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13 Pathophysiology andPrinciples ofManagement ofHereditary Aneurysmal…

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different TGF-β ligands exist in humans, TGF-β1, TGF-β2 and TGF-β3 encoded by their respective TGFB1, TGFB2 and TGFB3 genes and exert a similar biological activity. TGF-β ligands are secreted as part of a tripartite large latent complex, composed of the mature TGF-β dimer, a propeptide dimer of its processed amino terminal propeptide (latency associated peptide) and a single molecule of latent TGF-β binding protein-isoforms 1,3 or 4 (LTBP 1,3 or 4) [70]. This complex formation occurs intracellularly and TGF-β remains associated with the pro-peptide when secreted, to prevent premature activation of its high afnity receptor. The ECM is able to capture the large latent complex by binding with disulde bonds of its cysteine residue to components of the ECM such as bronectin and microbrils composed of brillin-1 [65].

Upon release from the large latent complex, TGF-β becomes active and is able to bind to type II TGF-β receptor unit (TGF-βR2) which then changes its conformation and phosphorylates type I TGF-β receptor unit (TGF-βR1), also known as activin receptor-like kinase 5 (ALK5). In the canonical (see Glossary) TGF-β signaling pathway receptor-regulated mothers against decapentaplegic homolog 2 and 3 (SMAD2/3) proteins are directly activated by the kinase activity of TGF-β-induced protein through phosphorylation of a serine residue at the carboxy terminus. Once associated with SMAD4, the trimeric complex (SMAD2/3/4) translocates to the nucleus where it will partner with other transcription factors and regulate TGF-β- mediated gene transcription [4, 70]. Canonical signaling is negatively regulated by SKI or SMAD7 by preventing nuclear translocation or initiating degradation of the trimeric complex respectively [71]. Dependent on the proteins recruited, TGF-β ligand binding to its receptor can also initiate noncanonical signalling cascades, including RhoA and the mitogen-activated protein kinases (MAPK) ERK, JNK and p38 [70, 71]. These kinases phosphorylate the regions between the two functionally active SMAD domains, i.e. Mad-homology 1 and 2 (MH1/2). However, the noncanonical TGF-β pathway still remains poorly understood [71].

Insights in the involvement of the TGF-β pathway in aneurysm pathogenesis were mainly obtained by the observation that TGFBR1/2 mutations result in LDS.Nuclear accumulation of phosphorylated SMAD2 (pSMAD2) and enhanced expression of TGF-β driven gene products such as connective tissue growth factor in aortic wall tissue of LDS patients, indicate enhanced TGF-β signaling [

32].

Analogous observations were made for mutations in the more recently identied LDS genes, TGFB2/3 and SMAD2/3, suggesting a presence of other compensatory mechanisms that further dysregulate the pathway [34–36]. Multiple hypotheses have been proposed to explain this paradox, for which further experimental validation is needed.

A rst hypothesis involves possible downregulation of auto-inhibitory pathways of the TGF-β pathway. TGF-β binding to its receptor can activate both the canonical and non-canonical pathway. Mutations in genes of the canonical pathway, can cause an initial decrease in TGF-β signaling but will result in a reduction in feedback inhibition in order to restore canonical signalling. Ligand expression and activation is subsequently increased leading to excessive activation of non-canonical signaling cascades [1, 26]. The second possible hypothesis is a shift in TGF-β ligand use.

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Similar to the cell-autonomous compensation, reduction of one TGF-β ligand due to mutations can cause pathological upregulation of the other ligands leading to an overall increase in TGF-β signaling [34].

