Instability In Coronary Artery Disease Research Articles

695 Upregulated monocyte expression of PLIN2 is associated with plaque instability in coronary artery disease

Abstract Aims Perilipin 2 (PLIN2), a protein associated with intracellular lipid droplets (LDs), is involved in lipid metabolism of macrophages resident in atherosclerotic plaques and its up-regulation leads to LDs accumulation. LDs enlargement results in the macrophage transformation into foam cells, a key step for the onset of atherosclerosis. In the present study, we investigated the role of PLIN2 and its regulation mechanisms in atherosclerosis and plaque instability in patients with a diagnosis of ST-elevation myocardial infarction (STEMI) and stable chronic angina (SA). Methods and results We enrolled 120 patients with a diagnosis of STEMI and 42 SA patients with symptoms of stable effort angina lasting more than 12 months. Peripheral blood mononuclear cells (PBMCs) were isolated from EDTA whole blood samples through standard gradient centrifugation over Ficoll-Hypaque. Monocytes were purified through indirect magnetic labelling of PBMCs. PLIN2 mRNA expression was investigated by Real Time-PCR and PLIN2 protein level was analysed in CD14+ monocytes by flow cytometry. Proteasome activity was assayed using AMC-tagged peptide substrate (Succ-LLVY-AMC), which releases free highly fluorescent AMC (Ex/Em 350/440 nm) in the presence of proteolytic activity. In CD14+ monocyte, PLIN2 protein expression was significantly increased in STEMI as compared to SA patients (P < 0.001), while PLIN2 mRNA level was not different in the two groups (P = n.s.). Despite proteasome activity was higher in STEMI as compared to SA patients (P < 0.001), significant inverse correlations were evident between PLIN2 levels and proteasome activity in the two groups (P = 0.05). Conclusions CD14+ monocyte PLIN2 protein expression was higher in STEMI as compared to SA patients suggesting an involvement in plaque instability. Despite proteasome activity was higher in STEMI patients, probably due to the elevated inflammatory burden, PLIN2 could escape proteasome degradation in a more efficient manner in STEMI as compared to SA patients.

Impact of counterbalance between macrophage migration inhibitory factor and its inhibitor Gremlin-1 in patients with coronary artery disease

Objective: Monocyte infiltration is a critical step in the pathophysiology of plaque instability in coronary artery disease (CAD). Macrophage migration inhibitory factor (MIF) is involved in atherosclerotic plaque progression and instability leading to intracoronary thrombosis. Gremlin-1 (Grem1) has been recently identified as endogenous inhibitor of MIF. To date there are no data on the clinical impact of this interaction in cardiovascular patients. Methods and results: Plasma levels of MIF and Grem1 were determined by enzyme-linked immunoassay in patients with acute coronary syndromes (ACS, n = 120; stable CAD, n = 166 and healthy control subjects, n = 25). MIF levels were significantly increased in ACS compared to stable CAD and healthy control (ACS: median 2.85; IQR 3.52 ng/ml; versus SAP: median 1.22; IQR 2.99 ng/ml; versus healthy control: median 0.10; IQR 0.09 ng/ml, p < 0.001). Grem1 levels were significantly higher in ACS and stable CAD patients compared to healthy control (ACS: median 211.00; IQR 130.47 ng/ml; SAP: median 220.20; IQR 120.93 ng/ml, versus healthy control: median 90.57; IQR 97.68 ng/ml, p < 0.001). Grem1/MIF ratio was independently associated with ACS, whereas the single parameters were not associated with the presence of ACS. Furthermore, Grem1/MIF ratio was associated with angiographic signs of intracoronary thrombi and severity of thrombus burden. Conclusion: These novel findings suggest a potential role of Grem1/MIF ratio to indicate acuity of CAD and the grade of plaque stability. Prospective angiographic cohort studies involving plaque imaging techniques are warranted to further characterize the prognostic role of this novel risk marker in CAD patients.

