Congenital heart disease (CHD) is the most common congenital anomaly in newborn babies. Cardiac malformations have been produced in multiple experimental animal models, by perturbing selected ...molecules that function in the developmental pathways involved in myocyte specification, differentiation, or cardiac morphogenesis. In contrast, the precise genetic, epigenetic, or environmental basis for these perturbations in humans remains poorly understood. Over the past few decades, researchers have tried to bridge this knowledge gap through conventional genome-wide analyses of rare Mendelian CHD families, and by sequencing candidate genes in CHD cohorts. Although yielding few, usually highly penetrant, disease gene mutations, these discoveries provided 3 notable insights. First, human CHD mutations impact a heterogeneous set of molecules that orchestrate cardiac development. Second, CHD mutations often alter gene/protein dosage. Third, identical pathogenic CHD mutations cause a variety of distinct malformations, implying that higher order interactions account for particular CHD phenotypes. The advent of contemporary genomic technologies including single nucleotide polymorphism arrays, next-generation sequencing, and copy number variant platforms are accelerating the discovery of genetic causes of CHD. Importantly, these approaches enable study of sporadic cases, the most common presentation of CHD. Emerging results from ongoing genomic efforts have validated earlier observations learned from the monogenic CHD families. In this review, we explore how continued use of these technologies and integration of systems biology is expected to expand our understanding of the genetic architecture of CHD.
Abstract
Aims
To assess the utility of machine learning algorithms on estimating prognosis and guiding therapy in a large cohort of patients with adult congenital heart disease (ACHD) or pulmonary ...hypertension at a single, tertiary centre.
Methods and results
We included 10 019 adult patients (age 36.3 ± 17.3 years) under follow-up at our institution between 2000 and 2018. Clinical and demographic data, ECG parameters, cardiopulmonary exercise testing, and selected laboratory markers where collected and included in deep learning (DL) algorithms. Specific DL-models were built based on raw data to categorize diagnostic group, disease complexity, and New York Heart Association (NYHA) class. In addition, models were developed to estimate need for discussion at multidisciplinary team (MDT) meetings and to gauge prognosis of individual patients. Overall, the DL-algorithms—based on over 44 000 medical records—categorized diagnosis, disease complexity, and NYHA class with an accuracy of 91.1%, 97.0%, and 90.6%, respectively in the test sample. Similarly, patient presentation at MDT-meetings was predicted with a test sample accuracy of 90.2%. During a median follow-up time of 8 years, 785 patients died. The automatically derived disease severity-score derived from clinical information was related to survival on Cox analysis independently of demographic, exercise, laboratory, and ECG parameters.
Conclusion
We present herewith the utility of machine learning algorithms trained on large datasets to estimate prognosis and potentially to guide therapy in ACHD. Due to the largely automated process involved, these DL-algorithms can easily be scaled to multi-institutional datasets to further improve accuracy and ultimately serve as online based decision-making tools.
Congenital heart disease is the most frequently occurring congenital disorder affecting ≈0.8% of live births. Thanks to great efforts and technical improvements, including the development of ...cardiopulmonary bypass in the 1950s, large-scale repair in these patients became possible, with subsequent dramatic reduction in morbidity and mortality. The ongoing search for progress and the growing understanding of the cardiovascular system and its pathophysiology refined all aspects of care for these patients. As a consequence, survival further increased over the past decades, and a new group of patients, those who survived congenital heart disease into adulthood, emerged. However, a large range of complications raised at the horizon as arrhythmias, endocarditis, pulmonary hypertension, and heart failure, and the need for additional treatment became clear. Technical solutions were sought in perfection and creation of new surgical techniques by developing catheter-based interventions, with elimination of open heart surgery and new electronic devices enabling, for example, multisite pacing and implantation of internal cardiac defibrillators to prevent sudden death. Over time, many pharmaceutical studies were conducted, changing clinical treatment slowly toward evidence-based care, although results were often limited by low numbers and clinical heterogeneity. More attention has been given to secondary issues like sports participation, pregnancy, work, and social-related difficulties. The relevance of these issues was already recognized in the 1970s when the need for specialized centers with multidisciplinary teams was proclaimed. Finally, research has become incorporated in care. Results of intervention studies and registries increased the knowledge on epidemiology of adults with congenital heart disease and their complications during life, and at the end, several guidelines became easily accessible, guiding physicians to deliver care appropriately. Over the past decades, the landscape of adult congenital heart disease has changed dramatically, which has to be continued in the future.
