Congenital heart disease
ICD-10 Code Q21-Q28
What is the clinical spectrum of congenital heart disease?
The term congenital heart disease (CHD) covers all structural heart defects present at birth, singly or in combination. Individuals with CHD present with an abnormal structure of the cardiac chambers, valves, or great vessels that alters the normal pattern of blood flow. Congenital heart defects can have severe consequences on individuals' development, cognition, learning, behaviour, physical fitness, educational and employment opportunities.
CHD has heterogenous presentations according to the varying simple, moderate and severe complexity of structural lesions. Bicuspid aortic valve (BAV), in which there are two abnormal instead of three normal leaflets that regulate the blood flow into the aorta, is the most common CHD, generally classified as mild. An example of moderate CHD is the ventricular septal defect (VSD), which accounts for about a fifth of all CHD. In VSD, a hole is present in the ventricular septum that normally separates the right ventricle from the left ventricle, enabling blood to flow between the left and the right ventricles, and causing left-to-right side abnormal pathways of blood flow called shunts. The severity of symptoms depends on the size of the hole, and range from asymptomatic to tachypnea, tachycardia, poor growth, and recurrent respiratory infections.
Long-lasting defects that cause left-to-right shunts, like in VSD, atrial septal defects (ASD), and patent ductus arteriosus (PDA), can lead to the Eisenmenger syndrome, classified as severely complex CHD causing cyanosis, dyspnea on exertion, fatigue, syncope, and heart failure. In the case of Tetralogy of Fallot (TOF), the shunt occurs the from right-to-left. This CHD form has four main abnormalities: an outlet VSD, a pulmonary stenosis, a right ventricular hypertrophy, and an overriding aorta positioned directly over the VSD. If left untreated, this condition can lead to developmental delays due to reduced oxygen delivery to the body, pulmonary hypertension, arrhythmia, heart failure, and sudden cardiac death.
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What do we know about the etiology of congenital heart disease?
Cohort studies show that both genetic and environmental factors contribute to the development of CHD. Importantly, as much as 70% of CHD cases do not have an identifiable genetic etiology. Owing to the complexity of genetic and environmental interactions, identifying causes of all CHD cases remains challenging.
The most frequent maternal diseases associated with CHD include pregestational diabetes, gestational diabetes diagnosed in the first or early second trimester, phenylketonuria, autoimmune disease such as Sjogren syndrome, and first trimester rubella infection.
Risk factors of genetic origin were shown to be variable, resulting in variable phenotypes. Certain aneuploidies, such as trisomy 21, account for 5 to 10% of patients with CHD. Other cases of genetic contributions to CHD involve sub-chromosomal deletions and duplications, or monogenic mutations. Copy number variants are often associated with congenital syndromes that affect multiple organs in addition to the heart, such as in DiGeorge syndrome and Williams-Beuren syndrome. About 20 to 30% of syndromic CHD cases are due to monogenic pathogenic variants, such as mutations in fibrillin-1 (Marfan syndrome), TXB5 (Holt-Oram syndrome), and PTPN11 (Noonan syndrome). In some instances, genetic risk factors for CHD are common variants that can contribute to CHD when combined with other common variants, epigenetic changes, and environmental factors.
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How similar are human and animal cardiovascular systems?
Cardiovascular systems of human and non-human animals differ at every level, from molecular to organism level, contributing to poor translation of animal studies to humans.
Species-specific differences in cardiomyocyte electrophysiology
Examples of inter-species differences with respect to electrophysiology include molecular and functional differences in major depolarizing currents, repolarizing currents, mechanisms of early afterdepolarizations, and delayed afterdepolarizations. For instance, species-specific differences in tissue size, conduction system structure, gap junction conductance, expression of ion channels, current expression, diastolic interval and restitution properties, play a part in inter-species variations to susceptibility to some of the common drivers of arrhythmia - re-entry, ectopy and dispersion of repolarization.
Species-specific differences in heart anatomy and bioenergetics
Although the heart anatomy, physiology, and bioenergetics of smaller mammals (rodents) and bigger mammals (humans, pigs, sheep) share several similarities, there are also massive inter-species differences in heart size, shape, and metabolic demands that lead to variations in cardiac electrical conduction structure, function, speed and efficiency.
