@article {795, title = {Moderate renal impairment and risk of dementia among older adults: the Cardiovascular Health Cognition Study.}, journal = {J Am Soc Nephrol}, volume = {15}, year = {2004}, month = {2004 Jul}, pages = {1904-11}, abstract = {

Renal impairment is associated with an increased risk of carotid atherosclerosis and stroke, determinants of cognitive dysfunction and dementia. The purpose of this study was to determine whether moderate renal impairment is associated with incident dementia among community-dwelling older adults. Participants in the Cardiovascular Health Cognition Study without prevalent dementia (n = 3349) were included in the analysis. Incident dementia was confirmed through neurologic testing. Renal function at baseline was estimated by the inverse of serum creatinine (1/SCr); moderate renal impairment was defined as SCr > or = 1.3 mg/dl for women and > or = 1.5 mg/dl for men. Cox regression models were used to estimate the association of renal impairment with incident dementia. Because SCr is also a function of muscle mass, the authors determined whether the relationship between SCr and dementia was particularly strong among individuals without severe co-morbidity at baseline, as reflected by self-reported general health status. There were 477 incident dementia cases over a median 6 yr follow-up. After adjustment for potential confounders, moderate renal insufficiency was associated with a 37\% increased risk of dementia (95\% CI = 1.06 to 1.78). Similarly, a 0.5-unit decrement in 1/SCr (equivalent to an increase in SCr from 1.0 to 2.0 mg/dl) was associated with a 26\% increased risk (95\% CI = 1.02 to 1.60). These associations were present only among the 84\% of older adults who reported good-excellent health. Among those in good-excellent health, higher SCr was associated with vascular-type dementia but not Alzheimer-type dementia. Moderate renal impairment, reflected by a higher SCr, is associated with an excess risk of incident dementia among individuals in good-excellent health. Strategies to prevent or delay the onset of dementia in patients with moderate renal impairment are needed.

}, keywords = {Aged, Alzheimer Disease, Cardiovascular Diseases, Creatinine, Dementia, Dementia, Vascular, Female, Humans, Kidney, Kidney Diseases, Male, Muscles, Proportional Hazards Models}, issn = {1046-6673}, doi = {10.1097/01.asn.0000131529.60019.fa}, author = {Seliger, Stephen L and Siscovick, David S and Stehman-Breen, Catherine O and Gillen, Daniel L and Fitzpatrick, Annette and Bleyer, Anthony and Kuller, Lew H} } @article {873, title = {Cystatin C and incident peripheral arterial disease events in the elderly: results from the Cardiovascular Health Study.}, journal = {Arch Intern Med}, volume = {165}, year = {2005}, month = {2005 Dec 12-26}, pages = {2666-70}, abstract = {

BACKGROUND: The association of cystatin C, a novel marker of renal function, with risk for developing complications related to peripheral arterial disease (PAD) has not been examined.

METHODS: We evaluated the hypothesis that a high cystatin C concentration is independently associated with future PAD events among 4025 participants in the Cardiovascular Health Study who underwent serum cystatin C measurement at the 1992-1993 visit and who did not have PAD at baseline. The association of cystatin C quintiles with time to first lower-extremity PAD procedure (bypass surgery, angioplasty, or amputation) was evaluated using multivariable proportional hazards models. Secondary analyses were conducted using quintiles of serum creatinine level and estimated glomerular filtration rate (eGFR).

RESULTS: The annualized risk of undergoing a procedure for PAD was 0.43\% per year among participants in the highest cystatin C quintile (>1.27 mg/L) compared with 0.21\% per year or less in all other quintiles. After multivariable adjustment for known risk factors for PAD, elevated cystatin C levels remained associated with the outcome (hazard ratio, 2.5 for highest vs lowest quintile of cystatin C, 95\% confidence interval, 1.2-5.1). The highest quintiles of serum creatinine level and eGFR were not associated with future PAD events in either unadjusted or adjusted analyses.

CONCLUSION: Elevated concentrations of cystatin C were independently predictive of incident PAD events among community-dwelling elderly patients.

}, keywords = {Aged, Cohort Studies, Cystatin C, Cystatins, Female, Health Surveys, Humans, Longitudinal Studies, Male, Peripheral Vascular Diseases, Predictive Value of Tests, Risk Factors, ROC Curve, United States}, issn = {0003-9926}, doi = {10.1001/archinte.165.22.2666}, author = {O{\textquoteright}Hare, Ann M and Newman, Anne B and Katz, Ronit and Fried, Linda F and Stehman-Breen, Catherine O and Seliger, Stephen L and Siscovick, David S and Shlipak, Michael G} } @article {862, title = {Cystatin C and subclinical brain infarction.}, journal = {J Am Soc Nephrol}, volume = {16}, year = {2005}, month = {2005 Dec}, pages = {3721-7}, abstract = {