Correlation between IL-7 and MCP-1 in diabetic chronic non healing ulcer patients at higher risk of coronary artery disease

Cytokines play an extremely important role in the pathogenesis of coronary artery disease (CAD) in which interleukin (IL)-7 is a major regulator of T-cell homeostasis which is conced in the stimulation of leukocyte–endothelial cell adhesion during inflammatory events. Circulating IL-7 is associated with activation of monocyte and natural killer cells, leading to enhanced production of inflammatory cytokines and chemokines observed in atherosclerosis and acute coronary syndromes. Plasma levels of IL-7, hs-CRP and monocyte chemoattractant protein (MCP)-1 were measured by an immunoenzymatic ELISA technique. Ninety neuropathic diabetic foot patients were divided into two groups: group B [those without CAD (n=45)] and group C [those with higher risk of CAD (n=45)]. Thirty-five healthy subjects were included as control (group H). Plasma concentration of IL-7, MCP-1 and hs-CRP were significantly higher in group C as compare with group H and B. Plasma IL-7 levels also showed significant positive correlations with plasma levels of hs-CRP and MCP-1. Abnormalities in lipid profile were also observed. In conclusion the positive correlation between plasma concentration of IL-7, MCP-1 and hs-CRP in diabetic foot patients observed herein, suggests a plausible role for IL-7 in the promotion of clinical instability in coronary artery disease.

Troponin-Specific Autoantibody Interference in Different Cardiac Troponin I Assay Configurations

Autoantibodies to cardiac troponins (cTnAAb) can interfere with the measurement of cardiac troponin I (cTnI) by immunoassays. The aim of this study was to explore the degree of cTnAAb interference in different cTnI assay configurations. Ternary troponin complex was added into samples (serum or plasma, n = 132, 68% cTnAAb positive) from individuals without known cardiac conditions. The recovery of cTnI was then measured with 6 investigational cTnI assays (2, 3, or 4 antibodies per assay). Three of these assays were then selected for further comparison by use of samples (plasma, n = 210, 33% cTnAAb positive) from non-ST-elevation acute coronary syndrome patients in the FRISC-II (FRagmin/Fast Revascularisation during InStability in Coronary artery disease) cohort. Finally, these results were compared to those obtained with 3 commercial cTnI assays. Analytical recoveries varied widely among the 6 investigational assays. Notably the low recoveries (median 9%) of the midfragment-targeting reference assay were normalized (median 103%) with the use of the 4-antibody assay construct (3 capture, 1 tracer antibody) with only 1 antibody against a midfragment epitope. Reduced analytical recoveries correlated closely with measured autoantibody amounts. cTnI concentrations from cTnAAb-positive patient samples determined with 3 investigational assays confirmed the reduced concentrations expected from the low analytical recoveries. The results from the commercial cTnI assays with antibody selections representative for contemporary assay constructs revealed a similar underestimation (up to 20-fold) of cTnI in cTnAAb-positive samples. A novel cTnI assay deviating from the conventional IFCC-recommended midfragment approach substantially improves cTnI detection in samples containing cTnAAbs.

Timing of Angiography With a Routine Invasive Strategy and Long-Term Outcomes in Non–ST-Segment Elevation Acute Coronary Syndrome: A Collaborative Analysis of Individual Patient Data From the FRISC II (Fragmin and Fast Revascularization During Instability in Coronary Artery Disease), ICTUS (Invasive Versus Conservative Treatment in Unstable Coronary Syndromes), and RITA-3 (Intervention Versus Conservative Treatment Strategy in Patients With Unstable Angina or

This study sought to investigate long-term outcomes after early or delayed angiography in patients with non-ST-segment elevation acute coronary syndrome (nSTE-ACS) undergoing a routine invasive management. The optimal timing of angiography in patients with nSTE-ACS is currently a topic for debate. Long-term follow-up after early (within 2 days) angiography versus delayed (within 3 to 5 days) angiography was investigated in the FRISC-II (Fragmin and Fast Revascularization During Instability in Coronary Artery Disease), ICTUS (Invasive Versus Conservative Treatment in Unstable Coronary Syndromes), and RITA-3 (Intervention Versus Conservative Treatment Strategy in Patients With Unstable Angina or Non-ST Elevation Myocardial Infarction) (FIR) nSTE-ACS patient-pooled database. The main outcome was cardiovascular death or myocardial infarction up to 5-year follow-up. Hazard ratios (HR) were calculated with Cox regression models. Adjustments were made for the FIR risk score, study, and the propensity of receiving early angiography using inverse probability weighting. Of 2,721 patients originally randomized to the routine invasive arm, consisting of routine angiography and subsequent revascularization if suitable, 975 underwent early angiography and 1,141 delayed angiography. No difference was observed in 5-year cardiovascular death or myocardial infarction in unadjusted (HR: 1.06, 95% confidence interval [CI]: 0.79 to 1.42, p=0.61) and adjusted (HR: 0.93, 95% CI: 0.75 to 1.16, p=0.54) Cox regression models. In the FIR database of patients presenting with nSTE-ACS, the timing of angiography was not related to long-term cardiovascular mortality or myocardial infarction. (Invasive Versus Conservative Treatment in Unstable Coronary Syndromes [ICTUS]; ISRCTN82153174. Intervention Versus Conservative Treatment Strategy in Patients With Unstable Angina or Non-ST Elevation Myocardial Infarction [the Third Randomised Intervention Treatment of Angina Trials (RITA-3)]; ISRCTN07752711).

