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Background: Circulating biomarkers can offer insight into subclinical cardiovascular stress and thus have the potential to aid in risk stratification and tailoring of therapy., Methods and Results: We measured plasma levels of 4 cardiovascular biomarkers, midregional pro-atrial natriuretic peptide (MR-proANP), midregional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1), and copeptin, in 3717 patients with stable coronary artery disease and preserved left ventricular ejection fraction who were randomized to trandolapril or placebo as part of the Prevention of Events With Angiotensin Converting Enzyme (PEACE) trial. After adjustment for clinical cardiovascular risk predictors and left ventricular ejection fraction, elevated levels of MR-proANP, MR-proADM, and CT-proET-1 were independently associated with the risk of cardiovascular death or heart failure (hazard ratios per 1-SD increase in log-transformed biomarker levels of 1.97, 1.48, and 1.47, respectively; P≤0.002 for each biomarker). These 3 biomarkers also significantly improved metrics of discrimination when added to a clinical model. Trandolapril significantly reduced the risk of cardiovascular death or heart failure in patients who had elevated levels of ≥2 biomarkers (hazard ratio, 0.53; 95% confidence interval, 0.36-0.80), whereas there was no benefit in patients with elevated levels of 0 or 1 biomarker (hazard ratio, 1.09; 95% confidence interval, 0.74-1.59; P(interaction)=0.012)., Conclusions: In patients with stable coronary artery disease and preserved left ventricular ejection fraction, our results suggest that elevated levels of novel biomarkers of cardiovascular stress may help identify patients who are at higher risk of cardiovascular death and heart failure and may be useful to select patients who derive significant benefit from angiotensin-converting enzyme inhibitor therapy., (© 2011 American Heart Association, Inc.)

Cardiac troponins are important biochemical markers for defining the presence of myocardial injury. However, limitations in troponin testing exist, including the relatively late increase in troponin after onset of ischemia. We therefore evaluated a more sensitive troponin assay for detection of myocardial injury in "early presenters." Discarded serial specimens were obtained from 103 patients who had a negative cardiac troponin I (cTnI) result followed by a positive cTnI result. Results were obtained using our current cTnI method and a new more sensitive assay, TnI-Ultra (Siemens Medical Solutions, Diagnostics Division, Tarrytown, NY). Medical records were reviewed to determine the clinical diagnosis. Precision studies yielded a 10% coefficient of variation at the diagnostic cut points for cTnI (0.10 ng/mL [0.10 microg/L]) and TnI-Ultra (0.04 ng/mL [0.04 microg/L]). TnI-Ultra was positive before cTnI in 66 (64.1%) of 103 cases. We conclude that the more sensitive assay, TnI-Ultra, has better analytic performance and has the potential to detect myocardial injury earlier than the current cTnI assay.

Objectives: We aimed to determine whether intensive statin therapy reduces hospitalization for heart failure (HF) in high-risk patients., Background: While the relationship between intensive statin therapy and ischemic events is well established, its relationship to the risk of HF after an acute coronary syndrome (ACS) is not well defined., Methods: The Pravastatin or Atorvastatin Evaluation and Infection Trial-Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI 22) study randomized 4,162 patients, stabilized after ACS, to either intensive statin therapy (atorvastatin 80 mg) or moderate statin therapy (pravastatin 40 mg). Hospitalization for HF occurring more than 30 days after randomization was determined during a mean follow-up of 24 months. B-type natriuretic peptide (BNP) levels were measured at baseline (median seven days after randomization)., Results: Treatment with atorvastatin 80 mg significantly reduced the rate of hospitalization for HF (2.3% vs. 3.9%, [corrected] hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.45 to 0.91, p = 0.012) [corrected] independently of a recurrent myocardial infarction or prior history of HF. The risk of HF increased steadily with increasing quartiles of BNP (HR 2.45, 95% CI 1.33 to 4.52, p = 0.004 [corrected] for the highest quartile compared with the lowest). Among patients with elevated levels of BNP (>80 pg/ml), treatment with atorvastatin significantly reduced the risk of HF compared with pravastatin (HR 0.50, 95% CI 0.27 to 0.93, p = 0.028). [corrected]. A meta-analysis of four trials that included 27,546 patients demonstrates a 27% reduction in the odds of hospitalization for HF with intensive statin therapy., Conclusions: Intensive statin therapy reduces the risk of hospitalization for HF after ACS with the most gain in patients with elevated levels of BNP.

