European Society of Cardiology quality indicators for the prevention and management of cancer therapy-related cardiovascular toxicity in cancer treatment.

AIMS: To develop quality indicators (QIs) for the evaluation of the prevention and management of cancer therapy-related cardiovascular toxicity. METHODS AND RESULTS: We followed the European Society of Cardiology (ESC) methodology for QI development which comprises (i) identifying the key domains of care for the prevention and management of cancer therapy-related cardiovascular toxicity in patients on cancer treatment, (ii) performing a systematic review of the literature to develop candidate QIs, and (iii) selecting of the final set of QIs using a modified Delphi process. Work was undertaken in parallel with the writing of the 2022 ESC Guidelines on Cardio-Oncology and in collaboration with the European Haematology Association, the European Society for Therapeutic Radiology and Oncology and the International Cardio-Oncology Society. In total, 5 main and 9 secondary QIs were selected across five domains of care: (i) Structural framework, (ii) Baseline cardiovascular risk assessment, (iii) Cancer therapy related cardiovascular toxicity, (iv) Predictors of outcomes, and (v) Monitoring of cardiovascular complications during cancer therapy. CONCLUSION: We present the ESC Cardio-Oncology QIs with their development process and provide an overview of the scientific rationale for their selection. These indicators are aimed at quantifying and improving the adherence to guideline-recommended clinical practice and improving patient outcomes.

Identification of novel biomarker candidates for hypertrophic cardiomyopathy and other cardiovascular diseases leading to heart failure.

In-depth proteome discovery analysis represents new strategy in an effort to identify novel reliable specific protein markers for hypertrophic cardiomyopathy and other life threatening cardiovascular diseases. To systematically identify novel protein biomarkers of cardiovascular diseases with high mortality we employed an isobaric tag for relative and absolute quantitation (iTRAQ) proteome technology to make comparative analysis of plasma samples obtained from patients suffering from non-obstructive hypertrophic cardiomyopathy, stable dilated cardiomyopathy, aortic valve stenosis, chronic stable coronary artery disease and stable arterial hypertension. We found 128 plasma proteins whose abundances were uniquely regulated among the analyzed cardiovascular pathologies. 49 of them have not been described yet. Additionally, application of statistical exploratory analyses of the measured protein profiles indicated the relationship in pathophysiology of the examined cardiovascular pathologies.

Glycogen phosphorylase BB as a potential marker of cardiac toxicity in patients treated with anthracyclines for acute leukemia.

OBJECTIVES: The aim of the presented study was to assess plasma glycogen phosphorylase BB (GPBB) concentrations in acute leukemia patients treated with anthracycline containing chemotherapy. BACKGROUND: Anthracyclines represent the highest risk for development of cardiotoxicity. GPBB belongs to proposed biomarkers of cardiac injury with a very limited experience in this context. METHODS: Totally, 24 adult patients with acute leukemia were enrolled. Plasma GPBB concentrations were measured by ELISA at diagnosis (before chemotherapy), after first chemotherapy with anthracyclines and 6 months after the completion of treatment. The cut-off value for GPBB positivity was 10.00 µg/L as recommended by the manufacturer. RESULTS: Before chemotherapy, the mean plasma GPBB concentration was 5.25±3.81 µg/L, increased above the cut-off in 1 patient (4.2 %). After the first chemotherapy, the mean GPBB was 6.61±5.54 µg/L, positive in 7 (29.2 %) patients. Six months after treatment, the mean GPBB was 10.06±11.41 µg/L, positive in 8 (33.3 %) patients. Six months after treatment, we found a significant correlation between elevation in GPBB and diastolic left ventricular dysfunction on echocardiography (r=0.621; p<0.0001). The differences in plasma GPBB between healthy blood donors and patients treated for acute leukemia were statistically significant (p<0.01 in all cases). CONCLUSION: Our results suggested that GPBB could become a potential biomarker for detection of acute and chronic cardiotoxicity associated with anthracycline containing chemotherapy. The predictive value for development of treatment-related cardiomyopathy in future is not clear and will be evaluated during the follow-up. Further studies are needed to define the potential role of GPBB and other biomarkers in the assessment of chemotherapy-induced cardiotoxicity (Ref. 21). Text in PDF www.elis.sk.

Routine pretreatment with abciximab versus standard periprocedural therapy in mechanically ventilated cardiogenic shock patients undergoing primary percutaneous coronary intervention: Subanalysis of the PRAGUE-7 study.

