Role and Applications of Experimental Animal Models of Fontan Circulation.

Over the last four decades, the Fontan operation has been the treatment of choice for children born with complex congenital heart diseases and a single-ventricle physiology. However, therapeutic options remain limited and despite ongoing improvements in initial surgical repair, patients still experience a multiplicity of cardiovascular complications. The causes for cardiovascular failure are multifactorial and include systemic ventricular dysfunction, pulmonary vascular resistance, atrioventricular valve regurgitation, arrhythmia, development of collaterals, protein-losing enteropathy, hepatic dysfunction, and plastic bronchitis, among others. The mechanisms leading to these late complications remain to be fully elucidated. Experimental animal models have been developed as preclinical steps that enable a better understanding of the underlying pathophysiology. They furthermore play a key role in the evaluation of the efficacy and safety of new medical devices prior to their use in human clinical studies. However, these experimental models have several limitations. In this review, we aim to provide an overview of the evolution and progress of the various types of experimental animal models used in the Fontan procedure published to date in the literature. A special focus is placed on experimental studies performed on animal models of the Fontan procedure with or without mechanical circulatory support as well as a description of their impact in the evolution of the Fontan design. We also highlight the contribution of animal models to our understanding of the pathophysiology and assess forthcoming developments that may improve the contribution of animal models for the testing of new therapeutic solutions.

Tetralogy of Fallot in Low- and Middle-Income Countries.

Low- and middle-incomes countries (LMICs) have limited resources for the diagnosis and treatment of congenital heart diseases such as tetralogy of Fallot. This is in part due to lack of infrastructures, financial means, and expertise. As a result, patients undergo surgery much later than in high-income countries. This delay in treatment results in right ventricular dysfunction, cardiac arrhythmias, and poor psychomotor development-complications that are all related to chronic hypoxia. There are limited data and a few small studies of patients treated for tetralogy of Fallot in LMICs, and, therefore, the aim of this review is to analyse and summarize the surgical outcomes of this LMIC population.

Dans les pays à revenu faible ou intermédiaire (PRFI), les ressources sont limitées pour diagnostiquer et prendre en charge les cardiopathies congénitales comme la tétralogie de Fallot. Cette situation est attribuable en partie au manque d'infrastructures, de moyens financiers et d'expertise. Les patients subissent donc une correction chirurgicale beaucoup plus tard que dans les pays à revenu élevé. Les délais de traitement peuvent entraîner une dysfonction ventriculaire droite, une arythmie cardiaque et des problèmes de développement psychomoteur : des complications toutes liées à l'hypoxie chronique. Il existe des données limitées et quelques études de faible envergure sur des patients traités pour une tétralogie de Fallot dans les PRFI. L'objectif du présent article de synthèse est donc d'analyser et de résumer les issues des interventions chirurgicales dans les PRFI pour cette population.

The Ross-Konno Procedure With or Without Mitral Valve Surgery: A Systematic Review With Individual Data Pooling.

Background: The Ross-Konno procedure is a technically demanding surgical option to treat multilevel left ventricular outflow tract obstruction. Methods: A systematic review with pooled analyses was conducted according to PRISMA criteria on studies published between January 2000 and May 2022 that assessed outcomes following the Ross-Konno intervention in children. Individual patient data were extracted from published Kaplan-Meier curves using digitalization software. Overall survival and freedom from reintervention were assessed by time-to-event approaches. Determinants of one-year survival were investigated by meta-regression analyses. Results: Ten studies with a total population of 274 patients were included. The overall pooled early (≤30 days) survival rate was 86.9% (95% CI [87.6%-78.4%]). Five-year survival rates in patients without and with (N = 50 [18.2%] of 274 total patients) concomitant mitral valve surgery were 82.5% (95% CI [87.6%-77.4%]) versus 56.1% (95% CI [74.1%-38.1%]), hazard ratio 2.67, 95% CI (1.44-4.93), P < .0001. Five- and ten-year freedom from pulmonary autograft reoperation rates were 93.5% and 90.9%, respectively. Five- and ten-year freedom from right ventricular outflow tract reoperation rates were 74.3% and 57.3%, respectively. By meta-regression analysis, resection of endocardial fibroelastosis (N = 32 [11.7%] of 274 total patients) was associated with superior one-year survival (P = .027). Conclusion: The Ross-Konno procedure is associated with substantial early mortality and gradual attrition thereafter. Mortality is higher in patients with concomitant mitral valve surgery. Resection of endocardial fibroelastosis is associated with superior survival. Right ventricular outflow tract reinterventions are common.