Long-Term Cardiovascular Mortality After Procedure-Related or Spontaneous Myocardial Infarction in Patients With Non–ST-Segment Elevation Acute Coronary Syndrome

Background— The present study was designed to investigate the long-term prognostic impact of procedure-related and spontaneous myocardial infarction (MI) on cardiovascular mortality in patients with non–ST-elevation acute coronary syndrome. Methods and Results— Five-year follow-up after procedure-related or spontaneous MI was investigated in the individual patient pooled data set of the FRISC-II (Fast Revascularization During Instability in Coronary Artery Disease), ICTUS (Invasive Versus Conservative Treatment in Unstable Coronary Syndromes), and RITA-3 (Randomized Intervention Trial of Unstable Angina 3) non–ST-elevation acute coronary syndrome trials. The principal outcome was cardiovascular death up to 5 years of follow-up. Cumulative event rates were estimated by the Kaplan-Meier method; hazard ratios were calculated with time-dependent Cox proportional hazards models. Adjustments were made for the variables associated with long-term outcomes. Among the 5467 patients, 212 experienced a procedure-related MI within 6 months after enrollment. A spontaneous MI occurred in 236 patients within 6 months. The cumulative cardiovascular death rate was 5.2% in patients who had a procedure-related MI, comparable to that for patients without a procedure-related MI (hazard ratio 0.66; 95% confidence interval, 0.36–1.20, P =0.17). In patients who had a spontaneous MI within 6 months, the cumulative cardiovascular death rate was 22.2%, higher than for patients without a spontaneous MI (hazard ratio 4.52; 95% confidence interval, 3.37–6.06, P &lt;0.001). These hazard ratios did not change materially after risk adjustments. Conclusions— Five-year follow-up of patients with non–ST-elevation acute coronary syndrome from the 3 trials showed no association between a procedure-related MI and long-term cardiovascular mortality. In contrast, there was a substantial increase in long-term mortality after a spontaneous MI. Clinical Trial Registration— URL: http://www.controlled-trials.com/ISRCTN82153174 (ICTUS); http://www.controlled-trials.com/ISRCTN07752711 (RITA-3).

Red blood cell distribution width – a strong prognostic marker in cardiovascular disease – is associated with cholesterol content of erythrocyte membrane

Red blood cell distribution width (RDW), a measure of the variability in size of circulating erythrocytes, has recently been shown to be a strong predictor of adverse outcomes in patients with a great spectrum of cardiovascular disease. Recently, cholesterol content of erythrocytes membranes (CEM) has been associated with clinical instability in coronary artery disease whilst it has been linked with red blood cells (RBC) size and shape. Since the biological mechanisms underlying the association of higher RDW with cardiovascular mortality risk are currently unclear, we studied the association of CEM with RDW. 296 consecutive angina patients (236 men, mean age 69 ± 2 years) were prospectively assessed; 160 had chronic stable angina (CSA) and 136 had an acute coronary syndrome (ACS). Patients presenting with ACS had increased CEM levels (121.6 μg/mg (40.1) vs 74.4 μg/mg (26.6), p < 0.001) as well as exhibited greater anisocytosis (13.9% (0.9) vs 13.3% (0.7), p < 0.001) compared to patients with CSA. Simple correlation analysis showed that CEM levels were positively associated with RDW values (r = 0.320, p < 0.001). Multivariable linear regression showed that CEM levels were associated with RDW values independently from possible confounders (inflammatory, nutritional renal or hematological). Data from the present study showed an independent association between cholesterol content of erythrocyte membranes and anisocytosis. Increased CEM levels -a novel biomarker of clinical instability in CAD - may facilitate our understanding why RDW is associated with increased morbidity and mortality in cardiovascular disease.

