Observational cohort study of ventricular arrhythmia in adults with Marfan syndrome caused by FBN1 mutations.

Ali Aydin,Sara Sheikhzadeh,Baran A Adsay,Meike Rybczynski,Jörg Schmidtke,Boris A Hoffmann,Daniel Steven,Stefan Blankenberg,Stephan Willems,Claudia Sondermann,Britta Keyser,Yskert Von Kodolitsch,Christian Detter,Peter N Robinson,Jürgen Berger,Fikret Er

doi:10.1371/journal.pone.0081281

Abstract

BackgroundMarfan syndrome is associated with ventricular arrhythmia but risk factors including FBN1 mutation characteristics require elucidation.Methods and ResultsWe performed an observational cohort study of 80 consecutive adults (30 men, 50 women aged 42±15 years) with Marfan syndrome caused by FBN1 mutations. We assessed ventricular arrhythmia on baseline ambulatory electrocardiography as >10 premature ventricular complexes per hour (>10 PVC/h), as ventricular couplets (Couplet), or as non-sustained ventricular tachycardia (nsVT), and during 31±18 months of follow-up as ventricular tachycardia (VT) events (VTE) such as sudden cardiac death (SCD), and sustained ventricular tachycardia (sVT). We identified >10 PVC/h in 28 (35%), Couplet/nsVT in 32 (40%), and VTE in 6 patients (8%), including 3 with SCD (4%). PVC>10/h, Couplet/nsVT, and VTE exhibited increased N-terminal pro–brain natriuretic peptide serum levels(P<.001). All arrhythmias related to increased NT-proBNP (P<.001), where PVC>10/h and Couplet/nsVT also related to increased indexed end-systolic LV diameters (P = .024 and P = .020), to moderate mitral valve regurgitation (P = .018 and P = .003), and to prolonged QTc intervals (P = .001 and P = .006), respectively. Moreover, VTE related to mutations in exons 24–32 (P = .021). Kaplan–Meier analysis corroborated an association of VTE with increased NT-proBNP (P<.001) and with mutations in exons 24–32 (P<.001).ConclusionsMarfan syndrome with causative FBN1 mutations is associated with an increased risk for arrhythmia, and affected persons may require life-long monitoring. Ventricular arrhythmia on electrocardiography, signs of myocardial dysfunction and mutations in exons 24–32 may be risk factors of VTE.

Highlights

Marfan syndrome is an autosomal-dominantly inherited disease of the connective tissue that is caused by mutations of the fibrillin-1 (FBN1) gene, which encodes fibrillin-1 monomers of the extracellular microfibrils [1]
Marfan syndrome with causative FBN1 mutations is associated with an increased risk for arrhythmia, and affected persons may require life-long monitoring
Ventricular arrhythmia on electrocardiography, signs of myocardial dysfunction and mutations in exons 24–32 may be risk factors of ventricular arrhythmia events (VTE)

Summary

Introduction

Marfan syndrome is an autosomal-dominantly inherited disease of the connective tissue that is caused by mutations of the fibrillin-1 (FBN1) gene, which encodes fibrillin-1 monomers of the extracellular microfibrils [1]. The scarce studies of SCD do not use current criteria of Marfan syndrome [9,10], they do not document presence of causative FBN1 mutations [9,10,11,12], and they do not investigate the role of different types of FBN1 mutations on the risk of ventricular arrhythmia and SCD [9,10,11,12] Such investigations may be important, especially in the light of a recent study of patients with coronary artery disease that documents association of SCD with TGFBR2 polymorphism and that thereby suggests a pathogenetic link between SCD and altered. Marfan syndrome is associated with ventricular arrhythmia but risk factors including FBN1 mutation characteristics require elucidation

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Discussion

Conclusion