Sacubitril/Valsartan Ameliorates Cardiac Hypertrophy and Preserves Diastolic Function in Cardiac Pressure Overload

Figures

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  Figure 1. Sacubitril/valsartan (sac/val) superiorly prevents myocardial hypertrophy. (A) Sac/val reduces left ventricular hypertrophy compared with both valsartan and vehicle, as assessed by weighing left ventricle (P = 0.04 vs. val, P = 0.01 vs. veh). Valsartan alone confers no reduction compared with vehicle (P = 0.92) (n = sham: 16, sac/val: 23, val: 24, veh: 19). (B) Mean peripheral arterial pressure was measured through tail cuff. Only animals treated with valsartan showed significant reduction compared with sham (P = 0.02), with sac/val and vehicle showing non‐significant reduction (sac/val vs. sham: P = 0.06; veh vs. sham: P = 0.41) (n = sham: 10, sac/val: 21, val: 22, veh: 15). (C) Representative mid‐ventricular short axis images from Cine magnetic resonance imaging: 1. sham; 2, sac/val; 3, val; 4, veh. Scale bar represents 10 mm. (D) Heart rate, measured by tail cuff, was not different between groups. Myh7 is only significantly up‐regulated in vehicle (P = 0.004) (n = sham: 14, sac/val: 22, val: 24, veh: 18), whereas atrial natriuretic peptide (ANP) and B‐type natriuretic peptide (BNP) are up‐regulated in all groups (ANP: Kruskal–Wallis test, P < 0.0001; BNP: one‐way ANOVA, P =…

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  Figure 2. Sacubitril/valsartan ameliorates diastolic dysfunction. Reduced early diastolic strain rate is a marker of diastolic dysfunction. Both animals treated with vehicle and valsartan showed significant decreases compared with sham (val vs. sham: P = 0.02; veh vs. sham: P = 0.03), indicating impaired relaxation. This decrease was not observed in animals treated with sacubitril/valsartan (sac/val vs. sham: P = 0.41), indicating a preservation of relaxation (n = sham: 9, sac/val: 17, val: 16, veh: 13) (* denotes P < 0.05 vs. sham).

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  Figure 3. Fibrosis is increased in left ventricle of all banded groups. (A) Aortic banding (AB) induced fibrosis as measured by ventricular expression of Col1 and 3 (Col1: one‐way ANOVA of log‐transformed data, P = 0.002, n = sham: 14, sac/val: 21, val: 24, veh: 18; Col3: one‐way ANOVA of log‐transformed data, P = 0.002, n = sham: 14, sac/val: 22, val: 24, veh: 18). Interstitial fibrosis was significantly increased compared with sham when all banded groups were pooled (unpaired t‐test with Welch's correction, P < 0.0001, n = sham: 14, AB: 66), while mean interstitial fibrosis was similar in all treatment groups (Kruskal–Wallis test, P = 0.92, n = sac/val: 22, val: 25, veh: 19). (B) Representative photomicrographs from 1, Sham; 2, sac/val; 3, val; 4, veh. Scale bar represents 2000 μm. Adjustment of contrast to match reference image has been applied in all images. (C) Mmp2, a known regulator of collagen turnover, was increased in all banded groups (one‐way ANOVA of log‐transformed data, P = 0.002, n = sham: 14, sac/val: 21, val: 24, veh: 18), while Timp4 showed no significant difference (one‐way ANOVA of log‐transformed data, P = 0.12, n = sham: 14, sac/val: 22, val: 24, veh: 18) (* denotes…

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  Figure 4. Left ventricular systolic function is depressed in all banded groups. Parameters of overt left ventricular systolic dysfunction showed no change in response to aortic banding (AB), including ejection fraction (EF) and circumferential strain. More sensitive markers of early left ventricular systolic dysfunction, such as longitudinal strain, and both longitudinal (not shown) and circumferential strain rate, demonstrated a depressed systolic function in all banded groups, with no difference between treatments. Cine (n = sham: 12, sac/val: 17, val: 17, veh: 16). Tissue phase mapping (TPM; circumferential: n = sham: 9, sac/val: 18, val: 17, veh: 16. Longitudinal: n = sham: 9, sac/val: 17, val: 16, veh: 13) (* denotes P < 0.05 vs. sham).