Subclinical brain infarcts (SBI) are common in the elderly and are associated with covert neurologic and cognitive impairment. Although renal impairment is associated with accelerated cerebrovascular disease and an increased risk for clinically apparent brain infarct, few studies have examined the relationship between renal function and SBI, and these may have been limited by the inaccuracy of creatinine as a renal function marker. A cross-sectional study was performed among older adults in the Cardiovascular Health Study to examine associations between SBI and two serum markers of renal function: Serum creatinine (SCr) and cystatin C (CysC). Patients had cranial magnetic resonance imaging and renal markers measured in 1992 to 1993. Logistic regression was used to estimate the associations between renal function (estimated by 1/SCr and 1/CysC) and SBI, controlling for potential confounding factors. SBI were present in 789 (28.7\%) of 2784 participants. A linear association with SBI was observed for 1/CysC (per 1-SD decrement; odds ratio [OR] 1.20; 95\% confidence interval [CI] 1.09 to 1.32; P < 0.001) but not for 1/SCr (OR 1.08; 95\% CI 0.98 to 1.19; P = 0.14), for which a quadratic U-shaped association was suggested (P = 0.004). In a model with both markers, 1/CysC was linearly associated with SBI (OR 1.26; P < 0.001), whereas 1/SCr was not (OR 1.06; P = 0.3). The prevalence of SBI was directly associated with quintile of CysC, whereas the association between SCr and SBI was U-shaped, with greater prevalence at high and low levels. Compared with creatinine, CysC, a novel marker of renal function, has a stronger and more direct association with SBI in the elderly.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Biomarkers, Brain Infarction, Confidence Intervals, Creatinine, Cross-Sectional Studies, Cystatin C, Cystatins, Disease Progression, Female, Geriatric Assessment, Humans, Incidence, Ischemic Attack, Transient, Magnetic Resonance Imaging, Male, Odds Ratio, Predictive Value of Tests, Prognosis, Risk Assessment, Sensitivity and Specificity, Severity of Illness Index, Sex Factors, Survival Analysis}, issn = {1046-6673}, doi = {10.1681/ASN.2005010006}, author = {Seliger, Stephen L and Longstreth, W T and Katz, Ronit and Manolio, Teri and Fried, Linda F and Shlipak, Michael and Stehman-Breen, Catherine O and Newman, Anne and Sarnak, Mark and Gillen, Daniel L and Bleyer, Anthony and Siscovick, David S} } @article {840, title = {Cystatin C and the risk of death and cardiovascular events among elderly persons.}, journal = {N Engl J Med}, volume = {352}, year = {2005}, month = {2005 May 19}, pages = {2049-60}, abstract = {

BACKGROUND: Cystatin C is a serum measure of renal function that appears to be independent of age, sex, and lean muscle mass. We compared creatinine and cystatin C levels as predictors of mortality from cardiovascular causes and from all causes in the Cardiovascular Health Study, a cohort study of elderly persons living in the community.

METHODS: Creatinine and cystatin C were measured in serum samples collected from 4637 participants at the study visit in 1992 or 1993; follow-up continued until June 30, 2001. For each measure, the study population was divided into quintiles, with the fifth quintile subdivided into thirds (designated 5a, 5b, and 5c).

RESULTS: Higher cystatin C levels were directly associated, in a dose-response manner, with a higher risk of death from all causes. As compared with the first quintile, the hazard ratios (and 95 percent confidence intervals) for death were as follows: second quintile, 1.08 (0.86 to 1.35); third quintile, 1.23 (1.00 to 1.53); fourth quintile, 1.34 (1.09 to 1.66); quintile 5a, 1.77 (1.34 to 2.26); 5b, 2.18 (1.72 to 2.78); and 5c, 2.58 (2.03 to 3.27). In contrast, the association of creatinine categories with mortality from all causes appeared to be J-shaped. As compared with the two lowest quintiles combined (cystatin C level, < or =0.99 mg per liter), the highest quintile of cystatin C (> or =1.29 mg per liter) was associated with a significantly elevated risk of death from cardiovascular causes (hazard ratio, 2.27 [1.73 to 2.97]), myocardial infarction (hazard ratio, 1.48 [1.08 to 2.02]), and stroke (hazard ratio, 1.47 [ 1.09 to 1.96]) after multivariate adjustment. The fifth quintile of creatinine, as compared with the first quintile, was not independently associated with any of these three outcomes.

CONCLUSIONS: Cystatin C, a serum measure of renal function, is a stronger predictor of the risk of death and cardiovascular events in elderly persons than is creatinine.

}, keywords = {Aged, Biomarkers, Cardiovascular Diseases, Cerebrospinal Fluid Proteins, Creatinine, Cystatin C, Cystatins, Female, Follow-Up Studies, Glomerular Filtration Rate, Humans, Kidney, Kidney Diseases, Male, Mortality, Multivariate Analysis, Prognosis, Risk}, issn = {1533-4406}, doi = {10.1056/NEJMoa043161}, author = {Shlipak, Michael G and Sarnak, Mark J and Katz, Ronit and Fried, Linda F and Seliger, Stephen L and Newman, Anne B and Siscovick, David S and Stehman-Breen, Catherine} } @article {912, title = {Cystatin C and prognosis for cardiovascular and kidney outcomes in elderly persons without chronic kidney disease.}, journal = {Ann Intern Med}, volume = {145}, year = {2006}, month = {2006 Aug 15}, pages = {237-46}, abstract = {

BACKGROUND: Cystatin C is an alternative measure of kidney function that may have prognostic importance among elderly persons who do not meet standard criteria for chronic kidney disease (estimated glomerular filtration rate [GFR] > or =60 mL/min per 1.73 m2).

OBJECTIVE: To evaluate cystatin C as a prognostic biomarker for death, cardiovascular disease, and incident chronic kidney disease among elderly persons without chronic kidney disease.

DESIGN: Cohort study.

SETTING: The Cardiovascular Health Study, a population-based cohort recruited from 4 communities in the United States.

PARTICIPANTS: 4663 elderly persons.

MEASUREMENTS: Measures of kidney function were creatinine-based estimated GFR by using the Modification of Diet in Renal Disease equation and cystatin C concentration. Outcomes were death, cardiovascular death, noncardiovascular death, heart failure, stroke, myocardial infarction, and incident chronic kidney disease during follow-up (median, 9.3 years).

RESULTS: At baseline, 78\% of participants did not have chronic kidney disease (estimated GFR > or =60 mL/min per 1.73 m2) and mean cystatin C concentration, creatinine concentration, and estimated GFR were 1.0 mg/L, 79.6 micromol/L (0.9 mg/dL), and 83 mL/min per 1.73 m2, respectively. Cystatin C concentrations (per SD, 0.18 mg/L) had strong associations with death (hazard ratio, 1.33 [95\% CI, 1.25 to 1.40]), cardiovascular death (hazard ratio, 1.42 [CI, 1.30 to 1.54]), noncardiovascular death (hazard ratio, 1.26 [CI, 1.17 to 1.36]), incident heart failure (hazard ratio, 1.28 [CI, 1.17 to 1.40]), stroke (hazard ratio, 1.22 [CI, 1.08 to 1.38]), and myocardial infarction (hazard ratio, 1.20 [CI, 1.06 to 1.36]) among these participants. Serum creatinine concentrations had much weaker associations with each outcome and only predicted cardiovascular death. Participants without chronic kidney disease who had elevated cystatin C concentrations (> or =1.0 mg/L) had a 4-fold risk for progressing to chronic kidney disease after 4 years of follow-up compared with those with cystatin C concentrations less than 1.0 mg/L.

