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Aims The objective of this study was to investigate the prognostic value of urinary N-terminal pro-brain natriuretic peptide (NT-proBNP) compared with plasma NT-proBNP in patients presenting with acute chest pain in the emergency department. Methods and results We measured simultaneously plasma and urinary NT-proBNP at admission in 301 patients with acute chest pain. In our cohort, 174 patients suffered from acute coronary syndrome (ACS). A follow-up (median of 55 months) was performed regarding the endpoints all-cause mortality and major adverse cardiac events (mortality, congestive heart failure, ACS with the necessity of a coronary intervention, and stroke). Fifty-four patients died during follow-up; 98 suffered from the combined endpoint. A significant and positive correlation of urinary and plasma NT-proBNP was found (r = 0.87, P < 0.05). Patients with troponin positive ACS had significantly elevated levels of plasma and urinary NT-proBNP compared with those with unstable angina pectoris or chest wall syndrome (each P < 0.05). The highest levels of both biomarkers were found in patients with congestive heart failure (each P < 0.05). According to Kaplan���Meier analysis, plasma and urinary NT-proBNP were significant predictors for mortality and the combined endpoint in the whole study cohort and in the subgroup of patients with ACS (each P < 0.05). Regarding Cox regression analysis, plasma and urinary NT-proBNP were independent predictors for mortality and the combined endpoint (each P < 0.05). Conclusions Urinary NT-proBNP seems to provide a significant predictive value regarding the endpoints all-cause mortality and major adverse cardiac events in patients with acute chest pain and those with ACS.

Aims The aim of the current study was to evaluate whether tubular markers kidney injury molecule-1 (KIM-1) and N-acetyl-ß-glucosaminidase (NAG) are related to acute kidney injury (AKI) and severe disease in patients with COVID-19. Methods and results In this prospective observational clinical trial we examined a cohort of 80 patients with proof of acute respiratory infection and divided them into a COVID-19 cohort (n = 54) and a control cohort (n = 26). KIM-1 and NAG were measured from urine samples collected in the emergency department. We assessed the development of AKI, admission to the intensive care unit (ICU) and intrahospital death as clinical endpoints. Urinary KIM-1 and NAG were not significantly different between patients with SARS-CoV-2 and those with other respiratory infections (each p = n.s.). Eight patients from the COVID-19 cohort and five of the non-COVID-19-patients suffered from acute kidney injury during their stay. Nine COVID-19 patients and two non-COVID-19 patients were admitted to the ICU. KIM-1 was significantly elevated in COVID-19 patients with, compared to those without AKI (p = 0.005), as opposed to NAG and creatinine (each p = n.s.). Furthermore, KIM-1 was significantly elevated in the patients with COVID-19 that had to be transferred to the ICU (p = 0.015), in contrast to NAG and creatinine (each p = n.s.). Conclusion Assessing KIM-1 in patients with COVID-19 might provide additional value in recognizing AKI at an early stage of disease. Further, KIM-1 might indicate higher risk for clinical deterioration as displayed by admission to the ICU. Graphical abstract

Increased left ventricular fibrosis has been reported in patients hospitalized with coronavirus disease 2019 (COVID-19). It is unclear whether this fibrosis is a consequence of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection or a risk factor for severe disease progression. We observed increased fibrosis in the left ventricular myocardium of deceased COVID-19 patients, compared with matched controls. We also detected increased mRNA levels of soluble interleukin-1 receptor-like 1 (sIL1-RL1) and transforming growth factor β1 (TGF-β1) in the left ventricular myocardium of deceased COVID-19 patients. Biochemical analysis of blood sampled from patients admitted to the emergency department (ED) with COVID-19 revealed highly elevated levels of TGF-β1 mRNA in these patients compared to controls. Left ventricular strain measured by echocardiography as a marker of pre-existing cardiac fibrosis correlated strongly with blood TGF-β1 mRNA levels and predicted disease severity in COVID-19 patients. In the left ventricular myocardium and lungs of COVID-19 patients, we found increased neuropilin-1 (NRP-1) RNA levels, which correlated strongly with the prevalence of pulmonary SARS-CoV-2 nucleocapsid. Cardiac and pulmonary fibrosis may therefore predispose these patients to increased cellular viral entry in the lung, which may explain the worse clinical outcome observed in our cohort. Our study demonstrates that patients at risk of clinical deterioration can be identified early by echocardiographic strain analysis and quantification of blood TGF-β1 mRNA performed at the time of first medical contact.

Aims We aimed to assess whether expression of whole‐blood RNA of sodium proton exchanger 1 (NHE1) and glucose transporter 1 (GLUT1) is associated with COVID‐19 infection and outcome in patients presenting to the emergency department with respiratory infections. Furthermore, we investigated NHE1 and GLUT1 expression in the myocardium of deceased COVID‐19 patients. Methods and results Whole‐blood quantitative assessment of NHE1 and GLUT1 RNA was performed using quantitative PCR in patients with respiratory infection upon first contact in the emergency department and subsequently stratified by SARS‐CoV‐2 infection status. Assessment of NHE1 and GLUT1 RNA using PCR was also performed in left ventricular myocardium of deceased COVID‐19 patients. NHE1 expression is up‐regulated in whole blood of patients with COVID‐19 compared with other respiratory infections at first medical contact in the emergency department (control: 0.0021 ± 0.0002, COVID‐19: 0.0031 ± 0.0003, P = 0.01). The ratio of GLUT1 to NHE1 is significantly decreased in the blood of COVID‐19 patients who are subsequently intubated and/or die (severe disease) compared with patients with moderate disease (moderate disease: 0.497 ± 0.083 vs. severe disease: 0.294 ± 0.0336, P = 0.036). This ratio is even further decreased in the myocardium of patients who deceased from COVID‐19 in comparison with the myocardium of non‐infected donors. Conclusions NHE1 and GLUT1 may be critically involved in the disease progression of SARS‐CoV‐2 infection. We show here that SARS‐CoV‐2 infection critically disturbs ion channel expression in the heart. A decreased ratio of GLUT1/NHE1 could potentially serve as a biomarker for disease severity in patients with COVID‐19.

