A contemporary approach to a young female patient with Loeys-Dietz syndrome and an uncomplicated type B aortic dissection: a case report.

BACKGROUND: Aortic dissection is a relatively uncommon, but often catastrophic disease that requires early and accurate diagnosis. It often presents in patients with congenital connective tissue disorders. The current aortic surgical techniques are related with serious early and late complications. This case report emphasizes the importance of early diagnosis of aortic root dilatation and the risk of dissection, especially in patients with congenital connective tissue disorders. We present an alternative, contemporary and multidisciplinary approach based on the present state of knowledge. CASE PRESENTATION: We present a rare case of a young female patient with Loeys-Dietz syndrome who was admitted with an uncomplicated aortic dissection (Stanford type B / DeBakey type III) and a dilated aortic root. After a period of close surveillance and extensive vascular imaging, thoracic endovascular aortic repair was deemed to be technically not possible. Medical treatment was optimized and our patient successfully underwent a personalised external aortic root support procedure (PEARS) as a contemporary alternative to existing aortic root surgical techniques. CONCLUSIONS: This case highlights the importance of interdisciplinary approach, close follow-up and multimodality imaging. The decision to intervene in a chronic type B aortic dissection is still challenging and should be made in experienced centers by an interdisciplinary team. However, if an acute complication occurs, thoracic endovascular aortic repair TEVAR is the method of choice. In all cases optimal medical treatment is important. There is increasing evidence that personalized external aortic root support procedure PEARS is effective in stabilizing the aortic root and preventing its dilatation and dissection not only in patients with Marfan syndrome, but also in other cases of aortic root dilation of other etiologies. Moreover, many publications have reported the additional benefit of reduction or even eradication of aortic regurgitation by improving coaptation of the aortic valve leaflets in dilated aortas.

Preventing a Catastrophe: Increasing Awareness of Loeys-Dietz Syndrome.

Loeys-Dietz syndrome is a genetic disorder that predisposes patients to aortic aneurysms. If left untreated, the natural history of the associated aortopathy often culminates in fatal aortic dissection. We describe the case of a 21-year-old man who was diagnosed with Loeys-Dietz syndrome after 2 family members died of aortic dissection. This case highlights the importance of increased physician awareness of this syndrome, which can play a crucial role in preventing premature sudden cardiac death caused by aortic catastrophe.

Pathophysiology and Management of Cardiovascular Manifestations in Marfan and Loeys-Dietz Syndromes.

Marfan syndrome (MFS) is an autosomal dominant heritable disorder of connective tissue that affects the cardiovascular, skeletal, ocular, pulmonary, and nervous systems and is usually caused by mutations in the FBN1 gene, which encodes fibrillin-1. MFS is traditionally considered to result from the structural weakness of connective tissue. However, recent investigations on molecular mechanisms indicate that increased transforming growth factor-ß (TGF-ß) activity plays a crucial role in the pathogenesis of MFS and related disorders, such as Loeys-Dietz syndrome (LDS), which is caused by mutation in TGF-ß signaling-related genes. In addition, recent studies show that angiotensin II type 1 receptor (AT1R) signaling enhances cardiovascular pathologies in MFS, and the angiotensin II receptor blocker losartan has the potential to inhibit aortic aneurysm formation. However, the relationship between TGF-ß and AT1R signaling pathways remains poorly characterized. In this review, we discuss the recent studies on the molecular mechanisms underlying cardiovascular manifestations of MFS and LDS and the ensuing strategies for management.

Marfan Syndrome and Related Disorders: 25 Years of Gene Discovery.

Marfan syndrome (MFS) is a rare, autosomal-dominant, multisystem disorder, presenting with skeletal, ocular, skin, and cardiovascular symptoms. Significant clinical overlap with other systemic connective tissue diseases, including Loeys-Dietz syndrome (LDS), Shprintzen-Goldberg syndrome (SGS), and the MASS phenotype, has been documented. In MFS and LDS, the cardiovascular manifestations account for the major cause of patient morbidity and mortality, rendering them the main target for therapeutic intervention. Over the past decades, gene identification studies confidently linked the aforementioned syndromes, as well as nonsyndromic aneurysmal disease, to genetic defects in proteins related to the transforming growth factor (TGF)-ß pathway, greatly expanding our knowledge on the disease mechanisms and providing us with novel therapeutic targets. As a result, the focus of the developing pharmacological treatment strategies is shifting from hemodynamic stress management to TGF-ß antagonism. In this review, we discuss the insights that have been gained in the molecular biology of MFS and related disorders over the past 25 years.

