Titin Serum Level Is Elevated in Patients with Myocarditis Depending on Their Genetic Background

Background: The molecular basis of myocarditis is often associated with genetic cardiomyopathies and truncating or loss-of-function variants in the titin gene (TTNtv/lof). Here, we hypothesize that titin serum levels increase in patients with myocarditis, and that this can depend on the genetic background of the disease. Methods: Forty-six patients with myocarditis were included in this study. Genotyping was performed using targeted panel sequencing. Serum titin levels and titin/creatinine ratios were measured in a subgroup of 27 patients. Results: Overall, 47 gene variants were identified, including 13 pathogenic and likely pathogenic variants and 34 variants of uncertain significance. The frequency of TTNtv/lof in patients with myocarditis was 11%. We detected significant differences between the TTNtv/lof group and the genotype-negative group in sustained ventricular tachycardia prevalence, myocardial reverse remodeling (∆ end-diastolic volume) and the prevalence of myocardial necrosis. Serum titin level was elevated in patients with myocarditis, negatively correlated with left ventricular ejection fraction, and was associated with ventricular arrhythmias and a low rate of myocardial reverse remodeling. Conclusions: In patients with biopsy-proven myocarditis, the rate of loss-of-function (LOF) variants was 28%, with a predominance of variants in structural and cytoskeletal genes, and TTNtv/lof variants were detected in 11% of patients. TTNtv/lof variant carriers were characterized by fewer morphological signs of inflammation and more favorable myocardial reverse remodeling. Serum titin levels were elevated in patients with myocarditis. Genotype-negative status of patients was characterized by the highest serum titin levels and titin/creatinine ratios, a lesser degree of myocardial reverse remodeling, sustained ventricular arrhythmias, and a larger area of necrosis.