Progressive enlargement of the aortic root, leading to dissection, is the main cause of premature death in patients with Marfan's syndrome. Recent data from mouse models of Marfan's syndrome suggest ...that aortic-root enlargement is caused by excessive signaling by transforming growth factor beta (TGF-beta) that can be mitigated by treatment with TGF-beta antagonists, including angiotensin II-receptor blockers (ARBs). We evaluated the clinical response to ARBs in pediatric patients with Marfan's syndrome who had severe aortic-root enlargement.
We identified 18 pediatric patients with Marfan's syndrome who had been followed during 12 to 47 months of therapy with ARBs after other medical therapy had failed to prevent progressive aortic-root enlargement. The ARB was losartan in 17 patients and irbesartan in 1 patient. We evaluated the efficacy of ARB therapy by comparing the rates of change in aortic-root diameter before and after the initiation of treatment with ARBs.
The mean (+/-SD) rate of change in aortic-root diameter decreased significantly from 3.54+/-2.87 mm per year during previous medical therapy to 0.46+/-0.62 mm per year during ARB therapy (P<0.001). The deviation of aortic-root enlargement from normal, as expressed by the rate of change in z scores, was reduced by a mean difference of 1.47 z scores per year (95% confidence interval, 0.70 to 2.24; P<0.001) after the initiation of ARB therapy. The sinotubular junction, which is prone to dilation in Marfan's syndrome as well, also showed a reduced rate of change in diameter during ARB therapy (P<0.05), whereas the distal ascending aorta, which does not normally become dilated in Marfan's syndrome, was not affected by ARB therapy.
In a small cohort study, the use of ARB therapy in patients with Marfan's syndrome significantly slowed the rate of progressive aortic-root dilation. These findings require confirmation in a randomized trial.
Aortic aneurysm is common, accounting for 1-2% of all deaths in industrialized countries. Early theories of the causes of human aneurysm mostly focused on inherited or acquired defects in components ...of the extracellular matrix in the aorta. Although several mutations in the genes encoding extracellular matrix proteins have been recognized, more recent discoveries have shown important perturbations in cytokine signalling cascades and intracellular components of the smooth muscle contractile apparatus. The modelling of single-gene heritable aneurysm disorders in mice has shown unexpected involvement of the transforming growth factor-β cytokine pathway in aortic aneurysm, highlighting the potential for new therapeutic strategies.
Loeys-Dietz syndrome is a connective tissue disorder predisposing individuals to aortic and arterial aneurysms. Presenting with a wide spectrum of multisystem involvement, medical management for some ...individuals is complex. This review of literature and expert opinion aims to provide medical guidelines for care of individuals with Loeys-Dietz syndrome.
Thoracic aortic aneurysms progressively enlarge and predispose to acute aortic dissections. Up to 25% of individuals with thoracic aortic disease harbor an underlying Mendelian pathogenic variant. An ...evidence-based strategy for selection of genes to test in hereditary thoracic aortic aneurysm and dissection (HTAAD) helps inform family screening and intervention to prevent life-threatening thoracic aortic events.
The purpose of this study was to accurately identify genes that predispose to HTAAD using the Clinical Genome Resource (ClinGen) framework.
We applied the semiquantitative ClinGen framework to assess presumed gene–disease relationships between 53 candidate genes and HTAAD. Genes were classified as causative for HTAAD if they were associated with isolated thoracic aortic disease and were clinically actionable, triggering routine aortic surveillance, intervention, and family cascade screening. All gene-disease assertions were evaluated by a pre-defined curator-expert pair and subsequently discussed with an expert panel.
Genes were classified based on the strength of association with HTAAD into 5 categories: definitive (n = 9), strong (n = 2), moderate (n = 4), limited (n = 15), and no reported evidence (n = 23). They were further categorized by severity of associated aortic disease and risk of progression. Eleven genes in the definitive and strong groups were designated as “HTAAD genes” (category A). Eight genes were classified as unlikely to be progressive (category B) and 4 as low risk (category C). The remaining genes were recent genes with an uncertain classification or genes with no evidence of association with HTAAD.