BACKGROUND: The clinical outcome of patients with myocardial infarction (MI) complicated by cardiogenic shock (CS) who require mechanical ventilation (MV) is poor. OBJECTIVE: To analyze the impact of abciximab pretreatment in this high-risk population of MI patients. METHODS: The present study was a retrospective subanalysis of the multicentre randomized Routine Upfront Abciximab Versus Standard Peri-Procedural Therapy in Patients Undergoing Percutaneous Coronary Intervention for Cardiogenic Shock (PRAGUE-7) study, which included 80 MI patients in CS undergoing primary percutaneous coronary intervention (PCI). Patients were randomly assigned into group A (routine pretreatment with an abciximab bolus followed by a 1 h abciximab infusion) and group B (standard therapy). The subanalysis included 37 patients requiring MV. Seventeen patients were in group A and 20 were in group B. The primary end point (death/stroke/reinfarction/new severe renal failure) at 30 days, procedural success (thrombosis in myocardial infarction [TIMI] flow) and frequency of bleeding were assessed. The χ(2) and Student's t tests were used for statistical analysis; P<0.05 was considered to be statistically significant. RESULTS: The primary end point occurred in nine (53%) patients in group A and 12 (60%) patients in group B (P=0.66). TIMI flow after primary PCI was higher in group A (2.75 versus 2.31; P<0.05). Major bleeding occurred in 12% of patients in group A versus 10% of patients in group B (P=0.86). Minor or minimal bleeding was more common in group A (29%) compared with group B (5%; P<0.05). CONCLUSION: The results of the present study suggest that routine pretreatment with abciximab before primary PCI in mechanically ventilated patients with MI complicated by cardiogenic shock was associated with better angiographic results but also with a higher incidence of bleeding.

High-sensitivity troponin T as a marker of myocardial injury after radiofrequency catheter ablation.

BACKGROUND: The aim of our study was to monitor radiofrequency catheter ablation-induced myocardial damage by measuring high-sensitivity cardiac troponin T (hs-cTnT). METHODS: Serum concentrations of hs-cTnT (Elecsys 2010 system, Roche) were measured in 73 healthy blood donors and serially in 27 patients who had samples taken both before and 24 h after radiofrequency ablation (RFA) for atrioventricular nodal re-entry tachycardia (AVNRT), atrial fibrillation (AF) or right atrial flutter (AFL). RESULTS: Significant increases of hs-cTnT were seen in patients after RFA (AVNRT: P = 0.0115, AF: P = 0.0011, AFL: P = 0.0009). Postprocedural serum hs-cTnT correlated with the number of radiofrequency applications and with the duration of RFA procedure. Spearman's coefficient of rank correlation (r) were as follows: hs-cTnT versus RFA duration: r = 0.771 (P < 0.001); hs-cTnT versus number of pulses: r = 0.708 (P < 0.001). Patients with the diagnosis of AVNRT had lower serum hs-cTnT concentration after RFA compared with AFL (P < 0.0001) and AF (P < 0.0001) patients. CONCLUSIONS: Our data indicate that RFA causes a significant increase of serum hs-cTnT concentration that could be used to monitor myocardial injury.

The use of cardiac biomarkers in detection of cardiotoxicity associated with conventional and high-dose chemotherapy for acute leukemia.

AIM: Monitoring of cardiotoxicity of conventional and high-dose chemotherapy (HD-CT) with multiple biomarkers of cardiac injury - glycogen phosphorylase BB (GPBB), heart-type fatty acid binding protein (H-FABP), cardiac troponins (cTnT, cTnI), creatine kinase MB (CK-MB mass), myoglobin. METHODS: A total of 47 adult acute leukemia patients were studied - 24 patients treated with conventional CT containing anthracyclines (ANT) and 23 patients treated with HD-CT (myeloablative preparative regimen) followed by hematopoietic cell transplantation (HCT). Cardiac biomarkers were assessed prior to treatment (before CT/HD-CT), after first CT with ANT, after last CT with ANT in the first group, after HD-CT and after HCT in the second group. Values above the reference range were considered elevated. RESULTS: Before CT/HD-CT, all biomarkers of cardiac injury were below the cut-offs in all patients. GPBB increased above the cut-off (7.30 microg/L) in 4 (16.7%) patients after first CT and in 5 (20.8%) patients after last CT with ANT. GPBB increased above the cut-off in 5 (21.7%) patients after HD-CT and remained elevated in 5 (21.7%) patients after HCT. CTnI became elevated (above 0.40 microg/L) in 2 (8.3%) patients after first and last CT with ANT. Both patients with cTnI positivity had elevated GPBB. Other tested biomarkers remained below the cut-offs during the study. CONCLUSION: Our results suggest that GPBB could become a sensitive biomarker for detection of acute cardiotoxicity associated with conventional CT containing ANT and HD-CT followed by HCT. The predictive value for development of cardiomyopathy in the future is not known and should be evaluated during a prospective follow-up. Based on our data, a larger prospective and multicenter study would be most desirable to define the potential role of new circulating biomarkers in the assessment of cardiotoxicity in oncology.