LIMITATIONS: Because this study did not directly measure GFR or albuminuria, the extent to which cystatin C may be influenced by nonrenal factors was not determined and participants with albuminuria might have been misclassified as having no kidney disease.

CONCLUSIONS: Among elderly persons without chronic kidney disease, cystatin C is a prognostic biomarker of risk for death, cardiovascular disease, and chronic kidney disease. In this setting, cystatin C seems to identify a "preclinical" state of kidney dysfunction that is not detected with serum creatinine or estimated GFR.

}, keywords = {Aged, Biomarkers, Cardiovascular Diseases, Creatinine, Cystatin C, Cystatins, Glomerular Filtration Rate, Humans, Kidney, Longitudinal Studies, Prognosis, Proportional Hazards Models, Renal Insufficiency, Chronic, Risk Factors}, issn = {1539-3704}, doi = {10.7326/0003-4819-145-4-200608150-00003}, author = {Shlipak, Michael G and Katz, Ronit and Sarnak, Mark J and Fried, Linda F and Newman, Anne B and Stehman-Breen, Catherine and Seliger, Stephen L and Kestenbaum, Brian and Psaty, Bruce and Tracy, Russell P and Siscovick, David S} } @article {1012, title = {Cystatin C concentration as a predictor of systolic and diastolic heart failure.}, journal = {J Card Fail}, volume = {14}, year = {2008}, month = {2008 Feb}, pages = {19-26}, abstract = {

BACKGROUND: Risk factors for heart failure (HF) may differ according to ejection fraction (EF). Higher cystatin C, a marker of kidney dysfunction, is associated with incident HF, but previous studies did not determine EF at diagnosis. We hypothesized that kidney dysfunction would predict diastolic HF (DHF) better than systolic HF (SHF) in the Cardiovascular Health Study.

METHODS AND RESULTS: Cystatin C was measured in 4453 participants without HF at baseline. Incident HF was categorized as DHF (EF > or = 50\%) or SHF (EF < 50\%). We compared the association of cystatin C with the risk for DHF and SHF, after adjustment for age, sex, race, medications, and HF risk factors. During 8 years of follow-up, 167 participants developed DHF and 206 participants developed SHF. After adjustment, sequentially higher quartiles of cystatin C were associated with risk for SHF (competing risks hazard ratios 1.0 [reference], 1.99 [95\% confidence interval 1.14-3.48], 2.32 [1.32-4.07], 3.17 [1.82-5.50], P for trend < .001). The risk for DHF was apparent only at the highest cystatin C quartile (hazard ratios 1.0 [reference], 1.09 [0.62-1.89], 1.08 [0.61-1.93], and 1.83 [1.07-3.11]).

CONCLUSIONS: Cystatin C levels are linearly associated with the incidence of systolic HF, whereas only the highest concentrations of cystatin C predict diastolic HF.

}, keywords = {Aged, Aged, 80 and over, Biomarkers, Cohort Studies, Confidence Intervals, Cystatin C, Cystatins, Echocardiography, Female, Heart Failure, Diastolic, Heart Failure, Systolic, Humans, Longitudinal Studies, Male, Predictive Value of Tests, Probability, Proportional Hazards Models, Risk Assessment, Sensitivity and Specificity, Stroke Volume, Survival Analysis}, issn = {1532-8414}, doi = {10.1016/j.cardfail.2007.09.002}, author = {Moran, Andrew and Katz, Ronit and Smith, Nicolas L and Fried, Linda F and Sarnak, Mark J and Seliger, Stephen L and Psaty, Bruce and Siscovick, David S and Gottdiener, John S and Shlipak, Michael G} } @article {1245, title = {Association of serial measures of cardiac troponin T using a sensitive assay with incident heart failure and cardiovascular mortality in older adults.}, journal = {JAMA}, volume = {304}, year = {2010}, month = {2010 Dec 08}, pages = {2494-502}, abstract = {

CONTEXT: Older adults comprise the majority of new-onset heart failure (HF) diagnoses, but traditional risk-factor prediction models have limited accuracy in this population to identify those at highest risk for hospitalization or death.

OBJECTIVES: To determine if cardiac troponin T (cTnT) measured by a highly sensitive assay would be detectable in the majority of community-dwelling older adults, and if serial measures were associated with risk of HF hospitalization and cardiovascular death.

DESIGN, SETTING, AND PARTICIPANTS: A longitudinal nationwide cohort study (Cardiovascular Health Study) of 4221 community-dwelling adults aged 65 years or older without prior HF who had cTnT measured using a highly sensitive assay at baseline (1989-1990) and repeated after 2 to 3 years (n = 2918).

MAIN OUTCOME MEASURES: New-onset HF and cardiovascular death were examined through June 2008 with respect to cTnT concentrations, accounting for clinical risk predictors.

RESULTS: Cardiac troponin T was detectable (>=3.00 pg/mL) in 2794 participants (66.2\%). During a median follow-up of 11.8 years, 1279 participants experienced new-onset HF and 1103 cardiovascular deaths occurred, with a greater risk of both end points associated with higher cTnT concentrations. Among those participants with the highest cTnT concentrations (>12.94 pg/mL), there was an incidence rate per 100 person-years of 6.4 (95\% confidence interval [CI], 5.8-7.2; adjusted hazard ratio [aHR], 2.48; 95\% CI, 2.04-3.00) for HF and an incidence rate of 4.8 (95\% CI, 4.3-5.4; aHR, 2.91; 95\% CI, 2.37-3.58) for cardiovascular death compared with participants with undetectable cTnT levels (incidence rate, 1.6; 95\% CI, 1.4-1.8 and 1.1; 95\% CI, 0.9-1.2 for HF and cardiovascular death, respectively). Among individuals with initially detectable cTnT, a subsequent increase of more than 50\% (n = 393, 22\%) was associated with a greater risk for HF (aHR, 1.61; 95\% CI, 1.32-1.97) and cardiovascular death (aHR, 1.65; 95\% CI, 1.35-2.03) and a decrease of more than 50\% (n = 247, 14\%) was associated with a lower risk for HF (aHR, 0.73; 95\% CI, 0.54-0.97) and cardiovascular death (aHR, 0.71; 95\% CI, 0.52-0.97) compared with participants with 50\% or less change. Addition of baseline cTnT measurements to clinical risk factors was associated with only modest improvement in discrimination, with change in C statistic of 0.015 for HF and 0.013 for cardiovascular death.

