Robert H. Christenson

Cardiac Troponin T Levels for Risk Stratification in Acute Myocardial Ischemia

Background The prognosis of patients hospitalized with acute myocardial ischemia is quite variable. We examined the value of serum levels of cardiac troponin T, serum creatine kinase MB (CK-MB) levels, and electrocardiographic abnormalities for risk stratification in patients with acute myocardial ischemia. Methods We studied 855 patients within 12 hours of the onset of symptoms. Cardiac troponin T levels, CK-MB levels, and electrocardiograms were analyzed in a blinded fashion at the core laboratory. We used logistic regression to assess the usefulness of base-line levels of cardiac troponin T and CK-MB and the electrocardiographic category assigned at admission — ST-segment elevation, ST-segment depression, T-wave inversion, or the presence of confounding factors that impair the detection of ischemia (bundle-branch block and paced rhythms) — in predicting outcome. Results On admission, 289 of 801 patients with base-line serum samples had elevated troponin T levels (>0.1 ng per milliliter). Mortality with...

Fibroblast Growth Factor 23 and Left Ventricular Hypertrophy in Chronic Kidney Disease

Background— Fibroblast growth factor 23 (FGF-23) is a phosphorus-regulating hormone. In chronic kidney disease (CKD), circulating FGF-23 levels are markedly elevated and independently associated with mortality. Left ventricular hypertrophy and coronary artery calcification are potent risk factors for mortality in CKD, and FGFs have been implicated in the pathogenesis of both myocardial hypertrophy and atherosclerosis. We conducted a cross-sectional study to test the hypothesis that elevated FGF-23 concentrations are associated with left ventricular hypertrophy and coronary artery calcification in patients with CKD. Methods and Results— In this study, 162 subjects with CKD underwent echocardiograms and computed tomography scans to assess left ventricular mass index and coronary artery calcification; echocardiograms also were obtained in 58 subjects without CKD. In multivariable-adjusted regression analyses in the overall sample, increased log FGF-23 concentrations were independently associated with increased left ventricular mass index (5% increase per 1-SD increase in log FGF-23; P=0.01) and risk of left ventricular hypertrophy (odds ratio per 1-SD increase in log FGF-23, 2.1; 95% confidence interval, 1.03 to 4.2). These associations strengthened in analyses restricted to the CKD subjects (11% increase in left ventricular mass index per 1-SD increase in log FGF-23; P=0.01; odds ratio of left ventricular hypertrophy per 1-SD increase in log FGF-23, 2.3; 95% confidence interval, 1.2 to 4.2). Although the highest tertile of FGF-23 was associated with a 2.4-fold increased risk of coronary artery calcification ≥100 versus <100 U compared with the lowest tertile (95% confidence interval, 1.1 to 5.5), the association was no longer significant after multivariable adjustment. Conclusions— FGF-23 is independently associated with left ventricular mass index and left ventricular hypertrophy in patients with CKD. Whether increased FGF-23 is a marker or a potential mechanism of myocardial hypertrophy in CKD requires further study.

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.

National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: Clinical Characteristics and Utilization of Biochemical Markers in Acute Coronary Syndromes

I. OVERVIEW OF THE ACUTE CORONARYSYNDROME e357A. Definition of Terms e357B. Pathogenesis and Management of ACS e357II. USE OF BIOCHEMICAL MARKERS IN THEINITIAL EVALUATION OF ACS e358A. Diagnosis of Myocardial Infarction e3581. Biochemical Markers of MyocardialNecrosis e3582. Optimal Timing of Sample Acquisition.......e3593. Criteria for Diagnosis of MI e3604. Additional Considerations in the Use ofBiomarkers for Diagnosis of MI e360B. Early Risk Stratification e3611. Biochemical Markers of Cardiac Injury.......e361a. Pathophysiology e361b. Relationship to Clinical Outcomes.........e361c. Decision-Limits e362d. Therapeutic Decision-Making e3622. Natriuretic Peptides e362a. Pathophysiology e362b. Relationship to Clinical Outcomes.........e363c. Decision-Limits e364d. Therapeutic Decision-Making e3653. Biochemical Markers of Inflammation........e365a. Pathophysiology e365b. Relationship to Clinical Outcomes.........e365c. Decision-Limits e365d. Therapeutic Decision-Making e3674. Biochemical Markers of Ischemia e3675. Multimarker Approach e3676. Other Novel Markers e368III. USE OF BIOCHEMICAL MARKERS IN THEMANAGEMENT OF NSTEACS e368A. Clinical Decision-Making e3681. Biochemical Markers of Cardiac Injury.......e3682. Other Biochemical Markers e369