Context: Elevated concentrations of B-type natriuretic peptide (BNP) at presentation in patients with acute coronary syndrome (ACS) are associated with long-term mortality. Few data exist regarding serial assessment of BNP levels during follow-up., Objective: To determine whether concentrations of BNP at study entry (prior to hospital discharge for ACS) and at outpatient follow-up at 4 months and 12 months are associated with subsequent clinical outcomes., Design, Setting, and Patients: Prospective observational substudy of 4497 patients with non-ST-elevation or ST-elevation ACS who were enrolled in phase Z of the A to Z trial, which was conducted in 41 countries at 322 acute care hospitals between 1999 and 2003., Main Outcome Measure: Death from any cause or new onset of congestive heart failure (CHF) through 2 years., Results: Levels of BNP were available in 4266 patients at study entry (prior to hospital discharge), 3618 patients at 4 months, and 2966 patients at 12 months. During follow-up there were 230 deaths and 163 incident cases of CHF. Adjusting for age, sex, index event, renal function, hypertension, prior heart failure, and diabetes, elevated levels of BNP (>80 pg/mL) were associated with subsequent death or new CHF when measured at study entry (111 [21%] vs 246 [7%]; adjusted hazard ratio [HR], 2.5; 95% confidence interval [CI], 2.0-3.3), at 4 months (34 [19%] vs 125 [4%]; adjusted HR, 3.9; 95% CI, 2.6-6.0), and at 12 months (19 [11%] vs 37 [1%]; adjusted HR, 4.7; 95% CI, 2.5-8.9). Patients with newly elevated levels of BNP at 4 months were at increased risk of death or new CHF (10 [15%] vs 105 [3%]); HR, 4.5; 95% CI, 2.3-8.6). Patients with elevated levels of BNP at study entry and with BNP levels lower than 80 pg/mL at 4 months tended to have only modestly increased risk (HR, 1.7; 95% CI, 1.0-2.9) compared with patients with BNP levels lower than 80 pg/mL at both visits., Conclusions: Serial determinations of BNP levels during outpatient follow-up after ACS predict the risk of death or new CHF. Changes in BNP levels over time are associated with long-term clinical outcomes and may provide a basis for enhanced clinical decision making in patients after onset of ACS.Clinical Trials Registration ClinicalTrials.gov Identifier: NCT00251576.

Objective: Patients with type 2 diabetes are at increased risk of developing heart failure (HF). Enhanced recognition of patients at risk for HF would help guide therapeutic decisions.Research Design and Methods: We investigated the prognostic implications of changes in N-terminal B-type natriuretic peptide (NT-proBNP) concentration in patients with type 2 diabetes and ischemic heart disease who were enrolled in the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) trial, a phase 3b trial of alogliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor. Patients with type 2 diabetes and a recent acute coronary syndrome event were eligible. NT-proBNP was measured at baseline and 6 months. Cardiovascular (CV) death or hospitalization for HF was the end point of principal interest for this analysis.Results: We observed a strong graded relationship between increasing baseline and 6-month NT-proBNP concentration and the incidence of major CV events (P < 0.001). After adjusting for potential confounders, NT-proBNP at baseline was independently associated with the development of major CV events, in particular hospitalization for HF. Patients who had persistently high NT-proBNP (P < 0.001) or developed high NT-proBNP at 6 months (P < 0.001) were at a significantly higher risk for CV death/HF than those in whom NT-proBNP remained low at both time points or who had a high NT-proBNP value at baseline that subsequently declined to the low category. Absolute changes in NT-proBNP by 6 months were also strongly associated with subsequent outcomes. Treatment with a DPP-4 inhibitor did not meaningfully alter NT-proBNP concentrations (P = 0.20).Conclusions: Serial monitoring of NT-proBNP in patients with type 2 diabetes and ischemic heart disease may be useful for identifying patients at highest risk for HF. [ABSTRACT FROM AUTHOR]

