Cardiovascular manifestations in Marfan syndrome and related diseases; multiple genes causing similar phenotypes

Authors, Journal, Affiliations, Type, DOI

• Cook JR, Carta L, Galatioto J, Ramirez F
• Clinical Genetics 2015;87:11–20
• Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY
• Review article
• DOI: 10.1111/cge.12436

Overview

This review from the Ramirez laboratory at Mount Sinai synthesises the clinical and experimental evidence for cardiovascular manifestations in Marfan syndrome (MFS) and four closely related diseases — Loeys-Dietz syndrome (LDS), Shprintzen-Goldberg syndrome (SGS), aneurysm-osteoarthritis syndrome (AOS), and syndromic thoracic aortic aneurysm (sTAA) — all united by dysregulated TGFβ signalling. A two-pathway model of TAA pathogenesis is proposed: a mechanosensing pathway (AT1R/integrins driven by wall stress) and a TGFβ feed-forward loop (from microfibril-deficient ECM). The review critically evaluates mouse model data against the emerging human trial evidence, and identifies dilated cardiomyopathy as a primary myocardial disorder driven by fibrillin-1 mechanosignaling — an important exception to broad anti-TGFβ therapy.

Keywords

angiotensin receptor blockers (ARBs), calcium channel blockers, cardiomyopathy, connective tissue, Ghent nosology, Marfan syndrome (MFS), mutations in gene for fibrillin-1 (FBN1), TGFβ, thoracic and abdominal aortic aneurysm, valvulopathy, β-blockers

Key Takeaways

MFS Overview and Diagnosis (Revised Ghent Nosology 2010)

• Incidence ~1 in 5,000 live births; autosomal dominant
• Revised Ghent 2010 criteria (Loeys et al. J Med Genet 2010): positive diagnosis requires either (a) two cardinal manifestations from: aortic root diameter Z-score >2, ectopia lentis, or inherited FBN1 mutation; OR (b) aortic root dilation plus systemic score >7 points
• Two distinct clinical courses: fatal cardiovascular presentation in neonatal life, or progressively severe cardiovascular morbidity during adolescence/adulthood

Aortopathy

• TAA characterized by increased tissue stiffness measurable by ECHO or MRI; histopathology = accelerated vessel aging and maladaptive remodelling
• Elastic lamellae fragmentation, excessive collagen + mucopolysaccharide accumulation, relative SMC deficiency
• Aortic stiffness is an independent risk factor for dissection (Nollen 2004 Eur Heart J); MFS aortopathy not solely driven by diameter
• Elastic fiber fragmentation occurs throughout all aortic segments (including descending and infra-renal) before vessel dilation is detectable in mgR/mgR mice (Schwill 2013)
• TAA detectable in fetal life by ECHO; rate of progression and dissection risk unpredictable
• AAA risk after TAA repair: prior TAA surgery is an independent risk factor for AAA development
• Pulmonary artery dilation occurs but does not carry same dissection risk; mechanism of vessel-type-specific protection not fully explained
• Annual ECHO standard; twice yearly for pediatric patients or those with accelerated aortic root growth
• MRI preferred over CT for surveillance to minimise cumulative radiation from serial scans

Valvulopathy

• MVP prevalence ~75% in MFS vs 1.3% in general population
• Neonatal MFS: MVP with severe regurgitation → congestive heart failure
• Adult MVP: surgical repair feasible but risk of acute TAA with rapid increase in cardiac output post-operatively

Cardiomyopathy

• LV dysfunction (systolic and diastolic) historically considered secondary to valvular insufficiency/volume overload
• Cook 2014 (JCI): DCM in Fbn1-mgR/mgR and conditional null mice shown to be a primary cardiomyopathy due to impaired tissue properties that chronically stimulate abnormal cardiomyocyte mechanosignaling; fibrillin-1 functions as a force-transmitting molecule indispensable for cardiac adaptation to increased workload
• DCM is an exception to broad anti-TGFβ therapy in MFS — mechanical stress signals from fibrillin-1-deficient ECM should also be considered as pharmacological targets in the ascending aorta

