Rationale: Activated cardiac fibroblasts (CF) are crucial players in the cardiac damage response; excess fibrosis, however, may result in myocardial stiffening and heart failure development. Inhibition of activated CF has been suggested as a therapeutic strategy in cardiac disease, but whether this truly improves cardiac function is unclear. Objective: To study the effect of CF ablation on cardiac remodeling. Methods and Results: We characterized subgroups of murine CF by single-cell expression analysis and identified periostin as the marker showing the highest correlation to an activated CF phenotype. We generated bacterial artificial chromosome–transgenic mice allowing tamoxifen-inducible Cre expression in periostin-positive cells as well as their diphtheria toxin-mediated ablation. In the healthy heart, periostin expression was restricted to valvular fibroblasts; ablation of this population did not affect cardiac function. After chronic angiotensin II exposure, ablation of activated CF resulted in significantly reduced cardiac fibrosis and improved cardiac function. After myocardial infarction, ablation of periostin-expressing CF resulted in reduced fibrosis without compromising scar stability, and cardiac function was significantly improved. Single-cell transcriptional analysis revealed reduced CF activation but increased expression of prohypertrophic factors in cardiac macrophages and cardiomyocytes, resulting in localized cardiomyocyte hypertrophy. Conclusions: Modulation of the activated CF population is a promising approach to prevent adverse cardiac remodeling in response to angiotensin II and after myocardial infarction.

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Funding Acknowledgements Type of funding sources: None. Background Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) is an advanced technique in extracorporeal life support (ECLS) used to support extreme circulatory failure including patients with cardiac arrest and cardiogenic shock refractory to conventional support. It is a long-standing belief that peripheral V-A ECMO poses increased afterload to the inured heart, but conventional echocardiographic measurements are often insensitive in detecting subtle changes in loading conditions. Purpose This study aimed to evaluate the effects of varying blood flow during peripheral V-A ECMO on intrinsic myocardial contractility, using detailed echocardiographic assessment including speckle tracking echocardiography (STE). Methods Adult patients with acute cardiogenic shock who were supported by peripheral V-A ECMO from April 2019 to September 2020 were recruited. Serial hemodynamic and cardiac performance parameters were measured by transthoracic echocardiogram (TTE) within 48 hours after implementation of V-A ECMO, at different levels of extracorporeal blood flow – 100%, 120% and 50% of target blood flow (TBF). Results A total of 30 patients were included. 22 (71%) were male, and the mean (SD) age was 54 (13) years. The major indications for V-A ECMO were myocardial infarction (19, 63% patients), and myocarditis (5, 17%). With a decrease in extracorporeal blood flow from 100% to 50% of TBF, mean arterial pressure (MAP) dropped from 76+/-3 to 64+/-3mmHg (p <0.001), and cardiac index (CI) increased from 0.89+/-0.13 to 1.27+/-0.18L/min/m2 (p < 0.001). All indices of left ventricular contractility improved at a lower extracorporeal blood flow: the myocardial contractility measured by global longitudinal peak systolic strain (GLPSS) improved from -3+/-0.7% to -5+/-0.8% (p < 0.001); left ventricular ejection fraction (LVEF) increased from 21.5+/-2.6% to 30.9+/-2.7% (p < 0.001) and 19.7+/-3.1% to 28.4+/-3.2% (p < 0.001) by biplane and linear methods, respectively; left ventricular index of myocardial performance (LIMP) improved from 1.51+/-0.12 to 1.03+/-0.09 (p < 0.001). Similar findings were reproduced when comparing left ventricular contractility at extracorporeal blood flows of 120% and 50% of TBF. Conclusions The ECMO blood flow rate in peripheral V-A ECMO is inversely related to myocardial contractility, and is quantifiable by myocardial strain measured by STE.