CONCLUSION: In this cohort of older adults without known HF, baseline cTnT levels and changes in cTnT levels measured with a highly sensitive assay were significantly associated with incident HF and cardiovascular death.

}, keywords = {Aged, Biomarkers, Cardiovascular Diseases, Cohort Studies, Female, Heart Failure, Humans, Incidence, Male, Predictive Value of Tests, Risk, Sensitivity and Specificity, Troponin T, United States}, issn = {1538-3598}, doi = {10.1001/jama.2010.1708}, author = {deFilippi, Christopher R and de Lemos, James A and Christenson, Robert H and Gottdiener, John S and Kop, Willem J and Zhan, Min and Seliger, Stephen L} } @article {1164, title = {Dynamic cardiovascular risk assessment in elderly people. The role of repeated N-terminal pro-B-type natriuretic peptide testing.}, journal = {J Am Coll Cardiol}, volume = {55}, year = {2010}, month = {2010 Feb 02}, pages = {441-50}, abstract = {

OBJECTIVES: This study sought to determine whether serial measurement of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in community-dwelling elderly people would provide additional prognostic information to that from traditional risk factors.

BACKGROUND: Accurate cardiovascular risk stratification is challenging in elderly people.

METHODS: NT-proBNP was measured at baseline and 2 to 3 years later in 2,975 community-dwelling older adults free of heart failure in the longitudinal CHS (Cardiovascular Health Study). This investigation examined the risk of new-onset heart failure (HF) and death from cardiovascular causes associated with baseline NT-proBNP and changes in NT-proBNP levels, adjusting for potential confounders.

RESULTS: NT-proBNP levels in the highest quintile (>267.7 pg/ml) were independently associated with greater risks of HF (hazard ratio [HR]: 3.05; 95\% confidence interval [CI]: 2.46 to 3.78) and cardiovascular death (HR: 3.02; 95\% CI: 2.36 to 3.86) compared with the lowest quintile (<47.5 pg/ml). The inflection point for elevated risk occurred at NT-proBNP 190 pg/ml. Among participants with initially low NT-proBNP (<190 pg/ml), those who developed a >25\% increase on follow-up to >190 pg/ml (21\%) were at greater adjusted risk of HF (HR: 2.13; 95\% CI: 1.68 to 2.71) and cardiovascular death (HR: 1.91; 95\% CI: 1.43 to 2.53) compared with those with sustained low levels. Among participants with initially high NT-proBNP, those who developed a >25\% increase (40\%) were at higher risk of HF (HR: 2.06; 95\% CI: 1.56 to 2.72) and cardiovascular death (HR: 1.88; 95\% CI: 1.37 to 2.57), whereas those who developed a >25\% decrease to

CONCLUSIONS: NT-proBNP levels independently predict heart failure and cardiovascular death in older adults. NT-proBNP levels frequently change over time, and these fluctuations reflect dynamic changes in cardiovascular risk.

}, keywords = {Aged, Biomarkers, Female, Heart Failure, Humans, Male, Natriuretic Peptide, Brain, Peptide Fragments, Prognosis, Prospective Studies, Risk Assessment, Risk Factors, United States}, issn = {1558-3597}, doi = {10.1016/j.jacc.2009.07.069}, author = {deFilippi, Christopher R and Christenson, Robert H and Gottdiener, John S and Kop, Willem J and Seliger, Stephen L} } @article {1330, title = {Left ventricular ejection fraction assessment in older adults: an adjunct to natriuretic peptide testing to identify risk of new-onset heart failure and cardiovascular death?}, journal = {J Am Coll Cardiol}, volume = {58}, year = {2011}, month = {2011 Sep 27}, pages = {1497-506}, abstract = {

OBJECTIVES: The goal of this paper was to determine whether assessment of left ventricular ejection fraction (LVEF) enhances prediction of new-onset heart failure (HF) and cardiovascular mortality over and above N-terminal pro-B-type natriuretic peptide (NT-proBNP) level in older adults.

BACKGROUND: Elevated NT-proBNP levels are common in older adults and are associated with increased risk of HF.

METHODS: NT-proBNP and LVEF were measured in 4,137 older adults free of HF. Repeat measures of NT-proBNP were performed 2 to 3 years later and echocardiography was repeated 5 years later (n = 2,375), with a median follow-up of 10.7 years. The addition of an abnormal (<55\%) LVEF (n = 317 [7.7\%]) to initially elevated or rising NT-proBNP levels was evaluated to determine risk of HF or cardiovascular mortality. Changes in NT-proBNP levels were also assessed for estimating the risk of conversion from a normal to abnormal LVEF.

RESULTS: For participants with a low baseline NT-proBNP level (<190 pg/ml; n = 2,918), addition of an abnormal LVEF did not improve the estimation of risk of HF and identified a moderate increase in adjusted risk for cardiovascular mortality (hazard ratio: 1.69 [95\% confidence interval: 1.22 to 2.31]). Among those whose NT-proBNP subsequently increased >=25\% to >=190 pg/ml, an abnormal LVEF was likewise associated with an increased risk of cardiovascular mortality but not HF. Participants with an initially high NT-proBNP level (>=190 pg/ml) were at greater risk overall for both outcomes, and those with an abnormal LVEF were at the highest risk. However, an abnormal LVEF did not improve model classification or risk stratification for either endpoint when added to demographic factors and change in NT-proBNP. An initially elevated NT-proBNP or rising level was associated with an increased risk of developing an abnormal LVEF.

