Conventional Cardiac Biomarkers Research Articles

CA-125 concentrations are associated with renal function decline but not congestion or prognosis in patients with chronic heart failure: results from EMPEROR-POOLED

Abstract Background Carbohydrate antigen 125 (CA-125, also described as cancer antigen 125), has emerged as a candidate biomarker of congestion in heart failure (HF). Effects of sodium/glucose cotransporter-2 inhibitor therapy on CA-125 and its role as a prognostic measure in HF remains uncertain. Purpose In study participants from the EMPEROR-Preserved and EMPEROR-Reduced trials, across a wide spectrum of ejection fraction (EF) and renal function, we sought to investigate associations between CA-125 and congestion, the effect of empagliflozin on CA-125 concentrations, and the ability of the biomarker to predict cardio-renal outcomes. Methods 1111 patients with HF and available biomarker data were included into this analysis. Serum CA-125 was measured at baseline, 12 and 52 weeks using an Electroluminescence assay. The measurements were performed within a biomarker research agreement of Boehringer Ingelheim, the sponsor of these trials and Roche Diagnostics International Ltd. Congestion signs or symptoms were evaluated across CA-125 tertiles. A mixed model for repeated measurements was used to compare the treatment effects on CA-125. Multivariable analyses adjusted for the prespecified EMPEROR baseline variables plus N-terminal pro-B type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) were used to examine the association of CA-125 with HF hospitalization or cardiovascular (CV) death and estimated glomerular filtration rate (eGFR) slope. Results Across CA-125 tertiles at baseline, no significant association was present with HF symptom severity, jugular vein distention, pulmonary rales, S3 gallop or peripheral oedema (all p-values >0.10). Treatment with empagliflozin was associated with 7% greater reduction of CA-125 level versus placebo to week 12 (adjusted geometric mean ratio: 0.93; 95% confidence interval [CI], 0.87-0.99, p = 0.03) but not to week 52 (adjusted geometric mean ratio: 0.97, 95% CI 0.90-1.06; p = 0.50). No significant association was found for tertiles of CA-125 at baseline with the risk of CV death/HF hospitalization; with a hazard ratio (HR) for higher vs lower CA-125 tertiles of 1.34 (95% CI 0.91–1.96). In the same model NT-proBNP and hs-cTnT were strongly prognostic (both p-values <0.0001). Compared to lower tertiles, study participants in the third CA-125 tertile had higher rate of kidney function decline with a more negative eGFR slope (p for trend = 0.03). Conclusion In chronic HF, across a wide range of EF and of renal function, CA-125 levels were not strongly associated with clinical signs or symptoms of congestion. Empagliflozin lowered CA-125 levels more than placebo at week 12 but not at week 52. Among individuals with HF, CA-125 concentrations did not provide additional prognostic information for CV death/HF hospitalization beyond conventional cardiac biomarkers but may predict subsequent kidney function decline.

Elevated levels of apelin predict favorable clinical course of heart failure in type 2 diabetes mellitus patients

