Abstract P135: Is Heart Failure With Preserved Ejection Fraction a Gut Disorder?
Background and Objective: Heart failure (HF) with preserved ejection fraction (HFpEF) accounts for ~50% of HF hospitalizations, is associated with poor quality of life and, has a mortality rate comparable with many cancers. To date, no therapies have proven effective in slowing disease progression, mainly due to limited understanding of underlying mechanisms. Mounting evidence suggests the intestine and gut microbiota play an important role in chronic inflammation in HF, and also hypertension, a history of which is present in most HFpEF patients. However, information about intestinal involvement in HFpEF is limited. Accordingly, we investigated the hypothesis that disturbed intestinal barrier function contributes to translocation of endotoxin and inflammation activation in HFpEF. Method and Results: Left ventricular (LV) function, intestinal permeability, circulating lipopolysaccharide (LPS, an endotoxin and strong inducer of pro-inflammatory cytokines) and high-mobility group box protein (HMGB1, a nuclear protein that triggers inflammation) were examined in a mouse model of HFpEF [4w continuous infusion of subpressor dose of angiotensin II (0.2mg/kg/d)] and 4 patients with HFpEF and 4 reference subjects. Impaired LV diastolic function (increase in LVEDP and Tau, both p<0.05) occurred in the mice with 3-fold increased intestinal permeability, 1.8-fold elevated LPS levels (137±7 vs control 77±6 pg/ml, p<0.005) and 4-fold increased HMGB1 levels (238±42 vs control 56±16 ng/ml, p<0.05). Stimulating human coronary artery endothelial cells with 10μg/ml LPS for 48h resulted in 3-fold elevation of HMGB1 (29±4 vs control 12±3 ng/ml, p<0.05) that was suppressed by butyrate (17±3 ng/ml). Patients with HFpEF had a 2-fold increase in zonulin (31±3 vs 14±2 ng/ml) and 4-fold LPS elevation (152±18 vs 32±3 pg/ml), (both p<0.05 vs reference subjects), confirming gut barrier dysfunction with translocation of endotoxin. Conclusions: HFpEF is associated with increased gut permeability that facilitates LPS translocation activating inflammation resulting in endothelial damage. Thus, the gut could be a novel target for therapeutic interventions in patients with HFpEF.