Abstract Body (Do not enter title and authors here): Introduction: Cardiac structure and function typically decline with age. Abnormal acceleration of this decline, known as cardiac age acceleration, can be estimated from MRI using deep learning. Both general and cardiac-specific mechanisms may contribute to cardiac aging. Longer telomere length in circulating leukocytes, which indicates greater cellular capacity for replication, has been associated with a lower risk of heart failure and more favorable cardiac structure and function Recent data have also suggested that longer telomeres contribute to risk of clonal hematopoiesis of indeterminate potential (CHIP), which has been linked to increased risk of atherosclerosis, heart failure and arrhythmia. Here we studied whether telomere length or CHIP status are associated with deep learning derived cardiac age acceleration.

Methods: We developed a deep learning model to estimate cardiac age acceleration in 70,805 UK Biobank participants from the cardiovascular MRI (four-chamber long axis view). Of these, we identified leukocyte telomere length (LTL) in 61,554 and were able to evaluate CHIP in 61,636. In an additional 372,465 participants unrelated to those with imaging, a genome-wide association study (GWAS) was conducted for LTL, and a GWAS of cardiac age acceleration was conducted in those with imaging; using these, a two-sample Mendelian randomization (MR) was performed to identify putatively causal relationships.

Results: In the 61,636 participants with both CHIP and cardiac age acceleration measurements, CHIP was not associated with cardiac age acceleration regardless of driver gene (p=0.79). In contrast, cardiac age acceleration was associated with a shorter LTL (Beta=-0.025 SD, p=5.4E-10). Shorter LTL was causally associated with cardiac age acceleration (Beta=-0.10, p=0.047).

Conclusions: These data suggest that general aging mechanisms conferred by shortening telomeres may contribute to the age-associated structural and functional decline of the heart as observed with MRI. In comparison, the relationship between CHIP and cardiovascular risk may not manifest in ways that cause apparent cardiac age acceleration.