Impact of Fontan Fenestration on Adverse Cardiovascular Outcomes: A Multicentre Study.

BACKGROUND: Fenestrating a Fontan baffle has been associated with improved perioperative outcomes in patients with univentricular hearts. However, longer-term potential adverse effects remain debated. We sought to assess the impact of a fenestrated Fontan baffle on adverse cardiovascular events including all-cause mortality, cardiac transplantation, atrial arrhythmias, and thromboemboli. METHODS: A multicentre North American retrospective cohort study was conducted on patients with total cavopulmonary connection Fontan baffle, with and without fenestration. All components of the composite outcome were independently adjudicated. Potential static and time-varying confounders were taken into consideration, along with competing risks. RESULTS: A total of 407 patients were followed for 10.4 (7.1-14.4) years; 70.0% had fenestration of their Fontan baffle. The fenestration spontaneously closed or was deliberately sealed in 79.9% of patients a median of 2.0 years after Fontan completion. In multivariable analysis in which a persistent fenestration was modelled as a time-dependent variable, an open fenestration did not confer a higher risk of the composite outcome (hazard ratio, 1.18; 95% confidence interval, 0.71-1.97; P = 0.521). In secondary analyses, an open fenestration was not significantly associated with components of the primary outcome: that is, mortality or transplantation, atrial arrhythmias, or thromboemboli. However, sensitivity analyses to assess the possible range of error resulting from imprecise dates for spontaneous fenestration closures could not rule out significant associations between an open fenestration and atrial arrhythmias or thromboemboli. CONCLUSIONS: In this multicentre study, no significant association was identified between an open fenestration in the Fontan baffle and major adverse cardiovascular events.

Long-term outcomes after heart transplantation in adult patients with univentricular versus biventricular congenital heart disease.

OBJECTIVES: Heart transplantation (HT) is the only life-extending therapy in adults with congenital heart disease (CHD) and end-stage heart failure. HT is considered at high risk in complex CHD given the anatomical complexity and past medical history. Little is known about long-term outcomes after HT in these patients. We aimed to evaluate early and long-term outcomes after HT in adult patients with univentricular versus biventricular CHD. METHODS: This multicentre retrospective cohort study included all adult CHD patients who underwent HT between 1988 and 2021 in 3 tertiary centres. Factors associated with early (<30 days) and conditional long-term survival were assessed in the entire cohort. RESULTS: Over a mean follow-up of 10.1 ± 7.8 years, 149 patients were included, of whom 55 (36.9%) had univentricular CHD. Sixty-four patients died during follow-up including 47 deaths before discharge from hospital. In multivariable analysis, univentricular physiology and female recipient gender were independently associated with a higher risk of early mortality (odds ratio 2.99; 95% confidence interval [1.33-6.74] and odds ratio 2.76; 95% confidence interval [1.23-6.20], respectively). For patients who survived the early period, conditional long-term survival was excellent for both groups and was not different between 2 groups (P = 0.764). CONCLUSIONS: Adult CHD patients have a high incidence of overall mortality due to a high rate of early mortality. Univentricular physiology was associated with a significant increased risk of early death compared to biventricular physiology. However, late mortality was excellent and no longer different between the 2 physiologies.

The medical device development ecosystem: Current regulatory state and challenges for future development: A review.