Objectives: This study sought to test 2 hypotheses: 1) fibroblast growth factor (FGF)-23 identifies patients with stable ischemic heart disease (SIHD) at high risk of cardiovascular events independent of clinical factors, renal function, and established cardiovascular biomarkers; and 2) FGF-23 identifies patients who derive greater clinical benefit from angiotensin-converting enzyme inhibitor therapy. Background: FGF-23 is an endocrine regulator of mineral metabolism and markedly elevated levels are associated with cardiovascular events in patients with chronic kidney disease. Data in patients with SIHD are more sparse. Methods: FGF-23 levels were measured in 3,627 patients with SIHD randomly assigned to trandolapril or placebo within the PEACE (Prevention of Events With Angiotensin-Converting Enzyme) trial and followed up for a median of 5.1 years. Results: After adjustment for clinical risk predictors, left ventricular ejection fraction, markers of renal function, and established cardiovascular biomarkers, FGF-23 concentration was independently associated with an increased risk of cardiovascular death or heart failure among patients allocated to placebo (quartile 4 hazard ratio: 1.73; 95% confidence interval, 1.09 to 2.74; p = 0.02) and significantly improved metrics of discrimination. Furthermore, among patients in the top quartile of FGF-23 levels, trandolapril significantly reduced cardiovascular death or incident heart failure (hazard ratio: 0.45; 95% confidence interval: 0.28 to 0.72), whereas there was no clinical benefit in the remaining patients (hazard ratio: 1.07; 95% confidence interval: 0.75 to 1.52; p interaction = 0.0039). This interaction was independent of and additive to stratification based on renal function. Conclusions: Elevated levels of FGF-23 are associated with cardiovascular death and incident heart failure in patients with SIHD and identify patients who derive significant clinical benefit from angiotensin-converting enzyme inhibitor therapy regardless of renal function. (Prevention of Events With Angiotensin-Converting Enzyme Inhibitor Therapy [PEACE]: NCT00000558) [Copyright &y& Elsevier]

Introduction: Use of high-sensitivity troponin (hsTn) in stable patients (pts) with established ischemic heart disease (SIHD) is an emerging application to identify heightened risk of major cardiovascular (CV) events. However, appropriate decision-limits are not yet defined. Methods: We measured serum hsTnI (Abbott ARCHITECT, limit-of-detection 2 ng/L, MI cut-point 26 ng/L) in a prospective nested cohort of 8,635 pts enrolled in the PEGASUS-TIMI 54 trial. All patients had SIHD with a myocardial infarction (MI) 1-3 years prior to enrollment. Previous studies have proposed 6 ng/L as a decision-limit for risk stratification. Pts were categorized based on baseline hsTnI: undetectable (<2), low (2-6), and high (>6 ng/L). The primary endpoint (PEP) was a composite of CV death, MI, or stroke. Pts were followed for a median of 33 months. Results: The median value of hsTnI was 4.2 ng/L (25th, 75th: 2.7, 7.2 ng/L) and 89.3% of pts had detectable hsTnI (≥2 ng/L) with 31.1% >6 ng/L. The 3y PEP rates for the undetectable, low, and high hsTnI groups were 2.8, 6.0, and 13.5%, respectively (Fig). Adjusting for age, diabetes, smoking, hypertension, stroke, CABG, peripheral artery disease, history of heart failure and chronic kidney disease, there remained a 2 and 4-fold higher risk for the PEP in the low and high hsTnI groups(Fig). Rates of MI in the undetectable, low, and high groups were 2.5, 4.3, and 8.7%, respectively, with adjusted HRs of 1.9 (95% CI 1.2-3.2, p=0.009) in the low and 3.6 (95% CI 2.2-6.0, p<0.0001) in the high group. No CV deaths occurred in pts with undetectable troponin. There was no significant interaction with efficacy of ticagrelor. Conclusion: hsTn demonstrates a strong independent graded association with recurrent major cardiovascular events in pts with SIHD. The increased risk is present in the low detectable range and progresses with higher levels. A single hsTnI >6 ng/L was present in nearly 1/3 of patients, identifying a 4-fold higher risk of recurrent cardiac event. [ABSTRACT FROM AUTHOR]

