Myocardial Aging among a Population-Based Cohort Is Associated with Adverse Cardiovascular Outcomes and Sex-Specific Differences among Older Adults.

INTRODUCTION: Despite growing calls to tackle aging-related cardiovascular disease (CVD), the role of detecting early diastolic dysfunction such as those observed in aging, prior to clinical disease, is of unclear clinical benefit. METHODS: Myocardial function determined by echocardiography was examined in association with incident cardiovascular outcomes or all-cause death by Cox proportional hazards model. Sex-based differences in outcomes were included. RESULTS: A total of 956 participants (mean age 63 ± 12.9 years, n = 424 males [44%]) were categorized based on mitral peak early-to-late diastolic filling velocity (E/A) ratios: E/A <0.8 (28%), E/A 0.8-1.2 (39%), E/A (29%), E/A >2.0 (4%). Incidence rate (IR) for non-fatal cardiovascular outcomes was 2.83 per 100 person-years (95% CI: 2.24-3.56) and 0.45 per 100 person-years (95% CI: 0.26-0.80) for all-cause death. Event-free survival from non-fatal cardiovascular outcomes was significantly different among E/A categories (log-rank p = 0.0269). E/A <0.8 (HR 1.80, 95% CI: 1.031, 3.14, p = 0.039) was associated with non-fatal cardiovascular outcomes. Among men, IR for cardiovascular outcomes was 3.56 per 100 person-years (95% CI: 2.62-4.84) and 0.75 per 100 person-years (95% CI: 0.39-1.44) for all-cause death. Among women, IR for cardiovascular outcomes was 2.22 per 100 person-years (95% CI: 1.56-3.16) and 0.21 per 100 person-years (95% CI: 0.067-0.64) for all-cause death. For E/A <0.8 category, women had significantly higher risks of non-fatal cardiovascular outcomes, compared to E/A 0.8-1.2 category (HR 2.49, 95% CI: 1.18, 5.23, p = 0.017). CONCLUSION: Myocardial aging was an independent predictor of cardiovascular outcomes in community-dwelling older adults prior to clinical CVD. Impaired myocardial relaxation was prevalent in both sexes but associated with worse outcomes in women, suggestive of sex differences in age-related biology.

Terminally Differentiated CD4+ T Cells Promote Myocardial Inflammaging.

The cardiovascular and immune systems undergo profound and intertwined alterations with aging. Recent studies have reported that an accumulation of memory and terminally differentiated T cells in elderly subjects can fuel myocardial aging and boost the progression of heart diseases. Nevertheless, it remains unclear whether the immunological senescence profile is sufficient to cause age-related cardiac deterioration or merely acts as an amplifier of previous tissue-intrinsic damage. Herein, we sought to decompose the causality in this cardio-immune crosstalk by studying young mice harboring a senescent-like expanded CD4+ T cell compartment. Thus, immunodeficient NSG-DR1 mice expressing HLA-DRB1*01:01 were transplanted with human CD4+ T cells purified from matching donors that rapidly engrafted and expanded in the recipients without causing xenograft reactions. In the donor subjects, the CD4+ T cell compartment was primarily composed of naïve cells defined as CCR7+CD45RO-. However, when transplanted into young lymphocyte-deficient mice, CD4+ T cells underwent homeostatic expansion, upregulated expression of PD-1 receptor and strongly shifted towards effector/memory (CCR7- CD45RO+) and terminally-differentiated phenotypes (CCR7-CD45RO-), as typically seen in elderly. Differentiated CD4+ T cells also infiltrated the myocardium of recipient mice at comparable levels to what is observed during physiological aging. In addition, young mice harboring an expanded CD4+ T cell compartment showed increased numbers of infiltrating monocytes, macrophages and dendritic cells in the heart. Bulk mRNA sequencing analyses further confirmed that expanding T-cells promote myocardial inflammaging, marked by a distinct age-related transcriptomic signature. Altogether, these data indicate that exaggerated CD4+ T-cell expansion and differentiation, a hallmark of the aging immune system, is sufficient to promote myocardial alterations compatible with inflammaging in juvenile healthy mice.