Clinical Management

• Lifestyle: restrict physical activity, minimise emotional stress (reduce HR and BP)
• Beta-blockers: standard of care; propranolol reduces aortic tension; evidence is modest — open-label trial positive (Shores 1994) but no randomised vs placebo trial; no benefit in mgR/mgR mice at hypotensive doses
• Calcium channel blockers: second-line for 10–20% intolerant to beta-blockers; verapamil prospective data (6 patients); calcium channel blocker vs beta-blocker RCT (16 patients) also reported
• Fibrillin-1 circulating fragments (Marshall 2013 Circ Res): TAA frequency and dissection associated with circulating fibrillin-1 fragment concentrations; potential biomarker in development
• Elective aortic replacement at significantly dilated or rapidly dilating aorta; surgical mortality <2% elective vs >10% at acute dissection
• Valve-sparing (reimplantation) procedures: minimise need for anticoagulation and antibiotic prophylaxis; long-term results favourable (David 2013)

Fibrillin-1 Structure and Function

• 350 kDa modular cysteine-rich glycoprotein; contains a single integrin-binding Arg-Gly-Asp (RGD) sequence
• Monomers polymerise extracellularly into 10 nm diameter microfibrils; interact with elastin, fibulins, MAGPs, proteoglycans → elastic fibers widely distributed in aortic media and myocardium
• Fibrillin-1 microfibrils sequester pro-TGFβ molecules bound to LTBPs as an ECM-bound latent complex; deficiency → promiscuous TGFβ activation and improper ECM remodelling gene expression
• TGFβ signals through TGFβRI and TGFβRII to activate either:
  • Canonical pathway (R-Smad-dependent): Smad2/3 phosphorylation
  • Non-canonical pathway (R-Smad-independent): MAPK/ERK activation
  • Both pathways implicated in MFS aortic disease

Mouse Models of MFS

• Fbn1−/−: 0% fibrillin-1; lethal ~P16; normal aortic wall at birth (fibrillin-1 not required for fetal aortic development)
• Fbn1-mgR/mgR: 20% fibrillin-1; kyphosis; progressively severe TAA with dissection; DCM; diffuse airspace widening; 50% survival P60–P90
• Fbn1-C1039G/+: 50% mutant/50% normal fibrillin-1; kyphosis; TAA + MVP; normal survival
• Fibrillin-1 expression peaks P0–P4; tropoelastin expression begins ~2 days later through P14 — microfibrils provide scaffold for elastin deposition
• Elastic lamellae degeneration involves: focal calcification → MMP-mediated elastolysis → inflammation → intimal hyperplasia → unproductive ECM remodelling (fibrosis)

Emerging Therapeutic Strategies

• Losartan (AT1R blocker): normalises R-Smad in C1039G/+ mice; in mgR/mgR mice reduces dilation and extends survival but normalises ERK1/2 NOT R-Smad (suggesting AT1R-driven ERK1/2 independent of TGFβ)
• Groenink 2013 (Eur Heart J) RCT: losartan vs no additional treatment (control: 70% on beta-blocker); losartan → significantly reduced aortic root diameter and rate of dilation over 3 years; no significant difference in ascending aorta diameter or surgical endpoints; modest but significant benefit particularly post-proximal aortic reconstruction
• Doxycycline (non-specific MMP inhibitor): extends survival in mgR/mgR mice; preserves vessel architecture
• Combination losartan + doxycycline: normalises aortic diameter + vessel architecture + R-Smad + ERK in mgR/mgR mice
• GxxPG fibrillin-1 fragment: proteolytic product; stimulates macrophage chemotaxis + MMP upregulation; neutralising antibodies reduced inflammation and TAA in mgR/mgR mice
• Pravastatin (HMG-CoA reductase inhibitor): reduced medial degeneration in C1039G/+ mice
• Non-canonical TGFβ pathway (Holm 2011 Science): ERK inhibitor reduces TAA in C1039G/+ mice; identifies non-canonical pathway as major aortic disease contributor
• AT2R signalling (Habashi 2011 Science): AT2R deletion exacerbates TAA + further increases ERK1/2 but NOT R-Smad → AT2R inhibits AT1R-mediated ERK1/2; protective balance

Two-Pathway TAA Model (Ramirez Lab Hypothesis)

• Pathway 1 (mechanosensing): hemodynamic load on structurally impaired tissue → AT1R/integrin mechanosensor activation → MMP and TGFβ gene upregulation
• Pathway 2 (TGFβ feed-forward loop): adaptive remodelling → excessive latent TGFβ activation from microfibril-deficient ECM → persistent TGFβ production and activation → unopposed feed-forward maladaptive remodelling
• Active TGFβ and proteolytic ECM products stimulate immune-inflammatory response → further TAA progression

