Key result
Heterozygous TGF-beta1 deficiency in mice reduces mortality ~76% vs wild-type, alongside less myocardial fibrosis.
Why the study?
Does heterozygous TGF-beta1 deficiency reduce age-associated myocardial fibrosis and mortality in mice?
Does heterozygous TGF-beta1 deficiency reduce age-associated myocardial fibrosis and mortality in mice?
Absolute Event Rate: 92% vs 66%
p-value: p=<0.05
Heterozygous TGF-beta1 deficiency in mice reduces age-associated myocardial fibrosis, improves left ventricular compliance, and increases survival to 24 months.
Heterozygous TGF-β1 deficiency may attenuate age-related fibrosis and mortality in mice; leaves open translation to human cardiac aging.
Aging is associated with an increase in myocardial extracellular matrix components and contractile dysfunction. Transforming growth factor- beta(1)(TGF- beta(1)) has been shown to regulate expression of collagen genes and extracellular matrix component synthesis in the heart, and may contribute to the increase in myocardial fibrosis with aging. Therefore, we examined whether TGF- beta(1)heterozygous mutant mice would exhibit less age-associated myocardial fibrosis than normal mice. Twelve heterozygous TGF- beta(1)(+/-) deficient mice and 26 wild-type controls were examined to determine if there was a difference in development of myocardial fibrosis or mortality at 24 months of age due to the loss of one TGF- beta(1)allele. Animals which survived to 24 months of age were killed, and morphometric and functional studies were performed in isolated perfused hearts and in hearts from 6 month old control mice. Pressure-volume relations of the LV were assessed in the isovolumic (balloon in LV) Langendorff preparation. Eleven of 12 (92%) TGF- beta(1)deficient mice survived to 24 months of age in comparison to 66% (12/18) age-matched controls (P<0.05). Hearts from the 24 month old TGF- beta(1)deficient mice exhibited a decrease in myocardial fibrosis (4+/-1 v. 10+/-1% average LV fibrosis in TGF- beta(1)(+/-) and age-matched controls, respectively (P<0.05) and greater compliance (i.e.,lower LV end-diastolic pressure at a given balloon volume), decreased myocardial stiffness, and shorter contractile duration in comparison to 24-month-old wild-type controls. This suggests that modulation of collagen production and/or degradation by TGF- beta(1)may contribute to changes in myocardial structure and function with age. Thus, loss of one TGF- beta(1)allele appears to ameliorate age associated myocardial fibrosis and improve LV compliance, which may contribute to increased survival over the life span of these mice.
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Brooks et al. (2000) studied Age-associated myocardial fibrosis (n=38). TGF-beta1 heterozygous mutation vs. Wild-type controls was evaluated on Survival to 24 months of age (p=<0.05). TGF-beta1 heterozygous deficient mice exhibited higher survival to 24 months compared to wild-type controls (92% vs 66%, P<0.05) and decreased myocardial fibrosis (4% vs 10%, P<0.05).
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