Aortic Valve Calcium Prevalence, Long-term Risk Factors, and progression to Severe Aortic Stenosis Among Persons >75 Years Old - The development and progression of calcific aortic valve disease (CAVD) is a complex and multifactorial process principally characterized by aortic valve calcification (AVC) that ultimately progresses to severe aortic stenosis (AS). The prevalence of AVC and severe AS has the highest prevalence among persons ≥75 years old. Currently, the only treatment for severe AS is aortic valve replacement (AVR) and as the US life expectancy continues to increase, the number of persons needing AVR is expected to double between 2025 and 2050 to 1.4 million. Recent provocative subgroup analyses from the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial and FOURIER trial testing the PCSK9 inhibitor evolocumab showed a 35-60% lower rate of severe AS with randomization to active treatment. These results suggest that it may be possible to prevent severe AS in appropriately selected patients and/or using novel treatment strategies. However, there is no risk- score/algorithm to identify older persons at high risk for severe AS. Our pioneering work in the MESA cohort of primarily middle-aged patients has demonstrated an extremely strong association between AVC measured using non-contrast cardiac CT and severe AS, which is even stronger than the association between coronary artery calcium (CAC) and coronary heart disease. Additionally, we have shown that persons with a high hsCRP and lipoprotein(a) have a significantly higher risk of developing incident AVC. The 2011 NIH Working Group on CAVD highlighted crucial areas for research including: 1) identifying risk factors for persons at high-risk for severe AS, 2) determining if AVC measurement may identify patients most likely to benefit from earlier intervention, & 3) determining if there are interactions between risk factors for AS. However, 13 years later, little is known about the potential synergy between acute phase reactants, inflammatory markers, lipoprotein(a), and other key traditional risk factors in the risk for AVC and severe AS. Furthermore, the distribution of AVC among older persons and its associated 5-10 year risk for severe AS among older persons is incompletely described. The population percentiles for AVC among older persons, a crucial reference for the clinical interpretation of AVC, is also incompletely described. We propose to use the previously quantified AVC and meticulously phenotyped risk factor data from the ARIC and MESA cohorts in which cardiac CT was performed among 3,242 participants age ≥75 years old to examine the middle-age risk factors for the long-term development of AVC, create AVC population percentiles, and adjudicate incident cases of severe AS to identify older persons at greatest risk for progression to severe AS. These results will have a direct impact on: 1) elucidating the long-term risk factors for the development of AVC, 2) clinical reporting of AVC results in this older age group with the highest prevalence of AVC, and 3) to help efficiently plan clinical trial enrollment of persons most likely to benefit from new treatment therapies. 1
