Clinical evaluation of a matrix metalloproteinase-12 cleaved fragment of titin as a cardiovascular serological biomarker
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RESEARCH
Open Access
Clinical evaluation of a matrix metalloproteinase-12 cleaved fragment of titin as a cardiovascular serological biomarker Efstathios Vassiliadis1,2*, Lars M Rasmussen3, Inger Byrjalsen1, Dorthe Vang Larsen1, Rajiv Chaturvedi4, Susanne Hosbond5, Lotte Saabye5, Axel CP Diederichsen5, Federica Genovese1, Kevin L Duffin6, Qinlong Zheng7, Xiaoliang Chen7, Diana J Leeming1, Claus Christiansen1 and Morten A Karsdal1,3
Abstract Background: Titin is a muscle-specific protein found in cardiac and skeletal muscles which is responsible for restoring passive tension. Levels and functioning of titin have been shown to be affected by cardiac damage. Due to the inherent difficulty of measuring titin levels in vivo in a clinical setting, we aimed to develop an assay that could reliably measure fragments of degraded titin in serum and potentially be used in the assessment of cardiac muscle damage. Methods: A competitive ELISA was developed to specifically measure levels of the titin sequence 12670’ NVTVEARLIK 12679’, derived by the degradation of titin by matrix metalloproteinase (MMP)-12. Serum samples from 90 individuals were divided into 3 equally sized groups. One group had been diagnosed with acute myocardial infarction (AMI) while the remaining two were asymptomatic individuals either with CT-scan signs of coronary calcium (CT-plusCa) or without coronary calcium (CT-noCa). Results: Mean geometric levels of the titin fragment in the CT-noCa group were 506.5 ng/ml (±43.88). The CT-plusCa group showed 50.6% higher levels of the marker [763 ng/ml (±90.14)] (P < 0.05). AMI patients showed 56.3% higher levels [792 ng/ml (±149)] (P < 0.05). Conclusions: The titin-12670 fragment is present in both individuals with undiagnosed and diagnosed CVD. The statistically significant increase in level of the marker in the AMI group is indicative that this neoepitope biomarker may be a useful serological marker in AMI. Keywords: Titin, CVD, MMP-12, Cardiovascular, Acute myocardial infarction, Biomarker, Neoepitope
Background Titin, also known as connectin, is a sarcomeric protein expressed in cardiac and skeletal muscle. It is the largest known protein in nature, with a molecular weight of up to 3700 kDa [1]. Its main function in the heart is to act as a long molecular spring by restoring passive tension during myocardial stretch and enhancing or terminating active force thus regulating the Frank-Starling mechanism of the heart [2-5]. Distinct passive stress differences * Correspondence: [email protected] 1 Nordic Bioscience A/S, Herlev Hovedgade 207, DK-2730 Herlev, Denmark 2 School of Endocrinology, University of Southern Denmark, Odense, Denmark Full list of author information is available at the end of the article
have been recorded between cardiac and skeletal muscles [6]. Titin has two isoforms that are co-expressed in the sarcomere, the N2A which is the larger of the two and is found in both skeletal and myocardial muscle, and the N2B isoform which is smaller, stiffer and is found in cardiac muscle [1,7-12]
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