Abstract Funding Acknowledgements Type of funding sources: None. Background Apelin is a regulatory peptide having positive inotrope and reparative abilities. Type 2 diabetes mellitus (T2DM) is common comorbidity that is associated to occurrence of HF mainly HF with preserved ejection fraction (HFpEF). The discriminative potency of conventional cardiac biomarkers such as natriuretic peptides in HFpEF was found to be sufficiently lower compared to HF with reduced / mildly reduced ejection fraction (HFrEF / HFmrEF). The aim of the study was to investigate whether serum levels of apelin predict HF in patients with T2DM. Methods A total of 108 HF patients (left ventricular ejection fraction [LVEF] <60%) with T2DM were prospectively involved in the study. Entire HF population consisted of 58 HFpEF patients and 50 HFmrEF / HFrEF aged from 41 to 62 years. Cardiac hemodynamic performances were obtained by B-mode echocardiography, Doppler and TDI. The levels of apelin, N-terminal pro-brain natriuretic peptide (NT-proBNP), high sensitive troponin T (hs-TnT) were measured by ELISA. Combined end-point for the study were defined as all-cause death and any non-fatal cardiovascular event or HF hospitalization during 52 weeks. Results The combined end-point occurred in 37 patients (34.3%) from entire population. The levels of apelin in patients who had the combined end-point were significantly lower (3.55 ng/mL, 95% confidence interval [CI]=3.12-3.95 ng/mL) compared with those who did not meet it (5.60 ng/mL; 95% CI = 4.10-7.10 ng/mL; P=0.001). ROC curve revealed that the best-balanced cut-off point for apelin levels, which predicted combined end-point occurrence, was 3.88 ng/mL (AUC=0.82; P=0.001). Cox regression showed that apelin levels > 3.55 ng/mL (Odds Ratio [OR]= 2.02; 95% CI=1.14-3.25; P=0.001), LVEF< 49% (OR=1.48; 95% CI=1.22-1.68, P = 0.001), NT-proBNP > 785 ng/mL (OR =2.08; 95% CI = 1.03–4.12; P = 0.001), global longitudinal strain < -8.6% (OR =2.02; 95% CI = 1.09–3.10; P = 0.001), hs-TnT > 0.4 ng/mL (OR=1.98; 95% CI=1.10-2.93; P=0.001), estimated glomerular filtration rate <60 mL/min/1.73 m2 (OR=1.46; 95% CI=1.09-2.55; P=0.001) and history of atrial fibrillation (OR=1.14; 95% CI=1.02-1.80; P=0.001) predicted the combined end-point. After adjustment for HFpEF, apelin levels > 3.55 ng/mL (OR=2.03; 95% CI=1.10-3.20; P=0.001) and NT-proBNP > 785 ng/mL (OR =2.10; 95% CI = 1.05–3.80; P = 0.001) remain independent predictors for the combined end-point. The addition of apelin to the ABC model (NT-proBNP > 785 ng/mL) improved the relative integrated discrimination indices by 10.5% and net-reclassification improvement for 11.5% for combined end-point. Kaplan – Meier curve showed that patients having the levels of apelin >3.55 ng/mL demonstrated better clinical course of HF compared with those who had lower apelin levels (log rank test p=0.001). In conclusion: We found that apelin levels >3.55 ng/mL regardless of NT-proBNP had positive discriminative ability for clinical course of HF in T2DM patients.

S100A1 is a sensitive and specific cardiac biomarker for early diagnosis and prognostic assessment of acute myocardial infarction measured by chemiluminescent immunoassay

BackgroundA member of the S100 family of Ca2+-binding proteins, S100A1 is highly expressed in cardiac muscle tissue. Although this protein is considered an indicator of acute myocardial infarction (AMI), high-throughput and sensitive detection methods are still urgently needed. We constructed a rapid and sensitive method for detecting S100A1 and to investigate the clinical utility of S100A1 as a biomarker for the early diagnosis of AMI and subsequent prognostic assessments. We developed an automated chemiluminescent immunoassay to detect S100A1. We then analyzed the performance of the newly developed assay including evaluation of the analytical sensitivity, analytical selectivity, linear range, accuracy and repeatability. MethodsWe recruited 87 patients with AMI or angina pectoris to explore the value of this marker for the early diagnosis and prognostic assessment. ResultsThe chemiluminescent-immune-based S100A1 assay had functional analytical sensitivity with a detection limit of 0.13 ng/ml, and a wide linear range of 0.13–31.66 ng/ml. It also exhibited good repeatability with intra-assay and inter-assay findings of <5% and <15%, respectively. Plasma S100A1 was found to have a higher diagnostic sensitivity than conventional cardiac biomarkers (creatine kinase-MB and cardiac troponin T). The survival analysis showed that a higher concentration of plasma S100A1 (>1.02 ng/ml) was notably associated with the poor prognosis of AMI patients after first PCI. ConclusionsMeasurement of circulating S100A1 concentrations with our newly developed chemiluminescent-immune-based assay shows potential for use in the clinic. This assay could enable early identification and prognostic assessment of AMI.

Circulating Cardiac Biomarkers in Diabetes Mellitus: A New Dawn for Risk Stratification-A Narrative Review.

