Juha Lund

Circulating Pregnancy-Associated Plasma Protein A Predicts Outcome in Patients With Acute Coronary Syndrome but No Troponin I Elevation

Background—Risk stratification in troponin (cTn)-negative acute coronary syndrome (ACS) remains a clinical challenge. We investigated the predictive value of circulating pregnancy-associated plasma protein A (PAPP-A), a novel marker of atherosclerotic plaque activity, in these patients. Methods and Results—Two hundred consecutive hospitalized ACS patients were included, of whom 136 (69 men and 67 women; mean±SD age, 66±16 years) remained cTnI-negative for up to 24 hours. PAPP-A was measured at admission, 6 to 12 hours, and 24 hours. During 6-month follow-up, 26 (19.1%) of the cTnI-negative patients reached a primary end point (cardiovascular death, myocardial infarction, or revascularization). At a cutoff level of 2.9 mIU/L, elevated PAPP-A was an independent predictor of adverse outcome (adjusted risk ratio [RR], 4.6; 95% confidence interval, 1.8 to 11.8; P =0.002). Another independent predictor was admission CRP >2.0 mg/L (RR, 2.6; P =0.03). Conclusions—Measurement of plasma PAPP-A, a zinc-binding matrix metalloproteinase, is a strong independent predictor of ischemic cardiac events and need of revascularization in patients who present with suspected myocardial infarction but remain troponin negative.

Pregnancy‐associated plasma protein A: A biomarker in acute ST‐elevation myocardial infarction (STEMI)

Background. Elevated circulating levels of pregnancy‐associated plasma protein A (PAPP‐A), a novel marker of atherosclerotic plaque instability, are associated with increased risk of future cardiac events in patients with acute coronary syndromes (ACS). However, little is known of the kinetics or clinical significance of circulating PAPP‐A after plaque rupture in acute ST‐elevation myocardial infarction (STEMI). Aim. To evaluate the 48‐hour release of pregnancy‐associated plasma protein A (PAPP‐A) and its association with 12‐month outcome in patients with acute ST‐elevation myocardial infarction (STEMI). Methods. Sixty‐two consecutive STEMI patients were included (40 men and 22 women, median age 67.5 years (range 34–84)), of whom 54 (87.1%) received reperfusion therapy. PAPP‐A was measured at admission and 6–12, 24 and 48 hours thereafter. In 14 patients, samples were obtained also at 1, 2 and 4 hours. Results. There was an early peak of circulating PAPP‐A during the first 12 hours from symptom onset, followed by rapid normalization. A second, late PAPP‐A elevation was noticed in 20/62 patients (32.3%). Admission PAPP‐A >10.0 mIU/L (highest tertile) was associated (P = 0.049) with increased 12‐month risk of cardiovascular death or non‐fatal myocardial infarction. Moreover, the combination of failed early reperfusion together with late PAPP‐A elevation was strongly (7/13 versus 10/49 patients, P = 0.016) associated with adverse outcome. Admission PAPP‐A did not correlate with admission C‐reactive protein or cardiac troponin I. Conclusions. PAPP‐A is elevated early in STEMI and then declines rapidly, a pattern consistent with release from the ruptured plaque. The variability of PAPP‐A kinetics at 48 hours reflects the success of reperfusion. This study also shows that PAPP‐A may have prognostic value in STEMI.

Early markers of myocardial injury: cTnI is enough☆

BACKGROUND We compared the early diagnostic and prognostic performance of a highly sensitive cardiac troponin I (cTnI) assay with heart-type fatty acid binding protein (H-FABP), in the early hours of acute coronary syndrome. METHODS Serum samples of 293 patients were studied using the Abbott Architect cTnI assay and the H-FABP assay. Special attention was paid to the diagnostic and prognostic value of admission blood samples taken <24 h after symptom onset. The prognostic endpoint was total mortality and reinfarction at 6 months. RESULTS To detect forthcoming myocardial injury, admission samples gave receiver operating curve (ROC) areas (AUC) of 0.908 for cTnI and 0.855 for H-FABP (p=0.068) when the delay from symptom onset was <6 h (60.4% of all patients). When the delay was 6-24 h, the corresponding AUC values were 0.995 for cTnI and 0.849 for H-FABP (p=0.002). In multivariate analysis cTnI but not H-FABP predicted adverse events in all 293 patients (RR 3.02, 95% CI 1.62-5.63) and in those with delays <6 h (RR 2.92, 95% CI 1.47-5.81). CONCLUSION In the era of highly sensitive cTnI assays, H-FABP appears to give no additional information even in patients who present within the first 6 h after acute MI.