We present here data regarding ADM in patients with COVID-19. Starting from March 2020, we included 45 adult patients presenting with signs of respiratory infection (cough and/or fever) to the Emergency Department in this ongoing study. ADM expression was significantly elevated in patients with COVID-19 than other respiratory infections despite similar clinical features at admission. In patients with COVID-19, ADM expression was significantly higher in patients with severe COVID-19 than in patients with less severe COVID-19. Further, ADM expression was not significantly different between patients with less severe COVID-19 and patients with other respiratory infections than COVID-19. According to ROC-analysis, ADM was able to differentiate severe from non-severe COVID-19 cases with an AUC of 0.82. Our findings suggest a potential role for ADM in severe COVID-19. While ADM might be a therapeutic target in sepsis and septic shock, further research is needed regarding ADM in COVID-19. Further, the diagnostic potential of ADM as a marker for progression to severe COVID-19 at first medical contact should be evaluated.

Aim Acute kidney injury (AKI) is often underdiagnosed due to several limitations of the renal marker creatinine. Tubular urinary biomarkers may substantially contribute to diagnose AKI early. For early detection of AKI, we evaluated for the first time N-acetyl-beta-d-glucosaminidase (NAG), Kidney-injury-molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) in acute chest pain. Methods We included 402 chest pain patients aged 18 to 95 years seen in the emergency department. From 311 subjects, blood and urine samples were collected. Results Thirty-three patients developed an AKI and showed a significant increase in all three tubular markers compared to patients without AKI (each P < .001). According to receiver operating characteristic (ROC) analysis, combining NAG and creatinine showed a significantly increased area under the curve (AUC) compared to creatinine alone (AUC: 0.75 vs 0.87; P < .001). KIM-1, NGAL and cystatin C showed no significant differences in AUC compared to creatinine. In 120 individuals with blood and urine sampling before contrast media exposure, ROC analysis showed a significantly improved diagnostic performance for the combination of both (AUC: 0.83 vs creatinine AUC: 0.66; P = .004). AKI occurrence showed no dependency from CM volume. NAG presented as an independent AKI predictor beside creatinine, age, the diagnosis of myocardial infarction and mean arterial pressure. Regarding the prognostic value for renal replacement therapy, the combination of NAG and creatinine showed a significantly lager AUC than creatinine (AUC: 0.95 vs AUC: 0.85; P < .001). Conclusion NAG presented as a promising marker of impending AKI and the necessity of renal replacement therapy.

Aim: We evaluated the role of the tubular biomarkers N-acetyl-ß-D-glucosaminidase (NAG), kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) in patients with chest pain. Methods: Serum and urine samples were collected of 223 patients and 47 healthy controls. None of them was exposed to contrast media. Results: NAG showed among others significant correlation with N-terminal pro brain natriuretic peptide (NTproBNP), troponin I and creatinine. KIM-1 and NGAL showed weaker correlations. NAG was significantly elevated in all subgroups of acute coronary syndrome (ACS) compared with chest wall syndrome and controls. NAG was an independent predictor for the diagnosis of myocardial infarction. Conclusion: NAG may demonstrate the presence of acute tubular injury due to cardiac impairment already in the emergency department. NAG should be evaluated as marker of acute cardiorenal syndrome in patients with chest pain.

Aims Left and right atria show compelling differences regarding organogenesis and specific clinical diseases. In congestive heart failure (CHF), remodelling of the atria occurs leading to increased arrhythmogenic susceptibility and deterioration of clinical symptoms. We aimed to assess the basal left and right atrial molecular set-up and different chamber-specific atrial changes in heart failure. Methods and results We combined an animal model of rapid ventricular pacing induced heart failure in the rabbit and a gel-based proteomic screening of left and right atrial specimen. A gene ontology over-representation analysis was performed for biological function. Ultrastructural adaptations were evaluated using transmission electron microscopy. Comparing left and right atria of healthy control animals (CTRL), 39 proteins displayed significant expression differences involving various biological functions. Upon further statistical analyses, four pathways of energy metabolism were confirmed to be significantly over-represented beneath the other biological processes. Rapid ventricular pacing induced severe left ventricular systolic dysfunction, symptomatic heart failure and a macroscopic atrial remodelling. In CHF versus CTRL, metabolic and antioxidative enzymes were differentially expressed and showed chamber-specific bidirectional alterations. Transmission electron microscopy visualized a remarkable and again chamber-specific ultrastructural disturbance of mitochondrial morphology. Conclusions Our data indicate a diverging basal left and right atrial molecular set-up in the adult healthy heart. In addition, metabolic and antioxidative enzymes are profoundly and chamber-specifically altered during atrial remodelling in progressive heart failure.