CONCLUSIONS: Assessment of LVEF in HF-free older adults based on NT-proBNP levels should be considered on an individual basis, as such assessments do not routinely improve prognostication.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Biomarkers, Cohort Studies, Death, Female, Follow-Up Studies, Heart Failure, Humans, Male, Natriuretic Peptide, Brain, Peptide Fragments, Prospective Studies, Risk Factors, Stroke Volume, Survival Rate, Ventricular Function, Left}, issn = {1558-3597}, doi = {10.1016/j.jacc.2011.06.042}, author = {deFilippi, Christopher R and Christenson, Robert H and Kop, Willem J and Gottdiener, John S and Zhan, Min and Seliger, Stephen L} } @article {1277, title = {Longitudinal association of depressive symptoms with rapid kidney function decline and adverse clinical renal disease outcomes.}, journal = {Clin J Am Soc Nephrol}, volume = {6}, year = {2011}, month = {2011 Apr}, pages = {834-44}, abstract = {

BACKGROUND AND OBJECTIVES: Depression is a risk indicator for adverse outcomes in dialysis patients, but its prognostic impact in individuals who are not yet on dialysis is unknown. This study examines whether depressive symptoms are longitudinally associated with renal function decline, new-onset chronic kidney disease (CKD), ESRD, or hospitalization with acute kidney injury (AKI).

DESIGN, SETTING, PARTICIPANTS, \& MEASUREMENTS: Depressive symptoms were measured in a longitudinal cohort study with the 10-item Centers for Epidemiologic Studies Depression scale using a previously validated cut-off value (>=8). CKD at study entry and during follow-up was defined as an estimated GFR (eGFR) < 60 ml/min per m(2). Outcomes were rapid decline in eGFR (>3 ml/min per m(2) per year), new-onset CKD, ESRD (U.S. Renal Data System-based), and AKI (based on adjudicated medical record review). The median follow-up duration was 10.5 years.

RESULTS: Depressed participants (21.2\%) showed a higher prevalence of CKD at baseline compared with nondepressed participants in multivariable analysis. Depression was associated with a subsequent risk of rapid decline in eGFR, incident ESRD, and AKI, but not incident CKD in unadjusted models. In multivariable analyses, only associations of depressive symptoms with AKI remained significant.

CONCLUSIONS: Elevated depressive symptoms are associated with subsequent adverse renal disease outcomes. The depression-related elevated risk of AKI was independent of traditional renal disease risk factors and may in part be explained by the predictive value of depression for acute coronary syndromes and heart failure hospitalizations that can be complicated by AKI.

}, keywords = {Acute Kidney Injury, Aged, Chronic Disease, Cohort Studies, Comorbidity, Depression, Female, Follow-Up Studies, Glomerular Filtration Rate, Humans, Kidney Diseases, Longitudinal Studies, Male}, issn = {1555-905X}, doi = {10.2215/CJN.03840510}, author = {Kop, Willem J and Seliger, Stephen L and Fink, Jeffrey C and Katz, Ronit and Odden, Michelle C and Fried, Linda F and Rifkin, Dena E and Sarnak, Mark J and Gottdiener, John S} } @article {1268, title = {Predictive value of depressive symptoms and B-type natriuretic peptide for new-onset heart failure and mortality.}, journal = {Am J Cardiol}, volume = {107}, year = {2011}, month = {2011 Mar 01}, pages = {723-9}, abstract = {

Depression and natriuretic peptides predict heart failure (HF) progression, but the unique contributions of depression and biomarkers associated with HF outcomes are not known. The present study determined the additive predictive value of depression and aminoterminal pro-B-type natriuretic peptide (NT-proBNP) for new-onset HF in HF-free subjects and mortality in patients with HF. The participants in the Cardiovascular Health Study were assessed for depressive symptoms using the Center for Epidemiologic Studies Depression Scale and NT-proBNP using an electrochemiluminescence immunoassay. The validated cutoff values for depression (Center for Epidemiologic Studies Depression Scale >=8) and NT-proBNP (>=190 pg/ml) were used. The risks of incident HF and mortality (cardiovascular disease-related and all-cause) were examined during a median follow-up of 11 years, adjusting for demographics, clinical factors, and health behaviors. In patients with HF (n = 208), depression was associated with an elevated risk of cardiovascular disease mortality (hazard ratios [HR] 2.07, 95\% confidence interval [CI] 1.31 to 3.27) and all-cause mortality (HR 1.49, 95\% CI 1.05 to 2.11), independent of the NT-proBNP level and covariates. The combined presence of depression and elevated NT-proBNP was associated with substantially elevated covariate-adjusted risks of cardiovascular disease mortality (HR 5.42, 95\% CI 2.38 to 12.36) and all-cause mortality (HR 3.72, 95\% CI 2.20 to 6.37). In the 4,114 HF-free subjects, new-onset HF was independently predicted by an elevated NT-proBNP level (HR 2.27, 95\% CI 1.97 to 2.62) but not depression (HR 1.08, 95\% CI 0.92 to 1.26) in covariate-adjusted analysis. In conclusion, depression and NT-proBNP displayed additive predictive value for mortality in patients with HF. These associations can be explained by complementary pathophysiologic mechanisms. The presence of both elevated depression and NT-proBNP levels might improve the identification of patients with HF with a high risk of mortality.

}, keywords = {Aged, Depression, Disease Progression, Female, Follow-Up Studies, Heart Failure, Humans, Incidence, Male, Natriuretic Peptide, Brain, Prognosis, Retrospective Studies, Risk Factors, Survival Rate, United States}, issn = {1879-1913}, doi = {10.1016/j.amjcard.2010.10.055}, author = {van den Broek, Krista C and deFilippi, Christopher R and Christenson, Robert H and Seliger, Stephen L and Gottdiener, John S and Kop, Willem J} } @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 {1547, title = {Physical activity, change in biomarkers of myocardial stress and injury, and subsequent heart failure risk in older adults.}, journal = {J Am Coll Cardiol}, volume = {60}, year = {2012}, month = {2012 Dec 18}, pages = {2539-47}, abstract = {

OBJECTIVES: The aim of this study was to evaluate the association between physical activity and changes in levels of highly sensitive troponin T (cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), and the subsequent risk of the development of heart failure (HF) in community-dwelling older adults.

