Abstract
Patients with Marfan syndrome (MFS) have an increased risk of aortic aneurysm formation, dissection and development of a subtle cardiomyopathy. We analyzed amino acid and lipid metabolic pathways in MFS patients, seeking biomarker patterns as potential monitoring tools of cardiovascular risk with deterioration of myocardial function. We assessed myocardial function in 24 adult MFS patients and compared traditional laboratory values and mass spectrometry-based amino acid, phospholipid and acylcarnitine metabolomes in patients with those in healthy controls. Analytes for which values differed between patients and controls were subjected to regression analysis. A high proportion of patients had signs of impaired diastolic function and elevated serum levels of NT-proBNP. Patients had lower serum levels of taurine, histidine and PCaeC42:3 than controls. The evidence of diastolic dysfunction, aortic root dimensions and history of aortic root surgery correlated with NT-proBNP and taurine levels. Alterations in serum levels of metabolism derived analytes link MFS pathophysiology with inflammation, oxidative stress and incipient cardiomyopathy.
Highlights
Marfan syndrome (MFS) is an autosomal-dominant systemic disorder of connective tissue
After applying all inclusion and exclusion criteria to the 40 patients who are actively managed in the aortopathy clinic of the Department of Pediatrics III (Pediatric Cardiology), Medical University of Innsbruck, Austria, 24 patients with confirmed MFS were eligible for the study
With a combined imaging and serum metabolomics approach in a group of adult MFS patients without major valve disease and heterogeneous in terms of presence or absence of prior aortic root surgery and type of surgical approach we found that a high proportion of patients revealed altered diastolic myocardial function and that their serum levels of histidine, taurine and PCaeC42:3—all of the three analytes reportedly involved in inflammation, oxidative stress, endothelial function processes—were lower than in controls
Summary
Marfan syndrome (MFS) is an autosomal-dominant systemic disorder of connective tissue. MFS is caused by mutations in FBN1, encoding the glycoprotein fibrillin-1. Assemblages of fibrillin-1 form microfibrils in the extracellular matrix, providing elasticity and structural integrity. By storing or releasing the critical agent transforming growth factor β (TGF-β), these microfibrils regulate its bioavailability; TGF-β usually is secreted in an inactivated (latent) form that requires proteolysis to permit induction of collagen synthesis and, in counterbalance, of matrix metalloproteinase (MMP) activity to degrade extracellular matrix proteins [3]. Mutated fibrillin-1 forms microfibrils poorly, with failed sequestration of latent TGF-β. Mutations in FBN1 and consequent deficiency in fibrillin-1, as in MFS, result in structural weakness of connective tissue due to impaired microfibril formation and in dysfunctional TGF-β signaling [4,5]
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