Species-specific differences in embryogenesis
Variations in molecular, cellular, tissue, organ and organism-level timing, regulatory networks and signaling pathways across species, have implications for understanding human-specific embryogenesis, for dissecting the impact of genetic, epigenetic, and environmental factors on the development of the human heart, for identifying factors that contribute to CHD, and for assessing the risk of developmental toxicity for new compounds. Human-based studies of embryogenesis have revealed numerous inter-species differences in pre-implantation, implantation, spatial relationship to extraembryonic tissues, gestational timing, and expression patterns of genes that are critical for the development of a fully functional heart.
Species-specific differences in genetics and gene expression
Genome-wide association studies indicate that 90–95% of CHD-associated genetic variants reside in the non-coding genome. However, many of these non-coding genomic regions show little evolutionary conservation between humans and model organisms. For instance, the 22q11.2 deletion DiGeorge syndrome involves haploinsufficiency of the DGCR8 gene, which is essential for miRNA processing. Comparative analysis of miRNA expressed in the heart of 20 species representative of all major vertebrate groups, including humans, macaques, dogs, and mice, has allowed to identify dozens of miRNA with expression profiles that are specific to a single species or a group of closely related species.
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Face validity - How well do animal models replicate the human congenital heart disease phenotype?
No single animal model, whatever the animal species and experimental method employed, faithfully recapitulates the phenotypes, heterogeneity, complexity and severity of human CHD.
Animal models of spontaneous CHD - Certain CHD types, such as DiGeorge and Williams syndrome, have not been naturally observed in animals. Other CHD were found to occur spontaneously in certain animal species, albeit at frequencies, presentations and responses to treatments that differ from humans. For example, naturally occurring CHD in dogs such as patent ductus arteriosus, pulmonary stenosis, and valvular aortic stenosis, show similarities to clinical features in humans. Yet, these similarities have, unfortunately, not translated to disease modifying treatments, neither for dogs nor for humans with valvular aortic stenosis.
Genetically-engineered animal models of CHD - Experimental methods that target genes involved in heart development and function, such as GATA4, NOTCH1, and TBX5, have succeeded in partially mimicking the phenotype of septal defects (ASD, VSD), outflow tract defects (TOF), and valve malformations (BAV) in mice. However, the full spectrum of human CHD presentations was not captured in this manner.
Chemically-induced animal models of CHD - Human thoracic aortic aneurysm (TAA) was modelled in animals by elastase, calcium chloride and angiotensin II induction. While some of the pathophysiological features of aneurysm may be partially mimicked, these chemically-induced TAA animal models do not fully reflect the human condition. For example, the hallmarks of human TAA, aortic thrombus, atherosclerosis, and rupture, are absent in calcium chloride-induced TAA animal models.
Surgically-induced animal models of CHD - In some instances surgical induction methods were employed to model CHD, such as by surgical creation of septal defects or by surgical altering of blood flow patterns. The response to surgical inductions were inconsistent across animal experiments, limiting the applicability of findings to humans.
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Construct validity - How well do the mechanisms of disease induction in animals reflect the currently understood etiology of human congenital heart disease?
Owing in great part to the lack of human relevance of experimental induction methods and to above mentioned species-specific features, the exact mechanisms responsible for CHD remain elusive.
Animal models of spontaneous CHD - Since the genetic, environmental, and epigenetic factors responsible for the formation of BAV differ between humans, hamsters, and mice, the exact mechanisms that underly BAV remain, understandably, unknown.
Genetically-engineered animal models of CHD - In many cases, the human CHD gene defects were not correctly modelled in animals, since they were genetically engineered as homozygous gene knockouts instead of heterozygous point or truncating mutations. Moreover, the human- and patient-specific complexity in genetics, genetic background, genetic origin of CHD, and combinatorial effect of multiple genes are not captured in mice.
Chemically-induced animal models of CHD - In STZ rodent models of pregestational diabetes-induced CHD, hyperglycemia is produced mainly through direct cytotoxic action on beta pancreatic cells rather than through a number of intermediate steps that lead to autoimmunity in T1DM. In addition, STZ does not allow to model insulin resistance and metabolic syndrome characteristic of T2DM. While angiotensin II infusion induced TAA, it was also found to cause aortic dissections.
