Abstract
In recent years there has been a growing awareness of and focus on connective tissue diseases (CTDs) and associated cardiovascular pathology, particularly in children. These diseases are hereditary disorders of the connective tissues of the body. Many CTDs impose risk of structural heart defects, including patent ductus arteriosus, bicuspid aortic valve, coarctation of the aorta, and atrioventricular valve disease.
Children with CTDs are prone to aortic dissection, aneurysm, and aortic rupture, and in fact, aortic dissection is the primary cause of morbidity and mortality in the most common CTDs.
Advances in genetic analysis have had a significant impact on the identification and management of children with CTDs, providing a better understanding of their cause and phenotypes, improving management strategies, and offering insights into long-term prognosis. In this chapter we provide a description of the most common CTDs that affect the pediatric population and their associated cardiovascular pathology.
Key words
connective tissue disorder, aneurysm, valve-sparing procedures, aortic valve disease, mitral valve disease, angiotensin receptor blocker, transforming growth factor-beta
The genetic basis for heart and vascular conditions is heterogeneous and includes both heritable and de novo mutations. More than 100 genes associated with congenital or progressive cardiovascular abnormalities have thus far been identified. In recent years there has been a growing awareness of and focus on connective tissue diseases (CTDs) and associated cardiovascular pathology, particularly in children. These diseases are hereditary disorders of the connective tissues of the body. Connective tissues are biologic tissues with an extracellular matrix (ECM) that serve to support and bind structures and organs across numerous systems. The ECM is a highly organized multimolecular structure that is essential for normal arterial tortuosity and aneurysm formation, with a risk of subsequent vascular (i.e., aorta and carotid artery) dissection and rupture. Furthermore, many CTDs also impose risk of structural heart defects, including patent ductus arteriosus (PDA), bicuspid aortic valve, coarctation of the aorta, and atrioventricular valve disease.
Children with CTDs are prone to aortic dissection, aneurysm, and aortic rupture. In fact, aortic dissection is the primary cause of morbidity and mortality in the most common CTDs. Although incidences of cardiovascular manifestations vary by disease type, mortality following aortic catastrophe in these patients is exceptionally high, with up to 40% of pediatric patients dying immediately and 1% to 3% expiring every hour in the first 24 hours following the initial event. Should the child reach the operating room alive, operative mortality as high as 25% has been reported. In response to these devastating statistics, various medical and surgical strategies have been developed to mitigate the risk of cardiovascular catastrophe by means of prophylactic intervention.
Advances in genetic analysis have had a significant impact on the identification and management of children with CTDs, providing a better understanding of the cause and phenotypes of disease, improving management strategies, and offering insights into long-term prognosis. In this chapter we provide a description of the most common CTDs that affect the pediatric population and their associated cardiovascular pathology. We will focus on the most common forms of cardiovascular phenotype (namely proximal aortic pathology and mitral valve disease) to define surgical indications and operative management.
Diagnostic Syndromes and Associated Heart Disease
The most common CTDs affecting the cardiovascular system include Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), Ehlers-Danlos syndrome (EDS), osteogenesis imperfecta (OI), and other nonsyndromic conditions such as familial thoracic aortic aneurysmal disease. All CTDs carry varying degrees of risk for aortic dissection and other cardiovascular pathology and, as such, require close surveillance and management to avert the risk of cardiovascular catastrophe. Patients with CTDs and proximal aortic aneurysms will often require aortic root replacement (ARR) to prevent aortic dissection or rupture, often warranting surgical intervention at an early age. Although children and young adults with bicuspid aortic valves, conotruncal abnormalities, Turner syndrome, and other anomalies may need surgical replacement of the proximal aorta, they do not fall into the CTD syndromes described herein.
