Titin expression in peripheral monocytes as a biomarker of left ventricular dysfunction in acute myocarditis

Background Myocarditis is a polymorphic disease characterized by marked heterogeneity in both clinical presentation and disease course. A fundamental clinical challenge in myocarditis is explaining why only a subset of individuals exposed to common triggers—predominantly viral infections—develop clinically significant myocardial inflammation, exhibiting highly variable phenotypes from spontaneous resolution to fulminant heart failure or chronic dilated cardiomyopathy. Genome-wide association studies identify immune loci (e.g., HLA-DR4) linked to excessive cytokine production (IL-1β, IL-17, TNF-α), matrix metalloproteinase dysregulation, and fulminant phenotypes.(1) Concurrently, cardiomyopathy-associated variants—particularly in titin (TTN), desmoplakin, and lamin —enrich in myocarditis cohorts (8-30% prevalence vs. <1% controls), supporting a "two-hit" hypothesis: genetic predisposition (hit 1) plus environmental insult (hit 2). (2) Specially (TTN), a giant structural and signaling protein of striated muscle, participates in intracellular signaling networks and cytoskeletal organization, potentially influencing cell activation, trafficking, and interactions with other tissues, including the heart. Methods In this pilot study, 29 patients with acute myocarditis and 10 healthy individuals were prospectively enrolled. Peripheral blood was obtained on the first day of hospital admission, total RNA was isolated from peripheral blood mononuclear cells (PBMCs), and TTN mRNA expression was quantified. All participants underwent a standard M-mode and two-dimensional (2D) echocardiographic examination as well 2D speckle-tracking strain analysis. Cardiac MRI with LGE protocols within the first week of hospital admission. Results TTN expression in Peripheral blood mononuclear cells (PBMCs ) was significantly higher in patients with acute myocarditis compared with healthy controls (p = 0.015), corresponding to a 2.8-fold median increase. Moreover, TTN expression showed a strong positive correlation with global longitudinal strain impairment (Spearman’s r = 0.576, p < 0.001), a moderate positive correlation with peak hs-cTnI levels (r = 0.435, p = 0.021; Figure 2), a moderate inverse correlation with baseline LVEF (r = −0.421, p = 0.025). Conclusions These findings support a pathophysiological link between TTN-related pathways in peripheral immune cells and myocardial injury in acute myocarditis and raise the hypothesis that TTN expression in monocytes may serve as a novel biomarker of disease severity and long-term ventricular remodeling. Further studies in larger cohorts are warranted to validate these results and to elucidate the mech-anistic role of titin in immune-cardiac cross-talk.