Key result
Cardiac-specific AT1R overexpression in mice significantly decreased shortening fraction (32.3% vs 47.1%, p<0.05) and induced diastolic dysfunction, which were completely reversed by losartan.
Why the study?
Does losartan improve systolic and diastolic ventricular function in mice overexpressing cardiac Ang II AT-1 receptor?
Does losartan improve systolic and diastolic ventricular function in mice overexpressing cardiac Ang II AT-1 receptor?
Absolute Event Rate: 32.3% vs 47.1%
p-value: p=<0.05
Cardiac-specific AT1R overexpression induces systolic and diastolic ventricular dysfunction which is completely reversed by AT1R blockade with losartan, independent of left ventricular mass changes.
Losartan reverses AT1R-induced dysfunction in mice; leaves open translation to human ventricular dysfunction and warrants clinical trials.
Angiotensin II (Ang II) is involved in various pathophysiological processes throughthe activation of angiotensin II AT-1 receptors. The purpose of this study was toassess in vivo and in vitro systolic and diastolic ventricular function in mice overexpressingthe cardiac-specific Ang II AT-1 receptor (AT1R). A second objective was todetermine whether ventricular function changes could be reversed with acute andchronic ATIR blockade.Mice were divided into four experimental groups. The first group included nontransgenicanimals (NTG, n=10), the second group consisted of transgenic mice (TG,n=7) with cardiac-specific AT1R overexpression and the third and fourth groupswere TG animals treated with losartan (L) for 7 (TG L7, n=9) and 30 days (TG L30,n=7), respectively. Transgenic animals exhibited left ventricular hypertrophy (LVH)which was only regressed with losartan treatment for 30 days. They also presented asignificant decrease in shortening fraction from 47.1±2.3% to 32.3±1.3% (p <0.05)and of +dP/dtmax from 7073 ± 674 to 3897.5 ± 209.7 mmHg/sec (p< 0.05). Systolicdysfunction recovered both with losartan treatment for 7 and 30 days.Isovolumic relaxation time and t1/2 were 24.1±1.3 and 5.1±0.5ms, respectively, inthe NTG group. These indexes increased to 33.1±2.2 and 8.4±0.4 ms, respectively,in TG mice (p<0.05). Diastolic dysfunction was completely reversed by losartantreatment for 7 and 30 days. In vitro ventricular function with controlled variablesconfirmed in vivo findings.In conclusion, cardiac-specific AT1R overexpression induces systolic and diastolicventricular dysfunction which is completely reversed by AT1R blockade. This beneficialeffect is independent of left ventricular mass changes.
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Matorra et al. (2013) studied Cardiac-specific Angiotensin II AT-1 receptor overexpression (n=33). Cardiac-specific AT1R overexpression and Losartan treatment vs. Non-transgenic mice and untreated transgenic mice was evaluated on Shortening fraction (p=<0.05). Cardiac-specific AT1R overexpression in mice significantly decreased shortening fraction (32.3% vs 47.1%, p<0.05) and induced diastolic dysfunction, which were completely reversed by losartan.
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