The ClinGen framework is useful to semiquantitatively assess the strength of gene–disease relationships for HTAAD. Gene categories resulting from the curation may inform clinical laboratories in the development, interpretation, and subsequent clinical implications of genetic testing for patients with aortic disease.
Abstract Objectives Prophylactic aortic root replacement improves survival in patients with Marfan syndrome with aortic root aneurysms, but the optimal procedure remains undefined. Methods Adult ...patients with Marfan syndrome who had Bentall or aortic valve-sparing root replacement (VSRR) procedures between 1997 and 2013 were identified. Comprehensive follow-up information was obtained from hospital charts and telephone contact. Results One hundred sixty-five adult patients with Marfan syndrome (aged > 20 years) had either VSRR (n = 98; 69 reimplantation, 29 remodeling) or Bentall (n = 67) procedures. Patients undergoing Bentall procedure were older (median, 37 vs 36 years; P = .03), had larger median preoperative sinus diameter (5.5 cm vs 5.0 cm; P = .003), more aortic dissections (25.4% vs 4.1%; P < .001), higher incidence of moderate or severe aortic insufficiency (49.3% vs 14.4%; P < .001) and more urgent or emergent operations (24.6% vs 3.3%; P < .001). There were no hospital deaths and 9 late deaths in more than 17 years of follow-up (median, 7.8 deaths). Ten-year survival was 90.5% in patients undergoing Bentall procedure and 96.3% in patients undergoing VSRR ( P = .10). Multivariable analysis revealed that VSRR was associated with fewer thromboembolic or hemorrhagic events (hazard ratio, 0.16; 95% confidence interval, 0.03-0.85; P = .03). There was no independent difference in long-term survival, freedom from reoperation, or freedom from endocarditis between the 2 procedures. Conclusions After prophylactic root replacement in patients with Marfan syndrome, patients undergoing Bentall and valve-sparing procedures have similar late survival, freedom from root reoperation, and freedom from endocarditis. However, valve-sparing procedures result in significantly fewer thromboembolic and hemorrhagic events.
Retrospective matched case cohort.
Compare postoperative opioid utilization and prescribing behaviors between patients with Marfan syndrome (MFS) and adolescent idiopathic scoliosis (AIS) after ...posterior spinal fusion (PSF).
Opioids are an essential component of pain management after PSF. However, due to the potential for opioid use disorder and dependence, current analgesic strategies aim to minimize their use, especially in younger patients. Limited information exists on opioid utilization after PSF for syndromic scoliosis.
Twenty adolescents undergoing PSF with MFS were matched with patients with AIS (ratio, 1:2) by age, sex, degree of spinal deformity, and the number of vertebral levels fused. Inpatient and outpatient pharmaceutical data were reviewed for the quantity and duration of opioid and adjunct medications. Prescriptions were converted to morphine milligram equivalents (MMEs) using CDC's standard conversion factor.
Compared with patients with AIS, patients with MFS had significantly greater total inpatient MME use (4.9 vs . 2.1 mg/kg, P ≤ 0.001) and longer duration of intravenous patient-controlled anesthesia (3.4 vs . 2.5 d, P = 0.001). Within the first 2 postop days, MFS patients had more patient-controlled anesthesia boluses (91 vs . 52 boluses, P = 0.01) despite similar pain scores and greater use of adjunct medications. After accounting for prior opioid use, MFS was the only significant predictor of requesting an opioid prescription after discharge (odds ratio: 4.1, 95% CI: 1.1-14.9, P = 0.03). Patients with MFS were also more likely to be discharged with a more potent prescription (1.0 vs . 0.72 MME per day/kg, P ≤ 0.001) and to receive a longer-duration prescription (13 vs . 8 d, P = 0.005) with a greater MME/kg (11.6 vs . 5.6 mg/kg, P ≤ 0.001) as outpatients.
Despite a similar intervention, patients with MFS and AIS seem to differ in their postoperative opioid usage after PSF, presenting an opportunity for further research to assist clinicians in better anticipating the analgesic needs of individual patients, particularly in light of the ongoing opioid epidemic.
