@article {895, title = {Cardiovascular morbidity and mortality in community-dwelling elderly individuals with calcification of the fibrous skeleton of the base of the heart and aortosclerosis (The Cardiovascular Health Study).}, journal = {Am J Cardiol}, volume = {97}, year = {2006}, month = {2006 May 01}, pages = {1281-6}, abstract = {

In the elderly, mitral annular calcification (MAC) and aortic valve sclerosis (AVS) are associated with increased cardiovascular morbidity and mortality. Aortic annular calcification (AAC) commonly occurs with MAC. However, the prognostic value of AAC, singly or in combination with MAC and AVS, for incident cardiovascular disease and mortality is unknown. From the Cardiovascular Health Study, we analyzed 3,782 participants (76 +/- 5 years of age, 60\% women) who had an echocardiogram at the 1994 to 1995 examination and who were prospectively followed for an average of 6.6 years (range 0.01 to 8.5). All 3 calcification categories were associated with incident congestive heart failure (MAC: hazard ratio [HR] 1.71, 95\% confidence interval [CI] 1.35 to 2.18, AAC: HR 1.62, 95\% CI 1.28 to 2.06, and AVS: HR 1.50, 95\% CI 1.19 to 1.89) and death. A stronger association with incident cardiovascular disease and mortality was observed with a larger number of calcification categories and with increased MAC severity. Moreover, in the participants with prevalent cardiovascular disease at echocardiographic examination (n = 1,054), MAC and AAC were still associated with cardiovascular mortality (MAC: HR 1.91, 95\% CI 1.04 to 3.50; AAC: HR 2.11, 95\% CI 1.16 to 3.85) even in fully adjusted models. In conclusion, MAC, AAC, and AVS are associated with a significant risk of incident congestive heart failure, cardiovascular and all-cause mortalities, and worse outcome in older patients with preexisting cardiovascular disease. Elderly patients with these findings represent a high-risk group and may require close medical attention.

}, keywords = {Aged, Aortic Valve, Calcinosis, Echocardiography, Female, Follow-Up Studies, Heart Failure, Heart Valve Diseases, Humans, Male, Mitral Valve, Prospective Studies, Risk Factors, Sclerosis, Severity of Illness Index, United States}, issn = {0002-9149}, doi = {10.1016/j.amjcard.2005.11.065}, author = {Barasch, Eddy and Gottdiener, John S and Marino Larsen, Emily K and Chaves, Paulo H M and Newman, Anne B} } @article {874, title = {Clinical significance of calcification of the fibrous skeleton of the heart and aortosclerosis in community dwelling elderly. The Cardiovascular Health Study (CHS).}, journal = {Am Heart J}, volume = {151}, year = {2006}, month = {2006 Jan}, pages = {39-47}, abstract = {

BACKGROUND: Mitral annular calcification (MAC), aortic annular calcification (AAC), and aortic valve sclerosis (AVS) are associated with aging, and MAC and AVS are markers of advanced atherosclerosis. No studies have examined the prevalence and the clinical relevance of all 3 forms of calcification in a single free-living elderly population.

METHODS: We used 2-dimensional echocardiography to evaluate MAC, AAC, AVS and all 3 combined in 3929 participants, mean age 76 +/- 5 years, 60\% women, in the Cardiovascular Health Study, a prospective community-based observational study designed to assess cardiovascular disease (CVD) risk factors and outcomes in elderly persons.

RESULTS: Mitral annular calcification was found in 1640 (42 \%) subjects, AAC in 1710 (44 \%), AVS in 2114 (54 \%), and all 3 combined in 662 (17 \%). The participants with these findings were older than those without them, and those with MAC had worse cardiovascular, renal, metabolic, and functional profile than those with AAC and AVS. Age-, sex-, and race-adjusted logistic regression analysis found a significant association between the 3 calcification categories and CVD, the strongest being between the combined group with congestive heart failure (odds ratio 2.04, 95\% CI 1.34-3.09). In highly adjusted models, only MAC was associated with CVD, and the strength of association was related to the severity of MAC.

CONCLUSIONS: In free-living elderly, MAC, AAC, and AVS are highly prevalent and are associated with CVD. Mitral annular calcification in particular has strong association with CVD, and with an adverse biomedical profile.

}, keywords = {Aged, Aortic Valve, Calcinosis, Female, Heart Valve Diseases, Humans, Male, Mitral Valve, Prevalence, Prospective Studies, Risk Factors, Sclerosis, Ultrasonography}, issn = {1097-6744}, doi = {10.1016/j.ahj.2005.03.052}, author = {Barasch, Eddy and Gottdiener, John S and Larsen, Emily K Marino and Chaves, Paulo H M and Newman, Anne B and Manolio, Teri A} } @article {1134, title = {Association between elevated fibrosis markers and heart failure in the elderly: the cardiovascular health study.}, journal = {Circ Heart Fail}, volume = {2}, year = {2009}, month = {2009 Jul}, pages = {303-10}, abstract = {

BACKGROUND: Myocardial fibrosis reflects excess collagen deposition in the extracellular left ventricular matrix, which has been associated with heart failure (HF). No studies have addressed the relation between fibrosis biomarkers and HF in the elderly.

