Aneurysms Caused by Connective Tissue Abnormalities

The primary structural proteins of connective tissue are collagen and elastin, which vary in type and amount within each of the body’s tissues; those constitutive of blood vessels are listed in Table 141.1 . A connective tissue disease is a genetic disease in which the primary target is either collagen or elastin protein assembly, disruption of which leads to an inherent predisposition to degeneration, loss of structural integrity, and consequent aneurysm formation or spontaneous vascular dissection and rupture. Although inflammation may affect these proteins and induce structural damage in some patients, such conditions often imply some element of autoimmune disorder and are termed collagen vascular diseases or mixed connective tissue diseases . Such conditions and arteriopathies related to the vascular tree, which are considered in Chapter 138 (Vasculitis and Other Uncommon Arteriopathies), may have genetic profiles that predispose to their development. Although clustering of aneurysms in multiple affected family members within these arteriopathies may indicate some element of an inheritance pattern, there are often greatly varying levels of expression and penetrance, and no defined genetic test is available to assist treatment. Herein we seek to define the common connective tissue diseases affecting the arterial tree, which have a studied natural history, a defined basis for genetic inheritance, and sufficiently understood pathophysiologic mechanisms to guide treatment paradigms. These “heritable disorders of connective tissue” have severe vascular manifestations, and most commonly include Marfan syndrome (MFS), the vascular type of Ehlers–Danlos syndrome (EDS IV or vEDS), Loeys–Dietz syndrome (LDS), and familial thoracic aortic aneurysm and dissection (TAAD).

TABLE 141.1

Structural Elements of Blood Vessels

Structural Proteins	Approximate Amount (% Dry Wt)	Function
Type I collagen	20–40	Fibrillar network
Type III collagen	20–40	Thin fibrils
Elastin, fibrillin	20–40	Elasticity
Type IV collagen, laminin	<5	Basal lamina
Types V and VI collagen	<2	Function unclear
Proteoglycans (>30 types)	<3	Resiliency

Marfan Syndrome

Antoine Bernard-Jean Marfan, a professor of pediatrics in Paris, in 1896 encountered a 5-year-old girl with congenital deformation of all four limbs. By the time she was 11 years old, thoracolumbar kyphoscoliosis, pectus carinatum, and signs of tuberculosis had developed. She died at age 16 from infection, and no autopsy was performed to document any vascular involvement. The first description of aortic pathology in MFS was published in 1943, a year after Marfan’s death. Although he correctly identified the many Mendelian features of the condition that would eventually bear his name, the pleiotropic disorder has benefited from decades of further description of clinical manifestations, molecular pathogenesis, and emerging therapeutic options.

Epidemiology and Natural History

The incidence of MFS is about 2 to 3 per 10,000 individuals, but this estimate relies on proper recognition of all affected and genetically predisposed individuals. A population-based study in Scotland found an incidence of 1 in 9802 live births, although this number would underestimate the true incidence inasmuch as the features of MFS, particularly the skeletal ones, become more apparent with growth. Furthermore, even though the disorder is passed as a dominant Mendelian trait, about 25% of cases are due to sporadic de novo mutations. The disease has no gender predisposition. Its incidence is increased in athletes, particularly in basketball and volleyball players, because the characteristic tall stature with long-bone overgrowth (dolichostenomelia) confers a competitive advantage. In a screening study of 415 high-school basketball and volleyball athletes performed with standard echocardiography, four (1%) of these subjects exhibited aortic root enlargement greater than 4.6 cm, and MFS was diagnosed in two.

The life span of individuals with MFS was significantly shortened before the widespread use and successful refinement of aortic root surgery. Before the adoption of thresholds for aortic root replacement, the cause of death was cardiovascular (aortic rupture, aortic dissection, or valvular disease) in 90% of cases at a mean of 38 years old. A report in the 1970s on the life expectancy of patients with MFS described longevity as only two-thirds that of unaffected individuals, with life-table mortality curves deviating in infancy. However, a later assessment of longevity in patients with MFS describes a nearly normal life expectancy as a result of improvement and refinement in diagnosis and treatment, particularly of the cardiovascular manifestations of the disorder.