Application of proteomics in biomarker discovery: a primer for the clinician.

Ever since proteomics was proven to be capable of characterizing a large number of differences in both protein quality and quantity, it has been applied in various areas of biomedicine, ranging from the deciphering molecular pathogenesis of diseases to the characterization of novel drug targets and the discovery of potential diagnostic biomarkers. Indeed, the biomarker discovery in human plasma is clearly one of the areas with enormous potential. However, without proper planning and implementation of specific techniques, the efforts and expectations may very easily be hampered. Numerous earlier projects aimed at clinical proteomics, characterized by exaggerated enthusiasm, often underestimated some principal obstacles of plasma biomarker discovery. Consequently, ambiguous and insignificant results soon led to a more critical view in this field. In this article, we critically review the current state of proteomic approaches for biomarker discovery and validation, in order to provide basic information and guidelines for both clinicians and researchers. These need to be closely considered prior to initiation of a project aimed at plasma biomarker discovery. We also present a short overview of recent applications of clinical proteomics in biomarker discovery.

[High sensitivity cardiac troponin assays 2009: clinical potential, current practice and benefits, the future]. / High-sensitivity metody stanovení srdecních troponinu 2009: klinický potenciál, soucasná praxe a prínos, perspektiva.

At present, determination of cardiac troponins (cTn) is the biomarker method of choice for diagnostics and risk stratification in patients with a myocardial injury. Past clinical practice had provided sound evidence that low cTn concentrations, measured with unacceptable imprecision by the currently used methods, hold important clinical, diagnostic and stratification potential. The new generation cTn assays, so called high-sensitivity assays, enable determination of very low cTn concentrations with satisfactory analytical precision and open the way to early identification of small but often prognostically important myocardial damage. Introduction of high-sensitivity cTn assays in practice is, however, associated with some difficulties: their superior diagnostic sensitivity to identify small injuries to myocardium is often linked to lower specificity, higher incidence of elevated cTn concentrations is frequently associated with less obvious clinical symptomatology (overdiagnosis), resulting in greater demand for further patient assessment (overcrowding), repeated analyses and trend monitoring of cTn fluctuation. These initial difficulties cannot lessen the by now indisputable, established benefit of high-sensitivity cTn assays that we briefly describe in the present paper.

Assessment of anthracycline-induced cardiotoxicity with electrocardiography.

AIM: Monitoring of anthracycline-induced cardiotoxicity with electrocardiography (ECG) and comparing ECG changes with findings on echocardiography (ECHO). METHODS: A total of 26 adult acute leukemia patients (mean age 46.2 -/+ 12.4 years, 15 males) treated with 2-6 cycles of anthracycline-based chemotherapy (CT) were studied. Cardiac evaluation was performed at the baseline (before CT), after first CT, after last CT (cumulative anthracycline dose 464.3 -/+ 117.5 mg/m2) and circa 6 months after CT. Time ECG parameters, QRS voltage, presence of repolarization changes, arrhythmias and other abnormalities were evaluated. RESULTS: During treatment and follow-up, we found a statistical significant QTc interval prolongation - 414.7 -/+ 16.0 ms (before CT), 419.6 -/+ 21.6 ms (after first CT), 428.0 -/+ 16.2 ms (after last CT) and 430.1 -/+ 18.4 ms (6 months after CT). Significant QTc interval prolongation (> 450 ms) occurred in 3 patients after first CT, in 4 patients after last CT and in 5 patients within 6 months after CT. Significant total QRS voltage lowering in the limb leads (> 1.0 mV versus before CT) occurred in 3 patients after first CT, in 5 patients after last CT and in 6 patients within 6 months after CT. We found a statistically significant correlation between decreased QRS voltage, QTc interval prolongation and left ventricular (LV) dysfunction on ECHO. Repolarization changes associated with oncology treatment were present in 9 patients within 6 months after CT. CONCLUSION: Anthracycline treatment is associated with changes in electrical activity of the myocardium. Prolonged QTc interval represents a risk for development of malignant ventricular arrhythmias. Decreased QRS voltage and prolonged QTc interval after anthracycline treatment could correlate with LV dysfunction on ECHO. Further studies will be needed to prove whether these ECG changes could serve as an accessible and non-invasive screening method indicating LV dysfunction after anthracycline treatment.