BACKGROUND/PURPOSE: There has been increasing emphasis on the development of new technology to mitigate unmet clinical needs in cardiovascular disease. This emphasis results in part from recognition that many devices, although being initially developed in the United States, were studied, and then eventually approved abroad before being returned to the U.S. for clinical application. The FDA (Food and Drug Administration) guidance document on Early Feasibility Studies (EFS) and then the 21st Century Cures Act from 2013 to 2016 focused on these issues. MATERIALS/METHODS: There are multiple components of medical device translational pathways to be considered in continuing to reach the goal of providing early access to safe and effective products to the U.S. POPULATION: This review article documents the various stages from early idea innovation to device design and iteration to clinical testing and then potential approval and application in the wide clinical practice of cardiovascular health care. RESULTS: The CDRH (Centers for Devices and Radiological Health) has focused on key components including EFS, Breakthrough Devices Program, Total Product Life Cycle, the Unique Device Identification Program, the establishment of a Digital Health Center of Excellence, and leveraging Collaborative Communities. Each of these initiatives focuses on improving the Medical Device Development Ecosystem. CONCLUSIONS: Major changes in device translational research have improved the device research climate in the United States. Goals remain including increased training and education for constituencies aspiring to work in the field of device development and regulation as part of a continuous health care learning system.

The Ross Operation in Young Patients: A 15-Year Experience Focused on Right Ventricle to Pulmonary Artery Conduit Outcomes.

Background: Data on long-term outcomes of the Ross operation in children and young adult patients are limited. The best pulmonary valve substitute for the right ventricular outflow tract reconstruction remains uncertain. This study aimed to assess the outcomes of right ventricular outflow tract reconstruction in the Ross operation in young patients using various pulmonary valve substitutes at a single institution. In addition, a comparison of reintervention rates between patients younger than 18 years and those older than 18 years was performed. Methods: The study assessed all patients (N = 110) who underwent the Ross operation at the University Hospital of Bordeaux, France, between 2004 and 2020. Results: The median follow-up time was 4.2 years, and the median age at operation was 15.9 years. There was no operative mortality and 1 late noncardiac death (0.8%). The overall survival rate at 10 years was 99.2%. The need for right ventricular outflow tract reoperation was lower with the pulmonary homograft compared with the Contegra conduit and Freestyle bioprosthesis: 94.3%, 93.8%, and 80% at 5 years, respectively, and 94.3%, 72.3%, and 34.3% at 10 years, respectively (P = 0.011). The probability of reintervention was not significantly different at 10 years among children vs adults (P = 0.22). Conclusions: The Ross procedure in children and young adults was associated with a lower requirement for right ventricular outflow tract reoperation when pulmonary homografts were used instead of xenografts.

Contexte: Il existe peu de données sur les résultats à long terme de l'intervention de Ross chez les enfants et chez les jeunes adultes. Par ailleurs, des doutes persistent quant au meilleur substitut pour remplacer la valve pulmonaire lors de la reconstruction de la voie d'éjection du ventricule droit. Notre étude visait à mesurer les résultats de la reconstruction de la voie d'éjection du ventricule droit après l'intervention de Ross chez de jeunes patients d'un même établissement chez qui différents substituts valvulaires ont été utilisés. De plus, le taux de réintervention chez les patients âgés de moins de 18 ans et celui chez les patients âgés de 18 ou plus ont été comparés. Méthodologie: Notre étude portait sur tous les patients (N = 110) ayant subi une intervention de Ross au Centre Universitaire de Bordeaux (France) entre 2004 et 2020. Résultats: La durée médiane du suivi a été de 4,2 années, et l'âge médian au moment de l'intervention chirurgicale était de 15,9 ans. Aucun décès précoce n'a été constaté au terme de l'intervention, mais un décès de cause non cardiaque est survenu ultérieurement (0,8 %). Le taux global de survie à 10 ans était de 99,2 %. La réintervention chirurgicale au niveau de la voie d'éjection du ventricule droit a été nécessaire moins fréquemment chez les patients ayant reçu une homogreffe que chez les patients ayant reçu un conduit Contegra ou une bioprothèse Freestyle : les taux sans réintervention s'élevaient respectivement à 94,3 %, 93,8 % et 80 % à 5 ans, et à 94,3 %, 72,3 % et 34,3 % à 10 ans (p = 0,011). En outre, les probabilités de réintervention chirurgicale chez les enfants et chez les adultes ne différaient pas de façon significative à 10 ans (p = 0,22). Conclusions: Le recours à des homogreffes pulmonaires plutôt qu'à des xénogreffes au cours des interventions de Ross pratiquées chez les enfants et les jeunes adultes est associé à un plus faible taux de réintervention.