METHODS AND RESULTS: Serum fibrosis markers were measured in 880 participants of the Cardiovascular Health Study (mean age 77+/-6 years, 48\% women). Participants with systolic HF (n=131, left ventricular ejection fraction <55\%) and those with diastolic HF (n=179, left ventricular ejection fraction > or =55\%) were compared with controls (280 with cardiovascular risk factors, and 279 healthy individuals) using a nested case-control design. Fibrosis markers included carboxyl-terminal peptide of procollagen type I, carboxyl-terminal telopeptide of collagen type I, and amino-terminal peptide of procollagen type III. Echocardiography was used to document systolic and diastolic function parameters. Analysis of variance and logistic regression analysis (per tertile odds ratios [OR]), adjusted by age, gender, race, hypertension, atrial fibrillation, coronary heart disease, baseline serum glucose, serum cystatin C, serum creatinine, C-reactive protein, any angiotensin-converting enzyme inhibitor, spironolactone or any diuretic, NT-proBNP, and total bone mineral density were performed. Systolic HF was associated with significantly elevated carboxyl-terminal telopeptide of collagen type I (OR=2.6; 95\% CI=1.2 to 5.7) and amino-terminal peptide of procollagen type III (OR=3.3; 95\% CI=1.6 to 5.8), when adjusting for covariates. Associations of diastolic HF were significant for carboxyl-terminal telopeptide of collagen type I (OR=3.9; 95\% CI=1.9 to 8.3) and amino-terminal peptide of procollagen type III (OR=2.7; 95\% CI=1.4 to 5.4). HF was not associated with elevated carboxyl-terminal peptide of procollagen type I (P>0.10), and fibrosis markers did not significantly differ between HF with diastolic versus those with systolic dysfunction (P>0.10) whereas NT-proBNP mean values were higher in systolic heart failure than in diastolic heart failure (P<0.0001).

CONCLUSIONS: Fibrosis markers are significantly elevated in elderly individuals with diastolic or systolic HF. These associations remained significant when adjusting for covariates relevant to the aging process.

}, keywords = {Aged, Aged, 80 and over, Female, Fibrosis, Heart Failure, Humans, Male, Myocardium, Ultrasonography}, issn = {1941-3297}, doi = {10.1161/CIRCHEARTFAILURE.108.828343}, author = {Barasch, Eddy and Gottdiener, John S and Aurigemma, Gerard and Kitzman, Dalane W and Han, Jing and Kop, Willem J and Tracy, Russell P} } @article {1132, title = {Association between depressive symptoms and fibrosis markers: the Cardiovascular Health Study.}, journal = {Brain Behav Immun}, volume = {24}, year = {2010}, month = {2010 Feb}, pages = {229-35}, abstract = {

OBJECTIVE: Fibrosis plays an important role in heart failure (HF) and other diseases that occur more frequently with increasing age. Depression is associated with an increased risk of heart failure and other age-related diseases. This study examined the association between depressive symptoms and fibrosis markers in adults aged 65 years and above.

METHODS: Fibrosis markers and depressive symptoms were assessed in 870 participants (age=80.9+/-5.9 yrs, 49\% women) using a case-control design based on heart failure status (307 HF patients and 563 age- and sex-matched controls, of whom 284 with CVD risk factors (hypertension, diabetes mellitus, or hypercholesterolemia) and 279 controls without these CVD risk factors). Fibrosis markers were procollagen type I (PIP), type I collagen (CITP), and procollagen type III (PIIINP). Inflammation markers included C-reactive protein, white blood cell counts and fibrinogen. Depression was assessed using the Center for Epidemiological Studies-Depression (CES-D) scale using a previously validated cut-off point for depression (CES-D > or = 8). Covariates included demographic and clinical variables.

RESULTS: Depression was associated with higher levels of PIP (median=411.0, inter-quartile range (IQR)=324.4-472.7 ng/mL vs. 387.6, IQR=342.0-512.5 ng/mL, p=0.006) and CITP (4.99, IQR=3.53-6.85 vs. 4.53, IQR=3.26-6.22 microg/L, p=0.024), but not PIIIINP (4.07, IQR=2.75-5.54 microg/L vs. 3.58, IQR=2.71-5.01 microg/L, p=0.29) compared to individuals without depression. Inflammation markers were also elevated in depressed participants (CRP, p=0.014; WBC, p=0.075; fibrinogen, p=0.074), but these inflammation markers did not account for the relationship between depression and fibrosis markers.

CONCLUSIONS: Depression is associated with elevated fibrosis markers and may therefore adversely affect heart failure and other age-related diseases in which extra-cellular matrix formation plays a pathophysiological role.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, C-Reactive Protein, Cardiovascular Diseases, Collagen Type I, Depression, Electrocardiography, Endomyocardial Fibrosis, Fatigue, Female, Fibrosis, Health Surveys, Heart Failure, Humans, Inflammation Mediators, Male, Multivariate Analysis, Peptide Fragments, Procollagen, Psychiatric Status Rating Scales, Risk Factors, Socioeconomic Factors}, issn = {1090-2139}, doi = {10.1016/j.bbi.2009.09.017}, author = {Kop, Willem J and Kuhl, Emily A and Barasch, Eddy and Jenny, Nancy S and Gottlieb, Stephen S and Gottdiener, John S} } @article {1292, title = {Association of annular calcification and aortic valve sclerosis with brain findings on magnetic resonance imaging in community dwelling older adults: the cardiovascular health study.}, journal = {J Am Coll Cardiol}, volume = {57}, year = {2011}, month = {2011 May 24}, pages = {2172-80}, abstract = {

OBJECTIVES: The objective of this study was to investigate the associations of mitral annular calcification, aortic annular calcification, and aortic valve sclerosis with covert magnetic resonance imaging (MRI)-defined brain infarcts.

