Abstract Body: Introduction: Cardiac fibroblasts regulate myocardial and extracellular matrix remodeling. Previous studies established cardiomyocyte (CM) hypocontractility expands cardiac fibroblast number, but whether this renders the heart susceptible to worsened remodeling in response to pathologic stimuli remains unknown.

Hypothesis: Increased cardiac fibroblast abundance is sufficient to worsen adverse cardiac remodeling in response to hypertensive stimuli.

Methods: CM hypocontractility was induced in FVB mice using a doxycycline (DOX)-repressible I61Q mutation in cardiac troponin C (cTnC). I61Q mice and non-transgenic controls (CON) were aged to 2 months, which doubles the number of cardiac fibroblasts without initiating collagen accrual and eccentric hypertrophic growth, then fed DOX chow for 1 month to repress the I61Q transgene and restore expression of wild-type cTnC and myocyte function. Mice were then implanted with osmotic minipumps bearing phenylephrine/angiotensin II (PE/ANGII) for 2 weeks, with water-infused pumps used as vehicle controls. Cardiac pathology was assessed using echocardiography and histology.

Results: PE/ANGII significantly increased left ventricular posterior wall thickness and cardiac fibrosis in both I61Q and CON mice, compared to vehicle-treated mice within each genotype. Fractional shortening, chamber diameter, and wall thickness were not altered between PE/ANGII-treated CON and I61Q mice. PE/ANGII elevated PDGFRa⁺ cardiac fibroblast abundance in CON mice compared to vehicle as expected, whereas I61Q mice, which already have elevated numbers of PDGFRa⁺ fibroblasts did not experience a further expansion with PE/ANGII, suggesting fibroblast number was already at a homeostatic set point. While cardiac fibrosis was unaltered between CON and I61Q PE/ANGII groups, PE/ANGII-treated I61Q mice had increased normalized heart weight compared to CON PE/ANGII mice.

Conclusions: CM hypocontractility elevates fibroblast abundance, predisposing the heart to worsened hypertrophic remodeling in response to hypertensive stimuli. Ongoing studies are investigating fibroblast-CM crosstalk in recovered I61Q mice before and after PE/ANGII, and the generalizability of these findings in other models of fibrosis.