Joint-preserving surgery for idiopathic bilateral osteonecrosis of the distal tibia: A case report.

Introduction: Osteonecrosis (ON) is a serious pathological condition that can affect weight-bearing areas of the lower limbs, including the distal tibia. Although trauma is a common cause of ON, the condition has multiple possible etiologies. ON has been associated with a range of factors, including trauma, medication use, alcoholism, and vascular disease. Interruption of blood flow to a particular bone region is the first step in the pathophysiology of ON. Conservative management is typically indicated in the early stages of ON, but joint-preserving procedures may be necessary in cases where conservative treatment fails. Case Report: This article presents a case of bilateral ON of the distal tibia in a 38-year-old female patient without a history of trauma or identifiable risk factors. The patient was initially managed conservatively but ultimately underwent joint-preserving surgery due to treatment failure. Conclusion: Joint-preserving procedures should be considered in cases of early-stage distal tibia ON that do not respond to conservative management to prevent joint collapse. This case highlights the importance of considering ON as a possible diagnosis even in the absence of identifiable risk factors or trauma.

Ventricular Fibrillation Is a Sign of Life.

Ventricular fibrillation (VF) is a deadly rhythm problem. With asystole, it represents one of the most extreme emergencies that may engage vital prognosis within only few minutes if appropriated treatment is not instituted. It is learned in all medical schools worldwide that VF is not compatible with consciousness and sustained life. Moreover, at 37°C, and without restauration of cardiac flow, VF may be responsible for severe and most often irreversible brain damage after 3 minutes.

The Biomedical Entrepreneurship Skills Development Program (BEEP): Educating a New Generation of Medical Innovators.

Innovative, new technologies are rapidly being introduced into the medical world, as scientists and inventors continually discover solutions to all kinds of health issues. However, comprehensive education in medical product development, business process and strategy is distinctly lacking for science students who aspire to become commercial medical innovators and entrepreneurs. Entrepreneurially minded professionals at the New York University Grossman School of Medicine developed, implemented, and integrated programs to train early scientists in the business side of science to accelerate the pace of commercialisation and encourage individuals to pursue venture creation and entrepreneurship to impact highly relevant healthcare solutions.

Ventricular Arrhythmias in Adults With Congenital Heart Disease, Part I: JACC State-of-the-Art Review.

Patients with congenital heart disease associated with a higher risk for ventricular arrhythmias (VA) and sudden cardiac death (SCD) can be divided conceptually into those with discrete mechanisms for reentrant monomorphic ventricular tachycardia (VT) (Group A) and those with more diffuse substrates (Group B). Part I of this review addresses Group A lesions, which predominantly consist of tetralogy of Fallot and related variants. Well-defined anatomic isthmuses for reentrant monomorphic VT are interposed between surgical scars and the pulmonary or tricuspid annulus. The most commonly implicated critical isthmus for VT is the conal septum that divides subpulmonary from subaortic outlets. Programmed ventricular stimulation can be helpful in risk stratification. Although catheter ablation is not generally considered an alternative to the implantable cardioverter-defibrillator (ICD) for prevention of SCD, emerging data suggest that there is a subset of carefully selected patients who may not require ICDs after successful monomorphic VT ablation.

Ventricular Arrhythmias in Adults With Congenital Heart Disease, Part II: JACC State-of-the-Art Review.