BACKGROUND: Clinically silent brain infarcts defined by MRI are associated with increased risk for cognitive decline, dementia, and future overt stroke. Left-sided cardiac valvular and annular calcifications are suspected as risk factors for clinical ischemic stroke.

METHODS: A total of 2,680 CHS (Cardiovascular Health Study) participants without clinical histories of stroke or transient ischemic attack underwent brain MRI in 1992 and 1993, 1 to 2 years before echocardiographic exams (1994 to 1995).

RESULTS: The mean age of the participants was 74.5 {\textpm} 4.8 years, and 39.3\% were men. The presence of any annular or valvular calcification (mitral annular calcification, aortic annular calcification, or aortic valve sclerosis), mitral annular calcification alone, or aortic annular calcification alone was significantly associated with a higher prevalence of covert brain infarcts in unadjusted analyses (p < 0.01 for all). In models adjusted for age, sex, race, body mass index, physical activity, creatinine, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, smoking, diabetes, coronary heart disease, and congestive heart failure, the presence of any annular or valve calcification remained associated with covert brain infarcts (risk ratio: 1.24; 95\% confidence interval: 1.05 to 1.47). The degree of annular or valvular calcification severity showed a direct relation with the presence of covert MRI findings.

CONCLUSIONS: Left-sided cardiac annular and valvular calcifications are associated with covert MRI-defined brain infarcts. Further study is warranted to identify mechanisms and determine whether intervening in the progression of annular and valvular calcification could reduce the incidence of covert brain infarcts as well as the associated risk for cognitive impairment and future stroke.

}, keywords = {Aged, Aortic Valve Stenosis, Brain, Brain Infarction, Calcinosis, Cohort Studies, Female, Humans, Magnetic Resonance Imaging, Male, Mitral Valve Stenosis, Retrospective Studies}, issn = {1558-3597}, doi = {10.1016/j.jacc.2011.01.034}, author = {Rodriguez, Carlos J and Bartz, Traci M and Longstreth, W T and Kizer, Jorge R and Barasch, Eddy and Lloyd-Jones, Donald M and Gottdiener, John S} } @article {1302, title = {Association of serum phosphate levels with aortic valve sclerosis and annular calcification: the cardiovascular health study.}, journal = {J Am Coll Cardiol}, volume = {58}, year = {2011}, month = {2011 Jul 12}, pages = {291-7}, abstract = {

OBJECTIVES: This study was conducted to evaluate mineral metabolism markers as potential risk factors for calcific aortic valve disease.

BACKGROUND: Mineral metabolism disturbances are common among older people and may contribute to cardiac valvular calcification. Associations of serum mineral metabolism markers with cardiac valvular calcification have not been evaluated in a well-characterized general population of older adults.

METHODS: We measured serum levels of phosphate, calcium, parathyroid hormone, and 25-hydroxyvitamin D in 1,938 Cardiovascular Health Study participants who were free of clinical cardiovascular disease and who underwent echocardiographic measurements of aortic valve sclerosis (AVS), mitral annular calcification (MAC), and aortic annular calcification (AAC). We used logistic regression models to estimate associations of mineral metabolism markers with AVS, MAC, and AAC after adjustment for relevant confounding variables, including kidney function.

RESULTS: The respective prevalences of AVS, MAC, and AAC were 54\%, 39\%, and 44\%. Each 0.5 mg/dl higher serum phosphate concentration was associated with greater adjusted odds of AVS (odds ratio [OR]: 1.17, 95\% confidence interval [CI]: 1.04 to 1.31, p = 0.01), MAC (OR: 1.12, 95\% CI: 1.00 to 1.26, p = 0.05), and AAC (OR: 1.12, 95\% CI: 0.99 to 1.25, p = 0.05). In contrast, serum calcium, parathyroid hormone, and 25-hydroxyvitamin D concentrations were not associated with aortic or mitral calcification.

CONCLUSIONS: Higher serum phosphate levels within the normal range were associated with valvular and annular calcification in a community-based cohort of older adults. Phosphate may be a novel risk factor for calcific aortic valve disease and warrants further study.

}, keywords = {Aged, Aortic Valve, Calcinosis, Calcium, Female, Heart Valve Diseases, Humans, Male, Mitral Valve, Parathyroid Hormone, Phosphates, Risk Factors, Sclerosis, Vitamin D}, issn = {1558-3597}, doi = {10.1016/j.jacc.2010.11.073}, author = {Linefsky, Jason P and O{\textquoteright}Brien, Kevin D and Katz, Ronit and de Boer, Ian H and Barasch, Eddy and Jenny, Nancy S and Siscovick, David S and Kestenbaum, Bryan} } @article {1321, title = {The relationship between serum markers of collagen turnover and cardiovascular outcome in the elderly: the Cardiovascular Health Study.}, journal = {Circ Heart Fail}, volume = {4}, year = {2011}, month = {2011 Nov}, pages = {733-9}, abstract = {

BACKGROUND: The deposition of collagen fibrils in the myocardial extracellular matrix increases with age and plays a key role in the pathophysiology of heart failure (HF). We sought to determine the predictive value of serum markers of collagen turnover for incident HF and cardiovascular (CV) morbidity, mortality, and all-cause mortality in elderly individuals.

