Cardiac Biomarkers and DM
Cardiac rhythm disturbances represent a cardinal feature and a leading cause of death in DM. To elevate the level of patient cardiac care, consensus-based care recommendations are now available for DM1, children with CDM or DM1, and DM2. The molecular basis of cardiac dysfunction in DM, however, has been difficult to discern. It has been suggested that serum levels of high-sensitive cardiac troponin T and N-terminal pro B-type natriuretic peptide may be predictive of cardiac risk and potentially useful for stratification (Valaperta et al., 2016 and 2017), but these have not yet shown promise as efficacy biomarkers for interventional clinical trials. Similarly, mis-splicing of SCN5A has been implicated in DM cardiac conduction defects (Freyermuth et al., 2016; Pang et al., 2018), but its value as a clinical trial tool has not been determined. Thus, specific biomarkers for cardiac involvement in DM have not yet been established and their absence represents an important gap in the ability to assess candidate therapeutics for a key phenotype in this patient group.
Assessing Mis-Splicing of Cardiac-Relevant Transcripts
Drs. Rosanna Cardani and Giovanni Meola (IRCCS-Policlinico San Donato and University of Milan) and colleagues initiated a study of alternative splicing of several genes that could be used to follow the cardiac phenotype in DM1 or DM2 patients. Analyses were performed in patients with and without cardiac involvement; molecular analyses focused on TNNT2 expression, in part because it is mis-spliced in both skeletal and cardiac muscle in DM. Dr. Laura Valentina Renna, a former MDF fellow, contributed to this work.
The research team evaluated skeletal muscle biopsies in 24 DM1, 9 DM2 patients, and 10 age-matched controls; subjects also underwent muscle strength evaluations (MRC scale), staging of DM1 (MIRS), ECG, and Holter tests. Their study also included a range of histologic and immunocytochemical markers to establish correlations between observed splicopathies and skeletal muscle status.
TNNT2 encodes cardiac troponin T (cTnT). The research team showed that TNNT2 mis-splicing was more evident in skeletal muscle biopsies from DM1 subjects (where the fetal isoform was > 50% of total transcript) versus DM2. The authors suggest that greater mis-splicing in DM1 may relate not only to the more severe myopathy, but to the general disease severity, including cardiac involvement, in DM1. Finally, the level of TNNT2 mis-splicing strongly correlated with QRS duration abnormalities in DM1 (but not DM2), suggesting that alternative splicing of TNNT2 may have value as a cardiac biomarker.
TNNT2 as a Biomarker of DM1 Severity?
Overall, the authors cannot conclude that TNNT2 mis-splicing is a specific biomarker of cardiac involvement in DM, only that data are suggestive that it may be when further data are acquired. They do argue that TNNT2 mis-splicing may function as a biomarker of disease severity in DM1, the potential of which should be explored in natural history studies and interventional clinical trials.
High-sensitive cardiac troponin T (hs-cTnT) assay as serum biomarker to predict cardiac risk in myotonic dystrophy: A case-control study.
Valaperta R, Gaeta M, Cardani R, Lombardi F, Rampoldi B, De Siena C, Mori F, Fossati B, Gaia P, Ferraro OE, Villani S, Iachettini S, Piccoli M, Cirillo F, Pusineri E, Meola G, Costa E.
Clin Chim Acta. 2016 Dec 1;463:122-128. doi: 10.1016/j.cca.2016.10.026. Epub 2016 Oct 22.
Cardiac involvement in myotonic dystrophy: The role of troponins and N-terminal pro B-type natriuretic peptide.
Valaperta R, De Siena C, Cardani R, Lombardia F, Cenko E, Rampoldi B, Fossati B, Brigonzi E, Rigolini R, Gaia P, Meola G, Costa E, Bugiardini R.
Atherosclerosis. 2017 Dec;267:110-115. doi: 10.1016/j.atherosclerosis.2017.10.020. Epub 2017 Oct 21.
Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy.
Freyermuth F, Rau F, Kokunai Y, Linke T, Sellier C, Nakamori M, Kino Y, Arandel L, Jollet A, Thibault C, Philipps M, Vicaire S, Jost B, Udd B, Day JW, Duboc D, Wahbi K, Matsumura T, Fujimura H, Mochizuki H, Deryckere F, Kimura T, Nukina N, Ishiura S, Lacroix V, Campan-Fournier A, Navratil V, Chautard E, Auboeuf D, Horie M, Imoto K, Lee KY, Swanson MS, de Munain AL, Inada S, Itoh H, Nakazawa K, Ashihara T, Wang E, Zimmer T, Furling D, Takahashi MP, Charlet-Berguerand N.
Nat Commun. 2016 Apr 11;7:11067. doi: 10.1038/ncomms11067.
CRISPR -Mediated Expression of the Fetal Scn5a Isoform in Adult Mice Causes Conduction Defects and Arrhythmias.
Pang PD, Alsina KM, Cao S, Koushik AB, Wehrens XHT, Cooper TA.
J Am Heart Assoc. 2018 Oct 2;7(19):e010393. doi: 10.1161/JAHA.118.010393.
TNNT2 Missplicing in Skeletal Muscle as a Cardiac Biomarker in Myotonic Dystrophy Type 1 but Not in Myotonic Dystrophy Type 2.
Bosè F, Renna LV, Fossati B, Arpa G, Labate V, Milani V, Botta A, Micaglio E, Meola G, Cardani R.
Front Neurol. 2019 Sep 27;10:992. doi: 10.3389/fneur.2019.00992. eCollection 2019.