@article {1138, title = {N-terminal pro-B-type natriuretic peptide is a major predictor of the development of atrial fibrillation: the Cardiovascular Health Study.}, journal = {Circulation}, volume = {120}, year = {2009}, month = {2009 Nov 03}, pages = {1768-74}, abstract = {

BACKGROUND: Atrial fibrillation (AF), the most common cardiac rhythm abnormality, is associated with significant morbidity, mortality, and healthcare expenditures. Elevated B-type natriuretic peptide levels have been associated with the risk of heart failure, AF, and mortality.

METHODS AND RESULTS: The relation between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and AF was studied in 5445 Cardiovascular Health Study participants with the use of relative risk regression for predicting prevalent AF and Cox proportional hazards for predicting incident AF. NT-proBNP levels were strongly associated with prevalent AF, with an unadjusted prevalence ratio of 128 for the highest quintile (95\% confidence interval, 17.9 to 913.3; P<0.001) and adjusted prevalence ratio of 147 for the highest quintile (95\% confidence interval, 20.4 to 1064.3; P<0.001) compared with the lowest. After a median follow-up of 10 years (maximum of 16 years), there were 1126 cases of incident AF (a rate of 2.2 per 100 person-years). NT-proBNP was highly predictive of incident AF, with an unadjusted hazard ratio of 5.2 (95\% confidence interval, 4.3 to 6.4; P<0.001) for the development of AF for the highest quintile compared with the lowest; for the same contrast, NT-proBNP remained the strongest predictor of incident AF after adjustment for an extensive number of covariates, including age, sex, medication use, blood pressure, echocardiographic parameters, diabetes mellitus, and heart failure, with an adjusted hazard ratio of 4.0 (95\% confidence interval, 3.2 to 5.0; P<0.001).

CONCLUSIONS: In a community-based population of older adults, NT-proBNP was a remarkable predictor of incident AF, independent of any other previously described risk factor.

}, keywords = {Aged, Aged, 80 and over, Atrial Fibrillation, Female, Humans, Immunoassay, Longitudinal Studies, Male, Natriuretic Peptide, Brain, Peptide Fragments, Predictive Value of Tests, Prevalence, Proportional Hazards Models, Risk Factors}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.109.873265}, author = {Patton, Kristen K and Ellinor, Patrick T and Heckbert, Susan R and Christenson, Robert H and DeFilippi, Christopher and Gottdiener, John S and Kronmal, Richard A} } @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 {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 {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} }