[Multi-marker approach in the diagnostics of cardiac diseases by protein biochip technology]. / Multianalytový prístup k diagnostice srdecních chorob technologií proteinových biocipu.

BACKGROUND: Multi-marker approach is recommended for rapid diagnostics and risk stratification of acute coronary syndrome. We tested the analytical performance of protein biochip technology for determination cardiac markers. METHODS: Analysis of cardiac markers: CK-MB mass, cTnl, myoglobin, glycogen phosphorylase BB (GPBB), heart type of fatty acid binding protein (h-FABP) and carbonic anhydrase III (CAIII) was performed by system Evidence Investigator (Randox). Analytical parameters of Cardiac array were tested. The Evidence Investigator results were compared with Elecsys 2010 (Roche) CK-MB mass and myoglobin methods. Markers of myocardial injury were determined in 28 blood donors, 28 patients with acute myocardial infarction diagnosis and 21 patients after chemotherapy containing anthracyclines (monitoring of cardiotoxicity). RESULTS: The Passing-Bablok regression shows statistically significant differences in results. The reasons for these differences are poor standardization of methods and discrepancies between calibrations. New substances h-FABP and GPBB are promising early markers of acute myocardial infarction and diagnostic sensitivity of h-FABP would be better than myoglobin test. These markers can be useful for monitoring of cardiotoxicity of anthracyclines. CONCLUSIONS: In future, the use of biochip technology in cardiology diagnostic represents an important challenge but it is a necessary standardization of immunochemical methods.

Multimarker approach to evaluation of cardiac toxicity during preparative regimen and hematopoietic cell transplantation.

Cardiac toxicity of preparative regimen (PR) containing high-dose Cyclophosphamide (120 mg/kg) followed by hematopoietic cell transplantation (HCT) was evaluated with 6 biomarkers of cardiac injury: N-terminal pro brain natriuretic peptide (NT-proBNP), creatine kinase MB (CK-MB mass), cardiac troponins (cTnT, cTnI), heart-type fatty acid binding protein (H-FABP), glycogen phosphorylase BB (GPBB). Twenty-three patients (mean age 44.5+/-10.6 years, 15 males) with acute leukemia were studied. All biomarkers were measured the day before PR, the day after PR, the day after HCT and 14 days after HCT. We found NT-proBNP elevations above 500 ng/L in 6 (26.1 %) patients after PR, in 9 (39.1 %) after HCT and in 7 (30.4 %) 14 days after HCT. GPBB became elevated (above 7.30 microg/L) in 5 (21.7 %) patients after PR, remained elevated in 5 (21.7 %) after HCT and in 2 (8.7 %) 14 days after HCT. A significant correlation between elevation in NT-proBNP and GPBB was found. Other markers remained within the reference range early after PR and HCT. Our findings show that administration of PR and HCT for acute leukemia is associated with acute neurohumoral activation of cardiac dysfunction (significant rise in NT-proBNP) and may lead to GPBB elevation. These changes could indicate acute cardiac toxicity due to treatment and require further follow-up. The predictive value for development of cardiomyopathy in the future is unclear. Further studies will be needed to define the potential role of new biomarkers in this context.

[Biomarkers of myocardial ischemia and necrosis in 2008]. / Biomarkery ischemie a nekrózy myokardu v roce 2008.

In the review article, the authors present current knowledge of biomarkers of myocardial ischemia and necrosis. They comment new definition of myocardial infarction resulted as consensus of European Society of Cardiology and American Heart Association. They added clinically interested data about routinely used cardiomarkers (cardiac troponins and creatinkinase). At the second part, the authors focused on new biomarkers (fatty acids binding proteins, ischemia-modified albumin, glycogen phosphorylase isoenzyme BB) and its significance in diagnosis of myocardial ischemia/necrosis and their prognostic significance. Some of new promising molecules are discussed in the last part of the article.

Re-expression of nestin in the myocardium of postinfarcted patients.