A randomized, double blind pilot study to assess the effects of losartan vs. atenolol on the biophysical properties of the aorta in patients with Marfan and Loeys-Dietz syndromes.

BACKGROUND: Patients with Marfan (MFS) and Loeys-Dietz (LDS) syndromes have been shown to have abnormal aortic biophysical properties. The purpose of this study was to compare the effects of 12-months of therapy with atenolol or losartan on vascular function in young patients with MFS and LDS. METHODS: Seventeen patients with MFS or LDS were recruited and randomized to treatment with atenolol, 25-50mg, or losartan, 25mg daily. Prior to treatment and following therapy, echocardiography for left ventricular size, function and aortic root size was performed. Pulse wave velocity (PWV), input (Zi, ZiF) and characteristic (Zc, ZcF) impedances, arterial stiffness (Ep and ß-index), total arterial compliance (TAC), mean (Wm) and total (Wt) hydraulic power, efficiency, power cost per unit of forward flow (Wt/CI) and brachial artery flow-mediated dilation (FMD) were measured. RESULTS: The atenolol group consisted of 9 females (17.6years) and the losartan group 7 males and 1 female (17.0years). Their height, weight, BSA, BMI, systolic and diastolic blood pressures were similar. Baseline to 12-month changes for atenolol and losartan were PWV (20% vs -14%), Zi (-2% vs -27%), Zc (-20% vs -27%), Ep (1%, vs -13%), ß-index (10% vs 14%), FMD (11% vs 20%), TAC (3% vs 42%), Wm (-24% vs 15%), Wt (-24% vs 17%), and Wt/CI (3% vs 21%). There was a trend for losartan to decrease PWV and stiffness indexes while atenolol decreased power and power/unit flow. CONCLUSION: This pilot study suggests that atenolol and losartan may have different mechanisms of action on vascular function. A larger clinical trial is needed to confirm these effects.Clinical trials registration NCT00593710 (ClinicalTrials.gov).

Loeys-Dietz syndrome.

Loeys-Dietz syndrome is an autosomal dominant aortic aneurysm syndrome characterized by multisystemic involvement. The most typical clinical triad includes hypertelorism, bifid uvula or cleft palate and aortic aneurysm with tortuosity. Natural history is significant for aortic dissection at smaller aortic diameter and arterial aneurysms throughout the arterial tree. The genetic cause is heterogeneous and includes mutations in genes encoding for components of the transforming growth factor beta (TGFß) signalling pathway: TGFBR1, TGFBR2, SMAD3 and TGFB2. Despite the loss of function nature of these mutations, the patient-derived aortic tissues show evidence of increased (rather than decreased) TGFß signalling. These insights offer new options for therapeutic interventions.

Connective tissue disorders and cardiovascular complications: the indomitable role of transforming growth factor-beta signaling.

Marfan Syndrome (MFS) and Loeys-Dietz Syndrome (LDS) represent heritable connective tissue disorders that cosegregate with a similar pattern of cardiovascular defects (thoracic aortic aneurysm, mitral valve prolapse/regurgitation, and aortic root dilatation with regurgitation). This pattern of cardiovascular defects appears to be expressed along a spectrum of severity in many heritable connective tissue disorders and raises suspicion of a relationship between the normal development of connective tissues and the cardiovascular system. Given the evidence of increased transforming growth factor-beta (TGF-ß) signaling in MFS and LDS, this signaling pathway may represent the common link in this relationship. To further explore this hypothetical link, this chapter will review the TGF-ß signaling pathway, heritable connective tissue syndromes related to TGF-ß receptor (TGFBR) mutations, and discuss the pathogenic contribution of TGF-ß to these syndromes with a primary focus on the cardiovascular system.