METHODS AND RESULTS: In 880 participants in the Cardiovascular Health Study (mean age, 77{\textpm}6 years; 48\% women), serum levels of carboxyl-terminal peptide of procollagen type I (PIP), carboxyl-terminal telopeptide of collagen type I (CITP), and amino-terminal peptide of procollagen type III (PIIINP) were measured in 4 groups: HF with reduced ejection fraction (HFREF; n=146, EF <55\%); HF with preserved EF (HFPEF; n=175, EF >=55\%), control subjects with CV risk factors but not HF (CVD; n=280), and healthy control subjects free of CV disease (n=279). Relationships between these serum markers and outcome at follow-up of 12{\textpm}4 years (range, 3-17 years) was determined in six models including those adjusted for conventional risk factors, renal function, NT-proBNP and agents which interfere with collagen synthesis. For the entire cohort, in unadjusted and adjusted models, both PIIINP and CITP were associated with myocardial infarction, incident HF, hospitalization for HF, cardiovascular and all-cause mortality. In healthy control subjects, CITP and PIIINP were associated with all-cause death. In control subjects with risk factors, CITP was associated with incident HF, and in participants with HFPEF, CITP was associated with hospitalization for HF. No collagen biomarker was associated with outcome in participants with HFREF, and PIP was not associated with outcome in the cohort or its subgroups.

CONCLUSIONS: In both healthy and elderly individuals with CV disease at risk of developing HF, CITP and PIIINP are significantly associated with multiple adverse cardiac outcomes including myocardial infarction, HF, and death. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00005133.

}, keywords = {Aged, Aged, 80 and over, Aging, Biomarkers, Cardiovascular Diseases, Case-Control Studies, Cohort Studies, Collagen, Collagen Type I, Female, Follow-Up Studies, Heart Failure, Humans, Incidence, Male, Peptide Fragments, Peptides, Predictive Value of Tests, Procollagen, Prospective Studies, Stroke Volume, Survival Rate}, issn = {1941-3297}, doi = {10.1161/CIRCHEARTFAILURE.111.962027}, author = {Barasch, Eddy and Gottdiener, John S and Aurigemma, Gerard and Kitzman, Dalane W and Han, Jing and Kop, Willem J and Tracy, Russell P} } @article {1389, title = {Cardiac microinjury measured by troponin T predicts collagen metabolism in adults aged >=65 years with heart failure.}, journal = {Circ Heart Fail}, volume = {5}, year = {2012}, month = {2012 Jul 01}, pages = {406-13}, abstract = {

BACKGROUND: Repeated myocardial microinjuries lead to collagen deposition and fibrosis, thereby increasing the risk of clinical heart failure. Little is known about the longitudinal association between increases in myocardial injury and the biology of collagen synthesis and deposition.

METHODS AND RESULTS: Repeated measures of highly sensitive cardiac troponin T (cTnT) were obtained in participants of the Cardiovascular Health Study (N=353; mean age, 74{\textpm}6 years; 52\% women) at baseline and at 3 years follow-up. Biomarkers of collagen metabolism were obtained at follow-up and included carboxyterminal propeptide of procollagen type I, carboxyterminal telopeptide of type I collagen, and aminoterminal propeptide of procollagen III. Multivariable linear regression analyses were used to examine the association between baseline cTnT and changes in cTnT with collagen metabolism markers at follow-up adjusting for demographics, heart failure status, and cardiovascular risk factors. Results indicated that cTnT increases over 3-years were significantly associated with higher levels of carboxyterminal telopeptide of type I collagen (β=0.22, P<0.001) and aminoterminal propeptide of procollagen III (β=0.12, P=0.035) at follow-up when adjusting for demographic, clinical, and biochemical covariates including baseline cTnT. These associations were stronger in patients with heart failure than in control subjects. Conclusions- Increases in myocardial microinjury measured by changes in cTnT adversely affect markers of collagen metabolism. These findings are important to the biology of myocardial fibrosis and tissue repair. Serial evaluation of cTnT combined with collagen metabolism markers may further elucidate the pathophysiology of heart failure.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Biomarkers, Case-Control Studies, Chi-Square Distribution, Collagen, Collagen Type I, Female, Fibrosis, Heart Failure, Humans, Linear Models, Longitudinal Studies, Male, Multivariate Analysis, Myocardium, Peptide Fragments, Peptides, Predictive Value of Tests, Procollagen, Prospective Studies, Risk Assessment, Risk Factors, Time Factors, Troponin T, Up-Regulation}, issn = {1941-3297}, doi = {10.1161/CIRCHEARTFAILURE.111.965327}, author = {Kop, Willem J and Gottdiener, John S and deFilippi, Christopher R and Barasch, Eddy and Seliger, Stephen L and Jenny, Nancy S and Christenson, Robert H} } @article {6541, title = {Fibrosis-related biomarkers and incident cardiovascular disease in older adults: the cardiovascular health study.}, journal = {Circ Arrhythm Electrophysiol}, volume = {7}, year = {2014}, month = {2014 Aug}, pages = {583-9}, abstract = {

BACKGROUND: Fibrotic changes in the heart and arteries have been implicated in a diverse range of cardiovascular diseases (CVD), but whether circulating biomarkers that reflect fibrosis are associated with CVD is unknown.

