Late-life trajectories of cardiac function to define pathways of cardiac resilience

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Heart failure (HF) disproportionately affects older adults, who carry a high burden of cardiovascular risk factors and experience accelerated decline in cardiac function. Subsets of older adults do not experience progressive cardiac dysfunction, but the factors related to late-life cardiac resilience are not well defined. This is a critical barrier – and missed opportunity – to identify novel interventions and treatment targets to prevent HF. The objective in this application is to define the lifestyle factors, social drivers, and molecular pathways underlying cardiac resilience in very late life. The central hypothesis is that in addition to optimal risk factor control, salutary health behaviors (exercise, diet) and favorable structural factors (less social adversity) protect from age-related cellular senescence (assessable via plasma proteomics) and promote trajectories of preserved cardiac function in late life. Leveraging rich longitudinal phenotypic data – including echocardiography – of participants in the community-based Atherosclerosis Risk in Communities (ARIC) study, sequential echocardiography will be performed in ~2,175 participants attending the 12th study visit (age ~86±4), in addition to functional assessments and measurement of plasma proteomics. The resulting three serial echocardiograms over 12 years will be used to identify trajectories of change in cardiac function and to address the following aims: (1) Define late-life behaviors and factors associated with cardiac resilience; (2) Identify proteins and protein networks underlying cardiac resilience with particular attention to circulating markers of cellular senescence; and (3) Determine the association of cardiac resilience with preservation of physical and neurocognitive function and freedom from frailty. The contribution of the proposed research will be to define the impact of modifiable individual behaviors and structural factors on trajectories of cardiac function in very late life, establish the role of a novel and targetable biologic pathway, and quantify the relation of these trajectories to functional and neurocognitive outcomes highly relevant to older adults. This contribution will be significant in enabling the identification of persons at high risk of progressive LV dysfunction in very late life when traditional risk factors perform poorly, and in determining the importance of a promising and targetable biologic pathway to preserve cardiac function – essential steps to decrease HF-associated morbidity and mortality. This research proposal is fundamentally innovative in: (1) focusing on longitudinal cardiac imaging in very late-life (75 to 91 years of age) when data is sparse but CVD burden is high; (2) interrogating a novel biological pathway (cellular senescence) potentially impacting late-life cardiac, physical, and neurocognitive function using serial high throughput proteomics integrated with genomic data; and (3) using innovative analytic approaches to identify trajectories, including Bayesian nonparametric trajectory mixture modeling. The project outcomes are expected to provide a novel understanding of the shared biologic pathways underlying preservation of cardiovascular, physical, and neurocognitive function in late life.