Key result
Apo A-I gene therapy reduces septal wall thickness by ~17% in pressure-overloaded mice.
Why the study?
Does selective HDL-raising human apo A-I gene therapy prevent cardiac hypertrophy and improve cardiac function in mice with chronic pressure overload?
Does selective HDL-raising human apo A-I gene therapy prevent cardiac hypertrophy and improve cardiac function in mice with chronic pressure overload?
Effect estimate: 16.5% reduction
Absolute Event Rate: 0.86% vs 1.03%
p-value: p=<0.001
Selective HDL-raising human apo A-I gene therapy potently counteracts pathological structural remodeling and improves cardiac function in a mouse model of pressure overload-induced cardiomyopathy.
Hypothesis-generating for apo A-I gene therapy in pressure-overload hypertrophy; leaves open translation to human heart failure.
Epidemiological studies support an independent inverse association between high-density lipoprotein (HDL) cholesterol levels and heart failure incidence. The effect of selective HDL-raising adeno-associated viral serotype 8-human apolipoprotein (apo) A-I (AAV8-A-I) gene transfer on cardiac remodeling induced by transverse aortic constriction (TAC) was evaluated in C57BL/6 low-density lipoprotein receptor-deficient mice. Septal wall thickness and cardiomyocyte cross-sectional area were reduced by 16.5% (p < 0.001) and by 13.8% (p < 0.01), respectively, eight weeks after TAC in AAV8-A-I mice (n = 24) compared to control mice (n = 39). Myocardial capillary density was 1.11-fold (p < 0.05) higher and interstitial cardiac fibrosis was 45.3% (p < 0.001) lower in AAV8-A-I TAC mice than in control TAC mice. Lung weight and atrial weight were significantly increased in control TAC mice compared to control sham mice, but were not increased in AAV8-A-I TAC mice. The peak rate of isovolumetric contraction was 1.19-fold (p < 0.01) higher in AAV8-A-I TAC mice (n = 17) than in control TAC mice (n = 29). Diastolic function was also significantly enhanced in AAV8-A-I TAC mice compared to control TAC mice. Nitro-oxidative stress and apoptosis were significantly reduced in the myocardium of AAV8-A-I TAC mice compared to control TAC mice. In conclusion, selective HDL-raising human apo A-I gene transfer potently counteracts the development of pressure overload-induced cardiomyopathy.
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Amin et al. (2017) studied Pressure overload-induced cardiomyopathy (n=166). AAV8-A-I gene therapy vs. Control AAV8-null vector was evaluated on Septal wall thickness (16.5% reduction, p=<0.001). Selective HDL-raising human apo A-I gene therapy reduced septal wall thickness by 16.5% and interstitial cardiac fibrosis by 45.3% in mice with chronic pressure overload.
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