Usefulness of the Admission Electrocardiogram to Predict Long-Term Outcomes After Non-ST-Elevation Acute Coronary Syndrome (from the FRISC II, ICTUS, and RITA-3 [FIR] Trials)

The aim of this study was to evaluate the independent prognostic value of qualitative and quantitative admission electrocardiographic (ECG) analysis regarding long-term outcomes after non-ST-segment elevation acute coronary syndromes (NSTE-ACS). From the Fragmin and Fast Revascularization During Instability in Coronary Artery Disease (FRISC II), Invasive Versus Conservative Treatment in Unstable Coronary Syndromes (ICTUS), and Randomized Intervention Trial of Unstable Angina 3 (RITA-3) patient-pooled database, 5,420 patients with NSTE-ACS with qualitative ECG data, of whom 2,901 had quantitative data, were included in this analysis. The main outcome was 5-year cardiovascular death or myocardial infarction. Hazard ratios (HRs) were calculated with Cox regression models, and adjustments were made for established outcome predictors. The additional discriminative value was assessed with the category-less net reclassification improvement and integrated discrimination improvement indexes. In the 5,420 patients, the presence of ST-segment depression (≥1 mm; adjusted HR 1.43, 95% confidence interval [CI] 1.25 to 1.63) and left bundle branch block (adjusted HR 1.64, 95% CI 1.18 to 2.28) were independently associated with long-term cardiovascular death or myocardial infarction. Risk increases were short and long term. On quantitative ECG analysis, cumulative ST-segment depression (≥5 mm; adjusted HR 1.34, 95% CI 1.05 to 1.70), the presence of left bundle branch block (adjusted HR 2.15, 95% CI 1.36 to 3.40) or ≥6 leads with inverse T waves (adjusted HR 1.22, 95% CI 0.97 to 1.55) was independently associated with long-term outcomes. No interaction was observed with treatment strategy. No improvements in net reclassification improvement and integrated discrimination improvement were observed after the addition of quantitative characteristics to a model including qualitative characteristics. In conclusion, in the FRISC II, ICTUS, and RITA-3 NSTE-ACS patient-pooled data set, admission ECG characteristics provided long-term prognostic value for cardiovascular death or myocardial infarction. Quantitative ECG characteristics provided no incremental discrimination compared to qualitative data.

Possible Role of Osteoprotegerin and Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand as Markers of Plaque Instability in Coronary Artery Disease

Osteoprotegerin (OPG) produced by cardiovascular system raising the possibility that alterations of OPG serum levels may be associated with coronary artery disease (CAD). Our aim is to assess the possible role of serum OPG and soluble tumor necrosis factor-related apoptosis-inducing ligand (s-TRAIL) in the pathology of CAD and their uses as markers of plaque stability. A total of 80 male participants were categorized into 3 groups: 28 patients with acute myocardial infarction (AMI), 32 established stable CAD, and 20 healthy controls were enrolled in this study. Acute myocardial infarction and CAD groups exhibited significantly higher OPG levels and lower s-TRAIL levels compared to the stable CAD and control participants. These results are aggravated as the number of affected coronary vessels increase in AMI and stable CAD groups. There is an association between raised serum OPG and reduced s-TRAIL in patients with CAD. Elevation of circulating OPG levels may represent a crucial compensatory mechanism to limit further vascular damage.

Long-Term Outcome of a Routine Versus Selective Invasive Strategy in Patients With Non–ST-Segment Elevation Acute Coronary Syndrome: A Meta-Analysis of Individual Patient Data

