AimsAngiotensin receptor-neprilysin inhibitors (ARNis) acts an ARB and neprilysin inhibitor. Diabetes mellitus significantly increases the risk of cardiovascular disease and heart failure (HF). Therefore, we evaluated the effects and mechanisms of ARNi in HF with reduced ejection fraction (HFrEF) Methods and resultsMale C57BL/6J mice were injected with streptozotocin to produce diabetic mice. After myocardial reperfusion injury, diabetic mice were randomized to treatment for 4 weeks with LCZ696 (60 mg/kg), valsartan (30 mg/kg), or no treatment (n = 26-28 in each group). Cardiac function was assessed by a pressure-volume Millar catheter. The ratios of heart weight to body weight in the valsartan (P = 0.02) and LCZ696 (P = 0.005) groups were significantly less than that in the control group. Treatment with LCZ696 improved LVEF (43 ± 3.4%) with a significantly reduction of atrial natriuretic peptide mRNA in the left ventricle compared with that in the control group (29 ± 3.2%) (P = 0.006). The fibrotic area in the LCZ696 group was significantly suppressed compared with those in the control (P = 0.003) and valsartan (P = 0.04) groups. Moreover, the mRNA level of transforming growth factor-(TGF-) in the left ventricle was suppressed in the LCZ696 group compared with that in the control (P = 0.002) group.

This study was performed to evaluate the safety and efficacy of additional antihypertensive therapy with angiotensin II type 1 receptor blocker (ARB; olmesartan or valsartan) after successful stent implantation in patients with coronary artery disease (CAD). Fifty patients with CAD after successful stent implantation were included in this study. They were divided into an ARB group, which initially received olmesartan (n¼20, 14±8 mg day À1 ) or valsartan (n¼20, 60±23 mg day À1 ) immediately after stent implantation, and a non-ARB group (n¼10) according to their blood pressure (BP). Follow-up coronary angiography, measurement of BP and blood sampling were performed before (at baseline) and 6-8 months after stent implantation (at follow-up). There were no significant differences in the baseline characteristics between the groups, except for BP. Although there were no changes in % diameter restenosis between the groups, the BP level in the ARB group at follow-up showed a significant reduction (125 ± 12/69 ± 9 mm Hg) and reached the target BP. There were no critical adverse effects in the ARB group throughout the study period. In addition, serum high-sensitive C-reactive protein (hs-CRP) and pentraxin 3 were significantly decreased in the ARB group but not in the non-ARB group. Although olmesartan and valsartan induced similar BP-lowering effects, olmesartan but not valsartan induced a significant decrease in hs-CRP, but did not increase serum uric acid. In conclusion, antihypertensive therapy with add-on low-dose ARB after stent implantation was safe and achieved the target BP. In particular, olmesartan had an anti-inflammatory effect.

We describe the case of a 43-year-old primiparous woman who had acute myocardial infarction. She underwent successful primary percutaneous coronary intervention. Elective cesarean section was performed uneventfully at 32 weeks gestation.

A recent clinical study indicated that an angiotensin II (Ang II) type 1 (AT) receptor-neprilysin inhibitor (ARNi) designated LCZ696 (sacubitril/valsartan, as combined sodium complex) was superior to enalapril at reducing the risks of death and hospitalization due to heart failure. Therefore, we investigated the possible mechanisms of the beneficial effect of LCZ696, in which the inhibition of neprilysin enhances atrial natriuretic peptide (NP) or brain NP (ANP or BNP)-evoked signals that can block Ang II/AT receptor-induced aldosterone (Ald) synthesis in human adrenocortical cells. The binding affinity of valsartan+LBQ657 (active moiety of sacubitril) to the AT receptor was greater than that of valsartan alone in an AT receptor-expressing human embryonic kidney cell-based assay. There was no difference in the dissociation from the AT receptor between valsartan+LBQ657 and valsartan alone. In Ang II-sensitized human adrenocortical cells, ANP or BNP alone, but not LBQ657 or valsartan alone, significantly decreased Ald synthesis. The level of suppression of Ald synthesis by ANP or BNP with LBQ657 was greater than that by ANP or BNP without LBQ657. The suppression of ANP was blocked by inhibitors of regulator of G-protein signaling proteins and cyclic GMP-dependent protein kinase. The inhibition of neprilysin did not change the mRNA levels of the AT receptor, ANP receptor A, regulator of G-protein signaling protein, renin or 3β-hydroxysteroid dehydrogenases. In conclusion, the inhibition of neprilysin by LBQ657 enhances the NP-evoked signals that can block Ang II/AT receptor-induced Ald synthesis in human adrenocortical cells.

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