@article {7488, title = {Relationship of bone mineral density with valvular and annular calcification in community-dwelling older people: The Cardiovascular Health Study.}, journal = {Arch Osteoporos}, volume = {12}, year = {2017}, month = {2017 Dec}, pages = {52}, abstract = {

Associations between bone mineral density and aortic valvular, aortic annular, and mitral annular calcification were investigated in a cross-sectional analysis of a population-based cohort of 1497 older adults. Although there was no association between continuous bone mineral density and outcomes, a significant association between osteoporosis and aortic valvular calcification in men was found.

INTRODUCTION: The process of cardiac calcification bears a resemblance to skeletal bone metabolism and its regulation. Experimental studies suggest that bone mineral density (BMD) and valvular calcification may be reciprocally related, but epidemiologic data are sparse.

METHODS: We tested the hypothesis that BMD of the total hip and femoral neck measured by dual-energy X-ray absorptiometry (DXA) is inversely associated with prevalence of three echocardiographic measures of cardiac calcification in a cross-sectional analysis of 1497 older adults from the Cardiovascular Health Study. The adjusted association of BMD with aortic valve calcification (AVC), aortic annular calcification (AAC), and mitral annular calcification (MAC) was assessed with relative risk (RR) regression.

RESULTS: Mean (SD) age was 76.2 (4.8)~years; 58\% were women. Cardiac calcification was highly prevalent in women and men: AVC, 59.5 and 71.0\%; AAC 45.1 and 46.7\%; MAC 42.8 and 39.5\%, respectively. After limited and full adjustment for potential confounders, no statistically significant associations were detected between continuous BMD at either site and the three measures of calcification. Assessment of WHO BMD categories revealed a significant association between osteoporosis at the total hip and AVC in men (adjusted RR compared with normal BMD~=~1.24 (1.01-1.53)). In graded sensitivity analyses, there were apparent inverse associations between femoral neck BMD and AVC with stenosis in men, and femoral neck BMD and moderate/severe MAC in women, but these were not significant.

CONCLUSION: These findings support further investigation of the sex-specific relationships between low BMD and cardiac calcification, and whether processes linking the two could be targeted for therapeutic ends.

}, issn = {1862-3514}, doi = {10.1007/s11657-017-0347-y}, author = {Massera, Daniele and Xu, Shuo and Bartz, Traci M and Bortnick, Anna E and Ix, Joachim H and Chonchol, Michel and Owens, David S and Barasch, Eddy and Gardin, Julius M and Gottdiener, John S and Robbins, John R and Siscovick, David S and Kizer, Jorge R} } @article {8787, title = {Cumulative burden of clinically significant aortic stenosis in community-dwelling older adults.}, journal = {Heart}, year = {2021}, month = {2021 Jun 02}, abstract = {

OBJECTIVES: Current estimates of aortic stenosis (AS) frequency have mostly relied on cross-sectional echocardiographic or longitudinal administrative data, making understanding of AS burden incomplete. We performed case adjudications to evaluate the frequency of AS and assess differences by age, sex and race in an older cohort with long-term follow-up.

METHODS: We developed case-capture methods using study echocardiograms, procedure and diagnosis codes, heart failure events and deaths for targeted review of medical records in the Cardiovascular Health Study to identify moderate or severe AS and related procedures or hospitalisations. The primary outcome was clinically significant AS (severe AS or procedure). Assessment of incident AS burden was based on subdistribution survival methods, while associations with age, sex and race relied on cause-specific survival methods.

RESULTS: The cohort comprised 5795 participants (age 73{\textpm}6, 42.2\% male, 14.3\% Black). Cumulative frequency of clinically significant AS at maximal 25-year follow-up was 3.69\% (probable/definite) to 4.67\% (possible/probable/definite), while the corresponding 20-year cumulative incidence was 2.88\% to 3.71\%. Of incident cases, about 85\% had a hospitalisation for severe AS, but roughly half did not undergo valve intervention. The adjusted incidence of clinically significant AS was higher in men (HR 1.62 [95\% CI 1.21 to 2.17]) and increased with age (HR 1.08 [95\% CI 1.04 to 1.11]), but was lower in Blacks (HR 0.43 [95\% CI 0.23 to 0.81]).

CONCLUSIONS: In this community-based study, we identified a higher burden of clinically significant AS than reported previously, with differences by age, sex and race. These findings have important implications for public health resource planning, although the lower burden in Blacks merits further study.

}, issn = {1468-201X}, doi = {10.1136/heartjnl-2021-319025}, author = {Owens, David S and Bartz, Traci M and B{\r u}zkov{\'a}, Petra and Massera, Daniele and Biggs, Mary L and Carlson, Selma D and Psaty, Bruce M and Sotoodehnia, Nona and Gottdiener, John S and Kizer, Jorge R} } @article {9416, title = {Traditional and novel risk factors for incident aortic stenosis in community-dwelling older adults.}, journal = {Heart}, year = {2023}, month = {2023 Jul 18}, abstract = {

OBJECTIVES: Calcific aortic stenosis (AS) is the most common valvular disease in older adults, yet its risk factors remain insufficiently studied in this population. Such studies are necessary to enhance understanding of mechanisms, disease management and therapeutics.

