The role of transforming growth factor-beta in Marfan syndrome

The starting point, in Marfan syndrome (MFS) appears to be the mutation of fi brillin-1 gene whose deconstructed protein product cannot bind transforming growth factor beta (TGF-b), leading to an increased TGF-b tissue level. The aim of this review is to review the already known features of the cellular signal transduction downstream to TGF-b and its impact onthe tissue homeostasis of microfibrils, and elastic fi bers. We also investigate current data onthe extracellular regulation of TGF-b level including mechanotransduction and the feedback cycles of integrin-dependent and independent activation of the latent TGF-b complex. Togetherthese factors, by the destruction of the connective tissue fi bers, may play an important role inthe development of the diverse cardiac and extracardiac manifestations of MFS and many of them could be a target of conservative treatment. We present currently investigated drugs for thetreatment of the syndrome, and explore possible avenues of research into pathogenesis of MFS in order to improve understanding of the disease

The effects of acute and elective cardiac surgery on the anxiety traits of patients with Marfan syndrome

BACKGROUND: Marfan syndrome is a genetic disease, presenting with dysfunction of connective tissues leading to lesions in the cardiovascular and skeletal muscle system. Within these symptoms, the most typical is weakness of the connective tissue in the aorta, manifesting as aortic dilatation (aneurysm). This could, in turn, become annuloaortic ectasia, or life-threatening dissection. As a result, life-saving and preventative cardiac surgical interventions are frequent among Marfan syndrome patients. Aortic aneurysm could turn into annuloaortic ectasia or life-threatening dissection, thus life-saving and preventive cardiac surgical interventions are frequent among patients with Marfan syndrome. We hypothesized that patients with Marfan syndrome have different level of anxiety, depression and satisfaction with life compared to that of the non-clinical patient population. METHODS: Patients diagnosed with Marfan syndrome were divided into 3 groups: those scheduled for prophylactic surgery, those needing acute surgery, and those without need for surgery (n = 9, 19, 17, respectively). To examine the psychological features of the patients, Spielberger's anxiety (STAI) test, Beck's Depression questionnaire (BDI), the Berne Questionnaire of Subjective Well-being, and the Satisfaction with Life scale were applied. RESULTS: A significant difference was found in trait anxiety between healthy individuals and patients with Marfan syndrome after acute life-saving surgery (p 0.1). Finally, a significant, medium size effect was found between patient groups on the Joy in Living scale (F (2.39) = 3.51, p = 0.040, eta2 = 0.15). CONCLUSIONS: Involving psychiatric and mental-health care, in addition to existing surgical treatment interventions, is essential for more successful recovery of patients with Marfan syndrome

Possible extracardiac predictors of aortic dissection in Marfan syndrome

BACKGROUND: According to previous studies, aortic diameter alone seems to be insufficient to predict the event of aortic dissection in Marfan syndrome (MFS). Determining the optimal schedule for preventive aortic root replacement (ARR) aortic growth rate is of importance, as well as family history, however, none of them appear to be decisive. Thus, the aim of this study was to search for potential predictors of aortic dissection in MFS. METHODS: A Marfan Biobank consisting of 79 MFS patients was established. Thirty-nine MFS patients who underwent ARR were assigned into three groups based on the indication for surgery (dissection, annuloaortic ectasia and prophylactic surgery). The prophylactic surgery group was excluded from the study. Transforming growth factor-beta (TGF-beta) serum levels were measured by ELISA, relative expression of c-Fos, matrix metalloproteinase 3 and 9 (MMP-3 and -9) were assessed by RT-PCR. Clinical parameters, including anthropometric variables - based on the original Ghent criteria were also analyzed. RESULTS: Among patients with aortic dissection, TGF-beta serum level was elevated (43.78 +/- 6.51 vs. 31.64 +/- 4.99 ng/l, p < 0.0001), MMP-3 was up-regulated (Ln2alpha = 1.87, p = 0.062) and striae atrophicae were more common (92% vs. 41% p = 0.027) compared to the annuloaortic ectasia group. CONCLUSIONS: We found three easily measurable parameters (striae atrophicae, TGF-beta serum level, MMP-3) that may help to predict the risk of aortic dissection in MFS. Based on these findings a new classification of MFS, that is benign or malignant is also proposed, which could be taken into consideration in determining the timing of prophylactic ARR