METHODS AND RESULTS: We determined the associations of 2 biomarkers of fibrosis, transforming growth factor- β (TGF-β), and procollagen type III N-terminal propeptide (PIIINP), with incident heart failure, myocardial infarction, and stroke among community-living older adults in the Cardiovascular Health Study. We measured circulating TGF-β (n=1371) and PIIINP (n=2568) from plasma samples collected in 1996 and ascertained events through 2010. Given TGF-β{\textquoteright}s pleiotropic effects on inflammation and fibrogenesis, we investigated potential effect modification by C-reactive protein in secondary analyses. After adjustment for sociodemographic, clinical, and biochemical risk factors, PIIINP was associated with total CVD (hazard ratio [HR] per SD=1.07; 95\% confidence interval [CI], 1.01-1.14) and heart failure (HR per SD=1.08; CI, 1.01-1.16) but not myocardial infarction or stroke. TGF-β was not associated with any CVD outcomes in the full cohort but was associated with total CVD (HR per SD=1.16; CI, 1.02-1.31), heart failure (HR per SD=1.16; CI, 1.01-1.34), and stroke (HR per SD=1.20; CI, 1.01-1.42) among individuals with C-reactive protein above the median, 2.3 mg/L (P interaction <0.05).

CONCLUSIONS: Our findings provide large-scale, prospective evidence that circulating biomarkers of fibrosis, measured in community-living individuals late in life, are associated with CVD. Further research on whether TGF-β has a stronger fibrogenic effect in the setting of inflammation is warranted.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Aging, Biomarkers, C-Reactive Protein, Cardiovascular Diseases, Female, Fibrosis, Heart Failure, Humans, Incidence, Male, Myocardial Infarction, Peptide Fragments, Procollagen, Prognosis, Prospective Studies, Risk Assessment, Risk Factors, Stroke, Time Factors, Transforming Growth Factor beta, United States}, issn = {1941-3084}, doi = {10.1161/CIRCEP.114.001610}, author = {Agarwal, Isha and Glazer, Nicole L and Barasch, Eddy and Biggs, Mary L and Djouss{\'e}, Luc and Fitzpatrick, Annette L and Gottdiener, John S and Ix, Joachim H and Kizer, Jorge R and Rimm, Eric B and Sicovick, David S and Tracy, Russell P and Mukamal, Kenneth J} } @article {6336, title = {Fibrosis-related biomarkers and risk of total and cause-specific mortality: the cardiovascular health study.}, journal = {Am J Epidemiol}, volume = {179}, year = {2014}, month = {2014 Jun 01}, pages = {1331-9}, abstract = {

Fibrosis has been implicated in diverse diseases of the liver, kidney, lungs, and heart, but its importance as a risk factor for mortality remains unconfirmed. We determined the prospective associations of 2 complementary biomarkers of fibrosis, transforming growth factor-β (TGF-β) and procollagen type III N-terminal propeptide (PIIINP), with total and cause-specific mortality risks among community-living older adults in the Cardiovascular Health Study (1996-2010). We measured circulating TGF-β and PIIINP levels in plasma samples collected in 1996 and ascertained the number of deaths through 2010. Both TGF-β and PIIINP were associated with elevated risks of total and pulmonary mortality after adjustment for sociodemographic, clinical, and biochemical risk factors. For total mortality, the hazard ratios per doubling of TGF-β and PIIINP were 1.09 (95\% confidence interval (CI): 1.01, 1.17; P = 0.02) and 1.14 (CI: 1.03, 1.27; P = 0.01), respectively. The corresponding hazard ratios for pulmonary mortality were 1.27 (CI: 1.01, 1.60; P = 0.04) for TGF-β and 1.52 (CI: 1.11, 2.10; P = 0.01) for PIIINP. Associations of TGF-β and PIIINP with total and pulmonary mortality were strongest among individuals with higher C-reactive protein concentrations (P for interaction < 0.05). Our findings provide some of the first large-scale prospective evidence that circulating biomarkers of fibrosis measured late in life are associated with death.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, Cause of Death, Female, Fibrosis, Follow-Up Studies, Humans, Likelihood Functions, Male, Multivariate Analysis, Peptide Fragments, Procollagen, Proportional Hazards Models, Prospective Studies, Risk Factors, Transforming Growth Factor beta}, issn = {1476-6256}, doi = {10.1093/aje/kwu067}, author = {Agarwal, Isha and Glazer, Nicole L and Barasch, Eddy and Biggs, Mary L and Djouss{\'e}, Luc and Fitzpatrick, Annette L and Gottdiener, John S and Ix, Joachim H and Kizer, Jorge R and Rimm, Eric B and Siscovick, David S and Tracy, Russell P and Zieman, Susan J and Mukamal, Kenneth J} } @article {6805, title = {Associations between metabolic dysregulation and circulating biomarkers of fibrosis: the Cardiovascular Health Study.}, journal = {Metabolism}, volume = {64}, year = {2015}, month = {2015 Oct}, pages = {1316-23}, abstract = {

AIM: Fibrosis is one postulated pathway by which diabetes produces cardiac and other systemic complications. Our aim was to determine which metabolic parameters are associated with circulating fibrosis-related biomarkers transforming growth factor-β (TGF-β) and procollagen type III N-terminal propeptide (PIIINP).

METHODS: We used linear regression to determine the cross-sectional associations of diverse metabolic parameters, including fasting glucose, fasting insulin, body mass index, fatty acid binding protein 4, and non-esterified fatty acids, with circulating levels of TGF-β (n = 1559) and PIIINP (n = 3024) among community-living older adults in the Cardiovascular Health Study.

RESULTS: Among the main metabolic parameters we examined, only fasting glucose was associated with TGF-β (P = 0.03). In contrast, multiple metabolic parameters were associated with PIIINP, including fasting insulin, body mass index, and non-esterified fatty acids (P<0.001, P<0.001, P=0.001, respectively). These associations remained statistically significant after mutual adjustment, except the association between BMI and PIIINP.