The aim of this narrative review is to update the current knowledge on the differential choice of circulating cardiac biomarkers in patients with prediabetes and established type 2 diabetes mellitus (T2DM). There are numerous circulating biomarkers with unconfirmed abilities to predict clinical outcomes in pre-DM and DM individuals; the prognostication ability of the cardiac biomarkers reported here has been established, and they are still being studied. The conventional cardiac biomarkers, such as natriuretic peptides (NPs), soluble suppressor tumorigenisity-2, high-sensitivity circulating cardiac troponins and galectin-3, were useful to ascertain cardiovascular (CV) risk. Each cardiac biomarker has its strengths and weaknesses that affect the price of usage, specificity, sensitivity, predictive value and superiority in face-to-face comparisons. Additionally, there have been confusing reports regarding their abilities to be predictably relevant among patients without known CV disease. The large spectrum of promising cardiac biomarkers (growth/differential factor-15, heart-type fatty acid-binding protein, cardiotrophin-1, carboxy-terminal telopeptide of collagen type 1, apelin and non-coding RNAs) is discussed in the context of predicting CV diseases and events in patients with known prediabetes and T2DM. Various reasons have been critically discussed related to the variable findings regarding biomarker-based prediction of CV risk among patients with metabolic disease. It was found that NPs and hs-cTnT are still the most important tools that have an affordable price as well as high sensitivity and specificity to predict clinical outcomes among patients with pre-DM and DM in routine clinical practice, but other circulating biomarkers need to be carefully investigated in large trials in the future.

Serum proteome profiling in canine chronic valve disease using a TMT-based quantitative proteomics approach

Chronic valve disease (CVD) is the most common clinically significant heart disease of dogs, affecting 20 to 40% of dogs. The aim of this study was to evaluate the serum protein profile of healthy and CVD affected dogs, by means of an isobaric tandem mass tag (TMT) label-based high-resolution quantitative proteomic approach. Additionally, conventional cardiac biomarkers were measured in the serum, functional bioinformatics analysis was employed for elucidating molecular mechanisms and pathways associated with CVD, and validation of proteomic results was performed by immunoassays and Western blotting. Of 290 identified and quantified proteins, 15 proteins showed significantly different abundances (p < .05), including antithrombin-III, alpha-2-antiplasmin, tetranectin, apolipoprotein M, adiponectin, inter-alpha-trypsin inhibitor heavy chain H1, gelsolin and apolipoprotein B-100. The identified proteins with differently abundances are involved in a number of pathways, such as complement and coagulation cascades, haemostasis, regulation of actin cytoskeleton, lipid metabolism and transport. We found comparative similarities with human disease in terms of identified proteins and GO pathways, which confirmed similar pathophysiology of this disease, but also differences, mainly in lipid metabolism. SignificanceThere have been few investigations of canine serum proteome despite the potential for biomarker discovery and comparative disease analysis. Establishing serum proteomic signatures in healthy dogs and dogs with CVD will benefit for understanding the aetiology of disease in dogs, identify putative biomarkers and provide models of comparative human disease. Circulating biomarkers are important for understanding of the mechanisms of cardiovascular disease and high incidence of CVD in dogs prioritizes the search for novel biomarkers.