Gene polymorphisms as risk factors for predicting the cardiovascular manifestations in Marfan syndrome

SummaryFolic acid metabolism enzyme polymorphisms are believed to be responsible for the elevation of homocysteine (HCY) concentration in the blood plasma, correlating with the pathogenesis of aortic aneurysms and aortic dissection. We studied 71 Marfan patients divided into groups based on the severity of cardiovascular involvement: no intervention required (n=27, Group A); mild involvement requiring intervention (n=17, Group B); severe involvement (n=27, Group C) subdivided into aortic dilatation (n=14, Group C1) and aortic dissection (n=13, Group C2), as well as 117 control subjects. We evaluated HCY, folate, vitamin B12 and the polymorphisms of methylenetetrahydrofo-late reductase (MTHFR;c.665C&gt;T and c.1286A&gt;C), methionine synthase (MTR;c.2756A&gt;G) and methionine synthase reductase (MTRR;c.66A&gt;G). Multiple comparisons showed significantly higher levels of HCY in Group C2 compared to Groups A, B, C1 and control group (p&lt; 0.0001, p&lt; 0.0001, p=0.001 and p=0.003, respectively). Fo-late was lower in Group C2 than in Groups A, B, C1 and control subjects (p&lt; 0.0001, p=0.02, p&lt; 0.0001 and p&lt; 0.0001, respectively). Group C2 had the highest prevalence of homozygotes for all four gene polymorphisms. Multivariate logistic regression analysis revealed that HCY plasma level was an independent risk factor for severe cardiovascular involvement (Group C; odds ratio [OR] 1.85, 95 % confidence interval [CI] 1.28–2.67, p=0.001) as well as for aortic dissection (Group C2; OR 2.49, 95 %CI 1.30–4.78, p=0.006). In conclusion, severe cardiovascular involvement in Marfan patients, and especially aortic dissection, is associated with higher HCY plasma levels and prevalence of homozygous genotypes of folic acid metabolism enzymes than mild or no cardiovascular involvement. These results suggest that impaired folic acid metabolism has an important role in the development and remodelling of the extracellular matrix of the aorta.</jats:p

Marfan-szindróma biobankjának létrehozása

A Marfan-szindróma a szervezet kötőszöveti állományát érintő öröklődő betegség, amely Magyarországon hozzávetőleg 2–3000 személyt érint. A betegség manifesztációi multiszisztémásak, ezért a kórismézés sokszor nehézségekbe ütközik. Az „Országos Marfan Regiszter” jelenleg közel 250 Marfan-szindrómában szenvedő beteg adatait tartalmazza, s ez a szám dinamikusan növekszik. Célok: A Marfan-szindrómás magyar személyek biológiai mintáinak, klinikai adatainak és életmódfelmérőinek összegyűjtése. Módszerek: A szelekció során olyan betegekre esett a választás, akiknél a cardiovascularis és a szisztémás érintettség, illetve a családi kórelőzmény alapján az átdolgozott Gent-nozológia értelmében egyértelműen megállapítható a Marfan-szindróma fennállása. Eredmények: Az adatbázis alapján 102 Marfan-szindrómában szenvedő személyt tartalmaz a biobank, amely 55 személy cDNS-mintáját, 102 személy genomi DNS- és szérummintáját foglalja magába. A biológiai minták mellett minden személyről nemzetközileg validált fizikai aktivitási, táplálkozási és pszichológiai kérdőívek alapján gyűjtött adatot is tartalmaz a biobank. Következtetések: A Marfan Biobank genetikai, génexpressziós és fehérjeszintű kutatások gyors megtervezését teszi lehetővé. A biobank hozzájárul a kórkép alaposabb megismeréséhez és a hazai betegek ellátásához egyaránt