This study was designed to determine: 1) whether a routine invasive (RI) strategy reduces the long-term frequency of cardiovascular death or nonfatal myocardial infarction (MI) using a meta-analysis of individual patient data from all randomized studies with 5-year outcomes; and 2) whether the results are influenced by baseline risk. Pooled analyses of randomized trials show early benefit of routine intervention, but long-term results are inconsistent. The differences may reflect differing trial design, adjunctive therapies, and/or limited power. This meta-analysis (n = 5,467 patients) is designed to determine whether outcomes are improved despite trial differences. Individual patient data, with 5-year outcomes, were obtained from FRISC-II (Fragmin and Fast Revascularization during Instability in Coronary Artery Disease), ICTUS (Invasive Versus Conservative Treatment in Unstable Coronary Syndromes), and RITA-3 (Randomized Trial of a Conservative Treatment Strategy Versus an Interventional Treatment Strategy in Patients with Unstable Angina) trials for a collaborative meta-analysis. A Cox regression analysis was used for a multivariable risk model, and a simplified integer model was derived. Over 5 years, 14.7% (389 of 2,721) of patients randomized to an RI strategy experienced cardiovascular death or nonfatal MI versus 17.9% (475 of 2,746) in the selective invasive (SI) strategy (hazard ratio [HR]: 0.81, 95% confidence interval [CI]: 0.71 to 0.93; p = 0.002). The most marked treatment effect was on MI (10.0% RI strategy vs. 12.9% SI strategy), and there were consistent trends for cardiovascular deaths (HR: 0.83, 95% CI: 0.68 to 1.01; p = 0.068) and all deaths (HR: 0.90, 95% CI: 0.77 to 1.05). There were 2.0% to 3.8% absolute reductions in cardiovascular death or MI in the low- and intermediate-risk groups and an 11.1% absolute risk reduction in highest-risk patients. An RI strategy reduces long-term rates of cardiovascular death or MI and the largest absolute effect in seen in higher-risk patients.

Independent and additive predictive value of total cholesterol content of erythrocyte membranes with regard to coronary artery disease clinical presentation

Background A new mechanism for clinical instability in coronary artery disease (CAD) has been proposed where erythrocytes could play an active role in atherosclerotic plaque growth and rupture. Clinical studies showed increased total cholesterol levels in the membrane of circulating erythrocytes (CEM) in acute coronary syndrome (ACS) patients compared to patients with chronic stable angina (CSA). We investigated the independent and incremental discriminating value of CEM along with N-terminal propeptide of BNP (NT-proBNP), high sensitivity C-reactive protein (hs CRP), myeloperoxidase (MPO) and apolipoprotein B (apoB) with regard to CAD clinical presentation. Methods 519 consecutive angina patients were assessed; 252 had CSA (195 men, 62 ± 9 years) and 267 had ACS (213 men, 62 ± 10 years).CEM levels and serum concentrations of NT-proBNP, hs CRP, MPO and apoB were measured upon study admission. Results Simple logistic regression models showed that all biomarkers could distinguish ACS, nevertheless CEM with greater potency (OR 9.26 95%CI 6.31–13.59, p < 0.001). Multiple logistic regression models after adjustment for all the variables that were different between the 2 groups as well as for other biomarkers showed that CEM continued to be a significant and an independent predictor of ACS (OR 22.27 95%CI 10.63–46.67, p < 0.001). An increment of the C-statistic was also shown when CEM levels were incorporated in the predictive model (including traditional vascular risk factors and new well established biomarkers i.e. hs CRP, MPO, apoB and NT-proBNP). Conclusions The present study showed that CEM levels are associated with clinical instability in CAD patients in an independent and incremental manner.

5-Year Clinical Outcomes in the ICTUS (Invasive versus Conservative Treatment in Unstable coronary Syndromes) Trial: A Randomized Comparison of an Early Invasive Versus Selective Invasive Management in Patients With Non–ST-Segment Elevation Acute Coronary Syndrome

We present the 5-year clinical outcomes according to treatment strategy with additional risk stratification of the ICTUS (Invasive versus Conservative Treatment in Unstable coronary Syndromes) trial. Long-term outcomes may be relevant to decide treatment strategy for patients presenting with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) and elevated troponin T. We randomly assigned 1,200 patients to an early invasive or selective invasive strategy. The outcomes were the composite of death or myocardial infarction (MI) and its individual components. Risk stratification was performed with the FRISC (Fast Revascularization in InStability in Coronary artery disease) risk score. At 5-year follow-up, revascularization rates were 81% in the early invasive and 60% in the selective invasive group. Cumulative death or MI rates were 22.3% and 18.1%, respectively (hazard ratio [HR]: 1.29, 95% confidence interval [CI]: 1.00 to 1.66, p = 0.053). No difference was observed in mortality (HR: 1.13, 95% CI: 0.80 to 1.60, p = 0.49) or MI (HR: 1.24, 95% CI: 0.90 to 1.70, p = 0.20). After risk stratification, no benefit of an early invasive strategy was observed in reducing death or spontaneous MI in any of the risk groups. In patients presenting with NSTE-ACS and elevated troponin T, we could not demonstrate a long-term benefit of an early invasive strategy in reducing death or MI. (Invasive versus Conservative Treatment in Unstable coronary Syndromes [ICTUS]; ISRCTN82153174).