Intact cardiac muscle cells in the adult heart do not express intermediate filament nestin. In this study, we report on widespread expression of intermediate filament nestin in human myocardium of patients who died from the myocardial infarction. Nestin was detected in cardiomyocytes, endothelial cells, and few interstitial cells. Elevated levels of nestin were observed in cardiac muscle cells in all specimens, although the intensity of immunoreactivity and distribution of the signal differed. The strongest immunoreactivity was observed from 4 days after myocardial infarction in the infarction border zone where nestin was distributed homogeneously in the entire sarcoplasm of cardiac muscle cells. Within the following week, nestin in immunoreactive cardiomyocytes was redistributed and restricted to small subsarcolemmal foci and to intercalated discs. Angiogenic capillaries that grew between vital nestin-positive cardiomyocytes and entered the necrotic area expressed also high levels of nestin. Nestin-positive endothelial cells were often observed in mutual interactions with nestin-positive cardiac muscle cells. These findings document a crucial role of nestin in remodeling cytoskeleton of cells in the human postinfarcted myocardium.

Use of multiple biomarkers for evaluation of anthracycline-induced cardiotoxicity in patients with acute myeloid leukemia.

AIM: To assess cardiac toxicity of anthracycline treatment with six biomarkers of cardiac injury: myoglobin, creatine kinase MB (CK-MB mass), cardiac troponin T (cTnT), cardiac troponin I (cTnI), heart-type fatty acid binding protein (H-FABP), glycogen phosphorylase BB (GPBB). METHODS: We evaluated anthracycline-induced cardiotoxicity in 12 acute myeloid leukemia patients (mean age 51.3-/+10.7 years, 7 females). All biomarkers were measured at the baseline, after first chemotherapy (CT) with anthracyclines, after last CT with anthracyclines (total cumulative dose 479.8-/+106.2 mg/m2) and 6 months thereafter. Values above the reference range were considered elevated. RESULTS: GPBB increased above the cut-off (7.30 microg/L) in 2 (16.7%) patients after first CT, in 3 (25.0%) patients after last CT and remained elevated in 2 (16.7%) patients within 6 months after CT. CTnI became elevated (above 0.40 microg/L) in 1 (8.3%) patient after first and last CT and within 6 months after CT. CTnT remained negative (below 0.01 microg/L) during CT in all patients. Six months after CT, delayed cTnT positivity was found in 1 (8.3%) patient. All patients with cTnI or cTnT positivity had elevated GPBB. Other biomarkers (myoglobin, CK-MB mass, H-FABP) remained within the reference range in all patients. CONCLUSION: Our preliminary results suggest that GPBB could be a new promising marker for detection of anthracycline-related cardiotoxicity and probably superior to cardiac troponins. The predictive value for development of cardiomyopathy in the future is not clear and will be evaluated during a prospective follow-up.

Monitoring of the very early changes of left ventricular diastolic function in patients with acute leukemia treated with anthracyclines.

AIM: To analyze the very early changes of diastolic LV function during and after chemotherapy (CT) in patients with newly diagnosed acute leukemia. METHODS: 26 patients with acute leukemia have been studied. The cardiac echo evaluation was performed at the baseline (before CT), after the first CT (mean cumulative anthracyclines dose 136.3-/+28.3 mg m(-2)), after the last CT (mean cumulative anthracyclines dose 464.3-/+117.5 mg m(-2)) and circa 6 months after the completion of CT. RESULTS: We found a significant decrease in LVEF (65.3-/+4.5' vs 60.2-/+5.7', p<0.01), the fractional shortening of the LV (34.8-/+3.7', vs 29.5-/+5.0', p<0.01), but the mitral flow rapid filling velocity (E-wave) was not changed (0.74-/+0.18 ms(-1), vs 0.67-/+0.17 ms(-1), p ns), and atrial filling velocity (A-wave) increased (0.66-/+0.15 ms(-1) vs 0.78-/+0.18 ms(-1), p<0.01). E/A ratio significantly decreased (1.18-/+0.35 vs 0.89-/+0.27, p<0.01). IVRT increased (71.5-/+11.6 ms vs 84.0-/+11.6 ms, p<0.01). DT E-wave velocity increased (162.3-/+25.8 ms vs 206.7-/+25.5 ms, p<0.01). After the first CT, the signs of LV diastolic dysfunction were detected in 5 (19.2') patients. 6 months after the last CT, two of these patients (7.7') developed LV systolic dysfunction with the clinical symptoms of heart failure. Six months after the last CT, 12 (46.2') patients developed the signs of LV diastolic dysfunction. CONCLUSION: Chemotherapy can induce early changes of diastolic left ventricular function. We consider using Doppler echocardiography as the election tool not only for baseline cardiologic screening but also for the monitoring of the earliest subclinical signs of cardiotoxicity.