Heart failure (HF) represents a leading cause of morbidity and mortality in the elderly. Despite the strong association between advanced age and HF, the underlying molecular mechanisms by which the aging process predisposes older adults to HF remain unclear. To that end, our group is exploring biological systems that potentially link aging to HF pathophysiology as an approach to identifying novel targets for HF therapy.

Using aptamer-based technology, we recently found that circulating levels of follistatin-like 3 (FSTL3), a biomarker of activin type II receptor (ActRII-A/B) pathway activation, markedly increases with aging. This finding strongly correlated with a concomitant age-related increase in circulating Activin-A levels, suggesting that Activin-A was likely a primary mediator of this phenomenon. Moreover, in a cohort of older adults with severe aortic stenosis (AS), FSTL3 levels correlated with increasing HF severity and frailty.

To elucidate the potential role of this pathway in HF pathophysiology, we have been actively investigating the effects of Activin-A and other related ActRII-A/B ligands (e.g. GDF11) on cardiac function. Current work in our laboratory suggests that ActRII-A/B pathway activation induces a pathologic form of cardiac atrophy that impairs myocardial function. This process is partially mediated through a catabolic mechanism that represses protective physiological hypertrophy pathways in the heart, resulting in impairments in calcium regulation and myocardial mechanics.

Interestingly, targeted inhibition of this pathway improves cardiac function in various murine models of HF. In a transverse aortic constriction model of AS and HF, ActRII-A/B inhibition not only prevents the development of systolic dysfunction, but can also restore the functional properties of an already failing heart. This functional effect of pathway inhibition is also seen in aging models of HF, in which ActRII-A/B inhibition improves cardiac performance and attenuates the age-related decline in exercise capacity.

In conclusion, this work identifies the ActRII-A/B pathway as a potential link between aging and HF pathophysiology that could provide a novel target for HF therapeutic development.

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