Role of Aging on cardiac macrophage dysfunction and heart failure during infection

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The United States elderly population is predicted to increase three-fold by 2050, reaching over 85 million. The burden of heart failure will also increase due to age associated cardiovascular and inflammatory diseases. For example, the elderly are more susceptible to cardiac infection due to chronic inflammation, termed “inflamm- aging.” Opportunistic infections of these individuals, which would normally be easily cleared, can result in severe cardiac distress, and death. Indeed, aging is a major prognostic factor for contraction of non-tuberculous mycobacterial (NTM) disease, and associated dissemination to the heart. There is also a clear need for treatment options, as there is up to a 40% risk for death in elderly persons with NTM infection. Innate and adaptive immune responses are tightly regulated in the heart to prevent maladaptive inflammation, which may malfunction during inflammaging. Recently we have demonstrated that infection with an opportunistic pathogen, NTM, predisposes aged mice to cardiac arrhythmia (Ageing Cell 2019). As there are currently no effective pharmacological therapies for cardiac NTM infection within the elderly, we believe understanding the mechanisms involved in associated inflammation and phenotypic changes could assist in rational therapy choice. We have discovered that, during infection of old hearts, beneficial CCR2-, MerTK+ cardiac resident macrophages (CRMs) are replaced with inflammatory myeloid-derived cells. Thus we hypothesize that inflammaging causes enhanced myeloid cell trafficking, epigenetic reprograming and phenotypic switch in CRMs phenotypes, and defective tissue repair, processes that contribute to infection-associated cardiac dysfunction. The goals of this research program are to: 1) Determine cellular and epigenetic identities of aged cardiac myeloid cells during infection, and 2) Determine whether enhancing the expression of MerTK in CRMs provides cardio protection in old mice. We will use young (2-3 months) and old (18-24 months) mice to study the impact of NTM in cardiac dysfunction. Application of multi-omics (Single Cell RNA and ATAC sequencing) technology will provide a general resource for studying infection, and aging, within the heart. Overall, our mission is to define cardiac macrophage subsets, identify the mechanism of macrophage phenotypic changes and its role during infection in young and old mice. Given the large, and growing, public health burden of opportunistic infection within aging hearts, and a lack of knowledge about fundamental immunological control mechanisms, this project is ideally suited for the R21 mechanism. Further, identifying macrophage populations responsible for aging-related dysfunction could lead to new approaches and drugs to treat cardiac dysfunction in elderly.