CONCLUSIONS: Isolated hyperglycemia is associated with higher serum concentrations of TGF-β, while a broader phenotype of insulin resistance is associated with higher serum PIIINP. Whether simultaneous pharmacologic targeting of these two metabolic phenotypes can synergistically reduce the risk of cardiac and other manifestations of fibrosis remains to be determined.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, Blood Glucose, Cardiovascular System, Cross-Sectional Studies, Diabetes Complications, Diabetes Mellitus, Fatty Acids, Nonesterified, Female, Fibrosis, Health, Humans, Insulin, Insulin Resistance, Male, Metabolic Diseases, Peptide Fragments, Procollagen, Transforming Growth Factor beta}, issn = {1532-8600}, doi = {10.1016/j.metabol.2015.07.013}, author = {Agarwal, Isha and Glazer, Nicole L and Barasch, Eddy and Djouss{\'e}, Luc and Gottdiener, John S and Ix, Joachim H and Kizer, Jorge R and Rimm, Eric B and Siscovick, David S and King, George L and Mukamal, Ken J} } @article {6665, title = {Fibrosis-related biomarkers and large and small vessel disease: the Cardiovascular Health Study.}, journal = {Atherosclerosis}, volume = {239}, year = {2015}, month = {2015 Apr}, pages = {539-46}, abstract = {

OBJECTIVE: Fibrosis has been implicated in a number of pathological, organ-based conditions of the liver, kidney, heart, and lungs. The objective of this study was to determine whether biomarkers of fibrosis are associated with vascular disease in the large and/or small vessels.

METHODS: We evaluated the associations of two circulating biomarkers of fibrosis, transforming growth factor-β (TGF-β) and procollagen type III N-terminal propeptide (PIIINP), with incident peripheral artery disease (PAD) and subclinical macrovascular (carotid intima-media thickness, flow-mediated vasodilation, ankle-brachial index, retinal vein diameter), and microvascular (retinal artery diameter and retinopathy) disease among older adults in the Cardiovascular Health Study. We measured TGF-β and PIIINP from samples collected in 1996 and ascertained clinical PAD through 2011. Measurements of large and small vessels were collected between 1996 and 1998.

RESULTS: After adjustment for sociodemographic, clinical, and biochemical risk factors, TGF-β was associated with incident PAD (hazard ratio [HR]~=~1.36 per doubling of TGF-β, 95\% confidence interval [CI]~=~1.04, 1.78) and retinal venular diameter (1.63~μm per doubling of TGF-β, CI~=~0.23, 3.02). PIIINP was not associated with incident PAD, but was associated with carotid intima-media thickness (0.102~mm per doubling of PIIINP, CI~=~0.029, 0.174) and impaired brachial artery reactivity (-0.20\% change per doubling of PIIINP, CI~=~-0.39,~-0.02). Neither TGF-β nor PIIINP were associated with retinal arteriolar diameter or retinopathy.

CONCLUSIONS: Serum concentrations of fibrosis-related biomarkers were associated with several measures of large vessel disease, including incident PAD, but not with small vessel disease. Fibrosis may contribute to large vessel atherosclerosis in older adults.

}, keywords = {Aged, Ankle Brachial Index, Biomarkers, Brachial Artery, Carotid Artery Diseases, Carotid Intima-Media Thickness, Cross-Sectional Studies, Female, Fibrosis, Humans, Incidence, Male, Peptide Fragments, Peripheral Arterial Disease, Predictive Value of Tests, Procollagen, Prognosis, Prospective Studies, Retinal Diseases, Risk Factors, Transforming Growth Factor beta, United States, Vasodilation}, issn = {1879-1484}, doi = {10.1016/j.atherosclerosis.2015.02.020}, author = {Agarwal, Isha and Arnold, Alice and Glazer, Nicole L and Barasch, Eddy and Djouss{\'e}, Luc and Fitzpatrick, Annette L and Gottdiener, John S and Ix, Joachim H and Jensen, Richard A and Kizer, Jorge R and Rimm, Eric B and Siscovick, David S and Tracy, Russell P and Wong, Tien Y and Mukamal, Kenneth J} } @article {7120, title = {Association of inflammatory, lipid and mineral markers with cardiac calcification in older adults.}, journal = {Heart}, year = {2016}, month = {2016 Jul 13}, abstract = {

OBJECTIVE: Calcification of the aortic valve and adjacent structures involves inflammatory, lipid and mineral metabolism pathways. We hypothesised that circulating biomarkers reflecting these pathways are associated with cardiac calcification in older adults.

METHODS: We investigated the associations of various biomarkers with valvular and annular calcification in the Cardiovascular Health Study. Of the 5888 participants, up to 3585 were eligible after exclusions for missing biomarker, covariate or echocardiographic data. We evaluated analytes reflecting lipid (lipoprotein (Lp) (a), Lp-associated phospholipase A2 (LpPLA2) mass and activity), inflammatory (interleukin-6, soluble (s) CD14) and mineral metabolism (fetuin-A, fibroblast growth factor (FGF)-23) pathways that were measured within 5 years of echocardiography. The relationships of plasma biomarkers with aortic valve calcification (AVC), aortic annular calcification (AAC) and mitral annular calcification (MAC) were assessed with relative risk (RR) regression.

RESULTS: Calcification was prevalent: AVC 59\%, AAC 45\% and MAC 41\%. After adjustment, Lp(a), LpPLA2 mass and activity and sCD14 were positively associated with AVC. RRs for AVC per SD (95\% CI) were as follows: Lp(a), 1.051 (1.022 to 1.081); LpPLA2 mass, 1.036 (1.006 to 1.066) and LpPLA2 activity, 1.037 (1.004 to 1.071); sCD14, 1.039 (1.005 to 1.073). FGF-23 was positively associated with MAC, 1.040 (1.004 to 1.078) and fetuin-A was negatively associated, 0.949 (0.911 to 0.989). No biomarkers were significantly associated with AAC.