Clinical and laboratory risk factors of thrombotic complications after pacemaker implantation: a prospective study

AIMS Venous lesions, including obstruction and thromboembolism (VTE), are not uncommon after pacemaker implantation. The purpose of this prospective study was to assess the role of various patient and procedure-related risk factors in the development of these complications. METHODS AND RESULTS A prospective venography-based study of 150 consecutive pacemaker implantations with a 6-month follow-up was conducted. Current case-control study included all cases (n = 47) with a new venous lesion, and their matched controls. Several surgical and technical factors, i.e. lead burden, choice of venous access, operator experience and procedure duration, as well as patient-related classic risk factors of VTE were assessed. Plasma markers of coagulation and endothelial activation [prothrombin fragment 1 + 2 (F1 + 2), D-dimer (DD), von Willebrand factor (vWF), thrombomodulin (Tm)] were used to evaluate the extent of acute surgical trauma. All cases with venous lesions were also screened for thrombophilia. None of the procedure-related variables were predictive of VTE. Mean levels of vWF, F1 + 2 and DD increased significantly (P < 0.001) and equally in both cases and controls. No single clinical factor predicted venous lesions, but significant (P < 0.05) clustering of classic clinical VTE risk factors was seen among the cases. Thrombophilia was overrepresented in patients with symptomatic pulmonary embolism (2/5, 40%). CONCLUSION Pacemaker implantation induces a transient hypercoagulable state, but its degree does not predict subsequent venous thromboembolism, and neither did the grade of endothelial damage as reflected by plasma markers. The aetiology of these lesions seems to be multifactorial, and clustering of classic thrombotic risk factors plays a role in the pathogenesis.

Safety of pacemaker and implantable cardioverter–defibrillator implantation during uninterrupted warfarin treatment — The FinPAC study

BACKGROUND Periprocedural management of oral anticoagulation (OAC) in patients undergoing cardiac rhythm management (CRM) device implantation is controversial. Prior studies demonstrate that uninterrupted OAC may be safe, but limited data from randomized trials exist. METHODS We conducted a multicenter, randomized trial to evaluate the safety of uninterrupted OAC during CRM device implantation. Patients on long-term warfarin (N=213) treatment with contemporary indication for CRM device implantation were randomized to uninterrupted versus interrupted (2 days) OAC therapy. The primary outcome included major bleeding events necessitating additional intervention and thromboembolic events during 4 weeks follow-up. RESULTS The randomized groups were well matched in terms of bleeding and thromboembolic risk. Only one (1%) patient in the uninterrupted OAC group (N=106) needed blood transfusion due to rupture of proximal cephalic vein. Large hematomas were detected in 6% of patients in both groups, but there was no need for pocket revision in either group. Any pocket hematoma was observed in 35 patients (33%) in the uninterrupted OAC group and in 43 patients (40%) with interrupted OAC and uninterrupted OAC strategy was non-inferior to interrupted OAC (HR 0.86, 95%, p=0.001 for non-inferiority). One patient with interrupted OAC had stroke 3 days after the procedure. Hospital stay was comparable in all patient groups. CONCLUSION Our randomized study demonstrates that CRM devices can be safely implanted without discontinuation of warfarin treatment.

Free vs Total Pregnancy-Associated Plasma Protein A (PAPP-A) as a Predictor of 1-Year Outcome in Patients Presenting with Non-ST-Elevation Acute Coronary Syndrome

BACKGROUND The free fraction of pregnancy-associated plasma protein A (FPAPP-A) was found to be the PAPP-A form released to the circulation in acute coronary syndrome (ACS). We estimated the prognostic value of FPAPP-A vs total PAPP-A (TPAPP-A) concentrations in forecasting death and nonfatal myocardial infarction (combined endpoint) in patients with non-ST-elevation ACS. METHODS We recruited 267 patients hospitalized for symptoms consistent with non-ST-elevation ACS and followed them for 12 months. FPAPP-A, TPAPP-A, C-reactive protein (CRP), and cardiac troponin I (cTnI) were measured at admission; cTnI was also measured at 6-12 h and 24 h. Because of the recently shown interaction between PAPP-A and heparin, we excluded patients treated with any heparin preparations before the admission blood sampling. RESULTS During the follow-up, 57 (21.3%) patients met the endpoint (22 deaths and 35 nonfatal myocardial infarctions). According to FPAPP-A (<1.27, 1.27-1.74, >1.74 mIU/L) and TPAPP-A (<1.98, 1.98-2.99, >2.99 mIU/L) tertiles, this endpoint was met by 12 (13.5%), 18 (20.2%), 27 (30.3%) (P = 0.02), and 17 (19.1%), 17 (19.1%), 23 (25.8%) (P = 0.54) patients, respectively. After adjusting for age, sex, diabetes, previous myocardial infarction, and ischemic electrocardiogram (ECG) findings, FPAPP-A >1.74 mIU/L [risk ratio (RR) 2.0; 95% CI 1.0-4.1, P = 0.053), increased cTnI, and CRP >/=2.0 mg/L were independent predictors of an endpoint. The prognostic performance of TPAPP-A was inferior to that of FPAPP-A. CONCLUSIONS FPAPP-A seems to be superior as a prognostic marker compared to TPAPP-A, giving independent and additive prognostic information when measured at the time of admission in patients hospitalized for non-ST-elevation ACS.

