Cardiosphere-Derived Cells Reverse Heart Failure With Preserved Ejection Fraction in Rats by Decreasing Fibrosis and Inflammation

摘要

Heart failure with preserved ejection fraction (HFpEF) has become a major public health concern. Its increasing prevalence now exceeds that of heart failure with reduced ejection fraction , , . Outcomes of patients with HFpEF are poor , , and so far, no treatment has been shown to decrease morbidity or mortality , . HFpEF is associated with various cardiovascular risk factors (especially hypertension), extracardiac comorbidities, and aging. The net result is impaired diastolic relaxation and filling of the left ventricle, increased myocardial stiffness, impaired vascular compliance, and increased diastolic pressure , . Myocardial fibrosis and inflammation have been associated with HFpEF , , , , , and with the transition from hypertensive left ventricular (LV) hypertrophy without HFpEF to hypertensive LV hypertrophy with HFpEF href="#bib15" rid="bib15" class=" bibr popnode">(15). Cardiosphere-derived cells (CDCs) are heart cell products with antifibrotic, anti-inflammatory, and angiogenic properties href="#bib16" rid="bib16" class=" bibr popnode">16, href="#bib17" rid="bib17" class=" bibr popnode">17, href="#bib18" rid="bib18" class=" bibr popnode">18, href="#bib19" rid="bib19" class=" bibr popnode">19, href="#bib20" rid="bib20" class=" bibr popnode">20. CDCs, which are currently in phase 2 human trials for scar reduction after myocardial infarction href="#bib5" rid="bib5" class=" bibr popnode">(5), have been shown to be beneficial in models of ischemic href="#bib17" rid="bib17" class=" bibr popnode">17, href="#bib18" rid="bib18" class=" bibr popnode">18, href="#bib21" rid="bib21" class=" bibr popnode">21 and nonischemic cardiomyopathy href="#bib16" rid="bib16" class=" bibr popnode">(16). Thus, we wondered whether CDCs might have disease-modifying activity in HFpEF.Dahl salt-sensitive (DS) rats develop hypertension, hypertrophy, and, eventually, HFpEF on a high-salt diet href="#bib22" rid="bib22" class=" bibr popnode">22, href="#bib23" rid="bib23" class=" bibr popnode">23, href="#bib24" rid="bib24" class=" bibr popnode">24, href="#bib25" rid="bib25" class=" bibr popnode">25, href="#bib26" rid="bib26" class=" bibr popnode">26. Increased fibrosis and inflammation underlie the development of HFpEF, with resultant cachexia, pulmonary congestion, and accelerated mortality href="#bib22" rid="bib22" class=" bibr popnode">22, href="#bib26" rid="bib26" class=" bibr popnode">26, href="#bib27" rid="bib27" class=" bibr popnode">27. Therefore, this model has been widely used to test new treatments for HFpEF href="#bib23" rid="bib23" class=" bibr popnode">23, href="#bib27" rid="bib27" class=" bibr popnode">27, href="#bib28" rid="bib28" class=" bibr popnode">28, href="#bib29" rid="bib29" class=" bibr popnode">29, href="#bib30" rid="bib30" class=" bibr popnode">30, href="#bib31" rid="bib31" class=" bibr popnode">31. Here, we tested the efficacy of CDCs in improving LV structure and function and overall outcome in DS rats with HFpEF.