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Cardiac fibroblasts influence cardiomyocyte structure and function through direct physical interaction and/or by the secretion of soluble factors. A role for cardiac fibroblasts in cardiomyopathies has been proposed but clear mechanisms are still lacking. This in vitro study set out to characterise the influence of cardiac fibroblasts from patients with dilated cardiomyopathy on cardiomyocyte Ca2+ cycling, a fundamental mechanism of cardiac function universally altered in cardiac disease. Human induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) were cultured with human DCM ventricular fibroblasts at a ratio of 2:1 (120,000 fibroblasts to 60,000 iPS-CMs) for 24 hours in three groups: iPS-CMs with fibroblast conditioned medium, co-cultured in transwells to allow bi-directional paracrine communication but prevent physical contact, and iPS-CMs in direct contact with fibroblasts. iPS-CMs alone were used as a baseline. iPS-CMs were field-stimulated at 1Hz and calcium transients were recorded optically. TGF-β, a cytokine previously shown to be important in fibroblast-myocyte interaction, was measured in culture supernate using an ELISA assay. Versus iPS-CMs alone, Ca2+ transient amplitude was reduced in the conditioned medium group but increased in co-culture (p<0.001, F/F0= 4.02±0.07, 3.01±0.03, 4.50±0.07, n= 264, 344 and 306 cells respectively). Time to peak was increased in conditioned medium vs. baseline (p<0.001, 296±5 ms vs. 255.6±3 ms) while reduced in co-culture and further reduced in direct contact (226±3 ms and 195±2 ms respectively, p<0.001). Conditioned medium and co-culture had no effect on time to 80% decay, but direct contact was significantly reduced (p<0.001 vs. baseline, 408±3 ms and 322±2 ms respectively). TGF- β concentration was higher in co-culture supernatant than conditioned medium (210.2 pg/ml vs. 183.7 pg/ml) and reduced in direct contact (137.7 pg/ml). Ventricular fibroblasts from cardiomyopathy patients influence iPS-CM calcium handling properties and the context of this interaction is important in determining the end effects. Effects of soluble mediators are prevented/reversed by culturing fibroblasts in direct contact with cardiac myocytes. Changes in concentration of TGF-β in culture supernates suggest interaction between these cell populations modulates their paracrine activity. Whether this interaction is mediated through physical intercellular connections, mechanical stretch or other paracrine factors is unclear. Further work is needed to identify possible mechanisms and explore the consequences of this interaction in vivo

cardiovascular research

267Direct contact between human cardiac fibroblasts and human induced pluripotent stem cell-derived cardiomyocytes counteracts changes in calcium cycling induced by soluble mediators