From biomarker to therapeutic target : the role of myo-inositol and SMIT1 in heart failure and cardiac fibrosis
(2025)
Files
ThèseJulienCumpsNov2025.pdf
Restricted Access - Adobe PDF
- 9.59 MB
Details
- Authors
- Supervisors
- Abstract
- Heart failure (HF) is a complex syndrome in which metabolic disturbances contribute significantly to disease progression. Among these, the cyclic polyol myo-inositol has recently emerged as a metabolite of interest. Transported into the heart by the sodium/myo-inositol transporter 1 (SMIT1), myo-inositol has been implicated in oxidative stress and maladaptive remodelling, yet its clinical and mechanistic relevance in heart failure has not been fully defined. In two large patient cohorts from Belgium and Canada, plasma myo-inositol concentrations were consistently higher in patients with HF than in controls, with the highest levels observed in HFpEF. In this subgroup it was independently associated with impaired renal function, poor clinical outcomes, and structural remodelling markers, particularly fibrotic. These observations suggest that circulating myo-inositol might not only be a biomarker but also a potential contributor to the pathogenesis of HFpEF. Mechanistic studies support this hypothesis. In vitro, exposure of human cardiac fibroblasts to myo-inositol stimulated proliferation, migration, and differentiation into contractile myofibroblasts, thereby enhancing extracellular matrix production. In HFrEF human hearts, SMIT1 expression was markedly increased in fibrotic regions, and transcriptomic analyses linked its upregulation to pro-fibrotic signaling networks. Consistently, mouse models of myocardial infarction demonstrated increased SMIT1 expression in areas of fibrosis. Moreover, cardiac fibroblasts derived from SMIT1-deficient mice showed blunted responses to TGF-β, with reduced myofibroblast differentiation, contractility, and collagen deposition. Taken together, these findings identify the myo-inositol/SMIT1 axis as a key driver of fibroblast activation and myocardial fibrosis. Elevated plasma myo-inositol provides prognostic information in HF, particularly HFpEF, while SMIT1-mediated transport enables the cellular processes that underlie adverse remodelling. This integrative evidence highlights the myo-inositol/SMIT1 pathway as both a marker of disease severity and a potential therapeutic target to mitigate fibrosis and improve outcomes in HF.
- Affiliations
Citations
Cumps, J. (2025). From biomarker to therapeutic target : the role of myo-inositol and SMIT1 in heart failure and cardiac fibrosis.