The Etiology and Prognostic Significance of Cardiac Troponin I Elevation in Unselected Emergency Department Patients

BACKGROUND Cardiac troponin elevations are associated not only with acute coronary syndromes (ACS) but also with multiple other cardiac and non-cardiac conditions. STUDY OBJECTIVES To investigate the etiology and clinical significance of cardiac troponin I elevations in an unselected Emergency Department (ED) patient cohort. METHODS The study population consisted of 991 consecutive troponin-positive patients admitted to the ED of a university hospital with ACS as the presumptive diagnosis. Cardiac troponin I was measured on admission and a follow-up sample was obtained at 6-12 h. Clinical diagnosis was ascertained retrospectively using all the available information including electrocardiogram, clinical data, laboratory tests, and available coronary angiograms. RESULTS At admission, 805 (81.2%) patients were already troponin positive; of these, the troponin elevation was related to myocardial infarction (MI) in 654 (81.2%) patients. Finally, 83.0% of the troponin elevations were due to MI, 7.9% were related to other cardiac causes, and 9.1% to non-cardiac diseases. The leading non-cardiac causes were pulmonary embolism, renal failure, pneumonia, and sepsis. Non-cardiac patients with elevated troponin I at admission showed significantly higher in-hospital mortality (26.7% vs. 13.4%, p = 0.002) compared to cardiac patients. CONCLUSION Elevated troponin levels for reasons other than MI are common in the ED and are a marker of poor in-hospital prognosis.

Cystatin C as a predictor of all-cause mortality and myocardial infarction in patients with non-ST-elevation acute coronary syndrome

OBJECTIVES To investigate the predictive value of cystatin C among patients diagnosed with non-ST-elevation acute coronary syndrome (nSTE-ACS). DESIGN AND METHODS Admission serum samples from 245 nSTE-ACS patients were measured with a novel cystatin C immunoassay based on a dry-reagent, double monoclonal design. Creatinine concentrations, estimated glomerular filtration rates (eGFR) and one-year follow-up data were available for these patients. RESULTS During the follow-up period, 34 (14%) of patients had myocardial infarction (MI) and 25 (11%) died. Increased serum cystatin C was an independent predictor of all-cause mortality and combined events (all-cause mortality and MI) after adjustment to non-biomarker baseline factors, hazard ratio (HR) 2.19 (per increase of 1 tertile; 95% Cl 1.28-3.78, p=0.0046) and 1.75 (1.22-2.51, p=0.0024), respectively. Corresponding values for eGFR were 2.56 (1.43-4.59, p=0.0016) and 1.76 (1.23-2.53, p=0.0022), respectively. Creatinine was not an independent predictor of endpoints (p>0.05). CONCLUSIONS Cystatin C was associated with an increased risk of death and combined events in patients with nSTE-ACS.

Improved early risk stratification and diagnosis of myocardial infarction, using a novel troponin I assay concept

Background  We evaluated the clinical performance of a novel cardiac troponin I (cTnI) assay specifically designed to improve the very early risk stratification in acute coronary syndromes.

Autoantibody prevalence with an improved immunoassay for detecting cardiac troponin-specific autoantibodies.

Abstract Background: Cardiac troponin-specific autoantibodies (cTnAAb) can interfere with the measurement of cardiac troponin I (cTnI) by immunoassays used for the diagnosis of myocardial infarction (MI). Here, an improved version of a previous autoantibody assay was validated and used to evaluate the cTnAAb prevalence in a cohort of consecutive chest pain patients presenting to an emergency department. Methods: Admission samples from 510 patients with suspected MI were analyzed in parallel with two sandwich-type cTnAAb assays based on different cTnI epitopes used to capture cardiac troponin-bound cTnAAbs. Results: Sample-specific backgrounds were lower for the new assay than for the old assay (median 1225 vs. 2693 counts, p<0.001). Net signals of cTnAAb-positive samples were higher for the new assay than for the old assay (median 5076 vs. 3921 counts, p<0.001). Of all patients, 9.2% were cTnAAb-positive for the new assay and 7.3% for the old assay (p=0.013). Previous cardiac problems were not associated with cTnAAb status and cTnAAb status did not correlate with the 12-month outcome. Conclusions: With our new and more sensitive autoantibody assay, approximately one out of ten patients who presented to the initial cardiac triage had detectable amounts of cTnAAbs in the circulation. Because these cTnAAbs can interfere with state-of-the-art cTnI assays, their high prevalence should be acknowledged by clinical chemists, physicians, and kit manufacturers.