Pathogenesis

As early as 1955 it was suggested that the basic structural defect in MFS was localized to the elastic fiber, with skin and aorta from affected patients showing decreased elastin content and fragmentation of elastic fibers. ^, Yet the elastin gene and molecule were poor targets to explain the clinical manifestations of MFS in tissues that are devoid of elastin, such as bone and the ciliary zonules in the eye. Further histochemical analysis demonstrated that the amorphous fragmented elastin tissues were surrounded by a rod-like material with a distinct staining pattern and distinguishable susceptibility to enzymatic digestion. ^, These so-called microfibrils are 10 to 14 nm in diameter and are constituents of all connective tissue. Sakai et al. first identified fibrillin-1 (FBN1) as the principal component of the extracellular matrix microfibril, present in all tissues with the phenotypic manifestations of MFS. Additional linkage analysis mapped the MFS locus to 15q21.1. The mutation is passed in an autosomal dominant manner with complete penetrance, so 50% of the offspring of an affected individual can inherit a genetic predisposition to the disorder.

Role of Fibrillin

The FBN1 gene encodes a large, 350-kD glycoprotein that is highly conserved among different species, thus suggesting its critical homeostatic importance. ^, These models demonstrated that normal FBN1 molecules are not needed to assemble an elastic fiber; rather, microfibrils are required to maintain normal elastic fibers during postnatal life. If proper connections among elastic fibers and vascular smooth muscle cells are not suitably maintained, aortic wall homeostasis is perturbed, and inflammation as well as calcification and structural weakening of elastic fibers may ensue. This pathology has been observed in large muscular arteries from patients with MFS, leading to appreciation of the classic lesion of cystic medial necrosis in large arteries of individuals with MFS. Verhoeff–van Gieson staining of elastic fibers in the aorta demonstrates classic lamellar disorganization in MFS secondary to errant elastic fiber maintenance ( Fig. 141.1 ).

Figure 141.1, ( A and B ) Photomicrographs illustrating the regular and parallel nature of the elastic lamellae found within the media of the normal ascending aorta. The lamellae are composed of elastic fibers running in parallel with intervening smooth muscle, ground substance, and collagen. The Verhoeff–van Gieson (VVG) stain highlights these major elastic fibers (black) (A, hematoxylin-eosin [H&E], ×100; B, VVG, ×100). ( C and D ) Photomicrographs showing profound fragmentation of the elastic fibers, with spaces left within the media of the ascending aorta. Though often referred to as cystic medial degeneration, the spaces created by this fragmentation lack a lining and hence are not truly “cysts.” These spaces often contain increased amounts of glycoproteins. The VVG stain further highlights the severe elastic fiber (black) fragmentation. The vertical black lines are fixation artifacts from folding of the elastic sheet (C, H&E; D, VVG).

Interaction with Transforming Growth Factor

The discovery of the role of microfibrils in regulating cytokines has further advanced our understanding of the pathogenesis of MFS and raised the possibility of a new treatment paradigm. FBN1 shares a high degree of homology with the latent transforming growth factor-β (TGF-β)–binding proteins. The TGF-β cytokines are secreted as large latent complexes consisting of TGF-β, a latency-associated peptide, and one of three latent TGF-β-binding proteins ( Fig. 141.2 ). In normal trafficking, the large latent complex is sequestered and bound to microfibrils, and TGF-β cytokine signaling is prevented. As depicted in Figure 141.2 , without proper microfibrils, the TGF-β complex cannot form, thereby leaving TGF-β in the milieu to incite excess signaling. This pathogenetic mechanism of dysregulated TGF-β activity seems more plausible in explaining the clinical features of MFS that are poorly reconciled with structural failure, such as long-bone overgrowth, craniofacial abnormalities, and muscle hypoplasia. ^,

Figure 141.2, Excess activation of transforming growth factor-β (TGF-β) causes many of the features of Marfan syndrome. Normal TGF-β metabolism requires binding of the cytokine to several proteins, including microfibrils, to prevent excess signaling. In Marfan syndrome, lack of normal microfibrillar assembly allows TGF-β to remain unsequestered in the extracellular space. As a consequence, excess TGF-β signaling can occur on the cell surfaces of TGF-β receptors. Once the TGF-β binds to its receptor, downstream receptor–associated SMAD proteins translocate to the nucleus to modulate transcriptional activity, alter protein expression, and yield phenotypic change .