BACKGROUND: Higher baseline levels of cTnT and NT-proBNP and increases over time correlate with the risk of HF in older adults. Factors modifying these levels have not been identified.

METHODS: NT-proBNP and cTnT were measured at baseline and 2 to 3 years later in adults 65 years of age and older free of HF participating in the Cardiovascular Health Study. Self-reported physical activity and walking pace were combined into a composite score. An increase was prespecified for NT-proBNP as a >25\% increment from baseline to >=190 pg/ml and for cTnT as a >50\% increment from baseline in participants with detectable levels (>=3 pg/ml).

RESULTS: A total of 2,933 participants free of HF had NT-proBNP and cTnT measured at both time points. The probability of an increase in biomarker concentrations between baseline and follow-up visits was inversely related to the physical activity score. Compared with participants with the lowest score, those with the highest score had an odds ratio of 0.50 (95\% confidence interval: 0.33 to 0.77) for an increase in NT-proBNP and an odds ratio of 0.30 (95\% confidence interval: 0.16 to 0.55) for an increase in cTnT, after adjusting for comorbidities and baseline levels. A higher activity score associated with a lower long-term incidence of HF. Moreover, at each level of activity, an increase in either biomarker still identified those at higher risk.

CONCLUSIONS: These findings suggest that moderate physical activity has protective effects on early heart failure phenotypes, preventing cardiac injury and neurohormonal activation.

}, keywords = {Aged, Biomarkers, Female, Heart Failure, Humans, Male, Motor Activity, Natriuretic Peptide, Brain, Peptide Fragments, Risk Assessment, Troponin}, issn = {1558-3597}, doi = {10.1016/j.jacc.2012.08.1006}, author = {deFilippi, Christopher R and de Lemos, James A and Tkaczuk, Andrew T and Christenson, Robert H and Carnethon, Mercedes R and Siscovick, David S and Gottdiener, John S and Seliger, Stephen L} } @article {6279, title = {Long-term trajectory of two unique cardiac biomarkers and subsequent left ventricular structural pathology and risk of incident heart failure in community-dwelling older adults at low baseline risk.}, journal = {JACC Heart Fail}, volume = {1}, year = {2013}, month = {2013 Aug}, pages = {353-360}, abstract = {

OBJECTIVES: This study sought to determine whether the combined trajectories of cardiac biomarkers identify those older adults with initial low levels who have an increased risk for structural heart disease, incident heart failure (HF), and cardiovascular (CV) death.

BACKGROUND: Initial low levels of high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) identify older adults at lower risk for CV events.

METHODS: We performed an observational study among older adults without prevalent HF in the CHS (Cardiovascular Health Study). NT-proBNP and hs-cTnT were measured at baseline and after 2 to 3 years. In those with low baseline levels, a significant increase was defined as cardiac troponin T (cTnT) >50\% and NT-proBNP >25\% increase to >190 pg/ml. Left ventricular ejection fraction and left ventricular mass were measured by echocardiography at baseline and 5 years. Cox regression was used to estimate the association of change in biomarkers with HF and CV mortality.

RESULTS: Among 2,008 participants with initially low biomarker concentrations, significant increases occurred in 14.8\% for cTnT only, 13.2\% for NT-proBNP only, and 6.1\% for both. After 10 years, cumulative HF incidence was 50.4\% versus 12.2\% among those with both biomarkers versus neither biomarker increased. The adjusted relative risk comparing those with increases in both biomarkers versus neither biomarker was 3.56 for incident HF (95\% confidence interval: 2.56 to 4.97) and 2.98 for CV mortality (95\% confidence interval: 2.98 to 4.26). Among 1,340 participants with serial echocardiography, the frequency of new abnormal left ventricular ejection fraction was 11.8\% versus 4\% for those with increases in both biomarkers versus neither biomarker (p = 0.007).

CONCLUSIONS: Among older adults without HF with initially low cTnT and NT-proBNP, the long-term trajectory of both biomarkers predicts systolic dysfunction, incident HF, and CV death.

}, keywords = {Aged, Biomarkers, Female, Heart Failure, Heart Ventricles, Humans, Male, Natriuretic Peptide, Brain, Peptide Fragments, Prospective Studies, Risk Assessment, Time Factors, Troponin T, Ultrasonography}, issn = {2213-1787}, doi = {10.1016/j.jchf.2013.04.007}, author = {Glick, Danielle and deFilippi, Christopher R and Christenson, Robert and Gottdiener, John S and Seliger, Stephen L} } @article {6238, title = {Age- and sex-dependent upper reference limits for the high-sensitivity cardiac troponin T assay.}, journal = {J Am Coll Cardiol}, volume = {63}, year = {2014}, month = {2014 Apr 15}, pages = {1441-8}, abstract = {

OBJECTIVES: The study sought to determine the 99th percentile upper reference limit for the high-sensitivity cardiac troponin T assay (hs-cTnT) in 3 large independent cohorts.

BACKGROUND: The presently recommended 14 ng/l cut point for the diagnosis of myocardial infarction using the hs-cTnT assay was derived from small studies of presumably healthy individuals, with relatively little phenotypic characterization.

METHODS: Data were included from 3 well-characterized population-based studies: the Dallas Heart Study (DHS), the Atherosclerosis Risk in Communities (ARIC) Study, and the Cardiovascular Health Study (CHS). Within each cohort, reference subcohorts were defined excluding individuals with recent hospitalization, overt cardiovascular disease, and kidney disease (subcohort 1), and further excluding those with subclinical structural heart disease (subcohort 2). Data were analyzed stratified by age, sex, and race.

