Reverse electrical remodeling in rats with heart failure and preserved ejection fraction
Jae Hyung Cho, Peter J. Kilfoil, Rui Zhang, Ryan E. Solymani, Catherine Bresee, Elliot M. Kang, Kristin Luther, Russell G. Rogers, Geoffrey de Couto, Joshua I. Goldhaber, Eduardo Marbán, Eugenio Cingolani
Jae Hyung Cho, Peter J. Kilfoil, Rui Zhang, Ryan E. Solymani, Catherine Bresee, Elliot M. Kang, Kristin Luther, Russell G. Rogers, Geoffrey de Couto, Joshua I. Goldhaber, Eduardo Marbán, Eugenio Cingolani
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Research Article Cardiology Stem cells

Reverse electrical remodeling in rats with heart failure and preserved ejection fraction

Abstract

Sudden death is the most common mode of exodus in patients with heart failure and preserved ejection fraction (HFpEF). Cardiosphere-derived cells (CDCs) reduce inflammation and fibrosis in a rat model of HFpEF, improving diastolic function and prolonging survival. We tested the hypothesis that CDCs decrease ventricular arrhythmias (VAs) and thereby possibly contribute to prolonged survival. Dahl salt-sensitive rats were fed a high-salt diet to induce HFpEF. Allogeneic rat CDCs (or phosphate-buffered saline as placebo) were injected in rats with echo-verified HFpEF. CDC-injected HFpEF rats were less prone to VA induction by programmed electrical stimulation. Action potential duration (APD) was shortened, and APD homogeneity was increased by CDC injection. Transient outward potassium current density was upregulated in cardiomyocytes from CDC rats relative to placebo, as were the underlying transcript (Kcnd3) and protein (Kv4.3) levels. Fibrosis was attenuated in CDC-treated hearts, and survival was increased. Sudden death risk also trended down, albeit nonsignificantly. CDC therapy decreased VA in HFpEF rats by shortening APD, improving APD homogeneity, and decreasing fibrosis. Unlike other stem/progenitor cells, which often exacerbate arrhythmias, CDCs reverse electrical remodeling and suppress arrhythmogenesis in HFpEF.

Authors

Jae Hyung Cho, Peter J. Kilfoil, Rui Zhang, Ryan E. Solymani, Catherine Bresee, Elliot M. Kang, Kristin Luther, Russell G. Rogers, Geoffrey de Couto, Joshua I. Goldhaber, Eduardo Marbán, Eugenio Cingolani

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Figure 1

Experimental protocol, generation of CDCs, and echocardiographic measurement of systolic and diastolic function.

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Experimental protocol, generation of CDCs, and echocardiographic measure...
(A) DSS rats were fed HS or NS diet from 7 weeks of age. At 14–15 weeks of age, baseline echocardiography was performed to assess EF, E/A, and E/E′ ratios. HS rats with diastolic dysfunction, preserved EF, and objective HF signs were diagnosed with HFpEF. PES was performed and arrhythmogenic HFpEF rats were randomly assigned to intracoronary injection of CDCs versus PBS. Follow-up experiments were performed 4 weeks after the injection. (B) Allogeneic CDCs were generated from cardiac explant from a Sprague Dawley rat as described in the Methods. CDCs from passages 4–6 were used for injection. (C) Representative M-mode of parasternal short axis views of transthoracic echocardiography. (D) EF was preserved 4 weeks after injection in both groups (65% ± 6% in CDCs vs. 65% ± 12% in PBS, P = 0.41). (E) Representative E/A ratio from pulse wave Doppler at the mitral level. (F) Both CDC- and PBS-injected rats normalized E/A ratio 4 weeks after injection (1.56 ± 0.31 in CDCs vs. 1.54 ± 038 in PBS, P = 0.99). (G) Representative E/E′ ratio from tissue Doppler imaging. (H) E/E′ ratio of CDC-injected rats was decreased compared with PBS-injected rats (13.7 ± 3.0 in CDCs vs. 19.2 ± 3.5 in PBS, P < 0.001), which verified the improvement in diastolic function. **P < 0.001. Error line indicates mean and standard deviation. Control rats were n = 13 at baseline and 4-week follow-up. PBS-injected HFpEF rats were n = 23 at baseline and n = 10 at 4 weeks. CDC-treated HFpEF rats were n = 21 at baseline and n = 15–16 at 4 weeks. Mixed-model regression was used for D, F, and H.