Trends of popularity of cardiac biomarkers: Insights from Google Trends

This study was aimed at assessing the trend of worldwide popularity, thus likely reflecting usage, of conventional cardiac biomarkers, including cardiac troponins, myoglobin and creatine kinase MB (CK-MB). Google Trends was interrogated using a combination of the three search terms “troponin” AND “myoglobin” AND “CK-MB”, with a time limit set between January 1, 2014 (i.e., the oldest searchable year) and present time (i.e., August 13, 2018). The raw data were entered into an Excel worksheet and reported as cumulative Google Trends scores per week for each cardiac biomarker. The popularity score of myoglobin and CK-MB has displayed a significantly decreasing trend since the 2004, whilst that of troponin has exhibited an apparently paradoxical Ushape behavior, with a more pronounced increase during the past 10 years. The correlation between time and cumulative Google searches was significant for all biomarkers, being r= 0.40 (P&lt;0.001) for troponin, r= -0.45 (P&lt;0.001) for myoglobin and r= - 0.79 (P&lt;0.001) for CK-MB. The score of overall Google searches for troponin was approximately 2.5-fold and 8.5-fold higher than for myoglobin and CK-MB, respectively. When the analysis was limited to the past ten years, the correlation between time and cumulative Google searches became even stronger for troponin (r= 0.85; P&lt;0.001), remained virtually identical for CK-MB (r= -0.80; P&lt;0.001), whilst it was no longer significant for myoglobin (r= - 0.13; P=0.150). The graphical analysis of Google search frequency also showed that CK-MB appears to be popular in Mexico, Brazil, Chile, Japan, Poland and Romania, myoglobin seems popular in Uruguay, Bolivia, Denmark, Kazakhstan and in some African Nations, whilst troponin is mostly predominant in the remaining parts of the world. The results of this study suggest that, despite all available guidelines share the principle that cardiac troponin should be considered the one and only reference biomarker for diagnosing myocardial ischemia, CK-MB and especially myoglobin are still popular worldwide, especially in certain geographic areas.

Heart-type fatty-acid-binding protein is a prognostic biomarker for sepsis outcome and sepsis-related left-ventricular dysfunction: a comparison with troponin I

Background Using heart-type fatty-acid-binding protein (H-FABP) in critically ill patients provides a superior results than the conventional cardiac biomarkers. Objective The aim of the study was to estimate the prognostic significance of H-FABP in patients with septic shock and the prevalence of sepsis-related myocardial dysfunction in comparison to troponin I. Patients and methods Fifty ICU patients with sepsis were enrolled in this study. All patients were evaluated using Acute Physiology and Chronic Health Evaluation II score on admission and every 24 h during ICU stay. Serum levels of both H-FABP and troponin I were investigated during the first 24 h after admission. Using modified Simpson’s method, echocardiographic left-ventricular end-diastolic volume (LVEDV), left-ventricular end-systolic volume (LVESV), and left-ventricular ejection fraction (LV%EF) were calculated on admission and after 24 h. Results The patients were divided into two groups: group 1, which included 12 patients (mean age: 50.2±21 years) suffering from sepsis; and group 2, which included 38 patients (mean age: 58.4±19.2 years) with septic shock. Compared with group 1, H-FABP of group 2 showed significant higher values (76.3 vs. 33.3% of patients, P Conclusion In septic shock, H-FABP can be used as a prognostic marker for mortality rathar than troponin I. The positive H-FABP patients showed a significant relation with sepsis-related left-ventricular systolic myocardial dysfunction.

Contemporary and Future Usage of Conventional Cardiac Biomarkers: A Novel Algorithm for the Early Diagnosis of AMI and CVA

We propose a contemporary and novel algorithm using cardiac specific biomarkers for patients presenting with chest pain and other disease states associated with elevated levels of troponin T (TnT) and/or creatine kinase (CK) isoforms. We predict the implementation of this novel algorithm will differentiate between a type-I and type-II myocardial infarction (MI). We summarize advances using high-sensitivity Tn assays (hs-Tn), which include a greater sensitivity for rapid diagnosis of MI within 1-3 hours of symptom onset and is predictive of patient prognosis. We summarize the use of CK isoenzymes as a diagnostic marker for various disease states, determine myocardial infarct size, differentiate MI type, and diagnose myocardial reinfarction. We propose further studies using CK isoforms to define transient ischemic attack (TIA) and cerebrovascular accident (CVA) in order to direct treatments for acute CVA.