RESULTS: The 99th percentile values for the hs-cTnT assay in DHS, ARIC, and CHS were 18, 22, and 36 ng/l (subcohort 1) and 14, 21, and 28 ng/l (subcohort 2), respectively. These differences in 99th percentile values paralleled age differences across cohorts. Analyses within sex/age strata yielded similar results between cohorts. Within each cohort, 99th percentile values increased with age and were higher in men. More than 10\% of men 65 to 74 years of age with no cardiovascular disease in our study had cardiac troponin T values above the current myocardial infarction threshold.

CONCLUSIONS: Use of a uniform 14 ng/l cutoff for the hs-cTnT assay may lead to over-diagnosis of myocardial infarction, particularly in men and the elderly. Clinical validation is needed of new age- and sex-specific cutoff values for this assay.

}, keywords = {Adult, Age Factors, Aged, Biological Assay, Biomarkers, Blood Chemical Analysis, Cohort Studies, Cross-Sectional Studies, Female, Humans, Male, Middle Aged, Myocardial Infarction, Reference Values, Risk Assessment, Sensitivity and Specificity, Severity of Illness Index, Sex Factors, Troponin T}, issn = {1558-3597}, doi = {10.1016/j.jacc.2013.12.032}, author = {Gore, M Odette and Seliger, Stephen L and deFilippi, Christopher R and Nambi, Vijay and Christenson, Robert H and Hashim, Ibrahim A and Hoogeveen, Ron C and Ayers, Colby R and Sun, Wensheng and McGuire, Darren K and Ballantyne, Christie M and de Lemos, James A} } @article {6735, title = {Older Adults, "Malignant" Left Ventricular Hypertrophy, and Associated Cardiac-Specific Biomarker Phenotypes to Identify the Differential Risk of New-Onset Reduced Versus Preserved Ejection Fraction Heart Failure: CHS (Cardiovascular Health Study).}, journal = {JACC Heart Fail}, volume = {3}, year = {2015}, month = {2015 Jun}, pages = {445-55}, abstract = {

OBJECTIVES: This study hypothesized that biomarkers of subclinical myocardial injury (high-sensitivity cardiac troponin T [hs-cTnT]) and hemodynamic stress (N-terminal pro-B-type natriuretic peptide [NT-proBNP]) would differentiate heart~failure (HF) risk among older adults with left ventricular hypertrophy (LVH).

BACKGROUND: The natural history of LVH, an important risk factor for HF, is heterogeneous.

METHODS: NT-proBNP and hs-cTnT were measured at baseline and after 2 to 3 years in older adults without prior HF or myocardial infarction in the CHS (Cardiovascular Health Study). LVH and left ventricular ejection fraction were determined by echocardiography. HF events were adjudicated over a median of 13.1 years and classified as preserved or reduced left ventricular ejection fraction (heart failure with preserved ejection fraction or heart failure with reduced ejection fraction [HFrEF]). Adjusted risk of HF by LVH and biomarker tertiles, and by LVH and longitudinal increase in each biomarker was estimated using Cox regression.

RESULTS: Prevalence of LVH was 12.5\% among 2,347 participants with complete measures. Adjusted risk of HF (N~=~643 events) was approximately 3.8-fold higher among participants with LVH and in the highest biomarker tertile, compared with those with low biomarker levels without LVH (NT-proBNP, hazard ratio [HR]: 3.78; 95\% confidence interval [CI]: 2.78 to 5.15 and hs-cTnT, HR: 3.86; 95\% CI: 2.84 to 5.26). The adjusted risk of HFrEF was 7.8 times higher among those with the highest tertile of hs-cTnT and LVH (HR: 7.83; 95\% CI: 4.43 to 13.83). Those with LVH and longitudinal increases in hs-cTnT or NT-proBNP were approximately 3-fold more likely to develop HF, primarily HFrEF, compared with those without LVH and with stable biomarkers.

CONCLUSIONS: The combination of LVH with greater hs-cTnT or NT-proBNP levels, and their longitudinal increase, identifies older adults at highest risk for symptomatic HF, especially HFrEF. These biomarkers may characterize sub-phenotypes in the transition from LVH to HF and suggest modifiable targets for prevention.

}, keywords = {Aged, Biomarkers, Echocardiography, Female, Heart Failure, Humans, Hypertrophy, Left Ventricular, Male, Natriuretic Peptide, Brain, Peptide Fragments, Phenotype, Prospective Studies, Risk Factors, Troponin T}, issn = {2213-1787}, doi = {10.1016/j.jchf.2014.12.018}, author = {Seliger, Stephen L and de Lemos, James and Neeland, Ian J and Christenson, Robert and Gottdiener, John and Drazner, Mark H and Berry, Jarett and Sorkin, John and DeFilippi, Christopher} } @article {6878, title = {Prognostic Significance of High-Sensitivity Cardiac Troponin T Concentrations between the Limit of Blank and Limit of Detection in Community-Dwelling Adults: A Metaanalysis.}, journal = {Clin Chem}, volume = {61}, year = {2015}, month = {2015 Dec}, pages = {1524-31}, abstract = {

BACKGROUND: There is controversy regarding whether to report concentrations of high-sensitivity cardiac troponin T (hs-cTnT) to the limit of blank (LOB) (3 ng/L) or the limit of detection (LOD) (5 ng/L) of the assay in community-based cohorts. We hypothesized that hs-cTnT concentrations between the LOB and LOD would be associated with poorer cardiovascular outcomes compared to concentrations below the LOB.

METHODS: hs-cTnT was analyzed in a total of 10 723 participants from the Cardiovascular Health Study (CHS), Atherosclerosis Risk in Communities (ARIC) study, and Dallas Heart Study (DHS). Participants were divided into 2 groups, those with hs-cTnT concentrations below the limit of blank (LOB) (<3 ng/L) and those with hs-cTnT between the LOB and limit of detection (LOD) (3-4.99 ng/L). Cross-sectional associations with traditional cardiovascular risk factors and cardiac structural measurements, and longitudinal associations with long-term cardiovascular outcomes of incident heart failure and cardiovascular death, were determined.

