Increased Left Ventricular mRNA Levels of the Inflammatory Biomarkers Pentraxin‐3 and Interleukin 1 Receptor‐Like 1 are Correlated with Diastolic Dysfunction in a Pre‐Clinical Swine Model of HFpEF

Abstract

Approximately 50% of heart failure cases are diagnosed as heart failure with preserved ejection fraction (HFpEF). HFpEF is challenging to accurately diagnose given traditional biomarkers, such as natriuretic peptide levels, have shown reduced prognostic value for HFpEF patients. Thus, the purpose of this study was to identify biomarkers considered potentially relevant to HFpEF in a new pre‐clinical Ossabaw swine model of heart failure. We hypothesized female Ossabaw swine fed a Western Diet and subject to chronic cardiac pressure‐overload would display physiologic features and biomarkers relevant to HFpEF. Animals were assigned into control (CON, n=5) and Western Diet‐fed aortic‐banded heart failure (WD‐AB, n=4) groups. WD‐AB animals were fed a Western Diet for 10 months started at 2 months of age, and subject to aortic‐banding for 6 months beginning at 6 months of age. Terminal studies were conducted at 12 months of age. Echocardiography was used to examine left ventricular (LV) mechanics (2‐dimensional speckle tracking) the week of terminal studies. RNA‐seq was performed on LV samples and Module Enrichment Analysis was performed on all expressed and varying genes, with networks generated using Ingenuity Pathway Analysis (IPA). qRT‐PCR was used to confirm RNA‐seq data, and group comparisons were made using a student's t‐test with significance reported at the P < 0.10 and P < 0.05 levels. IPA found enrichment of inflammatory and immune gene networks with significance to heart failure in WD‐AB animals. Gene interactions within these lists indicated activation of Pentraxin‐3 (PTX3) and interleukin 1 receptor‐like 1 (IL1RL1), which were chosen for validation given their potential relevance to HFpEF as inflammatory biomarkers. The approximate 5‐fold increase in PTX3 reported by RNA‐seq in WD‐AB compared to CON animals was confirmed separately using qRT‐PCR, as was an increase in IL1RL1 mRNA level. Both PTX3 and IL1RL1 mRNA levels (X‐axis) showed a significant negative correlation with LV apical early diastolic rotation rate (i.e. LV untwisting; Y‐axis), a 2D speckle tracking measure of diastolic function. Group means reflected a right and downward shift along the regression line for both PTX3 and IL1RL1 versus LV untwisting in the WD‐AB group compared to CON, indicating an increase in LV levels of these biomarkers is associated with a decline in LV diastolic mechanical function. In conclusion, WD‐AB animals express increased LV mRNA levels of the inflammatory biomarkers PTX3 and IL1RL1 that are significantly correlated with diastolic function. These data suggest studies in this Ossabaw pre‐clinical model may be useful for elucidating and testing biomarkers with diagnostic value potentially relevant to HFpEF.Support or Funding InformationHL112998 (CAE); VA‐Merit I01BX003271 (RSR); HL125503 (JP); HL136292 (TLD); HL122737, HL123295, & HL129639 (YW).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.