sacubitril and Hypertension--Pulmonary

Right ventricular (RV) function is a major prognostic factor in patients with cardiopulmonary disease. Effective medical therapies are available for left heart failure, but they are usually less effective or even ineffective in right heart failure. Here, we tested the hypothesis that LCZ696 (sacubitril/valsartan) can attenuate pressure overload-induced RV remodeling by inhibiting pyruvate dehydrogenase kinase 4 (PDK4).. Adult male C57 mice were subjected to transverse aortic constriction (TAC), pulmonary artery constriction (PAC), or sham surgery. Bioinformatics analysis was used to screen for common differentially expressed genes (DEGs) between TAC and PAC. Chemical compounds targeting DEGs were predicted by molecular docking analysis. Effects of LCZ696 on PAC-induced RV remodeling and the associated PDK4-related mechanisms were investigated.. We found 60 common DEGs between PAC and TAC, and Pdk4 was one of the downregulated DEGs. From 47 chemical compounds with potential cardiovascular activity and PDK4 protein binding ability, we selected LCZ696 to treat PAC-induced RV remodeling because of its high docking score for binding PDK4. Compared with vehicle-treated PAC mice, LCZ696-treated mice had significantly smaller RV wall thickness and RV diameters, less myocardial fibrosis, lower expression of PDK4 protein, and less phosphorylation of glycogen synthase kinase-3β (p-GSK3β). In PAC mice, overexpression of Pdk4 blocked the inhibitory effect of LCZ696 on RV remodeling, whereas conditional knockout of Pdk4 attenuated PAC-induced RV remodeling.. Pdk4 is a common therapeutic target for pressure overload-induced left ventricular and RV remodeling, and LCZ696 attenuates RV remodeling by downregulating Pdk4 and inhibiting PDK4/p-GSK3β signal.

Topics: Animals; Biphenyl Compounds; Disease Models, Animal; Drug Combinations; Glycogen Synthase Kinase 3 beta; Heart Failure; Hypertension, Pulmonary; Male; Mice; Molecular Docking Simulation; Valsartan; Ventricular Remodeling

Patients with heart failure with preserved ejection fraction (HFpEF) and pulmonary hypertension have poor survival, and established medical therapies for both conditions are not available. In this retrospective study of 69 patients with HFpEF and either isolated postcapillary pulmonary hypertension (IpcPH, n = 53) or combined postcapillary and precapillary pulmonary hypertension (CpcPH, n = 16), we investigated the effects of sacubitril/valsartan on pulmonary hypertension measured using right heart catheterization at baseline (ie, presacubitril/valsartan) and 99 (94-123) days after switching to sacubitril/valsartan. After switching to sacubitril/valsartan, right heart catheterization showed significantly lower pulmonary artery pressures (systolic/diastolic/mean) in both patient groups compared with presacubitril/valsartan [IpcPH: 44 (38-52)/15 (12-19)/28 (22-33) mm Hg vs. 47 (40-55)/18 (15-23)/31 (26-35) mm Hg, P < 0.01; CpcPH: 54 (43-57)/18 (12-23)/34 (30-36) mm Hg vs. 61 (50-79)/24 (19-30)/40 (31-53) mm Hg, P < 0.05]. The median sacubitril/valsartan dose at follow-up was 24/26 (24/26-49/51) mg twice daily in both patients with IpcPH and CpcPH. Clinically, the New York Heart Association functional class improved by at least 1 class in 32 of 69 patients ( P < 0.01). In conclusion, sacubitril/valsartan therapy improves pulmonary hypertension in patients with HFpEF and either IpcPH or CpcPH. Further prospective randomized trials are needed for confirmation of our results.

Topics: Angiotensin Receptor Antagonists; Biphenyl Compounds; Drug Combinations; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Retrospective Studies; Stroke Volume; Tetrazoles; Valsartan

Prior studies have not fully characterized the haemodynamic effects of the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan in heart failure with preserved ejection fraction and pulmonary hypertension (HFpEF-PH). The aim of the Treatment of PH With Angiotensin II Receptor Blocker and Neprilysin Inhibitor in HFpEF Patients With CardioMEMS Device (ARNIMEMS-HFpEF) study is to assess pulmonary artery pressure (PAP) dynamics by means of implanted PAP monitors in patients with HFpEF-PH treated with sacubitril/valsartan.. This single-arm, investigator-initiated, interventional study included 14 consecutive ambulatory symptomatic HFpEF-PH patients who underwent CardioMEMS implantation prior to enrolment [mean ejection fraction 60.4 ± 7.2%, baseline mean PAP (mPAP) 33.9 ± 7.6 mmHg]. Daily PAP values were examined during three periods: a 6 week period after CardioMEMS implantation and before sacubitril/valsartan treatment (pre-ARNI), a 6 week period with sacubitril/valsartan treatment (ARNI ON), and a 6 week period of sacubitril/valsartan withdrawal (ARNI OFF). The primary endpoint was change in mPAP with and without sacubitril/valsartan. Secondary endpoints included changes in 6 min walking distance, B-line sum in lung ultrasound, and quality of life (QoL). During the study period, 1717 mPAP measurements were recorded. Between pre-ARNI vs. ARNI ON, mPAP significantly declined by -4.99 mmHg [95% confidence interval (CI) -5.55 to -4.43]. Between ARNI ON vs. ARNI OFF, mPAP significantly increased by +2.84 mmHg [95% CI +2.26 to +3.42]. Between pre-ARNI vs. ARNI ON, we found an improvement in 6 min walking distance, B-lines, and QoL. Mean loop diuretic management did not differ between periods.. Sacubitril/valsartan significantly reduced mPAP in patients with HFpEF-PH, independent of loop diuretic management, together with improvement in functional capacity, lung congestion, and QoL. Sacubitril/valsartan may be a therapeutic alternative in HFpEF-PH.

Topics: Aminobutyrates; Arterial Pressure; Biphenyl Compounds; Heart Failure; Humans; Hypertension, Pulmonary; Neprilysin; Quality of Life; Sodium Potassium Chloride Symporter Inhibitors; Stroke Volume; Tetrazoles; Valsartan