Key result
LCZ696 significantly decreased cardiac interstitial fibrosis caused by continuous exposure to isoproterenol in rats compared to isoproterenol alone (0.19% vs 0.41%, p<0.01), but did not reduce cardiac hypertrophy.
Why the study?
Does LCZ696 improve cardiac hypertrophy, fibrosis, and hemodynamics in isoproterenol-treated rats compared to valsartan alone?
Does LCZ696 improve cardiac hypertrophy, fibrosis, and hemodynamics in isoproterenol-treated rats compared to valsartan alone?
In a rat model of isoproterenol-induced cardiac damage, LCZ696 significantly attenuated cardiac fibrosis and improved diastolic hemodynamics compared to valsartan alone, though it did not prevent cardiac hypertrophy.
Extends preclinical ARNI data on fibrosis in catecholamine models; leaves open hypertrophy effects and human translation.
BACKGROUND: Recent clinical studies have shown that treatment with LCZ696, a complex containing the angiotensin receptor blocker valsartan and neprilysin inhibitor sacubitril, improves the prognosis of heart failure patients with a reduced ejection fraction. This study evaluated whether LCZ696 affects left ventricular hypertrophy, fibrosis, and hemodynamics in isoproterenol (ISO)-treated rats compared with valsartan alone. METHODS: Male Wistar rats received subcutaneous saline (n = 10), subcutaneous ISO (2.4 mg/kg/day; n = 10), subcutaneous ISO + oral LCZ696 (60 mg/kg/day; n = 20) (ISO-LCZ), or subcutaneous ISO + oral valsartan (30 mg/kg/day; n = 20) (ISO-VAL) for 7 days. RESULTS: LCZ696 and valsartan did not significantly reduce the increased heart weight/body weight ratio in rats treated with ISO. Echocardiography showed that the deceleration time shortened by ISO was restored by LCZ696 but not valsartan alone (p = 0.01 vs. the ISO group). Histological analysis showed that cardiac interstitial fibrosis increased by ISO was decreased significantly by LCZ696 but not valsartan alone (control: 0.10 ± 0.14%; ISO: 0.41 ± 0.32%; ISO-LCZ: 0.19 ± 0.23% [p < 0.01 vs. the ISO group]; ISO-VAL: 0.34 ± 0.23% [p = 0.34 vs. the ISO group]). Quantitative polymerase chain reaction showed that mRNA expression of Tgfb1, Col1a1, Ccl2, and Anp increased by ISO was significantly attenuated by LCZ696 but not valsartan alone (p < 0.05 vs. the ISO group). CONCLUSIONS: LCZ696 improves cardiac fibrosis, but not hypertrophy, caused by continuous exposure to ISO in rats.
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Miyoshi et al. (2018) studied Isoproterenol-induced cardiac hypertrophy and fibrosis (n=60). LCZ696 vs. Isoproterenol alone (and valsartan 30 mg/kg/day) was evaluated on Cardiac interstitial fibrosis area (%) (p=<0.01). LCZ696 significantly decreased cardiac interstitial fibrosis caused by continuous exposure to isoproterenol in rats compared to isoproterenol alone (0.19% vs 0.41%, p<0.01), but did not reduce cardiac hypertrophy.
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