@article {709, title = {Frailty and activation of the inflammation and coagulation systems with and without clinical comorbidities: results from the Cardiovascular Health Study.}, journal = {Arch Intern Med}, volume = {162}, year = {2002}, month = {2002 Nov 11}, pages = {2333-41}, abstract = {

BACKGROUND: The biological basis of frailty has been difficult to establish owing to the lack of a standard definition, its complexity, and its frequent coexistence with illness.

OBJECTIVE: To establish the biological correlates of frailty in the presence and absence of concurrent cardiovascular disease and diabetes mellitus.

METHODS: Participants were 4735 community-dwelling adults 65 years and older. Frail, intermediate, and nonfrail subjects were identified by a validated screening tool and exclusion criteria. Bivariate relationships between frailty level and physiological measures were evaluated by Pearson chi2 tests for categorical variables and analysis of variance F tests for continuous variables. Multinomial logistic regression was performed to evaluate multivariable relationships between frailty status and physiological measures.

RESULTS: Of 4735 Cardiovascular Health Study participants, 299 (6.3\%) were identified as frail, 2147 (45.3\%) as intermediate, and 2289 (48.3\%) as not frail. Frail vs nonfrail participants had increased mean +/- SD levels of C-reactive protein (5.5 +/- 9.8 vs 2.7 +/- 4.0 mg/L), factor VIII (13 790 +/- 4480 vs 11 860 +/- 3460 mg/dL), and, in a smaller subset, D dimer (647 +/- 1033 vs 224 +/- 258 ng/mL) (P< or =.001 for all, chi2 test for trend). These differences persisted when individuals with cardiovascular disease and diabetes were excluded and after adjustment for age, sex, and race.

CONCLUSIONS: These findings support the hypothesis that there is a specific physiological basis to the geriatric syndrome of frailty that is characterized in part by increased inflammation and elevated markers of blood clotting and that these physiological differences persist when those with diabetes and cardiovascular disease are excluded.

}, keywords = {Aged, Aged, 80 and over, Blood Coagulation Disorders, Cardiovascular Diseases, Cohort Studies, Diabetes Complications, Diabetes Mellitus, Female, Frail Elderly, Geriatric Assessment, Humans, Inflammation, Longitudinal Studies, Male}, issn = {0003-9926}, doi = {10.1001/archinte.162.20.2333}, author = {Walston, Jeremy and McBurnie, Mary Ann and Newman, Anne and Tracy, Russell P and Kop, Willem J and Hirsch, Calvin H and Gottdiener, John and Fried, Linda P} } @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 {1216, title = {Autonomic nervous system dysfunction and inflammation contribute to the increased cardiovascular mortality risk associated with depression.}, journal = {Psychosom Med}, volume = {72}, year = {2010}, month = {2010 Sep}, pages = {626-35}, abstract = {

OBJECTIVE: To investigate prospectively whether autonomic nervous system (ANS) dysfunction and inflammation play a role in the increased cardiovascular disease (CVD)-related mortality risk associated with depression.

METHODS: Participants in the Cardiovascular Health Study (n = 907; mean age, 71.3 {\textpm} 4.6 years; 59.1\% women) were evaluated for ANS indices derived from heart rate variability (HRV) analysis (frequency and time domain HRV, and nonlinear indices, including detrended fluctuation analysis (DFA(1)) and heart rate turbulence). Inflammation markers included C-reactive protein, interleukin-6, fibrinogen, and white blood cell count). Depressive symptoms were assessed, using the 10-item Centers for Epidemiological Studies Depression scale. Cox proportional hazards models were used to investigate the mortality risk associated with depression, ANS, and inflammation markers, adjusting for demographic and clinical covariates.

RESULTS: Depression was associated with ANS dysfunction (DFA(1), p = .018), and increased inflammation markers (white blood cell count, p = .012, fibrinogen p = .043) adjusting for covariates. CVD-related mortality occurred in 121 participants during a median follow-up of 13.3 years. Depression was associated with an increased CVD mortality risk (hazard ratio, 1.88; 95\% confidence interval, 1.23-2.86). Multivariable analyses showed that depression was an independent predictor of CVD mortality (hazard ratio, 1.72; 95\% confidence interval, 1.05-2.83) when adjusting for independent HRV and inflammation predictors (DFA(1), heart rate turbulence, interleukin-6), attenuating the depression-CVD mortality association by 12.7\% (p < .001).

CONCLUSION: Autonomic dysfunction and inflammation contribute to the increased cardiovascular mortality risk associated with depression, but a large portion of the predictive value of depression remains unexplained by these neuroimmunological measures.

}, keywords = {Aged, Autonomic Nervous System Diseases, Biomarkers, C-Reactive Protein, Cardiovascular Diseases, Cause of Death, Cohort Studies, Comorbidity, Depressive Disorder, Electrocardiography, Female, Follow-Up Studies, Heart Rate, Humans, Inflammation, Interleukin-6, Leukocyte Count, Male, Risk Factors}, issn = {1534-7796}, doi = {10.1097/PSY.0b013e3181eadd2b}, author = {Kop, Willem J and Stein, Phyllis K and Tracy, Russell P and Barzilay, Joshua I and Schulz, Richard and Gottdiener, John S} } @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 {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} }