BIOCHEMICAL MARKERS OF BONE METABOLISM : AN OVERVIEW

OBJECTIVES An overview of biochemical markers of bone metabolism is presented along with indications for their clinical utilization. DESIGN AND METHODS The structure, cyclical metabolism, and hormone regulation of bone is reflected by markers of resorption, formation and/or turnover. Markers of resorption representing degradation of type 1 collagen, include N-telopeptides, C-telopeptides, hydroxyproline, and the collagen crosslinks pyridinoline and deoxypyridinoline; acid phosphatase, a marker of osteoclast activity, and urinary calcium are also indicators of bone resorption. Bone formation markers indicate osteoblast activity; bone-specific alkaline phosphatase and the N-terminal and C-terminal extension peptides of procollagen reflect formation of organic matrix in bone. Osteocalcin, produced by osteoblasts but also released during osteoclastic degradation, may indicate either formation when resorption and formation are coupled or turnover when they are uncoupled. RESULTS Bone markers respond to intervention more rapidly than techniques such bone mineral density. Resorption markers respond approximately 1 to 3 months after intervention; markers of formation respond later, after 6 to 9 months. Bone markers may add useful information for assessing fracture risk and for monitoring osteoporosis, Pagets disease of bone, cancer metastasis, and metabolic disease. Various therapeutic interventions may affect release of some bone markers. CONCLUSION Bone disease has high prevalence in adults so bone markers will become even more important for assessing fracture risk and monitoring therapy as populations age. Characteristics of bone markers are dependent on biology and the assay used. Substantial work remains in characterizing existing assays, identifying better markers and performing the clinical studies to define which bone markers should be measured and when.

Mid-Region Pro-Hormone Markers for Diagnosis and Prognosis in Acute Dyspnea: Results From the BACH (Biomarkers in Acute Heart Failure) Trial

OBJECTIVES Our purpose was to assess the diagnostic utility of mid-regional pro-atrial natriuretic peptide (MR-proANP) for the diagnosis of acute heart failure (AHF) and the prognostic value of mid-regional pro-adrenomedullin (MR-proADM) in patients with AHF. BACKGROUND There are some caveats and limitations to natriuretic peptide testing in the acute dyspneic patient. METHODS The BACH (Biomarkers in Acute Heart Failure) trial was a prospective, 15-center, international study of 1,641 patients presenting to the emergency department with dyspnea. A noninferiority test of MR-proANP versus B-type natriuretic peptide (BNP) for diagnosis of AHF and a superiority test of MR-proADM versus BNP for 90-day survival were conducted. Other end points were exploratory. RESULTS MR-proANP (> or =120 pmol/l) proved noninferior to BNP (> or =100 pg/ml) for the diagnosis of AHF (accuracy difference 0.9%). In tests of secondary diagnostic objectives, MR-proANP levels added to the utility of BNP levels in patients with intermediate BNP values and with obesity but not in renal insufficiency, the elderly, or patients with edema. Using cut-off values from receiver-operating characteristic analysis, the accuracy to predict 90-day survival of heart failure patients was 73% (95% confidence interval: 70% to 77%) for MR-proADM and 62% (95% confidence interval: 58% to 66%) for BNP (difference p < 0.001). In adjusted multivariable Cox regression, MR-proADM, but not BNP, carried independent prognostic value (p < 0.001). Results were consistent using NT-proBNP instead of BNP (p < 0.001). None of the biomarkers was able to predict rehospitalization or visits to the emergency department with clinical relevance. CONCLUSIONS MR-proANP is as useful as BNP for AHF diagnosis in dyspneic patients and may provide additional clinical utility when BNP is difficult to interpret. MR-proADM identifies patients with high 90-day mortality risk and adds prognostic value to BNP. (Biomarkers in Acute Heart Failure [BACH]; NCT00537628).

The Associations of Fibroblast Growth Factor 23 and Uncarboxylated Matrix Gla Protein With Mortality in Coronary Artery Disease: The Heart and Soul Study