Growth-Differentiation Factor-15 for Long-Term Risk Prediction in Patients Stabilized After an Episode of Non–ST-Segment–Elevation Acute Coronary Syndrome

Growth-differentiation factor-15 (GDF-15) has emerged as a prognostic biomarker in patients with non-ST-segment-elevation acute coronary syndrome. This study assessed the time course and the long-term prognostic relevance of GDF-15 levels measured repetitively in patients with non-ST-segment-elevation acute coronary syndrome during 6 months after the acute event. GDF-15 and other biomarkers were measured at randomization, after 6 weeks, and after 3 and 6 months in 950 patients with non-ST-segment-elevation acute coronary syndrome included in the FRagmin and Fast Revascularization during InStability in Coronary artery disease II study. Study end points were death, recurrent myocardial infarction, and their composite during 5-year follow-up. Median GDF-15 levels decreased slightly from 1357 ng/L at randomization to 1302 ng/L at 6 months (P<0.001). GDF-15 was consistently related to cardiovascular risk factors and biochemical markers of hemodynamic stress, renal dysfunction, and inflammation. Moreover, GDF-15 was independently related to the 5-year risk of the composite end point when measured at both 3 months (adjusted hazard ratio, 1.8 [1.0 to 3.0]) and 6 months (adjusted hazard ratio, 2.3 [1.3 to 4.1]). Serial measurements of GDF-15 at randomization and 6 months helped to identify patient cohorts at different levels of risk, with patients with persistently elevated GDF-15 levels >1800 ng/L having the highest rate of the composite end point. GDF-15 is independently related to adverse events in non-ST-segment-elevation acute coronary syndrome both in the acute setting and for at least 6 months after clinical stabilization. Therefore, continued research on GDF-15 should be focused on the usefulness of GDF-15 for support of clinical management in acute and chronic ischemic heart disease.

Should We Manage Patients With Non-ST Segment Elevation Myocardial Infarction With Renal Failure With an Invasive Strategy?

Szummer and colleagues raise an important question: Should we manage patients presenting with non-ST-segment elevation myocardial infarction (NSTEMI) with an early invasive strategy?1 It makes good sense to do this. We know that patients with renal dysfunction are at high risk,2 and the American College of Cardiology/American Heart Association and European Society of Cardiology guidelines both recommend an early invasive strategy for patients with unstable angina/NSTEMI who are high risk.3,4 Neither guideline, however, specifically notes that renal dysfunction should be a specific indication for an invasive strategy. Article see p 851 The investigators analyzed 23262 consecutive NSTEMI patients who had been included in a nationwide coronary care unit registry between 2003 and 2006 called the Swedish Web System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART).1 Patients were divided into medically or invasively treated if revascularized within 14 days of admission. They found that for patients with worse renal function, the rate of performing revascularization was lower. This “risk paradox” has been seen in other registries, in which higher-risk patients are actually managed less intensively.5 They also found that 1-year mortality was substantially higher for those on dialysis or having an estimated glomerular filtration rate (GFR) <15 mL/min (≈55%) versus ≈40% for those with estimated GFR 15 to 29 mL/min and <5% for those with normal renal function. Thus, estimated GFR is clearly an important risk marker. They went on to compare mortality between medically managed patients and those who had revascularization and found overall a difference in mortality, with 36% lower adjusted mortality among those who had revascularization. They then split out the group by baseline renal function and found a lower mortality for those who had been revascularized versus not in most groups but not …

Prognostic Value of Biomarkers During and After Non–ST-Segment Elevation Acute Coronary Syndrome