TGF-beta regulates many aspects of cellular performance relevant to tissue morphogenesis and homeostasis. Postnatal perturbation of TGF-beta signaling contributes to the pathogenesis of many disease ...states, as recently exemplified through the study of Marfan syndrome (MFS), including aortic aneurysm and skeletal muscle myopathy. Heterogeneity in the regulation and consequences of TGF-beta signaling, amplified in the context of disease, has engendered confusion and controversy regarding its utility as a therapeutic target. Three studies recently published in the JCI, including one in this issue, underscore the complexity of this subject. Heydemann and colleagues implicate dimorphic variation in latent TGF-beta-binding protein 4 (LTBP4), a regulator of TGF-beta bioavailability and activation, as a modifier of muscular dystrophy in gamma-sarcoglycan-deficient mice. In contrast to experience with ascending aortic aneurysm in MFS, Wang and colleagues show that systemic abrogation of TGF-beta signaling worsens (rather than attenuates) Ang II-induced abdominal aortic aneurysm progression in mice. Tieu and colleagues define alterations in the regulation of vascular inflammation in the pathogenesis of Ang II-induced aneurysm and dissection in mice, which may help shed some light on this apparent paradox.
In systemic sclerosis (SSc), a common and aetiologically mysterious form of scleroderma (defined as pathological fibrosis of the skin), previously healthy adults acquire fibrosis of the skin and ...viscera in association with autoantibodies. Familial recurrence is extremely rare and causal genes have not been identified. Although the onset of fibrosis in SSc typically correlates with the production of autoantibodies, whether they contribute to disease pathogenesis or simply serve as a marker of disease remains controversial and the mechanism for their induction is largely unknown. The study of SSc is hindered by a lack of animal models that recapitulate the aetiology of this complex disease. To gain a foothold in the pathogenesis of pathological skin fibrosis, we studied stiff skin syndrome (SSS), a rare but tractable Mendelian disorder leading to childhood onset of diffuse skin fibrosis with autosomal dominant inheritance and complete penetrance. We showed previously that SSS is caused by heterozygous missense mutations in the gene (FBN1) encoding fibrillin-1, the main constituent of extracellular microfibrils. SSS mutations all localize to the only domain in fibrillin-1 that harbours an Arg-Gly-Asp (RGD) motif needed to mediate cell-matrix interactions by binding to cell-surface integrins. Here we show that mouse lines harbouring analogous amino acid substitutions in fibrillin-1 recapitulate aggressive skin fibrosis that is prevented by integrin-modulating therapies and reversed by antagonism of the pro-fibrotic cytokine transforming growth factor β (TGF-β). Mutant mice show skin infiltration of pro-inflammatory immune cells including plasmacytoid dendritic cells, T helper cells and plasma cells, and also autoantibody production; these findings are normalized by integrin-modulating therapies or TGF-β antagonism. These results show that alterations in cell-matrix interactions are sufficient to initiate and sustain inflammatory and pro-fibrotic programmes and highlight new therapeutic strategies.
Marfan's syndrome Judge, Daniel P; Dietz, Harry C
Lancet,
12/2005, Volume:
366, Issue:
9501
Journal Article, Book Review
Peer reviewed
Open access
Marfan's syndrome is a systemic disorder of connective tissue caused by mutations in the extracellular matrix protein fibrillin 1. Cardinal manifestations include proximal aortic aneurysm, ...dislocation of the ocular lens, and long-bone overgrowth. Important advances have been made in the diagnosis and medical and surgical care of affected individuals, yet substantial morbidity and premature mortality remain associated with this disorder. Progress has been made with genetically defined mouse models to elucidate the pathogenetic sequence that is initiated by fibrillin-1 deficiency. The new understanding is that many aspects of the disease are caused by altered regulation of transforming growth factor β (TGFβ), a family of cytokines that affect cellular performance, highlighting the potential therapeutic application of TGFβ antagonists. Insights derived from studying this mendelian disorder are anticipated to have relevance for more common and non-syndromic presentations of selected aspects of the Marfan phenotype.
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