METHODS: The Cardiovascular Health Study is a population-based investigation of older adults that completed adjudication of incident AS over long-term follow-up. We evaluated traditional cardiovascular risk factors or disease, as well as novel risk factors from lipid, inflammatory and mineral metabolism pathways, in relation to incident moderate or severe AS (including AS procedures) and clinically significant AS (severe AS, including procedures).

RESULTS: Of 5390 participants (age 72.9{\textpm}5.6 years, 57.6\% female, 12.5\% black), 287 developed moderate or severe AS, and 175 clinically significant AS, during median follow-up of 13.1 years. After full adjustment, age (HR=1.66 per SD (95\% CI=1.45, 1.91)), male sex (HR=1.41 (1.06, 1.87)), diabetes (HR=1.53 (1.10, 2.13)), coronary heart disease (CHD, HR=1.36 (1.01, 1.84)), lipoprotein-associated phospholipase-A (LpPLA) activity (HR=1.21 per SD (1.07, 1.37)) and sCD14 (HR=1.16 per SD (1.01, 1.34)) were associated with incident moderate/severe AS, while black race demonstrated an inverse association (HR=0.40 (0.24, 0.65)), and creatinine-based estimated glomerular filtration rate (eGFR) showed a U-shaped relationship. Findings were similar for clinically significant AS, although CHD and sCD14 fell short of significance, but interleukin-(IL) 6 showed a positive association.

CONCLUSION: This comprehensive evaluation of risk factors for long-term incidence of AS identified associations for diabetes and prevalent CHD, LpPLA activity, sCD14 and IL-6, and eGFR. These factors may hold clues to biology, preventive efforts and potential therapeutics for those at highest risk.

}, issn = {1468-201X}, doi = {10.1136/heartjnl-2023-322709}, author = {Massera, Daniele and Bartz, Traci M and Biggs, Mary L and Sotoodehnia, Nona and Reiner, Alexander P and Semba, Richard D and Gottdiener, John S and Psaty, Bruce M and Owens, David S and Kizer, Jorge R} } @article {9906, title = {Plasma Proteomic Assessment of Calcific Aortic Valve Disease in Older Adults.}, journal = {J Am Heart Assoc}, volume = {14}, year = {2025}, month = {2025 Mar 04}, pages = {e036336}, abstract = {

BACKGROUND: Calcific aortic valve disease (CAVD), and ensuing severe aortic stenosis (AS), is the foremost valvular disorder of aging, yet preventive therapies are lacking. A better understanding of the molecular underpinnings of aortic valve calcification (AVC) is necessary to develop pharmacologic interventions.

METHODS AND RESULTS: We undertook large-scale plasma proteomics in a cohort study of adults >=65 years old, the CHS (Cardiovascular Health Study), to identify individual proteins associated with echocardiographic AVC and incident moderate/severe AS. Proteomics measurements were performed with the aptamer-based SomaLogic platform of ~5000 proteins. Significant proteins were validated in a second cohort, the AGES-RS (Age, Gene/Environment Susceptibility-Reykjavik Study), which assessed AVC and AS by computed tomography. The potential causal associations of replicated proteins were tested in 2-sample Mendelian randomization using identified cis protein quantitative trait loci in consortia having computed tomography-quantified AVC or AS as outcomes. Six proteins showed Bonferroni-corrected significant relationships with AVC in CHS. Three of these, CXCL-12 (C-X-C chemokine ligand 12), KLKB1 (kallikrein), and leptin, replicated in AGES-RS, of which the former 2 are novel. Only 1 protein, CXCL6, which showed a near-significant association with AS in the replication cohort, was significantly (positively) associated with incident AS. Mendelian randomization analysis was conducted for KLKB1, CXCL12, and CXCL6, which supported a causal relationship for higher KLKB1 with lower AVC (beta=-0.25, =0.009).

CONCLUSIONS: This study of older adults newly identified and largely replicated associations of 3 circulating proteins with calcific aortic valve disease, of which the relationship of plasma KLKB1 may have a causal basis. Additional investigation is necessary to determine if KLKB1 could be harnessed for calcific aortic valve disease therapeutics.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Aortic Valve, Aortic Valve Stenosis, Biomarkers, Blood Proteins, Calcinosis, Chemokine CXCL12, Echocardiography, Female, Humans, Male, Mendelian Randomization Analysis, Proteomics, Severity of Illness Index}, issn = {2047-9980}, doi = {10.1161/JAHA.124.036336}, author = {Bortnick, Anna E and Austin, Thomas R and Hamerton, Emily and Gudmundsdottir, Valborg and Emilsson, Valur and Jennings, Lori L and Gudnason, Vilmundur and Owens, David S and Massera, Daniele and Dufresne, Line and Yang, Ta-Yu and Engert, James C and Thanassoulis, George and Tracy, Russell P and Gerszten, Robert E and Psaty, Bruce M and Kizer, Jorge R} }