Surgically-induced animal models of CHD - Surgical induction of CHD does not accurately replicate the multifactorial basis of human CHD, and is therefore unlike to provide human-relevant insights on CHD disease mechanisms.
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Predictive validity – How well do animal models predict safety and efficacy of therapies in patients with congenital heart disease?
Patients with CHD benefit from drugs that manage cardiac hypertension, pulmonary hypertension, arrhythmia and heart failure. Many drugs used to treat CHD are also used for patients with acquired heart diseases as some of the underlying mechanisms may overlap. These treatments often include diuretics, angiotensin-converting enzyme inhibitors, and negative inotrope beta-blockers.
Surgery is the mainstay of treatment for CHD. In many cases, such as Tetralogy of Fallot, transposition of the great arteries, and Ebstein's anomaly, surgical repair is the only definitive treatment. Depending on the complexity and severity of the defect type, the result of surgery can be curative, reparative or palliative. Surgery in patients that suffer from severely complex CHD forms, such as Eisenmenger syndrome, tricuspid atresia or single ventricle, does not fully correct the underlying defect, as consequence of which treated patients may have significant lifelong impairment of function.
Despite being necessary and lifesaving in many cases, surgical correction is not without risks for patients and can have long-term consequences. Even when surgical treatment corrects the anomaly, patients may still have late complications, requiring careful monitoring and adapted treatments.
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Ethical validity - How well do animal experiments align with human ethical principles?
Preclinical - Animal research is unethical in essence by human standards, since it involves physical constraint, psychological suffering and deprivation of freedom, social interactions, natural environment, and life purpose. In addition to this baseline, experiments inflict severe clinical harm in animals.
Clinical - Statistics consistently show that clinical success rates of drugs developed and tested in animals is very low, raising the question of whether it is ethical to put the health of patients at risk.
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Intrinsic validity - How well do animal models capture the clinical heterogeneity of human congenital heart disease?
Animal models of CHD do not recapitulate the human-specific inter-individual heterogeneity in clinical features and pathophysiology.
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Extrinsic validity - How well does animal experimentation generate reliable and reproducible outcomes?
In spite of significant investment in dissemination, various incentives and training of animal researchers, the ARRIVE - Animal Research: Reporting of In Vivo Experiments - guidelines remain poorly implemented and the majority of animal experiments irreproducible. While in vitro methods are not immune to issues of reproducibility, the moral weight of irreproducible animal studies is not the same.
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Key takeaways
Congenital heart disease (CHD) is characterized by structural heart defects present at birth. Depending on the complexity of structural lesions, CHD can have severe consequences on individuals' development, health, and lifespan.
Animal models of CHD do not faithfully recapitulate human-specific CHD phenotypes, heterogeneity, complexity and severity.
The multifactorial etiology of human CHD types is not captured in spontaneous, chemical, genetic and surgical animal models.
Inter-species differences in heart anatomy, development, electrophysiology, and gene expression represent a major barrier for understanding precise mechanisms that underpin individual CHD types.
While efforts to optimize clinical practice and perioperative care have resulted in small incremental improvements, they have not led to major advances in clinical outcomes for CHD patients. At the same time, the severity of animal experiments employed in the context of CHD modeling and treatment testing is high, frequently raising ethical concerns.
A better understanding of human-relevant risk factors and patient-specific disease mechanisms can further improve prevention, survival and quality of life of individuals with CHD.
How is human-based in vitro the answer to advance biomedical research into congenital heart disease?
The following section explores how researchers can leverage complex human-based in vitro technologies to ultimately improve the quality of life and survival of individuals with CHD. The list of over 20 examples and suggestions includes employing 3D bioprinting and microfluidic technologies to fabricate heart models with specific CHD defects, simulating conditions that mimic pregestational diabetes, phenylketonuria and autoimmune diseases to study the impact of maternal chronic diseases on CHD, assessing the risk of developmental toxicity for new chemicals and drugs, and testing the efficacy of combination treatments in CHD patient-specific tissues.
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