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Treatment with the Soluble Guanylate Cyclase Stimulator IW‐1973 Reduces N‐terminal Pro B‐type Natriuretic Peptide and Improves Heart Function in Rat Models of Heart Failure with Preserved Ejection Fraction and Heart Failure with Reduced Ejection Fraction
Author(s) -
Shea Courtney,
Liu Guang,
Sarno Renee,
Lonie Elisabeth,
Zimmer Dan,
Currie Mark,
Masferrer Jaime
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.676.2
Subject(s) - heart failure , medicine , ejection fraction , natriuretic peptide , cardiology , endocrinology , cardiac function curve , heart failure with preserved ejection fraction
Intracellular cGMP levels are reduced in many cardiovascular diseases, including heart failure, due to high levels of reactive oxygen species, which inactivate NO, the endogenous ligand of soluble guanylate cyclase (sGC). sGC “stimulators” bind sGC receptors and synergize with NO to increase cGMP production. IW‐1973 is a novel sGC stimulator in clinical development that has been previously shown to lower mean arterial pressure and heart hypertrophy in Dahl Salt‐Sensitive (Dss) rats. Hypothesis We assessed the hypothesis that sGC stimulator IW‐1973 would preserve cardiac function in 2 rat models of heart failure: Dss (HFpEF) and post MI (HFrEF). Methods In male Dss rats, heart failure was induced by high salt diet (8%); IW‐1973 (10 mg/kg/day in chow; n=8) was added after 2 weeks, for 5 more weeks. In a post MI model, heart failure was induced by surgical ligation of the left coronary artery of male Sprague Dawley rats (n=10), IW‐1973 (10 mg/kg/day in chow) was administered for 8 weeks. In both models, echocardiography was conducted at the end of the experiment; at necropsy, plasma, serum, urine and tissues samples were collected. All comparisons are vs untreated controls (n=9 and 11). Results In Dss, IW‐1973‐treated rats had lower heart/body mass ratio (3.8±0.1 vs 4.6±0.1 g/kg, p<0.05), liver/body mass (43.2±1.1 vs 49.2±1.8 g/kg, p<0.05) and albumin creatinine ratio (1.2±0.1 vs 2.4±0.3 g/g creat/kg, p<0.05) vs controls. By echocardiography IW‐1973‐treated rats had higher ejection fraction vs controls (85±2 vs 70±3%, p<0.05). In post MI, IW‐1973‐treated rats had lower left ventricular end systolic area vs controls (32±2 vs 39±2 mm 2 , p< 0.05). In Dss and post MI, IW‐1973‐treated rats had lower levels of N‐terminal pro B‐type natriuretic peptide (NT‐proBNP) vs controls (271±13 vs 585±98, p<0.05, 274±28 vs 581±81, pg/ml p<0.05, respectively.) Conclusions IW‐1973 preserved heart function in rat models of HFpEF and HFrEF, including reducing levels of the clinically relevant heart failure biomarker, NT‐proBNP.