Longitudinal lipidomic markers of cardiac aging and risk of coronary heart disease in American Indians: the Strong Heart Family Study

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Age-related decline in left ventricular (LV) diastolic function is a hallmark of cardiac aging and an early precursor to cardiovascular disease. While dyslipidemia is a known driver of coronary heart disease (CHD), the molecular pathways linking lipid metabolism to cardiac aging and subsequent CHD risk remain poorly understood. Furthermore, longitudinal lipidomic profiling of cardiac aging in large human populations has not been systematically conducted. Using an untargeted LC-MS, we repeatedly measured 1542 fasting plasma lipid species in 1801 American Indians across two clinical exams in the Strong Heart Family Study (SHFS) (mean age at baseline: 40.0 years; mean interval: 5.5 years apart). We examined longitudinal associations between individual lipid species and measures of cardiac aging (E/A ratio, isovolumic relaxation time, and deceleration time) using generalized estimation equation (GEE), adjusted for demographic, lifestyle, and clinical factors. Significant associations were then replicated in the Bogalusa Heart Study (BHS) (mean age at baseline: 48.1 years). Frailty Cox proportional hazards models were used to examine whether cardiac aging-related lipids predicted incident CHD over a 20-year follow-up. We found that multiple lipid species, primarily glycerophospholipids, glycerolipids, and sphingomyelins, were associated with measures of cardiac aging, with the majority showing inverse associations. Some of these associations were confirmed in a biracial cohort of African American and White participants. Additionally, baseline levels of specific glycerophospholipids and fatty acids associated with diastolic function (E/A ratio and deceleration time) were linked to a reduced risk of CHD (HR range: 0.21-0.86). Conversely, other E/A-associated glycerophospholipids were linked to increased CHD risk (HR range: 1.24-1.34). In summary, we identified distinct lipidomic signatures associated with trajectories of subclinical cardiac aging, several of which also predict later-life CHD risk. These findings highlight molecular correlates of cardiac aging from midlife into older adulthood and suggest that lipidomic pathways may serve as early biomarkers for future: Keywords are required, The following are suggested: "Cardiac aging, Risk, Lipidomic markers". Please check if correct. CHD.

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