CONCLUSION: This study shows novel associations of circulating FGF-23 and fetuin-A with MAC, and LpPLA2 and sCD14 with AVC, confirming that previously reported for Lp(a). Further investigation of Lp and inflammatory pathways may provide added insight into the aetiology of AVC, while study of phosphate regulation may illuminate the pathogenesis of MAC.

}, issn = {1468-201X}, doi = {10.1136/heartjnl-2016-309404}, author = {Bortnick, Anna E and Bartz, Traci M and Ix, Joachim H and Chonchol, Michel and Reiner, Alexander and Cushman, Mary and Owens, David and Barasch, Eddy and Siscovick, David S and Gottdiener, John S and Kizer, Jorge R} } @article {7350, title = {Relation of the Myocardial Contraction Fraction, as Calculated from M-Mode Echocardiography, With Incident Heart Failure, Atherosclerotic Cardiovascular Disease and Mortality (Results from the Cardiovascular Health Study).}, journal = {Am J Cardiol}, volume = {119}, year = {2017}, month = {2017 Mar 15}, pages = {923-928}, abstract = {

We evaluated the association between 2-dimensional (2D) echocardiography (echo)-determined myocardial contraction fraction (MCF) and adverse cardiovascular outcomes including incident heart failure (HF), atherosclerotic cardiovascular disease (ASCVD), and mortality. The MCF, the ratio of left ventricular (LV) stroke volume (SV) to myocardial volume (MV), is a volumetric measure of myocardial shortening that can distinguish pathologic from physiological hypertrophy. Using 2D echo-guided M-mode data from the~Cardiovascular Health Study, we calculated MCF in subjects with LV ejection fraction (EF) >=55\% and used Cox models to evaluate its association with incident HF, ASCVD, and all-cause mortality after adjusting for clinical and echo parameters. We assessed whether log2(SV) and log2(MV) were consistent with the expected 1:-1 ratio used in the definition of MCF. Among 2,147 participants (age 72 {\textpm} 5 years), average MCF was 59 {\textpm} 13\%. After controlling for clinical and echo variables, each 10\% absolute increment in MCF was associated with lower risk of HF (hazard ratio [HR] 0.88; 95\% confidence interval [CI] 0.82, 0.94), ASCVD (HR 0.90; 95\% CI 0.85, 0.95), and death (HR 0.93; 95\% CI 0.89, 0.97). Moreover, the MCF was still significantly associated with ASCVD and mortality, but not HF, after adjustment for percent-predicted LV mass. Significant departure from the 1:-1 ratio was not observed for ASCVD or death, but did occur for HF, driven by a stronger association for MV than SV. In conclusion, among older adults without CVD or low LV ejection fraction, 2D echo-guided M-mode-derived MCF was independently associated with lower risk of adverse cardiovascular outcomes, but this ratiometric index may not capture the full relation that is apparent when its components are modeled separately in the~case of HF.

}, issn = {1879-1913}, doi = {10.1016/j.amjcard.2016.11.048}, author = {Maurer, Mathew S and Koh, William J H and Bartz, Traci M and Vullaganti, Sirish and Barasch, Eddy and Gardin, Julius M and Gottdiener, John S and Psaty, Bruce M and Kizer, Jorge R} } @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 {9154, title = {The association of aortic valve sclerosis, aortic annulus increased reflectivity, and mitral annular calcification with subsequent aortic stenosis in older individuals. Findings from the Cardiovascular Health Study.}, journal = {J Am Soc Echocardiogr}, year = {2022}, month = {2022 Sep 09}, abstract = {

BACKGROUND: While aortic valve sclerosis (AVS) is well-described as preceding aortic stenosis (AS), the association of AS with antecedent mitral aortic annular calcification and aortic annulus increased reflectivity (MAC and AAIR, respectively) has not been characterized. In a population-based prospective study, we evaluated whether MAC, AAIR, and AVS are associated with the risk of incident AS.

METHODS: Among participants of the Cardiovascular Health Study (CHS) free of AS at the 1994-1995 visit, the presence of MAC, AAIR, AVS, and the combination of all three were evaluated in 3041 participants. Cox proportional hazards regression was used to assess the association between the presence of calcification and the incidence of moderate/severe AS in three nested models adjusting for factors associated with atherosclerosis and inflammation both relevant to the pathogenesis of AS.

RESULTS: Over a median follow-up of 11.5 years (IQR 6.7 to 17.0), 110 cases of incident moderate/severe AS were ascertained. Strong positive associations with incident moderate/severe AS were found for all calcification sites after adjustment for the main model covariates: AAIR (HR=2.90, 95\% CI=[1.95, 4.32], p<0.0005), AVS (HR=2.20, 95\% CI=[1.44, 3.37], p<0.0005), MAC (HR=1.67, 95\% CI=[1.14, 2.45], p=0.008), and the combination of MAC, AAIR, and AVS (HR=2.50, 95\% CI=[1.65, 3.78], p<0.0005). In a secondary analysis, the risk of AS increased with the number of sites at which calcification was present.

