Cardiosphere-derived cells reverse heart failure with preserved ejection fraction (HFpEF) in rats by decreasing fibrosis and inflammation.

BACKGROUND: The pathogenesis of HFpEF is unclear, but fibrosis, inflammation and hypertrophy have been put forth as likely contributors. CDCs are heart-derived cell products with anti-fibrotic and anti-inflammatory properties.

OBJECTIVES: We questioned whether allogeneic rat CDCs might be able to decrease manifestations of HFpEF in hypertensive rats.

METHODS: Starting at 7 weeks of age, Dahl salt-sensitive rats were fed a high-salt diet for 6-7 weeks and randomized to receive intracoronary CDCs or placebo. Dahl rats fed normal chow served as controls.

RESULTS: High-salt rats developed hypertension, left ventricular (LV) hypertrophy and diastolic dysfunction, without impairment of ejection fraction. Four weeks after treatment, diastolic dysfunction resolved in CDC-treated rats but not in placebo. The improved LV relaxation was associated with lower LV end-diastolic pressure, decreased lung congestion and enhanced survival in CDC-treated rats. Histology and echocardiography revealed no decrease in cardiac hypertrophy after CDC treatment, consistent with the finding of sustained, equally-elevated blood pressure in CDC- and placebo-treated rats. Nevertheless, CDC treatment decreased LV fibrosis and inflammatory infiltrates. Serum inflammatory cytokines were likewise decreased after CDC treatment. Whole-transcriptome analysis revealed major HFpEF-related, CDC-reversed changes in numerous transcripts, including many involved in inflammation and/or fibrosis.

CONCLUSION: CDCs normalized LV relaxation and LV diastolic pressure while improving survival in a rat model of HFpEF. The benefits of CDCs occurred despite persistent hypertension and cardiac hypertrophy. By selectively reversing inflammation and fibrosis, CDCs may be beneficial in the treatment of HFpEF.