There are marked variations in the incidence of sudden cardiac death (SCD) and in the substrates for ventricular arrhythmias (VAs) across the gamut of congenital heart defects. In this 2-part review, patients with higher-risk forms of congenital heart disease (CHD) were conceptually categorized into those with discrete anatomic isthmuses for macro-reentrant ventricular tachycardia (VT) (Group A) and those with more diffuse or less well-defined substrates (Group B) that include patchy or extensive myocardial fibrosis. The latter category encompasses CHD lesions such as Ebstein anomaly, transposition of the great arteries with a systemic right ventricle (RV), and congenital aortic stenosis. For Group B patients, polymorphic VT and ventricular fibrillation account for a higher proportion of VA. The prognostic value of programmed ventricular stimulation is less well established, and catheter ablation plays a less prominent role. As cardiomyopathies evolve over time, pathophysiological mechanisms for VA among Groups A and B become increasingly blurred.

Association of Arterial Blood pH at Cannulation With 1 Year Survival Among Veno-Arterial Extracorporeal Membrane Oxygenation Recipients: The Three Seven Rule.

We aimed to describe the clinical outcomes of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) therapy in our institution considering clinical context and pH at cannulation. All patients treated by VA-ECMO during the 2005-2020 period with 1 year complete follow-up were included. Our cohort was divided in three groups according to the pH level at cannulation: pH <7 (group 1), pH 7-7.2 (group 2), and pH>7.2 (group 3). Survival was analyzed using Kaplan-Meier method. Association between pH group and survival was estimated using a Cox model. A total of 572 patients were included: 60 patients in group 1, 115 in group 2, and 397 in group 3. Refractory cardiogenic shock (36%) was the main indication. One year survival rates were 13%, 36%, and 43% in groups 1, 2, and 3, respectively ( p < 0.001). Death mainly occurred within the first month. The strong correlation between pH and lactates led to propose a simple "three seven rule": pH <7 and lactate >7 was associated with <7% survival. Veno-arterial extracorporeal membrane oxygenation should be considered with caution in patients with pH <7. Lactates and pH might be important parameters to elaborate a new score to predict survival in this population. The "three seven rule" can be very relevant when facing emergency situations.

Systematic Electrophysiological Study Prior to Pulmonary Valve Replacement in Tetralogy of Fallot: A Prospective Multicenter Study.

BACKGROUND: Ventricular arrhythmias and sudden death are recognized complications in tetralogy of Fallot. Electrophysiological studies (EPS) before pulmonary valve replacement (PVR), the most common reintervention in tetralogy of Fallot, could potentially inform therapy to improve arrhythmic outcomes. METHODS: A prospective multicenter study was conducted to systematically assess EPS with programmed ventricular stimulation in patients with tetralogy of Fallot referred for PVR from January 2020 to December 2021. A standardized stimulation protocol was used across all centers. RESULTS: A total of 120 patients were enrolled, mean age 39.2±14.5 years, 53.3% males. Sustained ventricular tachycardia was induced in 27 (22.5%) patients. When identifiable, the critical isthmus most commonly implicated (ie, in 90.0%) was between the ventricular septal defect patch and pulmonary annulus. Factors independently associated with inducible ventricular tachycardia were history of atrial arrhythmia (odds ratio, 8.56 [95% CI, 2.43-34.73]) and pulmonary annulus diameter >26 mm (odds ratio, 5.05 [95% CI, 1.47-21.69]). The EPS led to a substantial change in management in 23 (19.2%) cases: 18 (15.0%) had catheter ablation, 3 (2.5%) surgical cryoablation during PVR, and 9 (7.5%) defibrillator implantation. Repeat EPS 5.1 (4.8-6.2) months after PVR was negative in 8 of 9 (88.9%) patients. No patient experienced a sustained ventricular arrhythmia during 13 (6.1-20.1) months of follow-up. CONCLUSIONS: Systematically performing programmed ventricular stimulation in patients with tetralogy of Fallot referred for PVR yields a high rate of inducible ventricular tachycardia and carries the potential to alter management. It remains to be determined whether a standardized treatment approach based on the results of EPS will translate into improved outcomes. REGISTRATION: URL: https://clinicaltrials.gov/ct2/show/NCT04205461; Unique identifier: NCT04205461.