Abstract: Background: Systemic risk factors and local hemodynamic factors both contribute to coronary atherosclerosis, but their possibly synergistic inter-relationship remains unknown. The purpose of this natural history study was to investigate the combined in-vivo effect of varying levels of systemic hypercholesterolemia and local endothelial shear stress (ESS) on subsequent plaque progression and histological composition. Methods: Diabetic, hyperlipidemic swine with higher systemic total cholesterol (TC) (n=4) and relatively lower TC levels (n=5) underwent three-vessel intravascular ultrasound (IVUS) at 3–5 consecutive time-points in-vivo. ESS was calculated serially using computational fluid dynamics. 3-D reconstructed coronary arteries were divided into 3mm-long segments (n=595), which were stratified according to higher vs. relatively lower TC and low (<1.2Pa) vs. higher local ESS (≥1.2Pa). Arteries were harvested at 9months, and a subset of segments (n=114) underwent histopathologic analyses. Results: Change of plaque volume (ΔPV) by IVUS over time was most pronounced in low-ESS segments from higher-TC animals. Notably, higher-ESS segments from higher-TC animals had greater ΔPV compared to low-ESS segments from lower-TC animals (p<0.001). The time-averaged ESS in segments that resulted in significant plaque increased with increasing TC levels (slope: 0.24Pa/100mg/dl; r =0.80; p<0.01). At follow-up, low-ESS segments from higher-TC animals had the highest mRNA levels of lipoprotein receptors and inflammatory mediators and, consequently, the greatest lipid accumulation and inflammation. Conclusions: This study redefines the principle concept that “low” ESS promotes coronary plaque growth and vulnerability by demonstrating that: (i.) the pro-atherogenic threshold of low ESS is not uniform, but cholesterol-dependent; and (ii.) the atherogenic effects of local low ESS are amplified, and the athero-protective effects of higher ESS may be outweighed, by increasing cholesterol levels. Intense hypercholesterolemia and very low ESS are synergistic in favoring rapid atheroma progression and high-risk composition. [Copyright &y& Elsevier]

Abstract: Background: While more sensitive cardiac troponin (cTn) assays may overcome current limitations in diagnosing acute coronary syndrome (ACS), clinicians and laboratorians are concerned about the clinical impact of higher rates of cTn positivity. Methods: We collected statistics on test volume and positivity rates before and after the implementation of a more sensitive assay. We divided patients into 6 groups based on their cardiac troponin I (cTnI) results and utilized additional laboratory test results to determine the impact of the new assay. In addition, we assessed the clinical significance of low-positive cTnI results (0.05–0.10 µg/l). Results: Lowering the diagnostic cutoff from 0.10 to 0.04 µg/l increased the number of positive test results by 44.2% hospital-wide and 114.4% in the emergency department without significantly changing test volume. In some patients, low-positive results were part of the typical rise and fall of cTnI consistent with myocardial damage. Diagnosis was more challenging in patients with consistently low-positive results. Patients in this group were significantly more likely to have impaired renal function than those with cTnI elevations >0.10 µg/l. Conclusions: More sensitive cTn assays will increase the number of positive results and allow for earlier detection of cardiac injury while also detecting non-ACS related pathologies. [Copyright &y& Elsevier]

Objectives: This study sought to determine whether the novel biomarker monocyte chemoattractant protein (MCP)-1 adds prognostic value to standard risk assessment tools and biomarkers after acute coronary syndromes (ACS). Background: Monocyte chemoattractant protein-1 is a chemokine recruiting signal for monocytes that may function as both a mediator and biomarker of ACS. Methods: Monocyte chemoattractant protein-1 was measured at baseline (n = 4,244), 4 months (n = 3,603), and 12 months (n = 2,950), and correlated with clinical events in the Z phase of the A to Z (Aggrastat to Zocor) trial, which compared early intensive versus delayed and less intensive statin therapy after ACS. Results: Rates of death and the composite end points of death or myocardial infarction (MI); death, MI, or heart failure; and cardiovascular death, MI, readmission for ACS, or stroke increased across baseline quartiles of MCP-1 and among patients with MCP-1 greater than versus less than or equal to the pre-specified threshold of 238 pg/ml (p < 0.01 for each). After adjustment for standard risk predictors and levels of C-reactive protein and B-type natriuretic peptide, MCP-1 >238 pg/ml remained independently associated with mortality (hazard ratio 2.16; 95% confidence interval 1.54 to 3.02) and with each composite end point, and increased the C-statistic of the fully adjusted mortality model from 0.76 to 0.78 (p < 0.0001). A value of MCP-1 >238 pg/ml at the 4-month follow-up visit was also independently associated with mortality after 4 months (hazard ratio 1.76; 95% confidence interval 1.12 to 2.76). Elevated MCP-1 levels did not identify patients who derived incremental benefit from intensive statin therapy. Conclusions: Monocyte chemoattractant protein-1 provides independent prognostic value in the acute and chronic phases after ACS and merits further evaluation as a prognostic marker and potential therapeutic target. [Copyright &y& Elsevier]