Clinical Manifestations and Diagnostic Evaluation

MFS is a multisystem disorder with manifestations principally within the cardiovascular, ocular, and skeletal systems. The disorder occurs worldwide, with no gender or race predilection. However, the cardinal manifestation of aortic root aneurysm and its risk of life-threatening aortic dissection or rupture can lead to a shortened life expectancy. Consequently the leading cause of mortality has been cardiovascular in more than 90% of cases (aortic dissection, valve disease, or congestive heart failure), which decreased life expectancy to approximately two-thirds that of unaffected individuals. Improvements in the recognition of MFS and surgical advances have returned life expectancy to the nearly normal range by addressing the most threatening manifestations of MFS – aortic catastrophe in the form of dissection or rupture of the ascending aorta.

Diagnostic Criteria

Ghent criteria

Clinical diagnostic criteria for MFS were outlined at the International Nosology of Heritable Connective Tissue Disorders in 1986 during the Connective Tissue Meeting in Berlin. Thereafter, the recognition that many individuals diagnosed by means of these original criteria did not have the FBN1 mutation (genetic testing became possible after 1986) led to a focused revision in 1996 and another in 2010. ^, Termed the Ghent criteria, the current nosology places emphasis on the cardinal manifestations of the syndrome, namely aortic root aneurysm, ectopia lentis, and genetic testing , versus the less predictive skeletal findings ( Box 141.1 ). Previously it was estimated that 10% of MFS causing mutations were missed by conventional screening methods ; however, with the advent of next generation sequencing (NGS) even small deletions, duplications and variants of unknown significance in a panel of known aortopathy genes can be detected. The diagnosis of MFS continues to rest primarily on physical clinical assessment based on the Ghent criteria but with increasing availability of highly sensitive genetic testing, more patients are able to obtain a genotypic diagnosis as well. Once MFS is diagnosed in an individual, all first-degree relatives should be evaluated for the presence of the condition. In children, repeated evaluations may be required to avoid missing the disorder in its evolution.

BOX 141.1

2010 Revised Ghent Criteria for the Diagnosis of Marfan Syndrome and Related Disorders

Ao, aortic diameter at the sinuses of Valsalva above indicated Z-score or aortic root dissection; EL, ectopia lentis; ELS, ectopia lentis syndrome; FBN1, fibrillin-1 mutation (as defined in Box 141.2 ); FBN1 not known with Ao, FBN1 mutation that has not previously been associated with aortic root aneurysm dissection; FBN1 with known Ao, FBN1 mutation that has been identified in an individual with aortic aneurysm; MASS, myopia, mitral valve prolapsed, borderline Z-score (<2) aortic root dilatation, striae, skeletal findings; MFS, Marfan syndrome; MVPS, mitral valve prolapsed syndrome; Systemic, systemic score (see Box 141.4 ); and Z, Z-score.

In the absence of family history:

1.
Ao (Z >2) AND EL = MFS
2.
Ao (Z >2) and FBN1 = MFS
3.
Ao (Z >2) and systemic score (>7 pts) = MFS
4.
EL and FBN1 with known Ao = MFS
EL with or without systemic and with an FBN1 not known with Ao or no FBN1 = ELS
Ao (Z <2) and systemic (>5 with at least one skeletal feature) without EL + MASS
MVP and Ao (Z > 2) and systemic (<5) without EL = MVPS

In the presence of family history:

1.
EL and FH of MFS (as defined above) = MFS
2.
Systemic (>7) and FH of MFS (as defined above) = MFS
3.
Ao (Z >2) above 20 years old, >3 below 20 years old + FH of MFS (as defined above) = MFS
Caveat: without discriminating features of SGS, LDS, VEDS and TGFBR1/2, collagen biochemistry, COL 3A1 testing as indicated. Other conditions/genes will emerge over time.

