Dynamic cardiovascular risk assessment in the elderly:The role of repeated amino terminal pro-B-type natriuretic peptide testing

OBJECTIVES: Determine if serial measurement of N-terminal pro B-type natriuretic peptide (NT-proBNP) in community dwelling elderly would provide additional prognostic information to traditional risk factors. BACKGROUND: Accurate cardiovascular risk stratification is challenging in the elderly. METHODS: NT-proBNP was measured at baseline and 2-3 years later in 2,975 community-dwelling older adults free of heart failure in the longitudinal Cardiovascular Health Study. This investigation examined the risk of new-onset heart failure (HF) and death from cardiovascular (CV) 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%CI [confidence interval] 2.46-3.78) and CV death (HR=3.02, 95%CI 2.36-3.86) compared to 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=1.68-2.71) and CV death (HR=1.91, 95%CI=1.43-2.53) compared to those with sustained low levels. Among participants with initially high NT-proBNP, those who developed >25% increase (40%) were at higher risk of HF (HR=2.06 95%CI 1.56 −2.72) and cardiovascular death (HR=1.88, 95%CI 1.37-2.57), whereas those who developed >25% decrease to ≤190pg/mL (15%) were at lower risk of HF (HR=0.58, 95%CI 0.36-0.93) and CV death (HR=0.57, 95%CI 0.32 −1.01) compared to those with unchanged high values. CONCLUSION: 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

Cardiac microinjury measured by Troponin T predicts collagen metabolism in adults aged ≥65 years with heart failure

BACKGROUND: Repeated myocardial micro-injuries 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±6 years, 52% women) at baseline and at three years follow-up. Biomarkers of collagen metabolism were obtained at follow-up and included carboxyterminal propeptide of procollagen type I (PIP), carboxyterminal telopeptide of type I collagen (CITP); and aminoterminal propeptide of procollagen III (PIIINP). 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 CITP (β=0.22, p<0.001) and PIIINP (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 heart failure patients than in controls. CONCLUSIONS: Increases in myocardial micro-injury 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

Predictive value of depressive symptoms and B-type natriuretic peptide for new-onset heart failure and mortality

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

Association of serial measures of cardiac troponin T using a sensitive assay with incident heart failure and cardiovascular mortality in older adults.

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

Trial design for assessing analytical and clinical performance of high-sensitivity cardiac troponin I assays in the United States: The HIGH-US study

Background: High-sensitivity cardiac troponin I (hs-cTnI) assays have been developed that quantify lower cTnI concentrations with better precision versus earlier generation assays. hs-cTnI assays allow improved clinical utility for diagnosis and risk stratification in patients presenting to the emergency department with suspected acute myocardial infarction. We describe the High-Sensitivity Cardiac Troponin I Assays in the United States (HIGH-US) study design used to conduct studies for characterizing the analytical and clinical performance of hs-cTnI assays, as required by the US Food and Drug Administration for a 510(k) clearance application. This study was non-interventional and therefore it was not registered at clinicaltrials.gov. Methods: We conducted analytic studies utilizing Clinical and Laboratory Standards Institute guidance that included limit of blank, limit of detection, limit of quantitation, linearity, within-run and between run imprecision and reproducibility as well as potential interferences and high dose hook effect. A sample set collected from healthy females and males was used to determine the overall and sex-specific cTnI 99th percentile upper reference limits (URL). The total coefficient of variation at the female 99th percentile URL and a universally available American Association for Clinical Chemistry sample set (AACC Universal Sample Bank) from healthy females and males was used to examine high-sensitivity (hs) performance of the cTnI assays. Clinical diagnosis of enrolled subjects was adjudicated by expert cardiologists and emergency medicine physicians. Assessment of temporal diagnostic accuracy including sensitivity, specificity, positive predictive value, and negative predictive value were determined at presentation and collection times thereafter. The prognostic performance at one-year after presentation to the emergency department was also performed. This design is appropriate to describe analytical characterization and clinical performance, and allows for acute myocardial infarction diagnosis and risk assessment. Keywords: High-sensitivity cardiac troponin, Immunoassay, Analytical characteristics, Clinical performance, 99th percentile, Sex-specific 99th percentile cutoff