The aim of this study was to assess risk prediction by different biomarkers in patients with an ongoing non-ST-segment elevation acute coronary syndrome (NSTE-ACS) and after clinical stabilization. Different biomarkers reflect different aspects of the pathobiology in NSTE-ACS. However, there is little information regarding their relative prognostic value during the time course of disease. The N-terminal pro-brain natriuretic peptide (NT-proBNP), C-reactive protein (CRP), cardiac troponin I (cTnI), and the estimated glomerular filtration rate (eGFR) were measured at randomization and after 6 weeks and 6 months in 877 NSTE-ACS patients included in the FRISC (FRagmin and fast revascularization during InStability in Coronary artery disease) II trial. The biomarkers' prognostic value during 5-year follow-up was evaluated by Cox regression models, calculation of the c-statistics, and estimation of the net reclassification improvement (NRI). Among the biomarkers measured at randomization, NT-proBNP was the strongest predictor for mortality (adjusted hazard ratio [HR]: 1.7; 95% confidence interval [CI]: 1.3 to 2.1; p < 0.001). Even during follow-up, NT-proBNP demonstrated the strongest association to the composite end point of death/myocardial infarction (adjusted HR at 6 weeks: 1.5; 95% CI: 1.3 to 1.7; p < 0.001; adjusted HR at 6 months: 1.4; 95% CI: 1.2 to 1.7; p = 0.001). Even CRP was independently predictive at 6 months for the composite end point (adjusted HR: 1.3; 95% CI: 1.1 to 1.5; p = 0.003). Only 6-week results of NT-proBNP provided significant incremental prognostic value to established risk indicators regarding the composite end point (c-statistics 0.69 [p = 0.03]; NRI 0.11 [p = 0.03]). The NT-proBNP is an independent risk predictor in patients with ongoing NSTE-ACS and after clinical stabilization. The CRP exhibits increasing predictive value at later measurements. However, only NT-proBNP provided incremental prognostic value and might therefore be considered as a complement for early follow-up controls after NSTE-ACS.

Value of Cardiac Troponin I Cutoff Concentrations below the 99th Percentile for Clinical Decision-Making

The aim of this study was to evaluate factors influencing the 99th percentile for cardiac troponin I (cTnI) when this cutoff value is established on a highly sensitive assay, and to compare the value of this cutoff to that of lower cutoffs in the prognostic assessment of patients with coronary artery disease. We used the recently refined Access AccuTnI assay (Beckman-Coulter) to assess the distribution of cTnI results in a community population of elderly individuals [PIVUS (Prospective Study of the Vasculature in Uppsala Seniors) study; n = 1005]. The utility of predefined cTnI cutoffs for risk stratification was then evaluated in 952 patients from the FRISC II (FRagmin and Fast Revascularization during InStability in Coronary artery disease) study at 6 months after these patients had suffered acute coronary syndrome. Selection of assay results from a subcohort of PIVUS participants without cardiovascular disease resulted in a decrease of the 99th percentile from 0.044 microg/L to 0.028 microg/L. Men had higher rates of cTnI elevation with respect to the tested thresholds. Whereas the 99th percentile cutoff was not found to be a useful prognostic indicator for 5-year mortality, both the 90th percentile (hazard ratio 3.1; 95% CI 1.9-5.1) and the 75th percentile (hazard ratio 2.8; 95% CI 1.7-4.7) provided useful prognostic information. Sex-specific cutoffs did not improve risk prediction. The 99th percentile of cTnI depends highly on the characteristics of the reference population from which it is determined. This dependence on the reference population may affect the appropriateness of clinical conclusions based on this threshold. However, cTnI cutoffs below the 99th percentile seem to provide better prognostic discrimination in stabilized acute coronary syndrome patients and therefore may be preferable for risk stratification.

Pathophysiologic mechanisms of persistent cardiac troponin I elevation in stabilized patients after an episode of acute coronary syndrome

Recently, a high prevalence of small persistent cardiac troponin I (cTnI) elevations has been reported in patients who had been stabilized after a recent episode of acute coronary syndrome (ACS). We now have studied the associations of persistently elevated cTnI levels to cardiac performance, inflammation, coagulation, coronary status, and treatment strategy in these patients. Cardiac troponin I was determined at 6 weeks, 3 months, and 6 months after randomization in 898 stabilized ACS patients from the FRagmin and Fast Revascularization during InStability in Coronary artery disease (FRISC) II trial and using the high-sensitive Access AccuTnI assay (Beckman Coulter, Fullerton, CA). All patients were followed up for at least 5 years. Persistent cTnI elevation >0.01 microg/L at the 3 measurement instances was detected in 233 patients (26%). N-terminal pro-brain natriuretic peptide (NT-proBNP) at 6 months (OR 2.5, 95% CI 2.0-3.1), male sex (OR 2.2, 95% CI 1.4-3.7), and randomization to an early invasive strategy (OR 1.8, 95% CI 1.2-2.7) independently predicted persistently elevated cTnI levels. Persistently cTnI-positive patients in the invasive cohort had significantly lower NT-proBNP levels compared to noninvasively treated patients, indicating that the mechanisms causing cTnI elevation in this group may be prognostically less harmful. No independent associations were found for markers of inflammation or coagulation. Persistent cTnI elevation occurs frequently late after an ACS. The NT-proBNP level at 6 months was the strongest predictor for elevated cTnI levels that thus appear to be predominantly related to impaired left ventricular function.