BOX 141.2

Criteria for Causal FBN1 Mutation

Mutation previously shown to segregate in Marfan family
De novo (with proven paternity and absence of disease in parents) mutation (one of the five following categories):
- o
  Nonsense mutation
- o
  In-frame and out-of-frame deletion/insertion
- o
  Splice-site mutations affecting canonical splice sequence or shown to alter splicing on messenger RNA/complementary DNA level
- o
  Missense mutation affecting/creating cysteine residues
- o
  Missense mutation affecting conserved residues of epidermal growth factor consensus sequence
Other missense mutations: segregation in family if possible + absence in 400 ethnically matched control chromosomes; if no family history, absence in 400 ethnically matched control chromosomes
Linkage of haplotype for n >6 meioses to the FBN1 locus.

Differential Diagnosis

Other conditions also associated with FBN1 mutations may be considered in the differential diagnosis of MFS. The MASS phenotype is based on the association of m itral valve prolapse, myopia, mild a ortic root dilatation, s triae, and mild s keletal changes. The skeletal features of MASS often include the mild manifestations of tall stature, mild dolichostenomelia (long-bone growth), and scoliosis. Occasionally, a major Ghent criterion from the skeletal system may be met but no other major criteria are noted. For patients with MASS, mutations in the FBN1 gene have generally created premature termination codons, and the mutant transcript can be easily and rapidly degraded.

Shprintzen–Goldberg syndrome is characterized by cra-niosynostosis, facial hypoplasia, anterior chest deformity, arachnodactyly (long, spider-like fingers), and aortic root dilatation. In contrast to MFS, developmental delay is common in Shprintzen–Goldberg. Point mutations in the SKI gene, which codes for a component protein of the TGF-β signaling pathway, and FBN1 have been found in some affected individuals, but phenotypic heterogeneity, specifically regarding development, intellectual disability, and aortic root involvement, probably indicates substantial genotypic variation. ^, The aortic root enlargement in Shprintzen–Goldberg syndrome is similar to that in MFS.

Homocystinuria is caused by a deficiency of cystathionine β-synthase. Patients with homocystinuria often have tall stature, long-bone overgrowth, and ectopia lentis but no aortic enlargement. Plasma homocysteine values are typically markedly elevated, easily distinguishing this disease from MFS. Congenital contractural arachnodactyly (CCA) shares many skeletal features with MFS but without the ocular and cardiovascular manifestations. The mutation in the few patients reported in the literature is located in the FBN2 gene, and physical therapy is key to maintaining joint range of motion.

The overlap of LDS and MFS is considered later in this chapter.

Surveillance

MFS is a pleiotropic disorder, and surveillance of the many systems at risk for abnormality is prudent. Regular examinations by an ophthalmologist for slit-lamp testing, a cardiologist for imaging of the aortic root, and an orthopedist for the development of scoliosis should be performed on an annual basis. In this section, focus is placed on aortic and vascular pathology. For recommendations with regard to the other body systems, the reader may find useful information at the National Marfan Foundation website ( www.marfan.org ). The clinical manifestations within the cardiovascular system that require preventive attention involve the atrioventricular valves, the annuloaortic valve mechanism, and the aortic root and ascending aorta.