Marfan Syndrome
First described in 1896, MFS is an inherited disorder resulting from mutations in the FBN1 gene and most commonly affects the ocular, skeletal, and cardiovascular systems. Although the syndrome is most commonly inherited in an autosomal dominant pattern, approximately 25% of cases result from de novo mutations. MFS has a prevalence of 1 in 5,000 to 10,000. The syndrome is characterized by a high degree of clinical variability, although ocular, cardiovascular, and skeletal manifestation are the true hallmark of this disorder.
Up to 90% of patients with a clinical diagnosis of MFS have mutations in FBN1, a gene that codes for fibrillin 1. Fibrillin 1 is a structural component of ECM microfibrils that provide mechanical stability and critical elastic properties to connective tissues. Furthermore, more recent studies suggest that the fibrillin-deficient state of MFS leads to upregulation of the effects of the cytokine transforming growth factor beta (TGFβ), which then results in dysregulation of this signaling cascade. This derangement in signaling is thought to be responsible for the diverse and variable phenotypic expression of the disease. Several hundred FBN1 mutations responsible for altered fibrillin 1 structure have been reported, although no major correlation between the specific mutation and subsequent phenotypic manifestations have been identified. Furthermore, clinical variability exists even in patients with identical genotypic mutations, suggesting a potential role of modifier genes in the phenotypic expression of MFS.
The clinical diagnosis of MFS is based on the revised Ghent criteria ( Box 53.1 ). These diagnostic criteria place a greater emphasis on cardiovascular manifestations than was done previously. The cardinal features of MFS based on the Ghent nosology are aortic root aneurysms and ectopia lentis. In the absence of family history the presence of these two clinical manifestations is alone sufficient for the diagnosis of MFS. In the absence of either aortic root aneurysm or ectopia lentis the presence of an FBN1 mutation or a combination of systemic score of 7 or higher and family history of FMS is sufficient for diagnosis. With a positive family history an isolated finding of ectopia lentis, aortic root enlargement, or a systemic score of 7 or higher suffices for diagnosis.
In the Absence of Family History
- 1.
Ao z score ≥2 AND ectopia lentis = MFS
- 2.
Ao z score ≥2 AND fibrillin 1 mutation = MFS
- 3.
Ao z score ≥2 AND systemic score ≥7 = MFS
- 4.
Ectopia lentis AND fibrillin 1 mutation = MFS
In the Presence of Family History
- 1.
Ectopia lentis and a family history of MFS = MFS
- 2.
Systemic score ≥7 and family history of MFS = MFS
- 3.
Ao z score ≥2 (above 20 years of age), ≥3 (below 20 years of age) and family history of MFS = MFS
Ao, Aortic diameter at the sinuses of Valsalva above the indicated z score or aortic dissection; MFS, Marfan syndrome.
Cardiovascular pathology is the leading cause of morbidity and early mortality in MFS. The most prominent cardiovascular manifestations of MFS are mitral valve prolapse and aortic dilation. Mitral valve prolapse in MFS is thought to develop as a result of fibromyxomatous changes in the leaflets and chordae tendineae, calcification of the annulus, abnormal annular compliance and distensibility, and, in some cases, mitral valve enlargement. These abnormalities result in prolapse of leaflets followed by mitral regurgitation (MR) and in severe cases, rupture of chordae tendineae. Mitral valve pathology is the most common structural heart pathology encountered in MFS, but tricuspid valve prolapse, dilation of the proximal pulmonary artery, (supra)ventricular arrhythmias, and impaired systolic and diastolic left ventricular (LV) function are not uncommon. FBN1 mutations also lead to arterial aneurysm formation, particularly of the ascending aorta. Although the walls of the entire arterial tree are weakened, dilation most commonly occurs at the sinuses of Valsalva. As the weakened proximal aorta dilates, aortic valve leaflet coaptation diminishes, and central regurgitation ensues. Eccentric regurgitation is seen when asymmetric enlargement of the root or cusp prolapse develops. These changes in the proximal aorta make aortic pathology the leading cause of mortality in MFS.