MFS-Related Diseases

• Loeys-Dietz Syndrome (LDS): TGFBR1/TGFBR2 LOF → paradoxical TGFβ upregulation; arterial tortuosity, craniofacial features, TAA; dissection at smaller diameters including medium-sized arteries (cerebral); valvular disease in ~20–30% of LDS patients (Attias 2009); single case report of cardiac dysfunction secondary to microvascular coronary artery disease
• Shprintzen-Goldberg Syndrome (SGS): now known to be caused by heterozygous mutations in SKI (TGFβ repressor) — NOT FBN1 as originally reported; aortic dilation, craniofacial features, intellectual disability; augmented Smad2/3 + ERK1 baseline activity in dermal fibroblasts; mechanism consistent with gain-of-function TGFβ upregulation (contrast to LDS/AOS/sTAA where LOF causes paradoxical signalling)
• Aneurysm-Osteoarthritis Syndrome (AOS): heterozygous inactivating SMAD3 mutations; aortic aneurysms + arterial tortuosity + early-onset osteoarthritis + craniofacial features similar to LDS; paradoxical TGFβ upregulation on immunohistochemistry; van de Laar 2011 Nat Genet
• Syndromic TAA (sTAA): TGFB2 mutations → paradoxical TGFβ1 upregulation + increased R-Smad; medial degeneration + fibrosis; Lindsay 2012 Nat Genet

Beyond MFS: Other FBN1 Diseases

• Stiff Skin Syndrome (SSS): FBN1 mutations in RGD-containing domain → congenital scleroderma; severe dermal fibrosis, joint contracture, short stature; mouse models show autoantibodies, progressive fibrosis, peripheral vasoconstriction; β1-integrin/TGFβ pathway
• Weill-Marchesani Syndrome (WMS): FBN1 mutations; MFS-like ocular disease + short stature + increased joint stiffness + muscle mass; also caused by ADAMTSL2 and ADAMTS10 mutations (which bind fibrillin-1 in vitro)
• Acromicric/Geleophysic Dysplasias (AD): FBN1 mutations; severe short stature + joint stiffness + skin thickening; also caused by ADAMTSL2/ADAMTS10; overlap with WMS
• All these are believed to reflect protein-protein interactions at functionally discrete fibrillin-1 domains

Limitations of the Document

• Review article from a single laboratory (Ramirez lab) — perspective inevitably reflects authors' own mouse model data and hypotheses
• Two-pathway TAA model is explicitly a working hypothesis, not yet validated
• Human clinical trial data for most emerging therapies (doxycycline, pravastatin, GxxPG antagonism) is absent; all evidence is from mouse models
• Groenink 2013 losartan RCT cited but COMPARE trial (published also ~2013, showing losartan not superior to beta-blockers) not cited in this review — may represent publication timing
• Cardiomyopathy studies in humans show highly variable DCM prevalence (0–68% in cross-sectional studies in Table 1) — methodological heterogeneity not fully addressed
• Pulmonary artery dilation mechanism acknowledged as unexplained

Key Concepts Mentioned

• concepts/Marfan-Syndrome — primary focus; Ghent 2010, MVP, DCM mechanosignaling, two-pathway TAA model, all management
• TGFβ signalling — canonical/non-canonical pathways
• Aortic stiffness and dissection risk

Key Entities Mentioned

• entities/FBN1 — structural protein; RGD sequence; force-transmitting role; circulating fragment biomarkers; SSS/WMS/AD fibrillinopathies
• entities/Loeys-Dietz-Syndrome — LDS; valvular disease 20-30%; LDS cardiac dysfunction case report
• entities/Aneurysm-Osteoarthritis-Syndrome — new entity; SMAD3 mutations; AOS features

Wiki Pages Updated

• Created wiki/sources/marfan-cv-clingene-2015.md
• Updated wiki/concepts/Marfan-Syndrome.md — source_count 2→3; Ghent 2010 criteria, MVP ~75%, aortic stiffness, canonical/non-canonical TGFβ, DCM primary cardiomyopathy, two-pathway TAA model, AOS/SGS-SKI/sTAA-TGFB2, losartan Groenink 2013, fibrillin-1 biomarkers, MRI preference
• Updated wiki/entities/FBN1.md — source_count 2→3; RGD sequence, fibrillin-1 fragments biomarker, force-transmitting role, SSS/WMS/AD fibrillinopathies
• Updated wiki/entities/Loeys-Dietz-Syndrome.md — source_count 2→3; valvular disease 20-30%, cardiac dysfunction case report
• Created wiki/entities/Aneurysm-Osteoarthritis-Syndrome.md — new entity
• Updated wiki/wikiindex.md — added AOS entity
• Updated wiki/sourceindex.md — added marfan-cv-clingene-2015