, the natural log of the reactive hyperemia index, or serum brain-type natriuretic peptide level. CONCLUSIONS: In the FUEL trial, treatment with udenafil (87.5 mg twice daily) was not associated with an improvement in oxygen consumption at peak exercise but was associated with improvements in multiple measures of exercise performance at the ventilatory anaerobic threshold. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02741115.

First human implant of the Alterra Adaptive PrestentTM : A new self-expanding device designed to remodel the right ventricular outflow tract.

Current balloon expandable transcatheter valves have limited applicability to patients with "native" right ventricular outflow tracts (RVOT), meaning those who have had previous surgery and are left with large, compliant, irregular RVOT. The Alterra Adaptive PrestentTM is a self-expanding, partially covered stent that was designed to internally reconfigure these types of RVOT, making them suitable for implantation of a commercially available balloon expandable heart valve, the SAPIEN 3. Herein, we describe the first human implant of this device.

Transcatheter Closure of Patent Ductus Arteriosus in Extremely Premature Newborns: Early Results and Midterm Follow-Up.

OBJECTIVES: The goal of this study was to describe early and midterm outcomes of extremely premature newborns (EPNs) who underwent transcatheter echocardiographically guided patent ductus arteriosus (PDA) closure. BACKGROUND: Surgical ligation of PDA in EPNs confers significant risk for procedural morbidity and adverse long-term outcomes. METHODS: The Amplatzer Vascular Plug II was used in all cases. Post-ligation syndrome was defined using previously published parameters. Patients were followed at pre-specified intervals, and prospectively collected data were reviewed. RESULTS: Transcatheter closure was attempted in 24 EPNs (mean procedural age 30 days [range 5 to 80 days], mean procedural weight 1,249 g [range 755 to 2,380 g]) and was successful in 88%. The 3 procedural failures were related to the development of left pulmonary artery (LPA) stenosis caused by the device, and all devices were removed uneventfully. Complications included 2 instances of device malposition, resolved with device repositioning, and 1 instance of LPA stenosis, requiring an LPA stent. There were no procedural deaths, cases of post-ligation syndrome, residual PDA, or device embolization. Survival to discharge was 96% (23 of 24), with a single late death unrelated to the procedure. After a median follow-up period of 11.1 months, all patients were alive and well, with no residual PDA or evidence of LPA or aortic coarctation. CONCLUSIONS: This newly described technique can be performed safely with a high success rate and minimal procedural morbidity in EPNs. Early and midterm follow-up is encouraging. Future efforts should be directed toward developing specific devices for this unique application.

Development of a novel hybrid strategy for transcatheter pulmonary valve placement in patients following transannular patch repair of tetralogy of fallot.

BACKGROUND: Transcatheter pulmonary valve replacement (tPVR) is an accepted therapy for treatment of dysfunctional right ventricular outflow tract (RVOT) conduits. At present, the majority of Fallot patients who undergo transannular patch (TAP) repair are not candidates for tPVR due to the large irregular nature of their RVOT. Herein, we describe a novel approach to assessing the RVOT in this group, which may then be used to design, test, and carry out hybrid RVOT modification and transcatheter valve implantation in this population. METHODS: A retrospective analysis of TAP patients who underwent 3D modeling of the RVOT which was then used to develop individualized hybrid procedures designed to modify the RVOT, thereby rendering patients suitable for transcatheter valve implantation. RESULTS: Eight consecutive patients underwent 3D RVOT modeling followed by hybrid implantation of a transcatheter valve via a perventricular approach. A landing zone stent was placed in all and four required additional intravascular geometric remodeling of the RVOT prior to valve implant. Transcatheter valves were successfully implanted in all. There were no instances of valve malposition, embolization, or death. There was one minor procedural complication. No patient had more than trivial pulmonary regurgitation at follow-up. CONCLUSIONS: Using a hybrid approach to remodel the RVOT in TAP patients supported by preprocedural 3D-model planning allows for successful tPVR implantation in this population. A larger cohort and longer follow-up will be needed to determine the ultimate utility of this approach.

Remote delivery of congenital cardiac magnetic resonance imaging services: a unique telemedicine model.

Cardiac magnetic resonance imaging (CMRI) is increasingly utilized in the management of patients with congenital heart disease. Unfortunately, the expertise to perform and interpret these studies is not universally available, despite an increasing population of congenital heart survivors. This retrospective analysis describes our experience providing on-site CMRI services compared with providing the same services over a geographic distance of 250 miles. There were 83 local scans with both physician and patient on-site compared with 91 scans controlled by a physician geographically remote from the patients. The patients were well-matched for age, sex, study duration, scan type, and history of prior cardiac intervention. There was no difference in use of deep sedation or diazepam for anxiolysis, or use of atropine for arrhythmia suppression. There were no patient safety issues and there was satisfaction on the part of the referring physicians who were able to obtain more timely studies, as well as the remote-scanning physicians who had a workflow comparable with the local scans, but no lost travel time. This experience suggests that remote delivery of cardiac MRI services for the congenital heart population is feasible and can be done with comparable success and safety to a traditional "local" model. We also suggest the configuration to provide such remote CMRI services with commercially available hardware and software.