Noncoding and coding mechanisms of aging heart failure with preserved ejection fraction with thyroid dysfunction.

Heart Failure with preserved Ejection Fraction (HFpEF) is a lethal, heterogeneous, geriatric syndrome. Long noncoding RNAs (lncRNAs) constitute the majority of the functional mammalian transcriptome and are key regulators in complex pathophysiology. However, the roles of lncRNAs in aging HFpEF associated with thyroid hormone (TH) dysfunction are unclear. We investigated the well-established ZSF1 model in early and severe, aged HFpEF (5-, 13-, and 20-months [mo]). Both serum THs significantly decreased in HFpEF in a temporal manner. Echocardiogram showed preserved cardiac function. Morphometric and histologic analyses showed significant cardiac hypertrophy in HFpEF. LncRNA microarray and RT-qPCR revealed that three lncRNAs were significantly increased predominantly in 13-mo HFpEF. LncRNA knockdown showed improvement in cell viability, which was further enhanced with T3 (active TH). Microarray analyses showed that two mRNAs were significantly altered in early HFpEF. We also identified previously unreported tissue and serum inflammatory cytokine markers in early and late HFpEF. Taken together, we have shown novel noncoding and coding markers in early and/or late-aged hypothyroid HFpEF. Further studies may develop translatable diagnostic and therapeutic targets for HFpEF.