Thirdly, paracrine overdrive between neighboring cell-types with different sensitivity to a perturbation of TGF-β signalling may explain the paradoxical overall increase in TGF-β signaling. Clinical observations demonstrate that very specic sites of the aorta have a predisposition to developing aneurysms, irrespective of haemodynamic stress. These sites correspond anatomically to regions where cells of divergent origins can interact, so-called transition regions. At the aortic root and the base of the pulmonary artery VMSCs are derived from specialized cardiogenic mesoderm, (secondary heart eld, see Glossary). The ascending aortic wall is chimaera between secondary heart eld VSMCs and VMSCs derived from ectodermal cardiac neural crest (CNC) with gradually more CNC-derived VSMCs in the more distal ascending aorta and aortic arch. An abrupt switch to VSMCs derived from somatic mesoderm occurs at the proximal descending thoracic aorta and to splanchnic mesoderm just below the diaphragm. Cells from different origins react differently upon TGF-β stimulation with cells of one lineage being more prone to perturbed TGF-β signaling compared to cells from another lineage. More sensitive cell types might attempt compensating for the initial loss in signalling by secreting excessive amounts of TGF-β ligand. Neighbouring cells that are intrinsically less vulnerable to heterozygous LDS mutations are then stimulated by the compensatory TGF-β ligand increment, leading to an excessive activation of the TGF-β signaling pathway [1, 72].

Fourth, there is important cross-talk to other TGF-β related pathways. Involvement of related pathways such as activin or angiotensin II signaling cascades can cause the observed enhanced pSMAD2 expression in aortic media [70]. Finally, a less well investigated hypothesis implies increased TGF-β receptor turnover. Another way of regulating signal transduction is the internalization of TGF-β receptors, which determines the amount of active receptors at the surface of the cells. A rst pathway of receptor internalization is the clathrin-mediated pathway, regulated by the SMAD anchor for receptor activation protein (SARA), which leads to the recycling and increase of TGF-β receptors available at the cell surface. Alternatively, the caveolin-mediated pathway can internalize TGF-β receptors, mediated by SMAD7 interactions, resulting in proteosomal degradation of the receptor. Mutations in the TGF-β2 receptor is thought to alter interactions with either SARA (promotion) or Smad7 (inhibition) leading to an overstimulation of the clathrin-mediated pathway and an increased TGF-β signaling [

73].

M. H. A. M. Perik et al.

13.7 TAA Management

Early diagnosis of a TAA is extremely important as aortic rupture or dissection can rapidly lead to dramatic consequences such as death. Although the incidence of thoracic aneurysmal diseases appears to be increasing, this is more likely due to

13 Pathophysiology andPrinciples ofManagement ofHereditary Aneurysmal…

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better awareness and incidental diagnosis rather than an actual increase in affected individuals [74, 75]. Moreover, improved follow up, surveillance and surgical techniques have contributed signicantly to reduced mortality rates.

309

13.7.1 Clinical Diagnosis

Aortic aneurysms usually remain unnoticed until dissection or rupture occurs. Many patients are diagnosed at routine check-up, or when a syndromic disorder is diagnosed which has a predisposition for the development of aneurysms. Vascular monitoring in these patients, in addition to medical treatment and/or surgical interventions, is very important to ensure timely intervention and to reduce complications. Currently there are several complementary non-invasive diagnostic tools for the assessment of TAA [76]. By complementing echocardiography with computed tomography (CT) or magnetic resonance imaging (MRI) for aortic imaging, diagnosis as well as accurate assessment of the location, extent and growth of the aneurysms can be determined. 6 months after initial diagnosis, repeat aortic imaging is performed to determine baseline rates of aortic growth, indicative for the risk of dissection or rupture. Thereafter, yearly imaging is generally recommended [4].

Each imaging technique has its own strength and limitations; therefore, a combined approach is recommended during long-term follow-up. Baseline transthoracic echocardiography (TTE) is an excellent imaging technique for diagnosis and follow- up of TAA’s and should be performed in all patients with suspected or known aortopathy [4]. Proximal aortic segments, aortic valve morphology/function, aortic annulus, root and proximal ascending aorta have an excellent axial resolution with TTE.Visualization of the more distal aorta and, however, is limited. Improved image quality can be obtained by transesophageal echocardiography (TEE), but this is more invasive and as such is less used in routine TAA surveillance [77].

CT is most commonly used for TAA diagnosis and monitoring due to its accurate and precise imaging of the aortic root, visualization of the tortuous arteries and assessment of aortic morphology. However, reproducible and standardized methods are needed for exact location of the imaging, ECG-gating and whether the aortic wall is included in the measurement of aortic diameters. Furthermore, centre-line measurements are needed in order to not to overestimate aortic size [

Similar to CT, MRI is also frequently used for TAA assessment because of its excellent temporal and spatial resolution. Measurements of aortic size, aneurysm location, tissue characterization and aortic wall morphology can accurately be obtained. An additional strength of MRI is the evaluation of aortic valve function and morphology, cardiac structure and function and inammation and oedema in the aortic wall [76]. However, this technique is less often performed due to the long imaging acquisition time, limited availability in most emergency departments, claustrophobic patients and incompatibility with metal devices such as pacemakers and some aneurysm clips [77].

