03140nas a2200289 4500008004100000022001400041245015000055210006900205260001300274300000700287490000700294520224800301100002102549700001302570700002002583700002202603700001902625700002102644700002002665700001802685700002202703700002402725700002102749700002402770700002002794856003602814 2017 eng d a1862-351400aRelationship of bone mineral density with valvular and annular calcification in community-dwelling older people: The Cardiovascular Health Study.0 aRelationship of bone mineral density with valvular and annular c c2017 Dec a520 v123 a

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.

1 aMassera, Daniele1 aXu, Shuo1 aBartz, Traci, M1 aBortnick, Anna, E1 aIx, Joachim, H1 aChonchol, Michel1 aOwens, David, S1 aBarasch, Eddy1 aGardin, Julius, M1 aGottdiener, John, S1 aRobbins, John, R1 aSiscovick, David, S1 aKizer, Jorge, R uhttps://chs-nhlbi.org/node/748802603nas a2200229 4500008004100000022001400041245010000055210006900155260001600224520188800240100002002128700002002148700002102168700002102189700001902210700002202229700002002251700002202271700002402293700002002317856003602337 2021 eng d a1468-201X00aCumulative burden of clinically significant aortic stenosis in community-dwelling older adults.0 aCumulative burden of clinically significant aortic stenosis in c c2021 Jun 023 a

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±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.

1 aOwens, David, S1 aBartz, Traci, M1 aBůzková, Petra1 aMassera, Daniele1 aBiggs, Mary, L1 aCarlson, Selma, D1 aPsaty, Bruce, M1 aSotoodehnia, Nona1 aGottdiener, John, S1 aKizer, Jorge, R uhttps://chs-nhlbi.org/node/878702684nas a2200229 4500008004100000022001400041245010400055210006900159260001600228520196100244100002102205700002002226700001902246700002202265700002502287700002202312700002402334700002002358700002002378700002002398856003602418 2023 eng d a1468-201X00aTraditional and novel risk factors for incident aortic stenosis in community-dwelling older adults.0 aTraditional and novel risk factors for incident aortic stenosis  c2023 Jul 183 a

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±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.

1 aMassera, Daniele1 aBartz, Traci, M1 aBiggs, Mary, L1 aSotoodehnia, Nona1 aReiner, Alexander, P1 aSemba, Richard, D1 aGottdiener, John, S1 aPsaty, Bruce, M1 aOwens, David, S1 aKizer, Jorge, R uhttps://chs-nhlbi.org/node/941603491nas a2200529 4500008004100000022001400041245008200055210006900137260001600206300001200222490000700234520202400241653001602265653000902281653002202290653001702312653002602329653001502355653001902370653001502389653002102404653002102425653001102446653001102457653000902468653003702477653001502514653003002529100002202559700002202581700002002603700002802623700002002651700002202671700002402693700002002717700002102737700001902758700001602777700002102793700002502814700002202839700002402861700002002885700002002905856003602925 2025 eng d a2047-998000aPlasma Proteomic Assessment of Calcific Aortic Valve Disease in Older Adults.0 aPlasma Proteomic Assessment of Calcific Aortic Valve Disease in  c2025 Mar 04 ae0363360 v143 a

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.

10aAge Factors10aAged10aAged, 80 and over10aAortic Valve10aAortic Valve Stenosis10aBiomarkers10aBlood Proteins10aCalcinosis10aChemokine CXCL1210aEchocardiography10aFemale10aHumans10aMale10aMendelian Randomization Analysis10aProteomics10aSeverity of Illness Index1 aBortnick, Anna, E1 aAustin, Thomas, R1 aHamerton, Emily1 aGudmundsdottir, Valborg1 aEmilsson, Valur1 aJennings, Lori, L1 aGudnason, Vilmundur1 aOwens, David, S1 aMassera, Daniele1 aDufresne, Line1 aYang, Ta-Yu1 aEngert, James, C1 aThanassoulis, George1 aTracy, Russell, P1 aGerszten, Robert, E1 aPsaty, Bruce, M1 aKizer, Jorge, R uhttps://chs-nhlbi.org/node/9906