RESULTS: Participants with hs-cTnT between the LOB and LOD for all 3 cohorts were older, more likely to be male, and have a higher burden of cardiovascular risk factors and structural pathology. A metaanalysis of the 3 cohorts showed participants with hs-cTnT between the LOB and LOD were at increased risk of new-onset heart failure (hazard ratio, 1.18; 95\% CI, 1.02-1.38) and cardiovascular mortality (hazard ratio, 1.29; 95\% CI, 1.06-1.57).

CONCLUSIONS: hs-cTnT concentrations between the LOB and LOD (3-4.99 ng/L) are associated with a higher prevalence of traditional risk factors, more cardiac pathology, and worse outcomes than concentrations below the LOB (<3 ng/L).

}, keywords = {Aged, Atherosclerosis, Biomarkers, Cross-Sectional Studies, Female, Heart Failure, Humans, Independent Living, Limit of Detection, Longitudinal Studies, Male, Middle Aged, Myocardial Infarction, Prognosis, Risk Assessment, Risk Factors, Sex Factors, Troponin T}, issn = {1530-8561}, doi = {10.1373/clinchem.2015.244160}, author = {Parikh, Ravi H and Seliger, Stephen L and de Lemos, James and Nambi, Vijay and Christenson, Robert and Ayers, Colby and Sun, Wensheng and Gottdiener, John S and Kuller, Lewis H and Ballantyne, Christie and deFilippi, Christopher R} } @article {8626, title = {Performance of the Pooled Cohort Equations to Estimate Atherosclerotic Cardiovascular Disease Risk by Body Mass Index.}, journal = {JAMA Netw Open}, volume = {3}, year = {2020}, month = {2020 10 01}, pages = {e2023242}, abstract = {

Importance: Obesity is a global health challenge and a risk factor for atherosclerotic cardiovascular disease (ASVCD). Performance of the pooled cohort equations (PCE) for ASCVD risk by body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) is unknown.

Objective: To assess performance of the PCE across clinical BMI categories.

Design, Setting, and Participants: This cohort study used pooled individual-level data from 8 community-based, prospective, longitudinal cohort studies with 10-year ASCVD event follow-up from 1996 to 2016. We included all adults ages 40 to 79 years without baseline ASCVD or statin use, resulting in a sample size of 37 311 participants. Data were analyzed from August 2017 to July 2020.

Exposures: Participant BMI category: underweight (<18.5), normal weight (18.5 to <25), overweight (25 to <30), mild obesity (30 to <35), and moderate to severe obesity (>=35).

Main Outcomes and Measures: Discrimination (Harrell C statistic) and calibration (Nam-D{\textquoteright}Agostino χ2 goodness-of-fit test) of the PCE across BMI categories. Improvement in discrimination and net reclassification with addition of BMI, waist circumference, and high-sensitivity C-reactive protein (hsCRP) to the PCE.

Results: Among 37 311 participants (mean [SD] age, 58.6 [11.8] years; 21 897 [58.7\%] women), 380 604 person-years of follow-up were conducted. Mean (SD) baseline BMI was 29.0 (6.2), and 360 individuals (1.0\%) were in the underweight category, 9937 individuals (26.6\%) were in the normal weight category, 13 601 individuals (36.4\%) were in the overweight category, 7783 individuals (20.9\%) were in the mild obesity category, and 5630 individuals (15.1\%) were in the moderate to severe obesity category. Median (interquartile range [IQR]) 10-year estimated ASCVD risk was 7.1\% (2.5\%-15.4\%), and 3709 individuals (9.9\%) developed ASCVD over a median (IQR) 10.8 [8.5-12.6] years. The PCE overestimated ASCVD risk in the overall cohort (estimated/observed [E/O] risk ratio, 1.22; 95\% CI, 1.18-1.26) and across all BMI categories except the underweight category. Calibration was better near the clinical decision threshold in all BMI groups but worse among individuals with moderate or severe obesity (E/O risk ratio, 1.36; 95\% CI, 1.25-1.47) and among those with the highest estimated ASCVD risk >=20\%. The PCE C statistic overall was 0.760 (95\% CI, 0.753-0.767), with lower discrimination in the moderate or severe obesity group (C statistic, 0.742; 95\% CI, 0.721-0.763) compared with the normal-range BMI group (C statistic, 0.785; 95\% CI, 0.772-0.798). Waist circumference (hazard ratio, 1.07 per 1-SD increase; 95\% CI, 1.03-1.11) and hsCRP (hazard ratio, 1.07 per 1-SD increase; 95\% CI, 1.05-1.09), but not BMI, were associated with increased ASCVD risk when added to the PCE. However, these factors did not improve model performance (C statistic, 0.760; 95\% CI, 0.753-0.767) with or without added metrics.

Conclusions and Relevance: These findings suggest that the PCE had acceptable model discrimination and were well calibrated at clinical decision thresholds but overestimated risk of ASCVD for individuals in overweight and obese categories, particularly individuals with high estimated risk. Incorporation of the usual clinical measures of obesity did not improve risk estimation of the PCE. Future research is needed to determine whether incorporation of alternative high-risk obesity markers (eg, weight trajectory or measures of visceral or ectopic fat) into the PCE may improve risk prediction.

}, keywords = {Adult, Aged, Body Mass Index, Cardiovascular Diseases, Cohort Studies, Correlation of Data, Female, Humans, Longitudinal Studies, Male, Middle Aged, Proportional Hazards Models, Prospective Studies, Risk Assessment, Risk Factors}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2020.23242}, author = {Khera, Rohan and Pandey, Ambarish and Ayers, Colby R and Carnethon, Mercedes R and Greenland, Philip and Ndumele, Chiadi E and Nambi, Vijay and Seliger, Stephen L and Chaves, Paulo H M and Safford, Monika M and Cushman, Mary and Xanthakis, Vanessa and Vasan, Ramachandran S and Mentz, Robert J and Correa, Adolfo and Lloyd-Jones, Donald M and Berry, Jarett D and de Lemos, James A and Neeland, Ian J} }