77].

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Biomarkers are currently being investigated for the prediction and follow up of aortic dissections. MMP9 and TGF-β levels are, for example, increased in patients with aortic dissections. MMP9 increases within 1h of the onset of aortic dissections, remaining elevated for the next 2months, while TGF-β levels can be a predictor aortic rupture and expansion after dissection [77].

M. H. A. M. Perik et al.

13.7.2 Molecular Diagnosis

Molecular conrmation when aortic disease is suspected is increasingly important for optimal patient management. For example, patients harbouring ACTA2 muta- tions are at increased risk of premature stroke and coronary artery disease [55]. Similarly, patients with LDS commonly develop aneurysms beyond the aorta [78]. As such, the frequency and location of cardiovascular imaging should be planned accordingly. Genetic defects are also being increasingly taken into account when deciding on surgical intervention. Overall, surgery is recommended when aortic diameters reach 5cm, when the aorta enlarges at an extremely rapid pace (≥5mm per year), or when severe aortic valve insufciency or stenosis occurs [8]. Patients with mutations in SMAD2, SMAD3, TGFBR1, and TGFBR2, however, should receive surgery earlier (that is, when the ascending aorta reaches a diameter of

4.0–4.5 cm). Given that TGFB2 and TGFB3 mutation carriers generally present with mild aortic phenotypes, one might expect that standard surgical thresholds would be appropriate for these patients. However, this remains to be validated experimentally. Surgical guidelines for patients with familial TAA are currently less well dened, largely owing to the very small number of patients with mutations in each of the identied genes. However, patients with mutations in ACTA2, MYH11, MYLK, or PRKG1 are recommended to receive surgery before their aortas reach a size of about 4.5cm because they generally undergo dissections at slightly dilated, or even normal, diameters [79]. While surgical outcomes are excellent in MFS and LDS patients, the risk of complications are much higher in vEDS patients, who thus need more careful consideration of the indications for surgery.

13.7.3 Medical Treatment

β-Blockers such as atenolol are widely used to delay the progression of TAA.These drugs lower blood pressure and heart rate, which in turn decreases aortic wall stress. Although β-blockers are considered the gold-standard treatment in the eld, different clinical trials have shown variable or even conicting outcomes since the initial reports [80, 81]. Patients who are intolerant of β-blockers might be treated with other antihypertensive agents such as calcium-channel blockers and angiotensinconverting- enzyme (ACE) inhibitors [82]. ACE inhibitors are also controversial in the eld and no large randomized trials support their efcacy.

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The latest therapeutic strategy for TAA was launched after the identication of dysregulated TGF-β signalling in syndromic aneurysmal disease. Given that TGF-β acts downstream of angiotensin signalling and increased expression of both angiotensin II and type 1 angiotensin II receptor were observed in MFS aortic tissue, angiotensin blockade was considered a promising therapeutic approach for MFS [83]. After the drug’s efcacy was established in mice, numerous clinical studies were conducted to investigate the efcacy of losartan therapy in patients with MFS.A large study by the Paediatric Heart Network did not nd signicant differences between a high dose of beta-blocker and regular dose of losartan [84]. More recently, the AIMS study in the United Kingdom showed a benet of irbesartan on top of existing beta-blocker treatment [85].

13.8 Conclusion

The understanding of the pathophysiology of hereditary aortopathies has grown exponentially over the past decades. Identication and functional characterization of disease genes pinpointed dysregulated ECM homeostasis, TGF-β signalling and VSMC contraction as key disease processes. Important knowledge gaps with respect to the molecular mechanisms underlying TAA formation remain though. Owing to the advent of next-generation sequencing we anticipate that more disease genes as well as modier genes explaining signicant intra- and interfamilial variability in TAA severity, will be discovered. This will enable further delineation of the disease pathways involved in TAA formation, identication of novel therapeutic targets as well as more personalized disease management.

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