Aortic Disease

Aortic aneurysm and dissection are the most life-threatening manifestations of MFS. The threat depends on age, with rupture and dissection rates increasing as the aortic root dilates. ^, Because root dilatation at the sinuses of Valsalva can begin in utero , lifelong transthoracic echocardiographic monitoring is needed. For patients in whom the aortic root and ascending aorta are poorly visualized as a result of anterior chest deformity, computed tomographic angiography or magnetic resonance angiography (to avoid radiation exposure) is a viable substitute. Absolute thresholds for replacement of the aortic root in children have not been established, given the observation that dissection is very rare in the young. However, if the aortic root is noted to grow more than 1 cm over consecutive annual assessments or if significant aortic regurgitation is present, early surgery may be necessary. In children and teenagers, a nomogram reflects the number of standard deviations of the patient’s aortic root from the mean aortic root diameter in the population and is termed a Z-score . If the child’s Z-score deviates rapidly from that of the population (>2 to 3 SD) under surveillance, aortic root repair may be justified to prevent rupture. In adults, surgical repair of the aortic root and ascending aorta to prevent aortic rupture and dissection is recommended when its greatest diameter exceeds 50 mm. ^, Earlier intervention may be warranted with a family history of aortic dissection at lesser diameters.

Prevention

Lifestyle modifications are routinely recommended once the diagnosis of MFS is established. On the basis of data from the United States, genetic cardiovascular diseases account for 40% of deaths in young athletes. ^, A consensus document states that “burst” or Valsalva-inducing exertions such as sprinting, weightlifting, basketball, and soccer should generally be avoided. Favored are sports in which energy expenditure is stable and consistent over long periods, such as recreational jogging, biking, and lap swimming. Importantly, litigation results suggest that physician reliance on consensus statements to determine medically reasonable levels of activity in patients with cardiovascular abnormalities is appropriate.

Medical Treatment

Medical treatment with β-adrenergic receptor blockade to delay aortic root growth or prevent aortic dissection in patients with MFS is currently considered a standard of care. ^, General recommendations are a resting heart rate lower than 70 beats per minute and a heart rate less than 100 beats per minute with submaximal exercise. The rationale for this treatment paradigm is focused on decreasing proximal aortic shear stress and dP/dt. The only randomized trial assessing the effect of beta blockade treated 70 patients, 32 of whom received titrated dosages of propranolol to maintain a heart rate of ∼100 beats/min during exercise and were monitored with serial echocardiograms correlated with age, height, and weight over a mean follow-up of 7 years. Fewer patients in the propranolol-treated group reached the primary endpoint of aortic regurgitation, aortic dissection, surgery, heart failure, or death (5 in treatment group versus 9 in control group). Aortic growth after normalization was lower in the propranolol-treated group (0.023 cm/year) than in the control group (0.084 cm/year, P <0.001). For patients with increased body weight or an end-diastolic aortic diameter greater than 40 mm, the response to beta blockade was worse, thus suggesting that beta-blockers must be given at an adequate doses and early in the course of the disorder to optimize benefit. ^, Unfortunately beta blockade is poorly tolerated by some patients, with approximately 10%–20% of patients intolerant due to asthma, fatigue, or depression.

In 2006, losartan, a U.S. Food and Drug Administration–approved antihypertensive medication and selective angiotensin II receptor blocker (ARB), was demonstrated to inhibit aortic aneurysm in murine models of MFS, identifying a potential new medical treatment paradigm. The feedback mechanisms by which losartan inhibits TGF-β signaling in the aortic wall are likely multiple and remain incompletely understood. A multicenter trial comparing beta blockade and losartan therapy for control of aortic root growth in children and young adults with MFS was conducted, which demonstrated equivalency of losartan both in stabilizing aortic dilation rates and preventing adverse clinical events at 3 and 5 years. ^, Retrospective data analysis of a large MFS cohort suggests that losartan therapy is associated with a statistically and clinically significant reduction in the risk of type B aortic dissection. Currently no recommendations exist regarding the superiority of either beta blockade or ARBs in MFS; however, some patients may tolerate one better than the other. While calcium channel blockers were historically used as an alternate blood pressure control method in MFS patients unable to tolerate ARBs or beta blockade, evidence from a murine model of MFS suggest these may paradoxically accelerate aneurysm growth and we tend to avoid these in our practice.

