Noncoding and coding mechanisms of aging-related heart failure with preserved ejection fraction associated 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 pathophysiological processes. However, the roles of lncRNAs in aging HFpEF associated with thyroid hormone (TH) dysfunction are unclear. We used the well-established ZSF1 rat model to investigate early and severe age-related HFpEF in 5-, 13- or 20-months-old (mo) animals. Both serum THs significantly decreased in HFpEF in a temporal manner. Echocardiograms showed preserved cardiac function. Gravimetric and histologic analyses showed significant cardiac hypertrophy in HFpEF. Microarrays and RT-qPCR revealed that three lncRNAs were significantly increased predominantly in 13-mo HFpEF. Knockdown of lncRNA 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-aging-related hypothyroid HFpEF. Further studies may develop translatable diagnostic and therapeutic targets for HFpEF.