Truncations of Titin and Left Atrial Cardiomyopathy: Comment on Henkens et al.'s article, Left Atrial Function in Patients With Titin Cardiomyopathy

Over the past 2 decades, truncating variants in the TTN gene (TTNtv), which encodes the sarcomeric protein titin, have emerged as a leading cause of dilated cardiomyopathy (DCM). 1 Gerull B Gramlich M Atherton J et al. Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy. Nat Genet. 2002; 30: 201-204https://doi.org/10.1038/ng815 Crossref PubMed Scopus (470) Google Scholar , 2 Gerull B Atherton J Geupel A et al. Identification of a novel frameshift mutation in the giant muscle filament titin in a large Australian family with dilated cardiomyopathy. J Mol Med. 2006; 84: 478-483https://doi.org/10.1007/s00109-006-0060-6 Crossref PubMed Scopus (65) Google Scholar , 3 Siu BL Niimura H Osborne JA et al. Familial dilated cardiomyopathy locus maps to chromosome 2q31. Circulation. 1999; 99: 1022-1026https://doi.org/10.1161/01.CIR.99.8.1022 Crossref PubMed Scopus (115) Google Scholar Present in approximately 10%–20% of individuals with DCM as compared with 1% of the general population, TTNtv are now considered the most prevalent genetic driver of the disease. 4 Haggerty CM Damrauer SM Levin MG et al. Genomics: first evaluation of heart disease associated with titin-truncating variants. Circulation. 2019; 140: 42-54https://doi.org/10.1161/circulationaha.119.039573 Crossref PubMed Scopus (0) Google Scholar ,5 Jordan E Peterson L Ai T et al. Evidence-based assessment of genes in dilated cardiomyopathy. Circulation. 2021; 144: 7-19https://doi.org/10.1161/CIRCULATIONAHA.120.053033 Crossref PubMed Scopus (142) Google Scholar The mechanisms by which TTNtv give rise to DCM remain uncertain, but both haploinsufficiency and “poison peptides” (incorporation of truncated TTN into the sarcomere) are thought to contribute. 6 McAfee Q Chen CY Yang Y et al. Truncated titin proteins in dilated cardiomyopathy. Sci Translat Med. 2021; 13: eabd7287https://doi.org/10.1126/scitranslmed.abd7287 Crossref PubMed Google Scholar ,7 Fomin A Gärtner A Cyganek L et al. Truncated titin proteins and titin haploinsufficiency are targets for functional recovery in human cardiomyopathy due to TTN mutations. Sci Translat Med. 2021; 13: eabd3079https://doi.org/10.1126/scitranslmed.abd3079 Crossref PubMed Google Scholar Studies of TTNtv in cardiomyopathy have largely examined the effects of TTNtv on the left ventricle (LV), with several reports associating TTNtv with both clinical and subclinical increases in LV size and reductions in LV contractile function. 8 Herman DS Lam L Taylor MRG et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012; 366: 619-628https://doi.org/10.1056/NEJMoa1110186 Crossref PubMed Scopus (954) Google Scholar ,9 Schafer S de Marvao A Adami E et al. Titin-truncating variants affect heart function in disease cohorts and the general population. Nature Genet. 2016; 49: 46-53https://doi.org/10.1038/ng.3719 Crossref PubMed Scopus (203) Google Scholar Left Atrial Function in Patients with Titin CardiomyopathyJournal of Cardiac FailurePreviewTruncating variants in titin (TTNtv) are the most prevalent genetic etiology of dilated cardiomyopathy (DCM). Although TTNtv has been associated with atrial fibrillation, it remains unknown whether and how left atrial (LA) function differs between patients with DCM with and without TTNtv. We aimed to determine and compare LA function in patients with DCM with and without TTNtv and to evaluate whether and how left ventricular (LV) function affects the LA using computational modeling. Full-Text PDF Open Access