Accelerated organ aging varies by sex in a population at high cardiovascular risk

Abstract Background Advanced age is one of the most important risk factors for heart failure (HF). Biological aging often differs from chronological aging and varies across individuals and tissues. Accelerated aging is involved in the pathogenesis of several chronic diseases, including HF. However, it remains unclear whether the aging of specific organs impacts HF severity and if that differs by sex. Purpose To assess the sex-specific association between proteomic-derived organ-specific aging of heart, kidney and artery and HF severity, and to investigate clinical drivers of organ aging. Methods We studied 556 patients referred to the Cardiology Center of the Netherlands for cardiac evaluation (2016-2019) with available plasma proteomics. We calculated the organ age of heart, artery and kidney by using the "organage" package and assessed the association between accelerated aging and 1) HF severity; 2) echocardiographic markers of HF, with multinomial and linear regression analysis. Secondly, cardiovascular risk factors for organ aging were investigated by multivariable linear regression analysis. Results Mean age was 63±9 years; 65% were female. Patients were classified as HF Class A (35%), B (29%) and C/D (36%). Accelerated heart aging was associated with higher odds of HF class C/D in both men (OR:1.18, 1.13;1.22) and women (1.12, 1.09;1.15). Conversely, accelerated artery aging related to HF class C/D only in women (1.10, 1.07; 1.12), while accelerated kidney aging related to HF class C/D only in men (1.19, 1.11; 1.27). Advanced aging across 2-3 organs yielded the highest odds of HF Class C/D (3.08, 2.52; 3.76). Accelerated organ aging was associated with lower ejection fraction (EF) and higher left ventricular mass index (LVMI) and E/E' ratio. Diabetes was the strongest driver of accelerated aging, particularly for artery (β: 2.16, 1.80; 2.51). After stratifying by sex, in women, diabetes (0.55, 0.12; 0.99) and elevated creatinine (1.56, 0.71; 2.41) were associated with accelerated heart aging, while diabetes was also associated with accelerated artery aging (1.84, 1.34; 2.34). In men, elevated creatinine was associated with accelerated heart aging (1.94, 0.89; 3.00), and hypertension, diabetes, smoking, higher BMI and creatinine were associated with accelerated kidney aging. Conclusions Plasma proteomics can be used to estimate specific organ aging, revealing sex-specific associations with HF severity. These findings highlight sex-specific pathways in HF. Targeted risk factor management, with a focus on vascular health and diabetes control in women, alongside monitoring kidney function in men, could improve outcomes and contribute to HF prevention.Central illustration