Although most patients with MFS present in late childhood or adolescence, a more severe form of MFS (infantile MFS) has been described. Infantile MFS typically presents with early onset of cardiovascular disease as well as severe skeletal manifestations, chest wall deformities, arachnodactyly, hyperextensible joints, micrognathia, and various ocular pathologies. The most salient and life-threatening feature of infantile MFS is its aggressive vascular phenotype. As many as 61% of infants with this syndrome will have substantial cardiac abnormalities, with the most common being mitral valve prolapse and annular enlargement; these can in turn result in severe congestive heart failure, with failure to thrive and ventilator dependance. In early series investigating infantile MFS, mitral valve prolapse was identified on echocardiography in the majority of these children, with almost all of these progressing to various degrees of MR. Thirty percent of these children will also manifest substantial proximal aortic root dilation.
Nonsurgical cardiovascular management of MFS typically focuses on close follow-up of the vascular tree, aimed at monitoring of aortic diameters and prevention of dissection or rupture. In addition, medical management with losartan and beta-blockers is part of the routine long-term nonsurgical management strategy. Longitudinal imaging, afterload reduction, and congestive heart failure management are the cornerstone of medical therapy of mitral valve regurgitation, which remains the most common structural abnormality in these patients. Guidelines for cardiovascular surveillance, indications for surgical intervention, and clinical follow-up strategies will be discussed later.
Over the past five decades, the life span of patients with MFS has markedly improved largely due to advances in both medical and surgical management of the cardiovascular manifestations of the disease. With appropriate medical and, when necessary, surgical intervention the life expectancy of patients with MFS approaches that of the general population. However, this improvement in outcome is maximized when the patient receives comprehensive cardiovascular care by a multidisciplinary team with extensive knowledge and experience in the care of patients with CTDs.
Loeys-Dietz Syndrome
LDS is an autosomal dominant CTD characterized by aortic aneurysms and generalized arterial tortuosity, hypertelorism, and bifid/broad uvula or cleft palate. It was first described in 2005. Although the clinical features of this disorder share some similarities with MFS, LDS is caused by mutations in the genes encoding the transforming growth factor beta receptor 1 (TGFBR1) or 2 (TGFBR2) . Additional syndromic features may include craniosynostosis, Chiari malformation, clubfeet, PDA, and the potential for aneurysmal enlargement or dissection throughout the arterial tree. In contrast to MFS, LDS less commonly presents with long bone overgrowth or lens dislocation. Additionally, aortic aneurysms in LDS tend to have accelerated growth when compared to those observed in MFS. As a consequence of this highly malignant vascular phenotype, children with LDS tend to present for surgical intervention at a younger age.
LDS results from mutations in the mothers against decapentaplegic homolog 3 (SMAD3) gene and the transforming growth factor beta 2 ligand gene (TGFB2) , which lead in turn to anomalies of TGFBR1 and/or TGFBR2. Chromosome deletions are responsible for these malformations, and the size of the microdeletion is thought to correlate with the broad spectrum of clinical presentation in LDS. Although LDS can be divided into four types based on the specific mutation, significant clinical variability exists within and between individuals of each type, and therefore guidelines for management and treatment are similar across all types.
The main organ systems affected in LDS include skeletal, craniofacial, cutaneous, and cardiovascular. Indications for surgical intervention will be detailed in subsequent sections, but as compared to MFS, arterial dissection can occur at diameters smaller than those observed in MFS, implying a need for earlier surgical intervention in LDS. Arterial tortuosity is observed throughout the entire arterial tree, and resulting complications may occur at any location. As a result, frequent and comprehensive surveillance as well as early surgical intervention is warranted.