CONCLUSIONS: In a large cohort of community-dwelling elderly individuals, there were strong associations between each of AAIR, AVS, MAC, and the combination of MAC, AAIR, and AVS with incident moderate/severe AS. The novel finding that AAIR had a particularly strong association with incident AS, even after adjusting for other calcification sites, suggests its value in identifying individuals at risk for AS, and potential inclusion in the routine assessment by transthoracic echocardiography.

}, issn = {1097-6795}, doi = {10.1016/j.echo.2022.08.013}, author = {Barasch, Eddy and Gottdiener, John S and Tressel, William and Bartz, Traci M and B{\r u}zkov{\'a}, Petra and Massera, Daniele and DeFilippi, Christopher and Biggs, Mary L and Psaty, Bruce M and Kizer, Jorge R and Owens, David} } @article {8974, title = {Relation of Cigarette Smoking and Heart Failure in Adults >=65~Years of Age (From the Cardiovascular Health Study).}, journal = {Am J Cardiol}, year = {2022}, month = {2022 Jan 16}, abstract = {

Cigarette smoking is associated with adverse cardiac outcomes, including incident heart failure (HF). However, key components of potential pathways from smoking to HF have not been evaluated in older adults. In a community-based study, we studied cross-sectional associations of smoking with blood and imaging biomarkers reflecting mechanisms of cardiac disease. Serial nested, multivariable Cox models were used to determine associations of smoking with HF, and to assess the influence of biochemical and functional (cardiac strain) phenotypes on these associations. Compared with never smokers, smokers had higher levels of inflammation (C-reactive protein and interleukin-6), cardiomyocyte injury (cardiac troponin T [hscTnT]), myocardial "stress"/fibrosis (soluble suppression of tumorigenicity 2 [sST2], galectin 3), and worse left ventricle systolic and diastolic function. In models adjusting for age, gender, and race (DEMO) and for clinical factors potentially in the causal pathway (CLIN), smoking exposures were associated with C-reactive protein and interleukin-6, sST2, hscTnT, and with N-terminal pro-brain natriuretic protein (in Whites). In DEMO adjusted models, the cumulative burden of smoking was associated with worse left ventricle systolic strain. Current smoking and former smoking were associated with HF in DEMO models (hazard ratio 1.41, 95\% confidence interval 1.22 to 1.64 and hazard ratio 1.14, 95\% confidence interval 1.03 to 1.25, respectively), and with current smoking after CLIN adjustment. Adjustment for time-varying myocardial infarction, inflammation, cardiac strain, hscTnT, sST2, and galectin 3 did not materially alter the associations. Smoking was associated with HF with preserved and decreased ejection fraction. In conclusion, in older adults, smoking is associated with multiple blood and imaging biomarker measures of pathophysiology previously linked to HF, and to incident HF even after adjustment for clinical intermediates.

}, issn = {1879-1913}, doi = {10.1016/j.amjcard.2021.12.021}, author = {Gottdiener, John S and B{\r u}zkov{\'a}, Petra and Kahn, Peter A and DeFilippi, Christopher and Shah, Sanjiv and Barasch, Eddy and Kizer, Jorge R and Psaty, Bruce and Gardin, Julius M} } @article {9574, title = {Association of thyroid dysfunction in individuals >= 65 years of age with subclinical cardiac abnormalities.}, journal = {J Clin Endocrinol Metab}, year = {2024}, month = {2024 Jan 06}, abstract = {

CONTEXT: The relationship between thyroid dysfunction and measures of myocardial disease in older individuals remains to be defined.

OBJECTIVE: To evaluate the impact of thyroid dysfunction on structure and function of the left-heart chambers and blood markers of cardiac disease.

DESIGN: Cross-sectional analysis.

SETTING: The Cardiovascular Health Study, a community-based cohort of older individuals recruited from four urban areas in the United States.

PATIENTS: Of 3163 participants studied, 2477 were euthyroid, 465 had subclinical hypothyroidism (SCH), 47 overt hypothyroidism (OH), 45 endogenous (endo) subclinical hyperthyroidism (endo-SCT), and 129 had exogenous (exo) SCT due to thyroid hormone supplementation.

INTERVENTIONS: Clinical evaluation, blood sampling and biomarker measurement, 2-dimensional and speckle-tracking echocardiography.

MAIN OUTCOME MEASURE(S): Left heart myocardial deformation, circulating biomarkers of diastolic overload (NT-proBNP), fibrosis (sST2, gal-3), and cardiomyocyte injury (hs-cTnT).

RESULTS: SCH was associated with higher NT-proBNP (beta = 0.17, p = 0.004), whereas OH was associated with higher hs-cTnT (beta = 0.29, p = 0.005). There were also suggestive associations of SCH with higher sST2, as well as endo-SCT with higher gal-3 and lower (worse) left atrial reservoir strain. Left ventricular longitudinal strain and end-diastolic strain rate did not differ significantly from euthyroid participants in SCH, OH, or exo-SCT.

CONCLUSIONS: In this free-living elderly cohort, subclinical and overt hypothyroidism were associated with abnormalities of blood biomarkers consistent with diastolic overload and myocardial necrosis respectively, whereas subclinical hyperthyroidism tended to be associated with myocardial fibrosis and decreased left atrial strain. Our findings could represent stage B heart failure and illuminate distinct aspects of the pathobiology of heart disease related to thyroid gland dysfunction with potential clinical implications.

}, issn = {1945-7197}, doi = {10.1210/clinem/dgae001}, author = {Barasch, Eddy and Gottdiener, John and B{\r u}zkov{\'a}, Petra and Cappola, Anne and Shah, Sanjiv and DeFilippi, Christopher and Gardin, Julius and Kizer, Jorge R} }