BACKGROUND Fibroblast growth factor 23 (FGF23), uncarboxylated matrix Gla protein (ucMGP), and fetuin-A are regulators of mineral metabolism and inhibitors of vascular calcification. Whether circulating levels of each are associated with cardiovascular disease (CVD) events or mortality in populations without end-stage renal disease is unknown. OBJECTIVE To evaluate the associations of FGF23, ucMGP, and fetuin-A with mortality and CVD events. DESIGN Observational study. SETTING 12 outpatient clinics in the San Francisco Bay area. PATIENTS 833 outpatients with stable coronary artery disease (CAD), recruited from 11 September 2000 to 20 December 2002. MEASUREMENTS Fibroblast growth factor 23, ucMGP, and fetuin-A concentrations were measured at baseline. Participants were followed until 1 December 2008 for mortality and CVD events. RESULTS During a median follow-up of 6.0 years, 220 participants died and 182 had CVD events. Compared with participants with FGF-23 levels in the lowest tertile, those in the highest tertile had 2-fold greater risk for mortality (hazard ratio [HR], 2.15 [95% CI, 1.43 to 3.24]) and CVD events (HR, 1.83 [CI, 1.15 to 2.91]) after adjustment for traditional CVD risk factors, C-reactive protein levels, and kidney function. The highest ucMGP tertile was associated with lower mortality risk (HR, 0.48 [CI, 0.31 to 0.75]) and showed a nonsignificant trend toward lower CVD event risk by tertile analysis (HR, 0.65 [CI, 0.40 to 1.05])-an association that was significant when modeled continuously (P = 0.029). No significant association of fetuin-A with mortality (HR, 0.84 [CI, 0.55 to 1.27]) or CVD events (HR, 0.99 [CI, 0.64 to 1.55]) was observed. LIMITATION Participants had prevalent CAD. CONCLUSION In outpatients with stable CAD, higher FGF23 and lower ucMGP levels are independently associated with mortality and CVD events. PRIMARY FUNDING SOURCE American Heart Association.

National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: Clinical Utilization of Cardiac Biomarker Testing in Heart Failure

### A. Context of Biochemical Marker Testing in Heart Failure Biochemical marker testing has revolutionized the approach to diagnosis and management of heart failure over the past decade. There is an unsurpassed excitement in the heart failure community that significant advances in our understanding of currently available and future cardiac biomarkers will facilitate improved characterization of heart failure disease states and promote individualized therapy in heart failure and beyond. However, like most novel diagnostic tests, the promising findings from pivotal trials have met with ongoing challenges when applied in the clinical setting. The material discussed in this guidelines document addresses clinical use of BNP/NT-proBNP and cardiac troponin testing in the context of heart failure diagnosis, risk stratification and management, including therapeutic guidance in adult (>18 year-old) patients. Together with the associated document titled “ National Academy of Clinical Biochemistry and IFCC Committee for Standardization of Markers of Cardiac Damage Laboratory Medicine Practice Guidelines: Analytical Issues for Biomarkers of Heart Failure ”, …

Value of Serial Troponin T Measures for Early and Late Risk Stratification in Patients With Acute Coronary Syndromes

BACKGROUND The baseline cardiac troponin T (cTnT) level strongly predicts short-term mortality in acute coronary syndromes, but the added value of later measures to predict short- and long-term outcome and in the context of baseline clinical characteristics is unclear. METHODS AND RESULTS Relations between baseline, peak, and 8- and 16-hour (late) cTnT results and outcomes were assessed in 734 patients in a GUSTO-IIa substudy. Proportional-hazards models assessed the prognostic information gained from late cTnT when added to a mortality model containing the baseline cTnT result and clinical factors. At baseline, 260 patients were cTnT-positive (>0.1 ng/mL), 323 became positive later, and 151 remained negative (</=0.1 ng/mL). Mortality at 30 days was 10% in the baseline-positive group, 5% in late-positive patients, and 0% in negative patients. After adjustment for baseline characteristics, any positive cTnT result predicted 30-day mortality (baseline, chi2=8.96, P=0.0113; 8-hour, chi2=6.51, P=0.0107; 16-hour, chi2=8.40, P=0.0038). Both the 8- and the 16-hour results added to the strength of the baseline result (baseline+8-hour, chi2=12.04, P=0.0072; baseline+16-hour, chi2=13.52, P=0.0036). Only age and ST-segment elevation were stronger predictors of 30-day mortality than baseline cTnT; results were similar for prediction of 1-year mortality. Most of the mortality difference between cTnT-positive and -negative patients occurred within the first 30 days. CONCLUSIONS The cTnT level is a strong, independent predictor of short-term outcome in acute coronary syndromes. The addition of later samples to a baseline level is useful to evaluate the risk of serious cardiac events.

ACCF 2012 Expert Consensus Document on Practical Clinical Considerations in the Interpretation of Troponin Elevations: A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents

This document has been developed as an Expert Consensus Document (ECD) by the American College of Cardiology Foundation (ACCF), American Association for Clinical Chemistry (AACC), American College of Chest Physicians (ACCP), American College of Emergency Physicians (ACEP), American College of