Aging in mice induced an HFpEF-like phenotype characterized by reduced E/A ratios (p<0.01), prolonged IVRT (p<0.001), increased fibrosis, and elevated platelet reactivity.
Does aging contribute to a HFpEF-like phenotype and increased platelet reactivity in wild-type mice?
Aged mice develop a HFpEF-like phenotype with reduced diastolic function and increased fibrosis, alongside elevated platelet reactivity and extracellular vesicle production.
Abstract Background Heart failure with preserved ejection fraction (HFpEF) is a major cause of hospitalizations and mortality in individuals aged 65 and older. HFpEF is a multifactorial and multisystemic syndrome, with a complex pathophysiology and phenotype. Unlike heart failure with reduced ejection fraction (HFrEF), its diagnosis is challenging since it cannot be reliably assessed by left ventricular ejection fraction alone. This necessitates individualized approaches that consider age-related changes and common comorbidities. Interestingly, megakaryocytes (Mk), the bone marrow cells responsible for platelet (Plt) production, undergo significant changes with aging, including alterations in function and gene expression, which may contribute to increased platelet reactivity, inflammation, and fibrosis, all of which are implicated in age-related cardiovascular diseases such as HFpEF Purpose This study aims to investigate the link between Mk/Plt aging and cardiac dysfunction, focusing particularly on Plt-derived extracellular vesicles (EVs) and their role in HFpEF. Methods We conducted comprehensive studies in young (4 months) and old (18 months) wild-type mice, including echocardiography, imaging, and biochemical analyses. Single-cell RNA sequencing (scRNAseq) was performed on Mk. Plt-derived circulating extracellular vesicles (CircEVs) were characterized. Results Despite preserved ejection fraction and fractional shortening in aged mice, indicating stable global left ventricular systolic function, significant age-related decline in diastolic function was observed. Aged mice exhibited reduced E/A ratios (p 0. 01) and prolonged isovolumic relaxation time (IVRT) (p 0. 001), characteristic for HFpEF-like phenotype. Additionally, aged mice demonstrated increased cardiac interstitial fibrosis, with upregulated expression of fibrosis markers such as collagen α-1 (I) chain (Col1a1; p 0. 0001) and collagen α-1 (III) chain (Col3a1; p 0. 001). A significant increase in left ventricular mass was also noted (p 0. 01), while anterior and posterior LV wall thicknesses remained constant with age. Bone marrow scRNAseq analysis showed that aging Mk/Plt significantly upregulates TGF-β1, a key mediator in cardiac remodeling. Given that platelets are a primary source of EVs, we analyzed circulating EVs and found an increase in CircEVs in aged mice (p 0. 001), suggesting heightened platelet reactivity with aging. Flow cytometry further confirmed elevated platelet reactivity in older mice following TRAP6 stimulation (p 0. 05). Conclusion Our findings indicate that aged mice develop a HFpEF-like phenotype, characterized by reduced diastolic function, increased fibrosis, and elevated Plt reactivity together with EVs and TGFβ1 production. The role of Plt-derived CircEVs in contributing to the cardiac phenotype warrants further investigation to establish a direct mechanistic link.
Balbi et al. (Sat,) conducted a other in Heart failure with preserved ejection fraction (HFpEF). Aging (18 months) vs. Young mice (4 months) was evaluated on Diastolic function (E/A ratio, IVRT) and fibrosis. Aging in mice induced an HFpEF-like phenotype characterized by reduced E/A ratios (p<0.01), prolonged IVRT (p<0.001), increased fibrosis, and elevated platelet reactivity.