Surgical Treatment

The traditional threshold for prophylactic surgical repair of the aortic root is 5 cm in patients with MFS. Operations on the arterial tree outside the ascending aorta have been reported ( Fig. 141.3 ) and can have acceptable outcomes. Indeed, as the life expectancy of individuals affected by MFS has increased with prophylactic root replacement, it is plausible that the remaining aorta or other large arteries may progress to require repair in the absence of antecedent dissection. For aortic arch and descending thoracic or thoracoabdominal aneurysms, standard criteria for repair generally follow that of atherosclerotic aneurysms – a threshold of 5.5 to 6.0 cm.

Figure 141.3, Distribution of vascular repairs in 300 patients with Marfan syndrome.

Descending Thoracic and Thoracoabdominal Aorta

The first successful replacement of the thoracoabdominal aorta in a patient with MFS was performed by Crawford in the 1980s. Elective surgical repair of descending thoracic aortic aneurysm and thoracoabdominal aortic aneurysms (TAAAs) in MFS has benefited from the general refinements and the introduction of adjuncts to reduce spinal cord injury and other major complications in a manner similar to standard atherosclerotic aneurysms (see Ch. 79 , Thoracic and Thoracoabdominal Aneurysms: Open Surgical Treatment). Prophylactic aortic replacement is indicated when the aortic diameter reaches 5.5 to 6.0 cm or if symptoms related to the aneurysm occur. Because of the frequent involvement of the descending and thoracoabdominal aorta with aneurysms of chronic dissection etiology, the extent of repairs in MFS tend to be greater than that of atherosclerotic aneurysms, with 42% to 78% of all MFS TAAAs being DeBakey type II. Paraparesis and paraplegia rates after TAAA repair in MFS compare favorably with those without connective tissue disease when matched for the extent of repair required. Because of the very young mean age of patients with MFS undergoing TAAA repair versus the older mean age of patients with degenerative TAAA, overall long-term survival was better for those with MFS.

Given the preponderance of type II TAAA repairs in the available series, the rate of freedom from further aortic repair is high because little aorta remains to degenerate. However, secondary aortic procedures after TAAA repair in patients with MFS are often performed for pseudoaneurysm or for aneurysmal degeneration of the inclusion or Carrel patch ( Fig. 141.4 ). Indeed, in the series reported by Lemaire et al., 95% of reoperations (19 of 20) after previous TAAA repair ( n = 178) in patients with MFS were performed for visceral patch aneurysm. In our series of 107 patients who underwent TAAA repair, including creation of visceral patches, 17 were known to have a connective tissue disease. With a mean time to diagnosis of 6.5 years, 3 of these 17 patients (17.6%) were found to have aneurysmal degeneration of the visceral patch. By comparison, visceral patch aneurysms were noted after only 5.6% of atherosclerotic TAAA repairs. All of these patients with MFS had inclusion patches that encompassed the celiac axis, superior mesenteric artery, and both renal arteries, thus suggesting that the visceral patch should have been much smaller in all patients with connective tissue diseases to prevent late degeneration. I, along with many surgeons, avoid patch inclusion entirely and use a prefabricated four-branch graft to perform individual bypasses to the renal and visceral aortic branches, which we have shown to have excellent long-term patency in connective tissue patients, superior to that of the degenerative population. Intercostal inclusion patches can be limited also, but those that degenerate to aneurysm may be treated with stent-graft therapy, although paraplegia concerns are paramount. Given the morbidity associated with repair of the patch aneurysm (2 intraoperative deaths in 5 patients taken to the operating room), Dardik et al. recommend maintaining an indication for repair of 6.0 cm or larger.

Figure 141.4, Ten-centimeter visceral patch aneurysm 7.5 years after a type II thoracoabdominal aortic aneurysm repair in a 48-year-old woman with Marfan syndrome. A hybrid open/endovascular stent-graft approach was used to repair the region. VRT reconstruction (left) ; lateral view demonstrating effacement of distance between superior mesenteric artery and celiac axis (right) .

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