Originally LDS patients were categorized into two types, depending on the prevalence and severity of craniofacial (type 1) or cutaneous (type 2) features. However, more recently, four types of LDS have been described based on genotype ( Table 53.1 ). LDS types 1 and 2 have significant craniofacial anomalies and also the most severe cardiovascular manifestations of disease. Type 4 is the least severe form of LDS in terms of risk of cardiovascular catastrophe. The various subtypes of LDS, associated genetic mutations, and phenotype characteristics are summarized in Table 53.1 .
| LDS Subtype | Gene | Other Disorders Reported |
|---|---|---|
| 1 | TGFBR1 | Thoracic aortic aneurysm and dissection |
| 2 | TGFBR2 | Thoracic aortic aneurysm and dissection, Marfan syndrome type 2 |
| 3 | SMAD3 | Aneurysms-osteoarthritis syndrome |
| 4 | TGFB2 | Aortic and cerebral aneurysm, arterial tortuosity, and skeletal manifestations |
Rapidly progressive aortic aneurysmal disease is a distinctive feature of LDS and can involve the ascending or descending aorta. Aortic dissection has been reported in children as young as 3 months. In fact, the initial reports of LDS types 1 and 2 described a mean age of death of 26.1 years, with aortic dissection and cerebral hemorrhage as the primary causes of death. Although improvements in diagnosis, surveillance, and early interventions have improved the life span of affected individuals, the severity of the cardiovascular manifestations of LDS cannot be overstated. Congenital heart defects such as bicuspid aortic valve, atrial septal defects, and PDA are more commonly seen in children with LDS types 1 and 2 when compared with the general population. In addition to mitral valve prolapse and dysfunction, pulmonary root dilation and tricuspid valve regurgitation have been observed. Of note, children with LDS may require aortic or mitral valve interventions even without presence of aortic root dilation, given the severity of structural valve disease. Atrial fibrillation, ventricular hypertrophy, ventricular arrhythmias, and heart failure have also been described.
In view of the vast cardiovascular expressions of disease, individuals diagnosed with LDS require echocardiography at frequent intervals (every 6 to 12 months) to monitor the status of heart valves, aortic root, and ascending aorta. Additionally, frequent imaging with magnetic resonance angiography (MRA) or computed tomography angiography (CTA) with three-dimensional reconstruction is recommended to monitor the entire arterial tree for aneurysmal enlargement and dissection. Although MRA and CTA may expose the patient to ionizing radiation and anesthesia, serial imaging is critical to prevention of cardiovascular catastrophe. Many advocate for surveillance CTA or MRA every 1 to 2 years depending on severity of disease. Cameron et al. reported that 33% of their originally reported surgical cohort of LDS 1 and 2 required multiple vascular surgical interventions, highlighting the need for judicious, lifelong surveillance.
Management of children with LDS mirrors that of children with MFS and is summarized in Box 53.2 . However, given the aggressive nature of disease, thresholds for intervention tend to be lower than with MFS. Well-defined guidelines for surgical intervention are limited and vary slightly based on the type of LDS and the severity of disease. Aortic dissections have been reported in individuals with maximal aortic diameters of less than 4.0 cm in LDS types 1, 2, or 3 and at less than 5.9 cm in LDS type 4. Therefore, given the aggressive nature of the disease and relatively low rate of complications with proximal aortic surgery in experienced centers, ARR is indicated when the root diameter reaches a threshold of 4.0 cm for LDS types 1 and 2. In children with LDS type 3, which is caused by mutations in SMAD3 and is moderately aggressive, ARR is recommended for aneurysms between 4.0 and 4.5 cm in size. LDS type 4 is the mildest phenotype, and therefore the threshold for intervention is slightly higher at 4.5 cm. Additionally, aneurysmal growth of greater than 0.5 cm/y warrants surgical intervention. However, regardless of type in these children, those with a concerning family history of aortic catastrophe and severe craniofacial features may warrant earlier intervention.
