Biologische Variabilität von Biomarkern der Herzinsuffizienz

Background: In heart failure (HF) biomarkers are used in diagnosis, risk stratification, monitoring of disease progression and therapy guidance. When it comes to the interpretation of serial measurements knowledge about the biomarker’s biological variation (BV) is crucial. There are previous studies enlighting the BV in healthy subjects and stable HF patients with reduced ejection fraction (rEF). Due to different pathophysiological mechanism and biomarker profiles, there is a paucity of data on the BV in HF subjects with preserved EF (pEF). Further, the effect of frequent comorbidities as arterial hypertension, diabetes mellitus and kidney insufficiency on the BV is unknown. Therefore, this study aimed to determine and compare BV of six biomarkers in HFrEF, HFpEF, arterial Hypertension (aHt) and diabetic nephropathy (DN). Methods: The biomarkers NT-proBNP, Galectin-3, sST2, hsTnT, Copeptin and NGAL were quantified twice in between one week in clinical stable patients with HFrEF, HFpEF, aHt and DN. The intraindividual coefficient of variation (CVi = BV) and the reference change value (RCV) were calculated providing a percentage range in which a concentration change is clinically not significant. Results: The BV of NT-proBNP was 28% in HFpEF, 24% in HFrEF and 25% in DN. The BV of hsTnT was 14% in HFrEF, 15% in HFpEF and 12% in DN. sST2 (8% - 12%) and NGAL (8% - 14%) present a low and in all study groups reliable BV. The BV differed significantly between the study groups for Copeptin (19% - 42%). Conclusion: This study determined the BV of NT-proBNP, Galectin-3, sST2, hsTnT, Copeptin and NGAL in patients with HFpEF, HFrEF, arterial Hypertension and dia-betic nephropathy and hereby provides more robust interpration of serial biomarker measurements in HFpEF- and multimorbid HF-patients.In der Herzinsuffizienz werden Biomarker in der Diagnostik, der Risikostratifizierung, dem Verlaufsmonitoring sowie als Argument in Therapieentscheidungen eingesetzt. Zur Interpretation von seriellen Messungen von Biomarkern ist es entscheidend, die biologische Variabilität (BV) eines Biomarkers zu kennen. Mit genauer Kenntnis der BV als zufälliger Schwankung eines Biomarkers ist es möglich zu beurteilen, ob die Konzentrationsänderung eines Biomarkers klinisch signifikant ist. In Vorarbeiten wurde die BV in gesunden Probanden und stabilen Patienten mit Herzinsuffizienz mit reduzierter Ejektionsfraktion (HFrEF) bestimmt. Bei sich unterscheidenden pathophysiologischen Prozessen und Biomarkerprofilen, gibt es aktuell keine Daten zur BV in Patienten mit Herzinsuffizienz mit erhaltener Ejektionsfraktion (HFpEF). Des Weiteren wurde die BV bislang nicht in Patienten mit arterieller Hypertonie oder multimorbiden Patienten mit Diabetischer Nephropathie untersucht. Diese Arbeit untersucht deshalb die biologische Variabilität von sechs Biomarkern in den vier Studiengruppen HFpEF, HFrEF, arterielle Hypertonie (aHt) und diabetische Nephropathie (DN). Methodik: Die Biomarker NT-proBNP, Galectin-3, sST2, hsTnT, Copeptin und NGAL wurden zweifach im Intervall von einer Woche in den vier Studiengruppen gemessen. Der intra-individuelle Coefficient of Variation (CVi = BV - biologische Variabilität) sowie der Reference change value (RCV) wurden nach der Methode von Fraser und Harris berechnet. Ergebnisse: Die BV von NT-proBNP in HFpEF war 28% im Vergleich zu 24% in HFrEF-Patienten. Die BV von hsTnT war 14% in HFrEF, 15% in HFpEF und 12% in Patienten mit DN. sST (8% - 12%) und NGAL (8% - 14%) hatten in allen Studiengruppen eine niedrige und konsistente BV. Die BV von Copeptin war hoch (19% - 42%) und hat sich zwischen den Studiengruppen signifikant unterschieden. Konklusion: In dieser Arbeit wird die BV von NT-proBNP, Galectin-3, sST2, hsTnT, Copeptin und NGAL in Patienten mit HFrEF, HFpEF, aHt und NGAL beschrieben, was eine bessere Interpretation von seriellen Biomarkermessungen in HFpEF-Patienten sowie multimorbiden Patienten ermöglicht