Circulating plasma serine208‐phosphorylated troponin T levels are indicator of cardiac dysfunction

Heart failure (HF) following myocardial infarction (MI) is characterized by progressive alterations of left ventricular (LV) structure and function, named LV remodelling. Although several risk factors such as infarct size have been identified, HF remains difficult to predict in clinical practice. Recently, using phosphoproteomic technology, we found that serine208-phosphorylated troponin T (P-Ser208-TnT) decreases in LV of HF rats. Our aim was to determine the performance of P-Ser208-TnT as plasma biomarker of HF compared to conventional cardiac biomarkers such as B-type natriuretic peptide (BNP), cardiac troponin I (cTnI), C-reactive protein (CRP) or tissue inhibitor of metalloproteinase I (TIMP-1) measured by x-MAP technology, as well as its capacity to reflect a pharmacological improvement of HF. We observed a significant increase of BNP, TnT and cTnI levels and a significant decrease of P-Ser208-TnT and TIMP-1 in the plasma of 2-month-MI rats compared with control rats with no modulation of CRP level. Circulating levels of P-Ser208-TnT were shown to be associated with most of the echocardiographic and haemodynamic parameters of cardiac function. We verified that the decrease of P-Ser208-TnT was not because of an excess of phosphatase activity in plasma of HF rats. Two-month-MI rats treated with the heart rate reducing agent ivabradine had improved LV function and increased plasma levels of P-Ser208-TnT. Thus, circulating phosphorylated troponin T is a highly sensitive biological indicator of cardiac dysfunction and has the potentiality of a new biomarker of HF post-MI, and of a surrogate marker for the efficacy of a successful treatment of HF.

Comparison of the temporal release pattern of copeptin with conventional biomarkers in acute myocardial infarction

BackgroundEarly detection of acute myocardial infarction (AMI) using cardiac biomarkers of myocardial necrosis remains limited since these biomarkers do not rise within the first hours from onset of AMI. We aimed to compare the temporal release pattern of the C-terminal portion of provasopressin (copeptin) with conventional cardiac biomarkers, including creatine kinase isoenzyme (CK-MB), cardiac troponin T (cTnT), and high-sensitivity cTnT (hs-cTnT), in patients with ST-elevation AMI.MethodsWe included 145 patients undergoing successful primary percutaneous coronary intervention (PCI) for a first ST-elevation AMI presenting within 12 h of symptom onset. Blood samples were taken on admission and at four time points within the first 24 h after PCI.ResultsIn contrast to all other markers, copeptin levels were already elevated on admission and were higher with a shorter time from symptom onset to reperfusion and lower systolic blood pressure. Copeptin levels peaked immediately after symptom onset at a maximum of 249 pmol/L and normalized within 10 h. In contrast, CK-MB, cTnT, and hs-cTnT peaked after 14 h from symptom onset at a maximum of 275 U/L, 5.75 μg/L, and 4.16 μg/L, respectively, and decreased more gradually.ConclusionsCopeptin has a distinct release pattern in patients with ST-elevation AMI, peaking within the first hour after symptom onset before conventional cardiac biomarkers and falling to normal ranges within the first day. Further studies are required to determine the exact role of copeptin in AMI suspects presenting within the first hours after symptom onset.

Blood cells characteristics as determinants of acute myocardial infarction

The aim of this study is to analyse the relation between red blood cells, platelets morphology and acute myocardial infarction (AMI), and to assess whether they could supplement the role of traditional cardiac biomarkers in the early identification of patients with AMI. All consecutive patients admitted to our emergency department between the 1st January and the 31st August 2009 due to chest pain of suspected cardiac origin were included in the study. All the patients underwent physical examination, a 12-lead ECG, blood sampling for determination of cardiac troponin I and a complete blood count. A percentage of 6.7% of the 1971 patients had a confirmed diagnosis of AMI. Mean corpuscular volume (MCV), red blood cells distribution width (RDW) and platelets count (Plt) did not differ between patients with and without AMI. However, the mean platelet volume (MPV) was significantly higher in AMI patients (7.9 vs. 7.7 fL; p=0.0457). After stratification for gender, men with AMI displayed a lower RDW (p=0.0464) and a higher MPV (p=0.0062) as compared with those without AMI. The MCV and Plt were not significantly different. Women with AMI had a higher RDW (p=0.0079) as compared with those without AMI, while the MCV, Plt and MPV were not significantly different. Our study partially confirms previous data on the association between MPV or RDW and AMI. The inclusion of these parameters along with other conventional cardiac biomarkers might be a valuable perspective when evaluating patients with suspected AMI, although gender differences should be taken in account.