Yearly echocardiography; shorter intervals depending on the extent of aortic disease
Angiotensin-receptor blockade, beta-blocker, or angiotensin-converting enzyme inhibitor for strict blood pressure control
Avoidance of contact/competitive sports, isometric exercises, strenuous exercise, blows to head/chest
Avoidance of stimulants and vasoconstrictors
Subacute bacterial endocarditis prophylaxis in those with artificial valves
Cardiac surgery consultation when surgical thresholds for intervention are approaching
Ehlers-Danlos Syndrome
EDS is inherited in an autosomal dominant pattern, affecting collagen synthesis with an estimated prevalence of 1 in 5000. To date, six major subtypes of EDS have been described (Villefranche nosology). Vascular EDS, also known as type IV EDS, results from mutations in the COL3A1 gene, which affects type III collagen synthesis. Characteristic features of vascular EDS include thin, translucent skin; characteristic facial appearance (large eyes, small chin, sunken cheeks, thin nose and lips, lobeless ears); vascular fragility demonstrated by extensive bruising; easy bleeding; and spontaneous arterial, intestinal, or uterine rupture. Cardiovascular manifestations of EDS include arterial aneurysms at any location throughout the arterial tree, mitral valve dysfunction, and venous malformations. The diagnosis of type IV EDS is based on clinical findings and confirmed by genetic analysis for the causative mutation or by identification of abnormal type III collagen synthesis.
The most common cause of death in EDS is secondary to aortic aneurysms and subsequent dissection or rupture, typically occurring in adulthood, with nearly 50% of all deaths in patients with type IV EDS attributable to aortic aneurysms. Similar to MFS and LDS, management strategies are dictated by the presence of aortic aneurysms and/or structural heart disease. Indications for surgical intervention are discussed later and are similar to those for patients with MFS. Given the severity of this subtype of EDS, long-term follow-up is required, with frequent imaging surveillance of the heart, aorta, and arterial tree.
Osteogenesis Imperfecta
OI is a group of CTDs caused by a defective synthesis of collagen type I. Cardinal clinical features include blue sclerae, pathologic long bone fractures, conductive and sensorineural hearing loss, and dental abnormalities. Although cardiovascular involvement is a less common feature of OI, up to 12% of patients may have pathology of the left-sided heart valves and enlargement of the proximal aorta. Mitral valve prolapse, for example, is present in up to 7% of patients with OI, and aortic regurgitation has been documented in up to 10% of these patients. Although data are limited, cardiac surgery in OI patients portends worse outcomes compared with patients without CTDs, with mortality rates as high as 15% to 25% in some series. Furthermore, as with other CTDs, tissue fragility leads to excessive bleeding and increased transfusion requirements in these patients as well as increased difficulty with valve repair. Screening with echocardiography in patients with OI should be considered to identify patients with valvular pathology or enlarged proximal aortas. Medical and surgical intervention guidelines are not well defined, but, given the nature of the disease, management guidelines similar to those previously described for CTDs are recommended.
Surgical Indications
Clinical indications for surgical interventions in children with CTDs vary based not only on type of disease but, in some cases, also on institutional guidelines. Although evidence exists for the management of more common CTDs, many have ill-defined surgical indications, and as such, surgeon- and center-specific preferences have emerged. In this section, indications for surgical intervention in proximal aortic aneurysms as well as mitral valve pathology in children with CTDs will be described.
Aortic Root Aneurysms
Indications for ARR in asymptomatic children are summarized in Table 53.2 . Clearly these indications change in those children who present with symptoms, aortic dissection, rupture, or substantial pathology of the aortic valve.
| Diagnosis | Criteria for VSRR in Children |
|---|---|
| Marfan syndrome |
|
| Loeys-Dietz syndrome | |
| Maximal diameter of >3.5-4.0 cm Increase in diameter of >0.5 cm/y Severe craniofacial features |
| Maximal diameter of >4.0-4.5 cm Increase in diameter of >0.5 cm/y |
| Maximal diameter of >4.5 cm Increase in diameter of >0.5 cm/y |
| Bicuspid aortic valve | Maximal diameter >5.5 cm |
| Nonsyndromic thoracic aortic aneurysms | Maximal diameter >5.5 cm |
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