Management for atrial arrhythmias in adults with complex congenital heart disease.

INTRODUCTION: The prevalence of congenital heart disease (CHD) is steadily increasing among adults. Atrial arrhythmias are frequent late complications and are associated with substantial morbidity. AREAS COVERED: We discuss key considerations regarding management strategies for atrial arrhythmias in common forms of CHD and offer future perspectives. EXPERT OPINION: An appreciation of the types of atrial arrhythmias encountered in patients with diverse forms of CHD, combined with the growing clinical and research experience, appears to be yielding favorable results, whereas little progress has been made on the antiarrhythmic drug front, indications for anticoagulation have considerably evolved. Advances in interventional techniques have propelled catheter ablation to the forefront to treat a variety of atrial arrhythmias in patients with complex CHD. Nevertheless, much work remains to be done to elucidate underlying pathophysiology, triggers, and critical substrates that predispose patients with specific CHD malformations to develop atrial arrhythmias. Future advances could allow for the implementation of individualized, possibly preemptive, approaches to arrhythmia management. With the prevalence of atrial fibrillation on the rise in the aging population with CHD, concerted efforts must be directed toward optimizing patient selection for catheter ablation as well as refining procedural aspects to safely and more effectively improve long-term outcomes.

Navigating Arrhythmias in Tetralogy of Fallot Throughout the Lifespan: A Case-based Review.

Arrhythmias are a common complication associated with tetralogy of Fallot (ToF), one of the most prevalent forms of congenital heart disease. As illustrated by this case-based review, various forms of arrhythmias can be encountered across the lifespan of patients with ToF, from infancy to older adulthood. These include atrioventricular block, junctional ectopic tachycardia, and atrial and ventricular arrhythmias. Arrhythmias have important implications on the health and quality of life of patients with ToF and require treatment by caregivers with dedicated expertise. The choice of pharmacologic and/or interventional therapies to alleviate symptoms, avoid complications, and mitigate risks depends in part on the type, severity, and frequency of the arrhythmia, as well as on the particularities of individual clinical scenarios. Preventing, monitoring for, and managing arrhythmias are an integral component of the care of patients with ToF throughout their lifespan that is critical to optimizing health outcomes.

L'arythmie est une complication fréquemment associée à la tétralogie de Fallot (TF), l'une des cardiopathies congénitales les plus courantes. Dans le présent article de synthèse basé sur des études de cas, nous illustrons les différentes formes d'arythmie tout au long de la vie des patients atteints de la TF, de la petite enfance à l'âge adulte avancé. Les formes d'arythmie décrites incluent le bloc atrioventriculaire, la tachycardie jonctionnelle ectopique et les arythmies auriculaire et ventriculaire. L'arythmie a des répercussions importantes sur l'état de santé et sur la qualité de vie des patients atteints de la TF, et elle requiert un traitement par des personnes dotées d'une expertise particulière. Le choix d'un traitement (pharmacologique, interventionnel ou les deux) pour soulager les symptômes, éviter les complications et réduire les risques dépend du type, de la sévérité et de la fréquence de l'arythmie, ainsi que des particularités de chaque tableau clinique. La prévention, la surveillance et la prise en charge de l'arythmie font partie intégrante des soins pour les patients atteints de la TF tout au long de leur vie, et elles sont cruciales pour optimiser les résultats cliniques.

Ventricular Fibrillation Is a Sign of Life

ABSTRACT Ventricular fibrillation (VF) is a deadly rhythm problem. With asystole, it represents one of the most extreme emergencies that may engage vital prognosis within only few minutes if appropriated treatment is not instituted. It is learned in all medical schools worldwide that VF is not compatible with consciousness and sustained life. Moreover, at 37°C, and without restauration of cardiac flow, VF may be responsible for severe and most often irreversible brain damage after 3 minutes.