Heart-Type Fatty Acid Binding Protein Is an Independent Predictor of Death and Ventricular Dysfunction After Coronary Artery Bypass Graft Surgery

Heart-type fatty acid binding protein (hFABP) functions as a myocardial fatty acid transporter and is released into the circulation early after myocardial injury. We hypothesized that hFABP is superior to conventional cardiac biomarkers for predicting early perioperative myocardial injury after coronary artery bypass graft (CABG) surgery. A prospective cohort study of 1298 patients undergoing primary CABG with cardiopulmonary bypass (CPB) was performed at 2 institutions. Four plasma myocardial injury biomarkers (hFABP; cardiac troponin I [cTnI]; creatine kinase, MB [CK-MB] fraction; and myoglobin) were measured at 7 perioperative time points. The association among perioperative cardiac biomarkers and ventricular dysfunction, hospital length of stay (HLOS), and up to 5-year postoperative mortality (median 3.3 years) was assessed using Cox proportional hazard models. We defined in-hospital ventricular dysfunction as a new requirement for 2 or more inotropes, or new placement of an intraaortic balloon pump, or ventricular assist device either during the intraoperative period after the patient separated from CPB or postoperatively in the intensive care unit. The positive and negative predictive values of mortality for hFABP are 13% (95% confidence interval [CI], 9%-19%) and 95% (95% CI, 94%-96%), respectively, which is higher than for cTnI and CK-MB. After adjusting for clinical predictors, both postoperative day (POD) 1 and peak hFABP levels were independent predictors of ventricular dysfunction (P < 0.0001), HLOS (P < 0.05), and 5-year mortality (P < 0.0001) after CABG surgery. Furthermore, POD1 and peak hFABP levels were significantly superior to other evaluated biomarkers for predicting mortality. In a repeated-measures analysis, hFABP outperformed all other models of fit for HLOS. Patients with POD2 hFABP levels higher than post-CPB hFABP levels had an increased mortality compared with those patients whose POD2 hFABP levels decreased from their post-CPB level (hazard ratio, 10.9; 95% CI, 5.0-23.7; P = 7.2 × 10(-10)). Mortality in the 120 patients (10%) with a later hFABP peak was 18.3%, compared with 4.7% in those who did not peak later. Alternatively, for cTnI or CK-MB, no difference in mortality was detected. Compared with traditional markers of myocardial injury after CABG surgery, hFABP peaks earlier and is a superior independent predictor of postoperative mortality and ventricular dysfunction.

Increased Mean Platelet Volume in Patients With Acute Coronary Syndromes

Despite remarkable progress, the diagnosis of acute coronary syndromes (ACS) is still challenging. The mean platelet volume (MPV), a simple and reliable indicator of platelet size that correlates with platelet activation, might be an emerging cardiovascular risk marker and potentially helpful in stratifying cardiovascular risk. We analyzed MPV values in 2304 adult patients who were consecutively admitted during a 1-year period to the emergency department of the University Hospital of Verona for chest pain suggestive of ACS. In all patients, a baseline blood sample was collected for routine hematologic testing, whereas cardiac troponin T measurements were collected both at baseline and after 4, 6, and 12 hours. A total of 456 patients (19.8% of total) had ACS. These patients, all having cardiac troponin T levels of 0.03 ng/mL or greater in addition to ischemic electrocardiographic changes, had higher MPV values than non-ACS patients with normal cardiac troponin T levels (median, 8.0 fL [5th to 95th percentiles, 6.7-10.0 fL] versus median, 7.4 fL [5th to 95th percentiles, 6.5-9.5 fL]; P < .001). The diagnostic accuracy of MPV, calculated as the area under the curve by the receiver operating characteristic analysis, was 0.661 (P < .001). At the 9.0-fL cutoff, the negative and positive predictive values of MPV were 83% and 43%, respectively. Because MPV is a simple and inexpensive laboratory measurement, it might be considered a useful rule-out test along with other conventional cardiac biomarkers for the risk stratification of ACS patients admitted to the emergency departments.