Persistent Cardiac Troponin I Elevation in Stabilized Patients After an Episode of Acute Coronary Syndrome Predicts Long-Term Mortality

In patients with non-ST-elevation acute coronary syndrome, any troponin elevation is associated with an increased risk for cardiovascular events. However, the prevalence and prognostic importance of persistent troponin elevation in stabilized patients after an episode of non-ST-elevation acute coronary syndrome are unknown and were therefore assessed in this study. Cardiac troponin I (cTnI) was measured in 1092 stabilized patients at 6 weeks and 3 and 6 months after enrollment in the FRagmin and Fast Revascularization during InStability in Coronary artery disease (FRISC-II) trial. cTnI was analyzed with the Access AccuTnI assay with the application of different prognostic cutoffs. Outcomes were assessed through 5 years. Elevated cTnI levels >0.01 microg/L were found in 48% of the study patients at 6 weeks, in 36% at 6 months, and in 26% at all 3 measurements. cTnI elevation was associated with increased age and other cardiovascular high-risk features. The lowest tested cTnI cutoff (0.01 microg/L) was prognostically most useful and was independently predictive of mortality (hazard ratio, 2.1 [95% confidence interval, 1.3 to 3.3]; P=0.001) on multivariable analysis adjusted for cardiovascular risk factors and randomization to an invasive versus noninvasive treatment strategy, whereas it was related to myocardial infarction only on univariate analysis. Persistent minor cTnI elevation can be detected frequently in patients stabilized after an episode of non-ST-elevation acute coronary syndrome with the use of a sensitive assay. Elevated cTnI levels >0.01 microg/L predict mortality during long-term follow-up. Our results emphasize the importance of further troponin testing in non-ST-elevation acute coronary syndrome patients after hospital discharge.

Growth Differentiation Factor 15 for Risk Stratification and Selection of an Invasive Treatment Strategy in Non–ST-Elevation Acute Coronary Syndrome

An invasive treatment strategy improves outcome in patients with non-ST-elevation acute coronary syndrome at moderate to high risk. We hypothesized that the circulating level of growth differentiation factor 15 (GDF-15) may improve risk stratification. The Fast Revascularization during InStability in Coronary artery disease II (FRISC-II) trial randomized patients with non-ST-elevation acute coronary syndrome to an invasive or conservative strategy with a follow-up for 2 years. GDF-15 and other biomarkers were determined on admission in 2079 patients. GDF-15 was moderately elevated (between 1200 and 1800 ng/L) in 770 patients (37.0%), and highly elevated (>1800 ng/L) in 493 patients (23.7%). Elevated levels of GDF-15 independently predicted the risk of the composite end point of death or recurrent myocardial infarction in the conservative group (P=0.016) but not in the invasive group. A significant interaction existed between the GDF-15 level on admission and the effect of treatment strategy on the composite end point. The occurrence of the composite end point was reduced by the invasive strategy at GDF-15 levels >1800 ng/L (hazard ratio, 0.49; 95% confidence interval, 0.33 to 0.73; P=0.001), between 1200 and 1800 ng/L (hazard ratio, 0.68; 95% confidence interval, 0.46 to 1.00; P=0.048), but not <1200 ng/L (hazard ratio, 1.06; 95% confidence interval, 0.68 to 1.65; P=0.81). Patients with ST-segment depression or a troponin T level >0.01 microg/L with a GDF-15 level <1200 ng/L did not benefit from the invasive strategy. GDF-15 is a potential tool for risk stratification and therapeutic decision making in patients with non-ST-elevation acute coronary syndrome as initially diagnosed by ECG and troponin levels. A prospective randomized trial is needed to validate these findings.

Raised interleukin-10 is an indicator of poor outcome and enhanced systemic inflammation in patients with acute coronary syndrome

Objectives:To re-evaluate the relation between plasma interleukin-10 (IL-10) concentration at hospital admission and outcome and to investigate the impact of single nucleotide polymorphisms (SNP) in the IL-10 gene in patients...