Angiotensin II-dependent TGF-ß signaling contributes to Loeys-Dietz syndrome vascular pathogenesis.

Loeys-Dietz syndrome (LDS) is a connective tissue disorder that is characterized by a high risk for aneurysm and dissection throughout the arterial tree and phenotypically resembles Marfan syndrome. LDS is caused by heterozygous missense mutations in either TGF-ß receptor gene (TGFBR1 or TGFBR2), which are predicted to result in diminished TGF-ß signaling; however, aortic surgical samples from patients show evidence of paradoxically increased TGF-ß signaling. We generated 2 knockin mouse strains with LDS mutations in either Tgfbr1 or Tgfbr2 and a transgenic mouse overexpressing mutant Tgfbr2. Knockin and transgenic mice, but not haploinsufficient animals, recapitulated the LDS phenotype. While heterozygous mutant cells had diminished signaling in response to exogenous TGF-ß in vitro, they maintained normal levels of Smad2 phosphorylation under steady-state culture conditions, suggesting a chronic compensation. Analysis of TGF-ß signaling in the aortic wall in vivo revealed progressive upregulation of Smad2 phosphorylation and TGF-ß target gene output, which paralleled worsening of aneurysm pathology and coincided with upregulation of TGF-ß1 ligand expression. Importantly, suppression of Smad2 phosphorylation and TGF-ß1 expression correlated with the therapeutic efficacy of the angiotensin II type 1 receptor antagonist losartan. Together, these data suggest that increased TGF-ß signaling contributes to postnatal aneurysm progression in LDS.

Dexamethasone normalizes aberrant elastic fiber production and collagen 1 secretion by Loeys-Dietz syndrome fibroblasts: a possible treatment?

Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder characterized by facial dysmorphism, cleft palate, dilation of the aortic arch, blood vessel tortuosity and a high risk of aortic dissection. It is caused by mutations in the transforming growth factor ß-receptor 1 and 2 (TGFß-R1 and TGFß-R2) genes. Fibroblasts derived from 12 Loeys-Dietz syndrome patients, six with TGFB-R1 mutations and six with TGFB-R2 mutations, were analyzed using RT-PCR, biochemical assays, immunohistochemistry and electron microscopy for production of elastin, fibrillin 1, fibulin 1 and fibulin 4 and deposition of collagen type I. All LDS fibroblasts with TGFß-R1 mutations demonstrated decreased expression of elastin and fibulin 1 genes and impaired deposition of elastic fibers. In contrast, fibroblasts with TGFß-R2 mutations consistently demonstrated intracellular accumulation of collagen type I in the presence of otherwise normal elastic fiber production. Treatment of the cell cultures with dexamethasone induced remarkable upregulation in the expression of tropoelastin, fibulin 1- and fibulin 4-encoding mRNAs, leading to normalization of elastic fiber production in fibroblasts with TGFß-R1 mutations. Treatment with dexamethasone also corrected the abnormal secretion of collagen type I from fibroblasts with TGFß-R2 gene mutations. As the organogenesis-relevant elastic fiber production occurs exclusively in late fetal and early neonatal life, these findings may have implications for treatment in early life. Further studies are required to determine if dexamethasone treatment of fetuses prenatally diagnosed with LDS would prevent or alleviate the connective tissue and vascular defects seen in this syndrome.

Loeys-Dietz syndrome: a Marfan-like syndrome associated with aggressive vasculopathy.

Loeys-Dietz syndrome is a recently-characterised genetic disorder with an autosomal-dominant inheritance due to mutations in the transforming growth factor beta-receptor Type 1 or Type 2 genes. We present a Chinese female neonate with genetically-confirmed Loeys-Dietz syndrome, cleft palate, hypertelorism, and an early dilatation of the aortic root and ascending aorta. This syndrome is associated with an aggressive arteriopathy, with an increased risk of dissection and rupture. Early diagnosis, close monitoring and early surgery may prolong the life in affected individuals. Losartan is an emerging therapy that may help slow down the rate of arterial dilatation.