Abstract Body: Introduction: Heart Failure (HF) with preserved ejection fraction (HFpEF) accounts for almost half of the HF population, and the elderly group is at higher risk. HFpEF can be life-threatening and management options are limited. We previously established the importance of thyroid hormones (THs) and inflammation in different cardiovascular disease models. However, the mechanisms of aging HFpEF pathogenesis are unclear. Long-noncoding ribonucleic acids (lncRNAs; >200 nucleotides) outnumber protein-coding counterparts by >4-fold and are clinically important. We hypothesized that lncRNAs act as mediators in aging HFpEF with thyroid dysfunction.
Methods: Wild-type control, ZSF1 lean control, and ZSF1 obese (HFpEF) rats at 5-, 13-, ± 20-month (mo) age groups were studied (males and females; maximum 14/group). We employed cardiac ultrasonography, morphometric analyses, lncRNA microarray, real-time qPCR, TH enzyme-linked immune-sorbent, inflammation, and epigenetic assays. Statistical analyses were performed using one-way or two-way ANOVAs and t-tests wherever applicable.
Results: Echocardiography showed that ZSF1 obese rats (HFpEF) had unaffected fractional shortening compared to both controls (51% to 53.8%; p>0.05). Morphometrics showed significant increases in weights of the body, kidney, liver, and/or left ventricle in the ZSF1 groups (worse in obese) at 5-, 13-, ± 20-mo time-points (p<0.05). Serum TH levels were significantly decreased at 5- and/or 13-mo in HFpEF vs. controls (p<0.05). LncRNA microarray showed several significant differentially expressed lncRNAs and mRNAs in HFpEF compared to controls. In addition, key lncRNAs were validated via real-time qPCR at 5-, 13-, ± 20-mo time-points (p<0.05; fold change ±1.5). Significantly enriched pathways including inflammation were also identified using GO and KEGG analyses. Correspondingly, inflammatory cytokines were significantly altered in HFpEF both in serum and cardiac tissues at 5- and 13-mo (p<0.05).
Conclusions: These results indicate that lncRNAs play important roles in HFpEF associated with hypothyroidism and inflammation. These studies serve as significant steps in the identification of key targets in HFpEF offering potentially valuable translational opportunities.