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Angiotensin‐Converting Enzyme Inhibition in a Mouse Model of Transverse Aortic Constriction with Reduced Variability of the Aortic Peak Pressure Gradient
Author(s) -
Neves Liomar,
Martinez Teresa,
Isbatan Ayman,
Chowdhury Shamim,
Senese Peter,
Gralinski Michael
Publication year - 2021
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.2021.35.s1.04963
Subject(s) - enalapril , constriction , medicine , pressure overload , aorta , aortic pressure , cardiology , angiotensin converting enzyme , blood pressure , muscle hypertrophy , anesthesia , cardiac hypertrophy
Transverse aortic constriction (TAC) is a useful tool to study the effectiveness of emerging drug therapy against the progression of cardiac dysfunction. Recently our lab has shown reduced variability of the aortic peak pressure gradient in the TAC model when the degree of constriction was based on aorta diameter obtained during surgery rather than using the standard 27G needle. In the current study, the therapeutic benefit of Enalapril, an angiotensin‐converting enzyme inhibitor, was assessed in the TAC model with reduced variability of the aortic peak pressure gradient. C57BL/6NCrl male mice (23.8‐26.1 g) underwent TAC or Sham surgery on Day 1. The transverse aorta diameter was determined at the time of surgery and TAC was induced by tying a ligature around the aorta against hypodermic tubing selected to induce 65%‐70% constriction. Sham (n=15) and TAC‐vehicle (n=17) mice received once daily oral administration of vehicle (0.5% methylcellulose/1% tween 80), and TAC‐Enalapril mice (n=17) had ad libitum access to water containing Enalapril (200 mg/L) starting on Day 1 through Day 56. Cardiac function was determined using both standard echocardiographic parameters at 4‑, 6‑ and 8‐weeks (W) and speckle tracking strain measurements at 4W and 8W. Hearts were harvested at 8W and weighed. A significant increase in the pressure gradient was observed for TAC‐vehicle (63±17 mmHg) and TAC‐Enalapril (64±11 mmHg) vs Sham (2.5±0.7 mmHg) mice. Progressive cardiac hypertrophy was observed in TAC‐vehicle as indicated by a significant increase in left ventricle (LV) mass at 4W (117±25 mg), 6W (128±35 mg) and 8W (146±40 mg) and in the heart weight (HW)/body weight (BW) ratio at 8W (9±3 mg/g) as compared to Sham (LV mass [mg] at 4W: 63±11, 6W: 59±7 and 8W: 63±11; HW/BW [mg/g] at 8W: 4±0.4). Dilated LV was also evident in TAC‐vehicle as shown by a significant increase in LV end‐diastolic volume (EDV) at 4W (110±19 µL), 6W (114±27 µL) and 8W (132±34 µL) as compared to Sham (4W: 82±13 µL, 6W: 79±15 µL and 8W: 79±16 µL). Diastolic dysfunction (E/E’ ratio at 4W: 58±33, 6W: 58±36 and 8W: 60±35; p<.05) and progressive decline in systolic function (ejection fraction [EF %] at 4W: 36± 11, 6W: 33±12 and 8W: 29±13; global circumferential strain [GCS %] at 4W: ‐10±4 and 8W: ‐8±5; p<.05) were also observed in TAC‐vehicle as compared to Sham (E/E’ ratio at 4W: 29±6, 6W: 30±4 and 8W: 30±7; EF [%] at 4W: 57±5, 6W: 56±8 and 8W: 56± 6; and GCS [%] at 4W: ‐17±3 and 8W: ‐17±4). Mice treated with enalapril showed a diminished LV hypertrophy (LV mass [mg] at 4W: 93±23 and 8W: 105±30; HW/BW [mg/g] at 8W: 7±1; p<.05) and LV dilation (LVEDV [µL] at 6W: 94±18 and 8W: 97±25; p<.05) compared to TAC‐vehicle. Enalapril treatment also blunted TAC‐induced diastolic dysfunction (E/E’ ratio at 4W: 34±6, 6W: 35±4 and 8W: 37±8; p<.05) and systolic dysfunction (EF [%] at 4W: 47±6, 6W: 43±6 and 8W: 42±8; GCS [%] at 4W: ‐14±4 and 8W: ‐13±4; p<.05). These results demonstrate that Enalapril treatment blunted TAC‐induced cardiac remodeling and dysfunction in a TAC model of reduced variability of the aortic peak pressure gradient.