PRediction of acute coronary syndrome in acute ischemic StrokE (PRAISE) – protocol of a prospective, multicenter trial with central reading and predefined endpoints

Background: Current guidelines recommend measurement of troponin in acute ischemic stroke (AIS) patients. In AIS patients, troponin elevation is associated with increased mortality and worse outcome. However, uncertainty remains regarding the underlying pathophysiology of troponin elevation after stroke, particularly regarding diagnostic and therapeutic consequences. Troponin elevation may be caused by coronary artery disease (CAD) and more precisely acute coronary syndrome (ACS). Both have a high prevalence in stroke patients and contribute to poor outcome. Therefore, better diagnostic algorithms are needed to identify those AIS patients likely to have ACS or other manifestations of CAD. Methods/design: The primary goal of the "PRediction of Acute coronary syndrome in acute Ischemic StrokE" (PRAISE) study is to develop a diagnostic algorithm for prediction of ACS in AIS patients. The primary hypothesis will test whether dynamic high-sensitivity troponin levels determined by repeat measurements (i.e., "rise or fall-pattern") indicate presence of ACS when compared to stable (chronic) troponin elevation. PRAISE is a prospective, multicenter, observational trial with central reading and predefined endpoints guided by a steering committee. Clinical symptoms, troponin levels as well as findings on electrocardiogram, echocardiogram, and coronary angiogram will be recorded and assessed by central academic core laboratories. Diagnosis of ACS will be made by an endpoint adjudication committee. Severe adverse events will be evaluated by a critical event committee. Safety will be judged by a data and safety monitoring board. Follow-up will be conducted at three and twelve months and will record new vascular events (i.e., stroke and myocardial infarction) as well as death, functional and cognitive status. According to sample size calculation, 251 patients have to be included. Discussion: PRAISE will prospectively determine the frequency of ACS and characterize cardiac and coronary pathologies in a large, multicenter cohort of AIS patients with troponin elevation. The findings will elucidate the origin of troponin elevation, shed light on its impact on necessary diagnostic procedures and provide data on the safety and diagnostic yield of coronary angiography early after stroke. Thereby, PRAISE will help to refine algorithms and develop guidelines for the cardiac workup in AIS. Trial registration: NCT03609385 registered 1st August 2018

Coronary angiography in acute ischemic stroke patients: frequency and determinants of pathological findings in a multicenter cohort study.

BACKGROUND Myocardial injury as indicated by cardiac troponin elevation is associated with poor prognosis in acute stroke patients. Coronary angiography (CAG) is the diagnostic gold-standard to rule-out underlying obstructive coronary artery disease (CAD) in these patients. However, weighing risks and benefits of coronary angiography (CAG) against each other is particularly challenging, because stroke patients undergoing CAG may have a higher risk for secondary intracranial bleeding. Current guidelines remain vague. Thus, the aim of this study was to analyze frequency of pathological findings of CAG and associated clinical factors. METHODS We analyzed indications and frequency of CAG performed in acute ischemic stroke patients in clinical routine in two European tertiary care hospitals from 2011 to 2018. All data were obtained retrospectively. Multiple logistic regression analyses were performed to identify variables associated with absence of obstructive coronary artery disease defined as presence of at least one coronary vessel stenosis ≥ 50%. RESULTS A total of 139 AIS patients underwent CAG. Frequent indications for CAG were suspected acute coronary syndrome (N = 114) or scheduled cardiac surgery (N = 25). Acute coronary stenting was applied in 51/139 patients. Among patients with suspected acute coronary syndrome, no obstructive CAD was found in 27/114 patients. Absence of obstructive CAD was associated with insular cortex lesions, no clinical symptoms for ACS, less than three cardiovascular risk factors, younger age and normal wall motion. CONCLUSION Several variables suggest absence of CAD in AIS patients and may help in clinical decision making in stroke patients with myocardial injury