The Fontan operation was first performed in 1968. Since then, this operation has been performed on thousands of patients worldwide. Results vary from very good for many decades to very bad with a ...pleiad of complications and early death. A good understanding of the physiology is necessary to further improve results. The Fontan connection creates a critical bottleneck with obligatory upstream congestion and downstream decreased flow; these two features are the basic cause of the majority of the physiologic impairments of this circulation. The ventricle, while still the engine of the circuit, cannot compensate for the major flow restriction of the Fontan bottleneck: the suction required to compensate for the barrier effect cannot be generated, specifically not in a deprived heart. Except for some extreme situations, the heart therefore no longer controls cardiac output nor can it significantly alter the degree of systemic venous congestion. Adequate growth and development of the pulmonary arteries is extremely important as pulmonary vascular impedance will become the major determinant of Fontan outcome. Key features of the Fontan ventricle are early volume overload and overgrowth, but currently chronic preload deprivation with increasing filling pressures. A functional decline of the Fontan circuit is expected and observed as pulmonary vascular resistance and ventricular filling pressure increase with time. Treatment strategies will only be successful if they open up or bypass the critical bottleneck or act on immediate surroundings (impedance of the Fontan neoportal system, fenestration, enhanced ventricular suction).
Life expectancy and quality of life for those born with congenital heart disease (CHD) have greatly improved over the past 3 decades. While representing a great advance for these patients, who have ...been able to move from childhood to successful adult lives in increasing numbers, this development has resulted in an epidemiological shift and a generation of patients who are at risk of developing chronic multisystem disease in adulthood. Noncardiac complications significantly contribute to the morbidity and mortality of adults with CHD. Reduced survival has been documented in patients with CHD with renal dysfunction, restrictive lung disease, anemia, and cirrhosis. Furthermore, as this population ages, atherosclerotic cardiovascular disease and its risk factors are becoming increasingly prevalent. Disorders of psychosocial and cognitive development are key factors affecting the quality of life of these individuals. It is incumbent on physicians who care for patients with CHD to be mindful of the effects that disease of organs other than the heart may have on the well-being of adults with CHD. Further research is needed to understand how these noncardiac complications may affect the long-term outcome in these patients and what modifiable factors can be targeted for preventive intervention.
Congenital heart disease is the most common congenital disorder in newborns. Advances in cardiovascular medicine and surgery have enabled most patients to reach adulthood. Unfortunately, prolonged ...survival has been achieved at a cost, as many patients suffer late complications, of which heart failure and arrhythmias are the most prominent. Accordingly, these patients need frequent follow-up by physicians with specific knowledge in the field of congenital heart disease. However, planning of care for this population is difficult, because the number of patients currently living with congenital heart disease is difficult to measure. Birth prevalence estimates vary widely according to different studies, and survival rates have not been well recorded. Consequently, the prevalence of congenital heart disease is unclear, with estimates exceeding the number of patients currently seen in cardiology clinics. New developments continue to influence the size of the population of patients with congenital heart disease. Prenatal screening has led to increased rates of termination of pregnancy. Improved management of complications has changed the time and mode of death caused by congenital heart disease. Several genetic and environmental factors have been shown to be involved in the etiology of congenital heart disease, although this knowledge has not yet led to the implementation of preventative measures. In this Review, we give an overview of the etiology, birth prevalence, current prevalence, mortality, and complications of congenital heart disease.
Ebstein anomaly and tricuspid valve dysplasia are rare congenital tricuspid valve malformations associated with high perinatal mortality. The literature consists of small, single-center case series ...spanning several decades. We performed a multicenter study to assess the outcomes and factors associated with mortality after fetal diagnosis in the current era.
Fetuses diagnosed with Ebstein anomaly and tricuspid valve dysplasia from 2005 to 2011 were included from 23 centers. The primary outcome was perinatal mortality, defined as fetal demise or death before neonatal discharge. Of 243 fetuses diagnosed at a mean gestational age of 27±6 weeks, there were 11 lost to follow-up (5%), 15 terminations (6%), and 41 demises (17%). In the live-born cohort of 176 live-born patients, 56 (32%) died before discharge, yielding an overall perinatal mortality of 45%. Independent predictors of mortality at the time of diagnosis were gestational age <32 weeks (odds ratio, 8.6; 95% confidence interval, 3.5-21.0; P<0.001), tricuspid valve annulus diameter z-score (odds ratio, 1.3; 95% confidence interval, 1.1-1.5; P<0.001), pulmonary regurgitation (odds ratio, 2.9; 95% confidence interval, 1.4-6.2; P<0.001), and a pericardial effusion (odds ratio, 2.5; 95% confidence interval, 1.1-6.0; P=0.04). Nonsurvivors were more likely to have pulmonary regurgitation at any gestational age (61% versus 34%; P<0.001), and lower gestational age and weight at birth (35 versus 37 weeks; 2.5 versus 3.0 kg; both P<0.001).
In this large, contemporary series of fetuses with Ebstein anomaly and tricuspid valve dysplasia, perinatal mortality remained high. Fetuses with pulmonary regurgitation, indicating circular shunt physiology, are a high-risk cohort and may benefit from more innovative therapeutic approaches to improve survival.
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